Kelley's Textbook of Rheumatology, 8th Edition

VOLUME

I

KELLEY’S

Textbook of Rheumatology EIGHTH EDITION

Gary S. Firestein, MD

Ralph C. Budd, MD

Edward D. Harris, Jr., MD

Iain B. McInnes, PhD, FRCP

Shaun Ruddy, MD

John S. Sergent, MD

Professor of Medicine Chief, Division of Rheumatology, Allergy, and Immunology Dean, Translational Medicine University of California, San Diego, School of Medicine La Jolla, California Professor of Medicine Director, Immunobiology Program University of Vermont College of Medicine Burlington, Vermont George DeForest Barnett Professor of Medicine, Emeritus Stanford University School of Medicine Academic Secretary to Stanford University, Emeritus Stanford University Stanford, California Professor of Experimental Medicine Honorary Consultant Rheumatologist Centre for Rheumatic Diseases, Faculty of Medicine University of Glasgow Glasgow, United Kingdom Professor Emeritus, Department of Internal Medicine, Division of Rheumatology, Allergy, and Immunology Virginia Commonwealth University School of Medicine at the Medical College of Virginia Richmond, Virginia Professor of Medicine Vice Chair for Education and Residency Program Director Vanderbilt University School of Medicine Nashville, Tennessee

1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

ISBN: 978-1-4160-3285-4 (Expert Consult) KELLEY’S TEXTBOOK OF RHEUMATOLOGY 978-1-4160-4842-8 (Expert Consult Premium Ed.) Copyright © 2009, 2005, 2001, 1997, 1993, 1989, 1985, 1981 by Saunders, an imprint of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Rights Department: phone: (+1) 215 239 3804 (US) or (+44) 1865 843830 (UK); fax: (+44) 1865 853333; e-mail: [email protected]. You may also complete your request on-line via the Elsevier website at http://www.elsevier.com/permissions.

Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher

Library of Congress Cataloging-in-Publication Data Kelley’s textbook of rheumatology / [edited by] Gary S. Firestein ... [et al.]. -- 8th ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4160-3285-4 1. Rheumatology. 2. Rheumatism. 3. Arthritis. I. Firestein, Gary S. II. Kelley, William N., 1939III. Title: Textbook of rheumatology. [DNLM: 1. Rheumatic Diseases. 2. Arthritis. WE 544 K29 2009] RC927.T49 2009 616.7'23--dc22 2007048387

Acquisitions Editor: Kimberly Murphy Developmental Manager: Cathy Carroll Developmental Editor: Angela Norton Publishing Services Manager: Linda Van Pelt Project Manager: Francisco Morales Design Direction: Ellen Zanolle Cover Design: Ellen Zanolle

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Sincerest thanks to my wonderful wife, Linda, and our children, David and Cathy, for their patience and support. Also, the editorial help of our two Cavalier King Charles puppies, Winston and Humphrey, was invaluable. Gary S. Firestein

Sincere thanks for the kind mentoring from Edward D. Harris Jr., H. Robson MacDonald, and C. Garrison Fathman, as well as for the support of my wife, Lenore, and my children, Graham and Laura. Ralph C. Budd

Many thanks to my mentor, Steve Krane, and for the support of the Harris boys, Ned, Tom, and Chandler, and Eileen . . . and for the happy smiles of the grandkids— Andrew, Eliza, Maeve, and Liam. Ted Harris

To my wife, Karin, for her patience, understanding, and love and to our wonderful girls, Megan and Rebecca, who continue to enlighten me. Iain B. McInnes

To my wife, Millie; our children, Christi and Candace; and our grandchildren, Kevin, Matthew, and Katharine. Shaun Ruddy

To Carole and our children, Ellen and Katie, and to our grandchildren, Kathryn, Henry, Emmaline, and Romy. John S. Sergent

CONTRIBUTORS

Steven B. Abramson, MD Professor of Medicine and Pathology New York University School of Medicine New York, New York   Neutrophils and Eosinophils; Pathogenesis of Osteoarthritis Leyla Alparslan, MD Instructor in Orthopaedic Radiology Uppsala University Faculty of Medicine Staff Radiologist, Akademiska Hospital Uppsala, Sweden   Imaging Modalities in Rheumatic Disease Thomas P. Andriacchi, PhD Professor Department of Mechanical Engineering Stanford University School of Engineering Department of Orthopaedics Stanford University School of Medicine Stanford VA Palo Alto Research & Development, Bone and Joint Research Center Palo Alto, California  Joint Biomechanics: The Role of Mechanics in Joint Pathology John P. Atkinson, MD Samuel B. Grant Professor of Medicine and Professor of Molecular Microbiology Washington University in St. Louis School of Medicine Physician, Barnes-Jewish Hospital St. Louis, Missouri   Complement System Stefan Bachmann, MD FMH Specialist in Internal Medicine and Rheumatology FMH Specialist in Physical Medicine and Rehabilitation Leitender Artz/Chefarzt-Stellvertreter Klinik für Rheumatologie und Rehabilitation des Bewegungsapparates Valens, Switzerland   Introduction to Physical Medicine and Rehabilitation Leslie R. Ballou, PhD Professor of Medicine and Molecular Sciences, Department of Rheumatology University of Tennessee College of Medicine Research Chemist, VA Medical Center and UT Health Science Center Memphis, Tennessee   Nonsteroidal Anti-inflammatory Drugs

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Stanley P. Ballou, MD Associate Professor of Medicine Case Western Reserve University School of Medicine Director of Rheumatology MetroHealth Medical Center Cleveland, Ohio   Acute-Phase Reactants and the Concept of Inflammation Walter G. Barr, MD Professor of Medicine Northwestern University Feinberg School of Medicine Chicago, Illinois   Mycobacterial Infections of Bones and Joints; Fungal Infections of the Bones and Joints Dorcas Eleanor Beaton, BScOT, MSc, PhD Assistant Professor, Department of Health Policy, Management and Evaluation University of Toronto Faculty of Medicine Scientist and Director, Mobility Program Clinical Research Unit St. Michael’s Hospital Toronto, Ontario, Canada   Assessment of Health Outcomes Robert M. Bennett, MD, FRCP, MACR Professor of Medicine and Nursing Research Oregon Health & Science University School of Medicine and School of Nursing Portland, Oregon   Overlap Syndromes Francis Berenbaum, MD, PhD Professor of Rheumatology Pierre and Marie Curie University (UPMC—Paris Universitas) Faculty of Medicine Hospital Saint-Antoine Paris, France   Clinical Features of Osteoarthritis Johannes W.J. Bijlsma, MD, PhD Professor and Chair, Department of Rheumatology   & Clinical Immunology University Medical Center Utrecht Utrecht, The Netherlands   Glucocorticoid Therapy Linda K. Bockenstedt, MD Harold W. Jockers Professor of Medicine Department of Internal Medicine, Section of Rheumatology Yale University School of Medicine New Haven, Connecticut   Lyme Disease

CONTRIBUTORS

Maarten Boers, MSc, MD, PhD Professor of Clinical Epidemiology Department of Clinical Epidemiology and Biostatistics VU University Amsterdam Faculty of Medicine Amsterdam, The Netherlands   Assessment of Health Outcomes Robert Alan Bonakdar, MD Assistant Clinical Professor, Department of Family and Preventive Medicine UC San Diego School of Medicine Director of Pain Management Scripps Center for Integrative Medicine La Jolla, California   Integrative Medicine in Rheumatology:   An Evidence-Based Approach Dimitrios T. Boumpas, MD, FACP Professor and Chairman, Department of Internal Medicine, Division of Rheumatology, Clinical Immunology, and Allergy University of Crete Medical School Chief of Medicine Heraklion University General Hospital Crete, Greece   Clinical Features and Treatment of Systemic Lupus Erythematosus Barry Bresnihan, MD Professor of Rheumatology University College Dublin School of Medicine   and Medical Science National University of Ireland Consultant Rheumatologist St. Vincent’s University Hospital Prinicipal Investigator Conway Institute of Biomedical Research Dublin, Ireland   Synovium Doreen B. Brettler, MD Professor of Medicine University of Massachusetts Medical School Director, New England Hemophilia Center University of Massachusetts Memorial Healthcare Worcester, Massachusetts   Hemophilic Arthropathy Paul L. Briant, PhD, MS VA Palo Alto Research & Development Bone and Joint Research Center Palo Alto, CA   Joint Biomechanics: The Role of Mechanics in Joint Pathology Ralph C. Budd, MD Professor of Medicine Director, Immunobiology Program University of Vermont College of Medicine Burlington, Vermont   T Lymphocytes

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Leonard H. Calabrese, DO Professor of Medicine and R.J. Fasenmyer Chair of Clinical Immunology Cleveland Clinic Lerner College of Medicine Vice Chairman, Department of Rheumatic and Immunologic Diseases Cleveland Clinic Foundation Cleveland, Ohio   Antineutrophil Cytoplasmic Antibody–Associated Vasculitis Amy C. Cannella, MD Assistant Professor, Department of Medicine, Section of Rheumatology and Immunology University of Nebraska College of Medicine Omaha, Nebraska   Methotrexate, Leflunomide, Sulfasalazine, Hydroxychloroquine, and Combination Therapies Eugene J. Carragee, MD Professor of Orthopaedic Surgery Stanford University School of Medicine Director, Spine Surgery Section Stanford University Hospital and Clinics Stanford, California   Low Back Pain Steven Carsons, MD Professor of Medicine State University of New York at Stony Brook School   of Medicine Stony Brook Chief, Division of Rheumatology, Allergy   and Immunology Winthrop University Hospital Mineola, New York   Sjögren’s Syndrome James T. Cassidy, MD Professor, Department of Child Health University of Missouri–Columbia School of Medicine Chief of Pediatric Rheumatology University of Missouri Health Sciences Center Columbia, Missouri   Systemic Lupus Erythematosus, Juvenile Dermatomyositis, Scleroderma, and Vasculitis Eliza F. Chakravarty, MD, MS Assistant Professor, Department of Medicine, Division   of Immunology and Rheumatology Stanford University School of Medicine Stanford, California   Musculoskeletal Syndromes in Malignancy Christopher Chang, MD, PhD Associate Clinical Professor, Department of Internal Medicine, Division of Rheumatology/Allergy/Clinical Immunology UC Davis School of Medicine Sacramento Staff, UC Davis Genome and Biomedical Services   Facility Davis, California   Osteonecrosis

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CONTRIBUTORS

Joseph S. Cheng, MD, MS Assistant Professor of Neurological Surgery Vanderbilt University School of Medicine Director, Neurosurgery Spine Program Vanderbilt University Medical Center Nashville, Tennessee   Neck Pain

Jeroen DeGroot, MD Operations Manager, Inflammatory and Degenerative Diseases BioSciences Division TNO Quality of Life Leiden, The Netherlands   Biologic Markers

Christopher P. Chiodo, MD Instructor in Orthopaedic Surgery, Department   of Orthopedic Surgery Harvard Medical School Chief, Foot and Ankle Division Brigham and Women’s Hospital Boston, Massachusetts   Foot and Ankle Pain

Christopher P. Denton, PhD, FRCP Professor of Experimental Rheumatology Royal Free and University College Medical School Honorary Consultant Rheumatologist, Centre for Rheumatology London, United Kingdom   Systemic Sclerosis and the Scleroderma-Spectrum Disorders

Paul P. Cook, MD Associate Professor of Medicine Division of Infectious Diseases Department of Infectious Diseases Department of Internal Medicine Brody School of Medicine at East Carolina University Greenville, North Carolina   Bacterial Arthritis

Clinton Devin, MD Orthopedic Surgeon, Department of Orthopaedics   and Rehabilitation Vanderbilt Sports Medicine Center Nashville, Tennessee   Neck Pain

Joseph E. Craft, MD Professor of Medicine and Immunobiology Chief, Section of Rheumatology, and Director, Investigative Medicine Yale University School of Medicine Chief of Rheumatology and Attending Physician Yale–New Haven Hospital New Haven, Connecticut   Antinuclear Antibodies Gaye Cunnane, MD, MB, PhD, FRCPI Senior Lecturer in Medicine Trinity College Dublin Faculty of Health Sciences School of Medicine Consultant in Rheumatology and Internal Medicine St. James’ Hospital Dublin, Ireland   Hemochromatosis Jody A. Dantzig, BS, PhD Medical Student University of Pennsylvania School of Medicine Philadelphia, Pennsylvania   Muscle: Anatomy, Physiology, and Biochemistry John M. Davis III, MD Assistant Professor of Medicine Division of Rheumatology Mayo Clinic Rochester, Minnesota   History and Physical Examination of the Musculoskeletal System

Betty Diamond, MD Professor, Department of Microbiology & Immunology   and Department of Medicine (Rheumatology) Albert Einstein College of Medicine Bronx Head and Investigator, Center for Autoimmune   and Musculoskeletal Diseases The Feinstein Institute for Medical Research Manhasset, New York   B Cells Federico Díaz-González, MD Associate Professor of Rheumatology Universidad de La Laguna Faculty of Medicine Staff Rheumatologist Hospital Universitario de Canarias La Laguna, Spain   Platelets and Rheumatic Diseases Paul E. Di Cesare, MD, FACS Professor and Michael W. Chapman Chair, Department   of Orthopaedic Surgery UC Davis School of Medicine Sacramento, California   Pathogenesis of Osteoarthritis Joost P.H. Drenth, MD, PhD Professor of Molecular Gastroenterology and Hepatology Department of Gastroenterology and Hepatology Radboud University Nijmegen Medical Centre Faculty of Medical Sciences Nijmegen, The Netherlands   Familial Auto-inflammatory Syndromes George F. Duna, MD, FACP Associate Professor of Medicine Baylor College of Medicine Houston, Texas   Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

CONTRIBUTORS

Michael L. Dustin, PhD Irene Diamond Professor of Immunology and Associate Professor of Pathology Department of Molecular Pathogenesis The Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine New York University School of Medicine New York, New York   Adaptive Immunity Including Organization of Lymphoid Tissues Hani S. El-Gabalawy, MD, FRCPC Professor of Medicine and Immunology and Head, Division of Rheumatology University of Manitoba Faculty of Medicine Rheumatologist Winnipeg Health Sciences Centre Winnipeg, Manitoba, Canada   Synovial Fluid Analysis, Synovial Biopsy, and Synovial Pathology Keith B. Elkon, MD Professor of Medicine and Immunology and Head, Division of Rheumatology Department of Medicine University of Washington School of Medicine Seattle, Washington   Cell Survival and Death in Rheumatic Diseases Doruk Erkan, MD Assistant Professor of Medicine Weill Medical College of Cornell University Associate Physician-Scientist and Assistant Attending Physician Barbara Volcker Center for Women and Rheumatic Diseases Hospital for Special Surgery New York, New York   Antiphospholipid Syndrome Gary S. Firestein, MD Professor of Medicine Chief, Division of Rheumatology, Allergy,   and Immunology Dean, Translational Medicine University of California, San Diego, School of Medicine La Jolla, California   Etiology and Pathogenesis of Rheumatoid Arthritis; Clinical Features of Rheumatoid Arthritis Oliver FitzGerald, MD, FRCPI, FRCP(UK) Newman Clinical Research Professor University College Dublin School of Medicine   and Medical Science National University of Ireland Consultant Rheumatologist St. Vincent’s University Hospital Dublin, Ireland   Psoriatic Arthritis

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John P. Flaherty, MD Professor of Medicine Associate Chief and Director of Clinical Services, Division of Infectious Diseases Northwestern University Feinberg School of Medicine Chicago, Illinois   Mycobacterial Infections of Bones and Joints; Fungal Infections of the Bones and Joints Adrienne M. Flanagan, MD, PhD Professor Institute of Orthopaedics and Musculoskeletal Science University College London London Royal National Orthopaedic Hospital Stanmore Department of Histopathology, University College Hospital London, United Kingdom   Synovium Karen A. Fortner, PhD Research Assistant Professor Immunobiology Program Department of Medicine University of Vermont College of Medicine Burlington, Vermont   T Lymphocytes Howard A. Fuchs, MD Associate Professor of Medicine Division of Rheumatology Vanderbilt University Tennessee Valley Healthcare System Department of Veterans Affairs Medical Center Nashville, TN   Polyarticular Arthritis Steffen Gay, MD Professor Department of Rheumatology University Hospital Zurich, Switzerland   Fibroblasts and Fibroblast-like Synoviocytes Mark C. Genovese, MD Professor of Medicine Stanford University School of Medicine Co-Chief, Division of Immunology and Rheumatology Stanford University Medical Center Stanford, California   Treatment of Rheumatoid Arthritis M. Eric Gershwin, MD Distinguished Professor of Medicine UC Davis School of Medicine Sacramento, California   Osteonecrosis

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CONTRIBUTORS

Allan Gibofsky, MD, JD, FACP, FCLM Professor of Medicine and Public Health Weill Medical College of Cornell University Adjunct Professor of Law Fordham University School of Law Attending Rheumatologist Hospital for Special Surgery New York, New York   Poststreptoccocal Arthritis and Rheumatic Fever Mark H. Ginsberg, MD Professor, Department of Medicine, Rheumatology Section UC San Diego School of Medicine La Jolla, California   Platelets and Rheumatic Diseases Joseph Golbus, MD Associate Professor of Medicine Northwestern University Feinberg School of Medicine Senior Attending Physician, Division of Rheumatology President Evanston Northwestern Healthcare Medical Group Chicago, Illinois   Monarticular Arthritis Yale E. Goldman, MD, PhD Professor, Department of Physiology University of Pennyslvania School of Medicine Director, Pennsylvania Muscle Institute Philadelphia, Pennsylvania   Muscle: Anatomy, Physiology, and Biochemistry Mary B. Goldring, PhD Weill Medical College of Cornell University Senior Scientist Hospital for Special Surgery New York, New York   Biology of the Normal Joint; Cartilage and Chondrocytes Steven R. Goldring, MD Weill Medical College of Cornell University Chief Scientific Officer Hospital for Special Surgery New York, New York   Biology of the Normal Joint Stuart B. Goodman, MD, PhD, FRCSC, FACS, FBSE Robert L. and Mary Ellenburg Professor of Surgery, Department of Orthopaedic Surgery Stanford University School of Medicine Attending Orthopaedic Surgeon, Stanford University Medical Center Consultant Orthopaedic Surgeon, Lucile Salter Packard Children’s Hospital at Stanford Stanford Consultant Orthopaedic Surgeon, Palo Alto Veterans Administration Hospital Palo Alto, California   Hip and Knee Pain

Carl S. Goodyear, PhD Lecturer and Arthritis Research Campaign University of Glasgow Faculty of Medicine NCCD Fellow, Division of Clinical Neurosciences Glasgow Biomedical Research Centre Glasgow, United Kingdom   Rheumatoid Factors and Other Autoantibodies in Rheumatoid Arthritis Siamon Gordon, MBChB, PhD, FRS, FMedSci Professor Emeritus Sir William Dunn School of Pathology University of Oxford Oxford, United Kingdom   Mononuclear Phagocytes in Rheumatic Diseases Adam Greenspan, MD, FACR Professor Emeritus of Radiology Department of Radiology, Section of Musculoskeletal Imaging UC Davis School of Medicine Sacramento, California Osteonecrosis Peter K. Gregersen, MD Professor of Medicine and Pathology New York University School of Medicine New York, New York   Genetics of Rheumatic Diseases Christine Grimaldi, PhD Assistant Professor, Department of Microbiology & Immunology Albert Einstein College of Medicine Bronx Assistant Investigator, Center for Autoimmune and Musculoskeletal Disease The Feinstein Institute for Medical Research Manhasset, New York   B Cells Bevra Hannahs Hahn, MD, FACR, MACR Professor and Vice Chair, Department of Medicine David Geffen School of Medicine at UCLA Chief, Rheumatology and Arthritis UCLA Medical Center Los Angeles, California   Pathogenesis of Systemic Lupus Erythematosus J. Timothy Harrington, MD Associate Professor, Department of Medicine University of Wisconsin School of Medicine and Public Health Madison, Wisconsin   Mycobacterial Infections of Bones and Joints; Fungal Infections of the Bones and Joints Edward D. Harris, Jr., MD, MACR George DeForest Barnett Professor of Medicine, Emeritus Stanford University School of Medicine Academic Secretary to Stanford University, Emeritus Stanford University Stanford, California   Clinical Features of Rheumatoid Arthritis

CONTRIBUTORS

David B. Hellmann, MD Aliki Perroti Professor of Medicine Johns Hopkins University School of Medicine Vice Dean and Chairman, Department of Medicine Johns Hopkins Bayview Medical Center Baltimore, Maryland   Giant Cell Arteritis, Polymyalgia Rheumatica,   and Takayasu’s Arteritis George Ho, Jr., MD Professor of Medicine Brody School of Medicine at East Carolina University Greenville, North Carolina   Bacterial Arthritis James I. Huddleston, MD Assistant Professor, Department of Orthopaedic Surgery Stanford University School of Medicine Stanford, California   Hip and Knee Pain Gene G. Hunder, MD Professor Emeritus Mayo Clinic College of Medical Sciences Emeritus Member Department of Internal Medicine, Division of Rheumatology Mayo Clinic Rochester, Minnesota   History and Physical Examination of the Musculoskeletal System

Arthur Kavanaugh, MD Professor of Medicine Center for Innovative Therapy, Division of Rheumatology, Allergy and Immunology UC San Diego School of Medicine La Jolla, California   Anticytokine Therapies Alisa E. Koch, MD Frederick G.L. Huetwell and William D. Robinson, MD Professor of Rheumatology University of Michigan Medical School Ann Arbor, Michigan   Cell Recruitment and Angiogenesis Deborah Krakow, MD Associate Professor of Obstetrics and Gynecology David Geffen School of Medicine at UCLA Attending Physician, Department of Obstetrics   and Gynecology Cedars-Sinai Medical Center Los Angeles, California   Heritable Diseases of Connective Tissue Joel M. Kremer, MD Pfaff Family Professor of Medicine Albany Medical College Director of Research The Center for Rheumatology Albany, New York   Nutrition and Rheumatic Diseases

Johannes W.G. Jacobs, MD, PhD Associate Professor, Department of Rheumatology   and Clinical Immunology Rheumatologist and Senior Researcher University Medical Center Utrecht Utrecht, The Netherlands   Glucocorticoid Therapy

Hollis E. Krug, BS, MD Associate Clinical Professor of Medicine University of Minnesota Medical School Staff Rheumatologist VA Medical Center Minneapolis, Minnesota   Management of Chronic Pain

Joanne M. Jordan, MD, MPH Associate Professor of Medicine and Orthopaedics Chief, Division of Rheumatology, Allergy, and Immunology University of North Carolina at Chapel Hill School   of Medicine Director, Thurston Arthritis Research Center Chapel Hill, North Carolina   Principles of Epidemiology in Rheumatic Disease

Irving Kushner, MD Professor of Medicine Case Western Reserve University School of Medicine Staff Rheumatologist MetroHealth Medical Center Cleveland, Ohio   Acute-Phase Reactants and the Concept of Inflammation

Joseph L. Jorizzo, MD Professor and Former (Founding) Chair, Department   of Dermatology Wake Forest University School of Medicine Winston-Salem, North Carolina   Behçet’s Disease Kenneth C. Kalunian, MD Professor of Medicine and Director of Rheumatology, Allergy and Immunology UC San Diego School of Medicine La Jolla, California   Rheumatic Manifestations of Hemoglobinopathies

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Robert B.M. Landewé, MD Professor of Rheumatology, Department of Internal Medicine, Division of Rheumatology Maastricht University Faculty of Medicine Staff Rheumatologist Atrium Medical Center Heerlen Maastricht, The Netherlands   Clinical Trial Design and Analysis Nancy E. Lane, MD Professor of Medicine and Rheumatology UC Davis School of Medicine Director, Center for Healthy Aging Sacramento, California   Metabolic Bone Disease

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CONTRIBUTORS

Daniel J. Laskin, DDS, MS Professor and Chairman Emeritus, Department of Oral   and Maxillofacial Surgery School of Dentistry and School of Medicine Virginia Commonwealth University Richmond, Virginia   Temporomandibular Joint Pain David M. Lee, MD Assistant Professor of Medicine Harvard Medical School Associate Physician Brigham and Women’s Hospital Boston, Massachusetts   Mast Cells Lela A. Lee, MD Professor of Dermatology and Medicine University of Colorado School of   Medicine Director of Dermatology Denver Health Medical Center Denver, Colorado   The Skin and Rheumatic Diseases Marjatta Leirisalo-Repo, MD, PhD Professor of Rheumatology, Department of Medicine, Division of Rheumatology Helsinki University Faculty of Medicine Staff Rheumatologist, Helsinki University Central Hospital Helsinki, Finland   Undifferentiated Spondyloarthritis and Reactive Arthritis David C. Leopold, MD, DABFM Faculty Physician and Director, Integrative Medical Education Scripps Center for Integrative Medicine La Jolla, California   Integrative Medicine in Rheumatology:   An Evidence-Based Approach Peter E. Lipsky, MD Chief, Autoimmunity Branch National Institute of Arthritis and Musculoskeletal   and Skin Diseases National Institutes of Health Bethesda, Maryland   Autoimmunity

B. Asher Louden, MD Resident in Dermatology Wake Forest University Baptist Medical Center Winston-Salem, North Carolina   Behçet’s Disease Carlos J. Lozada, MD, FACP, FACR Associate Professor of Medicine University of Miami Miller School of Medicine Director, Rheumatology Fellowship Program   and Rheumatology Clinical Services Jackson Memorial Hospital Miami, Florida   Management of Osteoarthritis Ingrid E. Lundberg, MD, PhD Professor of Medicine and Head, Rheumatology Unit, Department of Medicine Karolinska Institute/Karolinska University Hospital Stockholm, Sweden   Inflammatory Diseases of Muscle and Other Myopathies Reuven Mader, MD Senior Clinical Lecturer B. Rappaport Faculty of Medicine, Technion Israel Institute of Technology Head, Rheumatic Diseases Unit Ha’Emek Medical Center Haifa, Israel   Proliferative Bone Diseases Rashmi M. Maganti, MD Fellow, Division of Rheumatology and Clinical Immunogenetics The University of Texas Health Science Center at Houston Houston, Texas   Rheumatic Manifestations of Human Immunodeficiency Virus Infection Maren Lawson Mahowald, MD Professor of Medicine University of Minnesota Medical School Rheumatology Section Chief Minneapolis VA Medical Center Minneapolis, Minnesota   Management of Chronic Pain

Michael D. Lockshin, MD, MACR Professor of Medicine and Obstetrics-Gynecology Weill Medical College of Cornell University New York, New York   Antiphospholipid Syndrome

Walter P. Maksymowych, MBChB, FRCPC, FACP, FRCP(UK) Professor of Medicine University of Alberta Faculty of Medicine Senior Scientist Alberta Heritage Foundation for Medical Research Edmonton, Alberta, Canada   Ankylosing Spondylitis

Kate R. Lorig, RN, DrPH Professor, Department of Medicine, Division of Immunology and Rheumatology Stanford University School of Medicine Director, Patient Education Research Center Stanford, California   Arthritis Self-Management

Scott David Martin, MD Assistant Professor of Orthopedics Harvard Medical School Attending Staff Physician, Department of Orthopedics Brigham and Women’s Hospital Boston, Massachusetts   Shoulder Pain

CONTRIBUTORS

Helena Marzo-Ortega, MD, MRCP Consultant Rheumatologist and Honorary Senior Lecturer Academic Section of Musculoskeletal Disease Leeds Institute of Molecular Medicine University of Leeds and Chapel Allerton Hospital Leeds, United Kingdom   Undifferentiated Spondyloarthritis and Reactive Arthritis Dennis McGonagle, PhD, FRCPI Professor of Investigative Rheumatology The University of Leeds Leeds, United Kingdom   Undifferentiated Spondyloarthritis and Reactive Arthritis Iain B. McInnes, PhD, FRCP Professor of Experimental Medicine Honorary Consultant Rheumatologist Centre for Rheumatic Diseases, Faculty of Medicine University of Glasgow Glasgow, United Kingdom   Cytokines; Atherosclerosis in Rheumatic Disease; Rheumatoid Factors and Other Autoantibodies in Rheumatoid Arthritis Kevin G. Moder, MD Consultant and Associate Professor Division of Rheumatology and Department of Internal Medicine Mayo Clinic Rochester, Minnesota   History and Physical Examination of the Musculoskeletal System Eamonn S. Molloy, MD, MRCPI Associate Staff Department of Rheumatic and Immunologic Disease Cleveland Clinic Foundation Cleveland, Ohio   Antineutrophil Cytoplasmic Antibody–Associated Vasculitis Kanneboyina Nagaraju, PhD, DVM Associate Professor of Pediatrics George Washington University School of Medicine   and Health Sciences Director, Murine Drug Testing Facility Center for Genetic Medicine Research Children’s Research Institute Children’s National Medical Center Washington, DC   Inflammatory Diseases of Muscle and Other Myopathies Stanley J. Naides, MD Medical Director, Immunology R&D Quest Diagnostics Nichols Institute San Juan Capistrano, California   Viral Arthritis

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Lee S. Newman, MD, MA Professor, Department of Medicine, Division of Allergy and Clinical Immunology and Division of Pulmonary Sciences and Critical Care Medicine Professor of Epidemiology, Department of Preventive Medicine and Biometrics University of Colorado School of Medicine Denver, Colorado   Sarcoidosis Peter A. Nigrovic, MD Instructor in Medicine Harvard Medical School Staff Rheumatologist Department of Rheumatology, Immunology, and Allergy, Brigham & Women’s Hospital Division of Immunology, Children’s Hospital Boston Boston, Massachusetts   Mast Cells Kiran Nistala, MD, MRCP, MSc Clinical Research Fellow in Paediatric Rheumatology Institute of Child Health University College London London, United Kingdome   Juvenile Idiopathic Arthritis James R. O’Dell, MD Larson Professor and Vice-Chairman, Department of Internal Medicine University of Nebraska College of Medicine Chief of Rheumatology and Residency Program Director, Department of Internal Medicine University of Nebraska Medical Center Omaha, Nebraska   Methotrexate, Leflunomide, Sulfasalazine, Hydroxychloroquine, and Combination Therapies Peter R. Oesch, MSc, Dipl PT Head, Department of Ergonomics and Clinical Research Valens Rehabilitation Clinic Valens, Switzerland   Introduction to Physical Medicine and Rehabilitation Yasunori Okada, MD, PhD Professor and Chairman, Department of Pathology Keio University School of Medicine Tokyo, Japan   Proteinases and Matrix Degradation Eugenia C. Pacheco-Pinedo, MD, MSc Postdoctoral Researcher Department of Medicine Molecular Cardiology Research Center Postdoctoral Researcher Department of Physiology Pennsylvania Muscle Institute Philadelphia, Pennsylvania   Muscle: Anatomy, Physiology, and Biochemistry

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CONTRIBUTORS

Richard S. Panush, MD Professor of Medicine Mount Sinai School of Medicine Chair, Department of Medicine Saint Barnabas Medical Center New York, New York   Occupational and Recreational Musculoskeletal   Disorders Thomas Pap, MD Professor of Experimental Medicine Head, Division of Molecular Medicine of Musculoskeletal Tissue University of Münster Institute of Experimental Musculoskeletal Medicine Director University Hospital Münster Münster, Germany   Fibroblasts and Fibroblast-like Synoviocytes Stanford L. Peng, MD, PhD Senior Director, Translational Medicine Leader Clinical Research and Exploratory Development Roche Palo Alto Palo Alto Assistant Clinical Professor, Department of Medicine, Division of Rheumatology–Arthritis University of California, San Francisco, School of Medicine San Francisco, California   Antinuclear Antibodies Harris Perlman, PhD Associate Professor, Department of Molecular Microbiology & Immunology Saint Louis University School of Medicine St. Louis, Missouri   Signal Transduction Jean-Charles Piette, MD Department of Internal Medicine Groupe Hospitalier Pitié-Salpêtrière Paris, France   Relapsing Polychondritis Michael H. Pillinger, MD Chief of Rheumatology New York Hospital for Joint Diseases New York, New York   Neutrophils and Eosinophils Robert S. Pinals, MD Acting Chief, Division of Rheumatology & Connective Tissue Research Professor, Department of Medicine UMDNJ–Robert Wood Johnson Medical School New Brunswick, New Jersey   Felty’s Syndrome

Steven A. Porcelli, MD Weinstock Professor of Microbiology & Immunology   and Professor of Medicine Albert Einstein College of Medicine Bronx, New York   Innate Immunity Mark D. Price, MD, PhD Chief Resident in Orthopedic Surgery Harvard Combined Orthopedic Surgery Program Massachusetts General Hospital Boston, Massachusetts   Foot and Ankle Pain Johannes J. Rasker, MD, PhD Professor Emeritus of Rheumatology Faculty of Behavioral Sciences, Department of Psychology and Communication of Health and Risk University of Twente Enschede, The Netherlands   Fibromyalgia John D. Reveille, MD Professor of Internal Medicine Director, Division of Rheumatology and Clinical Immunogenetics Department of Internal Medicine University of Texas Medical School at Houston Houston, Texas   Rheumatic Manifestations of Human Immunodeficiency Virus Infection W. Neal Roberts, Jr., MD Rheumatology Fellowship Program Director Chas. W. Thomas Professor of Medicine Virginia Commonwealth University School of Medicine, Medical College of Virginia Campus Richmond, Virginia   Psychosocial Management of Rheumatic Diseases James T. Rosenbaum, MD Edward E. Rosenbaum Professor of Inflammation Research and Professor of Ophthalmology, Medicine, and Cell Biology Chair, Division of Arthritis and Rheumatic Diseases Vice-Chair, Department of Ophthalmology Oregon Health & Science University School of Medicine Portland, Oregon   The Eye and Rheumatic Diseases Andrew E. Rosenberg, MD Associate Professor Harvard Medical School Director of Surgical Pathology Massachusetts General Hospital Boston, Massachusetts   Tumors and Tumor-like Lesions of Joints and Related   Structures

CONTRIBUTORS

Clinton T. Rubin, PhD Distinguished Professor and Chair Department of Biomedical Engineering State University of New York Stony Brook University School of Medicine Stony Brook, New York   Biology, Physiology, and Morphology of Bone

David C. Seldin, MD, PhD Professor of Medicine and Microbiology Boston University School of Medicine Director, Amyloid Treatment and Research Program Boston Medical Center Boston, Massachusetts   Amyloidosis

Janet E. Rubin, MD Professor of Medicine and Pharmacology University of North Carolina at Chapel Hill School   of Medicine Chapel Hill, North Carolina   Biology, Physiology, and Morphology of Bone

Jérémie Sellam, MD, PhD Assistant Professor of Rheumatology Paris Universitas – Pierre & Marie Curie Paris VI Assistant Professor of Rheumatology Saint-Antoine Hospital Paris, France   Clinical Features of Osteoarthritis

Holly M. Sackett, MSPH Senior Professional Research Assistant University of Colorado Denver Colorado School of Public Health Denver, Colorado   Sarcoidosis Jane E. Salmon, MD Professor of Medicine Professor of Obstetrics and Gynecology Weill Medical College of Cornell University Attending Physician Hospital for Special Surgery New York Presbyterian Hospital New York, New York   Antiphospholipid Syndrome Jonathan Samuels, MD Instructor in Medicine (Rheumatology) NYU School of Medicine Director, Clinical Immunulogy Laboratory NYU Langone Medical Center   Pathogenesis of Osteoarthritis Naveed Sattar, MBChB, PhD, MRCPath Professor of Metabolic Medicine British Heart Foundation Glasgow Cardiovascular Research Centre University of Glasgow Honorary Consultant Endocrinologist Glasgow Royal Infirmary Glasgow, United Kingdom   Atherosclerosis in Rheumatic Disease John C. Scatizzi, PhD Post-Doctoral Fellow, Division of Rheumatology, Allergy, & Immunology UC San Diego School of Medicine La Jolla, California   Signal Transduction Jose U. Scher, MD Teaching Assistant Department of Medicine, Division of Rheumatology New York University School of Medicine New York, New York   Neutrophils and Eosinophils

xv

John S. Sergent, MD, MACR Professor of Medicine Vice Chair for Education and Residency Program Director Vanderbilt University School of Medicine Nashville, Tennessee   Polyarticular Arthritis; Polyarteritis and Related Disorders; Isolated Angiitis of the Central Nervous System; Arthritis Accompanying Endocrine   and Metabolic Disorders Richard M. Siegel, MD, PhD Investigator, Autoimmunity Branch National Institute of Arthritis and Musculoskeletal   and Skin Diseases National Institutes of Health Bethesda, Maryland   Autoimmunity Karl Sillay, MD Assistant Professor and Director, Functional Surgery, Department of Neurological Surgery University of Wisconsin School of Medicine and Public Health Neurosurgeon, University of Wisconsin Hospital and Clinics, William S. Middleton Memorial Veterans Hospital, St. Mary’s Hospital Medical Center, and Meriter Hospital Madison, Wisconsin   Neck Pain Anna Simon, MD, PhD Clinical Investigator, Department of General Internal Medicine Radboud University Nijmegen Medical Centre Faculty   of Medical Sciences Nijmegen, The Netherlands   Familial Auto-inflammatory Syndromes Dawd S. Siraj, MD, MPH, TM Assistant Professor of Medicine Brody School of Medicine at East Carolina University Director ECU Physicians International Travel Clinic, Section   of Infectious Diseases Greenville, North Carolina   Bacterial Arthritis

xvi

CONTRIBUTORS

Martha Skinner, MD Professor of Medicine Boston University School of Medicine Boston, Massachusetts   Amyloidosis Kathleen A. Sluka, PT, PhD Professor of Physical Therapy Graduate Programs in Physical Therapy and Rehabilitation Science, in Pain Research, and in Neuroscience University of Iowa Carver College of Medicine Iowa City, Iowa   Neurological Regulation of Inflammation C. Michael Stein, MBChB, MRCP Dan May Professor of Medicine and Professor   of Pharmacology Vanderbilt University School of Medicine Nashville, Tennessee   Immunoregulatory Drugs John H. Stone, MD, MPH Clinical Director of Rheumatology Massachusetts General Hospital Boston, Massachusetts   The Classification and Epidemiology of Systemic Vasculitis; Immune Complex–Mediated Small Vessel Vasculitis Bob Sun, MD Instructor, Department of Medicine, Division of Rheumatology Northwestern University Feinberg School of Medicine Attending Rheumatologist Evanston Northwestern Healthcare Evanston, Illinois   Rheumatic Manifestations of Hemoglobinopathies Carrie R. Swigart, MD Assistant Professor, Department of Orthopaedics and Rehabilitation, Hand and Upper Extremity Section Yale University School of Medicine New Haven, Connecticut   Hand and Wrist Pain Zoltán Szekanecz, MD, PhD, DSc Professor, Department of Medicine, Division of Rheumatology and Immunology Institute for Internal Medicine, Rheumatology Division University of Debrecen Medical and Health Science Center Debrecen, Hungary   Cell Recruitment and Angiogenesis Paul P. Tak, MD, PhD Professor of Medicine and Director, Division of Clinical Immunology & Rheumatology Academic Medical Center/University of Amsterdam Faculty of Medicine Amsterdam, The Netherlands   Biologic Markers

Ioannis O. Tassiulas, MD Senior Investigator, Department of Medicine, Division   of Rheumatology University of Crete Medical School Heraklion, Greece   Clinical Features and Treatment of Systemic Lupus Erythematosus H. Guy Taylor, MBChB, MRCP(UK), FRACP, Dipl MSM(Otago) Consultant Rheumatologist Wanganui Hospital Wanganui, New Zealand   Immunoregulatory Drugs Peter C. Taylor, MA, PhD, FRCP Professor of Experimental Rheumatology Head, Clinical Trials Kennedy Institute of Rheumatology Division Faculty of Medicine Imperial College London London, United Kingdom   Cell-Targeted Biologics and Emerging Targets: Rituximab, Abatacept, and Other Biologics Robert Terkeltaub, MD Professor of Medicine Rheumatology Training Program Director and Associate Division Director for Rheumatology–Allergy/ Immunology UC San Diego School of Medicine La Jolla Section Chief, Rheumatology–Allergy VA Medical Center San Diego San Diego, California   Diseases Associated with Articular Deposition of Calcium Pyrophosphate Dihydrate and Basic Calcium Phosphate Crystals Thomas S. Thornhill, MD Professor of Orthopedics Harvard Medical School Chief of Orthopedics Brigham and Women’s Hospital Boston, Massachusetts   Shoulder Pain Helen Tighe, BSc, PhD Associate Adjunct Professor, Department of Medicine, Division of Rheumatology, Allergy, and Immunology UC San Diego School of Medicine La Jolla, California   Rheumatoid Factors and Other Autoantibodies in Rheumatoid Arthritis Betty P. Tsao, PhD Professor of Medicine, Department of Medicine, Division of Rheumatology David Geffen School of Medicine at UCLA Los Angeles, California   Pathogenesis of Systemic Lupus Erythematosus

CONTRIBUTORS

Peter Tugwell, MSc, MD, FRCPC Professor of Medicine, Department of Medicine Ottawa Health Research Institute University of Ottawa Faculty of Medicine Ottawa, Ontario, Canada   Assessment of Health Outcomes Zuhre Tutuncu, MD Associate Professor, Department of Rheumatology, Allergy, and Immunology UC San Diego School of Medicine La Jolla, California   Anticytokine Therapies Katherine S. Upchurch, MD Associate Professor of Medicine University of Massachusetts Medical School Clinical Chief, Division of Rheumatology UMass Memorial Medical Center Worcester, Massachusetts   Hemophilic Arthropathy Wim B. Van den Berg, PhD Professor of Experimental Rheumatology, Rheumatology Research, and Advanced Therapeutics Radboud University Nijmegen Medical Centre Faculty of Medical Sciences Nijmegen, The Netherlands   Animal Models of Inflammatory Arthritis

John Varga, MD Hughes Distinguished Professor of Medicine Department of Medicine, Division of Rheumatology Northwestern University Feinberg School of Medicine Chicago, Illinois   Systemic Sclerosis and the Scleroderma-Spectrum Disorders Philippe Vinceneux, MD Medecine Interne 2 Hospital Pitié-Salpêtrière Paris, France   Relapsing Polychondritis Benjamin W.E. Wang, MD, FRCPC Associate Professor, Department of Medicine, Division   of Rheumatology University of Tennessee College of Medicine Memphis, Tennessee   Nonsteroidal Anti-inflammatory Drugs Lucy R. Wedderburn, MD Reader in Paediatric Rheumatology Rheumatology Unit, Institute of Child Health–University College London London, United Kingdom   Juvenile Idiopathic Arthritis

Filip Van den Bosch, MD, PhD Rheumatologist University Hospital Gent—Department of Rheumatology Ghent, Belgium   Undifferentiated Spondyloarthritis and Reactive Arthritis

Barbara N. Weissman, MD Professor of Radiology Harvard Medical School Director, Radiology Residency Program Vice Chair, Department of Radiology Brigham & Women’s Hospital Boston, Massachusetts   Imaging Modalities in Rheumatic Disease

Désirée M. F. M. Van der Heijde, MD, PhD Professor of Rheumatology, Department of   Rheumatology Leiden University Faculty of Medicine Leiden, The Netherlands   Clinical Trial Design and Analysis; Ankylosing   Spondylitis

Victoria P. Werth, MD Professor of Dermatology and Medicine University of Pennsylvania School of Medicine Chief of Dermatology Philadelphia VA Medical Center Philadelphia, Pennsylvania   The Skin and Rheumatic Diseases

Sjef M. van der Linden, MD Professor of Rheumatology, Department of Medicine University of Maastricht Faculty of Health, Medicine,   and Life Sciences CAPHRI Research Institute Head, Division of Rheumatology, Department of   Medicine University Hospital of Maastricht Maastricht, The Netherlands   Ankylosing Spondylitis

Karin N. Westlund-High, PhD Professor, Department of Physiology University of Kentucky College of Medicine Lexington, Kentucky   Neurological Regulation of Inflammation

Jos W.M. van der Meer, MD, PhD, FRCP Department of General Internal Medicine Radboud University Nijmegen Medical Centre Nijmegen, The Netherlands   Familial Auto-inflammatory Syndromes

xvii

Michael S. Wildstein, MD President Wildstein Spine Center Charleston, South Carolina   Low Back Pain

xviii

CONTRIBUTORS

Christopher M. Wise, MD W. Robert Irby Professor of Medicine Department of Medicine, Division of Rheumatology, Allergy, and Immunology Virginia Commonwealth University School of Medicine, Medical College of Virginia Campus Richmond, Virginia   Arthrocentesis and Injection of Joints and Soft Tissue Frederick Wolfe, MD Clinical Professor of Medicine University of Kansas School of Medicine Director, National Data Bank for Rheumatic   Diseases Wichita, Kansas   Fibromyalgia Frank A. Wollheim, MD, PhD, FRCP Emeritus Professor, Department of Rheumatology Lund University Faculty of Medicine/Lund University Hospital Lund, Sweden   Enteropathic Arthritis Patricia Woo, MBBS, BSc, PhD, CBE, FRCP, FMedSci Professor of Paediatric Rheumatology Faculty of Medicine University College London London, United Kingdom   Juvenile Idiopathic Arthritis Anthony D. Woolf, BSc, MBBS, FRCP Professor of Rheumatology Peninsula College of Medicine and Dentistry, Universities of Exeter & Plymouth Exeter Consultant Rheumatologist Duke of Cornwall Rheumatology Unit, Royal Cornwall Hospital Truro, United Kingdom   Economic Burden of Rheumatic Diseases

Robert L. Wortmann, MD Professor of Medicine Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire   Gout and Hyperuricemia David Tak Yan Yu, MD Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles, California   Undifferentiated Spondyloarthritis and Reactive Arthritis John B. Zabriskie, MD Professor Emeritus Rockefeller University New York, New York   Poststreptoccocal Arthritis and Rheumatic Fever Robert B. Zurier, MD Professor, Department of Medicine, Division   of Rheumatology University of Massachusetts Medical School Worcester, Massachusetts   Prostaglandins, Leukotrienes, and Related Compounds Anne-Marie Zuurmond, PhD Biosciences Division TNO Quality of Life Leiden, The Netherlands   Biologic Markers

PREFACE

“Plus ça change, plus c’est la même chose” –Jean-Baptiste Alphonse Karr As we, the editors, worked on the 8th edition of Kelley’s Textbook of Rheumatology, we were struck by Monsieur Karr’s quote from 160 years ago. This textbook continues to change and evolve. The incomparable Ted Harris, who was editor-in-chief of the 7th edition, has stepped down, leaving Gary Firestein to fill his shoes. For the first time, a European editor, Iain McInnes, joined the group and helped create a truly international edition. Full color was introduced, new chapter formats were designed to assure a consistent look and feel for each topic, and algorithms for diagnosis and treatment as well as key point boxes were included. In addition, new authors were added to the list of luminaries that already contribute to the book, and there was a major effort to provide greater availability through electronic versions of reference material and on-line access. While change has been in the air regarding many aspects of the book, some things never vary. The book was initially designed decades ago to provide scholarly rigor to the field of rheumatology and to offer definitive reviews of scientific advances as they apply to clinical medicine. This remained the touchstone of our enterprise for the past 4 years, just as it was for the previous seven editions. The painstaking job of identifying the premier authors to present definitive



i­nformation on each topic required months of work, culminating in an editors’ meeting in Costa Rica to finalize the chapters (well, it wasn’t all work!). The arduous process of guiding, reviewing, and editing the outstanding contributions of our authors was time consuming but paled compared with the efforts that the authors put into creating their chapters. The thread connecting the past to the present was also evident in the continued effort of our valued co-editors John Sergent, Ralph Budd, and Shaun Ruddy. Our trusted colleagues at Elsevier, including Cathy Carroll and Kimberly Murphy, were always available and suffered with us in Costa Rica as well. The present looks very encouraging indeed. Kelley’s Textbook of Rheumatology, 8th edition, is a beautiful tome that is designed to carry on the tradition of being the definitive rheumatology resource. Looking to the future, we expect that this work will continue to evolve and change. New editors, new science, new authors, and new technology will be the rule rather than the exception. As you begin to use this edition, please know that it is truly a labor of love. We have enjoyed the experience and hope that it is as valuable to you as the previous editions. The Editors



xix

Part

1

Structure and Function of Bone, Joints, and Connective Tissue

1

Biology of the Normal Joint Steven R. Goldring  •  Mary B. Goldring

KEY POINTS

CLASSIFICATION OF JOINTS

Condensation of mesenchymal cells, which differentiate into chondrocytes, results in formation of the cartilage anlagen, which provides the template for the developing skeleton.

Human joints provide the structures by which bones join with one another and may be classified according to the histologic features of the union and the range of joint motion. There are three classes of joint design: (1) synovial or ­diarthrodial joints (Fig. 1-1), which articulate with free movement, have a synovial membrane lining the joint cavity, and contain synovial fluid; (2) amphiarthroses, in which adjacent bones are separated by articular cartilage or a fibrocartilage disk and are bound by firm ligaments permitting limited motion (e.g., pubic symphysis, intervertebral disks of vertebral bodies, distal tibiofibular articulation, and ­sacroiliac joint articulation with pelvic bones); and (3) synarthroses, which are found only in the skull (suture lines) where thin, fibrous tissue separates adjoining cranial plates that interlock to prevent detectable motion before the end of normal growth, yet permit growth in childhood and adolescence.1 Joints also can be classified according to the connective tissues present. Symphyses have a fibrocartilaginous disk separating bone ends that are joined by firm ligaments (e.g., symphysis pubis and intervertebral joints). In synchondroses, the bone ends are covered with articular cartilage, but there is no synovium or significant joint cavity (e.g., sternomanubrial joint). In syndesmoses, the bones are joined directly by fibrous ligaments without a cartilaginous interface (the distal tibiofibular articulation is the only joint of this type outside the cranial vault). In synostoses, bone bridges are formed between bones, producing ankylosis. The synovial joints are classified further according to their shapes, which include ball-and-socket (hip), hinge (interphalangeal), saddle (first carpometacarpal), and plane (patellofemoral) joints. These configurations reflect the varying functions, as the shapes and sizes of the opposing surfaces determine the direction and extent of motion. The various designs permit flexion, extension, abduction, adduction, or rotation. Certain joints can act in one (humeroulnar), two (wrist), or three (shoulder) axes of motion. This chapter concentrates on the developmental biology and relationship between structure and function of a “prototypic,” “normal” human diarthrodial joint—the joint most likely to develop arthritis. Most research that has been done

During development of the synovial joint, growth differentiation factor-5 regulates interzone formation, and interference with movement of the embryo during development impairs joint cavitation. Members of the bone morphogenetic protein/transforming growth factor-β, fibroblast growth factor, and Wnt families and the parathyroid hormone–related peptide/Indian hedgehog axis are essential for joint development and growth plate formation. The synovial lining of diarthrodial joints is a thin layer of cells lacking a basement membrane and consisting of two principal cell types—macrophages and fibroblasts. The articular cartilage receives its nutritional requirements via diffusion from the synovial fluid, and interaction of the cartilage with components of the synovial fluid contributes to the unique low-friction surface properties of the articular cartilage.

The normal joint is a specialized, integrated structure consisting of multiple connective tissue elements, including muscles, tendons, ligaments, synovium and capsule, cartilage, and bone, organized in a manner that permits stability and movement of the human skeleton. The joint structures are positioned to distribute normal mechanical stresses optimally and are organized for low-friction load bearing. Deviations from normal structure and physiology of joint tissues have been implicated in the pathogenesis of various forms of arthritis. The differentiation of articular tissues during embryonic development dictates their capacity to respond to insults in later life. Physiologic cellular processes involved in normal joint development, such as differentiation, angiogenesis, macrophage recruitment, and fibroblast proliferation, may reappear in the mature joint and contribute to the pathogenesis of joint disease. Knowledge of the development, structure, and function of normal joint tissues is essential for understanding the underlying mechanisms involved in the pathogenesis of human joint diseases.





GOLDRING 

| 

Biology of the Normal Joint

Cartilage Bone

Homogeneous 3-Layered interzone Mesenchyme Perichondrium Synovial interzone Blastema mesenchyme Cartilage

Tide mark

Periosteum

A

B

D Cavities Capsule Synovium Figure 1-1  A normal human interphalangeal joint, in sagittal section, as an example of a synovial, or diarthrodial, joint. The tidemark represents the calcified cartilage that bonds articular cartilage to the subchondral bone plate. (From Sokoloff L, Bland JH: The Musculoskeletal System. Baltimore, Williams & Wilkins, 1975. © 1975, the Williams & Wilkins Co, Baltimore.)

concerns the knee because of its accessibility, but other joints are described when appropriate.

DEVELOPMENTAL BIOLOGY OF THE DIARTHRODIAL JOINT Skeletal development is initiated by the differentiation of mesenchymal cells that arise from three sources: (1) neural crest cells of the neural ectoderm that gives rise to craniofacial bones; (2) the sclerotome of the paraxial mesoderm, or somite compartment, which forms the axial skeleton; and (3) the somatopleure of the lateral plate mesoderm, which yields the skeleton of the limbs.2 The appendicular skeleton develops in the human embryo from limb buds, which are first visible at around 4 weeks of gestation. Structures resembling adult joints are generated at approximately 4 to 7 weeks of gestation.3 Many other crucial phases of musculoskeletal development follow, including vascularization of epiphyseal cartilage (8 to 12 weeks), appearance of villous folds in synovium (10 to 12 weeks), evolution of bursae (3 to 4 months), and appearance of periarticular fat pads (4 to 5 months). The upper limbs develop approximately 24 hours earlier than the analogous portions of the lower limbs. Proximal structures, such as the glenohumeral joint, develop before more distal ones, such as the wrist and hand. As a consequence, insults to embryonic development during limb formation affect a more distal portion of the upper limb than of the lower limb. Long bones form as a result of replacement of the cartilage template by endochondral ossification. The stages of limb development are well described by O’Rahilly and Gardner3,4 and are shown in Figure 1-2. The ­developmental sequence of the events occurring during

C

E Articular capsule

Articular cavity

Synovial tissue and fold

Figure 1-2  The development of a synovial joint. A, Condensation. Joints develop from the blastema, not the surrounding mesenchyme.  B, Chondrification and formation of the interzone. The interzone remains avascular and highly cellular. C, Formation of synovial mesenchyme. Synovial mesenchyme forms from the periphery of the interzone and is invaded by blood vessels. D, Cavitation. Cavities are formed in the central and peripheral interzone and merge to form the joint cavity. E, The  mature joint. (From O’Rahilly R, Gardner E: The embryology of movable joints. In Sokoloff L (ed): The Joints and Synovial Fluid, Vol 1. New York, ­Academic Press, 1978.)

synovial joint formation and some of the regulatory factors and extracellular matrix components involved are summarized in Figures 1-3 and 1-4. INTERZONE FORMATION AND JOINT CAVITATION The morphology of the developing synovial joint and the process of joint cavitation have been described in many classic studies done on the limbs of mammalian and avian embryos.5 In the human embryo, cartilage condensations, or chondrifications, can be detected at stage 17, when the embryo is small, approximately 11.7 mm long.3,4 In the region of the future joint, following formation of the homogeneous chondrogenic interzone at 6 weeks (stages 18 and 19), a three-layered interzone is formed at approximately 7 weeks (stage 21), which consists of two chondrogenic, perichondrium-like layers that cover the opposing surfaces of the cartilage anlagen and are separated by a narrow band of densely packed cellular blastema that remains and forms the interzone. Cavitation begins in the central interzone at about 8 weeks (stage 23). Although these cellular events associated with joint formation have been recognized for many years, only more recently have the genes regulating these processes been elucidated. These genes include growth differentiation factor (GDF)-5, Wnt-14, bone morphogenetic protein (BMP)-2, BMP-4, BMP-6, BMP-7, and the GDF-BMP antagonists.5-8 In addition, joint formation is ­accompanied by the expression of several fibroblast growth factor (FGF) family members, including FGF-2 and FGF-4.9 The balance of signaling between BMP and FGF determines the rate of

PART 1 

Mesenchymal cell condensation

| 

STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

Chondrocyte proliferation

Chondrocyte differentiation

TGF-β Wnt-3A, 7A FGF-2, 4, 8,10 Sonic Hh BMP-2, 4, 7

IGF-1 FGF-2/FGFR2 BMP-2, 4, 7, 14

HoxA, HoxD Sox9 Gli3

PTHrP

FGFR2

FGF-2

FGFR3

Ihh BMP-2

Ossification

FGF-18/FGFR3 BMP-2, 7 Bone PTHrP collar Ihh/Ptc

VEGF FGF-2/FGF-R1 Wnt14/ β-catenin

Stat1 Gli3, 2 Runx2 Fra2/JunD

Runx2 Osterix TCF/Lef1

Epiphyseal ossification center (secondary) Diaphyseal ossification center (primary)

Growth plate

Periarticular (resting) Proliferating

BMP-7

FGF-18 Ptc

Perichondrium

FGF-2 BMPs

Gli

Sox9, 5, 6

Chondrocyte hypertrophy and vascular invasion



Prehypertrophic

FGFR1 Hypertrophic

BMP-6

Collagen II, IX, XI Aggrecan COMP Collagen X Osteocalcin

Figure 1-3  The stages of diarthrodial joint formation, and the temporal pattern of expression of the genes involved in regulation at different stages. Subperiosteal ring

TGF-β FGF-2,4,8,10 Wnt3A,7A Shh BMP-2,4,7 Gli3 HoxA, D r-Fng Lmx1b RA Mesenchymal condensation

Sox9,5,6 IGF-1 FGF-2,18 BMP-2,4,7,14 PTHrP Ihh

Diaphyseal ossification center

Wnt14 GDF-5 BMP-2,4 FGF-2 Runx2 Cux1 Erg5

Epiphyseal ossification center Synovial capsule Hyaluronan CD44

Interzone formation Interzone Joint initiation and chondrocyte formation and ossification differentiation Figure 1-4  Development of long bones from cartilage anlagen.

proliferation, adjusting the pace of the differentiation.10 Two transcription factors, Cux-1, a homeobox factor, and the ETS factor ERG/C-1-1, are expressed concurrently with GDF-5 and Wnt-14 at the onset of joint formation.11,12 Hartmann and Tabin13 have proposed two major roles for Wnt-14. First, it acts at the onset of joint formation as a negative regulator of chondrogenesis. Second, it facilitates interzone formation and cavitation by inducing the expression of GDF-5 (also known as cartilage-derived morphogenetic protein-1 [CDMP-1]), Wnt-4, chordin, and the hyaluronan receptor, CD44.13-15 Paradoxically, application of GDF-5 to developing joints in mouse embryo limbs in organ culture causes joint fusion,16 suggesting that temporospatial interactions among distinct cell populations are important for the correct response. The current view

Cavitation

C-1-1 Articular cartilage

Joint maturation

is that GDF-5 is required at the early stages of condensations, where it stimulates recruitment and differentiation of chondrogenic cells, and later, when its expression is restricted to the interzone. The distribution of collagen types and keratan sulfate in developing avian and rodent joints has been characterized by immunohistochemistry.17-21 Collagen types I and III characterize the matrix produced by mesenchymal cells, which switch to the production of types II, IX, and XI collagens that typify the cartilaginous matrix at the time of condensation.22 The messenger RNAs encoding the small proteoglycans, biglycan and decorin, may be expressed at this time, but the proteins do not appear until after cavi­ tation in the regions destined to become articular cartilage.23 The interzone regions are marked by the expression



GOLDRING 

| 

Biology of the Normal Joint

C

A

B

C C

C

D

C C

E

F

Figure 1-5  In situ hybridization of a 13-day-old (stage 39) chicken embryo middle digit, proximal interphalangeal joint, midfrontal sections. A, Brightfield image showing developing joint and capsule (C). B, Equivalent paraffin section of opposite limb of same animal, showing onset of cavitation laterally (arrow). C, Expression of type IIA collagen mRNA in articular surface cells, perichondrium, and capsule. D, Type IIB collagen mRNA is expressed only in chondrocytes of the anlagen. E, Type XI collagen mRNA is expressed in the surface cells, perichondrium, and capsule, with lower levels in chondrocytes. F, Type I collagen mRNA is present in cells of the interzone and capsule. C through F images are dark field. Calibration bar = 1 μm. (From Nalin AM, Greenlee TK Jr, Sandell LJ: Collagen gene expression during development of avian synovial joints: Transient expression of types II and XI collagen genes in the joint capsule. Develop Dyn 203:352-362, 1995.)

of type IIA ­ collagen by chondrocyte progenitors in the perichondrial layers, type IIB and XI collagens by overt­ chondrocytes in the cartilage anlagen, and type I collagen in the interzone and in the developing capsule and perichondrium (Fig. 1-5).24 The interzone region contains cells in two outer layers that are destined to differentiate into chondrocytes and become incorporated into the epiphyses, and in a thin intermediate zone that are programmed to undergo joint cavitation and may remain as articular chondrocytes.25 Fluid and macromolecules accumulate in this space and create a nascent synovial cavity. Blood vessels appear in the surrounding capsulosynovial blastemal mesenchyme before separation of the adjacent articulating surfaces.26 Although it was first assumed that these interzone cells should undergo necrosis or programmed cell death (apoptosis),27 some investigators have found no evidence of DNA ­fragmentation preceding

cavitation.24,25,28,29 There also is no evidence that metalloproteinases are involved in loss of tissue strength in the region undergoing cavitation.30 Instead, the actual joint cavity seems to be formed by mechanospatial changes induced by the synthesis of hyaluronan via uridine diphosphoglucose dehydrogenase (UDPGD) and hyaluronan synthase. Interaction of hyaluronan with its cell surface receptor, CD44, modulates cell migration, but it is thought that the accumulation of hyaluronan and the associated mechanical influences play the major role in forcing the cells apart and inducing rupture of the intervening extracellular matrix by tensile forces.20,31 This mechanism accounts for the observation that joint cavitation is incomplete in the absence of movement.32,33 Equivalent data from human embryonic joints are difficult to obtain. In all large joints in humans, complete joint cavities are apparent at the beginning of the fetal period.

PART 1 

| 

STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

CARTILAGE FORMATION AND ENDOCHONDRAL OSSIFICATION The skeleton develops from the primitive, avascular, densely packed cellular mesenchyme, termed the skeletal blastema. Common precursor mesenchymal cells divide into chondrogenic, myogenic, and osteogenic lineages that determine the differentiation of cartilage centrally, muscle peripherally, and bone. The surrounding tissues, particularly epithelium, influence the differentiation of mesenchymal progenitor cells to chondrocytes in cartilage anlagen. The cartilaginous nodules appear in the middle of the blastema, and simultaneously cells at the periphery become flattened and elongated to form the perichondrium. In the vertebral column, cartilage disks arise from portions of the somites surrounding the notochord, and nasal and auricular cartilage and the embryonic epiphysis form from the perichondrium. In the limb, the cartilage remains as a resting zone that later becomes the articular cartilage, or undergoes terminal hypertrophic differentiation to become calcified (growth plate formation) and is replaced by bone (endochondral ossification). The latter process requires extracellular matrix remodeling and vascularization (angiogenesis). These events are controlled exquisitely by cellular interactions with the surrounding matrix, growth and differentiation factors, and other environmental factors that initiate or suppress cellular signaling pathways and transcription of specific genes in a temporospatial manner. Condensation and Limb-Bud Formation Formation of the cartilage anlage occurs in four stages: (1) cell migration, (2) aggregation regulated by mesenchymal-epithelial cell interactions, (3) condensation, and (4) overt chondrocyte differentiation, or chondrification.3,4,34 Interactions with the epithelium determine mesenchymal cell recruitment and migration, proliferation, and condensation.34-36 The aggregation of chondroprogenitor mesenchymal cells into precartilage condensations was first described by Fell37 and depends on signals initiated by cell-cell and cell-matrix interactions, the formation of gap junctions, and changes in the cytoskeletal architecture. Before condensation, the prechondrocytic mesenchymal cells produce extracellular matrix that is rich in hyaluronan and type I collagen and type IIA collagen, which contains the exon2-encoded aminopropeptide found in noncartilage collagens.38 The initiation of condensation is associated with increased hyaluronidase activity and the appearance of the cell adhesion molecules, neural cadherin (N-cadherin) and neural cell adhesion molecule (N-CAM), which facilitate cell-cell interactions. Before chondrocyte differentiation, the cell-matrix interactions are facilitated by fibronectin binding to syndecan, downregulating N-CAM and setting the condensation boundaries. Increased cell proliferation and extracellular matrix remodeling, with the disappearance of type I collagen, fibronectin, and N-cadherin, and the appearance of tenascins, matrilins, and thrombospondins, including cartilage oligomeric protein, initiate the transition from chondroprogenitor cells to a fully committed chondrocyte.2,36,39,40 N-cadherin and N-CAM disappear in differentiating chondrocytes and are detectable later only in perichondrial cells.



The differentiated chondrocytes can proliferate and undergo the complex process of hypertrophic maturation or remain within cartilage elements in articular joints. Zwilling41 proposed that positional information for organization of the limb bud was imparted by diffusible agents generated at the tip of the limb bud and along its posterior margin, promoting the development of a cartilaginous anlage along proximal-distal and anterior-posterior axes. Limb buds develop from the lateral plate mesoderm.42 The patterning of limb mesenchyme is due to interactions between the mesenchyme and the overlying epithelium.35 The embryonic limb possesses two signaling centers, the apical ectodermal ridge (AER) and the zone of polarizing activity (ZPA), which produce signals responsible for directing the proximal-distal outgrowth (AER)and anterior-­posterior patterning (ZPA).2,39 Much of the current understanding of limb development is based on early studies in chickens and more recently in mice. The regulatory events are controlled by interacting patterning systems involving FGF, hedgehog, BMP, and Wnt pathways, each of which functions sequentially over time (see Fig. 1-3).42 Wnt signaling via β-catenin is required to induce FGFs, such as FGF-10 and FGF-8, which act in positive feedback loops.42,43 FGF-2, FGF-4, and FGF-8 (induced by Wnt-3A44), from the specialized epithelial cells in the AER that are covering the limb-bud tip, control proximaldistal (shoulder/finger) outgrowth.45 The homeobox (Hox) transcription factors encoded by the HoxA and HoxD gene clusters, which are crucial for the early events of limb patterning in the undifferentiated mesenchyme, are required for the expression of FGF-8 and Sonic hedgehog (Shh),46 and they modulate the proliferation of cells within the condensations.34 Among the Hox genes, Hoxa13 and Hoxd13 enhance and Hoxa11 and Hoxd11 suppress early events in the formation of the cartilage anlagen. Wnt7a is expressed early during limb bud development where it acts to maintain Shh expression.42 Shh, produced by a small group of cells in the posterior zone of the ZPA (in response to retinoic acid in the mesoderm47 and FGF-4 in the AER48), plays a key role in directing anterior-posterior (e.g., little finger/thumb) patterning47,49 and stimulating expression of BMP-2, BMP-4, BMP-7, and Hox genes.50-52 Shh signaling, which is required for early limb patterning, but not for limb formation, is mediated by the Shh receptor Patched (Ptc1), which activates another transmembrane protein, Smoothened (Smo), and inhibits processing of the Gli3 transcription factor to a transcriptional repressor.43,53 Dorsal-ventral (e.g., knuckles/palm) patterning depends on the secretion of Wnt-7A54 and expression of the following transcription factors: radical fringe (r-Fng) by the dorsal ectoderm, and engrailed (En-1) and Lmx1b (which is induced by Wnt-7A) by the ventral endoderm.43,55 BMP-2, BMP-4, and BMP-7 coordinately regulate the patterning of limb elements within the condensations depending on the temporal and spatial expression of BMP receptors, involving SMAD-dependent and SMAD­independent signaling and BMP antagonists, such as noggin and chordin.42,56-58 In vitro and in vivo studies have shown that BMP signaling is required for the formation of precartilaginous condensations and for the differentiation of precursors into chondrocytes.59 Growth of the condensation ceases when noggin inhibits BMP signaling and permits



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overt ­differentiation to chondrocytes, which are often designated as “chondroblasts.” The cartilage formed serves as a template for formation of cartilage elements in the vertebra, sternum, and rib, and for limb elongation or endochondral bone formation. Molecular Signals in Cartilage Morphogenesis and Growth Plate Development The cartilage anlagen grow by cell division and deposition of the extracellular matrix and by apposition of proliferating cells from the inner chondrogenic layer of the perichondrium. The nuclear transcription factor, Sox9, is one of earliest markers expressed in cells undergoing condensation and is required for the subsequent stage of chondrogenesis characterized by the deposition of matrix containing collagens II, IX, and XI and aggrecan in the cartilage anlagen.60,61 Two additional Sox family members, L-Sox5 and Sox6, which are not present in early mesenchymal condensations, but are coexpressed with Sox9 during chondrocyte differentiation,62 have a high degree of sequence identity with each other, but have no sequence homology with Sox9 except in the HMG box. They can form homodimers or heterodimers, which bind more efficiently to pairs of HMG box sites than to single sites, and in contrast to Sox9, they contain no transcriptional activation domain. The expression of SOX proteins depends on BMP signaling via BMPR1A and BMPR1B, which are functionally redundant and active in chondrocyte condensations, but not in the perichondrium.59 L-Sox5 and Sox6 are required for the expression of Col9a1, aggrecan, link protein, and Col2a1 during overt chondrocyte differentiation.63 The runt-domain transcription factor, Runx2 (also known as core binding factor, Cbfa1), also is expressed in all condensations, including those that are destined to form bone.64-66 Throughout chondrogenesis, the balance of signaling by BMPs and FGFs determines the rate of proliferation, adjusting the pace of the differentiation.10 In the long bones, long after condensation, BMP-2, BMP-3, BMP-4, BMP-5, and BMP-7 are expressed primarily in the perichondrium, and only BMP-7 is expressed in the proliferating chondrocytes.10 BMP-6 is found later exclusively in hypertrophic chondrocytes along with BMP-2. More than 23 FGFs have been identified so far.67 The specific ligands that activate each FGF receptor (R) during chondrogenesis in vivo have been difficult to identify because the signaling depends on the temporal and spatial location of not only the ligands, but also the receptors.68 FGFR2 is upregulated early in condensing mesenchyme and is present later in the periphery of the condensation along with FGFR1, which is expressed in surrounding loose mesenchyme. FGFR3 is associated with proliferation of chondrocytes in the central core of the mesenchymal condensation and may overlap with FGFR2. Proliferation of chondrocytes in the embryonic and postnatal growth plate is regulated by multiple mitogenic stimuli, including FGFs, which converge on the cyclin D1 gene.69 In the growth plate, FGFR3 serves as a master inhibitor of chondrocyte proliferation via phosphorylation of the Stat1 transcription factor, which increases the expression of the cell cycle inhibitor p21.70 More recent studies suggest that FGF-18 is the preferred ligand of FGFR3 because Fgf18-deficient mice have an expanded zone of

proliferating chondrocytes similar to that in Fgfr3-deficient mice, and that FGF-18 can inhibit Indian hedgehog (Ihh) expression.71 FGF18 and FGF9 are expressed in the perichondrium and periosteum and form a functional gradient from the proximal proliferating zone, where FGF18 acts via FGFR3 to downregulate proliferation and subsequent maturation.71,72 FGF18 and FGF9 interact with FGFR1 in the prehypertrophic and hypertrophic zones, where more recent evidence indicates that they regulate vascular invasion by inducing the expression of vascular endothelial growth factor (VEGF) and VEGFR1. As the epiphyseal growth plate develops, FGFR3 disappears, and FGFR1 expression is upregulated in prehypertrophic and hypertrophic chondrocytes, suggesting a role for FGFR1 in the regulation of cell survival and differentiation and possibly cell death.68 The proliferation of chondrocytes in the lower proliferative and the prehypertrophic zones is under the control of a local negative feedback loop involving signaling by parathyroid hormone related protein (PTHrP) and Ihh.73 Ihh expression is restricted to the prehypertrophic zone, and the PTHrP receptor is expressed in the distal zone of periarticular chondrocytes. The adjacent, surrounding perichondrial cells express the Hedgehog receptor patched (ptc), which on Ihh binding, similar to Shh in the mesenchymal condensations, activates Smo and induces Gli transcription factors, which can feedback regulate Ihh target genes in a positive (Gli1 and Gli2) or negative (Gli3) manner.74 Ihh induces expression of PTHrP in the perichondrium,75 and PTHrP signaling stimulates cell proliferation via its receptor expressed in the periarticular chondrocytes.76 These interactions are modulated by a balance of BMP and FGF signaling that adjusts the pace of chondrocyte terminal differentiation to the proliferation rate.10 FGF-18 or FGFR3 signaling can inhibit Ihh expression,71 and BMP signaling upregulates the expression of Ihh in cells that are beyond the range of the PTHrP-induced signal.10 Evidence indicates that Ihh acts independently of PTHrP on periarticular chondrocytes to stimulate differentiation of columnar chondrocytes in the proliferative zone, whereas PTHrP acts by preventing premature differentiation into prehypertrophic and hypertrophic chondrocytes, suppressing premature expression of Ihh.77 Ihh and PTHrP, by transiently inducing proliferation markers and repressing differentiation markers, function in a temporospatial manner to determine the number of cells that remain in the chondrogenic lineage versus the number that enter the endochondral ossification pathway.73,78 Endochondral Ossification The development of long bones from the cartilage anlagen occurs by a process termed endochondral ossification, which involves terminal differentiation of chondrocytes to the hypertrophic phenotype, cartilage matrix calcification, vascular invasion, and ossification (see Fig. 1-4).28,78-80 This process is initiated when the cells in the central region of the anlage begin to hypertrophy, increasing cellular fluid volume by almost 20 times. Ihh plays a pivotal role in regulating endochondral bone formation by synchronizing perichondrial maturation with chondrocyte hypertrophy, which is essential for initiating the process of vascular invasion.81 Ihh is expressed in prehypertrophic chondrocytes as they exit the proliferative phase and enter the hypertrophic

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STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

phase, at which time they begin to express the hypertrophic chondrocyte marker, type X collagen (Col10a1) and alkaline phosphatase. These cells are responsible for laying down the cartilage matrix that subsequently undergoes mineralization. Runx2, which serves as a positive regulatory factor in chondrocyte maturation to hypertrophy,82 is expressed in the adjacent perichondrium and in prehypertrophic chondrocytes, but less in late hypertrophic chondrocytes,83,84 overlapping with Ihh, Col10a1, and BMP-6.78,85 BMP-induced Smad1 interacts with Runx2, and Runx2 and Smad1 are important for chondrocyte hypertrophy.82,86,87 An essential role for Runx2 in the process of chondrocyte hypertrophy is supported by the observation that the late stages of chondrocyte hypertrophy are blocked in Runx2-deficient mice.65,88 Interactions with components of the extracellular matrix also contribute to regulation of the process of chondrocyte hypertrophy. Matrix metalloproteinase (MMP)-13, a downstream target of Runx2, is expressed by terminal hypertrophic chondrocytes,89-92 and MMP-13 deficiency results in significant interstitial collagen accumulation leading to the delay of endochondral ossification in the growth plate with increased length of the hypertrophic zone.93,94 In contrast, Col10a1 knockout mice and transgenic mice with a dominant interference Col10a1 mutation have subtle growth plate phenotypes with compressed proliferative and hypertrophic zones and altered mineral deposition.95 Mutations in the COL10A1 gene are associated with the dwarfism observed in human chondrodysplasias. These mutations affect regions of the growth plate that are under great mechanical stress, and it has been suggested that the defect in skeletal growth may be due partly to alteration of the mechanical integrity of the pericellular matrix in the hypertrophic zone, although a role for defective vascularization also has been proposed.96 The extracellular matrix remodeling that accompanies chondrocyte terminal differentiation is thought to induce an alteration in the environmental stress experienced by hypertrophic chondrocytes, which eventually undergo apoptosis.78,97,98 Together these studies indicate that the composition and remodeling of the extracellular matrix play an important role in processes associated with chondrocyte hypertrophy, vascular invasion, and, as discussed subsequently, osteoblast recruitment and subsequent bone formation.91 Vascular invasion of the hypertrophic zone is required for the replacement of calcified cartilage by bone.85,92 The angiogenic factor, VEGF, promotes vascular invasion by specifically activating localized receptors, including Flk expressed in endothelial cells in the perichondrium or surrounding soft tissues, neuropilin 1 (Npn1) expressed in late hypertrophic chondrocytes, or Npn2 expressed exclusively in the perichondrium.28 VEGF is expressed as three different isoforms: VEGF188, a matrix-bound form, is essential for metaphyseal vascularization, whereas the soluble form, VEGF120 (VEGFA), regulates chondrocyte survival and epiphyseal cartilage angiogenesis.99-101 VEGF164 can be either soluble or matrix bound and may act directly on chondrocytes via Npn2. VEGF is released from the extracellular matrix by MMPs, including MMP-9, membranetype (MT)1-MMP (MMP-14), and MMP-13. MMP-9 is expressed by endothelial cells that migrate into the central region of the hypertrophic cartilage.91 MMP-14, which has a broader range of expression than MMP-9, is essential for



chondrocyte proliferation and secondary ossification,102 whereas MMP-13 is found exclusively in late hypertrophic chondrocytes.83 These events of cartilage matrix remodeling and vascular invasion are required for the migration and differentiation of osteoclasts and osteoblasts, which remove the mineralized cartilage matrix and replace it with bone. DEVELOPMENT OF THE JOINT CAPSULE AND SYNOVIUM The interzone and the contiguous perichondrial envelope, of which the interzone is a part, contain the mesenchymal cell precursors that give rise to other joint components, including the joint capsule, synovial lining, menisci, intracapsular ligaments, and tendons.3,4,103,104 The external mesenchymal tissue condenses as a fibrous capsule. The peripheral mesenchyme becomes vascularized and is incorporated as the synovial mesenchyme, which differentiates into a pseudomembrane at about the same time as cavitation begins in the central interzone (stage 23, approximately 8 weeks). The menisci arise from the eccentric portions of the articular interzone. In common usage, the term synovium refers to the true synovial lining and the subjacent vascular and areolar tissue, up to—but excluding—the capsule. Synovial lining cells can be distinguished as soon as the multiple cavities within the interzone begin to coalesce. At first, these are exclusively fibroblast-like (type B) cells. As the joint cavity increases in size, synovial-lining cell layers expand by proliferation of fibroblast-like cells and recruitment of macrophage-like (type A) cells from the circulation.105 The synovial lining cells express the hyaluronan receptor, CD44, and UDPGD, the levels of which remain elevated after cavitation. This increased activity likely contributes to the high concentration of hyaluronan in joint fluids.31,106 Further synovial expansion results in the appearance of synovial villi at the end of the second month, early in the fetal period, which greatly increases the surface area available for exchange between the joint cavity and the vascular space. The role of innervation in the developing joint is not well understood. A dense capillary network develops in the subsynovial tissue, with numerous capillary loops that penetrate into the true synovial lining layer. The human synovial microvasculature is already innervated by 8 weeks (stage 23) of gestation, around the time of joint cavitation,103 as is shown by immunoreactivity for the neuronal “housekeeping” enzymes.107 Evidence of neurotransmitter function is not found until much later, however, with the appearance of the sensory neuropeptide, substance P, at 11 weeks. The putative sympathetic neurotransmitter, neuropeptide Y, appears at 13 weeks of gestation, along with the catecholamine­synthesizing enzyme tyrosine hydroxylase. The finding that the Slit2 gene, which functions for the guidance of neuronal axons and neurons, is expressed in the mesenchyme adjacent to the AER (stages 20 to 22) and in peripheral mesenchyme of the limb bud (stages 23 to 28) suggests that innervation is an integral part of synovial joint development.108 DEVELOPMENT OF NONARTICULAR JOINTS In contrast to articular joints, the temporomandibular joint develops slowly, with cavitation at a crown-rump length of 57 to 75 mm (i.e., well into the fetal stage).109 This slow



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development may be because this joint develops in the absence of a continuous blastema and involves the insertion between bone ends of a fibrocartilaginous disk that arises from muscular and mesenchymal derivatives of the first pharyngeal arch. The development of other types of joints, such as synarthroses, is similar to that of diarthrodial joints except that cavitation does not occur, and synovial mesenchyme is not formed. In these respects, synarthroses and amphiarthroses resemble the “fused” peripheral joints induced by paralyzing chicken embryos,110 and they may develop as they do because there is relatively little motion during their formation. Human vertebrae and intervertebral disks develop as units, each derived from a homogeneous blastema arising from a somite. Each embryonic intervertebral disk serves as a rostral and caudal chondrogenic zone for the two adjacent evolving vertebral bodies. The periphery of the embryonic “disk” is replaced by the anulus fibrosus.111 The intervertebral disk bears many similarities to the joint; the anulus is the joint capsule, the nucleus pulposus is the joint cavity, and the vertebral end plates are the cartilage-covered bone ends composing the articulation. The proteoglycans and collagens expressed during development of the intervertebral disk have been mapped and reflect the complex structure-function relationships that allow flexibility and resistance to compression in the spine.112-115 DEVELOPMENT OF ARTICULAR CARTILAGE In the vertebrate skeleton, cartilage is the product of cells from three distinct embryonic lineages. Craniofacial cartilage is formed from cranial neural crest cells, the cartilage of the axial skeleton (intervertebral disks, ribs, and sternum) forms from paraxial mesoderm (somites), and the articular cartilage of the limbs is derived from the lateral plate mesoderm.2 In the developing limb bud, mesenchymal condensations, followed by chondrocyte differentiation and maturation, occur in digital zones, whereas undifferentiated mesenchymal cells in the interdigital web zones undergo cell death.116 Embryonic cartilage is destined for one of several fates: It can remain as permanent cartilage, as on the articular surfaces of bones, or it can provide a template for the formation of bones by endochondral ossification. During development, chondrocyte maturation expands from the central site of the original condensation, which forms the cartilage anlage resembling the shape of the future bone, toward the ends of the forming bones. During joint cavitation, the peripheral interzone is absorbed into each adjacent cartilaginous zone, evolving into the articular surface. The articular surface is destined to become a specialized cartilaginous structure that does not normally undergo vascularization and ossification. More recent evidence indicates that postnatal maturation of the articular cartilage involves an appositional growth mechanism originating from progenitor cells at the articular surface, rather than by an interstitial mechanism.113 The chondrocytes of mature articular cartilage are terminally differentiated cells that continue to express cartilage-specific matrix molecules, such as type II collagen and aggrecan (see following section).19,21,24 Through the processes described previously, the articular joint spaces are developed and lined

on all surfaces either by cartilage or by synovial lining cells. These two different tissues merge at the enthesis, the region at the periphery of the joint where the cartilage melds into bone, and where ligaments and the capsule are attached.117 In the postnatal growth plate, the differentiation of the perichondrium also is linked to the differentiation of the chondrocytes in the epiphysis into different zones of the growth plate, and contributes to longitudinal bone growth.28,78

ORGANIZATION AND PHYSIOLOGY OF THE MATURE JOINT The unique structural properties and biochemical components of diarthrodial joints make them extraordinarily durable load-bearing devices.118 The mature diarthrodial joint is a complex structure, influenced by its environment and mechanical demands (see Chapter 6). There are structural differences between joints determined by their different functions. The shoulder joint, which demands an enormous range of motion, is stabilized primarily by muscles, whereas the hip, requiring motion and antigravity stability, has an intrinsically stable ball-and-socket configuration. The components of the “typical” synovial joint are the synovium, muscles, tendons, ligaments, bursae, menisci, articular cartilage, and subchondral bone. The anatomy and physiology of muscles are described in detail in Chapter 5. SYNOVIUM The synovium lines the joint cavity and is the sight of production of synovial fluid that provides the nutrition for the articular cartilage and lubricates the cartilage surfaces. It is a thin membrane between the fibrous joint capsule and fluid-filled synovial cavity that attaches to skeletal tissues at the bone-cartilage interface and does not encroach on the surface of the articular cartilage. It is divided into functional compartments: the lining region (synovial intima), the subintimal stroma, and the neurovasculature (Fig. 1-6). The synovial intima, also termed synovial lining, is the superficial layer of the normal synovium that is in contact with the intra-articular cavity.106,119 The synovial lining is loosely attached to the subintima, which contains blood vessels, lymphatics, and nerves. Capillaries and arterioles generally are located directly underneath the synovial intima, whereas venules are located closer to the joint capsule. A transition from loose to dense connective tissue occurs from the joint cavity to the capsule. Most cells in the normal subintimal stroma are fibroblasts and macrophages, although adipocytes and occasional mast cells are present.106 These compartments are not circumscribed by basement membranes, but nonetheless have distinct functions; they are separated from each other by chemical barriers, such as membrane peptidases, which limit the diffusion of regulatory factors between compartments. Synovial compartments are unevenly distributed within a single joint. Vascularity is high at the enthesis where synovium, ligament, and cartilage coalesce.120 Far from being a homogeneous tissue in continuity with the synovial cavity, synovium is highly heterogeneous, and synovial fluid may be poorly representative of the tissue-fluid composition of any synovial tissue compartment. In rheumatoid arthritis, the synovial lining of diarthrodial joints is the site of the initial inflammatory

PART 1 

Intimal macrophage

Intimal fibroblasts

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STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE



Synovial fluid

Subintimal fibroblast Subintimal macrophage Blood vessels

A

B

Figure 1-6  A, Schematic representation of normal human synovium. The intima contains specialized fibroblasts expressing vascular cell adhesion molecule-1 (VCAM-1) and uridine diphosphoglucose (UDPG) and specialized macrophages expressing FcγRIIIa. The deeper subintima contains ­unspecialized counterparts. B, Microvascular endothelium in human synovium contains receptors for the vasodilator/growth factor substance P. Silver grains represent specific binding of [125I]Bolton Hunter–labeled substance P to synovial microvessels (arrows). Arrowheads indicate the synovial surface. Emulsion-dipped in vitro receptor autoradiography preparations with hematoxylin and eosin counterstain. Calibration bar = 1 μm. (A from Edwards JCW: Fibroblast biology: Development and differentiation of synovial fibroblasts in arthritis. Arthritis Res 2:344-347, 2000.)

process.121,122 This lesion is characterized by proliferation of the synovial lining cells, increased vascularization, and infiltration of the tissue by inflammatory cells, including lymphocytes, plasma cells, and activated macrophages (see Chapter 65).123-125 Synovial Lining The synovial lining, a specialized condensation of mesenchymal cells and extracellular matrix, is located between the synovial cavity and stroma. In normal synovium, the lining layer is two to three cells deep, although intra-articular fat pads usually are covered by only a single layer of synovial cells, and ligaments and tendons are covered by synovial cells that are widely separated. At some sites, lining cells are absent, and the extracellular connective tissue constitutes the lining layer.126 Such “bare areas” become increasingly frequent with advancing age.127 Although the synovial lining is often referred to as the synovial membrane, the term membrane is more correctly reserved for epithelia that have basement membranes, tight intercellular junctions, and desmosomes. Instead, synovial lining cells lie loosely in a bed of hyaluronate interspersed with collagen fibrils. This is the macromolecular sieve that imparts the semipermeable nature of the synovium. The absence of any true epithelial tissue, including basement membrane, is a major determinant of joint physiology. Early electron microscopic studies characterized lining cells as macrophage-derived type A synoviocytes and fibroblast-derived type B synoviocytes.128 High UDPGD activity and CD55 are used to distinguish type B synovial cells, whereas nonspecific esterase and CD68 typify type A cells.129,130 Normal synovium is lined predominantly by fibroblast-like cells, whereas macrophage-like cells compose only 10% to 20% of lining cells (see Fig. 1-6). Type A, macrophage-like synovial cells contain vacuoles, a prominent Golgi apparatus, and filopodia, but they have little rough endoplasmic reticulum. These cells express numerous cell surface markers of the monocyte-macrophage lineage, including CD11b, CD68, CD14, CD163, and the

IgG Fc receptor, FcγRIIIa.106 Synovial intimal macrophages are phagocytic and may provide a mechanism by which particulate matter can be cleared from the normal joint cavity. Similar to other tissue macrophages, these cells have little capacity to proliferate and are likely localized to the joint during development. The op/op osteopetrotic mouse that is deficient in macrophages because of an absence of macrophage colony-stimulating factor also lacks synovial macrophages.131 This finding provides further evidence that type A synovial cells are of a common lineage with other tissue macrophages. Although they represent only a small percentage of the cells in the normal synovium, the macrophages are recruited from the circulation during synovial inflammation, partly from subchondral bone marrow through vascular channels near the enthesis. The type B, fibroblast-like synovial cell contains fewer vacuoles and filopodia than type A cells and has abundant protein-synthetic organelles. Similar to other fibroblasts, lining cells express the collagen synthesis enzyme prolyl hydroxylase and synthesize extracellular matrix components, including collagens, sulfated proteoglycans, fibronectin, fibrillin-1, and tenascin.106,132 They have the potential to proliferate, although proliferation markers are rarely seen in normal synovium.133 In contrast to stromal fibroblasts, synovial intimal fibroblasts express UDPGD and synthesize hyaluronan, an important constituent of synovial fluid.106 They also synthesize lubricin, which, together with hyaluronan, is necessary for the low-friction interaction of cartilage surfaces in the diarthrodial joint. Despite not being a true epithelium, synovial lining cells bear abundant membrane peptidases on their surface, capable of degrading a wide range of regulatory peptides, such as substance P and angiotensin II.134 These enzymes may be important in limiting the diffusion of these potent peptide mediators away from the immediate vicinity of their site of release and action. Normal synovial lining cells also express a rich array of adhesion molecules, including CD44, the principal receptor for hyaluronan; vascular cell adhesion molecule (VCAM)-1; and intercellular adhesion molecule (ICAM)-1.106,135-137 These are probably essential for cellular attachment to

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Biology of the Normal Joint

specific matrix components in the synovial lining region, preventing loss into the synovial cavity of cells subjected to deformation and shear stresses during joint movement. Adhesion molecules such as VCAM-1 and ICAM-1 potentially also are involved in the recruitment of inflammatory cells during the evolution of arthritis. Cadherins mediate cell-cell adhesion between adjacent cells of the same type. The identification of cadherin-11 as a key adhesion molecule that regulates the formation of the synovial lining during development and the synoviocyte function postnatally has provided the opportunity to examine its role in inflammatory joint disease.138 Cadherin-11 deficiency or treatment with cadherin-11 antibody or a cadherin-11 fusion protein reduced synovial inflammation and reduced cartilage erosion in an animal model of arthritis.139 Synovial Vasculature The subintimal synovium contains blood vessels, providing the blood flow that is required for solute and gas exchange in the synovium itself and for the generation of synovial fluid.120 The avascular articular cartilage also depends on nutrition in the synovial fluid, derived from the synovial vasculature. The vascularized synovium behaves similar to an endocrine organ, generating factors that regulate synoviocyte function and serving as a selective gateway that recruits cells from the circulation during stress and inflammation.140 Finally, synovial blood flow plays an important role in regulating intra-articular temperature. The synovial vasculature can be divided, on morphologic and functional grounds, into arterioles, capillaries, and venules. In addition, lymphatics accompany arterioles and larger venules.106,120 Arterial and venous networks of the joint are complex and are characterized by arteriovenous anastomoses that communicate freely with blood vessels in periosteum and periarticular bone. As large synovial arteries enter the deep layers of the synovium near the capsule, they give off branches, which bifurcate again to form “microvascular units” in the subsynovial layers. The synovial lining region, the surfaces of intra-articular ligaments, and the entheses (in the angle of ligamentous insertions into bone) are particularly well vascularized.120 The distribution of synovial vessels, which were formed largely as a result of vasculogenesis during development of the joint, displays considerable plasticity. Vasculogenesis is a dynamic process that depends on the cellular interactions with regulatory factors and the extracellular matrix that are also important in angiogenesis. In inflammatory arthritis, the density of blood vessels decreases relative to the growing synovial mass, creating a hypoxic and acidotic environment.141,142 Angiogenic factors such as VEGF, acting via VEGF receptor 1 and 2 (Flt-1 and Flk-1), and basic FGF promote proliferation and migration of endothelial cells, a process that is facilitated by matrix-degrading enzymes and adhesion molecules such as integrin αvβ3 and E-selectin, expressed by activated endothelial cells.143-145 Vessel maturation is facilitated by angiopoietin-1 acting via the Tie-2 receptor. The angiogenic molecules are restricted to the capillary epithelium in normal synovium, but their levels are elevated in inflamed synovium in perivascular sites and areas remote from vessels.146,147

Regulation of Synovial Blood Flow Synovial blood flow is regulated by intrinsic (autocrine and paracrine) and extrinsic (neural and humoral) systems. Locally generated factors, such as the peptide vasoconstrictors angiotensin II and endothelin-1, act on adjacent arteriolar smooth muscle to regulate regional vascular tone.120 Normal synovial arterioles are richly innervated by sympathetic nerves containing vasoconstrictors, such as norepinephrine and neuropeptide Y, and by “sensory” nerves that also play an efferent vasodilatory role by releasing neuropeptides, such as substance P and calcitonin gene–related peptide.148,149 Arterioles regulate regional blood flow. Capillaries and postcapillary venules are sites of fluid and cellular exchange. Correspondingly, regulatory systems are differentially distributed along the vascular axis. Angiotensin-converting enzyme, which generates angiotensin II, is localized predominantly in arteriolar and capillary endothelia and decreases during inflammation.150 Specific receptors for angiotensin II and for substance P are abundant on synovial capillaries, with lower densities on adjacent arterioles. Dipeptidyl peptidase IV, a peptide-degrading enzyme, is specifically localized to the cell membranes of venular endothelium. The synovial vasculature is not only functionally compartmentalized from the surrounding stroma, but also highly specialized along its arteriovenous axis. Other unique characteristics of the normal synovial vasculature include the presence of inducible nitric oxidase synthase–independent 3-nitrotyrosine, a reaction product of peroxynitrite,151 and the localization of the synoviocyte-derived CXCL12 chemokine on heparan sulfate receptors on endothelial cells,152 suggesting physiologic roles for these molecules in normal vascular function. JOINT INNERVATION Dissection studies have shown that each joint has a dual nerve supply, consisting of specific articular nerves that penetrate the capsule as independent branches of adjacent peripheral nerves and articular branches that arise from related muscle nerves. The definition of joint position and the detection of joint motion are monitored separately and by a combination of multiple inputs from different receptors in varied systems. Nerve endings in muscle and skin and in the joint capsule mediate sensation of joint position and movement.153,154 Normal joints have afferent (sensory) and efferent (motor) innervations. Fast-conducting, myelinated A fibers innervating the joint capsule are important for proprioception and detection of joint movement; slow­conducting, unmyelinated C fibers transmit diffuse pain sensation and regulate synovial microvascular function. Normal synovium is richly innervated by fine, unmyelinated nerve fibers that follow the courses of blood vessels and extend into the synovial lining layers.148 These nerve fibers do not have specialized endings and are slow-conducting fibers; they may transmit diffuse, burning, or aching pain sensation. Sympathetic nerve fibers surround blood vessels, particularly in the deeper regions of normal synovium. They contain and release classic neurotransmitters, such as norepinephrine, and neuropeptides that constrict synovial blood vessels. Neuropeptides that are markers of sensory nerves include substance P, calcitonin gene–related peptide, neuropeptide Y, and vasoactive intestinal peptide.148,155-157

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STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

Afferent nerves containing substance P also have an efferent role in the synovium. Substance P is released from peripheral nerve terminals into the joint, and specific, G protein–coupled receptors for substance P are localized to microvascular endothelium in normal synovium. Abnormalities of articular innervation that are associated with inflammatory arthritis may contribute to the failure of synovial inflammation to resolve.148,158 Excessive local neuropeptide release may result in the loss of nerve fibers owing to neuropeptide depletion. Synovial tissue proliferation without concomitant growth of new nerve fibers may lead to an apparent partial denervation of synovium.148,158 Studies in patients suggest that free nerve endings containing substance P may modulate inflammation and the pain pathway in osteoarthritis.159 Afferent nerve fibers from the joint play an important role in the reflex inhibition of muscle contraction. Trophic factors generated by motoneurons, such as the neuropeptide calcitonin gene–related peptide, are important in maintaining muscle bulk and a functional neuromuscular junction.160 Decreases in motoneuron trophic support during articular inflammation probably contribute to muscle wasting. Mechanisms of joint pain have been reviewed in detail.161,162 In a noninflamed joint, most sensory nerve fibers do not respond to movement within the normal range; these are referred to as silent nociceptors. In an acutely inflamed joint, however, these nerve fibers become sensitized by mediators, such as bradykinin, neurokinin 1, and prostaglandins (peripheral sensitization), such that normal movements induce pain. Pain sensation is upregulated or downregulated further in the central nervous system, at the level of the spinal cord and in the brain, by central sensitization and “gating” of nociceptive input. Although the normal joint may respond predictably to painful stimuli, there is often a poor correlation between apparent joint disease and perceived pain in chronic arthritis. Pain associated with joint movements within the normal range is a characteristic symptom described by patients with chronically inflamed joints caused by rheumatoid arthritis. Chronically inflamed joints may not be painful at rest, however, unless acutely inflamed.163 TENDONS Tendons are functional and anatomic bridges between muscle and bone.164,165 They focus the force of a large mass of muscle into a localized area on bone and, by splitting to form numerous insertions, may distribute the force of a single muscle to different bones. Tendons are formed of longitudinally arranged collagen fibrils embedded in an organized, hydrated proteoglycan matrix with blood vessels, lymphatics, and fibroblasts.166 Cross-links between adjacent collagen chains or molecules contribute to the tensile strength of the tendon. 167,168 Tendon collagen fibrillogenesis is initiated during early development by a highly ordered process of alignment involving the actin cytoskeleton and cadherin-11.169,170 Many tendons, particularly tendons with a large range of motion, run through vascularized, discontinuous sheaths of collagen lined with mesenchymal cells resembling synovium. Gliding of tendons through their sheaths is enhanced by hyaluronic acid produced by the lining cells. Tendon movement is essential for the embryogenesis and

11

maintenance of tendons and their sheaths. Degenerative changes appear in tendons, and fibrous adhesions form between tendons and sheaths when inflammation or surgical incision is followed by long periods of immobilization.171 At the myotendinous junction, recesses between muscle cell processes are filled with collagen fibrils, which blend into the tendon. At its other end, collagen fibers of the tendon typically blend into fibrocartilage, mineralize, and merge into bone through a fibrocartilaginous transition zone termed the enthesis, or insertion site.172 Tendon fibroblasts synthesize and secrete collagens, proteoglycans, and other matrix components, such as fibronectin and tenascin C, and MMPs and their inhibitors, which can contribute to the breakdown and repair of tendon components.166,173-176 Collagen fibrils in tendon are composed primarily of type I collagen with some type III collagen, but there are regional differences in the distribution of other matrix components. The compressed region contains the small proteoglycans, biglycan, decorin, fibromodulin, and lumican, and the large proteoglycan versican.177,178 The major components in the tensile region of the tendon are decorin, microfibrillar type VI collagen, fibromodulin, and proline and arginine-rich end leucine-rich repeat protein. The presence of cartilage oligomeric matrix protein, aggrecan, and biglycan and collagen types II, IX, and XI is indicative of fibrocartilage.179,180 The collagen fiber orientation at the tendon-to-bone enthesis is important for maintaining microarchitecture, by reducing the stress concentrations and shielding the outward splay of the insertion from the highest stresses.181 Understanding the structure has implications for tendon repair because motion between a tendon graft and bone tunnel may impair early graft incorporation and lead to tunnel widening secondary to bone resorption.182 Failure of the muscle-tendon apparatus is rare, but when it does occur, it is secondary to enormous, quickly generated forces across a joint and usually occurs near the tendon insertion into bone.183,184 Factors that may predispose to tendon failure are aging processes, including loss of extracellular water and an increase in intermolecular cross-links of collagen; tendon ischemia; iatrogenic factors, including injection of glucocorticoids; and deposition of calcium hydroxyapatite crystals within the collagen bundles. Alterations in collagen fibril composition and structure are associated with tendon degeneration during aging and may predispose to osteoarthritis.185,186 Evidence indicates that BMPs promote tendon repair if osteogenic signaling is impaired.187 LIGAMENTS Ligaments provide a stabilizing bridge between bones, permitting a limited range of movement.188 The ligaments often are recognized only as hypertrophied components of the fibrous joint capsule and are structurally similar to tendons.189 Although the fibers are oriented parallel to the longitudinal axis of both tissues,164 the collagen fibrils in ligaments are nonparallel and arranged in fibers that are oriented roughly along the long axis in a wavy, undulating pattern, or “crimp,” which can straighten in response to load. Some ligaments have a higher ratio of elastin to collagen (1:4) than tendons (1:50), which permits a greater degree of stretch. Ligaments also have larger amounts of reducible cross-links, more type III collagen, slightly less total ­collagen,

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and more glycosaminoglycans compared with tendons. The cells in ligaments seem to be more metabolically active than the cells in tendons because they have more plump cellular nuclei and higher DNA content. During postnatal growth, the development of ligament attachment zones involves changes in the ratios and distribution of collagen types I, III, and V and the synthesis of type II collagen and proteoglycans by fibrochondrocytes that develop from ligament cells at the attachment zone.190,191 Attachment zones are believed to permit gradual transmission of the tensile force between ligament and bone. Ligaments play a major role in the passive stabilization of joints, aided by the capsule and, when present, menisci. In the knee, the collateral and cruciate ligaments provide stability when there is little or no load on the joint. As compressive load increases, there is an increasing contribution to stability from the joint surfaces themselves and the surrounding musculature. Injured ligaments generally heal, and structural integrity is restored by contracture of the healing ligament so that it can act again as a stabilizer of the joint.192 BURSAE The many bursae in the human body facilitate gliding of one tissue over another, much as a tendon sheath facilitates movement of its tendon. Bursae are closed sacs, lined sparsely with mesenchymal cells similar to synovial cells, but they are generally less well vascularized than synovium. Most bursae differentiate concurrently with synovial joints during embryogenesis. During life, however, trauma or inflammation may lead to the development of new bursae, hypertrophy of previously existing ones, or communication between deep bursae and joints. In patients with rheumatoid arthritis, communications may exist between the subacromial bursae and the glenohumeral joint, between the gastrocnemius or semimembranosus bursae and the knee joint, and between the iliopsoas bursa and the hip joint. It is unusual, however, for subcutaneous bursae, such as the prepatellar bursa or olecranon bursa, to develop communication with the underlying joint.193 MENISCI The meniscus, a fibrocartilaginous, wedge-shaped structure, is best developed in the knee, but also is found in the acromioclavicular and sternoclavicular joints, the ulnocarpal joint, and the temporomandibular joint.194,195 Until more recently, menisci were thought to have little function and a quiescent metabolism with no capability of repair, although early observations indicated that removal of menisci from the knee may lead to premature arthritic changes in the joint.196 Evidence from an arthroscopic study of patients with anterior cruciate ligament insufficiency indicates that the pathology of the medial meniscus correlates with that of the medial femoral cartilage.197 The meniscus is now considered to be an integral component of the knee joint that has important functions in joint stability, load distribution, shock absorption, and lubrication.194,195 The microanatomy of the meniscus is complex and age dependent.198 The characteristic shape of the lateral and the medial menisci is achieved early in prenatal

d­ evelopment. At that time, the menisci are cellular and highly vascularized; with maturation, vascularity decreases progressively from the central margin to the peripheral margin. After skeletal maturity, the peripheral 10% to 30% of the meniscus remains highly vascularized by a circumferential capillary plexus and is well innervated.199 Tears in this vascularized peripheral zone may undergo repair and remodeling.200 The central portion of the mature meniscus is an avascular fibrocartilage, however, without nerves or lymphatics, consisting of cells surrounded by an abundant extracellular matrix of collagens, chondroitin sulfates, dermatan sulfates, and hyaluronic acid. Tears in this central zone heal poorly, if at all. Collagen constitutes 60% to 70% of the dry weight of the meniscus and is mostly type I collagen, with lesser amounts of types III, V, and VI. A small quantity of cartilage-specific type II collagen is localized to the inner, avascular portion of the meniscus. Collagen fibers in the periphery are mostly circumferentially oriented, with radial fibers extending toward the central portion.201-204 Elastin content is around 0.6%, and proteoglycan content is around 2% to 3% dry weight. Aggrecan and decorin are the major proteoglycans in the adult meniscus.205,206 Decorin is the predominant proteoglycan synthesized in the meniscus from young individuals, whereas the relative proportion of aggrecan synthesis increases with age. Although the capacity of the meniscus to synthesize sulfated proteoglycans decreases after the teenage years, the age-related increases in expression of decorin and aggrecan mRNA suggest that the resident cells are able to respond quickly to alterations in the biomechanical environment.207 The meniscus was defined originally as a fibrocartilage, based on the rounded or oval shape of most of the cells and the fibrous microscopic appearance of the extracellular matrix.208 Based on molecular and spatial criteria, three distinct populations of cells are recognized in the meniscus of the knee joint202: 1. The fibrochondrocyte is the most abundant cell in the middle and inner meniscus, synthesizing primarily type I collagen and relatively small amounts of type II and III collagens. It is round or oval in shape and has a pericellular filamentous matrix containing type VI collagen. 2. The fibroblast-like cells lack a pericellular matrix and are located in the outer portion of the meniscus. They are distinguished by long, thin, branching cytoplasmic projections that stain for vimentin. They make contact with other cells in different regions via connexin 43–containing gap junctions. The presence of two centrosomes, one associated with a primary celium, suggests a sensory, rather than motile, function that could enable the cells to respond to circumferential tensile loads, rather than compressive loads.209 3. The superficial zone cells have a characteristic fusiform shape with no cytoplasmic projections. The occasional staining of these cells in the uninjured meniscus with α-actin and their migration into surrounding wound sites suggest that they are specialized progenitor cells that may participate in a remod­ eling response in the meniscus and surrounding tissues.210,211

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STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

MATURE ARTICULAR CARTILAGE Articular cartilage is a specialized connective tissue that covers the weight-bearing surfaces of diarthrodial joints.118,212,213 The principal functions of cartilage layers covering bone ends are to permit low-friction, high-velocity movement between bones, to absorb the transmitted forces associated with locomotion, and to contribute to joint stability. Lubrication by synovial fluid provides frictionless movement of the articulating cartilage surfaces. Chondrocytes (see Chapter 3) are the single cellular component of adult hyaline articular cartilage and are responsible for synthesizing and maintaining the highly specialized cartilage matrix macromolecules. The cartilage extracellular matrix is composed of an extensive network of collagen fibrils, which confers tensile strength, and an interlocking mesh of proteoglycans, which provides compressive stiffness through the ability to absorb and extrude water. Numerous other noncollagenous proteins also contribute to the unique properties of cartilage (Table 1-1). Histologically, the tissue appears to be fairly homogeneous and clearly distinguished from the calcified cartilage and underlying subchondral bone (Fig. 1-7). The organization of articular cartilage and structure-function relationships of cartilage matrix components are described in Chapter 3. SUBCHONDRAL BONE INTERACTIONS WITH ARTICULAR CARTILAGE The subchondral bone plate beneath the calcified base of articular cartilage may have many effects on the cartilage above it. Its stiffness modifies the compressive forces to which articular cartilage is subjected, its blood supply may be important in cartilage nutrition (see following section), and its cells may produce peptides that regulate chondrocyte function. Several studies have suggested that the responses of the subchondral bone to mechanical stimulation may transmit signals into the articular cartilage.214 Tidemark advancement with thickening of the calcified cartilage and thinning of articular cartilage is associated with fibrillation of the cartilage surface during aging.215 An increase in subchondral bone density is an early feature of osteoarthritis.216 Radin and Rose217 proposed that the initiation of fibrillation is caused by an increase in subchondral bone stiffness. These changes in subchondral bone stiffness may be secondary to cartilage deterioration, but are necessary for progression of osteoarthritic lesions, and involve bone and calcified cartilage close to the joint.218-220 Also, at the junction of the articular hyaline cartilage and adjacent subchondral bone, there is evidence of vascular invasion and advancement in the zone of calcified cartilage in the region of the so-called tidemark that contributes further to a decrease in articular cartilage thickness.221 A more recent study showed that angiogenesis in the osteochondral junction is independent of synovial angiogenesis and synovitis, but is associated with cartilage changes and clinical disease activity.222 These structural alterations in the articular cartilage and periarticular bone may lead to modification of the contours of the adjacent articulating surfaces.217,223-225 Because increased trabecular bone volume with trabecular sclerosis and increased bone turnover are features of osteoarthritis pathogenesis, therapies that target bone have been proposed. Examples are calcitonin,226,227

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b­ isphosphonates,228 and estrogen.229 Although receptor activator of nuclear factor ĸB (NFĸB) ligand (RANKL), which mediates osteoclast differentiation and activity, and its receptor RANK, a member of the tumor necrosis factor receptor family, are expressed in adult articular chondrocytes, exogenous RANKL does not activate NFĸB or stimulate the production of collagenase or nitric oxide.230 Inhibition of RANKL expression does not block cartilage destruction in ­ inflammatory models,231 although RANKL may have indirect effects on cartilage by its protective effect on bone.232 Table 1-1  Extracellular Matrix Components   of Articular Cartilage* Collagens Type II Type IX Type XI Type VI Types XII, XIV Type X (hypertrophic chondrocyte) Proteoglycans Aggrecan Versican Link protein Biglycan (DS-PGI) Decorin (DS-PGII) Epiphycan (DS-PGIII) Fibromodulin Lumican Proline/arginine-rich and leucine-rich repeat protein (PRELP) Chondroadherin Perlecan Lubricin (SZP) Other Noncollagenous Proteins (Structural) Cartilage oligomeric matrix protein (COMP) or thrombospondin-5 Thrombospondin-1 and thrombospondin-3 Cartilage matrix protein (matrilin-1) and matrilin-3 Fibronectin Tenascin-C Cartilage intermediate layer protein (CILP) Fibrillin Elastin Other Noncollagenous Proteins (Regulatory) Glycoprotein (gp)-39, YKL-40 Matrix Gla protein (MGP) Chondromodulin-I (SCGP) and chondromodulin-II Cartilage-derived retinoic acid–sensitive protein (CD-RAP) Growth factors Cell Membrane–Associated Proteins Integrins (α1β1, α2β1, α3β1, α5β1, α6β1, α10β1, αvβ3, αvβ5) Anchorin CII (annexin V) Cell determinant 44 (CD44) Syndecan-3 Discoidin domain receptor 2 *The collagens, proteoglycans, and other noncollagenous proteins in the cartilage matrix are synthesized by chondrocytes at different stages during development and growth of cartilage. In mature articular cartilage, proteoglycans and other noncollagen proteins are turned over slowly, whereas the collagen network is stable unless exposed to proteolytic cleavage. Proteins that are associated with chondrocyte cell membranes also are listed because they permit specific interactions with extracellular matrix proteins. The specific structure-function relationships are discussed in Chapter 3 and described in Table 3-1. DS-PG, dermatan sulfate proteoglycan; SCGP, small cartilage–derived glycoprotein; SZP, superficial zone protein; YKL-40, 40KD chitinase 3-like glycoprotein.

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Figure 1-7  A and B, Representative sections of normal human adult articular cartilage, showing nearly the same field in plain (A) and polarized (B) light. Note the clear demarcation of the articular cartilage from the calcified cartilage below the tidemark and the underlying subchondral bone.  (Hematoxylin-eosin stain; original magnification ×60.) (Courtesy of Edward F. DiCarlo, MD, Pathology Department, Hospital for Special Surgery, New York, NY.)

A

SYNOVIAL FLUID AND NUTRITION OF JOINT STRUCTURES The volume and composition of synovial fluid are determined by the properties of the synovium and its vasculature. Fluid in normal joints is present in small quantities (2.5 mL in the normal knee) sufficient to coat the synovial surface, but not to separate one surface from the other. Tendon sheath fluid and synovial fluid are biochemically similar. Both are essential for the nutrition and lubrication of adjacent avascular structures, including tendon and articular cartilage, and for limiting adhesion formation, maintaining movement. Characterization and measurement of synovial fluid constituents have proved useful for the identification of locally generated regulatory factors, markers of cartilage turnover, and the metabolic status of the joint, and for the assessment of the effects of therapy on cartilage homeostasis. Interpretation of such data requires, however, an understanding of the generation and clearance of synovial fluid and its various components. GENERATION AND CLEARANCE OF SYNOVIAL FLUID Synovial fluid concentrations of a protein represent the net contributions of synovial blood flow, plasma concentration, microvascular permeability, and lymphatic removal and its production and consumption within the joint space. Synovial fluid is a mixture of a protein-rich ultrafiltrate of plasma and hyaluronan synthesized by synoviocytes. Generation of this ultrafiltrate depends on the difference between intracapillary and intra-articular hydrostatic pressures and between colloid osmotic pressures of capillary plasma and synovial tissue fluid. Fenestrations, small pores covered by a thin membrane, in the synovial capillaries and the macromolecular sieve of hyaluronic acid facilitate rapid exchange

B

of small molecules, such as glucose and lactate, assisted—in the case of glucose—by an active transport system.233 Proteins are present in synovial fluid at concentrations inversely proportional to molecular size, with synovial fluid albumin concentrations being about 45% of those in plasma (Fig. 1-8).234 Concentrations of electrolytes and small molecules are equivalent to those in plasma.235 Synovial fluid is cleared through lymphatics in the synovium, assisted by joint movement. In contrast to ultrafiltration, lymphatic clearance of solutes is independent of molecular size. In addition, constituents of synovial fluid, such as regulatory peptides, may be degraded locally by enzymes, and low-molecular-weight metabolites may diffuse along concentration gradients into plasma. The kinetics of delivery and removal of a protein must be determined (e.g., using albumin as a reference solute) to assess the significance of its concentration in the joint.236 Hyaluronic acid is synthesized by fibroblast-like synovial lining cells, and it appears in high concentrations in synovial fluid at around 3 g/L, compared with a plasma concentration of 30 μg/L. Lubricin, a glycoprotein that assists articular lubrication, is another constituent of synovial fluid that is generated by the lining cells.363 It is now believed that hyaluronan functions in fluid-film lubrication, whereas lubricin is the true boundary lubricant in synovial fluid (see following). Because the volume of synovial fluid is determined by the amount of hyaluronan, water retention seems to be the major function of this large molecule.233,237 Despite the absence of a basement membrane, synovial fluid does not mix freely with extracellular synovial tissue fluid. Hyaluronan may trap molecules within the synovial cavity by acting as a filtration screen on the surface of the synovial lining, resisting the movement of synovial fluid out from the joint space.237 Synovial fluid and its constituent proteins have a rapid turnover time (around 1 hour

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STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

Probably RA

1.0

Gout Osteoarthritis Classic RA

Ratio

Normal

SF .10 S Conc.

Oroso- Trans- Cerulomucoid ferrin plasmin

44

74

160

α2 Macroglobulin

820

.01 1

100

1000

Molecular Weight (×103) Figure 1-8  Ratio of the concentration of proteins in synovial fluid to that found in serum, plotted as a function of molecular weight. Larger proteins are selectively excluded from normal synovial fluid, but this macromolecular sieve is less effective in diseased synovium. Conc., concentration; RA, rheumatoid arthritis; S, serum; SF, synovial fluid. (From Kushner I, Somerville JA: Permeability of human synovial membrane to ­plasma proteins. Arthritis Rheum 14:560, 1971. Reprinted with permission of the American College of Rheumatology.)

in normal knees), and equilibrium is not usually reached among all parts of the joint. Tissue fluid around fenestrated endothelium reflects plasma ultrafiltrate most closely, with a low content of hyaluronate compared with synovial fluid. Alternatively, locally generated or released peptides, such as endothelin and substance P, may attain much higher perivascular concentrations than those measured in synovial fluid. The turnover time for hyaluronan in the normal joint (13 hours) is an order of magnitude slower, however, than that of small solutes and proteins. Association with hyaluronan may result in trapping of solutes within synovial fluid.238 In normal joints, intra-articular pressures are slightly subatmospheric at rest (0 to −5 mm Hg).239 During exercise, hydrostatic pressure in the normal joint may decrease further. Resting intra-articular pressures in rheumatoid joints are around 20 mm Hg, whereas during isometric exercise, they may increase to greater than 100 mm Hg, well above capillary perfusion pressure and, at times, above arterial pressure. Repeated mechanical stresses can interrupt synovial perfusion during joint movement, particularly in the presence of a synovial effusion. SYNOVIAL FLUID AS AN INDICATOR OF JOINT FUNCTION In the absence of a basement membrane separating synovium or cartilage from synovial fluid, measurements made on synovial fluid may reflect the activity of these structures. A wide range of regulatory factors and products

15

of ­synoviocyte metabolism and cartilage breakdown may be generated locally within the joint, resulting in marked differences between the composition of synovial fluid and plasma ultrafiltrate. Because there is little capacity for the selective concentration of solutes in synovial fluid, solutes present at higher concentrations than in plasma are probably synthesized locally. It is necessary to know the local clearance rate, however, to determine whether the solutes present in synovial fluid at lower concentrations than in plasma are generated locally.235 Although microvascular permeability to protein in highly inflamed rheumatoid joints is more than twice that in osteoarthritic joints, synovial fluid protein concentrations vary little between the two joint diseases240 because the enhanced entry of proteins through the microvasculature is largely offset by the increased lymphatic clearance.241 Because clearance rates from synovial fluid may be slower than those from plasma, however, synovial fluid levels of drugs or urate may remain elevated after plasma levels have declined.233 Comparisons of synovial fluid constituents between disease groups are often limited by the sparseness of data on normal synovial fluid as a result of difficulties in its collection. Extrapolation from synovial fluid concentrations to local synthetic rates is complicated further because of variations in clearance rates and in synovial fluid volume. Plasma proteins are less effectively filtered in inflamed synovium, perhaps because of increased size of endothelial cell fenestrations or because interstitial hyaluronate-protein complexes are fragmented by enzymes associated with the inflammatory process.234 Concentrations of proteins, such as α2-macroglobulin (the principal proteinase inhibitor of plasma), fibrinogen, and IgM, are elevated in inflammatory synovial fluids (see Fig. 1-8), as are associated protein-bound cations. Membrane peptidases may limit the diffusion of regulatory peptides from their sites of release into synovial fluid. In inflammatory arthritis, fibrin deposits may retard flow between the tissue and the liquid phase. The cautious interpretation of synovial fluid analysis has important implications in understanding how to use data on biomarkers of cartilage damage and repair in rheumatoid arthritis and osteoarthritis (see Chapter 48). LUBRICATION AND NUTRITION OF THE ARTICULAR CARTILAGE Lubrication Synovial fluid serves as a lubricant for articular cartilage and a source of nutrition for the chondrocytes within. Lubrication is essential for protecting cartilage and other joint structures from friction and shear stresses associated with movement under loading. There are two basic categories of joint lubrication. In fluid-film lubrication, cartilage surfaces are separated by an incompressible fluid film; hyaluronan functions as the lubricant. In boundary lubrication, specialized molecules attached to the cartilage surface permit surface-to-surface contact, while decreasing the coefficient of friction. During loading, a noncompressible fluid film is trapped between opposing cartilage surfaces and prevents the surfaces from touching. Irregularities in the cartilage surface and its deformation during compression may augment this

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trapping of fluid. This stable film is approximately 0.1 μm thick in the normal human hip joint, but it can be much thinner in the presence of inflammatory synovial fluids or with increased cartilage porosity.242,243 Lubricin is the major boundary lubricant in the human joint.244 It is a glycoprotein, also called superficial zone protein and proteoglycan 4, which is synthesized by synovial cells and chondrocytes.245-248 It has a molecular weight of 225,000, is 200 nm in length, and is 1 to 2 nm in diameter.249 Dipalmitoyl phosphatidylcholine, which constitutes 45% of the lipid in normal synovial fluid, acts together with lubricin as a boundary lubricant.250 More recent work indicates that lubricin functions as a phospholipid carrier via a mechanism that is common to all tissues.251,252 Lipid composes 1% to 2% of dry weight of cartilage,253 and experimental treatment of cartilage surfaces with fat solvents impairs lubrication qualities.254 Nutrition As observed by Hunter in 1743,255 normal adult articular cartilage contains no blood vessels. Vascularization of cartilage would be expected to alter its mechanical properties. Blood flow would be repeatedly occluded during weight bearing and exercise, with reactive oxygen species generated during reperfusion, resulting in repeated damage to cartilage matrix and chondrocytes. Chondrocytes synthesize specific inhibitors of angiogenesis that maintain articular cartilage as an avascular tissue.256-258 As a result of the lack of adjacent blood vessels, the chondrocyte normally lives in an hypoxic and acidotic environment, with extracellular fluid pH values around 7.1 to 7.2,259 and it uses anaerobic glycolysis for energy production.260 High lactate levels in normal synovial fluid, compared with paired plasma measurements, partially reflect this anaerobic metabolism.261 There are two sources of nutrients for articular cartilage: (1) the synovial fluid and (2) subchondral blood vessels. The synovial fluid and, indirectly, the synovial lining, through which synovial fluid is generated, are the major sources of nutrients for articular cartilage. Nutrients may enter cartilage from synovial fluid either by diffusion or by mass transport of fluid during compression-relaxation cycles.262 Molecules as large as hemoglobin (65 kD) can diffuse through normal articular cartilage,263 and the solutes needed for cellular metabolism are much smaller. Diffusion of uncharged small solutes, such as glucose, is not impaired in matrices containing large amounts of glycosaminoglycans, and diffusivity of small molecules through hyaluronate is enhanced.264,265 Intermittent compression may serve as a pump mechanism for solute exchange in cartilage. The concept has arisen from observations that joint immobilization or dislocation leads to degenerative changes. In contrast, exercise increases solute penetration into cartilage in experimental systems.263 During weight bearing, fluid escapes from the load-bearing region by flow to other cartilage sites. When the load is removed, cartilage re-expands and draws back fluid, exchanging nutrients with waste materials.266 In a growing child, the deeper layers of cartilage are vascularized, such that blood vessels penetrate between columns of chondrocytes in the hypertrophic zone of the growth plate. It is likely that nutrients diffuse from these

tiny end capillaries through the matrix to chondrocytes. Diffusion from subchondral blood vessels is not considered a major route for the nutrition of normal adult articular cartilage because of the barrier provided by its densely calcified lower layer, the “tidemark.” Nonetheless, partial defects may normally exist in this barrier,267 and in arthritis, neovascularization of the deeper layers of articular cartilage may contribute to cartilage nutrition and to entry of inflammatory cells and cytokines.221,268 In aging and osteoarthritis, tidemark “duplication” may indicate communication between the bone and cartilage.218,269 Experimental studies have indicated that cartilage lesions of chondromalacia may develop if the subchondral blood supply of the patella is compromised.270

SUMMARY AND CONCLUSION Normal human synovial joints are complex structures that comprise interacting connective tissue elements that permit constrained and low-friction movement of adjacent bones. The development of synovial joints in the embryo is a highly ordered process involving complex cell-cell and cell-matrix interactions that lead to the formation of the cartilage anlage and interzone and joint cavitation. Understanding of the cellular interactions and molecular factors involved in cartilage morphogenesis and limb development has provided clues to understanding the functions of the synovium, articular cartilage, and associated structures in the mature joint. The synovial joint is uniquely adapted to responding to environmental and mechanical demands. The synovial lining is composed of two to three cell layers, and there is no basement membrane separating the lining cells from the underlying connective tissue. The synovium produces synovial fluid, which provides nutrition and lubrication to the avascular articular cartilage. Normal articular cartilage contains a single cell type, the articular chondrocyte, which is responsible for maintaining the integrity of the extracellular cartilage matrix. This matrix consists of a complex network of collagens, proteoglycans, and other noncollagenous proteins, which provide tensile strength and compressive resistance. Proper distribution and relative composition of these proteins is required for the function of cartilage in protecting the subchondral bone from adverse environmental influences. Maintenance of the unique composition and organization of each joint tissue is crucial for normal joint function, which is compromised in response to inflammation, biomechanical injury, and aging. Knowledge of the normal structure-function relationships within joint tissues is essential for understanding the pathogenesis and consequences of joint diseases.

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PART 1 

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STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

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2

Synovium BARRY BRESNIHAN  •  ADRIENNE M. FLANAGAN

KEY POINTS The synovium provides nutrients to cartilage and produces lubricants for the joint. The intimal lining of the synovium introduces macrophagelike and fibroblast-like synoviocytes. The sublining contains scattered immune cells, fibroblasts, blood vessels, and fat cells. Fibroblast-like synoviocytes in the intimal lining express specialized proteins that synthesize proteoglycans such as hyaluronic acid.

STRUCTURE The synovium is a membranous structure that extends from the margins of articular cartilage and lines the capsule of diar­ throdial joints, including the temporomandibular joint1 and the facet joints of vertebral bodies (Fig. 2-1).2 The healthy synovium covers intra-articular tendons and ­ ligaments, and fat pads, but not articular cartilage or meniscal tissue. Synovium also ensheathes tendons where they pass beneath ligamentous bands. Normally, the synovial membrane has two components—the intima, or lining cells, and the sub­ intima, otherwise referred to as the sublining or supportive layer. The intima represents the interface between the cav­ ity containing synovial fluid and the subintimal layer. There is no well-formed basement membrane to separate the intima from the subintima. The subintima is composed of fibrovascular connective tissue and merges with the densely collagenous fibrous joint capsule. SYNOVIAL LINING CELLS The synovial intimal layer is composed of synovial lining cells (SLCs), which have an epithelial-like arrangement on the luminal aspect of the joint cavity. SLCs, termed synoviocytes, are one to three cells deep, depending on the anatomic location, and they extend 20 to 40 μm beneath the lining layer surface. The major and minor axes of SLCs measure 8 to 12 μm (major axis) and 6 to 8 μm (minor axis). SLCs have poorly defined cell borders and elliptical nuclei with generally a single small nucleolus.3 Ultrastructure of Synovial Lining Cells Transmission electron microscopic analysis shows that the intimal cells form a discontinuous layer, something not appre­ ciated under transmission light microscopy, so that the subin­ timal matrix is in direct contact with the synovial fluid (Fig. 2-2). The existence of two distinct cell types, type A and type B

SLCs, originally was described by Barland and associates,4 and several lines of evidence, including animal models, detailed ultrastructural studies, and immunohistochemical analysis, indicate that these cells represent macrophages (type A SLCs) and fibroblasts (type B SLCs). Studies of the SLC populations in a variety of species, including humans, have found that macrophages make up approximately 20% and fibroblast-like cells approximately 80% of the lining cell.5,6 The existence of the two cell types has been substantiated by similar findings in a wide variety of species, including hamsters, cats, dogs, guinea pigs, rabbits, mice, rats, and horses.6-14 Distinguishing the different cell populations that form the synovial lining is impossible by hematoxylin and eosin staining under transmission light microscopy. At an ultra­ structural level, the type A cells are characterized by a con­ spicuous Golgi apparatus, large vacuoles, and small vesicles, and contain little rough endoplasmic reticulum, giving them a macrophage-like phenotype (Fig. 2-3A and B). The plasma membrane of type A cells possesses numerous fine extensions, termed filopodia, which are characteristic of mac­ rophages. These cells are located for the most part on the lin­ ing surface, where it is more than one cell thick. Type A cells cluster at the tips of the synovial villi, and this uneven dis­ tribution at least partly explains early reports that suggested type A cells were the predominant intimal cell type.4,8 Type B SLCs have prominent cytoplasmic extensions that extend onto the surface of the synovial lining (Fig. 2-3C and D).15 Frequent invaginations are seen along the plasma membrane, and a large indented nucleus relative to the area of the surrounding cytoplasm is also a feature. Type B cells have abundant rough endoplasmic reticulum widely distrib­ uted in the cytoplasm, and the Golgi apparatus, vacuoles, and vesicles are generally inconspicuous, although some cells have small numbers of prominent vacuoles at their apical aspect. Type B SLCs also are known to contain lon­ gitudinal bundles of different-sized filaments, supporting their classification as fibroblasts. Desmosomes and gaplike junctions have been described in rat, mouse, and rabbit synovium, but the existence of these structures has never been documented in human SLCs. Cells exhibiting the ultrastructure of type A and type B SLCs have been classified as intermediate, or type AB. The existence of intermediate cells has been refuted on the basis of detailed electron microscopic studies, and it is now accepted that a proportion of type B cells have conspicu­ ous vacuoles, and that rough endoplasmic reticulum appears in activated macrophages.16,17 The putative existence of an intermediate SLC implies that type A and type B SLCs are part of the same cell lineage. This concept is contrary to all current evidence, which finds that type A and type B SLCs are histogenetically and functionally distinct. 23

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Figure 2-2  Transmission electron photomicrograph of synovial intimal cells. The cell on the left exhibits the dendritic appearance of a synovial intimal fibroblast (type B cell). Other overlying fibroblast dendrites can be observed. The presence of intercellular gaps allows the synovial fluid to be in direct contact with the synovial matrix. 500 µm Figure 2-1  The cartilage-synovium junction. Hyaline articular cartilage occupies the left half of this image, and fibrous capsule and synovial membrane occupy the right half. A sparse intimal lining layer with a fibrous subintima can be observed extending from the margin of the cartilage across the capsular surface to assume a more cellular intimal morphology with areolar subintima.

Immunohistochemical Profile of Synovial Intimal Cells Synovial Intimal Macrophages. Synovial macrophages and fibroblasts express lineage-specific molecules, which can be detected by immunohistochemistry. Synovial macrophages express common hematopoietic antigen CD45 (Fig. 2-4A); monocyte/macrophage receptors CD163 and CD97; and ly­ sosomal enzymes CD68 (Fig. 2-4B), neuron-specific esterase, and cathepsin B, L, and D. Cells expressing CD14, a mol­ ecule that acts as a coreceptor for the detection of bacterial lipopolysaccharide, and expressed by circulating monocytes and monocytes newly recruited to tissue, are rarely seen in the healthy intimal layer, but small numbers are found close to venules in the subintima.18-24 The Fcγ receptor, FcγRIII (CD16), expressed by Kupffer cells of the liver and type II alveolar macrophages of the lung, also is expressed on a subpopulation of synovial mac­ rophages.25-27 The synovial macrophage population also expresses the major histocompatibility complex (MHC) class II molecule which plays an important role in the immune response. More recently, the macrophages, which are responsible for the removal of debris, blood, and par­ ticulate material from the joint cavity and possess antigen processing properties, have been found to express a new complement-related protein, Z39Ig, a cell surface receptor and immunoglobulin superfamily member, which is involved in the induction of HLA-DR, and implicated in the reg­ ulation of phagocytosis and antigen-­mediated immune responses.28-30 The expression of the β2 integrin chains, CD18, CD11a, CD11b, and CD11c, varies; CD11a and CD11c may be absent, or weakly expressed, on a few lining cells.31,32 Osteoclasts, which are tartrate-resistant, acid phosphatase– positive, and express the αvβ3 vitronectin and calcitonin receptors, do not appear in the normal synovium. Synovial Intimal Fibroblasts. Synovial intimal and subin­ timal fibroblasts are indistinguishable by light microscopy. They are generally considered to be closely related in terms

of cell lineage, but because of their different microenviron­ ments, they do not always share the same phenotype. They possess prominent synthetic capacity and produce the es­ sential joint lubricants hyaluronic acid (HA) and lubricin.33 Intimal fibroblasts express uridine diphosphoglucose dehy­ drogenase (UDPGD), an enzyme involved in HA synthesis, which is recognized as a specific marker for this cell type. UDPGD converts UDP-glucose to UDP-glucuronate, one of the two substrates required by HA synthase for assembly of the HA polymer.34 CD44 expression, the nonintegrin re­ ceptor for HA, is expressed by all SLCs.32,35,36 Synovial fibroblasts also synthesize normal matrix com­ ponents, including fibronectin, laminin, collagens, pro­ teoglycans, lubricin, and other identified and unidentified proteins. They also have the capacity to produce large amounts of metalloproteinases, metalloproteinase inhibi­ tors, prostaglandins, and cytokines. This capacity must provide essential biologic advantages, but the complex physiologic mechanisms relevant to normal function are incompletely delineated. The expression of selected adhe­ sion molecules on synovial fibroblasts probably facilitates the trafficking of some cell populations, such as neutrophils, into the synovial fluid, and the retention of others, such as mononuclear leukocytes, in the synovial tissue. Metal­ loproteinases, cytokines, adhesion molecules, and other cell surface molecules are strikingly upregulated in inflamma­ tory states. Specialized intimal fibroblasts also express many other molecules that are not expressed by the intimal macrophage population, including decay-accelerating factor (CD55), previously identified by the antibody Mab67; vascular cell adhesion molecule 1; intracellular adhesion molecule33,37-40; and cadherin 11.41,42 PGP.95, a neuronal marker, is reported as being specific for type B synoviocytes in horses.43 Decayaccelerating factor, also expressed on the cells of other body cavities and cells in bone marrow, interacts with CD97, a glycoprotein that is present on the surface of most acti­ vated leukocytes, including intimal macrophages, and is thought to be involved in the signaling processes early after leukocyte activation.44,45 In contrast, FcγRIII is expressed only by macrophages when they are in close contact with decay-accelerating factor–positive fibroblasts, or decayaccelerating factor–coated fibrillin-1 microfibrils in the extracellular matrix.26 Cadherins are a class of tissue-restricted transmem­ brane proteins that play important roles in homophilic

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Figure 2-3  Transmission electron photomicrographs of synovial intimal macrophages (type A cells) and fibroblasts (type B cells). A, Low-powered magnification showing the surface fine filopodia, characteristic of macrophages, and a smooth-surfaced nucleus. B, The boxed area in A is shown at a higher magnification and reveals numerous vesicles characteristic of macrophages. The absence of rough endoplasmic reticulum also is noted. C, The convoluted nucleus along with the prominent rough endoplasmic reticulum (boxed area) is characteristic of a synovial intimal fibroblast (type B cell).  D, The rough endoplasmic reticulum is shown at greater magnification.

intercellular adhesion and are involved in maintaining the integrity of tissue architecture. Cadherin 11, which was cloned from rheumatoid arthritis synovial tissue, also is expressed in normal synovial intimal fibroblasts, but not in intimal macrophages. The finding that fibroblasts trans­ fected with cadherin 11 are induced to form a lining-like structure in vitro implicates this molecule in the architec­ tural organization of the synovial lining.41,42,46 This sugges­ tion is supported by the observation that cadherin-deficient mice have a hypoplastic synovial lining and are resistant to inflammatory arthritis.47

β1 and β3 integrins are present on all SLCs, forming recep­ tors for laminin (CD49f and CD49b), collagen types I and IV (CD49b), vitronectin (CD51), and fibronectin (CD49d and CD49e). In contrast, the integrin collagen receptors, CD49a, CD54 (a member of the immunoglobulin superfam­ ily), and CD4 and CD62 (selectin) present on lymphocytes, and involved in their homing to high endothelial venules, are not observed on these cells. CD31 (platelet–endothelial cell adhesion molecule), a member of the immunoglobulin superfamily that is expressed on endothelial cells, platelets, and monocytes, is only weakly expressed on SLCs.32

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Figure 2-4  Transmitted light photomicrographs depicting synovial intimal macrophages by immunohistochemistry. A and B, Macrophages are decorated with CD45 (arrow in A) and CD68 (B), markers that identify hematopoietic cells (CD45) and macrophages (CD68).

Turnover of Synovial Lining Cells Proliferation of SLCs in humans is low, as shown when normal human synovial explants, exposed to a pulse of 3H thymidine, resulted in the SLCs having a labeling index of approximately 0.05% to 0.3%48; this bears a striking con­ trast with labeling indices of approximately 50% for bowel crypt epithelium. Similar evidence of low proliferation has been found in the synovium of rats and rabbits. The advent of immunohistochemistry saw this observation substanti­ ated when Revell and others reported that the proportion of SLCs expressing the proliferation marker Ki67 was between 1 in 2800 and 1 in 30,000.49 It was subsequently shown that the type B SLCs, the synovial fibroblasts, proliferated in situ,22,50 a finding consistent with the concept that type A synovial cells are macrophages. Mitotic activity of SLCs also is low in inflammatory conditions, such as rheuma­ toid arthritis, a condition associated with SLC hyperplasia. Coulton and coworkers51 reported “a few” mitotic figures in only 1 of 600 cases of rheumatoid arthritis synovium sam­ ples analyzed. Apart from the knowledge that synovial fibroblasts pro­ liferate slowly, little is known about their natural life span, recruitment, or mode of death. Apoptosis likely is involved in maintaining synovial homeostasis, but there is little in the literature on this subject. The dearth of information is likely to be explained by the lack of normal synovium avail­ able for analysis, in addition to the difficulty encountered when quantifying this process on histological sections owing to the rapid clearance of apoptotic bodies.52 Origin of Synovial Lining Cells There is little doubt that the type A SLC population iden­ tified by Barland and associates4 is bone marrow derived and represents cells of the mononuclear phagocyte system. The studies conducted by Edwards53,54 proved informative when they exploited the Beige (bg) mouse, which harbors a homozygous mutation that confers the presence of giant lysosomes in macrophages. It was shown that normal mice, bone marrow depleted through irradiation, were rescued

with bone marrow cells obtained from the bg mouse. Elec­ tron microscopic analysis of the synovium from the recipi­ ent animals revealed that type A SLCs contained the giant lysosomes of the donor bg mouse, and that these structures were never identified in type B cells. These findings pro­ vided powerful evidence that the type A SLCs represent macrophages, that they are recruited from the bone mar­ row, and that they were unrelated histogenetically to type B SLCs. In addition to immunohistochemistry, several other lines of evidence have added weight to the concept that type A SLCs are recruited from the bone marrow: (1) The op/op mouse, a spontaneously occurring mutant that fails to produce macrophage colony-stimulating factor because of a missense mutation in the csf-1 gene,55-57 has low numbers of circulating and resident macrophage colony-­stimulating factor–dependent macrophages, including those in the synovium. (2) Type A cells in rat synovium do not occur until after the development of synovial blood vessels.22 (3) Others have reported that type A SLCs were conspicu­ ous around vessels in the synovium in neonatal mice.6 (4) When synovial explants are placed in culture, the reduction in the type A SLCs is partially explained by their migration into the culture medium, an observation that reflects the process of migration of macrophages into the synovial fluid in vivo.1,58 (5) Macrophages are found around venules in disease states and constitute 80% of the intimal cells in inflammatory conditions, such as rheuma­ toid arthritis. Type B intimal cells represent a resident fibroblast popu­ lation in the synovial lining, but little is known about the cells from which they derive, and how their recruitment is regulated. The existence of a mesenchymal stem cell in the synovium is a prime candidate for the origin of the syno­ vial lining fibroblast, but this has not been substantiated. To date, a transcription factor directing mesenchymal stem cell differentiation into synovial fibroblast, similar to the factors required for commitment by this multipotential population into bone (cbfa-1), cartilage (Sox 9), and fat (peroxisome proliferator-activated receptor γ [PPARγ]), has not been identified.

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SUBINTIMAL LAYER SLCs are not separated from the underlying subintima by a well-formed basement membrane composed of the typical trilaminar structure that is seen beneath epithelial mucosa elsewhere. Nevertheless, most components of basement membrane are present in the extracellular matrix surround­ ing SLCs. These components include tenascin X, perlecan (a heparin sulfate proteoglycan), collagen type 4, laminin, and fibrillin-1.59,60 Of note is the absence of laminin-5 and integrin α3β3γ2, which are components of epithelial hemidesmosomes.61 The subintima is composed of loose connective tissue of variable thickness and variable proportions of fibrous/col­ lagenous and adipose tissue depending on the anatomic site. Under normal healthy conditions, inflammatory cells are virtually absent from the subintima apart from a sprinkling of macrophages. A few mast cells also are present.62 Human synovial tissue also is a rich source of mesenchymal stem cells, and although it is unknown which compartment contains this cell population, some cells have the ability to self-renew, and differentiate into bone, cartilage, and fat in vitro, a phe­ nomenon that reflects its ability to regenerate in vivo.63-65

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There are three well-defined categories of subintima— the areolar, fibrous, and fatty/adipose types. Under the light microscope, areolar-type subintima, the most commonly studied, is generally found in larger joints where there is free movement (Fig. 2-5A). It is composed of fronds with a cel­ lular intimal lining and loose connective tissue in the sub­ intima, with little in the way of dense collagen fibers, and a rich vasculature. The fibrous subintima is composed of scant dense fibrous, poorly vascularized connective tissue and has an attenuated layer of SLCs (Fig. 2-5B). The adipose type contains abundant mature fat cells and has a single layer of SLCs. This is seen more commonly with aging and in intraarticular fat pads (Fig. 2-5C). The subintima contains collagen types I, III, V, and VI; glycosaminoglycans; proteoglycans; and extracellular matrices including tenascin and laminins. Integrin recep­ tors for collagens, laminin, and vitronectin are absent or at best weakly expressed by the subintimal cells. In con­ trast, receptors for fibronectin (CD49d and CD49e) are detected, and CD44, the HA receptor, is strongly expressed in most subintimal cells. β2 integrins are largely limited to perivascular areas, particularly in the subintimal zone, as is CD54.66

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Figure 2-5  Transmitted light photomicrographs of different morphologic types of synovial tissue. All photomicrographs show an intimal layer of one to two cells in depth. A, The areolar synovium is composed of villous fronds. Beneath the intimal lining layer, there is cellular loose fibrovascular fatty subintima. B, The fibrous synovium comprises dense collagenous material in the subintimal layer. C, The subintimal layer of the fatty synovial tissue is composed of less cellular mature adipose tissue with little collagen deposition.

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Subintimal Vasculature The vascular supply to the synovium is provided by many small vessels and is partly shared by the joint capsule, epiph­ yseal bone, and other perisynovial structures. Arteriovenous anastomoses communicate freely with the vascular supply to periosteum and to periarticular bone. As large synovial arteries enter the deep layers of the synovium near the cap­ sule, they branch, and branch again to form microvascular units in the more superficial subsynovial layers. Precapillary arterioles probably play a major role in controlling circula­ tion to the lining layer. The surface area of the synovial cap­ illary bed is large, and because it runs only a few cell layers deep to the surface, it has a role in trans-synovial exchange of molecules. Numerous physical factors influence synovial blood flow. Heat increases blood flow through synovial capillaries. Exer­ cise also increases synovial blood flow to normal joints, but may reduce the clearance rate of small molecules from the joint space. Experiments have shown a substantial vascu­ lar reserve capacity in normal articulations. Immobilization reduces synovial blood flow, and the pressure on synovial membrane from joint effusions can act to tamponade syno­ vial blood supply. The vascular endothelial lining cells express CD34 and CD31 (Fig. 2-6A). They also express receptors for the major components of basement membrane, including laminin and collagen IV, and the integrin receptors CD49a (laminin and collagen receptors), CD49d (fibronectin receptor), CD41, CD51 (vitronectin receptor), and CD61, the β3 integrin sub­ unit. Endothelial cells also express CD44, the HA receptor, and CD62, P-selectin, which acts as a receptor that supports binding of leukocytes to activated platelets and endothe­ lium. They are only weakly positive, however, for expres­ sion of CD54, intercellular adhesion molecule-1, an integral membrane protein of the immunoglobulin superfamily. The endothelial cells of capillaries in the superficial zone of the subintima are strongly positive for HLA-DR expression by immunohistochemistry, whereas cells in the larger vessels in the deep aspect of the membrane are negative.32,34 Subintimal Lymphatics Detailed analysis of the number and distribution of lym­ phatic vessels has been made possible with the use of the antibody to the lymphatic vessel endothelial HA ­receptor (LYVE-1) (Fig. 2-6B).67 This antibody is highly specific for lymphatic endothelial cells in lymphatic vessels and lymph node sinuses and does not react with endothelial cells of capillaries and other blood vessels that express CD34 and factor VIII–related antigen. The expression of LYVE-1 in lymphatic endothelial cells has been used as a marker to show that lymphatic vessels are less common in the fibrous synovium compared with the areolar and adipose variants of human subsynovial tissue. Detection of this molecule also reveals that lymphatics are present in the ­ superficial, intermediate, and deeper layers of synovial membrane from normal, osteoarthritic, and rheumatoid arthritic joints, although the number in the superficial subintimal layer is low in normal synovium. Little difference in the distribu­ tion and number is noted between normal and osteoarthritic synovium, where there is no villous ­hypertrophy. Lymphatic

channels are plentiful, however, in the subintimal layer in the presence of villous edema hypertrophy and chronic inflammation. Subintimal Nerve Supply The synovium has a rich network of sympathetic and sensory nerves. The former, which are myelinated and detected with the antibody against S100 protein, terminate close to blood vessels, where they regulate vascular tone (Fig. 2-6C, D, and E). The sensory nerves respond to proprioception and pain via large myelinated nerve fibers, and small (<5 μm), either unmyelinated or myelinated fibers with unmyelinated free nerve ends (nociceptors). The latter are immunoreactive in the synovium for neuropeptides, including substance P, calcitonin gene–related peptide, and vasoactive intestinal peptides.69,70

FUNCTION The known synthetic and protective functions of individual synovial cell populations are multiple and complex. The composite synovial structure, including the cell populations and their products, vasculature, nerves, and the intercellular matrix, possesses several specialized functions that are essen­ tial for normal joint movement, synovial fluid formation, chondrocyte nutrition, and cartilage protection at multiple anatomic locations. These functions must be preserved over a lifetime to maintain maximal mobility and independence. Absence of essential constituents of synovial fluid, or inad­ equate cartilage protection, results in early articular mal­ function, which may progress to local or generalized joint failure. JOINT MOVEMENT Three characteristics of the synovium are essential for joint movement—deformability, nonadherence, and cartilage lubrication. In health, the synovium is a highly deformable structure that facilitates movement between other adjacent, nondeformable structures within the joint. This unique facil­ ity of the synovium to enable movement between, rather than within, tissues has been emphasized,71 and can be attributed to the presence of a free surface that allows synovial tissue to remain separated from adjacent tissues. The ensuing space is maintained by the presence of synovial fluid. Deformability The deformability of normal synovium is considerable because it must accommodate the extreme positional range available to the joint and its adjacent tendons, ligaments, and capsule. When flexing a finger, the palmar synovium of each interphalangeal joint contracts, while the dorsal synovium expands, and as the finger extends, the reverse occurs. This normal contraction and expansion of synovium seems to involve a folding and unfolding component and an elastic stretching and relaxation of the tissue. It is essen­ tial that during repeated rapid movement, synovial lining does not become pinched between cartilage surfaces and can ­successfully retain its integrity and the integrity of the synovial blood vessels and lymphatics.

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Figure 2-6  Transmission light photomicrographs of synovium showing lymphovascular and nervous structures by immunohistochemistry. A and  B, Areolar synovium featuring thin-walled vessels are highlighted with antibody to CD31 (A), and lymphatic vessels in an inflamed synovium are  highlighted with antibody to LYVE-1 (B). C, Deep in the synovial subintima close to the joint capsule, there are medium-sized neurovascular bundles with the nerves highlighted by antibody to S100. D, Within the more superficial synovium, small nerves decorated with S100 also are identified. E, The boxed area in D is shown at higher magnification; upper arrow is nerve; lower arrow is directed at a small vessel.

Nonadherence The second important characteristic of the synovium that facilitates joint movement is its nonadherence to opposing surfaces. The intimal cells on the synovial surface adhere to underlying cells and matrix, but do not adhere to ­opposing

synovial and cartilage surfaces. The mechanism that pre­ serves this phenomenon of nonadherence is unknown and may involve the arrangement of cell surface and tissue matrix molecules, such as collagen, fibronectin, and HA. Alternatively, nonadherence may result partially from the regular movements of the normal synovial lining.

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Lubrication The third characteristic of synovium that is essential for joint motion is an efficient lubrication mechanism to facilitate cartilage movement on cartilage. The mechanisms of joint lubrication are complex and are an integral component of synovial physiology. In an articulating joint, cartilage is sub­ jected to numerous compressive and frictional forces every day. Friction and wear can never be eliminated from a func­ tioning joint. Adult chondrocytes do not normally divide in vivo, and damaged cartilage has limited capacity for selfrepair. For a joint to maintain its function throughout a life­ time of use, there must be protective biologic mechanisms, such as lubrication, which help minimize the wear and dam­ age that result from normal daily activities. Boundary lubrication refers to the protective effect of par­ ticular lubricating molecules adsorbing to a surface and repel­ ling its opposing interface.73 Bearing surfaces must generate a mutual repulsion to be lubricated in the boundary mode. Boundary lubricants exert their effects by changing the physi­ cochemical characteristics of a surface and reduce articular friction and wear by providing a smooth and slippery coating. Friction is reduced by an interposed film of protective fluid that allows one surface to ride freely over another. The carti­ lage matrix is integral to this phenomenon because it is fluidfilled and compressible. Loaded cartilage extrudes lubricant fluid from its surface, and the expressed fluid contributes to the separation of the two articulating surfaces. Scanning electron microscopy has shown a continuous film of fluid, only 100 nm thick, which separates one surface from the other, prevent­ ing direct abrasive contact.74 This ultrathin coating of lubri­ cant also resists distraction of the two articulating surfaces, enhancing joint stability. Another essential advantage of an intra-articular lubrication system is the effective prevention of pinching of adjacent, well-vascularized synovial membrane. Hyaluronic Acid HA, a high-molecular-weight polysaccharide, is a major component of synovial fluid and cartilage.75 It is produced in large amounts by mechanosensitive, fibroblast-like sy­noviocytes.76,77 HA, of which there are three mammalian forms designated HAS1, HAS2, and HAS3,78 is synthesized by HA synthase at the plasma membrane and extruded directly into the extracellular compartment. HA synthase activity and HA secretion are stimulated by proinflamma­ tory cytokines, including interleukin-1β and transforming growth factor-β.76,79,80 HA also is synthesized by many other skeletal cells and is an important component of extracellular matrices. It is simultaneously a solid phase matrix element of cartilage and other tissues, and a fluid phase element in the synovial space under normal and abnormal conditions. HA has many biologic functions, which include effects on cell growth, migration, and adhesion.72 The regulatory role of HA is mediated through HA-binding proteins and receptors, including CD44, which are present on the cell sur­ faces of chondrocytes, lymphocytes, and other mononuclear cell populations. HA plays a crucial role in morphogenesis and in wound healing. Additionally, HA is a vital structural component of the synovial lining, and it has an essential role in the induction of joint cavitation during embryogene­ sis. HA, produced by synovium, was originally thought to be

primarily a joint lubricant, and it is generally accepted that it plays a major physiologic role in maintaining synovial fluid viscosity. It is important in normal joint function, not least through its capacity to provide effective shock absorption. It has been suggested that HA is a particularly important viscohydrodynamic lubricant at low-load interfaces, such as synovium-on-synovium and synovium-on-cartilage.81 Syno­ vial fluid HA, acting in combination with albumin, also has a role in the attenuation of fluid loss from the joint cavity, particularly during periods of increased pressure, which can occur during sustained joint flexion.82-84 Lubricin. Compelling evidence suggests that lubricin, first described in the 1970s,85 is the factor primarily responsible for boundary lubrication of diarthrodial joints.86 Lubricin, a large secreted, mucin-like proteoglycan with an apparent molecular weight of 280 kD, is a product of the gene proteo­ glycan 4 (PRG4). It is a major component of synovial fluid and is present at the cartilage surface. The gene is highly ex­ pressed by human synovial fibroblasts and by superficial zone chondrocytes.87 Lubricin is closely related to superficial zone protein, megakaryocyte-stimulating factor, and hemangio­ poietin. Superficial zone protein is expressed by SLCs and by the superficial zone chondrocytes at the cartilage surface, but not by intermediate or deep zone chondrocytes.88 It has been suggested that lubricin may bind to the much longer hyaluronate polymers, distributing shear stress and stabiliz­ ing essential lubricant molecules.89 In an experimental model, lubricin seemed to have multi­ ple functions in articulating joints and tendons that included the protection of cartilage surfaces from protein deposition and cell adhesion and the inhibition of synovial cell over­ growth.90 Prg4−/− mice, consistently normal at birth, showed progressive loss of superficial zone chondrocytes and increas­ ing synovial cell hyperplasia (Fig. 2-7). The essential role of lubricin in maintaining joint integrity was shown by the iden­ tification of disease-causing mutations in patients with the autosomal recessive disorder ­ camptodactyly–­arthropathy– coxa vara–pericarditis (CACP) syndrome.91 CACP is a large joint arthropathy associated with the absence of lubri­ cin from synovial fluid and ineffective boundary lubrication provided by the synovial fluid (Fig. 2-8).89,92 In other studies of lubricin biology and joint integrity, experimental injury resulted in reduced synovial fluid lubricin concentrations, decreased boundary-lubricating ability, and increased carti­ lage matrix degradation, each of which could be attributed to trauma-induced inflammatory processes.87 Others have argued against the primacy of lubricin in joint lubrication by proposing that surface-active phos­ pholipid, also secreted by intimal fibroblasts, is the essen­ tial boundary lubricant that reduces cartilage friction to remarkably low levels.93 It was hypothesized that lubricin acts as the carrier of surface-active phospholipid to articular cartilage, but is not the lubricant per se, a function that is similar to the well-characterized alveolar surfactant binding proteins in the lung. FORMATION OF SYNOVIAL FLUID In health, a constant volume of synovial fluid is important during joint movement as a cushion for synovial tissue and as a reservoir of lubricant for cartilage. Many of the soluble

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–/–

Figure 2-7  Clinical appearance and radiographic changes in Prg4−/− mice. A and B, Photographs of the hind paws of 6-month-old Prg4−/− (A) and wildtype (B) mice. Note the curved digits in the mutant mouse and the swelling at the ankle joint. C and D, Radiographs of the ankle joint of 9-month-old wild-type (C) and Prg4−/− mice (D). The structures corresponding to the tibia (t) and talus (ta) are indicated. Note the calcification of structures adjacent to the ankle (arrows in D). E, Lateral knee x-ray of a 4-month-old wild-type mouse. The structures corresponding to the patella (p), femoral condyle (f), tibial plateau (t), and fibula (fib) are indicated. F, Lateral knee x-ray of a 4-month-old Prg4−/− mouse. Note the increased joint space between the patella and femur (arrow), and osteopenia of the patella, femoral condyles, and tibial plateau. G, Shoulder x-ray of a 4-month-old wild-type mouse. The structures corresponding to the humeral head (h), glenoid fossa of the scapula (s), and lateral portion of the clavicle (c) are indicated. H, Shoulder x-ray of a 4-month-old Prg4−/− mouse. Note the increased joint space between the humerus and scapula (arrow), and the osteopenia of the humeral head. (From Rhee DK, Marcelino J, Baker M, et al: The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth. J Clin Invest 115: 622-631, 2005.)

components and proteins in synovial fluid exit the syno­ vial microcirculation through pores or fenestrations in the vascular endothelium, then diffuse through the intersti­ tium before entering the joint space. Synovial fluid is par­ tially a filtrate of plasma to which additional components, including HA and lubricin, are added and removed by the SLCs (Fig. 2-9).72 The concentrations of electrolytes and small molecules in synovial fluid are equivalent to those in plasma. Synovial permeability to most small molecules is determined by a process of free diffusion through the double barrier of endothelium and interstitium, limited mainly by the intercellular space between the SLCs. For most small molecules, synovial permeability is inversely related to the dimensions of the molecule. Experimental evidence suggests that the exchange of small solutes is determined predominantly by the synovial inter­ stitium, and that permeability to proteins is mainly deter­ mined by the microvascular endothelium. The synovium should not be regarded as simply an inert membrane, but as a complex regulatory tissue system. The small physiologic molecules that traverse the endothelium of synovial blood vessels and diffuse through the intercellular spaces of the synovial lining before entering the synovial fluid include water, glucose, and many other essential nutrients and waste tissue metabolites. Evidence suggests that the passage of some solutes across the synovium is facilitated by specific transport systems providing, possibly, a “pump” mechanism capable of moving water out of the joint space.

All plasma proteins are capable of crossing the endothe­ lium, traversing the synovial interstitium, and entering the synovial fluid. The efficiency of this process is determined by the molecular size of the protein and the diameter of the endothelial pores. Smaller proteins, such as albumin, enter easily, whereas larger molecules, such as fibrinogen, gain access with greater difficulty. In contrast, the clear­ ance or removal of proteins and other synovial fluid con­ stituents is unrestricted, and considerably more efficient, through lymphatic drainage. The synovial fluid concentra­ tion of any protein reflects the dynamic balance between ingress and egress at a given time. Because egress is more efficient than ingress, joint space pressure is normally sub­ atmospheric. The negative intra-articular pressure also is thought to be important in maintaining joint stability. The synovial fluid-to-serum ratio of plasma proteins is inversely related to the molecular size of the protein. When the joint becomes inflamed, greater endothelial permeability permits more profuse ingress of all proteins, and the most obvi­ ous changes are in the concentrations of larger molecules. Increased synovial fluid volume also reduces the stability of the joint. In contrast to hydrophilic molecules, fat-soluble mole­ cules can diffuse through and between cell membranes, and their passage across the synovial surface is less restricted. The entire surface area of the synovium is available to lipo­ philic molecules that diffuse in and out of the joint space. Physiologically, the most important fat-soluble molecules

32

bresnihan 

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Synovium

A

B

C Figure 2-8  Clinical features of camptodactyly–arthropathy–coxa vara–pericarditis (CACP) syndrome. A, The characteristic deformity of the hands is shown. B, Chest x-ray shows an enlarged cardiac outline caused by pericarditis. C, X-ray of the pelvis highlights coxa vara in a boy with CACP. (B and C courtesy of Ronald Laxer, MD, Hospital for Sick Children, Toronto.) Synovium Sublining

Lining Matrix

Blood vessel Lymphatic Egress of SF components unrestricted

Synovial fluid

Cartilage

Hydrophillic molecules: water, electrolytes, glucose, proteins Lipophilic molecules: O2, CO2 Lubricants Hyaluronan Lubricin

hypoxia and acidosis can have serious implications for the synovial microcirculation and chondrocyte metabolism. NUTRITION OF CHONDROCYTES

Superficial zone chondrocytes

Figure 2-9  Schematic representation of the formation of synovial fluid. Many of the soluble components and proteins in synovial fluid exit the synovial subintimal microcirculation through pores or fenestrations in the vascular endothelium, then diffuse through the interstitium before entering the joint space. Synovial permeability to most small molecules is determined by a process of free diffusion through the double barrier of endothelium and interstitium, limited mainly by the intercellular space between the synovial lining cells. Fat-soluble molecules can diffuse through, and between, cell membranes, and their passage across the synovial surface is less restricted. Additional components, including hyaluranon and lubricin, are produced by the synovial lining cells.

are the respiratory gases—oxygen and carbon dioxide. When the joint is inflamed, synovial fluid may exhibit low partial pressure of oxygen, high partial pressure of carbon dioxide, decreased pH, and increased lactate production. The resultant

Another important function of synovium is to facilitate the nutrition of chondrocytes, which are resident in artic­ ular cartilage (see Chapter 3). Because articular cartilage is avascular, the delivery of nutrients to chondrocytes and the removal of metabolic breakdown products from the cartilage are believed to occur through the synovial fluid and the synovial tissue arterioles and venules.33 Morpho­ logic, physiologic, and pathologic studies have confirmed that solutes pass easily from the synovial fluid into carti­ lage, and that cartilage does not survive without synovial fluid contact in vivo. Within the cartilage matrix, three potential ­mechanisms for nutrient transfer have been pro­ posed—­diffusion, active transport by chondrocytes, and pumping by intermittent compression of cartilage matrix. A large proportion of hyaline cartilage lies within 50 μm of a synovial surface and its rich supply of blood vessels. Chondrocytes are oxygen sensitive and well adapted to liv­ ing in hypoxic conditions. Low oxygen tension promotes the expression of the chondrocyte phenotype and cartilagespecific matrix formation. Reactive oxygen species also may play a crucial role in the regulation of some normal chon­ drocytic activities, such as cell activation, proliferation, and matrix remodeling.

PART 1 

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STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

SUMMARY The normal human synovial membrane is a highly special­ ized, multifunctional organ that is vital for mobility, inde­ pendence, and survival. The intimal layer is composed of two distinct cell phenotypes with characteristics of macro­ phage and fibroblast lineages. Synovial macrophages express CD45, CD163 and CD97, CD68, neuron-specific esterase, and cathepsins B, L, and D. Cells expressing CD14 are rarely seen in the healthy intimal layer. FcγRIII (CD16), expressed by Kupffer cells of the liver and type II alveolar macrophages of the lung, is expressed on a subpopulation of synovial mac­ rophages. Synovial macrophages also express the MHC class II molecule, and play a central role in phagocytosis and in antigen-mediated immune responses. Synovial intimal fibroblasts possess prominent synthetic capacity and produce the essential joint lubricants HA and lubricin. They also synthesize normal matrix components, including fibronectin, laminin, collagens, proteoglycans, lubricin, and other identified and unidentified proteins. They have the capacity to produce large amounts of metal­ loproteinases, metalloproteinase inhibitors, prostaglandins, and cytokines. The expression of selected adhesion mole­ cules on synovial fibroblasts probably facilitates the traffick­ ing of some cell populations, such as polymorphs, into the synovial fluid, and the retention of others, such as mono­ nuclear leukocytes, in the synovial tissue. The subintimal layer is composed of a loose connective tissue matrix and contains branching blood and lymphatic vessels; a nerve supply; and a variety of resident cell popu­ lations, including infiltrating macrophages and fibroblasts. The nerve supply is important in regulating synovial blood flow. The lymphatic vessels allow egress of metabolic break­ down products from the synovium and synovial fluid. The morphology of the subintimal layer varies according to the anatomic location and local functional requirements. The coordinated functions of the composite synovial membrane are essential for normal joint movement, forma­ tion of synovial fluid, nutrition of chondrocytes, and protec­ tion of cartilage. These functions must be preserved over a lifetime at multiple anatomic locations. The absence of essential constituents of synovial fluid, such as lubricin, or inadequate cartilage protection results in early articular malfunction, which may progress to variable degrees of joint failure. The characteristics of lubricin deficiency have been elegantly described in animal models and in humans. Fur­ ther studies may define novel clinical categories of degen­ erative polyarthritis that are associated with other specific disorders of synovial membrane function. Acknowledgments The authors thank Suhel Miah, Institute of Orthopaedics and Musculo­ skeletal Science, and Bethany Crane and Steve Crane, Royal National Orthopaedic Hospital, for preparing many of the images included in this chapter.

REFERENCES   1. Nozawa-Inoue K, Takagi R, Kobayashi T, et al: Immunocytochemical demonstration of the synovial membrane in experimentally induced arthritis of the rat temporomandibular joint. Arch Histol Cytol 61:451-466, 1998.

33

  2. Vandenabeele F, Lambrichts I, Lippens P, et al: In vitro loading of human synovial membrane with 5-hydroxydopamine: Evidence for dense core secretory granules in type B cells. Arch Histol Cytol 64: 1-16, 2001.   3. Castor CW: The microscopic structure of normal human synovial tis­ sue. Arthritis Rheum 3:140-151, 1960.   4. Barland P, Novikoff A, Novikoff AB, et al: Electron microscopy of the human synovial membrane. J Cell Biol 14:207-220, 1962.   5. Krey PR, Cohen AS: Fine structural analysis of rabbit synovial cells in organ culture. Arthritis Rheum 16:324-340, 1973.   6. Okada Y, Nakanishi I, Kajikawa K: Ultrastructure of the mouse syno­ vial membrane: Development and organization of the extracellular matrix. Arthritis Rheum 24:835-843, 1981.   7. Groth HP: Cellular contacts in the synovial membrane of the cat and the rabbit: An ultrastructural study. Cell Tissue Res 164:525-541, 1975.   8. Roy S, Ghadially FN: Ultrastructure of normal rat synovial membrane. Ann Rheum Dis 26:26-38, 1967.   9. Wyllie JC, More RH, Haust MD: The fine structure of normal guinea pig synovium. Lab Invest 13:1254-1263, 1964. 10. Fell HB, Glauet AM, Barratt ME, et al: The pig synovium, I: The intact synovium in vivo and in organ culture. J Anat 122:663-680, 1976. 11. Watanabe H, Spycher MA, Ruttner JR, et al: Ultrastructural studies of rabbit synovitis induced by autologous IgG fragments, II: Infiltrating cells in the sublining layer. Scand J Rheumatol Suppl 15:15-22, 1976. 12. Linck G, Stoerkel ME, Petrovic A, et al: Morphological evidence of a polypeptide-like secretory function of the B cells in the mouse syno­ vial membrane. Experientia 33:1098-1099, 1977. 13. Johansson HE, Rejno S: Light and electron microscopic investigation of equine synovial membrane: A comparison between healthy joints and joints with intraarticular fractures and osteochondrosis dissecans. Acta Vet Scand 17:153-168, 1976. 14. Ghadially FN: Fine Structure of Joints. London, Butterworths, 1983. 15. Iwanaga T, Shikichi M, Kitamura H, et al: Morphology and functional roles of synoviocytes in the joint. Arch Histol Cytol 63:17-31, 2000. 16. Graabaek PM: Ultrastructural evidence for two distinct types of sy­noviocytes in rat synovial membrane. J Ultrastruct Res 78:321-339, 1982. 17. Graabaek PM: Characteristics of the two types of synoviocytes in rat synovial membrane: An ultrastructural study. Lab Invest 50:690-702, 1984. 18. Edwards JCW: Fibroblast biology: Development of differentiation of synovial fibroblasts in arthritis. Arthritis Res 2:344-347, 2000. 19. Athanasou NA: Synovial macrophages. Ann Rheum Dis 54:392-394, 1995. 20. Athanasou NA, Quinn J: Immunocytochemical analysis of human synovial lining cells: Phenotypic relation to other marrow derived cells. Ann Rheum Dis 50:311-315, 1991. 21. Athanasou NA, Quinn J, Heryet A, et al: The immunohistology of synovial lining cells in normal and inflamed synovium. J Pathol 155:133-142, 1988. 22. Izumi S, Takeya M, Takagi K, et al: Ontogenetic development of syno­ vial A cells in fetal and neonatal rat knee joints. Cell Tissue Res 262: 1-8, 1990. 23. Edwards JC: The nature and origins of synovium: Experimental approaches to the study of synoviocyte differentiation. J Anat 184: 493-501, 1994. 24. Lau SK, Chu PG, Weiss LM: CD163: A specific marker of macrophages in paraffin-embedded tissue samples. Am J Clin Pathol 122:794-801, 2004. 25. Tuijnman WB, van Wichen DF, Schuurman HJ: Tissue distribution of human IgG Fc receptors CD16. CD32 and CD64: An immunohisto­ chemical study. APMIS 101:319-329, 1993. 26. Edwards JCW, Blades S, Cambridge G: Restricted expression of Fc gammaRIII (CD16) in synovium and dermis: Implications for tis­ sue targeting in rheumatoid arthritis (RA). Clin Exp Immunol 108: 401-406, 1997. 27. Bhatia A, Blades S, Cambridge G, et al: Differential distribution of Fc gamma RIIIa in normal human tissues and co-localization with DAF and fibrillin-1: Implications for immunological microenvironments. Immunology 94: 56-63, 1998. 28. Walker MG: Z39Ig is co-expressed with activated macrophage genes. Biochem Biophys Acta 1574:387-390, 2002.

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29. Kim JK, Choi EM, Shin HI, et al: Characterization of monoclonal antibody specific to the Z39Ig protein, a member of immunoglobulin superfamily. Immunol Lett 99:153-161, 2005. 30. Lee MY, Kim WJ, Kang YJ, et al: Z39Ig is expressed on macrophages and may mediate inflammatory reactions in arthritis and atherosclero­ sis. J Leukoc Biol 80:922-928, 2006. 31. el-Gabalawy H, Canvin J, Ma GM, et al: Synovial distribution of alpha d/CD18, a novel leukointegrin: Comparison with other integrins and their ligands. Arthritis Rheum 39:1913-1921, 1996. 32. Demaziere A, Athanasou NA: Adhesion receptors of intimal and sub­ intimal cells of the normal synovial membrane. J Pathol 168:209-215, 1992. 33. Edwards JCW: The synovium. In Hochberg MC, Silman AJ, Smolen JS, et al (eds): Rheumatology, 3rd ed. Edinburgh, Mosby, 2003, pp 159-166. 34. Wilkinson LS, Pitsillides AA, Worrall JG, et al: Light microscopic characterization of the fibroblast-like synovial intimal cell (synovio­ cyte). Arthritis Rheum 35:1179-1184, 1992. 35. Johnson BA, Haines GK, Haclous LA, et al: Adhesion molecule expression in human synovial tissue. Arthritis Rheum 36:137-146, 1993. 36. Henderson KJ, Edwards JCW, Worrall JG: Expression of CD44 in nor­ mal and rheumatoid synovium and cultured fibroblasts. Ann Rheum Dis 53:729-734, 1994. 37. Stevens CR, Mapp PI, Revell PA: A monoclonal antibody (Mab 67) marks type B synoviocytes. Rheumatol Int 10:103-106, 1990. 38. Pitsillides AA, Wilkinson LS, Mehdizadeh S, et al: Uridine diphospho­ glucose dehydrogenase activity in normal and rheumatoid synovium: The description of a specialized synovial lining cell. Int J Exp Pathol 74:27-34, 1993. 39. Wilkinson LS, Edwards JD, Paston RN, et al: Expression of vascu­ lar cell adhesion molecule-1 in normal and inflamed synovium. Lab Invest 68:82-88, 1993. 40. Edwards JC, Wilkinson LS, Speight P, et al: Vascular cell adhesion molecule 1 and alpha 4 and beta 1 integrins in lymphocyte aggregates in Sjogren’s syndrome and rheumatoid arthritis. Ann Rheum Dis 52:806-811, 1993. 41. Valencia X, Higgins JM, Kiener HP, et al: Cadherin-11 provides specific cellular adhesion between fibroblast-like synoviocytes. J Exp Med 200:1673-1679, 2004. 42. Kiener HP, Brenner MB: Building the synovium: Cadherin-11 medi­ ates fibroblast-like synoviocyte cell-to-cell adhesion. Arthritis Res Ther 7:49-54, 2005. 43. Kitamura HP, Yanase H, Kitamura H, et al: Unique localization of pro­ tein gene product 9.5 in type B synoviocytes in the joints of the horse. J Histochem Cytochem 47:343–352, 1999. 44. Hamann J, Wishaupt JO, van Lier RA, et al: Expression of the activa­ tion antigen CD97 and its ligand CD55 in rheumatoid synovial tissue. Arthritis Rheum 42:650-658, 1999. 45. Hamann J, Vogel B, van Schijadel GM, et al: The seven-span trans­ membrane receptor CD97 has a cellular ligand (CD55, DAF). J Exp Med 184:1185-1189, 1996. 46. Kiener HP, Lee DM, Agarwal SK, et al: Cadherin-11 induces rheuma­ toid arthritis fibroblast-like synoviocytes to form lining layers in vitro. Am J Pathol 168:1486-1499, 2006. 47. Lee DM, Kiener HP, Agarwal SK, et al: Cadherin-11 in synovial lining formation and pathology in arthritis. Science 315:1006-1010, 2007. 48. Mohr W, Beneke G, Mohing W: Proliferation of synovial lining cells and fibroblasts. Ann Rheum Dis 34:219-224, 1975. 49. Lalor PA, Garcia CH, O’Rourke LM, et al: Proliferative activity of cells in the synovium as demonstrated by a monoclonal antibody, Ki67. Rheumatol Int 7:183-186, 1987. 50. Qu Z, Henderson B, Bitensky L, et al: Local proliferation of fibroblast-like synoviocytes contributes to synovial hyperplasia: Results of proliferating cell nuclear antigen/cyclin, c-myc, and nucleolar organizer region stain­ ing. Arthritis Rheum 37:212-220, 1994. 51. Coulton LA, Coates PJ, Ansari B, et al: DNA synthesis in human rheumatoid and nonrheumatoid synovial lining. Ann Rheum Dis 39:241-247, 1980. 52. Hall PA, Edwards JC, Willoughby DA, et al: Regulation of cell num­ ber in the mammalian gastrointestinal tract: The importance of apop­ tosis. J Cell Sci 107:3569-3577, 1994. 53. Edwards JC, Willoughby DA: Demonstration of bone marrow derived cells in synovial lining by means of giant intracellular granules as genetic markers. Ann Rheum Dis 41:177-182, 1982.

54. Edwards JC: The nature and origin of synovium: Experimental approach to the study of synoviocyte differentiation. J Anat 184: 493-501, 1994. 55. Yoshida H, Cecchini MG, Fleisch H, et al: The murine mutation osteopetrosis is in the coding region of the macrophage colony stimu­ lating factor gene. Nature 345:442-444, 1990. 56. Felix R, Cecchini MG, Fleisch H: Macrophage colony stimulating fac­ tor restores in vivo bone resorption in the op/op osteopetrotic mouse. Endocrinology 127:2592-2594, 1990. 57. Naito M, Palmer DG, Revell PA, et al: Abnormal differentiation of tissue macrophage populations in ‘osteopetrosis’ (op) mice defec­ tive in the production of macrophage colony-stimulating factor. Am J Pathol 139:657-667, 1991. 58. Hogg N, Palmer DG, Revell PA: Mononuclear phagocytes of normal and rheumatoid synovial membrane identified by monoclonal antibodies. Immunology 56:673-681, 1985. 59. Li TF, Boesler EW, Jimenez SA, et al: Distribution of tenascin-X in different synovial samples and synovial membrane-like interface tis­ sue from aseptic loosening of total hip replacement. Rheumatol Int 19:177-183, 2000. 60. Dodge GR, Boesler EW, Jimenez SA: Expression of the basement mem­ brane heparan sulfate proteoglycan (perlecan) in human synovium and in cultured human synovial cells. Lab Invest 73:649-657, 1995. 61. Konttinen YT, Hoyland JA, Denton J, et al: Expression of laminins and their integrin receptors in different conditions of synovial mem­ brane and synovial membrane-like interface tissue. Ann Rheum Dis 58:683-690, 1999. 62. Dean G, Kruetner A, Ferguson AB, et al: Mast cells in the synovium and synovial fluid in osteoarthritis. Br J Rheumatol 32:671-675, 1993. 63. Bentley G, Kreutner A, Ferguson AB: Synovial regeneration and articular cartilage changes after synovectomy in normal and steroidtreated rabbits. J Bone Joint Surg (Br) 57:454-462, 1975. 64. De Bari C, Sekiya I, Yagishita K, et al: Multipotent mesenchymal stem cell from adult human synovial membrane. Arthritis Rheum 44:1928-1942, 2001. 65. Sakaguchi Y, Athanasou NA: Comparison of human stem cells derived from various mesenchymal tissues: Superiority of synovium as a cell source. Arthritis Rheum 52:2521-2529, 2005. 66. Demaziere A, Athanasou NA: Adhesion receptors of intimal and sub­ intimal cells of the normal synovial membrane. J Pathol 168:209-215, 1992. 67. Xu H, Edwards J, Banerji S, et al: Distribution of lymphatic vessels in normal and arthritic human synovial tissues. Ann Rheum Dis 62:1227-1229, 2003. 68. Deleted in press. 69. Bohnsack M: Distribution of substance-P nerves inside the infrapa­ tellar fat pad and the adjacent synovial tissue: A neurohistological approach to anterior knee pain syndrome. Arch Orthop Trauma Surg 125:592-597, 2005. 70. McDougall JJ: Arthritis and pain: Neurogenic origin of joint pain: A review. Arthritis Res Ther 10:220-230, 2006. 71. Henderson B, Edwards JCW: Functions of synovial lining. In The Synovial Lining in Health and Disease. London, Chapman & Hall, 1987, pp 41-74. 72. Deleted in press. 73. Mazzucco D, Spector M: The role of joint fluid in the tribology of total joint arthroplasty. Clin Orthop 429:17-32, 2004. 74. Clark JM, Norman AG, Kaab MJ, et al: The surface contour of articu­ lar cartilage in an intact, loaded joint. J Anat 195:45-56, 1999. 75. Prehm P: Hyaluronan. In Steinbuchel A (ed): Biopolymers. Wein­ heim, Whiley-VCH-Verlag, 2002, pp 379-400. 76. Momberger TS, Levick JR, Mason RM: Hyaluronan synthesis by rab­ bit synoviocytes is mechanosensitive. Matrix Biol 24:510-519, 2005. 77. Momberger TS, Levick JR, Mason RM: Mechanosensitive synovio­ cytes: A Ca2+-PKCα-MAP kinase pathway contributes to stretchinduced hyaluronan synthesis in vitro. Matrix Biol 25:306-316, 2006. 78. Weigel PH, Hascall VC, Tammi M: Hyaluronan synthases. J Biol Chem 272:13997-14000, 1997. 79. Recklies AD, White C, Melching L, et al: Differential regulation and expression of hyaluronan in human articular cartilage, synovial cells and osteosarcoma cells. Biochem J 354:17-24, 2001. 80. Tanimoto K, Itoh H, Sagawa N, et al: Cyclic mechanical stretch regu­ lates the gene expression of hyaluronic acid synthetase in cultured rab­ bit synovial cells. Connect Tissue Res 42:187-195, 2001.

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STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

81. Murakami T, Higaki H, Sawae Y, et al: Adaptive multimode lubrica­ tion in natural synovial joints and artificial joints. Proc Inst Mech Eng 212:23-35, 1998. 82. Levick JR: Fluid movement across synovium in healthy joints: Role of synovial fluid macromolecules. Ann Rheum Dis 54:417-423, 1995. 83. Scott D, Coleman PJ, Mason RM, et al: Molecular reflection by syno­ vial lining is concentration dependent and reduced in dilute effusions in a rabbit model. Arthritis Rheum 43: 1175-1182, 2000. 84. Sabaratnam S, Mason RM, Levick JR: Hyaluranon molecular reflection by synovial lining is concentration dependent and reduced in dilute effusions in a rabbit model. Arthritis Rheum 54:1673-1681, 2006. 85. Swann DA, Sotman S, Dixon M, et al: The isolation and partial char­ acterization of the major glycoprotein from the articular lubricating fraction from bovine synovial fluid. Biochem J 161:473-485, 1977. 86. Jay GD, Britt DE, Cha C-J: Lubricin is a product of megacaryocyte stimulating factor gene expression by human synovial fibroblasts. J Rheumatol 27:594-600, 2000. 87. Elsaid KA, Jay GD, Warman ML, et al: Association of articular car­ tilage degradation and loss of boundary-lubricating ability of synovial fluid following injury and inflammatory arthritis. Arthritis Rheum 52:1746-1755, 2005.

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88. Schumacher BL, Hughes CE, Kuettner KE, et al: Immunodetection and partial cDNA sequence of the proteoglycan, superficial zone protein, synthesized by cells lining synovial joints. J Bone Joint Surg 17:110-120, 1999. 89. Jay GD, Tantravahi U, Britt DE, et al: Homology of lubricin and superficial zone protein (SZP): products of megacaryocyte stimulating factor (MSF) gene expression by human synovial fibroblasts and artic­ ular chondrocytes localized to chromosome 1q25. J Orthop Res 19: 677-687, 2001. 90. Rhee DK, Marcelino J, Baker M, et al: The secreted glycoprotein lubri­ cin protects cartilage surfaces and inhibits synovial cell overgrowth. J Clin Invest 115:622-631, 2005. 91. Marcelino J, Carpten JD, Suwairi WM, et al: CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Nat Genet 23:319-322, 1999. 92. Rhee DK, Marcelino J, Sulaiman A-M, et al: Consequences of diseasecausing mutations on lubricin protein synthesis, secretion, and posttranslational processing. J Biol Chem 280:31325-31332, 2005. 93. Hills BA, Crawford RW: Normal and prosthetic synovial joints are lubricated by surface-active phospholipids: A hypothesis. J Arthro­ plasty 18:499-505, 2003.

3

Cartilage and Chondrocytes Mary B. Goldring

KEY POINTS Articular cartilage matrix is heterogeneous and contains numerous extracellular matrix (ECM) proteins, of which the large aggregating proteoglycan aggrecan and collagen types II, IX, and XI are the major constituents. The collagen network of cartilage confers tensile strength, and aggrecan provides resistance to compression. Adult articular chondrocytes are nonmitotic cells that survive at low oxygen tension in the absence of a vascular supply. In response to trauma or inflammation, the metabolic activity of the chondrocyte is increased in response to catabolic and anabolic factors that regulate remodeling of the ECM. Under physiologic conditions, the chondrocyte maintains low-turnover repair of proteoglycans, but the repair capacity, responses to anabolic factors, cell survival, and quality of the matrix decline with age.

Hyaline cartilage, including the articular cartilage of diarthrodial joints, consists of a single cellular component, the chondrocyte, which is embedded in a unique and complex matrix. Adult articular chondrocytes are considered to be fully differentiated cells that maintain matrix constituents in a low-turnover state of equilibrium. Chondrocytes serve diverse functions during development and postnatal life. In the embryo, the chondrocyte arises from mesenchymal progenitors from diverse sources, including the cranial neural crest of the neural ectoderm, cephalic mesoderm, sclerotome of the paraxial mesoderm, and somatopleure of the lateral plate mesoderm. The chondrocyte synthesizes the templates, or cartilage anlagen, for the developing limbs in a process termed chondrogenesis. After mesenchymal condensation and chondroprogenitor cell differentiation, the chondrocytes undergo proliferation, terminal differentiation to chondrocyte hypertrophy, and apoptosis in a process termed endochondral ossification, whereby the hypertrophic cartilage is replaced by bone. A similar sequence of events occurs in the postnatal growth plate and leads to rapid growth of the skeleton. The processes that control the different stages of skeletal development are described in Chapter 1. In adults, the anatomic distribution of cartilage is restricted primarily to the joints, trachea, and nasal septum, where the major function is structural support. In joints, cartilage has the additional function of providing low-friction articulation. Adult articular cartilage comprises a specialized matrix of collagens, proteoglycans, and other cartilage-­specific and nonspecific proteins. Adult articular chondrocytes, remnants of the resting, or reserve, chondrocytes that laid down the original cartilage matrix during

chondrogenesis, are inactive metabolically, owing partially to the absence of a vascular supply and innervation in the tissue.1 The clinical importance of the adult chondrocyte resides in its capacity to respond to mechanical stimuli, growth factors, and cytokines that may influence normal homeostasis in a positive or negative manner. In rheumatoid arthritis (RA), cartilage destruction occurs primarily in areas contiguous with the proliferating synovial pannus, although there is evidence that the chondrocyte can respond to the inflammatory milieu and participate in degrading its own matrix.2 In osteoarthritis, the chondrocyte plays a key role by reacting to structural changes in the surrounding cartilage matrix through the production of catabolic cytokines and anabolic factors, which act in an autocrine-paracrine manner.3,4 Nevertheless, the chondrocyte has limited capacity, which declines with age, to regenerate the normal cartilage architecture with the zonal variations in the matrix network that was formed originally. This chapter focuses on the structure and function of normal articular cartilage and the role of the chondrocyte in maintaining cartilage homeostasis and responding to adverse environmental insults that may modify cartilage integrity.

CARTILAGE STRUCTURE Normal articular cartilage is a specialized tissue characterized macroscopically by its milky, shelled-almond (hyaline) appearance. It is an avascular tissue nourished by diffusion from the vasculature of the subchondral bone and from the synovial fluid. Articular cartilage is more than 70% water, and it is hypocellular compared with other tissues; chondrocytes constitute only 1% to 2% of its total volume.5-7 Most of the dry weight of cartilage consists of two components: type II collagen and the large aggregating proteoglycan, aggrecan. Several “minor” collagens and small proteoglycans also seem to play a role in cartilage-matrix organization, however.8,9 Organic constituents represent only about 20% of the wet weight. Collagen, primarily type II, accounts for approximately 15% to 25% of the wet weight and about half of the dry weight except in the superficial zone, where it represents most of the dry weight. Proteoglycans, primarily aggrecan, account for 10% of the wet weight and about 25% of the dry weight. The highly cross-linked type II collagen–containing fibrils form a systematically oriented network that traps the highly negatively charged proteoglycan aggregates.10 Histochemical analysis of cartilage shows that proteoglycans can be stained reliably with safranin O, toluidine blue, or alcian blue, although at low substrate concentrations, these methods are not stoichiometric.11 Collagen also can be stained efficiently, but differentiation of collagen types requires imm­ unostaining with specific antibodies. 37

38

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Cartilage and Chondrocytes

Articular surface Superficial zone

Superficial cell protein (also known as lubricin) Decorin and biglycan Pericellular region (decorin, type VI collagen)

Middle zone

Territorial region (more intact aggrecan)

Deep zone Aggrecan most concentrated and collagen content at its lowest here

Interterritorial region (degraded aggrecan)

Tidemark Type X collagen Calcified zone Hypertrophic chondrocyte Subchondral bone Subchondral bone marrow Figure 3-1  The structure of human adult articular cartilage, showing the zones of cellular distribution and the pericellular, territorial, and interterritorial regions of matrix organization. Insets show the relative diameters and orientations of collagen fibrils in the different zones. The positions of the tidemark and subchondral bone and other special features of matrix composition also are noted. (From Poole AR, Kojima T, Yasuda T, et al: Composition and structure of articular cartilage: A template for tissue repair. Clin Orthop 391S:S26-S33, 2001. Copyright Lippincott Williams & Wilkins.)

Despite its thinness (≤7 mm) and apparent homogeneity, mature articular cartilage is a heterogeneous tissue with four distinct regions: (1) the superficial tangential (or gliding) zone, (2) the middle (or transitional) zone, (3) the deep (or radial) zone, and (4) the calcified cartilage zone, which is located immediately below the tidemark and above the subchondral bone (Fig. 3-1).7,10,12,13 In the superficial zone, the chondrocytes are flattened, and the matrix comprises thin collagen fibrils in tangential array, associated with a high concentration of the small proteoglycan decorin and a low concentration of aggrecan. The middle zone, composing 40% to 60% of the cartilage weight, consists of rounded chondrocytes surrounded by radial bundles of thick collagen fibrils. In the deep zone, the chondrocytes frequently are grouped in columns or clusters (Fig. 3-2). In this region, the collagen bundles are the thickest and are arranged in a radial fashion.

The cell density progressively decreases from the surface to the deep zone, where it is one half to one third of the density in the superficial zone14; the chondrocytes in the deep and middle zones have a cell volume that is twice that of the superficial chondrocytes.15 Water is 75% to 80% of the wet weight in the superficial zone and progressively decreases to 65% to 70% with increasing depth. Greater amounts of collagen relative to proteoglycans are present in the superficial zone, compared with the middle and deep zones, and type I collagen may be synthesized in addition to type II collagen.16,17 With increasing depth, the proportion of proteoglycan increases to 50% of the dry weight in the deep zone.15,18-20 The calcified zone is formed as a result of endochondral ossification and persists after growth plate closure as the tidemark.21 The calcified zone serves as an important mechanical buffer between the uncalcified articular cartilage and the subchondral bone.

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S T

U

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in cartilage abnormalities.27-32 Deficiencies or disruptions in genes that encode the cartilage-specific collagens result, in some cases, in premature osteoarthritis.32 Knowledge of the composition of the cartilage matrix has permitted the development of methods for identifying molecular markers in serum and synovial fluid that can be used to monitor changes in cartilage metabolism and to assess cartilage damage in osteoarthritis or RA.33-36 Changes in the structural composition of cartilage can markedly affect its biomechanical properties (see Chapter 6). CARTILAGE COLLAGENS

L

M B 1 Figure 3-2  Light micrograph of vertically sectioned adult human cartilage (femoral condyle), illustrating its subdivision into superficial (S), transitional (T), upper radial (U), lower radial (L), and calcified cartilage (M) zones; the last-mentioned abuts on the subchondral bone plate (B). Saw-cut, 100-μm thick, surface-stained with basic fuchsin, McNeil’s tetrachrome, and toluidine blue O. (From Hunziker EB: Articular cartilage structure in humans and experimental animals. In Kuettner KE, Schleyerbach R, Peyron JG, et al [eds]: Articular Cartilage and Osteoarthritis. New York, Raven, 1992, pp 183-199.)

The physical properties of articular cartilage are determined by the unique fibrillar collagen network, which provides tensile strength, interspersed with proteoglycan aggregates that bestow compressive resilience.22-24 The proteoglycans are ass­ociated with large quantities of water bound to the hydrophilic glycosaminoglycan chains. This cartilaginous extracellular matrix (ECM), with its tightly bound water, provides a high degree of resistance to deformation by compressive forces. The capacity to resist compressive forces is associated with the ability to extrude water as the cartilage compresses. When the compression is released, the proteoglycans (now depleted of balancing counter ions that were removed with the water) contain sufficient fixed charge to reabsorb osmotically the water and small solutes into the matrix, which then rebounds to its original dimensions.25,26

STRUCTURE-FUNCTION RELATIONSHIPS OF CARTILAGE MATRIX COMPONENTS The ECM components synthesized by chondrocytes include highly cross-linked fibrils of triple-helical type II collagen molecules that interact with other collagens, aggrecan, small proteoglycans, and other cartilage-specific and nonspecific matrix proteins (Table 3-1).6,8,9,12 The importance of these structural proteins may be observed in heritable disorders, such as chondrodysplasias, or in transgenic animals in which mutations or deficiencies in cartilage genes result

The major component of the collagen network in adult articular cartilage is the triple-helical type II collagen molecule, which is composed of three identical α chains, [α1(II)]3. These molecules are assembled in fibrils in a quarter-­stagger array that can be observed by electron microscopy.8,37,38 These fibrils are thinner than the type I collagen–containing fibrils in skin because of the higher numbers of hydroxylysine residues that can form cross-links and the presence of other collagen and noncollagen components in the fibril. The type IIB collagen in articular cartilage is a product of alternative splicing and lacks a 69-amino acid, cysteine-rich domain of the amino-terminal propeptide, which is encoded by exon 2 in the human type II collagen gene (COL2A1).39 This domain is found in type IIA procollagen, which is expressed by chondroprogenitor cells during development, and in the amino propeptides of other interstitial collagen types, and may play a feedback-inhibitory role in collagen biosynthesis. The reappearance of type IIA collagen in the midzone pericellular matrix and type X collagen, the hypertrophic chondrocyte marker, in the deep zone of osteoarthritis cartilage suggests reversion to a developmental phenotype as an attempt to repair the damaged matrix.40,41 Although collagen types VI, IX, XI, XII, and XIV are quantitatively minor components, they may have important structural and functional properties. Types IX and XI are specific to cartilage, whereas types VI, XII, and XIV are widely distributed in other connective tissues.8 Type VI collagen, which is present in cartilage as microfibrils in very small quantities in the pericellular matrix, may play a role in cell attachment and interacts with other matrix proteins, such as hyaluronan, decorin, and biglycan. There are small amounts of type III collagen in cartilage, and type III and type VI collagens may increase in osteoarthritis cartilage.41 Type IX collagen is a proteoglycan and a collagen because it contains a chondroitin sulfate chain attachment site in one of the noncollagen domains. The helical domains of the type IX collagen molecule form covalent cross-links with type II collagen telopeptides and are attached to the fibrillar surface, as observed by the electron microscope. Type IX collagen may function as a structural intermediate between type II collagen fibers and the proteoglycan aggregates, serving to enhance the mechanical stability of the fibril network and resist the swelling pressure of the trapped proteoglycans. Destruction of type IX collagen accelerates cartilage degradation and loss of function.8,41 The α3 chain of type XI collagen has the same primary sequence as the α1(II) chain, and the heterotrimeric type XI collagen molecule is buried in the same fibril as type II collagen. Type XI collagen may have a role in regulating fibril

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Table 3-1  Extracellular Matrix Components of Cartilage Molecule

Structure and Size

Function and Location

Type XI Type VI

[α1(II)]3; fibril-forming [α1(IX)α2(IX)α3(IX)]; single CS or DS chain;   α1(II) gene encodes α3(IX); FACIT [α1(XI)α2(XI)α3(XI)]; fibril-forming [α1(VI)α2(VI)α3(VI)]; microfibrils

Type X

[α1(X)]3; hexagonal network

Type XII

[α1(XII)]3; FACIT large cruciform NC3 domain

Type XIV Type XVI Type XXVII

[α1(XIV)]3; FACIT [α1(XVI)]3; FACIT Col27a1 gene: 156 kb, 61 exons

Tensile strength; major component of collagen fibrils Tensile properties, interfibrillar connections; cross-links to surface of collagen fibril, NC4 domain projects into matrix Nucleation/control of fibril formation; within collagen fibril Forms microfibrillar network, binds hyaluronan, biglycan, ­decorin; pericellular Support for endochondral ossification; hypertrophic zone and ­calcified cartilage Associated with collagen I fibrils in perichondrium and articular surface Associated with type I collagen; superficial zone Integrates with collagen II/XI fibrils Fibril-forming; developing cartilage

Collagens Type II Type IX

Proteoglycans Aggrecan Versican Perlecan Biglycan Decorin Asporin Fibromodulin Lumican PRELP Chondroadherin

255-kD core protein; CS/KS side chains;   C-terminal EGF and lectin-like domains 265-370 kD core protein; CS/DS side chains;   C-terminal EGF, C-type lectin, and CRP-like ­domains 400-467 kD core protein; HS/CS side chains; no   HA-binding 38 kD; LRR core protein with two DS chains (76 kD) 36.5 kD; LRR core protein with one CS or   DS side chain (100 kD) 40 kD; LRR core protein; N-terminal extension of 15 aspartate residues 42 kD; containing KS chains in central LRR region and N-terminal tyrosine sulfate domains 38 kD; structure similar to fibromodulin 44 kD; LRR core protein; proline-rich and   arginine-rich N-terminal binding domain   for heparin and HS 45 kD; LRR core protein without N-terminal   extension

Compressive stiffness through hydration of fixed charge density; ­binding through G1 domain to HA stabilized by link protein Low levels in articular cartilage throughout life; calcium-binding and selectin-like properties

1000-3000 kD

Retention of aggrecan within matrix

38.6 kD 550 kD; five 110-kD subunits;   thrombospondin-like Three 50-kD subunits with vWF and EGF domains

Stabilizes attachment of aggrecan G1 domain to HA Interterritorial in articular cartilage; stabilizes collagen network or promotes collagen fibril assembly; calcium binding Tightly bound to aggrecan in immature cartilage

92 kD; homology with nucleotide ­pyrophosphohydrolase without active site 39 kD; chitinase homology

Restricted to middle/deep zones of cartilage; increase in early and late osteoarthritis Marker of cartilage turnover; chondrocyte proliferation; ­superficial zone of cartilage

Dimer of 220-kD subunits

Cell attachment and binding to collagen and proteoglycans; increased in osteoarthritis cartilage Binds syndecan-3 during chondrogenesis; angiogenesis

Cell-matrix adhesion; pericellular Binds collagen VI and TGF-β; pericellular Controls size/shape of collagen fibrils, binds collagen II and   TGF-β; interterritorial Binds collagen, modulates TGF-β function Same as decorin Same as decorin Mediates cell binding through HS sulfate in syndecan Binding to cells via α2β1 integrin

Other Molecules Hyaluronic acid   (HA; hyaluronan) Link protein Cartilage oligomeric ­matrix protein (COMP) Cartilage matrix ­protein (CMP, or matrilin-1); ­matrilin-3 Cartilage ­intermediate layer protein (CILP) Glycoprotein (gp)-39,   YKL-40, or chitinase   3-like protein 1 (CH3L1) Fibronectin Tenascin-C Superficial zone ­protein (SZP), ­lubricin, or ­proteoglycan (PRG) 4

Six 200-kD subunits forming hexabrachion   structure 225 kD, 200 nm length

Joint lubrication; superficial zone only

Membrane Proteins CD44 Syndecan-3 Anchorin CII   (or annexin V) Integrins (α1, α2, α3, α5, α6, α10; β1, β3, β5) Discoidin domain   receptor 2

Integral membrane protein with extracellular   HS/CS side chains N-terminal HS attachment site; cytoplasmic tyrosine residues 34 kD; homology to calcium-binding proteins   calpactin and lipocortin Two noncovalently linked transmembrane   glycoproteins (α and β subunits) Receptor tyrosine kinase

Cell-matrix interactions; binds HA Receptor for tenascin-C during cartilage development; cell-matrix interactions Cell surface attachment to type II collagen; calcium binding Cell-matrix binding: α1β1/collagen 1 or VI, α2β1 or α3β1/collagen II, α5β1/fibronectin; intracellular signaling Binds native type II collagen fibrils; Ras/ERK signaling

CRP, complement regulatory protein; CS, chondroitin sulfate; DS, dermatan sulfate; EGF, epidermal growth factor; FACIT, fibril-associated collagens with interrupted triple helices; HA, hyaluronic acid; HS, heparan sulfate; KS, keratan sulfate; LRR, leucine-rich repeat; NC, noncollagen; PRELP, proline-rich and arginine-rich end leucine-rich repeat protein; TGF, transforming growth factor; vWF, von Willebrand factor.

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diameter. The more recently discovered nonfibrillar fibrilassociated collagens with interrupted triple helices, XII and XIV, which are structurally related to type IX collagen, do not form fibrils by themselves, but coaggregate with fibrilforming collagens and modulate the packing of collagen fibers by domains projecting from their surfaces.8,37,38 CARTILAGE PROTEOGLYCANS The major proteoglycan in articular cartilage is the large aggregating proteoglycan, or aggrecan, which consists of a core protein of 225 to 250 kD with covalently attached side chains of glycosaminoglycans, including approximately 100 chondroitin sulfate chains, 30 keratan sulfate chains, and shorter N-linked and O-linked oligosaccharides.6,9,42,43 Link protein, a small glycoprotein, stabilizes the noncovalent linkage between aggrecan and hyaluronic acid (also called hyaluronan) to form the proteoglycan aggregate that may contain 100 aggrecan monomers. The G1 and G2 N-terminal globular domains of aggrecan and its C-terminal G3 domain have distinct structural properties that function as integral parts of the aggrecan core protein and as cleavage products that accumulate with age or in osteoarthritis. The G2 domain is separated from G1 by a linear interglobular domain and has two proteoglycan tandem repeats, but it does not bind to hyaluronic acid. The G3 domain contains sequence homologies to epidermal growth factor, lectin, and complement regulatory protein, and it participates in growth regulation; cell recognition; intracellular trafficking; and the recognition, assembly, and stabilization of the ECM. About half of the aggrecan molecules in adult cartilage lacks the G3 domain, probably as a result of proteolytic cleavage during matrix turnover. Small amounts of other large proteoglycans are found in cartilage, including versican, which forms aggregates with hyaluronic acid, and perlecan, which is nonaggregating; however, these proteoglycans function primarily during skeletal development, where versican is expressed in prechondrogenic condensations, and perlecan is expressed in the cartilage anlagen after expression of type II collagen and aggrecan.43 The nonaggregating small proteoglycans are not specific to cartilage, but in cartilage they may serve important roles in matrix structure and function, primarily by modulating collagen-fibril formation.44-46 Of the more than 10 leucine-rich repeat (LRR) proteoglycans discovered so far, only osteoadherin is not present in cartilage. The 24-amino acid central LRR domain is conserved, but the N-terminal and C-terminal domains have patterns of cysteine residues involved in intrachain disulfide bonds that distinguish the four subfamilies: (1) biglycan, decorin, fibromodulin, and lumican; (2) keratocan and proline and arginine-rich end leucine-rich repeat protein (PRELP); (3) chondroadherin; and (4) epiphycan/PG-Lb and mimecan/osteoglycin. Biglycan has two glycosaminoglycan chains, either chondroitin sulfate or dermatan sulfate, or both, attached near the N-terminus through two closely spaced serine-glycine dipeptides. Decorin contains only one chondroitin sulfate or dermatan sulfate chain. Fibromodulin and lumican contain keratan sulfate chains linked to the central domain of the core protein and several sulfated tyrosine residues in the N-terminus. The negatively charged glycosaminoglycan

41

side chains contribute to fixed charge density of the matrix and, together with the highly anionic tyrosine-sulfation sites, permit multiple-site linkage between adjacent collagen fibrils, stabilizing the network. Decorin, the most extensively studied LRR proteoglycan, binds to several collagens present in cartilage, including types II, VI, XII, and XIV, and to fibronectin and thrombospondin. Biglycan, decorin, and fibromodulin bind transforming growth factor (TGF)-β and the epidermal growth factor receptor and may modulate growth, remodeling, and repair. PRELP and chondroadherin may regulate cell-matrix interactions through binding to syndecan and α2β1 integrin. OTHER EXTRACELLULAR MATRIX AND CELL SURFACE PROTEINS Several other noncollagenous matrix proteins may play important roles in determining cartilage matrix integrity. Cartilage oligomeric protein (COMP), a member of the thrombospondin family, is a disulfide-bonded, pentameric, 550-kD, calcium-binding protein that constitutes approximately 10% of the noncollagenous, nonproteoglycan protein in normal adult cartilage. COMP is located in the interterritorial matrix of adult articular cartilage where it interacts with the col3 and NC4 domains of type IX collagen that protrude from the fibril, stabilizing the collagen network. COMP is pericellular in the proliferating region of the growth plate, where it may have a role in cell-matrix interactions.47 The cartilage matrix protein (or matrilin-1) and matrilin-3 are expressed in cartilage at certain stages of development and are present in tracheal cartilage, but not in mechanically loaded adult articular or intervertebral disk cartilage.48,49 Tenascin-C, a glycoprotein that is regulated in development, is characteristic of nonossifying cartilage.50 Similar to fibronectin, alternative splicing of tenascin-C mRNA gives rise to different protein products at different stages of chondrocyte differentiation. Both proteins are increased in osteoarthritis cartilage and may serve specific functions in remodeling and repair. A splice variant of tenascin-C mRNA is found in chondrosarcomas.51 The cartilage intermediate-layer protein is expressed by chondrocytes in the middle to deep zones of articular cartilage as a precursor protein. When cleaved during secretion, cartilage intermediatelayer protein has structural similarities with nucleotide pyrophosphohydrolase, although it lacks the catalytic site, and it may play a role in pyrophosphate metabolism and calcification.52,53 Asporin is related to decorin and ­biglycan and, similar to those other LRR proteins, may interact with and sequester growth factors such as TGF-β.54-56 YKL-40/ HC-gp39, also known as chitinase 3-like protein 1, is found only in the superficial zone of normal cartilage and stimulates proliferation of chondrocytes and synovial cells.57 Chitinase 3-like protein 1 is induced by inflammatory cytokines and may function as a feedback regulator because it inhibits cytokine-induced cellular responses.58,59 Synthesis or release of these proteins or fragments is often increased in cartilage that is undergoing repair or remodeling, and they have been investigated as markers of cartilage damage in arthritis.33,34 A related member of the chitinase family, YKL-39, may be a more specific serum marker as a cartilagederived ­autoantigen.60,61

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MORPHOLOGY, CLASSIFICATION, AND NORMAL FUNCTION OF CHONDROCYTES MORPHOLOGY The characteristic feature of the chondrocyte embedded in cartilage matrix is its rounded or polygonal morphology. The exception occurs at tissue boundaries, such as the articular surface of joints, where chondrocytes may be flattened or discoid. Intracellular features, including a rough endoplasmic reticulum, a juxtanuclear Golgi apparatus, and deposition of glycogen, are characteristic of a synthetically active cell. Stockwell and Meachim62 calculated that the cell density of full-thickness, human, adult, femoral condyle cartilage is maintained at 14.5 (± 3.0) × 103 cells/mm2 from age 20 to 30 years. Because senescence of chondrocytes is known to occur with aging, it is logical to suppose that dead chondrocytes are replaced by mitosis. Mitotic figures are not observed, however, in normal adult articular cartilage. The morphology, density, and synthetic activity of an adult chondrocyte vary according to its position within the different zones of articular cartilage.63-65 In the region of highest cell density, the superficial zone, the cells are flattened and oriented parallel to the surface along with the collagen fibers. Chondrocytes within the middle zone appear larger and more rounded and display a random distribution within the matrix, where the collagen fibers also are more randomly arranged. The chondrocytes in the deeper zones form columns that, along with the collagen fibers, are oriented perpendicular to the cartilage surface. The chondrocytes may exhibit different behaviors depending on their position within the different layers, and these zonal differences in synthetic properties may persist in primary chondrocyte cultures.63,64 Chondrocyte volume in situ increases from the superficial through the deep zones and with the degree of cartilage degeneration.7 A study using confocal scanning laser microscopy of live, unfixed cartilage has revealed fine cytoplasmic processes extending from the cell bodies of 40% of chondrocytes.66 These processes are proposed to permit interactions among the chondrocytes and the cartilage matrix at near and remote sites. They are distinct from the cilia, which are observed by electron microscopy,67 but not by confocal scanning laser microscopy.66 CLASSIFICATION: CELL ORIGIN AND DIFFERENTIATION The chondrocyte arises in the embryo from mesenchymal origin during chondrogenesis, which is the earliest phase of skeletal development involving mesenchymal cell recruitment, migration, and condensation and differentiation of the mesenchymal chondroprogenitor cells.68 As described in detail in Chapter 1, chondrogenesis results in the ­formation of cartilage anlagen, or templates, at sites where skeletal elements form. This process is controlled by cell-cell and cell-matrix interactions and by growth and differentiation factors that initiate or suppress cellular signaling ­pathways and transcription of specific genes in a temporospatial ­manner. Vertebrate limb development is controlled by interacting patterning systems involving fibroblast growth factor (FGF), hedgehog, bone morphogenetic protein (BMP), and Wnt pathways. Wnt signaling, via the canonical β-catenin

pathway and activation of TCF/Lef transcription factors, functions in a cell-autonomous manner to induce osteoblast differentiation and suppress chondrocyte differentiation in early chondroprogenitors.69 During chondrogenesis, Wnt/ β-catenin acts at two stages, at low levels to promote chondroprogenitor differentiation and later at high levels to promote chondrocyte hypertrophic differentiation and subsequent endochondral ossification.70,71 The transcription factor, Srytype high mobility group box 9 (Sox9) is an early marker of the differentiating chondrocyte that is required for the onset of expression of type II collagen, aggrecan, and other cartilage-specific matrix proteins, such as type IX ­collagen.72 Two other members of the SOX family, L-Sox5 and Sox6, are not present in early mesenchymal condensations, but are required during overt chondrocyte differentiation, forming heterodimers that induced transcription more efficiently than Sox9 by itself.72 The expression of SOX proteins depends on BMP signaling via SMADs, which are functionally redundant and active in differentiating chondrocytes.73 A long form of c-Maf interacts with Sox9 at early stages to upregulate COL2A1 gene expression,74 whereas C/EBPβ and C/EBPγ and AP-2α may inhibit chondrocyte differentiation by blocking transcription of COL2A1, aggrecan, and other cartilage-specific genes by direct or indirect mechanisms.75,76 In the embryonic or postnatal epiphyseal growth plates, the upregulation of molecules that promote matrix remodeling and angiogenesis facilitates endochondral ossification, whereby bone replaces the calcified cartilaginous matrix in the hypertrophic zone (see Chapter 1). The differentiated chondrocytes that remain in the reserve, or resting, zone become the cartilage elements in articular joints, or they can proliferate and undergo the complex process of terminal differentiation to hypertrophy marked by type X collagen. Indian hedgehog and parathyroid hormone–related protein transiently induce proliferation and repress differentiation, determining the number of cells that enter the hypertrophic maturation pathway.77 The runt-domain transcription factor, Runx2 (also known as core binding factor or Cbfa1), serves as a positive regulatory factor in chondrocyte maturation to the hypertrophic phenotype and subsequent osteogenesis.78 Runx2 is expressed in the adjacent perichondrium and in prehypertrophic chondrocytes, but less in late hypertrophic chondrocytes, and is required for the expression of type X collagen and other markers of terminal differentiation.79 Numerous other transcription factors positively or negatively regulate chondrocyte terminal differentiation by regulating the expression or activity of Runx2.80 BMP-induced Smad 1 and interactions between Smad 1 and Runx2 are required for the induction of chondrocyte hypertrophy. Because there is no SMAD site on the Runx2 promoter, it has been proposed that homeodomain proteins such as Dlx3 may activate Runx2 signaling in response to BMP-2 during endochondral ossification, whereas Dlx5, Dlx6, and Msx2 are known to inhibit Runx2-mediated activation of genes such as osteocalcin at later stages.81 The homeodomain protein Nkx3.2, which is an early BMP-induced signal required at the onset of chondrogenesis, is a direct transcriptional repressor of Runx2 promoter activity.82 The bHLH factor Twist transiently inhibits Runx2 function and prevents premature osteoblast differentiation,83 whereas cooperation of the Groucho homologue Grg5 or the leucine zipper protein ATF4 with Runx2 promotes chondrocyte maturation.84

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­ is­tone deacetylase 4 (HDAC4), which is expressed later H in prehypertrophic chondrocytes, prevents premature chondrocyte hypertrophy by interacting with Runx2 and inhibiting its activity.85 The hypoxia-inducible factor (HIF)-1α is required for chondrocyte survival during hypertrophic differentiation, owing partially to its regulation of vascular endothelial cell growth factor (VEGF) expression.86 The leucine zipper proteins Fra2, ATF2, and c-Maf are required for gene expression during late-stage hypertrophy.87 One major function of the chondrocyte is growth of the skeleton through increases in cell proliferation, production of ECM, and cell volume through hypertrophy. After cessation of growth, the resting chondrocyte remains as part of the supporting structures in articular, tracheal, and nasal cartilages, indicating that the fate of a chondrocyte depends on origin and location (Fig. 3-3). NORMAL FUNCTION OF THE ADULT ARTICULAR CHONDROCYTE The mature articular chondrocyte embedded in its ECM is a resting cell with no detectable mitotic activity and a low rate of synthetic activity. Because articular cartilage is not vascularized, the chondrocyte must rely on diffusion from the articular surface or subchondral bone for the exchange of nutrients and metabolites. Chondrocytes maintain active membrane transport systems for exchange of cations, including Na+, K+, Ca2+, and H+, whose intracellular concentrations fluctuate with load and changes in the composition of the cartilage matrix.88 The chondrocyte cytoskeleton is composed of actin, tubulin, and vimentin filaments, and the composition of these filament systems varies in the different cartilage zones.89,90 Chondrocyte metabolism operates at low oxygen tension within the cartilage matrix, ranging from 10% at the surface to less than 1% in the deep zone. The consumption of oxygen by cartilage on a per-cell basis is only 2% to 5% of that in liver or kidney, although the amounts of lactate produced are comparable. Chondrocytes do not normally contain abundant mitochondria, energy metabolism depends strongly on the glucose supply, and the energy requirements may be modulated by mechanical stress.91 Glucose serves as the major energy source for the chondrocytes and as an essential precursor for glycosaminoglycan synthesis.92 Facilitated glucose transport in chondrocytes is mediated by several distinct glucose transporter proteins (GLUTs) that are either constitutively expressed (GLUT3 and GLUT8) or cytokine-inducible (GLUT1 and GLUT6).93,94 A proteomic study of chondrocytes identified 93 different intracellular proteins known to be involved in cell organization (26%), energy (16%), protein fate (14%), metabolism (12%), and cell stress (12%).95 The relative expression of these proteins may determine the capacity of chondrocytes to survive in cartilage matrix and to modulate metabolic activity in response to the environmental changes. When cultured in a range of oxygen tensions between severe hypoxia (0.1% oxygen) and normoxia (21% oxygen), chondrocytes adapt to low oxygen tensions by upregulating HIF1α. Hypoxia via HIF-1α can stimulate chondrocytes to express GLUTs94 and angiogenic factors such as VEGF96,97 and numerous genes associated with cartilage anabolism and chondrocyte differentiation, including Sox9, TGF-β, and connective

43

tissue growth factor.98,99 In the growth plate, hypoxia and HIF-1α are associated with type II collagen production.100 HIF-1α is expressed in normal and osteoarthritis articular cartilage, where it maintains tonic activity during physiologic hypoxia in the deeper layers associated with increased proteoglycan synthesis.101 It is not completely degraded, however, as it is in other tissues, when normoxic conditions are applied.102 Long-term systemic hypoxia (13%) may downregulate collagen and aggrecan gene expression in articular cartilage,103 whereas hyperoxia (55% oxygen) may increase the breakdown of cartilage collagens in articular cartilage in the presence of vascularized rheumatoid synovium.104 By modulating the intracellular expression of survival factors such as HIF-1α, chondrocytes have a high capacity to survive in the avascular cartilage matrix and to respond to environmental changes. Findings that catabolic stress and inflammatory cytokines upregulate HIF-1α also suggest that it may serve as a survival factor in osteoarthritis cartilage.101,105,106 CHONDROCYTE SYNTHETIC FUNCTION The chondrocyte maintains a steady-state metabolism secondary to equilibrium between anabolic processes and catabolic processes that results in the normal turnover of matrix molecules. In normal adult articular cartilage, the turnover of matrix components is low. The turnover of collagen has been estimated to occur with a half-life of more than 100 years.107,108 In contrast, the glycosaminoglycan constituents on the aggrecan core protein are more readily replaced; the half-life of aggrecan subfractions has been estimated to range from 3 to 24 years.109 Other cartilage ECM components, including biglycan, decorin, COMP, tenascins, and matrilins, incorporated previously into the matrix during ­development, also may be synthesized by chondrocytes under low-turnover conditions. There are regional differences in the remodeling activities of chondrocytes, however, and matrix turnover may be more rapid in the immediate pericellular zones.110 The metabolic potential of these cells also is indicated by their capacity to proliferate in culture and synthesize matrix proteins after enzymatic release from the cartilage of even elderly individuals. The complex composition of the articular cartilage matrix is more difficult for the chondrocyte to replicate if severe damage to the collagen network occurs. During the initial stages of osteoarthritis, chondrocytes in vivo respond to structural changes in the surrounding cartilage matrix by increasing cell proliferation and synthesis of matrix proteins, proteinases, and anabolic and catabolic factors. The aberrant behavior of osteoarthritis chondrocytes is reflected in the appearance of fibrillations; matrix depletion; cell clusters; and changes in quantity, distribution, or composition of matrix proteins.111,112 Evidence of phenotypic modulation is reflected in increased type I and III collagens113 and the appearance of the hypertrophic chondrocyte marker, type X collagen, and other chondrocyte differentiation genes, suggesting a recapitulation of a developmental program.40,114 There is evidence, however, of compensatory increases in type II collagen synthesis in deeper regions of the articular cartilage.112 Genomic and proteomic analyses of global gene expression in cartilage have confirmed the increased levels of type II collagen (COL2A1) mRNA levels in early ­osteoarthritis cartilage.115-117 The increased levels of anabolic factors,

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Mesenchymal precursor cell TGF-β FGF-2,4,8,10 Wnt-3A,7A Sonic Hh BMP-2,4,7

Condensation

Chondroprogenitor Chondrogenesis

Chondrocyte proliferation and differentiation

Type I collagen Hyaluronan

Collagen IIA Tenascin Vimentin

BMP-2,4,7,14 IGF-1 FGF-2/FGFR2

Collagen II, IX, XI Aggrecan S-100

Proliferating chondrocyte FGF-18/FGFR3 BMP-2,7 TGF-β PTHrP Indian Hh VEGF

Resting chondrocyte

BMP-2,7,13 IGF-1

Differentiated chondrocyte

Hypertrophy

Hypertrophic chondrocyte Collagen X Osteocalcin Alkaline phosphate MMP-13

Retinoic acid Serum/FGF-2 IL-1

In vitro

Collagen II, IX, XI Aggrecan S-100 Collagen I, III

Dedifferentiated chondrocyte

Figure 3-3  Schematic representation of cellular phenotypes associated with developmental fates during condensation, chondrogenesis, chondrocyte proliferation, differentiation, and hypertrophy. Some of the regulatory factors active at different stages are listed to the left of the arrows. The major extracellular matrix genes are listed to the right of each cell type in which they are differentially expressed. BMP, bone morphogenetic protein; FGF, fibroblast growth factor; Hh, hedgehog; IGF, insulin-like growth factor; IL-1, interleukin-1; MMP, matrix metalloproteinase; PTHrP, parathyroid  hormone–related protein; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor; Wnt, wingless type.

BMP-2 and inhibin βA/activin, members of the TGF-β superfamily,116,118,119 and prostaglandins120 suggest a possible mechanism. Nevertheless, Aigner and coworkers117 have shown that expression of the type II collagen gene (COL2A1) is suppressed in upper zones of osteoarthritis cartilage with progressing matrix destruction, whereas global COL2A1 gene expression is increased in late-stage osteoarthritis cartilage compared with normal and early degenerative cartilage. The capacity of the adult articular chondrocyte to regenerate the normal cartilage matrix architecture is limited, and the damage becomes irreversible, unless the destructive process is interrupted.

CULTURE MODELS FOR STUDYING CHONDROCYTE METABOLISM Primary cultures of articular chondrocytes isolated from various animal and human sources have served as useful models for studying the mechanisms controlling responses to

growth factors and cytokines.121-124 A challenge to researchers in cartilage biology is the maintenance of chondrocyte morphology and cartilage-specific gene expression during in vitro studies. In primary monolayer cultures, chondrocytes maintain a rounded, polygonal morphology (Fig. 3-4), but there is a progressive loss of cartilage phenotype with passage of time and after subculture. High-density cultures maintain the gene expression and synthesis of cartilage-specific matrix proteins until they are subcultured, although gene expression of type II collagen is generally more labile than that of aggrecan. During this loss of phenotype or dedifferentiation, chondrocytes lose the rounded, polygonal morphology and express some, but not all, characteristics of the fibroblast phenotype, such as type I collagen. It is possible to expand the cultures through a limited number of subcultures and “redifferentiate” the cells in fluid or gel suspension cultures, in which the chondrocytes regain morphology, and the cessation of proliferation is associated with increased expression of cartilage-specific matrix proteins. ­ Alternatively,

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of cartilage matrix synthesis and degradation by proteinases, inflammatory cytokines, retinoic acid, and anabolic growth factors. Monolayer Cultures

A

B Figure 3-4  Morphology of human articular chondrocytes grown in monolayer culture on plastic. Chondrocytes were isolated from articular cartilage and cultured in growth medium containing 10% fetal calf serum until confluent. The cultures were changed to serum-free defined ­medium, interleukin-1β (IL-1β) was added the next day, and incubation was continued for 24 hours. A, Untreated chondrocytes display the characteristic cobblestone morphology. B, IL-1β-treated cultures respond with a dramatic morphologic change.

explant cultures of articular cartilage in which the chondrocytes remain encased within their own ECM have been used as in vitro models to study cartilage biochemistry and metabolism, as described in the following section. ARTICULAR CHONDROCYTES Cartilage Explant (Organ) Cultures Based on the pioneering work of Fell,125 who showed that it was possible to maintain pieces of cartilage in culture, the explant culture system was developed to characterize chondrocyte function in cartilage from various species, including humans, at different ages. The early work in bovine cartilage established the mechanisms of biosynthesis of cartilage proteoglycans under the influence of different serum concentrations and determined the turnover rate whereby the chondrocyte could maintain the balance between anabolic and catabolic pathways.126 Methods developed for measuring the proteoglycan content in cartilage and the incorporation of 35S-sulfate into newly synthesized proteoglycans are used widely as the standard assays for assessing cartilage metabolism.127 Cartilage organ cultures also maintain ­constant ­levels of type II collagen during several weeks of ­ culture and the characteristic morphology and banding pattern of collagen fibers. These cultures have been useful for studying the regulation

Primary monolayer cultures of chondrocytes isolated from young animals that maintain the cartilage-specific phenotype at least throughout primary culture are easily obtained and have been used widely to assess differentiated chondrocyte functions. When chondrocytes are isolated from their matrix and cultured in monolayer, they adhere to the culture dish and readily respond to serum growth factors that stimulate proliferation of the normally quiescent cells. Freshly isolated human articular or costal chondrocytes express cartilagespecific type II collagen and continue to do so for several days to weeks in primary monolayer culture.128,129 In addition to cartilage-specific collagens and aggrecan, chondromodulin and protein S-100 are useful markers expressed in primary chondrocyte cultures.130-132 The more recent identification of cell surface markers that determine chondrogenic capacity is expected to enable the enrichment of subpopulations for further characterization.133 Early attempts to culture chondrocytes from various animal and human sources were frustrated by the tendency of these cells to acquire a fibroblast-like morphology associated with the appearance of type I collagen synthesis.4,123 When plated at high density, the cells maintain a polygonal, although flattened, morphology. At low plating densities, with prolonged culture, and on expansion in serial subculture, the cells gradually assume a more elongated, “fibroblastlike” morphology. Early work suggested that this change in morphology is associated with a loss of phenotype, whereby the synthesis of cartilage-specific matrix molecules, such as type II collagen and aggrecan, decreases or disappears. This “dedifferentiated phenotype,” which has been described so far only in vitro, is marked by the appearance of synthesis of type I and type III collagens, and it can be accelerated by plating the cells at low densities or by treatment with cytokines such as interleukin (IL)-1 or retinoic acid. A lack of correlation between cell shape and chondrocyte phenotype has been reported. The dedifferentiation of chondrocytes in monolayer culture seems to be associated, however, with the increased expression of genes involved in cell proliferation, such as cyclin D1.130 The substrate on which the chondrocytes are plated can influence the differentiation capacity of articular chondrocytes.134 The use of chondrocytes of adult human origin in studies related to the pathogenesis of joint diseases has been problematic because the source of the cartilage cannot be controlled, sufficient numbers of cells are not readily obtained from random operative procedures, and the phenotypic stability of adult human chondrocytes is lost more quickly on expansion in serial monolayer cultures than in cells of juvenile human or embryonic or postnatal animal origin. High-density micromass cultures are useful if sufficient numbers of chondrocytes can be obtained, particularly for studying proteoglycan biosynthesis.135 Serum-free defined media of varying compositions, but usually including insulin, also have been used, frequently in combination with monolayer and other culture systems mentioned in the following section.136,137

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Three-Dimensional Culture Systems Early studies showed that phenotype could be maintained if the isolated chondrocytes are placed in suspension cultures in spinner flasks or in dishes coated with nonadherent substrates.4,123 Freshly isolated or subcultured chondrocytes also can be embedded in three-dimensional matrices, such as collagen gels or sponges,138,139 agarose,140,141 or alginate.142,143 In these three-dimensional matrices, chondrocytes have the normal spherical shape, synthesize and secrete abundant cell-associated ECM components, and may maintain phenotypic stability for several months. Because articular chondrocytes are unable to proliferate in fluid or gel suspension culture, expansion in monolayer culture followed by transfer to alginate or other suspension culture has been used as a strategy to obtain sufficient numbers of differentiated chondrocytes for study. After prolonged culture in monolayer, however, dedifferentiated chondrocytes may lose irreversibly their chondrogenic potential.144 The high-density pellet culture system, originally developed to study growth plate hypertrophy, also has been used as a three-dimensional model because it permits articular chondrocytes to deposit a well-organized ECM containing type II collagen and aggrecan.133,145,146 Isolated chondrons containing one or more chondrocytes within a capsule of pericellular matrix also have been used for in vitro studies of chondrocyte metabolism within a three-dimensional environment. PREHYPERTROPHIC AND HYPERTROPHIC CHONDROCYTES: MODELS OF THE GROWTH PLATE AND TERMINAL DIFFERENTIATION Tissues or cells from embryonic or young animals at specific developmental stages or with different developmental fates have been used widely to recapitulate in vitro the transitional stages of chondrogenesis, chondrocyte hypertrophy, and endochondral ossification.4,123 A common feature of these models is the requirement for deposition of a collagenous matrix by sufficient numbers of cells after cessation of proliferation of chondrogenic cells in high-density micromass, pellet, or three-dimensional matrix cultures. Epi­ physeal chondrocytes isolated from the long bones of postnatal immature rats and rabbits and cultured at high density ­progress through a differentiation pathway that mimics the transition from a type II collagen–producing, proliferating chondrocyte phenotype to the terminally differentiated type X collagen–producing hypertrophic phenotype associated with growth plate formation and endochondral ossification. Alkaline phosphatase, osteocalcin, and osteopontin also have been used as markers of terminal differentiation. The pellet culture system has been used widely to study terminal differentiation and hypertrophy because it mimics the distribution of cells within the growth plate and is sufficiently organized to permit calcification in situ. Arrest of cell proliferation and activation of type X collagen expression occur when the serum concentration is reduced from 10% to 2% or lower. Insulin-like growth factor (IGF)-I or insulin added in serum-free medium or as a constituent of serum seems to be a universal basal requirement in these culture systems. Ascorbic acid and treatments such as thyroxine 1,25-­dihydroxyvitamin D3, retinoic acid, or dexamethasone promote terminal differentiation in vitro. Ectopic matrix mineralization also may

require a phosphate donor such as β-glycerophosphate. In contrast, certain BMPs alone or in the presence of ascorbic acid may induce hypertrophy and mineralization in the absence of other additives, if the appropriate progenitor cell population is used. CHONDROCYTE CELL LINES Because primary human chondrocytes in monolayer cultures maintain phenotype only until they are passaged, researchers have attempted to develop chondrocyte cell lines with variable success. Immortalization of chondrocytes from mice, rats, and other species with viral oncogenes has generated cell lines with high proliferative capacities and at least some differentiated chondrocyte properties.147,148 Attempts to generate cell lines that can undergo chondrogenesis and terminal differentiation to the hypertrophic phenotype have been more successful because of the availability and plasticity of progenitor cell populations. Cells derived from the ribs of transgenic mice harboring the temperature-sensitive mutant of simian virus 40 (SV40) large T antigen (TAg) are able to undergo hypertrophic differentiation,149,150 and bone marrow–derived mesenchymal stem cells derived from these mice contain osteogenic, adipogenic, myogenic, and chondrogenic progenitor cells. Several chondrogenic cell lines from mice or rats, including ATDC5, C3H10T1/2, RCJ3.1, CK2, and C1, are now used widely in the field, as reviewed by Johnstone and colleagues.151 Human chondrosarcoma cell lines express some aspects of the chondrocyte phenotype, but are tumorigenic.152,153 Stable expression of SV40-TAg using plasmid or retroviral vectors has yielded immortalized human chondrocyte cell lines that are useful for studying the regulation of gene expression under defined conditions, but do not produce sufficient amounts of matrix proteins to form cartilage matrix owing to high rates of proliferation.154 Human articular chondrocyte cell lines also have been established using temperature-sensitive SV40-TAg,155 the human papillomavirus type 16 early function genes E6 and E7,156 and telomerase.157 A general observation is that phenotypic stability of immortalized chondrocytes is lost during serial subculture in monolayer, but can be restored by transfer to three-­dimensional culture in alginate155 or hyaluronan156 or to suspension culture in poly-2-hydroxyethyl methacrylate–coated dishes.157 Immortalized chondrocytes may continue to proliferate in three-dimensional culture, however, and if the scaffold cannot be remodeled, necrotic clusters form. The studies to date indicate that mature chondrocytes removed from the ideal cartilage environment in vivo are incapable of replicating normal phenotype in vitro, and the perfect chondrocyte culture model that reproduces the human articular chondrocyte has yet to be fabricated, as confirmed by gene profiling studies.158,159

INTERACTIONS OF CHONDROCYTES WITH THE EXTRACELLULAR MATRIX Chondrocytes in vivo respond to structural changes in the cartilage ECM. The ECM not only provides a framework for the chondrocytes suspended within it, but also its constituents interact with cell surface receptors and provide signals that regulate many chondrocyte functions.90,160,161

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INTEGRINS The most prominent of the ECM receptors are the integrins, which bind specifically with different cartilage matrix components and induce the formation of intracellular signaling complexes that regulate cell proliferation, differentiation, survival, and matrix remodeling. Integrins also may serve as mechanoreceptors and mediate responses to normal and abnormal loading of cartilage.162-164 Chondrocytes express many different integrins that interact with cartilage ECM ligands, although most are not specific to this cell type.37,90,160,165 They include the integrins that are receptors for collagen (α1β1, α2β1, α3β1, α10β1), fibronectin (α5β1, αvβ3, αvβ5), and laminin (α6β1). The integrin α1β1 has broader ligand specificity than the other collagen-binding integrins and mediates chondrocyte adhesion to the pericellular type VI collagen and to the cartilage matrix protein, matrilin-1. The α2β1 integrin also binds to chondroadherin. The αv-containing integrins bind to vitronectin and osteopontin in addition to serving as alternative fibronectin receptors. The α5β1 and αvβ3 integrins also serve as receptors for different conformations of COMP.166 Because α1β1, α2β1, and α10β1 all are receptors for cartilage-specific type II collagen, there is great interest in determining whether they mediate differential responses of chondrocytes to changes in the ECM resulting from normal loading or pathologic changes.162-164 The α5β1 integrin is the prominent integrin in human adult articular cartilage. Depending on the method of analysis, adult chondrocytes also express α1β1 and αvβ5 integrins accompanied by weaker expression of α3β1 and αvβ3. Normal adult articular chondrocytes express little or no α2β1, whereas the expression of α2β1 and α3β1 integrins is associated with a proliferative phenotype, as in fetal chondrocytes and in chondrosarcoma and chondrocyte cell lines.167,168 In growth plate chondrocytes, α5β1, αvβ5, and α10β1 are important for joint formation, chondrocyte proliferation, hypertrophy, and survival.169-173 Knockout of β1 integrin results in severe growth plate abnormalities and chondrodysplasia,174 whereas α1 integrin knockout mice develop osteoarthritis without growth plate abnormalities.175 Cellular binding to immobilized ECM proteins or integrin receptor aggregation with activating antibodies can promote numerous intracellular signaling events.90 As in other cell types, integrin signaling is mediated by interaction with intracellular protein tyrosine kinases, such as pp125 focal adhesion kinase and pyk2, which interact with the integrin cytoplasmic tail and induce a conformational change in the receptor subunits. Changes in organization of the cytoskeleton are associated with the formation of integrin signaling complexes, which contain scaffolding proteins such as talin, paxillin, and α-actinin in addition to focal adhesion kinase and the integrin-linked kinase. Mice lacking integrin-linked kinase in cartilage display chondrodysplasia, a phenotype similar to that of the cartilage-specific β1 integrin knockout mice.174 Other signaling kinases, such as Src, Ras/Raf, Sos, and Mek family members, may be associated with integrin signaling complexes and mediate downstream signaling cascades in a cell type–specific and ligand-specific manner. Cooperative signaling among integrins and growth factors is a fundamental mechanism in the regulation of cellular functions. Integrin aggregation and receptor occupancy

47

enhance phosphorylation of growth factor receptors and activation of mitogen-activated protein kinases (MAPKs) in many cell types. The anchorage-dependent mitogenic response to growth factors is thought to be due to synergy between integrin and growth factor signaling. The induction of chondrocyte proliferation by FGF requires fibronectin binding to α5β1 integrin.169 The β1 integrin subunit also interacts with the IGF-I receptor on treatment of chondrocytes with IGF-I.176 Fibronectin increases FGF-stimulated and IGF-I-stimulated proteoglycan synthesis in chondrocytes, and nitric oxide, which disrupts focal adhesion signaling complexes, inhibits this process.177 Type II collagen increases TGF-β-induced type II collagen and aggrecan gene expression by a feedback mechanism that is mediated by β1 integrin.178 The primary fibronectin receptor, α5β1, may play a role in cartilage degradation through binding to fibronectin fragments that upregulate matrix metalloproteinases (MMPs), such as MMP-3 and MMP-13.179-181 Extensive studies in cultured chondrocytes have shown that α5β1 is crucial in the hyperpolarization response to mechanical load.164 Normal chondrocytes use α5β1 as a mechanoreceptor, and subsequent to activation of the integrin-signaling cascade by mechanical stimulation, there is secretion of IL-4, which acts in an autocrine manner via the janus activating kinase (JAK)/ signal transducer and activator of transcription (STAT) pathway to increase aggrecan mRNA and decrease MMP-3 mRNA levels.182 Chondrocyte adhesion to fibronectin or binding to fibro­ nectin fragments also increases the production of cytokines, such as IL-1, tumor necrosis factor (TNF), IL-6, and granulocyte-macrophage colony-stimulating factor. Synergies between fibronectin/α5β1 and IL-1 have been shown in chondrocytes.183,184 Osteoarthritis chondrocytes seem to respond to α5β1 ligation by production of IL-1β and other proinflammatory mediators, whereas αvβ3 integrin ligation attenuates these responses.183 Nevertheless, there is good evidence that fibronectin fragments or blocking antibodies to α2β1 and α5β1 integrins can directly stimulate signaling via extracellular signal-regulated kinase (Erk)-1 or Erk-2, c-Jun N-terminal kinase (JNK), and p38 MAPK in chondrocytes and increase MMP-13 production independent of autocrine production of IL-1β.180 This response requires reactive oxygen species.185 Collagen binding to α1β1 and α2β1 integrins also results in activation of distinct signaling pathways and may lead to opposite cellular responses.186 The downregulation of IL-1-induced responses by dynamic compression also is mediated by integrins.187 The specificity of the response may depend on the relative expression of α-integrin subunits on the chondrocyte cell surface. OTHER CELL SURFACE RECEPTORS IN CHONDROCYTES Other integral membrane proteins found in chondrocytes include cell determinant 44 (CD44), anchorin CII, and syndecan-3.188 CD44 is a receptor for hyaluronan and binds collagen and fibronectin. Through specific interac­ tions with hyaluronan, CD44 has a role in assembly, organization, and maintenance of the chondrocyte pericellular matrix.189 In chondrocyte cultures, the assembly of a newly synthesized pericellular matrix can be prevented or

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reversed by ­ incubation with hyaluronan hexasaccharides or with a CD44 monoclonal antibody. CD44 expression is upregulated in chondrocytes in articular cartilage from RA patients and in experimental osteoarthritis.190 Hyaluronan binding to CD44 increases MMP-13 and nitric oxide production by chondrocytes.191 Although blocking CD44 has no effect on attachment of chondrocytes to a cut cartilage surface, more recent evidence indicates that CD44 mediates the expression of MMP-1, MMP-2, MMP-9, and MMP-13, the MMP-specific cleavage of type II collagen and nitric oxide production induced by the heparin-binding fibronectin fragment in articular cartilage.192,193 Because fibronectin fragments and IL-l enhance CD44 expression in chondrocytes, cell-matrix interactions mediated by such cell surface receptors represent alternative mechanisms for cartilage damage in joint disease. During joint disease, CD44-mediated co-internalization with hyaluronic acid may be one important mechanism for the elimination of residual aggrecan fragments after extracellular degradation.194 Aggrecanase-mediated depletion of proteoglycan does not require CD44, however.195 Anchorin CII, also known as annexin V, is a 34-kD integral membrane protein that binds type II collagen and shares extensive homology with the calcium-binding proteins calpactin and lipocortin.196,197 Three types, annexins II, V, and VI, have been detected in chondrocytes, where they likely play roles in physiologic mineralization of skeletal tissues and in pathologic mineralization of articular cartilage.198 Annexin V, or anchorin CII, was first detected in chick cartilage and described as a type II collagen–binding protein that anchors the chondrocytes to the ECM. In growth plate chondrocytes, annexins are required for calcium ion uptake and subsequent mineralization. Annexin V antibodies block chondrocyte attachment to immobilized type II collagen more effectively than integrin antibodies, but not to a cut cartilage surface, where the N-terminal collagen binding site may not be exposed.188 In contrast to integrins, annexin V binds to the N-telopeptide of type II collagen, but not to triple-helical fragments.199 Syndecan-3 links to the cell surface via glycosyl phosphatidylinositol and binds tenascin-C and growth factors, proteases and inhibitors, and other matrix molecules, through heparan sulfate side chains on the extracellular domain. Syndecans have important roles during cartilage development. Syndecan-1 and syndecan-3 are upregulated in human and mouse osteoarthritis.200,201 In contrast to mammalian collagen receptors that bind collagen fragments, discoidin domain receptor 2 binds specifically to type II and X collagen fibrils, leading to activation of its integral receptor tyrosine kinase.202,203 Discoidin domain receptor 2 is upregulated in osteoarthritis cartilage and induces specifically the expression of MMP-13 associated with cleavage of type II collagen.204

ANGIOGENIC AND ANTIANGIOGENIC FACTORS Adult articular cartilage is among the few avascular tissues in mammalian organisms, and this property and the presence of angiogenesis inhibitors make it resistant to vascular angiogenesis and invasion by inflammatory and neoplastic cells. In conditions in which there is extensive remodeling

of ECM, as in arthritis, the cartilage becomes susceptible to invasion by vascular endothelial and mesenchymal cells from the synovium and subchondral bone.205 In osteoarthritis, the upregulation of angiogenic factors may contribute to ingrowth of blood vessels, tidemark advancement, and cartilage calcification in the deep zone. In RA, the ingrowth of blood vessels and synovial pannus into cartilage contributes to the degradation of the cartilage matrix. Troponin I, MMP inhibitors, chondromodulin-I, and endostatin, a 20-kD proteolytic fragment of type XVIII collagen, all function as endogenous angiogenic inhibitors.206-209 VEGF, which is an essential mediator of angiogenesis during endochondral ossification (see Chapter 1), is induced by hypoxia and mechanical overload.210,211 In osteoarthritis, in which abnormal biomechanics and joint effusions cause severe hypoxia, chondrocytes may produce VEGF, inducing angiogenesis at the chondro-osseous junction and contributing to cartilage destruction.212,213 Intercellular adhesion molecules also contribute to angiogenesis. These include vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, which are expressed by human articular chondrocytes and synovial and endothelial cells. Their function on chondrocytes may not be significant, however, unless damage to the matrix permits cell-cell interactions.214 Vascular cell adhesion molecule-1, VEGF, FGF, and TNF-α contribute to angiogenesis during synovitis and to activation of chondrocytes during cartilage degradation.215,216 In RA, VEGF expression may be upregulated by inflammatory cytokines in chondrocytes and synovial cells and by hypoxia.217,218 The importance of this mechanism is supported by findings in Vegfb knockout mice, which are protected against synovial angiogenesis in experimental inflammatory models.219

ROLES OF GROWTH AND DIFFERENTIATION, OR ANABOLIC, FACTORS IN NORMAL CARTILAGE METABOLISM Growth and differentiation factors generally are considered positive regulators of homeostasis of mature articular cartilage because of their capacity to stimulate chondrocyte anabolic activity and, in some cases, inhibit catabolic activity (see Chapter 1).220 The most well-characterized anabolic factors in the context of their production and action in articular cartilage include IGF-I, FGFs, and members of the TGF-β/BMP family.221-225 Many of these factors also regulate chondrogenesis and endochondral ossification during skeletal development.68 In adult cartilage, their expression declines with age, a risk factor for osteoarthritis, and their activities are downregulated.220 INSULIN-LIKE GROWTH FACTOR IGF-I, also known as somatomedin C, was first discovered as a serum factor controlling sulfate incorporation by articular cartilage in vitro and was later found to have the capacity specifically to stimulate or maintain chondrocyte phenotype in vitro by promoting the synthesis of type II collagen and aggrecan. IGF-I is categorized more appropriately as a differentiation factor because its limited mitogenic activity

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seems to depend on the presence of other growth factors, such as FGF-2 or BMP-7.142,226 IGF-I is considered an essential mediator of cartilage homeostasis through its capacity to stimulate proteoglycan synthesis, promote chondrocyte survival, and oppose the activities of catabolic cytokines.143,227,228 IGF-I and insulin can activate either the cell surface IGF-I tyrosine kinase receptor or the type I insulin receptor at concentrations proportional to their binding affinities. Specific IGF-binding proteins (IGFBPs) that do not recognize insulin also regulate IGF-I activity. Chondrocytes at different stages of differentiation express IGF-I and IGF receptors and different arrays of IGFBPs, providing a unique system by which IGF-I can exert different regulatory effects on these cells. IGFBP-2 seems to be a positive regulator in chondrocytes because its induction by TGF-β or estrogen is associated with increased proteoglycan synthesis.229 Binding of IGFBP-3 to IGF-I is thought to regulate negatively the anabolic functions of IGF-I, although IGFBP-3 may directly inhibit chondrocyte proliferation in an IGF-­independent manner. In osteoarthritis cartilage, the normal anabolic function of IGF-I may be disrupted because chondrocytes from animals with experimental arthritis and from patients with osteoarthritis are hyporesponsive to IGF-I, despite normal or increased IGF-I receptor levels. This hyporesponsiveness has been attributed to increased levels of IGFBPs that may interfere with IGF-I actions.230,231 Disturbances in the balance of IGF-I to IGFBPs that have been reported in osteoarthritis and RA joints may contribute to defective chondrocyte responses to IGF-I.230-233 Small-molecule inhibitors of IGF-I/IGFBP interactions that could restore IGF-I-dependent proteoglycan synthesis in cartilage have been proposed for treatment of osteoarthritis.228 Although IGF-I can oppose the effects of inflammatory cytokines that promote cartilage degradation and inhibit proteoglycan synthesis,234 these cytokines also increase the production of IGFBP-3 by chondrocytes.235 Overproduction of nitric oxide also may contribute to IGF-I resistance by chondrocytes through disruption of integrin signaling, reducing phosphorylation of the IGF-I receptor, stimulation of cyclic guanosine monophosphate production, or suppression of mitochondrial oxidative metabolism.227,236-239 More recent evidence indicates that suppressor of cytokine signaling 3 acts as a negative feedback regulator during IGF-I desensitization in the absence of nitric oxide by inhibiting insulin receptor substrate-1 phosphorylation.240 FIBROBLAST GROWTH FACTOR Members of the FGF family, including FGF-2, FGF-4, FGF-8, FGF-9, FGF-10, and FGF-18, together with the FGF receptors, FGFR1, FGFR2, and FGFR3, coordinate patterning and cell proliferation during chondrogenesis and endochondral ossification in embryonic and postnatal growth plates.241 The most extensively studied is FGF-2, or basic FGF, which is a potent mitogen for adult articular chondrocytes,224 but findings on its effects on the synthesis of cartilage matrix are contradictory, showing stimulation, inhibition, or no effect on proteoglycan synthesis.242

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Early studies suggested that low concentrations of FGF-2 could stimulate chondrocyte mitogenesis and proteoglycan synthesis, whereas high concentrations might have opposite effects.243 More recent studies showing that FGF-2 stored in the adult cartilage matrix is released with mechanical injury or with loading suggest a mechanism for modulating chondrocyte proliferation and anabolic activity.244,245 Although FGF-2 and FGF-9 stimulate the expression of Sox9 and increase the activity of the Sox9-dependent, chondrocytespecific enhancer in the type II collagen gene,246,247 FGF-2 can inhibit the anabolic activities of IGF-I and osteogenic protein-1 (OP-1) in vitro.142 FGF-9 and FGF-18 increase matrix synthesis by mature chondrocytes.248-251 A study showed that FGF-18 promotes cartilage repair in a rat meniscal tear model of osteoarthritis.252 FGF-2 stimulates, whereas IGF-I inhibits, expression of matrix Gla protein, which is a marker for the chondrocyte survival during endochondral ­ ossification.253,254 FGFs and FGF receptors have important roles in cartilage homeostasis during prenatal and postnatal life. TRANSFORMING GROWTH FACTOR-β/BONE MORPHOGENETIC PROTEIN SUPERFAMILY Activities of the TGF-β/BMP superfamily in the skeleton were first discovered as constituents of demineralized bone that induced new bone formation when implanted into extraskeletal sites in rodents.255 These bioactive morphogens subsequently were extracted, purified, and cloned and found to regulate the early commitment of mesenchymal cells to the chondrogenic and osteogenic lineages during cartilage development and endochondral bone formation (Table 3-2).68,256 The TGF-β/BMP superfamily includes activins, inhibins, müllerian duct inhibitory substance, nodal, glial-derived neurotrophic factor, OP-1 (or BMP-7), and growth differentiation factors (GDFs), also called cartilage-derived morphogenetic proteins (CDMPs). In addition to regulating cartilage condensation and chondrocyte differentiation, members of this superfamily play key roles in site specification and cavitation of synovial joints (see Chapter 1) and participate in the development of other organ systems. Many of these factors, including BMP-2, BMP-6, BMP-7, BMP-9, TGF-β, and CDMP-1, are able to induce chondrogenic differentiation of mesenchymal progenitor cells in vitro. They also may have direct effects on mature articular chondrocytes in vivo and in vitro. Transforming Growth Factor-β TGF-β was named based on its discovery as a factor that could transform cells to grow in soft agar. TGF-β is not a potent inducer of chondrocyte proliferation, however; rather, it controls early mesenchymal cell condensation and differentiation to chondrocytes at early and late stages of endochondral ossification (see Chapter 1). Inhibition and stimulation of the synthesis of aggrecan and type II collagen by TGF-β have been observed in vitro. TGF-β, by itself, cannot rescue the type II collagen phenotype, however, when the cells have undergone dedifferentiation during serial passaging. The levels of TGF-β measured in synovial fluids of osteoarthritis and RA patients may reflect anabolic processes in cartilage

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Table 3-2  Bone Morphogenetic Protein   Superfamily Bone Morphogenetic Protein

Other Names

Potential Function

BMP-2

BMP-2A

Cartilage and bone morphogenesis

BMP-3

Osteogenin, GDF-10

Bone formation

BMP-4

BMP-2B

Cartilage and bone morphogenesis

BMP-6

Vegetal-related-1   (Vgr-1)

Cartilage hypertrophy

BMP-7

Osteogenic   protein-1 (OP-1)

Cartilage and bone morphogenesis

BMP-8

Osteogenic   protein-2 (OP-2)

Bone morphogenesis

BMP-9

GDF-2

Cartilage ­morphogenesis

BMP-5

Bone morphogenesis

BMP-10

Unknown

BMP-11

GDF-11

Unknown

BMP-12

GDF-7, CDMP-3

Cartilage ­morphogenesis

BMP-13

GDF-6, CDMP-2

Cartilage ­morphogenesis

BMP-14

GDF-5, CDMP-1

Cartilage ­morphogenesis

CDMP, cartilage-derived morphogenetic protein; GDF, growth and differentiation factor.

and other joint tissues. TGF-β also may promote anabolism by inducing the expression of tissue inhibitors of MMP (TIMP). Nevertheless, TGF-β1, TGF-β2, and TGF-β3 generally are considered as potent stimulators of proteoglycan and type II collagen synthesis in primary chondrocytes and cartilage explants in vitro.257 Microarray analysis of chondrocytes in vitro indicates that TGF-β is able to counteract the expression of numerous IL-1-induced genes involved in cartilage injury.258 Although intra-articular injection of TGF-β stimulates proteoglycan synthesis and limits cartilage damage in inflammatory arthritis models, injection or adenovirus-mediated delivery of TGF-β1 may result in side effects in joint tissues, such as osteophyte formation, swelling, and synovial hyperplasia.259,260 Administration of agents that block TGF-β activity, such as the soluble form of TGF-βRII, inhibitory SMADs, or the physiologic antagonist, latencyassociated peptide-1, increases proteoglycan loss and cartilage damage in an experimental model of osteoarthritis.261,262 A more recent finding that TGF-β induces expression of ADAMTS (a disintegrin and metalloproteinase [ADAM family] with thrombospondin-1 domains)-4 in primary human chondrocytes and promotes the degradation of aggrecan suggests that it may be involved in normal turnover of proteoglycans in mature cartilage.263 Findings that IL-1 differentially regulates inhibitory SMADs and transcriptional mediators of TGF-β and BMP signaling,264 and decreases TGF-β signaling associated with the loss of a protective effect of TGF-β during osteoarthritis progression265 suggest that the balance of inhibitory and stimulatory molecules determines cartilage homeostasis.

Bone Morphogenetic Proteins The BMPs constitute a large subclass of the TGF-β superfamily that are essential for normal appendicular skeletal and joint development.68,221,256,266 The isolation and cloning of the first BMP family members from bone prompted a search for the cartilage-derived BMPs, CDMPs, CDMP-1, CDMP-2, and CDMP-3, which are classified as GDF-5, GDF-6, and GDF-7. The BMPs may be divided into four distinct subfamilies based on the similarity of primary amino acid sequences: (1) BMP-2 and BMP-2B (BMP-4), which are 92% identical in the 7-cysteine region; (2) BMP-3 (osteogenin) and BMP-3B (GDF-10); (3) BMP-5, BMP-6, BMP-7 (OP-1), BMP-8 (OP-2), BMP-9 (GDF-2), BMP-10, and BMP-11 (GDF-11); and (4) BMP-12 (GDF-7 or CDMP-3), BMP-13 (GDF-6 or CDMP-2), BMP-14 (GDF-5 or CDMP1), and BMP-15. BMP-1 is not a member of this family, but is an astacin-related MMP that cleaves the BMP inhibitor chordin and acts as a procollagen C-proteinase.267 Several BMPs, including BMP-2, BMP-7 (OP-1), and GDF-5/CDMP-1, can stimulate differentiation of mesenchymal precursors into chondrocytes and promote the ­differentiation of hypertrophic chondrocytes.268,269 BMP-2, BMP-4, BMP-6, BMP-7, BMP-9, and BMP-13 can enhance the synthesis of type II collagen and aggrecan by articular chondrocytes in vitro.223,270,271 In addition, BMP-7 reverses many of the catabolic responses induced by IL-1β, including induction of MMP-1 and MMP-13, downregulation of TIMP expression, and downregulation of proteoglycan synthesis in primary human articular chondrocytes.223 CDMP-2 is found in articular cartilage, skeletal muscle, placenta, and hypertrophic chondrocytes of the epiphyseal growth plate. CDMP-1 and CDMP-2 maintain the synthesis of type II collagen and aggrecan in mature articular chondrocytes, although they are less effective initiators of chondrogenesis than other BMPs in early progenitor cell populations in vitro.272 BMP-7 is expressed in mature articular cartilage and is possibly the strongest anabolic stimulus for adult chondrocytes in vitro because it increases aggrecan and type II collagen synthesis more strongly than IGF-I.223 BMP-2 also is expressed in normal and osteoarthritis articular cartilage,119 and it is a molecular marker, along with type II collagen and FGF receptor 3 (FGFR3), for the capacity of adult articular chondrocyte cultures to form stable cartilage in vivo.140 BMP-2, BMP-7, and BMP-9 are able to oppose many of the detrimental effects of IL-1 on chondrocyte metabolism in vitro and in vivo.269,273 BMP-7 can prevent retinoic acid–induced dedifferentiation of articular chondrocytes.274 BMPs have pleiotropic effects in vivo, however, acting in a concentration-dependent manner. While initiating chondrogenesis in the limb bud, they generally set the stage for bone morphogenesis (see Chapter 1). Several BMPs also are true morphogens for other tissues, such as kidney, eye, heart, and skin. RECEPTORS, SIGNALING MOLECULES, AND ANTAGONISTS THAT MEDIATE CHONDROCYTE RESPONSES TO GROWTH AND DIFFERENTIATION FACTORS The major pathways activated by the growth and differentiation factors discussed earlier involve members of the ERK1/2, p38 MAPK, and phosphatidylinositol-3′-kinase

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(PI-3K)/AKT pathways.275 As in other cell types, FGF family members activate ERK1/2 and p38 kinases in chondrocytes. Specific inhibitors of these pathways block FGF2-induced and FGF-18-induced mitogenesis in chondrocytes and prevent FGF-2 induction of Sox9 in primary chondrocytes.246,251 The PI-3K pathway is required for the stimulation of proteoglycan synthesis by IGF-I in primary human articular chondrocytes, whereas the ERK1/2 pathway acts as a negative regulator.276 TGF-β and BMP family members transduce signals ­thro­ugh the formation of heteromeric complexes of ligandspecific  receptors,  which  have  serine-threonine kinase  activity. The specificity of subsequent signals is determined mainly by the type I receptors. Type I and type II receptors are required for signal transduction (Fig. 3-5).266,277,278 Seven types of type I receptors, called activin receptor-like kinases (ALK), have been identified in mammals and have similar structures. TGF-β interacts with the type II receptor (TβRII), which recruits a TGF-β type I receptor (principally TβRI) to form a heterotrimeric receptor complex. The ­constitutively active TβRII kinase phosphorylates TβRI at serine and threonine residues. Three type I receptors, BMP type IA (BMPR-IA or ALK-3), BMPR-IB (ALK-6), and ALK-2, mediate BMP signaling. Although type I BMP receptors are able to bind ligand in the absence of type II BMP receptors, cooperativity has been shown in binding assays. On ligand binding, analogous to TβRI and TβRII, BMP type I receptors are phosphorylated by the BMP type II receptors, which include activin (Act) RII, ActRIIB, and T-ALK. Spatial and temporal differences in the distribution of these receptors in different tissues can govern the response patterns to different members of the TGF-β/BMP family. Signaling by TGF-β and BMP is mediated by the canonical SMAD pathway, through phosphorylation of receptor­activated SMADs (R-SMADs), BMP-induced Smad 1, Smad 5, and Smad 8 for BMPs and TGF-β-induced Smad 2 and Smad 3. The SMADs are related to the Drosophila ­mothers against decapentaplegic and nematode SMA signaling molecules. These regulatory SMADs form complexes with the common Smad 4 and translocate to the nucleus, where they bind to SMAD elements in the promoters of target genes.278 Other BMP-induced transcription factors include JunB, JunD, and ID and DLX family members, suggesting alternative pathways of signaling. TGF-β and BMPs also can signal by activating TGF-β activated kinase 1 (TAK1),279 which interacts with MEKK1 and activates p38 and JNK cascades, or by activating Ras/ERK1/2 or RhoA/ROCK signaling.266,278 Findings of numerous studies suggest that the differentiation of chondrocytes from mesenchymal precursors is positively regulated by p38 kinase and negatively regulated by ERK1/2.266,280 ERK1/2 activation cross-interacts with BMP-2-induced signaling to regulate chondrogenesis in a positive manner, whereas p38 activity is essential for the TGF-β induction of proteoglycan synthesis in articular chondrocytes.281,282 Cytoskeletal compartmentation of SMAD signaling complexes may regulate the differentiation of chondroprogenitor cells into chondrocytes.273 Inhibitory Smad 6 and Smad 7, which prevent phosphorylation of the R-SMADs, also control BMP-induced and TGF-β-induced activities. An additional SMAD-interacting molecule, Tob1, negatively regulates signaling by sequestering R-SMADs and is an antiproliferative protein that

51

BMPs Noggin Chordin Dan

Extracellular matrix Collagens I and IV Heparan sulfate

BMPR-IB

Cytoplasm BMPR-IA P

P

P

SMAD-6

P SMAD-7

BMPR-II

SMAD-1 P SMAD-1

SMAD-5 P SMAD-5

+

+

SMAD-4

SMAD-4

P SMAD-1

P SMAD-5

SMAD-4

SMAD-4

Nucleus SMAD-6

SMAD-7

BMP response genes Figure 3-5  Bone morphogenetic protein (BMP) receptors and ­signaling cascade. BMPs are dimeric ligands with a single interchain, disulfide bond.  BMPs interact with type I and II BMP receptors (BMPR-I and BMPR-II). BMPR-II phosphorylates BMPR-I and activates the serine/threonine  kinase receptor. The BMP-RI protein serine/threonine kinase phosphorylates cytoplasmic signaling substrates Smad 1 or Smad 5. This phosphorylation is modulated and inhibited by inhibitory Smad 6 and Smad 7. Phosphorylated Smad 1 and Smad 5 interact with a common co-Smad 4 and are translocated into the nucleus to initiate the transcription of BMPresponse genes. A Smad interacting protein (SIP) modulates binding of the Smad 1/Smad 4 complex to DNA. The bioavailability of BMP for interaction with cognate receptors depends on BMP binding proteins and antagonists, such as noggin and chordin, and extracellular matrix components, such as collagens I and IV and heparan sulfate. (From Reddi AH: Role of morphogenetic proteins in skeletal tissue engineering and regeneration. Nat Biotech 16:247-252, 1998.)

is downregulated in osteoarthritis cartilage.283 BMP antagonists play important roles in spatial and temporal regulation of BMP activities during skeletal development. Originally discovered in Xenopus, they act as antagonists by determining the bioavailability of BMPs for binding to BMP receptors. The roles of noggin and chordin seem to be crucial for determining boundaries during joint morphogenesis. They display different spatial and temporal patterns of expression, binding affinities, and susceptibility to proteinases that release BMP. BMPs bind to chordin and noggin via cysteine-rich domains that are similar to domains in the N-terminal propeptides of fibrillar procollagens I, II, III, and V, which also bind BMPs and are susceptible to cleavage by MMPs.284 BMP may be released from chordin by cleavage with MMPs or BMP-1/tolloid, whereas noggin binds BMP with high affinity and cannot be cleaved to release BMP.

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Follistatin, gremlin, chordin, and chordin-like 2 are upregulated in osteoarthritis cartilage.285-287 Follistatin, which has been linked to inflammatory processes; gremlin, which is associated with hypertrophic phenotype; and chordin appear at different stages of osteoarthritis and with different topographic distribution. Because each antagonist binds preferentially to different BMPs, the differential expression may serve as a feedback mechanism to balance anabolic activities at different stages.

Direct analysis of cartilage or chondrocytes from osteoarthritis patients undergoing joint replacement has yielded more information than that available from RA patients, where cartilage damage is extensive. These studies indicate that chondrocytes produce not only proinflammatory cytokines, but also inhibitory and anabolic cytokines that modulate the responses. The impact of cytokines on chondrocyte function, particularly with respect to their various roles in cartilage destruction, has been reviewed extensively.2-4,87,351

ROLE OF THE CHONDROCYTE IN CARTILAGE PATHOLOGY

CARTILAGE MATRIX-DEGRADING PROTEINASES

The chondrocyte, the unique cell type in mature cartilage, maintains a stable equilibrium between the synthesis and the degradation of matrix components. During aging and joint diseases, such as RA and osteoarthritis, this equilibrium is disrupted, and the rate of loss of collagens and proteoglycans from the matrix exceeds the rate of deposition of newly synthesized molecules. The cartilage destruction in osteoarthritis is believed to be chondrocyte mediated in response to biomechanical insult, which may occur directly or indirectly through the production of cytokines and cartilage matrix-degrading proteinases in cartilage and other joint tissues (Fig. 3-6). Cartilage destruction in RA occurs primarily in areas contiguous with the proliferating synovial pannus as a result of the release and activation of proteinases from the synovial cells and, to some extent, at the cartilage surface exposed to matrix-degrading enzymes from polymorphonuclear neutrophils in the synovial fluids. In addition to the direct action of proteinases, the RA synovial tissues contribute indirectly to cartilage loss by releasing cytokines and other mediators that act on the chondrocytes to produce dysregulation of chondrocyte function.288 Understanding of basic cellular mechanisms regulating chondrocyte responses to inflammatory cytokines has been inferred from numerous studies in vitro using cultures of cartilage fragments or isolated chondrocytes and is supported by studies in experimental models of inflammatory arthritis, such as collagen-induced arthritis and antigen-induced arthritis in mice.289,290

Chondrocytes synthesize and secrete MMPs in latent forms, which are activated outside the cells via activation cascades. An important cascade in cartilage is initiated by plasmin, the product of plasminogen activator activity, which may be produced by the chondrocyte; plasmin activates latent stromelysin (MMP-3), an activator of latent collagenases. In early studies, chondrocytes were among the first identified sources of TIMP-1, and they are now known to synthesize additional TIMPs. Chondrocytes are assumed to be a major source of the TIMPs and MMPs, detected in synovial fluids, where they reflect an adaptive response to the local imbalance caused by increased production of active MMPs by chondrocytes and other joint tissues. The collagenases 1, 2, and 3 (MMP-1, MMP-8, and MMP-13); gelatinases (MMP-2 and MMP-9); stromelysin-1 (MMP-3); membrane type I MMP (MT1)MMP (MMP-14); and the aggrecanases, ADAMTS-4 and ADAMTS-5, specifically degrade native collagens and proteoglycans in cartilage matrix (Table 3-3) (see also Chapter 7).300,301,314 MMPs, aggrecanases, and the cleavage fragments generated by them are localized in regions of cartilage degradation110,291,292 and are detected in synovial fluids and cartilage from osteoarthritis and RA patients.33,293 The expression of MMP-13 in osteoarthritis and RA cartilage and its ability to degrade type II collagen more effectively suggest a major role for this enzyme in cartilage degradation. Postnatal overexpression of constitutively active MMP-13 in cartilage in mice produces osteoarthritis-like changes in

CARTILAGE IL-1

Figure 3-6  The role of chondrocyte-derived proteinases in ­ cartilage ­destruction in osteoarthritis. ­Although studies in vitro and in vivo have shown that the chondrocyte can respond directly to mechanical loading, to catabolic cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), and to cartilage breakdown products, the initiating signals and their relative importance have not been defined clearly. MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase; uPA, urinary plasminogen activator. (From Goldring MB: Osteoarthritis and cartilage: The role of cytokines. Curr Rheumatol Rep 2:459-465, 2000.)

Chondrocytes Active aggrecanases

(−)

Active MMPs

TIMPs Latent MMPs MMP-14 Plasmin uPA

(-)

Plasminogen PA inhibitors

SYNOVIUM Genetic Mechanical Biochemical Factors

Synovial fibroblasts

IL-1 ± TNF-α

Cartilage breakdown products

Synovial macrophages

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knee joints.294 Although elevated levels of MMPs in RA synovial fluids likely originate from the synovium, intrinsic chondrocyte-derived chondrolytic activity is present at the Table 3-3  Chondrocyte Proteinases That Mediate ­Degradation of Cartilage Matrix Proteinase Class

Cartilage Matrix Substrates

Activity

Matrix Metalloproteinases Collagenase-1, ­collagenase-2, ­collagenase-3   (MMP-1, MMP-8, MMP-13)

Stromelysins-1   (MMP-3, MMP-10)

Gelatinases   (MMP-2, MMP-9)

MT-MMP-1,   MT-MMP-2, MT-  MMP-3, MT-MMP-4 (MMP-14, MMP-15, MMP-16, MMP-17)

Matrilysin (MMP-7) Enamelysin   (MMP-20)

Collagen II

Aggrecan core   protein Aggrecan core   protein Collagens IX, XI Link protein, ­fibronectin proMMPs, proTNF Collagens II, XI Proteoglycans, link protein Collagen II

Fibrillar domain, 3/4 from N-terminus

N-telopeptide ­  (MMP-13) Asn341-Phe342 IGD Asn341-Phe342 IGD Telopeptide region

Telopeptide or ­denatured ­collagen chains Telopeptide

Fibronectin, aggrecan, pro­MMP-2,   proMMP-13 ProTNF Link protein COMP, link   protein

Aggrecanases Aggrecan core   ­protein IGD

Glu373-Ala374, Glu1545-Gly1546, Glu1714-Gly1715, Glu1819-Ala1820, Glu1919-Leu1920

Plasminogen   activators   (tPA, uPA)

Aggrecan,   ­fibronectin,   proMMPs

Activation of ­plasminogen gives rise to plasmin

Cathepsin G

Aggrecan,   collagen II,   proMMPs

(ADAMTS-1,   ADAMTS-4,   ADAMTS-5)

Serine

Collagens IX, XI

Telopeptides (optimal pH 4.0-6.5)

Link protein; ­aggrecan Aspartate Cathepsin D

Phagocytosed ECM components

cartilage-­pannus junction and in deeper zones of cartilage matrix in some RA specimens.295,296 MMP-1 does not derive from the RA synovial pannus, but is produced by chondrocytes.297 MMP-10, similar to MMP-3, activates procollagenases and is produced by the synovium and chondrocytes in response to inflammatory cytokines.298 MMP-14, produced principally by the synovial tissue, is important for synovial invasiveness, and antisense mRNA inhibition of this membrane proteinase has been shown to reduce cartilage destruction.299 Several of the MMPs, including MMP-3, MMP-8, MMP-14, MMP-19, and MMP-20, are capable of degrading proteoglycans. The members of the reprolysin-related proteinases of the ADAM family, particularly ADAMTS-4 and ADAMTS-5, are now regarded as the principal mediators of aggrecan degradation.300-302 The activities of MMPs and aggrecanases are complementary, however.303 Of the aggrecanases, to date, only aggrecanase-2, ADAMTS-5, seems to be associated with increased susceptibility to osteoarthritis, as shown in Adamts5-deficient mice.304,305 TIMP-3, but not TIMP-1, TIMP-2, or TIMP-4, is a potent inhibitor of ADAMTS-4 and ADAMTS-5 in vitro.306,307 The cysteine proteinases, cathepsins B and L, and the aspartic proteinase, cathepsin D, are lysosomal enzymes that may play a secondary role in cartilage degradation via intracellular digestion of products released by other proteinases. Cathepsin B also may have a role in extracellular degradation of collagen telopeptides, collagens IX and XI, and aggrecan. Cathepsin K is expressed in synovial fibroblasts on the cartilage surface at the pannus-cartilage junction and is upregulated by inflammatory cytokines.308 Among the known cathepsins, cathepsin K is the only proteinase that is capable of hydrolyzing type I and type II collagens at multiple sites within the triple-helical regions, and its requirement for acidic pH may be provided by the microenvironment between the synovial pannus and the cartilage.309 MT1-MMP (MMP-14) also may serve as an activator of other MMPs produced by chondrocytes. Other MMPs, including MMP-16 and MMP-28,310,311 and numerous ADAM/ ADAMTS family members, including ADAM-17/TACE (TNF-α converting enzyme),312 are expressed by chondrocytes, but their roles in cartilage have yet to be defined.313,314 Identification of the precise roles of these proteinases and their endogenous inhibitors in chondrocyte-mediated cartilage deg­ radation has provided the opportunity to develop targeted therapies that interfere with the activities of aggrecanases or MMPs without disrupting physiologic homeostasis.300,301,315 BALANCE OF CYTOKINES IN CARTILAGE DESTRUCTION

Cysteine Cathepsins B, K, L, S

53

In lysosomes (optimal pH 3.0-6.0)

ADAMTS, a distintegrin and metalloproteinase with thrombospondin-1 ­domains; COMP, cartilage oligomeric matrix protein; ECM, extracellular ­matrix; IGD, interglobular domain; MMP, matrix metalloproteinase; MT-MMP, membrane-type MMP; proMMP, proenzyme form of MMP; TNF, tumor ­necrosis factor.

Of the cytokines that affect cartilage metabolism, most are pleiotropic factors that were identified originally as immunomodulators, but were found to regulate cellular functions in cells of mesenchymal origin. IL-1 and TNF-α not only stimulate chondrocytes to synthesize cartilage matrix-degrading proteinases, but they also regulate matrix protein synthesis and cell proliferation. Considerable redundancy and overlap in the biologic activities exist among the individual cytokines, and they do not act alone, but rather in synergy or partnership with or in opposition to other cytokines via cytokine networks. In addition to IL-1 and TNF-α, IL-17

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and IL-18 have been characterized as catabolic cytokines, and their actions may be modulated by inhibitory or anabolic cytokines produced by the chondrocytes themselves or by other cells in joint tissues (Table 3-4). Investigations in vitro and in vivo have begun to sort out the complexities of the cytokine networks and to determine how the balance in normal homeostasis can be restored when it is disrupted (Fig. 3-7). Examination of type II collagen–induced arthritis and other types of induced arthritis in transgenic animals with overexpressed or deleted genes encoding cytokines, their receptors, or activators has provided further insights into the roles of these factors in cartilage destruction. Interleukin-1 and Tumor Necrosis Factor-α IL-1 and TNF-α are the predominant catabolic cytokines involved in the destruction of the articular cartilage. The first recognition of IL-1 as a regulator of chondrocyte function stems largely from the early work of Fell and ­ others,316,317 who identified a soluble factor, termed catabolin, in supernatants of normal, noninflamed porcine synovial fragment cultures that stimulated chondrocytes to degrade the surrounding cartilage matrix. Similar activities in ­ culture supernatants from mononuclear cells and rheumatoid synovium were attributed to IL-1,318,319 and the catabolin isoforms were identified as IL-1α and IL-1β.320 Since those early findings, numerous studies in vitro and in vivo indicate that IL-1 and TNF-α, originating primarily from the inflamed synovium, are the predominant catabolic cytokines involved in the destruction of the articular cartilage in RA.288-290

Table 3-4  Cytokines That Regulate Cartilage   Destruction Catabolic

Interleukin (IL)-1 Tumor necrosis factor (TNF)-α IL-17 IL-18

Modulatory

IL-6 Leukemia inhibitory factor (LIF) Oncostatin M IL-11

Inhibitory

IL-4 IL-10 IL-13 IL-1 receptor antagonist (IL-1Ra)

The major events in osteoarthritis pathogenesis occur within the cartilage itself, and there is evidence that the chondrocytes participate in this destructive process not only by responding to the cytokines released from other joint tissues, but also by synthesizing them.321,322 They may be exposed continuously to the autocrine and paracrine effects of IL-1 and other inflammatory mediators at high local concentrations. Chondrocytes in osteoarthritis cartilage, especially those in clonal clusters, are positive for IL-1 immunostaining and express IL-1β converting enzyme (caspase-1) and type 1 IL-1 receptor (IL-1R1).323 IL-1 colocalizes with TNF-α, MMP-1, MMP-3, MMP-8, MMP-13, and type II collagen cleavage epitopes in regions of matrix depletion in osteoarthritis cartilage.110,292,324 The increased sensitivity of osteoarthritis chondrocytes to IL-1 and TNF-α may be associated with increased levels of IL-1R1 and p55 TNF-R at localized sites.325,326 Colocalization of these cytokines, MMPs, and type II collagen cleavage epitopes also has been reported in regions of matrix depletion in RA ­cartilage.132,327 Originally known as cachectin, TNF-α produces many effects on chondrocytes in vitro that are similar to those of IL-1, including stimulation of the production of matrixdegrading proteinases and suppression of cartilage matrix synthesis.321,322 Although IL-1 is 100-fold to 1000-fold more potent on a molar basis than TNF-α, strong synergistic effects occur at low concentrations of the two cytokines together, eliciting more severe cartilage damage than injection of either cytokine alone.289 The concept that TNF-α drives acute inflammation, whereas IL-1 has a pivotal role in sustaining inflammation and cartilage erosion, has been derived from work in animal models of RA using cytokine-specific neutralizing antibodies, soluble receptors, or receptor antagonists and in transgenic or knockout mouse models.289,290 In a surgically induced osteoarthritis model, IL-1 knockout mice are protected against cartilage damage.328 A more recent study showed that crossing arthritic human TNF transgenic (hTNFtg) mice with IL-1α-­deficient and IL-β-deficient mice protects against cartilage erosion without affecting synovial inflammation.329 Cytokine Networks IL-1 and TNF-α also can induce chondrocytes to produce several other proinflammatory cytokines, including IL-6, leukemia inhibitory factor, IL-17, and IL-18, and chemokines.321,322,330 IL-6 seems to play a dual role by increasing Cartilage

Figure 3-7  The cytokine balance in cartilage metabolism. The soluble mediators toward the left of the balance promote the loss of cartilage matrix. The mediators on the right side prevent the synthesis or actions of the catabolic cytokines and prevent the loss of cartilage matrix. The anabolic factors, including insulin-like growth factor I (IGF-I) and bone morphogenetic proteins (BMPs), and prostaglandin E2 (PGE2) maintain or promote cartilage matrix synthesis. (Adapted from Goldring MB: Osteoarthritis and cartilage: The role of cytokines. Curr Rheumatol Rep 2:459-465, 2000.)

IL-1 TNF-α

Cartilage matrix degradation

IL-17 IL-18

LIF OSM

IL-6 IL-8

IL-4 IL-10 IL-13

IL-1Ra sTNF-R

IGF-I BMPs PGE2

matrix synthesis

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the IL-1 receptor antagonist, soluble TNF receptor, and TIMPs, while also enhancing immune cell function and inflammation.311,331 The activity of IL-6 requires soluble IL-6 receptor to synergize with IL-1 to stimulate the expression of MMPs and ADAMTS and to downregulate COL2A1 and aggrecan in cultured chondrocytes.332,333 IL-6 knockout mice are more susceptible to cartilage degeneration during aging,334 however, suggesting that this cytokine may play a protective role in normal physiology. Other members of the IL-6 family that act via receptors that heterodimerize with gp130 also may serve modulatory roles. IL-11 shares several actions of IL-6, including stimulation of TIMP production without affecting MMP production by chondrocytes,332 and may inhibit cartilage destruction.335 Leukemia inhibitory factor participates in a positive feedback loop by increasing the production of IL-6 by chondrocytes. Oncostatin M (OSM), a product of macrophages and activated T cells, is a potent stimulator of chondrocyte production of MMPs and aggrecanases in synergism with IL-1 or TNF-α.298,332,336 Direct evidence supporting a role for OSM in contributing to cartilage loss in inflammatory arthritis is provided by studies in animal models.337,338 IL-17 and IL-18 are potent catabolic factors that stimulate the production of IL-1β, MMPs, IL-6, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, and microsomal PGE synthase-1 (mPGES-1) by human chondrocytes.339 IL-17 is produced by activated T helper type 1 (Th1), or CD4+, lymphocytes and binds to a receptor that is not related to any known cytokine receptor family. IL-17A, one of at least six family members, is primarily a product of Th17 cells, a newly described subset of T cells, and is a potent inducer of catabolic responses in chondrocytes by itself or in synergy with other cytokines.340 IL-17 can drive T cell–dependent erosive arthritis in TNF-deficient and IL-1Ra knockout mice, and treatment of collagen-induced arthritis or antigen-induced arthritis mice with neutralizing IL-17 antibody effectively inhibits cartilage destruction in those models of RA.341 A role for IL-17 in the promotion of angiogenesis through induction of VEGF in osteoarthritis chondrocytes and synovial fibroblasts has been proposed.217 IL-18 is produced by macrophages, its receptor shares homology with IL-1RI, and it has effects similar to IL-1 in human chondrocytes, but stimulates chondrocyte apoptosis.342,343 IL-18 deficiency or blockade with IL-18-neutralizing antibody or IL-18-binding protein reduces cartilage destruction and inflammation, and IL-18 gene transfer promotes IL-1-driven cartilage destruction in a TNF-α-independent manner.344 Of the other members of the IL-1 family identified by DNA database searches, IL-1F8 seems to be capable of stimulating IL-6, IL-8, and nitric oxide production by human chondrocytes, but at 100-fold to 1000-fold higher concentrations than IL-1.345 IL-32, a more recently discovered cytokine that induces TNF-α, IL-1β, IL-6, and chemokines and is expressed in the synovia of patients with RA, contributes to TNF-α-dependent inflammation and cartilage proteoglycan loss.346 Inhibitory Cytokines IL-4, IL-10, IL-13, and the naturally occurring IL-1Ra are classified as inhibitory cytokines because they decrease the production and activities of the catabolic and proinflammatory

55

cytokines in chondrocytes in vitro and suppress cartilage destruction in vivo (see Table 3-4).289,323,347,348 IL-4 and IL-10 inhibit cartilage-degrading proteinases and reverse some effects of the catabolic cytokines in vitro, and together they produce a synergistic suppression of cartilage destruction in vivo. The efficacy of IL-4, IL-10, and IL-13 in retarding cartilage damage may be related partly to their stimulatory effects on IL-1Ra production,323,349 and their therapeutic application has been proposed as a means of restoring the cytokine balance in RA.350 IL-1Ra is capable of blocking the actions of IL-1 if added at sufficiently high concentrations in vitro and is among the first agents to be developed for anticytokine therapy.288,351 IL-1Ra can be produced by the same cells that secrete IL-1 and exists as at least three isoforms, including an intracellular form. Despite the capacity of IL-4 to inhibit the effects of proinflammatory cytokines on chondrocyte function,352,353 differential effects have been observed in mice depending on the model.354,355 Gene transfer of IL-10 in combination with IL-1Ra inhibits cartilage destruction by a mechanism involving activin, a TGF-β family member.356 IL-10 is part of the response induced by immunomodulatory neuropeptides that have been shown to inhibit inflammation and cartilage and bone destruction by downregulating the Th1-driven immune response and upregulating IL-10/TGFβ–producing T regulatory lymphocytes.357 IL-13 decreases the breakdown of collagen and proteoglycans by inhibiting IL-1-induced and OSM-induced MMP-3 and MMP-13 expression.358 Local gene transfer of IL-13 inhibits chondrocyte death and MMP-mediated cartilage degradation despite enhanced inflammation in the immune complex arthritis model.359 The inhibitory cytokines may have direct effects on cartilage metabolism and indirect effects by mediating the production and actions of catabolic cytokines. Other Mediators The balance of mediators determining normal homeostasis is complex, and modulation of their activities may produce positive or negative effects on chondrocyte function. In addition to inducing the synthesis of MMPs and other proteinases by chondrocytes, IL-1 and TNF-α upregulate the production of nitric oxide via iNOS (or NOS2), and prostaglandin (PG) E2 by stimulating the expression or activities of COX-2, mPGES-1, and soluble phospholipase A2. In the production of prostaglandins, mPGES-1, which is induced by IL-1 in chondrocytes, is a major player.360,361 Although PGE2 and nitric oxide have been well characterized as proinflammatory mediators, there is evidence that they also may be protective and play roles in chondrocyte survival and responses to mechanical stress. COX-2 is involved in the chondrocyte response to high shear stress, associated with reduced antioxidant capacity and increased apoptosis.362 The mechanisms of cross-talk between prostaglandins and nitric oxide in chondrocytes have been reviewed.322 Another regulator is peroxisome proliferator-activated receptor γ (PPARγ), which is activated by the endogenous ligand 15-deoxy-∆12,14 PGJ2, or 15-deoxy-∆ 12,14. PPARγ activation opposes the induction of COX-2, iNOS, MMPs, and mPGES-1 and the suppression of aggrecan synthesis by IL-1.339,363 Evidence indicates that PPARα agonists may

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protect chondrocytes against IL-1-induced responses by increasing the expression of IL-1Ra.364 The IL-1-induced COX-2 response depends on the differentiated phenotype of chondrocytes, and PGE2 opposes the effects of IL-1 by stimulating type II collagen and inhibiting type I collagen gene expression.365,366 Roles for nitric oxide as a mediator of other IL-1-induced responses, including the inhibition of aggrecan synthesis, enhancement of MMP activity, and reduction in IL-1Ra synthesis, also have been suggested.367 Nitric oxide also may increase chondrocyte susceptibility to injury by other oxidants and contribute to the resistance to the anabolic effects of IGF-I. Nitric oxide also has been implicated as an important mediator in chondrocyte apoptosis. PGE2 may mediate directly the induction of apoptosis by nitric oxide or sensitize chondrocytes to nitric oxide–induced apoptosis.368 There is evidence, however, that nitric oxide may inhibit cytokine production or activity in chondrocytes. IL-1 seems to protect chondrocytes from CD95-induced apoptosis by a mechanism that is independent of IL-1-induced nitric oxide. Novel mediators that affect chondrocyte metabolism include the IL-1-induced suppressor of cytokine signaling 3, which acts as a negative feedback regulator during IGF-I desensitization in the absence of nitric oxide by inhibiting insulin receptor substrate-1 phosphorylation.240 The receptor for advanced glycation end products interacts preferentially with S100A4, a member of the S100 family of calcium-binding proteins, in chondrocytes and stimu­ lates MMP-13 production.369 The fibroblast activation protein α, a membrane serine proteinase, which colocalizes in synovium with MMP-1 and MMP-13 and is induced by IL-1 and OSM in chondrocytes, may play a role in collagen degradation.370,371 Many of these proteins may be activated during the chondrocyte response to abnormal stimuli and may serve as endogenous mediators of cellular responses to stress and inflammation. Adipokines, which were identified originally as products of adipocytes, also have roles in cartilage metabolism.372 White adipose tissue is a major source of proinflammatory and anti-inflammatory cytokines, including IL-1Ra and IL-10,373 and the dysregulated balance between leptin and other adipokines, such as adiponectin, promotes destructive processes during inflammation.374 Leptin expression is enhanced during acute inflammation, correlating negatively with inflammatory markers in RA sera,375 and may serve as a link between the neuroendocrine and immune systems.376 The elevated expression of leptin in osteoarthritis cartilage and in osteophytes and its capacity to stimulate IGF-I and TGF-β1 synthesis suggest a role for this adipokine in anabolic responses of chondrocytes.377 Leptin synergizes with IL-1 or interferon-γ to increase nitric oxide production in chondrocytes,378 and leptin deficiency attenuates inflammatory processes in experimental arthritis.379 Chemokines Chemokines, which are small heparin-binding cytokines identified originally as chemotactic factors, are classified as C, CX3C, or CC molecules, indicating the presence of distinct N-terminal cysteine (C) residues. Chondrocytes, when activated by IL-1 and TNF-α, express several chemokines, including IL-8, monocyte chemoattractant protein

Table 3-5  Chemokines and Receptors   in Chondrocytes Functional Name

Systematic Name

Chemokine Receptor

GROα

CXCL1

CXCR1, CXCR2

IL-8

CXCL8

CXCR1, CXCR2

MCP-1

CCL2

CCR2

MIP-1α

CCL3

CCR1, CCR5

MIP-1β

CCL4

CCR5

RANTES

CCL5

CCR1, CCR3, CCR5

SDF-1

CXCL12

CXCR4

Groα, growth-related oncogene α; IL-8; interleukin-8; MCP-1, monocyte chemoattractant protein-1; MIP-1, macrophage inhibitory protein-1; RANTES, regulated on activation, normal T cell expressed and secreted; SDF-1, stromalderived growth factor-1. Chemokines are classified according to the positions of the first two cysteines (C) of the four conserved N-terminal cysteines: CC chemokine ligand (CCL), first two cysteines are adjacent; CXC chemokine ligand (CXCL), first two cysteines are separated by amino acid X other than cysteine. CCR, CC chemokine receptor; CXCR, CXC chemokine receptor.

(MCP)-1, MCP-4, macrophage inhibitory protein (MIP)1α, MIP-1β, RANTES (regulated on activation normal T cell expressed and secreted), and growth-related oncogene (GRO) α, and the receptors that enable responses to some of these chemokines, and may feedback regulate synovial cell responses (Table 3-5).380,381 The first report of ­expression of functional CC and CXC chemokine receptors (CCR and CXCR) on chondrocytes showed that interaction of these receptors with their corresponding ligands, MCP-1, RANTES, and GROα, resulted in upregulation of MMP-3.380,382 Normal and osteoarthritis chondrocytes express the C-C chemokines, MCP-1, MIP-1α, MIP-1β, and RANTES. RANTES increases expression of its own receptor, CCR5. MCP-1 and RANTES increase MMP-3 expression, inhibit proteoglycan synthesis, and enhance proteoglycan release from the chondrocytes. The RANTES receptors CCR3 and CCR5, but not CCR1, are expressed in normal cartilage, whereas all three receptors are expressed in osteoarthritis cartilage or after stimulation of normal chondrocytes by IL-1β. RANTES induces the expression of iNOS, IL-6, and MMP-1. High levels of stromal cell–derived factor 1 are detected in RA synovial fluids, and its receptor, CXCR4, is expressed by chondrocytes, but not synovial fibroblasts, suggesting a direct influence of this chemokine on cartilage damage.383 Microarray studies have elucidated many chemokines that are inducible in chondrocytes by fibronectin fragments and cytokines.184 Stromal cell–derived factor 1 and several other cytokines also increase the synthesis of S100A, N-acetyl-β-D-glucuronidase, cathepsin B, and MMPs by chondrocytes and DNA synthesis, cell proliferation, and PGE2 production.384,385 Osteoarthritis chondrocytes in contact with autologous T lymphocytes produce enhanced levels of MMP-1, MMP-3, MMP-13, and RANTES.386 In addition to recruiting leukocytes to sites of inflammation in arthritic joints and mediating synovial fibroblast responses and actions, chemokines are capable of modulating chondrocyte functions that are associated with cartilage degradation.

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STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

CYTOKINE SIGNALING PATHWAYS INVOLVED IN CARTILAGE METABOLISM Human articular chondrocytes are capable of expressing receptors of the IL-1R/Toll-like receptor (TLR) superfamily, including TLR1, TLR2, and TLR4. IL-1, TNF-α, peptidoglycans, lipopolysaccharide, or fibronectin fragments induce the expression of TLR2, associated with increased production of MMPs, nitric oxide, PGE, and VEGF.387-389 Cartilage proteoglycan loss in streptococcal cell wall–induced arthritis is predominantly dependent on TLR2 signaling.390 In immune complex–mediated arthritis, TLR4 regulates cartilage destruction by IL-10-mediated upregulation of Fcγ receptor expression and enhanced cytokine production.391 Although the receptors for IL-1 and TNF-α and associated adapter molecules are distinct, they share the capacity to activate some of the same signaling pathways (Fig. 3-8).322,348,392,393 The major pathways induced by catabolic cytokines involve signal transduction by the stress-activated protein kinases JNKs and p38 kinases and the nuclear factor κB (NFκB) and PI3K pathways. The JAK/STAT ­signaling

pathway is important for signaling by gp130 cytokines, including IL-6 and OSM.394 Specific adapter molecules involved in the pathways induced by TNF-α receptors, which are members of the TNF receptor superfamily, are different from the adapter molecules used by IL-1 signaling pathways. The TNF receptor pathway uses TNF receptor associated factor 2 (TRAF2), TRAF6, and the receptor interacting protein kinase, whereas the IL-1 receptor pathway uses TRAF6, IL-1 receptor-associated kinase, and evolutionarily conserved signaling intermediate in Toll pathways as adapter molecules. Signaling through TNF-RI associated with TNF receptor–associated death domain receptor activates apoptosis, whereas TNF-RII signaling through TRAF2 activates JNK and NFκB. In contrast to ERK-1 and ERK-2, p38 and JNK are weakly activated by growth factors. Studies in chondrocytes in vitro have shown that the p38 and JNK cascades mediate the induction of proteinases and proinflammatory genes by IL-1 and TNF-α.348 These pathways also may be activated in chondrocytes by mechanical stress and cartilage matrix products via integrins and other receptor-­mediated events.395-397

IL-1

IL-1RAcP

gp130

IL-1R1

TIR

RIP NIK

SAPK/JNK

IKK1/2

P ETS

P

P Jun P

Nuclear Translocation Sp1 B Basal Transcriptio n

DNA Binding

IκB

P

NFκB

P P

Stat3

P ATF- 2

AkT

Stat3

MKK4/7

IκB P Fo s

3

3

TRAF6

at

DD IRAK2

MEKKI

p38 MAPK

St

DD IRAK

P

P

MyD88

at

MyD88

MKK3/6

JAK

JAK

PI3K TIR

57

St

PART 1 

CBP B Target Gene Transactivation

Figure 3-8  Intracellular signaling pathways activated by interleukin-1 (IL-1) in chondrocytes. Binding of IL-1 to the type I IL-1 receptor (IL-1R1) leads to the recruitment of the IL-1R accessory protein (IL-1RAcP). The cytoplasmic Toll/IL-1 receptor (TIR) domains of the receptor recruit the MyD88 via its TIR, and the MyD88 death domain (DD) recruits the IL-1 receptor–associated kinases (IRAK and IRAK2) to the receptor complex before being rapidly phosphorylated and degraded. The IRAKs mediate tumor necrosis factor receptor–associated factor 6 (TRAF6) oligomerization, initiating various protein kinase cascades, the major ones of which involve (1) the stress-activated protein kinases, p38 mitogen-activated protein kinase (MAPK), and c-Jun  N-terminal kinase (JNK), which lead to activation of activator protein-1 (AP-1) (c-Fos/c-Jun), activating transcription factor-2 (ATF-2), and E Twenty Six (ETS) factors, among other transcription factors, and (2) inhibitor of κB (IκB) kinases 1 and 2 (IKK-1 and IKK-2), which lead to activation of nuclear factor κB (NFκB). TNF-α also stimulates these pathways, but via TRAF2 and TRAF5. Other signaling pathways also may influence the target gene responses, such as the growth factor–induced or chemokine-induced phosphatidylinositol 3-kinase (PI3K) via the serine/threonine kinase, Akt/protein kinase B, and the gp130 cytokine–induced janus activating kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. The responses of the target genes depend on the presence of DNA sequences within the respective promoters that bind to the various transcription factors.

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The upregulation of IL-1 and TNF-α expression via these pathways suggests their involvement as secondary mediators in a feedback mechanism. At least four isoforms of p38 MAPK exist with different substrate specificities and differential effects on essential chondrocyte functions. JNKs are serine threonine protein kinases that phosphorylate Jun family members, components of AP-1 transcription factors, and they exist as three JNK isoforms, JNK1, JNK2, and JNK3, in humans. A potent JNK1/2 inhibitor, SP600125, which blocks inflammation and joint damage in animal models of RA, and other JNK isoform–specific inhibitors are useful tools for analyzing chondrocyte function in vitro and in vivo. Activated JNK is detected in osteoarthritis, but not in normal cartilage, and JNK inhibition attenuates cytokine-induced chondrocyte responses.398,399 NFκB is a “master switch” of the inflammatory cascade.400 NFκB is actvated when the IκB kinases IKK-1 and IKK-2 phosphorylate IκB, dissociating it from NFκB and permitting translocation of active NFκB to the nucleus. NFκB mediates the expression of cytokines and chemokines induced by fibronectin fragments,184 and inhibition of DNA-binding activity of NFκB by agents that deplete polyamine blocks IL-1 and TNF-α without promoting chondrocyte apoptosis.401 In addition to NFκB, transcription factors that are members of the C/EBP, ETS, and AP-1 families are important for the regulation of gene expression by IL-1 and TNF-α in chondrocytes.87

ROLE OF THE CHONDROCYTE IN CARTILAGE REPAIR AGING OF ARTICULAR CARTILAGE It is important, but often difficult, to distinguish among the effects of aging itself and diseases such as osteoarthritis that become more common with increasing age.220,402 In both cases, biochemical alterations in matrix composition are reflected in changes in cartilage structure.403 The thickness of articular cartilage, as shown by magnetic resonance imaging, decreases with increasing age.404 Fatigue fracture of superficial collagen bundles and a heterogeneous depletion of glycosaminoglycans at the periphery of joint surfaces may contribute to the mild splitting and fraying of superficial cartilage, which is termed fibrillation. If fibrillation progresses into deeper layers of cartilage, abnormal multicellular clusters of chondrocytes that stain intensely for glycosaminoglycans are found at the base of clefts. These changes include decreased size and aggregation of aggrecan and increased collagen denaturation, resulting in the loss of compressive stiffness and tensile strength.9 Zonal differences in tensile strength and compressive resistance are related to differences in matrix composition and can be observed to change during the aging of adult articular cartilage and in response to traumatic damage. The territorial, or pericellular, matrix and the interterritorial matrix differ in the amounts and types of matrix proteins. The chondrocytes are normally surrounded by a 2-μm pericellular matrix, composed of a highly branched filamentous network of collagen VI tetramers, which serves as a scaffold for decorin, biglycan, perlecan, and chondroadherin, which predominate in this region, and hyaluronan, fibrilin-1, and PRELP. The interterritorial region, in contrast, contains primarily

a collagen II/XI fibril network, which binds decorin, fibromodulin, collagen IX, and COMP, and large numbers of intact aggrecan molecules attached via link protein to long chains of hyaluronic acid. In the deep zone, the interterritorial region most remote from the cells contains a larger number of degraded aggrecan molecules that lack the G3 domain. Proteoglycans in aged cartilage have a wide range of sizes, with small forms resulting from low substitution of glycosaminoglycan residues and shorter lengths compared with glycosaminoglycans in young articular cartilage.9 Unsubstituted proteoglycan core proteins of aggrecan and biglycan are detectable in articular cartilage from elderly subjects. Hyaluronan content increases in aged cartilage, but with a reduced mean chain length, and link protein also seems to be fragmented. Collagen fibrils become thinner with age and are less densely packed. Nonenzymatic glycation results in the formation and accumulation of the advanced-­glycation end product pentosidine in long-lived proteins, including cartilage collagen and aggrecan.405 Such biochemical changes may result partly from changes in chondrocyte synthetic function and from increased susceptibility of the matrix to degradation.406 Increased and more extensive collagen degradation can be observed in cartilage from older, healthy individuals, and similar to cartilage in early osteoarthritis, the damage is concentrated closer to the ­articular surface and colocalizes with MMP-13 activity.110 (See Chapter 89 for a detailed discussion of the pathogenesis of osteoarthritis.) AGING CHONDROCYTE Chondrocyte function, including mitotic and synthetic activity, deteriorates with age. Degradative changes are generally due to the actions of proteinases and are, at least partially, the cumulative consequences of adverse conditions, such as mechanic insults or inflammation, to which the chondrocyte is exposed throughout life. Deficiencies in cartilage matrix proteins also may disrupt chondrocyte-matrix interactions that are important to cell survival. The decline in chondrocyte number also may be attributed to increased cell death with age. Although programmed cell death, or apoptosis, increases with age in adult rats and mice, this may be due to skeletal growth that occurs throughout life in these animals. In human adult cartilage, apoptotic cell removal does not seem to be common, however.41 Replicative senescence, detected as β-galactosidase activity and decreased telomere length, has been proposed to contribute to the age-related changes in the proliferative potential of adult articular chondrocytes.407,408 TGF-β, FGFs, IGF-I, and other anabolic factors that support cartilage matrix biosynthesis are expressed at declining levels with aging, or their activities are downregulated.220 The capacity of BMP-6 to stimulate proteoglycan synthesis and the production of BMP-7 (OP-1) decline with age.223,270 Chondrocytes also show an age-related decline in the anabolic response to IGF-I, possibly owing to increased synthesis of IGFBP-3, which is itself antiproliferative. Chondrocytes from elderly donors depend strongly on IGF-I and IGF-II for survival.226 It has been proposed that the reduction in TGF-β signaling in aging chondrocytes may be a factor in their reduced capacity to repair cartilage.409

PART 1 

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STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

MARKERS OF CARTILAGE MATRIX DEGRADATION AND TURNOVER With increasing knowledge of the composition of the cartilage matrix, molecular markers in body fluids have been identified for monitoring changes in cartilage metabolism and for assessing joint damage in arthritis.33-35,410 Molecules originating from the articular cartilage, including aggrecan fragments, which contain chondroitin sulfate and keratan sulfate; type II collagen fragments; collagen pyridinoline cross-links; and COMP, are usually released as degradation products as a result of catabolic processes. Specific monoclonal antibodies have been developed for analyzing osteoarthritis and RA body fluids for products of proteoglycan or collagen degradation (catabolic epitopes) or synthesis of newly synthesized matrix components (anabolic neoepitopes), which represent attempts to repair the damaged matrix. Different monoclonal antibodies can distinguish subtle biochemical differences in chondroitin sulfate or keratan sulfate chains that result from degraded versus newly synthesized proteoglycans. Such epitopes can be detected in the synovial fluids and serum of patients with osteoarthritis and RA, and the synovial fluid-to-serum ratio has been suggested as a potential diagnostic indicator. The degradation of aggrecan in cartilage has been characterized using antibodies 846, 3B3(−), and 7D4, which detect chondroitin sulfate neoepitopes; 5D4, which detects keratan sulfate epitopes; and the VIDIPEN and NITEGE antibodies, which recognize aggrecanase and MMP cleavage sites within the interglobular G1 domain of aggrecan (see Chapter 32).300,301 Similarly, the synthesis of type II collagen can be monitored by measuring serum and synovial fluid levels of the carboxyl-terminal propeptide, and urinary excretion of hydro­ xylysyl pyridinoline cross-links may indicate collagen degradation.34,35 Specific antibodies that recognize epitopes on denatured type II collagen at the collagenase cleavage site are promising diagnostic reagents. These include the C2C antibody (previously known as Col2-3/4C Long mono) that has been used to detect cleavage of the triple helix of type II collagen in experimental models and in osteoarthritis and RA cartilage.110,327 The ratios of these markers to the synthetic marker, CPII, are associated with a greater likelihood of radiologic progression in osteoarthritis patients.36 These biomarker assays have been used as research tools and are currently being developed and validated as diagnostic tools for monitoring cartilage degradation or repair in osteoarthritis and RA patient populations and for assessment of treatment (see Chapters 67 and 91). Although a single marker may be insufficient, it may be possible eventually to determine a combination of biomarkers that may discriminate between different stages of osteoarthritis in different populations. REPAIR OF ARTICULAR CARTILAGE Articular cartilage has a poor capacity for regeneration, and pharmacologic enhancement of cartilage repair would have considerable potential in the treatment of arthritides and intra-articular fractures. The extent of intrinsic repair of a cartilage defect depends on the depth of the lesion and whether the defect penetrates the subchondral bone plate.411 Repair of superficial defects occurs if the chondrocytes

59

remain viable. Owing to the avascularity of cartilage, it differs from most other tissues in its response to injury. The vascular-dependent inflammatory and reparative phases of the classic healing response are unavailable. Partial defects generally do not regenerate because resident chondrocytes cannot migrate into the defect, and there is no vascular access for progenitor cells. Deep cartilage defects with disruption of the subchondral bone plate initiate vascular responses, however, including bleeding, fibrin clot ­ formation, and inflammation, which permit cell invasion from the blood or underlying bone marrow. The lesion becomes filled by granulation tissue, which is eventually replaced by fibrocartilage, but rarely by true hyaline cartilage. Current procedures for cartilage repair include joint lavage, tissue débridement, microfracture of the subchondral bone, and the transplantation of autologous or allogeneic osteochondral grafts, in addition to the ultimate therapy of total joint replacement.411 These procedures may lead to the formation of fibrous tissue, chondrocyte death, and further cartilage degeneration and have variable success rates. Transplantation of cultured autologous chondrocytes has been used successfully to repair small, full-thickness lesions in knee cartilage in young adults with sports injuries.412 Evidence of successful repair has been shown by turnover and remodeling of the initial fibrocartilaginous matrix formed by the transplanted chondrocytes owing to enzyme degradation and new synthesis of type II collagen.413 The donor site, although not load bearing, may undergo significant morbidity and osteoarthritic changes. A randomized, controlled trial suggests little difference in efficacy compared with microfracture of the subchondral bone.414 Major challenges for cartilage repair are the restoration of the three-dimensional collagen structure and integration of the newly synthesized matrix with the resident tissue.411,415 Novel approaches using autologous chondrocytes genetically engineered ex vivo to express anabolic factors have been explored to promote differentiation before implantation in the defect.225,416 The induction of the synthesis of IGF-I, TGF-β, BMP-2, and BMP-7 by gene transfer increases the synthesis of cartilage proteoglycans and collagens in cultured chondrocytes.417 Many of these factors, including BMP-2, BMP-4, BMP-6, BMP-7, BMP-9, TGF-β, and CDMP-1, are able to induce chondrogenic differentiation of mesenchymal progenitor cells in vitro.418,419 BMP-2 and BMP-7 (OP-1) are approved for multiple indications in the area of bone fracture repair and spinal fusion and can promote cartilage repair in various models of focal cartilage defects. The introduction of BMPs into joints via in vivo or ex vivo gene delivery or in injectable or implantable carriers has been investigated for the repair of small defects in animal models.420 Findings in vitro using BMP-2, BMP-9, and BMP-13 suggest, however, that they may serve as potent anabolic factors for juvenile cartilage, which contains chondroprogenitors, but not for adult cartilage.421 Several studies have shown that injection of free TGF-β or adenovirus-mediated delivery of TGF-β promotes fibrosis and osteophyte formation, while stimulating proteoglycan synthesis in cartilage. Based on these observations, local application of molecules that block endogenous TGF-β sig­ nal­ing, such as the soluble form of TGF-βRII, inhibitory SMADs, or the physiologic antagonist, latency-associated peptide-1, have been proposed as a means for blocking

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osteophyte formation.422 Gene transfer of combinations of anabolic factors and inhibitory cytokines combined with cartilage engineering approaches may be a long-term goal for repair of the extensive defects in RA or late osteoarthritis patients and for the prevention of further damage. The use of bone marrow–derived chondroprogenitor cells or mesenchymal stem cells from other sources as gene delivery vehicles to the site of cartilage damage is a promising strategy for the future, although many challenges remain.

SUMMARY AND CONCLUSION As the single cellular component in adult articular cartilage, chondrocytes are responsible for maintaining the ECM components in a low-turnover state. The composition and organization of matrix macromolecules, unique to this tissue, are determined during chondrocyte differentiation in embryonic and postnatal development of cartilage. Adult chondrocytes exist in a hypoxic environment within articular cartilage. They are inactive metabolically, partially as a result of an absence of blood vessels and nerves, and display a rounded morphology that reflects their quiescent state. Chondrocyte culture models have been developed with the aim of maintaining differentiated phenotypes, characterized by the major collagen and proteoglycan constituents, type II collagen and aggrecan. Chondrocytes interact with specific ECM components via integrins, annexins, and CD44 on the cell surface. Studies in vitro and in vivo have shown that adult articular chondrocytes are capable of responding to biologic and mechanical stimuli that are anabolic or catabolic. Anabolic factors include members of the TGF-β/BMP family and IGF-I. Catabolic factors include proinflammatory cytokines, such as IL-1, TNF-α, IL-17, and IL-18, which stimulate the synthesis of matrix-degrading proteinases, such as MMPs and aggrecanases, and inhibit cartilage matrix-protein synthesis. Many of the signaling pathways and transcription factors that mediate the responses of chondrocytes to these factors have been elucidated, but how they orchestrate the specific chondrocyte functions is complex and not fully understood. Under physiologic conditions, the adult articular chondrocyte maintains a stable equilibrium between the synthesis and the degradation of matrix components. Adult chondrocytes have a poor capacity for mediating effective repair of extensive cartilage lesions, and this capacity declines with age. Age-related changes in chondrocyte function decrease the ability of the cells to maintain the tissue, including decreased synthetic activity, synthesis of smaller and less uniform aggrecan molecules and less functional link proteins, and decreased responsiveness to anabolic growth factors. Further understanding of how the adult articular chondrocyte functions within its unique environment would aid in the development of rational strategies for maintaining homeostasis and protecting against cartilage damage. REFERENCES   1. Benedek TG: A history of the understanding of cartilage. Osteoarthritis Cartilage 14:203-209, 2006.   2. Otero M, Goldring MB: Cells of the synovium in rheumatoid arthritis. Chandrocytes. Arthritis Res Ther, 9:220, 2007.   3. Goldring MB, Goldring SR: Osteoarthritis. J Cell Physiol 213: 626-634, 2007.

  4. Goldring MB: Update on the chondrocyte lineage and implications for cell therapy in osteoarthritis. In Sharma L, Berenbaum F (eds): Osteoarthritis. A Companion to Rheumatology. Philadelphia, Mosby, 2007, pp 53-76.   5. Goldring MB: The musculoskeletal system, B: Articular cartilage. In Klippel JH, Crofford LJ, Stone JH, et al (eds): Primer on the Rheumatic Diseases. Atlanta, Arthritis Foundation, 2001, pp 10-16.   6. Poole AR: Cartilage in health and disease. In Koopman W (ed): Arthritis and Allied Conditions: A Textbook of Rheumatology. Philadelphia, Lippincott Williams & Wilkins, 2005, pp 223-269.   7. Stockwell RA: Metabolism of cartilage. In Hall BK (ed): Cartilage: Structure, Function and Biochemistry, Vol 1. New York Academic Press, 1983, pp 253-280.   8. Eyre DR, Weis MA, Wu JJ: Articular cartilage collagen: An irreplaceable framework? Eur Cell Mater 12:57-63, 2006.   9. Dudhia J: Aggrecan, aging and assembly in articular cartilage. Cell Mol Life Sci 62:2241-2256, 2005. 10. Poole AR, Pidoux I, Reiner A, et al: An immunoelectron microscope study of the organization of proteoglycan monomer, link protein, and collagen in the matrix of articular cartilage. J Cell Biol 93:921-937, 1982. 11. Hyllested JL, Veje K, Ostergaard K: Histochemical studies of the extracellular matrix of human articular cartilage—a review. Osteoarthritis Cartilage 10:333-343, 2002. 12. Poole AR, Kojima T, Yasuda T, et al: Composition and structure of articular cartilage: A template for tissue repair. Clin Orthop 391:S26-S33, 2001. 13. Hunziker EB, Michel M, Studer D: Ultrastructure of adult human articular cartilage matrix after cryotechnical processing. Microsc Res Tech 37:271-284, 1997. 14. Stockwell RA: Inter-relationship of articular cartilage thickness and cellularity. Ann Rheum Dis 31:424, 1972. 15. Wong M, Wuethrich P, Buschmann MD, et al: Chondrocyte biosynthesis correlates with local tissue strain in statically compressed adult articular cartilage. J Orthop Res 15:189-196, 1997. 16. Muir H, Bullough P, Maroudas A: The distribution of collagen in human articular cartilage with some of its physiological implications. J Bone Joint Surg Br 52:554-563, 1970. 17. Stanescu V, Stanescu R, Maroteaux P: [Differences in distribution of type I and type II collagens in the superficial and intermediary zones of articular cartilage]. C R Acad Sci Hebd Seances Acad Sci D 283:279-282, 1976. 18. Maroudas A, Muir H, Wingham J: The correlation of fixed negative charge with glycosaminoglycan content of human articular cartilage. Biochim Biophys Acta 177:492-500, 1969. 19. Franzen A, Inerot S, Hejderup SO, et al: Variations in the composition of bovine hip articular cartilage with distance from the articular surface. Biochem J 195:535-543, 1981. 20. Ratcliffe A, Fryer PR, Hardingham TE: The distribution of aggregating proteoglycans in articular cartilage: Comparison of quantitative immunoelectron microscopy with radioimmunoassay and biochemical analysis. J Histochem Cytochem 32:193-201, 1984. 21. Lane LB, Villacin A, Bullough PG: The vascularity and remodelling of subchondrial bone and calcified cartilage in adult human femoral and humeral heads: An age- and stress-related phenomenon. J Bone Joint Surg Br 59:272-278, 1977. 22. Kempson GE, Muir H, Swanson SA, et al: Correlations between stiffness and the chemical constituents of cartilage on the human femoral head. Biochim Biophys Acta 215:70-77, 1970. 23. Kempson GE, Muir H, Pollard C, et al: The tensile properties of the cartilage of human femoral condyles related to the content of collagen and glycosaminoglycans. Biochim Biophys Acta 297:456472, 1973. 24. Schmidt MB, Mow VC, Chun LE, et al: Effects of proteoglycan extraction on the tensile behavior of articular cartilage. J Orthop Res 8:353-363, 1990. 25. Urban JP, Maroudas A, Bayliss MT, et al: Swelling pressures of proteoglycans at the concentrations found in cartilaginous tissues. Biorheology 16:447-464, 1979. 26. Lai WM, Hou JS, Mow VC: A triphasic theory for the swelling and deformation behaviors of articular cartilage. J Biomech Eng 113: 245-258, 1991. 27. Savarirayan R, Rimoin DL: The skeletal dysplasias. Best Pract Res Clin Endocrinol Metab 16:547-560, 2002. 28. Helminen HJ, Saamanen AM, Salminen H, et al: Transgenic mouse models for studying the role of cartilage macromolecules in osteoarthritis. Rheumatology (Oxf) 41:848-856, 2002.

PART 1 

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STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

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STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

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Cartilage and Chondrocytes

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192. Yasuda T, Poole AR, Shimizu M, et al: Involvement of CD44 in induction of matrix metalloproteinases by a COOH-terminal heparin-binding fragment of fibronectin in human articular cartilage in culture. Arthritis Rheum 48:1271-1280, 2003. 193. Yasuda T, Kakinuma T, Julovi SM, et al: COOH-terminal heparin-binding fibronectin fragment induces nitric oxide production in rheumatoid cartilage through CD44. Rheumatology (Oxf) 43:11161120, 2004. 194. Embry Flory JJ, Fosang AJ, Knudson W: The accumulation of intracellular ITEGE and DIPEN neoepitopes in bovine articular chondrocytes is mediated by CD44 internalization of hyaluronan. Arthritis Rheum 54:443-454, 2006. 195. Stewart MC, Fosang AJ, Bai Y, et al: ADAMTS5-mediated aggrecanolysis in murine epiphyseal chondrocyte cultures. Osteoarthritis Cartilage 14:392-402, 2006. 196. von der Mark K, Mollenhauer J: Annexin V interactions with collagen. Cell Mol Life Sci 53:539-545, 1997. 197. Brachvogel B, Welzel H, Moch H, et al: Sequential expression of annexin A5 in the vasculature and skeletal elements during mouse development. Mech Dev 109:389-393, 2001. 198. Kirsch T: Annexins—their role in cartilage mineralization. Front Biosci 10:576-581, 2005. 199. Lucic D, Mollenhauer J, Kilpatrick KE, et al: N-telopeptide of type II collagen interacts with annexin V on human chondrocytes. Connect Tissue Res 44:225-239, 2003. 200. Salminen-Mankonen H, Saamanen AM, Jalkanen M, et al: Syndecan-1 expression is upregulated in degenerating articular cartilage in a transgenic mouse model for osteoarthritis. Scand J Rheumatol 34:469-474, 2005. 201. Pfander D, Swoboda B, Kirsch T: Expression of early and late differentiation markers (proliferating cell nuclear antigen, syndecan-3, annexin VI, and alkaline phosphatase) by human osteoarthritic chondrocytes. Am J Pathol 159:1777-1783, 2001. 202. Xu L, Peng H, Wu D, et al: Activation of the discoidin domain receptor 2 induces expression of matrix metalloproteinase 13 associated with osteoarthritis in mice. J Biol Chem 280:548-555, 2005. 203. Leitinger B, Kwan AP: The discoidin domain receptor DDR2 is a receptor for type X collagen. Matrix Biol 25:355-364, 2006. 204. Xu L, Peng H, Glasson S, et al: Increased expression of the collagen receptor discoidin domain receptor 2 in articular cartilage as a key event in the pathogenesis of osteoarthritis. Arthritis Rheum 56: 2663-2673, 2007. 205. Walsh DA, Bonnet CS, Turner EL, et al: Angiogenesis in the synovium and at the osteochondral junction in osteoarthritis. Osteoarthritis Cartilage 15:743-751, 2007. 206. Moses MA, Wiederschain D, Wu I, et al: Troponin I is present in human cartilage and inhibits angiogenesis. Proc Natl Acad Sci U S A 96:2645-2650, 1999. 207. Shukunami C, Hiraki Y: Role of cartilage-derived anti-angiogenic factor, chondromodulin-I, during endochondral bone formation. Osteoarthritis Cartilage 9(Suppl A):S91-S101, 2001. 208. O’Reilly MS, Boehm T, Shing Y, et al: Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277-285, 1997. 209. Pufe T, Petersen WJ, Miosge N, et al: Endostatin/collagen XVIII—an inhibitor of angiogenesis—is expressed in cartilage and fibrocartilage. Matrix Biol 23:267-276, 2004. 210. Pfander D, Kortje D, Zimmermann R, et al: Vascular endothelial growth factor in articular cartilage of healthy and osteoarthritic human knee joints. Ann Rheum Dis 60:1070-1073, 2001. 211. Pufe T, Petersen W, Tillmann B, et al: The splice variants VEGF121 and VEGF189 of the angiogenic peptide vascular endothelial growth factor are expressed in osteoarthritic cartilage. Arthritis Rheum 44:1082-1088, 2001. 212. Pufe T, Kurz B, Petersen W, et al: The influence of biomechanical parameters on the expression of VEGF and endostatin in the bone and joint system. Ann Anat 187:461-472, 2005. 213. Mentlein R, Pufe T: New functions of angiogenic peptides in osteoarthritis cartilage. Curr Rheum Rev 1:37-43, 2005. 214. Green DM, Noble PC, Ahuero JS, et al: Cellular events leading to chondrocyte death after cartilage impact injury. Arthritis Rheum 54:1509-1517, 2006. 215. Fearon U, Griosios K, Fraser A, et al: Angiopoietins, growth factors, and vascular morphology in early arthritis. J Rheumatol 30:260-268, 2003. 216. Szekanecz Z, Gaspar L, Koch AE: Angiogenesis in rheumatoid arthritis. Front Biosci 10:1739-1753, 2005.

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STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

217. Honorati MC, Neri S, Cattini L, et al: Interleukin-17, a regulator of angiogenic factor release by synovial fibroblasts. Osteoarthritis Cartilage 14:345-352, 2006. 218. Fearon U, Mullan R, Markham T, et al: Oncostatin M induces angiogenesis and cartilage degradation in rheumatoid arthritis synovial tissue and human cartilage cocultures. Arthritis Rheum 54:3152-3162, 2006. 219. Mould AW, Tonks ID, Cahill MM, et al: Vegfb gene knockout mice display reduced pathology and synovial angiogenesis in both antigeninduced and collagen-induced models of arthritis. Arthritis Rheum 48:2660-2669, 2003. 220. Loeser RF: Molecular mechanisms of cartilage destruction: Mechanics, inflammatory mediators, and aging collide. Arthritis Rheum 54:1357-1360, 2006. 221. Reddi AH: Cartilage morphogenetic proteins: Role in joint development, homeostasis, regeneration. Ann Rheum Dis 62(Suppl 2):ii73ii78, 2003. 222. van der Kraan PM, Buma P, van Kuppevelt T, et al: Interaction of chondrocytes, extracellular matrix and growth factors: Relevance for articular cartilage tissue engineering. Osteoarthritis Cartilage 10:631-637, 2002. 223. Chubinskaya S, Kuettner KE: Regulation of osteogenic proteins by chondrocytes. Int J Biochem Cell Biol 35:1323-1340, 2003. 224. Trippel SB: Growth factor inhibition: Potential role in the etiopathogenesis of osteoarthritis. Clin Orthop 427:S47-S52, 2004. 225. Lories RJ, Luyten FP: Bone morphogenetic protein signaling in joint homeostasis and disease. Cytokine Growth Factor Rev 16: 287-298, 2005. 226. Loeser RF, Pacione CA, Chubinskaya S: The combination of insulin-like growth factor 1 and osteogenic protein 1 promotes increased survival of and matrix synthesis by normal and osteoarthritic human articular chondrocytes. Arthritis Rheum 48:2188-2196, 2003. 227. Studer RK, Decker K, Melhem S, et al: Nitric oxide inhibition of IGF-1 stimulated proteoglycan synthesis: Role of cGMP. J Orthop Res 21:914-921, 2003. 228. De Ceuninck F, Caliez A, Dassencourt L, et al: Pharmacological disruption of insulin-like growth factor 1 binding to IGF-binding proteins restores anabolic responses in human osteoarthritic chondrocytes. Arthritis Res Ther 6:R393-R403, 2004. 229. Morales TI, Hunziker EB: Localization of insulin-like growth factor binding protein-2 in chondrocytes of bovine articular cartilage. J Orthop Res 21:290-295, 2003. 230. Morales TI: The insulin-like growth factor binding proteins in uncultured human cartilage: Increases in insulin-like growth factor binding protein 3 during osteoarthritis. Arthritis Rheum 46:2358-2367, 2002. 231. Iwanaga H, Matsumoto T, Enomoto H, et al: Enhanced expression of insulin-like growth factor-binding proteins in human osteoarthritic cartilage detected by immunohistochemistry and in situ hybridization. Osteoarthritis Cartilage 13:439-448, 2005. 232. Whellams EJ, Maile LA, Fernihough JK, et al: Alterations in insulinlike growth factor binding protein-3 proteolysis and complex formation in the arthritic joint. J Endocrinol 165:545-556, 2000. 233. Neidel J: Changes in systemic levels of insulin-like growth factors and their binding proteins in patients with rheumatoid arthritis. Clin Exp Rheumatol 19:81-84, 2001. 234. Tyler JA: Insulin-like growth factor 1 can decrease degradation and promote synthesis of proteoglycan in cartilage exposed to cytokines. Biochem J 260:543-548, 1989. 235. Olney RC, Wilson DM, Mohtai M, et al: Interleukin-1 and tumor necrosis factor-alpha increase insulin-like growth factor-binding protein-3 (IGFBP-3) production and IGFBP-3 protease activity in human articular chondrocytes. J Endocrinol 146:279-286, 1995. 236. Clancy R: Nitric oxide alters chondrocyte function by disrupting cytoskeletal signaling complexes. Osteoarthritis Cartilage 7:399-400, 1999. 237. van den Berg WB, van de Loo F, Joosten LA, et al: Animal models of arthritis in NOS2-deficient mice. Osteoarthritis Cartilage 7: 413-415, 1999. 238. Johnson K, Jung A, Murphy A, et al: Mitochondrial oxidative phosphorylation is a downstream regulator of nitric oxide effects on chondrocyte matrix synthesis and mineralization. Arthritis Rheum 43:1560-1570, 2000. 239. Loeser RF, Carlson CS, Del Carlo M, et al: Detection of nitrotyrosine in aging and osteoarthritic cartilage: Correlation of oxidative damage with the presence of interleukin-1beta and with chondrocyte resistance to insulin-like growth factor 1. Arthritis Rheum 46:2349-2357, 2002.

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240. Smeets RL, Veenbergen S, Arntz OJ, et al: A novel role for SOCS3 in cartilage destruction via induction of chondrocyte desensitization towards IGF-1. Arthritis Rheum 54:1518-1528, 2006. 241. Ornitz DM: FGF signaling in the developing endochondral skeleton. Cytokine Growth Factor Rev 16:205-213, 2005. 242. Veilleux N, Spector M: Effects of FGF-2 and IGF-1 on adult canine articular chondrocytes in type II collagen-glycosaminoglycan scaffolds in vitro. Osteoarthritis Cartilage 13:278-286, 2005. 243. Sah RL, Chen AC, Grodzinsky AJ, et al: Differential effects of bFGF and IGF-I on matrix metabolism in calf and adult bovine cartilage explants. Arch Biochem Biophys 308:137-147, 1994. 244. Vincent T, Hermansson M, Bolton M, et al: Basic FGF mediates an immediate response of articular cartilage to mechanical injury. Proc Natl Acad Sci U S A 99:8259-8264, 2002. 245. Vincent TL, Hermansson MA, Hansen UN, et al: Basic fibroblast growth factor mediates transduction of mechanical signals when articular cartilage is loaded. Arthritis Rheum 50:526-533, 2004. 246. Murakami S, Kan M, McKeehan WL, et al: Up-regulation of the chondrogenic Sox9 gene by fibroblast growth factors is mediated by the mitogen-activated protein kinase pathway. Proc Natl Acad Sci U S A 97:1113-1118, 2000. 247. Schaefer JF, Millham ML, de Crombrugghe B, et al: FGF signaling antagonizes cytokine-mediated repression of Sox9 in SW1353 chondrosarcoma cells. Osteoarthritis Cartilage 11:233-241, 2003. 248. Weksler NB, Lunstrum GP, Reid ES, et al: Differential effects of fibroblast growth factor (FGF) 9 and FGF2 on proliferation, differentiation and terminal differentiation of chondrocytic cells in vitro. Biochem J 342(Pt 3):677-682, 1999. 249. Ellsworth JL, Berry J, Bukowski T, et al: Fibroblast growth factor-18 is a trophic factor for mature chondrocytes and their progenitors. Osteoarthritis Cartilage 10:308-320, 2002. 250. Au A, Polotsky A, Krzyminski K, et al: Evaluation of thermoreversible polymers containing fibroblast growth factor 9 (FGF-9) for chondrocyte culture. J Biomed Mater Res A 69:367-372, 2004. 251. Shimoaka T, Ogasawara T, Yonamine A, et al: Regulation of osteoblast, chondrocyte, and osteoclast functions by fibroblast growth factor (FGF)-18 in comparison with FGF-2 and FGF-10. J Biol Chem 277:7493-7500, 2002. 252. Moore EE, Bendele AM, Thompson DL, et al: Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis. Osteoarthritis Cartilage 13:623-631, 2005. 253. Newman B, Gigout LI, Sudre L, et al: Coordinated expression of matrix Gla protein is required during endochondral ossification for chondrocyte survival. J Cell Biol 154:659-666, 2001. 254. Stheneur C, Dumontier MF, Guedes C, et al: Basic fibroblast growth factor as a selective inducer of matrix Gla protein gene expression in proliferative chondrocytes. Biochem J 369:63-70, 2003. 255. Reddi AH: Marshall R. Urist: A renaissance scientist and orthopaedic surgeon. J Bone Joint Surg Am 85A(Suppl 3):3-7, 2003. 256. Pogue R, Lyons K: BMP signaling in the cartilage growth plate. Curr Top Dev Biol 76:1-48, 2006. 257. Grimaud E, Heymann D, Redini F: Recent advances in TGF-beta effects on chondrocyte metabolism: Potential therapeutic roles of TGF-beta in cartilage disorders. Cytokine Growth Factor Rev 13:241-257, 2002. 258. Takahashi N, Rieneck K, van der Kraan PM, et al: Elucidation of IL1/TGF-beta interactions in mouse chondrocyte cell line by genomewide gene expression. Osteoarthritis Cartilage 13:426-438, 2005. 259. Bakker AC, van de Loo FA, van Beuningen HM, et al: Overexpression of active TGF-beta-1 in the murine knee joint: evidence for synovial-layer-dependent chondro-osteophyte formation. Osteoarthritis Cartilage 9:128-136, 2001. 260. Mi Z, Ghivizzani SC, Lechman ER, et al: Adverse effects of adenovirus-mediated gene transfer of human transforming growth factor beta 1 into rabbit knees. Arthritis Res 5:R132-R139, 2003. 261. Scharstuhl A, Glansbeek HL, van Beuningen HM, et al: Inhibition of endogenous TGF-beta during experimental osteoarthritis prevents osteophyte formation and impairs cartilage repair. J Immunol 169:507-514, 2002. 262. Scharstuhl A, Vitters EL, van der Kraan PM, et al: Reduction of osteophyte formation and synovial thickening by adenoviral overexpression of transforming growth factor beta/bone morphogenetic protein inhibitors during experimental osteoarthritis. Arthritis Rheum 48:3442-3451, 2003.

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Goldring 

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Cartilage and Chondrocytes

263. Moulharat N, Lesur C, Thomas M, et al: Effects of transforming growth factor-beta on aggrecanase production and proteoglycan degradation by human chondrocytes in vitro. Osteoarthritis Cartilage 12:296-305, 2004. 264. Kaiser M, Haag J, Soder S, et al: Bone morphogenetic protein and transforming growth factor beta inhibitory Smads 6 and 7 are expressed in human adult normal and osteoarthritic cartilage in vivo and are differentially regulated in vitro by interleukin-1beta. Arthritis Rheum 50:3535-3540, 2004. 265. Blaney Davidson EN, Vitters EL, van der Kraan PM, et al: Expression of TGF-beta and the TGF-beta signaling molecule SMAD-2P in spontaneous and instability-induced osteoarthritis: Role in cartilage degradation, chondrogenesis and osteophyte formation. Ann Rheum Dis 65:1414-1421, 2006. 266. Yoon BS, Lyons KM: Multiple functions of BMPs in chondrogenesis. J Cell Biochem 93:93-103, 2004. 267. Li SW, Sieron AL, Fertala A, et al: The C-proteinase that processes procollagens to fibrillar collagens is identical to the protein previously identified as bone morphogenic protein-1. Proc Natl Acad Sci U S A 93:5127-5130, 1996. 268. Gruber R, Mayer C, Bobacz K, et al: Effects of cartilage-derived morphogenetic proteins and osteogenic protein-1 on osteochondrogenic differentiation of periosteum-derived cells. Endocrinology 142:20872094, 2001. 269. Majumdar MK, Wang E, Morris EA: BMP-2 and BMP-9 promotes chondrogenic differentiation of human multipotential mesenchymal cells and overcomes the inhibitory effect of IL-1. J Cell Physiol 189:275-284, 2001. 270. Bobacz K, Gruber R, Soleiman A, et al: Expression of bone morphogenetic protein 6 in healthy and osteoarthritic human articular chondrocytes and stimulation of matrix synthesis in vitro. Arthritis Rheum 48:2501-2508, 2003. 271. Grunder T, Gaissmaier C, Fritz J, et al: Bone morphogenetic protein (BMP)-2 enhances the expression of type II collagen and aggrecan in chondrocytes embedded in alginate beads. Osteoarthritis Cartilage 12:559-567, 2004. 272. Bobacz K, Gruber R, Soleiman A, et al: Cartilage-derived morphogenetic protein-1 and -2 are endogenously expressed in healthy and osteoarthritic human articular chondrocytes and stimulate matrix synthesis. Osteoarthritis Cartilage 10:394-401, 2002. 273. Vinall RL, Lo SH, Reddi AH: Regulation of articular chondrocyte phenotype by bone morphogenetic protein 7, interleukin 1, and cellular context is dependent on the cytoskeleton. Exp Cell Res 272:3244, 2002. 274. Nishihara A, Fujii M, Sampath TK, et al: Bone morphogenetic protein signaling in articular chondrocyte differentiation. Biochem Biophys Res Commun 301:617-622, 2003. 275. Beier F: Cell-cycle control and the cartilage growth plate. J Cell Physiol 202:1-8, 2005. 276. Starkman BG, Cravero JD, Delcarlo M, et al: IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK. Biochem J 389:723-729, 2005. 277. Reddi AH: Interplay between bone morphogenetic proteins and cognate binding proteins in bone and cartilage development: Noggin, chordin and DAN. Arthritis Res 3:1-5, 2001. 278. Derynck R, Zhang YE: Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425:577-584, 2003. 279. Qiao B, Padilla SR, Benya PD: Transforming growth factor (TGF)beta-activated kinase 1 mimics and mediates TGF-beta-induced stimulation of type II collagen synthesis in chondrocytes independent of Col2a1 transcription and Smad3 signaling. J Biol Chem 280:17562-17571, 2005. 280. Bobick BE, Kulyk WM: The MEK-ERK signaling pathway is a negative regulator of cartilage-specific gene expression in embryonic limb mesenchyme. J Biol Chem 279:4588-4595, 2004. 281. Seghatoleslami MR, Roman-Blas JA, Rainville AM, et al: Progression of chondrogenesis in C3H10T1/2 cells is associated with prolonged and tight regulation of ERK1/2. J Cell Biochem 88: 1129-1144, 2003. 282. Studer RK, Bergman R, Stubbs T, et al: Chondrocyte response to growth factors is modulated by p38 mitogen-activated protein kinase inhibition. Arthritis Res Ther 6:R56-R64, 2004. 283. Gebauer M, Saas J, Haag J, et al: Repression of anti-proliferative factor Tob1 in osteoarthritic cartilage. Arthritis Res Ther 7:R274-R284, 2005.

284. Zhu Y, McAlinden A, Sandell LJ: Type IIA procollagen in development of the human intervertebral disc: Regulated expression of the NH(2)-propeptide by enzymic processing reveals a unique developmental pathway. Dev Dyn 220:350-362, 2001. 285. Tardif G, Pelletier JP, Hum D, et al: Differential regulation of the bone morphogenic protein antagonist chordin in human normal and osteoarthritic chondrocytes. Ann Rheum Dis 65:261-264, 2006. 286. Nakayama N, Han CY, Cam L, et al: A novel chordin-like BMP inhibitor, CHL2, expressed preferentially in chondrocytes of developing cartilage and osteoarthritic joint cartilage. Development 131:229-240, 2004. 287. Kawabata D, Tanaka M, Fujii T, et al: Ameliorative effects of follistatin-related protein/TSC-36/FSTL1 on joint inflammation in a mouse model of arthritis. Arthritis Rheum 50:660-668, 2004. 288. Dayer JM: The process of identifying and understanding cytokines: From basic studies to treating rheumatic diseases. Best Pract Res Clin Rheumatol 18:31-45, 2004. 289. van den Berg WB, van Riel PL: Uncoupling of inflammation and destruction in rheumatoid arthritis: Myth or reality? Arthritis Rheum 52:995-999, 2005. 290. van den Berg WB: Animal models of arthritis: What have we learned? J Rheumatol Suppl 72:7-9, 2005. 291. Hembry RM, Bagga MR, Reynolds JJ, et al: Immunolocalisation studies on six matrix metalloproteinases and their inhibitors, TIMP1 and TIMP-2, in synovia from patients with osteo- and rheumatoid arthritis. Ann Rheum Dis 54:25-32, 1995. 292. Tetlow LC, Adlam DJ, Woolley DE: Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage. Arthritis Rheum 44:585-594, 2001. 293. Struglics A, Larsson S, Pratta MA, et al: Human osteoarthritis synovial fluid and joint cartilage contain both aggrecanase- and matrix metalloproteinase-generated aggrecan fragments. Osteoarthritis Cartilage 14:101-113, 2006. 294. Neuhold LA, Killar L, Zhao W, et al: Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J Clin Invest 107:35-44, 2001. 295. Tetlow LC, Woolley DE: Comparative immunolocalization studies of collagenase 1 and collagenase 3 production in the rheumatoid lesion, and by human chondrocytes and synoviocytes in vitro. Br J Rheumatol 37:64-70, 1998. 296. Cunnane G, FitzGerald O, Hummel KM, et al: Synovial tissue protease gene expression and joint erosions in early rheumatoid arthritis. Arthritis Rheum 44:1744-1753, 2001. 297. Ainola MM, Mandelin JA, Liljestrom MP, et al: Pannus invasion and cartilage degradation in rheumatoid arthritis: Involvement of MMP3 and interleukin-1beta. Clin Exp Rheumatol 23:644-650, 2005. 298. Barksby HE, Milner JM, Patterson AM, et al: Matrix metalloproteinase 10 promotion of collagenolysis via procollagenase activation: Implications for cartilage degradation in arthritis. Arthritis Rheum 54:3244-3253, 2006. 299. Rutkauskaite E, Volkmer D, Shigeyama Y, et al: Retroviral gene transfer of an antisense construct against membrane type 1 matrix metalloproteinase reduces the invasiveness of rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 52:2010-2014, 2005. 300. Arner EC: Aggrecanase-mediated cartilage degradation. Curr Opin Pharmacol 2:322-329, 2002. 301. Nagase H, Kashiwagi M: Aggrecanases and cartilage matrix degradation. Arthritis Res Ther 5:94-103, 2003. 302. Plaas A, Osborn B, Yoshihara Y, et al: Aggrecanolysis in human osteoarthritis: Confocal localization and biochemical characterization of ADAMTS5-hyaluronan complexes in articular cartilages. Osteoarthritis Cartilage 15:719-734, 2007. 303. Sandy JD: A contentious issue finds some clarity: On the independent and complementary roles of aggrecanase activity and MMP activity in human joint aggrecanolysis. Osteoarthritis Cartilage 14:95-100, 2006. 304. Glasson SS, Askew R, Sheppard B, et al: Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434:644-648, 2005. 305. Stanton H, Rogerson FM, East CJ, et al: ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434: 648-652, 2005. 306. Kashiwagi M, Tortorella M, Nagase H, et al: TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAMTS5). J Biol Chem 276:12501-12504, 2001.

PART 1 

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STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

307. Hashimoto G, Aoki T, Nakamura H, et al: Inhibition of ADAMTS4 (aggrecanase-1) by tissue inhibitors of metalloproteinases (TIMP-1, 2, 3 and 4). FEBS Lett 494:192-195, 2001. 308. Hou WS, Li W, Keyszer G, et al: Comparison of cathepsins K and S expression within the rheumatoid and osteoarthritic synovium. Arthritis Rheum 46:663-674, 2002. 309. Salminen-Mankonen HJ, Morko J, Vuorio E: Role of cathepsin K in normal joints and in the development of arthritis. Curr Drug Targets 8:315-323, 2007. 310. Kevorkian L, Young DA, Darrah C, et al: Expression profiling of metalloproteinases and their inhibitors in cartilage. Arthritis Rheum 50:131-141, 2004. 311. Cawston TE, Wilson AJ: Understanding the role of tissue degrading enzymes and their inhibitors in development and disease. Best Pract Res Clin Rheumatol 20:983-1002, 2006. 312. Overall CM, Blobel CP: In search of partners: Linking extracellular proteases to substrates. Nat Rev Mol Cell Biol 8:245-257, 2007. 313. Burrage PS, Huntington JT, Sporn MB, et al: Regulation of matrix metalloproteinase gene expression by a retinoid X receptor-specific ligand. Arthritis Rheum 56:892-904, 2007. 314. Murphy G, Lee MH: What are the roles of metalloproteinases in cartilage and bone damage? Ann Rheum Dis 64(Suppl 4):iv44-iv47, 2005. 315. Baker AH, Edwards DR, Murphy G: Metalloproteinase inhibitors: Biological actions and therapeutic opportunities. J Cell Sci 115: 3719-3727, 2002. 316. Fell HB, Jubb RW: The effect of synovial tissue on the breakdown of articular cartilage in organ culture. Arthritis Rheum 20:13591371, 1977. 317. Dingle JT, Saklatvala J, Hembry R, et al: A cartilage catabolic factor from synovium. Biochem J 184:177-180, 1979. 318. Dayer J-M, Russell RGG, Krane SM: Collagenase production by rheumatoid synovial cells: Stimulation by a human lymphocyte factor. Science 195:181-183, 1977. 319. Meats JE, McGuire MB, Russell RGG: Human synovium releases a factor which stimulates chondrocyte production of PGE and plasminogen activator. Nature 286:891-892, 1980. 320. Saklatvala J, Pilsworth LM, Sarsfield SJ, et al: Pig catabolin is a form of interleukin 1: Cartilage and bone resorb, fibroblasts make prostaglandin and collagenase, and thymocyte proliferation is augmented in response to one protein. Biochem J 224:461-466, 1984. 321. Goldring SR, Goldring MB: The role of cytokines in cartilage matrix degeneration in osteoarthritis. Clin Orthop 427:S27-S36, 2004. 322. Goldring MB, Berenbaum F: The regulation of chondrocyte function by proinflammatory mediators: Prostaglandins and nitric oxide. Clin Orthop 427:S37-S46, 2004. 323. Fernandes JC, Martel-Pelletier J, Pelletier JP: The role of cytokines in osteoarthritis pathophysiology. Biorheology 39:237-246, 2002. 324. Attur MG, Dave M, Cipolletta C, et al: Reversal of autocrine and paracrine effects of interleukin 1 (IL-1) in human arthritis by type II IL-1 decoy receptor: Potential for pharmacological intervention. J Biol Chem 275:40307-40315, 2000. 325. Westacott CI, Barakat AF, Wood L, et al: Tumor necrosis factor alpha can contribute to focal loss of cartilage in osteoarthritis. Osteoarthritis Cartilage 8:213-221, 2000. 326. Barakat AF, Elson CJ, Westacott CI: Susceptibility to physiological concentrations of IL-1beta varies in cartilage at different anatomical locations on human osteoarthritic knee joints. Osteoarthritis Cartilage 10:264-269, 2002. 327. Fraser A, Fearon U, Billinghurst RC, et al: Turnover of type II collagen and aggrecan in cartilage matrix at the onset of inflammatory arthritis in humans: Relationship to mediators of systemic and local inflammation. Arthritis Rheum 48:3085-3095, 2003. 328. Glasson SS: In vivo osteoarthritis target validation utilizing genetically-modified mice. Curr Drug Targets 8:367-376, 2007. 329. Zwerina J, Redlich K, Polzer K, et al: TNF-induced structural joint damage is mediated by IL-1. Proc Natl Acad Sci U S A 104:1174211747, 2007. 330. Aida Y, Maeno M, Suzuki N, et al: The effect of IL-1beta on the expression of inflammatory cytokines and their receptors in human chondrocytes. Life Sci 79:764-771, 2006. 331. Connell L: McInnes IB: New cytokine targets in inflammatory rheumatic diseases. Best Pract Res Clin Rheumatol 20:865-878, 2006. 332. Rowan AD, Koshy PJ, Shingleton WD, et al: Synergistic effects of glycoprotein 130 binding cytokines in combination with interleukin-1 on cartilage collagen breakdown. Arthritis Rheum 44:1620-1632, 2001.

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333. Legendre F, Dudhia J, Pujol JP, et al: JAK/STAT but not ERK1/ERK2 pathway mediates interleukin (IL)-6/soluble IL-6R down-regulation of type II collagen, aggrecan core, and link protein transcription in articular chondrocytes: Association with a down-regulation of SOX9 expression. J Biol Chem 278:2903-2912, 2003. 334. de Hooge AS, van de Loo FA, Bennink MB, et al: Male IL-6 gene knock out mice developed more advanced osteoarthritis upon aging. Osteoarthritis Cartilage 13:66-73, 2005. 335. Sack U, Sehm B, Kahlenberg F, et al: Investigation of arthritic joint destruction by a novel fibroblast-based model. Ann N Y Acad Sci 1051:291-298, 2005. 336. Hui W, Barksby HE, Young DA, et al: Oncostatin M in combination with tumour necrosis factor {alpha} induces a chondrocyte membrane associated aggrecanase that is distinct from ADAMTS aggrecanase-1 or -2. Ann Rheum Dis 64:1624-1632, 2005. 337. Rowan AD, Hui W, Cawston TE, et al: Adenoviral gene transfer of interleukin-1 in combination with oncostatin M induces significant joint damage in a murine model. Am J Pathol 162:1975-1984, 2003. 338. van de Loo FA, de Hooge AS, Smeets RL, et al: An inflammationinducible adenoviral expression system for local treatment of the arthritic joint. Gene Ther 11:581-590, 2004. 339. Li X, Afif H, Cheng S, et al: Expression and regulation of microsomal prostaglandin E synthase-1 in human osteoarthritic cartilage and chondrocytes. J Rheumatol 32:887-895, 2005. 340. Lubberts E, Koenders MI, van den Berg WB: The role of T cell interleukin-17 in conducting destructive arthritis: Lessons from animal models. Arthritis Res Ther 7:29-37, 2005. 341. Koenders MI, Joosten LA, van den Berg WB: Potential new targets in arthritis therapy: Interleukin (IL)-17 and its relation to tumour necrosis factor and IL-1 in experimental arthritis. Ann Rheum Dis 65(Suppl 3):iii29-iii33, 2006. 342. Dai SM, Shan ZZ, Nishioka K, et al: Implication of interleukin 18 in production of matrix metalloproteinases in articular chondrocytes in arthritis: Direct effect on chondrocytes may not be pivotal. Ann Rheum Dis 64:735-742, 2005. 343. John T, Kohl B, Mobasheri A, et al: Interleukin-18 induces apoptosis in human articular chondrocytes. Histol Histopathol 22:469-482, 2007. 344. Joosten LA, Smeets RL, Koenders MI, et al: Interleukin-18 promotes joint inflammation and induces interleukin-1-driven cartilage destruction. Am J Pathol 165:959-967, 2004. 345. Magne D, Palmer G, Barton JL, et al: The new IL-1 family member IL1F8 stimulates production of inflammatory mediators by synovial fibroblasts and articular chondrocytes. Arthritis Res Ther 8:R80, 2006. 346. Joosten LA, Netea MG, Kim SH, et al: IL-32, a proinflammatory cytokine in rheumatoid arthritis. Proc Natl Acad Sci U S A 103:3298-3303, 2006. 347. Bessis N, Boissier MC: Novel pro-inflammatory interleukins: Potential therapeutic targets in rheumatoid arthritis. Joint Bone Spine 68:477-481, 2001. 348. Goldring MB: Update on the biology of the chondrocyte and new approaches to treating cartilage diseases. Best Pract Res Clin Rheumatol 20:1003-1025, 2006. 349. Palmer G, Guerne PA, Mezin F, et al: Production of interleukin-1 receptor antagonist by human articular chondrocytes. Arthritis Res 4:226-231, 2002. 350. van de Loo FA, Geurts J, van den Berg WB: Gene therapy works in animal models of rheumatoid arthritis. . .so what! Curr Rheumatol Rep 8:386-393, 2006. 351. Arend WP, Goldring MB: The development of anti-cytokine therapeutics for rheumatic diseases. Arthritis Rheum 58:5102-5109, 2008. 352. Chowdhury TT, Bader DL, Lee DA: Anti-inflammatory effects of IL-4 and dynamic compression in IL-1beta stimulated chondrocytes. Biochem Biophys Res Commun 339:241-247, 2006. 353. Schuerwegh AJ, Dombrecht EJ, Stevens WJ, et al: Influence of pro-inflammatory (IL-1 alpha, IL-6, TNF-alpha, IFN-gamma) and anti-inflammatory (IL-4) cytokines on chondrocyte function. Osteoarthritis Cartilage 11:681-687, 2003. 354. Ho SH, Hahn W, Lee HJ, et al: Protection against collageninduced arthritis by electrotransfer of an expression plasmid for the interleukin-4. Biochem Biophys Res Commun 321:759-766, 2004. 355. Nandakumar KS, Holmdahl R: Arthritis induced with cartilagespecific antibodies is IL-4-dependent. Eur J Immunol 36:1608-1618, 2006.

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356. Neumann E, Judex M, Kullmann F, et al: Inhibition of cartilage destruction by double gene transfer of IL-1Ra and IL-10 involves the activin pathway. Gene Ther 9:1508-1519, 2002. 357. Gonzalez-Rey E, Chorny A, Varela N, et al: Therapeutic effect of urocortin on collagen-induced arthritis by down-regulation of inflammatory and Th1 responses and induction of regulatory T cells. Arthritis Rheum 56:531-543, 2007. 358. Cleaver CS, Rowan AD, Cawston TE: Interleukin 13 blocks the release of collagen from bovine nasal cartilage treated with proinflammatory cytokines. Ann Rheum Dis 60:150-157, 2001. 359. Nabbe KC, van Lent PL, Holthuysen AE, et al: Local IL-13 gene transfer prior to immune-complex arthritis inhibits chondrocyte death and matrix-metalloproteinase-mediated cartilage matrix degradation despite enhanced joint inflammation. Arthritis Res Ther 7:R392-R401, 2005. 360. Masuko-Hongo K, Berenbaum F, Humbert L, et al: Up-regulation of microsomal prostaglandin E synthase 1 in osteoarthritic human cartilage: Critical roles of the ERK-1/2 and p38 signaling pathways. Arthritis Rheum 50:2829-2838, 2004. 361. Whiteman M, Spencer JP, Zhu YZ, et al: Peroxynitrite-modified collagen-II induces p38/ERK and NF-kappaB-dependent synthesis of prostaglandin E2 and nitric oxide in chondrogenically differentiated mesenchymal progenitor cells. Osteoarthritis Cartilage 14:460-470, 2006. 362. Healy ZR, Lee NH, Gao X, et al: Divergent responses of chondrocytes and endothelial cells to shear stress: Cross-talk among COX-2, the phase 2 response, and apoptosis. Proc Natl Acad Sci U S A 102:14010-14015, 2005. 363. Cheng S, Afif H, Martel-Pelletier J, et al: Activation of peroxisome proliferator-activated receptor gamma inhibits interleukin-1betainduced membrane-associated prostaglandin E2 synthase-1 expression in human synovial fibroblasts by interfering with Egr-1. J Biol Chem 279:22057-22065, 2004. 364. Francois M, Richette P, Tsagris L, et al: Activation of the peroxisome proliferator-activated receptor alpha pathway potentiates interleukin-1 receptor antagonist production in cytokine-treated chondrocytes. Arthritis Rheum 54:1233-1245, 2006. 365. Thomas B, Thirion S, Humbert L, et al: Differentiation regulates interleukin-1β-induced cyclo-oxygenase-2 in human articular chondrocytes: Role of p38 mitogen-activated kinase. Biochem J 362: 367-373, 2002. 366. Riquet RB, Lai W-FT, Birkhead JR, et al: Suppression of type I collagen gene expression by prostaglandins in fibroblasts is mediated at the transcriptional level. Mol Med 6:705-719, 2000. 367. Abramson SB, Attur M, Amin AR, et al: Nitric oxide and inflammatory mediators in the perpetuation of osteoarthritis. Curr Rheumatol Rep 3:535-541, 2001. 368. Kuhn K, D’Lima DD, Hashimoto S, et al: Cell death in cartilage. Osteoarthritis Cartilage 12:1-16, 2004. 369. Yammani RR, Carlson CS, Bresnick AR, et al: Increase in production of matrix metalloproteinase 13 by human articular chondrocytes due to stimulation with S100A4: Role of the receptor for advanced glycation end products. Arthritis Rheum 54:2901-2911, 2006. 370. Bauer S, Jendro MC, Wadle A, et al: Fibroblast activation protein is expressed by rheumatoid myofibroblast-like synoviocytes. Arthritis Res Ther 8:R171, 2006. 371. Milner JM, Kevorkian L, Young DA, et al: Fibroblast activation protein alpha is expressed by chondrocytes following a pro-inflammatory stimulus and is elevated in osteoarthritis. Arthritis Res Ther 8:R23, 2006. 372. Loeser RF: Systemic and local regulation of articular cartilage metabolism: Where does leptin fit in the puzzle? Arthritis Rheum 48:30093012, 2003. 373. Dayer JM, Chicheportiche R, Juge-Aubry C, et al: Adipose tissue has anti-inflammatory properties: Focus on IL-1 receptor antagonist (IL1Ra). Ann N Y Acad Sci 1069:444-453, 2006. 374. Lago F, Dieguez C, Gomez-Reino JJ, et al: Adipokines as emerging mediators of immune response and inflammation. Nat Clin Pract Rheumatol 12:716-724, 2007. 375. Popa C, Netea MG, Radstake TR, et al: Markers of inflammation are negatively correlated with serum leptin in rheumatoid arthritis. Ann Rheum Dis 64:1195-1198, 2005. 376. Otero M, Lago R, Gomez R, et al: Towards a pro-inflammatory and immunomodulatory emerging role of leptin. Rheumatology (Oxf) 45:944-950, 2006.

377. Dumond H, Presle N, Terlain B, et al: Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum 48:3118-3129, 2003. 378. Otero M, Lago R, Lago F, et al: Leptin, from fat to inflammation: Old questions and new insights. FEBS Lett 579:295-301, 2005. 379. Palmer G, Aurrand-Lions M, Contassot E, et al: Indirect effects of leptin receptor deficiency on lymphocyte populations and immune response in db/db mice. J Immunol 177:2899-2907, 2006. 380. Borzi RM, Mazzetti I, Marcu KB, et al: Chemokines in cartilage degradation. Clin Orthop 427:S53-S61, 2004. 381. Iwamoto T, Okamoto H, Iikuni N, et al: Monocyte chemoattractant protein-4 (MCP-4)/CCL13 is highly expressed in cartilage from patients with rheumatoid arthritis. Rheumatology (Oxf) 45:421-424, 2006. 382. Goldring MB, Goldring SR: Role of cytokines and chemokines in cartilage and bone destruction in arthritis. Curr Opin Orthopaed 13:351-362, 2002. 383. Kanbe K, Takemura T, Takeuchi K, et al: Synovectomy reduces stromal-cell-derived factor-1 (SDF-1) which is involved in the destruction of cartilage in osteoarthritis and rheumatoid arthritis. J Bone Joint Surg Br 86:296-300, 2004. 384. Mazzetti I, Magagnoli G, Paoletti S, et al: A role for chemokines in the induction of chondrocyte phenotype modulation. Arthritis Rheum 50:112-122, 2004. 385. Masuko-Hongo K, Sato T, Nishioka K: Chemokines differentially induce matrix metalloproteinase-3 and prostaglandin E2 in human articular chondrocytes. Clin Exp Rheumatol 23:57-62, 2005. 386. Nakamura H, Tanaka M, Masuko-Hongo K, et al: Enhanced production of MMP-1, MMP-3, MMP-13, and RANTES by interaction of chondrocytes with autologous T cells. Rheumatol Int 26:984-990, 2006. 387. Su SL, Tsai CD, Lee CH, et al: Expression and regulation of Toll-like receptor 2 by IL-1beta and fibronectin fragments in human articular chondrocytes. Osteoarthritis Cartilage 13:879-886, 2005. 388. Kim HA, Cho ML, Choi HY, et al: The catabolic pathway mediated by Toll-like receptors in human osteoarthritic chondrocytes. Arthritis Rheum 54:2152-2163, 2006. 389. Varoga D, Paulsen F, Mentlein R, et al: TLR-2-mediated induction of vascular endothelial growth factor (VEGF) in cartilage in septic joint disease. J Pathol 210:315-324, 2006. 390. Joosten LA, Koenders MI, Smeets RL, et al: Toll-like receptor 2 pathway drives streptococcal cell wall-induced joint inflammation: Critical role of myeloid differentiation factor 88. J Immunol 171:6145-6153, 2003. 391. van Lent PL, Blom AB, Grevers L, et al: Toll-like receptor 4 induced FcgammaR expression potentiates early onset of joint inflammation and cartilage destruction during immune complex arthritis: Toll-like receptor 4 largely regulates FcgammaR expression by interleukin 10. Ann Rheum Dis 66:334-340, 2007. 392. Berenbaum F: Signaling transduction: Target in osteoarthritis. Curr Opin Rheumatol 16:616-622, 2004. 393. Malemud CJ: Protein kinases in chondrocyte signaling and osteoarthritis. Clin Orthop 427:S145-S151, 2004. 394. Katoh M: STAT3-induced WNT5A signaling loop in embryonic stem cells, adult normal tissues, chronic persistent inflammation, rheumatoid arthritis and cancer. Int J Mol Med 19:273-278, 2007. 395. Fanning PJ, Emkey G, Smith RJ, et al: Mechanical regulation of mitogen-activated protein kinase signaling in articular cartilage. J Biol Chem 278:50940-50948, 2003. 396. Fitzgerald JB, Jin M, Dean D, et al: Mechanical compression of cartilage explants induces multiple time-dependent gene expression patterns and involves intracellular calcium and cyclic AMP. J Biol Chem 279:19502-19511, 2004. 397. Agarwal S, Deschner J, Long P, et al: Role of NF-kappaB transcription factors in antiinflammatory and proinflammatory actions of mechanical signals. Arthritis Rheum 50:3541-3548, 2004. 398. Ahmed S, Rahman A, Hasnain A, et al: Phenyl N-tert-butylnitrone down-regulates interleukin-1 beta-stimulated matrix metalloproteinase13 gene expression in human chondrocytes: Suppression of c-Jun NH2-terminal kinase, p38-mitogen-activated protein kinase and activating protein-1. J Pharmacol Exp Ther 305:981-988, 2003. 399. Loeser RF, Forsyth CB, Samarel AM, et al: Fibronectin fragment activation of proline-rich tyrosine kinase PYK2 mediates integrin signals regulating collagenase-3 expression by human chondrocytes through a protein kinase C-dependent pathway. J Biol Chem 278:2457724585, 2003.

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400. Firestein GS: NF-kappaB: Holy Grail for rheumatoid arthritis? Arthritis Rheum 50:2381-2386, 2004. 401. Facchini A, Borzi RM, Marcu KB, et al: Polyamine depletion inhibits NF-kappaB binding to DNA and interleukin-8 production in human chondrocytes stimulated by tumor necrosis factor-alpha. J Cell Physiol 204:956-963, 2005. 402. Carrington JL: Aging bone and cartilage: Cross-cutting issues. Biochem Biophys Res Commun 328:700-708, 2005. 403. Hough AJ: Pathology of osteoarthritis. In Seibel MJ, Robins SP, Bilezekian JP (eds): Dynamics of Bone and Cartilage Metabolism: Principles and Clinical Applications. San Diego, Academic Press, 2006, pp 51-72. 404. Burstein D, Gray ML: Is MRI fulfilling its promise for molecular imaging of cartilage in arthritis? Osteoarthritis Cartilage 14: 1087-1090, 2006. 405. Verzijl N, Bank RA, TeKoppele JM, et al: AGEing and osteoarthritis: A different perspective. Curr Opin Rheumatol 15:616-622, 2003. 406. Hollander AP, Pidoux I, Reiner A, et al: Damage to type II collagen in aging and osteoarthritis starts at the articular surface, originates around chondrocytes, and extends into the cartilage with progressive degeneration. J Clin Invest 96:2859-2869, 1995. 407. Martin JA, Buckwalter JA: Aging, articular cartilage chondrocyte senescence and osteoarthritis. Biogerontology 3:257-264, 2002. 408. Price JS, Waters JG, Darrah C, et al: The role of chondrocyte senescence in osteoarthritis. Aging Cell 1:57-65, 2002. 409. Blaney Davidson EN, Scharstuhl A, Vitters EL, et al: Reduced transforming growth factor-beta signaling in cartilage of old mice: Role in impaired repair capacity. Arthritis Res Ther 7:R1338-R1347, 2005. 410. Poole AR: Can serum biomarker assays measure the progression of cartilage degeneration in osteoarthritis? Arthritis Rheum 46: 2549-2552, 2002. 411. Hunziker EB: Articular cartilage repair: Basic science and clinical progress: A review of the current status and prospects. Osteoarthritis Cartilage 10:432-463, 2002.

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412. Brittberg M, Lindahl A, Nilsson A, et al: Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 331:889-895, 1994. 413. Roberts S, Hollander AP, Caterson B, et al: Matrix turnover in human cartilage repair tissue in autologous chondrocyte implantation. Arthritis Rheum 44:2586-2598, 2001. 414. Knutsen G, Engebretsen L, Ludvigsen TC, et al: Autologous chondrocyte implantation compared with microfracture in the knee: A randomized trial. J Bone Joint Surg Am 86A:455-464, 2004. 415. Kuo CK, Li WJ, Mauck RL, et al: Cartilage tissue engineering: Its potential and uses. Curr Opin Rheumatol 18:64-73, 2006. 416. Evans CH: Novel biological approaches to the intra-articular treatment of osteoarthritis. BioDrugs 19:355-362, 2005. 417. Gooch KJ, Blunk T, Courter DL, et al: Bone morphogenetic proteins-2, -12, and -13 modulate in vitro development of engineered cartilage. Tissue Eng 8:591-601, 2002. 418. Huang JI, Kazmi N, Durbhakula MM, et al: Chondrogenic potential of progenitor cells derived from human bone marrow and adipose tissue: A patient-matched comparison. J Orthop Res 23:1383-1389, 2005. 419. Palmer GD, Steinert A, Pascher A, et al: Gene-induced chondrogenesis of primary mesenchymal stem cells in vitro. Mol Ther 12: 219-228, 2005. 420. Seeherman H, Wozney JM: Delivery of bone morphogenetic proteins for orthopedic tissue regeneration. Cytokine Growth Factor Rev 16:329-345, 2005. 421. Hills RL, Belanger LM, Morris EA: Bone morphogenetic protein 9 is a potent anabolic factor for juvenile bovine cartilage, but not adult cartilage. J Orthop Res 23:611-617, 2005. 422. Blaney Davidson EN, van der Kraan PM, van den Berg WB: TGF-beta and osteoarthritis. Osteoarthritis Cartilage 15:597604, 2007.

4

Biology, Physiology, and Morphology of Bone Janet E. Rubin  �  Clinton T. Rubin

KEY POINTS Bone function is structural and metabolic. Cellular remodeling of bone requires the orchestrated action of the following: Osteoblasts—bone-forming cells Osteoclasts—bone-resorbing cells Osteocytes—bone-sensing cells Skeletal development is controlled by multiple genes, mutations in which lead to disease. Skeletal homeostasis involves chemical and biophysical signals, as follows: Chemical factors largely regulate metabolic function Mechanical factors largely regulate structural function

Bone is an extremely complex tissue that regulates its mass and architecture to meet two crucial and competing responsibilities, one structural and the other metabolic. First, the skeleton provides a sophisticated framework for the body: It protects vital organs and facilitates locomotion. Second, it serves as a mineral reservoir containing 99% of the body’s total calcium and 85% of its phosphorus. This dual responsibility creates conflicting goals and competing stimuli in the catabolic and anabolic regulation of skeletal tissues. Metabolic aberrations, such as hypocalcemia, hyperparathyroidism, renal failure, and aging, can cause impairment in the structural integrity of the skeleton, whereas regulatory controls struggle to maintain calcium homeostasis. The skeleton perceives another set of regulatory controls over its structural morphology and adapts to meet altered functional demand. This structural adaptation can proceed apace, ignoring potential consequences of rapid fluctuations in serum calcium levels (e.g., renal lithiasis, hypercalcemia). Despite what seem to be independent sets of regulatory controls for metabolic and structural needs of the organism, however, skeletal integrity and the viability of the organism are ­critically dependent on maintaining an intricate balance between them. The balance between structural and metabolic responsibilities is achieved via the complex and tightly regulated ­cellular processes of formation and resorption of bone tissue. ­Beginning at the level of the cell, this ­ chapter discusses local and ­systemic factors that influence bone turnover and growth of the skeleton, the composition and mineralization of the matrix, the architecture and ­ material properties of the tissue, and the adaptive capacity of the skeleton. This multilevel, multidisciplinary overview is ­intended to provide the reader with an appreciation of not only the ­complexity of bone, but also its success in ­ meeting its wide-ranging responsibilities.

CELLULAR BASIS OF BONE REMODELING The constant modeling and remodeling of skeletal tissue is necessary during growth and for the repair of skeletal defects caused by fracture and inflammation. Remodeling also is essential for the rapid mobilization of mineral required for metabolic homeostasis and for the fine adjustment of skeletal mass and morphology needed to achieve an effective and efficient supporting structure. The skeleton’s capacity to adapt to changes in its functional and metabolic milieu is achieved through its sophisticated network of osteoregulatory cells. These cells—osteoblasts, osteocytes, and osteoclasts—mediate the remodeling balance of the skeleton and provide the cellular machinery necessary for the maintenance of calcium homeostasis in the extracellular fluid. OSTEOBLASTS Function The primary function of the osteoblast is to synthesize and mineralize the extracellular matrix. Osteoblasts are interconnected to one another via extended cell processes that communicate via gap junctions,1 establishing a single, continuous blanket of cells on the bone surface (Fig. 4-1). The cytoplastic elements of the plump, cuboidal osteoblast include abundant endoplasmic reticulum with cisternae, a well-developed Golgi body, and numerous free ribosomes that are responsible for the basophilia seen in sections stained with hematoxylin and eosin. These features help to distinguish osteoblasts from the thin, flat mesenchymal precursors (preosteoblasts) that are found on bone surfaces. Together, these two cell types are known as bone-lining cells. Morphologically, the tight canopy of the lining cells enables the selective isolation of the mineralized surface from the extracellular milieu, which is crucial for the site-specific control of mineralization or resorption.2 In forming bone, the osteoblast secretes an extracellular matrix termed osteoid (see section on composition of bone matrix), which is subsequently mineralized. Although it is unclear whether mineralization itself necessitates the ­presence of the osteoblast (see Chapter 1), this cell’s ­synthesis of a panel of proteins, including type I collagen, several ­ noncollagenous proteins, and proteoglycans, is critical to the appropriate orchestration of the remo­deling response (Table 4-1). Many of these proteins, whether ­secreted or ­ displayed by osteoblasts, have signaling roles in bone remodeling, such as the role of osteocalcin to recruit ­ osteoclasts,3 the ­ initiation of collagen breakdown 71

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Table 4-1  Composition of Bone Osteoid Collagen   Type I, some types III, V, XI, XIII Proteoglycans   Biglycan, decorin, hyaluronan Glycoproteins   Osteonectin, bone sialoprotein, osteopontin, thrombospondin, fibronectin, γ-carboxyglutamic acid–containing proteins (osteocalcin, matrix gla protein) Enzymes   Alkaline phosphatase, collagenase, cysteine proteinases, plasminogen activator, tissue inhibitor of metalloproteinases Growth factors   Fibroblast growth factor, insulin-like growth factor, transforming growth factor, bone morphogenetic protein, ­α2HS-glycoprotein Proteolipids

Figure 4-1  Polyhedral osteoblasts lying on the surface of newly formed bone matrix. (Courtesy of Dr. B. Boothroyd.)

by pla­sminogen activator,4 and the signal for osteoclast recruitment by expression of receptor activator of nuclear factor к B (NFкB) ligand (RANKL).5 Other proteins, such as osteopontin and bone sialoprotein, are crucial components of osteoid, strongly binding ionic calcium and se­rving as cell attachment factors.6 The functional life of the osteoblast ranges in different species from 3 days in young rabbits7 to 8 weeks in humans.8 A typical active osteoblast in humans produces a seam of osteoid about 15 μm thick, at a rate of 0.5 to 1.5 μm/day,9 suggesting the average osteoblast life in humans to be 15 days. Although osteoid seams can exceed 70 mm,10 such seam widths also can indicate a disruption or flaw in the mineralization process (e.g., rickets or osteomalacia). Several reports suggest that a contraction of the life span of the osteoblast might underlie pathophysiologic conditions. In the presence of glucocorticoids, an increased rate of ­programmed cell death, or apoptosis, is seen, which may ­account for the decrease in bone quality recognized in ­patients with ­glucocorticoid excess.11 Differentiation Studies of the molecular mechanisms involved in o­ steoblast maturation have revealed a complex set of interacting factors. A specific helix-loop-helix nuclear factor termed Runx2/cbfa1 directs entry of the pluripotent mesenchymal stem cell into the osteoblast lineage in vitro12 and in vivo, where heterozygous loss of Runx2 in several human kindreds causes cleidocranial dysplasia. Osteoblast expression of osteopontin and type I collagen is delayed, with resultant late ossification of the clavicle.13 This condition, defined by short stature and hypoplasia of the clavicles,14 predicted a similar phenotype generated by targeted di­sruption of the Runx2 gene in mice.15 In the transgenic Runx2 knockout mouse, the cartilaginous skeleton never ossifies, however, emphasizing how necessary Runx2 is to the normal skeleton. Since the de­scription of

the Runx2-null transgenic mouse, many other genes, such as Lrp5 and osterix, have been shown to be important to osteoblast differentiation and function, with proof-ofconcept in transgenic animals. Transgenic Models Inform Osteoblast Pathophysiology Although this chapter cannot document all the genes necessary for osteoblast function, a few, besides Runx2, warrant mention. A second transcription factor, osterix, was discovered while scientists attempted to learn more about the role bone morphogenetic proteins (BMPs) play in osteoblast function. Although osterix seems to function distal to Runx2, its absence precludes finding either osteoblasts or bone tissue in osterix-null transgenic animals.16 The cartilaginous skeleton in the absence of osterix is normal. Scientists seeking to understand human kindreds with very high bone mineral densities uncovered the involvement of the Wnt pathway in osteoblast function and perhaps differentiation. These kindreds turned out to have mutations of the Lrp5 protein, which inhibits signaling by the developmental protein Wnt.17,18 Knockout of Lrp5 in mice caused a decrease in osteoblast proliferation and osteopenia.19 Because soluble mediators can interact with the Wnt signaling pathway, manipulation of this pathway would surely offer means of controlling osteoblast function in the future. Identification of the sclerostin gene arose through study of human genetics, in this case a group of diseases consistent with increased bone mass, including van Buchem’s disease20 and sclerosteosis.21 Both diseases are associated with mutations in sclerostin that alter its ability to bind members of the family of BMPs, leading to their overactivity,22 and seem to bind Lrp5/6 receptors, preventing activation of the Wnt pathway.23 Other genes have been linked to abnormalities in mesenchymal condensation and differentiation, including phenotypes with extra digits. One of these is synpolydactyly, which involves an abnormal HOXD-13 gene.24 Similar to other members of the Hox gene family, HOXD-13 is involved in skeletal patterning. Fibrodysplasia ossificans progressiva is a disabling disorder characterized by a gradual and continuous heterotopic

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STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

HC

OL

Figure 4-2  Ground section of bone photographed in normal light showing empty osteocyte lacunae (OL) connected by fine, darkly stained canaliculi. The central haversian canal (HC) is seen in the upper left-hand corner; the reversal line (*) marking the junction between two adjacent osteons and the cement line (arrows) separating adjacent lamellae also can be seen.

ossification of soft tissues. This autosomal-dominant disorder is associated with misexpression of the growth factor BMP-425 and has been shown to be due to a mutation in the ACVR1 gene, which encodes an activin receptor.26 The process by which the mutation in ACVR1 leads to the exoskeleton seen in this disease is unknown. OSTEOCYTES As mineralization proceeds, the osteoblast may become engulfed in its own calcifying osteoid matrix, becoming the osteocyte.27 Osteocytes are connected to each other via cytoplasmic extensions that pass through a network of catacombs radiating outward from the central vascular canal (Fig. 4-2). The volume of bone occupied by this syncytium is approximately 5% for the canalicular network and 2% for the lacunar spaces.28 These interconnecting canaliculi are ideal pathways for chemical, electric, and stress-generated fluid communication through the dense bone matrix.29 The processes themselves are interconnected by gap junctions composed of the protein connexin 43, which facilitates the integration of many of these regulatory messages.30 The surface area of the lacunar and canalicular system is at least 250 m2/L of calcified bone matrix and communicates with a submicroscopic, interfibrillar space, representing 35,000 μm2/mm3. Exchange of minerals, nutrients, and chemical and physical stimuli through this enormous network is facilitated, which is critical, considering the need for rapid mobilization of minerals in the homeostatic control of the skeleton. Also, this cell syncytium deteriorates markedly with increasing age and may contribute to the age-related insensitivity of bone ­ tissue to chemical and physical signals. Although osteoblasts and osteoclasts are largely responsible for executing the appropriate modeling-remodeling responses, given the time required to recruit these cells in the adult skeleton, it is likely that the extensive network of resident cells, the osteocytes and bone-lining cells, actually orchestrate the adaptive response. Past work has provided strong evidence that the osteocyte is capable of

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rapidly ­responding to changes in the bone’s chemical and mechanical environment. Mechanical strain increases osteocyte levels of glucose-6-phosphate dehydrogenase activity31 and c-fos mRNA levels within 60 minutes of loading, evidence that osteocytes are intimately—and rapidly—involved in the osteogenic response to mechanical signals.32 Physiologic levels of mechanical strain reduce the rate of osteocyte apoptosis, suggesting that matrix deformation affects cell survival.33 When bone is subject to disuse, osteocytes are capable of expressing collagenase,34 emphasizing that this cell has the ability to regulate the recruitment of bone-forming and bone-resorbing cells and to modulate its own immediate microenvironment. OSTEOCLASTS Function The osteoclast, functioning as a bone-specific macrophage, is found wherever bone mineral is being removed. This large, multinucleated cell migrates on the bone surface, creating irregular, scalloped cavities termed Howship’s lacunae (Fig. 4-3). An activated osteoclast can travel 100 μm/day, resorbing a cavity 300 μm in diameter and excavating 200,000 μm3 of bone. The reclamation of this volume of bone requires 7 to 10 generations of working osteoblasts to fill the resorption space.35 An absence of osteoclasts or a population of dysfunctional osteoclasts leads to osteopetrosis, or marble bone disease, which can be fatal in childhood secondary to pancytopenias caused by decreased marrow space.36 Through the interactions of systemic and local factors, a cellular symbiosis exists in which an integrated “activation, resorption, reversal, and formation” occurs, reflecting an intricate control of osteoblasts and osteoclasts.37 To initiate this sequence, osteoclasts are activated by chemical or physical signals that recruit them to specific remodeling areas. When activated and attached to the matrix, they begin the resorption cycle. When resorption is completed, new bone formation begins within Howship’s cavity, a process that leaves a boundary designated in histologic sections as a reversal line.38 This “pocket” of new bone is known as a bone structural unit.39 A similar line, called a cement line, is seen between adjacent lamellae of bone (see Fig. 4-2). Mature osteoclasts possess several unique ultrastructural characteristics that allow their very active functional phenotype (Fig. 4-4). These include abundant pleomorphic mitochondria, vacuoles, and lysosomes, which store the multiple secretory products necessary for the digestion of bone substance.40 The apical membrane of the osteoclast is tightly sealed to the calcified matrix, creating a clear zone that has no cellular organelles, but is rich in contractile proteins. Toward the center of the cell, the membrane becomes deeply folded, creating the characteristic ruffled ­ border.41 Under the ruffled border is the resorption pit, where the osteoclast secretes lysosomal enzymes and generates an acid environment by secreting protons through a vacuolar proton pump.42 Protons are generated for the pump through the actions of carbonic anhydrase II, an enzyme subtype also associated with vacuolar proton pumps in the renal cortex and the gastric parietal cell. Deficiencies in carbonic anhydrase II lead to a mild form of osteopetrosis.43 The bicarbonate resulting from this activity is transported via a

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Mitochondria HCO3 H2O + CO2 Cl Clear zone

cAMP

Carbonic anhydrase II H+ Proton pump Ruffled border

A

H+

Lysosomal enzymes

Figure 4-4  The osteoclast is a polarized cell that adheres to bone, generating a subosteoclastic space where bone resorption occurs. Into this space, the osteoclast pumps hydrogen ions and lysosomal enzymes. The protons that create the acid pH in the resorption space derive from the action of carbonic anhydrase II on bicarbonate, which has entered  the cell via a chloride bicarbonate exchanger on the marrow side of the cell. Calcitonin receptors distinguish this cell, as does the characteristic ruffled border seen on electron micrographs.

B Figure 4-3  A, Paragon-stained mineralized section with large, multinucleated osteoclasts lying along the pale-staining bone surface. B, Microradiograph of the same area showing Howship’s lacunae in the areas of osteoclastic resorption. (From Jowsey J, Gordan G: In Bourne GH [ed]: The Biochemistry and Physiology of Bone, 2nd ed, Vol III. New York, Academic Press, 1972, pp 201-238.)

chloride-­bicarbonate exchanger on the marrow-facing side of the osteoclast. The osteoclast’s highly polarized nature allows unidirectional secretion of protons into the resorption bay at its basal membrane and transport of resorbed products out of its apical region.44 Protons accumulate within the ­confined subosteoclastic space, reducing the pH to a level sufficient to dissolve the mineral phase of the matrix (pH of 2 to 4) and activate osteoclastic hydrolytic enzymes. Osteoclast acid secretion can be inhibited through regulation of calmodulin kinase. Tamoxifen, an antiestrogen that prevents postmenopausal bone loss, can directly inhibit this kinase and prevent osteoclast acidification.45 The remaining organic matrix is subsequently dissolved by lysosomal enzymes (e.g., cathepsin B), leaving the ­osteoclast’s signature scalloped resorption cavity.46 As the excavation proceeds, the ionized calcium levels just beyond the clear zone increase from a base level of 1 to 2 mM to 20 mM.47 Other clinically useful modulators of osteoclast development and function include the bisphosphonates, which are widely used to prevent osteoporotic fractures.48 Bisphosphonates are incorporated into bone mineral in place of phosphate and prevent osteoclast recruitment and activity, increasing bone mineral density by slowing resorption.49 Differentiation Osteoclast precursors arise from hematopoietic stem cells in the bone marrow.50 The processes controlling osteoclast differentiation can be reduced, at least in tissue culture, to

three basic elements: the osteoclast precursor cell, which arises out of the macrophage lineage of hematopoietic stem cells; macrophage colony-stimulating factor (M-CSF), which is necessary for the ­differentiation, proliferation, and survival of cells of macrophage lineage; and RANKL.51,52 Loss of M-CSF action engenders deficiencies of osteoclasts and macrophages: The osteopetrotic op/op mouse is deficient in M-CSF.53 Further progression into the osteoclast lineage with appearance of functional osteoclast characteristics, such as calcitonin receptor and carbonic anhydrase II expression, requires other local stimuli, including the physical presence of bone stromal or osteoblast cells54-56 that display RANKL on their membranes.51,52 In the absence of RANKL, normal osteoclastogenesis does not progress, as in the osteopetrotic RANKL-null transgenic mouse.57 A secreted form of RANKL also suffices for osteoclastogenesis and can cause bone turnover when secreted by activated T lymphocytes in rheumatic joints.58 RANKL binding can be prevented by competition with a soluble decoy receptor, osteoprotegerin, and overexpression of osteoprotegerin leads to an inhibition of osteoclastogenesis and decreased bone turnover.59 Human deficiency of osteoprotegerin is now known to be responsible for juvenile Paget’s disease, a familial disorder characterized by a large head and expanded and bowed extremities that are osteoporotic.60 The list of factors that influence the progression of osteoclast differentiation grows steadily each year. ­Osteoactive systemic factors, such as 1,25-dihydroxyvitamin D, parathyroid hormone (PTH), and tumor ­necrosis factor, enhance the development of osteoclasts from ­hematopoietic progenitor cells in the presence of stromal elements from bone.55 Each of these three factors induces the expression of RANKL by bone cells. Cytokines, such as interleukin-6 and interleukin-11, also influence osteoclast development and may have particular significance in pathogenic states, such as postmenopausal osteoporosis61 and Paget’s disease.62

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Transgenic Models Inform Osteoclast Pathophysiology Many other cofactors participating in osteoclast lineage ­selection have been discovered as a result of gene dysfunction or knockout experiments. Knockout of the murine ­tyrosine kinase c-fos gene inhibits the divergence of cells from macrophage lineage into that of osteoclasts, despite normal levels of M-CSF and RANKL.63 Knockout of the transcription factor PU.1 inhibits early osteoclast precursor development by disallowing entry into the macrophage lineage,64 and the abnormal function of the helix-loop-helix factor MITF inhibits late differentiation of osteoclasts.65 Knockout of signaling cascades necessary for RANKL ­ action (i.e., NFκB) also results in deficient osteoclast differentiation.66 Upregulation of signal cascades that enhance ­osteoclastic differentiation and function should increase bone turnover, as is evidenced by knockout of the src homology 2–containing inositol-5′phosphatase (SHIP). The SHIP-null transgenic mouse has increased numbers of osteoclast precursors and overactive osteoclasts, resulting in an osteoporotic skeleton.67 The unexpected finding of osteopetrosis after homologous knockout of the ubiquitous src protein kinase in the mouse68 has precipitated study of the roles of osteoclast attachment and movement. The src-deficient mouse has osteoclasts, but these cells are unable to resorb bone. The src tyrosine kinase is important in the downstream signaling required for ­ osteoclast function at the bone surface.69 Scientists also have begun to examine the motility of the osteoclast and its ability to transcytose resorbed materials liberated from the mineralized matrix.44 The motility of the osteoclast is under the control of many factors, including factors recognized by its polarized basal surface connected to the mineral and matrix by an integrin such as vitronectin.70 As might be predicted, knockout of the β3 integrin subunit leads to dysfunction of osteoclasts and osteosclerosis in transgenic mice.71 The list of deletion knockouts that have human homologues continues to grow, as charted in numerous more recent reviews.72

DEVELOPMENT OF THE SKELETON GROWTH Most of the bones of the skeleton appear first in the ­embryo as cartilaginous models, which are later resorbed and replaced by bone tissue. The cartilage template, or anlage, is formed by the condensation of mesenchymal cells in the developing limb bud. Although the shape of the anlage ­resembles that of the adult bone and seems to be genetically determined, the bone that replaces the cartilage template is greatly influenced by physical factors (e.g., weight bearing, muscle pull) and is constantly modeled and remodeled as these forces change according to the dicta of Wolff’s law.73 The cartilage anlage, or template, expands and elongates by interstitial growth, in which chondrocytes divide, enlarge, and surround themselves with the new matrix. At about the same time, cells in the connective tissues surrounding the anlage (perichondrium) begin to lay down bone tissue and form a collar of bone around the center of the cartilage model. At the time it is formed, the anlage is pierced by a capillary that begins the process of matrix

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e­ xcavation and allows entry of osteoblast precursors that replace ­cartilage with bone. This process of vascular invasion of the cartilage ­model, followed by bone deposition, is referred to as ­enchondral ossification. The process continues until the entire shaft of the anlage is replaced by marrow and bone, confining the growth process of chondrocyte multiplication to the epiphyseal ends of the bone, away from the primary center of ossification. As the epiphysis swells, the central chondrocytes find themselves too remote from the blood supply to survive solely by means of diffusion. Cartilage canals facilitate the diffusion of nutrients and provide conduits for subsequent capillary ingrowth. The hypertrophic ­ chondrocytes survive and elaborate angiotrophic substances. Parathyroid hormone–related peptide (PTHrp) has emerged as one of the most important factors ­ controlling the complex process of embryologic bone growth and ­maturation. PTHrp, which has long been known to be the most common causative factor in neoplastic hypercalcemia, binds to the PTH receptor.74 During fetal development of the cartilaginous anlage, the product of the Indian ­hedgehog (Ihh) gene is released by hypertrophic chondrocytes in the growth plate. The Ihh protein induces PTHrp release by the perichondrium at the end of the long bones.75 PTHrp binds to receptors in the proliferating chondrocytes, causing a delay of their maturation and allowing further elongation of the anlage before entry of osteoblasts and ossification. In the absence of PTHrp, the developing bone ossifies prematurely and ends up foreshortened. The interplay of Ihh and PTHrp, which has such profound effects during embryologic development, may have a subtler role in the adult skeleton involved in the modulation of osteoblast response to the continual need for bone maintenance. Although growth in length occurs at the growth plate, growth in diameter occurs by the centrifugal proliferation of cartilage cells along the groove of Ranvier,76 an anatomic structure bordered outwardly by a continuation of the fibrous periosteum and inwardly by the physeal cartilage. When swelling of the cartilaginous anlage first begins, a condensed layer of mesenchyme develops around it as a membrane of cells and collagen, termed perichondrium. As the cartilage is replaced by bone, this membrane is termed periosteum. In the growing skeleton, periosteum is clearly divided into an inner cellular layer and an outer fibrous layer, which merges gradually into the surrounding muscle. Muscles originate from the periosteum. Collagen bundles can be traced flowing from tendon and ligament through the periosteum to anchor directly into the bone via Sharpey’s fibers.77 Along with the genetic regulation discussed previously, there are epigenetic regulatory mechanisms, including control by mechanical stresses as proposed by Roux.78 General considerations of how mechanical stress might control skeletal growth abound, including the proposal of Carter and coworkers.79 They proposed that intermittently applied shear stresses promote enchondral ossification, and that intermittent hydrostatic compression inhibits cartilage degeneration and ossification. The contribution of mechanical stresses to bone growth is not yet understood. Rosenberg and colleagues80 characterized the changes that occur during ossification of the anlage, including the deposition of a 35,000-kD molecular weight protein (probably osteocalcin) and the modification of existing proteoglycans.

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Mineral deposition begins in the matrix vesicles located in the columns between the last hypertrophic chondrocytes on the extreme metaphyseal end of the physis.81 Invasion by osteoblasts and osteoclasts results in the resorption of this woven bone and its replacement by mature lamellar bone.82 The hydroxyapatite formed during primary ossification is a rough crystal whose imperfections may render it more vulnerable to resorption,83 which also implies the facility with which woven bone is removed. Numerous cell-secreted factors are important in the regulation of growth and the cascade of processes l­eading to adequate mineralization of bone by osteoblasts. Urist’s identification of a factor in demineralized bone powder that initiated bone formation has led to the cloning and sequencing of at least seven BMPs belonging to the transforming growth factor (TGF)-β family of growth potentiators.84 These polypeptide factors seem to be important regulators of bone growth and repair through their ab­ility to activate migration of mesenchymal cells and induce osteoblastic differentiation followed by proliferation.85 TGF-β itself is abundant in bone matrix. In vitro cell work has shown that TGF-β has positive and negative effects on osteoblast proliferation, differentiation, and matrix s­ynthesis.86-88 TGF-β is released during the process of osteoclastic bone resorption89 and may initiate the formative part of the bone-remodeling unit, the “coupling” of formation to resorption.90 The differential effects of the various BMPs to induce cartilage and bone formation in vivo are being examined to determine their potential to accelerate the healing of complex fractures and to improve the rate of allograft and autograft successes.91 BMP-4 initiates the sequential gene expression of osteopontin and osteocalcin in chondrocytes and osteoblasts.92 BMP-6 may be involved in the earliest part of the differentiation of osteoblast cells.93 Osteoblasts also produce numerous growth factors and cytokines that are crucial to the process of bone formation, remodeling, and repair (Fig. 4-5). Many of these soluble products also are released by circulating macrophages and lymphocytes. Insulin-like growth factor-I, or somatomedin C, directly stimulates osteoblast replication and function94 and may increase remodeling by inducing RANKL.95 Many of these regulatory compounds are discussed in the section on bone remodeling.

GENETIC ABNORMALITIES Many genetic diseases have predominant skeletal ­phenotypes, including at least 150 osteochondrodysplasias. The fact that dysfunction of many single genes is likely to cause skeletal manifestations arises from the great number of genes involved in the complex processes of skeletal development, growth, and remodeling. Numerous genes not pr­eviously suspected to be associated with skeletal physiology generate abnormal skeletal phenotypes when deleted from transgenic mice. Examples are the ubiquitous c-src tyrosine kinase68 and the intranuclear factor c-fos.63 Deletion of either gene leads to osteopetrosis. The association of genes with processes crucial to normal skeletal physiology is a growing area of research; only a few striking examples are offered here. A receptor for fibroblast growth factor has been implicated in achondroplasia, the most common form of chondroplasia in humans. This disease is characterized by short-limbed dwarfism combined with a large head. Gene abnormalities in multiple subjects consist of point mutations in the fibroblast growth factor receptor-3,24 which result in a constitutively active receptor,96 indicating that fibroblast growth factor limits the expansion of the growth plate. Another gene regulating elongation of the growth plate is PTHrp. Interruption of PTHrp action causes a shortening of long bone.97 In comparison, increasing PTHrp action, as seen in the constitutively activated PTHrp receptor associated with Jansen’s metaphyseal chondrodysplasia, causes metaphyseal abnormalities.98 Alterations in either the organic (e.g., collagen) or the inorganic (e.g., hydroxyapatite) matrix components bring about changes in the bone structure, some of which are indirect, and some of which can be catastrophic. An entire spectrum of bone diseases, including osteogenesis imperfecta, is discussed in Chapter 92. With even this briefest of presentations, the reader should be aware of the virtual explosion of the knowledge base with regard to the genes controlling skeletal growth and homeostasis. Targeted disruption of genes in animals, genetic studies of human kindreds with abnormal skeletal phenotypes, and the sequencing of the human genome are expected to lead rapidly to a fuller understanding of the many heritable diseases affecting the skeleton.

CFU-GM Figure 4-5  Osteoclasts and osteoblasts interact through cytokines released into the bone micromilieu. Macrophages secrete macrophage colony-stimulating factor (M-CSF), various interleukins (IL), and tumor necrosis factor (TNF), all of which promote osteoclast differentiation from hematopoietic stem cells, from the colony-forming unit for granulocyte-macrophages (CFU-GM) and the CFU for macrophage (CFU-M) to terminal osteoclast phenotype. Osteoblasts interact by secreting factors that affect osteoclasts, including  M-CSF and transforming growth factor (TGF)-β, and factors affecting bone mineralization and progression of their own phenotype, such as insulin-like growth factors (IGFs) and basic fibroblast growth factors (FGFs).

CFU-M

Osteoclast

Macrophage

M-CSF IL-6 IL-11 TNF-α

BMP M-CS-F TGF-β IGFs FGFs

Osteoblast

Preosteoblast

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SYSTEMIC REGULATION OF BONE REMODELING CALCIUM METABOLISM Calcium is crucial to many processes in the body, including most signaling cascades and synaptic signaling, creating a requirement for tight control of systemic calcium concentrations. As stated at the beginning of this chapter, the skeleton is the reservoir for calcium, and bone remodeling is one of the processes crucial to calcium regulation. Hormones involved in calcium homeostasis have profound effects on the skeleton. Parathyroid Hormone The primary function of PTH is to maintain serum ionized calcium levels within a narrow physiologic range. PTH secretion increases as calcium levels decrease to less than 8 mg/dL, controlled by decreased binding of the calcium ion to the calcium receptor on the parathyroid cell.99 When a serum calcium value greater than 10 mg/dL accompanies a high level of serum PTH, a diagnosis of hyperparathyroidism can be made.100 Other circulating factors, such as vitamin D, tumor necrosis factor-α, and prostaglandins, also are involved in regulating calcium balance. By stimulating osteoclast activity and bone resorption, PTH provides calcium and phosphate for mineral homeostasis. Membrane receptors for PTH on osteoblasts stimulate substantial morphologic and metabolic changes in these cells and subsequently in osteoclasts.101 The distal effects of PTH occur by increases in levels of intracellular cyclic adenosine monophosphate (cAMP) and mobilization of cytosolic calcium ion.102 Although PTH receptors probably do not exist on osteoclasts,103 these cells are activated within minutes of osteoblast exposure to PTH. PTH also targets renal 1α-hydroxylase, which is the final step in the activation of vitamin D. PTH contributes to maintaining serum calcium levels by direct and indirect interactions with the skeleton. Vitamin D Vitamin D has effects on bone remodeling and calcium homeostasis. A 10-minute exposure of the skin to ultraviolet light from the sun causes endogenous production of sufficient quantities of vitamin D3 from 7-dehydrocholesterol to allow normal calcium balance. Vitamin D3 is first hydroxylated to 25-hydroxyvitamin D in the liver, followed by 25-hydroxyvitamin D hydroxylation in the kidney. Often referred to as calcitriol, the active metabolite, 1,25-dihydroxyvitamin D, stimulates intestinal absorption of calcium, providing the mineral necessary to build bone. An absence of vitamin D action, such as in vitamin D–resistant rickets secondary to mutations in the vitamin D receptor104 or in pseudovitamin D rickets resulting from an abnormality of 1α-hydroxylase,105 leads to hypocalcemia and severe rachitic bone disease. Although adequate levels of 1,25-dihydroxyvitamin D are necessary to provide calcium for bone formation, supraphysiologic levels induce bone resorption by stimulating the differentiation of osteoclast precursors.106 This occurs through the effect of 1,25-dihydroxyvitamin D

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of increasing bone stromal cell production of M-CSF107 and RANKL expression.108 Besides the role of vitamin D in ensuring calcium ­acquisition from the intestine, vitamin D has subtle effects on the formation and resorption of bone.109 Allelic variants of the vitamin D receptor may have subtle effects on bone density, but this is controversial and may be subject to et­hnicity.110-113 Full understanding of the role of vitamin D in skeletal development requires continued epidemiologic and basic studies. Calcitonin and Other Calcium-Regulating Factors Calcitonin is a calcium regulatory hormone that works ­independently of PTH and vitamin D and possesses a potent capacity to modulate serum calcium and phosphate levels.114 Similar to the control of PTH secretion from parathyroid cells, serum calcium levels regulate the secretion of calcitonin from parafollicular or C cells of the thyroid. In contrast to PTH, which is secreted in inverse proportion to serum calcium levels, calcium ion directly stimulates the secretion of calcitonin115 by its binding to the calcium receptor on the parafollicular C cells.116 The binding of calcitonin to ­ receptors on osteoclasts117 causes a marked decrease in osteoclast metabolic activity along with cell retraction.118,119 For these reasons, calcitonin has been used successfully in the acute treatment of humoral hypercalcemia of malignancy and in treatment of Paget’s disease. The use of calcitonin in the treatment of hyperresorptive osteoporosis also is salutary.120 The response to calcitonin is transitory, however, because it downregulates its cognate receptor within hours.121 Osteoblasts also secrete prostaglandin E2 (PGE2) in response to hormonal or mechanical stimuli. PGE2 can stimulate bone formation and resorption and serve as a chemotactic factor for osteoclasts.122 Although PGE2 and PTH stimulate the same second messengers in osteoblasts, PGE2 directly affects osteoclasts through its ubiquitous receptor. PGE2 stimulates several second-messenger responses in bone cells, including an increase in cytosolic calcium, ­ elevated cAMP production, and activation of the phosphatidylinositol pathway.123 In the anabolic response to loading, prostaglandins may be particularly important because prostaglandin levels increase during loading and can reproduce some specific responses of load when given in vitro.124 MATURATION: SEX STEROIDS The rapid decline of skeletal mass after menopause ­underscores the crucial regulatory role of sex steroids in bone cell metabolism. The expression of estrogen receptors125,126 and androgen receptors127 within osteoblasts ­ designates bone cells as targets of these sex steroids. Elevated estrogen levels increase osteoblast proliferation128 and attenuate the osteoblast response to PTH.129 In addition, estrogens increase osteoblastic collagen gene expression28 and ­insulinlike growth factor-II production130 and may even directly regulate the production of osteoclastic lysosomal enzymes.131 It also has been recognized that interleukin-6 can stimulate osteoclastic bone resorption only in the estrogen-deficient state.61 Estrogen has been shown to have effects on the RANKL-osteoprotegerin equilibrium. Estrogen deficiency,

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although not changing RANKL expression on osteoclast precursors, blunts the intracellular signaling stimulated by RANKL binding, essentially decreasing osteoclastogenesis.132 Also, estrogen has been shown to increase osteoprotegerin in the circulation, diminishing RANKL effect by preventing its access to potential osteoclasts.133 Further appreciation of estrogen action has emerged with evidence of effects on the male skeleton. A unique male patient shown to be unresponsive to estrogen because of an abnormal estrogen receptor never fused his epiphyses, despite an intact androgen axis.134 A second patient, still growing taller at age 30 years, was found to lack estrogen action in bone, in this case through the complete absence of the cytochrome P-450 aromatase necessary to convert androgen to estradiol.135 This patient was noted to have extremely low bone mineral density. Treatment with low doses of estradiol not only caused epiphyseal fusion, but also increased bone mineral density by nearly 10% over the first year of treatment, with a continued increase during the subsequent 3 years.136 These concepts have led workers in osteology to promote a “unifying model” suggesting that bone mineral density in men and women depends on su­fficient estrogen levels, and that androgen may have completely separate, unknown effects on skeletal growth and mass.137 REGULATION OF BONE MINERAL DENSITY Humans attain a mature skeleton by age 30 years, when bone mineral density peaks. The peak bone mineral density is largely controlled by hereditary factors, which are not well understood.138,139 After this peak, long-lived individuals are subject to a continual decline in mineral status, increasing skeletal susceptibility to fracture. With much attention directed toward osteoporosis in the last several decades, clinicians have recognized that some pathologic conditions can prevent the achievement of peak bone mass, and other conditions can promote the normal decline in bone mineral density after maturity. Although a detailed discussion of this complex and thoroughly studied process is beyond the scope of this chapter, several points can be made. First, as suggested previously, normal sex steroids are required to attain peak bone mass, as shown by the failure of young hypogonadal adults to reach normal peak bone mineral density.140 Deficiency of either estrogen or testosterone after attaining adult bone mass increases the rate of mineral loss, largely through increased resorption.141 Insulin-like growth factor-I, a critical factor for bone development and mineralization, seems to enhance normal mineralization,142 but also may promote bone remodeling by decreasing osteoprotegerin and increasing RANKL.95 Certain medical conditions are associated with increased resorption and decreased bone formation, such as excess glucocorticoids— either iatrogenic or in Cushing’s disease.143 Increased loss of bone mineral density also is associated with any coexisting illness,144 undoubtedly due to multifactorial causes, including the inevitable decline in exercise that parallels aging, which stimulates bone loss secondary to decreased function.145,146 The Wnt pathway has been implicated in osteoblast ­function and bone mineral content, an extension of the many roles that Wnt signaling has in development

and ­ maintenance of multiple tissues. Two kindreds with increased bone mineral density with abnormalities in Lrp5 protein, which leads to enhanced Wnt signaling, have been described so far.17,18 On the distaff side, loss-of-function mutations in human Lrp5 cause the osteoporosis-pseudoglioma syndrome, where bone density is reduced.147 A growing literature suggests that Wnt signaling regulates osteogenesis at points from the mesenchymal stem cell all the way toward mineralization.148 BIOPHYSICAL STIMULI Working systemically or locally, chemical factors, such as sex steroids, vitamin D, M-CSF, and TGF-β, play vital roles in the regulation of skeletal modeling and remodeling. There is increasing evidence that these “mediators of change” may be orchestrated by local factors that are not chemical in origin. One of the most potent influences of the development and maintenance of the skeleton are byproducts of function (during use), referred to as biophysical factors (i.e., mechanical-electric, discussed in detail at the end of this chapter). Whether it is an increase in bone mass as a result of exercise or work habits, or a decrease in bone mass resulting from bed rest, cast immobilization, or space flight, physical factors are key to determining the ultimate structural success of the skeleton. It is essential to keep the role of chemical mediators in perspective and acknowledge physical factors as a crucial control mechanism in the regulation of tissue differentiation, growth, repair, and remodeling.149 Although the molecular mechanisms are not well understood, studies proving an effect of biophysical stimuli on bone microstructure and mineral density are increasing in number.150,151 Physical stimuli as potent determinants of skeletal morphology have been postulated as primary regulators of chondro-osseous morphogenesis,152 although the specific mechanical parameters that control the process have not yet been determined. Nevertheless, more recent studies have documented the potential efficacy of biophysical stimuli in improving bone quantity and quality; departing from the premise that larger signals are better, extremely small mechanical strains (<10 microstrain) were shown to be strongly anabolic to trabecular bone, indicating the potential for a nonpharmacologic intervention for osteoporosis.153

COMPOSITION OF BONE MATRIX Bone is composed of inorganic mineral (70% of weight), organic matrix and cells (25%), and water (5%). Before its calcification, newly synthesized bone matrix is essentially completely organic and is termed osteoid. Collagen is the predominant organic component in bone, accounting for approximately 94% of the unmineralized matrix (see Table 4-1). Other noncollagenous proteins unique to bone are found in osteoid, accounting for approximately 4% of its weight. These include glycoproteins and phosphoproteins, such as osteonectin154 and sialoproteins, which are predominantly osteopontin,155 osteocalcin,156 and BMP.157 Extracts of bone also include enzymes, hormones, growth factors, and other metabolites essential for bone metabolism.158 Bone cells, for all their responsibility to mineral and structural homeostasis, constitute only 2% of the organic tissue.159

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COLLAGEN AND PROTEOGLYCANS The major protein secretory product of the osteoblast is collagen, whose complex primary, secondary, and tertiary structure lends strength to bone and allows the seeding of hydroxyapatite crystals from a supersaturated extracellular fluid. Collagen is a crucial element of the skeleton, and abnormalities in its structure and regulation lead to severe skeletal phenotypes. Osteoblast formation of collagen is typified by cross-linking of lysine and proline residues to form procollagen ­trimers. The processed collagen is organized into parallel fiber sheets of tropocollagen.160 Within each sheet, or lamella, the fibers lie parallel to each other,161 whereas the fibril orientation on adjacent lamellae runs in directions distinct from this axis (Fig. 4-6), contributing to the strength of bone, as in the structure of plywood. This structure also facilitates the seeding of hydroxyapatite crystals from a supersaturated extracellular fluid. Bone collagen is primarily type I and resembles other type I collagens found in skin and tendon. The basic unit of bone collagen, the tropocollagen molecule, is a triple ­helix of three polypeptide α chains, each with ­ approximately 1000 amino acids.162 By stabilization of these soluble molecules with cross-links of hydroxylysine and lysine, the bone ­ collagen fibrils become insoluble.163 Type I collagen differs from the type II collagen of cartilage in several salient aspects. Each of the three α chains of type II ­collagen is ­ identical to the others, although their amino acid ­composition differs from that of any of the three (one

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pair, one unique) α chains of the type I tropocollagen of bone.164 Compared with the chains of type I collagen, the chains of type II collagen contain much more glycosylated hydroxylysine, making cartilage all the more resistant to degradation by collagenase. The triple helix of type I collagen forms a linear molecule approximately 300 nm long.165 Each molecule is aligned parallel to the next, producing a collagen fibril. Within the collagen fibril, gaps called hole zones exist between the end of one molecule and the beginning of the next. It is thought that noncollagenous proteins reside in these spaces, which chemotactically attract and initiate the mineralization process.159 The fibrils are grouped further in bundles to form the collagen fiber. Proteoglycans constitute the principal noncollagenous protein in the mineralized matrix. Bone proteoglycan is similar in structure to the proteoglycan found in cartilage, consisting of a thin protein core with multiple covalently bound glycosaminoglycan chains.166 Although the role of these proteins in bone has not been determined, it has been proposed that they may store information after functional activity, serving as a form of strain memory.167 These molecules deform rapidly in response to load, but re-establish their original relative orientation after unloading. Although speculative, this matrix cell interaction may serve as a signal ­transduction mechanism to transfer mechanical information from the matrix to the entombed osteocytes. OSTEOCALCIN Also present in the matrix are substantial quantities of o­ steocalcin, a protein found almost exclusively in bone and that constitutes 1% to 2% of the total bone protein. Osteocalcin synthesis occurs in the osteoblasts during the carboxylation of glutamate, a vitamin K–dependent reaction.168 1,25-Dihydroxyvitamin D enhances the synthesis of this noncollagenous protein.169 The osteocalcin knockout mouse, which required that three gene isoforms be deleted to achieve the unique phenotype, is characterized by a late-onset increase in bone mineral density, suggesting that an absence of the osteocalcin signal for activation of osteoclasts results in a thicker, less remodeled, bone.12 Osteocalcin also seems to have a role in regulating mineral properties.170 HYDROXYAPATITE

Figure 4-6  Ground section of bone photographed with polarized light showing the concentric lamellar structure of the basic unit of mature bone, the osteon. The central vascular canal (empty in this preparation) is surrounded by multiple lamellae of bone. The adjacent lamellae are composed of collagen bundles with differing orientations, giving rise to alternating light and dark bands in polarized light.

Bone mineral is generically referred to as hydroxyapatite (Ca10[PO4]6[OH]2), a platelike crystal 20 to 80 nm long and 2 to 5 nm thick. Bone hydroxyapatite differs from naturally occurring apatite because it contains numerous impurities, including sodium, fluorine, strontium, lead, and radium. It is smaller in size than natural apatites (10 nm versus 40 nm) and more reactive and soluble because of its less-perfect atomic arrangement.171 The nucleation sites of bone mineral may not be the plates of hydroxyapatite, but the more energetically favorable crystal spicules, such as amorphous ca­lcium phosphate and octacalcium phosphate.172 It is believed these unstable precursors are formed first and gradually transformed to the more crystalline hydroxyapatite.173 Mineral exchange is facilitated by the enormous surface area

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of ­ amorphous ­ calcium phosphate, including its hydration shell. This is reflected in the greater avidity of new bone for “bone-seeking” isotopes (e.g., technetium, fluorine, strontium). The bone mineral continues to mature throughout an individual’s lifetime,174 becoming more and more “perfect” and exposing less surface area for a given volume of mineral. BONE MARKERS Physicians have sampled serum for products released during bone remodeling as surrogates for histology and ­visualization of bone architecture. Although no one serum marker has been found to predict adequately disease or response to th­erapy, panels of markers can be used to su­ggest the p­resence of osteoblast or osteoclast activity. Alkaline phosphatase, in long use, is still an inexpensive marker of increased osteoblast function and is only slightly less ac­curate than bone-specific alkaline phosphatase. Osteocalcin also reflects bone formation activity.175 The presence of active osteoclasts in bone can be measured with serum and urine collagen breakdown products, such as N-telopeptides176 and pyridinolines177 (see Chapter 32). Successful treatment of high-bone-turnover states should be accompanied by decreases in these markers.178 MORPHOMETRIC ASSESSMENT OF BONE DENSITY AND STRUCTURE The “gold standard” of measurement of bone mineral density is dual-energy x-ray absorptiometry. The density units are given in grams per centimeter squared, as opposed to cubed, and they are indicative more of an apparent—rather than real—density because the two-dimensional rendering does not account fully for the bone size.179 In contrast, quantitative computed tomography (CT) measurement is a true volumetric measure of bone mineral density, but it is used infrequently because of the necessity of technical expertise and cost. Quantitative CT has been used more recently to show differential effects of PTH on trabecular compared with cortical bone.180 Ultimately, to determine bone’s true physical properties, assays such as transcutaneous ultrasound,181 magnetic resonance imaging, quantitative CT, and real-time micro-CT182 may provide more specific information regarding the quantity and the quality of the bone.

MINERALIZATION OF BONE TISSUE The mineralization of bone begins 10 to 15 days after the organic osteoid matrix has been laid down.183 At this point, mineral increases almost immediately to 70% of the ultimate content, whereas deposition of the final 30% takes several months.184 The process of mineralization is extremely complex and temporally dynamic.185 There is emerging evidence that hydroxyapatite deposition and seeding of mineralization are strongly interdependent on cartilage-derived and bone-derived macromolecules, such as osteonectin, phosphoproteins, and proteolipids. The initial sites of calcium phosphate nucleation in growing bone, fracture callus, and calcifying cartilage appear to be not at the bone surface, but on the processes of matrix vesicles.186 Matrix vesicles are small, round, extracellular lipid-bilaminar bound organelles that bud from hypertrophic chondrocytes or osteoblasts

undergoing the process of apoptosis187 and from cell processes originating from the plasma membrane.188 There is a definite polarity to the vesicles, with mineralization occurring in a predictable and organized way adjacent to the requisite phosphatases on the inner leaflet of the membrane.189 The matrix vesicles contain alkaline phosphatase, adenosine triphosphatase, inorganic pyrophosphatase, 5′-nucleotidase, and adenosine triphosphate–pyrophosphohydrolase190 in addition to phospholipids (especially phosphatidyl serine), which have a strong affinity for calcium ions.191 These ions are believed to accumulate in the matrix vesicle because of their affinity for the phospholipids and because of a membrane-bound calcium pump. At a point of supersaturation, nucleation of the mineral begins.192 In retrospect, the question of whether mineralization is an active or passive process remains to be answered. H­artgerink and colleagues193 have created nanofibers that assemble in structures reminiscent of the osteoid matrix. These asse­mbled nanofibers are able to direct mineralization of hydroxyapatite in the absence of cells. The ost­eoblast may enable passive mineralization entirely through pr­oduction of the extracellular matrix. NUCLEATION Alkaline phosphatase, a biosynthetic product of osteoblasts, is present in very high concentrations during development and osteoid production.194 The regulatory role of this disulfide-linked dimer is unknown, but its presence may increase local concentrations of phosphate and facilitate hydroxyapatite deposition.195 Increasing the concentration of phosphate in the micromilieu exceeds the local solubility product and catalyzes deposition along the inner leaflet of the vesicle. After this accretion, the destruction of the membrane has been attributed to an increasing concentration of lysophospholipids within the matrix vesicles, which suggests that they are programmed to self-destruct.196 After dissolution of the matrix vesicle membrane, the hydroxyapatite crystals are exposed to the extravesicular environment, where additional mineral accretes to the newly formed crystal.197 The crystal is believed to move chemotactically toward and bind preferentially at the hole zones between collagen fibrils, precipitated by the nesting osteonectin198 and fibronectin.199 Mineralization proceeds and extends over the collagen matrix, with the long axis of the hydroxyapatite crystal parallel to the collagen fiber. The arrangement of the collagen matrix that is synthesized during osteoblast activity ultimately determines the orientation of the bone mineral crystal.161 In the extravesicular milieu, glycosaminoglycans inhibit the calcification process by modulating the advancing mineral front.200 It may be just these proteoglycan macromolecules, found in high concentrations in noncalcifying collagenous structures such as ligament, tendon, and skin, that may prevent mineral deposition.201 Other theories for the lack of calcification of dense connective tissues include the tighter packing of their collagen fibrils; limited access of phosphate ions to the interfibrillar nucleation sites; and the existence of crystallization inhibitors, such as pyrophosphate, present in synovial fluid, plasma, and urine at concentrations sufficient to prevent deposition of calcium

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carbonates.202 When the concentration of these inhibitors reaches a threshold, mineralization is halted, leaving a thin layer of osteoid between the lining cells and the mineralization front. This establishes the syncytium, or cellular canopy, which must be retracted to expose the mineral and reinitiate the remodeling cycle.

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bone remodeling. The product of this sophisticated and interdependent process is an extremely successful tissue that serves as a structural organ and as a mineral reservoir. Many substitutes for bone, derived from calcium phosphate and hydroxyapatite mixtures (e.g., coral), have been used successfully in the clinic as bone substitutes in allografts or as an osteoconductive surface on implants.

TURNOVER In undecalcified ground sections, microradiography shows subtle differences in the calcium content of the bone tissue, allowing separation into “old” and “new” bone on the basis of contrast intensity (Fig. 4-7). Young osteons, in the process of formation, have large central vascular canals that narrow with infilling, showing progressively less mineralization toward the center. This contrasts sharply with the active tunneling process of resorption, in which case the inside rim of the osteon appears equally mineralized as the outer rings. Static remodeling parameters, such as the osteoid seam width, the number of resorptive events, and the number of formative events, can be inferred from these morphologic characteristics. By using double-fluorescent labels (e.g., tetracyclines) administered at known intervals, the clinician can determine dynamic parameters of bone remodeling (i.e., rates of turnover, infilling, and formation). Static and dynamic histomorphometric studies, quantified by means of biopsy specimens harvested from such areas as the iliac crest, are extremely powerful means of evaluating the systemic state of the skeleton.203 The complex, composite nature of bone achieved through the secretion of the collagen matrix and its subsequent mineralization is a product of the synergistic interrelationships of the cell types, the systemic regulators of calcium metabolism, and the matrix-bound proteins that locally control

Figure 4-7  Microradiograph of cortical bone showing osteons in various degrees of mineralization with numerous interstitial fragments (*).

ARCHITECTURE OF BONE Macroscopic Organization Bones are remarkably well suited for their structural role. At the gross level, as hollow tubes they derive maximal strength from minimal weight.204 At the next-lower structural level, cortical and cancellous morphology is strategically arranged to distribute functional stresses evenly.205 Lower still, the arrangement of the collagen within the cancellous or cortical bone, combined with the two-phase composite matrix of the collagen and mineral, provides tensile and compressive strength.206 The ultimate tensile strength of bone approaches that of cast iron, and its capacity to absorb and release energy is twice that of oak, yet the weight of bone is only one third that of steel. While proving a resilient and resistant material, this tissue’s capacity to remodel, adapt, and repair itself—without leaving a scar—is what identifies bone as the ultimate biomaterial. Martin and colleagues207 provide an excellent review of the architecture of bone. The structural success of skeletal morphology can be examined at a series of levels, as follows: 1. Gross anatomy and functional responsibility 2. Ultrastructural morphology (cortical or cancellous) 3. Microscopic organization (lamellar or woven) 4. Mineralization process (enchondral or intramembranous) At the gross structural level, each bone has diverse and distinct morphologic features. Regardless of function, each bone is composed of dense cortical tissue (e.g., diaphyseal shaft) and cancellous tissue, such as the trabecular cascades found in the neck of the femur or the metaphysis of the proximal tibia (Fig. 4-8). At the microscopic level, two types of bone are identified: the disorganized, hypercellular woven bone and the highly organized, relatively hypocellular lamellar bone. Essentially, all bone tissue can be described by one of these two morphologic patterns, whether mature, growing, pathologic, or healing. Woven bone is a product of rapid bone formation. Architecturally, it has an irregular, disorganized pattern of collagen orientation and osteocyte distribution (Fig. 4-9). Although woven bone is characteristic of embryonic and fetal development, it also is found in the healthy adult skeleton at li­gament and tendon insertions and in specific disease states, such as Paget’s disease, osteogenic sarcoma, and metastases. Under less severe pathologic conditions (fracture callus, inflammatory responses, stress fractures), woven bone is usually reabsorbed and replaced by lamellar bone within a few weeks of its deposition.208 Mechanical ­ stimulation, if potent enough, can even cause a rapid production of woven bone, which ultimately remodels into dense lamellar bone.209 Many consider woven bone an aberrant response. That it is laid down so quickly and is so readily remodeled

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Figure 4-8  A, Macerated preparation of the human knee showing the trabecular structure that supports the flared articular surface. B, Radiograph of the specimen shown in A.

A

Figure 4-9  Outer cortex of bone showing the results of rapid periosteal bone formation producing woven bone (arrows), followed by the slower formation of primary osteons surrounding blood vessels.

distinguishes this type of bone, however, as a wise strategy in accommodating new, intense structural challenges. Lamellar, or mature, bone can be packed tightly to form the dense cortex of a bone, or it can be organized as the trabecular struts in cancellous bone. In contrast to the random and disorganized structure of woven bone, the lamellar appearance of this mature bone is the product of highly organized mineralized plates. In cancellous bone, the ­ lamellae run parallel to the trabeculae. In cortical bone, several ­patterns occur. The predominant one is that found in ­osteons, which are composed of small, concentric lamellar cylinders surrounding a central vascular channel, similar to the rings in a tree trunk (Fig. 4-10). Osteons are typically 200 to 300 μm in diameter, consisting of six or seven concentric osteocyte rings, which are co­mposed of 20 lamellar plates.210 Canaliculi in lamellar bone are

B

c­onsistent in diameter and orientation and, in total, contain fewer osteocytes per unit volume than woven bone (20,000 cells/μm3 versus 80,000 cells/μm3). During growth in diameter, new bone must be added appositionally. After the formation of the periosteal cuff around the primary center of ossification, bone increases its diameter by one of two methods. During rapid growth, spicules of new woven bone are formed perpendicular to the surface, which allows maximal radial expansion with minimal material. The gaps between the spicules are subsequently filled in and consolidated by the formation of lamellar bone. In this process, individual periosteal blood vessels that lie in the valley of the spicules are surrounded by the encroaching new lamellar formation, creating primary osteons parallel to the long axis of the bone. An osteon that has formed de novo, as in the woven bone consolidation process just described, is known as a primary osteon. If this occurs intracortically by a resorptive process to replace preexisting bone tissue, it is referred to as a secondary osteon, or haversian system, and constitutes the bulk of adult human bone.211 When slow diametric growth occurs, seams of new bone are laid appositionally on the existing surface. As discussed previously, the birefringent pattern of circumferential ­lamellae and single osteons is believed to arise through directional changes between collagen bundles in layers, maximizing strength in many different planes. Although the collagen bundles within each of these lamellar plates are highly oriented, individual fibers often traverse interlamellar spaces. Such a composite integration increases the individual osteon’s resistance to external loads and the effective strength of the bone structure.212 An alternative theory for the polarized light ­birefringence of an osteon is based on fiber-rich, fiber-poor lamellar rings, in which the thinner (1- to 2-μm) plates contain a greater degree of glycosaminoglycans (ground substance) than the adjacent 5- to 7-μm, collagen-rich layers.213 These glycosaminoglycans are thought to be continuous from the “thin” lamellar plate, through the cement line, to interdigitate with the ground substance of the “thick” plate. This architecture,

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Mature haversian system (2 osteon) 1 Osteon Circumferential lamellae Woven bone Resorption cavity (osteoclastic and osteoblastic activity) Periosteal capillary and vein

Lamellar bone (in trabecula of cancellous bone) Forming osteon

Endosteal capillary and vein Volkmann’s canal

Periosteum

Haversian canal

Osteoclast Osteoid Osteoblast Capillary loop

Cutting cone

Figure 4-10  Architectural organization of cortical bone.

with a true continuity between plates, would produce an ­increase in the stiffness of each osteon or each circumferential plate. The morphology of lamellar bone may prove to be some combination of these two postulations, maximizing the stiffness of the material (continuity of ground substance) and its toughness (integration of collagen layers). CORTICAL DRIFTS: FLEXURAL NEUTRALIZATION If periosteal surface modeling were to occur in the absence of endosteal resorption, the overall thickness of the cortex would increase with increasing age, leaving too much bone and too little marrow space. This occurrence is avoided by coordinating the increasing periosteal diameter with a concomitant increase in the diameter of the endosteal envelope, which is achieved through resorption at this inner surface.214 Although these rapid surface drifts diminish in the mature skeleton, they increase again in elderly individuals. In the aged skeleton, the rate of surface erosion of the endosteal surface exceeds the formation rate of the periosteum, resulting in a net decrease in total bone mass. This age-related expansion of the cortex establishes a biomechanical compensatory mechanism, however, by the concurrent increase in the cross-sectional moments of inertia, which results in an increased capacity of the bone to resist bending loads.215 METAPHYSEAL RESHAPING During growth in length, the changes in periosteal and ­endosteal compartments are directed toward periosteal ­resorption accompanied by endosteal extension. As the metaphysis and diaphysis elongate, resorption at the periosteal surface must be closely coordinated with deposition

at the endosteum, a process known as metaphyseal reshaping.216 Under these circumstances, some of the cortical bone within the epiphyseal shell is spared and subsequently becomes a component of the cancellous structure within the metaphysis. Where fragments of osteons and new lamellae and abundant cement lines are seen, the ultrastructural organization of trabeculae reflects their cortical origin. HAVERSIAN REMODELING Bone remodeling is a process of “real-time” tissue r­ eplacement. In places, trabeculae are covered with ­osteoblasts making new bone; in others, osteoclasts are eroding the surface. This process of resorption and formation can rapidly alter the orientation of the trabeculae to accommodate changes in the manner of loading or shifts in alignment secondary to disease or fracture.217 To remodel cortical bone so that intracortical damage or dead tissue can be replaced, the cortex first must be resorbed from within, creating a surface for apposition. When haversian systems replace or remodel existing bone, this is not achieved through the identical pathway of the original osteon. These secondary osteons can persist directly through an existing arrangement of osteons and circumferential lamellae, leaving only remnants of these preexisting structures. These fragments of ­ lamellar or woven bone are termed interstitial lamellae. Because the structural integrity of the bone must be preserved during this remodeling, the replacement process requires close integration between resorption and formation. The cutting cone of the osteoclast must be followed rapidly by capillary invasion and the simultaneous intrusion of a population of osteoblasts infilling the lamellar rings of the secondary osteon. As discussed previously, matrix-bound proteins, such as TGF-β, which are released

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by the resorption process, may be crucial to integration of this coupling process. Although levels of intracortical remodeling may be elevated by changes in the organism’s nutritional status (e.g., calcium deficiency218), endocrine imbalance (e.g., hyperparathyroidism, menopause219), or even aging (e.g., osteopenia220), one of the most potent stimuli for remodeling is a change in the level of physical activity.221 If physical demands are altered (e.g., changing activity), or if the manner in which the bone is loaded is changed (e.g., distribution of strain or loading rate), the bone remodels internally to adapt to the new demands.222 Evidence of this osteonal turnover has been shown in rabbits, in which a 150% increase in the number of labeled secondary osteons occurred in the subchondral plate of the proximal tibia subjected to repetitive loads.223 Not only does loading activate modeling and remodeling, but also by-products of loading are believed to influence morphology. One of the strongest correlates to elevated intracortical turnover is an increased strain rate.224 Another alternative to strain magnitude, strain frequency, is a potent determinant of bone morphology.225 This sensitivity to discrete components of the biophysical milieu opens several distinct avenues for the treatment of musculoskeletal disorders, including induced electric fields226; low-intensity ultrasound227; and low-magnitude, high-frequency mechanical stimulation.228 BLOOD SUPPLY OF BONE Bone is extremely vascular and requires approximately 10% of the cardiac output.229 Blood supply to the cortical diaphysis is derived from the nutrient artery and the periosteal vessels. In the metaphyseal ends of the bone, where metabolism is most active, the periosteal vessels are large and abundant and are also referred to as metaphyseal arteries, although they are entirely analogous to the periosteal capillaries. The third set of vessels, the epiphyseal arteries, supplies the subarticular ends of the bones and assumes special importance because of the growth process in this area and the vulnerability of these vessels to injury. During infancy and adolescence, the epiphyseal plate serves as a barrier separating the epiphysis from the metaphysis. Although a few vessels crossing the plate have been described, it is widely accepted that there is no effective circulation across the plate. Essentially, the epiphyses have an isolated blood supply via the epiphyseal arteries, but those few vessels do present a potential route for the spread of infection or tumor from the metaphysis into the epiphysis. In most joints, there are abundant soft tissue attachments to the epiphyses (muscles, ligaments, capsule) so that numerous vessels supply the bone through these attachments (Fig. 4-11). In a few locations, such as the proximal femur, the entire epiphysis may be intra-articular and may be covered by articular cartilage. Because neither the articular nor the growth cartilage is penetrated by vessels, the few epiphyseal arteries must pass alongside the growth plate, covered by a thin layer of periosteum, to perforate the epiphysis.230 This route of blood supply is extremely vulnerable to trauma (fractures through the growth plate), increased intra-articular pressure (joint infections or bleeding into the joint), or idiopathic interruption (Legg-Calvé-Perthes disease in children, avascular necrosis in adults).

Epiphyseal vessels arborize within the bony nucleus to supply the marrow, the cancellous bone, the dividing chondrocytes in the microepiphyseal plates in the depths of the articular cartilage, and the growth plate itself. Because of this, interruption of the vessels leads to cessation of longitudinal growth and diametric growth of the epiphysis and joint surface. Within the cortex of bone, capillaries travel primarily in the longitudinal direction within haversian canals. Occasional branching is seen, and lateral communication with the periosteal vessels through Volkmann’s canals provides collateral circulation. The usual haversian system is 100 mm or less in diameter. Individual osteocytes are not more than 50 mm from their blood supply. The rich system of canaliculi radiating out from the central canal enhances microcirculation to the most distant osteocytes.

MECHANICAL PROPERTIES OF BONE Even considering the elaborate cell kinetics, mineralization process, and morphology of bone, its success as a structure is ultimately a product of bone’s mechanical properties: how stiff it is, how resilient it is to fatigue, and how effectively it withstands the extremes of physical activity. The skeleton’s structural success can be jeopardized by genetic disorders

A

B Articular cartilage

Periosteum

Growth plate

Epiphyseal area Vein Artery Bone plate Germinal Proliferative Hypertrophic (calcified cartilage)

Growth plate

Vascular invasion Vein Artery Metaphyseal area

C

Figure 4-11  Epiphyseal blood supply of growing bone. A, The blood supply of most secondary centers of ossification is abundant by virtue of the numerous soft tissue attachments. B, Certain secondary centers, such as the proximal femur, are devoid of soft tissue attachments, and the blood supply follows a tenuous route through the joint, where it is liable to injury. C, The blood supply to the growth plate showing the contribution of the epiphyseal artery to the germinal portion of the growth plate. (From Sledge CB: Biology and development of the growth plate. In Cave EF [ed]: Trauma Management. Chicago, Year Book Medical Publishers, 1974.)

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such as osteogenesis imperfecta, metabolic diseases such as Paget’s disease, or even the bone loss that parallels the aging process (i.e., osteopenia). To appreciate the structural risks that accompany metabolic bone diseases, several interdependent concepts of bone’s biomechanical properties must be considered.231 The mechanical strength of fully mature osteonal bone is greater than that of immature bone, which is composed of circumferential lamellae and a few osteons that may be only partially mineralized.232 Values for the mechanical properties of individual osteons range from a tensile elastic modulus of 12 GPa and 114 MPa ultimate tensile strength for a fully mature, mineralized osteon to less than half that modulus and only 75% of the ultimate tensile strength for a younger, less mineralized osteon. For normal tensile or compressive loading, the stiffness of the material, or elastic modulus, shows human haversian bone to be about 17 GPa in the longitudinal direction, 11.5 GPa in the transverse direction, and 3.3 GPa in shear.233 The degree of ­mineralization (young bone) or porosity (old bone) compromises the stiffness of the bone and reduces the elastic modulus. The “effective” modulus of the bone can compensate for decreased stiffness, however, by changes in morphology (e.g., periosteal expansion). STRENGTH A major contributor to the strength of bone is derived through its composite nature of haversian, circumferential, and interstitial lamellae that work synergistically to avoid yield, or ultimate strain. Strain, a dimensionless unit of change in length divided by its original length, is used in bone physiology as 10−6 strain, or microstrain. The yield strain of bone, or the degree of deformation reached at which the bone does not elastically recover, is approximately 7000 microstrain. A 0.7% change in length causes irreversible damage to the tissue. Ultimate strain in bone, or the degree of deformation at which the material actually fractures, is 15,000 microstrain.234 An analogy of a bundle of straws versus a solid stick illustrates how a composite structure, such as bone, can prove more successful in resisting loads by avoiding yield and the ultimate strain of the material. This analogy is often put into practice with the use of multistranded wire rather than single-stranded wire. During flexion, each individual strand slips relative to its neighbor rather than straining, minimizing the generation of potentially damaging levels of strain. In the same manner, individual lamellae “slip” relative to adjacent lamellae, dissipating energy and minimizing strain levels within the ­material, allowing the entire system to react in a more elastic manner, rather than sustain brittle failure or ultimate fracture. TOUGHNESS As an organ, bone needs to be stiff (to resist deformation) and tough (to prevent crack propagation). There is a compromise, however, between these two objectives because they are attained through a balance of the composite of the resiliency to crack propagation provided by collagen and the resiliency to deformation provided by mineral. Comparatively

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small changes in the mineral content of bone tissue can have substantial effects on its properties as a material, as shown by Curry235 in his determination of the mechanical properties of diverse types of bone. By comparing the bovine femur, the deer antler, and the whale tympanic bulla, Curry235 illustrated that as the morphologic responsibility of the skeletal element changed, so did its mineral content. In the extreme, the mineral content ranged from 86% in the bulla, which requires high acoustic impedance, to 59% in the antler, which must be resilient to high-impact loads. The consequence of this high mineral content is revealed by comparing the relative work-to-fracture ratio of these bones. The work-to-fracture ratio of the bulla is only 3% that of the antler. The material properties of the appendicular skeleton remain remarkably consistent through a wide range of animals.236 Over an animal mass range of 0.09 to 700 kg, the bending strength of the bones relegated to traditional load-bearing responsibilities remains approximately 200 to 250 MPa, with an elastic modulus consistently approaching 20 GPa. To adapt to changes in the physical demands placed on it, it seems that the appendicular skeleton responds not by changing its material properties, but by altering its shape and morphology.237 This is achieved by functionally regulated alterations in bone mass and architecture. STRUCTURAL ADAPTATION IN BONE Bone tissue has the capacity to adapt to its functional environment such that its morphology is “optimized” for its mechanical demand. The concept proposed in 1892—that the course and balance of bone remodeling can be affected by mechanical function—is one of the oldest in modern medicine and is widely referred to as Wolff’s law.73 But what component of the functional environment is osteoregulating, and what is the structural objective of bone morphology? Strains measured during functional activity should indicate what the architecture of the skeleton is trying to amplify or suppress. Loads can be sustained with the smallest strains if they are applied axially. The axial component of functional activity is responsible, however, for only a small percentage of the total strain measured at the bone surface. The femur, humerus, radius, ulna, and tibia all show that greater than 80% of the measured strain is caused by bending moments.238 As the neutral axis of strain typically passes across the marrow cavity, a significant portion of the tissue is subjected to tension.239 Although bending moments cannot be extinguished, their effect would be minimized if the bone’s longitudinal curvature were oriented such that the moment created by curvature counteracted the moments externally imposed by activity. Long bone curvature does not appear to be directed toward the neutralization of bending, and in some cases this curvature is oriented such that bending is increased.240 Perhaps bone curvature, a morphologic modification attributable to functional loading,241 acts to accentuate bone strain, rather than cancel it. Similarity of Peak Strain Magnitudes in Functionally Loaded Bone Contrary to normal interpretation of Wolff’s law, it seems that minimizing strain is not the ultimate goal of adaptation; instead, skeletal morphology strives to generate a

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certain type of strain. What kind of strain is morphology trying to achieve? Although vertebrate design and function are diverse, at the level of small volumes of tissue all loads and bending moments resolve into strain. Peak strain magnitudes measured in adult species, including horse, human, lizard, sheep, goat, goose, pig, macaque, turkey, sunfish, and dog, are remarkably similar, ranging from 2000 to 3500 microstrain. This relationship has been called dynamic strain similarity and suggests that skeletal morphology and locomotion character combine to elicit a specific and perhaps beneficial level of strain.242 The interspecies similarity in strain magnitudes is strong evidence for the existence of a common strain-sensitive cellular population within the skeletal tissues of each of these animals. It also suggests the existence of a generic cellular mechanism that strives toward a common, strain-determined structural goal that is desired by and beneficial to the bone cell population. Strain-Regulated Adaptation Although the nature of this structure-function relationship is only poorly understood, it has been proposed that bone remodeling is continually influenced by the level and distribution of the functional strains within the bone.243 One striking example of the skeleton’s capacity to adapt to its functional environment has been shown in professional tennis players. By comparing the humeral mass of the racquet arm to the side that simply throws the ball into the air, Jones and colleagues244 observed a 35% increase in men and a 28% increase in women in the cortical thickness of the more active humerus. The converse also can be shown; immobilization and bed rest can cause negatively balanced bone remodeling locally or within the entire skeleton. Healthy men restricted to complete bed rest for 36 weeks showed a total body calcium loss averaging 4.2%. Bone mineral content measurements of the calcaneus showed a mean decrease of 34%. In one case, 45% of bone mineral was lost,245 showing that at specific weight-bearing sites the negatively balanced bone remodeling stimulated by diminished demand can be severe. Attempts to identify the aspects of the skeleton’s functional milieu that are responsible for generating and controlling this adaptive response have shown that alterations in bone mass, turnover, and internal replacement are sensitive to changes in the magnitude,246 distribution,247 and rate of strain224 generated within the bone tissue. A loading regimen must be dynamic. Static loads do not influence bone morphology,248 but the full osteogenic potential of bone is achieved after only an extremely short exposure to this stimulus.249 The potency of the stimulus is proportional to the magnitude of the strain.246 As strain levels that are acceptable in one location induce adaptive remodeling in others, each region of each bone may be genetically programmed to accept a particular amount and pattern of intermittent strain as normal. Deviation from this optimal strain environment stimulates changes in the bone’s remodeling balance, resulting in adaptive increases or decreases in its mass. It is unclear whether a discrepancy in strain is detected at the level of each individual osteocyte, whether the cell has the ability to manipulate the structural milieu of its adjacent space, or whether the osteocyte network somehow spatially

integrates the load information across the cortex.34,250 Bone mass is substantially influenced, however, by strain situations engendered by short periods of particularly osteogenic activity (e.g., vigorous and diverse exercise), rather than by the strain situation experienced during a predominant activity (e.g., walking) or by the fatigue damage that this might produce. Isolating specific components of the physical milieu that regulate skeletal morphology has been difficult; no single parameter of the mechanical environment has been shown to predict bone remodeling reliably in all naturally observed or experimentally created conditions.222 Perhaps the limited success in identifying these elusive stimuli has been due partly to the presumption that structural efficiency (minimal strain with minimal mass) is an essential goal of skeletal morphology. That the skeleton has “optimized” its structure is supported by the similarity in peak strains generated in the cortex regardless of animal or activity (2000 to 3000 microstrain), indicating a common, peak strain–determined goal. Contrasting with this perspective is the nonuniform, but consistent distribution of normal and shear strains that exist throughout the stance phase, leaving large areas of the diaphyseal shaft subjected only to extremely low levels of strain-energy density.251 Rather than a signal to repair accumulated damage, a new strain milieu needs to be applied for only a short time to maximize the tissue response.246 The engineering perspective that strain is harmful to bone, and that remodeling is a repair-driven process needs to be reconsidered. Instead, there may be some by-product of strain, such as stress-generated potentials, piezoelectric currents, or increased perfusion, that enhances the viability of the bone cell population.252 Very-low-intensity electric fields (<10 μV/cm253) and low-magnitude strains (<10 microstrain254), when induced within a specific, hyperphysiologic (10- to 50-Hz) frequency band, influence bone mass as effectively as stimuli of greater intensity induced at more “physiologic” frequencies. Strains at this frequency and magnitude are induced as by-products of muscle contractions, which resonate between 20 and 50 Hz, and they imply that skeletal diseases such as osteopenia may result not only from dysfunction of the bone cell population, but also from the decline of the musculature, as is the case with sarcopenia.255 Perhaps we should be more hesitant to presume skeletal morphology to be a product of dominant strain parameters with the structural goal of minimizing strain, and instead consider the matrix and cellular advantages of a tissue exposed to a dynamic functional milieu. MECHANICAL SIGNALING IN BONE CELLS Although these data show some relationship of function to form, they do not suggest the means by which the physical signal is transduced by the cell and extracellular matrix into the adaptive process. It has been shown that most eukaryotic cells, including osteoblasts, stromal cells, and osteocytes, respond to strain, shear, and pressure.256 Vascular channels within haversian systems, combined with the lacunae and canaliculi occupied by cells and the microporosity of the matrix, may consume 10% of the bone tissue’s volume and are filled with fluids or cellular components or both. The deformation of the skeleton caused by functional activity initiates this fluid to flow, similar to the way in which water

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flows through a sponge that is stretched or compressed. In this way, cells residing in the skeleton are subject to deformation, fluid shear, changes in dynamic electric potential, and transient pressure waves. The forces generated during exercise stimulate signals within bone cells that lead to activation of proliferation and differentiation programs. Whatever the signal transduction pathway of transforming physical information to something the cell population can perceive and respond to, it is clear that the capacity of bone tissue to adapt to its functional demands is crucial to the skeleton’s structural success. As clinicians attempt to evaluate the cellular mechanisms responsible for the positive control of bone mass, the osteogenic potential of physical stimuli cannot be ignored.

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121. Takahashi S, Goldring S, Katz M, et al: Downregulation of calcitonin receptor mRNA expression by calcitonin during human osteoclastlike cell differentiation. J Clin Invest 95:167-171, 1995. 122. Raisz LG, Niemann I: Effect of phosphate, calcium and magnesium on bone resorption and hormonal responses in tissue culture. Endocrinology 85:446-452, 1969. 123. Yamaguchi DT, Hahn TJ, Beeker TG, et al: Relationship of cAMP and calcium messenger systems in prostaglandin-stimulated UMR106 cells. J Biol Chem 263:10745-10753, 1988. 124. Cheng MZ, Zaman G, Rawlinson SC, et al: Mechanical loading and sex hormone interactions in organ cultures of rat ulna. J Bone Miner Res 11:502-511, 1996. 125. Eriksen EF, Colvard DS, Berg NJ, et al: Evidence of estrogen receptors in normal human osteoblast-like cells. Science 241:84-86, 1988. 126. Komm B, Terpening C, Benz D, et al: Estrogen binding, receptor mRNA, and biologic response in osteoblast-like osteosarcoma cells. Science 241:81-84, 1988. 127. Colvard DS, Eriksen EF, Keeting PE, et al: Identification of androgen receptors in normal human osteoblast-like cells. Proc Natl Acad Sci U S A 86:854-857, 1989. 128. Ernst M, Schmid CH, Froesch ER: Enhanced osteoblast proliferation and collagen gene expression by estradiol. Proc Natl Acad Sci U S A 85:2307-2310, 1988. 129. Rouleau MF, Warshawsky H, Goltzman D: Parathyroid hormone binding in vivo to renal, hepatic, and skeletal tissues of the rat using a radioautographic approach. Endocrinology 118:919-931, 1986. 130. Gray TK, Mohan S, Linkhart TA, et al: Estradiol stimulates in vitro the secretion of insulin-like growth factors by the clonal osteoblastic cell line, UMR 106. Biochem Biophys Res Commun 158:407-412, 1989. 131. Oursler MJ, Pederson L, Pyfferoen J, et al: Estrogen modulation of avian osteoclast lysosomal gene expression. Endocrinology 132:1373-1380, 1993. 132. Shevde NK, Bendixen AC, Dienger KM, et al: Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression. Proc Natl Acad Sci U S A 97:7829-7834, 2000. 133. Khosla S, Atkinson EJ, Dunstan CR, et al: Effect of estrogen versus testosterone on circulating osteoprotegerin and other cytokine levels in normal elderly men. J Clin Endocrinol Metab 87:1550-1554, 2002. 134. Smith EP, Boyd J, Frank GR, et al: Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 16:1056-1061, 1994. 135. Carani C, Qin K, Simoni M, et al: Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 337:91-95, 1997. 136. Bilzekian JP, Morishima A, Bell J, et al: Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. N Engl J Med 339:599-603, 1998. 137. Riggs BL, Khosla S, Melton LJ: A unitary model for involutional osteoporosis. J Bone Miner Res 13:763-773, 1998. 138. Christian JC, Yu P, Slemenda CW, et al: Heritability of bone mass. Am J Hum Genet 44:429-433, 1989. 139. Pocock NA, Eisman JA, Hopper JL, et al: Genetic determinants of bone mass in adults. J Clin Invest 80:706-710, 1987. 140. Finkelstein JS, Klibanski A, Neer RM: A longitudinal evaluation of bone mineral density in adult men with histories of delayed puberty. J Clin Endocrinol Metab 81:1152-1155, 1996. 141. Han ZH, Palnitkar S, Sudhaker Rao D, et al: Effects of ethnicity and age or menopause on the remodeling and turnover of iliac bone: Implications for mechanisms of bone loss. J Bone Miner Res 12:498-508, 1997. 142. Zhao G, Monier-Faugere MC, Langub MC, et al: Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: Increased trabecular bone volume without increased osteoblast proliferation. Endocrinology 141:2674-2682, 2000. 143. Adachi JD: Corticosteroid-induced osteoporosis. Am J Med Sci 313:41-49, 1997. 144. Mussolino ME, Looker AC, Madans JH, et al: Risk factors for hip fracture in white men: The NHANES I epidemiologic follow-up study. J Bone Miner Res 13:918-924, 1998. 145. Nguyen TV, Sambrook PN, Eisman JA: Bone loss, physical activity and weight change in elderly women: The Dubbo osteoporosis epidemiology study. J Bone Miner Res 13:1458-1467, 1998. 146. Zerwekh JE, Ruml LA, Gottschalk F, et al: The effects of 12 weeks of bed rest on bone histology, biochemical markers of bone turnover, and calcium homeostasis in 11 normal subjects. J Bone Miner Res 13:1594-1601, 1998.

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Biology, Physiology, and Morphology of Bone

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174. Bonar LC, Roufosse AH, Sabine WK, et al: X-ray diffraction studies of the crystallinity of bone mineral in newly synthesized and density fractionated bone. Calcif Tissue Int 35:202-209, 1983. 175. Lian JB, Gundberg CM: Osteocalcin: Biochemical considerations and clinical applications. Clin Orthop 262:267-291, 1988. 176. Rosen CJ, Chesnut CH III, Mallinak NJ: The predictive value of biochemical markers of bone turnover for bone mineral density in early postmenopausal women treated with hormone replacement or calcium supplementation. J Clin Endocrinol Metab 82:1904-1910, 1997. 177. Ross PD, Knowlton W: Rapid bone loss is associated with increased levels of biochemical markers. J Bone Miner Res 13:297-302, 1998. 178. Greenspan SL, Parker RA, Ferguson L, et al: Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy in representative elderly women: A randomized clinical trial. J Bone Miner Res 13:1431-1438, 1998. 179. Seemon E: From density to structure: Growing up and growing old on the surfaces of bone. J Bone Miner Res 12:509-521, 1997. 180. Black DM, Bilezikian JP, Ensrud KE, et al: One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis. N Engl J Med 353:555-565, 2005. 181. Howard GM, Nguyen TV, Harris M, et al: Genetic and environmental contributions to the association between quantitative ultrasound and bone mineral density measurements: A twin study. J Bone Miner Res 13:1318-1327, 1998. 182. Genant HK, Jiang Y: Advanced imaging assessment of bone quality. Ann N Y Acad Sci 1068:410-428, 2006. 183. Christoffersen J, Landis WJ: A contribution with review to the description of bone and other calcified tissues in vivo. Anat Rec 230:435-450, 1991. 184. Jowsey J: Microradiography: A morphologic approach to quantitating bone turnover. Excerpta Medica International Congress Series No. 270. Amsterdam, Excerpta Medica Foundation, 1972, p 114. 185. Glimcher MJ, Lian JB (eds): The Chemistry and Biology of ­Mineralized Tissues. Proceedings of the Third International ­ Conference on the Chemistry and Biology of Mineralized Tissues. New York, Gordon & Breach Science, 1988. 186. Wuthier RE, Jajeska RJ, Collins GM: Biosynthesis of matrix vesicles in epiphyseal cartilage, I: In vivo incorporation of 32P-orthophosphate into phospholipid of chondrocyte, membrane and matrix vesicle fractions. Calcif Tissue Res 23:135-139, 1977. 187. Kerr JFR, Wyllie AH, Currie AR: Apoptosis: A basic biological phenomenon with wide ranging implications in tissue kinetics. Br J Cancer 26:239, 1972. 188. Russell RGG, Caswell AM, Hearn PR, et al: Calcium in mineralized tissues and pathological calcification. Br Med Bull 42:435, 1986. 189. Anderson HC: Electron microscopic studies of induced cartilage development and calcification. J Cell Biol 35:81, 1967. 190. Anderson HC: Matrix vesicle calcification: Review and update. In Peck WA (ed): Bone and Mineral Research, Vol 3. New York, Elsevier, 1985, pp 109-150. 191. Wuthier RE: Lipid composition of isolated cartilage cells, membranes and matrix vesicles. Biochim Biophys Acta 409:128, 1975. 192. Endo A, Glimcher MJ: The potential role of phosphoproteins in the in vitro calcification of bone collagen. In Goldberg VM (ed): Transactions of the 32nd Meeting of Orthopaedic Research Society. Chicago, Adept Printing, 1986, p 221. 193. Hartgerink JD, Beniash E, Stupp SI: Self-assembly and mineralization of peptide-amphiphile nanofibers. Science 294:1684-1688, 2001. 194. Puzas JE: Phosphotyrosine phosphatase activity in bone cells: An old enzyme with a new function. Adv Protein Phosphatases 3:237-256, 1986. 195. Anderson HC: Biology of disease: Mechanism of mineral formation in bone. Lab Invest 60:320, 1989. 196. Wuthier RE: The role of phospholipids in biological calcification: Distribution of phospholipase activity in calcifying epiphyseal cartilage. Clin Orthop 90:191, 1973. 197. Peress NS, Anderson HC, Sajdera SW: The lipids of matrix vesicles from bovine fetal epiphyseal cartilage. Calcif Tissue Res 14:275, 1974. 198. Termine JD, Belcourt AB, Conn KM, et al: Mineral and collagenbinding proteins of fetal calf bone. J Biol Chem 256:10403, 1981. 199. Hynes RO: The molecular biology of fibronectin. Annu Rev Cell Biol 1:67, 1985. 200. Glimcher MJ, Krane SM: The organization and structure of bone and the mechanism of calcification. In Ramachandran GN, Gould BS (eds): Treatise on Collagen, Vol 11B. Biology of Collagen. New York, Academic Press, 1968, p 68.

PART 1 

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STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

201. Baylink D, Wengedal J, Thompson E: Loss of protein polysaccharides at sites where bone mineralization is initiated. J Histochem Cytochem 20:279, 1972. 202. Glimcher MJ: Composition, structure and organization of bone and other mineralized tissues and the mechanism of calcification. In Handbook of Physiology: Endocrinology, Vol VII. Baltimore, ­ Williams & Wilkins, 1976, p 25. 203. Parfitt AL: Bone histomorphometry: Proposed system for standardization of nomenclature, symbols and units. Calcif Tissue Int 42:284-286, 1988. 204. Hayes WC, Gerhart TN: Biomechanics of bone: Applications for assessment of bone strength. In Peck WA (ed): Bone and Mineral Research, 3rd ed. New York, Elsevier, 1985, p 259. 205. Lanyon LE: Analysis of surface bone strain in the calcaneus of sheep during normal locomotion: Strain analysis of the calcaneus. J Biomech 6:41-49, 1973. 206. Ascenzi A: The micromechanics versus the macromechanics of cortical bone: A comprehensive presentation. J Biomech Eng 110:357-363, 1988. 207. Martin RB, Burr DB, Sharkey N: Skeletal Tissue Mechanics. New York, Springer-Verlag, 1998. 208. Jones BH, Harris JM, Vinh TN, et al: Exercise-induced stress fractures and stress reactions of bone: Epidemiology, etiology, and classification. Exerc Sport Sci Rev 17:379-422, 1989. 209. Rubin CT, Gross T, McLeod K, et al: Morphologic stages in lamellar bone formation stimulated by a potent mechanical stimulus. J Bone Miner Res 10:488-495, 1995. 210. Albright JA, Skinner HCW: Bone: Structural organization and remodeling dynamics. In Albright JA, Brand RA (eds): The ­Scientific Basis of Orthopaedics, 2nd ed. East Norwalk, Conn, Appleton & Lange, 1987, pp 161-198. 211. Frost HM: Secondary osteon population densities: An algorithm for estimating the missing osteons. Yearbook Phys Anthropol 30: 221-238, 1987. 212. Ascenzi A, Benvenuti A: Orientation of collagen fibers at the boundary between two successive osteonic lamellae and its mechanical interpretation. J Biomech 19:455-463, 1986. 213. Schaffler MB, Burr DB, Fredrickson RG: Morphology of the osteonal cement line in human bone. Anat Rec 217:223-228, 1987. 214. Garn SM: The course of bone gain and the phases of bone loss. Orthop Clin North Am 3:503, 1972. 215. Ruff CV, Hayes WC: Subperiosteal expansion and cortical remodeling of the human femur and tibia with aging. Science 217:945, 1982. 216. Enlow DH: Principles of Bone Remodeling. Springfield, Ill, Charles C Thomas, 1963. 217. Koch JC: The laws of bone architecture. Am J Anat 21:177, 1917. 218. Lanyon LE, Rubin CT, Baust G: Modulation of bone loss during calcium insufficiency by controlled dynamic loading. Calcif Tissue Int 38:209-216, 1986. 219. Bain SD, Rubin CT: Metabolic modulation of disuse osteopenia: Endocrine-dependent site specificity of bone remodeling. J Bone Miner Res 5:1069-1075, 1990. 220. Rubin CT, Bain S: McLeod KJ: Suppression of the osteogenic response in the aging skeleton. Calcif Tissue Int 50:306-313, 1992. 221. Rubin CT: The benefits and consequences of structural adaptation in bone. In Fitzgerald R (ed): Non-Cemented Total Hip Arthroplasty. New York, Raven Press, 1988, pp 41-48. 222. Brown TD, Pedersen DR, Gray ML, et al: Toward an identification of mechanical parameters initiating periosteal remodeling: A combined experimental and analytic approach. J Biomech 23:893-905, 1990. 223. Radin EL, Martin RB, Burr DB, et al: Effects of mechanical loading on the tissues of the rabbit knee. J Orthop Res 2:221-234, 1984. 224. O’Connor JA, Lanyon LE, MacFie H: The influence of strain rate on adaptive bone remodeling. J Biomech 15:767-781, 1982. 225. Rubin C, Gross T, Donahue H, et al: Physical and environmental influences on bone formation. In Brighton CT, Friedlaender GE, Lane JM (eds): Bone Formation and Repair. Rosemont, Ill, American Academy of Orthopaedic Surgeons, 1994, pp 61-78. 226. Bassett CA: Fundamental and practical aspects of therapeutic uses of pulsed electromagnetic fields (PEMFs). Crit Rev Biomed Eng 17:451-529, 1989. 227. Heckman J, Ryaby J, McCabe J, et al: Acceleration of tibial fracture healing by noninvasive low intensity ultrasound. J Bone Joint Surg Am 76:165-374, 1994. 228. Rubin C, Turner AS, Muller R, et al: Quantity and quality of trabecular bone in the femur are enhanced by a strongly anabolic, noninvasive mechanical intervention. J Bone Miner Res 17:349-357, 2002.

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229. Shim SS: Physiology of blood circulation of bone. J Bone Joint Surg Am 50:812, 1968. 230. Sledge CB: Epiphyseal injuries. In Cave EF, Burke JF, Boyd RJ, (eds): Trauma Management. Chicago, Year Book Medical, 1974, pp 152-161. 231. Cowin SC: Bone Mechanics. Boca Raton, CRC Press, 2001. 232. Ascenzi A, Bell GH: Bone as a mechanical engineering problem. In Bourne GH (ed): The Biochemistry and Physiology of Bone, Vol 1: Structure. New York, Academic Press, 1972, p 311. 233. Reilly DT, Burstein AH: The elastic and ultimate properties of compact bone tissue. J Biomech 8:393-405, 1975. 234. Carter DR, Harris WH, Caler WE: The mechanical and biological response of cortical bone to in vivo strain histories. In Cowin SC, (ed): Mechanical Properties of Bone, Vol 45. New York, American Society of Mechanical Engineers, 1981, pp 81-92. 235. Curry JD: Mechanical properties of bone with greatly differing functions. J Biomech 12:313, 1979. 236. Lanyon LE, Rubin CT: Functional adaptation in skeletal structures. In Hildebrand M, Bramble DM, Leim KF, Wake DB (eds): ­Functional Vertebrate Morphology. Cambridge, Harvard University Press, 1985, pp 1-25. 237. Woo SLY: The relationships of changes in stress levels on long bone remodeling. In Cowen S (ed): Mechanical Properties of Bone, AMD, Vol 45. New York, American Society of Mechanical ­Engineers, 1981, p 107. 238. Rubin CT, Lanyon LE: Limb mechanics as a function of speed and gait: A study of functional strains in the radius and tibia of horse and dog. J Exp Biol 101:187-211, 1982. 239. Gross T, McLeod K, Rubin C: Characterizing bone strain distributions in vivo using three triple rosette strain gauges. J Biomech 25:1081-1087, 1992. 240. Rubin CT: Skeletal strain and the functional strain significance of bone architecture. Calcif Tissue Int 36:S11-S18, 1984. 241. Lanyon LE: The influence of function on the development of bone curvature: An experimental study on the rat tibia. J Zool Lond 192:457-466, 1980. 242. Rubin CT, Lanyon LE: Dynamic strain similarity in vertebrates: An alternative to allometric limb bone scaling. J Theoret Biol 107:321-327, 1984. 243. Rubin CT, Lanyon LE: Osteoregulatory nature of mechanical stimuli: Function as a determinant for adaptive remodeling in bone. J Orthop Res 5:300-310, 1987. 244. Jones HH, Pries JD, Hayes WC, et al: Humeral hypertrophy in response to exercise. J Bone Joint Surg Am 59:204-208, 1977. 245. Donaldson CL, Hulley SB, Vogel JM, et al: Effect of prolonged bed rest on bone mineral. Metabolism 19:1071, 1970. 246. Rubin CT, Lanyon LE: Regulation of bone mass by mechanical ­loading. Calcif Tissue Int 37:411, 1985. 247. Lanyon LE, Goodship AE, Pye C, et al: Mechanically adaptive bone remodeling: A quantitative study on function adaptation in the radius following ulna osteotomy in sheep. J Biomech 15:141-154, 1982. 248. Lanyon LE, Rubin CT: Static versus dynamic loads as an influence on bone remodeling. J Biomech 17:897, 1984. 249. Rubin CT, Lanyon LE: Regulation of bone formation by applied dynamic loads. J Bone Joint Surg Am 66:397-402, 1984. 250. Sun Y, McLeod K, Rubin C: Upregulation of collagen type 1 mRNA following mechanical loading as measured by in situ RT PCR. Trans 41st Orthop Res Soc 20:290, 1995. 251. Rubin CT, McLeod KJ: Biologic modulation of mechanical ­influence in bone remodeling. In Mow VC, Ratcliffe A, Woo SLY (eds): ­Biomechanics of Diarthrodial Joints, Vol II. New York, Springer­Verlag, 1990, pp 97-118. 252. You L, Cowin SC, Schaffler MB, et al: A model for strain amplification in the actin cytoskeleton of osteocytes due to fluid drag on pericellular matrix. J Biomech 34:1375-1386, 2001. 253. McLeod KJ, Rubin CT: The effect of low frequency electric fields on osteogenesis. J Bone Joint Surg Am 74:920-929, 1992. 254. Rubin CT, Sommerfeldt DW, Judex S, et al: Inhibition of osteopenia by low magnitude, high-frequency mechanical stimuli. Drug Discov Today 6:848-858, 2001. 255. Fritton SP, McLeod KJ, Rubin CT: Quantifying the strain history of bone: Spatial uniformity and self-similarity of low-magnitude strains. J Biomech 33:317-325, 2000. 256. Rubin J, Rubin C, Jacobs C: Molecular pathways of mechanical signaling in bone. Gene 367:1-16, 2006.

5

Muscle: Anatomy, Physiology, and Biochemistry Jody A. Dantzig  •  Eugenia C. Pacheco-Pinedo  •  Yale E. Goldman

KEY POINTS Muscles have a complex developmental process and structure. Various types of muscle fibers are specialized in terms of metabolic requirements, fatigue susceptibility, speed, and power. The structure, function, and protein isoform expression can change rapidly and are sensitive to the type of innervation and level of activity (i.e., plasticity). The smallest functional unit of muscle, the sarcomere, is composed of an almost crystalline array of filamentous proteins that transduce metabolic energy into motion and work. Muscles are connected to the skeleton through collagenous tendons and the epimysium. Skeletal muscle contraction is controlled by the central nervous system through motoneurons, the neuromuscular junction, and the intricate internal membrane system of the muscle fiber. Force is transmitted to the exterior through two sets of protein cell adhesion complexes: integrins and dystroglycans. Mature muscle fibers can regenerate after insult using components of the myogenesis process.

Approximately 660 skeletal muscles support and move the body under the control of the central nervous system. They constitute up to 40% of the adult human body mass. Most skeletal muscles are fastened by collagenous tendons across joints in the skeleton. The transduction of chemical energy into mechanical work by the muscle cells leads to muscle shortening and consequent movement. A high degree of specialization in this tissue is evident from the intricate architecture and kinetics of the intracellular membrane systems, the contractile proteins, and the molecular components that transmit force extracellularly to the basement membrane and tendons. Muscle cells normally exhibit wide variations in activity level and are able to adapt in size, isoenzyme composition, membrane organization, and energetics. In pathologic states, they often become deconditioned. These examples of plasticity can be surprisingly swift and extensive. This chapter outlines the structure and function of muscle and its relationship to the associated connective tissue. It also introduces the basis for the highly adaptive response to altered functional demands and diseases. Two excellent Web sites can be accessed for further ­information.1,2

MUSCLE DEVELOPMENT During embryogenesis, connective tissue, bone, and skeletal muscle are derived from mesodermal cells of the somites (Fig. 5-1). Developmental studies have shown that highly regulated sequential expression of transcription factors such as Sonic Hedgehog, bone morphogenetic proteins, and others3-5 are secreted from nearby structures, including the neural tube, notochord, dorsal ectoderm, and lateral mesoderm.3 These patterning factors participate in the commitment and delamination of mesodermal muscle precursors, which later migrate to the limb buds under the influence of other morphogenetic transcription factors.6-8 Once in the limb bud, the cells proliferate and differentiate under the stimulation of muscle regulatory factors such as myogenesis determining factor (MyoD), myogenic factor 5 (Myf-5), myogenic regulatory factor 4 (Mrf-4), and myogenin6,8; Myf-5 strongly promotes myoblast proliferation, whereas MyoD predominantly induces cell cycle arrest and differentiation (see Fig. 5-1). The migrating mesodermal precursors withdraw from the cell cycle, differentiate into spindle-shaped myoblasts (see Fig. 5-1), and begin to synthesize embryonic isoforms of muscle-specific proteins9 (Fig. 5-2A). Myoblasts align in columns and fuse to produce multinucleated primary myotubes (see Figs. 5-1 and 5-2B and C). The contrac­tile organelle, the myofibril, comprises long columns of sarcomeres and self-assembles on cytoskeletal scaffolding (see Fig. 5-2D and E).10-12 Myofibrils first appear near the periphery of the myotubes (see Fig. 5-2D) and fill in toward the center of the newly formed skeletal muscle fibers. Myofibrillogenesis continues until the cytoplasm is packed with parallel, laterally aligned sarcomeres (see Fig. 5-2E). Myoblasts continue to proliferate, and later generations elongate, fuse, and differentiate within the basal laminae of the primary myotubes, forming independent secondary myotubes.11,12 The nuclei migrate from the center to the periphery, where they remain in mature, multinucleated muscle fibers (see Fig. 5-2D and E). Central nuclei in adult muscle biopsies are thus diagnostic of abnormal muscle cell turnover (see Chapter 78). Both primary and secondary myotubes develop into phenotypically distinct muscle fiber types by sequentially expressing a series of embryonic, neonatal, and mature isoforms of the contractile proteins (Table 5-1).5,12 Some of the developmental and mature isoforms of the contractile proteins that appear in fast, slow, and cardiac muscle are encoded by multigene families, whereas others are differentially expressed by alternative splicing of messenger RNA. An extracellular matrix of type IV collagen, proteoglycans, fibronectin, and laminin is secreted by the myotubes to form the basal lamina, which fully ensheathes the fiber membrane (sarcolemma) except at the neuromuscular 93

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Epaxial dermomyotome

Noggin Shh Wnts BMP Notch

Neural tube

Pitx2 Pax-3 C-Met

Hypaxial dermomyotome

Pax 3 C-Met / HGF Lbx1

Mesodermal progenitor cells Pax-3 C-Met Msx-1 Mox-2 Six Myf-5 Myo D

Delamination Presomitic and somitic stages

Sclerotome Notochord Somite

Migration Mesodermal precursor cells

Muscle damage Numb IGF-1 Pitx-2 Pax-7

Proliferation

Satellite cell activation Notch

Myoblast precursors in the limb bud

Replenishment

Innervation and maturation

Satellite cells

Determination

Differentiation and fusion

Sarcolemma Basal Lamina Myofiber

Mrf4 MLP Pax7

Multinucleated early myotube

Myogenin Mef 2 Six-1 MyoD Myf-6(Mrf4) Slug(snail)

Myoblasts

Myf-5 MyoD Cyclin D1 Id Rb

Figure 5-1  Myogenesis and cell regeneration of skeletal muscle. The long red arrow indicates the initiation of muscle regeneration due to disease or injury. The somite is composed of a dermomyotome and a sclerotome. BMP, bone morphogenetic protein; C-Met, hepatocyte growth factor receptor; HGF, hepatocyte growth factor; Id, originally identified as dominant negative antagonists of the basic helix-loop-helix transcription factor family; IGF-1,  insulin-like growth factor 1; Lbx1, ladybird homeobox homolog 1; Mef-2, myocyte enhancing factor 2; MLP, muscle lim protein; Mox-2, membrane glycoprotein; Mrf-4, myogenic regulatory factor 4; Msx-1, homeobox msh-like 1; Myf-5, myogenic factor 5; Myf-6, myogenic factor 6; MyoD, myogenesis determining factor; Pax-3, paired box gene 3; Pax-7, paired box gene 7; Pitx2, paired-like homeo­domain transcription factor 2; Rb, product of the retinoblastoma tumor suppressor gene; Shh, Sonic Hedgehog; Six-1, homolog of Drosophila sine oculis homeobox 1; Slug(Snail), muscle LIM protein; Wnt, wingless-type mouse mammary tumor virus integration site family.

j­unction.13 Cell matrix interactions also feed back to the gene expression apparatus, as shown by experiments in which the lineage of cultured mesenchymal stem cells was modulated by the mechanical stiffness of the substrate.14 Under normal conditions, the number of muscle fibers within a skeletal muscle is virtually constant throughout life. Myogenic stem cells (satellite cells) remain situated in mature muscle fibers between the sarcolemma and basal lamina (see Fig. 5-1), providing a reservoir for muscle repair and growth.15 When a muscle fiber is damaged or necrosed, mitogenic factors and peptide regulators released from the damaged cells5,16 trigger satellite cells to proliferate and migrate into the affected area, guided by the basal lamina. Some satellite cells differentiate into myoblasts (see Fig. 5-1, red arrow, and following steps), fuse, and form new muscle fibers. Others replenish the satellite cell niche. The supply of these stem cells is limited, however, which diminishes the potential for repair in severe degenerative conditions. Recent studies suggest that other stem cell populations, such as muscle side populations17 and a small percentage of bone marrow cells,18-21 may also participate in muscle repair and satellite cell replenishment. Many of the genes involved in muscle myogenesis are also induced in the muscle repair process.5,6 For this reason,

knowledge of the mechanism of myogenesis may assist us in understanding regeneration and lead to new therapeutic strategies for treating muscle injuries and diseases.

STRUCTURE MUSCLE TISSUE Parallel, aligned bundles of skeletal muscle fibers make up approximately 85% of muscle tissue. Nerves, blood supply, and connective tissue structures that provide support, elasticity, and force transmission to the skeleton (discussed later) constitute the remaining volume. Muscle fibers range in length from a few millimeters to many centimeters and range in diameter from 10 to 150 μm. This elongated shape is determined by the organization of the contractile proteins that occupy the majority of the sarcoplasm. Each muscle has a limited range of shortening that is amplified into large motions by lever systems of the skeleton, usually operating at a mechanical disadvantage. Variations in the geometric arrangements of the fibers—parallel, fan shaped, fusiform (spindle-like), or pennate (feather-like)—determine some of the mechanical properties. For example, the slant of the fibers in a pennate muscle increases the magnitude of force

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Muscle myosin II filaments Titin Nuclei

Actin Non-muscle α-actinin Muscle α-actin Non-muscle myosin IIB

A

Stress fibers

Myoblasts

B

Premyofibrils

C

Fusing myoblasts

Nascent myofibrils

Primary myotube

Mature myofibrils

D Secondary myotubes

E

Mature myofibrils

Myotubes Figure 5-2  Developmental progression of myoblasts during fusion into myotubes. A, Unicellular myoblasts. B, Initial fusion of myoblasts.  C, Multinucleated myotubes. D, Myoblast fusing to multinucleated myotube; interface between myotube and mature myofibril. E, Mature myofibril.

generation at the expense of speed and range of movement, compared with a similarly sized muscle with fibers aligned parallel to the tendons.22 Muscles designed for strength (e.g., gastrocnemius) are typically pennate, whereas those designed for speed (e.g., biceps) tend to have parallel fibers. Muscles are commonly arranged around joints as antagonistic pairs, facilitating bidirectional motion. When one muscle (the agonist) contracts, another (its antagonist) is relaxed and passively extended. Their roles reverse to actively generate the opposite motion, unless it occurs passively by the force of gravity. An extensive network of connective tissue, forming the endomysium, surrounds each muscle fiber. Fine nerve branches and the small capillaries, necessary for the exchange of nutrients and metabolic waste products, penetrate this layer. The endomysium is continuous with the perimysium, a connective tissue network that ensheathes small parallel bundles of muscle fibers known as fasciculi, intrafusal fibers, larger nerves, and blood vessels. The epimysium encompasses the whole muscle. All three layers of connective tissue contain collagen, mostly types I, III, IV, and V; types IV and V predominate in the basement membranes surrounding each skeletal muscle fiber. The α12α2-chain composition of the collagen IV isoform is the most prevalent and provides the mechanical stability and flexibility of the basal lamina.23,24 The perimysium and endomysium merge at the junction between the muscle fibers and the tendons, aponeuroses, and fasciae. These layers give the attachment

sites great tensile strength and distribute axial force into shear forces over a larger surface area. FIBER TYPES Muscles adapt to their specific functions. In any given muscle, part of this adaptation arises from its composition and the organization of fiber types. Fibers can be classified according to their size, twitch duration, speed of contraction, balance between aerobic and glycolytic metabolism, and resistance to fatigue (Table 5-2). In addition, isoenzymes of the signaling, regulatory, and contractile proteins and the surface area of the sarcoplasmic reticulum (SR) membranes are key features that distinguish the functional properties of the different fiber types. For instance, the duration of the twitch is influenced by the rates of release and reuptake of calcium ions (Ca2+) by the SR, and the velocity of shortening is determined by myosin isoenzyme composition. Type IIB (fast) fibers are less “red” than the other fiber types because they contain less of the iron-heme–containing proteins, myoglobin, and mitochondrial cytochromes. Classification schemes are not, however, absolute, because some groups of fibers have composite or intermediate functional, ultrastructural, and histochemical characteristics. During development, fiber-type specificity may be partly determined before innervation.25 Although the biological events and signals responsible for designating functional specialization in muscle fibers are not fully understood,

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Table 5-1  Signaling and Contractile Proteins of Skeletal Muscle Protein Acetylcholine receptor Annexins Dihydropyridine receptor

Dysferlin

Molecular Weight (kD) 250 38 380

Location

Function

5 × 50

Postsynaptic membrane of   neuromuscular junction

Neuromuscular signal transmission

—

F-actin binding protein

Membrane repair

1 × 160 1 × 130 1 × 60 1 × 30

T tubule membrane

Voltage sensor

—

Periphery of myofibers

Membrane repair

4 × 450

Terminal cisternae of SR

SR Ca2+ release channel

110

—

Longitudinal SR

Uptake of Ca2+ into SR

Calsequestrin

63

—

SR terminal cisternae lumen

Binding and storage of Ca2+

Troponin

78

1 × 18 1 × 21 1 × 31

Thin filament

Regulation of contraction

70

2 × 35

Thin filament

Regulation of contraction

500

2 × 220 2 × 15 2 × 20

Thick filament

Chemomechanical energy transduction

Ryanodine receptor Ca -ATPase 2+

Tropomyosin Myosin

230

Subunits (kD)

1800

Actin

42

—

Thin filament

Chemomechanical energy transduction

MM creatine   phosphokinase

40

—

M line

ATP buffer, structural protein

α-Actinin

2 × 95

Z line

Structural protein

3000

—

From Z line to M line

Structural protein

Nebulin

600

—

Thin filaments, in the I band

Structural protein

Dystrophin

400

—

Subsarcolemma

Structural integrity of sarcolemma

Titin

190

ATP, adenosine triphosphate; SR, sarcoplasmic reticulum.

classic cross-innervation experiments demonstrated that innervation can dynamically specify and modify the type of muscle fiber.26 After cross-innervation, the functional and histological properties listed in Table 5-2 shift toward the target fiber type over a few weeks’ time, indicating the ability of muscles to adapt and remodel in accordance with the pattern of neuronal activity.

EVENTS DURING MUSCLE CONTRACTION NEURAL CONTROL Normally, a skeletal muscle fiber is activated briefly and then relaxes. This twitch, lasting for 5 to 40 msec, is initiated by an action potential propagated from the central nervous system along an alpha motoneuron, synaptic transmission across the neuromuscular junction, and an action potential in the muscle sarcolemma. Muscle fibers are typically innervated at one or two sites along their length by branches of an alpha motoneuron axon arising from the ventral horn of the spinal column. A motoneuron and the approximately 5 to 1600 homogeneous muscle fibers it innervates constitute a motor unit. Although the spatial domains of different units are intermingled, when an alpha motoneuron is excited, all fibers in the motor unit are triggered to contract together. Functional properties, such as speed and susceptibility to fatigue, vary with the dynamic requirements set by the neuronal firing pattern and the mechanical load, but they are homogeneous within

a motor unit. The level of muscle activity is controlled by varying the firing rate of twitches and the number of active motor units. As activity increases, more and larger units are recruited. A second class of fibers, the intrafusal fibers, are innervated by gamma motoneurons and control the sensitivity of the Golgi tendon organs and spindle receptors that provide local feedback to the spinal cord regarding muscle length and force. Afferent feedback pathways modulate activity to control the desired movement. The same feedback system generates the monosynaptic stretch reflex. NEUROMUSCULAR TRANSMISSION At the neuromuscular junction, the axon tapers and loses its myelin sheath. The postsynaptic sarcolemmal membrane (the motor end plate) is indented into folds that increase its surface area (Fig. 5-3). Mitochondria and nuclei are ­ concentrated in this region. The junctional cleft is a 50-nm-wide space between the presynaptic axonal membrane and the sarcolemma. When the nerve action potential reaches the presynaptic terminal, local Ca2+ channels are gated open for the influx of Ca2+. This triggers the fusion of acetylcholine-loaded membrane vesicles with the neuronal presynaptic membrane.27 Exocytosed acetylcholine rapidly diffuses across the junctional cleft and binds to nicotinic acetylcholine-gated ion channels in the crests of the postsynaptic membrane folds. Ligand gating of the acetylcholine receptors increases

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Table 5-2  Classification of Muscle Fiber Types General Features

I

IIA

IIB

IIC

Size

Moderate

Small

Large

Small

Mitochondria

Many

Intermediate

Few

Intermediate

Capillary blood supply

Extensive

Sparse

Sparse

Sparse

SR membrane

Sparse

Extensive

Extensive

Extensive

Z line

Wide

Wide

Narrow

Narrow

MHCI ELC1s

MHCIIA ELC1f, ELC3f

MHCIIB ELC1f, ELC3f

MHCI, MHCIIA ELC1f, ELC3f, ELC1s

RLC2s

RLC2f

RLC2f

RLC2f, RLC2s

Protein isoforms Myosin heavy chain (MHC) Myosin essential light chain   (ELC) Myosin regulatory light   chain (RLC) Regulatory proteins

Slow

Fast

Fast

Fast

Mechanical properties Contraction time SR calcium ATPase rate Actomyosin ATPase rate Shortening velocity Resistance to fatigue

Slow/sustained Low Low Slow High

Fast twitch High High Fast Moderate

Fast twitch High High Fast Low

Moderate twitch High Moderate Moderate Moderate

Metabolic profile Oxidative capacity Glycolytic capacity NADH-TR/SDH/MDH LDH and phosphorylase Glycogen Myoglobin

High Moderate High Low Low High

Intermediate High Moderate Medium High Medium

Low High Low High High Low

High High Moderate Moderate Variable High

f, fast; LDH, lactate dehydrogenase; MDH, malate dehydrogenase; NADH-TR, nicotinamide adenine dinucleotide tetrazolium reductase; s, slow; SDH, succinate dehydrogenase; SR, sarcoplasmic reticulum.

their cation permeability, locally depolarizing the muscle cell. This change of membrane potential initiates a regenerative action potential, mediated by voltage-gated sodium (Na+) and potassium (K+) channels. The action potential propagates at velocities up to 5 m/sec from the motor end plate throughout the sarcolemma. Thus, the entire fiber and motor unit contract at the same time. EXCITATION-CONTRACTION COUPLING Invaginations of the sarcolemma at regular intervals constitute the transverse tubule (T tubule) network, which pervades the fiber and surrounds the contractile apparatus with connected longitudinal and lateral segments (Fig. 5-4). The lumen of this network is open to the extracellular space, and it contains the high-Na+ and low-K+ concentrations of interstitial fluid.28 Action potentials at the surface membrane invade the entire T tubular system. A specialized type of endoplasmic reticulum forms the entirely intracellular SR. Prevalent structures termed triads contain a T tubule flanked by two terminal cisternae of the SR to form junctional complexes (see Fig 5-4). Terminal cisternae contain the oligomers of the Ca2+-binding protein calsequestrin, which provide the fiber with an internal reservoir of Ca2+. Dihydropyridine receptors (DHPRs) are Ca2+ channels localized in the T tubule membranes facing the cytoplasmic domain of SR Ca2+-release channels (the ryanodine receptors [RyRs], or foot proteins) in the terminal cisternae membranes.29 These membrane proteins are further characterized in Table 5-1. When an action potential depolarizes the T tubular membrane, the DHPRs, which are primarily voltage ­sensors

in skeletal muscle (but not in myocardium), transfer a signal from the T tubules to the RyRs by direct interprotein coupling. Ca2+ is then released cooperatively through the RyRs from the SR into the myoplasm, where it activates the contractile machinery.30 This sequence of events is termed excitation-contraction coupling. Mutations in the α-subunit of the DHPR in dysgenic mice lead to paralysis because, in these mutants, depolarization of the skeletal muscle membrane does not initiate the release of Ca2+ from the SR. Excitation-contraction coupling can be restored in cultured cells from these mice by transfection with the complementary DNA encoding for the DHPR,31 and transfections using chimeric constructs32 have pinpointed the domain within the DHPR that specifies skeletal- or cardiac-type excitation-­contraction ­coupling.33 ­ Isoforms of the RyRs also help determine the characteristics of the coupling between T tubules and the SR.34 Channelopathies in human skeletal and heart muscle have been linked to DHPR mutations.35,36 Human malignant hyperthermia occurs in individuals with mutant RyRs that become trapped in the open state after exposure to halothane anesthetic agents.37 CONTRACTILE APPARATUS The specific locations and functions of the contractile proteins are listed in Table 5-1. Myofibrils are long, 1-μm-diameter cylindrical organelles that contain the contractile protein arrays responsible for work production, force generation, and shortening (Fig. 5-5). Each myofibril is a column of sarcomeres, the basic contractile units, which are approximately 2.5 μm long and delimited by Z lines (see

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Fig. 5-5D and E) containing the densely packed structural protein α-actinin. The contractile and structural proteins within each sarcomere form a highly ordered, nearly crystalline lattice of interdigitating thick and thin myofilaments (see Fig. 5-5E, I, and J).38 Myofilaments are remarkably uniform in both length and lateral registration, even ­ during

Muscle fiber

Nerve Motor end plate

10µm

A

Myofibrils Postsynaptic Membrane

Synaptic Cleft Synaptic Vesicles

Presynaptic Terminal

B

1µm

Figure 5-3  Neuromuscular junction. A, Scanning electron micrograph of an alpha motoneuron innervating several muscle fibers in its motor unit. B, Transmission electron micrograph. (A, From Bloom W, Fawcett DW: A Textbook of Histology, 10th ed. Philadelphia, WB Saunders, 1975. B, Courtesy of Dr. Clara Franzini-Armstrong, University of Pennsylvania, Philadelphia.)

contraction,39 resulting in the cross-striated histological appearance of skeletal and cardiac muscles. This highly periodic organization has facilitated biophysical studies of muscle by sophisticated structural38 and spectroscopic techniques.40,41 Thick filaments (1.6 μm long) containing the motor protein myosin are located in the center of the sarcomere in the optically anisotropic A band (see Fig. 5-5D). The thick filaments are organized into a hexagonal lattice stabilized by M protein42 and muscle-specific creatine phosphokinase43 in the M line (see Fig. 5-5D and E). Myosin (see Fig. 5-5K) is a highly asymmetric 470-kD protein containing two 120-kD globular NH2-terminal heads, termed cross-bridges or subfragment-1 (S-1; see Fig. 5-5L), and an α-helical coiled-coil rod. Two light chains—essential and regulatory, ranging from 15 to 22 kD—are associated with the heavy chain in each S-1 (see Fig. 5-5L). The rod portions of approximately 300 myosin molecules polymerize in a three-stranded helix to form the backbone of each thick filament (see Fig. 5-5K). The cross-bridges, protruding from these backbones, contain adenosine triphosphatase (ATPase) and actin-binding sites responsible for the conversion of chemical energy into mechanical work. Besides their role in muscle contraction, at least 20 classes of nonmuscle myosins accomplish diverse tasks in cell motility such as chemotaxis, cytokinesis, pinocytosis, targeted vesicle transport, and signal transduction.44 Thus, myosin is the target for mutations leading to a number of inherited muscular and neurologic diseases.45,46 Thin filaments (see Fig. 5-5I) are double-stranded helical polymers of actin that extend 1.1 μm from each side of the Z line and occupy the optically isotropic I band (see Fig. 5-5D and E). A regulatory complex containing one tropomyosin molecule and three troponin subunits (TnC, TnT, and TnI) is associated with each successive group of seven actin monomers along the thin filament (see Fig. 5-5J).38 In the region where the thick and thin filaments overlap, the thin filaments are positioned within the hexagonal lattice equidistant from three thick filaments (see Fig. 5-5F). Both sets of filaments are polarized. In an active muscle, an interaction between the two filaments causes a concerted translation of the thin

Myofibril Ca2+-release channels Transverse (T) tubules formed from invaginations of plasma membrane Sarcoplasmic reticulum 0.5µm Figure 5-4  Membrane systems that relay the excitation signal from the sarcolemma to the cell interior. In the electron micrograph, two T tubules are cut in cross section. The electron densities spanning the gap between the T tubules and the sarcoplasmic reticulum membranes are the ryanodine receptors, channels that release calcium into the myoplasm. (From Alberts B, Bray D, Lewish J, et al: Molecular Biology of the Cell, 2nd ed. New York, Garland, 1989. Micrograph courtesy of Dr. Clara Franzini-Armstrong, University of Pennsylvania, Philadelphia.)

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A Muscle

B

Muscle fasciculus

C

Muscle fiber H band

M line

A I band band

Z line

D

Z Sarcomere Z

Myofibril

I E

H

Troponin complex

Tnl Tnc TnT

Actin

Tropomyosin Actin thin filament

Sarcomere

F

J

H

G

Single myosin molecule

Subfragment 1

Tail Myosin filament

K

L ATP pocket Actin binding site

RLC ELC

ain

ain

m do

S2 S1

Light meromyosin

h tc

h Lig Motor domain Myosin subfragment 1

Myosin molecule

Figure 5-5  Components of the contractile apparatus. Components are shown at successively increasing magnifications from the whole muscle  (A) to the molecular level (I-L). The myofibril (D) shows the banding pattern created by the lateral alignment of the myofilaments (I, J) in the sarcomeres (D, E). Parts F to H show the cross-sectional structure of the filament lattice at various points within the sarcomere. Myosin is shown at the single twoheaded molecule level (K), and the crystal structure of the globular motor domain is shown (L, S-1) with the essential and regulatory light chains. (From Juanqueira LC, Carneiro J, Long JA: Basic Histology, 5th ed. Norwalk, Conn, Appleton-Lange, 1986. Modified from Bloom W, Fawcett DW: A Textbook of Histology, 10th ed. Philadelphia, WB Saunders, 1975; and Rayment I, Rypniewski WR, Schmidt-Base K, et al: Three-dimensional structure of myosin subfragment-1: A molecular motor. Science 261:50, 1993.)

fi­ laments toward the M line, which shortens the sarcomere and thus the whole muscle. Actin is ubiquitous in the cytoskeleton of eukaryotic cells and, like myosin, fulfills many roles in determining cell shape and motion.47,48 Control of the actin cytoskeleton and diseases due to mutations in actin-binding proteins are being intensively investigated.49

Two of the largest identified proteins, titin and nebulin, function in the assembly and maintenance of the sarcomeric structure. Individual titin molecules (∼3000 kD) are associated with the thick filament and extend from the M line to the Z line.50 Titin contains repeating fibronectin-like immunoglobulin and unusual proline-rich domains that confer molecular elasticity on the resting sarcomere.51 Nebulin

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ADP

(c)

(d)

ADP

Z-line Force generation and filament sliding (b)

ADP

(e)

ADP Pi Figure 5-6  The actomyosin cross-bridge cycle. Myosin molecules normally have two globular head regions (cross-bridges), but for clarity, only one is shown. The ⊗ within the globular domain of myosin represents a hinge point with maximal flexibility. Each head binds with two actin monomers. The sequence of reactions is attachment (a); the force-generating transition (b); orthophosphate (Pi) release (c); force generation and filament sliding (d); adenosine diphosphate (ADP) release (e); adenosine triphosphate (ATP) binding and detachment (f); and ATP hydrolysis (g). The shadowed heads near the detached and force-generating myosin heads indicate high mobility of the cross-bridges in these states.

Atached (a)

ADP Pi

ATP (g)

FORCE GENERATION AND SHORTENING At rest, the thin-filament regulatory proteins troponin and tropomyosin inhibit contraction (see Fig. 5-5I). During a twitch, Ca2+ released from the SR binds to TnC, relieving this inhibition and thus allowing cross-bridges to attach to actin. A contraction results from a cyclic interaction between actin and myosin (the cross-bridge cycle) that produces a relative sliding force between the thin and thick filaments.53 The energy source is the hydrolysis of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and orthophosphate (Pi). A simplified model of the chemomechanical events in the cross-bridge cycle is illustrated in Figure 5-6. Motor proteins, including myosin, can now be studied by singlemolecule biophysical techniques, which provide unprecedented details of their dynamics.54 When Ca2+ is present, a complex of myosin, ADP, and Pi attaches to the thin filament (step a in Fig. 5-6), and a structural change within the myosin S-1 initiates force production and the release of Pi (steps b and c).55,56 The conformational change in the cross-bridge that leads to force generation is a tilting motion of the light-chain region.41,57,58 The filament sliding that leads to shortening of the sarcomere occurs during a strain-dependent transition between two ADP states (step d). After ADP is released (step e), ATP binds to the active

Hydrolysis Primed

ATP Myosin thick filament

Actin thin filament

(∼800 kD) is associated with the Z line and thin filaments.50 Protein connections from the contractile apparatus through the sarcolemma to the extracellular matrix are described later in this chapter. The cytoskeleton of muscle fibers also contains cytoplasmic actin, microtubules, and intermediate filaments.52

Rigor

(f)

Detached

site and dissociates myosin from actin (step f). Myosin then hydrolyzes ATP (step g) to form the ternary myosinADP-Pi complex, which can reattach to actin for the next cycle. If the mechanical load on the muscle is high, the contractile apparatus produces a force without changing length (an isometric contraction). If the load is moderate, the thin filaments slide actively toward the center of the sarcomere, resulting in shortening of the whole muscle. The width of the muscle increases during shortening, so the volume stays constant. Work production (concomitant force and sliding) is associated with an increase in the ATPase rate. The thermodynamic efficiency (mechanical power divided by energy liberated by ATPase activity) approaches 50%— a remarkable figure, considering that manufactured combustion engines seldom achieve ­ efficiencies greater than 20%. RELAXATION The twitch is terminated by reversal of all the steps in activation. Ca2+ released from the SR is taken up again by Ca2+ATPase pumps located in longitudinal membranes of the SR. The myoplasmic Ca2+ concentration then decreases, and Ca2+ dissociates from TnC, deactivating the thin filament. When the number of attached cross-bridges declines below a certain threshold, tropomyosin inhibits further cross-bridge attachment, and tension declines to the resting level. Ca2+ diffuses within the longitudinal SR to the calsequestrin sites in terminal cisternae, ready to be released in the next twitch. Myosin continues to hydrolyze ATP at a low rate in relaxed muscle, accounting for a sizable proportion of basal metabolism.

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the membrane. Its absence or truncation causes Duchenne’s and Becker’s muscular dystrophies.61 The N-terminus of dystrophin binds to actin via a region with sequence homology to the actin-binding domain of α-actinin. This end of the dystrophin molecule may be linked to the basal lamina via the same proteins described previously for the focal adhesion-like complexes (see Fig. 5-7). The C-terminus binds to a transmembrane dystroglycan-sarcoglycan complex, which in turn binds to the laminins. Muscular dystrophies of varied severity are associated with a loss of these components (see Table 5-3).62 Dystroglycans are also required for early embryonic development of muscle, possibly organizing laminin localization and assembly.63,64 Utrophin, a smaller dystrophin-related protein (395 kD), may also link the actin cytoskeleton to the dystroglycans, especially near the neuromuscular junction and in nonmuscle cells. Overexpression of this protein or truncated dystrophin constructs are promising avenues for gene therapy in Duchenne’s muscular dystrophy.65 The unusual intricacy of cell matrix connection systems in muscle may relate to the high forces generated during contraction.

TRANSMISSION OF FORCE TO THE EXTERIOR CELL MATRIX ADHESIONS The muscle cell is closely connected to the basal lamina along its entire surface. Several transmembrane macromolecular complexes link the myofibrils and actin cytoskeleton to laminins and collagen in the extracellular matrix. Attachment complexes for muscle, analogous to the focal adhesions of motile and epithelial cells and to the adhesion plaques and intercalated disks in cardiac muscle, contain filamentous actin, vinculin, talin, and integrin (primarily the α7β1 isoform), which is the transmembrane link to laminin (Fig. 5-7). In muscle, the main laminin isoforms are laminin-2 (α2β1γ1) and laminin-4 (α2β2γ1), which are collectively termed merosin. In addition to providing mechanical coupling between the cytoskeleton and the extracellular matrix, the laminin-integrin system may provide a signaling pathway to regulate localized protein expression.59 Defects in the expression of many of the cytoskeletal proteins lead to various forms of muscular dystrophy (Table 5-3).60 A specialized linkage between the cytoskeleton and basal lamina in muscle, complementary to the integrin focal adhesion system, is the dystrophin-glycoprotein complex (see Fig. 5-7). Dystrophin, a 427-kD peripheral cytoskeletal protein, has been postulated to function as a mechanical link between the cytoskeleton and the cell membrane or as a shock absorber, or to contribute mechanical strength to

MYOTENDINOUS JUNCTION The force of muscle contraction is transmitted to the skeleton via the tendons, which are composed of type I and III collagens, blood vessels, lymphatic ducts, and fibroblasts. At the ends of the muscle fibers, myofibrils are separated by invaginations of sarcolemma filled with long bundles of

Collagen

Basal lamina

Laminin Dysferlin

A1 A2 Annexins

β

ε

δ

γ

β

α

Sarcoglycans

α1

α-dystrobrevin

Sarcospan α

ζ

nNOS α1

Laminin Integrins

Dystroglycans

α

Syntrophins

101

β

Sarcolemma Vinculin

Caveolin 3 Talin

Dystrophin

N

C Cytoplasm Actin

Syncoilin

Figure 5-7  Connections between the muscle cytoskeleton and extracellular matrix. Actin is linked through integrins to the matrix, as in many cell types. Dystrophin forms an extra link through the dystroglycan-sarcoglycan complex of glycosylated proteins. The helical section of dystrophin is homologous to spectrin and may form homodimers or oligomers. Dystrophin links two intricate systems connecting the sarcolemma to the basal lamina. The COOH-terminus of dystrophin (N) is associated with the sarcoglycans, dystroglycans, dystrobrevin, syncoilin, neuronal nitric oxide synthase (nNOS), and syntrophins. The NH3-terminus links actin, vinculin, and the integrins with laminin and the basal lamina. These two adhesion systems provide a supportive substructure to maintain the integrity of the sarcolemma. The annexins and dysferlin have a role in muscle regeneration.

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Table 5-3  Classification of Muscular Dystrophies Disease

Protein

Outcome

Duchenne’s, Becker’s

Genetic Locus

Inheritance XR

Dystrophin

Lethal

Emery-Dreifuss

XR

Emerin, laminins A and C

40% lethality

Limb-girdle muscular dystrophies (LGMDs) LGMD 1A LGMD 1B LGMD 1C LGMD 1D LGMD 1E LGMD 1F LGMD 1G LGMD 2A LGMD 2B LGMD 2C LGMD 2D LGMD 2E LGMD 2F LGMD 2G LGMD 2H LGMD 2I LGMD 2J LGMD 2K

5q31 1q11-q21 3p35 6q23 7q 7q32 4p21 15q15.1-q21.1 2p13 13q12 17q12-q21.33 4q12 5q33-q34 17q11-q12 9q31-q34.1 19q13.3 2q24.3 9q34

AD AD AD AD AD AD AD AR AR AR AR AR AR AR AR AR AR AR

Myotilin Laminin A or C Caveolin — — — — Calpain 3 Dysferlin γ-Sarcoglycan α-Sarcoglycan β-Sarcoglycan δ-Sarcoglycan Telethonin E3 ubiquitin ligase (TRIM32) Fukutin-related protein Titin Protein   O-mannoslytransferase

CMDs with CNS involvement Fukuyama CMD Walker-Warburg CMD Muscle-eye-brain CMD

9q31 1p32 1p32-34

AR AR AR

Fukutin O-Mannosyltransferas O-MNAGAT

LE, 11-16 yr LE, <3 yr LE, 10-30 yr

CMDs without CNS involvement Merosin-deficient classic type

6q2

AR

Merosin (laminin A2)

Merosin-positive classic type

4p16.3

AR

Selenoprotein N1, collagen VI α2

Integrin-deficient CMD

12q13

AR

Integrin α7

Many patients never walk; others have LGMD pattern Course stabilizes in late childhood; many patients continue to walk into adulthood Presents early in infancy with hypotonia and delayed milestones

4q35 14q11.2-q13

AD AD/AR

19q13.3

AD

— Polyadenylate binding   protein nuclear 1 DMPK, CCHC-type zinc   finger, CNBP

Other dystrophies Facioscapulohumeral Oculopharyngeal Myotonic dystrophy

Less severe forms can emerge during first 3 decades of life, leading to loss of ambulation after age 30 yr; most severe forms start at age 3-5 yr and progress rapidly

20% wheelchair bound Onset ∼48 yr; 100% symptomatic by age 70 yr 50% show signs by age   20 yr; variable severity

AD, autosomal dominant; AR, autosomal recessive; CCHC, cysteine and histidine amino acid sequence; CMD, congenital muscular dystrophy; CNBP, cellular nucleic acid binding protein; CNS, central nervous system; DMPK, dystrophia myotonica protein kinase; LE, life expectancy; O-MNAGAT, O-mannose β-1,2-N acetylglucosaminyl transferase; XR, X chromosome related.

collagen arising from the tendon. These membrane folds increase the surface area for bearing the mechanical load by approximately 30-fold. Instead of terminating in the Z disks, actin filaments insert into a subsarcolemmal matrix containing α-actinin, vinculin, talin, and integrin. The force is transmitted through laminin to the collagen of the tendon.

ENERGETICS Metabolic pathways in muscle cells are specialized for the variable, and at times extreme, rates of ATP splitting by the contractile apparatus and membrane ionic pumps. Because the muscle tissue compartment is large, and because certain protein isoforms are specific to muscle tissue, circulating

levels of some metabolic enzymes (e.g., lactate dehydrogenase, creatine phosphokinase) are useful in the diagnosis of sarcolemmal disruption. Among the dozens of enzymes present, only the most important ones related to normal muscle function are mentioned here. BUFFERING OF ADENOSINE TRIPHOSPHATE CONCENTRATION The ATP content (∼5 mM) is sufficient for only a few seconds of contraction, so rapid and effective buffering of ATP during contraction is essential for the maintenance of activity. ADP formed by the hydrolysis of ATP is rephosphorylated by transfer of a phosphate group from creatine phosphate (20 mM in a resting cell), by creatine phosphokinase located within the

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M line of the sarcomere, in the myoplasm, and between the inner and outer membranes of the mitochondria. Adenylate kinase, known in muscle as myokinase, catalyzes the transfer of a phosphate group between two ADP molecules, forming ATP and adenosine monophosphate (AMP). The by-products of the rapid enzymatic reactions that maintain ATP concentration are, therefore, creatine, Pi, and AMP. Some of the AMP is converted to inosine monophosphate by adenylate deaminase. A creatine phosphate shuttle has been proposed to enhance energy flux.66 According to this hypothesis, creatine phosphate is split within the contractile apparatus, and creatine is predominantly rephosphorylated in the mitochondria. GLYCOLYSIS Muscles use glucose as fuel when possible; otherwise, they use fatty acids and ketone bodies (acetoacetate and 3-hydroxybutyrate). The muscle compartment contains most of the body storage of glycogen, which is converted to glucose 6-phosphate for local use. Muscle fibers lack glucose-6-phosphatase and thus do not export glucose. During intense activity, especially in anaerobic conditions, the rate of glycolysis and the production of pyruvate exceed the rate of pyruvate consumption by the citric acid cycle. The excess pyruvate is reduced to lactate by lactate dehydrogenase, which has tissue-specific isoforms. The lactate dehydrogenase reaction also produces nicotinamide adenine dinucleotide (NAD+), which is necessary for glycolysis, but otherwise, lactate is not useful within the muscle. Lactate is freely permeable through the sarcolemma, and a local increase in the extracellular lactate concentration or acidification produces exertional pain (“the burn”). Lactate is transported through the blood to the liver, where it is converted back to pyruvate and then glucose, which is released into the blood for use by other tissues, such as muscle and brain. This sequence of steps, termed the Cori cycle, transfers some of the high metabolic load to the liver and “buys time” until oxidative metabolism is available. OXIDATIVE PHOSPHORYLATION In aerobic conditions, pyruvate enters the mitochondria, where it is oxidized to carbon dioxide and water, generating reduced NAD (NADH). A hydrogen ion (H+) gradient across the mitochondrial membrane is produced by the electron transport chain, and, finally, ADP is phosphorylated to ATP by the mitochondrial ATP synthase. This remarkable rotary motor generator has been studied extensively using single-molecule biophysical techniques.67 By combining glycolysis and oxidative phosphorylation, up to 38 ATP molecules can be generated by the oxidation of each molecule of glucose. This process is energetically much more favorable than the production of lactate, but it can occur only when molecular oxygen is available. Myoglobin is an iron-heme complex protein that facilitates oxygen transport within the muscle cells. The tissue hydrostatic pressure in a contracting muscle often exceeds arterial perfusion pressure, so the strongest contractions are anaerobic. The content of oxidative enzymes, myoglobin, and mitochondria determines the predominant type of

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energy metabolism and varies in different muscle types, as discussed previously (see Table 5-2).

FATIGUE AND RECOVERY During intense or prolonged activity, muscle fatigue is caused by alterations of metabolite levels that suppress force ­generation at the contractile apparatus,68 in excitation-contraction coupling, or both.69 Markedly increased ­myoplasmic Pi and H+ concentrations and decreased creatine phosphate levels have been detected by magnetic resonance spectroscopy.70 When the creatine phosphate level declines, maintained activity depends on glycogenolysis until glycogen stores are depleted. During prolonged intense activity, the respiratory and circulatory systems are unable to meet the oxygen demands of tissues. Force production declines well before the ATP concentration is compromised. The chemomechanical link between Pi release and force generation (see Fig. 5-6) implies that the increase of myoplasmic Pi in fatigued muscle reduces the magnitude of force simply by mass action.56 Decreased muscle pH, partly from lactate accumulation, and insufficient acetylcholine at the neuromuscular junction, leading to failure of synaptic transmission, also contribute to decreased work production. Because the respiratory and circulatory systems do not supply sufficient oxygen to support the metabolism during intense activity, an oxygen debt is incurred. Blood flow and oxygen uptake continue at an enhanced level after the period of exercise to reclaim this energy. Rephosphorylation of creatine can take place within a few minutes, but glycogen resynthesis requires several hours. Recovery processes also involve the restoration of ionic gradients across the membrane-bound compartments and require the consumption of additional energy.

PLASTICITY The strength and endurance of a muscle are altered dramatically within weeks after changes in the demand for its use, its mobility, or its hormonal or metabolic environment. The effects of this adaptive response should be considered in any clinical situation that causes a substantial shift in these factors and in terms of the patient’s long-term quality of life. ADAPTATION TO EXERCISE Exercise leads to adaptations in the muscle fibers, including alterations in specific contractile, regulatory, structural, and metabolic proteins, as well as optimization of motor unit recruitment. The frequency, intensity, and duration of a training stimulus and the external load influence the adaptive response.71 Trophic factors liberated from the nerve play a minor role, if any. Strength training causes cross-­sectional hypertrophy of fast type IIB fibers (see Table 5-2), the expression of fast myosin isoforms, an increase in amino acid uptake, and decreased synthesis of mitochondrial proteins. Endurance training enhances the oxidative capacity and volume density of mitochondria in oxidative type I and IIA fibers, redistributes blood flow to these motor units, and increases the synthesis of contractile proteins. Long-term hyperplasia does not usually occur after training in humans. Although hypertrophy of preexisting fiber types is observed, training also induces changes in myosin isoform distribution,

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especially in fibers already containing more than one isoform. There is little evidence that voluntary training regimens can switch fibers between the major categories. When physical activity is reduced, such as during limb immobilization, the cross section of the fibers decreases, and endurance is reduced as a result of a decreased metabolic reserve. Acute exercise hypertrophy and disuse atrophy are both reversible, but after extensive alterations, the restoration may be incomplete.72 ENDOCRINE CONTROL Endocrine factors also participate in adaptation. For example, normal circulating levels of thyroid hormones are required during muscle development and differentiation.73 Experimental alterations of thyroid hormone concentrations promote changes in the relative levels of myosin and regulatory protein isoforms, as well as changes in the activity of some metabolic enzymes.74 An intact nerve supply is required for these thyroid effects. Myogenesis is partly controlled by the release of growth hormone from the pituitary via the production of insulin-like growth factor 1 (IGF-1) in the liver. IGF-1 activates satellite cells for muscle regeneration and stimulates the hypertrophy of mature muscle cells.75,76 Abuse of growth factors, drugs, steroids, and metabolites by athletes (primarily young men) to increase muscle mass and strength is a significant medical and societal problem.77,78 The use of androgenic-anabolic steroids (e.g., synthetic testosterone) to increase muscle mass and improve body image induces an increase in lean muscle mass as a result of skeletal muscle hypertrophy. Along with the increase in cross-sectional area of the muscle comes strength enhancement, with or without concurrent exercise training. Side effects of these performance-enhancing drugs include acne, erratic aggression, hirsutism, and male pattern baldness. These compounds also decrease high-density lipoprotein levels, increase erythropoiesis, increase bone density, and elevate liver enzymes. Most of the physiological changes are reversible. Acute cessation can lead to severe depression in many individuals. As in other tissues, insulin regulates the entry of glucose through the cell membrane. In muscle, it also promotes the uptake of branched-chain amino acids (valine, leucine, and isoleucine), which are necessary for rapid protein synthesis, and it inhibits protein degradation. Muscle weakness and fatigue may also be symptoms of changes in serum insulin and glucose levels.

AGING Normal individuals exhibit an approximately 30% decrease in total muscle mass between the ages of 30 and 80 years. The cross-sectional area of the fibers decreases, leading to a ­significant loss of strength. Gradual decreases in muscle activity, as well as neuronal changes, contribute to this muscle atrophy, which can exacerbate age-related joint degeneration and make joints less stable and more prone to injury. A decline in estrogen and testosterone levels in aging individuals has been hypothesized to affect muscle strength. Aging also produces a marked decrease in the level of IGF-1 and the subsequent ability to repair or build new muscle. Recombinant IGF-1 delivered via virus-mediated gene

transfer has been shown to increase the muscle mass and strength of the aged mouse.79 Further manipulations of specific growth factors may ameliorate muscle loss due to muscular dystrophies, other chronic illnesses, and aging.80,81 Muscle mass, strength, and flexibility are major factors in the maintenance of an independent and productive lifestyle among the elderly.

SUMMARY The complex functional capacity of muscle to produce finely tuned and coordinated movements is ultimately expressed as the transduction of chemical to mechanical energy by actomyosin. A twitch is initiated by an action potential propagated from the central nervous system along an alpha motoneuron, neuromuscular chemical transmission, direct protein-protein communication at the T tubule–SR junction, Ca2+ diffusion in the myoplasm, and Ca2+ binding to thin-filament regulatory proteins. Because the central nervous system controls activity through the recruitment of motor units, the gradation and coordination of movement depend on the pattern of connections between the alpha motoneurons and the muscle fibers and on the variation of properties among motor units. The development, maintenance, and aging of the muscular system involve a complex series of genetic programs and cellular interactions that are beginning to be understood at the molecular level. Adaptation of motor unit properties is evident not only in training regimens but also in reduced activity caused by pain or joint immobilization and in compromised metabolic, hormonal, or nutritional conditions. Hence, the plasticity of muscle affects the clinical course of many diseases. In addition to its importance in pathophysiology, muscle serves as an excellent substrate for understanding the molecular basis of cell development, protein structure-function relationships, cell signaling, and energy transduction processes.

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 39. Sosa H, Popp D, Ouyang G, Huxley HE: Ultrastructure of skeletal muscle fibers studied by a plunge quick freezing method: Myofilament lengths. Biophys J 67:283, 1994.  40. Thomas DD: Spectroscopic probes of muscle cross-bridge rotation. Ann Rev Physiol 49:691, 1987.  41. Irving M, Allen TS, Sabido-David C, et al: Tilting of the light-chain region of myosin during step length changes and active force generation in skeletal muscle. Nature 375:688, 1995.  42. Chowrashi PK, Pepe FA: M-band proteins: Evidence for more than one component. In Pepe FA, Sanger JW, Nachmias VT (eds): Motility in Cell Function. New York, Academic Press, 1979. 43. Walliman T, Pelloni G, Turner DC, Eppenberger HM: Removal of the M-line by treatment with Fab′ fragments of antibodies against MMcreatine kinase. In Pepe FA, Sanger JW, Nachmias VT (eds): Motility in Cell Function. New York, Academic Press, 1979.  44. Mermall V, Post PL, Mooseker MS: Unconventional myosins in cell movement, membrane traffic, and signal transduction. Science 279:527, 1998.  45. Hasson T: Unconventional myosins, the basis for deafness in mouse and man. Am J Hum Genet 61:801, 1997. 46. Redowicz MJ: Myosins and deafness. J Muscle Res Cell Motil 20:241, 1999.  47. Small JV, Rottner K, Kaverina I, Anderson KI: Assembling an actin cytoskeleton for cell attachment and movement. Biochim Biophys Acta 1404:271, 1998.  48. Sheterline P, Clayton J, Sparrow JC (eds): Actin, 4th ed. New York, Oxford University Press, 1998. 49. Ramaekers FC, Bosman FT: The cytoskeleton and disease. J Pathol 204:351, 2004.  50. Wang K: Sarcomere-associated cytoskeletal lattices in striated muscle. In Shay JW (ed): Cell and Muscle Motility, vol 6. New York, Plenum Press, 1985.  51. Labeit S, Kolmerer B: Titins: Giant proteins in charge of muscle ultrastructure and elasticity. Science 270:293, 1995.  52. Toyama Y, Forry-Schaudies S, Hoffman B, Holtzer H: Effects of Taxol and Colcemid on myofibrillogenesis. Proc Natl Acad Sci U S A 79:6556, 1982.  53. Goldman YE: Wag the tail: Structural dynamics of actomyosin. Cell 93:1, 1998.  54. Leuba SH, Zlatanova J (eds): Biology at the Single Molecule Level. England, Pergamon Press, 2001. 55. Goldman YE: Kinetics of the actomyosin ATPase in muscle fibers. Annu Rev Physiol 49:637, 1987.  56. Dantzig JA, Goldman YE, Millar NC, et al: Reversal of the crossbridge force-generating transition by photogeneration of phosphate in rabbit psoas muscle fibres. J Physiol 451:247, 1992.  57. Dobbie I, Linari M, Piazzesi G, et al: Elastic bending and active tilting of myosin heads during muscle contraction. Nature 396:383, 1998.  58. Forkey JN, Quinlan ME, Shaw MA, et al: Three-dimensional structural dynamics of myosin V by single-molecule fluorescence polarization. Nature 422:399, 2003.  59. Chicurel ME, Singer RH, Meyer CJ, Ingber DE: Integrin binding and mechanical tension induce movement of mRNA and ribosomes to focal adhesions. Nature 392:730, 1998.  60. Kanagawa M, Toda T: The genetic and molecular basis of muscular dystrophy: Roles of cell-matrix linkage in the pathogenesis. J Hum Genet 51:915, 2006. 61. Durbeej M, Campbell KP: Muscular dystrophies involving the dystrophin-glycoprotein complex: An overview of current mouse models. Curr Opin Genet Dev 12:349, 2002.  62. Matsumura K, Ohlendieck K, Ionasescu VV, et al: The role of the dystrophin-glycoprotein complex in the molecular pathogenesis of muscular dystrophies. Neuromuscul Disord 3:533, 1993.  63. Henry MD, Campbell KP: A role for dystroglycan in basement membrane assembly. Cell 95:859, 1998.  64. Campbell KP, Stull JT: Skeletal muscle basement membrane-sarcolemma-cytoskeleton interactions minireview series. J Biol Chem 278:12599, 2003.  65. Wells DJ, Wells KE: Gene transfer studies in animals: What do they really tell us about the prospects for gene therapy in DMD? Neuromuscul Disord 12:S11, 2002.  66. Bessman SP, Carpenter CL: The creatine-creatine phosphate energy shuttle. Annu Rev Biochem 54:831, 1985.  67. Kinosita K Jr, Yasuda R, Noji H: F1-ATPase: A highly efficient rotary ATP machine. Essays Biochem 35:3, 2000.

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6

Joint Biomechanics: The Role of Mechanics in Joint Pathology PAUL L. BRIANT  • THOMAS P. ANDRIACCHI

Key Points Mechanical loads can damage joint tissues by acute mechanical damage, slowly progressing degeneration, or mechanical stimulus of enzymatic degradation. Cartilage responds differently to applied mechanical loads depending on the health of the tissue. Mechanical loads influence joint tissue health by regulating tissue organization and cellular metabolism. The peak adduction moment during walking is a strong ­predictor of progression of medial compartment knee ­osteoarthritis. Treatments that reduce adduction moment during walking provide symptomatic relief.

Human diarthrodial joints must sustain large forces, provide dynamic joint stability, and permit the movement needed for normal joint function throughout life. The exceptional mechanical demand placed on human joints is one of the primary reasons most individuals incur some type of joint difficulty during their lifetime. Familiarity with the mechanics occurring at human joints is important for understanding normal and pathologic joint function. Joint biomechanics is the study of the interplay between mechanical loads and joint motions and the relationship between these loads and the mechanical demands on joint tissues. Mechanical loads can damage joint tissues through acute interactions, such as a traumatic knee ligament tear secondary to an acute overload, or by chronic repetitive loading causing cumulative microscopic degradation in the tissue matrix. The resulting tissue damage is typically associated with a biologic response from the tissue and changes in tissue morphology and mechanical properties. These tissue modifications alter the joint mechanics during ambulation and potentially can initiate a cascade of self-consistent events that lead to clinical symptoms and influence treatment outcome. Understanding this complex relationship between joint tissue structure, biology, and joint mechanics is essential for properly understanding and treating many joint pathologies. The interplay between mechanics and biology is most evident when considering the mechanics of ambulation at an in vivo joint level.1 This interplay is easily visualized at the knee joint, which is used throughout this chapter to illustrate many of the concepts presented, although the underlying principles can be extended to most diarthrodial joints. During ambulatory movement, the forces created by muscle activity and limb segment inertial properties cause complex joint motions and tissue strains. During activities

such as walking, the motions at the knee involve much more than rotation around a single axis, and the forces developed within the knee can reach several times the body weight of the individual.2 These macroscopic joint loads must be sustained by the tissue matrix and are ultimately transmitted to the cells, which respond to the mechanical load by altering their metabolic rates of matrix synthesis and degradation,3,4 changing the tissue mechanical properties. The biologic response of joint tissue to mechanical loads means that mechanics can play a large role in the initiation and the progression of many joint diseases. Osteoarthritis provides a common example in which mechanics are clearly implicated in pathology and clinical presentation. Although the cartilage degeneration associated with osteoarthritis has been commonly considered to result from “use-related” degeneration at the joint (“wear and tear”), such degeneration is more likely caused by a tissue biologic response to mechanical load, rather than direct mechanical wear.5 In healthy joints, articular cartilage tends to be thickest in the regions of highest load, suggesting that healthy cartilage responds positively to increased loading.1 These regions of highest load also tend to degrade most quickly when thinning has begun, however, suggesting that load is detrimental to osteoarthritic cartilage.1 The mechanisms causing this switch in load response are currently unknown; however, clinical treatments, such as high tibial osteotomy,6 that shift the load distribution within the knee, have been shown to produce symptomatic relief. This chapter addresses some of the fundamental principles of joint biomechanics. The focus is primarily on joint-level forces, motions, and structures, but how these joint-level phenomena are translated down to the tissue and cellular levels also is discussed.

JOINT ANATOMY IN BIOMECHANICAL TERMS A joint is defined as a location where two bones meet and are connected by soft tissue. The most common type of joint in the body is a diarthodial (synovial) joint. Diarthodial joints allow a large range of different types of motions and include joints such as the knee, wrist, and shoulder. The other types of joints in the body are fibrous joints, which are connected by dense fibrous tissue and allow virtually no relative movement, and cartilaginous joints, which are connected entirely by cartilage and allow a small amount of movement. The knee represents a typical diarthrodial joint, comprising ligaments, muscles and tendons, articular cartilage, joint capsule, and synovial fluid. The ligaments connect the two bones directly and, along with the bony geometry, provide 107

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however, the secondary motions (internal-external rotation and anterior-posterior translation) also are active and are important for normal knee function.10,11 The range of motion of each DOF is constrained by the passive mechanical stiffness of the joint tissues, and

JOINT MOTION

35

Flexion/Extension Rotation

30 25 20 15

Extension (-)

10 5 0 10

20

30

40

50

60

70

80

90 100

80

90 100

80

90 100

-5 Anterior/Posterior Translation

3.0 Posterior

All joints have six independent movements, or degrees of freedom (DOF). Three of these DOF are translations along the anterior-posterior, medial-lateral, and inferior-superior axes defined at the joint (Fig. 6-1), whereas the other three DOF are rotations around each axis. Because of the deformable nature of joint soft tissues and the inherent laxity within joints, movement occurs in all six DOF during physiologic motion (although most joints have a limited number of DOF with a large range of motion). Figure 6-2 shows plots of the flexion-extension rotation, anterior-posterior translation, and internal-external rotation at the knee during a single walking cycle captured for a normal individual during gait analysis. The primary motion is flexion-extension;

Flexion (+)

passive support and stability for the joint during motion. The articular cartilage covers the ends of each bone and is a smooth, fluid-filled tissue that provides a low-friction surface for smooth joint motion. The synovial fluid brings nutrients to the articular cartilage and aids in lubricating the joint.7 The muscles and tendons actively move the joint and provide a large amount of active stability during physiologic motion.8,9 This active stability is important because the passive structures alone are often insufficient to provide adequate joint stability during physiologic motion. In addition, the knee contains the meniscus, which is a fibrocartilage structure that improves joint congruity.

(°)

108

2.5 2.0 1.5 1.0

(cm)

Inferior-superior translation

0.5 0 10

20

30

40

50

60

70

Anterior

-0.5 -1.0

Internal-external rotation

Internal/External Rotation

-1.5

Medial-lateral translation

(°)

Anterior-posterior translation

Flexion-extension rotation

External (+)

6 Varus-valgus rotation

4 2 0 10

20

30

40

50

60

70

-2

Internal (-)

-4

Figure 6-1  The six degrees of freedom of the knee joint. Rotation ­(flexion-extension) around the medial-lateral axis is the primary degree of freedom; however, the other degrees of freedom also are important for normal physiologic motion.

-6 -8

Percent Stance Phase (%)

Figure 6-2  Plots of flexion-extension rotation, anterior-posterior translation, and internal-external rotation degrees of freedom of the tibia with respect to the femur during the stance phase of walking.

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109

M = Fxd

d

d

F

c Figure 6-3  The small anterior displacement (d) results in a large change in contact location (c), owing to the curvature of the knee.

e­ xcessive motion beyond the natural range of motion for a joint is a common cause of acute joint pathology (i.e., ligament tear). Subtle, long-term changes in joint motion also are important in joint pathology, especially chronic diseases such as osteoarthritis. As a result of the curvature of the knee geometry, small changes in joint kinematics, especially the secondary motions,12,13 can greatly alter the cartilage contact locations between the femur and the tibia (Fig. 6-3). This shift in contact alters the mechanical loads applied to the cartilage and over time may elicit a biologic response of the chondrocytes leading to tissue degeneration.14,15

JOINT LOADS During the above-described physiologic joint motions, forces are developed at the joints, which must be sustained by the joint tissues. Tissues such as ligaments and tendons undergo primarily tensile forces, whereas cartilage undergoes primarily compressive forces. The forces and motions are generated by muscle forces, inertial (mass) forces of the body segments, external forces (e.g., a foot contacting the ground), and friction forces. Joint loads during ambulation in the lower limbs can significantly exceed body weight by several orders as a result of upward accelerations against gravity and muscle cocontraction.2 Muscle cocontraction occurs when antagonistic muscle groups create equal force in opposite directions, resulting in no joint movement, but high joint forces. Cocontraction occurs frequently during ambulation and provides increased active joint stability. Each of the six kinematic DOF has a loading DOF associated with it. The three translational loads are referred to as forces and consist simply of a load causing an object to translate (move in a straight line). The loads causing rotational motion are called moments (torques). A planar moment is calculated as the product of the force magnitude causing the rotation times the perpendicular distance between the line of the force and the center of rotation. The moment created at the knee by an external horizontal force at the ground is calculated as the magnitude of the force times the

Figure 6-4  An adduction moment (M) at the knee is produced by the product of the horizontal component of the ground reaction force (F) multiplied by the perpendicular distance (d) from its line of action to the knee center.

p­ erpendicular distance from the knee to the line of action of the force (Fig. 6-4). The net joint loads for all six DOF are determined through experimental gait analysis. An analysis of the joint loads can provide insight into the role of mechanics in disease initiation and progression. Studies have shown the adduction moment at the knee during walking to be a strong predictor for the progression of medial compartment knee osteoarthritis.16 The adduction moment is the moment around the anterior-posterior axis of the knee, and an increase in adduction moment produces a more varus alignment and increases the load on the medial compartment of the knee (Fig. 6-5). Osteoarthritis patients with a higher adduction moment during walking tended to have thinner cartilage on the medial compartment relative to the lateral compartment, suggesting that load is detrimental to osteoarthritic cartilage.1 For healthy patients, an increased adduction moment has been associated with thicker medial compartment knee cartilage. Healthy cartilage seems to respond differently to load than osteoarthritic cartilage, although the mechanisms causing this switch in load response are currently unknown.1,16 Mechanical loads play a complex role in joint disease initiation and progression. Most loads applied to joint tissues are almost entirely compressive loads (cartilage), or tensile loads (tendon/ligament). There can be a small amount of friction applied to the tissues, however, as a result of sliding motion at joints. Healthy cartilage is very smooth, resulting in very little shearing loads applied to the surface, despite the large amount of sliding that can occur. It has been suggested, however, that as the cartilage degenerates during osteoarthritis, the cartilage surface roughens owing to fibrillation, increasing the friction at the surface.1 This increase in friction would alter the mechanical loads applied to the chondrocytes and elicit a change in cell metabolism. Shear loads applied to chondrocytes in culture have caused an increase in enzymes

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Medial load Center of mass

Lateral load

Adduction moment

B

A

Aduction moment

Ground reaction force

Figure 6-5  A, The adduction moment at the knee tends to cause the knee to be more varus (bow-legged). The moment is caused by the offset ­ etween the center of mass of the individual and the reaction force at the ground. B, An increase in adduction moment causes an increase in load on b the medial compartment.

known to degrade the cartilage matrix,4,14 which may be responsible for the negative correlation between load and cartilage thickness in osteoarthritic cartilage.1

JOINT BIOMECHANICS AT A TISSUE LEVEL The joint loads calculated in the preceding discussion are the net loads that must occur at the joint to produce the motion of the adjoining limb segments. These loads are applied directly to the joint tissues, which deform according to their mechanical properties. The deformation of the joint tissues determines the loads applied to individual matrix elements and the cells within the tissue, both of which may influence the health of the tissue. BASIC TISSUE MECHANICS When a force is applied to a tissue, it deforms over time by either elongating or compressing. The deformation that occurs depends on the area the force is applied over and the size of the tissue. For this reason, the loads applied to tissues are best described by the quantity stress (force per unit area), whereas the deformation is described by strain (deformation per unit length). The ratio between the applied

stress to resulting strain (force to deformation) is called the tissue stiffness. Stiffness is an important structural property for joint tissues and provides a measure of how much a tissue would deform under a given force. The higher the stiffness of a tissue, the less it would deform under the same load. The stiffness depends on internal properties of the tissue, including the tissue composition, and the organization of the constituents. A tissue with a highly organized collagen matrix is likely to have a higher tensile stiffness than a tissue with a more random collagen organization. The tissue mechanical properties also are inhomogeneous, meaning they vary from point to point within the tissue,17,18 and anisotropic, meaning the properties vary with direction. Such inhomogeneity and anisotropy are due to the spatial variations of the tissue constituents and may reflect an adaptation of the tissue to the local mechanical environment.17,19,20 The collagen matrix organization is one of the most important factors governing the responses of joint tissues to mechanical load.18 The organization of the collagen seems to be highly associated with the mechanical loads applied to the tissue, especially the tensile load.17 Ligaments and tendons undergo almost entirely tensile forces along the length of their main axis and, correspondingly, have a highly aligned collagen matrix along the axis. This

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gives them a very high tensile stiffness along their axis, but a very low stiffness if they are loaded perpendicular to their axis. The collagen organization in cartilage also seems to be associated with the tensile loads, although the load distribution and extracellular matrix organization are more complex and not as well understood. In general, the collagen fibers in cartilage are predominantly tangential to the surface in the superficial zone, but transition to be perpendicular to the surface in the deep layer (Fig. 6-6).5 Topographic analyses of tibial plateau cartilage have shown, however, that the collagen matrix in the superficial zone varies from highly aligned in the peripheral regions to more randomly organized in the central region (Fig. 6-7).17,21 This varied organization may be due to the nonuniform mechanical loads within the cartilage. The compressive loads applied to the tibial cartilage have been shown to be highest near the center of the plateau, and lower near the periphery.22 A simple nonconforming contact analysis of the knee joint surfaces suggests that under such loading, the stress in the superficial zone is compressive in the central, high-load region of the cartilage, but transitions to tensile near the periphery.23,24 Because it is known that the primary function of collagen in cartilage is to resist tensile forces,18,19 the higher tensile loads in the peripheral region may be responsible for the more organized collagen. Both of these examples show the apparent conditioning of joint tissues to mechanical load,1,5 and highlight the importance of mechanical load in the development and maintenance of healthy joints.5 In addition to being inhomogeneous and anisotropic, joint tissues are viscoelastic, meaning their stiffness depends on the rate of applied loading. This viscoelasticity is due primarily to the fluid flow that occurs within tissues under load. In addition to collagen, which is the primary constituent of most joint tissues, cartilage contains proteoglycans, Articular surface Superficial zone Transitional zone

Deep zone

Figure 6-6  The collagen fiber arrangement in normal articular cartilage. The fibers transition from being parallel to the articular surface in the tangential zone to perpendicular to the surface in the radial zone.

111

which draw water into the tissue because of their strong electrostatic charge. This water creates an osmotic gradient, causing the tissue to swell, which is resisted by the collagen matrix.25 When the cartilage is loaded compressively, the superficial zone collagen matrix is thought to collapse, effectively sealing the water inside the cartilage, causing the water to bear much of the compressive load, rather than the collagen matrix.26 Because water is nearly incompressible, this process gives cartilage a very high dynamic (short-term) compressive stiffness. Over time, however, the water is able to “seep out,” effectively decreasing steady-state (long-term) stiffness. JOINT TISSUE DEGENERATION The effect of mechanics on joint tissues is important to understand because most joint diseases result in degradation of the joint tissue matrix. Damage to any joint tissue matrix causes a biologic response, whether the triggering event is acute or chronic, and potentially can lead to further tissue degeneration, potentially at an anatomically distinct location. During anterior cruciate ligament rupture, subluxation at the knee often occurs, damaging the underlying bone and causing the response of acute bone marrow edema under the lateral tibial plateau.27 Chronic collagen fibrillation is a more subtle change, but also can alter the mechanics of cartilage by allowing fluid to escape when the cartilage is loaded and increasing the friction at the surface.1 Such changes potentially can cause long-term metabolic changes leading to chronic joint disease.28 In addition, proinflammatory cytokines, such as interleukin-1 and tumor necrosis factor-α, cause the release of matrix metalloproteinases 1 and 13 in cartilage,29 which break down the matrix further. Nonmechanical factors such as joint inflammation can cause tissue degeneration and degrade the ability of the cartilage to sustain mechanical loads, ultimately leading to more rapid degradation.

JOINT BIOMECHANICS AT A CELLULAR LEVEL CELLULAR LOADS AND DEFORMATIONS The cells in joint structures are responsible for maintaining the extracellular matrix through an active balance of tissue production and resorption. This balance is regulated partly by the mechanical loads applied to the cells, through the process of mechanotransduction. The loads applied to the cells are generated by deformation of the extracellular matrix, interstitial fluid pressurization, and interstitial fluid flow. Understanding the role of the cells in the initiation and progression of joint pathologies is challenging because neither the loads applied to the cells in vivo nor the fundamental mechanisms by which cells respond to load are currently known. Determining the in vivo loads applied to the cells requires bridging many length scales, from the macroscopic joint loads, down to the tissue loads, and finally to the cells. One study has attempted to determine chondrocyte deformation in situ by tracking the cells during compression of cartilage explants30; however, knowing the cellular deformation does not elucidate all of the loads applied to

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Superficial zone thickness

A

Superficial zone thickness

Figure 6-7  A and B, The superficial zone collagen in the region adjacent to the direct load (A) is thicker and substantially more organized, with more parallel ­collagen fibers than the directly loaded central region (B) with only pockets of parallel fibers.

B

the cells. To determine how cells respond to load, culture experiments can be used to apply specific loads to cells and measure the metabolic response patterns.3,4 Future studies are needed to determine the cellular deformations and cellular responses to load in more physiologic conditions. ROLE OF CELLS IN JOINT PATHOLOGY It is now recognized that cellular pathways comprising local tissue fibroblasts, chondrocytes, and osteoclasts/osteoblasts and infiltrating leukocyte populations are crucial in the pathogenesis of a variety of articular conditions (precise details are provided in chapters detailing the pathogenesis of distinct conditions and are not directly relevant to this discussion). Most acute joint pathologies, such as a ligament rupture or strain, are caused by direct mechanical overload and do not involve cells in the short term, although it is increasingly recognized that even in this acute event there is a contribution from local tissue mesenchymal cells and invading cells of the innate immune response as the lesion progresses. Changes that occur over a long time, such as in rheumatoid arthritis or osteoarthritis associated with

increased tissue laxity, may be caused, however, by direct mechanical damage to the extracellular matrix or through enzymatic degradation as a result of changes in cellular metabolism (e.g., the release of matrix metalloproteinases by synovial fibroblasts). Distinguishing between these two effects is important for determining the underlying causality of the various components of the pathologic lesion. Determining the pathways by which cells respond to their mechanical environment would enhance the development of new treatments for joint pathologies, including tissueengineered approaches. The latter, if achieved, would represent a novel complementary approach to the management of complex articular disorders.

IMPORTANCE TO RHEUMATOLOGISTS Joint mechanics play an important role in the initiation and the progression of many joint pathologies. One of the fundamental aspects of joint biomechanics is the relationship across scales, from the macroscopic joint motions and loads to the microscopic matrix and cellular responses. Owing to the close coupling of these components, changes to any one

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STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

of them would alter the overall joint mechanics and joint function. In addition to helping understand the cause of many joint diseases, joint biomechanics are important because many treatments involve altering the mechanical loads applied to joint tissues to relieve symptoms. Examples include high tibial osteotomy21 or modified footwear orthotics, which are designed to reduce load on the medial compartment to slow the progression of medial compartment knee osteoarthritis. Although it has been shown in clinical trials that such interventions are often successful,21 the fundamental mechanisms causing the symptomatic relief on a tissue and cellular level are currently unknown. A proper understanding of the role of mechanics, ranging from the joint level to the cellular level, would allow for the development of improved treatment methods and techniques. REFERENCES 1. Andriacchi TP, Mundermann A, Smith RL, et al: A framework for the in vivo pathomechanics of osteoarthritis at the knee. Ann Biomed Eng 32:447-457, 2004. 2. Schipplein OD, Andriacchi TP: Interaction between active and passive knee stabilizers during level walking. J Orthop Res 9:113-119, 1991. 3. Das P, Schurman DJ, Smith RL: Nitric oxide and G proteins mediate the response of bovine articular chondrocytes to fluid-induced shear. J Orthop Res 15:87-93, 1997. 4. Smith RL, Trindade MC, Ikenoue T, et al: Effects of shear stress on articular chondrocyte metabolism. Biorheology 37:95-107, 2000. 5. Carter DR, Beaupré GS: Skeletal Function and Form: Mechanobiology of Skeletal Development, Aging, and Regeneration. Cambridge, Cambridge University Press, 2000. 6. Prodromos CC, Andriacchi TP, Galante JO: A relationship between gait and clinical changes following high tibial osteotomy. J Bone Joint Surg Am 67:1188-1194, 1985. 7. Jay GD, Haberstroh K, Cha CJ: Comparison of the boundary­lubricating ability of bovine synovial fluid, lubricin, and Healon. J Biomed Mater Res 40:414-418, 1998. 8. Harrington IJ: Static and dynamic loading patterns in knee joints with deformities. J Bone Joint Surg Am 65:247-259, 1983. 9. Hsieh HH, Walker PS: Stabilizing mechanisms of the loaded and unloaded knee joint. J Bone Joint Surg Am 58:87-93, 1976. 10. Andriacchi TP, Alexander EJ, Toney MK, et al: A point cluster method for in vivo motion analysis: Applied to a study of knee kinematics. J Biomech Eng 120:743-749, 1998. 11. Lafortune MA, Cavanagh PR, Sommer HJ 3rd, et al: Three-dimensional kinematics of the human knee during walking. J Biomech 25:347-357, 1992. 12. Andriacchi TP, Briant PL, Bevill SL, et al: Rotational changes at the knee after ACL injury cause cartilage thinning. Clin Orthop 442: 39-44, 2006.

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13. Andriacchi TP, Dyrby CO: Interactions between kinematics and loading during walking for the normal and ACL deficient knee. J Biomech 38:293-298, 2005. 14. Frank EH, Jin M, Loening AM, et al: A versatile shear and compression apparatus for mechanical stimulation of tissue culture explants. J Biomech 33:1523-1527, 2000. 15. Gray ML, Pizzanelli AM, Grodzinsky AJ, et al: Mechanical and physiochemical determinants of the chondrocyte biosynthetic response. J Orthop Res 6:777-792, 1988. 16. Miyazaki T, Wada M, Kawahara H, et al: Dynamic load at baseline can predict radiographic disease progression in medial compartment knee osteoarthritis. Ann Rheum Dis 61:617-622, 2002. 17. Briant PL, Bevill SL, Torzilli PA, et al: Collagen organization in the superficial layer of articular cartilage relative to the mechanical environment. American Society of Mechanical Engineers, Summer Bioengineering Conference, Vail, Colorado, 2006, 152691. 18. Laasanen MS, Toyras J, Korhonen RK, et al: Biomechanical properties of knee articular cartilage. Biorheology 40:133-140, 2003. 19. Akizuki S, Mow VC, Muller F, et al: Tensile properties of human knee joint cartilage, I: Influence of ionic conditions, weight bearing, and fibrillation on the tensile modulus. J Orthop Res 4:379-392, 1986. 20. Farquhar T, Dawson PR, Torzilli PA: A microstructural model for the anisotropic drained stiffness of articular cartilage. J Biomech Eng 112:414-425, 1990. 21. Appleyard RC, Burkhardt D, Ghosh P, et al: Topographical analysis of the structural, biochemical and dynamic biomechanical properties of cartilage in an ovine model of osteoarthritis. Osteoarthritis Cartilage 11:65-77, 2003. 22. Baratz ME, Fu FH, Mengato R: Meniscal tears: The effect of meniscectomy and of repair on intraarticular contact areas and stress in the human knee: A preliminary report. Am J Sports Med 14:270-275, 1986. 23. Johnson KL: Contact Mechanics. Cambridge, Cambridge University Press, 1985. 24. Wilson W, Driesson NJB, van Donkelaar CC, et al: Prediction of collagen orientation in articular cartilage by a collagen remodeling algorithm. Osteoarthritis Cartilage 14:1196-1202, 2006. 25. Maroudas AI: Balance between swelling pressure and collagen tension in normal and degenerate cartilage. Nature 260:808-809, 1976. 26. Soltz MA, Ateshian GA: Experimental verification and theoretical prediction of cartilage interstitial fluid pressurization at an impermeable contact interface in confined compression. J Biomech 31: 927-934, 1998. 27. Johnson DL, Urban WP Jr, Caborn DNM, et al: Articular cartilage changes seen with magnetic resonance imaging-detected bone bruises associated with acute anterior cruciate ligament rupture. Am J Sports Med 26:409-414, 1998. 28. Grodzinsky AJ, Levenston ME, Jin M, et al: Cartilage tissue remodeling in response to mechanical forces. Annu Rev Biomed Eng 2: 691-713, 2000. 29. Shi J, Schmitt-Talbot E, DiMattia DA, et al: The differential effects of IL-1 and TNF-α on proinflammatory cytokine and matrix metalloproteinase expression in human chondrosarcoma cells. Inflamm Res 53:377-389, 2004. 30. Guilak F, Ratcliffe A, Mow VC: Chondrocyte deformation and local tissue strain in articular cartilage: A confocal microscopy study. J Orthop Res 13:410-421, 1995.

7

Proteinases and Matrix Degradation Yasunori Okada

Key Points Proteinases are generally classified into aspartic proteinases, cysteine proteinases, serine proteinases, and metalloproteinases according to catalytic mechanism. Because of the acidic pH optima and intracellular localization within lysosomes, most of the aspartic proteinases and cysteine proteinases are involved in intracellular degradation of extracellular matrix (ECM) components. Serine proteinases and metalloproteinases are neutral proteinases and play a central role in extracellular degradation of ECM macromolecules. ECM-degrading metalloproteinases are composed of the MMP (matrix metalloproteinase) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene families. Endogenous proteinase inhibitors are proteinase class specific, whereas α2-macroglobulin inhibits the activities of all proteinases. The activities of ECM-degrading proteinases at the local tissues are regulated by the balance between the proteinases and their inhibitors, which may be determined by production rates of proteinases and inhibitors, their secretion, activation of proenzymes, and anchoring systems of the activated proteinases to cell surfaces. ProMMPs (zymogens of MMPs) are activated via the extracellular, intracellular, and pericellular pathways depending on the MMP species. Aggrecan and type II collagen, two major ECM components, in articular cartilage may be degraded by differential or complementary actions of the MMP and ADAMTS species in arthritides. In rheumatoid arthritis, articular cartilage is destroyed by proteinases accumulated in synovial fluid, direct contact of proteolytic synovium and pannus tissue, and proteinases derived from chondrocytes, whereas bone is resorbed by osteoclasts mainly by the action of cathepsin K and MMP-9 under acidic and hypercalcemic conditions in subosteoclastic compartments. In osteoarthritis, chondrocyte-derived metalloproteinases, including the MMP and ADAMTS species, contribute primarily to the breakdown of articular cartilage.

Extracellular matrix (ECM) plays critical roles in normal development and function of the organism by interacting with cells and supporting tissue structures. The in vivo cellular functions regulated by cell-ECM interaction include proliferation, differentiation, apoptosis, and motility. The proteolytic turnover and remodeling of ECM is transient

and highly controlled under physiologic conditions, and excessive degradation of ECM components by proteinases causes tissue destruction in many pathologic conditions. In rheumatoid arthritis and osteoarthritis, ECM-­degrading proteinases are elevated without sufficient endogenous inhibitors, and they are believed to play central roles in the destruction of articular cartilage and bone on the basis of a local imbalance between proteinases and inhibitors. This chapter provides up-to-date information about the ECMdegrading proteinases and their inhibitors. Developments in the areas of proteinases and matrix degradation occurring since the seventh edition of this book was published in 2005 are discussed. Chapters from earlier editions offer a more comprehensive coverage of the older literature.1,2

EXTRACELLULAR MATRIX–DEGRADING PROTEINASES ECM is degraded by endopeptidases (i.e., proteinases) that act internally on polypeptide chains; little evidence is present for the roles of exopeptidases that cleave one or a few amino acids from the N or C terminus. Proteinases comprise aspartic proteinases, cysteine proteinases, serine proteinases, and metalloproteinases, which are classified according to catalytic mechanism. Proteinases from each of the four classes are involved in the degradation of ECM macromolecules. ASPARTIC PROTEINASES Most aspartic proteinases have two aspartic acid residues in their catalytic sites, where the nucleophile that attacks the scissile peptide bond is an activated water molecule. Among the proteinases belonging to this group, cathepsin D is the major aspartic proteinase involved in ECM degradation (Table 7-1). It exhibits proteolytic activity against most substrates, such as aggrecan and collagen telopeptides, with pH optima between pH 3.5 and 5.0. Because of the acidic pH optima and intracellular localization within lysosomes, cathepsin D is probably responsible for intracellular degradation of phagocytosed ECM fragments that previously were degraded in the extracellular spaces. A study on cartilage explant cultures using the aspartic proteinase inhibitor suggests, however, the possibility that cathepsin D secreted extracellularly contributes to the degradation of aggrecan in articular cartilage.3 CYSTEINE PROTEINASES Cysteine proteinases are endopeptidases in which the nucleophile of the catalytic site is the sulfhydryl group of a cysteine residue. The ECM-degrading cysteine ­ proteinases 115

116

OKada 

Table 7-1 

| 

Proteinases and Matrix Degradation

Proteinases That May Be Involved in Degradation of Extracellular Matrix

Enzyme

Molecular Mass (kD)

Source

Inhibitor

34

Lysosome

Pepstatin

25 24 24 29 110 (80 +30)

Lysosome Lysosome Lysosome Lysosome Cytosol

Cystatins Cystatins Cystatins Cystatins Calpastatin

30 30 29 94 88/85 46 67-72 54/33 30-35 26

Neutrophils Neutrophils Neutrophils Plasma Plasma Glandular tissues Endothelial cells; chondrocytes Fibroblasts; chondrocytes Mast cells Mast cells

α1-PI α1-Antichymotrypsin α1-PI, elafin Aprotinin Aprotinin Aprotinin; kallistatin PAI-1; PAI-2 PAI-1; PAI-2; PN-1 Trypstatin α1-PI

52/56*

Fibroblasts; synovial cells; chondrocytes;   macrophages; endothelial cells; cancer cells Neutrophils Chondrocytes; breast carcinoma cells

TIMPs

Aspartic Proteinases Cathepsin D Cysteine Proteinases Cathepsin B Cathepsin L Cathepsin S Cathepsin K Calpain Serine Proteinases Neutrophil elastase Cathepsin G Proteinase 3 Plasmin Plasma kallikrein Tissue kallikrein tPA uPA Tryptase Chymase MMPs Secreted-type MMPs Collagenases Interstitial collagenase (MMP-1) Neutrophil collagenase (MMP-8) Collagenase-3 (MMP-13) Gelatinases Gelatinase A (MMP-2) Gelatinase B (MMP-9) Stromelysins Stromelysin-1 (MMP-3) Stromelysin-2 (MMP-10) Matrilysins Matrilysin-1 (MMP-7) Matrilysin-2 (MMP-26) Furin-activated MMPs Stromelysin-3 (MMP-11) Epilysin (MMP-28) Other secreted-type MMPs Metalloelastase (MMP-12) RASI-1 (MMP-19) Enamelysin (MMP-20) MMP-21 MMP-27

75* 65

TIMPs TIMPs

Fibroblasts; chondrocytes; mesangial cells;   macrophages; endothelial cells Neutrophils; macrophages; osteoclasts;   trophoblasts; T lymphocytes; cancer cells

TIMPs; RECK

57/59* 56

Synovial cells; chondrocytes; fibroblasts Cancer cells; T lymphocytes

TIMPs TIMPs

28

TIMPs

28

Cancer cells; chondrocytes; macrophages;   mesangial cells; gland cells Placenta; endometrium

TIMPs

58 56

Cancer stromal cells Epidermis; testis; lung; cancer cells

TIMPs TIMPs

54 57 54 Unknown Unknown

Macrophages Synovial cells; ovary Enameloblast Unknown Unknown

TIMPs TIMPs TIMPs Unknown Unknown

66 68 64 63

Cancer cells; glioma cells; chondrocytes;   fibroblasts; synovial cells Cancer cells; glioma cells Glioma cells Brain; glioma cells

TIMPs except for TIMP-1; RECK TIMPs except for TIMP-1 TIMPs except for TIMP-1 Unknown

Unknown Unknown

Unknown Leukemia cells

Unknown Unknown

Unknown

Ovary; endometrium; testis; prostate

Unknown

72 92*

TIMPs

Membrane-anchored MMPs Type I transmembrane-type MMPs MT1-MMP (MMP-14) MT2-MMP (MMP-15) MT3-MMP (MMP-16) MT5-MMP (MMP-24) GPI-linked MMPs MT4-MMP (MMP-17) MT6-MMP (MMP-25) Type II transmembrane-type MMPs MMP-23

*Glycosylated form. MMP-4, MMP-5, and MMP-6 are missing MMPs. MMP-18 (Xenopus collagenase 4; from Stolow MA, et al: Identification and characterization of a novel collagenase in Xenopus laevis: possible roles during frog development. Mol Biol Cell 7:1471, 1996), and MMP-22 (chick MMP; from Yang M, Kurkinen M: Cloning and characterization of a novel matrix metalloproteinase CMMPJ, CMMP, from chicken embryo fibroblasts. CMMP, Xenopus XMMP, and human MMP19 have a conserved unique cysteine in the catalytic domain. J Biol Chem 273:17893, 1998) are not mammalian and thus are omitted from this list. PAI, plasminogen activator inhibitor; PI, proteinase inhibitor, PN, proteinase nexin; RECK, reversion-inducing, cysteine-rich protein with Kazal motifs; TIMP, tissue inhibitor of metalloproteinases; tPA, tissue-type plasminogen activator; uPA, urokinase-type plasminogen activator.

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STRUCTURE AND FUNCTION OF BONE, JOINTS, AND CONNECTIVE TISSUE

include lysosomal cathepsins B, L, S, and K and the calpains (see Table 7-1). Cathepsins B and L digest the telopeptide regions of fibrillar collagen types I and II, the nonhelical regions of collagen types IX and XI, and aggrecan at acidic pH.1 Cathepsin S has a similar spectrum of substrates within a broad range of pH values. Cathepsin K, also called cathepsin O, O2, or X, is a ­collagenolytic cathepsin that efficiently cleaves type I collagen at the triple helical regions at pH values between 4.5 and 6.6.4 The proteinase also degrades gelatin and osteonectin. Because cathepsins B, L, S, and K are expressed in synovium or articular cartilage or both in rheumatoid arthritis and osteoarthritis, they may be involved in the cartilage destruction through degradation of the ECM macromolecules. Cathepsin K also plays a key role in bone resorption in such joint diseases (see later). Calpains are Ca2+-dependent, papain-like cysteine proteinases and are ubiquitously distributed among mammalian cells. The best-characterized members of the calpain superfamily are μ-calpain and m-calpain, which also are called conventional (μ-calpain) and classic (m-calpain) calpains.5 Calpains are involved in various pathologic conditions, such as muscle dystrophy, by acting intracellularly. They are present in the extracellular spaces and in osteoarthritic synovial fluid, and they can degrade aggrecan. SERINE PROTEINASES Serine proteinases require the hydroxyl group of a serine residue acting as the nucleophile that attacks the peptide bond. They include the largest number of proteinases classified to about 40 families. Most can degrade ECM macromolecules. The major ECM-degrading serine proteinases in joint tissues are subsequently described (see Table 7-1). Neutrophil Elastase and Cathepsin G Neutrophil elastase and cathepsin G are serine proteinases that are synthesized as precursors in promyelocytes in bone marrow and subsequently stored in the azurophil granules of polymorphonuclear leukocytes as active enzymes. Mature leukocytes do not synthesize elastase, but they mobilize azurophil granules to the cell surface and release the proteinases in response to various stimuli. Monocytes have low levels of elastase, but lose the enzyme during the differentiation into macrophages. Neutrophil elastase and cathepsin G are basic glycoproteins with isoelectric points larger than 9 (neutrophil elastase) and about 12 (cathepsin G). They can be readily trapped in cartilage matrix that has a negative charge. Neutrophil elastase and cathepsin G cleave elastin; the telopeptide region of fibrillar collagen types I, II, and III; other collagen types IV, VI, VIII, IX, X, and XI; and other ECM components, such as fibronectin, laminin, and aggrecan at neutral pH. These serine proteinases also can be involved indirectly in the breakdown of ECM by activating the zymogen of pro-matrix metalloproteinases (proMMPs)6 and by inactivating endogenous proteinase inhibitors, such as α2-antiplasmin, α1-antichymotrypsin, and tissue inhibitors of metalloproteinases (TIMPs).

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Mast Cell Chymase and Tryptase Chymase and tryptase are packaged in secretory granules together with histamine and other mediators in mast cells, which are infiltrated in rheumatoid synovium. Chymase is a chymotrypsin-like proteinase with a broad spectrum of activity against ECM components such as type VI collagen7 and aggrecan. It also activates proMMPs, such as proMMP-1, proMMP-3, and proMMP-9.6 Although prochymase is activated intracellularly and stored in the granules, the activity in the granules is limited at low pH and becomes fully active when released extracellularly. Tryptase is a trypsin-like proteinase that degrades collagen type VI7 and fibronectin; it also activates proMMP-3.6 Plasmin and Plasminogen Activators Plasminogen is synthesized in liver and secreted to plasma. It can bind to fibrin and to cells, and after activation by plasminogen activators, plasmin readily digests fibrin. Membrane-bound plasmin also degrades many ECM components, including proteoglycan, fibronectin, type IV collagen, and laminin.8 Another important function of plasmin is to initiate the activation of proMMPs,6 activate latent cell­associated transforming growth factor (TGF)-β1, and act as proenzyme convertase. Plasmin is generated through activation of plasminogen mainly by plasminogen activators, principally two serine proteinases, tissue-type ­plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). The tPA is synthesized as a proenzyme of 70 kD and is secreted into the circulating blood primarily by endothelial cells, fibroblasts, chondrocytes, and tumor cells.8 In addition to being a major activator of plasminogen for fibrinolysis, tPA plays a key role in the clearance of fibrin from the circulation. The uPA molecule was first purified from urine as a proenzyme of 54 kD.8 It is converted to the active form of two chains of 30 kD and 24 kD linked by a disulfide bond. Another fully active form of 33 kD is generated by plasmin. Although the expression of uPA is limited to certain cells such as renal tubules and bladder urothelium under physiologic conditions, it is more widely expressed in various cells, including invasive cancer cells, migrating keratinocytes, and activated leukocytes, in pathologic situations. Pro-uPA and two-chain uPA bind to a specific uPA receptor, a single-chain glycoprotein with a glycosylphosphatidylinositol (GPI) moiety expressed on fibroblasts, macrophages, and tumor cells. Receptor-bound uPA preferentially activates cell membrane–bound plasminogen into plasmin. Cell membrane–bound plasmin can activate receptor-bound pro-uPA. Among its specificities, uPA has a limited action on fibronectin. Kallikreins Two types of kallikreins, plasma and tissue kallikreins, are known. Plasma kallikrein, with two disulfide-linked chains (36 kD and 52 kD), is generated from prokallikrein of 88 kD by coagulation factor XIIa or by kallikrein itself. It activates kininogens to bradykinin and activates proMMP-1 and proMMP-3.6 Tissue kallikrein is synthesized in glandular

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tissues. It releases Lys-bradykinin from kininogen and activates proMMP-8.6 METALLOPROTEINASES Similar to aspartic proteinases, metalloproteinases are endopeptidases in which the nucleophilic attack on a peptide bond is mediated by a water molecule. A divalent metal cation, usually zinc, activates the water molecule. Among the

metalloproteinase groups, MMPs (matrix metalloproteinases), which are also designated matrixins (a subfamily of the metzincin superfamily), are key ECM-degrading, zincdependent endopeptidases (Table 7-2; see Table 7-1). More recently accumulated evidence indicates, however, that some members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family, which is an MMP-related gene family, also are involved in ECM degradation (Table 7-3).

Table 7-2  Substrates of Human Matrix Metalloproteinases Enzymes

ECM Substrates

Non-ECM Substrates

Collagens I, II, III, VII, X; gelatins; aggrecan; link protein; entactin; tenascin; perlecan Collagens I, II and III; gelatins; aggrecan; link protein Collagens I, II, III, IV, IX, X, XIV; aggrecan; Fn; tenascin

α2-Macroglobulin; α1-PI; α1-antichymotrypsin;   IGF-BP-2, -3, -5; pro-IL-1β; CTGF α1-PI CTGF; pro-TGF-β; α1-antichymotrypsin

Gelatins; collagens IV, V, VII, XI; Ln; Fn; elastin; aggrecan; link protein Gelatins; collagens III, IV, V; aggrecan; elastin; entactin;   link protein

Pro-TGF-β; FGF receptor I; MCP-3; IGF-BP-5;   pro-IL-1β; galectin-3; plasminogen Pro-TGF-β; IL-2 receptor α; Kit-L; IGF-BP-3;   pro-IL-1β; α1-PI; galectin-3

Stromelysin-1 (MMP-3)   

Aggrecan; decorin; gelatins; Fn; Ln; collagens III, IV, IX, X; tenascin; link protein; perlecan 

Stromelysin-2 (MMP-10)

Aggrecan; Fn; Ln; collagens III, IV, V; link protein

IGF-BP-3; pro-IL-1β; HB-EGF; CTGF; E-cadherin; α1-­antichymotrypsin; α1-PI; α2-macroglobulin; plasminogen; uPA Unknown

Aggrecan; gelatins; Fn; Ln; elastin; entactin; collagen IV; tenascin; link protein Gelatin; collagen IV; Fn; fibrinogen

Pro-α-defensin; Fas-L; β4 integrin; E-cadherin;   pro-TNF-α; CTGF; HB-EGF α1-PI

Fn; Ln; aggrecan; gelatins Unknown

α1-PI; α2-macroglobulin; IGF-BP-1 Unknown

Elastin; Fn; collagen V; osteonectin Collagen IV; gelatin; Fn; tenascin; aggrecan; COMP; Ln; nidogen Amelogenin; aggrecan; gelatin; COMP Unknown Unknown

Plasminogen; apolipoprotein A Unknown 

Collagens I, II, III; gelatins; aggrecan; Fn; Ln; fibrin; Ln-5 Fn; tenascin; nidogen; aggrecan; perlecan; Ln Collagen III; Fn; gelatin PG

CD44; tissue transglutaminase Tissue transglutaminase Tissue transglutaminase Unknown

Gelatin; fibrinogen Gelatin; collagen IV; fibrin; Fn; Ln

Unknown Unknown

Gelatin

Unknown

Secreted-type MMPs Collagenases Interstitial collagenase (MMP-1) Neutrophil collagenase (MMP-8) Collagenase-3 (MMP-13) Gelatinases Gelatinase A (MMP-2)  Gelatinase B (MMP-9) Stromelysins

Matrilysins Matrilysin-1 (MMP-7)  Matrilysin-2 (MMP-26) Furin-activated MMPs Stromelysin-3 (MMP-11) Epilysin (MMP-28) Other Secreted-type MMPs Metalloelastase (MMP-12) RASI-1 (MMP-19)  Enamelysin (MMP-20) MMP-21 MMP-27

Unknown Unknown Unknown

Membrane-anchored MMPs Type I Transmembrane-type MMPs MT1-MMP (MMP-14) MT2-MMP (MMP-15) MT3-MMP (MMP-16) MT5-MMP (MMP-24) GPI-linked MMPs MT4-MMP (MMP-17) MT6-MMP (MMP-25) Type II Transmembrane-type MMP MMP-23

COMP, cartilage oligomeric matrix protein; CTGF, connective tissue growth factor; ECM, extracellular matrix; Fn, fibronectin; GPI, glycosylphosphatidylinositol; HB-EGF, heparin-binding epidermal growth factor; IGF-BP, insulin-like growth factor binding protein; IL-1, interleukin-1; Ln, laminin; MCP, monocyte ­chemoattractant protein; PG, proteoglycan; PI, proteinase inhibitor; TGF, transforming growth factor; TNF, tumor necrosis factor; uPA, urokinase-type plasminogen activator.

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Matrix Metalloproteinases The human MMP family comprises 23 different members, which have MMP designations (numbered according to a sequential numbering system) and common names coined by the authors of the published reports (see Tables 7-1 and 7-2). Based on the biochemical properties provided by the domain structures and on their substrate specificity, these family members are classified into two major subgroups: secreted-type MMPs and membrane-anchored MMPs. MMP-4, MMP-5, and MMP-6 are excluded from the list because they are identical to other known MMPs (i.e., MMP-3 and MMP-2). MMP-18 and MMP-22 also are missing in Tables 7-1 and 7-2 because they are assigned to Xenopus collagenase-4 and chicken MMP. Most secreted-type MMPs, including collagenases, stro­ melysins, and other MMPs, are composed of three basic domains—the propeptide, catalytic, and hemopexin-like domains—that are preceded by hydrophobic signal peptides (Fig. 7-1). The N-terminal propeptide domain has one unpaired cysteine in the conserved sequence of PRCGXPD. The cysteine residue in the sequence interacts with the essential zinc atom in the catalytic domain to prevent it from binding the catalytic water molecule, maintaining the proenzyme in an inactive state. The catalytic domain has the zinc-binding motif HEXGHXXGXXH, in which three histidines bind to the catalytic zinc atom. The four-blade,

C-terminal hemopexin-like domain, which is connected to the catalytic domain by a proline-rich hinge region, interacts with ECM components and can play a role in determining the substrate specificity in some MMPs. Gelatinases have these domains with additional insertions of collagen-binding type II repeats of fibronectin in the catalytic domain (see Fig. 7-1); this provides them with collagenbinding properties. Matrilysins are the shortest, lacking the hemopexin-like domains. Furin-activated MMPs contain insertions of a basic motif with a cleavage site by proprotein convertases including furin at the end of the propeptide domains (see Fig. 7-1). Membrane-anchored MMPs include three different types of MMPs—type I transmembrane-type MMPs, GPI-linked MMPs, and type II transmembrane-type MMP. MT1-, MT2-, MT3-, and MT5-MMPs have type I transmembrane domains in the C-terminal region, but MT4- and 6-MMPs ­contain GPI anchors in the C-terminal region without transmembrane domains (see Fig. 7-1). MMP-23 is unique in that it has type II transmembrane domain, a cysteine array, and an immunoglobulin-like domain instead of a hemopexin-like domain (see Fig. 7-1). Secreted-type Matrix Metalloproteinases Collagenases (MMP-1, MMP-8, and MMP-13). The collagenases include MMP-1 (interstitial collagenase, collagenase-1), MMP-8 (neutrophil collagenase, collagenase-2),

Table 7-3  Members of the ADAMTS Gene Family Demonstration of Proteinase Activity*

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Functions and Biochemical Features

ADAMTS

Other Names

ADAMTS1

C3-C5; METH1; KIAA1346

+

Digestion of aggrecan and   versican; binding to heparin

Kidney; heart; cartilage

Tissue and Cell Expression

ADAMTS2

Procollagen N-proteinase; hPCPNI; PCINP

+

Processing of collagen I and II N-propeptides

Skin; tendon

ADAMTS3

KIAA0366

+

Processing of collagen   N-propeptides

Brain

ADAMTS4

KIAA0688; aggrecanase-1; ADMP-1

+

Digestion of aggrecan,   brevican, and versican

Brain; heart; cartilage

ADAMTS5

ADAMTS11; aggrecanase-2; ADMP-2

+

Digestion of aggrecan

Uterus; placenta; cartilage Placenta

ADAMTS6

—

−

—

ADAMTS7

—

−

—

Various tissues

ADAMTS8

METH-2

+

Digestion of aggrecan;   inhibition of angiogenesis

Lung; heart

ADAMTS9

KIAA1312

+

Digestion of aggrecan

Cartilage

ADAMTS10

—

−

—

—

ADAMTS12

—

−

—

Lung (fetus)

ADAMTS13

VWFCP; C9orf8

+

Cleavage of von Willebrand factor

Liver; prostate; brain

ADAMTS14

—

+

Processing of collagen   N-propeptides

Brain; uterus

ADAMTS15

—

+

Digestion of aggrecan

Liver (fetus); kidney (fetus)

ADAMTS16

—

−

—

Prostate; brain; uterus

ADAMTS17

FLJ32769; LOC123271

−

Prostate; brain; liver

—

ADAMTS18

ADAMTS21; HGNC:16662

−

Prostate; brain

—

ADAMTS19

—

−

—

Lung (fetus)

ADAMTS20

—

−

—

Brain; testis

*Proteinase activities are shown in 10 members of the ADAMTS family, but not in 9 other members.

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Secreted-type MMP N Collagenases C Stromelysins Zn Other MMPs

N F

Tm

Zn

C Type I

MT1, 2, 3, 5-MMPs

N C

Zn

Gelatinases

N

C

GPI

Zn

F N Zn

Matrilysins

C

MT4, 6-MMPs

N F

Tm Furin-activated C MMPs

Zn

F

Zn

N Type II

C

MMP-23 ADAMTS

Membrane-type ADAM N

N F

Zn

D

Ts

S

C

F

Zn

D

C E

Tm

C

Figure 7-1  Domain structures of two types of matrix metalloproteinases (MMPs) (secreted-type MMP and membrane-anchored MMP) and two types of a disintegrin and metalloproteinases (ADAMs) (a disintegrin and metalloproteinase with thrombospondin motifs [ADAMTS] and membrane-type ADAM). The typical domain structure of most secreted-type MMPs (collagenases, stromelysins, and other MMPs) is composed of a prodomain, catalytic domain, hinge, and hemopexin-like domain. Gelatinases (MMP-2 and MMP-9) have additional insertions of collagen-binding type II repeats of fibronectin in the catalytic domain, whereas matrilysins (MMP-7 and MMP-26) lack a hemopexin-like domain. Furin-activated MMPs (MMP-11 and MMP-28) contain an RKRR sequence (furin recognition site = F) at the end of the propeptide. Membrane-anchored MMPs are composed of type I transmembranetype MMPs (MT1-, MT2-, MT3-, MT5-MMPs), GPI-linked MMPs (MT4, MT6-MMPs), and type II transmembrane-type MMP (MMP-23). All of them have furin recognition sites. ADAMTS has a prodomain, a furin recognition site (F), a catalytic domain, a hinge, a disintegrin domain (D), thrombospondin motifs (Ts), and a spacer domain (S). Membrane-type ADAM is composed of a prodomain, furin recognition site (F), catalytic domain, hinge, disintegrin domain (D), cysteine-rich domain (C), EGF-like domain (E), and transmembrane domain (Tm).

and MMP-13 (collagenase-3). These MMPs attack triple helical regions of interstitial collagen types I, II, and III at a specific single site following a glycine residue Gly (Ile or Leu)-(Ala or Leu), located about three fourths of the distance from the N terminus. This cleavage generates fragments approximately three fourths and one fourth of the size of the collagen molecules. A biochemical study has ­disclosed the molecular mechanism of the cleavage: MMP1 unwinds the triple helical structure by interacting with the α2(I) chain of type I collagen and cleaves the three α chains in succession.9 MMP-13 is unique in that it cleaves α chains of type II collagen at two sites of the Gly906-Leu907 and Gly909-Gln910 bonds.10 All of these collagenases degrade the interstitial collagens, but their specific activities against the collagens are different; MMP-1, MMP-8, and MMP-13 preferentially digest collagen types III, I, and II.10,11 ­Although rodents such as mice were originally thought to have only two collagenases (MMP-8 and MMP-13) and to lack the MMP-1 gene, rodent homologues of the human MMP-1 gene were cloned and named mouse collagenase A and B (Mcol-A and Mcol-B).12

In addition to the interstitial fibrillar collagens, MMP-1, MMP-8, and MMP-13 degrade many other ECM macromolecules. MMP-1 digests entactin, collagen X, gelatins, perlecan, aggrecan, and cartilage link protein (see Table 7-2). MMP-8 digests aggrecan, gelatins, and cartilage link protein (see Table 7-2). MMP-13 hydrolyzes aggrecan; types IV, IX, X, and XIV collagens; fibronectin; and tenascin.1 Non-ECM substrates of MMP-1, MMP-8, and MMP-13 include α2-macroglobulin, α1-antiproteinase inhibitor, α1-antichymotrypsin, and insulin-like growth factor binding protein (IGF-BP)-2 and IGFBP-3 (see Table 7-2). Gelatinases (MMP-2 and MMP-9). MMP-2 (gelatinase A) and MMP-9 (gelatinase B) belong to the gelatinase subgroup. Both MMPs readily digest gelatins and cleave ­collagen types IV and V.13,14 Elastin, aggrecan, and cartilage link protein also are substrates of the gelatinases. Although MMP-2 and MMP-9 share such substrates, they have different activities on several ECM macromolecules. MMP-2, but not MMP-9, digests fibronectin and laminin,13 and type III collagen and α2 chains of type I collagen are degraded only by MMP-9.14 The gelatinases also process directly TGF-β

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into an active ligand (see Table 7-2). MMP-2 and MMP9 cleave fibroblast growth factor receptor type I and interleukin (IL)-2 receptor type α (see Table 7-2). MMP-9 also releases soluble Kit-ligand.15 MMP-2 processes monocyte chemoattractant protein (MCP)-3 into an MCP-3 fragment deleting the N-terminal four amino acids, which can bind to CC-chemokine receptors and act as a general chemokine antagonist.16 Stromelysins (MMP-3 and MMP-10). The subgroup of stromelysins consists of MMP-3 (stromelysin-1) and MMP-10 (stromelysin-2). They share 78% identity in amino acid sequence and have similar enzymatic properties.17 The enzymes hydrolyze numerous ECM macromolecules, including aggrecan, fibronectin, laminin, and collagen IV (see Table 7-2).18 Collagen types III, IX, and X and telopeptides of collagen types I, II, and XI also are digested by MMP-3.19 In addition to the ECM components, MMP-3 is active on IGF-BP-3, IL-1β, heparin-binding epidermal growth factor (HB-EGF), connective tissue growth factor (CTGF), E-cadherin, α1-antichymotrypsin, and α1proteinase inhibitor (see Table 7-2). MMP-3 also activates many proMMPs.6 A similar activator function has been identified for MMP-10.20 Matrilysins (MMP-7 and MMP-26). Matrilysins include MMP-7 (matrilysin-1) and MMP-26 (matrilysin-2), which are the smallest of the MMPs, having only the propeptide and catalytic domains. The substrate specificity of MMP-7 is similar to that of stromelysins, digesting numerous ECM components, including aggrecan; gelatins; fibronectin; laminin; elastin; entactin; collagen types III, IV, V, IX, X, and XI; fibrin/fibrinogen; vitronectin; tenascin; and link protein (see Table 7-2). Although these substrates overlap with the substrates of other MMPs, the specific activity of MMP-7 to most substrates is the highest among the MMPs.21,22 NonECM molecules, such as α-defensin, Fas ligand, β4 integrin, E-cadherin, plasminogen, tumor necrosis factor (TNF)-α, and CTGF, also are the substrates for MMP-7 (see Table 7-2). MMP-26 degrades gelatin, type IV collagen, fibronectin, fibrinogen, and α1-proteinase inhibitor,23-25 but information about other substrates is still limited. Furin-activated Matrix Metalloproteinases (MMP-11 and MMP-28). MMP-11 (stromelysin-3) and MMP-28 (epilysin) contain an RKRR sequence at the end of the propeptide, which is a unique motif for intracellular processing of proproteins to mature molecules by furin and other proprotein convertases. ProMMP-11 is activated intracellularly by the action of furin.26 MMP-11 shows only weak ­proteolytic activity against gelatin, laminin, fibronectin, and aggrecan,27 but it has respectable catalytic action in digesting α1proteinase inhibitor, α2-macroglobulin, and IGF-BP-1 (see Table 7-2).28,29 MMP-28 can degrade casein, but its natural substrates are unknown.30 Other Secreted-type Matrix Metalloproteinases (MMP12, MMP-19, MMP-20, MMP-21, and MMP-27). MMP12 (metalloelastase),31 MMP-19 (RASI-1),32 MMP-20 (enamelysin),33 MMP-21,25 and MMP-27 have structural characteristics similar to collagenases and stromelysins. These MMPs are not classified into the above-mentioned subgroups, however, because their substrates and other biochemical characters are not fully examined at present. Overall information on the substrate specificity of MMP12,31 MMP-19,34,35 and MMP-2033,35 suggests that they

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are stromelysin-like proteinases. MMP-1231 digests elastin, fibronectin, collagen V, osteonectin, and plasminogen (see Table 7-2). MMP-19, which was originally reported as MMP-18 but renamed as MMP-19, cleaves type IV collagen, laminin, fibronectin, gelatin, tenascin, entactin, fibrin/fibrinogen, aggrecan, and cartilage oligomeric matrix protein (COMP) (see Table 7-2).34,35 MMP-20 also digests amelogenin, aggrecan, and COMP.35 Substrates of MMP-21 and MMP-27 are unknown, however. Membrane-anchored Matrix Metalloproteinases. Type I transmembrane-type MMPs include MT1-MMP (MMP14),36 MT2-MMP (MMP-15),37 MT3-MMP (MMP-16),38 and MT5-MMP (MMP-24).39 All of these MT-MMPs can activate proMMP-2, but MT1-MMP may play a major role in the activation of proMMP-2 in various tissues (see later). Besides the activator function, however, MT1-MMP digests the triple helical portions of interstitial collagen types I, II, and III and other ECM components, including fibronectin, laminin, aggrecan, and gelatin (see Table 7-2).40 MT2MMP also digests fibronectin, tenascin, nidogen, aggrecan, perlecan, and laminin.41 MT3-MMP cleaves collagen type III, fibronectin, and gelatins.42 MT4-MMP (MMP-17)43 and MT6-MMP (MMP-25)44 are GPI-linked MMPs. MT4-MMP and MT6-MMP can digest gelatin and fibrin/fibrinogen (see Table 7-2).44-46 MMP-23 (cysteine array-MMP, MIFR) is a type II transmembane-type MMP47; almost identical genes are cloned, called MMP-23A and MMP-23B. MMP-23 digests gelatin,48 but no information about other substrates is available (see Table 7-2). A unique aspect of MMP-23 is that this MMP is expressed in only female and male reproductive organs, such as endometrium, ovary, testis, and prostate,48 but its functions are not well established. ADAM Family Members of the ADAM (a disintegrin and metalloproteinase) gene family, which also are called mammalian reprolysins, are classified into two groups based on the C-terminal structural differences of the molecules (see Fig. 7-1): membrane-type ADAM with transmembrane domain (ADAM) and secreted-type ADAM with thrombospondin motifs (ADAMTS). The active sites in the catalytic domains of most members of both groups contain a common sequence of HEXGHXXGXXHD with the “Met-turn,” which also is present in MMP members. ADAMTS subgroup includes 19 members. Although information about substrates and biologic functions is still limited, ADAMTS1, ADAMTS2, ADAMTS3, ADAMTS4, ADAMTS5, ADAMTS8, ADAMTS9, ADAMTS14, and ADAMTS15 all are ECM-degrading proteinases (see Table 7-3). ADAMTS1,49 ADAMTS4,50 ADAMTS5,51 ADAMTS8, ADAMTS9, and ADAMTS15 can preferentially cleave aggrecan at the five Glu-X bonds, including the Glu373-Ala374 bond (the aggrecanase site). Because of aggrecan-degrading activity, ADAMTS4 and ADAMTS5 are named aggrecanase-1 and aggrecanase-250,51; versican also is digested by these proteinases,52 and brevican is cleaved by ADAMTS4 (see Table 7-3).53 The C-terminus-truncated ADAMTS4 also degrades fibromodulin and decorin.54 ADAMTS2 and ADAMTS3 ­ process the N-terminal propeptides of type I and II collagens and are named procollagen

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N-proteinase. Activity of procollagen N-proteinase also is known with ADAMTS14. ADAMTS13 is a von Willebrand factor–cleaving proteinase, and its mutation causes thrombotic thrombocytopenic purpura. Proteinase activities of other ADAMTS species are still unknown. Two thirds of the membrane-type ADAM molecules are catalytically inactive nonproteolytic homologues (Table 7-4). Among the ADAMs, ADAM8, ADAM9, ADAM10, ADAM12, ADAM15, ADAM17, ADAM19, and ADAM28 are shown to have proteinase activity (see Table 7-4). Although ADAM10 and ADAM15 degrade type IV collagen, the main substrates of these ADAMs are various membrane proteins, which include precursors of cytokines and growth factors such as TNF-α, HB-EGF and neuregulin, IGF-BPs, receptors such as p75 TNF receptor, IL-1 receptor II, and other membrane proteins related to development such as Notch ligand and ephrin (see Table 7-4).55-60 According to these data, a major function of the ADAMs is shedding of the membrane proteins. ADAM17 cleaves a proform of TNF-α at the physiologic processing site into the soluble form of TNF-α and is called TNF-α-conversing enzyme. ADAM17 also is involved in release of L-selectin, TGF-α, and p75 TNF ­ receptor.55 ADAM9, ADAM12, and ADAM17 can shed HB-EGF from its precursor. ADAM12 and ADAM28 cleave IGF-BP-3 and IGF-BP-5.60,61 CD23 is shed by ADAM8, ADAM15, and ADAM28.62 Other functions of ADAMs include binding to integrins, cell-cell interaction, cell ­ migration, and signal transduction (see Table 7-4).63

ENDOGENOUS PROTEINASE INHIBITORS Endogenous proteinase inhibitors control the activities of proteinases in vivo. The inhibitors are derived from plasma or cells in the local tissues. Plasma contains ­several ­proteinase inhibitors, and about 10% of all the plasma proteins are proteinase inhibitors. Most are proteinase class specific, but α2-macroglobulin inhibits the activities of proteinases from all four groups. Major endogenous inhibitors of the ECM-degrading proteinases are listed in Table 7-5. α2-MACROGLOBULIN The α2-macroglobulin molecule is a large plasma glycoprotein of 725 kD, which consists of four identical subunits of 185 kD that are linked in pairs by disulfide bonds. The pairs assemble noncovalently. Almost all active proteinases, regardless of the proteinase classes, bind and attack the so-called bait region, located near the center of the subunit. After cleaving within the bait region, the proteinase is physically trapped within the molecule by inducing a conformational change of the inhibitor, resulting in a proteinase/α2-macroglobulin complex. Although the proteinase in the complex remains active against very small substrates, it is trapped by the arms of the α2-macroglobulin from degrading larger proteins. Besides the function as a proteinase inhibitor, α2-macroglobulin may act as a carrier protein because it also binds to numerous growth factors and cytokines, such as platelet-derived growth factor, basic fibroblast growth factor, TGF-β, insulin, and IL-1β. The α2-macroglobulin molecule is synthesized mainly in liver, but also locally by macrophages, fibroblasts, and ­adrenocortical cells. Concentration of the inhibitor in

plasma is 250 mg/dL. Because of its large molecular weight, it is not present in noninflammatory synovial fluid. During synovial inflammation, α2-macroglobulin penetrates into the joint cavity. Rheumatoid synovial fluid has about the same concentration of the inhibitor as plasma. INHIBITORS OF SERINE PROTEINASES The primary inhibitors of serine proteinases include the members of the serpin (serine proteinase inhibitor) gene family, Kunitz-type inhibitors, and others (see Table 7-5). The serpins are glycoproteins of 50 to 100 kD and share homology with human α1-proteinase inhibitor.64 The major serpins involved in the regulation of ECM-degrading serine proteinases are α1-proteinase inhibitor, α1-antichymotrypsin, α2-antiplasmin, plasminogen activator inhibitors (PAI1 and PAI-2), protein C inhibitor (PAI-3), C1-inhibitor, kallistatin, and proteinase nexin-1 (PN-1). The main proteinases inhibited by these molecules are listed in Table 7-5. Although PAI-1 and PAI-2 inhibit tPA and uPA, the inhibition by PAI-1 and PAI-2 is more effective to tPA and uPA, respectively. Kunitz-type inhibitors include aprotinin, trypstatin, and PN-2, which is identical to a β-amyloid protein precursor. Secretory leukocyte proteinase inhibitor, which inhibits neutrophil elastase and cathepsin G, is present in many secretory and inflammatory fluids and in cartilage. Elafin is a serine proteinase inhibitor with 38% identity with the second domain of secretory leukocyte proteinase inhibitor; it inhibits neutrophil elastase and proteinase 3. INHIBITORS OF CYSTEINE PROTEINASES The members of the cystatin superfamily and calpastatin belong to the family of inhibitors of ECM-degrading cysteine proteinases (see Table 7-5). Cystatins capable of inhibiting lysosomal cysteine proteinases consist of three groups. Subgroup 1 comprises stefins A and B. Each has a molecular mass of 11 kD, and the stefins reside within cells. Subgroup 2 comprises cystatin C and S, each with a molecular mass of 13 kD. They occur at relatively high concentrations in cerebrospinal fluid and saliva. Subgroup 3 comprises the kininogens. Kininogens that participate in blood ­ coagulation and inflammation also are inhibitors of cysteine proteinases. Calpains are not inhibited by cystatins, but are inhibited by calpastatin (120 kD), which is a cytosolic-specific inhibitor of calpain. TISSUE INHIBITORS OF METALLOPROTEINASES TIMPs are a gene family consisting of four different members with approximately 40% to 50% sequence identity (i.e., TIMP-1, TIMP-2, TIMP-3, and TIMP-4), which have molecular masses ranging from 21 to 28 kD in humans.65-69 Virtually all TIMPs inhibit the activities of MMPs by binding in a 1:1 molar ratio to form tight, noncovalent complexes65 except that TIMP-1 does not inhibit efficiently MT-MMPs.41,42,70 TIMPs contain 12 highly conserved cysteine residues that form six intrachain disulfide bonds, which are essential for maintaining the correct ternary structure of the molecule67,71 and stable inhibitor activity.65 The TIMP molecules have two structurally distinct subdomains: an

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Table 7-4  Members of the ADAM Gene Family Proteinase-type (P) or Non–Proteinase-type (NP)

Functions and Biochemical Features

Tissue and Cell Expression

ADAM

Other Names

ADAM1

PH-30α; Fertilin-α

NP

Sperm/egg binding/fusion; binding to integrin  α9β1

Sperm

ADAM2

PH-30β; Fertilin-β

NP

Sperm/egg binding/fusion; binding to integrin α4β1, α6β1, and α9β1

Sperm

ADAM3

Cyritestin; tMDC; CYRN

NP

Binding to integrin α4β1, α6β1, and α9β1

Sperm

ADAM4

tMDC V

NP

—

Testis

ADAM5

tMDC II

NP

—

Testis

ADAM6

tMDC IV

NP

—

Testis

ADAM7

EAP I; GP-83

NP

Binding to integrin α4β1, α4β7, and α9β1

Testis

ADAM8

MS2 (CD156)

P

Neutrophil infiltration; shedding of CD23

Macrophages;   neutrophils

ADAM9

MDC9; MCMP; ­Meltrin-γ

P

Shedding of HB-EGF; TNF-p75 receptor; cleavage of APP; digestion of fibronectin and gelatin; ­binding to integrin α2β1, α6β1, α6β4, α9β1, and αVβ5

Various tissues

ADAM10

MDAM; Kuzbanian

P

Release of TNF-α; digestion of collagen IV, gelatin, and myelin basic protein; cleavage of Delta,   APP, L1, and CD44; shedding of HB-EGF; presence of RRKR sequence

Kidney; brain; ­chondrocytes

ADAM11

MDC

ADAM12

Meltrin-α; MCMP; MLTN; MLTNA

ADAM13

xMDC13a;   xADAM13a

ADAM14

ADM-1

ADAM15

Metargidin; MDC15; AD56; CR II-7

ADAM16

xMDC16

ADAM17

TACE; cSVP

NP

Tumor suppressor gene (?)

Brain

Muscle formation; presence of RRKR sequence; ­binding to integrin α4β1 and α9β1; digestion   of IGF-BP-3 and –5; shedding of HB-EGF;   digestion of collagen IV, gelatin, and fibronectin

Osteoblasts; muscle cells; chondrocytes; placenta

NP

Movement of neural crest

Xenopus laevis

NP

—

Caenorhabditis elegans

Expression in arteriosclerosis; binding to integrin αvβ3, α5β1, and α9β1; digestion of collagen IV and gelatin; shedding of CD23

Smooth muscle cells; chondrocytes; endothelial cells; osteoclasts

P

P

NP P

X. laevis Macrophages; various   tissues; carcinoma tissue

ADAM18

tMDC III

—

Testis

ADAM19

Meltrin-β; FKSG34

P

Formation of neuron; digestion of neuregulin; ­binding to integrin α4β1 and α5β1

Testis

ADAM20

—

P

Formation of sperm

Testis

ADAM21

—

P

—

Testis

ADAM22

MDC2

NP

—

Brain

ADAM23

MDC3

NP

Binding to integrin αvβ3

Brain; heart

ADAM24

Testinase-1

NP

Sperm/egg binding/fusion

Testis

ADAM25

Testinase-2

NP

—

Testis

ADAM26

Testinase-3

NP

—

Testis

ADAM28

e-MDC II; MDC-Lm; MDC-Ls

Digestion of myelin basic protein and IGF-BP-3; shedding of CD23; binding to integrin α4β1,   α4β7, and α9β1

Testis; lung; lymphocytes; pancreas; uterus

ADAM29

svph 1

NP

—

Testis

ADAM30

svph 4

P

—

Testis

NP

—

Testis

Mutation in bronchial asthma patients; binding to integrin α4β1, α5β1, and α9β1

Lung (fibroblasts, smooth muscle cells)

—

Testis

ADAM32

AJ131563

ADAM33

—

ADAM34

Testinase-4

NP

— Shedding of TNF-α, TGF-β, TNF-p75 receptor,   RANKL, and HB-EGF; presence of RRKR   sequence; cleavage of APP, Notch, L-selectin,   and CD44; binding to integrin α5β1

P

P NP

APP, amyloid precursor protein; HB-EGF, heparin-binding epidermal growth factor; IGF-BP, insulin-like growth factor binding protein; RANKL, receptor activator of nuclear factor кB ligand; TGF, transforming growth factor; TNF, tumor necrosis factor.

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Table 7-5  Endogenous Inhibitors of Extracellular Matrix–Degrading Proteinases Inhibitor

Molecular Mass (kD)

Source

Target Enzyme

α2-Macroglobulin

725

Plasma (liver); macrophages; fibroblasts

Most proteinases from all classes

α1-Proteinase inhibitor

52

Plasma; macrophages

α1-Antichymotrypsin

58

Plasma

α2-Antiplasmin Proteinase nexin-1

67 45

Plasma Fibroblasts

PAI-1

45

PAI-2 Protein C inhibitor

47 57

Endothelial cells; fibroblasts; platelets; plasma Plasma; macrophages Plasma; urine

Neutrophil elastase, cathepsin G, proteinase 3 Cathepsin G; chymotrypsin; chymase; tissue kallikrein Plasmin Thrombin; uPA; tPA; plasmin; trypsin; trypsin-like serine proteinase tPA; uPA

C1-inhibitor Kallistatin

96 92

Plasma Plasma; liver; stomach; kidney; pancreas

7 6 100

Mast cells Mast cells Fibroblasts

Plasmin; kallikrein Tryptase EGF binding protein, NGF-γ, trypsin, chymotrypsin, factor XIa

SLPI

15

Elafin

7

Bronchial secretions; seminal plasma; cartilage Horny layers of skin

Neutrophil elastase; cathepsin G; chymotrypsin; trypsin Neutrophil elastase; proteinase 3

11 11 13 13 50-78/108-120 120

Cytosol Cytosol Body fluids Seminal plasma; tears; saliva Plasma Cytosol

Cysteine proteinases Cysteine proteinases Cysteine proteinases Cysteine proteinases Cysteine proteinases Calpains

28 22 21/24* 21 Unknown

Connective tissue cells; macrophages Connective tissue cells; macrophages Fibroblasts; synovial cells Heart; brain; testis Many tissue cells; fibroblasts

MMPs MMPs MMPs; ADAMs; ADAMTS MMPs MMP-2; MT1-MMP

Inhibitors of Serine Proteinase Serpins

uPA; tPA Active protein C; tPA; uPA; tissue kallikrein Plasma kallikrein; C1 esterase Tissue kallikrein

Kunins Aprotinin Trypstatin Proteinase nexin-2   (β-amyloid protein precursor) Others

Inhibitors of Cysteine Proteinase Stefin A Stefin B Cystatin C Cystatin S Kininogens Calpastatin Metalloproteinase Inhibitors TIMP-1 TIMP-2 TIMP-3 TIMP-4 RECK

*Glycosylated form. EGF, epidermal growth factor; NGF, nerve growth factor; PA, plasminogen activator; PAI, plasminogen activator inhibitor; RECK, reversion-inducing, cysteinerich protein with Kazal motifs; SLPI, secretory leukocyte proteinase inhibitor; TIMP, tissue inhibitor of metalloproteinases; tPA, tissue-type plasminogen activator; uPA, urokinase-type plasminogen activator.

N-terminal subdomain that consists of loops 1 through 3 and a C-terminal subdomain that consists of loops 4 through 6. The N-terminal subdomain of each TIMP molecule contains the inhibitory activity for MMPs.65 Studies on the crystal structures of the MMP/TIMP complexes show that the wedge-shaped TIMPs bind with their edge into the entire length of the active-site cleft of their cognate MMPs.67 High affinity and efficient inhibitor activity of TIMP-2 to MT1-MMP are explained by the interaction between a quite long hairpin loop of TIMP-2 and a loop over the rim of the active-site cleft of MT1-MMP.72 TIMP-1 and TIMP-2 are unique in that they make the complexes with proMMP-9 and proMMP-2 (i.e., the proMMP-9/TIMP-1 and proMMP-2/TIMP-2 complexes). Similar complex formation also is known between TIMP-4 and proMMP-2. Because the complexes are made through

the interaction between their C-termini,65 TIMPs in the complexes retain inhibitor activity against MMPs. The activation of proMMP-9 and proMMP-2 is suppressed in the complex forms; the complex formation may be a safety device for these gelatinases.14 The proMMP-2/TIMP-2 complex is useful for the efficient activation of proMMP-2 by MT1-MMP on the cell membranes because MT1-MMP captures proMMP-2 to the cell membranes through the trimolecular complex formation between the catalytic domain of MT1-MMP and the N-terminal domain of TIMP-2 (see later).73,74 Besides the inhibition and interactions of TIMPs to MMPs, TIMP-3, among the TIMPs, most efficiently inhibits the activities of ADAM10, ADAM12, ADAM17, ADAM28, and ADAM33,75 although ADAM8, ADAM9, and ADAM19 are not inhibited by TIMPs. Because TIMP-3

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also efficiently inhibits the aggrecan-degrading activity of ADAMTS4 and ADAMTS5, TIMP-3 may be a common tissue inhibitor of the ADAM members. The N-­terminal subdomain of TIMP-3 is critical to the inhibition of the activities of ADAM members and MMPs, but the inhibition mechanism seems to be different.76 TIMPs are multifunctional proteins with more diverse actions than MMP/ADAM inhibitors, including growth factor activity, antiangiogenic activity, and regulatory activity of apoptosis.69 Another new MMP inhibitor is RECK (reversion-inducing, cysteine-rich protein with Kazal motifs).77 RECK is a GPI-linked glycoprotein harboring three inhibitor-like domains and inhibits the activities of at least MMP-2, MMP-9, and MT1-MMP. Although this inhibitor seems to play a key role in the angiogenic processes in vivo, its biochemical mechanism as an MMP inhibitor and functions in pathologic conditions such as arthritides remain unknown.

REGULATION OF PROTEINASE ACTIVITY The activities of ECM-degrading proteinases in tissues are regulated by the balance between the proteinases and their inhibitors. The balance at the local tissues depends on several factors, including production rates of proteinases and inhibitors, their secretion, activation of proenzymes, and anchoring systems of the activated proteinases to cell surfaces. Production levels of the proteinases and inhibitors within the cells are controlled mainly by their gene expression. Activation processes of proMMPs and membrane anchoring of their activities have been established by extensive experimental work. GENE EXPRESSION OF PROTEINASES AND INHIBITORS Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases Normal cells except for inflammatory cells do not produce MMPs or TIMPs in the tissues under physiologic conditions, but their expression is stimulated by many factors under pathologic conditions. Neutrophils and macrophages synthesize MMP-8 and MMP-9 during the differentiation and store them within the granules of the differentiated cells. Tumor cells express many MMPs, such as MMP-1, MMP-7, MMP-9, MMP-10, and MT1-MMP, and TIMP-1 predominantly by oncogenic transformation. The gene expression of MMPs and TIMPs in the tissue cells other than inflammatory cells and tumor cells is regulated by numerous factors, however, including cytokines, growth factors, and chemical and physical stimuli. Much information is available for regulators of MMP1 and MMP-3, which are coordinately expressed in many cell types after stimulation with cytokines and growth factors, factors acting at the cell surface, and chemical agents (Table 7-6). The induced production of MMP-1 and MMP-3 is suppressed by retinoic acid, TGF-β, and glucocorticoid. The gene expression of MMP-7 and MMP-9 is regulated by similar factors, but the regulation is stricter, and fewer factors modulate the expression (see Table 7-6). MT1-MMP expression is upregulated by phorbormyristate acetate (12O-tetradecanoylphorbol-13-acetate), concanavalin A, basic

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fibroblast growth factor, and TNF-α, and it is downregulated by glucocorticoids in various cells. TNF-α and IL-1α stimulate osteoarthritic chondrocytes to express the MT1-MMP gene.78 In contrast to these MMPs, MMP-2 and TIMP-2 are unique in that factors capable of enhancing the production of MMP-1, MMP-3, and TIMP-1 are inactive. TIMP-1 expression is enhanced or suppressed in response to many factors, including cytokines, growth factors, and oncogenic transformation (see Table 7-6). Effects of these stimulatory factors are common to the gene expression of MMPs, but they are regulated independently. TGF-β, retinoic acid, progesterone, and estrogen enhance TIMP-1 expression in fibroblasts, but they suppress the expression of MMP-1 and MMP-3. Although information about stimulating and suppressive factors of TIMP-1, TIMP-2, and TIMP3 is available (see Table 7-6), factors controlling the gene expression of TIMP-4 are not well known. Previous studies have identified the elements in the promoters of MMPs and TIMPs,2 which are related to or responsible for the stimulation or suppression of the gene expression with various factors. Regulation of the gene expression is generally explained by the structural characteristics of the promoters.2 Serine Proteinases and Their Inhibitors Neutrophil elastase, cathepsin G, chymase, and tryptase are stored within the secretory granules and secreted into the extracellular milieu after activation of neutrophils and mast cells. The expression of these serine proteinases is controlled mainly by the cellular differentiation. Precursors of plasmin and plasma kallikrein are constitutively synthesized predominantly in liver, circulate in blood as zymogen forms (i.e., plasminogen and prekallikrein), and reach the inflamed tissues by being released from blood vessels. The proteinase activities in the tissues are controlled mainly through activation of the proenzymes by activators. The uPA and tPA molecules, activators of plasminogen, are synthesized by tissue cells, and their gene expression is regulated by many factors (Table 7-7). The uPA synthesis is upregulated in many normal cell types and in transformed cells by agents that increase intracellular cyclic adenosine monophosphate (cAMP) levels (e.g., calcitonin, vasopressin, cholera toxin, cAMP analogues), growth factors (e.g., EGF, plateletderived growth factor, vascular endothelial growth factor); cytokines (IL-1, TNF-α), and phorbol esters, whereas glucocorticoid decreases the expression.8 The expression of tPA is regulated by similar factors (see Table 7-7). In endothelial cells, proteinases are enhancers; thrombin and plasmin stimulate the production of tPA.8 PAI-1 and PAI-2 also are regulated by common factors, many of which also enhance the production of uPA and tPA (see Table 7-7). Most serpins are constitutively produced in liver and secreted to plasma. Lysosomal Cysteine and Aspartic Proteinases The expression of lysosomal cysteine proteinases, cathepsins B, L, and K, is generally constitutive, but cellular transformation is often associated with increased synthesis of cathepsins B and L. Cathepsin B transcription varies with cell type and the state of differentiation of tumor cells; it is increased in chondrocytes by IL-1. Malignant transformation, tumor promoters, and growth factors stimulate the

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Table 7-6  Factors That Modulate Synthesis of Matrix Metalloproteinases and Tissue Inhibitors   of Metalloproteinases Enzyme or TIMP

Stimulating Factor*

Suppressive Factor

MMP-1

Cytokines and growth factors: IL-1; TNF-α; EGF; PDGF; bFGF; VEGF; NGF; TGF-α; IFN-α; IFN-β; IFN-γ; leukoregulin; relaxin

Retinoic acids; glucocorticoids; estrogen; progesterone;   TGF-β; transmembrane neural cell adhesion molecule; cAMP; INF-γ; adenovirus E1A

Factors acting at cell surface: calcium ionophore A23187; cell fusion; collagen; concanavalin A; integrin receptor antibody; crystals of urate, hydroxyapatite, and calcium pyrophosphate; SPARC (osteonectin/BM 40);   iron; extracellular matrix metalloproteinase inducer (EMMPRIN/CD147/basigin/M6 antigen); phagocytosis Chemical agents: cAMP; colchicine; cytochalasins B and D; LPS; pentoxifylline; TPA; calmodulin inhibitors; serotonin; 1,25-(OH)2 vitamin D3; platelet-activating factor; serum amyloid A; β-microglobulin Physical factors: heat shock; ultraviolet irradiation Others: viral transformation; oncogenes; autocrine agents; aging of fibroblasts MMP-2

TGF-β; concanavalin A; H-ras transformation; extracellular matrix metalloproteinase inducer (EMMPRIN/CD147/  basigin/M6 antigen)

Adenovirus E1A

MMP-3

IL-1; TNF-α; EGF; concanavalin A; SPARC (osteonectin/BM   40); LPS; TPA; extracellular matrix metalloproteinase ­inducer (EMMPRIN/CD147/basigin/M6 antigen); viral ­transformation; oncogenes; integrin receptor antibody; heat shock; calcium ionophore A23187; cytochalasin B

Retinoic acids; glucocorticoids; estrogen; progesterone;  TGF-β; adenovirus E1A

MMP-7

IL-1; TNF-α; EGF; TPA; LPS

Unknown

MMP-8

TNF-α; TPA; IL-1

Unknown

MMP-9

IL-1; TNF-α; EGF; TGF-β; TPA; H-ras; v-Src; SPARC   (osteonectin/BM40)

Retinoic acids; adenovirus E1A

MMP-10

TPA; A23187; TGF-β; EGF

Unknown

MMP-11

Retinoic acids

bFGF

MMP-13

bFGF; TNF-α; TGF-β

Unknown

MT1-MMP

Concanavalin A; TPA; bFGF; TNF-α; IL-1α

Glucocorticoids

TIMP-1

IL-1; IL-6; IL-11; TPA; TGF-β; TNF-α; retinoic acids; LPS; ­progesterone; estrogen; oncogenic transformation;   viral infection

Extracellular matrix; cytochalasins

TIMP-2

Progesterone

TGF-β; LPS

TIMP-3

EGF; TGF-β; TPA; TNF-α; glucocorticoids; oncostatin M

Unknown

*Factors regulating gene expression of other MMPs excluded from this table and TIMP-4 are unknown. bFGF, basic fibroblast growth factor; cAMP, cyclic adenosine monophosphate; EGF, epidermal growth factor; IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; NGF, nerve growth factor; PDGF, platelet-derived growth factor; TGF, transforming growth factor; TNF, tumor necrosis factor; TPA, 12-O-tetradecanoylphorbol-13-acetate; VEGF, vascular endothelial growth factor.

synthesis of cathepsin L. Cathepsin K gene expression in monocyte-macrophage lineage depends on the cellular differentiation to osteoclasts, but all-trans retinoic acid upregulates the expression in rabbit osteoclasts. Lysosomal aspartic proteinase, cathepsin D, is constitutively expressed in almost all cells, although estradiol, calcitriol, and retinoic acid can regulate the expression. ACTIVATION MECHANISMS OF THE ZYMOGENS OF METALLOPROTEINASES All of the MMPs are synthesized as inactive zymogens (pro­ MMPs), and activation of proMMPs is prerequisite to their functioning in vivo. ProMMPs are kept inactive by an interaction between a cysteine-sulfhydryl group in the conserved propeptide sequence PRCGXPD and the zinc ion bound to the catalytic domain, preventing the formation of a waterzinc complex that is essential to the enzymatic reaction.

Activation requires proteolytic removal of the propeptide domain. There are three pathways of the proMMP activation—extracellular, intracellular, and pericellular (Fig. 7-2). Extracellular Activation Extracellular activation, which is applicable to many secreted MMPs (e.g., proMMP-1, proMMP-3, proMMP7, proMMP-8, proMMP-9, proMMP-10, proMMP-12, and proMMP-13), is initiated through the disruption of the CysZn2+ interaction by treatment with nonproteolytic agents or proteinases and completed by autocatalytic processing.6,69 Nonproteolytic activators used in vitro include thiol-modifying reagents (e.g., mercurial compounds, iodoacetamide, N-ethylmaleimide, oxidized glutathione), hypochlorous acid, sodium dodecyl sulfate, chaotropic agents, and physical factors (heat and acid exposure).6 Most of these factors, especially 4-aminophenylmercuric acetate (APMA), enable

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proMMP molecules to generate a short-lived intermediate, which is formed by removal of a part of propeptide by an intramolecular reaction.6 The fully activated form is made by an intermolecular autocatalysis cleaving three amino acids downstream from the conserved sequence PRCGXPD Table 7-7  Factors That Regulate Expression   of Plasminogen Activators and Their Inhibitors Enzyme or Inhibitor

Stimulatory Factor

Suppressive Factor

uPA

TPA; IL-1; INF-γ; EGF;   PDGF; bFGF; VEGF;   TGF-β; cholera toxin; cAMP; estrogen;   calcitonin; vasopressin; disruption of E-cadherin–dependent cell-cell adhesion

Glucocorticoids; TGF-β

tPA

TPA; EGF; bFGF; VEGF; retinoic acids; glucocorticoids; cAMP; thrombin; plasmin; follicle-stimulating hormone; luteinizing hormone; gonadotropin-releasing hormone

TNF-α

PAI-1

IL-1; TNF-α; TGF-β; bFGF; VEGF; TPA; glucocorticoids

cAMP

PAI-2

TPA; LPS; TNF-α; colonystimulating factor; cholera toxin; dengue virus

Glucocorticoids

PN-1

TPA; EGF; thrombin

Unknown

bFGF, fibroblast growth factor; cAMP, cyclic adenosine monophosphate; EGF, epidermal growth factor; IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; PAI, plasminogen activator inhibitor; PDGF, platelet-derived growth factor; PN, proteinase nexin; TGF, transforming growth factor; TNF, tumor necrosis factor; TPA, 12-O-tetradecanoylphorbol-13-acetate; tPA, tissue-type plasminogen activator; uPA, urokinase-type plasminogen activator; VEGF, vascular endothelial growth factor.

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and leading to generation of active MMPs starting with Tyr or Phe at the N terminus. Such a process may not be essential, however, for proMMP-9 activation by APMA because a fully active form retaining the PRCGVPD sequence is generated by the cleavage of the Ala74-Met75 bond upstream of the conserved sequence.14 Concerning proMMP-9 activation during cerebral ischemia in vivo, nitric oxide is reported to activate proMMP-9 by S-nitrosylation.79 A similar stepwise activation is proposed for the proteolytic activation of proMMPs. Proteinases initially attack the proteinase-susceptible bait regions in the propeptides and generate proteolytically active intermediates through destabilization of the Cys-Zn2+ interaction.6 In the second step, the final activation site is autolytically catalyzed by the active intermediate instead of the trigger proteinases, and active MMPs without propeptides are made. In many cases, the bait region sequences in the propeptide dictate which proteinases can become an activator of a particular MMP.6 Potential activators of proMMPs are listed in Table 7-8. Plasmin may play a major role in the activation of proMMP-3 and proMMP-10 in vivo because treatment of these proMMPs with plasmin leads to full activation in vitro.80 ProMMP-1 activation by plasmin alone results in only about 25% of the potential MMP-1 activity, however, and full activation requires the subsequent cleavage of the Gln80-Phe81 bond by active MMP-3, MMP-7, or MMP-10.6,22 MMP-3 and MMP-10 can directly activate proMMP-7,22 proMMP-8, proMMP-9,14,20 and proMMP1311 into fully active forms. This intermolecular activation cascade of MMPs may be important to in vivo activation of proMMPs. Intracellular Activation Because proMT-MMPs proMMP-23, proMMP-11, and proMMP-28 have basic motifs containing an RXKR sequence at the end of the propeptide domains, proprotein convertases, such as furin, a processing enzyme in the transGolgi apparatus, are considered to activate these ­proMMPs

Active MMP-2

Active MMP-3

Zn

Zn

Extracellular activation Active MMP-11

Zn Ct

Zn

Zn Zn

Pericellular activation

Active MT1-MMP Zn Ct

TIMP-2 Zn

ProMMP-3

Zn

Zn

F

Zn

Intracellular activation

F Zn

ProMMP-2 ProMT1-MMP

ProMMP-11

Figure 7-2  Activation mechanisms of proMMPs. Most secreted-type proMMPs, such as proMMP-3, are activated extracellularly by many proteinases (extracellular activation). Furin-activated secreted proMMPs, including proMMP-11, and proMTMMPs, such as proMT1-MMP, are intracellularly activated through removal of the propeptides (arrowheads) by the action of proprotein convertases such as furin (intracellular activation). ProMMP-2 is activated on the cell membrane by MT1-MMP; this activation requires the trimolecular complex of MT1-MMP/TIMP2/proMMP-2 and dimerization of MT1-MMP (pericellular activation). Ct, C-terminal domain of TIMP-2; F, furin recognition site.

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Table 7-8  Activators of Pro-Matrix Metalloproteinases ProMMP

Activator

ProMMP-1

Trypsin (partial); plasmin (partial); plasma kallikrein (partial); chymase (partial); MMP-3; MMP-7; MMP-10; MMP-11

ProMMP-2

MT1-MMP; MT2-MMP; MT3-MMP; MT5MMP

ProMMP-3

Plasmin; plasma kallikrein; trypsin;   tryptase; chymase; cathepsin G;   chymotrypsin; neutrophil elastase; thermolysin

ProMMP-7

MMP-3; MMP-10 (partial); trypsin; plasmin (partial); neutrophil elastase (partial)

ProMMP-8

MMP-3; MMP-10; tissue kallikrein; neutrophil elastase; cathepsin G; trypsin

ProMMP-9

MMP-3; MMP-2; MMP-7; MMP-10 (partial); MMP-13; trypsin; chymotrypsin; cathepsin G; tissue kallikrein

ProMMP-10

Plasmin; trypsin; chymotrypsin

ProMMP-11

Furin

ProMMP-13

MMP-2; MMP-3; MT1-MMP; plasmin

ProMT1-MMP

Furin

intracellularly (see Fig. 7-2). Intracellular activation of proMMP-11 and proMT1-MMP by furin is shown.26,81 After the activation, MMP-11 is secreted from the cells, and MT1MMP is expressed on the cell membranes. Because other proMT-MMPs, proMMP-23 and proMMP-28 also have the motif, furin is presumably responsible for the intracellular activation of these proMMPs. Pericellular Activation ProMMP-2 is unique in that it is activated pericellularly by MT1-MMP, MT2-MMP, MT3-MMP, MT5-MMP, and MT6-MMP, but not by ordinary MMP-activatable endopeptidases.13 MT4-MMP does not activate proMMP-2. This pericellular activation has been extensively studied with MT1-MMP and found to occur in a two-step manner. MT1-MMP cleaves the Asn37-Leu38 bond in the propeptide of proMMP-2, generating an intermediate form that is converted to a fully activated enzyme by an intermolecular autocatalytic mechanism.70 TIMP-2 is essential to the efficient pericellular activation of proMMP-2 by MT1-MMP. The N-terminal inhibitor and C-terminal tail domains of TIMP-2 bind to the catalytic domain of MT1-MMP and the C-terminal hemopexin-like domain of proMMP-2, forming a trimolecular complex of MT1-MMP/TIMP-2/ proMMP-2 on the cell membranes (see Fig. 7-2). Capturing proMMP-2 by the trimolecular complex formation on the cell membranes facilitates proMMP-2 activation by increasing a local concentration of proMMP-2 and presenting it to the near, noninhibited MT1-MMP.73 Dimerization of MT1-MMP through an interaction of the C-terminal hemopexin-like domain is required for the efficient activation of proMMP-2 by MT1-MMP.82 MT1-MMP initiates proMMP-2 ­activation by attacking a part of the proMMP-2 propeptide, and another already activated MMP-2 finally activates proMMP-2 by removing a residual portion of the propeptide. Integrins such as αvβ3 may be involved in

the process as an additional receptor for transferring activated MMP-2 to the integrin.83 MT2-MMP, MT3-MMP, or MT5-MMP can activate proMMP-2 in the transfected cells,37-39,84 but the activation mechanisms for these MTMMPs are not well understood. MT1-MMP also activates proMMP-13 on the cell surface,85 and this activation does not seem to require TIMP-2.86 Pericellular activation of proMMP-7 has been discovered through screening proMMP-7-binding molecules by a yeast two-hybrid system.87 ProMMP-7 is captured on the cell membrane by the interaction of the proMMP-7 propeptide with the C-terminal extracellular loop of CD151, a member of the transmembrane 4 superfamily, and is pericellularly activated.87 This new pericellular activation of proMMP-7 requires a substrate of MMP-7. Integrins such as α3β1 and α6β4, α chains of which interact with CD151, also may be involved in the activation. Although the precise molecular mechanisms of this pericellular activation system, including the activator itself, are still unclear, proMMP-7 and CD151 are overexpressed in osteoarthritic chondrocytes, and proMMP-7 is activated by the interaction with CD151 in articular cartilage of osteoarthritis.88 PERICELLULAR DOCKING OF MATRIX METALLOPROTEINASES Discovery of membrane-anchored MMPs (i.e., MT1-, MT2-, MT3-, MT4-, MT5-, MT6-MMPs and MMP23) and subsequent studies of proMMP-2 activation by MT1-MMP have established pericellular actions of these MMPs including MMP-2. Secreted MMPs were originally thought to digest ECM macromolecules extracellularly after the activation, but more recent studies have indicated the possibility that they also may function on the cell membranes through their cell surface docking.74,89,90 Besides the proMMP-2/TIMP-2/MT1-MMP system, several secreted MMPs are reported to interact with cell membrane proteins, which include α2 chains of integrin α2β1 and CD147 (EMMPRIN) for MMP-1,91 αvβ3 integrin and caveolin-1 for MMP-2,83,92 CD44 heparan sulfate proteoglycan and cholesterol sulfate on the cell surface for MMP-7,93,94 and CD44 for MMP-9.95 Because all of these cell membrane proteins bind to active forms of the MMPs, their proteolytic activities can be used on the cell surfaces to digest ECM and non-ECM molecules located close to the cell membranes. The importance of pericellular docking of secreted MMPs in arthritic tissues should be shown by further work.

JOINT DESTRUCTION AND PROTEINASES DEGRADATION OF EXTRACELLULAR MATRIX IN ARTICULAR CARTILAGE In most joint diseases, such as rheumatoid arthritis and osteoarthritis, articular cartilage is the major target tissue for destruction, and excessive degradation of cartilage ECM by proteinases is a key process in the destruction. Histologically, depletion of proteoglycans from articular cartilage (degradation of proteoglycans) is a common initial change in these joint diseases, and subsequently collagen fibrils are degraded, leading to fibrillation and laceration secondary to

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destruction of the arcade structures of collagen fibrils in the articular cartilage (Fig. 7-3). Aggrecan, a major proteoglycan in cartilage, is susceptible to degradation by many proteinases, including MMPs, ADAMTS species, neutrophil elastase, cathepsin G, and cathepsin B. Because most of these proteinases mainly cleave the peptide bonds located in the interglobular G1G2 domain, the major glycosaminoglycan-bearing aggrecan fragments are detached from the hyaluronan attachment site (G1 domain) after the cleavage and released from the cartilgae matrix. The two major aggrecan fragments with the N-terminal sequences starting from Phe342 or Ala374 of the core protein are detected in joint fluids from patients with various inflammatory arthritides and osteoarthritis.96 Many MMPs, including MMP-1, MMP-2, MMP-3, MMP-7, MMP8, MMP-9, MMP-13, and MT1-MMP, preferentially cleave the Asn341-Phe342 bond (the MMP site).21 ADAMTS species, including ADAMTS1,49 ADAMTS4,50 ADAMTS5,51 ADAMTS8, ADAMTS9, and ADAMTS15, clip the Glu373Ala374 bond (the aggrecanase site) in addition to other sites in the G2-G3 domains. Members of the MMP and ADAMTS families may play central roles in the aggrecan degradation in arthritides. Based on the data that synthetic MMP inhibitors do not efficiently prevent aggrecan degradation in articular cartilage, ADAMTS species have been focused as aggrecan-degrading proteinases in arthritides. It is not settled, however, whether MMP and ADAMTS species play differential or complementary roles in the aggrecan degradation. Decorin, a leucine-rich repeat proteoglycan, also is digested by MMP-2, MMP-3, and MMP-797 and ADAMTS4.54 Information about proteinases responsible for the degradation of other proteoglycans, including fibromodulin, ­ lumican, bi­glycan, PRELP (arginine-rich end leucine repeat protein), chondroadherin, and syndecan present in articular cartilage is limited, although fibromodulin is cleaved by C-terminustruncated ADAMTS4.54 Fibrillar interstitial collagens (i.e., types I, II, and III collagens) are extremely resistant to most proteinases because of their triple-helical structures. In general, classic collagenases, including MMP-1, MMP-8, and MMP-13, are responsible for degradation of these collagens. Among them, MMP-13 may be most important for the degradation of cartilage collagen because it preferentially digests type II collagen.11 MT1-MMP degrades types I, II, and III collagens.40 Type III collagen also is susceptible to degradation by MMP-3,80 MMP-9,14 MT3-MMP,42 and neutrophil elastase. Cleavage of the telopeptides by the telopeptidase activity of MMP-3,19 MMP-9,14 neutrophil elastase, cathepsin G, and cysteine proteinase cathepsins is important for depolymerization of the cross-linked collagens.1 When the collagen molecules are cleaved, the helical structures are unwound at 37°C (i.e., body temperature) and become denatured into gelatins, which are digested into smaller peptides by gelatinases (MMP-2 and MMP-9)13,14 and other nonspecific tissue proteinases. Type V collagen is readily digested by MMP-213 and MMP-9.14 In contrast, type VI collagen is resistant to most MMPs, including MMP-1, MMP-2, MMP-3, MMP7, MMP-9, MMP-10, and MT1-MMP, but is susceptible to neutrophil elastase, cathepsin G, chymase, and tryptase.7 Type IX collagen is degraded by MMP-3.19 Type X collagen is susceptible to MMP-1 and MMP-2, and type XI collagen is degraded by MMP-2.

Cartilage destruction in rheumatoid arthritis Synovium Normal cartilage

(a) Proteinases in synovial fluid

(b) Proteolytic synovium and pannus

I

II

III

(c) Proteinases from chondrocytes

Pannus

IV Figure 7-3  Structure of normal articular cartilage and its destruction by proteinases in rheumatoid arthritis. Normal articular cartilage is divided into four zones (I, II, III, and IV). Collagen fibrils are aligned parallel to the articular surface in the superficial zone, and they blend with radial fibers and form plates or sheets sweeping vertically through the middle zone, showing arcade structures that originate from the calcified zone (IV). In rheumatoid arthritis, synovial tissue cells and inflammatory cells produce various proteinases, most of which are secreted into synovial fluid. These proteinases in synovial fluid attack the surface of the articular cartilage from the synovial fluid (a). At the periphery of the articular surface, proteolytic synovium degrades cartilage by direct contact, and pannus ­tissue covers and invades cartilage (b). Chondrocytes, which secrete proteinases by stimulation with various cytokines and growth factors, also are implicated in cartilage destruction (c).

Fibronectin is degraded by many MMPs, including MMP2, MMP-3, MMP-7, MMP-10, MMP-11, MMP-13, MMP19, MT1-MMP, MT2-MMP, MT3-MMP, and other serine proteinases. Link protein also is susceptible to many proteinases, such as MMP-1, MMP-2, MMP-3, MMP-7, MMP8, MMP-9, MMP-10, neutrophil elastase, and cathepsin G. COMP is digested by MMP-19 and MMP-20.35 Proteinases capable of digesting cartilage matrix protein and cartilage intermediate layer protein are unknown, however. CARTILAGE DESTRUCTION BY PROTEINASES IN RHEUMATOID ARTHRITIS Articular cartilage in rheumatoid arthritis is destroyed by proteinases in three pathways: (1) destruction from surfaces of articular cartilage by proteinases present in synovial fluid, (2) destruction through direct contact of proteolytic synovium or pannus tissue or both to articular cartilage, and (3) intrinsic destruction by proteinases derived from chondrocytes (see Fig. 7-3). Rheumatoid arthritis is characterized by chronic proliferative synovitis, which shows hyperplasia of the synovial lining cells, inflammatory cell infiltration, and angiogenesis in the sublining cell layer. Hyperplastic synovial lining cells overproduce MMP-1, MMP-3, MMP-9, MT1-MMP, and ADAMTS4 and TIMP-1 and TIMP-3.1,98-100 Sublining fibroblasts produce MMP-2 and TIMP-2.1 Polymorphonuclear leukocytes infiltrated in the synovium and joint cavity contain MMP-8 in the specific granules and MMP-9

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and neutrophil elastase, cathepsin G, and proteinase 3 in the azurophil granules. They are released from cells during phagocytosis of tissue debris and immune complexes. Other inflammatory cells in the synovium include macrophages, lymphocytes, and mast cells. Macrophages produce MMP1, MMP-9, TIMP-1, and TIMP-2. uPA and cathepsins B, L, and D also are secreted from activated macrophages. T lymphocytes in the synovium synthesize MMP-9. Chymase and tryptase are degranulated from mast cells in response to activation by immune complexes. Endothelial cells express many MMPs, including MMP-1, MMP-2, MMP-3, MMP-9, and MT1-MMP; tPA; and their inhibitors. These proteinases may be involved in tissue remodeling during angiogenesis in the synovium instead of cartilage destruction. All of these proteinases and inhibitors produced by synovial tissue cells and inflammatory cells seem to be secreted into the synovial fluid and attack the surfaces of articular cartilage when active proteinases overwhelm inhibitors. MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, TIMP-1, and TIMP-2 are detectable in rheumatoid synovial fluids, and the molar ratios of MMPs to TIMPs correlate with metalloproteinase activity, which is detectable in rheumatoid synovial fluids.101 MMPs are thought to be in favor of proteinase in rheumatoid synovial fluids. The cartilage in the central part of the articular surface shows surface irregularity (fibrillation) and proteoglycan depletion without being covered by pannus tissue even in the early stage of rheumatoid arthritis (Fig. 7-4). This cartilage degradation may be ascribed to the proteolytic damage by the action of the proteinases present in synovial fluid (see Fig. 7-3). Articular cartilage at the margins of the articular surface, to which synovial tissue can directly attach, is progressively degraded even in the early stage (see Fig. 7-4). Because rheumatoid synovial lining cells exhibit strong gelatinolytic activity, which is probably generated through activation of proMMP-2 by the action of MT1-MMP,98 direct contact of the proteolytically active synovial tissue to articular cartilage is a destruction pathway of the cartilage (see Fig. 7-3). Although rheumatoid synovium contains high concentrations of active proteinases, the synovium can avoid the attack by MMPs because type VI collagen, a major component in the lining cell layer,102 is resistant to the activities of MMP-1, MMP-2, MMP-3, and MT1-MMP.40,102 Pannus tissue is a connective tissue growing from the marginal transitional zone on the surface of the partially degraded articular cartilage. It is unknown whether pannus tissue formation is a sign of active destruction or repair of the articular cartilage, but the balance of data favors the former. Immunolocalization of MMP-1 and phagocytosis of collagen fibrils by pannus cells at sites of pannus-cartilage junction may suggest a role of the tissue in the cartilage destruction. In addition to the extrinsic pathway for the cartilage damage, cartilage may be destroyed by proteinases derived from chondrocytes (see Fig. 7-3). Chondrocytes under stimulation are capable of expressing various proteinases, including MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, MT1-MMP, MT3-MMP, ADAM9, ADAM10, ADAM17, ADAMTS4, and other classes of proteinases. In rheumatoid arthritic cartilage, MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, and MT1-MMP are expressed in the chondrocytes located in the proteoglycan-depleted zone. When large areas of the cartilage surface are ulcerated

after degradation of cartilage ECM, death of chondrocytes occurs, leading to further progressive cartilage destruction. MONITORING OF RHEUMATOID SYNOVITIS BY SERUM MMP-3 LEVELS The data that rheumatoid synovium produces and secretes many proteinases into the extracellular milieu suggest that measuring of the proteinases in joint fluid or serum samples is a useful method to monitor the activity of rheumatoid synovitis. Among the proteinases, measuring of serum MMP-3 levels has been established and used as a monitoring system for rheumatoid synovitis.103,104 Serum MMP-3 concentrations are known to increase in rheumatoid patients even at the early stage of the disease and become an indicator of joint destruction in patients with early rheumatoid arthritis.103 MMP-3 levels also reflect the effectiveness of antirheumatic therapy, such as anti–TNF-α antibody treatment105 and arthroplasty of major joints such as knee and hip joints.104 Although the concentrations increase in some patients with systemic lupus erythematosus, connective tissue diseases, or glomerulonephritis and secondary to corticosteroid therapy in patients with rheumatoid arthritis, determination of serum MMP-3 levels is a simple and noninvasive method for monitoring synovial inflammation and pathologic processes underlying joint destruction in rheumatoid arthritis.104 BONE RESORPTION IN RHEUMATOID ARTHRITIS Bone is resorbed by osteoclasts even in the early stage of rheumatoid arthritis. This is commonly observed at the bare zone, where pannus-like granulation tissue invades the bone marrow and destroys subchondral bone. Activated osteoclasts attach to only mineralized bone matrix, and this

Synovium Figure 7-4  Destruction of articular cartilage of the proximal interphalangeal joint obtained by autopsy from an early-stage rheumatoid  patient. Articular cartilage shows fibrillation and proteoglycan depletion at the central part of the articular surface (small arrows) and marked ­destruction at the marginal area, which contacts synovium (large arrows). Alcian blue staining for proteoglycans.

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cell-matrix contact is carried out between αvβ3 integrin of osteoclasts and Arg-Gly-Asp (RGD) sequence of osteopontin in the matrix. ECM degradation of the mineralized bone is possible only after demineralization of the bone matrix by proton secreted by osteoclasts because proteinases cannot permeate the matrix components in the mineralized tissues. Matrix degradation by osteoclasts is performed in the ­subosteoclastic compartments, which have acidic (pH 4 to 5) and hypercalcemic (40 to 50 mM Ca2+) conditions.106 The major component of the ECM proteins in mature bone is insoluble, highly cross-linked type I collagen, although type III and V collagens also are present. Other minor components in bone matrix are leucine-rich repeat proteoglycans (decorin and biglycan) and glycoproteins such as osteopontin, osteonectin (SPARC), osteocalcin (bone Gla-protein), and thrombospondin. Among collagenolytic cysteine proteinases, including cathepsins B, K, L, and S, cathepsin K is considered to be most important for bone resorption because of its collagenolytic activity with a broad pH optimum and selective expression in osteoclasts and giant cells of giant cell tumors.1 Mutations of human cathepsin K are responsible for pyknodysostosis, an autosomal recessive osteochondrodysplasia characterized by osteopetrosis and short stature.107 Cathepsin K–deficient mice have a similar phenotype. Despite the importance of cathepsin K in bone resorption, osteoclastic bone resorption cannot be completely inhibited by cysteine proteinase inhibitors; it is inhibited to a similar degree by MMP inhibitors.106 MMP-9 is highly expressed in osteoclasts in normal and rheumatoid bones108 and giant cells of giant cell tumors. MMP-9 has telopeptidase activity against soluble and insoluble type I collagen and strong gelatinolytic activity.14,108 ProMMP-9 is activated by acid exposure, and when activated, it is proteolytically active under acidic and hypercalcemic conditions.108 MMP-9-deficient mice show a transient disturbance of growth plate development. Cathepsin K and MMP-9 may be involved in bone resorption in rheumatoid arthritis. Although MT1-MMP is reportedly expressed in osteoclasts in rheumatoid arthritis,109 evidence of the direct involvement in osteoclastic bone resorption is limited. A more recent study shows that prostate cancer–induced osteolysis is carried out via the solubilization of receptor activator of nuclear factor кB ligand by the action of MMP-7 expressed by osteoclasts in rodents.110 No data are available, however, for the involvement of MMP-7 in the osteoclastic bone resorption in rheumatoid arthritis. CARTILAGE DESTRUCTION BY PROTEINASES IN OSTEOARTHRITIS In osteoarthritis, no prominent inflammatory changes occur in the synovium during early stages of the disease, but elevated production of enzymes by the chondrocytes themselves contributes to the breakdown of cartilage. Many MMPs, including MMP-1,111 MMP-2,78,112 MMP-3,113 MMP-7,114 MMP-8,111 MMP-9,112 MMP-13,10,111 and MT1-MMP,78 are expressed in osteoarthritic cartilage. MMP-3, MMP-7, and MT1-MMP are immunolocalized to chondrocytes in the proteoglycan-depleted zone of osteoarthritic cartilage, and the levels of their staining correlate directly with the histologic Mankin score.78,113,114 Among the classic collagenolytic MMPs (i.e., MMP-1, MMP-8, and

131

MMP-13), MMP-13 may be most important for degradation of the cartilage collagen because of preferential digestion of type II collagen over type I and III collagens.10,11 Because MT1-MMP efficiently activates proMMP-2 within the osteoarthritic cartilage,78 and it can activate proMMP-13,86 MT1-MMP may play a key role in cartilage degradation through activation of proMMP-2 and proMMP-13 and its own proteolytic activity against cartilage ECM. Considering intermolecular activation cascade for proMMPs by active MMPs, another key MMP in osteoarthritic cartilage tissue is MMP-3, which can activate proMMP-1, proMMP-7, proMMP-8, proMMP-9, and proMMP-13. MMP-3 not only digests many cartilage ECM components such as aggrecan, type IX collagen, and link protein, but also activates those proMMPs. ProMMP-7 is activated pericellularly after being anchored via the complex formation with CD151 in osteoarthritic chondrocytes.88 Because CD151 immunoreactivity directly correlates with the Mankin score and the degree of chondrocyte cloning, and MMP-7 not only digests cartilage ECM, but also sheds precursors of growth factors such as HB-EGF, MMP-7 may be involved in cartilage destruction or chondrocyte cloning or both.88 Other proteinases implicated in cartilage destruction in osteoarthritis are members of the ADAMTS family. Chondrocytes are known to express ADAMTS1, ADAMTS4, and ADAMTS5. Based on the data that the cartilage destruction in experimental osteoarthritis is prevented in ADAMTS5 knockout mice, but not ADAMTS4 knockout mice, ADAMTS5 is considered to play a key role in the cartilage destruction in mice.115 Information about the expression of ADAMTS species and regulation of the activities in human osteoarthritic cartilage is still limited, however. Members of the membrane-type ADAM family (i.e., ADAM10, ADAM12, ADAM15, and ADAM17) are expressed in osteoarthritic cartilage, but the functions of these ADAMs in osteoarthritic cartilage are unknown. REFERENCES   1. Okada Y: Proteinases and matrix degradation. In Ruddy S, Harris ED Jr, Sledge CB (eds): Kelley’s Textbook of Rheumatology, 6th ed. Philadelphia, WB Saunders, 2001, pp 55-72.   2. Okada Y: Proteinases and matrix degradation. In Harris ED Jr, Budd RC, Firestein GS, et al (eds): Kelley’s Textbook of Rheumatology, 7th ed. Philadelphia, WB Saunders, 2005, pp 63-81.   3. Handley CJ, Mok MT, Ilic MZ, et al: Cathepsin D cleaves aggrecan at unique sites within the interglobular domain and chondroitin sulfate attachment regions that are also cleaved when cartilage is maintained at acid pH. Matrix Biol 20:543-553, 2001.   4. Bromme D, Okamoto K, Wang BB, et al: Human cathepsin O2, a matrix protein-degrading cysteine protease expressed in osteoclasts: Functional expression of human cathepsin O2 in Spodoptera frugiperda and characterization of the enzyme. J Biol Chem 271:21262132, 1996.   5. Sorimachi H, Suzuki K: The structure of calpain. J Biochem (Tokyo) 129:653-664, 2001.   6. Nagase H: Activation mechanisms of matrix metalloproteinases. Biol Chem 378:151-160, 1997.   7. Kielty CM, Lees M, Shuttleworth CA, et al: Catabolism of intact type VI collagen microfibrils: Susceptibility to degradation by serine proteinases. Biochem Biophys Res Commun 191:1230-1236, 1993.   8. Saksela O, Rifkin DB: Cell-associated plasminogen activation: Regulation and physiological functions. Annu Rev Cell Biol 4:93126, 1988.   9. Chung L, Dinakarpandian D, Yoshida N, et al: Collagenase unwinds triple-helical collagen prior to peptide bond hydrolysis. EMBO J 23:3020-3030, 2004.

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10. Mitchell PG, Magna HA, Reeves LM, et al: Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. J Clin Invest 97:761-768, 1996. 11. Knauper V, Lopez-Otin C, Smith B, et al: Biochemical characterization of human collagenase-3. J Biol Chem 271:1544-1550, 1996. 12. Balbin M, Fueyo A, Knauper V, et al: Identification and enzymatic characterization of two diverging murine counterparts of human interstitial collagenase (MMP-1) expressed at sites of embryo implantation. J Biol Chem 276:10253-10262, 2001. 13. Okada Y, Morodomi T, Enghild JJ, et al: Matrix metalloproteinase 2 from human rheumatoid synovial fibroblasts: Purification and activation of the precursor and enzymic properties. Eur J Biochem 194: 721-730, 1990. 14. Okada Y, Gonoji Y, Naka K, et al: Matrix metalloproteinase 9 (92kDa gelatinase/type IV collagenase) from HT 1080 human fibrosarcoma cells: Purification and activation of the precursor and enzymic properties. J Biol Chem 267:21712-21719, 1992. 15. Heissig B, Hattori K, Dias S, et al: Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 109:625-637, 2002. 16. McQuibban GA, Gong JH, Tam EM, et al: Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3. Science 289:1202-1206, 2000. 17. Nagase H, Ogata Y, Suzuki K, et al: Substrate specificities and activation mechanisms of matrix metalloproteinases. Biochem Soc Trans 19:715-718, 1991. 18. Okada Y, Nagase H, Harris ED Jr: A metalloproteinase from human rheumatoid synovial fibroblasts that digests connective tissue matrix components: Purification and characterization. J Biol Chem 261:14245-14255, 1986. 19. Wu J, Lark MW, Chun LE, et al: Sites of stromelysin cleavage in collagen types II, IX, X, and XI of cartilage. J Biol Chem 266: 5625-5628, 1991. 20. Nakamura H, Fujii Y, Ohuchi E, et al: Activation of the precursor of human stromelysin 2 and its interactions with other matrix metalloproteinases. Eur J Biochem 253:67-75, 1998. 21. Fosang AJ, Neame PJ, Last K, et al: The interglobular domain of cartilage aggrecan is cleaved by PUMP, gelatinases, and cathepsin B. J Biol Chem 267:19470-19474, 1992. 22. Imai K, Yokohama Y, Nakanishi I, et al: Matrix metalloproteinase 7 (matrilysin) from human rectal carcinoma cells: Activation of the precursor, interaction with other matrix metalloproteinases and enzymic properties. J Biol Chem 270:6691-6697, 1995. 23. Uria JA, Lopez-Otin C: Matrilysin-2, a new matrix metalloproteinase expressed in human tumors and showing the minimal domain organization required for secretion, latency, and activity. Cancer Res 60:4745-4751, 2000. 24. Park HI, Ni J, Gerkema FE, et al: Identification and characterization of human endometase (matrix metalloproteinase-26) from endometrial tumor. J Biol Chem 275:20540-20544, 2000. 25. Marchenko GN, Ratnikov BI, Rozanov DV, et al: Characterization of matrix metalloproteinase-26, a novel metalloproteinase widely expr­essed in cancer cells of epithelial origin. Biochem J 356:705-718, 2001. 26. Pei D, Weiss SJ: Furin-dependent intracellular activation of the human stromelysin-3 zymogen. Nature 375:244-247, 1995. 27. Noel A, Santavicca M, Stoll I, et al: Identification of structural determinants controlling human and mouse stromelysin-3 proteolytic activities. J Biol Chem 270:22866-22872, 1995. 28. Pei D, Majmudar G, Weiss SJ: Hydrolytic inactivation of a breast carcinoma cell-derived serpin by human stromelysin-3. J Biol Chem 269:25849-25855, 1994. 29. Manes S, Mira E, Barbacid MM, et al: Identification of insulin-like growth factor-binding protein-1 as a potential physiological substrate for human stromelysin-3. J Biol Chem 272:25706-25712, 1997. 30. Lohi J, Wilson CL, Roby JD, et al: Epilysin, a novel human matrix metalloproteinase (MMP-28) expressed in testis and keratinocytes and in response to injury. J Biol Chem 276:10134-10144, 2001. 31. Shapiro SD, Kobayashi DK, Ley TJ: Cloning and characterization of a unique elastolytic metalloproteinase produced by human alveolar macrophages. J Biol Chem 268:23824-23829, 1993. 32. Pendas AM, Knauper V, Puente XS, et al: Identification and characterization of a novel human matrix metalloproteinase with unique structural characteristics, chromosomal location, and tissue distribution. J Biol Chem 272:4281-4286, 1997.

33. Llano E, Pendas AM, Knauper V, et al: Identification and structural and functional characterization of human enamelysin (MMP-20). Biochemistry 36:15101-15108, 1997. 34. Stracke JO, Hutton M, Stewart M, et al: Biochemical characterization of the catalytic domain of human matrix metalloproteinase 19: Evidence for a role as a potent basement membrane degrading enzyme. J Biol Chem 275:14809-14816, 2000. 35. Stracke JO, Fosang AJ, Last K, et al: Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP). FEBS Lett 478:52-56, 2000. 36. Sato H, Takino T, Okada Y, et al: A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 370:61-65, 1994. 37. Will H, Hinzmann B: cDNA sequence and mRNA tissue distribution of a novel human matrix metalloproteinase with a potential transmembrane segment. Eur J Biochem 231:602-608, 1995. 38. Takino T, Sato H, Shinagawa A, et al: Identification of the second membrane-type matrix metalloproteinase (MT- MMP-2) gene from a human placenta cDNA library: MT-MMPs form a unique membranetype subclass in the MMP family. J Biol Chem 270:23013-23020, 1995. 39. Pei D: Identification and characterization of the fifth membrane-type matrix metalloproteinase MT5-MMP. J Biol Chem 274:8925-8932, 1999. 40. Ohuchi E, Imai K, Fujii Y, et al: Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. J Biol Chem 272:2446-2451, 1997. 41. d’Ortho MP, Will H, Atkinson S, et al: Membrane-type matrix metalloproteinases 1 and 2 exhibit broad-spectrum proteolytic capacities comparable to many matrix metalloproteinases. Eur J Biochem 250:751-757, 1997. 42. Shimada T, Nakamura H, Ohuchi E, et al: Characterization of a truncated recombinant form of human membrane type 3 matrix metalloproteinase. Eur J Biochem 262:907-914, 1999. 43. Itoh Y, Kajita M, Kinoh H, et al: Membrane type 4 matrix metalloproteinase (MT4-MMP, MMP-17) is a glycosylphosphatidylinositolanchored proteinase. J Biol Chem 274:34260-34266, 1999. 44. Pei D: Leukolysin/MMP25/MT6-MMP: A novel matrix metalloproteinase specifically expressed in the leukocyte lineage. Cell Res 9:291-303, 1999. 45. Wang Y, Johnson AR, Ye QZ, et al: Catalytic activities and substrate specificity of the human membrane type 4 matrix metalloproteinase catalytic domain. J Biol Chem 274:33043-33049, 1999. 46. English WR, Puente XS, Freije JM, et al: Membrane type 4 matrix metalloproteinase (MMP17) has tumor necrosis factor-alpha convertase activity but does not activate pro-MMP2. J Biol Chem 275:14046-14055, 2000. 47. Pei D, Kang T, Qi H: Cysteine array matrix metalloproteinase (CAMMP)/MMP-23 is a type II transmembrane matrix metalloproteinase regulated by a single cleavage for both secretion and activation. J Biol Chem 275:33988-33997, 2000. 48. Velasco G, Pendas AM, Fueyo A, et al: Cloning and characterization of human MMP-23, a new matrix metalloproteinase predominantly expressed in reproductive tissues and lacking conserved domains in other family members. J Biol Chem 274:4570-4576, 1999. 49. Rodriguez-Manzaneque JC, Westling J, Thai SN, et al: ADAMTS1 cleaves aggrecan at multiple sites and is differentially inhibited by metalloproteinase inhibitors. Biochem Biophys Res Commun 293:501-508, 2002. 50. Tortorella MD, Burn TC, Pratta MA, et al: Purification and cloning of aggrecanase-1: A member of the ADAMTS family of proteins. Science 284:1664-1666, 1999. 51. Abbaszade I, Liu RQ, Yang F, et al: Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family. J Biol Chem 274:23443-23450, 1999. 52. Sandy JD, Westling J, Kenagy RD, et al: Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. J Biol Chem 276:13372-13378, 2001. 53. Nakamura H, Fujii Y, Inoki I, et al: Brevican is degraded by matrix metalloproteinases and aggrecanase-1 (ADAMTS4) at different sites. J Biol Chem 275:38885-38890, 2000. 54. Kashiwagi M, Enghild JJ, Gendron C, et al: Altered proteolytic activities of ADAMTS-4 expressed by C-terminal processing. J Biol Chem 279:10109-10119, 2004.

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55. Peschon JJ, Slack JL, Reddy P, et al: An essential role for ectodomain shedding in mammalian development. Science 282:1281-1284, 1998. 56. Sunnarborg SW, Hinkle CL, Stevenson M, et al: Tumor necrosis factor-alpha converting enzyme (TACE) regulates epidermal growth factor receptor ligand availability. J Biol Chem 277:12838-12845, 2002. 57. Black RA: Tumor necrosis factor-alpha converting enzyme. Int J Biochem Cell Biol 34:1-5, 2002. 58. Yan Y, Shirakabe K, Werb Z: The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G protein-coupled receptors. J Cell Biol 158:221-226, 2002. 59. Asakura M, Kitakaze M, Takashima S, et al: Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: Metalloproteinase inhibitors as a new therapy. Nat Med 8:35-40, 2002. 60. Mochizuki S, Shimoda M, Shiomi T, et al: ADAM28 is activated by MMP-7 (matrilysin-1) and cleaves insulin-like growth factor binding protein-3. Biochem Biophys Res Commun 315:79-84, 2004. 61. Loechel F, Fox JW, Murphy G, et al: ADAM 12-S cleaves IGFBP3 and IGFBP-5 and is inhibited by TIMP-3. Biochem Biophys Res Commun 278:511-515, 2000. 62. Fourie AM, Coles F, Moreno V, et al: Catalytic activity of ADAM8, ADAM15, and MDC-L (ADAM28) on synthetic peptide substrates and in ectodomain cleavage of CD23. J Biol Chem 278:30469-30477, 2003. 63. Reiss K, Ludwig A, Saftig P: Breaking up the tie: Disintegrin-like metalloproteinases as regulators of cell migration in inflammation and invasion. Pharmacol Ther 111:985-1006, 2006. 64. Potempa J, Korzus E, Travis J: The serpin superfamily of proteinase inhibitors: Structure, function, and regulation. J Biol Chem 269:15957-15960, 1994. 65. Murphy G, Willenbrock F: Tissue inhibitors of matrix metalloendopeptidases. Methods Enzymol 248:496-510, 1995. 66. Gomez DE, Alonso DF, Yoshiji H, et al: Tissue inhibitors of metalloproteinases: Structure, regulation and biological functions. Eur J Cell Biol 74:111-122, 1997. 67. Bode W, Fernandez-Catalan C, Tschesche H, et al: Structural properties of matrix metalloproteinases. Cell Mol Life Sci 55:639-652, 1999. 68. Brew K, Dinakarpandian D, Nagase H: Tissue inhibitors of metalloproteinases: Evolution, structure and function. Biochim Biophys Acta 1477:267-283, 2000. 69. Visse R, Nagase H: Matrix metalloproteinases and tissue inhibitors of metalloproteinases: Structure, function, and biochemistry. Circ Res 92:827-839, 2003. 70. Will H, Atkinson SJ, Butler GS, et al: The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propeptide of progelatinase A and initiates autoproteolytic activation: Regulation by TIMP-2 and TIMP-3. J Biol Chem 271:17119-17123, 1996. 71. Gomis-Ruth FX, Maskos K, Betz M, et al: Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1. Nature 389:77-81, 1997. 72. Fernandez-Catalan C, Bode W, Huber R, et al: Crystal structure of the complex formed by the membrane type 1-matrix metalloproteinase with the tissue inhibitor of metalloproteinases-2, the soluble progelatinase A receptor. EMBO J 17:5238-5248, 1998. 73. Kinoshita T, Sato H, Okada A, et al: TIMP-2 promotes activation of progelatinase A by membrane-type 1 matrix metalloproteinase immobilized on agarose beads. J Biol Chem 273:16098-16103, 1998. 74. Seiki M: The cell surface: The stage for matrix metalloproteinase regulation of migration. Curr Opin Cell Biol 14:624-632, 2002. 75. Huovila AP, Turner AJ, Pelto-Huikko M, et al: Shedding light on ADAM metalloproteinases. Trends Biochem Sci 30:413-422, 2005. 76. Wei S, Kashiwagi M, Kota S, et al: Reactive site mutations in tissue inhibitor of metalloproteinase-3 disrupt inhibition of matrix metalloproteinases but not tumor necrosis factor-alpha-converting enzyme. J Biol Chem 280:32877-32882, 2005. 77. Oh J, Takahashi R, Kondo S, et al: The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell 107:789-800, 2001. 78. Imai K, Ohta S, Matsumoto T, et al: Expression of membrane-type 1 matrix metalloproteinase and activation of progelatinase A in human osteoarthritic cartilage. Am J Pathol 151:245-256, 1997.

133

79. Gu Z, Kaul M, Yan B, et al: S-nitrosylation of matrix metallopro­ teinases: Signaling pathway to neuronal cell death. Science 297: 1186-1190, 2002. 80. Nagase H: Human stromelysins 1 and 2. Methods Enzymol 248: 449-470, 1995. 81. Sato H, Kinoshita T, Takino T, et al: Activation of a recombinant membrane type 1-matrix metalloproteinase (MT1-MMP) by furin and its interaction with tissue inhibitor of metalloproteinases (TIMP)-2. FEBS Lett 393:101-104, 1996. 82. Itoh Y, Takamura A, Ito N, et al: Homophilic complex formation of MT1-MMP facilitates proMMP-2 activation on the cell surface and promotes tumor cell invasion. EMBO J 20:4782-4793, 2001. 83. Brooks PC, Stromblad S, Sanders LC, et al: Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin alpha v beta 3. Cell 85:683-693, 1996. 84. Morrison CJ, Butler GS, Bigg HF, et al: Cellular activation of MMP2 (gelatinase A) by MT2-MMP occurs via a TIMP-2-independent pathway. J Biol Chem 276:47402-47410, 2001. 85. Cowell S, Knauper V, Stewart ML, et al: Induction of matrix metalloproteinase activation cascades based on membrane-type 1 matrix metalloproteinase: associated activation of gelatinase A, gelatinase B and collagenase 3. Biochem J 331:453-458, 1998. 86. Knauper V, Bailey L, Worley JR, et al: Cellular activation of proMMP13 by MT1-MMP depends on the C-terminal domain of MMP-13. FEBS Lett 532:127-130, 2002. 87. Shiomi T, Inoki I, Kataoka F, et al: Pericellular activation of proMMP-7 (promatrilysin-1) through interaction with CD151. Lab Invest 85:1489-1506, 2005. 88. Fujita Y, Shiomi T, Yanagimoto S, et al: Tetraspanin CD151 is expressed in osteoarthritic cartilage and is involved in pericellular activation of pro-matrix metalloproteinase 7 in osteoarthritic chondrocytes. Arthritis Rheum 54:3233-3243, 2006. 89. Sternlicht MD, Werb Z: How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17:463-516, 2001. 90. Egeblad M, Werb Z: New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:161-174, 2002. 91. Guo H, Li R, Zucker S, et al: EMMPRIN (CD147), an inducer of matrix metalloproteinase synthesis, also binds interstitial collagenase to the tumor cell surface. Cancer Res 60:888-891, 2000. 92. Puyraimond A, Fridman R, Lemesle M, et al: MMP-2 colocalizes with caveolae on the surface of endothelial cells. Exp Cell Res 262:28-36, 2001. 93. Yu WH, Woessner JF Jr, McNeish JD, et al: CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes Dev 16:307-323, 2002. 94. Yamamoto K, Higashi S, Kioi M, et al: Binding of active matrilysin to cell surface cholesterol sulfate is essential for its membrane-associated proteolytic action and induction of homotypic cell adhesion. J Biol Chem 281:9170-9180, 2006. 95. Yu Q, Stamenkovic I: Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 14:163-176, 2000. 96. Fosang AJ, Last K, Maciewicz RA: Aggrecan is degraded by matrix metalloproteinases in human arthritis: Evidence that matrix metalloproteinase and aggrecanase activities can be independent. J Clin Invest 98:2292-2299, 1996. 97. Imai K, Hiramatsu A, Fukushima D, et al: Degradation of decorin by matrix metalloproteinases: Identification of the cleavage sites, kinetic analyses and transforming growth factor-beta1 release. Biochem J 322:809-814, 1997. 98. Yamanaka H, Makino K, Takizawa M, et al: Expression and tissue localization of membrane-types 1, 2, and 3 matrix metalloproteinases in rheumatoid synovium. Lab Invest 80:677-687, 2000. 99. Yamanishi Y, Boyle DL, Clark M, et al: Expression and regulation of aggrecanase in arthritis: The role of TGF-beta. J Immunol 168: 1405-1412, 2002. 100. Takizawa M, Ohuchi E, Yamanaka H, et al: Production of tissue inhibitor of metalloproteinases 3 is selectively enhanced by calcium pentosan polysulfate in human rheumatoid synovial fibroblasts. Arthritis Rheum 43:812-820, 2000. 101. Yoshihara Y, Nakamura H, Obata K, et al: Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids from patients with rheumatoid arthritis or osteoarthritis. Ann Rheum Dis 59:455-461, 2000.

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102. Okada Y, Naka K, Minamoto T, et al: Localization of type VI collagen in the lining cell layer of normal and rheumatoid synovium. Lab Invest 63:647-656, 1990. 103. Yamanaka H, Matsuda Y, Tanaka M, et al: Serum matrix metalloproteinase 3 as a predictor of the degree of joint destruction during the six months after measurement, in patients with early rheumatoid arthritis. Arthritis Rheum 43:852-858, 2000. 104. Kobayashi A, Naito S, Enomoto H, et al: Serum MMP-3 levels of matrix metalloproteinase-3 (stromelysin 1) for monitoring synovitis in rheumatoid arthritis. Arch Pathol Lab Med 131:563-570, 2007. 105. Catrina AI, Lampa J, Ernestam S, et al: Anti-tumour necrosis factor (TNF)-alpha therapy (etanercept) down-regulates serum matrix metalloproteinase (MMP)-3 and MMP-1 in rheumatoid arthritis. Rheumatology (Oxford) 41:484-489, 2002. 106. Delaisse J, Vaes G: Mechanism of mineral solubilization and matrix degradation in osteoclastic bone resorption. In Rifkin BR, Gay CV (eds): Biology and Physiology of the Osteoclast. Boca Raton, CRC Press, 1992, pp 289-314. 107. Gelb BD, Shi GP, Chapman HA, et al: Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273:1236-1238, 1996. 108. Okada Y, Naka K, Kawamura K, et al: Localization of matrix metalloproteinase 9 (92-kilodalton gelatinase/type IV collagenase = gelatinase B) in osteoclasts: Implications for bone resorption. Lab Invest 72:311-322, 1995.

109. Pap T, Shigeyama Y, Kuchen S, et al: Differential expression pattern of membrane-type matrix metalloproteinases in rheumatoid arthritis. Arthritis Rheum 43:1226-1232, 2000. 110. Lynch CC, Hikosaka A, Acuff HB, et al: MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell 7:485-496, 2005. 111. Shlopov BV, Lie WR, Mainardi CL, et al: Osteoarthritic lesions: Involvement of three different collagenases. Arthritis Rheum 40:2065-2074, 1997. 112. Mohtai M, Smith RL, Schurman DJ, et al: Expression of 92-kD type IV collagenase/gelatinase (gelatinase B) in osteoarthritic cartilage and its induction in normal human articular cartilage by interleukin 1. J Clin Invest 92:179-185, 1993. 113. Okada Y, Shinmei M, Tanaka O, et al: Localization of matrix metalloproteinase 3 (stromelysin) in osteoarthritic cartilage and synovium. Lab Invest 66:680-690, 1992. 114. Ohta S, Imai K, Yamashita K, et al: Expression of matrix metalloproteinase 7 (matrilysin) in human osteoarthritic cartilage. Lab Invest 78:79-87, 1998. 115. Glasson SS, Askew R, Sheppard B, et al: Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434:644-648, 2005.

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8

Mononuclear Phagocytes in Rheumatic Diseases SIAMON GORDON

Key Points Macrophages play an important role in tissue homeostasis and in cellular and humoral innate and adaptive immunity. Macrophages, dendritic cells, and osteoclasts derive from blood monocytes. Tissue macrophages display marked phenotypic ­heterogeneity, depending on their local microenvironment. Distinct subsets of monocytes are recruited to inflammatory sites in tissues. Microbes and cytokines (e.g., interferon-γ, interleukin [IL]-4, IL-10) regulate macrophage activation selectively. Macrophages express a range of opsonic and nonopsonic receptors to recognize and take up foreign and altered host components. Toll-like membrane and NOD-like cytosolic receptors induce alterations in macrophage gene expression and secretion of inflammatory mediators. Macrophages and their products contribute to tissue damage and repair and chronic inflammation and autoimmunity.

Mononuclear phagocytes are widely distributed, biosynthetically active cells derived from hematopoietic precursors that circulate as monocytes and enter tissues constitutively and in response to inflammatory stimuli. In connective tissue and bone, they play a major role in homeostasis, growth, and remodeling, as mature macrophages and osteoclasts (Fig. 8-1). Myeloid dendritic cells (DCs) represent a distinct form of differentiation, specialized to maintain immune tolerance or to induce humoral and cellular immunity through B lymphocytes and T lymphocytes. Through their recognition, antigenpresenting, regulatory, and effector mechanisms, mononuclear phagocytes contribute to a range of inflammatory, infectious, autoimmune, metabolic, and degenerative rheumatic ­diseases, providing targets for therapeutic intervention. Growth of knowledge in mononuclear phagocyte biology has developed in close association with understanding of pathogenesis and treatment of chronic arthritis. (See Table 8-1

for a selective review of historical milestones.) Relevant examples include the development of steroidal and nonsteroidal anti-inflammatory agents and of anti–tumor necrosis factor (TNF)-α monoclonal antibodies.1 Genetic lesions in macrophage colony-stimulating factor (M-CSF) cause osteoclast deficiency and osteopetrosis in mouse models, whereas human mutations in cytosolic Nucleotide Oligomerisation Domain (NOD)-like receptors (NLRs) result in interleukin (IL)-1β overproduction and hyperinflammatory syndromes,2 often associated with persistent joint disease. Immune complex deposition and complement activation combine with Toll-like receptor (TLR) recognition to induce effector pathways of tissue destruction and repair. This chapter reviews general aspects of mononuclear phagocyte differentiation, recruitment, and activation, integrating the properties of different cellular subtypes. Studies on the biology of macrophages, DCs, and osteoclasts have diverged to the extent that common features have been overlooked in the understandable search for specificity. This review is an attempt, in part, to reintegrate these differentiated sublineages. General features that are especially relevant to physiologic and pathologic consequences of their presence in bone, joints, and connective tissues are discussed, and gaps in our knowledge are pointed out. The emphasis is on studies on humans, where available, with reference to murine models where applicable. The subject area encompasses innate3,4 and acquired immunity, autoimmunity, and “osteoimmunology,”5 a reflection of local specialization of mononuclear phagocyte and lymphocyte biology. Relevant topics discussed elsewhere in this textbook include innate immunity (see Chapter 16), cytokines and chemokines (see Chapter 23), osteoclast functions (see Chapter 4) and antiTNF-α therapy (see Chapter 58). For further details in connection with macrophage6-10 and DC biology,11 see reviews cited in this chapter.

OVERVIEW Circulating monocytes give rise to tissue macrophages, which display considerable phenotypic microheterogeneity in different organs.12 Similarly, and with some overlap in properties, myeloid DCs are present as heterogeneous 135

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N

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Mononuclear Phagocytes in Rheumatic Diseases

Ly

M

Figure 8-1  Thin section of a bone marrow–derived mouse macrophage. Cells were cultured for 7 days, fixed, and processed for conventional electron microscopy. Ly, lysosome; M, mitochondrion; N, nucleus. Bar = 2 μm. (Courtesy of Chantal de Chastellier, Centre d’Immunologie de Marseille-Luminy, Marseille, France).

sentinel cells at mucosal and cutaneous surfaces,13-16 undergoing a complex maturation process as they migrate to lymphoid organs after capture of antigens. Plasmacytoid DCs may represent a distinct sublineage, specialized to produce high levels of type I interferon in response to viral stimuli.17 Mononuclear precursors in the blood give rise to multinucleated osteoclasts, specialized to resorb bone.18 Circulating monocytes are themselves heterogeneous, using distinct chemokine and adhesion receptors to give rise to different tissue mononuclear phagocytes.19 These cells differ in life span depending on the recruitment stimuli and on local factors in their environment, and express diverse plasma membrane receptors, making it possible for them to interact with many different cell types and with microbial and modified host components. Phagocytosis is a hallmark of the ability of macrophages and DCs to engulf particulates, including foreign materials, bacteria,20 and dying host cells generated by apoptosis or necrosis.21 These particulates are recognized by nonopsonic receptors, including scavenger and lectin-like receptors, or after opsonization with antibodies or complement or both that enhance uptake via Fc and complement receptors. In addition, other humoral proteins, such as Pentraxins, interact with their target ligands,22 bridging them to less well-defined macrophage receptors, which regulate early cellular responses during innate immunity. TLRs play an important role in sensing the nature of the captured cargo, often interacting with the extensive repertoire of non-TLR receptors (NTRs). An extended family of nod-like receptors (NLRs) sense various cytosolic ligands, resulting in a complex assembly of ­proteins (inflammasomes), caspase activation, and release of IL-1β.23 Uptake of particulate and soluble antigen, directly or by “cross-priming,”24 induces DC maturation, ­processing, and association with major ­ histocompatibility complex

(MHC) II molecules, and presentation of peptides to naive CD4 T lymphocytes. Endogenously generated or foreign peptides generated during biosynthesis of virus glycoproteins associate with MHC I molecules for surface recognition by cytotoxic T cells (mainly CD8). DCs and possibly macrophages regulate T cell activation or tolerance through additional costimulatory surface antigens and cytokines, depending partly on concomitant TLR stimulation. Activated T lymphocytes and their products, such as interferon-γ, IL-4/IL-13, and IL-10, regulate the effector functions of mononuclear phagocytes. Digestion of macromolecules occurs in the vacuolar compartment involving dynamic membrane traffic and interactions with the cytoskeleton.25 Complex intracellular pathways transduce surface and vacuolar-derived stimuli to initiate formation of intracellular protein signaling complexes. Transcription factors translocate to the nucleus and form activation or inhibitory chromatin-binding complexes that regulate gene expression and biosynthesis of secretory ­products, such as TNF-α. Other, low-molecular-weight metabolites are generated by nontranscriptional mechanisms, yielding inflammatory mediators and antimicrobial activities. Osteoclasts are able to secrete Hydrochloric  Acid (HCL) and potent proteolytic enzymes into sealed-off localized areas of bone, to which they adhere tightly through specialized podosomes and actin rings. The secretory activities of mononuclear phagocytes influence a range of cellular and extracellular targets to maintain tissue homeostasis, but also are responsible for tissue destruction. Their trophic actions,26 through cellular contact with other stromal cells and extracellular matrix and secretion, regulate tissue catabolism, cell growth, angiogenesis, and repair. In addition to local effects, macrophages contribute to systemic integration of proinflammatory and anti-­inflammatory effects, acting on the central nervous system, endocrine organs, liver, and energy stores. Overall, the activation phenotype of mononuclear phago­ cytes is modulated by extrinsic factors (e.g., cytokines and hormones), by balance of surface receptors with activating/ inhibitory cytoplasmic motifs, by cytosolic regulators such as the suppressors of cytokine synthesis (SOCS)27 proteins, by phosphorylation/dephosphorylation of signaling molecules, and by assembly of transcription factor complexes on chromatin. Microarray analysis of macrophages has made it possible to distinguish characteristic signatures of gene expression after innate activation via TLRs, deactivation via glucocorticoids, or modulation via cytokines. As a result, the phenotype of tissue macrophages is markedly heterogeneous, making for complexity of function in different sites in health and disease, but also providing opportunities for novel state-specific or tissue-specific targeting by drugs.

LIFE HISTORY AND HETEROGENEITY (MACROPHAGES, DENDRITIC CELLS, AND OSTEOCLASTS) In an adult, all three sublineages of mononuclear phagocytes originate from CD34+ committed progenitor cells in the bone marrow (Fig. 8-2). These diverge from lymphoid cells and subsequently from polymorphonuclear leukocytes, although many genes are still expressed, but not translated, in both types of phagocytic cell. In vitro, bone marrow and

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Table 8-1  Milestones in the History of Mononuclear Phagocytes Subject

Comment

Investigators

Phagocytosis

Cellular defenses in innate immunity

Metchnikoff

Opsonization

Humoral interactions

Wright

Clearance

Reticuloendothelial system

Aschoff

Monocytic origin

Circulating precursors,  heterogeneity

Gowans; Ebert and Florey;   Ziegler-Heitbrock; Geissmann et al

Mononuclear phagocyte   system

Integrative classification of diverse tissue macrophages

Van Furth et al

Marginal zone spleen

Capture capsulated bacteria

Humphrey; Kraal

Osteoclasts

Mononuclear origin

Loutit

Dendritic cells

Unique antigen-presenting cells

Steinman and Cohn

Intracellular pathogens

Bacille Calmette-Guérin, Toxoplasma, Listeria, Legionella pneumophila

Mackaness; Jones and Hirsch; North; Portnoy; Horwitz

Glucocorticoids and   mucopolysaccharides

An important, still neglected aspect of   anti-inflammatory actions

Thompson and Van Furth

Cell biology

Culture mouse/human macrophages

Cohn

Endocytosis

Membrane flow

Steinman; Unanue

Lysosomes

Fusion and acidification, inhibition Mycobacterium ­tuberculosis (MTB): Vacuolar system, antigen degradation

D’Arcy Hart

Cytoskeleton

Abundant

Stossel

Adhesion receptors

Migration

Springer; Arnaout

Fc and C receptors

Receptor function

V. Nussenzweig; Rabinovitch; Silverstein

Opsonic phagocytosis

Cloning

Mellman; Unkeless; Ravetch; Aderem

Secretion

Acid hydrolases Lysozyme, neutral proteinases Reactive oxygen and nitrogen radicals

Allison; Davies Gordon; Werb Karnovsky; Babior; Rossi; Nathan; Segal

Cytokines

Macrophage colony-stimulating factor growth   factor osteopetrosis Granulocyte-macrophage colony-stimulating factor Tumor necrosis factor-α role in host defense,   granuloma formation Interferon-γ classic macrophage activation Interleukin-4/13 alternative activation

Stanley; Wiktor-Jedrzejczak; Metcalf Cerami  Kindler; Vassalli Dalton; Gray Mantovani

Inborn errors

Dominant mutations leading to immunodeficiency

Newport; Levine; Casanova

Gene expression

PU-1

McKercher; Singh; Hume

Signaling

Stats

Schreiber

N-ramp

Iron exchange in vacuole and genetic resistance   to intracellular pathogens

Skamene; Gros; Bradley; Blackwell

Toll-like receptors (mammalian)

Lipopolysaccharide mutant; CD14   (lipopolysaccharide-binding protein receptor)

Beutler; Medzhitov; Akira; Wright

Scavenger receptors

Foam cell formation

Brown and Goldstein

Atherogenesis

Krieger; Kodama

Mannose receptor

C-type lectin, endocytosis, receptor recycling

Stahl

β-Glucan receptors

Fungal recognition by Dectin-1

Brown

NOD-like receptors

Hyperinflammatory syndromes, inflammasomes

Tschopp

Note. This is a highly selective, personal list. No attempt has been made to ascribe priority, and the author apologizes to all omitted. For references, see general reviews.

blood monocytes can be stimulated by growth factors28 to generate macrophages (M-CSF or granulocyte-macrophage colony-stimulating factor [GM-CSF]), DCs (GM-CSF, with or without IL-4), or osteoclasts (M-CSF and Rank ligand). Some of these growth factors also are essential in vivo (e.g., osteopetrotic, M-CSF-deficient mice lack many, but not all, populations of tissue macrophages and osteoclasts).29,30 Monocytopoiesis is less well understood in humans and may depend on M-CSF and GM-CSF. Trophic interactions between hematopoietic precursors and stromal cells in the bone marrow (mesenchymal and hematopoietic in

origin) are mediated by cell contact, via surface receptors,26 and by soluble factors (e.g., c-kit and its ligand and IL-1). ­Transcription factors that are essential for monocyte/macrophage production and related cells include Pu-1,31,32 other ets family members, maf,33 and mi, implicated in microphthalmia. Although bone marrow precursors proliferate vigorously as they differentiate in the presence of M-CSF or GM-CSF, monocytes become refractory to these growth stimuli (e.g., as to the growth-promoting actions of IL-3, IL-4, or IL-13). Restriction of DNA synthesis is associated with chromatin

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Bone marrow

Peripheral blood

Progenitor

CCR2CD62LX3CR1high-

Tissues

Resident tissue MØ? e.g., splenic MØ, Kupffer cells, alveolar MØ, microglia, osteoclasts Resident tissue DC?

Monoblast Figure 8-2  Differentiation and distribution of mononuclear phagocytes. Distinct subpopulations of circulating  monocytes are thought to give rise to resident tissue macrophages (MØ), dendritic cells (DC), and osteoclasts compared with cells recruited by an inflammatory stimulus. Further phenotypic heterogeneity arises from microenvironmental stimuli, such as cytokines and microbial products. For further details of morphologic and other properties of cells in different tissues, see Gordon and colleagues49 and Gordon and Hughes.12

Inflammation

CD14++

Pathogen clearance

MØ

Promonocytes CCR2+ CD62L+ CX3CR1low

Monocytes

condensation, whereas RNA and protein synthesis persists and can be modulated by a variety of stimuli, as discussed further subsequently. Tissue macrophages, DCs, and osteoclasts all derive from circulating monocytes, although these already may display heterogeneity (see Fig. 8-2). Cells are recruited constitutively to peripheral sites in the steady state. Additional monocytes can be recruited to local sites in response to infectious, inflammatory, and metabolic stimuli. Such “elicited” cells display distinct properties from the “resident” cells, which in the case of macrophages and DCs also display marked diversity, depending on their location. A considerable body of evidence, although incomplete, indicates that different subsets of macrophages and DCs originate from distinct monocyte populations in peripheral blood.34-37 Apart from marker antigens (e.g., CD14, the receptor for lipopolysaccharide-binding proteins, and Gr-1, a mouse Ly-6 antigen expressed by polymorphonuclear neutrophils and by some monocytes), levels of chemokine receptors for fractalkine (CX3CR1) and CCL2 (MCP1) seem to distinguish monocyte subsets that give rise to inflammatory and resident macrophages (see Fig. 8-2). Resident macrophages and immature DCs are present in many lymphohematopoietic and nonlymphoid organs; selected markers and properties are listed in Table 8-2. The CD68 antigen, a late endosomal mucin-like glycoprotein related to the LAMP family, is the most broadly expressed marker for all mononuclear phagocytes, although its function is still obscure. Osteoclasts and resident macrophages are found on the surface of bone and display distinct phenotypes. Although antigenic markers for human and mouse mononuclear phagocytes are useful for phenotypic analysis, no single marker is definitive in their classification, and it is impossible, in most

Resolution of inflammation DC Antigen presentation

tissues, to distinguish locally activated resident cells from “elicited,” newly recruited, and locally activated monocytes. This problem is due partially to rapid modulation of antigen expression in blood monocytes when they enter a particular tissue microenvironment. Species differences in anatomy and of marker expression are a further confounding factor. Apart from the expression of chemokine receptors,38 adhesion molecules play a role in selective monocyte “homing,” but their differential expression by ­ macrophages, DCs, and osteoclasts is still less well defined than for lymphocyte subpopulations. These include various heterodimeric integrins implicated in adhesion to endothelium, to extracellular matrix, and to bone. There is considerable scope for characterization of additional receptors and markers—one example is the EGF-TM7 family of leukocyte receptors illustrated in Figure 8-3.39 Although the F4/80 antigen has been extremely useful as a differentiation marker in the mouse, the human counterpart (EMR1) has not been of comparable value, showing a predilection for eosinophils. EMR2, a related human myeloid cell receptor, is a useful marker, however, expressed by many tissue mononuclear phagocytes; it binds chondroitin sulfate proteoglycans broadly present in connective tissue and has been implicated in leukocyte adhesion, migration, and activation.40 In joints, there is a resident synovial macrophage population, and recruited monocytes and macrophages are prominent in inflammatory, autoimmune, and infectious diseases, together with DCs and other myeloid and lymphoid cells. To my knowledge, these resident and recruited mononuclear phagocytes have not yet been attributed to particular monocyte subsets. These may not be the same monocyte subpopulations that give rise to resident and recruited mononuclear phagocytes in other tissues and in response to different pathologies.41

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Table 8-2  Selected Properties of Mononuclear ­Phagocytes and Related Cells

F4/80 EMR1 1

EMR2

1

CD97

139

1

Monocytes/Macrophages: Antigen Marker

2

2

2

F4/80 (mouse) EMR2-EGF module containing receptor (human) CD68 Complement receptor 3 (CR3) (CD11b) Sialoadhesin (Siglec-1) Scavenger receptors: Scavenger receptor A (SR-A) Macrophage receptor collagenous domain (MARCO) Mannose receptor Macrophage colony-stimulating factor receptor (M-CSFR) Other properties Opsonic phagocytosis Lysozyme secretion Abundant acid hydrolases

3

3

3

4

4

4

5

5

5

6

Myeloid Dendritic Cells: Antigens Major histocompatibility complex class II Costimulatory molecules CD11c CD8α+/− DEC205 Dendritic Cell-specific ICAM-grabbing non-integrin (DC-SIGN) Dendritic Cell-Lysosome associated membrane Protein (DC-LAMP) Other properties Activation of naive CD4 T lymphocytes Plasmacytoid Dendritic Cells: Antigens CD123 B220 Lectin-like receptors (Siglec H) Other properties Type I interferon production In vitro growth by flt-3 ligand Osteoclasts CD68 Tartrate Resistant Acid Phosphatase (TRAP) Calcitonin receptor αvβ3 Vacuolar H+ ATPase Proteinase K Resorption of living bone Note. Marker expression varies, depending on cell localization, maturation, and activation. Some markers also are present on other myeloid cells (e.g., polymorphonuclear neutrophils) and selected endothelial cells. Structures and functions of receptor antigens are described elsewhere in this chapter.

MOBILIZATION OF MONONUCLEAR PHAGOCYTES Similar to other white blood cells, mononuclear phagocytes are distributed in intravascular and extravascular compartments, sharing common mechanisms of mobilization, but also displaying distinct features, among themselves and compared with other cell types. Exit from the bone marrow is controlled constitutively and on demand, but this process is not well understood except for the role of chemokine receptors, such as CCR2 (ligands MCP1 through MCP4).42 What determines differentiation into the mature macrophages that form part of the stromal microenvironment in bone marrow is unknown; one possibility is re-entry of circulating monocytes from blood to bone, as for ­osteoclasts. Apart from the circulating pool of monocytes, many mature macrophages adopt a sinusoidal distribution in liver (Kupffer cells) and in selected lymphoid and endocrine organs. These

Figure 8-3  Myeloid cell antigens of the EGF-TM7 family. These G protein coupled receptor(GPCR) related receptors have a large extracellular domain consisting of multiple epidermal growth factor (EGF) modules. The F4/80 antigen, an excellent marker for mouse macrophages, has been implicated in peripheral tolerance.127 The human orthologue EMR1 is a marker for human eosinophils. EMR2 is not expressed in the mouse, but is present on human monocytes, macrophages, immature myeloid dendritic cells, and activated polymorphonuclear neutrophils. It is a useful surface marker for macrophages in tissues, including rheumatoid arthritic joints. CD97, expressed on myeloid cells and selected nonmyeloid cells, is a receptor for the complement regulatory protein, CD55.128 EMR2 and CD97 bind chondroitin sulfate B.40

cells are distinct from, but share endocytic properties with, sinusoidal endothelial cells. The constitutive exit through vascular endothelium to become tissue macrophages and DCs is not understood, whereas induced mobilization is well characterized, sharing many features with that of polymorphonuclear neutrophils. Figure 8-4 summarizes stages and molecules implicated in monocyte egress.43,44 Although most monocytes exit the microvasculature by diapedesis between endothelial cells, there is evidence for an alternative transcytotic mechanism, as for lymphocytes.45 The roles of L-selectin, β2 and other integrins,46 the immunoglobulin superfamily molecule CD31, and CD99 have been established by analysis of genetic deficiencies in humans and mice,47 and by use of monoclonal antibodies against these48 and other defined adhesion molecules, such as VCAM and VLA-4. Endothelial cell ligands implicated in monocyte adhesion include fractalkine, a tethered chemokine; other chemokines may be presented by glycosaminoglycans. The subsequent migration and fate of mononuclear phagocytes in tissues differ strikingly. Although many resident macrophage and DC subpopulations in tissues are well characterized,12,49 the origins of several functionally specialized cell types related to this overall lineage remain unclear.50,51 Macrophages become sessile, but can be induced by inflammatory stimuli to migrate to draining lymph nodes and remain there, without re-entering the circulation. Immature DCs respond to antigenic and inflammatory stimuli by migration to draining lymphoid tissues, transporting antigens for presentation to lymphocytes (Fig. 8-5). DC maturation is accompanied by major changes in DC properties (Fig. 8-6 and Table 8-3). DCs become highly motile and

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Rolling

Firm adhesion CD62L shedding

Increase in CD11b Extravasation

CD29

CD54

PSGL1

CD62P

JAM

CD62L

Chemokines (e.g., CCR2/MCP-1)

CD11b CD11a

Chemokine receptor (e.g., CCL2)

N-Glycans

CD31/PECAM

CD99

CD49d

Figure 8-4  Stages and molecular interactions implicated in monocyte recruitment by inflammatory stimuli. Diapedesis of monocytes shares features with that of polymorphonuclear neutrophils.

T cells Dendritic cells Follicular DCs

B Blood

Peripheral tissues Afferent lymphatics

B B

B

Blood

T

T

Bone marrow

Figure 8-5  Positioning of dendritic cells (DCs) within lymphoid tissues. Blood-derived monocytic precursors enter skin and mucosal peripheral tissues and differentiate into Langerhans cells within epithelia and into other immature DCs. When established, Langerhans cells turn over independently from bone marrow–derived cells58 (e.g., after ultraviolet irradiation). On exposure to stimuli (foreign antigens, local infections) and constitutively (after uptake of apoptotic cells, such as in the gastrointestinal tract), DCs undergo maturation, upregulate CCR7, and enter afferent lymphatics and secondary lymphoid tissues, where they interact with CD4 T lymphocytes. CD4 T lymphocytes become activated, interacting with B cells or CD8 T lymphocytes, and re-enter blood, homing to peripheral sites. DCs also are able to interact with innate lymphocytes and natural killer cells. Follicular DCs in  B cell areas have a distinct, poorly defined bone marrow origin, express novel antigenic markers, and are able to capture immune complexes through complement activation.50 Plasmacytoid DCs have a distinct interfollicular location and express markers of a myeloid and a lymphoid nature. (Courtesy of R. Steinman.)

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Table 8-3  Maturation Markers for Human   Monocyte-Derived ­Dendritic Cells Immature

Mature

Low Low High

High High De novo Moderate/low

High

Low

Low Low High High Low

High High Low Low High

Moderate

High

Moderate

High

High

Low

Enhancer/Costimulatory Molecules CD80 (B7-1) CD86 (B7-2) CD83 EMR2 (CD312)

Microbial products Cytokines CD40 ligation Innate lymphocytes, Etc

Antigen Uptake FcγRII Signaling

Antigen capture

T cell immunity Cytokines, chemokines B7 and TNF costimulators

Figure 8-6  Dendritic cell (DC) maturation. In the steady state, immature DCs are actively endocytic, capturing antigens efficiently through pattern recognition receptors. In response to a range of exogenous and endogenous stimuli, they translocate major histocompatibility complex class II to the surface, express a range of costimulatory molecules and secretory products, and become efficient antigen-presenting cells. As a result, DCs control adaptive immunity or induce tolerance. TNF, tumor necrosis factor. (Courtesy of R. Steinman.)

express a range of chemokine and adhesion receptors. Entry of myeloid DCs and tissue macrophages into lymphatics is less well understood, but may involve interactions with the mannose receptor. As a result, DCs can present exogenous antigens and self-antigens to CD4 T lymphocytes, to activate or tolerize their responses. Although in vitro systems are widely used to generate DCs by cultivation of monocytes or bone marrow precursors in cytokine-supplemented media (GM-CSF, with or without IL-4), their properties may not correspond to those of DC populations in vivo. Mononuclear phagocytes use integrins and receptors for extracellular matrix such as CD44, regulating the dynamics of their adhesion and migration. Osteoclast adhesion to bone depends on αvβ3 and possibly other adhesion ­ molecules implicated in podosome attachment. Plasma membrane receptors such as CD97 and EMR2, members of the EGFTM7 family, and TREM-1,52 an immunoglobulin superfamily molecule with an ITAM-based activation motif (see later), regulate myeloid cell effector functions and adhesion and migration in extravascular tissue compartments. Monocytes recruited to tissues by poorly degradable foreign materials or by selected microbial pathogens or parasites form granulomata, organized structures rich in macrophages, incorporating other myeloid and lymphoid cells and fibroblasts and extracellular matrix. Pathogen-induced granuloma formation53 depends on adhesion molecules such as CR3, a β2 integrin, TNF-α, and chemokine receptors such as CCR4; granuloma macrophages express abundant secretory products such as lysozyme54 and proinflammatory cytokines. Characteristic morphologic evidence of macrophage differentiation in granulomata includes epithelioid cell and multinucleated giant cell formation, such as with Mycobacterium tuberculosis infection. Giant cells arise by monocyte recruitment and macrophage fusion, rather than by impaired cytokinesis.55 Cytokines such as IL-4 and IL-13,56 acting

CD40 CXCR4 CCR5 CCR6 CCR7 Antigen Presentation HLA-DR (major histocompatibility complex class II) HLA-DQ (major histocompatibility complex class II) CD1a Others DC-SIGN (CD209) CD14 CD123 (IL-3R)

High Low High/moder- Negative ate Low High

Note. In addition to the listed antigens and antigen-presenting cell functions, dendritic cell production of, and response to, other growth factors, chemokines and cytokines, microbial products, and immune complexes varies during maturation and activation in vitro. Validation in vivo is ­incomplete.

through a common receptor chain,57 and GM-CSF promote macrophage fusion. Foreign surfaces including biomaterials also can play a role in granuloma formation, and chemokine receptors have been implicated in the induction of foreign body–induced giant cells. The surface molecules involved in these examples of macrophage homokaryon formation and the functional significance of induced fusion are still poorly understood. By contrast, multinucleation in osteoclasts is a physiologic process, dependent on M-CSF and RANK ligand, and several plasma membrane (CD44, CD9, TREM-2, DC-STAMP) and intracellular (c-src, c-fos) molecules have been implicated in this differentiation process. Multinucleation is thought to favor efficient localized resorption of bone. Osteo­ clasts become polarized for secretion and display highly active plasma membrane ruffling. Interactions with osteoblasts; local cytokines, such as osteoprotegerin; and circulating hormones, including calcitonin, parathormone, and vitamin D metabolites, regulate their gene expression and function, as discussed in Chapter 4. Vitamin D receptors also modulate the function of macrophages and DCs. The turnover of different mononuclear phagocytes varies, depending on their activation status and tissue localization.58 Resident macrophages can live for weeks or months, whereas inflammation reduces survival to hours or days. DCs are relatively short-lived cells; osteoclast turnover in vivo has not been studied in detail. The role of apoptosis in mononuclear phagocyte turnover is poorly characterized, in contrast to in polymorphonuclear neutrophils, but cell

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IL-1R or TLR5

TLR1-TLR2 or TLR2-TLR6

TLR7, TLR8 or TLR9

TLR4

TLR3

Plasma membrane TIR domain

MyD88

MAL TRIF

NF-κB

NF-κB

NF-κB IRF3 IRF5 IRF7

TRAM

NF-κB IRF5

NF-κB IRF3

NF-κB IRF5 IRF7 IRFI (in mDCs)

SARM Figure 8-7  Overview of transcription factor activation through TIR domain–containing adapters for the TLR/IL-1R superfamily. Each adapter is differentially used by receptor complexes to regulate transcription factor activation positively. The exception is SARM (sterile α- and armadillo motif–  containing protein), which inhibits TRIF (Toll/IL-1R [TIR] domain–containing adapter protein inducing interferon [IFN]-β)-mediated transcription factor activation. IL-1R, interleukin-1 receptor; IRF, IFN regulatory factor; MAL, MyD88 (myeloid differentiation primary response gene 88) adapter-like protein; mDC, myeloid dendritic cell; NF B, nuclear factor B; TLR, Toll-like receptor; TRAM, TRIF-related adapter molecule. (From O’Neill LA, Bowie AG: The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7:353-364, 2007.)

survival is regulated by growth factors such as M-CSF and interactions with neighboring cells and pathogens.

RECOGNITION In the past decade, emphasis on the problem of immune recognition has shifted to a considerable extent from somatically rearranged receptors for peptide, on lymphocytes, to germline-encoded receptors on myeloid antigen-presenting cells (APCs).59-61 Previous studies on myeloid cells focused on well-known opsonic receptors for antibody (Fc receptors) and complement (complement receptor). The concept of direct pattern recognition receptors for conserved structures on microbes provided an impetus to studies on innate immunity, reinforced by the discovery of TLRs. More recently, the investigation of numerous NTRs, including a range of lectin-like recognition molecules and of scavenger receptors, markedly enhanced knowledge of the recognition repertoire.62 Finally, came the discovery of cytosolic recognition proteins, the NLR family,23 implicated in genetic and microbial-induced hyperinflammatory syndromes and in Crohn’s disease. These molecules are mainly, although not exclusively, expressed by macrophages and DCs and play an important role in immune responses to foreign or modified host ligands, resulting in inflammation and autoimmunity. Given the complexity of microbial and cellular particulates compared with discrete soluble ligands, different receptors collaborate and synergize with one another to activate or inhibit subsequent APC responses. The original distinction drawn between pattern recognition receptors for exogenous,

so-called pathogen-associated molecular patterns and for endogenous, host-derived ligands has been eroded to some extent because individual receptors are able to bind both types of ligand,63 although their distinct cellular expression and signaling responses may account for discrimination by host APCs. In particular, the recognition and uptake of apoptotic cells results in downregulation of macrophage effector molecules,64 as opposed to the proinflammatory effects induced by microbial ligands. The signaling pathways induced by other, modified host-derived ligands, such as oxidized lipoproteins and hyaluronates, are not wellcharacterized. This section summarizes selected receptor structures, indicates some of their ligands, and addresses briefly signaling and antigen processing pathways. Further details are provided in Chapter 16, which also illustrates interactions between humoral and cellular arms of the innate response. TOLL-LIKE RECEPTORS Key features of TLRs are illustrated in Figure 8-7.65-67 TLRs consist of homodimers or heterodimers of transmembrane glycoproteins containing extracellular leucine-rich repeats (LRR) and cytoplasmic TIR domains, similar to the intracellular domain of the IL-1 receptor, which contains extracellular immunoglobulin superfamily domains. TLRs are expressed on the surface of APCs or, in the case of TLR3, TLR7/8, and TLR9, on vacuolar membranes, contributing to proinflammatory and immunogenic signaling after “sensing” of cargo. Isolated TLRs do not bind ligands directly, but collaborate with humoral factors and with other plasma membrane glycoproteins, as in the well-studied case of TLR4, the

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N CR CR

N CR

Cysteine-rich domain Fibronectin type II CTLD Potential N-linked glycosylation

C

C

C C

C

ITAM

C N

MR

DEC205

DC-SIGN

N βGR Murine Dectin-1

Glycosyl phosphoinositide (GPI)-anchored CD14 receptor for the plasma lipopolysaccharide-binding protein,68 and the membrane-associated molecule MD2. NON–TOLL-LIKE RECEPTORS NTRs constitute a variety of lectin-like,62,69 scavenger, and other plasma membrane glycoprotein nonopsonic receptors; selected examples are illustrated in Figures 8-8 and 8-9. They include type 1 and 2 transmembrane molecules, with C-type lectin or lectin-like, collagenous, or immunoglobulin superfamily domains. In addition, macrophages express sialic acid–binding receptors, members of the SIGLEC family.70 Table 8-4 summarizes known ligands and potential functions relevant to their role in homeostasis and immunity. Apart from direct recognition of selected self, modified self, and foreign structures, they play an important role in cell-cell and cell-matrix interactions; in phagocytosis and endocytosis; and in less well-understood processes, such as targeted delivery of antigens to peripheral lymphoid organs.71 Receptors that promote rapid clearance of apoptotic cells, directly or after opsonization by complement and other extracellular proteins, are shown in Figure 8-10. More recent research has shown collaboration of different receptors at the cell surface,72 regulating cellular responses. Other regulatory surface receptors include transmembrane molecules with tyrosine-based activating (ITAM) or inhibitory (ITIM) cytoplasmic motifs, for example, C-type lectin-like molecules, immunoglobulin superfamily members such as Fc receptors, discussed further subsequently, and receptor-ligand pairs that

ITAM N

ITAM N

βGR-A βGR-B Human Dectin-1

Figure 8-8  Selected lectin-like rece­ ptors expressed by macrophages and dendritic cells (DCs). (See Table 8-4 for ligands.) These receptors play an ­important role in nonopsonic adhesion,  cell-cell interactions, endocytosis, and  phagocytosis. The cysteine-rich domain of the mannose receptor130 has been postulated to play a role in transport of glycoconjugates to peri­ pheral lymphoid organs, for clearance or antigen-dependent activation of B lymphocytes.71 Dec205 has been used to show efficient targeting of antigens to DCs.131 The ITAM-like motif of Dectin-1, the β-glucan receptor, is essential for myeloid cell responses to fungal particles, in collaboration with TLR69,72,132 and NLR.109 CTLD, C-type lectin domain.

regulate macrophage activation (CD200/CD200R)73 and phagocytosis (SIRPα and CD47) (Fig. 8-11).74 COMPLEMENT RECEPTORS Complement receptors are heterogeneous receptors exp­ressed by APCs (Fig. 8-12) that mediate direct and lectin and antibody-dependent binding of activated complement components and play a role in cell migration and phagocytosis and immune regulation.75,76 The discovery of a novel complement receptor selectively expressed by Kupffer cells suggests that mononuclear phagocyte heterogeneity in complement receptor function merits ongoing study.77 Genetic deficiencies in complement receptor expression and their ligands have provided insights into the pathogenesis of autoimmune diseases and of rheumatic joint injury.78 ­Complement deposition on follicular DCs has been implicated in the activation of B cell responses.50,79 Complement regulatory proteins are expressed by many cell types and APCs and play an important role in limiting cell activation. In addition, complement receptors collaborate with other receptors to modulate myeloid cell responses. Their signaling pathways are less well defined than those of Fc receptors. Fc RECEPTORS APCs express diverse receptors for monomeric and complexed immunoglobulins regulating effector responses to antigens.80-83 Figure 8-13 illustrates the properties of human Fc receptors with activating or inhibitory motifs in their

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C

C

C

SRCR

Collagen-like C

C

C N

α-Helical coiled coil CTLD

N N N

N N N

N N N

SR-AI

SR-AII

MARCO

C CD163

N

C

CD36

GPI-anchor CD14

N LOX-1

Figure 8-9  Selected scavenger receptors. These non-TLRs consist of diverse structures and bind a range of microbial and endogenous ligands (see Table 8-4). They differ in regulation and expression, providing useful markers of macrophage activation (CD14, MARCO),133-137 heterogeneity (CD163, the scavenger receptor for clearance of haptoglobin-hemoglobin complexes),119 and lipid homeostasis (SR-A, CD36, LOX-1).138,139 Scavenger receptors such as MARCO can collaborate with TLRs in APC responses to microbes.140 CTLD, C-type lectin domain.

cytoplasmic tails. Fc receptor polymorphisms have been implicated in autoimmune human diseases such as systemic lupus erythematosus. Studies on genetically manipulated mouse models have led to considerable insights into the role of individual Fc receptors in immunopathogenesis. Fc receptors are able to cooperate with chemokine84 and other receptors. The nature and role of Fc-independent interactions of antibody with APCs are under investigation and include lectin-like recognition of sialylated85 and mannosyl residues. NOD-LIKE RECEPTORS The identification of microbial peptidoglycan breakdown and other products as ligands for an intracellular family of LRR-containing cytosolic sensors that regulate caspase activation and IL-1β secretion provided a major impetus to this burgeoning field.86 Other chapters describe examples of NLRs and their role in hyperinflammatory syndromes. NLRs also participate in signaling pathways implicated in TLR-induced and NTR-induced functions.

RESPONSES AND MODULATION For convenience, I distinguish the cellular pathways that precede altered gene transcription and subsequent effector responses. This section summarizes some of the major cell

biologic effects, resulting in antigen processing and presentation by APCs. Other chapters address related topics, such as recognition of lipids by CD1 and intracellular trafficking of related molecules. PHAGOCYTOSIS AND ENDOCYTOSIS: ANTIGEN PROCESSING The vacuolar apparatus of APCs is illustrated schematically in Figure 8-14.87-90 Internalization of the plasma membrane results in phagosome/endosome formation, with progressive acidification and digestion, depending on delivery of vesicles and their hydrolytic contents. Membrane and receptors are recruited, modified by maturation, and retrieved by recycling. Further fusion with Golgi-derived vesicles and primary lysosomes yields phagolysosomes and secondary lysosomes, reaching a pH of approximately 5.5 to 6.0. Depending on the bulk of plasma membrane internalized and the size of the particle, the uptake process involves cytoskeletal components91 and small GTPases92 and docking machinery. Guanosine triphosphate (GTP) hydrolysis provides an important mechanism to control intracellular membrane traffic and coupling to the cytoskeleton.93 Cytokines such as interferon-γ can have a major effect on activation and relocation of GTP-binding proteins, contributing to host cell–pathogen interactions.94,95

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Table 8-4  Ligands for Selected Nonopsonic, Non–Toll-like Receptors Class

Receptor

Microbial Ligands

Endogenous Ligands

Function

Scavenger   receptors

SR-A I/II

Gram-positive/  gram-negative bacteria Lipoteichoic acid

Apoptotic cells

Phagocytosis

Modified low-density   lipoproteins AGE-modified proteins β Amyloid

Endocytosis

MARCO

CD36

Lipid A Neisserial surface   proteins Gram-positive/  gram-negative bacteria Neisserial surface proteins

Marginal zone B   lymphocytes Uteroglobin-related protein

Diacylated lipopeptide from   gram-positive bacteria

Apoptotic cells (with   thrombospondin and   vitronectin receptor) High-density lipoprotein (HDL) Outer rod segments

Plasmodium falciparum–  parasitized erythrocytes Lectins

Dectin-1

β-Glucan

DC-SIGN

Mannosyl/fucosyl   glycoconjugates including viruses (e.g., human immunodeficiency virus-1, dengue) Mannosyl/fucosyl   glycoconjugates on   bacteria, viruses, fungi, parasites

Mannose receptor: CRD Cysteine-rich   domain Fibronectin type II domain

Adhesion Foam cell formation Adhesion Phagocytosis Innate activation Uptake, exchange  of lipids Adhesion

T lymphocytes   (noncarbohydrate) ICAM 2/3  T lymphocytes  Lysosomal hydrolases

Fungal uptake and   immunomodulation Adhesion  Endocytosis  Endocytosis

Thyroglobulin  Ribonuclease B  Amylase Sulfated carbohydrates in marginal zone (spleen)   and subcapsular sinus (lymph node) Collagens

Adhesion Antigen targeting

Adhesion

Note. This table illustrates the dual recognition properties and diverse cellular functions of selected non–Toll-like receptors. For further details, see references 15, 20, 62, 139, 147-150.

Proteomic analysis of isolated phagolysosomes has revealed more than 600 constituents, classified according to the source of membrane and various putative functions.96 Although most membrane constituents are derived from the plasma membrane, descriptions of contributions from the endoplasmic reticulum have caused considerable interest, with different estimates of their extent.96,97 Another controversial aspect relates to the role of TLR engagement in enhancing the kinetics of the maturation process, a transcription-independent process.98 Variations on this theme occur depending on the cell type and maturity, whether the extracellular cargo is microbial or host-derived, and whether the process arises by autophagy,99 rather than heterophagy. The role of autophagy in cellular resistance to intracellular pathogens, such as M. tuberculosis, is receiving increasing consideration.100,101 Immature DCs are actively endocytic and phagocytic, but poor APCs, whereas mature DCs downregulate uptake, but acquire highly efficient APC function.25 Changes associated with DC maturation and antigen presentation are illustrated in Figure 8-15. Pathogenic intracellular organisms vary in their subversion of the aforementioned process, interfering with different stages, such as cytosolic signaling mechanisms, fusion, or acidification, and in selected cases, inducing a novel membrane composition.102,103 Organisms

can replicate in immature or mature compartments, or translocate their genome to the cytosol by acid-induced envelope fusion or by disruption of the vacuolar membrane. SIGNALING The best-characterized signaling responses in macrophages include the TLR,104 type I interferon,105 and Fc receptor–induced pathways.106,107 The various signaling cascades are complex, interact with one another, and result in phosphorylation/dephosphorylation, formation of cytosolic protein complexes, and activation of signaling proteins such as nuclear factor B, which enter the nucleus to regulate transcription. In the case of TLR-dependent sensing, a restricted number of adapters, such as MyD88, channel the flow of information into the cell (see Fig. 8-7). There is emerging evidence that NTR-induced signaling (e.g., by the β-­glucan receptor [Dectin-1] cytoplasmic ITAM-like motif)69 collaborates with TLR and NLR signaling pathways, with differential involvement of syk108 and CARD9109 in effector responses in different mononuclear phagocytes. Distinct, but interlinked pathways involve interferon regulatory factors, part of an amplification pathway with broader immunoregulatory functions than antiviral responses alone.105 A more recently defined cytosolic specialized antiviral pathway

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b. Recognition of altered self Mer

Scavenger receptors

Phagocyte

CD36

PtdSer

β2-GPI receptor

LOX-1 CD68

β2-GPI

SRA

Gas6

a. Innate recognition of non-self

MFGE8 ABC1

PtdSer exposure C3b

β2-Integrin receptors

C1q

TSP1 binding sites

Apoptotic cell

ανβ3vitronectin receptor

ABC1 c. Recognition of non-detaching self Integrins (ανβ3, ανβ5)

TSP1 CD36

CD91 CD91

MBL

ACAMP3 ICAM3

Disabled CD31

CD31

CD14

Figure 8-10  Phagocytic receptors for apoptotic cell phagocytosis. Macrophages (MØ) and immature myeloid dendritic cells (DC) are the main  immune cells involved in the clearance of apoptotic cells. They express broadly similar multiple receptors, which can bind directly or via opsonic soluble proteins (e.g., mannose-binding lectins [MBL] to ligands). Phosphatidylserine (PtdSer) becomes exposed on the outer surface of the apoptotic cell, and a receptor for this ligand has been long sought. A new receptor (TIM4 and related TIM1) has been discovered on resident MØ, with specificity for PtdSer. Other MØ populations use MFGE8 (a milk fat globulin protein secreted by MØ) as an opsonin. Discrimination of nonself and altered self may involve combinations of different phagocyte receptors. Apoptotic cell uptake results in an anti-inflammatory response by MØ (e.g., release of TGF-β and PGE2), but also has been implicated in cross-presentation by DC. (From Savill J, Dransfield I, Gregory C, et al: A blast from the past: Clearance of apoptotic cells regulates immune responses. Nat Rev Immunol 2:965-975, 2002.) MFGE8, milk fat globule-EGF factor 8 protein; PGE, prostaglandin E2; PtdSer, phosphatidy­m­serine; TIM, T cell immunoglobulin mucin; TGF, transforming growth factor.

involves interaction with mitochondrial components. Cell surface or intracellular proteins serve as negative regulators, as exemplified by members of the SOCS family. Figure 8-15 illustrates the pathway by which effector response–derived antigens are transported to the cytosol during synthesis, are processed in proteasomes, and become associated with MHC class I molecules for presentation at the cell surface. Effector response chaperones, such as heat shock protein, may contribute to the surface delivery of antigens. The inflammasome is another example of a multiprotein assembly within the cytosol, by which NLRs bring about IL-1 activation. Several of the above-described processes involve proteolytic enzymes, including cathepsins and caspases, and lipidinteracting chaperones. The ubiquitin pathway provides an important mechanism for cytosolic degradation of proteins. In addition, vacuolar H+ATPases contribute to acidification in the different mononuclear phagocytes, especially relevant to osteoclast function. Comparison and further elucidation of the coupling between extracellular and intracellular signaling pathways in macrophages, DCs, and osteoclasts would be of great interest.

EFFERENT PATHWAYS: GENE EXPRESSION AND SECRETION The complex responses of different mononuclear phagocytes to intrinsic and extrinsic stimuli have been defined by microarray studies and, in some cases, by protein and functional analysis. Although the major differentiation pathways (macrophages, immature and mature DCs, and osteoclasts) involve selective, stereotypic changes in gene expression, the extensive heterogeneity and plasticity of phenotypes characterizing these cells in situ have begun to be appreciated only more recently.8,110 Macrophages are known to express numerous nuclear receptors,111 which undergo dynamic changes depending on cellular differentiation and the microenvironment. Exposure to particular cytokines, hormones, and other stimuli, such as microbial antigens and immune complexes, modulates gene expression profoundly and selectively and induces post-­transcriptional and post-translational changes. Through alternative splicing, glycosylation, and poorly characterized protein modifications (e.g., methylation and acetylation of nuclear and cytoplasmic macromolecules), it provides different

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CD200

ITAM

S S

ITIM

Immunoglobulin domain

+

S S

S S

+

– –

TREM1/DAP12

S S

S S

S S

CD47

S S

+ – Charged amino acids

147

S S

S S

S S

S S

– –

CD200R

TREM2/DAP12

SIRPα Figure 8-11  Surface receptors that, singly or as paired receptors, modulate macrophage responses. Illustrated are immunoglobulin superfamily and associated transmembrane molecules using ITAM or ITIM motifs to generate activating or inhibitory signals. DAP12 can associate with a range of other membrane molecules as signaling partner in macrophages, dendritic cells, and natural killer cells.142 Note charged amino acid residues in transmembrane domains. CD200 and CD47, which are broadly expressed in tissues, generate inhibitory signals in macrophages via CD200R and SIRPα.74 In CD200 ko mice, macrophages show spontaneous activation.125 Macrophages themselves are induced by Toll-like receptor stimuli to express CD200 (Mukhopadhyay S: unpublished).

N-terminal repeats with β propeller structure

S S

I-domain I-like domain Short consensus repeats/ Complement control protein repeats

V

CR1

β2

CR3

αX

GPI anchor Cysteine rich domain

S S

S C2 S

αM

Immunoglobulin domain

V

S S

β2

CR4

huCRig(L)

huCRig(S) CD55

CD59

Complement regulators Figure 8-12  Complement receptors and membrane regulators expressed by macrophages. CR1 is broadly expressed by nucleated cells, acting as a “sink” for activated complement; CR3 (CD11b/CD18), a phagocytic receptor for C3b-coated particles, and CR4 (CD11c/CD18) are β2 integrins, which, together with LFA-1 (CD11a/CD18), mediate adhesion of myeloid cells to endothelium and extracellular matrix and migration. huCRIg (L and S) are long and short forms of a newly described complement-binding receptor on Kupffer cells, which mediate uptake of opsonized bacteria.77 CD55143 and CD59144 are Glycosyl phosphoinositide (GPI)-anchored regulators of complement activation.

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Ig-like domain

Mucin-rich region

Lectin-like domain

ITAM ITIM

GPI

ITAM-like

α

α

Fcα/µR

FcγRI

α YY

YY

YY FcαR1

α

FcγRIIa FcγRIIb

ζ ζ ζ Y FcγRIIIa

β

YY FcγRIIIb

β

FcεRI

FcεRII

Figure 8-13  Human Fc receptors. Myeloid cells express a range of classic Fc receptors that initiate a variety of cellular responses, including phagocytosis, antibody-dependent cell-mediated toxicity, antigen presentation, respiratory burst, and release of inflammatory mediators. Immunoglobulin subclasses are bound by extracellular domains; signaling via cytoplasmic ITAM or ITIM is mediated by associated membrane-spanning polypeptides. Activation and inhibitory receptors usually are coexpressed on the cell surface and function in concert, determining the magnitude of effector cell responses. A range of Fc receptor–like molecules (Ig-SF extracellular domains), with similar ITAM/ITIM cytoplasmic motifs, are mainly expressed by B or T/natural killer cells; they may regulate lymphocytic differentiation and responses.145 GPI, Glycosyl phosphoinositide; ITAM, Immunotyrosine activation motif; ITIM, Immunotyrosine inhibition motif.

Figure 8-14  Schematic presentation of phagocytosis and endocytosis. Particulates are taken up by actin-dependent sequential maturation processes, involving membrane fusion and fission, which intersect with the endocytic pathway at several stages. Cytosolic small GTPases (Rabs) determine organelle-specific interactions. Membrane is recycled to the plasma membrane, with processed antigen (see Fig. 8-15). Progressive acidification and delivery of lysosomal hydrolases result in terminal degradation. Compartment membranes express marker proteins such as LAMP1; the pan-macrophage CD68 antigen is associated with late endosomes and lysosomes.

Antigen presentation

Actin polymerization Pseudopod formation/ membrane invagination Membrane recruitment Membrane closure

Partial degradation

­ ononuclear phagocytes with extensive diversity in adaptam tion and function. Table 8-5 provides a partial list of macrophage secretory products; these include low-molecular-weight metabolites (oxygen, nitrogen, and lipid-derived) implicated in inflammation and its resolution112 and in antimicrobial responses; other products include proinflammatory and anti-inflammatory cytokines and neutral proteinases. The cell biology of the secretory pathway in macrophages has only begun to be studied.113 The differential effect of T helper type 1 and T helper type 2 cytokines on nitric oxide production versus its destruction is thought to be relevant to microbicidal mechanisms versus repair.114 The secretory activity of DCs and osteoclasts is less defined except in regard to their specialized functions (lymphocyte activation, bone remodeling).

Early endosome

Rab4, Rab5 and other fusion proteins

Late endosome

Phagosome maturation by interaction with endocytic pathway

Phagolysosome

Rab7, Rab9, cathepsin Lysosome

LAMP1, LAMP2, LAMP3

Table 8-6 shows a classification of characteristic effects induced by prototypic activating and inhibitory stimuli. It is convenient to distinguish the phenotype of mononuclear phagocytes stimulated by an innate stimulus, including exposure to microbial products such as lipopolysaccharide; by a classic immune activating cytokine such as interferon-γ; and by IL-4/IL-13 induction of an alternative activation pathway7,115,116 by IL-4/IL-13.57 Other stereotypic responses are induced by immune complexes that selectively modulate IL-12/IL-10 expression.117 Innate and immune cytokine stimuli are able to potentiate one another. Conversely, deactivating stimuli such as IL-10 and TGFβ64 and glucocorticosteroids118 induce their own distinctive patterns of gene expression. Upregulation of CD163, a hemoglobin-haptoglobin scavenger receptor is a striking

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CD8 CD4 MHC I-peptide

Endocytosed antigens

Plasma membrane Cytosolic antigens

MHC I-peptide

C

A

Endosome

Cytosolic division of endocytosed antigen

Proteasome

Pathogen

B

Antigenic peptides

MIIC/CIIV Golgi

TAP MHC II-I

Antigen peptides

MHC I

MHC I-peptide

MHC I-CLP MHC II-peptide

Endoplasmic reticulum MHC I-I

Figure 8-15  Different antigen-processing pathways for the major histocompatibility complex (MHC) class I and class II molecules. A, MHC class I molecules present peptides that are primarily derived from endogenously synthesized proteins of either self or pathogen origin. These proteins are degraded into peptides by the proteasome and transported through the transporters of antigen-processing (TAP) molecules into the endoplasmic reticulum for loading on MHC class I molecules. B, MHC class II molecules present proteins that enter the cell through the endocytic route. During maturation of MHC class II molecules, they are prevented from binding to endogenous antigens in the endoplasmic reticulum by association with the invariant chain (li). Invariant chain–MHC class II complexes (MHC II-li) move through the Golgi to the MIIC/CIIV compartment where the invariant chain is degraded to class II–associated invariant-chain peptide (CLIP). CLIP is removed from the CLIP–MHC class II (MHC-CLIP) complexes and exchanged for antigenic peptide. C, Dendritic cells can endocytose antigens from other cells and cross-present them to CD8+ cytotoxic T lymphocytes. In most cases, these antigens also are processed into the MHC class II presentation pathway for recognition by CD4+ helper T cells. CIIV, MHC II vesicles; MIIC, MHC II loading compartment. (From Heath WR, Carbone FR: Cross-presentation in viral immunity and self-tolerance. Nat Rev Immunol 1:126-134, 2001.)

example of glucocorticosteroid-enhanced endocytic function.119 These extracellular mediators and poorly defined interactions with surface expressed molecules make the different APCs reciprocally interactive with other immune cells (helper and regulatory CD4 T cells, CD8 T cells, natural killer cells, and Natural Killer T (NKT) cells) and with nonhematopoietic cells, such as fibroblasts, epithelium, and neurons. Induced responses on macrophages include altered MHC class II and costimulatory molecule expression, marker antigens involved in cellular interactions, phagocytosis and antigen presentation, and altered secretion. As a result, different mononuclear phagocytes are able to modulate their interactions with CD4 T lymphocytes, with endothelial and other cell types, with extracellular matrix, and with bone to induce trophic and cytostatic/cidal and catabolic effects. Human inborn errors of defects in macrophage responses to intracellular pathogens such as mycobacteria120 have validated studies on cell activation in the mouse.121 The ­immunosuppressive effects of macrophages in immune tolerance to an allogeneic fetus have been ascribed to induction of indoleamine-2,3-dioxygenase, which catabolizes the essential amino acid, L-tryptophan.122 Macrophage products act mainly locally, but also can have profound systemic effects, regulating metabolic and regulatory responses within the host. These effector programs and products provide targets for pharmacologic intervention.

RELEVANCE TO SELECTED RHEUMATIC DISEASES Although the different mononuclear phagocytes have been addressed as part of a general host homeostatic system, there are good examples in human rheumatic diseases and in animal models of arthritis in which these cells play a role in either the local initiation or effector phase of the pathology. Primary defects in osteoclast ­differentiation and function contribute to osteopetrosis or, if overactive, osteoporosis. I have referred to autoinflammatory syndromes and the newly discovered NLRs. Gout also may fall in this category because uric acid provides a metabolic stimulus for NLR activation. Macrophages play a role in the pathogenesis and complications of osteoarthritis, including the response to foreign implants. DCs and macrophages play a part in the induction and effector mechanisms of autoimmune arthritis, in concert with T lymphocytes and B lymphocytes and their products, immune complexes and complement. The catabolic role of TNF-α, IL-1, neutral proteinases, reactive oxygen radicals, and arachidonate metabolites is well known. Less well appreciated are the trophic interactions of macrophages with fibroblasts, through production of TGF-β, growth and angiogenic factors, and modulation by alternative activation pathways.123 Although animal models may not mimic the natural diseases in humans, more recent examples suggest that

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Table 8-5  Selected Secretion Products of Macrophages Proteins

Product

Comment

Enzymes

Lysozyme Urokinase-type plasminogen activator Collagenase Elastase Metalloproteinases Complement Arginase Angiotensin-converting   enzyme Chitotriosidase

Bulk product Regulated by inflammation Regulated by inflammation Regulated by inflammation Also inhibitors All components and regulators Alternative activation Induced glucocorticoids, granulomas

Inhibitors

Acid hydrolases TIMP

All classes (mainly intracellular)

Chemokines

Many C-C, C-X-C, CX3C (e.g., MCP, RANTES, IL-8)

Initiates acute and long-term recruitment of myeloid   and lymphoid cells

Cytokines

IL-1β, TNF-α, IL-6, IL-10, IL-12, IL-18, IL-23 Type I interferon

Proinflammatory and anti-inflammatory Also antagonists (e.g., IL-1Ra) Autocrine and paracrine amplification

Apolipoproteins

Apolipoprotein E

Local source, bone marrow origin after   adoptive transfer

Growth/differentiation factors

TGF-β

Gaucher’s disease, lysosomal storage disease

Also other family members (activins)   Myeloid growth and differentiation

M-CSF GM-CSF FGF PDGF VEGF

  Fibrosis   Repair   Angiogenesis

Opsonins

Fibronectin,   pentraxin (PTX3)

Also uncharacterized receptor on   macrophages

Soluble receptors

Mannose receptor

Soluble mannose receptor

Cationic peptides

Defensins

Subpopulations and species variation

Lipids

Procoagulant Arachidonate metabolites

Initiation clotting Proinflammatory and anti-inflammatory   mediators

Prostaglandins Leukotrienes Thromboxanes Resolvins Metabolites

Reactive oxygen intermediates Reactive nitrogen intermediates Hemoglobin breakdown (bile pigments) Iron, vitamin B12 binding protein Vitamin D metabolites

Note. For references, see references 152 and 153. FGF, fibroblast growth factor; GM-CSF, granulocyte macrophage colony stimulating factor; M-CSF, M-colony stimulating factor; PDGF, platelet derived growth factor; TIMP, tissue inhibitor of mellaproteinase; VEGF, vascular endothelial growth factor.

APC membrane receptors involved in recognition of modified self and foreign microbial ligands could be relevant to arthritis—in streptococcal rheumatic disease and in exacerbation of recurrent arthritis by zymosan in T cell transgenic mice, acting via Dectin-1, the APC receptor for β-glucans.124 In addition, inhibitory plasma membrane receptor interactions (CD200/CD200R) limit macrophage activation and collagen-induced murine arthritis.73,125 Impaired clearance of apoptotic cells by (uncharacterized) C1q receptors of mononuclear phagocytes may contribute to autoimmune diseases such as lupus.78 Finally, macrophages could contribute to wider connective tissue disorders, such as scleroderma, because they are able to regulate fibroblast and matrix synthesis and turnover through metalloproteinases and TGF-β; dysregulation of these pathways has been neglected as a pathogenetic mechanism in these metabolic diseases.

ISSUES FOR FURTHER INVESTIGATION As we take stock of how increasing knowledge of mononuclear phagocyte biology has affected pathogenesis and therapy of rheumatic diseases, further questions arise regarding basic mechanisms and new selective targets. Treating macrophages, DCs, and osteoclasts as specialized forms of a unitary mononuclear phagocyte family helps to bring out their common and distinctive properties. The selective expression and signaling pathways of pattern recognition receptors by macrophages and DCs are still poorly characterized—the regulation of TLR signaling has already received considerable attention as a possible drug target. Discrimination of microbial and host-derived ligands may account for mimicry and autoantigen cross-reactivity, but mechanisms of regulating homeostatic and tolerogenic responses are still unclear.

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Table 8-6  Immunomodulation of Macrophage Phenotype Stimulus

Category

Markers

Function

Microbial (bacterial)

Innate

Induction of MARCO

Enhanced phagocytosis

Activation

Costimulatory molecules CD200

Antigen presentation Inhibition (CD200R)

Classic activation

Induction of MHC II

Cell-mediated immunity/  delayed-type hypersensitivity

Interferon-γ

Potentiation of innate markers TNF-α iNOS induction NADPH, respiratory burst LGP47 induction Downregulation of MR Modulation of FcR expression Proteosomal composition IL-4/IL-13

IL-10

Alternative activation Upregulation

Deactivation

TGF-β

Enhanced MR Induction of arginase Induction of YM1 FIZZ1 (mouse) Induction of CCL17 (MDC) and CCL22   (TARC) Fusion, giant cell formation CD23 (FcRε)

Proinflammatory Antimicrobial (NO), signaling Host defense, inflammation Association with phagosome/  intracellular pathogen killing Unknown Antigen presentation Endocytosis Humoral immunity Th2-responses Allergy, antiparasitic Immunity Repair/fibrosis

Downregulation of MHC II Downregulation, ­  proinflammatory NO and ROI

Immune complexes

Modified activation

Selective IL-12 downregulation IL-10 induction

Glucocorticoids

Deactivation

CD163 induction Monocyte recruitment   downregulated ACE induction

Anti-inflammatory Homeostatic clearance Hemoglobin/haptoglobin   complexes

Stabilin induction Note. For references, see references 7, 22, and 154. ACE, angiotensin converting enzyme; LGP47, lysosomal glycoprotein; MDC, macrophage derived ­chemokine; MR, mannose receptor; NADPH, nicotinamide adenine inucleotide phosphate-oxidase; iNOS, inducible nitric oxide synthase; ROI, reactive ­oxygen intermediates; TARC, thymus and activation-regulated chemokine.

On the effector side, success with anti-TNF-α monoclonal antibodies suggests that targeting of individual effector molecules can succeed, especially when these are expressed at the cell surface and are proximal in cascade reactions. The role of inhibitory/activating pairs of surface molecules as modulators of APC pathways is unexplored and likely to move center stage. One neglected aspect of differentiation and function for osteoclasts and granuloma macrophages is the mechanism of fusion and the possible functional ­significance of multinuclear giant cell formation.126 Basic knowledge is still lacking and may provide useful insights into the pathogenesis of metabolic bone diseases and the increased perception of links with the immune system, both innate and adaptive. Although powerful tools of mRNA and proteomic analysis and for gene silencing by RNAi inhibition have become available, the heterogeneity and complexity of mononuclear phagocytes in human tissues, especially at early stages of disease, need improved characterization in situ and at different sites. Much remains to be learned concerning trophic processes and repair and their relationship to resolution of inflammation and fibrosis. These involve cell-cell interactions that are still poorly understood, but increasingly amenable to investigation.

Acknowledgments The author thanks Christine Holt for preparation of the manuscript and present and past members of his laboratory for help with illustrations. Work in the Gordon laboratory has been supported by the Medical Research Council, United Kingdom; the Wellcome Trust; the Arthritis Research Campaign; and the British Heart Foundation.

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  66. Beutler B, Hoebe K, Georgel P, et al: Genetic analysis of innate immunity: Identification and function of the TIR adapter proteins. Adv Exp Med Biol 560:29-39, 2005.   67. Doyle SL, O’Neill LA: Toll-like receptors: From the discovery of NFkappaB to new insights into transcriptional regulations in innate immunity. Biochem Pharmacol 72:1102-1113, 2006.   68. Haziot A, Ferrero E, Köntgen F, et al: Resistance to endotoxin shock and reduced dissemination of gram-negative bacteria in CD14-deficient mice. Immunity 4:407-414, 1996.   69. Brown GD: Dectin-1: A signalling non-TLR pattern-recognition receptor. Nat Rev Immunol 6:33-43, 2006.   70. Crocker PR, Paulson JC, Varki A: Siglecs and their roles in the immune system. Nat Rev Immunol 7:255-266, 2007.   71. Taylor PR, Gordon S, Martinez-Pomares L: The mannose receptor: Linking homeostasis and immunity through sugar recognition. Trends Immunol 26:104-110, 2005.   72. Dostert C, Tschopp J: DEteCTINg fungal pathogens. Nat Immunol 8:17-18, 2007.   73. Barclay AN, Wright GJ, Brooke G, et al: CD200 and membrane protein interactions in the control of myeloid cells. Trends Immunol 23:285-290, 2002.   74. Barclay AN, Brown MH: The SIRP family of receptors and immune regulation. Nat Rev Immunol 6:457-464, 2006.   75. Barrington R, Zhang M, Fischer M, et al: The role of complement in inflammation and adaptive immunity. Immunol Rev 180:5-15, 2001.   76. Roozendaal R, Carroll MC: Emerging patterns in complement­mediated pathogen recognition. Cell 125:29-32, 2006.   77. Helmy KY, Katschke KJ Jr, Gorgani NN, et al: CRIg: A macrophage complement receptor required for phagocytosis of circulating pathogens. Cell 124:915-927, 2006.   78. Taylor PR, Carugati A, Fadok VA, et al: A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J Exp Med 192:359-366, 2000.   79. Taylor PR, Pickering MC, Kosco-Vilbois MH, et al: The follicular­ dendritic cell restricted epitope, FDC-M2, is complement C4: Localization of immune complexes in mouse tissues. Eur J Immunol 32:1888-1896, 2002.   80. Daeron M: Fc receptor biology. Annu Rev Immunol 15:203-234, 1997.   81. Daeron M, Lesourne R: Negative signaling in Fc receptor complexes. Adv Immunol 89:39-86, 2006.   82. Ravetch JV, Bolland S: IgG Fc receptors. Annu Rev Immunol 19:275-290, 2001.   83. Hogarth PM: Fc receptors are major mediators of antibody based inflammation in autoimmunity. Curr Opin Immunol 14:798-802, 2002.   84. Florey OJ, Johns M, Esho OO, et al: Antiendothelial cell antibodies mediate enhanced leukocyte adhesion to cytokine-activated endothelial cells through a novel mechanism requiring cooperation between FcγRIIa and CXCR1/2. Blood 109:3881-3889, 2007.   85. Kaneko Y, Nimmerjahn F, Ravetch JV: Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313: 670-673, 2006.   86. Fritz JH, Ferrero RL, Philpott DJ, et al: Nod-like proteins in immunity, inflammation and disease. Nat Immunol 7:1250-1257, 2006.   87. Aderem A, Underhill DM: Mechanisms of phagocytosis in macrophages. Annu Rev Immunol 17:593-623, 1999.   88. Gordon S (ed): Phagocytosis—The Host. Stamford, Conn, JAI Press, 1999.   89. Heinsbroek SEM, Gordon S: Macrophages. In Brown GD, Netea M (eds): Immunology of Fungal Infections, ch2. Dordrecht, The Netherlands,­ Springer, 2007, pp 3-25.   90. Stuart LM, Ezekowitz RA: Phagocytosis: Elegant complexity. Immunity 22:539-550, 2005.   91. May RC, Machesky LM: Phagocytosis and the actin cytoskeleton. J Cell Sci 114:1061-1077, 2001.   92. Caron E, Hall A: Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases. Science 282:1717-1721, 1998.   93. Martens S, Sabel K, Lange R, et al: Mechanisms regulating the positioning of mouse p47 resistance GTPases LRG-47 and IIGP1 on cellular membranes: Retargeting to plasma membrane induced by phagocytosis. J Immunol 173:2594-2606, 2004.   94. MacMicking JD: Immune control of phagosomal bacteria by p47 GTPases. Curr Opin Microbiol 8:74-82, 2005.   95. MacMicking JD, Taylor GA, McKinney JD: Immune control of tuberculosis by IFN-gamma-inducible LRG-47. Science 302: 654-659, 2003.

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  96. Desjardins M: ER-mediated phagocytosis: A new membrane for new functions. Nat Rev Immunol 3:280-291, 2003.   97. Touret N, Paroutis P, Terebiznik M, et al: Quantitative and dynamic assessment of the contribution of the ER to phagosome formation. Cell 123:157-170, 2005.   98. Blander JM, Medzhitov R: Regulation of phagosome maturation by signals from toll-like receptors. Science 304:1014-1018, 2004.   99. Swanson MS: Autophagy: Eating for good health. J Immunol 177:4945-4951, 2006. 100. Deretic V: Autophagy in innate and adaptive immunity. Trends Immunol 26:523-528, 2005. 101. Gutierrez MG, Master SS, Singh SB, et al: Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119:753-766, 2004. 102. Gorvel J-P (ed): Intracellular Pathogens in Membrane Interactions and Vacuole Biogenesis. Amsterdam, Kluwer Academic/Plenum, 2003. 103. Roy CR, Salcedo SP, Gorvel JP: Pathogen-endoplasmic-reticulum interactions: In through the out door. Nat Rev Immunol 6:136-147, 2006. 104. Akira S, Takeda K: Toll-like receptor signalling. Nat Rev Immunol 4:499-511, 2004. 105. Honda K, Taniguchi T: IRFs: Master regulators of signalling by Tolllike receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol 6:644-658, 2006. 106. Greenberg S: Diversity in phagocytic signalling. J Cell Sci 114: 1039-1040, 2001. 107. Nimmerjahn F, Ravetch JV: Fcgamma receptors: Old friends and new family members. Immunity 24:19-28, 2006. 108. Crowley MT, Costello PS, Fitzer-Attas CJ, et al: A critical role for Syk in signal transduction and phagocytosis mediated by Fcgamma receptors on macrophages. J Exp Med 186:1027-1039, 1997. 109. Gross O, Gewies A, Finger K, et al: Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 442:651-656, 2006. 110. Stout RD, Suttles J: Functional plasticity of macrophages: Reversible adaptation to changing microenvironments. J Leukoc Biol 76: 509-513, 2004. 111. Barish GD, Downes M, Alaynick WA, et al: A nuclear receptor atlas: Macrophage activation. Mol Endocrinol 19:2466-2477, 2005. 112. Serhan CN, Brain SD, Buckley CD, et al: Resolution of inflammation: State of the art, definitions and terms. FASEB J 21:325-332, 2007. 113. Murray RZ, Kay JG, Sangermani DG, et al: A role for the phagosome in cytokine secretion. Science 310:1492-1495, 2005. 114. Munder M, Eichmann K, Modolell M: Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: Competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype. J Immunol 160:5347-5354, 1998. 115. Stein M, Keshav S, Harris N, et al: Interleukin 4 potently enhances murine macrophage mannose receptor activity: A marker of alternative immunologic macrophage activation. J Exp Med 176:287-292, 1992. 116. Goerdt S, Orfanos CE: Other functions, other genes: Alternative activation of antigen-presenting cells. Immunity 10:137-142, 1999. 117. Anderson CF, Mosser DM: A novel phenotype for an activated macrophage: The type 2 activated macrophage. J Leukoc Biol 72: 101-106, 2002. 118. Yona S, Gordon S: Inflammation: Glucocorticoids turn the monocyte switch. Immunol Cell Biol 85:81-82, 2007. 119. Kristiansen M, Graverson JH, Jacobsen C, et al: Identification of the haemoglobin scavenger receptor. Nature 409:198-201, 2001. 120. Casanova JL, Abel L: Genetic dissection of immunity to mycobacteria: The human model. Annu Rev Immunol 20:581-620, 2002. 121. Dalton DK, Pitts-Meek S, Keshav S, et al: Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science 259:1739-1742, 1993. 122. Mellor AL, Munn DH: Tryptophan catabolism and regulation of adaptive immunity. J Immunol 170:5809-5813, 2003. 123. Wynn TA: Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol 4:583-594, 2004. 124. Yoshitomi H, Sakaguchi N, Kobayashi K, et al: A role for fungal β-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice. J Exp Med 201:949-960, 2005. 125. Hoek RM, Ruuls SR, Murphy CA, et al: Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290:1768-1771, 2000.

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126. Helming L, Gordon S: Macrophage fusion induced by IL-4 alternative activation is a multistage process involving multiple target molecules. Eur J Immunol 37:33-42, 2007. 127. Lin HH, Faunce DE, Stacey M, et al: The macrophage F4/80 receptor is required for the induction of antigen-specific efferent regulatory T cells in peripheral tolerance. J Exp Med 201:1615-1625, 2005. 128. Hamann J, Vogel B, van Schijndel GM, et al: The seven-span transmembrane receptor CD97 has a cellular ligand (CD55, DAF). J Exp Med 184:1185-1189, 1996. 129. O’Neill LA, Bowie AG: The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7: 353-364, 2007. 130. East L, Isacke CM: The mannose receptor family. Biochim Biophys Acta 1572:364-386, 2002. 131. Bonifaz L, Donnyay D, Mahnke K, et al: Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J Exp Med 196:1627-1638, 2002. 132. Taylor PR, Tsoni SV, Willment JA, et al: Dectin-1 is required for beta-glucan recognition and control of fungal infection. Nat Immunol 8:31-38, 2007. 133. Elomaa O, Kangas M, Sahlberg C, et al: Cloning of a novel bacteria-binding receptor structurally related to scavenger receptors and expressed in a subset of macrophages. Cell 80:603-609, 1995. 134. Mukhopadhyay S, Bowdish D, Gordon S: The scavenger receptor MARCO. Mod Asp Immunobiol 20:15, 2006. 135. Mukhopadhyay S, Chen Y, Sankala M, et al: MARCO, an innate activation marker of macrophages, is a class A scavenger receptor for Neisseria meningitidis. Eur J Immunol 36:940-949, 2006. 136. Mukhopadhyay S, Gordon S: The role of scavenger receptors in pathogen recognition and innate immunity. Immunobiology 209: 39-49, 2004. 137. Mukhopadhyay S, Peiser L, Gordon S: Activation of murine macrophages by Neisseria meningitidis and IFN-gamma in vitro: Distinct roles of class A scavenger and Toll-like pattern recognition receptors in selective modulation of surface phenotype. J Leukoc Biol 76: 577-584, 2004. 138. Febbraio M, Hajjar DP, Silverstein RL: CD36: A class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J Clin Invest 108:785-791, 2001. 139. Peiser L, Mukhopadhyay S, Gordon S: Scavenger receptors in innate immunity. Curr Opin Immunol 14:123-128, 2002.

140. Mukhopadhyay S, Herre J, Brown GD, et al: The potential for Tolllike receptors to collaborate with other innate immune receptors. Immunology 112:521-530, 2004. 141. Savill J, Dransfield I, Gregory C, et al: A blast from the past: Clearance of apoptotic cells regulates immune responses. Nat Rev Immunol 2:965-975, 2002. 142. Turnbull IR, Colonna M: Activating and inhibitory functions of DAP12. Nat Rev Immunol 7:155-161, 2007. 143. White J, Lukacik P, Esser D, et al: Biological activity, membranetargeting modification, and crystallization of soluble human decay accelerating factor expressed in E. coli. Protein Sci 13:2406-2415, 2004. 144. Farkas I, Baranyi L, Ishikawa Y, et al: CD59 blocks not only the insertion of C9 into MAC but inhibits ion channel formation by homologous C5b-8 as well as C5b-9. J Physiol 539:537-545, 2002. 145. Maltais LJ, Lovering RC, Taranin AV, et al: New nomenclature for Fc receptor-like molecules. Nat Immunol 7:431-432, 2006. 146. Heath WR, Carbone FR: Cross-presentation in viral immunity and self-tolerance. Nat Rev Immunol 1:126-134, 2001. 147. Geijtenbeek TB, Engering A, Van Kooyk Y: DC-SIGN, a C-type lectin on dendritic cells that unveils many aspects of dendritic cell biology. J Leukoc Biol 71:921-931, 2002. 148. Kraal G, van der Laan LJ, Elomaa O, et al: The macrophage receptor MARCO. Microbes Infect 2:313-316, 2000. 149. Platt N, Gordon S: Is the class A macrophage scavenger receptor (SR-A) multifunctional? The mouse’s tale. J Clin Invest 108: 649-654, 2001. 150. Taylor PR, Zamze S, Stillion RJ, et al: Development of a specific system for targeting protein to metallophilic macrophages. Proc Natl Acad Sci U S A 101:1963-1968, 2004. 151. van der Laan LJ, Döpp EA, Haworth R, et al: Regulation and functional involvement of macrophage scavenger receptor MARCO in clearance of bacteria in vivo. J Immunol 162:939-947, 1999. 152. MacMicking J, Xie QW, Nathan C: Nitric oxide and macrophage function. Annu Rev Immunol 15:323-350, 1997. 153. Nathan CF: Secretory products of macrophages. J Clin Invest 79:319-326, 1987. 154. Herbert DR, Hölscher C, Mohrs M, et al: Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity 20:623-635, 2004.

9

T Lymphocytes RALPH C. BUDD  •  KAREN A. FORTNER

KEY POINTS T cells develop primarily in the thymus. Thymic selection consists of a positive phase in which T cells must recognize self-MHC molecules, and a negative phase in which thymocytes bearing high-affinity TCRs for self-MHC peptide are deleted through apoptosis. Developing T cells first express the TCR β chain during the late CD4–CD8– stage. Expression of one TCR β chain suppresses further rearrangement and expression of another TCR β chain (allelic exclusion). The TCR β chain pairs briefly with the invariant pre-Tα chain until the actual TCR α chain rearranges at the CD4+CD8+ stage. The α chain is not subject to allelic exclusion, so further rearrangements are possible. T cells emerge from the thymus as naive T cells that are quiescent and, when activated, express low to negligible levels of most cytokines. Once they acquire a memory phenotype (CD44 high, CD45RO+), they can produce high levels of cytokines. Naive T cells can spontaneously undergo homeostatic proliferation to self-MHC peptides in peripheral lymphoid tissues to generate a critical number of T cells. This requires IL-7 and IL-15. The importance of the thymus is underscored by the complete absence of T cells in patients in whom a thymus has failed to develop (e.g., complete DiGeorge syndrome).

The immune system is foremost an organ of defense against infection. The evolutionary pressures that have molded the particular structures of the immune response and promoted a highly diverse repertoire clearly derive from infectious agents. Two very different strategies exist. The more primitive innate immune response (see Chapter 16) uses a limited repertoire of nonpolymorphic receptors that recognize structural motifs that are common to many microorganisms. These include small glycolipids and lipopeptides. The evolutionarily newer adaptive immune response (see Chapter 17) relies on the generation of myriad different receptors that might recognize a wide array of foreign compounds from infectious agents. Whereas the innate immune response is rapid, the adaptive one permits a wider array of responses as well as immune memory. T lymphocyte development constantly confronts the dilemma of combating infection without provoking a response in the host. The trade-off of generating an increasingly varied population of antigen receptors that can recognize a wide spectrum of pathogens is the progressive risk of producing self-reactive lymphocytes that can provoke an autoimmune diathesis. To minimize the possibility of creating self-reactive cells, T lymphocytes are subjected to

a rigorous selection process during development in the thymus. In addition, premature activation of mature T cells is prevented by requiring two signals for activation. Finally, the tremendous expansion of T cells that occurs during the response to an infection is resolved by the active induction of cell death. In perhaps no other organ are the processes of cell proliferation and death more dynamically displayed than by lymphocytes during an immune response. The consequences of inefficient lymphocyte removal at any one of these junctures can be devastating to the health of the organism. This is vividly displayed in both humans and mice, where naturally arising mutations in death receptors such as Fas result in the massive accumulation of lymphocytes and autoimmune sequelae. These are discussed in more detail in Chapter 24. The activation of T lymphocytes yields a variety of effector functions that are pivotal to arresting infectious processes. Cytolytic T cells can kill infected cells through the expression of perforin, which produces holes in cell membranes, or ligands for death receptors such as Fas or tumor necrosis factor-α (TNF-α) receptor. The production of T cell cytokines such as interferon-γ (IFN-γ) can inhibit viral replication, whereas other cytokines such as interleukin (IL)-4 and IL-5 are critical for optimal B cell growth and immunoglobulin production.1,2 However, this same armamentarium can also precipitate damage to host tissues and provoke autoimmune responses. This is most dramatically apparent when T cell infiltration can be observed histologically, such as in the synovium of inflammatory arthritides, pancreatic islets in type 1 diabetes, and the central nervous system in multiple sclerosis. Damage in these cases need not be the direct result of recognition of target tissues by T cells. T cells may be activated elsewhere and then migrate to the tissue and damage innocent bystander cells. T cells may also promote an autoimmune diathesis through the augmentation of B cell responses. In describing the development and function of T lymphocytes in this chapter, emphasis is placed on the various junctures where autoreactive T cells may arise through their inefficient elimination, accidental clonal expansion by means of cross-reactivity between infectious and selfantigens, or nonspecific activation and resulting bystander injury.

T CELL DEVELOPMENT T cells must overcome two stringent hurdles during their development. First, a T cell must successfully rearrange the genes encoding the two chains of the T cell antigen receptor (TCR). Second, a T cell must survive thymic selection, during which self-reactive T cells are eliminated. The ­survival 155

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rate of these two independent selection processes is less than 3%, which is in part necessary to minimize the chance of autoreactive T cells escaping to the periphery. The TCR is an 80- to 90-kD disulfide-linked heterodimer composed of a 48- to 54-kD α chain and a 37- to 42-kD β chain. An alternative TCR composed of γ and δ chains is expressed on 2% to 3% of peripheral blood T cells and is discussed later. The TCR has an extracellular ligand binding pocket and a short cytoplasmic tail that, by itself, cannot signal. Consequently, it is noncovalently associated with as many as five invariant chains of the CD3 complex. Not surprisingly, the structure of the TCR gene is very similar to what was first described for immunoglobulin genes in B cells (see details in Chapter 10). Each overcame the problem of how to encode approximately 10 million different T or B cell specificities within the human genome, which contains only about 30,000 genes. To economically package this diversity, the process of gene rearrangement and splicing evolved using machinery similar to that which already existed to promote gene translocations. The β and δ chain genes of the TCR contain four segments known as the V (variable), D (diversity), J (joining), and C (constant) regions. The α and γ chains are similar but lack the J component. Each of the segments has several family members (approximately 50 to 100 V, 15 D, 6 to 60 J, and 1 to 2 C members). An orderly process occurs during TCR gene rearrangement in which a D segment is spliced adjacent to a J segment, which is subsequently spliced to a V segment. Following transcription, the VDJ sequence is spliced to a C segment to produce a mature TCR messenger RNA. Arithmetically, this random rearrangement of a single chain of the TCR locus can give rise to a minimum of 50V × 15D × 6J × 2C, or about 9000 possible combinations. At the site of each splice, which must occur in-frame to be functional, additional nucleotides not encoded by the genome (so-called N-region nucleotides) can be incorporated, adding further diversity to the rearranging gene. Theoretically, the combinations from the two TCR chains, plus N-region diversity, yield at least 108 possible combinations. The cutting, rearranging, and splicing are directed by specific enzymes. Mutations in the genes for these processes can result in an arrest in lymphocyte development. For example, mutation in the gene encoding a DNA-dependent protein kinase required for receptor gene recombination results in a severe combined immunodeficiency (SCID). TCR gene recombination thus represents the first of the two major hurdles for developing lymphocytes. Because the developing T cell has two copies of each chromosome, there are two chances to successfully rearrange each of the two TCR chains. As soon as successful rearrangement occurs, further β-chain rearrangements on either the same or the other chromosome are suppressed, a process known as allelic exclusion. This limits the chance of dual TCR expression by an individual T cell. The high percentage of T cells that contain rearrangements of both β-chain genes attests to the inefficiency of this complex event. Rearrangement of the α chain occurs later in thymocyte development in a similar fashion, although without apparent allelic exclusion. This can lead to dual TCR expression by a single T cell. Development of T cells occurs within a microenvironment provided by the thymic epithelial stroma. The thymic anlage is formed from embryonic ectoderm and endoderm

and is then colonized by hematopoietic cells, which give rise to dendritic cells, macrophages, and developing T cells.2 The hematopoietic and epithelial components combine to form two histologically defined compartments: the cortex, which contains immature thymocytes, and the medulla, which contains mature thymocytes (Fig. 9-1A). As few as 50 to 100 bone marrow–derived stem cells enter the thymus daily.3 The stages of thymocyte development can be defined by the status of rearrangement and expression of the two genes that encode the α and β chains of the TCR and the expression of CD4 and CD8, proceeding in an orderly fashion: CD4–CD8– → CD4+CD8+ → CD4+CD8– or CD4–CD8+ (Fig. 9-1B). CD4 and CD8 define, respectively, the helper and cytolytic subsets of mature T cells. CD4–CD8– thymocytes can be further subdivided based on their expression of CD25 (the high-affinity IL-2 receptor α chain) and CD44 (the hyaluronate receptor).4 Development proceeds in this order: CD25–CD44+ → CD25+CD44+ → CD25+CD44– → CD25–CD44–. These subpopulations correspond to discrete stages of thymocyte differentiation. CD25–CD44+ cells express low levels of CD4, and their TCR genes are in germline configuration. These cells downregulate CD4 and upregulate CD25 to give rise to CD25+CD44+ thymocytes, which now express surface CD2 and low levels of CD3ε. At the next stage (CD25+CD44–), there is a brief burst of proliferation, followed by upregulation of the recombination-activating enzymes RAG-1 and RAG-2, and the concomitant rearrangement of the genes of the TCR β chain. A small subpopulation of T cells rearranges and expresses a second pair of TCR genes known as γ and δ. Productive TCR β-chain rearrangement results in downregulation of RAG and a second proliferative burst. Loss of CD25 then yields CD25–CD44– thymocytes. The TCR β chain cannot be stably expressed without an α chain. Because the TCR α chain has not yet rearranged, a surrogate invariant TCR pre-α chain is disulfide linked to the β chain.5 When associated with components of the CD3 complex, this allows a low-level surface expression of a pre-TCR and progression to the next developmental stage. Failure to successfully rearrange the TCR β chain results in developmental arrest at the transition from CD25+CD44– to CD25–CD44–. This occurs in RAG-deficient mice as well as in mice and humans with SCID.6,7 A number of signaling molecules are required for early T cell development (Fig. 9-2).8 The IKAROS gene encodes a family of transcription factors required for the development of cells of lymphoid origin. Notch-1, a molecule known to regulate cell fate decisions, is also required at the earliest stage of T cell lineage development.9 Cytokines, including IL-7, promote the survival and expansion of the earliest thymocytes.10 In mice deficient for IL-7, its receptor components IL-7Rα or γc, or the cytokine receptor-associated signaling molecule JAK-3, thymocyte development is inhibited at the CD25–CD44+ stage. In humans, mutations in γc or JAK-3 result in the most frequent form of SCID.11 Pre-TCR signaling is required for the transition from CD25+CD44– to CD25–CD44–. Thus, loss of signaling components, including Lck, SLP-76, and LAT-1, results in a block at this stage of T cell development.12 TCR signals are also required for differentiation of CD4+ or CD8+ cells. Humans deficient in ZAP-70 have CD4+ but not CD8+ T cells in the thymus and periphery.13

PART 2 

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TCR-β + pre-Tα

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CD4-CD8+

CD4+CD8+

CD4-CD8-

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CD44+CD25- CD44+CD25+ CD44-CD25+ CD44-CD25-

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Cortex

Thymus Figure 9-1  Sequence of thymocyte development. A, The earliest thymocyte precursors lack expression of CD4 and CD8 (CD4–CD8–). These can be divided into four subpopulations based on the sequential expression of CD44 and CD25. It is at the CD44–CD25+ stage that the T cell antigen receptor (TCR) β chain rearranges. The scid mutation or deficiencies in the rearrangement enzymes RAG-1 and RAG-2 result in an inability to rearrange the β chain, and maturational arrest occurs at this stage. Those thymocytes that successfully rearrange the β chain express it associated with a surrogate α chain known as pre-Tα. Concomitant with a proliferative burst, development can then progress to the CD4+CD8+ stage in the cortex, where the TCR α chain rearranges and pairs with the β chain to express a mature TCR complex. These cells then undergo thymic positive and negative selection (see Fig. 9-3B). Successful completion of this rigorous selection process results in mature CD4+ or CD8+ T cells in the medulla, which eventually migrate to peripheral lymphoid sites. B, Schematic flow cytometry showing subpopulations of thymocytes defined by CD4 and CD8 expression in their relative proportions.

Corticosubcapsular region

Cortex

CD4-CD8- (5-8%) Lymph. precursor

CD25CD44+

CD25+ CD44+

Ikaros, Notch-1

CD25+ CD44-

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C-M Medulla junction (10-15%) Selection CD4+ CD8+ CD4+ CD8+ CD4(65-85%) CD8+

TCR α-chain rearrangement

IL-7Ra, IL-7, c-kit/gc RAG, Ku-80, Lck/Fyn, ZAP-70/Syk Jak 3, SLP-76, LAT-1, p38 Lck CD45, ZAP-70, Vav

CD25–CD44– cells upregulate expression of CD4 and CD8 to become CD4+CD8+. It is as a CD4+CD8+ thymocyte that the α chain of the TCR rearranges. Unlike the β chain, allelic exclusion of the α chain is not apparent. Rearrangement of the α chain can occur simultaneously on both

(5-10%)

Figure 9-2  Sequence of αβ T cell development in the thymus. The earliest thymocyte precursors lack expression of CD4 and CD8 (CD4– CD8–). These can be divided into four subpopulations based on the sequential expression of CD25 and CD44. At the CD25+CD44– stage, the T cell antigen receptor (TCR) β chain rearranges and associates a surrogate α chain known as pre-Tα. Concomitant with a proliferative burst, thymocytes progress to the CD4+CD8+ stage, rearrange the TCR α chain, and express a mature TCR complex. These cells then undergo thymic positive and negative selection. Those thymocytes that survive this rigorous selection process differentiate into mature CD4+ or CD8+ T cells. Also shown are the various signaling molecules involved at specific stages of thymic development.

chromosomes, and if one attempt is unsuccessful, repeat rearrangements to other Vα segments are possible. Dual TCR expression has been reported in as many as 30% of mature T cells in which the same T cell expresses different α chains paired with the same β chain.14 However, in most

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cases of dual TCR α chains, one is downregulated during positive selection by Lck and Cbl through ubiquitination, endocytosis, and degradation.15 Although the structure of immunoglobulin and TCR are quite similar, they recognize fundamentally different antigens. Immunoglobulins recognize intact antigens in isolation, either soluble or membrane bound, and are often sensitive to the tertiary structure. The TCRαβ recognizes linear stretches of antigen peptide fragments bound within the grooves of either major histocompatibility complex (MHC) class I or class II molecules (Fig. 9-3A). Thymic selection molds the repertoire of emerging TCRs so that they recognize peptides within the groove of selfMHC molecules, ensuring the self-MHC restriction of T cell responses. The MHC structure is described in detail in Chapter 17. Pockets within the MHC groove bind particular residues along the peptide sequence of 7 to 9 amino acids for MHC class I molecules and 9 to 15 amino acids for MHC class II molecules. As a result, depending on the particular MHC molecule, certain amino acids make strong contact with the MHC groove, while others contact the TCR. The contact between the TCR and antigen-MHC has been revealed by crystal structure to be remarkably flat, rather than the deep lock-and-key structure one might imagine.16,17 The TCR axis is tipped about 30 degrees to the long axis of the MHC class I molecule and is slightly more skewed to MHC class II. The affinity of the TCR for antigen-MHC is in the micromolar range.18 This is less than many antibody-antigen affinities and is several logs less than many enzyme-substrate affinities. This has led to the notion that TCR interactions with antigen-MHC are brief and that successful activation of the T cell requires multiple interactions, resulting in a cumulative signal. Once the T cell has successfully rearranged and expressed a TCR in association with the CD3 complex, it encounters the second major hurdle in T cell development: thymic selection. Selection has two phases, positive and negative, and the outcome is based largely on the intensity of TCR signaling in response to interactions with self-MHC peptides expressed on thymic epithelium and dendritic cells. TCR signals that are either too weak (death by neglect) or too intense (negative selection) result in elimination by apoptosis, whereas those with intermediate signaling intensity survive positive selection (Fig. 9-3B). Successful positive selection at the CD4+CD8+ stage is coincident with upregulation of surface TCR, the activation markers CD5 and CD69, and the survival factor Bcl-2.19-21 T cells bearing a TCR that recognizes MHC class I maintain CD8 expression, downregulate CD4, and become CD4–CD8+. T cells expressing a TCR that recognizes MHC class II become CD4+CD8–. Not surprisingly, a variety of signaling molecules activated by TCR engagement are important to thymic selection. Lck, the Ras∏Raf-1∏MEK1∏ERK kinase cascade, the kinase ZAP-70, and the phosphatases CD45 and calcineurin are involved with positive selection.12 Among these, the Ras ∏ERK pathway is particularly important, because dominant negative versions of these molecules can disrupt positive selection. Conversely, an activator of Ras known as GRP1 assists the positive selection of thymocytes expressing weakly selecting signals.22 These molecules are discussed in more detail in the section on TCR signaling. By contrast, although

A

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TCR signal intensity Figure 9-3  T cell antigen receptor (TCR) interaction with the major histocompatibility complex (MHC)–peptide complex. A, Polymorphic residues within the variable region of the α and β chains of the TCR make contact with determinants of the MHC molecule on an antigen presenting cell (APC), as well as with the peptide fragment that sits in the MHC binding groove. B, Diagram illustrating that during thymocyte development, those TCRs conferring either a very low signal intensity (null  selection) or a high signal intensity (negative selection) lead to apoptosis. Only those thymocytes whose TCRs can engage MHC peptides and confer moderate signal intensity survive by positive selection.

a number of molecules may promote negative selection (e.g., the MAP kinases JNK and p38), there appears to be sufficient redundancy so that elimination of any one of these molecules rarely affects the deletion of thymocytes. The few exceptions include CD40, CD40L, and CD30; preservation of at least some thymocytes bearing self-reactive TCR can be observed in mice deficient in these molecules.23-25 The survivors of these two stringent processes of TCR gene rearrangement and thymic selection represent less than 3% of total immature thymocytes. This is reflected by the presence of a high rate of cell death in developing thymocytes. This can be visualized by the measurement of DNA degradation, a hallmark of apoptosis, as shown in ­Figure 9-4. The survivors become either CD4+ helper or CD8+ cytolytic T cells and reside in the thymic medulla for 12 to 14 days before emigrating to the periphery. The decision to become a CD4+ versus a CD8+ T cell involves further developmental signals, including (once again) Notch-1.26 Notch-1 signaling is required for progression to CD8+ but not CD4+

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Figure 9-4  TUNEL assay for nicked DNA in thymocytes undergoing apoptosis. Thymus sections were made from wild-type mice, fixed, and stained by the TUNEL assay. The DNA repair enzyme TdT inserts biotinylated d-uridine triphosphate residues at sites of double-stranded breaks, which is then revealed by avidin horeseradish peroxidase. Sections are shown at magnifications of 100× (top) and 400× (bottom). Apoptotic thymocytes reflect those undergoing negative selection from a T cell antigen receptor (TCR) signal that is either too intense or too weak.

thymocytes. This parallels the observation that long TCR interactions are required for CD4 progression, whereas shorter TCR engagement is required for CD8 progression.27 EXTRATHYMIC T CELL DEVELOPMENT In the absence of a thymus, as in nude (nu/nu) mice, T cell populations in the lymph nodes and spleen are severely reduced and oligoclonal, but they are not absent. Whereas some of this extrathymic T cell development occurs within the liver, a significant amount also occurs in contact with the intestinal epithelium. Intestinal intraepithelial lymphocytes (IELs) have a very different phenotype from thymus-derived T cells. In contrast to the predominance of CD4+ T cells over CD8+ T cells in normal lymph nodes, IELs contain large proportions of CD8+ and CD4– T cells.28 Many CD8+ IELs express only the CD8 α chain as an αα homodimer. γδ T cells also ­constitute a significant portion of IELs. The antigens to which IELs respond are not known, although in humans, some of the γδ IELs recognize the MHC class Ib molecule MICA.29 IELs have a memory CD44+ T cell phenotype (see later) and are cytolytic when freshly isolated. ABNORMALITIES OF HUMAN T CELL DEVELOPMENT Given the vast number of developmental events in T cell development, it is not surprising that a multiplicity of causes can underlie human T cell immunodeficiencies.30,31

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The influence of the thymic stroma on thymocyte ontogeny is underscored in the DiGeorge anomaly, in which development of the pharyngeal pouches is disrupted and the thymic rudiment fails to form.32 This results in the failure of normal T cell development. Less severe T cell deficiencies are associated with a failure to express MHC class I or class II (the “bare lymphocyte syndrome”); these deficiencies are directly involved with interactions required to induce the positive selection of, respectively, CD8+ and CD4+ mature T cells. Metabolic disorders can affect thymocytes more directly. The absence of functional adenosine deaminase and purine nucleoside phosphorylase results in the buildup of metabolic by-products that are toxic to developing T and B lymphocytes. This ultimately produces forms of SCID. The inability to express a number of surface molecules important in TCR and cytokine signaling also has the potential to perturb development. The failure to express TCR-CD3 components (specifically CD3γ and CD3ε), CD18, and IL-2Rγ has been noted among patients who exhibit varying degrees of T cell deficiency or dysfunction.33 All these molecules are involved in the signaling of thymocyte development and survival, and their absence clearly has the potential to alter developmental fate.

PERIPHERAL MIGRATION OF T CELLS The migration of naive T cells to peripheral lymphoid structures or their infiltration into other tissues requires the coordinated regulation of an array of cell adhesion molecules. T cell recirculation is essential for host surveillance and is carefully regulated by a specific array of homing receptors. Entry from the circulation to tissues occurs via two main anatomic sites: the flat endothelium of the blood vessels, or specialized postcapillary venules known as high endothelial venules.34 A three-step model has been proposed for lymphocyte migration: rolling, adhesion, and migration.35 L-selectin expressed by naive T cells binds via lectin domains to carbohydrate moieties of GlyCAM-1 and CD34 (collectively known as peripheral node addressin), which are expressed on endothelial cells, particularly high endothelial venules. The weak binding of CD62L to its ligand mediates a weak adhesion to the vessel wall; this, combined with the force of blood flow, results in rolling of the T cell along the endothelium. The increased cell contact facilitates the interaction of a second adhesion molecule on lymphocytes, the integrin leukocyte function–associated antigen 1 (LFA-1; CD11a/CD18), with its ligands, intercellular adhesion molecule 1 (ICAM-1; CD54) and ICAM-2 (CD102). This results in the arrest of rolling and firm attachment. Migration into the extracellular matrix of tissues may involve additional lymphocyte cell surface molecules such as the hyaluronate receptor (CD44) or integrin α4β7 (CD49d/β7), which binds the mucosal addressin cell adhesion molecule 1 on endothelium of Peyer’s patches and other endothelial cells. Other cytokines known as chemokines may contribute to lymphocyte homing. Chemokines are structurally and functionally related to proteins bearing an affinity for heparan sulfate proteoglycan, and they promote the migration of various cell types.36,37 The chemokines RANTES, MIP-1α, MIP-1β, MCP-1, and IL-8 are produced by a number of cell

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types, including endothelium, activated T cells, and monocytes, and are present at inflammatory sites such as rheumatoid synovium (see also Chapter 65). A more recently recognized capacity of peripheral T cells is homeostatic proliferation.38,39 This reflects the ability of mature T cells to undergo proliferation in lymphopenic environments. Experimentally, this is studied by the adoptive transfer of T cells into RAG-deficient or irradiated mice. However, a similar phenomenon occurs in normal newborn mice.40 Newborn mice do not acquire adult levels of T cells until day 7 in lymph nodes and day 15 in the spleen. Because this expansion of T cells requires the presence of self-MHC peptides, as well as IL-7 and IL-15, this area may be of considerable interest in future studies of autoimmune mechanisms. In this regard, it is notable that one of the standard models of autoimmunity is day 3 thymectomy, which results in lymphopenia.41,42 It will be useful to determine the possible contribution of homeostatic proliferation to this syndrome.

T CELL RECEPTORS AND TYROSINE KINASES TCRs αβ and γδ have very short cytoplasmic domains and, by themselves, are unable to transduce signals.43,44 The molecules of the noncovalently associated CD3 complex couple the TCR to intracellular signaling machinery (Fig. 9-5). The CD3 complex contains nonpolymorphic members known as CD3ε, CD3γ, CD3δ, as well as ζ and η chains that are alternatively spliced forms of the same gene and are not genetically linked to the CD3 complex. Although the functional stoichiometry of the TCR complex is not completely defined, current data indicate that each TCR heterodimer is associated with three dimers: CD3εγ, CD3εδ, and ζζ or ζ.45 CD3ε, γ, and δ have an immunoglobulin-like extracellular domain, a transmembrane region, and a modest cytoplasmic domain, whereas ζ contains a longer cytoplasmic tail. The transmembrane domains of ζ and the CD3 chains contain a negatively charged residue that interacts with positively charged amino acids in the transmembrane domain of the TCR. None of the proteins in the TCR complex has intrinsic enzymatic activity. Instead, the cytoplasmic domains of the invariant CD3 chains contain conserved activation domains that are required for coupling the TCR to intracellular signaling molecules. These immunoreceptor tyrosine-based activation motifs (ITAMS) contain a minimal functional consensus sequence of paired tyrosines (Y) and leucines (L): (D/E)XXYXXL(X)6-8YXXL.46 ITAMs are substrates for cytoplasmic protein tyrosine kinases (PTKs) and, upon phosphorylation, recruit additional molecules to the TCR complex.47 Each ζ chain contains three ITAMs, whereas there is one in each of the CD3ε, γ, and δ chains. Thus, each TCR complex can contain 10 ITAMs.

ACTIVATION OF T CELLS T cell activation initiates intracellular signaling cascades, which activate transcription factors and induce new gene transcription. This ultimately results in proliferation, effector function, or death, depending on the developmental stage of the cell. To guard against premature or excessive activation, T cells require two independent signals for full activation. Signal 1 is an antigen-specific signal provided by the binding of the TCR to antigenic peptide complexed with MHC. Signal 2 is mediated by either cytokines or the engagement of costimulatory molecules such as B7-1 (CD80) and B7-2 (CD86) on the antigen presenting cell (APC).

TCR

Nck Raf-1

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IκB α/β p50/p65

NFAT

JNK Fos

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IL-2

Figure 9-5  T cell antigen receptor (TCR) signal pathways. Diagram showing the principal signal pathways resulting from TCR activation and how they impinge on the regulatory region of the interleukin-2 (IL-2) gene. See text for details.

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Activation of PTKs is one of the earliest signaling events following TCR stimulation. Four families of PTKs are known to be involved in TCR signaling: Src, Csk, Tec, and Syk.48 The Src family members Lck and Fyn(T) have a central role in TCR signaling and are expressed exclusively in lymphoid cells. Src PTKs contain multiple structural domains, including (1) N-terminal myristylation and palmitylation sites, which allow association with the plasma membrane; (2) a Src homology (SH) 3 domain, which associates with proline-rich sequences; (3) an SH2 domain that binds phosphotyrosine-containing proteins; and (4) a carboxy-terminal negative regulatory site. Their catalytic activity is regulated by the balance between the actions of kinases and phosphatases. Activity is repressed by phosphorylation of a conserved carboxy-terminal tyrosine, and dephosphorylation by the phosphatase CD45 is critical for the initiation of TCR-mediated signal transduction. In addition, autophosphorylation of other tyrosines within the kinase domain enhances catalytic activity. Lck is physically and functionally associated with CD4 and CD8. Fifty percent to 90% of total Lck molecules are associated with CD4, and 10% to 25% with CD8. CD4 and CD8 physically associate with the TCR-CD3 complex during antigen stimulation as a result of their interaction with MHC class II and class I molecules and thus enhance TCR-mediated signals by recruiting Lck to the TCR complex. Lck phosphorylates the CD3 chains, TCRζ, ZAP-70, phospholipase C-γ1 (PLCγ1), Vav, and Shc. Fyn binds TCRζ and CD3ε, and although their substrates are less well defined, T cells lacking Fyn have diminished response to TCR signals.49,50 In addition, the SH2 and SH3 domains of Src PTKs can mediate their association with phosphotyrosine- and proline-containing molecules, respectively. Somewhat less is known about the Csk and Tec PTKs. Csk negatively regulates TCR signaling by phosphorylating the carboxy-terminal tyrosine of Lck and Fyn. Dephosphorylation of this negative regulatory tyrosine is mediated by the transmembrane tyrosine phosphatase CD45. CD45 activity is essential for TCR signaling, and CD45-deficient T cells fail to activate by TCR stimulation.51 The Tec family member Itk is preferentially expressed in T cells. T cells from Itk-deficient mice have a diminished response to TCR stimulation.52 The mechanism by which Itk regulates TCR signaling has not been determined, although recent studies have shown that Itk is an important component of the pathway leading to increased intracellular calcium ions (Ca2+). Phosphorylation of the ITAMs on the CD3 complex recruits the Syk kinase family member ZAP-70 by its tandem SH2 domains. ZAP-70 is expressed exclusively in T cells and is required for TCR signaling. Like the Src family PTKs, ZAP-70 is positively and negatively regulated by its phosphorylation. Phosphorylation of tyrosine 493 by Lck activates ZAP-70 kinase activity. In murine thymocytes and ex vivo T cells, inactive nonphosphorylated ZAP-70 is constitutively associated with the basally phosphorylated TCRζ chain via the SH2 domain of ZAP-70.53 TCR stimulation is required for ZAP-70 phosphorylation and activation. The recruitment of ZAP-70 to the TCR complex facilitates the tyrosine phosphorylation and activation of ZAP-70 by Lck. These data suggest that the receptor signaling complex in these cells is primed, but an initiating event is still required

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to activate ZAP-70. ZAP-70 can also act as a scaffold, binding to other proteins via its SH2 domain and phosphorylated tyrosines. ZAP-70 interacts with Lck, Ras-GAP, Vav, the phosphatase SHP-1, and Cbl, and these proteins may regulate ZAP-70 activity or serve as substrates. ZAP-70 phosphorylates tyrosine residues in a number of molecules, including PLCγ1 and the adapter proteins SLP-76 and LAT (see the next section). ADAPTER PROTEINS Phosphorylation of tyrosine residues in ITAMs and PTKs following TCR stimulation creates docking sites for adapter proteins. Adapter proteins contain no known enzymatic or transcriptional activities but mediate protein-protein interactions or protein-lipid interactions.54 They function to bring proteins in proximity to their substrates and regulators, as well as to sequester signaling molecules to specific subcellular locations. The protein complexes formed can function as either positive or negative regulators of TCR signaling, depending on the molecules they contain. Two critical adapter proteins for linking proximal and distal TCR signaling events are SH2-domain-containing leukocyte protein of 76 kD (SLP-76) and Linker for activation of T cells (LAT) (see Fig. 9-5). Loss of these adapter proteins has profound consequences for T cell development. Mice deficient for LAT or SLP-76 manifest a block in T cell development at the CD4–CD8– CD25+CD44+ stage. LAT is constitutively localized to lipid rafts and, following TCR stimulation, is phosphorylated on tyrosine residues by ZAP-70. Phosphorylated LAT then recruits SH2-domaincontaining proteins, including PLCγ1, the p85 subunit of phosphoinositide-3 kinase, IL-2 inducible kinase (Itk), and the adapters Grb2 and Gads. Because the SH3 domain of Gads is constitutively associated with SLP-76, this brings SLP-76 to the complex, where it is phosphorylated by ZAP-70. SLP-76 contains three protein binding motifs: tyrosine phosphorylation sites, a proline-rich region,and an SH2 domain. The N-terminus of SLP-76 contains tyrosine residues that associate with the SH2 domains of Vav, the adapter Nck, and Itk. Vav is a 95-kD protein that acts as a guanine nucleotide exchange factor for the Rho/Rac/cdc42 family of small G proteins. Through its association with Vav and Nck, SLP-76 links TCR signals to Rac/Rho GTPases and the actin cytoskeleton. The association of phosphorylated LAT with PLCγ1 and Grb2 couples the TCR signaling to both the Ras and the phosphatidylinositol pathways (see later). Grb2 contains a central SH2 domain flanked by two SH3 domains and associates with the proline-rich regions of Sos, a guanine nucleotide exchange factor for Ras. Recruitment of Grb2 to the receptor brings Sos to the plasma membrane, where it activates Ras. The complex of LAT, SLP-76/Gads, PLCγ1, and associated molecules results in the full activation of PLCγ1 and activation of Ras. The use of statins as immunomodulators has generated interest. Although statins have been prescribed extensively as cholesterol-lowering agents, recent studies suggest that they may have a role in the treatment of autoimmune diseases. Modulation of post-translational protein prenylation appears to be a key mechanism by which statins confer this function.55

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In addition to acting as positive regulators for TCR signaling, adapters can mediate negative regulation. As described previously, the activity of the Src family of kinases is regulated by the interaction of kinases (Csk) and phosphatases (CD45) specific for inhibitory C-terminal phosphotyrosine, which is determined by the subcellular localization of these regulatory molecules. The interactions that control the localization of CD45 are currently being analyzed. The localization of Csk is dependent on an adapter known as phosphoprotein, associated with glycosphingolipid-enriched microdomains (PAG or Csk binding protein [CBP]). Collectively, the data suggest the following model: PAG is constitutively associated with membrane lipid rafts. In resting cells, PAG or CBP is tyrosine-phosphorylated, which mediates the association with the SH2 domains of Csk. This colocalizes Csk with Src family kinases in lipid rafts and controls the basal activation of Src family PTK through the phosphorylation of inhibitory C-terminal tyrosine residues. Upon TCR stimulation, PAG becomes dephosphorylated, resulting in the dissociation of Csk. Loss of Csk from the rafts reverses the inhibition of Src PTK activity and permits the initiation of downstream signaling. A second mechanism by which adapter proteins can negatively regulate TCR stability is through the regulation of protein stability. c-Cbl and Cbl-b are members of a conserved family of proteins that contains a highly conserved N-terminal region containing a tyrosine kinase–binding and RING-finger domains. The c-Cbl RING finger domain binds the E2 ubiquitin-conjugating enzymes. Active E2 enzymes are brought into proximity with tyrosine kinase–binding proteins, resulting in their ubiquitination and degradation by the proteasome complex. Syk and ZAP-70 associate with c-Cbl, whereas Vav, ZAP-70, Lck, PLCγ1, and the p85 subunit of PI3K associate with Cbl-b. DOWNSTREAM TRANSCRIPTION FACTORS The previously mentioned signaling events couple TCR stimulation to downstream pathways, culminating in the changes in gene transcription that are required for proliferation and effector function (see Fig. 9-5). One of the bestcharacterized genes induced following T cell activation is the T cell growth factor IL-2. Transcription of the IL-2 gene is regulated in part by the transcription factors activator protein-1 (AP-1), nuclear factor of activated T cells (NFAT), and nuclear factor κB (NFκB), all of which are activated following TCR stimulation. Proximal signaling events lead to the activation of Ras and PLCγ.56,57 Ras initiates a cascade of kinases, including Raf-1, MEK, and the MAP kinase ERK, which leads to the production of the transcription factor Fos. Ligation of the costimulatory molecule CD28 results in the activation of another member of the MAP kinase family, c-Jun N-terminal kinase (JNK), and phosphorylation of the transcription factor c-Jun. c-Jun and Fos associate to form AP-1. PLCγ hydrolyzes membrane inositol phospholipids to generate phosphoinositide second messengers, including inositol 1,4,5 triphosphate (IP3) and diacylglycerol. IP3 stimulates the mobilization of calcium from intracellular stores. Diacylglycerol activates protein kinase C (especially PKCθ in T cells) and, along with CARMA, connects with the NFκB pathway.57

Increased intracellular calcium is central to many forms of cellular activation. Calcium activates the ­ calcium­calmodulin–dependent serine phosphatase calcineurin, which dephosphorylates NFAT. 58 Dephosphorylated NFAT translocates to the nucleus and, together with AP-1, forms a trimolecular transcription factor for the IL-2 gene. The immunosuppressive agents cyclosporine-A and FK-506 specifically inhibit the calcium-dependent activation of calcineurin, thereby blocking the activation of NFAT and the transcription of NFAT-dependent cytokines such as IL-2, IL-3, IL-4, and granulocyte-macrophage colony-stimulating factor. Recently, it has been appreciated that differences in the amplitude and duration of calcium signals mediate different functional outcomes. Although high spikes of calcium are easily measured in lymphocytes during the first 10 minutes following antigen stimulation, sustained lowlevel calcium spikes over a few hours are necessary for full activation.59 These more subtle calcium fluxes appear to be controlled by cyclic ADP-ribose and ryanodine receptors.60 Selective inhibitors exist for these molecules, leading to the potential for new, specific blockers of T cell activation. A surprising discovery in the field of T cell activation was the observation that caspase activity, particularly caspase-8, is required to initiate T cell proliferation and activation of NFκB.61-63 Previously, the role of caspases had been confined to apoptosis. However, it is now appreciated that following TCR ligation, caspase-8 is activated and forms a complex that includes the NFκB adapter proteins CARMA1, Bcl-10, and MALT1.64 How T cells manage to activate a sufficient level of caspase to promote proliferation, but not so much as to precipitate cell death, remains a mystery. However, this means that inhibition of caspase activity might be therapeutic in preventing T cell activation. COSTIMULATION Signal 2 is mediated either by growth factor cytokines or through a costimulatory molecule; the prototype of the latter is CD28 interacting with B7-1 (CD80) or B7-2 (CD86). CD28 is a disulfide-linked homodimer constitutively expressed on the surface of T cells.65 Virtually all murine T cells express CD28, whereas in human T cells, nearly all CD4+ and 50% of CD8+ cells express CD28. The CD28– subset of T cells appears to represent a population that has undergone chronic activation and can manifest suppressive activity.66 Increased levels of CD28– T cells have been reported in several inflammatory and infectious conditions, including Wegener’s granulomatosis, cytomegalovirus, and mononucleosis.67-69 The cytoplasmic domain of CD28 has no known enzymatic activity, but it does contain one SH2 and two SH3 binding sites. CD28 interacts with PI3-kinase and GRB2 and promotes JNK activation, as noted earlier. CD28 ligation alone does not transmit a proliferative response to T cells; however, in conjunction with TCR engagement, it augments IL-2 production at the level of both transcription and translation. It also increases the production of other cytokines, including IL-4, IL-5, IL-13, IFN-γ, and TNF-α, as well as the chemokines IL-8 and RANTES.70 The ligands for CD28, CD80 (B7-1), and CD86 (B7-2) are expressed in a restricted distribution on B cells, dendritic cells, monocytes, and activated T cells. CD80 and CD86 have similar structures but share only 25% amino acid

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homology. They each contain rather short cytoplasmic tails that may signal directly, and they bind to CD28 with different avidities. IMMUNOLOGIC SYNAPSE Antigen-specific interaction between the T cell and the APC results in the formation of a specialized contact region called the immunologic synapse (Fig. 9-6) or supramolecular activation cluster.71 Synapse formation is an active, dynamic process that requires a specific antigen to drive synapse formation; TCR-MHC interaction alone is not sufficient. The synapse also overcomes the obstacles to close T cell–APC contact involving short molecules (e.g., TCR, MHC, CD4, CD8) caused by interactions recruiting long molecules (ICAM-1, LFA-1, CD45). Two stages of assembly have been described. During the nascent stage, cell adhesion molecules—such as ICAM-1 on APCs and LFA-1 on T cells—make contact in a central zone, surrounded by an annulus of close contact between MHC and TCR.71 Within minutes, the engaged TCR migrates to the central area, resulting in a mature synapse in which the initial relationships are reversed—the central area now contains TCR, CD2, CD28, and CD4 and is enriched for Lck, Fyn, and PKCθ.72,73 Surrounding the central domain is a peripheral ring that contains CD45, LFA-1, and associated talin. T cell activation leads to compartmentalization of activated TCR and TCR signaling molecules to plasma membrane

0.5

1.5

microdomains called rafts.74,75 Rafts are composed primarily of glycosphingolipids and cholesterol and are enriched in signaling molecules, actin, and actin-binding proteins.76,77 Src family kinases, Ras-like G proteins, LAT, and phosphatidylinositol-anchored membrane proteins have all been shown to localize to raft domains. During T cell stimulation, activation of many tyrosine kinases precedes formation of the immunologic synapse.78,79 After TCR ligation, rafts become enriched for Vav, Shc, phosphorylated ζ, PLCγ1, and ZAP-70.75,80 TCR engagement induces rapid reorganization of the T cell cytoskeleton toward the T cell–APC junction.81 This results in the redistribution of surface molecules and the release of cytokines and cytotoxic mediators toward the site of the T cell stimulus.82 Among the known molecules connecting signaling and structural proteins is the Wiskott-Aldrich syndrome protein (WASp). WASp contains a GTPase binding domain that mediates binding to activated cdc42.83 This promotes the coupling of TCR engagement to actin polymerization. Full T cell activation requires engagement of a minimum of about 100 to 200 MHC-peptide molecules on an APC, which can serially stimulate 2000 to 8000 TCRs. It has been estimated that naive T cells also require a sustained signal for 15 to 20 hours to commit to proliferation.84 T cells face a number of obstacles to achieving full activation, including the small size of the TCR and MHC molecules compared with other cell surface molecules, the low affinity of TCR for the MHC-peptide complex, and the low number

Time (minutes) 5

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Figure 9-6  Formation of the immunologic synapse. A, Contact areas of T cells over time, indicated as dark gray against a light background. B, Images containing Oregon green Ek-antigen (mouse cytochrome peptide 88-103) and Cy5 intercellular adhesion molecule 1 (ICAM-1). C, Density of accumulated Ek-MCC88-103. D, Total accumulated Ek-MCC88-103. E, Density of accumulated ICAM-1. (From Grakoui A, et al: The immunological synapse: A molecular machine controlling T cell activation. Science 285:221-227, 1999.)

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of MHC molecules present on the APC that contain antigenic peptide.85 The immunologic synapse may provide the mechanism for overcoming these barriers and achieving the duration of TCR stimulation necessary to commit the cell to proliferation.71 The spatial organization of the synapse juxtaposes the membranes of the APC and T cell, facilitating the interaction of the TCR and MHC-peptide complex. The available MHC-peptide complexes and TCRs are concentrated at the site of contact via actin cytoskeletonmediated transport. The multistep process of mature synapse formation may also enable the T cell to discriminate between the potential antigen-containing MHC-peptide complexes it encounters on the APC surface. Recently, it has been shown that costimulatory signals may contribute to synapse formation by initiating the transport of membrane rafts containing the kinases and adapter molecules required for TCR signaling to the site of contact.86,87 Although it has been appreciated for some time that chronic infection can lead to an unresponsive state, or “exhausted” T cells, the molecular explanation was un­­ known. More recently, it was observed that chronically activated CD8+ T cells contain more mRNA encoding the inhibitory receptor PD1 (programmed death 1) that acutely activates CD8+ T cells.88 In parallel, one of the ligands for PD1, PDL1, was highly expressed by chronically infected splenocytes. Treatment of mice with a blocking antibody to PDL1 caused virus-specific CD8+ T cells to undergo marked expansion. The fact that many tumors also express PDL1 enhances the interest in reversing the suppression of immune responses during infection and tumorigenesis. The fact that PD1-deficient mice develop spontaneous autoimmunity leads to the possibility of manipulating PD1 for therapeutic purposes.89 TOLERANCE AND CONTROL OF AUTOREACTIVE T CELLS The immune system is constantly confronted by the problem of how to ensure that T cells are activated only when there is a true need to respond to a foreign pathogen and not merely a self-component. This is not a trivial point because, like all biologic filters, the thymus is not 100% efficient, and not all self-reactive T cells are eliminated. Hence, a variety of failsafe mechanisms are engaged to suppress the premature clonal expansion of these errant T cells. Part of nature’s ingenious solution was to require two distinct signals from separate molecules to be coordinately triggered in order for T cell activation and proliferation to proceed. If only one signal is received, the T cell will not proliferate and will actually enter a nonresponsive state known as tolerance or anergy. The anergy that results from the absence of a CD28 costimulatory signal manifests at a signal level by failure to fully couple the TCR signal to the Ras-MAP kinase pathway and consequent AP-1 transcriptional activity. An additional method of provoking an incomplete TCR signal and unresponsiveness is to make amino acid substitutions in the recognized peptide antigen. These so-called altered peptide ligands cause a suboptimal phosphorylation of TCRζ and consequent inefficient recruitment of ZAP-70.90 Following the discovery of CD28 as a costimulatory molecule, a related structure known as CTLA-4 was found to

bind to CD80 and CD86 with a 20-fold higher affinity than CD28. Unlike CD28, CTLA-4 is expressed only transiently following T cell activation and confers an inhibitory signal for T cell proliferation.91 The mechanism by which this occurs is not clearly defined, although two reports suggested that the phosphatase SHP-2 may associate with the cytoplasmic tail of CTLA-4.86,92 A more recent report showed that CTLA-4 signaling keeps CD3ζ out of the immunologic synapse and thus diminishes the density of surface TCR and its consequent signaling.93 In this capacity, CTLA-4 functions to limit T cell clonal expansion induced by CD28. The consequences of the loss of this negative regulation are striking. The genetic deletion of the ctla-4 gene in mice results in enormous uncontrolled T cell expansion and an autoimmune diathesis.94,95 Chronic exposure to certain inflammatory cytokines, most notably TNF-α, can also induce anergy. It has been known for some time that T cells from rheumatoid synovium manifest profound deficiencies of proliferation and cytokine production.96,97 Because TNF-α is one of the major cytokines detectable in rheumatoid synovial fluid, it was soon recognized that chronic exposure of T cell clones to TNF-α for 10 to 12 days suppresses proliferative and cytokine responses to antigen by as much as 70%.98 Further, a single administration of anti–TNF-α receptor monoclonal antibody to patients with rheumatoid arthritis rapidly restores the response of peripheral T cells to mitogens and recall antigens.98 Similar observations have been made in TCR transgenic mice following TNF-α exposure.99 The observation that chronic TNF-α exposure inhibits calcium responses following TCR ligation99 supports the view that TNF-α may uncouple TCR signaling. It is conceivable that other members of the TNF-α family may invoke similar T cell anergy. An additional negative regulator for T cells is B lymphocyte­–induced maturation protein 1 (Blimp-1), previously thought to be expressed only in B lymphocytes. Blimp-1–deficient mice manifest augmented levels of peripheral effector T cells and develop severe colitis as early as 6 weeks of age.100 Blimp-1 mRNA expression increases with TCR stimulation, and Blimp-1–deficient T cells proliferate more and produce more IL-2 and IFN-γ following activation.100 Another layer of regulation involves the long-held theoretical concept that a subset of T cells might exist that can actively suppress the immune response. In the past, clear demonstration of these cells was elusive, as was their acceptance by the immunology community. More recently, however, a phenotypically defined subpopulation of CD4+CD25+ regulatory T cells has been identified with an ability to inhibit antigen-induced proliferation.101 This subset is expressed in the periphery at a low frequency and appears to be thymic dependent. The latter point may be of interest, because it suggests that the absence of regulatory T cells following day 3 thymectomy may be involved with the subsequent development of autoimmune disease in these animals.102 Indeed, diminished levels of CD4+CD25+ regulatory T cells have been observed in other autoimmune syndromes, and the transfer of regulatory T cells to autoimmune mice has resulted in some alleviation of symptoms. At present, the lineage of CD4+CD25+ cells is unclear, as is their exact mechanism of suppression. The production of

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transforming growth factor-β (TGF-β) and IL-10 appears to be critical to the suppressive activity of these cells.103 CD4+CD25+ cells express Foxp3, a regulatory gene that, upon transfection into naive T cells, confers the functional characteristics of regulatory T cells.104 More recently, an alternative marker appears to be low levels of surface IL-7 receptor α chain (CD127).105 This is an active area of research because of the potential therapeutic implications for autoimmune diseases and the possible role in generating IL-17–producing CD4+ T cells (Th17; see later).106

SUBSETS AND FUNCTIONS OF PERIPHERAL T CELLS CD4 HELPER AND CD8 CYTOLYTIC T CELLS αβ T cells can be divided into two main subsets based on their recognition of peptides presented by MHC class I or class II molecules and their respective expression of CD8 or CD4. CD4+ and CD8+ T cells have different functions and recognize antigens derived from different cellular compartments. The peptides presented by MHC class I molecules are produced by the proteasomes107,108 and can be derived from either self-proteins or intracellular foreign proteins, as might occur during viral infection. MHC class II–bound peptides are derived largely from extracellular infectious agents or self–cell surface proteins that have been engulfed and degraded in the lysosomal complex. CD4+ T cells express a variety of cytokines and cell surface molecules that are important to B cell proliferation, immunoglobulin production, and CD8+ T cell function. After antigen stimulation, CD4+ T cells differentiate into two major classes of effector T cells based on their cytokine profiles: T helper 1 (Th1) and T helper 2 (Th2).109 The CD4 molecule is structurally related to immunoglobulins and has an affinity for nonpolymorphic residues on the MHC class II molecule. In this capacity, CD4 presumably increases the efficiency with which CD4+ T cells recognize antigen in the context of class II molecules, which are restricted in their expression to B cells, macrophages, dendritic cells, and a few other tissues during states of inflammation. In addition, the cytoplasmic tail of CD4 binds to Lck and promotes signaling by the TCR, as described earlier. However, ligation of CD4 before engagement of the TCR renders the T cell susceptible to apoptosis on subsequent engagement of the TCR.110 This is clinically important in human immunodeficiency virus (HIV) infections in which the gp120 molecule of HIV binds to CD4 and primes the T cell to undergo cell death when later triggered by the TCR.111 Accelerated ­apoptosis of CD4+ T cells has been demonstrated in patients with acquired immunodeficiency syndrome (AIDS).112 CD8+ T cells are very efficient killers of pathogen-infected cells. Given the ubiquitous expression of class I molecules, mature cytolytic T cells can recognize viral infections in a wide array of cells, in contrast to the more restricted distribution of class II molecules and their recognition by CD4+ T cells. Cytolytic T cells induce lysis of target cells through the production of perforin, which induces holes in cell membranes, and through the expression of FasL and TNF-α, which induce apoptosis. In this capacity, cytolytic T cells kill virally infected target cells in an attempt to restrict the spread of infection. Similar to CD4, CD8 manifests an

165

a­ ffinity for MHC class I molecules, enhances the signaling of cytolytic T cells, and also binds Lck by its cytoplasmic tail. T CELLS IN THE INNATE IMMUNE RESPONSE In addition to the broad array of antigens recognized by αβ T cells, there is growing appreciation that the immune system contains small subpopulations of specialized T cells that may recognize conserved structures that are uniquely expressed either by prokaryotic pathogens or on stressed host cells. These are discussed in detail in Chapter 8. Such common antigenic motifs include bacterial lipoproteins recognized by Toll-like receptor (TLR)-2 and TLR-4, double-stranded RNA from RNA viruses that binds TLR-3, methylated cytosine residues in bacterial CpG sequences, or anti-DNA–DNA complexes that bind to TLR-9.113 TLR expressed by APCs can trigger the release of cytokines and costimulatory molecules for T cells. Another family of molecules that likely binds bacterial components is CD1. CD1 structurally resembles MHC class I but contains a deeper and more hydrophobic binding pocket that can accommodate certain lipopeptides and glycolipids.114 By using such molecular strategies to focus on common and nonpolymorphic molecules, the immune system may be able to respond quickly during the early phase of infection. This response is part of innate immunity. Even though it may represent the remnants of an evolutionarily primitive immune response, it provides a vital early-defense system. Among T cells, this function is provided by γδ and natural killer (NK) T cells. γδ T Cells Among immunology’s oddities, the γδ T cell is one of the oddest. Study of these cells was precipitated by the serendipitous discovery of rearranged genes while searching for the TCR α-chain gene, rather than by a preexisting knowledge of their presence and biologic function.115 Structurally, the γ-chain locus contains at least 14 Vγ region genes, of which 6 are pseudogenes, each capable of rearranging to any of 5 Jγ regions and 2 Cγ regions. The δ-chain genes are nested within the α-chain gene locus between Vα and Jα. There are about six Vδ regions, two Dδ and two Jδ regions, and a single Cδ gene. Transcription of rearranged γ and δ genes begins before that of αβ genes and is apparent on days 15 to 17 of mouse thymus development, after which it declines in the adult thymus. In addition to the ordered appearance of TCR γδ before TCR αβ, there is a highly ordered expression of γ and δ V-region genes during early thymic development. This results in successive waves of oligoclonal γδ T cells migrating to the periphery. The reason for this remarkable regimentation remains unclear. γδ T cells manifest a number of differences from αβ T cells. For instance, γδ T cells are often anatomically sequestered to epithelial barriers or sites of inflammation,116 and they frequently manifest cytotoxicity toward a broad array of targets.117 In contrast to αβ T cells, γδ T cells can respond to antigen directly, without evidence of MHC restriction,118 or, conversely, they can react to MHC molecules without peptide.119 Human γδ T cell clones, particularly those expressing the Vδ2 gene and derived from peripheral blood of normal

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individuals or synovial fluid of rheumatoid arthritis patients, frequently react to mycobacterial extracts.120 Although a few of these Vδ2 clones respond to a heat shock protein, the major stimulatory components were recently identified as phosphate-containing nonpeptide molecules such as nucleotide triphosphates,121 prenyl pyrophosphate,122,123 and alkylamines.124 These molecules are, respectively, subunits in DNA and RNA, substrates in lipid metabolism for the synthesis of farnesyl pyrophosphate, and products of pathogenic organisms. In mammalian cells, farnesyl addition is a critical modification for targeting certain signaling molecules to the cell membrane, such as Ras. This process appears to be critical to cell transformation. These phosphate-containing nonpeptides can be found in both microbial and mammalian cells. This suggests that γδ cells may recognize a class of antigens shared by a number of pathogens, as well as by damaged or transformed mammalian cells, and it may provide insight into the role of γδ cells in infection and their accumulation at sites of inflammation. Recently, a subpopulation of γδ T cells typically found in the intestine and expressing the Vδ1 gene (which is also found in inflamed synovial fluid) was shown to react to newly discovered MHC class I–like molecules known as MICA and MICB.29 Unlike classic MHC class I molecules, which are expressed ubiquitously and continuously, MICA and MICB expression appears to be restricted to gut epithelium and occurs only during times of stress, similar to a heat shock response. The contribution of γδ T cells to defense against infection has been examined in mice using a number of pathogens, including Listeria,125 Leishmania,126 Mycobacterium,127 Plasmodium,128 and Salmonella.129 All these studies showed a moderately protective role for γδ T cells. In some cases of rapid bacterial growth, γδ T cells appear to provide protection early during infection by reducing bacterial growth,125 whereas in less virulent infections such as influenza or Sendai virus, γδ cells appear later in inflammatory lesions.130 In only a few instances, however, have γδ clones derived from an infected animal been shown to react to the causative organism. In human infections, γδ T cells from cutaneous lesions of leprosy patients respond to Mycobacterium leprae,131 and γδ cells from Lyme arthritis synovial fluid respond to the causative spirochete, Borrelia burgdorferi.132 This response by Lyme synovial γδ cells requires lipidated hexapeptides of the outer surface proteins of B. burgdorferi, and the tripalmitate lipid moiety is as important for activation of γδ T cells as the hexapeptide portion is. γδ T cells accumulate at inflammatory sites in autoimmune disorders such as rheumatoid arthritis,133 celiac disease,134 and sarcoidosis.135 The reason for this accumulation remains an enigma. However, there is evidence that γδ cells can be highly cytolytic toward a variety of tissues, including CD4+ T cells,136 in part owing to their high and sustained expression of surface Fas-ligand.137 Their presence can strongly bias the cytokine profiles of the infiltrating CD4+ cells—in some instances, toward Th1 profiles,138 and in others, toward Th2.139 Natural Killer T Cells A minor subpopulation of T cells bearing the NK determinant manifests perhaps the most restricted of TCR repertoires and determinants of recognition. NK T cells are found

within the CD4+ and CD4–CD8– subsets of T cells and, in both mouse and human, express a very limited number of TCR Vβ chains and an invariant α chain (Vα 14 in mice and Vα 24 in humans).140 Further, most NK T cells are restricted in their response to a monomorphic MHC class I–like molecule, CD1d. Recent crystallographic analysis of CD1d has shown that it contains a deeper groove than traditional MHC molecules and is highly hydrophobic, suggesting that it may bind lipid moieties.114 Until recently, the sea sponge sphingolipid α-galactosylceramide was the only known CD1d ligand. Now both endogenous and bacterial (sphingomonas and B. burgdorferi) sources of CD1d-binding sphingolipids have been identified.141,142 This may represent another type of innate T cell response whereby bacterial lipids or lipopeptides may be presented to NK T cells to provoke a rapid early immune response. The potential importance of NK T cells in autoimmune disease stems from their production of high levels of certain cytokines, particularly IL-4 and IFN-γ.140 In this capacity, the IL-4 response may be important for modulating inflammatory responses dominated by Th1 infiltrates. This has been noted in the nonobese diabetic (NOD) mouse model of diabetes, which has reduced levels of NK T cells.143 Adoptive transfer of NK T cells into NOD mice blocks the onset of diabetes.144 A recent study extended this observation to human type 1 diabetes. The NK T cells of diabetic individuals produced more IFN-γ and less IL-4 than did the cells of their unaffected siblings.145 More recently, NK T cells were found to be the predominant CD4+ T cells in the airways of asthma patients.146 Thus, this minor population of T cells may play a pivotal role in early innate responses to certain infections and in the regulation of inflammatory lesions. Naive versus Memory T Cells CD4+ and CD8+ T cells emigrate from the thymus bearing a naive phenotype. Naive T cells produce IL-2 but only low levels of other cytokines; as a result, they manifest little B cell helper activity. They express high levels of Bcl-2 and can survive for extended periods without antigen but require the presence of MHC molecules. Naive T cells circulate from the blood to lymphoid tissues of the spleen and lymph nodes, which concentrates antigen, APCs, T cells, and B cells. Particularly important APCs in this environment are dendritic cells, which are derived from both lymphoid and myeloid progenitors and are particularly adept at concentrating and presenting antigen. Dendritic cells can migrate from other areas of the body, such as the skin, and thus transport antigen to lymphoid tissues (see Chapter 8). These specialized cells express high and constitutive levels of MHC class II and costimulatory molecules B7-1 (CD80) and B7-2 (CD86), which are critical to promoting the proliferation of naive T cells. In this capacity, dendritic cells are particularly adept at promoting clonal expansion of antigenspecific T cells, which may be present at a frequency as low as 1 in 106 before immunization but can increase to 1 in 100 or more within 1 week. The recent development of antigen peptide–MHC tetramer technology has led to the more direct quantitation of these values using flow cytometry and suggests that their frequency may be considerably higher.147 During the process of clonal expansion of naive T cells and their differentiation into effector and ­eventually

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167

Table 9-1  Surface Markers on Naive and Memory T Cells Expression Molecule

Other Designation

Molecular Weight (kD)

Characteristic

Memory

Naive

CD58

LFA-3

45-66

Ligand for CD2

++

+

CD2

T11

50

Alternative activation pathway

+++

++

CD11a/CD18

LFA-1

180-195

Receptor for ICAM-1, ICAM-2, ICAM-3

+++

++

CD29

130

β chain of β1 (VLA) integrins

++++

+

CD45RO

220

Isoform of CD45

++++

−

CD45RA

80-95

Isoform of CD45

−

++++

CD44

Pgp-1

90

Receptor for hyaluronic acid

+++

++

CD54

ICAM-1

120

Counterreceptor for LFA-1

+

−

CD26

40

Dipeptidyl peptidase IV

+

−

CD7

Multichain complex

T cell lineage marker

+/−

++

Part of TCR complex

+

+

CD3

CD, cluster of differentiation; ICAM, intercellular adhesion molecule; LFA, leukocyte function–associated antigen; TCR, T cell antigen receptor; VLA, very late activation antigen.

memory T cells, as many as 100 genes are induced. These manifest primarily as increased expression of certain surface molecules involved with cell adhesion and migration (CD44, ICAM-1, LFA-1, α4β1 and α4β7 integrins, the chemokine receptor CXCR3), activation (change of CD45 from high-molecular-weight CD45RA to lower-molecularweight CD45RO isotype), cytokine production (increased production of IFN-γ, IL-3, IL-4, and IL-5), and death receptors (e.g., Fas/CD95) (Table 9-1). More transiently induced are CD69, the survival factor Bcl-xL, and the high-­affinity IL-2 receptor α chain (CD25), the last being necessary for T cell proliferation. Survival of effector T cells to the memory stage is partly dependent on the cytokines IL-7 and IL-15.148,149 The concept of immune memory has existed since ­Jenner’s first successful vaccinations for smallpox. For years, memory T cells could be identified at a functional level only by demonstrating the presence of an enhanced proliferative response of PBL from an individual previously vaccinated against an antigen, such as tetanus toxoid. In the late 1980s, a series of cell surface memory T cell markers were identified. The first of these was CD44, the hyaluronate receptor.150 Surface CD44 is low on mature, single, positive T cells as they emerge from the thymus, but its expression is upregulated upon the first encounter with antigen stimulation in the periphery. Several other markers have been shown to change upon primary antigenic stimulation. Most notable for human T cells is CD45; an isoform known as CD45RA is expressed on naive T cells, whereas CD45RO expression characterizes memory T cells (see Table 9-1). By using these markers, it has been possible to identify a variety of differences between naive and memory T cells. Activation of memory T cells appears to be more efficient than that of naive T cells and is not absolutely dependent on costimulation. Memory T cells are also able to migrate to nonlymphoid tissues such as lungs, skin, liver, and joints.151 Th1 versus Th2 T Cells Th1 cells participate in cell-mediated inflammatory reactions, activate macrophages, and produce IL-2, TNF-β, and IFN-γ. Th2 cells activate B cells and produce IL-4,

IL-5, IL-6, and IL-10. IL-4 and IL-5 are important B cell growth factors, as are surface CD40-ligand and the recently described BAFF.152 In addition, IL-4 promotes B cell secretion of immunoglobulin (Ig) G1 and IgE, whereas IFN-γ drives IgG2a production. Because Th1 and Th2 cells mediate different functions, the type of response generated can influence susceptibility to disease. In response to repetitive antigenic stimulation, responding CD4+ cells can differentiate into effector cells expressing polarized patterns of cytokine production. Th1 cells are characterized by the production of IL-2, IFN-γ, TNF-α, and TNF-β, whereas Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13.109 A list of cytokines and their properties is provided in Table 9-2. These patterns have been best characterized during chronic infections. In general, a Th1 response helps eradicate intracellular microorganisms, such as Leishmania major and Brucella abortus,109 whereas a Th2 cell response can better control extracellular pathogens, such as the helminth Nippostrongylus brasiliensis.153 The cytokine profiles of Th1 and Th2 cells are mutually inhibitory; thus, the Th1 cytokine IFN-γ, or IL-12 from APCs, suppresses Th2 responses and augments Th1 cytokine gene expression, whereas the Th2 cytokine IL-4, or IL-6 from APCs, promotes the opposite pattern.154 Polarization of the cytokine environment also occurs at the sites of inflammation in many autoimmune syndromes. Th2 skewing has been observed in models of systemic lupus erythematosus, where increased levels of immunoglobulins and autoantibodies are typical, as well as in chronic allergic conditions such as asthma.155 Frequently, however, the infiltrating lymphocytes exhibit a bias toward Th1 cytokines. This occurs with brain-infiltrating lymphocytes in multiple sclerosis and its animal model, experimental allergic encephalomyelitis,156 β islet lymphocytes in diabetes,157 and synovial lymphocytes in inflammatory arthritides.158,159 Unlike the beneficial effects of Th1 responses during infections, these same cytokines can be quite deleterious in autoimmune disorders. Thus, therapies based on the inhibition of certain Th1 cytokines have generated considerable interest and are often ameliorative, such as anti–TNF-α treatment of experimental allergic encephalomyelitis156 and rheumatoid arthritis.160 Several cytokines can be pleiotropic, and predicting the effects of modulating

IL-3

IL-4

IL-5

IL-6

IL-8

IL-9

Interleukin-3

Interleukin-4

Interleukin-5

Interleukin-6

Interleukin-8

Interleukin-9

Cytokine synthesis inhibition factor   (CSIF) B cell-derived T cell growth factor   (B-TCGF)

P40, mast cell growth-enhancing   activity; T cell growth factor-3

Neutrophil-activating protein (NAP-1), granulocyte chemotactic protein   (GCP)

Interferon-β2 (IFN-β2), B cell   stimulatory factor-2 (BSF-2),   hepatocyte stimulatory factor II   (HSF-II), hybridoma plasmacytoma growth factor (HPGF, IL-HP1),   myeloma cell growth factor (MCGF)

B cell growth factor II (BCGF-II), T cell replacing factor, eosinophil   differentiation factor (EDF),   IgA-enhancing factor (IgA-EF)

B cell stimulatory factor 1 (BSF-1),   B cell differentiation factor-γ   (BCDF-γ), T cell growth factor-2   (TCGF-2), mast cell growth factor-2 (MCGF-2)

35-40

32-39

6-8

26

45

15-20

14-30

15-20

160

126

77

183

115

129

133

133

159

1

5

4

7

5

5

5

4

2

IL-10R is single chain, p90-110

IL-9R is single chain, p64

High affinity: IL-8R, CDw128, p58-67 Low affinity: IL-8R also binds   GRO/MGSA, NAP-2

High affinity: IL-6R α chain (p80) +   gp130; gp130 is nonbinding and   forms homodimer when complexed with IL-6Rα; acts to transduce signal

Low affinity: CD125, IL-5α, p60; IL-5R β chain is nonbinding and shared with IL-3R and GM-CSFR

High affinity: IL-4Rα + IL-2R γ chain or “common γ chain,” γc; CD124 is   IL-4R α chain, p140 Low affinity:   IL-4R reported; soluble IL-4Rα is a potent IL-4 antagonist

α Chain, p70; β chain, p120; IL-3R   associated with tyrosine kinase   activity

Low affinity: CD25, IL-2Rα, p55; CD122, IL-2Rβ, p75; non-IL-2 binding p64   IL-2γ Intermediate affinity: IL-2R,   IL-2Rα/γ, or IL-2Rβ/γ High affinity:   IL-2Rα/β/γ; γ chain associated with   IL-4R, IL-7R, IL-15R (? IL-13R and IL-9R)

Single chain; CDw121a; type I receptor;   80 kD or p80; binds IL-1α, IL-1β, and IL-1R antagonist

Activity

Stimulates Th2 cell and thymocyte growth; inhibits Th1 cell proliferation, IL-2 and IFN-γ production; inhibits   macrophage cytokine production

Produced by activated Th2 cells; enhances T cell proliferation, mast cell lines, and erythroid precursors

Produced by many cell types; acts mainly as neutrophil and lymphocyte   chemoattractant and activation factor

Enhances IL-2 production from T cells and Ig production by B cells; myriad effects on nonlymphoid cells

Promotes growth of cytotoxic cells and differentiation of B cells

Promotes growth and differentiation of   T cells, B cells; enhances tumoricidal activity of macrophages, but inhibits IL-1 and TNF-α production

Stimulates proliferation and   differentiation of precursors of all hematopoietic cell lineages

Promotes growth and differentiation of activated T and B cells; activates NK cells, macrophages

Costimulates T and B cell activation and the secretion of cytokines (IL-2, IFN-γ) and antibody; increases killing by NK cells; myriad effects on nonlymphoid cells

| 

Interleukin-10 IL-10

T cell growth factor (TCGF)

IL-2

Interleukin-2

17.5

Mr of Natural Amino Acids of ChromoProtein (kD) Mature Protein some Receptor

BUDD 

Multipotential colony-stimulating   factor (multi-CSF), mast cell growth   factor (MCGF), erythroid colony­stimulating factor (ECSF), mega­ karyocyte colony-stimulating factor (Meg-CSF), eosinophil   colony-­stimulating factor (Eo-CSF)

Lymphocyte-activating factor (LAF), endogenous pyrogen (EP),   catabolin, osteoclast-activating   factor (OAF), epidermal cell-derived thymocyte-activating factor (ETAF)

Abbreviation Other Names

Interleukin-1α IL-1α

Cytokine

Table 9-2  T Cell–Derived Cytokines

168 T Lymphocytes

Murine P600

High-molecular-weight B cell growth   factor (HMW-BCGF)

None

Colony-stimulating factor-α,   pluripoietin, colony-stimulating   factor 2

Macrophage-activating factor (MAF)

Interleukin-13 IL-13

Interleukin-14 IL-14

Interleukin-15 IL-15

Granulocyte- GM-CSF macrophage colonystimulating factor

Interferon-γ

Cachectin

None

Tumor necro- TNF-α sis factor-α

Transforming TGF-β growth   factor-β

25

52

25

2 × 112

157

171

143

127

114

483

112

196/306

19/14

6

6

12

5

?

?

5

?

Three receptors; high-affinity type I and II, p55 and p80; low-affinity type III, p250-300

Same as LT

Type I receptor, CD120a, p55; second receptor is type II receptor, CD120b, p75; both members of NGFR/TNFR superfamily

High affinity: CDw119, binding chain, second chain transduces signal

Low affinity: CDw116, α chain, p80; β chain, p130, shared with IL-3R and   IL-5R High affinity: α + β chains

IL-15R binding chain unknown; shares IL-2Rβ and γ chains (not IL-2Rα)

Unknown; also binds Bb component of complement

Unknown; may share nonbinding chain with IL-4

High affinity: IL-12R, type I receptor,   p180

Ig, immunoglobulin LAK, lymphokine-activated killer; NGFR, nerve growth factor receptor; TNFR, tumor necrosis factor receptor.

Tumor necrosis factor-β (TNF-β)

20-25

22

14-15

60

10-17

30-33 35-44

Inhibits T cell growth and cytokine   secretion; inhibits B cell growth and   differentiation; counteracts effects of IFN-γ on nonimmune cells

Same as LT

LT and TNF-α have the same activities; enhance T and B cell proliferation; enhance B cell differentiation; increase killing by NK cells

Enhances differentiation of T and B cells; counteracts effects of IL-4; enhances killing by NK cells; activates macrophages; induces class II MHC molecules on many nonimmune cells

Activates macrophages

Produced by many cells; enhances T cell proliferation, cytotoxic activity, and LAK activity

Produced by activated T cells; promotes B cell proliferation, inhibits Ig secretion; shares homology with complement factor Bb

Produced by activated T cells; inhibits production of inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-8); induces CD23 on B cells, promotes human B cell proliferation and Ig secretion

Induces Th1 cell differentiation; enhances IFN-γ production by T cells and NK cells; stimulates proliferation of T cells

| 

Lymphotoxin LT

IFN-γ

Natural killer cell stimulatory factor   (NKSF) Cytotoxic lymphocyte maturation   factor (CLMF)

Interleukin-12 IL-12

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169

170

BUDD 

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T Lymphocytes

their levels can be complex. For example, despite the tendency of IL-6 to promote a Th2 cytokine profile, blocking IL-6 can be extremely beneficial in rheumatoid arthritis.161 Costimulatory molecules and other cytokines ­ produced by APCs can also influence cytokine polarization. B7-1 (CD80) and IL-12 promote a Th1 emergence,162,163 whereas B7-2 (CD86), IL-4, and IL-6 can evoke a Th2 predominance.154,163,164 Th1 cells are also generally thought to be more readily tolerogenic and more susceptible to activation-induced cell death (AICD),165,166 perhaps because they express more Fas-ligand than Th2 cells do.167,168 Increased expression of Fas-associating phosphatase-1 by Th2 cells may also contribute to their resistance to AICD by inhibiting Fas signaling.165 However, other investigators have observed that Th1 and Th2 cells are equally sensitive to apoptosis upon Fas ligation.167 Th17 Cells A newly recognized subset of IL-17–producing CD4+ T cells (Th17) is critical for promoting a variety of autoimmune disorders. TGF-β (possibly originating from regulatory T cells), accompanied by IL-6 (probably from dendritic cells), appears to be pivotal for the appearance of Th17 cells.103,106 IL-23 may also be important for the survival, but perhaps not the appearance, of Th17 cells. Injections of IL-23 into skin produce increased IL-17 in the epidermis and inflammatory lesions that resemble psoriasis.169,170 Th17 cells are increased in human psoriatic plaques,170 in rheumatoid arthritis synovial fluid, and in multiple sclerosis.171 MOLECULAR MIMICRY Perhaps the oldest concept of autoimmunity is that of molecular mimicry, the notion that the immune system’s response to a foreign substance may provoke cross-reactivity to a selfprotein. This is best established in rheumatic heart disease, where a B cell antibody response to a group A streptococcal cell wall component can precipitate cross-reactivity to cardiac myosin. Similarly for T cells, investigators used the peptide sequence of myelin basic protein (MBP) recognized by specific T cell clones from patients with multiple sclerosis to search a database of infectious agents. Some of the candidate sequences obtained were able to stimulate the MBPreactive T cell clones.172 This suggested for the first time that T cells responding to an infectious agent might manifest cross-reactivity to self-peptides. More recently, it was observed that one of the outer surface proteins of B. burgdorferi, known as OspA, may trigger a cross-reactive response in Lyme arthritis.173 Further, a T cell immunodominant peptide of OspA has been identified in a subset of HLA-DR4 patients who are more resistant to antibiotic treatment and manifest an antibody as well as a T cell response to OspA.174 By using a sequence algorithm to identify homologous peptides that bind the DR4 pocket, a sequence in LFA-1 was identified that bound DR4 and stimulated a T cell response from these OspA-reactive patients.173 The technology of peptide-MHC tetramers discussed earlier will enable investigators to determine whether a given subpopulation of T cells within an inflammatory synovium might manifest dual specificity for both a foreign pathogen and a cross-reacting self-protein.

DEATH OF T CELLS The rapid removal of effector T cells following clearance of the infection is as important as the initial clonal expansion of responding T cells for the health of the organism. Failure to clear activated lymphocytes increases the risk of cross-reactivity with self-antigens and a sustained autoimmune reaction. To ensure the rapid resolution of the immune response, a number of processes promote active cell death of clonally expanded T cells. One means to control T cell proliferation is through the limited availability of growth factors. Upon activation, T cells express receptors for various growth cytokines for approximately 7 to 10 days, but they produce cytokines only during the first 48 hours. This results in an unstable situation in which T cells tend to outgrow the availability of cytokines. For example, T cells expressing IL-2R in the absence of IL-2 rapidly undergo programmed cell death. Another method is the restimulation of TCRs on actively dividing T cells, which triggers AICD. The discovery of a family of death receptors expressed by T cells elucidated an additional regulatory process. These molecules are described more extensively in Chapter 24 on apoptosis and are discussed here only as they relate to T cell function. The best described of these is Fas (CD95). Both Fas-deficient mice175 and humans bearing Fas mutations (Canele-Smith syndrome)176 manifest a profound lymphadenopathy accompanied by an autoimmune diathesis. This underscores the importance of efficiently removing T cells after their activation. Nearly all cells have some level of surface Fas, whereas expression of its ligand (FasL) is restricted primarily to activated T cells and B cells. Consequently, regulation of Fas-mediated apoptosis is, to a large extent, under the governance of the immune system. FasL expression has also been reported in certain components of the eye, the Sertoli cells of the testis, and perhaps some tumors.177 Expression of FasL by these nonlymphoid cells is thought to prevent immune responses at sites where such inflammation might cause tissue damage. For years, immunologists have been aware of these so-called immune-privileged sites where immune responses are difficult to initiate. During T cell activation, expression of FasL is rapidly induced at the level of RNA, and the ability to kill Fas­sensitive target cells is easily demonstrated. Expression of surface FasL protein has been difficult to demonstrate, however. This may be due to the sensitivity of surface FasL to certain proteinases, which results in its rapid cleavage and release from the cell, similar to the release of TNF-α, another member of the Fas family. Resting T cells are not sensitive to Fas-induced death but must first enter the cell cycle for approximately 3 days. During this period, the cellular level of an endogenous Fas inhibitor known as c-FLIP is downregulated, and this presumably allows Fas signaling to progress.178 Thus, c-FLIP may function to protect resting T cells from unnecessary death and restrict apoptosis to activated T cells to limit their expansion. The importance of c-FLIP as an inhibitor of cell death is reinforced by the discovery that certain herpesviruses express a homologue of mammalian FLIP called E8 that can prevent the death of host cells.179 E8 expression may alter the tumorigenic potential of herpesviruses.180 Although it is generally well accepted that Fas is a major regulator of AICD in vitro, it is less clear whether

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Fas plays much of a role in the death and removal of T cells following activation in vivo. The sequence of T cell activation followed by cell death is graphically displayed after the administration to mice of bacterially or virally derived compounds called superantigens. Superantigens activate T cells by directly cross-linking MHC class II molecules with particular β-chain V families of the TCR (see Fig. 9-3). The superantigen staphylococcal enterotoxin B strongly activates Vβ8+ T cells.181 This initiates a rapid expansion of Vβ8+ T cells over 2 to 3 days, followed by an equally rapid loss of these cells, such that by day 7, very few Vβ8+ T cells remain. A similar process of T cell activation occurs in the human disease toxic shock syndrome, in which a related staphylococcal toxin stimulates the expansion of Vβ2+ T cells.182 The devastating illness that results from this profound activation of a large proportion of T cells underscores the need to rapidly eliminate such cells. At least some of the damage in toxic shock syndrome likely results from the extensive T cell expression of FasL and TNF-α, particularly in certain tissues such as the liver. Hepatocytes are exquisitely sensitive to damage by these ligands.183 Activation of T lymphocytes leads to homing to the liver, and the administration of antigen to TCR transgenic mice can yield a syndrome resembling autoimmune hepatitis.184 Thus, certain autoimmune disorders may result from the death or damage of “innocent bystander” cells as a consequence of the migration of activated T cells to an organ and nonspecific damage due to the expression of FasL family members. It was initially assumed that Fas would largely regulate this process; however, Fas-deficient mice eliminate T cells activated by either traditional antigens or superantigens nearly as efficiently as wild-type mice do. It now appears that a more recently identified family of compounds known as Bim, Bad, and Bax regulate AICD in vivo.185 These molecules are related to the cell survival molecule Bcl-2, but they are more truncated, containing only the BH3 domain of Bcl-2—hence their designation as the “BH3-only” family. They function as sentinels within the cell, in that they are attached to various cytoskeletal proteins and organelles and can sense cellular damage. If damage occurs, they are released from these sequestered areas and migrate to the mitochondria to inhibit the survival function of Bcl-2.185 T CELLS AT SITES OF INFLAMMATION The observation that T cells infiltrate target organs in ­autoimmune diseases such as rheumatoid arthritis, type 1 diabetes mellitus, and multiple sclerosis quickly led to an analysis of T cell subsets and, more recently, to a more detailed study of the T cell repertoire based on TCR expression. In many of these disorders, the known HLA class II association is paralleled by a predominant, though by no means exclusive, infiltration of CD4+ T cells.186 Many of these CD4+ T cells also manifest a Th1-like cytokine profile, as discussed earlier.156,157,159 Evidence of the importance of these CD4+ cells derives from numerous studies showing the efficacy of CD4 depletion in animal models of these disorders.187 A parallel situation often occurs in humans with these autoimmune diseases who concurrently become infected with HIV. The CD4 depletion that occurs during AIDS can actually ameliorate rheumatoid arthritis.188 ­ However, the resulting

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CD8 predominance during HIV infection can exacerbate psoriatic arthritis and Sjögren’s syndrome, suggesting that the CD8+ subset of T cells may be important in these disorders.188 The ability to assess the TCR repertoire of infiltrating T cells has provided additional insight into the degree of clonality present within inflamed tissues. Many studies have examined the TCR β chain because of its association with superantigen responses, as well as the TCR α chain.189 Based on dozens of publications, it is clear that a very broad array of TCR types is observed in most T cell–mediated diseases. In the few studies that have analyzed the earliest lesions, T cell oligoclonality has been observed.190 However, it is possible that the oligoclonality in these situations may simply reflect the limited number of T cells in early lesions. These are nonetheless provocative findings that warrant further analysis. REFERENCES   1. Pawson T, Scott JD: Signaling through scaffold, anchoring, and adaptor proteins. Science 278:2075-2080, 1997.   2. Rudd CE: Adaptors and molecular scaffolds in immune cell signaling. Cell 96:5-8, 1999.   3. Scollay R, Smith J, Stauffer V: Dynamics of early T cells: Prothymocyte migration and proliferation in the adult mouse thymus. Immunol Rev 91:129-157, 1986.   4. Godfrey DI, Kennedy J, Suda T, Zlotnik A: A developmental pathway involving four phenotypically and functionally distinct subsets of CD3-CD4-CD8- triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. J Immunol 150:4244-4252, 1993.   5. von Boehmer H, Fehling HJ: Structure and function of the pre-T cell receptor. Annu Rev Immunol 15:433-452, 1997.   6. Bosma GC, Custer RP, Bosma MJ: A severe combined immunodeficiency mutation in the mouse. Nature 301:527-530, 1983.   7. Mombaerts P, et al: RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68:869-877, 1992.   8. Rodewald HR, Fehling HJ: Molecular and cellular events in early thymocyte development. Adv Immunol 69:1-112, 1998.   9. Radtke F, et al: Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10:547-558, 1999. 10. Peschon JJ, et al: Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med 180:1955-1960, 1994. 11. Uribe L, Weinberg KI: X-linked SCID and other defects of cytokine pathways. Semin Hematol 35:299-309, 1998. 12. Farrar MA, Doerfler P, Sauer K: Signal transduction pathways regulating the development of alpha beta T cells. Biochim Biophys Acta 1377:F35-F78, 1998. 13. Elder ME, et al: Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science 264:1596-1599, 1994. 14. Padovan E, et al: Expression of two T cell receptor α chains: Dual receptor T cells. Science 262:422-424, 1993. 15. Niederberger N, et al: Allelic exclusion of the TCR α chain is an active process requiring TCR-mediated signaling and c-Cbl. J Immunol 170:4557-4563, 2003. 16. Garboczi DN, et al: Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature 384:134-141, 1996. 17. Garcia KC, et al: An ab T cell receptor structure at 2.5 A and its orientation in the TCR-MHC complex. Science 274:209-219, 1996. 18. Matsui K, et al: Low affinity interaction of peptide-MHC complexes with T cell receptors. Science 254:1788-1791, 1991. 19. Yamashita I, Nagata T, Tada T, Nakayama T: CD69 cell surface expression identifies developing thymocytes which audition for T cell antigen receptor-mediated positive selection. Int Immunol 5:1139-1150, 1993. 20. Punt JA, Osborne BA, Takahama Y, et al: Negative selection of CD4+CD8+ thymocytes by T cell receptor-induced apoptosis requires a costimulatory signal that can be provided by CD28. J Exp Med 179:709-713, 1994.

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132. Vincent MS, et al: Lyme arthritis synovial gamma delta T cells respond to Borrelia burgdorferi lipoproteins and lipidated hexapeptides. J Immunol 161:5762-5771, 1998. 133.  Brennan FM, et al: T cells expressing chain receptors in rheumatoid arthritis. J Autoimmun 1:319-326, 1988. 134. Rust C, et al: Phenotypical and functional characterization of small intestinal TcR T cells in coeliac disease. Scand J Immunol 35:459468, 1992. 135. Balbi B, Moller DR, Kirby M, et al: Increased numbers of T lymphocytes with gd+ antigen receptors in a subgroup of individuals with pulmonary sarcoidosis. J Clin Invest 85:1353-1361, 1990. 136. Vincent MS, et al: Apoptosis of Fas high CD4+ synovial T cells by Borrelia-reactive Fas-ligand(high) gamma delta T cells in Lyme arthritis. J Exp Med 184:2109-2117, 1996. 137. Roessner K, et al: High expression of Fas ligand by synovial fluidderived gamma delta T cells in Lyme arthritis. J Immunol 170: 2702-2710, 2003. 138. Huber S, Shi C, Budd RC: Gamma delta T cells promote a Th1 response during coxsackievirus B3 infection in vivo: Role of Fas and Fas ligand. J Virol 76:L6487-L6494, 2002. 139. Schramm CM, et al: Proinflammatory roles of T-cell receptor (TCR) gamma delta and TCR alpha beta lymphocytes in a murine model of asthma. Am J Respir Cell Mol Biol 22:218-225, 2000. 140. Bendelac A, Rivera MN, Park SH, Roark JH: Mouse CD1-specific NK1 T cells: Development, specificity, and function. Annu Rev Immunol 15:535-562, 1997. 141. Kinjo Y, et al: Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 434:520-525, 2005. 142. Kinjo Y, et al: Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria. Nat Immunol 7:978-986, 2006. 143. Lehuen A, et al: Overexpression of natural killer T cells protects Va14-Ja281 transgenic nonobese diabetic mice against diabetes. J Exp Med 188:1831-1839, 1998. 144. Baxter AG, Kinder SJ, Hammond KJ, et al: Association between abTCR+CD4–CD8– T-cell deficiency and IDDM in NOD/Lt mice. Diabetes 46:572-582, 1997. 145. Wilson SB, et al: Extreme Th1 bias of invariant Va24JaQ T cells in type 1 diabetes. Nature 391:177-181, 1998. 146. Akbari O, et al: Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat Med 9:582-588, 2003. 147. Doherty PC: The new numerology of immunity mediated by virusspecific CD8+ T cells. Curr Opin Microbiol 1:419-422, 1998. 148. Purton JF, et al: Antiviral CD4+ memory T cells are IL-15 dependent. J Exp Med 204:951-961, 2007. 149. Shin H, Blackburn SD, Blattman JN, Wherry EJ: Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection. J Exp Med 204:941-949, 2007. 150. Budd RC, Cerottini JC, MacDonald HR: Phenotypic identification of memory cytolytic T lymphocytes in a subset of Lyt-2+ cells. J Immunol 138:1009-1013, 1987. 151. Masopust D, Vezys V, Marzo AL, Lefrancois L: Preferential localization of effector memory cells in nonlymphoid tissue. Science 291:2413-2417, 2001. 152. Schneider P, et al: BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med 189:1747-1756, 1999. 153. Coffman RL, Seymour BW, Hudak S, et al: Antibody to interleukin-5 inhibits helminth-induced eosinophilia in mice. Science 245: 308-310, 1989. 154. Rincon M, Anguita J, Nakamura T, et al: Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells. J Exp Med 185:461-469, 1997. 155. Fuss IJ, et al: Characteristic T helper 2 T cell cytokine abnormalities in autoimmune lymphoproliferative syndrome, a syndrome marked by defective apoptosis and humoral autoimmunity. J Immunol 158:1912-1918, 1997. 156. Ruddle NH, et al: An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J Exp Med 172:1193-1200, 1990. 157. Heath WR, et al: Autoimmune diabetes as a consequence of locally produced interleukin-2. Nature 359:547-549, 1992. 158. Saxne T, Palladino MA Jr, Heinegard D, et al: Detection of tumor necrosis factor a but not tumor necrosis factor b in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum 31:1041-1045, 1988.

159. Yssel H, et al: Borrelia burgdorferi activates a T helper type 1-like T cell subset in Lyme arthritis. J Exp Med 174:593-601, 1991. 160. Elliott MJ, et al: Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 344:1105-1110, 1994. 161. Choy EH, et al: Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: A randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis Rheum 46:3143-3150, 2002. 162. Hsieh CS, et al: Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260:547-549, 1993. 163. Kuchroo VK, et al: B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: Application to autoimmune disease therapy. Cell 80:707-718, 1995. 164. Le Gros G, Ben-Sasson SZ, Seder R, et al: Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J Exp Med 172:921-929, 1990. 165. Zhang X, et al: Unequal death in T helper cell (Th)1 and Th2 effectors: Th1, but not Th2, effectors undergo rapid Fas/FasL-mediated apoptosis. J Exp Med 185:1837-1849, 1997. 166. Gilbert KM, Hoang KD, Weigle WO: Th1 and Th2 clones differ in their response to a tolerogenic signal. J Immunol 144:2063-2071, 1990. 167. Ramsdell F, et al: Differential ability of Th1 and Th2 T cells to express Fas ligand and to undergo activation-induced cell death. Int Immunol 6:1545-1553, 1994. 168. Suda T, et al: Expression of the Fas ligand in cells of T cell lineage. J Immunol 154:3806-3813, 1995. 169. Zheng Y, et al: Interleukin-22, a T(H)17 cytokine, mediates IL23-induced dermal inflammation and acanthosis. Nature 445:648651, 2007. 170. Chan JR, et al: IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med 203:2577-2587, 2006. 171.  Steinman L: A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med 13:139-145, 2007. 172. Wucherpfennig KW, Strominger JL: Molecular mimicry in T cellmediated autoimmunity: Viral peptides activate human T cell clones specific for myelin basic protein. Cell 80:695-705, 1995. 173.  Gross DM, et al: Identification of LFA-1 as a candidate autoantigen in treatment-resistant Lyme arthritis. Science 281:703-706, 1998. 174. Kalish RA, Leong JM, Steere AC: Association of treatment-resistant chronic Lyme arthritis with HLA-DR4 and antibody reactivity to OspA and OspB of Borrelia burgdorferi. Infect Immun 61:2774-2779, 1993. 175. Budd RC, Van Houten N, Clements J, Mixter PF: Parallels in T lymphocyte development between lpr and normal mice. Semin Immunol 6:43-48, 1994. 176. Vaishnaw AK, et al: The molecular basis for apoptotic defects in patients with CD95 (Fas/Apo-1) mutations. J Clin Invest 103: 355-363, 1999. 177. Griffith TS, Brunner T, Fletcher SM, et al: Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 17:1189-1192, 1995. 178. Irmler M, et al: Inhibition of death receptor signals by cellular FLIP. Nature 388:190-195, 1997. 179. Thome M, et al: Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386:517-521, 1997. 180. Tschopp J, Thome M, Hofmann K, Meinl E: The fight of viruses against apoptosis. Curr Opin Genet Dev 8:82-87, 1998. 181. Kawabe Y, Ochi A: Selective anergy of V beta 8+,CD4+ T cells in Staphylococcus enterotoxin B-primed mice. J Exp Med 172: 1065-1070, 1990. 182. Choi Y, et al: Selective expansion of T cells expressing V beta 2 in toxic shock syndrome. J Exp Med 172:981-984, 1990. 183. Kennedy NJ, Russell JQ, Michail N, Budd RC: Liver damage by infiltrating CD8+ T cells is Fas dependent. J Immunol 167:6654-6662, 2001. 184. Russell JQ, et al: Liver damage preferentially results from CD8+ T cells triggered by high affinity peptide antigens. J Exp Med 188: 1147-1157, 1998.

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185. Hildeman DA, et al: Activated T cell death in vivo mediated by proapoptotic bcl-2 family member bim. Immunity 16:759-767, 2002. 186. Steere AC, Duray PH, Butcher EC: Spirochetal antigens and lymphoid cell surface markers in Lyme synovitis: Comparison with rheumatoid synovium and tonsillar lymphoid tissue. Arthritis Rheum 31:487-495, 1988. 187. Ranges GE, Sriram S, Cooper SM: Prevention of type II collageninduced arthritis by in vivo treatment with anti-L3T4. J Exp Med 162:1105-1110, 1985.

175

188. Winchester RJ: HIV infection and rheumatic disease. Bull Rheum Dis 43:5-8, 1994. 189. Wucherpfennig KW, et al: T cell receptor Va-Vβ repertoire and cytokine gene expression in active multiple sclerosis lesions. J Exp Med 175:993-1002, 1992. 190. Yang Y, Charlton B, Shimada A, et al: Monoclonal T cells identified in early NOD islet infiltrates. Immunity 4:189-194, 1996.

10

B Cells Betty Diamond  •  Christine Grimaldi

KEY POINTS The immunoglobulin Fc’ region defines the immunoglobulin isotype (IgM, IgG, IgA, IgE, IgD) and mediates different effector functions. The variable region of the immunoglobulin binds to specific antigenic epitopes. The random combination of multiple V, D, and J gene segments generates a diverse array of immunoglobulin molecules with myriad antigenic specificities. Secreted immunoglobulin mediates distinct effector functions, including neutralization of antigen, antigen uptake by phagocytic cells, complement activation, and antigendependent cell-mediated cytotoxicity. Surface immunoglobulin acts as a signal transduction molecule and is a major component of the B cell receptor, which plays a critical role in regulating B cell selection, survival, and activation. B cells are derived from hematopoietic precursors in the bone marrow and undergo several stages of development and selection before becoming immunocompetent, mature, naive B cells that reside in peripheral lymphoid organs. The final stages of B cell development, which occur in peripheral lymphoid organs following antigen activation, include affinity maturation and generation of long-lived memory B cells and immunoglobulin-secreting plasma cells. Distinct B cell subsets participate in different types of immune responses to pathogens. Follicular B cells respond to T cell– dependent antigenic responses; B1 and marginal zone B cells respond to distinct classes of T cell–independent antigens. Autoreactive B cells are generated in all individuals. There are multiple checkpoints that extinguish autoreactive B cells during early and later stages of B cell development. One or more of these checkpoints are breached in autoimmuneprone individuals, leading to the maturation and activation of autoreactive B cells.

IMMUNOGLOBULIN STRUCTURE AND FUNCTION The principal role of B lymphocytes (Fig. 10-1) in the immune system is the synthesis of immunoglobulins (also referred to as antibodies), which are globular proteins that bind foreign substances known as antigens. Immunoglobulins exist as secreted proteins that circulate throughout the body or as cell membrane–associated receptors that help mediate B cell survival, activation, and maturation. The tertiary structure of an antibody molecule consists of a Y-shaped conformation that contains two functional moieties: two identical variable regions and the constant region

(Fig. 10-2). Each variable region of an antibody molecule contains an antigen-binding pocket; the constant region directs immunoglobulin effector functions that mediate the killing and removal of invading organisms and both the activation and homeostasis of the immune system. The amino acid composition of the immunoglobulin variable region exhibits great diversity, which facilitates the recognition of a wide array of antigens. As the name implies, the constant region exhibits far less diversity and can be subdivided into a few distinct classes known as isotypes. The fundamental units of an immunoglobulin are the light (L)-chain polypeptide, which has an apparent molecular mass of 25 kD, and the heavy (H)-chain polypeptide, which has an apparent molecular mass of 50 to 65 kD. An immunoglobulin monomer consists of two identical L-chain molecules covalently linked by disulfide bonds to two identical H-chain molecules that are also linked by disulfide bonds (see Fig. 10-2). Early studies analyzing proteolytic fragments of molecules demonstrated distinct functional components.1 Cleavage with papain generates the antigen-binding fragment (Fab); either of two identical fragments retains the ability to recognize antigen. The Fab portion is composed of the variable region domains of the H and L chains, the first H-chain constant region domain (CH1), and the L-chain constant region domain (CL). Cleavage with pepsin occurs below the disulfide linkage of the two H chains and generates a molecule that contains two disulfide-bonded Fab fragments called F(ab′)2. The presence of two Fab regions in a single immunoglobulin monomer creates a bivalent binding capacity to interact with repetitive determinants present in multivalent antigens (i.e., polysaccharide) or two separate antigen molecules containing the same antigenic determinant. The remaining component, termed fragment crystallizable (Fc), based on its ability to readily undergo crystal formation, is unable to interact with antigen but contains the CH2 and CH3 domains of the H chain that mediate immune effector functions. Within the variable region of the immunoglobulin molecule are discrete regions, known as complementaritydetermining regions, that make direct contact with antigen. The amino acid sequences of the complementarity-determining regions are highly variable and are flanked by more conserved amino acid sequences called framework regions. The H- and L-chain molecules each contain three complementarity-determining regions and four framework regions (see Fig. 10-2). The minimal antigenic determinant recognized by the H and L complementarity-determining regions is known as an epitope, which may be a continuous or discontinuous region on a protein, carbohydrate, lipid, or nucleic acid.

  Supplemental images available on the Expert Consult Premium Edition website.

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to cytotoxic and phagocytic cells that mediate the destruction and removal of pathogens. There are two ways in which the Fc region directs the destruction of pathogens: activation of the complement cascade, and engagement of Fc-specific receptors on effector cells such as monocytes, macrophages, neutrophils, and natural killer (NK) cells. In mice and humans, there are five different types of H-chain constant regions, or isotypes, designated IgM (μ), IgD (δ), IgG (γ), IgA (α), and IgE (ε); each is encoded by a distinct constant region gene segment present in the H-chain locus. Each immunoglobulin molecule is capable of specific effector functions, depending on its H-chain constant region. The number of CH domains, presence of a hinge region to increase flexibility between Fab regions, serum half-life, ability to form polymers, complement activation, and Fc receptor binding vary among isotypes. Characteristics of the different immunoglobulin H-chain isotypes are presented in Table 10-1.2-4 These isotypes may also differ in the intracellular signaling they initiate when bound by antigen in their membrane-associated form. Figure 10-1  Micrograph of a B cell. (Courtesy of Professor Peter Groscurth, University of Zurich.) F(ab´)2 FWR

VH VL CH1 Fab

CDR

CL Hinge

CH2 Fc CH3

Figure 10-2  Schematic of the antibody molecule. An antibody monomer consists of two heavy (H)-chain molecules covalently linked to two light (L)-chain molecules. The variable region is composed of the VH and VL domains of the H and L chains, respectively. Within the VH and VL domains are four framework regions (FWRs) and three complementarity-  determining regions (CDRs), which together make up the antigen-binding pocket. Papain digestion generates the Fab portion, which consists of VH, CH1, VL, and CL domains, and pepsin digestion generates two covalently linked Fabs, known as the F(ab’)2. The Fc region of the H-chain constant region, which mediates immune effector functions, consists of the hinge domain (only in IgG, IgA, and IgD), which increases flexibility, and CH2 and CH3 domains.

Immunoglobulin M IgM is the first isotype generated in developing B cells and the first antibody secreted during a primary immune response. The secreted form of IgM exists mainly as a pentamer. IgM also exists as a hexamer, which represents approximately 5% of total serum IgM.5 Pentameric IgM is linked by a molecule called the J chain, whereas the hexameric form is not. IgM antibodies usually exhibit low affinity for antigen because the process that increases antibody affinity for a particular antigen (affinity maturation) has not yet been initiated during the early stages of a primary immune response. However, polymeric IgM displays high avidity for antigen. The presence of multiple Fab regions makes the IgM molecule suitable to bind large, multimeric antigens. IgM is found predominantly in serum but is also present in mucosal secretions and breast milk. The Fc region of IgM (as well as some of the IgG isotypes) is a potent activator of the classic complement pathway.3 The complement cascade is composed of a series of enzymes that, on activation, mediate the removal and lysis of invading organisms. In general, antibody molecules bound to antigen can activate the classic complement pathway. Deposition of antibody molecules or complement components on the surface of the antigen facilitates phagocytosis. Proteins, such as antibody and complement, that enhance phagocytosis are called opsonins. Once the complement cascade has been activated, monocytes, macrophages, or neutrophils engulf opsonized particles through specific receptors present on phagocytic cells (CD21) that recognize fragments of the C3 complement component. Activation of the complement pathway also results in the generation of the membrane attack complex, which is composed of late complement components and directly lyses C3-opsonized pathogens.

IMMUNOGLOBULIN CONSTANT REGION The specific binding interactions that occur between the immunoglobulin variable region and the antigen may be sufficient to block microbial infectivity or neutralize toxins. However, the ability to eliminate pathogens is mediated by the Fc portion of the molecule. The Fc regions of antigenantibody complexes are made accessible to serum factors or

Immunoglobulin G IgG is the most common isotype found in serum. IgG antibodies are usually of higher affinity than IgM antibodies and predominate in a secondary or memory immune response. There are four subclasses of IgG in humans: IgG1, IgG2, IgG3, and IgG4. All IgG subclasses exist as monomers. Each

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Table 10-1  Properties of Human Immunoglobulin (Ig) Isotypes Characteristic

IgM

IgG

IgA

IgE

IgD

Valency

Pentamer,   hexamer

Monomer

Dimer (IgA2),   monomer (IgA1)

Monomer

Monomer

CH domains

4

3

3

4

3

Serum values (mg/mL)

0.7-1.7

9.5-12.5

1.5-2.6

.0003

.04

Serum half-life (days)

5

23

6

2.5

3

Complement activation   (classic)

Yes

Yes

No

No

No

Complement activation   (alternative)

No

Yes

Yes

No

Yes

FcR binding

No

Yes

Yes

No

Yes

FcR-mediated phagocytosis

No

Yes

Yes

No

No

Antigen-dependent cell-  mediated cytotoxicity

No

Yes

No

No

No

Placental transfer

No

Yes

No

No

No

Presence in mucosal   secretions

Yes

No

Yes

No

No

of the four subclasses appears to predominate in different immune responses. IgG1 and IgG2 antibodies are observed in responses to polysaccharide antigens; IgG1, IgG3, and IgG4 participate in immune responses to viral and protein antigens; and IgG4 also participates in responses to nematodes.6 IgG1 and IgG3 are more potent activators of the classic complement pathway than are IgG2 and IgG4. Several immunoglobulin isotypes, including IgG1, are capable of initiating the alternative complement pathway (see also Chapter 19). The mechanisms by which antibody activates the alternative pathway are poorly understood, but specific binding sites for the C3 complement component have been identified on some immunoglobulin isotypes.7,8 All IgG subclasses engage specific Fc gamma receptors (FcγRs) present on macrophages, neutrophils, and NK cells to mediate phagocytosis of antibody-coated antigens and to initiate antibody-dependent cell-mediated cytotoxicity. The FcγRs on phagocytic cells, such as monocytes, macrophages, and neutrophils, mediate the removal of immune complexes.4 Engagement of FcγRs with immune complexes results in receptor activation. This, in turn, stimulates phagocytic cells to ingest opsonized antigens and destroy them in the phagosome compartment. The FcγRs on NK cells mediate the killing of antibody-coated cells by the antibody-dependent cell-mediated cytotoxicity pathway, resulting in the release of granules that contain perforin, a pore-forming protein, and enzymes known as granzymes that induce programmed cell death (apoptosis) of target cells.9 Another important role of IgG is that it is the only source of maternal antibodies for a developing fetus during pregnancy. The transcytosis of maternal IgG antibodies into the fetal blood supply is mediated by two other Fc receptors, FcRn and FcRγIIB2.10,11 FcRn expressed on endothelial cells regulates the half-life of serum IgG by blocking IgG catabolism.10 Immunoglobulin A There are two subclasses of IgA in humans: IgA1 and IgA2.3 IgA1 exists mainly as a monomer and is present in serum; IgA2 exists as a dimer linked by the J chain and is the

p­ redominant isotype in saliva, tears, colostrum, breast milk, and respiratory and vaginal secretions. Secretory IgA (and IgM) is produced by B cells in the lamina propria, which is beneath the mucosal lining of polarized epithelial cells. Specific receptors for secretory immunoglobulin, termed polymeric immunoglobulin receptors, are expressed on the basolateral surface of epithelial cells and mediate the transport of immunoglobulin polymers across the epithelium.12 The polymeric immunoglobulin receptor binds dimeric IgA with higher affinity than IgM. During transport, the polymeric immunoglobulin receptor undergoes proteolytic cleavage to generate a fragment called the secretory component. Before transcytosis is complete, the IgA dimer associates with the secretory component, which renders it resistant to enzymatic degradation. It has been suggested that secretory IgA plays an important role in protecting against foreign organisms by directly blocking infection and neutralizing toxins in the mucosa. IgA is unable to activate complement through the classic pathway, but IgA1 can activate the alternative complement pathway.8 Patients with IgA deficiency have reduced levels of both serum and secretory IgA, and at least half these patients experience increased respiratory and diarrheal infections.13 An increase in autoimmune disorders has also been observed in patients with IgA deficiency. An IgAspecific FcαR has been identified. The physiologic role of this receptor is not well understood, but there is evidence that the FcαR expressed on monocytes, macrophages, neutrophils, and eosinophils mediates the phagocytosis of IgAcoated pathogens.14 Immunoglobulin E IgE exists as a monomer. Only a small amount of IgE is detectable in serum. IgE triggers immune responses associated with allergic reactions.6 The Fc region of IgE interacts with the high-affinity IgE Fc receptor, FcεR, which is found on the surface of mast cells and basophils.4 When multimeric antigen cross-links the variable region of IgE molecules bound to FcεR molecules, mast cells and basophils degranulate and release vasoactive molecules ­ associated

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with anaphylaxis, such as histamine, prostaglandin D2, and leukotrienes. IgE has been implicated in the protection against parasitic infections, because cross-linking of FcεR results in the activation of mast cells, which are involved in immune responses to parasites and help skew the T cell response to parasites to a Th2 cytokine profile through the production of IL-4 (see Chapter 9). Immunoglobulin D Little is known about the function of IgD. The membrane form of IgD is coexpressed with the membrane form of IgM. Surface expression of IgD occurs during the later stages of B cell development (see “B Cell Development”). The role of IgD in a humoral immune response is unclear. Unlike the other four H-chain isotypes, IgD is not secreted from activated B cells and is therefore unlikely to play a protective role against infection. Studies performed with IgD transgenic mice suggest that surface IgD protects against tolerance induction because autoreactive IgM+, IgD+ B cells, but not IgM+, IgD– B cells, are resistant to deletion by antigen.15 Targeted disruption of the IgD gene in mice, however, does not appear to interfere with normal immune functions. Although the total number of B cells is slightly reduced and affinity maturation is delayed, there is no evidence of autoreactivity.16,17 LIGHT CHAINS There are two distinct L-chain polypeptides designated kappa (κ) and lambda (λ). L chains contain a variable region and a single constant region domain. Amino acid residues in the L-chain variable region interact with residues in the H-chain variable region to create the antigenbinding cleft. Even though there are two L-chain isotypes, there is no known function associated with the L-chain constant region. The κ chain is used more often than the λ chain in human (65%) and mouse (95%) immunoglobulin molecules.18 IMMUNOGLOBULIN VARIABLE REGION To allow the recognition of a virtually unlimited number of antigens, immunoglobulin molecules must be generated that possess different antigenic specificities. The molecular basis of immunoglobulin diversity is now well understood. Immunoglobulin H- and L-chain genes are encoded by distinct gene segments residing on separate chromosomes; the H-chain locus is on human chromosome 14, the κ-chain locus is on chromosome 2, and the λ-chain locus is on chromosome 22. Individual genes encode the variable and constant regions of an immunoglobulin molecule. A limited number of separate H- and L-chain variable region gene segments undergo somatic rearrangement to generate a multitude of immunoglobulin molecules bearing different antigenic specificities.19 The H-chain variable region is composed of a variable (VH), a diversity (DH), and a joining (JH) gene. The L chain is composed of either Vκ and Jκ or Vλ and Jλ genes; it does not contain D genes. Immunoglobulin genes can exist as functional gene segments, which can be expressed as H- or L-chain polypeptides, or as pseudogenes, which are unable to be expressed. The human H-chain locus

contains approximately 51 VH, 30 DH, and 6 JH functional genes. The κ-chain locus contains approximately 32 Vκ genes and 5 Jκ functional genes; the λ-chain locus contains 29 Vλ genes and 4 Jλ functional genes.20 Variable Region Gene Rearrangement During VDJ rearrangement, different VH, DH, and JH or VL and JL gene segments are randomly combined to generate a large number of different immunoglobulin molecules (Fig. 10-3). VDJ recombination occurs in the absence of antigen stimulation. The molecular mechanism that regulates VDJ rearrangement is activated during B cell maturation in primary lymphoid tissue (see “B Cell Development”). Specific DNA sequences that flank the V, D, and J gene segments are recognized by components of the recombination machinery. These highly conserved sequences that compose the recombination signal sequences are either 7 base pairs (heptamer) or 9 base pairs (nonamer) in length, followed by DNA spacers that are 12 or 23 base pairs in length.21 Specific enzymes termed recombination-activating gene 1 (RAG-1) and recombination-activating gene 2 (RAG-2) initiate VDJ gene rearrangement at the H-chain or L-chain loci by generating double-stranded DNA breaks at recombination signal sequence sites. The cleaved V, D, and J segments are joined by a complex of several polypeptides that includes Ku70, Ku80, and DNA-dependent protein kinase.22 The same recombination machinery also mediates the somatic rearrangement of gene segments for the T cell receptor (see Chapter 9). Variable Region Diversity The random recombination that occurs among V, D, and J gene segments can generate a diverse immunoglobulin repertoire without the need for a large number of germline H- and L-chain genes. During H-chain recombination, nucleotides may be added at VHDH and DHJH junctions by the enzyme terminal deoxynucleotidyl transferase. These non-germline-encoded sequences are known as N additions. As long as these nucleotide changes do not disrupt the reading frame or lead to the incorporation of premature stop codons, the random addition of N sequences increases the diversity of the amino acid sequence. Further, imprecise ligation at the coding junctions may result in the loss of nucleotides, thereby altering the amino acid sequence. The expression of different H- and L-chain combinations also contributes to the creation of diverse binding specificities.3 A process known as somatic mutation can further increase variable region diversity.23 Somatic mutations are point mutations that occur at a high frequency (approximately 10−3 per base pair per cell division) in the variable region of H- and L-chain genes. Unlike the other genetic events that increase diversity in developing B cells, somatic mutations occur in mature, antigen-stimulated B cells present in secondary lymphoid tissue in discrete regions called germinal centers (see “B Cell Activation”). Nucleotide changes that occur in the complementarity-determining region can increase the affinity of the immunoglobulin variable region for a particular antigen or, in some cases, change the specificity from one antigen to another.24 Antigen selection results in more replacement mutations in the

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D H2

VH2

VH3

VHn

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DH2

JH2

D H3

D H3

DH3

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D Hn

JH1

JH2

JH3

JHn

VH3

D H2

JH3

VH3

D H2

JH3 µ

J H3

181

µ δ γ3 γ1 α1 γ2 γ4 ε α2 µ δ γ3 γ1 α1 γ2 γ4 ε α2

VDJ-Cµ transcript

JH2

D H2

JH3

DH2 JH3 Figure 10-3  VDJ recombination at the immunoglobulin gene locus. VDJ recombination at the heavy (H)-chain locus is depicted at the top. A single VH gene segment randomly recombines with a DH and JH gene segment residing on the same chromosome. Following VHDHJH recombination, a transcript containing the IgM H-chain constant region gene (Cμ) is generated. The inset represents an example of VDJ recombination occurring between a single DH and JH gene segment. The white squares represent the heptamer, and the black squares represent the nonamer recombination recognition sequences. Following recognition and cleavage of these sequences, the coding junctions of the rearranged DH and JH gene segments are ligated. A VH gene segment then recombines with the rearranged DHJH segment. Light (L)-chain rearrangement is mediated by the same mechanism.

complementarity-determining regions and fewer in the framework regions.

B CELL DEVELOPMENT The development of undifferentiated hematopoietic stem cells into mature B lymphocytes is divided into two phases: the early stages of B cell lymphopoiesis take place in primary lymphoid tissue, whereas differentiation into B cells that either secrete large quantities of immunoglobulin or persist as long-lived memory cells occurs in secondary or peripheral lymphoid tissue. Primary lymphoid tissue includes the fetal liver and the bone marrow. One of the major events associated with B cell lymphopoiesis in these tissues is immunoglobulin gene rearrangement. Mature, naive B cells exit the primary lymphoid tissue and home to secondary lymphoid tissue, such as the spleen, lymph nodes, tonsils, and Peyer’s patches of the intestine. It is at these sites where B cells interact with foreign antigens and specific humoral immune responses are activated. SITES OF B CELL LYMPHOPOIESIS Hematopoiesis begins during fetal development and persists throughout adulthood.25 Studies of mouse embryonic development show that the first anatomic sites of hematopoiesis are the yolk sac and the aorta-gonad-mesonephros beginning at day 7 post conception. At day 12, hematopoiesis begins in the fetal liver, and before birth, hematopoesis takes place in the bone marrow, which becomes the exclusive site of hematopoiesis after birth and throughout adulthood. Chemokines and adhesion molecules are believed to direct the temporal and spatial changes in hematopoiesis

that occur during embryogenesis. Data suggest that the fetal liver and bone marrow are able to give rise to all B cell subsets, although this is still an area of controversy (see “B Cell Subsets”). B CELL SUBSETS Two subsets of B lymphocytes exist: B1 and B2. The B1 subset is produced earlier in ontogeny than are the B2 cells; the B2 subset includes “conventional” B cells that are replenished from precursor cells in the bone marrow. B1 Cells B1 cells represent a minor population of B cells that reside predominantly in the pleural and peritoneal cavities. B1 cells can be distinguished from B2 cells on the basis of their expression of specific cell surface molecules and the types of humoral immune responses in which they participate (Table 10-2). B1 cells are subdivided into B1a and B1b cells. One of the characteristic markers expressed on B1a cells is constitutive expression of the CD5 surface molecule, which is absent on B1b cells and can be induced on B2 cells. The CD5 molecule is also a common marker for chronic lymphocytic leukemia, which is a B cell-derived tumor.26 Data from mouse studies suggest that B1a cells provide a preexisting source of natural antibody against pathogens, whereas B1b cells produce protective antibodies in response to foreign antigens. There is strong evidence that CD19 and CD21, which form the B cell coreceptor complex, are important for B1 maintenance, because mice deficient in the genes that encode this complex have a reduced number of B1 cells.27

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Table 10-2  Characteristics of B Cell Subsets Characteristic

B1a

B1b

Follicular

Marginal Zone

Surface IgM

High

High

Low

High

Surface IgD

Low

Low

High

Low

CD5

+

–

–

–

CD21

–

–

+

++

CD23

–

–

+

–

CD11b/CD18*

+

+

–

–

Bone marrow progenitors

–

+

+

+

Self-renewal capacity

+

+

–

–

Response to T cell–  independent antigens

+

+

+/–

+

Response to T cell–  dependent antigens

+/–

+/–

+

+/–

Predominant isotype

IgM

IgM

IgG

IgM

Anatomic locations

Peritoneum,   pleura, spleen

Peritoneum,   pleura, spleen

Spleen, lymph nodes,   Peyer’s patches,   tonsils, peripheral blood

Spleen, tonsils

Ig, immunoglobulin. *B1 cells in the spleen do not express CD11b/CD18.

The origin of B1 cells has been debated, but data suggest that most B1 cells arise predominantly from a distinct developmental lineage present in the fetal liver and, to a lesser extent, from precursor cells present in the postnatal bone marrow. Some may arise in the adult bone marrow as well.28 The immunoglobulin repertoire of B1 cells appears to be more restricted than that of B2 cells. Another feature of B1 cells is that terminal deoxynucleotidyl transferase is not expressed in this subset, which is consistent with the absence of N nucleotide additions at the VHDH and JHDH junctions observed in H-chain genes of B1 cells.

expressed on B cell progenitors.20,29 Although many of the soluble factors important in B cell lymphopoiesis have yet to be definitively identified, there is evidence that CXCchemokine ligand 12 (CXCL12), fms-related tyrosine kinase 3 ligand (Flt3L), stem cell factor (SCF), receptor activator of nuclear factor κB ligand (RANKL), interleukin (IL)-7, and sex hormones play a role in human B cell development.30,31 As B cells begin to express surface IgM molecules, they migrate toward the center of the bone marrow cavity and become less dependent on direct interaction with the stroma.

B2 Cells and the Bone Marrow Microenvironment

BONE MARROW STAGES

In humans and mice, B2 cells first arise in the fetal liver, and after birth, they are continually renewed throughout adulthood. Self-renewing pluripotent progenitor cells present in the bone marrow, which give rise to all blood cell types, generate B2 cells. The microenvironment of the bone marrow stroma—which consists of several different cell types, including reticular cells, endothelial cells, macrophages, osteoblasts, and adipose tissue surrounded by extracellular matrix components—provides the environmental cues required for B2 cell development. Hematopoietic stem cells fail to differentiate in vitro in the absence of cultured stromal cells. Thus, the reconstitution of B cell differentiation in vitro using stromal cell lines has led to the discovery of a number of cell surface molecules and soluble factors that are required for B cell lymphopoiesis. Some of these cell surface interactions include the following: vascular adhesion molecule 1 (VCAM-1), expressed on endothelial cells and macrophages, with very late antigen 4 (VLA-4), expressed on B cell progenitors; intercellular adhesion molecule, expressed on stromal cells, with VLA-5, expressed on B cell progenitors; hyaluronate, present on stromal cells, with CD44, expressed on B cell progenitors; and neural cell adhesion molecule (NCAM), expressed on stromal cells, with the membrane proteoglycan syndecan,

The stages of B cell development are defined, in part, by the differential expression of surface markers and genes associated with immunoglobulin gene rearrangement. In the laboratory, these markers are identified by flow cytometry with specific antibodies or by reverse transcription polymerase chain reaction. Many of the cell surface markers used to define particular B cell subsets mediate important signal transduction events associated with maturation and activation, whereas others have no known function at present. Because the events associated with B cell development are not strictly linear, the nomenclature and classification of particular stages vary slightly among the different laboratories working in this field. For simplicity, we have divided the stages of B cell lymphopoiesis into pro-B, pre-B, immature, transitional, and mature cell stages (Table 10-3). Pro-B Cell Stage In humans, the earliest hematopoietic stem cells express the CD34 surface marker. The progression from CD34+ cells to B cell progenitors is regulated by specific transcription factors, including PU.1, Ikaros, E2A, EBF, PAX-5, and Lef-1.32 Pro-B cells continue to express CD34 as well as the surface markers CD19, CD10, CD20, CD21, CD22, CD38, CD40,

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Table 10-3  Human B Cell Maturation Markers during Early B Cell Development Marker

HSC

Pro-B

Pre-B

Immature

Transitional Type 1

Transitional Type 2

CD34

+

+

–

–

–

–

CD19

–

+

+

+

+

+

CD10

–

+

+

+

+

+

CD20

–

+

+

+

+

+

CD21

–

–

–

–

–

+

CD22

–

–

+

+

+

+

CD23

–

–

–

–

–

+

CD38

–

+

+

+

+

+

CD40

–

+

+

+

+

+

CD45

–

+

+

+

+

+

RAG-1

–

+

+

+/–

+/–

+/– +/–

RAG-2

–

+

+

+/–

+/–

Tdt

–

+

+

–

–

–

Igα

–

+

+

+

+

+

Igβ

–

+

+

+

+

+

Heavy chain

–

– (DH-JH)

+ (VH-DH-JH)

+

+

+

Pre-BCR

–

–

+

–

–

–

Surface IgM

–

–

–

+

+

+

Surface IgD

–

–

–

–

–

+

Light chain

–

–

+ (Vк-Jк Vλ-Jλ)

+

+

+

BCR, B cell receptor; HSC, hematopoietic stem cell; Ig, immunoglobulin.

and CD45RB and the major histocompatibility complex (MHC) class II. The surface immunoglobulin accessory molecules Igα and Igβ are also expressed during the pro-B stage. Pro-B cells are dependent on interactions with endothelial cells present in the stroma. The VLA-4 integrin receptor and the CD44 molecules, which mediate adhesion to stromal cells, are highly expressed at this stage and are believed to be important for continued development.20 Pro-B cells also express high levels of Bcl-2. As will be discussed later, this molecule plays a pivotal role in protecting against apoptosis. At the onset of pro-B cell development, the variable gene segments on both H- and L-chain loci are in the unrearranged germline configuration. Before VDJ rearrangement, the genes required for recombination (e.g., those encoding RAG-1, RAG-2, terminal deoxynucleotidyl transferase, and the Ku complex) are expressed. After expression of the recombination machinery, a DH gene segment on one H-chain chromosome rearranges with a JH gene segment residing on the same chromosome (see Fig. 10-3), often with the inclusion of nontemplate nucleotides at the junction. Pre-B Cell Stage During the pre-B cell stage of development, a VH gene rearranges to the DHJH gene fragment. Completion of VHDHJH gene rearrangement leads to the generation of an H-chain transcript that contains the IgM constant region (Cμ), the constant region gene most proximal to the variable region genes on the chromosome (see Fig. 10-3). The different H-chain transcripts encode either a transmembrane molecule or a secretory molecule, determined by alternative splicing. In pre-B cells, however, only transmembrane Cμ is produced.

A critical developmental checkpoint in B cell lymphopoiesis is the cell surface expression of the pre-B cell receptor (pre-BCR) complex at the pre-B cell stage. Before L-chain gene rearrangement, the transmembrane form of the Cμ polypeptide expressed in pre-B cells associates with two other polypeptides, Vpre-B and lambda 5 (λ5), which form the surrogate L chain.33,34 The genes for these molecules are located on human chromosome 22, which also carries the λ-chain locus. There are three separate genes for λ5, known as 14.1, 16.1, and Fλ1; however, only 14.1 encodes a protein. A disulfide-linked complex is formed between the Cμ and the surrogate L chain, which is expressed on the cell surface in association with the accessory molecules Igα and Igβ. It is believed that signals transmitted by the surface pre-BCR complex play an important role in B cell maturation. Surface expression of the pre-BCR transduces a signal to the developing pre-B cell that VDJ rearrangement was successful and halts recombination of the second H-chain allele. This process of allelic exclusion ensures that all immunoglobulin molecules generated within each B cell are identical and have the same antigenic specificity. If rearrangement of the first allele is nonproductive (e.g., genes contain a premature stop codon and cannot be translated into a full-length polypeptide), the absence of pre-BCR signaling permits rearrangement of the second H-chain allele. If the second rearrangement also results in a nonproductive H-chain molecule, the absence of pre-BCR-mediated signal induces apoptosis. Because it has been estimated that about two thirds of VDJ rearrangements are nonproductive, the inability to express the pre-BCR complex ensures that B cells without a productive H chain will not undergo further differentiation. Targeted disruption of genes encoding the pre-BCR complex, such as the IgM transmembrane

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constant region domain, λ5, or the Igα and Igβ accessory molecules, results in a profound decrease in developing B cells. Also, defects in the adapter molecule BLNK or the tyrosine kinase Btk block pre-B cell maturation. After expression of the H-chain polypeptide, L-chain rearrangement occurs. Because terminal deoxynucleotidyl transferase expression is reduced at this stage, L chains do not usually contain N sequences at the VLJL junction. Igα, Igβ, CD10, CD19, CD20, CD21, CD22, CD38, CD40, CD45RB, and MHC class II expression continues throughout the pre-B cell stage; the antiapoptotic molecule Bcl-XL is upregulated in pre-B cells, whereas expression of Bcl-2 is downregulated. Immature B Cell Stage L-chain gene rearrangement marks the transition from the pre-B cell stage to the immature B cell stage. The rearranged transmembrane Cμ and L-chain polypeptides assemble into functional immunoglobulin molecules. At this stage, surface immunoglobulin, which is also known as the B cell receptor (BCR), is expressed. It is believed that surface expression of the BCR on immature B cells transduces signals that enforce allelic exclusion at the L-chain locus and downregulate expression of the RAG genes. As discussed later in this chapter, one of the functions of surface immunoglobulin is to mediate negative selection of autoreactive B cells arising in the bone marrow. Despite the necessity to express a single H- and L-chain molecule in each B cell, circumstances exist that permit the rearrangement of a second H- or L-chain allele. Autoreactivity generated during B cell development in the bone marrow can arise by the random expression of different H and L chains. One of the mechanisms that prevents the survival of potentially autoreactive B cells is a process called receptor editing. Re-expression of the RAG genes in immature B cells permits rearrangement and expression of the second H- or L-chain allele in autoreactive B cells, thus altering antibody specificity. Expression of the antiapoptotic molecule Bcl-XL has been implicated in receptor editing.35 This molecule may prevent apoptosis of autoreactive B cells and extends the window for receptor editing to occur. The mechanism of receptor editing and its role in the regulation of autoreactivity are discussed later in more detail (see “Negative Selection”). Transitional B Cell Stage Murine studies have demonstrated that the later stages of B cell maturation occur in the spleen. Immature B cells differentiate into a phenotypically distinct population known as transitional type 1 (T1) B cells and migrate to the spleen to undergo further maturation to transitional type 2 (T2) B cells. It has not been clearly established whether T2 B cells are direct precursors of mature B cell subsets or whether they undergo additional maturation steps to generate mature B cell precursor cells. The B cell survival factor known as B cell–activating factor of the tumor necrosis factor family (BAFF; also known as Blys) appears to play an important role in T2 B cell development, because blockade of BAFF leads to arrested development at the T2 stage.36 During the transitional B cell stage, an IgD (Cδ) H chain is coexpressed

that bears the same variable region as the previously rearranged Cμ H chain and associates with the same L chain. The switch from IgM+, IgD– to IgM+, IgD+ occurs at the level of transcription. A long transcript containing both Cμ and Cδ genes undergoes alternative splicing to generate both IgM and IgD H chains. The existence of T1 and T2 B cell subsets has also been identified in humans, and these display similar properties as the murine subsets.37 Mature B Cell Stage The final stages of maturation that occur in the spleen and give rise to naive B cell subsets have not been fully elucidated, but the prevailing theory is that T2 B cells give rise to the mature B2 cell populations—follicular and marginal zone B cells. These mature subsets are both phenotypically and functionally distinct and thus respond to different types of antigens (see “B Cell Activation”). Follicular B cells are IgM+, IgD+, CD23+ and display intermediate expression of CD21. The follicular B cell is the most predominant B cell subset in the spleen, and it recirculates throughout the body. As discussed later, follicular B cells require the help of antigen-specific T cells to undergo activation and further maturation into antigen-responsive B cells. Marginal zone B cells are IgM+, IgD–, CD23– and display high expression of CD21. The population is restricted mainly to the marginal sinuses of the spleen. This B cell subset responds to a distinct set of antigens and does not require antigen-specific T cell help. Unlike follicular B cells, marginal zone B cells are absent in humans younger than 2 years; therefore, these young children are unable to generate immune responses to certain antigens. GERMINAL CENTER STAGE Following T cell–dependent B cell activation, B cells undergo further maturation into germinal center cells. Germinal center B cells form the germinal centers present in secondary lymphoid tissue, which are the sites where the final stages of T cell–dependent B cell maturation occur. Following activation, B cells mature into centroblasts. Centroblasts undergo rapid proliferation, and it is at this developmental stage that the process of somatic hypermutation and isotype class switching occurs. Centroblasts develop into centrocytes, which are quite susceptible to programmed cell death unless they receive survival signals from specialized helper T cells and follicular dendritic cells (FDCs) present in the germinal center. Cells that emerge from the centrocyte stage develop into effector memory B cells or plasma cells. Development into memory or plasma cells is regulated by different sets of transcription factors. Memory B cells leave the germinal center and recirculate throughout the body, where they can undergo antigen-dependent activation. Plasma cells home to the bone marrow and secondary lymphoid tissue such as lymph nodes and tonsils, where they secrete copious amounts of antigen-specific antibody. Memory B Cells Memory B cells typically express immunoglobulin genes that have undergone isotype class switching and possess somatic mutations. It is believed that the CD40-CD40L interaction

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directs centrocytes to undergo maturation into long-lived memory B cells. The exact life span of memory B cells is unknown, but it has been postulated that these B cells may persist throughout the lifetime of the host.38 Memory B cells circulate throughout the body in a quiescent state until specific antigen is re-encountered and triggers a potent secondary immune response. Much less antigen is required to activate a secondary response than a primary response. Further, a secondary immune response is generated more quickly than a primary one. Memory B cells ingest antigen and express peptide–MHC class II fragments. After antigen presentation of peptide to helper T cells, memory B cells are activated to undergo expansion and maturation, giving rise to a second wave of plasma cells or memory B cells. Follicular, marginal zone, and B1 cells can generate memory responses. Follicular B cells follow the pathway outlined earlier in which T cells drive their expansion and differentiation into centroblasts, followed by competition for antigen as centrocytes. Evidence for T cell–independent memory responses also exists.39 Marginal zone B cells play an important role in immunity against blood-borne pathogens to generate memory in response to bacterial components.40 B1b cells induce memory responses to carbohydrate antigens.41 Despite the ability of marginal zone and B1b subsets to mediate a memory response, unlike follicular B cells, these T cell–independent subsets do not undergo somatic mutation or affinity maturation. Thus, the preimmune repertoire of marginal zone and B1 cells contributes to the “natural” or “innate” memory response. Plasma Cells The B cell maturation cascade ends with the generation of plasma cells, which are factories for the secretion of soluble antibody molecules. B cells undergoing differentiation into plasma cells exit the lymphoid follicles and migrate to extrafollicular regions of secondary lymphoid tissue or to the bone marrow, where the final stage of plasma cell maturation occurs. There is evidence that IL-5 and IL-6 help induce plasma cell differentiation, whereas engagement of CD40CD40L molecules blocks this differentiation pathway. The transcriptional repressor known as B lymphocyte–induced maturation transcription factor (Blimp-1) plays a critical role in the differentiation into plasma cells.42 Plasma cells are terminally differentiated and have a finite life span, which can be quite long.43 Studies performed with immunized mice demonstrate that long-lived plasma cells generated within germinal centers have a half-life of more than 100 days; short-lived plasma cells that arise from extrafollicular B cells have a half-life of less than 10 days.44

B CELL HOMING Lymphoid tissues contain the microenvironment necessary for the homing, retention, and activation of B cells. As mentioned earlier, several different types of secondary lymphoid tissue exist, including the spleen, lymph nodes, and mucosaassociated lymphoid tissue (e.g., Peyer’s patches, appendix, tonsils). Secondary lymphoid tissues are well adapted to trap circulating antigen. Peripheral lymphoid tissue contains specialized antigen presenting cells known as dendritic cells

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(see also Chapter 8). The Peyer’s patches of the intestines collect foreign antigen in specialized epithelial cells known as M cells. Even though peripheral lymphoid tissues vary in structure and cellular organization, they all possess antigen presenting cells and B cell–containing follicles surrounded by T cell–rich zones. As explained in the following section, antigen, T cells, and dendritic cells are required for B cell activation and differentiation into immunoglobulinsecreting plasma cells or memory B cells. B1 cells typically home to the peritoneal and pleural cavities and, to a lesser extent, the spleen. Follicular B cells enter the peripheral circulation by passing through the endothelial lining of the sinusoids of secondary lymphoid tissue and recirculate throughout the follicles of secondary lymphoid tissues. Because follicular B cells require antigen-specific T cell help for activation, the localization of this subset near a T cell zone of B cell follicles facilitates the chance encounter between antigen-specific B cells and cognate T cells. Conversely, marginal zone B cells respond to antigen without the help of cognate T cells. They localize exclusively in the spleen of mice and in the spleen and tonsils of humans owing to interactions between adhesion molecules and chemokine receptors that sequester marginal zone B cells within the marginal sinuses. The location of marginal zone B cells makes them well suited to capture blood-borne antigens. As mentioned earlier, chemokines play a major role in the formation of secondary lymphoid tissue and the localization and retention of B cells in environmental niches.45,46 The chemokines CCL19 and CCL21, which bind to the CCR7 receptor on T cells and dendritic cells, mediate the formation of the T cell zones where cognate T cell–B cell interactions occur. The CXCR5 molecule expressed on B cells mediates the migration to follicles in response to the chemokine CXCL13, which is regulated in turn by the cytokine lymphotoxin a, made by B cells. In mucosal tissue, CCL20 is responsible for the recruitment and retention of CCR6-positive B cells, and CCL25-CCR9 interactions play a role in localizing plasma cells to the small intestine. Dysregulation of the chemokine response is thought to play a role in the formation of ectopic lymphoid aggregates that resemble secondary lymphoid tissue and occur in several inflammatory diseases, including rheumatoid arthritis and Sjögren’s syndrome. Chemokines also play an important role in germinal center responses. The chemokine CXCL12 retains centroblasts in the dark zone during the process of somatic hypermutation and isotype class switching. CXCL13 regulates migration to the light zone, where survival and selection events are mediated by interactions with CXCR5-expressing follicular helper T cells and FDCs. In addition, CXCL12 promotes the migration of plasmablasts to the bone marrow, where they undergo further development into long-lived plasma cells.

B CELL ACTIVATION REGULATION OF B CELL ACTIVATION Engagement of surface immunoglobulin by antigen triggers a series of cellular events that regulate B cell proliferation and differentiation. Receptor cross-linking leads to relocation of

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the BCR to microdomains known as lipid rafts, which leads to the rapid activation of proximal mediators of the BCR signal transduction pathway.47 This results in the activation of second messengers such as phospholipase C, phosphatidylinositol 3-kinase, and Ras pathways. Induction of these pathways ultimately transmits signals to the nucleus, initiating new gene expression. Depending on the type of signal delivered and the stage of maturation, B cells can undergo either differentiation into memory B cells and plasma cells or apoptosis. Along with surface immunoglobulin, several other membrane receptors modulate antigen-induced signal transduction. POSITIVE REGULATORS The BCR complex is composed of surface immunoglobulin, along with the accessory molecules Igα and Igβ. The role of surface immunoglobulin is to recognize foreign antigen; the Igα and Igβ molecules are responsible for the induction of signal transduction pathways required for B cell activation. The cytoplasmic domains of Igα and Igβ contain a specific signaling motif known as the immunoreceptor tyrosine-based activation motif (ITAM). The ITAM amino acid sequence contains two tyrosine residues that are critical for signaling. After phosphorylation of these tyrosine residues,

the ITAM acts as a docking site to recruit other signaling molecules. The binding of antigen to surface immunoglobulin results in BCR clustering on the cell surface and lipid raft formation. This triggers a cascade that first leads to kinase activation, followed by the activation of second messenger pathways. Once the receptors are cross-linked, the BCR-associated tyrosine kinases mediate phosphorylation of the Igα and Igβ ITAM tyrosine residues (Fig. 10-4). Signaling through the BCR leads to numerous events, such as B cell activation and endocytosis of antigen-antibody complexes, B cell proliferation, B cell differentiation, and apoptosis. Many molecules can modulate BCR signal transduction, either enhancing or diminishing the signal transduced by antigen; B cell coreceptor complex (CD19/CD21/CD81/Leu-13), CD45, SHP1, SHP-2, SHIP, CD22, FcγRIIB1, CD5, CD72, PIR-B, and PD-1 (see Fig. 10-4) determine the threshold for activation as well as the strength of the BCR signal. CD45 Receptor tyrosine kinases require activation by phosphorylation of specific tyrosine residues; they also require inactivation. Their inactivation in resting B cells is maintained

Activation

Inhibition

BCR

CD21 CD19

PIR-B

CD72

PD-1

FcγR IIB-1

CD5

I T I M

I T I M

I T I M

I T I M

I T I M

SHP-1

SHP-1

SHP-1 SHP-2

SHP-1

SHP-1 SHP-2

SHIP

CD22

CD45

CD81 Leu-13 Igα

Igβ

I T A M

I T A M

Blk Fyn Lyn Lyn

Syk and Btk

Vav Fyn Lyn

I T A M

BLNK PLC/PKC/Ras

P-Tyr MAPK

Nucleus

Tyr

Gene expression

Figure 10-4  Molecules that regulate the activation state of B cells. Coligation of surface immunoglobulin results in tyrosine phosphorylation at specific tyrosine residues present in the immunoreceptor tyrosine activation motif (ITAM) of Igα and Igβ cytoplasmic domains. This occurs after the removal of the inhibitory tyrosine residues of the B cell receptor (BCR)–associated cytoplasmic kinases such as Blk, Fyn, and Lyn, which is mediated by CD45. The phosphorylated ITAMs recruit and activate the Syk and Btk kinases, which in turn activate a series of second messenger pathways (PLC, PKC, and Ras) that result in the upregulation of genes required for B cell activation and survival. Coligation of the pre-BCR complex (CD19, CD21, CD81, and Leu-13) results in phosphorylation of tyrosine residues residing in the cytoplasmic domain of CD19. Cytoplasmic kinases, including Vav, Fyn, and Lyn, become activated and enhance the signaling mediated by the BCR. Following the activation of distal mediators of BCR signaling such as PLC, PKC, and Ras, molecules of the MAPK pathway become activated and translocate to the nucleus to regulate gene expression. Signals mediated by CD22, PIR-B, CD72,  PD-1, FcγRIIB1, and CD5 deliver negative signals that block the activation of distal molecules. Following phosphorylation of the immunoreceptor tyrosine inhibition motif (ITIM), present in the cytoplasmic tail of these molecules, the phosphatases SHP-1, SHP-2, and SHIP are recruited and activated.

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by the phosphorylation of specific inhibitory tyrosine residues. For B cell activation to occur, phosphate groups must first be removed from the inhibitory tyrosine residues of the BCR-associated Src tyrosine kinases by CD45. CD45 has an extensive extracellular domain, with no clearly defined ligand specificity, and a cytoplasmic domain that possesses tyrosine phosphatase activity. Mice deficient for CD45 display a diminished response to antigen and have a decreased number of mature B cells, indicating that some level of BCR activation is required for the transition from immature to mature B cells during lymphopoiesis.48 CD45 is generally considered to be a positive regulator of BCR signaling, but it can also act as a negative regulator by initiating a feedback loop to limit the extent of BCR activation (see “CD22”). CD19 and CD21 The B cell coreceptor complex is composed of CD19, CD21, CD81, and an interferon-inducible molecule called Leu-13.5 CD19 has also been shown to associate with surface immunoglobulin.49 After antigen cross-linking of surface immunoglobulin, specific tyrosine residues contained within the CD19 cytoplasmic domain rapidly become phosphorylated. To date, the natural ligand for CD19 is not known. In vitro studies have demonstrated that ligation of CD19 with anti-CD19 antibody lowers the threshold required for BCRmediated B cell activation and enhances the proliferative effect of anti-IgM treatment on B cells.50 A role for CD19 in B cell activation has been clearly defined in mice that either are deficient in or overexpress CD19.27 The CD19 molecule is required for germinal center formation and humoral responses to T cell–dependent antigens and possibly T cell–independent antigens. The CD21 molecule serves as a receptor for cleavage fragments of the C3 component of complement—iC3b, C3dg, and C3d. Mice deficient in CD21 also have impaired responses to T cell–dependent and T cell–independent antigens and a defect in germinal center formation.27,51 A proposed mechanism for the function is that co-cross-linking of the BCR and CD21 with complement-coated antigen triggers the activation of the cytoplasmic tail of CD19. The functions of the remaining two components of the B cell coreceptor complex, CD81 and Leu-13, have not been characterized, although it has been suggested that these molecules may mediate homotypic cell adhesion. INTRACELLULAR KINASES AND DOWNSTREAM PATHWAYS The signal transduction events that occur after BCR crosslinking are mediated by the subsequent recruitment and activation of intracellular kinases, including Lyn, Fyn, Btk, and Syk. The most proximal event following BCR cross-linking is the activation of Lyn, which results in the activation of CD45 to remove the inhibitory phosphates on the ITAMs of Igα and Igß; the activation of Lyn leads to the activation of Syk and Btk.52 There is evidence that ligation of CD19 leads to recruitment and activation of Vav, phosphatidylinositol 3-kinase, Fyn, Lyn, and Lck.53 Subsequently, the tyrosine kinases Syk and Btk interact with the phosphorylated ITAM and are activated by tyrosine phosphorylation. The phosphorylation of Syk triggers the activation of

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phospholipase C, phosphatidylinositol 3-kinase, and Ras pathways. The activation of Syk appears to be absolutely critical for BCR-mediated signal transduction, because Sykdeficient cell lines exhibit a loss of BCR-induced signaling. Btk also appears to be required for the activation of second messenger pathways. In patients with X-linked agammaglobulinemia, a mutation in the Btk gene results in impaired BCR signaling at the pre-B cell stage.52 As a consequence, these patients have a greatly reduced number of mature B cells and generate poor antibody responses. In mice, however, a mutation in Btk leads to a disease known as X-linked immunodeficiency. B cell development is impaired at the transitional T2 stage, and B cells that do go on to maturity are unable to respond to certain T cell–independent antigens. Following recruitment and activation of the intracellular kinases, downstream pathways are initiated. Btk, Syk, and the adapter molecule BLNK are required for the phospholipase C gamma. This leads to breakdown of phosphatidylinositol 4-phosphate to DAG and IP3 to trigger calcium release from intracellular stores and the subsequent translocation of nuclear factor of activated T cells (NFAT) to the nucleus. In addition, Btk activates Ras, which leads to nuclear translocation of the transcription factor activator protein-1 (AP-1). BCR cross-linking also activates nuclear factor κB (NFκB) via the degradation of IKKα and ERK MAP kinases; ultimately, NFκB regulates cellular processes such as activation apoptosis. NEGATIVE REGULATORS CD22 The CD22 receptor is a surface molecule that can also associate with the BCR, presumably through interaction with α2,6-sialylate sugars present on IgM.54 Although CD22 contains an ITAM and is able to recruit Src tyrosine kinase to its cytoplasmic domain,55 CD22 is primarily a negative regulator of BCR activation. Within the cytoplasmic domain of CD22 is a specific motif known as the immunoreceptor tyrosine-based inhibition motif (ITIM). As with the ITAM, a critical tyrosine residue resides in the ITIM that mediates signal transduction events. After activation of Lyn by CD45, it is believed that the ITIM of CD22 is phosphorylated by Lyn, leading to the recruitment of intracellular phosphatases such as SHP-1.54 B cells of mice deficient for CD2255 and Lyn56 have a phenotype similar to the SHP-1–deficient viable moth-eaten mice (see later). FCγRIIB1 FcγRIIB1 appears to be expressed exclusively on B cells, and unlike other types of FcγR, it is unable to mediate phagocytosis. The simultaneous ligation of both the BCR and FcγRIIB1 sends an inhibitory signal to prevent antigen activation of naive B cells. In the presence of high levels of circulating immune complexes, this inhibitory signal provides a negative feedback mechanism to attenuate an antigen-induced antibody response. Recruitment and activation of SHIP by FcγRIIB1 is required for downregulation of BCR signaling.57 After coligation of FcγRIIB1 and the BCR, it is believed that Lyn phosphorylates FcγRIIB1.56 SHIP then

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associates with the FcγRIIB1 and mediates the dephosphorylation of CD19, thereby terminating BCR signaling.58 Depending on the genetic background, mice deficient in FcγRIIB1 display a lupus-like phenotype.59 CD5 The role of CD5 in B1a cell function is not well understood. After BCR cross-linking, CD5 is thought to mediate signals that induce apoptosis and block proliferation.60 Cross-linking of CD5 with an anti-CD5 monoclonal antibody results in apoptosis. There is some evidence that CD5 recruits the inhibitory phosphatase SHP-1 to its cytoplasmic domain. However, unlike CD22 and FcγRIIB1, CD5 does not contain a strong ITIM consensus sequence and may recruit SHP-1 indirectly.61 The ligand-binding region of CD5 remains to be elucidated, but recent evidence demonstrates that CD5 is a ligand for another negative regulator of BCR signaling, CD72.

B cells develop without bias for a particular antigenic specificity, ensuring that a diverse repertoire of different immunoglobulin molecules is produced. Despite the expression of antiapoptotic molecules such as Bcl-2, naive B cells are short-lived unless they are activated in the presence of antigen and accessory cells, such as dendritic cells and T cells. Antigen-activated B cells undergo clonal expansion; B cells that do not interact with antigen are destined to undergo programmed cell death in a matter of days or weeks. The B1 and B2 cell subsets are regulated by different activation mechanisms and are involved in different immune responses (see Table 10-2). INHIBITORY PHOSPHATASES SHP-1

CD72 is a transmembrane receptor that is expressed as a homodimer. The cytoplasmic tail of CD72 contains ITIMs, and experiments have shown that CD72 recruits SHP-1. Mice with a targeted disruption of the CD72 gene reveal that CD72 plays a negative role in B cell activation. The B cells of CD72-deficient mice are similar to those of viable moth-eaten mice. They have an expansion of B1 cells and B cells that are hyperresponsive to BCR cross-linking and are more resistant to BCR-mediated apoptosis.62 There are several putative ligands for CD72, including CD5 and CD100.

SHP-1, another tyrosine phosphatase, is a potent negative regulator of BCR signaling. SHP-1 is a cytosolic protein found in association with transmembrane proteins such as CD22, FcγRIIB1, CD5, CD72, and PIR-B. SHP-1 antagonizes BCR signaling by inactivating tyrosine kinases associated with signaling. Potential candidates for SHP-1 dephosphorylation include Igα and Igβ, CD19, and Syk.61 The function of SHP-1 has been extensively studied in mice that bear a naturally occurring mutation in the SHP-1 gene. Mice with this genetic defect are known as moth-eaten mice because of the appearance of their fur. These mice have a decreased number of conventional B cells and an expansion of B1 cells, accompanied by high titers of autoreactive IgM antibodies.65 This defect in B cell regulation underscores the importance of SHP-1 in limiting the extent of BCR signaling.

PIR

SHP-2

Paired immunoglobulin-like receptor (PIR)-A and PIR-B are expressed in a pair-wise fashion, as the name implies. These receptors are believed to have opposing functions, with PIR-A inducing an activation signal and PIR-B inducing an inhibition signal. The ligands for PIR-A and PIR-B remain to be elucidated. Although little is known about the role of PIR-A in B cell activation, recent data demonstrate that PIR-B plays a role in downregulating B cell responses. The cytoplasmic tail of PIR-B possesses several ITIMs that recruit inhibitory phosphatases. Mice that harbor a targeted disruption of the PIR-B gene exhibit a phenotype similar to mice that are deficient in the other ITIM-bearing inhibitory receptors, such as an expansion of B1 cells and B cell hyperresponsiveness.63

The intracellular tyrosine phosphatase SHP-2 is structurally similar to SHP-1. As with SHP-1, SHP-2 is recruited to the ITIM of inhibitory receptors. Mice deficient in SHP-2 are not viable, suggesting that SHP-2 plays a role in embryonic development.66 Studies of chimeric mice suggest that SHP-2 plays a role in hematopoiesis and that SHP-1 and SHP-2 act in an antagonistic fashion.67

CD72

PD-1 PD-1 is an inhibitory molecule expressed predominantly on activated B and T cells. The ligand-binding domain binds PD-1L, and the cytoplasmic tail of PD-1 contains ITIMs that recruit SHP-2 to attenuate BCR signals. The B cells of PD-1–deficient mice are hyperresponsive to BCR signaling, and these mice display an augmented response to T cell–independent type II antigens. On certain genetic backgrounds, PD-1 deficiency leads to an autoimmune phenotype.64

SHIP SHIP is an inositol phosphatase that inhibits B cell activation by hydrolyzing the 5' phosphate from phosphatidylinositol 3,4,5-triphosphate, a critical component of numerous signaling pathways. As with SHP-1 and SHP-2, SHIP is recruited to ITIMs following BCR cross-linking. The role of SHIP in downregulating BCR-induced signals is demonstrated by its association with FcγRIIB1. Mice deficient in SHIP display splenomegaly and elevated levels of serum antibody.68 SIGNAL TRANSDUCTION IN IMMATURE VERSUS MATURE B CELLS An important event in BCR signaling is the recruitment of signaling components to lipid rafts, which are lipid-rich microdomains of the membrane. In the resting state, the

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BCR is excluded from lipid rafts, but following antigen engagement, the BCR translocates into rafts, and the BCR signaling cascade ensues due to the clustering of signaling components. In addition to activating signals, however, inhibitory signals are mediated by recruitment of FcγRIIb into lipid rafts. As discussed later, BCR ligation mediates negative selection during the immature and transitional B cell stages and B cell activation during the mature B cell stage. The reason for these two distinct outcomes is not clear, because the same signal components are present; however, differences in membrane cholesterol limit recruitment of the BCR to lipid rafts in immature B cells.69 There is also evidence that the signal strength and duration and stagespecific expression patterns of signaling elements may differ between immature and mature B cells.70 B1 CELL ACTIVATION B1 cells present in the pleural and peritoneal cavities respond to T cell–independent antigens. There are two classes of T cell–independent antigens: type I, which includes lipopolysaccharide, and type II, which includes large multivalent antigens with repetitive epitopes, often found on the surface of bacteria. T cell–independent antigens can directly activate B cells, resulting in the secretion of antibody. Soluble factors, such as IL-5 and IL-10, also appear to be involved in the maintenance and activation of B1 cells. B1 cells do not require activation by antigen-specific T cells. However, activated T cells and macrophages may augment B1 cell activation, enhance immunoglobulin production, and influence isotype class switching. The main H-chain isotypes produced by B1 cells in response to T cell– independent antigens are IgM, IgA, and IgG. MARGINAL ZONE B CELL ACTIVATION Marginal zone B cells are similar to B1 cells, in that they do not require cognate T cell help for activation. Marginal zone B cells respond to T cell–independent type II antigens and play an important role in early protection against particulate blood-borne pathogens. They are situated in the marginal sinuses, where specialized macrophages trap and remove antigen from the circulation. Soluble factors, such as BAFF, and T cell–derived cytokines appear to be important for marginal zone B cell activation. Following activation by antigen, marginal zone B cells differentiate rapidly into antibody-secreting plasma cells. Marginal zone B cells secrete predominantly IgM antibodies and, to a lesser extent, IgG antibodies. FOLLICULAR B CELL ACTIVATION As naive follicular B cells leave the circulation and contact antigen and antigen-specific Th cells, those cells with a BCR specific for antigen are sequestered and activated. Engagement of the BCR by antigen signals the B cells to engulf the antigen, process it intracellularly, and express peptide fragments bound to MHC class II molecules on the B cell surface. After the expression of peptide fragments bound to MHC class II molecules, antigen-activated B cells present peptide to primed helper T cells. B cells and T cells interact through

189

Antigen BCR CD40L

CD40 CD4 Naive B cell

MHC II

Peptide

Activated TH

TCR CD28

B7

Activated B cell

Cytokines IL-2 IL-3 IL-4 IL-5 IL-10 IFN-γ

Figure 10-5  B cells as antigen presenting cells. Antigen bound to surface immunoglobulin on naive B cells triggers endocytosis and intracellular processing of the antigen. B cells engage antigen-specific helper  T (TH) cells through the recognition of foreign peptide by the T cell receptor (TCR) and through the binding of a conserved region of the MHC II molecule by CD4. Along with antigen binding, coligation of CD40 and B7 (expressed on B cells) with CD40L and CD28 (expressed on T cells) provides critical costimulatory signals and the secretion of cytokines required for B cell activation.

T cell receptor recognition of a peptide-MHC complex on the B cell and through engagement of costimulatory molecules B7 and CD40 (Fig. 10-5). The B7 molecule, which interacts with CD28 on helper T cells, is not constitutively expressed on B cells but is induced after antigen uptake by B cells. Helper T cells secrete cytokines, such as IL-3, IL-4, IL-5, and IL-10, and provide costimulatory signals that are important for B cell maturation and differentiation.71 B cell activation during a T cell–dependent immune response also depends on engagement of the CD40 receptor expressed on B cells with the CD40 ligand (CD40L) expressed on T cells.72 The importance of signal transduction events mediated by CD40-CD40L engagement is evident from studies of patients with a type of X-linked hyper-IgM syndrome, an immunodeficiency disease resulting from a defect in CD40L. These individuals do not mount strong immune responses to T cell–dependent antigens; they have high concentrations of circulating IgM but only trace amounts of IgG isotypes and no affinity maturation of the antibody response. Activated follicular B cells can undergo two different fates. Some of the activated B cells begin to proliferate to form primary foci.73 These B cells can differentiate into short-lived plasma cells that secrete an immediate supply of antigen-specific antibody during a primary immune response (i.e., the first time a particular antigen is encountered by the immune system). The antibodies produced by these short-lived plasma cells are usually of the IgM isotype and are of low affinity because of the absence of somatic mutations. Alternatively, the proliferating B cells, along with the activating antigen-specific helper T cells, can migrate to the primary follicles of secondary lymphoid tissue. During a primary immune response, antigen-activated follicular B cells form discrete structures in the primary follicles,

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known as germinal centers. Isotype class switching, affinity ­maturation, and differentiation into memory B cells or longlived plasma cells are part of the germinal center reaction. MATURATION IN GERMINAL CENTERS Germinal centers can be subdivided into separate regions where the different stages of B cell maturation take place (Fig. 10-6). The dark zone is composed of rapidly dividing cells called centroblasts, which develop into cells known as centrocytes. Centrocytes migrate to the light zone, where they encounter a dense network of FDCs and follicular helper T cells. B cells that do not express moderate- to high-affinity BCRs are excluded from the light zone; B cells that receive vital survival signals differentiate into plasma or memory cells. Each stage of maturation is characterized by the differential expression of B cell surface markers (Table 10-4). Centroblasts in the dark zone are rapidly proliferating cells derived from a relatively small number of antigen-activated B cells. Expression of the antiapoptotic Bcl-2 protein is low in these cells, whereas expression of the proapoptotic Fas protein is upregulated.74 Low levels of Bcl-2 expression render developing B cells sensitive to apoptosis, but these cells can be rescued by antigen and CD40-CD40L interactions provided by antigen-specific helper T cells. The process of somatic mutation is activated during the centroblast stage. As discussed earlier, somatic mutation is a process that introduces nucleotide base-pair changes in the DNA sequence of immunoglobulin genes, giving rise to antibodies with a potentially higher affinity for antigen. The mechanisms that regulate the somatic mutation process are poorly understood. Current data show that (1) somatic mutations are introduced only into rearranged immunoglobulin genes, (2) cis-acting DNA elements that flank immunoglobulin genes may help target the variable region genes for mutation, and (3) immunoglobulin gene transcription is required.23 Activation-induced cytidine deaminase (AID) plays a critical role in somatic mutation and also isotype class switching (see later), because the immunoglobulin variable regions of humans and mice with genetic lesions in the AID gene are largely unmutated and display no H-chain class switching.75,76 The insertion of somatic mutations occurs throughout the coding region of the variable gene segment and within 1 kilobase in each direction of the coding region between the promoter region and constant region of the rearranged immunoglobulin gene. DNA sequences known as “hot spot” motifs have been identified that appear to be targeted by the somatic mutation machinery with a higher frequency than are non–hot spot sequences.77 B cell clones that express surface immunoglobulin with an increased affinity for antigen are selectively expanded during the affinity maturation process, whereas B cells that express somatically mutated immunoglobulins with low affinity for antigen or novel binding to self-antigens are targeted for apoptosis or inactivation. The importance of somatic mutation and affinity maturation during an immune response is underscored by the fact that patients with mutations in the AID gene are severely immunocompromised. Centroblasts give rise to centrocytes located in the basal region of the germinal center light zone.74 Because

Resting B cell

FDC

Centrocyte

Centroblast

Follicular mantle zone

Memory cell TH or

Plasma cell

Apical light zone

?

TH

Basal light zone

Dark zone Figure 10-6  B cell maturation in germinal centers. Following exposure to antigen, B cells in the primary follicles form germinal centers or migrate to previously formed germinal centers. Centroblasts located in the dark zone undergo proliferation and acquire somatic mutations. A small number of proliferating centroblasts can give rise to a larger number of centrocytes present in the basal light zone. As these cells pass through a dense network of follicular dendritic cells (FDCs) and helper T cells (TH), centrocytes bearing surface immunoglobulin receptors with high affinity for antigen undergo positive selection. Centrocytes in the apical light zone are nondividing cells that undergo differentiation into memory B cells or plasma cells. It has been suggested that centrocytes may return to the dark zone, where additional somatic mutations may be acquired. Resting B cells that are not activated by antigen are pushed aside to form the follicular mantle zone.

centrocytes are short-lived cells and express high levels of Fas and low levels of Bcl-2, they require survival signals from FDCs. FDCs differ from the other types of antigen pre­ senting cells in that they do not process antigen and pre­ sent peptide–MHC class II complexes on the cell surface. Instead, they trap antigen by collecting antigen-antibody complexes known as iccosomes (immune complex-coated bodies) on the cell surface. Iccosomes bind to FcγR present on FDCs and deliver an antigen-specific signal to B cells through the BCR (Fig. 10-7). Centrocytes with specificity for antigen on FDCs are saved from apoptosis by upregulation of the Bcl-2 molecule. Engagement of the complement receptors CR1 and CR2 (CD21 and CD35, respectively) on B cells by components of the C3 complement protein (iC3b, C3dg, and C3d) bound to FDCs may mediate a secondary costimulatory signal.78 If centrocytes do not receive these positive selection signals, they rapidly die. As antigenselected centrocytes move into the apical light zone, they no longer divide but continue maturing into memory B cells or plasma cells. Concurrent with the positive selection of antigen-specific centrocytes in germinal centers, signaling events mediated by CD40L-CD40 and helper T cell–derived cytokines promote isotype class switching in B cells. Helper T cells secrete IL-4, which mediates class switching to IgG4 and

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Table 10-4  Markers of Antigen-Activated B Cells in Secondary Lymphoid Tissue Marker

Naive

Centroblast

Surface IgD

+

–

Surface IgM, IgG, IgA,   or IgE

+

–

CD10

–

+

CD20

+

CD38

–

Centrocyte

Memory

Plasma

–

–

–

+

+

–

+

–

–

+

+

+

–

+

+

–

+

CD77

–

+

–

–

–

Presence of somatic   mutation

–

+

+

+

+

Isotype class switch

–

–

+

+

+

Bcl-2

+

–

+/–*

+

+

Fas

+

+

+

+

–

AID

–

+

–

-

–

Blimp-1

–

–

–

?

+

AID, activation-induced cytidine deaminase; Ig, immunoglobulin. *Bcl-2 is expressed in centrocytes only after interaction with follicular dendritic cells.

REPERTOIRE SELECTION NEGATIVE SELECTION

GC B cell α

β CD21

BCR

CD21L (C3 fragments)

Antigen-antibody complex

CD21

FcR FDC

Figure 10-7  Engagement of B cells with follicular dendritic cells. In­ teraction between follicular dendritic cells (FDCs) and B cells results in signals that mediate the positive selection of B cells in germinal centers (GCs). Antigen-antibody complexes trapped on the FDC surface deliver a signal to the B cell receptor (BCR). A second signal is delivered by the binding of CD21 on B cells to C3 complement components on the surface of FDCs.

IgE and IL-10, which mediates class switching to IgG1 and IgG3. Switching occurs by a deletional mechanism that brings a downstream constant region gene in juxtaposition with the VDJ gene segment.6 Upstream of each constant region gene segment are switch recombination sequences that contain binding sites for proteins known as switch factors. A putative enzyme known as switch recombinase catalyzes the removal of the upstream constant region gene sequences. The AID molecule, which plays a critical role in somatic mutation, is also required for isotype class switching, and patients and mice with mutations in the AID gene exhibit a hyper-IgM syndrome due to a defect in class switching.76 Although it is clear that follicular B cells participate in a germinal center reaction, some data suggest that marginal zone B cells can form germinal centers in response to a T cell–dependent antigen.79

An important feature of the immune system is the discrimination between foreign and self-antigens. Self-antigens are molecules derived from intracellular or extracellular components of the host. B cells with surface immunoglobulin receptors that recognize self-components are subjected to a process known as negative selection, or tolerance induction, to avoid autoreactivity. The immune system has evolved several mechanisms to selectively inactivate B cells that recognize self-antigen while still permitting the activation and expansion of B cells that recognize foreign antigen. In an intact immune system, autoreactive B cells that are generated in either the bone marrow or the periphery can be regulated by various mechanisms; the tolerance mechanism activated depends on the strength of the BCR signal delivered by the self-antigen and the developmental stage of the B cell. The concentration of self-antigen and the affinity of the antibody for self-antigen determine the degree of receptor occupancy of surface immunoglobulin and the strength of the BCR signal. If there is little receptor cross-linking, either because antigen concentration is low or because the affinity of the antibody is weak, there is no BCR signaling, and the autoreactive B cells are not tolerized. If receptor cross-linking reaches the threshold necessary to trigger a signaling cascade, an autoreactive B cell (in the absence of T cell help) undergoes tolerance induction. Three mechanisms are currently believed to mediate tolerance induction: receptor editing, anergy, and deletion. When mechanisms that regulate autoreactive B cells fail, the breakdown of self-tolerance can lead to the development of autoimmune disease. CENTRAL AND PERIPHERAL TOLERANCE There are two stages in B cell development when autoreactive B cells can be generated. The first wave of autoreactivity arises in the bone marrow after VDJ rearrangement and

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expression of surface immunoglobulin on immature B cells. Because of the vast number of different antibody molecules that can be formed through the random recombination of H- and L-chain variable region genes, all individuals generate autoreactive B cells. The process that prevents the exit of autoreactive B cells from the bone marrow is known as central tolerance. Immature B cells are particularly sensitive to tolerance induction, probably owing to the absence of Bcl-2 expression and the lack of costimulation by helper T cells. Peripheral tolerance refers to the downregulation of autoreactive B cells in peripheral lymphoid tissue. Transitional B cells may undergo peripheral tolerance if they encounter autoantigen for the first time in the periphery. Antigen-activated B cells that have acquired autoreactivity by somatic mutation in germinal centers may also undergo peripheral tolerance. At this developmental stage, it is crucial that the maturation of autoreactive B cells into memory B cells or plasma cells be blocked. RECEPTOR EDITING Cross-linking of the BCR on autoreactive B cells with a high affinity for self-antigen results in tolerance induction. However, these B cells can be salvaged if the original autospecificity is modified by a process known as receptor editing. In this process, the immunoglobulin surface receptor undergoes revision to acquire a new, nonautoreactive specificity. This occurs by secondary gene rearrangement events, such as intrachromosomal deletion accompanied by VH or VL replacement, novel intrachromosomal rearrangement of upstream VL genes and downstream JL genes, or rearrangement of H- and L-chain genes on an unrearranged locus.80 Studies from transgenic mice suggest that receptor editing occurs in both immature and transitional B cells and possibly in germinal center B cells as well. Autoreactive B cells in transgenic mice expressing self-reactive specificities, such as anti–double-stranded DNA81 or anti–MHC class I haplotype,82 encounter self-antigen in the bone marrow. They continue to express RAG-1 and RAG-2 and generate DNA excision products resulting from secondary immunoglobulin gene rearrangement events. In these models, survival of edited B cells depends on the expression of a second L-chain molecule that is able to associate with the transgene-encoded H chain and displace the initial L chain. There is evidence that H-chain receptor editing can also occur in the bone marrow.83,84 It remains controversial whether mature B cells in the periphery can also undergo receptor editing during the germinal center stage of B cell development. ANERGY Some autoreactive B cells enter a hyporesponsive state known as anergy. Anergy is thought to be induced in immature B cells when they undergo a modest degree of BCR cross-linking. Anergic B cells downregulate surface immunoglobulin receptors and display a desensitization of the BCR, blocking activation of downstream mediators of signaling. Further, anergic B cells are short-lived. Goodnow and colleagues85 performed classic studies on B cell tolerance induction in mice engineered to express an anti–hen egg lysozyme (HEL) antibody, along with soluble HEL,

which acts as a self-antigen. In the anti-HEL transgenic mouse model, B cells that encounter soluble, monovalent­ HEL are anergized. These B cells populate secondary lymphoid tissue but do not secrete anti-HEL antibody and cannot be recruited into a germinal center response. This phenomenon is known as follicular exclusion.86 It appears that anergy can be reversed under certain conditions. Experimentally, anergy is broken in vitro by treatment with lipopolysaccharide or anti-CD40 antibody and IL-4. Exposure of anergic B cells in vivo to multivalent antigen in the presence of activated helper T cells may also lead to their activation.87 It has been suggested that anergic B cells serve as a potential source of autoantibody and may be activated in inflammatory conditions. DELETION Extensive BCR cross-linking in the absence of helper T cell costimulation leads to a type of tolerance induction called deletion. In the transgenic model described earlier, when anti-HEL B cells encounter multivalent membrane-bound HEL autoantigen in the bone marrow, they are deleted.88 These results suggest that when antigen binding exceeds the threshold for anergy induction, cell death is triggered. Deletion of autoreactive B cells also occurs in the periphery and may be a means to control B cells expressing somatically mutated, high-affinity autoantibodies. B cells are deleted from the immune system by a process known as apoptosis, or programmed cell death. Apoptosis is a highly regulated event that is distinct from necrotic cell death, which results from destruction of the plasma membrane (see Chapter 24). Apoptotic cell death is mediated primarily through the activation of a series of endogenous proteases. Once apoptosis is triggered, characteristic morphologic and cellular changes take place, including a decrease in cell volume, membrane blebbing, movement of phosphatidylserine to the outer leaflet of the plasma membrane, chromatin condensation, and DNA fragmentation. The pathways that regulate apoptosis at the different stages of B cell development are not entirely understood, but at least two pathways have been shown to play an active role in regulating B cell death: the Fas pathway and the Bcl-2 pathway. Fas (also known as CD95 or Apo-1), a member of the tumor necrosis factor receptor gene family, and Fas ligand are transmembrane proteins expressed on a variety of cell types. Because Fas ligand is a homotrimeric molecule, it can bind three Fas molecules. Clustering of Fas on the cell surface, which occurs when Fas molecules bind Fas ligand, activates a cascade of intracellular enzymes, known as caspases, that mediate apoptosis.89 It appears that when B cells engage CD40L expressed on helper T cells in the absence of BCR ligation, Fas signaling induces apoptosis.90,91 Other triggers for Fas-mediated death have not been clearly identified. Mutations in Fas (lpr) or Fas ligand (gld) in mice result in a systemic lupus erythematosus–like syndrome characterized by the production of pathogenic autoantibodies and lymphadenopathy. In humans, similar mutations lead to lymphadenopathy and antierythrocyte antibodies, but anti-DNA antibodies and glomerulonephritis are not present in these individuals.92 The Bcl-2 gene family is composed of molecules that either protect against or induce apoptosis in many cell

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types. Relative levels of these molecules dictate cell fate. For example, excess Bcl-2 promotes cell survival, whereas excess Bax induces cell death.93 The expression pattern of the antiapoptotic molecules Bcl-2 and Bcl-XL during B cell development suggests that they may play an important role in B cell survival. Levels are low at times of repertoire selection in the bone marrow or germinal centers and increase concomitantly with positive selection. B cells from mice deficient in Bcl-2 undergo spontaneous apoptosis,94 whereas certain mouse strains that overexpress Bcl-2 in B cells produce autoantibodies.95 ACTIVE TOLERANCE Recently it has been shown that B cells can be blocked from activation if they are chronically exposed to antigen and IL-6. If IL-6 is removed from the microenvironment, those chronically activated B cells will secrete antibody.96

B CELL AUTOIMMUNITY B cell activation must be tightly regulated at multiple levels to prevent the development of autoantibody-mediated autoimmune diseases. Many autoimmune disorders, including several rheumatologic diseases, involve the production of autoantibodies. The specific autoantigens and the affected organ systems vary. It has been speculated that B cell– associated autoimmune diseases may be linked by a common defect in the machinery that regulates B cell tolerance, but the cause of most autoimmune diseases remains unknown. ORIGIN OF AUTOREACTIVE B CELLS One of the fundamental questions surrounding B cell autoimmunity is the origin of autoreactive B cells. There is evidence that both B1 and B2 cell subsets contribute to autoimmunity.97 B1 cells have been suggested as a source of autoantibodies because this subset is known to secrete high levels of polyreactive antibody and can be directly activated by BCR cross-linking with multivalent antigens in the absence of antigen-specific T cell help.98 Despite the production of autoreactive antibodies by this population, it is not clear whether these antibodies contribute to disease. B1 cells in nonautoimmune individuals produce low-affinity autoantibodies that are nonpathogenic. It has been proposed that these autoantibodies may actually play a protective role against the tissue damage from more pathogenic autoantibodies. There is also some evidence that marginal zone B cells can secrete autoantibodies; however, there is no direct evidence that these antibodies are pathogenic. Further, it is not clear whether B1 and marginal zone B cells can also secrete high-affinity autoantibodies in autoimmune individuals. However, a number of recently described genetically engineered mice have increased numbers of marginal zone B cells, produce autoantibodies, and exhibit autoantibody-mediated tissue damage. Antibody production by the follicular subset requires the involvement of T cells. These B cells undergo H-chain class switching and somatic mutation in germinal centers. Analysis of autoantibodies produced in both NZB/NZW F1 mice and MRL/lpr mice that spontaneously develop systemic lupus erythematosus demonstrates extensive somatic ­mutation and

193

class switching to IgG isotypes, suggesting that they arise from follicular B cells.99,100 The relative importance of each B cell subset in the generation of autoreactive B cells is still being debated. INITIATION AND PROPAGATION OF AUTOIMMUNITY There are several prevailing theories that attempt to explain the activation and expansion of B cells that should normally be silenced. Autoimmunity is thought to arise by a combination of environmental factors, such as infectious agents that initiate an autoimmune response, and genetic defects that alter B cell regulation. Proposed models for autoimmunity include (1) cross-reactivity of foreign antigen with selfantigen, (2) inappropriate costimulation, and (3) altered thresholds for BCR signaling. Much of our understanding of the breakdown of selftolerance and the progression of autoimmunity comes from the examination of mouse models. Autoimmune mouse models can be divided into three broad categories: induced autoimmunity, spontaneously occurring autoimmunity, and genetically manipulated mice. Even though the progression of autoimmunity in humans is thought to be a highly complex process that involves multiple genetic and environmental factors, these animal models have provided much information about the molecular events that maintain self-tolerance. MOLECULAR MIMICRY One proposed model for the initiation of autoreactivity is that cross-reactive anti–self-, antiforeign B cells escape central tolerance because self-antigen is present at too low a concentration to trigger tolerance induction or because the affinity of the antibody for autoantigen is below the signaling threshold. These B cells become activated in the periphery by foreign pathogens resembling self-antigen and produce antibodies that bind both foreign and self-antigen. This cross-reactivity is known as molecular mimicry. Molecular mimicry is a popular model to explain the induction of many autoimmune disorders.101 Once the pathogen is cleared, the autoantibody response is terminated because antigen-specific T cell help is no longer present. In the case of autoimmune-prone individuals, it is possible that intrinsic B cell defects prevent the downregulation of autoantibody production, even after foreign antigen disappears. The data that support molecular mimicry as a trigger for B cell–mediated autoimmunity are circumstantial; antigens from infectious agents have been identified that cross-react with self-molecules associated with specific autoimmune diseases101-105 (Table 10-5). The strongest evidence for molecular mimicry as a trigger for autoimmune disease is the cross-reactivity observed between the M protein of group A streptococcus and cardiac myosin in rheumatic heart disease. There is also experimental evidence that phosphorylcholine, a component of the cell wall found in many bacterial strains, mimics the structure of double-stranded DNA. Immunization of a nonautoimmune mouse strain with phosphorylcholine coupled to a protein carrier routinely generates anti–double-stranded DNA antibodies in germinal center B cells.106 However, these B cells are normally downregulated before contributing to a serum response.

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Table 10-5  Evidence for Antibody Cross-reactivity   between Foreign and Self-Antigens Foreign Antigen

Self-Antigen

Yersinia, Klebsiella, Streptococcusa Epstein-Barr virus nuclear antigen

DNA 1a

Ribonucleoprotein SmD

Streptococcus M proteinb

Cardiac myosin

Coxsackie B3 capsid proteinc

Cardiac myosin

Klebsiella nitrogenased

HLA B27

Yersinia lipoproteine

Thyrotropin receptor

Mycobacteria heat shock proteinf

Mitochondrial components

Escherichia, Klebsiella, Proteusg

Acetylchloline receptor

gpD derived from herpes   simplex virusg

Acetylcholine receptor

Autoimmune disorders exhibiting cross-reactive antibodies: a, systemic lupus erythematosus; b, rheumatic fever; c, myocarditis; d, ankylosing spondylitis; e, Graves’ disease; f, primary biliary cirrhosis; g, myasthenia gravis.

In general, an initial immune response is generated against a dominant set of epitopes, followed by a later response to secondary or “cryptic” epitopes, a process known as epitope spreading.107 Epitope spreading is an important aspect of a protective immune response, because the ability to recognize multiple antigenic determinants increases the efficiency of the neutralization and removal of pathogens. When an autoimmune response has been triggered, epitope spreading can lead to the production of additional autoantibodies with specificity for multiple self-antigens. There are several proposed mechanisms by which epitope spreading triggers a cascade of T and B cell activation. For instance, antigen presenting cells present a foreign peptide that mimics a self-peptide to T cells (Fig. 10-8A). These cross-reactive T cells become activated and provide costimulation to autoreactive B cells that recognize self-antigen. This results in the production of autoantibodies specific for the antigen recognized by the T cell. After internalization of the self-antigen by the autoreactive B cells, the autoantigen is processed, and new cryptic epitopes of the self-antigen are presented to T cells. A B cell binding to the self-antigen internalizes not only that self-antigen but also any complex of molecules that includes the self-antigen. The B cell may, therefore, present cryptic epitopes of many self-antigens and activate autoreactive T cells with multiple autospecificities. In the periphery, T cells are present that have not been tolerized to these epitopes and thus are activated by self-peptide. These activated T cells in turn help provide costimulation and activate other autoreactive B cells. Alternatively, cross-reactive B cells may be activated first after exposure to foreign antigen and T cell help (Fig. 10-8B). These B cells internalize self-antigen and present cryptic peptides to T cells that have not been tolerized, leading to activation of autoreactive T cells and initiation of the cascade. Thus, molecular mimicry and epitope spreading can lead to the activation of T cells and B cells specific for multiple autoantigens so long as the autoantigens form a complex in vivo. Both nonautoimmune and autoimmune-prone individuals have the capacity to generate autoantibodies. Therefore, it is not likely that cross-reactivity between foreign and self-antigens is solely responsible for the breakdown of tolerance that leads to autoimmunity. A plausible explanation

is that foreign antigen acts as a molecular trigger to initiate an autoimmune response to self-molecules, and a defect in the mechanism that regulates B cell activation leads to the propagation of an autoimmune response. COSTIMULATION It is evident that costimulatory signals provided by T cells play a critical role in B cell activation. Therefore, inappropriate costimulation could lead to the propagation of an immune response directed against a self-antigen. The interaction between B7 on B cells and CD28 on T cells is crucial for the activation of antigen-specific T cells and B cells. When a genetically engineered protein that inhibits B7-CD28 interactions is administered to NZB/NZW F1 lupus-prone mice, progression of disease is blocked.108 Reciprocally, autoreactive B cells present in mice that constitutively overexpress B7 are not sensitive to Fas killing and display high serum autoantibody titers.109 Overexpression of CD40 or CD40L may also activate autoreactivity. In vitro studies have demonstrated that CD40-CD40L ligation in the presence of IL-4 activates anergic cells. It has been suggested that CD40L may be overexpressed in lymphoid cells of patients with systemic lupus erythematosus.110,111 Roquin, a recently identified member of the ubiquitin ligase family, regulates the function of a distinct subset of helper T cells known as follicular helper T cells.112 The role of these cells is to select for somatically mutated B cells with high affinity for antigen during an immune response. Recent studies suggest that roquin is essential for the negative selection of autoreactive B cells in the germinal center. Roquin belongs to a family of RING-type ubiquitin ligases involved in the post-translational regulation of gene expression and appears to repress the expression of ICOS, which plays an important role in follicular helper T cell function. Mice harboring a mutation in the roquin gene display high-affinity dsDNA antibodies owing to increased numbers of germinal centers and follicular helper T cells. Interferon regulatory factor-4 binding protein (IBP) has also been shown to regulate T cell costimulatory signals.113 IBP is a novel regulator of Rho GTPases and is recruited to the immunologic synapse following T cell receptor crosslinking to mediate the reorganization of the cytoskeleton. Mice deficient in IBP exhibit an autoimmune phenotype characterized by the production of dsDNA antibodies and glomerulonephritis. IBP plays an important role in the survival and effector function of memory T cells and underscores a novel role for Rho GTPases in regulating interactions between T cells and autoreactive B cells. Toll-like receptors (TLRs) belong to a family of pattern recognition receptors that initiate innate immune responses to various components of pathogens. TLR7, which recognizes RNA, and TLR9, which recognizes unmethylated CpG-containing nucleic acid sequences, are expressed on B cells and have been implicated in autoimmunity. There are numerous data suggesting that co-cross-linking of the BCR and TLR with autoimmune complexes containing nuclear antigens triggers the activation of antinuclear B cells, implying that TLR 7 and TLR9 enhance the activation of autoreactive B cells.114-116 Cytokines such as IL-4, IL-6, and IL-10 are important survival factors for B cells and are secreted primarily by T cells,

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I. Self-antigen complex

APC

Antibody #1-specific for self-antigen MHC II Self peptide

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Self-antigen complex Antibody #1-specific for self-antigen

MHC II

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Antibody #2-specific for cryptic epitope

es

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TCR II. MHC II

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Figure 10-8  Epitope spreading. A, Epitope spreading by activation of cross-reactive T cells. I. Following antigen presentation of a foreign peptide  that is recognized by cross-reactive T cells, costimulatory signals are delivered to B cells with surface immunoglobulin receptors that recognize a selfantigen as part of a complex of self-molecules. II. The complex is engulfed by a self-reactive B cell, and antibodies specific for self-antigen are generated. III. Self-reactive B cells process the self-molecules and present cryptic peptide–MHC II complexes on the cell surface. IV. If these cryptic peptides are recognized by nontolerized autoreactive T cells, B cells specific for these cryptic peptides are activated, and the autoantibody response spreads to other components of the self-antigen complex. B, Epitope spreading by activation of autoreactive B cells. I. A foreign antigen that mimics a self-molecule can mediate the endocytosis of a self-molecule that is included in a self-antigen complex. The self-molecules of the complex are processed and expressed on the cell surface of the B cell as cryptic peptide–MHC II complexes. II. If the cryptic peptides are recognized by nontolerized autoreactive T cells,  III. These T cells provide costimulation to B cells that recognize cryptic peptides, resulting in the production of additional self-reactive antibodies.

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monocytes, and dendritic cells. BAFF plays an important role in B cell development, survival, and antibody secretion. Enhanced survival and activation of autoreactive B cells have been demonstrated in mice that overexpress BAFF.117 An increase in serum levels of BAFF has been observed in some patients with lupus, rheumatoid arthritis, and Sjögren’s syndrome,118 which supports the notion that autoreactive B cells have a survival advantage in the presence of excess BAFF. The concept of B effector (Be) cells has been established recently, with Be1 cells secreting IL-2, IL-12, and interferon-γ and Be2 cells secreting IL-4, IL-5, and IL-10.119 This raises the possibility that B cells can influence the polarization of T cells and may also establish a cytokine autocrine loop that enhances the survival and activation of B cells. In addition, B cells reportedly secrete transforming growth factor-β (TGF-ß).120 TGF-ß is known to be immunosuppressive, and it has been suggested that B cell production of TGF-ß induces apoptosis to limit a B cell response. In agreement with these observations, mice deficient in TGF-ß or the TGF-ß receptor exhibit an autoimmune phenotype. B CELL SIGNALING THRESHOLDS The effects of altering the threshold for BCR signaling have been demonstrated in several mouse models. In transgenic mice that overexpress the BCR coreceptor complex

c­ omponent CD19, anergic B cells are activated and secrete autoantibody.121 These results suggest that a decrease in the minimal requirement for antigen engagement of the BCR can lead to inappropriate activation of autoreactive B cells. Viable moth-eaten mice also develop an autoimmune syndrome due to a naturally occurring deficiency in the SHP-1 phosphatase, a potent negative regulator of BCR signaling.65 In these mice, B1 cells are responsible for the production of IgM anti-DNA antibodies. Transgenic mice deficient in other signaling molecules that alter threshold activation, such as CD2255 and Lyn,56 also produce autoantibodies. Thus, changes in thresholds for antigen-induced B cell activation can lead to the activation of autoreactive B cells.

SUMMARY The generation of a diverse repertoire of antibody molecules provides an important line of defense against microbial infections. The immune system is exquisitely controlled at multiple levels to allow the maturation of B cells that produce protective antibodies while attempting to avoid the production of autoantibodies (Fig. 10-9). Only a small percentage of B cell precursors generated completes the maturation scheme. During the pro-B and pre-B cell stages of development, B cells with aberrantly rearranged H- or L-chain genes are eliminated. As the remaining precursor

Bone marrow Spleen Pro-B MZ HC rearrangement

Negative selection (2) Transitional 2

FO

Pre-B LC rearrangement

Negative selection (1)

Transitional 1

GC

Negative selection (3)

Plasmablast Immature Negative selection (4)? Bone marrow

Memory

Periphery

Plasma Figure 10-9  Selection checkpoints during B cell maturation. Autoreactive B cells can be censored at multiple developmental checkpoints: (1) Fol­lowing surface expression of surface immunoglobulin, immature B cells that encounter autoantigen in the bone marrow are subject to negative selection. (2) B cells that are not eliminated in the bone marrow may under go negative selection during the transitional B cell stage. Transitional B cells that emerge from this development stage give to rise to follicular (FO) or marginal zone (MZ) B cells. Follicular B cells activated by antigen and the help of cognate T cells progress to the germinal center (GC) B cell stage. (3) Germinal center B cells that acquire high affinity for autoantigen by the process of somatic hypermutation may be eliminated in the germinal center to block their further maturation into long-lived plasma cells or memory cells.  (4) There is evidence that autoreactive plasmablasts may also be subject to negative selection. Long-lived plasma cells that emerge from the selection process home primarily to the bone marrow, and memory B cells circulate throughout the periphery. HC, heavy chain; LC, light chain.

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cells transit into the immature B cell stage, they are subjected to negative selection; that is, immature B cells bearing autospecificity are either deleted or inactivated, whereas B cells that can potentially bind foreign antigen are released into the periphery. B cells that are stimulated by foreign antigen are selectively expanded and undergo further immunoglobulin gene diversification in peripheral lymphoid tissue. During this stage of development, B cells that express high-affinity immunoglobulin receptors undergo positive selection, whereas B cells with a diminished affinity or those that have acquired autoreactivity are eliminated. B cells that pass through these critical developmental checkpoints differentiate into long-lived memory B cells or plasma cells. The underlying causes of B cell–associated autoimmunity are not well understood, but just as there are multiple checkpoints for the survival or activation of autoreactive B cells, it seems likely that multiple defects in the regulatory mechanisms that control B cell maturation and differentiation contribute to autoimmune disease. REFERENCES   1. Janeway JA, Travers P, Walport M, et al: The structure of a typical antibody molecule. In Immunobiology, 5th ed. New York, Garland, 2001, p 96.   2. Janeway JA, Travers P, Walport M, et al: Structural variation in immunoglobulin constant regions. In Immunobiology, 5th ed. New York, Garland, 2001, p 142.   3. Frazer JK, Capra JD: Immunoglobulins: Structure and function. In Paul WE (ed): Fundamental Immunology. Philadelphia, LippincottRaven, 1999, p 37.   4. Raghavan M, Bjorkman PJ: Fc receptors and their interactions with immunoglobulins. Annu Rev Cell Dev Biol 12:181, 1996.   5. Bradbury LE, Kansas GS, Levy S, et al: The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules. J Immunol 149:2841, 1992.   6. Snapper CM, Finkelman FD: Immunoglobulin class switching. In Paul WE (ed): Fundamental Immunology. Philadelphia, LippincottRaven, 1999, p 831.   7. Shohet JM, Pemberton P, Carroll MC: Identification of a major binding site for complement C3 on the IgG1 heavy chain. J Biol Chem 268:5866, 1993.   8. Hiemstra PS, Biewenga J, Gorter A, et al: Activation of complement by human serum IgA, secretory IgA and IgA1 fragments. Mol Immunol 25:527, 1988.   9. Froelich CJ, Hanna WL, Poirier GG, et al: Granzyme B/perforin-mediated apoptosis of Jurkat cells results in cleavage of poly(ADP-ribose) polymerase to the 89-kDa apoptotic fragment and less abundant 64-kDa fragment. Biochem Biophys Res Commun 227:658, 1996. 10. Ghetie V, Ward ES: FcRn: The MHC class I-related receptor that is more than an IgG transporter. Immunol Today 18:592, 1997. 11. Takizawa T, Anderson CL, Robinson JM: A novel Fc gamma Rdefined, IgG-containing organelle in placental endothelium. J Immunol 175:2331, 2005. 12. Aroeti B, Casanova J, Okamoto C, et al: Polymeric immunoglobulin receptor. Int Rev Cytol 137B:157, 1992. 13. Burrows PD, Cooper MD: IgA deficiency. Adv Immunol 65:245, 1997. 14. Stewart WW, Kerr MA: The specificity of the human neutrophil IgA receptor (Fc alpha R) determined by measurement of chemiluminescence induced by serum or secretory IgA1 or IgA2. Immunology 71:328, 1990. 15. Carsetti R, Kohler G, Lamers MC: A role for immunoglobulin D: Interference with tolerance induction. Eur J Immunol 23:168, 1993. 16. Nitschke L, Kosco MH, Kohler G, et al: Immunoglobulin D-deficient mice can mount normal immune responses to thymus-independent and -dependent antigens. Proc Natl Acad Sci U S A 90:1887, 1993.

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99. Marion TN, Bothwell AL, Briles DE, et al: IgG anti-DNA autoantibodies within an individual autoimmune mouse are the products of clonal selection. J Immunol 142:4269, 1989. 100. Shlomchik M, Mascelli M, et al: Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation. J Exp Med 171:265, 1990. 101. Davies JM: Molecular mimicry: Can epitope mimicry induce autoimmune disease? Immunol Cell Biol 75:113, 1997. 102. Cunningham MW: Bacterial antigen mimicry. In Bona C, Siminovitch K, Zanetti M, et al (eds): Molecular Pathology of Autoimmune Diseases. Chur Switzerland, Harwood Academic, 1993, p 245. 103. Zhang H, Kaur I, Niesel DW, et al: Lipoprotein from Yersinia enterocolitica contains epitopes that cross-react with the human thyrotropin receptor. J Immunol 158:1997, 1976. 104. El-Roiey A, Sela O, Isenberg DA, et al: The sera of patients with Klebsiella infections contain a common anti-DNA idiotype (16/6) and anti-polynucleotide activity. Clin Exp Immunol 67:507, 1987. 105. Putterman C, Limpanasithikul W, Edelman M, et al: The double edged sword of the immune response: Mutational analysis of a murine anti-pneumococcal, anti-DNA antibody. J Clin Invest 97:2251, 1996. 106. Ray SK, Putterman C, Diamond B: Pathogenic autoantibodies are routinely generated during the response to foreign antigen: A paradigm for autoimmune disease. Proc Natl Acad Sci U S A 93:2019, 1996. 107. McCluskey J, Farris AD, Keech CL, et al: Determinant spreading: Lessons from animal models and human disease. Immunol Rev 164:209, 1998. 108. Daikh DI, Finck BK, Linsley PS, et al: Long-term inhibition of murine lupus by brief simultaneous blockade of the B7/CD28 and CD40/gp39 costimulation pathways. J Immunol 159:3104, 1997. 109. Rathmell JC, Fournier S, Weintraub BC, et al: Repression of B7.2 on self-reactive B cells is essential to prevent proliferation and allow Fas-mediated deletion by CD4+ T cells. J Exp Med 188:651, 1998. 110. Koshy M, Berger D, Crow MK: Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. J Clin Invest 98:826, 1996.

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111. Desai-Mehta A, Lu L, Ramsey-Goldman R, et al: Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest 97:2063, 1996. 112. Vinuesa CG, Cook MC, Angelucci C, et al: A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435:452, 2005. 113. Fanzo JC, Yang W, Jang SY, et al: Loss of IRF-4-binding protein leads to the spontaneous development of systemic autoimmunity. J Clin Invest 116:703, 2006. 114. Christensen SR, Shupe J, Nickerson K, et al: Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25:417, 2006. 115. Berland R, Fernandez L, Kari E, et al: Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice. Immunity 25:429, 2006. 116. Leadbetter EA, Rifkin IR, Hohlbaum AM, et al: Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416:603, 2002. 117. Mackay F, Woodcock SA, Lawton P, et al: Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med 190:1697, 1999. 118. Groom J, Kalled SL, Cutler AH, et al: Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjogren’s syndrome. J Clin Invest 109:59, 2002. 119. Harris DP, Haynes L, Sayles PC, et al: Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat Immunol 1:475, 2000. 120. Douglas RS, Woo EY, Capocasale RJ, et al: Altered response to and production of TGF-beta by B cells from autoimmune NZB mice. Cell Immunol 179:126, 1997. 121. Inaoki M, Sato S, Weintraub BC, et al: CD19-regulated signaling thresholds control peripheral tolerance and autoantibody production in B lymphocytes. J Exp Med 186:1923, 1997.

11

Fibroblasts and Fibroblast-like Synoviocytes Thomas Pap  • Steffen Gay

KEY POINTS Fibroblasts provide the structural basis of organ composition and function but are more than just structure-building cells. Fibroblasts are very sensitive to environmental changes and actively regulate the composition and cellular dynamics of connective tissues, including internal organs and membranes such as the synovium. Under disease conditions such as inflammation, fibroblasts are critical switches that regulate the response to tissue injury, contribute to the resolution or chronicity of the organ-specific pathology, and determine the consequences of disease. In rheumatoid arthritis, fibroblasts are a key part of the local immune system and, through the integration of signals from different sources, contribute to both disease initiation and perpetuation. While responding to environmental stimuli, rheumatoid Synovial fibroblasts undergo fundamental changes that result in their stable activation, which is maintained even in the absence of continuous stimulation by inflammatory triggers. Fibroblast-like synoviocytes are prominently involved in the accumulation and pathologic differentiation of inflammatory cells in the diseased synovium of rheumatoid arthritis.

PHYSIOLOGIC CHARACTERISTICS AND FUNCTIONS OF FIBROBLASTS Fibroblasts are ubiquitous cells of mesenchymal origin that are present in virtually every body compartment. They are the primary resident cells of all connective ­ tissues and, as such, provide the structural basis of organ composition and function. Fibroblasts are involved ­ prominently in the remodeling of the extracellular matrix (ECM), have barrier functions, and play an important role in tissue repair. However, it has become increasingly clear that fibroblasts are far more than just structural cells that provide the meshwork in which organ-specific cells reside and into which organ function is embedded.1 Rather, fibroblasts react very specifically to environmental triggers, including soluble mediators, ECM components, and chemical stimuli such as oxygen tension and pH, and they actively regulate the composition

and cellular dynamics of their respective tissues (Fig. 11-1). Consequently, fibroblasts in different regions of the body have distinct functions. PRODUCTION OF EXTRACELLULAR MATRIX COMPONENTS Ensuring the homeostasis of the ECM is one of the primary functions of fibroblasts. Fibroblasts produce a number of ECM molecules, including collagens, fibronectin, proteoglycans, and others, and are critical in the assembly of these molecules into a three-dimensional network. The types of ECM molecules produced by individual populations of fibroblasts differ from tissue to tissue, reflecting the diversity of fibroblasts in different organs. For example, dermal fibroblasts produce significant amounts of type VII collagen, which holds together the epidermal and dermal layers in the skin. Fibroblasts in other organs, such as the lung and kidney, produce mainly interstitial collagens (particularly types I and III), and specific features of fibroblasts from other origins, such as the gingiva, have been reported.2 In the synovial membrane, fibroblasts also have a barrier function, in that they provide the joint cavity and the adjacent cartilage with lubricating molecules such as hyaluronic acid and with plasma-derived nutrients. One peculiarity of the synovial membrane is that it lacks a basement membrane and, thus, the classic architecture of epithelium. As a consequence, the most superficial layer of the synovium, the intimal lining layer, must assume these functions. Recent data demonstrate that although cellular contacts between the fibroblast-like synoviocytes also lack tight junctions and desmosomes, the recently discovered adhesion ­molecule cadherin-11 mediates a strong homophilic adhesion between synoviocytes and is largely responsible for their organization into tissue.3 Production of ECM components and cross-linking these components into a specific three-dimensional structure constitute a very active process in which fibroblasts have to migrate to sites of tissue injury or remodeling and interact with ECM molecules through specific surface receptors. Through such receptors, fibroblasts must sense changes in both the structure and the cellular composition of connective tissues. They respond dynamically by adjusting the production of ECM components and cross-linking them into the appropriate matrix. ATTACHMENT TO AND INTERACTION WITH THE EXTRACELLULAR MATRIX In the context of attachment to and interaction with the ECM, integrins are important. Integrins are a complex ­family of adhesion molecules that contain heterodimers of α and β chains. So far, at least 16 different α chains and 8 201

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Cell-cell interactions (inflammatory cells, endothelial cells)

Chemical stimuli (e.g., pH oxygen tension)

Paxillin Soluble mediators (e.g., cytokines, growth factors)

Extracellular matrix (e.g., collagen, fibronectin) Fibroblasts

Integrin receptor

Organ-specific reaction (production and resorption of extracellular matrix, production of soluble mediators, expression of surface adhesion molecules)

Figure 11-1  Fibroblast stimulation signals. Fibroblasts are very s­ ensitive cells that integrate signals from soluble mediators, cell-cell interactions, chemical stimuli, and the extracellular matrix into a coordinated, organ-specific response. This response includes remodeling of the extracellular matrix, the secretion of soluble mediators, and the expression of surface molecules for cell-cell and cell-matrix interactions.

different β chains have been described that can combine into at least 24 different integrins. For the attachment of fibroblasts to the ECM components of connective tissue and cartilage, β1 integrins are especially important. α1β1, α2β1 Integrins are the main adhesion molecules responsible for the attachment of fibroblasts to collagen, but some data suggest that the recently described α10β1 and α11β1 integrins might also be involved. Other β1 integrins, such as α4β1 and α5β1 integrins, mediate the attachment of fibroblasts to fibronectin and its spliced variants; in addition, αv integrins are responsible for the attachment to vitronectin. The engagement of integrin receptors on the surface of fibroblasts results in the formation of focal adhesion complexes. These focal adhesion complexes activate intracellular signaling cascades that regulate the transcription of genes, thereby controlling cell proliferation and survival, the secretion of certain cytokines and chemokines, and matrix deposition and resorption (Fig. 11-2). Among the signaling molecules that transmit signals from the integrins to the cell interior, focal adhesion kinase (FAK) plays a central role.4 FAK, a tyrosine kinase, is recruited into newly established focal contacts and, in turn, recruits other adapter proteins such as p130Cas and Grb2. This leads to the activation of phosphatidylinositide 3-kinase (PI3K) and Src-kinase and promotes the initiation of a variety of signaling cascades, such as the Raf-MEKERK pathway. It is important to note, however, that these signaling pathways can also be activated through FAKindependent signaling events, such as through growth factors. The exact mechanisms by which different signals cooperate to mediate a specific response of fibroblasts and how this translates into distinct pathologies are not yet fully defined. The picture is further complicated by the fact that in addition to integrins, other cell surface molecules are involved in the attachment of fibroblasts to ECM components and in their response to growth factors. Among these, transmembrane heparan sulfate proteoglycans have generated special interest recently. Syndecans, a family of such transmembrane heparan sulfate proteoglycans, possess

Alpha subunit

Beta subunit RAS

p130Cas FAK

SHC SOS FYN Grb2

Src

MEK

P13K Actin stress fibers

Akt

Raf

ERK

Transcription factors

Figure 11-2  Integrin signaling in fibroblasts. The engagement of ­integrins on the cell surface of fibroblasts results in the initiation of signaling cascades that result in changes in (1) cell motility through ­reorganization of the cytoskeleton, (2) cell survival (e.g., through ­activation of the Akt-NFκB pathway), and (3) the production of matrix molecules, matrix-degrading enzymes, and soluble mediators through the activation of mitogen-activated protein kinases.

highly conserved cytoplasmic and transmembrane domains but have highly variable extracellular domains. The extracellular domains of syndecans contain different numbers of glycosaminoglycan side chains through which they interact with factors released during tissue injury, such as growth factors and interleukins (ILs), but also with many ECM components and adhesion molecules5 (Fig. 11-3). Syndecans are expressed on fibroblasts in a tissue-specific and development-dependent manner. Data from syndecan knockout mice indicate that syndecan-4 is particularly important for the fibroblast response to tissue injury. Syndecan-4– ­deficient mice show no gross abnormalities and are viable. Under certain stress conditions, however, these mice show differences compared with wild-type controls. They exhibit alterations in wound healing, and the response of syndecan-4–deficient fibroblasts to fibronectin attachment is significantly altered.6 Also, syndecan-4–deficient fibroblasts are compromised in their ability to differentiate into α-smooth muscle actin–expressing myofibroblasts. The exact mechanisms by which syndecans are involved in the functions of different fibroblast populations remain to be determined, but it appears that syndecans are important cell surface receptors that, owing to their unique properties, can integrate signals from ECM components and soluble ­factors.

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Growth factors

Heparan sulfate attachment sites Cell adhesion domain (NXIP) Shedding sites for plasmin and thrombin Transmembrane domain C1 V C2

Conserved (C) and variable (V) intracellular domains

Figure 11-3  Structure of syndecans. Syndecans are transmembrane heparan sulfate proteoglycans, some of which (e.g., syndecan-4) are expressed prominently on mesenchymal cells, particularly fibroblasts. Through their heparan sulfate side chains, they are able to bind not only matrix components such as fibronectin but also growth factors. Their intracellular part contains two highly conserved regions (C1 and C2), as well as one variable domain (v). Activation of syndecans results in both the engagement of focal contacts and the initiation of intracellular signaling cascades that are not yet fully understood.

DEGRADATION OF EXTRACELLULAR MATRIX BY FIBROBLASTS In addition to being responsible for the deposition of ECM molecules and their assembly, fibroblasts are involved in the destruction and removal of the ECM. To this end, fibroblasts produce a great variety of matrix-degrading enzymes, including matrix metalloproteinases (MMPs) and cathepsins, that can cleave ECM components. A detailed description of the enzymes responsible for the degradation of cartilage- and boneassociated matrix components is provided in Chapter 7. However, it is important to note that fibroblasts constitute a major source of these enzymes and thus are prominently involved in the degradation of ECM, particularly under disease conditions. With the exception of MMP-2 and the MT-MMPs, which are constitutively expressed by fibroblasts, MMP expression is regulated by extracellular signals via transcriptional activation in fibroblasts. Three major groups of inducers can be differentiated: proinflammatory cytokines, growth factors, and matrix molecules. Among the cytokines, IL-1 is perhaps the most potent inducer of a variety of MMPs, including MMP-1, -3, -8, -13, and -14. Fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF) are also known inducers of MMPs in fibroblasts, as they potentiate the effect of IL-1 on MMP expression. Matrix proteins (collagen, fibronectin) and especially their degradation ­products activate MMP expression in fibroblasts, providing the possibility for site-specific MMP activation in regions of matrix breakdown.7 Interestingly, studies have shown that ­microparticles derived from immune cells can directly stimulate the expression of both inflammatory cytokines and ­disease-relevant MMPs in fibroblast-like synoviocytes.8 In fibroblasts, several pathways mediate signaling for the transcriptional activation of MMPs. The activator protein-1 (AP-1) binding site is present in the promoter region of all

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MMPs (except MMP-2), ­suggesting a central role of Jun/Fos transcription factor binding. Indeed, there is ample experimental evidence that all three mitogen-activated protein kinase MAPK families—extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 kinase— integrate extracellular signals upstream from jun/fos and are involved in the regulation of MMP expression. Especially, the induction of MMP-1, -9, and -13 is ­mediated through MAPK signaling.9-11 Aside from AP-1, the promoter regions of some MMPs contain nuclear factor κB (NFκB),9-11 STAT,12 and Ets13 binding sites. Activation of these transcription factors occurs during the induction of MMP-1, -3, and -13, which are also thought to be essential for the joint damage in rheumatoid arthritis (RA). Activation of the various MAPK and transcription factors, none of which are tissue-specific signaling molecules, occurs in distinct subcompartments of the rheumatoid joint, thus determining a particular pattern of MMP expression in the synovium.14 HETEROGENEITY OF FIBROBLASTS Although fibroblasts share a number of characteristic ­features, as outlined earlier, they are far from being a uniform cell lineage. Rather, fibroblasts differ substantially from one tissue to another. These differences become obvious when their growth and proliferation are investigated together with the distinct profiles of the ECM components they produce. There are also differences in the production of cytokines, chemokines, and growth factors by fibroblasts from different organs. These differences can be explained by the distinct embryonic origins of fibroblasts in various body sites, as well as by the specific tissue environment in the adult organism. More importantly, however, there are significant differences between fibroblasts within tissues. Heterogeneity of fibroblasts has been shown in the skin and the lung, as well as in the synovial membrane, where fibroblasts in the most superficial lining differ substantially from those in the deeper layers (also called the sublining). Under disease conditions such as RA, the heterogeneity of fibroblasts is an important factor in the pathogenesis of disease; fibroblasts of the most superficial layer of the rheumatoid synovium play a key role in the progressive destruction of articular cartilage and bone, thus contributing to disease progression.

FIBROBLASTS IN RHEUMATIC DISEASES As outlined earlier, fibroblasts play a central role in ­ensuring physiologic tissue homeostasis. Under disease conditions such as inflammation, the role of fibroblasts becomes even more central: they are critical switches that regulate the response to tissue injury. Thus, fibroblasts contribute to the resolution or perpetuation of organ-specific pathology and largely determine the consequences of disease. In addition to the production and resorption of matrix components, fibroblasts are involved in angiogenesis and regulate the accumulation of inflammatory cells. To this end, fibroblasts secrete chemokines and mediate the subsequent recruitment of inflammatory cells to sites of tissue injury. In addition, they can inhibit programmed cell death in inflammatory cells15 and modulate the activity and behavior of many cell lineages through direct cell-to-cell interactions16 (Fig. 11-4).

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Disease-specific activation

Production and resorption of extracellular matrix

Accumulation of inflammatory cells Fibroblasts Neoangiogenesis

Figure 11-4  Role of fibroblasts in disease. Under disease conditions, fibroblasts becomes important triggers that can, for instance, mediate the switch from acute resolving to chronic persisting inflammation. The role of fibroblasts in inflammatory diseases is not restricted to the production of extracellular matrix; it also includes the recruitment and accumulation of inflammatory cells as well as neoangiogenesis.

Elucidation of the mechanisms by which fibroblasts c­ ontribute to the perpetuation of inflammatory disease and the progression of rheumatic disorders has significantly changed our view of these cells.17 Initially, fibroblasts were thought to be more or less passively responding cells that, upon stimulation by environmental triggers, reacted by changing the deposition or resorption of matrix. This view has been replaced by the realization that these cells are central components of organ-specific homeostasis and pathology. It is understood that fibroblasts are a key part of the immune system and integrate signals from different sources into a coordinated tissue response.18 In this context, fibroblasts themselves may undergo fundamental changes while responding to environmental stimuli. This is obvious, based on observations that, during wound healing and under fibrotic conditions, fibroblast-like cells are transformed into myofibroblasts, which are distinct from fibroblasts in terms of both their phenotype and their behavior.19 Such fibrotic transformation of fibroblasts is also characteristic of systemic sclerosis, a generalized fibrotic disorder that affects the skin and various internal organs such as the lungs, heart, and gastrointestinal tract. The overproduction of ECM components, particularly type I, III, VI, and VII collagen, by skin fibroblasts is a hallmark of the disease and is closely linked to the disease-specific activation of these fibroblasts. This pattern of activation includes not only a distinct profile of ECM overproduction but also altered responses to both inflammatory mediators and immune cells.20 Several lines of evidence suggest that in chronic, ­destructive arthritides such as RA, there is also stable activation of fibroblast-like cells of the synovial intimal lining, and this activation is maintained even in the absence of continuous stimulation by inflammatory triggers.21 This process appears to be distinct from that seen in fibrotic disorders, and fibroblasts that have undergone this ­activation show certain features of tumor cells, such as anchorage-independent growth, firm attachment to ECM molecules of the cartilage, alterations in their response to apoptotic stimuli, and invasiveness toward articular cartilage and bone (see later). This activation process is sometimes referred to as tumor-like transformation. The underlying mechanisms for this transition are not entirely clear. However, there is ­evidence that the chronic ­exposure

of fibroblast-like cells in the synovial lining to the combination of inflammatory ­ cytokines, growth factors, and ECM components, together with less clearly defined environmental triggers such as reactive oxygen or nitrogen hypoxia22 and possibly bacterial or viral products23 and microparticles,8 results in the imprinting or stable activation of these cells into an aggressive phenotype. As a consequence of this stable activation, the disease process is perpetuated and might even progress when inflammation is ameliorated or controlled through anti-inflammatory treatment.

FIBROBLAST-LIKE SYNOVIOCYTES IN RHEUMATOID ARTHRITIS About one third of the cells in the most superficial lining layer of the rheumatoid synovium appear to originate from resident synovial cells, which have a fibroblast-like appearance and lack specific surface markers. They have been called type B synoviocytes or fibroblast-like syno­ viocytes and can be identified by antibodies recognizing prolyl-4-hydroxylase24 or antibodies against Thy-1/CD90.25 In addition to infiltration with inflammatory cells, the increased number of these fibroblast-like synoviocytes contributes significantly to many aspects of synovial pathology—namely, hyperplasia (especially that of the lining layer), joint destruction, and perpetuation of chronic inflammation.17,26 It is important to note that fibroblasts in the rheumatoid synovium differ significantly from normal fibroblast-like synoviocytes and, as part of a complex cellular network, contribute to joint destruction by direct mechanisms as well as through interaction with neighboring cells.27 In RA, fibroblast-like synoviocytes show features of stable cellular activation, which provides the basis for both their direct and indirect effects on joint destruction. STABLE ACTIVATION OF FIBROBLASTS IN THE RHEUMATOID SYNOVIUM The hypothesis that activated fibroblast-like synoviocytes are involved in rheumatoid joint destruction is based on observations that date back to the 1970s.28 By analyzing large numbers of synovial specimens from RA patients, it was found that invasion of cartilage and subchondral bone by synovial lining cells did not require the presence of inflammatory cells. Moreover, fibroblast-like ­ synoviocytes from RA patients exhibit considerable morphologic alterations, including an abundant cytoplasm; a dense, rough endoplasmic reticulum; and large, pale nuclei with several prominent nucleoli21,28 (Fig. 11-5). Based on these ­morphologic ­analyses, studies in mice with severe combined ­immunodeficiency (SCID) were performed to investigate the “transformed-appearing” phenotype of rheumatoid fibroblasts. In this model, RA fibroblast-like synoviocytes were coimplanted with normal human cartilage into SCID mice (Fig. 11-6). Because of their defective immune systems, these mice did not reject the implants, allowing investigators to study the aggressive behavior of RA fibroblasts in the absence of human inflammatory cells and their factors. It was shown that rheumatoid fibroblasts in this model not only exhibited an invasive phenotype but also, and even more intriguingly, were able to maintain this phenotype over ­prolonged periods in the absence of ­continuous stimulation

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Rheumatoid fibroblasts or control fibroblasts

Invasion

Figure 11-5  Phase contrast picture of rheumatoid arthritis fibroblastlike synoviocytes.

by an ­inflammatory environment. A number of groups set out to characterize the specific phenotype of fibroblast-like synoviocytes in RA, and interest focused mainly on the characteristics of these cells at the cellular and molecular levels, as well as on the mechanisms of activation with respect to their destructive properties. The results have shown that the stable activation of RA fibroblast-like synoviocytes is accompanied by alterations in a variety of proto-oncogenes and tumor ­suppressors and ultimately results in the activation of adhesion molecules, the production of matrix-degrading enzymes, and changes in the susceptibility to programmed cell death (Fig. 11-7). ALTERED EXPRESSION OF PROTO-ONCOGENES Expression of proto-oncogenes and transcriptional factors in fibroblast-like synoviocytes is a major indication of the activated nature of these cells.29 A number of oncogenes such as c-fos, ras, raf, sis, myb, and myc have been detected at elevated levels in RA patients and are predominantly expressed by synovial cells attaching cartilage and bone.29 Binding sites for early-response genes such as egr-1 can be identified in the promoters of the oncogenes sis and ras, and about 70% of RA patients exhibit high expression of Ras and Myc proteins in synovial lining cells.30 The cysteine proteinase cathepsin L, which is the major ras-induced protein in rastransformed murine NIH 3T3 cells, was detected in 50% of RA cases, predominantly in synovial cells.31 Interestingly, cathepsin L was colocalized with ras and myc. Some of these proto-oncogenes appear to be directly involved in the regulation of different MMPs. Gelatinases (MMP-2 and MMP-9) and MT1-MMP are likely regulated by growth factors that mediate their effects through the ras proto-oncogene, and c-Ras plays a critical role in the increased expression and proteolytic activation of MMPs in fibroblasts.32,33 Recently, gene transfer with dominant negative (dn) mutants of Raf-1 and c-Myc demonstrated the relevance of the Ras-RafMAPK pathways for the activation and invasive behavior of

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Normal human articular cartilage

No invasion

Figure 11-6  Severe combined immunodeficiency (SCID) mouse model of rheumatoid cartilage destruction. Rheumatoid arthritis fibroblast-like synoviocytes are implanted along with normal human cartilage into SCID mice. These mice do not reject the implants, allowing investigators to study the aggressive behavior of rheumatoid arthritis fibroblasts in the absence of human inflammatory cells and their factors for at least 60 days. Rheumatoid fibroblasts (left) exhibit an invasive phenotype and maintain this phenotype over prolonged periods in the absence of ­continuous stimulation by an inflammatory environment; in ­ contrast, there is no such invasion with normal or osteoarthritic fibroblasts (right). This experiment can be taken as evidence of the stable activation of rheumatoid fibroblasts. At the same time, this model can be used to study therapeutic effects on the fibroblasts.

­rheumatoid fibroblast-like synoviocytes.34 The clear effect of dn-Raf-1 and dn-c-Myc on the invasiveness of rheumatoid fibroblast-like synoviocytes in the SCID mouse model is in line with the concept that the activation of relevant signaling pathways is maintained in RA fibroblast-like synoviocytes in the absence of human inflammatory cells. Taken together, different data suggest that the pathologic expression of proto-oncogenes constitutes an important step leading to the expression of matrix-degrading enzymes in RA and progressive joint destruction. Alterations in different tumor suppressor genes may explain some features of fibroblast activation and survival in RA. For instance, somatic mutations of the tumor suppressor gene p53 have been described in rheumatoid synoviocytes.35 Based on additional evidence that some of these mutations can exert dominant negative effects, it has been hypothesized that the accumulation of p53 mutations may contribute to the activation of rheumatoid fibroblast-like synoviocytes. Although mutations in the p53 gene appear to show great variability, such mutations may nonetheless constitute one mechanism that imprints the aggressive behavior into RA fibroblast-like synoviocytes. This notion is supported by data showing that inhibition of p53 in normal fibroblast-like synoviocytes results in an invasive, RA-like phenotype.36 RA-specific ­expression of p53 in the synovial tissue in both the early and late stages of RA has been demonstrated.37 Hence, the local environment in the rheumatoid joint might cause altered expression and function of p53 in a subset of ­rheumatoid fibroblasts, which in turn contributes to the stable ­activation of these cells.38

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Proto-oncogenes tumor suppressors

Fas FLIP SUMO-1 BcI-2 Stable activation

β1-integrins syndecans

MMPs cathepsins

Altered apoptosis

Attachment to cartilage

Matrix degradation Figure 11-7  Invasive phenotype of rheumatoid arthritis fibroblast-like synoviocytes. As a result of the stable activation of rheumatoid arthritis fibroblasts, these cells show three distinct features: increased expression of adhesion molecules, leading to attachment to the articular cartilage; upregulated production of matrix-degrading enzymes such as matrix metalloproteinases and cathepsins; and alterations in programmed cell death, which contribute to synovial hyperplasia.

Aggressive RA fibroblast-like ­synoviocytes lack the expression of mRNA for the tumor suppressor phosphatase and ­tensin homolog (PTEN). PTEN is a tyrosine phosphatase that shows homology to the cytoskeletal proteins tensin and auxillin. Mutations in PTEN have been described in different malignancies and are associated with their invasiveness and metastatic properties.39,40 In RA, no mutations of PTEN have been found, but rheumatoid synovium shows a distinct pattern of PTEN expression, with negligible staining in the lining but very strong expression in the sublining.41 These data suggest that the lack of PTEN expression is an intrinsic feature of rheumatoid fibroblast-like synoviocytes,41 which is of interest because PTEN is involved in the regulation of FAK,42 and some data indicate that PTEN is an essential mediator of FasLmediated apoptosis through the PI3K–Akt–NFκB pathway.43 Interesting data have come from studies of the transcriptional factor NFκB in RA fibroblast-like synoviocytes. NFκB is a dimeric (p65, p50), regulatory, DNA-binding protein that interacts with a number of different signal cascades. Several studies have demonstrated that NFκB is highly activated in the synovial membrane of RA patients and constitutes a key integrating factor for intracellular as well as cytokine-mediated activation pathways.44 Thus, NFκB is an important molecule that mediates the resistance of fibroblasts against apoptosis45,46 and regulates inflammatory cytokines,45,47 adhesion molecules,45,48 and matrix-degrading enzymes.45,49 The activation of NFκB in RA fibroblastlike synoviocytes appears to constitute an important link among synovial inflammation, hyperplasia, and matrix ­degeneration.44,45

RESISTANCE AGAINST APOPTOSIS Synovial fibroblasts from patients with RA are activated but do not proliferate faster than those from patients with osteoarthritis. Using thymidine incorporation, only 1% to 5% of synovial cells have been found to proliferate,50 and immunohistochemistry for specific proliferation markers such as Ki-67 revealed a very low number of positive cells.51 Also, only 1% of fibroblast-like cells expressing proto-oncogenes such as jun-B and c-fos were positive for Ki-67, indicating that the majority of RA fibroblast-like synoviocytes do not show accelerated proliferation.52 In contrast, more recent data provide growing evidence of changes in the apoptotic pathways in RA synovium, particularly within the lining layer (for a review, see reference 53). When examined by ultrastructural methods, less than 1% of lining cells exhibit morphologic features of apoptosis.54 Mitochondrial Pathways of Apoptosis Generally, apoptosis can be induced by intrinsic mitochondrial pathways or triggered through cell surface death receptors.53,55 Members of the Bcl family have been identified as important regulators of mitochondrial pathways of apoptosis. Specifically, Bcl-2 exerts strong antiapoptotic effects and contributes to the pathogenesis of experimental arthritis.56 In situ analysis has shown an increased presence of Bcl-2 in human RA fibroblast-like synoviocytes,57 and enhanced expression of Bcl-2 in rheumatoid fibroblast-like synoviocytes correlates with synovial lining thickening and

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­inflammation.58 Of interest, stimulation of RA fibroblast-like synoviocytes with IL-15 suppresses Bcl-2 and Bcl-x(L) mRNA.59 Apoptosis can be increased when the autocrine stimulation of fibroblast-like synoviocytes with IL-15 is inhibited. Pathways of Receptor-Mediated Apoptosis In addition to changes in the mitochondrial pathway of apoptosis, there is evidence that fibroblast-like synoviocytes are resistant to receptor-induced apoptosis. These receptors include members of the tumor necrosis factor (TNF) receptor family, specifically, TNF receptor 1 (TNFR1), TNFrelated apoptosis-inducing ligand (TRAIL) receptors 1 and 2, and Fas receptor. They all possess conserved intracellular motifs, termed death domains, that, upon receptor activation, induce the formation of a signaling complex that initiates the apoptotic cascade. Several factors are involved in this resistance of fibroblastlike synoviocytes against death receptor–induced cell death, but the ultimate mechanisms are incompletely understood. It is currently estimated that only about 15% of synovial fibroblasts are susceptible to Fas.21 It has been conjectured that the extensive resistance to Fas-induced apoptosis despite the surface expression of Fas is conveyed by inflammatory cytokines present in the synovial fluid, such as TNF-α and transforming growth factor-β (TGF-β), but also by soluble Fas, elevated levels of which have been found in the synovial fluid of patients with RA.60 However, this resistance against Fas-induced apoptosis is maintained in vitro, indicating that intrinsic factors are also responsible for this feature. Some evidence points to a role for the PI3K-Akt pathway in Fas resistance. The antiapoptotic FLICE inhibitory protein (Flip) is also elevated in the rheumatoid synovium, especially in the lining layer,61 and it correlates with low levels of apoptosis in early RA.62 It is induced by TNF-α63 and prevents the interaction of caspase-8 with the Fas-associated death domain adapter protein. Its downregulation sensitizes rheumatoid fibroblasts to Fas-induced apoptosis.64 Another molecule that modulates downstream mechanisms of Fas is SUMO-1. It is a small ubiquitin-like protein that, in contrast to ubiquitination, does not lead to the degradation of proteins. Rather, SUMOylation results in altered binding of modified proteins to subsequent substrates and significantly affects the signaling of SUMOylated proteins.65 SUMO-1 also interacts with the Fas- and TNFR1-associated death domain and protects against Fas- and TNFR1-induced apoptosis.66 In the rheumatoid synovium, there is marked expression of SUMO-1, predominantly in fibroblasts of the lining layer and at sites of cartilage invasion. Normal synovial tissues and synovial tissues of osteoarthritis patients do not show prominent expression of SUMO-1.67 Intriguingly, rheumatoid fibroblasts maintain the high expression of SUMO-1 when analyzed in the SCID mouse model, and recent data suggest that SUMO-1 is indeed involved functionally in rheumatoid fibroblasts’ resistance to Fas-induced apoptosis. Tumor Necrosis Factor-α Although TNF-α can activate the apoptotic pathway through caspase-3 and caspase-8, it can also initiate pathways diverging downstream of the TNF receptor–binding protein TNF

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Receptor-Associated Death Domain (TRADD) and leading to the activation of NFκB,68 which in TNF Receptor-Associated Death Domain (turn promotes cell survival and the production of proinflammatory factors.69 In RA fibroblasts, TNF-α inhibits apoptosis and induces cell death only after the inhibition of NFκB.70 TNF-α has been demonstrated to rapidly and potently activate Akt kinase via PI3K, and inhibition of PI3K strongly potentiates TNF-α–induced apoptosis.71 Apparently, however, not all the antiapoptotic effects of TNF-α through the Akt pathway depend on NFκB.50 According to some studies, TNF-α interferes with Fas-mediated apoptosis at physiologic levels and induces apoptosis only at 100-fold higher levels. Of note, stimulation of rheumatoid fibroblast cell cultures with TNF-α also significantly increases the production of soluble Fas.72 In this context, it was recently shown that the tissue inhibitor of metalloproteinase-3 (TIMP-3) can sensitize rheumatoid fibroblast to Fas ligand–induced apoptosis when expressed through adenoviral gene transfer.72 In addition, adenoviral delivery of TIMP-3 completely reverses the apoptosis-inhibiting effects of TNF-α in these cells. These findings provide a link between matrix degradation and rheumatoid fibroblasts’ resistance to apoptosis and indicate that overexpression of TIMP-3 in such cells may have beneficial effects by both inhibiting matrix degradation and facilitating cell death. Taken together, these data suggest that apoptosis­suppressing signals outweigh apoptosis-inducting signals, which can cause an imbalance of pro- and antiapoptotic pathways in synoviocytes. This may lead to an extended life span of synovial lining cells and result in a prolonged expression of matrix-degrading enzymes at sites of joint destruction.73 ATTACHMENT The attachment of fibroblast-like synoviocytes to joint cartilage is one of the most prominent features of joint destruction. This process appears to be pivotal for inflammatory arthritis. Integrins Integrins, which are key adhesion molecules for fibroblasts (discussed earlier), are of interest not only because of their function as receptor molecules but also because of their interaction with several signaling pathways and cellular proto-oncogenes.74 For instance, the expression of early cell-cycle genes such as c-fos and c-myc is also ­ stimulated by integrin-mediated cell adhesion, and gene ­ expression driven by the fos promoter strongly synergizes with integrinmediated adhesion.75 Studies have demonstrated that, apart from being expressed on lymphocytes, several β1 integrins are highly expressed on fibroblast-like synoviocytes.76,77 The binding of fibroblast-like synoviocytes to ECM is inhibited, at least in part, by anti–ß1 integrin antibodies, with the blocking efficacy being significantly higher in rheumatoid than in normal fibroblast-like synoviocytes.76 Of note is that different integrins function as fibronectin receptors, which is why the fibronectin-rich environment of the cartilage surface might facilitate the adhesion of fibroblast-like synoviocytes to cartilage. In this context, it is important to determine how the loss of ­cartilage components during disease progression affects the adhesion of fibroblast-like sy­noviocytes to the articular cartilage.

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Integrins not only facilitate the attachment of cells to the ECM but also mediate intracellular signaling pathways. Integrin signals are crucial for the growth of a number of cell types. Specifically, rheumatoid fibroblasts require integrin cosignaling for proliferation upon PDGF binding.78 Integrins contribute to Ras-dependent pathways79 involving ERK, JNK, and Akt and modulate the activation of MAPKs in response to growth factors.80 Importantly, the activation of ß1 integrins induces the expression of proteases contributing to ECM degradation,81 and their inhibition by antibodies reduces the invasive capacity of fibroblast-like synoviocytes.82 Vascular Adhesion Molecule 1 Vascular adhesion molecule 1 (VCAM-1; CD106) is a member of the immunoglobulin gene superfamily and may contain either six or seven immunoglobulin domains of the H type.83 Several studies have demonstrated increased VCAM-1 expression in inflamed synovium compared with normal and osteoarthritic synovial tissues. Although some data suggest that macrophage-like cells are the major source of VCAM-1 in RA synovial tissue,84 most studies reveal high expression of VCAM-1 mainly in fibroblast-like synoviocytes. Moreover, different data suggest that VCAM-1 is particularly upregulated in the subpopulation of activated lining fibroblasts.85-87 Increased expression of VCAM-1 is associated with cell and subsequently articular cartilage invasion.85 Studies in the SCID mouse model revealed increased expression of VCAM-1 in RA fibroblast-like synoviocytes, even in the absence of human inflammatory cells.88 In addition to mediating the attachment to cartilage, VCAM-1 produced by fibroblast-like synoviocytes might contribute to T cell anergy,89 B cell pseudoemperipolesis,16 and angiogenesis.90 MATRIX DEGRADATION Progressive joint destruction distinguishes RA from other inflammatory joint diseases and is mediated by the concerted action of various proteinases. The most prominent of these are MMPs and cathepsins,91,92 and several reports have implicated MMPs in joint destruction (for a more comprehensive review of MMPs in RA, see reference 91). Expression of Matrix Metalloproteinases MMP-1 is found in the synovial membranes of all RA patients but is present in the synovial samples of only about 55% to 80% of trauma patients.93 Synovial lining cells produce MMP-1 in the diseased synovium, and MMP-1 is released from these cells immediately after production (for a review, see reference 94). As a result, expression of MMP-1 in the synovial fluid correlates with the degree of synovial inflammation.95 However, serum concentrations of MMP-1 do not appear to reflect the levels in the synovial fluid; therefore, measuring serum MMP-1 has not been established as a marker for disease activity. MMP-3, or stromelysin, has a key role in joint ­destruction because it not only degrades matrix molecules but also activates other pro-MMPs into their active forms. MMP-3 is produced abundantly by ­ fibroblast-like ­ synoviocytes when

stimulated with ­ macrophage-­conditioned medium,96 and fibroblast-like synoviocytes in the lining layer are a major source of MMP-3 in synovium.97 Synovial fluids from patients with RA contain about 100-fold higher concentrations of MMP-3 than control samples,98 and increased levels of MMP-3 have been found in the sera of patients with RA.99 These increased serum levels correlate with systemic inflammation at clinical and serologic levels,100-102 but it is unclear whether levels of circulating MMP-3 reflect radiographic damage. No correlation between serum MMP-3 levels and radiographic or functional scores was found,101 and there were no differences in the serum levels of MMP-3 in long-standing RA patients with low versus high erosion scores.102 In contrast, other data indicate that serum MMP-3 levels predict joint damage at early stages of the disease.103 MMP-13, or collagenase-3, is also expressed at the mRNA104 and protein levels,105 especially in the lining layer of inflammatory synovium. Because of this localization, along with its substrate specificity for collagen type II and its relative resistance to known MMP inhibitors, MMP-13 is thought to play an important role in joint destruction. Of interest, expression of MMP-13 correlates with elevated levels of systemic inflammation markers,106 but studies of osteoarthritis clearly demonstrated that the expression of MMP-13 is not specific for RA. Rather, it appears that MMP-13 is closely associated with the degeneration of cartilage in several pathologies. MT-MMPs are also abundantly expressed in cells that aggressively destroy cartilage and bone in RA.107 MT1-MMP is produced constitutively by fibroblast-like synoviocytes, and elevated levels have been found in RA. This is important because MT1-MMP degrades ECM components as well as activates other disease-relevant MMPs such as MMP-2 and MMP-13. In a recent study that compared the expression of MT-MMPs in RA, MT1-MMP was found to be of particular relevance to RA.107 In this analysis, the expression of MT3-MMP mRNA was seen in fibroblasts and some macrophages, particularly in the lining layer; however, the expression of MT2- and MT4-MMP was characterized by scattered staining of only a few CD68– fibroblasts. Regulation of Matrix Metalloproteinases The expression of MMPs in synovial cells is regulated by several extracellular signals, including inflammatory cytokines, growth factors, and molecules of the ECM. Among the inflammatory cytokines, IL-1 and TNF-α are important inducers of MMPs. IL-1 induces the expression of a variety of MMPs, including MMP-1, -3, -8, -13, and -14.91 However, as demonstrated in several studies using antigen-induced arthritis in animals, IL-1 not only enhances the production of MMPs but also suppresses the synthesis of ­proteoglycans.108 In some of these studies, anti–IL-1 treatment ­normalized chondrocyte synthetic function and reduced the activation of MMPs.109 These data support observations that overexpression of the IL-1 ­receptor antagonist using retroviral gene transfer significantly reduces perichondrocytic matrix degradation in the SCID mouse model.110 However, the mechanisms by which ­ cytokines such as IL-1 induce MMPs are variable and depend on the cell type.

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Other macrophage-derived inflammatory cytokines such as TNF-α have also been shown to amplify the destructive process by stimulating the expression of some MMPs. For example, TNF-α can stimulate the production of MMP-1 in cultured synovial cells.111,112 However, animal models of arthritis indicate a difference in the relative importance of TNF-α and IL-1 with respect to inflammation and joint destruction. Whereas TNF-α appears to be responsible primarily for the extent of synovitis, IL-1 seems to have a greater impact on the destruction of cartilage.113 Other cytokines that regulate the expression of MMP in the RA synovium include IL-17 (MMP-1 and -9)114 and TGF-β (MMP-13).115 Growth factors such as FGF and PDGF are also potent inducers of MMPs and potentiate the effect of IL-1.116 MMP expression can also be induced by matrix proteins such as collagen and fibronectin; their degradation products in particular can activate the expression of MMPs in chondrocytes and fibroblasts, which suggests the possibility of specific activation of MMPs at sites of matrix degradation.7,117 As a consequence, the synthesis of matrix-degrading enzymes in inflamed joints is regulated not only by inflammatory cytokines and growth factors but also by cleavage products of the destroyed matrix itself in an amplifying fashion. A close correlation between the expression of MMP-1, -3, and -10 with the invasive growth of RA fibroblast-like synoviocytes has been reported,118 but the specific contribution of individual MMPs to matrix degradation is only partly understood. Using gene transfer of ribozymes to MMP-1, specific inhibition of MMP-1 significantly reduced the production of this enzyme in RA fibroblast-like synoviocytes and inhibited the cells’ invasiveness in the SCID mouse model.119 In a similar study, gene transfer of antisense RNA expression constructs against MT1-MMP, a membrane-anchored MMP, also inhibited the invasiveness of RA fibroblast-like synoviocytes. These techniques might clarify the role of individual MMPs in joint destruction and permit the development of drugs that selectively target disease-relevant MMPs. Tissue Inhibitors of Metalloproteinase MMP activity is normally balanced by the naturally ­occurring tissue inhibitors of metalloproteinase such as TIMP-1 and TIMP-2. They interact with MMP-1 and MMP-3 and are synthesized and secreted by chondrocytes, fibroblast-like synoviocytes, and endothelial cells.120-122 In situ hybridization studies demonstrated striking amounts of TIMP-1 mRNA in the synovial lining of patients with RA.120 However, the molar ratio of MMP to TIMP, rather than the absolute level of TIMP, is crucial for joint destruction. In RA, the amount of MMPs produced far outweighs the TIMPs produced, allowing destruction to take place. This notion has been supported by data demonstrating that the overexpression of TIMP-1 and TIMP-3 by gene transfer may result in a marked reduction in the invasiveness of RA fibroblast-like synoviocytes.123 Of interest, in addition to inhibiting the degradation of ECM, TIMP-3 has a number of distinctive features; for example, TIMP-3 prevents the shedding of cell membrane proteins such as TNF receptor124 and IL-6 receptor125 and of TNF-α converting enzyme.126 Another ­interesting feature of TIMP-3 is its ability to induce

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­apoptosis in ­ different cell types.127-130 It can also sensitize fibroblast-like synoviocytes to Fas ligand–induced apoptosis when expressed through adenoviral gene transfer.131 Cathepsins Cathepsins are another major group of proteases involved in joint destruction.92 They are classified by their catalytic mechanism and cleave cartilage types II, IX, and XI, as well as proteoglycans. Expression of the cysteine proteases cathepsin B and L is increased in RA synovium, especially at sites of cartilage invasion.31,132,133 As with MMPs, cathepsin production is induced by proto-oncogenes. Transfection of fibroblasts with the ras proto-oncogene leads to cellular transformation and the induction of cathepsin L.134 Several studies have also shown that inflammatory cytokines such as IL-1 and TNF-α can stimulate the production of cathepsins B and L by fibroblast-like synoviocyte-like cells.135,136 In this context, gene transfer of ribozymes to cathepsin L can significantly inhibit the fibroblast-mediated cartilage degradation both in vitro and in vivo.137 Cathepsin K is a cysteine proteinase that plays an important role in osteoclast-mediated bone resorption. In addition, cathepsin K expression by RA fibroblast-like synoviocytes and macrophages has been reported, especially at the site of synovial invasion into articular bone, suggesting that it participates in bone destruction.138 INTERACTIONS BETWEEN FIBROBLAST-LIKE SYNOVIOCYTES AND INFLAMMATORY CELLS The accumulation of inflammatory and immune cells, ­particularly macrophages, B cells, and T cells, is one of the hallmarks of many forms of chronic arthritis. These inflammatory cells release a variety of cytokines that stimulate neighboring cells and contribute to the specific environment in the rheumatoid joint. Cytokines derived from ­inflammatory cells, such as TNF, IL-1, interferon-γ, and ­others, contribute to the aggressive behavior of fibroblast-like synoviocytes in diseases such as RA. It is now evident that in addition to the effect of inflammatory cells on fibroblast-like synoviocytes, these resident fibroblast-like synoviocytes contribute significantly to the accumulation and survival of inflammatory cells. RA fibroblasts interact with and regulate important functions of T cells, B cells, and macrophages. They are sentinels that, upon contact with bacterial products such as lipopolysaccharide and poorly defined components of necrotic cells through Toll-like receptors, produce chemokines to recruit inflammatory cells to the site of inflammation.23 Recruitment of T Cells Interactions between fibroblasts and T cells appear to be important for the specific composition of the inflamed synovium. There is now agreement that activated fibroblasts contribute to impaired apoptosis and anergy of synovial lymphocytes.15 It is mainly through the regulation of local cytokine ­levels that fibroblasts play a key role in modulating the transition from acute resolving inflammation to a persistent immune response accompanied by chronic inflammation.17

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Several inflammatory cytokines have been implicated in the interaction of rheumatoid fibroblasts and T cells. Prominent examples include IL-8,139 IL-16,140,141 and IL-7 and IL-15,142 both activators of T cells. In addition, stromal cell–derived factor 1,143 which stimulates the migration and inhibits the activation-induced apoptosis of T cells, and particularly IL-6, a highly abundant cytokine in inflammatory synovial fluid that supports antigen-independent inflammation, have been associated with maintenance of the inflammatory milieu. Monocyte chemoattractant proteins have also been implicated in diseases characterized by monocyte-rich infiltrates, including RA.8,23,144 IL-16 levels in the synovial fluid correlate with the chemotactic activity toward CD4+ T cells; these levels are highest in early RA.140 IL-16 expression is strongly induced in fibroblasts by IL-1ß,145 a key inflammatory cytokine. Most interestingly, IL-16 is induced by immunoglobulin G, targeting the insulin-like growth factor-1 receptor in RA but not in osteoarthritis. This mechanism may provide a link between B cell activity and T cell infiltration and potentially identify a novel therapeutic target.141 Interactions between rheumatoid fibroblast-like synoviocytes and T cells are important determinants of the cellular composition of inflamed synovium. Thus, human thymocytes and mitogen-activated peripheral blood T cells bind to RA synoviocytes, whereas fresh peripheral blood T cells do not exhibit this behavior. Of note, antibodies against CD2 and synovial cell lymphocyte function-associated antigen-3 inhibit this binding.146 Interaction of Fibroblast-Like Synoviocytes and B Cells Fibroblast-like synoviocytes have been implicated in the direct attraction and accumulation of B lymphocytes in inflamed joints. For instance, rheumatoid fibroblasts can act as follicular dendritic cells and bind to B cells.147 This function is intrinsic to RA fibroblasts and quite specific for these cells when compared with non-RA fibroblast-like synoviocytes. Also, B cells cocultured with rheumatoid fibroblasts show reduced apoptosis and an increase in mitochondrial apoptosis inhibitors such as Bcl-X(L).148 Fibroblasts promote the survival of B cells mainly through the induction of BclX(L) expression and block their apoptosis through VLA-4 (CD49d/CD29)–VCAM-1 interactions. Other studies have shown that B cells cocultured with fibroblast-like synoviocytes are protected from cell death in a cell contact– and VCAM-1– dependent mechanism.149 Interaction of Fibroblast-Like Synoviocytes and Synovial Macrophages A variety of data support the notion that fibroblasts play a significant role in the activation of macrophages and their differentiation into multinucleated, bone-resorbing cells. Specifically, the osteoclast differentiating factor known as the receptor activator of NFκB (RANKL) has been identified as a major factor promoting osteoclastogenesis in RA synovium. Synoviocytes produce large amounts of RANKL in vivo, and these high levels of RANKL correlate with the ability of the fibroblasts to generate osteoclasts from PBMCs in vitro.150 These data suggest that fibroblast-like

Macrophages IL-15 IL-18 Lymphocytes SDF-1α VCAM-1 IL-15 IL-16

RANKL

MCP-1 RANKL IFNγ IL-2 RANKL TNFα IL-1 IL-15

RANKL Osteoclasts

Fibroblasts

Figure 11-8  Fibroblasts contribute to the accumulation and differentiation of inflammatory cells in the rheumatoid arthritis synovium. Fibroblasts are part of a cellular network in the diseased synovial membrane. As such, they are stimulated by inflammatory cells and, in turn, contribute actively to the accumulation and differentiation of these cells.

s­ ynoviocytes contribute to ECM degradation not only directly through the release of matrix-degrading enzymes but also indirectly through the differentiation and activation of osteoclasts. The cooperation of synovial macrophages and fibroblasts is also mediated by direct cell-cell interactions through the ligation of CD55 on FLS and CD97 on macrophages.151 Interestingly, these interactions take place predominantly in the synovial lining, which mediates the progressive destruction of cartilage and bone (Fig. 11-8).

SUMMARY Fibroblasts are structural mesenchymal cells that form the cellular infrastructure for most internal organs as well as for bordering membranes such as the synovial membrane. They are prominently involved in the deposition and resorption of the ECM and thus are responsible for maintaining tissue homeostasis. However, fibroblasts are far more than just passively responding cells that build the “backbone” for organ-specific function. Rather, they are very sensitive to environmental changes. They react in a very specific manner to a variety of stimuli and are capable of actively influencing not only the composition of the ECM but also the cellular composition of tissues and barrier membranes. Under disease conditions such as inflammation, fibroblasts, as a critical part of the organ-specific immune system, are involved in the progression of organ damage as well as in the switch from acute resolving to chronic persisting ­inflammation. This notion is particularly true for fibroblast-like ­synoviocytes, which play a critical role in the pathogenesis of RA. In addition to contributing to the recruitment of inflammatory cells to the joint, they modulate the behavior of these cells and are, in turn, regulated by the newly recruited cells. More important, fibroblast-like synoviocytes are crucial components in the hyperplastic lining layer and in cartilage destruction. Further, rheumatoid fibroblasts retain many of their specific characteristics, including the ability to invade and degrade cartilage in environments devoid of ­inflammatory cells.

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­ 45. Georganas C, Liu H, Perlman H, et al: Regulation of IL-6 and IL-8 expression in rheumatoid arthritis synovial fibroblasts: The ­dominant role for NF-kappa B but not C/EBP beta or c-jun. J Immunol 165:7199-7206, 2000. ­ 46. Makarov SS: NF-kappaB in rheumatoid arthritis: A pivotal ­regulator of inflammation, hyperplasia, and tissue destruction. Arthritis Res 3:200-206, 2001. ­ 47. Karin M, Lin A: NF-kappaB at the crossroads of life and death. Nat Immunol 3:221-227, 2002. ­ 48. Li P, Sanz I, O’Keefe RJ, et al: NF-kappa B regulates VCAM1 expression on fibroblast-like synoviocytes. J Immunol 164: 5990-5997, 2000. ­ 49. Vincenti MP, Coon CI, Brinckerhoff CE: Nuclear factor kappaB/p50 activates an element in the distal matrix metalloproteinase 1 ­promoter in interleukin-1beta-stimulated synovial fibroblasts. Arthritis Rheum 41:1987-1994, 1998. ­ 50. Nykanen P, Bergroth V, Raunio P, et al: Phenotypic characterization of 3H-thymidine incorporating cells in rheumatoid arthritis synovial membrane. Rheumatol Int 6:269-271, 1986. ­ 51. Petrow P, Theis B, Eckard A, et al: Determination of ­ proliferating cells at sites of cartilage invasion in patients with rheumatoid ­arthritis. Arthritis Rheum 40(Suppl):S251, 1997. 52. Kinne RW, Palombo Kinne E, Emmrich F: Activation of synovial fibroblasts in rheumatoid arthritis. Ann Rheum Dis 54:501-504, 1995. ­ 53. Baier A, Meineckel I, Gay S, et al: Apoptosis in rheumatoid arthritis. Curr Opin Rheumatol 15:274-279, 2003. ­ 54. Matsumoto S, Muller Ladner U, Gay RE, et al: Multistage ­apoptosis and Fas antigen expression of synovial fibroblasts derived from patients with rheumatoid arthritis. J Rheumatol 23:1345-1352, 1996. ­ 55. Pope RM: Apoptosis as a therapeutic tool in rheumatoid arthritis. Nat Rev Immunol 2:527-535, 2002. ­ 56. Perlman H, Liu H, Georganas C, et al: Differential expression ­pattern of the antiapoptotic proteins, Bcl-2 and FLIP, in experimental ­arthritis. Arthritis Rheum 44:2899-2908, 2001. ­ 57. Matsumoto S, Muller Ladner U, Gay RE, et al: Ultrastructural ­demonstration of apoptosis, Fas and Bcl-2 expression of rheumatoid synovial fibroblasts. J Rheumatol 23:1345-1352, 1996. ­ 58. Perlman H, Georganas C, Pagliari LJ, et al: Bcl-2 expression in ­synovial fibroblasts is essential for maintaining mitochondrial homeostasis and cell viability. J Immunol 164:5227-5235, 2000. ­ 59. Kurowska M, Rudnicka W, Kontny E, et al: Fibroblast-like ­synoviocytes from rheumatoid arthritis patients express functional IL-15 receptor complex: Endogenous IL-15 in autocrine fashion enhances cell proliferation and expression of Bcl-x(L) and Bcl- 2. J Immunol 169:1760-1767, 2002. ­ 60. Hasunuma T, Kayagaki N, Asahara H, et al: Accumulation of soluble Fas in inflamed joints of patients with rheumatoid arthritis. Arthritis Rheum 40:80-86, 1997. ­ 61. Perlman H, Pagliari LJ, Liu H, et al: Rheumatoid arthritis ­synovial macrophages express the Fas-associated death domain-like ­interleukin1beta-converting enzyme-inhibitory protein and are refractory to Fasmediated apoptosis. Arthritis Rheum 44:21-30, 2001. ­ 62. Catrina AI, Ulfgren AK, Lindblad S, et al: Low levels of apoptosis and high FLIP expression in early rheumatoid arthritis synovium. Ann Rheum Dis 61:934-936, 2002. ­ 63. Schedel J, Gay RE, Kuenzler P, et al: FLICE-inhibitory protein expression in synovial fibroblasts and at sites of cartilage and bone erosion in rheumatoid arthritis. Arthritis Rheum 46:1512-1518, 2002. ­64. Palao G, Santiago B, Galindo M, et al: Down-regulation of FLIP sensitizes rheumatoid synovial fibroblasts to Fas-mediated apoptosis. Arthritis Rheum 50:2803-2810, 2004. ­ 65. Melchior F: SUMO—nonclassical ubiquitin. Annu Rev Cell Dev Biol 16:591-626, 2000. ­ 66. Okura T, Gong L, Kamitani T, et al: Protection against Fas/APO-1and tumor necrosis factor-mediated cell death by a novel protein, sentrin. J Immunol 157:4277-4281, 1996. ­ 67. Franz JK, Pap T, Hummel KM, et al: Expression of sentrin, a novel antiapoptotic molecule, at sites of synovial invasion in rheumatoid arthritis. Arthritis Rheum 43:599-607, 2000. ­ 68. Hsu H, Shu HB, Pan MG, et al: TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 84:299-308, 1996.

­ 69. Mountz JD, Hsu HC, Matsuki Y, et al: Apoptosis and rheumatoid arthritis: Past, present, and future directions. Curr Rheumatol Rep 3:70-78, 2001. ­ 70. Liu H, Pope RM: The role of apoptosis in rheumatoid arthritis. Curr Opin Pharmacol 3:317-322, 2003. ­ 71. Reddy SA, Huang JH, Liao WS: Phosphatidylinositol 3-kinase as a mediator of TNF-induced NF-kappa B activation. J Immunol 164:1355-1363, 2000. ­ 72. Drynda A, Quax PH, Neumann M, et al: Gene transfer of tissue inhibitor of metalloproteinases-3 reverses the inhibitory effects of TNF-alpha on Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts. J Immunol 174:6524-6531, 2005. ­ 73. Pap T, Cinski A, Baier A, et al: Modulation of pathways regulating both the invasiveness and apoptosis in rheumatoid arthritis synovial fibroblasts. Joint Bone Spine 70:477-479, 2003. ­ 74. Schwartz MA: Integrins, oncogenes, and anchorage independence. J Cell Biol 139:575-578, 1997. ­ 75. Dike LE, Ingber DE: Integrin-dependent induction of early growth response genes in capillary endothelial cells. J Cell Sci 109: 2855-2863, 1996. ­ 76. Rinaldi N, Schwarz EM, Weis D, et al: Increased expression of integrins on fibroblast-like synoviocytes from rheumatoid arthritis in vitro correlates with enhanced binding to extracellular matrix proteins. Ann Rheum Dis 56:45-51, 1997. ­ 77. Ishikawa H, Hirata S, Andoh Y, et al: An immunohistochemical and immunoelectron microscopic study of adhesion molecules in synovial pannus formation in rheumatoid arthritis. Rheumatol Int 16:53-60, 1996. ­ 78. Sarkissian M, Lafyatis R: Integrin engagement regulates ­proliferation and collagenase expression of rheumatoid synovial fibroblasts. J Immunol 162:1772-1779, 1999. ­ 79. Lin TH, Chen Q, Howe A, et al: Cell anchorage permits efficient signal transduction between ras and its downstream kinases. J Biol Chem 272:8849-8852, 1997. ­ 80. Inoue H, Yamashita A, Hakura A: Adhesion-dependency of seruminduced p42/p44 MAP kinase activation is released by retroviral oncogenes. Virology 225:223-226, 1996. ­ 81. Ravanti L, Heino J, Lopez-Otin C, et al: Induction of collagenase-3 (MMP-13) expression in human skin fibroblasts by three-­dimensional collagen is mediated by p38 mitogen-activated protein kinase. J Biol Chem 274:2446-2455, 1999. ­ 82. Wang AZ, Wang JC, Fisher GW, et al: Interleukin-1beta-stimulated invasion of articular cartilage by rheumatoid synovial f­ibroblasts is inhibited by antibodies to specific integrin receptors and by ­collagenase inhibitors. Arthritis Rheum 40:1298-1307, 1997. ­ 83. Osborn L, Hession C, Tizard R, et al: Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell 59:1203-1211, 1989. ­ 84. Higashiyama H, Saito I, Hayashi Y, et al: In situ hybridization study of vascular cell adhesion molecule-1 messenger RNA expression in rheumatoid synovium. J Autoimmun 8:947-957, 1995. ­ 85. Kriegsmann J, Keyszer GM, Geiler T, et al: Expression of vascular cell adhesion molecule-1 mRNA and protein in rheumatoid synovium demonstrated by in situ hybridization and immunohistochemistry. Lab Invest 72:209-214, 1995. ­ 86. Morales DJ, Wayner E, Elices MJ, et al: Alpha 4/beta 1 integrin (VLA-4) ligands in arthritis: Vascular cell adhesion molecule-1 expression in synovium and on fibroblast-like synoviocytes. J ­Immunol 149:1424-1431, 1992. ­ 87. Matsuyama T, Kitani A: The role of VCAM-1 molecule in the ­pathogenesis of rheumatoid synovitis. Hum Cell 9:187-192, 1996. ­ 88. Muller-Ladner U, Kriegsmann J, Franklin BN, et al: Synovial ­fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am J Pathol 149:1607-1615, 1996. ­ 89. Kitani A, Nakashima N, Izumihara T, et al: Soluble VCAM-1 induces chemotaxis of Jurkat and synovial fluid T cells bearing high affinity very late antigen-4. J Immunol 161:4931-4938, 1998. ­ 90. Koch AE, Halloran MM, Haskell CJ, et al: Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1. Nature 376:517-519, 1995. ­ 91. Pap T, Schett G, Gay S: Matrix metalloproteinases. In Smolen J, Lipsky J (eds): Targeted therapies in Rheumatology. London, Martin Dunitz, 483-497, 2002.

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­ 92. Muller-Ladner U, Gay RE, Gay S: Cysteine proteinases in arthritis and inflammation. Perspect Drug Discovery Design 6:87-98, 1996. ­ 93. Konttinen YT, Ainola M, Valleala H, et al: Analysis of 16 ­different matrix metalloproteinases (MMP-1 to MMP-20) in the synovial membrane: Different profiles in trauma and rheumatoid arthritis. Ann Rheum Dis 58:691-697, 1999. ­ 94. Sorsa T, Konttinen YT, Lindy O, et al: Collagenase in synovitis of rheumatoid arthritis. Semin Arthritis Rheum 22:44-53m 1992. ­ 95. Maeda S, Sawai T, Uzuki M, et al: Determination of interstitial collagenase (MMP-1) in patients with rheumatoid arthritis. Ann Rheum Dis 54:970-975, 1995. ­ 96. Okada Y, Takeuchi N, Tomita K, et al: Immunolocalization of matrix metalloproteinase 3 (stromelysin) in rheumatoid synovioblasts (B cells): Correlation with rheumatoid arthritis. Ann Rheum Dis 48:645-653, 1989. ­ 97. Tetlow LC, Lees M, Ogata Y, et al: Differential expression of ­gelatinase B (MMP-9) and stromelysin-1 (MMP- 3) by rheumatoid synovial cells in vitro and in vivo. Rheumatol Int 13:53-59, 1993. ­ 98. Beekman B, van El B, Drijfhout JW, et al: Highly increased levels of active stromelysin in rheumatoid synovial fluid determined by a selective fluorogenic assay. FEBS Lett 418:305-309, 1997. ­ 99. Taylor DJ, Cheung NT, Dawes PT: Increased serum proMMP-3 in inflammatory arthritides: A potential indicator of synovial ­inflammatory monokine activity. Ann Rheum Dis 53:768-772, 1994. 100. Yoshihara Y, Obata K, Fujimoto N, et al: Increased levels of ­stromelysin-1 and tissue inhibitor of metalloproteinases-1 in sera from patients with rheumatoid arthritis. Arthritis Rheum 38: 969-975, 1995. 101. Manicourt DH, Fujimoto N, Obata K, et al: Levels of ­ circulating ­collagenase, stromelysin-1, and tissue inhibitor of matrix ­metalloproteinases 1 in patients with rheumatoid arthritis: ­Relationship to serum levels of antigenic keratan sulfate and systemic parameters of inflammation. Arthritis Rheum 38:1031-1039, 1995. 102. So A, Chamot AM, Peclat V, et al: Serum MMP-3 in rheumatoid arthritis: Correlation with systemic inflammation but not with ­erosive status. Rheumatology (Oxford) 38:407-410, 1999. 103. Yamanaka H, Matsuda Y, Tanaka M, et al: Serum matrix ­metalloproteinase 3 as a predictor of the degree of joint destruction during the six months after measurement, in patients with early ­rheumatoid arthritis. Arthritis Rheum 43:852-858, 2000. 104. Petrow P, Hummel KM, Franz JK, et al: In-situ detection of MMP-13 mRNA in the synovial membrane and cartilage-pannus junction in rheumatoid arthritis. Arthritis Rheum 40:S336, 1997. 105. Lindy O, Konttinen YT, Sorsa T, et al: Matrix-metalloproteinase 13 (collagenase 3) in human rheumatoid synovium. Arthritis Rheum 40:1391-1399, 1997. 106. Westhoff CS, Freudiger D, Petrow P, et al: Characterization of ­collagenase 3 (matrix metalloproteinase 13) messenger RNA ­expression in the synovial membrane and synovial fibroblasts of patients with rheumatoid arthritis. Arthritis Rheum 42:1517-1527, 1999. 107. Pap T, Shigeyama Y, Kuchen S, et al: Differential expression pattern of membrane-type matrix metalloproteinases in rheumatoid arthritis. Arthritis Rheum 43:1226-1232, 2000. 108. van de Loo FA, Joosten LA, van Lent PL, et al: Role of ­interleukin-1, tumor necrosis factor alpha, and interleukin-6 in cartilage proteoglycan metabolism and destruction: Effect of in situ blocking in murine antigen- and zymosan-induced arthritis. Arthritis Rheum 38: 164-172, 1995. 109. van den Berg WB, Joosten LA, Helsen M, et al: Amelioration of ­ established murine collagen-induced arthritis with anti-IL-1 ­treatment. Clin Exp Immunol 95:237-243, 1994. 110. Muller-Ladner U, Roberts CR, Franklin BN, et al: Human IL-1Ra gene transfer into human synovial fibroblasts is chondroprotective. J Immunol 158:3492-3498, 1997. 111. Dayer JM, Beutler B, Cerami A: Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med 162:2163-2168, 1985. 112. Brinckerhoff CE, Auble DT: Regulation of collagenase gene ­expression in synovial fibroblasts. Ann N Y Acad Sci 580:355-374, 1990. 113. Kuiper S, Joosten LA, Bendele AM, et al: Different roles of TNFα and IL-1 in murine streptococcal wall arthritis. Cytokine 10:690-702, 1998.

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114. Jovanovic DV, Martel-Pelletier J, Di Battista JA, et al: ­Stimulation of 92-kd gelatinase (matrix metalloproteinase 9) production by ­interleukin-17 in human monocyte/macrophages: A possible role in rheumatoid arthritis. Arthritis Rheum 43:1134-1144, 2000. 115. Ravanti L, Toriseva M, Penttinen R, et al: Expression of human ­collagenase-3 (MMP-13) by fetal skin fibroblasts is induced by ­transforming growth factor beta via p38 mitogen-activated protein kinase. FASEB J 15:1098-1100, 2001. 116. Bond M, Fabunmi RP, Baker AH, et al: Synergistic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: An absolute requirement for transcription factor NF-kappa B. FEBS Lett 435:29-34, 1998. 117. Forsyth CB, Pulai J, Loeser RF: Fibronectin fragments and ­blocking antibodies to alpha2beta1 and alpha5beta1 integrins stimulate ­mitogen-activated protein kinase signaling and increase ­collagenase 3 (matrix metalloproteinase 13) production by human articular chondrocytes. Arthritis Rheum 46:2368-2376, 2002. 118. Tolboom TC, Pieterman E, van der Laan WH, et al: Invasive ­properties of fibroblast-like synoviocytes: Correlation with growth characteristics and expression of MMP-1, MMP-3, and MMP-10. Ann Rheum Dis 61:975-980, 2002. 119. Rutkauskaite E, Zacharias W, Schedel J, et al: Ribozymes that inhibit the production of matrix metalloproteinase 1 reduce the ­invasiveness of rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 50: 1448-1456, 2004. 120. Firestein GS, Paine MM: Stromelysin and tissue inhibitor of ­metalloproteinases gene expression in rheumatoid arthritis synovium. Am J Pathol 140:1309-1314, 1992. 121. Clark IM, Powell LK, Ramsey S, et al: The measurement of ­collagenase, TIMP and collagenase-TIMP complex in synovial fluids from patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum 36:372-380, 1993. 122. DiBattista JA, Pelletier JP, Zafarullah M, et al: Coordinate regulation of matrix metalloproteases and tissue inhibitor of metalloproteinase expression in human synovial fibroblasts. J Rheumatol Suppl 43: 123-128, 1995. 123. van der Laan WH, Quax PH, Seemayer CA, et al: Cartilage ­degradation and invasion by rheumatoid synovial fibroblasts is ­inhibited by gene transfer of TIMP-1 and TIMP-3. Gene Ther 10:234-242, 2003. 124. Smith MR, Kung H, Durum SK, et al: TIMP-3 induces cell death by stabilizing TNF-alpha receptors on the surface of human colon carcinoma cells. Cytokine 9:770-780, 1997. 125. Hargreaves PG, Wang F, Antcliff J, et al: Human myeloma cells shed the interleukin-6 receptor: Inhibition by tissue inhibitor of ­metalloproteinase-3 and a hydroxamate-based metalloproteinase inhibitor. Br J Haematol 101:694-702, 1998. 126. Amour A, Slocombe PM, Webster A, et al: TNF-alpha ­ converting enzyme (TACE) is inhibited by TIMP-3. FEBS Lett 435:39-44, 1998. 127. Ahonen M, Baker AH, Kahari VM: Adenovirus-mediated gene delivery of tissue inhibitor of metalloproteinases-3 inhibits invasion and induces apoptosis in melanoma cells. Cancer Res 58:2310-2315, 1998. 128. Baker AH, Zaltsman AB, George SJ, et al: Divergent effects of ­tissue inhibitor of metalloproteinase-1, -2, or -3 overexpression on rat ­vascular smooth muscle cell invasion, proliferation, and death in vitro: TIMP-3 promotes apoptosis. J Clin Invest 101:1478-1487, 1998. 129. Baker AH, George SJ, Zaltsman AB, et al: Inhibition of invasion and induction of apoptotic cell death of cancer cell lines by ­overexpression of TIMP-3. Br J Cancer 79:1347-1355, 1999. 130. Majid MA, Smith VA, Easty DL, et al: Adenovirus mediated gene delivery of tissue inhibitor of metalloproteinases-3 induces death in retinal pigment epithelial cells. Br J Ophthalmol 86:97-101, 2002. 131. Drynda A, Quax PH, Neumann M, et al: Gene transfer of tissue inhibitor of metalloproteinases-3 reverses the inhibitory effects of TNF-alpha on Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts. J Immunol 174(10): 6524-6531, 2005. 132. Keyszer G, Redlich A, Haupl T, et al: Differential expression of cathepsins B and L compared with matrix metalloproteinases and their respective inhibitors in rheumatoid arthritis and osteoarthritis: A parallel investigation by semiquantitative reverse transcriptasepolymerase chain reaction and immunohistochemistry. Arthritis Rheum 41:1378-1387, 1998.

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133. Keyszer GM, Heer AH, Kriegsmann J, et al: Comparative ­ analysis of cathepsin L, cathepsin D, and collagenase messenger RNA ­expression in synovial tissues of patients with rheumatoid ­ arthritis and ­ osteoarthritis, by in situ hybridization. Arthritis Rheum 38: 976-984, 1995. 134. Joseph L, Lapid S, Sukhatme V: The major ras induced protein in NIH3T3 cells is cathepsin L. Nucleic Acids Res 15:3186, 1987. 135. Huet G, Flipo RM, Colin C, et al: Stimulation of the secretion of latent cysteine proteinase activity by tumor necrosis factor alpha and interleukin-1. Arthritis Rheum 36:772-780, 1993. 136. Lemaire R, Huet G, Zerimech F, et al: Selective induction of the secretion of cathepsins B and L by cytokines in synovial fibroblastlike cells. Br J Rheumatol 36:735-743, 1997. 137. Schedel J, Seemayer CA, Pap T, et al: Targeting cathepsin L (CL) by specific ribozymes decreases CL protein synthesis and cartilage destruction in rheumatoid arthritis. Gene Ther 11:1040-1047, 2004. 138. Hummel KM, Petrow PK, Franz JK, et al: Cysteine proteinase ­cathepsin K mRNA is expressed in synovium of patients with ­rheumatoid arthritis and is detected at sites of synovial bone ­destruction. J Rheumatol 25:1887-1894, 1998. 139. Min DJ, Cho ML, Lee SH, et al: Augmented production of ­chemokines by the interaction of type II collagen-reactive T cells with ­ rheumatoid synovial fibroblasts. Arthritis Rheum 50: 1146-1155, 2004. 140. Franz JK, Kolb SA, Hummel KM, et al: Interleukin-16, produced by synovial fibroblasts, mediates chemoattraction for CD4+ T ­lymphocytes in rheumatoid arthritis. Eur J Immunol 28:2661-2671, 1998. 141. Pritchard J, Tsui S, Horst N, et al: Synovial fibroblasts from patients with rheumatoid arthritis, like fibroblasts from Graves’ disease, express high levels of IL-16 when treated with Igs against insulin-like growth factor-1 receptor. J Immunol 173:3564-3569, 2004. 142. McInnes IB, al Mughales J, Field M, et al: The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis. Nat Med 2:175-182, 1996.

143. Nanki T, Hayashida K, El Gabalawy HS, et al: Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis synovium. J Immunol 165:6590-6598, 2000. 144. Koch AE, Kunkel SL, Harlow LA, et al: Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis. J Clin Invest 90:772-779, 1992. 145. Sciaky D, Brazer W, Center DM, et al: Cultured human fibroblasts express constitutive IL-16 mRNA: Cytokine induction of active IL-16 protein synthesis through a caspase-3-dependent mechanism. J Immunol 164:3806-3814, 2000. 146. Haynes BF, Grover BJ, Whichard LP, et al: Synovial microenvironment-T cell interactions: Human T cells bind to fibroblast-like ­synovial cells in vitro. Arthritis Rheum 31:947-955, 1988. 147. Lindhout E, van Eijk M, van Pel M, et al: Fibroblast-like ­synoviocytes from rheumatoid arthritis patients have intrinsic properties of ­follicular dendritic cells. J Immunol 162:5949-5956, 1999. 148. Hayashida K, Shimaoka Y, Ochi T, et al: Rheumatoid arthritis ­sy­novial stromal cells inhibit apoptosis and up-regulate Bcl-xL ­expression by B cells in a CD49/CD29-CD106-dependent ­mechanism. J Immunol 164:1110-1116, 2000. 149. Reparon-Schuijt CC, van Esch WJ, van Kooten C, et al: ­Regulation of synovial B cell survival in rheumatoid arthritis by vascular cell ­ adhesion molecule 1 (CD106) expressed on fibroblast-like ­synoviocytes. Arthritis Rheum 43:1115-1121, 2000. 150. Shigeyama Y, Pap T, Kunzler P, et al: Expression of osteoclast ­differentiation factor in rheumatoid arthritis. Arthritis Rheum 43:2523-2530, 2000. 151. Hamann J, Wishaupt JO, van Lier RA, et al: Expression of the ­activation antigen CD97 and its ligand CD55 in rheumatoid synovial tissue. Arthritis Rheum 42:650-658, 1999.

12

Neutrophils and Eosinophils Michael H. Pillinger  •  Jose U. Scher  •  Steven B. Abramson

KEY POINTS Neutrophils are myeloid-lineage cells that are characterized by the presence of large quantities of granules containing enzymes and other potentially toxic agents involved in host defense. Neutrophils are short-lived, terminally differentiated cells that exist primarily in the bloodstream, where they participate in host surveillance of foreign organisms. Neutrophils function in acute inflammation and provide an ­essential defense against acute bacterial infections; ­ abnormalities of neutrophil function are uncommon and impair ability to respond to life-threatening infections. The main role of the neutrophil is to phagocytose foreign ­particles, primarily bacteria, and degrade them through ­activation of proteases, activation of other antibiotic ­molecules, and generation of toxic oxygen radicals. Neutrophils play a role as a major inflammatory cell in many rheumatic conditions and may be attracted into tissues by noninfectious stimuli, such as complement activation and lipid inflammatory mediators. Eosinophils are myeloid-lineage cells that contain many cytoplasmic granules containing proteins such as major basic protein, eosinophil cationic protein, eosinophil-derived ­neurotoxin, and eosinophil peroxidase. Eosinophils are thought to function in the defense of ­helminths and other parasites; however, evidence for such an antihelminthic role is limited. In contrast to neutrophils, eosinophils are not primarily phagocytic cells, but are thought to discharge their granule contents adjacent to the much larger organisms that may be their targets. Eosinophilia may be seen in many rheumatic diseases, ­including Churg-Strauss syndrome and less common diseases such as eosinophilic fasciitis and the idiopathic ­hypereosinophilic syndromes.

Polymorphonuclear leukocytes constitute a family of hematopoietically derived cells that share the feature of a multilobed nucleus. These leukocytes also share a property of possessing highly developed populations of intracytoplasmic granules, divisible into subsets and distinct between cell types. The presence of these granules permits the further designation of polymorphonuclear leukocytes as granulocytes. Based on the histocytochemical staining properties of their respective granules, three classes of polymorphonuclear leukocytes have been identified: neutrophils, eosinophils, and basophils. Neutrophil (polymorphonuclear neutrophil) granules stain with neutral dyes, the granules of eosinophils are most ­effectively stained

with acidic dyes such as eosin, and basophil granules stain with basic dyes. In a standard polychromatic Wright stain of a peripheral blood smear, the cytoplasm of neutrophils, eosinophils, and basophils appears blue-pink (neutrophils), pink (eosinophils), and blue (basophils). These classes of polymorphonuclear leukocytes differ with respect to not only appearance, but also biochemistry and function. ­Polymorphonuclear leukocytes constitute an important part of the organism’s system of innate immunity: Their responses to foreign organisms or antigens or both are preprogrammed and do not depend on prior exposure to the particle. This chapter reviews the salient features of neutrophils and eosinophils.

NEUTROPHILS Neutrophils are the body’s first line of defense against ­foreign invaders and constitute the major cell type involved in acute and some forms of chronic inflammatory disease. The importance of neutrophils in bacterial defense is shown by patients who have hereditary defects in neutrophil function and are prone to repeated and often life-threatening infections. ­Neutrophils are the most prevalent leukocyte in the bloodstream, typically constituting greater than 50% of all bloodstream leukocytes. During bacterial infection, the percentage of neutrophils may increase to 80% or more. In contrast, tissue concentrations of resting (inactive) neutrophils seem to be quite low. Neutrophils may be thought of as surveillance cells—sweeping through the bloodstream scanning for infections or other inflammatory events. The capacity of neutrophils to destroy foreign organisms is matched in some circumstances, however, by a capacity for host tissue destruction. NEUTROPHIL MYELOPOIESIS AND CLEARANCE The neutrophil majority in the bloodstream is duplicated in the marrow, where 60% of hematopoietic capacity may be dedicated to neutrophil production. Daily, 1011 neutrophils may be released into the bloodstream. Neutrophil development in the marrow takes about 14 days, originating with the hematopoietic stem cell. Stem cells fated to become neutrophils first differentiate into myeloblasts, which retain the capacity to develop into eosinophils, basophils, and neutrophils. Subsequent differentiation leads to the neutrophilic promyelocyte, a dedicated precursor of the neutrophil, and proceeds through the stages of neutrophilic myelocytes, metamyelocyte, band cell, and mature neutrophil. At the metamyelocyte stage, neutrophil mitosis ceases, whereas neutrophil development and organization of granules ­ continues. Neutrophils are terminally differentiated; they neither divide nor alter their gross phenotype after their release from the marrow. 215

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A

B

C

1.0 µm

D

2.0 µm

Figure 12-1  Resting and stimulated neutrophil morphology. A and B, Transmission (A) and scanning (B) electron micrographs of resting neutrophils. In A, note the multilobed nucleus and the rich population of granules. At least two granule populations of granules may be discerned: The larger, darker granules represent the primary (azurophilic) granules, whereas the smaller, slightly paler granules are predominantly secondary (specific) granules and may include a population of gelatinase granules (arrow indicates primary granule). In B, note the relatively smooth surface area with some membrane surface irregularities. C and D, Transmission (C) and scanning (D) electron micrographs of neutrophils 1 minute after stimulation with zymosan. The cellular diameter is enlarged, and the overall surface (plasma) membrane area is greatly increased. Most of the membrane contributing to the increased surface area is supplied via the fusion of internal granule membranes with the plasma membrane. In C, this fusion is apparent as the depletion of granules, leading to an appearance of empty vesicles (arrow indicates a partially depleted primary granule; clear circular areas represent fully depleted vesicles whose membranes are fused to the plasma membrane). In D, this fusion is apparent as the increase in plasma surface membrane extensions, known as lamellipodia.

Given the origin of neutrophils in a pluripotent stem cell, and the precise phases of their development, the mechanisms regulating neutrophil differentiation are of considerable interest. Although incompletely understood, studies have emphasized the role of a particular complement of cytokines that seem to direct the early cells toward neutrophil development. Principal among the cytokines described to date are granulocyte colony-stimulating factor (G-CSF) and granulocytemacrophage colony-stimulating factor (GM-CSF).1 Neutrophils released from the marrow have a bloodstream half-life of approximately 6 hours and a tissue half-life only marginally longer. The high output and short half-life of neutrophils imply that neutrophil clearance mechanisms must exist. When exposed to appropriate stimuli such as tumor necrosis factor (TNF)-α and Fas (CD95) ligand, neutrophils undergo apoptosis or programmed cell death.2,3 Senescent or apoptotic bloodstream neutrophils are cleared largely by liver and spleen macrophages (reticuloendothelial system). It is a matter of speculation whether tissue neutrophils are cleared primarily via local macrophages. NEUTROPHIL MORPHOLOGY AND CONTENT Neutrophil nuclei tend to have more lobes than nuclei of other polymorphs, typically three to five (Fig. 12-1). The multilobed nature of this nucleus reflects a condensation of chromatin that suggests that neutrophils might be incapable of transcription. It is now appreciated, however, that

­ eutrophils retain the capacity for constitutive and stimun lated protein synthesis, albeit at a limited rate. Neutrophil granules identifiable by classic histochemical staining comprise two classes (see Fig. 12-1). Neutrophil primary granules form first and, by virtue of their staining tendencies, are also referred to as azurophilic granules. These granules are oval or round and vary in size. They are similar, and functionally equivalent, to the lysosomes of other cells. In contrast, neutrophil secondary granules constitute a population unique to neutrophils, a fact reflected in the alternative nomenclature of specific granules often used to describe these structures. Characteristic of ­ azurophilic granules is the presence of myeloperoxidase, an enzyme that catalyzes the formation of hypochlorous acid from chloride in the presence of superoxide anion (O2−).4 The presence of large amounts of this enzyme in azurophilic granules lends collections of neutrophils (pus) their typical greenish yellow color. ­Consistent with their role as lysosomes, azurophilic granules also contain a variety of proteases and other enzymes, including elastase, lysozyme, acid phosphatase, and cathepsins and enzymes directed at nucleic acids and sugars. One particularly important family of ­ proteinases found in neutrophils are the matrix metalloproteinases (MMPs), including neutrophil collagenase-2 (MMP-8), gelatinase-B (MMP-9), and stromelysin (MMP-3). In ­ contrast to ­ azurophilic granules, specific granules possess an extensive array of membraneassociated proteins, including cytochromes, ­ signaling molecules, and receptors. ­Specific granules ­constitute a reservoir

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Table 12-1  Neutrophil Granule Contents Secretory Vesicles

Gelatinase Granules

Specific Granules

Azurophilic Granules

Relative size

Smallest

Intermediate

Intermediate

Largest

Soluble components

Plasma proteins

Gelatinase   Acetyltransferase

Gelatinase MMP-3 MMP-8 MMP-9 Lactoferrin β2-microglobulin

Myeloperoxidase Glucuronidase Elastase Lysozyme Proteinase 3 α1-antitrypsin Defensins Cathespsin BP1

Membrane-associated components

FMLP receptor CD11b/CD18 Cytochrome b558 Alkaline phosphatase Uroplasminogen activator CD10, CD13, CD16, CD45 CR1 Decay accelerating factor

FMLP receptor CD11b/CD18 Deacylating enzyme

FMLP receptor CD11b/CD18 Cytochrome b558 CD66, CD67 Fibronectin receptor TNF-α receptor

CD63, CD68

BPI, bactericidal/permeability-increasing protein; FMLP, formyl-methionyl-leucyl-phenylalanine; MMP, matrix metalloproteinase; TNF, tumor necrosis factor.

of proteins destined for topologically external surfaces of phagocytic vacuoles themselves and the plasma membrane (Table 12-1).4 Further study has confirmed the existence of two additional classes of vesicles. Gelatinase granules are almost identical in size to specific granules and share some proteins in common with them. As their name implies, however, gelatinase granules are noteworthy for their high concentrations of gelatinase, a latent enzyme with the capacity for tissue destruction.5 Secretory vesicles are smaller and lighter than the other classes and do not seem to contain proteolytic enzymes.6 Rather, they are noteworthy for an extensive series of membrane-associated proteins, including receptors otherwise identified with the plasma membrane.7 These and other data suggest that the secretory vesicle is a reservoir of neutrophil plasma membrane and membrane proteins. Azurophilic and specific granules further contain antimicrobial proteins and peptides that are a cornerstone of innate immunity. A detailed description of the neutrophil’s armamentarium against foreign invaders is beyond the scope of this chapter, but a few whose mechanisms of action have more recently been elucidated warrant mention. Elastase, already mentioned previously, aids in the killing of gram-negative bacteria via degradation of bacterial outer membrane protein A.8 Elastase-deficient mice are more susceptible to infection with gram-negative (but not gram-positive) organisms than wild-type mice. The defensins, normally located in azurophilic granules, are found in mg/mL concentrations in the phagocytic vacuole (see later) and render target cell membranes permeable. Bactericidal/permeability-inducing protein, also located in azurophilic granules, acts in concert with the defensins; it potently neutralizes endotoxin and is cytotoxic to gram-negative bacteria.9 Bactericidal/permeability-inducing protein also enhances the activity of secretory phospholipase A2, which has activity against gram-negative and gram-positive bacteria. Lactoferrin (found in specific granules) deprives microorganisms of iron and has antiviral and antibacterial effects. Neutrophil proteases play important roles beyond their antimicrobial effects; they also may amplify or dampen the

innate and adaptive immune response. Lactoferrin released during phagocytosis may inhibit proliferation of mixed lymphocyte cultures by decreasing release of interleukin (IL)-2, TNF-α, and IL-1. Proteinase 3 has been found to augment release of active TNF-α and IL-1 in monocyte/neutrophil cocultures by releasing the membrane bound forms of these cytokines.10 Gelatinase B has been shown to convert latent IL-1 into its active form11 and to potentiate IL-8 activity by truncating this chemoattractant and increasing its release, amplifying neutrophilic influx.12 Neutrophil elastase also may play a proinflammatory role by virtue of its ability to cleave and disrupt phosphatidyl serine receptors on macrophages. Apoptotic cells undergo membrane alterations that lead to expression of phosphatidyl serine on their outer membrane surface, and interaction of phosphatidyl serine with its receptor leads to macrophage responses that downregulate inflammation through the generation of transforming growth factor (TGF)-β.13 By disrupting these interactions, the presence of neutrophil elastase may permit inflammation to continue.14 NEUTROPHIL ACTIVATION AND FUNCTION For bloodstream neutrophils to destroy foreign targets in the periphery, they first must sense the presence of such targets at a distance. They must adhere to and pass through the endothelium of postcapillary venules (diapedesis) and migrate to the source of the signal (chemotaxis). Finally, neutrophils must encounter a target, engulf it, and destroy it. Collectively, these processes are referred to as neutrophil activation. Because of the potential for tissue destruction, neutrophil activation must be carefully regulated. The internal responses through which a cell translates an encounter with a stimulus into a particular phenotypic response are termed signal transduction (Fig. 12-2).15,16 Stimuli and Receptors Classic chemoattractants include lipid mediators (e.g., leukotriene B4 [LTB4], platelet-activating factor) and proteins/peptides (e.g., formylated peptides, the complement

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Endothelial ICAM FcγRII

CD11b

Growth factor

CD18

P Rac

P

Chemoattractant

Tyrosine kinase receptor

Grb2

SOS

Serpentine seven receptor

Ras GTP

α GTP

γ β

Rho

Heterotrimeric G protein

Raf Membrane ruffling, superoxide generation

Stress fiber formation

P13K

Translocation

ERK

DAG

IP3

PKC

Ca++

cPLA2

ERK

AA Calmodulin kinase

AP-1 system Transcriptional regulation

PLC

MEK

Nucleus

Adhesion, superoxide generation

Figure 12-2  Signaling pathways in neutrophil activation. Engagement of Fc, growth factor, and chemoattractant receptors and adhesion molecules initiate signaling pathways that result in proinflammatory neutrophil responses, including cytoskeletal and morphologic changes, activation of adhesion molecules and the superoxide generating system (NADPH oxidase), and regulation of transcription. Some of the well-established pathways participating in these responses are illustrated (see text for details).

split product C5a, and IL-8). Chemoattractants in vivo are formed at sites of inflammation—either produced at the site by inflammatory cells, such as LTB4 or IL-8, or liberated from already synthesized proteins, as in the case of C5a. The ability of formylated peptides, such as N-formyl-methionylleucyl-phenylalanine, to stimulate neutrophils probably represents a particularly ancient arm of the innate immune response because prokaryotic, but not eukaryotic, cells synthesize proteins whose first amino acid is a formylated methionine. Chemoattractants also have the capacity to stimulate most other aspects of neutrophil activation. Their individual potencies for particular responses may differ,17 however, suggesting that they may serve overlapping, but distinct functions in neutrophil activation. Bloodstream activation of neutrophils depends on the presence of specific surface receptors. Chemoattractant receptors belong to a class known as seven-transmembranedomain receptors, or “serpentine seven” receptors, composed of a single protein chain whose seven hydrophobic domains span the plasma membrane. Binding of a particular chemoattractant occurs in a pocket on the cytoplasmic face, close to or below the level of the plasma membrane. Receptors for soluble ligands other than chemoattractants also have been identified on neutrophils, including receptors for growth factors, colony-stimulating factors, and cytokines.16 These receptors fall into several families

distinct from the ­ serpentine sevens. Growth factor receptors are members of the protein tyrosine kinase receptor family, in which ligand interaction with two identical or related receptors brings them into proximity, causing their phosphorylation and activation. Some nonchemoattractant ligands do not directly activate neutrophils, but may modulate their function. Pretreatment of neutrophils with either insulin or GM-CSF results in amplification of subsequent neutrophil responses to chemoattractants, a process referred to as priming. G Proteins Ligation of seven-transmembrane-domain receptors results in the interaction of cytoplasmic elements of the receptor with a class of effectors known as heterotrimeric guanosine triphosphate (GTP)–binding proteins (G proteins). G proteins are composed of α, β, and γ subunits, and individual G protein types are distinguished by their particular combination of subunits. In neutrophils, the predominant G proteins are of the Gi family.15 G protein γ subunits are modified by the addition of prenyl (polyisoprene) and carboxyterminal methyl groups, which serve to anchor them to the plasma membrane. All G proteins share the capacity, localized to their α subunits, to bind GTP and subsequently to hydrolyze it to guanosine diphosphate (GDP). G proteins are active when GTP

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bound, but inactive in the GDP-bound form. Engagement of the appropriate seven-transmembrane-domain receptor results in the binding of GTP on the α subunit. As a consequence of GTP binding, heterotrimeric G proteins dissociate into α and β/γ components, each with specific effector functions. A monomeric class of low-molecular-weight (20 to 25 kD) GTP-binding proteins (LMW-GBPs) also has been described. Because the first, prototypical LMW-GBP to be described was the proto-oncogene ras, these also are referred to as ras-related proteins. LMW-GBPs combine, in one molecule, the prenyl and methyl modifications of the G protein γ subunit with the GTP-binding capacity of the α subunit. At least four families of LMW-GBP have been described: the Ras family, whose members play roles in cell growth and division; the Rho family, which functions in cytoskeletal rearrangements18; and the Rab and Arf families, which are crucial for vesicular and endomembrane trafficking.19 All four classes of LMW-GBPs are represented in neutrophils. Second Messengers Second messengers are small, diffusible molecules that are generated in response to stimuli and transmit signals from membrane receptors to downstream effector proteins. In the classic model of neutrophil activation, engagement of receptors results in the activation of phospholipase C, which cleaves phosphoinositol triphosphate into diacyl­ glycerol and inositol 1,4,5-triphosphate. ­Diacylglycerol and inositol 1,4,5-triphosphate mediate the influx of cytosolic calcium and the activation of protein kinase C. Other phospholipases present in the neutrophil include phospholipase A2, which cleaves phosphatidylcholine or ethanolamine or both and is responsible for the ­ generation of arachidonic acid, and phospholipase D, which cleaves phosphatidylcholine into phosphatidic acid and choline.20 Although the above-described second messengers all have been implicated in neutrophil activation, other lipid ­ mediators may have negative regulatory effects. Sphingosine and ceramide each inhibits neutrophil phagocytosis.21 In addition to lipids, other organic and inorganic messenger molecules have been characterized. Intracellular concentrations of cyclic adenosine monophosphate (cAMP), a classic second messenger, increase rapidly in neutrophils exposed to stimuli and inhibitors. cAMP in these settings is likely to provide a negative regulatory (off) signal because direct exposure to cAMP inhibits neutrophil responses, probably through the activation of protein kinase A.17,22 In contrast, increases in cyclic guanosine monophosphate have a modest enhancing effect on some neutrophil responses. Nitric oxide (NO), an important molecule in the regulation of host defense, also is produced in neutrophils, albeit in low levels.23 Endogenously produced NO in neutrophils is likely to play an important role in signal transduction; several studies have documented the capacity of exogenously added NO to exert a variety of effects, including inhibition of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, actin polymerization, and chemotaxis (see later). Excessive NO production has been implicated in many rheumatic diseases.24

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Kinases and Kinase Cascades There has been explosive growth in understanding of how kinases—proteins capable of enzymatically adding phosphate groups to target molecules—contribute to signaling in myeloid and nonmyeloid cells. Nonetheless, it is likely that studies to date have elucidated only a small portion of the molecules involved. Protein kinase C (PKC), actually a family of kinases, was among the first kinases implicated in neutrophil activation and is activated in response to chemoattractants. The ability of phorbol myristate acetate—a synthetic activator of PKC—to stimulate neutrophil responses, including adhesion and O2− generation, supports a role for PKC in neutrophil activation.25 In addition, inhibitors of PKC block stimulation of neutrophil functions. The mitogen-activated protein kinases are a family of serine threonine kinases including the ERK, p38, and Jun kinase (JNK) families. In neutrophils, chemoattractants and other stimuli are capable of activating p38, Jnk, and Erk, on time courses consistent with neutrophil activation.26,27 A role for Erk activation in signaling for neutrophil O2− has been ­proposed, but remains controversial; a role in neutrophil adhesion and phagocytosis seems to be better established.17,28 Phosphatidylinositol 3-kinase is a set of related enzymes that are found in abundance in neutrophils and ­ primarily catalyze the phosphorylation, not of proteins, but of the 3position of phosphatidylinositol phospholipids. The main active product of phosphatidylinositol 3-kinases seems to be phosphatidylinositol triphosphate. Chemoattractants rapidly activate phosphatidylinositol 3-kinase in neutrophils, where it seems to play a role in diverse neutrophil functions, including O2− generation, adhesion, and degranulation.29 Phosphatidylinositol 3-kinase also may regulate neutrophil survival and apoptosis.30 Neutrophil Adhesion One of the earliest, crucial aspects of the inflammatory response is the ability of bloodstream neutrophils to adhere to vascular endothelium preparatory to movement into the tissues (Fig. 12-3). Stimulated neutrophils also possess the ability to adhere to each other, a process termed homotypic aggregation, which may bring in vivo bloodstream neutrophils into proximity with neutrophils already adherent to the vessel or concentrate them at a site of inflammation. Extensive investigation has provided significant insight into the mechanisms involved in neutrophil adhesion. Several families of interacting adhesion molecules have been shown to exist on neutrophils and endothelial cells, including the selectins, integrins, intercellular adhesion molecules (ICAMs), and sialylated glycoproteins. The selectins consist of three related molecules (Lselectin on leukocytes, E-selectin on endothelial cells, and P-selectin on activated platelets and endothelial cells) sharing a common structure of two or more complement regulatory domains, an epidermal growth factor–like domain, and a lectin domain. Each binds to a sialylated glycoprotein on the surface of its interacting cell: E-selectin binds to the sialyl Lewisx antigen on neutrophils, P-selectin binds P-selectin glycoprotein-1 on neutrophils, and L-selectin binds P-selectin glycoprotein-1 and GlyCAM-1 on the endothelium. Selectin expression is largely constitutive,

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Rolling

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Tight Adhesion

Diapedesis

Selectin Selectin Integrin (inactive)

Basement membrane

Sialylated glycoprotein

Cytokines

Integrin (active)

Endothelial cell

ICAM

Chemoattractants

Figure 12-3  Neutrophil adhesion to the vascular endothelium. Left, Rolling. An unstimulated neutrophil adheres with low affinity to the unstimulated endothelium of a postcapillary venule, a process mediated by the interaction of selectins (on neutrophil and endothelium) with ­sialylated glycoproteins and resulting in the rolling of neutrophils along the vessel wall. Center, Tight adhesion. Exposure of the neutrophil to chemoattractants results in activation of integrins (CD11a/CD18, CD11b/ CD18); exposure of endothelium to cytokines results in the expression of ICAMs. These molecules interact, resulting in tight adhesion. Concurrently, selectins may be shed from the cell surfaces. Right, Diapedesis. A neutrophil undergoes diapedesis, passing across the endothelium and making its way through the basement membrane. Bloodstream neutrophils have the capacity to adhere to and move out of the vasculature in response to tissue signals for inflammation.

but selectin/sialylated glycoprotein interactions are of low affinity and transient. The result of these interactions is that a pool of bloodstream neutrophils is, at any one time, loosely marginated to the vascular surface and moving along it slowly in a rolling, tumbleweed-like motion. Exposure of neutrophils and endothelium to appropriate stimuli (e.g., adrenergic discharge, corticosteroids) leads to shedding of selectins and neutrophil release (stress demargination), with apparent increases in the peripheral neutrophil count. The integrins are a large family of heterodimeric molecules generated by various combinations of α and β chains. Similar to the selectins, they require divalent cations (Ca2+ or Mg2+ or both) to engage their ligands. Neutrophils express three β2-type integrins, each constructed from a distinct α subcomponent (CD11a, CD11b, or CD11c) and a common β2 chain (CD18). Integrins use the ICAMs as their counterligands. CD11b/CD18 (also called Mac-1 or CR3) binds to fibrinogen, factor X, heparin, and the complement component iC3b in addition to ICAM and is most strongly implicated in neutrophil/endothelial and neutrophil/neutrophil interactions. In contrast to the selectins, neutrophil CD11b/ CD18 is constitutively expressed, but inactive; stimulation of neutrophils by chemoattractants and other agents results in changes in the activation state of CD11b/CD18 and increases its affinity for ICAMs and other ligands.31 Stimulation of endothelium with cytokines such as IL-1 results in increased expression of ICAM-1 and ICAM-2, providing a coordinate mechanism for the regulation of adhesion. In contrast to selectin-mediated adhesion, integrin/ICAM interactions are high affinity and persistent. Stimulation of rolling neutrophils results in their tight adhesion to vessel walls and constitutes the first committed step in the movement of neutrophils into the tissues. ­Additionally, engagement of integrins by their counterligands sends signals into the cell (“outside in” signaling), regulating selective cell responses such as ­cytoskeletal ­reorganization, oxidant ­production, and

Figure 12-4  Neutrophil diapedesis through the vascular endothelium. A neutrophil passaging between, or through, one or more endothelial cells is illustrated. The characteristic neutrophil multilobed nucleus and multiple granule types are visible. The leading edge of the neutrophil, passing through the endothelium, is relatively devoid of granule contents, suggesting that it represents the formation of a specialized structure for diapedesis, including the formation of F-actin cytoskeleton.

degranulation. Outside-in signaling through CD11b/CD18 also coordinates with signaling through Fc receptor FcγRIII (see later) to mediate phagocytosis of particles opsonized by IgG and the complement component iC3b. Crosstalk between neutrophils and endothelial cells also has been shown to be a CD11b/CD18-dependent event: Cross-­linking of CD18 on neutrophils leads to increased permeability of endothelial cells, probably through the release of neutrophil proteases.32 The function of CD11a/CD18 on neutrophils has been controversial, but accumulating data indicate that this molecule may be necessary for neutrophil adhesion and emigration.33 The function of CD11c/CD18 is less clear, although it may play a role in neutrophil phagocytic activity.34 Diapedesis and Chemotaxis The mechanism by which neutrophils pass through the endothelial barrier is unclear. One report suggests a model in which neutrophils pass directly through pores generated within the endothelial cells themselves, but neutrophils alternatively may pass between endothelial cells by disruption of cell-cell junctions (Fig. 12-4).35 Diapedesis occurs via homotypic interactions between adhesion molecules found on neutrophils and endothelial cells known as ­ platelet­endothelial cell adhesion molecules (PECAMs). These molecules are concentrated at endothelial cell junctions, and antibodies that block PECAM inhibit transmigration in vitro by limiting neutrophils to the apical surface of the endothelium. Transmigrating neutrophils undergo upregulation of α6β1, an integrin that mediates binding to laminin (a key component of the perivascular basement membrane). Antibodies to α6β1 generally block neutrophil transmigration, but fail to do so in a PECAM knockout mouse, ­implicating α6β1/PECAM as crucial to the passage of neutrophils out of the vasculature.36 CD47, otherwise known as

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integrin-associated protein,37 and CD99, expressed on neutrophils and endothelial junctions, also have been implicated in neutrophil passage through the endothelium.38 When beyond the endothelium, most neutrophils pause for a time before essaying the basement membrane (basal lamina). Classic studies by Huber and Weiss39 suggest that neutrophils pass through the basement membrane via active disruption of its patency, without elucidation of known proteases or oxygen radicals. The disruptions are rapidly repaired by an unknown mechanism, probably involving the endothelium. Chemotaxis in the direction of a gradient is achieved by the extension of membrane ruffles (lamellipodia), followed by anchorage of the ruffles to the substrate and withdrawal of the trailing edge of the cell in the direction of movement. These changes are accomplished primarily through rearrangement of the actin cytoskeleton. Actin is a 41-kD protein that exists as a soluble, globular monomeric form (gactin) and as an insoluble linear polymer (f-actin). F-actin may be assembled (extended) at one end (barbed end) and disassembled at the other, under the control of regulatory molecules. During chemotaxis, f-actin formation and extension is concentrated at the leading edge of the neutrophil, permitting extension of the cell membrane (see Fig. 12-4). Chemoattractant receptors also concentrate at the leading edge, defining the cell’s directional response to the gradient (headlight phenomenon). As the neutrophil moves along, receptors that were formerly at the leading edge are swept to the tail and internalized.40 Phagocytosis and Degranulation Neutrophil phagocytosis of an encountered bacterium or other particle requires direct contact. Neutrophils are generally poor at phagocytosing unmodified targets, particularly encapsulated bacteria. Optimal phagocytosis depends on opsonization (from the Greek, “to prepare for the table”), the modification of a target via its decoration with immunoglobulin or complement components or both. Neutrophils express two families of receptors for the Fc portion of complexed or aggregated IgG: low-affinity FcγRIIa and high-affinity FcγRIIIb. During some infections, or after in vitro stimulation with interferon or G-CSF, neutrophils also express the high-affinity receptor FcγRI, which binds ­monomeric IgG. FcγRIIa binds subclasses of IgG with varying efficiency depending on a polymorphism at amino acid position 131. Confusingly, the “low-responder” allotype (so named because of its weak interaction with mouse IgG1) binds human IgG2 efficiently, whereas the “high-responder” allotype (which binds mouse IgG1 efficiently) does not. FcγRIIIb polymorphisms of neutrophil antigens NA1 and NA2 also determine binding to IgG subclasses. Individuals homozygous for the NA2 allele have a lower capacity to mediate phagocytosis than individuals homozygous for the NA1 allele. These differences have important implications for rheumatic diseases in which immune complexes play an important role (see later). Phagocytosis is an active process that involves extension of the neutrophil membrane (filopodia and lamellopodia formation) and invagination of the neutrophil at the locus of the target. Engagement of FcγR and complement

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­receptors results in the activation of diverse signaling pathways. Elegant studies by Caron and Hall indicate that FcγR and complement receptors play distinct roles in phagocytosis40a. Although engagement of CR3 (CD11b/CD18) results in actin stress fiber formation and invagination, engagement of FcγRII results primarily in extension of membranes out from and around the target. Signaling by these receptors depends on the activation of distinct members of the Rho family of LMW-GBPs. These observations remain to be specifically confirmed for neutrophils, however. On activation, neutrophils degranulate, a term actually reflecting two distinct processes. Vesicles can fuse with the plasma membrane, spilling their contents into the extracellular space (see Fig. 12-1), or they can fuse with the phagocytic vacuole to form a phagolysosome. The former type of degranulation is regulated differentially from the latter and favors mobilization of lighter granules in response to stimuli (secretory vesicles > gelatinase granules > specific granules > azurophilic granules). In the latter type of degranulation (phagolysosome formation), fusion of azurophilic granules with the phagocytic vacuole results in the delivery of proteolytic enzymes, myeloperoxidase, and antibacterial proteins to the site of the ingested bacterium. Fusion of specific granules with the phagocytic vacuole permits the delivery of collagenase and the appropriate localization of cytochrome b558, a requisite for NADPH oxidase (see later). Containment of potentially toxic substrates within the phagolysosome keeps host tissue damage and neutrophil autodestruction in check.41 As discussed subsequently, however, in several of the rheumatic diseases, neutrophilic activation plays an important role in abetting inflammation and host tissue damage. Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase System In addition to the collection of proteases and other antibacterial proteins contained in their granules, neutrophils have the capacity to kill bacteria through the generation of toxic oxygen metabolites. This process, frequently referred to as the respiratory burst, is extremely potent and requires tight regulation to prevent neutrophil autodestruction. Studies in cell-free systems have established the so-called minimal system required for O2− generation—NADPH oxidase.42,43 The central component of NADPH oxidase is cytochrome b558, which is localized to the membranes of specific granules and consists of two subunits: a 22-kD component (gp22phox, for phagocyte oxidase) and a 91-kD component (gp91phox). This cytochrome lacks independent activity, however. Three cytosolic proteins also are required: a 47-kD and a 67-kD component (p47phox and p67phox) and a LMW-GBP, p21rac. On neutrophil stimulation, the p47phox and p67phox components translocate to the membranes to form an active complex with the cytochrome.44 Although p21rac also translocates in response to stimuli, the significance of its translocation is more controversial.45 A fifth protein, p40phox, also has been reported to be associated with p47/p67 in the cytosol. Evidence suggests that p40phox may regulate the oxidase system in a positive and a negative manner (Fig. 12-5).46 When assembled and activated, the NADPH oxidase transfers electrons from NADPH to generate O2−: Oxidase 2O 2 + NADPH NADPH  → O 2 − + NADP + + H +

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p22phox

gp91phox

GDP

p21rac p67phox

p47phox

p40phox rho GDI

Activation _ 2O2 ï

p22phox

p21rac GTP

p67phox

gp91phox

p47phox

p40phox

a key role in the body’s defense against microorganisms. The current view that oxidant production, via the production of hypochlorous acid by myeloperoxidase, is the neutrophil’s most powerful tool against microbes has been challenged, however. Mice lacking either NADPH oxidase or elastase and cathepsin G are susceptible to infection, implying that both arms of defense—oxidant production and proteasemediated microbial destruction—are equally crucial. Superoxide production in phagocytic vacuoles causes the pH to rise (secondary to the consumption of protons necessary to make H2O2), which causes an influx of K+. The resulting increase in ionicity liberates cationic proteases from the anionic proteoglycan matrix, freeing them to kill bacteria. In this new model, oxidants are not primarily destructive to microbes, but rather necessary to facilitate proteolytic damage.47 In support of this model is the fact that myeloperoxidase deficiency is common (1:2000), yet surprisingly benign. NEUTROPHIL PRODUCTION OF PROINFLAMMATORY MEDIATORS

2O2 + NADPH NADP+ + H+

rho GDI Figure 12-5  Assembly of the neutrophil NADPH oxidase system. Top, Basic components of the NADPH oxidase as they are distributed in a resting state. The cytochrome-b558, composed of the two subunits gp91phox and p22phox, are membrane associated, whereas p47phox, p67phox, and the more recently identified p40phox exist as a complex in the cytoplasm. p21rac in an inactive, GDP-bound form also resides in the cytoplasm, in association with a chaperone (Rho-GDI) that sheaths its hydrophobic tail to permit solubility. Bottom, Activation of the neutrophil leads to translocation of the cytosolic components of the oxidase to the neutrophil membrane, where they form an active complex with the cytochrome, resulting in the generation of oxygen. The potentially damaging oxidase system is carefully regulated through the segregation and assembly of its component parts.

A subsequent, spontaneous dismutase reaction rapidly produces hydrogen peroxide: O 2 − + 2H + → H 2 O 2 + O 2 Although O2− and H2O2 can kill organisms in vitro, they are short-lived and probably do not account for most of the bacterial killing capacity of the system under normal circumstances. (Many bacteria possess catalase, an enzyme that degrades H2O2.) Rather, the production of H2O2 within the same space into which the myeloperoxidase has been released permits the generation of large quantities of hypochlorous acid (chlorine bleach), a powerful oxidant with potent killing capacity. Hypochlorous acid may interact further with proteins to form chloramines, less potent but longer-lived oxidants. Neutrophil oxidant production plays

Arachidonic Acid Metabolites The capacity of stimulated neutrophils to liberate arachidonic acid from membranes has implications for the propagation of acute inflammation. Although arachidonic acid itself has chemoattractant and neutrophil stimulatory properties,28,48,49 its metabolites are more crucial to regulation of inflammation. Best recognized among these are the leuko­ trienes. Neutrophils have the capacity to produce LTB4,48 a highly potent lipid mediator for the chemoattraction of other neutrophils. Intermediates of leukotriene production, such as 5-hydroxyeicosatetraenoic acid, also are produced by neutrophils and may have stimulatory properties.28,50 An alternative class of lipoxygenase products, the lipoxins, have been characterized.48 Synthesis of lipoxins requires coordinated activity of neutrophil 5-lipoxygenase and a related enzyme (either 12-lipoxygenase or 15-lipoxygenase) in another cell type—either platelets or endothelial cells (Fig. 12-6).51 In contrast to leukotrienes, lipoxins inhibit neutrophil function and are anti-inflammatory,52 suggesting that the assembly of a mixed population of inflammatory cells may trigger the synthesis of anti-inflammatory molecules (resolvins), contributing to the subsequent resolution of inflammation. Aspirin has been shown to stimulate the generation of biologically active epilipoxins, suggesting a previously unappreciated mechanism for its anti-inflammatory action.53 The cyclooxygenase (COX) (endoperoxide synthase) pathway is the other major pathway of arachidonic acid metabolism. Arachidonic acid metabolized by COX is converted into prostaglandin H,54 which undergoes further cell type–specific conversion to a variety of other prostaglandins. The prostaglandins of most relevance to inflammation are those of the E series, particular prostaglandin E2. Prostaglandins of the E series have numerous proinflammatory effects, including increased vasodilation, vascular permeability, and pain. The direct effects of prostaglandin E on neutrophils seem to be inhibitory, probably through elevations of intracellular cAMP.55 Although resting neutrophils exhibit little COX activity, persistent neutrophil activation results in

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LXA4 12-LO

LTA4

LXB4 12-LO

Neutrophil

Platelet

LXA4 AA

15-LO

15-HETE

5-LO LXB4 Neutrophil

Epithelial cell Figure 12-6  Generation of the anti-inflammatory lipoxins A4 and B4 ­depends on the interaction between two different classes of inflammatory cells. Top, Lipoxin generation by neutrophils and platelets. Arachidonic acid (AA) generated by activated neutrophils is converted by neutrophil 5-lipoxygenase (5-LO) into leukotriene A4 (LTA4). LTA4 may be converted by 12-LO in nearby platelets into lipoxin A4 (LXA4) and lipoxin B4 (LXB4). Bottom, Lipoxin generation by epithelial cells and neutrophils. AA generated by epithelial cells may be converted by 15-LO into  15-­hydroxyeicosatetraenoic acid (15-HETE). In the setting of inflammation, 5-LO from adjacent neutrophils subsequently may convert 15-HETE into LXA4 and LXB4.

upregulation of COX-2,56 suggesting that neutrophils may contribute prostaglandin E2 to the proinflammatory brew and the downregulation of their own activity. Cytokine Production Although the relative amount of cytokine production by neutrophils is small, the large numbers of neutrophils present in infected or inflammatory sites suggests that overall neutrophil cytokine production may play a role in recruiting additional neutrophils to the target area. Among the cytokines produced by neutrophils are IL-1, IL-8, IL-12, TNF-α, TNF-β, MIP-1α, oncostatin M, MCP-1, and TGF-β.57,58 TGF-β is a powerful neutrophil chemoattractant,59 and its recruitment of neutrophils into an inflammatory space may lead to additional neutrophil cytokine production, including further production of TGF-β.60 TGF-β also has potent anti-inflammatory effects,13 however, suggesting that neutrophils also may participate in the resolution of inflammation. Activated neutrophils also produce an antagonist to IL-1, the IL-1 receptor antagonist.61,62 The efficacy of recombinant IL-1 receptor antagonist (anakinra) in the treatment of rheumatoid arthritis and in autoinflammatory diseases such as Still’s disease63 emphasizes its clinical importance in downregulating synovial inflam­mation. An intriguing mechanism has been defined through which neutrophils might downregulate the action of protein inflammatory mediators. Apoptotic neutrophils (present during the resolving phase of inflammation) show increased expression of the chemokine receptor CCR5 on their surface, and this receptor can scavenge, and reduce the soluble

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concentration of, chemokines such as CCL3 and CCL5. These data emphasize again that neutrophils are not only inflammatory cells, but also may play a direct role in the subsequent resolution of inflammation.64 HERITABLE DISORDERS OF NEUTROPHIL FUNCTION A wide variety of acquired conditions result in neutrophil dysfunction or depletion or both, including malignancies (myeloid leukemias), metabolic abnormalities (diabetes), and drugs (corticosteroids, chemotherapy). In addition, many rare, congenital disorders of neutrophils have been identified (Table 12-2). In general, patients with impaired neutrophil function are prone to infection by bacteria (predominantly Staphylococcus aureus, Pseudomonas species, Burkholderia) and fungi (Aspergillus, Candida),65 but not viruses and parasites. The major sites of infection include skin, mucous membranes, and lungs, but any site may be affected, and spreading abscesses are common. Most of these diseases are potentially life-threatening in the absence of available effective therapy. Diseases of Diminished Neutrophil Number Severe congenital neutropenia (Kostmann’s syndrome) results from marrow arrest of bone marrow myelopoiesis and leads to neutrophil counts persistently less than 0.5 × 109 cells/L. Autosomal dominant and autosomal recessive subtypes have been identified.66 Patients are prone from early infancy to severe bacterial infections, including omphalitis, pneumonia, otitis, gingivitis, and perirectal infections. Because acute inflammation is lacking, infections tend to spread extensively before coming to attention. Mortality has been high. Therapy consists of antibiotics and longterm therapy with recombinant human G-CSF, which may help maintain normal or near-normal neutrophil counts.67 A milder form of neutropenia (benign congenital neutropenia) with higher neutrophil counts and fewer infections also has been observed. Another variant is cyclic neutropenia, which causes transient, recurrent neutropenia on a 21-day cycle. Studies suggest that defects in neutrophil elastase affect neutrophil survival in the marrow and may be responsible for severe congenital and cyclic neutropenia.68 Leukocyte Adhesion Deficiencies Leukocyte adhesion deficiency type 1 (LAD1) results from an autosomal recessive defect in production of the CD18 chain of β2 integrins. Consequently, neutrophil β2 integrins fail to form,69 and bloodstream neutrophils are unable to adhere firmly to vascular endothelium and to transmigrate to sites of infection. Phagocytosis also is impaired. The clinical picture is similar to that of the neutropenias, with recurrent life-threatening infections. Peripheral neutrophil counts are typically elevated, however, reflecting the inability of cells to exit the vasculature. Complete LAD1 manifests in infancy.70 LAD2 results from an autosomal recessive defect in the glycosylation of sialyl Lewisx, the neutrophil counterligand for endothelial selectins. Patients with LAD2 have neutrophils that are unable to roll along the endothelium and have symptoms similar to LAD1, but also may have mental retardation, short stature, distinctive facies, and the

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Table 12-2  Heritable Disorders of Neutrophil Function Disorder

Defect

Inheritance

Presentation

Therapy

Typical Prognosis

Maturation arrest   (<0.5 × 109 PMN/L)

AR (HAX1 ­mutations)

RhG-CSF

Improved with ­treatment

(0.2-2 × 109 PMN/L)

?

Bacterial infections ­(omphalitis, abscesses, gingivitis, UITs) Mild infections

None

Good

Stem cell defect, elastase gene deficiency (nadir every 21 days)

AD (ELA2 ­mutations)

Infection during   nadirs

RhG-CSF

Improved with ­treatment

Leukocyte adhesion ­deficiency type 1

Absent or abnormal CD18; deficiency in   β2-­integrin chain of leukocyte ­adhesion molecules

AR

Marrow ­transplant

Fair-poor

Leukocyte adhesion ­deficiency type 2

Absent sialyl-Lewisx

AR

Leukocyte adhesion ­deficiency type 3

Impaired activation of Rap1 GTPase

AR

Leukocytosis   recurrent infections   (skin mucous, ­membranes,   gastrointestinal   tract) Neutrophilia; infection ­retardation, short stature Leukocytosis; recurrent infections; bleeding tendency

Chemotaxis defect

AD

eczema, recurrent ­infections and elevated serum lgE levels

Skin care; ­antibiotics

Good

Defective lysosomal   trafficking regulator   gene Abnormal/reduced specific and azurophilic granules (lactoferrin deficiency) Myeloperoxidase absent

AR

Albinism; infection

Marrow transplant; antibiotics

Poor

AR?

Infection of skin, mucous membranes, lungs

Variable   (mostly AR)

None

Defective endosomal adapter protein gene

Recessive

Albinism; infection; short stature

gp91phox absent p22phox absent p47phox absent p67phox absent

X-linked 50% AR 5% AR 35% AR 5%

Early childhood infections, especially skin and mucous ­membranes, abscesses

Neutropenia Severe congenital ­neutropenia (Kostmann’s syndrome) Chronic benign neutropenia Cyclic ­neutropenia

Adhesion Deficiency

poor poor

Chemotaxis Deficiency Hyper-lgE syndrome

Granule Disorders Chédiak-Higashi   syndrome Specific granule   deficiency Myeloperoxidase   deficiency

p 14 deficiency

Fair-good Transfusion of HLA identical leukocytes if severe None known to date

Excellent

Interferon-γ

Improved with ­treatment

?

Oxidase Defects Chronic granulomatous ­disease (multiple types)

AR, autosomal, recessive; PMN, polymorphonuclear neutrophil; RhG-CSF, recombinant human granulocyte colony-stimulating factor; UTIs, urinary tract ­infections.

Bombay (hh) blood type.70,71 An additional leukocyte adhesion deficiency also has been identified (LAD3). Patients with LAD3 have normal populations of leukocyte surface integrins, but lack the ability to signal these molecules into an active state. Because integrin activation in this condition also is deficient in platelets, patients with LAD3 are at increased risk for infection and bleeding.72 Neutrophil Granule Defects The best-known defect in neutrophil granule formation is Chédiak-Higashi syndrome. Chédiak-Higashi syndrome is an autosomal recessive disorder in which granule ­subtypes—

in neutrophils, but also in lymphocytes, melanocytes, Schwann cells, and others—undergo disordered fusion, resulting in giant, dysfunctional granules.70 The cause seems to relate to a defect in the gene for lysosomal transport protein (Lyst).73 Patients with Chédiak-Higashi syndrome present with partial oculocutaneous albinism, neutropenia, frequent infection, mild bleeding diathesis, and neurologic abnormalities. Approximately 85% of patients who survive childhood enter a so-called accelerated phase, a lymphomalike infiltration of lymphocytes and histiocytes throughout the body, which is generally fatal. Other diseases of neutrophil granules have less ominous prognoses. A novel immunodeficiency syndrome relating to lack of the endosomal

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adapter protein p14 also has been described. Patients with this syndrome have congenital neutropenia with structurally abnormal neutrophil primary granules and abnormalities of B cells, cytotoxic T cells, and melanocytes. In addition to immunodeficiency, clinical findings include short stature and partial albinism.74

serum and joint fluid ­contain antiproteases and antioxidants, the “protected space” between a neutrophil and a surface (e.g., cartilage) may exclude these factors. Release of hypochlorous acid, myeloperoxidase, and proteinases into the extracellular milieu may inactivate the protective compounds and act as an “antiproteinase shield.”41

Oxidase Deficiencies—Chronic Granulomatous Disease

Neutrophil Fc Receptor Polymorphisms

Chronic granulomatous disease resembles other diseases of neutrophil dysfunction in that it results in severe, recurrent infections of the skin and mucous membranes. Osteomyelitis and intra-abdominal abscesses are common. In contrast to the other diseases, infection in patients with chronic granulomatous disease generally results in a delayed, but quantitatively normal neutrophil response. Because of incapacity to kill organisms, however, the accumulation of neutrophils at a site of infection generally results in granuloma formation, rather than clearance of the target. Cutaneous infections tend to show persistent drainage and scarring. The presence of even partially responsive neutrophils results in a lower frequency of sepsis in these patients relative to patients with absolute neutropenia. Chronic granulomatous disease is typically a disease of early childhood, although some milder cases may be recognized later in life.70 Chronic granulomatous disease comprises a group of diseases. In each, a genetic defect in a different component of NADPH oxidase results in failure of neutrophils (and other phagocytes) to generate O2−. Previously, treatment for chronic granulomatous disease consisted of aggressive antibiotic prophylaxis and therapy. The addition of longterm therapy with recombinant human interferon-γ has improved the outcome significantly for patients with this disease, and pilot attempts at gene therapy have yielded encouraging results.75 Neutrophils engaged in host defense entered into a novel death program, resulting in the elucidation of neutrophil extracellular traps, extracellular structures composed of chromatin and granule proteins that bind and kill microorganisms. This process depends on the generation of reactive oxygen species, however, and patients with chronic granulomatous disease lack the capacity to produce neutrophil extracellular traps. The inability to generate neutrophil extracellular traps may contribute to the immune deficiency seen in chronic granulomatous disease.76,77 NEUTROPHIL RELEVANCE TO RHEUMATIC DISEASE Neutrophil-mediated Tissue Destruction Despite sophisticated regulatory mechanisms, tissue ­destruction by neutrophils is common. Several mechanisms may permit the release of neutrophil proteases and oxygen radicals into the extracellular milieu. First, necrosis or destruction of neutrophils, or both, may liberate cellular contents indiscriminately. Second, studies have revealed that degranulation and O2− generation may begin before complete closure of the phagocytic vacuole, releasing products either into the external environment or against a target surface. Neutrophils may destroy host tissues that they have been misdirected to attack. Although

Given that polymorphisms of FcγR determine phagocytic capacity of IgG isotypes, it is not surprising that they determine susceptibility to diseases in which autoantibodies play a key role. Phagocytes from individuals with one FcγRIIa polymorphism (H131) allele are able to bind and phagocytose IgG2; phagocytes from individuals with a different polymorphism (R131) cannot. In white European and African American populations, patients with lupus nephritis have a higher frequency of the FcγRIIa-R131 allele than control groups; their relative inability to clear immune complexes may make them more susceptible to renal disease.78-80 The significance of different Fc receptor polymorphisms may vary among rheumatologic diseases. Tse and colleagues81,82 found no association between FcγRIIa polymorphisms and likelihood of developing antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides, but they found an overrepresentation of homozygosity for the FcγRIIIb NA1 allele among patients with antimyeloperoxidase antibodies. Few studies have been published on Fc polymorphisms and susceptibility or severity of rheumatoid arthritis. A more recent study found no association between FcγRIIa type and rheumatoid arthritis susceptibility, but did find a correlation between patients with extra-articular disease and the homozygous R/R 131 genotype.83 In contrast, FcγRIII receptor expression might be increased in rheumatoid arthritis.84 Gout Gout may be the quintessential neutrophilic rheumatic disease. Although the initiation of an acute gouty attack seems to involve the phagocytosis of urate crystals by synovial macrophages and the generation of cytokines such as IL-1 and IL-8, the hallmark of acute gout is the presence of enormous numbers of neutrophils (sometimes >100,000/ mm3) in the affected joint space. Urate crystals in the joint are capable of nonspecifically binding immunoglobulin and fixing complement by the classic and alternative pathways. C5a liberated from the complement fixation process attracts neutrophils to the joint space, where they phagocytose opsonized crystals via receptor-dependent mechanisms, resulting in further activation of the neutrophil and production of LTB4, IL-8, and other mediators. Activation of neutrophils results in the ingress of additional neutrophils. Neutrophils in the gouty joint may damage joint structures through discharge of contents directly into the joint fluid during crystal phagocytosis, or directly against cartilage during attempted phagocytosis of urate crystals embedded in or adherent to cartilage. In addition, interaction of phagocytosed urate crystals with lysosomal membranes results in the dissolution of the latter, spilling lysosomal proteases into the cytoplasm and, eventually, into the extracellular space.85

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Rheumatoid Arthritis Although the focus in rheumatoid arthritis in recent years has been on the role of T cells, B cells, synovial fibroblasts, and mononuclear cells, the first inflammatory cell type to be appreciated in rheumatoid arthritis was the neutrophil. Rheumatoid arthritis in the joint may be conceptualized as a two-compartment inflammatory disease: In the synovium, lymphocytes, fibroblasts, and macrophages predominate, but the joint space contains neutrophils almost exclusively. Although the numbers of neutrophils in the rheumatoid joint tend to be less than those seen in gout, they are still quite large, with 10 billion cells per day cycling through a 30-mL effusion. The classic model suggests that rheumatoid factor–based immune complexes, produced in the pannus and present in the joint space in high concentrations, can fix complement and draw neutrophils into the joint space in high numbers. Once there, in vitro studies have documented the ability of neutrophils to bind to cartilage surfaces embedded with immune complexes and to damage them via incomplete phagocytosis. No adequate in situ demonstration of direct neutrophil attack on cartilage has been offered yet, however. The fact that seronegative arthritides, such as psoriatic arthritis, lack rheumatoid factor, but nonetheless share with rheumatoid arthritis the presence of synovial hyperplasia and a large neutrophilic infiltrate in the joint space suggests that immune complex formation may be important, but not absolutely required, for neutrophil influx. The ability of rheumatoid synovial monocytic leukocytes to secrete IL-1 and IL-8 and other cytokines indicates that pannus itself may play an important role in the attraction of neutrophils out of the bloodstream and into the joint. Although few in number, neutrophils within the pannus have been documented to concentrate at the pannus/cartilage border, suggesting a possible role in pannus-driven marginal erosion.53 In addition to promoting joint destruction, neutrophils in the rheumatoid joint may contribute to the propagation of pannus and of rheumatoid inflammation. As noted earlier, neutrophils themselves can produce proinflammatory cytokines; expression of several such cytokines, including oncostatin M, MIP-1α, IL-1β, and IL-8, is increased in rheumatoid neutrophils, especially from rheumatoid arthritis synovial fluid.86 Injection of lysates of neutrophil granules into joints in animal models produces a synovitis indistinguishable histologically from rheumatoid synovitis, an effect that can be reproduced by injection with purified active or inactive myeloperoxidase.87,88 Neutrophil proteins also may regulate synovial proliferation through effects on other resident or immigrant cell populations. Neutrophil proteinase 3 may enhance the proinflammatory effects of monocytes, by cleaving and releasing active IL-1 and TNF-α from the surface of the latter. Neutrophil defensins enhance phagocytosis by macrophages and stimulate the activation and degranulation of mast cells, an interesting observation in light of a report that mice deficient in mast cells are resistant to the development of erosive arthritis.89 Neutrophil proteases also enhance the adherence of rheumatoid synovial fibroblasts to articular cartilage,90 and neutrophils may regulate synovial vascularization through the production of vascular endothelial growth factor, leading to endothelial proliferation.91 Finally, several studies have raised the possibility that, under certain conditions of stimulation,

­ eutrophils can serve as antigen presenting cells. Neutron phils in rheumatoid arthritis synovial fluid synthesize and express large amounts of class II major histocompatibility complex.92 The importance of neutrophils to the rheumatoid process may be underscored by rheumatoid arthritis animal models in which mice deficient in neutrophils are resistant to the arthritic process.93,94 Vasculitis Neutrophils may be identified, to a greater or lesser degree, in the lesions of virtually all kinds of vasculitis. The mechanisms of neutrophil accumulation may vary, however, with different mechanisms predominating in different conditions. The early observation that infusions of allospecies serum produced acute inflammation in skin and joints (serum sickness), together with the appreciation that subcutaneous rechallenge with previously administered antigen leads to intense local inflammation (Arthus reaction), led to the development of a model in which immune complex deposition in the blood vessels results in complement activation and an influx of neutrophils to the affected site. Because immune complex formation is a hallmark of many primary rheumatic vasculitides (e.g., essential mixed cryoglobulinemia, hypersensitivity vasculitis, Henoch-Schönlein purpura), it is likely that immune complex deposition is crucial to the genesis of these diseases. In several of these vasculitides, neutrophil disruption and fragmentation—clasis—is a prominent pathologic finding, leading to their designation under the rubric leukocytoclastic vasculitis. In some rheumatic diseases in which vasculitis is a secondary phenomenon, such as rheumatoid arthritis and systemic lupus erythematosus, the role of immune complex deposition also is implicit. It also has been suggested that patients with lupus experience transient accumulations of neutrophils (leukoaggregation) in small vessels of the lungs and other tissues, as a result of complement activation within these vessels or in the soluble phase.95 Upregulation of adhesion molecules on endothelial cells or neutrophils themselves or both is an alternative mechanism through which neutrophil accumulation in vessels may be propagated. The Schwartzmann phenomenon, in which reinjection of cellular material leads to vascular inflammation via a cytokine-dependent, immune complex–independent mechanism, is a model for this avenue to vasculitis. Adhesion molecule upregulation may be particularly relevant to vasculitides in which immune complex formation is not a hallmark, such as giant cell (temporal) arteritis. Detailed analyses of the inflammatory cells involved in giant cell arteritis indicate the presence of T cells producing IL-1β and IL-6 that may act on vascular endothelium.96 It is likely that many rheumatic diseases employ immune complex–dependent and immune complex–independent mechanisms in the pathogenesis of neutrophil ingress into vascular structures. In addition to the role of immune ­complexes, Belmont and coworkers97 have shown the induction of adhesion molecules in patients with systemic lupus erythematosus. Several vasculitides are noteworthy for the presence, in the serum of affected patients, of antibodies directed at cytoplasmic components of neutrophils (ANCA).97 ANCA-positive vasculitides are discussed in detail in Chapter 82.

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Neutrophilic Dermatoses and Familial Mediterranean Fever Sweet’s syndrome, named after the physician who first described it in 1964, is characterized by fever; neutrophilia; and painful erythematous papules, nodules, and plaques. It can be subdivided into five groups: idiopathic, parainflammatory (associated with inflammatory bowel disease or infection), paraneoplastic (most commonly in the setting of leukemia), pregnancy related, and drug associated (usually after treatment with G-CSF). Most important clinically, it is a diagnosis of exclusion. Sweet’s syndrome frequently appears after an upper respiratory tract infection and has a propensity to involve the face, neck, and upper extremities. When found on the legs, Sweet’s syndrome lesions can be confused with erythema nodosum. Histopathology is characterized by dense neutrophilic infiltrate in the superficial dermis and edema of the dermal papillae and papillary dermis. Leukocytoclasia may suggest leukocytoclastic vasculitis, although vascular damage is absent. It is typically accompanied by peripheral neutrophilia. Treatment with systemic corticosteroids usually induces a dramatic resolution of the lesions and the systemic symptoms. Although the etiology of the disease is unclear, many authors believe that Sweet’s syndrome may represent a form of hypersensitivity reaction to microbial or tumor antigens. Antibiotics do not influence the course of the disease in most patients. Pyoderma gangrenosum is characterized by painful ulcerating cutaneous lesions over the lower extremities, usually in patients with an underlying inflammatory illness. Inflammatory bowel disease, rheumatoid arthritis, and seronegative arthritis are the most common associations, although an association with malignancy also has been reported. Fifteen percent of patients have a benign monoclonal gammopathy, usually IgA. Similar to Sweet’s syndrome, pyoderma gangrenosum is a diagnosis of exclusion; is characterized on biopsy specimen by neutrophilic infiltrate; and usually remits with systemic corticosteroids, although topical and intralesional injections of corticosteroids also may be beneficial. Other rare neutrophilic dermatoses include rheumatoid neutrophilic dermatitis, described as symmetric erythematous nodules on extensor surfaces of joints; bowel-associated dermatosis-arthritis syndrome occurring after bowel bypass surgery for obesity; and neutrophilic eccrine hidradenitis, sometimes linked to acute myelogenous leukemia. In familial Mediterranean fever (discussed in detail in Chapter 113), patients experience episodic inflammatory exacerbations, characterized by large influxes of neutrophils. A defect in an anti-inflammatory protein, pyrin, seems to permit the inappropriate development of inflammation. Pyrin has been shown to be expressed exclusively in myeloid cells, including neutrophils and eosinophils.98 Effects of Antirheumatic Agents on Neutrophil Functions Many antirheumatic therapies currently in use have been documented to act at least partly at the level of the neutrophil. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently used class of antirheumatic agents. By virtue of their ability to inhibit COX activity and ­prostaglandin production, moderate doses of NSAIDs have

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diverse effects on inflammation, including inhibition of vascular permeability and modulation of pain. At higher, clinically anti-inflammatory concentrations, NSAIDs inhibit chemoattractant-stimulated neutrophil CD11b/CD18dependent adhesion and degranulation and NADPH oxidase activity.99-101 It is unlikely, however, that these effects are due solely to COX inhibition because (1) as noted earlier, neutrophils exhibit little COX activity under normal circumstances, and (2) concentrations of NSAIDs required to inhibit neutrophil function exceed the concentrations required to inhibit COX. High-dose NSAIDs seem to have other, pleiotropic effects on neutrophil signaling. Our laboratory has shown the capacity of aspirin and the poor COX inhibitor sodium salicylate to inhibit Erk activation in a manner consistent with inhibition of adhesion, suggesting that salicylates may have unique effects on inflammation.102 Similar to nonsteroidals, glucocorticoids exert potent effects on neutrophils, including inhibition of neutrophil phagocytic activity and adhesive function. The ability of steroids to increase peripheral blood neutrophil counts acutely—an effect known as demargination—may be directly attributable to the release of neutrophils adherent to vessel walls. In addition, glucocorticoids inhibit phospholipase A2 and leukotriene and prostaglandin production. Glucocorticoids also may regulate the expression of COX-2 and stimulate the release of lipocortins, compounds with anti-inflammatory effects on neutrophils. Although the ability of glucocorticoids to interact with cytosolic receptors and to regulate transcription is unlikely to be directly relevant to neutrophil function, these longer term effects may have indirect relevance in that steroids possess the capacity to reduce production of IL-1 and other cytokines at inflammatory sites. Other anti-inflammatory/immunomodulatory agents also have well-established effects on neutrophils. Methotrexate, widely used in rheumatoid arthritis, has no direct neutrophil effect, but is capable of producing indirect effects, probably by virtue of its ability to stimulate the release of adenosine from surrounding cells. Some data suggest that ­methotrexateinduced adenosine release might inhibit phagocytosis, O2− production and adhesion,103 and that treatment of patients with methotrexate inhibits the capacity of neutrophils to generate LTB4.104 Colchicine, a standard agent in the treatment of gout and familial Mediterranean fever, inhibits microtubule formation and has pleiotropic effects on neutrophils, including inhibition of adhesion via decrements in selectin expression.105 Colchicine has been observed to stimulate the expression of pyrin in neutrophils. Because pyrin deficiencies are implicated in familial Mediterranean fever, this observation suggests a previously unappreciated mechanism of action of colchicine in neutrophilic diseases.98 Sulfasalazine has been shown to inhibit neutrophil responsiveness to chemoattractants; to inhibit chemotaxis, degranulation, and O2− production; to decrease LTB4 production; and to scavenge oxygen metabolites. Similar to sulfasalazine, gold salts may scavenge toxic metabolites. Gold salts, still in use for rheumatoid arthritis in many parts of the world, also decrease neutrophil collagenase activity and reduce E-selectin expression on endothelium.106 The current era of biologic therapies has been ushered in through the introduction of agents designed to block the

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effects of TNF-α or IL-1. As noted earlier, IL-1 and TNF-α directly affect neutrophil function, including priming for stimulus-induced responses such as O2− production, cartilage destruction, and production of cytokines such as IL-8 and LTB4. Nonetheless, studies examining the effects of antiTNF treatment on neutrophil function measured ex vivo have not indicated extensive action. Treatment of patients with etanercept107 or adalimumab108 induced no effect on neutrophil ex vivo responses, including chemotaxis, phagocytosis, and superoxide generation (although CD69 levels were reduced). Reduction of neutrophil populations in rheumatoid arthritis joint effusions after anti-TNF therapy is more likely due to alteration of the inflammatory environment, rather than to direct effects on the neutrophils themselves. Consistent with this suggestion, etanercept inhibited neutrophil rolling and adhesion in vivo in a rat model of uveitis.109

EOSINOPHILS The eosinophil line shares many features with the other families of polymorphonuclear granulocytes. In contrast to the neutrophil, however, the eosinophil is primarily a tissue-localized cell. Eosinophils are produced in numbers smaller than neutrophils, and their half-life in the blood is shorter (3 to 8 hours) owing to higher rates of diapedesis. Normal bloodstream levels of eosinophils tend to be low— typically less than 5% of blood leukocytes. When in the tissues, eosinophils are more long-lived than their neutrophil cousins, with estimates ranging from 2 to 14 days. Tissue eosinophils are found in greatest concentrations in gastrointestinal mucosa, suggesting that they participate in barrier rather than bloodstream surveillance.1,110 EOSINOPHIL DEVELOPMENT AND MORPHOLOGY Similar to neutrophils, eosinophils follow a classic pattern of granulocyte differentiation, passing through blast, promyelocyte, myelocyte, metamyelocyte, and band stages before reaching maturity.1 Along the way, eosinophils successively acquire morphologically distinct classes of granules. The factors required for eosinophil differentiation include GM-CSF and IL-3, which also are required for neutrophil differentiation and cannot account for eosinophil commitment. An essential role for IL-5 in eosinophil development also has been described, supported by the observation that intravenous administration of IL-5 rapidly results in peripheral eosinophilia. IL-5 may not be completely eosinophilspecific, however, because studies in animal models suggest that it is also trophic for B cells. Similar to IL-5, IL-2 can stimulate eosinophilia. The IL-2 effect seems to be mediated via production of IL-5, however. CCL11 (eotaxin-1) also may cause bone marrow release of mature eosinophils and eosinophil precursors,111 via engagement of CCR3 receptors, which are mainly expressed on eosinophils.112 Cooperation between IL-5 and eotaxins, in particular eotaxin-1, seems to be needed to induce tissue eosinophilia. Knockout mice with targeted deletion of CCR3 show deficiency in gastrointestinal eosinophils. When viewed under hematoxylin and eosin staining, the eosinophil appears slightly larger than the neutrophil (12

to 17 μm). Its nucleus is typically bilobed. Most striking is the presence of large, pink-staining granules. In addition, lipid bodies occasionally may be seen—nonvesicular accumulations of arachidonic acid and other lipids, presumably liberated from plasma membrane. These are not unique, however, and may be detected occasionally in neutrophils as well. Eosinophils contain at least three distinguishable classes of granules (Table 12-3). Primary granules form first and are analogous to the primary (azurophilic) granules of neutrophils. In contrast to neutrophils, eosinophil primary granules lack myeloperoxidase. Eosinophil primary granules are most numerous in eosinophilic promyelocytes and persist in smaller numbers in mature forms. As a result, eosinophil primary granules have been less thoroughly studied than their neutrophil counterparts. In mature eosinophils, a lysophospholipase that is present in large quantities (7% to 10% of total eosinophil protein) has been tentatively localized to primary granules, which when released extracellularly precipitates into bipyramidal structures known as Charcot-Leyden crystals.113 The deposition of these crystals in tissues is frequently taken as evidence of present or past ­eosinophilia. The large granules visible in mature eosinophils are specific granules, which form during the myelocyte stage. When viewed under scanning electron microscopy, specific granules show a dense crystalline core surrounded by an intermediate-density matrix. Because of their greater size and number (>90% of overall granule population), eosinophilspecific granules have yielded to isolation and immunocytochemical examination, and their contents have been at least partially evaluated. Among the contents probably localized to the specific granules are lysosomal enzymes (acid and neutral hydrolases, collagenase, cathepsin, and gelatinase), lectins, and components of the oxidase system. Most distinct is the presence of four highly basic proteins that lend the granule its tinctorial properties. Major basic protein (MBP), an 11,000-kD protein with an isoelectric point value of 11, accounts for more than 50% of the total granule protein and is the major, or possibly sole, component of the crystalline core. Trace amounts of MBP (<0.1% of that found in eosinophils) also may be observed in basophils. Eosinophil cationic protein (ECP), actually a heterogeneous group of several related proteins (18 to 21 kD molecular weight), also is present in large amounts (upto 10% on weight/weight basis). Table 12-3  Eosinophil Granule Contents

Relative size

Arylsulfatase Primary Granules Granules

Specific Granules

Smallest

Largest

Intermediate

contents Arylsulfatase Lysophospholipase Major basic protein Acid phosphaEosinophil cationic tase protein Eosinophil-derived neurotoxin Eosinophil peroxidase Acid hydrolases Neutral hydrolase Collagenase Cathepsin Gelatinase

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Eosinophil-derived neurotoxin (18 kD molecular weight), the third of the basic granular proteins, is slightly less basic (isoelectric point value of 8.9) than the aforementioned proteins and is present in smaller quantities. In contrast to MBP and ECP, which have likely roles in host defense, eosinophil-derived neurotoxin is mainly recognized for its function as a neurotoxin for myelinated neurons, the evolutionary advantage of which is unclear. The Gordon phenomenon, in which injection of eosinophil-laden tissue into an animal produces profound neurologic deficits, is likely due to eosinophil-derived neurotoxin. Finally, eosinophil-specific granules contain large quantities of eosinophil peroxidase, an enzyme distinctly different from neutrophil myeloperoxidase, but probably subsuming the same function of generating hypohalides for cell killing and the activation of latent proteinases.114 ECP, EDW, and eosinophil peroxidase are localized within the primary granule matrix region. A third population of smaller eosinophilic granules has been identified by virtue of its acid phosphatase and arylsulfatase B content and is present mainly in tissue eosinophils. EOSINOPHIL ACTIVATION AND DISTRIBUTION Similar to neutrophils, eosinophils undergo activation in response to stimuli and are capable of adhesion, chemotaxis, phagocytosis, degranulation, and O2− generation. Eosinophils respond to many of the same chemoattractant stimuli as neutrophils, although with different sensitivities. In addition, eosinophils respond to numerous stimuli that do not affect neutrophils, including IL-3, IL-5, RANTES, and MIP-1α. Whether the distribution of these factors is sufficient to explain the tissue distribution of eosinophils relative to other granulocytes is uncertain; however, eosinophils and mast cells secrete IL-3 and IL-5, suggesting their capacity to attract additional eosinophils to sites of atopy. Eosinophils not only express adhesion molecules identified on neutrophils—CD11a/CD18, CD11b/CD18, and Lselectin—but also others, such as the α4β1 integrin VLA-4. IL-4 and IL-13 induce the expression of the VLA-4 counterligand, VCAM-1, via an eotaxin-1, STAT6-dependent pathway.115 Oncostatin-M, an IL-6/gp130 family member, also seems to upregulate VCAM-1 in an eotaxin-1, STAT6dependent manner and to play a role in eosinophil accumulation in a mouse model.116 Eosinophils also differ from neutrophils in their repertoire of immunoglobulin receptors. Although eosinophils possess IgG receptors, they are relatively sparse. Rather, the predominant immunoglobulin receptors on the eosinophil surface are high affinity for IgA, consistent with the eosinophil’s role in barrier defense.117 Although eosinophils are activated by IgG and IgA, they are most potently activated by secretory IgA, probably owing to the presence of a receptor unique for the secretory component.118 In contrast to earlier teaching, expression of IgE receptors on eosinophils surfaces is minimal and most likely of little biologic significance.119,120 NORMAL EOSINOPHIL FUNCTION Although many studies have shown the capacity of eosinophils to phagocytose bacteria, others have indicated that these cells are poor at phagocytosis, and it is likely that

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antibacterial defense is not a primary eosinophil function. Eosinophils most likely participate in host defense against multicellular, helminthic parasites. Host eosinophilia in response to parasitic, but not bacterial infection supports such an interpretation. Although eosinophils can phagocytose small parasitic forms, more typically they attach, in a polarized manner, to the surface of larger parasites, and discharge their granular contents into the protected space between the parasite and the eosinophil. Although O2− generation and proteinase release may play a role in this attack, the specific granule-associated, basic proteins are probably the major weapon in the eosinophil’s antiparasitic armamentarium. In vitro studies have shown the capacities of these proteins, particularly ECP and MBP, to kill protozoa. Although ECP is about 10-fold more potent, the higher concentration of MBP present in the granules has led to the consensus that it is the dominant parasite toxin. Parasitic killing by each of the proteins seems to depend on its capacity to disrupt the plasma membrane; in the case of ECP, membrane disruption occurs through the formation of pores or channels.1 Eosinophils (similar to neutrophils) have been reported to present antigen to T cells; it is not established whether antigen presentation plays any role in the antiparasitic effect.121 Although epidemiologic and in vitro evidence supports a role for eosinophils in parasitic defense, in vivo confirmation of such a role is equivocal. In particular, several studies indicate that eosinophil ablation (through IL-5 depletion) has no effect on the course of parasite infections in mice.122,123 This might reflect redundancy of antiparasitic defenses. EOSINOPHIL RELEVANCE TO RHEUMATIC DISEASE Asthma Although perhaps not strictly a rheumatic disease, asthma represents the most common inflammatory/autoimmune disease in which eosinophils predominate. Although the presence of blood and pulmonary eosinophilia in asthma has been appreciated for a century, the role of eosinophils in the pathogenesis of this disease remains a subject of intense study. Asthmatic eosinophilia is stimulated by high levels of IL-5 and other cytokines. Eosinophils possess multiple mechanisms through which they can, at least potentially, enhance the asthmatic response. Similar to neutrophils, stimulated eosinophils synthesize LTA4 from arachidonic acid. In contrast to neutrophils, however, eosinophil metabolism of LTA4 leads to the production not of LTB4, but of LTC4 and LTD4 (cysteinyl leukotrienes), both potent bronchoconstrictors.124 Eosinophils themselves are exquisitely sensitive to the effects of cysteinyl leukotrienes, which stimulate eosinophil adhesion, migration, and degranulation and the proliferation of eosinophil progenitors.125-127 The cysteinyl leukotriene receptor antagonists (lukasts) are effective in the treatment of asthma and have been shown to have direct effects on eosinophils in vivo and in vitro, including reduction of eosinophil transmigration and reduction of pulmonary and peripheral eosinophilia.128-130 Lukasts seem to have beneficial effects on other diseases characterized by eosinophilia, including cystic fibrosis, eosinophilic gastroenteritis, and atrophic dermatitis.131-133

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Platelet-activating factor also is produced by stimulated eosinophils and has bronchoconstricting activities. Release of specific granule proteins per se have multiple proasthmatic effects, including (1) epithelial damage secondary to membrane perturbations similar to those seen in parasites and (2) activation of mast cells with subsequent histamine and leukotriene production. MBP also may act specifically as an antagonist of muscarinic M2 receptors, resulting in enhanced vagal tone and increased bronchospasm.134 Eosinophils and Rheumatic Diseases Although hypereosinophilia occasionally can be observed in virtually all rheumatic diseases, it is relatively uncommon in most, owing in part to the widespread use of corticosteroid therapy.135 In Churg-Strauss vasculitis, hypereosinophilia is the classic laboratory abnormality accompanying a constellation of pulmonary and renal vasculitis and asthma. In some cases, peripheral eosinophil counts in Churg-Strauss vasculitis have been reported to exceed 50% of total leukocytes. The cluster of asthma and eosinophilia accompanying Churg-Strauss vasculitis suggests that this syndrome may represent an atopic response to a foreign antigen. IgE response varies, however, and asthma may precede the rest of the disease by years. The presence of antimyeloperoxidase antibody (perinuclear ANCA), an IgG class antibody, is common, suggesting a broader autoimmune response. Eosinophilia-myalgia syndrome was first observed in 1989 in New Mexico and was defined by the Centers for Disease Control and Prevention for surveillance purposes as peripheral eosinophilia and muscle pains unexplained by other illnesses. Rash and skin edema are common findings. Follow-up of cases over time revealed the frequent appearance of fibrosing fasciitis, which in more severe disease results in skin retraction, particularly over the veins, where it gives rise to a train-track appearance. Intensive epidemiologic investigation pinpointed the likely cause of the epidemic to the consumption of l-tryptophan supplements produced by a single manufacturer, probably owing to trace contaminants. Discontinuation of the sale of the supplement led to resolution of the epidemic, although sporadic, tryptophan-independent cases continue to be reported.136 Eosinophilic fasciitis, a condition first described in 1975, resembles eosinophilia-myalgia syndrome in that it involves fasciitis and eosinophilia, but differs in that myalgias are not a prominent feature, and organ involvement is unusual. Clinically, the skin of patients with eosinophilic fasciitis bears some resemblance to the skin of patients with systemic sclerosis, but the distribution is typically on the distal extremities with sparing of the hands and feet. An epidemic similar to eosinophilia-myalgia syndrome was seen in Spain in 1981, relating to the consumption of adulterated rapeseed oil (toxic oil syndrome). Although in these syndromes it is unclear whether the eosinophils act as mediators of fasciitis or merely as reporters of exposure to an atopic antigen, the capacity of eosinophils to produce TGF-β suggests a potential role for these cells in the generation of fibrous tissue. The presence of eosinophils in the affected tissues varies, however, with most of the infiltrates comprising other leukocytes.137 A single study has shown indirect evidence for the presence of increased numbers of eosinophils (Charcot-Leyden

crystal deposition) in progressive systemic sclerosis. The ­relevance of this observation remains to be determined. Primary Eosinophilic Syndromes Idiopathic hypereosinophilic syndrome has been defined as (1) persistent eosinophils numbering 1500/mm3 for 6 or more months (or until death); (2) absence of parasites, allergy, or other cause of eosinophilia; and (3) signs and symptoms of organ involvement relating directly to eosinophils or eosinophil accumulation. Morbidity is largely from eosinophil tissue infiltration, and granuloma formation may occur.138 Idiopathic hypereosinophilic syndrome has gained attention with the description of patients with a genetic rearrangement, del4 (q12q12), that results in fusion of the platelet-derived growth factor receptor-α (PDGFRα) and Fip1-like 1 (FIP1L1) genes, generating a novel, constitutively active tyrosine kinase responsible for the clonal expansion of eosinophils. Targeted therapy with the selective tyrosine kinase inhibitor imatinib has become an effective tool in many cases of hypereosinophilic syndrome associated with the FIP1L1-PDGFRA fusion gene.139 A placebocontrolled trial indicated that mepolizumab, an anti-IL-5 monoclonal antibody, also might offer benefit.140 To date, corticosteroids remain the primary treatment for idiopathic hypereosinophilic syndrome. Eosinophilic esophagitis is a more recently recognized entity defined by the accumulation of eosinophils in the esophagus, which, in contrast to gastroesophageal reflux disease, does not respond to therapy with proton-pump inhibitors.141 Patients with eosinophilic esophagitis are predominantly young men and have high levels of eosinophils in the esophageal mucosa, extensive hyperplasia, a high rate of atopic disease, and normal pH monitoring compared with patients with gastroesophageal reflux disease. The prevalence seems to be increasing, notably among whites from Western countries.142 Oral fluticasone propionate and mepolizumab have been proven effective in initial trials.143,144 Löffler’s syndrome is a self-limiting eosinophilic pneumonitis with peripheral eosinophilia, presumably a hypersensitivity reaction. Allergic bronchopulmonary aspergillosis also represents a hypersensitivity reaction and may be indistinguishable from Löffler’s syndrome. A novel eosinophilic syndrome has been described, consisting of nodules, eosinophilia, rheumatism, dermatitis, and swelling (NERDS); because only a few cases have been reported to date, the clinical identity of this illness awaits validation.145 Addison’s Disease Addison’s disease is a disorder of adrenal failure resulting in underproduction of steroid hormones. Addison’s disease frequently is accompanied by peripheral eosinophilia. In contrast to increases in peripheral neutrophil counts, the ability of glucocorticoids to reverse the eosinophilia of Addison’s disease implicates that class of agents as a key regulator in the downregulation of eosinophil number. Glucocoticoids rapidly reduce eosinophil numbers in most hypereosinophilic and nonhypereosinophilic patients, a fact enshrined in the clinical maxim that detectable levels of eosinophils in a patient on long-term glucocorticoid therapy may be

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evidence of noncompliance with medication. Whether glucocorticoids have their effect on eosinophil production, release, or survival remains to be determined. Regardless of the mechanism of their effect, the use of glucocoticoids to reduce eosinophil count is an important strategy in reducing morbidity from hypereosinophilic diseases. Acknowledgments The authors express their gratitude to Dr. Gerald Weissmann for generously sharing images for figures. The authors also thank Ms. Madeline Rios for her excellent judgment and tireless editorial support.

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88. Weissmann G, Spilberg I, Krakauer K: Arthritis induced in rabbits by lysates of granulocyte lysosomes. Arthritis Rheum 12:103-116, 1969. 89. Befus AD, Mowat C, Gilchrist M, et al: Neutrophil defensins induce histamine secretion from mast cells: mechanisms of action. J ­Immunol 163:947-953, 1999. 90. McCurdy L, Chatham WW, Blackburn WD Jr: Rheumatoid synovial fibroblast adhesion to human articular cartilage: enhancement by neutrophil proteases. Arthritis Rheum 38:1694-1700, 1995. 91. Kasama T, Kobayashi K, Yajima N, et al: Expression of vascular endothelial growth factor by synovial fluid neutrophils in rheumatoid arthritis (RA). Clin Exp Immunol 121:533-538, 2000. 92. Cross A, Bucknall RC, Cassatella MA, et al: Synovial fluid neutrophils transcribe and express class II major histocompatibility complex molecules in rheumatoid arthritis. Arthritis Rheum 48:2796-2806, 2003. 93. Chen M, Lam BK, Kanaoka Y, et al: Neutrophil-derived leukotriene B4 is required for inflammatory arthritis. J Exp Med 203:837-842, 2006. 94. Wipke BT, Allen PM: Essential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis. J Immunol 167:1601-1608, 2001. 95. Abramson SB, Dobro J, Eberle MA, et al: Acute reversible hypoxemia in systemic lupus erythematosus. Ann Intern Med 114:941-947, 1991. 96. Goronzy JJ, Weyand CM: Cytokines in giant-cell arteritis. Cleve Clin J Med 69(Suppl 2):SII-91-SII-94, 2002. 97. Belmont HM, Buyon J, Giorno R, et al: Up-regulation of endothelial cell adhesion molecules characterizes disease activity in systemic lupus erythematosus: The Shwartzman phenomenon revisited. Arthritis Rheum 37:376-383, 1994. 98. Centola M, Wood G, Frucht DM, et al: The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood 95: 3223-3231, 2000. 99. Pillinger MH, Abramson SB: The neutrophil in rheumatoid arthritis. Rheum Dis Clin N Am 21:691-714, 1995. 100. Cronstein BN, Van de Stouwe M, Druska L, et al: Nonsteroidal antiinflammatory agents inhibit stimulated neutrophil adhesion to endothelium: Adenosine dependent and independent mechanisms. Inflammation 18:323-335, 1994. 101. Neal TM, Vissers MC, Winterbourn CC: Inhibition by nonsteroidal anti-inflammatory drugs of superoxide production and granule enzyme release by polymorphonuclear leukocytes stimulated with immune complexes or formyl-methionyl-leucyl-phenylalanine. Biochem Pharmacol 36:2511-2517, 1987. 102. Pillinger MH, Capodici C, Rosenthal P, et al: Modes of action of aspirin-like drugs: Salicylates inhibit erk activation and integrindependent neutrophil adhesion. Proc Natl Acad Sci U S A 95: 14540-14545, 1998. 103. Cronstein BN, Eberle MA, Gruber HE, et al: Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells. Proc Natl Acad Sci U S A 88:2441-2445, 1991. 104. Sperling RI, Benincaso AI, Anderson RJ, et al: Acute and chronic suppression of leukotriene B4 synthesis ex vivo in neutrophils from patients with rheumatoid arthritis beginning treatment with methotrexate. Arthritis Rheum 35:376-384, 1992. 105. Cronstein BN, Molad Y, Reibman J, et al: Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. J Clin Invest 96:994-1002, 1995. 106. Pillinger NH, Abramson SB: The neutrophil in rheumatoid arthritis. Rheum Dis Clin North Am 21:691-714, 1995. 107. Moreland LW, Bucy RP, Weinblatt ME, et al: Immune function in patients with rheumatoid arthritis treated with etanercept. Clin Immunol 103:13-21, 2002. 108. Capsoni F, Sarzi-Puttini P, Atzeni F, et al: Effect of adalimumab on neutrophil function in patients with rheumatoid arthritis. Arthritis Res Ther 7:R250-R255, 2005. 109. Koizumi K, Poulaki V, Doehmen S, et al: Contribution of TNF-alpha to leukocyte adhesion, vascular leakage, and apoptotic cell death in endotoxin-induced uveitis in vivo. Invest Ophthalmol Vis Sci 44:2184-2191, 2003. 110. Rosenberg HF: Eosinophils. In Gallin JI, Snyderman R (eds): Inflammation: Basic Principles and Clinical Correlates, 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 1999, pp 61-76.

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111. Mattes J, Foster PS: Regulation of eosinophil migration and Th2 cell function by IL-5 and eotaxin. Curr Drug Targets Inflamm Allergy 2:169-174, 2003. 112. Ponath PD, Qin S, Post TW, et al: Molecular cloning and characterization of a human eotaxin receptor expressed selectively on eosinophils. J Exp Med 183:2437-2448, 1996. 113. Weller PF, Bach DS, Austen KF: Biochemical characterization of human eosinophil Charcot-Leyden crystal protein (lysophospholipase). J Biol Chem 259:15100-15105, 1984. 114. Abu-Ghazaleh RI, Dunnette SL, Loegering DA, et al: Eosinophil granule proteins in peripheral blood granulocytes. J Leukoc Biol 52:611-618, 1992. 115. Rosenwasser LJ, Zimmermann N, Hershey GK, et al: Molecular mechanisms in allergy and clinical immunology. J Allergy Clin Immunol 111:227-242, 2003. 116. Fritz DK, Kerr C, Tong L, et al: Oncostatin-M up-regulates VCAM-1 and synergizes with IL-4 in eotaxin expression: involvement of STAT6. J Immunol 176:4352-4360, 2006. 117. Nourshargh S: Mechanisms of neutrophil and eosinophil accumulation in vivo. Am Rev Respir Dis 148(6 Pt 2):S60-S64, 1993. 118. Wines BD, Hogarth PM: IgA receptors in health and disease. Tissue Antigens 68:103-114, 2006. 119. Gould HJ, Sutton BJ, Beavil AJ, et al: The biology of IGE and the basis of allergic disease. Annu Rev Immunol 21:579-628, 2003. 120. Seminario MC, Saini SS, MacGlashan DW Jr, et al: Intracellular expression and release of Fc epsilon RI alpha by human eosinophils. J Immunol 162:6893-6900, 1999. 121. Weller PF, Rand TH, Barrett T, et al: Accessory cell function of human eosinophils: HLA-DR-dependent, MHC-restricted antigenpresentation and IL-1 alpha expression. J Immunol 150:2554-2562, 1993. 122. Klion AD, Nutman TB: The role of eosinophils in host defense against helminth parasites. J Allergy Clin Immunol 113:30-37, 2004. 123. Grimaldi JC, Yu NX, Grunig G, et al: Depletion of eosinophils in mice through the use of antibodies specific for C-C chemokine receptor 3 (CCR3). J Leukoc Biol 65:846-853, 1999. 124. Bandeira-Melo C, Weller PF: Eosinophils and cysteinyl leukotrienes. Prostaglandins Leukot Essent Fatty Acids 69:135-143, 2003. 125. Nagata M, Saito K, Tsuchiya K, et al: Leukotriene D4 upregulates eosinophil adhesion via the cysteinyl leukotriene 1 receptor. J Allergy Clin Immunol 109:676-680, 2002. 126. Ohshima N, Nagase H, Koshino T, et al: A functional study on CysLT(1) receptors in human eosinophils. Int Arch Allergy Immunol 129:67-75, 2002. 127. Braccioni F, Dorman SC, O’Byrne PM, et al: The effect of cysteinyl leukotrienes on growth of eosinophil progenitors from peripheral blood and bone marrow of atopic subjects. J Allergy Clin Immunol 110:96-101, 2002. 128. Virchow JC Jr, Faehndrich S, Nassenstein C, et al: Effect of a specific cysteinyl leukotriene-receptor 1-antagonist (montelukast) on the transmigration of eosinophils across human umbilical vein endothelial cells. Clin Exp Allergy 31:836-844, 2001. 129. Finsnes F, Lyberg T, Christensen G, et al: Leukotriene antagonism reduces the generation of endothelin-1 and interferon-gamma and inhibits eosinophilic airway inflammation. Respir Med 96:901-906, 2002. 130. Minoguchi K, Kohno Y, Minoguchi H, et al: Reduction of eosinophilic inflammation in the airways of patients with asthma using montelukast. Chest 121:732-738, 2002. 131. Daikh BE, Ryan CK, Schwartz RH: Montelukast reduces peripheral blood eosinophilia but not tissue eosinophilia or symptoms in a patient with eosinophilic gastroenteritis and esophageal stricture. Ann Allergy Asthma Immunol 90:23-27, 2003. 132. Capella GL, Grigerio E, Altomare G: A randomized trial of leuko­ triene receptor antagonist montelukast in moderate-to-severe atopic dermatitis of adults. Eur J Dermatol 11:209-213, 2001. 133. Schmitt-Grohe S, Eickmeier O, Naujoks C, et al: Effects of ­ longterm treatment with montelukast in mild cystic fibrosis (long term treatment with montelukast in cystic fibrosis). Respir Med 101:684, 2007. 134. Jacoby DB, Gleich GJ, Fryer AD: Human eosinophil major basic ­protein is an endogenous allosteric antagonist at the inhibitory ­muscarinic M2 receptor. J Clin Invest 91:1314-1318, 1993.

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135. Kargili A, Bavbek N, Kaya A, et al: Eosinophilia in rheumatologic diseases: A prospective study of 1000 cases. Rheumatol Int 24: 321-324, 2004. 136. Margolin L: Non-L-tryptophan related eosinophilia-myalgia syndrome with hypoproteinemia and hypoalbuminemia. J Rheumatol 30:628-629, 2003. 137. Clauw DJ, Crofford LJ: Eosinophilic rheumatic disorders. Rheum Dis Clin N Am 21:231-246, 1995. 138. Fauci AS, Harley JB, Roberts WC, et al: NIH conference: The ­idiopathic hypereosinophilic syndrome: Clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med 97:78-92, 1982. 139. Cools J, DeAngelo DJ, Gotlib J, et al: A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 348:1201-1214, 2003. 140. Garrett JK, Jameson SC, Thomson B, et al: Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes. J Allergy Clin Immunol 113:115-119, 2004.

141. Furuta GT: Emerging questions regarding eosinophil’s role in the esophago-gastrointestinal tract. Curr Opin Gastroenterol 22: 658-663, 2006. 142. Blanchard C, Wang N, Rothenberg ME: Eosinophilic esophagitis: Pathogenesis, genetics, and therapy. J Allergy Clin Immunol 118:1054-1059, 2006. 143. Konikoff MR, Noel RJ, Blanchard C, et al: A randomized, doubleblind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis. Gastroenterology 131:1381-1391, 2006. 144. Stein ML, Collins MH, Villanueva JM, et al: Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis. J Allergy Clin Immunol 118:1312-1319, 2006. 145. Butterfield JH, Leiferman KM, Gleich GJ: Nodules, eosinophilia, rheumatism, dermatitis and swelling (NERDS): A novel eosinophilic disorder. Clin Exp Allergy 23:571-580, 1993.

13

Mast Cells Peter A. Nigrovic  •  David M. Lee

KEY POINTS Mast cells (MCs) arise in the bone marrow, circulate as immature precursors, and develop into functional MCs after entering peripheral tissues. The phenotype of MCs is diverse, plastic, and governed by signals from the local microenvironment. In healthy tissues, MCs serve as immunologic sentinels and participate in the defense against bacteria and parasites. MCs accumulate in injured and inflamed tissue, where they contribute to the inflammatory response and the remodeling of surrounding tissues. MCs have been implicated in autoimmune diseases, including inflammatory arthritis.

Although the mast cell (MC) is best known for its role in allergy and anaphylaxis, the immune function of this bone marrow–derived lineage far outstrips its participation in IgE-driven disease. MCs reside broadly in vascularized tissues, but cluster near interfaces with the external world, in the linings of vulnerable body cavities, and near blood vessels and nerves. In these locations, MCs serve as immune sentinels, equipped with an array of pathogen receptors and an armamentarium of mediators capable of rapidly recruiting immune effector cells. MCs also accumulate in sites of tissue injury and chronic inflammation, although their role in such locations is uncertain. Other functions for this lineage, conserved by evolution for more than 500 million years, continue to be defined. Circumstantial and experimental evidence implicates MCs in the pathogenesis of rheumatic diseases. MCs reside constitutively in the normal synovium and are found in large numbers in inflamed synovial tissue, whereas MC mediators are identified in inflammatory joint fluid. Models have indicated that MCs may contribute importantly to the pathogenesis of experimental arthritis. MCs also have been implicated in other autoimmune conditions, including multiple sclerosis, bullous pemphigoid, and systemic sclerosis. This chapter reviews the basic biology of MCs and their potential role in human inflammatory diseases.

BASIC BIOLOGY OF MAST CELLS DEVELOPMENT AND TISSUE DISTRIBUTION MCs have a distinctive appearance. Ranging in size from 10 to 60 μM and with a centrally located round or oval nucleus, their abundant cytoplasm is filled with multiple small granules. They were named Mastzellen in 1878 by the German pathologist Ehrlich, who believed incorrectly that they were

overfed connective tissue cells (mästen, German, “to feed or fatten an animal”).1 Electron microscopy reveals that the plasma membrane of the MC exhibits multiple thin cytoplasmic extensions, providing a broad interface with the surrounding tissue (Fig. 13-1). The tissue distribution of MCs is extensive; within tissue, MCs tend to cluster around blood vessels and nerves and near epithelial and mucosal surfaces. They also are found in the lining of vulnerable body cavities, such as the peritoneum and the diarthrodial joint. Given this localization, MCs are among the first immune cells to encounter pathogens invading into tissue from the external world or via the bloodstream, consistent with their role as immune sentinel cells.2 MCs are of hematopoietic origin, arising in the bone marrow and depositing in tissues after migrating through the bloodstream (Fig. 13-2).3,4 In contrast to most other myeloid cells, such as monocytes and neutrophils, MCs do not terminally differentiate in the bone marrow, but rather circulate as committed progenitors, bearing the surface signature CD34+/c-kit+/CD13+.5 Further developmental details have been worked out most extensively in mice. On entering the tissues, murine MCs may mature into classic granulated cells or remain as ungranulated progenitors, awaiting local signals to mature fully. Tissue homing and migration is under the control of integrin adhesion molecules. Comparison of murine lung and intestine has shown that these tissues use distinct pathways to regulate the constitutive and inducible recruitment of MC progenitors, illustrating that MC homing is a precisely controlled process.6 When MCs reside in tissues, they may live for many months.7 In contrast to other myeloid lineage cells, such as macrophages and neutrophils, mature MCs remain capable of mitosis, although recruitment of circulating progenitors seems to exceed greatly local replication as a pathway to expand the number of MCs in a tissue.8 Mechanisms of reducing MC numbers include apoptosis, shown in tissue MCs deprived of the cytokine stem cell factor (SCF), a crucial survival signal for MCs.9,10 Under certain conditions, MCs also may emigrate via the lymphatics, appearing in draining lymph nodes similar to dendritic cells.11 Mast Cell Heterogeneity: Common Progenitor, Multiple Subsets, Phenotypic Plasticity Although all types of MCs derive from a common progenitor lineage, the phenotype of fully differentiated tissue MCs is heterogeneous. Human MCs are conventionally divided into two broad classes on the basis of the protease contents of their granules (see Fig. 13-2).12 MCTC display rounded granules containing the enzymes tryptase and chymase, whereas the smaller and more irregularly shaped granules of 235

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N

N

A

B

Figure 13-1  Mast cell morphology. A, Intact mast cell. B, Mast cell that has undergone anaphylactic degranulation; note how fusion of intracellular granules has resulted in formation of a labyrinth of interconnected channels by which granule contents may be expelled from the cell. Arrows indicate remaining granules. N, nucleus. (Courtesy of Dr. A. Dvorak, Beth Israel Deaconess Medical Center, Boston. From Dvorak AM, Schleimer RP, Lichtenstein LM: Morphologic mast cell cycles. Cell Immunol 105:199, 1987; and Galli SJ, Dvorak AM, Dvorak HF: Basophils and mast cells: Morphologic insights into their biology, secretory patterns, and function. In Ishizaka K [ed]: Progress in Allergy: Mast Cell Activation and Mediator Release, Vol 34. Basel, S. Karger, 1984, p 1.)

MCT contain tryptase, but not chymase.13 MCTC also express other proteases, including carboxypeptidase and cathepsin G. MCC, bearing only chymase, have been reported, but are controversial. These subtypes differ in tissue distribution. MCTC tend to be found in connective tissue, such as in normal skin, muscle, intestinal submucosa, and synovium, whereas MCT predominate in mucosal sites, including the lining of the gut and respiratory tract; both are present in many locations.14,15 Beyond protease signature, other differences between these subsets include their profile of cytokine elaboration and cell surface receptor expression; however, tissue-specific phenotypic differences are noted within each type. The relationship between MCTC and MCT is controversial. Are they committed subsets, akin to CD4 and CD8 lymphocytes, or functional states that MCs assume under the influence of the microenvironment? In mice, where an analogous distinction exists between connective tissue MCs and mucosal MCs, evidence for phenotypic plasticity is strong. In culture and in vivo, single connective tissue MCs may differentiate into (or give rise to) mucosal MCs, and vice versa.16,17 MCs with intermediate protease expression are found, and serial observations suggest that exposure to an inflammatory stimulus can induce progressive change from one class to another, although it has not been definitively established whether this occurs at a single-cell level.18 Similarly, in murine and human mastocytosis, clonally expanded MCs display divergent phenotypes depending on tissue of residence.19,20 In aggregate, these data favor the hypothesis that MCs assume a particular phenotype under

the control of the local environment, but can change radically if these conditions change. Stem Cell Factor One of the most important signals from tissue to local MCs is SCF.9 The receptor for SCF, c-kit, is expressed widely on hematopoietic lineages early in differentiation, but among mature lineages only MCs express c-kit at a high level. Stimulation of MCs by SCF promotes maturation and phenotypic differentiation, blocks apoptosis, and induces chemotaxis. It also may activate MCs directly to release mediators. In mice and humans, SCF is an irreplaceable survival signal for tissue MCs. Mice with defects in SCF or c-kit are strikingly deficient in mature tissue MCs (e.g., W/Wv, Sl/Sld, and Wsash strains). Similarly, clonal MCs obtained from patients with systemic mastocytosis commonly exhibit activating mutations in c-kit.21 SCF occurs in two alternate forms resulting from differential mRNA splicing: soluble and membrane-bound.9 The importance of this latter form is clear from Sl/Sld mice, which lack only the membrane-bound isoform, yet exhibit very few tissue MCs.22 SCF is synthesized by multiple lineages, including MCs themselves. Expression by fibroblasts is likely especially important, given the intimate physical contacts observed between fibroblasts and MCs in situ. Rodent MCs cocultured with fibroblasts show enhanced survival, connective tissue phenotypic differentiation, and heightened capacity to elaborate proinflammatory eicosanoids, effects mediated at least partly by direct contact, including interactions between SCF

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Different Functions for Mucosal Mast Cells and Connective Tissue Mast Cells

Bone marrow

Circulation

Mast cell progenitor

Tissue

T cell SCF tissue environment

MCT

MCTC Phenotypic plasticity

The preservation of distinct types of MCs in multiple species implies distinct and nonoverlapping roles for these subtypes. The understanding of functional differences between MCT and MCTC is limited, however. One hypothesis is that MCT play a proinflammatory role, whereas MCTC specialize in matrix remodeling.31 This hypothesis makes sense of the promotion of MCT development by T cells patrolling the tissues, of the partition of MCT and MCTC to inflamed (MCT) and fibrotic (MCTC) areas, and of the preferential expression of the proinflammatory mediators IL-5 and IL-6 by MCT and the profibrotic mediator IL-4 by MCTC.32 Not all observations fit comfortably into this dichotomy. The potently proinflammatory anaphylatoxin receptor C5aR (CD88) is expressed on MCTC, but not MCT.33 Ultimately, too little is known about the actual functional importance of these subsets to permit firm conclusions. MAST CELL ACTIVATION

Figure 13-2  Mast cell origin and differentiation. Mast cells arise in the bone marrow, circulate as committed progenitors, and differentiate into mature mast cells on entering tissue. Human mast cells may be classified on the basis of granule proteases into tryptase-positive mast cells (MCT) and tryptase-positive/chymase-positive mast cells (MCTC), with characteristic tissue localization and mediator production. SCF, stem cell factor. (Adapted from Gurish MF, Austen KF: The diverse roles of mast cells. J Exp Med 194:F1, 2001. Graphic design by Steven Moskowitz.)

and c-kit.23,24 The extent of similar regulation in human MCs is uncertain.25 Expression of SCF also has been documented on other lineages, including macrophages, vascular endothelium, and airway epithelium, and is likely a crucial pathway by which tissues modulate the local MC population. T Lymphocytes T lymphocytes exert a profound effect on the phenotype of a major subset of tissue MCs. SCID mice lacking T cells fail to develop mucosal MCs, a defect that may be corrected by T cell engraftment.26 An analogous observation has been made in human patients deficient in T cells secondary to congenital immunodeficiency or acquired immunodeficiency syndrome. Intestinal biopsy specimens in these patients show that mucosal MCs (MCT) are strikingly reduced, whereas connective tissue MCs (MCTC) are present in normal numbers.27 The pathways by which T cells exert this striking effect are undefined, although clearly T cell cytokines, such as interleukin (IL)-3, IL-4, IL-6, and IL-9, may have profound effects on MCs matured in culture, skewing toward either MCT or MCTC phenotype.28,29 By contrast, interferon-γ inhibits MC proliferation and may induce apoptosis. These observations imply that cells recruited to an inflamed tissue may have a profound impact on the phenotype and survival of local MCs. The rheumatoid synovium may exemplify this phenomenon: normally populated by MCTC, large numbers of MCT are identified in the inflamed synovium, typically in the regions rich in infiltrating leukocytes, whereas MCTC reside in the deeper, more fibrotic areas of the joint.30

IgE The canonical pathway to MC activation is via IgE and its receptor FcεRI. With an association constant Ka of 1010/M, this receptor is essentially constantly saturated with IgE at typical serum concentrations.34 Cross-linking FcεRI-bound IgE by multivalent antigen induces a brisk and vigorous response. Within minutes, granules within the MC fuse together and with the surface membrane, creating a set of labyrinthine channels that allow rapid release of granule contents (see Fig. 13-1B).35 This compound exocytosis event, termed anaphylactic degranulation, is followed within minutes by the elaboration of eicosanoids newly synthesized from arachidonic acid cleaved from internal membrane lipids. Finally, signals transduced via FcεRI induce the transcription of new genes and elaboration of a wide range of chemokines and cytokines (Fig. 13-3). On termination of the stimulation event, the surface membrane closes over the granule-formed channels, and these subsequently bud off within the cytoplasm, recreating discrete granules using the original membranes.35 These granules become recharged with mediators in a process that occurs gradually over days to weeks.36 IgG and Immune Complexes IgE is only one among many pathways of MC activation. One key trigger for MC activation in humans and mice is IgG, acting via receptors for the Fc portion of IgG (FcγR). The importance of this pathway was shown first in mice rendered genetically deficient in IgE. Contrary to expectations, these animals remained susceptible to anaphylaxis mediated through IgG and the low-affinity IgG receptor FcγRIII.37,38 The human counterpart of this receptor, FcγRIIa, is equally capable of inducing activation of human MCs.39 Human MCs exposed to interferon-γ also may be induced to express the high-affinity IgG receptor FcγRI, rendering them susceptible to IgG-mediated activation, although expression of this receptor in vivo has not been shown.40

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Mast cell IgE IgG Complement TLR agonists SCF, cytokines Cell-cell contact Trauma

Granule contents Proteases Tryptase, chymase, carboxypeptidase-A Proteoglycans Heparin, chondroitin sulfate Vasoactive amines Histamine, serotonin Cytokines TNF, IL-4, bFGF, VEGF, IL-16 Lipid metabolites PGD2, LTC4, LTB4, PAF Newly synthesized mediators Cytokines IL-1, IL-3, IL-6, IL-8, IL-16, IL-18 TNF, SCF, TGF-β Chemokines MCP-1, MCP-1α, MCP-1β, RANTES Eotaxin, TARC, Lymphotactin Growth factors GM-CSF, M-CSF, bFGF, PDGF, VEGF

Figure 13-3  Mediator production by human mast cells (partial list). The set of mediators liberated on activation varies depending on the state of differentiation of the mast cell and the nature of the stimulus. See Galli and colleagues80 for a complete mediator list and references. bFGF, basic fibroblast growth factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; LTB4, leukotriene B4; LTC4, leukotriene C4; MCP, monocyte chemoattractant protein; M-CSF, macrophage colony-stimulating factor; PAF, platelet-activating factor; PDGF, platelet-derived growth factor; PGD2, prostaglandin D2, RANTES, released on activation, normal T cell expressed and secreted; SCF, stem cell factor; TARC, thymus and activation-related chemokine TGF-β; transforming growth factor-β; TLR, Toll-like receptor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

These IgG receptors contribute to involvement of MCs in IgG-driven diseases. In mice, MCs participate in IgG-mediated immune complex peritonitis, the cutaneous Arthus reaction, and experimental murine bullous pemphigoid.41-43 Activation via Fc receptors also mediates MC participation in antibody-mediated murine arthritis.44 Soluble Mediators and Cell-Cell Contact MCs may coordinate with immune and nonimmune lineages via mechanisms beyond antibody response, including soluble mediators and surface receptors. Examples of such signals include the cytokine tumor necrosis factor (TNF)-α and the neurogenic peptide substance P, which can induce MC degranulation.45,46 Physical contact with other cells also can induce MC activation. CD30 on lymphocytes can interact with CD30L on MCs to induce the production of a range of chemokines.47 Ligation of CD30L does not induce release of granule contents or lipid mediators, illustrating the selectivity of response of which MCs are capable. Danger and Injury MCs are equipped to recognize danger in the absence of guidance from other lineages via a range of pathogen receptors, including multiple Toll-like receptors and CD48, a surface protein recognizing the fimbrial antigen FimH.48 These receptors

are implicated in the response of MCs to pathogens.49 MCs also may be activated through complement, including the anaphylatoxins C3a and C5a.46 MCs can respond directly to physical stimuli, including trauma, temperature, and osmotic stress.50 Together, these receptors enable MC involvement in a broad range of immune and nonimmune processes. Inhibitory Signals for Mast Cells As with other immune lineages, MCs are subject to negative and positive regulation. Examples of inhibitory receptors on the surface of MCs include the IgG receptor FcγRIIb and the integrin-binding immunoglobulin superfamily member gp49b1. The importance of these receptors is shown in genetically deficient animals. Mice lacking FcγRIIb show a striking propensity to activation via IgG and IgE (which binds with low affinity to FcγRIIb as well as strongly to FcεRI, respectively),51,52 whereas gp49b1-null mice are unusually susceptible to IgE-mediated anaphylaxis.53 Modulating the surface expression of inhibitory receptors serves as an important mechanism for regulation of the activation threshold of MCs in tissues.54 MAST CELL MEDIATORS Granule Contents: Proteases, Amines, Proteoglycans, and Cytokines Mature MCs package a range of mediators in their granules, ready for immediate release through fusion with the surface membrane. The most abundant of these are the neutral proteases, named for their enzymatic activity at neutral (physiologic extracellular) pH, but vasoactive amines, proteoglycans such as heparin, and preformed cytokines play distinct roles in the biologic consequences of MC degranulation. The release of these mediators is not all or none. In addition to anaphylactic degranulation, MCs may release only a few granules at a time in a process termed piecemeal degranulation.55 Alternatively, under other conditions, MCs may elaborate cytokines and chemokines without any release of granule contents, as illustrated by activation via CD30L.47 Although the MC is well equipped to release of large volumes of preformed mediators, it is equally capable of responses tailored to the activating stimulus. Tryptase. Named for its enzymatic similarity to pancreatic trypsin, tryptase is the most abundant granule protein in human MCs.56 It also is an essentially specific marker for MCs, synthesized in scant amounts by basophils but by no other lineage.57 The enzyme found in granules is the β isomer, which is enzymatically active on formation of a homotetramer that relies on the scaffolding function of the proteoglycan heparin.58 MCs also synthesize α-tryptase, a protein incapable of forming homotetramers and so enzymatically inactive. In contrast to β-tryptase, the α isomer is not stored in granules, but constitutively released into circulation, where its function is unknown. The distinction between tryptase isomers is important for diagnostic reasons: As a marker of degranulation, systemic levels of β-tryptase constitute a marker of recent anaphylaxis.59 By contrast, α-trypsin levels reflect total body MC load and serve as a useful biomarker in systemic mastocytosis.60

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Tryptase directly cleaves structural proteins, such as fibronectin and type IV collagen, and enzymatically ­ activates stromelysin, an enzyme responsible for activating collagenase.61 Tryptase also promotes hyperplasia and activation of fibroblasts, airway smooth muscle cells, and epithelium. Cleavage of protease-activated receptors, such as PAR2, likely contributes to these activities.62-64 In aggregate, these effects suggest an important role for tryptase in matrix remodeling. A further contribution to the inflammatory milieu is suggested by the capacity of tryptase to promote neutrophil and eosinophil recruitment and to cleave C3 to generate the anaphylatoxin C3a.65,66 Chymase. Chymase is a chymotrypsin-like neutral protease found in the MCTC subset of human MCs, packaged within the same granules as tryptase.13 Similar to tryptase, chymase can cleave matrix components and activate stromeolysin; it also can activate collagenase directly, suggesting a role in matrix remodeling.67 Chymase also can affect cytokine function, with the capacity to cleave pro-IL-1β to generate active cytokines and to inactivate proinflammatory cytokines, such as IL-6 and TNF-α.68,69 Vasoactive Amines. Human MCs are capable of synthesizing and storing the biogenic amines histamine and serotonin, implicated in vascular leaks.70 Histamine, by far the more abundant, is a vasoactive amine found in MCT and MCTC, although it is not unique to this lineage. Histamine is involved in the wheal-and-flare response to cutaneous allergen challenge, via augmented vascular permeability, transendothelial vesicular transport, and neurogenic vasodilation. These effects are mediated principally via the H1 receptor. Three other histamine surface receptors, H2 through H4, are distributed widely on immune and nonimmune lineages, with effects as diverse as gastric acid secretion, Langerhans cell migration, and B cell proliferation.71 Heparin and Chondroitin Sulfate E. Heparin and chondroitin sulfate E are large proteoglycans that enable the ordered packing of mediators within human MC granules.72,73 Negatively charged carbohydrate side chains complex tightly with positively charged proteins, allowing very high concentrations of β-tryptase and other proteases. Heparin, produced exclusively by MCs, facilitates the activity of tryptase by making possible proteolytic self-activation within the granule and stabilizing the active tetrameric form of this enzyme.74 Heparin also has a wide range of effects beyond the MC, and is potently angiogenic.75 Heparin binding activates antithrombin III, providing the basis for use as an anticoagulant, and inhibits chemokines and classic and alternative pathways of complement activation.76 The physiologic role of these extracellular activities of MCderived heparin is uncertain. Preformed Cytokines. MCs are able to store certain cytokines in their granules for rapid release. The first of these to be documented was TNF-α.77 In mice, this pool of TNF-α is implicated in the rapid recruitment of neutrophils to the peritoneum during peritonitis.41,78 Other cytokines that may be stored in granules include IL-4, IL-16, basic fibroblast growth factor, and vascular endothelial growth factor.

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Newly Synthesized Mediators: Lipid Mediators, Cytokines, Chemokines, and Growth Factors Beyond preformed mediators stored within granules, activated MCs elaborate a range of mediators that are generated de novo. These mediators are released minutes to hours after stimulation, broadening and extending the impact of activated MCs on surrounding tissues. Lipid Mediators. Within minutes of activation, MCs begin to release metabolites of membrane phospholipids. This process is rapid because the relevant enzymes, beginning with phospholipase A2 responsible for harvesting phospholipids from the outer leaflet of the nuclear membrane, already are present in the cytoplasm and need only to be activated through signals mediated by calcium flux and the phosphorylation of intracellular messengers. The hallmark prostaglandin of human MCs is prostaglandin D2, capable of inducing bronchoconstriction, vascular leak, and neutrophil recruitment. Smaller amounts of other prostaglandins and thromboxane also are made. MC-derived leukotrienes have similar but generally more potent activity. Leukotriene C4 is the major leukotriene species generated by human MCs; leukotriene C4 and its metabolites leukotriene D4 and leukotriene E4 serve as potent inducers of vascular leak. Smaller amounts of the chemotaxins leukotriene B4 and platelet-activating factor also are generated. The particular profile of lipid mediators produced by MCs can change with local environmental signals and the resulting state of differentiation. MCs from skin generate more prostaglandin D2 than leukotriene C4, whereas both species are elaborated in roughly equal proportion by MCs isolated from lung and osteoarthritic synovium.79 Cytokines, Chemokines, and Growth Factors. Within 2 hours of activation, MCs begin to elaborate newly synthesized mediators as the end result of induced gene transcription and translation. The range of such mediators is broad (see Fig. 13-3). They include the canonical proinflammatory mediators TNF-α, IL-1, and IL-6; the T helper cytokines IL-4, IL-5, IL-10, and IL-13; chemotactic factors including IL-8, macrophage inflammatory protein (MIP)-1α, and RANTES (released on activation, normal T cell expressed and secreted); and growth factors for fibroblasts, blood vessels, and other cells such as basic fibroblast growth factor, vascular endothelial growth factor, and platelet-derived growth factor.80 As noted earlier, some of these also may be stored preformed in granules for rapid release. The panel of mediators generated depends on the state of differentiation and the activating signal and may occur in the absence of degranulation.

ROLE OF MAST CELLS IN HEALTH AND DISEASE Understanding of the role of MCs in health and disease has been aided greatly by the availability of mice lacking MCs through defects in the SCF/c-kit axis. Although these mice exhibit multiple phenotypic abnormalities, they are viable, excluding an obligate basal role for MCs in the structure and function of most tissues. Yet under physiologic stress, such as imposed by experimental models of disease, multiple differences from wild-type mice become evident. In many cases, these abnormalities may be corrected by engraftment with cultured

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Table 13-1  Participation of Mast Cells in Murine Models of Disease Beneficial to Host

References

Harmful to Host

References

Angiogenesis

122

Anaphylaxis*

Bacterial cystitis

49

Arthritis*

82 138, 139

Bacterial peritonitis*

78, 87

Asthma*

84

Bone remodeling

117

Bullous pemphigoid*

43

Envenomation*

145

Cardiomyopathy

146

Glomerulonephritis*

147

Dermatitis, irritant*

148

Graft tolerance*

108

Dermatitis, sunburn

149

Parasites, intestine

89, 91

Gastritis

150

Parasites, skin

151

Glomerulonephritis*

152

Thromboembolism

153

Immune complex peritonitis*

41

Wound healing*

111

Ischemia-reperfusion injury

154, 155

Multiple sclerosis*

102

Neurogenic inflammation*

100, 101

Peritonitis, irritant*

156

Peritoneal adhesions

157

Pneumonitis

158

Scleroderma

114, 115

Tumor angiogenesis

159

Note: Mast cells are implicated in these processes by virtue of phenotypic abnormalities in mast cell–deficient mice. *The phenotype has been shown to be reversible by engraftment with cultured mast cells, providing more direct evidence for a role for this lineage.

MCs,81 directly implicating MCs in a remarkably broad range of disease processes (Table 13-1). Interpretation of such experiments is limited by incomplete physiologic restoration of the MC compartment and by residual effects of deficient c-kit signaling in other lineages. Together with in vitro experiments and careful observation of normal ­subjects, animal experiments in MC-deficient mice have contributed greatly to progress in understanding MC physiology and pathophysiology. MAST CELLS IN ALLERGIC DISEASE: ANAPHYLAXIS, ALLERGIC DISEASE, AND ASTHMA MCs are the primary mediators of systemic anaphylaxis. This is shown in MC-deficient mice, in which resistance to IgE-mediated anaphylaxis may be restored by engraftment with MCs.82 In humans, participation of MCs in anaphylaxis has been documented through the detection of elevated serum levels of β-tryptase, a specific marker of MC degranulation.59 MCs accumulate in atopic mucosal tissues, where they degranulate on exposure to antigen and contribute prominently to tissue edema and the overproduction of mucus.34 MCs also accumulate in the asthmatic airway, including within the smooth muscle lining the airways, and have been implicated by human and animal data in airway hyperreactivity and mucosal changes.83,84 MAST CELLS IN NONALLERGIC INFLAMMATION Pathogen Defense: Mast Cells as Sentinels of Innate Immunity The involvement of MCs in atopic disease is well documented, but it does not explain their remarkable evolutionary conservation. MCs must somehow contribute to the

survival of the organism. The most probable mechanism by which MCs convey a survival advantage is in the defense against infection. This role is reflected in the localization of MCs near epithelial surfaces, around blood vessels, and in other locations of potential invasion by pathogens. MCs are competent defensive cells against bacteria. They express Toll-like receptors and other receptors against bacterial antigens, and on activation they are able to phagocytose bacteria and generate antimicrobial molecules, such as cathelicidin.85,86 Given their relatively small numbers, however, the most important function of MCs in immune defense is to serve as sentinels, monitoring for early traces of infection and rapidly mobilizing neutrophils and other inflammatory cells when needed. Such a role has been shown in mouse models of bacterial peritonitis, where MC-deficient animals exhibit a high mortality. This susceptibility correlates with delayed recruitment of neutrophils via TNF-α and leukotrienes; neutrophil influx and survival may be restored by correction of the MC deficit.78,87,88 Clearance of bacteria from lung also is delayed in MC-deficient mice and can be similarly restored.78 Analogous observations have been made in other models of bacterial infection.48 MCs play an important role in the defense of the host against bacterial infection. MCs also are implicated in the defense against parasites. MC-deficient animals exhibit abnormal clearance of multiple parasites from gut and skin, in a manner promoted by IgE.89,90 The mechanism of this defense is uncertain, but may include direct attack on pathogens, recruitment of inflammatory lineages such as neutrophils and eosinophils, and lysis of tight junctions in the mucosal lining to facilitate the expulsion of helminths.89,91

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241

Mast Cells and the Adaptive Immune Response

Mast Cells as Anti-inflammatory Cells

In addition to recruiting innate effector cells, MCs mobilize T lymphocytes and B lymphocytes, the adaptive arm of the immune system.80 MCs may express major histocompatibility complex II proteins and costimulatory molecules, such as CD80 and CD86, rendering them effective antigen presenting cells for CD4 T cells. They may migrate from peripheral tissues to lymph nodes carrying antigen and contribute to the recruitment of T cells to lymph nodes via mediators, including MIP-1β and TNF-α.11,92 Infection-induced lymph node hyperplasia is abrogated in the absence of MCs. MCs can recruit CD4 and CD8 effector T cells to peripheral tissues via leukotriene B4, among other mediators.93-95 MCs can contribute to the migration of cutaneous Langerhans cells (dendritic cells) to lymph nodes via mediators, including histamine.96,97 By means of the inducible expression of CD40L and cytokines, MCs may stimulate B cells and induce class-switching to IgE entirely in the absence of T cell help.98 The physiologic importance of these effects varies with circumstances. Under some conditions, delayed-type hypersensitivity responses in skin are MC-dependent, whereas under others MCs seem to play no role.80

In recent years, it has become evident that MCs also may help to moderate the immune response. One mechanism for this effect is by degradation of proinflammatory mediators. MC proteases may cleave and inactivate the cytokines IL-5, IL-6, IL-13, TNF-α and endothelin-1 and the anaphylatoxin C3a.66,69,106,107 The importance of this activity has been shown in a murine sepsis model, where MCs reduced mortality by restraining excess inflammation in a protease-dependent manner.107 Data also suggest that MCs may interact with regulatory T cells to promote immunologic tolerance to skin grafts, although the pathway by which MCs prevent rejection is undefined.108

Neurogenic Inflammation In addition to their perivascular localization, MCs cluster near and even within peripheral nerves. A discrete function for MCs in these locations has not yet been identified, although the potential for bidirectional neuroimmune interaction is clear. MC mediators such as histamine may activate neurons directly, whereas MCs residing near stimulated neurons may be induced to degranulate.99 Vascular leak and neutrophil infiltration arising from infiltration of skin with the neurogenic mediator substance P are mediated by MCs.100,101 Neurons may recruit MCs as local effectors to initiate neurogenic inflammation.

MAST CELLS AND CONNECTIVE TISSUE Wound Healing and Tissue Fibrosis MCs have long been noted to accumulate at the borders of healing wounds.109 In normal human subjects undergoing experimental wounding and recurrent biopsies, MC numbers increase sixfold by day 10 after initial incision. These MCs localize preferentially to fibrotic areas of the wound and strongly express IL-4, a cytokine capable of inducing fibroblast proliferation and collagen synthesis.8 In vitro studies confirm the stimulatory effects of MCs on fibroblast growth110; candidate fibroblast mitogens in addition to IL-4 include tryptase, histamine, leukotriene C4, and basic fibroblast growth factor. MC-deficient W/Wv animals exhibit delayed contracture and healing of skin wounds in a manner reparable by local engraftment with cultured MCs.111 MCs also accumulate in sites of pathologic fibrosis, including the skin and lungs of patients with scleroderma.112,113 Because experimental skin fibrosis proceeds in MC-deficient mice with only relatively subtle differences in intensity or kinetics, it is unlikely that MCs are an obligate effector lineage in human scleroderma, although they may contribute to disease progression.114,115

Autoimmune Disease Reconstitution experiments in MC-deficient mice have implicated MCs in a variety of pathologic inflammatory states (see Table 13-1). These include murine models of multiple autoimmune diseases, such as bullous pemphigoid, multiple sclerosis, scleroderma, and inflammatory arthritis. In pemphigoid, MCs triggered via IgG antibodies against a hemidesmosomal antigen recruit neutrophils that are responsible for blister formation.43 The role of MCs in murine experimental autoimmune encephalomyelitis is more complex. Although the resistance of W/Wv mice to experimental autoimmune encephalomyelitis corrects with MC engraftment, these cells fail to repopulate the brain and spinal cord, indicating that MCs are not obligate local effector cells in this model.102,103 One mechanism for this activity seems to be the promotion of the adaptive immune response because MC engraftment into W/Wv animals improves T cell responses to immunization with the inciting myelin antigen.104,105 The contribution of MCs to human multiple sclerosis is unknown. The participation of MCs in scleroderma and arthritis is discussed subsequently.

Bone MCs also are implicated in the remodeling of bone. MCs accumulate at sites of healing fracture, and under normal circumstances they may contribute productively to normal bone turnover.116,117 MCs accumulate in osteoporotic bone, however, and systemic osteoporosis is a known complication of systemic mastocytosis.118,119 Heparin is one potentially important mediator of bone loss because it directly promotes differentiation and activation of osteoclasts.120 MC products such as IL-1, TNF-α, and MIP-1α have similar activity. Angiogenesis A final and potentially quite important activity of MCs on the stroma is the promotion of angiogenesis. MCs are not required for the development of the normal vasculature, as evident in the viability of MC-deficient mice. MCs cluster at sites of early blood vessel growth in tumors, however, and contribute appreciably to physiologic angiogenesis under certain experimental conditions.121,122 Heparin was the first proangiogenic MC mediator identified75; basic fibroblast

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growth factor and vascular endothelial growth factor are other potent stimulators of endothelial migration and proliferation.

MAST CELLS IN ARTHRITIS The normal synovium features a small population of resident MCs. These cells are not found in the immediate lining layer, but rather are found in the synovial sublining, near blood vessels and nerves, constituting almost 3% of cells within 70 μM of the intra-articular space.123 In mice and humans, their phenotype is principally MCTC, similar to MCs found in most other connective tissue sites.30,124 The severalfold increased density of MCs in the immediate vicinity of the synovial lining, compared with more distant connective tissue, supports the hypothesis that MCs contribute to surveillance of the articular cavity.30 Extrapolating from the activity of MCs near other vulnerable body cavities, such as the peritoneum, it is likely that one function of synovial MCs is to monitor the joint for early evidence of infection. No direct support for a protective effect of MCs against joint sepsis is available, however. In arthritis, the population of synovial MCs may expand remarkably (Fig. 13-4). More than two thirds of synovial specimens from patients with rheumatoid arthritis (RA) exhibit abnormal numbers of MCs, averaging more than 10-fold above normal.125 Consistent with these histologic findings, synovial fluid from rheumatoid joints contains appreciable quantities of histamine and tryptase.126,127 In contrast to normal joints, in joints with RA, both subtypes of MCs are present in roughly equal numbers; MCT are located nearer to the pannus and infiltrating leukocytes, whereas MCTC cluster in deeper, more fibrotic areas of the synovium.30 MCs have been noted near the junction of pannus and cartilage.128 Rarely, MCs also are identified in synovial fluid.129 The absence of mitotic figures and of staining for the proliferation antigen Ki-67 in this population suggests that they arise not from local replication, but rather by recruitment of circulating progenitors.130 Although the

signals driving this recruitment are unknown, inflammatory cytokines, such as TNF-α, enhance expression of the MC chemotactic and survival factor SCF on synovial fibroblasts, suggesting one mechanism for this dramatic expansion.131 Degree of inflammation is the best predictor of the number of MCs within the joint.125,132,133 Incompletely identified factors in RA synovial fluid can potently promote MC differentiation and growth.134 Hyperplasia of the MC population is not specific for RA, but is observed in a wide range of inflammatory joint disorders (Table 13-2). Expansion also is noted in osteoarthritis, often to numbers seen in RA.30,130,135,136 The levels of histamine and tryptase in osteoarthritis synovial fluid also are comparable. In contrast to in RA, the expansion in osteoarthritis results from an increase in numbers of MCT, the subtype generally associated with T cells and inflammation.30,137 Mast Cells in Acute Arthritis: Insights from Animal Models Experimental work in mice has begun to shed light on the role of MCs in inflammatory arthritis. Several MC-deficient strains show striking resistance to arthritis induced by IgG autoantibodies, a defect that may be repaired by engraftment with cultured MCs expressing receptors for IgG.44,138,139 Numerous mechanisms contribute to this arthritogenic activity. First, MCs induce vascular permeability, facilitating entry of autoantibody into the joint.140,141 Second, MCs release proinflammatory mediators, including IL-1, that help to establish inflammation, presumably via effects on endothelium and other local populations, such as macrophages and fibroblasts.44 These actions seem to be most crucial at the initiation of disease, constituting a “jump start” for acute inflammation within the joint. This function is in line with the activity of MCs in other models of IgGmediated disease, such as IgG-mediated immune complex peritonitis, murine bullous pemphigoid, and anaphylaxis. In each of these models, MCs resident in tissue for the purpose of immune defense become co-opted by autoantibodies to initiate inflammatory pathology (Fig. 13-5). Mast Cells in Chronic Arthritis In contrast to the acute phase of joint inflammation, the contribution of MCs to established arthritis has not been explored in animal models. The sheer numbers of these cells

Table 13-2  Joint Diseases with Documented   Synovial Mastocytosis Chronic infection Gout Juvenile rheumatoid arthritis Osteoarthritis Psoriatic arthritis Figure 13-4  Mast cells in the rheumatoid synovium. Stained red by an antibody against tryptase, mast cells are abundant in this synovial biopsy specimen from a patient with chronic rheumatoid arthritis. Note the proliferation of mast cells in the synovial sublining. (From Nigrovic PA, Lee DM: Synovial mast cells: Role in acute and chronic arthritis. Immunol Rev, 217: 19-37, 2007.)

Rheumatoid arthritis Rheumatic fever Traumatic arthritis See Nigrovic and Lee142 for tuberculous arthritis relevant references.

PART 2 

Histamine, Leukotrienes, TNF, IL-1

Synovial mast cell Normal bone

Tryptase, IL-4, TNF, bFGF

TNF, IL-1, Chemokines, Eicosanoids

Cartilage

Synoviocyte activation (fibroblast, macrophage)

PMN Monocyte Lymphocyte

Angiogenesis

243

PMNs Elastase Chondrocyte activation Histamine, IL-1

bFGF, PDGF, LTC4, histamine tryptase

Heparin, bFGF, VEGF

MMPs

Fibroblast, proliferation Tryptase, Chymase, IL-4

Pannus Heparin, MIP-1α, TNF, IL-1

Acute arthritis

Leukocyte recruitment and activation

CELLS INVOLVED IN AUTOIMMUNE DISEASES AND INFLAMMATION

Osteoclast differentiation and bone remodeling

Chronic arthritis

Endothelium Permeability Adhesion molecules ( )

| 

Matrix remodeling and fibrosis

Figure 13-5  Potential roles of mast cells in acute and chronic arthritis. In the acute phase of joint inflammation, mast cells may contribute to initiation of arthritis by inducing vascular permeability, recruiting and activating circulating leukocytes, and stimulating local fibroblasts and macrophages. In established arthritis, these activities may be joined by effects on the stroma, including the promotion of pannus formation, angiogenesis, fibrosis, and injury to cartilage and bone. Potential anti-inflammatory effects of mast cells are not depicted. The mediators listed are representative and do not constitute a complete list. bFGF, basic fibroblast growth factor; IL, interleukin; LTC4, leukotriene C4; MIP, macrophage inflammatory protein; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; PMN, polymorphonuclear neutrophil; TNF, tumor necrosis factor; VEGF, vascular  endothelial growth factor. (From Nigrovic PA, Lee DM: Synovial mast cells: Role in acute and chronic arthritis. Immunol Rev, 217: 19-37, 2007. Illustration by Steven Moskowitz.)

in arthritic synovium implies a substantial role. Taking into account the spectrum of MC activity elsewhere, it is likely that MCs participate both in the inflammatory process and in the mesenchymal response (see Fig. 13-5).142 An ongoing contribution of MCs to inflammatory arthritis is suggested by several observations. First, as noted, prominent among infiltrating synovial MCs are MCT, typically associated elsewhere with the elaboration of cytokines, such as IL-6, with documented pathogenic activity in RA. Immunofluorescence staining also has identified TNF-α in RA synovial MCs,10 and the elaboration of other proinflammatory mediators is probable. Second, MCs from RA, but not osteoarthritis, synovium express the receptor for the anaphylatoxin C5a, a mediator readily documented in synovial fluid.143 Immune complexes within RA joints provide another likely pathway to activation of synovial MCs.144 Ultrastructural data support ongoing degranulation of MCs in the RA synovium.137 The effect of MCs on the established inflammatory synovial infiltrate is difficult to predict. As in acute arthritis, activated MCs may promote the recruitment and activation of leukocytes, although the proinflammatory contribution of this lineage relative to macrophages and other synoviocytes remains to be determined. Alternatively, protease cleavage of inflammatory mediators and the elaboration of mediators

such as TGF-β could down-modulate inflammation, potentially under the direction of regulatory T cells, as has been observed in tolerance of skin grafts in mice.108 MCs likely modulate the stromal response to inflammation as well. Expansion and activation of synovial fibroblasts is a key pathogenic process within RA, and the capacity of MCs to promote such changes is well established. By their interaction with osteoclasts, MCs also may promote focal erosions and periarticular osteopenia. Together, these effects may contribute to joint injury. Finally, by producing proangiogenic mediators, MCs may enable the growth of the vascular supply required for the profound expansion of the thin synovial layer into thick pannus. Confirmation of these roles awaits further experimental data.

SUMMARY MCs are potent immune cells characterized by phenotypic diversity and an extremely broad range of functions in health and disease. In addition to mediating atopic disease, MCs represent important sentinels against pathogen invasion. Under certain conditions, it is likely that they also participate in the remodeling of tissue matrix. Aberrant activation of MCs by antoantibodies and potentially other signals has been identified in a variety of inflammatory diseases, including

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14

Platelets and Rheumatic Diseases Federico Díaz-González  •  Mark H. Ginsberg

KEY POINTS Platelets are small circulating cytoplasmic fragments that play a crucial role in hemostasis. Platelets release a variety of factors that contribute to inflammation, including chemotactic factors for leukocytes; factors that alter vascular tone and permeability; and transforming growth factor-β, a potent stimulus of fibrosis. Platelet surface proteins also participate in inflammation by serving as sites for leukocyte adhesion (e.g., P-selectin, Glycoprotein Ibα [GPIbα]) or as agonists for counter-receptors on leukocytes (e.g., CD40 ligand, platelet-activating factor). Platelets have been implicated in the pathogenesis of several rheumatic diseases, including rheumatoid arthritis and systemic lupus erythematosus; in the latter case, they have been particularly implicated in atherothrombotic complications. The ongoing development of antiplatelet agents offers the promise of new therapeutic modalities.

Platelets are small circulating cytoplasmic fragments that play a crucial role in hemostasis. They are produced in the bone marrow by megakaryocytes. Single platelets circulate freely in the bloodstream; after vascular injury, platelets adhere to the subendothelium resulting in responses that contribute to the formation of the hemostatic plug. These responses include aggregation, secretion of bioactive compounds, and production of procoagulant activity. Platelets also secrete soluble factors that contribute to wound repair by altering vascular tone and permeability, promoting cell growth, and stimulating scavenger cells such as monocytes. During the inflammatory response, many of the activities that lead to the hemostasis contribute to inflammation.1 Inflammation initiates clotting, decreasing the activity of natural anticoagulant mechanisms and impairing the fibrinolytic system. Conversely, activated platelets release ­chemotactic factors that promote leukocyte adhesion, which facilitates their extravasation into inflammatory foci. Platelets secrete a variety of factors that can alter vascular tone and permeability. Lastly, platelets are a major source of transforming growth factor (TGF)-β, a potent stimulus of fibrosis. Taken together, these activities make platelets ­contributors to the inflammatory response and to the pathogenesis of ­systemic rheumatic diseases.2 This chapter focuses on platelet functions, particularly as they pertain to the inflammatory response and rheumatic diseases.

GENERAL CHARACTERISTICS OF PLATELETS Platelets are the smallest blood cells; they are cytoplasmic fragments derived from their bone marrow precursor, the megakaryocyte. Resting platelets have a smooth disk shape and are 3.6 ± 0.7 μm in diameter. On activation, platelets undergo a shape change becoming a compact sphere with numerous long dendritic extensions markedly increasing their surface area. In humans, normal platelet counts range from 150,000/μL to 450,000/μL. The main function of platelets is to maintain the vascular integrity, playing a crucial role in hemostasis. The plasma membrane of platelets is a typical lipid bilayer, having an extensive series of complex invaginations termed the canalicular system. The role of this surface-connected tubular system seems to be to facilitate the quick release of secreted substances to the extracellular environment. The platelet membrane bears numerous ­glycoprotein (GP) receptors.3 Platelet surface phospholipids play an important role in coagulation4 and are a source of arachidonic acid, a precursor of important vasoactive substances such as thromboxane A2, a potent vasoconstrictor and platelet-aggregating agent, and of leukotrienes, which can amplify the inflammatory response. Platelet surface GPs are receptors that mediate the adhesion to subendothelial tissue and the subsequent aggregation to form the hemostatic plug.5-7 The largest GP is termed I and the smallest Ix. The a and b distinguish between two separate electrophoretic bands that initially were considered one (e.g., GPI became GPIa and GPIb). The platelet GPIb-IX-V is an important receptor that binds to von Willebrand’s factor (vWF) exposed in the subendothelial matrix, causing the attachment of platelets.8 Deficiency of any component of the GPIb-IX-V complex or of vWF leads to the congenital bleeding disorders Bernard-Soulier disease (GPIb-IX-V complex)7 and von Willebrand’s disease (vWF).9 ADAMTS-13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats 13) is a plasma protease that cleaves vWF into smaller multimers, reducing its hemostatic potency.10 Mutations in the ADAMTS-13 gene11 and autoantibodies against ADAMTS-1312,13 have been shown to cause familial and acquired thrombotic thrombocytopenic purpura. In mice, ADAMTS-13 has a powerful natural antithrombotic activity, and recombinant ADAMTS-13 has the potential to be used as an antithrombotic agent.14 Other interactions that contribute to the initial platelet adhesion are mediated by collagen receptors GPIa-IIa (integrin α2β1) and GPVI, which bind to collagen in the subendothelial matrix.15 The most abundant platelet surface receptor, GPIIb-IIIa (integrin αIIbβ3), is activated by adhesion to collagen or vWF or by soluble agonists, such 249

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as thrombin. After activation, GPIIb-IIIa binds fibrinogen, leading to platelet aggregation.5 Deficiency of this GP results in Glanzmann thrombasthenia, a disorder characterized by petechial bleeding and the absence of platelet aggregation and clot retraction.16 The cytoplasm of platelets is rich in actin and myosin, which provide platelets the ability to change shape and to retract clots. Platelet cytoplasm has mitochondria, lysosomes, glycogen stores, and three types of granules that ­ contain numerous biologically active molecules (Table 14-1). These granules are classified according to their ultrastructure, density, and contents as alpha granules, lysosomes, and dense granules. Although most of the contents of these granules are made in megakaryocytes, some are taken up from the plasma by megakaryocytes and platelets. Alpha granules contain numerous proteins and growth factors, such as platelet-derived growth factor (PDGF), TGF-β, platelet factor-4 (also referred as CXCL4), and vWF, which are synthesized in the megakaryocyte.17 Other proteins, such as fibrinogen, enter the alpha granules from the plasma via GPIIb-IIIa receptor-mediated endocytosis.18,19 P-selectin (CD62P), an adhesion molecule, also is ­localized in the membrane of alpha granules20,21 and redistributes to the cell surface during platelet activation. Platelet P-­selectin has been implicated in stabilizing platelet ­ aggregates.22 The best documented high-affinity counter-receptor for P-­selectin is P-selectin glycoprotein ligand-1 (PSGL-1), a transmembrane sialomucin found on leukocytes and ­lymphoid cells,23 through whose interaction ­ platelets participate in the inflammatory response.24 Dense granules contain serotonin, adenosine diphosphate (ADP), adenosine triphosphate, and calcium. The dense granule membrane bodies are made in megakaryocytes, but they do not acquire their content of serotonin and calcium until platelets are released into the circulation.25 Another series of intracellular membrane vesicles serves as a reserve to increase membrane surface area on platelet activation. As stated previously, platelets are small cytoplasmic fragments derived from megakaryocytes. Although megakaryocytes are rare in the bone marrow (approximately 0.1% of Table 14-1  Platelet Granule Compounds and   Granule Membrane Components with Role   in the Hemostatic/Inflammatory Response Platelet Granules Actions

Contents

Dense granule

Proaggregating factors

Serotonin, histamine, ADP, ATP, Ca2+, Mg2+

Alpha granule

Adhesive   glycoproteins

P-selectin, CD31, GPIIb-IIIa, fibronectin, vitronectin, thrombospondin Growth factors TGF-β, PDGF, EGF, VEGF Platelet   β-Thromboglobulin, PF4 aggregation   (CXCL4), CC and CXC and chemotaxis chemokines Hemostasis factors Fibrinogen, vWF

Lysosome

Tissue destruction

Hydrolases, collagenase, cathepsins D and E

ADP, adenosine diphosphate; ATP, adenosine triphosphate; EGF, epidermal growth factor; GPIIb-IIIa, glycoprotein IIb-IIIa; PDGF, platelet-derived growth factor; PF4 platelet factor-4; TGF, transforming growth factor; VEGF, vascular endothelial growth factor; vWF, von Willebrand factor. Modified from Rendu F, Brohard-Bohn B: The platelet release reaction: Granules’ constituents, secretion and functions. Platelets 12:261, 2001.

all nucleated cells), megakaryocytes are easily recognized by their giant size (50 to 100 μm diameter) and large, multilobed nucleus. Megakaryocytes have two unique characteristics: (1) They undergo a process known as endomitosis, in which the nucleus accumulates many times the normal number of chromosomes, and (2) they have specialized structures in the cytoplasm that permit fragments to be shed, as platelets, into the bloodsteam.26 Every day, about 2 × 1011 platelets are released into the bloodsteam of healthy adults by mature megakaryocytes. This quantity can be increased 10-fold under specific conditions.27 In humans, as in other species, there is an inverse relationship between the platelet count and the mean platelet volume.28 This suggests that platelet production by bone marrow megakaryocytes is regulated to maintain a constant total platelet mass. The tendency toward a stable platelet mass explains the wide variation in the platelet count in healthy donors (150,000/μL to 450,000/μL).29 Megakaryocytes normally replace about 10% of the platelet mass daily.30 In response to the increased need for platelets, megakaryocytes modify their number, size, and ploidy.31,32 Changes in free thrombopoietin levels, the main physiologic regulator of platelet production, are responsible for these morphologic and functional adaptations in megakaryocytes. Thrombopoietin is an 80- to 90-kD GP produced mainly by the liver33 and released at a constant rate into the circulation. Thrombopoietin acts through its receptor, the thrombopoietin receptor, also known as c-Mpl, which is present in platelets, megakaryocytes, and, to a lesser extent, most other hematopoietic precursor cells. Thrombopoietin prevents apoptosis of megakaryocytes, while increasing their number, size, and maturation,31,32 but it does not seem to increase the rate of shedding of platelets into circulation.34 On circulating platelets, thrombopoietin is not a sufficiently strong stimulus to trigger platelet function, but reduces the threshold for activation by other agonists, such as ADP.35 Binding to the platelet thrombopoietin receptor is the major route of catabolism, however, of circulating thrombopoietin. When the platelet production rate decreases, the platelet mass and the quantity of thrombopoietin receptor decrease; consequently, thrombopoietin concentrations increase and megakaryocyte growth is stimulated. In conditions of high platelet mass (e.g., hypertransfusion of platelets), the amount of thrombopoietin receptors increases, thrombopoietin concentrations decrease, and megakaryocyte growth decreases. In addition to thrombopoietin, other soluble factors, such as interleukin (IL)-3 and IL-11, seem to promote megakaryocyte maturation, and these cytokines may play a relevant role in thrombocytosis conditions.36,37 The life span of platelets in circulation is 7 to 10 days. Under normal conditions, the spleen stores about one third of circulating platelets. Circumstances that increase splenic volume, such as hepatic cirrhosis or portal hypertension, cause a reduction in the circulating platelet count by a sequestration within the splenic sinusoids.38 Hypersplenism does not reduce platelet life span, however; rather, it reduces the circulating platelets available for effective hemostasis. After senescence, platelets are removed from circulation by the reticuloendothelial system. Only a small fraction of ­circulating platelets is consumed in forming hemostatic plugs to maintain vascular integrity.

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FUNCTION OF PLATELETS In response to vascular injury, platelets adhere to subendothelium, secreting a variety of potent agonists and aggregating to form a hemostatic plug. During the inflammatory response, these physiologic responses of platelets can promote and exacerbate inflammation. In this sense, platelets are authentic inflammatory cells. HEMOSTASIS When a blood vessel is injured, a complex process, which involves biochemical reactions and cell-cell and cell-matrix interactions, termed hemostasis, occurs. The initial hemostatic response is mediated by platelets that form the platelet plug (Fig. 14-1). Under physiologic conditions, the undamaged endothelium prevents the adherence of platelets by several mechanisms. These mechanisms include a cell-associated ecto-ADPase (CD39) and the production of nitric oxide and prostacyclin.39 When blood vessel integrity is disrupted, the first reaction is vasoconstriction, which reduces blood loss. Simultaneously, subendothelial matrix elements are exposed, and platelets are rapidly transformed into sticky cellular elements capable of adhering to the underlying surface. Platelet adhesion is initially mediated by the interaction of GPIb-IX-V receptor complex with vWF in the subendothelial matrix.8 This interaction transduces signals through the GPIb-IX-V complex that activate platelet integrins.40,41 The activation of GPIa-IIa and GPIIb-IIIa integrins allows the binding to collagen (GPIa-IIa) and vWF (GPIIb-IIIa), mediating the stable adhesion of platelets to subendothelial surface. In addition to vWF, the active form of GPIIb-IIIa binds fibrinogen.42 The association of soluble fibrinogen with GPIIb-IIIa creates bridges between platelets that result in platelet aggregation and thrombus growth. In concert

with aggregation, platelets release their intracellular granules, amplifying the hemostatic response (see Table 14-1).43,44 The outcome is the formation of a platelet plug and the triggering of the coagulation cascade, which leads to thrombin generation and resulting fibrin clot formation (Fig. 14-2). One response of platelets to activation by stimuli such as shear stress or collagen is the release of vesicles called platelet microparticles, fragments 0.1 to 0.2 μm in diameter that carry antigens present in intact platelets. These platelet-derived microparticles may play a role in normal hemostasis.45,46 The number of clinical disorders associated with elevated platelet microparticles is increasing,47,48 including several rheumatic diseases.49-52 The relevance of plateletderived microparticles in the physiopathology of those disorders needs to be fully clarified, however. GLYCOPROTEIN IIb-IIIa GPIIb-IIIa is a member of a family of cell-adhesion receptors termed integrins. It also is referred to as integrin αIIbβ3 or CD41/CD61. Although integrins are expressed on virtually all nucleated cells, GPIIb-IIIa is restricted to megakaryocytes and platelets. It is the most abundant receptor on the platelet surface, averaging 80,000 copies per platelet. GPIIbIIIa recognizes at least five different adhesive ligands53: fibronectin, fibrinogen, vWF, thrombospondin, and vitronectin. Cells can modify integrin functions through dynamic modulation of receptor affinity.53 On resting platelets, GPIIb-IIIa does not bind soluble fibrinogen. After platelet stimulation (e.g., by thrombin, collagen, or ADP), GPIIb-IIIa undergoes a conformational change, however, and is converted from a low-affinity to a high-affinity fibrinogen receptor, a process known as “inside-out” signaling. In this situation, fibrinogen bridges the activated platelets, and platelet aggregation occurs. Simultaneously, the cytosolic portion of the activated GPIIb-IIIa binds to platelet cytoskeleton proteins and mediates platelet spreading and clot retraction in what is referred to as “outside-in” integrin signaling. GPIIb-IIIa integrates receptor-ligand interactions on the external face of the membrane with cytosolic events in a bidirectional fashion.5 This is the final common pathway for platelet aggregation,

Amplification

Adhesion

Aggregation

P

Secretion

P F

P Exposure of subendothelial matrix Figure 14-1  Platelet plug formation. Platelet activation can be initiated by several mechanical (vessel wall injury, disruption of atherosclerotic plaques) or chemical (adenosine diphosphate, epinephrine, thromboxane A2, thrombin) stimuli. In response to vessel wall injury, platelets attach to subendothelial matrix (adhesion), which is followed by fibrinogen­mediated, platelet-platelet interaction (aggregation). Simultaneously, platelets release their intracellular granule contents (secretion), which leads to the recruitment of additional circulating platelets (amplification).

d

P EC P Figure 14-2  Anatomy of a platelet plug. Electron micrograph of a group of platelets (P) attached to an endothelial cell (EC) in the initial platelet plug formation. Several dense granules (d) and alpha granules (α) are visible. The central platelet shows long dendritic extensions or  filopodia (F). (Courtesy of Dr. Lucio Díaz-Flores.)

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regardless of the mode of platelet stimulation. The importance of GPIIb-IIIa integrin is illustrated by Glanzmann thrombasthenia, a bleeding disorder caused by mutations in the gene for either the αIIb or the β3 subunit,16 and by the clinical utility of GPIIb-IIIa antagonists as antithrombotic agents in the treatment of thrombotic diseases. ROLE OF PLATELETS IN THE INFLAMMATORY RESPONSE The accumulation of leukocytes in tissue is an essential event for the inflammatory response. The current paradigm of leukocyte extravasation requires a multistep cascade of sequential leukocyte–endothelial cell interactions, in which members of three different families of adhesion receptors participate: selectins, integrins, and the immunoglobulin superfamily.54 Platelets contribute in many ways to leukocyte accumulation in the inflammatory foci (Table 14-2). In flowing blood, leukocytes roll on adherent activated platelets, mainly through the interaction of platelet Pselectin with its major leukocyte ligand, PSGL-1.55-57 This initial rolling of leukocytes on platelet P-selectin is followed by their firm adhesion and subsequent migration, processes that depend on the leukocyte integrin Mac-1 (αMβ2, CD11b/CD18).57,58 Mac-1 adheres firmly to platelets through direct binding to Glycoprotein Ibα (GPIbα, CD42b).59 These interactions provide molecular mechanisms for leukocyte recruitment to hemostatic plugs where platelets have been previously deposited in response to vascular injury.60,61 Parallel lines of investigation have shown that resting platelets are able to roll on activated endothelial cells,62 apparently through an interaction between PSGL-1 expressed in platelets and the endothelial P-selectin.63 The physiologic function of platelet rolling on stimulated endothelial cells needs to be clarified. If this contact results in activation of platelets, however, those platelets may release proinflammatory mediators, such as cytokines, chemokines,64,65 and eicosanoid precursors,66-68 or growth factors that stimulate tissue healing. Activated platelets in circulation stimulate secretion of Weibel-Palade bodies from endothelial cells in vivo, which leads to P-selectin-mediated leukocyte rolling.69 Considering the important role of platelet P-selectin in the chronic inflammatory processes,70,71 this effect of activated platelets might represent an important pathway of platelet-induced inflammation. In addition to the adhesion molecules, activated platelets express on their surface two major proinflammatory mediators: platelet-activating factor (PAF) and CD40 ligand (CD154). PAF is a potent platelet aggregating phospholipid produced by macrophages, mast cells, platelets, endothelial cells, neutrophils, and monocytes. On cell activation, PAF is rapidly synthesized and translocated to the plasma membrane of endothelial cells, where it recognizes its receptor in neutrophils, resulting in β2 integrin–mediated adhesion of leukocytes to the endothelial surface.72 In the same way, PAF can signal neutrophils when it is displayed on the surface of adherent activated platelets acting in cooperation with P-selectin to tether neutrophils.72 The biologic action of PAF is physiologically inactivated by a plasma and cellular acetylhydrolase.73 A role of PAF in the pathogenesis of chronic inflammatory arthritis has been proposed74,75;

Table 14-2  Platelet Components Implicated   in the Inflammatory Response Platelet Component

Actions

Surface molecules P-selectin (CD62-P), Adhesive targets for PECAM (CD31), GPIbα leukocytes PAF, ROS Neutrophil activation CD154 (CD40 ligand) Agonist for   endothelial cells Soluble factors

Serotonin, histamine

Regulators of vascular permeability β-Thromboglobulin, PF4 Chemotaxis Acid hydrolases, ROS Tissue destruction PDGF, TGF-β Cellular mitogens, chemoattractant

End products of Thrombin, fibrin platelet procoagulant activity

Promote leukocyte accumulation

GPI, glycosylphosphatidylinositol; PAF, platelet-activating factor; PDGF, platelet-derived growth factor; PECAM, platelet-endothelial cell adhesion molecule; PF4, platelet factor-4; ROS, reactive oxygen species; TGF, transforming growth factor.

however, a well-controlled clinical trial failed to show any beneficial effect of a PAF antagonist in patients with active rheumatoid arthritis (RA).76 CD40 is a transmembrane protein member of the tumor necrosis factor receptor family. CD40 is present on many cells, including B cells, monocytes, macrophages, dendritic cells, and vascular endothelial cells.77 Platelets are the major peripheral blood source of CD154, the ligand of CD40, and they express it on their surface within seconds of exposure to an agonist.78 The interaction of CD154 on activated platelets with CD40 on endothelial cells causes a proinflammatory reaction of the endothelium characterized by the expression of inflammatory adhesion molecules, such as E-selectin, vascular cell adhesion molecule-1 (CD106), and intercellular adhesion molecule-1 (CD54), and the secretion of the chemokines IL-8 (CXCL8) and monocyte chemotactic protein-1 (CCL2).78 CD154 expressed on activated platelets can provide a potent stimulus to the inflammatory response. Clinical data suggest that the blockade of CD154 may induce a prothrombotic state in patients with lupus79 through a mechanism that needs to be clarified. When platelets adhere, they release numerous growth factors, such as PDGF, TGF-β, and other factors that are chemotactic for monocytes, macrophages, and fibroblasts. These growth factors may play an important role in the chronic inflammatory response by mediating a fibroproliferative response. PDGF is a homodimer or heterodimer molecule of A and B chains80 produced by platelets, monocytes or macrophages, endothelial cells, and vascular smooth muscle cells (under some conditions). This molecule plays an essential role in tissue repair and wound healing.81 PDGF is a potent mitogen and chemoattractant for smooth muscle cells, connective tissue cells, and macrophages,82-85 which ­contributes to the formation of lesions of atherosclerosis,85,86 a disorder strongly related to the inflammatory response.87 It has been shown that PDGF is a potent mitogen for synovial fibroblasts isolated from patients with RA.88 TGF-β has three isoforms (TGF-β1, TGF-β2, and TGFβ3) secreted by virtually all cell types as latent complexes that need to be processed to exhibit biologic activity.89 Several effects have been associated with TGF-β: (1) It is

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chemotactic for various cell types, including leukocytes; (2) it inhibits proliferation of most cells; (3) it induces the synthesis and deposition of extracellular matrix, and (4) it stimulates the formation of granulation tissue.90 The net result is that TGF-β is mainly an inhibitor of the inflammatory response.91,92 The systemic administration of TGF-β1 has antagonized the development of polyarthritis in susceptible rats.93 Carefully regulated expression of active TGF-β is essential for resolution of inflammation and repair. Overproduction of this cytokine has been associated with several fibrosis processes,94-96 including scleroderma. Several reactive oxygen species are released from unstimulated platelets and after platelet stimulation with agonists such as collagen or thrombin.97,98 Because reactive oxygen species have been implicated in direct tissue injury and in inflammatory reactions through the promotion of adhesive interactions between inflammatory and endothelial cells,99 reactive oxygen species originating from platelets may act as an autocrine or paracrine mediator that participates in the amplification of the inflammatory response in disorders such as rheumatic diseases.

PLATELETS AND RHEUMATIC DISEASES ALTERATIONS IN PLATELET NUMBERS IN RHEUMATIC DISEASES Increases in platelet counts have three major causes: (1) reactive or secondary thrombocytosis; (2) familial thrombocytosis; and (3) clonal thrombocytosis, including essential thrombocythemia and related myeloproliferative disorders. The platelet count is frequently elevated in patients with active RA and juvenile chronic arthritis, owing to reactive thrombocytosis. The level of thrombocytosis correlates with clinical and laboratory parameters of disease activity. Relapses of RA are often accompanied by increases in platelet count, whereas remissions are associated with their reduction, to normal limits.100 This activity indicates that the thrombocytosis observed in patients with rheumatic disease is reactive or secondary to the chronic inflammatory process. Although the mechanism involved in this thrombocytosis is uncertain, increased intravascular coagulation with a compensatory increase in platelet production has been suggested as a possible cause.101 More recently, several studies have suggested that inflammatory cytokines with a minor role in the physiologic production of platelets, such as IL-6, IL-1, or tumor necrosis factor-α, among others,102-105 may be active mediators in the regulation of thrombopoiesis during the reactive thrombocytosis that occurs in the inflammatory process. Reduced platelet count, or thrombocytopenia, is ­common in rheumatic diseases. The mechanisms involved in thrombocytopenic states are reduction in platelet ­ production, sequestration, and rapid platelet destruction. Several drugs used in rheumatic diseases are able to suppress the bone marrow. Among drugs that can produce thrombocytopenia because of megakaryocytic hypoplasia are gold, cyclophosphamide, methotrexate, penicillamine, and azathioprine. The effect these compounds have on suppressing megakaryocyte replication depends on the time and dose of exposure; reduced elimination of these drugs places patients at increased risk for this complication.106

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The normal spleen contains about 30% of the platelet mass, and splenomegaly can result in a low circulating count without reduction in the platelet life span.107 Several rheumatic diseases may lead to this type of thrombocytopenia. The most well known is Felty’s syndrome, an uncommon but severe subset of seropositive RA complicated by granulocytopenia and splenomegaly. In this disorder, thrombocytopenia usually is not life-threatening. Another related disease is immune-mediated platelet destruction,108 a disorder termed idiopathic thrombocytopenic purpura. Autoantibodies cause idiopathic thrombocytopenic purpura, and platelet surface proteins, including GPIIbIIIa, GPIb-IX, GPIa-IIa, GPIV, and GPV can be antigenic targets of such autoantibodies.109,110 Circulating platelets coated with IgG autoantibodies undergo an accelerated clearance through Fcγ receptors expressed by macrophages in the spleen and liver. In some cases of idiopathic thrombocytopenic purpura, platelet production seems to be reduced, either by intramedullary destruction of antibody-coated platelets or by the inhibition of megakaryocytopoiesis.111 The level of thrombopoietin is not increased,112 suggesting a normal megakaryocyte mass. Idiopathic thrombocytopenic purpura is present in 15% to 25% of patients with systemic lupus erythematosus113 and in about 25% of patients with antiphospholipid syndrome.114 The outcome in these cases is rarely severe. In contrast, the thrombocytopenia that occurs during episodes of systemic vasculitis has a more complex pathogenesis, a worse clinical course, and a poorer outcome.115,116 Immune thrombocytopenia is rare in RA except when related to therapy. Among the drugs that can produce thrombocytopenia in RA, intramuscular gold salts are the most clearly associated with drug-induced immune thrombocytopenia. About 1% to 3% of patients receiving intramuscular gold salts for the treatment of RA develop a thrombocytopenia, which may be life-threatening. Although, as stated previously, bone marrow suppression can occur in patients undergoing gold treatment, thrombocytopenia is usually due to immune destruction of platelets associated with an active marrow.117,118 ROLE OF PLATELETS IN THE PATHOGENESIS OF RHEUMATIC DISEASES The role that platelets play in the amplification of the inflammatory response provides a basis for their involvement in rheumatic diseases. Most of the available evidence implicating platelets in the pathogenesis of rheumatic disorders is indirect and circumstantial, however. Platelets have been implicated in the pathogenesis of RA2 based on several studies that have documented the presence of platelets in the synovial fluid of RA patients119,120 and mainly on the observation that labeled platelets localize only to joints with clinically active inflammation.121 Levels of plasma-soluble P-selectin are increased in RA patients compared with controls,122 indicating platelet activation in this disease. A direct correlation has been described between platelet-derived microparticle levels and disease activity in RA patients, which suggests that generation of platelet mi­ cro­particles49 contributes to the pathogenesis of RA. Several studies have focused on the presence of activated platelets in patients with systemic lupus erythematosus.123-125 The risk

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for thrombosis is increased significantly in these patients, and platelets have been implicated in the prothrombotic state of systemic lupus erythematosus through the release of microparticles52 and by the increased deposition of complement-activation product C4d on platelet surface.126 Patients with essential thrombocythemia have an increased prevalence of antiphospholipid antibodies, which may be associated with a higher risk of thrombosis.127 The presence of activated platelets and enhanced aggregation of platelets have been described in patients with antiphospholipid syndrome,124 systemic sclerosis,128,129 and primary Raynaud’s phenomenon.128 INHIBITION OF PLATELET FUNCTION BY PHARMACOLOGIC AGENTS Nonsteroidal anti-inflammatory drugs (NSAIDs) are a foundation of therapy in many rheumatic diseases. NSAIDs inhibit prostaglandin synthesis130 through the blockade of cyclooxygenase. These agents can interfere with platelet aggregation and secretion131,132 through the inactivation of platelet cyclooxygenase-1. In platelets, this enzyme is a rate-limiting step in the transformation of arachidonic acid into thromboxane A2, a potent platelet-aggregating agent. In addition, some NSAIDs reduce platelet aggregation by interfering with the activation of GPIIb-IIIa, through a cyclooxygenase-independent mechanism.133 NSAIDs inhibit platelet function and can lead to bleeding complications in patients with rheumatic diseases. The development of potent new antithrombotic agents also may provide new weapons in the treatment of rheumatic diseases. Among these are ticlopidine and its analogue, clopidogrel, two inhibitors of the of the P2Y12 ADP receptor. These agents have greater efficacy than aspirin for prevention of recurrent stroke134 and may find a place in the antirheumatic armamentarium as a result of their anti-inflammatory properties.135,136 Agents that interfere directly with the adhesive function of integrin GPIIb-IIIa137 have come into therapeutic use. This new group of agents includes monoclonal antibodies, peptides, and other small molecules that have been approved for intravenous coronary angioplasty and stent procedures. Orally active GPIIb-IIIa blockers have been developed for long-term therapy, including secondary and even primary prevention of thrombotic diseases. Available data from the clinical trials of these oral agents have failed to show clinical benefits, however, whereas they have shown unexplained increased mortality.138 Acknowledgments This work was supported by grants from the NIH and FIS FIS04/1275 from Instituto de Salud Carlos III of Spain.

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effector mechanisms in autoimmunity and inflammation

15

Autoimmunity Richard M. Siegel  •  Peter E. Lipsky

KEY POINTS Autoimmune diseases can be classified along two axes—organ-specific versus systemic and adaptive versus innate. Autoreactivity is much more common than autoimmune disease and does not always result in illness. Animal models of autoimmune disease allow detailed study of specific features of autoimmunity, but rarely model an entire disease. Autoimmune diseases can best be understood as resulting from multistep processes beginning with loss of self-tolerance and requiring the development of auto­ reactivity and the initiation of effector mechanisms. Genetic and environmental factors contribute to autoimmune diseases. Common genetic polymorphisms modulate susceptibility to multiple autoimmune diseases. Single-gene autoimmune diseases are rare, but give insights into disease pathogenesis. Successful biologic therapies often target key pathways in autoimmune disease pathogenesis.

OVERVIEW OF AUTOIMMUNE DISEASE PATHOGENESIS The human immune system has evolved to recognize and contain a wide variety of potentially pathogenic micro­organisms. Operationally, the immune system can be divided into innate and adaptive arms. The innate immune system, consisting of phagocytes, natural killer (NK) cells, dendritic cells (DCs), epithelial surfaces, and a variety of antigen-nonspecific soluble molecules, functions as a first line of host defense, and greatly influences the type of immune response that is ultimately generated.1 The adaptive immune system, consisting of B cells and T cells and their secreted products, amplifies, focuses, and allows recall of antigen-specific immune responses. Innate immune recognition is “hard-wired” by a fixed number of surface and intracellular receptors, whereas the cells of the adaptive immune system recognize antigen with surface receptors encoded by DNA segments that can rearrange and, in the

case of B cells, mutate to enable specific recognition of an almost limitless variety of antigens (see Chapters 16 and 17). T cells are distinguished by the presence of the T cell receptor (TCR) for antigen and recognize antigens presented by major histocompatibility complex (MHC) molecules on antigenpresenting cells. B cells (see Chapter 10) are identified by the expression of surface immunoglobulin, which functions as the specific B cell receptor (BCR) for antigen. Adaptive immunity also has the special property of immunologic memory, allowing a more prompt and specific immune response to occur with repeated exposure to a pathogen. The type of priming provided by innate immune cells significantly influences the specificity, type, and strength of an adaptive immune response.2 Conversely, cytokines and antibodies produced by adaptive immune cells can activate innate immune cells, creating a potential positive feedback loop that can maintain autoimmunity. Normally, the immune system does not make pathogenic responses to the individual’s own tissues. This selective unresponsiveness to self-antigens, termed immunologic tolerance, has long been recognized as a fundamental feature of the normal immune system. The balance between the need to respond to the universe of potential pathogens and the need to prevent autoimmunity is imperfect, however. Consequently, about 5% of humans have autoimmune and chronic inflammatory diseases that stem from unregulated activation of the immune system and failure of self-tolerance. REQUIREMENTS FOR SELF-RECOGNITION AND TISSUE DAMAGE Autoimmune diseases are a heterogeneous group of disorders in which recognition of self-antigens by lymphocytes is centrally involved in pathologic organ damage. Not all immune-mediated destruction of self-organs is autoimmune in nature. The liver damage that occurs in hepatitis B infection is primarily due to immune responses directed at the virus and not at liver self-antigens. In contrast, some autoimmune diseases, such as rheumatic heart disease, may be triggered initially by the immune response to an infectious organism, but the pathologic response is autoimmune in nature because of cross-reactivity between bacterial and host antigens. In chronic Lyme arthritis, disease progression 259

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may be antibiotic resistant, and Borrelia burgdorferi antigens may be undetectable, but the T cells isolated from joints continue to show reactivity to this bacterium’s outer surface protein A antigens.3 A subset of these T cells can cross-react with a normal lymphocyte surface protein, lymphocyte function–associated protein 1.4 Whether chronic Lyme arthritis depends on T cells directed to undetectable but present bacterial antigens or cross-reactive autoimmune responses has yet to be determined. Autoantibodies associated with systemic autoimmune diseases, such as anti–double-stranded DNA (dsDNA) in systemic lupus erythematosus (SLE), are present in genetically diverse individuals with the disease and in many different animal models. After the discovery that innate and adaptive immune cells express invariant receptors for pathogen-­encoded molecular patterns, it was found that many autoantigens have the ability to stimulate these receptors, activating immune cells in parallel with their recognition by the TCR or BCR. This type of molecule has been termed an autoadjuvant because of similarity to immune adjuvants that are derived from or mimic infectious agents.5 This principle may apply to innate immune cells as well; certain chemical structures, such as crystalline uric acid, can initiate inflammation in neutrophils through cross-reactive activation with the intracellular receptor CIAS1 (also known as NALP3 or NLR family, pyrin domain containing 3), which normally recognizes pathogen-derived muramyl dipeptides and nucleic acids.6,7 As is well known clinically, however, autoimmune responses do not follow uric acid–induced inflammation in gout, suggesting that other steps are necessary to progress from inflammation to autoimmunity. CLASSIFYING AUTOIMMUNE AND AUTOINFLAMMATORY DISEASES BY PATTERN OF ORGAN DAMAGE AND EFFECTOR CELL TYPE Autoimmune diseases traditionally have been categorized as organ specific or systemic or both. Examples of common organ-specific autoimmune diseases include thyroiditis, in which damage to thyroid cells may lead to hypothyroidism; type 1 diabetes, in which the insulin-secreting beta cells in pancreatic islets are destroyed; and multiple sclerosis, in which central nervous system myelin is damaged. Many organ systems are targeted by organ-specific autoimmune diseases (Table 15-1). In these diseases, it is rare to find evidence of systemic inflammation or production of autoantibodies to antigens other than those found in the target organ, although expanded clones of T cells and B cells directed against the target organ have been detected in peripheral blood by sensitive means.8,9 The organ-­specific autoimmune diseases may represent examples of normal immune responses that produce disease because they are “misdirected” against a self-antigen or organ. Organ-specific autoimmune diseases can be classified into groups depending on whether pathology is mediated primarily through autoantibodies or autoreactive T cells (see Table 15-1). In Graves’ disease, antibodies bind to the thyroid-stimulating hormone receptor and cause hyperthyroidism. In contrast, T cells seem to be primarily responsible for the myelin damage and neurologic deficits in multiple sclerosis, although antibodies to myelin-associated antigens also may play a role. The presence of autoantibodies does not imply a role in pathogenesis

because autoantibodies can just be a marker of the underlying T helper cell response or reflect benign responses to damaged tissue. Such a scenario may occur in type 1 diabetes, in which IgG autoantibodies to insulin and other pancreatic islet cell antigens are generated, but islet cell destruction seems to be mediated primarily by CD4+ and CD8+ T cells. By contrast, in systemic autoimmune diseases, multiple organs are targets for immune attack, and chronic activation of innate and adaptive immune cells is usually present. SLE is considered to be the prototypic systemic autoimmune disease, and IgG autoantibodies directed to different autoantigens are primarily responsible for the multitude of possible clinical manifestations (see Chapter 74). Although CD4+ T cells may not directly cause tissue damage in SLE, they can provide immunologic “help” for the generation of pathogenic autoantibodies. Rheumatoid arthritis (RA) is commonly characterized as an organ-selective or joint-selective disease process, but it is systemic in that autoantibodies to organ-nonselective autoantigens, such as rheumatoid factor and citrulline-containing proteins, are usually present. Severe arthritis in RA is usually associated with these autoantibodies and often accompanied by extra-articular manifestations (see Chapter 66). Just as the immune system can be thought of as divided into innate and adaptive arms, rheumatic and other immune-mediated diseases can be thought of as lying on a spectrum in which the primary pathology is mediated by cells of the innate or adaptive immune system, or a combination of both.10 Rheumatic diseases can be placed on these two classification axes (Fig. 15-1). In organ-specific autoimmune diseases and SLE, tissue damage is primarily mediated by T cells and B cells, putting this disease in the autoimmune/adaptive category. There are many rheumatic diseases, however, in which there is inflammation and tissue damage without evidence of abnormal adaptive immune cell activation or involvement of autoantigen-specific T cells or B cells in the pathophysiology of the disease. Numerous single-gene diseases that share the symptoms of periodic fevers, episodic arthritis, and chronic elevation of acute-phase proteins, such as familial Mediterranean fever, tumor necrosis factor (TNF) receptor–associated periodic syndrome, and neonatal-onset multisystem inflammatory disease, involve activation of innate immune cells and tissue damage related to amyloid deposition without any evidence of lymphocyte activation or autoantibody production. Because of the prominent inflammatory component and lack of B cell or T cell involvement, these diseases have been termed autoinflammatory to distinguish them from other autoimmune conditions. Systemic juvenile RA, adult Still’s disease, and gout are polygenic diseases in which innate immune system activation predominates and are being recognized as part of the spectrum of autoinflammatory disease. Often, immune damage seems to result from collaboration between adaptive and innate immune mechanisms. In RA, activation of the innate immune system can lead to tissue damage through the action of inflammatory cytokines on tissue cells, but there also is evidence to suggest the involvement of T cells and B cells in the pathogenesis of RA. Similar data exist for inflammatory bowel disease. As discussed subsequently, autoimmune disease can be sustained by a positive feedback loop reinforcing the activation of adaptive and innate immune cells.

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Examples of Organ-Specific Autoimmune Diseases

Organ

Disease(s)

Self-Antigen (Example)

Major Autoimmune Mechanism

Adrenal cells

Addison’s disease

Cytochrome P-450 antigens

Autoantibodies

Brain/spinal cord

Multiple sclerosis

Myelin proteins (myelin basic   protein)

T cells

Eye

Uveitis

Uveal antigens

T cells

Gastrointestinal tract   Stomach

Pernicious anemia

Gastric parietal cell antigens   (H+/ATPase, intrinsic factor) Transglutaminase Unknown Myocardial cell proteins (myosin) Myocardial antigens

Autoantibodies/T cells Autoantibodies/T cells T cells Autoantibodies/T cells Autoantibodies

Platelet antigens (GP llb/llla)

Autoantibodies

  Red blood cells   Neutrophils   Kidney/lung

Idiopathic thrombocytopenic   purpura Autoimmune hemolytic anemia Autoimmune neutropenia Goodpasture’s syndrome

Red blood cell membrane proteins Neutrophil membrane proteins Basement membrane antigens   (type IV collagen α3 chain)

Autoantibodies Autoantibodies Autoantibodies

Liver   Bile duct cells

Primary biliary cirrhosis

Autoantibodies/ T cells

  Hepatocytes

Autoimmune hepatitis

Intrahepatic bile duct/­mitochondrial antigens/2-oxoacid   dehydrogenase complexes (­pyruvate dehydrogenase   complex protein) Hepatocyte antigens   (cytochrome P450IID6)

Muscle

Myasthenia gravis

Acetylcholine receptors

Autoantibodies

Pancreatic islets

Type 1 diabetes

Beta cell antigens (glutamic acid decarboxylase, insulin)

T cells (autoantibodies present)

Skin

Pemphigus/other bullous diseases

Desmogleins

Autoantibodies

Testes/ovaries

Orchitis/oophoritis

Unknown/multiple

Autoantibodies

Thyroid

Hashimoto’s thyroiditis

Thyroid cell antigens   (e.g., thyroglobulin) Thyroid-simulating hormone   ­receptor

T cells/autoantibodies

  Small bowel   Large bowel   Heart Hematopoiteic system   Platelets

Celiac sprue (gluten enteropathy) Ulcerative colitis or Crohn’s disease Myocarditis Rheumatic heart disease

Graves’ disease

T cells/antibodies

Autoantibodies

ATPase, adenosine triphosphatase; GP, glycoprotein.

AUTOIMMUNE DISEASE VERSUS AUTOREACTIVITY Although many self-reactive T cells and B cells are eliminated during immune cell development during the establishment of central immune tolerance, it is clear from many lines of evidence that many self-reactive cells do survive to populate the immune system. These self-reactive lymphocytes can become pathogenic if not held in check by numerous mechanisms collectively referred to as peripheral immune tolerance. In experimental animal models of organ-specific autoimmune disease, peripheral tolerance can be “broken” through immunization with self-antigens in the presence of strong innate immune stimulants, termed adjuvants, which provoke sustained activation of self-reactive lymphocytes and autoimmune disease. Regulatory T cells are enriched in autoreactive specificities and play a role in maintaining peripheral tolerance, as discussed subsequently. Nonpathogenic, autoreactive B cells exist in the normal peripheral immune system, and they can be identified more easily by the antibodies that their progeny secrete. A large fraction of serum immunoglobulins in healthy animals and humans binds to self-antigens, and these have been labeled “natural” autoantibodies (see Chapter 10). Most of these

antibodies are IgM, bind to self-antigens with low affinity, frequently cross-react with multiple antigens, and are independent of T cell help for production. Natural autoantibodies seem to be an important component of the normal immune system, and B cells with these self-specificities are positively selected during development. Their cross-reactivity to bacterial glycoproteins or glycolipids may be part of the early immune response to pathogens. Natural autoantibodies also function to help in the clearance of senescent cells or cell constituents after cell death or in the removal of immune complexes. Studies in humans and mice also suggest that a major portion of these autoantibodies are secreted by the B-1 B cell lineage, including CD5+ B cells (see Chapter 10). In mice, the genetic origin and characteristics of pathogenic autoantibodies are thought to be different from those of natural autoantibodies. The origin of natural autoantibodies in humans is less clear, however. B cells whose progeny produce natural autoantibodies should be recognized as another component of the normal immune system and distinguished from potentially pathogenic B cells. Even autoantibodies thought of as being associated with autoimmune disease, such as rheumatoid factor or antinuclear antibodies, are found in a small subset of the ­normal

SIEGEL 

Polygenic diseases

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Autoimmunity

Monogenic diseases

Autoimmune/ adaptive

Organ-specific

Organ-specific IPEX autoimmune diseases APCED (see Table 15-1)

Environment

ALPS

Systemic lupus erythematosus

Multiple sclerosis Rheumatoid arthritis Inflammatory bowel disease Gout and other crystal arthropathies

E.g., smoking, UV light, infectious agents

Individual

Genetic factors

Innate immune responsiveness Self-limiting nonspecific inflammation

Systemic

262

Familial fever syndromes

Host defense genes (TLR7, FcR, TNF)

Adaptive immune system activation Loss of selftolerance

Systemic JRA Immunoregulation (Treg, clonal deletion, anergy)

Gender, ethnic origin

Proinflammatory cytokines

Immune-response genes (HLA-DR, PTPN22, FcRIIB, IL-10, CTLA4, PD-1, Fas)

Autoinflammatory/innate Figure 15-1  Classification of autoimmune and rheumatic diseases. Specific diseases are grouped according to the two axes described. ­Organ-specific autoimmune diseases are described in more detail in Table 15-1. ALPS, autoimmune lymphoproliferative syndrome; APECED, autoimmune polyendocrinopathy syndrome, with candidiasis and ectodermal dysplasia; IPEX, immunodysregulation, polyendocrinopathy, and enteropathy, X-linked (syndrome); JRA, juvenile rheumatoid arthritis.

population without apparent consequence, particularly older individuals and first-degree relatives of patients with autoimmune disease. Other autoantibodies, such as anticitrullinated peptide antibodies in rheumatoid arthritis, and anti-DNA and anti-Sm in SLE, seem to be more specifically associated with a particular autoimmune disease. This finding indicates that the mere presence of these antibodies does not produce autoimmune disease. In individuals who do develop autoimmune disease, retrospective studies have shown that characteristic autoantibodies can precede the development of autoimmune disease by years.11 Potentially pathogenic autoantibodies can be induced by certain infections, drugs, or tissue injury. Examples include the production of antinuclear antibodies after treatment with drugs such as procainamide and hydralazine and the development of anticitrullinated peptide antibodies in smokers with certain HLA haplotypes linked to RA susceptibility.12 Some of these antibodies, as in the case of drug-induced SLE, can result in pathologic consequences, but in these cases, autoantibodies usually are transient and disappear in weeks to months. MODEL FOR THE PATHOGENESIS OF AUTOIMMUNE DISEASE Because autoreactive lymphocytes are present in the normal mature immune system, the pathogenesis of autoimmune disease must involve escape by these cells from normal immune regulation, the perpetuation of these responses, and induction of immunopathology. Figure 15-2 presents a conceptual framework for the pathogenesis of autoimmune disease. Considerable evidence from genetic epidemiology, association, and linkage studies indicates that the development of most autoimmune diseases has a strong genetic basis (see Chapter 18). Except in certain rare diseases, autoimmune

Autoaggressive T cells

Autoantibody production

Autoimmunity Tissue damage

Tissue-response genes

Figure 15-2  Steps and pathways influencing the development and perpetuation of autoimmune diseases. Environmental (external, e.g., UV light, and internal, e.g., cytokine milieu) factors are listed in the left column, and genetic factors are listed in the right column.

disease is inherited as a complex trait, with multiple loci controlling various aspects of disease susceptibility. More recently, some of these susceptibility genes have been identified, and these are listed in the right-hand column of Figure 15-2. The contribution of susceptibility genes may occur at several levels, from the breakdown of tolerance to immune-mediated end-organ damage (Table 15-2). Certain environmental influences, such as cigarette smoke, ultraviolet light, or infectious agents, may interact with this genetic predisposition to result in disease, although for most autoimmune diseases, the exact environmental triggers are undefined. As in conventional immune responses, evidence is emerging that activation of autoimmune B cells and T cells can be influenced by innate immune receptors, such as Toll-like receptors (TLRs), which primarily recognize pathogen-derived molecular structures but may cross-react with host molecules, particularly nucleic acids. A second phase of autoimmune disease pathogenesis involves conversion from transient to sustained T cell or B cell activation, which may perpetuate autoimmune disease in a “vicious circle” of positive feedback. As depicted in the lower part of Figure 15-2, autoreactive T cell and B cell activation can lead to tissue damage through autoantibodies, direct attack of tissues by autoreactive T cells, and cytokine production. Signals released from damaged tissues, such as cytokines, recruit and activate macrophages and neutrophils. Unscheduled necrotic cell death secondary to tissue damage or production of apoptotic blebs containing nuclear antigens may lead to more release of self-antigens. In the presence of autoantibodies, these antigens can form

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Table 15-2  Selected Susceptibility Genes for Autoimmune Diseases Gene Product

Animal Model

Human Disease

Function

Principle Illustrated

References

ZAP-70

SKG mouse

—

T cell receptor signal ­transduction

Weak T cell receptor signaling can   block deletion of autoreactive ­thymocytes

28

Fas

MRL lpr/lpr   mouse

ALPS

Induction of programmed cell death

Apoptosis eliminates   autoreactive immune cells

159, 160

TLR7

BSXB yaa   mouse

—

Sensing single-stranded RNA in endosome

Increased levels of TLR7 can lead to B cell hyperactivation

22, 23

AIRE

AIRE knockout mouse

APECED

Regulates transcription of   self-antigen genes in the thymus

Tissue-restricted antigens need to be expressed in the thymus for deletion of autoreactive ­thymocytes

27

Roquin

San Roque   mouse

—

Ubiquitin ligase, suppresses follicular helper T cells and interleukin-21

Follicular helper T cells and   interleukin-21 can promote ­autoimmunity

48

FoxP3

Scurfy mouse; FoxP3   knockout

IPEX

Transcription factor ­crucial for induction and maintenance of regulatory T cells

Regulatory T cells essential in ­maintaining self-tolerance of ­peripheral T cells

119, 120

Complement   C4

C4 knockout

C4 deficiency

Classic complement component, aids in rapid clearance of ­immune complexes

Clearance of immune complexes   suppresses autoimmunity

161

CTLA4

CTLA4­knockout

Linked to multiple autoimmune diseases

Negative regulator of T cell activation

Regulation of T cell activation ­suppresses autoimmunity

77

ALPS, autoimmune lymphoproliferative syndrome; APECED, autoimmune polyendocrinopathy syndrome, with candidiasis and ectodermal dysplasia; IPEX, immunodysregulation, polyendocrinopathy, and enteropathy, X-linked (syndrome).

immune complexes and become immunostimulatory, providing “fuel for the fire” of autoimmunity.13 Numerous immunoregulatory mechanisms can dampen or potentially terminate autoimmune tissue damage (see Fig. 15-2, lower left). Regulatory T cells (see Chapter 9) can inhibit T cell activation and cytokine production or limit the function of effector cells. Reduction of regulatory T cell function or numbers, in genetic diseases or experimentally, results in the unmasking of multiple T cell–mediated autoimmune pathologies. Elimination of autoreactive T cells through programmed cell death or rendering them “anergic” or unresponsive to TCR stimulation also has been shown to ameliorate autoimmune disease. Inflammatory cytokines, such as TNF-α and interleukin (IL)-6, have been shown to inhibit the functionality of regulatory T cells.14,15 This inhibition may sustain or allow autoimmunity to develop in the setting of chronic infection or inflammation.

INSIGHTS FROM ANIMAL MODELS AND HUMAN GENETIC DISEASES Studies using animal models have contributed greatly to understanding of the immunopathogenesis of autoimmune disease, although each model generally captures only one or a few aspects of a particular human disease. Models of disease can be divided into three broad categories based on how disease occurs, as follows: (1) spontaneous diseases, occurring because of a single gene mutation or interaction of many genes; (2) diseases induced by immunization, cell transfer, or other exogenous agent; or (3) diseases developing after genetic manipulation, usually by transgenic expression or knockout of single genes. In addition to these models of disease, genetically manipulated TCR and BCR transgenic mice have been invaluable in tracing the fate of self-­reactive T cells and B cells. In recent years, mutations

underlying an increasing number of human single-gene diseases that involve autoimmunity and inflammation have been identified, providing parallel insights into the mechanisms of autoimmunity. ANIMAL MODELS WITH SPONTANEOUS DISEASE AND HUMAN DISEASE COUNTERPARTS The animal models most similar to human autoimmune disease include strains of mice that develop a high incidence of spontaneous autoimmune disease. Polygenic models include the nonobese diabetic (NOD) mouse, which develops a disease similar to type 1 diabetes,16 and several models of lupuslike disease.17 New Zealand hybrid mice, in which crosses or inbred recombinant strains of New Zealand black (NZB) and New Zealand white (NZW) mice develop lupus-like disease, have been intensively studied as a polygenic spontaneous autoimmune disease model.17,18 As mapping of complex loci responsible for autoimmune disease models has progressed, it has become clear that many loci that strongly contribute to disease phenotype contain many linked genes that may contribute independently to disease penetrance and severity.17,18 The Sle1 locus on chromosome 1 derived from the NZW background emerged as a major determinant of disease phenotype in the NZB/NZW mouse model of SLE. Generation of congenic strains with portions of the Sle1 locus backcrossed to a nonautoimmune background revealed, however, at least four segments of this locus, designated Sle1a through Sle1d, which could independently modify the susceptibility to autoantibody formation. Within Sle1b, mutations that affect the level of expression of members of the SLAM family of surface adhesion receptors were identified that may contribute to autoimmunity by altering the threshold for deletion of autoreactive B cells.19,20 Within a separate NZB-derived locus on chromosome 1,

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Nba2, the gene interferon-inducible 202 (ifi 202) may be another immunoregulatory susceptibility gene.21 ifi 202 was found to be expressed at higher levels in autoimmune progeny, and this correlated with resistance to experimentally induced B cell apoptosis.21 As in the authentic human diseases, the genetic contributions of each locus to disease pathogenesis and the interactions between loci have proved to be exceedingly complex in polygenic models of autoimmunity. Another autoimmune susceptibility locus, the murine Y chromosome–linked autoimmune accelerator yaa, originally described in the BXSB/MpJ autoimmune-prone strain, has been shown to be caused by a translocated copy of an X-chromosomal segment that results in expression of an extra copy of TLR7.22,23 TLR7 recognizes single-stranded RNA, and cells harboring the extra copy of TLR7, including B cells, become hyperresponsive to stimulation by TLR7 agonists. Breeding TLR7 deficiency onto the MRL (lpr/lpr) autoimmune-prone strain ameliorated many features of the SLE-like disease found in these mice.24 These discoveries illustrate how small changes in expression level of key regulatory proteins, particularly cell surface receptors, can significantly alter the threshold for autoimmunity by changing the intrinsic responsiveness of lymphocytes. In contrast to most spontaneous autoimmune disease models, single-gene mutations that lead to autoimmune disease reveal crucial genes that, if mutated, can lead with high frequency to autoimmune disease. Background genes and the environment also modify the phenotype of mice carrying even these mutations, however. lpr/lpr mice, which are homozygous for the lymphoproliferation (lpr) mutation in the gene encoding the death receptor Fas, produce autoantibodies including antinuclear antibody and anti-dsDNA. On the MRL background, lpr/lpr mice develop fatal glomerulonephritis and other autoimmune disease manifestations.25 A subset of MRL (lpr/lpr) mice also develop arthritis associated with rheumatoid factor production. The Fas mutation in lpr mice abrogates expression of this TNF family receptor, which induces cell death of numerous immune cell types. A human genetic autoimmune disease, autoimmune lymphoproliferative syndrome (ALPS), was found to result from heterozygous dominant negative mutations in the Fas gene, causing a similar inhibition of Fas-induced apoptosis as in lpr/lpr mice.26 Patients with ALPS can develop a variety of autoantibody-mediated disease manifestations, chiefly autoimmune hemolytic anemia and thrombocytopenia, but rarely develop kidney disease, illustrating that effects of genetic background also are important in human singlegene autoimmune diseases. Mutations in genes that control T cell repertoire selection and signaling have been identified in many single-gene spontaneous models of autoimmunity. The autoimmune regulator (AIRE) transcription factor promotes the expression of tissue-restricted genes in the ­thymus. When AIRE is absent, deletion of T cells specific for these gene products in the thymus is impaired, and T cell–driven autoimmune destruction of numerous target organs results in AIREdeficient mice or the human disease autoimmune polyendocrinopathy syndrome, with candidiasis and ectodermal dysplasia (APECED).27 Another spontaneous arthritis model, known as the SKG mouse, has allowed insights into mechanisms controlling the generation and activation of

arthritogenic CD4+ T cells.28 SKG mice develop macroscopic hallmarks of arthritis at 8 weeks of age and produce high titers of rheumatoid factor and type II collagen–specific autoantibodies. Transfer of SKG CD4+ T cells into T cell–deficient mice led to the development of arthritis, emphasizing that arthritis in these mice is a T cell–intrinsic disease. Genetic mapping experiments revealed that these mice have a mutation in the SH2 domain of ZAP-70 that renders the T cells hyporesponsive to TCR signals. It is thought that altered signaling through the TCR leads to a selection shift during thymic development, disrupting central T cell tolerance and allowing arthritogenic cells to escape into the periphery. The disease spectrum of SKG mice varies depending on the mouse background strain and is lost when mice are bred in a pathogen-free environment, indicating that other genetic and extrinsic factors are important in producing this specific disease phenotype. ANIMAL MODELS IN WHICH DISEASE IS INDUCED BY IMMUNOLOGIC MANIPULATION A second category of experimental models depends on induction of disease in susceptible strains, typically by immunization with a self-antigen. These models usually rely on complete Freund’s adjuvant, which is a mixture of mineral oil and mycobacteria, to prime antigen-presenting cells and overcome self-tolerance, and are better models for the effector phase of autoimmune disease rather than for the study of immune tolerance. These types of models also have proved useful for evaluating the effect of a specific gene or pathway in a disease process through performing the experiment in the presence of neutralizing antibodies against mediators of that pathway or in gene knockout mice. Although most of these immunization models use organ-specific antigens (e.g., myelin basic protein, acetylcholine receptor, thyroglobulin, retinal antigens, type II collagen), some models have used ubiquitous nuclear antigens to induce lupus-like autoantibodies and disease.29 One well-studied induced disease model relevant to inflammatory arthritis in humans is collagen-induced arthritis (CIA), in which mice or rats are usually immunized with type II collagen isolated from bovine, chicken, or human cartilage.30,31 In susceptible mouse strains, cross-reactivity of immune responses to murine type II collagen, involving autoreactive T cells and autoantibodies, results in the development of peripheral arthritis. This model has provided insight into the effector mechanisms that lead to inflammation in patients with arthritis. Other cartilage proteins also can be used to induce arthritis in susceptible mice.32 Despite synovial pathology reminiscent of RA, it is unclear whether these rodent models of induced arthritis are ­ recapitulating the specific immune responses in RA. None results in rheumatoid factor production, although a more recent study showed induction of antibodies against cyclic citrullinated peptides and suggested a pathogenic role for these antibodies in CIA.33 Another class of animal models of induced autoimmunity involves depletion of natural regulatory T cells, either through neonatal thymectomy or through mutation of the X-linked regulatory T cell–specific transcription factor FoxP3 in the scurfy mouse. These mice develop multiorgan autoimmunity (including gastritis, oophoritis/orchitis, and

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thyroiditis). The human syndrome of immunodysregulation, polyendocrinopathy, and enteropathy, X-linked, also has been linked to loss-of-function FoxP3 mutations and results in a similar constellation of findings, including autoantibody production, but not arthritis or glomerulonephritis. When T cells depleted of regulatory T cells are transferred into immunodeficient hosts, extensive division and differentiation of these T cells occurs, and autoimmune disease, principally colitis, results. Colitis can be prevented by the simultaneous transfer of regulatory T cells.34,35 Graft-versus-host disease induced by the injection of allogeneic lymphocytes shares many features with SLE, including autoantibody production, and has been used as a model for understanding the steps that lead to autoantibody production in the setting of strong T cell stimulation by a pseudo–self-antigen. ANIMAL MODELS WITH AUTOIMMUNE DISEASE AFTER GENETIC MANIPULATION A third category of experimental disease model involves engineered manipulations of the mouse genome. Numerous genetically engineered mouse strains with single-gene gain or loss of function develop autoimmunity, with varied underlying mechanisms. Lupus-like disease has resulted from genetic deficiencies that cause defects in lymphocyte apoptosis, unregulated B cell or T cell activation, defects in the ability to clear apoptotic cells or cellular debris, and altered cytokine production.36,37 Mice with gene knockouts of IL-2, IL-2 receptor, IL-10, or depletion of various T cell subsets have been shown to develop inflammatory colitis.37 In some cases, the background strain of the knockout mouse can alter greatly the form of immunopathology that ensues. IL-2 gene knockouts can lead to inflammatory colitis or autoimmune hemolytic anemia, depending on the background strain. Knockout of the gene that encodes the type IIB low-affinity receptor for IgG (FcRIIB) results in a severe lupus-like syndrome when bred on one type of nonautoimmune (C57BL/6) background, but almost no pathology on a different nonautoimmune (BALB/c) background.38 This genetic deficiency results in unregulated B cell activation; the reason for the different expression on the two different genetic backgrounds is currently unclear. The single-gene models do not recapitulate the complex genetics of human autoimmune disease, but are useful to point to particular genes and mechanistic pathways for study in human disease. Knockout mice have provided at least a partial basis for genetic studies in humans that have identified SLE patients with deficient DNase I genes39,40 and with variant alleles of the gene encoding programmed death-1 (PD-1), which negatively regulates T cells and B cells after activation.41,42 Genetic manipulations have produced surprising systems to study the development of autoimmune disease, including arthritis. A model generating wide interest (referred to as the K/B x N model) involves mice with transgenes encoding a TCR that recognizes a foreign antigen (bovine ribonuclease) in the context of the mouse MHC class II allele, I-Ak. As in other TCR transgenics, nearly all of the T cells in these mice express one type of TCR. When these TCR transgenic mice are bred with mice expressing a different MHC class II molecule (I-Ag7 from the NOD strain), the progeny develop a severe and destructive arthritis with histologic features reminiscent of RA.38 These investigators subsequently showed

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265

that in the context of I-Ag7, the transgenic TCR recognizes a peptide derived from a glycolytic self-enzyme (glucose6-phosphate isomerase), and this unexpected cross-reactivity allows for a T cell–dependent IgG antibody response to this ubiquitous cytoplasmic antigen. Arthritis in these mice is mediated by autoantibodies, and transfer of a small amount of anti–glucose-6-phosphate isomerase autoantibody causes severe arthritis in recipients.43,44 Although different in pathogenesis from human RA, investigation of arthritis caused by injection of anti–glucose-6-phosphate isomerase antibodies has provided insights into the signaling pathways and cells necessary for initiation of arthritis downstream of autoantibody–self-antigen recognition. Experimental systems frequently have used mice expressing transgenes that encode a TCR or BCR specific for one autoantigen or for an exogenous antigen introduced genetically so as to become an autoantigen. In these mice, numerous T cells or B cells with the same autoreactive receptor can be easily identified and tracked, greatly facilitating their characterization. One of the first, and most elegant, systems of this kind is the H-Y TCR, which encodes a receptor specific for a peptide in the H-Y male-specific antigen gene. In female TCR transgenic mice, predominantly CD8+ T cells with high reactivity against H-Y develop, recapitulating the developmental fate of the CD8+ T cell from which this TCR was derived. In male mice, most transgenic T cells are deleted during thymic development, however, and the remaining T cells downmodulate CD8 and are refractory to stimulation through the TCR, illustrating multiple mechanisms for enforcing T cell self-tolerance.45 B cells in BCR transgenic mice bearing self-reactive specificities also tend to be deleted or anergized depending on the expression pattern or abundance of the self-antigen. When BCR transgenic mice encoding anti-DNA or rheumatoid factor specificities are bred onto autoimmune-prone mouse strains, these same self-reactive B cells become activated and can produce pathogenic autoantibodies.46,47 An alternative approach to discovering susceptibility genes for autoimmunity has been through using “reverse genetics,” in which the entire mouse genome is subjected to mutagenesis, and mice are inbred and screened for autoantibody production or other phenotypes similar to human autoimmune disease. Current mapping techniques can rapidly identify loci segregating with a disease phenotype, leading to identification of the culprit mutation. This approach has identified many genes that predispose to autoimmunity not discovered through other means. A previously uncharacterized Ring-type ubiquitin ligase named Roquin encoded on chromosome 1 in mice and humans was identified by this method. Roquin mutant mice develop severe autoimmune disease.48 Although the pathogenesis of disease in Roquin mutant mice is unclear, T cells producing the cytokine IL-21, a B cell growth and differentiation factor, were found in elevated levels in these mice. IL-21 also has been implicated in other models of systemic autoimmunity.

GENETIC CONTRIBUTIONS TO AUTOIMMUNE DISEASE Considerable evidence indicates that most autoimmune diseases have a strong genetic predisposition.17,18,49-51 Initially, this evidence came from genetic epidemiolog studies

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of disease prevalence within families in which there is an affected individual compared with the prevalence in the general population and from analyses of disease prevalence in monozygotic versus dizygotic twins. The concordance of rheumatic autoimmune disease in monozygotic twins ranges from 12% to 15% in RA to 24% to 57% in SLE (see Chapter 18).52 Concordances never approach 100%, however, indicating a role for the environment or epigenetic factors. Common autoimmune diseases are complex genetic traits, which, by definition, are not inherited in a simple mendelian way. By contrast, many rare autoimmune disease syndromes are inherited as single-gene diseases, and the mutations responsible for these diseases identify a special class of genes that can strongly predispose to autoimmune disease with a lesser contribution by genetic variation within the human population. For common autoimmune diseases, the low penetrance of each contributing gene (i.e., the small increase in probability of disease expression given a particular disease allele) is the main reason that autoimmune diseases are so complex genetically. Overt autoimmune disease frequently does not occur, however, even in the presence of a full complement of susceptibility alleles, as in the identical twin of an affected individual. Genetic complexity in autoimmunity also is determined by genetic heterogeneity, in which the same phenotype (e.g., anti-dsDNA autoantibody production or lupus nephritis) is the result of a different set of genes. Gene alleles that increase the risk of autoimmune disease also can occur frequently in the general population, making their identification as a disease allele difficult. Initial genetic studies of human autoimmune diseases have focused on the association of particular alleles with disease, MHC genes, and other immunologically relevant genes (see Chapter 18). Association studies are, however, potentially subject to inherent biases such that spurious associations are revealed because of the lack of appropriate controls. The interpretation of associations may be complicated further by the presence of linkage disequilibrium with the actual causal gene.49 Association studies also require an a priori hypothesis that a particular candidate gene is involved in the disease process and are not suitable to investigate the many unknown non-MHC genetic contributions to disease. Because of the availability of high-density singlenucleotide polymorphic markers covering the human genome, and the discovery of “haplotype blocks,” which reduce the number of single-nucleotide polymorphic markers that need to be tested,53,54 it is now possible to perform genome-wide screens for susceptibility loci to complex diseases.55 Screens done by numerous consortia have identified susceptibility genes for many common rheumatic diseases, many of which would likely not have been identified solely through the candidate gene approach.56 Some of the same disease-associated genetic polymorphisms have been identified in patients with different autoimmune diseases. Loci identified in a genome-wide scan of patients with RA from multiplex families also have been found to be linked in separate cohorts to inflammatory bowel disease, multiple sclerosis, and ankylosing spondylitis.57 It is well known clinically that autoimmune diseases, such as type 1 diabetes, autoimmune thyroiditis, Addison’s disease, autoimmune polyendocrine syndromes, vitiligo, and celiac disease, may cluster in some families. These observations

have raised the possibility that common susceptibility genes may contribute to multiple autoimmune diseases among related individuals. ASSOCIATION OF MAJOR HISTOCOMPATIBILITY COMPLEX GENES WITH AUTOIMMUNE DISEASES Polymorphisms in the mouse MHC or the analogous human leukocyte antigen (HLA) locus have a powerful influence on T cell and NK cell immune responses, and the HLA locus has been linked to different autoimmune diseases in multiple cohorts (see Chapter 18). The HLA region spans approximately 3.6 megabases on chromosome 6, encompasses more than 200 genes, and is highly polymorphic. The HLA locus consists of genes encoding classic class I (A, B, and C) and class II (DR, DQ, and DP) HLA molecules that present peptide antigens to CD8+ and CD4+ T cells. Many nonclassic HLA molecules that function to present protein-based and lipid-based antigens to NK/T cells bearing a restricted repertoire of αβ or γδ TCRs also reside in this locus. In addition, many other immunologically related genes, such as the TNF family members TNF, LTα, and LTβ and complement components C2, C4A, and C4B, lie within the HLA region. Tight linkage between genes in this region has often made it difficult to identify the specific HLA genes (and alleles) that explain the association of a particular haplotype (usually identified by its HLA-DR and HLA-DQ genes) with autoimmune disease. Within a given ethnic group, certain HLA-DR alleles are frequently inherited with a similar set of DQ alleles and other genes within the HLA region. Genome-wide scans have confirmed a major role for the HLA in determining the risk of developing RA, with most, but not all, of that risk conferred by polymorphisms in the DR beta chain gene (DRB) (see Chapters 18 and 65).57,58 DRB1*0401 and DRB1*0404 predominate in white patients, but other DR4 subtypes (DR4*0405, DR4*0408) and DRB1*0101, DRB1*1402, and DRB1*1001 also have been implicated in disease susceptibility. Disease-associated DR alleles all share a sequence motif at positions 67 to 74 (L-L-E-Q-R/K-R-A-A) in the third hypervariable region of the DRB1 gene. This shared segment has been called the “shared epitope.”49,58 The increased risk for disease development in carriers of one copy of a shared epitope has been estimated to be fivefold to sixfold for DRB1*0404 and DRB1*0401, with absolute risks of 1 in 20 (DRB1*0404) and 1 in 35 (DRB1*0401). For individuals carrying both alleles (i.e., DRB1*0401/*0404), the increased risk for developing RA has been estimated to be about 30-fold, with an absolute risk of 1 in 7.5. Individuals with two *04 alleles also seem to have an increased risk of more severe destructive joint disease and extra-articular involvement.59 The association of particular DR alleles with RA is frequently cited as the most compelling evidence for the important role of CD4+ T cells in this disease, although the exact peptides that are being presented in the context of class II molecules that contain the shared epitope are currently unknown.60 A clear association between particular MHC haplotypes and development of SLE generally has been more difficult to establish. Modest associations of HLA-DR3 (DRB1*0301) and DR2 (DRB1*1501) have been shown in white SLE patients. The increased risk from haplotypes with these HLA-DR alleles has been confirmed in transmission

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­disequilibrium studies in families with SLE.61 Although it has been suggested that the association of particular haplotypes with SLE relates to genes distinct from DR and DQ, such as those encoding complement component C4A and TNF, studies using a dense map of markers across the HLA region strongly suggested that it is the class II genes (e.g., DR and DQ) that underlie the increased risk of disease from a particular HLA haplotype.59 A strong association of SLE with particular class II alleles also has been shown when patients are grouped according to the specific types of autoantibodies produced. Autoantibodies to Ro/SS-A (plus La/SS-B), U1RNP, Sm, phospholipids (i.e., anticardiolipin antibodies or the lupus anticoagulant), and dsDNA have been associated with particular DQ alleles. These data suggest that the contribution of class II MHC molecules in SLE is predominantly at the level of specific autoantibody production, consistent with an impact on CD4+ T cell help. A different mechanism may underlie the strong association of spondyloarthropathies with individuals who carry the HLA-B27 class I allele. A specific region of the peptidebinding groove of the B27 molecule is conserved among HLA subtypes linked to spondyloarthropathies, and it was originally postulated that the structural features of HLA-B27 may favor binding of a particular set of peptides, perhaps self-peptides cross-reacting with a pathogenic stimulus that predisposes to spondyloarthropathies. In human reactive arthritis and ankylosing spondylitis, HLA-B27-restricted reactivity to bacterial and collagen self-peptides has been identified.62-64 An alternative hypothesis builds on the observation that HLA-B27 proteins exhibit inefficient folding and are exported to the cytoplasm and degraded more rapidly than other HLA alleles,65 perhaps because of the formation of abnormal disulfide-linked HLA-B27 dimers.66 Misfolded proteins may trigger a generalized cellular stress response termed the unfolded protein response, which can induce the transcription of proinflammatory genes under some conditions. These observations may explain how transgenic expression of HLA-B27 in rats results in colitis and spontaneous inflammatory disease with some similarities to ankylosing spondylitis.67 In these animals, restoring HLA-B27 folding with additional β2-microglobulin expression eliminated colitis, but did not prevent arthritis and spondylitis,68 suggesting that these manifestations may operate through different mechanisms. ASSOCIATION OF NON–MAJOR HISTOCOMPATIBILITY COMPLEX GENES WITH AUTOIMMUNE DISEASE Multiple non-MHC candidate genes have been studied for associations with autoimmune diseases. Studies of SLE have addressed genes encoding complement genes, Fc receptor alleles, mannose-binding protein, various cytokines such as IL-10 and TNF, and gene segments of the TCR and immunoglobulin gene complexes (see Chapter 74). Alleles determining deficiencies of classic pathway complement components have shown strong associations with SLE (see Chapter 19).40,69,70 Most individuals with genetically determined complete deficiencies of complement C1q or C1r/C1s develop a syndrome resembling SLE. C2 and C4, encoded within MHC, also have alleles that result in deficiencies, and

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complete deficiencies of these molecules markedly increase the risk of developing SLE. The association of these deficiency states and SLE is likely to be an etiologic one, but the mechanism for the influence of genetic complement deficiencies in SLE is unclear. Studies have suggested that complement deficiencies may lead to SLE through defects in the clearance of apoptotic cells and cellular debris, as in DNase I–deficient humans and mice,39 or alternatively through defects in the clearance of immune complexes.69 These genetic contributions may allow enhanced deposition or formation of immune complexes in the kidney or possibly affect the inflammatory response or end-organ response to complexes. Associations also have been shown between SLE and alleles of the genes encoding cell surface receptors for IgG (i.e., Fcγ receptors).71,72 Investigators have shown an association between SLE and alleles of the gene encoding FcγRIIA (CD32), expressed by monocytes or macrophages and neutrophils.71 Alleles of this gene differ substantially in the ability to bind human IgG2, and studies found a decrease in the prevalence of the high-affinity binding allele in SLE, particularly in patients with lupus nephritis. Possibly similar to complement deficiencies, the genetic contribution of this Fcγ receptor deficiency may reflect a relatively late event in the pathogeneisis of SLE-related immune complex damage, such as in lupus nephritis. Consistent with this hypothesis, other studies have noted the underrepresentation of a high-binding FcγRIIIA allele (expressed by NK cells and monocytes) in patients with SLE, especially with lupus nephritis.72 Expression of the inhibitory Fcγ receptor FcγRIIB seems to be extremely important in controlling the generation of lupus-like disease in mouse models. Deficiency of the gene encoding FcγRIIB, which negatively regulates B cell activation, can cause lupus-like disease in some otherwise normal mouse strains.38 Reduction in expression of the inhibitory FcγRIIB linked to a promoter polymorphism has been associated with numerous autoimmune-prone mouse strains.73 FcγRIIB can recruit phosphatases that negatively regulate BCR signaling and has been shown more recently to induce apoptosis in mouse and human plasmablasts.74 Genome-wide linkage analyses of families with affected siblings also have been reported in human type 1 diabetes, autoimmune polyendocrine syndromes, autoimmune thyroid disease, multiple sclerosis, SLE, and RA.17,18,36,49,75,76 These studies are beginning to yield candidate autoimmune disease–predisposing genes and have revealed an interesting principle in autoimmune disease genetics: Often single loci seem to predispose to multiple autoimmune diseases. A chromosome 2q33 locus mapped in human families with type 1 diabetes and autoimmune thyroid disease has led to the identification of a variant allele of the gene encoding CTLA4 and points to an important role for alternative splice forms of this gene.77,78 In type 1 diabetes, other identified susceptibility genes based on linkage analyses include the insulin gene in the human disease and the gene encoding IL-2 in the NOD mouse model.36 Gene identification after linkage studies in human SLE and mouse models of lupus also has begun to provide new insight into the immunopathogenesis of disease. One study of human families has suggested that a locus on chromosome 2 is related to a polymorphism in the gene encoding PD-1 (PDCD1), which provides a negative signal to activated T cells.42

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A candidate gene screening approach in a cohort of sib pairs affected with RA resulted in the identification of a missense polymorphism in the tyrosine phosphatase PTPN22, also known as lyp (858C > T, resulting in the amino acid substitution R620W) strongly predisposing to RA,79 a finding that has been replicated in multiple cohorts.80 PTPN22 polymorphisms predict RA independently of carriage of “shared epitope” positive HLA class II genes. The same variant was identified as a susceptibility allele in patients with type 1 diabetes,81 and carriers of the variant allele also have been shown to be more susceptible to Graves’ disease, Addison’s disease, and familial SLE. When studied biochemically, the PTPN22 R620W variant enhances the tyrosine phosphatase activity of the enzyme, resulting in dominant inhibition of T cell activation through the TCR.82 This finding led to speculation that the R620W mutation predisposes to autoimmune disease by selectively impairing TCRinduced apoptosis or regulatory T cell function. Genome-wide scans to identify susceptibility genes are under way in many autoimmune diseases and already have identified novel candidate genes. Functional variants in NOD2, a sensor for bacteria-induced inflammation, were found to account for approximately 10% of the risk for Crohn’s disease through mapping of a susceptibility locus on chromosome 16.83 Another susceptibility gene more recently identified in Crohn’s disease patients is the IL-23 receptor. This variant could function through enhancing the action of the cytokine IL-23, which sustains a population of proinflammatory IL-17-producing T cells in the gastrointestinal mucosa.84 HUMAN MENDELIAN AUTOIMMUNE DISEASES In contrast to the polymorphisms discussed previously that predispose to common autoimmune diseases and occur with significant frequency in healthy human populations, many rare autoimmune diseases are inherited in a mendelian fashion, and disease-causing mutations in these genes carry a high risk of producing disease. These mutations give insights into crucial checkpoints in self-tolerance. Development of autoimmune disease even in carriers of these powerful mutations can be influenced, however, by other genes and the environment. Mutations in the TNF family receptor Fas and its ligand FasL result in the lpr and gld recessive autoimmune syndromes in mice, and dominant-negative mutations in Fas underlie similar immunologic symptoms in the autosomal dominant ALPS in humans.85 FasL triggers apoptotic programmed cell death in chronically stimulated T cells and B cells, and the disruption of this pathway because of lpr and gld mutations results in the acceleration of lupus-like autoimmunity and in a massive accumulation of CD4−CD8− T cells.25 Although the mechanism by which mutations in Fas lead to accelerated autoimmunity is not completely clear, the most likely mechanism is that self-reactive T cells fail to undergo apoptosis in the peripheral immune system after chronic stimulation. Studies have shown that T cells and B cells must carry the lpr mutation in Fas for maximal autoantibody production to occur. Surface expression of Fas on B cells may be important in preventing inappropriate CD4 T cell–dependent expansion of autoreactive B cells in the periphery. Although lpr and gld mice can develop

nephritis and other hallmarks of SLE on the MRL genetic background, humans with ALPS develop primarily hematopoietic autoimmune disease, such as autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura, and rarely produce antinuclear antibodies or develop nephritis, presumably because of the need for other disease-modifying genes. In addition, Fas or FasL mutations have not been identified in cohorts of patients with SLE despite extensive efforts to do so. Mutations in the AIRE gene affect central T cell tolerance and lead to autoimmune disease in mice and humans. AIRE is a transcription factor that specifically upregulates transcription of genes in medullary thymic epithelial cells that are otherwise expressed only in peripheral tissues. Without AIRE expression, T cells developing in the thymus with TCRs recognizing peptides derived from these proteins would not be deleted during negative selection in the thymus. Mutations in AIRE deficiency lead to the recessive autoimmune polyendocrine syndrome 1 (APECED), in which patients develop autoimmune disease affecting multiple endocrine organs. AIRE-deficient mice develop similar abnormalities. These findings show that peripheral tolerance mechanisms cannot always compensate for lack of deletion of T cells in the thymus in preventing T cell–mediated autoimmune disease.

ENVIRONMENTAL TRIGGERS AND INFLUENCES It seems likely that environmental triggers or influences interact with susceptibility genes to result in autoimmune disease (see Fig. 15-2). The effect of the environment in autoimmune disease has been extremely difficult to define, however. In some diseases, this difficulty may reflect the fact that such a trigger does not exist, or that it is ubiquitous in different populations. Relevant to rheumatic diseases, one example of the latter may be infection with Epstein-Barr virus (EBV), which is highly prevalent in most adult populations worldwide. Geographic clustering not explained by genetic variation strongly suggests an environmental effect. Case clustering has been documented in multiple sclerosis and type 1 diabetes, but not in SLE or RA.86-88 Case reports and epidemiologic studies suggest that infection with particular viruses, such as congenital rubella or enteroviruses, is associated with an increased risk of developing type 1 diabetes in susceptible individuals. Studies of animal models also have emphasized that stochastic events are important in the development of autoimmunity and expression of autoimmune disease. The fact that approximately 75% of monozygotic twins are discordant for SLE has been used as evidence to support the existence of an environmental trigger in this disease. Lupus-prone strains of mice also can be created, however, such that 25% reproducibly develop disease or produce particular autoantibodies, and careful examination of autoimmune mice has excluded environmental effects as the major factor in variable expression.17,36 In SLE-prone mice, eliminating bacterial commensal antigens also had no effect on the development of systemic autoimmunity.89 In these mice, the probability of disease seems to be genetically determined, with random events, including perhaps the generation of the BCR and TCR repertoire, contributing to disease incidence.

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Because of their ability to trigger prolonged immune responses, infectious microorganisms are obvious candidates to consider in the triggering of autoimmune diseases.36 Infections of target tissues could result in the release or expression of normally sequestered antigens or in the ability to present self-antigens that are normally prevented from being exposed to the immune system.90 Closely tied to this effect may be the release of inflammatory cytokines at the infected site and surrounding lymphoid tissues, which would mobilize and activate inflammatory cells to allow effective presentation of foreign antigens and self-antigens. Ligands for TLRs in infectious organisms and numerous cytokines produced during infections, such as type I (αβ) interferons, interferon-γ, and IL-12, all are known to activate DCs and potentiate their ability to present foreign antigens and tissue-derived self-antigens. As discussed earlier, inflammatory cytokines produced in response to infection may dampen the effectiveness of regulatory T cells and potentiate the differentiation of T helper type 1 (Th1) and Th17 T cell subsets associated with tissue damage in autoimmune diseases. Infections also may induce an immune response to the pathogen that cross-reacts with some host antigen. Possible infectious triggers of RA and SLE have been vigorously pursued. Conclusive data linking the presence of an etiologic agent to disease have been elusive, however. One agent that continues to generate interest in RA and SLE is EBV.91,92 Studies have shown that RA patients generate increased and qualitatively different antibody responses and different T cell responses to the virus and its effects. Studies also have shown that a subset of clonally expanded CD8+ T cells in the joints of patients is directed to EBV proteins. One study showed that children with SLE have a higher prevalence of EBV infection than control groups.93 Which condition is predisposing to the other has yet to be clarified. Environmental influences on the expression of disease manifestations also are seen in autoimmune diseases. In SLE, exacerbation of rash or systemic symptoms after sun exposure and exacerbations of disease after viral or bacterial infections have been observed in patients. It is possible that the latter associations are related to the exacerbating influence of interferons on disease activity in SLE.94 Most autoimmune diseases, including RA, SLE, and autoimmune thyroiditis, are more common in women than men, suggesting a role for steroid hormones in the pathogenesis of some autoimmune diseases. Changes in disease activity also have been noted after administration of exogenous hormones. Epidemiologic data and studies of animal models support the contention that estrogens can increase the risk of developing SLE or exacerbate disease. A randomized trial of combined estrogen-progesterone hormone replacement therapy in postmenopausal women with SLE showed that hormone replacement therapy increased mild, but not severe, flares of disease.95 Long-term treatment of patients with certain drugs (e.g., procainamide, hydralazine) can induce the production of antinuclear antibodies and a lupus-like disease. Drug-induced lupus seems to be a different disease from SLE, however, with a distinct natural history, autoantibody profile, and genetic predisposition. Other environmental triggers being studied in the pathogenesis of autoimmune diseases include quantifiable risks, such as cigarette smoke. A history of smoking increases the probability of rheumatoid factor–positive and anti–cyclic citrullinated protein–positive RA, especially in ­individuals

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harboring high-risk HLA-DR alleles.96 The mechanisms of how cigarette smoke influences RA pathogenesis are unclear, but may depend on polymorphisms in glutathione S-transferases, which are believed to have an important role in detoxifying carcinogens in tobacco smoke.97

CELLULAR MECHANISMS OF AUTOIMMUNE DISEASE ROLE OF T CELLS IN INITIATING AND REGULATING AUTOIMMUNITY The TCR repertoire of early immature T cells seems to depend solely on the random rearrangement of TCR genes. This process culminates in the generation of “doublepositive” T cells bearing moderate levels of the TCR and CD4 and CD8. Subsequently, two major processes in the thymus modify this repertoire (see Chapter 9). Positive selection allows cells bearing a TCR with low affinity for self-MHC/peptides to mature, which “tunes” the mature T cell repertoire to recognize foreign antigens in the context of self-MHC (i.e., self-MHC restriction). Cells that are not positively selected undergo programmed cell death within the thymus, sometimes termed death by neglect. The other intrathymic process deletes T cells that have a high level of interaction with self-MHC/peptide complexes, termed negative selection. Thymocytes whose TCR and CD4 molecules engage MHC class II/peptide complexes generally mature into CD4+ T cells, whereas cells that are positively selected on class I MHC molecules become the CD8+ population. Mature thymocytes subsequently migrate to peripheral lymphoid tissues, where they maintain these surface characteristics. There is little evidence to support the contention that defects in central (intrathymic) tolerance lead to systemic autoimmune disease, such as SLE.98 Studies in mouse models of SLE have repeatedly shown that high-affinity responses to self-antigens are tolerized normally in the thymus. In contrast, accumulating data suggest that defects in central tolerance may underlie disease in some individuals with organ-specific autoimmunity, such as patients with autoimmune endocrine diseases. Clonal deletion in the thymus may be the major process for eliminating T cells reactive to self-antigens with high affinity, as long as the antigen is present or expressed in the thymus during T cell development. Studies have indicated that numerous antigens previously thought to be organ specific and organ sequestered are expressed and presented by thymic epithelial cells under control of the transcriptional activator AIRE. Organ-specific autoimmune disease, primarily directed at endocrine organs resulting from genetic deficiencies in AIRE, validates the role of central tolerance through this mechanism in preventing autoimmune diseases.99,100 There is abundant evidence that potentially autoreactive T cells can mature and reach the periphery in most individuals. Numerous “loopholes” in self-tolerance may allow this. Some organ-sequestered antigens are never presented adequately in the thymus. In addition, some selfpeptides may not be processed and presented efficiently in the thymus. T cells that escape negative selection against these peptides may be activated in the periphery when these peptides are created by altered proteolysis during

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Table 15-3  Mechanisms of Peripheral T cell   Tolerance Mechanism of Peripheral T cell Tolerance

Modes of Tolerance Breakdown

Immune ignorance

Release of sequestered antigens Aberrant expression of MHC class II Increased expression of autoantigen/ MHC class II Molecular mimicry Epitope spreading

Anergy

Release of inflammatory mediators Increased expression or function of costimulatory molecules Suppression of IDO

Regulatory T cells

Release of inflammatory mediators

Apoptosis

Defects in apoptosis signaling Viral apoptosis inhibitors

IDO, indoleamine 2,3-dioxygenase; MHC, major histocompatibility complex.

inflammation and by post-translational modifications of peptides, such as glycosylation or citrullination.101,102 As discussed previously, several well-studied animal models are generated by immunization of animals with peripheral organ antigens, such as type II collagen in collagen-induced arthritis and myelin-associated proteins in ­ Experimental Allergic Encephalomyelitis (EAE), which can engender robust T cell responses in the presence of appropriate adjuvants. In addition, immunization of normal mice with nuclear antigens or peptides derived from these antigens can result in lupus-like autoantibody production.29,103,104 These experiments indicate that peripheral autoreactive T cells exist and likely need to be kept under control to prevent autoimmunity. Many cellular mechanisms prevent peripheral selfreactive T cells from mediating autoimmune responses (Table 15-3). T cells specific for antigens that are physically sequestered or not efficiently presented are effectively “ignorant” of self-antigen. This type of immune ignorance has been seen in numerous TCR transgenic mouse models when the antigen recognized by the TCR is specifically expressed in a particular target organ, such as the pancreas, in which T cells do not regularly traffic.105 If no other mechanisms are active, this type of tolerance can be reversed easily in animal models by the induction of inflammation in the self-antigen–expressing tissue, which can reverse immune ignorance by activating antigen-presenting cells to process and present antigens from the tissue, and upregulation of MHC class I and II molecules on tissue cells. Cross-reactive peptides from infectious organisms also can reverse this type of T cell tolerance. Often, T cell tolerance is maintained through more active processes. Activation of T cells without costimulation through receptors such as CD28 can induce a reversible state of unresponsiveness to TCR stimulation, termed T cell anergy or abortive T cell activation, resulting in postactivation cell death through apoptosis.106,107 This state of unresponsiveness may occur when self-antigens are presented to T cells under noninflammatory conditions or by cells that cannot make the CD28 ligands B7-1 (CD80) and B7-2 (CD86). Inflammatory cytokines, such as TNF and interferon-γ, can reverse this type of tolerance through their

well-known ability to upregulate costimulatory molecules such as on antigen-presenting cells. Other molecules in the CD28 costimulatory family, such as CTLA4, bind B7-1 and B7-2 with higher affinity than CD28, but deliver a negative signal to T cells. This function of CTLA4 is required to keep autoreactive T cells from becoming activated, as dramatically illustrated by the T cell hyperactivation and infiltration of multiple organs that results in death of CTLA4-deficient mice.108 Blockade of T cell costimulation can be effected with a variety of agents, including a fusion protein of CTLA4 with immunoglobulin (CTLA4-Ig). Additional costimulatory ­pathways that are relevant to autoimmunity include the PD-1 interaction with its ligand, which also delivers a negative regulatory signal to chronically activated T cells.7678 Deficiencies of PD-1 have been implicated in lupus-like disease in animals36 and as a possible gene contribution to SLE.37 Members of the TNF family, including LIGHT, 41BB, OX40L, and CD70, also have costimulatory activity on T cells, which can regulate autoimmunity.109,110 Another mechanism that can induce proliferative arrest and unresponsiveness in T cells is the secretion of the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase (IDO). Originally described as an enzyme secreted by trophoblasts and macrophages that prevents rejection of allogeneic fetuses,111 IDO has now been recognized to be synthesized by plasmacytoid DCs in the mouse and in human DCs after stimulation through B7 costimulatory molecules, which can be ligated by CTLA4-Ig,112 although the correlation between IDO expression and regulatory function of DCs has been questioned.113 IDO catabolizes tryptophan, which can induce local tryptophan deficiency and induce proliferative arrest in T cells through the induction of the stress-responsive kinase GCN2.114 A more permanent form of T cell tolerance occurs in the setting of chronic exposure to antigens, which leads to apoptosis through the action of surface receptors such as Fas and likely underlies the predisposition to autoimmunity that occurs in Fas-deficient animals and patients with the ALPS.115 Considerable evidence has emerged in recent years that certain subsets of classic αβ TCR–expressing T cells have the ability to suppress responder T cell proliferation and in vivo T cell responses to self-antigens and foreign antigens.116,117 NK cells and NK/T cells also possess intrinsic self-reactivity and may participate in the regulation of autoimmunity.118 Natural regulatory T cells are a subset of 5% to 10% of peripheral CD4+ cells with a repertoire enriched in self-reactive specificities. These T cells can be identified by their constitutive expression of high levels of the T cell activation marker CD25 and CTLA4. Natural regulatory T cells express a unique transcription factor, FoxP3, which confers many of their properties, such as poor proliferation when activated and the ability to suppress proliferation and cytokine secretion by other T cells activated in coculture with natural regulatory T cells, in a cell contact–dependent, but non–antigen-specific manner.119 Genetic deficiency in regulatory T cells secondary to mutations in FoxP3 in the scurfy mouse and the human familial syndrome IPEX results in systemic autoimmune disease,120 and more recent experiments in animal models show that experimental elimination of regulatory T cells in adult animals can lead quickly to autoimmune disease.121

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Regulatory T cells also may have a physiologic role in dampening immune responses against pathogens. Other regulatory T cell populations that may be involved in controlling regulating peripheral anergy include IL-10 producing “Tr1” cells and transforming growth factor (TGF)-β producing Th3 cells. These populations do not express FoxP3 and suppress by means of their secreted cytokines.122 Given this evidence, it has been tempting to propose that human autoimmune diseases may be treated by increasing the production of regulatory T cells, and such strategies have worked in the mouse to reduce diseases induced by autoreactive T cells in the setting of regulatory T cell deficiencies. Regulatory T cells have been found in abundance, however, in the setting of autoimmune inflammation, such as in the pancreatic lymph nodes and islets of mice with autoimmune diabetes and in the inflamed synovium,123,124 suggesting that simply increasing their numbers may not be sufficient. A large body of evidence suggests that T cells are required for the full expression of most rheumatic and other autoimmune diseases.125 In particular, HLA associations, the presence of infiltrating CD4+ T cells at the sites of pathology in various organ-specific autoimmune diseases, and evidence for T cell help in the repertoire of autoantibodies all point to a role for T cell help in autoimmune disease. Pathogenic autoantibodies in SLE exhibit isotype switching and somatic mutation that are hallmarks of T cell help.98 Most animal models of lupus, type 1 diabetes, and antigen-induced autoimmune disease can be prevented and in most cases ameliorated by T cell depletion. In humans, this has been more difficult to accomplish, but antibodies against the TCR are effective in treating acute graft rejection and new-onset type 1 diabetes.126,127 The importance of CD4+ T cells in the initiation and perpetuation of RA has been a controversial issue, mostly related to studies showing that T cell–derived cytokines are scarce in synovium compared with cytokines derived from macrophage or fibroblast-like synoviocytes, and related to the failure to define the antigens to which the synovial T cells are responding.128 This situation led to the concept that T cells may be important in initiating disease in RA, but more dispensable in later stages of the disease.60 Although small trials of CD4+ T cell depletion in RA showed limited efficacy and significant toxicity, blockade of T costimulation with CTLA4-Ig (abatacept) has proved to be efficacious in RA.129,130 The success of costimulatory T cell blockade in early and advanced RA validates the role of T cells in RA pathogenesis. ROLE OF B CELLS B cell repertoire formation in the fetal liver and adult bone marrow is random, and B cells with self-reactivity are generated. Negative selection of some autoreactive B cells, involving deletion and anergy, is a normal part of B cell development (see Chapter 10). A separate mechanism has been described in which immature B cells with specificity for self-antigens can modify their receptors through a process termed receptor editing.131 In contrast to T cells, mature B cells also have the ability to modify their BCRs in the peripheral lymphoid tissues through a process of somatic mutation (see Chapter 10). This process allows a secondary immune response to generate antibodies with higher affinity

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for the stimulating antigen, but offers additional opportunity for the generation of self-reactive B cells. Multiple checkpoints are involved in the prevention of activation of autoreactive B cells in the peripheral lymphoid tissues.132 Autoreactive B cells are part of the normal peripheral B cell repertoire, and defects in central B cell ­tolerance do not seem to be necessary to allow for pathogenic autoantibody production.98 The escape of autoreactive T cells secondary to intrathymic deficiency of AIRE is sufficient for the subsequent development of autoantibodies to multiple organs.100 The transfer of alloreactive CD4+ T cells and generation of chronic graft-versus-host disease causes pathogenic lupus-like autoantibody production in normal recipient animals.133 The ability of normal animals to generate diverse antinuclear antibody responses after immunization with one nuclear antigen is further support of this conclusion.103,104 Similar to regulation of autoreactive T cells, studies suggest that regulation of B cells in the peripheral lymphoid tissues may be important for the prevention of B cell autoimmunity. B cells seem, however, to be more important in the development of autoimmune disease than just as a source of autoantibodies, with important functions in cytokine production and antigen presentation.134,135 Studies in murine lupus have indicated that T cell activation in some circumstances may depend on the presence of B cells136; this also may be a mechanism why B cells are important for continued disease activity in RA. The antigen-presenting function of B cells is likely to be important in the broadening of autoantibody repertoire that occurs during the progression of autoantibody disease that is termed epitope spreading. Autoantigen-specific B cells can promote epitope spreading because they can internalize macromolecular self-antigen complexes through their autoreactive BCR and efficiently process and present linked autoantigen epitopes to T cells, allowing T cell help to develop against “spread” epitopes.137 Epitope spreading may explain how a response to one epitope can mature into a full-blown autoimmune response. INFLUENCE OF ANTIGEN PRESENTING AND TISSUE ENVIRONMENT ON AUTOIMMUNITY It has been increasingly evident that the manner and environment in which T cells and B cells are activated can have profound effects on their subsequent differentiation and susceptibility to peripheral tolerance mechanisms.138,139 Stimuli derived from different pathogens can instruct DCs to differentiate into different subtypes that prime T cells to become different effector subtypes. Schistosome egg antigen influences DCs to prime T cells to differentiate into Th2 effector cells secreting IL-4, which is important for immunity against this extracellular parasite, whereas DCs exposed to toxoplasmosis-derived antigens strongly bias T cells toward differentiation into Th1 cells that secrete interferon-γ. DCs presenting self-antigen without activation or through alternative activation pathways can induce T cell anergy or promote T cell differentiation into IL-10-producing or FoxP3-positive regulatory T cells. The cytokine TGF-β seems to be crucial for this alternative activation pathway, at least in animal models. Major differences between tissues in the responsiveness and cytokine secretion patterns of immune and nonimmune

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cells also are important in the control of immunity and autoimmunity.140 Resident cells in the lung make large amounts of the suppressive enzyme IDO when stimulated by microbial DNA. By contrast, the spleen makes little IDO after challenge with the same stimuli.141 These different patterns of responsiveness most likely evolved to allow organ-specific responses to pathogens by tissues that are exposed to commensal bacteria in different ways, but also likely affect the manifestations of autoimmunity in a tissue-specific way. The influence of the synovium on immune responses is likely relevant to inflammatory joint disease. HELPER T CELL SUBSETS AND THE CYTOKINE NETWORK Although more sharply defined in mice than in humans, naive T cells, after activation, may evolve into multiple subtypes of helper T cells, distinguished by the cytokines that they produce. The first two subsets to be defined, Th1 and Th2, secrete different patterns of cytokines, with Th1 cells producing predominantly interferon-γ, TNF, lymphotoxin, and other inflammatory cytokines, and Th2 cells ­producing IL-4, IL-5, IL-10, and IL-13. The DC-derived cytokine IL12 is crucial for the induction of Th1 cells. Th1 and Th2 cells reciprocally regulate each other, such that Th1-derived cytokines repress Th2 differentiation and vice versa.142-144 Also, these two effector T cell subsets express specific transcription factors that program and maintain these effector cell subtypes, largely preventing conversion from one to another. In host defense, Th1 cells primarily enhance cell-mediated inflammatory immune responses, such as delayed-type hypersensitivity reactions, which frequently involve activation of macrophages and effector T cells. The ability to mediate an effective immune response against certain intracellular pathogens seems to depend strongly on the generation of a Th1 response. In contrast, Th2 cells mainly provide help for B cells by promoting class switching and enhancing the production of certain IgG isotypes and production of IgE, including in allergic diseases. T cells producing the cytokine IL-21 also may be important in promoting B cell functions.145 The Th2 cytokines IL-4 and IL-10 also can function to limit macrophage activity,146 and Th2 cells may negatively regulate inflammation in autoimmune disease. Although Th1 cells were associated with organ-specific autoimmune disease models such as CIA, EAE (multiple sclerosis), and other induced diseases, more recent findings in mouse models have shown that another T helper subset that produces the cytokine IL-17 (Th17) is required for the development of many of these diseases, including CIA and EAE.147 IL-23, a cytokine that shares a common p40 subunit with IL-12, but also uses a unique p19 subunit, is important for the maintenance of Th17 cells, and blocking antibodies against the IL-23-specific p19 subunit or genetic deletion of p19 block the development of CIA, EAE, and T cell– dependent models of inflammatory bowel disease.148-152 In mice, there may be a reciprocal relationship between Th17 and regulatory T cells in that TGF-β can promote development of FoxP3-positive T cells from naive T cells, but addition of inflammatory cytokines such as IL-6 and TNF to TGF-β promotes Th17 cell development.153,154 How these different cytokines and T helper subsets influence human

autoimmune disease is just beginning to be worked out, but it is notable that large amounts of IL-17 can be detected at sites of inflammation, such as rheumatoid synovium.155,156 Blockade of p40, which makes up IL-12 and IL-23, has proved to be effective in treating human inflammatory bowel disease.157 In cases in which genetic lesions result in overproduction of specific cytokines, such as IL-1 production in the neonatal-onset multisystem inflammatory disorder, blocking IL-1 produces prompt and almost complete remission of symptoms,158 but in sporadic autoimmune or inflammatory disease, such treatments are unlikely to be as universally effective. Therapies that modulate cytokine production and action are potentially powerful immunostimulants or suppressants and need to be tested with caution, but could be an important addition to the armamentarium of antirheumatic treatments.

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139. Banchereau J, Steinman RM: Dendritic cells and the control of immunity. Nature 392:245-252, 1998. 140. Raz E: Organ-specific regulation of innate immunity. Nat Immunol 8:3-4, 2007. 141. Hayashi T, Beck L, Rossetto C, et al: Inhibition of experimental asthma by indoleamine 2,3-dioxygenase. J Clin Invest 114:270-279, 2004. 142. Coffman RL, Mocci S, O’Garra A: The stability and reversibility of Th1 and Th2 populations. Curr Top Microbiol Immunol 238:1-12, 1999. 143. Mosmann TR, Coffman RL: TH1 and TH2 cells: Different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145-173, 1989. 144. Agnello D, Lankford CS, Bream J, et al: Cytokines and transcription factors that regulate T helper cell differentiation: New players and new insights. J Clin Immunol 23:147-161, 2003. 145. Leonard WJ, Spolski R: Interleukin-21: A modulator of lymphoid proliferation, apoptosis and differentiation. Nat Rev Immunol 5: 688-698, 2005. 146. Oswald IP, Gazzinelli RT, Sher A, et al: IL-10 synergizes with IL-4 and transforming growth factor-beta to inhibit macrophage cytotoxic activity. J Immunol 148:3578-3582, 1992. 147. Dong C: Diversification of T-helper-cell lineages: Finding the family root of IL-17-producing cells. Nat Rev Immunol 6:329-333, 2006. 148. Kastelein RA, Hunter CA, Cua DJ: Discovery and biology of IL-23 and IL-27: Related but functionally distinct regulators of inflammation. Annu Rev Immunol 25:221-242, 2007. 149. Oppmann B, Lesley R, Blom B, et al: Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13:715-725, 2000. 150. Langrish CL, Chen Y, Blumenschein WM, et al: IL-23 drives a pathogenic T cell population that induces autoimmune ­ inflammation. J Exp Med 201:233-240, 2005. 151. Langrish CL, McKenzie BS, Wilson NJ, et al: IL-12 and IL-23: Master regulators of innate and adaptive immunity. Immunol Rev 202:96-105, 2004. 152. Lieberman LA, Cardillo F, Owyang AM, et al: IL-23 provides a ­limited mechanism of resistance to acute toxoplasmosis in the absence of IL-12. J Immunol 173:1887-1893, 2004. 153. Bettelli E, Carrier Y, Gao W, et al: Reciprocal developmental ­pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235-238, 2006. 154. Mangan PR, Harrington LE, O’Quinn DB, et al: Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441:231-234, 2006. 155. Koenders MI, Joosten LA, van den Berg WB: Potential new targets in arthritis therapy: Interleukin (IL)-17 and its relation to tumour necrosis factor and IL-1 in experimental arthritis. Ann Rheum Dis 65(Suppl 3):iii29-iii33, 2006. 156. Lubberts E, Joosten LA, Oppers B, et al: IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis. J Immunol 167:1004-1013, 2001. 157. Mannon PJ, Fuss IJ, Mayer L, et al: Anti-interleukin-12 antibody for active Crohn’s disease. N Engl J Med 351:2069-2079, 2004. 158. Goldbach-Mansky R, Dailey NJ, Canna SW, et al: Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med 355:581-592, 2006. 159. Watanabe-Fukunaga R, Brannan CI, Copeland NG, et al: Lympho­ proliferation disorder in mice explained by defects in Fasantigen that mediates apoptosis. Nature 356:314-317, 1992. 160. Straus SE, Lenardo MJ, Puck JM, et al: Autoimmune lymphoproliferative syndrome: An inherited disorder of lymphocyte apoptosis. Ann Intern Med, 130:591-601, 1998. 161. Chen Z, Koralov SB, Kelsoe G: Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2. J Exp Med 192:1339-1352, 2000.

16

Innate Immunity Steven A. Porcelli

KEY POINTS Innate immunity depends on recognition of conserved ­molecular patterns found in many microorganisms. Several families of pattern-recognition receptors are ­responsible for triggering innate immune responses. Toll-like receptors and other pattern-recognition receptors with leucine-rich repeat domains play a key role in innate ­immune recognition. Antimicrobial peptides are important effectors of innate ­immunity. Phagocytic cells and several types of innate-like lymphocytes are key cell types in mediating innate immunity. Innate immune responses have a strong impact on the ­development of adaptive immunity. Some defects in the innate immune system are associated with a predisposition to infections or to autoimmune diseases.

It has become common practice in immunology to divide the mechanisms involved in host defense into adaptive and innate components, and this provides a useful framework for classifying the numerous cells, receptors, and effector molecules that combine to make up the vertebrate immune system (Table 16-1). A specific immune response, such as the production of antibodies or T cells against a particular pathogen, is referred to as adaptive immunity because it represents an adaptation that occurs during the lifetime of an individual as a result of exposure to that pathogen. Adaptive immune responses involve the clonal expansion of T and B lymphocytes bearing a large repertoire of somatically generated receptors that can be selected to recognize virtually any pathogen. The adaptive immune system of any given individual is profoundly molded by the immunologic challenges encountered by that individual during the course of a lifetime. A hallmark of adaptive immune responses is that they are highly specific for the triggering agent, and they provide the basis for immunologic memory. This property of memory endows the adaptive immune response with its “anticipatory” property, which provides increased resistance against future infection with the same pathogen and also allows vaccination against future infectious threats. Adaptive immunity is essential for the survival of all ­mammals and most other vertebrates, but a wide variety of other mechanisms that do not involve antigenspecific lymphocyte responses are also involved in successful immune protection. These diverse mechanisms are collectively known as innate immunity because they are not

dependent on prior exposure to specific pathogens for their ­amplification. Such responses are controlled by the products of germline genes that are inherited and similarly expressed by all normal individuals. Innate immune mechanisms involve both constitutive and inducible components and use a wide variety of recognition and effector mechanisms. It has become clear in recent years that innate immune responses have a profound influence on the generation and outcome of adaptive immune responses. This ability of the innate immune system to instruct the responses of the adaptive immune system suggests many ways in which innate immunity can influence the development of both long-term specific immunity and autoimmune diseases.

EVOLUTIONARY ORIGINS OF INNATE IMMUNITY In spite of its obvious importance for most vertebrate ­organisms, the adaptive immune system is a relatively recent evolutionary development (Fig. 16-1). In the great majority of present-day vertebrate species, the adaptive immune system is based on the ability to generate large ­families of variable lymphocyte receptors with immunoglobulin-like structures. This ability has been conserved owing to the acquisition of a specialized recombination system that ­mediates the assembly of gene segments in the T cell and B cell receptor ­families, which most likely occurred through the invasion of the genome of a primitive vertebrate by a transposable element or virus carrying this machinery.1,2 This critical step in the evolution of the immune system can be traced back to the emergence of the ancestors of present-day jawed fish, which represent the most primitive extant species that are known to have adaptive immune systems based on the generation of large families of specific immunoglobulin-type receptors.3 Recently, other ­ systems of variable lymphocyte receptors that are unrelated to immunoglobulins but also provide the basis for an adaptive immune response have been discovered in primitive jawless fish such as lampreys and hagfish.4,5 This finding shows that at least two different strategies for the creation of an adaptive immune system emerged at the dawn of vertebrate evolution about 500 million years ago, and it emphasizes the importance of adaptive immunity for the survival and further evolution of the vertebrate lineages.6 Given this key role of adaptive immunity in the ­evolution and survival of vertebrates, it is surprising that all invertebrate animals, and possibly some of the lowest vertebrate species as well, completely lack the ability to generate ­lymphocyte populations bearing large families of clonally diverse antigen receptors.7,8 In these animals, protection against pathogen invasion depends entirely on innate 277

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Table 16-1  Contrasting Features of the Innate and Adaptive Immune Systems Property

Innate Immune System

Adaptive Immune System

Receptors

Relatively few (several hundred?) Fixed in genome Gene rearrangement not required

Many (potentially 1014 or more) Encoded in gene segments Gene rearrangement required

Distribution

Nonclonal All cells of a class identical

Clonal All cells of a class distinct

Targets

Conserved molecular patterns Lipopolysaccharides Lipoteichoic acids Glycans and peptidoglycans Others

Details of molecular structure Proteins Peptides Carbohydrates

Self-nonself   discrimination

Perfect: selected over evolutionary time

Imperfect: selected in individual somatic cells

Action time

Immediate or rapid (seconds to hours)

Delayed (days to weeks)

Response

Microbicidal effector molecules Antimicrobial peptides Superoxide Nitric oxide Cytokines (IL-1, IL-6, others) Chemokines (IL-8, others)

Clonal expansion or anergy of specific T and B lymphocytes Cytokines (IL-2, IL-4, IFN-γ, others) Specific antibody production Specific cytolytic T cell generation

IFN, interferon; IL, interleukin. Adapted and modified from Medzhitov R, Janeway CA Jr: Innate immune recognition. Annu Rev Immunol 20:197, 2002.

immunity, elements of which appear to exist in all animals and plants and must have evolved with the ­earliest multicellular forms of life. In many cases, components of the innate immune system are significantly conserved in structure and function in animals from the lowliest invertebrates to the most complex vertebrates.7 This preservation of innate immune mechanisms, with their functions largely intact, over such vast ­ evolutionary distances is a clear indication of their importance, even in animals that have developed sophisticated adaptive immune responses.

PATHOGEN RECOGNITION BY THE INNATE IMMUNE SYSTEM Some mechanisms of innate immunity are constitutive, meaning that they are continuously expressed and not ­significantly modulated by the presence or absence of infection. Examples include the barrier functions provided by epithelial surfaces that are continuously exposed to microbial flora, such as those of the skin and intestinal and ­genital tracts. In contrast, the inducible mechanisms of innate immunity involve the increased production of mediators and the upregulation of effector functions that eliminate microorganisms. Induction occurs as a result of exposure to a wide variety of microbes and represents a less specific form of immune recognition than that associated with the specific antibodies and T cells that mediate adaptive immunity. The basic principle underlying this form of response is a process known as pattern recognition. This recognition strategy is based on the detection of commonly occurring and conserved molecular patterns that are essential products or structural components of microbes. PATHOGEN-ASSOCIATED MOLECULAR PATTERNS The general name given to the targets of innate immune recognition is pathogen-associated molecular patterns (PAMPs). These are structural features or components

­distinctive for microorganisms and are not normally found in the animal host. The best-known example of a PAMP is bacterial lipopolysaccharide (LPS), a ubiquitous glycolipid constituent of the outer membranes of gram-negative bacteria. Another important example is the peptidoglycan structure present as the basic cell wall component in nearly all bacteria. These structures may vary partially from one bacterium to another, but the basic elements are conserved, thus providing the possibility of recognizing a broad array of pathogens by sensing a single or a relatively small number of PAMPs. Many PAMPs that serve as targets of recognition for the innate immune response are now known to be associated with bacteria, fungi, and viruses. PATTERN-RECOGNITION RECEPTORS The recognition of PAMPs is mediated by a collection of germline-encoded molecules known collectively as pattern-recognition receptors (PRRs) (Table 16-2). These receptors are host proteins that have evolved, through many millions of years of natural selection, to possess defined specificities for particular PAMPs expressed by microorganisms. The total number of PRRs present in complex vertebrates such as humans is estimated to be several hundred, a number limited by the size of the genome of any animal and the number of genes it can dedicate to immune protection. The human genome, for example, is estimated to contain approximately 20,000 to 35,000 genes, most of which are not related directly to the immune system. This demonstrates one of the strong points of contrast between the innate and adaptive immune systems, because the latter can possess in the range of 1014 different somatically generated receptors for foreign antigens in the form of antibodies and T cell receptors. With its much more limited array of receptors, the innate immune system uses the strategy of targeting highly conserved PAMPs that are shared broadly by large classes of microorganisms. Because most pathogens

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Variable lymphocyte receptors (lg type) Antibody, T cells MHC Thymus, spleen Complement (CCP, ACP, LCP, C3, MAC) Lectins and other PRRs Antimicrobial peptides

Mammalia

0

| 

250 Amphibia

Time to present (million years)

Osteichthyes (bony fish)

No antibody or T cells MHC? Thymus? Spleen? Variable lymphocyte receptors (LRR type) Complement (ACP, LCP, C3) Lectins and other PRRs Antimicrobial peptides

Chondrichthyes (sharks, rays) Agnatha (jawless fish)

450

Arthropoda (insects) Protochordates (sea squirt)

750

Annelida (earthworm)

Mollusca

Echinodermata (sea urchin)

Deuterostomes

Protostomes

No antibody or T cells No variable lymphocyte receptors? MHC? Lectins and other PRRs Antimicrobial peptides Complement in some (all?)

Coelomates

900

Porifera (sponges)

Acoelomates

Figure 16-1  Ancient evolutionary origin of the innate immune system. Studies of the immune systems of a wide range of vertebrates and invertebrates have revealed that even the most primitive invertebrates possess many components of innate immunity (e.g., pattern-recognition receptors of the lectin and Toll-like families, antimicrobial peptides, complement proteins). The innate immune system is thus extremely ancient, having arisen early in the evolution of multicellular life. In contrast, the adaptive immune system is a much more recent development that did not appear until the emergence of the ancestors of present-day sharks and rays, approximately 400 million years ago. The first species to acquire an adaptive immune system based on immunoglobulin-type receptors must have arisen after the appearance of the direct ancestors of present-day jawless fish (lampreys and hagfish), which are the most highly evolved living species that lack the ability to generate large families of variable immunoglobulin-type lymphocyte receptors (arrow). ACP, alternative complement pathway; CCP, classic complement pathway; Ig, immunoglobulin; LCP, lectin-activated complement pathway; LRR, leucine-rich repeat domain; MAC, membrane attack complex; MHC, major histocompatibility complex; PRR, pattern-recognition receptor. (Adapted from Sunyer JO, Zarkadis IK, Lambris JD: Complement diversity: A mechanism for generating immune diversity? Immunol Today 19:519, 1998.)

c­ ontain PAMPs, this strategy allows the generation of at least partial immunity against most infections. PRRs are expressed by many cell types, some of which are specialized effector cells of the immune system (e.g., neutrophils, macrophages, dendritic cells, lymphocytes), and some of which are not generally regarded as part of the immune system (e.g., epithelial and endothelial cells). Unlike the T and B cell receptors used for adaptive immune recognition, the expression of PRRs is not clonal, which means that all the receptors displayed by a given cell type (e.g., macrophages) have identical structure and ­specificity. When PRRs are engaged by recognition of their associated PAMPs, effector cells bearing the PRRs are triggered to perform their immune effector functions immediately, rather than after undergoing proliferation and expansion, as in the case of adaptive immune responses. This accounts for the much more rapid onset of innate immune responses. In recent years, considerable progress has been made toward identifying many of the important PRRs involved in the induction of innate immunity. These receptors can

be classified into three functional classes: secreted, endocytic, and signaling PRRs (see Table 16-2). In addition, many of the known PRRs can be classified into structurally defined families on the basis of a few characteristic protein domains. Among these, the best known include proteins with calcium-dependent lectin domains, scavenger receptor domains, and leucine-rich repeat domains. Pattern-Recognition Receptors of the Lectin Family Calcium-dependent lectin domains are common modules of secreted and membrane-bound proteins involved in the binding of carbohydrate structures. A well-characterized PRR belonging to this class is the mannan-binding lectin (MBL), also known as soluble mannose binding protein, which represents a secreted PRR that functions in the initiation of the complement cascade (Fig. 16-2).9,10 This protein is synthesized primarily in the liver on a constitutive basis, although its production can be increased as an acute-phase reactant following many types of infection. MBL binds to

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Table 16-2  Pattern-Recognition Receptors (PRRs) Prominent Sites of Expression

Receptor Class

Examples

Secreted PRRs

Collectins Mannan-binding lectin Ficolins Surfactant proteins (SP-A, SP-B) Pentraxins Short pentraxins (CRP, SAP) Long pentraxins

Plasma

Major Ligands

Function

Carbohydrate arrays typical of ­bacterial capsules, fungi, and   other microbes Apoptotic cells and cellular debris, including chromatin

Complement activation Opsonization

Endocytic PRRs

Lectin-family receptors Macrophage mannose receptor DEC-205 Dectin-1 Scavenger receptor A MARCO Complement receptors CD11b/CD18 (CR3) CD21/35 (CR2/1)

Macrophages, dendritic Cell wall polysaccharides (­mannans Pathogen uptake by cells, some endothelia, and glucans), LPS, LTA, and ­phagocytes epithelia, and smooth ­opsonized cells and particles Delivery of ligands to muscle cells antigen-processing ­compartments Clearance of cellular and extracellular debris

Signaling PRRs

Toll-like receptors CARD/NOD proteins PYRIN domain proteins

Macrophages, dendritic cells, epithelia

Multiple conserved pathogen­associated molecular patterns (LPS, LTA, dsRNA, lipoproteins, ­flagellin, bacterial DNA, others)

Activation of inducible   innate immunity   (antimicrobial peptides, ­cytokines, reactive oxygen or ­nitrogen intermediates) Instruction of adaptive ­immune response

CARD, caspase activation and recruitment domain; CR, complement receptor; CRP, C-reactive protein; DEC-205, dendritic and epithelial cells, 205 kD; dsRNA, double-stranded RNA; LPS, lipopolysaccharide; LTA, lipoteichoic acid; MARCO, macrophage receptor with collagenous structure; NOD, nucleotide-binding oligomerization domain; SAP, serum amyloid P protein; SP, surfactant protein.

carbohydrates on the outer membranes and capsules of many bacteria,11-13 as well as fungi,14 some viruses,15,16 and parasites.17 Although mannose and fucose sugars bound by MBL can also be found on the surfaces of normal mammalian cells, they are present at too low a density or in the wrong orientation to efficiently engage the lectin domains of MBL. In contrast, the coats of many microorganisms contain an array of these sugars, which allows strong binding of MBL. Thus, in this case, the spacing and orientation of specific carbohydrate residues constitute the PAMP that triggers the activation of innate immunity by MBL. MBL functions as one of a small number of secreted PRRs that can initiate the lectin pathway of complement activation. At least two other soluble proteins with lectin activity in human plasma, known as ficolins (ficolin/P35 and H-ficolin), can also activate this pathway following their interaction with bacterial polysaccharides.18 Several of the soluble lectin-type PRRs also play an important role in the opsonization of microbes by binding to their surfaces and directing them to receptors on phagocytic cells. Among these are two pulmonary surfactant proteins, SP-A and SP-D, which similarly recognize and bind to the surface sugar codes of microbes in the respiratory tract.19-21 These molecules are similar in structure to MBL, having both collagen-like and lectin domains, and together they constitute a family of soluble PRRs known as collectins. Another family of soluble PRRs that performs a ­ similar function in plasma is the pentraxins, so called because they are formed by the association of five identical protein subunits.22,23 This family includes the acute-phase reactants C-reactive protein (CRP) and serum amyloid P protein (SAP), along with a number of so-called long pentraxins, which have an extended polypeptide structure with

homology to the classic short pentraxins (i.e., CRP and SAP) only at their carboxy-terminal domains. Long pentraxins are expressed in a ­variety of different tissues and cells, and their specific functions are mostly unknown. However, the long pentraxin PTX3 has been shown to play an important, nonredundant role in resistance to fungal infections in mice, and recent studies indicate that PTX3 is essentially a functional ancestor of antibodies that recognizes microbes and promotes their clearance through complement activation and phagocytosis.24 In addition to these soluble proteins, a large number of membrane-bound glycoproteins with lectin domains are known to exist, and some of them participate in innate immunity by serving as endocytic PRRs for the uptake of microbes or microbial products25 (Fig. 16-3). One of the most extensively studied of these is the macrophage mannose receptor (MMR).26 Although originally identified on alveolar macrophages and known to be expressed on macrophage subsets throughout the body, this receptor is also expressed on a variety of other cell types, including certain endothelia, epithelia, and smooth muscle cells. The MMR is a membrane-anchored, multilectin domain-­containing protein that mediates the binding of a broad range of pathogens, leading to their internalization via ­endocytosis and phagocytosis.26-29 Although the major function of the MMR appears to be directing the uptake of its ligands, there is evidence that this receptor may be capable of signaling to modify macrophage functions following receptor ­engagement.30 Another member of this receptor family, the ­ß-glucan binding cell surface lectin known as Dectin-1, has a role in the modulation of inflammation in a mouse model of infection-induced arthritis.31

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MBL

281

C3 MASP3

C4 MASP2

sMAP

MASP1

C2

C3

C2a C4b

Cysteine- Collagen-like rich region domain

Carbohydrate recognition domain

C3b C3a

Carbohydrates C3b

Bacterial surface

Figure 16-2  Structure and function of mannan-binding lectin (MBL), a soluble pattern-recognition receptor. Left, MBL is a multimer protein s­ tructure with multiple carbohydrate-binding lectin domains. Three identical 32- kD polypeptides associate to form a subunit, which then oligomerize to form functional complexes (the trimeric form consisting of three subunits is illustrated, which is one of several different oligomer sizes that has been observed for MBL). Each polypeptide in the subunit contains an N-terminal cysteine-rich domain, a collagen-like domain, a neck region, and a C-terminal carbohydrate-recognition domain. Right, Initiation of the lectin pathway for complement activation by MBL. The carbohydrate-recognition domains of MBL bind to carbohydrates that are characteristic of bacterial surfaces. This leads to the recruitment of several other serum proteins, including small MBL-associated protein (sMAP), and the three MBL-associated serine proteases (MASP1, MASP2, MASP3). The protease activity of MASP2 cleaves complement C4 and C2 subunits, generating the C3 convertase (C4bC2a). MASP1 is able to cleave C3 directly. The deposition of C3 cleavage products on the bacterial surface results in opsonization and phagocytosis of the bacterial cell. C C C

N d

N

e C C C a

f C

C

C

b c Extracellular

NN N

NN N

SR-A I

SR-A II

Cytoplasmic NN N C MR MARCO

C DEC-205

Lectin family Scavenger receptor family Figure 16-3  Endocytic pattern-recognition receptors of the ­scavenger receptor and lectin families. Left, Illustrations of three ­ members of the scavenger receptor family. These are trimeric complexes of type II ­transmembrane polypeptides that have their N-terminals positioned in the cytoplasm and their C-terminals in the extracellular space. Three distinct extracellular structural domains are indicated: (a) the scavenger receptor cysteine-rich (SRCR) domain (absent in SR-A II), which has no currently known function; (b) the collagen-like domain, which is ­implicated in the binding of polyanionic ligands; and (c) the α-helical coiled-coil ­domain (absent in MARCO), which is believed to assist in receptor ­trimerization. Right, Two examples of multilectin domain endocytic pattern-­recognition receptors—macrophage mannose receptor (MMR) and DEC-205. Distinct extracellular domains in these receptors include (d) a ­­cysteine-rich N ­terminal domain, (e) a fibronectin-like domain, and  (f) multiple ­­calcium-dependent (C-type) lectin domains that bind various carbohydrate ­ ligands. (Reproduced in part from Peiser L, Mukhopadhyay S, Gordon S: Scavenger receptors in innate immunity. Curr Opin Immunol 14:123, 2002.)

Pattern-Recognition Receptors of the Scavenger Receptor Family The scavenger receptor family contains a broad range of structurally diverse cell surface proteins that are expressed most prominently on macrophages, dendritic cells, and endothelial cells25,32 (see Fig. 16-3). Although they were originally defined by their ability to bind and take up modified serum lipoproteins, they also bind a wide range of other ligands, including bacteria and some of their associated products. Two members of this family that have been implicated as PRRs for innate immunity are the scavenger receptor A (SR-A) and a related molecule called the macrophage receptor with collagenous structure (MARCO).33-36 Both these molecules contain a scavenger receptor cysteine-rich domain in the distal ends of their membranes and a collagenlike stalk with a triple-helical structure. Both are known to bind bacteria, and SR-A also binds well-known PAMPs such as lipoteichoic acids and LPS.37,38 Mice that have been made deficient in SR-A by targeted gene disruption show increased susceptibility to infections caused by a variety of bacteria, thus providing strong evidence of scavenger receptors’ role in protective immunity, most likely through the activation of innate immune mechanisms.39-41 Although these members of the scavenger receptor family clearly function as endocytic PRRs in the uptake of microbes, their potential to serve as signaling receptors has not yet been established. Pattern-Recognition Receptors with Leucine-Rich Repeat Domains Leucine-rich repeat domains (LRRs) are structural modules found in many proteins, including PRRs involved in signaling the activation of innate immunity. Molecules in this class include, most notably, the family of mammalian

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a MD-2

b

LPS

Ligand

CD14

CD14 c

PKR IRAK-2

PI3 Kinase p110

NF-κB

Akt

TLR2 TLR6

p85

Tollip

MyD88

MAPKs

IRAK

MyD88

MAPKs

Rac1

Tollip IRAK

TLR4 TLR4

TIRAP/MAL

Plasma membrane

NF-κB

Figure 16-4  Toll-like receptors (TLRs) and associated proteins. Left, TLR4 is a transmembrane polypeptide present in the plasma membrane as a homodimer. The TLR4 polypeptide has three distinct extracellular regions: (a) an N-terminal flanking domain; (b) the leucine-rich repeat (LRR) region, which contains 21 leucine-rich motifs and is thought to be directly involved in binding to lipopolysaccharide (LPS) and other ligands; and (c) a C-terminal flanking cysteine-rich domain. The cytoplasmic domains of TLR4 and all other TLRs have homology to the human interleukin (IL)-1 receptor and are designated Toll-IL-1 receptor (TIR) domains. The extracellular portion of TLR4 associates with at least two other proteins, CD14 and MD-2, which are involved in ligand recognition. The intracellular TIR domains associate with multiple adapter proteins (MyD88, TIRAP/MAL, Tollip), which link the receptor complex to kinases that activate signaling cascades. For TLR4, and probably for most other TLRs as well, activation of the IL-1 receptor-associated kinase (IRAK) is an important step leading to the release of the active form of transcription factor nuclear factor B (NF B). In addition, signaling through TLR4 leads to signal transduction through the activation of mitogen-activated protein kinases (MAPKs), double-stranded RNA-binding protein kinase (PKR), and other members of the IRAK family such as IRAK-2. Right, A different set of ligands is recognized by TLR2, which functions as part of a heterodimeric complex with other TLRs such as TLR6. The TLR2-TLR6 complex shares many features with the TLR4 complex in terms of its associated proteins. However, the TIR domain of TLR2 also appears to recruit phosphatidyl-3-OH kinase (PI3 kinase, p85 and p110 subunits) and the membrane-associated GTPase Rac1, which allows the activation of other signaling molecules, such as the serine-threonine kinase Akt. Thus, although the major signaling pathways activated by different TLRs are similar or identical (i.e., activation of NF B and MAPKs), it is likely that each TLR complex has subtle differences in its secondary pathways of signal transduction. These differences may lead to partially overlapping but distinct outcomes in response to ligands recognized by different TLR complexes. (Adapted from Underhill DM, Ozinsky A: Toll-like receptors: Key mediators of microbe detection. Curr Opin Immunol 14:103, 2002.)

Toll-like receptors (TLRs), which are membrane-bound signal-transducing molecules that play a central role in the recognition of extracellular and vacuolar pathogens.42 Two families of cytoplasmic LRR-containing receptors have also been identified, and they play a prominent role in the innate immune recognition of PAMPS expressed by intracellular pathogens. These are the family of caspase activation and recruitment domain (CARD) proteins and the PYRIN domain proteins.43 These molecules are closely related in structure and function to proteins found in invertebrates and plants that are involved in pathogen resistance, highlighting the ancient origin of these pathways for host defense, which appear to have been recognizably conserved through approximately 1 billion years of evolution.44,45 Toll-Like Receptors. The first member of the Toll family to be discovered was the Drosophila Toll protein, which was identified as a component of a signaling pathway controlling dorsoventral polarity during the development of the fly embryo.46 The sequence of Toll showed it to be a transmembrane protein with a large extracellular domain containing multiple tandemly repeated LRRs at the N-terminal end, followed by a cysteine-rich domain and an intracellular signaling domain (Fig. 16-4). A role for Toll in immune responses was suggested by the observation that its intracellular domain shows homology to the mammalian interleukin-1 receptor (IL-1R) cytoplasmic domain.47 This association was later confirmed in studies showing that Toll

was critical for the antifungal response in the fly, linking this pathway for the first time to innate immunity.48 The identification of Drosophila Toll eventually led to a search for similar proteins in mammals, and this effort has been richly rewarded, yielding 11 Toll-like receptors (TLRs) in mice and humans.42 Among these, TLR1 through TLR9 are conserved between mouse and human; TLR10 is present only in humans, and TLR11 is expressed only in mice.43 All these molecules contain large extracellular domains with multiple LRRs, as well as intracellular signaling domains known as Toll/IL-1R, or TIR, domains.43 Many of these TLRs have now been linked to the innate immune responses against various PAMPs of different microorganisms.49 Toll-Like Receptor 4 and the Response to Lipopolysaccharide. The first human TLR to be identified was the molecule now designated TLR4, which is a major component in the response to one of the most common of all PAMPs, bacterial LPS.50 Earlier studies on the response to LPS had identified two proteins, CD14 and LPS-binding protein, as molecules involved in the binding of LPS to the surface of LPS-responsive cells. However, these molecules did not ­possess any potential for transducing signals into the cell, so it was unclear how LPS binding would lead to the activation of cellular responses associated with gram-negative bacterial infection. The answer was provided by positional cloning studies of the LPS gene in the LPS-hyporesponsive C3H/HeJ mouse.51,52 This revealed a single amino acid

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s­ ubstitution in the signaling domain of TLR4. Specific deletion of the TLR4 gene by targeted gene disruption in mice subsequently confirmed the essential role of this molecule in the response to LPS: these TLR4 knockout mice have almost no response to LPS and are highly resistant to endotoxic shock.53-55 Biochemical studies provide further support for TLR4 as a component of the LPS receptor; they show that LPS bound to the surface of cells is in close contact with both CD14 and TLR4, as well as another protein called MD-2 that appears to perform an accessory function in the binding of LPS to the receptor complex.56 Further studies have elucidated many of the downstream elements in the signaling pathways that connect TLR4 to the activation of genes associated with inducible innate immunity57-61 (see Fig. 16-4). Studies of Toll signaling pathways in Drosophila identified the transcription factor nuclear factor B (NF B) as one of the key effectors of gene activation following the engagement of Toll, and this basic pathway in the fly appears to be largely conserved in TLR signaling in higher animals, including mammals.62 Other Pathogen-Associated Molecular Patterns Recognized by Toll-Like Receptors. The search for ligands that lead to signaling through ­ various TLRs has demonstrated that this family of PRRs is ­ collectively responsible for innate immune responses to an extraordinary array of PAMPs. In addition to its central role in the signaling of responses to LPS, TLR4 is involved in responses to multiple different self- and nonself-ligands.42 The antimitotic agent Taxol has been shown to mimic LPS-induced signaling in mouse cells through a pathway that requires both TLR4 and MD2.63-65 Other foreign ligands of TLR4 are the fusion protein (F protein) of respiratory syncytial virus66,67 and heat-shock protein 60 (HSP60) of chlamydia.68,69 Interestingly, TLR4 can also signal in response to mammalian HSP60, a protein expressed at increased levels and most likely released by stressed or damaged cells.70 This represents a variation of the pattern-recognition principle in which the pattern is not a PAMP produced directly by a pathogen but rather a structural feature associated with infected or physically damaged cells of the host. Other examples of TLR4’s recognition of self-components include responses to oligosaccharide breakdown products of tissue hyaluronans and respon­ ses to the extra domain A region of fibronectin produced by alternative RNA splicing in response to tissue injury or inflammation.71,72 The range of PAMPs recognized through TLR2 is probably even greater than for TLR4. TLR2 is known to be involved in signaling in response to multiple PAMPs of gram-­negative and gram-positive bacteria, including such structures as bacterial glycolipids, bacterial lipoproteins, parasite-derived glycolipids, and fungal cell wall polysaccharides.54,73-76 TLR2 does not function independently in responding to these PAMPs; it forms heterodimers with either TLR1 or TLR6. This ability to pair with other TLRs appears to be unique to TLR2, because other TLRs that have been studied carefully (e.g., TLR4, TLR5) most likely function only as monomers or homodimers. Other TLRs with currently defined ligands are TLR5 (involved in the response to bacterial flagellin),77 TLR3 (double-stranded RNA),78 TLR7 (single-stranded RNA),79 and TLR9 (unmethylated bacterial DNA).80 It is apparent that most,

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if not all, microbes contain multiple PAMPs that are recognized by different TLRs. For example, a typical bacterium expressing LPS also contains unmethylated DNA and thus generates signals not only through TLR4 but potentially through TLR9 as well. Because different TLRs are capable of activating distinct signaling cascades (see Fig. 16-3), the ability of a single cell to detect several different features of a pathogen simultaneously with multiple TLRs may help the innate immune response be more finely tuned to respond to a particular challenge.81 CARD and PYRIN Domain Proteins. A large number of ­cytosolic proteins that have structural similarities to the membrane-bound TLRs and also function as sensors for PAMPs of intracellular pathogens and regulators of innate immune responses have been identified. Many of these proteins contain LRR domains and have been classified based on their incorporation of a CARD or PYRIN domain. The nomenclature and classification schemes for this growing family of innate immune sensors and regulators are still evolving, and it has been proposed that they all be grouped and classified as members of a single family designated the CATERPILLER (CARD, R [purine]-binding, pyrin, lots of leucine repeats) family.82 The first intracellular microbial sensors in this family to be described were the Nod1 and Nod2 proteins, which contain LRR domains linked to a central nucleotide binding and oligomerizaion (NOD or NACHT) domain and an N-terminal CARD domain.83 As in the case of TLRs, the LRR domains of these proteins appear to be involved in the recognition of pathogen-derived molecules, and their CARD domains are linked to downstream signaling for the activation of innate immunity. Although originally implicated in responses to bacterial LPS, it is now well accepted that both Nod1 and Nod2 are primarily involved in the recognition of muropeptide monomers released from bacterial cell wall peptidoglycans.43 Signals resulting from the recognition of peptidoglycan components by Nod1 and Nod2 lead to activation of the NF B pathway, as in the case of TLR signaling. However, other signaling pathways also appear to be engaged, such as the activation of procaspase-1 and caspase-9 by CARD domain interactions, leading to increased production of IL-1β and cell death by apoptosis.84 The PYRIN domain–containing proteins are believed to signal in response to microbial invasion or cellular stress. The prototype member of this family is pyrin, which is the product of the gene that is mutated in those with familial Mediterranean fever.82 Although pyrin itself lacks an LRR domain, there are numerous other members of this family that contain an LRR linked to a central NOD domain and an N-terminal PYRIN domain. These include cryopyrin, which is mutated in patients with a range of hereditary inflammatory diseases now referred to collectively as cryopyrin-associated periodic syndromes. These multiple related proteins constitute the Nalp family (NACHT-LRR-PYDcontaining proteins).43,82,85,86 The human genome contains 14 genes encoding Nalp proteins, the precise functions of which are mostly unknown. However, two of these (Nalp6 and Nalp12) have been shown to activate or regulate the NF B pathway.43 In addition, several Nalp proteins have been identified as key components in the formation of intracellular complexes known as “inflammasomes,” which are involved in the activation of caspases required for the

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processing of inflammatory cytokines, including IL-1β and IL-18.87 The direct recognition of specific PAMPs by Nalp proteins remains to be established, although initial studies implicate these proteins as either direct or indirect ­sensors of various stimuli, including constituents of bacteria (­peptidoglycan, bacterial RNA, exotoxins), viruses (doublestranded RNA), and uric acid crystals.88-91

EFFECTOR MECHANISMS OF INNATE IMMUNE RESPONSES The ability to recognize pathogens through PRRs allows numerous antimicrobial effector mechanisms to be activated by the innate immune response. These responses lead to the killing of pathogens through the production of ­effector molecules with direct microbicidal activities, including the membrane attack complex of complement, a variety of antimicrobial peptides, and the caustic reactive oxygen and reactive nitrogen intermediates generated within phagocytic cells. In invertebrates, these mechanisms represent virtually the entire protective response against microbial invaders. However, in most vertebrates, including mammals, innate immune recognition also has profound effects on triggering and programming the adaptive immune response that follows somewhat later. This ability of the innate immune system to instruct the adaptive response has major implications for the development of long-term protective immunity to infections and may also play a critical role in mechanisms leading to autoimmunity.

CELL TYPES MEDIATING INNATE IMMUNITY Many types of cells have the ability to mount at least a limited response to PAMPs, but the most effective cell types in this regard are the specialized phagocytes, such as macrophages, neutrophils, and dendritic cells. Upon recognition of microbial stimuli, these cells have the ability to upregulate NADPH oxidase by assembling the components of this enzyme complex on phagosomal membranes, leading to an oxidative burst that produces microbicidal superoxide ions.92 Many phagocytic cells also increase their expression of inducible nitric oxide synthase (iNOS, or NOS2) upon contact with various PAMPs.93,94 This leads to the production of reactive nitrogen intermediates, including nitric oxide and peroxynitrite, which have potent direct antimicrobicidal activities. These responses are synergistic because the antimicrobial activity of the phagocyte oxidase system is frequently enhanced by the expression of reactive nitrogen intermediates. INNATE-LIKE LYMPHOCYTES A number of distinct lymphocyte subsets also play important roles in innate immune responses. One group of such lymphocytes, the natural killer (NK) cells, appears to be a true member of the innate immune system. These lymphocytes do not express receptors generated by somatic ­recombination and thus depend on germline-encoded receptors for signaling their responses against pathogen-infected cells.95 NK cells participate in the early innate response against virally, and probably bacterially, infected cells through the expression of cytotoxic activity and the secretion of cytokines.96

Several other subsets of lymphocytes belonging to the T and B cell lineages have been identified as participants in the rapid response against pathogens to which the host has not previously been exposed. Although these cells express clonally variable, somatically rearranged antigen receptors (T cell antigen receptors or membrane immunoglobulins) and thus could be classified as components of the adaptive immune system, their manner of functioning is much more characteristic of innate than adaptive immunity. These innate-like lymphocytes (ILLs) may represent the remnants of the earliest primitive adaptive immune system, and they appear to have been conserved to varying degrees because they ­ continue to make specialized contributions to host immunity.97 Among the currently recognized ILLs are two B cell populations, known as the B1 and marginal zone B cell subsets.98,99 These are involved in the spontaneous production of natural antibodies, which are largely germline-encoded immunoglobulins that are reactive to commonly expressed microbial determinants. In addition, both these B cell populations generate rapid T cell–independent responses following bacterial challenges and thus contribute to the first line of immune defense that precedes the onset of adaptive immunity. Among the T cells, two populations of ILLs have been identified and characterized in detail: γδ T cells and NK T cells. The γδ T cells express somatically rearranging receptors that use a limited number of variable region genes and are thought to recognize a narrow spectrum of foreign or self-ligands.100 In humans, the specificities of two subsets of γδ T cells have been at least partially defined. One of these, the major circulating population expressing the Vδ2 gene product, responds rapidly and without prior immunization to a variety of small alkyl phosphate and alkyl amine compounds that are produced by many bacteria. Another subset, characterized by its expression of the Vδ1 gene product, responds to major histocompatibility complex (MHC) class I–related self-molecules of the MHC class I chain–related A and B (MICA/B) and CD1 families.101,102 These molecules may serve as markers of cellular stress and are upregulated on cells in the context of infection or inflammation, leading to the activation of Vδ1-bearing γδ T cells. A similar principle appears to be involved in the ­functioning of NK T cells, which are so named because of their coexpression of an αβ T cell antigen receptor and a variety of receptor molecules that are typically associated with NK cells.103 Like γδ T cells, NK T cells have somatically rearranged antigen receptors that use a limited array of V genes and most likely recognize a narrow range of foreign or self-antigens. A major population of NK T cells is reactive with the MHC class I–like CD1d molecule, and these ILLs appear to be activated by recognition of a variety of lipid or glycolipid ligands that can be presented by CD1d. Recently, several bacterial glycolipids have been identified as specific antigens that stimulate NK T cells, suggesting that these cells may be rapid responders that contribute to innate antibacterial immunity.104-106 A wide variety of mouse disease models have shown that NK T cells also make significant contributions to the development of adaptive immune responses and may play a particularly important role in immunoregulation to prevent autoimmunity.103

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ANTIMICROBIAL PEPTIDES Antimicrobial peptides are the key effector molecules of inducible innate immunity in many invertebrates and are now being increasingly recognized as important elements of innate immunity in higher animal species, including mammals.107 They are evolutionarily ancient components of host defense that are widely distributed throughout all ­multicellular organisms in the animal and plant kingdoms. More than 800 such peptides have been identified (for a current list, see  h ttp://www.bbcm.univ.trieste.it/∼tossi/amsdb.html), and their diversity is so great that it is difficult to categorize them. However, at a structural and mechanistic level, most of these peptides share several basic features. They are generally composed of amino acids arranged to create an amphipathic structure with hydrophobic and cationic regions. The cationic regions target a fundamental difference in ­membrane design between microbes and multicellular animals, which is the abundance of negatively charged phospholipid headgroups on the outer leaflet of the lipid bilayer. The preferential association of antimicrobial peptides with microbial membranes leads to a membrane-disrupting activity, most likely involving the interaction of the hydrophobic regions of the peptide with membrane lipids.108-110 Antimicrobial peptides produced in response to engagement of various PRRs account for the majority of the in­d­ucible immunity against microbes in many invertebrate animals and plants. Although these peptides are probably less central to host immunity in most vertebrates, there is evidence that they make important contributions to immunity in more highly evolved animals, including mammals.111 In humans, active antimicrobial peptides, such as the α- and β-defensins, are either constitutively or inducibly produced in skin and in epithelia of the gastrointestinal and respiratory tracts.112-116 These molecules most likely act as natural preservatives of epithelia that are colonized or frequently exposed to microbial flora. Because the acquisition of resistance against these agents by sensitive microbial strains is extremely unusual, antimicrobial peptides are of great interest as templates for the development of new antimicrobial pharmaceuticals.117

INFLUENCE OF INNATE MECHANISMS ON ADAPTIVE IMMUNITY In addition to functioning as a first line of defense against invading pathogens, another critical feature of the innate immune system in higher animals such as mammals is its effect on activating the adaptive immune system. In fact, it is now clear that in most situations, the adaptive immune system mounts a response to a pathogen only after the pathogen has generated signals via PRRs of the innate immune system. This principle is the basis for the adjuvant effect, which is the observation that antibody and T cell responses are efficiently generated against protein antigens only if these are introduced together with a nonspecific ­ activator of the immune system, which is generically known as an adjuvant. Most adjuvants are in fact extracts or ­products of bacteria, and it is now clear that in most or all cases, ­adjuvant effects result from activation of the innate immune response.118

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PAMPs (e.g., LPS)

Signaling PPR e.g., TLR4

Cytokines IL-1,-6,-12, etc.

Pathogen Endocytic PPR (e.g., MR)

NF-kB

B7 CD28 MHC

+ + + +

TCR +

Endo/Lys Antigen processing

T cell

APC Figure 16-5  Instruction of the adaptive immune response by the innate immune system. When an antigen presenting cell (APC) comes into contact with pathogen-bearing pathogen-associated molecular patterns (PAMPs), responses are triggered via innate immune mechanisms that dramatically alter the ability of the APC to stimulate an adaptive  (T cell–mediated) immune response. For example, signals generated by contact with PAMPs such as lipopolysaccharide (LPS) with Toll-like receptor 4 (TLR4) lead to the activation of transcription factor nuclear factor B (NF B), which enters the nucleus of the APC and assists in switching on genes for cytokines (e.g., interleukin [IL]-1, -6, and -12 and a variety of chemokines) and costimulatory molecules (e.g., the B7 family members CD80 and CD86). In addition, binding of the pathogen to endocytic pattern-recognition receptors (PRRs) such as the mannose receptor leads to the delivery of the pathogen to endosomes (Endo) and lysosomes (Lys). There, the protein antigens of the pathogen are partially degraded to generate antigenic peptides that can be presented by major histocompatibility complex (MHC) class II molecules for recognition by the T cell antigen receptors (TCRs) of specific T cells. These effects of pattern recognition by the innate immune system lead to expression of the signals required for the activation of quiescent antigen-specific T cells and the subsequent generation of specific antibodies. (Adapted from Medzhitov R, Janeway C Jr: Innate immunity. N Engl J Med 343:338, 2000.)

There are many ways in which innate immune responses can prime or potentiate the adaptive immune response (Fig. 16-5). In the case of T cell responses, one extremely ­important and well-recognized mechanism involves the upregulation of costimulatory molecules. T cells require at least two signals to become activated from a naive, resting state. One signal is provided through the T cell antigen receptor by its binding to a specific peptide ligand ­presented by an MHC class I or II molecule. The second signal is provided by one of several costimulatory ligands that are expressed by specialized antigen presenting cells such as dendritic cells. The best studied of these are the molecules of the B7 family—B7-1 (CD80) and B7-2 (CD86)—which engage the activating receptor CD28 on the surface of the T cell. The expression of B7 family costimulatory molecules on the surface of antigen presenting cells is controlled by the innate immune system, such that these molecules are induced to appear at functional levels only after PRRs, such as members of the TLR family, have been activated by ­recognition of their cognate PAMPs.50 Recent studies have shown that innate immune ­signaling through TLRs has a major impact on the responses of ­phagocytic antigen presenting cells, and it also provides an important second signal for immunoglobulin production by B cells. In the case of phagocytic cells, the uptake

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of microbes by phagocytosis and the subsequent maturation of the phagosome are stimulated by concurrent TLR signaling.119 In dendritic cells, which are the major antigen presenting cells for the priming of T cell responses, TLR signaling has a major impact on whether antigens from ­phagocytosed microbes are effectively presented on MHC class II molecules.120 For B cells responding to foreign antigens, it has been demonstrated that concurrent ­ signaling through TLRs is necessary for the efficient stimulation of T cell–dependent differentiation into plasma cells and subsequent antibody secretion.121 This concept is also relevant for T cell responses to ­autoantigens, including ­several prominent nuclear antigens that are targets of autoantibodies in rheumatic diseases.122-124 Innate immune responses also trigger the production of many cytokines and chemokines, which enhance the development of adaptive immune responses and change the nature of the adaptive response generated. For example, contact between dendritic cells and PAMPs such as LPS or bacterial lipoproteins leads to the production of IL-12 as a result of signaling through TLRs.74,118,125 This cytokine acts on ­antigen-specific T cells to promote their differentiation into T helper type 1 cells, which are associated with the production of interferon-γ and other effector mechanisms that favor the clearance of bacterial pathogens.126 In the case of myeloid-lineage dendritic cells, signaling through TLRs (and potentially other PRRs) induces a process known as maturation, which is associated with the increased ­ expression of antigen presenting and costimulatory molecules that enables the efficient priming of naive antigen-specific T cells.118,127 This requirement for the innate immune response to “switch on” the expression of molecules required for the priming and differentiation of T cell responses helps ensure that proinflammatory adaptive immune responses occur mainly in the setting of a relevant infectious challenge. After activation, helper T cells control other components of adaptive immunity, such as the activation of cytotoxic T cells, B cells, and macrophages. Innate immune recognition, there­ fore, appears to control all the major aspects of the adaptive immune response through the initial recognition of infectious microbes by PRRs. Recently, this paradigm has been extended and slightly reinterpreted by the observation that certain selfmolecules upregulated by cellular stress or damage can substitute for PAMPs of infectious microbes in activating adaptive immune responses.70,72 This more extended view, sometimes referred to as the “danger model,” helps explain why certain self-ligands produced or released in the setting of infection or tissue damage can function in essentially the same manner as the PAMPs associated with microorganisms.128-130

DISEASE ASSOCIATIONS INVOLVING INNATE IMMUNITY Given the obvious role of the innate immune response in virtually all types of infectious diseases, one might expect that gross defects in the mechanisms of innate immunity occur relatively rarely and in association with clinical immunodeficiency. In fact, there is increasing evidence that mutations that inactivate various innate immune pathways can lead to increased pathogen sensitivity in both laboratory mice and humans.12,40,111,131-133 Because many of the pathways leading to innate immunity are amplified

during recurrent or prolonged activation of the immune system, they must also participate in mediating tissue damage in chronic inflammatory diseases. In addition, certain ­ ­self-molecules that are produced or released at increased levels as a result of inflammation, including heat-shock proteins, nucleic acids, and microcrystals of monosodium urate or calcium pyrophosphate, may act in a manner analogous to PAMPs.70,122,124,134,135 These may signal through TLRs or other PRRs to stimulate adjuvant-like effects that increase the potential for autoreactive lymphocytes to be activated. Perhaps a more surprising finding has been that some defects in innate immunity are associated with a markedly increased predisposition to autoimmune disease. Several different mechanisms have been proposed to explain this paradoxical association. Mechanisms of the innate immune response play an important role in the clearance of self-antigens released from necrotic or apoptotic cells, resulting in a noninflammatory clearance of self-antigens that tends to favor tolerance rather than the stimulation of immune responses.136 Failure of such clearance may lead to excessive exposure to self-antigens, triggering normally silent autoreactive lymphocyte clones to expand and differentiate into effector cells. This may account for the development of lupus-like autoimmunity in mice with targeted deletion of the gene for the short pentraxin SAP, which, along with other components of the innate immune system, appears to play a significant role in the clearance of DNA-chromatin complexes.22,137 Reduced levels of serum mannose-binding lectin in humans also appears to be a risk factor for the development of systemic lupus erythematosus, possibly because of the role of this soluble PRR in facilitating the clearance of apoptotic cells.138 Deficiencies of the early components of the classic ­pathway of complement activation have been strongly associated with lupus-like autoimmunity in both humans and mouse models.139-143 This may also be the result of alterations in the clearance of apoptotic cells or other sources of selfantigens, resulting in the increased stimulation of normally silent autoreactive lymphocytes.144-146 An alternative, but nonexclusive, mechanism relates to the ­involvement of the complement system, particularly the early components C1 and C4, in facilitating the induction of self-­tolerance by the adaptive immune system by increasing the localization of autoantigens such as double-stranded DNA and nucleoproteins within the primary lymphoid compartment.140,147,148 Thus, a deficiency of C1 or C4 appears to result in a failure to delete or functionally inactivate autoreactive B cell clones as they arise during lymphopoiesis in the bone marrow.147,149 Studies carried out in mouse ­models ­suggest that this ­ tolerance-inducing mechanism is also ­ partially disrupted in animals that are deficient in a variety of other components of innate immunity, including SAP and the complement receptors CD21/CD35.137,147 Multiple examples of links between defects in signaling receptors of the innate immune system and chronic inflammatory diseases have emerged from studies of the CARD and PYRIN families of cytosolic PRRs. The first association of this type was provided by genetic mapping studies that identified the Nod2 protein as the product of the IBD1 locus, which contributes to disease susceptibility in a subset of patients with Crohn’s disease.150-153 This soluble PRR of the CARD family normally functions by inducing cytokine production in response to bacterial peptidoglycan, but

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mutant alleles associated with an increased risk of Crohn’s disease are defective in this function.150 In this case, it may be a failure of innate immunity to adequately control bacterial colonization or infection in the intestine that leads to the final expression of disease. Consistent with this view, a recent study has demonstrated diminished expression of a class of antimicrobial peptides (β-defensins known as ­cryptdins) in the Paneth cells from the ileum of patients with Crohn’s disease and Nod2 mutations.154 Other studies have established links between various members of the PYRIN family and specific chronic inflammatory disorders. These include the causative association of mutations in pyrin with familial Mediterranean fever and of cryopyrin with the cryopyrin-associated periodic syndromes.82 These diseases and other chronic inflammatory or autoimmune disorders associated with specific deficiencies in innate immune mechanisms are now frequently considered together as autoinflammatory diseases.155 The recognition that these diseases are frequently associated with a dysregulation of inflammatory cytokine production, in particular IL-1β, has led to some striking therapeutic advances in the treatment of selected patients using the systemic administration of the IL-1 receptor antagonist anakinra.156-158 Deficiencies in at least two populations of ILLs—NK cells and NK T cells—have also been associated with multiple autoimmune syndromes in both humans and mice.103,159-161 This is believed to reflect a significant role for these ILLs in regulating adaptive immune responses, although the precise mechanisms by which they act are still not fully understood. Given the complex interplay between innate and adaptive immunity, it is extremely likely that associations between alterations in innate immunity and autoimmune diseases will continue to emerge. As for some of the examples cited here, a fuller understanding of these associations is likely to lead to new and successful therapies for autoimmune and autoinflammatory diseases. REFERENCES   1. Agrawal A, Eastman QM, Schatz DG: Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system. Nature 394:744, 1998.   2. Schatz DG: Transposition mediated by RAG1 and RAG2 and the evolution of the adaptive immune system. Immunol Res 19: 169, 1999.   3. Flajnik MF: Churchill and the immune system of ectothermic vertebrates. Immunol Rev 166:5, 1998.   4. Alder MN, Rogozin IB, Iyer LM, et al: Diversity and function of adaptive immune receptors in a jawless vertebrate. Science 310: 1970, 2005.   5. Pancer Z, Saha NR, Kasamatsu J, et al: Variable lymphocyte receptors in hagfish. Proc Natl Acad Sci U S A 102:9224, 2005.   6. Pancer Z, Cooper MD: The evolution of adaptive immunity. Annu Rev Immunol 24:497, 2006.   7. Mushegian A, Medzhitov R: Evolutionary perspective on innate immune recognition. J Cell Biol 155:705, 2001.   8. Hoffmann JA, Reichhart JM: Drosophila innate immunity: An evolutionary perspective. Nat Immunol 3:121, 2002.   9. Fraser IP, Koziel H, Ezekowitz RA: The serum mannose-binding protein and the macrophage mannose receptor are pattern recognition molecules that link innate and adaptive immunity. Semin Immunol 10:363, 1998. 10. Stover C, Endo Y, Takahashi M, et al: The human gene for mannanbinding lectin-associated serine protease-2 (MASP-2), the effector component of the lectin route of complement activation, is part of a tightly linked gene cluster on chromosome 1p36.2-3. Genes Immun 2:119, 2001.

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38. Dunne DW, Resnick D, Greenberg J, et al: The type I macrophage scavenger receptor binds to gram-positive bacteria and recognizes lipoteichoic acid. Proc Natl Acad Sci U S A 91:1863, 1994. 39. Suzuki H, Kurihara Y, Takeya M, et al: A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection. Nature 386:292, 1997. 40. Thomas CA, Li Y, Kodama T, et al: Protection from lethal grampositive infection by macrophage scavenger receptor-dependent phagocytosis. J Exp Med 191:147, 2000. 41. Haworth R, Platt N, Keshav S, et al: The macrophage scavenger receptor type A is expressed by activated macrophages and protects the host against lethal endotoxic shock. J Exp Med 186:1431, 1997. 42. Takeda K, Kaisho T, Akira S: Toll-like receptors. Annu Rev Immunol 21:335, 2003. 43. Werts C, Girardin SE, Philpott DJ: TIR, CARD and PYRIN: Three domains for an antimicrobial triad. Cell Death Differ 13:798, 2006. 44. Dangl JL, Jones JD: Plant pathogens and integrated defence responses to infection. Nature 411:826, 2001. 45. Medzhitov R, Janeway C Jr: Innate immune recognition: Mechanisms and pathways. Immunol Rev 173:89, 2000. 46. Hashimoto C, Hudson KL, Anderson KV: The Toll gene of Drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein. Cell 52:269, 1988. 47. Gay NJ, Keith FJ: Drosophila Toll and IL-1 receptor. Nature 351:355, 1991. 48. Lemaitre B, Nicolas E, Michaut L, et al: The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973, 1996. 49. Kawai T, Akira S: Pathogen recognition with Toll-like receptors. Curr Opin Immunol 17:338, 2005. 50. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr: A human homologue of the Drosophila Toll protein signals activation of adap­ tive immunity. Nature 388:394, 1997. 51. Poltorak A, He X, Smirnova I, et al: Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in TLR4 gene. Science 282:2085, 1998. 52. Qureshi ST, Lariviere L, Leveque G, et al: Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (TLR4). J Exp Med 189:615, 1999. 53. Hoshino K, Takeuchi O, Kawai T, et al: Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: Evidence for TLR4 as the LPS gene product. J Immunol 162:3749, 1999. 54. Takeuchi O, Hoshino K, Kawai T, et al: Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 11:443, 1999. 55. Takeuchi O, Akira S: Genetic approaches to the study of Toll-like receptor function. Microbes Infect 4:887, 2002. 56. da Silva CJ, Soldau K, Christen U, et al: Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex transfer from CD14 to TLR4 and MD-2. J Biol Chem 276:21129, 2001. 57. Medzhitov R, Preston-Hurlburt P, Kopp E, et al: MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell 2:253, 1998. 58. Fitzgerald KA, Chen ZJ: Sorting out Toll signals. Cell 125:834, 2006. 59. Horng T, Barton GM, Flavell RA, et al: The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 420:329, 2002. 60. Yamamoto M, Sato S, Hemmi H, et al: Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420:324, 2002. 61. Kawai T, Akira S: TLR signaling. Cell Death Differ 13:816, 2006. 62. Belvin MP, Anderson KV: A conserved signaling pathway: The Drosophila Toll-dorsal pathway. Annu Rev Cell Dev Biol 12:393, 1996. 63. Kawasaki K, Akashi S, Shimazu R, et al: Involvement of TLR4/MD-2 complex in species-specific lipopolysaccharide-mimetic signal transduction by Taxol. J Endotoxin Res 7:232, 2001. 64. Kawasaki K, Gomi K, Nishijima M: Cutting edge: Gln22 of mouse MD-2 is essential for species-specific lipopolysaccharide mimetic action of Taxol. J Immunol 166:11, 2001. 65. Kawasaki K, Akashi S, Shimazu R, et al: Mouse Toll-like receptor 4.MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. J Biol Chem 275:2251, 2000.

66. Haynes LM, Moore DD, Kurt-Jones EA, et al: Involvement of Tolllike receptor 4 in innate immunity to respiratory syncytial virus. J Virol 75:10730, 2001. 67. Kurt-Jones EA, Popova L, Kwinn L, et al: Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol 1:398, 2000. 68. Sasu S, LaVerda D, Qureshi N, et al: Chlamydia pneumoniae and chlamydial heat shock protein 60 stimulate proliferation of human vascular smooth muscle cells via Toll-like receptor 4 and p44/ p42 mitogen-activated protein kinase activation. Circ Res 89: 244, 2001. 69. Vabulas RM, Ahmad-Nejad P, da Costa C, et al: Endocytosed HSP60s use Toll-like receptor 2 (TLR2) and TLR4 to activate the Toll/interleukin-1 receptor signaling pathway in innate immune cells. J Biol Chem 276:31332, 2001. 70. Ohashi K, Burkart V, Flohe S, et al: Cutting edge: Heat shock protein 60 is a putative endogenous ligand of the Toll-like receptor-4 complex. J Immunol 164:558, 2000. 71. Jiang D, Liang J, Fan J, et al: Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med 11:1173, 2005. 72. Okamura Y, Watari M, Jerud ES, et al: The extra domain A of fibronectin activates Toll-like receptor 4. J Biol Chem 276:10229, 2001. 73. Aliprantis AO, Yang RB, Mark MR, et al: Cell activation and apoptosis by bacterial lipoproteins through Toll-like receptor-2. Science 285:736, 1999. 74. Brightbill HD, Libraty DH, Krutzik SR, et al: Host defense mechanisms triggered by microbial lipoproteins through Toll-like receptors. Science 285:732, 1999. 75. Campos MA, Almeida IC, Takeuchi O, et al: Activation of Toll-like receptor-2 by glycosylphosphatidylinositol anchors from a protozoan parasite. J Immunol 167:416, 2001. 76. Akira S, Takeda K, Kaisho T: Toll-like receptors: Critical proteins linking innate and acquired immunity. Nat Immunol 2:675, 2001. 77. Hayashi F, Smith KD, Ozinsky A, et al: The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410:1099, 2001. 78. Alexopoulou L, Holt AC, Medzhitov R, et al: Recognition of doublestranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732, 2001. 79. Diebold SS, Kaisho T, Hemmi H, et al: Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529, 2004. 80. Hemmi H, Takeuchi O, Kawai T, et al: A Toll-like receptor recognizes bacterial DNA. Nature 408:740, 2000. 81. Underhill DM, Ozinsky A: Toll-like receptors: Key mediators of microbe detection. Curr Opin Immunol 14:103, 2002. 82. Ting JP, Kastner DL, Hoffman HM: CATERPILLERs, pyrin and hereditary immunological disorders. Nat Rev Immunol 6:183, 2006. 83. Kufer TA, Banks DJ, Philpott DJ: Innate immune sensing of microbes by Nod proteins. Ann N Y Acad Sci 1072:19, 2006. 84. Kufer TA, Fritz JH, Philpott DJ: NACHT-LRR proteins (NLRs) in bacterial infection and immunity. Trends Microbiol 13:381, 2005. 85. Neven B, Callebaut I, Prieur AM, et al: Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cellmediated autoinflammatory disorders CINCA/NOMID, MWS, and FCU. Blood 103:2809, 2004. 86. Tschopp J, Martinon F, Burns K: NALPs: A novel protein family involved in inflammation. Nat Rev Mol Cell Biol 4:95, 2003. 87. Martinon F, Burns K, Tschopp J: The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10:417, 2002. 88. Martinon F, Petrilli V, Mayor A, et al: Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237, 2006. 89. Kanneganti TD, Ozoren N, Body-Malapel M, et al: Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/ Nalp3. Nature 440:233, 2006. 90. Kanneganti TD, Body-Malapel M, Amer A, et al: Critical role for cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J Biol Chem 281(48):36560-36568, 2006. 91. Boyden ED, Dietrich WF: Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet 38:240, 2006. 92. Babior BM, Lambeth JD, Nauseef W: The neutrophil NADPH oxidase. Arch Biochem Biophys 397:342, 2002.

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93. Xie QW, Cho HJ, Calaycay J, et al: Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science 256:225, 1992. 94. Nathan C: Inducible nitric oxide synthase in the tuberculous human lung. Am J Respir Crit Care Med 166:130, 2002. 95. Vilches C, Parham P: KIR: Diverse, rapidly evolving receptors of innate and adaptive immunity. Annu Rev Immunol 20:217, 2002. 96. Biron CA, Nguyen KB, Pien GC, et al: Natural killer cells in antiviral defense: Function and regulation by innate cytokines. Annu Rev Immunol 17:189, 1999. 97. Bendelac A, Bonneville M, Kearney JF: Autoreactivity by design: Innate B and T lymphocytes. Nat Rev Immunol 1:177, 2001. 98. Berland R, Wortis HH: Origins and functions of B-1 cells with notes on the role of CD5. Annu Rev Immunol 20:253, 2002. 99. Martin F, Kearney JF: Marginal-zone B cells. Nat Rev Immunol 2:323, 2002. 100. Carding SR, Egan PJ: Gamma delta T cells: Functional plasticity and heterogeneity. Nat Rev Immunol 2:336, 2002. 101. Wu J, Groh V, Spies T: T cell antigen receptor engagement and specificity in the recognition of stress-inducible MHC class I-related chains by human epithelial gamma delta T cells. J Immunol 169: 1236, 2002. 102. Dutronc Y, Porcelli SA: The CD1 family and T cell recognition of lipid antigens. Tissue Antigens 60:337, 2002. 103. Yu KO, Porcelli SA: The diverse functions of CD1d-restricted NKT cells and their potential for immunotherapy. Immunol Lett 100: 42, 2005. 104. Mattner J, Debord KL, Ismail N, et al: Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434:525, 2005. 105. Kinjo Y, Wu D, Kim G, et al: Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 434:520, 2005. 106. Kinjo Y, Tupin E, Wu D, et al: Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria. Nat Immunol 7: 978, 2006. 107. Zasloff M: Antimicrobial peptides of multicellular organisms. Nature 415:389, 2002. 108. Shai Y: Mechanism of the binding, insertion and destabilization of phospholipid bilayer membranes by alpha-helical antimicrobial and cell non-selective membrane-lytic peptides. Biochim Biophys Acta 1462:55, 1999. 109. Yang L, Weiss TM, Lehrer RI, et al: Crystallization of antimicrobial pores in membranes: Magainin and protegrin. Biophys J 79: 2000, 2002. 110. Matsuzaki K: Why and how are peptide-lipid interactions utilized for self-defense? Magainins and tachyplesins as archetypes. Biochim Biophys Acta 1462:1, 1999. 111. Nizet V, Ohtake T, Lauth X, et al: Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature 414: 454, 2001. 112. Harder J, Bartels J, Christophers E, et al: Isolation and characterization of human beta-defensin-3, a novel human inducible peptide antibiotic. J Biol Chem 276:5707, 2001. 113. Harder J, Bartels J, Christophers E, et al: A peptide antibiotic from human skin. Nature 387:861, 1997. 114. Singh PK, Jia HP, Wiles K, et al: Production of beta-defensins by human airway epithelia. Proc Natl Acad Sci U S A 95:14961, 1998. 115. Cunliffe RN, Mahida YR: Expression and regulation of antimicrobial peptides in the gastrointestinal tract. J Leukoc Biol 75:49, 2004. 116. Cunliffe RN: Alpha-defensins in the gastrointestinal tract. Mol Immunol 40:463, 2003. 117. Shai Y: From innate immunity to de-novo designed antimicrobial peptides. Curr Pharm Des 8:715, 2002. 118. Schnare M, Barton GM, Holt AC, et al: Toll-like receptors control activation of adaptive immune responses. Nat Immunol 2: 947, 2001. 119. Blander JM, Medzhitov R: Regulation of phagosome maturation by signals from Toll-like receptors. Science 304:1014, 2004. 120. Blander JM, Medzhitov R: Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature 440:808, 2006. 121. Pasare C, Medzhitov R: Control of B-cell responses by Toll-like receptors. Nature 438:364, 2005. 122. Leadbetter EA, Rifkin IR, Hohlbaum AM, et al: Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416:603, 2002.

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123. Christensen SR, Kashgarian M, Alexopoulou L, et al: Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J Exp Med 202:321, 2005. 124. Lau CM, Broughton C, Tabor AS, et al: RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J Exp Med 202:1171, 2005. 125. Barton GM, Medzhitov R: Control of adaptive immune responses by Toll-like receptors. Curr Opin Immunol 14:380, 2002. 126. Constant SL, Bottomly K: Induction of Th1 and Th2 CD4+ T cell responses: The alternative approaches. Annu Rev Immunol 15: 297, 1997. 127. Banchereau J, Steinman RM: Dendritic cells and the control of immunity. Nature 392:245, 1998. 128. Matzinger P: The danger model: A renewed sense of self. Science 296:301, 2002. 129. Seong SY, Matzinger P: Hydrophobicity: An ancient damageassociated molecular pattern that initiates innate immune responses. Nat Rev Immunol 4:469, 2004. 130. Shi Y, Evans JE, Rock KL: Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425:516, 2003. 131. Mockenhaupt FP, Cramer JP, Hamann L, et al: Toll-like receptor (TLR) polymorphisms in African children: Common TLR-4 variants predispose to severe malaria. Proc Natl Acad Sci U S A 103: 177, 2006. 132. Schroder NW, Diterich I, Zinke A, et al: Heterozygous Arg753Gln polymorphism of human TLR-2 impairs immune activation by Borrelia burgdorferi and protects from late stage Lyme disease. J Immunol 175:2534, 2005. 133. Schroder NW, Schumann RR: Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis 5:156, 2005. 134. Liu-Bryan R, Scott P, Sydlaske A, et al: Innate immunity conferred by Toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystalinduced inflammation. Arthritis Rheum 52:2936, 2005. 135. Liu-Bryan R, Pritzker K, Firestein GS, et al: TLR2 signaling in chondrocytes drives calcium pyrophosphate dihydrate and monosodium urate crystal-induced nitric oxide generation. J Immunol 174: 5016, 2005. 136. Gershov D, Kim S, Brot N, et al: C-reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components, and sustains an antiinflammatory innate immune response: Implications for systemic autoimmunity. J Exp Med 192:1353, 2000. 137. Bickerstaff MC, Botto M, Hutchinson WL, et al: Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity. Nat Med 5:694, 1999. 138. Tsutsumi A, Takahashi R, Sumida T: Mannose binding lectin: Genetics and autoimmune disease. Autoimmun Rev 4:364, 2005. 139. Walport MJ: Complement and systemic lupus erythematosus. Arthritis Res 4(Suppl 3):S279, 2002. 140. Einav S, Pozdnyakova OO, Ma M, et al: Complement C4 is protective for lupus disease independent of C3. J Immunol 168: 1036, 2002. 141. Paul E, Pozdnyakova OO, Mitchell E, et al: Anti-DNA autoreactivity in C4-deficient mice. Eur J Immunol 32:2672, 2002. 142. Mitchell DA, Pickering MC, Warren J, et al: C1q deficiency and autoimmunity: The effects of genetic background on disease expression. J Immunol 168:2538, 2002. 143. Chen Z, Koralov SB, Kelsoe G: Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2. J Exp Med 192:1339, 2000. 144. Korb LC, Ahearn JM: C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: Complement deficiency and systemic lupus erythematosus revisited. J Immunol 158:4525, 1997. 145. Cutler AJ, Botto M, van Essen D, et al: T cell-dependent immune response in C1q-deficient mice: Defective interferon gamma production by antigen-specific T cells. J Exp Med 187:1789, 1998. 146. Mitchell DA, Taylor PR, Cook HT, et al: Cutting edge: C1q protects against the development of glomerulonephritis independently of C3 activation. J Immunol 162:5676, 1999. 147. Prodeus AP, Goerg S, Shen LM, et al: A critical role for complement in maintenance of self-tolerance. Immunity 9:721, 1998. 148. Paul E, Carroll MC: SAP-less chromatin triggers systemic lupus erythematosus. Nat Med 5:607, 1999.

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17

Adaptive Immunity Including Organization of Lymphoid Tissues Michael L. Dustin

KEY POINTS Lymphocytes are born and many self-reactive cells deleted in primary lymphoid tissues. Immune responses are usually initiated in secondary ­lymphoid tissues. Tertiary lymphoid tissue can be generated at sites of ­inflammation and may promote tissue-specific autoimmunity. Self-tolerance is established by antigen recognition in primary lymphoid tissues or elsewhere in the absence of ­inflammation. Generation of an adaptive immune response depends on ­innate immune system activation. Dendritic cells sense tissue-specific factors and innate ­immune stimuli in shaping T cell responses to antigens.

The adaptive immune system is so named because it can adapt to virtually any pathogen or toxin that enters the body. Although invertebrates defend themselves through innate immunity alone,1 vertebrates all have developed some form of adaptive immunity—the ability to generate novel receptors by genetic recombination mechanisms that can be selected to recognize diverse macromolecules associated with rapidly evolving pathogens.2 A molecule that can be recognized by the adaptive immune system is known as an antigen (Table 17-1). The ability to produce molecules and cells that can attack any biologic structure is a double-edged sword.2 Pathologic autoimmunity is not described in invertebrates, which evolved with a hard-wired immune system, whereas it is a common problem in vertebrates.3-6 Self-recognition must be offset by redundant mechanisms to produce self-tolerance. This chapter discusses some mechanisms involved in this process and the anatomy behind these. In addition to self-antigen, animals with adaptive immunity also are exposed to many harmless environmental antigens that have the potential to induce allergic reactions.7 Mechanisms to distinguish self from foreign, and benign foreign from harmful foreign, macromolecules are crucial processes in successful adaptive immunity. At the core of these mechanisms is the essential partnership of adaptive and innate immunity, first formulated by Janeway.8 Although the adaptive immune system can recognize any foe and focus powerful effector mechanisms to destroy this foe, its ability to calculate the relative risks of mounting an immune response or becoming tolerant to a given recognized structure is guided by innate recognition of pathogen-associated molecule patterns or inflammation associated with tissue destruction.

The function of the adaptive immune system is tightly linked to its anatomy.9-11 T lymphocytes are cells without boundaries that can be found in almost any tissue at any time. T lymphocytes and B lymphocytes are readily monitored in patients because they are reliably found in the blood of normal individuals. Most T lymphocytes and B lymphocytes are located in secondary lymphoid tissues, however, where they search for antigens. Three types of tissues concentrate lymphocytes—the primary lymphoid tissues, where these cells are born; the secondary lymphoid tissues, where they search for antigens; and tertiary lymphoid tissues, which form at sites of chronic inflammation. Secondary and tertiary lymphoid tissues have a characteristic and functionally important organization into B cell and T cell zones. All of the above-mentioned histologic findings are directly related to functional goals of the adaptive immune system, as is discussed subsequently. This chapter addresses the basics of adaptive immunity and its partnership with innate immunity in the anatomic contexts in which these responses occur.

LYMPHOCYTE MIGRATION PARADIGMS FOR HOMING, INTERSTITIAL NAVIGATION, AND EGRESS Because adaptive immunity is discussed in the context of secondary lymphoid tissues, this is a good time to review what is known about lymphocyte migration. It has been appreciated since the early 1960s that lymphocytes “recirculate” between secondary lymphoid tissues and the blood, and that on activation they take on different tissue-specific homing properties that are important for function.12 If one arbitrarily begins this circuit with a naive T cell in the blood, three distinct transitions can be considered: (1) interaction with the vessel wall and extravasation; (2) interstitial locomotion in the tissue parenchyma; and (3) egress from the tissue parenchyma back into the blood, sometimes via lymph. General features of these three steps are addressed here, and relevant details are commented on in different functional contexts in relation to adaptive immunity. MULTISTEP PARADIGM FOR EXTRAVASATION The movement of lymphocytes from blood to tissues is complicated by the high flow rates in blood vessels. Springer and Butcher established the current paradigm called the “multistep model” for T cell extravasation.13,14 The first step is the initial tethering of the free-flowing leukocyte to the vessel wall. A special class of adhesion molecules known as selectins and their carbohydrate ligands mediates this step (see Table 17-1).15,16 There are three 291

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Table 17-1  Terms and Definitions Antigen

Any molecular structure recognized by the adaptive immune system. The ligand for B cell receptor/antibody or T cell receptor

Chemokine

Family of small secreted or shed proteins (typically 8 kD) that bind to G protein–coupled ­receptors and activate or attract cells. A chemical (chemo-) that induces movement (-kine)

Integrin

Family of adhesion molecules that are specialized for stable adhesion and locomotion. Noncovalent heterodimers that are regulated rapidly by signaling from chemokine ­receptors and antigen receptors

Selectin

Family of adhesion molecules that are specialized for ­mediating initial attachment of leukocytes from flowing blood to the vessel wall. Have N-terminal C-type lectin domains and interact with carbohydrate ligands that can incorporate protein determinants

­ embers of the selectin family, called L-selectin, E-selectin, m and P-selectin.17 L-selectin is expressed on naive T cells and B cells and is essential for the entry of these cells into lymph nodes, but not the spleen.18,19 The ligand for L-selectin is a structure of sulfated sialic acid bearing complex carbohydrates linked to different protein backbones expressed on high endothelial cells in postcapillary venules in primary, secondary, and tertiary lymphoid tissues.15 E-selectin and Pselectin are expressed on activated endothelial cells at sites of inflammation in diverse tissues.20 They bind to glycoprotein ligands expressed on leukocytes, which have terminal sialyl-Lewisx blood group antigens, and can incorporate other structural modification.16 The high-affinity ligand for P-selectin is the protein backbone PSGL-1 with a stretch of sulfated tyrosines that compose part of the ligand.21,22 PSGL1 can be expressed by lymphocytes without the necessary secondary modification to make it a ligand for P-selectin. A fusion of P-selectin to immunoglobulin Fc that can be purified and fluorescently tagged is the best probe to determine if a leukocyte is competent to bind to P-selectin expressing endothelial cells.23 The genetic basis of forming selectin ligands is complex with requirements for expression of core proteins, specific sialotransferases, fucosyltransferases, and sulfotransferases.16 Defects in fucose metabolism are the basis for a rare genetic immunodeficiency/mental retardation syndrome called leukocyte adhesion deficiency type II.24 Selectins mediate only leukocyte tethering and rolling, not arrest and extravasation. Selectin-mediated tethering allows the leukocyte to bring G protein–coupled receptors close enough to the vascular wall to bind ligands either attached to glycoproteins or diffusing in the thin unstirred layer near the endothelial surface.25,26 Chemokine receptor signaling is crucial to activate closely linked integrin family members to bind their ligands.27 This chemokine signal is pertussis toxin ­sensitive, indicating

that it involves Giα coupled receptors. With respect to lymphocyte recirculation, there are three important chemokine receptors—CCR7, CXCR4, and CXCR5. CCR7, binding to ligands CCL19 and CCL21, is the most important chemokine system for entry of T cells into secondary lymphoid tissues.28 CXCR4 binding to its ligand CXCL12 also contributes to entry of T cells and B cells.29,30 CXCR5, binding to its ligand CXCL13, is the major system controlling entry of B cells into B cell follicles.31,32 After activation, CCR7 is downregulated on many effector T cells, and other chemokine receptors are upregulated allowing these cells to home to peripheral sites of inflammation.33,34 Activated endothelial cells in these tissues express ligands that selectively recruit subsets of activated T cells. In contrast, activated B cells either become memory cells that retain CXCR5 and CCR7 expression35,36 or differentiate into plasma cells that downregulate CXCR5 and CCR7 and upregulate CXCR4, targeting these cells to medullary cords and bone marrow.37 Integrin family members are the close recipients of chemokine signals to produce immediate arrest of rolling leukocytes and to initiate the extravasation process.27 The major integrin that mediates homing to secondary lymphoid tissues is LFA-1, which is composed of the αL and β2 subunits.38 LFA-1 is expressed only on leukocytes and binds to five different intercellular adhesion molecules (ICAMs) named ICAM-1 through ICAM-5, all of which are members of the immunoglobulin superfamily.39,40 ICAM-1 and ICAM-2 are the major ICAMs expressed on endothelial cells, with ICAM-1 displaying regulated expression in response to inflammatory mediators, such as tumor necrosis factor and interferon-γ.41,42 The deficiency of the integrin β2 subunit is the basis of a rare genetic syndrome known as leukocyte adhesion deficiency type I.43 In this disease, leukocyte extravasation at sites of inflammation is defective, and patients are highly susceptible to bacterial infections of the skin and mucous membranes. Patients with leukocyte adhesion deficiency type I are developmentally normal and can be treated by bone marrow transplantation with a high success rate.44 A leukocyte adhesion deficiency type III also has been described, in which multiple leukocyte integrins show defects in regulation of Rap1, a small G protein important in LFA-1 regulation.45 The structure of integrins reveals remarkable machinery for regulated adhesion.46-48 The inactive form is folded into a compact globular structure, in which the ligand-binding domain points toward the leukocyte surface.47 After activation by chemokines, the integrin extends to twice its original height and projects the ligand binding site to greater than 20 nm from the leukocyte membrane, with orientation toward the endothelial cell surface.47,49 This dramatic change is closely coupled to cytoskeletal association, providing anchorage needed for arrest and cell spreading after ligand binding.50,51 A second integrin expressed on naive lymphocytes called VLA-4 is composed of the α4 and β1 subunits and can play a small role in entry into lymph nodes, but a major role in entry into inflamed sites.52 Its ligand is VCAM, also a member of the immunoglobulin superfamily regulated by inflammatory cytokines.53 When T lymphocytes are activated to home to mucosal effector sites, they upregulate expression of the integrin β7 subunit, which also ­ associates with α4 to form the gut homing ­ integrin

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α4β7,54 and bind a ­ different immunoglobulin superfamily ligand called MAdCAM (for mucosal addressin) expressed on endothelial cells in the gut.55 The extravasation process involves the movement of lymphocytes between or through endothelial cells.56 The endothelial junctional complexes include special adhesion molecules that need to be transiently disengaged to allow lymphocyte passage between endothelial cells.57 Although the observation that lymphocytes seem to move through endothelial cells by a transcellular route was first made by Marchesi and Gowans in the early 1960s,58 the molecular basis of this transcellular route and its acceptance as a legitimate pathway have been more recent. The transcellular pathway may be dominant in situations in which the endothelial junctions are particularly sturdy, as in the brain, thymus, or lymph nodes. Junctional and transcellular routes involve active processes in the leukocyte and endothelial cells, but this step is not thought to be regulated to control homing decisions. Three types of receptor ligand pairs define the key regulated steps in lymphocyte homing. The compatibility of all three is required to gain entry into the tissue. If a compatible selectin-ligand pair is not available, the leukocyte is unable to initiate adhesion to the endothelial wall and flows past. If a chemokine receptor–chemokine pair is unavailable, it is impossible to activate integrins, even if the selectin-ligand pair mediates rolling or tethering, and the cell eventually releases and remains in the blood. If the integrin-ligand pair is incompatible, the cells are unable to arrest and extravasate, even if the selectin-ligand pair and chemokine-ligand systems are engaged. These molecular pairs can be thought of as a hierarchic area code for lymphocyte homing—the digits defined by the compatible interactions, each of which must be correctly engaged to allow entry.59 TISSUE ORGANIZATION AND INTERSTITIAL MIGRATION Classic histology and mouse genetics have been used to establish the molecular mechanisms that account for the segregation of T cells and B cells within secondary lymphoid tissues. The T cell zone is defined by the production of CCL19 and CCL21 by stromal cells and the expression of CCR7 on T cells.28,60 These are the same signals that trigger the arrest of T cells on endothelial cells for tissue entry. T cell zones also are amply populated by conventional dendritic cells (DCs), which express CCR7 as they mature. DCs seem to form a network on a scaffold of reticular fibers.61 The parenchyma of lymph nodes and splenic white pulp nodules are crisscrossed by thick collagen bundles sheathed in fibroblastic reticular cells.62-65 The inner compartment of these fibers forms a network of conduits in the lymph node and spleen that allows DCs in the parenchyma access to the afferent lymph or blood. The B cell follicles depend on CXCL13 expressed by follicular stromal cells and CXCR5 expressed on B cells.60 The balance of CXCR5 and CCR7 expression by B cells controls their proximity to the boundary between T cell zone and B cell zone, where B cells can encounter helper T cells.35,36 B cell zones also are populated by variable numbers of follicular DCs, which are differentiated stromal cells, rather than cells of hematopoietic origin.66,67

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The dynamics of immune cells in secondary lymphoid tissues has been revealed by intravital fluorescence microscopy. The leading model for T cell interaction with DCs in the lymph node was based on thinking of the reticular fiber network as defining corridors along which the T cells would migrate to make contact with lined-up DCs, a “receiving line” model.9 Two-photon laser scanning fluorescence microscopy of fluorescently labeled T cells in explanted lymph nodes in short-term cultures and later in live mice revealed a totally different reality.68-71 The T cells did not migrate in lines at all, but appeared to migrate randomly within the T cell zones. The boundaries for confinement in the T cell zone were large compared with the imaged areas such that quantitative analysis revealed a true random walk with a short persistence length of a few micrometers between changes in direction. The speed of migration was up to 30 μm/min with an average speed of approximately 12 μm/min, which is fast for ameboid locomotion. B cells in follicles move about 30% more slowly, but in a similar random pattern. When mice in which all DCs were fluorescently labeled were imaged, it appeared that the antigen presenting cells were largely sessile.61 The process by which a DC that has brought antigen from the periphery can show this antigen to many T cells is based on forming random contacts with thousands of T cells per hour. Because of its random nature, this model has been referred to as “stochastic repertoire scanning.” The signals that stimulate the rapid and random migration in lymph nodes are unknown. The speed of B lymphocyte migration is significantly reduced in mice lacking Giα2 subunit of G protein–coupled receptors, suggesting that chemokines may have a role in this process.72 Chemokines can act as chemoattractants, but also can stimulate migration in a random fashion—called chemokinesis—under some conditions. It is possible that the conditions in the lymph node are highly favorable for chemokine-induced chemokinesis, and that this is the signal for the rapid, random migration of T cells and B cells in the steady state. Although the initial scanning process is random, when antigen bearing DCs begin to interact with antigen-specific T cells, many nonrandom elements of migration are established. B cells that recognize antigen upregulate CCR7 and downregulate CXCR5 such that they are attracted to the boundary between the T cell and B cell zones.35 DCs that have been in contact with CD4+ T cells produce CCL3 and CCL4, which attract CD8+ T cells under inflammatory conditions.73 This directed migration of CD8+ T cells biases the scanning of the CD8+ T cell repertoire toward DCs that have received T cell help and have come into contact with foreign antigens. This process likely increases the efficiency of repertoire scanning. IMMUNOLOGIC SYNAPSES MAINTAIN ANTIGEN-SPECIFIC INTERACTIONS WITH DENDRITIC CELLS The most extreme change in lymphocyte migration during an immune response is the near full arrest referred to as an immunologic synapse.74,75 In vitro analysis has revealed elaborately organized structures underlying the arrest of T cell migration in contact with DCs bearing appropriate major histocompatibility complex (MHC)–peptide complexes.76,77

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In vivo imaging analysis has repeatedly revealed stable T cell–DC interactions as a common feature of tolerance and immunity induced by high-affinity ligands.78-80 This ability of antigen presenting cells to stop T cells seems to be more related to MHC-peptide strength than the level of innate stimulation, although this may differ for CD8+ versus CD4+ T cells.80-82 EGRESS FROM LYMPH NODES AND THE THYMUS—SPHINGOSINE-1-PHOSPHATE The recirculation of lymphocytes required that they periodically cease their scanning activity in the relevant secondary lymphoid tissue zones and exit the tissue to the lymph or blood. Such egress processes also are important for recently matured lymphocytes to leave the bone marrow or thymus to enter into the recirculating pool. Insights into the molecular processes controlling egress from lymph nodes and the thymus were provided through investigation of the fungal metabolite FTY720, which is in clinical trials as an immunosuppressive drug.83 FTY720 administration rapidly induced reduction in T cells and B cells in the peripheral blood. FTY720 was found to be phosphorylated by sphingosine kinase and to act as an agonist for many sphingosine-1-phosphate receptors that are expressed on lymphocytes and endothelial cells.84 Further insight was provided by the study of bone marrow chimeric mice in which fetal liver cells from embyronic lethal sphingosine1-phosphate receptor 1 (S1P1) knockout mice were used to reconstitute lethally irradiated syngeneic wild-type mice.85 The S1P1-deficient single positive thymocytes were unable to exit the thymus. When single positive thymocytes were transferred into wild-type recipients, they were able to enter lymph nodes normally, but could not exit. These results suggested a T cell autonomous defect in egress from the thymus and lymph node. Although FTY-720-P is an agonist of S1P1, it has the effect of downregulating expression of the receptor such that the compound recapitulates the knockout phenotype. A parallel study with reversible S1P1 agonists and antagonists suggested that S1P1 also has a role in controlling lymphatic endothelium permeability to T cell transmigration.86

PRIMARY LYMPHOID TISSUES: SITES WHERE T CELLS AND B CELLS ARE GENERATED, AND SELF-TOLERANCE MECHANISMS ARE INITIATED The critical event in the birth of T cells and B cells is the rearrangement of the antigen receptor genes to generate T cell antigen receptors (TCR) and B cell antigen receptors (BCR) that are expressed on the cell surface. Each T cell and B cell has a single antigen receptor as birth certificate and identification card. The life, death, or expansion of each of these cells controls the availability of this antigen binding structure to the adaptive immune system. This is the heart of the clonal selection theory first proposed by Burnett in the 1950s. Self-reactive cells need to be deleted or inactivated shortly after birth. This process occurs in the bone marrow for B cells and the thymus for T cells. The anatomy of these two sites is very different in keeping with

the dramatically different recognition mode employed by B cells and T cells. The bone marrow space is discussed first followed by the functional anatomy of the thymus. B CELL DEVELOPMENT IN THE BONE MARROW Immature B cells express surface BCR composed of surface immunoglobulin noncovalently complexed to the signal transducing subunits Igα and Igβ.87 Self-tolerance can be established if these immature B cells are exposed to self-­antigens leading to apoptosis or inactivation of the B cells.88,89 Three major sources for this antigen can be identified anatomically. The first source is the bone marrow stroma and other developing hematopoietic cells. If BCR encounter surface immobilized antigens on these cells, they undergo apoptosis.90 The second source is the blood. The bone marrow parenchyma is bathed in blood plasma antigens owing to fenestrated endothelial cells lining bone marrow sinusoids. When soluble antigens bind to BCR, the B cells may undergo apoptosis if the antigen is multivalent and cross-links the BCR inducing strong signaling. If the antigen is monovalent, the B cell may become anergic—a form of nonresponsiveness that is induced by weaker signaling through the BCR.90 The third source is mature DCs that populate the bone marrow parenchyma. These cells seem to migrate from secondary lymphoid tissues via the efferent lymph such that these cells may be responsible for bringing tissue-specific antigens to the bone marrow to allow negative selection of immature B cells specific for these antigens.91 The idea that conventional DCs (distinct follicular DCs are discussed later) present intact antigens to B cells has gained strength in recent years.92 The identification of a migration pathway for mature DCs to the bone marrow has been described only recently, and the implications for tolerance induction have not been fully investigated. T CELL DEVELOPMENT IN THE THYMUS T cell precursors arrive in the thymus and initiate TCR gene rearrangement in this microenvironment. The thymus is an epithelial organ formed during development from the third pharyngeal arch. Histologically, the tissue has a clearly distinguishable cortex, medulla, and vascular corticomedullary junction.11 Figure 17-1 shows fluorescence staining with Ulex europeus antigen-1 lectin, a marker for the thymic medulla, on the left side and MHC class II antigen in the thymic cortex on the left side.93 The stepwise path of thymocyte migration is outlined on the left. Early CD4− and CD8− progenitors enter via postcapillary venules at the corticomedullary junction (step 1) and migrate to the subcapsular region of the cortex where TCR gene rearrangement occurs, and CD4 and CD8 become expressed on the surface of immature T cells, also called thymocytes (step 2). These cells migrate randomly among thymic epithelial cells in the cortex sampling self-MHC– peptide complexes (step 3). If they express a TCR that recognizes self-MHC–peptide complexes with low affinity, they undergo “positive selection.” Positively selected thymocytes mature into CD4+ or CD8+ cells that migrate to the medulla under control of CCR7 ligands (step 4).94,95 Medullary thymic epithelial cells express a transcription factor called AIRE

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Figure 17-1  Section of mouse thymus stained with Ulex europeus antigen-1 lectin (left) or anti–major histocompatibility complex (MHC) class II (right) visualized with immunofluorescence microscopy. The Ulex europeus antigen-1 staining is strongest in the medulla, but also highlights the capsule and stroma of the cortex. The cortical thymic epithelial cells are strongly positive for MHC molecules, which allow negative and positive selection of thymocytes. (Courtesy of Richard Lewis, Stanford University. From Bhakta NR, Oh DY, Lewis RS: Calcium oscillations regulate thymocyte motility during positive selection in the three-dimensional thymic environment. Nat Immunol 6:143-151, 2005.)

that mediates expression of numerous tissue-specific genes.96 Rare patients lacking expression of AIRE have a complex autoimmune syndrome characterized by polyendocrinopathy and other tissue-specific autoimmune diseases. The hypothesis is that AIRE-mediated transcription of tissue-specific genes in thymic epithelial cells promotes negative selection of some autoreactive T cells and may promote generation of tissue antigen–specific regulatory T cells (step 5). The small percentage of thymocytes that express a TCR that pass positive and negative selection downregulate CD69 and S1P1 and exit the lymph nodes as naive mature T cells (step 6).

SECONDARY LYMPHOID TISSUES: SITES WHERE ANTIGEN FINDS RARE SPECIFIC T CELLS AND B CELLS The frequency of naive T cells that recognize any particular antigen is so low that it has been challenging to estimate. Enrichment methods using antibody-coated magnetic beads have been developed that facilitate direct measurement of precursors by flow cytometry with high-avidity MHC-peptide–based probes known as tetramers.97 The number of cells specific for commonly used model antigens is approximately 500 in most mouse strains when pooling cells from all secondary lymphoid tissues (spleen and lymph nodes). There are approximately 500 million total CD4+ T cells in these tissues, such that antigen presenting DCs need to make contact with 1 million irrelevant T cells to find one specific T cell. A few antigen-positive DCs early in an infection need to have access to highly concentrated swarms of T cells in secondary lymphoid tissues to sample enough T cells to find a few specific precursors to activate and expand. As described earlier, this search process is initially random, but may become more directed and efficient as a response progresses. Although naive T cells recirculate in an unbiased manner through secondary lymphoid tissues, the antigen carrying cells, primarily DCs, have a high degree of regional bias in their movement, such that they are thought to relay information about innate immune stimulation and tissue of origin of antigens. When these antigen-specific cells come into contact with DCs, they form immunologic synapses; integrate signals through the TCR and costimulatory ligands, which represent part of the innate immune system contribution to T cell activation; and divide more than 20 times with very

short cell cycle times of approximately 6 hours.98,99 Expansion of CD8+ T cells, which give rise to cytotoxic effector cells, is greater in general than expansion of CD4+ T cells, which give rise to various types of helper T cells. After expansion, which peaks around 7 to 10 days, the infectious agent is often eradicated, and most of the effector T cells undergo apoptosis. The flulike symptoms associated with viral infections are due to cytokines produced by the dividing and differentiating T cells. Because primary adaptive responses take a week or longer to develop, the host depends on innate immune mechanisms, such as natural antibodies, neutrophils, interferons, and natural killer cells, to control the infection until sufficient numbers of effector T cells are generated. Thousands of the expanded T cells that survive after the pathogen is destroyed become memory cells.100,101 There are two subsets of memory T cells: Central memory cells express L-selectin, CCR7, and LFA-1 and recirculate via secondary lymphoid tissues, and effector memory cells lack L-selectin and CCR7, but may express P-selectin and E-selectin ligands and other chemokine receptors, such as CXCR4, CCR5, CCR4, and CCR9.33,102 These effector memory cells migrate to peripheral sites of inflammation and are equipped for rapid effector function if they encounter antigen. Memory cells respond rapidly to recurrence of the same infection and together with antibodies rapidly eradicate that same agent if it is encountered a second time. These memory cells also may cross-react with other pathogens, and depending on the degree of cross-reaction, this type of response can result in rapid clearance of a new pathogen or sometimes an impaired response.103 ANTIGENS FROM BLOOD ARE DETECTED MOST EFFICIENTLY IN SPLEEN AND LIVER (PORTAL SYSTEM) The spleen is a large visceral organ that filters approximately 5% of the cardiac output. The red pulp is an important location for removal of aged red blood cells from the circulation. The red pulp also contains many DCs that come into direct contact with naive T cells that are in the blood. The function of these red pulp DCs is unknown. Most attention has been focused on the white pulp nodules and the marginal zone as sites of T cell–DC interaction and antigen capture (Fig. 17-2, left). Blood flows into

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Figure 17-2  Organization of the spleen. Left, Tissue section from a mouse injected with low-molecular-weight (blue) and high-molecular-weight (red) fluorescent dextrans. The low-molecular-weight dextran labels the red pulp (blue) and the high-molecular-weight dextran labels macrophages in the marginal zone (red) such that the white pulp nodule containing approximately 109 lymphocytes per cm3 is dark. The white pulp nodule forms around a central arteriole from which smaller arterioles branch to the red pulp sinuses. B and T cells are segregated into follicles (B cells) and the periarteriolar lymphoid sheath (T cells). (Scale bar 0.2 mm.) Right, Image of a live mouse spleen during injection of low-molecular-weight fluorescent dextran. The blood carrying the dextran passes through the white pulp in small blood vessels (arrows) emanating from the central arteriole (not shown) and connected to red pulp sinuses that rapidly fill with blood, which fills the marginal sinus, but not the white pulp itself. In this image, approximately 0.3% of the T cells in the periarteriolar lymphoid sheath are labeled with a fluorescent dye. These areas are packed with T and B cells. Marginal zone macrophages and  B cells have direct access to blood to capture pathogens. White pulp lymphocytes are not in direct contact with blood and need antigen presentation by cells that migrate from the marginal zone or antigens that are delivered to dendritic cells via reticular fibers.65 (Scale bar 0.1 mm.) (Courtesy of Janelle Waite, New York University.)

the spleen via an artery that splits into arterioles, which empty into venous sinuses in the marginal zone and red pulp (Fig. 17-2, right). The blood is then recollected into a venous system that drains to the liver, joining with the portal tract. The arterioles are surrounded by sheaths of T cells (periarterial lymphoid sheath [PALS]) that make up the T cell zones of the white pulp. Bridging channels connect the red pulp, where lymphocytes leave the blood, to the PALS, where they migrate in a pertussis toxin–sensitive manner.104 B cell follicles and the marginal zone surround the PALS. Macrophages, DCs, and marginal zone B cells line the marginal zone where they have direct access to blood antigens. DCs that pick up antigens in the marginal zone migrate to the PALS.105 A reticular fiber network connects the marginal zone to the PALS and allows soluble antigens from the blood to reach resident DCs in the PALS.65 The spleen provides multiple opportunities to mount primary and recall responses to particulate or soluble antigens in the blood. As mentioned previously, the spleen drains into the liver. Immune responses in the liver are poorly understood, but this is an important site because many pathogens colonize the liver.103,106 Two blood circulations supply the liver—the portal vein with deoxygenated blood from the gut and spleen and the hepatic artery with oxygenated blood. These circulations mix in the liver sinusoids, a low-pressure network of blood spaces between sheets of hepatocytes connecting the portal tract and the central collecting vein. Most of the liver parenchyma appears as plates of hepatocytes alternating with blood-carrying sinusoids (Fig. 17-3, left). The liver is rich in a type of sessile macrophage called a Kupffer cell and patrolling lymphocytes, particularly natural killer T cells (Fig. 17-3, right).107 The major antigen presenting cell in the liver is not the

Kupffer cell, but the perivascular Ito cells.108 The liver also plays an important role in the clearance of B cells mediated by therapeutic anti-CD20 antibodies that are used to treat patients with rheumatoid arthritis.109 ANTIGENS FROM MUCOSAL SURFACES ARE DETECTED MOST EFFICIENTLY IN PEYER’S PATCHES AND MESENTERIC LYMPH NODES The mucosal-associated lymphoid tissues include the tonsils, Peyer’s patches, lamina propria, cryptopatches, and appendix. Populations of Peyer’s patch and lamina propria DCs have different mechanisms for sampling the contents of the gut lumen. Peyer’s patches are composed of large B cell follicles with smaller T cell zones (Fig. 17-4, left). They have high endothelial venules that allow efficient entry of naive T cells and B cells and memory cells with gut homing phenotypes.110 The large size of the follicles in Peyer’s patches causes a domelike effect with the epithelium protruding into the lumen. Some of the microvilli-laden absorptive epithelial cells in this dome region are replaced by smooth-surfaced M cells. These cells act as relay points for entry of enteric pathogens into the dome region of Peyer’s patches where a population of CCR6+ DCs efficiently presents pathogenrelated antigens to induce rapid local T cell responses (Fig. 17-4, bottom left).111 In contrast to Peyer’s patches, the core of the villi in the terminal ilium is populated by activated T cells, plasma cells, and CX3CR1+ DCs. These DCs, project thin processes through the epithelial sheet directly into the gut lumen (Fig. 17-4, right).112,113 The function of these cells is unknown, but they seem to actively sample the gut contents and then could migrate to mesenteric lymph nodes via the large lymphatic ducts. Because the mesenteric lymph nodes are sites at which

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Figure 17-3  Microcirculation and immune cells in liver. Left, Intravital imaging of blood space in mouse liver. Confocal imaging of hepatocytes (green autofluorescence) and blood space (red fluorescent dextran). The flow pattern is toward the center of the image panel. Right, Intravital imaging of NKT cells (bright green) and SIGN R1+ Kupffer cells in liver sinusoids (dark spaces) between hepatocytes (faint green autofluorescence). The Ito cells also would be lining the sinusoids, but on the other side of the endothelial cells in the space of Disse. (Courtesy of Tom Cameron, New York University.)

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tolerance to food antigens is established, it is possible that this more direct sampling of the gut lumen has a role in oral tolerance to food antigens.82 ANTIGENS FROM OTHER TISSUES AND SOLID ORGANS ARE DETECTED IN PERIPHERAL LYMPH NODES An extensive network of peripheral lymph nodes filters lymph from the skin, organs, and nervous system. Lymph is composed of fluid that leaves blood vessels and then must be collected from the tissues in afferent lymphatic vessels, passes through at least one lymph node, exits the lymph node as efferent lymph, and is returned to the blood via conduits such as the thoracic duct. The afferent lymphatics of a lymph node connect to the capsule

Figure 17-4  Gut-associated lymphoid tissues. Top left, Immuno­ fluorescence image of Peyer’s patches with B cells in green and T cells in red.31 Bottom left, A similarly ­oriented view of Peyer’s patches from mouse in which CCR6+ ­dendritic cells also express GFP owing to ­targeting of green fluorescent protein (GFP) to CCR6 locus.111 Right, Images of CD11c+ ­ dendritic cells in the tips of microvilli in the terminal ilium after exposure to Salmonella bacteria. The dendritic cells extend processes through the epithelial layer to facilitate bacterial uptake.113 The CCR6+ dendritic cells, rather than the CX3CR1+ lamina propria dendritic cells, seem to be the most important for the T cell ­response to Salmonella antigens.

of the node and drain into the subcapsular sinus, which contains many macrophages (Fig. 17-5). The floor of the subcapsular sinus covers the lymph node parenchyma and is the point of origin of the reticular fiber network that connects to the high endothelial venules and medullary cords, where cells move from the parenchyma into the efferent lymph. Lymph does not come into direct contact with cells in the parenchyma, but cells lining the reticular fibers and a space between the high endothelial venules and the reticular fibroblast sheath are exposed to lymph fluid.9,62,63 The parenchyma is divided into T cell and B cell zones defined by CCL19/21 and CXCL13 producing stroma (see Fig. 17-5). DCs migrate from peripheral tissues in a CCR7dependent manner and join networks of DCs in the T cell zones with scattered cells in the follicles.61,114 Emigrant DCs

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Figure 17-5  Lymph node schematic and dendritic cell morphologies. Schematic: B, B cell follicles; M, medullary cords; T, T cell zone. Other structures are labeled. Lymph enters via the afferent lymphatics and exits via the efferent lymphatics. T cells enter the lymph nodes via the high endothelial ­venules and exit via medulla to the efferent lymphatics. Intravital microscopy–based images of dendritic cells in lymph nodes of CD11c-YFP marker mice are linked to a schematic of the lymph node. (All scale bars 50 μm.) (From Lindquist RL, Shakhar G, Dudziak D, et al: Visualizing dendritic cell networks in vivo. Nat Immunol 5:1243-1250, 2004.)

have been reported to array around high endothelial venules where they are efficiently encountered by newly extravasated T cells and B cells. Antigen-positive DCs have been shown in experimental models to stop B cell and T cell migration during antigen encounter.78,92 These ­immunologic synapses, discussed earlier, play an important role in antigen transfer for B cells and for priming of proliferative response in T cells. Different populations of DCs, such as dermal DCs and Langerhans cells, actually populate different subregions of the T cell zones, but the significance of this is unclear. PERIPHERAL TOLERANCE INDUCTION UNDER STEADY-STATE CONDITIONS Lymph nodes are associated with peripheral tolerance induction. DC presentation of antigens in the steady state induces proliferation of T cells, which are then deleted or anergic by 7 days.115-117 This process may be particularly important to tissue-specific antigens that are not present in the thymus in the steady state.118 Low-affinity self-antigens can escape peripheral tolerance induction by this mechanism.118,119 Low-affinity, self-antigen–specific T cells that are activated in the context of infection by a pathogen with strong innate stimulation may induce tissue-specific autoimmunity.118

REGULATORY T CELLS REDUCE AUTOREACTIVITY BY INHIBITING IMMUNOLOGIC SYNAPSE FORMATION Regulatory T cells are CD25+, IL-2-dependent T cells that express the transcription factor FoxP3 and have the ability to suppress immune responses to tissue­specific self-antigens.120,121 These cells represent another layer of regulation to prevent autoimmune attack by the adaptive immunity. One way in which regulatory T cells function is to block immunologic synapse formation between T cells and autoantigen presenting DCs.122,123 This mechanism seems to operate on low-affinity selfantigens that are the most likely type of self-reactive T cell to escape peripheral tolerance mechanisms. Prevention of long-lived T cell–DC interactions may reduce proliferation and cytokine production by autoreactive T cells. CHANGES IN THE LYMPH NODE DURING INFECTION OR VACCINATION Infection or vaccination in tissues induces a strong reaction in draining lymph nodes. Innate signals trigger production of inflammatory cytokines, which leads to increased

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blood flow and increased adhesion molecule and chemokine expression to increase T cell and B cell entry and suppression of T cell and B cell exit by downregulation of S1P1.124 DCs in reactive lymph nodes express higher levels of costimulatory ligands such as CD80 and CD86 and promote robust proliferation, survival, and differentiation of antigen-specific T cells.80 T cells that are activated in the lymph nodes regain expression of S1P1 after 3 to 4 days and a new repertoire of homing molecules and migrate to effector sites.

GERMINAL CENTER REACTIONS ARE SITES OF ANTIBODY AFFINITY MATURATION AND CLASS SWITCH RECOMBINATION B cell activation by antigens in conjunction with costimulation via complement receptor or other forms of innate immune stimulation can lead to immediate proliferation of the B cells and the formation of plasma cells producing IgM antibodies from daughter cells.128 Specific T cell help may promote the formation of germinal centers within the B cell zone of any secondary lymphoid tissues.129-131 Germinal centers are roughly spherical collections of hundreds of antigen-specific B cells that undergo somatic mutation and class switching in the light zone and proliferation and apoptosis in the dark zone (Fig. 17-6).132 The light zone is populated by stromal follicular DCs, which, in contrast to conventional DCs, are of ­ nonhematopoietic

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TISSUE ENVIRONMENT OF IMMATURE DENDRITIC CELLS DETERMINES T CELL IMPRINTING When T cells are activated in lymph nodes, the repertoire of homing molecules expressed by the activated effector T cells is determined partly by the origin of the DC.125 DCs arise from a common monocyte-like precursor that migrates into tissues via the blood. DCs that drain from the gut produce retinoic acid from vitamin A.126 On maturation and migration to draining lymph nodes, these DCs secrete retinoic acid, which induces activated T cells to express gut homing chemokine receptors such as CCR9 and gut-specific integrins such as α4β7. Because gut-associated postcapillary venules express MAdCAM and present CCL25 (a CCR9 ligand), these effector T cells tend to home to the gut. In the absence of retinoic acid produced by gut-derived DCs, the signals induced by skin-derived DCs favor expression of ligands for E-selectin and P-selectin and CCR4 on T cells.125 Because endothelial cells of skin-associated postcapillary venules express P-selectin and present CCL17, these T cells tend to home to inflamed skin. It has been shown more recently that DCs in the skin metabolize vitamin D to generate a signal for T cell expression of CCR10, which allows these cells to move to migrate to the epidermis in response to CCL27.127 Although DCs strongly skew T cells to home back to the sites from which the DCs migrated, the expression of homing receptors and chemokines on lymphocytes also has a stochastic component, which means that these effector cells and memory cells also show up in diverse peripheral sites scattered throughout the animal—giving effector T cells their ability to appear in any tissue at any time.34 Overall, these results show that DCs sense their tissue environment and innate immune activation signals in the process of shaping T cell responses.

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FDC-M1+ Reticular fibers Specific B cells 25 µm

Plasma cells Medulla

Figure 17-6  Germinal center in living mouse lymph node. A germinal center was induced by vaccination after introduction of fluorescent ­antigen-specific B cells and antigen. Follicular dendritic cells were labeled with FDC-M1 antibody conjugated to a red fluorescent dye. Reticular fibers, which serve as antigen conduits into the follicle, are labeled blue. The germinal center (GC) is outlined and divided into a dark zone (DZ) containing aggregated centroblasts (green) and a light zone (LZ) containing loosely aggregated centrocytes, follicular dendritic cells (FDC-M1+) and follicular T cells (not shown). The surrounding follicle is densely packed with bystander B cells (not shown), which often enter and traverse the LZ. Green cells in the medullary region are plasma cells produced in the germinal center reaction. (From Schwickert TA, Lindquist RL, Shakhar G, et al: Germinal center imaging reveals a dynamic open structure. Nature 446:83-87, 2007.)

origin, and CXCR5+ follicular helper T cells. Follicular DCs use complement receptors to hold immune complexes on their surface for sampling by antigen-specific B cells. The follicular helper T cells provide cytokine help to B cells that maintain or increase their affinity for antigens and can provide cytokine signals to promote class switching.133 Intravital microscopy studies show that germinal centers are dynamic open structures in which antigen-specific B cells are continuously in motion, and follicular DCs are accessible to interaction with B cells having diverse receptor specificity.134 Antigen-specific B cells can be recruited into germinal center reactions at any time in the process and can compete openly with B cells that were present earlier. Interactions between follicular helper T cells and centrocytes in the light zone also are highly dynamic.135 Because most somatic mutations destroy the BCR or decrease its affinity, there is a large amount of apoptosis in the germinal center in addition to proliferation to provide substrates for mutations.

TERTIARY LYMPHOID TISSUES: GENERATED AT SITES OF CHRONIC INFLAMMATION Tertiary lymphoid tissues resemble secondary lymphoid tissues in many respects, but are formed in adults in response to chronic inflammation in locations where such tissues do

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not exist in steady-state conditions. The induction of tertiary lymphoid tissues can be compared with the formation of lymph nodes during normal development. Normal lymph node development involves the colonization of connective tissues in characteristic vascular nexus by RORγt-dependent, CD4+, lymphotoxin-positive lymph node inducer cells.136 These cells use surface lymphotoxin and tumor necrosis factor to induce local stromal cells to express ICAM-1 and VCAM-1 and produce CXCL13 leading to development of lymph node stroma with a reticular fiber conduit system that is integrated into the developing lymphatic vessel system.137 Constitutive use of inflammatory cytokines plays a key role in this process. This normal process also can be recapitulated in adults as chronic inflammation induces production of tumor necrosis factor and lymphotoxin in normal tissues leading to the induction of stromal cells to form organized follicles and T cell zones within the inflamed tissues.138 Induction of stromal cells to produce CCL19/21 or CXCL13 or both is probably important in this process because transgenic expression of CXCL13 in ectopic locations in mice leads to formation of fully developed B cell follicles in these tissues.139,140 B cells may have a particular capacity to induce tertiary lymphoid tissues. Tertiary lymphoid tissues often are associated with autoimmune diseases, including rheumatoid arthritis, and the local infiltration of naive T cells in an area with high concentrations of tissue-specific self-antigens and innate stimulation may promote progression of disease by recruiting new T cell and B cell specificities into the autoimmune process.141,142 Breaking this cycle may be a key target of anticytokine and anti–B cell therapies that have been remarkably effective; these therapies are discussed in later chapters.

FOUR MAJOR TYPES OF EFFECTOR T CELLS CD8+ effector T cells are generally cytotoxic and involved in killing of infected cells. CD8+ T cell responses can be initiated without CD4+ T cell help, but CD4+ T cell help is required for effective CD8+ T cell memory.143 An important transcription factor for effector CD8+ T cell differentiation is Eomesodermin.144 Three major types of effector CD4+ T cells are recognized. The first defined axis for CD4+ T cell differentiation was between interferon-γ-producing T cells expressing the master transcription factor Tbet and IL-4-producing T cells using the master transcription ­factor GATA3.145 The interferon-γ-producing cells are referred to as Th1 cells and help inflammatory cytotoxic T cell and macrophage responses; the IL-4-producing cells are called Th2 cells and help antiparasitic B cell responses leading to IgE production and eosinophilic infiltration. The major cytokines that initiate Th1 responses are interferon-γ and IL-12 in the absence of IL-4, whereas IL-4 is the major cytokine that initiates the Th2 program.146 It has been appreciated more recently that a third type of effector T cell produces IL-17 and is important in many inflammatory diseases. Differentiation of these Th17 cells requires the orphaned nuclear hormone receptor RORγt.147 The cytokine conditions that lead to development of Th17 cells are transforming growth factor-β plus IL-6, with IL23 for maintenance.148 The role of transforming growth factor-β places Th17 cells on the same axis with induced

regulatory T cells, with the deciding factor being the presence of IL-6 to favor Th17 over Treg induction. These are highly proinflammatory T cells that recruit neutrophils, but not CD8+ effectors.149 Although Th1, Th2, and Th17 cells and memory T cells may have certain biases with respect to homing molecules, it has been observed that imprinting by DCs for tissue-specific homing and the cytokines that control differentiation into Th1, Th2, and Th17 are independent.100

SUMMARY Adaptive immune responses have a degree of flexibility that is unparalleled in molecular recognition systems. This flexibility has a dangerous side that is constrained by anatomy and strong coupling to innate immunity. Autoimmune disease may result when weak points in tolerance mechanisms intersect with infection or tissue damage leading the adaptive system to attack self-organs in a self-amplifying process of tissue destruction, inflammation, and inappropriate anatomic adaptation, such as tertiary lymphoid tissue genesis. These processes are highly relevant to rheumatoid diseases. A mouse model for autoimmune rheumatic disease called the KRN transgenic mouse develops a T cell– and B cell– dependent joint disease.150-152 Strategies to break these cycles by attacking innate or adaptive immune system components nonspecifically have met with success, but more specific strategies would reduce negative consequences of general immunosuppression.

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133. Chtanova T, Tangye SG, Newton R, et al: T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J Immunol 173:68-78, 2004. 134. Schwickert TA, Lindquist RL, Shakhar G, et al: Germinal center imaging reveals a dynamic open structure. Nature 446:83-87, 2007. 135. Allen CD, Okada T, Tang HL, et al: Imaging of germinal center selection events during affinity maturation. Science 315:528-531, 2007. 136. Sun Z, Unutmaz D, Zou YR, et al: Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science 288:2369-2373, 2000. 137. Mebius RE: Organogenesis of lymphoid tissues. Nat Rev Immunol 3:292-303, 2003. 138. Cupedo T, Jansen W, Kraal G, et al: Induction of secondary and tertiary lymphoid structures in the skin. Immunity 21:655-667, 2004. 139. Luther SA, Bidgol A, Hargreaves DC, et al: Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J Immunol 169:424-433, 2002. 140. Yu P, Wang Y, Chin RK, et al: B cells control the migration of a subset of dendritic cells into B cell follicles via CXC chemokine ligand 13 in a lymphotoxin-dependent fashion. J Immunol 168:5117-5123, 2002. 141. Weninger W, Carlsen HS, Goodarzi M, et al: Naive T cell recruitment to nonlymphoid tissues: A role for endothelium-expressed CC chemokine ligand 21 in autoimmune disease and lymphoid neogenesis. J Immunol 170:4638-4648, 2003. 142. Takemura S, Klimiuk PA, Braun A, et al: T cell activation in rheumatoid synovium is B cell dependent. J Immunol 167:4710-4718, 2001. 143. Masopust D, Ahmed R: Reflections on CD8 T-cell activation and memory. Immunol Res 29:151-160, 2004. 144. Pearce EL, Mullen AC, Martins GA, et al: Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science 302:1041-1043, 2003. 145. Szabo SJ, Sullivan BM, Peng SL, et al: Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol 21:713-758, 2003. 146. Hsieh CS, Macatonia SE, Tripp CS, et al: Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260:547-549, 1993. 147. Ivanov II, McKenzie BS, Zhou L, et al: The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121-1133, 2006. 148. Veldhoen M, Hocking RJ, Atkins CJ, et al: TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179-189, 2006. 149. Langowski JL, Zhang X, Wu L, et al: IL-23 promotes tumour incidence and growth. Nature 442:461-465, 2006. 150. Mangialaio S, Ji H, Korganow AS, et al: The arthritogenic T cell receptor and its ligand in a model of spontaneous arthritis. Arthritis Rheum 42:2517-2523, 1999. 151. Ji H, Korganow AS, Mangialaio S, et al: Different modes of pathogenesis in T-cell-dependent autoimmunity: Clues from two TCR transgenic systems. Immunol Rev 169:139-146, 1999. 152. Mandik-Nayak L, Allen PM: Initiation of an autoimmune response: Insights from a transgenic model of rheumatoid arthritis. Immunol Res 32:5-13, 2005.

18

Genetics of Rheumatic Diseases PETER K. GREGERSEN

KEY POINTS HLA molecules are among the most highly variable (polymorphic) proteins encoded in the genome. HLA variability is a major factor in controlling immune ­responses. HLA variability is likely to be directly responsible for a portion of the genetic susceptibility to autoimmune diseases. Genetic associations, including HLA associations, must be interpreted with caution because of confounding ­factors, such as linkage disequilibrium and hidden population ­stratification.

Nobel prize. The HLA molecules and their counterparts in rodents subsequently were shown to be directly responsible for immune response differences between individuals and for determining the likelihood of graft rejection.1-4 There are numerous different HLA genes within the MHC, and they exhibit an enormous degree of structural variability. In addition to influencing immune response patterns, many of these alleles are associated with susceptibility to a wide spectrum of autoimmune diseases, making the MHC an essential starting point for anyone wishing to understand the genetics of rheumatic diseases.

Large-scale genetic analysis of the entire genome is revealing additional risk genes for autoimmunity, independent of HLA.

HUMAN LEUKOCYTE ANTIGEN MOLECULES AND ANTIGEN-SPECIFIC T CELL RECOGNITION

The current genetic data strongly suggest that multiple genes are involved in autoimmunity, and that many of these genes predispose to multiple different autoimmune disorders.

The primary function of HLA molecules is the presentation of antigenic peptides to T cells. In the case of α/β T cells, most antigen recognition events involve the formation of a trimolecular complex consisting of the HLA molecule, its bound peptide, and the α/β T cell receptor (see Chapters 9 and 17). When this recognition occurs in the appropriate context, it may result in signal transduction and activation of the T cell. The requirement for MHC molecules to present antigenic peptides to T cells is frequently referred to as MHC-restricted T cell recognition. In each individual, T cells generally are restricted to recognize antigens presented by the individual’s own HLA molecules. The allelic variations among different HLA molecules are a major factor accounting for differences in the types of antigenic peptides to which an individual responds or in the types of T cells that are used in an immune response.

Currently, the genetic analysis of human disease is undergoing a dramatic transformation. Any textbook chapter on the genetics of human rheumatic diseases becomes outdated in many details soon after publication. The principles underlying genetics are more stable, however, than the details; a firm understanding of basic genetic principles should permit practitioners and researchers to interpret the wealth of new genetic findings that will be forthcoming in the next few years. This chapter emphasizes approaches and concepts at least as much as genetic findings, in the hope that this provides a foundation for keeping up with advances in the field. The first section deals with the major histocompatibility complex (MHC) because the human leukocyte antigens (HLAs) encoded in this region form a cornerstone for integrating immunology and genetics into the understanding of rheumatic diseases. The second section of the chapter deals with rapidly emerging data on relevant genes outside of the MHC and provides a background on the approaches and technologies that ultimately will bring genetic knowledge into the daily practice of rheumatologists.

MAJOR HISTOCOMPATIBILITY COMPLEX The MHC, which encodes the HLAs, has been associated with susceptibility to many different diseases since the late 1970s. The chromosomal region containing the MHC was originally identified because of the ability of genes in this region to regulate transplant rejection1 and to control the immune responses of mice and guinea pigs to simple ­antigens,2 a series of observations that led to the 1980

HUMAN LEUKOCYTE ANTIGEN CLASS I AND CLASS II MOLECULES The original serologic and biochemical studies of HLA molecules revealed the presence of two major isotypes: HLA class I and HLA class II. The basic structural features of these classic HLA molecules are summarized in Figure 18-1. HLA class I molecules consist of a 45-kD α chain encoded within the MHC that is noncovalently associated with the 12-kD β2-microglobulin chain (encoded on chromosome 15). HLA class II molecules consist of noncovalently associated α (32 kD) and β (28 kD) chains, both of which are encoded within the MHC. HLA class I and class II molecules are cell surface glycoproteins, anchored to the membrane by hydrophobic transmembrane segments. A major breakthrough in the understanding of HLA molecules came in 1987, when Bjorkman and colleagues5,6 reported the crystal structure of the HLA class I molecule, HLA-A2. This work was followed by the solution of other 305

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MHC class I α2

S S

α3

S S S S

MHC class II α1

β 2m

β1

S S

β2

S S

α1

S S

α2

α1

α2

N N

C

Cytoplasm

C

C

C

Membrane

Figure 18-1  Schematic comparison of the structural features of major histocompatibility complex (MHC) class I and class II molecules. MHC class I molecules are anchored in the membrane by a single transmembrane segment contained in the 45-kD α chain. The MHC class I α chain is noncovalently associated with β2-microglobulin. There are four external domains, three of which contain intramolecular disulfide bonds, as indicated. In contrast, MHC class II molecules consist of noncovalently associated α (32 kD) and β (28 kD) chains, both of which are anchored within the membrane. The overall domain organization of the two molecules is highly similar, however. Glycosylation sites on both molecules are indicated by the black dot (•).

MHC class I and class II structures relevant to rheumatic disease.7,8 A side view of the class I molecule taken from Bjorkman’s original article is shown in Figure 18-2A. The base of the molecule (directly adjacent to the cell membrane) is formed by β2-microglobulin and the immunoglobulinlike α3 domain. The α1 and α2 domains form a distinct cleft or groove at the top of the molecule. The function of this cleft is to bind antigenic peptides for presentation to T cells. A top view of this cleft is shown in Figure18-2B. The “floor” of the peptide-binding cleft consists of β-sheets, whereas the “walls” of the cleft are bounded by extended regions of α-helical structure. The size of the HLA class I cleft is approximately 10 to 20 Å, and it generally can accommodate antigenic peptides that are 9 amino acids long.9,10 HLA class II molecules have a structure that is highly similar to that of class I molecules, with a prominent peptide-binding cleft at the membrane distal portion, sitting on top of a base formed by the α2 and β2 immunoglobulin-like domains. The overall size and shape of the cleft in the two classes of HLA molecules are almost superimposable. Subtle differences exist, however, particularly at the ends of the cleft, and this allows for some differences in the sizes of antigenic peptides that are presented by HLA class II molecules compared with class I molecules. Direct analysis of peptides bound to HLA class II molecules has shown that their size commonly varies from 12 to 19 amino acids.10 Relatively longer peptides lie in the cleft of class II molecules and may extend beyond the ends of the cleft, whereas class I molecules contain much shorter peptides that are buried within the cleft at either end. Finally, x-ray crystallographic analyses have been done of the entire trimolecular complex consisting of an HLA molecule, its bound peptide, and the T cell receptor. ­Figure 18-3 shows an example of this structure for an HLA-DRB1*0401

C β2m α3

A

B

N

Figure 18-2  Three-dimensional structure of an HLA class I molecule, based on the x-ray crystallographic analysis of Bjorkman.5 A, A side view is shown. A peptide-binding cleft is formed by the α1 and α2 domains at the top of the molecule. The α3 and β2-microglobulin domains are similar in structure to immunoglobulin domains; essentially, they act as a platform on which the peptide-binding cleft rests and provide contact sites for the CD8 molecule during CD8+ T cell recognition. B, A top view of the empty peptide-binding cleft is shown. This “T cell view” of the major histocompatibility complex molecule would normally include a peptide bound within the cleft. The disulfide bond connects the α-helix of the α2 domain with the floor of the cleft.

allele presenting influenza Ha peptide to its cognate α/β T cell receptor.11 Three-dimensional versions of this HLA structure (entry code 1J8H) can be viewed on the Protein Data Bank (PDB) website at http://www.rcsb.org/pdb/home/ home.do. HUMAN LEUKOCYTE ANTIGEN CLASS I AND CLASS II ISOTYPES: FUNCTIONAL CORRELATES HLA class II molecules have a restricted tissue distribution, generally limited to antigen-presenting cells of the immune system, such as B cells, macrophages, dendritic cells, and some subsets of T cells. This distribution reflects

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GENETIC ORGANIZATION OF THE HUMAN MAJOR HISTOCOMPATIBILITY COMPLEX

Figure 18-3  Ribbon diagram derived from the three-dimensional ­crystal structure of the trimolecular complex of a human α/β-T cell ­receptor (top, green), influenza Ha antigen peptide, and the major histocompatibility complex class II molecule DRB1*0401.11 The peptide is contained with the peptide-binding cleft of the HLA-DR molecule. The polymorphisms associated with the “shared epitope” are located on α helical rim (DRB1 chain) of the peptide-binding cleft where they may interact with either the bound peptide antigen or the T cell receptor.

the fact that HLA class II molecules are primarily involved in ­presenting foreign antigens to CD4+ T cells during the initiation and propagation of the immune response. The expression of HLA class II molecules also can be induced on a variety of other cell types by inflammatory cytokines, such as ­ interferon-γ, enabling these cells to engage in antigen presentation to CD4+ T cells. In contrast, HLA class I molecules are widely distributed on all somatic cells except for red blood cells. This distribution reflects their predominant role in presenting antigen to CD8+ effector or cytotoxic T cells. Another major functional difference between class I and class II molecules is related to the source of peptide antigens that are found in the antigen-binding cleft. Generally, class I molecules present peptide antigens derived from proteins that are actively synthesized within the endoplasmic reticulum, whereas HLA class II molecules present antigens that are taken up from outside of the cell by endocytosis. These differences are reflected in the antigen-processing machinery and the different trafficking patterns of class I and class II molecules inside the cell. This complex process is discussed in detail in Chapters 8 and 17.

The human MHC extends over approximately 4 million base pairs on the short arm of chromosome 6 (6p21.3). The HLA class I and class II gene clusters are found in distinct locations, as indicated on the highly abridged genetic map shown in Figure 18-4. Only genes that are traditionally associated with immune function are shown in Figure 18-4. More than 200 genes have been identified in the MHC, one of the most gene-rich regions in the human genome.12 Detailed genetic maps with the complete DNA sequence of the MHC and a complete list of genes in the region can be found online at http://www.sanger.ac.uk/HGP/Chr6/MHC. shtml. The HLA class I α chain genes are found on the telomeric side of the MHC, including the classic class I genes, HLAA, HLA-B, and HLA-C; these three genes also are referred to as the class Ia genes. Several other class I genes have been defined, including the HLA-G, HLA-E, and HLA-F loci, also known as class Ib genes. Initially, these class Ib genes were thought to be nonfunctional because they exhibit limited polymorphism. Some of these genes do have significant immune functions, however. HLA-G and HLA-E can act as ligands for natural killer cell inhibitory receptors.13 In a surprising twist, HLA-E molecules bind and present peptides that are derived from the leader peptide of the class Ia genes and HLA-G.14 The HLA class II genes are situated centromeric to the class I region and have a more complicated organization. The three major subregions of the class II cluster are designated DR, DQ, and DP. Each of these subregions contains a variable number of α and β chain genes. Particularly in the case of the DR subregion, this variability has led to ­confusion regarding the nomenclature to describe these genes. An international standard for this nomenclature has been agreed on.15 The DR subregion contains a single α chain gene, designated DRA, which does not exhibit significant allelic variation. In contrast, the genes encoding the DR β chains (DRB) are highly polymorphic and vary in number among different individuals in the population. This is shown in the boxed area of Figure 18-4, in which several examples of common DR haplotypes are displayed. (A haplotype refers to a group of alleles at closely linked loci that are commonly inherited together.) Many of these DRB genes are nonfunctional pseudogenes (indicated by the symbol ψ), although all haplotypes contain at least one functional DRB1 gene, and many haplotypes contain a second functional DRB gene (DRB3, DRB4, or DRB5). The DQ subregion contains one pair of functional α and β chain genes, designated DQA1 and DQB1. These two genes encode all the known HLA-DQ molecules. Protein products of the DQA2 and DQB2 loci have not been reported. A similar situation exists in the DP subregion, in which only the DPA1 and DPB1 genes give rise to known protein products, the HLA-DP molecules. In addition to the HLA class II molecules, several other genes distributed within the class II region are involved in peptide antigen processing. The TAP1 and TAP2 genes have been of particular interest because they exhibit a modest degree of polymorphism and are involved in delivering

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HLA class I region HLA-F HLA-A HLA-E

HLA-B

“Central” MHC

HLA class II region

NFKBIL1 AIF1 Ly-6 family members

BTNL2

DR

Telomere

DQ

DP 6p21

HLA-G

HLA-C LTa-TNF-α-LTB C4A-C4B-factorB-C2

DRA

DRB1

ψDRB DRB1 ψDRB DRB1

DRB5

DRB3 ψDRB DRB1 DRB4 ψDRB ψDRB DRB1 DRB1

DQA1 DQA2 DQB1 DQB2

DR1,10 DR15,16 DR3,11,12,13,14

DPA1 DPA2 DPB1 DPB2

Loci encoding peptide loading (DMA/DMB), peptide transport (TAP1 and TAP2) and proteosome subunits (LMP1 and LMP2)

DR4,7,9 DR8

DRB gene organization varies by haplotype family Figure 18-4  Map of the human major histocompatibility complex (MHC). The HLA class I and class II molecules are encoded in distinct regions of the MHC. The HLA class II region contains three subregions—DR, DQ, and DP. Each of these contains a variable number of α and β chain genes. HLA class II loci with known functional protein products are labeled in the shaded red box. In the case of DR, different numbers of DRB genes are present in different haplotypes. A summary of the most common of these is shown in the box. The DQ and DP subregions each contain one pair of functional α and β chain genes. Many genes involved in antigen processing and presentation by class I molecules are situated between the DP and DQ subregions. The HLA class I region contains the three classic class I genes—HLA-A, HLA-B, and HLA-C—and other related class I molecules (see text). The “central MHC” also contains many genes related to immune function, including the complement components (C4A, C4B, C2, and factor B) and tumor necrosis factor (TNF)-α   and TNF-β. Other potentially interesting genes in this region (NFKB1L1, AIF1, and BTNL2) are discussed in the text and by Price and colleagues.24

peptides for loading onto HLA class I molecules.16 Other proteins encoded in this region are involved in peptide loading onto class II molecules, such as the DM molecule (encoded by the DMA and DMB genes) and the DO/DN heterodimer (encoded by DOB and DNA). The “central” MHC is located in between the MHC class I and class II regions. It contains numerous genes involved in immune function, including those for tumor necrosis factor (TNF)-α and TNF-β and the complement components C4A, C4B, C2, and factor B. The central MHC is gene dense, and it contains many other genes with potential relevance to immune function and disease susceptibility.17 Several of these, such as NFKBIL1, AIF1, and BTNL2, have been implicated in various autoimmune and inflammatory disorders.18-20 The role of many genes in central MHC and class I regions is still largely unknown, however. POLYMORPHIC NATURE OF HUMAN LEUKOCYTE ANTIGEN MOLECULES One of the most dramatic features of the HLA system is the extreme degree of polymorphism at most of these loci. The formal definition of polymorphism (Table 18-1) usually requires that the most common allele at the locus does not exceed a frequency of 98%. In contrast, at many HLA loci, it is uncommon for a single HLA allele to exceed a frequency of 50% in the population. The number of different alleles present in the population is much larger than in any

other known polymorphic locus encoding functional genes. At the HLA-A locus, more than 100 different alleles have been reported; at HLA-B, the number of reported alleles is greater than 200. A similar degree of allelic diversity is seen at the DRB1 locus and to a lesser degree at DQA and DQB. Until more recently, the naming of these various HLA alleles has been a major source of confusion in the literature. The difficulty with the nomenclature stems partly from the different methods that have been used to define HLA polymorphisms. Originally, HLA class I alleles were detected through the use of alloantisera (Table 18-2); the prefix allorefers to genetic differences that exist between individuals of the same species. Alloantisera directed toward HLA molecules are commonly found in the context of pregnancy, in which the mother mounts an immune response against the “foreign” HLA molecules carried by the fetus (derived from the father). Anti-HLA responses also are seen after blood transfusion because the HLA molecules on the donor cells are highly immunogenic. In the case of HLA class II alleles, differences were originally detected using mixed lymphocyte responses. When T cells from a responder are mixed with lymphocytes from another individual, differences in HLA class II alleles cause the responder’s T cells to proliferate. Data on mixed lymphocyte culture typing dominated the early HLA literature, and it was the method first used to detect the HLA class II associations with rheumatoid arthritis (RA).21 Subsequently, serologic methods also were employed to detect class II polymorphisms.

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Table 18-1  Glossary of Terms Allele

Alternative form, or variant, of a gene at a particular locus

Alloantisera

Antisera that detect antigenic differences between individuals in the population; the term is most often used to refer to sera that detect antigenic (i.e., structural) differences among human leukocyte antigen molecules carried by different individuals

Haplotype

A group of alleles at adjacent or closely linked loci on the same chromosome that are usually inherited ­together as a unit

Heterozygote

An individual who inherits two different alleles at a given locus on two homologous chromosomes

Heterozygosity

A measure at a particular locus of the frequency with which heterozygotes occur in the population

Linkage

The tendency toward the coinheritance within a family of two genes that lie near each other on the ­  genome; complete linkage occurs when parents who are heterozygous at each locus are unable to   produce ­recombinant gametes

Linkage disequilibrium

The preferential association in a population of two alleles or mutations that occurs more frequently than predicted by chance; linkage disequilibrium is detected statistically, and except in unusual circumstances, it implies that the two alleles lie near each other on the genome

Polymorphism

The degree of allelic variation at a locus within a population; specific criteria differ, but a locus is said to be polymorphic if the most frequent allele does not occur in >98% of the population; occasionally, polymorphism can be used in the same way as allele to refer to a particular genetic variant

Penetrance

The conditional probability of disease (or phenotype) given the presence of a risk genotype

Table 18-2  Comparison between Modern, Sequence-based Nomenclature, and Older Naming Conventions   for Class I and Class II Alleles Belonging to HLA-B27 and HLA-DR4 Serologic Groups* HLA-B Locus: HLA-B27 Alleles Definitive Nomenclature Based on DNA Sequence B*2701 B*2702 B*2703 B*2704 B*2705

HLA-DRB1 Locus: HLA-DR4 Alleles

Serologic ­Designation (Defined by ­Alloantisera)

Definitive Nomenclature Based on DNA Sequence

Serologic ­Designation (Defined by ­Alloantisera)

Cellular Typing (Based on MLC)

DRB1*0401 DRB1*0402 DRB1*0403 DRB1*0404 DRB1*0405

DR4 DR4 DR4 DR4 DR4

Dw4 Dw10 Dw13 Dw14 Dw15

B27 B27 B27 B27 B27

*The list of alleles is incomplete. The B27 allele family contains at least 17 members, and the HLA-DR4 allele family contains at least 35 members. See http://www.ebi.ac.uk/imgt/hla/for a complete list of all HLA alleles. MLC, mixed lymphocyte culture.

The current names of the HLA class I and class II alleles are attached to the specific DNA sequence and locus for each allele and are definitive.22 Many older publications have used the serologically derived names for alleles, however. It is important to have some concept of how these naming conventions are related. The modern definitive (sequencebased) allele names are derived from the older serologic names because the serologic techniques frequently detected whole groups of related alleles. Two examples of this are shown in Table 18-2. The designation of HLA-B27 was developed for individuals carrying an HLA-B allele that was recognized by the B27-specific alloantisera. Sequencing of the HLA-B alleles carried by these individuals revealed the existence of at least 17 different alleles, however, 5 of which are listed in Table 18-2. A similar situation exists for HLA class II allele families, such as HLA-DR4 (see Table 18-2). In this case, the DR4 allospecificity already was known to detect many different alleles that could be discriminated further on the basis of mixed lymphocyte culture typing.23 These alleles have been defined and named by their sequence (see Table 18-2). A full list of all HLA alleles at the major loci can be found at http://www.ebi.ac.uk/imgt/hla/. Despite the precision of the molecular definition of HLA alleles, the old serologic names are often used in oral discussion because they are less cumbersome. The DRB1*03011

allele is common in white populations (10% in some ­populations) and is often referred to as simply DR3, after its original serologic designation. There are at least 16 distinct alleles that are detected by such DR3 alloantisera, and the term DR3 is imprecise. When used in the context of a discussion about white populations, however, DR3 is assumed to refer to the predominant DRB1*03011 allele. LINKAGE DISEQUILIBRIUM OF HUMAN LEUKOCYTE ANTIGEN ALLELES In addition to their highly polymorphic nature, a characteristic feature of HLA genes is the tendency for certain HLA alleles to be found together on the same haplotype. This phenomenon is termed linkage disequilibrium, and it is central to understanding the significance of HLA associations (or any other genetic associations) with disease. Linkage disequilibrium exists when the frequency of two alleles occurring together on the same haplotype exceeds that ­predicted by chance. A common haplotype that exhibits linkage disequilibrium in whites carries a certain combination of alleles— A*0101-B*0801-DRB1*03011—commonly referred to as the A1-B8-DR3 haplotype, and more recently designated the “8.1” haplotype.24 This haplotype is ­ present in about 9% of the Danish population, a typical white Northern

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­ uropean group. To understand why this haplotype reflects E the presence of linkage disequilibrium, consider the fact that the A1 allele is present in 17% of Danes and the B8 allele is present in 12.7% of Danes. They could be expected to be found together only 12.7% × 17% = 2.1% of the time, much less than what is observed (9%). There are three likely explanations for linkage disequilibrium. First, the population may have originated from a mixture of two populations, one of which had a very high frequency of a particular haplotype (in this case, A1-B8DR3). If this happened recently, there would not have been time (i.e., a sufficient number of generations) to randomize alleles at closely linked loci by recombination at meiosis. Inasmuch as human history is marked by large population migrations,25 it is probable that population admixture explains many examples of linkage disequilibrium. A second explanation, related to the first, rests on the observation that certain regions of the genome tend to exhibit low levels of meiotic recombination. Genetic variants within these regions tend to stay together on the same haplotype over many generations, even if haplotypes were introduced into a population in the distant past. The importance of this concept for understanding linkage disequilibrium is still under active debate in the genetics community and is discussed further in a later section. A third explanation for linkage disequilibrium posits that the alleles in linkage disequilibrium may be maintained together because of a selective advantage. A1 and B8 (and other genes closely linked to them) could confer an advantage for immune defense when they are present together in the same individual. Although plausible, this hypothesis is difficult to prove for any particular haplotype, and there is no direct evidence for it.

HUMAN LEUKOCYTE ANTIGEN ASSOCIATIONS WITH RHEUMATIC DISEASES POPULATION ASSOCIATION STUDIES AND CALCULATION OF THE ODDS RATIO, AN ESTIMATE OF RELATIVE RISK The ideal way to establish whether a genetic variant (allele) confers risk for a disease is by performing a prospective cohort study. In this kind of study, a group of individuals carrying (exposed to) the allele is compared with a matched control group that does not carry the allele. These two groups are followed over time (preferably over a lifetime) to see if disease develops more frequently in the exposed group. The results can be displayed in contingency tables (Tables 18-3 and 18-4). On examining Table 18-3, it is apparent that the fraction of exposed individuals who get the disease is a/(a + b), whereas the fraction of unexposed individuals who develop the disease is c/(c + d). The ratio of these two fractions is known as the relative risk = a/(a + b) ÷  c/(c + d) = (ac + ad)/(ac + bc). If the disease is rare in the population, ac is very small, and the relative risk is approximated by (a × d)/(b × c), also referred to as the cross product. In reality, such prospective cohort studies are usually impractical, and a retrospective case-control design is used. In this type of study, subjects are initially identified ­according to whether they have the disease, and individuals without

Table 18-3  Contingency Table for Cohort Study* Disease

No Disease

Exposed

a

b

Not Exposed

c

d

*a, b, c, d = number of individuals observed in each category.

Table 18-4  Contingency Table for Case-Control   Study* Exposed

Not Exposed

Disease

a

b

No Disease

c

d

*a, b, c, d = number of individuals observed in each category.

the disease are the controls. The data can be tabulated as in Table 18-4. In this case, the cross product or (a × d)/(b × c) is known as the odds ratio. In practice, this quantity is often reported as the estimated relative risk because the cross product is close to the relative risk when the disease is rare. An odds ratio of 1 indicates that the genetic factor confers no risk for the disease. An odds ratio less than 1 suggests that the genetic factor under study is negatively associated with the disease. (Odds ratios of <1 are occasionally reported as the negative inverse value; an odds ratio of >0.5 also may be reported −2.0.) With the exception of HLA-B27-associated diseases, most HLA associations with rheumatic diseases have odds ratios of less than 10. Several examples of typical HLA associations with rheumatic and autoimmune disorders are shown in Table 18-5. HUMAN LEUKOCYTE ANTIGEN CLASS I ASSOCIATIONS: HLA-B27 AND SPONDYLOARTHROPATHIES One of the strongest and earliest26 reported HLA associations with rheumatic diseases is the association of HLA-B27 with ankylosing spondylitis. In white populations, more than 90% of patients with ankylosing spondylitis carry HLA-B27, in contrast to approximately 8% of normal individuals, giving estimated relative risk values of 50 to 100 or higher. The consistency of this finding across most ethnic groups lends support to the contention that the HLA-B27 alleles are directly involved in the pathogenesis of ankylosing spondylitis.27,28 HLA-B27 also is associated with reactive arthritis, including Reiter’s syndrome, and with arthritis seen in the context of inflammatory bowel disease. As shown in Table 18-5, the strength of these associations is lower in terms of estimated relative risk compared with ankylosing spondylitis. The serologic specificity of HLA-B27 encompasses many distinct HLA class I alleles. These alleles differ from one another at many amino acid positions, most of which involve amino acid substitutions in and around the peptide-binding pocket. This fact leads naturally to the question of whether there are differences among these B27 alleles in terms of disease association. Most data indicate that this is not the case, although there may be some exceptions in some populations.27 These exceptions may provide clues to the role of the HLA-B27 molecule in pathogenesis. Overall, however, it seems that most of the structural differences among the B27 alleles do not affect disease risk.28

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311

Table 18-5  Common HLA Associations with Rheumatic and Autoimmune Diseases Disease

HLA Allele (Serologically Defined)

Approximate Allele Frequency in White Patients (%)

Approximate Allele Frequency in White Controls (%)

Approximate Relative Risk

Ankylosing spondylitis

B27

90

8

90

Reiter’s syndrome

B27

70

8

40

Spondylitis in inflammatory bowel disease

B27

50

8

10

Rheumatoid arthritis

DR4

70

30

6

Systemic lupus ­erythematosus

DR3

45

20

3

Multiple sclerosis

DR2

60

20

4

Juvenile diabetes mellitus   (type 1)

DR4

75

30

6

Some hypotheses can be derived by combining the sequence information on the various B27 alleles with structural information about the HLA-B27 molecule and the peptides bound to it.7,29 The structure of the B*2705 allele (the most common allele in white populations) has been solved by x-ray crystallography and reveals the presence of a characteristic “pocket” in the floor of the peptide-binding cleft. This has been referred to as the “45 pocket” because amino acid position 45 is situated at the base of this pocket, and in the case of the B27 alleles, it contains a negatively charged glutamic acid.7 The peptides that bind to B27 alleles are all 9 amino acids long and invariably contain a positively charged arginine at the second position from the N terminus.7 This arginine appears to be situated within the 45 pocket when a peptide is bound to the HLA-B27 molecule. This sequence motif is distinct from peptides that are bound to other HLA class I alleles, such as HLA-A2, which lacks a glutamic acid in the 45 pocket. Many other sequence motifs of B27-associated peptides also have been described. These data suggest that the reason for the HLA-B27 association with spondylitic disease may be related to the specific peptides that are bound and presented to CD8 T cells by these molecules. Because a negatively charged 45 pocket is not uniquely present in B27 alleles, but also is found in class I molecules that are not associated with spondyloarthropathies, this feature cannot be a complete explanation for the B27 associations with ankylosing ­spondylitis. HUMAN LEUKOCYTE ANTIGEN CLASS II ASSOCIATIONS WITH AUTOIMMUNE DISEASES Numerous HLA class II associations with autoimmune diseases have been described.30 Generally, the disease associations with HLA class II alleles are weaker and more complex than those seen with HLA-B27. RA has received particularly intense scrutiny, but the precise reasons for the HLA associations with this disease are still unknown. In the case of systemic lupus erythematosus (SLE) and related illnesses, many of the HLA class II alleles are associated with the presence of specific autoantibodies or clinical phenotypes. More recent data in RA indicate that the major HLA-DR associations are with anticitrullinated protein antibody–positive disease, suggesting that control of autoantibody responses may be a primary mechanism underlying these associations in RA as well.

RHEUMATOID ARTHRITIS: HLA-DRB1 ASSOCIATIONS AND THE SHARED EPITOPE The first associations of RA with HLA class II alleles were reported in the 1970s by Stastny.21 Stastny used cellular31 and antibody reagents32 that are no longer routinely used for HLA typing; however, as discussed earlier, the nomenclature for HLA alleles still derives from these early typing methods. The DRB1*0401 allele (corresponding to the “Dw4” type in Stastny’s original report31) was the first HLA polymorphism to be associated with RA. Numerous studies have generally confirmed that this allele is the most strongly associated with RA, at least in white populations.33-35 Several other HLADRB1 alleles also have been associated with RA, although the strength of these associations varies.34,36,37 In some ethnic groups, RA is not associated with HLADR4 alleles, but rather with HLA-DR138 or HLA-DR10.39 It is now widely accepted that the following alleles are the major contributors to RA risk at the DRB1 locus: DRB1*0401, DRB1*0404, DRB1*0405, DRB1*0101, and DRB1*1001. In addition, minor variants of these alleles and others (DRB1*140240) may contribute to susceptibility, and DRB1*0901 is a susceptibility in Asians, where this allele is common.41 Most of these risk alleles share a common sequence, as shown in Table 18-6. This consensus amino acid sequence 70Q or K-R-R-A-A74 has been termed the shared epitope.42 This structural feature is located on the α-helical portion of the DR β chain in a position where it may influence peptide binding and T cell receptor interactions with the DRB1 molecule. (In the case of the DRB1*1001 risk allele, one amino acid varies from this consensus by a conservative change, with an R at position 70, as does DRB1*0901, which is commonly associated with RA in Asian populations) (Table 18-7). Many different hypotheses have been advanced to explain the shared epitope association with RA.43,44 Two of these follow directly from knowledge about the role of HLA molecules in antigen presentation and immune regulation. It has been suggested that a particular peptide antigen, or set of related antigens, may be involved in the initiation or propagation of RA, and that shared epitope positive DRB1 alleles possess a unique, or enhanced, ability to bind or pre­ sent these peptides to the immune system.43 It has been difficult to address this hypothesis directly because the identity of these putative disease-causing peptide antigens is unknown.

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Table 18-6  Amino Acid Substitutions That Compose the Shared Epitope at Positions 70 through 74 of DRB1 Alleles ­Associated with Rheumatoid Arthritis Amino Acid Position DRB1 Alleles

70

71

72

73

74

0101

Gln

Arg

Arg

Ala

Ala

0401

—

Lys

—

—

—

0404

—

—

—

—

—

0405

—

—

—

—

—

0408

—

—

—

—

—

1402

—

—

—

—

—

1001

Arg

—

—

—

—

Table 18-7  Genotype Relative Risks of DRB1   Genotypes for Rheumatoid Arthritis Relative Risk

P Value

0101/DRX

2.3

10−3

0401/DRX

4.7

  10−12

0404/DRX

5

10−9

0101/0401

6.4

10−4

0401/0404

31.3

  10−33

DRB1 Genotype

Data from Hall FC, Weeks DE, Camilleri JP, et al: Influence of the HLA-DRB1 locus on susceptibility and severity in rheumatoid arthritis. QJM 89:821-829, 1996.

In view of the strong association of the shared epitope alleles with anticitrullinated protein antibodies,45 it is of interest that citrullinated peptides may have a particular affinity for DRB1*0401 alleles.46 A second major hypothesis posits that these risk alleles regulate the formation of the peripheral T cell repertoire, by acting to select for particular T cell receptors during thymic selection.44 There is elegant experimental evidence in humans to support a role for DR4 alleles in shaping the peripheral T cell repertoire.47 It is unclear, however, whether this effect on the T cell receptor repertoire is actually related to disease susceptibility. Many other interesting hypotheses have been proposed, involving molecular mimicry,48,49 allele-specific differences in intracellular trafficking,50 and regulation of nitric oxide production,51 but these require further experimental confirmation. More recently, the shared epitope hypothesis itself has come under renewed scrutiny, with some investigators proposing a direct role for HLA-DQ polymorphisms,52,53 based partly on studies in transgenic mice.54 As can be seen in Figure 18-5, the HLA-DQ α and β chains are encoded just centromeric to DRB1, and alleles at this locus are in strong linkage disequilibrium with DRB1 alleles. The strong linkage disequilibrium between the DR and DQ loci makes it difficult to tease apart the effects of DR versus DQ based solely on population genetic studies; the arguments for a DQ effect generally depend on showing the enrichment of rare genotypes in the RA patient group compared with controls. Overall, a primary role for DQ alleles is not strongly supported by large HLA association studies that have examined this issue.55 Regardless of whether HLA-DQ alleles are involved in RA susceptibility, the shared epitope hypothesis is not a complete explanation for the HLA associations with RA. This is evident from the fact that not all shared epitope

DQB1 *0201

DQβ chain

DQA1 *0201

DRB1 *0301

DQα chain

DQ molecule encoded on a “DR3-DQ2” haplotype

DQB1 *0201

DQβ chain

DQA1 *0501

DRB1 *0701

DQα chain

DQ molecule encoded on a “DR7-DQ2” haplotype

Figure 18-5  Combinatorial diversity of HLA-DQ molecules. The serologically defined “DQ2” molecule may contain the same DQβ chain paired with different DQα chain alleles. This is different from HLA-DR molecules, in which the DRα chain does not vary among different major histocompatibility complex haplotypes.

(SE) positive alleles carry the same degree of genetic risk, and the strength of the association varies in different populations. Generally, DRB1*0101 alleles carry lower levels of relative risk for RA than the DRB1*0401 and DRB1*0404 alleles,35 yet DRB1*0101 is the major risk allele in some ethnic groups.56,57 The shared epitope itself does not seem to associate strongly with RA in African-American and some Hispanic populations.58,59 Certain combinations of DRB1 alleles carry especially high risk, as originally observed by Nepom and colleagues.60 The combination of DRB1*0401 with DRB1*0404 carries a relative risk of more than 30 in white populations35; this compares with relative risk values in the range of 4 or 5 for either allele alone. Some of these relationships are summarized in Table 18-6. Attempts have been made to formalize the gradient of risk conferred by the various shared epitope alleles.61 It is unclear, however, whether these effects are mediated by the HLA-DR molecules themselves, or reflect the action of other genes on these haplotypes. HLA-DQ ASSOCIATIONS WITH AUTOIMMUNE DISEASES Many of the first HLA class II associations with autoimmune disorders were detected using alloantisera for HLA-DR alleles, as indicated in Table 18-5. As knowledge increased about the genetic organization of the class II region, it became apparent that for some diseases, the genetic associations are stronger with HLA-DQ alleles. Although juvenile diabetes does exhibit HLA associations with HLA-DR4 and HLADR3, it is likely that a group of associated HLA-DQ alleles are responsible for these observations.62 As discussed subsequently, the HLA associations with particular autoantibodies in SLE also probably reflect the effects of HLA-DQ alleles. The DQ subregion presents special challenges for the newcomer to HLA because the old serologic nomenclature does not usually have a simple correlation with a group of alleles at a single locus. Because most of the HLA correlations with autoantibodies in SLE involve the DQ loci, it is important to understand this at the outset. The problem arises because the α and β chains are polymorphic in DQ molecules. The serologic specificity of DQ2 may detect one of three closely related DQB1 alleles—DQB1*0201, DQB1*0202, or DQB1*0203. This is similar to the DR serologic specificity detecting a group of related DRB1 alleles (see Table 18-2). In the case of DQ, the DQ2 serologic specificity also detects these alleles on several different haplotypes that may encode quite different DQ α chains. (This is ­different from

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HLA-DR molecules, in which the DR α chain structure is constant and does not vary among haplotypes.) In white populations, the DQB1*0201 allele is commonly found on DR3 haplotypes (associated with DQA1*0501) and DR7 haplotypes (associated with DQA1*0201), but both of these haplotypes would type serologically as DQ2 (see Fig. 18-5). Especially when reading the older literature and discussing DQ polymorphisms, it is important to distinguish serologically defined polymorphisms, which may vary within the group of alleles on the α and β chains, from polymorphisms defined by sequence at a specific locus (DQA1 or DQB1). The HLA associations with the Ro (SS-A) and La (SS-B) autoantibody systems have been thoroughly studied. The anti-Ro response is present in 25% to 50% of patients with SLE63 and even more frequently in patients with primary Sjögren’s syndrome.64 Although early serologic studies indicated an association with HLA-DR3 and HLA-DR2, a detailed molecular analysis of these HLA haplotypes has provided evidence that HLA-DQ alleles in linkage disequilibrium with HLA-DR2 and HLA-DR3 are responsible for controlling this autoantibody response; heterozygous individuals who inherit a DR2-DQ1 haplotype and a DR3-DQ2 haplotype tend to have very high anti-Ro antibody titers in the setting of SLE or Sjögren’s syndrome.65 The strongest associations involve a DQA1*0501DQB1*0201 haplotype (frequently found in linkage disequilibrium with DR3) and a DQA1*06-DQB1*06 haplotype (frequently found in linkage disequilibrium with DR2). Reveille and colleagues66 attempted to refine further these associations by looking at DQ alleles in Ro antibody–positive patients who do not inherit one of these two associated haplotypes. These data led to the hypothesis that particular amino acid substitutions in the DQ α chain (glutamine at position 34) and DQ β chain (leucine at position 26) may be involved in risk for developing a Ro antibody response.66 Proof of this hypothesis is unlikely to come solely from additional genetic studies, but rather from experiments that directly test the influence of these DQ polymorphisms on the immune response to specific autoantigen.67,68 HLA-DQ associations also have been reported for other autoantibody systems, such as antiphospholipid antibodies69 and anti-Sm responses.70 The overall pattern of HLA-DQ associations with these antibody responses is similar to that seen for antiRo responses, although the alleles involved are different. POPULATION ASSOCIATION STUDIES: WHAT DO THEY MEAN? Almost all of the studies on HLA and disease involve population associations that are detected by means of retrospective case-control studies. It is essential to understand the strengths and weaknesses of this approach to genetic analysis to judge the significance of these HLA associations. Generally, there are three possible reasons for detecting an association between a particular allele and a disease. First, the allele under investigation may be directly involved in the pathogenesis of the disease. This assumption underlies most of the foregoing discussion on HLA and rheumatic disease. The studies described reflect the search for an ever more precise definition of particular amino acid substitutions or unifying structural characteristics of diseaseassociated alleles. This effort derives from the idea that HLA

EFFECTOR MECHANISMS IN AUTOIMMUNITY AND INFLAMMATION

DR2 DR4

313

DR3 DR5

DR3 DR4 Figure 18-6  Family structure used for determination of haplotype relative risk. The affected child carries the DR3 and DR4 alleles. A fictitious “control” individual can be constructed from the noninherited DR2 and DR5 alleles and used for a relative risk calculation. Such families also can be used for transmission disequilibrium testing, as discussed in the text.

alleles directly predispose to disease by virtue of their ability to control the immune response.4 As discussed previously, this may involve many mechanisms, including preferential peptide binding and the influence of the MHC on thymic selection of the peripheral T cell repertoire. The second possible reason for observing an HLA association is that a gene in linkage disequilibrium with HLA may be the disease gene. Linkage disequilibrium over long distances is a particularly prominent feature of the HLA region, particularly for certain haploytpes.24,71 Many genes with immunologic function within the MHC complex may themselves be directly involved in predisposing to autoimmunity. As shown in Figure 18-4, genes involved in antigen processing (TAP1 and TAP2), complement activation (C4, C2, factor B), and cytokines such as TNF-α all are encoded in this region and could be responsible for disease risk. As discussed in a later section, it is likely that for many autoimmune diseases, MHC genes other than, or in addition to, the classic HLA alleles are involved in disease ­susceptibility. A third reason to consider with any HLA association is the possibility that the result is an artifact of population stratification of patients and controls. The specific concern is that the control group may not be genetically matched to the disease group at loci that are unrelated to disease. This often results from a failure to study a control group that is ethnically matched to the disease group. This is emerging as a major issue generally in genetic case-control studies, and several approaches to control for this have been proposed,17 including the use of single-nucleotide polymorphism (SNP) markers that can specifically determine ethnic background.72 As yet, these methods for correcting for underlying populations have not been widely used. ALTERNATIVES TO THE CASE-CONTROL METHOD FOR DETECTING DISEASE ASSOCIATION To avoid the confounding effects of population stratification in case-control studies, family-based controls also can be used for doing association studies. Consider the family shown in Figure 18-6. The affected child carries DR4 and DR3, each of which is inherited from one parent. The laws of mendelian inheritance specify that one DR haplotype from each parent is not inherited by any given offspring—in this example, DR2 in the father and DR5 in the mother. These two noninherited haplotypes can be thought of as forming

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a genotype for a “control” individual. In this manner, issues of population stratification are eliminated because patients and controls are sampled from the identical (parental) gene pool. This approach to disease association was originally proposed by Falk and Rubinstein73 and was called the haplotype relative risk method. Its validity depends on numerous assumptions, including that the genetic marker under study does not influence mating preference or the production of gametes. A popular extension of this approach is called the transmission disequilibrium test.74 Using the family in Figure 186, for a given heterozygous parent (e.g., the father carrying DR2 and DR4), there is a probability of 0.5 that any given allele, such as DR4, would be transmitted to the child. If the DR4 allele has no bearing on disease risk, the probability of transmission (T) to an affected child is equal to the probability of nontransmission (NT). This can be stated simply as P (T|D) = P (NT|D), in which D indicates the presence of disease in the offspring. If the allele being examined is associated with disease risk, however, P (T|D) > P (NT|D). If large numbers of heterozygous parents with affected offspring are examined, transmission disequilibrium testing can establish an association between disease and the test allele compared with the (noninherited) control alleles. The advantages for getting around the problem of case-control matching are compelling. The transmission disequilibrium test does require the availability of parents, however, and case-control studies still have a major role to play, particularly for diseases with adult onset where parents are unlikely to be available in many cases. COMPLEXITY OF HLA ASSOCIATIONS WITH RHEUMATIC DISEASES: EVIDENCE FOR MULTIPLE-RISK GENES WITHIN THE MAJOR HISTOCOMPATIBILITY COMPLEX The foregoing discussion largely assumes that for a given disease or autoimmune phenotype, a set of alleles at a single HLA locus is likely to explain the association. For many autoimmune diseases, however, it is likely that multiple genes within the MHC contribute independently to disease risk. In the case of RA, numerous studies have indicated that a separate locus in the central MHC may be associated with the disease, independently of the HLADRB1 locus.75-77 In addition, there is evidence that genes in the MHC class I region may influence the risk conferred by certain HLA-DRB1*0404 haplotypes,77 or may interact with other non-MHC genes.78 Similar analyses in SLE,79,80 juvenile arthritis,81,82 multiple sclerosis,83 and myasthenia gravis84 all point to the fact that multiple different genes within the MHC can contribute to disease susceptibility. This issue is currently a major focus of research efforts in autoimmune diseases, and it is highly likely that additional risk genes in the MHC will be defined in the next few years using the dense SNP mapping techniques discussed in the next section.

GENETICS IN THE WHOLE-GENOME ERA As pointed out in the introduction, there has been an explosion in new genetic knowledge over the past few years, and this is likely to continue for some time. A major ­foundation was

laid by the completion of the Human Genome ­Project,85,86 which provided a reference sequence for the entire 3.2 billion base pairs of the human genome. Subsequently, the human HapMap Project87 has provided a catalog of the common sequence variations across the human genome, with more than 10 million SNPs now defined. In addition to SNPs, there are tens of thousands of variable numbers of tandem repeats, a common form of which is termed a microsatellite. Microsatellites have been used extensively for linkage analysis over the past decade.88 It also has become apparent more recently that large insertions and deletions are common across the genome,89 some of which arise de novo,90 providing another source of individual genetic variation that can be associated with human disease. Against this background of basic information about DNA variation, there has been sweeping technologic change, so that it is now possible to obtain hundreds of thousands or even millions of SNP genotypes on many individuals in a matter of days.91 This change has provoked the development of sophisticated statistical approaches to large datasets, at the same time highlighting the need to integrate the genetic knowledge with clinical data in ways that are manageable and meaningful to researchers and ultimately to practitioners. Although many of the basic principles of association and linkage disequilibrium discussed in the context of the HLA association are still valid, these have been extended in new ways, as discussed subsequently in the section on haplotype block structure. Another unsettled issue concerns the overall genetic “architecture” of human disease.92 Until more recently, there has been an assumption that common allelic variants are likely to account for most of the genetic risk for autoimmunity in the population. The HLA alleles that are associated with rheumatic diseases are examples, as are several of the new associations with RA and other autoimmune disorders, such as PTPN22.93 By common variants, we generally mean variants that are present in the population at frequencies of 5% or more and not less than 1%. There is no a priori reason, however, to reject the hypothesis that lots of rare variants account for a significant fraction of the genetic burden of disease. The main reason that common variants have been a focus of research is because the current technologies are particularly well suited to investigate them. This situation is about to change, with the advent of new technologies that permit resequencing on a massive scale, with routine resequencing of individual human genomes probably less than a decade away. Some examples in the literature now show that lots of different rare genetic variants can account for a common phenotype, such as plasma levels of lipoproteins.94,95 We are still early in the whole-genome era of genetic mapping. ESTIMATING THE SIZE OF THE GENETIC CONTRIBUTION TO RHEUMATIC DISEASES Since the last edition of this chapter, several genes outside of the MHC have been definitively associated with autoimmune and rheumatic diseases, including PTPN22,96,97 IRF5,98,99 and several genes in the interleukin (IL)-12/IL-23 pathway (see later). Until these observations were made, however, the evidence for additional risk genes outside of the MHC was largely based on the epidemiology of familial

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aggregation and twin concordance for autoimmune diseases. The general approach is to compare disease prevalence in groups of individuals with different degrees of genetic relatedness. The most common groups used for such studies are genetically identical monozygotic individuals (MZ twins), individuals who share approximately 50% of their genes in common (dizygotic twins and siblings), and unrelated individuals in the population whose overall degree of genetic similarity (at polymorphic loci) is relatively low, with about 0.1% difference over the entire genome. A 0.1% difference among unrelated subjects implies approximately 3 million base pair differences over the entire genome of 3.2 billion base pairs, assuming only SNPs. On average, siblings and dizygotic twins should differ by about 1.5 million SNPs. The use of such family and background population prevalence data to calculate risk ratios remains a primary method of estimating the overall size of the genetic component in complex diseases.100 One can estimate the relative risk of disease for siblings of affected individuals compared with the general population. This leads to a value called λs, or relative risk to sibs, which is calculated as follows: λs

=

EFFECTOR MECHANISMS IN AUTOIMMUNITY AND INFLAMMATION

315

Table 18-8  Familial Clustering of Selected   Autoimmune Diseases, as Measured by the Relative   Risk to Siblings (λS) and Monozygotic Twins (λMZ) Disease

λS

λMZ

Type 1 diabetes mellitus

15

60

Rheumatoid arthritis

3-10

20-60

Multiple sclerosis

20

250

Systemic lupus   erythematosus

20

250

Ankylosing ­spondylitis

54

500

From Lander ES, Linton LM, Birren B, et al: Initial sequencing and analysis of the human genome. Nature 409:860-921, 2001.

be interpreted in light of the background population prevalence of the disease. A low MZ twin concordance rate does not imply a low genetic component to the disorder. The absence of complete concordance for disease among MZ twins indicates the need to include environmental, developmental, and stochastic factors to understand the role of genetics fully.

Disease prevalence in siblings of affected individuals Diisease prevalence in general population

Obtaining a reliable value of λs depends on having accurate estimates of disease prevalence in the two comparison groups. This is not a trivial matter. In the case of RA, the estimation of population prevalence is fraught with potential sources of error. A firm diagnosis of RA is difficult to make in large surveys, with errors in both directions possible. Underestimation may occur because of the lack of reporting of disease that is no longer active. Overestimation may result from inadequate distinction between RA and other forms of polyarthritis. Similar problems may occur in estimates of population prevalence of SLE, in which mild disease may be overlooked, or variability in phenotypic expression may confound the issue. Accurate detection and assessment of disease phenotype also are involved in the determination of sibling affection rates. Despite these difficulties, a range of values for λs has been established for many of the common autoimmune disorders.101 Representative examples are shown in Table 18-8. With the exception of ankylosing spondylitis, most autoimmune disorders seem to have a λs in the range of 10 to 20. Table 18-8 also shows the estimates for λMZ. Analogous to the calculation for λs, λMZ is calculated as follows: λ MZ =

Disease prevalence in identical (MZ) cotwins of affecteed individuals Disease prevalence in general population

The value λMZ can be interpreted as an estimate of the maximal genetic risk for the disease. This interpretation assumes that all of the increased risk to an MZ cotwin of an affected individual results from the fact that they share the same genetic polymorphisms. This is clearly not the case because at least some environmental sharing probably contributes to the risk. It is notable, however, that the estimated value for λMZ is quite high for many autoimmune disorders, and this emphasizes the fact that MZ twin concordance rates must

SCREENING THE ENTIRE GENOME FOR DISEASE GENES: APPROACHES BASED ON LINKAGE Case-control association studies have been the primary means of detecting the involvement of HLA or other genetic loci in susceptibility to the rheumatic diseases. These types of studies generally are limited to a few candidate markers and have the major disadvantage that the candidate genes to be tested are selected on the basis of incomplete knowledge about the disease. This is the “hypothesis-driven” approach to human genetics, and although still valuable if applied properly, it often has resulted in the publication of false-positive results, partly because of publication bias.102 The alternative is to take a “discovery-driven” approach, in which the entire genome is interrogated without any a priori assumptions about what genes are involved. There are two basic methods of whole-genome analysis— one based on linkage, and the other based on association.103 Linkage methods depend on the ability to track polymorphic genetic markers in families and to show that these genetic markers cosegregate with the disease phenotype in families in which there are multiple members affected. Multiplex families are required for linkage analysis. The details of the statistical methods are complex, but are generally based on examining the likelihood of a particular pattern of coinheritance of marker and disease (linkage) compared with the likelihood that there is no linkage (the null hypothesis). A measure of this likelihood is referred to as the LOD (log of the odds) score, with a LOD score greater than 3 generally interpreted to indicate significant evidence of linkage when markers across the entire genome are examined. Further details of linkage methods can be found in Ott.104 One advantage of linkage analysis is that the entire genome can be effectively interrogated using less than 500 informative microsatellite markers.88 Linkage analysis has been applied with great success to the analysis of rheumatic diseases that exhibit a clear mendelian pattern of inheritance (e.g., dominant or ­recessive).

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Markers at locus X:

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Genetics of Rheumatic Diseases

3,4

1,2

#1

#2

1,3

1,3 1,4 2,3 2,4

Haplotypes shared by siblings: Expected frequency:

Possible combinations of alleles inherited from parents

0

1

2

25%

50%

25%

Figure 18-7  A nuclear family with two affected children (affected ­sibling pair). The possible distribution of alleles at an autosomal ­ locus, X, is shown for sib 2, along with the predicted frequency of shared ­haplotypes among the sibs. Such families can be used to detect linkage using affected sibling pair analysis (see text).

In 1992, familial Mediterranean fever was mapped to chromosome 16,105 and this led to the identification of the gene for this disease in 1997.106 In addition, an entirely new class of familial periodic fever syndromes has been localized to mutations in the TNF receptor 1 gene on chromosome 12.107,108 For highly penetrant mendelian disorders, classic linkage analysis is a powerful means of identifying the underlying molecular basis of disease. One of the drawbacks to classic linkage analysis is, however, that, to be most useful, it should be applied to disorders with a high penetrance and a known genetic model (e.g., dominant versus recessive). An alternative approach based on linkage, broadly termed allele sharing, is preferred for the study of autoimmune diseases that have a complex genetic basis.103 The most common approach to allele sharing is the affected sibling pair method. This method is based on a simple question: When two sibs are affected with a disease, do they share alleles at particular genetic markers more frequently than would be expected by chance? The basic approach is illustrated in Figure 18-7. In this family, two siblings are affected, and the first-born sibling (sib 1) has inherited alleles 1 and 3 at a marker locus, X. By the laws of mendelian inheritance, sibling 2 has a 25% chance of inheriting these same two alleles and has a 25% chance of inheriting neither of these alleles (i.e., sib 2 inherits 2 and 4 and shares nothing with sib 1 at locus X). By a similar reasoning, there is a 50% chance that these two siblings would share one allele in common. This 25:50:25 distribution of sharing 0, 1, or 2 haplotypes is expected if there is no linkage between the disease and the marker locus. If a gene that lies very near the marker locus is involved in disease risk, however, a significant deviation toward increased sharing among affected siblings would be observed. The closer the marker is to the disease locus, the greater the deviation would be from a 25:50:25 distribution. By examining large numbers of affected sibling pairs in this manner, the investigator can develop statistical evidence that this is the case using a standard χ2 analysis, with the null hypothesis being that there is no increased sharing at the marker locus.

Affected sibling pair analysis has many distinct advantages and disadvantages. Only affected individuals are used, and the problem of falsely assigning a family member as “unaffected” is eliminated. This is a major issue for diseases such as RA because the disease may not express itself until later in life. Affected sibling pair analysis can be done without committing to a specific model of inheritance (i.e., recessive or dominant). As with linkage in general, the affected sibling pair methods have relatively low power to detect genes that confer only modest risk.103 This means that quite large numbers (hundreds or thousands) of multiplex families are required to obtain statistically significant results. Linkage analysis based on allele sharing began to be applied to genetically complex rheumatic and autoimmune diseases in the 1990s and has resulted in a few successes, most notably the identification of the NOD2 gene as a major risk factor for Crohn’s disease.109,110 Linkage analysis has provided evidence for numerous risk genes involved in SLE,111 although precise gene identification has not yet been done for most of these loci. More recently, the presence of a linkage peak (LOD score >3.5) on chromosome 2q in RA sibling pairs112 has led to the identification of STAT4 as a risk gene for RA and SLE.113 Although challenging to carry out, linkage can be applied successfully to complex diseases that do not have a clear mendelian pattern of segregation. WHOLE-GENOME ASSOCIATION STUDIES Compared with linkage analysis, association methods have much greater statistical power to detect genetic effects.103 In contrast to the hundreds of markers used for linkage, however, large numbers of genetic markers are required to carry out a comprehensive genome-wide study using association methods. Because of dramatic advances in technology and the rapid decline in costs of genotyping, we are now in an era where whole-genome association with hundreds of thousands (or even 1 million) SNPs is becoming a standard approach to gene discovery in complex disease. For scanning the whole genome, this has generally replaced linkage methods except in special situations. The success of whole-genome association studies depends on the underlying haplotype structure of the genome. Although SNPs have been most commonly used in the context of candidate gene association studies, it is now apparent that combinations of SNPs can be employed to define common haplotype “blocks” that exist by virtue of strong linkage disequilibrium between alleles at adjacent SNP markers.114,115 This concept emerged from early studies of a region on chromosome 5q114 that contains numerous cytokine genes and is associated with inflammatory bowel disease,116 as shown in Figure 18-8. Consider the first block on the right of the figure (labeled “block 1”). There are eight SNPs defined within an 84-kb segment of DNA in this region of chromosome 5q31. In principle, any combination of these eight SNPs could occur in this region, giving rise to 28256 possible combinations. Only two of these (GGACAACC and AATTCGGG) occur with high frequency in the population (76% and 18%), however, and together they account for 96% of all the possible 256 haplotypes in the population (line b in Figure 18-8). Figure 18-8 illustrates this principle of limited haplotype variation for 10 additional haplotype blocks in this region. The HapMap project

92%

BLOCK 2 3 kb

97%

77%

19%

BLOCK 1 84 kb

96%

76%

18%

b

c 37% 14% 19% 21%

94%

BLOCK 4 30 kb

CGCGCCCGGAT TTGCCCCGGCT CTGCTATAACC CTGCCCCAACC

RAD50

CCGAT CTGAC CTGAC ATACT

IRFI

35% 9% 13% 35%

93% 41% 9% 29% 18%

97%

BLOCK 5 BLOCK 6 25 kb 11 kb

CCAGC CAACC GCGCT CCACC

IL5

OCTN1 PDLIM3

40% 14% 27% 12%

93%

BLOCK 7 92 kb

CCCTGCTTACGGTGCAGTGGCACGTATT*CA CATCACTCCCCAGACTGTGATGTTAGTATCT TCCCATCCATCATGGTCGAATGCGTACATTA CCCCGCTTACGGTGCAGTGGCACGTATATCA

OCTN2

38% 8% 31% 7%

91%

BLOCK 8 21 kb

CGTTTAG TAATTGG TGTT*GA TGATTAG

P4HA2

36% 10% 33% 9%

92%

BLOCK 9 27 kb

ACAACA GTGACG GCGGTG ACGGTG

98% 29% 16% 51%

42% 8% 36%

BLOCK 11 19 kb

TATAG TATCA CGGCG

90%

BLOCK 10 55 kb

GTTCTGA TGTGCGG TG*GTAA

CSF2 IL3

FACL6

Figure 18-8  A schematic map of a 1-megabase region on chromosome 5q31 with a summary of the haplotype block pattern of single-nucleotide polymorphism (SNP) variation in the region. Each tick mark on the top bar marks 50 kb. The genes in the region are shown above the bar, with direction of transcription as indicated at the left. Section a summarizes the major haplotype blocks, with colors highlighting the most common combinations of SNP alleles for each haplotype block. Section b shows the percent of the total haplotypes in each block that are captured by the major haplotypes. Section c gives the percentages for each specific haplotype. Two to four haplotypes account for greater than 90% of the haplotypes in each block. This haplotype diversity is dramatically reduced from what would be expected if each SNP were randomly associated with other SNPs in the same block. A fuller description of these patterns of haplotype diversity can be found in Daly and colleagues.114 (From Daly MJ, Rioux JD, Schaffner SF, et al: High-resolution haplotype structure in the human genome. Nat Genet 29:229-232, 2001.)

36% 26% 28%

BLOCK 3 14 kb

CCCAA

AATTCGTG

a

CGGAGACGA GACTGGTCG CGCAGACGA

IL4 IL13

TTACG

SEPT8

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GGACAACC

SNPs

Genes

Genes

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has shown that this limited haplotype diversity is typical of the entire human genome.87 The reasons for this are related partly to the discontinuous nature of meiotic recombination, so that regions between blocks tend to exhibit higher rates of recombination than within blocks.115,117 Population history and migration also contribute to these patterns of genetic variation. Effectively, these patterns of haplotype variation lead to the view that a large portion of the common human variation can be described as a “bar code” of common haplotype blocks. By picking SNPs that “tag” these haplotypes, it is possible to screen the whole human genome with a much reduced set of SNPs, much fewer than the 10 million or more common SNP variants that have been defined in human populations. Generally, most of the common variation can be captured with 300,000 to 500,000 SNPs, and standard platforms are now widely available to perform these analyses on large populations of cases and controls. In addition, the International HapMap Project has established online resources (www.hapmap.org) that allow users to explore easily the haplotype structure of any region of the genome.118 The HapMap website also contains informative tutorials on genetic diversity and the use of this resource. Whole-genome association studies for human disease are already bearing fruit. In 2005, the complement regulatory protein factor H was identified as a significant risk factor for age-related macular degeneration.119,120 In addition, the IL-23 receptor was identified as a risk gene for Crohn’s disease in late 2006.121 Many other whole-genome association studies are in progress for a variety of complex disorders and phenotypes,122 and a deluge of such data is expected in the coming year. OVERLAPPING SUSCEPTIBILITY GENES AND PATHWAYS FOR AUTOIMMUNE DISEASES It should be clear from the previous discussion that a full catalog of common susceptibility genes for autoimmunity is forthcoming. Nevertheless, some themes are already emerging from the current data. In particular, common genes and pathways seem to be involved in multiple different autoimmune disorders. In 2004, an association between the intracellular phosphatase, PTPN22, was reported for many autoimmune diseases, including type 1 diabetes,97 RA,96 SLE,123 and autoimmune thyroid disease.124 With odds ratios consistently in the range of 1.5 to 2, this was a compelling demonstration that a specific common allelic variant can confer risk for multiple different autoimmune phenotypes. In this case, a nonsynonymous change in one of several SH3 binding sites in PTPN22 (a tryptophan substitution for arginine at codon 620) was shown to disrupt the normal association of PTPN22 with a Csk, an intracellular tyrosine kinase.96,97 The exact functional consequence of this finding is uncertain, although an increase in phosphatase activity has been reported for PTPN22 as a result of this change.125 The role of PTPN22 in immune regulation is still a matter of debate, but seems partly related to setting thresholds for T cell receptor signaling through Lck.93 PTPN22 also is found in many other hematopoietic cells, and its function in these cells is largely unknown. Nevertheless, since

these first reports, the association of the PTPN22 R620W allele with multiple autoimmune diseases has been widely ­replicated.93 All of the autoimmune diseases associated with PTPN22 have a prominent autoantibody component, and a specific role in regulating humoral immunity seems to be a unifying feature. Despite a lack of understanding of the precise mechanisms, PTPN22 is a prime example of how the discovery of disease associations with relatively modest effect can redirect hypothesis-driven research onto new pathways. In 2005, interferon regulatory factor 5 (IRF5) was shown to be associated with susceptibility to SLE98 and replicated shortly thereafter.99 This was a satisfying observation because upregulation of interferon pathways is central to the pathogenesis of SLE and related disorders.126 Interferon dysregulation is not a prominent feature of RA, and IRF5 is not associated with RA. In contrast to PTPN22, IRF5 seems to be specific for a more narrow subgroup of SLE-related autoimmune disorders in which interferon pathways play a significant role. The details of the genetic data are particularly instructive because there are complex interactions between several alleles on the risk haplotype.127 Some risk alleles give rise to splice variation, others regulate levels of expression, and a third risk allele is related to an insertion deletion. The presence of all of these variants on the same haplotype confers maximal risk. There are three levels of risk, however, including a protective effect, depending on which specific alleles are present.127 The IRF5 association with SLE illustrates that even when a risk gene is identified, the molecular details and allelic patterns of association can be quite complex. Finally, several more recent discoveries in the IL-12/ IL-23/STAT4 pathways show that multiple genes within related pathways can have contrasting effects on risk for different autoimmune diseases. As noted earlier, the IL-23 receptor was shown to be associated with Crohn’s disease in late 2006.121 IL-12B and IL-23R have been associated with susceptibility to psoriasis.128 Significant associations between IL-23R and ankylosing spondylitis also have been observed.128a IL-12 and IL-23 can signal through STAT4,129 and RA and SLE have been associated with polymorphisms in STAT4.113 The influence of STAT4 gene knockout is different in animal models—it is protective for arthritis models,130 but exacerbates nephritis in SLE-prone mouse strains.131 Inhibition of STAT4 with RNAi can ameliorate ongoing arthritis in animals,130 suggesting utility as a therapeutic target. The STAT4 association also raises the possibility that the balance of T helper type 1 and T helper type 17 may be important for understanding disease susceptibility because IL-12 and IL-23 have contrasting effects in this regard.132 These and other genetic discoveries are emerging as a compelling rationale for focusing attention on particular disease pathways for hypothesis-driven research. Even if particular genetic variants play a role in only a small subset of patients or only in certain environmental settings, their elucidation nevertheless provides important insights into disease pathogenesis and potentially ­provides for diagnostic and therapeutic specificity. This is the most important reason for pursuing the genetics of complex diseases.

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Future Directions This chapter has discussed some of the fundamental concepts and techniques that have been applied to the study of rheumatic diseases, highlighting the more ­recent emerging genetic data. Although the underlying concepts will not change, further advances are around the corner. As the genetic underpinnings of disease are identified, a major challenge will be to define and ­integrate the multiple genetic and environmental factors into an overall understanding of disease pathogenesis. It is likely that a renewed appreciation will develop for the commonality between, and heterogeneity of, ­rheumatic diseases. This appreciation will provide ­opportunities for new and more specific approaches to diagnosis and ­treatment.

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  94. Cohen JC, Pertsemlidis A, Fahmi S, et al: Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels. Proc Natl Acad Sci U S A 103: 1810-1815, 2006.   95. Cohen JC, Kiss RS, Pertsemlidis A, et al: Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305: 869-872, 2004.   96. Begovich AB, Carlton VE, Honigberg LA, et al: A missense singlenucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 75:330-337, 2004.   97. Bottini N, Musumeci L, Alonso A, et al: A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 36:337-338, 2004.   98. Sigurdsson S, Nordmark G, Goring HH, et al: Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet 76: 528-537, 2005.   99. Graham RR, Kozyrev SV, Baechler EC, et al: A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet 38:550-555, 2006. 100. Risch N: Linkage strategies for genetically complex traits, II: The power of affected relative pairs. Am J Hum Genet 46:229-241, 1990. 101. Vyse TJ, Todd JA: Genetic analysis of autoimmune disease. Cell 85:311-318, 1996. 102. Hirschhorn JN, Lohmueller K, Byrne E, et al: A comprehensive review of genetic association studies. Genet Med 4:45-61, 2002. 103. Risch NJ: Searching for genetic determinants in the new millennium. Nature 405:847-856, 2000. 104. Ott J: Analysis of Human Genetic Linkage. Baltimore, Johns Hopkins University Press, 1999. 105. Pras E, Aksentijevich I, Gruberg L, et al: Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. N Engl J Med 326:1509-1513, 1992. 106. Consortium TIF: Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell 90:797-807, 1997. 107. McDermott MF, Aksentijevich I, Galon J, et al: Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97:133-144, 1999. 108. Hull KM, Drewe E, Aksentijevich I, et al: The TNF receptor-associated periodic syndrome (TRAPS): Emerging concepts of an autoinflammatory disorder. Medicine (Baltimore) 81:349-368, 2002. 109. Hugot JP, Chamaillard M, Zouali H, et al: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411:599-603, 2001. 110. Ogura Y, Bonen DK, Inohara N, et al: A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603-606, 2001. 111. Forabosco P, Gorman JD, Cleveland C, et al: Meta-analysis of genome-wide linkage studies of systemic lupus erythematosus. Genes Immun 7:609-614, 2006. 112. Amos CI, Chen WV, Lee A, et al: High-density SNP analysis of 642 Caucasian families with rheumatoid arthritis identifies two new linkage regions on 11p12 and 2q33. Genes Immun 7:277-286, 2006. 113. Remmers EF, Plenge RM, Lee AT, et al: STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med, 357:977-986, 2007. 114. Daly MJ, Rioux JD, Schaffner SF, et al: High-resolution haplotype structure in the human genome. Nat Genet 29:229-232, 2001.

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115. Jeffreys AJ, Kauppi L, Neumann R: Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat Genet 29:217-222, 2001. 116. Rioux JD, Daly MJ, Silverberg MS, et al: Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet 29:223-228, 2001. 117. Myers S, Bottolo L, Freeman C, et al: A fine-scale map of recombination rates and hotspots across the human genome. Science 310:321-324, 2005. 118. Thorisson GA, Stein LD: The SNP Consortium website: Past, present and future. Nucleic Acids Res 31:124-127, 2003. 119. Klein RJ, Zeiss C, Chew EY, et al: Complement factor H polymorphism in age-related macular degeneration. Science 308:385389, 2005. 120. Zareparsi S, Branham KE, Li M, et al: Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration. Am J Hum Genet 77:149-153, 2005. 121. Duerr RH, Taylor KD, Brant SR, et al: A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314:1461-1463, 2006. 122. Saxena R, Voight BF, Lyssenko V, et al: Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science, 316:1331-1336, 2007. 123. Kyogoku C, Langefeld CD, Ortmann WA, et al: Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet 75:504-507, 2004. 124. Criswell LA, Pfeiffer KA, Lum RF, et al: Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: The PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet 76:561-571, 2005. 125. Vang T, Congia M, Macis MD, et al: Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet 37:1317-1319, 2005. 126. Baechler EC, Batliwalla FM, Reed AM, et al: Gene expression profiling in human autoimmunity. Immunol Rev 210:120-137, 2006. 127. Graham RR, Kyogoku C, Sigurdsson S, et al: Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proc Natl Acad Sci U S A 104:6758-6763, 2007. 128. Cargill M, Schrodi SJ, Chang M, et al: A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80:273-390, 2007. 128a. Wellcome Trust Case Control Consortium. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 39(11):1329-1337, 2007. 129. Watford WT, Hissong BD, Bream JH, et al: Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev 202:139-156, 2004. 130. Hildner KM, Schirmacher P, Atreya I, et al: Targeting of the transcription factor STAT4 by antisense phosphorothioateoligonucleotides suppresses collagen-induced arthritis. J Immunol 178:3427-3436, 2007. 131. Jacob CO, Zang S, Li L, et al: Pivotal role of Stat4 and Stat6 in the pathogenesis of the lupus-like disease in the New Zealand mixed 2328 mice. J Immunol 171:1564-1571, 2003. 132. Mathur AN, Chang HC, Zisoulis DG, et al: Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol 178:4901-4907, 2007.

19

Complement System John p. atkinson

KEY POINTS: RHEUMATIC DISEASES— GENERAL CONCEPTS Autoantibodies may activate the complement system, which then contributes to damage at the site of autoantigen ­expression. Urate crystals, like other types of self-debris, activate innate immunity, including the complement system. The complement system plays a key role in the handling of immune complexes, especially those that arise in the ­circulation. Complement activation is an efficient means to coat antigens so that they adhere to peripheral blood cells and are then phagocytosed or carried to the spleen and liver for disposal. In these organs, the immune complexes are transferred to tissue macrophages for destruction or an ­immune response. Complement measurements are helpful in diagnosing and following patients with systemic lupus erythematosus. A low C4 and C3 in the presence of antinuclear antibodies has nearly a 100% specificity for lupus. In rheumatic diseases featuring complement activation, we lack sensitive day-to-day markers to monitor disease activity. Therefore, we do not know how much complement ­inhibition is required to favorably modulate a disease process. We also lack knowledge as to whether C3a/C5a, C4b/C3b, or the membrane attack complex is the key mediator of pathology, as well as which pathway and at which step to block. The complement system is activated in the joints in ­rheumatoid arthritis and in vessel walls in vasculitis.

In this chapter, the workings of the complement system are reviewed, with a focus on how the system functions in rheumatic diseases. The involvement of the complement system has long been recognized in two of the most common inflammatory diseases treated by rheumatologists: systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). What has been learned about the complement system’s role in these two diseases likely applies to related syndromes. The goal of this chapter is to help the rheumatologist appreciate the biologic and pathologic relevance of the complement system in rheumatic diseases. This information can also assist in the clinical interpretation of laboratory tests of complement proteins and in the determination of the significance of complement activation fragments in pathologic specimens.

HISTORICAL ASPECTS Today, complement is a collective term designating a group of plasma and membrane proteins that play a key role in innate and adaptive immunity. The complement system is

ancient, predating chordates such as the lamprey and hagfish.1,2 Complement was discovered in the late 19th century by experimental pathologists attempting to understand the protective basis of vaccination and the cause of transfusion reactions.3 In these studies, it became apparent that the cellfree portion of blood contained a lytic substance for bacteria and for transfused red blood cells (RBCs). The factor was heat labile (destroyed by heating at 56°C for 30 minutes or by leaving serum on the bench top overnight) and was innate or nonspecific (all individuals had this lytic substance). It was contrasted to antibody, which was heat stable and specific because immunized animals contained this substance. Through mixing experiments, two factors were found to be required for lysis—a specific recognition piece (antibody) and a nonspecific lytic piece (complement). In retrospect, this was the discovery of the classic complement pathway and led to its characterization as a heat-labile bactericidal factor that “complemented” the acquired factor raised by immunization. Similarly, in the blood of patients who recovered from transfusion reactions, a heat-stable substance (antibody) was found that recognized the transfused erythrocytes. However, it did not lyse the transfused cells; rather, it cooperated with a second lytic substance (complement) present in fresh serum. From this discussion, it is apparent why lysis became linked to the complement system and why the study of antibody and complement dominated the field of immunology for the next half century. Of interest, the first autoimmune disease to be recognized as such was a hemolytic anemia (paroxysmal cold hemoglobinuria) in which the same pair of reactants, antibody and complement, was shown to mediate RBC lysis.4 Consequently, this double-edged sword aspect of the complement system was recognized early, but not until the 1960s was there such a clear-cut demonstration of its protective versus injurious role. Compared with normal mice, C5-deficient mice were 100-fold more sensitive to death from pneumococcal infection but 100-fold less sensitive to tissue destruction by autoantibodies. Even more to the point, we now know that inherited deficiencies of C1, C4, and C2 strongly predispose to SLE, yet immune complex (IC) deposition and complement activation contribute to tissue damage in SLE.

FUNCTION A major activity of the complement system is to modify membranes and soluble antigens through strong (covalent) attachment of its activation fragments (Fig. 19-1). For example, several million C3b molecules can bind to a bacterial surface in less than 2 minutes. One goal of these deposited complement proteins is to opsonize the target. 323

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Complement Membrane modification

Lectin Cellular activation

Alternative

Classic

Pathogen C3b Direct lysis

Opsonization

Degranulation

Chemotaxis

Outcomes 1. Microbial destruction 2. Inflammation 3 Instructions to adaptive immunity Figure 19-1  Function of the complement system. The most important function of the complement system is to alter the membrane of a pathogen by coating its surface with clusters of activation fragments. In one case, they facilitate the key process of opsonization, as C4b and C3b interact with complement receptors. In the other case, as with certain gram-negative bacteria and viruses, the membrane attack complex lyses the organism. The second critical function of complement is to activate cells and thus promote inflammatory and immune responses. The complement fragments C3a and C5a (known as anaphylatoxins) stimulate many cell types, such as mast cells, to release their contents and stimulate phagocytic cells to migrate to sites of inflammation (chemotaxis). Through these phenomena of opsonization and cell activation, complement serves as nature’s adjuvant to prepare, facilitate, and instruct the host’s adaptive immune response. Because complement activation  occurs in a few seconds, this innate immune system initially engages most pathogens, especially those that try to enter the vascular space.

C3b (and its degradation fragments) and C4b are ligands for complement receptors on peripheral blood cells, tissue macrophages, and antigen presenting cells such as follicular dendritic cells. Complement ligands and their receptors are particularly adept at this coupling process, known as immune adherence. On phagocytic cells, this often leads to ingestion of the infectious particle, IC, or debris. Additionally, the membranes of some microorganisms (e.g., gram-negative organisms) and some host cells can be lysed by the terminal complement components (C5b-C9). In many cases, however, microbes possess capsules, making them resistant to lysis (e.g., most gram-positive organisms). In human diseases featuring autoantibodies, cells and tissues are similarly opsonized, and membrane integrity can be compromised. A recent extension of this opsonic function relates to complement’s role in the clearance of cellular debris following necrosis or apoptosis. In particular, one hypothesis to explain autoantibody formation in SLE is the complement system’s failure to properly clear or handle apoptotic cells.5 A second function of the complement system is cellular activation. It prepares the local environment for defense against infection (see Fig. 19-1). In the proteolytic steps of the early complement activation process, mediators are released that activate nearby cells. These low-molecularweight fragments (C4a, C3a, C5a) are termed anaphylatoxins because, if released in excessive amounts, they induce shock. C3a and C5a, the two most powerful mediators, bind to their respective receptors at sites of complement activation. This causes histamine release by mast cells and chemotaxis to the area by phagocytic cells. With improved reagents and newer technology, receptors for C3a and C5a have now been shown to be much more widely expressed

Inflammation (C3a/C5a)

Opsonization (C3b/C4b) Membrane attack (lysis) (C5b-C9)

Figure 19-2  Simplified diagram of the three pathways of complement activation. Deposition of clusters of C3b on a target is the primary goal. As shown by the broken line, the alternative pathway also serves as a feedback loop to amplify C3b deposition (regardless of which cascade deposited the C3b).

than initially thought; for example, they are expressed by epithelial cells, T cells, hepatocytes, endothelial cells, neurons, and other cell types. C3a and C5a may engage their receptors on endothelial and neuronal cells to alter blood flow and modulate cellular function.

NOMENCLATURE There are three activation cascades: the classic pathway (CP), the alternative pathway (AP), and the lectin pathway (LP) (Fig. 19-2). These converge to activate C3 and then the membrane attack complex (MAC). The nine proteins of the CP are designated by the uppercase letter C, followed by a number (Table 19-1). These numbered components act in numerical order, except for C4, which is cleaved in parallel with C2 and before C3. Components of the AP are designated by capital letters (e.g., factor B). Regulatory proteins are designated by a descriptive title (e.g., C4 binding protein) or a letter (e.g., factor H) (Table 19-2). Single components or multimeric complexes that have enzymatic activity are designated by a bar (e.g., C1 ). The loss of hemolytic potential by a component is usually designated by a lowercase prefix (e.g., iC3b). Fragments generated during complement activation are designated by a lowercase letter suffix (e.g., C3a, C3b). Except for the fragments of C2 (which are opposite), the a fragment is liberated into the surrounding milieu, whereas the b fragment becomes cell bound and continues the cascade. Receptors were named in order of their discovery but are also commonly identified relative to their ligand specificity and CD number (Tables 19-3 to 19-5). For example, complement receptor type 1 may be referred to in the literature as CR1, the C3b/C4b receptor, the immune adherence receptor, or CD35.

ACTIVATION CASCADES Because many rheumatic diseases feature autoantibodies and therefore ICs, an understanding of the general principles of the activation cascades is essential to characterizing complement’s role in a disease such as SLE3,6-9 (Fig. 19-3; see also Fig 19-2).

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Table 19-1  Components of the Complement   Activation Cascades Component

Serum Concentration (µg/mL) Function

Classic Pathway (CP) C1   C1q subcomponent

50

  C1r subcomponent   C1s subcomponent C4 C2

Lectin Pathway (LP) MBL MASP-1 MASP-2

200-500 20

150 (wide range) 5 5

Binds IC to trigger CP Binds Fc portion of IgG, IgM Protease: cleaves C1s Protease: cleaves C4 and C2 Opsonin* (C4b), C4a† Protease: cleaves   C3 and C5 as part of the convertases Binds sugars to trigger LP Protease Protease: cleaves C4 and C2

Alternative Pathway (AP) Factor D Factor B

1-2 150-250

Properdin Central protein  C3

25 550-1200

Protease: cleaves factor B Protease: cleaves C3 and C5 as part of the convertases Stabilizes AP convertases Opsonin† (C3b), C3a†

Terminal Pathway (TP) C5

70

C6 C7 C8

60 60 60

C9

60

MAC component (C5b), C5a† MAC component MAC component MAC component (pore formation) MAC component (pore formation)

*C4b forms part of the CP C3 and C5 convertases. It anchors the enzyme complex to the target. Likewise, for the AP C3 and C5 convertases, C3b anchors these enzyme complexes to the target. C3b is also part of the CP C5 convertase. † C4a, C3a, and C5a are liberated upon cleavage of C4, C3, and C5. IC, immune complex; Ig, immunoglobulin; MAC, membrane attack complex; MASP, mannan-associated serine protease; MBL, mannan-binding ­lectin.

CLASSIC PATHWAY The CP is activated primarily by ICs and a few other substances, including C-reactive protein.10 Human immunoglobulin (Ig) M and IgG subclasses 1 and 3 efficiently activate the CP. Once C1 is bound to an activator—by means of the Fc portion of IgG or IgM interacting with the C1q subunit of the C1 complex (Fig. 19-4)—the C1r enzymatic subcomponent autoactivates by proteolysis and then cleaves C1s to form C1 . C4 is a substrate for C1 and is cleaved by C1 to C4b, releasing the C4a fragment (Fig. 19-5). The C4b fragment, having had its thioester bond disrupted, now has the transient ability (a few microseconds) to covalently bind to a hydroxyl or amino group on a nearby target. C2 is also a substrate for C1, and C2 is cleaved by C1 to yield C2a and C2b. C2a interacts with 10% to 20% of the target-bound C4b to form the CP C3 convertase C4bC2a (Fig. 19-6). The

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325

enzymatic or catalytic domain of this complex is C2a, which cleaves C3 to form C3a and activated C3b (Fig. 19-7). Activated C3b attaches to the target by binding covalently to a hydroxyl group (analogous to the interaction of C4b with a hydroxyl or amino group), where it serves as the major opsonin of the complement system. In addition, some of the newly activated C3b binds covalently to a specific region on the C4b component of C3 convertase to form the CP C5 convertase C4bC2aC3b (see Fig. 19-6). CP activation by polyclonal antibodies is efficient on membranes of cells, bacteria, and viruses. In one illustrative study, complement activation by IgG binding to a membrane antigen of nucleated cell produced about 2.5 million bound C4b molecules, and about 0.5 million C2a molecules subsequently attached to these C4bs to form convertases.11 In less than 5 minutes, 21 million (representing a 10× amplification over the number of attached C4b molecules) C3b molecules were deposited. Further, only about 10% to 20% of the C4b and C3b molecules generated bound to the target. The rest were inactivated by hydrolysis in the fluid phase and then degraded by fluid-phase inhibitors. Concomitantly, C4a, C3a, and C5a anaphylatoxins were generated equal to the number of C4b, C3b, and C5b fragments produced. Approximately 1 million MACs were formed. Fragment attachment to and amplification on soluble antigens is a less efficient process, particularly the formation of the C3 and C5 convertases. A single IgM can activate the CP. In contrast, two IgGs in close proximity (side by side) are required before C1 can be bound. On erythrocytes, this means that several thousand IgGs must bind to an antigen before activation can occur. Consequently, antigenic density and display play a role in determining whether complement is activated. For example, in warm antibody (IgG)-mediated autoimmune hemolytic anemia, complement is usually not fixed (despite the autoantibody’s being of an appropriate IgG subclass) because of low antigenic density. LECTIN PATHWAY Lectins are carbohydrate-binding proteins,5,12,13 (see Fig. 19-4). Initially, they were described as proteins capable of agglutinating RBCs. They are important players in innate immunity and in rheumatic diseases. In particular, mannan­-binding lectin (MBL) is a hepatocyte-­synthesized plasma protein that preferentially binds to repeating mannoses and certain other oligosaccharides of pathogens. MBL resembles C1q (it belongs to the same family of proteins, known as collectins), consisting of an oligomer with a terminal collagenous domain on one end and a globular domain on the other (see Fig. 19-4). The main difference is that the carboxyl-terminus of MBL possesses a ­ carbohydrate-recognition domain, whereas C1q has an Ig-­binding domain. Like C1q binding to the Fc portion of IgG, MBL engagement with its sugar ligand leads to activation of serine proteases similar to C1r and C1s, called mannan-­associated serine proteases (MASPs). MASP-2 cleaves C4 and C2. MBL was discovered during an investigation into the cause of bacteremia in young children. The role of MBL deficiency as a predisposing factor for SLE and RA, as well as its contribution to disease pathology, is under intensive study.

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Table 19-2  Complement Regulatory Proteins Protein

Tissue Distribution

Function

Disease Association

Plasma

Inactivates C1r, C1s and MASPs; a SERPIN

Hereditary angioedema

Factor I

Plasma

Infections (secondary to low C3), HUS*

Membrane cofactor protein Decay-accelerating factor C4-binding protein

Most cells Most cells Plasma

Factor H

Plasma

Complement receptor type 1 (CR1)

Blood cells

Cleaves C3b and C4b; requires a cofactor protein Cofactor for cleavage of C4b and C3b Decays C3 and C5 convertases Cofactor for cleavage of C4b; decays CP C3   and C5 convertases Cofactor for cleavage of C3b; decays AP C3   and C5 convertases Receptor for C3b and C4b; cofactor activity   for C3b and C4b; decays C3 and C5   convertases

Infections (secondary to low C3), HUS*, type II MPGN, AMD None‡ Reduced levels in diseases featuring   immune complexes

Plasma Most cells

Blocks fluid-phase MAC Blocks MAC on host cells

None‡ PNH

Plasma

Inactivates C3a, C4a, and C5a

Urticaria, angioedema

Initiation C1 inhibitor Convertases

HUS* PNH None†

Membrane Attack Complex S protein (vitronectin) CD59 Anaphylatoxins Anaphylatoxin inactivator

*Most patients with HUS are heterozygous for function-altering mutations. † Insufficient number of cases of complete deficiency described to establish an association. ‡ Complete deficiency has not been reported. AMD, age-related macular degeneration; AP, alternative pathway; CP, classic pathway; HUS, hemolytic uremic syndrome; MAC, membrane attack complex; MASP, mannan-associated serine protease; MPGN, membranoproliferative glomerulonephritis; PNH, paroxysmal nocturnal hemoglobinuria; SERPIN, serine protease inhibitor. 18

Table 19-3  Receptors for C3 and C4 Receptor

Primary Ligand

Location

Function

CR1

C3b/C4b

Peripheral blood cells (except for most T cells   Immune adherence > phagocytosis; antigen localization and and platelets), FDCs, B cells, podocytes retention; complement regulation

CR2

C3dg/C3d

B lymphocytes, FDCs

Coreceptor for signaling through B cell receptor; antigen   localization and processing

CR3/CR4

iC3b

Myeloid lineage

Phagocytosis > adherence

The CD numbers are as follows: CR1, CD35; CR2, CD21; CR3, CD11b/CD18; CR4, CD11c/CD18. FDC, follicular dendritic cell.

Table 19-4  Receptors for Anaphylatoxins Receptor Ligand Location C3aR

C5aR

C3a

C5a

Function

Myeloid lineage, Cell activation, including including mast granule exocytosis,   cells; smooth upregulation of muscle, epithelial, adhesins, chemotaxis, endothelial, and cytoskeletal effects neuronal cells Similar to C3aR

Similar to C3aR, but with more chemotactic effects

The LP shares many features with the CP.7,8,12,13 The differences occur during the first few steps when MBL binds to an activating surface, such as bacteria with the appropriate repeating oligosaccharides. Each element of the MBLMASP complex is structurally and functionally homologous to the corresponding elements in the CP. C1q and MBL have globular ends through which they attach to their respective substrates. The MASP-2 in the complex cleaves C4 to form C4a and C4b (see Fig. 19-5) and C2 to form C2a and C2b— identical to C1 cleaving C4 and C2. The C4b2a complex formed is the same C3 convertase generated in the CP (see Fig. 19-6). The LP is a key player in innate immunity, where

Table 19-5  Receptors for C1q* Receptor

Ligand

Location

Function

CD91

Collagen-like   region

Phagocytic cells

Enhance phagocytosis

CD93

Collagen-like   region

Cell surface; Enhance phagocymonocytes, tosis platelets, endothelial cells, neutrophils

Calreticulin

Globular head

Intracellular

Bridge between C1q and CD93 and CD91

CR1

Globular head

Hematopoietic cells

Adherence

Others

Globular head

CR1

Probably facilitates adherence

*See reference 25 for a progress report in this evolving area. CR1, complement receptor 1 (CD35).

MBL and related lectins such as surfactants and ficolins bind to their cognate residues on microbes to trigger complement activation. At one time, MASPs (and possibly C1) directly activated C3, but through the evolution of C4 and C2, a more efficient C3 activating process was engineered.13

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Activation

Lectin Classic

MASP

Alternative

C1 C4 C2

Inflammation (C3a/C5a)

C3

B, D, P

C3b

Opsonization (C3b/C4b) Membrane attack (lysis) (C5b-C9)

Positive feedback loop

Figure 19-3  The complement activation pathways. Note that C4 and C2 serve identical purposes in the classic pathway (CP) and the lectin pathway (LP). They are cleaved by mannan-associated serine protease-2 (MASP-2) in the LP and by C1 in the CP. The convertases that cleave C3 are shown in Figure 19-6. C1 connects immune complexes to the CP as the C1q subcomponent binds to the Fc of antibody and the C1s subcomponent cleaves C4 and C2. In the LP, lectin carries a MASP that cleaves C4 and C2. IgG and IgM binding site

EFFECTOR MECHANISMS IN AUTOIMMUNITY AND INFLAMMATION

Carbohydrate binding site

-C1s or MASP-2

C4

327

C4b

+ C4a

C4d

+ C4c

Degradation C4b

Factor I plus cofactor protein

Figure 19-5  C4 activation and degradation. The boxed activation fragment is the one that remains covalently attached to the target. The other fragments are released into the surrounding milieu. C4a is a weak anaphylatoxin but has direct killing activity for bacteria. Factor I is a serine protease and cannot cleave C4b at a specific site unless accompanied by a cofactor protein. In the plasma, C4bp serves this role; on cells, it is a function of MCP (CD46) or CR1 (CD35).

Convertase

Classic/Lectin

Alternative

C3

C4bC2a

C3bBbP

C5

C3b C4bC1a

C3b C3bBbP

Figure 19-6  Proteins of the C3 and C5 convertases. C4b or C3b anchors the enzyme complex to the target. The catalytic domains are the serine proteases C2a and Bb. The C3 convertase becomes a C5 convertase when a C3b attaches to a preferred acceptor site on C4b or C3b. Properdin (P) stabilizes the alternative pathway convertases. Activation C1q

MBL

Figure 19-4  Similarity of C1q and mannan-binding lectin (MBL) structure. Ficolins, surfactins, and other members of the collectin family of proteins also share this general structure. Many activate the lectin pathway upon interaction with ligand. The C1r and C1s in the case of the classic pathway and mannan-associated serine protease-2 (MASP-2) in the case of the lectin pathway are wrapped around the stalk of these tulip-like structures. It is the nonantigen or Fc portion of immunoglobulin (Ig) G and IgM that engage the C1q subcomponent of C1.

C3

C3b

+ C3a

iC3b

+ C3f

C3dg

+ C3c

C3d

+ C3g

Degradation C3b

iC3b

Factor I plus cofactor protein Factor I plus CRI

ALTERNATIVE PATHWAY The AP was the second complement activation pathway discovered (hence the name), but it is phylogenetically the most ancient.1,2 In contrast to the CP and LP, the AP does not require antibody or a lectin to be triggered. It likely plays a larger role in rheumatic diseases than previously appreciated because of its so-called feedback or amplification loop.14 Thus, if C3b is deposited on a target by the CP or LP, the AP can enhance C3b deposition many-fold. The AP is also continuously active at a low level (like an idling car). The plasma inhibitors factor H and factor I and host cell surface regulators keep the system in check. In the absence of these regulators, as exemplified by inherited deficiencies, the system fires to exhaustion. The AP routinely “kicks into gear” in the setting of microbes. If C3b deposits on an activating surface (i.e., one that lacks regulators), the system’s feedback loop allows several million C3b molecules to be deposited in a few minutes. In this pathway, factor B, structurally and functionally homologous to C2, binds to the deposited C3b and is then cleaved by the constitutively active factor D to Bb and Ba. C3bBb is the AP C3 convertase (see Fig. 19-6).

C3 convertases

Proteases C3dg

Figure 19-7  C3 activation and degradation. The boxed activation fragment is the one that remains covalently attached to the target. The other fragments are released into the surrounding milieu. C3a is a potent anaphylatoxin and kills bacteria directly. C3f may be a bone marrow–  mobilizing factor for neutrophils. C3c and C3g have no known function.

It is stabilized by properdin (P). The catalytic serine protease Bb of the C3bBbP enzyme complex then cleaves C3 to C3a and C3b; thus, a feedback loop is set up. Some of the newly generated C3b molecules bind covalently to C3b already deposited on the target to form a C5 convertase (C3b2Bb). In vivo, the C3 and C5 AP convertases are short-lived owing to spontaneous decay, unless stabilized by properdin. MEMBRANE ATTACK COMPLEX The terminal pathway begins with the cleavage of C5 by either the CP-LP or the AP C5 convertase. The liberated C5a fragment is a potent cell activator (anaphylatoxin) and

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chemotactic factor. The C5b binds C6, which in turn engages C7 to yield the fluid phase C5b67. This lipophilic complex can now interact with cell membranes. Following membrane insertion, it next binds C8. The C5b678 complex forms an initial pore in the plasma membrane and then recruits multiple (5 to 10) C9 molecules to yield C5b6789. This complex is an efficient membrane channel former and is responsible for cell lysis. Many organisms and cell types are not easily lysed, however. The MAC has multiple nonlytic effects on cells as well. The majority of these lead to activation of signaling pathways, as has been seen in the case of neurons and kidney cells. Some of the organ dysfunction seen in SLE, especially if transient or correctable with treatment, may be secondary to these nonlytic effects of the MAC.

DAF: Decay accelerating activity C4b C2a Binding Decay DAF

DAF C4c

MCP: Cofactor activity

Binding MCP

Factor I

C4d

MCP

MCP

REGULATORS PHYSIOLOGIC REGULATION Unregulated, the complement system would fire to exhaustion, as illustrated by inborn errors of plasma regulatory proteins.15-17 The complement system has evolved to allow unimpeded activation on a microbe but to limit the proc­ ess in time and space. The reaction must be finite in time to avoid excessive consumption of components in any one reaction and finite in space to minimize damage to surrounding host tissue. Thus, a typical complement reaction on a microbial target occurs within a few minutes, and during this time, self-tissue is protected by plasma and membrane regulators. Many of these inhibitors act at the critical step of convertase formation. The convertase enzyme complexes intrinsically have short half-lives, and many of the inhibitors act to prevent their formation or to dissociated (decay) already formed complexes. FLUID-PHASE AND MEMBRANE INHIBITORS These inhibitors, distributed both in plasma and on cells, regulate primarily at the initiating events (see Fig. 19-3), the formation of the C3 and C5 convertases (see Fig. 19-6), and the insertion of the MAC. A major function of the plasma inhibitors is to prevent fluid-phase activation (no target), while the membrane inhibitors prevent activation on self-tissue (wrong target). In some situations, the plasma inhibitors bind to damaged cells and exposed extracellular matrix, where they now function as a membrane regulator.7,8,18 C1 inhibitor is a serine protease inhibitor (SERPIN) and binds to C1r and C1s and to MASPs. The C1 complex is thereby disrupted, leaving C1q bound to antibody in the IC. C1q may then interact with C1q receptors to facilitate disposal of the IC. C1 inhibitor also prevents excessive and chronic fluid-phase C1 activation.19 The C3 and C5 convertases are regulated by a family of proteins that include the membrane proteins decay-­accelerating factor (DAF, or CD55) and membrane cofactor protein (MCP, or CD46) and the serum inhibitors C4-binding protein and factor H.7-9,15-17 These proteins act in three ways: they prevent convertase assembly, disassemble convertases (decay-accelerating activity; Fig. 19-8A), and serve as cofactors for the proteolytic inactivation of C4b and C3b (cofactor activity; Fig. 19-8B). The latter

A DAF: Decay accelerating activity C3b Bb Binding Decay DAF

DAF

Membrane

MCP: Cofactor activity

Binding MCP

C3f

Factor I MCP

MCP

B Figure 19-8  Regulation of convertases. A, Classic pathway C3 convertase. Decay-accelerating factor (DAF) irreversibly displaces the protease C2a from the anchoring piece C4b. C4b is cleaved by factor I. This reaction requires a cofactor protein, membrane cofactor protein (MCP); C4bp in plasma and CR1 can serve this role. The residual bound C4d has no known biologic activity. Classic pathway C5 convertase is similarly inactivated. B, Alternative pathway C3 convertase. The alternative pathway C3 and C5 convertases are disassembled in a similar fashion by DAF and MCP. In the case of C3b, it is cleaved to iC3b and then to C3dg. C3dg and C3d serve as adjuvants to promote an immune response. They accomplish this by reacting with the complement receptor 2 (CR2; CD21) on follicular dendritic cells and B lymphocytes. These two activities of DAF and MCP are synergistic in their control of the convertases. They prevent complement activation in blood and on normal host cells and tissues.

­process is mediated by the plasma serine protease factor I. The MAC is also regulated by plasma and cell-anchored protein. CD59 is a widely expressed glycolipid-anchored membrane protein that binds C8 and C9 to prevent their membrane insertion, while the plasma protein vitronectin (S protein) inactivates fluid-phase MAC. As a result of this regulatory activity, complement attack is focused on foreign surfaces (which usually lack complement regulators) and is held in check on host cells and in body fluids. Interestingly, a number of microorganisms have “captured” complement regulators (e.g., pox viruses) or have evolved proteins (herpesviruses) that inhibit

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­complement activation (virulence factors).20 However, the activation of the CP by antibody is extremely rapid and efficient, such that the inhibitors generally have modest effects on limiting damage by complement-fixing antibodies. The host inhibitors, however, are efficient at preventing fluid-phase activation and especially amplification via the feedback loop.

COMPLEMENT RECEPTORS The complement system exerts many of its effects through receptors (see Tables 19-3 to 19-5). During the activation process, target-bound and locally released fragments serve as ligands for complement receptors. For example, the vasomodulatory and chemotactic effects of C3a and C5a are due to interaction with their respective receptors. The opsonic fragments C4b and C3b mediate clearance of ICs and bacteria through adherence and phagocytosis to CR1. Degradation of C3b by regulators leads to the formation of iC3b and then C3dg, which in turn interact with CR3/CR4 and CR2, respectively. CR1 plays an important role in IC clearance. On erythrocytes, CR1 binds C3b/C4b-coated ICs (the immune adherence phenomenon) for processing and transport to the liver and spleen.21 In these organs, the ICs are transferred from the erythrocyte to tissue macrophages, allowing the erythrocyte to return to the circulation for another round of clearance. CR1 on granulocytes and monocytes binds and ingests ICs, whereas CR1 on B lymphocytes, tissue macrophages, and follicular dendritic cells facilitates trapping and processing of IC in lymphoid organs. CR2 is expressed by B lymphocytes and follicular dendritic cells, where it facilitates antigen trapping and is a coreceptor for activation of the B cell antigen receptor.22 Several new receptors for C3-bearing ICs have been described.23,24 The identification and role of C1q receptors remain problematic, but they are likely important in the proper handling of antigens that have undergone complement activation on their surface.25

Table 19-6  Complement System in Immunity First line of defense as part of innate immune response (takes place within seconds)   Mediates inflammatory response   Modifies membranes of microbes Instructive role to adaptive immunity   Facilitates antigen identification, processing, transportation, and retention   Activates cells to synthesize costimulatory molecules and to secrete cytokines and other mediators of an immune response; lowers threshold for B lymphocyte activation

EFFECTOR MECHANISMS IN AUTOIMMUNITY AND INFLAMMATION

COMPLEMENT IN THE INNATE AND ADAPTIVE IMMUNE RESPONSE INNATE IMMUNITY The complement system is activated by at least three mechanisms that are independent of an adaptive immune response (Table 19-6): natural antibodies, lectins, and the AP itself (Fig. 19-9). Complement activation is therefore one of the earliest reactions to microbes at sites of infection. The complement response opsonizes organisms for adherence, phagocytosis, and antigen processing while releasing fragments to activate immunocompetent cells and trigger an inflammatory milieu. ADAPTIVE IMMUNITY As pointed out earlier, complement was discovered because of its role as an effector arm of humoral immunity. IgM and IgG subclasses 1 and 3 efficiently activate the CP. More recently, an important role for complement on the afferent side has been “rediscovered.”3,22 Accumulating evidence indicates that complement is an instructor of the adaptive immune response. Nearly 30 years ago, the injection of cobra venom factor was used to destroy an animal’s complement activity. In such experimental systems, a requirement for complement in an animal’s immune response was clearly demonstrated. An attenuated IgM response, a lack of class switching from IgM to IgG, and a failure to generate memory B cells were features of a complement-deficient animal. Similarly, in multiple subsequent studies, C4- or C2-deficient guinea pigs and humans were shown to have a defective response to the intravenous administration of a phage antigen. Although they produced IgM antibody, these two species did not class-switch from IgM to IgG antibody or demonstrate immunologic memory. In other studies, blocking CR2 reduced the antibody response to T-dependent antigens and prevented isotype switching. Further, animals with a targeted gene deletion of CR1/CR2 also had a lower IgM response and failed to isotype-switch. If larger doses of antigen or antigen plus adjuvants were administered, the complement-deficient animals responded normally. Finally, coating of antigen with C3d increases its immunogenicity up to 10,000-fold.22,26,27 Consequently, vaccines containing complement-coated antigens are likely to be more immunogenic. Taken together, these data indicate a contribution of the CP and complement receptors to an adaptive immune response.

Effector arm of humoral immunity (“complements” antibody) Recognition of injured, apoptotic, and necrotic cells to enhance cleanup, proper disposal (without an adaptive immune response), and wound healing Recognition of extracellular debris (crystals, pigments, lipids,   proteins)* *Examples are urate crystals in gout, lipofusion pigments in drusen in age-related macular degeneration; oxidized lipids in atherosclerosis, and amyloid in Alzheimer’s disease.

329

Natural Ab

Alternative pathway

Target

Lectins

Figure 19-9  Activation of the complement system in innate immunity. Shown are three means of complement activation in a nonimmune host.

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CLEARANCE OF DEAD, DAMAGED, AND APOPTOTIC CELLS The complement system likely plays an important role in facilitating the removal of injured cells and cellular debris.5-8,28 Natural antibodies, lectins, and the AP recognize certain altered surface characteristics of damaged cells and, through opsonization, promote their proper removal. Such a system probably evolved to efficiently remove injured tissue, especially traumatized skin and apoptotic cells. In this process, a second goal is to avoid an immune response. If this system fails, as might happen in C1q or C4 deficiency, the individual is predisposed to developing autoantibodies (the so-called garbage- or waste-disposal hypothesis to explain autoimmunity in SLE). Ischemia-reperfusion injury is a related situation in which complement activation has clearly been shown to mediate damage to viable but at-risk tissues.29 Altered self-debris engages the innate immune system. Examples are urate crystals in gout, amyloid proteins in Alzheimer’s disease, oxidized lipids in atherosclerosis, and lipofusion (pigments) in age-related macular degeneration. In these chronic processes, relatively minor changes in complement regulatory activity may accelerate tissue damage. This has been shown most clearly in age-related macular degeneration, where about 50% of the genetic risk appears to be due to a subtle loss of function in a polymorphic variant of factor H.30

IMMUNE COMPLEX CLEARANCE The complement system is important for the processing and clearance of ICs.6-9,21,31 As ICs form, activation of the CP leads to C4b and C3b deposition, which in turn prevents the ICs from precipitating in a vessel wall or tissue site (called maintenance of IC solubility). The deposition of C3b on the antibody and antigen reduces the antibody’s ability to crosslink and thereby precipitate ICs. Even preformed ICs can be solubilized by exposure to fresh serum. The soluble IC­bearing clusters of C3b become bound to peripheral blood

cells, especially erythrocytes (immune adherence). Erythrocytes possess more than 80% of the CR1 in blood. They serve as a “taxi” or “shuttle” to transport the ICs to the liver and spleen, where they are dissociated from the RBCs. Most such ICs are then destroyed by macrophages in the liver or spleen. This transfer of ICs from the red cells to tissue macrophages may be mediated by simple affinity differences, because tissue monocytes or macrophage possess multiple types of C3 and Fc receptors. Further, there is evidence for a proteolytic cleavage event at tissue sites that occurs near the stalk of CR1 to release ICs. The RBCs return to the circulation, possibly minus a few complement receptors, but ready for another round of immune adherence. This processing system for ICs evolved to prevent ICs from depositing in undesirable locations, such as the kidney glomerulus. This clearance process could fail due to (1) a CP component deficiency, up to and including C3; (2) a complement receptor deficiency; (3) synthesis of a non-CP fixing antibody, such as IgG4 or IgA; (4) severe hepatic dysfunction; or (5) splenectomy.31 This concept of IC clearance plays out in many infectious diseases and is especially pertinent to syndromes featuring ICs, such as SLE, mixed cryoglobulinemia, serum sickness, and other vasculitic syndromes.

COMPLEMENT MEASUREMENT Complement can be assessed by antigenic and functional assays (Tables 19-7 and 19-8). In clinical practice, the most common functional measurement is the total hemolytic or whole complement assay (THC or CH50). The assay is based on the ability of the patient’s serum sample to lyse sheep erythrocytes optimally sensitized with a rabbit antisheep cell antibody. All nine components of the CP (i.e., C1 through C9) are required for a normal THC. A result of 200 units indicates that at a dilution of 1:200, the test serum lysed 50% of the antibody-coated sheep ­ erythrocytes. THC is a useful screening tool for detecting a homozygous deficiency

Table 19-7  Assays for Complement Activation in Human Disease Method

Use

Comments

CH50 or THC

Screen for component deficiency or activation of classic pathway

Functional assay—requires appropriate sample handling

AP50

Screen for component deficiency or activation of alternative pathway

Functional assay—requires appropriate sample handling

Antigenic (ELISA, immunodiffusion, Standard method for C3, C4, factor B, C1 inhibitor, nephelometry) MBL, and factor H

Widely available, easy to perform, reliable, inexpensive

Antigenic or hemolytic assay of an individual component

Further define a suspected deficiency

Samples usually sent to labs specializing in complement assays

Activation fragments C3a, C5a, Bb, C1r/C1s, C5b-9 (neoantigen)

May be elevated in the setting of normal comple­ ­ ment levels

Expensive; sample collection important; commercial labs often perform these assays; more sensitive than   assays of static levels

C1 inhibitor function

Clinical picture consistent with HAE, but C1 inhibitor 15% of HAE kindreds have normal or elevated levels of levels by antigenic assay are normal or elevated a nonfunctional protein

Immunofluorescence

Demonstration of complement activation fragments C1q and cleavage fragments of C4 and C3 are most in tissue commonly analyzed, especially in kidney and skin biopsies

Antiglobulin testing (non-gamma Coombs)

Demonstration of C3 fragments on erythrocytes in hemolytic anemias

Usual fragment detected is C3d

AP50, alternative pathway equivalent; CH50 or THC, total hemolytic assay for classic pathway; ELISA, enzyme-linked immunosorbent assay; HAE, hereditary angioedema; MBL, mannan-binding lectin.

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Table 19-8  Interpretation of Results of Complement Determinations THC (units/mL)

C4 (mg/dL)

C3 (mg/dL)

Interpretation

150-250

16-40

100-180

Normal range

250

40

200

Acute-phase response (all are high)

100

10

80

CP activation (low C4 and C3)

100

30

50

AP activation (normal C4 and low C3)

<10 or 0

30

140

Inherited deficiency or in vitro activation*

50

<8

100

Partial C4 deficiency or fluid-phase activation†

*In vitro activation is more common than an inherited deficiency state. The lack of activity (THC <10) in the setting of normal C4 and C3 antigenic levels ­suggests (1) an improperly handled sample, (2) cold activation (e.g., by cryoglobulins) following collection of the sample, or (3) homozygous component deficiency (most commonly C2 with a lupus presentation or, with a Neisseria infection, an AP or membrane attack complex component). † Because THC is detectable, this cannot be a complete deficiency of C4. A partial C4 deficiency, such as of C4A, could give this result. Some types of immune complexes, especially cryoglobulins, and a deficiency of the C1 inhibitor (hereditary angioedema) also give this pattern. In these cases, measurement of C2 is often helpful: a low value suggests activation, whereas a normal value suggests an inherited, partial C4 deficiency. Also, C4A and C4B alleles can be assessed by commercial laboratories. AP, alternative pathway; CP, classic pathway; THC, total hemolytic complement or CH50. Modified from Primer on the Rheumatic Diseases, 12th ed. 2001, p 71.

Table 19-9  Clinical Manifestations of Complement Component Deficiency Deficient Component

Clinical Syndrome*

Classic Pathway C1q C1r/C1s C4 C2

SLE, infections SLE, infections SLE, infections SLE, infections

Lectin Pathway MBL Central component   C3 Membrane attack component   C5, C6, C7, C8 or C9

Infections Severe infections, GN, SLE Neisseria infections

Alternative Pathway Properdin, factor D

Neisseria infections

*With early component deficiencies of the classic pathway (C1, C4, or C2), infections are caused by the commonly encountered pyogenic organisms. With a late component (C5–C9) or an alternative pathway component ­deficiency, Neisseria infections predominate, especially meningococcal ­infections. GN, glomerulonephritis; MBL, mannan-binding lectin; SLE, systemic lupus erythematosus.

of a single component (C1 through C8), because total deficiency of a component produces a result of less than 10 units or undetectable THC. Deficiency of C9 results in a low but detectable THC. THC can screen for total deficiency as well as provide an overall assessment of complement activation. It is particularly recommended in the initial evaluation of most SLE patients. Other commonly used tests, especially to follow a patient’s clinical course, are antigenic assays for C4 and C3. They are widely available, relatively inexpensive, and simply and accurately measured by nephelometric-based immunoassays. They are useful in the initial diagnosis of lupus and related syndromes and for following the course of patients undergoing treatment, particularly if the concentrations were reduced when the disease process was active. Upon treatment, a return to normal values correlates with clinical improvement and bodes a better outcome. Table 19-8 provides examples of serum complement test results and their interpretation in rheumatic diseases.

Gaining in use are tests for the detection of activation fragments (e.g., C3a, C5a, C4d, C3d, Bb). Their clinical utility relates to the fact that they are dynamic parameters and thus reflect ongoing turnover of the system. Also, they are not affected by partial inherited deficiencies or alterations in synthetic rates. However, they are more costly, not as widely available, and unnecessary in most clinical situations. A potential advance in this area of biomarkers is the measurement of C4 and C3 fragments bound to RBCs, platelets, and lymphocytes.32 Analogous to monitoring blood glucose by measuring HbA1c in diabetes mellitus, the magnitude of complement activation is proportional to the quantity on the cell surface. Thus, RBCs reflect disease activity over the past several months while platelets reflect disease activity over the past week. Longitudinal studies are in progress to assess the utility of this approach in rheumatic diseases featuring complement activation.

COMPLEMENT DEFICIENCY Inherited deficiencies of complement components predispose to bacterial infections (this was expected) or to autoimmunity (this was unexpected), especially SLE7-9,28,33 (Tables 19-9 to 19-11). Most deficiencies are inherited as autosomal codominant (recessive) traits, except for the C1 inhibitor, which is autosomal dominant, and properdin and factor D, which are X-linked. A thorough analysis of this subject has been published, including tables listing every reported case of early complement component deficiency in humans.28 Several other pertinent reviews are also available.33-36 CLASSIC PATHWAY The prevalence of lupus in homozygous C1q, C4, or C2 deficiency is 90%, 75%, and 15%, respectively.28,33-36 The female-male ratio is approximately 1:1 in C1q or C4 deficiency but 7:1 in C2 deficiency. Concordance rates for SLE are 2% among dizygotic twins and 24% among monozygotic twins; concordance of SLE between siblings with C1q, C4, or C2 deficiency is 90%, 80%, and 58%, respectively. These complement-deficient individuals with SLE usually present before age 20 years and often have prominent cutaneous (90%) and renal (50%) manifestations.

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Table 19-10  Autoimmune Disorders in Complete Complement Component Deficiencies Component

Number of Cases

C1q

35

Dominant Phenotype (%)

Other Phenotype*

SLE (94)

Infections Infections

C1r/s

11

SLE (55)

C4

24

SLE (75)

Infections

C2

110

SLE (32)

Infections†

C3

21

Severe infections (75)

GN, SLE, vasculitis

*Infections may be the presenting manifestation and dominate the clinical course, particularly in C1q, C4, or C2 deficiency. † A few cases of Sjögren’s syndrome, systemic sclerosis, Henoch-Schönlein purpura, and other immune-mediated syndromes have been reported with C2 deficiency. GN, glomerulonephritis; SLE, systemic lupus erythematosus.

Table 19-11  Classic Pathway Complement   Component Deficiency Leading to Autoimmunity There are two leading hypothesis; they are not mutually exclusive. 1.  Defective immune complex handling   For foreign antigens   For self-antigens (apoptotic and necrotic debris) 2.  Defective immune responses   Reduced humoral immune responsiveness   Failure to regulate autoreactive B cells

Antinuclear antibody tests are positive in about 75% of patients. Most patients are DNA negative, and antibodies to extractable nuclear antigens (especially antibodies to Ro) are detected in about 70%. The disease process tends to be more severe in C1q and C4 than in C2 deficiency. Less than 1% of lupus patients have a complete complement component deficiency, with C2 deficiency being the most common. About one third of SLE patients develop C1q deficiency secondary to anti-C1q antibody. These antibodies probably develop after the onset of SLE and are therefore a secondary phenomenon.28,37 These patients tend to have renal disease and low complement levels (C4 and C3). The C4 genes are duplicated (all four must be deleted or defective to result in total C4 deficiency), giving rise to C4A (acidic) and C4B (basic) types.38 C4A deficiency occurs in about 15% of Caucasian SLE patients (compared with 1% to 3% of controls). Because C4A preferentially binds amino groups, it reacts more efficiently with some types of ICs than does C4B. This may explain why homozygous C4A deficiency is an independent risk factor for SLE. The association generally occurs across multiple ethnic backgrounds as well as in the absence of the European ancestral autoimmune haplotype (HLA-A1, C7, B8, C4AQ*0, C4B1, DR3, DQ2). The clinical course is similar to that of idiopathic lupus, but there may be less renal disease.39-41 In fact, one group has argued for caution in the use of immunosuppressive therapy because of the generally favorable course of renal disease in most patients.39 Assessment of the number of C4A and C4B genes is available through commercial laboratories. The most common homozygous complement deficiency is C2 deficiency (occurring in 1 in 10,000 to 20,000 individuals).28 Heterozygotes are present in 1% to 2% of the Caucasian population. SLE occurs in about 15% of homozygous C2 null individuals. Notable differences in the setting of C2 deficiency are fewer renal and central nervous

system ­manifestations but more cutaneous (prominent photosensitivity) involvement, earlier age of onset, and higher frequency of anti-Ro antibodies. Heterozygosity for C2 deficiency does not appear to predispose to SLE. ALTERNATIVE PATHWAY C3 deficiency is associated with recurrent pyogenic infections and, less commonly, glomerulonephritis. For the latter, antinuclear antibodies are usually not detected, and other systemic features of SLE are lacking. Deficiency of properdin, factor B (one case), and factor D (a few cases) is strongly associated with meningococcal infections but not autoimmunity.42 LECTIN PATHWAY Polymorphisms producing low serum MBL are associated with SLE across several ethnic backgrounds. In one series, the incidence of SLE was increased twofold in patients with MBL deficiency,43 but this association does not appear to be holding up. Impressively, infectious complications, particularly severe pneumonias in association with immunosuppressive therapy, were much more frequent in MBL-deficient patients. This combination of MBL deficiency and C4 gene deficiency may be a particularly strong predisposing factor for SLE. In RA, MBL deficiency may be a modest risk factor.44 Of perhaps greater interest, MBL deficiency was associated with earlier age of onset, more severe erosive disease, and increased frequency of infectious complications during treatment. Again, as more studies have been reported, these associations have become controversial. ACQUIRED COMPLEMENT DEFICIENCY STATES Acquired complement deficiency usually results from accelerated consumption. CP activation is observed in more than 50% of lupus patients. Generally, the more active the disease process, the more likely that complement levels will be low as consumption progressively outstrips the liver’s synthetic capacity. Low complement values (C4, C3, or THC) are a poor prognostic factor and correlate with antibodies to native DNA, nephritis, and, overall, more severe disease. Complement deposition in tissue, especially in the glomerulus (as detected by immunofluorescence), assists in the diagnosis and classification of lupus nephritis. Antibodies to C1q occur in about 30% of SLE patients and are associated with low complement concentrations and renal disease.28,37

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C3 nephritic factor is an autoantibody against the AP C3 convertase. The autoantibody stabilizes the convertase to the point that excessive C3 cleavage and a secondary deficiency of C3 result. Patients with C3 nephritic factor are predominantly children, who may present with glomerulonephritis, partial lipodystrophy, or frequent infections with encapsulated bacteria. In many cases, an underlying deficiency of factor I or factor H predisposes to excessive AP turnover, leading to the secondary formation of an autoantibody to the C3 convertase. KEY POINTS: SYSTEMIC LUPUS ERYTHEMATOSUS AND RELATED SYNDROMES Deficiency of C1q, C4, or C2 is the only single-gene defect that causes SLE in humans. Partial deficiency of C4 also predisposes to SLE. Once autoantibodies are present and ICs are deposited in undesirable tissue sites, such as the kidney, complement activation contributes to the inflammation and tissue damage. Complement measurements are helpful in following ­lupus ­patients, particularly if C4 and C3 were low at the time of ­diagnosis. If so, the levels usually increase in response to treatment and may become a useful marker of disease ­activity. However, this point has to be established for each patient. The complement system is activated in most SLE patients, even though serum levels are not always reduced. Evidence for this statement comes from the assessment of complement turnover studies, the measurement of activation fragments, and, most convincingly, the demonstration of complement fragments in more than 70% of patients on skin biopsy (the old lupus band test). Even in normal skin, there is a remarkable deposition of C3 fragments at the dermal-epidermal junction. Anti-C1q antibodies are present in about 30% of SLE patients and in about 70% of lupus patients with nephritis. They probably arise in response to the high quantities of C1-fixing IC. They likely contribute to the hypocomplementemia that is common in such patients, as well as to glomerular damage. In mouse models of SLE, decreased activity of the early components of the CP accelerate disease development, while deficiencies of the late components (C5 to C9) ameliorate disease severity. The literature in this area is not easy to inter­ pret because the models may or may not accurately reflect ­human disease, and the mouse complement system has many ­differences from its human counterpart. For instance, mouse complement is a less potent activating system overall, and Fc receptors seem to be responsible for more of the proinflammatory reaction in mice than in humans.

MODELS OF INFLAMMATORY DISEASE FEATURING COMPLEMENT ACTIVATION In general, in vivo models have explored complement activation as a mediator of tissue damage and inflammation in diseases featuring complement as an effector arm of humoral immunity.7-9,14 More recently, complement’s role in promoting inflammation and cellular migration, enhancing the afferent limb of the immune response, and handling debris (including apoptotic cells) have received attention.

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DEFICIENT ANIMALS Before knockout mice were available, guinea pigs deficient in C4, C2, or C3; rats and rabbits deficient in C6; dogs deficient in C3; and pigs deficient in factor H had been characterized.3 Further, in the 1960s, many inbred mouse strains were shown to be deficient in C5. Experiments with these species clearly indicated the double-edged sword aspect of the complement system. The deficient animals were more sensitive to challenges with bacteria but were more resistant to antibody-mediated tissue damage. They were also widely used to determine the role of complement in inflammatoryimmune models—the Arthus reaction, serum sickness, and Forssman shock. These models are discussed briefly because they demonstrate the range of reactions requiring complement activation. In the Arthus model, antibodies to a foreign antigen are raised, and then the antigen is reinjected into the immune host. If the antigen is injected in a joint, ICs form in the joint space, complement is activated, Fcγ receptors are engaged, and an inflammatory reaction ensues. It is a transient and nondestructive process unless antigen is injected repeatedly. Emphasis has recently been placed on separating the effects of IgG antibody working through Fcγ receptors (FcγRs) on phagocytes and B cells from those induced by antibody-activating complement.3,14,45-48 For example, it had generally been believed that the Arthus reaction was mediated by complement activation. The immigration of neutrophils in this process was thought to be caused primarily by the local formation of C5a. This concept was challenged when it became possible to generate, by homologous recombination, mice with C3 deficiency or FcγR deficiency. In the mouse, FcγRIII but not complement was required for the Arthus reaction in skin. However, complement was critical in IC-mediated peritonitis in mice and IC-mediated lung disease in rats. Interestingly, complement is also of major importance in IC-mediated skin disease in guinea pigs and rats. Thus, the species, the tissue site of activation, the genetic background, and undoubtedly additional factors are critical in determining the importance of complement versus FcγR in disease pathogenesis. In most cases, these two effector systems operate conjointly, both in the response to pathogens and in autoimmunity. In the usual serum sickness model in the rabbit employing bovine serum albumin(BSA)–anti-BSA, a polyarthritis develops that is mediated by the deposition of IC in joints. In the preantibiotic era, a serum sickness reaction was observed in patients receiving horse serum containing antibodies to treat infectious diseases. The human or rabbit clinical illness lasted 1 to 2 weeks, resolving as the host went into antibody excess and cleared the foreign protein. Of course, if more antigen was injected, an accelerated serum sickness reaction developed. These conditions are likely to be met in SLE and in mixed cryoglobulinemia secondary to chronic hepatitis B or hepatitis C infection. In these conditions, nuclear antigens from cellular turnover and viral antigens synthesized in the liver are continuously present in a host with preformed antibodies. Forssman antigen is a widely distributed lipopolysaccharide.3 Species that are Forssman negative, such as the rabbit, develop an immune response to the RBCs of sheep, a

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Forssman-positive species. The rabbit responds to the injection of sheep RBCs with high-titer anti-Forssman antibody. Upon intravenous injection of this rabbit antibody into guinea pigs, a Forssman-positive species, the antibody travels to the lung, where it causes alveolar capillary fluid leakage and hemorrhage that is CP dependent. Phagocytes are not important in this cataclysmic reaction that causes death in a few minutes secondary to pulmonary edema. The lytic activities of complement are essential, however. This model and the Arthus reaction have been used to test the effect of anticomplement reagents in preventing tissue damage. GENE TARGETED DEFICIENCIES Most components, regulators, and receptors have now been deleted by gene targeted insertional mutagenesis.6-8,14,33,49,50 C1q, C4, C2, C3, and CR1/CR2 mice demonstrated substantial defects in T cell–dependent immune responses and have the expected defects in IC clearance. Thus, for most strains with a defect in the CP or AP, defective clearance of bacteria and viruses was shown. The C1q- and C4-deficient mice (depending on the genetic background) have enhanced humoral immunity, glomerulonephritis (lupus-like picture), and problems in the clearance of apoptotic bodies. The C5aR-deficient mice have a decrease in inflammatory cell infiltrates. Although there are substantial differences between the human and mouse complement systems, these mice have been useful in clarifying complement’s role in host defense against infection, the immune response, and autoimmunity. ANTIPHOSPHOLIPID ANTIBODY SYNDROME The antiphospholipid syndrome is often associated with hypocomplementemia in the absence or presence of a positive test for antinuclear antibodies. In a recent review of a large number of such patients, hypocomplementemia was just as frequent as in patients with SLE.51 Complement activation is also a common event in recurrent pregnancy loss.52 In a mouse model of antiphospholipid antibody–induced pregnancy loss, complement-deficient mice were protected from disease development.53 Complement activation by the antiphospholipid antibody is a required intermediary event in the pathogenesis of fetal injury. In particular, complement activation by the autoantibodies causes a dysregulation of angiogenic factors such as vascular endothelial growth factor.54 Clinical trials are under way to assess the role of complement activation and angiogenesis in patients with the antiphospholipid syndrome. COMPLEMENT ACTIVATION IN POLYARTHRITIS Human Rheumatoid Arthritis A long-standing observation in RA and juvenile RA is that complement is activated locally, in the synovial fluid and surrounding joint tissue.14,55,56 Thus, if the functional activity of joint fluid C4, C2, or C3 is determined, it is low compared with that obtained for a concomitant antigenic level. Such data have established that complement components in RA joint fluid are antigenically intact but functionally inactive. In other words, the components have already been engaged

in an immune reaction, and activation fragments are largely being measured. Further, essentially every complement activation fragment is elevated in RA joint fluid. The activation profile is primarily that of the CP (low C4 and C2), although there is also substantial evidence for contribution of the AP. Clinical correlations with measures of complement activation in RA include a more severe, erosive, and seropositive disease process. From about 1950 to 1980, B cells, rheumatoid factors, and complement were postulated to play a predominant role in mediating the synovial inflammation in RA. Then, for the next 2 decades, T cell–mediated immunity was thought to be the predominant system responsible for the synovial reaction in RA. Today, a more prominent role for B cells, autoantibodies, and complement is again thought to exist; their critical role in animal models of RA has been recognized, and antibodies to citrullinated peptides have been identified. Both humoral and cellular immunity are almost certainly required to produce a persistent synovitis in the RA syndrome.

KEY POINTS: RHEUMATOID ARTHRITIS AND RELATED SYNOVITIDES Complement activation fragments are present in joint fluid and deposited in synovial tissue. Autoantibodies (e.g., to citrullinated peptides) may activate the complement system to trigger inflammation. Rheumatoid factor augments the effects of IgG bound to an antigen by promoting both agglutination of the IC and complement activation. Low C4 and C3 are common in rheumatoid vasculitis, indicating CP activation by ICs; similarly, cryoglobulins and other types of ICs activate the CP. In mouse models of rheumatoid arthritis featuring autoantibodies, complement inhibitors and complement deficiency protect against disease development and reduce its severity.

Collagen-Induced Arthritis Complement activation products are prominent in the joint fluid and synovial tissue of rat and mouse models of collagen-induced arthritis.14,56-58 The disease is mild or absent in C5-deficient mice, mice treated with a monoclonal antibody to C5, mice treated with the potent complement inhibitor soluble CR1, and factor B–deficient mice.49,59 The C5 monoclonal antibody treatment also ameliorated established disease. These results implicate the AP in generating C5a, C5b to C9 (MAC), or a combination thereof as being responsible for synovitis. One might have predicted that C3 activation products would be major contributors to disease pathogenesis, but that is not the case. Mouse Model A spontaneous mouse model was generated by crossing the T cell receptor (TCR) transgenic mouse line (known as KRNxC56BL/6) with the nonobese diabetic (NOD) mouse strain.60,61 Autoantibodies that arise in the K/BxN mouse

PART 3 

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EFFECTOR MECHANISMS IN AUTOIMMUNITY AND INFLAMMATION

335

Table 19-12  Complement Activation Inhibitors Undergoing Clinical Trials Product

Description

Actions

Company

TP10

Soluble recombinant CR1 (sCR1)

Degrades C3b/C4b (CA) and decays   C3/C5 convertases (DAA)

Avant Immunotherapeutics   ­(Needham, Mass)

H5G1.1; h5G1.1-scFv

Humanized, high-affinity anti-C5   mAb; single-chain version

Blocks cleavage of C5 by C5   conver­­­­tases

Alexion Pharmaceuticals   (New Haven, Conn)

CA, cofactor activity; DAA, decay-accelerating activity; mAb, monoclonal antibody.

recognize the ubiquitously expressed enzyme glucose-6phosphate isomerase. Important features of this model are as follows: (1) a destructive small-joint arthritis develops that resembles RA; (2) the autoantibodies are pathogenic, as the disease can be transferred to other strains by antibody alone; and (3) complement is required for the arthritis to develop. Surprisingly, the CP is not necessary; mice deficient in C1q or C4 are as susceptible as wild-type mice. Mice deficient in C3 or AP component factor B, however, did not develop arthritis. Moreover, C5-deficient mice or mice treated with a monoclonal antibody to C5 were resistant to the disease. C5a receptor–deficient mice were protected from developing arthritis. Thus, AP-derived C5a interacts with its receptor to mediate the complement effect required for disease development. Another insight from this model is a putative role for the complement regulatory proteins in “allowing” a local inflammatory process.60 Thus, the pathogenic antibody in this model also binds to the kidney glomerulus, but there is no excessive C3b deposition and no development of glomerulonephritis. A likely explanation is that both antigen accessibility and a permissive local environment for complement activation are required. Joint cartilage is relatively devoid of complement regulatory proteins. In this setting, the AP is engaged. The CP is not activated because the autoantibody is predominantly of the IgG1 subclass, which, in the mouse, has poor complement-fixing ability. Nevertheless, antibodies bound to an antigen can protect the cascade from regulation by inhibitors and thereby trigger the AP.62 Though it remains unclear why the autoantibody arises, this model has provided provocative insights into how an autoantibody- and complement-mediated inflammatory arthritis could occur in humans. Further, the recent discovery of an autoantibody system in about one third of human RA patients (anticitrullinated peptide antibodies) provides a parallel with the mouse model system.63

THERAPEUTIC IMPLICATIONS The study of the complement system has undergone a renaissance. Much of this revival relates to (1) the development of inhibitors for experimental and clinical use; (2) the association of deficiency states with autoimmunity (especially the C1q, C4, C2–lupus association); (3) greater appreciation of the role of the innate immune system and its role in instructing the adaptive immune system; (4) the availability of gene targeted mice to more precisely assess the role of complement in the normal immune response and in mouse models of autoimmunity; and (5) whole genome screens with single nucleotide polymorphism analyses that have identified partial deficiencies and polymorphisms in complement regulatory proteins as causing a predisposition to atypical hemolytic uremic syndrome64 and age-related macular degeneration.30

The development of complement inhibitors for clinical use is a long-sought goal. One such compound, a humanized monoclonal antibody to C5, has been used successfully to treat a complement-mediated hemolytic anemia65-68 (Table 19-12). This agent and others ameliorate inflammatory responses in animal models, where considerable evidence has already been accumulated relative to complement’s participation (e.g., Arthus reaction, serum ­ sickness, SLE). Complement inhibition, however, also reduced infarct size in experimental models of myocardial infarction and tissue damage in many other types of ischemia-reperfusion injury.29 Further, a role for complement in clearing apoptotic cells is likely.28 A complement inhibitor for clinical use is much anticipated. REFERENCES   1. Zarkadis IK, Mastellos D, Lambris JD: Phylogenetic aspects of the complement system. Dev Comp Immunol 25:745-762, 2001.   2. Nonaka M, Kimura A: Genomic view of the evolution of the complement system. Immunogenetics 58:701-713, 2006.   3. Frank MM, Atkinson JP: Complement system. In Austen KF, Frank MM, Atkinson JP, et al (eds): Samter’s Immunologic Diseases, 6th ed. Philadelphia, 2001, Lippincott Williams & Wilkins, pp 281-299.   4. Silverstein AM: A History of Immunology. San Diego, Academic Press, 1989.   5. Nauta AJ, Daha MR, van Kooten C, et al: Recognition and clearance of apoptitic cells: A role for complement and pentraxins. Trends Immunol 24:148-154, 2003.   6. Volanakis JE: Overview of the complement system. In Volanakis JE, Frank MM (eds): The Human Complement System in Health and Disease, 10th ed. New York, Marcel Dekker, 1998, pp 9-32.   7. Walport MJ: Complement: First of two parts. N Engl J Med 344:1058-1066, 2001.   8. Walport MJ: Complement: Second of two parts. N Engl J Med 344:1140-1144, 2001.   9. Morgan BP: Complement: Clinical Aspects and Relevance to Disease. London, Harcourt Brace Jovanovich, 1990. 10. DuClos TW: Function of C-reactive protein. Ann Med 32:274-278, 2000. 11. Ollert MW, Kadlec JV, David K, et al: Antibody-mediated complement activation on nucleated cells: A quantitative analysis of the individual reaction steps. J Immunol 153:2213-2221, 1994. 12. Turner MW: Mannose-binding lectin: The pluripotent molecule of the innate immune system. Immunol Today 17:532-540, 1996. 13. Fujita T: Evolution of the lectin-complement pathway and its role in innate immunity. Nat Rev Immunol 2:346-353, 2002. 14. Thurman JM, Holers VM: The central role of the alternative complement pathway in human disease. J Immunol 176:1305-1310, 2006. 15. Liszewski MK, Farries TC, Lublin DM, et al: Control of the complement system. Adv Immunol 61:201-283, 1996. 16. Morgan BP, Harris CL: Complement regulators in therapy. In ­Morgan BP, Harris CL (eds): Complement Regulatory Proteins. San Diego, Academic Press, 1999, p 250. 17. Parker CM: Membrane Defenses against Attack by Complement and Perforins. Berlin, Springer-Verlag, 1992. 18. Zipfel PF, Skerka C, Caprioli J, et al: Complement factor H and hemolytic uremic syndrome. Int Immunopharmacol 1:461-468, 2001. 19. Davis AE III: C1 inhibitor gene and hereditary angioedema. In ­Volanakis JE, Frank MM (eds): The Human Complement System in Health and Disease. New York, Marcel Dekker, 1998, pp 455-480.

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20. Kotwal GJ: Poxviral mimicry of complement and chemokine system components: What’s the end game? Immunol Today 21:242-248, 2000. 21. Hebert LA: The clearance of immune complexes from the circulation of man and other primates. Am J Kidney Dis 17:353-361, 1991. 22. Nielsen CH, Leslie RG: Complement’s participation in acquired immunity. J Leukoc Biol 72:249-261, 2002. 23. Kang YS, Do Y, Lee HK, et al: A dominant complement fixation pathway for pneumococcal polysaccharides initiated by SIGN-R1 interacting with C1q. Cell 125:47-58, 2006. 24. Helmy KY, Katschke KJ Jr, Gorgani NN, et al: CRIg: A macrophage complement receptor required for phagocytosis of circulating pathogens. Cell 124:915-927, 2006. 25. Tarr J, Eggleton P: Immune function of C1q and its modulators CD91 and CD93. Crit Rev Immunol 25:305-330, 2005. 26. Fearon DT, Locksley RM: The instructive role of innate immunity in the acquired immune response. Science 272:50-54, 1996. 27. Dempsey PW, Allison ME, Akkaraju S, et al: C3d of complement as a molecular adjuvant: Bridging innate and acquired immunity. Science 271:348-350, 1996. 28. Pickering MC, Botto M, Taylor PR, et al: Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol 76: 227-324, 2000. 29. Moore FD Jr: Therapeutic regulation of the complement system in acute injury states. Adv Immunol 56:267-299, 1994. 30. Hageman GS, Anderson DH, Johnson LV, et al: A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 102:7227-7232, 2005. 31. Atkinson JP, Schifferli JA: Complement system and systemic lupus erythematosus. In Kammer GM, Tsokos GC (eds): Lupus: Molecular and Cellular Pathogenesis. Totowa, NJ, Humana Press, 1999, pp 529-540. 32. Navratil JS, Manzi S, Kao AH, et al: Platelet C4d is highly specific for systemic lupus erythematosus. Arthritis Rheum 54:670-674, 2006. 33. Barilla-LaBarca ML, Atkinson JP: Rheumatic syndromes associated with complement deficiency. Curr Opin Rheumatol 15:55-60, 2003. 34. Welch TR: The complement system in renal diseases. Nephron 88:199-204, 2001. 35. Sullivan KE: Complement deficiency and autoimmunity. Curr Opin Pediatr 10:600-606, 1998. 36. O’Neil KM: Complement deficiency. Clin Rev Allergy Immunol 19:83-108, 2000. 37. Trendelenburg M: Antibodies against C1q in patients with systemic lupus erythematosus. Springer Semin Immunopathol 27:276-285, 2005. 38. Atkinson JP, Schneider PM: Genetic susceptibility and class III complement genes. In Lahita RG (ed): Systemic Lupus Erythematosus, 3rd ed. San Diego, Academic Press, 1999, pp 91-104. 39. Welch TR, Frenzke M: Glomerulonephritis associated with deficiencies and polymorphisms of complement components encoded in the class III region of the MHC. Front Biosci 6:D898-903, 2001. 40. Welch TR, Brickman C, Bishof N, et al: The phenotype of SLE associated with complete deficiency of complement isotype C4A. J Clini Immunol 18:48-51, 1998. 41. Petri M, Watson R, Winkelstein JA, et al: Clinical expression of systemic lupus erythematosus in patients with C4A deficiency. Medicine (Baltimore) 72:236-244, 1993. 42. Figueroa JE, Densen P: Infectious diseases associated with complement deficiencies. Clin Microbiol Rev 4:359-395, 1991. 43. Garred P, Madsen HO, Halberg P, et al: Mannose-binding lectin polymorphisms and susceptibility to infection in systemic lupus erythematosus. Arthritis Rheum 42:2145-2152, 1999. 44. Garred P, Madsen HO, Halberg P, et al: The association of variant mannose-binding lectin genotypes with radiographic outcome in rheumatoid arthritis. Arthritis Rheum 43:515-521, 2000. 45. Takai T: Roles of Fc receptors in autoimmunity. Nat Rev Immunol 2:580-592, 2002. 46. Ravetch JV, Bolland S: IgG Fc receptors. Annu Rev Immunol 19: 275-290, 2001.

47. Baumann U, Chouchakova N, Gewecke B, et al: Distinct tissue sitespecific requirements of mast cells and complement components C3/ C5a receptor in IgG immune complex-induced injury of skin and lung. J Immunol 167:1022-1027, 2001. 48. Shushakova N, Skokowa J, Schulman J, et al: C5a anaphylatoxin is a major regulator of activating versus inhibitory Fc gamma receptors in immune complex-induced lung disease. J Clin Invest 110:1823-1830, 2002. 49. Holers VM: Phenotypes of complement knockouts. Immunopharmacology 49:125-131, 2000. 50. Einav S, Pozdnyakova OO, Ma M, Carroll MC: Complement C4 is protective for lupus disease independent of C3. J Immunol 168: 1036-1041, 2002. 51. Ramos-Casals M, Campoamor MT, Chamorro A, et al: Hypocomplementemia in systemic lupus erythematosus and primary antiphospholipid syndrome: Prevalence and clinical significance in 667 patients. Lupus 13:777-783, 2004. 52. Caucheteux SM, Kanellopoulos-Langevin C, Ojcius DM: At the innate frontiers between mother and fetus: Linking abortion with complement activation. Immunity 18:169-172, 2003. 53. Holers VM, Girardi G, Mo L, et al: Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J Exp Med 195:211-220, 2002. 54. Girardi G, Yarilin D, Thurman JM, et al: Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J Exp Med 203:2165-2175, 2006. 55. Neumann E, Barnum SR, Tarner IH, et al: Local production of complement proteins in rheumatoid arthritis synovium. Arthritis Rheum 46:934-945, 2002. 56. Linton SM, Morgan BP: Complement activation and inhibition in experimental models of arthritis. Mol Immunol 36:905-914, 1999. 57. Wang Y, Kristan J, Hao L, et al: A role for complement in antibodymediated inflammation: C5-deficient DBA/1 mice are resistant to collagen-induced arthritis. J Immunol 164:4340-4347, 2000. 58. Wang Y, Rollins SA, Madri JA, et al: Anti-C5 monoclonal antibody therapy prevents collagen-induced arthritis and ameliorates established disease. Proc Natl Acad Sci U S A 92:8955-8959, 1995. 59. Banda NK, Thurman JM, Kraus D, et al: Alternative complement pathway activation is essential for inflammation and joint destruction in the passive transfer model of collagen-induced arthritis. J Immunol 177:1904-1912, 2006. 60. Ji H, Ohmura K, Mahmood U, et al: Arthritis critically dependent on innate immune system players. Immunity 16:157-168, 2002. 61. Matsumoto I, Maccioni M, Lee DM, et al: How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease. Nat Immunol 3:360-365, 2002. 62. Fearon DT, Austen KF: Current concepts of immunology: The alternative pathway of complement—a system for host defense to microbial infection. N Engl J Med 303:259-263, 1980. 63. Cantaert T, De Rycke L, Bongartz T, et al: Citrullinated proteins in rheumatoid arthritis: Crucial . . . but not sufficient! Arthritis Rheum 54:3381-3389, 2006. 64. Dragon-Durey M-A, Fremeaux-Bacchi V: Atypical haemolytic uraemic syndrome and mutations in complement regulator genes. Springer Semin Immunopathol 27:359-374, 2005. 65. Liszewski MK, Atkinson JP: Complement inhibition. In Smolen J, Lipsky P (eds): Biological Therapy in Rheumatology. London, Martin Dunitz, 2002, pp 453-461. 66. Klickstein LB, Moore FD Jr, Atkinson JP: Therapeutic inhibition of complement activation with emphasis on drugs in clinical trials. In Austen KF, Burakoff SJ, Strom TB, et al (eds): Therapeutic Immunology Malden, Mass, Blackwell Science, 2000, pp 287-301. 67. Kirshfink M: Targeting complement in therapy. Immunol Rev 180: 177-189, 2001. 68. Bhole D, Stahl GL: Therapeutic potential of targeting the complement cascade in critical care medicine. Crit Care Med 31(1 Suppl): S97-S104, 2003.

20

Signal Transduction John C. Scatizzi  • Harris Perlman

KEY POINTS Mitogen-activated protein kinase (MAPK) pathways are a cascade of kinases engaged by environmental stress, leading to the activation of multiple transcription factors. Inhibitor of κB (IκB) sequesters nuclear factor κB (NFκB) in the cytoplasm and after stimulation by the IKK signal complex, IκB is marked for degradation, allowing for NFκB to translocate to the nucleus and activate transcription. Ligand binding to Toll-like receptors initiates a signal cascade that involves MyD88, IRAK1, and IRAK4 and results in the activation of MAPK pathways and the NFκB pathways. The extrinsic pathway of apoptosis is initiated by the binding of death ligands to receptors (TNFR1, Fas, TRAIL). The intrinsic pathway is regulated by the Bcl-2 protein family, which is divided into proapoptotic and antiapoptotic members. p53 stimulates cell cycle arrest and DNA repair by inducing p21 and GADD45 and can induce the apoptotic cascade through activation of proapoptotic Bcl-2 family members.

Signal transduction is a biochemical event by which cells transmit a signal from the cell exterior (e.g., by a hormone, growth factor, cytokine, or chemokine) through the cell membrane and into the cytoplasm. This event involves many molecules, including receptors, kinases, and secon­ dary messengers. The result of multiple signal transduction pathways is the binding of transcription factors to DNA, affecting gene transcription. Signal transduction pathways are highly diverse, yet show an extraordinary degree of spec­ ificity for transcription factors. The binding of extracellular signaling molecules to their receptors may directly induce transcription factors such as nuclear factor κB (NFκB) or NFAT or activate signal transduction pathways, including mitogen-activated protein kinases (MAPKs), resulting in the subsequent activation of transcription factors such as AP-1 and ATF-2. Many transcription factors and their sig­ naling pathways have been implicated in the expression of genes that mediate the inflammatory response and are con­ sidered novel therapeutic targets for treating inflammatory diseases.

MITOGEN-ACTIVATED PROTEIN KINASE FAMILY MAPKs control many cellular functions, including cell proliferation and hormonal responses.1,2 MAPK cascades contain at least three upstream kinases and are activated by multiple environmental stress. Extracellular signal-regulated

kinases (ERKs) are generally activated by growth factors and phorbol esters, whereas c-Jun aminoterminal kinases (JNKs) and p38 isoforms are activated by cellular stress and cytokine stimulation. MAPKs are activated by mito­ gen-activated protein kinase kinases (MAPKKs), which are phosphorylated by upstream mitogen-activated protein kinase kinase kinases (MAPKKKs). MAPKKKs are engaged by small guanosine triphosphate (GTP) proteins such as Ras or other upstream kinases (Fig. 20-1). MAPKs are serine/ threonine kinases, which are activated by dual phosphoryla­ tion of threonine and tyrosine residues located within their activation loops. MAPKs form tight complexes with their substrates and phosphorylate serine/threonine residues. Phosphorylation of MAPKs either directly or indirectly regulates at least three transcription factors—activated pro­ tein-1 (AP-1), NFκB, or signal transducers and activators of transcription (STAT), each of which is linked to inflamma­ tory diseases.3 There are five ERK proteins (ERK1 through ERK5) that are activated in response to growth factors and phor­ bol esters. ERK1 and ERK2 are expressed in all tissues and are activated by dual sequential phosphorylation, first on a tyrosine then on a threonine residue. Two major events that initiate the signal cascade are the binding of GTP ligand to Ras and phosphorylation of active Raf-1. In rest­ ing cells, ERK1 and ERK2 are found throughout the cell; however, after activation, ERK1 and ERK2 accumulate in the nucleus. Phosphorylated ERK1 and ERK2 bind to the transcription factor Pax6, steroid receptor coactivator-1 (SRC-1), NFATc, or STAT3,4 whereas ERK5 influences c-Jun-mediated transcription. Taken together, these data suggest that ERK1 and ERK2 are the major isoforms that are activated during an inflammatory response. JNKs (also called stress-activated protein kinases) are activated by cytokines and cellular stress, including ultra­ violet irradiation, growth factor deprivation, or agents that interfere with DNA or protein synthesis. There are three different JNK isoforms: JNK1 and JNK2 are ubiquitously expressed, whereas JNK3 is primarily expressed in neural tissue.5 JNKs are activated by the dual phosphorylation of tyrosine and threonine residues separated by a proline resi­ due in their activation loops. Activated JNK1 and JNK2 phosphorylate two serine residues on the amino terminus of the transcription factor c-Jun, which results in marked increase in transcriptional activity. JNK phosphorylates p53, the transcription factors Elk-1 and NFAT4, the glu­ cocorticoid receptor, and members of the Bcl-2 family.5 p38 is a MAPK that is activated by environmental stresses (oxidative stress, hypoxia, and ultraviolet irradia­ tion) and inflammatory cytokines. There are four isoforms of p38, each of which is encoded by a separate gene. p38 α 337

338

A

SCATIZZI 

Signal

| 

B

Signal Transduction

Cellular stress or cytokines

Phorbalesters or growth factors

MAPKKK

MAPKKK

MAPKKK

MAPKKK

MAPKK

MAPKK3/6

MAPKK4/7

MAPK1/2

MAPK

p38α/β/γ/δ

JNK1/2

ERK1/2

Transcription factor

SAP-1

c-Jun

EIK-1

Figure 20-1  Overview of mitogen-activated protein kinase (MAPK) signaling pathways. A, Following an extracellular signal, a MAP kinase kinase kinase (MAPKKK) is activated, which phosphorylates a MAP kinase kinase (MAPKK). MAPKK phosphorylates a MAPK, which activates various transcription factors. B, Cellular stress or proinflammatory cytokines activate either p38 or JNK, resulting in the activation of SAP-1 and c-Jun transcription factors. Phorbol esters, growth factors, and some cytokines activate ERK, which results in the activation of the Elk-1 transcription factor.

and β are widely expressed; γ is predominantly expressed in skeletal muscle; and δ is expressed in testes, pancreas, synovium, and small intestine.6 p38 is localized in the cyto­ plasm and nucleus of resting cells, but the significance of its distribution within the cell is not well understood. Activa­ tion of p38 results from the dual phosphorylation of tyrosine and threonine residues in the TGY motif. p38 then phos­ phorylates and enhances the activity of many transcription factors, including ATF-1 and ATF-2, SAP-1, NFκB, and p53.6 p38 also regulates the expression of genes by stabiliz­ ing the mRNA through the binding to AU-rich elements.6 These data suggest that p38 mediates the transcription or message stability of various genes involved in the immune response. AP-1 is a transcription factor that controls the regula­ tion of the inflammatory response, including the induced transcription of proinflammatory cytokines and matrix metalloproteinase (MMP) genes. AP-1 transcription fac­ tors are divided into two groups, Jun (c-jun, jun B, and jun D) and Fos (c-fos, fos B, Fra-1, and Fra-2), which form Jun-Jun homodimers, Jun-Jun heterodimers, or Jun-Fos heterodimers. AP-1 is classified in the basic region leucinezipper (bZip) family. The basic domain allows transactiva­ tion, and the leucine-zipper domain mediates dimerization and DNA binding. All three MAPKs are involved in tran­ scriptional regulation of Jun and Fos family genes through the phosphorylation and subsequent activation of the Ets family transcription factors ELK-1 or SAP-1. MAPKs also are responsible for post-translational modifications of AP-1. Phosphorylated AP-1 associates with CBP/p300 and RNA polymerase III and has enhanced transcriptional activity.7 JNK1 and JNK2 phosphorylate two aminotermi­ nal serine residues found in the transactivation domain of c-jun, which results in a substantial increase in the tran­ scriptional activity of AP-1. ATF-2 is another transcription factor in the bZip family, which is activated by p38 or JNK. ATF-2 binds to DNA either as a homodimer or as a het­ erodimer with c-jun or other members of the bZip family. ATF-2 transcriptional activity is induced by phosphoryla­ tion of its transactivation domain.

NUCLEAR FACTOR κB TRANSCRIPTION FACTOR NFκB was first described as a B cell–specific protein that binds to a short DNA sequence motif located in the immu­ noglobulin κ light-chain enhancer. It is expressed in virtu­ ally all cell types and has been shown to play a broad role in gene transcription, including interleukin (IL)-2, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GMCSF), intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)1, and major histocompatibility class I.8 The NFκB family has been implicated in the tran­ scriptional activation of numerous targets in rheumatoid arthritis, including tumor necrosis factor (TNF)-α, IL-1, IL-6, monocyte chemotactic protein-1, GM-CSF, MMP-1, MMP-3, ICAM, VCAM, inducible nitric oxide synthase, cyclooxygenase-2, Bcl-2, and Bcl-xL.9 The family consists of five members (Rel A [p65], c-Rel, Rel B, p50, and p52) that share an N-terminal Rel homology domain, which is nec­ essary for DNA binding, dimerization, and nuclear trans­ location. p65, c-Rel, and RelB, but not p50 or p52, have C-terminal transcriptional activation domains. p50 and p52 are synthesized as p105 and p100 precursors, which are processed into the smaller isoforms and may dimerize with other NFκB members to become transcriptionally active. NFκB members are retained in the cytoplasm as a result of their association with their inhibitor, IκB (α, β, ε, γ).10 IκB blocks the nuclear localization signal on NFκB either by masking it or by covering it. IκBα has a nuclear export signal that prevents nuclear entry by NFκB. IκBα and β preferentially associate with p65, but not with c-Rel, whereas IκBε binds to p65 and c-Rel.11,12 For NFκB to become transcriptionally active, it must be released from IκB. This release is mediated by phosphorylation and ubiquitination of IκB followed by its degradation (Fig. 20-2). IκB proteins are phosphorylated (Ser32 and Ser36 for IκBα and Ser 19 and Ser21 for IκBβ) by a protein complex (IKK signalosome) that consists of two catalytic subunits IKKα and IKKβ and a regulatory subunit, IKKγ NFκB essential modulator (NEMO). IKK signalosome is activated by a multitude of cytokines and Toll-like recep­ tor (TLR) agonists, including TNF-α, IL-1β, and lipopoly­ saccharide (LPS). Phosphorylated IκB is targeted for ubiquitination and subsequent degradation by the 26S proteasome. IKKγ is crucial for transporting IKKβ toward its activating kinase. TNF-α stimulation leads to recruitment of TAK1, TAB2, TAB3, MEKK3, TRAF2, and RIP1 to the cytoplasmic tail of TNF-α receptor. IKKγ is required for the attachment of lysine 63-linked polyubiquitin chain to the coiled region of RIP1, which is necessary for IKK signaling and NFκB activity.13 Selective disruption of IKKβ results in a failure to phosphorylate IκB in response to stimulation with TNF, IL-1, or TLR agonists. Deletion of p65, IKKβ, or IKKγ results in the identical phenotype—embryonic lethality associated with massive hepatic apoptosis.14 These data indicate that IKKβ plays a central role in phosphorylation of IκB, and that IKKγ is required for IκB phosphorylation even though it lacks a catalytic subunit. Although IKKα may have a redundant role in the phosphorylation of IκB,15 studies have shown that IKKα mediates an alternative pathway. This pathway involves the lymphotoxin-β or BAFF receptor

PART 3 

EFFECTOR MECHANISMS IN AUTOIMMUNITY AND INFLAMMATION

Extracellular space

Stress, cytokines, and pathogens IKK signal complex

| 

P P

B.

C.

Cytoplasm P P

uuuuu

A.

D. I-κB

NF-κB dimer

E.

NF-κB directed gene transcription

Nucleus Figure 20-2  Schematic of nuclear factor κB (NFκB) activation. A, NFκB dimers normally form a complex with inhibitor κB (IκB). The binding of IκB covers the nuclear localization signal on the NFκB dimers, sequestering the complex in the cytoplasm. B, Activation of NFκB begins with an extracellular signal activating the IKK signal complex to phosphorylate IκB. C, Phosphorylation of IκB results in the addition of a ubiquitin tag. D, The ubiquitin tag marks IκB for proteolytic degradation and subsequently releases the nuclear localization signal on the NFκB dimer.  E, NFκB dimers translocate to the nucleus and bind promoter regions of NFκB-responsive genes, directing their transcription.

mediated activation of NFκB-inducing kinase (NIK), which leads to the processing of p100 protein into p52 and forma­ tion of RelB dimers.16

JAK/STAT/SOCS FAMILY IL-6, interferon (IFN)-α, IFN-β, and IFN-γ in addition to various other cytokines activate the JAK (Janus kinases) family, which associate with their cognate receptors and lead to the phosphorylation of the cytoplasmic domains to create docking sites for src homology 2 (SH2)–contain­ ing proteins. The STAT (signal transducers and activators of transcription) family of proteins are one of the most important substrates for JAKs.17 The SOCS (suppressor of cytokine signaling) proteins have been shown to func­ tion as inhibitors of JAK/STAT proteins and are induced through a negative feedback loop.17 The importance of STAT is shown in mice lacking the various components of the JAK/STAT/SOCS family. Mice expressing a knockin mutant of the gp130 receptor, which has all the STAT binding sites deleted, have gastrointestinal ulceration and severe arthritis.18 SOCS1−/− mice are normally lethal, but are viable on an IFN-γ−/− background. These data show that the JAK/STAT/SOCS family is crucial for the proper signal transduction pathway that occurs by the docking of cyto­ kines to their receptors.

TOLL-LIKE RECEPTOR SIGNALING TLRs are a family of evolutionarily conserved ­ receptors, which are crucial for initiating the innate immune response.19,20 TLRs and IL-1 receptors (IL-1Rs) have con­ served regions located in their cytoplasmic tails known as

339

Toll/IL-1 receptor (TIR) domains, which are required for downstream signaling. The extracellular domains of TLRs contain leucine-rich sequences (LRR domains) and hydro­ phobic sequences, whereas IL-1Rs have three immuno­ globulin domains in their extracellular portion. Despite the conservation among the extracellular domains of TLRs, different TLRs can recognize structurally unrelated ligands. Location of TLRs also dictates ligand specificity: TLR3 (double-stranded RNA), TLR7 (single-stranded RNA), and TLR9 (CpG-containing DNA) are not expressed on the cell surface, whereas TLR1 (triacyl lipopeptides), TLR2 (peptidoglycans from gram-positive bacteria, lipoproteins, or yeast), and TLR4 (LPS) are located on the cell surface and are recruited to phagosomes after their activation. After ligand binding, TLRs/IL-1Rs dimerize and undergo a conformational change resulting in the recruitment of downstream signaling molecules. Myeloid differentiation primary-response protein 88 (MyD88) is one of the initial signaling molecules recruited to the activated TLR. MyD88 contains an aminoterminal death domain (DD) and a car­ boxyterminal TIR domain, which dimerizes with the TIR domain located on the cytoplasmic tail of the TLR. MyD88 is an adapter molecule that recruits and associates with IRAK, a serine/threonine kinase with an N-terminal death domain. There are four IRAK proteins (IRAK1 through IRAK4); however, only IRAK1 and IRAK4 have detectable kinase activity, which increases after TLR stimulation and is nec­ essary for the activation of NFκB. TLR ligand engagement results in the activation of IRAK4, which associates and phosphorylates IRAK1. TNF ­ receptor–­associated factor 6 (TRAF6) is recruited to IRAK1, which results in the dis­ sociation of IRAK1 and TRAF6 from IRAK4. TRAF6 is a member of a family of evolutionary ­ conserved adapter proteins, which also play a major role in TNF receptor superfamily signaling. TRAF6 contains a RING finger-zinc finger region required for downstream signaling events. IRAK1 and TRAF6 associate with transforming growth factor β–activated kinase (TAK1), TAK1 binding protein 1 (TAB1), and TAB2, which results in the activation of the transcription factors AP-1 and NFκB. TAK1 is a member of the MAPKKK family, and its activation directly leads to the activation of the MAPK pathways (Fig. 20-3).

SIGNALING IN APOPTOSIS Apoptosis is an evolutionarily conserved cell death ­pathway—components of this mechanism exist from worms to humans.21 An apoptotic stimulus induces an ini­ tiation phase followed by an execution or commitment phase and ending in a degradation phase.22 Characteristics of the degradative phase of apoptosis are membrane bleb­ bing, mitochondrial dysfunction, cellular and cytoplasmic shrinkage, chromosomal fragmentation and condensation, and endonuclease activation resulting in the characteristic 180-bp nucleosomal DNA ladder.23 In contrast to necro­ sis, the apoptotic process does not induce an inflammatory response because the cell forms an apoptotic body that is either expelled into a lumen or phagocytosed by neigh­ boring cells,24 avoiding the release of subcellular antigens. Apoptosis in mammals proceeds through two distinct path­ ways—an “extrinsic” pathway, which transduces an apop­ totic signal after the ligation of death receptors on the cell

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Signal Transduction

TLR ligand TLR receptor TIR domain MyD 88

IRAK 4

IRAK 1

TRAF 6

Activation NF-κB pathway

TRAF 6 TAB2 TAK 1 TAB1 Activation of MAP kinase pathways

IKK signal complex Figure 20-3  Toll-like/interleukin-1 receptor signaling. After Toll-like receptor (TLR) ligand binding, dimerization of receptors occurs, which allows recruitment of MyD88 to the Toll/interleukin-1 receptor (TIR) ­domains of receptor cytoplasmic tail. MyD88 contains a death domain, which allows for its interaction with IRAK proteins. The recruitment of IRAK4 by MyD88 allows phosphorylation of IRAK1 by IRAK4. TRAF6 is ­recruited to the receptor complex by phosphorylated IRAK1. Phosphorylated IRAK1 and TRAF6 dissociate from the receptor complex. ­ After ­degradation of IRAK1, TRAF6 forms a complex with TAK1, TAB1, and TAB2. TAK1 is activated after TRAF6 ubiquitination and phosphorylates the IKK complex and mitogen-activated protein kinases (MAPK). This ­activates the nuclear factor κB (NFκB) and MAPK signaling pathways, resulting in the activation of multiple transcription factors.

surface, and an “intrinsic” pathway, in which mitochondria play a crucial role. Caspases, an enzymatic family of cyste­ ine proteases (caspase 1 through 14) that cleave adjacent to aspartate residues and regulate the degradative phase of apoptosis. DEATH RECEPTOR SIGNALING The induction of apoptosis by the extrinsic pathway is ini­ tiated by binding of death ligands to its cognate receptor. The TNF superfamily, including Fas, TRAIL RI (DR4) and RII (DR5), and TNF-α receptor (TNFRI), are ubiquitously expressed type I membrane receptors that share a homol­ ogous region (death domain). The ligands for the death receptors are type II membrane proteins and include Fas ligand (FasL), TRAIL, and TNF-α. Oligomerization of Fas by binding to FasL induces the recruitment of an adapter protein FADD and a cysteine protease procaspase 8 (see later) to the C-terminus of Fas, forming the death-inducing signaling complex.25 In contrast to Fas, TNF-α rarely induces apoptosis unless NFκB activity is suppressed. After binding of TNF-α to TNFR1, an adapter protein TRADD is recruited to the C-terminus of TNFR1, and this recruits the serine/theon­ ine kinase RIP1, which is required for NFκB signaling, and TRAF2, which is necessary for JNK signaling. The TRADDRIP1-TRAF2 complex is released from the cytoplasmic tail of TNFR1 and forms an additional complex with caspase 8 and FADD in cells that are sensitive to TNF-α-induced apoptosis.26 Aggregation or oligomerization of procaspase 8 leads to autocatalysis/activation. Active ­caspase 8 induces

the degradative phase of apoptosis through the activation of caspases 3 and 7.25 FADD27 and caspase 828 are essential for the transmission of the Fas-death signal because FADD­deficient or caspase 8–deficient embryonic fibroblasts are insensitive to Fas-FasL-induced death. An additional pathway of Fas-induced cell death involves the apoptotic agonist Bid, a Bcl-2-family protein.29 Death receptor– mediated apoptosis is blocked at the death-inducing signal­ ing complex by the naturally occurring dominant negative caspase 8 protein termed Flice inhibitory protein (Flip).30 Two isoforms of Flip are produced owing to alternate splic­ ing, a larger, FlipL, and a smaller protein, FlipS. Flip binds to procaspase 8 or FADD through the death effector domains preventing the formation of the death-inducing signaling complex. Mice deficient for Flip die in utero at embryonic day 10.5 (E10.5),31 and embryonic fibroblasts isolated from Flip-null mice are susceptible to all forms of death recep­ tor–mediated cell death, including Fas.31 These data show that direct inhibition of Fas-induced apoptosis is mediated by Flip.31 Bcl-2 FAMILY SIGNALING The intrinsic pathway is regulated by the Bcl-2 protein ­family, which is divided into antiapoptotic (Bcl-2, Bcl-xL, Mcl-1, A1/Bfl-1, and Bcl-w) and proapoptotic (Bax, Bak, Bad, Bim/Bod, Bok/Mtd, Bik/Blk/Nbk, Bid, Hrk/DP5, Bmf, Noxa, PUMA/Bbc3) members.32 Bcl-2-related proteins con­ tain Bcl-2-homology (BH1 through BH4) domains, which are crucial for homodimer and heterodimer formation between the family members.33 Although the antiapoptotic Bcl-2-like proteins contain all four (or at least three) BH domains, the proapoptotic Bcl-2–related proteins are sub­ divided into two categories—the multi-BH domain (BH1 through BH3, e.g., Bak, Bax) and the BH3-only proteins (e.g., Bad, Bim).34 Studies using peptides that correspond to the BH3 domains have shown that BH3-only proteins also are subdivided into two categories based on their ability to induce apoptosis.35 Bid and Bim are sufficient to sequester antiapoptotic Bcl-2 family members and induce oligomer­ ization of Bak and Bax, permeabilization of liposomes, and release of cytochrome c.35 In contrast, Bad, Bmf, Hrk, Noxa, and PUMA are sensitizers for apoptosis because they are able to bind only to the antiapoptotic Bcl-2 members and require Bid or Bim to induce the death response.35-40 Many Bcl-2 family members are localized to the mito­ chondrial outer membrane (and certain other intracellular membranes), suggesting that mitochondrial dysfunction is involved in apoptosis.22,29,32 During intrinsic apoptosis sig­ naling, the integrity of the outer mitochondrial membrane is lost, leading to the dissipation of the transmembrane poten­ tial through the opening of mitochondrial permeability transition pores22 and release of apoptogenic mitochon­ drial intermembrane proteins, such as cytochrome c.41,42 In the cytoplasm, cytochrome c binds to the adapter protein Apaf-1, which causes aggregation and activation of the ini­ tiator caspase 9. Caspase 9 activates the effector caspases 3 and 7,43 which cause the downstream degradative events in apoptosis.44 Apoptosis signaling through the intrinsic path­ way is inhibited by overexpression of any of the Bcl-2-like prosurvival members or by loss of both multi-BH domain proteins Bak and Bax.45

PART 3 

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p53, CELL CYCLE ARREST, AND APOPTOSIS p53 is a transcription factor that has been ascribed prop­ erties of a tumor suppressor. p53 induces various cellular responses, including differentiation, cell cycle arrest, DNA repair, and apoptosis.46 p53 stimulates cell cycle arrest or DNA repair or both by inducing the transcription of p21 and GADD45, whereas p53 activates the apoptosis cascade through the induction of proapoptotic Bcl-2 proteins, such as Bax, PUMA, and Noxa. The mechanism that controls which pathway is activated by p53 is poorly understood. One possibility is that binding affinity of p53 to specific cell cycle or apoptotic promoters may be a crucial determinant and is related to the level of p53 after cellular stress.47 Alter­ natively, post-translational modifications to p5348 or recruit­ ment of cofactors by p53 may decide the fate of the cell.49 Dysregulation of cell cycle arrest, DNA repair, and apoptosis have been suggested to contribute to chronic inflammatory diseases.

SUMMARY There has been a substantial increase in recent years in understanding of the signal transduction pathways that are activated in inflammatory and autoimmune diseases. This increased understanding has led to the development of small molecules to inhibit each pathway, including NFκB, JNK, and p38. Blocking these signaling pathways repre­ sents a major potential therapeutic approach to rheumatic ­diseases. REFERENCES   1. Murphy LO, Blenis J: MAPK signal specificity: The right place at the right time. Trends Biochem Sci 31:268-275, 2006. 2. Qi M, Elion EA: MAP kinase pathways. J Cell Sci 118:3569-3572, 2005. 3. Firestein GS, Manning AM: Signal transduction and transcription factors in rheumatic disease. Arthritis Rheum 42:609-621, 1999.   4. Nishimoto S, Nishida E: MAPK signalling: ERK5 versus ERK1/2. EMBO Rep 7:782-786, 2006.   5. Davis RJ: Signal transduction by the JNK group of MAP kinases. Cell 103:239-252, 2000.   6. Ashwell JD: The many paths to p38 mitogen-activated protein kinase activation in the immune system. Nat Rev Immunol 6:532-540, 2006.   7. Ransone LJ, Verma IM: Nuclear proto-oncogenes fos and jun. Annu Rev Cell Biol 6:539-557, 1990. 8. Firestein GS: NF-kappaB: Holy Grail for rheumatoid arthritis? Arthritis Rheum 50:2381-2386, 2004. 9. Karin M: Nuclear factor-kappaB in cancer development and progression. Nature 441:431-436, 2006. 10. Gilmore TD: Introduction to NF-kappa B: players, pathways, perspec­ tives. Oncogene 25:6680-6684, 2006. 11. Malek S, Chen Y, Huxford T, et al: IkappaBbeta, but not IkappaBal­ pha, functions as a classical cytoplasmic inhibitor of NF-kappaB dimers by masking both NF-kappaB nuclear localization sequences in resting cells. J Biol Chem 276:45225-45235, 2001. 12. Malek S, Huxford T, Ghosh G: Ikappa Balpha functions through direct contacts with the nuclear localization signals and the DNA binding sequences of NF-kappaB. J Biol Chem 273:25427-25435, 1998. 13. Kovalenko A, Wallach D: If the prophet does not come to the moun­ tain: Dynamics of signaling complexes in NF-kappaB activation. Mol Cell 22:433-436, 2006. 14. Pasparakis M, Luedde T, Schmidt-Supprian M: Dissection of the NF-kappaB signalling cascade in transgenic and knockout mice. Cell Death Differ 13:861-872, 2006. 15. Li Q, Estepa G, Memet S, et al: Complete lack of NF-kappaB activity in IKK1 and IKK2 double-deficient mice: additional defect in neurulation. Genes Dev 14:1729-1733, 2000.

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16. Senftleben U, Cao y, Xiao G, et al: Activation by IKKalpha of a sec­ ond, evolutionary conserved, NF-kappa B signaling pathway. Science 293:1495-1499, 2001. 17. Walker JG, Smith MD: The Jak-STAT pathway in rheumatoid arthritis. J Rheumatol 32:1650-1653, 2005. 18. Ernst M, Inglese M, Waring P, et al: Defective gp130-mediated signal transducer and activator of transcription (STAT) signaling results in degenerative joint disease, gastrointestinal ulceration, and failure of uterine implantation. J Exp Med 194:189-203, 2001. 19. Akira S, Takeda K: Toll-like receptor signalling. Nat Rev Immunol 4:499-511, 2004. 20. Medzhitov R: Toll-like receptors and innate immunity. Nat Rev Immunol 1:135-145, 2001. 21. Ameisen JC: The origin of programmed cell death. Science 272: 1278-1279, 1996. 22. Zamzami N, Brenner C, Marzo I, et al: Subcellular and submito­ chondrial mode of action of Bcl-2-like oncoproteins. Oncogene 16: 2265-2282, 1998. 23. Yang E, Korsmeyer SJ: Molecular thanatosis: A discourse on the BCL2 family and cell death. Blood 88:386-401, 1996. 24. Thompson CB: Apoptosis in the pathogenesis and treatment of dis­ ease. Science 267:1456-1462, 1995. 25. Green DR: Apoptotic pathways: The roads to ruin. Cell 94:695-698, 1998. 26. Micheau O, Tschopp J: Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114:181-190, 2003. 27. Yeh WC, Pompa JL, McCurrach M, et al: FADD: Essential for embryo development and signaling from some, but not all, inducers of apopto­ sis. Science 279:1954-1958, 1998. 28. Varfolomeev EE, Schuchmann M, Luria V, et al: Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9:267-276, 1998. 29. Green DR, Reed JC: Mitochondria and apoptosis. Science 281: 1309-1312, 1998. 30. Irmler M, Thome M, Hahne M, et al: Inhibition of death receptor signals by cellular FLIP. Nature 388:190-195, 1997. 31. Yeh WC, Itie A, Elia AJ, et al: Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic devel­ opment. Immunity 12:633-642, 2000. 32. Adams JM, Cory S: The Bcl-2 protein family: arbiters of cell survival. Science 281:1322-1326, 1998. 33. Kroemer G: The proto-oncogene Bcl-2 and its role in regulating apop­ tosis. Nat Med 3:614-620, 1997. 34. Opferman JT, Korsmeyer SJ: Apoptosis in the development and main­ tenance of the immune system. Nat Immunol 4:410-415, 2003. 35. Galonek HL, Hardwick JM: Upgrading the BCL-2 network. Nat Cell Biol 8:1317-1319, 2006. 36. Letai A, Bassik MC, Walensky LD, et al: Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype can­ cer therapeutics. Cancer Cell 2:183-192, 2002. 37. Certo M, DelGaizo Moore V, Nishino M, et al: Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9:351-365, 2006. 38. Chen L, Willis SN, Wei A, et al: Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apop­ totic function. Mol Cell 17:393-403, 2005. 39. Willis SN, Chen L, Dewson G, et al: Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev 19:1294-1305, 2005. 40. Kuwana T, Bouchier-Hayes L, Chipor JE, et al: BH3 domains of BH3only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 17:525-535, 2005. 41. Yang J, Liu X, Bhalla K, et al: Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked. Science 275:1129-1132, 1997. 42. Kluck RM, Bossy-Wetzel E, Green DR, et al: The release of cyto­ chrome c from mitochondria: A primary site for Bcl-2 regulation of apoptosis. Science 275:1132-1136, 1997. 43. Kuida K, Haydar TF, Kuan CY, et al: Reduced apoptosis and cyto­ chrome c-mediated caspase activation in mice lacking caspase 9. Cell 94:325-337, 1998. 44. Rao L, White E: Bcl-2 and the ICE family of apoptotic regulators: Making a connection. Curr Opin Genet Dev 7:52-58, 1997.

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45. Lindsten T, Ross AJ, King A, et al: The combined functions of pro­ apoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 6:1389-1399, 2000. 46. Vousden KH, Woude GF: The ins and outs of p53. Nat Cell Biol 2:E178-E180, 2000. 47. Inga A, Storici F, Darden TA, et al: Differential transactivation by the p53 transcription factor is highly dependent on p53 level and pro­ moter target sequence. Mol Cell Biol 22:8612-8625, 2002.

48. Brooks CL, Gu W: p53 ubiquitination: Mdm2 and beyond. Mol Cell 21:307-315, 2006. 49. Mihara M, Erster S, Zaika A, et al: p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11:577-590, 2003.

21

Prostaglandins, Leukotrienes, and Related Compounds Robert B. Zurier

KEY POINTS

BIOSYNTHESIS OF EICOSANOIDS

Eicosanoid biosynthesis is catalyzed by cyclooxygenases and lipoxygenases.

PHOSPHOLIPASES

Conversion of the endoperoxide intermediate prostaglandin H2 requires activity of specific terminal synthases. Eicosanoid receptors have been identified. Eicosanoids regulate inflammatory and immune responses. Eicosanoid synthesis is modified by administration of ­precursor fatty acids.

The addition of oxygen to arachidonic acid and other polyunsaturated fatty acids not bound to membrane phospholipids in nearly all human cell types results in formation of several classes of bioactive products termed eicosanoids. These include prostaglandins (PGs), prostacyclin, thromboxanes (TXs), leukotrienes (LTs), and lipoxins. All of these compounds are crucial to the regulation of immunity and inflammation, among other physiologic and pathologic processes. Although eicosanoids are derived from C20 polyunsaturated fatty acids (eicosa = 20), only a small percentage of these polyenoic acids form the eicosanoids: dihomogamma linolenic acid (DGLA), which is 8,11,14-eicosatrienoic acid; arachidonic acid (AA), which is 5,8,11,14-eicosatetraenoic acid; and eicosapentaenoic acid (EPA), which is 5,8,11,14,17-EPA (Fig. 21-1). Two groups of fatty acids are essential to the body: the omega-6 series derived from linoleic acid (18:2 n-6) and the omega-3 series derived from α-linolenic acid (18:3 n-3). The n refers to the number of carbon atoms from the methyl (omega) end of the fatty acid chain to the first double bond (i.e., omega-3 and omega-6 designations). Using this notation, 18 refers to the number of carbon atoms in the fatty acid. The degree of unsaturation (the number of double carbon-carbon bonds) follows the number of carbon atoms. Fatty acids are metabolized by an alternating sequence of desaturation (i.e., removal of two hydrogens) and elongation (i.e., addition of two carbons). Membrane phospholipids are the main storage site for polyunsaturated fatty acids and are particularly rich in eicosanoid precursors, which are located at the sn-2 position (Fig. 21-2).Because mammalian cells cannot interconvert n-3 and n-6 fatty acids, the composition of membrane phospholipids is determined by exogenous sources of fatty acids.

Phospholipase A2 (PLA2) in lysosomes or bound to cell membranes catalyzes the breaking of the sn-2 bond, facilitating release of AA or other polyunsaturated fatty acids (see Fig. 21-2). The enzyme is crucial to regulation of eicosanoid synthesis because it is in the nonesterified state that the polyunsaturated precursors enter into the cascades leading to eicosanoid formation. Only a scant amount of oxidation at carbon 15 of AA occurs catalytically when the fatty acid is still covalently bound as part of a phospholipid.1 Lysophospholipids “left over” after the action of PLA2 are direct precursors of platelet-activating factor (PAF), a potent mediator of inflammation, which is generated by acylation (addition of fatty acid) in the open sn-2 position of the lysophospholipid. One member of the PLA2 superfamily, lipoprotein PLA2, may serve as a marker for cardiovascular risk.2 Four distinct types of PLA2 activities hydrolyze fatty acids esterified at the sn-2 position: Secretory PLA2 (sPLA2) has small disulfide cross-linked proteins that require Ca2+ in mM for optimal activity. Cytoplasmic PLA2 (cPLA2) has larger proteins requiring Ca2+ in μM, which are AA-selective and can deacylate diacylphospholipids completely, preventing accumulation of potentially toxic lysophospholipids. Ca2+-independent PLA2 (iPLA2) exhibits specificity for plasmalogen substrates. Finally, PAF acetylhydrolase (PAF-PLA2) has a series of isozymes specific for short chains.2 Under basal conditions, AA is liberated by iPLA2, then reincorporated into cell membranes (reacylated), and is unavailable for appreciable eicosanoid biosynthesis. The acylase enzymes competitively inhibit the cyclooxygenase (COX) isoenzymes. After receptor activation and cell stimulation, intracellular Ca2+ levels increase, and the Ca2+-dependent cPLA2 liberates arachidonate at a rate that exceeds the rate of reacylation, leading to arachidonate metabolism by COX isoenzymes. Initial formation of PGE2 seems to be due to preferential coupling between cPLA2, COX-1, and cytosolic PGH-PGE isomerase. More intense inflammation leads to participation of secreted sPLA2 and amplification of PGE2 biosynthesis by inducible COX-2. It is an oversimplification to regard availability of AA as the sole rate-limiting step in cellular eicosanoid biosynthesis. The coordinated action of phospholipases and the restricted expression and altered activation of COX isoenzymes also are important.3 Phospholipase C (PLC) hydrolyzes the polar head group (e.g., inositol, choline) from phospholipids to yield diacyl­ glycerol (DAG) and the polar head group. Direct protein 343

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Prostaglandins, Leukotrienes, and Related Compounds

OMEGA 6 (n-6) FATTY ACIDS

OMEGA 3 (n-3) FATTY ACIDS COOH

COOH

CH3

CH3 Linoleic acid (18:2)

Alpha linolenic acid (18:3) Delta-6 desaturase

COOH

COOH CH3

CH3

Gamma linolenic acid (18:3)

6,9,12,15 Octadecatetraenoic acid (18:4) Elongase

COOH

Cyclooxygenase PGE1

CH3 LTC3 Dihomogamma linolenic acid (20:3) Lipoxygenase

COOH CH3 Stearadonic acid (20:4)

Delta-5 desaturase COOH

COOH

CH3

CH3

Arachidonic acid (20:4)

Figure 21-1  Metabolic pathways of essential fatty acids. The pathways are ones of progressive desaturation alternating with elongation. Eicosanoid precursors include dihomogamma linolenic acid, arachidonic acid, and eicosapentaenoic acid. PG, prostaglandins; LT, leukotriene; TX, thromboxane.

Cyclooxygenase

Eicosapentaenoic acid (20:5)

Lipoxygenase

PGE2, PGI2, TXA2 LTA4, LTB4, LTC4

isolation and molecular-cloning studies have revealed ­multiple PLC isozymes in mammalian tissues. Phosphatidylinositol-PLC occurs in cytosolic (cPLC) and secreted (sPLC) forms and can be divided into three major classes (PLC-β, PLC-γ, and PLC-δ) based on substrate specificity. PLC with specificity for phosphatidylinositol and phosphorylated phosphatidylinositol is a key component of phosphatidylinositol-mediated signaling pathways. DAG is an activator of protein kinase C (PKC), and rapid production of this lipid by phosphatidylinositol-PLC hydrolysis of the phosphorylated phosphatidylinositol pool is a primary step in signaling. Further AA is made available by the sequential actions of diglyceride lipase and monoglyceride lipase.4 PLC with activity on phosphatidylcholine also has been identified. Peripheral blood monocytes from patients with rheumatoid arthritis (RA) exhibit greater PLA2 and PLC activity than cells from healthy volunteers. The greatest increases in enzyme activity were seen in cells from patients with the most severe, persistent, proliferative disease, not in cells from patients with the most active disease at the time the cells were studied.5

Cyclooxygenase

Lipoxygenase

PGE3, TXA3

LTB5

Hydrolysis of phospholipids by phospholipase D (PLD) produces phosphatidic acid (PA) and the respective polar head groups. The capacity of cells to interconvert PA and DAG through the action of specific cellular phosphatases and kinases (Fig. 21-3) suggests that AA release from DAG and a variety of intracellular signaling and protein-trafficking events may be regulated by PLD activity. PLD may be activated after or independent of PLC activation. The tetraenoic precursor (AA) is the most abundant of the three precursor fatty acids in cells of individuals who eat usual Western-style diets. Metabolites of AA constitute the “2” series (dienoic) PGs (two double bonds in the molecule), and the metabolic pathway has acquired the familiar name AA cascade. Figure 21-4 illustrates the COX and 5-lipoxygenase pathways of the cascade. CYCLOOXYGENASE PATHWAY The first step in the biosynthesis of the “prostanoids” (e.g., PGs, TXs, prostacyclin) is catalyzed by the bifunctional PG endoperoxide synthase isozyme (PGHS)-1 (COX-1) and

PART 3 

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EFFECTOR MECHANISMS IN AUTOIMMUNITY AND INFLAMMATION

Lysophospholipid PLC

Diacylglycerol O CH2

P O

CH

CH2

O

C H2 CH2

N+(CH3)3

O

Ca2+

IP3 DAG

PIP PI

PKC Pi

DAG kinase

PA hydrolase PA

O

O O

O

PIP2

Polar Head Group

PLC

345

PLA2

Phosphatidylcholine CH3

PLD

Choline

Figure 21-3  Reactions catalyzed by phospholipases C and D, i­ llustrating interconversion of diacylglycerol (DAG) and phosphatidic acid (PA).

Regulation of Cyclooxygenase-1 Expression Arachidonic Acid

R Figure 21-2  Arachidonic acid release from phospholipid. Shown here is phosphatidylcholine, the major membrane storage site for polyunsaturated fatty acids. PLA2, phospholipase A2; PLC, phospholipase C.

PGHS-2 (COX-2). To form the characteristic five-carbon ring structure (TXs contain a six-member ring), the precursor fatty acids must have double bonds at carbons 8, 11, and 14 (numbering from the carboxyl group). When a molecule of oxygen is inserted across carbons 9 and 11, ring closure occurs enzymatically across C8 and C12, creating the unstable PG endoperoxide PGG. Subsequent peroxidation yields PGH with formation of the cyclopentane ring. PGH serves as the common precursor for PGs, prostacyclin, and TXs that are formed under the influence of terminal synthases (see Fig. 21-4). In addition to the activity of phospholipases, regulation of PG synthesis also occurs at the level of PGHS gene expression. PGHS levels are increased by interleukin (IL)-1, platelet-derived growth factor, and epidermal growth factor, agents that increase PG synthesis. Cell membranes constitute the source of substrate AA and the site of action of eicosanoid-forming enzymes. PG synthesis also can form at lipid bodies, which are non– membrane-bound, lipid-rich cytoplasmic inclusions that develop in cells associated with inflammation. Lipid bodies isolated from human monocytes express PGHS activity, are reservoirs of arachidonyl phospholipids, and can function as domains of PG synthesis during an inflammatory reaction.6 PGHS, the well-known target of nonsteroidal antiinflammatory drugs (NSAIDs), exists in two isoforms. These isoforms are similar in terms of amino acid identities (about 60%), catalytic properties, and substrate specificity, but they differ in their genomic regulation.7

COX-1 is preferentially expressed constitutively at high levels in selected cells, including endothelium, monocytes, platelets, renal collecting tubules, and seminal vesicles. Because the expression level of the enzyme does not vary greatly, it has been difficult to study its transcriptional regulation. The gene has a TATA-less promoter that contains multiple start sites for transcription. It also is known that Sp1/Cis regulatory elements in the promoter bond the Sp1 transcription factor to induce COX-1 gene expression. In addition, COX-1 (COX-2) splice variants may function in tissue-specific normal and pathologic processes and may represent new targets for therapy.8 The localization of COX-1 in nearly all tissues under basal conditions suggests that its major function is to provide eicosanoids for physiologic regulation. This is seen clearly in platelets that do not have nuclei and cannot produce an inducible enzyme on activation. Rather, TXs are produced constitutively so that platelet aggregation can be completed. Regulation of Cyclooxygenase-2 Expression The regulated formation of eicosanoids implies that cells have an appreciable ability to amplify the rate and amount of eicosanoid synthesis. Several processes contribute to that regulation, including silencing of sPLA2 expression by COX-2 and autoinactivation (“suicide inactivation”) of COX-2 and other oxygenases and synthases. In addition, the COX-2 transcript contains at least 12 copies of the AUUUA RNA motif, which makes it unstable and subject to rapid degradation. Factors that regulate COX-2 expression are specific for the physiologic processes involved. Expression of COX-2 in the macula densa in the kidney depends on luminal salt concentrations. Transcriptional activation of the COX-2 gene by mediators of inflammation such as IL-1β and tumor necrosis factor (TNF)-α is likely regulated by the transcription factors nuclear factor κB (NFκB) and C/EBP. Perhaps the most crucial of the several demonstrated regulatory sequences in the 5′ flanking regions of the COX-2 gene is the ATF/CRE, a site that is activated by the transcriptional activator protein-1 (AP-1) and the cyclic adenosine monophosphate (cAMP) regulatory binding protein. Depending on cell and tissue specificity, several signaling pathways (kinases, Rho, cyclic guanosine monophosphate, wnt) and transcription factors (NFκB, AP-1, nuclear factor of activated T cells (NFAT)) are involved in COX-2 expression.9

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9

7

8

5

6

4

1 2 COOH

3

10 11

12

13

14

15

16

17

18

19

COOH

Arachidonic Acid

CH3

CH3 20

Cyclooxygenase +2 O2

Prostanoic Acid. The basic structure of a 20-carbon fatty acid, with C8-C12 closed to form a five-membered ring.

COOH

O

CH3

O O

O

Dioxygenase COOH O

CH3

PGG2

O OOH

Prostaglandin Endoperoxide Synthase

Prostacyclin COOH

O

COOH

Prostacyclin O

Synthase

OH

Thromboxane Synthase

OH COOH

COOH

Isomerase

CH3 O

CH3 OH

PGD2

OH

CH3

Isomerase Isomerase

O

OH

OH COOH

PGH2

CH3 O

O

OH

MDA

CH3 OH

HHT COOH

COOH

CH3

CH3

PGE2

O OH

Figure 21-4 

OH

O

O

TXA2

PGF2α

OH

OH

Cyclooxygenase pathway of arachidonic acid metabolism. PG, prostaglandins; MDA, malondialdehyde; TX, thromboxane.

COX-1 and COX-2 effect a balance in several physiologic and pathologic situations. Of particular interest are their actions in kidney and stomach. During times of low blood volume, the kidney releases angiotensin and other factors to maintain blood pressure by systemic vasoconstriction. Angiotensin also provokes PG synthesis in the kidney. COX-1, expressed in vessels, glomeruli, and collecting ducts, produces vasodilating PGs, which maintain renal plasma flow and glomerular filtration during conditions of systemic vasoconstriction. In the antrum of the stomach, COX-1 leads to production of PGs, which increase gastric blood flow and mucus secretion. Inhibition of COX-1 by NSAIDs prevents these protective mechanisms and results in renal ischemia and damage and gastric ulcers (mainly antral) in susceptible individuals. These observations have led to development of NSAIDs that selectively inhibit COX-2 and spare COX-1. AA gains access to the active site of the COX via a hydrophobic channel, and access is blocked by insertion of an acetyl residue on Ser 530 in COX-1 and Ser 516 in COX-2. The irreversibility of the interaction and the unique expression of COX-1 in the anucleate platelet is the reason for the clinical efficacy of low-dose aspirin. Nonacetylated NSAIDs compete with arachidonate for the active site and can interfere with the sustained effects

of aspirin. Although the structures of COX isozymes are similar, COX-2 is characterized by a side-pocket extension to the hydrophobic channel, which is where the selective COX-2 inhibitors localize.7 The major adverse effects of NSAIDs, gastroduodenal injury and impaired renal function, are caused by inhibition of COX-1, whereas the analgesic and anti-inflammatory activities of NSAIDs rest in part on their ability to inhibit COX-2. COX-2 also seems to have a regulating role, however, in renal, brain, gastrointestinal, ovarian, and bone function. COX-2 also is expressed in endothelial cells, and inhibition suppresses prostacyclin synthesis by endothelial cells.10 COX-2 acts in the initiation and the resolution of inflammation. Its expression increases transiently early in the course of carrageenan-induced pleurisy in rats. Later in the response, COX-2 is expressed at even higher levels, leading to synthesis of PGD2 and its dehydration product 15-deoxyδ12,14-PGJ2 (15δPGJ2). Early expression of COX-2 is associated with production of inflammatory PGs, whereas the later peak results in production of PGs that suppress inflammation.11 That inflammation occurs in COX-2 knockout mice12 reminds us, as Lewis Thomas stated,13 “inflammation will take place at any cost.”

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Cyclooxygenase-3 Acetaminophen, similar to NSAIDs, suppresses pain and fever. It is not an anti-inflammatory agent, and its mechanism of action—despite its extensive use—has not been apparent. The finding that acetaminophen inhibits COX activity more in canine brain homogenates than in spleen homogenates gave rise to the concept that variants of the COX enzyme exist that are differentially sensitive to acetaminophen. A distinct COX isoenzyme, COX-3, is made from the COX-1 gene (splice variant), is expressed in canine brain, and has been characterized in rat cerebral endothelial cells.14 In humans, COX-3 mRNA is expressed as an approximately 5.2-kb transcript most abundant in cerebral cortex and heart. COX-3 (COX-1b) possesses glycosylation-dependent COX activity that is selectively inhibited by analgesic or antipyretic drugs, such as acetaminophen and phenacetin. Prostaglandin Synthases Conversion of the endoperoxide intermediate PGH2 to PGs requires the activity of specific terminal synthases: Hematopoietic PGD synthase (H-PGDS) catalyzes the isomerization of PGH2 to PGD2 in immune and inflammatory cells, cytosolic PGE synthase (cPGES) is responsible for constitutive expression of PGE2, and microsomal PGE synthase (mPGES-1) induces PGE in response to inflammatory stimuli. At least 10 enzymes convert PG precursors into biologically active PGs.15 Suppression of PG synthase activity might be considered as an alternative strategy that would fall between global blockade by inhibition of COX and blockade of a single eicosanoid receptor.16

PRODUCTS OF THE CYCLOOXYGENASE PATHWAY PROSTAGLANDINS The basic structure of all PGs is a “prostanoic acid” skeleton, a 20-carbon fatty acid with a five-membered ring at C8 through C12 (see Fig. 21-4, inset). The term prostaglandins is employed widely, but should be used to describe only the oxygenation products that contain the five-membered carbon ring. A family of acidic lipids found first in human seminal fluid, PGs were misnamed because it was thought they were produced in the prostate gland rather than in the seminal vesicles.17-19 The alphabetic PG nomenclature (e.g., PGE, PGF, PGD) is related to the chemical architecture of the cyclopentane ring. PGE and PGF differ only in the presence of a ketone or hydroxyl function at C9 (see Fig. 21-4). These compounds are made by a variety of cells (e.g., PGE2 and PGD2 by isomerases, PGF2α by a reductase). In the nomenclature, a subscript numeral after the letters indicates the degree of unsaturation in the alkyl and carboxylic acid side chains. The numeral 1 indicates the presence of a double bond at C13-C14 (PGE1), 2 marks the presence of an additional double bond at C5-C6 (PGE2), and 3 denotes a third double bond at C17-C18 (PGE3). PGs are produced on demand and seem to exert their effects on the cell of origin or nearby structures. Abundant experimental evidence supports the view that PGs

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p­ articipate in development of the inflammatory response. Administration to rats of a monoclonal antibody to PGE2 prevents carrageenan-induced pain and inflammation.20 PGs are probably better at potentiating the effects of other mediators of inflammation than they are at inducing inflammation directly. PGE compounds and intermediate hydroperoxides of AA increase pain sensitivity to bradykinin and histamine. The effects of PGE are cumulative, depending on concentration and time. Even very small amounts of PGs, if allowed to persist at the site of injury, may in time cause pain. PGE2 stimulates bone resorption,21 and its 13,14-dihydro derivative is nearly as potent, which is of interest because derivatives of the biologically active PGs are usually assumed not to be of functional significance. Addition of serum to the culture medium stimulates bone resorption, a process that is complement dependent and PG mediated. The mechanism may help explain bone erosion in joints of patients with RA, in which complement is activated, and PGE2 concentrations are high. The observation that PGE1 can stimulate bone formation22 suggests that PGs physiologically participate in coordination of bone formation and resorption. Many effects of IL-1 and TNF-α on cells are associated with stimulation of PG production and inflammation. Cartilage explants from osteoarthritis patients express COX-2 (but not COX-1) and release 50 times more PGE2 in culture than cartilage from healthy subjects and 18 times more PGE2 than normal cartilage stimulated with cytokines plus lipopolysaccharide. Explants from osteoarthritis patients release IL-1β, whereas normal cartilage does not express mRNA for pro-IL-1β or release IL-1β spontaneously. It seems that in osteoarthritis—and probably in RA— upregulation of cartilage IL-1β and subsequent production of PGE2 leads to cartilage degradation.23 Mast cells, often overlooked as important in ­inflammatory responses, are seen in large numbers in synovium from patients early in the course of RA. PGD2, the major PG formed by mast cells, also can mediate histamine release from mast cells exposed to anti-IgE antibody. PGJ2, formed from the dehydration of PGD2, seems to function as a brake on the inflammatory response. It reduces macrophage activation, reduces nitric oxide production from stimulated cells, and induces apoptosis in tumor cell lines. PGJ2 is metabolized to 15-deoxy-δ12,14 PGJ2 and δ12 PGJ2, which also are biologically active.24 PROSTACYCLIN Prostacyclin, discovered in 1976,25 has been purified, and the cDNA for prostacyclin synthase has been cloned. In addition to a cyclopentane ring, a second ring is formed by an oxygen bridge between carbons 6 and 9. It is generated from PGH2 by a distinct prostacyclin synthase, a 56-kD member of the cytochrome P-450 superfamily of enzymes found predominantly in endothelial and vascular smooth muscle cells.15 Production of prostacyclin can be stimulated by thrombin or generated by transfer of PGH2 from platelets (the endoperoxide steal), contact with activated leukocytes, or stretching of the arterial wall. It is a powerful vasodilator and inhibits platelet aggregation through activation of adenylate cyclase, which leads to an increase in intracellular cAMP. It is metabolized rapidly (half-life in plasma is less

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than one circulation time) to the more stable, less biologically active 6-keto-PGF1α. The enzymatic products of its conversion—2,3-dinor-6 keto-PGF1α and 6,15-di-keto2,3-dinor PGF1α—also are chemically stable and have very little biologic activity. They are the major metabolites of prostacyclin excreted in urine, in which they can be assayed as indicators of prostacyclin generation. Prostacyclin generated in the vessel wall has antiplatelet and vasodilator actions, whereas TXA2 generated by platelets from the same precursors induces platelet aggregation and vasoconstriction. These two eicosanoids represent biologically opposite poles of a mechanism for regulating the interaction between platelets and the vessel wall and of formation of hemostatic plugs and intra-arterial thrombi. Given the central role of platelets in inflammatory reactions, an appropriate prostacyclin-TX balance is important to regulation of inflammation. The balance may be altered in patients with antiphospholipid antibody syndrome; in patients treated with cyclosporine; and in patients treated with NSAIDs, most especially patients treated with selective COX-2 inhibitors. Although COX-2 inhibitors reduce recurrence of colorectal adenomas, they increase the risk for cardiovascular events, such as myocardial infarction and stroke.26 Intravascular infusion of prostacyclin also reduces some of the clinical changes associated with pulmonary embolism. The instability of prostacyclin makes it cumbersome to administer therapeutically. Nonetheless, it has been used with limited success to treat peripheral vascular disease, including Raynaud’s phenomenon. New therapeutic approaches for treatment of pulmonary hypertension include prostacyclin analogues, such as epoprostenol, beraprost, and iloprost.27 In addition to its vasodilator effects, prostacyclin suppresses endothelial cell proliferation. Prostacyclin analogues might prove useful as adjunct treatment for some cancers. THROMBOXANES The endoperoxide PGH2 can be converted into TXs after the action of the enzyme TX synthase, a microsomal 60-kD member of the cytochrome P-450 family, which is quite active in the platelet. The gene that encodes the enzyme has been cloned. TXs contain a six-member oxane ring instead of the cyclopentane ring of the PGs. TX synthase converts PGH2 into equal amounts of TXA2 and 12Lhydroxy-5,8,10-heptadecatrienoic acid. TXA2 stimulates platelet activation, contributes to intravascular aggregation of platelets, and contracts arteriolar and bronchiolar smooth muscles. It is hydrolyzed rapidly (half-life is 30 seconds) to the inactive, stable, measurable product, TXB2; its actions are limited to the microenvironment of its release. The extraordinary rapidity with which platelets adhere to damaged tissue, aggregate, and release potent biologically active materials suggests that the platelet is well suited to be a cellular trigger for the inflammatory process. Efforts directed at suppression of TX synthesis and platelet aggregation may result in limitation of inflammatory responses, especially in coronary arteries. Inhibition of platelet aggregation may be important to the anti-inflammatory effects of aspirin and other NSAIDs. Long-term administration of low doses of aspirin (40 mg/day—the lowest dose predicted to

cause total inhibition of TX formation in serum, according to mathematic modeling) has inhibitory effects on platelet function ex vivo that are indistinguishable from the effects caused by giving 325 mg/day of aspirin.28 Nonetheless, the response to aspirin can vary among individuals. It has been suggested29 that serum TXB2 levels be monitored to ensure the efficacy of aspirin therapy. Even low-dose aspirin has some depressive effect on prostacyclin synthesis, however. This means recovery of vascular prostacyclin production may be more difficult to attain in elderly patients.30 Selective inhibition of TX synthase represents an approach that may be put into effect without depressing prostacyclin formation. The endoperoxide steal seems to function in vivo after administration of a TX synthase inhibitor. Antagonists of the receptors shared by endoperoxide and TXA2 have been developed, and these agents inhibit platelet aggregation in patients who are recalcitrant to TX synthase inhibition. More specific inhibition of TX action may become possible now that TX receptors have been cloned and characterized.31 LIPOXYGENASE PATHWAYS In contrast to the COX pathway, in which stable products have three atoms of oxygen covalently attached to AA from 2 moles of molecular oxygen, lipoxygenases insert a single oxygen atom into the molecular structure of AA. Separate lipoxygenases exist in certain cells and have strict structural requirements for their substrates. Three major mammalian lipoxygenases exist that insert their oxygen atoms into the 5, 12, or 15 position of AA, with formation of a new double bond and hydroperoxy group. The hydroperoxy fatty acids (hydroxyperoxy-eicosatetraenoic acid [HPETE]) can be reduced by peroxidases in the cell to yield the corresponding hydroxy fatty acids (hydroxy-eicosatetraenoic acid [HETE]). The exclusive lipoxygenase product of the human platelet is 12-HPETE, which on reduction of the hydroperoxy group yields 12-HETE. In contrast, the human neutrophil makes predominantly 5-HPETE, but when high concentrations of AA are added, 15-lipoxygenase can be shown. Lipoxygenases that act on AA are found in the cytosol fraction of cells. The human 5-lipoxygenase gene has been isolated and characterized32,33 and produces a 78-kD enzyme. In myeloid cells, the 5-lipoxygenase pathway leads to formation of the biologically active LTs (Fig. 21-5) that were originally found in leukocytes and that contain three conjugated double bonds (trienes). Cell activation leads to translocation of 5-lipoxygenase from cytosol to the nuclear membrane, where it encounters the 18-kD, 5-lipoxygenase-activating protein. AA also is translocated to 5-lipoxygenase-­activating protein for presentation to 5-lipoxygenase. The ability of macrophages and dendritic cells to respond appropriately during innate immune responses is likely regulated by 5-lipoxygenase and 12-lipoxygenase.34 The unstable HPETE is the initial metabolite of each lipoxygenase pathway. HPETE is reduced to the more stable HETE or is converted by 5-lipoxygenase to LTA4. LTA4 can be converted to LTB4 (in neutrophils and macrophages) or conjugated with reduced glutathione to form LTC4 (in eosinophils, mast cells, endothelial cells, and macrophages). In contrast to lipoxygenase, which is mainly distributed in myeloid

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Arachidonic Acid

CH3

15-Lipoxygenase

12-Lipoxygenase

5-Lipoxygenase COOH

15-HPETE

12-HPETE

CH3

15-HETE

12-HETE

+O2 +H

5-HPETE

LTA4

COOH

OOH

CH3

5-HETE

OH

O

COOH

COOH

CH3

CH3

Glutathione S-Transferase

Epoxide Hydrolase

S-R

COOH

OH

OH

LTC,D,E

OH

CH3

COOH CH3

LTC4: R=

LTB4

γ Glutamyl Transpeptidase

Dipeptidase

LTD4: R= Peptidase

LTE4: R=

CH2CHCONHCH2COOH NHCOCH2CH2CHCOOH NH2 CH2CHCONHCH2COOH NH2

CH2CHCONHCH2COOH NH2

cells, LTA4 hydrolase (5,12-dihydroxy-eicosatetraenoic acid), a zinc-requiring enzyme that converts LTA4 to LTB4, is widely distributed. From the cDNA sequence, it was suggested that mRNA for LTA4 may have a short half-life, which could account for the properties of extremely rapid production and shutdown of LTB4 and other eicosanoid biosynthesis. LTA4 can be exported from the cell of origin and converted in other cells by LTA4 hydrolase to LTB4. This variation on the endoperoxide steal—perhaps better called transcellular metabolism—also applies to conversion of LTA4 to LTC4 by LTC4 synthase, a glutathione-S-transferase.35 Although human endothelial cells do not produce terminal products of the 5-lipoxygenase system, they do generate LTC4 from LTA4 provided by neutrophils. LTC4 and its products, LTD4 and LTE4, constitute the biologic mixture previously known as slow-reacting substance of anaphylaxis. LTD4 and LTE4 arise from LTC4 after sequential removal of γ-glutamic acid and

Figure 21-5  5-Lipoxygenase pathway of arachidonic acid metabolism. LT, leukotriene; HETE, hydroxy-eicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid.

glycine from LTC4. The enzyme γ-glutamyl transpeptidase is present in many cells as part of a complex enzymatic system involved in glutathione biosynthesis and amino acid transport. In many systems, the major sulfidopeptide LT has been reported to be LTD4, rather than the precursor LTC4. Removal of glycine from LTD4 results in LTE4 with concomitant loss of a significant amount of biologic activity. The principal route of inactivation of LTB4 is by omega oxidation. PRODUCTS OF THE LIPOXYGENASE PATHWAYS The biologic effects of compounds produced in the lipoxygenase pathway indicate their importance in inflammatory ­diseases.36 They are the major mediators of inflammation formed by the oxygenation of AA and are implicated as key mediators in several diseases, including inflammatory bowel disease, psoriasis, bronchial asthma, and RA.

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5-HETE and 5-HPETE stimulate the generation of superoxide in human neutrophils. These compounds also augment intracellular calcium levels, facilitating PKC-dependent activation of a superoxide generating system of neutrophils. LTB4 increases adherence of leukocytes to endothelial cells, a response that is augmented by exposure of the endothelial cells to TNF-α. LTB4 does not seem to have a direct vascular contractile action because it is inactive in the hamster cheek pouch preparation and several other microvasculature systems. In rabbit skin, administration of LTB4 with a vasodilator PG induces plasma exudation, which suggests that LTB4 may facilitate enhanced vascular permeability. Increased venule permeability does occur in response to LTC4, LTD4, and LTE4. LTB4 is a potent chemotactic factor for neutrophils and is weakly chemotactic for eosinophils. LTB4, and to a lesser extent 5-HETE, enhance migration of T lymphocytes in vitro. Synovial cells produce 5-HETE, but do not seem to produce significant amounts of LTB4. Macrophages that invade the synovium in RA patients generate substantial quantities of 5-lipoxygenation and 15-lipoxygenation products, however, including LTB4. In addition to the local signs of inflammation induced by products of the lipoxygenase pathway, these compounds may contribute to the pain, tenderness, and aching common in RA patients. LTB4 also seems to serve an immunoregulatory function. It stimulates differentiation of competent CD8+ T lymphocytes from precursors lacking the CD8 marker. LTB4 also stimulates interferon-γ and IL-2 production by T cells and biosynthesis of IL-1 by monocytes.37 Synovial cell proliferation and endothelial cell proliferation are central to propagation of the rheumatoid joint lesion. LTB4 and the cysteinyl LTs act as growth or differentiation factors for numerous cell types in vitro. These compounds also increase proliferation of fibroblasts when PG synthesis is inhibited,38 findings that emphasize the importance of interactions between the COX and lipoxygenase pathways, and that suggest limitations to NSAID therapy for RA patients. Strategies for inhibiting production or antagonizing the actions of LTs include development of selective LT receptor antagonists and inhibition of the production of LT by blocking the action of 5-lipoxygenase. Inhibition of enzymes distal in the LT cascade, such as LTA4 hydrolase,39 also is a promising strategy for development of anti-inflammatory drugs. A compound that inhibits binding of 5-lipoxygenase to 5-lipoxygenase-activating protein exhibits anti-inflammatory effects in animal models. Lipoxygenase inhibitors have not been useful for treatment of RA patients. New compounds, mainly resulting from natural products chemistry, seem more promising.40 In addition, the existing agents may be aiming at the wrong target. Fibroblasts—such as synovial cells—do not make much LTB4, but they do make 12-HETE, which is a growth factor, through a cytochrome P-450 pathway.41 Cytochrome P-450 inhibitors may be more to the therapeutic point. Some inhibitors are more active when activated by exposure to light.42 These inhibitors might prove useful as topical agents for treatment of inflammatory skin disease. Lipoxygenase activities do not lead solely to production of mediators of inflammation. DGLA is converted by 15-lipoxygenase into 15-HETE, which is incorporated into DAG and exerts anti-inflammatory effects partly by

interfering with PKC-β activity. A lipoxygenase product of ­linoleic acid, 13-hydroxyoctadecadienoic acid, also suppresses inflammation and cell proliferation by means of a similar mechanism.43 EPA is converted by lipoxygenase into 15-hydroxyeicosapentaenoic acid, which also exhibits anti-inflammatory properties.44 LIPOXINS Another large family of AA metabolites arises from the sequential action of 5-lipoxygenases and 15-lipoxygenases. Addition of 15-HPETE and 15-HETE to human leukocytes results in formation of a pair of oxygenated products containing a unique conjugated tetraene. One compound (lipoxin A4 [LXA4]) was identified as 5,6,15L-trihydroxy-7,9,11,13-eicosatetraenoic acid, and the other proved to be its positional isomer (lipoxin B4 [LXB4]), 5D-14,15-trihydroxy-6,8,10,12-eicosatetraenoic acid (Fig. 21-6). Because both of these compounds can arise through an interaction between lipoxygenase pathways, the trivial name lipoxins (i.e., lipoxygenase interaction products) was introduced. Platelet 12-lipoxygenase can transform neutrophil LTA4 to lipoxins. The complete stereochemistry and multiple routes of biosynthesis for the biologically active LXA4 and LXB4 have been ­determined.45 That macrophages of rainbow trout generate ­ lipoxins rather than LTs or PGs as their major products of AA metabolism indicates that lipoxins have a long evolutionary history. LTs and lipoxins can be generated in parallel in fish. In humans, the process has diverged to a two-cell system. Biosynthesis of eicosanoids by transcellular and cell-cell interactions is recognized as an important way to generate and amplify lipid-derived mediators. Lipoxins can be generated within the vascular lumen during platelet-leukocyte interactions and at mucosal surfaces via leukocyte–epithelial cell interactions. In humans, lipoxins are formed in vivo during multicellular responses, such as inflammation, atherosclerosis, and in asthma. These tetraene-containing products serve as stop signals in that they prevent leukocyte-mediated tissue injury. A major problem in joints of patients with RA is that inflammation usually does not resolve. Lipoxins and aspirin-induced 15-epilipoxins are endogenous components of events governing resolution of inflammation. Aspirin acetylation of COX-2 in endothelial cells suppresses PG synthesis, but leads to generation of 15RHETE from AA, which is transformed to 15-epilipoxin by leukocytes in a transcellular biosynthetic route involving vascular endothelial cells or epithelial cells. These 15-epilipoxins exhibit anti-inflammatory and antiproliferative actions in vitro and in vivo. Stable analogues of LXA4 and of aspirin-triggered lipoxin also suppress inflammation in animal models.46 These observations may lead to the development of new anti-inflammatory drugs. Induction by interferon of particular genes seems ­important to the pathogenesis of systemic lupus erythematosus. A stable synthetic analogue of LXA4 suppresses several interferon-induced genes and reduces kidney damage in a murine model of immune-mediated nephritis.47 Lipoxins block human polymorphonuclear ­leukocyte chemotaxis, but stimulate monocyte chemotaxis and ­adherence.

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Arachidonic Acid

15-Lipoxygenase

COOH CH3 OOH 5-Lipoxygenase

COOH CH3 O2

OH

OOH CH3 OH

COOH CH3

OH

HO

OH

OH

COOH OH CH3

COOH CH3 OH

Lipoxin A4

351

ISOEICOSANOIDS Isoeicosanoids, isomers of enzymatically derived ­eicosanoids, are derived from auto-oxidation of polyunsaturated fatty acids, including omega-3 fatty acids.48 They include members of the F, D, and E isoprostanes, isothromboxanes, and isoleukotrienes. Analysis of the isoprostanes indicates that they reflect lipid peroxidation in vivo. Theoretically, 64 F-type isoprostanes may be formed, although few have been characterized. As more isoprostanes are identified, the nomenclature probably will continue to change. One F-type isoprostane, isoprostane F2α III (formerly 8-isoprostaglandin F2α) has been studied in detail because of its biologic activity in vitro. Isoprostane F2α III (Fig. 21-7) is a potent vasoconstrictor and may function as a mitogen, with actions that are blocked by TX receptor antagonists. Although isoprostanes may act as ligands at TX or PG receptors (8,12-­ isoprostane F2α III activates the PGF2α receptor), they also may activate specific isoprostane receptors. Isoprostanes

COOH

O

EFFECTOR MECHANISMS IN AUTOIMMUNITY AND INFLAMMATION

OH

Lipoxin B4

Figure 21-6  Lipoxin biosynthesis. The lipoxins result from the ­sequential action of 15-lipoxygenase and 5-lipoxygenase on arachidonic acid.

Monocytes do not release mediators of ­ inflammation in response to lipoxins, however, and ­ lipoxins are converted rapidly by monocytes to inactive compounds. This selective effect on chemotaxis suggests that lipoxins can play a role in wound healing. LXA4 antagonizes LTD4-induced vasoconstriction in vivo and blocks binding of LTD4 to its receptors on mesangial cells. LXA4 suppresses LTB4-induced plasma leakage and leukocyte migration and blocks LTB4induced neutrophil inositol triphosphate generation and calcium mobilization, but not superoxide anion generation. Conversely, LXA4 activates PKC and is more potent in this regard than DAG and AA. LXA4 seems to be specific for the γ subspecies of PKC. These results indicate that lipoxins may regulate the actions of vasoconstrictor LTs and suggest that LXA4 may be an important modulator of intracellular signal transduction.

What all isoprostanes have in common, and what distinguishes them from the PGs, is the fact that the top (α) and the bottom (ω) side chains are always syn—that is, crowded together on the same face of the cyclopentane ring. The minimal requirement for generation of an isoprostane is a polyunsaturated fatty acid with three contiguous methyleneinterrupted double bonds, a requirement met by dozens of naturally occurring polyunsaturated fatty acids. Fatty acids formed from docosahexaenoic acid might be important markers for brain disorders. In contrast to conventional, enzymatically derived PGs that are formed intracellularly and released immediately, isoprostanes are formed in the cell membrane, cleaved by phospholipases, circulate in plasma, and are excreted in urine. They are increased in several diseases, including acute respiratory distress syndrome, in which polymorphonuclear leukocytes generate reactive oxygen species that damage pulmonary epithelium. The immune cells in inflamed tissues are exposed to reactive oxygen intermediates produced by neutrophils and other phagocytic cells. Oxidants also are generated as mediators in intracellular signaling pathways by cytokines such as IL-1β and TNF-α. Isoprostanes are likely to be proved to be important in inflammatory conditions, such as vasculitis and RA. Because isoprostanes are released preformed, their production is not blocked by NSAIDs, which suppress metabolism of free AA. It is possible that inflammation unresponsive to NSAIDs may yield to inhibition of isoprostanes. In keeping with the notion of eicosanoids as regulators, however, some isoprostanes suppress release of mediators of inflammation from macrophages.49 ENDOCANNABINOIDS Groups of naturally occurring members of the eicosanoid superfamily that can activate cannabinoid receptors and are derivatives of long-chain fatty acids have been referred to as endocannabinoids. One of the most important endocannabinoids is anandamide (from the Sanskrit word for “bliss”), the amide conjugate of AA and ethanolamine ­(arachidonoyl ethanolamide) (Fig. 21-8). Anandamide is

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COOH

Arachidonic Acid HO

HO

OH COOH

COOH

HO Figure 21-7  Isoprostane F2α structures. Jagged lines indicate that stereochemistry is uncertain.

OH

III

CONHCH2CH2OH Anandamide Figure 21-8  nolamide).

HO

Chemical structure of anandamide (arachidonoyl etha-

not stored in cells. Rather, it is synthesized rapidly in response to stimuli in the manner of PGs and LTs. Anandamides and other endocannabinoids, such as 2-arachidonylglycerol and virodamine, seem to modulate immune responses.50,51 Discovery of naturally occurring and synthetic analogues and metabolites of anandamide suggest that a family of such biologically active substances exists. The polyunsaturated amides dihomogammalinolenoyl (20:3 n-6) and adrenoyl (22:4 n-6) ethanolamides have been found in mammalian brain.52 It is likely that n-3 fatty acid ethanolamides also exist in mammalian tissues. That anandamide can enhance its own synthesis in macrophages suggests the presence of a rapid response to counter excessive inflammatory or immune responses. Anandamide is converted by COX-2 (but not by COX-1) into PGE2 or PGF2α ethanolamide directly, without going through free AA.52 These novel PGs (“prostamides”) are pharmacologically active.53 Because anandamide is a substrate for COX-2, inhibitors of COX-2 may reduce anandamide metabolism with a subsequent increase in concentration of the anandamide. A combination of anandamide with ibuprofen produced synergistic analgesia in rats.54 In addition, anandamide is metabolized by fatty acid amide hydrolase. Compounds that inhibit fatty acid amide hydrolase and maintain anandamide levels may be useful anti-inflammatory agents. A naturally occurring lipoamino acid, N-arachidonylglycine, is also a substrate for COX-2, giving rise to amino acid conjugates of the PGs.55

EICOSANOID RECEPTORS For many years, it was thought that the lipophilic ­eicosanoids—in contrast to the peptide molecules for which receptors were characterized routinely—simply “diffused” into cell membranes or were carried in by a binding protein. The isolation and cloning of eicosanoid receptors changed that thinking.56

IV

PROSTAGLANDIN RECEPTORS PGs exert most of their actions through G protein–­coupled receptors. They also bind to peroxisome proliferator­activated receptors (PPARs) in vitro, but it is not clear that PPARs mediate PG effects in vivo. Receptors for the COX products are designated P receptors, depending on the prostanoid that has most affinity for them. These receptors include the PGD receptor (DP); four subtypes of the PGE receptor (EP1 through EP4); the PGF receptor (FP); the PGI receptor (IP); and the TX receptor (TP). The IP, DP, EP2, and EP4 receptors mediate increases in cellular cAMP, whereas TP, FP, and EP1 receptors induce calcium mobilization. EP2, EP4, and IP regulate macrophage cytokine production in a similar manner. As might be expected, signaling through these receptors is more complicated. Although PGI2 analogues are ligands for IP and increase cAMP, high concentrations of PGI2 analogues activate phospholipase C and induce calcium mobilization. It does seem clear that modification of immune cell and surrounding cell functions by prostanoids during immune or inflammatory responses is influenced by the different repertoire of PG receptors expressed on these cells. Knowledge of the roles of the P receptors in physiologic and pathologic processes has been advanced by experiments with mice deficient in the receptors (knockout mice). As noted previously, PGE can suppress or induce bone formation. EP2 and EP4 knockout mice exhibit impaired osteoclastogenesis and inflammation-induced bone resorption. The receptor mediating PGE-induced bone formation is unknown. In animal models, acute inflammation and pain are completely absent in IP-deficient mice. The profile of PG formation changes as the inflammatory response evolves to a more chronic state, so other receptors are probably involved. It is unlikely that blockade of one receptor would block completely an inflammatory response. More encouraging is the fact that PGs participate in allodynia, a pain response to a usually nonpainful stimulus. Knowing the contribution of P receptors to allodynia might lead to better treatment of neuropathic pain and myofascial pain syndromes such as fibromyalgia. The availability of cloned P receptors should facilitate development of more effective receptor-active compounds. The PGI2 analogue iloprost is useful for treatment of

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peripheral vascular disease and pulmonary hypertension. Although iloprost binds to IP with high affinity, it also binds EP1 and EP3. It may be that targeting activation, blockade, or both of a single P receptor or a specific set of P receptors would provide advantages over compounds that work “upstream,” such as the COX-2 inhibitors or traditional NSAIDs. The implications for therapy derived from this new knowledge are clear and exciting, but prostanoid analogues with selective binding properties need to be developed. Some progress has been made, and it seems that deletion of P receptors, with the exception of EP4, is not associated with serious problems of fetal development or physiologic function in animals. LEUKOTRIENE RECEPTORS Less is known about the surface receptors for LTs. Receptors for LTB4 (LTB4 R-1 and LTB4 R-2) and for the cysteinyl LTs also exert their actions through transmembrane spanning G protein–coupled protein receptors.57 High-affinity LTB4 receptors transduce chemotaxis and adhesion responses, whereas low-affinity receptors are responsible for secretion of granule contents and superoxide generation. The receptor for cysteinyl LTs includes two subtypes—Lys LT1 and Cys LT2—that have been identified pharmacologically, although their molecular structures are unknown. Most actions of the cysteinyl LTs are mediated by Cys LT1. More than a dozen chemically distinct, specific, and selective antagonist drugs that block the binding of LT to Cys LT1 have been identified. Clinical use of these compounds has mainly been in the treatment of asthma. A 5-lipoxygenase-specific inhibitor reduced whole-blood LTB4 production, but did not suppress synovitis in a 4-week trial of RA patients.58 A challenge in designing “antireceptor therapy” is the genetic variation in G protein–coupled receptors that can be associated with disease.59 Adding to the complexity is the fact that variants may result in altered predisposition to disease, rather than manifestation of the disease. Each variant provides an opportunity to understand receptor function, such as recycling or desensitizartion, enhancing the potential for development of therapy. LIPOXIN RECEPTORS Lipoxins can act at their own specific receptors for LXA4 and LXB4, and LXA4 can interact with a subtype of LTD4 receptors. Lipoxins also can act at intracellular targets within their cell of origin or after uptake by another cell. The cDNA for the seven-transmembrane-spanning, G protein–coupled LXA4 receptor named ALX has been cloned and characterized. Its signaling involves a novel polyisoprenyl-phosphate pathway that regulates phospholipase D.60 Lipoxin actions are cell type–specific. The monocyte and neutrophil LXA4 receptors are identical at the cDNA level, but they evoke different responses, and the LXA4 receptor on endothelial cells seems to be a structurally distinct form.

EFFECTOR MECHANISMS IN AUTOIMMUNITY AND INFLAMMATION

repression. PPARs were first cloned as nuclear ­receptors that mediate the effects on gene transcription of synthetic compounds called peroxisome proliferators. Interest in PPARs increased dramatically when they were shown to be activated by medically relevant compounds, including NSAIDs and PGD2 and its metabolite 15-deoxy-δ12,14 PGJ2.61 Most information available on a potential role of PPARs in inflammation relates to PPARγ. Upregulation of PPARγ reduces expression of several mediators of inflammation, raising the possibility that PPARγ ligands may be therapeutic for diseases characterized by inflammation. The metabolite 15-deoxy-δ12,14 PGJ2 also can exhibit anti-inflammatory activity in a PPARγ-independent manner, however. PPARα is expressed mainly in tissues that have a high fatty acid catabolism, including liver and the immune system. LTB4 is an activator and natural ligand of PPARα.62 Activation of PPARα results in induction of genes involved in fatty acid oxidation pathways that degrade fatty acids and derivatives, including LTB4. A feedback mechanism is established that controls inflammation. Experiments with PPAR knockout (−/−) mice indicate that PPARα suppresses LTB4-induced inflammation. PPARs are being considered as therapeutic targets for a wide range of immune-mediated diseases characterized by chronic inflammation.63

Platelet-Activating Factor PAF, 1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine, is a potent mediator of inflammation that causes neutrophil activation, increased vascular permeability, vasodilation, and bronchoconstriction in addition to platelet activation. PAF is formed by a smaller number of cell types than the eicosanoids—mainly leukocytes, platelets, and endothelial cells. Because of the extensive distribution of these cells, however, the actions of PAF can manifest in virtually every organ system. In contrast to the two long-chain acyl groups present in phosphatidylcholine, PAF contains a long-chain alkyl group joined to the glycerol backbone in an ether linkage at position 1 and an acetyl group at position 2 (Fig. 21-9). PAF represents a family of phospholipids because the alkyl group at position 1 can vary in length from 12 to 18 carbons. PAF, similar to the eicosanoids, is not stored in cells. Rather, it is synthesized when cells are stimulated, at which time the composition of the alkyl group may change. The immediate effects of PAF seem to be mediated through cell surface G protein–coupled receptors, whereas long-term responses depend on intracellular—probably nuclear—receptor ­activation.64 Despite the potent inflammatory effects of PAF, its ­inhibition in animal models does not lead to marked suppression of inflammatory responses. Plasma PAF acetylhydrolase, an enzyme that hydrolyzes PAF, may be a particularly

O CH2

C

CH2 O

O(CH2)xCH3 O

CH CH2

Nuclear Receptors PPARs are members of the nuclear receptor family of transcription factors, a large and diverse group of proteins that mediate ligand-dependent transcriptional activation and

353

O

P

O

CH2

CH2

N+(CH3)3

O Figure 21-9 

Chemical structure of platelet-activating factor.

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Prostaglandins, Leukotrienes, and Related Compounds

i­mportant terminator of PAF-induced tissue injury and may find a place among strategies designed to suppress ­inflammation.65 In addition, PAF production is suppressed by adenosine,66 which may account for some of the therapeutic efficacy of methotrexate. Given the involvement of PAF in immediate-hypersensitivity reactions and inflammation, further search for PAF antagonists is warranted.

Eicosanoids as Regulators of Inflammation and Immune Responses The role of PGs in the inflammatory process is not as well defined as previously supposed because the stable PGs PGE and PGI2 have anti-inflammatory and inflammatory effects.67 PGJ and lipoxins seem to act as brakes to protect against runaway inflammatory responses. Even LTB4 seems capable of modulating inflammation and immune responses.37 The observation that PGE1 inhibits platelet aggregation led to the notion that COX products of AA metabolism might have anti-inflammatory activity. As it becomes clearer that NSAIDs have anti-inflammatory effects other than interference with COX production and subsequent PG ­inhibition, the potential protective effects of PGs are being ­considered. PGE1 has remained an orphan among the eicosanoids, mainly because of a long-held notion that not enough of it is made by human cells to be of use, and that its biologic effects are no different from the effects of PGE2 and PGI2. Contrary to popular belief, PGE1 is found in physiologically important amounts in humans. Lost in the vast literature on the “AA cascade” are the early observations of Bygdeman and ­Samuelsson,68 who found (using bioassay) the concentration of PGE1 in human seminal plasma (16 μg/mL) to be higher than PGE2 (13 μg/mL), PGE3 (3 μg/mL), PGF1α (2 μg/mL), and PGF2α (12 μg/mL). Karim and associates69 found PGE1 to be the sole PGE in the human thymus. PG immunoassays usually do not distinguish between PGE1 and PGE2. To identify PGE1, it must first be separated from PGE2 by thin-layer or high-performance liquid chromatography. When such methods have been used, PGE1 has been identified consistently in platelets, leukocytes, macrophages, vas deferens, oviducts, uterus, heart, and skin.70 Evidence from in vitro and in vivo experiments indicates that PGs, notably PGE compounds, can suppress diverse effector systems of inflammation. PGE can enhance and diminish cellular and humoral immune responses, observations that reinforce a view of these compounds as regulators of cell function. These actions of eicosanoids depend on the stimulus to inflammation, the predominant eicosanoid produced at a particular time in the host response, and the profile of eicosanoid-receptor expression.71,72 As noted,11,45,47,48,60 PGJ, lipoxins, and epilipoxins facilitate resolution of inflammation. These compounds are referred to collectively as “resolvins.”

Modulation of Eicosanoid Synthesis by Administration of Precursor Fatty Acids The relationship between essential fatty acids and PGs was discovered simultaneously and independently by van Dorp and coworkers73 and Bergstrom and associates.74 Both groups reported that AA was converted to PGE2, and shortly

thereafter they showed that PGE1 is formed from DGLA.75 Attempts to modulate eicosanoid production have been directed at providing fatty acids other than AA as substrates for oxygenation enzymes in an effort to generate a unique eicosanoid profile with immunosuppressive and anti-inflammatory effects.44,76 The fatty acids themselves, by virtue of their incorporation into signal-transduction elements, also have effects that are independent of eicosanoid effects on cells involved in inflammation and immune responses.77 Experiments directed at suppression of TX synthesis, enhancement of prostacyclin production, and inhibition of platelet aggregation have been done in an effort to limit inflammatory responses. EPA is not found in appreciable amounts in cells from individuals who eat a Western-style diet. Fish oil lipids, rich in EPA (20:5 n-3), inhibit formation of COX products (e.g., TXA2, PGE2) derived from AA, and the newly formed TXA3 has much less ability than TXA2 to constrict vessels and aggregate platelets. Production of PGI2 (prostacyclin) by endothelial cells is not reduced appreciably by increased EPA content, and the physiologic activity of newly synthesized PGI3 is added to that of PGI2. Administration of fish oil to humans leads to reduced production of LTB4 by means of 5-lipoxygenase in stimulated neutrophils and monocytes and induces EPA-derived LTB5, which is far less biologically active than LTB4. Fish oil also reduces production of IL-1β, TNF-α, and PAF by activated blood monocytes. Fish oil supplements in the treatment of RA for 6 to 12 months result in significant reductions in number of tender joints and time of morning stiffness compared with the same measures done at baseline. Fish oil treatment allowed patients to reduce or stop NSAID treatment.78 Human endothelial cells treated with aspirin in vitro convert EPA to anti-inflammatory lipoxins; these novel compounds also are found in inflammatory exudates from animals administered aspirin and fish oil.45 The other “alternative” eicosanoid precursor fatty acid, DGLA (20:3 n-6), also can be increased by administration of certain plant-seed oils, notably oils extracted from the seeds of Oenothera biennis (evening primrose) and Boragio officinalis (borage), which contain relatively large amounts of γ-linolenic acid (GLA). GLA is converted to DGLA, the immediate precursor of PGE1, an eicosanoid with known anti-inflammatory and immunoregulating properties. Administration of GLA to volunteers and RA patients results in increased production of PGE1 and reduced production of the inflammatory eicosanoids PGE2, LTB4, and LTC4 by stimulated peripheral blood monocytes. In addition to competing with AA for oxidative enzymes, DGLA cannot be converted to inflammatory LTs. Rather, it is converted by means of 15-lipoxygenase to a 15-hydroxy-DGLA, which has the capacity to inhibit 5-lipoxygenase and 12-lipoxygenase activities. DGLA should have anti-inflammatory actions because of its capacity to reduce synthesis of oxygenation products of AA through the COX and the lipoxygenase pathways.79 In addition to their roles as precursors of eicosanoids, essential fatty acids are important for the maintenance of cell membrane structure and function and protect the gastric mucosa from NSAID-induced injury. DGLA can modulate immune responses in an eicosanoid-independent manner. DGLA suppresses IL-2 production by human peripheral blood monocytes in vitro, suppresses ­ proliferation of

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IL-2-dependent human peripheral blood and synovial tissue T lymphocytes, and reduces expression of activation markers on T lymphocytes directly in a manner that is independent of its conversion to eicosanoids. Oral administration of oils enriched in GLA, but not administration of oils enriched in linoleic acid (the parent n-6 fatty acid) or α-linolenic acid (the parent n-3 fatty acid) reduce proliferation of human lymphocytes activated through the T cell receptor ­complex.80 Addition to peripheral blood mononuclear cells in vitro or administration of GLA in vivo reduces secretion of IL-1β and TNF-α from stimulated human cells. GLA also reduces autoinduction of IL-1β in human monocytes, preserving the protective effects of IL-1β, while suppressing excessive production of the cytokine.81,82 IL-1β and TNF-α are important polypeptide mediators of inflammation and joint tissue injury in patients with RA, and both cytokines have become targets of therapy for patients with RA. GLA suppresses acute and chronic inflammation, including arthritis, in several animal models, and randomized, double-blind, placebo-controlled trials of GLA in patients with RA and active synovitis indicate that GLA treatment results in statistically significant and clinically relevant reduction in signs and symptoms of disease activity compared with baseline and placebo.83 In addition, treatment with GLA reduced the need for NSAID and corticosteroid therapy. EPA suppresses conversion of DGLA to AA, and a ­combination of EPA-enriched and GLA-enriched oils exhibits synergy in its capacity to reduce synovitis in animal models.84 A combination of GLA and EPA may be useful therapy for RA patients. Continued study of the eicosanoids and their precursor fatty acids should delineate mechanisms by which these lipids influence the function of cells that participate in immune responses and inflammatory reactions. REFERENCES   1. Brash AR: Specific lipoxygenase attack on arachidonic acid and ­linoleate esterified in phosphatidylcholine: Precedent for an ­alternative mechanism in activation of eicosanoid biosynthesis. Adv ­Prostaglandin Thromboxane Leukot Res 15:197, 1985.   2. Zalewski A, Nelson JJ, Hegg L, et al: LpPLA2: A new kid on the block. Clin Chem 529:1645, 2006.   3. Farooqui AA, Horrocks LA: Signaling and interplay mediated by phospholipases A2, C, and D in LA-n-1 cell nuclei. Reprod Nutr Dev 45:613, 2005.   4. Hasham SN, Pillarisetti S: Vascular lipases, inflammation, and ­atherosclerosis. Clin Chim Acta 372:179, 2006.   5. Bomalaski JS, Clark MA, Zurier RB: Enhanced phospholipase ­activity in peripheral blood monocytes from patients with rheumatoid ­arthritis. Arthritis Rheum 29:312, 1986.   6. Bozza PT, Yu W, Penrose JF, et al: Eosinophil lipid bodies: Specific, inducible intracellular sites for enhanced eicosanoid formation. J Exp Med 186:909, 1997. 7. Smith WL, DeWitt DL, Garavito RM: Cyclooxygenases: Structural, cellular, and molecular biology. Annu Rev Biochem 69:145, 2000.   8. Roos KL, Simmons DL: Cyclooxygenase variants: The role of ­alternative splicing. Biochem Biophys Res Commun 338:62, 2005.   9. Telliez A, Furman C, Pommery N, Henichart J-P. Mechanisms ­leading to COX-2 expression and COX-2 induced tumorigenesis: ­ Topical ­therapeutic strategies targeting COX-2 expression and activity. ­Anticancer Agents Med Chem 6:187, 2006. 10. Debey S, Meyer-Kirchrath J, Schror K: Regulation of cyclooxygenase-2 expression in iloprost in human vascular smooth muscle cells: Role of transcription factors CREB and ICER. Biochem Pharmacol 65:979, 2003.

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41. Nieves D, Moreno JJ: Hydroxyeicosatetraenoic acids released through cytochrome P450 pathway regulate 3T6 fibroblast growth. J Lipid Res 47:2681-2689, 2006. 42. Herre S, Schadendorf T, Ivanov T, et al: Photoactivation of the 12/15 lipoxygenase pathway. Chembiochemistry 7:1089, 2006. 43. Mani I, Iversen L, Ziboh VA: Upregulation of nuclear PKC and MAPkinase during hyperproliferation of guinea pig epidermis: Modulation by 13-(s) hydroxyoctadecadienoic acid (13-HODE). Cell Signal 10:143, 1998. 44. Calder PC: Polyunsaturated fatty acids and inflammation. Prostaglandins Leukotr Fatty Acids 75:197, 2006. 45. Serhan CN, Cish CB, Brannon J, et al: Anti-microinflammatory lipid signals generated from dietary N-3 fatty acids via cyclooxygease-2 and transcellular processing: A novel mechanism for NSAID and N-3 PUFA therapeutic actions. J Physiol Pharmacol 51:643, 2000. 46. Chiang N, Serhan CN: Cell-cell interaction in the transcellular ­biosynthesis of novel omega-3 derived lipid mediators. Methods Mol Biol 341:227, 2006. 47. Ohse T, Ota T, Godson C, et al: Modulation of interferon induced genes by lipoxin analogue in anti-glomerular basement membrane nephritis. J Am Soc Nephrol 15:919, 2004. 48. Lawson JA, Kim S, Powell WS, et al: Oxidized derivatives of omega-3 fatty acids: Identification of IPF3alpha-VI in human urine. J Lipid Res 47:2515-2524, 2006. 49. Milne G, Morrow JD: Isoprostanes and related compounds: Update 2006. Antioxid Redox Signal 8:1379, 2006. 50. Burstein S: The cannabinoid acids: Nonpsychoactive derivatives with therapeutic potential. Pharmacol Ther 82:87, 1999. 51. Rockwell CE, Snider NT, Thompson JT, et al: Interleukin-2 ­suppression by 2-arachidonylglycerol is mediated through peroxisome proliferator activated receptor gamma independently of cannabinoid receptorrs 1 and 2. Mol Pharmacol 70:101, 2006. 52. Burstein SH, Rossetti RG, Yagen B, et al: Oxidative metabolism of anandamide. Prostaglandins Other Lipid Mediat 61:29, 2000. 53. Ross RA, Craib SJ, Stevenson LA, et al: Pharmacological characterization of the anandamide cyclooxygenase metabolite: Prostaglandin E2 ethanolamide. J Pharmacol Exp Ther 301:900, 2002. 54. Guindon J, DeLean A, Beaulieu P: Local interactions between ­anandamide, an endocannabinoid, and ibuprofen, a nonsteroidal antiinflammatory drug, in acute and inflammatory pain. Pain 21:85, 2006. 55. Kohno M, Hasegawa H, Inoue A, et al: Identification of N-arachidonylglycine as the endogenous ligand for the orphan G-protein-coupled receptor GPR18. Biochem Biophys Res Commun 347:827, 2006. 56. Hata AN, Breyer RM: Pharmacology and signaling of prostaglandin receptors: Multiple roles in inflammation and immune modulation. Pharmacol Ther 103:147, 2006. 57. Sharma JN, Mohammed LA: The role of leukotrienes in the pathophysiology of inflammatory disorders: Is there a case for revisiting leukotrienes as therapeutic targets? Inflammopharmacology 14:99, 2006. 58. Weinblatt ME, Kremer JM, Coblyn JS, et al: Zileuton, a 5-lipoxygenase inhibitor in rheumatoid arthritis. J Rheumatol 19:1537, 1992. 59. Thompson MD, Burnham WM, Cole DE: The G-protein coupled receptors: Pharmacogenetics and disease. Crit Rev Clin Lab Sci 42:311, 2005. 60. Chiang N, Serhan CN, Dahlen S-E, et al: The lipoxin receptor ALX: Potent ligand-specific and stereoselective actions in vivo. Pharmacol Rev 58:463, 2006. 61. Ricote M, Li AC, Willson TM, et al: The peroxisome-proliferatoractivated receptor-gamma is a negative regulator of macrophage activation. Nature 391:79, 1998. 62. Devchand PR, Keller H, Peters JM, et al: The PPARα-leukotriene B4 pathway to inflammation control. Nature 384:39, 1996. 63. Sundararajan S, Jiang Q, Heneka M, et al: PPARgamma as a therapeutic target in central nervous system diseases. Neurochem Int 49:136, 2006.

64. Zhu T, Gobeil F, Vazquez-Tello A, et al: Intracrine signalling through lipid mediators and their cognate nuclear G-protein coupled receptors: A paradigm based on PGE2, PAF, and LPA1 receptors. Can J Physiol Pharmacol 84:377, 2006. 65. Zimmerman GA, McIntyre TM, Prescott SM, et al: The platelet activating factor signaling system and its regulators in syndromes of inflammation and thrombosis. Crit Care Med 30(Suppl 5):S294, 2002. 66. Flamand N, Lefebvre J, Lapointe G, et al: Inhibition of platelet activating factor biosynthesis by adenosine and histamine in human neutrophils: Involvement of cPLA2alpha and reversal by lysoPAF. J Leukoc Biol 79:1043, 2006. 67. Zurier RB: Prostaglandins, fatty acids, and arthritis. In CumminghamRundles S (ed): Nutrient Modulation of the Immune Response. New York, ­Marcel Dekker, 1993, p 201. 68. Bygdeman M, Samuelsson B: Quantitative determination of ­prostaglandins in human semen. Clin Chim Acta 10:566, 1964. 69. Karim SMM, Soindler M, Williams ED: Distribution of prostaglandins in human tissues. Br J Pharmacol Chemother 31:340, 1967. 70. Horrobin DF: The roles of essential fatty acids in the development of diabetic neuropathy and other complications of diabetes mellitus. Prostaglandins Leukot Essent Fatty Acids 31:181, 1988. 71. Tilley SL, Coffman TM, Koller BH: Mixed messages: ­ Modulation of inflammation and immune responses by prostaglandins and ­thromboxanes. J Clin Invest 108:15, 2001. 72. Brash AR: Arachidonic acid as a bioactive molecule. J Clin Invest 107:7700, 2001. 73. van Dorp DA, Beer Thuis RK, Nugteren DH: The biosynthesis of prostaglandins. Biochim Biophys Acta 90:204, 1964. 74. Bergstrom S, Daniellson H, Samuelsson B: The enzymatic formation of prostaglandin E2 from arachidonic acid. Biochim Biophys Acta 90:207, 1964. 75. Bergstrom S, Daniellson H, Klenberg D, et al: The enzymatic ­conversion of essential fatty acids into prostaglandins. J Biol Chem 239:4006, 1964. 76. Calder PC, Zurier RB: Polyunsaturated fatty acids and rheumatoid arthritis. Curr Opin Clin Nutr Metabol Care 4:115, 2001. 77. Vassilopoulos D, Zurier RB, Rossetti RG, et al: Gammalinolenic acid and dihomogammalinolenic acid suppress the CD3 mediated signal transduction pathway in human T cells. Clin Immunol Immunopathol 83:237, 1997. 78. Kremer JM: Effects of modulation of inflammatory and immune ­parameters in patients with rheumatic and inflammatory disease receiving dietary supplementation of n-3 and n-6 fatty acids. Lipids 31:S253, 1996. 79. DeLuca P, Rothman D, Zurier RB: Marine and botanical lipids as immunomodulatory and therapeutic agents in the treatment of ­rheumatoid arthritis. Rheum Dis Clin North Am 21:759, 1995. 80. Rossetti RG, Seiler CM, DeLuca P, et al: Oral administration of ­ unsaturated fatty acids: Effects on human peripheral blood T lympho­cyte proliferation. J Leukoc Biol 62:438, 1997. 81. Furse RK, Rossetti RG, Zurier RB: Gamma linolenic acid, an ­unsaturated fatty acid with antiinflammatory properties, blocks ­amplification of IL-1β production by human monocytes. J Immunol 167:490, 2001. 82. Furse RK, Rossetti RG, Seiler CM, et al: Oral administration of ­gamma linolenic acid, an unsaturated fatty acid with antiinflammatory properties, modulates interleukin-1β production by human monocytes. J Clin Immunol 22:83, 2002. 83. Zurier RB, Rossetti RG, Jacobson EW, et al: Gamma linolenic acid treatment of rheumatoid arthritis: A randomized, placebo-controlled trial. Arthritis Rheum 39:1808, 1996. 84. Tate G, Mandell BF, Karmali RA, et al: Suppression of monosodium urate induced inflammation by diets enriched with gamma-linolenic acid and eicosapentaenoic acid. Arthritis Rheum 31:1543, 1988.

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Cell Recruitment and Angiogenesis ZoltÁn Szekanecz  • Alisa E. Koch

KEY POINTS Leukocyte recruitment through the vessel wall into the synovium is a crucial process in the pathogenesis of arthritis. A number of cell adhesion molecules are involved in leukocyte extravasation. Chemokines and their receptors are involved in the chemotaxis of neutrophils, lymphocytes, and monocytes into tissues. Angiogenesis, the formation of new vessels, is involved in inflammation and tumor progression. A number of soluble and cell-bound factors, including chemokines and adhesion receptors, may stimulate or inhibit angiogenesis. Specific targeting of leukocyte adhesion, chemokines, or angiogenesis, primarily by the use of agents with multiple actions, may be useful for the future management of arthritis.

Many cell types, including inflammatory leukocytes, endothelial cells (ECs), and synovial fibroblasts, as well as soluble mediators and cell adhesion molecules (CAMs), are involved in cell trafficking into inflammatory sites in diseases such as rheumatoid arthritis (RA).1-6 In arthritis, leukocyte ingress into the synovium occurs by leukocyte adhesion to ECs and then by transendothelial migration (Fig. 22-1).2-4 The chemotaxis of these cells is regulated mainly by chemotactic mediators termed chemokines.7-10 The formation of blood vessels, termed angiogenesis, is a key event underlying tissue inflammation, which perpetuates the recruitment of leukocytes.8,11 Several CAMs interacting with soluble inflammatory mediators, such as cytokines and chemokines, are involved in leukocyte extravasation and angiogenesis.2,3,8,10,11 In this chapter, we use the example of inflammatory synovitis to describe the role of vascular ECs in the pathogenesis of rheumatic diseases. The role of CAMs and chemokines is also discussed, followed by a description of the two key processes: leukocyte recruitment and angiogenesis. Some aspects of the regulatory mechanisms and the clinical importance of adhesion and angiogenesis research are discussed as well.

MORPHOLOGY AND FUNCTION OF THE VASCULAR ENDOTHELIUM IN INFLAMMATION It is now clear that ECs are not just passive bystanders but are very active players in inflammation. The vascular endothelium undergoes morphologic changes, including vasodilation and increased permeability (leakage), during the evolution of ­ synovitis.5,6,12 Vasodilation itself may promote leakage. Increased endothelial permeability results from several

mechanisms, including EC contraction and retraction, leukocyte- or anti-EC antibody–mediated vascular injury, and EC regeneration.5,6,12 ECs secrete several mediators resulting in vasodilation, including prostacyclin, nitric oxide, and platelet-activating factor.12,13 Thrombin, histamine, and leukotriene C4 may support the synthesis of these vasodilators.5,6,13 The morphologic basis for increased vascular permeability and leakage is EC retraction and contraction, resulting in wider intercellular gaps.12 Several mediators, including histamine, serotonin, complement factors (C3a, C5a), bradykinin, leukotrienes, platelet-activating factor, and anti-EC antibodies, may promote vascular leakage.5,6,12,13 The gaps form as a result of EC contraction mediated by vasoactive agents.12 Cytoskeletal reorganization leading to EC retraction may be regulated by proinflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), or interferon-γ (IFN-γ). Treatment of cultured EC monolayers with any of these cytokines results in EC retraction and increased vascular permeability lasting for days.5,6,14 Thus, the mechanism of EC retraction, which is long term and is influenced by cytokines, is different from that of EC contraction, which occurs more rapidly and is rather histamine dependent. Further, whereas EC retraction is an example of EC stimulation, EC contraction is a result of EC activation.5,6,12,13 Among other soluble mediators, anti-EC antibodies have been detected in several autoimmune and inflammatory diseases, including RA, lupus, vasculitis, and others.5,6,15 Moreover, the production of anti-EC antibodies has been correlated with some markers of clinical activity in these disorders.15 Circulating anti-EC antibodies may be markers of vascular damage.5,6,15 Leukocyte-EC interactions (described later) may themselves trigger EC injury and thus vascular leakage. Briefly, the key mediators in this process are reactive oxygen intermediates and matrix metalloproteinases (MMPs) produced by inflammatory leukocytes.5,6 The outcome of leukocytemediated EC injury depends on activated leukocytes, because nonactivated neutrophils extravasate without affecting endothelial permeability.5,6 Vascular regeneration occurring after injury or during angiogenesis may also be associated with leakage.5,6,8,11,16 Endothelial regeneration may occur without the formation of new blood vessels, when regeneration is accompanied by increased capillary permeability.5,6

INTERCELLULAR ADHESION MOLECULES Adhesion of peripheral blood leukocytes to ECs leads to the process of leukocyte transendothelial migration into inflammatory sites1-4 (see Fig 22-1). For example, in arthritis, the 357

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Lymphocyte

Firm adhesion

Transendothelial migration

β1, β2, and β7 integrins

PECAM-1, β2 integrins; β1 and β7 integrins (?)

Chemokines (e.g., IL-8, MCP-1, MIP-1β) PAF PECAM-1 E-selectin

ICAM-1; ICAM-2 VCAM-1; MAdCAM-1

PECAM-1 ICAM-1 VCAM-1 (?)

Cytokines (e.g., GM-C5F-IL-8) Chemoattractants (e.g., C5a, FMLP) Chemokines (e.g., IL-8, MCP-1)

Cytokines (e.g., TNF-α, IL-1, IFN-γ, IL-4)

Chemokines Chemoattractants

Activation

Rolling SLex, CIA,and other Sialylated fucosylated structures L-selectin

Cytokine, chemokine, and chemoattractant receptors

Subendothelial migration β1 and β2 integrins; CD44

Endothelial P-selectin L-selectin Ligand E-selectin CD34 MadCAM-1

Tissue

Histamine Thrombin Oxidants LPS Leukotrienes Cytokines (e.g., IL-1, TNF-α)

Extracellular matrix Components Chemokines Chemoattractants

Figure 22-1  The process of leukocyte extravasation into the synovium.

cascade of events begins with the adhesion of neutrophils, lymphocytes, and monocytes to the specialized, fenestrated synovial ECs.2,3 Microvessels resembling high endothelial venules, found primarily in lymphoid organs and involved in the physiologic “homing” of lymphocytes, are also present in synovial tissue2 (see Fig. 22-1). Thus, inflammatory leukocyte recruitment to the synovium and to other tissues may be considered “pathologic homing.”1-4 EC adhesion to synovium-infiltrating leukocytes or to extracellular matrix components is mediated by adhesion receptors and their ligands. These CAMs have been classified into a number of distinct superfamilies, including integrins, selectins, immunoglobulins, cadherins, and others2-4,17,18 (Table 22-1). The selectin superfamily includes E-, P- and L-selectin. All selectins contain a lectin-like extracellular N-terminal domain, an epidermal growth factor (EGF)–like motif, and two to nine moieties related to complement regulatory proteins. E- and P-selectin are expressed by ECs, while L-selectin is expressed mainly by leukocytes.2-4,17-19 ­During leukocyte transendothelial migration, selectins mediate the initial tethering and rolling of leukocytes, which enable subsequent firm adhesion mediated mostly by integrins.4,18-20 E-selectin is a good marker for cytokine-induced EC activation.2,19 Ligands for E-selectin, such as E-selectin ligand-1 and P-selectin ligand-1, contain sialylated glycan motifs, such as sialyl Lewis-X..2,3,17,19 E-selectin has been associated with RA synovitis.2,3,17 There is abundant expression of E-selectin in RA synovial tissues and increased production of soluble E-selectin in RA synovial fluids.2-4 P-selectin is constitutively present on the membrane of EC Weibel-Palade bodies.2,19 Proinflammatory cytokines upregulate P-selectin expression on ECs within seconds. Thus, P-selectin is involved in the very early phases of leukocyte-EC adhesion.21 P-selectin is expressed by synovial ECs.2-4

L-selectin is absent from ECs but present on most leukocytes. L-selectin serves as a lymphocyte homing receptor, where it mediates the physiologic recirculation of naive lymphocytes through specialized high endothelial venules.17-19 In addition, L-selectin may be involved in leukocyte-EC interactions underlying arthritis.2,3 In the synovium, L-selectin is expressed by synovial lining cells and sublining leukocytes.2,3,22 Integrins are αß heterodimers and are classified into subfamilies with respect to their common ß subunits. Each of the common ß chains is associated with one or more a subunits.2-4,17 Each subunit contains a long extracellular domain, a transmembrane region, and a cytoplasmic domain. The last may be connected to the actin cytoskeleton and thus may trigger signal transduction events.17 Cell adhesion to the extracellular matrix is mediated mainly by ß1, while intercellular adhesion is facilitated through both ß1 and ß2 integrins binding to CAMs belonging to the immunoglobulin superfamily.4,17 Both ß1 and ß3 integrins are expressed on ECs.2,3,17 Integrin-mediated adhesion pathways have been implicated in leukocyte-EC interactions during inflammation. For example, ß1 and ß2 integrins are involved in animal models of arthritis.2,3,23 Abundant expression of EC integrins was described in human synovitis.2-4 Without going into detail, the α1, α2, α3, α4, α5, α6, αV, αL, αM, αX, ß1, ß2, ß3, ß4, ß5, and ß7 integrin subunits have been detected on various cells in the inflamed synovium.2-4 The immunoglobulin superfamily is a group of transmembrane glycoproteins containing one or more immunoglobulinlike motifs of 60 to 100 amino acids.17 Vascular cell adhesion molecule-1 (VCAM-1) is a member of this superfamily. VCAM-1 is constitutively expressed on resting ECs; however, its expression is strongly upregulated by proinflammatory cytokines.2,3,17 There is abundant VCAM-1 ­expression in the inflamed synovium.2-4,24 Soluble VCAM-1 has been detected in RA sera and synovial fluid samples.2,3,25

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Table 22-1  Relevant Members of the Selectin,   Integrin, Immunoglobulin, and Cadherin Adhesion   Molecule Superfamilies Adhesion Receptors

Ligands

Selectins L-selectin (CD62L, LAM-1) E-selectin (CD62E, ELAM-1) P-selectin (CD62P, PADGEM)

Sialylated carbohydrates,   GlyCAM-1 Sialyl-Lewis-X Sialyl-Lewis-X

Integrins α1β1 (VLA-1) α2β1 (VLA-2) α3β1 (VLA-3) α4β1 (VLA-4) α5β1 (VLA-5) α6β1 (VLA-6) αLβ2 (LFA-1, CD11a/CD18) αMβ2 (Mac-1, CD11b/CD18) αXβ2 (CD11c/CD18) αEβ7 α4β7

Laminin, collagen Laminin, collagen Laminin, collagen, fibronectin Fibronectin, VCAM-1 Fibronectin Laminin ICAM-1, ICAM-2, ICAM-3, JAM-A ICAM-2, iC3b iC3b, fibrinogen E-cadherin Fibronectin, VCAM-1, MadCAM-1

Immunoglobulins ICAM-1 (CD54) ICAM-2 ICAM-3 VCAM-1 MadCAM-1 CD2 PECAM-1 (CD31)

LFA-1, Mac-1 LFA-1 LFA-1 α4β1, α4β7 α4β7, L-selectin LFA-3 PECAM-1, αVβ3

Cadherins E-cadherin (cadherin-1) N-cadherin (cadherin-2) Cadherin-11

E-cadherin N-cadherin Cadherin-11

See text for abbreviations.

Intercelluar adhesion molecule-1 (ICAM-1) is a ligand for the ß2 integrins LFA-1 (αLß2), Mac-1 (αMß2), and αXß2.4,17,26 ICAM-1 expression on ECs can be induced by IL-1, TNF-α, and IFN-γ.12 The ICAM-1–ß2 integrin–dependent adhesion pathway is crucial in inflammation; patients with leukocyteadhesion deficiency syndrome who have mutations in the ß2 integrin subunit show minimal inflammatory response.27 ICAM-1 is highly expressed on ECs in inflammatory sites, such as in RA synovium.2-4,24 Again, high levels of soluble ICAM-1 have been detected in the synovia of RA patients.2,3 Other CAMs involved in leukocyte-EC adhesion underlying inflammation include LFA-3, CD44, vascular adhesion proteins (VAP-1 and VAP-2), endoglin, E-cadherin, N-cadherin, cadherin-11, junctional adhesion molecules (JAMs), platelet-endothelial cell adhesion molecule-1 (PECAM-1, CD31), CD99, and possibly ICAM-3.2-4,17,22,28-30 Both LFA-3 and its counterreceptor, CD2, are members of the immunoglobulin superfamily. LFA-3 is present on ECs, and the CD2–LFA-3 adhesion pathway is involved in T cell adhesion to ECs in various inflammatory responses.2,3,28 LFA-3 is present on synovial ECs and on lining and sublining cells.28 PECAM-1, another member of the immunoglobulin superfamily, mediates homotypic adhesion as well as heterotypic adhesion by recognizing the αVß3 integrin.2,3,17 PECAM-1 is a marker of activated ECs, and it is expressed in RA synovium.2,17 CD44 is a receptor for hyaluronate17 and is expressed on activated ECs in inflammatory sites.2,22 VAP-1

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was originally isolated from synovial ECs. The expression of VAP-1 is increased in RA.2,29 Endoglin is a receptor for transforming growth factor-ß (TGF-ß). Endoglin is involved in EC adhesion and is expressed in synovitis.2,3 Cadherins mediate homophilic, calcium-dependent adhesion.4,17 The cytoplasmic tail of cadherins interacts with ß-catenin, forming a link between the cadherin-catenin complex and the cytoskeleton. Cadherins are primarily involved in embryogenesis; however, E-cadherin, N-cadherin, and cadherin-11 are present in the inflamed synovium as well.4,17,31 JAM-1, JAM-2, and JAM-3, as well as CD99, have also been ­ implicated in leukocyte migration through endothelial junctions.5,6,30 ICAM-3 is a leukocyte CAM, which is a known ligand for LFA-1. It is absent from most types of ECs. However, it is present on some RA synovial ECs.2,26

CHEMOKINES AND CHEMOKINE RECEPTORS Chemokines are small proteins exerting chemotactic activity toward immune cells.7-9,32,33 Chemokines drive leukocytes to inflamed tissues.33 Chemokines have been classified into supergene families with respect to their structure.7-9,32 According to the location of cysteine (C) residues, these families are designated as CXC, CC, C, and CX3C chemokines, and the four respective chemokine receptor groups are CXCR, CCR, CR, and CX3CR7-9,32 (Table 22-2). More than 50 chemokines and 19 chemokine receptors have been identified.7-9,32 Some years ago, a new nomenclature was introduced whereby chemokines are considered ligands of chemokine receptors, and each chemokine has been designated CXCL, CCL, XCL or CX3CL1.9,32 Recently, chemokine–chemokine receptor pairs have also been categorized according to their function: some of them are primarily homeostatic (also called ­constitutive, housekeeping, or lymphoid), and others are inflammatory (or inducible), although these functions often overlap.9,33 Generally, all chemokines involved in the pathogenesis of arthritis can be considered inflammatory. Homeostatic chemokines generally play a role in physiologic ­lymphocyte recruitment and the development of lymphoid ­ tissues. However, some homeostatic chemokines have also been implicated in inflammation-associated B cell migration.9,33 Most CXC chemokines chemoattract neutrophils.34 However, platelet factor-4 (PF-4)/CXCL4 and IFN-γ-inducible 10-kD protein (IP-10)/CXCL10 recruit lymphocytes and monocytes.7,34 In addition, some CXC chemokines promote angiogenesis, while others inhibit it (discussed later).8 IL-8/ CXCL8, epithelial-neutrophil activating protein-78 (ENA78)/CXCL5, growth-regulated oncogene α (Groα)/CXCL1, connective tissue–activating peptide III (CTAP-III)/CXCL7, granulocyte chemotactic protein-2 (GCP-2)/CXCL6, IP-10/ CXCL10, PF-4/CXCL4, monokine induced by IFN-γ (Mig)/ CXCL9, stromal cell–derived factor-1 (SDF-1)/CXCL12, B cell–activating chemokine-1 (BCA-1)/CXCL13, and, recently, CXCL16 have been implicated in arthritis.7-9 These chemokines were detected in the synovial fluid or synovial tissue of RA patients.7-9 Thus, these chemokines may be considered inflammatory.7-9,33 CC chemokines stimulate monocyte chemotaxis, but some members of this subclass may also recruit lymphocytes.35

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Table 22-2  Chemokine Receptors and Their Most   Relevant Ligands Chemokine Receptor

Chemokine Ligand

CXC Chemokine Receptors CXCR1 CXCR2 CXCR3 CXCR4 CXCR5 CXCR6 CXCR7

IL-8/CXCL8 IL-8/CXCL8, ENA-78/CXCL5, Groα/ CXCL1, CTAP-III/CXCL7 IP-10/CXCL10, PF-4/CXCL4, Mig/ CXCL9, ITAC/CXCL11 SDF-1/CXCL12 BCA-1/CXCL13 CXCL16 SDF-1/CXCL12, ITAC/CXCL11

CC Chemokine Receptors CCR1 CCR2 CCR3 CCR4 CCR5 CCR6 CCR7 CCR8 CCR9 CCR10

MIP-1α/CCL3, RANTES/CCL5, MCP-3/CCL7, MPIF-1/CCL23 MCP-1/CCL2, MCP-3/CCL7 RANTES/CCL5, MCP-2/CCL8 TARC/CCL17, MDC/CCL22 MIP-1α/CCL3, MIP-1β/CCL4, RANTES/CCL5 MIP-3α/CCL20 MIP-3β/CCL19, SLC/CCL21 I-309/CCL1 TECK/CCL25 CTACK/CCL27, MEC/CCL28

C Chemokine Receptors XCR1

Lymphotactin/XCL1

CX3C Chemokine Receptors CX3CR1

Fractalkine/CX3CL1

Other DARC

Duffy antigen, some CC and CXC chemokines

chemokines implicated in synovitis, plays a crucial role in inflammation and angiogenesis. CXCR3 is a receptor for angiostatic CXC chemokines.7-9,39 Chemokine receptors have also been associated with various subtypes of inflammatory response. It has been suggested that CXCR3 and CCR5 are involved in T helper type 1 (Th1) diseases such as RA, whereas CCR3, CCR4, and CCR8 have been implicated in asthma-associated T helper type 2 (Th2) inflammation.7,33 Several CXC and CC chemokine receptors, as well as XCR1 and CX3CR1, are expressed in the arthritic synovium.7-9

PROCESS OF LEUKOCYTE RECRUITMENT Inflammatory leukocyte adhesion to ECs occurs in a sequence of well-regulated steps. An early, weak adhesion, termed “rolling,” occurs first; this event is mediated mainly by selectins and their ligands. This is followed by leukocyte activation, which is dependent on interactions between chemokine receptors expressed on leukocytes and proteoglycans on ECs. Activation-dependent, firm adhesion involves mostly α4ß1 integrin–VCAM-1, LFA-1–ICAM-1, and JAM-integrin interactions, as well as the secretion of numerous chemokines described earlier. Chemokines may also upregulate integrin expression via phosphatidylinositol 3-kinase (PI3K)–mediated pathways (discussed in more detail later). Transendothelial migration or diapedesis involving integrins occurs when chemokines bind to endothelial heparan sulfate. Chemokines preferentially attract EC-bound leukocytes1,18,20 (see Fig. 22-1).

See text for abbreviations.

ANGIOGENESIS: ROLE OF CHEMOKINES AND ADHESION RECEPTORS

Among these chemokines, monocyte chemoattractant protein-1 (MCP-1)/CCL2, macrophage inflammatory protein1a (MIP-1a)/CCL3, MIP-3a/CCL20, RANTES/CCL5, Epstein-Barr virus–induced gene 1 ligand chemokine (ELC)/ CCL19, SLC/CCL21 and, recently, chemokine-like factor1 (CKLF1) have been implicated in inflammatory mechanisms underlying synovitis.7-9 The C chemokine family contains two members: lymphotactin/XCL1 and single C motif 1ß (SCM-1ß)/XCL2.36 ­Lymphotactin/XCL1 has been detected on T cells in RA.7,8,36 The CX3C subset contains a single member: fractalkine/ CX3CL1.7,8,37 Fractalkine is a mononuclear cell chemoattractant, but is also serves as a CAM.7,8,37 This chemokine has been detected in RA synovial fluid and tissue samples.37 Fractalkine/CX3CL1 is also angiogenic.8 It has been implicated in the development of accelerated atherosclerosis,38 which is the primary cause of death in RA patients. There is a redundancy between the CXC and CC chemokine receptors and their ligands (see Table 22-2). For example, CXCR2, CCR1, and CCR3 have numerous chemokine ligands. In contrast, CXCR6, CCR8, and CCR9 are specific receptors for their respective single ligands.7-9 There may be a relationship between a certain chemokine receptor and the function of its ligand. Single-ligand receptors, such as CCR8 or CCR9, bind mostly to homeostatic chemokines. In contrast, CXCR2, a receptor for most CXC

Angiogenesis, the formation of new blood vessels, is pathologically enhanced in a number of inflammatory diseases, such as RA and psoriasis, as well as in malignancies.8,11 The outcome of such angiogenic diseases is dependent on the balance or imbalance between angiogenic mediators and angiostatic factors (Fig. 22-2). Several cytokines, growth factors, chemokines, certain CAMs, and other mediators can modulate neovascularization. Angiogenesis inhibition by blocking the action of angiogenic mediators, or by the administration of angiostatic compounds, may be useful for suppressing various inflammatory processes, such as arthritis8,11,40,41 (Table 22-3). Here, we focus on the role of chemokines and CAMs in angiogenesis, because they are crucial in leukocyte recruitment. Other angiogenic and angiostatic factors, such as growth factors, cytokines, proteases, and others, are included in Table 22-3. In general, the angiogenic or angiostatic action of chemokines depends on whether their structure contains the ELR amino acid motif or not.39 ELR-containing chemokines, such as IL-8/CXCL8, ENA-78/CXCL5, Groα/CXCL1, and CTAP-III/CXCL7, stimulate neovascularization. In contrast, the ELR-lacking PF-4/CXCL4, IP-10/CXCL10, and Mig/CXCL9 inhibit angiogenesis.8,9,39 However, an exception to the rule is SDF-1/CXCL12, which is angiogenic even though it lacks the ELR sequence.7-9,11 Among CXC chemokines, IL-8/CXCL8 is a major ­regulator of angiogenesis in RA.7-9,11,39 In addition, ENA-78/ CXCL5, CTAP-III/CXCL7, and Groα/CXCL1 also stimulate

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Angiogenic factors

Chemokines Adhesion molecules Matrix components Cytokines Growth factors Proteases Others

| 

EFFECTOR MECHANISMS IN AUTOIMMUNITY AND INFLAMMATION

Macrophage

Fibroblast

Lumen

Endothelium

361

Angiostatic factors

Chemokines Cytokines Matrix components Protease inhibitors DMARDs Anti-TNF agents Others

Lumen

Angiogenesis Figure 22-2  Imbalance between angiogenic and angiostatic factors in the inflamed synovium. DMARD, disease-modifying antirheumatic drug;  TNF, tumor necrosis factor.

­neovascularization in RA.7-9,11 All these chemokines have been detected in the blood or synovia of RA patients.7-9 SDF-1/CXCL12 is a specific ligand for CXCR4. SDF-1/ CXCL12, despite lacking the ELR motif, promotes neovascularization.8,42 This chemokine induces EC chemotaxis in vitro and angiogenesis in mice in vivo.42 Thus, SDF-1 may be the first angiogenic CXC chemokine that lacks the ELR motif. Circulating human CD34+ cells expressing the vascular endothelial growth factor-2 (VEGF-2) receptor have been identified and characterized as EC precursor cells.43 Virtually all CD34+/VEGF-2 receptor–positive cells express CXCR4 and migrate in response to SDF-1/ CXCL12.42,43 In contrast, IP-10/CXCL10 exerts proinflammatory but antiangiogenic effects in RA.7-9,11 However, a recent study suggests that the effect of VEGF on ECs may be mediated, in part, by IP-10/CXCL10.44 IP-10/CXCL10 inhibits VEGFinduced EC motility.45 Thus, VEGF and IP-10/CXCL10 may form an autocrine regulatory loop in angogenesis.44,45 The ELR-lacking Mig/CXCL9 and PF-4/CXCL4 are also angiostatic.8,11,39 All these chemokines have been implicated in the pathogenesis of RA.7-9,11 Among CXC chemokine receptors, CXCR2 recognizes the most important proinflammatory and proangiogenic CXC chemokines described earlier.7-9 CXCR2 is expressed in the RA synovium.7-9 The role of the SDF-1/CXCL12 receptor CXCR4 in neovascularization and the migration of EC progenitor cells has already been discussed.42,43 It is generally believed that SDF-1/CXCL12 has a single receptor, CXCR4; recently, however, CXCR7, an alternative receptor for this chemokine and for IFN-inducible T cell a chemoattractant (I-TAC)/CXCL11, has been implicated in angiogenesis.46 Because the angiostatic IP-10/CXCL10 and Mig/CXCL9 bind to CXCR3, this receptor may be involved in chemokine-mediated angiogenesis inhibition.8,11 There is little evidence of the role of CC chemokines in angiogenesis. MCP-1/CCL2 induces EC chemotaxis in vitro and angiogenesis in vivo.8,47 MCP-1/CCL2–induced

Table 22-3  Angiogenic and Angiostatic Factors   in Rheumatoid Arthritis Factor

Mediators

Inhibitors

Chemokines

IL-8/CXCL8, ENA-78/ CXCL5, Groα/CXCL1, CTAP-III/CXCL7,   SDF-1/CXCL12,   MCP-1/CCL2, SLC/ CCL21, MPIF/CCL23, fractalkine/CX3CL1

PF-4/CXCL4, IP-10/ CXCL10, Míg/ CXCL9, SLC/CCL21

Matrix   molecules

Type I collagen,   fibronectin, laminin, heparin, heparan sulfate

Thrombospondin, RGD sequence

Cell adhesion   molecules

β1 and β3 integrins,   E-selectin, P-selectin, CD34, VCAM-1,   endoglin, PECAM-1, VE-cadherin, Ley/H, MUC-18

RGD sequence   (integrin ligand)

Growth factors

VEGF, bFGF, aFGF,   PDGF, EGF, IGF-1,   HIF-1, TGF-β*

TGF-β*

Cytokines

TNF-α, IL-6*, IL-15, IL-18

IL-4, IL-6*, IFN-α, IFN-γ

Proteases

MMPs, plasminogen activators

TIMPs, plasminogen activator inhibitors

Others

Angiogenin,   substance P,   prolactin

DMARDs, infliximab, etanercept, angiostatin, endostatin

See text for abbreviations. *Mediators with both pro- and antiangiogenic effects.

neovascularization was associated with binding to its receptor, CCR2.8,47 MPIF-1/CCL23 has been implicated in the migration of vascular ECs and the angiogenesis-associated production of matrix metalloproteinases.48 With regard to angiogenesis-suppressing CC chemokines, secondary lymphoid tissue chemokine (SLC/CCL21) exerts strong angiostatic and antitumor effects.49

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Fractalkine/CX3CL1 is involved in neovascularization and the pathogenesis of atherosclerosis.8,37,38 Fractalkine/ CX3CL1 is abundantly produced in RA.37 DARC cannot be grouped into one of the four classic chemokine receptor subclasses (see Table 22-2). DARC binds the Duffy blood group antigen, as well as some CXC and CC chemokines. Recently, DARC has been detected in RA synovial ECs, and it is involved in tumor-associated angiogenesis.9,50 Extracellular matrix macromolecules and CAMs mediate adhesive interactions between ECs during ­neovascularization.11 Among extracellular matrix components, type I collagen, fibronectin, heparin, laminin, and tenascin promote angiogenesis.11,40 Some endothelial CAMs—including soluble E-selectin; soluble P-­selectin; the L-selectin ligand CD34; soluble VCAM-1; some endothelial ß1, ß3, and ß5 integrins; PECAM-1 (CD31); endoglin (CD105); and some cadherins—have been implicated in angiogenesis.8,11,51-55 Among glycoconjugates with adhesive properties, Ley/H promotes neovascularization.56 MUC-18 (CD146) has also been implicated in synovial angiogenesis.57 As described earlier, most of these extracellular matrix components and CAMs play an important role in cell adhesion and migration underlying synovial inflammation.1-4 There may be interactions between chemokines and CAMs during angiogenesis. For example, MCP-1/CCL2 acts via the upregulation of the Ets-1 transcription factor, and activation of Ets-1 also involves integrin-dependent adhesive mechanisms.47

REGULATION OF LEUKOCYTE-ENDOTHELIAL ADHESION AND ANGIOGENESIS Leukocyte-EC interactions depend on numerous factors (see Fig. 22-1). Physical factors, such as altered shear stress, stimulate the neutrophil adhesion to EC.21 The state of leukocyte activation is also important. For example, resting neutrophils readily adhere to E-selectin and VCAM-1 but not to ICAM-1, while activated neutrophils adhere to ICAM-1 as well.5,6,12 TNF-α, IL-1, and IFN-γ may upregulate EC CAM expression and stimulate leukocyte-EC interactions.5,6,12 As described earlier, chemokines may also act in concert with integrins.47 ECs themselves produce a number of inflammatory mediators.5,6 Certain CAMs can also cross-talk with each other: for example, E- and P-selectin stimulate the adhesive activity of ß2 integrins on neutrophils.58 The cross-talk between selectins and integrins is crucial for the transition from rolling to firm adhesion.18,20 Finally, intercellular contact itself may result in increased cytokine release and CAM expression.59 These mechanisms may synchronize the adhesive events described earlier, as well as the steps of neovascularization.

REGULATION OF CHEMOKINE PRODUCTION DURING LEUKOCYTE RECRUITMENT There is a temporal regulation of chemokine and chemokine receptor production in the inflamed synovium. We have assessed the temporal expression of CXC and CC chemokines in the sera and joint homogenates of rats with

adjuvant-induced arthritis (AIA). The production of ENA78/CXCL5 and MIP-1a/CCL3 was increased very early, before the appearance of clinical symptoms. In contrast, MCP-1/CCL2 was involved in the later phase of AIA.60 When we assessed the temporal regulation of chemokine receptors in rat AIA, CCR1 exhibited high constitutive expression on macrophages throughout the disease course, whereas CCR2 expression on ECs was downregulated during progression of the disease.61 Proinflammatory cytokines regulate chemokine production in the arthritic synovium.7-10 For example, TNF-α, IL-1, IL-6, IL-15, and IL-18 may enhance chemokine production, while others, such as IL-4, may suppress it.7-10 These data suggest that the Th1-Th2 balance or imbalance may influence the local chemokine pattern in the synovium.9,33 CD4+/CD28– T cells resemble a functionally enddifferentiated, nondividing, short-lived effector memory T cell subpopulation. These cells, when adoptively transferred into human RA synovium–SCID (severe combined immunodeficient) mouse chimeras, coexpressed the CCR5, CCR7, and CXCR4 chemokine receptors and migrated in response to RANTES/CCL5 and SDF-1/CXCL12.62 Toll-like receptors (TLRs) may also be involved in the regulation of chemokine function. TLR2 ligands activate synovial fibroblasts. Peptidoglycan, a TLR2 ligand, stimulates IL-8/ CXCL8, Groα/CXCL1, MCP-1/CCL2, MIP-1a/CCL3, and RANTES/CCL5 mRNA expression by these fibroblasts.63 There may be distinct histologic patterns of synovitis in RA, which may be associated with different chemokine profiles. There are at least two distinguishable histologic types: some synovial biopsy samples show diffuse lymphoid infiltrates, while others are classified as “follicular synovitis,” showing the formation of germinal center–like structures. Serum levels of IL-8/CXCL8, MCP-1/CCL2, and RANTES/CCL5 were significantly higher in the follicular type than in the diffuse histologic variant.64 The molecular mechanisms and signaling pathways of chemokine-induced CAM expression have recently been described. Briefly, an atypical protein kinase C, PKC- ξ, has been identified. Treatment of cells with chemokines induces PKC- ξ activity through its interaction with PI3K. This leads to increased cell surface integrin expression via additional signaling steps.1

INHIBITION OF CELL ADHESION, CHEMOKINES, AND ANGIOGENESIS: FUTURE PERSPECTIVES IN ANTIRHEUMATIC THERAPY The inhibition of cell adhesion and migration, angiogenesis, and chemokines with the use of specific antibodies or purified ligands has provided an important perspective on the molecular pathogenesis of RA. Some of these strategies may be included in the future therapy of arthritis.65 In anti-CAM trials, an anti–human ICAM-1 antibody (enlimomab) was used to treat refractory RA, and many patients reported improvement in their status. A transient increase in the number of circulating T cells after the administration of the antibody suggested that leukocyte extravasation into the synovium was inhibited.2,65,66 Unfortunately, repeated administration of this antibody resulted in diminished efficacy and frequent adverse events suggestive

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of neutrophil activation and immune complex formation.66 In addition, anti–ICAM-1 and anti–ß2 integrin antibodies prevented the development of arthritis in rats and rabbits, respectively.2,3,65 Two anti-CAM strategies, efalizumab (anti– LFA-1) and alefacept (LFA-3-Ig fusion protein), have been used to treat inflammatory diseases, primarily psoriasis.4,67,68 Natalizumab (anti–α4 integrin) has been tried in multiple sclerosis and Crohn’s disease,4,69 and a monoclonal antibody to the α4ß7 integrin was administered to patients with ulcerative colitis.4,70 These and other anti-CAM strategies may be useful in other inflammatory conditions, including RA.2-4,65 Chemokines and chemokine receptors can be targeted in a number of ways. In humans, disease-modifying antirheumatic drugs (DMARDs) and anti-TNF biologics, currently used in the treatment of RA, may indirectly influence chemokine production. For example, sulfasalazine and sulfapyridine inhibited chemokine production by cultured RA synovial explants and ECs, respectively.7,9 Infliximab reduced synovial expression of IL-8/CXCL8 and MCP-1/ CCL2 in RA patients. Decreased chemokine release was associated with diminished inflammatory cell ingress into the synovium.71 Treatment of RA patients with infliximab or etanercept resulted in the sustained retention of CXCR3+ T cells in the circulation, indicating clearance of these cells from the synovium.72 Regarding direct chemokine inhibition in animal models of arthritis, antibodies to IL-8/CXCL8 prevented arthritis in rabbits.73 A neutralizing polyclonal anti–ENA-78/CXCL5 antibody was administered intravenously to rats using the AIA model. The antibody injected before the onset of arthritis attenuated the severity of the disease. This antibody also prevented the ingress of IL-1–expressing leukocytes into the synovium.74 IP-10/CXCL10 and PF-4/CXCL4 have also been targeted in several ways.7-9,65 Recently, an anti-CXCL16 monoclonal antibody suppressed murine collagen-induced arthritis (CIA).75 Passive immunization of mice with anti–MIP-1a/CCL3 postponed the onset and decreased the severity of CIA.9 Antibodies to MCP-1/CCL2 reduced ankle swelling and prevented the recruitment of 111 In-labeled T cells into the rat synovium.7,9 An antibody to fractalkine/CX3CL1 reduced synovial leukocyte infiltration and bone erosion and ameliorated murine CIA.76 Recent studies have addressed the use of combined chemokine blockade. For example, a combination of MCP1/CCL2 and Groα/CXCL1 inhibition resulted in more pronounced arthritis suppression than did MCP-1/CCL2 blockade alone in a murine AIA model.77 However, there may be increased toxicity using combined strategies.9 Regarding chemokine receptor targeting, an oral CXCR2 antagonist inhibited IL-8/CXCL–induced rabbit arthritis.9,65 AMD3100, a CXCR4 antagonist, inhibited CIA in IFN-γ–deficient mice.9,65 Several CCR1 and CCR2 antagonists have been developed in recent years, and some of them have undergone human trials.9,65,78 Met-RANTES, a CCR1/CCR5 antagonist, suppressed leukocyte infiltration of the joint and the development of murine CIA.9,65 When anti-CCR2 antibodies were administered during the initiation of murine CIA, clinical symptoms improved markedly, whereas blockade during the later stages of the disease aggravated both clinical and histologic signs of arthritis.9 Hence, CCR blockade using antibodies or other inhibitors may be a promising therapy in the future.

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There have been a limited number of human antichemokine studies. There was one trial using an anti–IL-8/CXCL8 antibody in RA, but results were not published, and the development of this compound was terminated.9 Numerous small-molecule CCR1 antagonists have been developed.78 In a 2-week phase Ib study, one of these inhibitors decreased the number of synovial macrophages. One third of the patients also fulfilled the ACR20 criteria for improvement.79 Some CCR2 inhibitors have also entered clinical trials.9,65 Angiogenesis can be inhibited by either blocking the action of angiogenic mediators or using angiostatic compounds. Focusing on leukocyte recruitment, CAMs, chemokines, and chemokine receptors involved in neovascularization may be targeted in several ways. These antiadhesive and antichemokine strategies were discussed earlier. A number of currently used antirheumatic agents such as dexamethasone, gold salts, chloroquine, sulfasalazine, methotrexate, azathioprine, cyclophosphamide, leflunomide, thalidomide, minocycline, anti-TNF agents, and possibly cyclosporine A suppress angiogenesis.8,11,41 For example, infliximab treatment reduced synovial VEGF expression and vascularity.11 Future antiangiogenic therapy, which also controls synovial inflammation in RA, may target growth factors or cytokines. There have been attempts to target VEGF, and a number of synthetic VEGF and VEGF receptor inhibitors and anti-VEGF antibodies are under development.80 It is likely that multipotent rather than specific immunotherapy may be useful to control inflammation and the progression of RA. For example, DMARD treatment or anti–TNF-α targeting has multiple beneficial effects in RA, including the inhibition of chemokine production, CAM expression, and neovascularization.8-11 Thus, the roles of chemokines, CAMs, and angiogenesis in RA are overlapping and may be useful for future targeting.

SUMMARY In this chapter we have discussed the putative role of leukocyte-EC adhesion, chemokines, and angiogenesis in leukocyte recruitment underlying the pathogenesis of inflammatory synovitis. The concepts are exemplary of ongoing processes in a variety of rheumatic disorders. A number of CAMs are involved in this process. These CAMs interact with soluble inflammatory mediators, such as cytokines and chemokines. The presence of various CAM pairs and the existence of distinct steps of rolling, activation, adhesion, and migration account for the diversity and specificity of leukocyte-EC interactions. Chemokines and their receptors drive inflammatory leukocytes into the synovium. A number of soluble and cell-bound factors may stimulate or inhibit angiogenesis. The outcome of inflammatory and other “angiogenic diseases,” such as various forms of arthritis, depends on the imbalance between angiogenic and angiostatic mediators. Some CAMs and chemokines are also involved in neovascularization. There have been several attempts to therapeutically interfere with their cellular and molecular mechanisms. Specific targeting of leukocyte adhesion, CAMs, chemokines, chemokine receptors, and angiogenesis, primarily by using agents with multiple actions, may be useful for the future management of a variety of inflammatory rheumatic diseases.

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Cell Recruitment and Angiogenesis

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30. Cunningham SA, Arrate MP, Rodriguez JM, et al: A novel protein with homology to the junctional adhesion molecule: Characterization of leukocyte interactions. J Biol Chem 275:34750-34756, 2000. 31. Valencia X, Higgins JM, Kiener HP, et al: Cadherin-11 provides specific cellular adhesion between fibroblast-like synoviocytes. J Exp Med 200:1673-1679, 2004. 32. Zlotnik A, Yoshie O: Chemokines: A new classification system and their role in immunity. Immunity 12:121-127, 2000. 33. Moser B, Loetscher P: Lymphocyte traffic control by chemokines. Nat Immunol 2:123-128, 2001. 34. Walz A, Kunkel SL, Strieter RM: C-X-C chemokines—an overview. In Koch AE, Strieter RM (eds): Chemokines in Disease. Austin, Tex, RG Landes, 1996, pp 1-25. 35. Taub DD: C-C chemokines—an overview. In Koch AE, Strieter RM (eds): Chemokines in Disease. Austin, Tex, RG Landes, 1996, pp 27-54. 36. Bazan JF, Bacon KB, Hardiman G, et al: A new class of membrane bound chemokine with a X3C motif. Nature 385:640-644, 1997. 37. Ruth JH, Volin MV, Haines GK III, et al: Fractalkine, a novel chemokine in rheumatoid arthritis and rat adjuvant-induced arthritis. Arthritis Rheum 44:1568-1581, 2001. 38. Lesnik P, Haskell CA, Charo IF: Decreased atherosclerosis in CX3CR1 –/– mice reveals a role for fractalkine in atherogenesis. J Clin Invest 111:333-340, 2003. 39. Strieter RM, Polverini PJ, Kunkel SL, et al: The functional role of the ELR motif in CXC chemokine-mediated angiogenesis. J Biol Chem 270:27348-27357, 1995. 40. Folkman J, Klagsbrun M: Angiogenic factors. Science 235:442-448, 1987. 41. Auerbach W, Auerbach R: Angiogenesis inhibition: A review. Pharmacotherapy 63:265-311, 1994. 42. Nanki T, Hayashida K, El-Gabalawy HS, et al: Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T-cell accumulation in rheumatoid arthritis synovium. J Immunol 165:6590-6598, 2000. 43. Peichev M, Naiyer AJ, Pereira D, et al: Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors. Blood 95:952-958, 2000. 44. Boulday G, Haskova Z, Reinders ME, et al: Vascular endothelial growth factor-induced signaling pathways in endothelial cells that mediate overexpression of the chemokine IFN-gamma-inducible protein of 10 kDa in vitro and in vivo. J Immunol 176:3098-3107, 2006. 45. Bodnar RJ, Yates CC, Wells A: IP-10 blocks vascular endothelial growth factor-induced endothelial cell motility and tube formation via inhibition of calpain. Circ Res 98:617-625, 2006. 46. Burns JM, Summers BC, Wang Y, et al: A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion and tumor development. J Exp Med 203:2201-2213, 2006. 47. Stamatovic SM, Keep RF, Mostarica-Stojkovic M, et al: CCL2 regulates angiogenesis via activation of Ets-1 transcription factor. J Immunol 177:2651-2661, 2006. 48. Son KN, Hwang J, Kwon BS, et al: Human CC chemokine CCL23 enhances expression of matrix metalloproteinase-2 and invasion of vascular endothelial cells. Biochem Biophys Res Commun 340: 498-504, 2006. 49. Vicari AP, Ait-Yahia S, Chemin K, et al: Antitumor effects of the mouse chemokine 6Ckine/SLC through angiostatic and immunological mechanisms. J Immunol 165:1992-2000, 2000. 50. Wang J, Ou ZL, Hou YF, et al: Enhanced expression of Duffy antigen receptor for chemokines by breast cancer cells attenuates growth and metastasis potential. Oncogene 25:7201-7211, 2006. 51. Koch AE, Halloran MM, Haskell CJ, et al: Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1. Nature 376:517-519, 1995. 52. Morbidelli L, Brogelli L, Granger HJ, et al: Endothelial cell migration is induced by soluble P-selectin. Life Sci 62:7-11, 1998. 53. Brooks PC, Clark RA, Cheresh DA: Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 264:569-571, 1994. 54. Horak ER, Leek R, Klenk N, et al: Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer. Lancet 340:1120-1124, 1992. 55. Szekanecz Z, Haines GK, Harlow LA, et al: Increased synovial expression of transforming growth factor (TGF)-ß receptor endoglin and TGF-ß1 in rheumatoid arthritis: Possible interactions in the pathogenesis of the disease. Clin Immunol Immunopathol 76:187-194, 1995.

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56. Halloran MM, Carley WW, Polverini PJ, et al: Ley/H: An endothelial-selective, cytokine-inducible, angiogenic mediator. J Immunol 164:4868-4873, 2000. 57. Neidhart M, Wehrli R, Bruhlmann P, et al: Synovial fluid CD146 (MUC18), a marker for synovial membrane angiogenesis in rheumatoid arthritis. Arthritis Rheum 42:622-627, 1999. 58. Lo SK, Lee S, Ramos RA, et al: Endothelial-leukocyte adhesion molecule 1 stimulates the adhesive activity of leukocyte integrin CR3 (CD11b/CD18, Mac-1) on human neutrophils. J Exp Med 173: 1493-1500, 1991. 59. Bombara MP, Webb DL, Conrad P, et al: Cell contact between T cells and synovial fibroblasts causes induction of adhesion molecules and cytokines. J Leukoc Biol 54:399-406, 1993. 60. Szekanecz Z, Halloran MM, Volin MV, et al: Temporal expression of inflammatory cytokines and chemokines in rat adjuvant-induced arthritis. Arthritis Rheum 43:1266-1277, 2000. 61. Haas CS, Martinez RJ, Attia N, et al: Chemokine receptor expression in rat adjuvant-induced arthritis. Arthritis Rheum 52:3718-3730, 2005. 62. Zhang X, Nakajima T, Goronzy JJ, et al: Tissue trafficking patterns of effector memory CD4+ T cells in rheumatoid arthritis. Arthritis Rheum 52:3839-3849, 2005. 63. Pierer M, Rethage J, Seibl R, et al: Chemokine secretion of rheumatoid arthritis synovial fibroblasts stimulated by Toll-like receptor 2 ligands. J Immunol 172:1256-1265, 2004. 64. Klimiuk PA, Sierakowski S, Latosiewicz R, et al: Histological patterns of synovitis and serum chemokines in patients with rheumatoid arthritis. J Rheumatol 32:1666-1672, 2005. 65. Szekanecz Z, Koch AE: Therapeutic inhibition of leukocyte recruitment in inflammatory diseases. Curr Opin Pharmacol 4:423-428, 2004. 66. Kavanaugh AF, Schulze-Koops H, Davis LS, et al: Repeat treatment of rheumatoid arthritis patients with a murine anti-ICAM-1 monoclonal antibody. Arthritis Rheum 40:849-853, 1997. 67. Gordon KB, Papp KA, Hamilton TK, et al: Efalizumab for patients with moderate to severe plaque psoriasis: AA randomized controlled trial. JAMA 290:3073-3080, 2003.

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68. Krueger GG, Ellis CN: Alefacept therapy produces remission for patients with chronic plaque psoriasis. Br J Dermatol 148:784-788, 2003. 69. Sandborn WJ, Colombel JF, Enns R, et al: Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med 353: 1912-1925, 2005. 70. Feagan BG, Greenberg GR, Wild G, et al: Treatment of ulcerative colitis with a humanized antibody to the α4ß7 integrin. N Engl J Med 352:2499-2507, 2005. 71. Nissinen R, Leirisalo-Repo M, Peltomaa R, et al: Cytokine and chemokine receptor profile of peripheral blood mononuclear cells during treatment with infliximab in patients with active rheumatoid arthritis. Ann Rheum Dis 63:681-687, 2004. 72. Aeberli D, Seitz M, Juni P, et al: Increase of peripheral CXCR3 positive T lymphocytes upon treatment of RA patients with TNF-alpha inhibitors. Rheumatology (Oxford) 44:172-175, 2005. 73. Akahoshi T, Endo H, Kondo H, et al. Essential involvement of interleukin-8 in neutrophil recruitment in rabbits with acute experimental arthritis induced by lipopolysaccharide and interleukin-1. Lymphokine Cytokine Res 13:113-116, 1994. 74. Halloran MM, Woods JM, Strieter RM, et al: The role of an epithelial neutrophil-activating peptide-78-like protein in rat adjuvant-induced arthritis. J Immunol 162:7492-7500, 1999. 75. Nanki T, Shimaoka T, Hayashida K, et al: Pathogenic role of CXCL16-CXCR6 pathway in rheumatoid arthritis. Arthritis Rheum 52:3004-3014, 2005. 76. Nanki T, Urasaki Y, Imai T, et al: Inhibition of fractalkine ameliorates murine collagen-induced arthritis. J Immunol 173:7010-7016, 2004. 77. Gong JH, Yan R, Waterfield JD, et al: Post-onset inhibition of murine arthritis using combined chemokine antagonist therapy. Rheumatology (Oxford) 43:39-42, 2004. 78. Pease JR, Horuk R: CCR1 antagonists in clinical development. Expert Opin Investig Drugs 14:785-796, 2005. 79. Haringman JJ, Kraan MC, Smeets TJM, et al: Chemokine blockade and chronic inflammatory disease: Proof of concept in patients with rheumatoid arthritis. Ann Rheum Dis 62:715-721, 2003. 80. Shibuya M: VEGF-receptor inhibitors for anti-angiogenesis. Nippon Yakurigaku Zasshi 122:498-503, 2003.

23

Cytokines Iain B. Mcinnes

KEY POINTS Cytokines are peptides that have a fundamental role in ­communication within the immune system and in allowing the immune system and host tissues cells to exchange information. Cytokines act via binding to a cognate receptor which in turn sends a signal to the recipient cell that leads to a change in function or phenotype of that cell. Such signal cascades are complex and allow the intebration of a variety of cytokine signals to one cell at any given time. Cytokines exist in broad families that are structurally related but may contain rather diverse function, e.g., TNF/TNF receptor superfamily, IL-1 superfamily. Cytokine targeting has proved efficacious in a variety of rheumatic diseases, particularly for TNF — many more cytokines are currently under investigation as therapeutic targets, or as therapeutic entities in their own right.

Immune function depends on the biologic activities of n­umerous small glycoprotein messengers, termed cytokines. Originally discovered and defined on the basis of their functional activities, cytokines are now designated primarily by structure. Typically, cytokines exhibit broad functional activities that mediate not only effector and regulatory i­mmune function, but also wider effects across a range of tissues and biologic systems. As such, cytokines play a role not only in host defense, but also in a variety of normal ph­ysiologic and metabolic processes. The human genome project has facilitated discovery of numerous cytokines, p­osing considerable challenges in resolving their respective and synergistic functions in complex tissues in health and disease. Such understanding is, however, essential with the advent of cytokine-targeting therapies in the clinic. This chapter reviews general features of cytokine biology and the cellular and molecular networks within which cytokines operate; the focus is on the effector functions of cytokines that are important in chronic inflammation and in ­rheumatic diseases.

CLASSIFICATION OF CYTOKINES In the absence of a unified classification system, cy­tokines are variously identified by numeric order of discovery (currently interleukin [IL]-1 through IL-35), by a given functional activity (e.g., tumor necrosis factor [TNF], granulocyte colony-stimulating factor), by kinetic or functional role in inflammatory responses (early or late, innate or adaptive, proinflammatory or anti-inflammatory) (Fig. 23-1), by primary cell of origin (monokine = monocyte derivation; lymphokine = lymphocyte derivation), and, more recently, by structural homologies shared with related molecules.

­Superfamilies of cytokines share sequence similarity and exhibit homology and some promiscuity in their reciprocal receptor systems. They do not exhibit functional similarity. Cytokine superfamilies also contain important regulatory cell membrane receptor-ligand pairs, reflecting evolutionary pressures that use common structural motifs in diverse immune functions in higher mammals. The TNF/TNF receptor superfamily1 contains immunoregulatory cytokines, including TNF-α; lymphotoxins; and cellular ligands, such as CD40L, which mediates B cell and T cell activation, and FasL (CD95), which promotes apoptosis. Similarly, the IL-1/IL-1 receptor superfamily2 contains cytokines, including IL-1β, IL-1α, IL-receptor antagonist, IL-18, and IL-33, which mediate physiologic and host-defense function, but this family also includes the Toll-like receptors, a series of mammalian pattern-recognition molecules with a crucial role in recognition of microbial species early in innate responses.

ASSESSING CYTOKINE FUNCTION IN VITRO AND IN VIVO Although originally identified by bioactivity and quantified by bioassay, most cytokines are now identified via homologous receptor binding or sequence homology in gene databases. They are quantified in biologic solutions by enzyme-linked immunosorbent assay or by multiplex technology, the latter allowing many (>25) cytokines to be measured in single, small sample volumes (approximately 20 μL). Function is thereafter assessed by identification of the cellular source of cytokine, determination of native stimuli, characterization of receptor distribution, and determination of function in target cells. Experimental in vivo models use the addition of neutralizing cytokine-specific antibodies or soluble receptors (often as fragment crystallizable fusion or pegylated proteins to enhance half-life and modulate functional interaction with leukocytes) to modulate cytokine function. Genetically modified knockout mice (cytokine or receptor rendered deficient by embryonic stem cell technology) or transgenic mice (tissue/cell lineage-specific overexpression) have proved particularly useful. Conditional gene-targeting approaches (e.g., using the cre system) facilitate circumvention of embryonic lethal deficiencies or allow kinetic evaluation of the relative contribution of a cytokine throughout a response. Cytokine function is assessed in vitro in primary or transformed cell lines stimulated in the presence or absence of recombinant cytokine or specific anticytokine antibody or soluble receptor. This general approach has proved crucial in rheumatic disease research. Studies in which cytokine addition and neutralization occurs in synovial tissue explants or dis­aggregated cell populations, chondrocyte explants, 367

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1 Stimulus e.g., Microbe Cell contact DNA Cytokine Antibody/IC Sheer stress Pressure

CYTOKINES

6

4 2

3

5

Effector function

Cytokine Receptor

Figure 23-1  Overview of cytokine regulatory function. Numerous and diverse stimuli (1) promote cytokine expression arising either from novel gene expression (2) or from activation of preformed cytokine (3). Cytokine proteins are thereafter expressed in the cytosol, on the cell membrane, or in soluble form in the extracellular environment (4). Cytokines bind to reciprocal receptors that reside either on the membrane of a target cell or in the soluble phase (5). Membrane receptors, on cytokine ligation, signal to the recipient cell nucleus (6) and drive novel gene expression to promote effector function. Each phase of cytokine function offers rich therapeutic potential. IC, immune complexes.

bone culture m­odels, skin, and renal tissue explants and lines all have proved informative. Ex vivo methodologies now include intracellular fluorescence activated cell sorter methods, confocal and laser scanning microscopy, and quantitative histologic evaluation using automated image analysis. Such modalities, particularly when employed in human therapeutic cytokine neutralization studies in which inflammatory tissues are obtained through therapy, are consid­erably advancing the understanding of basic and pathogenetic cytokine function. Analysis of synovial biopsy specimens obtained during infliximab, rituximab, IL-1Ra, IL-10, and interferon (IFN)-β administration in rheumatoid arthritis provides the strongest evidence for the success of this approach.3,4

CYTOKINE RECEPTORS Cytokine receptors exist in structurally related superfamilies and comprise high-affinity molecular signaling complexes that facilitate cytokine-mediated communication. Such complexes often include heterodimeric or heterotrimeric structures that use unique, cytokine-specific recognition receptors together with common receptor chains shared across a cytokine superfamily. Examples include the use of the common γ chain receptor by IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, and glycoprotein 130 (gp130) by members of the IL-6 family.5,6 Alternatively, distinct receptors may use shared signaling domains. Homologous death domains are found in many TNF-receptor family members. Similarly, the IL-1 signaling domain is common to not only IL-1R, but also to other IL-1R superfamily members, including IL-18R, ST2, and the Toll-like receptors.2 Signaling pathways dependent on these are discussed in detail elsewhere. It has been recognized more recently that unrelated cytokine receptor systems exhibit close cross-communication on the cell membrane, allowing a cell to integrate a variety of external stimuli to optimize signaling pathways and the cellular response in real-time in a changing environment. Although best elucidated in the epidermal growth factor receptor system, this also has been identified for members of the common γ chain signaling family.

Cytokine receptors can operate via several mechanisms. Membrane receptors, with intracellular signaling domains intact, can transmit signals to the target cell nucleus after soluble cytokine binding and promote effector function. Membrane receptors may bind cell membrane cytokines facilitating cross-talk between adjacent cells. Membranebound and soluble cytokines may promote distinct receptor function. TNF-α binds TNF-RI and TNF-RII with similar affinity, but it has a slower rate of dissociation from TNF-RI. Soluble TNF-α may dissociate rapidly from TNF-RII to bind TNF-RI, promoting preferential signaling by the latter (ligand passing).1 In contrast, during cell-cell contact, stable TNF-α/TNF-RI and TNF-α/TNF-RII complexes form, allowing for differential signaling contribution by TNF-RI and TNF-RII. Cytokine receptor/cytokine complexes also may operate in trans, whereby component parts of the ligand-receptor complex are derived from adjacent cells. IL-15/IL-15Rα complexed on one cell may bind IL-15Rβ/γ on another.7 Receptors also exist in soluble form, derived either from alternative mRNA processing to generate receptor-lacking transmembrane or intracellular domains or from enzymatic cleavage of receptor from the cell surface (e.g., sTNF-R, sIL-1R1). Soluble receptors may act to antagonize cytokine function, regulating responses. Soluble receptors also may preform complexes with cytokine to promote su­bsequent ligand-receptor assembly on the target cell membrane and enhance function. Soluble receptors can deliver cytokine to the cell membrane via ligand passing. Finally, it is now recognized that some cytokines with the capacity to be retained in the membrane may themselves function as signaling molecules (reverse signaling).

REGULATION OF CYTOKINE EXPRESSION Cytokines are synthesized in the Golgi and may traffic through the endoplasmic reticulum to be released as soluble mediators, or they may remain membrane bound, or they may be processed into cytosolic forms that can traffic intracellularly, even returning to the nucleus where they can act as transcriptional regulators. Cytokines mediate autocrine function either through release or membrane expression and immediate receptor ligation on the source cell or intracellularly within the source cell. Alternatively, cytokines operate in a paracrine manner, allowing cellular communication beyond that facilitated by local cell-cell contact. The distance and kinetics for effective function may be limited,8 however, by numerous factors, including physicochemical considerations of the peptide structure itself, extracellular matrix binding (e.g., to heparan sulfate), enzymatic degradation (e.g., serine protease degradation of IL-18), or the presence of soluble receptors (e.g., TNF-α/soluble TNF-RI and TNF-RII, IL-2/soluble IL-2Rα) or novel cytokinebinding proteins (e.g., IL-18/IL-18 binding protein) in the inflammatory milieu. Numerous factors promote cytokine expression in vivo (Fig. 23-1), including cell-cell contact, immune complexes/ autoantibodies, local complement activation, microbial sp­ecies and their soluble products, reactive oxygen and nitrogen intermediates, trauma, sheer stress, ischemia, ra­diation, ultraviolet light, extracellular matrix components, DNA (mammalian or microbial), heat shock proteins, and cy­tokines themselves in autocrine loops. Commonly used in

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Late Early

Kinetics

Anti Inflammatory potential

Pro

Figure 23-2  Placing cytokines in functional context. Cytokines often exhibit pleiotropic functions that vary throughout an immune response and according to the nature of a stimulus. Cytokines could be envisaged at one point in three-dimensional space, representing their hierarchic capacity to contribute to an inflammatory lesion over time. A given cytokine might have early proinflammatory function but late, net anti-inflammatory function within an evolving immune response. Similarly, at an early stage, a cytokine might function atop a hierarchy, but later function primarily as an effector downstream moiety. Cytokines may have roles in innate and acquired responses that are discrete. A cytokine might have distinct functions in different tissues and in response to different stimuli. This has important implications for predicting the effect of cytokine targeting in vivo.

vitro stimuli include many of these and chemical entities, including phorbol esters, calcium ionophores, lectins (e.g., phytohemagglutinin), and receptor-specific antibodies such as anti-CD3 and anti-CD28 for T cell activation or antiimmunoglobulin and anti-CD40 for B cells. Cytokine regulation within the cell can be usefully considered at several levels. Transcriptional regulation depends on the recruitment of discrete transcription factors to the cytokine promoter region. Transcription factor binding allows for numerous signal pathways to regulate cytokine expression across a range of stimuli. Several transcription factors (e.g., nuclear factor κB [NFκB], activator protein-1 [AP-1], nuclear factor of activated T cell) are crucial in cytokine production. Inhibition of NFκB activity using either chemical inhibitors or adenoviral delivery of regulatory peptides leads to amelioration of inflammatory synovitis in vivo and in vitro.9 Sequence polymorphism within cytokine promoters offers potential for differential cytokine expression between individuals that could confer selective advantage against infection, but also could increase susceptibility to, or progression of, autoimmunity. This is best exemplified in the TNF-α and IL-1 promoters.10,11 Single nucleotide polymorphisms in the TNF-α promoter region (e.g., −308) are associated with altered TNF-α release on leukocyte stimulation in vitro. Similarly, homozygotes for the A2 allele at +3954 in the IL-1β gene produce more IL-1β with lipopolysaccharide stimulation. Polymorphisms also exist in the IL-1Ra gene, rendering the functional significance of individual single nucleotide polymorphisms on IL-1 protein release difficult to interpret. In general, the net effect of haplotypes may be more important at the functional level, particularly when their relevance to disease entities is considered. Post-transcriptional regulation is important in determining longevity of cytokine expression. This regulation may operate by promoting translational initiation, mRNA

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s­ tability, and polyadenylation. AU-rich elements (AREs) within the 5′ or 3′ untranslated regions (UTRs) of cytokine mRNA are crucial for stability; 3′ UTR AREs downregulate TNF expression such that transgenic knockin mice that lack TNF-α AREs develop spontaneous inflammatory arthritis and bowel disease.12 Regulatory proteins bind AREs to mediate such effects. HuR and AUF1 exert opposing effects, stabilizing and destabilizing ARE-containing transcripts.13 TIA-1 and TIAR have been identified as RNA recognition motif family members14 that function as translational silencers. Macrophages from TIA-1-deficient macrophages produce excess TNF-α, whereas TIA-1-deficient lymphocytes exhibit normal TNF-α release, suggesting distinctions in mRNA regulation in discrete cell types.15 Alternatively, cytokines may generate stable mRNA a priori to facilitate subsequent rapid response in tissues. IL-15 mRNA 5′ UTR contains 12 AUG triplets that significantly reduce the efficiency of IL-15 translation. Deletion of this sequence permits IL-15 secretion. IL-15 mRNA can produce a 48-amino acid signal peptide that allows IL-15 release and a shorter 21-amino acid signal peptide that targets intracellular distribution. IL-15 forms thus generated exhibit discrete functions.16 Post-translational regulation also modulates cytokine expression via several mechanisms. Patterns of glycosylation are important for cytokine function and may regulate intracellular trafficking.16 Modified leader sequences may alter intracellular trafficking of cytokines. Some cytokines are translated without functional leader sequences. Their secretion depends on nonconventional secretory pathways that are so far poorly understood. IL-1β employs a purine receptor–dependent pathway (P2X7) for cellular release.17 Enzymatic activation of cytokines is common, whereby nonfunctional promolecules are cleaved to gene­ rate functional subunits. Examples include the ­ cleavage by caspase 1 of pro-IL-1β to generate active IL-1β and, similarly, of pro-IL-18 to generate an active 18-kD ­species.18 This is an organized process sequentially and in the orientation within the cell. IL-1 processing occurs in a protein complex within the cytosol termed the ­inflammasome. Alternative processing pathways for cytokines include the serine proteases, proteinase 3 and elastase, and adamolysin family members. Enzyme cleavage pathways operate within and outside cells, providing for extracellular cytokine activation. Similarly, cell membrane enzymes serve to cleave membrane-expressed cytokine. Members of the adamolysin family regulate TNF-α release; TNFα-converting enzyme cleaves and mediates the release of TN­F-α and its receptors.19 Extensive molecular machinery exists to regulate tightly not only the production and stability of cytokine mRNA, but also its translation and cellular expression and distribution. At each level, opportunities exist for intervention and therapeutic cytokine modulation.

EFFECTOR FUNCTION OF CYTOKINES Cytokines possess pleiotropic and potent effector function in acute and chronic inflammatory responses. The identity, receptor specificity, and key effects of cytokines understood to have particular importance in pathogenesis of human autoimmunity and chronic inflammation are summarized in Tables 23-1 through 23-8.

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Table 23-1  Interleukin-1 Superfamily Cytokines with Roles in Rheumatic Disease Cytokine

Size (kD)*

Receptors

Major Cell Sources

Key Functions

IL-1β

35 (pro)

IL-1RI

Monocytes; B cells; fibroblasts;   chondrocytes; keratinocytes

17 (active)

IL-1RAcP IL-1RII (decoy)

Fibroblast cytokine, chemokine, MMP, iNOS, PG release ↑ Monocyte cytokine, ROI, PG ↑ Osteoclast activation Chondrocyte GAG synthesis ↓; iNOS, MMP, and aggrecanase ↑ Endothelial adhesion-molecule expression

35 (pro)†

IL-1RI

Monocytes; B cells; PMNs;   epithelial cells; keratinocytes

Similar to IL-1β

17 (active)

IL-1RAcP

IL-1α

Autocrine growth factor (e.g., keratinocytes)

IL-1RII (decoy) IL-1Ra

22

IL-1RI IL-1RAcP IL-1RII

Monocytes

Antagonize effects of IL-1β and IL-1α

IL-33

30 (pro)

ST2L

Epithelial cells; monocytes; smooth muscle cells; keratinocytes

Promote Th2 cell activation, mast cell activation, and cytokine production

18 (active)

IL-1RAcP

23 (pro)

IL-18R

Monocytes; PMNs; dendritic cells;   platelets; endothelial cells

18 (active)

IL-18Rβα

T cell effector polarization (Th1 with IL-12/Th2 with IL-4) Chondrocyte GAG synthesis ↓; iNOS expression NK activation; cytokine release; cytotoxicity Monocyte cytokine release; adhesion molecule expression PMN activation; cytokine release; migration Endothelial cells—proangiogenic

IL-18

*Pro forms cleaved to active moieties by proteases, including caspase-1, calpain, elastase, and cathepsin G. †Pro-IL-1α retains bioactivity before cleavage. GAG, glycosaminoglycan; iNOS, inducible nitric oxide synthase; MMP, matrix metalloproteinase; NK, natural killer; PG, peptidoglycan; PMN, ­polymorphonuclear neutrophil; ROI, reactive oxygen intermediates.

Table 23-2  Tumor Necrosis Factor Superfamily Cytokines* with Potential Role in Rheumatic Disease Cytokine Size (kD) Receptors

Major Cell Sources

Selected Functions

TNF-α

Monocytes; T, B, NK cells; PMNs; eosinophils; mast cells; fibroblasts; keratinocytes; glial cells; osteoblasts; smooth muscle

Monocyte activation, cytokine, and PG ↑

T cells; monocytes; fibroblasts; astrocytes;   myeloma; endothelial cells; epithelial cells

Peripheral lymphoid development

26 (pro)

TNF-RI (p55) TNF-RII (p75)

TNF-RI

PMN priming, apoptosis, oxidative burst ↑ Endothelial cell adhesion molecule, cytokine release ↑; fibroblast proliferation and collagen synthesis ↓ MMP and cytokine ↑ T cell apoptosis; clonal (auto)regulation; TCR dysfunction Adipocyte FFA release ↑ Endocrine effects—ACTH, prolactin ↑; TSH, FSH, GH ↓

LTα

22-26

RANK   ligand

35

RANK

Stromal cells; osteoblasts; T cells

Stimulates bone resorption via osteoclast maturation and activation Modulation of T cell-DC interaction

TNF-RII

Otherwise similar bioactivities to TNF-α

OPG

55

RANKL

Stromal cells, osteoblasts

Soluble decoy receptor for RANKL

BLyS†

18-32

TACI BCMA BLyS-R

Monocytes; T cells; DCs

B cell proliferation, Ig secretion, isotype switching, survival T cell costimulation

APRIL

—

TACI BCMA

Monocytes; T cells; tumor cells

B cell proliferation Tumor proliferation

*Additional members of importance include TRAIL, TWEAK, CD70, FasL, and CD40L. At least 18 members of the family are now described. †Also called BAFF. ACTH, adrenocorticotropic hormone; APRIL, a proliferation inducing ligand; BAFF, B cell activating factor belonging to the TNF family; BCMA, B cell maturation protein; BLyS, B lymphocyte stimulator protein; DC, dendritic cell; FFA, free fatty acid; GAG, glycosaminoglycan; LT, lymphotoxin; MMP, matrix metalloproteinase; NK, natural killer; OPG, osteoprotegerin; PG, peptidoglycan; PMN, polymorphonuclear neutrophil; RANK, receptor activator of NFB ligand; TACI, transmembrane activator and calcium modulator and cyclophilin ligand; TNF, tumor necrosis factor; TRAIL, TNF related apoptosis-inducing ligand; TWEAK, TNF-like weak inducer of apoptosis.

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Table 23-3  Cytokines Associated Predominantly with Effector Function for T Cells* Cytokine

Size (kD)

Receptors

Major Cell Sources

Key Functions

20-25

IFNγR

Th/c1 cells; NK cells; γδT cells;   B cells; macrophage/DCs

Macrophage activation, DC APC function ↑

Type II Interferon IFN-γ

Endothelial adhesion molecule ↑ MHC class II expression ↑ T cell growth ↓; opposes Th2 responses Bone resorption ↓; fibroblast collagen synthesis

4a-Helix Family IL-2

15

IL-2Rα

Th/c cells; NK cells

IL-2/15Rβ γ-chain IL-4

20

IL-4Rα/γ-chain IL-4Rα/IL-13R1

Th/c cells (Th2); NK cells

IL-5

25 monomer

IL-5Rα

50 homodimer

IL-5Rβ

Th/c2 cells; NK cells; mast cells; epithelial cells

IL-17A

20-30

IL-17R

T cells (Th17); fibroblasts

IL-25 (IL-17E)

20-30

IL-17R

Th2 cells

T cell division; maturation; cytokine release; cytotoxicity NK cell cytokine release; cyotoxicity; monocyte activation Lymphocyte apoptosis ↓ Th2 differentiation, maturation, apoptosis ↓ B cell maturation; isotype switch (IgE) Eosinophil migration, apoptosis ↓ Endothelial activation; adhesion molecule expression B cell differentiation; immunoglobulin   production (IgA) Eosinophil differentiation and activation Th/c maturation

IL-17 Family† Chemokine release, fibroblast cytokine release, MMP release ↑ Osteoclastogenesis; hematopoiesis Chondrocyte GAG synthesis ↓ Leukocyte cytokine production ↑ Th2 cytokine release; B cell IgA and IgE synthesis; eosinophilia; epithelial cell hyperplasia

*Additional T cell–derived cytokines of potential interest include IL-13 from Th2 and NK2 cells. †IL-17 family also contains IL-17B, IL-17C, and IL-17F, the distinct functions of which are currently unclear. APC, antigen presenting cell; DC, dendritic cell; GAG, glycosaminoglycan; IFN, interferon; MHC, major histocompatibility complex; MMP, matrix metalloproteinase; NK, natural killer; Th/c, T helper/cytotoxic.

CYTOKINES IN ACUTE INFLAMMATION Cytokines operate at every stage in the crucial early events that promote acute inflammation. Cells that make up the innate immune response, including neutrophils, natural killer cells, ­macrophages, mast cells, and eosinophils, all produce and respond to cytokines generated within seconds of tissue insult. Cytokines prime leukocytes for response to microbial and ­chemical stimuli; upregulate adhesion molecule expression on migrating leukocytes and endothelial cells; and amplify the release of reactive oxygen intermediates, nitric oxide, vasoactive amines, and neuropeptides, and the activation of kinins and arachidonic acid derivatives, prostaglandins, and leukotrienes, which regulate cytokine release. Similarly, cytokines regulate the expression of complement processing and membrane defense molecules, scavenger receptors, NOD Like ­ Receptor (NLR), and Toll-like receptors. Cytokines, particularly IL-1, TNF-α, and IL-6, are crucial in driving the acute-phase response. Tables 23-1 through 23-8 provide descriptions of the function of cytokines expressed within the acute inflammatory response.

be considered fluid states in which individual cells under cytokine control transiently contribute to organized functional subunits—such as the ectopic germinal center, synovial lining layer, or renal interstitial nephritis—yet remain competent to migrate thereafter under the influence of chemotactic gradients on the extracellular matrix. Cytokines also may promote cell death (apoptosis) either by withdrawal (e.g., IL-2, IL-7, IL-15) or by binding cytokine receptors containing death domains (e.g., TNF-R1). Cytokines contribute at every stage of inflammatory lesion development in a dynamic equilibrium, rather than in a static, linear manner. Chronic inflammation in rheumatic disease usually contains cytokine activities reminiscent of innate and acquired immune responses. For convenience, cytokines can be considered by their effect on cell subsets and cellular interactions (Fig. 23-2 describes a notional positioning for cytokine activity in a developing and chronic lesion). Investigation of cytokine-regulated pathways in several rheumatic diseases has identified several common pathways.

CYTOKINES IN CHRONIC INFLAMMATION

T Cell Effector Function in Chronic Inflammation

Cytokines critically modulate the cellular interactions that characterize chronic inflammation. Studies using real-time image analytic techniques, such as two-photon microscopy and confocal scanning, suggest continuous cellular motility during inflammation. Inflammatory lesions might properly

T cells depend on cytokine function at every develop­ m­ental stage from bone marrow stem cell maturation, through thymic education, to functional determination and maturation after primary or secondary antigen exposure. The last-mentioned is of prime importance

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Table 23-4  Cytokines Described Initially with Primary Role in Regulation of T Cells* Cytokine

Size

Receptors

Major Cell Sources

Key Functions

IL-12

IL-12/23p40 IL-12p35

IL-12Rα IL-12Rβ1 IL-12Rβ2

Macrophages; DCs

Th1 cell proliferation, maturation T cell cytotoxicity B cell activation

IL-23

IL-12/23p40

IL-23R

Macrophages; DCs

Th17 cell expansion and activation; IL-17 release

IL-23p19

IL-12Rβ1

15 kD

IL-15Rα

Monocytes; fibroblast; mast   cells; B cells; PMNs; DCs

T cell chemokinesis, activation, memory maintenance NK cell maturation, activation, cytotoxicity Macrophage activation, suppression (dose dependent) PMN activation, adhesion molecule, oxidative burst Fibroblast activation B cell differentiation and isotype switching

Activated T cells; others (?)

B cell activation

IL-15

IL-2/15Rβ γ-chain

IL-21

15 kD

IL-21R γ-chain

*Cytokines included in this table are now understood to exhibit considerable functional heterogeneity as shown. Other T cell regulatory cytokines have been described, including IL-27, the functions of which are currently under investigation. DC, dendritic cells; NK, natural killer; PMN, polymorphonuclear neutrophil.

Table 23-5  IL-10 Superfamily Cytokines* Cytokine

Receptors

Cellular Sources

Key Functions

IL-10

IL-10R1

Monocytes; T cells; B cells; DCs;   epithelial cells; keratinocytes

Macrophage cytokine release, iNOS, ROI ↓; soluble receptor ↑ T cell cytokine release, MHC expression ↓; anergy induction Treg cell maturation; effector function (?) DC activation, cytokine release ↓ Fibroblast MMP, collagen release ↓; no effect on TIMP B cell isotype switching enhanced

IL-10R2

IL-19

IL-20R1/IL-20R2

Monocytes; others (?)

Monocyte cytokine and ROI release; monocyte apoptosis

IL-20

IL-22R/IL-20R2 IL-20R1/IL-20R2

Keratinocytes; others (?)

Autocrine keratinocyte growth regulation

IL-22

IL-22R/IL-10R2

Th17 cells; CD8 T cells; γδ T cells;   NK cells

Acute-phase response, keratinocyte activation proliferation ↑

IL-24

IL-22R/IL-20R2 IL-20R1/IL-20R2

Monocytes; T cells

Tumor apoptosis; Th1 cytokine release by PBMC

*Additional members include IL-26, IL-28, and IL-28A. Many functions of IL-10 superfamily are as yet poorly understood, but they likely reside beyond the immune system. DC, dendritic cell; iNOS, inducible nitric oxide synthase; MMP, matrix metalloproteinase; NK, natural killer; PBMC, peripheral blood mononuclear cells; ROI, reactive oxygen intermediates; TIMP, tissue inhibitor of metalloproteinase.

because re-education of phenotypic T cell responses may be achieved through alteration of the ambient cytokine milieu. T cell receptor–peptide–major histocompatibility complex (MHC) interactions during T cell–dendritic cell interaction rely on costimulatory molecule and local cytokine expression to determine functional outcome (see Tables 23-3 and 23-4). IL-12, in the presence of IL18, promotes type 1 phenotypic development, characterized ultimately by IFN-γ producing T helper type 1 (Th1) effector cells.20 IFN-γ drives macrophage priming and activation and adhesion molecule expression and promotes granuloma formation and microbial killing. IFN-γ has a complex role in tissue destruction, however, with contradictory data obtained in inflammation models in IFN-γ-deficient and IFN-γ receptor–deficient mice. IFN-γ ultimately may retard tissue destruction, perhaps by suppressing osteoclast activation.21

A novel T cell subset has been defined that secretes IL-17A predominantly (Th17 effector cells), together with IL-22. Th17 cells are generated in the presence of IL6 and transforming growth factor (TGF)-β, expanded by IL-1β and IL-23, and antagonized by IL-25 (IL-17E) and paradoxically by IFN-γ. IL-17A provides a direct and rapid route to tissue damage via such means as osteoclast activation or FLS activation.22 The precise contribution of Th17 cells in human autoimmune disease is currently unclear. There are, however, persuasive data from rodent models indicating that Th17 cells may be of primary importance as initiator and effector cells. IL-4 dominance during T cell– dendritic cell interactions in the presence of IL-18 leads to type 2 responses, which promote humoral ­ immunity driven by Th2 cells synthesizing primarily IL-4, IL-5, IL10, and IL-13. Resulting pathogenesis more likely may be B cell–mediated. Cytokines that predispose to regulatory

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Table 23-6  IL-6 Superfamily Cytokines* Cytokine

Size (kD) Receptors

Major Cell Sources

Key Functions

Monocytes; fibroblasts; B cells; T cells

B cell proliferation; immunoglobulin production Hematopoiesis, thrombopoiesis T cell proliferation, differentiation, cytotoxicity Hepatic acute-phase response Hypothalamic-pituitary-adrenal axis Variable effects on cytokine release by monocytes

IL-6

21-28

IL-6R†

Oncostatin M

28

OMR gp130

Monocytes; activated T cells

Megakaryocyte differentiation Fibroblast, TIMP, and cytokine release Acute-phase reactants, fibroblast protease inhibitors ↑ Monocyte TNF release ↓; IL-1 effector function ↓ Hypothalamic-pituitary axis ↑; corticosteroid release Modulatory effect on osteoblast (?) Proinflammatory effects in some models (?)

Leukemia   inhibitory   factor

58

LIFR gp130

Fibroblasts; monocytes; lymphocytes; mesangial cells; smooth muscle cells; epithelial cells; mast cells

Acute-phase reactants ↑

gp130

Hematopoiesis, thrombopoiesis Role in neural development, neural effector function, implantation Bone metabolism; extracellular matrix regulation Leukocyte adhesion molecule expression Eosinophil priming Mixed proinflammatory versus anti-inflammatory   effects in models *Additional members of potential importance include IL-11, cardiotropin-1, and ciliary neurotrophic factor. Note overlapping effects within family. †Membrane or soluble form can dimerize gp130 to promote signaling, which promotes signal transduction. LIFR, leukemia inhibitory factor receptor; OMR, oncostatin M receptor; TIMP, tissue inhibitor of metalloproteinase; TNF, tuimor necrosis factor.

T cell development are unclear, although high levels of IL10 or TGF-β have been suggested in this context.23 Effector T cells can operate via secretion of cytokines to patterns determined by their prior activatory conditions. Cognate Cellular Interactions In many inflammatory lesions, there is relative paucity of inducer T cell–derived cytokines (especially IFN-γ), despite abundant proinflammatory cytokine expression. Cell-cell membrane interactions between leukocyte subsets and between tissue cells and leukocytes have emerged as a do­minant mechanism sustaining chronic inflammation. Cytokines contribute to these interactions at several levels (Fig. 23-3), including directly as membrane-expressed ligands, indirectly via activating cells, and synergistically by enhancing their subsequent cognate activities. The importance of cytokine-cell contact interactions is best studied in synovial tissues, but applies to many inflammatory lesions. Many data now show that cognate interactions between T cells and adjacent macrophages constitute a major pathway driving cytokine release, and that cytokines sustain this pathway (see Fig. 23-3). Such interactions do not depend on T cell receptor–mediated T cell activation and provide a route to expansion of inflammation by T cells, but independent of local autoantigen recognition. Vey and colleagues24 first observed monocyte activation via cell contact with mitogen-stimulated T cells. Freshly isolated synovial T cells activate macrophages by this mechanism, confirming that contact-induced cellular activation is a fundamental property of inflammatory T cells.25 Antigen-independent, cytokine-mediated bystander activation confers this capacity on human CD4+ memory T cells.26 Studies using synovial T cells from rheumatoid

arthritis and psoriatic arthritis tissues reveal that exposure of memory T cells to synergistic combinations of cytokines are most potent in this respect, particularly IL-15, TNF-α, and IL-6.27,28 Cytokine activities also operate directly on macrophages to synergize with T cell contact. IFN-γ and IL-18 are most potent in this respect, acting via increased adhesion molecule expression. Activated memory CD4+ and CD8+ T cells promote cytokine release from macrophages via diverse membrane ligands, including LFA-1/ICAM-1, CD69, and CD40/CD154.27,29 After contact with T cells, macrophages release increased concentrations of TNF-α and IL-1, but not IL-10, and they exhibit reduced levels of IL-1Ra. Th1 cells promote relatively greater proinflammatory cytokine release than do Th2 cells after coculture. This finding suggests that their functional phenotype extends beyond cytokine secretion to include a differential membrane receptor array.30 This su­ggestion is borne out further in the relative phenotypic distinctions between Th1 (CD40L, CCR5, IL-18Rα) and Th2 (ST2, CXCR3) cells. The role of Th17 cells in this context is unknown. Signaling pathways engaged in monocytes after such T cell–membrane interactions are distinct from the pathways activated by conventional c­ytokine-inducing agents. Distinct use of phosphatidylinositol 3-kinase, NFκB, and p38 mitogenactivated protein kinase pathways is observed.31 Similarly, discrete macrophage signals follow contact with cytokine-activated T cells (which resemble synovial T cells) compared with T cell receptor–activated T cells.32 Such distinctions offer therapeutic potential in targeting cytokine-activated, T cell–driven pathways, leaving antigen-driven responses relatively intact. The activation state of memory T cells necessary for the previously discussed interactions to proceed remains controversial. Purified resting T cell subsets activate synovial fibroblasts to release IL-6, IL-8, matrix metalloproteinase 3 (MMP3), and prostanoids, in synergy with IL-17.33

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Table 23-7  Growth Factors Relevant to Rheumatic Diseases Cytokine

Receptors

Cellular Sources

Key Functions

TGF-β*

Type I TGFβR

Broad—including fibroblasts,   monocytes, T cells, platelets

Wound repair, matrix maintenance, and fibrosis

Isoforms 1-3†

Type II TGFβR

Initial activation then suppression of inflammatory responses T cell (Treg and Th17) and NK cell proliferation and effector function ↓ Early-phase leukocyte chemoattractant, gelatinase, and integrin expression ↑ Early macrophage activation then suppression, reduced iNOS expression

Others

BMP family   (BMP2-15)

BMPRI

Varied (e.g., epithelial and   mesenchymal embryonic tissues);   bone-derived cell lineages

Regulate critical chemotaxis, mitosis, and differentiation processes during chondrogenesis and osteogenesis, tissue morphogenesis (e.g., heart, skin, eye)

Platelets; macrophages; endothelial   cells; fibroblasts; glial cells; astrocytes;   myoblasts; smooth muscle cells

Local paracrine or autocrine growth factor for variety of lineages

BMPRII PDGF

PDGFRα

Wound healing

PDGFRβ FGF family

FGFR (various)

Widespread

Growth and differentiation of mesenchymal,   epithelial, and neuroectodermal cells

Basic FGF Acidic FGF *Members of TGF-β superfamily include BMP, growth and differentiation factor, inhibinA, inhibinB, müllerian inhibitory substance, glial-derived neurotrophic factor, and macrophage inhibitory cytokine. †Bound to latency-associated peptide to form small latency complex and to latent TGF-β binding protein to form large latent complex; activated by ­proteolytic and nonproteolytic pathways. BMP, bone morphogenetic protein; FGF, fibroblast growth factor; iNOS, inducible nitric oxide synthase; NK, natural killer; PDGF, platelet-derived growth factor; TGP, transforming growth factor.

It is likely that T cells may be activated by interactions with diverse moieties, including extracellular matrix c­omponents and potentially autoantigens. Nevertheless, it is now clear that cytokines can promote chronicity by a­ctivating T cells to promote inflammation regardless of local (auto)antigen recognition, and that this has enormous therapeutic potential (see Fig. 23-3). Agonist/Antagonist Cytokine Activities in Chronic Inflammation Complex regulatory interactions exist to suppress ongoing inflammatory responses. This is often achieved via parallel secretion of antagonistic cytokines and soluble receptors to regulate cytokine effector pathways. Th1 responses are suppressed partly by cytokines of Th2 type (e.g., IL-4 or IL-10), and consequently exaggerated Th1 responses arise in models in which the Th2 response is deficient.20 Th1 and Th2 cells similarly limit Th17 cell expansion.22 Similar regulatory loops operate for other leukocytes, exemplified by the yin-yang effects of TNF-α and IL-10 on macrophage cytokine release and effector function.34 Inhibitory cytokine activities usually are defined with respect to a proinflammatory cytokine, and in other contexts they may have quite distinct function, rendering prediction of their net contribution to an inflammatory response difficult. IL-10 opposes many of the proinflammatory effects of TNF-α and IL-1β (e.g., reduces adhesion molecule expression, MHC expression, and MMP release), but it potently activates B cell activation and immunoglobulin secretion.34 Similarly, TNF-α, which is normally considered a proinflammatory moiety, may have an important role in ­ regulating

T cell function because T cells removed from sites of chronic inflammation exhibit suppressed capacity to signal via their T cell receptor that recovers on TNF-α neutralization.35 Such regulation is complicated further by the precise ratio of cytokine to soluble receptor, such as TNF to sTNFR or IL-10 to sIL-10R, within the local environment. Commensurate with this, administration of anti-inflammatory cytokines, such as IL-4, IL-10, and IL-11, has generally proved disappointing in the context of clinical inflammatory diseases. An important caveat is the potential requirement of combinations of cytokines to suppress inflammation optimally (e.g., combinations including IL-4, IL-10, and IL-11). Further functional antagonism is exemplified in the antagonistic activities of IL-1β and IL-1Ra and of IL-18 and IL-18 binding protein in regulating macrophage activation. The role of cytokines in regulating cognate interactions between leukocytes also has emerged more recently. Although anti-inflammatory pathways are poorly induced after cell contact, cytokine-activated T cells can induce IL-10 release by monocytes.32 Rheumatoid arthritis synovial membrane IL-10 release, which is partially T cell dependent, feeds back to regulate TNF-α release. Cytokine production from adjacent cell lineages within an inflammatory lesion also may be suppressive. IFN-β reduces mitogenactivated, T cell–induced macrophage release of TNFα and IL-1, whereas IL-1Ra release is enhanced.36 This provides a mechanism whereby type I IFNs could modify proinflammatory cytokine production. Regulation extends beyond co­nventional cytokine activities. Prostaglandins and lipoprotein moieties, particularly high-density lipoprotein, can suppress cytokine-mediated, T cell–macrophage ­interactions.37

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Table 23-8  Miscellaneous Cytokines with Potential Roles in Rheumatic Diseases Cytokine

Size (kD)

Receptors

Cellular Sources

Key Functions

MIF

12

Unclear

Macrophages; activated T cells;   fibroblasts (synoviocytes)

Macrophage cytokine release, phagocytosis, NO release ↑ T cell activation; DTH Fibroblast proliferation; COX expression; PLA2 expression Intrinsic oxidoreductase activity   (“cytozyme”)

HMGB1

30

RAGE, dsDNA

Widespread expression; necrotic cells;   macrophages; pituicytes

DNA-binding transcription factor

Others (?)

GM-CSF

14-35

GM-CSFRα

Necrosis-induced inflammation Macrophage activation—delayed proinflammatory cytokine Smooth muscle chemotaxis Disrupts epithelial barrier function Bactericidal (direct) T cells; macrophages; endothelial cells;   fibroblasts

Granulocyte and monocyte maturation; hemopoietic effects Leukocyte PG release; DC maturation Pulmonary surfactant turnover

Monocytes; PMNs; endothelial cells;   fibroblasts; various tumor cells;   stromal cells

Granulocyte maturation; promotes PMN function

GM-CSFRβ G-CSF

19

G-CSFR

M-CSF

28-44

M-CSFR

Monocytes; fibroblasts; endothelial cells

Monocyte activation, maturation

IL-32α-δ

Unknown

Unknown

Monocytes; T cells; NK cells; epithelial cells

Promotes proinflammatory cytokine release from variety of cells

Type I   interferons IFNα/β   family

Various

IFNαβR

Widespread

Antiviral response

Broad immunomodulatory effects (promotes MHC expression) Macrophage activation; lymphocyte activation and survival Antiproliferative, cytoskeletal alteration, differentiation ↑ COX, Cyclooxygenase; DC, dendritic cell; DTH, delayed-type hypersensitivity; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HMGB, high mobility group box chromosomal protein; IFN, interferon; M-CSF, macrophage colony-stimulating factor; MIF, macrophage inhibitory factor; NO, nitric oxide; PG, prostaglandin; PLA, phospholipase A; PMN, polymorphonuclear neutrophil; RAGE, receptor for advanced glycation end products.

Disease-Modifying Antirheumatic Drugs Conventional disease-modifying antirheumatic drugs also can act via modulation of cytokine production. Methotrexate modulates release of various cytokines in vitro, in part mediated via adenosine–cyclic adenosine monophosphate pathway.38 The active metabolite of the dihydroorotate dehydrogenase inhibitor leflunomide, A77 11726, reduces TNF-α, IL-1β, IL-6, and MMP-1, but it does not reduce IL-1Ra release by monocytes after mitogen-activated T cell contact.39,40 Leflunomide may mediate these activities through modulation of inhibitor of NFκB (IκB)α phosphorylation and degradation and AP-1 and c-Jun N-terminal protein kinase activation.41 Finally, sulfasalazine is an inhibitor of proinflammatory cytokine-induced NFκB. Biologic agents also potently modify cytokine expression in a variety of disease states. Cellular Interactions across Diverse Tissues Cytokines promote cognate cellular interactions across a range of tissues. In contrast to T cell–macrophage and T cell–dendritic cell interactions, in which adhesion ­molecule

and costimulatory pathways are often implicated, cell-cell membrane communications apart from leu­kocyte-leukocyte interactions are often mediated through membrane cytokine expression (see Fig. 23-3). T cell contact–mediated activation of fibroblasts operates via membrane TNF-α and IFN-γ to enhance fibroblast cytokine release and MMP—but not tissue inhibitors of metalloproteinase—expression, favoring tissue destruction.29 The source and activation status of the fibroblast are vital; fibroblast-like synoviocytes, but not cutaneous fibroblasts, are potently activated by this route. Other studies have shown T cell contact–mediated activation of neutrophils, keratinocytes, mesangial cells (via a combination of membrane cytokine and CD40L expression), platelets, and renal tubule epithelial cells. Cytokine-­activated macrophages (via IFN-γ and sCD40L) may interact via cell contact with mesangial cells to activate adhesion molecule and chemokine release by the latter. Cell-cell contact between cells of the immune system and beyond likely represents a ubiquitous mechanism whereby perpetuation of chronic inflammation is potently influenced by local production of cytokines.

376

Mcinnes 

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CYTOKINES

Fibroblast

DC IL-12, IL-23 Chemokines, ECM Co-stimulation

± IL-17, IL-22 IFN-γ

IL-17 IL-22

?

TNF-α LTβ IL-1 IL-15 IL-18 IL-6 IL-20 IL-32 IL-33 RANKL GM-CSF

T1/T17

Cell contact, costimulation

Macrophage TLR NLR Peptidoglycan Lipopolysaccharide Heat shock proteins

Neutrophil

Mast cell

Tissue cell

IL-10 IL-1Ra IL-18BP sIL-1R sTNFR IL-27 IL-35 TGF-β

Endothelial cell

C H R O N I C I N F L A M M A T I O N

FcR Immune complexes Acute phase reactants Complement

B cell

BLyS APRIL

Figure 23-3  Cytokines regulate complex cellular networks in chronic inflammation. Cytokines regulate interactions between T1 cells and antigen presenting cells (dendritic cells [DC]), and thereafter they promote cell-cell contact and soluble interactions between T cells, macrophages, neutrophils, endothelial cells, fibroblasts, B cells, and target tissue cells (e.g., mesangial cells, renal tubular epithelial cells, keratinocytes). Tissue cells may make ­substantial contributions to organ dysfunction through inflammatory mediator release. Crucial to these pathways are the synergistic combinations of cytokines that operate as “cassettes” (synergistic teams) or together with cell-cell, contact-dependent interactions. The latter are mediated via membrane cytokine expression or through cell surface receptors, including integrin and immunoglobulin superfamily adhesion molecules and members of the interleukin (IL)-1R and tumor necrosis factor (TNF)–receptor superfamilies. Chronicity is maintained on the basis of overproduction of proinflammatory moieties relative to the presence of anti-inflammatory mediators. Soluble cytokines also regulate activation of additional effector leukocytes (see Tables 23-1 through 23-8), including mast cells and eosinophils, which are not shown here because they may not be characteristic of the T helper type 1 (Th1) response shown. They may be relevant, however, in inflammatory arthritis. ECM, extracellular matrix; FcR, Fc receptor; IFN, interferon; TGF, transforming growth factor; TLR, Toll-like receptor.

B Cells and Cytokine Release in Chronic Inflammation

Growth Factors in Chronic Inflammation

Cytokines are crucial to B cell maturation, proliferation, activation, isotype switching, and survival (see Chapter 10). Cytokine-mediated B cell activation is important in immune complex generation, B cell antigen presentation, B cell–T cell interactions, and germinal center formation. Particular importance has been placed on the TNF superfamily cytokines, BLyS and APRIL. These cytokines are crucial for B cell development, survival, and optimal activation. B cells represent a potent source of cytokines such as IL-6 and IL-10. B cells also have been considered important inducers of macrophage-derived cytokine release. This process may operate primarily via immune complex formation42 or through regulation of T cell activation (with B cell help). Complex regulatory feedback loops involving cytokine expression and B cells are likely important in a range of rheumatic diseases in which B cells are of paramount pathophysiologic importance.

Many data document the importance of growth factor families in chronic inflammation. TGF-β superfamily members, including TGF-β isoforms and bone morphogenetic protein family members, warrant particular reference. TGF-β is critically involved in processes of cell proliferation, diff­ erentiation, inflammation, and wound healing.43 Bone morphogenetic proteins, in addition to regulating inflammatory responses, are paramount in determining cartilage and bone tissue development and remodeling.44 As such, they are of increasing interest in the pathogenesis of several rheumatic diseases.

Innate Cell Lineages in Chronic Inflammation Cytokines potently activate innate response cells that c­ontribute to the chronic inflammatory lesion of a variety of rheumatic diseases. Tables 23-1 through 23-8 document relevant examples in which neutrophils, natural killer cells, eosinophils, and mast cells may be recruited and activated by the presence of appropriate cytokine combinations.

CYTOKINE EFFECTS BEYOND IMMUNE REGULATION A striking feature of the cytokine field concerns the broad functional pleiotropy exemplified in the effects of cytokines in normal physiologic and adaptive processes. Cytokine activities are found in muscle, adipose tissue, central nervous system, and liver, mediating normal regulation of metabolic pathways and modulation imposed by altered tissue conditions. Examples are found not only in the release of adipokines that regulate adipose metabolic pathways, but also in the release of conventional cytokines by fat pads in inflammatory synovitis.

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SUMMARY Cytokines represent a diverse family of glycoproteins active across a broad range of tissues. Their pleiotropic functions and propensity for synergistic interactions and functional redundancy render them intriguing therapeutic targets. So far, single cytokine targeting has proved useful in several rheumatic disease states. Further elucidation of the biology and functional interactions within this expanding family of bioactive moieties is likely to prove informative in resolving pathogenesis and in generating novel therapeutic options. REFERENCES   1. Locksley RM, Killeen N, Lenardo MJ: The TNF and TNF receptor superfamilies: Integrating mammalian biology. Cell 104:487, 2001.   2. Marshak-Rothstein A: Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol 6:823, 2006.   3. Bresnihan B, Baeten D, Firestein GS, et al: OMERACT 7 Special Interest Group: Synovial tissue analysis in clinical trials. J Rheumatol 32:2481, 2005.   4. Haringman JJ, Gerlag DM, Zwinderman AH, et al: Synovial tissue macrophages: A sensitive biomarker for response to treatment in patients with rheumatoid arthritis. Ann Rheum Dis 64:834, 2005.   5. Gadina M, Hilton D, Johnston JA, et al: Signaling by type I and II cytokine receptors: Ten years after. Curr Opin Immunol 13:363, 2001.   6. Bravo J, Heath JK: Receptor recognition by gp130 cytokines. EMBO J 19:2399, 2000.   7. Dubois S, Mariner J, Waldmann TA, et al: IL-15Ralpha recycles and presents IL-15 in trans to neighboring cells. Immunity 17:537, 2002.   8. Francis K, Palsson BO: Effective intercellular communication distances are determined by the relative time constants for cyto/chemokine secretion and diffusion. Proc Natl Acad Sci U S A 94:12258, 1997.   9. Feldmann M, Andreakos E, Smith C, et al: Is NF-kappaB a useful therapeutic target in rheumatoid arthritis? Ann Rheum Dis 61(Suppl 2):13, 2002. 10. Hajeer AH, Hutchinson IV: TNF-alpha gene polymorphism: Clinical and biological implications. Microsc Res Tech 50:216, 2000. 11. Hurme M, Lahdenpohja N, Santtila S: Gene polymorphisms of interleukins 1 and 10 in infectious and autoimmune diseases. Ann Med 30:469, 1998. 12. Kontoyiannis D, Pasparakis M, Pizarro TT, et al: Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: Implications for joint and gut-associated immunopathologies. Immunity 10:387, 1999. 13. Anderson P: Post-transcriptional regulation of tumour necrosis factor alpha production. Ann Rheum Dis 59:3, 2000. 14. Gueydan C, Droogmans L, Chalon P, et al: Identification of TIAR as a protein binding to the translational regulatory AU-rich element of tumor necrosis factor alpha mRNA. J Biol Chem 274:2322, 1999. 15. Saito K, Chen S, Piecyk M, et al: TIA-1 regulates the production of tumor necrosis factor in macrophages, but not in lymphocytes. Arthritis Rheum 44:2879, 2001. 16. Budagian V, Bulanova E, Paus R, et al: IL-15/IL-15 receptor biology: A guided tour through an expanding universe. Cytokine Growth Factor Rev 17:259, 2006. 17. Ferrari D, Chiozzi P, Falzoni S, et al: Extracellular ATP triggers IL-1 beta release by activating the purinergic P2Z receptor of human macrophages. J Immunol 159:1451, 1997. 18. Fantuzzi G, Dinarello CA: Interleukin-18 and interleukin-1 beta: Two cytokine substrates for ICE (caspase-1). J Clin Immunol 19:1, 1999. 19. Wallach D, Varfolomeev EE, Malinin NL, et al: Tumor necrosis factor receptor and Fas signaling mechanisms. Annu Rev Immunol 17:331, 1999. 20. Liew FY: T(H)1 and T(H)2 cells: A historical perspective. Nat Rev Immunol 2:55, 2002. 21. Takayanagi H, Kim S, Taniguchi T: Signaling crosstalk between RANKL and interferons in osteoclast differentiation. Arthritis Res 4(Suppl 3):S227, 2002.

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22. Weaver CT, Harrington LE, Mangan PR, et al: Th17: An effector CD4 T cell lineage with regulatory T cell ties. Immunity 24:677, 2006. 23. Shevach EM, DiPaolo RA, Andersson J, et al: The lifestyle of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells. Immunol Rev 212:60, 2006. 24. Vey E, Zhang JH, Dayer JM: IFN-gamma and 1,25(OH)2D3 induce on THP-1 cells distinct patterns of cell surface antigen expression, cytokine production, and responsiveness to contact with activated T cells. J Immunol 149:2040, 1992. 25. McInnes IB, Leung BP, Sturrock RD, et al: Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-alpha ­production in rheumatoid arthritis. Nat Med 3:189, 1997. 26. Unutmaz D, Pileri P, Abrignani S: Antigen-independent activation of naive and memory resting T cells by a cytokine combination. J Exp Med 180:1159, 1994. 27. McInnes IB, Leung BP, Liew FY: Cell-cell interactions in synovitis: Interactions between T lymphocytes and synovial cells. Arthritis Res 2:374, 2000. 28. Sebbag M, Parry SL, Brennan FM, et al: Cytokine stimulation of T lymphocytes regulates their capacity to induce monocyte production of tumor necrosis factor-alpha, but not interleukin-10: Possible relevance to pathophysiology of rheumatoid arthritis. Eur J Immunol 27:624, 1997. 29. Dayer JM, Burger D: Cytokines and direct cell contact in synovitis: Relevance to therapeutic intervention. Arthritis Res 1:17, 1999. 30. Ribbens C, Dayer JM, Chizzolini C: CD40-CD40 ligand (CD154) engagement is required but may not be sufficient for human T helper 1 cell induction of interleukin-2- or interleukin-15-driven, contactdependent, interleukin-1beta production by monocytes. Immunology 99:279, 2000. 31. Hayes AL, Smith C, Foxwell BM, et al: CD45-induced tumor necrosis factor alpha production in monocytes is phosphatidylinositol 3-kinase-dependent and nuclear factor-kappaB-independent. J Biol Chem 274:33455, 1999. 32. Foey A, Green P, Foxwell B, et al: Cytokine-stimulated T cells induce macrophage IL-10 production dependent on phosphatidylinositol 3-kinase and p70S6K: Implications for rheumatoid arthritis. Arthritis Res 4:64, 2002. 33. Yamamura Y, Gupta R, Morita Y, et al: Effector function of resting T cells: Activation of synovial fibroblasts. J Immunol 166:2270, 2001. 34. Fickenscher H, Hor S, Kupers H, et al: The interleukin-10 family of cytokines. Trends Immunol 23:89, 2002. 35. Cope AP: Studies of T-cell activation in chronic inflammation. Arthritis Res 4(Suppl 3):S197, 2002. 36. Jungo F, Dayer JM, Modoux C, et al: IFN-beta inhibits the ability of T lymphocytes to induce TNF-alpha and IL-1beta production in monocytes upon direct cell-cell contact. Cytokine 14:272, 2001. 37. Hyka N, Dayer JM, Modoux C, et al: Apolipoprotein A-I inhibits the production of interleukin-1beta and tumor necrosis factor-alpha by blocking contact-mediated activation of monocytes by T lymphocytes. Blood 97:2381, 2001. 38. Chan ES, Cronstein BN: Molecular action of methotrexate in inflammatory diseases. Arthritis Res 4:266, 2002. 39. Breedveld FC, Dayer JM: Leflunomide: Mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis 59:841, 2000. 40. Burger D, Begue-Pastor N, Benavent S, et al: The active metabolite of leflunomide, A77 1726, inhibits the production of prostaglandin E(2), matrix metalloproteinase 1 and interleukin 6 in human fibroblast-like synoviocytes. Rheumatology (Oxf) 42:89, 2003. 41. Manna SK, Mukhopadhyay A, Aggarwal BB: Leflunomide suppresses TNF-induced cellular responses: Effects on NF-kappa B, activator protein-1, c-Jun N-terminal protein kinase, and apoptosis. J Immunol 165:5962, 2000. 42. Chantry D, Winearls CG, Maini RN, et al: Mechanism of immune complex-mediated damage: Induction of interleukin 1 by immune complexes and synergy with interferon-gamma and tumor necrosis factor-alpha. Eur J Immunol 19:189, 1989. 43. Chen W, Wahl SM: TGF-beta: Receptors, signaling pathways and autoimmunity. Curr Dir Autoimmun 5:62, 2002. 44. Abe E: Function of BMPs and BMP antagonists in adult bone. Ann N Y Acad Sci 1068:41, 2006.

24

Cell Survival and Death in Rheumatic Diseases Keith B. Elkon

KEY POINTS The three types of cell death are apoptosis, autophagy, and necrosis. Apoptosis proceeds through defined biochemical pathways that are initiated through death receptors on the cell surface or by intracellular signals emanating from damaged organelles. Phagocytes recognize alterations on the surface of dead and dying cells signaling them to engulf the intact apoptotic cell or necrotic cell debris. Defects in apoptosis and defective clearance of dead and dying cells lead to immune responses to self (autoimmunity). Many anti-inflammatory, immunomodulatory, and newer biologics affect cell survival pathways and offer new opportunities for therapeutic intervention.

HISTORY AND CONCEPTS APOPTOSIS Illustrations of cells undergoing apoptosis were made almost as soon as stains were used to examine the appearance of cells in different tissues. Drawings of ovarian follicles undergoing cell death made more than 100 years ago show cell shrinkage and nuclear condensation. Subsequent descriptions of the appearance of subcellular particles during cell death, referred to as “pyknosis,” chromatin margination, and other terms, included many features now recognized as apoptosis. The history of this subject is reviewed elsewhere.1 The modern understanding of apoptosis began with the electron microscopic descriptions of morphologic changes characterized by shrinkage of hepatocytes (i.e., shrinkage necrosis) after ischemic or toxic injury to the liver. The term apoptosis was coined by Kerr and colleagues in 19722 to describe the form of death that was “consistent with an active, inherently controlled phenomenon” characterized by cell shrinkage, nuclear condensation, and cell blebbing (Fig. 24-1).2 This term also conveyed the concept of cell death that was similar to leaves falling from a tree (apo means “from” and ptosis means “a fall” in Greek), implying a regulated “mechanism of cell deletion, which is complementary to mitosis.”2 Further developments in apoptosis paralleled advances in molecular biology, genetics, and biochemistry. The detection of a nucleosomal ladder3 was important because it defined a biochemical event (i.e., nucleosomal cleavage) and provided a simple electrophoretic test for detection of apoptotic cell death that remains a standard in

the field (see Methods of Detection later in this chapter). Another landmark was the discovery in the 1980s that the death of cells during the development of the nematode Caenorhabditis elegans was under strict genetic control. The death of these cells could be perturbed by mutation of a few genes called ced (for cell death abnormal) genes.4 Ellis and Horvitz4 determined that two ced genes, ced3 and ced4, encoded death effectors, whereas ced9 was an antiapoptotic gene. Most of the remaining ced genes were responsible for engulfment and removal of the “corpses.” This simple model in which CED-3 is the main death protease that is activated by CED-4 and inhibited by CED-9 has served as a paradigm for defining apoptotic pathways in mammalian cells (Fig. 24-2). In 2002, Horvitz was awarded the Nobel Prize for his discoveries in regard to genetic regulation of programmed cell death. Mammalian cells are more complex and, as discussed later in detail, have multiple defined pathways that follow the basic C. elegans model. The molecules within these pathways, the downstream effectors of apoptosis, the caspases (cysteine aspartate proteases), and the proteins implicated in the clearance of apoptotic cells are discussed in detail later. Regulation of cell death is important in many diseases, including cancers, autoimmune diseases, and degenerative disorders.5,6 The relevance of apoptosis to rheumatic disorders is summarized at the end of this chapter. PROGRAMMED CELL DEATH Although the term apoptosis originally referred to the appearance of dying cells in certain contexts as explained previously, the concepts of atrophy, cellular or tissue involution or regression, and degeneration also had been appreciated for hundreds of years, yet the two phenomena were not associated until more recently. Perhaps the most precise descriptions of cells that died in an orderly and apparently programmed fashion were documented in developmental biology. Examples included the involution of cells between digits, metamorphosis of insect larvae, and the death of specific cells during the development of C. elegans. NECROSIS Necrosis (from the Greek nekros meaning “corpse”) is distinguished from apoptosis predominantly by morphologic appearances.7 Necrotic cells are swollen, and electron microscopy reveals disorderly fragmentation of chromatin and severe damage to the mitochondria (see Fig. 24-1). The cellular membrane loses integrity and becomes permeable to vital dyes such as trypan blue and propidium iodide (Fig. 24-3). The distinction between apoptosis and necrosis remains 379

380

ELKON 

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Cell Survival and Death in Rheumatic Diseases

M

C P C

P

V

P

M

A

B

C

Figure 24-1  Electron microscopic morphology of apoptosis. A, Cytotoxic T cell (lower left) conjugated to its target, P815 (a murine mast cell), before the initiation of cell death. B, Induction of apoptotic changes in P815. Note the reduction in target cell size, nuclear condensation, and vacuoles with relative preservation of organelles. C, Osmotic lysis and necrosis in P815 induced by antibody and complement. Note the increased size of the nucleus and apparently random fragmentation of the chromatin. Organelles are severely disrupted. C, dense chromatin; M, mitochondria; P, nuclear pore;  V, vacuoles. (Adapted from Russell JH, Masakowski V, Rucinsky T, et al: Mechanisms of immune lysis, III: Characterization of the nature and kinetics of the cytotoxic T lymphocyte induced nuclear lesion in the target. J Immunol 128:2087, 1982.)

C. elegans

Mammalian

Egl-1

? Bax

CED-9

Bcl-2

CED-4

Apaf-1

CED-3

Caspase 9

CED-2

crkII

CED-12

ELMO

CED-5

DOCK 180

CED-10

Rac

CED-1

CD91

CED-6

GULP

CED-7

ABC-1

Regulation

Execution

1. Engulfment 2.

Figure 24-2  Caenorhabditis elegans paradigm of apoptosis. Genes involved in the regulation, execution, and clearance of apoptotic cells during the development of C. elegans and their mammalian homologues are shown. In this figure, only the most closely related homologues are indicated, but, as described in the text and shown in subsequent figures, the complexity in mammalian cells is much greater. At least half of the CED proteins are involved in engulfment and removal of apoptotic corpses. There are two distinct, but partially overlapping pathways of engulfment in C. elegans: CED-2, CED-12, CED-5, and CED-10, which most likely regulate cytoskeletal changes, and CED-1 and CED-6, which may be involved in recognition (CED-1) and upstream signal transduction (CED-6). CED-7 is homologous to the mammalian ATP-binding cassette transporter-1 (ABC-1),  which likely affects membrane dynamics. The lower right panel shows a schematic of the two proposed pathways for apoptotic cell ingestion in mammalian cells. In pathway (1), an unknown receptor triggers activation of the GTPase, RhoG, which leads to transport of the scaffolding protein, ELMO, to the cell membrane. There, Dock 180, a guanine exchange factor, promotes Rac activation leading to activation of the cytoskeleton and phagocytosis. In pathway (2), activation of the CED1 homologue (most likely CD91) interacts with the adapter protein, GULP, and downstream activation of the cytoskeleton.

important from numerous perspectives. In contrast to the genetic and biochemical programs that regulate apoptosis, necrotic cells usually result from death “by accident”— from thermal or drug injury, infection, or infarction of an organ. Because of the uncontrolled release of lysosomal and granular contents, necrotic cells induce a proinflammatory immune response, whereas apoptotic cells usually elicit an anti-inflammatory response. The same inducers (e.g., ischemia, hydrogen peroxide) may produce apoptosis or necrosis, depending on the severity of the injury and the rapidity of cell death. The cell’s fate is determined partly by cellular energy reserves, especially adenosine triphosphate (ATP).8 ATP is generated by oxidative phosphorylation in mitochondria and by glycolysis in the cytosol. Some inducers may cause apoptosis initially followed by necrosis (postapoptotic necrosis). This is likely to occur when removal of the apoptotic cells is delayed. AUTOPHAGY Autophagy is an alternative, nonapoptotic form of programmed cell death that has gained attention more recently. The term autophagy means to eat oneself, and in this process, cells switch to a catabolic program in which cellular constituents are degraded for energy production as a survival mechanism during periods of nutrient stress. In cells undergoing autophagy, a double membrane vesicle forms and encapsulates whole organelles leading to degradation after fusion with lysosomes. The ATG gene family, including ATG7 and beclin1, a protein that is highly conserved from yeast through humans, is involved in autophagic cell death.9 The protein beclin1 is monoallelically deleted in a variety of human cancers and may function in control of cell growth and tumor suppression.10 When metabolic substrates are depleted, autophagic death shares many morphologic features with necrotic cell death11 and may be seen in neuronal cell death associated with polyglutamine repeats. Autophagy may play a role in the survival of lymphocytes after growth factor withdrawal.11 Additional details of the autophagic process are reviewed elsewhere.12

100

101

102

103

100

101

102 Annexin V

103

104

200 160 120 80 40 0

F

0

200

B

Counts

101

G0/G1

M1

100

M1

TMRM

102

M1

103

104

C

0

4

6 hr

D

0 200 400 0 200 400 G H Figure 24-3  Methods for detection of apoptotic cells. A variety of methods are available for the identification and quantification of dying cells; a sampling is shown here. Methods A-C depend on changes to the cell surface membrane, mitochondria, and caspase activation, whereas methods D-H detect changes in the nucleus. A, Apoptotic thymocytes were incubated with fluorescein isothiocyanate–  conjugated annexin V in the presence of the dye propidium iodide (PI), which permeates cells with severely damaged cell membranes. Cells in the bottom left quadrant (not stained for annexin or PI) are alive; cells in the lower right quadrant are early apoptotic; cells in the upper right quadrant are late apoptotic (stain with annexin and admit PI). For cells in suspension, such as lymphocytes, annexin V binding to phosphatidylserine is the most commonly used method to detect early apoptotic cells. B, Human embryonic kidney cells were incubated in medium alone (upper panel) or medium containing valinomycin, an ionophore that increases ionic permeability of the inner mitochondrial membrane (lower panel). The cells were incubated with tetramethylrhodamine methyl ester (TMRM), a cell-permeable dye that binds to the outer mitochondrial membrane proportional to its membrane potential (Δψ), and analyzed by flow cytometry. The fluorescence intensity for the apoptotic cells is lower as a result of loss of mitochondrial membrane potential. Other probes used in similar assays for mitochondrial potential are rhodamine 123 and the carbocyanine dye DiOC6. C, Cells were induced to undergo apoptosis by anti-Fas antibodies. Cell extracts taken at 0, 4, and 6 hours postinduction were analyzed for poly-ADP ribose polymerase (PARP) cleavage by Western blot analysis. The 4-hour and 6-hour samples show partial cleavage of PARP (arrow). Western blot for detection of activated caspase 3 also is used. D, Mouse peritoneal macrophages were incubated with apoptotic thymocytes, cytocentrifuged onto glass slides, and stained with Diffquik (Dade Behring, AG, Deefield, IL). Arrows indicate ingested apoptotic cells with condensed nuclei. E, Jurkat T cells were induced to undergo apoptosis, stained with the dye bisBENZIMIDE (Hoechst No. 33342; Sigma, St. Louis, Mo) and viewed by immunofluorescence microscopy. Arrows indicate condensed nuclei. F, Normal (left panel) or apoptotic (right panel) cells were permeabilized and incubated with RNase, and their DNA was stained with PI according to the method of Nicoletti and colleagues.81 The cells were analyzed by flow cytometry, and staining in the subdiploid peak (smaller than the G0/G1 peak and labeled M1 in the histogram) reflects the extent of apoptosis. G, Normal and apoptotic cells were lysed, and the nuclei were removed by centrifugation. Cytosolic extracts were applied to agarose gels, and components were resolved by electrophoresis. Ethidium bromide staining of the extract made from live cells reveals high-molecular-weight DNA that remains close to the application well (left lane), whereas the extract from apoptotic cells shows loss of high-molecular-weight DNA and the appearance of the typical ladder of nucleosomes. H, Six-micrometer sections were made from a normal mouse thymus. The cells were permeabilized and incubated with biotinylated deoxyuridine triphosphate in the presence of terminal deoxynucleotidyl transferase. Nicked DNA incorporated the labeled deoxynucleotide and was detected by staining with peroxidase-labeled streptavidin and substrate (dark area).

E

A

PI

104

| 

Counts

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Cell Survival and Death in Rheumatic Diseases

Module*

Component of

DD

Death receptors, adapters,   Protein-protein interaction kinases

DED

Adapters, caspases

Protein-protein interaction

CARD

Caspases, adapters, NODs

Protein-protein interaction

BH (1-4)

Bcl-2 family

Protein-protein interaction

Pyrin

Pyrin family

Protein-protein interaction

LRR

Pyrin family, NODs

Protein-protein interaction

­Receptors in the TNF family (TNFR) include at least six receptors capable of transmitting apoptosis (see later) and receptors such as CD40, CD30, BlyS/BAFF/TALL, and TACI15 that trigger survival or proliferation or both partly through activation of nuclear factor kB (NFkB). Although most receptors of the TNFR family exert their effects primarily within the immune system, some members (e.g., p75NGFR, TNFR I and II) seem to serve important functions in the nervous system and other organs. Some TNFRlike proteins, such as PV-T2, PV-A53R, and CAR1, are encoded by viruses and may contribute to their virulence.15

NBS/NOD

Pyrin family, NODs

Nucleotide binding,   oligomerization

DEATH RECEPTORS

Table 24-1  Modular Components of Proteins   Involved in Apoptosis and Inflammation* Function

*See references 50 and 161 for further discussion. BH, Bcl-2 homology; CARD, caspase recruitment domain; DD, death domain; DED, death effector domain; LRR, leucine-rich repeats; NBS, nucleotide binding site; NOD, nucleotide oligomerization domain.

BIOCHEMISTRY OF APOPTOSIS A schematic diagram of the cell death program is shown in Figure 24-2. A brief outline of each major functional component within the program, from the signals for death to removal of the apoptotic cells, is discussed here, but space limitations preclude a detailed analysis of the layers of regulation at each step of the pathway. Post-translational protein modifications, such as phosphorylation, nitrosylation, and oxidation, provide additional complexities that are under intense study. Apoptosis and its Relevance to Autoimmunity13 offers more detailed reviews of the biochemistry and relationship of apoptotic pathways to immune function. The specialized proteins involved in apoptosis and its regulation contain numerous modules or domains that are predominantly involved in promoting protein-protein interactions (Table 24-1). These domains may be found in receptors, adapters, effectors, or inhibitors. As discussed subsequently, these domains occur in proteins involved in apoptosis and inflammation. It has been suggested that death domain (DD), death effector domain (DED), caspase recruitment domain (CARD), and Pyrin domains all evolved from the prototypic DD fold corresponding to an antiparallel six-helix bundle.14 In general, similar domains bind so as to facilitate homotypic interactions leading to oligomerization of the same protein or binding to different proteins in a signaling pathway. These changes usually lead to conformational alterations, which lead to further protein recruitment. Other domains, such as nucleotide binding site (NBS), specify nucleotide binding.

DEATH LIGANDS, RECEPTORS, AND SIGNALS Death of a cell may result from intracellular stress activating an intrinsic death program or may be forced on the cell by the interaction of a death ligand with a death receptor (see Fig. 24-2). Death receptors belong to the tumor necrosis factor (TNF) receptor superfamily of proteins, which comprises approximately 25 members.15,16 This family of receptors is responsible for diverse biologic responses, such as inflammation, proliferation, antiviral activity, and cell death.

The death receptors identified, including Fas, TNFR I, DR-3 (TRAMP/wsl/APO-3), DR-4 (TRAIL), DR-5, and DR-6, share homology in their intracellular domains over a 70-amino-acid region termed the death domain.17 Three decoy receptors have been identified, two (DcR1 and DcR2) that bind and inhibit their ligand, TRAIL, and one (DcR3) that binds Fas ligand. These decoy receptors presumably modulate cytotoxic function of the ligands, but the biologic contexts remain to be fully defined. Alternative splice forms and shedding of the receptors and ligands also down-modulate their function. TNFR family members are characterized by two to six cysteine-rich domains (CRDs) in their extracellular regions.15 The co-crystal structure of TNFR I and lymphotoxin-α indicates that the CRDs project from the cell surface in a linear array, making distinct contacts with ligands at subunit interfaces. The first CRD also may be responsible for preassembly of the receptor as trimers that undergo further conformational alterations on ligand engagement. The three-dimensional structure of the DD has been solved by nuclear magnetic resonance spectroscopy and has been shown to consist of six amphipathic α-helices that create a unique fold.18 Functionally, the DD seems to be a novel protein-protein association motif that facilitates homotypic interactions. The DD of Fas and TNFR I self-associate, recruiting adapter proteins that also contain DD and that directly or indirectly mediate receptor signal transduction (see Fig. 24-2). DEATH RECEPTOR SIGNAL TRANSDUCTION This section focuses predominantly on signaling from Fas and TNFR because these are the best-characterized members of the death receptor subfamily, and it is likely that other death receptors signal through similar pathways. As illustrated in Figure 24-4, Fas and TNFR1 share a common death pathway. Binding of Fas ligand to Fas causes conformational changes in the receptor cluster leading to recruitment of intracellular adapter molecules. Initially, aggregation of Fas induces uptake of the adapter protein, FADD, to the DD of Fas. FADD has two structural domains—a C-terminal DD, which mediates Fas binding, and an N-terminal DED. The FADD DED allows recruitment of procaspase 819,20 and procaspase 1021 through DED-DED interactions. Procaspases 8 and 10 have a bipartite structure comprising a DED and an enzymatic caspase domain, the latter linking Fas aggregation with the execution phase of apoptosis. The apposition of procaspases 8 and 10 to the activated Fas complex leads to autocatalytic cleavage and conversion of the proenzymes to activated proteases, which

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Bax

Pore Bip Cyt c

FADD

TRADD RIP DED

ER stress

Bak

DD

TRAF IRE

Bid

TRAF NFκB

383

Abnormal protein processingfolding, glycosylation Increased Ca2+

Mitochondrial stress

Fas

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Genotoxic damage, p53 Drugs, loss of growth factor

Death receptors

TNFR

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Caspase 9

PERK

Caspase 12, (7)

Apoptosome Caspase 8,10

Execution Attenuation of protein synthesis

JNK, ATF6

Caspase 3, (6)

Dissolution

PS

CAD, Acinus, AIF, DNase II Potential binding of β2 glycoprotein, annexin V, clotting factors

Cleavage of structural (fodrin, lamins), functional (DNA-PK,Ö) proteins Chromatin cleavage

nucleosomes

Figure 24-4  Mammalian apoptotic pathways. Cell death can be initiated by multiple pathways, including an extrinsic ligand-induced pathway (left panel), an intrinsic pathway mediated by the mitochondria (middle panel), and an intrinsic pathway mediated through the endoplasmic reticulum (ER) (right panel). Examples of stimuli that can induce each of these pathways are shown and discussed in further detail in the text. These pathways differ in the upstream caspases activated, but converge to cleave the effector caspases, such as caspase 3, during execution of apoptosis. Tumor necrosis factor receptor (TNF-R) and other “death receptors” also can signal cell survival by activation of NFкB. During ER stress, unfolded proteins release the ER chaperone protein, Bip, from binding to the stress sensor proteins, IRE, PERK, and ATF6. PERK attenuates protein synthesis, whereas ATF6 and JNK are transcription factors that upregulate the expression of proapoptotic proteins that contain unfolded protein response elements such as CHOP (GADD 153) and caspases. In mice, caspase 12 is the initiator caspase, whereas in human cells, caspase 4 and caspase 7 have been implicated. The alterations that occur during dissolution of the cell are too numerous to mention, but a few are highlighted in view of their potential relevance to autoimmunity (see text). Exposure of phosphatidylserine (PS) on the cell surface (left lower panel) provides a simple means for detection of apoptotic cells through binding annexin V and may be relevant to the generation of antiphospholipid autoantibodies and coagulation disorders in vivo. Cleavage products of chromatin (lower middle panel) and proteins, such as lamins and DNA-PK, may be antigenic. AIF, apoptosis-inducing factor; CAD, caspase-activated

are released and able to initiate a proteolytic cascade leading to programmed cell death. In some cell lines, caspase 8 cleavage also results in cleavage of the proapoptotic molecule Bid, which activates the mitochondrial amplification cascade (type II pathway) (see Fig. 24-4).22 Although the six DD-containing receptors initiate cell death in certain contexts, all may signal cell survival and proliferation in different cell types and in different contexts. The ability to signal an opposite cell fate depends on the recruitment of proteins such as the TNFR-associated factors that activate NFкB, promoting cell survival (see later). DEATH LIGANDS Fas ligand (FasL) (CD178) is a 40-kD type II transmembrane protein that shares 15% to 35% amino acid identity with the TNF superfamily of ligands. FasL is expressed constitutively

in the anterior chamber of the eye and in the testis, but is induced when CD8+ cells, T helper type 1 CD4+ T cells, and some natural killer cell populations become activated.23 In lymphocytes, expression of ligand is tightly regulated, and activity on the cell surface is short-lived because metalloproteases cleave the extracellular portion of the ligand into soluble, functional molecules. The zinc metalloprotease, TNF-α converting enzyme (TACE), is a membraneanchored member of the disintegrin family of proteases that cleaves active TNF-α from the cell surface.24,25 FUNCTION IN IMMUNE REGULATION Although the role of Fas and FasL interactions in the thymus is controversial,26 this pathway is involved in the maintenance of immune privilege in the eye and the testis, in the pathogenesis of graft-versus-host disease, and in immune

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evasion by tumors.23 The major physiologic function of Fas and FasL in the immune system is the preservation of peripheral tolerance. This preservation is achieved by the phenomenon of activation-induced cell death, whereby CD8+ cells, T helper type 1 CD4+ T cells, and possibly natural killer cells induce apoptosis of activated T cells, B cells, and macrophages. The deletion of activated immune cells removes the source of proinflammatory molecules, prevents the continued presentation of self-peptides by primed (high levels of costimulatory molecules) antigen presenting cells, and eliminates B cells that have mutated to self-specificity in the germinal centers.27 These topics are discussed in greater detail elsewhere in this textbook, and the consequences of Fas deficiency are described later in this chapter. Although TRAIL signals apoptosis through DR4 and DR5 predominantly in tumor cells, more recent evidence suggests that TRAIL plays a role in negative selection of thymocytes.28 Similarly, DR3 (the receptor for the ligand TWEAK) also has been implicated in negative selection.29 Finally, DR6 plays a role in immunologic homeostasis as evidenced by enhanced T cell and B cell proliferation in DR6-deficient mice.30

INTRINSIC CELL DEATH PATHWAYS: INITIATION AND EXECUTION OF APOPTOSIS Cells need constant sources of nutrition and depend on a variety of signals for active maintenance of survival. Loss of signals from neighboring cells31 or withdrawal of growth factors or cytokines results in initiation of a cell death program. Damage or stress to intracellular organelles may be induced from outside or within the cell. This section discussses injury or stress to DNA, mitochondria, and the endoplasmic reticulum. GENOTOXIC INJURY Mutations occur frequently in mammalian DNA and usually are promptly repaired. If repair fails, or DNA is severely damaged by radiation or drugs, the transcription factor p53 (“guardian of the genome”) is upregulated and phosphorylated by DNA damage sensors, such as ATR and ATM. Activated p53 induces a cell cycle arrest through induction of the cyclin-dependent kinase inhibitor p21. If the DNA damage is repaired, cell cycle arrest is abrogated, whereas if the injury cannot be repaired, the cell undergoes apoptosis. The importance of p53 as a tumor suppressor is illustrated by the high frequency of p53 mutations in cancers.32 p53 induces apoptosis partly by transcription of death effectors, such as Bax, which cause mitochondrial stress. In addition, activation of the transcription factor Foxo-1 upregulates the expression of Bim, FasL, and TRAIL.33 MITOCHONDRIAL STRESS Mitochondria are cytoplasmic organelles that contain their own 16-kb genome encased by inner and outer membranes with numerous proteins, including cytochrome c, situated between these membranes (see Fig. 24-4). Mitochondria help to maintain redox potential and constitute the energy powerhouse of the cell through the generation of ATP by

oxidative phosphorylation. These biochemical pathways create an electrochemical gradient (Δψ) that is positive and acidic on the outside and alkaline on the inside of the mitochondrial membrane. Spanning the inner membrane is the adenine nuclear translocator, which mediates ATP transport (with the voltage-dependent anion channel [VDAC]—see later) to the cytosol. The VDAC, which is permeable to solutes of approximately 5000 kD, is situated on the outer mitochondrial membrane.34 Genotoxic injury, reduced supply of nutritional or growth factors, increased intracellular calcium, reactive oxygen intermediates, and exposure to certain chemicals, such as staurosporine, cause mitochondrial stress. These initiating factors lead to selective mitochondrial membrane permeabilization with the resulting dissipation of the proton gradient responsible for the Δψ (permeability transition), permeabilization of the outer membrane, and loss of ATP production. Mitochondria themselves are the major producers of reactive oxygen intermediates, which in excess damage nucleic acids, proteins, and membrane lipids. When mitochondrial membrane permeabilization is initiated, cytochrome c is released from the intermitochondrial space into the cytosol (see Fig. 24-4). In the cytosol, cytochrome c and the cofactors Apaf-1 and ATP or dATP assemble with caspase 9 to form a molecular aggregate called the apoptosome that promotes the cleavage of procaspase 9 into its active form.35 Caspase 9 acts on effector caspases, such as caspase 3, resulting in the caspase cascade that leads to the cleavage and inactivation of a wide variety of substrates within the cell (see Fig. 24-4). A caspase-independent, apoptosis-inducing factor (AIF) also is released from the mitochondria and induces nuclear changes and cell death by less well-defined pathways.36 ENDOPLASMIC RETICULUM STRESS The main functions of the endoplasmic reticulum are to regulate intracellular calcium flux and to promote proper folding of nascent proteins. In the contiguous conduit, the Golgi apparatus, post-translation modifications, such as glycosylation and isoprenylation, are executed. Elaborate mechanisms are in place to ensure that errors in protein folding do not occur, but if they do, an “unfolded protein response” is initiated (see Fig. 24-4). The endoplasmic reticulum/Golgi apparatus initiates apoptosis if calcium flux is excessive, if unfolded proteins persist, or if post-translational protein modification is abnormal.37 Release of the cleaved IRE protein leads to degradation of 28S RNA and termination of protein synthesis. In contrast to the death receptor or mitochondrial pathways, apoptosis is executed through caspase 12 in mice and possibly caspase 4 in mammals.38 Many of the same molecules that regulate apoptosis in the mitochondria, the Bcl-2 family in particular, also affect endoplasmic reticulum–mediated apoptosis, however, possibly through control of intraluminal calcium. ANTIAPOPTOTIC PROTEINS: FLIP, Bcl-2, IAPs, and Akt Cellular homeostasis within each bodily system is carefully regulated. Excessive cell growth or premature cell death translates into diseases, as discussed in the last part

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of this chapter. The death and survival pathways are finely balanced, and each cell death program may be attenuated, often at multiple levels. Before discussion about how the death program is executed, the way in which cell death is regulated by inhibitors of apoptosis is discussed. Inhibition of Death Receptors In most resting cell types that express Fas on their cell surface (e.g., lymphocytes), the receptor is nonfunctional. Resistance to death is explained by low levels of expression of the receptor and by active inhibition by a protein called Fas long inhibitory protein (FLIP). FLIP resembles the structure of caspase 8 and competes with caspase 8 for recruitment to FADD. This prevents FADD from initiating apoptosis. When lymphocytes become activated, FLIP is usually degraded, allowing Fas signal transduction to occur unimpeded. Similarly, a protein called SODD (silencer of death domain), attenuates TNFR1 signal transduction. Bcl-2 Family of Cell Death Regulators The Bcl family comprises more than 18 members.39 Bcl-2 is the prototype antiapoptotic protein that was first discovered to be overexpressed in certain B cell lymphomas (Bcl). Of particular significance, Bcl-2 overexpression did not enhance cell proliferation (most cells were in the G0/G1 phase of the cell cycle), but rendered the cells more resistant to death. The antiapoptotic members (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, and A1) contain three to four of the characteristic Bcl-2 homology (BH) domain motifs, and most possess the N-terminal BH4 domain and the hydrophobic C-terminal membrane anchor, accounting for their attachment to mitochondrial, endoplasmic reticulum, and nuclear membranes. Virus-encoded proteins (BHRF1, LMW5-HL, ORF16, KS-Bcl-2, and E1B-19K) have similar antiapoptotic functional properties to Bcl-2. The proapoptotic members of this family can be subdivided into two groups—the Bax/Bak-like proteins (Bax, Bak, Bok, and BCl-Xs), which contain two to three BH3 domains, and the BH3-only subset (Bad, Bik, Bid, Hrk, Bim, Noxa, Puma, and Bmf), which contain only the single domain. Bcls are regulated at the transcriptional and the post-transcriptional levels by a multitude of stimuli. How do Bcls regulate apoptosis? One level of regulation is conferred by binding interactions (homodimerization or heterodimerization) between members via their BH1, BH2, and BH3 domains.40 Although the outcomes vary for each specific pair, homodimerization of Bcl-2 or Bax potentiates their antiapoptotic or proapoptotic function respectively, whereas heterodimers may potentiate or abrogate function of one member of the pair. Bax and Bak have been shown to be pivotal downstream effectors of intrinsic apoptotic pathways. A possible model is that Bcl-2 (or homologues) usually heterodimerizes with Bax and Bak preventing apoptosis. Increased expression of a BH3 proapoptotic protein binds to Bcl-2, releasing Bax and Bak to induce apoptosis. Bcls such as Bcl-2 and Bcl-XL also may bind to Apaf-1 and prevent it from activating caspase 9, analogous to the regulation of CED-4 by CED-9 in C. elegans (see Fig. 24-1). Bcl regulation of cell death is closely connected to mitochondrial function. The physical association of Bcl-2 family proteins with the outer mitochondrial membrane and

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the close structural similarity between the BH1 and BH2 domains and bacterial pore-forming proteins such as colicin41 allow them to regulate ion fluxes or the transfer of small molecules from the membrane. In vitro models suggest that Bax and Bak promote opening of the VDAC, allowing the release of cytochrome c into the cytosol, whereas Bcl-2 binds directly to the VDAC and closes it.34 Intracellular Inhibitors of Apoptosis Intracellular inhibitors of apoptosis (IAPs) are a separate family of antiapoptotic proteins that are highly conserved through evolution. The neuronal apoptosis inhibitory protein (NAIP) was discovered through the association of NAIP mutations in patients with the severe form of spinal muscular atrophy. Seven additional members of the family (c-IAP-1, c-IAP-2, X-IAP, survivin, ILP2, ML-IAP, and Bruce) that share a baculovirus IAP repeat domain have subsequently been identified, and most contain a RING domain that functions as an E3 ligase presumably targeting interacting proteins for proteasomal degradation. IAPs such as X-IAP directly inhibit effector caspases.42 IAPs block apoptosis induced by a variety of stimuli, including Fas, TNF-α, ultraviolet irradiation, and serum withdrawal, and survivin is overexpressed in certain cancers and in the rheumatoid arthritis (RA) synovium.43 In some cells, the antiapoptotic effect of IAPs is eliminated by the release of a protein called Smac/Diablo from the mitochondria. Akt Akt is a cytosolic protein kinase (protein kinase B) that plays a special role in prevention of apoptosis because it links cell activation through PI-3 kinase with multiple transcription factors. Phosphorylation of Akt is antagonized by the phosphatase PTEN. When phosphorylated, Akt promotes cell survival by altering the function of the intrinsic (mitochondrial) and the extrinsic (death receptor) pathways of apoptosis. Specifically, this includes inactivation of proapoptotic molecules, such as caspase 9 and Bad, and activation of survival pathways that include NFкB and forkhead transcription factors that inhibit FasL.44 The antiapoptotic molecules also may be cell type specific or context specific.

CASPASES Caspases are cysteine-containing proteases that have an unusual substrate specificity for peptidyl sequences with a P1 aspartate residue.45,46 These proteases are 30 to 50 kD in size and comprise an aminoterminal prodomain, a large subunit domain, and a small subunit domain. The active site cysteine residue is contained within the conserved pentapeptide, QACxG, on the large subunit of the enzyme, whereas most of the substrate specificity is determined by the small subunit. The upstream caspases 8, 9, 10, 2, and 4 have large prodomains that interact with regulatory proteins such as FADD for caspases 8 and 10 and Apaf-1 for caspase 9 (see Fig. 24-4). Presumably, clustering of these complexes allows autocatalytic cleavage of the large and small subdomains to form the active tetramer. Effector caspases such as caspases 3, 6, and 7 have small prodomains and are thought to be cleaved into their active forms by the upstream caspases.

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Members of the caspase family can be divided into three functional subgroups based on their substrate specificities.47 Group I members (caspases 1, 4, and 5) are potently inhibited by the serpin CrmA; group II members (caspases 2, 3, and 7) are specific for DExD; and group III members (caspases 6, 8, 9, and 10) are specific for I/V/LExD, a sequence that also is contained at the junctions of the caspase subunits themselves. Granzyme B produced by cytotoxic T cells has a substrate specificity similar to that of group III caspases and is capable of inducing apoptosis through this pathway. Identification of the substrate specificity of caspases has led to numerous practical applications, including the ability to quantify activity using fluorogenic tetrapeptide substrates and blockade of proteolytic activity with noncleavable cellpermeable tetrapeptide analogues. The effector caspases are necessary for the execution of apoptosis. They cleave specific substrates, such as the structural proteins fodrin, gelsolin, and lamins, key intracellular enzymes involved in DNA repair (e.g., poly-ADP ribose polymerase, DNA-PK) (see Fig. 24-4). These changes facilitate inactivation of synthetic functions of the cell, dissolution of the nuclear membrane, and packaging of cellular proteins into apoptotic blebs on the cell surface. Caspases also cleave regulatory proteins such as Bcl family members and the inhibitor of caspase-activated DNase (CAD). Cleavage of CAD inhibitor leads to the release of active CAD, which enters the nucleus and cleaves nucleosomes at the linker region, yielding the characteristic “DNA ladder” (see Figs. 24-3 and 24-4).48,49 Not all caspases are involved in the execution of apoptosis. Human caspases 1, 4, 5, and 12 and mouse caspases 1, 4, 11, and 12 are most likely involved in inflammation. Caspase 1 originally was defined as the enzyme that cleaves interleukin (IL)-1β (IL-1-converting enzyme) into its active form. It has been shown more recently that caspase 1 and caspase 5 interact and form a multiprotein complex that has been called the inflammasome (analogous to the apoptosome).50 Caspase 1 and caspase 5 bind to the adapter proteins ASC (PYCARD) (caspase 1) and NALP1 (DECAP) (caspase 5) by their CARD domains. ASC and NALP1 are mutidomain proteins that contain many of the protein interaction domains listed in Table 24-1. The N-terminus of the protein, pyrin, which is mutated in familial Mediterranean fever, binds to ASC. More recent studies indicate, however, that the C-terminus of pyrin, which is mutated in familial Mediterranean fever, binds directly to IL-1β, suggesting that pyrin normally directly exerts an inhibitory effect on IL-1β.51 Caspases are tightly regulated by their own prodomains and by Bcl and IAP family members. In addition, viral proteins, such as the serpin CrmA, produced by cowpox, and p35, produced by baculovirus, are potent inhibitors of caspases.

REMOVAL AND DEGRADATION OF APOPTOTIC AND NECROTIC CELLS Of the 14 C. elegans death genes (ced1 through ced14), at least half encode proteins that are required for engulfment of apoptotic cells (see Fig. 24-2).52 CED-7 is present in the membrane of the apoptotic cell and the phagocyte, whereas the remaining proteins function in the phagocyte to execute

two partially overlapping pathways of engulfment. CED-1 is a receptor that recognizes changes in the apoptotic cell and signals through CED-6 to activate the phagocyte. CED-2, CED-5, CED-10, and CED-12 most likely form a functional complex that promotes the cytoskeletal changes required to engulf the apoptotic prey.53 The mammalian counterparts are described in Figure 24-2, and their signaling pathways are discussed in detail elsewhere.54 Within the immune system alone, more than 109 apoptotic cells are removed from the body each day. These apoptotic cells are generated in vast numbers in the central lymphoid organs, such as the thymus and bone marrow, by out-of-frame rearrangements of antigen receptors, negative selection, or simple “neglect.” A significant load of apoptotic cells is produced in the peripheral immune system because of the relatively short life span of lymphocytes and myeloid cells and secondary selection of high-affinity B cells in germinal centers. The specialized sites of selection (i.e., thymus, bone marrow, and lymphoid follicles) have remarkably efficient phagocytes that rapidly remove the dying cells. An early event that occurs in apoptotic cells is the appearance of phosphatidylserine on the cell surface membrane (see Fig. 24-4). This membrane asymmetry (phosphatidylserine is usually located on the inner surface of the membrane) is caused by the reduced function of a translocase and possibly by activation of a lipid scramblase.55 Phosphatidylserine probably does not act as a ligand itself, although oxidation of phosphatidylserine or phosphatidylcholine may engage the scavenger receptor, CD36.56 Phosphatidylserine is recognized by numerous serum opsonins, such as annexin I, Gas6, β2 glycoprotein 1, and milk fat globule epidermal growth factor 8 (MFG-E8). This heterogeneity allows the protein bridge to interact with different receptors (Fig. 24-5). MFG-E8 facilitates apoptotic cell clearance in germinal centers,57 whereas C1q deficiency leads to apoptotic cell accumulation in the kidney.58 Complement components, such as C1q and iC3b, also opsonize apoptotic cells for recognition and efficient clearance by macrophages as discussed later. Natural IgM antibodies and acute-phase proteins such as C-reactive protein amplify serum complement deposition.59,60 Other serum opsonins or bridging molecules include thrombospondin, which bridges the αvβ3 and CD36 receptors,61 and collectins (mannose binding protein, C1q and surfactant proteins). Collectin binding receptors are controversial (see Stuart and colleagues62 for discussion). The endoplasmic reticulum protein calreticulin is unique in that it is translocated from the endoplasmic reticulum to the cell surface of apoptotic cells, but also can be detected at low concentrations on live cells.63 Despite the detection of only limited chemical alterations on the apoptotic cell membrane, blockade of a large and diverse number of receptors on phagocytes can impair the uptake of apoptotic cells (see Fig. 24-5). This diversity may be explained partly by the different cells and conditions used for phagocytic assays, but it likely also reflects the overlapping and partially redundant function of each individual receptor. All of the receptors identified have other functions, perhaps reflecting an evolution from receptors designed to remove apoptotic cells during development to pattern recognition receptors useful for host defense.64 Many of the receptors are integrins comprising the vitronectin receptor, αvβ3,65 αvβ5,66 complement receptors 3 (CD11b/CD18)

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Phagocyte

Annexin I CD91

CRT Gas6

PS

MER

MFG-E8 αv β3/5 Ox CD36

? TSP LFA-3

CD14 C3bi CR3, CR4

LyPtC lgM/ CRP Mannose

? CD91

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Engulfment of apoptotic cells or necrotic cell debris is the first step of the “clean-up” process, but swift degradation of cellular contents within the phagocyte and extracellularly is equally important. It has been shown that self-nucleic acids may be potent inducers of type 1 interferons and other inflammatory cytokines through activation of Toll-like receptors and Toll-like receptor–independent pathways.77 Extracellularly, opsonins, such as C-reactive protein, function as a scavenger for nucleoproteins,78 and serum contains a potent DNase, DNase 1, and abundant RNases. Within the cell, a specific acid-activated DNase, DNase II, resides in lysosomes and degrades ingested DNA, whereas multiple different RNases have been described. Failure to degrade these molecules likely explains why the debris from necrotic cells induces type 1 interferon, TNF-α, and other proinflammatory cytokines.72,79

DETECTION OF APOPTOSIS Numerous methods have been devised to detect cells undergoing apoptosis. These methods depend on the ­biochemical changes in the cell described earlier and are depicted in Figure 24-3. Electron microscopic examination (see Fig. 24-1) is still regarded as the “gold standard.”

Collectins Figure 24-5  Receptors, ligands, and opsonins (bridging proteins) implicated in recognition or phagocytosis of apoptotic cells (see text for details). CRP, C-reactive protein; CRT, calreticulin; LyPtC, lysophosphatidylcholine; Ox, oxidized form; PS, phosphatidylserine; PSR, phosphati­ dylserine receptor; TSP, thrombospondin.

and 4 (CD11c/CD18),67 and class A and B scavenger receptors. Nonintegrin receptors include the ATP-binding cassette transporter (ABC1)68; CD1469; and the closely related Tyro 3 family receptor tyrosine kinases, c-Mer, TYRO, and Axl.70 CD91 (low-density lipoprotein receptor–related protein), a multifunctional receptor, recognizes 30 different ligands, calreticulin being one.63 According to the “tether and tickle” model,71 some receptors, such as CD14 or CR3, serve as recognition structures and contribute to adhesion; others, such as CD91, convey signals for engulfment; and others, such as SIRP-α, prevent uptake. The ingestion of apoptotic cells has significant effects on the phagocyte and potentially on the T cell response to ingested antigens. In vitro72,73 and some in vivo74 studies suggest that uptake of apoptotic cells by macrophages induces the expression of immunosuppressive cytokines, such as transforming growth factor (TGF)-β1, prostaglandin E2, and possibly IL-10, by macrophages. These cytokines tend to dampen an immune response to self-antigens. Ligands for c-Mer, such as Gas6 and protein S on apoptotic cells, suppress production of IL-12 or TNF-α by macrophages. Apoptotic cells activate a specific transcriptional repressor of IL-12, GC-BP,75 which also suppresses adaptive immune responses. Because some peptides derived from apoptotic cells can be presented to lymphocytes by dendritic cells and possibly by macrophages through crosspriming,66,76 a question of paramount importance to studies of autoimmunity is whether self-peptides are presented after phagocytosis of apoptotic cells, and under what conditions they induce tolerance or immunity.

CELL MEMBRANE ALTERATIONS Annexin V binds to negatively charged phospholipids in a calcium-dependent manner and can readily detect the flip of phosphatidylserine to the outer surface of the cell membrane (see Fig. 24-3A). When annexin V is conjugated to fluorescein isothiocyanate, biotin, or other markers, it provides a convenient tag for detecting apoptotic cells by flow cytometry.80 Flow cytometry detection with annexin V is simple, is sensitive, and detects cells at an early stage of apoptosis. Annexin V also binds to necrotic cell membranes before complete rupture of the cell. Entry of trypan blue, as seen by light microscopy, or propidium iodide, as quantified by flow cytometry, into the cell indicates profound damage to the cell membrane indicative of necrosis. LOSS OF MITOCHONDRIAL MEMBRANE POTENTIAL As discussed earlier, multiple stimuli lead to apoptosis through the intrinsic mitochondrial pathway resulting in a loss of membrane potential. Several dyes, including rhodamine 123, tetramethylrhodamine methyl ester (see Fig. 24-3B), and DiOC6, bind selectively to mitochondria and provide a fairly sensitive measure of membrane potential. CASPASE ACTIVATION As discussed previously, caspases are normally present in an inactive state, but when activated, caspases recognize­ specific tetrapetide sequences. Caspase activity can be quantified directly in intact cells by flow cytometry­ analysis with cellpermeable fluorochrome tetrapeptide conjugates or in cell extracts by enzyme-linked immunosorbent assay that detects release of colorimetric dyes conjugated to the ­ tetrapeptides. Caspase activation also can be quantified indirectly, by Western blot analysis with antibodies specific for cleaved (activated)

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caspase 3 or by cleavage of specific caspase substrates. Cleavage of the nuclear protein, poly-ADP ribose polymerase, also is used to evaluate activation of caspase 3 (see Fig. 24-3C). CHROMATIN CONDENSATION AND DNA FRAGMENTATION Condensation of chromatin can be seen by light microscopy after nuclear staining (see Fig. 24-3D). This can be a sensitive screening method depending on the experience of the viewer, but confirmation with a more specific assay usually is required for verification. Chromatin condensation is more easily seen by staining with vital dyes, such as Hoechst No. 33342 bisBENZIMIDE (2′-(4-ethoxyphenyl)-5-(4-methyl-1-piperazinyl)-2,5′-bi-1H-benzimidazole) or DAPI (4′,6-diamidino-2-phenylindole), and inspection under fluorescence microscopy (see Fig. 24-3E). For precise quantification of nuclear condensation, DNA staining with propidium iodide and flow cytometry analysis of condensed (subdiploid) DNA is widely used (see Fig. 24-3F).81 As mentioned previously, DNA is cleaved by multiple DNases leading to the cleavage of nucleosomes at the linker region between histone binding, yielding the characteristic 180-bp DNA ladder (see Fig. 24-3G). DNA fragmentation results in free 3′-OH groups, which can be detected within the nuclei in tissue sections using biotinylated dNTPs (TUNEL assay) (see Fig. 24-3H).82 Although formation of the ladder is specific to apoptosis, generation of free ends of DNA is not and may be detected in DNA damaged by necrosis. It has been reported that TUNEL and in situ DNA incorporation methods may yield positive results in cells undergoing extensive DNA repair or rapid proliferation.83,84

APOPTOSIS IN RELATION TO RHEUMATIC DISORDERS The regulation of apoptosis is highly relevant to the pathogenesis and treatment of rheumatic disorders. Pertinent examples are discussed in the following sections.

(>5%) in ­circulating double-negative T cells. These patients had defective lymphocyte apoptosis in response to anti-Fas antibodies or FasL when tested in vitro, and most had heterozygous mutations in Fas affecting DD. These mutations impair Fas-mediated apoptosis through a dominant negative effect.89,90 Although Fas/FasL mutations are an exceptionally rare contributory factor to systemic lupus erythematosus (SLE), the Canale-Smith syndrome is informative because it suggests that defective apoptosis of cells of the immune system can cause systemic autoimmune diseases, such as idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and Guillain-Barré syndrome. It illustrates (as do the mouse models) that even when a single gene has a powerful effect on predisposition to systemic autoimmunity, the clinical expression of disease depends on the precise nature of the mutation89,90 and the interaction with modifying genes. There are several other examples of genetic alterations in death or survival genes that lead to lupus-like diseases in mice.91 Of particular interest is the overexpression of the ligand for the BlyS/BAFF/TALL/zTNF receptor that promotes the survival of B lymphocytes92 because increased expression of this ligand has been reported in SLE, Sjögren’s syndrome, and RA.93 Mutations in the p55/TNFR1/CD120a receptor in humans results in a periodic autoinflammatory syndrome called TNFR-associated periodic syndrome. Mutations predominantly occur in the first two CRDs of the receptor, resulting in reduced shedding of the extracellular domain of the receptor and reduced neutralization of circulating TNF-α.94 Increased lymphocyte survival resulting from overexpression of Bcl-2, knockout of Bim, reduction in PTEN activity,95 and increased survival of dendritic cells96,97 causes lupus-like autoimmunity in mice. Defective apoptosis of B cells or T cells may lead to inappropriate survival of self-reactive cells in the central (thymus or bone marrow) or peripheral immune system. Enhanced survival of dendritic cells may promote the activation and expansion of low-affinity self-reactive T cells.

DEFECTIVE APOPTOSIS OF IMMUNE CELLS

DEFECTIVE UPTAKE AND PROCESSING OF APOPTOTIC CELLS

Mice with mutations of Fas or FasL develop a syndrome characterized by lymphoproliferation (lpr) and generalized lymphadenopathy (gld) together with systemic autoimmunity.85 As might be expected from the key role described for Fas in activation-induced cell death, lymphadenopathy and splenomegaly are the consequence of failure of activated lymphocytes to die, resulting in an absolute increase in the numbers of T and B lymphocytes and by the accumulation of an unusual subset of T cells that do not express CD4+ or CD8+ coreceptors (i.e., double-negative T cells). The nature and extent of systemic autoimmunity vary according to the strain into which the Fas or FasL mutation has been bred.85 A syndrome of massive lymphadenopathy with systemic autoimmunity in children was reported by Canale and Smith in 1967. Subsequently, these and other lpr patients were found to have mutations in Fas.86-88 The syndrome (called Canale-Smith syndrome or autoimmune lympho­ proliferative syndrome) is characterized by lymphadenopathy or splenomegaly, autoimmune cytopenias (most commonly affecting platelets and red blood cells), and an increase

Autoantibodies were discovered in the 1940s and 1950s, and their molecular and functional identities were characterized in the 1980s and 1990s. Why the immune system targets a select subset of self-antigens (mainly nucleoproteins) in each disease has never been satisfactorily explained. The facts that autoantibodies target nucleosomes in SLE,98,99 and certain anticardiolipin antibodies cross-react with phosphatidylserine, which translocates to the cell surface during apoptosis,100 support the idea that autoantibodies target the products of apoptotic cells. Additional inferential evidence for this hypothesis comes from detection of lupus antigens in apoptotic blebs,101 modification of antigens by cleavage, and phosphorylation during apoptosis.102,103 Because apoptosis occurs on a vast scale in the central lymphoid organs and should render the host tolerant, under what conditions would apoptotic cells immunize? If apoptosis occurs in the presence of an adjuvant (virus, bacteria, or chemicals), tolerance may be lost, at least transiently. Abnormalities leading to the accelerated apoptosis of cells in the periphery or reduced uptake of dying cells allow

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cells to undergo postapoptotic necrosis which provokes a proinflammatory cytokine response from phagocytes72 as explained earlier. An increase in the rate of apoptosis of SLE peripheral blood mononuclear cells has been observed in vitro,104,105 suggesting that accelerated apoptosis occurs in vivo. Although SLE macrophage survival in vitro also is compromised, reduced macrophage phagocytosis of apoptotic cells has been reported in SLE.106 Experiments in mice and in human cells in culture indicate that phagocytosis of apoptotic cells is impaired in the absence of early complement components,58,67 and it is well known that deficiencies of early complement components predispose to human SLE.107 Knockout of members of the Tyro 3 receptor tyrosine kinases is associated with defective clearance of apoptotic cells and the expression of a lupuslike disease.70,108 It also is likely that the lupus-like diseases that occur in mice deficient in the acute-phase protein SAP result from reduced clearance of apoptotic cell debris.109,110 As mentioned previously, mammalian nucleic acids can potently stimulate Toll-like receptor–dependent and Tolllike receptor–independent pathways to generate inflammatory cytokines. A deficiency of DNase 1 led to lupus, and a conditional deficiency of DNase II caused RA-like disease in mice.110,111 In addition, nucleic acids contained within immune complexes have been shown to stimulate interferon-α by plasmacytoid dendritic cells, providing a plausible explanation for increased interferon-α observed in SLE and amplification of disease activity.112 PROLONGED EXPOSURE TO GROWTH FACTORS Histologically, RA is characterized by an accumulation of inflammatory cells in the synovium, leading to pannus formation and destruction of cartilage and bone. Although Fas and FasL can be detected in RA synovium, and evidence of apoptosis has been detected in RA synoviocytes,113,114 the extent of synoviocyte apoptosis is inadequate to counteract ongoing proliferation. This imbalance is explained by many factors. First, FasL is expressed at relatively low levels on synovial T cells,115 and soluble Fas or FasL competitors may impede Fas-induced apoptosis. Cytokines, such as TNF-α, IL-1β, and TGF-β1, which are overexpressed in the joints of patients with RA, favor synoviocyte proliferation and inhibit susceptibility to apoptosis.116-118 These and other signals reduce apoptosis of synoviocytes through activation of NFkB and increased expression of antiapoptotic proteins, including X-IAP and Akt.119-121 Growth of the pannus is compounded by inflammatory changes such as oxidation, which result in upregulation and mutations of the growth suppressor protein p53122 and IL-23, which promote or stabilize IL-17-producing T helper cells (Fig. 24-6). IL-23 has been shown to promote cell survival.123 The observations regarding apoptosis regulators in RA are significant because they provide an opportunity for therapeutic manipulation. Local administration of anti-Fas monoclonal antibodies to human T cell lymphotropic virus-1 tax transgenic mice or Fas ligand to collagen arthritis (mouse models of RA) led to an improvement in arthritis.124,125 Several strategies to modulate NFkB attenuate the growth of synovial cells. Administration of TRAIL also attenuated experimental arthritis, although this was not thought to be due to apoptosis,126 and an antibody to TRAIL-R2 (DR5)

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Growth cytokines, TNF-α, IL-1-β, TGF-β

Bcls

NFkB

Lymphocytes

Fas ligand flow Bcls

p53 NFκB

IAPs

Bcls

O*, NO Figure 24-6  Antiapoptotic phenotype of rheumatoid synovial fibroblasts. Cytokines and growth factors produced by macrophages and T cells lead to activation of NFкB and overexpression of antiapoptotic proteins, such as B cell lymphoma-2 (Bcl-2) family (Bcls). Inflammatory stimuli, release of nitric oxide (NO), and reactive oxygen intermediates (O*) upregulate and induce mutations of p53. Infiltrating lymphocytes have a Fas ligand “low” phenotype. IAPs, intracellular inhibitors of apoptosis; IL, interleukin; TGF, transforming growth factor; TNF, tumor necrosis factor.

induced apoptosis of RA synovial fibroblasts.127 Evidence is accumulating that fibroblasts in scleroderma also may be more resistant to apoptosis, and that TGF-β may promote this phenotype.128 TISSUE INJURY IN ORGAN-SPECIFIC AUTOIMMUNITY In contrast to systemic autoimmune diseases that are characterized by B lymphocyte stimulation leading to antibodymediated and immune complex–mediated tissue injury, many organ-specific autoimmune diseases are caused by a cell-mediated attack leading to the death of specific cell types within the organ. Cell targets are beta cells of the islets of Langerhans of the pancreas in insulin-dependent diabetes mellitus, oligodendrocytes in the brain in multiple sclerosis, the salivary and lacrimal glands in Sjögren’s syndrome, and myocytes in polymyositis.129 Programmed pathways of cell death (apoptosis) can be implicated in pathogenesis of some of these diseases, as illustrated by the resistance of Fas-deficient (lpr) mice to diseases such as diabetes and experimental encephalomyelitis. In many of these diseases, cell death at the site of injury also can be directly shown by DNA fragmentation (TUNEL staining) in situ. Apoptosis usually is considered noninflammatory, but, as discussed earlier, the context of cell death influences the immune response. Cytotoxic lymphocytes that induce cell death predominantly by perforin-mediated cell lysis (necrosis, although apoptotic changes also are observed through caspase 3 activation) or macrophage defects leading to delayed clearance of dying cells promote the release of proinflammatory cytokines, such as TNF-α.

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In most organ-specific autoimmune diseases, especially diseases for which adoptive transfers have been performed in animal models, CD4+ T cells have been shown to be critically involved in disease pathogenesis. Disease-promoting CD4+ T cells are restricted by major histocompatibility complex class II molecules and are unlikely to exert a direct cytotoxic action on the class I–bearing target cell (although CD4+ T cells can upregulate FasL). CD4+ cells may arm other effectors through the production of cytokines (interferon-γ); they may induce tissue injury through a “bystander pathway” involving macrophages or induce receptors for cell death on the target cell “assisted suicide pathway.” In Sjögren’s syndrome in humans, there is controversy about whether Fas or FasL is constitutively expressed in normal salivary glands, but the coexpression of both molecules in patients with Sjögren’s syndrome presumably causes cell death of acinar and ductal cells.130 Inflammatory myopathies, such as polymyositis and dermatomyositis, are autoimmune diseases that result in destruction of skeletal muscle fibers. Although Fas is upregulated on the myocytes in these diseases, expression also is increased in nonautoimmune muscle disorders, such as in metabolic myopathies, denervating disorders, and muscular dystrophies, but not in normal human muscle tissue.131 Detection of FasL on mononuclear cells invading the muscles in polymyositis and dermatomyositis patients with apoptosis of muscle cells implicates Fas/FasL in tissue injury in myositis.132 Increased expression of the T cell cytotoxic mediator perforin in some polymyositis and dermatomyositis patients133 indicates that granzyme-mediated myocyte injury also is involved. The tRNA synthetase antigens or their cleavage products may perpetuate inflammation by exerting chemotactic recruitment of immune cells through chemokine receptors.134 ACCELERATED APOPTOSIS IN DEGENERATIVE RHEUMATIC DISORDERS Apoptosis of chondrocytes occurs during normal development of joints, and accelerated cell death may be important in diseases such as osteoarthritis. The main mechanism underlying primary or secondary osteoarthritis is degradation of cartilage. Degradation is mediated by enzymatic and nitric oxide–induced breakdown of the extracellular matrix and insufficient new matrix synthesis. Normal and osteoarthritis-derived chondrocytes in the superficial and middle cartilage zones, the major areas involved in early cartilage degeneration, express Fas and are sensitive to Fasmediated death.135 Chondrocytes obtained from patients with osteoarthritis have enhanced spontaneous apoptosis in these zones compared with normal controls.136,137 Although nitric oxide also is capable of inducing apoptosis in chondrocytes, it does not seem to act through the Fas pathway.135 In an experimental model of osteoarthritis, transgenic mice lacking type II collagen, the main constituent of the extracellular matrix in cartilage, had high levels of apoptosis in their chondrocytes.138 Together, these findings suggest that apoptosis of chondrocytes plays a role in osteoarthritis, and that inhibitors of nitric oxide synthesis may be valuable in treating this disease. The therapeutic use of intra-articular Fas agonists in RA may be deleterious to chondrocytes.

Osteoporosis is a common disorder resulting from increased bone resorption, decreased bone synthesis, or a combination of the two. Several reports support the concept that estrogen exerts its beneficial effect in preventing osteoporosis by the induction of apoptosis in the bone-resorbing osteoclasts,139,140 and glucocorticoid-induced osteoporosis may be explained by an increased rate of apoptosis of osteoblasts and osteocytes.141 In the presence of macrophage colony-stimulating factor, osteoclasts differentiate from a myeloid precursor common to macrophages and dendritic cells. In addition to the numerous factors influencing bone turnover,142 a soluble member of the TNFR family, osteoprotegerin or osteoclastogenesis-inhibitory factor, inhibits osteoclast activity after binding to its cognate ligand, RANK ligand (osteoprotegerin ligand/TRANCE).143,144 RANK ligand is expressed on osteoblasts and on activated T cells. Engagement of the membrane form of the receptor induces activation of NFкB, enhancing the formation, survival, and resorptive activity of osteoclasts. A monoclonal antibody that blocks RANK ligand is currently in clinical trial for treatment of osteoporosis. DRUGS THAT AFFECT APOPTOTIC PATHWAYS Until more recently, therapy for inflammatory rheumatic disorders has been largely empiric. The types of drugs used include anti-inflammatory agents, such as corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs); immunomodulatory drugs, such as cyclosporine; and cytotoxic drugs, such as cyclophosphamide and azathioprine. Because most of these drugs impinge on crucial biochemical events within the cell, they have effects on pathways of apoptosis. Anti-inflammatory Drugs Glucocorticoids at high doses induce the death of lymphoid cells through transcriptional regulation by the glucocorticoid receptor. Corticosteroids modulate expression of numerous molecules that affect apoptotic programs—cytokines, cell cycle control proteins, c-myc, and Bcl-2—and inhibit NFкB activation, but the precise pathways that may operate in a cell-specific fashion145 and that are relevant to clinical efficacy remain to be defined. Patients on long-term steroid therapy also are susceptible to osteoporosis and osteonecrosis, which may be explained by bone loss caused by apoptosis of osteoblasts and osteocytes.141 The major mechanism of action of NSAIDs is inhibition of cyclooxygenases, which reduce the production of proinflammatory cytokines and prostaglandins (see Chapter 54). NSAIDs also are effective in the chemoprevention of colorectal tumors in genetically susceptible individuals. Their antineoplastic properties may be explained by an increase of the prostaglandin precursor arachidonic acid and by conversion of sphingomyelin to ceramide, a proapoptotic lipid.146,147 Immunomodulatory Drugs Cyclosporine and a closely related macrolide antibiotic, FK506, have potent immunosuppressive properties and are used to prevent allograft rejection. Both drugs modulate T cell and B cell immune responses by interfering with IL-2

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gene transcription mediated by nuclear factor of activated T cells, nitric oxide synthase activation, cell degranulation, and apoptosis.148 The reduced cytotoxic T lymphocyte activity is explained partly by impaired FasL induction secondary to the effect on nuclear factor of activated T cells,149,150 but effects on mitochondrial function also have been shown. Certain cell types, such as renal proximal tubules and synoviocytes or endothelial cells in RA, may be more susceptible to the proapoptotic effects of cyclosporine.151 Cytotoxic Drugs Many cytotoxic or immunosuppressive drugs that induce the suicide of lymphocytes, mostly through the p53 pathway (see Fig. 24-4), exert some anti-inflammatory effect. Although methotrexate has effects on adenosine receptors, even low-dose methotrexate induces apoptosis of activated lymphocytes in vitro and in RA patients, probably in a Fas-independent manner.152 Cyclophosphamide is an alkylating agent commonly used to treat many human cancers and severe autoimmune disease. Its efficacy has been attributed partly to apoptosis of tumor cells and perhaps of mesangial cells in glomerulonephritis.153 Induction of apoptosis also may account for certain adverse effects, such as oligospermia or azoospermia and pancreatic beta cell destruction. Bisphosphonates are the most potent antiresorptive drugs available and are widely used to treat various metabolic bone diseases, such as Paget’s disease, bone tumors, ectopic calcification, and osteoporosis. Although individual members of this family differ in their effects, their general mechanisms of action include direct and indirect effects on osteoclast recruitment, function, and survival.154 BIOLOGICS The remarkable success of anti-TNF-α therapy for the treatment of RA, other arthritides, and Crohn’s disease is generally attributed to blockade of TNF-α stimulation of the proinflammatory NFkB pathway (see Fig 24-4).155 In Crohn’s disease, it also has been reported, however, that anti-TNF-α monoclonal antibodies ameliorate disease through binding to cell-associated TNF-α and induction of apoptosis of macrophages and T cells.156,157 Etanercept and infliximab induced apoptosis of monocyte/macrophages in RA synovial tissue.158 B cell depletion therapy with anti-CD20 (rituximab) and other B cell antigens is becoming an increasingly used therapeutic modality. The mechanism of action has been studied most intensively in chronic lymphocytic leukemia B cells. Rituximab depletes B cells by induction of apoptosis associated with down-modulation of Bcl-2 and XIAP, activation of complement, and antibody-dependent, cell-mediated cytotoxicity.159 See also Chapters 58 and 59.

THERAPEUTIC INTERVENTION Understanding the biochemical pathways that regulate apoptosis offers new opportunities for therapeutic intervention, some of which are already in practice (Fig. 24-7). In antibody-mediated diseases, induction of apoptosis of B cells is effective. In cell-mediated diseases, such as Sjögren’s

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syndrome and polymyositis, it may be beneficial to induce apoptosis of the cytotoxic effector cell. In diseases characterized by macrophage activation and inflammatory tissue growth, induction of macrophage apoptosis by anti-TNF-α reagents already has been shown to be effective in RA and Crohn’s disease (see Fig. 24-7, A1). If a death receptor is selectively expressed on the cell to be killed, a death ligand could be administered. Examples of such a strategy are the use of Fas agonists or anti-TRAIL receptor antibodies in arthritis. Proapoptotic pathways also could be initiated from within the cell by gene therapy approaches (see Fig. 24-7, A2). Examples include blockade of NFkB or overexpression of Bax. Similarly, as discussed earlier, a cytokine or unwanted growth/differentiation promoter, such as TNF-α in RA or osteoprotegerin/RANK ligand in osteoporosis, can be blocked by a monoclonal antibody or soluble receptor fusion ­protein (see Fig. 24-7, A3). In diseases in which apoptotic cell death leads to loss of organ function, the death ligand could be blocked by a

A

Effector or target cell

2

Key: 1

3

B

Target cell

Activator Inhibitor Death receptor Growth receptor

1

2 Caspases

3 Figure 24-7  Avenues for therapeutic manipulation of apoptosis—  biologics in practice or clinical trials. Anti–tumor necrosis factor (TNF)  reagents work in part by engaging membrane TNF (mTNF) on activated macrophages and inducing apoptosis. Anti-CD20 antibodies eliminate B cells in part by inducing apoptosis. Anti-BAFF/BLyS reagents reduce B cell and possibly macrophage survival. Antibodies to RANK ligand reduce differentiation or survival of osteoclasts. Estrogens promote osteoclast apoptosis and bisphosphonates prevent it. Other approaches to modulation of apoptotic pathways are discussed in the text.

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­ onoclonal antibody or soluble receptor fusion protein (see m Fig. 24-7, B1). Even when the death pathway has not been fully ­determined, attempts can be made to interfere with upstream components of apoptosis well before the “point of no return.” Antiapoptotic genes with limited (e.g., protein FLIP blocks Fas pathway) or broad (e.g., Bcl-2 family) specificity can be introduced into the cell (see Fig. 24-7, B2). Further downstream, cell-permeable caspase inhibitors can block the execution phase of apoptosis in vivo, as illustrated experimentally (see Fig. 24-7, B3).160 All of these approaches are feasible, but they are limited by their potential adverse effects. Therapy must be relatively specific for the target cell because widespread prevention of cell death for sustained periods is likely to predispose to neoplasia.

SUMMARY Appreciation that death and survival of cells are highly regulated, and dissection of the biochemical pathways that are activated by different modes of intracellular stress have made an enormous contribution to understanding of the pathophysiology of human disease. Inherited mutations of apoptosis-regulatory molecules may cause systemic autoimmunity, dysregulation, or misdirection of other cell death and survival molecules, contributing to a whole range of musculoskeletal disorders. Many of the drugs used to treat musculoskeletal disorders exert potent effects on apoptotic programs. New biologic therapies that induce apoptosis of selected targets are already in use in rheumatic diseases, and many more, perhaps with greater selectivity, are likely to be developed. All of these findings suggest that further understanding of the regulation of apoptosis would have widespread implications for the pathogenesis and therapeutic manipulation of rheumatic disorders.

ADDENDUM Two additional receptors for the uptake the apoptotic cells have recently been described. Tim (T-cell immunoglobulinand mucin-domain-containing molecule) 4 is a member of the Tim family of type I membrane proteins that contain an immunoglobulin variable region-like domain, a mucinlike domain, a transmembrane region, and a variable intracellular domain. Tim4 is expressed on macrophages and dendritic cells and is reported to bind to PS on apoptotic cells and exosomes.162 The second receptor is brain specific angiogenesis inhibitor 1 (BAI1).163 BAI1 is a 7 transmembrane protein that belongs to the adhesion-type-G-protein coupled receptor (GPCR) family. The large extracellular portion of the molecule contains an integrin binding motif and thrombospondin type 1 repeats that mediate binding to PS. BAI1 is highly expressed on astrocytes in the brain but is also expressed on peripheral macrophages. Of note, BAI1 binds to ELMO (see Fig. 24-2) and is therefore considered the putative receptor for the type 1 pathway.

Acknowledgments Help and discussion from current and past laboratory members is gratefully acknowledged.

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106. Herrmann M, Voll RE, Zoller OM, et al: Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum 41:1241-1250, 1998. 107. Morgan BP, Walport MJ: Complement deficiency and disease. ­Immunol Today 12:301-306, 1991. 108. Scott RS, McMahon EJ, Pop SM, et al: Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411: 207-211, 2001. 109. Bickerstaff MCM, Botto M, Hutchinson WL, et al: Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity. Nat Med 5:694-697, 1999. 110. Napirei M, Karsunky H, Zevnik B, et al: Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat Genet 25:177-181, 2000. 111. Kawane K, Ohtani M, Miwa K, et al: Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443:998-1002, 2006. 112. Ronnblom L, Eloranta ML, Alm GV: The type I interferon ­system in systemic lupus erythematosus. Arthritis Rheum 54: 408-420, 2006. 113. Nakajima T, Aono H, Hasunuma T, et al: Apoptosis and functional Fas antigen in rheumatoid arthritis synoviocytes. Arthritis Rheum 38:485-491, 1995. 114. Firestein GS, Yeo M, Zvaifler NJ: Apoptosis in rheumatoid arthritis synovium. J Clin Invest 96:1631-1638, 1995. 115. Cantwell MJ, Hua T, Zvaifler NJ, et al: Deficient Fas ligand ­expression by synovial lymphocytes from patients with rheumatoid arthritis. Arthritis Rheum 40:1644-1652, 1997. 116. Kawakami A, Eguchi K, Matsuoka N, et al: Thyroid-stimulating ­hormone inhibits Fas antigen-mediated apoptosis of human thyrocytes in vitro. Endocrinology 137:3163-3169, 1996. 117. Tsuboi M, Eguchi K, Kawakami A, et al: Fas antigen expression on synovial cells was downregulated by interleukin 1. Biochem Biophys Res Commun 218:280-285, 1996. 118. Salmon M, Scheel-Toellner D, Huissoon AP, et al: Inhibition of T cell apoptosis in the rheumatoid synovium. J Clin Invest 99:439-446, 1997. 119. Fujisawa K, Aono H, Hasunuma T, et al: Activation of transcription factor NF-κB in human synovial cells in response to tumor necrosis factor. Arthritis Rheum 39:197-203, 1996. 120. Marok R, Winyard PG, Coumbe A, et al: Activation of the transcription factor nuclear factor κ-B in human inflamed synovial tissue. Arthritis Rheum 39:583-591, 1996. 121. Sugiyama M, Tsukazaki T, Yonekura A, et al: Localization of apoptosis and expression of apoptosis-related proteins in the synovium of patients with rheumatoid arthritis. Ann Rheum Dis 55:442-449, 1996. 122. Tak PP, Smeets TJ, Boyle DL, et al: P53 overexpression in synovial tissue from patients with early and longstanding rheumatoid arthritis compared with patients with reactive arthritis and osteoarthritis. Arthritis Rheum 42:948-953, 1999. 123. Langowski JL, Zhang X, Wu L, et al: IL-23 promotes tumour incidence and growth. Nature 442:461-465, 2006. 124. Fujisawa K, Asahara H, Okamoto K, et al: Therapeutic effect of the anti-Fas antibody on arthritis in HTLV-1 tax transgenic mice. J Clin Invest 98:271-278, 1996. 125. Zhang H, Yang Y, Horton JL, et al: Amelioration of collageninduced arthritis by CD95 (Apo-1/Fas)-ligand gene transfer. J Clin Invest 100:1951-1957, 1997. 126. Song K, Chen Y, Goke R, et al: Tumor necrosis factor-related ­apoptosisinducing ligand (TRAIL) is an inhibitor of autoimmune inflammation and cell cycle progression. J Exp Med 191:1095-1104, 2000. 127. Ichikawa K, Liu W, Fleck M, et al: TRAIL-R2 (DR5) mediates apoptosis of synovial fibroblasts in rheumatoid arthritis. J Immunol 171:1061-1069, 2003. 128. Jelaska A, Korn JH: Role of apoptosis and transforming growth ­factor beta1 in fibroblast selection and activation in systemic sclerosis. Arthritis Rheum 43:2230-2239, 2000. 129. Ohsako S, Elkon KB: Apoptosis in the effector phase of autoimmune diabetes, multiple sclerosis and thyroiditis. Cell Death Diff 6:13-21, 1999. 130. Kong L, Ogawa N, Masago R, et al: Bcl-2 family in salivary gland from Sjogren’s syndrome: Bax may be involved in the destruction of SS salivary glandular epithelium. Arthritis Rheum 39:S289, 1996.

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131. Behrens L, Bender A, Johnson MA, et al: Cytotoxic mechanisms in inflammatory myopathies: Co-expression of Fas and protective Bcl-2 in muscle fibres and inflammatory cells. Brain 120:929-938, 1997. 132. Sugiura T, Murakawa Y, Nagai A, et al: Fas and Fas ligand ­interaction induces apoptosis in inflammatory myopathies: CD4+ T cells injury in polymyositis. Arthritis Rheum 42:291-298, 1999. 133. Goebels N, Michaelis D, Engelhardt M, et al: Differential expression of perforin in muscle-infiltrating T cells in myositis and dermatomyositis. J Clin Invest 97:2905-2910, 1996. 134. Howard OM, Dong HF, Yang D, et al: Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T lymphocytes and immature dendritic cells. J Exp Med 196:781-791, 2002. 135. Hashimoto S, Setareh M, Ochs RL, et al: Fas/Fas ligand ­expression and induction of apoptosis in chondrocytes. Arthritis Rheum 40:1749-1755, 1997. 136. Hashimoto S, Ochs RL, Komiya S, et al: Linkage of chondrocyte apoptosis and cartilage degradation in human osteoarthritis. ­Arthritis Rheum 41:1632-1638, 1998. 137. Blanco FJ, Guitian R, Vazquez ME, et al: Osteoarthritis chondrocytes die by apoptosis: A possible pathway for osteoarthritis pathology. Arthritis Rheum 41:284-289, 1998. 138. Yang C, Li SW, Helminen HJ, et al: Apoptosis of ­ chondrocytes in transgenic mice lacking collagen II. Exp Cell Res 235: 370-373, 1997. 139. Kameda T, Mano H, Yuasa T, et al: Estrogen inhibits bone ­resorption by directly inducing apoptosis of the bone-resorbing osteoclasts. J Exp Med 186:489-495, 1997. 140. Okahashi N, Koide M, Jimi E, et al: Caspases (interleukin-1betaconverting enzyme family proteases) are involved in the regulation of the survival of osteoclasts. Bone 23:33-41, 1998. 141. Weinstein RS, Jilka RL, Parfitt AM, et al: Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids: Potential mechanisms of their deleterious effects on bone. J Clin Invest 102:274-282, 1998. 142. Jilka RL, Weinstein RS, Bellido T, et al: Osteoblast programmed cell death (apoptosis): Modulation by growth factors and cytokines. J Bone Miner Res 13:793-802, 1998. 143. Yasuda H, Shima N, Nakagawa N, et al: Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A 95:3597-3602, 1998. 144. Kong YY, Yoshida H, Sarosi I, et al: OPGL is a key regulator of ­osteoclastogenesis, lymphocyte development and lymph-node ­organogenesis. Nature 397:315-323, 1999. 145. Wang D, Muller N, McPherson KG, et al: Glucocorticoids engage different signal transduction pathways to induce ­apoptosis in thymocytes and mature T cells. J Immunol 176: 1695-1702, 2006. 146. Chan TA, Morin PJ, Vogelstein B, et al: Mechanisms underlying nonsteroidal antiinflammatory drug-mediated apoptosis. Proc Natl Acad Sci U S A 95:681-686, 1998. 147. Schwenger P, Bellosta P, Vietor I, et al: Sodium salicylate induces apoptosis via p38 mitogen-activated protein kinase but inhibits tumor necrosis factor-induced c-Jun N-terminal kinase/stress-activated protein kinase activation. Proc Natl Acad Sci U S A 94: 2869-2873, 1997.

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148. Thomson AW, Bonham CA, Zeevi A: Mode of action of tacrolimus (FK506): Molecular and cellular mechanisms. Therap Drug Monitor 17:584-591, 1995. 149. Anel A, Buferne M, Boyer C, et al: T cell receptor-induced Fas ligand expression in cytotoxic T lymphocyte clones is blocked by protein tyrosine kinase inhibitors and cyclosporin A. Eur J Immunol 24:2469-2476, 1994. 150. Migita K, Eguchi K, Kawabe Y, et al: FK506 augments activationinduced programmed cell death of T lymphocytes in vivo. J Clin Invest 96:727-732, 1995. 151. Cutolo M, Barone A, Accardo S, et al: Effect of cyclosporin on ­apoptosis in human cultured monocytic THP-1 cells and synovial macrophages. Clin Exp Rheumatol 16:417-422, 1998. 152. Genestier L, Paillot R, Fournel S, et al: Immunosuppressive ­properties of methotrexate: Apoptosis and clonal deletion of ­activated ­peripheral T cells. J Clin Invest 102:322-328, 1998. 153. Cha DR, Feld SM, Nast C, et al: Apoptosis in mesangial cells induced by ionizing radiation and cytotoxic drugs. Kidney Int 50:1565-1571, 1996. 154. Hughes DE, Wright KR, Uy HL, et al: Bisphosphonates ­ promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res 10:1478-1487, 1995. 155. Tak PP, Taylor PC, Breedveld FC, et al: Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis ­ factor α monoclonal antibody treatments in patients with rheumatoid ­arthritis. Arthritis Rheum 39:1077-1081, 1996. 156. Lugering A, Schmidt M, Lugering N, et al: Infliximab induces ­apoptosis in monocytes from patients with chronic active Crohn’s disease by using a caspase-dependent pathway. Gastroenterology 121:1145-1157, 2001. 157. Van den Brande JM, Braat H, van den Brink GR, et al: Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease. Gastroenterology 124: 1774-1785, 2003. 158. Catrina AI, Trollmo C, af Klint E, et al: Evidence that anti-tumor necrosis factor therapy with both etanercept and infliximab induces apoptosis in macrophages, but not lymphocytes, in rheumatoid arthritis joints: Extended report. Arthritis Rheum 52:61-72, 2005. 159. Clark EA, Ledbetter JA: How does B cell depletion ­ therapy work, and how can it be improved? Ann Rheum Dis 64(Suppl 4):iv-77-iv-80, 2005. 160. Rodriguez I, Matsuura K, Ody C, et al: Systemic injection of a tripeptide inhibits the intracellular activation of CPP32-like proteases in vivo and fully protects mice against Fas-mediated fulminant liver destruction and death. J Exp Med 184: 2067-2072, 1996. 161. Martinon F, Tschopp J: NLRs join TLRs as innate sensors of ­pathogens. Trends Immunol 26:447-454, 2005. 162. Miyanishi M, Tada K, Koike M et al. Identification of Tim4 as a phosphatidylserine receptor. Nature 450:435-439, 2007. 163. Park D, Tosello-Trampont AC, Elliott MR, et al. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/ Rac module. Nature 450:430-434, 2007.

25

Animal Models of Inflammatory Arthritis Wim B. Van Den Berg

KEY POINTS Animal models of arthritis do not fully resemble human rheumatoid arthritis. Animal models are tools to mimic various aspects of rheumatoid arthritis. Arthritis can be induced in animals by immunization with cartilage components, nonspecific immune stimuli, bacterial or viral components, or transgenic manipulation. Models have a defined onset and are useful for the kinetic evaluation of arthritis, cell and mediator involvement, and detailed analysis of joint erosion. Animal models provide direction for novel approaches to treatment, such as cytokine inhibition.

amounts of defined antibody cocktails and that chronicity and joint erosions are markedly amplified by the presence of a T cell component. Apart from insights into immune regulation, the further identification of downstream mediators of synovial macrophage and fibroblast activation and their involvement in joint erosion remains a prime focus. The process of cartilage erosion is hard to evaluate in patients. Synovial biopsies are now performed in many early arthritis clinics, but samples of damaged bone and cartilage become available only late in the process, after joint replacement. Models therefore provide the optimal tools for the detailed evaluation of mechanisms and kinetics of cartilage and bone destruction.

MODELS OF ARTHRITIS INDUCED MODELS Experimental animal models of arthritis have contributed to the understanding of basic mechanisms of joint disease. There is marked diversity among the numerous models, and arthritis has been induced by various stimuli, including the generation of autoimmunity to cartilage components, nonspecific skewing of autoimmunity with adjuvants, and triggering with exogenous agents such as bacteria and viruses. More recently, focused transgenic manipulation has added novel variants. No single animal model of arthritis truly represents the human disease. The wide variety of agents that can induce experimental arthritis with clinical and histopathologic features close to those of human arthritides indicates that disparate etiologic pathways may exist in rheumatoid arthritis (RA). Aspects peculiar to individual models are of value but must be interpreted with caution. Much can be learned from the general validity of mediator involvement and other common concepts. In particular, models provide valuable preclinical data for the development of novel treatments, both pharmacologic and biologic, and insights into relevant mechanisms common to both experimental arthritis and RA. Characteristic histopathologic features include immune complexes (ICs) in the articular cartilage layers and variable amounts of macrophages, T cells, and plasma cells in the synovium, often accompanied by fibrosis and synovial hyperplasia. Formation of autoantibodies, including rheumatoid factor and anticitrulline antibodies, is prominent, making B cell activation and IC-mediated cellular inflammation likely contributors to pathogenesis. Indeed, perceptions have changed over the years, and it is now accepted that IC arthritis models have their value, although it must be emphasized that erosive arthritis is achieved only with high

The models most widely used in a historical context for the investigation of RA were adjuvant arthritis (AA), collagen-induced arthritis (CIA), antigen-induced arthritis (AIA), and streptococcal cell wall (SCW) arthritis (Table 25-1).1 These models are classic examples of three driving elements: nonspecific immune deviation, targeted cartilage autoimmunity, and abundant exogenous or infectious triggers. T cells play a dominant part in all these models, and this feature is a major principle of chronic erosive arthritis. Although T cell–directed therapy in RA was once questionable, new insight into T cell subclasses and more subtle targeting of CTLA4 on T cell subsets show promise in this regard. The recent discovery of T helper type 17 (Th17) cells as a distinct, pathogenic T cell subset will boost the interest in T cell–driven arthritis models. A second common principle in the classic arthritis models is the presence of a chronic stimulus, either a persistent antigen or autoantigen akin to joint structures. Examples of persisting exogenous antigens are nondegradable bacterial cell walls in the synovial tissue or antigen trapped in collagenous reservoirs such as ligaments and articular cartilage. Both conditions reflect escape from proper clearance by the phagocytic system. By nature, autoantigens from the articular cartilage, such as collagen type II and proteoglycans, are persistent stimuli. These potential triggers become true arthritogens when tolerance is lost. Regulation of tolerance and underlying mechanisms of sensitivity of various mouse and rat strains has been a major research topic in animal models. It remains to be identified whether tolerance against endogenous autoantigens or so-called exogenous but commensal bacterial or viral antigens is regulated differently. Intriguingly, progression in human RA tends to decline when cartilage is fully destroyed. Moreover, total joint 397

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Table 25-1  Models of Arthritis Model

Abbreviation

IC†

T Cell

AI AI AI

– – –

+ + +

2, 5 3 4, 6

DBA mouse BALB/c mouse

CII-AI PG-AI

+ +

+ +

10, 11 12, 13

–

+

15, 16

– + –

+ + +

18, 19 23, 24 26

Species*

Feature

AA OIA PIA

Lewis rat DA rat DA rat

CIA PG-A

Referencess

Trigger-Induced Models, Nonspecific Immune Stimuli Adjuvant arthritis Oil-induced arthritis Pristane-induced arthritis Cartilage-Directed Autoimmunity Collagen-induced arthritis Proteoglycan-­induced arthritis

Infectious Agents, Exogenous Triggers Streptococcal cell wall arthritis

SCW-A

Lewis rat

Flare Antigen-induced arthritis Flare

SCW-F AIA AIA-F

Mouse Rabbit, mouse Mouse

Persistent bacteria–AI Th17 Persistent antigen Th17

HTLV KRN SKG GP130 TNFtg IL-1ra –/– IL-1tg

Mouse K/BxN mouse Mouse Mouse Mouse BALB/c mouse Mouse

Viral Tax antigen GPI-AI ZAP-70 T cell defect STAT3, T cell defect TNF overexpression Autoimmune T cells IL-1 overexpression

– + – – – ± –

+ + + + – + –

28 29, 30 31, 32 33, 34 35, 36 40, 41 39

P-CA P-GPI PLL-L

DBA mouse BALB/c mouse DBA mouse

Mouse CII antibody Mouse GPI antibody Cationic antigen

+ + +

– – –

30, 47 44

Transgenic Spontaneous Models HTLV-induced arthritis KRN arthritis SKG arthritis GP130 arthritis TNF transgenic arthritis IL-1ra transgenic arthritis IL-1 transgenic arthritis Immune Complex Models Collagen type II KRN serum PLL-lysozyme

*Used most commonly. †Immune complex (IC) as an early feature. AI, autoimmune; CII, collagen type II; GP, glycoprotein; GPI, glucose-6-phosphate isomerase; HTLV, human T cell leukemia virus; IL, interleukin; PLL, poly-Llysine; Th17, T helper type 17; TNF, tumor necrosis factor.

replacement often results in complete remission of arthritis in that joint, without the need for synovectomy. These are arguments for a direct role of cartilage antigens in the pathogenesis of arthritis or for an indirect role of cartilage components in the maintenance of arthritis. Structural mimicry does exist between bacterial peptidoglycans and cartilage proteoglycans, and bacterial triggers may influence autoimmune responses through their nonspecific adjuvant properties or antigenic mimicry. Bacterial flora has a major impact on numerous arthritis models, and the recent discovery of Toll-like receptors (TLRs) mediating bacterial signaling has boosted interest in its role in ­arthritis. TRANSGENIC MODELS Transgenic variants have been developed in recent years. They provide attractive new models by virtue of distinct engineering yet follow many of the aforementioned principles. Although these models can identify potential disturbances underlying autoimmune arthritis and the ensuing cytokines or autoantibodies that drive it, transgenic models are not necessarily more useful for the development of advanced targeted therapy in RA. Several examples are worthy of mention here and are discussed in more detail later.

Transgenic overexpression of a T cell viral antigen results in chronic arthritis, suggesting that a viral infection may be involved in RA. The production of autoantibodies and the accelerated onset of human T cell leukemia virus (HTLV) arthritis after collagen type II immunization implies that viral skewing of T cell responses to cartilage antigens may be one of the underlying mechanisms. In the KRN arthritis model, overexpression of a selfreactive T cell receptor leads to skewed regulation of T cell tolerance, with an ensuing excessive production of anti–glucose-6-phosphate isomerase (GPI) antibodies. This model resembles both CIA and AIA, where IC formation at the cartilage surface is a salient feature. GPI is a cationic endogenous protein with affinity for the articular cartilage, and autoantibodies accumulate at that site, explaining the predominance of joint disease in this general autoimmune model. Intriguingly, when regulatory control of interleukin (IL)1 is lost, T cell–dependent arthritogenic autoimmunity can develop. This was found in BALB/c mice depleted of IL-1ra, and IL-1, tumor necrosis factor (TNF), and IL-17 appeared to be critical players. It is likely that excessive cytokine production, including IL-1, is also an underlying mechanism in the classic adjuvant or oil-induced models. Other examples of manipulated T cell function leading to autoimmune arthritis are the SKG and GP130­ arthritis

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models. In SKG arthritis, aberrant T cell receptor function allows the positive selection of autoimmune T cells; in the GP130 model, a mutation in the IL-6 receptor induces enhanced signaling, illustrating that excessive IL-6 signaling can drive T cell–dependent autoimmune arthritis. Apart from these examples of T cell–related arthritis, transgenic models have taught us that cytokine overexpression is a driving arthritic principle, without the need for T or B cells. TNF transgenic mice develop arthritis that can be transferred with fibroblasts. Likewise, IL-1–­overproducing transgenic mice develop nonimmune arthritis. Human TNF transgenic mice have been instrumental in the ­development of the successful anti-TNF therapy with monoclonal ­antibodies and soluble receptors in RA patients. IMMUNE COMPLEX MODELS In line with the growing belief that autoantibodies are of pathogenic importance in RA, models based on the passive administration of autoantibodies have gained popularity. This has been enhanced by the successful introduction of anti–B cell therapy (rituximab) in RA and the identification of anticitrulline antibodies as early markers of RA development. Standard models use a cocktail of monoclonal anti–type II collagen (CII) antibodies or serum containing anti-GPI antibodies obtained from arthritic K/BxN mice. A fully passive system can be generated by the transfer of antilysozyme antibodies to mice bearing planted cationic lysozyme in the joint. The IC models are best suited for the identification of pathways of inflammation and tissue destruction downstream of IC activation. Such models are not suited for investigating B cell targeting. In addition, it should be stressed that excessive IC formation is needed for tissue destruction and that the models miss the unequivocal accelerating and exaggerating potential of combined IC and T cell triggering, which is evident in CIA and AIA.

MECHANISMS OF ARTHRITIS IN SPECIFIC MODELS RESPONSE TO NONSPECIFIC IMMUNOLOGIC STIMULI Injection of nonspecific agents with adjuvant activity—that is, the capacity to elicit an indirect immunologic response— can provoke experimental arthritis in certain species. The classic example is adjuvant arthritis (AA) in the Lewis rat.2 The precise contributions of the oil and mycobacterial components of Freund’s complete adjuvant in the pathologic pathway of this experimental disease remain unclear, but both may contribute. Adjuvant and Pristane Arthritis A bacterium-specific pathogenesis seems likely in AA, because conventionally bred rats are generally resistant to AA, whereas germ-free Fischer or Wistar rats are susceptible. Germ-free rats lack early contact with bacteria and therefore are not tolerized. This is in sharp contrast to ­pristane (mineral oil)–induced arthritis, which is suppressed in germ-free mice.

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Incomplete Freund’s adjuvant (lacking mycobacteria) and pristane can also induce arthritis in susceptible rats and mice, indicating that oil can override natural tolerance.3,4 Ultimately, arthritogenic consequences appear to depend on a reaction against either exogenous or autologous antigens. Heat shock proteins may be regulators in AA.5 In susceptible strains of animals, macrophages phagocytose nondegradable oil components, become intensely activated, produce large concentrations of proinflammatory cytokines (IL-1, IL-6, TNF), and subsequently may activate T and B cells. The results of polyclonal activation are apparent in pristane-induced arthritis, in which lymphadenopathy and hypergammaglobulinemia precede the onset of disease. Naturally occurring T cells that recognize T cell receptor peptides may regulate susceptibility, because these cells become activated before the development of disease. Regulatory network reactions, which, by definition, are autoimmune in nature, can skew responses toward pathogenic consequences. Expansion of autoreactive T and B cell populations can occur as a consequence of the adjuvant activation process, resulting in the migration of cells to the joint and subsequent immune-mediated joint damage and the production of a spectrum of autoantibodies against cartilage antigens. Production of rheumatoid factors in pristane-induced arthritis may amplify the autoreactive process. Disease onset is rapid in AA (2 weeks), often followed by spontaneous remission. Pristane arthritis has a slower onset (months) and exhibits remissions and relapses, with no indication of B cell involvement at the onset. The pristane model is highly suited to study genes controlling onset, severity, and chronicity.6 The spontaneous remission and lack of susceptibility to reinduction makes AA a suitable model for studies on the regulation of T cell tolerance. Histopathology of AA reveals major involvement of the bone marrow, marked bone erosion, and bone apposition and minor direct cartilage damage at early stages (Table 25-2). Indirect cartilage damage occurs later, mainly as a consequence of the loss of underlying bone. The latter may explain the cartilage protective effect of treatment with osteoprotegerin, which is a selective inhibitor of the osteoclast activator RANKL.7,8 Combination blocking of TNF and IL-1 results in optimal control of arthritis and joint destruction.9 AUTOIMMUNITY TO CARTILAGE COMPONENTS Articular cartilage is an intriguing tissue. It is the target of the disease, but it may also function as the trigger by releasing potential autoantigens and trapping exogenous antigens in its avascular matrix. Destructive forms of RA tend to decline when cartilage is fully destroyed, and arthritis also wanes in joints undergoing replacement surgery, both of which argue for cartilage’s crucial role in the arthritic process. Collagen and Proteoglycan Arthritis Classic arthritis models based on cartilage autoimmunity can be induced by immunization with either of the two major components of hyaline cartilage: CII and aggrecan proteoglycans. More recently, similar models have ­identified

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Table 25-2 Features of Common Arthritis Models Feature

AA

SCW-A

CIA

AIA

P-GPI

TNFtg

IL-1ra –/–

Impact of flora*

+

+

–

–

?

?

+

+

Induction

Systemic FCA

Systemic bacterial Systemic CII, Local antigen fragment FCA injection

Systemic serum

Transgenic

Transgenic

Transgenic

Arthritic stimulus

Bacteria, oil

Persistent bacteria CII

Planted antigen

GPI

TNF

IL-1, bacteria

Yeast

Mechanism

T cell

T cell

T cell, IC

T cell, IC

IC

TNF

IL-1–IL-17

IL-1– IL-17

Self-limited arthritis

+

–

±

–

–

–

–

–

Flares

Refractory

Spontaneous

Inducible

Inducible

Inducible

–

–

–

Chronic synovitis

±

++

+

++

+

++

++

++

Bone marrow inflammation†

++

+

±

±

–

+

+

+

Main site of expression

Ankle

Ankle

Peripheral

Various‡

Paw

Paw

Ankle

Ankle

Bone erosion

++

+

++

+

++

++

+

+

Bone apposition

+++

+

++

+

+

–

+

+

Cartilage erosion

±

±

++

++

++

±

+

+

Salient feature

Periostitis

Fibrosis

Fast erosion Local Fast erosion hyperreactivity

Role of IL-1 Role of IL-17 in erosion

SKG

Role of IL-17

*Impact of microflora on susceptibility of strains. †As an early feature. ‡Chosen by intra-articular injection. AA, adjuvant arthritis; AIA, antigen-induced arthritis; CIA, collagen-induced arthritis; CII, collagen type II; FCA, Freund’s complete adjuvant; GPI, glucose-6­phosphate isomerase; IC, ­ immune complex; IL, interleukin; P-GPI, passive GPI arthritis; SCW-A, streptococcal cell wall arthritis; TNFtg, tumor necrosis factor transgenic­.

other, less abundant cartilage components as potential autoantigens in arthritis. In principle, any cartilage matrix component can be a potential arthritogen, provided it is released in substantial amounts and natural tolerance is lost. CIA can be elicited in mice, rats, and primates,10,11 whereas proteoglycan arthritis has been established only in distinct BALB/ c mice.12,13 Both models require the induction of a vigorous immune response directed initially against the immunizing (heterologous) cartilage antigen, which subsequently reacts with autologous cartilage antigens. Susceptible strains of animals immunized with either CII or high-density aggrecan proteoglycans in adjuvant recognize specific epitopes. Autoreactive CD4+ T cells respond against either cross-reactive epitopes (antigens common to both the heterologous and autologous cartilage components) or cryptic epitopes (privileged antigens normally concealed from immune surveillance), and they elicit connective tissue antigen-specific T helper cells and autoantibodies. Adoptive and passive transfer experiments suggest that both immunologic elements are required for the generation of chronic arthritis, although transient but destructive forms can be elicited with cocktails of anti-CII autoantibodies only. The localization of antibody and reactive cells in synovial joints causes immunemediated cartilage damage, and the immune response may be perpetuated by the release of cartilage antigens. The pathologies of CIA and proteoglycan arthritis appear to be similar and include synovial hypertrophy and hyperplasia, giving rise to pannus formation, and severe cartilage erosion (Fig. 25-1). Although both models are considered T helper 1 (Th1) driven, interferon-γ (IFN-γ) deficiency makes BALB/c mice more susceptible to CIA, whereas it

prevents proteoglycan arthritis. Diversity in the antibody subclasses involved and skewed participation of the classic Th1 IFN-γ–producing and Th17 IL-17–producing cells may be responsible for this difference. Neutralization of TNF is efficacious in early CIA, whereas IL-1 blockade suppresses both early and fully established arthritis.14 INFECTIOUS AGENTS AND EXOGENOUS TRIGGERS The development of arthritis as a consequence of infection is apparent in both natural and induced animal models. Infectious agents may be trophic for the joint as a result of expression of adhesins or other molecules that promote sequestration within synovial tissues. Bacterial cell wall and mycoplasma membrane components may also provide nonspecific immune activation through mitogenic activity. Viral infection of synovial cells may elicit novel cell surface antigens or abnormal expression of activation antigens and the overproduction of autoantigens. Viral infection may also disrupt immune regulation, increasing proinflammatory cytokines and immune activity against normally immunologically privileged components of the joint. Streptococcal Cell Wall Arthritis Persistence of antigens from microorganisms within the joint is critical for the induction of arthritis. SCW experimental arthritis15 is induced in Lewis rats by the systemic injection of cell wall fragments of group A streptococci, which are highly resistant to biodegradation. A similar

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Figure 25-1  Macroscopic signs of peripheral inflammation in murine collagen arthritis. Histology shows examples of mild cartilage proteoglycan loss in the superficial cartilage layer at an early stage, advancing to full surface loss at later stages.

d­ isease can be induced with cell wall fragments from other bacteria, such as Lactobacillus casei or Eubacterium aerofaciens. The underlying principle is the poor degradability of the fragments, thereby creating a persistent stimulus. The Lactobacillus and Eubacterium models are of particular interest for human disease, because these bacteria are part of the normal gastrointestinal flora.16 Extrapolation of this model to humans suggests that an enormous load of potential arthritogenic stimuli is continuously present in the normal gastrointestinal tract; from there, it may spread to other tissues and therefore requires tight immunoregulation. Within 24 hours of the administration of cell wall fragments in rats, acute inflammation develops in peripheral joints, coincident with dissemination of cell wall fragments in blood vessels of the synovium and subchondral bone marrow. Acute, complement-dependent inflammation subsides over the next week and is followed within 2 weeks by a chronic, T cell–dependent erosive polyarthritis involving mainly peripheral joints. In contrast with the acute-phase lesion, chronic joint inflammation develops only in susceptible strains that lose tolerance and display SCW-specific T cell responses, with the highest incidence in Lewis rats. It is tempting to speculate that similar loss of tolerance may occur in RA patients. Mouse strains studied so far are not susceptible to the single-injection model. In addition to SCW-specific T cell reactions, cross-reactive autoimmunity to cartilage proteoglycans may contribute to chronicity. However, it is unlikely that this cross-reactivity is a major factor at the onset, because the loss of proteoglycans from articular cartilage is limited at that stage. Only later are marked pannus formation and severe erosions of underlying cartilage and bone frequently observed. In line with the tumor-like behavior of synovial cells in patients with RA, synovial cells from arthritic rats show continued proliferation ex vivo, with apparent paracrine and autocrine regulation by growth factors.17 This observation delineates that sustained macrophage-fibroblast activation by retained bacterial components may be a perpetuating principle, but

in vivo, the T cell is still a critical, driving factor. Studies on the involvement of cytokines in SCW arthritis show a combined role of TNF and IL-1, as is found in AA.9,18 In mice, a chronic relapsing SCW model can be induced by repeated weekly injection of SCW fragments directly into the knee joint, displaying a gradually increasing role of T cell–derived IL-17 and synovial IL-17 receptor–bearing cells with every flare.19 TLR2 is the driving receptor of SCW recognition, and arthritis is markedly suppressed in TLR2 –/– mice and absent in MyD88 –/– mice.20 As an extension of the involvement of bacteria in ­arthritis, bacterial DNA can induce arthritis. In particular, the CpG motifs in bacterial DNA are arthritogenic, and substantial amounts can be found in joint tissues.21 Macrophages play a major role in this arthritis through the ­production of TNF. However, in comparison to cell wall fragments, the ­cytokine-inducing capacity is weak. Normal joints of individuals contain both bacterial fragments and bacterial cpG (CP61) motifs, and it is conceivable that both factors contribute to arthritis. ANTIGEN-INDUCED ARTHRITIS AIA provides an antigen-defined model, reflecting a sustained immune reaction to a persistent trigger in joint tissues—in this case, an exogenous protein antigen. It is elicited by local injection of a high dose of antigen in the knee joint of an animal previously hyperimmunized with that antigen in Freund’s complete adjuvant. Such a model was first developed by Dumonde and Glynn22 in rabbits. In principle, it can be induced in any species, provided that proper immunity to a particular antigen can be mounted. Applications have been developed in mice, rats, and guinea pigs. In contrast to the polyarthritis models described so far, this type of arthritis remains confined to the injected joint. Commonly used antigens are ovalbumin, bovine serum albumin (BSA), fibrin, or cationic forms such as methylated BSA. Preimmunization

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with antigen in complete Freund’s adjuvant induces strong humoral as well as cell-mediated immunity. Arthritis is usually induced 3 weeks later by local injection of a large amount of antigen in the knee joint. Initially, an IC-type reaction dominates, followed by T cell–mediated chronic inflammation. In the rabbit, chronicity may last for years. Histopathology shows a granulocyte-rich exudate in the joint space, thickening of the synovial lining layer, and, at later stages, a predominantly mononuclear infiltrate in the synovium, which later includes numerous T cells and clusters of plasma cells. Interestingly, a large proportion (50%) of these plasma cells are making antibodies to the inciting antigen, suggesting that retained antigen is a driving force in chronic arthritis. Intense IC formation is seen in superficial layers of the articular cartilage, which may contribute to localized cartilage destruction. Early loss of proteoglycans, followed by pannus formation and cartilage and bone erosion, is a common finding. Two important principles emerge from this model: first, chronicity is found only in the presence of sufficient antigen retention in joint tissues, in combination with proper T cell–mediated delayed hypersensitivity; second, joints contain numerous non- or avascular collagenous tissues such as cartilage, ligaments, and tendons, which allows for prolonged antigen retention by antibody-mediated trapping and charge-mediated binding.23,24 Importantly, antigen injected in the skin produces transient inflammation, whereas a similar dose in the joints causes chronic inflammation. Chronicity is due to the generation of local hyperreactivity. Antigen that is initially trapped in collagenous tissues is slowly released, sustaining low-grade chronic arthritis. As a consequence, the local T cell infiltrate gains specificity, because the retention of specific T cells is shaped by homologous antigen. Small amounts of antigen are sufficient to sustain arthritis, whereas relatively large amounts are needed for induction. This condition forms the basis for exacerbations (flares) of arthritis with low doses of antigen (described later). In rabbits, antibody responses are generally high and allow for sufficient IC-mediated trapping of antigen in the joint. Cationic antigens are effective arthritogens in the murine model, owing to their ability to stick to the negatively charged collagenous structures of the joint and to accumulate IC formation at the surface.24 Of interest, this principle may extend to cationic bacterial or viral components and appears to be important in the more recently developed transgenic KRN model of arthritis, where antiGPI antibodies stick to GPI antigen trapped at cartilage surfaces. In AIA in the rabbit and the mouse, elimination of TNF-α and IL-1 was poorly effective in suppressing joint inflammation, pointing to substantial “overkill” by other mediators in this severe-onset arthritis. However, elimination of IL-1 yielded impressive protection against cartilage destruction.25 The model of AIA is most suited to studies of the mechanism of cartilage destruction as induced by a mix of ICs and T cell reactivity. It is facilitated by knowledge of the exact time of onset, accessibility of the knee joint (as compared with the ankle), and the presence of a contralateral control joint. Moreover, the model can be used to evaluate the regulation of local T cell hyperreactivity against a retained foreign antigen.

FLARES OF ARTHRITIS In comparison to the chronicity of human RA, most ­animal models show a relatively short duration of severe, ­rapidly destructive inflammation. In that respect, models of repeated flares of arthritis, with the slower development of lesions, provide a valuable extension. An arthritic joint bearing retained antigen and a chronic antigen-specific T cell infiltrate displays a state of local hyperreactivity. This situation is not restricted to retained antigen but also applies to new antigen entering the sensitized joint from the circulation. Flares of smoldering arthritis can be induced with as little as 10 ng of antigen and are highly dependent on T cell–derived IL-17.26 Flares can be induced by local, intravenous, or even oral rechallenge. An interesting situation is exacerbation induced by cytokines. Joints bearing a macrophage infiltrate are more sensitive to IL-1 and IL-17 and easily allow for marked cytokine­mediated destruction. In addition to flare models based on protein antigen, similar models have been developed in rats and mice using bacterial cell wall constituents. In contrast to small protein antigens, which are inflammatory only in the context of an immune response, bacterial fragments may function as an antigen but directly trigger TLRs as well; the ensuing reactions are a mixture of T cell– and macrophage-fibroblast– driven processes. The generation of local hyperreactivity requires large, persistent bacterial peptidoglycan-polysaccharide components, but a recurrence may be induced with a variety of components, ranging from cell wall fragments, lipopolysaccharide, CpG motifs, and cytokines such as IL-1. The strongest flares occur in the presence of T cell immunity, and a correlation is found between the fragments’ potential to induce an exacerbation and to elicit cell wall–specific T cell proliferation. In the mouse system, flares are a mixture of macrophage and T cell reactivity. Separate roles of TNF and IL-1 are found in swelling and erosion.18 A TNFdependent swelling response is seen in each flare, but IL-1 is dominant in the chronic erosive process. Erosion is absent in IL-1–deficient mice but does occur in TNF-deficient mice (Fig. 25-2). The model is more severe and erosive in DBA mice than in C57Bl mice; erosion is absent in T or B cell– deficient RAG mice, and both IL-12 and IL-18 promote an erosive phenotype. Of note, considerable cross-reactivity occurs between cell walls from different bacterial origins, and flares may result from homologous as well as heterologous fragments.27 This may extend to cross-reactive autoantigens from cartilage, which underlines the fact that arthritis may start against a particular antigen but spread to other antigens, including autoantigens. Recently, TLRs have been identified as pattern-recognition molecules for bacteria; TLR4 in particular cross-reacts with numerous fragments of damaged connective tissue components. Their presence on dendritic cells and their role in regulating autoimmune responses are intriguing. These principles open up a wide range of putative stimuli involved in exacerbations, simultaneously complicating the search for the driving “antigen” in humans. Figure 25-3 illustrates the erosive character of flares, which can be efficiently blocked with a combination of antibodies to TNF, IL-1, and IL-17.19,26 The potential efficacy of TLR blockers remains to be elucidated.

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Figure 25-2  Safranin O staining of a joint subjected to repeated flares of streptococcal cell wall arthritis (day 28) in wild-type mice (left) and TNF –/– mice (right). Note the full progression of synovitis and joint damage in the TNF –/– condition.

TRANSGENIC MODELS Transgenic animals, defined as novel strains generated by the manipulation of particular genes, have resulted in several new models that prove the importance of certain principles in arthritis and are useful for distinct screening. They do not necessarily provide better translational models for drug targeting in RA. Some recent examples of skewed T cell responses are discussed below. HTLV Arthritis Mice transgenic for the env-pX region of the HTLV type 1 genome develop a spontaneous chronic arthritis as a result of expression of the tax gene.28 Onset occurs at 2 to 3 months of age in female mice but is delayed several months in male animals. Ankle joints are most frequently affected, and pannus formation leading to severe erosions of cartilage and bone is observed in transgenic mice after several months of disease. The mice produce autoantibodies, and collagen immunization can provoke the onset or exacerbation of arthritis. It is tempting to speculate that a retrovirus could be involved in the pathogenesis of RA, possibly by influencing T cell responses to cartilage antigens. KRN Arthritis An intriguing, novel arthritis model emerged from experiments in transgenic mice overexpressing a self-reactive T cell receptor (TCR). The cross of K/BxN mice developed arthritis.29 In principle, many insults or adjuvants that skew the regulation of T cell tolerance have the potential to create autoimmune pathology, including joint inflammation. The

major breakthrough of the KRN model is the elucidation of the driving antigen and the finding that passive transfer with antibodies induces a protracted arthritis. The TCR recognizes the ubiquitous self-antigen GPI and provokes, through B cell differentiation and proliferation, high levels of anti-GPI antibodies. These antibodies are directly pathogenic upon transfer and appear to recognize endogenous GPI, which seems to associate preferentially with the cartilage surface.30 The latter finding may underlie the dominance of joint pathology in these mice, although GPI is also abundant at other body sites. Immunoglobulin (Ig) G1 antibodies are the major subclass and cause a sustained, erosive arthritis after continued transfer, with BALB/c mice showing high sensitivity. The pathology brings the model close to passive CIA or IC arthritis, with IC formation at the cartilage surface (see the section on passive IC arthritis for details). Differences between the models relate to the IgG subclasses involved.

SKG and GP130 Arthritis Another recent example of a transgenic T cell model is provided by the occurrence of chronic autoimmune arthritis in mice with a point mutation of the gene encoding ZAP-70, a key signal transduction molecule in T cells.31 The aberrant TCR function leads to positive selection of otherwise negatively selected autoimmmune T cells. Of great interest is that these mice fail to develop disease under a ­microbially clean condition, despite the active production of arthritogenic autoimmune cells. A single injection of zymosan provokes arthritis in a Dectin-1–dependent but TLR–­independent manner.32 The latter is in sharp contrast with the arthritis

Figure 25-3  Impact of IL-17 blocking in flares of antigen-induced arthritis. Note the marked synovitis and cathepsin K–positive osteoclastmediated bone attack in the control flare (left) and suppression of this reaction in the anti–IL-17 treated joint (right).

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in IL-1ra –/– mice, which is similarly dependent on flora but clearly TLR4 dependent as well. Th17 cells play a crucial role in this model and show that environmental factors such as yeast may drive or accelerate Th17 arthritis pathology. Mice with a homozygous mutation in the GP130 IL-6 receptor subunit show enhanced signal transduction and STAT3 activation and develop a lymphocyte-mediated RA-like joint disease. This is another example of skewed T cell function resulting in arthritis. Increased proliferation of CD4+ T cells occurs due to the elevated production of T cell–activating IL-7 by nonhematopoietic cells.33,34 Tumor Necrosis Factor Transgenic Arthritis An elegant series of experiments provided insight into the possible role of TNF in arthritis induction. By introducing into mice a modified human TNF transgene (lacking a TNF 3'UTR region, involved in the translational repression of TNF), it was shown that pronounced TNF overexpression results in chronic polyarthritis with a 100% incidence.35 Hyperplasia of the synovium, inflammatory infiltrates in the joint space, pannus formation, and cartilage and bone destruction were observed. Intriguingly, a similar form of arthritis also developed in targeted mutant mice lacking the 3'AU-rich elements, confirming the role of these elements in maintaining a physiologic TNF response in the joint.36 A proposed mechanism is the inability of natural anti-inflammatory signals, such as IL-10, to suppress TNF production under these conditions. These exciting findings stimulated a major search for functional mutations around TNF production in RA patients; however, no clear indications have been found so far. The model is of great interest to identify pathways of TNF-induced arthritis and to screen the efficacy of various TNF-directed therapies. It is not surprising that anti-TNF treatment blocks the pathology, but it is a remarkable observation that antibodies to the IL-1 receptor also prevent arthritis, suggesting that much of this arthritis occurs by the induction of IL-1.37 The model does not need T or B cells, because arthritis occurs in TNF transgenics backcrossed to RAG mice, and the pathology can be transferred with selected TNF-producing fibroblasts. Further investigation of TNF receptor involvement showed a crucial role for the p55 type I receptor in mediating TNF pathology and a suppressive role for the p75 type II receptor. Apparently, the type II receptor does not have a clear suppressive role in inflammatory bowel disease, another pathology found in TNF transgenic mice. The latter is a T or B cell–dependent disease. It is known that cytotoxic anti-TNF and TNF and lymphotoxin scavenging TNF-soluble receptor treatments have different efficacies in human RA compared with Crohn’s disease, but the reason is not fully understood. Recent studies substantiate a dual proinflammatory and immunosuppressive role for TNF and the heterogeneity of TNF receptor usage in autoimmune suppression versus inflammatory tissue damage.38 These observations provide a rationale for the future treatment of RA with selective anti–TNF receptor instead of anti-TNF. However, full understanding of this system is complicated by the finding of cooperative activity of p55 and p75 TNF receptors in arthritis induced with membrane-bound TNF, in line with the identification of preferential binding of transmembrane TNF to the p75

receptor. It remains to be elucidated to what extent human RA is driven by soluble or membrane TNF. Of note, soluble TNF is hard to detect in RA synovial fluid, and models with dominant overexpression of soluble TNF hamper the proper identification of the role of p75 TNF receptor. Interleukin-1 Transgenic Mice Transgenic IL-1α overexpression has been shown to induce chronic, destructive arthritis.39 Transgenic mice expressing human IL-1α had high serum levels of IL-1 and developed a severe polyarthritis by 4 weeks of age. Hyperplasia of the synovial lining, pannus formation, and, ultimately, cartilage destruction were evident. T and B cells were scant, but active granulocytes were abundant. The opposite approach—elimination of IL-1 control by gene targeting of the endogenous IL-1 receptor antagonist (IL-1ra)—yielded a T cell–driven model of arthritis. IL-1ra deficiency in a BALB/c background resulted in pronounced arthritis at age 8 weeks.40 Marked synovial and periarticular inflammation was noted, with invasion of granulation tissue and articular erosion (Fig. 25-4). Moreover, elevated levels of antibodies against immunoglobulins, CII, and double-stranded DNA were found, suggesting an autoimmune response. Intriguingly, IL-1ra deficiency in a C57Bl/6j background did not yield arthritis; arteritis was produced instead. This genetic variation, though not well understood, underscores an immunologic pathogenic pathway. Overexpression of a range of cytokines, including IL-1b, TNF, and IL-6, was observed in the joints before the onset of arthritis. Interestingly, autoantibody levels did not correlate with disease severity, which may imply a reaction to damaged joint tissue. In sharp contrast to the TNF transgenic model, the arthritis in IL-1ra –/– mice seems to be dependent on T cells, in line with the strong genetic restriction. It is consistent with the view that IL-1 is a crucial regulator of T cell function. Impaired T cell activation is demonstrated in IL-1–deficient mice, linked to low levels of CD40 ligand and OX40 expression on T cells, and it underlies the suppression of CIA in IL-1β –/– mice. Undisturbed IL-1 action, in the absence of IL-1ra, probably permits the activation of IL-17–producing T cells directed against exogenous triggers or endogenous autoantigens. The spontaneous arthritis in IL-1ra –/– mice does not develop under germ-free conditions and is reduced in TLR4-deficient mice. Both TNF and IL-17 deficiency prevent the onset of arthritis.41,42 IMMUNE COMPLEX ARTHRITIS Autoantibodies such as rheumatoid factor and anticitrulline antibodies are a key feature of RA, and the recent success of treatment with an anti–B cell drug (rituximab) has enhanced the belief in a pathogenic role. In some of the models discussed earlier, such as CIA, proteoglycan arthritis, and AIA, IC formation at joint tissues is a major element of pathogenesis. Although excessive IC formation can cause destructive arthritis, chronicity is limited and may be promoted by T cells. The latter may be linked to T cells’ need to sustain antibody production and the greater potential of T cell–macrophage interaction to sustain joint pathology. Minute amounts of antigen suffice to stimulate

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One hind paw Two hind paws Hind + front paw(s)

75 50 25 0 0

5

10

15

Age (weeks)

Figure 25-4  Arthritis expression in IL-1ra –/– mice. Marked synovial villi and joint erosions.

T cells, whereas considerable amounts of ICs are needed to stimulate the release of inflammatory mediators from phagocytes. It is likely that IC models mimic part of the RA pathology. With availability of a range of transgenic knockouts, there is growing interest in the use of passive IC models to identify crucial pathways of inflammation and tissue destruction. The advantage of passive systems is the lower dependence on genetic background, avoiding excessive backcrossing to create transgenics in suitable, susceptible mouse strains.

to be retained in the joint for prolonged periods. The association with synovial tissue and the heavy sticking to cartilage surfaces contribute to chronicity and cartilage destruction. An intriguing observation is the more chronic and destructive nature of this arthritis in DBA/1j mice compared with BALB/c mice(Fig. 25-5),43 which seems to be related to high sustained levels of activating Fcγ receptors on macrophages of DBA/1j mice. The model shows strong dependence on IL-1, whereas TNF blockade is ineffective.44 FcγRI rather than III appears to be crucial in cartilage damage.45

Passive Collagen Arthritis

Passive Glucose-6-Phosphate Isomerase Arthritis

Passive transfer of collagen arthritis can be performed with a critical mixture of a number of anti-CII monocloclonal antibodies, including complement-binding IgG2a. Sets are now commercially available, routinely recommending DBA mice as sensitive recipients. Accepted concepts of inflammation pathways include IC-mediated complement activation and Fcγ receptor triggering on phagocytes. Proteoglycan antibodies from the proteoglycan arthritis model can induce transient arthritis upon transfer, with concomitant proteoglycan loss from the cartilage but no erosive damage. IgG1 seems to be the critical subclass; the limited destructive potential is unclear.

Antibodies present in the serum of arthritic KRN mice are directly pathogenic upon systemic transfer. They recognize endogenous GPI, which associates preferentially with the cartilage surface.30 This tendency may underlie the dominance of joint pathology in these mice, although GPI is also abundant at other body sites. IgG1 antibodies are the major subclass and cause a sustained, erosive arthritis after continued transfer, with high sensitivity of BALB/c mice. Repeat injections enhance chronicity and joint destruction. The model comes close to passive CIA and IC arthritis with planted cartilage-associated antigen; all these types have IC formation at the cartilage surface as a salient feature. Recently, an arthritis model was developed by immunization with GPI in Freund’s adjuvant. Serum from this model was not capable of transferring arthritis, indicating that antibodies alone are poorly arthritogenic. Upscaling or the use of a critical mixture of multiple epitope-recognizing antibodies is needed, in line with observations related to anti-CII antibodies.

Passive Poly-L-Lysine–Lysozyme Arthritis An IC model emerging from the murine AIA model and using the principle of cationic retention is the passive transfer of antilysozyme antibodies to mice that are locally injected in one knee joint with poly-L-lysine (PLL)–lysozyme. PLL-coupled lysozyme is highly cationic and sufficiently large

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Figure 25-5  Histology of day 7 passive poly-L-lysine– lysozyme arthritis in two mouse strains (BALB/c and DBA). The upper panel shows almost resolved arthritis, with limited cartilage damage. The lower panel shows aggressive cartilage surface erosion and bone erosion.

Passive Citrulline Arthritis After the identification of anticitrulline antibodies as an early marker of the RA process, many groups attempted to induce citrulline arthritis. So far, anticitrulline antibodies are poorly arthritogenic on their own but can amplify existing IC arthritis.46 This amplifying principle also applies to rheumatoid factor, as discovered previously. Intriguingly, mice tolerized to citrulline responses show reduced collagen arthritis, suggesting a contribution of citrulline responses in CIA. Strain and Cytokine Dependency of Passive Immune Complex Arthritis As mentioned earlier for passive IC complex models, severity is dependent on complement factors and Fcγ receptors. Activation of complement through the alternative pathway is crucial in GPI arthritis, consistent with the dominance of IgG1. Because the activity of complement and the level of expression of Fcγ receptors on phagocytes are different in various mouse strains, such factors largely determine the variable susceptibility. BALB/c mice are hyperreactive, whereas DBA/1 and C57Bl6 mice are less susceptible; minor responsiveness is seen in 129/Sv mice, in strong contrast to the low sensitivity of BALB/c mice in other passive IC arthritis models. GPI antibodies are found in some but not all RA patients, and levels are moderate. Their role in RA remains to be identified.47 The involvement of IL1 and TNF follows earlier observations in similar models. IL-1 is obligatory, with no arthritis in IL-1–deficient mice. TNF is also essential but is less critical than IL-1, because a proportion of TNF-deficient mice develop robust arthritis. Compared with the passive arthritis induced with antibodies to the cationic antigen PLL-lysozyme, a higher TNF sensitivity is apparent, as well as a dependence on mast cells. These findings suggest a role of environmental initiating

elements. It is likely that the onset of mild GPI arthritis is facilitated by local TNF generation and mast cell–dependent histamine release, whereas a model with an injected cationic antigen in the joint generates sufficient nonspecific inflammation to initiate arthritis without the need for additional facilitating mediators such as TNF. Once the joint is affected, the role of TNF is limited; this is also the case in GPI arthritis. T cell IL-17 can accelerate and enhance the expression of GPI arthritis,48 making TNF redundant. This illustrates the remarkable potency of the combination of IC and T cell activation in determining the severity and chronicity of arthritis.

CYTOKINES AS TARGETS IN SUSCEPTIBILITY AND DESTRUCTION Findings supporting TNF, IL-1, and IL-17 involvement in arthritis pathogenesis have been partly addressed under the headings of the various models. TNF is a major mediator in early stages of joint inflammation in every model. Although IL-1 is not a dominant early inflammatory cytokine in all models, it is the pivotal cytokine in the inhibition of chondrocyte proteoglycan synthesis in all models studied so far, and blocking of IL-1 has a great beneficial impact on net cartilage destruction.49 In line with this, chronic destructive arthritis cannot be induced in IL-1–deficient mice using any of the classic arthritis models. In contrast, TNF deficiency reduces the incidence of autoimmune arthritis expression, but once joints become afflicted, full progression to erosive arthritis occurs (see Fig. 25-2).50 It is still unclear why IL-1 is such a dominant target in IC and T cell–driven murine models, as well as a pivotal secondary mediator in TNF transgenic arthritis; the role of IL-1 in autoimmune RA is still being debated. The novel T cell cytokine IL-17 provides an additional target apart from TNF and IL-1. Local

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o­ verexpression shows that it can accelerate inflammation and tissue destruction in CIA, independent of IL-1, and IL-17 blocking appears to be superior in the T cell flare of AIA.26 In addition, the macrophage-derived cytokines IL15, IL-18, and IL-23 are abundant in RA synovia; they can contribute to T cell maturation and activation and were shown to promote collagen arthritis.51,52 Recently, it was discovered that IL-23 rather than IL-12 stimulates Th17 cells and drives arthritis,53,54 making this cytokine an attractive therapeutic target. REGULATION OF ARTHRITIS SUSCEPTIBILITY Apart from insight into the role of arthritogenic cytokines, models are well suited to identify modulatory cytokines. IL-4, IL-10, transforming growth factor-β, and IL-27 appear to be of prime importance. In general, the endogenous Th2 cytokines IL-4 and IL-10 are protective, although at the local level, IL-4 can be inflammatory as well. An enhanced incidence of CIA and proteoglycan arthritis is seen in IL-4– and IL-10–deficient mice, and treatment with IL-4 or IL-10 suppresses arthritis.55 In addition, IL-12 and IL-18 promote such diseases through the enhancement of T cell reactivity, and strong immunization with high or repeated adjuvant exposure makes seemingly resistant mouse strains susceptible. Enhanced expression of autoimmune arthritis can be induced with a single lipopolysaccharide or bacterial fragment injection shortly before the expected onset through the generation of IL-12, the promotion of TNF and IL-1 production, and the boosting of T cell responses. It reflects the potential impact of environmental pressure. Of note, TLR4 blocking ameliorates collagen arthritis, and TLR4 deficiency reduces erosive arthritis in IL-1ra –/– mice (Fig. 25-6). A similar example is provided by the promoting effect of fungal glucans in the induction of SKG arthritis.32 Much attention has been given to identifying the role of regulatory T cells in arthritis. It is claimed that this ­function

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is defective in RA. Animal model studies show that the engineered absence of regulatory T cells allows arthritis in K/BxN mice to spread to joints not normally affected and to become more destructive.56 Another intriguing example is the demonstration of the immunoregulatory role of a subset of IL-10–producing B cells in collagen arthritis.57 Of note, rituximab appears to be efficacious in RA patients when it induces a strong IL-10 response shortly after treatment. Finally, the local architecture of the synovial tissue is of prime importance for arthritis expression. Liposomal depletion of synovial lining cells,58 as well as disturbed synovial architecture in cadherin-11–deficient mice,59 prevents arthritis. The presence of mast cells makes a joint susceptible to GPI arthritis,60 explaining the preferential expression at distinct joints. CARTILAGE AND BONE DESTRUCTION Animal models are excellent tools to characterize destructive pathways. Cartilage damage observed in models ranges from a reversible loss of proteoglycans to collagen damage, cell death, and complete surface erosion (see Fig. 25-1). This underlines that arthritic processes can be more or less destructive, depending on the underlying (immune) process and cytokine mixture. Collagen breakdown and aggressive cartilage loss are noted predominantly in the presence of IC deposition, whereas milder, more gradual forms of damage are seen in models driven by macrophage or T cell activation (see Table 25-1). Large variations in progressive destruction are also observed in patients with RA, and the presence or absence of autoantibodies (RF, anti-CCP) make a difference. Studies in ADAMTS4 and ADAMTS5 knockout mice identified the crucial role of ADAMTS5 in early proteoglycan loss in AIA.61 This makes ADAMTS5 a promising target in RA, potentially preventing cartilage damage if treatment is started early enough. Studies in immune models in various Fcγ receptor knockout mice found that

Figure 25-6  Hematoxylin and eosin stain (upper) and safranin O stain (lower) of IL-1ra –/– mice, crossed with wild-type BALB/c (left) or TLR4 –/– mice. Note the marked protection from arthritis and damage in TLR4 –/–.

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Figure 25-7  VDIPEN neoepitope staining in cartilage from antigen-induced arthritis on day 7 in wild-type mice (left) and FcγRI –/– mice (right), indicative of metalloproteinase activation. Note that activation is almost fully absent in FcγRI –/–.

Fcγ receptor type I is pivotal in driving IC-mediated cell activation, metalloproteinase activation, and concomitant cartilage erosion62,63 (Fig. 25-7). Cytokines such as TNF, IL-1, and IL-17 cause bone erosion through the upregulation of RANKL. Like cartilage damage, bone erosion may occur in the absence of inflammation. Initially, local gene transfer with IL-4 seemed to be ineffective because it did not suppress joint inflammation; however, it markedly reduced cartilage and bone destruction in CIA through the suppression of RANKL.64 Likewise, in RANKL-deficient mice, joint inflammation continues in the passive GPI-type IC arthritis, but bone erosion is prevented. Similarly, when TNF transgenic mice were crossed with c-fos–deficient mice, joint inflammation continued, but bone erosion was absent. C-fos mice lack functional osteoclasts, and in this background, TNF transgenic mice show a nondestructive phenotype. Treatment with osteoprotegerin, which is the natural inhibitor of RANKL, does not reduce inflammation in AA and TNF transgenic mice, but bone erosion is reduced.8,65 These examples show that inflammation, bone erosion, and cartilage erosion are separate processes that may require selective therapy. Improvements in therapy, including bone repair, can be achieved by the combined blocking of cytokines and RANKL, as well as by providing an additional bone anabolic stimulus such as parathyroid hormone.66,67 Models also show that bone repair is possisble, but cartilage repair is more difficult. Anabolic stimulation and tissue engineering approaches are needed when structural damage is advanced. A final remark about bone erosion versus bone apposition is in order. Unlike the situation in RA patients, many arthritis models exhibit bone erosion as well as pronounced new bone formation at distinct sites. The latter is virtually absent in TNF transgenic mice, and a TNF-inducible regulator of bone apposition, DKK-1, was recently identified.68 It might be argued that most murine arthritis models are relatively devoid of TNF compared with human RA. Intriguingly, IL-32, a novel human cytokine driving TNF, was recently discovered. It induces arthritis in mice,69 but an endogenous murine analogue has not been found yet.

SUMMARY A variety of animal arthritis models have been described that facilitate the investigation of pathogenetic mechanisms of inflammatory arthritis. Their variety clearly illustrates the need for a broad approach in determining

their utility as predictive models for therapeutic targeting. That being said, their major role is in unraveling the complex inflammatory and matrix modeling, and their use on this basis remains critical in attempts to elucidate pathology and treatment. REFERENCES   1. Wooley PH: Animal models of rheumatoid arthritis. Curr Opin Rheumatol 3:407-420, 1991.   2. Pearson CM: Development of arthritis, periarthritis and periostitis in rats given adjuvants. Proc Soc Exp Biol (NY) 91:95-101, 1956.   3. Kleinau S, Erlandsson H, Holmdahl R, et al: Adjuvant oils induce arthritis in the DA rat. I. Characterization of the disease and evidence for an immunological involvement. J Autoimmun 4:871-880, 1991.   4. Wooley PH, Seibold JR, Whalen JD, et al: Pristane induced arthritis: The immunologic and genetic features of an experimental murine model of autoimmune disease. Arthritis Rheum 32:1022-1030, 1989.   5. Van Eden W, van der Zee R, Prakken B: Heat shock proteins induce T cell regulation of chronic inflammation. Nat Rev Immunol Rev 5: 318-330, 2005.   6. Holmdahl R, Lorentzen JC, Lu S, et al: Arthritis induced in rats with nonimmunogenic adjuvants as models for RA. Immunol Rev 184:184-202, 2001.   7. Kong YY, Feige U, Sarosi I, et al: Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402:304-309, 1999.   8. Pettit AR, Ji H, von Stechow D, et al: TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol 159:1689-1699, 2001.   9. Bendele AM, Chlipala ES, Scherrer J, et al: Combination benefit of treatment with the cytokine inhibitors IL-1ra and PEGylated soluble TNF receptor type I in animal models of RA. Arthritis Rheum 43:2648-2659, 2000. 10. Trentham DE, Townes AS, Kang AH: Autoimmunity to type II collagen: An experimental model of arthritis. J Exp Med 146:857-868, 1977. 11. Holmdahl R, Malmstrom V, Vuorio E: Autoimmune recognition of cartilage collagens. Ann Med 25:251-264, 1993. 12. Finnegan A, Mikecz K, Tao P, et al: Proteoglycan (aggrecan)-induced arthritis in BALB/c mice is a Th1-type disease regulated by Th2 cytokines. J Immunol 163:5383-5390, 1999. 13. Otto JM, Chandrasekeran R, Vermes C, et al: A genome scan using a novel genetic cross identifies new susceptibility loci and traits in a mouse model of RA. J Immunol 165:5278-5286, 2000. 14. Joosten LAB, Helsen MMA, van de Loo FAJ, et al: Anticytokine treatment of established type II collagen-induced arthritis in DBA/1 mice: A comparative study using anti-TNFα, anti-IL-1α/β and IL-1ra. Arthritis Rheum 39:797-809, 1996. 15. Cromartie WJ, Craddock JG, Schwab JH, et al: Arthritis in rats after systemic injection of streptococcal cell walls. J Exp Med 146: 1485-1602, 1977. 16. Hazenberg MP, Klasen IS, Kool J, et al: Are intestinal bacteria involved in the etiology of rheumatoid arthritis? APMIS 100:1-9, 1992.

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17. Lafyatis R, Thompson NL, Remmers EF, et al: Transforming growth factor-β production by synovial tissues from rheumatoid patients and streptococcal cell wall arthritic rats. J Immunol 143:1142-1148, 1989. 18. Kuiper S, Joosten LAB, Bendele AM, et al: Different roles of TNFα and IL-1 in murine streptococcal cell wall arthritis. Cytokine 10:690-702, 1998. 19. Lubberts E, Schwarzenberger P, Huang W, et al: Requirement of IL-17 receptor signaling in resident synoviocytes for development of full blown destructive arthritis. J Immunol 175:3360-3368, 2005. 20. Joosten LA, Koenders MI, Smeets RL, et al: TLR2 pathways drives SCW induced joint inflammation: Critical role of MyD88. J Immunol 171:6145-6153, 2003. 21. Deng GM, Tarkowski A: Synovial cytokine mRNA expression during arthritis triggered by CpG motifs of bacterial DNA. Arthritis Res 3:48-53, 2001. 22. Dumonde DC, Glynn LE: The production of arthritis in rabbits by an immunological reaction to fibrin. Br J Exp Pathol 43:373-383, 1962. 23. Cooke TDV, Hird ER, Ziff M, et al: The pathogenesis of chronic inflammation in experimental antigen induced arthritis. J Exp Med 135:323-338, 1972. 24. Van den Berg WB, van de Putte LBA, Zwarts WA, et al: Electrical charge of the antigen determines intraarticular antigen handling and chronicity of arthritis in mice. J Clin Invest 74:1850-1859, 1984. 25. Van Meurs JBJ, van Lent PLEM, Singer II, et al: IL-1ra prevents expression of the metalloproteinase-generated neoepitope VDIPEN in antigen-induced arthritis. Arthritis Rheum 41:647-656, 1998. 26. Koenders MI, Lubberts E, Oppers-Walgreen B, et al: Blocking of IL-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and IL-1. Am J Pathol 167:141-149, 2005. 27. Van den Broek MF, van den Berg WB, van de Putte LBA, et al: Streptococcal cell wall induced arthritis and flare-up reactions in mice induced by homologous and heterologous cell walls. Am J Pathol 133:139-149, 1988. 28. Iwakura Y, Tosu M, Yoshida E, et al: Induction of inflammatory arthropathy resembling rheumatoid arthritis in mice transgenic for HTLV-I. Science 253:1026-1028, 1991. 29. Korganow AS, Ji H, Mangialaio S, et al: From systemic T cell selfreactivity to organ-specific autoimmune disease via immunoglobulins. Immunity 10:451-461, 1999. 30. Maccioni M, Zeder-Lutz G, Huang H, et al: Arthritogenic monoclonal antibodies from K/BxN mice. J Exp Med 195:1071-1077, 2002. 31. Hata H, Sakaguchi N, Yoshitomi H, et al: Distinct contribution of IL-6, TNF-alpha, IL-1 and IL-10 to T cell-mediated spontaneous autoimmune arthritis in mice. J Clin Invest 114:582-588, 2004. 32. Yoshitomi H, Sakaguchi N, Kobayashi K, et al: A role for fungal βglucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice. J Exp Med 201:949-960, 2005. 33. Atsumi T, Ishihara K, Kamimura D, et al: A point mutation of Tyr-759 in IL-6 family cytokine receptor subunit gp130 causes autoimmune arthritis. J Exp Med 196:979-990, 2002. 34. Sawa S, Kamimura D, Jin GH, et al: Autoimmune arthritis associated with mutated IL-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4+ T cells. J Exp Med 203:1459-1470, 2006. 35. Keffer J, Probert L, Cazlaris H, et al: Transgenic mice expressing human tumor necrosis factor: A predictive genetic model of arthritis. EMBO J 13:4025-4031, 1991. 36. Kontoyiannis D, Pasparakis M, Pizarro TT, et al: Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: Implications for joint and gut-associated immunopathologies. ­Immunity 10:387-398, 1999. 37. Kollias G, Douni E, Kassiotis G, et al: On the role of TNF and receptors in models of multiorgan failure, RA, multiple sclerosis and inflammatory bowel disease. Immunol Rev 169:175-194, 1999. 38. Kassiotis G, Kollias G: Uncoupling the proinflammatory from the immunosuppressive properties of TNF at the p55 TNF receptor level: Implications for pathogenesis and therapy of autoimmune demyelination. J Exp Med 193:427-434, 2001. 39. Niki Y, Yamada H, Seki S, et al: Macrophage- and neutrophil-dominant arthritis in human IL-1 alpha transgenic mice. J Clin Invest 107:1127-1135, 2001. 40. Horai R, Saijo S, Tanioka H, et al: Development of chronic inflammatory arthropathy resembling RA in IL-1ra-deficient mice. J Exp Med 191:313-320, 2000.

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41. Nakae S, Saijo S, Horai R, et al: IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc Natl Acad Sci U S A 100:5986-5990, 2003. 42. Horai R, Nakajima A, Habiro K, et al: TNFα is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist-deficient mice. J Clin Invest 114:1603-1611, 2004. 43. Blom AB, van Lent PLEM, van Vuuren H, et al: FcgammaR expression on macrophages is related to severity and chronicity of synovial inflammation and cartilage destruction during experimental immune-complex-mediated arthritis (ICA). Arthritis Res 2: 489-503, 2000. 44. Van Lent PLEM, van de Loo FAJ, Holthuysen AEM, et al: Major role for IL-1 but not for TNF in early cartilage damage in immune complex arthritis in mice. J Rheumatol 22:2250-2258, 1995. 45. Nabbe KCAM, Boross P, Holthuysen AEM, et al: Joint inflammation and chondrocyte death become independent of FcγrIII by local overexpression of IFN-γ during immune complex mediated-arthritis. Arthritis Rheum 52:967-974, 2005. 46. Kuhn KA, Kulik L, Tomooka B, et al: Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J Clin Invest 116:961-973, 2006. 47. Monach PA, Benoist C, Mathis D: The role of antibodies in mouse models of rheumatoid arthritis, and relevance to human disease. Adv Immunol 82:217-248, 2004. 48. Koenders MI, Lubberts E, van de Loo FAJ, et al: Interleukin-17 acts independently of TNF-α under arthritic conditions. J Immunol 176:6262-6269, 2006. 49. Van den Berg WB: What we learn from arthritis models to benefit arthritis patients. Baillieres Clin Rheumatol 14:599-616, 2000. 50. Campbell IK, O’Donnell K, Lawlor KE, et al: Severe inflammatory arthritis and lymphadenopathy in the absence of TNF. J Clin Invest 107:1519-1527, 2001. 51. Gracie JA, Forsey RJ, Chan WL, et al: A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest 104:1393-1401, 1999. 52. McInnes IB, Liew FY: Interleukin-15: A proinflammatory role in rheumatoid arthritis synovitis. Immunol Today 19:75-79, 1998. 53. Murphy CA, Langrish CL, Chen Y, et al: Divergent pro and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 198:1951-1957, 2003. 54. Cho ML, Kang JW, Moon YM, et al: STAT3 and NF-kappaB signal pathways required for IL-23 mediated IL-17 production in spontaneous arthritis model IL-1ra deficient mice. J Immunol 176:5652-5661, 2006. 55. Joosten LAB, Lubberts E, Durez P, et al: Role of IL-4 and IL-10 in murine collagen-induced arthritis: Protective effect of IL-4 and IL-10 treatment on cartilage destruction. Arthritis Rheum 40: 249-260, 1997. 56. Nguyen LT, Jacobs J, Mathis D, et al: Where FoxP3-dependent regulatory T cells impinge on the development of inflammatory arthritis. Arthritis Rheum 56:509-520, 2007. 57. Evans JG, Chavez-Rueda KA, Eddaoudi A, et al: Novel suppressive function of transitional 2 B cells in experimental arthritis. J Immunol 178:7868-7878, 2007. 58. van Lent PL, van den Hoek AE, van den Bersselaar LA, et al: In vivo role of phagocytic synovial lining cells in onset of experimental arthritis. Am J Pathol 143:1226-1237, 1993. 59. Lee DM, Kiener HP, Agarwal SK, et al: Cadherin-11 in synovial lining formation and pathology in arthritis. Science 315:1006-1010, 2007. 60. Nigrovic PA, Binstadt BA, Monach PA, et al: Mast cells contribute to initiation of autoantibody-mediated arthritis via IL-1. Proc Natl Acad Sci U S A 104:2325-2330, 2007. 61. Stanton H, Rogerson FM, East CJ, et al: ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434: 648-652, 2005. 62. Van den Berg WB: Uncoupling of inflammatory and destructive mechanisms in arthritis. Semin Arthritis Rheum 30(Suppl 2):7-16, 2001. 63. van Lent PL, Grevers L, Lubberts E, et al: FcgR mediate cartilage but not bone destruction in murine AIA: Uncoupling of cartilage damage from bone erosion and joint inflammation. Arthritis Rheum 54:3868-3877, 2006. 64. Lubberts E, Joosten LAB, Chabaud M, et al: IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion. J Clin Invest 105:1697-1710, 2000.

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65. Redlich K, Hayer S, Ricci R, et al: Osteoclasts are essential for TNFαmediated joint destruction. J Clin Invest 110:1419-1427, 2002. 66. Zwerina J, Hayer S, Tohidast-Akrad M, et al: Single and combined inhibition of TNF, IL-1 and RANKL pathways in TNF-induced arthritis: Effects on synovial inflammation, bone erosion, and cartilage destruction. Arthritis Rheum 50:277-290, 2004. 67. Redlich K, Gortz B, Hayer S, et al: Repair of local bone erosions and reversal of systemic bone loss upon therapy with anti-TNF in combination with osteoprotegerin or parathyroid hormone in TNF-mediated arthritis. Am J Pathol 164:543-555, 2004.

68. Diarra D, Stolina M, Polzer K, et al: Dickkopf-1 is a master regulator of joint remodeling. Nat Med 13:156-163, 2007. 69. Joosten LA, Netea MG, Kim SH, et al: IL-32 a proinflammatory cytokine in RA. Proc Natl Acad Sci U S A 103:3298-3303, 2006.

26

Neurologic Regulation of Inflammation Kathleen A. Sluka  •  Karin N. Westlund-High

Key Points Neurogenic inflammation is defined as release of inflammatory substances from the peripheral terminals of primary afferent fibers. Neuropeptides, substance P and calcitonin gene–related peptide, released from peripheral terminals of nociceptors cause plasma extravasation and vasodilation. The neurotransmitter glutamate increases in joint inflammatory conditions, increasing blood flow, extravasation, swelling, and inflammation. Increased release of glutamate activates transcription factors to turn on gene transcription. The axon reflex is a local reflex that contributes to neurogenic inflammation when the nociceptor is activated. The dorsal root reflex, which occurs after prolonged intense stimulation, originates in the spinal cord dorsal horn and results in antidromic activation of primary afferent fibers and peripheral release of neuropeptides and excitatory amino acids. The sympathetic nervous system contributes to neurogenic inflammation through activation of α1-adrenoreceptors or neuropeptide Y2 receptors.

Arthritis is a major debilitating disease that involves inflammation of a joint. Arthritis may take numerous forms, but all varieties result in severe destruction of the synovial tissue, cartilage, and bone microenvironment. Although arthritis is a multifactorial disease, the hallmark, similar to all inflammatory reactions, is release of proinflammatory immune mediators, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1. There is now consensus concerning the triggers of the inflammatory cascade, but the continuing inflammation of the chronic disease flares repeatedly despite aggressive therapy with steroids and nonsteroidal antiinflammatory drugs suggesting the presence of a persistent trigger. Blood-borne and local factors have been considered the primary players in the development of inflammation, although early studies suggested a neurogenic component.1 In addition to blood-borne or local factors, the nervous system plays a significant role in the amplification of inflammation and the consequent pain.2-4 The involvement of the nervous system in inflammation is termed neurogenic inflammation and is defined as release of inflammatory substances from the peripheral terminals of primary afferent fibers. Peripheral and central neuronal mechanisms control and contribute to neurogenic inflammation. This chapter reviews the evidence and mechanisms that account for neurogenic inflammation.

The cardinal signs of inflammation include heat, redness, swelling, pain, and decreased function. These five cardinal signs are interrelated and serve as markers to assess the impact of inflammation on an individual’s quality of life. The most sensitive factors are swelling, pain, and decreased function. The swelling associated with inflammation results from vasodilation and plasma extravasation of proteins to the site of injury. The pain results from activation of primary afferent nociceptors that transmit information to the spinal cord and to higher brain centers, where perception occurs. The degree of pain is related to the severity of the inflammation, and if inflammation decreases, pain also is expected to decrease. Decreased function is the physical consequence of increases in inflammation and pain. This chapter discusses data not only regarding the inflammation, but also regarding the pain associated with inflammation in an attempt to determine mediators and mechanisms of neurogenic inflammation.

PRIMARY AFFERENT FIBERS In the peripheral nervous system, primary afferent fibers release neuropeptides that result in plasma extravasation and vasodilation at the site of inflammation. Multiple clinical reports have appeared that indicate damage to nervous pathways and peripheral nerves owing to neurologic insults, such as stroke and peripheral nerve damage, can provide a protective effect against development of arthritis on the affected side, proportional to the magnitude of the neurologic insult.5-13 These clinical reports show that primary afferent fibers and the central nervous system play key roles in the development of arthritis. Primary afferent nerves are key components of neurogenic inflammation. Neurogenic inflammation is a form of inflammation that is initiated by activation of afferent sensory nerves.14,15 Activation of thinly myelinated, Aδ or type III, and unmyelinated, C fiber or type IV, primary afferent fibers results in vasodilation and plasma extravasation.16-19 Electric stimulation at intensities that activate Aδ fibers produces vasodilation; increasing the intensity to include C fibers also produces plasma extravasation.16,19,20 In contrast, removal of C fibers by treating the neonatal rat with capsaicin decreases plasma extravasation and the severity of the pathologic changes induced by inflammation.21,22 Acute depletion of neuropeptides with capsaicin similarly reduces plasma extravasation.23 Selective destruction of Aδ fibers by neonatal treatment with nerve growth factor decreases vasodilation that results from antidromic stimulation of Aδ or C fibers.17 Aδ and C fiber activation is necessary for generation of neurogenic inflammation. Neurogenic inflammation is known to contribute to nu­­­­ merous pathophysiologic states. Clinically relevant examples 411

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include arthritis; gastrointestinal nausea, emesis, distention, and pain; asthma; and urinary bladder incontinence.24 ­Neurogenic inflammation was first described, however, for skin because it can be observed easily there as the erythemic flare after bee stings. The term neurogenic implies that this form of inflammation is generated through mechanisms that depend on the innervation of an organ. This dependence is shown by the fact that denervation prevents this type of inflammation.25,26

PERIPHERAL NEUROTRANSMITTERS Neuropeptides The neuropeptides found in Aδ and C fibers include substance P and calcitonin gene–related peptide (CGRP) and promote plasma extravasation (substance P) and vasodilation (CGRP) on their release. Electric stimulation of primary afferent fibers releases substance P.27,28 Substance P infused into rat knee joint results in pathologic changes associated with arthritis, vasodilation, and plasma extravasation (Fig. 26-1).23,29,30 Substance P has been reported to

A

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increase in rat arthritic joints31 and to increase the severity of arthritis if added to the joint by increasing protein/plasma extravasation2,32 in experimentally induced animal models of inflammation, and substance P and CGRP are found in inflammatory exudates in human subjects.33-35 In contrast, substance P antagonists delivered at the site of inflammation reduce the plasma extravasation and the severity of the inflammation.16,29,30,36 Similarly, direct application of a substance P antagonist to an inflamed knee joint reduces hyperalgesia.37 Substance P plays a role in the hyperalgesia associated with joint inflammation. A single dose of a substance P receptor antagonist has no effect, however, on the joint swelling when it is fully developed.37 Substance P and CGRP are found in human subjects with arthritis, are released peripherally from primary afferent nerve fibers, and contribute to plasma extravasation and vasodilation ultimately to enhance inflammation. CGRP is found almost exclusively in primary afferent nerves.38 CGRP has been shown to block the degradation of substance P39 and contributes to the enhanced effects of substance P during inflammation. Increases in neuropeptide content in afferent endings in the dorsal horn, and

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Vasodilation 1nmol SP 1nmol SP + 10 nmol FK888 *τ

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Plasma protein extravasation 1 µM SP 1 µM SP +1 00 µM FK888 *

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Figure 26-1  A, Radiograph of a normal knee joint. B, Radiograph after infusion of substance P in an arthritic joint (arrow). C, Radiograph after  infusion of a substance P antagonist into an arthritic joint (arrow). D, Amount of vasodilation from direct application of substance P (SP) onto the knee joint measured with laser Doppler imaging in a normal animal and an animal with knee joint inflammation. The vasodilation was greater in animals  with inflammation than in animals without and was reduced by the substance P antagonist FK888. *, significantly increased from control; #, significantly less than infusion of substance P; τ, significantly greater than normals. E, Plasma protein extravasation is produced by infusion of substance P into the knee joint (*), and this is prevented by blockade of substance P receptors with FK888 (#). F, Plasma protein extravasation by substance P (*) is  potentiated by combining with calcitonin gene–related peptide (CGRP) (#). (A from Levine JD, Clark R, Devor M, et al: Intraneuronal substance P ­contributes to the severity of experimental arthritis. Science 226:547-549, 1984; D and E redrawn from Lam FY, Ferrell WR, Scott DT: Substance P-induced ­inflammation in the rat knee joint is mediated by neurokinin 1 (NK1) receptors. Regul Peptides 46:198-201, 1993; F redrawn from Gamse R, Saria A: Eur J Pharmacol 115: 61-66, 1985.)

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α-CGRP mRNA in spinal cord also are observed in arthritic animals.40-43 There are related neurogenic contributions to increased blood flow and vasodilation already described for substance P and CGRP in the knee joint.2,30,44,45 Administration of substance P and CGRP simultaneously potentiates the plasma extravasation (see Fig. 26-1).46,47 It is concluded that substance P and CGRP found in the joints of human subjects with arthritis are released peripherally from primary afferent fibers and contribute to plasma extravasation and vasodilation that ultimately enhance inflammation. The neuropeptide substance P also has been shown to potentiate the release of glutamate in the spinal cord dorsal horn.48,49 Substance P interacts with glutamate at peripheral nerve endings to enhance and increase the duration of glutamate-induced behavioral responses.31 Substance P also promotes release of histamine by degranulating mast cell and leukocyte migration.50 Various lines of evidence have implicated glutamate and substance P in peripheral interactive events. Colocalization of glutamate, substance P, and CGRP occurs in some dorsal root ganglia soma and primary afferent nerve endings.51-54 Corelease and interactions between these neuromodulators have been reported, including (1) potentiation of glutamate receptor effects,55,56 (2) activation of second messenger systems increasing intracellular calcium levels,57 and (3) increased release of glutamate into the extracellular space.58 The modification of receptor and cellular events produces long-term facilitation of spinal cord neuronal responses to peripheral stimuli leading to central sensitization; this can be mimicked experimentally with intrathecal injection of substance P or N-methyl-d-aspartate (NMDA), which produces an immediate increase in prostaglandin (substance P) or cyclooxygenase-2 (NMDA) release.59 The plasma membrane substance P receptors on dorsal horn neurons that may be spinothalamic tract cells undergo internalization after noxious stimulation.60 Glutamate In addition to the neuropeptides, the excitatory neurotransmitter glutamate plays a significant role in the inflammatory process and is thought to interact with substance P. Glutamate receptors have been described peripherally on lymphocytes, fibroblasts, and nerve endings in the skin.61,62 Increased content in primary afferent fibers of the excitatory neurotransmitter glutamate (well above metabolic levels) in primary afferent fibers is found in twice as many type III (Aδ) and type IV (C) fibers in the medial ­articular nerve innervating inflamed knee joints compared with controls (Fig. 26-2).63 Direct knee joint injection of ­glutamate receptor agonists increases joint blood flow, ­extravasation, and swelling.64 Excitatory amino acids released into the joint are doubled during knee joint inflammation (see Fig. 26-2)65 and can be reduced by lidocaine. Direct knee joint administration of the excitatory amino acids glutamate and aspartate induces persistent nociceptive behavior in rats (see Fig. 26-2).66 Substance P interacts with excitatory amino acids at peripheral nerve endings to enhance and increase the duration of glutamate-induced behavioral responses.31 In contrast, administration of NMDA or non-NMDA glutamate receptor antagonists directly into the knee joint

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a­ ttenuates hyperalgesic responses induced by either the acute kaolin and carrageenan (K/C) model or the chronic CFA model.66 In human clinic patients with arthritis, increases in glutamate and aspartate also are found in the inflammatory exudates.67 Exogenously applied glutamate increases TNF-α in human synovial cultures.68 In human subjects with arthritis, increases in glutamate and aspartate initiate inflammatory mediator cascades resulting in inflammation of the knee joint in conjunction with other neuromediators.

POTENTIAL MECHANISMS Signal Transduction Extracellular and intracellular neurogenic environmental changes that occur in response to inflammation lead to changes induced by signal transduction elements regulating the transcription of target genes. These factors usually increase (although they sometimes decrease) the rate of gene transcription, increasing the formation of mRNA and protein. One of these glutamate receptor–mediated effects is to promote rapid activation of nuclear factor κB (NFκB) for coordinated activation of target genes.69,70 Activation of NFκB occurs in many pathogenic settings, including exposure to glutamate and its agonists.71,72 NFκB regulates the expression of many immune and inflammatory activators forming an intracellular amplification loop involving glutamate, NFκB, and inflammatory activators. Glutamate receptor agonists induce nuclear translocation of NFκB in the developing cerebellum, whereas glutamate receptor antagonists abolish NFκB binding activity.73 Activation in astrocytes requires the cytokines IL-1α and TNF-α. An endogenous loop of glutamate receptor activation and subsequent NFκB activation is suggested, with particular involvement of neuronal NMDA glutamate receptors. There are related increases in nitric oxide seen in the joints of arthritic rats,74 along with the increased glutamate, owing to concomitant increases in cytoplasmic calcium, which upregulates nitric oxide synthase.75 In an animal model, a nitric oxide synthase inhibitor reverses the behavioral changes and attenuates the joint circumference increases.76 Increased nitric oxide has been shown in a human model to increase chemokine and cytokine production, specifically, MIP-1α, MCP-1, IL-8, IL-1β, and TNF-α.77 Axon Reflex Two potential mechanisms have been proposed that can account for the response of the nervous system to insult that precipitates the release of neurotransmitters and neuromodulators and inflammation. The classic theory used to explain that the release of inflammatory neuropeptides from the peripheral terminals of primary afferent fibers is the axon reflex. This theory suggests that nociceptive afferent fibers bifurcate peripherally, with one branch forming the sensory receptor and the other supplying a blood vessel. When the sensory receptors are activated in the periphery, action potentials are propagated not only centrally to the spinal cord for transmission of nociceptive information, but also peripherally to branches supplying blood vessels to release neuropeptides (Fig. 26-3).1,16,18,78-80

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Figure 26-2  A, Electron micrograph showing an unmyelinated glutamate axon in the medial articular nerve of the knee joint innervating an inflamed knee joint. Glutamate immunoreactivity was identified using postembedding immunogold labeling. Adjacent unmeylinated axons are unlabeled. Bar = 0.2 mm. B, Release of glutamate into the knee joint measured with microdialysis and high-performance liquid chromatography before and for 8 hours after induction of inflammation with 3% kaolin and 3% carrageenan. The increases occur immediately after injection and last for approximately 3 hours. ARG, arginine; ASP, aspartate; CTN, citrulline; GLU, glutamate. C, Withdrawal latency to heat before and after induction of inflammation with kaolin and carrageenan into the knee joint (closed circles). In rats treated intra-articularly with glutamate receptor antagonists to N-methyl-d-aspartate (NMDA) receptors (AP7, open circles; ketamine, open triangles) or to non-NMDA receptors (CNQX, closed triangles), there was a delayed onset in the development of hyperalgesia. D, Withdrawal threshold to mechanical stimuli before and after induction of inflammation with kaolin and carrageenan into the knee joint (closed circles). In rats treated intra-articularly with glutamate receptor antagonists to NMDA receptors (AP7, open circles; ketamine, open triangles) or to non-NMDA receptors (CNQX, closed triangles), there was a delayed onset in the development of hyperalgesia. E, Rate histograms showing the responses of primary articular afferents to infused activators of glutamate receptors (1 mM, intra-arterial). Coactivation with two glutamate receptor agonists produced an amplified response compared with the limited duration excitatory response produced by a single glutamate receptor agonist shown in E. Time of injections is indicated by the lines above the traces. ACPD, (1S, 3R)-1-aminocyclopentane-1, 3-dicarboxylic acid; ASP, aspartate.   (A from Westlund KN, Sun YC, Sluka KA, et al: Neural changes in acute arthritis in monkeys, II: increased glutamate immunoreactivity in the medial articular nerve. Brain Res Rev 17:15-27, 1992; B from Lawand NB, Willis WD, Westlund KN: Excitatory amino acid receptor involvement in peripheral nociceptive transmission in rats. Eur J Pharmacol 324:169-177, 1997; C and D from Lawand NB, McNearney T, Westlund KN: Amino acid release into the knee joint: Key role in nociception and inflammation. Pain 86:69-74, 2000; E and F from Lawand NB, Willis WD, Westlund KN: unpublished data, 1998.)

Dorsal Root Reflex It has been known for a century that activity in primary afferent fibers supplying the skin can cause “antidromic vasodilation,”81 and it has been assumed that the activity is generated locally (axon reflex). Depolarization of the central end of primary afferent fibers in the spinal cord also can occur, however, with “sufficient and prolonged” activation resulting in the generation of action potentials that propagate outward toward the periphery (see Fig. 26-3)82-85 and play a significant role in neurogenic inflammation.4 Initial studies show that severing the dorsal nerve roots on the side of inflammation reduces joint inflammation by half in the rat model86 and reduces neutrophilic infiltration in a rat

model of skin inflammation.87 After acute or chronically induced inflammation in rats, dorsal root reflexes develop in articular afferent fibers,88,89 including Aδ and C fibers (Fig. 26-4).90 Dorsal rhizotomy, peripheral application of lidocaine, or crushing the medial articular nerve ­proximal to the recording site also eliminates dorsal root reflex ­activity, showing that the action potentials involve dorsal roots and are generated in the central nervous system. Generation of dorsal root reflex activity occurs when the dorsal horn becomes sensitized, and there is an associated release of neurotransmitters from the central terminals of the primary afferent fibers.4,85,91,92 Blockade of non-NMDA glutamate and γ-aminobutyric acid (GABAA) receptors in the spinal cord eliminates the

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Figure 26-4  A and B, The dorsal root reflexes shown are from an Aδ (A) or a C fiber (B) in animals with knee joint inflammation. Samples of dorsal root reflexes were recorded from two electrodes spaced 20 mm (A) or 10 mm (B) apart. The top traces are from the proximal electrode, and the bottom traces are from the distal electrode. (From Sluka KA, Rees H, ­ Westlund KN, et al: Fiber types contributing to dorsal root reflexes induced by joint inflammation in cats and monkeys. J Neurophysiol 74: 981-989, 1995.)

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Figure 26-3  A, The axon reflex is a local reflex that is initiated when a nociceptor is activated. The nociceptor sends information through the spinal cord for transmission of nociceptive information to higher brain centers. The peripheral branches of the primary afferent also are depolarized resulting in release of substance P and calcitonin gene–related peptide from the peripheral terminals. This results in vasodilation and plasma extravasation to enhance inflammation. B, The dorsal root reflex is a mechanism by which neurogenic inflammation is initiated in the spinal cord. Antidromic action potentials are created in the central terminals of primary afferent fibers through activation of non–N-methyl-d-aspartate glutamate receptors on GABAergic neurons, and GABAA receptors on the central terminals of primary afferent fibers. Peripheral release of substance P (SP) and calcitonin gene–related peptide (CGRP) from the primary afferent terminals enhances the inflammatory response. DRG, dorsal root ganglion.

dorsal root reflex activity recorded in the medial articular nerve of inflamed joints (Fig. 24-5).88 In parallel, blockade of non-NMDA glutamate and GABAA receptors in the spinal cord reduces inflammation by approximately 50%.86,93,94 Spinal blockade of adenosine-1 receptors decreases neutrophilic infiltration and bone and cartilage destruction associated with inflammation.87,95 These findings suggest that dorsal root reflexes are an important mechanism for the amplification and persistence of inflammation. The dorsal root reflex involves a loop initiated by primary afferent fibers ending at the site of tissue damage and evolving inflammation. It is proposed that persistent afferent nerve fiber activity occurs in response to peripheral insult. The afferent fibers transmit information through the spinal cord circuitry, and if the activation is of sufficient strength and persists long enough in the sensitized dorsal horn, nerve activity is generated in recruited primary afferent fibers sending this activity back out to the site of inflammation (see Fig. 26-3). When sensitized dorsal horn neurons act as a neurogenic drive, they contribute to inflammation

in the joint and the accompanying persistent pain state. Excessive stimulation sensitizes the dorsal horn circuitry through ionotropic non-NMDA glutamate, GABAA, and adenosine-1 receptors, initiating dorsal root reflexes (i.e., neuronal activity that travels back out afferent nerves to the periphery). The dorsal root reflex likely is responsible for release of glutamate and vasoactive peptides into the joint, which triggers release of inflammatory cytokines, which can elicit increased firing in nociceptive afferent fibers to result in increased hyperalgesia and inflammation.68 Sympathetic Nervous System It is evident that there is some neural linkage between the spinal cord dorsal horn and the knee joint that is important in the development of the inflammation. The linkage between the spinal cord dorsal horn and the knee joint that contributes to the development of the inflammation does not seem to be the sympathetic nervous system because a surgical sympathectomy does not affect the development of the inflammation.96 Spinal administration of bicuculline94 or dorsal rhizotomies96 also prevented half of the swelling of the knee joint and the temperature increase. Interrupting the output of preganglionic sympathetic neurons also does not have these effects.97 In animals that have an intact sympathetic outflow, antagonists of α1 adrenoreceptors or of neuropeptide Y2 receptors reduce the flare and the dorsal root reflexes evoked by a capsaicin injection, but antagonists of α2 adrenoreceptors or of neuropeptide Y1 receptors do not.98 Evidently, release of norepinephrine acting at α1 adrenoreceptors and of neuropeptide Y acting at neuropeptide Y2 receptors helps maintain the responsiveness of nociceptive afferents to capsaicin and their ability to trigger dorsal root reflexes and flare.98 The mechanism for this is unclear, although it seems possible that the effects of these neurotransmitters could be mediated indirectly by actions on transient receptor potential vanilloid-1 (TRPV1).

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0 Baseline inflammation AP7 CNQX Figure 26-5  A and B, Histograms show the dorsal root reflex responses to mechanical stimuli applied to the lower limb (points a-e) in animals with knee joint inflammation (control). A, Treatment with 2 mM of AP7 to block N-methyl-d-aspartate (NMDA) glutamate receptors in the spinal cord had no effect on the dorsal root reflex activity. B, Treatment of the spinal cord with 0.27 mM of CNQX to block non-NMDA receptors prevented the dorsal root reflex responses in the medial articular nerve. C, Joint circumference difference from baseline increase by approximately 2 cm in animals with knee joint inflammation (*). Treatment of the spinal cord with 2 mM of AP7 had no effect on the development of joint swelling. Treatment of the spinal cord with 1 mM of CNQX reduced the development of inflammation by approximately 50%. D, Behavioral responses to heat decreased after induction of inflammation, an indicator that heat hyperalgesia had developed (*). Treatment of the spinal cord with 2 mM of AP7 or 1 mM of CNQX prevented the development of heat hyperalgesia (#). * , significantly increased from baseline; #, significantly less than controls. (A and B from Rees H, Sluka KA, Westlund KN, et al: The role of glutamate and GABA receptors in the generation of dorsal root reflexes by acute arthritis in the anaesthetized rat. J Physiol 484:437-445, 1995; C and D from Sluka KA, Westlund KN: Centrally administered non-NMDA but not NMDA receptor antagonists block peripheral knee joint inflammation. Pain 55:217-225, 1993.)

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Although the neural links between the knee joint and the spinal cord include sensory afferent fibers and effects of neuropeptides on vasomotor tone, sympathetic output is not responsible for the neurogenic inflammation observed for the knee joint as it is in the skin. The composition of the knee joint nerve is almost entirely small unmyelinated and lightly myelinated sensory nerves.99 Somatic motor activity also is not involved because inflammation could be produced even when the musculature was paralyzed. The neurogenic link for joint tissues has to be the sensory axons. The sympathetic nervous system plays a role in the inflammatory process. Specifically, it is thought that the sympathetic nervous system is more involved in chronic inflammation than acute inflammation. Acutely, adrenergic blockers have no effect on inflammation associated with antidromic stimulation of primary afferent fibers.18 Surgical and chemical sympathectomy or systemic depletion of catecholamines similarly has no effect on the acute inflammation induced by carrageenan.96,100 Sympathectomy reduces the severity of injury induced in chronic adjuvant arthritis.2,101 These studies suggest that involvement of the sympathetic nervous system is a key difference between acute and chronic inflammation.

CLINICAL SIGNIFICANCE Clinical reports have appeared in support of neurogenic modulation of the arthritic process. Bland and Eddy9 pointed out in 1968 that hemiplegia can improve arthritic conditions. When arthritis develops after hemiplegia, there is a protective effect on the hemiplegic side. The degree of protection is proportional to the magnitude of the paralysis, but is not

attributable to disuse.9,102,103 The cases reported include two in which there was nearly complete reversal of the arthritic changes after stroke on the affected side. These reports include radiologic evidence for extensive disease only on the patients’ unaffected side, including gross osteoporosis, gross subluxation, typical massive rheumatoid erosions, and absorption and loss of bone. On the paralyzed side, however, radiology documented incomplete reversal of the disease process, with resolution of erosions and joint space narrowing. Rheumatoid nodules, evidence of more severe systemic involvement, were confined to the unaffected side in these patients. Four additional reports documented protection of a single limb after a lesion of the peripheral nerve.5,104-106 The clinical reports of protection support the notion of a neurogenic contribution to arthritis in humans. Box 26-1

Unresolved Issues in the Field with Clinical Relevance in Years to Come 1. Treatment with anti-inflammatory agents does not completely resolve arthritic pain. 2. Neurogenic initiators are not addressed by current treatment regimens. 3. Treatments with neurotransmitter receptor antagonists affect other neuronal systems. 4. Central neuronal sensitization is not reduced by current medications. 5. Intracellular cascades and signal transduction are only beginning to be defined.

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Future Experimental Directions 1. Role of neuronal ion channels and receptors located on inflammatory cells 2. Interactions of neurotransmitters with non-neuronal inflammatory mediators 3. Interactions of the sympathetic nervous system with peripheral neurotransmitters 4. Continued efforts to resolve intracellular signaling to abrogate neuronal initiators effectively 5. Consideration of neuronal initiators of peripheral inflammation 6. Consideration of neuronal receptor–mediated events affecting joint inflammation

Acknowledgments The authors wish to thank Jacob Sluka for help with illustrations and carol leigh for secretarial support.

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41. Donaldson LF, Harmar AJ, Mcqueen DS, et al: Increased expression of preprotachykinin, calcitonin gene-related peptide, but not vasoactive intestinal peptide messenger RNA in dorsal root ganglia during the development of adjuvant monoarthritis in the rat. Mol Brain Res 16:143-149, 1992. 42. Sluka KA, Westlund KN: Behavioral and immunohistochemical changes in an experimental arthritis model in rats. Pain 55:367-377, 1993. 43. Kuraishi Y, Nanayama T, Ohno H, et al: Calcitonin gene-related peptide increases in the dorsal-root ganglia of adjuvant arthritic rat. Peptides 10:447-452, 1989. 44. Lam FY, Ferrell WR: Specific neurokinin receptors mediate plasma extravasation in the rat knee joint. Br J Pharmacol 103:12631267, 1991. 45. Lam FY, Ferrell WR: Acute inflammation in the rat knee joint attenuates sympathetic vasoconstriction but enhances neuropeptidemediated vasodilation assessed by laser Doppler perfusion imaging. Neuroscience 52:443-449, 1993. 46. Gamse R, Posch M, Saria A, et al: Several mediators appear to interact in neurogenic inflammation. Acta Physiol Hung 69:343-354, 1987. 47. Brain SD, Williams TJ: Inflammatory oedema induced by ­synergism between calcitonin gene-related peptide (CGRP) and mediators of increased vascular permeability. Br J Pharmacol 86:855-860, 1985. 48. Kangrga I, Randic M: Tachykinins and calcitonin gene-related peptide enhance release of endogenous glutamate and aspartate from the rat spinal dorsal slice. J Neurosci 10:2026-2038, 1990. 49. Smullin DH, Skilling SR, Larson AA: Interactions between substance-P, calcitonin gene-related peptide, taurine and excitatory amino acids in the spinal cord. Pain 42:93-101, 1990. 50. Kawana S, Liang ZF, Nagano M, et al: Role of substance P in stressderived degranulation of dermal mast cells in mice. J Dermatol Sci 42:47-54, 2006. 51. Battaglia G, Rustioni A: Coexistence of glutamate and substance P in dorsal root ganglion neurons of the rat and monkey. J Comp Neurol 277:302-312, 1988. 52. DeBiasi S, Rustioni A: Glutamate and substance P coexist in primary afferent terminals in the superficial laminae of spinal cord. Proc Natl Acad Sci U S A 85:7820-7824, 1988. 53. Jessell TM, Dodd J: Neurotransmitters and differentiation antigens in subsets of sensory neurons projecting to the spinal dorsal horn. In Martin B, Barchas JD (eds): Neuropeptides in Neurologic and Psychiatric Disease, New York, Raven Press, 1986, pp 111-131. 54. Wiesenfeld-Hallin Z, Hokfelt T, Lundberg JM, et al: Immunoreactive calcitonin gene-related peptide and substance P coexist in sensory neurons to the spinal cord and interact in spinal behavioral responses of the rat. Neurosci Lett 52:199-204, 1984. 55. Dougherty PM, Willis WD: Enhancement of spinothalamic neuron responses to chemical and mechanical stimuli following combined micro-iontophoretic application of N-methyl-D-aspartic acid and substance-P. Pain 47:85-93, 1991. 56. Murase K, Ryu PD, Randic M: Excitatory and inhibitory amino acids and peptide-induced responses in acutely isolated rat spinal dorsal horn neurons. Neurosci. Lett 103:56-63, 1989. 57. Womack MD, MacDermott AB, Jessell TM: Sensory transmitters regulate intracellular calcium in dorsal horn neurons. Nature 334:351-353, 1988. 58. Sorkin LS, Westlund KN, Sluka KA, et al: Neural changes in acute arthritis in monkeys, IV: time-course of amino-acid release into the lumbar dorsal horn. Brain Res Rev 17:39-50, 1992. 59. Dirig DM, Isakson PC, Yaksh TL: Spinal and systemic cyclooxygenase (COX) inhibitors suppress paw carrageenan-evoked thermal hyperalgesia in rats. Anesthesiology 87:A721, 1997. 60. Mantyh PW, Demaster E, Malhotra A, et al: Receptor endocytosis and dendrite reshaping in spinal neurons after somatosensory stimulation. Science 268:1629-1632, 1995. 61. Lombardi G, Dianzani C, Miglio G, et al: Characterization of ionotropic glutamate receptors in human lymphocytes. Br J Pharmacol 133:936-944, 2001. 62. Boldyrev AA, Kazey VI, Leinsoo TA, et al: Rodent lymphocytes express functionally active glutamate receptors. Biochem Biophys Res Commun 324:133-139, 2004. 63. Westlund KN, Sun YC, Sluka KA, et al: Neural changes in acute arthritis in monkeys, II: increased glutamate immunoreactivity in the medial articular nerve. Brain Res Rev 17:15-27, 1992.

64. Lawand NB, Reddig WJ, Cashin AE, et al: NMDA receptors and associated signaling pathways: A role in knee joint blood flow regulation. Eur J Pharmacol 499:155-161, 2004. 65. Lawand NB, McNearney T, Westlund KN: Amino acid release into the knee joint: Key role in nociception and inflammation. Pain 86:69-74, 2000. 66. Lawand NB, Willis WD, Westlund KN: Excitatory amino acid receptor involvement in peripheral nociceptive transmission in rats. Eur J Pharmacol 324:169-177, 1997. 67. McNearney T, Speegle D, Lawand N, et al: Excitatory amino acid profiles of synovial fluid from patients with arthritis. J Rheumatol 27:739-745, 2000. 68. McNearney T, Baethge BA, Cao S, et al: Excitatory amino acids, TNF-alpha, and chemokine levels in synovial fluids of patients with active arthropathies. Clin Exp Immunol 137:621-627, 2004. 69. Guerrini L, Blasi F, Denisdonini S: Synaptic activation of Nf-kappa-B by glutamate in cerebellar granule neurons in vitro. Proc Natl Acad Sci U S A 92:9077-9081, 1995. 70. Barnes PJ, Karin M: Nuclear factor-kappa B: A pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 336:10661071, 1997. 71. Kaltschmidt C, Kaltschmidt B, Baeuerle PA: Stimulation of ionotropic glutamate receptors activates transcription factor Nf-kappa-B in primary neurons. Proc Natl Acad Sci U S A 92:9618-9622, 1995. 72. Kopp EB, Ghosh S: NF-kappa B and related proteins in innate immunity. Adv Immunol 58:1-27, 1995. 73. Guerrini L, Molteni A, Wirth T, et al: Glutamate-dependent activation of NF-kappa B during mouse cerebellum development. J Neurosci 17:6057-6063, 1997. 74. Willis WD, Sluka KA, Rees H, et al: Cooperative mechanisms of neurotransmitter action in central nervous sensitization. Prog Brain Res 110:151-166, 1996. 75. Wu J, Lin Q, Lu Y, et al: Changes in nitric oxide synthase isoforms in the spinal cord of rat following induction of chronic arthritis. Exp Brain Res 118:457-465, 1998. 76. Lawand NB, Willis WD, Westlund KN: Blockade of joint inflammation and secondary hyperalgesia by L-NAME, a nitric oxide synthase inhibitor. Neuroreport 8:895-899, 1997. 77. Beck KF, Eberhardt W, Frank S, et al: Inducible NO synthase: Role in cellular signalling. J Exp Biol 202:645-653, 1999. 78. Lewis T: Experiments relating to cutaneous hyperalgesia and its spread through somatic nerves. Clin Sci 2:373-417, 1936. 79. Szolcsanyi J: Antidromic vasodilatation and neurogenic inflammation. Agents Actions 23:4-11, 1988. 80. Pierau FK, Szolcsanyi J: Neurogenic inflammation—axon reflex in pigs. Agents Actions 26:231-232, 1989. 81. Bayliss SW: The Vaso-Motor System. London, Longmans, Green & Co, 1923. 82. Gotch F, Horseley V: On the mammalian nervous system, its functions and their localizations, determined by an electrical method. Philos Trans B 182:267-326, 1891. 83. Toennies JF: Reflex discharge from the spinal cord over the dorsal roots. J Neurophysiol 1:378-390, 1938. 84. Barron DH, Matthews BHC: The interpretation of potential changes in the spinal cord. J Physiol 92:276-321, 1938. 85. Eccles JC, Kozak W, Magni F: Dorsal root reflexes of muscle group I afferent fibres. J Physiol 159:128-146, 1961. 86. Sluka KA, Jordan HH, Westlund KN: Reduction in joint swelling and hyperalgesia following post treatment with a non-NMDA glutamate receptor antagonist. Pain 59:95-100, 1994. 87. Sorkin LS, Moore J, Boyle DL, et al: Regulation of peripheral inflammation by spinal adenosine: Role of somatic afferent fibers. Exp Neurol 184:162-168, 2003. 88. Rees H, Sluka KA, Westlund KN, et al: The role of glutamate and GABA receptors in the generation of dorsal root reflexes by acute arthritis in the anaesthetized rat. J Physiol 484:437-445, 1995. 89. Rees H, Sluka KA, Lu Y, et al: Dorsal root reflexes in articular afferents occur bilaterally in a chronic model of arthritis in rats. J Neurophysiol 76:4190-4193, 1996. 90. Sluka KA, Rees H, Westlund KN, et al: Fiber types contributing to dorsal root reflexes induced by joint inflammation in cats and monkeys. J Neurophysiol 74:981-989, 1995. 91. Eccles RM, Willis WD: Presynaptic inhibition of the monosynaptic reflex pathway in kittens. J Physiol 165:403-420, 1962. 92. Duchen MR: Excitation of mouse motoneruones by GABA-mediated primary afferent depolarization. Brain Res 379:182-187, 1986.

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93. Sluka KA, Westlund KN: Centrally administered non-NMDA but not NMDA receptor antagonists block peripheral knee joint inflammation. Pain 55:217-225, 1993. 94. Sluka KA, Willis WD, Westlund KN: Joint inflammation and hyperalgesia are reduced by spinal bicuculline. Neuroreport 5:109-112, 1993. 95. Boyle DL, Moore J, Yang L, et al: Spinal adenosine receptor activation inhibits inflammation and joint destruction in rat adjuvantinduced arthritis. Arthritis Rheum 46:3076-3082, 2002. 96. Sluka KA, Lawand NB, Westlund KN: Joint inflammation is reduced by dorsal rhizotomy and not by sympathectomy or spinal cord transection. Ann Rheum Dis 53:309-314, 1994. 97. Lin Q, Zou XJ, Fang L, et al: Sympathetic modulation of acute cutaneous flare induced by intradermal injection of capsaicin in anesthetized rats. J Neurophysiol 89:853-861, 2003. 98. Lin Q, Zou X, Ren Y, et al: Involvement of peripheral sympathetic modulation neuropeptide Y receptors in of acute cutaneous flare induced by intradermal capsaicin. Neurol Sci 123:337-347, 2004. 99. Heppelmann B, Messlinger K, Neiss WF, et al: Fine sensory innervation of the knee joint capsule by group III and group IV nerve fibers in the cat. J Comp Neurol 351:415-428, 1995.

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100. Lam FY, Ferrell WR: Neurogenic component of different models of acute inflammation in the rat knee joint. Ann Rheum Dis 50: 747-751, 1991. 101. Levine JD, Dardick SJ, Roizen MF, et al: Contribution of sensory afferents and sympathetic efferents to joint injury in experimental arthritis. J Neurosci 6:3423-3429, 1986. 102. Thompson M, Bywaters EG: Unilateral rheumatoid arthritis following hemiplegia. Ann Rheum Dis 21:370-377, 1962. 103. Velayos EE, Cohen BS: The effect of stroke on well-established rheumatoid arthritis. Md State Med J 21:38-42, 1972. 104. Hench PS: Heberden’s nodes: Heredity in hypertrophic arthritis of the finger joints (a discussion). JAMA 115:2050, 1940. 105. Stecher RM, Karnosh LJ: Heberden’s nodes, IV: The effect of nerve injury upon formation of degenerative joint disease of the fingers. Am J Med Sci 213:181-189, 1947. 106. Kamermann JS: Protective effects of traumatic lesions on rheumatoid arthritis. Ann Rheum Dis 25:361-373, 1966.

27

Atherosclerosis in Rheumatoid Arthritis Naveed Sattar  •  Iain B. McInnes

KEY POINTS Patients with rheumatoid arthritis (RA) are at an elevated ­(approximately 1.5-fold to 2-fold) risk for vascular events. Patients with RA tend to experience less angina, but may experience more sudden deaths and unrecognized myocardial infarctions. The excess vascular risk is driven principally by systemic inflammation via direct and indirect mechanisms. Current evidence suggests disease-modifying antirheumatic drugs and biologics lessen vascular risk, whereas chronic high-dose steroids may increase vascular risk. All patients with RA would benefit from cardiovascular ­ disease (CVD) risk factor screening and using existing risk scores. Patients at high absolute CVD risk, estimated at 1.5 times Framingham risk score or equivalent in those with longer duration or more severe disease, would benefit from statin therapy. Other CVD risk factors, such as hypertension and smoking, should be managed aggressively. Rheumatologists may benefit from wider training on methods of CVD risk assessment.

The excess risk of vascular disease in the rheumatic diseases has been known for many decades,1 but at the clinical level, coronary heart disease (CHD) or global cardiovascular disease (CVD) risk assessment and related preventive treatment have been less well characterized. Increasing awareness in the 1990s of inflammation as a novel player in the origin of CVD in the general (nonrheumatic diseases) population2 has stimulated resurgent interest in potential mechanisms underpinning excess CVD risk in rheumatic diseases. This chapter summarizes more recent evidence in this field, including discussions on epidemiology, pathogenesis, and cardiovascular risk screening. Extrapolating from work in the CVD arena, we discuss how best to incorporate findings into clinical practice to improve management of CVD risk in the rheumatic diseases. The focus is mainly on rheumatoid arthritis (RA) because this is the rheumatic disease for which most data are available. Increased risk in systemic lupus erythematosus (SLE) also is considered.

CARDIOVASCULAR RISK IN RHEUMATOID ARTHRITIS EPIDEMIOLOGY Extent of Coronary Heart Disease Risk in Rheumatoid Arthritis Van Doornum and colleagues3 summarized evidence from 21 observational studies published before and including the year 2000 that examined CHD risk levels in RA. These investigators noted 17 of the 21 studies show an increased standardized morality ratio in RA, and that life expectancy is shortened by 3 to 18 years. Pooled analysis of these studies suggests a 70% increased risk of death in RA patients. Most such studies examined RA patients with duration of disease of 10 years or longer. More recent studies have corroborated and extended earlier evidence. Solomon and associates4 compared incidence rates of myocardial infarction and stroke in subjects with and without RA among the 114,342 women in the Nurses’ Health Study. Multivariate pooled logistic regression was used to adjust for potential cardiovascular risk factors. During 2.4 million person-years of follow-up, 527 incident cases of RA and 3622 myocardial infarctions and strokes were confirmed. The adjusted relative risk of myocardial infarction in women with RA compared with women without RA was 2.0 (95% confidence interval [CI] 1.23 to 3.29). Women who had RA for at least 10 years had a relative risk for myocardial infarction of 3.10 (95% CI 1.64 to 5.87). The end point data were prospectively gathered and validated with record acquisition. In addition, the risk for myocardial infarction was hardly attenuated after adjustment for most traditional risk factors, although high-density lipoprotein (HDL) cholesterol was not included as a potential confounder. Future epidemiologic studies should address this deficiency because low HDL cholesterol is closely linked to excess CVD risk generally and is one of the most consistent findings in RA patients. Similarly, analysis of the relevant data from the United Kingdom General Practice Research Database (>2 million patients) confirms elevated CHD risk in RA patients.3 Finally, investigators in Malmo5 reported a standardized mortality ratio of 176 for myocardial infarction in RA patients compared with the general population. Relevant evidence from all studies suggests CHD risk is equally elevated in men and women with RA, increases with disease severity and evidence of extra-articular disease, and increases with disease duration.3,4 There is consistent evidence of higher CVD risk in RA patients. It is difficult to give a precise estimate of the level of this excess risk, but it seems to be about 1.5-fold to 2-fold 421

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higher. This risk is lower than the excess risk of CVD seen in patients with type 2 diabetes, although previous comparisons on the CVD risk in the two conditions have been made. When Does Risk Begin and How Does It Manifest? More recent analyses from the Minnesota residents’ cohort have suggested that the excess CVD risk began early. In the 2 years before fulfillment of the American College of Rheumatology criteria, RA patients were about three times more likely to be hospitalized for acute myocardial infarction, and nearly six times more likely to have experienced an unrecognized myocardial infarction compared with individuals without RA.6 This excess risk did not seem to be accounted for by traditional CHD risk factors, although adjustments did not take account of continuous measures, but used cat­ egorical variables,6 so residual confounding is possible. In the study by Maradit-Kremers and coworkers,6 in addition to a higher risk of unrecognized myocardial infarction, ­sudden death was more likely in RA patients. Perhaps in keeping with these findings, RA patients were less likely to have a history of angina and, perhaps related to this, had lower rates of coronary artery bypass grafting. An analysis of all cases of first cardiovascular event in Victoria, Australia, revealed a higher 30-day case-fatality rate (1.6; 95% CI 1.2 to 2.2) in patients with RA compared with patients without RA.7 This excess risk was mostly accounted for by excess death after myocardial infarction, although CIs were large because of small numbers of events. Nevertheless, consistent with this finding, Solomon and colleagues8 also noted a higher 30-day mortality rate (1.89; 95% CI 1.56 to 2.30) in RA patients after a CVD event in their examination of relevant data from British Columbia. In the latter study, if RA patients survived through this period, their subsequent vascular risk was not elevated compared with patients without RA.8 These observations merit further investigation. Summary of Vascular Risk in Rheumatoid Arthritis from Epidemiologic Findings From available epidemiologic data, the following broad conclusions can be made: • CHD risk is greater in patients with RA by approximately 1.5-fold to 2-fold (i.e., relative risk). This excess risk does not seem to be accounted for by most traditional risk factors, although more studies are needed to clarify this. • Absolute risk of a vascular event in RA must include use of traditional risk factor algorithms, which include age, sex, blood pressure, smoking, and lipids. When determined, risk could be multiplied by 1.5 in RA ­patients with modest-to-severe disease severity and longer duration (i.e., >5 years). • An elevated CHD risk in RA may begin early in the course of the disease, but on balance, relative risk seems greater with greater evidence of systemic disease and longer duration of RA. • The excess vascular risk manifests differently in RA patients compared with patients without RA, with less angina, but more sudden deaths and unrecognized myocardial infarctions.

• Early 30-day case-fatality after a cardiovascular event seems to be greater in RA patients versus patients without RA. These findings make it clear that RA patients not only have higher cardiovascular risk, but also they are less likely to be symptomatic and more likely to die before getting to the hospital if they have a myocardial infarction. Even if RA patients with a myocardial infarction survive until they get to the hospital, they are more likely to die in the first 30 days after myocardial infarction. These findings make arguments for routine CHD risk screening in patients with RA more compelling. PATHOGENESIS Inflammation and Atherogenesis in the General Population To understand fully the excess CHD risk in RA, one first must appreciate the link between inflammation and CHD or CVD risk in the general population. Interest in understanding CHD risk in RA has been stimulated by recognition of the inflammatory basis for cardiovascular disease in general. Plaque composition of unstable coronary lesions includes an abundance of inflammatory moieties and immune cells at the shoulder region, with erosion of the collagen cap that separates the atheromatous material of the plaque from the lumen.2 This appearance is strikingly similar to the phenotype of inflammatory synovitis in RA.9 Although elevated systemic markers of inflammation, albeit at considerably lower levels than those apparent in RA, independently predict CHD events in the general population, the level of independent prediction afforded by, for example, C-reactive protein (CRP), is debated.10 There also remain uncertainties about causality of the “low-grade” inflammation in the atherogenic process. Some investigators argue that the inflammatory features within an evolving plaque may largely be consequent to entry of atherogenic low-density lipoprotein (LDL) species into the vessel wall, which sets in motion a chain of molecular events leading to macrophage recruitment (and associated molecular and cellular features), and subsequent foam cell formation.11 Elevated systemic inflammatory markers may arise from diseased blood vessels—so-called reverse causation. Alternatively, elevated (low-grade) systemic inflammation levels may stem from multiple lifestyle factors that can increase CHD risk by mechanisms other than inflammation (Fig. 27-1). Adiposity especially,12 but also smoking, poor diet, low physical activity, and social deprivation are linked to elevated detectable inflammation in the general population, manifest by systemic CRP estimation, but such factors also are linked to many other atherogenic pathways. Adiposity explains about 20% of the systemic inflammatory burden in population studies, and more recent evidence indicates obesity per se leads to excess and likely detrimental macrophage recruitment into adipose tissue.13 Further studies are required to disentangle the link between “lowgrade” inflammation and cardiovascular disease, including genetic studies and clinical trials determining the vascular effects of specific anti-inflammatory agents.

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Low-grade inflammation CRP 0-6 mg/L, on average 1-3 mg/L Adiposity Diet Genes Low physical activity Smoking Deprivation

Risk factor pathways, e.g.,lipids, insulin resistance, hemostatic abnormalities

B

CHD

Statins

RA synovitis

High-grade systemic inflammation CRP often far in excess of 6 mg/L, typically 10-50 mg/L

Atherogenic effects on numerous risk factor pathways

DMARD or Anti-inflammatory therapy

Accelerated atherogenesis

Atherogenic lipid pool Insulin resistance Hemostatic abnormalities Oxidative stress Endothelial progenitor cell effects Elevations in homocysteine Endothelial dysfunction

CHD

Myocardial microvascular abnormalities Independent of narrowed coronary vessels

Figure 27-1  Comparing and contrasting links between low-grade versus high-grade inflammation and coronary heart disease (CHD). A, Low-grade i­nflammation. The complex potential links between low grade inflammation and CHD are shown. Although low-grade inflammation, stemming from a combination of lifestyle and genetic factors, may be causally related to the pathogenesis of CHD either directly or indirectly via its influence on other risk factors, it is possible that low-grade inflammation is a noncontributory correlate in the risk factor–CHD relationship, or a consequence rather than a cause of blood vessel disease. B, High-grade systemic inflammation. Systemic inflammation levels in individuals with rheumatoid arthritis (RA) are generally far greater than in individuals without RA, well above levels attributed to lifestyle factors (e.g., obesity, smoking) or diseased blood vessels. Rather, the driver to systemic acute-phase reactants in RA is predominantly synovial inflammation. Resultant concentrations of circulating cytokines alter the function of distant tissues, including adipose, skeletal muscle, liver, and vascular endothelium, to generate a spectrum of proatherogenic changes that include an atherogenic lipid pattern, insulin resistance, pro-oxidative and procoagulative effects, and endothelial dysfunction and damage. Myocardial microvascular effects may contribute to the burden of CHD in RA independent of accelerated atherogenesis, but this requires further investigation. This model predicts CHD risk reduction with inflammatory suppression, and evidence for this (see text) is emerging. Because most RA patients continue to exhibit significant systemic inflammation despite potent therapy, however, consideration of established CHD risk reduction strategies in RA patients at elevated risk would seem appropriate. Statins have been shown to reduce lipid levels in RA markedly and may offer a modest disease-modifying effect. CRP, C-reactive protein; DMARD, disease-modifying antirheumatic drug. (Modified from Sattar N, McInnes IB: Vascular comorbidity in rheumatoid arthritis: Potential mechanisms and solutions. Curr Opin Rheumatol 17:286-292, 2005.)

Inflammation and Atherogenesis in Rheumatoid Arthritis In contrast to the complexities of linking low-grade inflammation and CHD pathogenesis, the inflammation-CHD link in RA is, paradoxically, easier to establish (see Fig. 27-1).14 Systemic inflammation levels in patients with RA are often far greater than in individuals without RA, well above levels attributed to lifestyle factors (e.g., obesity, smoking) or diseased blood vessels (Fig. 27-2). The major driver explaining elevation in systemic acute-phase reactants in RA is predominantly synovial inflammation and subsequent cross-talk with the liver via cytokine release. On the basis of several lines of evidence, we15 and others have argued that such “high-grade” inflammation is likely pivotal to the accelerated CHD in RA. Several prior studies and more recent studies are described to support this hypothesis (Table 27-1): • CHD risk in RA is related to number of inflamed joints3 and seems to be greatest in RA patients with extra-articular disease or patients in tertiary referral centers. • Conventional risk factors do not account for excess CHD risk in RA patients. In an analysis from the Nurses’ Health Study, although inflammatory markers

Typical profile in RA patient [CRP] 50 mg/L

6 mg/L

Uper end of ‘normal’ range High-sensitivity range: CHD risk increases by∼50% in general population with CRP rising from <1 mg/L to >3 mg/L

Time Figure 27-2  The magnitude and chronicity of systemic inflammation in individuals with rheumatoid arthritis (RA) are particularly deleterious, such that, even during quiescent phases of the disease, systemic levels of cytokines remain high relative to individuals without RA and, as such, may continue to promote vascular risk. CHD, coronary heart disease; CRP, C-reactive protein. (Modified from Sattar N, McCarey DW, Capell H, et al: Explaining how “high-grade” systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation 108:2957-2963, 2003.)

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Table 27-1  Risk Factor Alterations in Rheumatoid Arthritis including Associations with the Inflammatory   Response in Cross-Sectional Studies, and Documented Improvements on Inflammatory Suppression* Strength of Evidence for Abnormality of Risk Factor in Rheumatoid Arthritis

Strength of Evidence Linking Metabolic Perturbances to Inflammatory Response in Rheumatoid Arthritis

+ + ++ +

ND + + ++

Steroids and SSZ may enhance insulin sensitivity in RA; TNF blockade improves

+ +/0 ++ ++ + ++

+ + ++ + + +

Anti-inflammatory treatment increases HDL-cholesterol or apolipoprotein AI; reduction in Lp(a) lipoprotein noted with TNF-α blockade

++ + + ++ ++

+ + + + +

MDA

+

+

↓ Vitamin antioxidants

+

+

++ + +

++ 0 ND

Coronary Heart Disease Risk Factors

Evidence for Improvement in Risk Factor on Inflammatory Suppression

Obesity/Insulin Body fat redistribution Hyperinsulinemia Insulin resistance ↓ SHBG (surrogate marker) Dyslipidemia FFAs Triglyceride ↓ HDL-cholesterol ↓ HDL2 Small, dense LDL Lp(a) lipoprotein Endothelial sICAM-1 vWF Microalbuminuria Impaired vasoreactivity Arterial stiffness

FMD/PWV improve with   anti-TNF-α therapy; sICAM declines with SSZ

Oxidative Stress Not examined, but ibuprofen   ↑ antioxidant levels in cancer subjects

Hemostatic Alterations Fibrinogen PAI-1 Blood pressure

TNF blockade reduces fibrinogen No data

Homocysteine Pathway ↓ Vitamin B6

++

+

Homocysteine

++

+

Steroids and TNF blockade can ↓ homocysteine­

*Most data stem from small, uncontrolled studies; 0 = lack of, or conflicting, evidence; + = moderate supporting evidence; ++ = consistent evidence; ND = no data. FFAs, free fatty acids; FMD, flow-mediated dilation; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MDA, malondialdehyde; PAI-1, plasminogenactivator inhibitor-1; PWV, pulse wave velocity; RA, rheumatoid arthritis; SHBG, sex hormone binding globulin; sICAM, soluble intracellular adhesion molecule; SSZ, sulfasalazine; TNF, tumor necrosis factor; vWF, von Willebrand factor. Modified from Sattar N, McCarey DW, Capell H, et al: Explaining how “high-grade” systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation 108:2957-2963, 2003.

(including CRP and intercellular adhesion molecule-1) were substantially elevated in women with RA compared with women without RA, most traditional CHD risk factors were similar.16 In addition, this group and others4,17 have shown more recently that adjustment for most traditional risk factors minimally attenuates the RA to non-RA difference in CHD event rates, although such adjustments have not always been comprehensive. • Carotid artery intima-media thickness (IMT) (and plaque), a U.S. Food and Drug Administration–­approved surrogate marker of vascular disease, was elevated in RA patients in association with elevated markers of inflammation.18 More significantly, arterial thickening in ­women with RA, as measured by change in carotid IMT over 18 to 36 months, was accelerated compared with healthy controls, and the increase in IMT was related independently to serum CRP concentration, but not conventional risk factors.19 More recently, carotid IMT in RA

patients has been shown to be related to disease duration so that patients with prolonged RA had more atherosclerosis than patients with more recent disease onset. The findings parallel our prior suggestion that ­atherosclerosis accelerates during the course of RA (Fig. 27-3). • Endothelial dysfunction has been suggested as an early event in the atherogenic process and as a novel predictor of CHD events; more recent longitudinal studies in the CHD arena provide some support for this proposition.20 Several studies employing various ­“direct” ­ measures of vascular function, such as pulse wave analysis,21 flow-mediated vasodilation,22 and venous occlusion plethysmography,23 confirm endothelial dysfunction in RA patients. Where examined, such dysfunction has been linked to systemic inflammatory markers. Vaudo and associates24 have provided more recent evidence for endothelial dysfunction in young to middle-aged patients with low disease activity (disease activity score [DAS] ≤3.2) and noted a strong

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Vascular risk

Accelerated atherogenesis in RA (plus other immunologic conditions) Slope largely dependent on aggregation of conventional risk factors

Slope or risk escalation a severity of systemic disease

Onset of RA

Additional major source of systemic cytokines from inflamed joints

Time Figure 27-3  Before onset of rheumatoid arthritis (RA), classic risk factors predict risk of an event. After onset of disease, the severity of the systemic inflammation secondary to RA joint disease is critical in the ­acceleration of atherogenesis, and risk factors influenced by systemic inflammation predict risk of future events. (Modified from Sattar N, McCarey DW, Capell H, et al: Explaining how “high-grade” systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation 108:2957-2963, 2003.)

a­ ssociation to average CRP levels. This finding agrees with the earlier observation of an early excess risk of vascular events in RA patients. Elevated LDL cholesterol also was an independent correlate to impaired vascular function in RA patients in the latter study. Other more recent studies also show impaired vessel stiffness with the technique of pulse wave velocity,25 and we have shown impaired forearm microvascular function using laser Doppler imaging in patients with RA in parallel with a greater systemic inflammatory response.26 • More recent longitudinal studies report improved endothelial function after anti–tumor necrosis factor (TNF)-α therapy,27,28 but this benefit seems to be transient and linked to the pattern of change in systemic inflammatory markers on TNF blockade. Treatment with disease-modifying antirheumatic drugs (DMARDs) also improves endothelial function in patients with RA,23 so the mechanism employed to achieve inflammatory control may not be crucial to improvement in endothelial function. • Numerous other risk factors beyond endothelial dysfunction can be directly and adversely influenced by the systemic inflammatory response in RA (see Fig. 27-1 and Table 27-1).15 The lipid profile, despite showing lower LDL cholesterol, is more atherogenic (e.g., low HDL cholesterol, greater preponderance of smaller atherogenic LDL species). There also is evidence of greater insulin resistance, altered body fat distribution (peripheral wasting, central fat accumulation), prothrombotic effects, and pro-oxidative stress. In addition, some evidence suggests inflammatory cytokines may elevate homocysteine concentrations in RA. Anti-inflammatory treatment can attenuate many of these changes, and in the context of a randomized placebo-controlled trial, we showed that a TNF blocking agent can reduce circulating concentrations of homocysteine, Lp(a) lipoprotein, and fibrinogen, and increase apolipoprotein A-I (the

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main ­ apolipoprotein in HDL particles, ­ associated with antiatherogenic actions) and sex hormone binding globulin, the last-mentioned used as a surrogate marker of insulin sensitivity.29 For balance, in the latter study, increases in triglyceride and apolipoprotein B were unexpected and require further investigation because elevated triglyceride and apolipoprotein B are associated with an increase in CVD risk.29 Predictions of the likely vascular end point effects on this TNF blocking agent based solely on a panel of biochemical parameters would seem to be difficult to make. • Cytokines released from inflamed synovial membrane can exert metabolic effects via effects on distant tissues, including adipose tissues, skeletal muscle, liver, and vascular endothelium. One consequence of this functional pleiotropy is that the intensity of the metabolic adaptation could parallel other cytokine effects. Cytokine-induced metabolic effects, which include transient alterations in lipids and peripheral insulin resistance, are favorable in the short-term and function as part of the host response to infection and acute inflammation to target specific metabolic fuels to and from essential organs. Chronic elevation in cytokine levels, regardless of magnitude or cause, is deleterious, however, and promotes accelerated atherogenesis via aggravation of several risk factor pathways as described earlier. From a developmental standpoint, cytokines or cytokine-like molecules, such as interleukin-630 or leptin,31 may have evolved to impart their systemic metabolic effects at very low levels or in rapid transient bursts. Even minor degrees of chronic elevation are damaging. As a result, as argued more recently,15 the magnitude and the chronicity of systemic inflammation in RA may be particularly deleterious. Even during “quiescent” phases of the disease, systemic levels of cytokines or their regulatory components often remain dysregulated relative to patients without RA and, as such, may continue to promote vascular disease.15 • There are numerous model data to support a proatherogenic role for cytokines.32,33 A study in apolipoprotein E knockout mice showed reduced atherosclerosis via inhibition of TNF-α.34 • Endothelial progenitor cells (EPCs) represent a population of bone marrow–derived cells that have the capacity to make a significant contribution to new blood vessels. Higher concentrations seem to be protective, whereas lower concentrations have been correlated with higher cardiovascular risk in patients without RA. Grisar and associates35 reported lower EPC concentrations in active RA and noted an inverse correlation between EPC quantity and disease activity score. In line with a link between inflammation and EPCs, a single dose of infliximab has been shown to improve the number and functional properties of EPCs.36 The systemic inflammatory response in RA seems to be associated with a largely reversible spectrum of proatherogenic changes in other risk factor pathways. From such observations, it seems that CVD risk in RA must be linked partly to disease activity, and, as discussed previously, there is plentiful evidence supporting this potential. CVD risk in

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RA patients is likely to decline with better and sustained suppression of disease activity in RA patients. The mode of inflammation suppression is relevant, and some anti­inflammatory drugs might have direct vascular damaging properties that overwhelm vascular benefits arising indirectly from their inflammatory suppression. Inflammation-Mediated Microvascular Dysfunction as a Cause of Myocardial Ischemia in Rheumatoid Arthritis Much of the more recent evidence in the general CHD area suggests that patients with exercise-proven myocardial ischemia do not show obstructed coronary vessels on angiography. Rather, as in women with cardiac syndrome X, myocardial ischemia may manifest from dysfunctional endothelium in coronary vessels or in the myocardial microvasculature, which under conditions of stress vasoconstrict to cause symptoms. We suggested that independent of obstructive coronary disease, insulin resistance could be a major contributor to myocardial ischemia via endothelial dysfunction.37 We proposed insulin sensitization as a novel mechanism to lessen anginal symptoms in subjects with and without diabetes. Such work is now ongoing in formal clinical trials. Consistent with this concept, Raza and colleagues38 reported complete reversal of significant myocardial ischemia (proven by thallium scanning) in a 62-year-old man with RA on intensive immunosuppression. Coronary angio­ graphy showed no significant atheroma. This group argued that systemic inflammation–driven myocardial microvascular abnormalities may be as important to the pathogenesis of ischemic heart disease in RA as atherosclerotic narrowing.38 Future studies will be needed to develop these important findings, but two additional factors merit comment. First, data from noninvasive measurement of endothelial function and carotid atheroma burden in patients with coronary artery disease suggest that structural and functional status of the vasculature are independent predictors of coronary events.39 Second, conventional coronary angiography can miss unstable lesions: Arterial wall remodeling permits accumulation of a large atherosclerotic burden before there is any detectable narrowing of the vessel lumen by conventional angiography.40 Novel imaging modalities, such as intravascular ultrasound, may allow better detection of these “silent” plaques.40 LESSENING VASCULAR RISK IN RHEUMATOID ARTHRITIS VIA INFLAMMATORY SUPPRESSION Methotrexate The foregoing arguments suggest that absolute and longterm suppression of the systemic inflammatory response in RA should lessen CHD risk by improving risk factors. The balance of evidence favors this likelihood, including more recent epidemiologic findings. In an 18-year follow-up of 1240 patients with RA, Choi and colleagues41 reported that methotrexate treatment, generally considered to be the most effective “nonbiologic” DMARD, reduced overall mortality by 60% (95% CI 20% to 80%) primarily by reducing CHD mortality by 70% (95% CI 30% to 80%). Non-CHD mortality was not significantly altered.

Disease-Modifying Antirheumatic Drugs Evidence suggests that DMARD use is associated with a reduction in acute myocardial infarction risk of about 20% in patients with RA.42 Myocardial infarction risk in this case-control study was reduced with all traditional DMARDs and, consistent with the Choi results,41 also seen with methotrexate use. Steroids It is unclear whether steroids increase or decrease risk or have a neutral effect. Davis and coworkers43 found no independent associations (adjusting for other cardiovascular risk factors and disease activity) between cumulative glucocorticoid exposure and CVD risk in RA patients followed for 15 years. By contrast, two nested case-control studies suggested an approximate 30% to 50% higher myocardial infarction risk with steroid use.42,44 In line with an excess risk, del Rincon and associates45 reported a higher incidence of carotid plaque and arterial stiffness in patients with RA on steroids. On balance, steroids may be one class of drugs where the vascular beneficial effects of inflammatory suppression are reversed by direct adverse effects on the vasculature. Biologics Given the mixed pattern of biochemical changes seen with TNF blocking agents on risk factors, it is difficult to predict vascular effects of these agents, even though TNF blocking agents consistently improve vascular function, albeit in a transient fashion. An observational study from Sweden compared CVD event rates in RA patients on anti-TNF therapy versus RA patients not on such therapy.46 The findings suggested an age-adjusted and sex-adjusted 54% decreased risk (95% CI 15% to 75%) of CVD event in patients on anti-TNF therapy. Solomon and colleagues44 have since reported a similar effect of biologics compared with methotrexate on CVD risk, which if we accept that the latter reduces CVD risk, is consistent with data from Sweden. Further robust data are needed to address this important issue, with appropriate attention to potential confounders because epidemiologic findings can give rise to incorrect conclusions (e.g., as in the case of hormone replacement therapy and CVD risk). TNF-α blockade may lead to other toxicities,47 including potential harm in patients with heart failure.48 Future Studies Examining Links between Rheumatoid Arthritis Treatments and Cardiovascular Disease Risk Robust epidemiologic studies and larger controlled trials are needed to expand the evidence base regarding RA therapies and CHD risk. The latter should include, wherever possible, a wide range of risk factors and established vascular measures. The use of carotid IMT measurement in trials is to be encouraged, and, in the near future, magnetic resonance imaging (MRI) and other novel imaging methods (e.g., intravascular ultrasound or novel noninvasive ­computed tomography scanning) may offer new ways to advance knowledge in the RA-CHD field. Because of multiple confounding factors

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and an ethical need to limit disease activity, study design is generally very complex in the RA arena, however. Only short-term mechanistic and surrogate vascular marker studies with anti-inflammatory and disease-­modifying agents are likely to be feasible. Statins to Lessen Coronary Heart Disease Risk in Rheumatoid Arthritis Because complete and absolute long-term suppression of systemic inflammation is rarely achieved in RA, even with the advent of more potent therapies, vascular risk will continue to be elevated. As a result, there is merit in considering other proven measures to lessen CHD or CVD risk in RA. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) reduce CVD morbidity and mortality by approximately 25% to 50% and, on the basis of an excellent evidence base, are widely used in primary and secondary prevention of vascular disease.49 Although operating predominantly through reduction in LDL cholesterol concentration, more recent studies suggest broader properties for statins, particularly in altering inflammatory pathways.50 Statins are potentially ideal drugs to target CVD risk in disease states (e.g., RA) associated with high-grade inflammation, and early evidence is supportive in this respect. In a placebo-controlled study of atorvastatin (40 mg/ day) in RA patients, we noted a significant reduction in LDL cholesterol and triglyceride (45% and 18%), disease activity score (disease activity score 28 [DAS28]; 10%), acute-phase parameters (CRP [50%] and erythrocyte sedimentation rate [28%]), and the swollen joint count (decrease of 2.16 joints relative to placebo) in patients presenting with active RA despite existing DMARD treatment.51 Although the magnitude of change in disease activity with atorvastatin was modest, this study provided the first clinical indication that pathways targeted by statins may be useful in the treatment of inflammatory disease. In parallel with the atorvastatin-induced reduction in CRP, plasma viscosity, fibrinogen, and interleukin-6 concentrations also were reduced relative to placebo. We observed no significant liver function or muscle abnormalities with atorvastatin,51 and the statin safety record in general is excellent. The long-term implication of this study may lie, however, more in showing the potential for attenuation of inflammation and vascular risk parameters by statins, rather than in providing a novel DMARD in available statin agents. Larger studies are required to corroborate the statininduced effects on RA disease activity and safety; our original positive report in murine collagen-induced arthritis52 was not confirmed by other investigators,53 although positive effects for statins have been reported across a range of murine autoimmune models. Nevertheless, in terms of vascular risk modification, the lipid-lowering effect noted by us51 was in keeping with the magnitude of changes seen in the non-RA population.43 This finding is important because, despite a tendency of statins to reduce LDL cholesterol in RA, the overall lipid pool in RA is highly atherogenic, and extrapolation from data from all statin end point trials suggests that the extent of LDL cholesterol reduction may account for most of the statin ­clinical

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­benefit.54 Statin-induced reductions in CVD risk occur even when starting LDL cholesterol values are considered “average” or “low,” and optimal LDL cholesterol levels may be 1.3 to 1.8 mmol/L.54 Van Doornum and colleagues55 confirmed that statins substantially improve RA lipids in a smaller uncontrolled study, which also reported statin-induced reduction in arterial stiffness, previously shown to be elevated in RA. End point studies with statins in RA would be ideal, but in the interim phase, statin effects on progression of carotid IMT would be informative. Finally, existing data indicate that lipids enter and are present in considerable quantity in diseased RA synovium. More recent studies suggest oxidized LDL may promote articular damage therein.56 If a statin-mediated reduction in RA disease activity is proven, statin-induced reduction in the systemic lipid load, rather than or in addition to direct anti-inflammatory effects, should be considered as potentially responsible. This theory requires future study. ASSESSING CARDIOVASCULAR DISEASE RISK IN RHEUMATOID ARTHRITIS Who to Screen The collective findings of higher CHD or CVD risk in RA patients that begins early, with greater propensity to sudden death, unrecognized myocardial infarctions, and less angina, plus greater 30-day case-fatality post-CVD, provide a compelling reason to consider universal CVD risk factor screening in RA patients. Given that absolute risk is low in young individuals even with other significant risk factors, however, it may be sensible to restrict universal screening for RA patients to individuals older than 40 years of age. CVD risk screening in younger subjects may be appropriate in the face of several other risk factors or a strong family history of premature vascular disease. How Best to Screen Presently Generally, the following parameters are used to assess risk in the primary prevention setting: age, sex, smoking, systolic blood pressure, and cholesterol-to-HDL cholesterol ratio. Diabetes is now no longer included in many primary prevention charts because patients with type 2 diabetes who are older than 40 years of age are now considered at sufficiently high risk to warrant statin therapy.57 All that is required in RA patients in addition to readily available clinical data (age, sex, smoking history) is the ­measurement of systolic blood pressure and cholesterol and HDL cholesterol concentrations in serum or plasma. With many laboratories now offering direct HDL cholesterol in nonfasting samples (cholesterol and HDL cholesterol levels are not appreciably altered whether fasting or not), such assessments can be made as part of routine RA assessment, regardless of the time of the day or whether patients are seen in a physician’s office or in a hospital. The collection of such data permits calculation of CHD risk based on existing charts. There may be some merit in considering obtaining an electrocardiogram in some patients with RA to screen for

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prior silent myocardial infarctions, but relevant ­studies assessing the detection rate for existing disease using electrocardiograms—never mind the economics of this approach—or more detailed cardiac investigations, are lacking. Such studies would be useful, however. Should CVD Risk Calculations Be Multiplied to Account for Unmeasured Factors in Rheumatoid Arthritis Patients? One could make an argument to multiply risk based on available CVD risk charts because most studies suggest that the excess CVD risk in RA patients is not accounted for by traditional risk factors. Only a few prospective RA studies have measured traditional CHD risk factors in RA patients, however, and even when measured, some important risk factors have been omitted (most commonly HDL cholesterol). Statistical adjustments generally have used only categorical data (e.g., adjusting for hypercholesterolemia), rather than continuous measurements, leading to loss of power to detect true confounding. There is a need for further prospective studies to assess the extent to which comprehensively measured traditional risk factors attenuate or otherwise affect the excess CHD risk in RA patients compared with patients without RA. We recommend adopting a conservative position with regards to assessing CVD risk in RA. Although evidence presented earlier4,5 suggests on balance 50% to 100% higher CHD event rates in RA patients compared with patients without RA (and perhaps higher in patients with more prolonged disease), rather than applying a multiplications factor of 2 to current CVD charts when assessing CVD risk in RA, it may be more judicious to use a conservative value of 1.5. If traditional risk factors suggest a 10-year global CVD risk of 10% in an individual who has had RA for several years (>5 years), we suggest the risk could be nearer 15%. Currently in the United Kingdom, statin therapy is targeted to patients without existing vascular disease if the global CVD risk level is calculated to be 20% over 10 years (i.e., one in five chance of any vascular event over the next 10 years).57 Other countries employ related algorithms for detecting individuals at high CVD risk and are able to adopt a similar approach. Widespread CVD risk screening in RA and multiplication of the derived absolute risk, perhaps applied to a subgroup of RA patients with more severe disease and longer duration, are important. These issues require further discussion by rheumatologists and cardiologists. A conservative multiplication factor of 1.5 rather than 2 also is sensible because statins are not without side effects, although these are often reversible on treatment cessation, and serious side effects (e.g., rhabdomyolysis) are rare. More data on statin safety in RA patients would be useful, together with a specific end point trial in RA patients. One such trial is ongoing in the United Kingdom and is expected to test the efficacy and safety of atorvastatin in more than 3000 RA patients. Even in advance of the results of this trial, the clear message is that CVD risk screening in RA patients should become the norm, rather than the exception. It may be useful for RA specialists to familiarize themselves with CVD risk screening and related issues, perhaps by attending relevant courses.

Secondary Prevention—Risk Charts Not Required Patients with RA who have prevalent vascular disease (whether CHD, stroke, or peripheral vascular disease) should be strongly considered for statin therapy regardless of risk factor measures because they fulfill secondary prevention categorization. There also is plentiful evidence to indicate that risk reduction would materialize independent of baseline cholesterol level in this case or in the context of primary prevention.57 Cardiovascular Disease Risk Screening Case Example Absolute risk of an event, rather than simply a high cholesterol level, dictates treatment.57 Consider a 45-year-old man with RA with modestly high cholesterol (6.2 mmol/L), who is a nonsmoker, is normotensive (blood pressure 130/75 mm Hg), and has an average HDL cholesterol (1.3 mmol/ L). These results give a 10-year CVD risk of less than 10%. Even if this man had long-standing or severe RA, and we multiplied his risk by 1.5 (on basis of the balance of epidemiology), his absolute CVD risk would still be well below the 20% cutoff, and statin therapy would not be warranted. If the man were 10 year older, had significant hypertension, or were a smoker, his risk would increase considerably. Cardiovascular risk calculations need to become commonplace in a rheumatology clinic and in RA patients seen in primary care. The above-described case example also shows the need to be comprehensive in addressing CVD risk; CVD risk factors should be measured and treated aggressively on the basis of conventional guidelines.57 Finally, in line with CVD risk screening guidelines in general,57 clinical judgment in CVD risk determination in RA has an important role. CVD risk calculation in a 50-year-old woman with mild RA of recent onset perhaps should not be multiplied by 1.5. Many gray-area cases are to be expected, and each requires careful consideration. Surrogate Noninvasive Measures of Vascular Disease We have previously discussed several noninvasive assessment methods—tests of vascular function (e.g., flowmediated vasodilation, pulse wave velocity, laser Doppler imaging) or tests of subclinical atherosclerosis (e.g., IMT or coronary artery calcification). There is now excellent and reasonably consistent evidence of perturbed vascular function, however measured, and in different vascular beds in RA patients in parallel with heightened systemic inflammatory levels. There is equally good evidence to show improvement in vascular function with inflammatory suppression in RA patients. No such measures are in routine clinical use for risk stratification in the non-RA population, however; part of the reason is lack of sufficient prospective data, but equally the variability of techniques does not make standardization easy. Such techniques remain firmly within the research domain. Measurement of carotid IMT is not used for general CVD risk screening, although, in recognized centers with robust methodology, it is accepted as a validated measure to assess efficacy (or otherwise) of novel CVD risk modalities. It also is unclear whether coronary artery calcification techniques and carotid IMT are sufficiently robust to

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gauge the extent of excess atherosclerosis risk in RA as presence of plaques; rather, IMT may be more relevant to RA vascular events and more informative. Further relevant studies are required. It also is possible that plaque composition rather than plaque volume may be most relevant in RA, but such assessments are in their infancy and require more detailed and complex methodologies, such as cardiac/carotid MRI or positron emission tomography scanning techniques.

VASCULAR RISK IN OTHER RHEUMATIC CONDITIONS Vascular risk is enhanced in other rheumatic conditions, such as SLE and psoriatic arthritis. Myocardial infarction risk is increased in SLE—an observation unexplained by traditional risk factors.58 In addition, compared with healthy controls, SLE patients exhibit greater carotid atherosclerosis, as determined by the presence of carotid plaques, at any given age.59 In line with factors associated with risk in RA, independent predictors of plaque in SLE in the latter study included a longer duration of disease and a higher damage index score.59 Coronary artery calcification scores also are elevated in patients with SLE.60 Similarly, myocardial infarction risk has been shown to be significantly elevated in patients with psoriasis, with greater relative risks associated with greater disease severity.61 Although a detailed description of risk in other conditions is beyond the scope of this chapter, the principal mechanisms operating in RA seem to share common features across the immunologic diseases. Distinct pathways could operate particularly in SLE, however, in which altered underlying signaling and inflammatory cascades that subserve immune-mediated tissue damage also could directly influence events within the vessel wall. Future intervention studies are under way in SLE. The outcome of these studies will be vital in determining how such clinical risk should be managed beyond the aggressive treatment of underlying autoimmune disease.

CONCLUSION Evidence for elevated CHD or CVD risk in RA is abundant and convincing—best estimates indicate that individuals who have had RA for several years have approximately a 1.5-fold to 2-fold higher risk for CVD compared with individuals without RA independent of most traditional risk factors. This excess CVD risk seems to be driven mainly by systemic inflammation directly by its deleterious effects on blood vessels and indirectly by its accentuation on multiple risk pathways, including lipids, insulin metabolism, clotting, and oxidative parameters. A contribution from existing antirheumatic therapies, in particular, steroids, also may be implicated, but this requires further direct study. Established therapies that lessen disease activity and dampen systemic inflammation likely reduce CVD risk, although there remains scope for larger, robust studies. Emerging evidence indicates that statins may have dual effects in RA with a modest disease-modifying effect (requiring confirmation) and a significant lipid-lowering effect, equivalent to the magnitude of lipid reduction in patients without RA. The

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latter finding is particularly important because extrapolation of data from all statin end point trials suggests that the extent of LDL cholesterol reduction accounts for most statin clinical benefit. It seems sensible to consider statin therapy in RA patients with existing vascular disease and to assess CVD risk in RA patients without prevalent CVD. The latter would involve minimal additional tests (blood pressure and nonfasting lipids in most cases) and use of available risk factor charts. Because most RA patients continue to exhibit significant systemic inflammation despite potent therapy, it seems sensible to multiply risk levels derived from such charts by a factor of around 1.5 to derive the likely level of risk in RA patients. This conservative estimate is a balance between excess risk and the lack of comprehensive prospective CVD studies in RA that have measured and adjusted properly for the full range of traditional risk factors. The CHD risk level, and not the cholesterol level (unless markedly elevated), dictates whether statin treatment is applicable. Finally, there is considerable interest in determining whether novel risk markers or noninvasive vascular tests can help predict RA patients at greatest subsequent risk. This work is currently in its infancy, with only limited prospective data linking such measures to future cardiovascular events in the general population and no such data in RA patients. Such methods are not proven for risk stratification. The current focus in clinical practice in RA and vascular risk should remain on established risk factor algorithms (e.g., employing smoking, lipids, blood pressure) together with a multiplying factor in selected patients to determine absolute CHD risk.

Future Directions 1. Larger comprehensive epidemiologic studies are needed to determine better the extent to which CVD risk is or is not explained by traditional risk factors. This goal would be best achieved by collaboration between several centers or countries to establish a large cohort with uniform baseline phenotyping and ascertainment of future events. Such a study also could assess whether markers of current disease severity or disease duration help improve risk factor stratification beyond traditional CVD risk factors (i.e., help discriminate individual patients with RA who will, or will not, experience an incident vascular event). 2. More detailed noninvasive atherosclerosis assessment in RA patients is needed using the best current methods to determine to what extent plaque burden or plaque composition, or both, is different from patients without RA and may explain higher CVD risk. 3. Assessment, wherever possible, is needed of the effects of all new RA therapies on a comprehensive panel of vascular risk measures. 4. End point statin study is needed to ascertain efficacy with respect to CVD events and disease severity and safety in RA patients. 5. More work is needed on body composition changes and metabolic changes in relation to systemic disease severity in RA patients.

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49. Gaw A, Packard CJ: At what level of coronary heart disease risk should a statin be prescribed? Curr Opin Lipidol 11:363-367, 2000. 50. McInnes IB, McCarey DW, Sattar N: Do statins offer therapeutic potential in inflammatory arthritis? Ann Rheum Dis 63:1535-1537, 2004. 51. McCarey DW, McInnes IB, Madhok R, et al: Trial of Atorvastatin in Rheumatoid Arthritis (TARA): Double-blind, randomised placebo-controlled trial. Lancet 363:2015-2021, 2004. 52. Leung BP, Sattar N, Crilly A, et al: A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol 170:1524-1530, 2003. 53. Palmer G, Chobaz V, Talabot-Ayer D, et al: Assessment of the efficacy of different statins in murine collagen-induced arthritis. Arthritis Rheum 50:4051-4059, 2004. 54. O’Keefe JH Jr, Cordain L, Harris WH, et al: Optimal low-density lipoprotein is 50 to 70 mg/dl: Lower is better and physiologically normal. J Am Coll Cardiol 43:2142-2146, 2004. 55. Van Doornum S, McColl G, Wicks IP: Atorvastatin reduces arterial stiffness in patients with rheumatoid arthritis. Ann Rheum Dis 63:1571-1575, 2004.

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56. Kakinuma T, Yasuda T, Nakagawa T, et al: Lectin-like oxidized lowdensity lipoprotein receptor 1 mediates matrix metalloproteinase 3 synthesis enhanced by oxidized low-density lipoprotein in rheumatoid arthritis cartilage. Arthritis Rheum 50:3495-3503, 2004. 57. JBS 2: Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice. Heart 91(Suppl 5):v1-v52, 2005. 58. Manzi S, Meilahn EN, Rairie JE, et al: Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: Comparison with the Framingham Study. Am J Epidemiol 145:408415, 1997. 59. Roman MJ, Shanker BA, Davis A, et al: Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 349:2399-2406, 2003. 60. Asanuma Y, Oeser A, Shintani AK, et al: Premature coronaryartery atherosclerosis in systemic lupus erythematosus. N Engl J Med 349:2407-2415, 2003. 61. Gelfand JM, Neimann AL, Shin DB, et al: Risk of myocardial infarction in patients with psoriasis. JAMA 296:1735-1741, 2006.

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Principles of Epidemiology in Rheumatic Disease Joanne M. Jordan

KEY POINTS

OVERVIEW OF EPIDEMIOLOGIC METHODS

Epidemiology is the study of the distribution of disease and its determinants in populations. Epidemiologic methods can be used to describe the frequency or development of disease and to determine underlying causes.

Epidemiology is the study of the distribution of disease and its determinants in populations.1 The purpose of epidemiology is to describe the frequency of disease and to determine causes responsible for variation in disease occurrence. Comparison of the relative strengths of the causes and assessment of their generalizability can allow “truth” to be inferred. This chapter explains basic epidemiologic concepts and definitions; describes the major study designs, their strengths and weaknesses, and their usefulness in inferring causality; and shows specific applications of these principles to the study of rheumatic diseases. For the purposes of this chapter, the term disease is used to represent a disease, death, or other health outcome of interest, and the term exposure is used to represent a risk or protective factor examined for its association with disease.

Prevalence is the frequency of disease in the population at a given time, including existing and new cases. ­Incidence ­measures the development of disease over time in a ­population initially free from the disease. The odds ratio compares the odds of disease in an exposed population with that in a population without the exposure or risk factor under study. The relative risk is the risk of development of disease over time in an exposed population ­compared with an unexposed population. In many instances, the odds ratio can estimate the relative risk. Threats to the validity of a study include chance, systematic bias, and confounding. Confounding occurs when an extraneous factor, related to the exposure of interest and the disease, but not part of the causal pathway between exposure and disease, is superimposed on the true risk factor/disease relationship. Case-control studies examine exposures in a population that already has the disease under study and compares them with exposures in an otherwise comparable population without the disease. This study design may be subject to recall bias, in which subjects with a disease report exposure to risk factors differently than subjects without the disease, but it may be the design of choice for rare diseases. Cohort studies follow groups of individuals with and without an exposure of interest for the development of disease over time. Because the exposure assessment precedes the disease, temporality can help determine causation. Controlled clinical trials most closely resemble formal ­experiments in which the exposure is manipulated by the ­investigator, and the response of disease is compared ­between groups that receive the active intervention and groups that receive a placebo or other comparator.

MEASURES OF DISEASE OCCURRENCE Prevalence Prevalence refers to the frequency of a disease in a population at any given time. It is measured at one point in time and is the proportion of individuals with a disease out of the total population under study. The numerator makes no distinction between new and established cases of disease. Multiple estimates of prevalence over time are commonly used to determine trends in disease occurrence or need for health services. Incidence To determine the likelihood that disease will develop over time, repeated observations of the same people are required to determine who develops disease and who does not. Incidence proportion is the frequency of new cases over a specified time in a group of people at risk for, but without, the disease at baseline. During the observation period, a person may develop the disease in question, die from competing risks, or be lost to follow-up. All of these situations result in that individual’s no longer contributing time at risk to the denominator. The concept of person-time allows the inclusion of the actual time at risk contributed by each individual. 433

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Figure 28-1  Hypothetical calculation of person-time at risk for a study of the incidence of systemic lupus erythematosus over 10 years. ¶, beginning of observation period; +, died; X, developed disease; LFU, lost to follow-up. Adapted from Hennekins CH, Buring JE: Epidemiology in Medicine. Boston, Little, Brown, 1987.

Consider the hypothetical example of incidence of systemic lupus erythematosus over a 10-year period (Fig. 28-1). Person A may not develop the disease during the observation period, but may die at year 5 of a competing cause; this person contributes 5-person years to the denominator. Person B might develop systemic lupus erythematosus 4 years after the study begins and is no longer at risk of developing the disease; this person contributes 4 person-years of time at risk to the denominator. Person C may join the study at year 2, but be lost to follow-up at year 4, contributing 2 years of time at risk. Incidence rate is defined by the following:2 New cases developing over time of observatioon Incidence rate = Person-time at risk for each individual without the diseease at study entry MEASURES OF EFFECT More important than just the description of frequency of disease or its development is the relationship between the disease and exposures to potentially causative factors. One way to examine this relationship is to compare the prevalence or incidence of disease in groups with a given exposure compared with groups without that exposure. It is crucial to the ability to assess potential causality of an exposure/disease association that the exposed and unexposed groups be comparable. Measures to delineate this relationship between disease occurrence and exposure vary according to study design. Cross-sectional surveys and case-control studies use the odds ratio, which is a measure of the odds of disease in the exposed group compared with the unexposed group. Longitudinal designs can calculate a relative risk of development of disease in the exposed compared with the unexposed groups.

STUDY DESIGNS Study designs include ecologic studies, cross-sectional surveys, case-control studies, cohort studies, and randomized controlled clinical trials—the last frequently considered the most rigorous study design and the one most closely representing a formal experiment. Each study design has its own

inherent strengths and weaknesses (Table 28-1), and the choice of study design depends on the research question, the rarity of the disease under study, the availability of appropriate study and comparable control populations, resources available to conduct the study, and logistics.2,3 ECOLOGIC STUDIES In the ecologic study design, the unit of observation is a group, rather than an individual.4 Aggregate data on rates of disease and risk factors are compared to examine associations between disease frequencies and exposures. The ecologic study is frequently a design of expediency and can generate hypotheses for more rigorous testing in studies using individual-level data.3 One of the chief drawbacks is its high susceptibility to confounding. Confounding occurs when an extraneous factor, not on the causal pathway, masks the true relationship between exposure and disease, by virtue of its association with both.5 Associations in the aggregate may not hold for the individual.3 This concept is termed the ecologic fallacy. As a hypothetical example, rates of specific kinds of cancers may be higher in countries in which cigarette sales also are high. Whether individuals who are buying, and presumably smoking, the cigarettes are the same individuals who develop cancer is unknown from this study design. CROSS-SECTIONAL SURVEYS The goal of the cross-sectional survey study design is usually descriptive, including all individuals, with and without the disease under study, in the population, or a representative sample of them, at one point in time with no follow-up period. Surveys can estimate prevalence of a particular ­ disease in the population and determine need for health services and resource allocation.3 Typically, information about risk factors is obtained simultaneously. Such risk factor data may or may not represent the most relevant time of exposure, and it cannot be determined whether the exposure preceded or resulted from the disease.2 An example of a cross-sectional survey, conducted approximately once per decade in the United States, is the National Health and Nutrition Examination Survey. This survey samples

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Table 28-1  Common Epidemiologic Study Designs and their Strengths and Weaknesses* Study Design

Definition

Ecologic

Aggregate data on exposures   and disease; unit of analysis is a group, not an individual

Cross-sectional   Data on exposures and disease   survey obtained at one time from all individuals in an area (or a sample thereof) with and without disease

Case-control

Study of exposure/disease relationship in cases with a disease and ­controls without the disease, who are selected from source population from which the cases arose

Measure of Effect

Strengths

Weaknesses

Odds ratio

Inexpensive Short duration Hypothesis-generating

Susceptibility to confounding Ecologic fallacy

Prevalence Odds ratio

Can study several   outcomes Short duration Can generate population   ­prevalence estimates of disease and risk factor ­distributions

May not be able to determine ­whether disease preceded ­exposure Potential survivor bias Not practical for rare diseases

Best for studying rare   conditions or conditions   with long latency

Inefficient for rare exposures

Short duration

Potential bias from sampling cases   and controls separately May not be able to determine whether exposure preceded disease Potential recall bias Potential survivor bias

Odds ratio

Small sample* Inexpensive* Odds ratio can   approximate relative risk

Cannot produce incidence or ­relative risk estimates

Cannot produce prevalence or incidence estimates Cohort

Prospective

Individuals without disease are folIncidence lowed over time to determine   which characteristics predict who will get the disease and who will not Relative   risk

Nested   Case-control study within the   case-­control context of a prospective or   retrospective cohort

Incidence

Frequently requires large samples

Less susceptibility to survivor bias   Not feasible for rare outcomes and bias in measuring predictors Can study multiple outcomes More expensive Long duration Can generate population   incidence, relative risk

Study sample selected by   Incidence Investigator control over   investigator and followed forward   selection of participants   in time for development of disease and measures Relative risk

Retrospective Study sample and measurement of ­  exposures and disease over time   have already occurred

Randomized clinical   trial

Can determine   sequence of events

Less expense

Increased expense Long duration Less control over selection of   participants and measures

Relative risk Short duration Incidence

Underlying cohort design

Relative   risk

Relatively inexpensive   compared with   measurement of entire   cohort

Exposure (pharmaceutical, nonphar- Relative   macologic device, educational risk ­intervention) manipulated by   investigator Hazard   ratio

May require bank of samples that can be assayed at a later date until or after outcomes occur

Most closely emulates   an experiment

Costly in time and money

Strongest design to produce   evidence for cause and effect

Some research questions unsuitable because of rare disease or ethical barriers May not be generalizable if highly controlled environment does not reflect “real world” common practice May have narrow scope and study question

Random assignment of intervention minimizes confounding May be faster and cheaper for   some study questions than   observational studies

*Relative to cohort study design. Adapted from Hennekins CH, Buring JE: Epidemiology in Medicine. Boston, Little, Brown, 1987; and Hulley SB, Cummings SR: Designing Clinical Research: An Epidemiologic Approach. Baltimore, Williams & Wilkins, 1988.

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a proportion of the residents in the contiguous 48 states and measures various health outcomes and habits, such as blood pressure, serum lipids, height, weight, smoking, and dietary intake. These surveys have been used in rheumatology to determine prevalence of radiographic knee and hip osteoarthritis in various age, sex, and race/ethnicity subgroups.6 CASE-CONTROL STUDIES Much maligned by the uninitiated because of its susceptibility to bias, the case-control study can be the study design of choice—or sometimes the only appropriate study design—in certain situations, particularly when the disease under study is rare. Usually, a case-control study includes fewer individuals—at much lower cost and higher efficiency—than would be required for a cohort study because it begins with ­individuals who already have the disease in question, rather than waiting for a small proportion of a large cohort to develop the disease over time. Most important in the design of a case-control study are (1) the choice of the control group, which must be comparable to the cases, and (2) recognition of potential biases that may threaten validity. Strictly defined, the case-control study is a study in which subjects with the disease (cases) are compared with a control population without the disease, drawn from the same source population from which the cases arose.1,5 The source population may be the residents of a particular geographic area or a hospital’s referral base. The control group serves as an estimate of the distribution of the exposure in the source population, and consequently, the control group must be sampled independently of exposure status.1,5 If one is interested in examining the possible association between smoking and progressive systemic sclerosis, the controls must be from the same source population that generated the cases, if this can be determined, and must be sampled without regard to their smoking status. Selection of Controls for Case-Control Study If the source of the cases is a well-defined population, the controls can be sampled directly from that population. If the source population is too large to allow a complete ­enumeration, controls may be matched to each case by their residence in the same neighborhood. Random-digit dialing can be used to select controls, but this labor-intensive method omits from selection individuals without telephones and individuals who cannot be reached.1 If the cases are drawn from a particular hospital or clinic, the source population should represent people who would be treated in that hospital or clinic if they developed the disease under study, but frequently, this source population can be difficult to identify and is influenced by referral practices.1 Hospital or clinic controls can be used, but this method can have particular pitfalls because the controls might not be selected independently of the exposure in the source population. In a hospital-based study of smoking in systemic lupus erythematosus, individuals hospitalized for other diseases, such as myocardial infarction or pneumonia, might have exposures different from the source population in general, especially if the exposure, in this case smoking, causes or prevents the “control” disease selected. One way to avoid this is to exclude diseases known to be associated with the exposure under study, but this may create other biases. Another tactic could be to select hospital controls with diseases that

are believed to be unrelated to the disease or exposures under study, such as traumatic leg fractures,1 or to use several control groups selected differently.3 The latter example might sample controls from hospitalized patients with other diseases than the disease under study, nonhospitalized patients in the same medical care system, or nonhospitalized individuals in the general population, comparing each control group separately with the diseased group. Weaknesses of the Case-Control Design It is impossible to derive incidence or prevalence estimates from a case-control study. The greatest threat to validity is the inherent susceptibility to bias that can exist in this study design because the cases and controls are sampled separately, and the assessment of exposure variables is retrospective.3 Matching the cases and controls on factors such as age, sex, or race/ethnicity, can help ensure comparability of cases and controls to a degree. As mentioned previously, more than one control group, selected in different ways, can be used to see if findings are consistent across control groups with different sampling biases. A nested case-control design, in which a case-control study is performed within a larger cohort study, has the advantage of minimizing sampling bias because the cases and the controls would have been sampled previously in identical fashion into the parent cohort study.3 The other chief source of bias in the case-control study is recall bias, which occurs when exposures predating the disease may be differentially reported by the controls and the cases, the latter of whom may have incentive to remember and report exposures. This bias can be partially prevented by using exposure data measured before the disease occurred, if available, and by blinding the observer and the subject to the exposure under investigation, or, if possible, blinding them even to the specific disease under study and to case or control status. In a case-control study examining racial/ethnic variation as the exposure variable of interest in systemic lupus erythematosus, race/ethnicity is immutable and so not subject to recall bias. In contrast, if study participants know or suspect that prior exposure to hair dye, for instance, is the exposure of interest in the same case-control study, participants with disease may be more prone to “remember” their exposure than might participants without disease. Investigators can obtain information about multiple potential exposures or even include several “dummy” exposures to mask the real hypothesis to try to minimize this type of bias.7 COHORT STUDIES Cohort studies follow groups of individuals without the disease in question over time to describe the development or incidence of disease and to compare the incidence of disease among groups with different risk factors or exposures. Cohorts can be prospective or retrospective.1,3 Prospective Cohort Study Prospective cohorts are characterized by the selection of the cohort and measurement of risk factors or exposures before the outcome has occurred, establishing time sequence or temporality, an important factor in determining causality. This is a distinct advantage over the

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case-control study, in which exposure and disease are assessed simultaneously. The primary disadvantage to the prospective cohort study is its expense, in that it requires large numbers of individuals followed for potentially long periods. Biases can creep in, particularly if there is significant loss to follow-up. This study design is highly inefficient and inappropriate to study rare diseases, but its efficiency increases as the frequency of the disease in the population increases.3 A prospective cohort study would be inappropriate to study progressive systemic sclerosis because of its rarity, but excellent to study a common condition such as osteoarthritis.8,9 Retrospective Cohort Study In a retrospective cohort, individuals are followed over time, but the cohort selection and collection of data have already occurred, sometimes for a different purpose than the current disease under study. For example, a cohort of ­individuals with small vessel vasculitis seen at a particular hospital between 1990 and 1992 could be identified, and data abstracted regarding baseline serologies, physical examination findings, and biopsy results when the patients were first evaluated. Then, examination of outcomes such as stroke or development of dialysis-dependent renal disease could be ascertained in 2000, by medical record review or by recontact with the individuals so identified. Because exposure or risk factor assessment precedes assessment of outcome, this study design can establish temporality, as in a prospective cohort, and is less subject to recall bias that can plague case-control studies. By selecting the cases and controls from the same source population, this study design also avoids some of the selection biases of casecontrol studies in which the cases and controls are sampled separately. The retrospective cohort design is cheaper and more efficient than a prospective cohort, but because the data collection has already occurred, inferences from such a study are highly dependent on the quality, completeness, and appropriateness of the original risk factor assessments to study their association with the disease in question.3 Nested Case-Control Studies Nested case-control studies are case-control studies that occur within the context of a prospective or retrospective cohort and are particularly useful in the assessment of risk factor variables that would be too expensive to measure on all members of the cohort.3 In this design, members of a cohort who have developed a particular outcome during the observation period are selected and compared with a sample of individuals within that same cohort who have not developed the outcome. Then, for example, stored biologic specimens from baseline may be assayed for an exposure of interest, such as vitamin D level, and compared between individuals who developed the disease and individuals who did not. CLINICAL TRIALS The study designs described previously in this chapter all were observational designs; there was no experimental manipulation of the exposure or outcome. Experimental study designs or interventions include clinical trials, field

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trials, and community intervention trials.4 Inferences from such trials of treatments assigned randomly to a large enough sample are much less likely to have biases and other threats to validity than are observational designs. Randomization theoretically should eliminate most confounding, although some variation in risk factors among the intervention groups may occur by chance and should always be ascertained and addressed in the analysis if necessary. The validity of conclusions from a clinical trial depends partly on the avoidance of loss to follow-up or participant dropout. Clinical trials can be conducted for pharmacologic or nonpharmacologic interventions, such as dietary, physical activity, assistive devices, or educational interventions. Trials can include single or multiple dosages of the study intervention, placebo controls, active comparator controls in which the intervention of interest is compared with another agent whose efficacy is known, and combinations of interventions. The Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) compared glucosamine hydrochloride alone, chondroitin sulfate alone, and the combination of glucosamine and chondroitin with placebo and with an active comparator, celecoxib, for their effects on symptoms of osteoarthritis of the knee.10 The Arthritis, Diet, and Activity Promotion Trial (ADAPT) was a ­ nonpharmacologic intervention in which diet, exercise, and the combination of diet and exercise were compared with a control group.11 Such nonpharmacologic trials may include an “attention-control,” in which the control group does not get the specific intervention of interest, but does get at least a minimal amount of attention from the investigator because it is known that even minimal contact with the participants in a study can improve outcomes.12 Optimally, to minimize bias, the study should be doubleblind, in which the assignment of treatment is unknown to the participant and to the data collector evaluating the participant’s response. A crossover design is a withinpatient design that allows each participant to be his or her own control and receive the active intervention followed by a “washout” period, in which no active or inactive treatment is given, and then the control treatment, or vice versa. This design has some advantages, particularly in sample size requirements, but can be biased if there is a significant carryover effect of the active treatment into the “control” observation period.4 Response to treatment also may differ depending on whether the active drug is received before or after the placebo or other comparator.13 Other important considerations in clinical trials are the selection and means of assessment of primary and secondary outcomes, which must be prespecified. Outcomes can include measures of disease modification, symptom modification, and frequency of side effects or other poor outcomes. Symptom modification trials are frequently of short duration and less expensive than disease modification trials, which generally are interested in longer term outcomes. In trials of biologics for rheumatoid arthritis, effects on symptoms frequently can be measured in weeks to months, whereas effects on prevention or healing of radiographic erosions may require longer follow-up times.14 Similarly, disease modification trials in osteoarthritis currently require large numbers of individuals followed for at least 2 years, predominantly because the metric of change in minimal joint space on knee radiographs is imprecise and can be fraught

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with measurement error.15 Outcomes based on magnetic resonance imaging, when validated, are expected to be more sensitive, to be less subject to measurement error, and to require smaller sample sizes and shorter observation periods to show an effective response.16 Other trial designs can apply interventions to entire communities or to health care workers with measurement of outcome in their patients. An example of the latter would be an educational intervention designed to increase physician prescription of physical therapy evaluation of all patients with knee or hip complaints. The physicians receive the intervention, but whether the physical therapy is prescribed, and whether it improves patient symptoms, is measured by assessing the patient. Although clinical trials represent the “ultimate” study design closest to a controlled experiment, there are significant potential threats to its validity. One of the most important biases can occur when there is large loss to ­follow-up. To minimize this type of bias, every effort should be made to continue to obtain outcome information on all participants, even those who otherwise discontinue study assignment to therapy. Because all predictors of dropout cannot be known, and because dropouts may differ from individuals who remain in a study in ways that cannot be controlled, statistical analytic methods are used to address this. Data always should be analyzed in an intention-to-treat fashion, in which all randomized participants are analyzed as members of the group to which they were initially randomly assigned, regardless of whether they actually adhered to the group assignment. Completer, or “according to protocol,” analyses also are often performed, in which only participants who adhered to their assigned group treatment are included in the analysis. Prerandomization screening and run-in periods before randomization can help to avoid randomly assigning individuals unlikely to adhere to or complete the protocol, minimizing expense and dilution of effects.17,18 Other issues to consider in the interpretation of results of clinical trials deal with generalizability and the difference between efficacy in a controlled environment and effectiveness in the real world of everyday practice. Postmarketing observations often can reveal side effects or unintended consequences of interventions that may not be apparent within the context of highly regulated trials. More detail regarding design of clinical trials can be found in Chapter 30.

SUMMARY Epidemiologic methods can be used to measure frequency or development of disease and evaluate risk or protective factors in disease occurrence. Choice of study design depends on multiple factors, including the research question, disease under study, availability of appropriate study populations, and resources available. Each study design has its own set of advantages and disadvantages, with the clinical trial considered the most rigorous.

REFERENCES   1. Rothman KJ: Epidemiology: An Introduction. New York, Oxford University Press, 2002.   2. Hennekins CH, Buring JE: Epidemiology in Medicine. Boston, Little, Brown, 1987.   3. Hulley SB, Cummings SR: Designing Clinical Research. Baltimore, Williams & Wilkins, 1988.   4. Rothman KJ, Greenland S: Modern Epidemiology, 2nd ed. Philadelphia, Lippincott Williams & Wilkins, 1998.    5. Rothman KJ: Modern Epidemiology. Boston, Little, Brown, 1986.   6. Dillon CF, Rasch EK, Gu Q, et al: Prevalence of knee osteoarthritis in the United States: Arthritis data from the Third National Health and Nutrition Examination Survey 1991-94. J Rheumatol 33:2271-2279, 2006.   7. Cooper GS, Dooley MA, Treadwell EL, et al: Smoking and use of hair treatments in relation to risk of developing systemic lupus erythematosus. J Rheumatol 28:2653-2656, 2001.   8. Felson DT, Zhang Y, Hannan MT, et al: Risk factors for incident radiographic knee osteoarthritis in the elderly: The Framingham study. Arthritis Rheum 40:728-733, 1997.   9. Jordan JM, Helmick CG, Renner JB, et al: Prevalence of knee symptoms and radiographic and symptomatic knee osteoarthritis in African Americans and Caucasians: The Johnston County Osteoarthritis Project. J Rheumatol 34:172-180, 2007. 10. Clegg DO, Reda DJ, Harris CL, et al: Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 354:795-808, 2006.  11. Messier SP, Loeser RF, Miller GD, et al: Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: The Arthritis, Diet, and Activity Promotion Trial. Arthritis Rheum 50:1501-1510, 2004.  12. Rene J, Weinberger M, Mazzuca SA, et al: Reduction of joint pain in patients with knee osteoarthritis who have received monthly telephone calls from lay personnel and whose medical treatment regimens have remained stable. Arthritis Rheum 35:511-515, 1992.  13. Pincus T, Koch GG, Sokka T, et al: A randomized, double-blind, crossover clinical trial of diclofenac plus misoprostol versus acetaminophen in patients with osteoarthritis of the hip or knee. Arthritis Rheum 44:1587-1598, 2001. 14. van der Heijde D, Klareskog L, Rodriguez-Valderde V, et al: Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: Two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum 54:1063-1074, 2006.  15. Brandt KD, Mazzuca SA, Conrozier T, et al: Which is the best radiographic protocol for a clinical trial of a structure modifying drug in patients with knee osteoarthritis? J Rheumatol 29:1308-1320, 2002.  16. Conaghan PG, Felson D, Gold G, et al: MRI and non-cartilaginous structures in knee osteoarthritis. Osteoarthritis Cartilage 14(Suppl A): A87-A94, 2006.  17. Brandt KD, Mazzuca SA, Katz BP: Effects of doxycycline on progression of osteoarthritis: Results of a randomized, placebo-controlled, double-blind trial. Arthritis Rheum 52:2015-2025, 2005. 18. Brandt KD, Mazzuca SA: Lessons learned from nine clinical trials of disease-modifying osteoarthritis drugs. Arthritis Rheum 52: 3349-3359, 2005.

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Economic Burden of Rheumatic Diseases Anthony D. Woolf

KEY POINTS Health economics provides information on the equity of care and informs the debate on resource allocation to improve health-related quality of life. Economic cost studies also help identify information gaps and research needs. In the Netherlands, several national cost-of-illness studies found that between 5.4% and 12.6% of total health expenditures was attributable to musculoskeletal conditions, ranking second after mental retardation. Musculoskeletal complaints are a major cause of absence from work in developed countries. They are the most common medical cause of long-term absence and are second only to respiratory disorders as a cause of short-term absence (<2 weeks). Musculoskeletal complaints are also a common reason for disability pensions. In people with rheumatoid arthritis, the direct and indirect costs of illness are twice as high compared with controls, but two thirds of that difference is related to comorbidities. The direct costs are initially high and then usually stabilize to a lower level until joint damage progresses and arthroplasty becomes necessary, but this may change with the earlier use of biologics. The direct costs of osteoarthritis depend on which joint is affected, disease severity, comorbidities, and access to arthroplasty. Nonsteroidal anti-inflammatory drug gastropathy has a significant effect on costs. Work loss is not as great as with rheumatoid arthritis because of the age of greatest impact. The indirect costs of ankylosing spondylitis are considerable, owing to the long duration of disease throughout working life and the limitation on activities due to spinal and extraspinal disease. The direct costs depend on access to rehabilitation and hospital care and the recent introduction of biologic therapy. The direct medical expenditures for osteoporosis are related predominantly to hospitalization following low trauma fracture, and the indirect costs are largely related to social care following hip fracture. The total cost of low back pain in Organization for Economic Cooperation and Development countries corresponds to 1% to 2% of the gross national product; about 10% of the costs are direct, and 90% are indirect. Most of the costs are related to work loss. The economic impact is dependent on systems of social support.

Musculoskeletal conditions are common and are characterized by pain and physical disability, along with consequential effects on activities.1 Their prevalence and impact are increasing worldwide with the aging of the population and changes in risk factors, such as physical ina­ctivity and ob­esity. Interventions are available to effectively prevent and control various musculoskeletal conditions.2 H­owever, at present, care is underprovided in most parts of the world, and priorities do not reflect the increasing needs and opportunities.3 The burden of musculoskeletal conditions on the individual is related to disability and loss of quality of life, as well as the economic burden on the affected person and his or her family and caregivers in terms of lost income. In ad­dition, there are the direct costs of health care and social support borne by the individual and by society. There is also a broader cost to society in terms of lost productivity by affected individuals and their caregivers. There needs to be a better understanding of the health, social, and economic burdens of these conditions, as well as the health and economic benefits of prevention and tr­eatment. This chapter focuses on the economic issues.

HEALTH ECONOMICS Health economics is important in a world where there are constraints on the resources available for health care and social support. Economic studies can guide health priorities and decision making about which approach is most beneficial to the greatest number of people. Health economics provides information on the equity of care and informs the debate about whether resources should be directed to health care or other activities that influence health-related quality of life. Economic cost studies also help identify information gaps and research needs. These studies should have a societal perspective—encompassing all costs, no matter who incurs them, and all benefits, regardless of who receives them. Health economics can take a macroeconomic perspective of the effect of illness on national economies, or it can take a microeconomic perspective of the effect on individuals.

ECONOMICS OF ILLNESS The economic impact of any health condition can be c­onsidered in terms of the gross loss to the economy. The cost of illness is the monetary burden on society caused by the morbidity and premature mortality associated with a particular illness.4 It can be measured as the societal cost of pro­viding services related to the delivery of health care and social support. It can also be considered in terms of the personal cost to the patient, family, or immediate community. 439

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These costs can be estimated within the framework of the direct, indirect, or intangible costs associated with the condition. In welfare economics, the total costs are less important than showing how money spent in one area could be b­etter spent elsewhere. Resources are limited, but the potential uses of those resources are unbounded. Health economics is concerned with how to allocate those resources to generate maximal health and social benefits. This notion of cost is based on the value that would be gained from using resources elsewhere and is referred to as opportunity cost. In practice, it is usually assumed that the price paid reflects the opportunity cost; a pragmatic approach is adopted, and ma­rket prices are used when possible. These opportunity costs may be within the health care sector or may be considered more broadly across society as a whole. DIRECT COSTS Direct costs are those health care and social costs directly associated with disease prevention, detection, treatment, and rehabilitation, including care in the community. The value of direct costs represents resources that would have been available for other uses in the health care and social system, as well as by the individual, if the disease had not happened. These costs may be disease specific, a direct result of the condition, or they may be disease associated, a consequence of the primary disease or its treatment. They are influenced by comorbidities, and it may be difficult to a­llocate the costs to a specific diagnosis. Direct costs include the costs of physician visits, diagnostic tests, prescription drugs and over-the-counter medications, hospital stays and procedures, aids and devices, and outpatient procedures. These expenditures may be borne solely or in combination by the patient, the health insurer, an employer, or a local or national governmental agency. Direct costs also include other things generally paid for by the patient, such as transportation to and from the doctor or other health care provider, nonphysician services such as complementary therapy, higher food bills associated with special diets, or expenditures to adapt the home environment to make it more functional. In addition, there are direct costs associated with any change in living status. The direct costs borne by the individual are called out-of-pocket expenditures, and the amount varies, depending on what is covered by the health insurance system. In addition, the costs that are included as direct costs can vary in economic analyses, depending on the perspective of the study—who is paying for care and who is receiving it. For example, in many cases, home care is a direct cost for the patient but an indirect cost for the funder. Many direct costs relate to the utilization of available resources and therefore do not reflect the burden if a need is unmet. Most direct costs are a consequence of treatment, not prevention. Direct costs are relatively easy to measure. They can be estimated by using a “top-down” approach, dividing the total health expenditure among different diseases, or a “bottom-up” approach in which the number of health care services for individuals who fulfill diagnostic criteria are counted and their costs determined. The certainty of case definition is better in the bottom-up approach. The total costs of disease can then be estimated. With comorbidities, it may be di­fficult to determine which costs to allocate to which condition, especially those costs related to rehabilitation and

changes in living status. However, it is important to avoid double-counting costs for several conditions. The attributable costs provide the clearest estimate of the potential savings, which can be identified by looking for the incremental costs after the onset of disease or an event such as a fracture. Alternatively, a case-control study can compare the total health care costs of individuals with the disease compared with healthy, matched controls. The c­a­se-control method has the advantage of allowing for comorbidities and associated events. INDIRECT COSTS Indirect costs result from the consequences of a condition, such as the limitation of usual activities. The human capital approach counts these costs as the value of lost production to society; these costs are less than the assumed loss of gross earnings, because not all healthy people are economically active. An alternative approach is to look at indirect costs as a consequence for individuals, their families, and their caregivers. These costs include work loss due to treatment, sick leave, reduced work productivity, early retirement, and death. Other losses attributable to the condition also constitute indirect costs; for example, the person may be prevented from getting a better-paying jobs or suffer from reduced employment opportunities. The additional costs related to self-care, maintenance of a home, schooling, or parenting are also included. Both patients and their caregivers may incur indirect costs. Chronic physical disability has a major impact on indirect costs. These costs are difficult to measure. Some can be given a monetary value, although this depends on local systems of social support, sickness benefits, and pensions. Lost work productivity is important in chronic musculoskeletal conditions but is not often included in economic evaluations.5 It can be estimated in different ways. With the human capital approach, the full replacement costs are used, irrespective of whether the worker is replaced. With the friction cost approach, only the productivity costs during the period required to restore the initial production level are considered, with a replacement worker obtained from the labor market. This results in lower estimates of lost productivity costs but is probably more realistic. Other indirect costs c­annot be given a specific value because reduced productivity or lost hours at school or household work are difficult to assign a monetary cost. Indirect costs are strongly influenced by people who are working, because employment-related costs are easier to quantify. The economic impact on children, women, the elderly, and the unemployed is not adequately captured. In the case of comorbidities, it can also be difficult to know which condition to attribute these costs to. INTANGIBLE COSTS Intangible costs are those associated with loss of function, increased pain, and reduced quality of life of patients, families, and caregivers. They also include the costs of lost opportunities. Intangible costs represent a negative benefit in terms of health economics and are generally not included in cost-of-illness studies. However, they are very important for musculoskeletal conditions, because disability is a significant

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Table 29-1  Health Cost Domains Relevant to Musculoskeletal Conditions Category

Domains

How to Identify Costs

Direct Costs Outpatient costs

Inpatient costs Personal costs Other disease-related costs

Change of living status

Visits to physicians (primary care and specialist) Outpatient surgery Emergency room Rehabilitation services (e.g., physiotherapist,   occupational therapist, social worker) Medication (prescription and nonprescription) Diagnostic or therapeutic procedures and tests Devices and aids Acute hospital facilities (without surgery) Acute hospital facilities (with surgery) Nonacute hospital facilities Transportation Patient time Caregiver time Home health care services Environmental adaptations Medical equipment (nonprescription) Nonmedical practitioner, alternative therapy Nursing home or residential home Home care services

Pharmacy records Radiology activity; laboratory tests Provision of equipment Hospital or insurer activity data on admissions, length of stay, procedures Rehabilitation activity; nursing home activity Transportation distance, frequency, methods Time spent on health care Time spent giving care Home health care activity Home, work, and transportation adaptations Equipment provision Therapist activity Nursing and residential home activity Formal and informal home care activity

Loss of productivity in employed patients   or their caregivers Opportunity costs—reduced employability at   present or higher level Out-of-pocket expenses

Sick leave, lost wages, work disability benefits, no longer working; disabilities leading to impaired housekeeping or activities of daily living; loss of productivity Survey

Deterioration in quality of life of patient, family,   caregivers, friends

Difficult to quantify

Hospital or insurer activity data

Indirect Costs Productivity costs

Out of pocket Intangible Costs

Modified from Merkesdal S, Ruof J, Huelsemann JL, et al: Development of a matrix of cost domains in economic evaluation of rheumatoid arthritis. J Rheumatol 28:657-661, 2001.

outcome, including limitations in activities of daily living, reduction in leisure and community activities, chronic pain, psychological problems such as depression and an­xiety, and reduced general health. The inverse of the intangible costs of arthritis is the benefit a patient receives from effective treatment. If measuring the costs of care is to have relevance for clinical decision making, it must also consider the effects of disease and therapy on the patient’s health and wellbeing. Intangible costs are, however, difficult to quantify and extremely difficult to give a monetary value. COST ITEMS AND ESTIMATES Many cost items can be used in the estimation of the cost of illness. They fall under the categories of direct, ­indirect, and intangible costs (Table 29-1). Not all items are considered in every health economic evaluation, and these omissions need to be recognized. The value of any evaluation is based on its consideration of all those cost items that might be influenced by the condition or its treatment. Omissions or different definitions can affect the interpretation and comparability of data. Attempts are being made to standardize the cost domains for musculoskeletal conditions.6 There also needs to be some standardization in the way these items are costed if there is to be any comparability among economic evaluations. Unfortunately, data collection can be very difficult, so various assumptions are often made, and modeling is used.

COST-OF-ILLNESS STUDIES The economics of health can be looked at in different ways, depending on the purpose. Cost-of-illness studies and cost analyses examine the resources used in the provision of health care related to a certain condition; they do not relate the costs to the benefits or outcomes of health care.7 These costs must be related to the effect of the condition and to its management, including any complications or side effects. Cost-of-illness studies sometimes include the effect on the individual’s ability to perform paid or unpaid work and the costs of social support. It is therefore important to examine what cost domains are included when examining any cost-of-illness study. For musculoskeletal diseases, which have different impacts on individuals during the disease course, information is also required about the different health states associated with the particular disease and the numbers of patients in those states. Cost-of-illness studies can be performed by a prevalencebased, top-down approach—looking at the total costs of di­sease in a population and assigning costs to specific diagnoses, which enables a comparison between diseases. An alternative is a bottom-up, prevalence approach using patient-derived data from a cross section of the patient ­population, which allows patient and disease characteristics to be related to resource use and costs. An incident approach considers the cost of the illness from its onset throughout its course, but this is challenging to do because of the amount of long-term data required.

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One weakness of cost-of-illness studies is that they look only at the supply side and quantify expenditures; there is no guarantee that the money has been well spent. High costs may reflect inefficient use of resources, and low costs may reflect limited availability of health care. Nor do these studies provide information on the costs of prevention. Low costs do not mean that a disease should be given low pr­iority, because it still may be amenable to a very cost-eff­ective intervention. In addition, increasing expenditures does not necessarily mean that better outcomes will be achieved, unless the money is spent efficiently. Cost analysis is not an economic evaluation because it does not measure benefits gained by resources consumed; rather, it provides an evidence base for such analysis. Its value is in measuring the economic burden and identifying how it is distributed among the health care system and other parts of the public sector, the patient, the family, and so­ciety as a whole. It can facilitate the identification of potential improvements in the provision of care, showing where change is likely to have the greatest effect. It can be used to aid policy-making decisions.8 The value to policy makers in choosing between alternatives is limited, however, because this requires a comparison, and the value of burden-of-di­sease and cost-of-illness studies in guiding policy has been criticized.9,10 Measures of indirect costs are difficult, because different studies include different cost domains, and various methods of ascribing cost can be used, which limits comparability between studies.

HEALTH ECONOMIC EVALUATIONS Health economic evaluations require methods that enable costs to be measured against health gains achieved by an intervention. The concept of cost-effectiveness involves the achievement of a predetermined goal or the ability to maximize the benefit from a limited resource. The m­ethods of health economic evaluation aim to show how well resources are used to achieve a desired outcome and enable the s­election of the most cost-effective option from a range of alternative interventions. Policy makers allocate resources on the basis of economic efficiency. Several concepts need to be considered. Efficiency describes how well resources are used to achieve a desired outcome. The allocative efficiency measures how resources can best be allocated to achieve a given outcome. Technical efficiency measures the extent to which the smallest amount of resources can be applied to achieve the greatest outcome. The benefit is measured as a health outcome, the definition and measurement of which are central to health economic evaluations. A range of outcomes is used relating to survival and quality of life. They are valued by individuals expressing their preference for specific outcomes or states of health—termed a utility value. There are many methods for placing values on these different states of health. A single combined measure can be used that considers both quality and quantity of life—quality-adjusted life-years (QALYs)— and enables the quality of life experienced by a patient to be scored: perfect health is equivalent to 1, death is equivalent to 0, and health states worse than death have negative values. QALYs therefore provide a common currency that enables the assessment of benefits gained from a variety of

interventions for a variety of conditions in terms of quality and quantity of life. Economic costs relate to the consumption of resources and to the fact that if resources are used in one way, they are not available to be used in another way, resulting in a loss of potential benefits. There may not be an actual financial payment. This loss of potential benefit from an alternative use of the resources is referred to as the opportunity cost. Health economics uses this concept of trade-offs. Economic evaluations provide a systematic and obj­ective framework for considering costs and benefits. They predominantly use randomized, controlled trials for evidence of the effects of any intervention, but what happens in real life is often different, because many people who have been treated with an intervention are not eligible to participate in clinical trials, and other factors such as self-efficacy can play a role. Because policy decisions are about real people, some argue that naturalistic studies should be used.11 There are four main methods of economic evaluation, all of which measure resources expended in monetary terms. The latter three differ in how the health outcome is measured. Cost minimization studies are used to compare alternative treatments for the same condition, and it is assumed that the outcomes from the different treatments are the same. Only the costs of interventions being evaluated are measured. The most effective treatment is the least costly. The value of such studies is limited because they do not consider secondary end points such as side effects. This method is seldom used today. Cost-effectiveness analysis is also used to compare treatments for the same condition, but it measures both the health effects of treatment and the costs. The outcomes measured are usually clinically relevant and directly quantifiable, such as life-years gained or morbid events averted. The most efficient therapy is that which has the lowest cost per unit of effect. These analyses are often used to evaluate pharmacotherapies that have single therapeutic goals. They cannot be used to compare interventions that may have different effects because they do not consider all the outcomes. Cost utility analysis uses a measure of outcome that can be applied to all health care interventions for different conditions, such as QALYs. This measurement should capture all health effects. It allows a comparison between health care technologies for different conditions and gives decision makers information to help them allocate limited resources. Other methods of measuring utility include time trade-off and standard gamble. Cost-benefit analysis brings in the public’s and the patient’s perspective when using economic information to set priorities and make choices between treatments for different conditions. Both costs and benefits are expressed in monetary terms. There are different ways of measuring the public or patient value of a treatment or condition, such as willingness to pay. The willingness-to-pay approach values what individuals are willing to pay (in monetary terms) for a change that results in improved health, such as a reduced probability of morbidity. This method allows individuals to indicate how they value health and death, and calculations can be made from a societal perspective. A wide variation in measures of clinical efficacy and whether and how costs of adverse events are incorporated have been found in health economic analyses by the OMERACT Health

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Table 29-2  Methodologic Issues for Economic Evaluation in Rheumatology Issue

Question to Ask

Model horizon

How long should costs and benefits be forecast?

Duration of treatment

What duration of treatment should be included in economic evaluations?

Extrapolation beyond trial duration

Can extrapolation beyond the duration of clinical trials be performed in a valid and reliable manner?

Modeling beyond trial duration

Can extrapolation beyond treatment duration be performed in a valid and reliable manner?

Synthesis of comparisons when clinical trials do not exist

Can comparisons be synthesized in a valid manner when experimental data are not available?

Outcome measures

What are the most meaningful clinical outcomes for economic evaluation?

Mortality

How should mortality be considered in economic analysis?

Valuation of health (e.g., QALYs)

What are the optimal sources of health state values?

Resource use

What are the optimal approaches to estimating resource use?

Classification and reporting of adverse events

What are the optimal approaches to measuring, classifying, and reporting toxicity?

Discontinuation of treatment

What are the optimal approaches to determining drug discontinuation and adherence rates?

Therapeutic strategies

Should data on therapeutic strategies (as opposed to individual treatments) be incorporated into economic evaluations?

Population risk stratification

What are the optimal approaches to incorporating data on the risk status of the population under study in economic evaluations?

QALY, quality-adjusted life-year. From Gabriel SE, Tugwell P, Drummond M: Progress towards an OMERACT-ILAR guideline for economic evaluations in rheumatology. Ann Rheum Dis 61:370-373, 2002.

Economics Working Group. As a consequence, several issues have been identified (Table 29-2), and a methodology with a standardized set of minimum criteria for economic evaluation in rheumatology has been proposed12; specific recommendations have been made for rheumatoid arthritis (RA).12 Cost-effectiveness studies, to be valid and meaningful, must rely on a fair, balanced, and explicit representation of the disease in a simulation model that includes all relevant outcomes and treatment consequences.13 One problem is that effectiveness estimates are usually derived from clinical trials, particularly for new treatments, but later ob­servational studies may not demonstrate the same outcomes. This results in different cost-effectiveness ratios, depending on the stu­dies considered, and it may affect access to treatment. These issues have been highlighted by studies of anti–tumor necrosis factor (TNF) therapy.11 Health economic evaluations for specific interventions are not discussed in detail in this chapter, because they must be considered in the context of the condition’s management. A central issue is the need to extend information beyond that which is available from clinical trials, such as the costs and health effects that occur after the clinical trial, particularly when considering long-term conditions. M­arkov modeling is frequently used. This chapter principally considers cost of illness and cost analysis data.

COST OF MUSCULOSKELETAL CONDITIONS Musculoskeletal problems are very common, affecting up to 20% of adults.1,14 Their overall economic impact can be measured by the use of health care and social care resources,

as well as by work disability. There have been several national cost-of-illness studies in developed countries in which the costs related to musculoskeletal conditions can be identified. These reflect the health care expenditures for the management of these conditions as well as their societal costs; they measure not only the impact of these diseases but also the current provision of health and social care for people with these conditions. They do not measure the costs of unmet needs due to a lack of adequate services, such as joint ­arthroplasty in many countries, or due to patients’ unwillingness to seek medical care because of the negative perception of what can be achieved.15,16 How an individual with a musculoskeletal condition in a certain country interacts with the health and social care systems, the normal patterns of care, and local support systems, such as home care and pensions, are all important factors, because these confounders can influence costs. Expenditures are influenced by the rules of reimbursement and other factors that influence the management approach to similar conditions in different countries. For example, inpatient care is available only for complicated RA in some countries, whereas in other countries, people commonly receive inpatient rehabilitation. In addition, the systems of care are changing in many countries; the trend is away from inpatient management, which is related to changes in therapeutic options, better outcomes, and the desire to reduce health care costs. Social care can be provided in different ways, from the extended family and caregivers to agencies prov­iding home care, each with a different cost— direct, indirect, and intangible. These factors, along with different methods of costing, make it difficult to compare findings in different countries or studies done at different times.

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There have been several national cost-of-illness studies looking at total health expenditures. An examination of comparable studies shows that between 5.4% and 12.6% of expenditures are attributable to musculoskeletal conditions.17 These differences can be caused by a range of methodologic issues that makes comparison difficult, and interpretation should be based on a set of key questions (Table 29-3). In Sweden, musculoskeletal conditions cost SKr 52.7 billion (US$5.3 billion) in 1994.18 The total costs were attributable to back pain (47%), osteoarthritis (14%), and RA (5.5%). Most of the costs were indirect and related to sick leave (31.5%) and early retirement (59%). Table 29-3  Checklist for the Interpretation   and Comparison of Cost-of-Illness Data Which types of costs are included? Only health care costs, or also other costs such as productivity losses and absence from work? Are all sectors of the health care system included, or are some left out? What is the definition of the disease, and how is it classified? Are the costs calculated bottom up or top down? Are productivity losses based on the human capital or the friction costs methodology? What is the year for which data were collected? Have foreign data been used, and if so, how? Is the study population representative of the national population, and is the treatment practice representative of the generally acknowledged method of treatment? Are the diagnoses well reported? How has comorbidity been dealt with? From Slobbe LCJ, Kommer GJ, Smit JM, et al: Cost of Illness in the Netherlands 2003. http://www.rivm.nl/bibliotheek/rapporten/270751010.pdf.

In the Netherlands, musculoskeletal conditions19 accoun­ ted for 6% of total health care costs in 1994,20 ranking second behind mental retardation (8.1%). Coronary heart diseases and other circulatory diseases accounted for 4.8%. This study considered only medical costs; if the costs of informal care had been included, this would have greatly increased the costs related to chronic disabling conditions such as musculoskeletal diseases. Costs were considerable at all ages, ranking fifth among those 15 to 44 years old, second among those 45 to 64 years, and third among those 65 to 84 years (after dementia and stroke). In Canada in 1998, musculoskeletal diseases ranked second and accounted for $16.4 billion of the total costs of illness (Fig. 29-1).21 Direct costs ($2.6 billion) were less than indirect costs ($13.7 billion). Musculoskeletal diseases were the leading cause of disability, accounting for about 39% of long-term disability costs ($12.6 billion), followed by diseases of the nervous system (12.9%; $4.2 billion), cardiovascular diseases (9.8%; $3.2 billion), and mental disorders (7.0%; $2.2 billion). Musculoskeletal diseases accounted for 10.3% ($1.0 billion) of total short-term disability costs in 1998. In contrast, the expenditure for research on musculoskeletal diseases was only 1.3% of the total. In the United States, the total cost of musculoskeletal conditions was estimated in 1995 at almost 3% of gross domestic product,7 compared with estimates of about 0.5% in 1963 and 1972. This included the spectrum of musculoskeletal diseases and connective tissue disorders, injuries, neoplasia, and deformities and anomalies. The direct cost amounted to $88.7 billion, of which 38% ($33.7 billion) was attributable to hospital admissions, 21% to nursing home admissions, and 17% to physicians’ visits. Similar to other established economies, indirect costs were far greater, amounting to 58% of the total ($126.2 billion). Because

Direct and indirect costs by diagnostic category in Canada*, 1998 Cardiovascular Musculoskeletal Cancer Injuries Respiratory Nerv. sys. / Sense org. Mental disorders Digestive Well-patient Ill-defined Endocrine and related Genitourinary Infectious Pregnancy Skin and related Birth defects Perinatal Blood Others (1) Unattributable (2)

Direct costs Indirect costs

0 Figure 29-1  Direct and indirect costs of illness in Canada (1998) by diagnostic category. (From Health Canada: The Economic Burden of Illness in Canada 1998. http://www. hc-sc.gc.ca.)

10

20

30

40

Cost (Canadian $ billion) * Based on total cost of illness of $159.4 billion (1) Refers to data for which coding is not provided (for diagnostic categories), or data that are grouped because of small counts. (2) Refers to data that could not be coded by ICD-9 code.

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musculoskeletal conditions are rarely fatal, 51% of the cost attributable to lost wages arose from morbidity. The costs were greatest in those aged 18 to 44 years and 45 to 64 years; in these groups, indirect costs were greatest due to work loss. In contrast, in those younger than 18 years and older than 65 years, most costs were related to medical care expenditures. Indirect costs relate not only to work loss but also to lost productivity. More than 7% of almost 30,000 working adults in the United States lost productive time because of back pain (3.3 hr/wk), arthritis (2.03 hr/wk), or other musculoskeletal pain (2.02 hr/wk), although absence was uncommon.22 The total cost of this lost productivity was estimated at $41.7 billion per year, of which about $31.5 billion occurs while employees are at work but performing suboptimally. If the costs of arthritis and other rheumatic conditions alone are considered, the total costs in 1997 were estimated from the 1997 Medical Expenditure Panel Survey and the 2002 Behavioral Risk Factor Surveillance System to be $86.2 billion, including $51.1 billion in incremental direct costs and $35.1 billion in indirect costs.23,24 This was approximately 1% of the U.S. gross domestic product, but the total expenditures for all medical care for any reason among people with arthritis was estimated in 1996 at $140 billion (in 2000 dollars), representing almost 2.8% of the gross national product.25 Most recently, based on data from the Medical Expenditure Panel Study,26 the mean expenditure among persons with arthritis and other rheumatic conditions (excluding injuries, neoplasia, deformities, and most back pain) was estimated at $6978 in 2003, a 10% increase over 1997 estimates.27 The proportion of outpatient costs increased from 29% to 32%, and prescription medication costs increased from $899 to $1635 in absolute terms and from 14% to 23% in relative terms from 1997 to 2003. This reflects changes in clinical practice. The total medical care expenditures in 2003 incurred by the estimated 46.114 million adult Americans with arthritis or other rheumatic conditions (excluding injuries, neoplasia, deformities, and most back pain) were estimated at $321.8 billion, or approximately 3% of gross domestic product.26 The direct costs of musculoskeletal conditions reflect the fact that such complaints are the second most common r­eason for consulting a doctor and constitute, in most cou­ntries, up to 10% to 20% of the primary care practice.28 There were 43.9 million ambulatory physician visits in the United States in 1997 for a primary diagnosis of arthritis or other rheumatic conditions.29 Of these, 36.5 million were arthritis vi­sits unrelated to injury; this constituted the largest di­agnostic category among chronic conditions. Most were visits to physicians’ offices; only 11% were visits to hospital outpatient facilities or emergency rooms. More than half the visits were to primary care physicians, 19% to orthopedic surgeons, and 16.5% to rheumatologists. Most visits involved people older than 45 years, and women had almost twice the rate of arthritis visits compared with men. Annually, a person with arthritis reported an average of eight physician visits for all conditions.25 In Europe, 20.4% were undergoing long-term treatment for arthritis and rheumatism in the ­Eurobarometer Survey.14 Five percent of drug expenditures in Canada was related to musculoskeletal ­conditions in 1998.30 In the United Kingdom, £363 million was spent on prescription drugs for musculoskeletal conditions in 2003.31

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The indirect costs reflect the fact that these conditions are the most common cause of long-term physical disab­ility. Musculoskeletal complaints are a major cause of absence due to sickness in developed countries.32,33 They are second only to respiratory disorders as a cause of short-term absence (<2 weeks).34 Musculoskeletal complaints are the most common medical cause of long-term absence, accounting for more than half of all illness-related absences longer than 2 weeks in Norway.35 They are also common reasons for disability pensions, as are mental disorders and cardiovascular disorders. In Sweden, up to 60% of persons taking early retirement or long-term sick leave claim musculoskeletal problems as the reason.36 In the United States in 2003, employment rates were 10.8% lower among those with arthritis or other rheumatic conditions (excluding injuries, neoplasia, deformities, and most of back pain); however, after controlling for comorbidities and demographic factors, the employment gap was 2.3%. In this study, the earnings losses were related mainly to lost work, but U.S. surveys of working adults have shown that a larger cost is related to lost productivity while at work if the full spectrum of musculoskeletal conditions is considered.22 Many U.S. studies do not include injuries and back pain, and these are major causes of work loss. Musculoskeletal disorders are the most common occupational reason for work loss. RHEUMATOID ARTHRITIS RA can be a devastating condition with a major impact on the individual and his or her family and friends, although modern treatment has significantly improved the ­prognosis. Knowledge of the natural history of the disease and the typical health interventions and their outcomes enables an understanding of the associated costs. The direct costs involve hospital and primary care medical consultations to assess disease activity and to monitor treatment safety and efficacy, drug costs, rehabilitation, and provision of equipment. Arthroplasty may be required. Indirect costs relate to loss of employment by the patient and often by the caregiver. Importantly, many people with RA or their caregivers do not have the employment opportunities, leading to a loss of productivity and income. The intangible costs of RA are great but difficult to quantify. Various studies have looked at the considerable health and social costs, but differences are difficult to interpret and are largely related to differences in disease severity and disability, different health and social systems that influence access, and variations in data sources and types of costs described. As a consequence, it is impossible to give an average cost. The direct and indirect costs of illness are twice as high in people with RA compared with controls,37 but two thirds of these are related to comorbidities; in part, this could reflect reimbursement rules for the care of people with RA. In a systematic review of 15 cost-of-illness studies done predominantly in the United States,38 it was found that the average direct annual costs were $5720 per person with RA. The costs are initially high and then usually stabilize to a lower level until joint damage progresses and arthroplasty becomes ­ necessary. A small proportion of patients is responsible for the majority of direct costs,38 which were highest for a younger population with a short duration of disease and greatest disease severity. Inpatient care strongly

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influences these costs, and admission rates varied between 12% and 26%. In the United States, the annual number of physician visits averages 11 to 12 per patient.25,39,40 In France, RA patients use health resources more fr­equently, more intensively, and in a more diverse manner than do nonarthritic subjects, and 5.1% of all patients had RArelated surgery in the previous year.41 In a 10-year follow-up of patients with early RA, 17% had undergone large joint replacements in Sweden.41a In Germany, the costs of RA were calculated for 2002 from the German Collaborative Arthritis Centres database,42 and the median and mean total direct costs were €2256 and €4727, respectively, attributable mainly to drug costs and inpatient treatments. Out-ofpocket expenses averaged €559 per year. Major cost drivers were function, positive rheumatoid factor, and disease activity. The costs of medication were less than 20% of direct costs in earlier studies,43 but this was before the widespread use of anti-TNF. Patients’ time spent on their health care is a direct cost that is often ignored, but it can be considerable in RA. Out-of-pocket expenses vary among countries, depending on what is covered by health insurance and on the use of alternative and complementary therapies, which can be a major contributor.44 Direct costs are high during the first 2 years, largely related to consultations; they then fall and gradually increase over subsequent years owing to the costs of devices and adaptations, which account for 40% of total costs after 10 years.45 Changes in clinical practice, such as shared management with primary care physicians and patients taking greater responsibility, reduce direct costs. Greater self-efficacy is associated with lower medical expenditures in Australia.46 The indirect costs are typically between 50% and 75% of the total in developed countries. They are strongly influenced by loss of work, either short or long term. Days lost from work vary in studies from 2.7 to 30 days per year.38 Employment is 20% lower in men with arthritis and 25% lower in women with arthritis compared with those without.47 Work capacity is restricted in one third of RA patients within 1 year48; within 3 years, about 40% will be considered disabled.49 In the United States, patients with RA lost their jobs, were unable to get jobs, or retired early due to their illness.50 Those who do work must often adjust their work schedules or activities, meaning a loss of potential income, and work-related disability is greatest among those doing manual jobs. Loss of activity is substantial, with people reporting 2 to 3 days of restricted activity within the previous 2 weeks.25 A systematic review found that work disability rates were similar in the United States and Europe.51 Age and Health Assessment Questionnaire (HAQ) disability index are predictors of high indirect costs, acute and nonacute institutional care,52 and work disability.53 Disease activity is also associated with higher costs. The mean indirect costs were $5822 per person in a syst­ematic review of 15 studies.38 In the recent German Collaborative Arthritis Centres study,42 the mean indirect costs due to sick leave and permanent work disability in 2002 were €10,901, applying the human capital approach; this was reduced to a mean of €3162 by applying the friction cost approach, which takes into account the fact that no economy achieves full employment. Costs increased with disease duration, mainly attributable to costs of permanent work disability. Sick leave is the predominant cost

in the initial phase, but as disability increases with disease duration, long-term disability benefits become an increasing cost. Help in the household is often needed, but in the United Kingdom, this was provided by family and friends and was seldom paid for directly.54 This loss of household productivity, if valued at the market equivalent, is considerable and has been estimated to be seven times higher than the costs from loss of paid productivity estimated by the friction costs method.45 RA also has a considerable impact on all aspects of qu­ality of life. Almost two thirds of patients in a cohort study were restricted in activities of daily living and required help from family or friends, which in many cases had an adverse effect on family relations.55 The costs of side effects related to treatment must be considered, such as fractures subsequent to steroid-induced osteoporosis or hospitalizations and deaths from nonsteroidal anti-inflammatory drug (NSAID)–related gastropathy.56 OSTEOARTHRITIS Osteoarthritis is the most common cause of joint pain, and many cases of self-reported arthritis are related to osteoarthritis. It can affect any joint but occurs most frequently in the hip, knee, and hands. The impact of osteoarthritis is related to which joints are affected as well as the presence and severity of comorbidities that may magnify the disability. The socioeconomic impact of osteoarthritis has not been studied extensively. The top-down approach to identifying costs is difficult because definitive diagnosis requires a radiograph; joint pain alone is often used, but this results in the inclusion of other causes, including some cases of inflammatory arthritis. It is also difficult to estimate the costs attributable to osteoarthritis because of the presence of comorbidities.57 National studies have largely identified the costs of arthritis as a whole. However, in Sweden, osteoarthritis was estimated to incur costs of SKr 7.4 billion (US$749.4 million) in 1994, of which SKr 739 million (US$75 million) was for inpatient care and SKr 6.4 billion for productivity losses.18 Based on national data from France, the costs of osteoarthritis were estimated at 0.1% of 1991 gross national product,58 which was equivalent to US$51.4 billion (in 2000 dollars). Almost two thirds of the total was attributable to direct costs of medical care. The total medical costs for those with osteoarthritis younger than 65 years are double compared with the similar individuals without osteoarthritis; they are 50% higher in those older than 65 years.59 In a case-control study of a large national managed care organization in the United States, of those with an International Classification of Diseases (ICD) diagnosis of osteoarthritis (ICDD-9), the attributable costs were $2827 per patient year in those younger than 65 years and $1963 per patient year in those 65 years and older (in 1993 dollars). Two thirds of these costs were related to health care facilities; attributable drug costs were 7% ($199) in those younger than 65 years but only 2% ($30) in those 65 years and older. In the United States, annual physician visits average 9 per person, and noninstitutionalized people with osteoarthritis have an average of 0.3 hospitalization lasting 8 to 9 days.25 Health resource utilization also relates to the complications of treatment, most commonly NSAID gastropathy,

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which results in increased outpatient care, hospitalization, and the prescribing of drugs to prevent gastropathy. It is estimated that the United Kingdom’s National Health Service spends an average of £251 million per year (range, £166 million to £367 million) on NSAID-induced gastric side effects.60 Complementary therapy is often used by those with osteoarthritis. One study found that nearly half the patients used at least one type of alternative therapy during a 20week period. The cost was estimated at $1127 per year on alternative care providers, compared with $1148 on ambulatory medical care services.61 End-stage osteoarthritis is the major indication for hip and knee replacement surgery, which is responsible for significant health care resource utilization. These costs reflect supply, not need, and there is a gap between these two factors in all countries. The estimated prevalence of primary total knee replacement was 8.4 joints per 1000 people aged 35 years and older in England; in contrast, the estimated requirement was 27.4 joints per 1000 people aged 35 years and older, based on the severity of knee disease.62 In Sweden, the rate of total knee replacement is less. The arthroplasty rate more closely meets needs in the United States.62a Total hip replacement rates in Organization for Economic Cooperation and Development (OECD) countries vary between 50 and 140 procedures per 100,000.63 The primary reason for such surgery is osteoarthritis, except in the very elderly, when it is more often done after hip fracture.64 The number of hip replacements performed depends on the resources available and on clinical criteria used to determine when total hip replacement is appropriate; there is no consensus on such criteria among physicians and ­orthopedic surgeons.65 In the United Kingdom, 47,932 total hip replacements were performed in 2000, 20% of which were revisions; this number is predicted to increase, particularly revisions.66 Forty-nine percent of primary hip replacements were done in patients aged 60 to 74 years; 33% were in those older than 75 years. This more closely meets the predicted requirement.66a The estimated cost was £4076 at 2000 National Health Service prices, compared with £641. 53 annual cost per patient for watchful waiting.67 Those with knee disease were more likely than those with hip disease to seek treatment from their primary care physicians but less likely to be referred to specialists or to be awaiting arthroplasty.62 Patient preferences influence resource utilization, and 30% to 55% of those with severe large joint osteoarthritis are unwilling to undergo arthroplasty.15,62 Indirect costs are difficult to estimate for previously stated reasons. National surveys in the United States estimated that between 0.1 and 0.3 day was lost from employment in the previous 2 weeks by those with osteoarthritis,39,40 More than half of those with symptomatic osteoarthritis reported work disability.68 Those with osteoarthritis are more likely to report a reduction in working hours or an inability to get a job due to their illness.50 However, work loss is not as great as with RA, because many patients are no longer of working age. In Australia, out-of-pocket expenses by those with osteoarthritis for medications, special equipment, and assistance from family and friends increased, despite a governmentfunded health care system.69 Loss of mobility is common in those with arthritis, especially those with osteoarthritis; 18% report a significant loss.

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Limitation of activities, defined as the inability to perform one’s major activity, was reported by 25% of people with osteoarthritis.39 These limitations increase with age. ANKYLOSING SPONDYLITIS Ankylosing spondylitis commonly starts in early adulthood and has a chronic, progressive course leading to increased disability, which results in considerable costs related to both health care and inability to perform paid work. Only recently have studies been performed to measure this cost of illness, stimulated by the introduction of effective but expensive therapies and the need to justify their use and cost-effectiveness. There is a long delay in the diagnosis and specialist management of ankylosing spondylitis, with a mean disease duration of 5.9 years before the first visit to a rheumatologist in the German Collaborative Arthritis Centres study.70 Following diagnosis, management varies by country; for example, there are differences in the frequency of routine clinical review, the use of physiotherapy and hydrotherapy, and inpatient care. The greatest differences are between Europe and the United States.71 In a study of patients in France, Belgium, and the Netherlands with ankylosing spondylitis of around 10 years’ duration, the average annual direct costs were €2640 (median, €1242) per patient.72 Direct health care costs accounted for 82% of this total; the rest was attributable to direct non–health care costs, such as exercise classes, household help, or transportation. The greatest direct costs were related to inpatient care (27%), combined formal and informal care (22%), physiotherapy (13%), and drugs (13%). Cost ­differences between ­countries were related to clinical practice and availability of or access to resources. In Germany, where costs were analyzed only among those of working age, the annual direct costs were €3676 (median, €1705); these costs were more similar to those in other European countries when all ages were considered.42 The difference in health care utilization is greater between Europe and the United States, where, for example, physiotherapy is not covered by health insurance and inpatient care is uncommon. As a consequence of this fact and the differences in clinical practice, the distribution of costs is considerably different.71,73 The direct health costs were only 26% of the total annual costs in the United States, with average direct costs of $1775. Of these direct costs, 42% were related to drugs, 16% to inpatient care, and 16% to ambulatory care; however, the majority of ambulatory care was related to medical visits, not physiotherapy.73 Higher costs are related to lower educational levels, higher depression scores, more pain and stiffness, longer disease duration, higher disease activity, and greater functional disability.71,73 The indirect costs of ankylosing spondylitis are considerable owing to the long duration of disease (throughout most of working life) and the limitation of activities due to spinal and extraspinal disease. In the German Collaborative Arthritis Centres study, indirect costs for those of working age due to sick leave, early retirement, and lost productivity were estimated as a mean of €7204 by the frictional costs method and €13,513 by the human capital approach,42 accounting for 49% or 72.8%, respectively, of the total cost of illness. Workforce participation was 11% lower, and ankylosing spondylitis–related work disability was 15% higher, than in

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the general Dutch population.74 In a 2-year follow-up study in three European countries among people of working age, lower employment was found only in the Netherlands, but there was increased work disability in all three countries, with an adjusted work disability rate of 41% in the Netherlands, 23% in France, and 9% in Belgium.75 It is clear that factors other than ankylosing spondylitis play a role in determining work status and productivity costs, and these factors, such as patient characteristics and differences in employment and social security systems, must be considered when interpreting data and making comparisons between populations.71 Patient costs and intangible costs can be substantial, but the data are limited. Out-of-pocket expenses can include a wide spectrum of additional costs, such as transportation, paid help in the home, home modifications, heating, and private physiotherapy. Such out-of-pocket expenses were a mean of €517 in the German study.42 It is more difficult to determine the impact on quality of life, the influence on career choices by the patient or caregiver, and many other consequences that ankylosing spondylitis can have. OSTEOPOROSIS Osteoporosis manifests clinically as fragility fractures, and its socioeconomic impact relates to these fractures. They occur most commonly at the distal forearm, hip, and spine. The prevalence of osteoporosis and the incidence of fragility increase with age. Their impact increases with comorbidity. Therefore, costs are dependent on the age of the population being considered. The costs incurred, and whether they are attributed to health or social care, depend on clinical management practices and existing systems of long-term care and support. The direct medical expenditure is attributable predominantly to hospitalization. In Sweden in 1996, there were 54,000 admissions for fractures in men and women aged 50 years or older, accounting for 600,000 hospital-bed days in a population of just over 9 million, 30% of whom were 50 years or older.76 Duration of hospital stay increased with age. Hip fractures accounted for 69% of hospital-bed days in men and 73% in women. The total direct medical expenditure for osteoporotic fractures in the United States in 1995 was estimated at $13.8 billion.77 In the United Kingdom, the total costs were estimated at £942 million in 1998 for all osteoporotic fractures, of which only 45% was estimated to be for direct costs,78 although the cost of antifracture therapy was not fully included. These estimates were revised to £1.7 b­illion in 200178a and are predicted to increase further with the aging population. In Sweden, hospital days for osteoporotic fr­actures accounted for higher costs than for myocardial infarction, breast cancer, and prostate cancer combined.76 Across Europe, it has been estimated that osteoporotic fractures cost €36,248 million—€24,353 million for hip fracture, €719 million for vertebral fracture, and €11,177 million for other osteoporotic fractures.79 The total costs for women are estimated to be threefold those for men. In Canada, the cost of hip fracture has been estimated at US$22,292 during the first year; 58% was related to the in­itial hospitalization and inpatient rehabilitation, but there was wide variation, depending on the patient’s age and the care setting before and after the fracture.80

Estimates of the total cost of hip fractures in the United States range from $24,000 to $33,500 (1995 dollars).81 In the United Kin­gdom, hip fractures are most expensive, estimated to account for 87% of the total costs of osteoporotic fractures in women; 60% of their cost is indirect owing to the need for long-term hospital and community care.78 The acute hospital cost of a hip fracture was estimated at £4808 in 1998, with a total cost per fracture of £12,124.78 A more recent bottom-up costing of hip fractures in the United Kingdom was ca­lculated at a mean of £12,163 for acute hospitalization costs per patient in 2003; ward costs contributed 84%, operative costs 9%, and investigations 7%.82 The direct costs of hip fracture in Sweden over 12 months, excluding community care, were estimated at SKr 63,420 (approximately €6000).83 The mean length of stay in Sweden is much shorter than in the United Kingdom—12 to13 days76 compared with 23 days.82 Direct costs of distal forearm fractures are less, but one in five men and women were admitted to a hospital in a U.K. study84; the proportion requiring admission increased with age, from 14.5% at age 50 to 59 years to 26% at age 80 years and older. Wrist fracture has been estimated to cost £468 (£368 for acute costs).78 Vertebral fractures present acutely in only about one third of cases, but they were responsible for almost 70,000 hospital admissions in 1997 in the U.S. Nationwide Inpatient Sample, about one fourth the number of admissions resulting primarily from hip fracture. Hospitalization rates increased with age and comorbidity. Hospital stays averaged almost 6 days each and generated charges of $8000 to $10,000.84a More than half the patients required posthospital discharge care. Hospitalization for vertebral fracture resulted in almost 400,000 total hospital days that generated charges in excess of $500 million a year. In the United Kingdom, vertebral fracture has been estimated to cost £479 (£96 for acute costs).78 In the age group that sustains hip fracture and the associated comorbidities, it is more meaningful to consider the attributable costs. In the United States, the attributable costs were $3300 for a hip fracture and $1300 for other nonvertebral fractures, based on Medicaid data.85 In a casecontrol study of osteoporotic fractures in Olmsted County, Minnesota, the incremental direct medical costs for the year following an osteoporotic fracture were found to be greatest following distal femur fracture ($11,756) and hip fracture ($11,241).86 Similar figures have been reported in Europe.87 The costs of fracture prevention need to be considered. This includes both testing, such as bone densitometry, and treatment, such as with bisphosphonates. There has been a 10-fold increase in bone mineral density testing in Ontario, Canada—from about 37,000 tests in 1992 to more than 404,000 in 2001; in addition, there has been an increase in the number of people filling at least one prescription for an antiresorptive agent—from about 12,000 in 1996 to nearly 226,000 in 2003.88 The indirect costs related to social care are a major component of the cost of hip fracture: only about 45% of patients are discharged home, and 20% require long-term residential care after discharge from the hospital.78 However, some were already in long-term care facilities before the fracture,76 so there would be little additional cost. Productivity loss is

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not important because of the age at which fractures occur, although caregivers may be affected. With the increased prevalence of fracture with age and the global increase in the aged population, it is estimated that the burden and associated costs will increase significantly—in Europe, from €36.3 million in 2000 to €76.8 million by 205079—unless effective preventive strategies are implemented. BACK PAIN Back pain is most often nonspecific in cause and transient, although it may be recurrent. A small number of patients have chronic back pain with continuous symptoms for more than 3 months, and they account for the largest percentage of costs.89 In the United States, only 4.6% to 8.8% of cases lasted longer than 1 year, but they accounted for 64.9% to 84.7% of the costs.89 In Jersey in the United Kingdom, only 3% of patients were absent from work for more than 6 months, but they accounted for 33% of the benefits paid.90 The total cost in OECD countries corresponds to 1% to 2% of the gross national product; about 10% of the costs are direct and 90% indirect.91 Most of the costs are related to work loss. The economic impact is dependent on the country’s system of social support, and the methods used to identify and estimate the costs vary, making comparisons between studies and countries difficult. A cost-of-illness study of low back pain in the United Kingdom estimated direct costs in 1998 at £1.7 billion; total costs were between £6.6 billion and £12.3 billion, depending on the method used.92 In Sweden in 1994 and 1995, back pain was responsible for almost half the economic burden related to musculoskeletal conditions, costing SKr 25 billion to 29 billion (US$2.5 billion to $3.0 billion), of which SKr 24 billion to 27 billion was spent on productivity losses.18 These societal costs of back pain equate to US$290 per inhabitant per year (1991 dollars) in Sweden and $323 in the Netherlands and about 80% to 90% of these amounts in the United Kingdom. In Sweden, the total costs of low back pain to society were estimated at €1860 million in 2001. The indirect costs due to lost productivity accounted for 84% of this total cost.93 This represented 11% of the total costs of short-term sick leave; about 13% of all early retirement pensions were granted for back problems. Although substantial, these costs have not changed greatly over 10 to 15 years. Health resource utilization varies between countries and is dependent on clinical practice and the use of inpatient treatment, including investigations such as magnetic resonance imaging and the frequency of surgery. In general, expenditures are related predominantly to ambulatory care and are distributed between physicians and ther­ apists (including osteopaths, chiropractors, and alternative the­rapists), depending on clinical practice. Physician visits vary from 1.1 per year in the Netherlands to 3.71 in the United Kingdom.91 Surgery is more common in the United States than in most European countries.94 Based on the 1998 Medical Expenditure Panel Survey, the total health care expenses incurred by individuals with back pain in the United States was estimated at $90.7 billion.95 The total incremental expenditure attributable to back pain was estimated at $26.3 billion; the health costs of individuals with

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back pain were about 60% higher than those without back pain.95 In those with back pain, 75% of the total service expenditure was attributable to the 25% of patients with the highest costs. Number of sick days varies between countries and says more about a country’s system of workers’ compensation than about disease severity. In the United States, the back was the body part most frequently affected in injuries involving days away from work in a worker health review.96 In the 1998 U.S. National Health Interview Survey,97 the prevalence of back pain lasting more than a week was 17.6%, and 4.6% had low back pain associated with lost work.98 This amounted to 149 million lost days annually. The annual cost of lost work time associated with chronic low back pain has been estimated at $1230 for males and $773 for females, based on data from the 1987 U.S. National Medical Care Expenditure Survey; this translates into annual productivity losses of about $28 billion.99 The annual compensation cost of work loss due to medically certified low back pain in the working population of Jersey, United Kingdom, was £3.16 million per 100,000 in 1994— 10.5% of the total paid for all claimed absences.90 Low back disorders are the most co­mmon reason for disability pensions in Norway.100

SUMMARY The economic impact of musculoskeletal conditions is great. They have a major effect on the indirect costs of health care. The direct costs reflect the supply rather than the demand and do not indicate what health gain is achieved. The documented expenditure is clearly an underestimate of need, as there is little priority for these conditions and not much investment in preventive approaches. Many patients do not present for treatment or do not comply for fear of side effects. Highlighting this significant economic impact can be a means of gaining priority for these conditions, but it can also help identify the spectrum of cost items that need to be considered in any economic evaluation of strategies to reduce the burden of musculoskeletal conditions.

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  8. Murray CJL, Lopez AD (eds): The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020. Cambridge, Mass, Harvard University Press, 1996.   9. Byford S, Torgerson DJ, Raftery J: Economic note: Cost of illness studies. BMJ 320:1335, 2000. 10. Mooney G, Wiseman V: Burden of disease and priority setting. Health Econ 9:369-372, 2000. 11. Maetzel A: Cost-effectiveness analysis: Out of touch with clinical reality? Arthritis Rheum 53:3-4, 2005. 12. Gabriel SE, Tugwell P, Drummond M: Progress towards an OMERACT-ILAR guideline for economic evaluations in rheumatology. Ann Rheum Dis 61:370-373, 2002. 13. Weinstein MC, O’Brien B, Hornberger J, et al: Principles of good practice for decision analytic modeling in health-care evaluation: Report of the ISPOR Task Force on Good Research Practices—Modeling Studies. Value Health 6:9-17, 2003. 14. European Opinion Research Group EEIG: Health, Food and Alcohol and Safety: Special Eurobarometer 186. Brussels, European Commission, Directorate General, Communication Public Opinion Analysis Sector, 2003. 15. Hawker GA, Wright JG, Coyte PC, et al: Differences between men and women in the rate of use of hip and knee arthroplasty. N Engl J Med 342:1016-1022, 2000. 16. Woolf AD, Zeidler H, Haglund U, et al: Musculoskeletal pain in Europe: Its impact and a comparison of population and medical perceptions of treatment in eight European countries. Ann Rheum Dis 63:342-347, 2004. 17. Slobbe LCJ, Kommer GJ, Smit JM, et al: Cost of Illness in the Netherlands 2003. http://www.rivm.nl/bibliotheek/rapporten/270751010.pdf. 18. Jonsson D, Husberg M: Socioeconomic costs of rheumatic diseases: Implications for technology assessment. Int J Technol Assess Health Care 16:1193-1200, 2000. 19. World Health Organization: International Classification of Diseases. 9th ed. Geneva, WHO, 1977. 20. Meerding WJ, Bonneux L, Polder JJ, et al: Demographic and epidemiological determinants of healthcare costs in Netherlands: Cost of illness study. BMJ 317:111-115, 1998. 21. Health Canada: The Economic Burden of Illness in Canada 1998. http://www.hc-sc.gc.ca. 22. Stewart WF, Ricci JA, Chee E, et al: Lost productive time and cost due to common pain conditions in the US workforce. JAMA 290:2443-2454, 2003. 23. Update: Direct and indirect costs of arthritis and other rheumatic conditions—United States, 1997. MMWR 53:388–389, 2004. 24. Direct and indirect costs of arthritis and other rheumatic conditions—United States, 1997. MMWR 52:1124–1127, 2003. 25. Dunlop DD, Manheim LM, Yelin EH, et al: The costs of arthritis. Arthritis Rheum 49:101-113, 2003. 26. Yelin E, Murphy L, Cisternas MG, et al: Medical care expenditures and earnings losses among persons with arthritis and other rheumatic conditions in 2003, and comparisons with 1997. Arthritis Rheum 56:1397-1407, 2007. 27. Yelin E, Cisternas MG, Pasta DJ, et al: Medical care expenditures and earnings losses of persons with arthritis and other rheumatic conditions in the United States in 1997: Total and incremental estimates. Arthritis Rheum 50:2317-2326, 2004. 28. Rasker JJ: Rheumatology in general practice. Br J Rheumatol 34: 494-497, 1995. 29. Hootman JM, Helmick CG, Schappert SM: Magnitude and characteristics of arthritis and other rheumatic conditions on ambulatory medical care visits, United States, 1997. Arthritis Rheum 47:571-581, 2002. 30. Coyte PC, Asche CV, Croxford R, Chan B: The economic cost of musculoskeletal disorders in Canada. Arthritis Care Res 11:315-325, 1998. 31. The Office of Health Economics Compendium, 18th ed. Abingdon UK, Radcliffe Publishing, 2007. 32. Szubert Z, Sobala W, Zycinska Z: [The effect of system restructuring on absenteeism due to sickness in the work place. I. Sickness absenteeism during the period 19989-1994]. Med Pr 48:543-551, 1997. 33. Tellnes G, Bjerkedal T: Epidemiology of sickness certification—a methodological approach based on a study from Buskerud County in Norway. Scand J Soc Med 17:245-251, 1989. 34. Stansfeld S, Feeney A, Head J, et al: Sickness absence for psychiatric illness: The Whitehall II study. Soc Sci Med 40:189-197, 1995.

35. Brage S, Nygard JF, Tellnes G: The gender gap in musculoskeletalrelated long-term sickness absence in Norway. Scand J Soc Med 26:34-43, 1998. 36. National Board of Health and Welfare (Sweden): Yearbook of Health and Medical Care 2001. Stockholm, Socialstyrelsen. 37. Birnbaum HG, Barton M, Greenberg PE, et al: Direct and indirect costs of rheumatoid arthritis to an employer. J Occup Environ Med 42:588-596, 2000. 38. Cooper NJ: Economic burden of rheumatoid arthritis: A systematic review. Rheumatology (Oxford) 39:28-33, 2000. 39. Felts W, Yelin E: The economic impact of the rheumatic diseases in the United States. J Rheumatol 16:867-884, 1989. 40. Kramer JS, Yelin EH, Epstein WV: Social and economic impacts of four musculoskeletal conditions: A study using national communitybased data. Arthritis Rheum 26:901-907, 1983. 41. Girard F, Guillemin F, Novella JL, et al: Health-care use by rheumatoid arthritis patients compared with non-arthritic subjects. Rheumatology (Oxford) 41:167-175, 2002. 41a. Kuper IH, Prevoo ML, van Leeuwen MA, et al: Disease-associated time consumption in early rheumatoid arthritis. J Rheumatol 2000; 27(5):1183-1189. 42. Huscher D, Merkesdal S, Thiele K, et al: Cost of illness in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and systemic lupus erythematosus in Germany. Ann Rheum Dis 65:1175-1183, 2006. 43. Fautrel B, Guillemin F: Cost of illness studies in rheumatic diseases. Curr Opin Rheumatol 14:121-126, 2002. 44. Hulsemann JL, Mittendorf T, Merkesdal S, et al: Direct costs related to rheumatoid arthritis: The patient perspective. Ann Rheum Dis 64:1456-1461, 2005. 45. Verstappen SM, Boonen A, Verkleij H, et al: Productivity costs among patients with rheumatoid arthritis: The influence of methods and sources to value loss of productivity. Ann Rheum Dis 64:1754-1760, 2005. 46. Cross MJ, March LM, Lapsley HM, et al: Patient self-efficacy and health locus of control: Relationships with health status and arthritis-related expenditure. Rheumatology (Oxford) 45:92-96, 2006. 47. Yelin E: The earnings, income, and assets of persons aged 51-61 with and without musculoskeletal conditions. J Rheumatol 24:2024-2030, 1997. 48. Jantti J, Aho K, Kaarela K, Kautiainen H: Work disability in an inception cohort of patients with seropositive rheumatoid arthritis: A 20 year study. Rheumatology (Oxford) 38:1138-1141, 1999. 49. Albers JM, Kuper HH, van Riel PL, et al: Socio-economic consequences of rheumatoid arthritis in the first years of the disease. Rheumatology (Oxford) 38:423-430, 1999. 50. Gabriel SE, Crowson CS, Campion ME, O’Fallon WM: Indirect and nonmedical costs among people with rheumatoid arthritis and osteoarthritis compared with nonarthritic controls. J Rheumatol 24:43-48, 1997. 51. Burton W, Morrison A, Maclean R, Ruderman E: Systematic review of studies of productivity loss due to rheumatoid arthritis. Occup Med 56:18-27, 2006. 52. Clarke AE, Zowall H, Levinton C, et al: Direct and indirect medical costs incurred by Canadian patients with rheumatoid arthritis: A 12 year study. J Rheumatol 24:1051-1060, 1997. 53. Eberhardt K, Larsson BM, Nived K, Lindqvist E: Work disability in rheumatoid arthritis—development over 15 years and evaluation of predictive factors over time. J Rheumatol 34:481-487, 2007. 54. Cooper NJ, Mugford M, Symmons DP, et al: Total costs and predictors of costs in individuals with early inflammatory polyarthritis: A community-based prospective study. Rheumatology (Oxford) 41: 767-774, 2002. 55. Hawley DJ, Wolfe F, Pincus T: Use of combination therapy in the routine care of patients with rheumatoid arthritis: Physician and patient surveys. Clin Exp Rheumatol 17(6 Suppl 18):S78-S82, 1999. 56. Henry D, Lim LL, Garcia Rodriguez LA, et al: Variability in risk of gastrointestinal complications with individual non-steroidal antiinflammatory drugs: Results of a collaborative meta-analysis. BMJ 312:1563-1566, 1996. 57. March LM, Bachmeier CJ: Economics of osteoarthritis: A global perspective. Baillieres Clin Rheumatol 11:817-834, 1997. 58. Levy E, Ferme A, Perocheau D, Bono I: [Socioeconomic costs of osteoarthritis in France]. Rev Rhum Fr Ed 60:63S-67S, 1993. 59. MacLean CH, Knight K, Paulus H, et al: Costs attributable to osteoarthritis. J Rheumatol 25:2213-2218, 1998. 60. Moore RA: The hidden costs of arthritis treatment and the cost of new therapy—the burden of non-steroidal anti-inflammatory drug gastropathy. Rheumatology (Oxford) 41(Suppl 1):7-15, 2002.

PART 4  61. Ramsey SD, Spencer AC, Topolski TD, et al: Use of alternative therapies by older adults with osteoarthritis. Arthritis Rheum 45: 222-227, 2001. 62. Juni P, Dieppe P, Donovan J, et al: Population requirement for primary knee replacement surgery: A cross-sectional study. Rheumatology (Oxford) 42:516-521, 2003. 62a. Holland R, Harvey I: Population needs assessment and knee replacement surgery. Rheumatology (Oxford) 2003; 42(4):503-506. 63. Merx H, Dreinhofer K, Schrader P, et al: International variation in hip replacement rates. Ann Rheum Dis 62:222-226, 2003. 64. Malchau H, Herberts P, Eisler T, et al: The Swedish Total Hip Replacement Register. J Bone Joint Surg Am 84(Suppl 2):2-20, 2002. 65. Dreinhofer KE, Feron JM, Herrera A, et al: Orthopaedic surgeons and fragility fractures: A survey by the Bone and Joint Decade and the International Osteoporosis Foundation. J Bone Joint Surg Br 86: 958-961, 2004. 66. Dixon T, Shaw M, Ebrahim S, Dieppe P: Trends in hip and knee joint replacement: Socioeconomic inequalities and projections of need. Ann Rheum Dis 63:825-830, 2004. 66a. Frankel S, Eachus J, Pearson N, et al: Population requirement for primary hip-replacement surgery: A cross-sectional study. Lancet 1999; 353(9161): 1304-1309. 67. Vale L, Wyness L, McCormack K, et al: A systematic review of the effectiveness and cost-effectiveness of metal-on-metal hip resurfacing arthroplasty for treatment of hip disease. Health Technol Assess 6:1-109, 2002. 68. Pincus T, Mitchell JM, Burkhauser RV: Substantial work disability and earnings losses in individuals less than age 65 with osteoarthritis: Comparisons with rheumatoid arthritis. J Clin Epidemiol 42:449-457, 1989. 69. Lapsley HM, March LM, Tribe KL, et al: Living with osteoarthritis: Patient expenditures, health status, and social impact. Arthritis Rheum 45:301-306, 2001. 70. Zink A, Thiele K, Huscher D, et al: Healthcare and burden of disease in psoriatic arthritis: A comparison with rheumatoid arthritis and ankylosing spondylitis. J Rheumatol 33:86-90, 2006. 71. Boonen A, Severens JL: Ankylosing spondylitis: What is the cost to society, and can it be reduced? Best Pract Res Clin Rheumatol 16:691-705, 2002. 72. Boonen A, van der Heijde D, et al: Direct costs of ankylosing spondylitis and its determinants: An analysis among three European countries. Ann Rheum Dis 62:732-740, 2003. 73. Ward MM: Functional disability predicts total costs in patients with ankylosing spondylitis. Arthritis Rheum 46:223-231, 2002. 74. Boonen A, Chorus A, Miedema H, et al: Employment, work disability, and work days lost in patients with ankylosing spondylitis: A cross sectional study of Dutch patients. Ann Rheum Dis 60:353-358, 2001. 75. Boonen A, van der Heijde D, et al: Work status and productivity costs due to ankylosing spondylitis: Comparison of three European countries. Ann Rheum Dis 61:429-437, 2002. 76. Johnell O, Kanis JA, Jonsson B, et al: The burden of hospitalised fractures in Sweden. Osteoporos Int 16:222-228, 2005. 77. Ray NF, Chan JK, Thamer M, Melton LJ III: Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: Report from the National Osteoporosis Foundation. J Bone Miner Res 12:24-35, 1997. 78. Dolan P, Torgerson DJ: The cost of treating osteoporotic fractures in the United Kingdom female population. Osteoporos Int 8:611-617, 1998. 78a. Torgerson DJ, Iglesias CP, Reid DM: The economics of fracture prevention. In Barlow DH, Francis RM, Miles A (eds): The Effective Management of Osteoporosis. UK Advances in Clinical Practice Series. London: Aesculapius Medical Press, 2001, pp 111-121. 79. Kanis JA, Johnell O: Requirements for DXA for the management of osteoporosis in Europe. Osteoporos Int 16:229-238, 2005.

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80. Wiktorowicz ME, Goeree R, Papaioannou A, et al: Economic implications of hip fracture: Health service use, institutional care and cost in Canada. Osteoporos Int 12:271-278, 2001. 81. Tosteson AN: Economic impact of fractures. In Orwoll E (ed): The Effects of Gender on Skeletal Health. San Diego, Calif, Academic Press, 1999, pp 15-27. 82. Lawrence TM, White CT, Wenn R, Moran CG: The current hospital costs of treating hip fractures. Injury 36:88-91, 2005. 83. Zethraeus N, Borgstrom F, Johnell O, et al: Costs and quality of life associated with osteoporosis related fractures: Results from a Swedish survey. SSE/EFI Working Paper Series in Economics and Finance No. 512, 2002. Stockholm School of Economics, ­Sweden. 84. O’Neill TW, Cooper C, Finn JD, et al: Incidence of distal forearm fracture in British men and women. Osteoporos Int 12:555-558, 2001. 84a. Gehlbach SH, Burge RT, Puleo E, Klar J: Hospital Care of osteoporosis-related vertebral fractures. Osteoporos Int 2003; 14(1):53-60. 85. Martin BC, Chisholm MA, Kotzan JA: Isolating the cost of osteoporosis-related fracture for postmenopausal women: A population-based study. Gerontology 47:21-29, 2001. 86. Gabriel SE, Tosteson AN, Leibson CL, et al: Direct medical costs attributable to osteoporotic fractures. Osteoporos Int 13:323-330, 2002. 87. Autier P, Haentjens P, Bentin J, et al: Costs induced by hip fractures: A prospective controlled study in Belgium. Belgian Hip Fracture Study Group. Osteoporos Int 11:373-380, 2000. 88. Jaglal SB, Weller I, Mamdani M, et al: Population trends in BMD testing, treatment, and hip and wrist fracture rates: Are the hip fracture projections wrong? J Bone Miner Res 20:898-905, 2005. 89. Hashemi L, Webster BS, Clancy EA: Trends in disability duration and cost of workers’ compensation low back pain claims (1988-1996). J Occup Environ Med 40:1110-1119, 1998. 90. Watson PJ, Main CJ, Waddell G, et al: Medically certified work loss, recurrence and costs of wage compensation for back pain: A follow-up study of the working population of Jersey. Br J Rheumatol 37:82-86, 1998. 91. Norlund AI, Waddell G: Cost of back pain in some OECD countries. In Nachemson A, Jonsson E (eds): Neck and Back Pain: The Scientific Evidence of Causes, Diagnosis, and Treatment. Philadelphia, Lippincott Williams & Wilkins, 2000, pp 421-425. 92. Maniadakis N, Gray A: The economic burden of back pain in the UK. Pain 84:95-103, 2000. 93. Ekman M, Johnell O, Lidgren L: The economic cost of low back pain in Sweden in 2001. Acta Orthop 76:275-284, 2005. 94. Deyo RA, Cherkin D, Conrad D, Volinn E: Cost, controversy, crisis: Low back pain and the health of the public. Annu Rev Public Health 12:141-156, 1991. 95. Luo X, Pietrobon R, Sun SX, et al: Estimates and patterns of direct health care expenditures among individuals with back pain in the United States. Spine 29:79-86, 2004. 96. Worker Health Chartbook 2004. Cincinnati, Ohio, U.S. Department of Health and Human Services, CDC (NIOSH), 2004. www. cdc.gov/niosh/docs/chartbook/pdfs/Chartbook_2004_NIOSH.pdf. 97. Guo HR, Tanaka S, Cameron LL, et al: Back pain among workers in the United States: National estimates and workers at high risk. Am J Ind Med 28:591-602, 1995. 98. Guo HR, Tanaka S, Halperin WE, Cameron LL: Back pain prevalence in US industry and estimates of lost workdays. Am J Public Health 89:1029-1035, 1999. 99. Rizzo JA, Abbott TA III, Berger ML: The labor productivity effects of chronic backache in the United States. Med Care 36:1471-1488, 1998. 100. National Insurance Administration, Norway. 1998.

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Clinical Trial Design and Analysis ROBERT B. M. LANDEWÉ • DÉSIRÉE M. F. M. VAN DER HEIJDE

KEY POINTS Clinical trials play an important role in new drug development, but also can serve to explore existing drugs or interventions further or refine their use. Pragmatic trials have a lower level of internal validity (methodologic robustness) compared with explanatory trials, but a higher level of external validity (generalizability). A fundamental choice in the consideration of the design of the study is to decide about a superiority design or a noninferiority design. An appropriate trial design is of decisive importance to optimize the likelihood that the trial would provide results that are interpretable, robust, and applicable. The decisions made during the design phase are a reflection of the continuous balance between internal validity and external validity. Disturbing factors, such as missing data, dropout, and confounding, may jeopardize the interpretation of the trial results. The consumers of trial results (investigators, pharmaceutical industry workers, readers of medical journals) should be challenged to interpret the results of a trial in the light of these potentially disturbing factors.

Clinical trials are studies designed to assess the efficacy and toxicity of drugs or other interventions. Although the term clinical trial often refers to randomized clinical trial (RCT), every study in which patients are exposed to an intervention and in which data are systematically collected can be considered as a clinical trial. Clinical trials play an important role in new drug development, but also can serve to explore existing drugs or interventions further or refine their use, such as the determination of predictive factors for treatment efficacy, or to test treatment strategies. This chapter is broadly confined to RCTs. It discusses methodologic principles of clinical trials and RCT analysis in the context of rheumatology, and it unveils limitations of RCTs, while briefly discussing alternative solutions in design and analysis. This chapter is intended as an introduction for clinicians and researchers working in rheumatology.

TRIAL DESIGN RANDOMIZED CLINICAL TRIALS The classic template of an RCT includes two (or more) trial arms, comparing the drug or intervention of interest (e.g., the new drug) with a control intervention. The latter may include a placebo or sham intervention, or an intervention that is considered to represent standard care. By definition, the treatment arms are created by the process of randomization, which is pivotal and is outlined subsequently in more detail.

To understand differences in trial design better, it is often helpful to distinguish explanatory RCTs and pragmatic RCTs.1-3 Trials of new drugs, such as trials designed for drug registration, aiming at showing efficacy and short-term safety, belong to the group of explanatory RCTs. Generally, all elements of trial design, such as the selection of patients, the sample size, the choice of the comparative intervention, and the duration of the trial, are chosen in such a manner that the trial can optimally show a treatment effect (i.e., a difference in efficacy between the new drug and the control intervention). The methodologic robustness of a trial, which depends on these elements of trial design, is referred to as internal validity. Explanatory trials do not always resemble clinical practice. For methodologic reasons, they often include patients with a high level of disease activity that form only a minority in clinical practice. The extent to which clinical trial results can be extrapolated to common clinical practice is referred to as external validity. As a rule of thumb, explanatory trials have a high level of internal validity, which may be at the cost of external validity. Pragmatic trials more closely resemble the clinical situation. Such trials aim at optimizing treatment by exploring existing drugs or treatment strategies further. Pragmatic trials incorporate fundamental principles of RCTs, such as randomization, but include a more realistic representation of patients, may have a longer duration, and may allow cointerventions. Generally, pragmatic trials have a lower level of internal validity compared with explanatory trials, but a higher level of external validity. Often, explanatory trials are initiated and sponsored by the pharmaceutical industry, whereas most pragmatic trials are investigator-driven initiatives sponsored by the academic community. Randomization Randomization, the process by which patients are assigned to treatment by chance, is the most important methodologic characteristic of an RCT and warrants some explanation. Randomization makes treatment arms similar for all variables except treatment, or, in other words, randomization divides all known and unknown variables that may or may not be of prognostic importance equally across treatment groups, reducing the probability that factors other than treatment may influence the results. Randomization does not completely preclude imbalances. Differences in variables that are of prognostic importance may occur simply by chance. Randomization precludes intentional imbalances, however (e.g., dissimilarities created by physicians who consider a particular treatment more appropriate for a particular patient [selection]). 453

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From a statistical perspective, chance differences occur more frequently in small study samples than in larger ones and may be of higher magnitude in small trials. It is necessary to compare treatment groups at baseline with respect to important prognostic variables, and to adjust for differences in the statistical analysis in case of doubt. Usually, computer-generated randomization lists are used to randomize patients in a RCT. Technically, randomization is often performed in “blocks” so that in every block of 4 or 10, there is an equal number of patients in the treatment and control groups. Randomizing in blocks ensures that if the sample size is less than expected, there is an equal proportion of patients in each treatment group. Often, in multicenter trials, one center is assigned one or more blocks, ensuring that the number of patients receiving the new drug and the control drug are distributed evenly per center. Some trials randomly enroll patients in strata (stratification) of equal or unequal size. Stratification (a better wording is stratified randomization) makes sense only if the variable subject for stratification represents a prognostically important feature. An appropriate example is a situation in which there is circumstantial evidence that the efficacy of a treatment is different in men compared with women. Stratified randomization with “men” and “women” as strata implies that randomization to treatment groups occurs after the assignment of the appropriate stratum. It allows a justifiable comparison between the treatment groups within each stratum because there is prognostic similarity at baseline. Appropriate stratified randomization requires a trial design and a sample size that allows such a comparison (see later discussion of statistical power). Stratified randomization should be distinguished from post-hoc subgroup analysis, in which the “strata” are determined during the analysis of the trial. In such posthoc comparisons, prognostic similarity cannot be ensured, and statistical adjustments can account only rarely for this.

In a superiority design, the question is whether the new treatment is more efficacious than the control intervention (e.g., placebo). Formally, such a study tests whether the null hypothesis of no difference between both treatment groups can be rejected. To do so, the investigators agree on a minimally clinically important difference (MCID) between the intervention of interest and the control intervention that such a study should be able to show, and they design the study in such a way that this difference can be shown with high likelihood (statistical power) when it really exists (see later). In a noninferiority design, the reasoning is opposite. The null hypothesis is that the new treatment is less efficacious than the control intervention.4,5 Even if the new intervention and the control intervention are truly similarly effective, a trial almost never would yield a result with a treatment effect of exactly zero (no difference). There would be variation around zero, and it is the task of the investigators to decide in the design phase of the study which deviation from a treatment effect of zero they would accept to conclude that the interventions are equivalent—termed the noninferiority margin. The determination of the MCID in a superiority design and the noninferiority margin in a noninferiority design is a subjective decision with important consequences for the sample size. When it is important in a superiority design to be able to show very small treatment effects with a high likelihood, large sample sizes are needed, and the same is true with a very narrow noninferiority margin in a noninferiority design. Especially in a noninferiority design, other considerations than efficacy alone may give guidance to the level of the noninferiority margin. If a new drug is less toxic or less costly than the existing drugs on the market, and as such may have additional benefits, one could be more lenient with regard to determining the noninferiority margin. Generally, noninferiority designs require (far) more patients than superiority designs. Subject Selection

Design Considerations A fundamental choice in the consideration of the design of the study is to decide about a superiority design versus a nonsuperiority design. The latter theoretically can be categorized further as a noninferiority design and an equivalence design. The basis supporting this choice is the null hypothesis underlying the study. The consequences of the choice for the design are important. If a new treatment is tested against placebo, the a priori hypothesis is that this new drug is more effective than placebo, and a superiority design is a rational choice. If treatments are already available for a particular disease or condition, it is ethically often not justifiable to subject patients to a placebo treatment for longer periods. It is not always rational to assume that a new treatment would be better than the best available treatment at that moment, and a superiority design would have a high likelihood of failure. In such situations, one can opt for a nonsuperiority design. These designs have the underlying hypothesis that the treatment to test is at least not worse than (or equivalent to) the comparative treatment, which can be the standard of care or, alternatively, the best currently available treatment.

Subjects who are entered into clinical studies should meet accepted criteria for the disease or disorder under study. Most rheumatologic conditions lack single and unequivocal diagnostic tests, and classification criteria have been developed to identify patients with similar characteristics.6 The classification criteria serve as eligibility criteria in an RCT. To homogenize patient populations for scientific purposes, classification criteria are designed to be highly specific. Consequently, sensitivity may fall short, and classification criteria are often of limited use in diagnosis. The high specificity of classification criteria has implications for the composition of the trial population. Generally, there is an overrepresentation of patients with classic, often severe disease and an underrepresentation of patients with early, less typical disease. In many trials in rheumatology, patients also must meet certain criteria for disease activity or duration. Some trials require that the patient experiences a flare after withdrawal of medication as evidence of active disease. Other studies define disease activity before withdrawal of medication as evidence of lack of response to current treatment. Disease severity can be defined by accepted clinical criteria or by

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lack of response to previous treatments. Rheumatoid arthritis (RA) studies may be limited to patients who have not yet received methotrexate (who presumably have early disease or mild disease) or to patients who have failed treatment with at least one other disease-modifying antirheumatic drug (more disease severity). There are ethical and methodologic reasons for the use of such activity or severity criteria. Ethical arguments may proscribe that a novel intervention is first tested in patients with severe, sometimes intractable disease in which common alternatives have failed. Methodologic arguments are that a treatment effect can be shown best in a population of patients prone to change. Most inflammatory rheumatic diseases have a cyclic course characterized by exacerbations and remissions. Patients with a high level of disease activity tend to improve over time, even without an intervention, a phenomenon known as regression toward the mean, and the additional effect of a new intervention compared with a control treatment can be shown more easily in such a context. Exclusion criteria usually include conditions such as cancer, cardiac, hepatic, or renal disease; abnormalities in hematologic parameters; medication allergies; and pregnancy. Exclusion criteria decrease the background noise or variability resulting from differences in patient characteristics. Generally, inclusion and exclusion criteria homogenize the trial patient population and contribute to an environment that is most optimal to show a treatment effect. Inclusion and exclusion criteria also prevent entry of patients in whom an adverse response is more likely to occur or patients for whom the experimental treatment could be dangerous a priori. Inclusion criteria and exclusion criteria contribute to a high level of internal validity, but this jeopardizes external validity. Explanatory trials usually have a comprehensive set of inclusion and exclusion criteria. Pragmatic trials are more lenient in this regard because they should reflect the common clinical practice better.

Informed Consent Ethical considerations determine whether eligible subjects participate in a clinical trial. Governmental agencies of most countries require that institutions involved in human research have a local institutional review board. The institutional review board reviews all protocols before implementation and monitors ongoing studies at an institution. A crucial element in the review of a trial is the informed consent process.7 The consent form should explain to the study participant the purpose of the study, all potential benefits and risks (including risks to pregnant mothers and fetuses), alternatives to participation, and who is responsible for conducting the study. Patient confidentiality should be ensured. The consent form should state clearly that participation is completely voluntary, and that refusal to participate or withdrawal from the study would not affect future care. If compensation is provided, it must be documented in the consent form. Participants should be given contact information for questions or in case of injury and a statement about whether any medical treatment would be given if injury occurs. Investigators are responsible for ensuring that the risk to subjects is minimized and appropriate for the anticipated benefits.

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Follow-Up Considerations The optimal duration of the trial is a compromise between economical, ethical, and methodologic considerations. A trial should not be too short because an intervention needs time to exert its potentially advantageous (but also deleterious) effects; in particular, a short trial does not reflect clinical reality of most rheumatologic conditions. Equally, a trial should not be too long because RCTs are expensive, patients should not be subjected to experimental interventions with uncertain adverse events for an excessive length of time, and too much longitudinal bias should be avoided. Longitudinal bias may occur if during the trial the treatment groups increasingly become dissimilar owing to selective dropout, cointerventions, and behavior of other patients or the treating physician. Selective dropout may occur if patients with a particular profile preferably withdraw from one of the treatment groups, creating prognostic imbalance. A common example is that of an RA trial comparing an effective drug with placebo. Patients with severe and active disease in the placebo group may preferably discontinue trial medication and drop out because they do not experience benefit, whereas the patients with less severe and less active disease remain in the trial. Cointerventions—allowed or not allowed—may similarly jeopardize prognostic similarity if they occur in an unbalanced (i.e., unequal) manner across the treatment groups. A common example is a trial that tests a nonsteroidal anti-inflammatory drug versus placebo with respect to pain relief. Simple analgesics that are preferentially used in the placebo group may inadvertently influence the pain scores and lead to incorrect conclusions. The treating physician also may contribute to prognostic imbalance by prescribing cointerventions, or in general terms treating patients differently according to their clinical response or the occurrence of adverse events. A short follow-up would decrease the likelihood that unintended events occur and as such contributes to maintaining prognostic similarity and increasing internal validity. Explanatory trials usually have a follow-up duration that is as short as possible, and cointerventions are prohibited. The most important limitation of short-term trials in lifelong rheumatologic diseases is that they do not appropriately reflect the course of the disease encountered in clinical practice. Sometimes, RCTs, especially pragmatic trials, have a long trial duration that better reflects the clinical reality. In such a trial, the internal validity is deliberately sacrificed to some extent in favor of an increased external validity (generalizability) and the yield of long-term information. Blinding In double-blind studies, neither the patient nor the investigator is aware of the treatment group assignment. In ­singleblind studies, the investigator is aware of the treatment allocation, but the patient is not. In open-label studies, the patient and the investigator are aware of the treatment assignment. The most important reason to blind treatment allocation is to avoid the possibility that any expectation about the kind of treatment could influence the measured outcome (expectation bias), especially (but not exclusively) if the measured outcome includes subjective components.

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Subjective refers to the patient (e.g., pain scores) and to the investigator (e.g., joint scores). To avoid the latter, many drug trials make use of independent (joint) assessors who are not responsible for decisions regarding patient care and are blinded to the treatment. Another common example of a blinded independent assessor in rheumatology is the reader of radiographs in imaging studies in RA, psoriatic arthritis, or ankylosing spondylitis. Regardless of any precaution, unblinding may inadvertently occur because of identifiable adverse reactions or minor side effects, lack of efficacy, or changes in laboratory parameters. A disturbing effect of such a type of unblinding is not easy to prove, and it cannot be adjusted for in the analysis. CHOICE OF THE OUTCOME VARIABLES Any clinical trial has one or more outcome variables of interest. Outcome is broadly defined and refers to a clinical situation or a change in a clinical situation that is quantifiable by using assessment instruments. Outcome variables can measure real outcome, which directly affects the patient (e.g., vertebral fracture in osteoporosis), or alternatively can reflect a situation that is associated with real outcome, but does not affect the patient per se (e.g., low bone mineral density in osteoporosis). The latter type of outcome is often termed surrogate outcome. Reasons to use surrogate outcome measures rather than real outcome measures are that the former occur (far) earlier and more frequently and often can be assessed on a continuous scale (which is a statistical advantage), whereas the latter often describe an event (the presence or absence of a clinical situation) with negative implications for statistical power. The Outcome and Measurement in Rheumatoid Arthritis Clinical Trials (OMERACT) initiative was started to bring unanimity in the multitude of outcome measures in rheumatology on the basis of expert consensus.8 It was initiated in RA and expanded to include most other rheumatologic diseases. The OMERACT framework is the so-called OMERACT filter, which describes the methodologic prerequisites that an appropriate outcome measure should fulfill to be considered valid for clinical trials. The OMERACT filter prescribes three validation requirements: An outcome measure should be truthful, discriminatory, and feasible. Truthful refers to whether or not an outcome measure truly measures what it is intended to measure, and approximates the concepts of face, content, and construct validity. It means that the disease activity score (DAS) in RA should truly measure what is considered important in RA (e.g., swelling and tenderness of joints) (content validity) and what is a relevant construct to describe the process of RA (e.g., the DAS is associated with radiographic progression and limited physical function) (construct validity). Discriminatory refers to whether or not an outcome measure can be measured reliably (intra­ observer variation and interobserver variation), whether it can distinguish between two stages of the disease (e.g., RA with high disease activity versus RA with low disease activity), whether it can be applied to groups of patients or an individual patient, whether the measure is sensitive to change (e.g., whether the DAS measurably decreases if the disease improves), and whether the measure can discriminate between groups of patients on effective therapy versus

placebo or less effective therapy. Feasible refers to whether or not an outcome measure is easily applicable and inexpensive in the setting in which it is intended to use. Eight biannual OMERACT conferences have now resulted in sets of outcome measures for almost all inflammatory rheumatologic diseases and for many noninflammatory disorders. These so-called core sets have importantly improved the homogeneity across different clinical trials, favoring comparability. In the design phase of a clinical trial, it is highly recommended to choose a primary outcome measure from these core sets, and to measure all components of the core set as secondary outcome measures. The reporting of all core set measures prevents the selective reporting of only positive results with respect to a few variables. Increasingly, indices replace single outcome variables in rheumatology. An index is a weighted or unweighted combination of single variables that together reflect a particular domain of outcome.9 A general rule is that indices perform better than single-item variables only if they consist of variables that correlate moderately with each other. If variables correlate at too high a level, there is redundancy of information (colinearity). If variables do not correlate, they reflect different domains, which complicates interpretability, and it is better to describe them separately. Important examples of useful indices in rheumatology are the already mentioned DAS10 and the American College of Rheumatology (ACR) response criteria in RA.11 MEASURING EFFECT After the choice of the outcome measures, it is important to consider how the change in outcome measures is assessed in the clinical trial. One could simply calculate a before/ after difference in a continuous variable (a change score), but this is statistically not the best. The ACR has developed the ACR20 response criteria as a tool to determine in clinical trials whether one drug is more efficacious than another or placebo.11 The ACR20 is an index, containing several outcome measures from the World Health Organization/International League against Rheumatism core set for RA,12 which is based on expert consensus about different measures to assess disease activity. The ACR20 response criteria require a 20% improvement and have been thoroughly validated in several validation steps, have been shown to perform better in trials than individual core set measures, and currently are the standard for measuring drug efficacy in clinical trials. The ACR50 and ACR70 response criteria have been derived from the ACR20 response criteria in that they require a higher level of improvement. These derivatives have never been appropriately validated, but have proved to be useful in drug research, despite an inferior discriminatory potential compared with the ACR20 response criteria.13 A specific limitation of the ACR70 is that the baseline disease activity needs to have a certain (high) level to allow a 70% improvement. The European League against Rheumatism (EULAR) has endorsed its own response criteria in RA, which are based on the DAS.14 The DAS is a continuous index measure that includes four core set measures in a statistically weighted manner. The advantage of the DAS, which also underwent numerous validation steps, is that it describes a

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state of disease activity, rather than a response, or a change. The EULAR response criteria are categorical response criteria (good response, moderate response, and no response) that are entirely based on the DAS and require an absolute change in the DAS and a certain state level of the DAS.14 Another disease in which response criteria have been developed for use in clinical trials is ankylosing spondylitis. The ASsessment in Ankylosing Spondylitis (ASAS) international working group has developed the ASAS20 response criteria, which includes four patient-oriented disease activity measures, for use in clinical trials of ankylosing spondylitis.15 In general, the consensus-based response criteria have contributed to better trial design, better trial conduct, and better comparability across trials. An important drawback is that the interpretability of the different indices (“what does it mean that a patient has experienced an ACR20 response?”) remains difficult. SAMPLE SIZE AND STATISTICAL POWER Statistical power is the likelihood that if a treatment effect truly exists (or drug A is truly better than drug B), the trial will show this with statistical significance. A power of 0.80 (80%) means that if there is a true difference between the treatment group and the control group, the likelihood that this RCT will confirm that difference is 80%. At the basis of this definition is the reasoning that truth (difference or not) is unknown—that we never will know the truth with absolute certainty, and that we can only approximate the truth by performing RCTs. Intuitively, an RCT does not always give the right answer. An RCT may conclude that there is a difference, whereas in truth there is not. Alternatively, a true difference would not be supported by the results of the trial. The former is termed a type I error; the latter is termed a type II error (Fig. 30-1). The theoretical problem is that—by definition—we do not know which RCT gives the right answer and which does not. Although we do not know the true answer, we try to design the trial in such a manner that type I error and type II error are minimal. The likelihood of type I and type II error is less with larger sample sizes. Consequently, the likelihood of correctly drawing a conclusion from the experiment of one RCT increases by increasing sample size. Apart from sample size, the likelihood that a study can detect a difference between treatment groups also depends on effect size (if the treatment has a larger effect, it is easier to detect with smaller sample sizes) and reliability of the outcome measure (if the outcome measure is more precise, or less influenced by measurement error, it is easier to detect with smaller sample size). The probability of a type I error (false positive) is referred to as alpha and is better known as the level of statistical significance. The probability of a type II error (false negative) is referred to as beta. Statistical power is defined as (1 − beta). If beta is 10%, there is a 90% likelihood of finding a difference between groups of the expected effect, or greater when this difference truly exists. Usually, alpha, or the P value, is set at 0.05, and beta is set between 0.2 and 0.1 (power of 80% to 90%). It is generally considered for ethical reasons that type I error should be avoided because it may directly and negatively affect patient care (a new drug is falsely ­ considered

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Truth Drug A is better than drug B

Drug A is better than drug B Trial result Drug A is not better than drug B

Drug A is not better than drug B

True-positive trial result False-positive trial result (Type I error) Correct rejection of null-hypothesis False-negative trial result (Type II error) Erroneous acceptance of null-hypothesis

Erroneous rejection of the null-hypothesis True-negative trial result

Correct acceptance of null-hypothesis

Figure 30-1  The interpretation of the trial result in the context of the unknown truth of a trial challenging the null hypothesis that drug A is not better than drug B.

to be better than an existing drug). Type II error is subtler, but should be avoided for more than one reason. First, new effective treatments would not reach the market for false reasons, but more importantly, trials with a high probability of type II error are truly inconclusive. Because new drugs may cause harm, a trial that a priori does not allow a firm scientific conclusion is ethically unjustifiable and spends a lot of money without any yield. Sample size is one of the most important determinants of the power of a study to find a treatment difference. To determine the appropriate sample size for a study, the investigator needs to have an estimation of the effect size of the intervention (i.e., difference in outcome between treatment groups, or MCID), the variability of the data (e.g., standard deviation), the statistical test to be used, and the alpha (P value) and beta (i.e., false-negative rate) level. It is important to consider nonspecific effects (placebo effect, regression toward the means), such as the proportion of subjects who meet criteria for improvement in the placebo group (reported 20% to 40% in studies of patients with RA). The variability or standard deviation of the outcome measure can be estimated from pilot data or from other published clinical trials. Often, the sample size in each treatment arm is the same, but unequal but proportional treatment groups also can be used (2:1 ratio of treated subjects to control). RCTs with equal-size treatment groups have greater statistical power, but unequal groups are sometimes used to maximize the number of patients who receive treatment, especially if information on safety is the most important reason for the trial. Also, patients are sometimes more willing to enter a trial in which they have a greater likelihood of receiving an active treatment. DECLARATION OF HELSINKI The World Medical Association’s Declaration of Helsinki (1964) is a document that spells out a set of ethical guidelines for physicians and other participants in medical research.16 It is considered the most widely recognized source of ethical guidance for biomedical research. The fifth and last revision (Edinburgh, October 2000)17 contains 32 paragraphs that

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aim to find a balance between the physician’s duty to “promote and safeguard the health of the people” (paragraph 2), implying that “the well-being of the human subject should take preference over the interests of science and society” (paragraph 5), and the scientific and societal appreciation that “medical progress is based on research which ultimately must rest in part on experimentation involving human subjects” (paragraph 4), inevitably involving “risks and burden” (paragraph 7). The Declaration is not a static document, and the current debate focuses on the place of placebo-controlled trials (paragraph 29).18 Although this paragraph—which raised a lot of argument—justifies placebo-controlled trials only in circumstances in which “no proven prophylactic, diagnostic or therapeutic method exists,” a Note of Clarification by the World Medical Association outlines a more liberal interpretation of this paragraph, providing circumstances in which placebo-controlled trials are allowed even if proven therapy is available. It is generally accepted and required by governmental institutions and institutional review boards that trial design, trial conduct, and trial report are in accordance with the stipulations of the Declaration of Helsinki. PLACE OF NONINFERIORITY DESIGNS IN RHEUMATOLOGY Paragraph 29 of the Declaration, issuing the place of placebocontrolled trials, has generated interest in designing noninferiority trials in rheumatology. The more recently developed biological therapies have had an important impact on the treatment of chronic inflammatory diseases. If paragraph 29 of the Declaration of Helsinki is interpreted conservatively, this means that placebo-controlled trials are ethically not justifiable anymore in RA, ankylosing spondylitis, and psoriatic arthritis. It immediately follows from paragraph 30 of the Declaration (“every patient entering into the study should be assured of access to the best proven … therapeutic methods identified by the study”) that future trials investigating new treatments in these diseases should include the best available treatments in the control arm. The introduction of these ethical principles are expected to have methodologic consequences because RCTs with a superiority design become virtually impossible because of the high level of efficacy in the control group. The only acceptable alternative is the noninferiority trial, which was discussed briefly earlier. An illustrative example of a noninferiority design, emerging from the more recent controversy about cardiovascular safety of nonsteroidal anti­inflammatory drugs and cyclooxygenase-2 inhibitors, is the Multinational Etoricoxib and Diclofenac Arthritis Longterm (MEDAL) study program,19 which we briefly discuss here. Although this program was focused on cardiovascular safety rather than on efficacy, the noninferiority principles underlying the study are applicable in different settings. The primary hypothesis of the MEDAL study was that treatment with etoricoxib was noninferior to treatment with diclofenac. As a noninferiority margin, a relative risk of 1.30 was chosen. It was defined before the start of the trial that the upper limit of the 95% confidence interval for the hazard ratio (etoricoxib versus diclofenac) should not exceed the noninferiority margin to justify the conclusion that etoricoxib was noninferior to diclofenac with respect to

causing cardiovascular events; this implies that the relative risk itself should be far less than 1.30 to justify a conclusion of noninferiority. It was assumed based on previous experience that diclofenac would give a cardiovascular event rate of 1.3%. With approximately 40,000 patient-years of exposure, it was possible to calculate that the maximal absolute event rate in the etoricoxib group that would still meet the noninferiority criterion would be 1.46%, or, in other words, greater than 1.6 cases per 1000 patient-years of treatment. This example illustrates that noninferiority trials always imply a certain expense (in this example, numerous excess cardiovascular events). It is possible to limit this expense by narrowing the bound of noninferiority, but this occurs at the cost of increased sample size in an exponential manner. The determination of the noninferiority margin is the result of careful considerations about drug safety (which require a margin very close to 1) on the one hand, and the statistical appreciation that the demonstration of true equivalence is not possible on the other hand. CONCLUSIONS An appropriate trial design is important to optimize the likelihood that the trial would provide results that are interpretable, robust, and applicable. Usually, the decisions made during the design phase are a reflection of the continuous balance between internal validity and external validity. Which of both characteristics prevails in the ultimate design depends on the aims and the context of the trial. The ideal trial design does not exist. It is the challenge of the investigators to find the most appropriate design for their goal.

TRIAL ANALYSIS HYPOTHESIS TESTING Suppose a scenario with a particular disease for which an effective treatment A exists, and a new treatment B is proposed. It is unknown whether the new treatment B would be more effective than the established treatment A, and a clinical trial should provide resolution. It is useful to realize that this trial provides only an approximation of the truth that we—by definition—do not know. If you could repeat this trial many times, you might find a mean treatment effect across trials that is the best possible approximation of the truth, and most trials would give results that are close to this mean treatment effect. A few trials would give more deviant results, however, simply by chance. Because you would not be able to carry out this trial numerous times, you would have to interpret the results of your particular trial in the context of numerous illusory trials with the same design. To do so, a null hypothesis of the truth should be carefully formulated. The character of the null hypothesis depends on the type of trial. In a classic superiority design in which a new drug is tested against an established drug, the null hypothesis of the truth states that the new treatment is as effective as the established (control) treatment. In a noninferiority design, however, the null hypothesis of the truth states that the new treatment is less effective than the established treatment. The statistical analysis would challenge the actually observed trial results against the null hypothesis of the truth.

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Essentially, the statistical test provides the probability that a treatment effect (e.g., the difference in proportion of ACR20 responders between the treatment groups, or the difference in mean decrease of DAS) can be found that is as large as what was shown in this trial—or even larger—whereas in truth such a difference does not exist. In the paragraph about statistical power, we referred to this scenario as type I error or alpha, and its likelihood is called the P value. Usually, we consider a probability of type I error of less than 5% (P < .05) sufficiently low to assume safely that the null hypothesis of the truth is not a valid hypothesis, and that it can be rejected. We now decide that the new drug is not as effective as the established drug. Note that not as effective may imply better than as well as worse than. Statistical testing does not differentiate between both scenarios (two-sided testing). The crude data should provide the correct interpretation. The advantage of thinking in probabilistic terms (this trial is only one example of many possible trials with similar design) is that you immediately accept that there is always a chance that—even with very convincing results—the interpretation of this trial may be false. The lower this chance is, the more convincing is the interpretation of the trial results. We also have alluded to the scenario that a trial does not show a treatment difference, whereas in truth there is—type II error or beta. Such a trial lacks (statistical) power. Sample size is most often of pivotal importance, and a classic example of potential type II error is the small clinical trial with a superiority design that tests a new drug against an established drug. Such a trial may give a treatment effect that is of potential clinical interest, but the P value exceeds 0.05 (not statistically significant). It is important to make numerous restrictions here. In analogy with type I error, you can never be certain whether type II error is truly responsible for not statistically showing a potentially important difference. You can only suspect type II error and approximate the probability that it occurs (power calculation). A priori power calculations during the design phase inform you about the probability that the designed trial would statistically “help you” (rightfully reject the null hypothesis) if a particular treatment effect is shown. Post-hoc power calculations can be made after the completion of the trial, using the actually shown treatment effect. Post-hoc power calculations inform you about the power of this trial to support statistically the observed difference if this difference would have been considered clinically important before the trial. Insufficient post-hoc power (e.g., 0.30) is an indication that type II error is operative, but it does not prove type II error. INTENTION TO TREAT A classic clinical trial with a superiority design is analyzed on the basis of intention to treat (ITT) by default. ITT means that every patient is analyzed as belonging to the group to which he or she was allocated by randomization, regardless of what happened with this patient afterward. In the extreme scenario, a patient who is randomly assigned to group A may drop out even before the first drug dose is administered and may be treated outside the clinical trial by his or her physician with the drug that is actually administered in group B (crossover of treatment). True ITT requires

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that this patient—regardless of the data that are present or missing—is analyzed in group A, even if he or she has experienced the effects of the drug in group B. ITT is considered the only means of analysis that preserves prognostic similarity that was created at baseline. Many trial reports mention an ITT analysis, but such an analysis is often not rigorously performed. Randomized patients who did not receive treatment are often excluded from the analysis. Alternatively, a trial analysis could be limited to only the patients who completed the study (completers analysis), or to the patients who completed the study while complying to the study protocol (per-protocol analysis). Both types of analysis may introduce bias, and consequently prognostic similarity should not be assumed. Dropout can occur because of lack of efficacy, and completers may be a less severe representation of the entire trial population (see later). Often, a completers analysis tends to enlarge the treatment effect, whereas an ITT analysis is more conservative. In a noninferiority trial, the situation is just the reverse: The ITT analysis tends to favor noninferiority, whereas the completers or the per-protocol analysis is more conservative in this regard. PROBLEM OF INCOMPLETE DATA A major threat for the interpretation of the results of clinical trials is early withdrawal or dropout. Early withdrawal can be due to a variety of reasons. Some patients withdraw consent immediately after randomization, even before the first drug dose, because they simply changed their mind. Patients may drop out because of actually occurring or feared adverse events, because of lack of efficacy (no response, disease progression, unrealistic expectations), because of a combination of both, or because they have died or have relocated. Usually, dropout results in missing data because most patients do not come back for outcome measurement. Often, patients who formally withdraw are encouraged to continue trial assessment, but it is difficult to decide how to handle the data of these patients because they are often treated with different drugs outside the trial. The trial analysis is negatively affected by missing data in several aspects. First, the individual response or disease course cannot be calculated anymore, but leaving out the entire patient jeopardizes statistical power, especially if the number of withdrawn patients is high (e.g., >20%). Second, early trial withdrawal is not a random process. It is easy to imagine that the most severe patients are at risk for efficacy failure, which may lead to selective dropout in a trial with high treatment contrast, or that certain subgroups of patients are at risk for particular adverse events that occur preferentially in one of the trial arms. The net result of these inadvertent selection processes can be that the treatment groups that were entirely similar at baseline lose their prognostic similarity during the trial. Indicators for selective dropout include a difference in the rate of dropouts between treatment groups, differences in the reasons for dropout between treatment groups, and a high rate of dropout for a specific reason that is reducible to a specific treatment. Usually, missing data are handled in the database by data imputation, to keep the patient in the trial analysis. Data imputation means that a missing data point is supplied by an imaginary value. There are several means of imputation, and there is no consensus about the best way

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to impute. Most likely, the best imputation method depends on the characteristics of the outcome measure, such as the natural course of this outcome measure. Last observation carried forward imputation is a frequently applied method of imputation, in which the last truly measured value is imputed (carried forward) in the subsequent (missing) data points. Other imputation rules are the imputation of a mean group score of the same or the comparator group, the imputation of the 95th percentile, or linear intrapolation or extrapolation. It is not easy to predict how different imputation rules affect the study results. Increasingly, investigators perform sensitivity analyses with different imputation rules to challenge the robustness of their trial results. A trial result that is robust to various means of imputation has more credibility than a trial result that depends on the means of missing data imputation. PRESENTATION OF TRIAL RESULTS An increasing number of journals require the presentation of trial results following consensus guidelines, such as the Consolidated Standards of Reporting Trials (CONSORT) guidelines,20 to increase the comprehensibility and to maximize information. Such guidelines require the exact presentation of the randomization process, a description of blinding, and eligibility criteria (about inclusion and exclusion). An appropriate trial report should include exact information about the fate of all patients after randomization, including the major reasons for withdrawal. It is essential that the total numbers of patients per group can be reconstructed. Increasingly, such information is provided in a flow chart. The initial part of data analysis is to examine the baseline characteristics of the trial groups, including demographics, previous and current treatments, and disease characteristics (e.g., severity scales, duration, extent of organ involvement) with descriptive statistics. Occasionally, baseline characteristics per group are statistically compared, and baseline similarity is assumed if no statistically significant differences between groups could be shown. Such an approach is useless and sometimes overtly false. Groups are similar by definition because they were formed by randomization. Randomization is a probabilistic procedure, and groups may statistically differ in one or more variables at baseline just by chance. Often, such differences are small in relation to the treatment effect, or the particular baseline characteristic is not associated with the measured outcome and is not contributory. Rarely, baseline differences are not negligible, and the trial result should be adjusted for these differences by multivariate analysis (e.g., regression analysis or analysis of covariance). A particular problem may occur in small trials, if even clinically important differences at baseline are not statistically significant, whereas their impact on the treatment effect may be substantial. A general rule is to “eyeball” baseline differences, and to adjust in the statistical analysis for variables that show potentially important differences. Descriptive Analysis Simple descriptive analysis includes the presentation of means and standard deviations in the case of a normal (parametric) distribution of continuous data (e.g., DAS),

or medians and key percentiles in the case of an abnormal distribution of continuous data (e.g., Sharp scores). Dichotomous data (e.g., ACR20 responses) are presented as proportions or rates, and ordinal/nominal or categorized data are presented as percentages per category. Graphic representations (e.g., line or bar graphs) are preferred because they give the clearest representation of the treatment effect. An illustrative example of visual presentation of data is the use of probability plots for radiographic data.21 The emphasis should be on the primary outcome variable, but all measured outcome variables should be presented. It is recommended to present data such that they can be used post-hoc for systematic reviews or meta-analysis. Status scores plus a measure of variability (e.g., mean DAS at baseline and at follow-up and standard deviations) and change scores plus a measure of variability (e.g., mean change score and standard deviation of change score) should be presented for primary and secondary outcome variables. Dichotomous outcome variables (e.g., ACR20 response criteria) should be accompanied by extensive information about the status values of (separate) variables. It is relevant to present not only response measures (e.g., ACR20), but also state measures (e.g., absolute DAS) because the combination of both gives additional information and increases the interpretability of trial results. A useful extension of state measures is the concept of patient-acceptable symptom state. The patient-acceptable symptom state reflects the level of symptom severity that best discriminates an acceptable situation from an unacceptable situation from the perspective of the patient.22 Patient-acceptable symptom state levels can be determined by different methodologies and are presented as proportions or rates. Statistical Analysis Because the process of randomization provides prognostic similarity at baseline, the statistical analysis of a clinical trial is simple, as long as one assumes that prognostic similarity is preserved during the trial. The statistical test of choice is a test for binomial data (e.g., χ2 test) if the outcome measure of choice is dichotomous (e.g., ACR20, ASAS20 response criteria), and a test for continuous data (e.g., Student t test or Mann-Whitney U test) if the outcome measure is continuous. An extension of the statistical test that provides useful information to increase interpretability is the 95% confidence interval of the treatment effect. The 95% confidence interval can be calculated for the treatment effect measured by continuous and dichotomous outcome variables. It provides the range within which the estimate of the treatment effect would lie in 95% of the cases in the imaginary situation that this trial would be repeated numerous times. If the lower limit of the 95% confidence interval of the mean treatment effect in a trial comparing drug A and drug B does not cross zero, this means that 95 out of 100 times that this trial is repeated, drug A is better than drug B, but 5 out of 100 times, drug A is not better than drug B. The formulation of the 95% confidence interval closely resembles that of the P value.

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STATISTICAL SIGNIFICANCE AND CLINICAL RELEVANCE Clinical trials can be designed in such a way that even very small treatment effects can be statistically shown. Explanatory trials in which new drugs are tested are often performed in a highly selected population of patients with strong adherence to the protocol, without comorbidity, and a high probability of responding. Sometimes, sample sizes are huge (“overpowered”). Such trials aim at a high level of internal validity and a low probability of type II error, but it is difficult to interpret the results in the clinical situation immediately because the mean treatment effect can be so small that it is considered irrelevant in the context of clinical practice, and patients in the trial often do not resemble the individual patients in practice (external validity). There are several guides to evaluate the quality of a clinical trial.23 A trial may show a small improvement in a primary outcome criterion that is statistically significant, but the effect may not have clinical importance because it is insufficient to affect quality of life or survival, or it does not outweigh the risk or cost of treatment. A result may be statistically and clinically significant, but have little medical relevance because the benefit does not outweigh the risk or cost of treatment, or because the benefit is seen only in a very small subgroup of patients. CONFOUNDING Confounding is a type of bias (systematic error) that can occur in a trial when the trial groups differ with respect to a particular factor other than trial treatment (prognostic dissimilarity). If this factor also is related to the outcome measure of interest, a fake treatment effect may emerge that would erroneously be attributed to the difference in treatment (confounding). As long as confounding factors are known, measurable and measured, one can adjust for them in the statistical analysis. If such variables that are referred to as prognostically important are not measured and even unknown, adjustment is impossible, however. The likelihood of confounding is far higher in observational studies than in randomized trials, and we use an example from an observational study to clarify. If in an observational database the efficacy of the disease-modifying antirheumatic drug sulfasalazine in the treatment of RA is compared with the efficacy of methotrexate, and it is common practice to give sulfasalazine treatment primarily to patients with less severe disease (rheumatoid factor–negative RA) and methotrexate to patients with more severe disease (rheumatoid factor–positive RA), radiographic progression may be less in patients treated with sulfasalazine than with methotrexate. It is difficult to determine whether this difference is due to differences in efficacy between sulfasalazine and methotrexate or to differences in severity of the RA that also may drive radiographic progression (prognostic dissimilarity). Variables such as rheumatoid factor in this example may confound the relationship between treatment and outcome (radiographic progression). In this example, with a well-known confounder, the analysis may adjust for differences in rheumatoid factor positivity. In theory, many unknown variables, or known but unmeasured variables, also can cause prognostic dissimilarity.

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We have mentioned previously that treatment groups in an RCT are prognostically similar only at baseline, and that prognostic similarity can be lost during follow-up. Consequently, confounding is possible in RCTs, and trial results should be judged in light of this possibility. INTERPRETATION OF SAFETY ANALYSES Safety is crucial in the consideration of whether or not a new drug or treatment should be approved. A detailed description of the process of drug approval is beyond the scope of this chapter, but there are a few methodologically important issues with regard to the interpretation of safety data in clinical trials. Usually, clinical trials aim at showing efficacy of a drug or treatment. Many relevant adverse events occur in a low frequency or (far) beyond the duration of the trial. Consequently, the probability that such a relevant adverse event would occur within the context and time frame of the clinical trial is low, and the interpretation of safety results of a clinical trial does not exclude important adverse events. Such information should be obtained from long-term observational studies or drug registries. CONCLUSIONS The descriptive and statistical analysis of clinical trial data is not an extremely challenging task and should follow the straightforward protocol imposed by the trial design. Universal guidelines are published to guide the investigator, and these guidelines are increasingly warranted by medical journals. The interpretation of the trial results is not always easy and straightforward, however. We have mentioned numerous disturbing factors that may jeopardize the interpretation of the trial results, such as missing data, dropout, and confounding, and the investigators and the readers of medical journals should be challenged to interpret the results of the trial in the light of these potentially disturbing factors.

SUMMARY Clinical trials are used to test the efficacy of new drugs and devices and to compare efficacy and safety of combinations of drugs. New drug development is a long and expensive process. The choice of clinical trial design and implementation is crucial for safe, efficient, and successful drug development. Because the cost of clinical trials for new drug development has increased substantially, research leading to regulatory approval of new treatments is done primarily by the pharmaceutical industry in multicenter clinical trials. Such trials usually are explanatory in nature, with internal validity prevailing over external validity. It is widely recognized in medical science that investigator-initiated clinical trials are crucial in studies addressing the effects of combinations of standard drugs, or standard drugs in combination with new treatments, and in the initial studies of the effects of newly approved drugs for other indications. Such trials are often more pragmatic in nature and have a higher level of external validity (generalizability). Important contributions in the field of investigator-initiated pragmatic RCTs have been published in the rheumatologic literature.24-26 It will be a considerable challenge to fund such trials in the

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future, and this may be an opportunity for collaborations between academic clinical scientists and pharmaceutical industry workers. The clinical trial is not the only type of clinical research study. An important drawback of clinical trials is that the duration is short, and as a result they have to rely on intermediate or process measures for outcomes, rather than the “hard” outcomes themselves. Longitudinal practice-based observational studies may fill in a gap in that they provide important information about the effects of a new treatment when used in diverse groups of patients; about drug toxicity; and about the long-term effects of a treatment on functional status, morbidity, and mortality. They may provide a wealth of information about the relationship between process or surrogate measures and “true” outcome measures. They also may provide useful information about prognostic factors for a certain outcome. A general judgment about the effectiveness of a particular treatment is in the end a compilation of impressions obtained from various sources, including explanatory drug registration trials, pragmatic trials better meeting the need of clinicians, and observational studies with a focus on true outcome and long-term safety. REFERENCES   1. Armitage P: Attitudes in clinical trials. Stat Med 17:2675-2683, 1998.   2. MacRae KD: Pragmatic versus explanatory trials. Int J Technol Assess Health Care 5:333-339, 1989.   3. McMahon AD: Study control, violators, inclusion criteria and defining explanatory and pragmatic trials. Stat Med 21:1365-1376, 2002.   4. D’Agostino RB Sr, Campbell M, Greenhouse J: Non-inferiority trials: Continued advancements in concepts and methodology (special papers for the 25th Anniversary of Statistics in Medicine 25[7]). Stat Med 25:1097-1099, 2006.   5. D’Agostino RB Sr, Massaro JM, Sullivan LM: Non-inferiority trials: Design concepts and issues—the encounters of academic consultants in statistics. Stat Med 22:169-186, 2003.   6. Fries JF, Hochberg MC, Medsger TA Jr, et al: Criteria for rheumatic disease: Different types and different functions. The American College of Rheumatology Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 37:454-462, 1994.   7. Prout TE: The ethics of informed consent. Control Clin Trials 1: 429-434, 1981.   8. Boers M, Brooks P, Strand CV, et al: The OMERACT filter for Outcome Measures in Rheumatology. J Rheumatol 25:198-199, 1998 (editorial).   9. Bombardier C, Tugwell P: A methodological framework to develop and select indices for clinical trials: Statistical and judgmental approaches. J Rheumatol 9:753-757, 1982. 10. van der Heijde DM, van’t Hof M, van Riel PL, et al: Development of a disease activity score based on judgment in clinical practice by rheumatologists. J Rheumatol 20:579-581, 1993.

11. Felson DT, Anderson JJ, Boers M, et al: Preliminary definition of improvement in rheumatoid arthritis. American College of Rheumatology. Arthritis Rheum 38:727-735, 1995. 12. Felson DT, Anderson JJ, Boers M, et al: The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. The Committee on Outcome Measures in Rheumatoid Arthritis Clinical Trials. Arthritis Rheum 36:729-740, 1993. 13. Felson DT, Anderson JJ, Lange ML, et al: Should improvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent? Arthritis Rheum 41:1564-1570, 1998. 14. van Riel PL, van Gestel AM, van de Putte LB: Development and validation of response criteria in rheumatoid arthritis: Steps towards an international consensus on prognostic markers. Br J Rheumatol 35(Suppl 2):4-7, 1996. 15. Anderson JJ, Baron G, van der Heijde D, et al: Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis. Arthritis Rheum 44:1876-1886, 2001. 16. World Medical Association: World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. Available at: www.wma.net/e/policy/b3.htm. Accessed October 8, 2007. 17. Macklin R: After Helsinki: Unresolved issues in international research. Kennedy Inst Ethics J 11:17-36, 2001. 18. Carlson RV, Boyd KM, Webb DJ: The revision of the Declaration of Helsinki: Past, present and future. Br J Clin Pharmacol 57:695-713, 2004. 19. Cannon CP, Curtis SP, Bolognese JA, et al: Clinical trial design and patient demographics of the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) Study Program: Cardiovascular outcomes with etoricoxib versus diclofenac in patients with osteoarthritis and rheumatoid arthritis. Am Heart J 152:237-245, 2006. 20. Begg C, Cho M, Eastwood S, et al: Improving the quality of reporting of randomized controlled trials—the CONSORT statement. JAMA 276:637-639, 1996. 21. Landewe R, van der Heijde D: Radiographic progression depicted by probability plots: Presenting data with optimal use of individual values. Arthritis Rheum 50:699-706, 2004. 22. Tubach F, Ravaud P, Baron G, et al: Evaluation of clinically relevant states in patient reported outcomes in knee and hip osteoarthritis: The patient acceptable symptom state. Ann Rheum Dis 64:34-37, 2005. 23. DerSimonian R, Charette LJ, McPeek B, et al: Reporting on methods in clinical trials. N Engl J Med 306:1332-1337, 1982. 24. Boers M, Verhoeven AC, Markusse HM, et al: Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 350:309-318, 1997. 25. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al: Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): A randomized, controlled trial. Arthritis Rheum 52:3381-3390, 2005. 26. Grigor C, Capell H, Stirling A, et al: Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): A single-blind randomised controlled trial. Lancet 364:263-269, 2004.

31

Assessment of Health Outcomes Dorcas Eleanor Beaton  •  Maarten Boers  •  Peter Tugwell

KEY POINTS Any single health outcome can give only a partial view of the impact of a disease on a patient. Core sets are minimal, but not exclusive, domains of outcomes agreed on by professional groups as important to include in studies; they are available for several rheumatologic conditions. Defining measurement need is key to the choice of the right instrument. Choosing an instrument follows a step-by-step process—looking for evidence of practical aspects of using the instruments and statistical properties. If an instrument lacks evidence of a certain property, a study can be conducted to create the evidence, rather than abandon the instrument.

In an era of rising health care costs, increased choice, and greater provider accountability,1 health outcome ­ measures have become essential tools for researchers, ­clinicians, and funding bodies. By definition, outcomes refer to “all possible effects of a disease or intervention.”2 Outcomes cover a spectrum of the burden of arthritis on a patient from biomarkers of disease to subjective appraisals of overall well-being. Other chapters refer to some of the most common measures of health and disease encountered in rheumatology, including the Disease Activity Scale (DAS, DAS28),3 the Health Assessment Questionnaire (HAQ),4 and the SF-36 (short form, 36 items).5 Using any one of these health outcome assessments is like looking out a window in a house, with the burden of arthritis the landscape outside. Each window in the house provides a view of the outside world, but it is a specific view defined by the size of the window and the side of the house it is on. Another window may offer a slightly better angle on what you would like to see. Different health outcome assessments can have a degree of overlap in their views, in which case an informed choice needs to be made between them, whereas others can hold quite distinct views. One assessment might be useful to compare the burden of arthritis against the general population, another might be useful to assess differences in the prevalence in different subgroups, and yet another might be useful to measure the specific benefits of an arthritis intervention. This chapter focuses on describing the different windows clinicians have on the burden of arthritis and how they relate to each other. A framework is provided for ensuring that a selected measure is the right one for a given need. This chapter addresses four questions: (1) What health outcome assessment tools are available generally and ­specifically for

use in rheumatology? (2) How do the different assessment tools relate to one another? (3) How does one characterize what one needs to measure? (4) How does one find a measure that can meet that need?

WHAT HEALTH OUTCOME ASSESSMENT TOOLS ARE AVAILABLE? In reading the rheumatology literature, and in monitoring the clinical care of patients, certain highly relevant outcomes emerge. A group of these often emerge and are termed core sets of outcomes. DISEASE-SPECIFIC MEASURES—THE CORE SETS Core sets are the minimal, but not exclusive, set of domains to be measured in a study of arthritis. Historically, they follow the Ds of outcome measurement in arthritis: disability, disease activity, damage, discomfort, dissatisfaction, and death.6,7 They are usually recommended by groups such as OMERACT, EULAR, ILAR, or ACR or groups formed around specific diseases, such as ASAS for ankylosing spondylitis or GRAPPA for psoriatic arthritis. All core sets have a great interest in agreeing on a common set of relevant and psychometrically sound outcomes that would allow them to compare findings across studies and of clinical care. Table 31-1 presents the list of core sets for clinical trials in six types of arthritis7-16; it also shows what each group recommends as additional domains or as needing more research before they become core set members. The first column on the left of Table 31-1 is the core set for longitudinal observational studies in rheumatology by Wolfe and colleagues7 with some minor additions. Wolfe’s core set is broader than the core sets presented in other columns because observational studies are often looking for a broader range of outcomes that are relevant for studies outside of treatment trials. It also is designed to be used across different forms of arthritis. The table also uses this broader list of outcomes as an axis against which the other core sets can be described. The remaining columns show that across different types of arthritis, the core sets have many common elements; most contain or recommend pain, physical function, patient and clinician global assessments, and markers of inflammation. Many also include disease activity indices, which are often an aggregation across other clinical findings (e.g., joint count, acute-phase reactants, global ratings of severity) into a score reflecting the activity of the disease at that point in time. Some core sets contain domains reflecting the unique aspects of the disease (e.g., spinal mobility in ankylosing spondylitis)17 or the unique target of the study using the outcomes (fractures are core outcomes only in osteoporosis studies focused on fracture prevention).18 463

R

R

✓ >1 yr

✓ ✓ ✓

✓

✓ 28 or 68 joints

✓ (EULAR DAS)

✓ Disability R

R(†)

✓

R (BL)/ ✓ (†) fractures R (BL)/ ✓ (†) Change height

✓ Bone mineral density

✓ Biochemical

R(†)

R (BL)(†) R (back)(†)

✓ >1 yr

✓ R O

O

O

✓

R ✓ Pain

Osteoarthritis13

R R

✓

✓ Damage index

R

✓ DAI, R = severity

R R

✓ R (fatigue)

Systemic Lupus Erythematosus14,19

✓ Spine and hip§

✓‡

✓ Spinal stiffness ✓ Spinal mobility ✓

✓ Peripheral (44 joints) Enthesitis‡

Pending

✓

✓Pain ✓ Fatigue

Ankylosing Spondylitis8

✓

✓Skin disease

✓ Structural

✓ ✓ ✓

✓

✓ DAS

✓

✓ ✓ Pain

Psoriatic Arthritis10,12

*The left-hand column is the broader set of measures recommended by Wolfe and colleagues7 for longitudinal studies. It serves here as a broader range of outcomes, and an axis for the organization of core outcomes in the other conditions (columns). ✓, core domain; R, recommended for further research and possible inclusion in core set; O, optional outcome (osteoarthritis category only). Osteoporosis: Core set depends on focus: BL, bone loss studies; †, studies aiming to reduce fracture rates. Ankylosing spondylitis: Core set elements vary depending on focus of study: ‡, clinical records and symptom modifying; §, disease modifying only; others = all. DAI, disease activity index; EULAR DAS, European League Against Rheumatism Disease Activity Scale (revised = DAS-28, 28-joint count).

Dollar costs [R] Work disability [R]

Death ✓

Disadvantages Toxicity effects ✓

Damage ✓ Radiography or imaging Deformity Surgery Organ damage

Disease process ✓ Aggregate index Biomarkers Joint tenderness Enthesitis Joint swelling Joint stiffness Global Patient Physician Acute-phase reactants

Physical function Psychosocial

R (utility) ✓ Pain

Health status/quality of life ✓ Quality of life Symptoms

Osteoporosis11

Clinical Trial Core Sets of Domains by Disease Group

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Rheumatoid Arthritis15,16

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Longitudinal Study Core Set of Domains7

Table 31-1  Core Sets for Six Rheumatologic Conditions and for Longitudinal Observational Studies*

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Table 31-1 focuses on the core domains that should be measured; the next step is deciding on the instrument that is able to provide that well in a reproducible, accurate manner. In some cases, an instrument choice has been suggested (e.g., the HAQ for disability in rheumatoid arthritis). Other times several options are provided. Strand and coworkers19 reviewed six disease activity indices in systemic lupus erythematosus and found they gave comparable results. In some cases, the domains are shared, but the measurement technique varies within or by disease; in rheumatoid arthritis, the DAS28 uses 28 joints,3 and in ankylosing spondylitis, 44 joints are counted.17 Some of the more commonly encountered instruments in arthritis are briefly reviewed. Health Status/Quality of Life General Health Status. Generic health outcomes provide information on an aspect of health across many conditions so that theoretically comparisons can be made to compare the burden of low back pain with that of arthritis or diabetes. This comparison depends on the ability of that measure to capture the burden in a disease group well. Generic measures have advantages of allowing comparisons across diseases and covering a broader range of health issues—things that may have been overlooked in a core set (e.g., mental health issues). Often because of their breadth, however, the generic measures tend not to delve as well into the depth of experience in any one disease. Arthritis-related fatigue is not detected well in many generic measures because a generic measure asks about being tired or not sleeping well. Because of this, a generic measure is usually weaker in its ability to detect specific changes and their sensitivity to different levels of disease activity and should usually be supplemented with disease-specific measures (described previously).20 Two commonly used generic measures are the Sickness Impact Profile (SIP)21 and the SF-36.22 The SIP is a 136item list of illness behaviors that provides a weighted score for the impact of a disease across 12 categories, such as bodily pain, work and role functioning, and dressing,21 which lead to global scores (physical, psychosocial, and overall). The SIP has been shown to measure illness across a wide variety of health conditions.20 The SF-36 is a 36-item questionnaire of which 35 items are used to obtain eight domain scores (including physical functioning, mental health, role functioning, and pain) scored on a 0-to-100 scale (with 100 = better health)22 and two summary scores (mental and physical); the questionnaire is scored with normal of 50 and standard deviation of 10. The SF-36 and briefer SF-12 are well supported on the website (www.qualitymetric.com) and through manuals that supply age and disease group distributions of scores.23 Direct comparisons of generic measures have shown differences in scores and health states attributable to the choice of measure.24-26 Studies or clinical results may not be comparable to each other if they are using different health status scales. Utilities—Value of Health State. Utility scales offer an overall score for the value of a health state, setting death at 0 and full health at 1. The emphasis is not on describing the state, but on assigning a value, worth, or preference to that state.27,28 Utilities are needed for economic appraisals and form the health assessment for cost per quality-adjusted

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life-years estimations. Utility states can be obtained by direct or indirect methods. Direct methods, such as standard gamble and time tradeoff, involve the respondent working through exercises to elicit the value for his or her own health state against things such as time or more or less favorable health situations.27 Indirect methods capture the state with standardized questions and apply predetermined weights.28 Examples include the EQ-5D which is five items (three response categories) combined to describe a health state. Similarly, the Health Utility Index gathers information on six or seven dimensions of health (depending on the version) on five-item to six-item response scales to define a health state.28 Both these scales then use weights determined in different populations to assign the value to these health states—hence the “indirect” weighting. The absolute value obtained across these different approaches varies.27 Generic measures of health and utility scores are very broad. They often do not perform as well as the more specific measures described in the following sections because they are designed to allow comparisons across populations and need to include items that might not be relevant in arthritis. In some areas, there are measures of quality of life that are designed for that disease, such as rheumatoid arthritis or osteoporosis, which offer a measure of the broad concept of quality of life in a disease-specific manner. Such measures would not allow comparisons across diseases. At the time of this writing, these were not yet recommended as core instruments. Symptoms. Pain is usually measured using a 10-cm visual analog scale or a 0-to-10 numeric rating scale of the intensity of the symptoms.29 This simple measure has been well tested and is easily understood by patients. Fatigue is another important symptom and quite distinct from being “tired.” The ankylosing spondylitis modified core set contains fatigue, and it is a recommended area of further research in rheumatoid arthritis and lupus. Measures are being tested or developed at present. Ankylosing spondylitis is currently using the 10-cm visual analog scale of fatigue from the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).30 Disability Scales. Physical disability in rheumatoid arthritis and osteoarthritis is often measured using the Health Assessment Questionnaire–Disability Index (HAQ-DI),31 which covers 20 items looking at different aspects of daily functioning. Patients score each item on a 0-to-3 scale, where 3 represents the greatest disability. Scores are obtained for each domain and summed into a total score expressed on the same 0-to-3 scale. Scores are adjusted to a 2/3 if an aid is used to ­complete a task. More details on the HAQ-DI are widely available in print and on the Internet. There are other scales asking about physical function such as the Arthritis Impact Measurement Scale (AIMS)32 and the AIMS233 and measures with even more specific foci, such as the Western Ontario McMaster (WOMAC) osteoarthritis index, which is commonly used in hip and knee osteoarthritis,34 and the AUSCAN osteoarthritis index for hand osteoarthritis.35 Disease Process (Activity, Severity) Core sets often include indices of disease process. Disease process can be divided into activity (inflammatory activity) and severity (overall severity of disease). There are several

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disease activity indices, the most commonly known being the DAS36 and DAS283 in rheumatoid arthritis. Using a subset of the core outcomes (i.e., acute-phase reactants, joint counts, global ratings), the EULAR group formulated a weighted index that provides a score of 2 to 10 (DAS) or 0 to 9 (DAS28). From this, cutoffs were established to define high, moderate, and low disease states. The low disease state (DAS28 <2.6) is considered an indicator of remission of arthritis and is touched on again later. More recently, the concept of “stable remission” has been proposed; it is defined as an initial DAS28 of less than 3.2 and a lack of change in DAS over time of 1.2 (2 standard errors).37 Disease activity indices track the level of inflammatory activity. There are others, such as the BASDAI30 or the six available in systemic lupus erythematosus.19 When more than one is available, look for direct comparisons such as Strand’s to see if similar information is provided.19,38 Damage Indices A great deal of work has gone into measures of joint damage in arthritis. van der Heijde and Landewe17 provide a succinct summary of the Sharp, van der Heijde, and Larsen/Scott techniques. Guidelines should be followed closely, focusing on the hands and feet. Changes in radiographic progression of joint damage often are measured by the smallest detectable difference, the boundary between measurement error (day-to-day variability) and change discernible from error.39,40

outcome. Similarly, Tugwell’s “effective consumer” captures the degree to which the patient is effectively managing his or her own health care decisions, interactions with the health care team, and disease monitoring.44 This may be a reasonable target for self-help interventions. EMERGING DOMAINS Work Productivity and Disability With the shift toward more aggressive management of earlier disease, more people with arthritis are working, and outcomes need to shift to track work disability (absenteeism and at-work productivity loss).7 Work is hard to measure because it depends on the job and the organization the individual works in. Absenteeism can mean many things, and measures should articulate how this was operationalized—full days off work, days on insurance payments, or full and part days off work. More challenging still is measuring the difficulty someone is having at work (presenteeism). There are several measures—16 were found in a more recent review45—but there are few direct comparisons of these conceptually diverse instruments. The most commonly used is the work limitations questionnaire (amount of time experiencing difficulty).46 Two scales developed in arthritis are promising—Gignac’s Work Activity Limitations Scale (amount of difficulty experienced)47 and Gillworth’s Work Instability Scale (risk of future work loss).48 Direct comparisons of these measures are under way.

Disadvantages—Toxicity/Adverse Events Medical and nonmedical management of many rheumatic conditions carries a risk of toxicity and adverse events,41 many of them unexpected. A comprehensive documentation of a range of adverse events is important in outcome assessments separate from the treatment benefits.42 An OMERACT group is currently working on standardizing reporting of toxicities in rheumatologic trials.43

Nonpaid Work Participation in valued nonpaid roles, such as parenting, volunteer work, or leisure activities, can be an important aspect of the burden of disease.49 Outcome measures reflecting this are needed to capture fully the concept of participation. Patient-Specific Domains

Death Arthritis is associated with increased mortality, and arthritisspecific mortality should be monitored. Death is not specifically mentioned in the disease-specific core sets for clinical trials, but would be important to monitor in observational studies. Attributing death to arthritis is challenging given its dependence on documentation at time of occurrence, which may or may not be linked to underlying arthritis in the coding. Dollar Costs The economic burden of arthritis and the cost of care are core outcomes for psoratic arthritis and recommended for consideration in observational studies and rheumatoid arthritis, osteoporosis, and lupus disease groups. Standards for what should be included in a cost analysis are under development. Disease Self-Management Lorig’s work in self-management programs often have focused on improving self-efficacy, which has been found to reduce pain and health care use.25 Self-efficacy is a health

Patient-specific scales, including the MACTAR or PET in arthritis,50,51 allow the patient to nominate his or her own scale content, within a guided framework. Most patients report three to five items that are particularly salient to them. A surprising number of these scales have been developed.52 Each taps relevant content for that patient, and because of this they also are responsive to change.53 The challenge is in the mathematics and how to analyze the numeric score when the items vary across patients. Analysis that focuses on individual level quantification is likely best. Satisfaction with Health Outcomes Satisfaction scales are often linked with the goals of a health care organization and focus on the attributes of the structure and process of care. Instruments developed to look at satisfaction with a specific health end point (e.g., how satisfied are you with the results of your surgery)54 become a health outcome. Satisfaction with outcome is complex, and Hudak and colleagues55 point out the complex balance of experiences and ability to “live with” ongoing limitations that influence a patient’s response.

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Health condition (disorder/disease)

Sleep The OMERACT patient group has identified sleep quality as an important domain for outcome assessment. The concept and measurement of it are expected to be addressed at the upcoming OMERACT 9 meeting in 2008.

HOW DO OUTCOME MEASURES RELATE TO ONE ANOTHER? With an array of potential measures, or windows to view the burden of disease, how does one organize them to get an accurate picture of the whole? Conceptual frameworks help one to understand how domains, such as those described previously, theoretically relate to one another when applied in research or clinical practice. They also usually provide an operational definition of each of their domains, which becomes essential when choosing between instruments or deciding how to model the outcome of an intervention and its modifying factors.56,57 Conceptual frameworks facilitate accurate communication and the generation of hypotheses of understanding of a disease process and impact. In the past, the most common conceptual framework was the main (sometimes causal) pathway of a biomedical model: Pathology leads to organ/system changes leads to pain/symptoms leads to functional loss leads to diminished quality of life. This is similar to a Wilson and Cleary model58 and might help in understanding that function and quality of life might relate more closely than sedimentation rate and quality of life—based on their proximity and distance in the model. Expanding on this type of model are conceptual frameworks such as Nagi59 or Verbrugge’s60 disablement process. In these models, there is a main pathway, with slightly different definitions, but there also are boxes of influence from outside this pathway—the patient’s personal factors and environmental factors. In 2001, the World Health Organization ratified the International Classification of Functioning (ICF),61 which offers an even more expanded framework based on a biopsychosocial understanding of disease. It is receiving wide endorsement in arthritis.56,62 In this model (Fig. 31-1), there are three main elements of burden. A disease can affect an individual by impairment (body part), activity limitations (individual’s ability to do a task), or participation restriction (restrictions in the execution of the individual’s roles in life situations). The boxes in Figure 31-1 are joined by bidirectional arrows because this model suggests that the right-side boxes also could influence the left with secondary problems (e.g., joint contractures or wounds secondary to prolonged bed rest). For the ICF, disablement is not a linear progression; it is a dynamic interaction influenced by several factors.57 The ICF strongly emphasizes the influence of personal factors and environmental factors on all three domains. Several initiatives are under way to examine the fit and usefulness of the ICF framework in various forms of arthritis.57,63,64 Readers are referred to Jette and Keysor65 for an excellent comparison of the ICF and Verbrugge models in the context of arthritis. In addition to providing the conceptual framework, the ICF undertook the task of a classification system listing

467

Body function and structure

Environmental factors

Activities

Participation

Personal factors

Figure 31-1  The International Classification of Functioning conceptual framework showing the hypothesized relationships between domains of impairment, activity limitations, and participation restrictions.

all possible categories of impact falling under each of the five main headings. Many groups, particularly in arthritis, have reviewed the categories and developed a list of the categories relevant to that form of arthritis. This list suggests which of these categories should be reflected in core set measures in arthritis, offering a form of standard for the content of scales.63 Frameworks define the realm of outcomes that should be considered, and the hypothetical relationships between them. They form the basis for understanding observations, testing hypotheses, or planning and executing an analysis. Shifting frameworks is challenging because different tools may vary in how they define certain aspects of health or disability. Shifts can prompt fruitful rethinking of concepts, however, and how they relate to each other.64

HOW DOES ONE CHARACTERIZE WHAT ONE NEEDS TO MEASURE? Just as investigators define a research question before embarking on a clinical trial, so should users of health outcomes define a measurement question before choosing an instrument. WHY MEASURE? Clarity about a measure’s intended purpose helps ensure the right one is selected. Measures can be used in three ways: to describe people at one point in time, to predict a future state, and to measure change over time.66,67 This chapter focuses on the purposes used for health outcome assessment: describing an end point state in a trial, which is descriptive, and evaluating change over time. WHAT TO MEASURE An understanding of concepts and definitions is important. It is not good enough to decide to measure physical function, for example; a better outcome would be physical function at the level of disability according to Verbrugge and Jette.60 Similarly, when measuring pain, is intensity more important than frequency? What about the degree to which

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pain interferes with daily activities? Questions such as these should be addressed before any instruments or core sets are reviewed. The instrument should meet the need, and not the reverse. WHO CONSTITUTES THE TARGET POPULATION The target population is crucial, but often overlooked. A given instrument may work well in severe osteoarthritis of the hip, but not be sensitive to the early symptoms of the disease. Equally important is to consider if one wants to measure for an individual patient or for describing a group of patients as a whole. The former demands much higher levels of measurement properties (e.g., reliability coefficients >0.90 as opposed to 0.75 to 0.80 being adequate for group descriptions).66

SELECTING THE OUTCOME THAT CAN MEET THE MEASUREMENT NEED The selection of an outcome measure depends entirely on a clear understanding of measurement need. Often a well-used instrument is used, rather than looking for one Need: Concept

Population

that matches the concept, population, and purpose. Many guidelines that offer more detail than can be described here are available, particularly for the acceptable levels of reliability and validity.66-72 This section describes a decision-making process for fit between a given instrument and the clinician’s need (Fig. 31-2). This process builds on the work of Law72 and the OMERACT filter69 and highlights key understandings in each area from the published guidelines. This decision-making process emphasizes three things. First, it begins by stating the measurement need (why, what, and in whom), which reinforces that a candidate measure meet one need, but not the next. Second, it emphasizes that a lot of the appraisal can be done without statistics. It is done by appraising the questionnaire or instrument itself and knowledge of its administration. Third, the inability to affirm each stage suggests that there is no need to continue. At the later data-based stages, the clinician may choose to run a small study to create the evidence (the “do-it” loops) in patients, rather than abandoning the instrument that seems like a good candidate. Given these three key features, the process from left to right is reviewed next. Intended purpose:

describe

evaluate change

Candidate measure: 1. Matches target concept?

Boxes marked with “do it loop” are those where you can create the evidence and continue on

No

a. One point in time (descriptive) Reliability -internal consistency -inter-rater reliability Construct validity -differentiates high/low levels -acts as expected with other indicator

3. Does it measure what it says it does? (truth)

No

Content

Face

Construct

4. Does it have purpose-specific properties in your population?

No

Choose another tool

Blue boxes = pre-data evaluation Yellow boxes = data-based evaluation

2. Feasable to use?

No

b. Change over time (evaluative) -test-retest reliability -inter-rater reliability -responsive to change that is similar to target situation

5. Is it interpretable? No

Benchmarking scores (states) Change thresholds Combinations: change and state

Good fit for your needs! Figure 31-2  Algorithm showing decision-making process for the fit of a candidate measure with your measurement need. The left-hand side of the page is done by appraising the instrument and its instructions. The right-hand side requires numeric evidence of the relevant measurement properties. Many instruments are weeded out as a poor fit in steps 1, 2, and 3. The “do-end” loop denotes stages at which you can pause to create evidence if it is missing and not have to abandon the instrument.

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STEP 1: IS THERE A MATCH BETWEEN THE INSTRUMENT’S CONCEPT AND THE MEASUREMENT NEED (CONCEPT, POPULATION, PURPOSE)? An operational definition of the target concept, the applicable populations (patients or general population), and intended purpose should be articulated by the developer and match your current need.42,68,71,73 If this is not the case, or if it is not a good match, start with another candidate measure because this one would not work.68 STEP 2: IS IT FEASIBLE TO USE? Feasibility covers the practical aspects of using this scale in the intended setting.42,69,72,73 Does it take too much time? Are the licensing costs too high? Does it require special equipment? Is it too burdensome for your patients (language, literacy, acceptability of questions)? Is it formatted well on the page, and do the responses make sense given the target and the question? Are the questions phrased in a clear and simple manner? Are the necessary scoring instructions available? A negative response to any of these questions could direct you to go to another, more feasible, instrument. Feasibility often makes or breaks a decision about a candidate measure.69 STEP 3: IS IT MEASURING WHAT IT SAYS IT IS MEASURING? (TRUTH) Does the instrument measure what it says it will measure? We divide this into three areas: content, face, and construct validity. Content validity appraises the items and domains of a scale. Have the authors covered what McHorney and Tarlov66 call the breadth and the depth of the concept, that is, all the important areas, but also enough depth to capture the range of experience of the patients? Face validity is an appraisal of the general direction of the scale—will it hit the target? Are the response options organized in a logical direction for high and low levels of this attribute? Does the scoring make sense? The stage of construct validity is the dividing point in the decision process between data-free and data-based appraisal. Up until now, the appraisal is done by looking at the instrument and its manuals. In construct validity, we begin to explore data to see if the numeric scores arising from the instrument make sense. Basic construct validity should be established regardless of the purpose. Sometimes it is de-emphasized in evaluative instruments; however, responsiveness without knowing if the instrument is measuring the target seems misplaced. We place it before the purpose-specific properties to emphasize its need as a basis. Construct validity is generally measured by comparisons with other similar scales or related constructs (i.e., high and low levels of pain and function) to see if the numeric scores are behaving in the way they should if this were a valid measure of the target concept. Theoretic situations are set up before analysis, the direction and magnitude of the expected relationship are declared, and then the relationship is tested.68,73 Comparisons also should be made between groups known to differ (high versus low severity) or with scales where no

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relationship is found—again based on an a priori theory—to see if the candidate measure behaves according to the theory. These add to the evidence that the instrument is measuring what it is supposed to measure.68 If the evidence is unavailable or is not in the intended population, you have a choice of abandoning the measure or doing a study to create that evidence and then continuing to advance. STEP 4: PURPOSE-SPECIFIC EVIDENCE IN YOUR POPULATION After getting a general sense of the construct validity of the instrument, the next step is to address the specific attributes needed for the instrument to function to meet your measurement need (discrimination component of the OMERACT filter).69 More attention is now paid to the intended purpose and the intended population and the properties of consistency in measurement (reliability—obtaining the same score in different settings) and additional validity (cross-sectional again or responsiveness or sensitivity to change). Descriptive Purpose Descriptive outcomes often are used to classify individuals as to severity of condition or to identify them by a prognostic group. In health outcome assessment, descriptive instruments are needed to classify individuals as responders or as being in a low disease activity state or remission. An instrument needs to be precise, that is, the observed score is very close to the true score with low error. This is estimated by the internal consistency of a multi-item scale or questionnaire and Cronbach alpha coefficients or Kuder Richardson 20 if the scale is dichotomous (yes/no). Internal consistency is a feature of a scale with many items measuring the same thing—are the responses similar across items within the instrument? It is not a feature of a scale containing weighted sums of different attributes, such as disease activity measures.37 If more than one person will be gathering the data, interrater/observer reliability should be measured and quantified with an intraclass correlation coefficient (ICC) for continuous measures or a weighted kappa for ordered categories.74 There are different types of ICC depending on the model used for the variance estimates; the type of ICC should be named.74 The ICC and weighted kappa measure the comparability of actual numeric scores and are preferred over correlation coefficients that look only for trends and not a direct match in number values. Cutoffs are always challenging, but in general, reliability (including test-retest) should be at minimum 0.7566,73 for group level analyses, and for describing an individual patient, it should be 0.90 to 0.95.66,73 The internal consistency reliability can be converted back into the scale score by calculating the precision limits—using 95% limits, the true score lists somewhere within 1.96 × s[1 − r]1/2 where r = internal consistency and s = standard deviation. This calculation tells us the range within which the true score for an individual can be found. If it is too wide (reliability too low), it is impractical to use that instrument. Construct validity is revisited for the descriptive instrument, but with more attention to looking for evidence close

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to the intended application. If the goal is to measure high versus low health, the sample should be divided into known groups with high and low health according to another accepted opinion, and then this scale is tested against it. The image of a window can help here in selecting comparators to use for testing. What else gives a bit (or more) of overlap with the target view? How much correspondence is expected between scores? For good construct validity, this a priori hypothesized relationship should be recreated with data, whether that be a strong correlation or no correlation at all. An instrument or measure is never universally valid and requires ongoing testing to improve understanding of the scores in different situations. Evaluative Purpose In evaluative measures, the intent of the study is to focus on the amount of change over time. Many clinical trials are doing this and comparing results between treatment and control groups. Interobserver reliability is important if more than one measurer is to be involved. The hallmark of a good evaluative measure relates, however, to time: First, do the scores remain the same when the target concept has not changed over time (test-retest reliability)? Second, when the concept changes, does the score on the instrument/measure change as well? Test-retest reliability requires two administrations of the measure over a time when no change has occurred. This may be easier said than done sometimes, but the authors should justify their design and how they ensured no change had occurred. Similar to interobserver reliability, the ICC is the preferred statistic for continuous scores, and weighted kappa, its equivalent, is preferred for categorical scores. The cutoffs are the same, and a coefficient can be converted into a “minimal detectable change”75 as 1.96 × s(2[1 − r])1/2, where s = standard deviation and r = test-retest reliability (ICC).66,75 Ninety-five percent of subjects who are stable have change scores less than this value; a change greater than this is not likely to occur in a stable patient, only in a changing one. It becomes a lower boundary of meaningful change—anything below that could be day-to-day fluctuations in scores. Responsiveness—the accurate detection of change when it has occurred—is sometimes best thought of as longitudinal construct validity. Similar to construct validity, responsiveness depends on an a priori theoretic relationship—one in which the attribute is changing over time. Often the focus is on the amount of change picked up, rather than the type or amount of change that had occurred. A large change is not useful if we were expecting a small one; rather it suggests noise. The construct embedded in a study of responsiveness should be described carefully and should be a clear match with the intended application (measurement need). If the goal is to detect change in a clinical trial, it is important to assess the instrument’s ability to detect the difference in change between treatment and control groups. If the goal is to detect change in a cohort, it might be more useful to examine change in a single group perhaps in a treatment of known efficacy (hip replacement) or in subjects who rated themselves as improved on an external anchor (global index of change). Responsiveness is summarized with statistics of signal (change) over noise (error), such as the standardized response mean (mean change/standard deviation of change),

t ­statistic (mean change/standard error), and effect size (mean change over standard deviation of baseline)74; each can be adapted to quantify the relative change between treatment and control groups.53,76 Deyo and Centor77 also described the correlational approach (correlate change and another indicator of change) and the receiver operator curve approach (various change scores against external “gold standard” that the person has changed) where the area under the curve is a summary statistic.77 The numeric summaries of responsiveness, such as effect sizes or areas under the curve, should correspond to the type of change expected (a priori theory). A large effect size or area under the curve does not mean an instrument is “responsive.” It should correspond with the change anticipated in the study—small or large. Comparisons of the effect sizes are helpful if different instruments are being compared in the same study, as done by Buchbinder and colleagues53 or by Verhoeven and coworkers,76 who focused on responsiveness in early rheumatoid arthritis. Responsiveness is a highly contextualized property, and the same instrument may not be responsive in another situation (e.g., early versus late disease, osteoarthritis versus rheumatoid arthritis).73 STEP 5: INTERPRETABILITY OF SCORES The final step, often deemed the most elusive,78 is the interpretability of the scores. Benchmarking States What is the meaning of a score of 2/10 on a pain score? Is it a good outcome? The meaning of different scores on an outcome assessment is used for classifying subjects at the beginning of a trial and at the end point. To do this, comparisons are made to other known health states—­severity indices, ability to work, self-rating as mild.79 Gradually, enough trends might be seen across different scenarios to gain confidence in the meaning of “good” or “mild.”80,81 In rheumatology, we see the emergence of low disease activity states82,83 or patient acceptable symptom states84 or remission criteria with the DAS2838 as thresholds below which subjects are considered to be in an acceptable state (either tolerable symptoms or disease activity where it does not require medication changes). At this point, these thresholds are being established, and similar to change thresholds, we may find variability in the values38 that need to be sorted out with methodologic work and application in clinical practice. Changes in State The second type of interpretability concerns change scores. American College of Rheumatology Response Criteria. The American College of Rheumatology took the core set measures and determined that if one observed an X% change in joint count and in swollen joint count and in at least three other areas—erythrocyte sedimentation rate or C-reactive protein, physician global, patient global, pain, or physical disability—one had a clinical response, and the individual would be classified as a responder. The percent is usually 20%, but 50% and 70% have been considered. The ACR20 is widely used, catches responses across a wide variety of domains, and discriminates well in clinical

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trials76; however, it is currently being revalidated owing to the changing nature of rheumatoid arthritis and its care.85 Minimal Clinically Important Differences and Improvements. Defining the threshold of change above which an individual has had an “important” shift in outcome is what Kirwan78 has described as the “elusive crock of gold at the end of the rainbow.” Nevertheless, important advances have been made. There are many sources of variation in score, including the method used, the baseline severity, and the type of change to be sought.86,87 In 2000, Wells and coworkers88 described nine different methods for deriving minimal clinically important differences from the literature. Some use distributional cutoffs (½ standard deviation, or effect size of 0.2 or 0.5),89 which have been criticized as lacking any meaningful anchor. Other methods depend on some external anchor that important improvement has occurred, but are sometimes challenged by the dependence on that anchor and the perspective of the individual who determines it (patient, physician, third-party payer). Minimal clinically important differences repeatedly have been shown to vary with baseline state90,91 and with improvement versus deterioration.92 Tubach and associates93 changed the term to minimal clinically important improvement and looked only at improvement. Minimal clinically important differences vary depending on the context of measurement. You need to plan on working with a range of values,42,86,87 to make sure the measurement situation is similar to your own (severity, timing, type of intervention), and to build confidence with congruence in minimal clinically important differences from across methods if you can achieve that. Combined Approaches: Change and State An attractive, although often overlooked, option is combining change and state. In 1996, EULAR defined clinical response as a change in DAS28 score of more than 1.2 (change) plus a final DAS28 score of less than 2.4 (final state).36 Jacobson and colleagues94 did the same in defining response to psychotherapy; change greater than error was used (minimal detectable change mentioned earlier) plus a final “normal” state. Studies from the patient’s perspective have often reflected the same thing.80,81,95 Treatment needs to induce a change, but perhaps it also needs to land patients in a healthy state to make them feel better. The approaches described previously focus on interpretation at the level of the individual, perhaps for use in clinical practice or in a response-type analysis of a clinical trial or economic appraisal (% responder). Verhoeven and ­coworkers76 showed that the same instrument may not perform equally well in a responder type of analysis and a group level change. At each stage of this appraisal, there is an element of judgment. It is likely there will never be perfect evidence across all stages. The user needs to assess the potential risk of accepting less than ideal evidence or abandon the scale. Users also may create the evidence, however, by doing it themselves. An instrument that makes it through this appraisal is likely a good fit with the measurement need. Anything short of that could lead to error and be prone to misinterpretation. By working from left to right, scales that are not targeting the right concept or are impractical to use in the intended setting can be eliminated quickly before

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reviewing the literature extensively for the measurement properties. SECTION 6: AREAS OF GROWTH IN HEALTH OUTCOME ASSESSMENT Item Response Theory Users of outcomes in arthritis come across item response theory (IRT) and computer adaptive testing (CAT). These terms relate to newer methods of ordering and calibrating items on a scale so that there is equal meaning in score increments across the scale. Most of our outcomes were developed in “classic test theory” (internal consistency, summed scores without weights). There are two schools within IRT: Rasch, which fixes the parameters and assesses if items in a scale fit or do not fit that model, and IRT itself, which fits a model to the data, rather than the reverse. IRT and Rasch are often presented as conflicting schools, but they are both working toward an item calibration that allows more accuracy and precision. In the future, direct comparisons may reveal their similarities and differences in practical ways. The weights are cumbersome to apply for the clinician, but can be easily integrated into a computer-based scoring system for easy data entry and CAT. CAT chooses items based on the previous set of responses and uses the fewest number of items to reach a precise score skipping easier items if confident the subject can do the harder ones. This streamlined scoring is quite attractive, but there are some limitations. It depends on technology that may not at this time be available in every setting. It also may be influenced by differential item functioning, which means an item might change weight, or order, in certain subgroups and necessitates more complex weights. An example of differential item functioning would be putting on a pullover sweater. It is a hard task if you have shoulder pain, but pretty easy if you have a hand problem and would require a different weight. The National Institutes of Health is currently funding PROMIS (Patient Reported Outcomes Measurement Information System; available at http://www.nihpromis.org/) to develop a CAT system (currently based on a two-parameter graded response model IRT) for common chronic diseases, including arthritis.96 Several measures have been pooled into a large database and are being refined and rescaled at the time of this writing. Well-known measures, such as the HAQ, also will be used to allow for cross-calibration with the newer items. All findings will be reported on the PROMIS website, as will access to the scoring algorithms. Use of Technology in Health Outcomes Assessment In addition to enabling efforts such as PROMIS to develop CAT systems, information technology has changed many aspects of health outcome assessments. Streamlined, customized assessments can be set up on the Internet or on a stand-alone computer with interfaces such as touch screen, light pens, or “point and click.” Patients can complete the questionnaires at home, at the clinic, on their PDA, or on a tablet. Language and literacy issues can be overcome with talking screens. Scoring becomes instantaneous, and reports can be printed immediately summarizing the scored results in time for the clinical visit.97,98 ­Comparisons

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between touch screens and traditional paper and pencils are promising, and the acceptability by patients with arthritis is good.97-99 New technology means that health outcome assessment can become part of the patient­clinician ­experience and facilitate the ability of the clinician to monitor the patient’s health.97 Adaptation to an Ongoing Disease This chapter has focused on the measurement of health states and their interpretation over time. Individuals with chronic diseases adapt to ongoing disease with behavioral strategies or cognitive reframing of their situation.100 In some circles, this is adjustment95; in others, it is response shift.101 The challenge in health outcomes assessment is to tell when a state is changing only because of adaptation and not the intervention. In many situations, we try to induce adaptation, or cognitive reframing, and it can be constructive. It does create a bias in measurement,101 however, and a challenge to the health outcome assessor. Numerous groups are researching how to incorporate adaptation into health outcome assessments.

SUMMARY There is considerable room for improvement in health outcome assessment in rheumatology, despite the work done to date. A battery of instruments have been developed, many of which exhibit the measurement properties described in this chapter and meet the challenge of a changing arthritis target (less severe, earlier disease), and several more measures are being considered for membership in core sets to capture a comprehensive view of the burden of arthritis. We are on the brink of deciding on the role to be played by IRT and CAT in widespread care settings. Despite progress in assigning a numeric value to a complex health state, however, we are now struggling with the back-translation—what does the numeric score mean in the real patient world. It is not always a simple translation from questionnaire score to clinical meaning. Health outcome assessment is well advanced in arthritis care, and we should recognize the years of work and commitment of many professional and patient/consumer groups. Advances will continue in the use of technology, the breadth and depth of outcomes, and the quality of measurement to keep pace with the needs of patients, clinicians, and researchers. Acknowledgments Dorcas Beaton is supported by a New Investigators Award through the Canadian Institutes of Health Research. Peter Tugwell holds a Canada Research Chair. The authors would like to thank Ms. Taucha Inrig, Dr. Claire ­Bombardier, Dr. Fred and Mrs. Janet Krieger, Mr. William Francis, and the OMERACT executive for their help with this manuscript, and Dr. M. Ward, whose chapter in the seventh edition of Kelley’s Textbook of Rheumatology was a helpful guide.

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52. O’Boyle CA, Hofer S, Ring L: Individualized quality of life. In ­Fayers P, Hays R (eds): Assessing Quality of Life in Clinical Trials: Methods and Practice, 2nd ed. New York, Oxford University Press, 2005, pp 225-242. 53. Buchbinder R, Bombardier C, Yeung M, et al: Which outcome measures should be used in rheumatoid arthritis clinical trials? Arthritis Rheum 38:1568-1580, 1995. 54. Solomon DH, Bates DW, Horsky J, et al: Development and validation of a patient satisfaction scale for musculoskeletal care. Arthritis Care Res 12:96-100, 1999. 55. Hudak PL, McKeever PD, Wright JG: Understanding the meaning of satisfaction with treatment outcome. Med Care 42:718-725, 2004. 56. Jette AM, Haley SM: Contemporary measurement technique for rehabilitation outcome assessment. J Rehabil 37:339-345, 2005. 57. Jette AM, Keysor JJ: Disability models: Implications for arthritis exercise and physical activity interventions. Arthritis Care Res 49: 114-120, 2003. 58. Wilson IB, Cleary PD: Linking clinical variables with health-related quality of life: A conceptual model of patient outcomes. JAMA 273:59-65, 1995. 59. Nagi SZ: A study in the evaluation of disability and rehabilitation potential. Am J Public Health 54:1568-1579, 1964. 60. Verbrugge LM, Jette AM: The disablement process. Soc Sci Med 38:1-14, 1994. 61. World Health Organization: International Classification of Functioning, Disability and Health. Geneva, World Health Organization, 2001. 62. Arts DGT, Keizer NF, Scheffer G: Defining and improving data quality in medical registries: A literature review, case study and generic framework. J Am Med Inform Assoc 9:600-611, 2002. 63. Stucki G, Boonen A, Tugwell P, et al: The World Health Organisation International Classification of Functioning, Disability and Health (ICF): A conceptual model and interface for the OMERACT process. J Rheumatol 34(3):600-606, 2007. 64. Jette AM: Toward a common language for function, disability and health. Phys Ther 86:726-734, 2006. 65. Jette AM, Keysor JJ: Uses of evidence in disability outcomes and effectiveness research. Milbank Q 80:325-345, 2002. 66. McHorneyCA, Tarlov AR: Individual patient monitoring in clinical practice: Are available health status surveys adequate? Qual Life Res 4:293, 1995. 67. Lohr KN, Aaronson NK, Alonso J, et al: Evaluating quality-of-life and health status instruments: Development of scientific review criteria. Clin Therap 18:979-992, 1996. 68. McDowell I, Jenkinson C: Development standards for health measures. J Health Serv Res Policy 1:238-246, 1996. 69. Boers M, Brooks P, Strand V, et al: The OMERACT Filter for outcome measures in rheumatology. J Rheumatol 25:198-199, 1998. 70. Kane RA, Kane RL: Assessing the Elderly: A Practical Guide to measurement. Toronto, Lexington Books, 1981, pp13-17. 71. Bergner M: Health status measures: An overview and guide for selection. Ann Rev Public Health 8:191-210, 1987. 72. Law M: Measurement in occupational therapy: Scientific criteria for evaluation. Can J Occup Ther 54:133-138, 1987. 73. Scientific Advisory Committee of the Medical Outcomes Trust: Assessing health status and quality of life instruments: Attributes and review criteria. Qual Life Res 11:193-205, 2002. 74. Hays RD, Revicki D: Reliability and validity (including responsiveness). In Fayers P, Hays R (eds): Assessing Quality of Life in Clinical Trials: Methods and Practice, 2nd ed. New York, Oxford University Press, 2005, pp 25-39. 75. Stratford PW, Binkley JM: Applying the results of self-report measures to individual patients: An example using the Roland-­Morris Questionnaire. J Orthop Sports Physical Ther 29:232-239, 1999. 76. Verhoeven A, Boers M, van der Linden S: Responsiveness of the core set, response criteria, and utilities in early rheumatoid arthritis. Ann Rheum Dis 59:966-974, 2000. 77. DeyoRA, Centor RM: Assessing the responsiveness of functional scales to clinical change: An analogy to diagnostic test performance. J Chronic Dis 39:897-906, 1986. 78. Kirwan J: Minimum clinically important difference: The crock of gold at the end of the rainbow? J Rheumatol 28:439-444, 2001. 79. Deyo RA, Carter WB: Strategies for improving and expanding the application of health status measures in clinical settings: A researcher-developer viewpoint. Med Care 30(5 Suppl): MS176-MS186, 1992.

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80. Tubach F, Dougados M, Falissard B, et al: Feeling good rather than feeling better matters more to patients. Arthritis Care Res 55: 526-530, 2006. 81. Beaton DE, Tarasuk V, Katz JN, et al: Are you better? A qualitative study of the meaning of being better. Arthritis Care Res 7:313-320, 2001. 82. Boers M, Anderson JJ, Felson D: Deriving an operational definition of low disease activity state in rheumatoid arthritis. J Rheumatol 30:1112-1114, 2003. 83. Tubach F, Wells GA, Ravaud P, et al: Minimal clinically important difference, low disease activity state and patient acceptable symptom state: Methodological issues. J Rheumatol 32:2025-2029, 2005. 84. Tubach F, Ravaud P, Baron G, et al: Evaluation of clinically relevant states in patient reported outcomes in knee and hip osteoarthrits: The patient acceptable symptom state. Ann Rheum Dis 64:34-37, 2005. 85. Felson DT, Furst DE, Boers M: Rationale and strategies for reevaluating the ACR20. J Rheumatol 34:1184-1187, 2007. 86. Beaton DE, Boers M, Wells GA: Many faces of the minimal clinically important difference (MCID): A literature review and directions for future research. Curr Opin Rheumatol 14:109-114, 2002. 87. Hays RD, Woolley JM: The concept of clinically meaningful difference in health-related quality of life research. PharmacoEconomics 18:419-423, 2000. 88. Wells GA, Beaton DE, Shea B, et al: Minimal clinically important differences: Review of methods. J Rheumatol 28:406-412, 2001. 89. Norman GR, Sloan JA, Wyrwich KW: Interpretation of changes in health-related quality of life: The remarkable universality of half a standard deviation. Med Care 41:582-592, 2003. 90. Salaffi F, Stancati A, Silvestri CA, et al: Minimal clinically important changes in chronic musculoskeletal pain intensity measures on a numerical rating scale. Eur J Pain 8:283-291, 2004. 91. Stucki G, Daltroy L, Katz JN, et al: Interpretation of change scores in ordinal clinical scales and health status measures: The whole may not be equal to the sum of the parts. J Clin Epidemiol 49:711-717, 1996.

92. Angst F, Aeschlimann A, Stucki G: Smallest detectable and minimal clinically important differences of rehabilitation intervention with their implications for required sample sizes using WOMAC and SF36 quality of life measurement instruments in patients with osteoarthritis of the lower extremities. Arthritis Care Res 45:384-391, 2001. 93. Tubach F, Ravaud P, Baron G, et al: Evaluation of clinically relevant changes in patient reported outcomes in knee and hip osteoarthritis: The minimal clinically important improvement. Ann Rheum Dis 64:29-33, 2005. 94. Jacobson NS, Roberts LJ, Berns SB, et al: Methods for defining and determining the clinical significance of treatment effects: Description, application, alternatives. J Consult Clin Psychol 67:300-307, 1999. 95. Norman G: Hi! How are you? Response shift, implicit theories and differing epistemologies. Qual Life Res 12:249, 2003. 96. National Institutes of Health: Patient Reported Outcome Measurement Information System (PROMIS) network. 2006. Available at: http://www.nihpromis.org/. 97. Athale N, Sturley A, Koczen Z, et al: A web-compatible instrument for measuring self-reported disease activity in arthritis. J Rheumatol 31:223-228, 2004. 98. Fransen J, Stucki G, Twisk J, et al: Effectiveness of a measurement feedback system on outcome in rheumatoid arthritis: A controlled clinical trial. Ann Rheum Dis 62:624-629, 2003. 99. Bischoff-Ferrari HF, Vandechend M, Bellamy N, et al: Validation and patient acceptance of a computer touch screen version of the WOMAC 3.1 osteoarthritis index. Ann Rheum Dis 64:80-84, 2004. 100. Shaul MP: From early twinges to mastery: The process of adjustment in living with rheumatoid arthritis. Arthritis Care Res 8:290-297, 1995. 101. Schwartz C, Sprangers M, Fayers P: Response shift: You know it’s there but how do you capture it? Challenges for the next phase of research. In Fayers P, Hays R (eds): Assessing Qualify of Life in Clinical Trials: Methods and Practice, 2nd ed. New York, Oxford University Press, 2005, pp 275-290.

32

Biologic Markers Jeroen Degroot  •  Anne-Marie Zuurmond  •  Paul P. Tak

KEY POINTS Uniform definitions of disease are essential for biomarker validation and comparison between studies. The validation process of a biomarker depends on the specific purpose of its use. For tissue homeostasis, the balance between anabolic and catabolic process is important; extracellular matrix remodeling biomarkers should reflect these different processes. Understanding tissue source, formation, and clearance of a biomarker is important for correctly interpreting biomarker data. Analyses of serial synovial biopsy specimens can potentially be used as a screening method to test new drug candidates requiring relatively small numbers of patients. Panels of biomarkers or biomarker profiles are potentially more powerful than single biomarkers.

Biomarkers are anatomic, physiologic, biochemical, or molecular parameters associated with the presence and severity of specific diseases and are detectable by a variety of methods, including physical examination, laboratory assays, and imaging. Here the focus is on biomarkers in senso stricto: markers that can be measured in patient samples, such as blood, urine, synovial fluid, and synovial tissue. Such molecules often first appear in studies on disease mechanisms, their application as biomarkers being secondary. Realizing the importance and potential of biologic markers, the identification, characterization, and validation of novel biomarkers is often a primary objective in many studies nowadays. Biomarkers are applied for various purposes, including diagnosis, prognosis, monitoring of disease progression, selection of patient populations in clinical trials, assessment of the efficacy of treatment, or unraveling of the pathobiology of a disease in the clinical and in a preclinical setting. More recently, biomarker validation level of evidence schemes have been proposed to optimize efficient use of biomarkers in these diverse research areas.1,2 For osteoarthritis and RA, the most important common feature is progressive destruction of articular tissues, resulting in impaired joint function and pain. Diagnosis is based on clinical symptoms and laboratory tests in combination with radiography, to visualize often irreversible degenerative and destructive changes in the joint. Radiologic evaluation

of joints mainly images bone and is relatively insensitive: A follow-up period of at least 1 year is needed to assess disease progression and effect of therapy. Magnetic resonance imaging (MRI) has the ability to visualize all joint tissues simultaneously; it is currently being optimized, but has yet not reached its full potential.3 All imaging techniques provide a cumulative historical view of damage that has already occurred, rather than assessing the current rate of disease progression (Fig. 32-1). Alternative methods that detect changes in the joints in an early stage of the disease in a quantitative, reliable, and sensitive manner are needed. The World Health Organization in its report Priority Medicine for Europe and the World states that biomarkers are essential for arthritis in general and osteoarthritis research in particular, and that the lack of adequate markers constitutes a major hurdle for osteoarthritis drug development.4 Molecular markers (i.e., markers that are used to monitor molecular events occurring during disease) are well suited for this purpose. A good marker is disease-specific, reflects actual disease activity, is sensitive to change after therapy, and can predict disease outcome. Most likely, all of these requirements are not met by a single marker: Different (combinations of) markers would have to be applied for different purposes. The fact that imaging techniques often focus on one joint (e.g., knee or hip) or joint group (e.g., hands, lumbar spine), whereas urine-derived or blood-derived biomarkers are determined by all of the joints in the body, further underscores the importance of using imaging and biomarker approaches as complementary tools. The molecular markers that are described for joint diseases can be arbitrarily classified as follows: 1. Immunologic and inflammatory markers (including acutephase proteins) 2. Markers that reflect extracellular matrix remodeling (Table 32-1) 3. Markers present in synovial tissue biopsy specimens 4. “Omics”-based biomarkers (e.g., genomics, transcriptomics, proteomics, metabolomics) 5. Genetic markers that have been shown to provide important information on risk factors for development and progression of osteoarthritis and RA; these are reviewed elsewhere5-8 and are not included in this chapter.

IMMUNOLOGIC AND INFLAMMATORY BIOMARKERS Extensively studied markers in inflammatory arthritis that are routinely used in clinical practice include acute-phase proteins such as C-reactive protein (CRP) and measurements such as the erythrocyte sedimentation rate (ESR), 475

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Radiograph

Marker

A

Radiograph/time

B X-ray

AUC of marker Time Figure 32-1  Relationship between radiology and biomarkers. Radiology and MRI provide a cumulative historical view of joint destruction, whereas biomarkers provide dynamic information on the current rate of joint destruction or disease activity. A, At any given time, the slope of the x-ray versus time plot should be compared with biomarker levels. B, Consequently, the progression of x-ray damage (Δ x-ray) must be related to the time-integrated marker levels (area under the curve [AUC]).

both of which provide information about the systemic in­­ flammatory process. Although such markers of inflammation are neither disease-specific nor tissue-specific, they may reflect disease activity,9 reflect the effects of immunosuppressive and immunomodulatory therapies,10 and, to a certain extent, predict disease progression in RA.11 A more diseasespecific marker for RA is the presence of anticitrullinated protein/peptide antibodies.12 It predicts with high probability the development of RA in patients with no clinical symptoms, distinguishes between RA and other rheumatic diseases, and is a valuable tool for prognostic prediction of joint destruction.13 RA patients often show elevated levels of a variety of cytokines, chemokines, and their receptors (for details see Chapter 23). Many of these molecules are subsequently used as disease biomarkers or studied as targets for intervention, analogous to the experience with tumor necrosis factor (TNF)-α. This cytokine has been shown to play a pivotal role in arthritis and has emerged as a major therapeutic target. TNF-α inhibitors (neutralizing antibodies or soluble receptors) strongly reduce clinical symptoms, joint inflammation, and biomarkers of inflammation and bone destruction in RA patients.10,14,15 Neither the serum levels of the TNF receptors nor those of interleukin-10 were reduced, however, in response to treatment of RA patients with methotrexate and anti-TNF treatment, despite a clear improvement in clinical disease parameters and a reduction

of CRP and ESR.16 In contrast, in synovial tissue, treatment with these drugs did reduce the local TNF level, indicating that for biomarker analysis it is important to select the right compartment.17,18 The observation that anti-TNF treatment may block joint destruction in patients who do not show a clinical response (i.e., ACR20 nonresponders) suggests that, similar to osteoarthritis, in RA uncoupling of inflammation and joint destruction may occur, which may affect the selection of biomarkers to monitor treatment effects. Although synovial inflammation is often regarded as a secondary process in osteoarthritis, cytokines and other signal molecules also have been proposed as markers in this disease. In clinical studies, often highly sensitive analysis of CRP is included because it is associated with osteoarthritis of the knee19,20 and hip,21 but validation of this biomarker to monitor treatment efficacy is hampered by the lack of effective treatments (as is the difficulty with all osteoarthritis biomarkers). In osteoarthritis patients, serum nitrate and nitrite (reflecting nitric oxide levels) are increased compared with healthy controls, but not as much as in inflammatory conditions such as RA.22 Also, similar to RA, high levels of soluble receptors of TNF-α are associated with reduced physical function and worse radiologic knee osteoarthritis.23 In addition, using a genomics approach, chondrocytes from osteoarthritis cartilage have been shown to upregulate the transcription of a variety of inflammatory genes.24 Synovial tissue from osteoarthritis patients also shows signs of hyperplasia and inflammation.25 Although osteoarthritis traditionally is viewed as a noninflammatory arthropathy, an osteoarthritic joint could be considered a mildly inflamed organ. The added value of inflammation biomarkers measured in peripheral blood in joint diseases is still undecided. Although the levels of many inflammatory molecules may change in various (stages of) diseases, such change does not mean that the molecule is directly involved in the disease process or is sensitive to change after intervention. Serum cytokine levels often do not predict clinical response. As such, it is crucial to understand the complex biologic networks and the mode of action of treatments to be able to select the right (relevant) molecules to use as biomarkers. In view of this, the ultimate application of inflammation biomarkers in osteoarthritis studies is likely to be different from RA studies.

EXTRACELLULAR MATRIX REMODELING BIOMARKERS Because of the aforementioned issues, the focus of many biomarker studies is on markers that mirror disease-related changes in the joints, especially markers for remodeling (i.e., degradation and synthesis) of the extracellular matrix.26 Concomitant changes may occur in all joint tissues (cartilage, bone, and synovium), and for a comprehensive assessment of these changes molecular markers are needed for each of these tissues.27,28 For the markers derived from these different tissues, there can be a substantial difference in which biologic fluid biomarker levels are determined. The concentration of markers in body fluids not only reflects the dynamics of the disease, but also the rate of

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Table 32-1  Molecular Markers That Reflect Extra Cellular Matrix Remodeling Marker

Joint Tissue

References

Bone, soft tissues Bone, soft tissues

23, 131 23

Cartilage Cartilage

27, 40 27, 56, 61, 62, 72

Soft tissues

39, 63-65, 131

Cartilage

51, 56, 57, 71-74

Bone Bone Cartilage Cartilage, synovium

23 24 131 42, 80-84, 131

Bone Bone Soft tissues Bone, soft tissues

33-35 24, 32, 33, 36, 131 29-31, 33 27

Cartilage Cartilage

24, 38-46, 131 27, 47-54

Bone, cartilage Bone Synovium

32, 33, 37, 55-57 32-35, 55-57 40, 58

Cartilage Cartilage Cartilage

23 51, 56, 57, 66-70 23

Cartilage, synovium Cartilage Cartilage, possibly synovium Bone

40, 72, 75-77, 94, 96-102, 131 75, 78, 79, 103-107 39, 56, 72, 85-95 56

Synthesis Collagen type I   N-propeptide (PINP)   C-propeptide (PICP) Collagen type II   N-propeptide (PIINP; PIIANP)   C-propeptide (PIICP; chondrocalcin) Collagen type III   N-propeptide (PIIINP) Proteoglycans and GAGs   Chondroitin sulfate (epitopes 846, 3-B-3, 7-D-4) Miscellaneous   Bone-specific alanine phosphatase   Osteocalcin   YKL-40 (CYLK-40, gp-39, chondrex)   Hyaluronan Degradation Collagen type I Cross-linked N-telopeptide (NTx) Cross-linked C-telopeptide (CTx) Cross-linked C-telopeptide (ICTP) Collagenase cleavage neoepitope (C1, 2C) Collagen type II   Cross-linked C-telopeptide (CTx-II; 2B4 epitope)   Collagenase cleavage neoepitope (9A4, C2C, C1, 2C) Pyridinolines   Hydroxylysylpyridinoline (HP, PYR)   Lysylpyridinoline (LP, D-PYR, DPD)   Glucosylgalactosyl-hydroxypyridinoline (GGHP) Proteoglycans and GAGs   Aggrecan core protein (fragments)   Keratan sulfate (epitope 5-D-4, AN9P1)   Chondroitin sulfate Miscellaneous   Matrix metalloproteinases   Aggrecanases   Cartilage oligomeric matrix protein (COMP)   Bone sialoprotein (BSP)        

GAGs, glycosaminoglycans.

clearance and the amount of remaining tissue. Cartilagederived markers diffuse out of the tissue and enter the synovial fluid, which may vary in volume depending on the severity of ongoing inflammation. Synovial fluid urea levels may be used to correct for this “dilution.”29 Clearance from the synovial fluid predominantly occurs via lymphatic drainage, and partial degradation may occur in the lymph nodes, depending on the marker studied. Synovial clearance may depend on the severity of the ongoing synovitis and be determined by the permeability of the synovial membrane microvasculature.30 When the marker enters the systemic circulation, dilution occurs (e.g., 5 mL of synovial fluid ­versus ­approximately 5 L of blood), and marker levels are confounded by molecules from other affected, or nonaffected, joints or even from nonarticular cartilage. Bone-derived and synovium-derived markers also may enter the circulation directly. When the marker enters the systemic circulation, it is diluted, mixed with markers derived from other joints or tissues, and potentially metabolized in the liver and kidneys. Excretion in the urine depends on the marker and the above-mentioned metabolic processes. In the discussion that follows, examples are given from studies of osteoarthritis and RA to illustrate their use in assessing disease-related tissue remodeling.

COLLAGEN MARKERS The main constituent of the extracellular matrix of connective tissues is collagen, which plays an essential role in the maintenance of tissue shape, strength, and integrity. Fibrillar collagen types I, II, and III are synthesized as propeptide-containing α chains that are post-translationally modified by hydroxylation of lysyl and prolyl residues and by glycosylation of hydroxylysyl residues. Triple helical collagen molecules are secreted from the cell, the propeptides are cleaved off, and fibrils are formed that are stabilized by intermolecular cross-links. This unique sequence of events provides a variety of tools that are used to study collagen synthesis (especially propeptides) and degradation (especially cross-links) in rheumatic diseases (Fig. 32-2).31 In bone, type I collagen constitutes 90% of the organic matrix, and markers of bone collagen turnover have proven valuable in monitoring diseases such as osteoporosis.32 For some bone markers, such as NTx (bone degradation [see later]) and osteocalcin (bone formation), assays have been approved by the U.S. Food and Drug Administration to monitor efficacy of antiresorptive therapies or bone formation, sometimes even as point-of-care test. For these bone

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Procollagen synthesis Glc

Glc Gal Hyl

Gal

Gal OH Hyl Lys

OH Lys

Post-translational hydroxylation, glycosylation and helix formation

Pro Pro OH

OH

Intracellular

Secretion Extracelllular

Figure 32-2  Collagen-based markers for joint destruction. Collagen is synthesized as propeptide-containing α chains that are post-translationally modified by hydroxylation of lysyl and prolyl residues and by glycosylation of hydroxylysyl residues. These modifications cease when three α chains ­entwine to form a collagen triple ­helix. Triple helical collagen molecules are secreted from the cell, and the propeptides are cleaved off extracellularly. Subsequently, collagen molecules spontaneously assemble into fibrils with quarter-staggered overlap of the individual triple helices. Finally, the ­ fibrils are stabilized by formation of ­ intermolecular pyridinoline crosslinks.

OH

N-terminal propeptide

O-Gal-Glc OH

N tx HP/LP

metabolites, there is a significant menopausal effect that requires properly matched control groups and careful interpretation of the data. Several assays have been used to assess collagen type I degradation in RA and osteoarthritis. The cross-linked carboxyterminal telopeptide (ICTP) is released by matrix metalloproteinase (MMP) cleavage of type I collagen, and its levels reflect MMP-mediated soft tissue degradation.33 The NTx/CTx-I assay and ICTP assay detect type I collagen degradation, but by different proteases. Cathepsin K–mediated osteoclastic bone resorption destroys ICTP antigenicity.33 Slightly elevated serum ICTP levels are found in RA compared with controls and are associated with disease activity measured by ESR, CRP levels, and swollen joint counts.34 In osteoarthritis, fourfold increased ICTP levels have been detected in patients with rapid progressive hip osteoarthritis compared with patients with slowly progressive disease.35 When the carboxyterminal or the aminoterminal telopeptide of type I collagen (CTx or NTx) is released from bone degraded by cathepsin K, an epitope is generated that is different from the MMP-mediated ICTP epitope. In osteoarthritis patients, serum and urinary CTx levels are decreased compared with controls, which suggests decreased bone remodeling in osteoarthritis.28,36 In RA, urinary NTx and CTx levels are increased compared with healthy controls and are sensitive to change after treatment.37-39

O-Gal-Glc

OH

O-Gal O-Gal-Glc OH OH

O-Gal

C-terminal propeptide

OH

ICTP CTx HP/LP

Collagenase cleavage neoepitopes

Although on initial examination CTx and ICTP seem to provide identical information, closer inspection reveals that these two markers, although based on the same principle of detecting type I collagen telopeptides, may provide valuable complementary information. CTx and NTx levels are very low in patients with pyknodysostosis, which is caused by a deficient activity of cathepsin K, whereas ICTP levels are elevated in this condition. It also has been shown that in postmenopausal women, anti–bone resorption therapy by hormone replacement reduced serum CTx levels, whereas ICTP levels did not change.40 In cartilage, type II collagen constitutes 80% of the dry weight of the tissue. Damage to the collagen network (collagen degradation and subsequent denaturation) is one of the first features of osteoarthritis and contributes significantly to the decreased mechanical properties of osteoarthritic cartilage.41 Using monoclonal antibodies, release of cross-linked type II collagen telopeptides (C-telopeptide, CTx-II) was shown to reflect cartilage degradation with high tissue specificity.42 Urinary CTx-II levels were significantly increased in RA and osteoarthritis patients compared with healthy controls, although the ranges overlapped considerably.42-44 In a population-based study, subjects with a CTx-II level in the highest quartile had a 4.2-fold increased risk of having radiographic osteoarthritis of the knee and hip (compared with subjects in the lowest quartile), and a 6-fold (knee) or

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8.4-fold (hip) increased risk for progression of osteoarthritis.45 In osteoarthritis patients, CTx-II levels correlated with radiologic joint space narrowing and joint surface area, but did not correlate with WOMAC indices of clinical status in these osteoarthritis patients.28 In patients with hip osteoarthritis, urinary CTx-II levels greater than 346 ng/mmol creatinine were associated with a twofold increase in radiographic disease progression compared with patients whose levels were less than 346 ng/mmol creatinine.46 Treatment of these patients with a candidate antiosteoarthritis drug (diacerein) seemed to modulate the CTx-II levels consistent with the effects on disease progression.46,47 In a study of patients with radiographic osteoarthritis in multiple joints, there was a significant association between the total Radiographic OA score and urinary CTx-II levels. Subsequent multivariate analysis showed that the joint site–specific ROA score at all joint sites except for spinal disk degeneration contributed independently to this association.48 In RA patients, increased baseline CTx-II levels were associated with progression of joint damage, which was independent of baseline damage, treatment, and disease activity.44 In patients with active RA, the decrease in urinary CTx-II levels that was observed 3 months after initiation of treatment predicted the radiographic disease progression over 5 years, suggesting that urinary CTx-II levels may be used as an early marker of treatment efficacy.49 CTx-II also can be used to monitor therapy effects: In osteoporosis, patients’ CTx-II levels suggested that bisphosphonates attenuate not only bone degradation, but also cartilage degradation.50 These initial results indicate that type II collagen–specific markers may reflect ongoing cartilage destruction, and that such markers eventually may be used in clinical practice. Apart from telopeptide fragments, neoepitopes resulting from the cleavage of type II collagen by collagenases (MMP-1, MMP-8, and MMP-13) have been used to monitor cartilage collagen damage.51-53 Urinary excretion of collagen fragments containing the carboxyterminal neoepitope (TIINE assay, using antibody 9A4) was increased in osteoarthritis patients compared with age-matched healthy controls.54 In synovial fluid, levels of a similar carboxyterminal neoepi­ tope (C2C epitope, using the Col2-3/4Clong antibody) were significantly higher in osteoarthritis than in RA.55 In RA patients, serum levels of these biomarkers (C2C and C1,2C, a similar epitope present in types I and II collagen) were associated with progression of radiographic joint damage.56 In a randomized, double-blind, placebo-controlled glucosamine discontinuation trial of 137 subjects with knee osteoarthritis, neither C2C level nor C1,2C level, or their ratio, was affected by the treatment.57 Urinary levels of the 622632 peptide of type II collagen (also known as HELIX-II) were increased in patients with primary knee osteoarthritis (281 ng/mmol creatinine) and RA patients (409 ng/mmol creatinine) compared with healthy controls (180 ng/mmol creatinine).53 These data indicate that collagen-derived markers also are promising candidates to serve as biomarkers for cartilage degradation and disease progression for osteoarthritis and RA. HELIX-II and CTx-II levels independently predicted radiographic progression in RA patients (Sharp score)53 and patients with hip osteoarthritis,58 which suggests that although both markers reflect collagen type II degradation, they reflect independent processes (spatially, temporally, or mechanistically) in cartilage destruction.

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Collagen Cross-Links Degradation of fibrillar collagen types I, II, and III results in the quantitative excretion of the cross-links hydroxylysylpyridinoline (HP), derived from bone and soft tissue, including cartilage, and lysylpyridinoline (LP), derived from bone, in the urine. In RA patients who received ­ combination therapy (sulfasalazine, methotrexate, and ­ prednisolone in the COBRA trial), time-integrated urinary HP ­ levels correlated with the progression of radiographic joint damage (Sharpe/van der Heide score) and bone mineral density.59 In osteoarthritis patients, urinary HP and LP ­levels were increased compared with age-matched controls.60 In the same patient population, followed for 1 year, only the cluster of baseline bone metabolism markers (comprising HP, LP, and serum bone sialoprotein)—out of the 14 molecular markers measured—significantly correlated with baseline clinical scores for pain, stiffness, and disease activity.61 None of the baseline cartilage or bone metabolism markers correlated with disease progression after 1 year of follow-up.61 In these patients, HP that is not derived from bone (extraosseous HP) showed a highly significant correlation with the acute-phase response, sug­ gesting that in osteoarthritis, cartilage degradation is related to the degree of inflammation.60 The glycosylated analogue of HP, glucosyl-galactosylpyridinoline (GGHP), is present in human synovial tissue and is released during its degradation in vitro. GGHP is virtually absent in bone, whereas low levels have been detected in muscle and liver, and intermediate levels have been detected in cartilage. Methodologic problems, such as the stability of HP during the alkaline hydrolysis that is needed to liberate glycosylated molecules from tissues, have so far prevented solid data on tissue distribution.62 Urinary GGHP levels were increased in early RA patients versus controls, and baseline levels correlated with disease progression, albeit weakly.44 Pending definite information on its tissue distribution, urinary GGHP might prove to be a marker for synovial tissue degradation. Overall, collagen cross-links seem useful in measuring bone and cartilage catabolism and contribute to understanding of the pathophysiology of osteoarthritis and RA. In this respect, age-related changes in articular cartilage may significantly affect its susceptibility to proteinase-mediated­ ­degradation63,64; this underscores the use of proper ­ agematched control groups. Results obtained in studies with young animals cannot be extrapolated to the adult human situation. Collagen Synthesis In an attempt to repair tissue damage, collagen synthesis is increased in osteoarthritis cartilage, leading to increased tissue levels of the C-terminal propeptide of type II collagen (PIICP, chondrocalcin).65 The rate of PIICP release is proportional to the rate of collagen synthesis; the propeptide has a half-life of approximately 18 hours.65 Synovial fluid PIICP levels also are increased and correlate with osteoarthritis severity and body mass index.66 PIICP levels were lower in serum of osteoarthritis patients than in that of healthy controls.60 Similarly, the serum N-propeptide of collagen type IIA (PIIANP, an alternative splice variant that

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is expressed in embryonic and osteoarthritic cartilage) is lowered in osteoarthritis serum versus controls. Preliminary studies indicate that the balance between cartilage synthesis (PIIANP) and cartilage degradation (urinary CTx-II) could be used to discriminate between patients with rapid compared with slow progression.44 In inflamed synovial tissue, the synthesis of type III collagen is upregulated, resulting in the production of its aminoterminal propeptide. In osteoarthritis patients and RA patients with knee involvement, serum PIIINP levels are increased compared with age-matched controls.43,67,68 In RA patients, prednisolone treatment that resulted in clinical improvement also reduced serum PIIINP levels by 25%, and levels remained suppressed until treatment was withdrawn.69 Thus far, collagen type III specific degradation markers have not been described, and because type III collagen has a broad distribution in soft tissues and blood vessels, its potential as a specific biomarker seems limited. PROTEOGLYCAN MARKERS The main noncollagenous constituent of articular cartilage is aggrecan, a large proteoglycan composed of a core protein to which glycosaminoglycan chains (e.g., keratan sulfate and chondroitin sulfate) are attached. A variety of assays to measure aggrecan metabolism have been described, but the available information is not always consistent. Depending on the antibodies used, serum keratan sulfate levels were reported to be either increased (antibody 5D4)70-72 or decreased (antibody AN9P1)73 in osteoarthritis patients compared with controls. Additionally, previous work has suggested that serum 5D4 reactive keratan sulfate levels are either similar72 or higher in osteoarthritis than in RA.55 In one study, the serum keratan sulfate levels (antibody AN9P1) were 30% lower in osteoarthritis patients than in age-matched controls.60,61 For RA patients, a negative correlation between serum keratan sulfate levels and inflammation has been found.74 The aggrecan epitope 846, which reflects the synthesis of proteoglycans in an attempt to repair, was increased in cartilage of osteoarthritis patients,75 and synovial fluid levels correlated with other markers, such as ­cartilage oligomeric matrix protein (COMP), PIICP, tissue inhibitor of metalloproteinases 1 (TIMP-1), MMP-1, and MMP-3, and with the degree of radiologic damage.76 The epitope 846 levels in serum were lower, however, in osteoarthritis patients than in healthy controls61,77 and RA patients.55,61 In the RA patients, elevated levels of epitope 846 could predict a benign course of the disease.78 Taken together, none of the aggrecan-derived markers has shown sufficient power to discriminate between patients and controls or to provide consistent information that can be used in clinical studies. This effect may be partly caused by diurnal variation of these biomarkers, which may obscure relevant differences between study groups, especially when serum or urine sampling is not standardized.79 Similarly, increased motility of patients after initiation of successful treatment may affect circulating proteoglycan biomarker levels. The identification of two members of the ADAM-TS family of proteases (ADAM-TS4 and ADAM-TS5) as aggre­can­ ases80 supplied new tools to develop aggrecan-based markers

for cartilage destruction. Antibodies directed at aggrecanase and MMP-generated neoepitopes in aggrecan core protein have been produced and applied in a variety of in vitro ­studies aimed at unraveling mechanisms of cartilage destruction in osteoarthritis. In synovial fluid from patients with a variety of joint diseases, MMP and aggrecanase-released aggrecan fragments have been detected.81-83 These studies also have shown that these two groups of proteases may have distinct roles in articular cartilage catabolism.84 HYALURONAN The glucuronic acid chain hyaluronan (hyaluronic acid) is a constituent of cartilage and synovium and is synthesized by many cell types. It functions as anchor for proteoglycans such as aggrecan, allowing the formation of the large aggregates that are responsible for the resilience of cartilage. In the synovial membrane, hyaluronan is synthesized by synovial fibroblasts and secreted into the synovial fluid to provide lubrication of the joint and to facilitate joint movement. Synovial fluid hyaluronan levels are decreased in osteoarthritis patients85 and may partly explain impaired joint function and pain. This provides the rationale for visco-supplementation therapy in osteoarthritis patients, consisting of intra-articular injections with hyaluronan derivatives. Elevated blood hyaluronan levels have been reported for osteoarthritis patients and RA patients. In RA, some studies failed to show a relationship between plasma hyaluronan levels and measures of disease activity,86 whereas others showed significant correlations between serum ­hyaluronan levels and a variety of measures of inflammation and destruction (e.g., CRP, ESR, Ritchie index, radiologic damage).87 In osteoarthritis patients, elevated serum hyaluronan levels correlated weakly with the degree of cartilage degeneration.86 In addition, baseline hyaluronan levels could predict progression of osteoarthritis,46,88 and serum levels were shown to increase with disease severity.89 These results suggest that an increase in circulating systemic hyaluronan levels could reflect synovial inflammation rather than cartilage ­destruction, prompting care in use of hyaluronan as a joint destruction marker. Also, the observation that diet and increased physical activity can influence its serum levels should be considered when using hyaluronan as a biomarker in joint diseases.79,90 CARTILAGE OLIGOMERIC MATRIX PROTEIN Since its discovery in the early 1990s, COMP has received much attention as a putative cartilage destruction marker. Although its exact function is unclear, COMP has been implicated in collagen fibrillogenesis. Increased COMP levels have been detected in the synovial fluid of osteoarthritis patients.91 In addition, COMP levels are increased in the serum of osteoarthritis patients compared with healthy controls43,92 and are associated with progression of radiographic signs of osteoarthritis.93 In osteoarthritis patients, the serum COMP levels were even higher than in RA patients.94 In early RA patients, increased serum COMP levels were identified as a strong predictor of early large joint destruction.95-97 These data generated interest in the use of measurement of COMP levels as a selective cartilage destruction marker.

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The expression of COMP in joint tissues other than cartilage, including synovium, tendons, ligaments, and menisci, raised concerns about its tissue specificity. High expression of COMP mRNA has been shown in murine osteoarthritis, indicating that synovial fluid COMP levels may reflect not only tissue degradation, but also the rate of new synthesis.98 The concerns about the use of COMP measurement as a specific cartilage ­degradation marker are fueled further by a study showing that the extent of synovial inflammation is one of the factors determining the serum COMP levels.99 Other ­investigators did not observe a relationship between markers of inflammation and serum COMP levels (using a polyclonal antiserum ­ recognizing all COMP forms) in RA patients.100 In this same study, COMP levels did not have any prognostic value with respect to progression of joint damage.100 ­ Similar to the CTx and ICTP assays for collagen degradation, the use of antibodies or antiserum recognizing different epitopes within ­(fragments of) the COMP molecule might explain the apparent inconsistent results in the literature.101 METALLOPROTEINASES In addition to cartilage breakdown products, metalloproteinases (MMPs and aggrecanases) and their endogenous inhibitors (TIMPs) that are involved in the pathologic ­degradation of joint tissues could serve as useful markers. Data on MMP levels as a predictor for the progression of joint erosion in early RA are rapidly accumulating. Serum and synovial fluid MMP-3 (stromelysin) levels are increased in RA patients compared with controls.44,102 MMP-3 levels correlate with inflammation markers and disease ­ activity in patients with untreated active RA103 and in early RA patients who received nonsteroidal anti-inflammatory drugs only.100,102 In these studies, serum MMP-3 levels were not related to radiographic progression.100 Another study revealed an association between serum proMMP-3 concentrations at disease onset and progression of joint destruction, which was independent of known risk factors, such as the presence of the shared epitope and serum levels of rheumatoid factor and CRP.104 In line with these observations, MMP-1 (collagenase) levels also have been shown to indicate joint erosion independent of ­inflammation. In early RA patients, there was a positive correlation between the area under the curve measurements of MMP-1 serum levels (but not the area under the curve of CRP levels) and the number of new joint erosions after 18 months of follow-up.102 Arthritic patients treated with anti-TNF-α antibodies (infliximab) for 14 weeks did not show reduced MMP-2 and MMP-9 levels (assessed by zymography, which does not reliably detect the other MMPs) despite clear clinical improvement.105 These data suggest that MMP levels, although they may be correlated with parameters of inflammation, do not reflect exactly the same pathways as do acute-phase reactants and could provide valuable ­additional information on joint destruction in RA. Extrapolated to osteoarthritis, in which secondary inflammation is usually mild, these data suggest that MMP levels may provide valuable predictive markers. In a crosssectional study in osteoarthritis patients, MMP-3 serum ­levels were similar, however, to levels in healthy controls.106 In a subset (120 patients) of 431 patients participating in a

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randomized, placebo-controlled trial evaluating the effects of ­ doxycycline treatment on unilateral knee osteoarthritis, baseline plasma MMP-3 levels predicted joint space ­narrowing.107 In another study, the serum levels of TIMP-1 did not differ significantly between patients with ­unilateral or bilateral hip osteoarthritis and healthy controls.108 Within the osteoarthritis group, patients with rapid disease progression (joint space ­narrowing >0.6 mm/yr; 1-year follow-up) had significantly lower serum TIMP-1 levels than patients with slow progression (joint space narrowing <0.6 mm/yr).108 Apart from these, comprehensive studies for ­ predictive MMP markers in osteoarthritis are not yet ­ available, and information about the use of MMP levels in osteoarthritis is still incomplete. In recent years, more data on the role of aggrecanase in degradation of the major proteoglycan of cartilage (aggrecan) became available. Its pivotal role in tissue destruction is now widely accepted.80,109,110 Because of the difficulties in measuring aggrecanase activity in biologic samples, however, their value as a biomarker to monitor joint destruction is not yet fully understood. It is hoped that the more recent development of several aggrecanase assays111-113 will facilitate its use as a biomarker. BIOLOGIC MARKERS IN SYNOVIAL TISSUE Because many inflammatory arthropathies, including RA, ­primarily involve the synovial tissue, there has been increased interest in investigations of the pathologic changes in synovial biopsy specimens. This development has been stimulated further by technical advances, such as the advent of new methods to obtain synovial tissue ­ specimens from actively inflamed joints and clinically quiescent joints under local anesthesia, and because of the development of immunohistologic methods, in situ hybridization, ­ quantitative polymerase chain reaction, and microarray technology. Previous work has shown the relationship between the features of rheumatoid synovial tissue on the one hand and arthritis activity114 and joint destruction115 on the other (see also Chapter 48). The importance of evaluation of synovial tissue samples has been underscored by the ­observation that clinical signs of arthritis activity are associated with histologic signs of synovitis after treatment of RA patients with the monoclonal antibody alemtuzumab (Campath-1H), despite profound depletion of circulating lymphocytes.116 Similarly, rituximab treatment leads to a rapid and significant decrease in synovial B cell numbers in only a subset of RA patients, whereas circulating B cells are completely depleted in nearly all patients (Fig. 32-3).117 Several methodologic questions needed to be answered before serial synovial biopsy could be used to screen for potentially relevant effects after antirheumatic treatment.118 It has been shown in cross-sectional studies that biopsy samples can be acquired by blind needle technique and by miniarthroscopy.119 There are limitations and disadvantages, however, of the use of serial blind needle biopsy in the evaluation of treatment. It is usually restricted to larger joints, such as the knee joint; the operator is not able to select the tissue visually, causing potential sampling error; and it is not always possible to obtain adequate tissue samples. This is especially true when clinically quiescent joints are investigated (e.g., after successful therapy). Comparison

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Figure 32-3  Variable tissue response to treatment with the anti-CD20 antibody rituximab in patients with rheumatoid arthritis. A-D, Arthroscopic samples were obtained before (A and B) and 4 weeks after (C and D) initiation of treatment. Rheumatoid synovial tissue from paired biopsy samples stained for CD22+ B cells. Single staining, peroxidase technique, counterstaining with Mayer’s Hämalaunlösung. Original magnification 200×.

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of the features of synovial inflammation in biopsy samples from inflamed knee joints and paired inflamed small joints of RA patients revealed that inflammation in one inflamed joint is generally representative of the inflammation in other inflamed joints.120 It is possible to use serial samples from the same joint, selecting either large or small joints, for the evaluation of antirheumatic therapy. Sampling error can be reduced by selecting at least six biopsy specimens from multiple regions, resulting in variance of less than 10%.17,121 When the biopsy samples are taken from an actively inflamed joint, there is on average no clear-cut difference in the features of synovial inflammation or the expression of mediators of inflammation and destruction at the pannuscartilage ­junction compared with other regions away from the pannus-cartilage junction.122-124 An extensive quality control system is required to allow reliable analysis by immunohistochemistry, tissue enzymelinked immunosorbent assay, quantitative polymerase chain reaction, or microarray analysis. Finally, sophisticated computer-assisted image analysis systems allow reliable and efficient evaluation of the synovial cell infiltrate and the expression of adhesion molecules, cytokines, and MMPs in innovative clinical trials.125 Using this approach, successful treatment with diseasemodifying antirheumatic drugs, such as gold,126 methotrexate17,127,128 and leflunomide,128 was shown to be associated with decreased mononuclear cell infiltration. Similarly, successful treatment of RA patients with infliximab,18,129,130 etanercept,131 and anakinra132 results in reduced synovial inflammation. The number of macrophages in the synovium was significantly decreased 48 hours after initiation of infliximab treatment.133 Similarly, high-dose intravenous methylprednisolone reduced expression of TNF-α in synovial biopsy samples 24 hours after treatment, a result that correlated with a clinical response to, and subsequent relapse after, methylprednisolone therapy.134 More recently, a randomized trial was designed to address formally the question of which feature in RA synovial tissue samples could be used as a biomarker for

clinical ­ efficacy in relatively small studies of short duration.135 Patients received either prednisolone according to the COBRA ­ regimen or placebo for 2 weeks. This study identified ­ sublining ­ macrophages as the best biomarker associated with the clinical response to corticosteroids. Next, the utility of macrophages in the synovial sublining as a candidate biomarker was tested across discrete interventions and kinetics.125 A strong correlation between the mean change in disease activity score (Δ DAS28) and the mean change in the number of sublining macrophages was observed. When patients from all actively treated studies were grouped (n = 70), the standardized response mean, a measure of sensitivity to change, was 1.16 for the change in DAS28 and 0.83 for the change in sublining macrophages, indicating good sensitivity to change for both variables. For the patients from the placebo groups, the standardized response mean was −0.23 (for DAS28) and 0.30 (for macrophages), consistent with the notion that the biomarker is less susceptible to placebo effects or expectation bias than clinical evaluation, which includes subjective measures of disease activity.125 In addition to its role as a marker of response to effective treatment, the change in numbers of sublining macrophages could potentially help to distinguish effective from ineffective treatment. Taken together, these studies suggest that analyses of serial biopsy samples can be used as a screening method to test new drug candidates requiring relatively small numbers of subjects. The absence of changes after treatment would suggest that the therapy is probably not effective. The demonstration of biologic changes at the site of inflammation could provide the rationale for larger, placebo-controlled trials, however. Most of the biopsy studies have been performed in RA patients, but more recent work suggests that the same approach can be used for the evaluation of novel therapies in patients with other rheumatologic disease, such as spondyloarthritis.136-138 As an alternative to immunohistologic and in situ hybridization methods, quantitative polymerase chain ­reaction on small synovial biopsy specimens can be employed to ­evaluate

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drug effects in clinical trials.118,121 Using this approach, ­prednisolone was shown to reduce expression of interleukin-8 and MMP-1 in synovial biopsy specimens of RA patients after 2 weeks of treatment.138a Because the biopsy specimens contain various cell types, it is important to realize that a change in gene expression level also may reflect a change in cellular composition of the biopsy, and not a change in the expression level within a certain cell type. BIOMARKER PANELS Almost none of the markers for osteoarthritis and RA that are currently used can distinguish successfully between patients and controls on an individual basis, although average marker levels differ among groups. Principal component analysis of 14 biochemical markers revealed that the markers segregate into five clusters: inflammation (interleukin-6, CRP, TNF receptor I, TNF receptor II, and eosinophil cationic protein), bone (HP, LP, and BSP), cartilage synthesis (CPII, epitope 846, and hyaluronan), cartilage degradation (COMP and keratan sulfate), and transforming growth factor-β1 (which is independent of all other markers).60 The combination of three of the markers (TNF receptor II, COMP, and epitope 846) from the independent clusters inflammation, cartilage degradation, and cartilage synthesis could discriminate correctly between osteoarthritis patients and controls in approximately 90% of the cases.60 In a study of 376 patients with hip osteoarthritis, a similar approach resulted in five different clusters with similar makeup: a cartilage and bone cluster (PINP, CTx-I, and CTx-II), a putative synovitis cluster (COMP, PIIINP, and HA), a putative systemic inflammation cluster (CRP and YKL-40), and MMP-1 and MMP-3 as two independent factors.67 Similarly, in RA, a combination of seven clinical scores and molecular markers provided a clinical prediction model that could discriminate, at the first visit, between three forms of arthritis—self-limiting arthritis, persistent nonerosive arthritis, and persistent erosive arthritis.139 Different clusters of biomarkers may relate to osteoarthritis at different joint sites, suggesting that pathophysiologic processes may be different between those sites.48 These studies support the notion that panels of biomarkers may provide a valuable additional tool in the monitoring of osteoarthritis patients and RA patients and in helping to understand disease processes. The progressive destruction of the articular cartilage is considered a major determinant of disability in patients with joint disease. A report showed that the balance between cartilage synthesis and degradation discriminates between osteoarthritis patients with rapid versus slow progression, as assessed by the change in joint space width and arthroscopically scored chondropathy.44 These studies support the hypo­thesis that the “-omics” approaches, combining even more markers than the few used previously, not only may be ­successful in the identification of disease-specific fingerprints, but also may provide tools to monitor tissue-specific degradation.

“-OMICS”-BASED BIOMARKERS The current technical progress in genomics, ­transcriptomics, proteomics, and metabolomics, in combination with advan­ ced bioinformatics,140 makes it possible to analyze numerous

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markers in one sample, which could be urine, serum, synovial fluid, or (synovial) tissue. The resulting profile combines the levels of a variety of markers to create a “disease fingerprint” that could serve as a powerful marker by itself. In addition to specific markers for early diagnosis, markers are needed that specifically reflect cartilage degradation. These technologies can arbitrarily be separated into three primary levels: genomics, which deals with variations in DNA composition (e.g., single nucleotide polymorphisms) and expression levels (differences in mRNA levels, also known as transcriptomics); proteomics, which analyzes the proteome, or total of proteins in a sample; and metabolomics, which focuses on metabolites. Variations on these themes include technologies such as lipidomics (profiling the lipids and free fatty acids in a cell or biologic fluid), degradomics (the study of protein degradation products), and toponomics (the study of the localization of molecules within a cell). GENOMICS Of all the “-omics” technologies, genomics was the first to evolve in the footsteps of the human genome project, and various aspects of genomics approaches to study joint diseases have been extensively reviewed.141-143 Comparisons in gene expression levels between controls, osteoarthritis, and RA have been made for a variety of tissues, such as ­ chondrocytes, blood-derived cells, and synovial tissue. Within a group of RA patients, cDNA microarray analysis with a focus on immune-related genes could separate classes of patients with potentially different pathogenicity based on the expression of genes involved in the adaptive immune response versus genes involved in tissue remodeling.144 In osteoarthritis, chondrocytes from cartilage have been shown to upregulate the transcription of a variety of inflammatory genes.24 In another study, 3543 genes were differentially expressed by blood cells of patients with mild knee osteoarthritis compared with healthy controls.145,146 Logistic ­regression indicated that nine of these genes were discriminatory between subjects with mild osteoarthritis and controls, with a sensitivity of 86% and specificity of 83% in a training set of 78 samples. The optimal biomarker combinations were evaluated using a blind test set (67 subjects), which showed 72% sensitivity and 66% specificity for the diagnosis of osteoarthritis.145 These data underscore that the combination of biomarkers (in this case the expression of nine genes) may be useful in differential diagnosis. Also in other rheumatic diseases, expression profiling has contributed to the understanding of disease pathways. In patients with systemic lupus erythematosus, several ­studies have shown that interferon-regulated genes are highly upregulated in peripheral blood cells and in kidney ­glomeruli.147 One of the ultimate uses of the identification of differentially expressed genes in a disease is illustrated by the antitumor drug trastuzumab (a recombinant monoclonal antibody against the human epidermal growth factor receptor 2 [HER2] protein), which would not have reached the marker if not for the accompanying prognostic test.148 Normal cells express low levels of HER2 protein on their plasma membrane. In approximately 25% of breast cancer patients, HER2 is overexpressed, changing the growth control of these cells. The prognostic test measures the expression

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l­evels of HER2, assisting in the selection of patients who would benefit from trastuzumab treatment. PROTEOMICS Similar to the genomics revolution, which was partly driven by technology that allowed the production of genechip and high-throughput DNA sequencing methods, the proteomics field was boosted by the development of better two-dimensional electrophoresis technologies and the rapid improvements in the area of mass spectroscopy, both of which facilitated the reproducible analysis of a panel of proteins within a sample. Two-dimensional gel electrophoresis has been used to identify proteins secreted into the culture medium of normal and osteoarthritic cartilage samples,149 but also to analyze the protein composition of the mitochondria of healthy human chondrocytes.150,151 Using surface-enhanced laser desorption/ionization time-of-flight mass spectroscopy, 103 serum samples of RA patients, osteoarthritis patients, patients with non-RA inflammatory conditions (psoriatic arthritis, asthma, Crohn’s disease), and controls were analyzed. This approach yielded several signals in the mass spectrum that contributed to the separation between RA patients and controls.152 A different approach was taken by Xiang and coworkers,153 who first separated human chondrocyte proteins by twodimensional electrophoresis, then blotted the proteins to a membrane, and finally incubated these membranes with serum of osteoarthritis patients, RA patients, and ­controls to identify which chondrocyte-derived autoantigens are present in these patients. This approach yielded triose­ phosphate isomerase as a potential osteoarthritis-specific biomarker. Yet another approach focuses on the panels of autoantibodies present in patients with various autoimmune diseases to act as biomarkers.154 Using an array of 30 antigens known to be expressed in the glomeruli, the clusters of autoantibodies that occur in the serum of lupus patients were studied and shown to be related to the patients’ disease activity.155,156 All biomarkers that are identified by the above-described examples studies naturally need further validation to establish their true usefulness for diagnostic, prognostic, or disease-monitoring application in patients with joint disease. METABOLOMICS Biologic fluids, such as urine, blood, and synovial fluid, ­contain numerous metabolites that may provide valuable ­information on the metabolism of an organism and about its health ­status. Metabolic profiling, also referred to as metabolomics, ­metabonomics, or related terms, is defined as the quantitative and qualitative analysis of the whole complement of small molecules in a sample (e.g., cell, tissue, body fluids).157 The technology has emerged from approaches used to profile body fluids that were developed many decades ago for the study of inborn errors of metabolism and the effects of nutrition. A wide array of analytic methods is used to analyze the various metabolites. Gas chromatography–mass spectroscopy and nuclear magnetic resonance (NMR) can be employed for a global insight into a broad range of metabolites, such as (phosphorylated) sugars, amino acids, fatty acids, nucleobases and nucleosides, amines, higher alcohols, and bile acids.

­Liquid chromatography–mass spectroscopy methods can be used not only to zoom in on free fatty acids and lipids, but also to ­analyze amino acids, peptides, sugars, and aminosugars and hormones and steroids. All of these analytic measures need to be combined with data preprocessing to obtain clean data. This is necessary to analyze these very large metabolite profiles reliably and to relate relevant changes in metabolites to biologic processes, using multivariate statistics. The application of metabolomics in the area of joint diseases is relatively recent. 1H-NMR (500 MHz) has been used to compare the effects of unilateral knee joint denervation on the biochemical profiles of synovial fluid in a ­bilateral canine anterior cruciate ligament transection model of osteoarthritis. Increases in glycerol, hydroxybuty­ rate, glutamine/glutamate, creatinine/creatine, acetate, and N-acetyl-glycoprotein concentrations were observed in synovial fluids from denervated osteoarthritis knees compared with normally innervated osteoarthritis knees.158 These metabolite profiles of denervated osteoarthritis knees support the idea of neurogenic acceleration of osteoarthritis in that the observed differences in metabolite concentrations found in the denervated knee fluids seem to correlate with metabolic changes resulting from aggravation of the osteoarthritis process caused by joint denervation.159 Using 1H-NMR (300 MHz) and multivariate data analysis, a metabolite profile was detected, which was strongly ­associated with osteoarthritis in 10- and 12-month-old Hartley guinea pigs that ­spontaneously develop osteoarthritis.160 1H-NMR also revealed a urinary metabolite profile that could distinguish osteoarthritis patients from healthy individuals.161 The human urine profile largely resembles the Dunkin Hartley guinea pig profile; the presence of hydroxybutyrate, pyruvate, creatine/creatinine, and glycerol in the metabolite profile could point to an enhanced use of fat and altered energy use, consistent with the canine synovial fluid ­composition.158,159,161

SYSTEMS BIOLOGY Although each is already tremendously powerful on its own, the combination of genomics (transcriptomics), proteomics, and metabolomics theoretically could deliver a full picture of a living system (cell, organ, or organism). Such a systems biology approach162 would provide insight into which disturbances of a healthy system cause it to shift toward a pathologic phenotype, which mechanisms are employed by the organism to maintain its equilibrium, and which factors indicate a point of no return, followed by failure of the intrinsic balancing mechanisms and disease initiation. As such, a systems biology approach would help to identify the most promising molecules that describe this shift and can act as biomarkers, while concomitantly key molecules can be detected that, when normalized, could rebalance the system, acting as therapeutic targets. The first steps in this area are being made for RA,163 but steps for osteoarthritis projects also have been initiated.

BIOMARKER VALIDATION Following or parallel to the crucial investigations to identify relevant biomarkers for disease, biologic validation studies need to be performed: Does the biomarker reflect the disease

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process, and how does it change with endogenous or druginduced changes in pathophysiologic processes? In addition, the actual application of such biomarkers in preclinical or clinical studies requires an in-depth analytic validation. The obvious reason for this is that to draw conclusions based on biomarker data, it is essential to be able to trust that a measured value is reliable and reproducible. Some of the essential steps in biomarker validation are described next. Details on validation procedures and requirements can be found elsewhere (http://www.fda.gov/cder/guidance/ 4252fnl.htm).164 The fundamental parameters to show that a given biomarker can be quantitatively measured in a given biologic matrix (e.g., serum, urine, synovial fluid, saliva) include the following: 1. Accuracy—how close is the mean measured concentration of at least five replicates to the true value of the analyte. 2. Precision—what is the variation between individual measurements of one sample. Typically, at each test concentration, the precision should not exceed the 15% of the coefficient of variation. 3. Selectivity or specificity—how well does the analytic method distinguish between the analyte of interest and other components of the samples. 4. Sensitivity—what is the smallest amount (or the largest amount) of analyte that can be reliably detected. 5. Reproducibility—how well can the measurements be repeated on a different day, by different operators, or by using different equipment and still result in the same measured values. 6. Stability—how stable is the analyte of interest in a certain matrix, tube, or storage condition. This also includes studies of the stability of the analyte on repeated freeze-thaw cycles and short-term and longterm storage at various temperatures. Other factors that are important in validating biomarker assays are the availability of references or calibrators that are used as external standards to quantify the results. Also the development of standard operating procedures and documentation is essential for optimal assay performance.

CONCLUSION Over the years, many reports have been published that employ molecular markers in body fluids to assess inflammation and tissue destruction in joint diseases. Starting from single markers with limited tissue or disease specificity, panels of biomarkers are increasingly used, and these become more and more tissue specific. The novel markers include collagen-based markers (telopeptides, neoepitopes, and crosslinks), COMP, and MMPs, which are often included in clinical trials. Apart from well-known markers, such as CRP, ESR, rheumatoid factor, anticitrullinated protein/peptide antibodies, and a few other autoantibodies, none of the markers has made it to the clinic for routine evaluation of patient disease status. The requirements for such a clinically useful marker are high because it should be superior to existing markers in being able to predict disease progression or monitor therapy efficacy in individual patients. In this respect, biomarkers for osteoarthritis provide the greatest challenge: Joint destruction often proceeds without signs of inflammation. Validation of osteoarthritis biomarkers is

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hampered by the absence of a generally accepted, effective treatment for the disease. In early RA patients, suppression of inflammation often, although not always, coincides with decreased joint destruction, and monitoring inflammation may fulfill its role as surrogate destruction marker. In later stages of the disease, when inflammation and destruction seem more uncoupled,165 specific destruction markers also are needed for RA patients. In general, the combination of multiple markers holds most promise to meet these needs to increase disease specificity or tissue specificity, or both, and to reduce the extensive overlap in marker levels that exists between patients and controls. Analysis of molecular markers in synovial tissue is increasingly used, especially in clinical trials on targeted therapies. Tissue specificity is not a problem, and examination of serial biopsy samples may be used to monitor the response in individual patients and screen for interesting biologic effects at the site of inflammation. This approach is generally well tolerated by patients, but it requires a more demanding setup. It can be anticipated that future development will include the use of more extensive markers of joint degradation—in addition to the available markers of inflammation—and the use of panels of biomarkers in synovial tissue samples. As illustrated by studies described in this chapter, many investigators measure different sets of biomarkers and may use different definitions of disease (or progression or both). In addition, common terminology to describe a biomarker is lacking, and investigators may have a historical bias in favor of (or against) certain biomarkers. In combination, these issues may slow down the urgently needed progress in the development of clinically applicable biomarkers for joint diseases. To solve this, further collaboration between researchers of various disciplines, and the execution of large, unbiased studies incorporating a wide panel of available (or newly developed) biomarkers and complementary methods, including imaging and patient assessments, are needed.166 REFERENCES   1. Lassere MN, Johnson KR, Boers M, et al: Definitions and validation criteria for biomarkers and surrogate endpoints: Development and testing of a quantitative hierarchical levels of evidence schema. J Rheumatol 34:607-615, 2007.    2. Bauer DC, Hunter DJ, Abramson SB, et al: Classification of osteoarthritis biomarkers: A proposed approach. Osteoarthritis Cartilage 14:723-727, 2006.   3. Biswal S, Hastie T, Andriacchi TP, et al: Risk factors for progressive cartilage loss in the knee. Arthritis Rheum 46:2884-2892, 2002.   4. Kaplan W, Laing R: Priority Medicines for Europe and the World. WHO/EDM/PAR/2004.7. Geneva, World Health Organization, 2004.   5. Peach CA, Carr AJ, Loughlin J: Recent advances in the genetic investigation of osteoarthritis. Trends Mol Med 11:186-191, 2005.   6. Brandi ML, Gennari L, Cerinic MM, et al: Genetic markers of osteoarticular disorders: Facts and hopes. Arthritis Res 3:270-280, 2001.   7. Williamson AA, McColl GJ: Early rheumatoid arthritis: Can we predict its outcome? Intern Med J 31:168-180, 2001.   8. Loughlin J: Polymorphism in signal transduction is a major route through which osteoarthritis susceptibility is acting. Curr Opin Rheumatol 17:629-633, 2005.   9. Otterness IG: The value of C-reactive protein measurement in rheumatoid arthritis. Semin Arthritis Rheum 24:91-104, 1994. 10. Maini R, St Clair EW, Breedveld F, et al: Infliximab (chimeric antitumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: A randomised phase III trial. ATTRACT Study Group. Lancet 354:1932-1939, 1999.

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11. Scott DL: Prognostic factors in early rheumatoid arthritis. Rheumatology (Oxf) 39(Suppl 1):24-29, 2000. 12. Avouac J, Gossec L, Dougados M: Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: A systematic literature review. Ann Rheum Dis 65:845-851, 2006. 13. van Venrooij WJ, Zendman AJ, Pruijn GJ: Autoantibodies to citrullinated antigens in (early) rheumatoid arthritis. Autoimmun Rev 6: 37-41, 2006. 14. Lipsky PE, van der Heijde DM, St Clair EW, et al: Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 343:1594-1602, 2000. 15. Torikai E, Kageyama Y, Takahashi M, et al: The effect of infliximab on bone metabolism markers in patients with rheumatoid arthritis. Rheumatology (Oxf) 45:761-764, 2006. 16. Macias I, Garcia-Perez S, Ruiz-Tudela M, et al: Modification of proand antiinflammatory cytokines and vascular-related molecules by tumor necrosis factor-α blockade in patients with rheumatoid arthritis. J Rheumatol 32:2102-2108, 2005. 17. Dolhain RJ, Tak PP, Dijkmans BA, et al: Methotrexate reduces inflammatory cell numbers, expression of monokines and of adhesion molecules in synovial tissue of patients with rheumatoid arthritis. Br J Rheumatol 37:502-508, 1998. 18. Ulfgren AK, Andersson U, Engstrom M, et al: Systemic anti-tumor necrosis factor alpha therapy in rheumatoid arthritis down-regulates synovial tumor necrosis factor alpha synthesis. Arthritis Rheum 43:2391-2396, 2000. 19. Sowers M, Jannausch M, Stein E, et al: C-reactive protein as a ­biomarker of emergent osteoarthritis. Osteoarthritis Cartilage 10:595-601, 2002. 20. Spector TD, Hart DJ, Nandra D, et al: Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease. Arthritis Rheum 40:723-727, 1997. 21. Cohen MP, Wu VY, Cohen JA: Glycated albumin stimulates fibronectin and collagen IV production by glomerular endothelial cells under normoglycemic conditions. Biochem Biophys Res Commun 239:91-94, 1997. 22. Ersoy Y, Ozerol E, Baysal O, et al: Serum nitrate and nitrite levels in patients with rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. Ann Rheum Dis 61:76-78, 2002. 23. Penninx BW, Abbas H, Ambrosius W, et al: Inflammatory markers and physical function among older adults with knee osteoarthritis. J Rheumatol 31:2027-2031, 2004. 24. Attur MG, Dave M, Akamatsu M, et al: Osteoarthritis or osteoarthrosis: The definition of inflammation becomes a semantic issue in the genomic era of molecular medicine. Osteoarthritis Cartilage 10:1-4, 2002. 25. Smith MD, Triantafillou S, Parker A, et al: Synovial membrane inflammation and cytokine production in patients with early osteoarthritis. J Rheumatol 24:365-371, 1997. 26. Saxne T, Heinegard D: Matrix proteins: Potentials as body fluid markers of changes in the metabolism of cartilage and bone in arthritis. J Rheumatol Suppl 43:71-74, 1995.  27. Garnero P, Rousseau JC, Delmas PD: Molecular basis and clinical use of biochemical markers of bone, cartilage, and synovium in joint diseases. Arthritis Rheum 43:953-968, 2000. 28. Garnero P, Piperno M, Gineyts E, et al: Cross sectional evaluation of biochemical markers of bone, cartilage, and synovial tissue metabolism in patients with knee osteoarthritis: Relations with disease ­activity and joint damage. Ann Rheum Dis 60:619-626, 2001. 29. Kraus VB, Huebner JL, Fink C, et al: Urea as a passive transport marker for arthritis biomarker studies. Arthritis Rheum 46:420-427, 2002. 30. Myers SL, Brandt KD, Eilam O: Even low-grade synovitis significantly accelerates the clearance of protein from the canine knee: Implications for measurement of synovial fluid “markers” of osteoarthritis. Arthritis Rheum 38:1085-1091, 1995. 31. Elsaid KA, Chichester CO: Review: Collagen markers in early arthritic diseases. Clin Chim Acta 365(1-2):68-77, 2006.  32. Szulc P, Delmas PD: Biochemical markers of bone turnover in men. Calcif Tissue Int 69:229-234, 2001. 33. Sassi ML, Eriksen H, Risteli L, et al: Immunochemical characterization of assay for carboxyterminal telopeptide of human type I ­collagen: Loss of antigenicity by treatment with cathepsin K. Bone 26:367-373, 2000.

34. Jensen T, Hansen M, Madsen JC, et al: Serum levels of parathyroid hormone and markers of bone metabolism in patients with rheumatoid arthritis: Relationship to disease activity and glucocorticoid treatment. Scand J Clin Lab Invest 61:491-501, 2001. 35. Berger CE, Kroner A, Stiegler H, et al: Elevated levels of serum type I collagen C-telopeptide in patients with rapidly destructive osteoarthritis of the hip. Int Orthop 29:1-5, 2005. 36. Takahashi M, Suzuki M, Naitou K, et al: Comparison of free and ­peptide-bound pyridinoline cross-links excretion in rheumatoid arthritis and osteoarthritis. Rheumatology (Oxf) 38:133-138, 1999. 37. St Clair EW, Moak SA, Wilkinson WE, et al: A cross sectional analysis of 5 different markers of collagen degradation in rheumatoid arthritis. J Rheumatol 25:1472-1479, 1998. 38. al-Awadhi AM, Olusi SO, al-Zaid NS, et al: Urine levels of type 1 collagen cross-linked N-telopeptides and deoxypyridinoline correlate with disease activity in rheumatoid arthritis. Clin Exp Rheumatol 16:569-572, 1998. 39. Seriolo B, Ferretti V, Sulli A, et al: Serum osteocalcin levels in premenopausal rheumatoid arthritis patients. Ann N Y Acad Sci 966:502-507, 2002. 40. Rosenquist C, Fledelius C, Christgau S, et al: Serum CrossLaps One Step ELISA: First application of monoclonal antibodies for measurement in serum of bone-related degradation products from C-terminal telopeptides of type I collagen. Clin Chem 44:2281-2289, 1998. 41. Bank RA, Soudry M, Maroudas A, et al: The increased swelling and instantaneous deformation of osteoarthritic cartilage is highly correlated with collagen degradation. Arthritis Rheum 43:2202-2210, 2000. 42. Christgau S, Garnero P, Fledelius C, et al: Collagen type II C-telopeptide fragments as an index of cartilage degradation. Bone 29:209-215, 2001. 43. Garnero P, Christgau S, Delmas PD: The bisphosphonate zoledronate decreases type II collagen breakdown in patients with Paget’s disease of bone. Bone 28:461-464, 2001. 44. Garnero P, Gineyts E, Christgau S, et al: Association of baseline levels of urinary glucosyl-galactosyl-pyridinoline and type II collagen C-telopeptide with progression of joint destruction in patients with early rheumatoid arthritis. Arthritis Rheum 46:21-30, 2002. 45. Reijman M, Hazes JM, Bierma-Zeinstra SM, et al: A new marker for osteoarthritis: Cross-sectional and longitudinal approach. Arthritis Rheum 50:2471-2478, 2004. 46. Mazieres B, Garnero P, Gueguen A, et al: Molecular markers of cartilage breakdown and synovitis at baseline as predictors of structural progression of hip osteoarthritis. The ECHODIAH Cohort. Ann Rheum Dis 65:354-359, 2006. 47. Dougados M: Disease controlling antirheumatic therapy in spondyloarthropathy. J Rheumatol Suppl 62:16-20, 2001. 48. Meulenbelt I, Kloppenburg M, Kroon HM, et al: Urinary ­ CTXII levels are associated with radiographic subtypes of osteoarthritis in hip, knee, hand, and facet joints in subject with familial ­osteoarthritis at multiple sites: The GARP study. Ann Rheum Dis 65:360-365, 2006. 49. Landewe R, Geusens P, Boers M, et al: Markers for type II collagen breakdown predict the effect of disease-modifying treatment on longterm radiographic progression in patients with rheumatoid arthritis. Arthritis Rheum 50:1390-1399, 2004. 50. Lehmann HJ, Mouritzen U, Christgau S, et al: Effect of bisphosphonates on cartilage turnover assessed with a newly developed assay for collagen type II degradation products. Ann Rheum Dis 61:530-533, 2002. 51. Otterness IG, Downs JT, Lane C, et al: Detection of collagenaseinduced damage of collagen by 9A4, a monoclonal C-terminal neoepitope antibody. Matrix Biol 18:331-341, 1999. 52. Billinghurst RC, Wu W, Ionescu M, et al: Comparison of the ­degradation of type II collagen and proteoglycan in nasal and ­articular cartilages induced by interleukin-1 and the selective ­ inhibition of type II collagen cleavage by collagenase. Arthritis Rheum 43: 664-672, 2000. 53. Charni N, Juillet F, Garnero P: Urinary type II collagen helical peptide (HELIX-II) as a new biochemical marker of cartilage degradation in patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum 52:1081-1090, 2005. 54. Downs JT, Lane CL, Nestor NB, et al: Analysis of collagenase­cleavage of type II collagen using a neoepitope ELISA. J Immunol Methods 247(1-2):25-34, 2001.

PART 4  55. Ishiguro N, Ito T, Oguchi T, et al: Relationships of matrix metalloproteinases and their inhibitors to cartilage proteoglycan and collagen turnover and inflammation as revealed by analyses of synovial fluids from patients with rheumatoid arthritis. Arthritis Rheum 44:2503-2511, 2001. 56. Verstappen SM, Poole AR, Ionescu M, et al: Radiographic joint damage in rheumatoid arthritis is associated with differences in cartilage turnover and can be predicted by serum biomarkers: An evaluation from 1 to 4 years after diagnosis. Arthritis Res Ther 8:R31, 2006. 57. Cibere J, Thorne A, Kopec JA, et al: Glucosamine sulfate and ­cartilage type II collagen degradation in patients with knee ­ osteoarthritis: Randomized discontinuation trial results employing biomarkers. J Rheumatol 32:896-902, 2005. 58. Garnero P: Use of biochemical markers to study and follow patients with osteoarthritis. Curr Rheumatol Rep 8:37-44, 2006. 59. Verhoeven AC, Boers M, Tekoppele JM, et al: Bone turnover, joint damage and bone mineral density in early rheumatoid arthritis treated with combination therapy including high-dose prednisolone. Rheumatology (Oxf) 40:1231–1237, 2001.   60. Otterness IG, Swindell AC, Zimmerer RO, et al: An analysis of 14 molecular markers for monitoring osteoarthritis: Segregation of the markers into clusters and distinguishing osteoarthritis at baseline. Osteoarthritis Cartilage 8:180-185, 2000. 61. Otterness IG, Weiner E, Swindell AC, et al: An analysis of 14 molecular markers for monitoring osteoarthritis: Relationship of the markers to clinical end-points. Osteoarthritis Cartilage 9:224-231, 2001. 62. Gineyts E, Garnero P, Delmas PD: Urinary excretion of glucosylgalactosyl pyridinoline: A specific biochemical marker of synovium degradation. Rheumatology (Oxf) 40:315-323, 2001. 63. DeGroot J, Verzijl N, Jacobs KM, et al: Accumulation of advanced glycation endproducts reduces chondrocyte-mediated extracellular matrix turnover in human articular cartilage. Osteoarthritis Cartilage 9:720-726, 2001. 64. DeGroot J, Verzijl N, Wenting-van Wijk MJG, et al: Age-related decrease in susceptibility of human articular cartilage to matrix metalloproteinase-mediated degradation: The role of advanced glycation end products. Arthritis Rheum 44:2562-2571, 2001. 65. Nelson F, Dahlberg L, Laverty S, et al: Evidence for altered synthesis of type II collagen in patients with osteoarthritis. J Clin Invest 102:2115-2125, 1998. 66. Kobayashi T, Yoshihara Y, Samura A, et al: Synovial fluid concentrations of the C-propeptide of type II collagen correlate with body mass index in primary knee osteoarthritis. Ann Rheum Dis 56:500-503, 1997. 67. Garnero P, Mazieres B, Gueguen A, et al: Cross-sectional association of 10 molecular markers of bone, cartilage, and synovium with disease activity and radiological joint damage in patients with hip osteoarthritis: The ECHODIAH cohort. J Rheumatol 32:697-703, 2005. 68. Hakala M, Aman S, Luukkainen R, et al: Application of markers of collagen metabolism in serum and synovial fluid for assessment of disease process in patients with rheumatoid arthritis. Ann Rheum Dis 54:886-890, 1995. 69. Sharif M, Salisbury C, Taylor DJ, et al: Changes in biochemical markers of joint tissue metabolism in a randomized controlled trial of glucocorticoid in early rheumatoid arthritis. Arthritis Rheum 41:1203-1209, 1998. 70. Sweet MB, Coelho A, Schnitzler CM, et al: Serum keratan sulfate levels in osteoarthritis patients. Arthritis Rheum 31:648-652, 1988. 71. Campion GV, McCrae F, Schnitzer TJ, et al: Levels of keratan sulfate in the serum and synovial fluid of patients with osteoarthritis of the knee. Arthritis Rheum 34:1254-1259, 1991. 72. Mehraban F, Finegan CK, Moskowitz RW: Serum keratan sulfate: Quantitative and qualitative comparisons in inflammatory versus noninflammatory arthritides. Arthritis Rheum 34:383-392, 1991. 73. Poole AR, Ionescu M, Swan A, et al: Changes in cartilage metabolism in arthritis are reflected by altered serum and synovial fluid levels of the cartilage proteoglycan aggrecan: Implications for pathogenesis. J Clin Invest 94:25-33, 1994. 74. Poole AR, Witter J, Roberts N, et al: Inflammation and cartilage metabolism in rheumatoid arthritis: Studies of the blood markers hyaluronic acid, orosomucoid, and keratan sulfate. Arthritis Rheum 33:790-799, 1990. 75. Rizkalla G, Reiner A, Bogoch E, et al: Studies of the articular cartilage proteoglycan aggrecan in health and osteoarthritis: Evidence for molecular heterogeneity and extensive molecular changes in disease. J Clin Invest 90:2268-2277, 1992.

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97. Wollheim FA, Eberhardt KB, Johnson U, et al: HLA DRB1* typing and cartilage oligomeric matrix protein (COMP) as predictors of joint destruction in recent-onset rheumatoid arthritis. Br J Rheumatol 36:847-849, 1997. 98. Salminen H, Perala M, Lorenzo P, et al: Up-regulation of cartilage oligomeric matrix protein at the onset of articular cartilage degeneration in a transgenic mouse model of osteoarthritis. Arthritis Rheum 43:1742-1748, 2000. 99. Vilim V, Vytasek R, Olejarova M, et al: Serum cartilage oligomeric matrix protein reflects the presence of clinically diagnosed ­synovitis in patients with knee osteoarthritis. Osteoarthritis Cartilage 9: 612-618, 2001. 100. Roux-Lombard P, Eberhardt K, Saxne T, et al: Cytokines, metalloproteinases, their inhibitors and cartilage oligomeric matrix protein: Relationship to radiological progression and inflammation in early rheumatoid arthritis: A prospective 5-year study. Rheumatology (Oxf) 40:544-551, 2001. 101. Vilim V, Lenz ME, Vytasek R, et al: Characterization of monoclonal antibodies recognizing different fragments of cartilage oligomeric matrix protein in human body fluids. Arch Biochem Biophys 341: 8-16, 1997. 102. Cunnane G, Fitzgerald O, Beeton C, et al: Early joint erosions and serum levels of matrix metalloproteinase 1, matrix metalloproteinase 3, and tissue inhibitor of metalloproteinases 1 in rheumatoid arthritis. Arthritis Rheum 44:2263-2274, 2001. 103. Ribbens C, Andre B, Jaspar JM, et al: Matrix metalloproteinase-3 serum levels are correlated with disease activity and predict clinical response in rheumatoid arthritis. J Rheumatol 27:888-893, 2000. 104. Tchetverikov I, Lard LR, Verzijl N, et al: ProMMP-3 levels predict joint destruction rate in early rheumatoid arthritis. Trans Orthop Res Soc 28, page 15, 2003. 105. Giannelli G, Iannone F, Marinosci F, et al: Infliximab therapy does not modify MMP-2 and MMP-9 serum concentrations in chronic arthritis. Clin Exp Rheumatol 23:867-872, 2005. 106. Ribbens C, Porras M, Franchimont N, et al: Increased matrix metalloproteinase-3 serum levels in rheumatic diseases: Relationship with synovitis and steroid treatment. Ann Rheum Dis 61:161-166, 2002. 107. Lohmander LS, Brandt KD, Mazzuca SA, et al: Use of the plasma stromelysin (matrix metalloproteinase 3) concentration to ­predict joint space narrowing in knee osteoarthritis. Arthritis Rheum 52:3160-3167, 2005. 108. Chevalier X, Conrozier T, Gehrmann M, et al: Tissue inhibitor of metalloprotease-1 (TIMP-1) serum level may predict progression of hip osteoarthritis. Osteoarthritis Cartilage 9:300-307, 2001. 109. Stanton H, Rogerson FM, East CJ, et al: ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434: 648-652, 2005. 110. Glasson SS, Askew R, Sheppard B, et al: Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434:644-648, 2005. 111. Will H, Dettloff M, Bendzko P, et al: A quantitative assay for aggrecanase activity. J Biomolec Tech 16:459-472, 2005. 112. Pratta MA, Su JL, Leesnitzer MA, et al: Development and characterization of a highly specific and sensitive sandwich ELISA for detection of aggrecanase-generated aggrecan fragments. Osteoarthritis Cartilage 14:702-713, 2006. 113. Thomas M, Sabatini M, Bensaude F, et al: A microplate assay for the screening of ADAMTS-4 inhibitors. Matrix Biol 25:261-267, 2006. 114. Tak PP, Smeets TJ, Daha MR, et al: Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum 40:217-225, 1997. 115. Cunnane G, Fitzgerald O, Hummel KM, et al: Synovial tissue protease gene expression and joint erosions in early rheumatoid arthritis. Arthritis Rheum 44:1744-1753, 2001. 116. Ruderman EM, Weinblatt ME, Thurmond LM, et al: Synovial ­tissue response to treatment with Campath-1H. Arthritis Rheum 38: 254-258, 1995. 117. Vos K, Thurlings RM, Wijbrandts CA, et al: Early effects of rituximab on the synovial cell infiltrate in patients with rheumatoid arthritis. Arthritis Rheum 56:772-778, 2007. 118. Gerlag D, Tak PP: Synovial biopsy. Best Pract Res Clin Rheumatol 19:387-400, 2005. 119. Youssef PP, Kraan M, Breedveld F, et al: Quantitative microscopic analysis of inflammation in rheumatoid arthritis synovial membrane samples selected at arthroscopy compared with samples obtained blindly by needle biopsy. Arthritis Rheum 41:663-669, 1998.

120. Kraan MC, Reece RJ, Smeets TJ, et al: Comparison of synovial tissues from the knee joints and the small joints of rheumatoid arthritis patients: Implications for pathogenesis and evaluation of treatment. Arthritis Rheum 46:2034-2038, 2002. 121. Boyle DL, Rosengren S, Bugbee W, et al: Quantitative biomarker analysis of synovial gene expression by real-time PCR. Arthritis Res Ther 5:R352-R360, 2003. 122. Smeets TJ, Kraan MC, Galjaard S, et al: Analysis of the cell infiltrate and expression of matrix metalloproteinases and granzyme B in paired synovial biopsy specimens from the cartilage-pannus junction in patients with RA. Ann Rheum Dis 60:561-565, 2001. 123. Kirkham B, Portek I, Lee CS, et al: Intraarticular variability of ­synovial membrane histology, immunohistology, and cytokine mRNA ­expression in patients with rheumatoid arthritis. J Rheumatol 26: 777-784, 1999. 124. Kane D, Jensen LE, Grehan S, et al: Quantitation of metalloproteinase gene expression in rheumatoid and psoriatic arthritis synovial tissue distal and proximal to the cartilage-pannus junction. J Rheumatol 31:1274-1280, 2004. 125. Haringman JJ, Gerlag DM, Zwinderman AH, et al. Synovial tissue macrophages: A sensitive biomarker for response to treatment in patients with rheumatoid arthritis. Ann Rheum Dis 64:834-838, 2005. 126. Rooney M, Whelan A, Feighery C, et al: Changes in lymphocyte infiltration of the synovial membrane and the clinical course of rheumatoid arthritis. Arthritis Rheum 32:361-369, 1989. 127. Firestein GS, Paine MM, Boyle DL: Mechanisms of methotrexate action in rheumatoid arthritis: Selective decrease in synovial collagenase gene expression. Arthritis Rheum 37:193-200, 1994. 128. Kraan MC, Reece RJ, Barg EC, et al: Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis: ­Findings in a prospective, randomized, double-blind, parallel-design ­clinical trial in thirty-nine patients at two centers. Arthritis Rheum 43: 1820-1830, 2000. 129. Tak PP, Taylor PC, Breedveld FC, et al: Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor alpha monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum 39:1077-1081, 1996. 130. Taylor PC, Peters AM, Paleolog E, et al: Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor alpha blockade in patients with rheumatoid arthritis. Arthritis Rheum 43:38-47, 2000. 131. Verschueren PC, Markusse HM, Smeets TJ, et al: Reduced cellularity and expression of adhesion molecules and cytokines after treatment with soluble human recombinant TNF receptor (P75) in rheumatoid arthritis patients. Arthritis Rheum 42:S197, 1999. 132. Cunnane G, Madigan A, Murphy E, et al: The effects of treatment with interleukin-1 receptor antagonist on the inflamed synovial membrane in rheumatoid arthritis. Rheumatology (Oxf) 40:62-69, 2001. 133. Smeets TJ, Kraan MC, van Loon ME, et al: Tumor necrosis factor alpha blockade reduces the synovial cell infiltrate early after initiation of treatment, but apparently not by induction of apoptosis in synovial tissue. Arthritis Rheum 48:2155-2162, 2003. 134. Youssef PP, Triantafillou S, Parker A, et al: Variability in cytokine and cell adhesion molecule staining in arthroscopic synovial biopsies: Quantification using color video image analysis. J Rheumatol 24:2291-2298, 1997. 135. Gerlag DM, Haringman JJ, Smeets TJ, et al: Effects of oral prednisolone on biomarkers in synovial tissue and clinical improvement in rheumatoid arthritis. Arthritis Rheum 50:3783-3791, 2004. 136. Kruithof E, De Rycke L, Vandooren B, et al: Identification of synovial biomarkers of response to experimental treatment in early-phase clinical trials in spondylarthritis. Arthritis Rheum 54:1795–1804, 2006. 137. Goedkoop AY, Kraan MC, Teunissen MB, et al: Early effects of tumour necrosis factor alpha blockade on skin and synovial tissue in patients with active psoriasis and psoriatic arthritis. Ann Rheum Dis 63:769-773, 2004. 138. Kraan MC, Van Kuijk AW, Dinant HJ, et al: Alefacept treatment in psoriatic arthritis: Reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis. Arthritis Rheum 46:2776-2784, 2002. 138a. Gerlag DM, Boyle DL, Rosengren S, et al: Real-time quantitative PCR to detect changes in synovial gene expression in rheumatoid arthritis after corticosteroid treatment. Ann Rheum Dis 66:545-547, 2007.

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153. Xiang Y, Sekine T, Nakamura H, et al: Proteomic surveillance of autoimmunity in osteoarthritis: Identification of triosephosphate isomerase as an autoantigen in patients with osteoarthritis. Arthritis Rheum 50:1511-1521, 2004. 154. Graham KL, Robinson WH, Steinman L, et al: High-throughput methods for measuring autoantibodies in systemic lupus erythematosus and other autoimmune diseases. Autoimmunity 37:269-272, 2004. 155. Li QZ, Xie C, Wu T, et al: Identification of autoantibody clusters that best predict lupus disease activity using glomerular proteome arrays. J Clin Invest 115:3428-3439, 2005. 156. Li QZ, Zhou J, Wandstrat AE, et al: Protein array autoantibody profiles for insights into systemic lupus erythematosus and incomplete lupus syndromes. Clin Exp Immunol 147:60-70, 2007. 157. Nicholson JK, Lindon JC, Holmes E: ‘Metabonomics’: Understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica 29:1181-1189, 1999. 158. Damyanovich AZ, Staples JR, Marshall KW: 1H NMR investigation of changes in the metabolic profile of synovial fluid in bilateral canine osteoarthritis with unilateral joint denervation. Osteoarthritis Cartilage 7:165-172, 1999. 159. Damyanovich AZ, Staples JR, Chan AD, et al: Comparative study of normal and osteoarthritic canine synovial fluid using 500 MHz 1H magnetic resonance spectroscopy. J Orthop Res 17:223-231, 1999. 160. Lamers RJ, DeGroot J, Spies-Faber EJ, et al: Identification of diseaseand nutrient-related metabolic fingerprints in osteoarthritic Guinea pigs. J Nutr 133:1776-1780, 2003. 161. Lamers RJ, van Nesselrooij JH, Kraus VB, et al: Identification of an urinary metabolite profile associated with osteoarthritis. Osteoarthritis Cartilage 13:762-768, 2005. 162. van der Greef J, McBurney RN: Innovation: Rescuing drug discovery: In vivo systems pathology and systems pharmacology. Nat Rev Drug Discov 4:961-967, 2005. 163. Glocker MO, Guthke R, Kekow J, et al: Rheumatoid arthritis, a complex multifactorial disease: On the way toward individualized medicine. Med Res Rev 26:63-87, 2006. 164. Lee JW, Smith WC, Nordblom GD, et al: Validation of assays for the bioanalysis of novel biomarkers: Practical recommendations for clinical investigation of new drug entities. In Bloom JC, Dean RA (eds): Biomarkers in Clinical Drug Development. New York, Marcel Dekker, 2003, pp 119-148. 165. van den Berg WB, van Riel PL: Uncoupling of inflammation and destruction in rheumatoid arthritis: Myth or reality? Arthritis Rheum 52:995-999, 2005. 166. Kraus VB: Do biochemical markers have a role in osteoarthritis ­diagnosis and treatment? Best Pract Res Clin Rheumatol 20:69-80, 2006.

33

Occupational and Recreational Musculoskeletal Disorders Richard S. Panush

KEY POINTS Some occupational and recreational activities have been linked with musculoskeletal syndromes or disorders. These include certain syndromes manifested by neck pain; ­shoulder, elbow, hand, or wrist pain or tendinitis; carpal tunnel ­syndrome; and hand-arm vibration syndrome. The concepts of so-called cumulative trauma disorders and ­repetitive strain disorders, though perhaps intuitive, are ­poorly supported by the literature. Causal relationships ­between most occupations or activities and these ­“syndromes” should not be considered well established. Some activities and mechanical stresses have been associated with osteoarthritis at certain sites—for example, the hips of ­farmers, the knees of workers whose jobs involve frequent knee bending, and the hands of workers doing repetitive tasks with their hands (e.g., seamstresses, diamond workers, textile ­workers). Certain rheumatic disorders have been related to environmental or occupational risks, such as Raynaud’s phenomenon with vibration and polyvinyl chloride; autoimmune disease with teaching school; systemic sclerosis with chlorinated ­hydrocarbons, organic solvents, and silica; scleroderma-like syndromes with rapeseed oil and l-tryptophan; lupus syndromes with canavanine, hydrazine, mercury, pesticides, and solvents; lupus, scleroderma, and Paget’s disease with pet ownership; rheumatoid arthritis with silica (Caplan’s syndrome); and saturnine gout with lead exposure. Putting a normal joint through its normal range of motion is not necessarily harmful for a normal individual; however, if the joint, motion, stress, or biomechanics are not normal, there may be a risk of joint harm. Most normal individuals comfortably engaging in reasonable recreational activities can do so without evidence of lasting soft tissue or articular damage; runners have been best studied. Conversely, individuals who exercise with pain, effusions, underlying joint abnormalities (e.g., ligamentous or meniscal damage), or abnormal or unusual biomechanics or as professional or elite athletes (e.g., boxers, American football or soccer players) seem to be at increased risk of joint injury. Performing artists, vocalists, dancers, and musicians seem to have a risk of soft tissue and joint injury analogous to that of athletes, but little information is available.

“The diseases of persons incident to this craft arise from three causes: first constant sitting, second the perpetual motion of the hand in the same manner, and thirdly the attention and application of the mind. . . . Constant writing also considerably fatigues the hand and whole arm on account of the continual and almost tense tension of the muscles and tendons. I knew a man who, by perpetual writing, began first to complain of an ­excessive weariness of his whole right arm, which could be

removed by no medicines, and which was at last succeeded by a perfect palsy of the whole arm.” —Ramazzini 17131 “When job demands . . . repeatedly exceed the biomechanical capacity of the worker, the activities become trauma-inducing. Hence, traumatogens are workplace sources of biomechanical strain that contribute to the onset of injuries affecting the musculoskeletal system.” —National Institute for Occupational Safety and Health (1986)2

This chapter discusses the possible association of certain occupational and recreational activities with musculoskeletal disorders. It has been conventional wisdom that “wear and tear” from at least some activities lead to reversible or irreversible damage to the musculoskeletal system.2-5 Despite the apparent logic that work or recreational activities might cause rheumatic and musculoskeletal disorders or soft tissue syndromes, this putative association is controversial and perhaps seriously flawed. There are confounding aspects to much of the available data, including imprecise diagnostic labels, the subjectivity of complaints, anecdotal and survey data, inadequate controls, differing definitions of disease and disability, limited duration of follow-up observations, inadequate epidemiology, inferential observations, difficulty quantifying activities and defining health effects, assumptions of the validity of claims data, variable quality of reported observations, psychological factors influencing symptoms, and conflicting data.

OCCUPATION-RELATED MUSCULOSKELETAL DISORDERS Many presumptive work-related musculoskeletal ­ disorders have been described and are summarized in Table 33-1.1-11 These have been reported as sprains, strains, inflammations, dislocations, and irritations. The cost of work-related disability from musculoskeletal disorders has been equivalent to approximately 1% of the United States’ gross national product, making these entities of considerable societal interest.12 Industries with the highest rates of musculoskeletal disorders include meatpacking, knit-­underwear manufacture, motor vehicle manufacture, poultry processing, mail and message distribution, health assessment and treatment, construction, butchery, food processing, machine operation, dental hygiene, data entry, hand grinding and polishing, carpentry, industrial truck and tractor operation, nursing assistance, and housecleaning. There have been imprecise associations between workrelated musculoskeletal syndromes and age, gender, fitness, and weight.6,10,11 491

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Table 33-1  Occupation-Related Musculoskeletal   Syndromes

Table 33-2  Selected Literature Describing Regional   Occupation-Related Musculoskeletal Syndromes No. of Epidemiologic Studies

Odds Ratio/ Relative Risk

Cherry pitter’s thumb

Gamekeeper’s thumb

Staple gun carpal tunnel syndrome

Espresso maker’s wrist

Bricklayer’s shoulder

Espresso elbow

Neck pain

26

0.7-6.9

Carpenter’s elbow

Pizza maker’s palsy

Shoulder tendinitis

22

0.9-13

Janitor’s elbow

Poster presenter’s thumb

Elbow tendinitis

14

0.7-5.5

Stitcher’s wrist

Rope maker’s claw hand

Hand-wrist tendinitis

16

0.6-31.7

Cotton twister’s hand

Telegraphist’s cramp

22

1-34

Writer’s cramp

Waiter’s shoulder

Carpal tunnel   syndrome

Bowler’s thumb

Ladder shins

8

0.5-41

Jeweler’s thumb

Tobacco primer’s wrist

Syndrome

Hand-arm vibration syndrome Data from references 5 and 6.

Carpet layer’s knee

A number of work-related regional musculoskeletal ­syndromes have been described. These include disorders of the neck, shoulder, elbow, hand and wrist, lower back, and lower extremities10 (Table 33-2); some of these are discussed in greater detail in other chapters. Neck musculoskeletal disorders are associated with repetition, forceful exertion, and constrained or static postures. Shoulder musculoskeletal­ disorders occur with work at or above shoulder height, lifting of heavy loads, static postures, hand-arm vibration, and repetitive motion. For elbow epicondylitis, risk factors are overexertion of finger and wrist extensors with the elbow in extension, as well as posture. Hand-wrist tendinitis and work-related carpal tunnel syndrome are noted with repetitive work, forceful activities, flexed wrists, and duration­ of continual effort.1,10 Hand-arm vibration syndrome ­(Raynaud-like phenomenon)13 has been linked to the intensity and duration of vibrating exposure. Work-related lower back disorders are associated with repetition, the weight of objects lifted, twisting, and poor biomechanics of lifting.13,14 Other risk factors for work-related musculoskeletal disorders involving the back include awkward posture, high static muscle load, high-force exertion at the hands and wrists, sudden applications of force, work with short cycle times, little task variety, frequent tight deadlines, inadequate rest or recovery periods, high cognitive demands, little control over work, cold work environment, localized mechanical stresses to tissues, and poor spinal support.1 The development of recommended treatment methods (rehabilitation) for these so-called occupational musculoskeletal disorders has included collaboration by workers, employers, insurers, and health professionals. The process has been divided into three phases: protection from and resolution of symptoms, restoration of strength and dynamic stability, and return to work. This process includes symptomatic therapies, physical therapy, and ergonomic evaluation.7 Prognosis for these maladies has not been well studied or defined.8 Until recently, the prevailing view was that musculoskeletal disorders were consistently and predictably work related. That understanding has now come under considerable scrutiny and criticism.2,15-24 Despite the quantity of published information (see Table 33-2), the previously cited literature about occupational musculoskeletal disorders is now considered flawed; its quality was uneven and perhaps poor in some cases. Definitions of musculoskeletal disorders were ­imprecise; diagnoses, by rheumatologic standards, were

infrequent; studies were usually not prospective, and there were selection biases; psychological influences and secondary gain were often ignored; questionnaires were often used without validation of subjective complaints; and quantification of putative causative factors was difficult. Indeed, a review of this literature concluded that none of the published studies satisfactorily established a causal relationship between work and distinct medical entities.20 In fact, certain experiences argued powerfully against the notion of workrelated musculoskeletal disorders. In Lithuania, for example, where insurance was limited and disability was not a societal expectation or entitlement, “whiplash” from auto accidents did not exist.19 In Australia, when legislation for compensability was made more stringent, an epidemic of whiplash and repetitive-strain injuries abated.21,23 In the United States, too, expressed symptoms correlated closely with the likelihood of obtaining compensation.25 In other cases, ergonomic interventions had no effect on alleged work-related symptoms, and close analysis of epidemics of work-related musculoskeletal disorders revealed serious inconsistencies.17 These concerns led the American Society for Surgery of the Hand to editorialize that “the current medical literature does not provide the information necessary to establish a causal relationship between specific work activities and the development of well-recognized disease entities. Until scientifically valid studies are conducted, the society urges the government to exercise restraint in considering regulations designed to reduce the incidence of these conditions, as premature regulations could have far-reaching legal and economic effects, and could have an adverse impact on the care of workers.”18 One review summarized that “most believe scientific data are insufficient to establish a definite causal relationship of these so-called cumulative trauma disorders to the worker’s occupation, and many believe the issue has become a sociopolitical problem.”9 Hadler2,15-17 has written particularly forcefully that popular notions about work-related musculoskeletal disorders have been based on inadequate science. Others, too, have expressed serious reservations about the cumulative trauma disorder hypothesis, including the Industrial Injuries Committee of the American Society for Surgery of the Hand, the Working Group of the British Orthopaedic Association, and the World Health Organization.2,15-17,20,22 An appreciation of the importance of psychosocial factors influencing work disability has emerged. These factors include lack of job control, fear of layoff, monotony, job ­dissatisfaction,

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unsatisfactory performance appraisals, distress and unhappiness with coworkers or supervisors, poor coping abilities, divorce, low income, and less education.2,15-25 This is reminiscent of the story of silicone breast implants and their putative association with rheumatic disease. In this instance—as seems to be the case with work-related musculoskeletal disorders—there was a coalescence of naively simplistic assumptions, untested hypotheses, confusion between the repetition of hypotheses and their scientific validation, media exaggeration, and public advocacy intertwined with politics and governmental regulatory agencies, dollar jackpots, litigation, and inadequate science. All these elements confounded and perverted the silicone breast implant story26,27 and may have confused the interpretation of evidence-based work-related musculoskeletal disorders as well. More research is needed to learn about work-related musculoskeletal disorders and to clearly identify the ­circumstances in which they occur. Work-related musculoskeletal disorders probably do exist, but they are likely to be less pervasive and less noxious than originally thought.

OCCUPATION-RELATED RHEUMATIC DISEASES Work-related rheumatic diseases have not been consistently well studied, but associations between occupations and welldefined rheumatic disorders are clearer than those involving musculosketetal disorders. This topic also recapitulates the simplistic notion that joints deteriorate with use. However, this perception is neither necessarily logical nor correct. The discussion focuses largely on osteoarthritis (OA); see also Chapters 90 and 91. OSTEOARTHRITIS Is OA caused, at least in part, by mechanical stress? One analytic approach to determining a possible relationship between activity and joint disease is to consider the ­epidemiologic evidence that degenerative arthritis may

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f­ollow ­ repetitive trauma. Most discussions of the pathogenesis of OA include a role for “stress.”28-31 Several studies have suggested an increased prevalence of OA of the elbows, knees, and spine in miners32-34; of the shoulders, elbows, wrists, and metacarpophalangeal joints in pneumatic drill operators35; of the intervertebral disks, distal interphalangeal joints, elbows, and knees in dockworkers33; of the hands in cotton workers,36 diamond cutters,32,37 seamstresses,37 and textile workers38,39; of the knees and hips in farmers; of the knees in shipyard workers and a variety of occupations involving knee bending; and of the spine in foundry workers40-43 (Table 33-3). Population studies have noted increased hip OA in farmers, firefighters, mill workers, dockworkers, female mail carriers, unskilled manual laborers, fishermen, and miners and have reported increased knee OA in farmers, firefighters, construction workers, house and hotel cleaners, craftspeople, laborers, and service workers.40-43 Activities leading to an increased risk for premature OA involve power gripping, carrying, lifting, increased physical loading, increased static loading, kneeling, walking, and bending.40-43 Studies of skeletons of several populations have suggested that age at onset, ­ frequency, and location of osteoarthritic changes were directly related to the nature and degree of physical activities.44 ­However, not all these studies adhered to ­contemporary standards, nor have they been confirmed. One report, for example, failed to find an increased incidence of OA in pneumatic drill users and criticized inadequate sample sizes, lack of statistical analyses, and omission of appropriate control populations in previous reports.34 The investigators further commented that earlier work was “frequently ­misinterpreted” and that their studies suggested that “impact, without injury or preceding abnormality of either joint contour or ligaments, is unlikely to produce osteoarthritis.”35 Do epidemiologic studies of OA implicate physical or mechanical factors related to disease predisposition or development? The first national Health and Nutrition Examination Survey of 1971 to 1975 (HANES I) and the Framingham studies explored cross-sectional associations between ­ radiographic OA of the knee and possible risk

Table 33-3  Occupational Physical Activity and Possible Associations with Osteoarthritis Occupation

Involved Joints

Risk of OA

References

Miner

Elbow, knee, spine

Increased

Lawrence33 (1955), Kellgren & Lawrence34 (1958), Felson43,44 (1997, 1998)

Pneumatic driller

Shoulder, elbow, wrist, MCP

Increased/none

Jurmain (1977) (cited in ref 40), Burke et al35 (1977)

Dockworker

Intervertebral disk, DIP,   elbow, knee

Increased

Lawrence33 (1955)

Cotton mill worker

Hand

Increased

Lawrence36 (1961)

Diamond worker

Hand

Increased

Kellgren & Lawrence32 (1957), Tempelaar   & van Breeman37 (1932)

Shipyard laborer

Knee

Increased

Goldberg & Montgomery (1987) (cited in refs 43, 44)

Foundry worker

Lumbar spine

Increased

Lawrence et al (1966) (cited in refs 43, 44)

Seamstress

Hand

Increased

Tempelaar & Van Breeman37 (1932)

Textile worker

Hand

Increased

Hadler et al39 (1978)

Manual laborer

MCP

Increased

Williams et al (1987) (cited in refs 43, 44)

Occupations requiring   knee bending

Knee

Increased

Felson et al40-43 (1988, 1991, 1997, 1998)

Farmer

Hip, knee

Increased

Felson40-43 (1988, 1991, 1997, 1998)

DIP, distal interphalangeal joint; MCP, metacarpophalangeal joint; OA, osteoarthritis.

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Table 33-4  Other Occupation-Related Rheumatic   Diseases Disease or Syndrome

Occupation or Risk Factor

Reflex sympathetic dystrophy

Trauma

Raynaud’s phenomenon

Vibration Chemicals (polyvinyl chloride)

Autoimmune disease

Teaching school

Systemic sclerosis

Chlorinated hydrocarbons Organic solvents Silica

Scleroderma-like syndromes

Rapeseed oil l-Tryptophan

Systemic lupus   erythematosus

Canavanine, hydrazine,   mercury, pesticides, solvents

Lupus, scleroderma,   and Paget’s disease

Pet ownership

Rheumatoid arthritis   (Caplan’s syndrome)

Silica

Gout (saturnine)

Lead

f­actors.40-46 Strong associations were noted between knee OA and obesity and those occupations involving the stress of knee bending, but not all habitual physical activities and leisure-time physical activities (running, walking, team sports, racquet sports, and others) were linked with knee OA.28-30 OTHER OCCUPATIONAL RHEUMATOLOGIC DISORDERS Certain rheumatic diseases other than repetitive strain or cumulative trauma disorders have been associated with occupational risks. These include reports of reflex sympathetic dystrophy after trauma; Raynaud’s phenomenon with vibration or exposure to chemicals (polyvinyl chloride); autoimmune disease from teaching school43,47; systemic sclerosis from chemicals and silica; scleroderma-like syndromes from rapeseed oil and l-tryptophan; systemic lupus erythematosus from canavanine, hydrazine, mercury, pesticides, and solvents48; lupus, scleroderma, and Paget’s disease from pets49; rheumatoid arthritis (Caplan’s syndrome) with silica; and gout (saturnine) with lead intoxication50 (Table 33-4).

RECREATION- AND SPORTS-RELATED MUSCULOSKELETAL DISORDERS Do recreational or sports-related activities lead to musculoskeletal disorders? Patients with sports injuries (such as from downhill skiing and football) to the anterior cruciate and medial collateral ligaments frequently develop the chondromalacia patellae and radiographic abnormalities of OA (20% to 52%).28-30 Retrospective studies suggest that the development of OA may be associated with varus deformity, previous meniscectomy, and relative body weight.51,52 Both partial and total meniscectomies have been associated with degenerative changes. Early joint stabilization and direct meniscus repair surgery may decrease the incidence of premature OA. These observations support the concept that abnormal ­ biomechanical

forces, either congenital or secondary to joint injury, are important factors in the development of exercise-related OA.28-30 Other factors considered important in the development of sports-related OA include certain physical characteristics of the participant, biomechanical­ and biochemical factors, age, gender, hormonal influences, nutrition, characteristics of the playing surface, unique features of particular sports, and duration and intensity of exercise participation, as has been reviewed extensively elsewhere.28-30 It is increasingly recognized that biomechanical factors have an important role in the ­ pathogenesis of OA. Is regular participation in physical activity associated with degenerative arthritis? Several animal studies have suggested, but not proved, a possible relationship between exercise and OA. It has been stated that the husky breed of dog has increased hip and shoulder arthritis associated with ­ pulling sleds, that tigers and lions develop foreleg OA related to sprinting and running, and that racehorses and workhorses develop OA in the forelegs and hind legs, respectively, consistent with their physical stress patterns.28-30 Rabbits with experimentally induced arthritis in one hind limb did not develop progressive OA when exercised on treadmills,54-59 but sheep in normal health walking on concrete did develop OA.53 Later studies found that beagle dogs running 4 to 20 km a day did not develop OA.60 Although these observations were not entirely consistent, they suggested, but did not prove, that physical activities in some circumstances might predispose to degenerative joint ­disease. There have been some pertinent, largely anecdotal, observations in human studies28-30 (Table 33-5). Wrestlers were reported to have an increased incidence of OA of the lumbar spine, cervical spine, knees, and elbows; boxers, of the carpometacarpal joints; baseball pitchers, of the shoulders and elbows; parachutists, of knees, ankles, and spine; cyclists, of the patella; cricketers, of the fingers; and gymnasts, of the shoulders, elbows, and wrists.28-30 Most of these reports were observational, and not all of them reflected confirmed associations. Soccer players have been reported to have talar joint, ankle, cervical spine, knee, and hip OA.28-30,61 Few studies of American football players have been reported, but it has been suggested that they are susceptible to OA of the knees, particularly those who sustained knee injuries while playing football. Among football players (average age 23 years) competing for a place on a professional team, 90% had radiographic abnormalities of the foot or ankle, compared with 4% of an age-matched control population; linemen had more changes than did ball carriers or linebackers, who in turn had more changes than did flankers or defensive backs. All those who had played football for 9 years or longer had abnormal findings on radiography.28-31 Most of these studies suffered in several respects: criteria for OA (or “osteoarthrosis,” “degenerative joint disease,” or “abnormality”) were not always clear, specified, or consistent; duration of follow-up was often not indicated or was inadequate to determine the risk of musculoskeletal problems at a later age; intensity and duration of physical activity were variable and difficult to quantify; selection bias toward individuals exercising or participating versus those not exercising or participating was not weighted; other possible risk factors and predispositions to musculoskeletal disorders were rarely

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Table 33-5  Sports Participation and Alleged Associations with Osteoarthritis Sport

Site (Joint)

References*

Ballet

Talus

Ottani & Betti (1953), Coste et al   (1960), Brodelius (1961),   Miller et al (1975)

Ankle Cervical spine Hip Knee Metatarsophalangeal

Washington (1978), Ende & Wickstrom (1982)

Elbow Shoulder

Adams (1965), Hansen (1982) Bennett (1941)

Boxing

Hand   (carpometacarpal joints)

Iselin (1960)

Cricket

Finger

Vere Hodge (1971)

Cycling

Finger

Bagneres (1967)

American football

Ankle Foot Knee Spine Elbow Shoulder Wrist Hip

Probably increased

Washington (1978)

Baseball

Gymnastics

Risk

Vincelette et al (1972) Rall et al (1964) Ferguson et al (1975), Albright et al   (1976), Moretz et al (1984)

Probably increased

Bozdech (1971) Murray & Duncan (1971)

Lacrosse

Ankle Knee

Thomas (1971)

Martial arts

Spine

Rubens-Duval et al (1960)

Parachuting

Ankle Knee Spine

Murray & Duncan (1971) Murray-Leslie et al (1977a)

Rugby

Knee

Slocum (1960)

Running

Knee

McDermott & Freyne (1983),   Lane et al (1986, 1987, 1998),   Panush et al (1986) Puranen et al (1975), de Carvalho   & Langfeldt (1977), McDermott   & Freyne (1983), Lane et al (1986,   1987, 1998), Panush et al (1986),   Konradsen et al (1990) Konradsen et al (1990), Marti et al (1990)

Small

Pellissier et al (1952), Pellegrini et al (1964) Sortland et al (1982) Klunder et al (1980) Pellissier et al (1952), Solonen (1966),   Klunder et al (1980) Brodelius (1961), Solonen (1966) Burel et al (1960)

Possibly increased

Hip

Ankle Soccer

Ankle-foot Hip Knee Talus Talofibular

Weightlifting

Spine

Wrestling

Cervical spine Elbow Knee

Aggrawal et al (1965), Muenchow   & Albert (1969), Fitzgerald   & McLatchie (1980)

Possibly increased

Layani et al (1960)

*Cited in Panush RS, Lane NE: Exercise and the musculoskeletal system. Baillieres Clin Rheumatol 8:79, 1994; Panush RS: Physical activity, fitness, and osteoarthritis. In Bouchard C, Shephard RJ, Stephens T (eds): Physical Activity, Fitness, and Health. International Proceedings and Consensus Statement. Champaign, Ill, Human Kinetics Publishers, 1994, pp 712-723; Panush RS: Does exercise cause arthritis? Long-term consequences of exercise on the musculoskeletal system. Rheum Dis Clin North Am 16:827, 1990.

considered; studies were not always properly controlled, and examinations were not always “blind”; little information regarding nonprofessional, recreational athletes was available; and little clinical information about functional status was provided.

Several studies have now examined a possible relationship between running and OA. Uncontrolled observations generally suggested that runners without underlying ­biomechanical problems of the lower extremity joints did not develop arthritis at a different rate from a normal

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p­ opulation of nonrunners. However, those individuals who had underlying articular biomechanical abnormalities from a previously injured joint (and perhaps elite athletes, particularly women) did appear to be at greater risk for the subsequent development of OA. Early studies showed that groups of long-duration, high-mileage runners and nonrunning control subjects had a comparable (and low) prevalence of OA and suggested that recreational running need not lead inevitably to OA.54,62 These observations have, in general, now been confirmed by others55-64 (Table 33-6). Eight- and 9-year follow-up observations were encouraging; most of the original runners were still running, with a prevalence of degenerative joint disease that was comparable with that of the control subjects.54,56 Perhaps even more significant is the growing evidence that running and other aerobic exercise protect against the development of disability and early mortality.64 Former college varsity long-distance runners were compared with former college swimmers in another study65;

there was no association between moderate levels of running or number of years running and the development of symptomatic OA. Other authors have concluded that running alone does not cause OA; rather, prior injuries and anatomic variances are directly responsible for some of the changes.62 Several additional reports have found that runners are not at risk for the development of premature OA of the knees or ankles.59,65-67 Studies examining degenerative hip diseases in former athletes58,68-71 noted that former champion distance runners had no more clinical or radiographic evidence of OA than did nonrunners.66 However, another study found more radiographic changes due to degenerative hip disease in former national team long-distance runners than in bobsled competitors and control subjects.68 In all the subjects studied, age and mileage run in 1973 were strong predictors of radiographic hip OA; for runners, running pace in 1973 was the strongest predictor of subsequent radiographic hip OA

Table 33-6  Studies of Running and Risk of Developing Osteoarthritis References

No. of Runners

Mean Age (yr)

Mean No. of Years Running

Miles/Wk

Comments

Minor et al (1989)   (cited in refs 28-30)

319

NA

NA

NA

OA noted more frequently in former runners (with underlying anatomic “tilt” abnormality—  epiphysiolysis) than in nonathletes

Puranen et al58 (1975)

74

56

21

NA

Champion distance runners had no more hip OA than did nonrunners in their sixth decade

De Carvalho   & Langfeldt59 (1977)

32

NA

NA

NA

X-ray findings of runners’ hips and knees were similar to those of control subjects

Marti et al69 (1990)

20

35

13

48

OA occurred in runners with underlying anatomic (biomechanical) abnormality

504

57

9-15

18-19

No association between moderate long-distance running and future development of OA (of hip and knees)

Panush et al62 (1986)

17

53

12

28

Comparable low prevalence of lower extremity OA in runners and nonrunners

Lane et al55 (1986)

41

58

9

(5 hr/wk)

No differences between runners and control subjects in cartilage loss, crepitus, joint stability, or symptoms

498

59

12

27

No differences between groups in ­conditions thought to predispose to OA and ­musculoskeletal disability

Marti et al68,69   (1989, 1990)

27

42

NA

61 (in referMore radiographic changes of hip OA in former ence years) Swiss national team long-distance runners than in bobsledders and control subjects; few ­runners had clinical symptoms of OA; no ­difference in ankle joints

Konradsen et al66   (1990)

30

58

40

12-24

No clinical or radiographic differences in hips, knees, and ankles between runners and   nonrunners

Sohn & Micheli65 (1985)

Lane et al (1987)   (cited in refs 28-30)

Vingard et al70 (1995)

114

50-80

NA

NA

Unvalidated questionnaire reported threefold increase of hip arthrosis in former athletes

Kujala et al67 (1994)

342

NA

NA

NA

More former athletes hospitalized with hip OA than expected

Kujala et al61 (1995)

28

60

32

NA

Women soccer players and weightlifters,   nonrunners were at risk of premature OA

Panush et al54 (1995)

16

13

22

22

8-yr follow-up of original observations made in 1986 still found no differences between runners and nonrunners

Lane et al56 (1998)

35

60

10-13

23-28

Running did not appear to influence the ­development of radiographic OA (with possible exception of spur formation in women)

NA, not available; OA, osteoarthritis.

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in 1988. These authors concluded that high-intensity, highmileage running should not be dismissed as a risk factor for premature OA of the hip. Other reports found that former top-level soccer players and weightlifters, but not runners, were at risk for the development of knee OA,61,71 but it was suggested elsewhere that former athletes seemed to be disproportionately represented in hospital admissions for OA of hip, knee, or ankle.71 A questionnaire of former elite and track-and-field athletes noted more hip OA.70 Similarly, radiographic OA of the hip and knee was reported in women who were formerly runners and tennis players.71 Cross-sectional studies on the effect of weight-bearing exercise on the development of OA of the hip, knee, or ankle and foot must be interpreted with caution, however. The radiographic scoring methods used by each group of investigators differ, and their reliability has not been adequately tested. This information is important when the major end points in the studies are radiographic features of OA.

PERFORMING ARTS–RELATED MUSCULOSKELETAL DISORDERS Musculoskeletal problems are common among performing artists. Performing artists—particularly musicians and ­dancers—have unique medical and musculoskeletal problems that deserve special consideration. Injuries that might be trivial to others may be catastrophic to such artists. These injuries are usually associated with overuse—the consequences of tissues stressed beyond anatomic or normal ­physical limits. INSTRUMENTALISTS The frequency of musculoskeletal problems in musicians rivals the frequency of disability in athletes. For example, one report found that 82% of orchestral musicians experienced medical problems related to their occupation. Musculoskeletal problems represented the bulk of the difficulties encountered by musicians.72 The causes of, mechanisms of, and therapies for these musculoskeletal problems are unclear (Table 33-7). An editorial suggested that overuse, tendinitis, cumulative trauma disorder, repetitive motion disorder, occupational cervicobrachial disorder, and regional pain syndrome may be critical risk factors in the development of joint laxity in musicians.72 Joint laxity declined with age and was associated with gender, starting earlier in men but persisting in women through their mid-40s. The presence or absence of hypermobility at certain sites was associated with musicians’ complaints of associated symptoms. Hypermobility in musicians might produce advantages or disadvantages, depending on the site of the laxity and the instrument played.73 Paganini, with his long fingers and reported hyperextensibility, had a wider ­finger reach on the violin than his contemporaries, but he may have had a predisposition to OA because of this. A review of studies found that 66% of professional symphony orchestra members reported severe musculoskeletal problems. Of interest and seemingly unexplained was the high frequency of symptoms among women (68% to 84%); perhaps this is related to their higher incidence of hypermobility.72 One group of disorders has not been clearly characterized clinically, probably because of the overlap of complaints. These include neurologic problems such as carpal

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tunnel syndrome and ulnar nerve compression syndromes at the wrist. On occasion, hand and wrist problems are due to cervical or cervicobrachial radiculopathies. Stress is a factor in all performance fields and contributes to motor function problems, such as occupational cramps; dealing with this problem often requires the best efforts of a team of ­physicians and therapists.72-75 VOCAL ARTISTS Musculoskeletal problems among singers have not been addressed extensively. In a report from the Royal Theater in Copenhagen, the frequency of musculoskeletal problems was the same in both instrumentalists and opera singers. However, singers had more hip, knee, and foot joint complaints, perhaps reflecting the effects of prolonged standing.74 DANCERS Dance has always been viewed as a demanding art form, but only recently have the athletic rigors of this discipline become widely appreciated. Classic ballet ranked first in activities generating physical and mental stress, followed by professional football and professional hockey. The dancer and athlete have much in common, but there are important differences in training and performance technique that influence the nature of their injuries. Other important sociocultural differences affect their care. Professional dancers (as well as musicians and vocalists) have traditionally been wary of physicians, and their conviction that physicians know little about dance (and music) is still common. Injured dancers seeking care have often been told that the treatment is to stop dancing. Others, seeking assistance with weight control, have been told to gain weight. Dancers frequently underreport their injuries and seek care from nonmedical therapists. It is difficult to generalize about dance injuries because dance is not a monolithic effort. It is a broad-based hierarchic endeavor in which thousands of local school-based and private amateur dance classes supply a much smaller number of university-based dance programs, which lead finally to relatively few professional dance companies. This system of training encompasses many forms of dance that are highly divergent, ranging from classic ballet to break dancing. Fortunately, the majority of injuries are from overuse and are rarely catastrophic, regardless of the dance style or setting. As with other overuse injuries in sports, they are influenced by a variety of factors that may be classified as intrinsic, such as biomechanical and anatomic variations, or extrinsic, such as those related to occupation or equipment.72 There are few reliable data on the epidemiology of amateur dance injuries, but a study of ballet dancers revealed a high lifetime incidence of a variety of injuries, including overuse injuries (reported by 63%), stress fractures (26%), and major (51%) and minor (48%) problems, throughout their careers. In a cumulative study of nine major surveys of dance-related injuries in ballet, modern, jazz, and theatrical dancers, more than 7000 injuries were classified. Not surprisingly, the majority (60% to 80%) involved the ankle, foot, or knee. The most common types of overuse injuries include strains of muscles and tendons and tendinitis (particularly of the Achilles and flexor hallucis longus tendons).

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Table 33-7  Musculoskeletal and Rheumatic Disorders Associated with Overuse in Performing Artists Instrument

Affliction (Common Name)

References*

Piano, keyboard

Myalgias Tendinitis

Hochberg et al (1983), Knishkowy & Lederman (1986) Hochberg et al (1983), Caldron et al (1986), Knishkowy & Lederman (1986), Newmark & Hochberg (1987) Hochberg et al (1983), Knishkowy & Lederman (1986) Hochberg et al (1983), Knishkowy & Lederman (1986)

Synovitis Contractures Nerve entrapment Median nerve   (carpal tunnel– pronator syndrome) Ulnar nerve Brachial plexus Posterior interosseous branch of radial nerve Thoracic outlet syndrome Motor palsies Osteoarthritis Strings Violin, viola

Cello

Bass

Viola da gamba Harp Woodwinds Clarinet and   oboe Flute

Brass Trumpet,   cornet English horn French horn Saxophone Percussion Drums Cymbals

Myalgias Tendinitis Epicondylitis Cervical spondylosis Rotator cuff tears Thoracic outlet syndrome Temporomandibular joint syndrome Motor palsies Garrod’s pads Nerve entrapment Ulnar Interosseous Myalgias Tendinitis Epicondylitis Low back pain Nerve entrapment Motor palsies Thoracic outlet syndrome Low back pain Myalgias Tendinitis Motor palsies Saphenous nerve compression (gamba leg) Tendinitis Nerve entrapment

Hochberg et al (1983), Knishkowy & Lederman (1986) Hochberg et al (1983), Knishkowy & Lederman (1986) Hochberg et al (1983), Knishkowy & Lederman (1986) Hochberg et al (1983), Charness et al (1985) Hochberg et al (1983), Knishkowy & Lederman (1986), Lederman (1987) Hochberg et al (1983), Schott (1983), Caldron et al (1986), Knishkowy   & Lederman (1986), Merriman et al (1986), Cohen et al (1987), Jankovic & Shale (1989) Bard et al (1984) Fry (1986b), Hiner et al (1987), Bryant (1989) Fry (1986b), Hiner et al (1987) Fry (1986b), Hiner et al (1987) Fry (1986b), Hiner et al (1987) Fry (1986b), Newmark & Hochberg (1987) Roos (1986), Lederman (1986) Hirsch et al (1982), Ward (1990), Kovera (1989) Schott (1983), Knishkowy & Lederman (1986), Hiner et al (1987), Jankovic & Shale (1989) Bird (1987) Knishkowy & Lederman (1986) Maffulli & Maffulli (1991) Fry (1986b) Caldron et al (1986), Fry (1986b) Fry (1986b) Fry (1986b) Caldron et al (1986), Knishkowy & Lederman (1986) Schott (1983) Lederman (1987), Palmer et al (1991) Fry (1986b) Fry (1986b) Caldron et al (1986), Fry (1986b), Mandell et al (1986) Caldron et al (1986) Schwartz & Hodson (1980), Howard (1982) Caldron et al (1986) Caldron et al (1986)

First web space muscle strain Tendinitis Motor palsies Myalgias Spine pain Temporomandibular joint syndrome Tendinitis Nerve entrapment Digital Posterior interosseous Thoracic outlet syndrome

Fry (1986b), Newmark & Hochberg (1987) Dawson (1986), Fry (1986b) Jankovic & Shale (1989) Fry (1986b) Fry (1986b) La France (1985) Patrone et al (1988)

Motor palsies Orbicularis oris rupture (Satchmo’s syndrome) de Quervain’s tenosynovitis Motor palsies Thoracic outlet syndrome

Turner (1893), Dibbell (1977), Dibbell et al (1979) Planas (1982, 1988), Planas & Kaye (1982) Studman and Milberg (1982) James & Cook (1983), Jankovic & Shale (1989) Lederman (1987)

Osteoarthritis Tendinitis Myalgias Nerve entrapment Bicipital tenosynovitis (cymbal player’s shoulder)

Caldron et al (1986) Fry (1986b), Caldron et al (1986) Fry (1986b) Makin & Brown (1985) Huddleston & Pratt (1983)

Cynamon (1981) Charness et al (1985) Lederman (1987)

*As cited in Greer JM, Panush RS: Musculoskeletal problems of performing artists. Baillieres Clin Rheumatol 8:103, 1994.

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Table 33-7  Musculoskeletal and Rheumatic Disorders Associated with Overuse in Performing Artists—cont’d Instrument Miscellaneous Guitar Congas Spoons

Affliction (Common Name)

References*

Tendinitis Synovitis Motor palsies Pigmenturia Tibial stress fracture (spoon player’s tibia)

Newmark & Hochberg (1987) Mortanroth (1978), Bird & Wright (1981) Mladinich & De Witt (1974), Cohen et al (1987), Jankovic & Shale (1989) Fenichel (1974), Furie & Penn (1974) O’Donoghue (1984)

*As cited in Greer JM, Panush RS: Musculoskeletal problems of performing artists. Baillieres Clin Rheumatol 8:103, 1994.

The distribution of injuries is strongly influenced by the type and style of dance and the age and sex of the population.73,76 For example, ballet dancers in companies whose choreography emphasizes bravura technique with big jumps and balances are more likely to develop Achilles tendinitis than are those in companies that do not. Men are more likely to have back injuries because of the requisite jumping and lifting, whereas women who dance on pointe are more prone to toe, foot, and ankle problems. The surface on which dancers perform is also critical. Touring companies may encounter nonflexible surfaces, including concrete; this predisposes dancers to injuries such as shin splints and stress fractures. Many dance injuries, particularly among nonprofessionals, stem from bodies that are poorly suited to perform the many unphysiologic positions and maneuvers demanded by a variety of dance techniques. For example, in ballet, the most important physical feature is proper turnout ­(external rotation) of the hip. The extent of a dancer’s turnout is determined primarily by anatomic factors as well as by the influence of training before the age of 10 or 11 years. In would-be dancers who are older, attempts to “force” a proper turnout generally result in severe strains to the lower extremity, particularly the knee and foot. Other anatomic factors are also important, including somatotype, lack of flexibility in general, and particularly lack of ankle-instep flexibility. Occupational factors, including long hours of practice and rehearsal, pressures to return to work quickly after an injury, and the “show must go on” mentality, must also be ­considered in the care of dancers.72 Physicians caring for dancers, particularly ballet dancers at any level, must be aware of the aesthetic pressures for extreme leanness and the potential consequences. Numerous studies have documented this leanness as well as the poor dietary balance and high incidence of disordered eating patterns among dancers.72,77,78 Dancers and other excessively lean athletes may suffer serious reproductive and skeletal sequelae as a result of such aberrant dietary practices. The combination of disordered eating, amenorrhea, and osteoporosis has been referred to as the female athletic triad and should be recognized by those caring for athletes, especially dancers. Unfortunately, the dance world is not lacking in other serious medical problems, including ­mental illness, drug abuse, and human immunodeficiency virus (HIV) infection.72 REFERENCES   1. Buckle PW: Work factors and upper limb disorders. BMJ 315:1360, 1997.   2. Hadler NM: Repetitive upper-extremity motions in the workplace are not hazardous. J Hand Surg Am 22:19, 1997.   3. Yassi A: Work-related musculoskeletal disorders. Curr Opin Rheumatol 12:124-130, 2000.

  4. Schouten SAG, de Bie RA, Swaen G: An update on the relationship between occupational factors and osteoarthritis of the hip and knee. Curr Opin Rheumatol 14:89-92, 2002.   5. Mani L, Gerr F: Work-related upper extremity musculoskeletal disorders. Primary Care 27:845-864, 2000.   6. Colombini D, Occhipinti E, Delleman N, et al: Exposure assessment of upper limb repetitive movements: A consensus document developed by the technical committee on musculoskeletal disorders of International Ergonomics Association endorsed by International Commission on Occupation Health. G Ital Med Lav Ergon 23:129-142, 2000.   7. Straaton KV, Fine PR, White MB, Maisiak RS: Disability caused by work-related musculoskeletal disorders. Curr Opin Rheumatol 10:141, 1998.   8. Cole DC, Hudak PL: Prognosis of nonspecific work-related musculoskeletal disorders of the neck and upper extremity. Am J Ind Med 29:657, 1996.   9. Millender L, Tromanhauser SG, Gaynot S: A team approach to reduce disability in work-related disorders. Orthop Clin 27:669, 1996. 10. Hales TR, Bernard BP: Epidemiology of work-related musculoskeletal disorders. Orthop Clin North Am 27:679, 1996. 11. Malchaire N, Cook N, Vergracht S: Review of the factors associated with musculoskeletal problems in epidemiologic studies. Arch Occup Environ Health 74:79-90, 2001. 12. Harrington JM: Occupational medicine and rheumatic diseases. Br J Rheumatol 36:153, 1997. 13. Hadler NM: Vibration white finger revisited. J Occup Environ Med 41:772, 1998. 14. Viikari-Juntura ERA: The scientific basis for making guidelines and standards to prevent work-related musculoskeletal disorders. Ergonomics 40:1097, 1997. 15. Hadler NM: Coping with arm pain in the workplace. Clin Orthop 351:57, 1998. 16. Hadler NM: A keyboard for “Daubert”. J Occup Environ Med 38:469, 1996. 17. Hadler NM: Occupational Musculosketal Disorders, 2nd ed., Philadelphia, Lippincott Williams & Wilkins, 1999. 18. Lister GD: Ergonomic disorders [editorial]. J Hand Surg Am 20:353, 1995. 19. Schrader H, Obelieniene D, Bovim G, et al: Natural evolution of late whiplash syndrome outside the medicolegal context. Lancet 347:1207, 1996. 20. Vender MI, Kasdan ML, Truppa KL: Upper extremity disorders: A literature review to determine work-relatedness. J Hand Surg Am 20:534, 1995. 21. Reilly PA, Travers R, Littlejohn GO: Epidemiology of soft tissue rheumatism: The influence of the law [editorial]. J Rheumatol 18:1448, 1991. 22. Panush RS: Osteoarthritis, regional rheumatic syndromes, fibromyalgia. In Sergent JS, LeRoy EC, Meenan RF, et al (eds): Yearbook of Rheumatology. St. Louis, Mosby, 1994, pp 247-249. 23. Bell DS: “Repetition strain injury”: An iatrogenic epidemic of simulated injury. Med J Austral 151:280, 1989. 24. Davis TR: Do repetitive tasks give rise to musculoskeletal disorders? Occup Med 49:257-258, 1999. 25. Higgs PE, Edwards D, Martin DS, Weeks PM: Carpal tunnel surgery outcomes in workers: Effect of workers’ compensation status. J Hand Surg Am 20:354, 1995. 26. Panush RS: Introduction to Chapter 1: Health sciences, epidemiology, and economics. In Panush RS, Hadler NM, Hellman D, et al (eds): Yearbook of Rheumatology. St. Louis, Mosby, 1999. 27. Angell M: Science on Trial: The Clash of Medical Evidence and the Law in the Breast Implant Case. New York, Norton, 1997.

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28. Panush RS, Lane NE: Exercise and the musculoskeletal system. Baillieres Clin Rheumatol 8:79, 1994. 29. Panush RS: Physical activity, fitness, and osteoarthritis. In Bouchard C, Shephard RJ, Stephens T (eds): Physical Activity, Fitness, and Health: International Proceedings and Consensus Statement. Champaign, Ill, Human Kinetics, 1994, pp 712-723. 30. Panush RS: Does exercise cause arthritis? Long-term consequences of exercise on the musculoskeletal system. Rheum Dis Clin North Am 16:827, 1990. 31. Callahan LF, Currey SS, Jonas Bl, et al: Osteoarthritis in retired National Football League (NFL) players: The role of injuries and playing position [abstract]. Arthritis Rheum 46:S415, 2002. 32. Kellgren JH, Lawrence JS: Radiological assessment of osteoarthrosis. Ann Rheum Dis 16:494, 1957. 33. Lawrence JS: Rheumatism in coal miners. III. Occupational factors. Br J Ind Med 1955; 12:249. 34. Kellgren JH, Lawrence JS: Osteoarthritis and disc degeneration in an urban population. Ann Rheum Dis 12:5, 1958. 35. Burke MJ, Fear EC, Wright V: Bone and joint changes in pneumatic drillers. Ann Rheum Dis 36:276, 1977. 36. Lawrence JS: Rheumatism in cotton operatives. Br J Ind Med 18:270, 1961. 37. Tempelaar HHG, Van Breeman J: Rheumatism and occupation. Acta Rheumatol 4:36, 1932. 38. Hadler NM: Industrial rheumatology: Clinical investigations into the influence of the pattern of usage on the pattern of regional musculo­ skeletal disease. Arthritis Rheum 21:1019, 1977. 39. Hadler NM, Gillings DB, Imbus HR: Hand structure and function in an industrial setting: The influence of the three patterns of stereotyped, repetitive usage. Arthritis Rheum 21:210, 1978. 40. Anderson J, Felson DT: Factors associated with knee osteoarthritis (OA) in the HANES I survey, evidence for an association with overweight, race and physical demands of work. Am J Epidemiol 128:179, 1988. 41. Felson DT, Hannan MTP, Naimark A, et al: Occupational physical demands, knee bending and knee osteoarthritis. J Rheumatol 18:1587, 1991. 42. Felson DT, Zhang Y, Hannan MT, et al: Risk factors for incident radiographic knee osteoarthritis in the elderly: The Framingham Study. Arthritis Rheum 40:728, 1997. 43. Felson DT, Zhang Y: An update on the epidemiology of knee and hip osteoarthritis with a view to prevention. Arthritis Rheum 41:1343, 1998. 44. Molleson T: The eloquent bones of Abu Hureyra. Sci Am 271:70, 1994. 45. Sutton AJ, Muir KR, Mocket S, et al: A care-control study to investigate the relation between low and moderate levels of physical activity and osteoarthritis of the knee using data collected as part of the allied Dunbar national fitness survey. Ann Rheum Dis 60:756-764, 2001. 46. Manninen P, Riihimaki H, Heliovaara M, et al: Physical exercise and risk of severe knee osteoarthritis requiring arthroplasty. Rheumatology 40:432-437, 2001. 47. Walsh SJ, DeChello LM: Excess autoimmune disease mortality among school teachers. J Rheumatol 28:1537-1545, 2001. 48. Cooper GS, Parks CG, Dooley MA, et al: Occupational exposures and risk of systemic lupus erythematosus [abstract]. Arthritis Rheum 46:S616, 2002. 49. Panush RS, Levine ML, Reichlin M: Do I need an ANA? Some thoughts about man’s best friend and the transmissibility of lupus. J Rheumatol 27:287-291, 2000. 50. Morse LH: Unusual occupational rheumatologic and musculoskeletal disorders. Occup Med 7:423, 1992. 51. McDermott M, Freyne P: Osteoarthrosis in runners with knee pain. Br J Sports Med 17:84, 1983. 52. Videman T: The effect of running on the osteoarthritic joint: An experimental matched-pair study with rabbits. Rheumatol Rehabil 21:1, 1982.

53. Radin EL, Evre D, Schiller AL: Effect of prolonged walking on concrete on the joints of sheep [abstract]. Arthritis Rheum 22:649, 1979. 54. Panush RS, Hanson CS, Caldwell JR, et al: Is running associated with osteoarthritis? An eight-year follow-up study. J Clin Rheum 1:35, 1995. 55. Lane NE, Bloch DA, Jones HH, et al: Long-distance running, bone density and osteoarthritis. JAMA 255:1147, 1986. 56. Lane NE, Oehlert JW, Bloch DA, Fries JF: The relationship of running to osteoarthritis of the knee and hip and bone mineral density of the spine: 9 year longitudinal study. J Rheumatol 25:334, 1998. 57. Murry RO, Duncan C: Athletic activity in adolescence as an etiological factor in degenerative hip disease. J Bone Joint Surg Br 53:405, 1971. 58. Puranen J, Ala-Ketola L, Peltokalleo P, Saarela J: Running and primary osteoarthritis of the hip. BMJ 1:424, 1975. 59. De Carvalho A, Langfeldt B: [Running practice and arthrosis deformans: A radiological assessment]. Ugeskr Laeger 139:2421, 1977. 60. Arokoski J, Kivirantal I, Jirvelin J, et al: Long-distance running causes site-dependent decrease of cartilage glycosaminoglycan content in the knee joints of beagle dogs. Arthritis Rheum 36:1451, 1993. 61. Kujala UM, Kettunen J, Paananen H, et al: Knee osteoarthritis in former runners, soccer players, weight lifters, and shooters. Arthritis Rheum 38:539, 1995. 62. Panush RS, Schmidt C, Caldwell J, et al: Is running associated with degenerative joint disease? JAMA 255:1152, 1986. 63. Wang WE, Ramey DR, Schettler JD, et al: Postponed development of disability in elderly runners: A 13-year longitudinal study. Arch Intern Med 162:2285-2294, 2002. 64. Lane NE, Hochberg MC, Pressman A, et al: Recreational physical activity and the risk of osteoarthritis of the hip in elderly women. J Rheumatol 26:849-854, 1999. 65. Sohn RS, Micheli LJ: The effect of running on the pathogenesis of osteoarthritis of the hips and knees. Clin Orthop Rel Res 198:106, 1985. 66. Konradesen L, Hansen EM, Sondegaard L: Long distance running and osteoarthritis. Am J Sports Med 18:379, 1990. 67. Kujala UM, Kapriio J, Samo S: Osteoarthritis of weight-bearing joints in former elite male athletes. BMJ 308:231, 1994. 68. Marti B, Knobloch M, Tschopp A, et al: Is excessive running predictive of degenerative hip disease? Controlled study of former elite athletes. BMJ 229:91, 1989. 69. Marti B, Biedert R, Howald H: Risk of arthrosis of the upper ankle joint in long distance runners: Controlled follow-up of former elite athletes. Sportverletz Sportschaden 4:175, 1990. 70. Vingard E, Sandmark H, Alfredsson L: Musculoskeletal disorders in former athletes. Orthop Scand 66:289, 1995. 71. Specter TD, Harris PA, Hart DJ, et al: Risk of osteoarthritis associated with long-term weight-bearing sports. Arthritis Rheum 39:988, 1996. 72. Baum J, Calabrese LH, Greer JM, Panush RS: Performing arts rheumatology. Bull Rheum Dis 44:5, 1995. 73. Larsson L-G, Baum J, Mudholkar GS, Kollia GD: Benefits and disadvantages of joint hypermobility among musicians. N Engl J Med 329:1079, 1993. 74. Greer JM, Panush RS: Musculoskeletal problems of performing artists. Baillieres Clin Rheumatol 8:103, 1994. 75. Hoppman RA: Instrumental musicians’ hazards. Occup Med 16: 619-631, 2001. 76. Zaza C: Playing-related musculoskeletal disorders in musicians: A systematic review of incidence and prevalence. CMAJ 158:1019, 1998. 77. Hoppmann RA, Reid RR: Musculoskeletal problems of performing artists. Curr Opin Rheumatol 7:147, 1995. 78. Lockwood AH: Medical problems of musicians. N Engl J Med 320:221, 1989.

34

KEY POINTS Complementary and alternative medicine (CAM) is used in some form by most rheumatology patients. Most patients do not discuss CAM use or preferences unless asked specifically about this by a clinician. CAM use is strongly linked to health beliefs and is most commonly used in conjunction with conventional care. Asking about patients’ current or potential use of CAM is important for the following reasons: Avoiding harmful or unproven therapies Coordinating therapies that have some evidence for benefit (e.g., acupuncture for knee osteoarthritis) Reviewing therapies that have equivocal evidence, but whose safety profile makes them worthy of a symptomatic trial

Defined in various ways, complementary and alternative medicine (CAM) has become an increasingly popular avenue of treatment and out-of-pocket expenditure for patients with rheumatologic conditions. Because many of these treatments traditionally have not been prescribed or recommended by a health care provider, there is often a lack of discussion and evidence-based coordination of care. This chapter provides an evidence-based overview of common treatments and insight into the prevalence, rationale, and approach to a patient who is considering CAM.

DEFINITION AND BACKGROUND The definition of CAM has evolved more recently. Previously, CAM was defined as therapies not taught as part of medical school training. This definition is no longer relevant because more than 60% of allopathic medical schools in the United States were providing some level of instruction in CAM as of 1998.1 More recently, CAM has been defined by the National Institutes of Health Center for Complementary and Alternative Medicine (NCCAM) as therapies or practices that are not typically part of the conventional treatment paradigm. This definition is likely to continue to evolve as clinicians incorporate selected evidence-based CAM options into mainstream care in a manner known as integrative medicine.2 The NCCAM definition attempts to classify CAM into categories that are helpful for discussion. These categories and examples are listed in Table 34-1.

Integrative Medicine in Rheumatology: An Evidence-Based Approach ROBERT ALAN BONAKDAR  •  DAVID C. ­LEOPOLD

PREVALENCE AND PREDICTORS OF USE CAM generally has become extremely popular over the last several decades. Total CAM usage was reported in one third of the population in 1990 and increased to 42% by 1997. This represented 628 million office visits and $27 million spent, which far exceeded out-of-pocket expenditure for all conventional care and the 328 million visits to primary care providers in the same year. A follow-up analysis showed that approximately one third of the total visits (628 million) to CAM providers were for the treatment of musculoskeletal pain.3 Most of the top 10 reasons for CAM usage in one survey were related to musculoskeletal issues.4 Numerous surveys have examined CAM usage specifically in a rheumatologic population.3-14 Prevalence of use varies widely from approximately one third of those surveyed to greater than 90% in some populations. The prevalence rate also is highly influenced by the definition of CAM in various surveys, which can include common practices such as prayer that are not included in other surveys. Overall, most surveys find a greater than 50% prevalence of CAM usage by individuals with musculoskeletal problems. Several condition-specific surveys have been completed in the areas of osteoarthritis, rheumatoid arthritis (RA), systemic lupus erythematosus, and fibromyalgia.15-18 Fibromyalgia patients show the highest level of use (93%), and more than two thirds of fibromyalgia patients have used multiple CAM modalities concomitantly.

EPIDEMIOLOGY The most common CAM modalities used by rheumatologic patients vary, although common choices found in nearly all surveys include dietary supplements, mind/body and spiritual practices, manual/manipulative therapies, biostimulation (acupuncture, magnets), and topical ointments. Several factors other than rheumatologic diagnoses predict CAM use. Typical CAM users are more likely to be women with a higher level of education and income, greater severity and duration of symptoms, and greater comorbidities such as insomnia and functional impairment. African­Americans tend to have higher levels of spiritual practice than other groups, and ethnic groups with traditional medicine use, such as Hispanic and Asian populations, tend to have higher levels of dietary supplement use. The health values of individuals considering CAM also are quite important. Individuals who are involved in “active coping behaviors,” such as greater physical activity, tend to view CAM use in a similar manner.5 Several surveys also show that individuals with a more “holistic 501

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Table 34-1  Categories of Complementary   and ­Alternative Medicine Category Overview

Examples

Alternative medical systems: Traditional Chinese medicine, ­Systems of care based on ayurveda, naturopathy, ­unifying health paradigms that ­homeopathy may incorporate ­individual treatments, including those noted in the following ­categories Mind-body interventions: Diverse Biofeedback, meditation, yoga, techniques that use ­cognitive, tai chi/qi gong, creative behavioral, and movement therapies (art, music, or therapies to modify and dance), ­relaxation, ­hypnosis, increase awareness between ­visualization/imagery, mental and physiologic ­cognitive-behavioral therapies, ­functioning group support, autogenic ­training, spirituality Biologically based therapies: Dietary modification (dietary Therapies that modify nutrient elimination, fasting, or intake either through dietary specific dietary regimens), intervention or through dietary supplements (herbal ­supplementation supplements—white willow bark; nonherbal supplements— ­glucosamine, vitamins [vitamin D], minerals [selenium]) Manipulative and body-based Chiropractic manipulation, methods: Techniques that use ­osteopathic manipulation, manipulation, movement, or manual and massage therapy stretching of one or more parts of the body Energy therapies (biofield therapies): Techniques that involve the application of human or nonhuman energy fields

Acupuncture, qi gong, healing touch, therapeutic touch

outlook” wish to use complementary methods, which may take this viewpoint into consideration.6 Although there has been speculation that CAM use is a sign of dissatisfaction with conventional care, the more prevalent view is that CAM is used as an adjunct to optimize care. Dissatisfaction with conventional care did not predict use of CAM in a previous national survey, and less than 5% of CAM users used CAM in isolation from conventional care. Most CAM users state that their motivations for CAM use include that it gives them more control over their health care, and 80% report substantial benefit from its use.5 As a corollary, CAM users have been noted to have more frequent relationships with a primary care physician, have regular physician follow-up, and have good compliance with recommended preventive health behaviors such as regular mammography.7

REGULATION The regulation of CAM varies with the type of modality, the training of practitioners, and state laws. Acupuncture done by a Licensed Acupuncturist or physician acupuncturist in the same state is regulated differently by the state board of oriental medicine, medical board, or department of consumer affairs. The level of training and oversight for acupuncture varies widely by state, and the referring clinician should guide patients in confirming the CAM practitioner’s credentials and certification whenever possible. Verification of licensure can be obtained by initially contacting the state’s

Table 34-2  Regulation Resources for Complementary and Alternative Medicine Organization/Agency

Website

Federation of State Medical Boards

http://www.fsmb.org/m_pub. html

American Academy of Medical Acupuncture

http://www.medicalacupuncture. org

National Certification   Commission for Acupuncture and Oriental Medicine

http://www.nccaom.org

American Chiropractic   ­Association

http://www.acatoday.org

National Certification Board for Therapeutic Massage and Bodywork

http://www.ncbtmb.com

medical board, department of consumer ­ affairs/­protection, or therapy-specific national certification body (see resources listed in Table 34-2). Dietary supplements are governed according to the Dietary Supplement Health and Education Act of 1994. In contrast to prescription medications that must proceed through multiphase trials to gain premarketing approval from the Food and Drug Administration (FDA), supplements (with established ingredients) are not required to have safety, efficacy, or bioavailability data before marketing. Ensuring these important qualities, along with having a clear and truthful label, is mainly the responsibility of the manufacturer. Because of many factors, the role of the FDA has often begun after a supplement is marketed as it monitors safety and label claims. The FDA must use adverse drug reports and product analysis to prove that a supplement poses significant health risks.8,9 Two more recent regulatory measures are expected to be helpful in this area. The Dietary Supplement and Non-Prescription Drug Consumer Protection Act (S. 3546) mandates the reporting of serious adverse events to the FDA beginning in December 2007 and should allow for improved monitoring and enforcement. In addition, the FDA published long awaited guidelines for good manufacturing practices for dietary supplements, which began in August 2007 and help to standardize the manufacturing process.10 In addition to governmental oversight, several independent agencies offer testing and monitoring services that allow manufacturers to demonstrate their adherence to regulatory standards. Manufacturers that pass inspection may carry an independent “seal of approval” on their label and advertising. Table 34-3 lists several government and independent agencies currently involved in testing. Clinicians should become familiar with well-regulated and wellresearched brands for the supplements that are likely to be discussed with patients.

APPROACH TO THE PATIENT Regardless of their personal beliefs about CAM, clinicians have an ethical obligation to discuss treatment alternatives with their patients. The interaction between patients and clinicians regarding CAM use typically creates a less than optimal environment for coordination of care. This situation is linked to several factors, which are reviewed subsequently,

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Table 34-3  Governmental and Independent   Regulatory Agencies Agency

Website

Governmental Food and Drug Administration www.fda.gov/medwatch (FDA) Medwatch Program for collecting adverse reactions to prescription and over-  the-counter medications and dietary supplements Federal Trade Commission (FTC) www.ftc.gov/ftc/complaint.htm site for submitting ­complaints on false or misleading ­advertising American Association of Poison www.poison.org or 800-222-1222 Control Centers for reporting and management of adverse effects Independent Laboratories Providing Supplement Testing Consumerlab Product Review www.Consumerlab.com Dietary Supplement Verification www.uspverified.org Program (DSVP) through the United States Pharmacopeia (USP) National Sanitation Foundation www.NSF.ORG/consumer/­ (NSF) dietary_supplements

including patient and clinician CAM knowledge base, level of CAM discussion, and management strategies such as charting and follow-up.

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Table 34-4  Selected Complementary and Alternative Medicine (CAM) Resources Internet National Center for Complementary and Alternative Medicine (NCCAM) (http://nccam.nih.gov): Overview of CAM fields and information on clinical trials and patient education materials CAM on PubMed (www.nlm.nih.gov/medlineplus/alternativemedicine. html): Focused search on PubMed for articles with a focus on alternative and complementary medicine Cochrane Library (www.cochrane.org): Collection of systematic reviews with a Complementary Medicine Field. NIH Office of Dietary Supplements and International Bibliographic Information on Dietary Supplements (IBIDS) (http://ods.od.nih.gov): Collaborative database of available abstracts on dietary supplements FDA Division of Dietary Supplement (http://vm:cfsan.fda.gov/~dms/ supplmnt/html): Discussion of dietary supplement regulation, including list of recalls and warnings Natural Medicines Comprehensive Database (www.naturaldatabase. com): Extensive collection of supplement information, including uses, indication, efficacy, and adverse effects with a drug interactions checker Longwood Herbal Taskforce (www.mcp.edu/herbal): Collection of clinically oriented monographs and reviewed Internet link Peer-Reviewed Information for Patients MedlinePlus (www.nlm.nih.gov/medlineplus/alternativemedicine. html): Patient-oriented summary of Medline published research and international health news National Center for Complementary and Alternative Medicine (NCCAM) (www.nccam.nih.gov): National Institutes of Health clearinghouse of government-funded initiatives in CAM, including research, fellowships, grants, and patient education materials Natural Medicine Comprehensive Database patient handouts (www. naturaldatabase.com)

KNOWLEDGE BASE The knowledge base of the average clinician and consumer regarding CAM is suboptimal to poor. The clearest example is found in the dietary supplement literature. Physician surveys have found that physicians may have an insufficient general understanding of commonly used supplements and their safety and interaction profiles.11,12 Similarly, consumers and patients tend to have misconceptions regarding product claims and efficacy. As pointed out by a previous Harris Poll, most consumers believed that the government ensured a higher level of safety and regulation than actually exists.13 Inaccurate or biased information may create a scenario of decreased perceived need for clinician guidance regarding CAM. One of the other key deficiencies in the CAM scenario is the level of clinician/patient discussion. An initial survey found that in approximately 70% of encounters, there was no discussion of CAM use.2 More recently, the percentage seems to be improving, but still leaves many encounters in which neither the patient nor the clinician introduces the topic.14 More concerning is the fact that if a patient is hospitalized by a specialist, CAM use is not identified 88% of the time.15 It is important to understand why patients do not discuss CAM use. Surveys indicate that factors including anticipation of a negative or disinterested clinician response and belief that the clinician would not provide useful information motivated nondisclosure.16 Most important may be clinician inquiry, however, because patients show a willingness to disclose use of supplements, but only if

asked by a clinician directly.17 A survey of physicians found that few of those surveyed felt comfortable discussing CAM with their patients. One of the major reasons for this lack of comfort was related to a need to improve one’s knowledge base regarding CAM (84% of responders). It is hypothesized that with improved education about CAM, physicians may be more willing to discuss and counsel patients.18 PATIENT AND CLINICIAN EDUCATION Numerous resources are available to clinicians interested in understanding CAM better as a means of increasing and improving patient communication. These resources are listed in Table 34-4 and include print and online information on evidence-based use of CAM and continuing medical education courses available to clinicians. The HERBAL mnemonic is an additional practice tool for alerting clinicians to the most important steps involved in managing CAM use (Table 34-5).

NUTRITION AND DIETARY SUPPLEMENTS DIET Alterations in the “standard American diet” can result in a significant decrease of inflammatory burden and may be ­especially significant for individuals with inflammationdriven diseases. Dietary intake of high-quality food has

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Table 34-5  HERBAL Mnemonic* H

Hear the patient out with respect

E

Educate the patient

R

Record

B

Be aware of potential interactions and side effects

A

Agree to discuss and follow up

L

Learn

*Copyright Robert Alan Bonakdar. Used with permission.

degenerated for most Western cultures over the past 100 years. Americans are eating an increased amount of processed animal products and foods, often high in trans fatty acids, omega-6 free fatty acids (O6FFAs), food additives, preservatives, and high-glycemic-index foods. These factors directly or indirectly stimulate inflammation and generally result in increased levels of arachidonic acid, a key component of many inflammatory mediators.19 Changes in omega-3 free fatty acid (O3FFA) and O6FFA ratios have resulted in a shift to a “proinflammatory” physiologic state (estimates place the ratio in the 1900s at 4:1, and now at 25:1 to 30:1). In many native cultures, a severalfold increase in the ratio of O6FFAs to O3FFAs has been observed as the dietary pattern shifts away from traditional diets to a more Western diet.20 In our current medical paradigm, we have multiple ways to deal with inflammation; most involve blockade of mediators when they are formed. An anti-inflammatory diet decreases stimulation of inflammatory pathways, provides blockade of mediators owing to high natural anti-­inflammatory ­components, provides novel ways of downregulating inflammatory mediator–producing cells, and provides “upstream” blockade of inflammatory pathways. An anti-inflammatory diet is a predominantly plantbased diet, with proper O6FFA-to-O3FFA ratios, and high in naturally occurring anti-inflammatories and antioxidants. In addition, there is reduced or minimal intake of “proinflammatory” components of diet, such as trans and saturated fatty acids, high glycemic foods, and foods causing known allergenic or sensitivity reactions. The essential fatty acids comprise a group of lipids that must be acquired from exogenous sources, most often plants or animals that have ingested plants rich in O3FFA (e.g., grasses, algae). Saturated fats include most animal products and coconut and palm oils. Monounsaturated fats include olive, avocado, and canola oils. Polyunsaturated fats include the O6FFAs (linoleic acid, gamma linolenic acid, and arachidonic acid), and the O3FFAs (alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid). Polyunsaturated fats have important effects on the prostaglandin pathways. The main essential fatty acids are linoleic acid (O6FFA) and linolenic acid (O3FFA). Linoleic acid can be elongated and desaturated to arachidonic acid, whereas alpha-linolenic acid is elongated and desaturated into eicosapentaenoic acid and docosahexaenoic acid. Eicosanoids derived from arachidonic acid are generally proinflammatory and prothrombotic, whereas O3FFAs tend to be less inflammatory and inhibit platelet aggregation. The Standard American diet provides a ratio of approximately 25:1 O6FFA to O3FFA, whereas an anti-inflammatory ratio is considered to be approximately 4:1. There is evidence

that the monounsaturated fats also affect these pathways, although not nearly as extensively. The anti-inflammatory effects from olive oil are believed to be more directly related to the oleanic acid components.21,22 The proposed mechanism of an anti-inflammatory diet is multifactorial and is typically described as involving inhibition of cyclooxygenase (COX) and leukotriene enzymatic pathways and inhibition of phospholipase A2. Bioactive substances also may be found in an anti-inflammatory diet that directly mediate promotion and inhibition of genetic transcription and the encoding of proteins and enzymes. These include peroxisome proliferator activated receptor gamma and other mediators and are exemplified by the following substances:23,24 • Isoflavones found in soy inhibit tumor necrosis factor (TNF)-α activation of nuclear factor κB in lymphocytes of healthy males.25 •  Epigallocatechin-3-gallate, found in colorful berries and teas, inhibits interleukin (IL)-1 in chondrocytes and inhibits COX-2 activity.26,27 •  Curcumin, found in turmeric, inhibits monocyte and alveolar macrophage production of IL-8, monocyte inflammatory protein-1, α-monocyte chemotactic protein-1, and TNF-α.28 •  Ursolic acid, a pentacyclic triterpene found in apples, Greek sage (Salvia triloba), oleander, rosemary, lavender, and thyme, is a moderate inhibitor of COX-2 and lipoxygenase. •  Oleanic acid, another pentacyclic triterpene found in olives and olive leaves, seems to inhibit phospholipase A2. Evidence for the Anti-Inflammatory Diet Several lines of evidence support the incorporation of an anti-inflammatory diet to improve serologic and symptomatic markers of inflammation. The anti-inflammatory diet can be characterized by the avoidance of proinflammatory constituents, incorporation of whole dietary patterns (Mediterranean and vegetarian diets), and incorporation of specific anti-inflammatory constituents (e.g., fiber and essential fatty acids). Avoidance. A hallmark of the anti-inflammatory diet includes avoidance of excess and high-glycemic-load calories. A study of 244 women identified a significant association between high glycemic loads and elevated plasma C-­reactive protein. These findings were found to be independent of heart disease risks.29 Inversely, RA patients completing a week-long modified fast showed anti-inflammatory-related serologic changes, including decreases in neutrophil release of lysozyme, aggregation of polymorphonuclear neutrophils, and production of leukotriene B4.30 Mediterranean Diet. The Mediterranean diet is typically characterized as a diet emphasizing high consumption of fruits, vegetables, and cereals with incorporation of virgin olive oil, fish, nuts, and small-to-moderate quantities of wine. Several studies have shown that subjects maintaining this diet, while adjusting for body mass index, age, diabetes, smoking, and ­ nonsteroidal anti-inflammatory drugs (NSAIDs) are able to reduce markers of inflammation,

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including C-reactive protein and IL-6.31,32 Studies of RA patients randomly assigned to a Mediterranean diet versus a standard Western diet for 3 months showed that patients on a Mediterranean diet had improved symptoms, including decreased joint swelling and functional ability.33,34 Vegetarian Diet. A vegetarian/vegan diet has been used in several controlled fibromyalgia and RA trials. A 3-month, randomized Finnish study of fibromyalgia patients found that patients placed on a vegan diet showed improvements in pain scores, joint stiffness, and sleep compared with controls.35 RA patients followed on a vegan diet for 2 years improved on all assessments for pain and functionality, ­ including morning stiffness, number of swollen and tender joints, and grip strength.36 Similarly, these dietary interventions have been correlated with changes noted in IgM, rheumatoid factor, and the complement components C3 and C4.37 Finally, a systematic review of studies of RA patients undergoing fasting followed by vegan diet of at least 3 months’ duration showed statistical benefit in long-term management of symptoms.38 Fiber. An inverse relationship between fiber intake and levels of C-reactive protein and incidence of inflammatory conditions has been noted. In the 1999-2000 National Health and Nutrition Examination Survey, subjects with the highest fiber intakes had lower C-reactive protein levels, and this has been shown in subjects following a high-fiber, vegetarian diet.39,40 A randomized study incorporating 30 g/day of fiber a day, through either diet or supplementation, was found to decrease C-reactive protein values significantly.41 Additionally, epidemiologic studies have identified an inverse relationship between high fiber–containing dietary components (cooked vegetables, cruciferous vegetables, and fruits) and RA risk.42 Essential Fatty Acids. The use of essential fatty acids for the treatment of pain is a broad and difficult-to-summarize topic. The variation in research stems from factors including the source (e.g., diet or supplements of fish, flax, borage, or other oils), the concentration of constituents (i.e., eicosapentaenoic acid, docosahexaenoic acid, gamma linolenic acid), and background diet. Several trials have attempted to ascertain the dietary and supplement intake levels necessary for clinical efficacy. Subjects with RA who used 1.8 g/day of O3FFA showed long-term improvement in disease parameters.43 In a another study of RA, 2.6 g/ day of O3FFA was required to decrease symptoms and pain medication use, which was maintained at 12 months.44 Fifty-one patients with RA were randomly assigned to 3.6 mg of omega-3 fish oils versus capsules containing standard dietary fats. After 12 weeks, the patients on fish oil were noted to have small but significant improvements in morning stiffness, joint tenderness, and C-reactive protein values.45 A multicenter study using the same protocol as the previous study found similar findings in morning stiffness and joint tenderness.46 Similar modest but clinically significant improvements were shown in a double-blind, placebo-controlled trial of 56 RA patients with use of 2.8 g/day of gamma linolenic acid.47 A survey of the literature concluded that in RA patients, doses of 2 to 8 g/day of gamma linolenic acid are required for 12 weeks to exhibit

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an anti-inflammatory effect that compared with therapy with NSAIDs.48 Preliminary research using essential fatty acids has been done in other rheumatologic conditions. A study from the University of Pittsburgh, Department of Neurosurgery, looked at 250 patients with nonsurgical back or neck pain.49 The patients used 1200 to 2400 mg of O3FFA for an average of 75 days; 59% of them reported improvement in joint pain, and 68% were able to discontinue prescription pain medications. Side effects were minimal, and 86% of patients noted they would continue to use the product. In a systematic review of 17 trials that examined the use of O3FFAs for an average of 3 to 4 months in inflammatory states, there was a significant improvement in patient-reported joint pain, minutes of morning stiffness, number of painful or tender joints, and NSAID consumption.50 Avoidance in Combination with Anti-inflammatory Diet. The effects of background diet have been examined as a factor affecting the potential benefit of essential fatty acid supplementation. Sixty-eight patients with RA were randomly assigned to 2 months of a standard Western diet or an antiinflammatory diet in which arachidonic acid intake was less than 90 mg/day. Patients in both groups were additionally randomly assigned to receive placebo or fish oil supplements at 30 mg/kg for a third month. With placebo supplementation, the anti-inflammatory diet decreased swollen joints by 14% compared with the Western diet. With the addition of fish oil, a significant difference in tender (28% versus 11%) and swollen (34% versus 22%) joints was noted (P < .01). Serologic studies also showed that an anti-inflammatory diet, especially with the combination of fish oils, caused significant decreases in leukotriene B4, 11-dehydrothromboxane B2, and prostaglandin metabolites. The authors concluded that an anti-inflammatory diet improved symptoms of RA and augmented the effects of fish oil supplementation.51 Although essential fatty acids have documented changes with in vitro and in vivo inflammatory markers and may have a role in clinical management in certain scenarios, there are several important notes regarding use. There have been many nonsignificant trials with use of essential fatty acids, including the use of alpha linoleic acid from flax seeds as a precursor of eicosapentaenoic acid and docosahexaenoic acid to treat RA.52 Side effects with use of essential oils are typically dose dependent and include gastrointestinal intolerance. The potential for symptom decrease or drugsparing benefit seems to be strongly related to the type and dose of the treatment and the disease state and background diet of the subjects studied. At this point, the strongest evidence appears in the literature for individuals consuming 2 g or greater of gamma linolenic acid or fish oil supplement per day, while limiting their intake of arachidonic acid (<90 mg/day) or (n-6) fatty acid intake (<10 g/day).48,53 Obesity and Inflammation It is now generally accepted that obesity itself has proinflammatory effects. Adipocytes, in particular central adipose tissue, are endocrinologically active and can sequester arachidonic acid. This effect eventually leads to increased production of cytokines, including IL-6 and TNF, and of proinflammatory adhesion. Although an

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anti-inflammatory diet is no guarantee of weight loss, the decrease in animal fats, the general increase in nutrientdense food, and subsequent avoidance of “empty calories” (e.g., fast foods, high-fat foods, and fried foods) could logically be expected to result in gradual and permanent weight loss. Anti-Inflammatory Diet Recommendations In recommending an anti-inflammatory diet, several important points should be kept in mind. First, initiation of the diet, similar to other lifestyle change, should be gradual to allow better tolerability and compliance. Second, for goalsetting purposes, the patient should not expect immediate results, allowing at least 12 weeks before re-evaluating benefit, and should be made aware that this intervention may have additional nonrheumatologic health benefits in the setting of cardiovascular diseases, diabetes, and cancer risk. Third, what is avoided is often as important as what is added. There should be a strong emphasis on avoidance of potentially proinflammatory foods while initiating an antiinflammatory diet (Table 34-6). Next, consultation with a dietitian to analyze current dietary patterns and understanding and to provide meal planning suggestions is highly recommended. Also, the patient should be told that a journal can be helpful in this process to monitor ongoing diet and symptom changes. DIETARY SUPPLEMENTS Willow Bark (Salix species) White willow bark has a long history of use in medicine with records describing Hippocrates recommending its use for pain relief. In 1898, aspirin (acetylsalicylic acid), as a synthetic derivative of white willow bark, was discovered and became a leading analgesic. The mechanism of benefit of white willow bark does not seem to be strictly based on salicylate levels, which are low compared with aspirin products, and may be linked to other active ingredients, including glycosides, phenolic glucosides, flavanoids, polyphenols, procyanidins, and tannins.54 In vitro, white willow bark has shown COX2, prostaglandin E2, and leukotriene inhibitory activity. Clinically, white willow bark has been tested for efficacy in arthritis and low back pain. A randomized double-blind, controlled trial of 78 subjects with hip or knee ­osteoarthritis treated with placebo or white willow bark containing 240 mg of salicin over a 2-week period showed a statistically ­significant improvement in WOMAC pain scores in the white willow bark group.55 Similar results were exhibited in a smaller randomized double-blind, placebo-controlled trial of 21 subjects taking white willow bark containing 240 mg of salicin over a 2-week period for knee and hip ­osteoarthritis. Results of the study showed a 40% decrease in WOMAC scores with white willow bark versus 18% with placebo.56 In the treatment of acute exacerbation of low back pain, 119 subjects were randomly assigned to white willow bark standardized to 120 mg or 240 mg of salicin versus placebo over 4 weeks. The study showed complete relief of pain in 39% in the high-dose white willow bark group, 21% in the low-dose white willow bark group, and 6% in the placebo

Table 34-6  Anti-Inflammatory Diet Foods to Minimize or Eliminate Trans fats/partially hydrogenated oils found in margarines, butter spreads, and shortening Oils—sunflower, safflower, cottonseed, and corn oils Refined sugar and high glycemic load foods (products with   high-fructose corn syrup, candy, fruit juices, and soda) High saturated fat foods—saturated animal fats, cheeses, egg yolks Fried foods—fast foods, doughnuts Highly processed foods—hot dogs, processed meats Refined starch products—muffins, tortillas, waffles, pasta, rice Baked and pastry goods Alcohol and caffeine in excess Foods to Incorporate Most of the diet should be derived from the following 4 areas with additional nutrients for support   Whole-grain products (whole-wheat breads and pastas)   Fresh fruits and vegetables   Legumes (soy, lentil)   Seeds and nuts (almonds, walnuts) The above provide rich sources of several anti-inflammatory ­components   Fiber—sources include whole-grain products, fruits and ­vegetables, legumes, soy   Isoflavones—found in soybeans and soy products, such as ­tempeh, tofu, and miso; isoflavones include genistein, daidzein, and others that lower levels of inflammatory mediators   Carotenoids (alpha carotene, beta carotene, lycopene, and lutein)—found in orange fruits and vegetables and tomatoes, spinach, and kale   Flavonoids—include flavonols such as quercetin, ­epigallocatechin-3-gallate (EGCG), and anthocyanidins; they are found in green tea, dark berries, citrus fruits, tomatoes, and in greens   Plant sterols and unesterified plant sterols (i.e., β-sitosterol)— found in soy foods and many vegetable-based foods   Omega-3 free fatty acids (flaxseed, fish oils, green leafy ­vegetables, walnuts, soy, algae, and hemp seeds)   Monounsaturated oils (olive and canola oil)   Probiotics-rich foods—yogurt, kefir, tempeh, and miso

group (P < .001). The pain relief with white willow bark was not immediate, but typically occurred within 1 week of initiating treatment. Additionally, one patient had an allergic reaction attributed to white willow bark.57 A 4-week, randomized, open-label study of standardized white willow bark (Assalix) containing 240 mg of salicin was found to be noninferior to 12.5 mg of rofecoxib in 228 patients with acute exacerbation of low back pain. Ginger (Zingiber species) Ginger (Zingiber officinale) has been used for more than 2500 years in traditional Chinese medicine, Ayurvedic (Indian) medicine, and Tibetan medicine for rheumatologic, gastrointestinal, and oncologic conditions. Numerous active ingredients have been isolated from the ginger plant, including the gingeroles, which exert direct anti-­inflammatory activity, and galanolactones, which have serotonin receptor activity and likely modulate gastrointestinal and anti-inflammatory actions. Additionally, animal studies have shown that some ginger subspecies have documented COX-2 and prostaglandin E2 inhibitory activities.58,59 In clinical pain trials, ginger has been used mostly for osteoarthritis of the knee. In a 6-week randomized doubleblind, placebo-controlled trial comprising 261 subjects with

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knee osteoarthritis, a combination ginger extract (EV.EXT 77) containing Z. officinale and Alpinia glanga was evaluated. In this intent-to-treat analysis, moderate improvement was noted in knee pain on standing and walking (P < .05). Mild gastrointestinal side effects in the ginger group were statistically greater than the side effects in the control group.60 In a more recent trial, an extract of Zingiberis rhizoma (Zintona EC) was tested against placebo in 29 patients with knee osteoarthritis. Patients were randomly assigned to 1000 mg/day or to placebo with crossover taking place at 3 months. The results showed significant improvement over placebo starting only at the 6-month mark.61 At this point, ginger is known to have many anti-inflammatory constituents, and future research is required to elucidate its potential clinical role. Devil’s Claw (Harpagophytum procumbens) Devil’s claw is a traditional South African plant used for arthritis and myalgia and as an external ointment for burns and sores. Its efficacy has been attributed to numerous active ingredients, most notably harpagosides, which have shown in vitro downregulation of the lipoxygenase-mediated and COX-mediated pathways and inhibition of TNF-α synthesis.62-64 Clinically, it has been used most commonly in osteoarthritis and low back pain. Two meta-analyses have found “moderate” evidence from high-quality studies for use of devil’s claw (standardized to 60 mg of harpagoside) in the treatment of osteoarthritis of the spine, hip, and knee and in higher doses (100 mg of harpagoside) in the treatment of acute exacerbations of chronic nonspecific low back pain.65,66 The 60-mg harpagoside dose was found not to be inferior to 12.5 mg/day of rofecoxib for chronic nonspecific low back pain in a well-controlled 6-week trial.67 Glucosamine and Chondroitin Glucosamine and chondroitin are discussed here jointly because of their general similarity in structural joint function and their combination in commonly used preparations. Both ingredients have been reported to reduce the progressive degradation of articular cartilage and to help stimulate proteoglycan synthesis in in vitro trials.68,69 In clinical trials, glucosamine and chondroitin have been evaluated for their ability to improve pain and functional ability, typically of the knee and hip. A Cochrane review of glucosamine versus placebo summarized that 12 of 13 trials were positive.70 Two additional meta-analyses have examined glucosamine and chondroitin in the treatment of osteoarthritis.71,72 These trials examined approximately 15 randomized double-blind, controlled trials with greater than 1500 patients. The metaanalysis by Richy and colleagues72 found that glucosamine at 1500 mg/day was associated with decrease in progression of joint space narrowing. Additionally, glucosamine at this dose and chondroitin at varying doses (200 to 1200 mg/day) were associated with statistically significant pain relief and improvement in joint mobility at 4 weeks. There were no significant adverse effects.71,72 Several important clinical notes exist regarding these formulations. The Cochrane systematic review pointed out that most studies were performed on the Rotta company’s crystalline glucosamine formulation (brand name, Dona), and that results may be difficult to extrapolate to other brands because

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studies have shown wide variations in glucosamine formulations.66 The meta-analysis by Richy and colleagues72 deemed the chondroitin trials to be of overall low quality with the combination of the two products not being evaluated. Products with glucosamine and chondroitin typically state that the two combined work better than either alone. The results of the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), although inconclusive, found benefit for the combination versus celecoxib or placebo in the treatment of moderate-to-severe knee osteoarthritis. Glucosamine hydrochloride or chondroitin alone was not superior in any of the subgroup analyses. A recent meta-analysis also confirmed the lack of significant benefit with the use of chondroitin alone.73 At this point, prudent recommendation includes the use of single ingredients that have proved effective as in the previous Cochrane review (i.e., glucosamine sulfate at 1500 mg/day for 8 to 12 weeks) to assess pain reduction and functional improvement, with possible use of combination products based on initial response and patient subgroup (moderate-to-severe osteoarthritis).74,75 S-adenosyl-l-methionine S-adenosyl-l-methionine (SAMe) is a sulfur-containing dietary supplement synthesized from reactions between adenosine triphosphate and methionine and promoted for treatment of numerous conditions, including depression, liver disease, and joint disease. Its role in these conditions is derived from potential intrinsic anti-inflammatory, serotoninergic, and proteoglycan stimulatory mechanisms.76-78 A meta-analysis of 11 randomized controlled trials showed improvement in functional ability and pain levels compared with placebo or NSAIDs in the treatment of osteoarthritis.79 Adverse effects from SAMe were similar to placebo and significantly decreased compared with NSAIDs. A more recent randomized controlled trial compared SAMe (1200 mg) with celecoxib (200 mg) in 61 subjects with knee osteoarthritis over 16 weeks.80 After 1 month of intervention, celecoxib showed greater pain reduction over SAMe (P = .024). From the second month onward, there was no significant difference between groups on pain scores and functional joint ability, however. The investigators concluded that SAMe had a slower onset of action, but similar efficacy to celecoxib. Individuals considering SAMe should be monitored for concomitant use of serotoninergic ­medication because of synergistic potential. Typical initial dosing is 600 mg/day in divided doses with titration up to 1200 mg/day. Doses of 1600 mg/day have been used in selected settings with monitoring. Avocado-Soybean Unsaponifiables The unsaponifiable portion of vegetable oils has been hypothesized to possess anti-inflammatory activity owing to sterol, tocopherol, and squalene content.81 A specific mixture derived from the unsaponifiables of avocado and soybean, typically in a ratio of 2:1, has been examined since the 1970s for use in scleroderma, periodontal conditions, and rheumatologic conditions.82 In vitro research has shown the ability of avocado-soybean unsaponifiables (ASUs) to decrease several key agents implicated in joint degradation and inflammation, including IL-1β-induced collagenase, stromelysin,

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IL-6, IL-8, and prostaglandin E2 release.83 In addition, there is in vitro evidence regarding a supportive role for ASUs in maintaining the joint matrix, including upregulation of transforming growth factor-β and aggrecan synthesis.75,84 In clinical trials, ASUs have been examined in the ­treatment of knee and hip osteoarthritis. In one multicenter randomized controlled trial, 300 mg/day or 600 mg/day of ASU was compared with placebo in patients with knee osteoarthritis. At 3 months, the number of patients decreasing NSAID or analgesic intake by more than 50% in either ASU dosage group was 71% versus 36% in the placebo group. Clinical improvements also were noted (P < .01) in many parameters, including Lequesne’s index, which decreased by 3.2 and 2.9 points (with high and low dose) versus 1.6 points in the placebo group.85 A second trial showed a treatment benefit for 8 months, including a 2-month follow-up while not on the supplement.86 A systematic review of four randomized controlled trials found three trials showing efficacy with ASUs in osteoarthritis.87 The negative trial examined joint space preservation, which was not significantly noted with ASUs. There were no significant differences between 300-mg and 600-mg dosage efficacy, and side effects have been shown to be similar to placebo and typically gastrointestinal in nature. At this point, the use of ASUs is promising; long-term efficacy trials are needed to confirm clinical and potential structural benefits in practice. Capsaicin and Other Botanicals Various topicals that possess counterirritant or substance P–depleting activity are used in rheumatologic conditions. Capsaicin is the most commonly used agent in this setting. Three trials show benefit in the setting of low back pain (versus placebo and homeopathic cream), and several small trials find benefit in the setting of localized arthritis.68,88,89 Several other botanicals, including green tea (Camellia sinensis), turmeric (Curcuma longa), cat’s claw (Uncaria tomentosa), and thunder god vine (Tripterygium wilfordii), are noted to be candidates in the setting of arthritis-related pain.27,90-92 ACUPUNCTURE Acupuncture is a component of traditional Chinese medicine that is typically defined as the therapeutic use of fine needles at specific body points. Acupuncture traditionally is used in conjunction with other traditional Chinese medicine treatments (Chinese herbal medicine, acupressure, moxibustion), which are collectively used to correct physiologic or energetic dysfunction. Because acupuncture has been the most popular and translatable component of traditional Chinese medicine, it has received increasing attention regarding its mechanism and potential efficacy in rheumatologic conditions. The mechanism for acupuncture’s benefits stems from potential local tissue, spinal cord, and cortical effects. The strongest evidence seems to focus on frequency-dependent increase of endomorphin-1, β-endorphin, encephalin, and serotonin levels after acupuncture, with partial reversal with naloxone.93-95 The clinical efficacy of acupuncture in rheumatology varies and seems to be based on several factors, such as the condition being treated and the specific methodology employed, including treatment protocol and randomization.

The most researched condition seems to be knee osteoarthritis, in which a National Institutes of Health–funded, placebo-controlled trial found that a course of 23 acupuncture treatments was significantly superior to placebo in decreasing knee osteoarthritis pain and dysfunction as assessed by WOMAC and patient global assessment.96 A meta-analysis of 10 randomized controlled trials (N = 329) confirmed the benefit of acupuncture compared with sham acupuncture in the setting of peripheral joint osteoarthritis.97 The results of acupuncture in RA are less certain, limited by the number of well-controlled trials.98 Acupuncture is a common treatment used by fibromyalgia patients. Although research findings are inconsistent, trials have shown benefit for fibromyalgia-related pain.99 Symptomatic improvement was not isolated to pain severity, but also noted in the level of fatigue and anxiety.100 In the treatment of low back pain, meta-analyses found acupuncture clinically effective and generally cost-effective in the relief of chronic low back pain.101 Because of its safety and potential benefit, acupuncture should be considered for a short-term trial, especially in the setting of refractory knee osteoarthritis, low back pain, and fibromyalgia. BIOSTIMULATION Biostimulation refers to the application of light, electrical, magnetic, or similar modalities for therapeutic purposes. Several biostimulation methods, such as ultrasound or transcutaneous electrical nerve stimulation (TENS) have become standard practice in the treatment of musculoskeletal dysfunction. Most types of biostimulation continue to be considered CAM. Low-Level Laser Therapy Low-level laser therapy refers to the application of lowintensity monochromatic wavelengths of light typically for the treatment of pain and inflammatory conditions. The treatment intensity is below that which is used for laser in other medical settings, such as surgical or dermatologic applications, and is also referred to as “cold laser.” Although low-level laser therapy has been used for several decades in Europe, the mechanism for low-level laser therapy has not been fully elucidated. It seems to be a nonthermal, photochemical cellular reaction, which may provide anti­inflammatory and tissue healing effects. Several more recent controlled trials have attempted to examine the role of low-level laser therapy in rheumatologic conditions. A 2005 Cochrane review of 222 RA patients included in five placebo-controlled trials found a statistically significant reduction in pain (visual analog scale) and morning stiffness duration by 27.5 minutes for low-level laser therapy versus placebo. Other outcomes, such as functional assessment, range of motion, and local swelling, did not differ between groups.102 Electromagnetic and Magnetic Stimulation Various types of electrical stimulation have been employed to treat rheumatologic conditions, especially RA and osteoarthritis. These have been used conventionally (i.e., stimulation of the area of dysfunction) and in an acupuncture-like

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setup (i.e., stimulation to acupuncture points). Although there is evidence in focused settings (neuromuscular electrical stimulation, TENS, and acupuncture-like TENS in the setting of knee OA103,104), most evidence regarding the use of electrostimulation is difficult to interpret.105 Several other types of biostimulation, including the use of thermotherapy (moist heat) or cryotherapy, have shown short-term benefit as a palliative therapy in RA.106 Magnets, static or pulsed, are often touted as helpful agents in arthritis. Selected pulsed electromagnetic fields have shown in vitro effects on bone and cartilage growth and are considered helpful in delayed bone healing.107 Limited evidence is available in the setting of knee osteoarthritis for pulsed electromagnetic fields as noted in a meta-analysis.108 Evidence for long-term benefit of static or pulsed magnets in other clinical applications, such as osteoarthritis, is limited, however, by shortterm assessment or contradictory research findings.109,110 MIND/BODY INTERVENTIONS The importance of stress management and control of depressive disorders in RA cannot be overstated. RA may be exacerbated by psychological or physiologic stressors, and these stressors may be involved to some extent in the actual etiology of the disease itself. Depression is a common comorbid condition that can exacerbate or be a result of RA. Depression and psychological stressors may account for 20% of the disability in RA, a substantial amount if one considers that the actual joint pain and dysfunction account for 14%. Feelings of helplessness also have been shown to have a direct effect on the disease activity.111-114 The effect of psychological factors on pain severity also has been noted in several studies. A 5-month study of 188 older women with RA and osteoarthritis found depression to affect the levels of pain and reactivity to perceived stress.115 A 12-month longitudinal study looking at pain and depression in RA patients found that physical disability, helplessness, and passive coping have a significant impact on the levels of pain and depression experienced by RA patients.116 As interventions, multiple mind/body techniques have been shown to reduce physiologic stress effectively. In addition to intrinsic benefits, stress management techniques, meditation, biofeedback, exercise, and prayer are potential means for controlling mood and psychological sequelae of rheumatologic conditions. Exercise Multiple studies confirm the benefits of aerobic and weight resistance types of exercise. The Arthritis, Diet, and Activity Promotion Trial (ADAPT) showed that the combination of modest weight loss plus moderate exercise provides better overall improvements in function and pain and in performance with knee osteoarthritis compared with either intervention alone.118 The Fitness and Arthritis in Seniors Trial (FAST) incorporated regular walking and leg strengthening exercises versus no exercise. At 1.5 years, the exercisers had less pain and disability compared with subjects who did not exercise. Positive effects were noted using both types of exercise. Notable markers of improvement were increased walking and stair climbing ability. Knee radiography confirmed no worsening of the joint.119 In a

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separate study, Sharma and coworkers120 showed reduced risk for poor arthritis-related functioning measured over 3 years in individuals performing at least 60 minutes of exercise per week. This study also showed that the aforementioned exercise regimen resulted in no worsening of knee osteoarthritis.120 The importance and positive health effects of exercise in patients with RA are well established.121-123 The evidencebased guidelines of the American College of Rheumatology and the European League Against Rheumatism endorse the early use of exercise in the management of knee osteoarthritis.124,125 Feinglass and associates126 concluded that even modest increases in the rates of physical activity could have a significant impact on disability-free life expectancy. Dunlop and colleagues127 reported that elderly adults with arthritis who participated in Asset and Health Dynamics of the Oldest Old Survey who regularly engaged in vigorous activity had the lowest risk for functional decline. Multiple studies conclude that not only is there no detriment to joint status, but also arthritis patients in structured programs (which may be home based) have decreased pain, decreased fatigue, increased strength, and increased quality of life.117,123,128 Moderate aerobic and weight resistance exercise should be a central component of treatment plans for patients with rheumatic conditions. Despite this body of positive evidence, however, less than half of patients with rheumatic conditions report receiving exercise advice.129 The role of the physician in encouraging patients to become physically active is well established, although often underused.130 Iversen and colleagues131 showed that when physicians initiated discussion of exercise, the subject was four times as likely to occur, with strong impact on the subsequent follow-through. The most profound limitation for exercise as a treatment modality may be physician indifference to the actual recommendation of exercise. Rest and inactivity of an RA joint results in decreased overall conditioning, stamina, and strength.132,133 Exercise has been found to decrease joint damage and maintain joint activity and range of motion while being cost-effective.134 Retrospective studies show that individuals who exercise do not sustain more rapid joint degeneration (barring severe joint injury) compared with nonexercisers. The benefits of exercise are multifactorial and not limited directly to rheumatologic conditions. RA frequently occurs in the setting of obesity, each compounding and exacerbating the other. In addition, RA patients often have significant comorbidities, such as coronary artery disease and diabetes, both of which can be improved with aerobic and anaerobic exercise. The positive benefits of exercise go beyond the joint itself; of direct benefit to RA patients is the fact that exercise increases pain tolerance (psychological and endorphin driven), and aerobic exercise increases tissue oxygen efficiency.131 Many RA patients get caught in the vicious cycle of pain limiting ability to exercise resulting in overall worsening of joints, worsening of pain, and perpetuation of the cycle. The myriad comorbidities that infiltrate this cycle (e.g., coronary artery disease, diabetes, obesity) all are worsened by lack of exercise and serve to drive the downward cycle. It is often up to the physician to help the patient break from this cycle, and exercise remains one of the most effective, easy to apply, and cost-effective methods of breaking this cycle.

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The American College of Sports Medicine recommends avoiding vigorous exercise during acute joint inflammation or systemic disease that is not controlled. Recommendations include 48 to 72 hours of rest during acute flares, but some advocate static strengthening and gentle range of motion. Recommendations are for gentle stretching exercise of all major joints once daily held for 6 seconds. Pain, stiffness, biomechanical deficiencies, and alterations in gait can increase the metabolic demands of RA patients by 50%, and training should be adjusted accordingly. Several studies confirm that weight resistance training improves function, improves activities of daily living, and decreases pain. In addition, these results are found in home training programs. There were no negative effects on RA activity or function noted. RA often limits joint stiffness, and maintenance of range of motion is crucial. Multiple studies conclude that RA patients can improve flexibility and retain range of motion through exercise programs.123 The main goals for exercise and RA should be (1) improving or stabilizing range of motion, (2) improving or maintaining strength and endurance leading to improved joint stability, (3) improving overall aerobic capacity, and (4) slowing or stabilizing the disabling process (with the corollary of a reduction of overall inflammatory burden). Fibromyalgia. The use of exercise for fibromyalgia has produced mixed results, with some studies positive and some not showing a positive response. Exercise likely benefits certain individuals with fibromyalgia and does not benefit others. Intensity and type of exercises may be key factors. It seems warranted to use exercise in motivated and compliant patients who tolerate it well, and not to force patients into exercise regimens. Richards and Scott135 looked at more than 100 patients with American College of Rheumatology criteria for fibromyalgia who were randomly assigned to 12 weeks of either cardiovascular or relaxation and flexibility exercises, twice weekly. The primary outcome was patient-rated global impression of change in symptoms, evaluation of the 18 specific tender points, and three standardized questionnaires addressing different aspects of mental and physical fatigue and the impact of fibromyalgia. Of the patients randomly assigned to cardiovascular exercise, 24 of 69 (35%) were much better or very much better at 3 months versus 12 (18%) of the patients randomly assigned to relaxation (statistically significant). These results were sustained at 1 year. Although tender points decreased significantly in both groups, at 1 year the difference between groups was significantly in favor of the cardiovascular exercise group.135 Another study looked at the use of exercise along with mind/body therapies to evaluate pain and function for fibromyalgia. This study showed increased efficacy of exercise compared with mind/body therapies with both superior to no treatment.136 A 2001 Cochrane review of exercise and fibromyalgia examined 16 studies with 724 participants. There was evidence from well-defined and conducted studies that markers such as pain threshold using pressure, global well-being (including ratings of general improvement in fibromyalgia syndrome), and aerobic performance were improved by short-term aerobic fitness training. Muscle strengthening

also was believed to be of potential benefit, but required further investigation. Flexibility training could not be evaluated conclusively because of significant study flaws. Recommendations for exercise include starting with motivated individuals and proceeding slowly with gradual time increase to a goal of 45 minutes daily (minimum 4 times a week). Initial consultation with American College of Sports Medicine–certified trainers familiar with fibromyalgia or pain patients is strongly recommended. It also is advisable to inform patients that some discomfort after exercise is normal, but to contact their physician if the pain does not lessen in 24 hours or involves the major joints. Medical clearance should be obtained when necessary. Recommended therapies to begin with include low impact and low joint stress (elliptical, yoga, swimming) exercises. All programs should include appropriate warm up and cool down. Physical therapists or trainers should be consulted for further advice on taping/bracing sore joints. Yoga. Most studies done are substandard to draw firm conclusions about efficacy for the use of yoga. A 1998 study using yoga for carpal tunnel syndrome done over 8 weeks showed improved grip and decreased pain.137 Wood showed that a 30-minute breathing technique done daily had “marked invigorating” effects, improving mood and physical energy, and was superior to relaxation and visualization.137a Multiple studies show that yoga relieves anxiety138 and decreases depression,139 both major contributors to RA. A small 1994 study published in the Journal of Rheumatology found yoga to be beneficial in improving pain, tenderness, and range of motion (finger) without difference in joint circumference or grip strength in osteoarthritis of the hands.140 Also in 1994, a study was published suggesting overall benefit from yoga in the treatment of RA.141 Yoga instruction for rheumatologic patients should be done with a skilled yoga instructor familiar with rheumatologic conditions and pain-related issues. Many national certifications are available for yoga instructors. OTHER INTERVENTIONS: BELIEF SYSTEMS AND COPING A host of additional interventions that are often considered CAM should be kept in mind because they may play an important role in patients’ coping strategies with ­rheumatologic issues. Several surveys have shown improved coping ability with pain and dysfunction when patients incorporate regular spiritual or reflective practices, such as prayer and journaling.142 Generally, patients should feel comfortable discussing interventions they are currently using for prevention, treatment, and coping with open discussion regarding the place of these interventions in the comprehensive management of their condition.

INTEGRATION INTO CLINICAL CARE: AN EXAMPLE The guideline for “Treatment of knee pain in older adults in primary care: development of an evidence-based model of care,” serves as an example of how complementary therapies can be incorporated into clinical care for rheumatology patients. This systematic survey completed by the Primary

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Table 34-7  Stepwise Approach to Treatment   of Knee Pain in Older Adults Step 1 Weight loss Paracetamol (acetaminophen) Exercise Written information Restorative sleep advice Thermotherapy Symptomatic slow-acting drugs (e.g., glucosamine, chondroitin, diacerein, avocado-soybean unsaponifiables) Step 2 Nonselective NSAIDs Compound opioid analgesics Physiotherapy Wedged insoles Selective NSAIDs Group education Capsaicin Acupuncture Appliances Walking aids Step 3 Intra-articular hyaluronan Intra-articular corticosteroids Occupational therapy Transcutaneous electrical nerve stimulation Topical NSAIDs Cognitive-behavioral therapy Step 4 Surgical referral NSAIDs, nonsteroidal anti-inflammatory drugs. From Porcheret M, Jordan K, Croft P; Primary Care Rheumatology Society: Treatment of knee pain in older adults in primary care: Development of an evidence-based model of care. Rheumatology (Oxf) 46:638-648, 2007.

Care Rheumatology Society outlines a stepwise approach for incorporating conventional, lifestyle, and complementary options (e.g., glucosamine, acupuncture, and ASUs).143 This example is outlined in Table 34-7. As more research is completed in this area, clinicians will have more guidance on the potential benefit and sequential role of specific complementary therapies in developing an integrative approach to rheumatologic care.

CONCLUSION Patients with acute and chronic inflammatory conditions continue to trend toward the use of nonpharmacologic remedies for rheumatologic conditions. It is imperative that health care practitioners remain informed on appropriate indications for use, risks, and limitations of such treatments. Paradoxically, it is even more important now, with widespread availability and free consumer access, that the appropriate use of CAM be overseen by knowledgeable health care professionals. An integrative approach using evidence-based CAM interventions is generally safe and often highly effective in treatment of acute aspects of rheumatologic conditions and in management of the chronic disease state. More importantly, these measures may offer additional preventive and palliative strategies to aid in the optimization of health care for patients with rheumatologic conditions.

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25. Davis JN, Kucuk O, Djuric Z, Sarkar FH: Soy isoflavone supplementation in healthy men prevents NF-kappa B activation by TNF-alpha in blood lymphocytes. Free Radic Biol Med 30:1293-1302, 2001. 26. Singh AK, Seth P, Anthony P, et al: Green tea constituent epigallocatechin-3-gallate inhibits angiogenic differentiation of human endothelial cells. Arch Biochem Biophys 401(1):29-37, 2002. 27. Ahmed S, Rahman A, Hasnain A: Green tea polyphenol epigallocatechin-3-gallate inhibits the IL-1β induced activity and expression of cyclooxygenase-2 and nitric oxide synthase-2 in human chondrocytes. Free Radic Biol Med 33:1097-1105, 2002. 28. Abe Y, Hashimoto S, Horie T: Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages. Pharmacol Res 39:41-47, 1999. 29. Liu S, Manson JE, Buring JE, et al: Relation between a diet with a high glycemic load and plasma concentrations of high-sensitivity­ C-reactive protein in middle-aged women. Am J Clin Nutr 75: 492-498, 2002. 30. Hafström I, Ringertz B, Gyllenhammar H, et al: Effects of fasting on disease activity, neutrophil function, fatty acid composition, and leukotriene biosynthesis in patients with rheumatoid arthritis. Arthritis Rheum 31:585-592, 1988. 31. Salas-Salvadó J, Garcia-Arellano A, Estruch R, et al: Components of the Mediterranean-type food pattern and serum inflammatory markers among patients at high risk for cardiovascular disease. Eur J Clin Nutr, 2007. 32. Tzoulaki I, Murray GD, Lee AJ, et al: C-reactive protein, interleukin6, and soluble adhesion molecules as predictors of progressive peripheral atherosclerosis in the general population: Edinburgh Artery Study. Circulation 112:976-983, 2005. 33. Sköldstam L, Hagfors L, Johansson G: An experimental study of a Mediterranean diet intervention for patients with rheumatoid arthritis. Ann Rheum Dis 62:208-214, 2003. 34. Sköldstam L, Brudin L, Hagfors L, et al: Weight reduction is not a major reason for improvement in rheumatoid arthritis from lactovegetarian, vegan or Mediterranean diets. Nutr J 44:15, 2005. 35. Kaartinen K, Lammi K, Hypen M, et al: Vegan diet alleviates fibromyalgia symptoms. Scand J Rheumatol 29:308-313, 2000. 36. Kjeldsen-Kragh J, Haugen M, Borchgrevink CF, Førre O: Vegetarian diet for patients with rheumatoid arthritis—status: Two years after introduction of the diet. Clin Rheumatol 13:475-482, 1994. (Erratum in: Clin Rheumatol 13:649, 1994.) 37. Kjeldsen-Kragh J, Mellbye OJ, Haugen M, et al: Changes in laboratory variables in rheumatoid arthritis patients during a trial of fasting and one-year vegetarian diet. J Rheumatol 24:85-93, 1995. 38. Müller H, de Toledo FW, Resch KL, et al: Fasting followed by vegetarian diet in patients with rheumatoid arthritis: A systematic review. Scand J Rheumatol 30:1-10, 2001. 39. King DE, Egan BM, Geesey ME: Relation of dietary fat, fiber to elevation of C-reactive protein. Am J Cardiol 92:1335-1339, 2003. (Erratum in Am J Cardiol 93:812, 2004.) 40. Jenkins DJ, Kendall CW, Marchie A, et al: Effects of a dietary portfolio of cholesterol-lowering foods vs. lovastatin on serum lipids and C-reactive protein. JAMA 290:502-510, 2003. 41. King DE, Egan BM, Woolson RF: Effect of a high-fiber diet vs a fiber-supplemented diet on C-reactive protein level. Arch Intern Med 167:502-506, 2007. 42. Cerhan JR, Saag KG, Merlino LA, et al: Antioxidant micronutrients and risk of rheumatoid arthritis in a cohort of older women. Am J Epidemiol 157:345-354, 2003. 43. Kremer JM, Bigauoette J, Michalek AV, et al: Effects of manipulation of dietary fatty acids on clinical manifestations of rheumatoid arthritis. Lancet 26(8422):184-187, 1985. 44. Guesens P, et al: Long-term effect of omega-3 fatty acid supplementation in active rheumatoid arthritis: A 12-month, double-blind, controlled study. Arthritis Rheum 37:824-829, 1994. 45. Faarvang KL, Nielsen GL, Thomsen BS, et al: [Fish oils and rheumatoid arthritis: A randomized and double-blind study]. Ugeskr Laeger 156:3495-3498, 1994. 46. Nielsen GL, Faarvang KL, Thomsen BS, et al: The effects of dietary supplementation with n-3 polyunsaturated fatty acids in patients with rheumatoid arthritis: A randomized, double blind trial. Eur J Clin Invest 22:687-691, 1992. 47. Zurier RB, Rossetti RG, Jacobson EW, et al: Gamma-Linolenic acid treatment of rheumatoid arthritis: A randomized, placebo-controlled trial. Arthritis Rheum 39:1808-1817, 1996.

48. MacLean CH, Mojica WA, Morton SC, et al: Effects of omega-3 fatty acids on lipids and glycemic control in type II diabetes and the metabolic syndrome and on inflammatory bowel disease, rheumatoid arthritis, renal disease, systemic lupus erythematosus, and osteoporosis. Evidence Report/Technology Assessment No. 89 (Prepared by Southern California/RAND Evidence-based Practice Center, under Contract No. 290-02-0003). AHRQ Publication No. 04-E012-2. Rockville, Md, Agency for Healthcare Research and Quality, 2004. 49. Maroon JC, Bost JW: Omega-3 fatty acids (fish oil) as an anti-inflammatory: An alternative to nonsteroidal anti-inflammatory drugs for discogenic pain. Surg Neurol 65:326-331, 2006. 50. Goldberg RJ, Katz J: A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain 129:210-223, 2007. 51. Adam O, Beringer C, Kless T, et al: Anti-inflammatory effects of a low arachidonic acid diet and fish oil in patients with rheumatoid arthritis. Rheumatol Int 23:27-36, 2003. 52. Nordström DC, Honkanen VE, Nasu Y, et al: Alpha-linolenic acid in the treatment of rheumatoid arthritis: A double-blind, placebo-controlled and randomized study: Flaxseed vs. safflower seed. Rheumatol Int 14:231-234, 1995. 53. Volker D, Fitzgerald P, Major G, Garg M: Efficacy of fish oil concentrate in the treatment of rheumatoid arthritis. J Rheumatol 27:23432346, 2000. 54. Schmid B, Kotter I, Heide L: Pharmacokinetics of salicin after oral administration of a standardized willow bark extract. Eur J Clin Pharmacol 57:387-391, 2001. 55. Schmid B, Lüdtke R, Selbmann HK, et al: Efficacy and tolerability of a standardized willow bark extract in patients with osteoarthritis: Randomized placebo-controlled, double blind clinical trial. Phytother Res 15:344-350, 2001. 56. Schaffner W: Eidenrinde-Ein Antiarrheumatikum der modernen Phytotherapie. In Chrubasik S, Wink M (eds): Rheumatherapie mit Phytopharmaka. Stuttgart, Hippokrates Verlag, 1997, pp 125-127. 57. Chrubasik S, Eisenberg E, Balan E, et al: Treatment of low back pain exacerbations with willow bark extract: A randomized double-blind study. Am J Med 109:9-14, 2000. 58. Murakami A: Zerumbone, a Southeast Asian ginger sesquiterpene, markedly suppresses free radical generation, proinflammatory protein production, and cancer cell proliferation accompanied by apoptosis: The alpha, beta-unsaturated carbonyl group is a prerequisite. Carcinogenesis 23:795-802, 2002. 59. Thomson M: The use of ginger (Zingiber officinale Rosc.) as a potential anti-inflammatory and antithrombotic agent. Prostaglandins Leukot Essent Fatty Acids 67:475-478, 2002. 60. Altman RD, Marcussen KC: Effects of a ginger extract on knee pain in patients with osteoarthritis. Arthritis Rheum 44:2531-2538, 2001. 61. Wigler I, Grotto I, Caspi D, Yaron M: The effects of Zintona EC (a ginger extract) on symptomatic gonarthritis. Osteoarthritis Cartilage 11:783-789, 2003. 62. Jang MH, Lim S, Han SM, et al: Harpagophytum procumbens suppresses lipopolysaccharide-stimulated expressions of cyclooxygenase-2 and inducible nitric oxide synthase in fibroblast cell line L929. J Pharmacol Sci 93:367-371, 2003. 63. Loew D, Möllerfeld J, Schrödter A, et al: Investigations on the pharmacokinetic properties of Harpagophytum extracts and their effects on eicosanoid biosynthesis in vitro and ex vivo. Clin Pharmacol Ther 69:356-364, 2001. 64. Fiebich BL, Heinrich M, Hiller KO, et al: Inhibition of TNFα synthesis in LPS-stimulated primary human monocytes by Harpagophytum extract SteiHap 69. Phytomedicine 8:28-30, 2001. 65. Gagnier JJ, Chrubasik S, Manheimer E: Harpagophytum procumbens for osteoarthritis and low back pain: A systematic review. BMC Complement Altern Med 4:13, 2004. 66. Gagnier JJ, van Tulder M, Berman B, et al: Herbal medicine for low pack pain. Cochrane Database Syst Rev 2:CD004504, 2006. 67. Chrubasik S, Model A, Black A, Pollak S: A randomized doubleblind pilot study comparing Doloteffin and Vioxx in the treatment of low back pain. Rheumatology (Oxf) 42:141-148, 2003. 68. Bassleer C, Rovati L, Franchimont P: Stimulation of proteoglycan production by glucosamine sulfate in chondrocytes isolated from human osteoarthritic articular cartilage in vitro. Osteoarthritis Cartilage 6:427-434, 1998.

PART 4  69. Uelbelhart D, Thonar EJ, Zhang J, Williams JM: Protective effect of exogenous chondroitin 4,6-sulfate in the acute degradation of articular cartilage in the rabbit. Osteoarthritis Cartilage 6(Suppl A):6-13, 1998. 70. Towheed TE, Anastassiades TP, Shea B, et al: Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 1: CD002946, 2001. 71. McAlindon T, Lavalley MP, Gulin JP, Felson DT: Glucosamine and chondroitin for the treatment of osteoarthritis. JAMA 283: 1469-1475, 2000. 72. Richy F, Bruyere O, Ethgen O, et al: Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis. Arch Intern Med 163:1514-1522, 2003. 73. Reichenbach R, Sterchi R: Martin Scherer M: Meta-analysis: Chondroitin for osteoarthritis of the knee or hip. Ann Intern Med 146:580590, 2007. 74. Clegg DO, Reda DJ, Harris CL, et al: Glucosamine, chondroitin ­sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 354:795-808, 2006. 75. Hochberg MC: Nutritional supplements for knee osteoarthritis—still no resolution. N Engl J Med 354:858-860, 2006. 76. Stramentinoli G: Pharmacologic aspects of S-adenosylmethionine. Am J Med 83(Suppl 5A):35-42, 1987. 77. Harmand MF, Vilamitjana J, Maloche E, et al: Effects of S-adenosylmethionine on human articular chondrocyte differentiation: An in vitro study. Am J Med 83:48-54, 1987. 78. Parcell S: Sulfur in human nutrition and applications in medicine. Altern Med Rev 7:22-44, 2002. 79. Soeken KL, Lee WL, Bausell RB, et al: Safety and efficacy of Sadenosylmethionine (SAMe) for osteoarthritis. J Fam Pract 51: 425-430, 2002. 80. Najm WI, Reinsch S, Hoehler F, et al: S-Adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: A double-blind cross-over trial. BMC Musculoskelet Disord 5:6, 2004. 81. Rosenblat G, et al: Chemical characteristics of lysyl oxidase inhibitor from avocado seed oil. JAOCS 72:225-229, 1995. 82. Reginster JY, Gillot V, Bruyere O, et al: Evidence of neutraceutical effectiveness in the treatment of osteoarthritis. Curr Rheumatol Rep 2:472-477, 2000. 83. Henrotin YE, Sanchez C, Deberg MA, et al: Avocado/soybean unsaponifiables increase aggrecan synthesis and reduce catabolic and proinflammatory mediator production by human osteoarthritic chondrocytes. J Rheumatol 30:1825-1834, 2003. 84. Boumediene K, Felisaz N, Bogdanowicz P, et al: Avocado-soya unsaponifiables enhance the expression of transforming growth factor beta1 and beta2 in cultured articular chondrocytes. Arthritis Rheum 42:148-156, 1999. 85. Appelboom T, Schuermans J, Verbruggen G, et al: Symptoms modifying effect of avocado-soybean unsaponifiables (ASU) in knee osteoarthritis: A double blind, prospective, placebo-controlled study. Scand J Rheumatol 30:242-247, 2001. 86. Maheu E, Mazières B, Valat JP, et al: Symptomatic efficacy of avocado-soybean unsaponifiables in the treatment of osteoarthritis of the knee: A prospective, randomized, double-blind, placebo-controlled, multicenter trial with a six-month treatment period and a two-month followup demonstrating a persistent effect. Arthritis Rheum 41: 81-91, 1998. 87. Ernst E: Avocado-soybean unsaponifiables (ASU) for osteoarthritis—a systematic review. Clin Rheumatol 22(4-5):285-288, 2003. 88. Deal CL, Schnitzer TJ, Lipstein E: Treatment of arthritis with topical capsaicin: A double-blind trial. Clin Ther 13:383-395, 1991. 89. McCleane G: The analgesic efficacy of topical capsaicin is enhanced by glyceryl trinitrate in painful osteoarthritis: A randomized, double blind, placebo controlled study. Eur J Pain 4:355-360, 2000. 90. Singh R, Ahmed S, Malemud CJ: Epigallocatechin-3-gallate selectively inhibits interleukin-1β-induced activation of mitogen activated protein kinase subgroup c-jun N-terminal kinase (JNK) in human osteoarthritis chondrocytes. J Orthop Res 21:102-109, 2003. 91. Liacini A, Sylvester J, Li WQ, et al: Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-κB) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes. Matrix Biol 21:251-262, 2002. 92. Ahmed S, Anuntiyo J, Malemud CJ, et al: Biological basis for the use of botanicals in osteoarthritis and rheumatoid arthritis: A review. Evid Based Complement Alternat Med 2:301-308, 2005.

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93. Cabyoglu MT, Ergene N, Tan U: The mechanism of acupuncture and clinical applications. Int J Neurosci 116:115-125, 2006. 94. White P: A background to acupuncture and its use in chronic painful musculoskeletal conditions. J R Soc Health 126:219-227, 2006. 95. Staud R, Price DD: Mechanisms of acupuncture analgesia for clinical and experimental pain. Expert Rev Neurother 6:661-667, 2006. 96. Berman BM, Lao L, Langenberg P: Effectiveness of acupuncture as adjunctive therapy in osteoarthritis of the knee: A randomized, controlled trial. Ann Intern Med 141:901-910, 2004. 97. Kwon YD, Pittler MH, Ernst E: Acupuncture for peripheral joint osteoarthritis: A systematic review and meta-analysis. Rheumatology (Oxf) 45:1331-1337, 2006. 98. Casimiro L, Barnsley L, Brosseau L, et al: Acupuncture and electroacupuncture for the treatment of rheumatoid arthritis. Cochrane Database Syst Rev 4:CD003788, 2005. 99. Singh BB, Wu WS, Hwang SH: Effectiveness of acupuncture in the treatment of fibromyalgia. Altern Ther Health Med 12:34-41, 2006. 100. Martin DP, Sletten CD, Williams BA, et al: Improvement in fibromyalgia symptoms with acupuncture: Results of a randomized controlled trial. Mayo Clin Proc 81:749-757, 2006. 101. Manheimer E, White A, Berman B: Meta-analysis: Acupuncture for low back pain. Ann Intern Med 142:651-663, 2005. 102. Brosseau L, Robinson V, Wells G, et al: Low level laser therapy (classes I, II and III) for treating rheumatoid arthritis. Cochrane Database Syst Rev 4:CD002049, 2005. 103. Talbot LA, Gaines JM, Ling SM, et al: A home-based protocol of electrical muscle stimulation for quadriceps muscle strength in older adults with osteoarthritis of the knee. J Rheumatol 30:1571-1578, 2003. 104. Osiri M, Welch V, Brosseau L, et al: Transcutaneous electrical nerve stimulation for knee osteoarthritis. Cochrane Database Syst Rev 4: CD002823, 2000. 105. Brosseau L, Judd MG, Marchand S, et al: Transcutaneous electrical nerve stimulation (TENS) for the treatment of rheumatoid arthritis in the hand. Cochrane Database Syst Rev 3:CD004377, 2003. 106. Robinson V, Brosseau L, Casimiro L, et al: Thermotherapy for treating rheumatoid arthritis. Cochrane Database Syst Rev 2:CD002826, 2002. 107. Trock DH: Electromagnetic fields and magnets: Investigational treatment for musculoskeletal disorders. Rheum Dis Clin N Am 26:51-62, 2000. 108. Hulme J, Robinson V, DeBie R: Electromagnetic fields for the treatment of osteoarthritis. Cochrane Database Syst Rev 1:CD003523, 2002. 109. Wolsko PM, Eisenberg DM, Simon LS: Double-blind placebo-controlled trial of static magnets for the treatment of osteoarthritis of the knee: Results of a pilot study. Altern Ther Health Med 10:36-43, 2004. 110. Kroeling P, Gross A, Houghton PE; Cervical Overview Group: Electrotherapy for neck disorders. Cochrane Database Syst Rev 2: CD004251, 2005. 111. Huyser B, Parker JC: Stress and rheumatoid arthritis: An integrative review. Arthritis Care Res 11:135-145, 1998. 112. Escalante A, del Rincon I: How much disability in rheumatoid arthritis is explained by rheumatoid arthritis? Arthritis Rheum 42: 1712-1721, 1999. 113. Parker JC, Smarr KL, Angelone EO, et al: Psychological factors, immunologic activation, and disease activity in rheumatoid arthritis. Arthritis Care Res 5:196-201, 1992. 114. Parker J, Smarr K, Anderson S, et al: Relationship of changes in helplessness and depression to disease activity in rheumatoid arthritis. J Rheumatol 19:1901-1905, 1992. 115. Zautra AJ, Smith BW: Depression and reactivity to stress in older women with rheumatoid arthritis and osteoarthritis. Psychosom Med 63:687-696, 2001. 116. Covic T, Adamson B, Spencer D, et al: A biopsychosocial model of pain and depression in rheumatoid arthritis: A 12-month longitudinal study. Rheumatology (Oxf) 42:1287-1294, 2003. 117. Deleted in press. 118. Messier SP, Loesser RF, Miller GD, et al: Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis. The Arthritis, Diet, and Activity Promotion Trial (ADAPT). Arthritis Rheum 50:1501-1510, 2004. 119. Ettinger WH Jr, Barns R, Messier SP, et al: The Fitness and Arthritis in Seniors Trial (FAST). JAMA 277:25-31, 1997.

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120. Sharma L, Cahue S, Song J, et al: Physical functioning over three years in knee osteoarthritis: Roles of psychosocial, local mechanical, and neuromuscular factors. Arthritis Rheum 48:3359-3370, 2003. 121. Hurley MV: The role of muscle weakness in the pathogenesis of osteoarthritis. Rheum Dis Clin N Am 25:283-298, 1999. 122. van Baar ME, Assendelft WJJ, Dekker J, et al: Effectiveness of exercise therapy in patients with osteoarthritis of the hip and knee: A systematic review of randomized clinical trials. Arthritis Rheum 42:1361-1369, 1999. 123. Minor MA: Exercise in the treatment of osteoarthritis. Rheum Dis Clin N Am 25:397-415, 1999. 124. Pendleton A, Arden N, Dougados M, et al: EULAR recommendations for the management of knee osteoarthritis: Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis 59:936944, 2000. 125. Altman RD, Hochberg MC, Moskowitz RW, et al: Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum 43:1905-1915, 2000. 126. Feinglass J, Thompson JA, He XZ, et al: Effects of physical activity on functional status among older middle age adults with arthritis. Arthritis Rheum 53:879-885, 2005. 127. Dunlop DD, Manheim LM, Yelin EH, et al: The costs of arthritis. Arthritis Rheum 49:101-113, 2003. 128. Hopman-Rock M, Westhoff MH: The effects of a health educational and exercise program for older adults with osteoarthritis of the hip or knee. J Rheumatol 27:1947-1954, 2000. 129. Dexter PA: Joint exercises in elderly persons with symptomatic osteoarthritis of the hip or knee: Performance patterns, medical support, and the relationship between exercising and medical care. Arthritis Care Res 5:36-41, 1992. 130. Andersen RE, Blair SN, Cheskin LJ, Bartlett SJ: Encouraging patients to become more physically active: The physician’s role. Ann Intern Med 127:395-400, 1997. 131. Iversen MD, Eaton HM, Daltroy LH: How rheumatologists and patients with rheumatoid arthritis discuss exercise and the influence of discussions on exercise prescriptions. Arthritis Rheum 51:63-72, 2004. 132. Häkkinen A, Sokka T, Kotaniemi A, et al: A randomized two-year study of the effects of dynamic strength training on muscle strength, disease activity, functional capacity, and bone mineral density in early rheumatoid arthritis. Arthritis Rheum 44:515-522, 2001.

133. Munneke M, de Jong Z, Zwinderman AH: Effect of a high-intensity weight-bearing exercise program on radiologic damage progression of the large joints in subgroups of patients with rheumatoid arthritis. Arthritis Rheum 53:410-417, 2005. 134. van den Hout WB, de Jong Z, Munneke M: Cost-utility and costeffectiveness analyses of a long-term, high-intensity exercise program compared with conventional physical therapy in patients with rheumatoid arthritis. Arthritis Rheum 53:39-47, 2005. 135. Richards SC, Scott DL: Prescribed exercise in people with fibromyalgia: Parallel group randomized controlled trial. BMJ 325:185-187, 2002. 136. Hadhazy VA, Ezzo J, Creamer P, Berman BM: Mind-body therapies for the treatment of fibromyalgia: A systematic review. J Rheumatol 27:2911-2918, 2000. 137. Garfinkel MS, Singhal A, Katz WA, et al: Yoga-based intervention for carpal tunnel syndrome. JAMA 280:1601-1603, 1998. 137a. Wood C: Mood change and perceptions of vitality: A comparison of the effects of relaxation, visualization and yoga. J R Soc Med 86(5): 254-258, 1993. 138. Smith C, Hancock H, Blake-Mortimer J, et al: A randomised comparative trial of yoga and relaxation to reduce stress and anxiety. Complement Ther Med 15:77-83, 2007. 139. Pilkington K, Kirkwood G, Rampes H, et al: Yoga for depression: The research evidence. J Affect Disord 89(1-3):13-24, 2005. 140. Garfinkel MS, Schumacher HR, Husain A, et al: Evaluation of a yoga based regimen for treatment of osteoarthritis of the hands. J Rheumatol 21:2341-2343, 1994. 141. Haslock I, Monro R, Nagarathna R, et al: Measuring the effects of yoga in rheumatoid arthritis. Br J Rheumatol 33:787-788, 1994. 142. Keefe FJ, Affleck G, Lefebvre J, et al: Living with rheumatoid arthritis: The role of daily spirituality and daily religious and spiritual coping. J Pain 2:101-110, 2001. 143. Porcheret M, Jordan K, Croft P: Primary Care Rhumatology Society: Treatment of knee pain in older adults in primary care: Development of an evidence-based model of care. Rheumatology (Oxf) 46:638-648, 2007.

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5

EVALUATION OF GENERALIZED AND LOCALIZED SYMPTOMS

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History and Physical Examination of the Musculoskeletal System John M. Davis iii  •  Kevin G. Moder  •  Gene G. Hunder

KEY POINTS Taking a detailed and accurate history is crucial for ­making the correct diagnosis for patients with musculoskeletal ­diseases. The cardinal symptoms of musculoskeletal disease are pain, stiffness, swelling, limitation of motion, weakness, and fatigue. Understanding the anatomy, the planes of motion, and ­particularly the configuration of the synovial lining is imperative for proper physical diagnosis of musculoskeletal diseases. It is important to record qualitative and quantitative aspects of the joint examination to monitor disease activity in patients with inflammatory arthropathies. Early recognition of how patients’ psychosocial factors ­affect their musculoskeletal symptoms and musculoskeletal ­examination enhances clinical assessment.

d­ iseases, however, and must be considered in light of the entire history and physical examination. The physician must assess compliance with therapies for musculoskeletal diseases. Noncompliance with the recommended treatment must be differentiated from treatment failure as the explanation for the patient’s lack of improvement. While the physician is taking the patient’s history, the patient provides verbal and nonverbal clues to the nature of the illness and how the patient has responded to it. Patients with early rheumatoid arthritis may hold their hands in a flexed posture to minimize intra-articular pressure and pain. Patients with fibromyalgia or chronic pain syndromes often dramatize in describing their symptoms. Some patients may be overly concerned, whereas others may seem inappropriately indifferent to their symptoms. The physician must appreciate the patient’s understanding of the illness and attitudes toward it to begin effective treatment. PAIN

HISTORY IN A PATIENT WITH MUSCULOSKELETAL DISEASE Taking an accurate and comprehensive history of a patient’s musculoskeletal symptoms is crucial for making the correct diagnosis. This history must include a precise understanding of what the patient means by the description of symptoms. The physician must obtain a detailed account of symptom onset, location, patterns of progression, severity, exacerbating and alleviating factors, and associated symptoms. The relationship of the symptoms to psychosocial stressors is important and should be determined. The impact of the symptoms on all aspects of the patient’s functioning must be assessed to guide therapy. The effects of current or previous therapy on the course of the illness are helpful in understanding the current ­symptoms. Response to anti-inflammatory or glucocorticoid medications may suggest an inflammatory etiology. Such responses are not specific to inflammatory rheumatic © 2006 Mayo Foundation for Medical Education and Research.   Video available on the Expert Consult Premium Edition website.

Pain is the most common symptom that brings a patient with musculoskeletal diseases to the physician. Pain is a ­subjective hurting sensation or experience described in ­various terms, often of actual or perceived physical damage. Pain is a complex sensation that is difficult to define, qualify, and measure. The patient’s pain may be modified by ­emotional factors and previous experiences. The character of the pain usually is best defined early in the interview because this can be helpful in ­categorizing the patient’s complaints. Aching in a joint area suggests an arthritic disorder, whereas “burning” or “numbness” in an extremity may indicate a neuropathy. Descriptions of pain as “excruciating” or “intolerable” when the patient is ­otherwise able to function provide a clue that emotional or psychosocial factors are contributing to or amplifying the symptoms. The physician must elicit the distribution of the patient’s pain and determine if this fits with anatomic structures. Patients describe their pain location in terms of body part names, but frequently the terms are used in a nonanatomic manner. Patients frequently complain of “hip” pain when actually referring to pain in the low back, buttock, or thigh. The interviewer must attempt to clarify this complaint by 515

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asking the patient to point to the area of pain with one finger. Pain localized in the distribution of a joint or joints likely reflects an articular disorder. Pain may localize to bursae, tendons, ligaments, or nerves, implying disorders of these structures. In contrast to superficial structures, deep structures often give rise to poorly localizing pain. Similarly, pain arising from small, peripheral joints is often more focal than pain arising from proximal, large joints, such as the shoulders and hips. Pain that is widespread, vaguely described, and not respecting anatomic distributions generally suggests a chronic pain syndrome, such as fibromyalgia or psychiatric disease. The severity of pain should be assessed. A common ap­proach is to ask the patient to describe the level of pain on a numeric scale of intensity from 0 (no pain) to 10 (very severe pain). For monitoring of disease activity of inflammatory arthritis, measuring pain on a visual analog scale by having the patient mark the severity of pain over the past week on a 100-mm line can be helpful. Similar scales are used in validated instruments such as the Health ­Assessment Questionnaire. The physician must determine what exacerbates and alleviates the pain. Joint pain present at rest but worse with movement suggests an inflammatory process, whereas pain occurring primarily with activity and relieved by rest generally indicates a mechanical disorder, such as degenerative arthritis. Timing of the pain symptoms during the day and night also provides important information, as discussed in the next section. STIFFNESS Stiffness is a common complaint among patients with arthritis. What is meant by stiffness varies from patient to patient, however. Some patients may use the term stiffness to refer to pain, soreness, weakness, fatigue, or limitation of motion.1 Rheumatologists generally use the term stiffness to describe discomfort and limitation on attempted movement of joints after a period of inactivity. This “gel” phenomenon occurs usually after an hour or more of inactivity. The duration of stiffness related to inactivity varies, with mild stiffness lasting minutes to severe stiffness lasting hours. Morning stiffness is an early feature of inflammatory arthropathies and is particularly noted in rheumatoid arthritis and polymyalgia rheumatica, in which morning stiffness may last for several hours. The absence of morning stiffness does not exclude inflammatory arthritis, but its absence is uncommon. A useful question to assess morning stiffness is: “In the morning, how long does it take for your joints to limber up as good as they are going to get for the day?” Morning stiffness associated with noninflammatory joint diseases, such as degenerative arthritis, is generally of short duration (usually <30 minutes) and less severe than stiffness of inflammatory joint disease. Additionally, the degree of stiffness in noninflammatory joint diseases is related to the extent of use of the damaged joint—stiffness is worse after excessive use, generally improving within several days to the baseline level. Morning stiffness is not specific for inflammatory arthropathies and may be described by patients with fibromyalgia or chronic idiopathic pain syndromes, neurologic disorders such as Parkinson’s disease (although ­generally without limbering up), and sleep-related ­breathing ­disorders.

LIMITATION OF MOTION Limitation of motion is a common complaint among patients with articular disorders. This complaint must be differentiated from stiffness, which is usually transient and variable, whereas limitation of motion secondary to joint disease is generally fixed and varies less over time. The interviewer should determine the extent of disability resulting from the restriction in joint motion. The duration of the restriction in joint motion frequently predicts the likelihood of improvement with interventions such as oral and intra-articular ­glucocorticoids or physical therapy. Determining the rapidity of onset of the limitation of motion may be helpful in the differential diagnosis; the abrupt onset of the limitation of motion suggests a structural derangement, such as a tendon rupture or torn knee cartilage, whereas an insidious onset of restricted joint motion is more common with inflammatory joint disease. SWELLING Joint swelling is an important symptom in patients with rheumatic diseases. The presence of true joint swelling narrows the differential diagnosis in a patient with arthralgia. To determine if the swelling is related to joint synovitis as opposed to soft tissue conditions, clarifying the anatomic location and distribution of the swelling is key. Diffuse soft tissue swelling can occur because of venous or lymphatic obstruction, soft tissue injury, or obesity. The description of swelling in patients with such conditions usually is illdefined or not in a distribution of particular joints, bursae, or tendons. Obese patients may interpret normal adipose tissue over the medial aspect of the elbow, the knee, or the lateral aspect of the ankle as joint swelling. In contrast, patients with inflammatory arthritis may describe swelling of joints in a distribution typical of a specific disease—symmetric swelling of the metacarpophalangeal joints and wrists in rheumatoid arthritis or swelling of several toes and a knee in psoriatic arthritis. It is useful to delineate the onset and progression of swelling and the factors that influence it. Swelling of a joint resulting from synovitis or bursitis frequently is ­ associated with discomfort with motion because of tension on the inflamed tissues. If the swollen tissues are periarticular, however, no discomfort may be present with joint motion because the inflamed tissues are not stressed. Swelling of a confined structure, such as a synovial cavity or bursa, is most painful when it has developed acutely, whereas a similar degree of swelling that has developed slowly is often much more tolerable. WEAKNESS Weakness is another common complaint that can be ­associated with myriad different subjective meanings. True weakness is the loss of muscle power. When present, it is demonstrable on physical examination. The temporal course of weakness is important to the differential diagnosis. Weakness of sudden onset without trauma often indicates a neurologic disorder, such as an acute cerebrovascular event, which generally results in a fixed, nonprogressive deficit. Weakness of insidious onset more often

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suggests a muscle disease, such as an ­inflammatory myopathy (i.e., polymyositis). The latter tends to be ongoing and progressive. Weakness that is intermittent suggests a disorder of the neuromuscular junction, such as myasthenia gravis. Patients with this disease may describe muscle fatigue with activity as opposed to true weakness. The physician should determine the distribution of the patient’s weakness. Proximal weakness that is bilateral and symmetric suggests an inflammatory myopathy. In contrast, inclusion body myositis causes an asymmetric and more ­distal weakness. The presence of a unilateral or isolated deficit generally indicates a neurogenic etiology. Distal weakness, in the absence of joint findings, generally indicates neurologic disorders, such as peripheral neuropathy. Patients with peripheral neuropathies also complain of pain and sensory symptoms, such as paresthesias. In contrast, patients with inflammatory myopathy typically present with painless weakness. Inquiring about the patient’s family history may provide valuable information. A history of other family members with similar symptoms may increase the likelihood that the patient has a hereditary disorder, such as muscular dystrophy or familial neuropathy. It also is important to review medication taken recently or currently. Many medications, including corticosteroids and lipid-lowering agents, can cause muscle injury. Less commonly, environmental exposures can lead to symptoms of weakness. Heavy metal poisoning causes a peripheral neuropathy. Dietary exposures also should be investigated such as eating undercooked pork as a source of trichinosis. ­ Excessive alcohol intake has been associated with ­neuropathy and myopathy. Taking a complete review of systems is helpful in evaluating a patient with weakness. Constitutional symptoms, such as weight loss and night sweats, may indicate the presence of a malignancy as the cause of generalized weakness. Rash, arthralgia, or Raynaud’s phenomenon may prompt further testing for a connective tissue disease. FATIGUE Patients with musculoskeletal disorders frequently complain of fatigue. Fatigue can be defined as an inclination to rest even though pain and weakness are not limiting factors. Fatigue after varying degrees of activity that is relieved by rest is normal. Patients with rheumatic diseases experience fatigue even without activity. Fatigue generally improves as the systemic rheumatic disease improves. Malaise frequently occurs with, but is not synonymous with, fatigue. Malaise indicates the lack of well-being that often occurs at the onset of an illness. Fatigue and malaise may occur in the absence of identifiable disease, and psychosocial factors, anxiety, or depression may account for the symptoms.

SYSTEMATIC METHOD OF EXAMINATION The musculoskeletal examination should be a systematic, thorough assessment of the status of the joints, periarticular soft tissues, tendons, ligaments, bursae, and muscles. Rheumatologists commonly begin by examining the upper extremities followed by the trunk and lower extremities, but many routines may be effective, provided that a systematic,

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consistent approach is used. Gentle handling of the tender and painful joints enhances cooperation by the patient and allows an accurate evaluation of the joints. The general aim of the examination of the joints is to detect abnormalities in structure and function. The key signs of articular disease are swelling, tenderness, limitation of motion, crepitation, deformity, and instability. SWELLING Swelling around a joint may be caused by intra-articular effusion, synovial proliferation, periarticular subcutaneous tissue inflammation, bursitis, tendinitis, bony enlargement, or extra-articular fat pads. A keen understanding of the anatomic configuration of each joint’s synovial membrane is crucial in differentiating soft tissue swelling secondary to a joint effusion from swelling of periarticular tissues. First, the examiner should inspect the joints for visible evidence of swelling, such as loss of normal landmarks or contours. It is frequently helpful to compare the same joints on both sides of the body visually to detect subtle evidence of swelling and to appreciate symmetry. Second, the examiner should palpate each joint. The normal synovial membrane is too thin to palpate, whereas the thickened synovial membrane in many chronic inflammatory arthritides, such as rheumatoid arthritis, may have a “doughy” or “boggy” consistency. In some joints, such as the knee, the extent of the synovial cavity can be delineated on physical examination by compressing the fluid into one of the extreme synovial recesses. The edge of the resulting bulge may be palpated more easily. If this palpable edge is within the anatomic confines of the synovial membrane and disappears on release of the compression, the distention usually represents synovial effusion; if it persists, it is an indication of a thickened synovial membrane. Reliable differentiation between synovial membrane thickening and effusion is not always possible by physical examination, however. Ultrasonography is being used increasingly as an extension of the physical examination, allowing the examiner to differentiate between synovial proliferation and effusion. TENDERNESS In the musculoskeletal examination, tenderness indicates unusual discomfort on palpating and putting pressure on articular and periarticular tissues. Localizing the tenderness to palpation may assist the examiner in determining whether the pathology is in an articular or a periarticular structure, such as a fat pad, tendon attachment, ligament, bursa, muscle, or skin. It can be useful to palpate structures that are not involved to assess the importance of tenderness. Finding tender joints in a patient who also has numerous other myofascial tender points is less concerning for arthritis than finding tender joints in a patient with no extra­articular tenderness. LIMITATION OF MOTION Limitation of motion is a common manifestation of articular disease; the examiner must know the normal type and range of motion of each joint. Comparison of the affected joint with an unaffected joint of the opposite extremity is

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invaluable to evaluate individual variation. The restricted joint motion may be caused by changes in the joint itself or in periarticular structures. To distinguish these possibilities, it is crucial to compare the passive range of motion with the active range of motion. If the passive range of motion is greater than the active range of motion, the restriction may be the result of pain, weakness, or the state of the articular and periarticular structures. It also is important to distinguish muscle tension from a true limitation of joint motion, emphasizing the importance of ensuring relaxation of the patient. Pain that occurs with attempting to move a joint passively to the limit of range of motion in one plane is referred to as stress pain. Pain in the joint with attempted active or passive range of motion usually indicates an abnormality in the joint. CREPITATION Crepitation is a palpable or audible grating or crunching sensation produced by motion. This sensation may or may not be accompanied by discomfort. Crepitation occurs when roughened articular or extra-articular surfaces are rubbed together by active motion or by manual compression. Fine crepitation is often palpable over joints involved by chronic inflammatory arthritis and usually indicates roughening of the opposing cartilage surfaces as a result of erosion or the presence of granulation tissue. Coarse crepitation may be caused by inflammatory or noninflammatory arthritis. Boneon-bone crepitus produces a higher frequency, palpable, and audible squeak. Crepitation from within a joint should be differentiated from cracking or popping sounds caused by the slipping of ligaments or tendons over bony surfaces during motion. The latter phenomena are usually less contributory to the diagnosis of joint disease and may be heard over normal joints. In scleroderma, a distinct, coarse, creaking, leathery crepitation may be palpable or audible over tendon sheaths. DEFORMITY Deformity of the joints may manifest as a bony enlargement, articular subluxation, contracture, or ankylosis in ­nonanatomic positions. Deformed joints usually do not function normally, frequently restrict activities, and may be associated with pain, especially with overuse. Occasionally, a deformed joint may function well, but is a cosmetic concern. Joint deformities may be reversible or irreversible. Multiple swan neck deformities of the fingers that can be corrected with manipulation may indicate Jaccoud’s arthropathy of lupus. In contrast, hand deformities in rheumatoid arthritis generally are not correctable. INSTABILITY Joint instability is present when the joint has greater than normal movement in any plane. Subluxation refers to a joint in which there is partial displacement of the ­articular surfaces, but still some joint surface-to-surface contact. A dislocated joint has lost all cartilage surface-to-surface contact. Instability is best determined by supporting the joint between the examiner’s hands and stressing the adjacent bones in directions in which the normal joint does not

move. The patient must be relaxed during the examination because muscle tension may stabilize an otherwise ­unstable joint. A knee with a deficient ligament might appear ­stable if the patient contracts the quadriceps muscles during ­evaluation. OTHER ASPECTS OF THE EXAMINATION Examinations of the cervical spine and low back are discus­ sed in Chapters 39 and 41.

RECORDING THE JOINT EXAMINATION Documentation of the joint examination is important in making decisions about therapy, monitoring the activity of arthritis, and determining the efficacy of interventions. Many different recording methods have been described. Abbreviations for each joint can be used, such as PIP for the proximal interphalangeal joints. The S-T-L system has been used historically to record the degree of swelling (S), tenderness (T), and limitation of motion (L) of each joint on the basis of a quantitative estimate of gradation.2 This method remains useful, but is used less commonly today because of the increasing reliance on electronic medical records. It is easier to describe the joint findings in narrative form; for example, “there is 2+ swelling of the second and third MCP joints,” where grade 0 indicates no swelling and grade 3 indicates maximal swelling for the metacarpophalangeal joint. An alternative method is to record the joint examination findings using a schematic skeleton or homunculus. When accuracy is necessary, the range of motion of individual joints may be measured using a goniometer. Joint counts are being used increasingly to monitor the activity of inflammatory arthritides in practice and in clinical trials.3 For monitoring disease activity of rheumatoid arthritis, a 28-joint count for tenderness and swelling has been recommended. To assess the tender joint count, the examiner documents which joints the patient indicates are painful on palpation with enough pressure to blanch the nail bed of the examiner’s thumb and index fingers. To assess the swollen joint count, the examiner documents which joints have palpable soft tissue swelling or fluctuance, excluding joints affected only by deformity or bony hypertrophy. The 28-joint count4 includes the shoulders, elbows, wrists, first to fifth metacarpophalangeal joints, first to fifth proximal interphalangeal joints, and knees on both sides of the body. Compared to more extensive joint counts, the 28-joint count has the advantage of being quick and easy to perform; however, it is limited by the fact that the ankles and metatarsophalangeal joints are not included, so active disease in the feet may be underestimated. The 28-joint count is used to calculate the disease activity score 28 (DAS28),5 which is a validated instrument to monitor disease activity. The function of the joints in normal use is not ­captured by the assessments of tenderness, swelling, or range of motion, so other examination techniques are necessary. The patient’s grip strength can be measured by asking the patient to squeeze a partially inflated (20 mm Hg) sphygmomanometer or by using a dynamometer. Other tests are available that attempt to measure joint function by

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assessing the patient’s ability to perform a coordinated task (i.e., measuring the 50-foot walk time). The results of such functional tests may vary, however. For observations such as joint tenderness or grip strength, interobserver variability is often greater than intraobserver variability. There may be considerable intraobserver variability in observations of the same patient, even over a short interval. Biologic factors contribute to variability, such as circadian changes in joint size and grip strength among rheumatoid patients observed during a 24-hour interval. These tests are best suited for clinical trials and tend to be less useful in observing individual patients.

EXAMINATION OF SPECIFIC JOINTS TEMPOROMANDIBULAR JOINT The temporomandibular joint is formed by the condyle of the mandible and the fossa of the temporal bone just anterior to the external auditory canal. It is difficult to visualize swelling of this joint. The examiner may palpate the joint by placing a finger just anterior to the external auditory canal and asking the patient to open and close the mouth and to move the mandible from side to side.6 The presence of synovial thickness or swelling of minimal or moderate degree can be detected most easily if the synovitis is unilateral or asymmetric compared with the other side. To assess vertical movement of the temporomandibular joint, the examiner should ask the patient to open the mouth maximally and then measure the distance between the upper and lower incisor teeth, normally 3 to 6 cm. Lateral movement can be determined by using incisor teeth as landmarks. Audible or palpable crepitus or clicking may be present in patients with and without evidence of severe arthritis. Many arthritides can affect the temporomandibular joints, including juvenile and adult rheumatoid arthritis. Children in whom these joints are affected may develop micrognathia, resulting from arrested bone growth of the mandible. Patients without inflammatory arthritis may develop arthralgias of the temporomandibular joint, consistent with the temporomandibular joint syndrome (see Chapter 45). This syndrome is thought by some investigators to result from bruxism and is likely to be a form of ­myofascial pain, similar to fibromyalgia. CRICOARYTENOID JOINTS The paired cricoarytenoid joints are formed by the articulation of the base of the small pyramidal arytenoid cartilage and the upper posterolateral border of the cricoid cartilage. The vocal ligaments (true vocal cords) are attached to the arytenoid cartilages. The cricoarytenoid joints are diarthrodial joints that normally move medially and laterally and rotate during the opening and closing of the vocal cords. Examination of these joints is done by direct or indirect laryngoscopy. Erythema, swelling, and lack of mobility during phonation may result from inflammation of the joints. The cricoarytenoid joints may be involved in rheumatoid arthritis, trauma, and infection. Involvement in rheumatoid arthritis is more common than clinically apparent. ­Symptoms may include hoarseness or a sense of fullness or discomfort in the throat, which is worse

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on speaking or swallowing. Severe airway obstruction may rarely occur. STERNOCLAVICULAR, MANUBRIOSTERNAL, AND STERNOCOSTAL JOINTS The medial ends of the clavicles articulate on each side of the sternum at its upper end to form the sternoclavicular joints. The articulations of the first ribs and the sternum (sternocostal joints) are immediately caudal. The articulation of the manubrium and body of the sternum is at the level of the attachment of the second costal cartilage to the sternum. The third through seventh sternocostal joints articulate distally along the lateral borders of the sternum. The sternoclavicular joints are the only articulations in this group that are always diarthrodial; the others are amphiarthroses or synchondroses. The sternoclavicular joints are the only true points of articulation of the shoulder girdle with the trunk. These joints are just beneath the skin; synovitis is usually visible and palpable. These joints have only slight movement, which cannot be accurately measured. The sternoclavicular joints are commonly involved by ankylosing spondylitis, rheumatoid arthritis, and degenerative arthritis, although this involvement is often subclinical. The sternoclavicular joint may be the site of septic ­arthritis, especially in injection drug users. These joints should be examined for tenderness, swelling, and bony abnormalities. Tenderness of the manubriosternal or sternocostal joints is much more frequent than actual swelling. Tenderness of these joints without actual swelling has been termed ­costochondritis; if actual swelling is present, Tietze’s syndrome may be the term used. ACROMIOCLAVICULAR JOINT The acromioclavicular joint is formed by the lateral end of the clavicle and medial margin of the acromion process of the scapula. Arthritis of the acromioclavicular joint is most commonly attributable to trauma leading to degenerative arthritis. Bony enlargement of this joint is ­typically observed, but soft tissue swelling is not usually visible or ­palpable. Tenderness or pain with adduction of the arm across the chest indicates pathology of the acromioclavicular joint. Movement of this joint occurs with shoulder motion, but is difficult to measure accurately. The acromioclavicular joint may be involved by rheumatoid arthritis or spondyloarthropathies, although these are often not severe enough to come to clinical attention. SHOULDER See Chapter 40. ELBOW The elbow joint is composed of three bony articulations (Fig. 35-1). The principal articulation is the humeroulnar joint, which is a hinge joint. The radiohumeral and ­proximal radioulnar articulations allow rotation of the forearm. To examine the elbow joint, the examiner places the thumb between the lateral epicondyle and the olecranon

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Humerus

Medial epicondyle

Lateral epicondyle

Olecranon

Annular ligament Coronoid process

Radius

Ulna

Figure 35-1  Diagram of the elbow. Posterior aspect of the elbow joint showing radius and ulna in extension and distribution of synovial membrane in distention. (From Polley HF, Hunder GG: Rheumatologic Interviewing and Physical Examination of the Joints, 2nd ed. Philadelphia, WB Saunders, 1978. Used with permission of Mayo Foundation for Medical Education and Research.)

process in the lateral paraolecranon groove and places one or two fingers in the corresponding groove medial to the olecranon. The examiner relaxes and passively moves the elbow through flexion, extension, and rotation. One should examine the skin around the elbow joint carefully, noting abnormalities such as psoriatic plaques, rheumatoid nodules, or tophi. It is useful to palpate the olecranon bursa carefully to exclude the presence of small nodules or tophi. Limitation of motion and crepitus should be noted. Synovial swelling is most easily palpated as it bulges under the examiner’s thumb when the elbow is passively extended. Synovial membrane sometimes can be palpated over the posterior aspect of the joint between the olecranon process and distal humerus. Synovitis or effusion generally results in limitation of elbow extension. The olecranon bursa overlies the olecranon process of the ulna. Olecranon bursitis is common after chronic local trauma and in rheumatic diseases, including rheumatoid arthritis and gout. A septic olecranon bursitis may occur. A patient who has olecranon bursitis usually presents with a swelling over the olecranon process, which is often tender and may be erythematous. Sometimes a large collection

of fluid over the area is palpable as a cystic mass and often requires aspiration and drainage. There is generally no pain with elbow movement. The medial and lateral epicondyles of the humerus are the sites of attachment of the common flexor and extensor tendons, controlling hand and wrist motion. Tenderness at the epicondyles without swelling or other signs of inflammation may indicate overuse tendinopathy, termed lateral epicondylitis (tennis elbow) and medial epicondylitis (golfer’s elbow). In lateral epicondylitis, discomfort can be elicited by resisted supination of the forearm or resisted extension of the pronated wrist.7 In medial epicondylitis, discomfort can be elicited by resisted flexion of the supinated wrist. To assess motor function of the elbow, flexion and ­extension can be assessed. The principal flexors of the elbow are the biceps brachii (nerve roots C5 and C6), brachialis (C5 and C6), and brachioradialis (C5 and C6) muscles. The principal extensor of the elbow is the triceps brachii muscle (C7 and C8). Occasionally, a patient may rupture the attachment site of one of the heads of the biceps, ­resulting in visible and palpable muscle swelling on the anterior upper arm.

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WRIST AND CARPAL JOINTS The wrist is a complex joint formed by many articulations between the radius, ulna, and carpal bones. The true wrist or radiocarpal articulation is a biaxial ellipsoid joint formed proximally by the distal end of the radius and the triangular fibrocartilage and distally by a row of three carpal bones: scaphoid (navicular), lunate, and triquetrum (triangular). The distal radioulnar joint is a uniaxial pivot joint. The midcarpal joints are formed by the junction of the proximal and distal rows of the carpal bones. The midcarpal and carpometacarpal articular cavities often communicate. The intercarpal joints refer to the articulations between the individual carpal bones. Movements of the wrist include flexion (palmar flexion), extension (dorsiflexion), radial deviation, ulnar deviation, and circumduction. Pronation and supination of the hand and forearm occur primarily at the proximal and distal radioulnar joints. The only carpometacarpal joint that moves to a notable degree is the carpometacarpal joint of the thumb. This joint is saddle-shaped and moves in three planes. Crepitus at this joint is common because it is frequently involved in degenerative arthritis. The wrist normally can be extended to 70 to 80 degrees and flexed to 80 to 90 degrees. Ulnar and radial deviation should allow 50 degrees (ulnar) and 20 to 30 degrees (radial) of movement. Loss of extension is the most incapacitating functional impairment of wrist motion. The long flexor tendons of the forearm musculature cross the volar aspect of the wrist and are enclosed in the flexor tendon sheath under the flexor retinaculum (transverse carpal ligament). The flexor retinaculum and the underlying carpal bones form the carpal tunnel. The median nerve passes through the carpal tunnel superficial to the flexor tendons. The extensor tendons of the forearm musculature are enclosed by six synovial-lined compartments. The palmar aponeurosis (fascia) spreads out into the palm from the flexor retinaculum. Dupuytren’s contracture is a fibrosing condition affecting the palmar aponeurosis, which becomes thickened and contracted and may draw one or more fingers into flexion at the metacarpophalangeal joint. The fourth finger is frequently affected first. Swelling of the wrist may be caused by effusion or synovial proliferation, or both, of the tendon sheaths (tenosynovitis), the wrist joint, or a combination thereof. When swelling is attributable to tenosynovitis, the swelling is localized to the distribution of a particular tendon sheath or compartment (i.e., ulnar swelling attributable to tenosynovitis of the flexor carpi ulnaris tendon), tends to be more localized, and moves with flexion and extension of the fingers. Articular swelling tends to be more diffuse and protrudes anteriorly and posteriorly from under the tendons. Synovitis of the wrist is best detected by palpation of the dorsal aspect of the joint. Accurate localization of the synovial margins is difficult because of structures overlying the volar and the dorsal aspects of the wrist. To examine the wrist, the examiner should palpate the joint gently between the thumbs dorsally and the fingers on the volar aspect. Thickening or frank synovial proliferation of the synovium should be noted. When this thickening or proliferation is severe, the range of motion of the wrist joint is frequently limited and associated with stress pain.

Figure 35-2  Subluxation of the wrist. Side view of the wrist of a patient with rheumatoid arthritis. Note the prominence of the ulna.

A ganglion is a cystic enlargement arising from a joint capsule. Ganglions characteristically occur at the volar or dorsal aspects of the wrist between the tendons. Subluxation of the ulna may develop as a result of severe chronic inflammatory arthritis (Fig. 35-2). The subluxated ulna appears as a prominence on the dorsomedial wrist. Chronic irritation of the extensor tendons, primarily the fourth and fifth finger extensor tendons, may cause these tendons to rupture. “Trigger fingers” secondary to stenosing tenosynovitis can be detected by palpating crepitus or nodules along the tendons in the palm while the patient slowly flexes and extends the fingers.8 The patient usually gives a history of the affected finger catching or locking with movement. Tenosynovitis of the first extensor compartment, which encloses the abductor pollicis longus and extensor pollicis brevis muscles of the thumb, is known as de Quervain’s tenosynovitis. Patients complain of pain at the radial aspect of the wrist. Tenderness may be elicited by palpating near the radial styloid process. The Finkelstein test for de Quervain’s tenosynovitis is performed by asking the patient to make a fist with the thumb enclosed in the palm of the hand, then moving the wrist into ulnar deviation. Severe pain over the radial styloid is a positive finding, often indicating stretching of the thumb tendons in a stenosed tendon sheath. Carpal tunnel syndrome results from pressure on the median nerve in the carpal tunnel. Carpal tunnel syndrome is discussed in detail in Chapter 44. Muscle function of the wrist may be measured by testing flexion and extension and supination and pronation of the forearm. The principal flexors of the wrist are the flexor carpi radialis (nerve roots C6 and C7) and flexor carpi ulnaris (C8 and T1) muscles. Each of these muscles can be tested separately. This testing can be accomplished if the examiner provides resistance to flexion at the base of the second metacarpal bone in the direction of extension and ulnar deviation in the case of the flexor carpi radialis muscle and resistance at the base of the fifth metacarpal in the direction of extension and radial deviation in the case of the flexor carpi ulnaris muscle. The principal extensors of the wrist are the extensor carpi radialis longus (C6 and C7), extensor carpi radialis brevis (C6 and C7), and extensor carpi ulnaris (C7 and C8) muscles. The radial and ulnar extensor muscles can be tested separately. The principal supinators of the forearm are the biceps brachii (C5 and C6) and supinator (C6) muscles. The principal pronators of the forearm are

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the pronator teres (C6 and C7) and pronator quadratus (C8 and T1) muscles.

The metacarpophalangeal joints are hinge joints. Lateral collateral ligaments that are loose in extension tighten in flexion, preventing lateral movement of the digits. The extensor tendons that cross the dorsum of each joint strengthen the articular capsule. When the extensor tendon of the digit reaches the distal end of the metacarpal head, it is joined by fibers of the interossei and lumbricales muscles and expands over the entire dorsum of the metacarpophalangeal joint and onto the dorsum of the adjacent phalanx. This expansion of the extensor mechanism is known as the extensor hood. The proximal and distal interphalangeal joints also are hinge joints. The ligaments of the interphalangeal joints resemble those of the metacarpophalangeal joints. When the fingers are flexed, the bases of the proximal phalanges slide toward the palmar side of the heads of the metacarpal bones. The metacarpal heads form the rounded prominences of the knuckles, with the metacarpal joint spaces situated about 1 cm distal to the apex of the prominences. To examine the metacarpophalangeal joints, the examiner should palpate the dorsal and volar aspects of each joint in 20 to 30 degrees of flexion (Fig. 35-3). The skin on the palmar surface of the hand is thick and covers a fat pad between it and the metacarpophalangeal joint. This makes palpation of the palmar surface of the joint difficult. It is especially helpful in examining the small joints to compare one with another to detect subtle synovitis. Gentle lateral compression with force applied at the base of the second and fifth metacarpophalangeal joints often elicits tenderness if synovitis is present (squeeze test). The proximal and distal interphalangeal joints are best examined by palpating gently over the lateral and medial aspects of the joint where the flexor and extensor tendons do not interfere with assessment of the synovial membrane.

Alternatively, the joint can be compressed anteroposteriorly by the thumb and index finger of one of the examiner’s hands, while the other thumb and index finger palpate for synovial distention medially and laterally. The Bunnell test is useful to differentiate synovitis of the proximal interphalangeal joints from tightening of the intrinsic muscles (see Chapter 44). Swelling of the fingers may result from articular or periarticular causes. Synovial swelling usually produces ­symmetric enlargement of the joint itself, whereas extraarticular swelling may be diffuse and extend beyond the joint space. Asymmetric enlargement, involving only one side of the digit or joint, is less common and usually indicates an extra-articular process. Diffuse swelling of an entire digit, known by the terms dactylitis and sausage digit, may result from tenosynovitis and is seen most commonly in the spondyloarthropathies, such as reactive arthritis or psoriatic arthritis. Rheumatoid nodules are firm periarticular swellings that ­frequently overlie the joints or bony prominences in patients with chronic rheumatoid disease (Fig. 35-4). Chronic swelling and ­ distention of the metacarpophalangeal joints tends to produce stretching and laxity of the articular capsule and ligaments. This laxity, combined with muscle imbalance and other forces, eventually results in the extensor tendons of the digits slipping off the metacarpal heads to the ulnar sides of the joints. The abnormal pull of the displaced ­tendons is one of the factors that causes ulnar deviation of the fingers in chronic inflammatory arthritis. Swan neck deformity describes a finger with a flexion contracture of the metacarpophalangeal joint, ­hyperextension of the proximal interphalangeal joint, and flexion of the distal interphalangeal joint. These changes are produced by contraction of the interossei and other muscles that flex the metacarpophalangeal joints and extend the ­ proximal interphalangeal joints. This deformity is characteristic of rheumatoid arthritis, but may be seen in other chronic arthritides (Fig. 35-5). Boutonnière deformity describes a finger with a flexion contracture of the proximal interphalangeal joint associated with hyperextension of the distal interphalangeal joint.

Figure 35-3  Palpation of the metacarpophalangeal joints is done with the examiner’s thumbs palpating the dorsal aspect of the joint, while the forefingers palpate the volar aspect of the metacarpal head. The joints should be examined while the examiner holds the patient’s hand in a relaxed position of partial flexion.

Figure 35-4  Chronic nodular rheumatoid arthritis. Swelling of both wrists is present. Rheumatoid nodules are present on the right thumb, right second proximal interphalangeal joint, right second and fourth metacarpophalangeal joints, and left second distal interphalangeal joint. The last-mentioned is notable for central purulence resulting from infection. A mild boutonnière deformity is present in the right third finger.

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Figure 35-5  Swan neck deformity in a patient with psoriatic arthritis. Note hyperextension of the proximal interphalangeal joint and hyperflexion of the distal interphalangeal joint of the second digit. Also note the psoriatic changes of the third and fourth fingernails.

The deformity is common in rheumatoid arthritis and results when the central slip of the extensor tendon of the proximal interphalangeal joint becomes detached from the base of the middle phalanx, allowing palmar dislocation of the lateral bands. The dislocated bands cross the fulcrum of the joint and act as flexors instead of extensors of the joint. Another abnormality is telescoping or shortening of the digits produced by resorption of the ends of the phalanges secondary to destructive arthropathy. This may be seen in the arthritis mutilans form of psoriatic arthritis. Shortening of the fingers is associated with wrinkling of the skin over involved joints and is also called opera-glass hand or la main en lorgnette. A mallet finger results from avulsion or rupture of the extensor tendon at the level of the distal interphalangeal joint. With this deformity, the patient is unable to extend the distal phalanx, which remains in a flexed position. This deformity frequently results from traumatic injuries. The Murphy sign is a test for lunate dislocation. The patient is asked to make a fist. The third metacarpal head is usually more prominent than the second and fourth. If the third metacarpal is level with the second and fourth, the finding is positive for lunate dislocation. Involvement of the distal interphalangeal joints in rheumatoid arthritis is uncommon. Bony hypertrophy and osteophyte formation are commonly seen, however, at the distal and the proximal interphalangeal joints in patients with osteoarthritis. Enlarged, bony, hypertrophic distal interphalangeal joints are called Heberden nodes, whereas similar changes at the proximal interphalangeal joints are called Bouchard nodes. These are usually easily differentiated from the synovitis of inflammatory arthritis because, on palpation, the enlargement is hard or bony. In addition, signs of inflammation are minimal. Heberden and Bouchard nodes should be easily distinguished from rheumatoid ­ nodules, but patients occasionally confuse these when describing ­swellings over joints. The examiner should be aware of other causes of nodules on the hands, including tophaceous gout (Fig. 35-6) and, rarely, multicentric reticulohistiocytosis. The first carpometacarpal joint also is often affected in osteoarthritis (Fig. 35-7).

Figure 35-6  Gout. Note the enlargement and deformity of the left second proximal interphalangeal joint. This patient has gout, and aspiration of this joint confirmed the presence of uric acid crystals.

The patient’s fingernails should be inspected for ­evidence of clubbing or other abnormalities. Often in patients with psoriatic arthritis, ridging, onycholysis, or nail pitting is present. Occasionally, patients with osteoarthritis develop a groove deformity of the nail on a digit with a Heberden node. (This nail deformity has been called a Heberden node nail.) The abnormality is believed to occur secondary to the synovial cyst encroachment on the nail bed by the evolving osteoarthritis process. With time, the nail may return to normal. A crude but sometimes useful assessment of hand function can be made by asking the patient to make a fist. An estimate of the patient’s ability to form a full fist can be recorded as a percentage fist, with 100% being a complete fist. A fist of 75% indicates that the patient can touch the palm with the fingertips. The ability to oppose fingers,

Figure 35-7  Osteoarthritis of the hands. Note the advanced hypertrophic enlargement at the base of both thumbs. Both second distal interphalangeal joints are notable for advanced bony enlargement, and more moderate changes are seen in the other interphalangeal joints.

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e­ specially the thumb, is crucial to hand function because of the necessity to grasp or at least pinch for objects. If the patient is unable to form a full fist, a demonstration of the ability or inability to pinch or oppose fingers can be made by asking the patient to pick up a small object. Strength of the hands can be assessed crudely by ­asking the patient to grip firmly two or more of the examiner’s ­fingers. More accurate measures of grip strength can be made by using a dynamometer or having the patient squeeze a partially inflated sphygmomanometer (at 20 mm Hg). It is sometimes useful to test the strength of the fingers separately. The prime movers of flexion of the second through fifth metacarpophalangeal joints are the dorsal and palmar interossei muscles (nerve roots C8 and T1). The lumbricales muscles (C6, C7, and C8) flex the metacarpophalangeal joints when the proximal phalangeal joints are extended. The flexors of the proximal interphalangeal joints are the flexor digitorum superficialis muscles (C7, C8, and T1), and the flexor of the distal interphalangeal joints is the flexor digitorum profundus muscle (C7, C8, and T1). The prime extensors of the metacarpophalangeal joints and interphalangeal joints of the second through fifth ­fingers are the extensor digitorum communis (nerve roots C6, C7, and C8), the extensor indicis proprius (C6, C7, and C8), and the extensor digiti minimi (C7) muscles. The interossei and lumbricale muscles simultaneously flex the metacarpophalangeal joints and extend the ­interphalangeal joints. The dorsal interossei (C8 and T1) and abductor digiti minimi (C8) muscles abduct the fingers, whereas the palmar interosseous muscles adduct the fingers. The thumb is moved by several muscles. The prime flexor of the first metacarpophalangeal joint is the flexor pollicis brevis muscle (nerve roots C6, C7, C8, and T1). The prime flexor of the interphalangeal joint is the flexor pollicis ­longus muscle (C8 and T1). The metacarpophalangeal joint of the thumb is extended by the extensor pollicis brevis muscle, and the prime extensor of the interphalangeal joint is the extensor pollicis longus muscle (C6, C7, C8, and C9). The principal abductors of the thumb are the abductor pollicis longus (nerve roots C6 and C7) and the abductor pollicis brevis (C6 and C7) muscles. Motion occurs ­primarily at the carpometacarpal joint. The principal adductor of the thumb is the adductor pollicis muscle (C8 and T1). Motion occurs primarily at the carpometacarpal joint. The principal movers in opposition of the thumb and fifth fingers are the opponens pollicis (C6 and C7) and opponens digiti minimi (C8 and T1) muscles. Sensation and nerve injuries in the upper extremity are discussed in Chapters 39 and 44. HIP The hip is a spheroidal or ball-and-socket joint formed by the rounded head of the femur and the cup-shaped ­acetabulum (see Chapter 42). Stability of the joint is ensured by the fibrocartilaginous rim of the glenoid labrum and the dense articular capsule and surrounding ligaments, including the iliofemoral, pubofemoral, and ischiocapsular ligaments that reinforce the capsule. Support also is provided by the powerful muscle groups that surround the hip. The principal hip flexor is the iliopsoas muscle assisted by the sartorius and the rectus femoris muscles. Hip adduction is accomplished

by the three adductors (longus, brevis, and magnus) plus the gracilis and pectineus muscles. The gluteus medius is the major hip abductor, whereas the gluteus maximus and hamstrings extend the hip. There are several clinically ­important bursae around the hip joint. Anteriorly, the iliopsoas bursa lies between the psoas muscle and the joint surface. The trochanteric bursa lies between the gluteus maximus muscle and the posterolateral greater trochanter, and the ­ischiogluteal bursa overlies the ischial tuberosity. Examination of the hip should begin by observing the patient’s stance and gait. The patient should stand in front of the examiner so that the anterior iliac spines are ­visible. Pelvic tilt or obliquity may be present and related to a structural scoliosis, anatomic leg-length discrepancy, or hip ­disease. Hip contractures may result in abduction or adduction deformities. To compensate for an adduction contracture, the pelvis is tilted upward on the side of the contracture. This allows the legs to be parallel during walking and weight bearing. With a fixed abduction deformity, the ­pelvis becomes elevated on the normal side during standing or walking. This elevation causes an apparent shortening of the normal leg and forces the patient to stand or walk on the toes of the normal side or to flex the knee on the abnormal leg. Viewed from behind with the legs parallel, the patient with hip disease and an adducted hip contracture may have asymmetric gluteal folds secondary to pelvic tilt, with the diseased side elevated. In this situation, the patient is unable to stand with the foot of the involved leg flat on the floor. In abduction contracture, the findings are reversed; with both legs extended and parallel, the uninvolved side is elevated. A hip flexion deformity commonly occurs in diseases of the hip. Unilateral flexion of the hip in the standing position reduces weight bearing on the involved side and relaxes the joint capsule, causing less pain. This posture is best noted by observing the patient from the side. There is a hyperlordotic curve of the lumbar spine to compensate for lack of full hip extension. Gait should be assessed in the patient with possible hip joint disease. With a normal gait, the abductors of the weight-bearing leg contract to hold the pelvis level or ­elevate the non–weight-bearing side slightly. Two abnormalities of gait may be commonly observed in patients with hip ­ disease. The most common abnormality seen with a painful hip is the antalgic (limping) gait. In this gait, the individual leans over the diseased hip during the phase of weight bearing on that hip, placing the body weight directly over the joint to avoid painful contraction of the hip abductors. In a Trendelenburg gait, with weight bearing on the affected side, the pelvis drops and the trunk shifts to the normal side. Although the antalgic gait is frequently seen with painful hips and the Trendelenburg gait is seen in patients with weak hip abductors, these gaits are not specific, and either may occur as a result of hip pain from one of several causes. A mild Trendelenburg gait is seen often in normal individuals. The Trendelenburg test assesses the stability of the hip together with the hip abductor muscle’s ability to stabilize the pelvis on the femur.9 It is a measure of the gluteus medius hip abductor strength. The patient is asked to stand bearing weight on only one leg. Normally, the abductors hold the pelvis level or the nonsupported side slightly elevated. If the

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non–weight-bearing side drops, the test is positive for weakness of the weight-bearing side hip abductors, especially the gluteus medius muscle. This test is nonspecific and may be observed in primary neurologic or muscle disorders and in hip diseases that lead to weakness of the hip abductors. The motion of the hip should be assessed with the patient in the supine position. The range of motion of the hip includes flexion, extension, abduction, adduction, internal and external rotation, and circumduction. The degree of flexion permitted varies with the manner with which it is assessed. When the knee is held flexed at 90 degrees, the hip normally flexes to an angle of 120 degrees between the thigh and long axis of the body. If the knee is held in extension, the hamstrings limit the hip flexion to about 90 degrees. The presence of a hip flexion contracture is ­ suggested by persistence of lumbar lordosis and pelvic tilt masking the ­contracture by allowing the involved leg to remain in ­contact with the examination table. The Thomas test shows the flexion contracture. In this test, the opposite hip is fully flexed to flatten the lumbar lordosis and fix the pelvis. The involved leg should be extended toward the table as far as possible. The diseased hip’s flexion contracture becomes more obvious and can be estimated in degrees from full extension. Measurement for leg-length discrepancy is performed with the patient supine and the legs fully extended. Each leg is measured from the anterior superior iliac spine to the medial malleolus. A difference of 1 cm or less is unlikely to cause any abnormality of gait and may be considered normal. In addition to true leg-length asymmetries, apparent leg-length discrepancies may result from pelvic tilt or abduction or adduction contractures of the hip. Abduction is measured with the patient supine and the leg in an extended position perpendicular to the pelvis. ­Pelvic stabilization is achieved by placing an arm across the pelvis with the hand on the opposite anterior iliac spine. With the other hand, the examiner grasps the patient’s ankle and abducts the leg until the pelvis begins to move. Abduction to about 45 degrees is normal. It is helpful to compare one side with the other because the normal range of motion may vary. Alternatively, the examiner could stand at the foot of the table, grasp both the patient’s ankles, and simultaneously abduct both legs. Abduction is commonly limited in hip joint disease. Adduction is assessed by grasping the patient’s ankle and raising the leg off the examination table by flexing the hip enough to allow the tested leg to cross over the opposite leg. Normal adduction is about 20 to 30 degrees. Hip rotation may be tested with the hip and knee flexed to 90 degrees or with the leg extended. Normal hip external rotation and internal rotation are to 45 degrees and 40 degrees. The difference in rotation between the flexed and extended hip is attributable to the increased stabilization of the joint by the surrounding ligaments in the extended position. Rotation decreases with extension. To test hip rotation, the extended leg is grasped above the ankle and rotated externally and internally from the ­neutral ­position. Limitation of internal rotation of the hip is a ­sensitive indicator of hip joint disease. Extension is tested with the patient in the prone position. Estimating hip extension can be difficult because some of the apparent motion arises from hyperextension of the lumbar spine, pelvis rotation, motion of the buttock soft tissue, and flexion of the opposite hip. The pelvis and lumbar spine

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can be partially immobilized by placing an arm across the posterior iliac crest and lower lumbar spine. The examiner places the other hand under the thigh with the knee flexed and hyperextends the thigh. Normal extension ranges from 10 to 20 degrees. Limitation of extension is often secondary to a hip flexion contracture. Swelling around the hip can only rarely be discerned on examination. The Patrick test or FABERE maneuver is a commonly used test to screen for pathologic conditions of the hip. (FABERE is a mnemonic for the movements required to elicit the response—flexion, abduction, external rotation, and extension.) In this test, the patient lies supine, and the examiner flexes, abducts, and externally rotates the patient’s test leg so that the foot of the test leg is on top of the opposite knee. The examiner then slowly lowers the test leg toward the examining table. For a negative test result, the test leg falls at least parallel to the opposite leg. A positive test result occurs when the test leg remains above the opposite leg. A positive result of the Patrick test may indicate hip disease, iliopsoas tightness, or sacroiliac abnormality. In children, two useful screening tests for congenital hip disease are the Ortolani maneuver and the Galeazzi sign. In the Ortolani maneuver, the examiner flexes the hips and grasps the legs of a supine infant so that the examiner’s thumbs are against the inner thighs and fingers are draped over the outer (lateral) side of the thighs. With gentle ­traction, the hips are abducted and laterally rotated. Resistance is usually felt at 30 to 40 degrees of lateral rotation and abduction. In a positive result of the Ortolani test, a click is felt before abduction to the normal 70 degrees can be attained. The Ortolani test should not be done repeatedly because it can lead to damage of the articular cartilage on the femoral head. The Galeazzi sign is useful for assessing unilateral congenital hip dislocation in children younger than 18 months. The child is placed supine with the knees and hips flexed to 90 degrees. Both knees should normally reside at the same level, and a positive test result is indicated if one knee is higher than the other. The iliotibial band is a part of the fascia lata extending from the iliac crest, sacrum, and ischium over the greater trochanter to the lateral femoral condyle, tibial condyle, and fibular head and along the lateral intermuscular system, separating the hamstrings from the vastus lateralis muscle. The tensor fasciae latae muscle may produce an audible snap as it slips over the greater trochanter if the weight-bearing leg moves from hip flexion and adduction to a neutral position, as in climbing stairs. Most commonly observed in young women, the snapping hip usually does not cause severe pain. The Ober test evaluates the iliotibial band for contracture. The patient lies on the side with the lower leg flexed at the hip and knee. The examiner abducts and extends the upper leg with the knee flexed at 90 degrees. The hips should be slightly extended to allow the iliotibial band to pass over the greater trochanter. The examiner slowly lowers the limb with the muscles relaxed. A positive test result indicative of an iliotibial band contracture occurs if the leg does not fall back to the level of the table top. A common cause of lateral hip pain is trochanteric bursitis. Patients with this condition often complain of pain and tenderness when they attempt to lie on the affected side or climb stairs. The greater trochanter should be palpated for tenderness and compared with the opposite side. In

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trochanteric bursitis, this area is usually exquisitely tender. The pain of trochanteric bursitis is aggravated by actively resisted abduction of the hip. Aching and tenderness over the buttock area may be secondary to an ischial bursitis. Other causes of lateral and posterior hip (buttock) discomfort include pain at muscle and tendon insertion sites. Anterior hip and groin pain may be secondary to hip abnormality, most commonly degenerative arthritis. Decreased range of motion should be noted in these patients. Other causes include iliopsoas bursitis, in which swelling and tenderness may be noted in the middle third of the inguinal ligament lateral to the femoral pulse. This pain is aggravated by hip extension and reduced by flexion. The bursitis may be a localized problem or represent extension of hip synovitis. It is usually impossible to distinguish between a localized bursitis and an extension of hip synovitis on the basis of the physical examination. If the patient is tender in the region of the iliopsoas bursa, but no swelling is palpable, the examiner also should consider tendinitis of the iliopsoas muscle. The inguinal region should be palpated for other abnormalities, such as hernias, femoral aneurysms, ­adenopathy, tumor, and psoas abscess or masses. Muscle strength testing should include the hip flexors, extensors, abductors, and adductors. The primary hip flexor is the iliopsoas muscle (nerve roots L2 and L3). Flexion may be tested with the patient sitting at the edge of a table. The examiner exerts downward pressure against the thigh proximal to the knee while the patient attempts to flex the hip. The pelvis may be stabilized by the examiner’s other hand placed on the ipsilateral iliac crest. Alternatively, with the patient supine and holding the leg in 90 degrees of flexion at the hip, the examiner may attempt to straighten the hip. Hip extension is tested with the patient lying prone. The primary hip extensor is the gluteus maximus muscle (L5 and S1). With the knee flexed to remove hamstring action, the patient is instructed to extend the hip and thigh off the ­surface of the table as the examiner places a forearm across the posterior iliac crest to stabilize the pelvis and applies downward pressure to prevent the lateral trunk muscles from elevating the pelvis and leg off the table. Abduction may be tested with the patient prone or supine. The patient should abduct the thigh and leg against resistance from the examiner applied at the midthigh level. The primary adductor is the adductor longus muscle (nerve roots L3 and L4). The examiner holds the upper leg proximal to the knee in slight abduction while the patient resists and attempts to adduct the leg. Testing for abduction and adduction also may be done in the two legs simultaneously. The patient lies supine with the legs fully extended and the hips moderately abducted. To test abduction, the patient actively pushes out against the examiner’s resistance against the lateral malleoli. Adduction is tested by movement against resistance at the medial malleoli. KNEE The knee is a compound condylar joint with three articulations: the patellofemoral and the lateral and medial tibiofemoral condyles with their fibrocartilaginous menisci.10 The knee is stabilized by its articular capsule, the patellar ligament, medial and lateral collateral ligaments, and anterior and posterior cruciate ligaments. The collateral

ligaments provide medial and lateral stability, whereas the cruciates provide anteroposterior and rotatory stability. Normal knee motion is a combination of flexion or extension and rotation. With flexion, the tibia internally rotates, and with extension, it externally rotates on the femur. The surrounding synovial membrane is the largest of the body’s joints; it extends 6 cm proximal to the joint as the suprapatellar pouch beneath the quadriceps femoris muscle. There are several important bursae around the knee, including the superficial prepatellar bursa, the superficial and deep infrapatellar bursae, the pes anserine bursa distal to the medial tibial plateau, and the posterior medial semimembranous and posterolateral gastrocnemius bursae. Knee extension is primarily mediated by the quadriceps femoris muscle; knee flexion is mediated by the hamstrings. The biceps femoris muscle externally rotates the lower leg on the femur, whereas the popliteus and semitendinous muscles mediate internal ­rotation. In taking the history of a patient with knee complaints, the patient should be asked about symptoms of locking, catching, or giving way. Locking is the sudden loss of ability to extend the knee; it is usually painful and may be associated with an audible noise, such as a click or pop. It often implies extensive intra-articular abnormality, including loose bodies or cartilaginous tears. Catching refers to a subjective sensation of the patient that the knee might lock; the patient may experience a momentary interruption in the smooth range of motion of the joint, but is able to continue with normal motion after this brief hesitation. Catching usually implies less abnormality than true locking and may occur in various pathologic conditions. True give-way indicates that the knee actually buckles and gives out in certain positions or with certain activities. It is important to elicit the details of the history to verify this common subjective complaint. Patients often experience a sensation that the knee will give out when it actually does not. Other patients say their knees are “giving out” to describe severe pain that necessitates stopping an activity. True give-way implies severe intra-articular abnormality, such as an unstable joint from ligamentous injury or incompetence. Examination of the knees should always include observation of the patient while standing and walking. Deviation of the knees, including genu varum (lateral deviation of the knee joint with medial deviation of the lower leg), genu valgum (medial deviation of the knee with lateral deviation of the lower leg), and genu recurvatum, is most easily appreciated with the patient standing. The patient also should be observed ambulating for evidence of gait abnormalities. Inspection should be done with the patient standing and supine. It is essential to compare side to side, noting any asymmetry that may be caused by swelling or muscle atrophy. Suprapatellar swelling with fullness of the distal anterior thigh that obliterates the normal depressed contours along the sides of the patella usually indicates knee joint effusion or synovitis. Localized swelling over the surface of the patella is generally secondary to prepatellar bursitis (Fig. 35-8). Patellar alignment should be noted, including highriding or laterally displaced patellae. The examiner also should inspect the knee from behind to identify popliteal swelling owing to a popliteal or Baker cyst, most ­commonly caused by medial semimembranous bursal swelling. If the calves appear asymmetric, calf circumference should be

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Right knee prepatellar bursa longitudinal

A

B

Figure 35-8  Prepatellar bursitis. A, Note the cystic swelling overlying the right patella with the appearance of two separate compartments of bursal swelling. B, High-resolution ultrasound image of the same patient showing collection of anechoic fluid with an internal septation.

measured and compared bilaterally. Popliteal cysts may rupture and dissect down into the calf muscles, resulting in enlargement and palpable fullness. Edema may be present if the cyst causes secondary venous or lymphatic obstruction. Acute rupture and dissection of a popliteal cyst can mimic thrombophlebitis, with local pain, heat, redness, and swelling. This is probably a more common cause of unilateral calf swelling in patients with rheumatoid arthritis than is deep venous thrombosis. The two conditions may be difficult to distinguish on physical examination alone. Quadriceps femoris muscle atrophy usually develops in chronic arthritis of the knee. Atrophy of the vastus medialis muscle is the earliest change and may be appreciated by comparing the two thighs for medial asymmetry and circumference. Measurement of the thigh circumference should be performed at 15 cm above the knee to avoid spurious results owing to suprapatellar effusions. Palpation of the knee should be performed with the joint relaxed. This is usually best accomplished with the patient supine and the knees fully extended and not touching. Palpation should begin over the anterior thigh approximately 10 cm above the patella. To identify the superior margin of the suprapatellar pouch, which is an extension of the knee joint cavity, the examiner should palpate the anterior thigh, moving distally toward the knee. Swelling, thickening, nodules, loose bodies, tenderness, and warmth should be noted. A thickened synovial membrane has a boggy, doughy consistency, which differs from the surrounding soft tissue and muscle. It is usually palpated earlier over the medial aspect of the suprapatellar pouch and medial tibiofemoral joint. To enhance detection of knee fluid, any fluid in the suprapatellar pouch is compressed with the palm of the hand placed just proximal to the patella. The synovial fluid forced into the inferior distal articular cavity is palpated with the opposite thumb and index finger laterally and medially to the

patella. If the examiner alternates compression and release of the suprapatellar pouch, the synovial thickening can be differentiated from a synovial effusion. An effusion intermittently distends the joint capsule under the thumb and index finger of the opposite hand, whereas synovial thickening does not. The examiner should not compress the suprapatellar pouch too firmly or push the tissues distally because the patella or normal soft tissue, including the fat pads, fill the palpated space and could be misinterpreted as synovitis or joint swelling. With a large effusion, the patella can be balloted by pushing it posteriorly against the femur with the right forefinger, while maintaining suprapatellar compression with the left hand. At the other extreme, effusions 4 to 8 mL can be detected by eliciting the bulge sign. This test is performed with the knee extended and relaxed. The examiner strokes or compresses the medial aspect of the knee proximally and laterally with the palm of a hand to move the fluid from the area. The lateral aspect of the knee is tapped or stroked, and a fluid wave or bulge appears medially (Fig. 35-9). A so-called spontaneous bulge sign occurs if, on compression along the medial side of the joint space, fluid reaccumulates without any pressure or compression along the lateral side of the joint. The medial and lateral tibiofemoral joint margins are palpated for tenderness and bony lipping or exostosis as can be seen in degenerative joint disease. Palpating the joint margins can be done easily with the hip flexed to 45 degrees, the knee flexed to 90 degrees, and the foot resting on the examining table. Tenderness localized over the medial or lateral joint margins may represent articular cartilage disease, medial or lateral meniscal abnormality, or medial or lateral collateral ligament injury. Other causes of tenderness include pathologic conditions in the underlying bony structures.

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A

B Figure 35-9  A and B, Demonstration of the bulge sign for a small synovial knee effusion. The medial aspect of the knee has been stroked to move the synovial fluid from this area (shaded depressed area in A).  B shows a bulge in the previously depressed area after the lateral aspect of the knee has been tapped.

Bursitis is another cause of localized tenderness around the knee, and the two most common sites are the pes anserine and prepatellar bursae. Exquisite local tenderness usually can be elicited if bursitis is present. Mild swelling also may be appreciated. Occasionally, the prepatellar bursa can become quite swollen. It is important not to interpret this swelling mistakenly as knee joint synovitis. The two can be differentiated because the bursal margins can be outlined by palpation; other features of true joint effusion, such as the bulge sign, are absent. Patellofemoral malalignment is another common cause of knee pain. It is more common in female patients because of the wider Q angle caused by the broader female pelvis. The Q angle is the angle formed between the quadriceps and the patellar tendon. Patients with patellofemoral disease may complain of stiffness in the knee after a period of flexion (the moviegoer sign) or have particular difficulty with stair climbing. Some patients may experience a sensation of catching as the patella moves over the distal femur. Patellar palpation is best performed with the knee extended and relaxed. The patella is compressed and moved so that its entire articular surface comes into contact with the underlying femur. Slight crepitation may be observed in many normally functioning knees. Pain with crepitation may suggest patellofemoral degenerative arthritis or chondromalacia patellae. Retropatellar pain occurring with active knee flexion and extension and secondary to patellofemoral disease may be differentiated from tibiofemoral articular pain. To test this, the examiner should attempt to lift the patella away from the knee, while passively moving the knee through

the range of motion. Painless motion during this maneuver indicates that the patellofemoral joint is the likely source. In addition, the “patellar grind” test is useful in patients with extensive patellofemoral abnormality. In this test, the examiner compresses the patella distally away from the femoral condyles, while instructing the patient to contract the quadriceps isometrically. Sudden patellar pain and quadriceps relaxation indicate a positive test result. This test has frequent false-positive results, however. The patellar stability should be assessed. The Fairbanks apprehension test is done with the patient supine, the quadriceps relaxed, and the knee in 30 degrees of flexion. The examiner slowly pushes the patella laterally. A sudden contraction of the quadriceps and a distressed reaction from the patient constitute a positive apprehension test result. A patient who has had previous patella dislocations usually has a positive apprehension test result. The patella also can be examined for subluxation while the knee is moved through a range of motion from full flexion to extension. The plica syndrome also occasionally causes symptoms that suggest patellofemoral disease. Plicae are bands of synovial tissue, most often located on the medial side of the knee. If present, a tender bandlike structure may be palpated parallel to the medial border of the patella. During flexion and extension, a palpable or audible snapping may be heard, and the patient may experience symptoms of catching. Many plicae are asymptomatic, however, and are common, so they may be considered a normal variant. The normal knee range of motion should be from full extension (0 degrees) to full flexion of 120 to 150 degrees. Some normal individuals may be able to hyperextend to 15 degrees. Loss of full extension that is generally reversible frequently occurs with a knee joint effusion, synovitis, or both. A frequently permanent loss of extension owing to flexion contracture is a common finding, however, that accompanies chronic arthritis of the knee. In advanced arthritis, such as in some cases of rheumatoid arthritis, a posterior subluxation of the tibia on the femur may be observed. Ligamentous instability is tested by applying valgus and varus stress to the knee and by using the drawer test. The knee should be extended and relaxed. The examiner performs the abduction or valgus test by stabilizing the lower femur, while placing a valgus stress on the knee by abducting the lower leg with the other hand placed proximal to the ankle. A medial joint line separation with the knee fully extended indicates a tear of the medial collateral ligament plus the posterior cruciate ligament. The test is performed with the knee in 30 degrees of flexion. If the test is negative at 0 degrees, but positive at 30 degrees, the instability represents a tear of the medial collateral ligament with the posterior cruciate ligament remaining intact. The adduction or varus test is performed with the knee extended and again at 30 degrees of flexion. Separation of the lateral joint line indicates a lateral collateral ligament tear—either associated or not with a posterior cruciate ligament tear. The degree of ligamentous laxity observed during testing can be graded on a scale of 1 to 3. A mild or grade 1 instability indicates that the joint surfaces separate 5 mm or less; for moderate or grade 2 instability, a separation of 5 to 10 mm is seen. Grade 3 instability is a separation greater than 10 mm. In cases of trauma, opening of the joint space indicates ligamentous instability secondary to rupture or stretching of

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the ligaments. In cases of chronic arthritis of the tibiofemoral compartment, there may be apparent medial or lateral separation as a result of the “pseudolaxity” created by loss of cartilage and bone. If the ligaments are intact, the resulting degree of valgus or varus displacement with stressing is not any greater than in the normal knee. The drawer test is performed with the hip flexed to 45 degrees and the knee flexed to 90 degrees. To stabilize the knee, the examiner either sits on the foot while grasping the posterior calf with both hands or supports the lower leg between his or her lateral chest wall and forearm. The anterior drawer test is performed by pulling the tibia forward. More than 6 mm of movement is abnormal and may indicate an anterior cruciate tear or laxity. Anterior subluxation may represent more complex instability, however. Rotatory instability of the knee also may exist. A positive result of the anterior drawer test, in which the lateral tibial plateau subluxates forward while the medial stays in normal position, can represent anterolateral rotatory instability. If both plateaus subluxate, tears of the middle third of the medial lateral capsular ligaments may be present. If the subluxation is not present with the tibia internally rotated, the posterior cruciate ligament is intact. A positive result of the anterior drawer test with the leg in external rotation represents a tear of the medial capsular ligament. The Lachman test is a modification of the anterior drawer sign and tests for one-plane anterior instability. At least six variations of this test have been described. In the test as originally described, the patient lies supine with the tested knee between full extension and 30 degrees of flexion. The femur is stabilized with a hand of the examiner while the hand pulls the proximal aspect of the tibia forward. A positive test result is indicated by a soft feel rather than a firm end point when the tibia moves forward on the femur. A positive result of the Lachman test may indicate an anterior cruciate injury or abnormality in the posterior oblique ligament or arcuate popliteus complex. A posterior drawer test may be done with the patient positioned as for an anterior drawer test, but the examiner pushes the tibia toward the patient. A positive test result suggests damage to the posterior cruciate ligament. During the complete joint examination, tests for meniscal injury should be included. Symptoms suggesting a meniscal tear include locking during joint extension, clicking or popping during motion, and localized tenderness along the medial or lateral joint line. To examine the menisci, the medial and lateral joint line should be palpated with the lower leg internally rotated and the knee flexed to 90 degrees. Localized tenderness over the medial or lateral joint line suggests involvement of the medial or lateral meniscus. The McMurray test12 evaluates for evidence of meniscal tear, especially in the posterior half of the menisci. The patient’s knee is placed in full flexion, and the examiner places a hand over the knee with the fingers along the side of the knee over the joint line and the thumb along the other side. The other hand holds the leg at the ankle and is used to rotate the lower leg medially and to apply varus stress. This test can be done repeatedly, with the knee in gradually decreasing degrees of flexion. A palpable or audible snap suggests a tear of the medial meniscus. The test can be done in a similar fashion by laterally rotating the tibia and applying valgus stress to test for

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a lateral meniscal injury. A positive result of a lateral test also may represent a tear of the popliteus tendon, which can accompany a lateral meniscal tear. The Apley grind test also evaluates for a torn meniscus.11 With the patient lying prone and the knee flexed to 90 degrees, the examiner places downward compression on the foot, while medially and then laterally rotating the tibia on the femur. Pain elicited during this maneuver suggests a meniscal tear. The distraction test is performed by the examiner’s placing his or her knee on the patient’s posterior thigh to stabilize the leg while applying an upward distractive force on the foot. Pain from rotating the tibia suggests ligament damage. A simple hyperflexion test is a useful screening test for meniscal damage. If the examiner is able to hyperflex the knee to more than 135 degrees without eliciting pain, it is unlikely that serious cartilaginous injury is present. If pain occurs with hyperflexion, the patient sometimes is able to localize it medially or laterally, which often correlates with the location of the meniscal injury. Although helpful, none of these tests for meniscal injury is completely reliable when verified by arthroscopy. Tenderness along the joint line is most sensitive, but is less specific than manipulative tests such as the McMurray test. Muscle strength testing includes testing flexion supplied by the hamstrings (i.e., the biceps femoris, semitendinosus, and semimembranosus) (nerve roots L5 to S3) and extension supplied by the quadriceps femori (L2, L3, and L4). The hamstrings are tested best with the patient prone and attempting to move the knee from 90 degrees to maximal flexion. The ankle should be kept in neutral position or dorsiflexed to remove gastrocnemius action. With the leg externally rotated, the biceps femoris, which inserts on the fibula and lateral tibia, is primarily tested, whereas flexion with internal rotation tests the semitendinosus and semimembranosus muscles, which insert on the medial side of the tibia. Extension is tested with the patient sitting upright with the knee fully extended. The examiner stabilizes the thigh with downward pressure just proximal to the knee and places downward pressure at the ankle to test the knee extensors. ANKLE The true ankle is a hinged joint, and movement is limited to plantar flexion and dorsiflexion. It is formed by the distal ends of the tibia and fibula and proximal aspect of the body of the talus. Inversion and eversion occur at the subtalar joint (see Chapter 43). The tibia forms the weight-bearing portion of the ankle joint, whereas the fibula articulates on the side of the tibia. The malleoli of the tibia and fibula extend downward beyond the weight-bearing part of the joint and articulate with the sides of the talus. The malleoli provide medial and lateral stability by enveloping the talus in a mortise-like fashion. The articular capsule of the ankle is lax on the anterior and posterior aspects of the joint, allowing extension and flexion, but it is tightly bound bilaterally by ligaments. The synovial membrane of the ankle on the inside of the capsule usually does not communicate with any other joints, bursae, or tendon sheaths. The medial and lateral ligaments surrounding the ankle contribute to medial and lateral stability of the joint. The deltoid ligament, the only ligament on the medial side of the

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History and Physical Examination of the Musculoskeletal System

Tibialis anterior muscle Tibialis posterior muscle Tibia Inferior extensor retinaculum

Soleus muscle Flexor hallucis longus muscle Posterior tibial artery Posterior tibial nerve Tendo calcaneus

Deltoid ligament

Figure 35-10  Diagram of the ankle. ­Medial aspect of the ankle shows the ­ relationship between the tendons, ligaments, artery, and nerve. (From Polley HF, Hunder GG: Rheumatologic Interviewing and Physical Examination of the Joints, 2nd ed. Philadelphia, WB Saunders, 1978. Used with permission of Mayo Foundation for Medical Education and Research.)

Flexor digitorum longus muscle

Flexor retinaculum

Extensor hallucis longus tendon sheath Abductor hallucis brevis muscle (cut)

ankle, is a triangle-shaped fibrous band that resists eversion of the foot. It may be torn in eversion sprains of the ankle. The lateral ligaments of the foot consist of three distinct bands forming the posterior talofibular, the calcaneofibular, and the anterior talofibular ligaments. These ligaments may be injured in inversion sprains of the ankle. All tendons crossing the ankle joint lie superficial to the articular capsule and are enclosed in synovial sheaths for part of their course across the ankle. On the anterior aspect of the ankle, the tendons and synovial tendon sheaths of the tibialis anterior, extensor digitorum longus, peroneus tertius, and extensor hallucis longus muscles overlie the articular capsule and synovial membrane. On the medial side of the ankle, posterior and inferior to the medial malleolus, lie the flexor tendons and tendon sheaths of the tibialis posterior, flexor digitorum longus, and flexor hallucis longus muscles (Fig. 35-10). All three of these muscles plantar flex and supinate the foot. The tendon of the flexor hallucis longus is located more posteriorly than the other flexor tendons and lies beneath the Achilles tendon for part of its course. The calcaneus tendon (Achilles tendon) is the common tendon of the gastrocnemius and soleus muscles and inserts into the posterior surface of the calcaneus, where it is subject to external trauma, various inflammatory reactions, and irritations from bone spurs beneath it. On the lateral aspect of the ankle, posterior and inferior to the lateral malleolus, a synovial sheath encloses the tendons of the peroneus longus and peroneus brevis. These muscles extend the ankle (plantar flex) and evert (pronate) the foot. Each of the tendons adjacent to the ankle may be involved separately in ­traumatic or disease processes. Three sets of fibrous bands or retinacula hold down the tendons that cross the ankle in their passage to the foot. The extensor retinaculum consists of a superior part (transverse crural ligament) in the anterior and inferior portions of the leg and an inferior part in the proximal portion of the dorsum of the foot. The flexor retinaculum is a thickened fibrous band on the medial side of the ankle. On the lateral

Tibialis posterior tendon Flexor digitorum longus tendon Tibialis anterior tendon Flexor hallucis longus tendon

Figure 35-11  Achilles tendinitis in a patient with reactive arthritis. Note swelling of the left Achilles tendon insertion caused by active enthesitis and milder swelling of the right Achilles tendon insertion.

side of the ankle, the peroneal retinaculum forms a superior and an inferior fibrous band. These bands bind down tendons of the peroneus longus and peroneus brevis muscles as they cross the lateral aspect of the ankle. Synovial swelling of the ankle joint is most likely to cause fullness over the anterior or anterolateral aspect of the joint because the capsule is more lax in this area. Mild swelling of the joint may not be apparent on inspection because of the many structures crossing the joint superficially. Efforts should be made to differentiate superficial linear swelling localized to the distribution of the tendon sheaths from more diffuse fullness and swelling attributable to involvement of the ankle joint. Swelling of the heels may be observed from behind the standing patient and may be caused by enthesitis of the Achilles tendon insertion, which can occur in spondyloarthropathies (Fig. 35-11).

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It is difficult to observe synovitis of the intertarsal joints. Intertarsal joint synovitis may produce an erythematous puffiness or fullness over the dorsum of the foot. From the normal position of rest in which there is a right angle between the leg and foot, labeled 0 degrees, the ankle normally allows about 20 degrees of dorsiflexion and about 45 degrees of plantar flexion. Inversion and eversion of the foot occur mainly at the subtalar and other intertarsal joints. From the normal position of the foot, the subtalar joint normally permits about 20 degrees of eversion and 30 degrees of inversion. To test the subtalar joint, the examiner grasps the calcaneus with a hand and attempts to invert and evert it, holding the ankle motionless. A general assessment of muscular strength of the ankle can be obtained by asking the patient to walk on toes and on heels. If the patient can walk satisfactorily on the toes and on the heels, the muscle strength of the flexors and extensors of the ankle can be considered normal. If this cannot be accomplished, it is desirable to test the muscles individually. The principal flexors of the ankle are the gastrocnemius (nerve roots S1 and S2) and the soleus (S1 and S2) muscles. The principal extensor (dorsiflexors) of the ankle is the tibialis anterior muscle (L4, L5, and S1). The tibialis posterior muscle (L5 and S1) is the principal inverter. To test the tibialis posterior muscle, the foot should be in plantar flexion. The examiner applies graded resistance on the medial border of the forefoot while the patient attempts to invert the foot. The principal everters of the foot are the peroneus longus (L4, L5, and S1) and peroneus brevis (L4, L5, and S1) muscles. FOOT See Chapter 43.

MUSCLE EXAMINATION A general examination of the patient should be done, looking for any signs of systemic illness. This should include an examination of the skin, in which signs of pallor (suggestive of anemia), and rashes that suggest lupus, vasculitis, and dermatomyositis are noted. The patient should be appropriately disrobed for muscle examination. The patient should be assessed for appearance of the muscles, including bulk, tone, and tenderness. Muscle bulk should be compared on one side of the body with the other to look for any asymmetry, hypertrophy, or atrophy. The distribution of the atrophy should be noted because this may indicate the underlying cause. Distal atrophy can

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be seen in patients with motor neuron disease. Fasciculations also are seen more commonly in this condition. Muscle tone also should be evaluated. Increased muscle tone and spasticity can be seen with demyelinating conditions. Muscle rigidity may be an indication of Parkinson’s disease. Muscle tenderness may be noted in patients with true weakness, such as infectious myopathies. Other conditions that do not cause true weakness, such as fibromyalgia, also can be associated with tender muscles. Strength testing should be done on distal and proximal muscle groups. Commonly tested areas include plantar flexion and dorsiflexion of the foot; hip abduction, adduction, and flexion; finger abduction; arm flexion; shoulder abduction; and neck flexion and extension. The patient should be seated, and both sides of the body should be compared for asymmetric weakness. Typically, resistance is noted against a force applied by the examiner. The examiner should attempt to confirm whether or not true weakness is present and, if it is, in what distribution. A neurologic examination also should be done. The examination should include reflex testing and testing for sensory loss. Typically, patients with inflammatory myopathies should not have severe abnormalities on examination of nerve function. REFERENCES   1. Woolf AD: How to assess musculoskeletal conditions: History and physical examination. Best Pract Res Clin Rheumatol 17:381-402, 2003.   2. Polley HF, Hunder GG: Rheumatologic Interviewing and Physical Examination of the Joints. 2nd ed. Philadelphia, WB Saunders, 1978.   3. Sokka T, Pincus T: Quantitative joint assessment in rheumatoid arthritis. Clin Exp Rheumatol 23:S58-S62, 2005.   4. Fuchs HA, Brooks RH, Callahan LF, et al: A simplified twenty-eightjoint quantitative articular index in rheumatoid arthritis. Arthritis Rheum 32:531-537, 1989.   5. Prevoo ML, van’t Hof MA, Kuper HH, et al: Modified disease activity scores that include twenty-eight-joint counts: Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38:44-48, 1995.   6. Doherty M, Hazleman BL, Hutton CW, et al: Rheumatology Examination and Injection Techniques, 2nd ed. London, WB Saunders, 1999.   7. Malanga GA, Nadler SF: Musculoskeletal Physical Examination: An Evidence-Based Approach. Philadelphia, Mosby, 2006.   8. Moore G: Atlas of the Musculoskeletal Examination. Philadelphia, American College of Physicians, 2003.   9. Waldman SD: Physical Diagnosis of Pain: An Atlas of Signs and Symptoms. Philadelphia, WB Saunders, 2006. 10. Press JM, Casazza BA, Young JL: Knee ligament injuries: Making the diagnosis, restoring use. J Musculoskel Med 13:14-28, 1996. 11. Gross J, Fetto J, Rosen E: Musculoskeletal Examination, 2nd ed. Malden, Mass, Blackwell Scientific, 2002.

36

Monarticular Arthritis Joseph Golbus

KEY POINTS The most common causes of acute monarthritis are infection, crystal-induced arthritis, or the onset of a chronic inflammatory arthropathy. Arthritis causes stiffness, reduced range of motion, and pain during normal use. Inflammatory arthritis is characterized by morning stiffness that improves with motion. Mechanical joint pain usually worsens with activity and ­improves with rest. An extremely rapid onset of pain (seconds to minutes) ­suggests an internal derangement, fracture, or trauma. An acute onset over hours to 2 days is typical of most forms of inflammatory arthritis. The most important laboratory test for acute monarthritis is synovial fluid analysis. Acute monarticular gout is defined by intracellular, negatively birefringent, needle-shaped crystals (sodium urate).

With rare exceptions, any joint disorder is capable of ­presenting initially as monarthritis. Monarthritis therefore represents a diagnostic challenge to even the most experienced clinician. The disorder often remains incompletely understood after the initial evaluation. Nonetheless, it is almost always possible to identify patients who require ­vigorous evaluation and treatment to prevent rapid disease progression, such as those with suspected septic arthritis. The physician can proceed in a measured and systematic manner with the remainder of patients, in whom the shortterm clinical course and response to simple therapeutic measures may provide additional useful information. This chapter is intended to aid the clinician in distinguishing true arthritis from syndromes that also manifest with pain in the ­surrounding joint structures, in narrowing the list of diagnostic possibilities based on the clinical presentation, and in using diagnostic tests effectively. Special attention is given to common entities that present as acute ­inflammatory arthritis suggesting joint sepsis.

DIFFERENTIAL DIAGNOSIS Confronted with a patient complaining of pain or ­swelling in the region of a single joint, the physician must first attempt to localize the anatomic site of the abnormality (Fig. 36-1). Joint pain can be the result of abnormalities in the joint itself, adjacent bone, surrounding ligaments, tendons, bursae, or soft tissues. It can also be referred, resulting

from nerve root impingement, an entrapment neuropathy, or even pathology in another joint. Pain from hip arthritis, for example, can be referred entirely or partially to the knee. It is also important to remember that the differential diagnosis of an acute monarthritis includes most causes of polyarticular arthritis, which can also present with a single painful or swollen joint. Arthritis involving a diarthrodial joint causes stiffness, reduced range of motion, and pain during normal use. With few exceptions (e.g., the patellofemoral joint in chondromalacia1), intra-articular abnormalities can be detected during passive and active range of motion. The patient history and physical examination are essential in determining the cause of the arthritis. Inflammatory forms of arthritis are characterized by stiffness of the joint that is most noticeable in the morning (i.e., morning stiffness) or after a period of inactivity (i.e., gelling) and that improves with motion. Inflammatory arthritis is often associated with systemic symptoms such as fever or malaise. Joint pain due to mechanical factors usually worsens with activity, improves with rest, and is not associated with systemic symptoms (Table 36-1). During physical examination, it is important to compare the abnormalities (e.g., swelling, warmth, redness) with findings in the contralateral joint. Although most inflamed joints show signs of inflammation, deeper-seated articulations, such as the shoulders, hips, and sacroiliac joints, may not. Effusions almost always result from intra-­articular pathology, although they may accompany osteomyelitis, fractures, or tumors.2 The presence of excess synovial fluid does not specifically indicate joint inflammation unless the white blood cell count is elevated. The disorders causing monarthritis are listed in Table 36-2. The conditions discussed in the following sections may be confused with arthritis (Table 36-3). INTERNAL DERANGEMENT Torn menisci or ligaments or loose bodies may ­episodically wedge into the joint, producing clicking, locking, or a sensation of “giving way.” These conditions may precede or accompany degenerative arthritis and can be a consequence of inflammatory arthritis when fronds of proliferative synovium become lodged within the joint. Symptoms are frequently intermittent. They can often be elicited on physical examination by repeatedly flexing and extending the joint in various degrees of internal and external rotation.3 Internal derangements of the hip, particularly tears of the acetabular labrum, are easily overlooked. Such tears may be treated arthroscopically by an orthopedic surgeon with sufficient experience in hip arthroscopy. 533

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Monarticular Arthritis

“Acute monarticular arthritis”

Periarticular syndrome

Tendinitis, bursitis, strain, sprain, osteomyelitis, soft tissue infection

Complete history and physical exam

Careful exam reveals polyarticular arthritis

True monarticular arthritis

Yes

Significant trauma or focal bone pain?

Effusion or inflammation?

Acute changes

Fracture, avulsion

Chronic changes

OA, CPPD

Radiograph

No

Severe CBC, ESR, and symptoms Ultrasound-guided physical aspiration or exam CT/MRI

Yes Synovial fluid WBC > 5000

Acute inflammatory arthritis

Figure 36-1  Initial approach to acute monarticular arthritis. CBC, complete blood count; CPPD, calcium pyrophosphate deposition disease; CT, computed tomography; ESR, erythrocyte sedimentation rate; MRI, magnetic resonance imaging; OA, osteoarthritis; WBC, white blood cell count.

BONE PAIN Bone pain usually results from a disease process involving the periosteum or the marrow space as a result of sensory nerves located in these areas. Bone pain is commonly caused by fractures, osteomyelitis, or periostitis, such as occurs in pulmonary hypertrophic osteoarthropathy, hemoglobinopathies, hematologic malignancy,4 primary or metastatic bone tumors, and occasionally with infiltrative processes such as Paget’s disease. Characteristically, bone pain is accompanied by tenderness to pressure over the involved periosteum or pain on weight bearing. When symptoms are long standing, radiographic findings are typically abnormal. Earlier disease may be identified by radionuclide scanning, computed tomography (CT), or magnetic resonance ­imaging (MRI).

Arthrocentesis

Synovial fluid bloody

–

Synovial fluid WBC < 1000

MRI

Noninflammatory arthritis (OA, internal derangement)

Occult fracture, tumor, internal derangement

Arthroscopy

+ Internal derangement

Paget’s disease may be associated with both bone pain and arthritic symptoms as a result of the expansion and deformity of subchondral bone and cartilage, particularly in the hips and knees.5 TENDINITIS OR BURSITIS Findings of tendinitis or bursitis are usually localized to one area around the joint.6 Local tenderness and pain often increase more with active motion than with passive motion of the joint, because active motion places more stress on the involved periarticular structures. An exception to this rule is supraspinatus tendinitis of the shoulder, in which passive and active motion may produce similar pain, and

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Table 36-1  Useful Clinical Features in the Initial Evaluation of Acute Monarticular Pain

Tendinitis

Noninflammatory Joint Pain (Osteoarthritis, Internal Derangement)

Localized, brief None With use Unusual, except with rotator   cuff tears or trigger fingers

Localized, brief None After prolonged use Suggests internal derangement  or loose body

Often greater than 15 min Present (fever, malaise) After prolonged inactivity None

Tenderness Inflammation Instability

Localized, periarticular Over tendon or bursa Uncommon

Mild, over joint line Unusual Occasional

Diffuse over exposed joint space Common Uncommon

Multisystem disease

No (occasionally with gonococcal infection)

No

Often

Feature

Systemic Rheumatic Disease

Symptoms Morning stiffness Constitutional symptoms Peak period of discomfort Locking or instability Signs

Modified from American College of Rheumatology Ad Hoc Committee on Clinical Guidelines: Guidelines for the initial evaluation of the adult patient with acute musculoskeletal symptoms. Arthritis Rheum 39:1-8, 1996.

Table 36-2  Differential Diagnosis of Monarticular ­Arthritis Usually Monarticular

Often Polyarticular

Septic arthritis Bacterial Tuberculous Fungal Lyme disease Crystal disease Gout Pseudogout Internal derangement Ischemic necrosis Hemarthrosis Coagulopathy Warfarin (Coumadin) Trauma or overuse Pauciarticular juvenile rheumatoid arthritis Neuropathic Congenital hip dysplasia Osteochondritis dissecans Reflex sympathetic dystrophy Hydroxyapatite deposition Hemoglobinopathies Loose body Palindromic rheumatism Paget’s disease involving joint Stress fracture Osteomyelitis Osteogenic sarcoma Metastatic tumor Synovial osteochondromatosis Pigmented villonodular synovitis Plant thorn synovitis Familial Mediterranean fever Synovioma Synovial metastasis Intermittent hydrarthrosis Pancreatic fat necrosis Gaucher’s disease Behçet’s disease Regional migratory osteoporosis Giant cell arteritis or Sea urchin spine Amyloidosis (myeloma)

Common Rheumatoid arthritis Osteoarthritis Psoriatic arthritis Reiter’s syndrome (idiopathic and human immunodeficiency virus) Calcium pyrophosphate deposition disease Chronic articular hemorrhage Most juvenile rheumatoid arthritis and juvenile spondylitis Erythema nodosum, sarcoid Serum sickness Acute hepatitis B Rubella Henoch-Schönlein purpura Systemic lupus erythematosus Lyme disease Parvovirus Dialysis arthropathy Other crystal-induced arthropathies Undifferentiated connective tissue disease Rare Relapsing polychondritis Enteropathic disease Ulcerative colitis Regional enteritis Bypass arthritis Whipple’s disease Chronic sarcoidosis Hyperlipidemia types II and IV Still’s disease Pyoderma gangrenosum Pulmonary hypertrophic osteoarthropathy Chondrocalcinosis-like syndromes, polymyalgia rheumatica due to ochronosis, hemochromatosis Wilson’s disease Rheumatic fever Paraneoplastic syndromes

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Monarticular Arthritis

Table 36-3  Regional Periarticular Syndromes Periarticular Syndrome

Monarticular Syndrome

Jaw

Temporomandibular joint dysfunction   (myofascial pain syndrome) Preauricular lymphadenitis

Temporal arteritis Molar dental problems Parotid swelling

Shoulder

Subacromial bursitis Long-head bicipital tendinitis Rotator cuff tear

Pancoast’s tumor Brachial plexopathy Cervical nerve root injury

Elbow

Olecranon bursitis Epicondylitis

Ulnar nerve entrapment

Wrist

Extensor tendinitis   (including de Quervain’s tenosynovitis) Gonococcal tenosynovitis

Carpal tunnel syndrome

Hand

Palmar fasciitis   (Dupuytren’s contracture) Ligamentous or capsular injury

Hip

Greater trochanteric bursitis Adductor syndrome Ischial bursitis Fascia lata syndrome

Meralgia paresthetica Deep infection Paget’s disease Neoplasm

Knee

Anserine bursitis Prepatellar bursitis Meniscal injury Ligamentous tear, laxity Baker’s cyst

Neoplasm Osteomyelitis

Ankle

Peroneal tendinitis Achilles tendinitis Retrocalcaneal bursitis Calcaneal fasciitis Sprain Erythema nodosum

Hypertrophic pulmonary ­osteoarthropathy Tarsal tunnel syndrome

Foot

Plantar fasciitis Pes planus (“fallen arches”)

Morton’s neuroma Vascular insufficiency Cellulitis

Region

localized tenderness may be absent. The clinical findings seen with tendinitis or bursitis can usually be reduced or eliminated by local instillation of lidocaine. The presence of a puncture site; a history of glucocorticoid injection; an adjacent source of infection, such as an ulcerated rheumatoid nodule7; or severe inflammation may signify infectious bursitis.8 Isolated tendinitis less commonly results from hematogenous spread of infection, except in the case of disseminated gonococcal disease, which commonly manifests with dorsal tenosynovitis of the wrists9; a similar septic tenosynovitis may complicate brucellosis.10 Infected olecranon or prepatellar bursae commonly mimic septic arthritis. These conditions can often be identified by high-resolution ultrasonography.11 NEUROPATHIC PAIN Compression or irritation of peripheral nerves may p­ roduce pain referred to the region of joints, such as pain radiating from the wrist to the palmar surface of the first four digits in carpal tunnel syndrome,12 pain in the hip region in lumbosacral radiculopathies, or shoulder pain with brachial plexopathies. Such symptoms are usually in the distribution of a peripheral nerve and tend to follow an irregular time course, with sudden exacerbations, particularly at night. Maneuvers that compress the affected nerve at the site of injury, such as straight leg raising or

percussion of the median nerve at the wrist, are helpful when they exactly reproduce the patient’s pain in the ­ distribution of a peripheral nerve. Diffuse polyneuropathies may produce pain that is poorly localized and superficially resembles joint pain in a stocking-glove distribution. Pain that localizes exactly to a joint in the setting of a polyneuropathy may be related to neuropathic joint disease or reflex sympathetic dystrophy, or it may have an unrelated cause.13 SOFT TISSUE INFECTION Soft tissue infections may simulate arthritis, particularly when they occur in the region of deeply buried joints that are difficult to examine. Hip pain may result from cellulitis, pyomyositis, psoas or retroperitoneal abscess, or intrapelvic pathology such as diverticulitis. Fever and the acute onset of hip pain and stiffness with normal radiographic and synovial fluid findings suggest soft tissue or bone infection. Pain referred to the sacroiliac joint may result from a variety of soft tissue infections, including perirectal abscesses. Infectious processes in these locations manifest with unremitting severe pain, marked elevation of the erythrocyte sedimentation rate, and variably severe sys­temic toxicity.14,15 Physical examination may reveal muscular rigidity and guarding, local tenderness, increased girth of the affected limb, or draining sinuses. Imaging studies such as radionuclide ­scanning,

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u­ ltrasonography, CT, or MRI may be essential in identifying deep infections.

use, improves with rest, and involves weight-bearing joints suggests mechanical disease.

MUSCULAR PAIN SYNDROMES

IS THE ARTHRITIS TRULY MONARTICULAR?

Muscular pain syndromes (e.g., myofascial pain, fi­ bromyalgia) consist of local or diffuse muscle tenderness that causes pain in characteristic regional zones. These can result in a variety of complaints, including headache; jaw, neck, or low back pain; and occasionally joint pain, particularly in the shoulder. They tend to be diffuse and symmetric and are often associated with complaints outside of the musculoskeletal system, such as fatigue, intermittent diffuse paresthesias, and irritable bowel syndrome (see Chapter 38). Trigger points represent specific sites of exaggerated sensitivity to pressure and are often seen in patients with fibromyalgia. Myofascial syndromes rarely cause monarticular pain but may be associated with exaggerated distress associated with benign causes of monarticular pain.

Careful inquiry may elicit evidence of antecedent or coincident involvement of additional joints. A history of inflammatory symptoms in multiple joints for more than 1 month suggests a chronic, noninfectious inflammatory condition. Diffuse arthralgias of shorter duration may accompany the onset of many illnesses, especially systemic infections. Truly migratory disease, in which there is only one inflamed joint but a clear-cut history of recent inflammatory arthritis of other joints occurring sequentially, suggests gonococcal arthritis or rheumatic fever. Coexistence of symptoms in the axial skeleton may provide a clue to the presence of a spondyloarthropathy.16-18 A careful physical examination may reveal involvement of additional joints at the time of presentation.

PATIENT HISTORY

ACUTE INFLAMMATORY MONARTHRITIS

IS THE ARTHRITIS ACUTE OR CHRONIC? An extremely rapid onset of pain (over seconds or ­ inutes) suggests an internal derangement, fracture, m trauma, or loose body. An acute onset over several hours to 2 days is typical of most forms of inflammatory arthritis, particularly bacterial infection and crystal-induced synovitis. When a careful history reveals marked ­worsening of long-standing symptoms in a joint, it is important to distinguish exacerbations of ­ preexisting disease (e.g., worsening of degenerative joint disease with excessive use) from a second superimposed process (e.g., ­infection).16 ARE THERE ASSOCIATED SYSTEMIC OR EXTRA-ARTICULAR SYMPTOMS? Associated systemic or extra-articular symptoms can often help establish a diagnosis. Signs or symptoms or other organ involvement, such as constitutional symptoms, rash, alopecia, Raynaud’s phenomenon, sicca symptoms, or pleuritic chest pain can suggest a systemic autoimmune disease, such as Sjögren’s syndrome or systemic lupus erythematosus. Bowel symptoms or genitourinary complaints may provide a clue to the diagnosis of a seronegative spondyloarthopathy or possible infection, such as gonorrhea or an enteric infection. Constitutional symptoms, fever, chills, or malaise also raise the possibility of infection, either intra-articular or remote.

Evaluation of an acute inflammatory monarthritis is vital, because immediate benefit may result from the identification and treatment of the underlying disease (Fig. 36-2). Although the differential diagnosis of acute inflammatory arthritis is long, the three most common considerations are infection, crystal-induced arthritis, and the onset of a potentially chronic inflammatory arthropathy. Each of these disorders is capable of manifesting with an explosive onset of inflammation over a few hours, but the hyperacute presentation is most typical of infection or crystal-induced disease. As a rule, the most important diagnostic study in the evaluation of an acute monarthritis is synovial fluid analysis, especially when infection or crystal disease is suspected (see Chapter 48). In most cases, the diagnosis of gout can be made immediately by aspirating joint fluid and examining it by polarizing microscopy. Calcium pyrophosphate crystals may be more difficult to identify. The diagnosis of pseudogout is often uncertain until repeated aspirations are performed and culture results are negative. The finding of chondrocalcinosis on radiography, however, can increase the examiner’s clinical suspicion. Infectious arthritis can be diagnosed by Gram stain in some patients and can be proved by culture in most cases within 48 hours. The presence of other conditions may be suggested by extraarticular disease features, but laboratory testing and continued observation are often needed before the diagnosis can be made with certainty. The following observations are intended to aid in the differential diagnosis of these entities.

IS THE ARTHRITIS MECHANICAL OR INFLAMMATORY?

INFECTIOUS ARTHRITIS

The question of an inflammatory versus a mechanical process is most reliably answered by the synovial fluid white blood cell count (Table 36-4). Waxing and waning of disease activity unrelated to patterns of use, including fluctuations of pain and swelling, protracted morning stiffness, and gelling, suggest inflammation. Pain that occurs only after

In evaluating an acutely inflamed joint, the physician must first ask whether the likelihood of septic arthritis is sufficient to hospitalize the patient and intervene immediately.19 Joint sepsis produces dramatic inflammation followed quickly by ­ irreversible destruction of cartilage and bone (see ­ Chapter 99). It may also be the initial

Turbid

P

Turbid to pus

−

− −

↑

↑ ↓

− −

− − − − +/− − − +/− +

↑ ↓

↓ ↓ ↓ ↓↓ ↓↓ ↑↓ ↑ ↓↓ ↓↓↓

−

−

−

↑

CPPD (approximately 60%) Mono­sodium urate (>90%)

−

−

− − −

−

−

−

−

−

−

+/− Occasional CPPD −

−

−

−

−

−

−

−

− − −

−

−

−

+−

+++

+++/−

+/− +/−

−

−

RBCs

↓↓↓

↓↓

↓

↓

↓↓↓

↓↓

↓ ↓

↓

↓

−

−

−

−

−

90%

Glucose

↑↑↑

↑↑↑

↑↑

↑↑

↑↑/↑↑  ↑

↑/↑↑↑

↑/↑↑

↑/↑↑

↑↑↑

↑/↑↑↑

−/↑

−/↑

1.5-2

Protein

↓

↑

−/↓

↓

−

−

Complement

+/−

−

+

+

−

Synovial fluid culture 20%-50% positive; culture portals of entry; urogenital Gram stain Gram stain—gram-positive organisms; synovial fluid, blood cultures

Repeated crystal examinations;  radiographs: chondrocalcinosis Serum uric acid unreliable

Synovial fluid leukocytes may be ≥100,000 Serum: positive ANA (50%) + ­rheumatoid factor (<20%) Chest radiographs; slit-lamp examination Negative rheumatoid factor, ­positive ANA Serum: positive rheumatoid factor   (50%-80%) + ANA PPD usually positive unless ­anergic; synovial biopsy ­essential

Congo red: synovial fluid; ­monoclonal gammopathy Positive stool occult blood; LE cells; serum autoantibodies

Synovial biopsy

MR scan, bone scan, radiograph in advanced cases Radiograph

MR scan, arthrogram (knee), arthroscopy Marked radiographic changes MR scan, CT scan

Small amount not demonstrable on physical examination Radiographs positive in advanced disease; synovial fluid findings variable

Cartilage Debris other

ANA, antinuclear antibody; CPPD, calcium pyrophosphate dihydrate; CT, computed tomography; LE, lupus erythematosus; M, mononuclear; MR, magnetic resonance; P, polynuclear; PPD, purified protein derivative; RBC, red blood cell.

P

Turbid

P

Nongonococcal bacteria

Turbid

M

Turbid to pus

Turbid

P

P

Slightly turbid Slightly turbid Slightly turbid

Slightly turbid

P

P P

Slightly turbid

M

Slightly turbid

M Slightly turbid

Brown, bloody

RBC

M/P

Cloudy, bloody

RBC

Gonococcal   infection

Sarcoidosis Reiter’s syndrome Psoriatic   arthritis Rheumatoid   arthritis Tuberculous   arthritis 10,000-150,000 CPPD   pseudogout Gout

Enteropathic   arthritis Systemic lupus ­erythematosus 5000-50,000 Juvenile   rheumatoid arthritis

Clear

Clear

M

−

Micro­ organisms Crystals

↑

Viscosity

| 

M

Clear

M

Predominant Cell Appearance

GOLBUS 

Structural Internal   derangement Neuropathic Osteochondritis   dissecans Ischemic   necrosis Traumatic 2000-10,000 Pigmented   villonodular   synovitis Amyloid

0-200 Normal 0-2000 Osteoarthritis

Synovial Fluid White Blood Cell Count (cells/mm3)

Table 36-4  Synovial Fluid and Associated Laboratory Findings in Monarticular Arthritis

538 Monarticular Arthritis

PART 5 

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EVALUATION OF GENERALIZED AND LOCALIZED SYMPTOMS

539

Acute inflammatory arthritis (synovial fluid WBC > 5000/cm3)

+ Infection

Gram stain

Gout, CPPD, r/o superinfection

+

Young: GC > staph. >strep. Old: staph. > strep. > GC Immunocompromised: staph., gram-negative; other unusual organisms

Crystal exam

(cultures pending) CBC, ESR, RF, ANA, Lyme titer

Systemic toxicity?

+

+

Empiric antibiotics × 24 hours, awaiting cultures

CPPD, Lyme disease, reactive arthritis, systemic rheumatic disease

Anti-inflammatory medication; F/U in 24-48 hours; Reaspirate joint if worsens

sign of a life-threatening systemic infection. In healthy adults, the signs are usually obvious. The patient complains of intense local pain and may resist attempts to examine the affected joint. Infected peripheral joints are swollen, warm, very tender, and sometimes red, and they have a markedly restricted range of motion. As a general rule, large joints are more frequently affected than small ones in the absence of local trauma or peripheral vascular disease.8 Unfortunately, persons at highest risk for joint sepsis are those in whom confounding factors obscure symptoms or blunt the inflammatory response. Infection should be strongly suspected in less sick-appearing patients when systemic risk factors (e.g., corticosteroid therapy; immunodeficiency or immunosuppression; diabetes; intravenous drug abuse; pulmonary, cardiac, or genitourinary focus of infection) and local pathology (e.g., inflammatory arthritis, effusions, penetrating trauma, previous injection of corticosteroids, prosthetic joint) are present.

Figure 36-2  Approach to acute inflammatory arthritis. ANA, antinuclear antibody test; CBC, complete blood count; CPPD, calcium pyrophosphate deposition disease; ESR, erythrocyte sedimentation rate; F/U, follow-up; GC, gonococcal infection; RF, rheumatoid factor; r/o, rule out; staph., staphylococcal infection; strep., streptococcal infection; WBC, white blood count.

Although the clinical picture is never diagnostic of a p­ articular infectious agent, certain presentations are characteristic. Gonococcal infection rarely escapes attention because it tends to manifest as an inordinately painful monarthritis or polyarthritis and a painful, diffuse tenosyn­ ovitis in an otherwise healthy individual.20 Skin lesions ranging from macules to pustules and vesicles are well described15,21 but may be subtle. Meningococcal arthritis occasionally presents with clinical and Gram stain findings identical to those of gonococcal disease. The diagnosis of gonococcal arthritis is typically based on the history, physical examination, synovial fluid cultures, and cultures of any skin lesions as well as the pharynx and anogenital area. The large increase in intravenous drug abuse in the past few decades has resulted in a dramatic increase in associated septic arthritis. In this situation, infectious material is introduced into the intravascular space, with subsequent hematogenous spread to the joints. Under unusual ­ conditions,

540

GOLBUS 

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Monarticular Arthritis

direct inoculation can also occur. These infections are most commonly caused by Staphylococcus aureus and gram­negative organisms, especially Pseudomonas. They commonly occur in unusual locations compared with septic arthritis in other populations. There is a marked predilection for infections in the fibrocartilaginous joints of the skeleton, such as the sternoclavicular joints, sacroiliac joints, and intervertebral disk spaces. Lyme arthritis manifests as a true inflammatory arthritis—most commonly in the knee—weeks to months after initial exposure and after the development of the early syndrome of fever, arthralgias, lymphadenopathy, and rash. This curable infection should be suspected in patients with compatible symptoms, a history of travel to endemic areas, or coexistent neurologic or cardiac abnormalities. The diagnosis can be difficult, however, because many affected individuals do not recall a tick bite or antecedent rash. If infection is suspected, serum antibodies to Borrelia burgdorferi should be obtained. Viral illnesses, including hepatitis B, infectious mononucleosis, parvovirus, rubella, and rubella vaccination, rarely present as monarticular synovitis (see Chapter 104). A number of arthritic syndromes that closely mimic known rheumatic diseases have now been described in association with human immunodeficiency virus (HIV) infection.22 Most of these are polyarticular and appear as arthralgias rather than true arthritis. Opportunistic infections in individuals infected with HIV can develop within one joint and in contiguous bone. In addition to the more typical organisms, such as S. aureus, less common microorganisms have been cultured from fluids of septic joints in patients with HIV infection, including Sporothrix schenckii, Cryptococcus neoformans, several Salmonella species, Ureaplasma urealyticum, and Campylobacter fetus. HIV-infected individuals can also experience an extremely painful, noninflammatory monarthritis. Although the mechanism of this syndrome is unknown, it usually resolves spontaneously in 24 to 28 hours (see Chapter 103). CRYSTAL-INDUCED ARTHRITIS Crystal-induced arthritis commonly manifests as acute monarticular arthritis. It is particularly likely when there is a ­ history of recurrent, self-limited attacks of inflammation of the same joint. Fortunately, the most fulminant ­arthropathy—gout—is also the most easily and reliably diagnosed. Monosodium urate crystals can be identified in at least 95% of acute joint effusions by polarized microscopy and even in some asymptomatic joints.23 Calcium pyrophosphate crystals are often not identified initially in patients who are later diagnosed with pseudogout.24 Hydroxyapatite crystals present a particular problem in diagnosis, because they are reliably identified only by electron microscopy or alizarin red stain.25 Occasionally, in patients with renal failure and an acute monarthritis, calcium oxalate crystals can be identified in joint fluid aspirates. As a general rule, identification of crystals in joint fluid does not prove the absence of coexistent infection. Crystal-induced arthropathies are particularly common and difficult to manage in patients who are uremic or undergoing dialysis. Gouty arthritis is definitely present when intracellular birefringent, needle-shaped crystals (sodium urate) are

identified in synovial fluid or confirmed by documentation of urate crystals in a tophus; it is probably present if the crystals are extracellular. The most characteristic clinical features are extremely rapid onset of severe pain and inflammation, with extension of the inflammatory process into the surrounding tissues, producing the appearance of cellulitis. Desquamation of overlying skin may occur as the attack subsides. In the ankle, the initial phases visually resemble the periarthritis of erythema nodosum, but the pain is much more severe.26 Podagra is characteristic but not pathognomonic of gout.27 First attacks of gout can occur in other large joints or in the small joints of the upper extremities (see Chapter 87). Calcium pyrophosphate dihydrate (CPPD) deposition is associated with acute or chronic inflammatory arthritis and may be superimposed on osteoarthritis.24 Pseudogout can be diagnosed by the finding of weakly positive, rhomboidshaped birefringent crystals in the white blood cells of synovial fluid aspirates (see Chapter 88). These are identified in half the effusions from patients presenting with monarthritis due to CPPD. Their presence does not exclude infection in a patient with a first episode of monarticular arthritis. The physician can also suspect the diagnosis in an elderly person with an acute monarthritis of the knee or wrist and chondrocalcinosis on radiographs if there are no obvious reasons to suspect infection. Less common forms of crystal-induced arthritis may result from deposition of hydroxyapatite (often in the shoulder) or calcium oxalate (especially in patients with renal failure). OTHER CAUSES OF ACUTE INFLAMMATORY ARTHRITIS Patients without Systemic Manifestations If a patient does not have one of the previously mentioned disorders, there is a significant likelihood that the cause will remain elusive for a time, and the physician will be obliged to make a practical decision about how aggressively to pursue a diagnosis. The initial workup under these circumstances should be as focused as possible so that a satisfactory result can be achieved most economically and with the least patient discomfort. Juvenile Rheumatoid Arthritis. Although most children with juvenile rheumatoid arthritis presenting with monarticular disease eventually exhibit involvement of additional joints, about 25% have isolated monarthritis that may recur intermittently into adulthood. Antinuclear antibodies are more common than rheumatoid factor; monarticular disease and antinuclear antibodies correlate with the development of iritis28 (see Chapter 97). Rheumatoid Arthritis. Rheumatoid arthritis may manifest with an acute or insidious onset of monarthritis. A detailed history often reveals the gradual onset of fatigue or arthralgias. Physical examination may reveal unsuspected involvement of other joints, particularly the metatarsophalangeal joints. Seronegative Spondyloarthropathies. The spondyloarthropathies were mentioned previously in the context of monarthritis accompanied by axial skeleton stiffness or pain.

PART 5 

Joints of the lower extremity are typically involved. There may also be extra-articular clues to the diagnosis, such as urethritis, diarrhea, inflammatory eye disease, nail pitting, or a psoriasiform rash. Joint swelling may be fusiform, creating “sausage digits.” Neuropathic Arthropathy. Neuropathic arthropathy (Charcot’s joints) should be suspected in patients with diabetes who present with a subacute or chronic monarthritis of the knee, ankle, or foot, usually with swelling and effusion but with little pain. The arthritis develops most commonly in those with peripheral neuropathy and sensory loss. The radiographic picture is usually pathognomonic. Hemarthroses. Hemarthroses may result from trauma, synovial hemangiomas, pigmented villonodular synovitis, excessive anticoagulation, or inherited coagulopathies. Lyme Arthritis. Lyme arthritis should be suspected in ­endemic areas, especially if there is a history of rash, tick bite, or exposure. Patients with Signs of Systemic Illness Enteropathic Arthritis. Whipple’s disease, which is rare, can appear with a monarticular arthritis when the bowel disease is not evident. Regional enteritis and ulcerative ­colitis are more likely to be symptomatic when arthritis develops29 (see Chapter 73). Celiac disease (sprue) is ­associated with rheumatic diseases, including rheumatoid arthritis and ­lupus. Systemic Autoimmune Disease. Systemic lupus erythematosus occasionally manifests with monarticular arthritis, although small joint polyarthritis is more common. Marked swelling of the wrist and tenosynovitis may also be accompanied by fever and severe systemic signs. Monarticular or large joint pain in a steroid-treated lupus patient suggests avascular necrosis30 or infection. Sarcoidosis often manifests as bilateral arthritis of the ankles, wrists, or knees, which may be associated with erythema nodosum or hilar adenopathy.31 Henoch-Schönlein purpura,32 Takayasu’s disease,33 overlap syndromes,34 polymyalgia rheumatica,35 and giant cell arteritis36 can all manifest with monarticular or polyarticular arthritis, although polyarthritis is the rule in many of these disorders. Familial Mediterranean fever typically causes exquisitely painful monarthritis with moderately impressive physical findings.37,38 The combination of fever and evanescent rash suggests Still’s disease39 or rheumatic fever.40

CHRONIC INFLAMMATORY MONARTICULAR ARTHRITIS Many disorders that manifest as acute monarticular inflammation progress to polyarticular involvement, remit and relapse, or spontaneously resolve. Persistent monarticular inflammation raises the concern that a more narrow spectrum of disorders is present, particularly chronic infections or tumors. For these at times difficult-to-diagnose conditions, intravenous drug use, travel to certain areas, and immunosuppression should raise one’s index of suspicion.

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EVALUATION OF GENERALIZED AND LOCALIZED SYMPTOMS

541

Synovial biopsy and arthroscopy may be useful in identifying the cause of chronic monarthritis (Fig. 36-3; also see Chapter 48). Chronic infections result from slow-growing organisms or the presence of foreign bodies in the joint. Typically, there are persistent signs of inflammation, including stiffness, pain, and warmth; characteristically, there is synovial thickening, regardless of whether an effusion is present. Tuberculosis, which is undergoing a resurgence in the United States, almost always affects a single diarthrodial joint41 (see Chapter 101). A positive tuberculin test may be the only clue. Infection with atypical mycobacteria or Candida, coccidioidomycosis, histoplasmosis, and blastomycosis can produce similar syndromes. Chronic infections may also result from penetrating wounds or the introduction of foreign bodies. Superficially located joints on the hands and feet are most likely to be penetrated during normal activity, often without awareness by the individual. Sporotrichosis should be suspected in a gardener with involvement of a hand joint, especially if there is a surrounding soft tissue reaction.42 Tumors, particularly pigmented villonodular synovitis,43 should be suspected when there is chronic monarticular inflammation in conjunction with a bloody effusion. Metastasis to synovium from solid tumors or joint involvement by hematologic malignancies is rare. Tumors involving periarticular structures can mimic arthritis.

NONINFLAMMATORY MONARTICULAR ARTHRITIS Structural joint disease should be suspected when there is little synovial inflammation in proportion to the degree of destruction of bone and cartilage and when the synovial fluid white blood cell count is less than 1000 to 2000 cells/ mm3. Truly noninflammatory fluid, however, contains fewer than 200 cells/mm3. An internal derangement of the knee is suggested by a history of trauma, episodes of joint locking or “giving way,” and tenderness at the joint margin; physical examination reveals locking or episodic pain during range of motion. It may be confirmed by MRI or arthroscopy, which demonstrates meniscal or ligamentous tears. Osteoarthritis frequently manifests as monarthritis, particularly in the knee, hip, acromioclavicular joint, first radiocarpal joint, or first metatarsophalangeal joint (i.e., hallux rigidus). Elderly patients with osteoarthritis may have inflammatory joint effusions that contain CPPD crystals.26 In monarticular disease, a predisposing factor should be sought, such as congenital dysplasia of the hip, trauma to or prior surgical removal of ligaments or fibrocartilage from the knee, prior inflammatory arthritis or infection, occupational stress, or obesity. Hip symptoms in a young patient suggest congenital dysplasia of the hip or a slipped capital femoral epiphysis.44,45 Spontaneous osteonecrosis may occur in the hip (Legg-Calvé-Perthes disease), metatarsal bones (Freiberg’s disease), capitellum of the humerus, or carpal lunate. Osteochondritis dissecans should be suspected in a child or teenager who, after minor trauma, has relatively severe knee pain followed by mechanical dysfunction.46 There is now considerable experience, especially in pediatric patients, using ultrasonography to identify hip effusions and periarticular abnormalities.47

542

GOLBUS 

| 

Monarticular Arthritis

Chronic monarticular arthritis Osteoarthritis

Radiograph

+

Inflammatory arthritis CPPD, other

Aspirate joint

Synovial WBC < 1000 mm3/mL

Synovial WBC >5000

Internal derangement, osteoarthritis

Crystal exam

Systemic rheumatic disease

RF, ANA, PPD, ESR, cultures

Figure 36-3  Approach to chronic monarticular arthritis. ANA, antinuclear antibody test; CPPD, calcium pyrophosphate deposition disease; ESR, erythrocyte sedimentation rate; PPD, purified protein derivative test for ­tuberculosis; RF, rheumatoid factor test; WBC, white blood cell count.

Rapid development of “osteoarthritis” should lead to a consideration of the possibility of fracture related to ­osteopenia, an adjacent destructive process such as metastatic tumor, or avascular necrosis. Osteonecrosis is a common cause of monarthritis of the hip, shoulder, and knee in young people with systemic diseases who require corticosteroid therapy. It also occurs in a variety of other conditions such as alcoholism, barotrauma, hemoglobinopathies, diabetes, hyperlipidemia, hyperuricemia, and systemic lupus erythematosus.

DIAGNOSTIC STUDIES SYNOVIAL FLUID ANALYSIS The most important laboratory test in the evaluation of acute monarthritis is synovial fluid analysis.25 The primary purpose of synovial fluid analysis is to answer the following questions: Is the effusion inflammatory? Is it infected? Does it contain intracellular or extracellular crystals? Even a few drops of fluid can be sufficient to obtain a white blood cell count and differential cell count, ­crystal

+

Gout, CPPD

Occult CPPD

Occult infection

analysis, and culture. No other tests are needed (see ­Chapter 48). If fluid is difficult to obtain, ultrasound-guided aspiration may yield fluid even from proximal interphalangeal joints. CULTURES If septic arthritis is a possibility, blood, synovial fluid, and urine cultures are indicated. If gonococcal arthritis is a consideration, cervicourethral, rectal, and pharyngeal samples should be placed on Thayer-Martin medium. Culture specimens from normally sterile sites, including the synovial cavity, tenosynovial space, and intracutaneous lesions, should be placed on chocolate agar without added preservative. Synovial fluid cultures are usually negative in gonococcal arthritis (see Chapter 99). LABORATORY STUDIES In the initial evaluation of monarthritis, diagnostic ­laboratory testing for rheumatic diseases should be ­ undertaken only after a careful history and physical examination.48 A complete blood count with differential, Westergren sedimentation rate,

PART 5 

C-reactive protein, tests of renal and liver function, and urinalysis can be useful if infection or a multisystem disease is suspected. In the appropriate clinical setting, studies that may be of value include a uric acid level, rheumatoid factor, anticyclic citrullinated peptide (anti-CCP), and certain serologic studies such as antinuclear antibody, antineutrophil cytoplasmic antibodies, Lyme disease, hepatitis, and parvovirus serologies. In the wrong clinical setting, routinely ordered serology studies, especially if bundled into “arthritis panels,” may cause confusion and lead to further unnecessary testing. RADIOGRAPHY

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EVALUATION OF GENERALIZED AND LOCALIZED SYMPTOMS

543

greatly facilitated by ultrasonography. It is possible to use “power Doppler” to identify areas of increased tissue perfusion.54 This may be helpful in localizing inflammation. The presence of lesions in tendons, such as an inflamed Achilles or patellar tendon, and the compromise of smaller tendons by rheumatoid nodules can also be identified by ultrasonography. The evaluation of structural abnormalities of joints, such as osteoarthritis or internal derangement, is more ­difficult. SYNOVIAL AND BONE BIOPSY

Plain radiographs of the affected and contralateral joints should almost always be obtained in patients with symptoms of more than several weeks’ duration. They may also be helpful for patients with an acute arthritis in whom infection or crystal disease is suspected. For those with no prior joint complaints, common findings are soft tissue calcification and evidence of intra-articular pathology unknown to the patient, such as osteoarthritis, chondrocalcinosis, or loose bodies. Occasionally, an unsuspected bony lesion (e.g., fracture) or evidence of osseous or hematologic malignancy, osteomyelitis, or Paget’s disease may be detected. Care should be taken to include enough surrounding bone in the radiograph to identify such lesions.

Although rarely needed, synovial biopsy may play a role in the diagnosis of chronic, unexplained monarticular arthritis.55 Tuberculous or fungal synovitis is more frequently identified by staining and culture of open biopsy material than by similar studies of synovial fluid. Closedneedle biopsy or arthroscopic biopsy of the knee is preferable to open biopsy because of reduced morbidity. In acute inflammatory arthritis, a surgical biopsy is indicated in the diagnosis of infection of fibrocartilaginous joints, such as the sacroiliac and sternoclavicular joints, and probably the symphysis pubis if an initial attempt at aspiration is not diagnostic.56 General anesthesia may be required for pain control. If osteomyelitis is suspected, the physician should consider obtaining a bone biopsy specimen before initiating antibiotic therapy.

NUCLEAR MEDICINE

REFERENCES

Radionuclide scans are useful primarily because of their ­sensitivity. They are used when it is important to search for a site of infection that cannot be detected or localized by other means, such as in deeply buried joints that are ­difficult to examine, fibrocartilaginous joints in which range of motion is poorly tested, and the spine (see Chapter 53).

  1. Radin EL: Chondromalacia of the patella. Bull Rheum Dis 34:1, 1984.   2. Lagier R: Synovial reaction caused by adjacent malignant tumors: Anatomico-pathological study of three cases. J Rheumatol 4:65, 1997.   3. Feagin JA Jr: The office diagnosis and documentation of common knee problems. Clin Sports Med 8:453, 1989.   4. Isenberg DA, Schoenfield Y: The rheumatologic complications of hematologic disorders. Semin Arthritis Rheum 12:348, 1983.   5. Hadjipavlou AG, Gaintanis IN, Kontalis GM: Paget’s disease of bone and its management. J Bone Joint Surg Am 84:160, 2002.   6. Larsson LG, Baum J: The syndromes of bursitis. Bull Rheum Dis 36:1, 1986.   7. Viggiano DA, Garrett JC, Clayton ML: Septic arthritis presenting as olecranon bursitis in patients with rheumatoid arthritis. J Bone Joint Surg Am 62:1011, 1980.   8. Ho O Jr, Su EY: Antibiotic therapy of septic bursitis. Arthritis Rheum 24:905, 1981.   9. Cucurull E, Espinoza LR: Gonococcal arthritis [review]. Rheum Dis Clin North Am 24:305-322, 1998. 10. Gotuzzo E, Alarcon GS, Bocanegra TS, et al: Articular involvement in human brucellosis: A retrospective analysis of 304 cases. Semin Arthritis Rheum 12:245, 1982. 11. Grassi W, Tittarelli E, Blasetti P, et al: Finger tendon involvement in rheumatoid arthritis: Evaluation with high-frequency sonography. Arthritis Rheum 38:786, 1995. 12. Dowart BB: Carpal tunnel syndrome: A review. Semin Arthritis Rheum 14:134, 1984. 13. Putten J: Neurological Differential Diagnosis. New York, SpringerVerlag, 1980. 14. Gibson RK, Rosenthal SJ, Lukert BP: Pyomyositis. Am J Med 11:421, 1982. 15. Kallen PS, Louie JS, Nies KM, et al: Infectious myositis and related syndromes. Am J Med 11:421, 1982. 16. Goldenberg DL: Infectious arthritis complicating rheumatoid arthritis and other chronic rheumatic disorders. Arthritis Rheum 32:496, 1989. 17. Resnick D, Niwayana G: Reiter’s disease. In Diagnosis of Bone and Joint Disorders, 2nd ed. Philadelphia, WB Saunders, 1988, pp 1218-1251.

MAGNETIC RESONANCE IMAGING MRI is superior to other imaging modalities in the diagnosis of ischemic necrosis of bone49 and possibly Legg­Calvé-Perthes disease,50 particularly in early cases. In addition, MRI is the study of choice to detect radiographically occult fractures, especially in the hip and pelvis.51 In the knee, MRI provides a more accurate and noninvasive alternative to arthrography for the detection of meniscal and cruciate ligament injuries.52 Because of their superior definition of soft tissue pathology, both MRI and ultrasonography are useful in investigating deep infections about the hip, such as psoas abscesses, which may mimic arthritis.53,54 Although superior in most cases to CT in detecting subchondral bone and marrow involvement by tumor or osteomyelitis, MRI is unable to provide the whole-body survey that is characteristic of radionuclide scans. ULTRASONOGRAPHY Musculoskeletal ultrasonography has advanced rapidly since the 1990s. It is possible to aspirate almost any joint under ultrasonic control, no matter how inaccessible or small. This facilitates the workup for infection. Evaluation for the presence of fluid in joints, bursae, and periarticular ­structures is

544

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18. Resnick D, Niwayana G: Psoriatic arthritis. In Diagnosis of Bone and Joint Disorders, 2nd ed. Philadelphia, WB Saunders, 1988, pp 1218-1251. 19. Cimmino MA: Recognition and management of bacterial arthritis. Drugs 54:50-60, 1997. 20. Seifert MH, Warin AP, Miller A: Articular and cutaneous manifestations of gonorrhea: Review of sixteen cases. Ann Rheum Dis 33:140, 1974. 21. Goldenberg DL: Septic arthritis. Lancet 351:197, 1998. 22. Rynes RI, Goldenberg DL, DiGiacomo R, et al: Acquiredimmunodeficiency syndrome-associated arthritis. Am J Med 84:810, 1988. 23. Bomalaski JS, Lluberas G, Schumacher HR Jr: Monosodium urate ­crystals in the knee joint of patients with asymptomatic ­nontophaceous gout. Arthritis Rheum 29:1480, 1986. 24. Masuda I, Ishikawa K: Clinical features of pseudogout attack: A review of fifty cases. Clin Orthop Rel Res 229:123, 1988. 25. Gatter RA, Schumacher HR Jr: A Practical Handbook of Synovial Fluid Analysis. Philadelphia, Lea & Febiger, 1991. 26. Yu T: Diversity of clinical features in gouty arthritis. Semin Arthritis Rheum 13:360, 1984. 27. McCarty DJ: Calcium pyrophosphate dihydrate crystal deposition ­disease—1975. Arthritis Rheum 19:275, 1976. 28. Chylack LT Jr: The ocular manifestations of juvenile rheumatoid arthritis. Arthritis Rheum 20(Suppl):224, 1976. 29. Weiner SR, Utsinger P: Whipple disease. Semin Arthritis Rheum 15:157, 1986. 30. Zizic TM, Hungerford DS, Stevens MB: Ischemic bone necrosis in ­systemic lupus erythematosus. Medicine (Baltimore) 59:134, 1980. 31. Spilberg I, Siltzbach LE, McEwen C: The arthritis of sarcoidosis. Arthritis Rheum 12:126, 1969. 32. Cream JJ, Gumpel JM, Peachey RDG: Schönlein-Henoch purpura in the adult. Q J Med 39:461, 1940. 33. Hall S, Barr W, Lie JT, et al: Takayasu arthritis. Medicine 64:89, 1985. 34. Bennett RM, O’Connell DJ: Mixed connective tissue disease: A clinicopathologic study of 20 cases. Semin Arthritis Rheum 10:25, 1980. 35. Healey L: Long-term follow-up of polymyalgia rheumatica: Evidence for synovitis. Semin Arthritis Rheum 23:322, 1984. 36. Ginsberg WW, Cohen MD, Hall SB, et al: Seronegative polyarthritis in giant cell arthritis. Arthritis Rheum 28:1362, 1985. 37. Meyerhoff J: Familial Mediterranean fever: Report of a large family, review of the literature, and discussion of the frequency of amyloidosis. Medicine (Baltimore) 59:66, 1980. 38. Sohar E, Pras M, Gafni J: Familial Mediterranean fever and its ­articular manifestations. Clin Rheum Dis 1:195, 1975.

39. van de Putte LB, Wouters JM: Adult-onset Still’s disease. Baillieres Clin Rheumatol 5:263, 1991. 40. Ben-Dov I, Berry E: Acute rheumatic fever in adults over the age of 45 years: An analysis of 23 patients together with a review of the ­literature. Semin Arthritis Rheum 10:100, 1980. 41. Nathanson L, Cohen W: A statistical and roentgen analysis of two hundred cases of bone and joint tuberculosis. Radiology 36:550, 1940. 42. Wilson DE, Mann JJ, Bennett JE, Utz P: Clinical features of ­extracutaneous sporotrichosis. Medicine (Baltimore) 63:25, 1984. 43. Docken WP: Pigmented villonodular synovitis. Semin Arthritis Rheum 9:1, 1979. 44. Wilson PD, Jacobs B, Schecter L: Slipped capital femoral epiphysis. J Bone Joint Surg Am 14:549, 1967. 45. Ponseti IV, McClintock R: The pathology of slipping of the upper femoral epiphysis. J Bone Joint Surg Am 38:71, 1956. 46. Pappa AM: The osteochondroses. Pediatr Clin North Am 14:549, 1967. 47. Harcke HT, Mandell GA, Cassell IL: Imaging techniques in childhood arthritis. Rheum Dis Clin North Am 23:523, 1997. 48. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines: Guidelines for the initial evaluation of the adult patient with acute musculoskeletal symptoms. Arthritis Rheum 39:1, 1996. 49. Imhof H, Breitenseher M, Trattnig S, et al: Imaging of avascular necrosis of bone. Eur Radiol 7:160, 1997. 50. Lamer S, Dorgeret S, Khairouni A, et al: Femoral head vascularization in Legg-Calvé-Perthes disease: Comparison of dynamic gadoliniumenhanced subtraction MRI with bone scintigraphy. Pediatr Radiol 32:580, 2002. 51. Sadro C: Current concepts in magnetic resonance imaging of the adult hip and pelvis. Semin Roentgenol 35:231, 2000. 52. Crotty JM, Monu JU, Pope TL: Magnetic resonance imaging of the musculoskeletal system. Part 4. The knee. Clin Orthop Rel Res 330:288, 1996. 53. Strouse PJ, DiPietro MA, Adler RS: Pediatric hip effusions: ­Evaluation with power Doppler sonography. Radiology 206:731, 1998. 54. Weintraub JC, Cohen JM, Maravilla KR: Iliopsoas muscles: MR study of normal anatomy and disease. Radiology 156:435, 1985. 55. Schumacher HR: Joint pathology in infectious arthritis. Clin Rheum Dis 4:33, 1978. 56. Gordon G, Kabins SA: Pyogenic sacroiliitis. Am J Med 69:50, 1980.

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Polyarticular Arthritis John S. Sergent  • Howard A. Fuchs

KEY POINTS

Onset

Synovial fluid analysis can differentiate inflammatory from noninflammatory arthritis.

The physician should direct attention early to the nature of the first symptoms. This is not always easy, especially if months or years have passed, because most patients prefer to discuss their current symptoms. It also may be difficult because many patients tend to discuss all the joint problems they have experienced in their lifetime, assuming all previous joint symptoms have been part of the same process, even if obviously caused by trauma.

Synovial fluid analysis can establish a diagnosis of gout or pseudogout. Osteoarthritis is largely defined by radiographic abnormalities, and another diagnosis must be considered when no radiographic abnormalities are present. Pretest probability of a specific diagnosis must be sufficiently high for laboratory testing to aid in diagnosis. History and physical examination findings are much more important than laboratory findings in establishing the ­diagnosis in a patient with inflammatory polyarthritis. Severe, prolonged morning stiffness, swelling in multiple joints, ­fatigue, weight loss, or fever suggests a systemic ­inflammatory process. Extra-articular manifestations often provide definitive ­diagnostic information in a patient with polyarthritis, ­particularly ocular and dermatologic involvement.

Course The physician must determine what has occurred since the onset of symptoms and at what rate. Chronic arthritis may be relentlessly progressive from the onset, or it may be intermittent, with periods of partial or complete remission. As individual joints become involved, the process may be migratory or additive. The term migratory polyarthritis implies that previously involved joints become asymptomatic as new joints become inflamed; the disease seems to migrate from joint to joint. Specific Joint Symptoms

Joint pain is extremely common and is almost always referred to as “arthritis” by the lay public. Because most patients who believe they have arthritis actually have some other cause for their pain, the initial challenge for the physician is to learn to differentiate between true arthritis and other causes of pain in and around joints.1,2 For patients whose polyarticular pain does seem to represent polyarthritis, the challenge is first to use the history, physical examination, and ancillary tests to develop a differential diagnosis, and then to establish a probable or, in most cases, a definitive diagnosis. Because polyarticular pain is the most frequent complaint bringing patients to rheumatologists, it is imperative that students of the field become proficient in this area.

HISTORY, PHYSICAL EXAMINATION, AND LABORATORY TESTS HISTORY As Mackenzie3 and others have pointed out, the clinical history is the most important diagnostic tool in the evaluation of polyarticular disorders. Many clinicians augment the history with the use of self-report patient questionnaires, which may be especially beneficial in following patients over time.4 Many items warrant special attention.

Specific symptoms include locking, localized pain, “giving way” without warning, palpable or audible crepitation, warmth, and swelling. Systemic Symptoms Patients who seek a physician’s help because of joint pain often do not perceive, unless asked, relationships between joint pain and other complaints, such as fever, night sweats, weight loss, and generalized muscle stiffness. The history of these symptoms should be sought specifically and, when possible, quantified. Rheumatic Disease Systems Review In addition to systemic symptoms, patients with arthritis must be asked specifically about conditions associated with various forms of arthritis, including rash (e.g., photosensitive, psoriatic, purpuric, or petechial), areas of alopecia, Raynaud’s phenomenon, sicca syndrome, uveitis, scleritis, oral and genital ulcers, urethritis or cervicitis, symptoms of inflammatory bowel disease, and pleuropericardial symptoms. Past History Previous diagnoses may be incorrect. A childhood history of rheumatic fever needs to be explored because many children will have had Still’s disease or another form of 545

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juvenile chronic polyarthritis instead; the reverse also may be true. Special emphasis should be given to events of the immediate weeks or months preceding the onset of joint disease, including sore throats, febrile illnesses, venereal disease, sexual contacts, diarrhea, rashes, and ocular inflammation. Family History In addition to asking about any type of arthritis, the examiner should inquire about a family history of any associated condition, such as psoriasis, uveitis, or inflammatory bowel disease. In patients suspected to have a spondyloarthropathy, it is important to obtain the history of any family members with chronic back pain and to attempt to determine the nature of that condition. PHYSICAL EXAMINATION A complete physical examination is essential. Special consideration must be given to searching for nonarticular features, such as rashes, patches of psoriasis, psoriatic nails, oral or genital ulcers, ocular abnormalities, murmurs, rubs, bruits, and abnormal peripheral pulses. A careful neurologic examination also is warranted. The details of a complete musculoskeletal examination are reviewed in Chapter 35. Each joint should be examined for warmth, synovial thickening, effusions, crepitation, deformity, and tenderness. The distribution also should be noted (e.g., distal interphalangeal, proximal interphalangeal, metacarpophalangeal, tendon insertions, a “ray” distribution of a whole digit) because specific patterns of involvement are seen with different disorders. Active and passive ranges of motion should be tested. The spinal examination should include the range of motion of the cervical and lumbar regions, chest expansion, tenderness of the spinous processes and sacroiliac joints, abnormal curves, and muscle spasm. LABORATORY TESTS Nonspecific tests of inflammation include hematocrit, erythrocyte sedimentation rate, C-reactive protein, and white blood cell count. Table 37-1 presents tests that are sometimes helpful in specific diseases. They must be ordered wisely because the background false-positive rate can be quite high. If obtainable, synovial fluid should be examined as described in Chapter 48. The primary benefit of synovial fluid examination is to differentiate among noninflammatory arthritis, inflammatory arthritis, and infection. Tests other than appearance, total white blood cell count and differential, crystal examination, and culture rarely are indicated. RADIOGRAPHIC FEATURES Important radiographic features that may help in patient evaluation include fracture, focal or diffuse cartilage loss, erosion, periarticular osteoporosis, osteophytes, subchondral sclerosis, periostitis, and soft tissue changes. In many cases, properly chosen radiographs may be virtually diagnostic or may eliminate certain diseases from further consideration.

Table 37-1  Laboratory Tests for Polyarthritis Significance Test

Positive

Negative

Rheumatoid factor   Helpful in young Prognostic significance ­individuals, in   only, not helpful in or anti–cyclic   citrullinated   whom background ­  individual cases peptide positivity is low Antinuclear   antibody

High titer, suggestive   Virtually rules out   of a rheumatic   active systemic ludisease pus erythematosus

Uric acid

Elevated levels,   indicating that   gout is possible

If repeated levels are   normal, gout unlikely

Antistreptolysin O

Recent streptococcal exposure

Rheumatic fever unlikely

HLA-B27

Possibly useful in   No benefit early-onset spondy­ loarthropathy

Anti-Borrelia

Only helpful if pretest probability is high

Chronic Lyme disease unlikely

PRINCIPLES OF DIAGNOSIS Physicians are expert in pattern recognition, and in no area is this more important than in rheumatology, where the specific joints involved, the sequence of events, and associated features—as opposed to specific diagnostic tests—define most diseases. Being competent in pattern recognition sometimes can be a two-edged sword if the clinician settles too quickly on a diagnosis or is inflexible about changing the presumed diagnosis as new data become available. After other causes of joint pain have been eliminated, and it seems that the patient does have polyarticular arthritis, numerous classification schemes may aid in determining the correct diagnosis. One might consider the size of the involved joints (small [digits] versus large), the age of onset, or other features. We have chosen a system based on the presence or absence of inflammation and the number and pattern of joint involvement. In most situations, the best determinant of inflammation is the synovial fluid examination (see Chapter 48) and especially the synovial fluid white blood cell count, which is less than 1000/mm3 in most noninflammatory conditions and significantly greater in inflammatory disease. There also are clinical features that suggest the arthritis is inflammatory in nature, including prolonged and severe morning stiffness, fever, night sweats, weight loss, and spontaneous (not activity-related) joint swelling. Physical examination in inflammatory arthritis often reveals local warmth, synovial thickening, and large effusions. In addition to inflammatory synovial fluid, other features suggesting inflammation include anemia, thrombocytosis, an increased erythrocyte sedimentation rate, and increased acute-phase reactants such as C-reactive protein and ferritin. Table 37-2 shows a classification of polyarthritis based on two features: the presence or absence of inflammation and the number and pattern of joint involvement. Figure 37-1 is an algorithm based on history and examination, which helps lead to appropriate further investigation.

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Table 37-2  Classification of Polyarthritis Inflammatory Peripheral polyarticular Rheumatoid arthritis Systemic lupus erythematosus Viral arthritis Psoriatic arthritis (occasionally) Peripheral pauciarticular Psoriatic arthritis Reiter’s syndrome Rheumatic fever Polyarticular gout Enteropathic arthritis Behçet’s disease Bacterial endocarditis Peripheral with axial involvement Ankylosing spondylitis (especially juvenile onset) Reiter’s syndrome Enteropathic arthritis Psoriatic arthritis Noninflammatory (osteoarthritis) Hereditary Osteoarthritis of the hands Primary generalized osteoarthritis Traumatic osteoarthritis Osteoarthritis after local injury Osteoarthritis of the knees in obese individuals Chondromalacia after aggressive exercise programs Osteoarthritis in the elderly Metabolic diseases (may have an unusual pattern) Hemochromatosis Ochronosis Acromegaly Idiopathic

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SYSTEMIC LUPUS ERYTHEMATOSUS Systemic lupus erythematosus (SLE; see Chapter 75) often manifests as chronic polyarthritis and may be confused with RA in such patients. The arthritis is typically intermittent, may be extremely painful, and is almost never erosive. Mixed connective tissue disease may cause an identical arthritis. SCLERODERMA The systemic sclerosis variant of scleroderma (see Chapter 77) typically begins as painful swollen hands, with early contractures as prominent features. The combination of puffy hands and Raynaud’s phenomenon may be referred to as undifferentiated connective tissue disease in recognition of the fact that the condition of the patient may evolve into SLE, scleroderma, mixed connective tissue disease, or RA. Some individuals may remain in the undifferentiated state for many years. Rarely, patients are seen with characteristic features of scleroderma and RA.7 PSORIATIC ARTHRITIS Although typically pauciarticular at onset, psoriatic arthritis may evolve into a polyarticular disease that resembles RA (see Chapter 72). Particular diagnostic problems occur in children, whose disease may resemble pauciarticular juvenile chronic arthritis at onset and may then evolve into a pattern resembling polyarticular juvenile or adult RA.8 GONOCOCCAL ARTHRITIS

POLYARTICULAR PERIPHERAL ARTHRITIS RHEUMATOID ARTHRITIS Rheumatoid arthritis (RA) is the prototype of the polyarticular peripheral arthritides (see Chapter 66). RA accounts for about one fourth of all patients referred to rheumatologists,1 and other forms of peripheral joint disease are often defined partly by how they differ from RA. Typically beginning in multiple small joints of the hands and feet in a symmetric fashion, RA has many variations, including months or years of recurrent monarthritis (palindromic rheumatism)5 before a typical pattern evolves. Disease duration of 12 weeks or more is strongly predictive of persistent RA.6 The symmetry of RA is sometimes overemphasized, and it must be appreciated that this is a general, rough symmetry. RA rarely causes extensive damage to one hand and completely spares the other. The arthritis of RA is typically additive, with sequential involvement of groups of joints. Most joints remain more or less symptomatic as new joints are involved. The earliest joints involved are usually small joints of the hands and feet, but the distal interphalangeal joints are spared until late in the course. Although arthritis is usually the presenting feature of RA, occasional patients have extra-articular features of the disease at roughly the same time or even earlier. Episcleritis, subcutaneous nodules, and pleural effusions are the most frequent early extra-articular features of the disease.

In contrast to the monarthritis typical of most septic joint diseases, gonococcal arthritis usually manifests with fever, tenosynovitis, and papular or pustular skin lesions. As it evolves over several days, it may gradually involve one or more joints in a frankly purulent arthritis (see Chapter 99). VIRAL ARTHRITIS Viral arthritis can cause impressive polyarticular pain, often lasting for weeks or months with pain out of proportion to physical examination findings (see Chapter 104). Parvovirus B19 is the prototype,9 but similar symptoms have been reported with rubella,10 mumps,11 hepatitis B,12 and other viruses. Reactive arthritis, psoriatic arthritis, or an acute painful polyarthritis may be the presenting manifestation of human immunodeficiency virus (HIV) infection.13 Another presentation of HIV infection resembles SLE, with fever, rash, polyarthritis, proteinuria, and hematologic abnormalities.14 Infectious polyarthritis also may complicate HIV infection. PAUCIARTICULAR PERIPHERAL ARTHRITIS In general, the term pauciarticular is used to describe arthritis that affects four or fewer joints, although certain latitude may be taken, such as counting the midfoot or wrist as a single joint. This term usually is limited to the early phase of the disease because many of these conditions gradually become polyarticular as the course progresses.

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Polyarticular joint pain YES

Joint effusion

Inflammation?

Crystals

NO Joint inflammation?

NO

Noninflammatory joint pain

NO

Gout or pseudogout

YES

Noninflammatory joint pain

YES Spinal involvement

YES

Spondyloarthropathy

NO Extra/juxtaarticular inflammation Skin/subcutaneous nodules Eye

(See Chapter 47)

(see Chapter 46) NO

Specific radiographic abnormalities of peripheral joints Osteoarthritis Periostiitis (spondyloarthropathy, acne-associate arthritis, HPOA-Chapter 113) Inflammatory arthritis NO, OR inflammatory arthritis on radiograph Order specific laboratory testing only if pretest probability is favorable RF ANA ASO Viral titers (e.g. Parvovirus B-19, hepatitis B and C) HLA-B27 Anti-Borrelia Ab Uric acid Blood culture Noninflammatory joint pain

Joint based pain

NO

Muscular tenderpoints in specific distribution?

YES

Fibromyalgia

NO Insertional tenderness YES

YES

NO

Nonarticular soft tissue pain

Tendinitis/bursitis Bony enlargement on exam or radiographic focal joint space narrowing, osteophytes, subchondral sclerosis YES Evidence for endocrine or metabolic abnormality or chondrocalcinosis on radiograph NO OSTEOARTHRITIS

YES

Specific laboratory testing Growth hormone Iron studies Homogentistic acid level Parathyroid hormone

Figure 37-1  Algorithm for assessment of polyarthritis. ANA, antinuclear antibody; ASO, antistreptolysin O; HPOA, hypertrophic pulmonary ­osteoarthropathy; RF, rheumatoid factor.

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PSORIATIC ARTHRITIS Subsets of psoriatic arthritis include rheumatoid-like, spondyloarthropathy with dactylitis and inflammation of tendon insertions (enthesitis), and a subset with a predilection for distal interphalangeal joint involvement, particularly in the presence of psoriatic nail involvement. This condition may precede skin disease in a few patients and usually begins as pauciarticular disease. The arthritis is typically asymmetric (Fig. 37-2), and occasional patients show severe damage to one group of joints with no involvement of the contralateral side (see Chapter 72). In many cases, entire digits are involved with arthritis and periostitis, producing the appearance of a sausage digit. REACTIVE ARTHRITIS Previously known as Reiter’s syndrome (arthritis, conjunctivitis, psoriasiform rash, or mucosal lesions following infections of the gut or genitourinary tract), reactive arthritis may become manifest in a manner similar to that of psoriatic arthritis, but with a greater predilection for the lower extremity. The arthritis is often asymmetric and is frequently associated with involvement of the heel, other entheses, or the sacroiliac joints (see Chapter 71). ADULT RHEUMATIC FEVER Apparently increasing in frequency of occurrence, adult rheumatic fever often causes a painful pauciarticular disease, which is most prominent in the larger joints of the lower extremities. The typical migratory pattern of childhood rheumatic fever is uncommon in adults,15 and the response to aspirin is less dramatic. Although some fever is usually present, carditis is uncommon, and other features, such as chorea, rash, and subcutaneous nodules, are rare. The ­presentation in adults may be less acute than in children, with a more insidious arthritis developing over several days or 1 to 2 weeks.

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superimposed on osteoarthritis of the finger joints.16 Examination of synovial fluid or material draining from a tophus yields the diagnosis. CALCIUM PYROPHOSPHATE DEPOSITION DISEASE Calcium pyrophosphate deposition disease is most easily recognized when it manifests as an acute monarthritis (pseudogout). It has many forms, however, including a chronic polyarthritis (see Chapter 88). Radiographically, it may manifest as osteoarthritis in an unusual area (e.g., wrists without previous trauma or metacarpophalangeal rows) or with characteristic chondrocalcinosis that is most commonly seen in the fibrocartilaginous portions of the joint. BEHÇET’S DISEASE Uncommon in the United States, Behçet’s disease almost invariably causes chronic polyarthritis limited to a few joints. It is characterized by painful acute flare-ups associated with oral, genital, and ophthalmologic manifestations (see Chapter 86). ENTEROPATHIC ARTHRITIS Enteropathic arthritis is associated with inflammatory bowel disease and characteristically involves large joints of the lower extremity or the lumbosacral spine (see Chapter 73). RELAPSING POLYCHONDRITIS Relapsing polychondritis usually causes severe inflam­ mation of the ears, nose, and sclerae and is associated with a pauciarticular arthritis of the knees or wrists (see Chapter 95). SARCOIDOSIS

GOUT Gout often manifests to the rheumatologist as undiagnosed chronic polyarthritis (see Chapter 87). Particularly confusing can be the syndrome of acute and chronic gouty arthritis

Sarcoidosis causes numerous articular problems. The most frequent is an oligoarthritis of the knees or ankles in association with erythema nodosum and bilateral hilar adenopathy. Joint effusions are rare. Occasionally, in patients with ­

Figure 37-2  Psoriatic arthritis. Note the asymmetry of the distal interphalangeal joint involvement and the associated psoriatic nail disease.

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long-standing sarcoidosis, a chronic, destructive ­polyarthritis resembling RA may develop with lytic bone lesions on radiographs (see Chapter 107). LYME DISEASE The arthritis of Lyme disease is usually monarticular or oligoarticular, but a chronic symmetric polyarthritis also has been described (see Chapter 100).17 BACTERIAL ENDOCARDITIS The arthritis of bacterial endocarditis also is typically monarticular or oligoarticular, usually in the lower extremities, although back pain also may be a presenting feature. About one quarter of patients have rheumatoid factor, which can add to the diagnostic difficulties.18

ENTEROPATHIC ARTHRITIS The arthritis of inflammatory bowel disease, enteropathic arthritis may manifest as axial or peripheral arthritis, or the two may coexist.22 The axial arthritis is identical to ankylosing spondylitis and is strongly associated with HLA-B27. When present, the spondylitis runs a progressive course regardless of the activity of the bowel disease.23 Spondylitis typically develops at around the same time as the bowel disease, but may precede it by years. PSORIATIC ARTHRITIS Psoriatic arthritis may cause an axial and a peripheral arthritis, but the axial disease is not a typical presenting feature.

AMYLOID ARTHROPATHY

WHIPPLE’S DISEASE

Amyloid arthropathy may include virtually all joints, but pauciarticular involvement of the upper extremities is most frequent. Bilateral shoulder disease may cause joint enlargement known as the “shoulder pad” sign. This finding, especially in association with carpal tunnel syndrome and purpura in skin folds, should always prompt the examiner to suspect primary amyloidosis. The amyloidosis caused by β2-microglobulin deposition in patients on long-term dialysis may manifest with an impressive destructive arthritis of large joints, especially the knees, shoulders, and hips (see Chapter 106).19

Most patients with Whipple’s disease may present with a chronic nondeforming migratory polyarthritis usually involving only a few joints at a time. The arthritis may precede other symptoms, such as weight loss, diarrhea, hyperpigmentation, or central nervous system involvement, by years.24

NONINFLAMMATORY POLYARTHRITIS

Ankylosing spondylitis is the prototype of this group of diseases. Although it typically begins in the patient’s late teens or early 20s with back pain and stiffness, when it begins in children or young teenagers, peripheral arthritis is common and may precede back symptoms by months or years. The arthritis involves predominantly the lower extremities and includes knees, ankles, and feet in most patients.20

Many of the features that support the diagnosis of noninflammatory polyarthritis (i.e., osteoarthritis) are simply the absence of features that suggest inflammation. Many specific findings are helpful, however, in establishing a diagnosis of osteoarthritis (see Chapter 90). The patient usually describes a history of pain primarily during and after use of the affected joints, with minimal pain at rest and minimal morning stiffness. Physical examination often reveals coarse crepitation, and loose bodies and other debris may be palpable while the joint is moved through its range of motion. Bony osteophytes may be palpable, especially in the fingers. Results of routine tests of inflammation are normal, unless another disease is present. Because osteoarthritis and rheumatoid factor positivity increase in frequency with advancing age, positive test results for rheumatoid factor become less valuable in older individuals. In a French study, nearly half of the patients seeking care for osteoarthritis had polyarticular arthritis.25 The ultimate diagnostic test for osteoarthritis is the radiograph. Numerous important biochemical changes in cartilage precede radiographic changes, but for all practical purposes, symptomatic osteoarthritis is nearly always accompanied by radiographic changes (see Chapter 53) and manifests as specific syndromes.

reactive arthritis

OSTEOARTHRITIS OF THE HANDS

Although only one fourth to one third of patients with reactive arthritis have overt back symptoms on presentation, most of these patients have unilateral or bilateral sacroiliitis and spine disease during the course of the disease.21

A hereditary disease much more prevalent in women, osteoarthritis of the hands typically develops within a few years of menopause and is often associated with mild inflammation for the first 1 or 2 years that a particular joint is involved. The joints may be intermittently warm and

INFLAMMATORY POLYARTHRITIS WITH AXIAL INVOLVEMENT Early involvement of the axial skeleton can be an extremely important clue to the correct diagnosis of inflammatory polyarthritis. For that reason, it may be helpful to question the patient carefully about neck and lumbar spine pain and prolonged stiffness to rule out unusual presentations of ankylosing spondylitis, reactive arthritis, or other spondyloarthropathies (see Chapters 70 and 71). ANKYLOSING SPONDYLITIS

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tender. After 1 or 2 years, the evidence of inflammation, if any, gradually subsides, and the typical osteophytes of Heberden’s and Bouchard’s nodes develop in the distal and proximal interphalangeal joints. The disease is strikingly symmetric, although the degree of involvement may vary (Fig. 37-3).26 PRIMARY GENERALIZED OSTEOARTHRITIS A rare, hereditary disease with osteoarthritis of multiple joints, primary generalized osteoarthritis usually begins in middle age and involves “typical” joints, such as the hips, knees, and hands.27 OSTEOARTHRITIS SECONDARY TO METABOLIC DISEASES Osteoarthritis secondary to metabolic diseases is increasingly recognized as particular patterns of osteoarthritis have been described in association with several disorders discussed next. Calcium Pyrophosphate Deposition Disease Calcium pyrophosphate deposition disease (CPPD) may be associated with generalized osteoarthritis, including severe involvement of specific joints (pseudo-Charcot joints) and involvement of joints not generally involved with osteoarthritis (wrists, ankles, elbows, metacarpophalangeal joints). The frequency of CPPD increases with age, and some elderly patients with osteoarthritis of the knee have chondrocalcinosis on radiographic examination or CPPD crystals on synovial fluid examination. More often than not, tricompartmental osteoarthritis with effusion indicates the presence of CPPD, especially with severe patellofemoral joint involvement (see Chapter 88). Underlying causes for which screening should be performed include hemochromatosis, hyperparathyroidism, and hypothyroidism. In patients with hand involvement, radiographs are sensitive for establishing the diagnosis early in the disease course.28

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Hemochromatosis Hemochromatosis, an underdiagnosed but common disorder,29 may manifest with osteoarthritis that is associated with CPPD. Osteoarthritis involving the second and third metacarpophalangeal joints is particularly common and may be confused clinically with RA, but it has distinct radiographic differences. Early-onset osteoarthritis of weight-bearing and large non–weight-bearing joints also may be seen in hemochromatosis (see Chapter 108). Hypothyroidism Hypothyroidism is associated with symmetric, noninflammatory, highly viscous effusions, frequently in joints with preexisting osteoarthritis (see Chapter 111). Acromegaly Acromegaly causes polyarthritis as a result of cartilage overgrowth early in disease and the subsequent development of significantly debilitating osteoarthritis, with the most severe involvement occurring in the hips and spine (see Chapter 111).30 CHONDROMALACIA Chondromalacia of the patella has multiple causes, but, as a clinical presentation, it is usually seen in physically active young and middle-aged women. Physical findings include small effusions, laxity of the patellar ligaments, and patellofemoral crepitation (see Chapters 42 and 90). OTHER CONDITIONS Obesity causes numerous joint problems, the most common of which is bilateral osteoarthritis of the knees, especially in women.31 Various developmental defects, such as congenitally shallow acetabula, are often asymptomatic until osteoarthritis develops later in life.

DIFFERENTIAL DIAGNOSIS ARTHRITIS VERSUS ARTHRALGIA Table 37-3 lists the major nonarticular considerations in patients with chronic polyarticular pain. The first challenge to the physician is to differentiate among arthritis, arthralgia, and periarticular disorders. TENDINITIS AND RELATED DISORDERS

Figure 37-3  Osteoarthritis. Although the left third proximal interphalangeal joint is involved most severely, the right also is involved, and there are several early Heberden’s nodes. The patient is a 60-year-old secretary who has moderate soreness in these joints at the end of the day.

Tendinitis and related disorders include painful shoulder syndromes, tennis elbow (lateral epicondylitis), golfer’s elbow (medial epicondylitis), trochanteric bursitis, iliotibial band syndrome, anserine bursitis, prepatellar bursitis, Achilles tendinitis, and tendinitis along the radial aspect of the wrist (de Quervain’s tenosynovitis). In these syndromes, pain is often maximal at the beginning of an activity and starts to subside as the activity is continued. A thorough history, including a description of job and sports activities, is essential. In many cases, physical examination reveals

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Table 37-3  Differential Diagnosis of Polyarticular   Pain Polyarthritis Tendinitis Muscle disorders Polymyalgia rheumatica Vasculitis Vaso-occlusive disease Neuropathies Diseases of the spine Primary bone diseases Periostitis Fibromyalgia Malingering

areas of local tenderness near, but distinct from, the joint. Pain may be exacerbated by movement of the affected structures against resistance. In tendinitis, swelling, if present, is usually minimal and limited to tendon sheaths and bursae, rather than joints. Thickening of tendons and subcutaneous tissues in patients with diabetes can cause a variety of clinical features, including Dupuytren’s contractures and, especially in patients with juvenile-onset diabetes, the diabetic stiff hand syndrome (Fig. 37.4) (see Chapter 111).32 MUSCLE DISORDERS Although weakness predominates in most of these conditions, and arthritis is not a serious consideration, occasional patients present with periarticular pain as a primary complaint (see Chapter 78).

Figure 37-4  “Prayer sign” in the diabetic stiff hand syndrome. As a result of progressive thickening of tendons, joint capsules, and subcutaneous tissues, progressive stiffness and flexion contractures develop in these patients.

NEUROLOGIC DISEASES Neurologic diseases include peripheral neuropathies, compression neuropathies such as carpal tunnel syndrome, and infiltrative diseases such as amyloidosis and Waldenström’s macroglobulinemia. Pain usually is associated with paresthesias and usually is worse at night. Although patients may have pain localized to joints, it is more typically diffuse, and examination reveals no objective joint abnormalities. DISEASES OF THE SPINE

POLYMYALGIA RHEUMATICA Because many patients with polymyalgia rheumatica (see Chapter 81) have preexisting polyarticular disorders, such as osteoarthritis and tendinitis, it may require skill and experience to differentiate among these problems. Several investigators33-35 have pointed out the difficulty of distinguishing polymyalgia rheumatica from older-onset RA and have stressed that in the early stages it may be impossible to tell them apart. VASCULITIS Frank arthritis is an uncommon manifestation of systemic vasculitis. Joint pain may be deep, aching, and constant. VASO-OCCLUSIVE DISEASES Vaso-occlusive diseases include atherosclerosis; cholesterol emboli; and emboli from cardiac sources such as a myxoma, diabetes, Raynaud’s disease, Buerger’s disease, and the antiphospholipid syndrome. These conditions rarely cause polyarticular pain without other manifestations of disease. Patients with cholesterol emboli may present with polyarthralgias, myalgias, renal disease, elevated erythrocyte sedimentation rates, eosinophilia, and positive test results for rheumatoid factor and antinuclear antibody.36

A variety of diseases of the neck and spine, including spinal stenosis (congenital or acquired), spondylolisthesis, and tumors of the lower cord and cauda equina, may manifest in a similar fashion. The pain is usually primarily in the buttocks and is worse with certain postures or activities. In spinal stenosis, pain is typically that of neurogenic claudication, with aching in the buttocks and thighs brought on by certain activities and that is often worse going down hills or steps (see Chapter 41). PRIMARY BONE DISEASES AND MALIGNANCY Metastatic tumors and myeloproliferative disorders may masquerade as polyarticular arthritis. Children with sickle cell crises and leukemia are especially likely to present with widespread joint pain, and any large series of children with the initial diagnosis of juvenile RA contains a small percentage who ultimately are found to have leukemia.37 In adults, myeloma and a variety of widely metastatic cancers manifest as bone and joint pain. In childhood leukemia, joint effusions, warmth, and tenderness may be present (see Chapter 112). These objective findings are rare in adults with leukemia or other malignancies. Other widespread bone diseases, especially osteonecrosis (see Chapter 94), occasionally may resemble polyarticular

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arthritis. When osteonecrosis involves peripheral joints, such as the knee and ankle, swelling and tenderness may be impressive.38 It is common to see stress fractures in runners or weekend athletes mimicking polyarthritis in the feet and ankles. PERIOSTITIS Periostitis, especially as part of the syndrome of hypertrophic pulmonary osteoarthropathy, may cause severe widespread joint pain, tenderness, and warmth. Careful examination reveals tenderness around joint structures and along the shafts of the involved long bones (see Chapter 112) typically associated with clubbing of the fingernail beds. FIBROMYALGIA AND PSYCHOGENIC PAIN SYNDROMES Objective examination of patients with the chronic pain syndrome of fibromyalgia reveals generalized tenderness that is not joint based, but distributed preferentially in typical trigger points (see Chapter 38).

SUMMARY Polyarticular arthritis, the most common indication for rheumatologic consultation, represents a challenge to the skills and experience of the clinician. By careful history taking and physical examination, along with appropriate tests, the physician almost always can establish the correct diagnosis, however, and institute appropriate therapy. In an era of increasing demand that medicine show that it is cost-effective, the bedside skills required to evaluate these patients prove particularly valuable. REFERENCES   1. Hooker RS, Brown JB: Rheumatology referral patterns. HMO Practice 4:61, 1990.   2. Pauker SG, Kassirer JP: Medical progress: Decision analysis. N Engl J Med 316:250, 1987.   3. Mackenzie AH: Differential diagnosis of rheumatoid arthritis. Am J Med 85(Suppl 4):2, 1985.   4. Wolfe F, Pincus T: Listening to the patient: A practical guide to selfreport questionnaires in clinical care. Arthritis Rheum 42:1797, 1999.   5. Hannonen P, Mottonen T, Oka M: Palindromic rheumatism: A clinical survey of sixty patients. Scand J Rheumatol 16:413, 1987.   6. Green M, Marzo-Ortega H, McGonagle D, et al: Persistence of mild, early inflammatory arthritis: The importance of disease duration, rheumatoid factor, and the shared epitope. Arthritis Rheum 42:2184, 1999.   7. Zimmerman C, Steiner G, Skriner K, et al: The concurrence of rheumatoid arthritis and limited systemic sclerosis: Clinical and serologic characteristics of an overlap syndrome. Arthritis Rheum 41:1938, 1998.   8. Southwood TR, Petty RE, Malleson PN, et al: Psoriatic arthritis in children. Arthritis Rheum 32:1007, 1989.   9. Moore TL: Parvovirus-associated arthritis. Curr Opinion Rheum 12:289, 2000. 10. Chambers RJ, Bywaters EG: Rubella synovitis. Ann Rheum Dis 22:263, 1963.

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11. Gordon SC, Lauter CB: Mumps arthritis: A review of the literature. Rev Infect Dis 6:338, 1984. 12. Sergent JS: Extrahepatic manifestations of hepatitis B infection. Bull Rheum Dis 33:1, 1983. 13. Winchester R: AIDS and the rheumatic diseases. Bull Rheum Dis 39:1, 1990. 14. Kopelman RH, Zolla-Pazner S: Association of human immunodeficiency virus infection and autoimmune phenomenon. Am J Med 84:82, 1988. 15. Wallace MR, Garst PD, Papadimos TJ, et al: The return of acute rheumatic fever in young adults. JAMA 262:2557, 1989. 16. Lally EV, Zimmerman B, Ho G Jr, et al: Urate-mediated inflammation in nodal osteoarthritis: Clinical and roentgenographic correlations. Arthritis Rheum 32:86, 1989. 17. Steere AC, Schoen RT, Taylor E: The clinical evolution of Lyme arthritis. Ann Intern Med 107:725, 1987. 18. Churchill MA, Geraci JE, Hunder GG: Musculoskeletal manifestations of bacterial endocarditis. Ann Intern Med 87:754, 1977. 19. Alfrey AC: Beta2-microglobulin amyloidosis. Nephrol Lett 6:27, 1989. 20. Khan MA: Editorial comment. J Rheumatol 16:634, 1989. 21. Lionarons RJ, van Zoeren M, Verhagen JN, et al: HLA-B27-­associated reactive spondyloarthropathies in a Dutch military hospital. Ann Rheum Dis 45:141, 1986. 22. Gravallese EM, Kantrowitz FG: Arthritic manifestations of inflammatory bowel disease. Am J Gastroenterol 83:703, 1987. 23. Burgos-Vargas R, Clark P: Axial involvement in the seronegative enteropathy and arthropathy syndrome and its progression to ankylosing spondylitis. J Rheumatol 16:192, 1989. 24. Durand DV, Leomte C, Cathebras P, et al: Whipple disease: Clinical review of 52 cases. The SNFMI Research group on Whipple Disease. Medicine 76:170-184, 1997. 25. Fautrel B, Hilliquiin P, Allaert F-A, et al: Who are the patients who consult for osteoarthritis? Arthritis Rheum 44:5237, 2001 (abstract). 26. Cushnaghan J, Dieppe P: Study of 500 patients with limb joint osteoarthritis, I: Analysis by age, sex, and distribution of symptomatic joint sites. Ann Rheum Dis 50:8, 1991. 27. Ala-Kokko L, Baldwin CT, Moskowitz RW, et al: Single base mutation in the type II procollagen gene (COL2A1) as a cause of primary osteoarthritis associated with a mild chondrodysplasia. Proc Natl Acad Sci U S A 87:6565, 1990. 28. Devauchelle-Pensec V, Berthelot JM, Jousse S, et al: Performance of hand radiographs in predicting the diagnosis in patients with early arthritis. J Rheumatol 33:1511-1515, 2006. 29. Edwards CQ, Griffen LM, Goldgar D, et al: Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. N Engl J Med 318:1355, 1988. 30. Biermasz NR, Pereira AM, Smit JW, et al: Morbidity after long-term remission for acromegaly: Persisting joint-related complaints cause reduced quality of life. J Clin Enodcrinol Metab 90:2731-2739, 2005. 31. Felson DT, Anderson JJ, Naimark A, et al: Obesity and knee osteoarthritis: The Framingham Study. Ann Intern Med 109:18, 1988. 32. Kapoor A, Sibbitt WL Jr: Contractures in diabetes mellitus: The syndrome of limited joint mobility. Semin Arthritis Rheum 18:168, 1989. 33. Healey LA: Late-onset rheumatoid arthritis vs. polymyalgia rheumatica: Making the diagnosis. Geriatrics 43:65, 1988. 34. Deal CL, Meenan RF, Goldenberg DL, et al: The clinical features of elderly-onset rheumatoid arthritis. Arthritis Rheum 28:987, 1985. 35. Healy LA: Polymyalgia rheumatica and seronegative RA may be the same entity. J Rheumatol 19:270, 1991. 36. Cappiello RA, Espinoza LR, Adelman H, et al: Cholesterol embolism: A pseudovasculitic syndrome. Semin Arthritis Rheum 18:240, 1989. 37. Kunnamo I, Kallio P, Pelkonen P, et al: Clinical signs and laboratory tests in the differential diagnosis of arthritis in children. Am J Dis Child 141:34, 1987. 38. Lotke PA, Steinberg ME: Osteonecrosis of the hip and knee. Bull Rheum Dis 35:1, 1985.

38

Fibromyalgia Frederick Wolfe  •  Johannes J. Rasker

KEY POINTS Fibromyalgia is a commonly recognized syndrome characterized by pain, sleep disturbance, and fatigue combined with a general increase in medical symptoms, including problems of memory or thinking, and often psychological distress. A formal diagnosis of fibromyalgia is unnecessary as long as fibromyalgia symptoms are recognized. There is no evidence that diagnosing fibromyalgia improves its outcome. Fibromyalgia has a quality of inexplicability and unexpectedness. The clinician is surprised by the extent and severity of symptoms and surprised at unexpected emotional distress. The prevalence of fibromyalgia is 2% to 4% worldwide. Treatment has a modest short-term effect. There is no ­evidence that treatments alter the long-term outcome.

There is substantial evidence against the existence of fibromyalgia as a distinct clinical or epidemiologic entity.1-5 However, right or wrong, fibromyalgia is a commonly diagnosed syndrome, with its own ICD code and criteria.6 The term fibromyalgia is used here to indicate an individual who satisfies the American College of Rheumatology (ACR) fibromyalgia criteria.6 In taking the schizoid position of writing about a condition that may not exist, we ask the reader to remember that “… all models are wrong; the practical question is how wrong do they have to be to not be useful,”7 a judgment we leave to the reader. Fibromyalgia is a bitterly controversial disorder. What is it about fibromyalgia, asked White,8 that provokes such venom and ire? Rarely, if ever, written about, but often spoken about within small groups of physicians and medical workers, fibromyalgia patients are often identified and characterized by unusual behaviors and psychological characteristics. Barsky and Borus9 characterize fibromyalgia as one of a group of “functional somatic syndromes.” Individuals with such syndromes: … share similar phenomenologies, high rates of cooccurrence, similar epidemiologic characteristics, and higher-than-expected prevalences of psychiatric comorbidity …. Suffering … is exacerbated by a self-perpetuating, self-validating cycle in which common, endemic, somatic symptoms are incorrectly attributed to serious abnormality …. The climate surrounding functional somatic syndromes includes sensationalized media coverage, profound suspicion of medical expertise and physicians, the mobilization of parties with a vested self-interest in the status of functional somatic syndromes, litigation, and a clinical approach that

overemphasizes the biomedical and ignores psychosocial factors …. These influences exacerbate and perpetuate the somatic distress of patients …, heighten their fears and pessimistic expectations, prolong their disability, and reinforce their sick role.9 To a large extent, the “venomous”8 opposition to fibromyalgia comes from opposition to the idea of characterizing this particular functional somatic syndrome as a “disease.”

HISTORICAL DEVELOPMENT Attempts to characterize and diagnose fibromyalgia have gone through several changes in conceptualization. The earliest roots of fibromyalgia can be found in the 19th century perception of abnormal connective tissue and muscles. In various forms, this concept held sway until the late 1970s, when a new emphasis on sleep disturbance and tender points led to proposed clinical criteria that included sleep disturbance and tenderness to palpation at 12 of 14 selected sites.10 In the early1980s, most of the other fibromyalgia-associated symptoms were identified, and criteria were proposed that combined these symptoms with tenderness. With the publication of the ACR criteria in 1990,6 opposition to fibromyalgia increased and has continued until the present.11-17 Among proponents, fibromyalgia was characterized first as an “affective symptom disorder”18,19 and later as the result of “… aberrant central pain transmission … [in which] purely behavioral or psychological factors are not primarily responsible for the pain and tenderness ….”20 This view is held by proponents in rheumatology and pain specialties; however, different views predominate in epidemiology, physical medicine, and psychiatry.

FIBROMYALGIA DEFINITIONS AND PROBLEMS In 1990, the ACR criteria for fibromyalgia were published (Table 38-1 and Fig. 38-1).6 They defined fibromyalgia as being present in patients who had “widespread pain” and tenderness at 11 of 18 tender point sites. The criteria rapidly came under attack. For individuals who did not believe in fibromyalgia as an entity, the criteria represented the false codifications of symptoms and the establishment of a nondisease.11-16 A second set of criticism addressed the circularity of the ACR criteria study, arguing that because the authors approached the study from the point of view of tender points, they could not fail to find that tender points were important.17 Later, epidemiologic and clinical studies showed that the fibromyalgia criteria identified a cut-point along a pain-distress continuum, rather than identifying a discrete entity.1-5 Despite these objections, the criteria and the underlying definition gained wide support. 555

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Table 38-1  1990 AMERICAN COLLEGE   OF ­RHEUMATOLOGY CRITERIA FOR   THE CLASSIFICATION OF FIBROMYALGIA* 1. History of widespread pain Definition: Pain is considered widespread when all of the following are present: pain in the left side of the body, pain in the right side of the body, pain above the waist, and pain below the waist. In addition, axial skeletal pain (cervical spine or anterior chest or thoracic spine or low back) must be present. In this definition, shoulder and buttock pain is considered as pain for each involved side. Low back pain is considered lower segment pain. 2. Pain in 11 of 18 tender point sites on digital palpation Definition: Pain, on digital palpation, must be present in at least 11 of the following 18 tender point sites:   Occiput: bilateral, at suboccipital muscle insertions   Low cervical: bilateral, at anterior aspects of intertransverse spaces at C5-C7   Trapezius: bilateral, at midpoint of upper border   Supraspinatus: bilateral, at origins, above the scapula spine near the medial border   Second rib: bilateral, at second costochondral junctions, just lateral to junctions on upper surfaces   Lateral epicondyle: bilateral, 2 cm distal to epicondyles   Gluteal: bilateral, in upper outer quadrants of buttocks in anterior fold of muscle   Greater trochanter: bilateral, posterior to trochanteric prominence   Knees: bilateral, at medial fat pad proximal to joint line Digital palpation should be performed with an approximate force of 4 kg For a tender point to be considered “positive” the subject must state that the palpation was painful; “tender” is not to be considered painful *For classification purposes, patients are said to have fibromyalgia if criteria 1 and 2 are satisfied. Widespread pain must have been present for at least 3 months. The presence of a second clinical disorder does not exclude the diagnosis of fibromyalgia.6 From Wolfe F, Smythe HA, Yunus MB, et al: The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia: Report of the Multicenter Criteria Committee. Arthritis Rheum 33:160-172, 1990.

Although the ACR criteria are classification criteria that are designed for use in research studies, they do not include many of the central symptoms of the syndrome. The dominant symptom of fibromyalgia in the ACR criteria study, but one not included in the criteria,6 was identified by the question, “Do you hurt all over?” In addition, some individuals who do not satisfy the ACR criteria seem to have fibromyalgia, which can be identified by clinical criteria in individuals with less than 11 tender points in the presence of characteristic fibromyalgia symptoms21; there is evidence that clinicians endorse this broader definition in their practices. In the ACR criteria study, various candidate definitions of criteria performed almost as well as the official criteria.6 One might conclude that the ACR criteria represent a manageable definition of fibromyalgia, perhaps for research studies, but only an incomplete and approximate definition for clinical care. There are other problems with diagnosis and definition by ACR criteria. Using the continuum of tender points as the central diagnostic variable, not only does an individual with 10 tender points not satisfy the diagnostic criteria, but also an individual who has 11 tender points during one examination and 10 tender points at the next examination has fibromyalgia at the first examination and does not have fibromyalgia at the latter examination. Such a use

Figure 38-1  Tender point sites of the 1990 American College of Rheumatology criteria for fibromyalgia. (From Wolfe F, Smythe HA, Yunus MB, et al: The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia: Report of the Multicenter Criteria Committee. Arthritis Rheum 33:160-172, 1990.)

of ­ diagnostic criteria is inconsistent with other rheumatic disease criteria and is not workable clinically. In clinical practice, however, when an individual is diagnosed with fibromyalgia, the diagnosis devolves to permanency. Clinicians who use the term fibromyalgia generally mean that the individual has fibromyalgia traits—pain and fatigue, which may vary in intensity from time to time and in response to stressors—and that fibromyalgia behaves as if it were a “trait,” not a state, a type of response to known or unknown stressors. From the point of view of clinical diagnosis and care, an individual who satisfies the criteria at one time generally can be considered to have fibromyalgia even when not subsequently satisfying the criteria.

OBJECTIONS TO THE CONCEPT OF FIBROMYALGIA There are a number of interrelated objections to ­fibromyalgia. The first is that what is called fibromyalgia is a nondisease, merely the end of a pain-distress continuum. The ­contrary

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view, expressed directly or acquiesced to, sees fibromyalgia as a disease, rather than as a collection of symptoms. This ­fundamental disagreement is called into view when patients ask, “Is it my fibromyalgia that causes me to be so tired (or to have any one of many symptoms)?” Clinicians who act as if fibromyalgia is a disease would answer, “Yes”; the objectionists, “No.” Stated slightly differently, “Do I have pain because I have fibromyalgia or do I have fibromyalgia because I have pain?” Individuals who object to the fibromyalgia concept go further. They see the term fibromyalgia as part of the problem. Use of the term de facto, even if not intended, results in fibromyalgia being seen or treated as a disease.12,13 There are consequences to treating a nondisease as a disease according to fibromyalgia opponents12,13: Fibromyalgia symptoms are seen as manifestations of a disease and subject to compensation for disability and injury; various traumas can “cause” this disease; individuals whose predominant problem is psychosocial distress can have their symptoms designated as a disease; insurance costs increase; court decisions institutionalize fibromyalgia; support groups multiply in support of this nondisease; medical practitioners spring up to treat nonillness, and pharmaceutical companies market drugs for its treatment. These problems are exactly those that Barsky and Borus9 identified as associated generally with “functional somatic syndromes.” Clinically, fibromyalgia seems to represent a cut-point along a continuum of pain, fatigue, and other symptoms in which “patients” with high-intensity symptoms (Fig. 38-2) and increased symptom prevalence can be found (Fig. 38-3). Observations similar to these are found in epidemiologic studies and may be summed up in this observation: “The evidence that fatigue is dimensionally distributed in the community, and that no cut-off exists to separate normal from abnormal fatigue, is overwhelming.”5 In addition, fibromyalgia overlaps with chronic fatigue and “… ­virtually

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EVALUATION OF GENERALIZED AND LOCALIZED SYMPTOMS

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every other medically unexplained syndrome, including tension headache, chemical sensitivity, irritable bowel syndrome, atypical chest pain, gynaecological syndromes, ­temporomandibular disorders, and mitral valve prolapse.”5

EPIDEMIOLOGY Fibromyalgia is diagnosed more frequently in women (9:1 ratio). Using ACR criteria, the prevalence of fibromyalgia in the adult general population is generally similar across the world. The prevalence of fibromyalgia in Wichita, Kansas, was 3.4% (95% confidence interval [CI] 2.3, 4.6) among women, 0.5% (95% CI 0.0, 1.0) among men, and 2% (95% CI 1.4, 2.7) overall22; among women in New York City, it was 3.7% (95% CI 3.2, 4.4).23 In Ontario, Canada, the estimated prevalence was 4.9% (95% CI 4.7, 5.1) among women, 1.6% (95% CI 1.3%, 1.9%) among men,24 and 3.3% (95% CI 3.2, 2.4) overall. The prevalence of fibromyalgia in these studies increased with age until about age 70, after which it decreased slightly. Outside of North America, reports indicate the prevalence in Bangladesh was 5.3% to 7.5% in women and 0.2% to 1.4% in men25; in North Pakistan, it was 2.1% overall26; in Italy, it was 2.2% (95% CI 1.4-3.2)27; in Turkey, it was 3.6% (95% CI 2.8-4.4) for ages 20 to 6428; in Brazil, it was 2.5% (95% CI 1.97-3.12)29; and in Southwest Sweden, it was 1.3% (95% CI 0.8-1.7).30 The prevalence of fibromyalgia in children in three studies was 1.2%,31 1.4%,32 and 6.2%.33 At a follow-up time of 1 year, approximately 25% of individuals meeting ACR criteria initially still satisfied the criteria.32,34 These data should not be interpreted as evidence of prognosis because some individuals not meeting criteria initially meet them at the 1-year follow-up. Instead, the data suggest that the concept of fibromyalgia in children may be dubious, particularly when dependent on tender point assessment.

Figure 38-2  A fibromyalgia pain diagram as completed in the clinic.

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Probability of sleep disturbance

Probability of parasthesias

1 .8 .6 .4 .2 0 0

2

4

6

8

.8 .6 .4 .2 0

10

0

2

Symptom intensity scale Probability of memory problem

Probability of depression

.8 .6 .4 .2 0 0

2

4

6

4

6

8

10

8

10

Symptom intensity scale

8

10

.8 .6 .4 .2 0 0

2

4

6

Symptom intensity scale Symptom intensity scale Figure 38-3  Graphs of characteristic fibromyalgia-type symptoms as a function of symptom intensity (SI) scale values, adjusted for age and sex. Predicted values and their 95% confidence intervals are generated by running line smooths of the symptom variable on SI scale, adjusted for age and sex. The vertical lines define the 5% and 95% confidence intervals for having and not having fibromyalgia by survey fibromyalgia criteria. The SI scale is combined measure of the extent of regional pain and the intensity of fatigue. (Modified from Wolfe F, Rasker JJ: The symptom intensity (SI) scale, fibromyalgia, and the meaning of fibromyalgia-like symptoms. J Rheumatol 2006; 33:2291-2299.)

The prevalence of fibromyalgia is generally greater in clinical settings than in epidemiologic studies. It was noted to be 5.7% in general medical clinics35 and 2.1% in family practice settings.36 In rheumatology clinics, fibromyalgia prevalence was expectedly higher: 12%37 to 20%38 of new patients.

ETIOLOGY AND PATHOPHYSIOLOGY Many theories have been proposed for fibromyalgia, but neither etiology nor the pathophysiologic mechanisms are known, and no model explains more than a little of the available data. In addition, because fibromyalgia symptoms are distributed as a continuum, pathophysiologic investigations that consider fibromyalgia as a discrete entity to be compared with “normal” controls distort the importance and understanding of observed mechanisms. Theories have shifted over time from peripheral pathology (muscles and insertions) to central dysfunction (pain processing), and from unicausal to multicausal hypotheses. It is likely that many mechanisms play overlapping roles in the pathophysiology of fibromyalgia symptoms. Central mechanisms, suggested by the presence of sleep disturbance, blunted stress response, hyperalgesia, and the diffuse nature of fibromyalgia pain, have been reviewed in detail.39-44 MUSCLES AND MICROTRAUMA Originally thought to be important in pathogenesis, muscle and tendon disorders have fallen out of favor because they do not explain adequately the systemic symptoms of fibromyalgia. In addition, changes found in muscle biopsy ­specimens are nonspecific, consistent with many types of muscle damage, ranging from ischemia to simple deconditioning, and are not different from changes found in individuals without fibromyalgia.

PSYCHOSOCIAL FACTORS Psychosocial factors, which include reduced education, nonmarried status, lower household income, smoking, and obesity, have been identified in many studies. GENETIC AND FAMILIAL FACTORS Fibromyalgia aggregates in families.45,46 Genetic factors may predispose individuals to fibromyalgia. A possible genetic linkage in the HLA region has been reported, based on sibship analysis.47 Patients with chronic widespread pain and fibromyalgia have been found to have low gene expression for the proinflammatory cytokines interleukin-4 and interleukin-10 and reduced levels of serum concentrations compared with controls. These findings might indicate a role for cytokines in the pathophysiology of fibromyalgia or as a sequela of chronic pain and its treatment.48 SLEEP DISTURBANCE Fibromyalgia patients often report unrefreshing and nonrestorative sleep.49 Electroencephalographic abnormalities initially were thought to play a major role in the pathogenesis of fibromyalgia, but it is now clear that such abnormalities are nonspecific findings. Sleep electroencephalographic studies show abnormalities of delta wave or stage 4 sleep by repeated alpha wave intrusion. Similar abnormalities are found in healthy individuals, and in individuals with emotional stress, fever, osteoarthritis, rheumatoid arthritis, and Sjögren’s syndrome. STRESS-RELATED NEUROENDOCRINE DYSFUNCTION Stress responses and endocrine axes are disturbed in fibromyalgia, but many of these changes are commonly seen in patients who have known external sources of ­chronic pain.

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It is unclear whether these endocrine disturbances in fibromyalgia are primary to the disorder or are secondary to the pain or distress associated with fibromyalgia. Patients with fibromyalgia report more past stressful life events and more daily stressful hassles than patients with rheumatoid arthritis or pain-free healthy controls. Similarly, fibromyalgia is associated with increased reports of virus infections and traumas preceding fibromyalgia and a higher frequency of sexual abuse in childhood. Work-related psychological factors such as work demands and factors such as job control, social support, and psychological distress are associated with reporting of musculoskeletal pain, particularly when pain is reported at multiple sites.50 PRIMARY NEUROENDOCRINE DYSREGULATION Primary neuroendocrine dysregulation found in fibromyalgia can be divided into changes in the two major stress systems, the hypothalamic-pituitary-adrenal axis and the autonomous nervous system. In fibromyalgia, almost all hormonal feedback mechanisms controlled by the hypothalamus are disrupted. After stimulation of the hypothalamic-pituitary-adrenal axis with exogenous corticotrophin-releasing hormone or by insulin-induced hypoglycemia, an exaggerated pituitary adrenocorticotropic hormone release has been observed with relative adrenal hyporesponsiveness.51 Serum thyroid hormone levels are normal, but after intravenous injection of thyrotropin-releasing hormone, patients with primary fibromyalgia responded with a significantly reduced secretion of thyrotropin and thyroid hormones.52 Growth hormone is secreted during stage 4 sleep and is important for muscle repair and strength. Low levels might explain extended periods of muscle pain after exertion in fibromyalgia patients. Serum growth hormone levels and levels of somatomedin C (insulin-like growth factor-I) have often been reported to be low, but results are inconsistent.53 It is possible that physical deconditioning, related to avoidance of physical activities because of pain, could lead to more fatigue, stiffness, and, via altered growth hormone metabolism, sleep disturbance. AUTONOMOUS NERVOUS SYSTEM Sympathetic function in fibromyalgia patients has been reported as low, normal, or functionally high. There is a derangement of sympathetic tone and reaction in some patients, being high or low, depending on the situation. One explanation for this finding may be that most studies did not control for physical activity levels of participants.54 It also has been suggested that fibromyalgia is a generalized form of reflex sympathetic dystrophy.55 ABNORMAL PAIN PROCESSING There are major differences between the sexes with respect to analgesic responses, across all animal species. This may explain the decreased pain tolerance in women with fibromyalgia compared with men. Patients with fibromyalgia have reduced pain tolerance to stimuli that are normally not painful, such as pressure, heat, and electric pulse, at the classic tender points and control points (allodynia). They also perceive pain as being more intense and extending for a longer time (hyperalgesia).

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This abnormal sensory pain processing could be explained by increased pain facilitation and reduced pain-inhibiting mechanisms on the spinal and cerebral levels. Fibromyalgia patients also displayed abnormal temporal summation of pain after a series of thermal stimulations, called “wind-up.”56 The concentration of substance P, a neuromodulator of pain, in the cerebrospinal fluid was threefold greater in fibromyalgia patients than in controls. Substance P may play a role in spreading of muscle pain. This elevation of substance P is not specific to fibromyalgia, however, and has been shown in patients with pain due to other causes. Measures of pain intensity in fibromyalgia patients are correlated with levels of metabolites of the excitatory amino acid neurotransmitters glutamate and aspartate. Sensitization of nociceptive neurons in the spinal dorsal horn by hyperexcitable receptors, such as the glutamate receptor N-methyl-d-aspartate, could be one of the mechanisms responsible for pain in fibromyalgia.44 DECREASED PAIN INHIBITION Pain inhibitory pathways, descending from the cortex, limbic system, hypothalamus, thalamus, and brainstem, modulate the activity of spinal nociceptive neurons. In fibromyalgia patients, regional blood flow seems to be reduced in the most important pain processing areas in the brain, the thalamus and caudatum, compared with controls.57 Serotonin is a neurotransmitter in the descending inhibitory pathways that inhibits release of substance P and excitatory amino acids from the terminals of primary afferent neurons. Serotonin also regulates NREM sleep. Low levels of serotonin metabolites have been reported in the cerebrospinal fluid and serum of patients with fibromyalgia and low back pain.44 Serotonin antibodies are found in fibromyalgia patients four times as frequently as in controls, but have no diagnostic relevance.58 The role of serotonin in the pathophysiology of fibromyalgia is unclear. Drugs that affect serotonin metabolism or action do not have a dramatic effect. PSYCHOLOGICAL ABNORMALITIES There has been disagreement as to whether psychiatric abnormalities represent reactions to chronic pain, or whether the symptoms of fibromyalgia are a reflection of psychiatric disturbance. Psychiatric disorders may interact with the neuroendocrine system as part of a stress reaction.59 The most common psychiatric conditions observed in patients with fibromyalgia include depression, dysthymia, panic disorder, and simple phobia.60 In the National Data Bank for Rheumatic Diseases,61 64% of patients report prior depression, and 8% report mental illness. Fibromyalgia also occurs in patients without significant psychiatric problems, however. Some individuals with fibromyalgia satisfy the American Psychiatric Association criteria for somatoform disorders (DSM 307.80 and 307.89).62 CLINICAL FEATURES Fibromyalgia is characterized by high levels of pain, sleep disturbance, and fatigue combined with a general increase in medical symptoms (Table 38-2), including problems of memory or thinking, and often ­ psychological distress.63

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Table 38-2  Prevalence of Specific Symptoms   among 2784 Patients with Fibromyalgia in   the National Data Bank for Rheumatic Diseases

Fibromyalgia probability

%

Sleep problems

89.1

Fatigue or tiredness

88.6

Muscle pain

85.2

Muscle weakness

70.2

Paresthesias

67.6

Cognitive problems

66.3

Headache

64.7

Dry mouth

53.3

Insomnia

51.8

Easy bruising

49.1

Dry eyes

47.5

Depression

47.5

Blurred vision

47

Irritable bowel syndrome

46.3

Heartburn

44.4

Itching

44.3

Dizziness

42.1

Constipation

41.9

Pain/cramps in abdomen

41.5

Ringing in ears

41.4

Pain in upper abdomen

40.3

Nervousness

39.7

Nausea

37.7

Diarrhea

33.6

Shortness of breath

32.3

Hearing difficulties

29.8

Hair loss

23.6

Oral ulcers

22.4

Wheezing

21.4

Loss of appetite

21.1

Raynaud’s phenomenon

20.1

Chest pain

19.2

Rash

17.1

Sun sensitivity

16.7

Loss/change in taste

14.4

Fever

13.4

Hives/welts

9.3

Vomiting

9.1

Seizures

1.7

I­ ndividuals with this syndrome are unusually sensitive to digital pressure (tender points) in certain body areas. Clinically, fibromyalgia is often identified or suspected by the inexplicability and severity of symptoms and by their number. The most common defining symptom is that of generalized pain (“pain all over”).6 The clinician may be surprised by the extent and severity of symptoms (see Table 38-2 and Fig. 38-2) and surprised at unexpected emotional distress (see Fig. 38-2). Fibromyalgia has a quality of inexplicability and unexpectedness.

.8 Probability of Fibromyalgia

Symptom

1

.6

.4

Symptom count

.2

0 0

10

20

30

40

Symptom count (0-37) Figure 38-4  The relationship between fibromyalgia diagnosis and the count of somatic symptoms in 2613 fibromyalgia patients and 3525 ­patients with other noninflammatory disorders. (From the National Data Bank for Rheumatic Diseases, 2006.)

Upper and lower back pain is the most common pain problem (>80%). Many patients, at the clinical interview, emphasize only a few areas of pain. Questions specifically directed to other areas may elicit reports of pain that were not stated spontaneously. Patients with fibromyalgia may complain of greater pain in an osteoarthritic joint than patients without fibromyalgia. Although musculoskeletal pain is central to fibromyalgia, patients may be more concerned about fatigue or memory problems. Fibromyalgia patients perform more poorly in formal cognitive testing than age-matched controls.64 In the National Data Bank for Rheumatic Diseases in 2006, 66% of 2784 fibromyalgia patients complained of memory or thinking problems compared with 31% of 24,479 patients with other rheumatic conditions. The most common symptoms, found in more than two thirds of patients, are sleep problems, fatigue, muscle pain, paresthesias, and cognitive problems (see Table 38-2). In addition, the prevalence of other important symptoms is as follows: headache 65%, depression 48%, and irritable bowel syndrome 46% (see Table 38-2). A high count of symptoms is characteristic of fibromyalgia and is frequently a key to diagnosis (Fig. 38-4). Fibromyalgia also is associated with increased reporting of comorbid conditions.65 The typical picture of fibromyalgia emphasizes certain symptoms (pain, fatigue, sleep disturbance, cognitive problems) and an abundance of symptoms and comorbidities. Given the high levels of symptom variables and membership at the tail of the pain-distress continuum, it is not surprising that evidence of psychosocial disruption is found. Considered as a whole, patients with fibromyalgia have less education and household income than individuals without fibromyalgia. They are less likely to be married, and they have greater rates of lifetime psychiatric illness.66

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Fibromyalgia occurs frequently in other rheumatic disorders, including rheumatoid arthritis, osteoarthritis, and systemic lupus erythematosus, in which the prevalence of fibromyalgia exceeds 20%. The clues to identifying fibromyalgia in the presence of other painful disorders are location of pain (nonarticular), continued pain and distress despite objective improvement, and unusual fatigue.

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Scale combines the Regional Pain Scale and a VAS fatigue scale to quantitate fibromyalgia symptom intensity.2 PHYSICAL MEASURES

No laboratory or imaging tests are routinely helpful or ­indicated in the diagnosis or management of fibromyalgia.

With the exception of the performance of the tender point examination, the physical examination of a patient suspected to have fibromyalgia does not differ from the examination of any other rheumatic disease patient or pain patient. Measurement of pain threshold by the tender point examination is the only routinely useful physical measurement. Although helpful for diagnosis (see Table 38-1 and Fig. 38-1), the tender point count is poorly correlated with other fibromyalgia symptoms and with change in symptom severity among fibromyalgia patients.78 Patients may improve or worsen substantially without important differences in the tender point count.

SELF-REPORT MEASURES

How to Perform the Tender Point Examination

Symptom severity, physical function, and work status are the key status and outcome variables in fibromyalgia, as in other rheumatic disorders. Assessments that can be useful routinely to clinicians include measurements of pain, fatigue, physical function, sleep quality, anxiety, depression, and work status. As a minimum, assessments should include visual analog scales (VAS) for pain and fatigue and a measure of functional status. Function can be assessed by one of the family of health assessment questionnaires, including the Health Assessment Questionnaire (HAQ),67 the Health Assessment Questionnaire–II (HAQ-II),68 and the Multi-Dimensional Health Assessment Questionnaire (MDHAQ).69 The HAQ is a 33-item questionnaire; the function scale of the HAQ-II and MDHAQ is a 10-item questionnaire. Scales for the assessment of anxiety, depression, and sleep disturbance also can be added.70,71 For simplicity and ease of administration, however, we recommend VAS assessments of pain and fatigue and either the HAQ-II or MDHAQ. The Fibromyalgia Impact Questionnaire (FIQ) is a widely used 20-item research assessment scale that addresses all of the key fibromyalgia variables and can be used in clinical care.72,73 The limitation of the FIQ is that it is suitable only for use in fibromyalgia patients, whereas the above-mentioned health assessment questionnaires are useful and have been used across the entire range of rheumatic disorders. In addition, the FIQ total scale has no simple interpretation. Functional questionnaire results have reduced validity among fibromyalgia patients. Compared with patients with rheumatoid arthritis and ankylosing spondylitis, there was striking discordance between observed and questionnairereported activities in patients with fibromyalgia.74 This discordance limits slightly the usefulness of functional questionnaires and alters their interpretation: Results may represent perceived rather than actual functional difficulties.

Fibromyalgia patients have a lower threshold for pain than do subjects without fibromyalgia.79 In the clinic, two methods exist by which tenderness can be elicited and measured21—digital palpation and dolorimetry.80 Tender point sites represent specific areas of muscle, tendon, and fat pads that are much more tender to palpation than surrounding sites. Sites selected as part of ACR criteria6 represent tender point sites that best discriminate between patients with and without fibromyalgia. To test for pain with digital palpation, the ACR criteria indicate that the examiner should press the tender point site with an approximate force of 4 kg. Usually the second and third fingers or the thumb is used for palpation, and a rolling motion is helpful in eliciting tenderness. The amount of force that the examiner uses is important because a large force would elicit pain in a subject without fibromyalgia, whereas a small force may miss tenderness. Because the 4-kg force requirement is a theoretic goal, and difficult to implement, clinicians need other guidelines for determining the amount of pressure to use. A good method for determining this is to palpate “normal” individuals of the same build and stature. The amount of force that does not elicit tenderness in an individual without fibromyalgia (just below the pressure pain threshold) is the correct force to use. In practice, less force is required in smaller, thinner, less muscled individuals. More force is needed in heavier and more muscular individuals. The pressure used by the examiner and the examiner’s interpretation of the patient’s response can influence results of palpation. The best and most appropriate way to perform the tender point count is to ask the patient if the palpation is painful,6 accepting only a “yes” as a positive reply, regardless of facial expression or body movement. Specifically, the frequently heard comment of patients to the digital examiner’s question regarding pain, “It’s tender,” is a negative rather than a positive response, and best should be followed by another question, such as, “Yes, but is it painful?”

ASSESSMENT OF A PATIENT WITH FIBROMYALGIA LABORATORY AND IMAGING TESTS

Research Questionnaires Almost any generic research scale is suitable for use in fibromyalgia, including commonly used scales such as the Medical Outcomes Scale Short-Form 36 (SF-36).75,76 Two fibromyalgia-related scales may be of special interest. The Regional Pain Scale is a questionnaire assessment of the number of painful nonarticular body regions.77 The Symptom Intensity

Limitations to the Tender Point Examination Although the tender point examination can provide clinically useful information when properly performed, it can be influenced by external factors. Physicians who believe the patient does or does not have fibromyalgia can influence the results by

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the amount of pressure applied. The meaning and use of the examination are widely known among physicians, patients, and patient support groups; in some circumstances where a positive or negative examination would seem to be desirable (e.g., in a disability or medicolegal examination), results might differ from those obtained during a routine examination. In addition, the tender point examination is inherently inaccurate around the “diagnostic” tender point count of 11. DIAGNOSIS The approach to fibromyalgia diagnosis should differ according to the setting and the physician’s underlying beliefs about fibromyalgia acceptability. Because of the limitations of the ACR criteria with respect to sensitivity and accuracy, clinical criteria may be the best method for diagnosis in the clinical setting because they consider all aspects of fibromyalgia, rather than just the number of tender points.21 Clinical criteria require 2 of 3 tender points of widespread pain, � 11 tender points, and characteristic fibromyalgia symptoms. The ACR criteria are a reasonable but not required alternative in the clinic.6 A diagnosis of chronic pain syndrome or the recognition of the presence of a chronic pain syndrome in the context of another illness also is sufficient as a diagnosis. Clinical trials require use of the ACR criteria.6 It is usually the case that patients with fibromyalgia have to satisfy the ACR criteria at the time of entry into the study whether or not they satisfied the criteria previously. In that respect, the ACR criteria represent not only a diagnostic method, but also a measure of severity because of the requirement for current high levels of tender points. You cannot improve and still have fibromyalgia according to the ACR criteria. The ACR criteria also present a problem for epidemiologic research because they require physical examination of any individual satisfying the widespread pain criterion. Such studies are complex and expensive to perform. In addition, they have the potential of bias that many “healthy” people would not voluntarily undergo a physical examination. The extent or importance of this bias is unknown. ACR criteria cannot be used in studies where physical examination is impossible, such as survey-based observational studies. Survey fibromyalgia criteria have been described and seem to work as well as ACR criteria.81 These criteria require high levels of fatigue and widespread pain, using a continuous scale for each measure. Survey criteria have an added advantage in the research setting, in that a clinical diagnosis is not required for their use; patients can be studied without labeling the subjects with a diagnosis. Diagnostic criteria also cause problems for physicians who recognize fibromyalgia symptoms, but disagree with the legitimacy or consequences of a diagnosis of fibromyalgia. Because there are no data to suggest that “correctly” diagnosing fibromyalgia improves treatment or outcome, formal diagnosis of fibromyalgia is unnecessary as long as fibromyalgia symptoms are recognized. PRIMARY, SECONDARY, AND SECONDARYCONCOMITANT FIBROMYALGIA Fibromyalgia is sometimes divided into primary, secondary, and secondary-concomitant fibromyalgia. The term primary fibromyalgia is most often used when there is not another

condition present whose symptoms could explain fibromyalgia symptoms. This division between primary and secondary fibromyalgia is artificial, however. Back pain in older individuals when age-related radiographic changes are present might be considered secondary fibromyalgia, whereas the same symptoms in younger individuals might be considered primary fibromyalgia. The ACR criteria study showed no difference between primary and secondary fibromyalgia with regard to symptoms and diagnosis.6 The usefulness of primary fibromyalgia occurs in clinical trials, in which it is desirable to be sure that symptoms are not coming from another well-established illness. A fibromyalgia diagnosis implies understanding of issues such as pain, fatigue, sleep, and cognitive and emotional problems. When fibromyalgia is considered only in patients without other musculoskeletal conditions, the “benefit” of fibromyalgia diagnosis—its consideration of such issues—is lost. If fibromyalgia is to be diagnosed or considered, such consideration should be applied to all patients. DIFFERENTIAL DIAGNOSIS Fibromyalgia is more frequently present in individuals with identifiable medical disorders than in individuals without such disorders. It is virtually never the case that there is a differential diagnosis problem between fibromyalgia and another medical disorder. When diagnosis is problematic, it is because the other medical condition is difficult to diagnose or has not been evaluated properly. It is not a case of fibromyalgia or lupus, but rather fibromyalgia and lupus. Disorders sometimes thought to be difficult to separate from fibromyalgia include early rheumatoid arthritis, systemic lupus erythematosus, polymyositis, hypermobility syndromes, and endocrine disorders. In each of these cases, the clue to understanding the patient’s illness is thoroughly evaluating the patient.

MANAGEMENT OF FIBROMYALGIA—RESEARCH STUDIES AND RECOMMENDATIONS Most long-term observational studies do not show improvement in fibromyalgia symptoms and outcomes, even when patients are followed in centers with special interest and knowledge of fibromyalgia.82,83 Service utilization (a measure of symptom activity) does not lessen after diagnosis.84 Benefit of treatment is generally not sustained in long-term randomized clinical trials.85 These data should be kept in mind when evaluating the results of clinical trials. The null hypothesis for a chronic, painful disorder should not be no short-term treatment effect, but instead no long-term treatment effect. Short-term studies should be regarded with suspicion, and most fibromyalgia studies are short-term. Compliance with treatment prescription is an important problem in fibromyalgia, and in fibromyalgia clinical trials, the dropout rate is high. Even when intention-to-treat analyses are performed, the effectiveness of treatment is overestimated. Patients who follow exercise recommendations have better outcomes than patients who do not; however, most patients in clinical practice do not or will not perform aerobic exercises. It is fair to conclude that ­exercise prescription is often an ineffective ­recommendation, rather than concluding that it is an effective treatment.

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Treatments without a true, contemporaneous control group cannot provide meaningful estimates of efficacy because they often exaggerate efficacy. In evaluating study results, the degree of improvement must be examined, and the degree of improvement must be clinically meaningful. Even when improvement is clinically meaningful, the baseline and final outcome values, such as values of pain and fatigue, must be considered. If the patients are selected for trials in relative (temporary) flare conditions, they may improve, but still have very high levels of the outcome variables at the conclusion of the trial. Numerous useful reviews of treatment in fibromyalgia are available.86,87 Most such reviews rely on the concept of efficacy and rank evidence as a function of study quality. One review indicates that “Evidence for treatment efficacy was ranked as strong (positive results from a meta-analysis or consistently positive results from more than 1 randomized controlled trial [RCT]), moderate (positive results from 1 RCT or largely positive results from multiple RCTs or consistently positive results from multiple non-RCT studies), and weak (positive results from descriptive and case studies, inconsistent results from RCTs, or both).”86 As noted by these authors, studies are needed “… to determine whether the improvement is maintained over months or years.” To which we would add, not only maintenance of improvement, but also maintenance of meaningful improvement and nondiscontinuation of treatment. Still another problem with the interpretation of fibromyalgia studies relates to study scales. Because patients diagnosed as having fibromyalgia have problems with pain, fatigue, cognition, and anxiety and depression, to name some issues in fibromyalgia, different studies may select different scales and outcomes according to the interests of the investigators. This leads to problems in comparing study results. In addition, when multiple outcomes and study instruments are selected, frequently studies can show positive results for one outcome and negative results for another. Even when an outcome such as pain is being measured, if there is more than one pain scale, positive results may be found with one pain scale and not with another. Complex scales also are difficult to interpret, as is the case with the commonly used FIQ total scale. This composite summary scale has no simple interpretation: A reader may note an improvement, but not have a clear idea of what such improvement means. From 6750 fibromyalgia patients screened in the National Data Bank for rheumatic diseases, the mean (standard deviation) VAS pain and fatigue scores were 6.3 (2.5) and 7.0 (2.5). As an aid in interpreting effect sizes, the following data are presented; assuming a baseline score of 7.0, the following are the effect size, change score, post-treatment score, and percent improvement: 0.3, 0.75, 6.25, 10.7%; 0.4, 1.25, 6.0, 14.3%; 0.5, 1.25, 5.75, 17.9%; 0.6, 1.5, 5.5, 21.4%. DIAGNOSIS Diagnosis may be an important aspect of treatment. Diagnosing fibromyalgia in individuals with short-term stressrelated illnesses is harmful and leads to prolonged illness and medicalization. There is no valid evidence to support the assertion that diagnosis of fibromyalgia in patients with long-term symptoms has a salutary effect. A study of primary care patients in the United Kingdom reported that

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“… patients who had been diagnosed as having [fibromyalgia] reported higher rates of illness and health care resource use for at least 10 years prior to their diagnosis, which suggests that illness behavior may play a role …. Diagnosis has a limited impact on health care resource use in the longer term, possibly because there is little effective treatment.”84 There is no evidence at the patient level that diagnosis is harmful. Using the diagnostic term in the presence of severe symptoms often makes it easier for physicians and patients to discuss the condition; when fibromyalgia is not diagnosed, patients sometimes ask directly, “Do I have fibromyalgia?” In considering making the diagnosis of fibromyalgia, the physician should consider the following comment by Barsky and Borus:9 “The hyperbole, litigation, compensation, and selfinterested advocacy surrounding the functional somatic syndromes can exacerbate and perpetuate symptoms, heighten fears and concerns, prolong disability, and reinforce the sick role. Excessive medical testing and treatment expose patients to iatrogenic harm and amplify symptoms.” If fibromyalgia is “diagnosed,” however, it is important to be clear to the patient that fibromyalgia is a name given to the symptoms, not a cause of the symptoms. EDUCATION Education in some reports may have a modest effect on fibromyalgia symptoms, such as fatigue, anxiety, and depression, but has limited to no effect on pain.88,89 What is called education is actually composed of two components—­education and rapport or engagement—and it is impossible to distinguish the two components. Most education studies are derived from formal university-based treatment programs; only one study was applicable to clinical practice,88 and the sample size was too small to evaluate the effect of the intervention in fibromyalgia. All studies had deficiencies in the validity of the control groups; there are no long-term data on the effect of education. Although it is sensible that education should always be part of any treatment program, and is part of establishing rapport, its content should depend on the patient, the duration of illness, and the diagnostic label already present. The goal of education is to help the patient understand and manage his or her symptoms optimally, reduce dependence on the medical system, and work effectively within that system when necessary. There are no data, however, as to whether, within the clinical setting, extensive education is more or less effective than limited education. In a group of 100 consecutive enrollees in a 1.5-day multidisciplinary group outpatient fibromyalgia treatment program, after 30 days a 12.8% improvement was noted in the 78 who completed the study.90 EXERCISE Aerobic exercise increases cardiovascular fitness and reduces pain and other fibromyalgia symptoms. In a short-term RCT, exercise improved aerobic performance by 16% and pain by 13%.91 A carefully done, well-powered RCT of a 12-week community-based exercise program compared with relaxation controls showed a 4% difference in FIQ scores at 1 year, but nonsignificant changes in McGill pain scores and SF-36 scores.92 At the 12-month follow-up, 38% of subjects in the exercise arm and 22% in the control arm rated

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t­ hemselves much better or very much better. Only 53% of patients attended more than half of the intervention sessions. A follow-up report at 12 months on patients who participated in a 23-week, three-times-per-week exercise program indicated general improvement compared with baseline values.93 The degree of improvement as measured by the FIQ was 5%. A Cochrane collaboration meta-analysis of “four high quality aerobic training studies” reported significantly greater improvements in the exercise groups versus control groups in aerobic performance (17.1% increase in aerobic performance with exercise versus 0.5% increase in the control groups), tender point pain pressure threshold (28.1% increase versus 7% decrease), and improvements in pain (11.4% decrease in pain versus 1.6% increase).91 A more recent noncontrolled study comparing water-based exercise with land-based exercise showed an average 36% reduction in pain.94 Exclusions in this study included 67 for work schedule incompatibility and 32 for nonspecified refusals; 60 patients were randomly assigned, and 52 completed the study. Practically, the problem with exercise prescription is that it is difficult to get fibromyalgia patients to participate. Exercise may produce “short-term increases in pain and fatigue that should abate within the first few weeks of exercising,”95 but this may be unacceptable to patients in ordinary clinical settings. Even in formal programs, adherence to exercise is poor.96,97 In a 4.5-year follow-up of a randomized trial of exercise, only 20% of patients maintained an adequate physical activity level.98 In the National Data Bank for rheumatic diseases in 2006, 24% of 2784 fibromyalgia patients reported performing some aerobic exercise weekly, but only 9% performed at levels substantial enough to result in increasing or maintaining aerobic fitness.

this trial, 48% in the active treatment group and 62% of placebo users were noncompleters in this 3-month trial. Psychotropic Agents

Cognitive behavioral therapy is a form of short-term, goaloriented psychotherapy. It has been the subject of some positive reports,99-102 some less positive reports,85,103 and some completely negative studies.104,105

Many drugs that have antidepressant and other psychotropic attributes have been used in fibromyalgia treatment. Such drugs reduce pain centrally, even in the absence of depression, and often are employed at doses that are insufficient to treat depression. Among drugs that have shown efficacy, effect sizes are in the range of 0.35 to 0.55, with pain improvement of 11% to 18% noted in short-term trials. A careful meta-analysis of the effect of amitriptyline and a review of other antidepressants was reported by Arnold and colleagues.109 The meta-analysis showed that amitriptyline had an overall effect size for all studied outcomes of approximately 0.44 and effect sizes for pain of 0.57 and for fatigue of 0.521. Of the nine amitriptyline trials studied, one lasted 26 weeks, and others lasted 3 to 12 weeks. A series of N-of-1 studies suggested that one third of fibromyalgia patients are benefited110; Arnold and colleagues109 indicated that significant clinical response to tricyclic agents was observed in 25% to 37% of patients with fibromyalgia, and that the overall degree of efficacy was modest in most studies. Similar, although slightly weaker, results are noted with cyclobenzaprine. Among newer agents, milnacipran showed efficacy in a 3-month trial.111 Duloxetine, a serotonin and norepinephrine reuptake inhibitor, generally improved symptoms and pain threshold in a 12-week RCT. Improvements included a 10% change in total FIQ score, improvement in the Brief Pain Inventory, but nonsignificant changes in FIQ pain, fatigue, and morning tiredness. Forty percent of patients did not complete the study. There is some evidence for efficacy of fluoxetine, sertraline, and venlafaxine.86 Compared with clinical trial results, results in longitudinal studies and clinical practice show marginal effectiveness of tricyclic antidepressants and similar treatments. A high-quality RCT found no difference in the response to amitriptyline and cyclobenzaprine.

PHARMACOTHERAPY

Other Pharmacologic Treatments

COGNITIVE BEHAVIORAL THERAPY

Analgesics and Nonsteroidal Anti-inflammatory Drugs Many drugs frequently used by patients diagnosed as having fibromyalgia have not been formally evaluated for efficacy or effectiveness.86 With respect to analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs), a 1998 multicenter study of 538 fibromyalgia patients noted the following usage in a 6-month period: aspirin 20.6%, NSAIDs 55.9%, acetaminophen 27.6%, opioid analgesics 6.4%, and nonopioid analgesics 21.5%.106 Tramadol use was 15%. These data are important because it is often suggested that NSAIDs are ineffective.86 A few analgesic and NSAID treatments have been for­­­ mally evaluated. Naproxen, 500 mg twice daily (n = approxi­­ mately 15), which is the only NSAID that has been studied, was indistinguishable from placebo (n = approximately 15) in a controlled clinical trial of relatively young subjects (age 48 years).107 The combination of tramadol and acetaminophen reduced pain 18.5% more than did the use of placebo.108 In

An 8-week trial of pregabalin resulted in a 13% reduction in pain compared with placebo.112 A 50% improvement was noted by 29% of the pregabalin group compared with 13% of the placebo-treated patients. The most common adverse effects were dizziness (49.9%) and somnolence (28%). Pregabalin has been approved by the U.S. Food and Drug Administration. The recommended dose is 300 to 450 mg/day. Dosing should begin at 150 mg two times per day, but may be increased after 1 week, as required. Based on the clinical trial criterion for efficacy, there is no evidence for efficacy of NSAIDs, corticosteroids, benzodiazepine and nonbenzodiazepene hypnotics, guaifenesin, melatonin, calcitonin, opioids, thyroid hormone, dehydroepiandrosterone and magnesium, or anti–tumor necrosis factor therapy.86 NONPHARMACOLOGIC TREATMENTS There is some evidence for efficacy of numerous nonmainstream treatments, including strength training91,113 and hypnosis.114 There is weak evidence for chiropractic, manual,

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and massage therapy, and no evidence of efficacy for tender or trigger point injections or flexibility exercise. Evidence for acupuncture is contradictory,115,116 as is evidence for the efficacy of biofeedback117-119 and balneotherapy.120-122 PRACTICAL RECOMMENDATIONS IN THE APPROACH TO A PATIENT WITH FIBROMYALGIA The goal of fibromyalgia treatment is to improve the physical and mental health of patients and their quality of life. This goal implies helping patients manage distressing symptoms, but with decreased dependence on the medical care system. There are no studies as to how often the simple recommendations of education, exercise, and limited pharmacologic treatment provide results at an acceptable level of symptoms and functional ability. Data from the National Data Bank for Rheumatic Diseases show, however, that 62% of 2772 fibromyalgia patients were somewhat or very dissatisfied with their health compared with 34% of 20,909 patients with rheumatoid arthritis. These data indicate that contemporary treatment of fibromyalgia is generally unsatisfactory. This high level of dissatisfaction is reflected in physician and patient interactions. An unknown but probably small proportion of rheumatology experts refuse to accept referral of fibromyalgia patients. A larger proportion is unhappy seeing such patients or is uncomfortable providing care. Patients, sensing this attitude, are equally unhappy with physicians: Patient support groups provide specific advice on finding positive, sympathetic physicians, including identifying them by name. Physician behavior results from a general uncomfortableness with illnesses that are often unresponsive to treatment and have strong psychological and psychosocial components. There is no simple resolution to this problem. Physicians who are unable to provide helpful care to patients with fibromyalgia should make that known to the patients. In considering fibromyalgia treatment, physicians should determine what resources are available in the community, and whether the resources are effective and helpful. The educational, exercise, and cognitive behavioral therapy programs described in the research studies earlier are almost never available to community physicians. Available programs may or may not be competent, appropriate, or helpful. Pain management programs sometimes mean little more than spinal blocks and “trigger point” injections, and physical therapy referral often results in treatments that are ineffective for fibromyalgia. The referring physicians should investigate the quality and outcomes of referral resources. Although the common recommendations of education, exercise, and pharmacotherapy are often appropriate, particularly in newly diagnosed cases, patients with established fibromyalgia have often experienced these recommendations and treatments. Whether such treatments have strong evidence for effectiveness or not, as measured by clinical trials, they are often not clinically effective enough, and patients return to the physician for additional suggestions and care. In circumstances such as these, Goldenberg and associates86 recommend, “Trials with selective serotonin reuptake inhibitor[s], serotonin and norepinephrine reuptake inhibitor[s], or tramadol …. Consider combination

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medication trial[s] or anticonvulsant[s].” Local injections in muscular areas of pain also are commonly employed by rheumatologists. The authors surveyed rheumatologists regarding the use of injections and found them to be used frequently, in agreement with others.86 Rheumatologists reported that patients “like injections,” but also that the rheumatologists did not know what else to do. The question arises as to how to approach a resistant patient with fibromyalgia, given the knowledge that after failure with several standard treatments, success with other medications is unlikely. Should the physician simply go from one (dubious) treatment to another? Should the physician use treatments of dubious or uncertain value? The adverse effects of inappropriate or unnecessary treatments are not inconsequential and include dependence, medicalization of common symptoms, overuse of medical care, increased costs, and side effects. The physician must be friendly and interested—a resource the patient can rely on. Testing should be limited and reserved for times when it is truly necessary to investigate comorbid conditions. Comorbid conditions, such as arthritis and obesity, should be treated because they can contribute to increasing physical and mental symptoms. The worst problem should be identified. Sometimes identifying where the pain problem began can offer clues to appropriate treatment of the coexisting condition. If many fibromyalgia treatments have been tried and have been unsuccessful, it is generally not a good idea to try even more similar, and soon to be unsuccessful, therapies. We often ask patients, “Which treatment has been most helpful,” and suggest (assuming treatment is needed and helped at all) that they return to that treatment. There is no blanket rule on the use of opioids. Experience has shown that they often do not truly help and very often cause problems. Opioids are generally not recommended. There are exceptions to this recommendation, however, and physicians should exercise clinical judgment and use opioids when they think such therapy is necessary, provided that appropriate guidelines are followed.123 “Tender points” never need injection therapy. Painful areas in muscle may respond to local injections of local anesthetics; corticosteroids are never indicated. If injections relieve pain for more than short periods of time, they may represent a reasonable therapy. In illnesses with strong psychosocial components, medically ineffective therapies can result in overall benefit to patients. The circumstances where dubious therapies might be used are limited; and the physician should understand clearly why he or she is administering such therapies, and what results are anticipated. Physical therapy is not recommended because the aerobic exercise required in fibromyalgia does not usually require formal physical therapy and increases medicalization. Because medical therapy is unsatisfactory, patients find their way to alternative therapies. Some of these therapies may be helpful to individual patients, such as massage, water therapy, spa treatment, and acupuncture. These therapies tend to have high cost-effectiveness ratios, and the decision to use such therapies is often best left to the patients and the reimbursement authority. That is not say that such treatments do not help—everything helps—but they do not help often enough and importantly enough, and some decision point is required. One important goal of therapy is to reduce medicalization and increase independence.

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A frustrated physician may not know where to turn next in a nonresponsive patient. Should the patient be referred to a pain clinic? Sometimes such a referral is inevitable. The quality of pain clinics varies, however, and the results in fibromyalgia are often not good. The decision to refer should depend on the experience with the available clinics and the results that they have produced. In some countries, reimbursement authorities limit referrals, providing a cost­effectiveness analysis that may be alien to the physicianpatient relationship. Treatment options sort themselves out over time. Decisions that are difficult resolve. In the end, the physician who provides support and interest is a strong resource and a guide for patients with fibromyalgia, even when medical therapies are limited.

MEDICOLEGAL ISSUES AND FIBROMYALGIA Frequently, fibromyalgia becomes a medicolegal issue when an individual with fibromyalgia asserts that he or she is unable to work because of fibromyalgia. Because fibromyalgia symptoms are felt only by the patient, there are no objective medical findings to help in the disability assessment. Gaining a disability award is complex, depending on the source of payment (e.g., government versus private insurance), the physician’s belief and documentation, the availability of legal services, and the impact of the illness on the patient. Various guidelines have been suggested for evaluating disability as they apply to fibromyalgia. Determination of disability does not depend on proving the existence of fibromyalgia. The second medicolegal issue arises when an individual claims that trauma caused him or her to develop or exacerbate fibromyalgia, and that the fibromyalgia is disabling. Although it is proposed that trauma can alter the central nervous system (“neural plasticity”) and cause fibromyalgia, the relationship between the severity of trauma and the report of fibromyalgia is very weak. There is no way to determine scientifically if trauma causes or caused fibromyalgia. In addition, it is often difficult to establish the severity of the fibromyalgia symptoms. In reality, the relationship between trauma and disability does not require a diagnosis of fibromyalgia because symptom severity and work impairment are important, not the presence of absence of fibromyalgia.

at the first observation now did meet criteria, however, with the result that the 19.9% fibromyalgia prevalence was reduced only to 19.5%, and the overall pain scale changed from 4.1 to 4.0. Because criteria reflect symptom change rather than “disease,” improvement does not really measure improvement unless worsening or the development of new cases is considered. When applied to tender points, the inherent inaccuracy of the measure always leads to shifting of the tender point count in individuals with 10 to 13 tender points. Many studies have addressed the issue of outcome. Some have suggested that “… knowledge of the potential reversibility of the syndrome [is] resulting in improved outcomes”124 and that “… outcome is good with minimal intervention.”125 In a prospective study of fibromyalgia of patients referred to a specialty clinic, 70 of 82 were reassessed after 3 years. The returnees were generally improved (pain reduced from 6.8 to 5.4 and fatigue reduced from 6.8 to 5.7). The authors concluded that, “The overall outcome … was favorable.”126 In 33 of 51 patients seen 6 to 8 years after initial participation in a fibromyalgia treatment study, pain was reduced from 6.7 to 5.3, and fatigue was reduced from 7.5 to 6.5. The authors concluded that the results of these returnees “… [suggest] a benign long-term outcome in these patients with [fibromyalgia].”127 A six-center, 7-year study of 538 patients noted that, “Although functional disability worsened slightly and health satisfaction improved slightly, measures of pain, global severity, fatigue, sleep disturbance, anxiety, depression, and health status were markedly abnormal at study initiation and were essentially unchanged over the study period. Half the patients are dissatisfied with their health, and 59% rate their health as fair or poor.”83 In one report of 45 of 70 patients who had participated in a 3-week trial 6 years earlier, symptoms of fibromyalgia persisted over 6 years.82 A study of prediagnosis and postdiagnosis use of services found that no changes in the high use rates were seen over time.84 Based on available data, it seems that among patients who return for follow-up, improvement of 15% to 20% may occur, although patients continue to have substantial symptom severity. Patients who did not return may be worse, however. Use of services remains high, and in a large multicenter study no change in symptom status occurred over 7 years.83 Finally, improvement may partly represent an artifact in diagnosis classification methodology, such that it would be almost impossible not to improve.

OUTCOME OF FIBROMYALGIA The outcome of fibromyalgia can be studied in the context of change and level of symptoms, use of services, and work disability. Interpretation of results is complex, however. Although some studies show improvement over time, these results might simply represent a shifting within the distribution of fibromyalgia symptoms, allied to random change, which in part can be thought of as representing regression to the mean. To illustrate this point, we examined 20,248 patients in the National Data Bank for Rheumatic Diseases on two consecutive occasions 6 months apart. At the start, 19.9% of patients satisfied survey fibromyalgia criteria. At follow-up, only 61.4% of patients who met criteria now satisfied the criteria. In addition, their pain scores decreased from 6.8 to 6.3. Some patients who did not meet the ­criteria

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35. Campbell SM, Clark S, Tindall EA, et al: Clinical characteristics of fibrositis, I: A “blinded,” controlled study of symptoms and tender points. Arthritis Rheum 26:817-824, 1983. 36. Hartz A, Kirchdoerfer E: Undetected fibrositis in primary care practice. J Fam Pract 25:365-369, 1987. 37. Wolfe F, Cathey MA: Prevalence of primary and secondary fibrositis. J Rheumatol 10:965-968, 1983. 38. Yunus MB, Masi AT, Calabro JJ, et al: Primary fibromyalgia (fibrositis): Clinical study of 50 patients with matched normal controls. Semin Arthritis Rheum 11:151-171, 1981. 39. Rowbotham MC: Is fibromyalgia a neuropathic pain syndrome? J Rheumatol Suppl 75:38-40, 2005. 40. Dworkin RH, Fields HL: Fibromyalgia from the perspective of neuropathic pain. J Rheumatol Suppl 75:1-5, 2005. 41. Levine JD, Reichling DB: Fibromyalgia: The nerve of that disease. J Rheumatol Suppl 75:29-37, 2005. 42. Price DD, Staud R: Neurobiology of fibromyalgia syndrome. J Rheumatol Suppl 75:22-28, 2005. 43. Crofford LJ: The relationship of fibromyalgia to neuropathic pain syndromes. J Rheumatol Suppl 75:41-45, 2005. 44. Mease P: Fibromyalgia syndrome: Review of clinical presentation, pathogenesis, outcome measures, and treatment. J Rheumatol Suppl 75:6-21, 2005. 45. Arnold LM, Hudson JI, Hess EV, et al: Family study of fibromyalgia. Arthritis Rheum 50:944-952, 2004. 46. Raphael KG, Janal MN, Nayak S, et al: Familial aggregation of depression in fibromyalgia: A community-based test of alternate hypotheses. Pain 110(1-2):449-460, 2004. 47. Yunus MB, Khan MA, Rawlings KK, et al: Genetic linkage analysis of multicase families with fibromyalgia syndrome. J Rheumatol 26:408-412, 1999. 48. Uceyler N, Valenza R, Stock M, et al: Reduced levels of antiinflammatory cytokines in patients with chronic widespread pain. Arthritis Rheum 54:2656-2664, 2006. 49. Roizenblatt S, Moldofsky H, Benedito-Silva AA, et al: Alpha sleep characteristics in fibromyalgia. Arthritis Rheum 44:222-230, 2001. 50. Bergman S, Herrstrom P, Hogstrom K, et al: Chronic musculoskeletal pain, prevalence rates, and sociodemographic associations in a Swedish population study 1338. J Rheumatol 28:1369-1377, 2001. 51. Griep EN, Boersma JW, Dekloet ER: Altered reactivity of the hypothalamic-pituitary-adrenal axis in the primary fibromyalgia syndrome. J Rheumatol 20:469-474, 1993. 52. Neeck G, Riedel W: Thyroid function in patients with fibromyalgia syndrome. J Rheumatol 19:1120-1122, 1992. 53. Dinser R, Halama T, Hoffmann A: Stringent endocrinological testing reveals subnormal growth hormone secretion in some patients with fibromyalgia syndrome but rarely severe growth hormone deficiency. J Rheumatol 27:2482-2488, 2000. 54. Petzke F, Clauw DJ: Sympathetic nervous system function in fibromyalgia. Curr Rheumatol Rep 2:116-123, 2000. 55. Martinez-Lavin M: Is fibromyalgia a generalized reflex sympathetic dystrophy? Clin Exp Rheumatol 19:1-3, 2001. 56. Staud R, Vierck CJ, Cannon RL, et al: Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain 91(1-2):165-175, 2001. 57. Kwiatek R, Barnden L, Tedman R, et al: Regional cerebral blood flow in fibromyalgia: Single-photon-emission computed tomography evidence of reduction in the pontine tegmentum and thalami. Arthritis Rheum 43:2823-2833, 2000. 58. Werle E, Fischer HP, Muller A, et al: Antibodies against serotonin have no diagnostic relevance in patients with fibromyalgia syndrome. J Rheumatol 28:595-600, 2001. 59. McBeth J, Silman AJ: The role of psychiatric disorders in fibromyalgia. Curr Rheumatol Rep 3:157-164, 2001. 60. Epstein SA, Kay G, Clauw D, et al: Psychiatric disorders in patients with fibromyalgia—a multicenter investigation. Psychosomatics 40:57-63, 1999. 61. Wolfe F, Michaud K: A brief introduction to the National Data Bank for Rheumatic Diseases. Clin Exp Rheumatol 23:S168-S171, 2005. 62. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), 4th ed. Washington, American ­Psychiatric Association, 1994. 63. Wolfe F: Fibromyalgia: The clinical syndrome. Rheum Dis Clin North Am 15:1-18, 1989.

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64. Park DC, Glass JM, Minear M, et al: Cognitive function in fibromyalgia patients. Arthritis Rheum 44:2125-2133, 2001. 65. Wolfe F, Hawley DJ: Evidence of disordered symptom appraisal in fibromyalgia: Increased rates of reported comorbidity and comorbidity severity. Clin Exp Rheumatol 17:297-303, 1999. 66. McBeth J, Silman AJ: The role of psychiatric disorders in fibromyalgia. Curr Rheumatol Rep 3:157-164, 2001. 67. Fries JF, Spitz PW, Kraines RG, et al: Measurement of patient outcome in arthritis. Arthritis Rheum 23:137-145, 1980. 68. Wolfe F, Michaud K, Pincus T: Development and validation of the health assessment questionnaire, II: A revised version of the health assessment questionnaire. Arthritis Rheum 50:3296-3305, 2004. 69. Pincus T, Swearingen C, Wolfe F: Toward a multidimensional Health Assessment Questionnaire (MDHAQ)—assessment of advanced activities of daily living and psychological status in the patientfriendly health assessment questionnaire format. Arthritis Rheum 42:2220-2230, 1999. 70. Wolfe F, Skevington SM: Measuring the epidemiology of distress: The rheumatology distress index. J Rheumatol 27:2000-2009, 2000. 71. Neumann L, Press J, Glibitzki M, et al: CLINHAQ scale—validation of a Hebrew version in patients with fibromyalgia. Clin Rheumatol 19:265-269, 2000. 72. Burckhardt CS, Clark SR, Bennett RM: The fibromyalgia impact questionnaire: Development and validation. J Rheumatol 18:728733, 1991. 73. Bennett R: The Fibromyalgia Impact Questionnaire (FIQ): A review of its development, current version, operating characteristics and uses. Clin Exp Rheumatol 23(5 Suppl 39):S154-S162, 2005. 74. Hidding A, Vansanten M, Deklerk E, et al: Comparison between self-report measures and clinical observations of functional disability in ankylosing spondylitis, rheumatoid arthritis and fibromyalgia. J Rheumatol 21:818-823, 1994. 75. Ware JE, Sherbourne CD: The MOS 36-Item Short-Form Health Survey (SF-36), 1: conceptual framework and item selection. Med Care 30:473-483, 1992. 76. Picavet HS, Hoeymans N: Health related quality of life in multiple musculoskeletal diseases: SF-36 and EQ-5D in the DMC3 study. Ann Rheum Dis 63:723-729, 2004. 77. Wolfe F: Pain extent and diagnosis: Development and validation of the regional pain scale in 12,799 patients with rheumatic disease. J Rheumatol 30:369-378, 2003. 78. Jacobs JW, Rasker JJ, Van der Heide A, et al: Lack of correlation between the mean tender point score and self-reported pain in fibromyalgia. Arthritis Care Res 9:105-111, 1996. 79. Simms RW, Goldenberg DL, Felson DT, et al: Tenderness in 75 anatomic sites: Distinguishing fibromyalgia patients from controls. Arthritis Rheum 31:182-187, 1988. 80. Fischer AA: Pressure algometry (dolorimetry) in the differential diagnosis of muscle pain. In Rachlin ES (ed): Myofascial Pain and Fibromyalgia: Trigger Point Management, St Louis, Mosby, 1994, pp 121-140. 81. Katz RS, Wolfe F, Michaud K: Fibromyalgia diagnosis: A comparison of clinical, survey, and American College of Rheumatology criteria. Arthritis Rheum 54:169-176, 2006. 82. Baumgartner E, Finckh A, Cedraschi C, et al: A six year prospective study of a cohort of patients with fibromyalgia. Ann Rheum Dis 61:644-645, 2002. 83. Wolfe F, Anderson J, Harkness D, et al: Health status and disease severity in fibromyalgia: results of a six-center longitudinal study. Arthritis Rheum 40:1571-1579, 1997. 84. Hughes G, Martinez C, Myon E, et al: The impact of a diagnosis of fibromyalgia on health care resource use by primary care patients in the UK: An observational study based on clinical practice. Arthritis Rheum 54:177-183, 2006. 85. Redondo JR, Justo CM, Moraleda FV, et al: Long-term efficacy of therapy in patients with fibromyalgia: A physical exercise-based program and a cognitive-behavioral approach. Arthritis Rheum 51:184192, 2004. 86. Goldenberg DL, Burckhardt C, Crofford L: Management of fibromyalgia syndrome. JAMA 292:2388-2395, 2004. 87. Littlejohn GO: Balanced treatments for fibromyalgia. Arthritis Rheum 50:2725-2729, 2004. 88. Alamo MM, Moral RR, Perula de Torres LA: Evaluation of a patientcentered approach in generalized musculoskeletal chronic pain/fibromyalgia patients in primary care. Patient Educ Couns 48:23-31, 2002.

89. Cedraschi C, Desmeules J, Rapiti E, et al: Fibromyalgia: A randomised, controlled trial of a treatment programme based on self management. Ann Rheum Dis 63:290-296, 2004. 90. Pfeiffer A, Thompson JM, Nelson A, et al: Effects of a 1.5-day multidisciplinary outpatient treatment program for fibromyalgia: A pilot study. Am J Phys Med Rehabil 82:186-191, 2003. 91. Busch A, Schachter CL, Peloso PM, et al: Exercise for treating fibromyalgia syndrome. Cochrane Database Syst Rev 3:CD003786, 2002. 92. Richards SC, Scott DL: Prescribed exercise in people with fibromyalgia: Parallel group randomised controlled trial. BMJ 325:185, 2002. 93. Gowans SE, deHueck A, Voss S, et al: Six-month and one-year followup of 23 weeks of aerobic exercise for individuals with fibromyalgia. Arthritis Rheum 51:890-898, 2004. 94. Assis MR, Silva LE, Alves AM, et al: A randomized controlled trial of deep water running: Clinical effectiveness of aquatic exercise to treat fibromyalgia. Arthritis Rheum 55:57-65, 2006. 95. Gowans SE, deHueck A: Effectiveness of exercise in management of fibromyalgia. Curr Opin Rheumatol 16:138-142, 2004. 96. Dobkin PL, Da CD, Abrahamowicz M, et al: Adherence during an individualized home based 12-week exercise program in women with fibromyalgia. J Rheumatol 33:333-341, 2006. 97. Dobkin PL, Abrahamowicz M, Fitzcharles MA, et al: Maintenance of exercise in women with fibromyalgia. Arthritis Rheum 53:724-731, 2005. 98. Wigers SH: Fibromyalgia outcome: The predictive values of symptom duration, physical activity, disability pension, and critical life events—a 4.5 year prospective study. J Psychosom Res 41:235-243, 1996. 99. Bennett R, Nelson D: Cognitive behavioral therapy for fibromyalgia. Nat Clin Pract Rheumatol 2:416-424, 2006. 100. Thieme K, Gromnica-Ihle E, Flor H: Operant behavioral treatment of fibromyalgia: A controlled study. Arthritis Rheum 49:314-320, 2003. 101. Singh BB, Berman BM, Hadhazy VA, et al: A pilot study of cognitive behavioral therapy in fibromyalgia. Altern Ther Health Med 4:6770, 1998. 102. White KP, Nielson WR: Cognitive behavioral treatment of fibromyalgia syndrome: A followup assessment. J Rheumatol 22:717-721, 1995. 103. Hadhazy VA, Ezzo J, Creamer P, et al: Mind-body therapies for the treatment of fibromyalgia: A systematic review. J Rheumatol 27:29112918, 2000. 104. Goossens ME, Rutten-van Molken MP, Leidl RM, et al: Cognitiveeducational treatment of fibromyalgia: A randomized clinical trial, II: Economic evaluation. J Rheumatol 23:1246-1254, 1996. 105. Vlaeyen JW, Teeken-Gruben NJ, Goossens ME, et al: Cognitiveeducational treatment of fibromyalgia: A randomized clinical trial, I: Clinical effects. J Rheumatol 23:1237-1245, 1996. 106. Wolfe F, Anderson J, Harkness D, et al: A prospective, longitudinal, multicenter study of service utilization and costs in fibromyalgia. Arthritis Rheum 40:1560-1570, 1997. 107. Goldenberg DL, Felson DT, Dinerman H: A randomized, controlled trial of amitriptyline and naproxen in the treatment of patients with fibromyalgia. Arthritis Rheum 29:1371-1377, 1986. 108. Bennett RM, Kamin M, Karim R, et al: Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: A double-blind, randomized, placebo-controlled study. Am J Med 114:537-545, 2003. 109. Arnold LM, Keck PE, Welge JA: Antidepressant treatment of fibromyalgia: A meta-analysis and review. Psychosomatics 41: 104-113, 2000. 110. Jaeschke R, Adachi JD, Guyatt G, et al: Clinical usefulness of amitriptyline in fibromyalgia: The results of 23 N-of-1 randomized controlled trials. J Rheumatol 18:447-451, 1991. 111. Gendreau RM, Thorn MD, Gendreau JF, et al: Efficacy of milnaci­ pran in patients with fibromyalgia. J Rheumatol 32:1975-1985, 2005. 112. Crofford LJ, Rowbotham MC, Mease PJ, et al: Pregabalin for the treatment of fibromyalgia syndrome: Results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 52:1264-1273, 2005. 113. Wigers SH, Stiles TC, Vogel PA: Effects of aerobic exercise versus stress management treatment in fibromyalgia: A 4.5 year prospective study. Scand J Rheumatol 25:77-86, 1996. 114. Haanen HCM, Hoenderdos HTW, Van Romunde LKJ, et al: Controlled trial of hypnotherapy in the treatment of refractory fibromyalgia. J Rheumatol 18:72-75, 1991.

PART 5  115. Deluze C, Vischer TL: Electroacupuncture in fibromyalgia—reply. BMJ 306:393, 1993. 116. Assefi NP, Sherman KJ, Jacobsen C, et al: A randomized clinical trial of acupuncture compared with sham acupuncture in fibromyalgia. Ann Intern Med 143:10-19, 2005. 117. Drexler AR, Mur EJ, Gunther VC: Efficacy of an EMG-biofeedback therapy in fibromyalgia patients: A comparative study of patients with and without abnormality in (MMPI) psychological scales. Clin Exp Rheumatol 20:677-682, 2002. 118. van Santen M, Bolwijn P, Verstappen F, et al: A randomized clinical trial comparing fitness and biofeedback training versus basic treatment in patients with fibromyalgia. J Rheumatol 29:575-581, 2002. 119. Ferraccioli GF, Ghirelli L, Scita F, et al: EMG-biofeedback training in fibromyalgia syndrome. J Rheumatol 14:820-825, 1987. 120. Altan L, Bingol U, Aykac M, et al: Investigation of the effects of poolbased exercise on fibromyalgia syndrome. Rheumatol Int 24:272-277, 2004.

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121. Neumann L, Sukenik S, Bolotin A, et al: The effect of balneotherapy at the Dead Sea on the quality of life of patients with fibromyalgia syndrome. Clin Rheumatol 20:15-19, 2001. 122. Zijlstra TR, van de Laar MA, Bernelot Moens HJ, et al: Spa treatment for primary fibromyalgia syndrome: A combination of thalassotherapy, exercise and patient education improves symptoms and quality of life. Rheumatology (Oxf) 44:539-546, 2005. 123. Ballantyne JC, Mao J: Opioid therapy for chronic pain. N Engl J Med 349:1943-1953, 2003. 124. Littlejohn GO, Walker J: A realistic approach to managing patients with fibromyalgia. Curr Rheumatol Rep 4:286-292, 2002. 125. Littlejohn G: The fibromyalgia syndrome: Outcome is good with minimal intervention [letter]. BMJ 310:1406, 1995. 126. Fitzcharles MA, Costa DD, Poyhia R: A study of standard care in fibromyalgia syndrome: A favorable outcome. J Rheumatol 30:154159, 2003. 127. Mengshoel AM, Haugen M: Health status in fibromyalgia—a followup study. J Rheumatol 28:2085-2089, 2001.

PART

6

DIFFERENTIAL DIAGNOSIS OF REGIONAL MUSCULOSKELETAL PAIN

39

Neck Pain Clinton Devin  •  Karl Sillay  •  Joseph s. Cheng

KEY POINTS Neck pain is a ubiquitous condition associated with enormous medical and legal costs in the United States. Physicians need to differentiate causes of neck pain that can be managed conservatively from causes that require more aggressive treatments. Knowledge of the anatomy helps diagnosis and the ­differentiation of symptoms from a musculoskeletal, ­neurogenic, or vascular etiology. The history and clinical examination help focus the ­differential diagnosis and help to identify the origin of the neck pain based on the anatomy and physiology. Indicated imaging studies, neurophysiologic procedures, and laboratory studies aid in diagnosis and determining a treatment plan for the patient’s symptoms. In the absence of spinal instability, neurologic deficit, infectious process, or neoplastic process, the patient may benefit from conservative treatment with expectant recovery in time.

EPIDEMIOLOGY Pain is an evolutionary protective mechanism to prevent further tissue damage, with neck pain being a nearly ubiquitous condition with a lifetime prevalence of 67% to 71%.1 The point prevalence of neck pain ranges from 10% to 15% with the annual total costs for neck and low back pain corresponding to 1% of the gross national product in Sweden, with direct health care costs representing only a small fraction of this percentage.2-4 The medical and legal expenses associated with neck pain can be enormous, such as in whiplash injuries, which costs an estimated $29 billion annually in the United States.5 Neck pain may originate from various anatomic structures, including paraspinal soft tissues, intervertebral joints and disks, compression of the spinal cord or nerves, and referred visceral pain (Fig. 39-1). The etiology of neck pain has a wide differential diagnosis, which can include trauma, degenerative changes, infection, and autoimmune disorders, such as rheumatoid arthritis and ankylosing spondylitis.

The perception and resultant reporting of neck pain varies significantly based on cultural and social circumstances. Honeyman and Jacobs6 noted that Australian aborigines significantly underreport pain and are rarely disabled by pain. Social circumstances also play an important role in an individual’s ability to cope with and overcome neck pain. Studies have shown worse outcomes after diskectomy for patients with a workers’ compensation claim or litigation surrounding their condition.7 These studies indicate nonorganic contributions to neck pain for secondary gain. Most episodes of acute neck pain resolve with patient education and the passage of time. Physicians need to be able to differentiate causes of neck pain that can be managed with a conservative approach from causes that require more aggressive treatments. An understanding of the anatomy and physiology and their association with the pathogenesis of neck pain provides the basis for obtaining a thorough history, physical examination, and ancillary data with the ultimate goal of effective treatment.

ANATOMY The cervical spine consists of seven vertebrae denoted as C1 through C7. The bony anatomy of the atlas (C1) and axis (C2) are unique, whereas C3 through C7 have fairly consistent anatomy (Fig. 39-2). The atlas is a ring, consisting of anterior and posterior arches with two lateral masses and no vertebral body. The superior aspects of the lateral masses articulate with the skull through the occipital condyles and form the atlanto-occipital joints, which are supported further by the anterior and posterior occipital membranes.8 The atlanto-occipital joint is responsible for approximately 50% of total flexion and extension in the neck, with clear functional implications when this motion is lost. The axis consists of two lamina, a spinous process, two lateral masses, two pedicles, a vertebral body, and the dens or odontoid peg, which projects upward and anterior to articulate with the posterior aspect of the anterior arch of the atlas. The principal stabilizer of the odontoid to the anterior arch of the atlas is the transverse ligament, with the alar and apical ligaments acting as secondary stabilizers. This is a true 571

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DEVIN 

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Neck Pain

Neck pain

History clinical exam

Axial neck pain

Conservative care soft collar, medications, PT

Continue conservative treatments

Radiculopathy

No improvement

Negative findings

Myelopathy

Trauma

Radiological studies X-ray, CT, MRI, bone scan

Rigid collar spine precautions

Mild findings neural compression bone lesion deformity

Severe findings neural compression bone lesion deformity

Neurodiagnostics EMG, NCS, SSEP

Conservative treatments with negative results

Suspected neoplasm or infection

Evidence of nerve or cord compression

Request spine surgeon consult

Figure 39-1  Neck pain algorithm.

Foramen for vertebral artery Synovial joint Intervertebral disk True transverse element of transverse process Costotransverse bar

Lambdoid suture Atlas Axis

External occipital protuberance

3 4

Foramen magnum

5 6

Odontoid peg (dens)

7

Costal element of transverse process

A

Superior nuchal line

B

Transverse process and Tubercle on posterior arch of atlas

First rib

Figure 39-2  Cervical spine anatomy. A, Cervical spine. Anterior view of articulated cervical vertebrae. B, Posterior view of the skull, seven cervical vertebrae, and first thoracic vertebra. (From Nakano KK: Neck pain. In Ruddy S, Harris ED Jr, Sledge CB [eds]: Kelley’s Textbook of Rheumatology, 6th ed. Philadelphia, Saunders, 2001, p 458.)

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synovial joint and susceptible to inflammatory processes, such as seen with rheumatoid arthritis. There is no intervertebral disk between the atlanto-occipital joint and atlantoaxial joint, and without the stability conferred by a disk, the area is often involved by destructive inflammatory arthritides, which may result in instability.9 The axis articulates with the vertebra above and below through the superior and inferior facets, also termed the zygapophyseal joints. Posteriorly, the axis has a large spinous process, which can be easily palpated just below the occiput. The atlantoaxial articulation also provides approximately 50% of rotatory motion of the cervical motion. The subaxial cervical spine consists of the C3 through C7 vertebrae, all with fairly similar anatomy. Each vertebra consists of a body, two interconnecting pedicles, two lateral masses, two transverse processes, two laminae, and a spinous process. The transverse and spinous processes project outward, providing attachment for ligaments and muscles and creating a moment arm to facilitate motion. The spinous processes of C3 through C6 are bifid, whereas the C7 spinous process usually is not. The C7 spinous process is large, however, and the next most prominent and easily palpable spinous process below C2. There are five articulations between each vertebra from C2 through C7, including the intervertebral disk, two uncovertebral joints, and two facet or zygapophyseal joints. The facet joints are true apophyseal joints with hyaline cartilage articulations, intervening menisci, synovial lining, and a joint capsule. This composition makes them susceptible to degenerative changes and systemic arthritides. The cartilage and synovial lining are not innervated, whereas the joint capsule is highly innervated by the dorsal primary ramus. The facet joints are angled approximately 45 degrees from the transverse plane, articulating with the vertebrae above and below in a pattern that has been described as shingles on a roof. The facet joints in concert with the uncovertebral joints and ligaments help limit excess movement of the vertebral column, which helps protect the spinal cord. The intervertebral disks increase in size from C2 downward, giving the cervical spine its characteristic lordotic shape. Each disk consists of an outer anulus fibrosus and an inner nucleus pulposus and a cephalad and caudad end plate. The anulus fibrosus consists of type I collagen, helping to give form to the disk and provide tensile strength. The anulus fibrosus is innervated by the sinuvertebral nerve, formed by branches of the ventral nerve root and the sympathetic plexus.10 The nucleus pulposus consists of type II collagen and proteoglycans, which interact with water to resist compressive stress. The pressure within the disk is highest with flexion, which may explain why individuals with a disk herniation find this position most uncomfortable.11 Disk degeneration with aging includes loss of water content with resultant loss of height, annular tears, and myxomatous changes, increasing the risk of disk herniation. Herniation typically occurs in the posterolateral aspect of the disk, where the posterior longitudinal ligament is not present and the anulus fibrosus is at its weakest. The disk is bordered on both sides by the uncovertebral joints, which are formed by an up-curving of the superior end plate to articulate with the vertebra above.

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Spheno-occipital synchondrosis Tectorial membrane PONS te

Pala

Margins of foramen magnum

Apical ligament Atlas

Remnant of disk uniting body and dens of axis

Dura Spinal cord Posterior longitudinal ligament Anterior longitudinal ligament Figure 39-3  Cervical spine anatomy. Sagittal view of the lower head and neck to show the relationship of the spinal cord and brainstem to the bones, ligaments, and joints between the bodies of the cervical vertebrae. The cervical lordosis and the relationship of the anterior and posterior longitudinal ligaments to intervertebral disks and the ligaments at the craniovertebral junction can be seen. (From Nakano KK: Neck pain. In Ruddy S, Harris ED Jr, Sledge CB [eds]: Kelley’s Textbook of Rheumatology, 6th ed. Philadelphia, Saunders, 2001, p 459.)

The spinal column is supported by an interplay of ligaments and muscles (Fig. 39-3). The anterior longitudinal ligament and posterior longitudinal ligament originate on the occiput and extend downward to the sacrum, coursing along the anterior and posterior aspects of the vertebral bodies. The anterior longitudinal ligament resists hyperextension, and the posterior longitudinal ligament resists hyperflexion. The posterior longitudinal ligament can become ossified, limiting motion and contributing to the degenerative process. The ligamentum flavum is a short ligament that joins the laminae of adjacent vertebrae. It can become thickened over time creating stenosis in the spinal canal and compressing the spinal cord and exiting nerve roots. In a similar manner, the intraspinous ligament joins the spinous processes of adjacent vertebrae. The supraspinous ligament originates as the nuchal ligament at the occiput and extends caudally as an aponeurosis until it attaches to the tip of the spinous processes of C7 and then continues to the lumbar region. There are 14 paired anterior, lateral, and posterior muscles that help orchestrate the complex movements of the neck. A brief review of the spinal cord and nerve roots is beneficial for assisting with a thorough evaluation. There is significantly more room for the spinal cord in the upper cervical spine than the lower cervical spine, making the upper cervical spine a less likely site of spinal cord compression. Grossly, the spinal cord is divided into the posterior column, the lateral columns, and the anterior column.

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Posterior longitudinal ligament Sympathetic ganglion Rami communicantes

Anterior ramus Sinuvertebral nerves Posterior ramus Figure 39-4 Cervical spine neural elements. ­ Localized ­ cervical pain is mediated primarily through the posterior primary ramus and the ­recurrent meningeal (sinuvertebral) nerves, which supply structures within the spinal canal. The recurrent meningeal nerves arise from rami ­communicantes and enter the spinal canal via intervertebral foramina; branches ascend and descend one or more levels, interconnecting with the recurrent ­meningeal nerves from other levels and innervating, among other structures, the anterior and posterior longitudinal ligaments, the anterior and posterior portion of the dura, and blood vessels. (From Levin KH [ed]: Neck and Back Pain. Continuum 7 (no. 1), Philadelphia, Lippincott Williams & Wilkins, 2002, p 9.)

The posterior column consists of the fasciculus cuneatus laterally and the fasciculus gracilis medially, which mediate proprioceptive, vibratory, and tactile sensation. The lateral column consists of the lateral corticospinal tract, which provides the conduit for motor fibers, and the spinothalamic tract, which provides pain and temperature sensation from the contralateral side of the body. The anterior column conveys crude touch sensation. There are eight total cervical nerve roots on each side as the dorsal and ventral roots converge to form the spinal nerve within the vertebral foramen. Cervical nerve roots enter the intervertebral foramina by passing over top of the corresponding pedicle except C8, which lies between C7 and T1. A C5-C6 posterolateral disk herniation affects the C6 nerve root. The nerve root occupies approximately one third of the foramen (Fig. 39-4). The space available for the nerve root is decreased with neck extension and degenerative changes and increased with neck flexion. The spinal cord is supplied by the anterior spinal artery and two posterior spinal arteries. The anterior spinal artery arises from the vertebral arteries and supplies most of the spinal cord, excluding the posterior columns. The ­posterior columns receive their blood supply from the two posterior spinal arteries, which originate from either the inferior ­cerebellar artery or the vertebral arteries. Blood supply to the spinal cord may be impaired in diseases such as ­arteriosclerosis, diabetes, and syphilis, with exacerbation of symptoms with various head positions, usually extension. The vertebral arteries arise from the subclavian arteries and course through the C6 transverse foramen cephalad, passing anterior to the emerging cervical nerve root at each level. They pass behind the lateral mass of C1 and enter the foramen magnum, where they join to form the basilar artery. Diseases such as vertebral artery dissection can be associated with severe neck pain and impairment of blood flow through the vertebral artery and can result in posterior circulation signs, including nystagmus, vertigo, drop attacks,

Dorsal root ganglion Ligamentum flavum

Table 39-1  Age and Normal Cervical Movement Flexion-­Extension Lateral Rotation Lateral Flexion Age (yr) (degrees) (degrees) (degrees) <30

90

90

45

31-50

70

90

45

>50

60

90

30

From Nakano KK: Neck pain. In Kelley WN, Harris ED Jr, Ruddy S, et al (eds): Kelley’s Textbook of Rheumatology, 5th ed. Philadelphia, WB Saunders, 1997, p 396.

dysarthria, and weakness. These symptoms are often associated with head position, and if a critical reduction of blood flow occurs, it can result in a cerebellar infarction. The cervical spine is the most mobile segment of the spine with approximately a 90-degree arc of motion in flexion and extension, with three fourths of this due to extension (Table 39-1). The maximal range of motion in the sagittal plane within the subaxial spine is at the C5-C6 level, making it a common site of disk degeneration. Rotation encompasses approximately 80 to 90 degrees of motion with 50% of this occurring at the atlantoaxial joint. Similar to extension, rotation also reduces the cross-sectional area of the spinal canal. The cervical spine has 30 degrees of lateral mobility in each direction, and this typically occurs with some degree of rotation secondary to the orientation of the facet joints.

AXIAL NECK PAIN Axial neck pain describes a pattern of pain that is localized to the occiput and neck region. It may originate from any tissue that receives innervation, including the facet joints, cervical disks, vertebral periosteum, posterior neck muscles, cervical dura mater, occipito-atlantoaxial joints, and vertebral artery. The etiology may include degenerative,

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traumatic, malignant, infectious, or systemic inflammatory processes. The facet joints and cervical disks have the most direct supporting data linking these sites as the origin of axial neck pain. Provocative injections into the facet joint in asymptomatic volunteers invoke a reproducible pattern of occipital or axial neck pain.12 This pattern of pain can be accurately diagnosed and treated, for at least a short time, with anesthetic injections targeted at the joint capsule itself or by blocking its respective dorsal primary ramus.13-15 Degenerative arthritis within the upper cervical spine can manifest as suboccipital headache and localized pain. This is termed cervicogenic headache and is thought to result from irritation of the greater occipital nerve. Typically, arthritis within the atlanto-occipital joints is worsened with provocative neck flexion and extension, whereas atlantoaxial arthritis is worsened with rotation. A study in which asymptomatic volunteers underwent injections at the atlanto-occipital and atlantoaxial joints reproduced this pattern of pain.16 Relief of suboccipital pain may be obtained by fluoroscopically guided injection of corticosteroid into the diseased joint or by fusion of these joints in recalcitrant cases.17 The cervical disk is a more controversial source of axial neck pain with pain secondary to injury to the highly innervated anulus fibrosus. This idea is based on provocative discography, whereby a diseased disk is fluoroscopically injected to a given pressure with reproduction of pain in reliable patterns. To be a true-positive study or a “concordant study,” an adjacent normal disk should not produce pain when injected. Using this method, several studies have implicated cervical disks as a source of axial neck pain.18-20 Even with careful technique, a false-positive study can occur, and it is not unusual to have a “nonconcordant study” with multiple disks eliciting a pain response despite being normal.18 Operative interventions directed at treating the disk for isolated axial neck pain have often been unsuccessful despite the fact that the cervical disk likely contributed to the neck pain. In addition, degeneration of the disk affects the space available for the nerve root with resultant radiculopathy, which is discussed in more detail later. Myofascial pain secondary to irritation of the muscles around the neck can contribute to axial neck pain. Patients with chronic myofascial pain have been shown to have a lower level of high-energy phosphates in the involved muscle tissue.21 It can be the original source of neck pain or, more commonly, a manifestation of postural adaptations and compensatory overuse of normal tissue that remains after the injured structure heals. A more generalized form is fibromyalgia, which is a widespread disorder, not causing isolated neck pain. By definition, fibromyalgia is a diffuse pain affecting all four quadrants of the body with at least 11 of 18 pressure points being positive. Patients have associated symptoms of fatigue; cognitive difficulties; irritable bowel syndrome; and a nondermatomal pattern of dysesthesias, weakness, and paresthesias.22 Systemic inflammatory arthropathies rarely cause isolated neck pain because these illnesses typically show the classic pattern of morning stiffness, polyarticular involvement, rigidity, and often cutaneous manifestations. Rheumatoid arthritis often involves the cervical spine, initially causing stiffness and later causing pain. This involvement can often affect the occipito-atlantoaxial joint causing instability and the potential for neurologic compromise. After the hands

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and feet, the cervical spine is the most common site of disease involvement in rheumatoid arthritis.23 Seronegative spondyloarthropathies that can manifest with neck pain include ankylosing spondylitis, psoriatic arthritis, and reactive arthritis. Psoriatic arthritis manifests with skin lesions before the development of arthritis in 70% of patients, and reactive arthritis rarely involves the cervical spine. Ankylosing spondylitis often affects the entire axial skeleton with early limitation of lumbar motion and chest expansion and later involvement of the cervical spine. In progressive patterns, the cervical spine takes on a kyphotic deformity, and as the spine fuses, it biomechanically becomes similar to a long bone. This condition has implications when ankylosing spondylitis patients are involved in even minor trauma, and neck pain should be taken very seriously in these patients. Even in the face of negative plain radiographs, these patients should be worked up extensively with strict spine precautions, with neutral alignment varying with baseline spinal curvature, and with frequent ­ neurologic evaluations to assess for development of an epidural hematoma. Infections and neoplasms can cause axial neck pain through bone destruction with irritation of vertebral body periosteal nerves and altered biomechanics of the facet joints and cervical disks. The onus is on the clinician to identify these patients at the initial visit because a delay in diagnosis can have catastrophic consequences. Red flags for axial neck pain that require further workup at the initial presentation include advanced age, history of malignancy, immunocompromise, fevers, chills, unexplained weight loss, fatigue, nighttime awakening, recent antecedent bacteremia, and severe nonmechanical neck pain.22

RADICULOPATHY AND MYELOPATHY The clinician must determine if there is evidence of nerve root compression, termed radiculopathy, versus spinal cord compression, termed myelopathy. Cervical radiculopathy resulting from nerve root compression is most often caused by degenerative changes, such as spondylosis. Initially, there are changes within the disk causing a loss of height with posterior bulging of the disk into the spinal canal and foramen. As the disk collapses, the posterior soft tissue structures, including the ligamentum flavum and facet joint capsule, fold inward, further compromising the spinal canal and neural foramen. Pressure that was once dispersed throughout the disk is transferred to the facet joints and uncinate processes, resulting in the development of bone overgrowth or osteophytes leading to extrinsic pressure on the nerve root or spinal cord. In radiculopathy, there is mechanical distortion of the nerve leading to increased vascular permeability, resulting in chronic edema and eventually fibrosis. This situation leads to hypersensitivity of the nerve root with an inflammatory response mediated by substances released from the cell bodies of sensory neurons and cervical disks.24 Compression of the dorsal root ganglion is believed to be especially important in producing radicular pain.25 Clinically, this compression manifests with pain in a dermatomal distribution. The dermatomes for the higher cervical nerve roots, including C3 and C4, are along the posterior scapula and should not be confused with isolated axial neck pain.26 When it is established that a patient has radiculopathy, it must be determined

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if a neurologic deficit is present. Persistent compression on a nerve root can lead to sensory loss and weakness. If these deficits are minor and tolerable, it is reasonable to treat with conservative care with close follow-up to ensure that the deficit is not progressive. Disabling deficits should be treated operatively because prolonged nerve compression can result in irreversible changes. In patients without a neurologic deficit, it is reasonable to expect a good outcome with conservative care.27 Myelopathy is the clinical presentation of long tract signs resulting from compression of the spinal cord. Myelopathy can be due to mass effect from a tumor or infection or instability owing to systemic arthritides or connective tissue disorders, but it is often a result of advanced degenerative changes within the cervical spine. Factors that contribute to the development of myelopathy include a congenitally narrow spinal canal, dynamic cord compression, dynamic thickening of the spinal cord, and vascular changes. The anteroposterior diameter in the subaxial spine for a normal adult measures 17 to 18 mm, and the cord measures 10 mm. Diameters of less than 13 mm are considered to be congenitally stenotic. The shape of the spinal cord deformity has a high association with the development of myelopathy; patients with a banana-shaped cord on axial views had evidence of myelopathy 98% of the time.28 Ono and associates29 described a ratio whereby the anteroposterior diameter of the spinal cord is divided by the transverse diameter of the cord. Patients with a ratio of less than 0.40 tended to have severe neurologic deficits. Some patients may have dynamic cord compression with signs and symptoms of myelopathy only during neck flexion and extension. The space available for the cord is decreased during neck extension as a result of infolding of the ligamentum flavum and overlapping of the lamina. In addition, the spinal cord shortens during neck extension, effectively increasing the diameter and making it more prone to compression by the posterior structures. In flexion, the cord lengthens and drapes over anterior degenerated disks and osteophytes.30 Myelopathy can be exacerbated by altered biomechanics from degenerated segments because when a given level stiffens, the level above can become hypermobile.31 A subset of patients can develop myelopathy in the absence of mechanical compression, which has been attributed to ischemic insult.32 It also has been shown in a canine model that in the setting of spinal cord compression, additive ischemia results in a significantly worse outcome because over time the spinal cord shows permanent irreversible changes.33 Caudad to the level of compression, the central gray matter and lateral columns may show cystic cavitation, demyelination, and gliosis. Cephalad to the level of compression, the posterior columns may undergo wallerian degeneration. Patients with mild cases of myelopathy that does not affect activities of daily living can be followed closely.34 Patients with more severe deficits tend to deteriorate over time with conservative care, and these patients should undergo surgery to decompress the spinal cord.35

CLINICAL FEATURES In terms of functional anatomic pathways, neck pain is mediated via somatic or autonomic pathways.36 Somatic pain is the most common, being perceived in dermatomes,

myotomes, or sclerotomes. Pain originating in the autonomic pathway, or sympathetic nervous system, may fall into somatic segmental distributions, vascular supply distributions, peripheral nerve distributions, or nonconforming patterns. Pain mediated by autonomic and somatic pathways has significant overlap, potentially confounding localization. Additional clinical information regarding characteristics of the neck pain and diagnostic studies complement the determination of the origin of the pain when localization based on functional anatomy is insufficient. PATIENT HISTORY Neck pain is the most common symptom of cervical spine pathology, and correctly characterizing it helps to identify conditions requiring immediate treatment versus conditions for which conservative treatments are indicated. Important characteristics include onset, distribution, frequency, duration, quality, aggravating factors, and the presence of neurologic symptoms other than pain. In general, pain present only intermittently may indicate instability or motion-related pain, whereas constant and increasing pain is concerning for a mass effect. Generalized neck pain of new onset with relatively short duration is likely related to benign pathology, including muscle strain, whereas a ­longer duration of symptoms indicates significant or progressive pathology. Well-localized pain indicates specific nerve root irritation, whereas poorly defined pain may derive from irritation of deep connective tissue structures, such as muscle, joint, bone, or disk. Aggravating and relieving factors may help elucidate biomechanical changes in the cervical spine that are contributing to the symptoms. Localized axial neck pain is commonly reported as originating posteriorly with extension into the shoulder or occiput. Localized pain of myofascial etiology may worsen with neck flexion, whereas discogenic neck pain worsens with neck extension or rotation. Referred pain to the occiput usually indicates pathologic changes in the upper cervical spine and may radiate down the neck and to the ear. Shoulder girdle pain develops secondary to postural adaptations from initial neck pain symptoms. Pain commonly is referred from the shoulder, heart, lungs, viscera, or temporomandibular joint to the neck region owing to overlapping nerve distribution. Symptoms may arise secondary to irritation or activation of receptors directly as with articular pain; pseudoarticular pain; vascular headache; cervicogenic headache; occipital headache; pseudo–angina pectoris; and eye, ear, or throat conditions. Articular symptoms arise from the facet and uncovertebral joints causing local pain and stiffness. Patients often state that their symptoms worsen with inactivity and describe feelings of clicking, grating, or “sand” in the neck. Pseudoarticular pain may be felt in the shoulder and elbow, with the true pathology originating from the neck. Vascular symptoms result from compression of the vertebral artery by osteophytes or a protruding disk. Symptoms may intensify with neck movement or certain postures. Tenosynovitis and tendinitis may involve the rotator cuff and tendons around the elbow, wrist, or hand. Stenosis or fibrosis of tendon sheaths or palmar fascia may be present along with trigger points over the affected joints, giving a false impression of local pathology.37

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Table 39-2  Cervical Nerve Root Segments and Corresponding Clinical Signs and Symptoms Nerve Root

Symptom

Correlate

C3 C4 C5

Suboccipital pain with extension to back of ear Pain from caudad aspect of neck to superior aspect of shoulder Numbness over shoulder and down lateral aspect of arm to ­midportion. Deltoid muscle may be weak and biceps reflex, which is innervated by C5-C6, may be affected

If C3, C4, C5 all are involved, may cause paradoxical breathing

C6

Radiating pain and numbness down lateral aspect of arm and forearm to thumb and index finger (“six shooter”). Weakness in wrist extension, elbow flexion, and supination. Diminished ­brachioradialis and biceps reflex

Sensory component can mimic carpal tunnel syndrome

C7

Numbness and pain down posterior aspect of arm and forearm to long finger. Weakness in triceps, wrist flexion, and finger ­extensors

Most frequent. Entrapment of posterior interosseous nerve can mimic motor component, but no sensory deficits are present

C8

Numbness into ulnar two digits. Weakness in FDP to IF and LF and FPL Numbness into ulnar aspect of forearm and weakness in hand intrinsics

Anterior interosseous nerve entrapment can mimic a radiculopathy of C8 or T1, but sensory changes and involvement of thenar muscles are not present. Ulnar nerve entrapment spares short thenar muscles with exception of adductor pollicis.

T1

FDP, flexor digitorum profundus; FPL, flexor pollicis longus; IF, index finger; LF, long flexor.

LOCALIZATION OF PAIN GENERATORS When localizing symptoms of pain and paresthesia, one must consider the classssification and localization of pain generators. Pain may be somatic or autonomic and is not always felt in precise anatomic zones. Overlapping sensory supplies and radiation in spinal segments by recruitment within the spinal column may be present causing difficulty in localization. Somatic pain is caused by cervical nerve root irritation. It is the most common type of pain, and diabetics are especially susceptible to this nerve root irritation. Neurologic deficits correspond to the offending disk level in 80% of patients.38 Neuralgic and myalgic pain describes symptoms secondary to compression of different areas of the nerve root. Neuralgic pain originates from irritation of the dorsal sensory root and has a “lightning” or “electric” sensation, which tends to be dermatomal and associated with numbness and paresthesias. The pain tends to manifest more proximally with paresthesias distally. Myalgic pain occurs with irritation of the ventral motor root. This pain is described as a deep, boring, unpleasant sensation, which tends to be poorly localized because of its referral to sclerotomal areas. These sensations conform to the areas of muscles present that are innervated by the compressed nerve root. Autonomic mediated symptoms result in dizziness, blurring of vision, tinnitus, retro-ocular pain, facial pain, and jaw pain. The various origins of pain generators in the cervical spine include mechanical, vascular, and nerve root sources and spinal cord compression. These pain generators may manifest with radicular, sclerotomal, myalgic, or autonomic symptoms, making the history an important component to identify key features specific to the origin. An informed hypothesis as to the origin of the pain can be formed, which can be tested by physical examination and invasive and noninvasive diagnostic studies so that a treatment plan can be established. It is important to determine if the axial neck pain is isolated, or if there is associated radiating pain, weakness, change in sensation, or alteration in proprioception. Compression of a nerve root often can be localized by identifying

the distribution of pain, paresthesias, or weakness as they follow the segmental distribution of the respective nerve root (Table 39-2). Sensory loss may be described by the patient in precise terms with a description of numbness, or alternatively there may be vague symptoms of the sensation of swelling or bogginess to the skin. Complete numbness indicates a more serious nerve or root lesion. If the face, head, or tongue is involved, the upper three nerve roots of the cervical plexus may be affected. Numbness of the neck, shoulder, arm, forearm, or fingers indicates involvement of C5-T1. Weakness, as with sensory changes, occurs in a graded fashion depending on the amount of compression on the nerve root. This weakness manifests clinically with an obvious functional deficit or more subtle findings, made obvious only after repetitive testing. The clinician must be attuned to these subtle complaints of weakness, which may be described by the patient as a feeling of heaviness of the limbs, early fatigue, or insufficient power grip. If obvious atrophy is present in a muscle, more than one nerve root is affected as a result of the evolutionary benefit of multiple levels of innervation for a given muscle. Alterations in proprioception are due to compression of the dorsal column of the spinal cord; this is described by the patient as symptoms of clumsiness, with complaints of tripping or dropping objects. This is concerning for the more ominous condition of myelopathy secondary to spinal cord compression. Cervical spinal disease classically causes isolated axial neck pain or radicular pain that radiates to the shoulder or down the upper extremity (Table 39-3). Less commonly, it can be the cause of headache, pseudo–angina pectoris, and otolaryngologic sensations. The cause of cervicogenic occipital headache is multifactorial, and headache is most often seen with degenerative changes in apophyseal joints of the upper cervical spine. These degenerative changes can be compounded by adaptive changes in the posterior occipital muscles. Cervicogenic occipital headaches often spread to the eye region and manifest as a dull, rather than pulsating, pain. These headaches are unique in that they are aggravated by neck movements. They typically have migrainelike symptoms, including phonophobia or photophobia.

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Table 39-3  Cervical Pain Referral Pathways Location of Pain

Source

Upper posterolateral cervical region

C0-1, C1-2, C2-3

Occipital region

C2-3, C3

Upper posterior cervical region

C2-3, C3-4, C3

Middle posterior cervical region

C3-4, C4-5, C4

Lower posterior cervical region

C4-5, C5-6, C4, C5

Suprascapular region

C4-5, C5-6, C4

Superior angle of scapula

C6-7, C6, C7

Midscapular region

C7-T1, C7

From Nakano KK: Neck pain. In Kelley WN, Harris ED Jr, Ruddy S, et al (eds): Textbook of Rheumatology, 5th ed. Philadelphia, WB Saunders, 1997, p 394.

Pseudo–angina pectoris has been reported to be due to cervical spinal disease, being confused with angina pectoris or breast pain in women (Fig. 39-5). In the presence of a C6-C7 lesion, neuralgic or myalgic pain may be present along with tenderness in the precordium or scapular region. A pressure sensation is felt in the chest, which increases with exercise, radiates down the arm, is aggravated by neck movement, and may be associated with torticollis or muscle spasm in the neck. Differentiation of heart disease from symptoms associated with C6-C7 dysfunction is made on the basis of muscle weakness, fasciculations, and sensory or reflex changes. Differentiation of these two pathologies may be difficult when true angina and pseudoangina coexist in the same patient.39 Cervical spinal disease may manifest in the form of eye, ear, and throat symptoms (see Fig. 39-4). Eye and ear symptoms may arise from irritation of the plexus surrounding the vertebral and internal carotid arteries. Eye symptoms can manifest with blurring of vision relieved by changing neck position, increased tearing, orbital and retro-orbital pain, and descriptions of eyes being “pulled backward” or “pushed forward.” Altered equilibrium with associated gait disturbances may result from irritation of the surrounding sympathetic plexus or from vertebral insufficiency. Hearing can be affected with tinnitus and altered auditory acuity. Throat symptoms, including dysphagia, may be related to anterior vertebral osteophytes causing direct compression and cranial nerve and sympathetic nerve communications. Symptoms of dyspnea, cardiac arrhythmia, and drop attacks may have a cervical spinal origin. Dyspnea can be related to a deficit in the C3-C5 innervation of the diaphragm. Palpitations and tachycardia secondary to cervical spine pathology can be differentiated from other causes by the fact that these symptoms are associated with unusual positions or hyperextension of the neck. This hyperextension is caused by irritation of C4 innervation of the diaphragm and pericardium or by irritation of the cardiac sympathetic nerve supply. Drop attacks suggest posterior circulation insufficiency. Patients with myelopathy, or spinal cord compression, initially present with subtle complaints of hand clumsiness or difficulty with balance. Patients report worsening handwriting or difficulty buttoning buttons. Patients also may have nausea and emesis caused by equilibrium dysfunction. Paresthesias and dysesthesias may be present, often involving bilateral upper extremities and not following a

dermatomal distribution. This is often mistaken for peripheral neuropathy or carpal tunnel syndrome, but should be considered when bilateral extremity symptoms are present. As the disease progresses over time, more advanced manifestations include wasting of hand intrinsics and bowel and bladder dysfunction. Neck pain may manifest concomitant with systemic disease with varied symptoms requiring further investigation. Examples include inflammatory arthritides, infection, tumor, multiple sclerosis, subacute combined degeneration, or syrinx. Inflammatory arthritides often manifest with morning stiffness, polyarticular involvement, rigidity, or cutaneous manifestations. Fever, weight loss, or night pain points to an infectious or neoplastic etiology. Pancoast’s tumor is a neoplastic process of the apical portion of the lung that can cause a mass effect on the caudad cervical nerve roots. Pancoast’s tumor always should be considered in an individual with radicular symptoms and a history of smoking, with workup including a chest x-ray. Idiopathic brachial plexus neuritis, formerly known as ParsonageTurner syndrome, is caused by viral infection of the brachial plexus manifesting with severe arm pain involving multiple nerve roots. When the acute phase resolves, patients are left with variable deficits. Subacute combined degeneration from vitamin B12 deficiency is a consideration when there is greater sensory deficit in the lower extremities. CLINICAL EXAMINATION A careful clinical examination provides additional focus to the differential diagnosis. The clinical examination helps to identify the origin of neck pain based on the anatomy, physiology, nature, and distribution of pain. The clinical examination begins with broadly observing the patient’s gait and head and neck posture. Further palpation, range of motion testing, and neurologic signs, including motor signs, reflexes, sensory signs, autonomic signs, and articular signs, are assessed (Table 39-4). Careful palpation with knowledge of key anatomic bony and soft tissue landmarks in the cervical spine may localize the lesion to a particular cervical level and location. Anteriorly or anterolaterally, the transverse process of C1 is palpated between the angle of the jaw and the styloid process. C3 is identified by palpation of the hyoid bone. C4-C5 is at the level of the thyroid cartilage, and C6 is at the level of the cricoid ring and the carotid tubercle. In the process of examining the neck, the clinician also notes the sagittal balance with retention or loss of normal cervical lordosis. Posteriorly and posterolaterally, the occiput, inion, superior nuchal line, mastoid processes, and spinous processes of C2 and C7-T1 are palpable. Soft tissues around the anterior and posterior triangles of the neck, occipital region, and posterior paraspinal muscles are examined. Borders of the anterior triangle are the sternocleidomastoid muscle, mandible, and suprasternal notch. The sternocleidomastoid muscle is involved with whiplash injuries causing abrupt hyperextension of the neck. The muscle may be tender to palpation, or the patient may be splinting the neck with the head turned away from the injured muscle. This posturing of the neck is termed torticollis, and the clinician should remember that the head is turned away from the side of the involved sternocleidomastoid. The

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Temporomandibular joint Hiatal hernia with complications

Chondrosternal joint

Temporomandibular joint

Cystic duct stone

Gallbladder; common duct stone Lesions of mediastinum and lung

Pancreatic disease Esophageal hernia Gastric ulcer

Cardiac disease

Gallbladder disease Hiatal hernia Duodenal ulcer with or without perforation Gastric ulcer

Costochondral junction separation

Perforated peptic ulcer involving pancreas Duodenal ulcer Head of pancreas Gallbladder

Tail of pancreas

A

Ophthalmic V

V

V Mandibular C4

C6

V C3

T2 T3 T4 T5

C5

V

C2

Maxillary

V

C2 C3

C4 T1 C5 C3 C6 T1 T2 T2 T3 T3 T4 T4 T5 T5 C5 T2 C6 T1

C2,3

Pancreas

Gallbladder

B

C2 C3 C4

T2 T3 T4 T5

V C2,C3 C5

C6 C5

T2

T1

T1 C6

C7

C7

C7

C6 C8

C8

C6

C8 C7

C Figure 39-5  Patterns of reflex-referred pain from visceral and somatic structures. A, Anterior distribution. B, Posterior distribution. C, Dermatome distribution of nerve fibers from C1 through T5, carrying senses of pain, heat, cold, vibration, and touch to the head, neck, arm, hand, and thoracic area. The sclerotomes and myotomes are similar, but with some overlap. Pain arising from structures deep to the deep fascia (myotome and sclerotome) do not precisely follow the dermatome distribution. (A and B from Nakano KK: Neck pain. In Ruddy S, Harris ED Jr, Sledge CB [eds]: Kelley’s Textbook of Rheumatology, 6th ed. Philadelphia, Saunders, 2001, p 463; C from Nakano KK: Neck pain. In Ruddy S, Harris ED Jr, Sledge CB [eds]: Kelley’s Textbook of Rheumatology, 6th ed. Philadelphia, Saunders, 2001, p 461.)

posterior triangle borders include the sternocleidomastoid muscle, the trapezius muscle (inion to T12), and the clavicle. Flexion injuries may traumatize the trapezius muscle. The occipital region and paraspinal muscles from the inion to C7-T1 should be palpated carefully. Midline cervical tenderness is more concerning for ligament injury, whereas paraspinal muscle tenderness is typically a more benign process.40 The greater

occipital nerves are located lateral to the inion and may be involved in traumatic inflammation associated with flexion or extension injuries resulting in suboccipital headaches. Skin markings or visible trauma should be noted at this time. Range of motion examination may reveal pain or limitations in flexion-extension, lateral bending, and rotation. Flexion limitation may be assessed by the examiner placing

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Table 39-4  Nerves and Tests of Principal Muscles Nerve

Nerve Roots

Muscle

Test

Accessory

Spinal

Trapezius

Spinal

Stemocleidomastoid

Elevation of shoulders Abduction of scapula Tilting of head to same side with rotation to opposite side

C5, C6 C7, C8, T1 C5, C6, C7 C4, C5 C4, C5, C6 (C4), C5, C6 C6, C7, C8

Pectoralis major Clavicular part Sternocostal part Serratus anterior Rhomboid Supraspinatus Infraspinatus Latissimus dorsi

Brachial plexus

Adduction of arm Adduction, forward depression of arm Fixation of scapula during forward thrusting of the arm Elevation and fixation of scapula Initiate abduction of arm External rotation of arm Adduction of horizontal, externally rotated arm, ­coughing

Axillary

C5, C6

Deltoid

Lateral and forward elevation of arm to horizontal

Musculocutaneous

C5, C6

Biceps Brachialis

Flexion of supinated forearm

Radial

C6, C7, C8 C5, C6 C6, C7

Triceps Brachioradialis Extensor carpi radialis longus

Extension of forearm Flexion of semiprone forearm Extension of wrist to radial side

Posterior interosseous

C5, C6 C7, C8 C7, C8 C7, C8 C7, C8

Supinator Extensor digitorum Extensor carpi ulnaris Extensor indicis Abductor pollicis longus

C7, C8 C7, C8

Extensor pollicis longus Extensor pollicis brevis

Supination of extended forearm Extension of proximal phalanges Extension of wrist to ulnar side Extension of proximal phalanx of index finger Abduction of first metacarpal in plane at right angle to palm Extension of first interphalangeal joint Extension of first metacarpophalangeal joint

C6, C7 C6, C7 C7, C8, T1 C8, T1

C8, T1

Pronator teres Flexor carpi radialis Flexor digitorum superficialis Flexor digitorum profundus (lateral part) Flexor pollicis longus (anterior interosseous nerve) Abductor pollicis brevis

C8, T1 C8, T1 C8, T1

Flexor pollicis brevis Opponens pollicis First and second lumbricals

C7, C8

Flexor carpi ulnaris

C8, T1 C8, T1 C8, T1

Flexor digitorum profundus (medial part) Hypothenar muscles Third and fourth lumbricals

C8, T1

Adductor pollicis

C8, T1 C8, T1

Flexor pollicis brevis Interossei

Median

C8, T1

Ulnar

Pronation of extended forearm Flexion of wrist to radial side Flexion of middle phalanges Flexion of terminal phalanges, index and middle fingers Flexion of distal phalanx, thumb Abduction of first metacarpal in plane at right angle to palm Flexion of proximal phalanx, thumb Opposition of thumb against fifth finger Extension of middle phalanges while proximal phalanges are fixed in extension Observation of tendons while testing abductor digiti minimi Flexion of distal phalanges of ring and little fingers Abduction and opposition of little finger Extension of middle phalanges while proximal phalanges are fixed in extension Adduction of thumb against palmar surface of index finger Flexion of proximal phalanx, thumb Abduction and adduction of fingers

From Nakano KK: Neck pain. In Kelly WN, Harris ED Jr, Ruddy S, et al (eds): Textbook of Rheumatology, 5th ed. Philadelphia, WB Saunders, 1997, p 399.

fingers between the patient’s chin and sternum at maximal flexion with 50% of the motion occurring at the occiput-C1 joint and the remaining 50% distributed over C2-C7. If the patient is unable to place the chin on the chest, the interval should be measured. One finger width shows a limitation of 10 degrees; three finger widths indicate a 30-degree limitation in flexion. On extension, the distance between the base of the occiput and spinous process of T1 should be measured. Lateral flexion should allow the ear to touch the shoulder with motion being shared across all cervical vertebrae. On rotation, the chin should touch the shoulder with

50% of rotation occurring at C1-C2 and the remaining 50% distributed in the subaxial spine between C3-C7. There is a natural decrease in range of motion with age, even in healthy individuals.41 Range of motion testing is dangerous if the patient is unable to protect the cervical spine because of sedation, analgesics, or distracting injuries. After ensuring the patient is able to comply safely with range of motion testing, active range of motion, passive range of motion, and motion against resistance are performed. Range of motion tests the ligaments, capsules, and fascia, and this range of motion is

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reduced in the presence of cervical spinal muscular spasm or pain. Patients with degenerative changes of the cervical spine have pain with decreased range of motion of the cervical spine. The most common findings secondary to changes in the cervical spine articulations are (in order): restriction of movement with or without pain, pain on movement, and local tenderness. Lateral flexion is the earliest and most impaired movement in degenerative diseases with rotation first impaired in rheumatoid arthritis owing to involvement of the odontoid peg. A uniformly stiff neck may be caused by diffuse idiopathic skeletal hyperostosis, which is present in a quarter of elderly patients, but also may be due to ankylosing spondylitis or recent trauma to the neck.42 If articular signs are found, the examiner must evaluate the entire vertebral column and peripheral joints for evidence of further ­arthritis and search for extra-articular manifestations. Motion against resistance testing is performed after active and passive range of motion is established. Firm resistance to movement is provided by the examiner to assess the origin and insertion of tendons and ligaments and motor strength. Muscle groups tested include the flexors and extensors of the neck. In testing flexor muscles, a hand is placed between the forehead and chest. The primary flexor is the sternocleidomastoid muscle with secondary flexors being the three scalene muscles and small prevertebral muscles. Extensors are tested by placing a hand on the shoulder and head for resistance. Primary extensors include the paravertebral extensor mass, splenius, semispinalis capitis, and trapezius. Secondary flexors include the small intrinsic muscles of the neck. Rotators are examined by placing a hand on the shoulder and chin for resistance. The sternocleidomastoid muscle and the intrinsic muscles of the neck provide rotational force. Motion against resistance testing should include active maximal effort strength testing to the extremes of flexion, extension, and rotation to assess muscle strength. Causes of decreased range of motion of the cervical spine include joint locking and bony ankylosis from degenerative changes or arthritides, fibrous contractures, muscle spasm, splinting over painful joints, and nerve root or spinal cord ­compression or irritation. Decreased range of motion in the presence of pain or weakness warrants further inves­ tigation. Sensation testing for light touch, pin prick, temperature, and proprioception should be performed. These tests are subjective, and both upper extremities should be compared to assess differences in sensation. Comparing an unaffected area, such as the face, with the area of decreased sensation also can be helpful. Pin prick can be performed using a sterile needle and temperature using an alcohol pad to assess function of the spinothalamic tract that traverses the anterolateral aspect of the spinal cord. Light touch and proprioception assess function of the posterior spinal column. Dermatomally, C1 and C2 innervate the occiput region; C3 and C4, the nape of the neck; C5, the deltoid region; C6, the radial aspect of the forearm; C7, the long finger; C8, the ulnar border of the hand; and T1, the medial border of the arm. T2-T12 provide innervation to the chest and abdomen, with T4 being at the nipple line, T10 at the umbilicus, and T12 at the inguinal ligament (see Fig. 39-5). The lower extremities have a unique dermatomal map that correlates with embryologic development whereby the limb starts in a supinated position and pronates with longitudinal growth.

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Table 39-5  Strength Grading in Motor Examination 0

No function with total paralysis

1

Trace movement with palpable or visible contraction

2

Full range of joint motion with gravity eliminated

3

Active movement against gravity

4

Active movement against slight resistance

5

Normal strength

Each segment contributes innervation from superolateral to inferomedial, mirroring this twisting motion that occurred during development. L1 and L2 contribute innervation below the inguinal ligament to the medial thigh, L3 provides sensation to the anterior midthigh, L4 provides sensation to the knee region and medial calf, L5 provides sensation to the lateral calf and first web space, and S1 provides sensation to the lateral aspect and sole of foot. The perineum region receives contributions from S3-S5. Perineal sensation and rectal tone are important to examine because an abnormality may indicate compression of the spinal cord or cauda equina, requiring immediate surgical intervention. Isolating the level of pathology can be challenging sometimes. Nerve roots with proximal compression are more susceptible to distal compression in a phenomenon termed “double crush.” The cervical spine should always be considered as the potential etiology in patients who present with symptoms of carpal or cubital tunnel syndrome and peripheral neuropathy. Ancillary imaging and nerve conduction studies can help elucidate the etiology. After palpation, range of motion testing, and assessment of sensation, muscle strength testing is continued for localization of any positive findings. Lower motor neuron disease is indicated by weakness, hypotonia, and fasciculations. Upper motor neuron disease is indicated by spasticity. Motor ­function should be graded using the standard 0-to-5 nomenclature, grade 0 having no function, 1 having trace, 2 having full range of joint motion with gravity eliminated, 3 having antigravity function, 4 having function against slight resistance, and 5 having normal strength against resistance (Table 39-5). A cursory examination can be performed assessing C5 with elbow flexion, C6 with wrist extension, C7 with elbow extensors or wrist flexion, C8 with finger flexion of the middle finger, and T1 with finger abduction of the fifth finger. If weakness is present, a more focused examination should be performed looking at other muscles innervated by the same nerve root. Deep tendon stretch reflexes should be performed and graded 0 to 3 with 0 being no response, 1 being ­hyporeflexive, 2 being normal, and 3 being hyperreflexive. C5 is tested by striking the biceps tendon; C6, brachioradialis; C7, triceps; L4, patellar tendon; and S1, Achilles tendon. To facilitate reflex testing, it may be helpful to use muscle loading or Jendrassik’s maneuver (performed by having the patient flex both sets of fingers into a hooklike form, interlocking the hands, and pulling apart). This maneuver creates a diversion to help relax the patient and assess lower extremity reflexes. If difficulty with reflex testing persists, the clinician should ensure that no peripheral neuropathy is present. In addition to deep tendon reflex testing, the abdominal reflexes, Babinski’s test, and bulbocavernosus test should

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be assessed. The abdominal reflex is performed by dividing the umbilicus and immediate surrounding area into four quadrants, with the umbilicus being the center. The umbilicus should deviate in the direction it is being stimulated with light scratching. Absence of a reflex may signify an upper motor neuron lesion, whereas asymmetrical loss of the reflex may indicate a localized lower motor neuron lesion. Babinski’s test is performed by stroking the lateral plantar aspect of the foot with a pathologic response indicated by an up-going great toe indicating an upper motor neuron lesion. The bulbocavernosus reflex is an important barometer in the setting of spinal shock in patients presenting with paralysis. This reflex typically occurs within 24 hours of injury owing to traumatic swelling around the neural tissues. In the presence of spinal shock, it cannot be predicted whether a lesion is complete or incomplete, and it cannot be determined whether decompression should be performed at the time of surgical intervention. The bulbocavernosus reflex is performed by pressure stimulation of the penis or clitoris or by placing traction on an indwelling Foley catheter while the examiner’s other finger is in the rectum. Presence of the reflex is indicated by concurrent contraction of the anal sphincter, and this indicates an incomplete paralysis. The bulbocavernosus reflex is unreliable with injuries around the conus medullaris (i.e., T12-L2) because the afferent nerve fibers synapse within the conus medullaris. Provocative tests that can be helpful in confirming compressive extradural monoradiculopathy include Spurling’s test, the arm abduction test, and the axial compression and traction test. All of these tests are meant to change the diameter of the neural foramen, increasing or decreasing the symptoms. Spurling’s test is performed by the patient extending his or her neck and rotating toward the side of pain. The test is positive if the radicular pain worsens in this position and indicates foraminal stenosis with potential compression of a nerve root. The arm abduction sign is positive if the patient’s pain is relieved by placing the hand on the affected side, on top of the head.43 The axial compression test is performed by pressing on top of the patient’s head with the neck in neutral position with a positive result if the radicular symptoms are exacerbated by this maneuver and relieved by placing traction on the head and opening up the foramina. Provocative tests that are helpful in diagnosing myelopathy include Hoffmann’s sign, finger escape sign, abnormal grip-release test, and Lhermitte’s sign. Hoffmann’s sign is obtained by holding the middle finger extended and suddenly extending the distal interphalangeal joint, resulting in flexion of the index finger and thumb if pathologic. A positive finger escape sign occurs when an individual cannot hold all of the fingers in an adducted and extended position without the ulnar two digits falling into flexion and abduction over time. The grip-release test is an inability to open and close a fist rapidly because of weakness and spasticity of the hand. Lhermitte’s sign evaluates for changes in the spinal cord itself and occurs when the patient’s neck is forcefully flexed resulting in electric-like shocks that travel down the arms and legs. This indicates changes in the white matter of the spinal cord and may be secondary to cervical myelopathy or multiple sclerosis.

DIAGNOSTIC EVALUATION After completing the history and clinical examination, indi­ cated imaging studies, neurophysiologic procedures, and laboratory studies may aid in completing the differential diagnosis and building a treatment plan for the patient’s neck pain. Imaging modalities useful in the diagnosis of neck pain include cervical radiographs, computed tomography (CT), nuclear bone scans, and magnetic resonance imaging (MRI). Cervical radiographs often show degenerative changes in asymptomatic individuals by age 60.44 In the absence of trauma, constitutional symptoms, or worsening neurologic deficit, 4 weeks of conservative care is indicated before obtaining radiographs.45 Complete static cervical spine imaging includes anteroposterior, lateral, oblique, and open mouth odontoid radiographs with attention to sagittal alignment, which has a normal lordosis of 21 ± 13 degrees. Flexion and extension views allow for evaluation of the dynamic properties of the cervical spine, but should not be performed in the acute trauma setting because neck muscle spasm can result in a false-negative test. Dynamic radiographs also should be used for screening patients with rheumatoid arthritis before endotracheal intubation, given the risk of cervical instability at C1-C2. One study showed that 61% of patients with rheumatoid arthritis had evidence of instability, defined by at least 3 mm of atlantoaxial subluxation on preoperative screening x-rays.46 In the presence of significant degenerative changes and end plate osteophytes, CT myelography can be helpful in characterizing the bony involvement further. CT ­myelography should be thought of as a complementary test to MRI.47 It should be used as the primary test to evaluate neural involvement only when MRI is contraindicated because MRI is superior for evaluating spinal cord changes, such as syringomyelia, myelomalacia, or neoplasm.48 MRI is indicated for progressive neurologic deficit, disabling weakness, and long tract signs and is recommended for patients with persistent cervical radiculopathy after 6 weeks of conservative care.45 The addition of gadolinium contrast enhancement is helpful in evaluating infection and neoplasm and in differentiating scar from recurrent disk herniation in patients who have undergone previous spinal surgery. MRI results must be correlated with physical examination findings given that asymptomatic volunteers have been found to have abnormal cervical spine MRI.49 If the MRI findings do not correlate with the history and physical examination findings, further studies may be required, such as CT myelography. Nuclear bone scanning techniques, including single photon emission CT, have been used to identify and characterize acuity in occult fractures, periosteal injury, and post-traumatic osteoarthritis in the absence of positive radiograph findings.50 Neurophysiologic procedures are indicated when the clinical examination and imaging studies fail to correlate, or when there is conflicting information. Electromyography, nerve conduction studies, and somatosensory evoked responses help differentiate cervical spine disorders from peripheral nerve entrapment syndromes and help in ­differentiating intrinsic joint pathology from a radiculopathy. Neck pain is typically secondary to mechanical causes, and laboratory studies generally are not helpful in its

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d­ iagnosis. Laboratory studies can be crucial, however, in ruling out infection, neoplasm, and systemic arthritides and should be obtained in patients with constitutional symptoms and for suspicion of systemic arthritides. Erythrocyte sedimentation rate may be elevated greater than 100 mm/hr with infection and neoplasm; less dramatic elevations are seen with rheumatoid arthritis and after surgery.51 C-reactive protein peaks by day 2 of an acute inciting event and returns to normal within 3 to 7 days of removing the insult.52 Complete blood count with differential and lumbar puncture also can be helpful if meningitis is a concern. If a systemic arthritis is suspected, the respective tests can be ordered as indicated.

DIFFERENTIAL DIAGNOSIS AND TREATMENT Using the history, physical examination, and diagnostic studies, it is helpful to divide the differential diagnosis into benign axial neck pain, radiculopathy, myelopathy, infection, neoplasm, systemic arthritides, and referred pain. Most axial neck pain is self-limiting and resolves with appropriate conservative care.53 Patients with isolated neck pain and a negative radiographic and laboratory workup are best treated with a multimodal approach. During the acute phase, patients can be treated with a soft collar to reduce inflammation, but this should not be worn for more than 2 weeks so as to avoid deconditioning. Multimodal treatments have been found to be the most effective at treating axial neck pain, including proprioceptive training, exercises with resisted strengthening, muscle relaxers during the acute period, and nonsteroidal anti-inflammatory drugs.54-59 There is inconclusive evidence regarding the effectiveness of radiofrequency denervation of facet joints, acupuncture, transcutaneous electric nerve stimulation unit, iontophoresis, electromyography biofeedback, local injections, or mechanical traction for treatment of axial neck pain.60-63 If there is a history of trauma and radiographic findings, a rigid cervical collar should remain in place with strict spine precautions and appropriate referral. A patient with acute neck pain in the setting of trauma with negative radiographic findings and no neurologic deficits should remain in a rigid cervical collar with follow-up in 2 weeks for cervical spine clearance. In addition to degenerative changes to the cervical spine, trauma, and acute disk herniations, there are more insidious causes of neck pain, including schwannomas, Pancoast’s tumor, brachial plexus neuritis, and reflex sympathetic dystrophy. Schwannomas, if intradural, may involve a sensory nerve root causing dermatomal pain in addition to causing a myelopathy or radiculopathy from compression. Pancoast’s tumor involving the lung apex may cause caudal cervical nerve root and sympathetic changes in addition to nerve root or brachial plexus compression. Brachial plexus neuritis (Parsonage-Turner syndrome) is of viral origin and causes severe arm pain followed by weakness and then pain resolution followed by return of arm strength. This condition may progress to reflex sympathetic dystrophy in a few cases associated with diffuse burning pain along with autonomic changes, including discoloration of the skin. Axial neck pain with associated radiculopathy also has a fairly benign course with 75% of patients having only

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one recurrence or mild symptoms at 19-year follow-up with conservative treatment.64 A soft collar can be used to aid in treating the associated muscle spasm, but this should not be worn for more than 2 weeks. Cervical traction may be prescribed when the acute muscle spasms subside, with a typical regimen of 8 to 10 lb for 15- to 20-minute sessions with the device at 20 to 25 degrees of flexion. Traction has shown only short-term relief of radicular symptoms, however.65 Epidural steroids have been shown to be extremely effective at treating lumbar radiculopathy, allowing 50% of patients to avoid surgery, but a similar study has not been undertaken in the cervical spine.66 Atlantoaxial facet joint osteoarthritis may be treated successfully with a facet block and nonsteroidal anti-inflammatory drugs. If conservative therapy with nonsteroidal anti-inflammatory drugs fails, a fusion may be indicated. Follow-up and vigilance are in order because a progressive neurologic deficit, segmental instability, and persistent radicular symptoms for at least 6 weeks may be indications for surgical intervention. In a prospective randomized study comparing surgery, physical therapy, or cervical collar use for long-standing cervical radiculopathy, no difference was found between the three groups at 12 months.67 Cervical myelopathy with very mild deficits can be followed closely; however, the natural course of the illness is long periods of stability with episodes of deterioration. Definitive indications for surgery include presence of myelopathy for 6 months or longer, progression of signs or symptoms, difficulty walking, or change in bowel or bladder function. Surgery is directed at decompressing the spinal cord and preventing further deterioration, rather than improving neurologic deficits. Systemic arthritides, infection, and tumors can affect the cervical spine with variable neurologic and constitutional symptoms. Rheumatoid arthritis typically causes atlantoaxial subluxation, atlantoaxial impaction, and subaxial subluxation (Table 39-6). Surgical stabilization is indicated with progressive neurologic deficit, persistent axial neck pain with Table 39-6  Rheumatologic Disorders Causing Neck Pain Rheumatoid arthritis Without disease of the C1-C2 joint With structural cervical abnormalities C1-C2 subluxation C1-C2 facet involvement Spondyloarthropathies Ankylosing spondylitis Reiter’s syndrome and reactive arthritis Psoriatic arthritis Enteropathic arthritis Polymyalgia rheumatica Osteoarthritis Fibromyalgia Nonspecific musculoskeletal pain Miscellaneous spondyloarthropathies Whipple’s disease Behçet’s disease Paget’s disease Acromegaly Ossification of the posterior longitudinal ligament Diffuse idiopathic skeletal hyperostosis

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radiographic evidence of instability, canal diameter of less than or equal to 14 mm, and odontoid migration of greater than or equal to 5 mm above McGregor’s line. In the setting of ­atlantoaxial subluxation or subaxial subluxation, the in­ vol­ved levels are fused posteriorly, and atlantoaxial impaction should be treated with occipitocervical fusion.9 Rheumatoid arthritis patients with evidence of instability show radiographic progression over time, but this correlates poorly with neurologic outcome.68 Regardless, these patients require close follow-up because when myelopathy develops, most patients die within 1 year.69 Ankylosing spondylitis commonly affects the cervical spine resulting in a kyphotic deformity over time with al­ te­red biomechanics, which has implications in the setting of trauma. Even minor falls can create significant instability owing to the lever arm effect. The kyphotic deformity can have significant functional implications because the individual’s gaze moves toward the floor, making interaction with the surrounding world difficult. Corrective osteotomies are available, but there is risk of neurologic deficit and intraoperative bleeding. It is hoped that earlier diagnosis through the use of MRI and treatment with tumor necrosis factor– blocking agents will help make cervical deformity a thing of the past.70 Infection and neoplastic processes can cause destruction with mechanical or nonmechanical neck pain, constitutional symptoms, and variable neurologic deficit. The goal is similar with eradication of the infection or tumor, decompression if a neurologic deficit exists, and stabilization of the spinal column. A careful history, physical examination, and ancillary studies help one arrive at a fairly narrow differential diagnosis. In the absence of spinal instability, neurologic deficit, infectious process, or neoplastic process, the patient may benefit from conservative treatment with expectant recovery with “tincture of time.” REFERENCES   1. Nachemson AL: Disc pressure measurements. Spine 6:93-97, 1981.   2. Makela M, Heliövaara M, Sievers K, et al: Prevalence, determinants, and consequences of chronic neck pain in Finland. Am J Epidemiol 134:1356-1367, 1991.   3. Andersson HI, Ejlertsson G, Leden I, et al: Chronic pain in a geographically defined general population: Studies of differences in age, gender, social class, and pain localization. Clin J Pain 9: 174-182, 1993.   4. Hansson EK, Hansson TH: The costs for persons sick-listed more than one month because of low back or neck problems: A two-year prospective study of Swedish patients. Eur Spine J 14:337-345, 2005.   5. Freeman MD, Craft AC, Rossignol AM, et al: A review and methodologic critique of the literature refuting whiplash syndrome. Spine 24:86-96, 1999.   6. Honeyman PT, Jacobs EA: Effects of culture on back pain in Australian Aboriginals. Spine 21:841-843, 1996.   7. Klekamp J, McCarty E, Spengler DM: Results of elective lumbar discectomy for patients involved in the workers’ compensation system. J Spinal Disord 11:277-282, 1998.   8. Daniels DL, Williams AL, Haughton VM: Computed tomography of the articulations and ligaments at the occipito-atlantoaxial region. Radiology 146:709-716, 1983.   9. Kim DH, Hilibrand AS: Rheumatoid arthritis in the cervical spine. J Am Acad Orthop Surg 13:463-474, 2005. 10. Bogduk N, Marsland A: The cervical zygapophyseal joints as a source of neck pain. Spine 13:610-617, 1988. 11. Nachemson AL, Waddell G, Norhlund AI: Neck and Back Pain: The Scientific Evidence of Causes, Diagnosis, and Treatment. Philadelphia, Lippincott Williams & Wilkins, 2000, pp 172-173.

12. Dwyer A, Aprill C, Bogduk N: Cervical zygapophyseal joint pain patterns, I: A study in normal volunteers. Spine 15:453-457, 1990. 13. Bogduk N, Windsor M, Inglis A: The innervation of the cervical intervetebral discs. Spine 13:2-8, 1988. 14. Aprill C, Dwyer A, Bogduck N: Cervical zygapophyseal joint pain patterns, II: A clinical evaluation. Spine 15:458-461, 1990. 15. Cavanaugh JM, Ying L, Chen C, et al: Pain generation in lumbar and cervical facet joints. J Bone Joint Surg 88A:63-67, 2006. 16. Dreyfuss P, Michaelsen M, Fletcher D: Atlantooccipital and lateral atlanto-axial joint pain patterns. Spine 1125-1131, 1994. 17. Kuklo TR, Riew KD, Orchowski JR, et al: Management of recalcitrant osteoarthritis of the atlanto-axial joint. Orthopedics 29:633-638, 2006. 18. Bogduk N, Aprill C: On the nature of neck pain, discography and cervical zygapophysial joint pain. Pain 54:213-217, 1993. 19. Schellhas KP, Smith MD, Gundry CR, et al: Cervical discogenic pain: Prospective correlation of magnetic resonance imaging and discography in asymptomatic subjects and pain sufferers. Spine 21:300-312, 1996. 20. Grubb SA, Kelly CK, Cervical discography: Clinical implications from 12 years of experience. Spine 25:1382-1389, 2000. 21. Bengtsson A, Henriksson KG, Larsson J: Reduced high-energy phosphate levels in the painful muscles of patients with primary fibromyalgia. Arthritis Rheumatol 29:817-821, 1986. 22. Dryer SJ, Boden S: Laboratory evaluation in neck pain. Physical Med Rehabil Clin N Am 14:589-604, 2003. 23. Crockard HA: Surgical management of cervical rheumatoid problems. Spine 20:2584-2590, 1995. 24. Cooper RG, Freemont AS, Hoyland JA, et al: Herniated intervertebral disc-associated periradicular fibrosis and vascular abnormalities occur ­without inflammatory cell infiltration. Spine 20:591-598, 1995. 25. Chabot MC, Montgomery DM: The pathophysiology of axial and radicular neck pain. Semin Spine Surg 7:2-8, 1995. 26. An HS, Riley L (eds): An Atlas of Surgery of the Spine: Anterior Cervical Spine Procedures. London, Martin Dunitz Ltd, 1998. 27. Truumees E, Herkowitz H: Cervical spondylotic myelopathy and radiculopathy. Instr Course Lect 29:339-360, 2000. 28. Houser OW, Onofrio B, Miller GM, et al: Cervical spondylotic stenosis and myelopathy: Evaluation with computed tomographic myelography. Mayo Clin Proc 69:557-563, 1994. 29. Ono K, Otai H, Tada K, et al: Cervical myelopathy secondary to multiple spondylotic protrusions: A clinicopathologic study. Spine 2: 109-125, 1977. 30. Breig A, Turnbull I, Hassler O: Effects of mechanical stresses on the spinal cord in cervical spondylosis. J Neurosurg 25:45-56, 1966. 31. Mihara H, Ohnari K, Hachiya M, et al: Cervical myelopathy caused by C3-C4 spondylosis in elderly patients: A radiographic analysis of pathogenesis. Spine 25:796-800, 2000. 32. Ferguson RJ, Caplan LR: Cervical spondylotic myelopathy. Neurol Clin 3:373-382, 1985. 33. Gooding MR, Wilson CB, Hoff ST: Experimental cervical myelopathy: Effect of ischemia and compression of the canine cervical spinal cord. J Neurosurg 43:9-17, 1975. 34. Nurick S: The pathogenesis of the spinal cord disorder associated with cervical spondylosis. Brain 95:87-100, 1972. 35. Sampath P, Bendebba M, Davis JD, et al: Outcome of patients treated for cervical myelopathy: A prospective, multicenter study with independent clinical review. Spine 25:670-676, 2000. 36. Romanelli P, Esposito V: The functional anatomy of neuropathic pain. Neurosurg Clin N Am 15:257-268, 2004. 37. Mackley RJ: Role of trigger points in the management of head, neck, and face pain. Funct Orthod 7:4-14, 1990. 38. Henderson CM, Hennessy RG, Shuey HM, et al: Posterior-lateral foraminotomy as an exclusive operative technique for cervical radi­ culopathy: A review of 846 consecutively operated cases. Neurosurgery 13:504-512, 1983. 39. Frobert O, Fossgreen J, Sondergaard-Peterson J, et al: Musculo-skeletal pathology in patients with angina pectoris and normal coronary angiograms. J Intern Med 245:237-246, 1999. 40. Hoffman JR, Mower WR, Wolfson AB, et al: National Emergency X-Radiography Utilization Study Group: Validity of a set of clinical criteria to rule out injury to the cervical spine in patients with blunt trauma. N Engl J Med 343:94-99, 2000. 41. Sforza C, Grassi G, Fragnito N, et al: Three-dimensional analysis of active head and cervical spine range of motion: Effect of age in healthy male subjects. Clin Biomech (Bristol, Avon) 17:611-614, 2002.

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42. Weinfeld RM, Olson PN, Maki DD, et al: The prevalence of diffuse idiopathic skeletal hyperostosis (DISH) in two large American Midwest metropolitan hospital populations. Skeletal Radiol 26:222-225, 1997. 43. Davidson RI, Dunn EJ, Metzmaker JN: The shoulder abduction test in the diagnosis of radicular pain in cervical extradural compressive monoradiculopathies. Spine 6:441-446, 1981. 44. Gore DR, Sepic SB, Gardner GM: Roentgenographic findings of the cervical spine in asymptomatic people. Spine 11:521-524, 1986. 45. Levine MJ, Albert T, Smith MD: Cervical radiculopathy: Diagnosis and nonoperative management. J Am Acad Orthop Surg 4:305-316, 1996. 46. Collins DN, Barnes CL, Fitz Randolph RL: Cervical spine instability in rheumatoid patients having total hip or knee arthroplasty. Clin Orthop 272:127-135, 1991. 47. Modic MT, Masaryk T, Mulopulos GP, et al: Cervical radiculopathy: Prospective evaluation with surface coil MR imaging, CT with metrizamide, and metrizamide myelography. Radiology 161:753-759, 1986. 48. Modic MT, Ross J, Masaryk TJ: Imaging of degenerative disease of the cervical spine. Clin Orthop 239:109-120, 1989. 49. Boden SD, McCowin PR, Davis DO, Dina TS, et al: Abnormal ­magnetic-resonance scans of the cervical spine in asymptomatic subjects. J Bone Joint Surg 72:1178-1184, 1990. 50. Seitz JP, Unguez CE, Corbus H, et al: SPECT of the cervical spine in the evaluation of neck pain after trauma. Clin Nucl Med 20:667-673, 1995. 51. Waddell G: An approach to backache. Br J Hosp Med 28:187-190, 1982. 52. Kushner HL: Acute phase response. Clin Aspects Autoimmun 3: 20-30, 1989. 53. Gore DR, Sepic SB, Gardner GM, et al: Neck pain: A long-term ­follow-up of 205 patients. Spine 12:1-5, 1987. 54. Taimela S, Takala EP, Asklof T, et al: Active treatment of chronic neck pain. Spine 25:1021-1027, 2000. 55. Waling K, Sundelin G, Ahlgren C, et al: Perceived pain before and after three exercise programs: A controlled clinical trial of women with work-related trapezius myalgia. Pain 85:201-207, 2000. 56. Bronfort G, Evans R, Nelson B, et al: A randomized clinical trial of exercise and spinal manipulation for patients with chronic neck pain. Spine 26:788-799, 2001.

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57. Gross AR, Kay T, Hondras M, et al: Manual therapy for mechanical neck disorders: A systematic review. Manual Ther 7:131-149, 2002. 58. Beebe FA, Barkin RL, Barkin S: A clinical and pharmacologic review of skeletal muscle relaxants for musculoskeletal conditions. Am J Ther 12:151-171, 2005. 59. Kay TM, Gross A, Goldsmith C, et al: Exercises for mechanical neck disorders. Cochrane Database Syst Rev 3:CD004250, 2005. 60. Irnich D, Behrens N, Molzen H, et al: Randomised trial of acupuncture compared with conventional massage and “sham” laser acupuncture for treatment of chronic neck pain. BMJ 322:1574-1578, 2001. 61. Niemisto L, Kalso E, Malmivaara A, et al: Radiofrequency denervation for neck and back pain: A systematic review of randomized controlled trials. Cochrane Database Syst Rev 1:CD004058, 2003. 62. Dagenais S, Haldeman S, Wooley JR: Intraligamentous injection of sclerosing solutions (prolotherapy) for spinal pain: A critical review of the literature. Spine J 5:310-328, 2005. 63. Kroeling P, Gross A, Goldsmith CH: A Cochrane review of electrotherapy for mechanical neck disorders. Spine 30:E641-E648, 2005. 64. Saal JS, Saal JA, Yurth EF: Nonoperative management of herniated cervical intervertebral disc with radiculopathy. Spine 21:1877-1883, 1996. 65. Carette S, FM: Clinical practice: Cervical radiculopathy. N Engl J Med 353:392-399, 2005. 66. Riew KD, Yuming Y, Gilula L: The effect of nerve-root injections on the need for operative treatment of lumbar radicular pain: A prospective, randomized, controlled, double-blind study. J Bone Joint Surg 82:1589-1593, 2000. 67. Persson LC, Carlsson CA, Carlsson JY: Long-lasting cervical radicular pain managed with surgery, physiotherapy, or cervical collar. Spine 22: 751-758, 1997. 68. Pellicci PM, Ranawat CS, Tsairis P, et al: A prospective study of the ­progression of rheumatoid arthritis of the cervical spine. J Bone Joint Surg 63:342-350, 1981. 69. Marks JS, Sharp J: Rheumatoid cervical myelopathy. QJM 50:301-319, 1989. 70. Mansour M, Cheemu GS, Naquwa SM, et al: Ankylosing spondylitis: A contemporary perspective on diagnosis and treatment. Semin Arthritis Rheum 36:210-223, 2007.

40

Shoulder Pain Scott David Martin  •  Thomas S. Thornhill

Key Points Understand the anatomy and function of the shoulder. Perform a thorough history and physical examination of the shoulder. Formulate a differential diagnosis of shoulder pain.

A detailed analysis of shoulder problems and the treatment of major trauma are beyond the scope of this chapter and have been addressed by other authors.1-5 Figure 40-1 is a useful algorithm that can direct the clinician in the initial treatment of traumatic and nontraumatic causes of shoulder pain.

Know appropriate diagnostic tests to assist in diagnosis. Develop an appropriate treatment plan.

Shoulder pain is one of the most common musculoskeletal complaints that may require evaluation in the office setting. Accurate diagnosis of shoulder pain is made difficult by the unique anatomy and position of the shoulder as a link between the upper extremity and thorax. One of the most complex and mobile joints of the body, the shoulder is traversed by muscle, tendon, and bone, and is surrounded by major neurovascular structures, all of which may serve as potential sources of local and referred pain. Determining the source of shoulder pain is essential in recommending the proper method of treatment. The examining physician must be able to differentiate the occurrence of shoulder pain caused by intrinsic, or local, factors and extrinsic, or remote, factors, or a combination of the two. Intrinsic factors originate from the shoulder girdle and include glenohumeral and periarticular disorders, whereas extrinsic factors occur outside of the shoulder girdle with secondary referral pain to the shoulder (Table 40-1). Examples of extrinsic factors include left shoulder pain as the initial presentation of coronary artery disease. Hepatic or splenic disease also may initally manifest as shoulder pain. Accurate evaluation, diagnosis, and treatment require a thorough understanding of shoulder anatomy, including pain referral patterns. A complete and systematic physical examination is crucial to an accurate diagnosis. During the initial evaluation, care must be taken to discern all possible causes of the shoulder pain. Final diagnosis may require repeated office examinations and correlation of diagnostic tests with symptoms and response to selective injections. Improvements in diagnostic tests, such as magnetic resonance imaging (MRI), computed tomography (CT)–arthrography, ultrasonography, and electromyography (EMG), have facilitated early diagnosis of shoulder pain and have provided a better understanding of shoulder pathology. This chapter provides practical guidelines for the diagnosis and treatment of painful shoulder disorders that may be encountered in a rheumatology or general practice.   Video available on the Expert Consult Premium Edition website.

ANATOMY AND FUNCTION Because of its complexity, an understanding of the structural and functional anatomy of the shoulder is required for the clinician treating shoulder pain. The shoulder joint is the most mobile joint of the body, although mobility is gained at the sacrifice of stability. Only 25% of the humeral head surface has contact with the glenoid at any time. The labrum increases the contact area of the articular surface and confers stability to the joint.6 Lesions of the labrum may result from instability, and the type of lesion may indicate the type of instability. Labral tears also may be a source of pain from internal derangement of the shoulder.7 Joint stability also is provided by a thin capsule and the glenohumeral ligaments, which are thickenings of the capsule anteriorly, posteriorly, and inferiorly.6 Anterior stability is predominantly conferred by the anterior band of the inferior glenohumeral ligament. The rotator cuff provides dynamic stability of the joint. It is composed of three musculotendinous units—the supraspinatus, infraspinatus, and teres minor—posteriorly and the subscapularis anteriorly. The shoulder consists of three joints—acromioclavicular (AC), sternoclavicular, and glenohumeral—and two gliding planes—the scapulothoracic and subacromial surfaces. Figure 40-2 shows the musculoskeletal and topographic localization of pain associated with common shoulder disorders. Figure 40-3 shows the relationship of the three posterior rotator cuff muscles coursing anteriorly underneath the acromion to insert on the greater tuberosity. The subscapularis, the only anterior rotator cuff muscle, inserts on the lesser tuberosity. By understanding the relationship between the rotator cuff and the subacromial region, bounded inferiorly by the humeral head and superiorly by the undersurface of the acromion, the clinician can visualize the problems of impingement syndrome and can accurately inject this space. Knowledge of the route of the tendon of the long head of the biceps through the bicipital groove and onto the superior aspect of the glenoid helps in understanding bicipital tendinitis. Before attempting to diagnose and treat shoulder pain, the clinician should review in detail one of the many sources describing the structural and functional relationships of the shoulder girdle.2,3 587

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Table 40-1  Common Causes of Shoulder Pain Intrinsic Causes Periarticular disorders Rotator cuff tendinitis or impingement syndrome Calcific tendinitis Rotator cuff tear Bicipital tendinitis Acromioclavicular arthritis Glenohumeral disorders Inflammatory arthritis Osteoarthritis Osteonecrosis Cuff arthropathy Septic arthritis Glenoid labral tears Adhesive capsulitis Glenohumeral instability Extrinsic Causes Regional disorders Cervical radiculopathy Brachial neuritis Nerve entrapment syndromes Sternoclavicular arthritis Reflex sympathetic dystrophy Fibrositis Neoplasms Miscellaneous Gallbladder disease Splenic trauma Subphrenic abscess Myocardial infarction Thyroid disease Diabetes mellitus Renal osteodystrophy

Pain intensity, character, location, and periodicity and aggravating or alleviating factors should be assessed. Pain should be graded on a visual analog scale of 0 to 10—0 indicates no pain, and 10 indicates the worst pain the patient has ever experienced. Another indication of the severity of pain is disruption of sleep. The patient should be asked whether the pain prevents sleep, if pain awakens the patient, and whether the patient can lie on the affected shoulder. Is the pain sharp or dull? Sharp, burning pain indicates a neurogenic origin, whereas a dull, aching pain suggests rotator cuff pathology with impingement. Location or distribution of the pain should be identified. Is it local around the shoulder girdle, or does the pain radiate down the arm? Is there concomitant sensory loss or weakness? Periodicity of the pain as constant or intermittent should be determined, as should factors that aggravate or alleviate the pain. Pain caused by rotator cuff tendinopathy usually is exacerbated by repetitive activities that involve the elbow away from the side of the body. Any history of neck pain should be considered, along with history of radicular pain. Radicular-type pain frequently extends below the elbow and is associated with sensory loss and ­ weakness. Pain located in the paracervical region may indicate a cervical origin, or it can be localized to the trapezius. Trapezial pain often is associated with shoulder pain and results from the patient trying to favor the shoulder. Assuming a military brace position may produce fatiguing and spasm of the trapezius. Any pertinent medical history, such as a history of malignancy, should be considered. Neurologic, visceral, and vascular disease can produce referred pain to the shoulder and should always be kept in mind, especially in a patient with a painless range of motion. PHYSICAL EXAMINATION

DIAGNOSIS CLINICAL EVALUATION OF THE SHOULDER Accurate diagnosis and successful treatment of a shoulder disorder begins with a thorough history and physical examination. Most of the information needed to make a correct diagnosis can be elicited with basic clinical skills, rather than relying on expensive and highly technologic investigative aids. Diagnostic tests should be used only to confirm an established diagnosis or to assist in cases with a challenging presentation. HISTORY In establishing a diagnosis, it is important to consider the patient’s age and chief complaint. The differential diagnosis of shoulder pain in a 70-year-old sedentary individual is entirely different from shoulder pain in a 20-year-old pitcher. Did the pain occur slowly over time or suddenly with a particular event? The gradual onset of pain over the anterolateral or deltoid region that is increased with forward elevation of the shoulder suggests impingement with rotator cuff tendinitis. The presence of significant weakness with pain on overhead activities suggests impingement with rotator cuff tear. Initiating factors relative to the onset of the symptoms should be elicited, and any history of shoulder pain or trauma should be carefully documented.

Proper physical examination of the shoulder includes close inspection of the shoulder girdle from the front and back. The evaluation is started by standing behind the patient, with both shoulders exposed. The normal shoulder is always inspected and compared with the injured shoulder. Examination can be started with the patient in the sitting or standing position. Contour and symmetry are observed and compared between shoulders, assessing any atrophy or asymmetry in shoulder position or level. Spinatus muscle atrophy may result from disuse, chronic cuff tear, or suprascapular or brachial neuropathy.8 If evidence of scapular winging is evident, the patient should be asked to do a wall push-up, which accentuates winging. Range of motion should be carefully recorded, noticing any absence of rhythmic shoulder motion or excessive scapulothoracic motion that may compensate for the lack of glenohumeral motion. Internal rotation of the shoulder is checked by having the patient reach behind the back with the thumb while the examiner notices the vertebral level. Loss of internal rotation is seen early with shoulder pain and usually indicates some tightness of the posterior shoulder capsule. Palpation of the biceps tendon, coracoid, lesser and greater tuberosities, and posterior cuff is done, and any tenderness is gauged (Fig. 40-4A). Tenderness on palpation of the long head of the biceps frequently is associated with rotator cuff tendinopathy and tenderness of the greater tuberosity. Any spasm or tenderness of the trapezius

Refer orthopedics or rheumatology?

No improvement Home PT Gradual resumption of overhead activity NSAIDs PRN

Improvement

Reevaluate 4-6 weeks

PT NSAIDs Ice Restrict overhead activity

No improvement

- Findings

Refer orthopedics or rheumatology

+ Findings

Continued pain

Reevaluate 3 months

Continue conservative Tx PT NSAIDs Cervical traction

- Radicular Sx

Home PT Gradually increase Refer activities orthopedics or No improvement rheumatology

X-ray Flex/ext views

Improvement

Improvement

Improvement

Refer orthopedics or rheumatology

PT NSAIDs Ice

Refer orthopedics or rheumatology

No improvement

Reevaluate 3 months

Continue home PT and NSAIDs

Improvement

Refer orthopedics or rheumatology

- Findings

MRI

- Joint changes

+ Findings No improvement

Reevaluate 3 months

+ GH arthridities Physical therapy Injection NSAIDs

Continue home PT and NSAIDs Gradual resumption of overhead activity

No improvement

Reevaluate 3 months

Reevaluate 3 months

? Radiographs Zanca view (AP or AC joint) 10-15 degree cephalic tilt 50% penetrance

? Radiographs True AP Scapular Y Axillary

Glenohumeral joint pain

DIFFERENTIAL DIAGNOSIS OF REGIONAL MUSCULOSKELETAL PAIN

Figure 40-1  Algorithmic evaluation of shoulder pain. AC, acromioclavicular; AP, anteroposterior; GH, glenohumeral; Hx, history; MRI, magnetic resonance imaging; NSAID, nonsteroidal anti-­inflammatory drug; PRN, as required; PT, physical therapy; R/O, rule out; ROM, range of motion; Sx, symptoms; trx, traction; Tx, therapy.

Home PT Resume overhead activity

Improvement

Reevaluate 3 months

Instability ± impingement

AC joint path + Pain palpation + Cross chest adductor test + Lidocaine injection test

Physical therapy Periscapular, cuff, and subscapularis strengthening NSAIDs Avoidance of above shoulder activity

Cervical spondylosis

+ X-ray

Reevaluate 6 weeks

PT Cervical trx Cervical collar NSAIDs

- X-ray

Cervical x-rays AP Lateral Obliques

Negative impingment signs Primary C-spine pain Radicular symptoms R/O Pancoast tumor

Refer orthopedics or Impingement series? rheumatology - AP of shoulder with 30-degree caudal tilt - Scapular Y with 10-degree caudal tilt + Radicular Sx - Axillary view Subacromial injection Continued PT NSAIDs MRI

Continued pain/weakness

No improvement

Refer orthopedics or rheumatology

+ Fracture + Dislocation

+ X-ray

Positive impingement signs Positive impingement test (Lidocaine injection) No instability Good strength/mild weakness Good ROM

NONTRAUMATIC

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Home PT Gradual resumption of shoulder activity

Improvement

Reevaluate 3-4 weeks

Rest/ice NSAIDs PT

- X-ray

Shoulder radiographs True AP Scapular Y Axillary Neuro exam

Hx trauma

HISTORY AND PHYSICAL EXAM

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3

1

7

4

5 6

2

8

Figure 40-2  A-D, Musculoskeletal (A and B) and topographic (C and D) areas localizing pain and tenderness associated with specific shoulder problems. 1, Subacromial space (ro-­ tator cuff tendinitis/impingement syndrome, calcific tendinitis, rotator cuff tear). 2, Bicipital groove (bicipi-­ tal tendinitis, biceps tendon sublux-­ ation and tear). 3, Acromioclavicular joint. 4, Anterior glenohumeral joint (glenohumeral arthritis, osteonecro-­ sis, glenoid labrum tears, adhesive capsulitis). 5, Sternoclavicular joint. 6, Posterior edge of acromion (rota-­ tor cuff tendinitis, calcific tendinitis, rotator cuff tear). 7, Suprascapular notch (suprascapular nerve entrap-­ ment). 8, Quadrilateral space (axil-­ lary nerve entrapment). These areas of pain and tenderness frequently overlap.

B

A 2

1

6

3 7

5

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C

or levator scapulae may be associated with rotator cuff disease or cervical spine disease. Cervical range of motion and palpation of the paracervical muscles are carried out. Paracervical tenderness and limited range of motion of the neck may indicate cervical spondylosis or neurogenic disease. A Spurling test is done by flexing the neck laterally while applying axial compression to the skull. The production of pain that radiates to the ipsilateral shoulder is considered a positive test result and indicates radiculopathy. To elicit the impingement sign, the shoulder is elevated passively in forward flexion, while depressing the scapula with the opposite hand, forcing the greater tuberosity against the anterior acromion and producing pain in cases of impingement (Fig. 40-4B).9 This maneuver also may be painful in conditions such as adhesive capsulitis, glenohumeral and AC arthritis, glenohumeral instability, and calcific tendinitis. A dynamic impingement test, the circumduction-adduction shoulder maneuver, also called the Clancy test, is 95% sensitive and 95% specific for diagnosing rotator cuff tendinopathy, including partial tears.10 The test is done with the patient in the standing position and with the head turned to the contralateral shoulder. The affected shoulder is circumducted and adducted across the body to shoulder level, keeping the elbow in extension, the shoulder in internal rotation, and the thumb pointing toward the floor (Fig. 40-4C). In this position, the patient is instructed to resist

D maximally as a uniform downward force is applied to the extended arm by the examiner. The test result is considered positive if pain or weakness is elicited during the maneuver, with pain being localized to the anterolateral aspect of the shoulder. There is a strong positive correlation of pain and weakness with complete cuff tear.10 The sternoclavicular and AC joints should be observed for prominences and palpated for stability and tenderness. Many patients with impingement have tenderness on direct downward palpation of the AC joint owing to impingement on the cuff from undersurface osteophytes of the distal clavicle.2,8 AC joint tenderness also may result from primary AC joint arthrosis and should be differentiated by physical examination, including the cross-chest adduction test and O’Brien’s test.11 Radiographic evidence of AC joint arthrosis is common in patients older than 40 years, but is not usually painful.12 The cross-chest adduction test or horizontal adduction test is performed by forward flexion of the shoulder 90 degrees with subsequent cross-chest adduction of the arm (Fig. 40-4D). Pain localized to the AC joint is considered a positive test result. If pain occurs posteriorly over the shoulder, a tight posterior capsule with impingement is suspected. O’Brien’s test is performed by forward flexing the arm 90 degrees and adducting the arm 10 degrees out of the sagittal plane of the body. The first part of the test is ­performed

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A Coracoclavicular ligament: Subscapularis tendon Trapezoid ligament Coracoid Supraspinatus tendon process Conoid ligament Infraspinatus tendon Teres minor tendon Clavicle Subscapularis muscle Acromion of scapula Coracoacromial ligament Spine of scapula Superior margin of scapula

B

Supraspinatus muscle Clavicle

Infraspinatus muscle Coracoid process

Acromioclavicular joint Acromion Coracoacromial ligament Supraspinatus tendon Subscapularis tendon Greater tuberosity Lesser tuberosity Humerus

Bicipital tendon groove

with the hand maximally pronated with the thumb pointed down. In this position, the patient is asked to resist as the examiner applies a downward force on the arm. If the test elicits pain, the patient is asked if the pain is on top of the shoulder or deep inside. Pain localized to the top of the shoulder indicates AC joint pain, and pain deep inside the shoulder indicates a superior labrum anterior posterior (SLAP) lesion. In the second part of the test, the patient is asked to supinate the hand maximally, while the examiner applies a downward force to the arm. If the patient notices significantly less pain, the test result is positive for a SLAP lesion. If the pain is unchanged and located on top of the shoulder, the test result is positive for AC joint pathology.11 If the cause of AC joint tenderness is still in question, a lidocaine injection should be administered, carefully avoiding injecting the subacromial space by advancing the needle too far inferiorly through the AC joint, which can lead to false interpretation. Painful degenerative changes of the AC joint may exist concomitantly with subacromial impingement

Figure 40-3  A, Superior view of the rotator cuff musculature as it courses anteriorly underneath the coracoacromial arch to insert on the greater tuberosity. B, Anterior view of the shoulder reveals the subscapularis, which is the only anterior rotator cuff muscle inserting on the lesser tuberosity. It internally rotates the humerus and provides dynamic anterior stability to the shoulder. (A from the Ciba Collection of Medical Illustrations, Volume 8, Part I. Reproduced by permission of Ciba-Geigy; B from Martin TL, Martin SD: Rotator cuff tendinopathy. Hosp Med 12:23-31, 1998.)

and should be evaluated thoroughly when surgical treatment (i.e., distal clavicle excision) is being considered.13 In patients with pain out of proportion to objective findings, other causes of shoulder pain should be sought, including calcific tendinitis, infection, reflex sympathetic dystrophy, and fracture. Patients with significant wasting of the supraspinatus and infraspinatus muscles and posterior shoulder pain, especially younger patients, may have suprascapular neuropathy or brachial plexopathy.8,14 Patients with chronic cuff disease frequently have variable disuse atrophy of the supraspinatus and infraspinatus fossae; in cases of chronic massive cuff tears, atrophy and weakness can be severe. Strength testing of external ­rotation should be done with the elbow at the side and supported by the examiner; the patient is asked to attempt external rotation of the shoulder from a neutral position (0 degrees of adduction), while the examiner applies resistance (see Fig. 40-4E).15 Weakness in this position may suggest a tear of the infraspinatus tendon. Abduction strength testing against

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Sternoclavicular Acromioclavicular joint joint Subdeltoid bursa

Examiner elevates shoulder here and...

Bicipital tendon groove Greater tuberosity Lesser tuberosity Glenohumeral joint space

A

Examiner applies force here

C

... depresses scapula here (from back)

B

Pain on palpation = acromioclavicular joint impingement

Arm adducted across chest

Pain on palpation = tight posterior capsule

Patient resists force here

D

Patient attempts external rotation of the shoulder 30

Examiner applies force here

90

E

Examiner applies force here

F

Patient resists force here

Figure 40-4  A, Tenderness on palpation of trigger points may help localize the site of pathology. Tenderness on palpation of the long head of the biceps and greater tuberosity suggests impingement with possible cuff tendinopathy. B, To elicit the impingement sign, the shoulder is elevated in forward flexion while the scapula is depressed with the opposite hand, forcing the greater tuberosity and rotator cuff against the anterior acromion and produc-­ ing pain when impingement exists. Relief of pain after injection of local anesthetics (i.e., impingement test) provides additional evidence of subacromial pathology. C, The Clancy test is performed with the patient standing and with the head turned toward the contralateral shoulder. The affected shoulder is circumducted and adducted across the body to shoulder level, keeping the elbow in extension with the arm internally rotated with the thumb pointed toward the floor. In this position, the patient is asked to resist maximally as a uniform downward force is applied to the extended arm by the examiner. The production of pain or weakness localized to the anterior lateral portion of the shoulder is considered a positive test result. D, The test is performed by for-­ ward flexion of the arm at 90 degrees and subsequent cross-chest adduction of the arm. Pain localized to the acromioclavicular joint is considered a posi-­ tive test result. E, The test is performed with the patient’s elbow flexed at 90 degrees and held at the patient’s side by the examiner. The patient is asked to attempt external rotation of the shoulder from a neutral position (0 degrees of adduction) as the examiner applies resistance to the forearm. Strength is compared with that of the contralateral arm. F, Abduction strength testing is performed with the patient’s shoulder in 30 degrees of forward flexion and 90 degrees of abduction and with the thumb pointed toward the floor. The patient is asked to resist as the examiner exerts a downward force on the abducted arm. Strength is compared with the contralateral shoulder. (From Martin TL, Martin SD: Rotator cuff tendinopathy. Hosp Med 12:23-31, 1998.)

resistance is done with the shoulder in 30 degrees of forward flexion and 90 degrees of abduction, and the thumb pointed toward the floor (see Fig. 40-4F).16,17 Weakness in this position may suggest a tear of the supraspinatus tendon. A liftoff test should be performed with the shoulder in internal

r­ otation; the patient is asked to try to hold the hand away from the back. Inability to do so indicates a subscapularis tear. If after a thorough physical examination impingement is suspected, an impingement test should be performed with injection of 5 mL of local anesthetic into the subacromial

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space.18,19 Before performing the test, the patient is asked to grade the pain during the impingement signs on a visual analog scale of 0 to 10, with 0 equal to no pain and 10 equal to the most severe pain the patient has ever experienced. The injection may be done anteriorly or posteriorly, depending on physician’s preference. Ten minutes after injection of local anesthetic into the subacromial space, the patient should be re-examined and asked to regrade the pain on the same visual analog scale. A 50% or more reduction in pain is thought to be a positive test result for impingement; otherwise, an alternative cause of shoulder pain should be sought, or inadequate placement of the anesthetic should be suspected. If the AC joint is thought to be contributing to the shoulder pain, 1 to 2 mL of local anesthetic should be injected into the joint, and the shoulder should be re-­examined. When subacromial impingement and the AC joint are thought to be contributing to shoulder pain, serial injections during separate office visits may be needed to evaluate the shoulder while minimizing discomfort to the patient.12 In cases of suspected bicipital tendinitis, Speed’s test is performed by having the patient flex the shoulder and extend the elbow while a downward force is applied to the arm. The production of pain over the long head of the biceps is a positive test result and suggests bicipital tendinitis. Upper extremity strength testing should be performed and compared with the contralateral side so that any atrophy is detected. Grip strength is checked, and the hands are examined carefully for evidence of intrinsic atrophy. The biceps (C5), triceps (C7), and brachioradialis (C6) reflexes are checked for symmetry and briskness. Light touch sensory testing should be conducted, and the dermatomal distribution of any deficits that may suggest cervical radiculopathy should be identified. The cervical, supraclavicular, axillary, and epitrochlear regions should be palpated for enlarged lymph nodes, which may suggest malignancy. RADIOGRAPHIC ASSESSMENT For nontraumatic painful shoulder evaluation, standard radiographic profiles are used. An impingement series should be obtained, which includes anteroposterior views with a 30-degree caudal tilt (Rockwood view), outlet view ­(scapular Y with 10- to 15-degree caudal tilt), and axillary view. Internal and external rotational views may be obtained if calcific tendinitis or instability is suspected. The Rockwood view can reveal any osteophytes off the anterior acromion and AC joint.20 In cases of traumatic injury, a trauma series is obtained that includes a true anteroposterior view, scapular Y view, and an axillary view. The axillary view is useful in assessing posterior or anterior subluxation of the humeral head. Additional views, such as the West Point view, which evaluates the glenoid for evidence of a bony Bankart lesion, or the Styker notch view, which assesses the humeral head for a Hill-Sachs lesion, may be obtained to assist the evaluation if the diagnosis of instability is in doubt. Secondary impingement-type rotator cuff tendinitis may be caused by increased anterior translation with subluxation of the humeral head. In such cases, an axillary view or fluoroscopy can help show the subluxation.21,22 When AC joint pathology is suspected, a 10-degree, cephalic-tilt view of the AC joint at 50% penetrance, as described by Zanca,23 should be obtained (Fig. 40-5). Stress

593

X-ray 10°

Figure 40-5  Zanca view of the acromioclavicular joint is obtained with a 10-degree cephalic tilt and 50% penetrance. (From Rockwood CA Jr, Young DC: Disorders of the acromioclavicular joint. In Rockwood CA Jr, Matsen TA III [eds]: The Shoulder. Philadelphia, WB Saunders, 1985, pp 413-476.)

views of the AC joint may be obtained by strapping 5 to 10 lb of weight to the patient’s forearms and determining AC separation. Comparing the coracoclavicular distance of both shoulders may be helpful. When clinically indicated, cervical spine radiographs should be obtained to exclude cervical spondylosis as a cause of shoulder pain. SCINTIGRAPHY Tc 99m MDP or gallium may be of diagnostic help in evaluating skeletal lesions around the shoulder joint. Bone scans generally are not helpful in the diagnosis of non-neoplastic or noninfectious shoulder disease. Scintigraphy may have a role in identifying patients with complete rotator cuff tears that proceed to cuff-tear arthropathy. This is an important distinction because patients with complete rotator cuff tears may do well, whereas patients who develop progressive changes of cuff-tear arthropathy have progressive arthritis, pain, and significant functional impairment. Synovitis or calcium pyrophosphate deposition disease may be an important factor in the pathogenesis of cuff-tear arthropathy. In such cases, scintigraphy may show the increased blood flow and blood pooling associated with chronic synovitis. ARTHROGRAPHY Double-contrast arthrotomography (DCAT) can be used to evaluate problems of the rotator cuff, glenoid labrum, biceps tendon, and shoulder capsule.24-27 Figure 40-6 shows normal DCAT of the shoulder. Rotator cuff tears can be

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RC

AC

BT

Figure 40-6  Normal double-contrast arthrography shows the inferior edge of the rotator cuff (RC) as it courses through the subacromial space to the greater tuberosity, the tendon of the long head of the biceps (BT), and the articular cartilage of the humeral head (AC).

Figure 40-8  Double-contrast arthrotomography shows a tear of the anterior-inferior portion of the glenoid labrum (arrow).

Figure 40-7  Multidetector CT revealing a superior labral tear of shoulder.

shown by single-contrast or double-contrast studies. The proponents of double-contrast arthrography believe that the extent of the tear, the preferred surgical approach, and the quality of the rotator cuff tissue are best determined by double-contrast studies.24-29 Arthrography without MRI or CT can be misleading and result in underestimating the extent of a rotator cuff tear. Multidetector CT can increase the accuracy of diagnosing labral and rotator cuff tears (Fig. 40-7). Tears of the glenoid labrum without shoulder dislocation are sources of anterior shoulder pain in athletes.7 Glenoid labrum tears (Fig. 40-8), with or without associated glenohumeral subluxation, frequently can be identified by DCAT.27,28 Kneisl and colleagues30 described 55 patients who underwent DCAT followed by diagnostic shoulder arthroscopy. DCAT predicted the arthroscopic findings in 76% of ­anterior labrum studies and 96% of posterior labrum studies. This test was 100% sensitive and 94% specific in

Figure 40-9  Double-contrast arthrography of a patient with calcific ten-­ dinitis (arrow) and adhesive capsulitis. Notice the contracted capsule with diminution of the synovial space and obliteration of the axillary recess.

diagnosing complete rotator cuff tears. Partial rotator cuff tears identified at arthroscopy were missed in 83% of patients undergoing DCAT. The investigators believed DCAT was better in diagnosing intra-articular and cuff pathology in cases of instability than when pain alone was the presenting diagnosis.30 Shoulder arthrography can confirm a diagnosis of adhesive capsulitis by showing a contracted capsule with an obliterated axillary recess (Fig. 40-9). The use of subacromial bursography has been beneficial in visualizing the outer surface of the rotator cuff and the subacromial space in cases of impingement.31,32 Fukuda and associates33 reported a small series of younger patients (average

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Figure 40-10  CT-arthrography of shoulder. A, Normal findings. B, Tear of the anterior glenoid labrum. C, A large defect of the articular surface of the posterior portion of the humeral head (Hill-Sachs lesion) (arrow). D, Loose body in the posterior recess (arrow).

age 41.8 years) who underwent subacromial bursography after a negative glenohumeral arthrographic result. These patients showed pooling of contrast medium on the bursal side of a tear, which was confirmed at the time of surgery. Subacromial bursography is not routinely used diagnostically, and in our opinion, it is of little value in planning surgical procedures. COMPUTED TOMOGRAPHY CT is helpful in evaluating the musculoskeletal system, and CT combined with contrast arthrography (CT-arthrography) has become a major diagnostic tool for the evaluation of glenoid labrum tears, loose bodies, and chondral lesions (Fig. 40-10). Rafii and coworkers34 reported using CT-arthrography in the evaluation of shoulder derangement. This study found a 95% accuracy of CT-­arthrography for investigating lesions of the labrum and articular surface.34 More recently, multidetector CT-arthrography scans have been used to evaluate partial cuff tears (Fig. 40-11A), cystic lesions (Fig. 40-11B), and calcific tendinopathy (Fig. 40-11C). ULTRASONOGRAPHY The technologic improvement of ultrasound equipment has allowed improved ultrasound study of the rotor cuff. The technique is noninvasive, is rapid, and involves no radiation

exposure.30-32,35 The cuff is examined in the horizontal and transverse planes with the arm in different positions to visualize various areas of the cuff. These techniques generally provide visualization of the distal cuff, where most rotator cuff tears are located. Figure 40-12 shows normal and abnormal ultrasound images of the rotator cuff in longitudinal and transverse planes. Several studies report a high sensitivity and specificity for the diagnosis of a rotator cuff tear by ultrasound.32-35 The specificity and sensitivity of the procedure are reported to be greater than 90% as determined by arthrographic and surgical correlations.34,35 This technique also has been used for the postoperative evaluation of a rotator cuff repair and for evaluation of abnormalities of the biceps tendon.36-40 Gardelin and Perin41 reported ultrasound to be 96% sensitive in determining rotator cuff and biceps tendon pathology. Mack and associates36 found ultrasound to be valuable in evaluating postoperative patients with recurrent shoulder symptoms. In a prospective study, Hodler and colleagues39 compared ultrasound with MRI and arthrography in evaluating rotator cuff lesions in 24 shoulders. Ultrasound identified 14 of 15 torn cuffs, MRI identified 10 of 15, and arthrography identified 15 of 15.39 Ultrasound identified seven of nine intact rotator cuffs, whereas MRI was accurate in eight of nine intact cuffs.39 Vestring and colleagues42 found ultrasound to be as accurate as MRI in

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Figure 40-11  Multidetector CT-arthrography. A, Partial rotator cuff tear (coronal view). B, Cystic humeral head erosions with calcification (axial view). C, Calcification within rotator cuff tendon (coronal view).

the diagnosis of humeral head defects and joint effusions, but inferior to MRI in the diagnosis of labrum lesions, rotator cuff lesions, subacromial spurs, and synovial inflammatory disease. In the hands of an experienced sonographer, ultrasound may be the most cost-effective test for the initial evaluation of a rotator cuff injury, but most surgeons require CT-arthrography or MRI confirmation before surgical exploration.36,39,41-43 ARTHROSCOPY The use of arthroscopy for the diagnosis of shoulder pathology increased in the 1980s, partially because of its accuracy, which was far greater than clinical examination and better than other diagnostic modalities of the time. With technologic advances of fiberoptics, video output, and arthroscopic instrumentation, the use of arthroscopy to diagnose and treat shoulder problems exponentially increased to include procedures previously considered reserved only for open techniques.44 Compared with DCAT, arthroscopy is more accurate in the diagnosis of intra-articular lesions associated with a painful shoulder.30 An additional benefit is that ­arthroscopy

can be used to diagnose and treat shoulder problems of the glenohumeral joint and the subacromial region. With the increased accuracy of MRI-arthrography in detecting partial cuff tears and labral lesions, diagnostic shoulder arthroscopy has become less common in the absence of clear indications and specific treatment plans. In combination with a detailed history and physical examination, and along with examination under anesthesia, shoulder arthroscopy has been helpful in the diagnosis of chronic instability patterns of the glenohumeral joint.44-47 The indications and usefulness of shoulder arthroscopy in the treatment of common pathologic conditions have continued to increase as the technology improves, and the understanding of the pathophysiology of shoulder problems grows. Shoulder arthroscopy has been routinely used to confirm and treat SLAP lesions, labral tears, partial cuff tears, refractory adhesive capsulitis, partial biceps tendon tears, and multidirectional instability. Other conditions that are routinely treated arthroscopically are rotator cuff tears, glenohumeral instability, AC joint pathology, loose bodies, sepsis, osteochondritis dissecans, synovitis, chondral lesions, subacromial impingement, and calcific tendinitis.7,13,44,47

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Figure 40-12  A, Normal longitudinal view of rotator cuff by ultrasound shows the humeral head (1), the superior articular surface (2), the rotator cuff (3), the deltoid tendon (4), and tapering of the cuff to its insertion on the greater tuberosity (5). B, Transverse view of a normal intact rotator cuff cover-­ ing the humeral head. C, Rotator cuff tear, showing a hypoechoic area (arrow) on a longitudinal view. D, Rotator cuff tear, showing hypoechoic area (arrows) on a transverse view.

MAGNETIC RESONANCE IMAGING MRI has been used to diagnose partial-thickness and fullthickness rotator cuff tears, biceps tendon tears, impingement of the rotator cuff, synovitis, articular cartilage damage, and labral pathology associated with glenohumeral instability.48-50 In rheumatoid arthritis, MRI is reported to be more sensitive than plain radiographs in determining soft tissue abnormalities and osseous abnormalities of the glenoid and humeral head.51 One of the most useful diagnostic uses of MRI is for rotator cuff pathology. Morrison and Offstein52 studied 100 patients with chronic subacromial impingement syndrome using arthrography and MRI. MRI was 100% sensitive, but only 88% specific in confirming arthrography-proven rotator cuff tears. Nelson and associates53 studied 21 patients with shoulder pain and found MRI to be more accurate than CT-arthrography or ultrasound in identifying partial­thickness cuff tears. These investigators also reported MRI to be as accurate as CT-arthrography in the diagnosis of abnormalities of the glenoid labrum.53 The characteristic MRI findings in rotator cuff tears in­clude a hypointense gap within the supraspinatus muscle tendon complex on T1-weighted films, absence of a demonstrable supraspinatus tendon with narrowing of the subacromial space, and an increased signal within the supraspinatus tendon on T2-weighted images.54 Seeger and colleagues,55

reporting the results of 170 MRI studies, found that T1weighted images were highly sensitive for identifying abnormalities within the supraspinatus tendon, but T2-weighted images were required to differentiate tendinitis from a small supraspinatus tendon tear. Large full-thickness tears could be identified, however, on T1-weighted and T2-weighted images. Figure 40-13 depicts common shoulder pathology as seen by MRI. MRI is almost as sensitive as and more specific than scintigraphy in the diagnosis of osteonecrosis and neoplastic lesions around the shoulder. ELECTROMYOGRAPHY AND NERVE CONDUCTION VELOCITY STUDIES EMG and nerve conduction velocity studies can help differentiate shoulder pain from pain of neurogenic origin. They also may be beneficial in determining the localization of neurogenic pain to a particular cervical root, the brachial plexus, or a peripheral nerve.56,57 INJECTION Injection of local anesthetics and glucocorticoids is a useful technique for the diagnosis and treatment of shoulder pain. The physician must have a thorough understanding of the anatomy of the shoulder girdle and a presumptive diagnosis to direct the injection properly. Injection of referred pain

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Figure 40-13  A, MRI proton densi-­ ty–weighted coronal view shows su-­ praspinatus tendon as a black band (A) that has an increased signal as it nears insertion on the greater tu-­ berosity (B). B, Similar view in a T2weighted image shows increased signal as gray (arrow), indicating partial-thickness tear or tendinitis. C, MRI proton density–weighted coronal view shows abrupt end of supraspinatus tendon as it courses right to left (A). From A to B is an area of increased signal followed by a short portion of tendon (B) inserting at the greater tuberosity. D, Similar view in a T2-weighted image shows increased signal as white (fluid den-­ sity), indicating fluid in the gap of a complete rotator cuff tear. E, MR arthrography shows normal rotator cuff. F, MR arthrography shows a chronic cuff tear with retraction.

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areas may be misleading. In a patient with lateral arm pain secondary to deltoid bursal involvement from calcific tendinitis of the supraspinatus tendon, injection should be in the subacromial space, rather than in the area of referred pain in the deltoid muscle. It is often better to use a posterior subacromial approach when injecting a rotator cuff tendinitis in a patient with anterior impingement symptoms because it is easier to enter the subacromial region posteriorly, and this approach is less traumatic to contracted anterior structures. The instillation of rapidly acting local anesthetics can be beneficial in determining the source of shoulder pain. Obliteration of pain by injection of a local anesthetic along the bicipital groove can confirm a diagnosis of bicipital tendinitis. The use of local anesthetics is less helpful when injecting the subacromial space because of its extensive communication with the rest of the shoulder girdle, but relief of symptoms

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by such an injection can exclude pain from conditions such as cervical radiculopathy or entrapment neuropathy. AUTHORS’ PREFERRED DIAGNOSTIC TESTS Table 40-2 lists the reimbursement and charges for various shoulder diagnostic tests based on 2006 Medicare fee schedules and 2006 charges at a single institution. Choice of a specific test depends on its sensitivity, specificity, and costbenefit analysis. History and physical examination are the most important factors in establishing diagnosis of the painful shoulder. Plain radiographs (three views) should be the first radiographic test performed. Although not as sensitive as the more sophisticated tests, plain radiographs can identify arthritic change, calcific tendinitis, established osteonecrosis, and most neoplasms.

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Table 40-2  Relative Costs of Shoulder Diagnostic Procedure in 2006 Procedure

Initial Fee ($)

Technical Fee ($)

Interpretation Fee ($)

Medicare B Fee Schedule Initial office visit (30 min) Plain radiography (3 views) Arthrography Ultrasonography Magnetic resonance imaging Computed tomography Tomography

154.00 36.28 156.08 74.70 531.28 233.06 78.53

23.09 34.07 41.62 81.42 66.77 39.69

164.00 455.00 239.00 2081.00 973.00

68.00 190.00 131.00 228.00 163.00

Institutional Charges Initial office visit (30 min) Plain radiography (3 views) Arthrography Ultrasonography Magnetic resonance imaging Computed tomography

196.00

If intra-articular pathology (e.g., labrum tear, capsular tear, loose body, or chondral defect) is suspected, MRIarthrography is preferable to CT-arthrography. In diagnosing acute rotator cuff tears in a younger patient, ultrasound is the most cost-effective test to confirm a clinical suspicion. In cases of impingement syndrome, MRI is sensitive, but it is difficult to differentiate tendinitis, partial tears, and small complete tears without MRI-arthrography. Orthopaedic surgeons prefer MRI-arthrography for verification of labral tears or partial rotator cuff tears. In the case of a suspected full-thickness rotator cuff tear, MRI is preferred to determine the size of the tear, amount of muscle atrophy and tendon retraction, and quality of the remaining tissue for repair.

INTRINSIC FACTORS CAUSING SHOULDER PAIN PERIARTICULAR DISORDERS Shoulder Impingement and Rotator Cuff Tendinopathy One of the most common nontraumatic causes of shoulder pain is impingement with rotator cuff tendinopathy. In 1972, Neer9 described his results of 100 anatomic shoulder dissections and coined the term impingement syndrome. Impingement may be defined as the encroachment of the acromion, coracoacromial ligament, coracoid process, or AC joint on the rotator cuff as it passes beneath them during glenohumeral motion. The function of the posterior rotator cuff is to abduct and externally rotate the humerus. The cuff with the biceps tendon serves as a humeral head depressor to maintain the head centered within the glenoid fossa as the cuff and deltoid elevate the arm.58-60 Controversy continues, however, as to the exact cause of impingement—whether it is a primary, intrinsic, degenerative event within the tendon with superior migration of the head on arm elevation and secondary impingement on the acromion or a purely mechanical attrition of the tendon with primary impingement against the acromion. The mechanical impingement of the rotator cuff may be influenced by variations in the shape and slope of the

a­ cromion.61,62 The supraspinatus outlet may become narrowed from proliferative spur formation of the acromion or degenerative changes of the AC joint. These changes, along with intrinsic degenerative changes of the rotator cuff, may lead to rotator cuff tear, but the exact pathogenesis remains controversial. Many studies have found a strong correlation between degenerative hypertrophic spur formation, with its resulting narrowing of the supraspinatus outlet, and the presence of full-thickness cuff tears,9,19,63-70 but clinical studies have failed to resolve whether the hypertrophic changes of the coracoacromial arch are caused by the cuff lesions or are a cause of the lesions themselves. Neer9 developed a staging system for description of im­­ pingement lesions of the shoulder. A stage I lesion involves edema and hemorrhage of the rotator cuff and is typically found in individuals younger than 25 years who are active in overhead athletics. The condition usually reponds to conservative treatment of rest, anti-inflammatory medication, and physical therapy. Stage II lesions usually occur in the 30s or 40s and represent the biologic response of fibrosis and thickening of the tendon after repeated episodes of mechanical impingement over time. The lesion also is treated conservatively, as in stage I, but attacks may recur. If symptoms persist despite adequate conservative management for more than 6 to 12 months, surgical intervention is warranted. Stage III lesions involve rotator cuff tears, biceps tendon rupture, and bone changes, and they rarely occur before age 40. Patients may present with pain, weakness, or supraspinatus atrophy, depending on the chronicity of the tear. Surgical treatment depends on the patient’s age, loss of function, weakness, and pain. Patients usually present to the clinician with a complaint of pain that has failed to resolve after a variable period. Pain can be sudden and incapacitating in cases of traumatic cuff tears, or more commonly it manifests as a dull ache in cases of chronic impingement. Pain usually is located over the anterior and lateral aspects of the shoulder and may radiate into the lateral deltoid. The pain may worsen with sleeping on the affected extremity and is exacerbated by overhead activity. Tenderness on palpation may be elicited over the greater tuberosity and long head of the biceps within the bicipital groove, indicating an associated biceps tendinitis. In cases with concomitant degenerative changes of the AC joint,

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Figure 40-14  The impingement sign is elicited by forced forward  elevation of the arm. Pain results as the greater tuberosity impinges on the acromion. The examiner’s hand prevents scapular rotation. This  maneuver may be positive in other periarticular disorders. (From Neer CS II: Impingement lesions. Clin Orthop 173:70, 1983.)

there may be tenderness on palpation over the AC joint as an offending osteophyte impinges on the rotator cuff beneath. The impingement sign as described by Neer9 (Fig. 40-14) is useful in the diagnosis of rotator cuff tendinopathy. The patient often describes a catch as the arm is brought into the overhead position. The patient may be observed to raise the arm by abduction and external rotation to clear the greater tuberosity of the acromion, bypassing the painful area. A typical painful arc usually occurs between 70 degrees and 110 degrees of abduction. Neer9 also described an impingement test that involves injection of lidocaine into the subacromial bursa. Relief of pain is a positive impingement test result and usually indicates rotator cuff origin of the shoulder pain. Radiographs in the early stages of cuff tendinopathy may be normal or may reveal a hooked acromion. As the disease progresses, there may be some sclerosis, cyst formation, and sclerosis of the anterior third of the acromion and the greater tuberosity. An anterior acromial traction spur may appear on the undersurface of the acromion lateral to the AC joint and represents contracture of the coracoacromial ligament. Late radiographic findings include narrowing of the acromiohumeral gap, superior subluxation of the humeral head in relation to the glenoid, and erosive changes of the anterior acromion.70 Arthrography, MRI, and ultrasound may be helpful in diagnosing a full-thickness tear of the rotator cuff in association with stage III disease. In some cases of chronic large rotator cuff tears, proximal migration of the humeral head leads to a pattern of degenerative arthritis termed cufftear arthropathy. The choice of treatment and frequently its result are functions of the stage of the impingement and response to pain. In stage I disease, in which there is little mechanical impingement, most patients respond to rest. It is important not to immobilize the shoulder for any period because contraction of the shoulder capsule and periarticular structures can produce an adhesive capsulitis. After a period of rest, a progressive program of stretching and strengthening exercises generally restores the shoulder to normal function. Use

of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) may shorten the symptomatic period. Modalities such as ultrasound, neuroprobe, and transcutaneous electrical nerve stimulation generally are not helpful. Patients with stage I and II disease may have a dramatic response to local injection of glucocorticosteroids and local anesthetic agents. For stage II disease in which there is fibrosis and thickening anteriorly, it is frequently better to inject through a posterior approach. We prefer a combination of 3 mL of 1% lidocaine (Xylocaine), 3 mL of 0.5% bupivacaine, and 20 mg of triamcinolone. This injection combines a short-acting anesthetic to help confirm the diagnosis, a longer acting anesthetic for analgesic purposes, and a steroid preparation in a depot form. An integrated program of occupational and physical therapy often precludes the need for surgery in patients with stage II disease. Job modification for individuals with impingement syndrome caused by overuse may alleviate symptoms. More businesses are becoming aware of the cost savings associated with proper job ergonomics.71,72 The initial rehabilitation in stage II impingement is the cessation of repetitive overhand activity. Ice, NSAIDs, and local injections also may be beneficial. Initial physical therapy includes passive, active assisted, and active range of motion combined with stretching and mobilization exercises to prevent contracture. As pain and inflammation subside, isometric or isotonic exercises are used to strengthen the rotator cuff musculature. Isokinetic training at variable speeds and in variable positions is instituted before returning the patient to full activity. For patients with a job-related injury, it is crucial to review and modify job mechanics to prevent recurrent episodes that can cause further disability and may precipitate the need for surgery.71 Neer19 suggested that a patient with refractory stage II disease may respond to division of the coracoacromial ligament and bursectomy of the subacromial bursa. Neer’s description of open anterior acromioplasty has become accepted as the procedure of choice for stage II and III impingement lesions, with many investigators reporting high success rates in treating impingement syndrome and rotator cuff tears.73-76 Reported results show good and excellent relief of symptoms in 71% to 87% of patients treated by the open surgical procedure.77-80 In 1985, Ellman45 described the technique of arthroscopic subacromial decompression. His initial results46 and the results of others are comparable to those of open surgical techniques.47,81 Arthroscopic subacromial decompression has become a widely accepted treatment for refractory stage II and III impingement lesions. The procedure can be done as outpatient surgery, and because no deltoid is detached as with the open technique, the procedure facilitates rehabilitation and overall recovery rates. Calcific Tendinitis Calcific tendinitis is a painful condition around the rotator cuff and is associated with deposition of calcium salts, primarily hydroxyapatite.82-84 The cause of calcific tendinitis is unknown. The commonly accepted cause is degeneration of the tendon, which leads to calcification through a dystrophic process.84 A common clinicopathologic correlation is three distinct phases of the disease process: the ­precalcific or

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f­ormative phase, which can be relatively painless; the calcific phase, which tends to be quiescent and may last months to years; and the resorptive or postcalcific phase, which tends to be painful, as calcium crystals are resorbed.82 Although it is more common in the right shoulder, there is at least a 6% incidence of bilaterality. Patients with bilateral shoulder involvement often have the syndrome of calcific periarthritis, in which calcium hydroxyapatite crystals are found at multiple sites.85 The patients usually present with impingement-type pain in the affected shoulder during overhead activity. The pain may seem to be out of proportion to any objective physical findings. There may be difficulty sleeping on the shoulder and in falling asleep. The symptoms may last a few weeks or a few months. The incidence of calcific tendinitis varies in the literature among asymptomatic individuals from 2.7% to 20%. Most calcification occurs in the supraspinatus tendon, and 57% to 76.7% of patients are women. The average age of patients is 40 to 50 years.82,86 Codman1 pointed out the localization of calcification within the tendon of the supraspinatus. He provided a detailed description of the symptoms and the natural history of this condition. In describing the phases of pain, spasm, limitation of motion, and atrophy, he noted the lack of correlation between symptoms and the size of the calcific deposit. According to Codman, the natural history includes degeneration of the supraspinatus tendon, calcification, and eventual rupture into the subacromial bursa. During the latter phase, pain and decreased motion can lead to adhesive capsulitis (see Fig. 40-9). Several factors may affect localization of the calcium within the supraspinatus. Many of these patients have an early stage of impingement, compressing the supraspinatus tendon on the anterior portion of the acromion.9,19 This long-standing impingement may lead to local degeneration of the tendon fibers. In patients without impingement, localization of the calcium within the supraspinatus may be related to the blood supply of the rotator cuff, which normally is derived from an anastomotic network of vessels from the greater tuberosity or the bellies of the short rotator muscles.83 The watershed of these sources is just medial to the tendinous attachment of the supraspinatus.87 Rathburn and Macnab88 referred to this watershed as the critical zone and pointed out that during abduction this area was rendered ischemic. Treatment of calcific tendinitis depends on the clinical presentation and the presence of associated impingement. These patients can have an acute inflammatory reaction that may resemble gout. The acute inflammation can be treated with local glucocorticoid injection, NSAIDs, or both. Ultrasound may be beneficial. If there is associated impingement, treatment depends on the stage at presentation. The radiographic appearance of the calcification can direct and perhaps predict the response to therapy. In the resorptive state, the deposits appear floccular, suggesting that the process is in the phase of repair, and that a conservative program is indicated. Patients with discrete calcification and perhaps associated adhesive capsulitis (see Fig. 40-9) may be at a stable phase in which the calcium produces a mechanical block and is unlikely to be resorbed. For these patients, mechanical removal of the calcific deposits and correction of ­associated

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pathologic lesions may be necessary.89-91 Percutaneous disruption of the calcified areas may be performed using a nee­ dle directed by fluoroscopy. This technique allows lavage and injection, but does not treat associated impingement. Subacromial arthroscopy allows the mechanical débridement of calcific deposits under direct visualization. This technique can be combined with arthroscopic removal of the inflamed bursa and decompression of associated impingement. In many cases of refractory calcific tendinitis associated with impingement, open or arthroscopic acromioplasty, subacromial bursectomy, and decompression are indicated. ROTATOR CUFF TEAR Pathophysiology Spontaneous tear of the rotator cuff in an otherwise normal individual is rare.19 It can occur in patients with rheumatoid arthritis or systemic lupus erythematosus as part of the pathologic process with invasion from underlying pannus. Metabolic conditions such as renal osteodystrophy or agents such as glucocorticoids occasionally are associated with cuff tears. Most patients report a traumatic episode, such as falling on an outstretched arm or lifting a heavy object. The usual presenting symptoms are pain and weakness of abduction and external rotation. There may be associated crepitus and even a palpable defect. Long-standing tears generally are associated with atrophy of the supraspinatus and infraspinatus muscles. It may be difficult to differentiate a painful tendinitis from a partial-thickness or small full-thickness cuff tear. Controversy exists about the exact cause of cuff tendinopathy.87,91-93 Most likely, the pathophysiology involves a combination of factors, including decreased vascularity and cellularity of the tendon along with changes in the collagen fibers of the tendon that occur with aging. Loss of motion with subsequent capsular tightness, particularly the posterior capsule, may lead to cephalad migration of the humeral head, with subsequent impingement of the cuff under the coracoacromial arch.94 Rehabilitation exercises stress regaining a normal range of motion. To achieve full, painless motion, the normal relationship of glenohumeral-to-scapulothoracic motion must be achieved.16,17,95 Diagnosis History. Patients with nontraumatic tears of the rotator cuff report symptoms of chronic impingement. There is often a loss of motion and feeling of stiffness with extremes of motion and difficulty during activities of daily living, such as combing the hair, hooking a bra strap, putting on a shirt or coat, and reaching into the back pocket. In chronic cases of cuff tendinopathy, there is usually a loss of motion. Limitation of internal rotation occurs initially, is caused by posterior capsular contracture, and is often associated with posterior shoulder pain with adduction of the ipsilateral shoulder. Further shoulder impingement occurs with forward flexion because of superior migration of the humeral head against the anterior inferior acromion. This upward translation is analogous to the action of a yo-yo climbing on a string.94,96 In time, loss of forward flexion, abduction, and external rotation occurs with passive and active motion of the ­shoulder.

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Imaging. In acute cases, there may be a history of trauma, such as a fall onto the affected shoulder. In cases involving an anterior shoulder dislocation with subsequent profound weakness of the rotator cuff, a large tear on greater tuberosity avulsion should be suspected in addition to axillary nerve palsy. In younger patients, traumatic failure of the cuff under tensile overload may result in cuff failure because of forced adduction of the affected shoulder or active abduction against resistance, and it may occur with traumatic dislocation. Repetitive tensile overload also can result in partial rotator cuff tears in an overhead athlete. Plain radiographs are used in initial evaluation of impingement-type shoulder pain with cuff tendinopathy. An impingement series should be ordered, including an anteroposterior radiograph with a 30-degree cephalic tilt (Rockwood view), which can reveal osteophytes of the anterior os acromion and AC joint; a scapular Y view with a 10-degree cephalic tilt (supraspinatus outlet view), which can evaluate the type of acromion and reveal anterior and AC osteophytes; and an axillary view, which can evaluate the acromion for possible os acromionale. Calcific deposits within the rotator cuff tendon can be viewed best with rotational anteroposterior radiographs. Cuff arthropathy should be suspected if the acromial-humeral distance is less than 7 mm, or there is cyst formation within the greater tuberosity, humeral head osteopenia, sclerosis around the greater tuberosity, or humeral head collapse. In advanced stages of cuff arthropathy, there may be complete loss of glenohumeral joint space with superior migration and abutment of the humeral head against the undersurface of the acromion.58 In the past, shoulder arthrography was considered the “gold standard” for diagnosing full-thickness and partialthickness rotator cuff tears, with greater than 90% sensitivity and specificity.33,97 Currently, arthrography with CT or MRI is routinely used to diagnose rotator cuff pathology, including full-thickness and partial-thickness tears. Ultrasonography has been accurate in the diagnosis of full-thickness rotator cuff tears.39,98-101 Ultrasonography has advantages of being inexpensive and noninvasive, but disadvantages include unproven effectiveness in determining subacromial impingement, capsular and labral abnormalities, and partial cuff tears. The procedure and its results are technician dependent. Ultrasonography may have a useful role in determining postoperative integrity of the cuff repair.38 MRI has been invaluable in evaluating rotator cuff tears. The sensitivity and specificity for diagnosing full-thickness cuff tears are 100% and 95%.102 Through the use of gadolinium or saline, partial tears that are otherwise difficult to detect with conventional imaging also can be detected. Diagnosing cuff tears with MRI usually is based on dis­ continuity of the tendon on T1-weighted images and consistency with fluid signal on T2-weighted images. Ancillary findings include fluid in the subacromial space on T2weighted images, loss of the subacromial fat plane on T1weighted images, and proliferative spur formation of the acromion or AC joint. Large, chronic cuff tears also may be associated with cephalad migration of the humeral head and fatty atrophy of the spinatus muscle. Periarticular soft tissues, including the capsulolabral complex and biceps tendon, and the rotator cuff can be thoroughly examined. The

degree of tear, tendon retraction, and evidence of muscle atrophy can be evaluated, all of which are crucial in preoperative planning for possible cuff repair. Treatment Nonsurgical Treatment. Codman and Akerson63 recommended early operative repair for acute full-thickness rotator cuff tears and reported the first documented repair in 1911. McLaughlin65 recommended early repair in cases of grossly displaced tuberosity fractures or massive tears. Several other clinical studies also supported the concept that a full-thickness tear does not preclude good shoulder function. DePalma103 reported that 90% of patients with rotator cuff tears responded to conservative measures, such as rest, analgesics, anti-inflammatory agents, and physiotherapy. The reported percentage of patients responding to nonsurgical treatment in the literature varies from 33% to 90%.3,18,104 Conservative treatment includes pain control with NSAIDs, ultrasound, heat before shoulder stretching and exercise, and ice after overhead activity. Deep massage therapy is employed to reduce trigger point tenderness within the trapezius, levator scapulae, and periscapular muscles. Patients on long-term anti-inflammatory medications are monitored periodically for evidence of gastrointestinal bleeding and for hepatic or renal toxicity. Opiate-based drugs are used only in the acute setting, such as after a fall, or in the perioperative period. Steroid and local anesthetic injections are used when the patient has significant pain that prohibits rehabilitation. Injections may be repeated once every 3 months if needed; injection into the cuff tendon is to be avoided. If the patient fails to improve after 3 months of conservative treatment, or does not continue to improve after three sequential injections, surgical options should be discussed. The mainstay of conservative therapy is exercise. Rehabilitation stresses pain relief with exercises aimed at restoring shoulder motion and strengthening the remaining cuff muscles, deltoid, and scapular stabilizers. Therapy can be divided into three phases. The goals of the initial phase of therapy are to relieve pain and restore shoulder motion. Motion therapy includes pendulum exercises, passive motion with use of a wand with the assistance of the uninvolved shoulder, an overhead pulley system, and posterior capsular stretching. The arc of motion is gradually increased and is guided by the patient’s discomfort to avoid painful impingement arcs. The second phase of therapy is entered after the patient has return of motion and little discomfort with overhead activity. Emphasis is placed on strengthening the remaining rotator cuff musculature and deltoid and periscapular muscles. Strengthening is done with elastic surgical tubing that provides variable degrees of resistance, depending on the size of the tubing. Initial strengthening is performed out of the impingement arc (70 to 120 degrees of shoulder flexion). The goal of this phase is to strengthen the shoulder to prevent dynamic proximal humeral migration with impingement during active shoulder elevation.58,60 Normal shoulder kinematics relies on combined and synchronous glenohumeral flexion and scapular rotation.59,91 In addition to strengthening the cuff and deltoid, the scapular rotators,

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including the trapezius and serratus anterior muscles, are emphasized.105 After the patient has successfully completed phase two of the rehabilitation program with minimal symptoms and good shoulder function, the final phase is entered. Phase three is characterized by a gradual return to normal overhead activities, including work and sporting activities. This part of the rehabilitation program should be tailored to the individual patient’s needs and the demands placed on the shoulder. Surgical Treatment. Severity and duration of pain are the primary indications for surgical intervention in a rotator cuff tear. Other factors important in surgical decision making include shoulder dominance, activity level, physiologic age, acuteness of the tear, degree of tear, loss of function, amount of tendon retraction, and fatty atrophy of the remaining cuff musculature. Acute Tears. Acute tears of the rotator cuff can be treated with conservative measures of periscapular and cuff strengthening along with capsular stretching to restore motion. Early surgical intervention should be considered in a young patient, however, especially an overhead athlete. Conservative shoulder rehabilitation should be maintained for 3 to 6 months before deciding on surgery for an older sedentary patient, in whom functional results without surgery may be acceptable. Many older patients may function well with chronic cuff tears, but they may become debilitated if an acute tear is superimposed on chronic changes. Surgical intervention may be required in these cases to return the patient to baseline function by repairing the acute tear and attempting to repair the chronic tear if possible. Chronic Tears. For elderly patients whose pain and weakness do not create a functional problem, a conservative program is preferable for chronic tears. Pain unresponsive to conservative management is the main indication for surgery in an older patient with a chronic rotator cuff tear. In these cases, surgery should be considered on an individual basis after at least 3 months of conservative treatment, including subacromial steroid injection. If the cuff tear is massive and irreparable, débridement and subacromial decompression may provide good pain relief without extensive surgery and prolonged immobilization.46,81,106-110 In a younger patient with a chronic tear and weakness, surgery to repair the cuff may be indicated to improve strength and prevent further extension of the tear.108 In cases of rotator cuff arthropathy with glenohumeral joint degeneration, a reverse total shoulder replacement may be indicated. This type of total shoulder replacement reverses the normal relationship between scapular and humeral components, moving the center of rotation ­medially and distally to increase the lever arm length of the deltoid muscle. The deltoid compensates for the deficient rotator cuff, allowing as near-normal function as possible (Fig. 40-15).

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biceps tendon aids in flexion of the forearm, supination of the pronated forearm if the elbow is flexed, and forward elevation of the shoulder.3 Bicipital tendinitis, subluxation or dislocation of the biceps tendon within the bicipital groove, and rupture of the long head of the biceps generally are associated with anterior shoulder pain. Bicipital tendinitis is sometimes an associated feature of a rotator cuff tear. The rotator cuff tear compromises centering of the humeral head on the glenoid. This compromise results in increased mechanical loading of the long head of the biceps, which initiates a hypertrophic tendinitis.112 Dislocation of the long head of the biceps usually is combined with a lesion of the subscapularis tendon.12 Isolated rupture of the long head of the biceps tendon is rare when the rotator cuff is intact. Rupture of the long head of the biceps is common, however, when there is a coexisting rotator cuff tear.113 The effect of rotator cuff tear and concomitant biceps tendon rupture on strength can be substantial.12 The early phases of bicipital tendinitis are associated with hypervascularity, edema of the tendon, and tenosynovitis.114 Persistence of this process leads to adhesions between the tendon and its sheath, with impairment of the normal gliding mechanism in the groove. Stretching of the adhesions may be associated with chronic bicipital tendinitis.115 The diagnosis of bicipital tendinitis is based on the localization of tenderness. It is often confused with impingement symptoms and is frequently seen with an impingement syndrome.24 Isolated bicipital tendinitis can be differentiated by the fact that the tender area migrates with the bicipital groove as the arm is abducted and externally rotated. Many eponyms are associated with tests to identify bicipital tendinitis.3 Yergason’s supination sign refers to pain in the bicipital groove when the examiner resists supination of the pronated forearm with the elbow at 90 degrees. Ludington’s

BICIPITAL TENDINITIS AND RUPTURE The long head of the biceps passes through the bicipital groove, crosses over the head of the humeral, and inserts on the superior rim of the glenoid (see Fig. 40-2A).111 The

Figure 40-15  Reverse total shoulder replacement in a 72-year-old man who had severe cuff arthropathy.

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sign refers to pain in the bicipital groove when the patient interlocks the fingers on top of the head and actively abducts the arms. Biceps tendon ruptures can occur in some patients who report no history of shoulder pain. The patients often complain of an acute onset of pain and ecchymosis around the anterior shoulder and sagging of the biceps muscle belly. In these cases, a concomitant rotator cuff injury should be excluded by clinical examination. More often, the biceps tendon rupture is preceded by painful shoulder symptoms that often improve or disappear after the rupture.115,116 Treatment generally is conservative and consists of rest, analgesics, NSAIDs, and local injection of glucocorticoids. The use of ultrasound and a neuroprobe is more beneficial in this condition than in isolated rotator cuff tendinitis. Patients with refractory bicipital tendinitis and recurrent symptoms of subluxation are treated by arthroscopic biceps tenodesis or open tenodesis, opening the bicipital groove and resecting the proximal portion of the tendon with tenodesis of the distal portion into the groove or beneath the pectoralis tendon. ACROMIOCLAVICULAR DISORDERS The AC joint is a common source of shoulder pain. Acute causes of AC joint pain are often related to direct trauma of the affected shoulder that may result in a distal clavicle injury with an intra-articular chondral fracture or in AC joint instability from ligamentous disruption.117 Post-traumatic distal clavicle osteolysis, with resorption of the distal clavicle, may ensue 4 weeks after a shoulder injury, leading to AC joint pain.118,119 Osteolysis may be caused by microfractures of the subchondral bone and subsequent attempts at repair.120 Other authors believe the cause to be an autonomic nerve dysfunction affecting the blood supply to the clavicle. The increased blood supply leads to resorption of bone from the distal clavicle.118,121 More commonly, chronic osteolysis results from repetitive microtrauma to the AC joint from activities such as weightlifting, gymnastics, and swimming.120,122,123 The underlying pathophysiology is believed to be an inflammatory process from stress fractures of the subchondral bone with hyperemic resorption of the distal clavicle.120,124 Other causes of osteolysis include rheumatoid arthrosis, hyperparathyroidism, and sarcoidosis, which should be considered in the differential diagnosis, especially in bilateral cases.118,119 Patients with atraumatic osteolysis of the distal clavicle should be forewarned that bilateral involvement may occur, with an incidence of 70% reported for one longterm follow-up.125 Other chronic causes of AC pain include idiopathic, intra-articular disk pathology, post-­traumatic degenerative arthrosis from joint incongruity, primary degen­ erative arthrosis, and rheumatoid arthrosis. Evaluation always should include a detailed history, physical examination, and radiographic evaluation. There may be a history of trauma to the AC joint from a direct fall or blow to the ipsilateral shoulder. Less commonly, the AC joint may be injured indirectly, such as during a fall on the outstretched arm with the forces being transmitted through the arm to the AC joint.117,126 Patients with osteolysis of the distal clavicle sometimes give a history of acute trauma, although the more common cause is repetitive microtrauma

to the AC joint from activities such as weightlifting or gymnastics.118,119,122,123 Patients frequently complain of pain over the AC joint when adducting the ipsilateral shoulder, such as during a golf swing or when buckling a seat belt. Often, there is pain when sleeping on the affected shoulder. Athletes may experience AC joint pain on bench pressing, push-ups, and dips.125,127,128 Pain and weakness of the affected shoulder also may be experienced with forward flexion and adduction of the arm.118 On physical examination, there may be a visible stepoff between the medial acromion and the distal clavicle, indicating a probable AC separation. Pain usually can be elicited on direct palpation of the AC joint and is made worse by a cross-arm adduction maneuver. This test is performed by internally rotating the arm, which is maximally adducted across the chest and is considered positive if pain is produced in the AC joint (see Fig. 40-4D). Pain also may be elicited by moving the arm from a horizontally abducted position to the extended position and on maximal internal rotation of the shoulder.127,129 These tests cause rotation and compression of the AC joint and are sensitive but less specific. They also may be positive with other disorders of the shoulder, such as posterior capsular stiffness.130 Frequently, AC joint pain coexists with subacromial impingement and rotator cuff pathology. In these cases, im­pingement signs are positive, and rotator cuff weakness may be present. Otherwise, there should be no detectable muscle weakness on manual resistance testing and no evidence of muscle atrophy.125,130,131 The AC joint and subacromial space may have to be injected on separate occasions to determine the true source of the symptoms. Some physicians have noticed an association of AC joint symptoms with shoulder instability.125 Glenohumeral motion can vary, depending on the chronicity and isolation of the problem to the AC joint. In isolated cases, there may be some loss of internal rotation of the affected shoulder because of pain. Radiographs should include anteroposterior views of the shoulder in the scapular plane in neutral, internal, and external rotation; a transcapular Y view; an axillary view; and a 15-degree cephalic tilt view of the AC joint at 50% penetrance as described by Zanca (see Fig. 40-5).23 Stress views may be obtained by strapping 5 to 10 lb of weight to the forearms and determining AC separation. Comparing the coracoclavicular distance of both shoulders also may be helpful. When clinically indicated, cervical spine radiographs should be obtained to exclude cervical spondylosis. Radiographic evaluation may reveal AC joint arthrosis with microcystic changes in the subchondral bone, sclerosis, osteophytic lipping, and joint space narrowing.132 In cases of osteolysis, radiographs may reveal a loss of subchondral bone detail with microcystic appearances in the subchondral region of the distal clavicle and osteopenia of the lateral one third of the clavicle.119,120,122,123 In the late stages of osteolysis, resorption of the distal end of the clavicle results in marked widening of the AC joint and sometimes complete resorption of the distal clavicle. There may be evidence of AC separation with widening of the coracoclavicular distance and post-traumatic ossification of the coracoclavicular ligaments. The AC symptoms do not always correlate with the radiographic appearance of the joint. DePalma133 found

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AC joint degeneration to be an age-related process, with symptoms not always correlating with radiographic findings of AC joint arthrosis.23 AC joint pain may occur despite normal radiographs.134 A technetium 99m phosphate bone scan may assist in the diagnosis, revealing increased uptake in the distal clavicle and medial acromion.120 In cases of atraumatic osteolysis of the distal clavicle, increased uptake may be isolated to the distal clavicle, but in approximately 50% of cases, there is increased scintigraphic activity of the adjacent medial acromion.125 The bone scan may reveal pathologic changes of the AC joint when plain radiographs appear normal. In selected cases, MRI can be valuable in determining a diagnosis and evaluating the glenohumeral and subacromial regions for coexisting pathology (Fig. 40-16). AC joint involvement may reveal increased fluid with synovitis, soft tissue enlargement, and periarticular ossifications with encroachment on the underlying bursal and cuff tissue. Patients with AC joint pain usually respond well to nonoperative treatment; however, complete relief of symptoms may take an extended period. Conservative therapy includes heat, NSAIDs, steroid injections, shoulder rehabilitation, and avoidance of painful positions and activities. Steroid injections are repeated at 3-month intervals if painful conditions persist. Open resection of the distal clavicle for chronic AC joint pain was initially reported by Gurd135 and by Mumford,136 both with good results. Since then, other surgeons have reported similar good results with open resection, but significant morbidity, such as disruption of the deltotrapezial fascia and anterior deltoid rupture, can occur.118,119,132,134,137 Arthroscopic resection of the distal clavicle has been described with results similar to open resection.13,124,129-131,138-141

Figure 40-16  Sagittal section MRI of the shoulder in a 32-year-old weightlifter complaining of shoulder pain. Fat-suppressed proton den-­ sity fast spin echo images of bursal-side high-grade partial cuff tear (small arrowheads).

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GLENOHUMERAL DISORDERS The various arthritides that affect the shoulder joint are discussed in detail in other chapters. They are presented here to address aspects that are unique to the glenohumeral joint. The usual presentation of intra-articular disorders is pain with motion and symptoms of internal derangement, such as locking and clicking. The pain is generalized throughout the shoulder girdle and sometimes referred to the neck, back, and upper arm. The usual response to pain is to decrease glenohumeral motion and substitution with increased scapulothoracic mobility. Patients with adequate elbow and scapulothoracic motion require little glenohumeral motion for activities of daily living; patients with glenohumeral arthrodesis can achieve adequate function.142,143 The response to pain is diminution of motion and secondary soft tissue contractures with muscle atrophy. With increasing weakness and involvement of adjacent joints, pain, limitation of motion, and weakness cause a substantial functional deficit. INFLAMMATORY ARTHRITIS Although the most common inflammatory arthritis involving the shoulder joint is rheumatoid arthritis, other systemic disorders, such as systemic lupus erythematosus, psoriatic arthritis, ankylosing spondylitis, Reiter’s syndrome, and scleroderma, may cause glenohumeral degeneration. Motion is limited by splinting of the joint with secondary soft tissue contractures or by primary soft tissue involvement with scarring or rupture. Plain radiographs confirm glenohumeral involvement (Fig. 40-17A). There is narrowing of the glenohumeral joint space, with erosion and cyst formation without significant sclerosis or osteophytes. As the disease progresses, superior and posterior erosion of the glenoid with proximal subluxation of the humeral head may occur. Eventually, there may be secondary degenerative changes and even osteonecrosis of the humeral head. Treatment is initially conservative and directed toward controlling pain, inducing a systemic remission, and maintaining joint motion by physical therapy. The use of intraarticular glucocorticoids may be beneficial in controlling local synovitis. In rheumatoid arthritis, the involvement of periarticular structures with subacromial bursitis and rupture of the rotator cuff magnifies the functional deficit. When the synovial cartilage interactions produce significant symptoms and radiographic changes that cannot be controlled by conventional therapy, glenohumeral resurfacing should be considered. When following a rheumatoid patient with shoulder involvement, the rheumatologist should assess range of motion carefully and obtain periodic radiographs. Patients with progressive loss of motion or radiographic destruction should be referred for evaluation for possible surgical treatment. The treatment of choice is an unconstrained total shoulder arthroplasty.144,145 Total shoulder arthroplasty is best performed in patients with rheumatoid arthritis before end-stage bony erosion and soft tissue contractions have occurred.146,147 Acute inflammatory arthritis of the glenohumeral joint also may be associated with gout, pseudo­gout, hydroxyapatite deposition of renal osteodystrophy, and recurrent hemophilic hemarthrosis.

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A

B

Figure 40-17  Plain radiographs. A, Rheumatoid arthritis with loss of joint space, cyst formation, glenohumeral erosion, and early proximal subluxation of the humerus, indicating a rotator cuff tear. B, Osteoarthritis with narrowing of the glenohumeral joint space, sclerosis, and osteophyte formation. Notice the preservation of the subacromial space, suggesting an intact rotator cuff.

OSTEOARTHRITIS Osteoarthritis of the glenohumeral joint is less common than that in the hip, its counterpart in the lower extremity; this is the result of the non–weight-bearing characteristics of the shoulder joint and the distribution of forces throughout the shoulder girdle. Osteoarthritis is divided into conditions associated with high unit loading of articular cartilage and conditions in which there is an intrinsic abnormality within the cartilage that causes abnormal wear at normal loads. Because the shoulder is normally a non–weight-bearing joint and is less susceptible to repeated high loading, the presence of osteoarthritis of the glenohumeral joint should alert the physician to consider other factors. Has the patient engaged in unusual activities, such as boxing, heavy construction, or chronic use of a pneumatic hammer? Is there some disorder, such as epiphyseal dysplasia, that has created joint incongruity with high unit loading of the articular cartilage? Is this a neuropathic process caused by diabetes, syringomyelia, or leprosy? Is there associated hemochromatosis, hemophilia, or gout that may have altered the ability of articular cartilage to withstand normal loading? Is unrecognized chronic dislocation responsible? Pain is the usual presentation, but it is generally not as acute or associated with the spasm seen in inflammatory conditions. Plain radiographs show narrowing of the glenohumeral joint, osteophyte formation, sclerosis, and some cyst formation (see Fig. 40-17B). Because the rotator cuff usually is intact, there is less bone erosion of the glenoid and proximal subluxation of the humerus. Patients with osteoarthritis of the glenohumeral joint frequently do well with functional adjustments and conservative therapy. Analgesics and NSAIDs may provide sympto­matic relief. The use of glucocorticoid injections is less beneficial, unless there is evidence of synovitis. Patients with severe involvement who fail to respond are best treated by ­shoulder arthroplasty.144-147 OSTEONECROSIS Osteonecrosis of the shoulder refers to necrosis of the humer­ ­al head seen in association with a variety of conditions. Symptoms are due to synovitis and joint incongruity ­resulting

from resorption, repair, and remodeling. The pathogenesis and various causes are discussed in Chapter 94. The most common cause of osteonecrosis of the shoulder is avascularity resulting from a fracture through the anatomic neck of the humerus.148 Fracture through this area disrupts the intramedullary and capsular blood supplies to the humer­ ­al head.149 Another common cause of osteonecrosis of the shoulder is steroid therapy in conjunction with organ transplantation, systemic lupus erythematosus, or asthma. Other conditions associated with osteonecrosis of the humeral head include hemoglobinopathies, pancreatitis, and hyperbarism. Early diagnosis is difficult because there is frequently a considerable delay until symptoms are present. Bone scans may be helpful in early cases before radiographic changes are evident. MRI is highly sensitive and more specific than scintigraphy. Plain radiographs show progressive phases of necrosis and repair (as discussed in Chapter 94). In the early stages, the films may be normal or show osteopenia or bone sclerosis. A crescent sign representing subchondral fracture or demarcation of the necrotic segment appears during the reparative process. Patients who fail to remodel show collapse of the humeral head with secondary degenerative changes. There is often a considerable discrepancy between symptoms and radiographic involvement. Patients with extensive bone changes may be asymptomatic. ­Treatment should be directed by the patient’s symptoms rather than the radiographs and is similar to that for osteoarthritis. Arthroscopy occasionally is helpful by removing loose chondral fragments and débriding chondral incongruities.150 Patients with severe symptoms that cannot be controlled by conservative means are best treated with an unconstrained shoulder arthroplasty, hemiarthroplasty, or resurfacing arthroplasty.144 CUFF-TEAR ARTHROPATHY In 1873, Adams described the pathologic changes in rheumatoid arthritis of the shoulder and a condition that has since been referred to as Milwaukee shoulder or cuff-tear arthropathy.151 McCarty called the condition Milwaukee shoulder and reported that the factors predisposing to this syndrome included deposition of calcium pyrophosphate dihydrate crystals, direct trauma, chronic joint overuse, chronic renal ­failure, and denervation.152 Patients with Milwaukee shoulder

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have elevated levels of synovial fluid 5-nucleotidase activity and elevated levels of synovial fluid inorganic pyrophosphate and nucleotide pyrophosphohydrolase activity.153 Neer and colleagues154 reported a similar condition in which untreated massive tears of the rotator cuff with proximal migration of the humeral head are associated with erosion of the humeral head. The erosion of the humeral head differs from that seen in other arthritides and is presumed to be caused by a combination of mechanical and nutritional factors acting on the superior glenohumeral cartilage. Patients with cuff-tear arthropathy present a difficult therapeutic problem because the bone erosion and disruption of the cuff jeopardize the functional result from an unconstrained prosthesis.146 Hemiarthroplasty or a reverse total shoulder arthroplasty may be indicated.155,156 The major question in treating cuff-tear arthropathy is to determine which patients with massive rotator cuff tears will proceed to the syndrome of cuff-tear arthropathy. Patients with massive rotator cuff tears who develop localized calcium pyrophosphate disease may be predisposed to further proximal migration and further joint destruction. This situation poses a dilemma for the treating physician. Many patients with massive rotator cuff tears remain stable and require little or no treatment. Occasionally, symptomatic patients can be treated by arthroscopic débridement of the cuff tear. It is crucial to define the patient who will proceed to the syndrome of cuff-tear arthropathy. If crystal deposition disease predisposes patients to proximal migration and joint destruction, joint aspiration with crystal analysis or scintigraphy to determine synovial reaction may be helpful diagnostic tools. Hamada and coworkers157 followed 22 patients with massive rotator cuff tears treated conservatively. The radiographic findings included narrowing of the acromiohumeral interval and degenerative changes of the humeral head, tuberosities, acromion, AC joint, and glenohumeral joint. Five of seven patients followed for more than 8 years progressed to cuff-tear arthropathy. The investigators concluded that progressive radiographic changes were associated with repetitive use of the arm in elevation, rupture of the long head of the biceps, impingement of the humeral head against the acromion, and weakness of external rotation.157 SEPTIC ARTHRITIS Septic arthritis can masquerade as any of the conditions classified as periarticular or glenohumeral disorders (see Chapters 90 and 100). Sepsis must be included in any differential diagnosis of shoulder pain because early recognition and prompt treatment are necessary to achieve a good functional result. The diagnosis is confirmed by joint aspiration with synovial fluid analysis and culture. Cultures should include aerobic, anaerobic, mycobacterial, and fungal studies. LABRAL TEARS The glenoid labrum increases the depth of the glenoid and serves as an anchor for the attachment of the glenohumeral ligaments. Historically, labral tears have been difficult to diagnose. Findings on physical examination can be confused with impingement and rotator cuff tendinopathy and bicipital tendinitis. Diagnosis can be confirmed with MRIarthrography, CT-arthrography, and DCAT.27 Arthroscopy

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has greatly increased the knowledge of the glenoid labrum in normal and pathologic situations and has aided the diagnosis and treatment of labral lesions. Labral tears can be divided into tears associated with symptoms of internal derangement and tears associated with anterior or posterior instability. A soft tissue Bankart lesion is associated with a tear of the anterior band of the inferior glenohumeral ligament and is associated with anterior instability. Isolated labral tears that do not involve detachment of the ligaments can cause internal derangement and may have an arthroscopic appearance similar to a meniscal tear of the knee. Andrews and associates7 first described lesions of the anterior superior labrum in throwing athletes; these lesions were often associated with biceps tendon tears (10%). The tear results from traction of the biceps tendon. Snyder and coworkers158 introduced the term SLAP lesion in 1990 to describe an injury involving the long head of the biceps tendon and the superior portion of the glenoid labrum. The long head of the biceps tendon originates at the supraglenoid tubercle and glenoid labrum in the superiormost portion of the glenoid. The major portion of the tendon blends with the posterior superior aspect of the labrum. The most common mechanism of a SLAP injury is a fall onto the outstretched arm with the shoulder in abduction and slight forward flexion.158 The lesion also can result from an acute traction on the arm and from an abduction and external rotation mechanism.160 Patients usually complain of pain with overhead activities and a frequent catching or popping sensation in the shoulder. The most reliable diagnostic test is the O’Brien test. The test is performed against resistance with the arm in forward flexion with the elbow extended and the forearm pronated. In the second part of the test, the arm is supinated. Less pain occurring during the latter part of the test suggests a SLAP lesion.158 The most accurate diagnostic test is MRI-arthrography with gadolinium.161 Treatment for symptomatic SLAP lesions is surgical. ADHESIVE CAPSULITIS Adhesive capsulitis, or frozen shoulder syndrome (FSS), is a condition characterized by limitation of motion of the shoulder joint with pain at the extremes of motion. It was first described by Putman162 in 1882 and later by Codman.1 The initial presentation is pain, which is generalized and referred to the upper arm, back, and neck. As the pain increases, loss of joint motion ensues. The process is generally self-limiting and in most cases resolves spontaneously within 10 months, unless there is an underlying problem. The exact cause of FSS is unknown.91,163 It is frequently associated with conditions such as diabetes mellitus, parkinsonism, thyroid disorders, and cardiovascular disease. When one of these conditions exists, there is often a history of some mild trauma that initiated the frozen shoulder. Major skeletal trauma and soft tissue injury may coexist with FSS. It also may be seen with a variety of other conditions, including apical lung tumors, pulmonary tuberculosis, cervical radiculopathy, and post–myocardial infarction.164-166 In one review of FSS, 3 of 140 patients with this syndrome had local primary invasive neoplasms.167 Another study reviewed three patients with adhesive capsulitis

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who subsequently were found to have a neoplastic lesion of the midshaft of the humerus.168 In a high-risk patient with an underlying disorder, even minor surgery or trauma in a remote location, such as the hand, can precipitate FSS.91,169,170 The pathophysiology involves a diffuse inflammatory synovitis with subsequent adherence of the capsule and a loss of the normal axillary pouch and joint volume, which leads to a significant loss of motion. Capsular contracture is thought to result from adhesion of the capsular surfaces or fibroblastic proliferation in response to cytokine production.163,169,171 The condition is more common in women in their 40s and 50s. Typically, the patient relays a history of diffuse, dull aching around the shoulder, with weakness and loss of motion occurring over a few months. Usually, there are three distinct clinical stages of the syndrome. Stage one is the painful or freezing phase. During this stage, the pain is severe, is exacerbated by any attempts at movement, and usually lasts a few weeks or months. The patient usually feels most comfortable with the arm at the side in an adducted and internally rotated position. Phase two is the adhesive or stiffening phase and generally lasts 4 to 12 months. Pain is usually minimal during this phase, although periscapular symptoms may develop from compensatory motion to achieve elevation of the arm. The third phase of the syndrome is the resolution or thawing phase and may last 5 to 26 months. During this time, the pain eases, and motion slowly improves, although some patients may improve dramatically over a short period.172 In the early stages, any attempts at motion may produce severe pain and associated weakness. The syndrome usually is associated with a prolonged period of immobilization.173 Night pain is common, with an inability to sleep on the associated shoulder, which is similar to findings of impingement syndrome. In patients with a history of minimal or no trauma and FSS, a metabolic cause should be excluded. A complete blood cell count, erythrocyte sedimentation rate, serum chemistry, and thyroid function tests are done as a screening panel. Further testing is done if the results suggest the possibility that the patient may have a systemic illness. Plain radiographs should include true anteroposterior, axillary, and scapular Y views of the shoulder. In patients with no underlying detectable illnesses and a negative workup, a Tc 99m pertechnetate scan may show increased uptake in FSS, but more importantly, it is used to exclude occult lesions or metastasis.174 Treatment of FSS is mainly conservative using intraarticular injections, heat, gentle stretching, NSAIDs, and modalities such as transcutaneous electrical nerve stimulation. The disease usually is self-limited and, after the painful phase, is not severely disabling. Communication between the physician and the patient, with a thorough explanation of the condition, is essential because resolution of the syndrome occurs slowly over time. Closed manipulation and surgery (open and arthroscopic) are reserved for patients whose condition is recalcitrant to conservative measures or for whom the diagnosis is in question. Paramount in the prevention of FSS is avoiding overimmobilization in a minor shoulder injury, in addition to careful identification of patients at risk for FSS. Fareed and Gallivan175 reported good results with hy­­ draulic distention of the glenohumeral joint using local

anesthetic agents. Rizk and associates176 conducted a prospective, randomized study to assess the effect of steroid or local anesthetic injection in 48 patients with FSS. There was no significant difference in outcome between individuals who received intrabursal or intra-articular injection. Steroid with lidocaine had no advantage over lidocaine alone in restoring shoulder motion. Transient pain relief occurred, however, in two thirds of the steroid-treated patients.176 General anesthesia occasionally is indicated for closed manipulation. Hill and Bogumill177 reported the results of manipulation of 17 frozen shoulders in 15 patients who did not respond to physical therapy. An average 2.6 months after manipulation, 78% of individuals working before their shoulder problems returned to work. The investigators concluded that manipulation allowed patients to return to a normal lifestyle and to work sooner than the reported natural history of the condition.177 Surgical intervention for adhesive capsulitis should be limited to treatment of an underlying problem, such as calcific tendinitis or an impingement syndrome. GLENOHUMERAL INSTABILITY Glenohumeral instability is a pathologic condition that manifests as pain associated with excessive translation of the humeral head on the glenoid during shoulder motion. Instability can range from excessive laxity with episodes of subluxation to frank dislocation of the joint. Traumatic dislocation of the glenohumeral joint has characteristic clinical and radiographic findings that are beyond the scope of this chapter and have been reviewed in detail elsewhere.178 The most common type of instability is anterior, although posterior and multidirectional laxity of the shoulder are increasingly recognized as causes of shoulder pain. Anterior dislocation usually occurs with the arm in an abducted and externally rotated position, and the diagnosis is usually obvious. Posterior dislocation is frequently associated with convulsive disorders or unusual trauma with the arm in a forward flexed and internally rotated position. The diagnosis is often missed and should always be suspected in the patient who is unable to rotate the arm externally after trauma. Recurrent subluxation without dislocation may be difficult to diagnose and may be mistakenly identified as impingement with chronic cuff tendinitis. An overhead athlete may experience repetitive stresses to the shoulder, causing microtrauma to the static stabilizers. Jobe and ­colleagues21 described the syndrome of shoulder pain in overhead or throwing athletes that manifests as impingement, but is caused by anterior subluxation of the joint with the humeral head impinging on the anterior aspect of the coracoacromial arch. Fu and coworkers179 underscored this distinction by dividing the cause of rotator cuff tendinitis into primary impingement of the tendon on the coracoacromial arch and anterior subluxation with secondary impingement in young athletes performing overhead movements. Walch and colleagues180 described intra-articular impingement between the undersurface of the rotator cuff (supraspinatus and infraspinatus) and the posterior superior glenoid rim and labrum. This “internal impingement” usually is observed in overhead athletes with subtle anterior glenohumeral instability and results in tendinitis or partial tears of the rotator cuff (see Fig. 40-17).

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The diagnosis of glenohumeral instability with subluxation in one or multiple directions is made by the combination of a detailed history and physical examination and the use of adjuncts, such as arthrography, CT, MRI, and arthroscopy with examination under anesthesia. The syndrome of multidirectional instability has been recognized in patients with symptomatic inferior instability in addition to anterior or posterior instability. Approximately 50% of affected patients have evidence of generalized laxity. Frequently, the syndrome occurs in young athletic patients who are loose jointed, in particular, in the dominant arm of pitchers, racket sports players, and swimmers. In this type of athlete, repetitive microtrauma may cause stretching of the shoulder, resulting in a large capsular pouch without labral detachment. A traumatic event may damage the shoulder, resulting in the syndrome of multidirectional instability and a Bankart lesion.181 The most common manifestation in these patients is pain, often mistakenly considered to be rotator cuff tendinitis. The patient may relate a history of minor trauma causing acute pain and a “dead arm” syndrome lasting minutes or hours. Other associated symptoms include a sense of instability, weakness, and radicular symptoms suggestive of neuropathy. There may be few or no positive physical findings associated with chronic subluxation or multidirectional instability. The patient may have signs of generalized ligamentous laxity, and pain may be reproduced by subluxating the glenohumeral joint in multiple directions. One particularly helpful sign for inferior laxity is the sulcus sign, which refers to the subacromial indentation that occurs when longitudinal traction is applied to the humerus with the arm at the side. The sign occurs with inferior translation of the humeral head. Because this syndrome frequently occurs in athletes with highly developed musculature around the shoulder girdle, these physical findings of subluxation may be difficult to reproduce in the office setting. Plain radiographs are generally normal, although some inferior subluxation may be shown by obtaining stress radiographs with weights. Special radiographs, as discussed previously, may show a Bankart lesion (i.e., avulsion of the anterior inferior glenoid rim) or a Hill-Sachs lesion (i.e., osteochondral defect of the posterior humeral head) occurring with subluxation of the humeral head in front of the anterior glenoid rim. CT-arthrography or MRI-arthrography may show increased capsular volume, a labral detachment, or a Hill-Sachs lesion (see Fig. 40-10). When surgery is indicated, examination under anesthesia and shoulder arthroscopy may assist in diagnosing the primary direction of instability in the syndrome of multidirectional instability. In selected patients with traumatic anterior dislocation without a history of multidirectional instability, arthroscopic stabilization may be done with stabilization of the capsulolabral complex. Treatment of chronic subluxation or the syndrome of multidirectional instability is first directed toward prolonged rehabilitation. Activities that stress the shoulder and produce symptoms are avoided. Strengthening exercises of the shoulder girdle may control symptoms, dynamically stabilizing the glenohumeral joint, and obviate the need for surgical intervention. If a conservative treatment program fails, surgery is performed on the side associated with the greatest amount of clinical instability. Stabilization is directed toward tightening of the capsular structures to stabilize the glenohumeral joint.181,182

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EXTRINSIC OR REGIONAL FACTORS CAUSING SHOULDER PAIN Because the shoulder girdle connects the thorax with the upper extremity, and the major neurovascular structures pass in proximity to the joint, shoulder pain is a hallmark of many nonarticular conditions. CERVICAL RADICULOPATHY Cervical pathology may manifest with associated shoulder pain. The area of referred pain is along a dermatomal pattern consistent with the distribution of the dermatomal nerve roots. Isolation of the pain usually defines the exact location of the associated cervical pathology. It can be differentiated from shoulder pain on the basis of history, physical examination, EMG, cervical radiographs, and myelography or MRI when indicated. Because conditions causing cervical neck pain and conditions causing shoulder pain, such as calcific tendinitis and cervical radiculopathy, may coexist, it is often difficult to distinguish which lesion is responsible for the symptoms. These conditions often can be differentiated by injection of local anesthetics to block certain components of the pain. The thoracic outlet is an interval created by the anterior and middle scalene muscles and the first rib through which the brachial plexus and vessels pass to the arm. In thoracic outlet syndrome, compression of these nerves and vessels often manifests as a vague shoulder pain with numbness of the ipsilateral fourth and fifth digits. Cervical rib or hypertrophy of the scalene muscles can be related to the onset of pain.183-185 Occurrence of pain also has been related to scapular ptosis, poor posture, and clavicular fracture with malunion or copious callus formation. BRACHIAL NEURITIS In the 1940s, Spillane186 and Parsonage and Turner187,188 described a painful condition of the shoulder associated with limitation of motion. As the pain subsided and motion improved, muscle weakness and atrophy became apparent. The deltoid, supraspinatus, infraspinatus, biceps, and triceps are the most frequently involved muscles,189 although diaphragmatic paralysis also has been reported.188,190 The cause is unclear, but the clustering of cases suggests a viral or postviral syndrome.187,188 Occasionally, an associated influenzalike syndrome or previous vaccination has been reported.189 Hershman and colleagues191 described acute brachial neuropathy in athletes. The findings that suggest an acute brachial neuropathy include acute onset of pain without trauma; persistent, severe pain that continues despite rest; and patchy neurologic signs. The diagnosis is confirmed by EMG and nerve conduction studies.191 The prognosis for recovery is excellent, although full recovery may take 2 to 3 years. Tsairis and associates192 reported 80% recovery within 2 years and more than 90% recovery by the end of 3 years. NERVE ENTRAPMENT SYNDROMES Peripheral compression neuropathies of the upper extremities also may produce referral pain to the shoulder. Distant compression neuropathies, such as carpal tunnel (median nerve) and cubital tunnel (ulnar nerve) syndromes, may

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manifest with concomitant and separate shoulder impingement with rotator cuff disease. Associated numbness and paresthesias with mapping of the dermatomal distribution and with peripheral neuropathy often direct the examiner to the appropriate diagnosis. Patients often give a history of dropping objects and a feeling of clumsiness with the affected hand. A Tinel sign may be elicited over the region of entrapment at the elbow or wrist. Provocative maneuvers such as Phalen’s test may be positive and usually indicate median nerve compression at the wrist. Diminished vibratory sensation is an early finding in the disease and is easily reproducible,193,194 whereas decreased two-point discrimination and intrinsic atrophy are late findings of peripheral compression neuropathy.193 The diagnosis usually can be made by clinical examination with exclusion of other possible causes. EMG and nerve conduction velocity tests may reveal slowed conduction and latency at the appropriate compression points to aid in diagnosis. Spinal accessory nerve injury with subsequent denervation of the trapezius may cause weakness and pain in the shoulder consistent with impingement. The injury can occur from traction injury to the neck or a direct blow or pressure to the base of the neck. Iatrogenic nerve injury may occur from surgical procedures on the neck such as lymph node biopsy.195 The injury produces weakness in shoulder abduction with associated pain that radiates from the neck into the trapezius and shoulder. Subsequent atrophy of the trapezius may lead to dyssymmetry and ptosis of the involved shoulder, with narrowing of the supraspinatus outlet and secondary impingement with shoulder pain. Definitive diagnosis can be made by EMG examination. Early treatment is conservative. If return of function is not evident at 6 months, surgical exploration of the nerve with possible tendon transfers may be indicated.196 Injury to the long thoracic nerve (cervical fifth, sixth, and seventh roots) can lead to scapular winging. The resultant scapular dysrhythmia and weakness can lead to a painful shoulder that may mimic rotator cuff disease.195 Patients also complain of pain and discomfort with active forward flexion of the shoulder. Patients who remain sympto­ matic after conservative treatment may require surgery for ­scapulothoracic fusion or tendon transfer using the pectoralis major or minor to stabilize the scapula.197,198 In quadrilateral space syndrome, the axillary nerve is compressed by fibrous bands in the quadrilateral space.195,199,200 This syndrome typically occurs when the arm is held in abduction and external rotation, with subsequent tightening of the fibrous bands across the nerve.201 It is most commonly seen in the dominant shoulder of young athletic individuals such as pitchers, tennis players, and swimmers who function with excessive overhead activity. The pain may occur throughout the shoulder girdle and radiate down the arm in a nondermatomal pattern. Neurologic and EMG testing may be normal. Diagnosis often is made by an arteriogram of the subclavian artery. A positive arteriogram reveals compression of the posterior humeral circumflex artery as it traverses the quadrangular space when the arm is in the abducted and externally rotated position. Surgical intervention may be required to release the fibrotic bands or tendon of the teres minor if the patient fails conservative treatment.195,202 Suprascapular nerve entrapment syndrome can result from a traction lesion, compression lesion, or both to the

nerve caused by tethering of the nerve at the suprascapular notch by the suprascapular ligament or the spinoglenoid notch by the transverse ligament. It also can result from direct compression of a space-occupying lesion, such as a ganglion or lipoma. Rengachary and coworkers203 described variations in the size and shape of the suprascapular notch that may predispose the nerve to entrapment. The resulting suprascapular neuropathy produces pain in the posterolateral aspect of the shoulder that may radiate into the ipsilateral extremity, shoulder, or side of the neck. Although uncommon, undiagnosed, it can have a prolonged and disabling course. Because the suprascapular nerve has no cutaneous innervation, there is no associated numbness, tingling, or paresthesias. There is usually weakness in abduction and external rotation, and significant atrophy is often noticed at diagnosis. The pain frequently is described as a deep burning or aching that can be well localized and often can be elicited by palpation over the region of the suprascapular notch. Any activity that brings the scapula forward, such as reaching across the chest, may aggravate the pain.204 The location of the pain and other symptoms can mimic more common entities, such as impingement, rotator cuff disease, cervical disk disease, brachial neuropathy, biceps tendinitis, thoracic outlet syndrome, AC disease, and instability of the shoulder.205 Fritz and colleagues206 reported the efficacy of MRI in the diagnosis of suprascapular nerve entrapment secondary to space-occupying lesions. Definitive diagnosis is made with EMG and nerve conduction studies. EMG changes usually reveal spontaneous activity in the muscle at rest and fibrillations indicating motor atrophy and denervation. Nerve conduction studies may reveal slowing across the site of entrapment. As with axillary nerve entrapment, the syndrome is often associated with young, athletic individuals with excessive overhead activity.207 It also has been associated with trauma.205,208,209 There has been a lack of consensus regarding the optimal treatment of suprascapular neuropathy.6,205,207,210,211 Post and Grinblat210 reported 25 of 26 cases to have goodto-excellent results with surgical treatment. No difference in residual atrophy and strength deficits has been shown, however, for operative and nonoperative treatments. Ferretti and coworkers207 evaluated 96 top-level volleyball players from the 1985 European Championships and found that 12 had isolated suprascapular neuropathy with atrophy of the infraspinatus of the dominant shoulder. All the players were unaware of any impairments, however, and played without limitations. After a space-occupying lesion has been excluded, a 6-month trial of conservative treatment may be indicated for some individuals. If the entrapment does not improve, or symptoms worsen with conservative treatment, surgical decompression is warranted for pain relief; however, resolution of atrophy and strength gains can vary.205 STERNOCLAVICULAR ARTHRITIS Occasionally, traumatic, nontraumatic, or infectious conditions can cause pain around the sternoclavicular joint (see Fig. 40-2). The most common problem is ligamentous injury and painful subluxation or dislocation. This can be diagnosed by palpable instability and crepitus over the

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s­ ternoclavicular joint. Sternoclavicular views may radiographically show dislocation.212 Inflammatory arthritis of the sternoclavicular joint has been associated with rheumatoid arthritis, ankylosing spondylitis, and septic arthritis. The association of palmoplantar pustulosis and sternoclavicular arthritis has been reported.213 Seven of 15 patients who underwent biopsies for this condition had cultures positive for Propionibacterium acnes, suggesting an infectious origin of the condition.213 Two other conditions involving the sternoclavicular joint are Tietze’s syndrome, a painful, nonsuppurative swelling of the joint and adjacent sternochondral junctions, and Friedrich’s syndrome, a painful osteonecrosis of the sternal end of the clavicle.3 Condensing osteitis of the clavicle is a rare benign idiopathic lesion of the medial one third of the clavicle. This condition, better described as aseptic enlarging osteosclerosis of the clavicle, is most commonly seen in middle-aged women and manifests as a tender swelling over the medial one third of the clavicle.214 REFLEX SYMPATHETIC DYSTROPHY Since its original description by Mitchell215 in 1864, reflex sympathetic dystrophy (RSD) has remained a poorly understood and frequently overlooked condition. Its cause is unknown, but may be related to sympathetic overflow or short-circuiting of impulses through the sympathetic system. Any clinician dealing with painful disorders must be familiar with the diagnosis and treatment of this condition. Bonica’s216 excellent review covers the clinical presentation, various stages of the disease, and importance of early intervention to ensure a successful outcome. RSD has been confusingly called causalgia, shoulderhand syndrome, and Sudeck’s atrophy. It is generally associated with minor trauma and is to be differentiated from causalgia, which involves trauma to major nerve roots.215 RSD is divided into three phases, which are important in determining treatment.216 Phase one is characterized by sympathetic overflow with diffuse swelling, pain, increased vascularity, and radiographic evidence of demineralization. If left untreated for 3 to 6 months, this may progress to phase two, which is characterized by atrophy. The extremity may now be cold and shiny, with atrophy of the skin and muscles. Phase three refers to progression of the trophic changes, with irreversible flexion contracture and a pale, cold, painful extremity. It has been speculated that phase one is related to a peripheral short-circuiting of nerve impulses, phase two represents short-circuiting through the internuncial pool in the spinal cord, and phase three is controlled by higher thalamic centers.216,217 Steinbrocker218 reported that recovery is possible as long as there is evidence of vasomotor activity with swelling and hyperemia. After trophic phase two or three is established, the prognosis for recovery is poor. Prompt recognition of the syndrome is important because early intervention to control pain is mandatory. Careful supervision and reassurance are crucial because many of these patients are emotionally labile as a result of the pain or an underlying problem. The syndrome may be remarkably reversed by a sympathetic block. Patients who receive transient relief from sympathetic blockade may be helped by surgical sympathectomy.

611

NEOPLASMS Primary and metastatic neoplasms may cause shoulder pain by direct invasion of the musculoskeletal system or by compression with referred pain.2,219 Primary tumors are more likely to occur in younger individuals. More common lesions have a typical distribution, such as the predilection of a chondroblastoma for the proximal humeral epiphysis or an osteogenic sarcoma for the metaphysis.220 The differential diagnosis of spontaneous onset of shoulder pain in older individuals should include metastatic lesions and myeloma. Neoplasms are best identified by plain radiographs, MRI, Tc 99m MDP scintigraphy, and CT. Neoplasms also may involve the shoulder region by me­­ tastases to the region. An associated history of carcinomas should alert the examiner to the possibility of a bone tumor, especially in patients who had malignancies with a predilection for metastasis to bone (e.g., thyroid, renal, lung, prostate, breast). Pain is often present at rest and exacerbated at night. Atypical pain distribution that is not relieved by injection without specific dermatomal distribution also should alert the examiner to the other underlying possibilities. Plain radiographs should be evaluated thoroughly for any cortical destruction or lytic lesions. Pancoast syndrome or apical lung tumor may manifest as shoulder pain or cervical radiculitis because of invasion of the brachial plexus or invasion of the C8 or T1 roots.221-223 With invasion of the cervical sympathetic chain, the patient also may develop Homer’s syndrome. MISCELLANEOUS CONDITIONS With the increasing numbers of patients undergoing longterm maintainence hemodialysis, a shoulder pain syndrome known as dialysis shoulder arthropathy has been described. It consists of shoulder pain, weakness, loss of motion, and functional limitation. The cause and pathogenesis of this syndrome are unclear, although rotator cuff disease, pathologic fracture, bursitis, and local amyloid deposition have been implicated as causative factors.224 There are insufficient surgical or necropsy data to confirm a specific diagnosis. These patients generally respond poorly to local measures of injection, heat, and NSAIDs, but they may improve with correction of underlying metabolic disorders, such as osteomalacia and secondary hyperparathyroidism.

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DIFFERENTIAL DIAGNOSIS OF REGIONAL MUSCULOSKELETAL PAIN

69. Ozaki J, Fujimoto S, Nakagawa Y, et al: Tears of the rotator cuff of the shoulder associated with pathologic changes of the acromion: A study in cadavers. J Bone Joint Surg 70:1224, 1988. 70. Skinner HA: Anatomical consideration relative to ruptures of the supraspinatus tendon. J Bone Joint Surg Br 19:137, 1937. 71. Ellman H: Occupational supraspinatus tendinitis: The rotator cuff syndrome. Ugeskr Laeger 151:2355, 1989. 72. Scheib JS: Diagnosis and rehabilitation of the shoulder impingement syndrome in the overhand and throwing athlete. Rheum Dis Clin North Am 16:971, 1990. 73. Jackson DW: Chronic rotator cuff impingement in the throwing athlete. Am J Sports Med 4:231, 1976. 74. Hawkins RJ, Kennedy JC: Impingement syndrome in athletes. Am J Sports Med 8:151, 1980. 75. McShane RB, Leinberry CF, Fenlin JM: Conservative open anterior acromioplasty. Clin Orthop 223:137, 1987. 76. Rockwood CA, Lyons FA: Shoulder impingement syndrome: Diagnosis, radiographic evaluation, and treatment with a modified Neer acromioplasty. J Bone Joint Surg Am 75:1593, 1993. 77. Hawkins RJ, Brock RM, Abrams JS, et al: Acromioplasty for impingement with an intact rotator cuff. J Bone Joint Surg Br 70:797, 1988. 78. Stuart MJ, Azevedo AJ, Cofield RH: Anterior acromioplasty for treatment of the shoulder impingement syndrome. Clin Orthop 260:195, 1990. 79. Bigliani LU, D’Alesandro DF, Dduralde XA, et al: Anterior acromioplasty for subacromial impingement in patients younger than 40 years of age. Clin Orthop 246:111, 1988. 80. Bjorkheim JM, Paavolainen P, Ahovuo J, et al: Surgical repair of the rotator cuff and the surrounding tissues: Factors influencing the results. Clin Orthop 236:148, 1988. 81. Levy HJ, Gardner RD, Lemak LJ: Arthroscopic subacromial decompression in the treatment of full-thickness rotator cuff tears. Arthroscopy 7:8, 1991. 82. McKendry RJR, Uhthoff HK, Sarkar K, et al: Calcifying tendinitis of the shoulder: Prognostic value of clinical, histologic, and radiographic features in 57 surgically treated cases. J Rheumatol 9:75, 1982. 83. Uhthoff HK, Sarkar K, Maynard JA: Calcifying tendinitis, a new concept of its pathogenesis. Clin Orthop 118:164, 1976. 84. Sarkar K, Uhthoff HK: Ultrastructure localization of calcium in calcifying tendinitis. Arch Pathol Lab Med 102:266, 1978. 85. Hayes CW, Conway WF: Calcium hydroxyapatite deposition disease. Radiographics 10:1031, 1990. 86. Vebostad A: Calcific tendinitis in the shoulder region: A review of 43 operated shoulders. Acta Orthop Scand 46:205, 1975. 87. Moseley HF, Goldie I: The arterial pattern of the rotator cuff of the shoulder. J Bone Joint Surg Br 45:780, 1963. 88. Rathburn JB, Macnab I: The microvascular pattern of the rotator cuff. J Bone Joint Surg Br 52:540, 1970. 89. Bosworth BM: Calcium deposits in the shoulder and subacromial bursitis: A survey of 12,122 shoulders. JAMA 116:2477, 1941. 90. Bosworth BM: Examination of the shoulder for calcium deposits. J Bone Joint Surg 23:567, 1941. 91. DePalma AF, Kruper JS: Long term study of shoulder joints afflicted with and treated for calcified tendonitis. Clin Orthop 20:61, 1961. 92. Linblom K: Arthrography and roentgenography in ruptures of the tendon of the shoulder joint. Acta Radiol 20:548, 1939. 93. Swiontkowski M, Iannotti JP, Herrmann HJ, et al: Intraoperative assessment of rotator cuff vascularity using laser Doppler flowmetry. In Post M, Morrey BE, Hawkins RJ (eds): Surgery of the Shoulder. St. Louis, Mosby, 1990, pp 208-212. 94. Matsen FA III, Arntz CT: Subacromial impingment. In Rockwood CA Jr, Matsen FA III (eds): The Shoulder. Philadelphia, WB Saunders, 1990, pp 623-646. 95. Neer CS II, Poppen NK: Supraspinatus outlet. Orthop Trans 11:234, 1987. 96. Clark J, Sidles JA, Matsen FA: The relationship of the glenohumeral joint capsule to the rotator cuff. Clin Orthop 254:29, 1990. 97. Samilson RL, Raphael RL, Post L, et al: Arthrography of the shoulder. Clin Orthop 20:21, 1961. 98. Collins RA, Gristina AG, Carter RE, et al: Ultrasonography of the shoulder. Orthop Clin North Am 18:351, 1987. 99. Crass JR, Craig EV, Feinberg SB: Ultrasonography of rotator cuff tears: A review of 500 diagnostic studies. J Clin Ultrasound 16:313, 1988.

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100. Crass JR, Craig EV, Feinberg SB: The hyperextended internal rotation view in rotator cuff ultrasonography. J Clin Ultrasound 15:415, 1987. 101. Mack LA, Gannon MK, Kilcoyne RF, et al: Sonographic evaluation of the rotator cuff: Accuracy in patients without prior surgery. Clin Orthop 234:21, 1988. 102. Iannotti JP, Zlatkin MB, Esterhai JL, et al: Magnetic resonance imaging of the shoulder: Sensitivity, specificity, and predictive value. J Bone Joint Surg Am 73:17, 1991. 103. DePalma AF: Surgery of the Shoulder, 2nd ed. Philadelphia, JB Lippincott, 1973. 104. Wolfgang GL: Surgical repair of tears of the rotator cuff of the shoulder: Factors influencing the result. J Bone Joint Surg Am 56:14, 1974. 105. Jobe FW, Moynes DR: Delineation of diagnostic criteria and a rehabilitation program for rotator cuff injuries. Am J Sports Med 10:336, 1982. 106. Earnshaw P, Desjardins D, Sakar K, et al: Rotator cuff tears: The role of surgery. Can J Surg 25:60, 1982. 107. Rockwood CA, Williams GR, Burkhead WZ: Debridement of massive, degenerative lesions of the rotator cuff. Presented at Seventh open meeting of the American Shoulder and Elbow Society Surgeons, Anaheim, Calif, March 10, 1991. 108. Martin SD, Andrews JR: The rotator cuff: Open and mini-open repairs. Presented at American Orthopaedic Society for Sports Medicine 20th Annual Meeting, Palm Desert, June 26, 1994. 109. Rockwood CA Jr: The shoulder: Facts, confusion and myths. Int Orthop 15:401, 1991. 110. Steffens K, Konermann H: Rupture of the rotator cuff in the elderly. Z Gerontol 20:95, 1987. 111. Goss CM: Gray’s Anatomy of the Human Body, 28th ed. Philadelphia, Lea & Febiger, 1966. 112. Neer CS, Craig EV, Fukuda H: Cuff tear arthropathy. J Bone Joint Surg Am 65:1232, 1983. 113. Neer CS II, Bigliani LU, Hawkins RJ: Rupture of the long head of the biceps related to subacromial impingement. Orthop Trans 1:111, 1977. 114. Crenshaw AH, Kilgore WE: Surgical treatment of bicipital tendonitis. J Bone Joint Surg Am 48:1496, 1966. 115. Hitchcock HH, Bechtol CO: Painful shoulder: Observations on the role of the tendon of the long head of the biceps brachii in its causation. J Bone Joint Surg Am 30:263, 1948. 116. Meyer AW: Spontaneous dislocation and destruction of the tendon of the long head of the biceps brachii, fifty-nine instances. Arch Surg 17:493, 1928. 117. Rockwood RA Jr, Williams GR, Young CD: Injuries to the acromioclavicular joint. In Rockwood CA Jr, Green DP, Bucholz RW (eds): Fractures in Adults. Philadelphia, JB Lippincott, 1991, pp 1181-1251. 118. Jacobs P: Post-traumatic osteolysis of the outer end of the clavicle. J Bone Joint Surg Br 46:705, 1964. 119. Murphy OB, Bellamy R, Wheeler W, et al: Post-traumatic osteolysis of the distal clavicle. Clin Orthop 109:108, 1975. 120. Cahill RB: Osteolysis of the distal part of the clavicle in male athletes. J Bone Joint Surg Am 64:1053, 1982. 121. Maden B: Osteolysis of the acromial end of the clavicle following trauma. Br J Radiol 36:822, 1963. 122. Scavenius M, Iversen BF: Nontraumatic clavicular osteolysis in weight lifters. Am J Sports Med 20:463, 1992. 123. Slawski DP, Cahill BR: Atraumatic osteolysis of the distal clavicle. Am J Sports Med 22:267, 1994. 124. Meyers JF: Arthroscopic debridement of the acromioclavicular joint and distal clavicle resection. In McGinty JB, Caspari RB, Jackson RW, et al (eds): Operative Arthroscopy. New York, Raven Press, 1991, pp 557-560. 125. Cahill BR, Lee MT: Atraumatic osteolysis of the distal clavicle. In Torg JS, Shephard RJ (eds): Current Therapy in Sports Medicine. St Louis, Mosby, 1995, pp 177-181. 126. Rockwood CA Jr: Disorders of the acromioclavicular joint. In Rockwood CA Jr, Matsen FA III (eds): The Shoulder. Philadelphia, WB Saunders, 1985, p 449. 127. Gartsman GM, Combs AH, Davis PF, et al: Arthroscopic acromioclavicular joint resection: An anatomic study. Am J Sports Med 19:25, 1991. 128. Fink EP: Injuries to the acromioclavicular joint. In Torg JS, Shephard RJ (eds): Current Therapy in Sports Medicine. St Louis, Mosby, 1995, pp 174-177.

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129. Gartsman GM: Arthroscopic resection of the acromioclavicular joint. Am J Sports Med 21:71, 1993. 130. Flatow EL, Cordasco FA, Bigliani LU: Arthroscopic resection of the outer end of the clavicle from a superior approach: A critical, quantitative, radiographic assessment of bone removal. Arthroscopy 8:55, 1992. 131. Flatow EL, Duralde XA, Nicholson GP, et al: Arthroscopic resection of the distal clavicle with a superior approach. J Shoulder Elbow Surg 4:41, 1995. 132. Worcester JN, Green DP: Osteoarthritis of the acromioclavicular joint. Clin Orthop 58:69, 1987. 133. DePalma AF: The role of the disks of the sternoclavicular and acromioclavicular joints. Clin Orthop 13:222, 1959. 134. Novack PJ, Bach BB, Romeo AA, et al: Surgical resection of the distal clavicle. J Shoulder Elbow Surg 4:35, 1995. 135. Gurd FB: The treatment of complete dislocation of the outer end of the clavicle: A hitherto undescribed operation. Ann Surg 63:1094, 1941. 136. Mumford EB: Acromioclavicular dislocation: A new operative treatment. J Bone Joint Surg Am 23:799, 1941. 137. Cook FF, Tibone JE: The Mumford procedure in athletes: An objective analysis of function. Am J Sports Med 16:97, 1988. 138. Bigliani LU, Nicholson GP, Flatow EL: Arthroscopic resection of the distal clavicle. Orthop Clin North Am 24:133, 1993. 139. Gartsman GM, Combs AH, Davis PF, et al: Arthroscopic acromioclavicular joint resection: An anatomic study. Am J Sports Med 19:2, 1991. 140. Kay SP, Ellman H, Harris E: Arthroscopic distal clavicle resection: Technique and early results. Clin Orthop 301:181, 1994. 141. Tolin BS, Snyder SJ: Our technique for the arthroscopic Mumford procedure. Orthop Clin North Am 24:143, 1993. 142. Cofield RH, Briggs BT: Glenohumeral arthrodesis. J Bone Joint Surg Am 61:668, 1979. 143. Rowe CR: Arthrodesis of the shoulder used in treating painful conditions. Clin Orthop 173:92, 1983. 144. Neer CS II, Watson KC, Stanton FJ: Recent experience in total shoulder replacement. J Bone Joint Surg Am 64:319, 1982. 145. Cofield RH: Unconstrained total shoulder prosthesis. Clin Orthop 173:97, 1983. 146. Thornhill TS, Karr MJ, Averill RM, et al: Total shoulder arthroplasty, the Brigham experience. Presented at Fiftieth Annual Meeting of the American Academy of Orthopedic Surgeons, Anaheim, Calif, 1983. 147. Thornhill TS, Barrett WP: Total shoulder arthroplasty. In Rowe CR (ed): The Shoulder. New York, Churchill Livingstone, 1988. 148. Neer CS II: Fractures and dislocations of the shoulder. In Rockwood CA, Green DP (eds): Fractures. Philadelphia, JB Lippincott, 1975. 149. Ficat RP, Arlet J: Ischemia and Necrosis of the Bone. Baltimore, Williams & Wilkins, 1980. 150. Hayes JM: Arthroscopic treatment of steroid-induced osteonecrosis of the humeral head. Arthroscopy 5:218, 1989. 151. McCarty DJ: Robert Adams’ rheumatic arthritis of the shoulder: “Milwaukee shoulder” revisited. J Rheumatol 32:668, 1989. 152. Halverson PB, Carrera GF, McCarty DJ: Milwaukee shoulder syndrome: Fifteen additional cases and a description of contributing factors. Arch Intern Med 150:677, 1990. 153. Wortmann RL, Veum JA, Rachow JW: Synovial fluid 5-­nucleotidase activity: Relationship to other purine catabolic enzymes and to arthropathies associated to calcium deposition disease. Arthritis Rheum 34:1014, 1991. 154. Neer CS II, Craig EV, Fukada H, et al: Cuff tear arthropathy. Exhibit at the Annual Meeting of the American Academy of Orthopedic Surgeons, New Orleans, 1982. 155. Post M, Haskell SS, Jablon M: Total shoulder replacement with a constrained prosthesis. J Bone Joint Surg Am 62:327, 1980. 156. Post M, Jablon M: Constrained total shoulder arthroplasty: Long term follow-up observations. Clin Orthop 173:109, 1983. 157. Hamada K, Fukuda H, Mikasa M, et al: Roentgenographic findings in rotator cuff tears: A long-term observation. Clin Orthop 254:92, 1990. 158. Snyder SJ, Karzel RP, Del Pizzo W, et al: SLAP lesions of the shoulder. Arthroscopy 6:274, 1990. 159. Burkhart SS, Fox DL: SLAP lesions in association with complete tears of the long head of the biceps tendon: A report of two cases. Arthroscopy 8:31, 1992. 160. Maffet MW, Gartsman GM, Moseley B: Superior labrum-biceps tendon complex lesions of the shoulder. Am J Sports Med 23:93, 1995.

161. Grauer JD, Paulos LE, Smutz WP: Biceps tendon and superior labral injuries. Arthroscopy 8:488, 1992. 162. Putman JJ: The treatment of a form of painful periarthritis of the shoulder. Boston Med Surg J 107:536, 1882. 163. Neviaser JS: Adhesive capsulitis of the shoulder: Study of the pathologic findings in periarthritis of the shoulder. J Bone Joint Surg 27:211, 1945. 164. McLaughlin HL: The “frozen shoulder.” Clin Orthop 20:126, 1961. 165. Johnson JTH: Frozen shoulder syndrome in patients with pulmonary tuberculosis. J Bone Joint Surg Am 41:877, 1959. 166. Dee PE, Smith RG, Gullickson MJ, et al: The orthopedist and apical lung carcinoma. J Bone Joint Surg Am 42:605, 1960. 167. Demaziere A, Wiley AM: Primary chest wall tumor appearing as frozen shoulder: Review and case presentations. J Rheumatol 18:911, 1991. 168. Smith CR, Binder AI, Paice EW: Lesions of the mid-shaft of the humerus presenting as shoulder capsulitis. Br J Rheumatol 29:386, 1990. 169. Dickson JA, Crosby EH: Periarthritis of the shoulder: An analysis of two hundred cases. JAMA 99:2252, 1932. 170. McLaughlin HL: On the frozen shoulder. Bull Hosp Joint Dis 12:383, 1951. 171. Lundberg BJ: The frozen shoulder. Acta Orthop Scand 119:59, 1969. 172. Rowe CR, Leffert RD: Idiopathic chronic adhesive capsulitis. In Rowe CR (ed): The Shoulder. New York, Churchhill Livingstone, 1988, pp 155-163. 173. Coventry MB: Problem of the painful shoulder. JAMA 151:177, 1953. 174. Waldburger M, Meier JL, Gobelet C: The frozen shoulder: Diagnosis and treatment. Clin Rheumatol 11:364, 1992. 175. Fareed DO, Gallivan WR Jr: Office management of frozen shoulder syndrome: Treatment with hydraulic distention under local anesthesia. Clin Orthop 242:177, 1989. 176. Rizk TE, Pinalls RA, Talaiver AS: Corticosteroid injections in adhesive capsulitis: Investigation of their value and site. Arch Phys Med Rehabil 72:20, 1991. 177. Hill JJ Jr, Bogumill H: Manipulation in the treatment of frozen shoulder. Orthopedics 11:1255, 1988. 178. Rowe CR: Dislocations of the shoulder. In Rowe CR (ed): The Shoulder. New York, Churchill Livingstone, 1988. 179. Fu FH, Harner CD, Klein AH: Shoulder impingement syndrome: A clinical review. Clin Orthop 269:162, 1991. 180. Walch G, Bioleau P, Noel E: Impingement of the deep surface of the supraspinatus tendon on the posterosuperior glenoid rim: An arthroscopic study. J Shoulder Elbow Surg 1:238, 1992. 181. Altchek DW, Warren RF, Ortiz G: T-plasty: A technique for treating multidirectional instability in the athlete. Orthop Trans 13:560, 1989. 182. Neer CS, Foster CR: Inferior capsular shift for involuntary and multidirectional instability of the shoulder: A preliminary report. J Bone Joint Surg Am 62:897, 1980. 183. Roos DB: Congenital anomalies associated with thoracic outlet syndrome: Anatomy, symptoms, diagnosis and treatment. Am J Surg 132:771, 1976. 184. Leffert RD: Thoracic outlet syndrome. In Gelberman RH (ed): Operative Nerve Repair and Reconstruction. Philadelphia, JB Lippincott, 1991, pp 1177-1195. 185. Urschel HC, Paulson DL, MacNamara JJ: Thoracic outlet syndrome. Ann Thorac Surg 6:1, 1968. 186. Spillane JD: Localized neuritis of the shoulder girdle: A report of 46 cases in the MEF. Lancet 2:532, 1943. 187. Parsonage MJ, Turner JWA: Neurologic amyotrophy: The shoulder girdle syndrome. Lancet 1:1973, 1948. 188. Turner JWA, Parsonage MJ: Neurologic amyotrophy (paralytic brachial neuritis): With special reference to prognosis. Lancet 2:209, 1957. 189. Bacevich BB: Paralytic brachial neuritis. J Bone Joint Surg Am 58:262, 1976. 190. Walsh NE, Dumitru D, Kalantri A, et al: Brachial neuritis involving the bilateral phrenic nerves. Arch Phys Med Rehabil 68:46, 1987. 191. Hershman EB, Wilbourn AJ, Bergfield JA: Acute brachial neuropathy in athletes. Am J Sports Med 17:655, 1989. 192. Tsairis P, Dyck PJ, Mulder DW: Natural history of brachial plexus neuropathy. Arch Neurol 27:109, 1972.

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DIFFERENTIAL DIAGNOSIS OF REGIONAL MUSCULOSKELETAL PAIN

193. Szabo RM: Carpal tunnel syndrome—general. In Gelberman RH (ed): Operative Nerve Repair and Reconstruction. Philadelphia, JB Lippincott, 1991, pp 869-888. 194. Slater RR, Bynum DK: Diagnosis and treatment of carpal tunnel syndrome. Orthop Rev 22:1095, 1993. 195. Narakas AO: Compression and traction neuropathies about the shoulder and arm. In Gelberman RH (ed): Operative Nerve Repair and Reconstruction. Philadelphia, JB Lippincott, 1991, pp 1147-1175. 196. Bigliani L, Perez-Sanz JR, Wolfe IN: Treatment of trapezius paralysis. J Bone Joint Surg 67:871, 1985. 197. Chavez JP: Pectoralis minor transplanted for paralysis of the serratus anterior. J Bone Joint Surg Br 33:21, 1951. 198. Marmor L, Bechtal CO: Paralysis of the serratus anterior due to electric shock relieved by transplantation of the pectoralis major muscle: A case report. J Bone Joint Surg 45:156, 1983. 199. Cahill BR, Palmer RE: Quadrilateral space syndrome. J Hand Surg 8:65, 1983. 200. Jobe FW, Tibone JE: The shoulder in sports. In Rockwood CA, Matsen FA (eds): The Shoulder. Philadelphia, WB Saunders, 1990, pp 961-990. 201. Cahill BR: Quadrilateral space syndrome. In Omer GE Jr, Spinner MD (eds): Management of Peripheral Nerve Problems. Philadelphia, WB Saunders, 1980, pp 56-65. 202. Bretzke CA, Crass JR, Craig EV, et al: Ultrasonography of the rotator cuff: Normal and pathologic anatomy. Invest Radiol 20:311, 1985. 203. Rengachary SS, Neft JP, Singer PA, et al: Suprascapular entrapment neuropathy: A clinical, anatomical and comparative study. Neurosurgery 5:441, 1979. 204. Habermeyer P, Rappaport D, Wiedermann E, et al: Incisura scapulae syndrome. Handchir Mikrochir Plast Chir 22:120, 1990. 205. Martin SD, Warren RF, Martin TL, et al: Suprascapular neuropathy. J Bone Joint Surg Am 79:1159, 1997. 206. Fritz RC, Helms CA, Steinbach LS, et al: Suprascapular nerve entrapment: Evaluation with MR imaging. Radiology 182:437, 1992. 207. Ferretti A, Cerullo G, Russo G: Suprascapular neuropathy in volleyball players. J Bone Joint Surg Am 69:260, 1987.

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208. Rask MR: Suprascapular nerve entrapment: A report of two cases treated with suprascapular notch resection. Clin Orthop 123:73, 1977. 209. Solheim LF, Roaas A: Compression of the suprascapular nerve after fracture of the suprascapular notch. Acta Orthop Scand 49:338, 1978. 210. Post M, Grinblat E: Suprascapular nerve entrapment: Diagnosis and results of treatment. J Shoulder Elbow Surg 2:197, 1993. 211. Hadley MN, Sonntag VK, Pittman HW: Suprascapular nerve entrapment: A summary of seven cases. J Neurosurg 64:843, 1986. 212. Rockwood CA Jr: Fractures and dislocations of the shoulder, part II. In Rockwood CA Jr, Green DP (eds): Fractures. Philadelphia, JB Lippincott, 1975, pp 262-270. 213. Edlund E, Johnsson U, Lidgren L, et al: Palmoplantar pustulosis and sternocostoclavicular arthro-osteitis. Ann Rheum Dis 47:809, 1988. 214. Lissens M, Bruyninckx F, Rossele N: Condensing osteitis of the clavicle: Report of two cases and review of the literature. Acta Belg Med Phys 13:235, 1990. 215. Mitchell SW: Phantom limbs. Lippincott 8:563, 1871. 216. Bonica JJ: Causalgia and other reflex dystrophies. In Bonica JJ (ed): Management of Pain. Philadelphia, Lea & Febiger, 1979, pp 139-142. 217. Evans JA: Reflex sympathetic dystrophy. Surg Gynecol Obstet 82:36, 1946. 218. Steinbrocker O: The shoulder-hand syndrome: Present perspective. Arch Phys Med 49:388, 1968. 219. Brown C: Compressive invasive referred pain to the shoulder. Clin Orthop 173:55, 1983. 220. Dahlin DC: Bone Tumors. Springfield, Ill, Charles C Thomas, 1978. 221. DePalma AF: Loss of scapulohumeral motion. Ann Surg 135:193, 1952. 222. Pancoast HK: Importance of careful roentgen ray investigation of apical chest tumors. JAMA 83:1407, 1923. 223. Vargo MM, Flood KM: Pancoast tumor presenting as cervical radiculopathy. Arch Phys Med Rehabil 71:606, 1990. 224. Brown EA, Arnold LR, Gower PE: Dialysis arthropathy: Complication of long term treatment with haemodialysis. BMJ 292:163, 1986.

41

Low Back Pain Michael s. Wildstein  •  EUGENE j. CARRAGEE

Key Points In adult population studies, the point prevalence and 1-year prevalence of low back pain (LBP) without sciatica, stenosis, or severe deformity has been estimated at 33% and 73%. Approximately 10% to 15% of physically active adults with LBP may expect a serious episode of LBP each year. Most of these individuals apparently experience significant resolution of their symptoms within 1 month without formal medical intervention. The utility (and wisdom) of ordering imaging early in the course of LBP illness is not supported by clinical evidence. Specific comorbidities are associated with risk of developing persistent, disabling LBP, including preexisting ­psychological distress, disputed compensation issues, chronic pain from other (nonlumbar) anatomic sites, and job dissatisfaction. The initial clinical determination involves two decision points: (1) Does the patient have a significant risk of a serious underlying illness? (2) Is the back pain accompanied by a specific pattern of pain radiation to the legs suggesting neurogenic claudication or sciatic-type syndromes (radicular pain, ­numbness, or tingling down one or both lower extremities)? A history of cancer, pain awakening the patient from sleep, recent weight loss, lethargy, or other constitutional symptoms suggested by the red flag survey warrant appropriate workup for neoplasm, infection, or inflammatory conditions. Such a history, along with associated neurologic findings, warrants use of magnetic resonance imaging (MRI) early in the course of an LBP episode. Patients with persistent, debilitating LBP lasting more than 4 to 6 weeks should be assessed carefully and possibly referred to the care of a spine specialist for secondary evaluation. Common degenerative findings (e.g., Schmorl’s nodes, end plate changes, disk desiccation) are expected on MRI and are most commonly unrelated to symptoms. Lumbar fusions performed on individuals for positive ­discographic findings are no more successful at reducing back pain than fusions performed on patients selected for fusion surgery without discography. Treatment of LBP with narcotic pain medicines over the long-term is usually discouraged. The tricyclic and the tetracyclic classes of antidepressants have been proved in randomized clinical trials to be effective treatments for LBP in patients without preexisting clinical depression. Patients with high “fear avoidance” characteristics (a disproportionate predilection to avoid activities or situations that may produce discomfort) have poorer outcomes and are at increased risk for developing chronic LBP illness than patients who remain active despite their pain. Exercise, no matter what type of regimen, seems to hasten patients’ return to usual lifestyle activities.

Concomitant medical and physical treatments seem to have better outcomes with respect to pain and disability than medical treatment alone. Lumbar epidural steroid injections, facet blocks, trigger point injections, and intradiscal anesthetics have not shown ­improvement in the outcomes of LBP patients who lack ­discrete radicular symptoms. Spinal fusion or decompression in patients with back pain and only common degenerative changes on imaging studies is not clearly effective. Short-term trials to date comparing disk replacement surgery and spinal fusion have failed to show significant differences in outcome.

For the internist or family physician, the problem of low back pain (LBP) is one of the most commonly assessed complaints. LBP is the most common cause of limitation of activity in patients younger than 45 years old, is the second most frequent reason for a visit to the physician’s office, is the third most common surgical indication, and ranks fifth among hospital admission diagnoses.1 Data from the 2002 National Health Interview Survey identified LBP as the most prevalent pain syndrome, eclipsing migraine headaches, neck pain, and face/jaw pain.2 The financial impact on society is even more staggering—$45 to $54 billion per year in lost wages, loss in household services and tax revenues, social security benefits, and lost productivity.3 In adult population studies, the point prevalence and 1-year prevalence of LBP without sciatica, stenosis, or severe deformity has been estimated at 33% (point prevalence)4 and 73% (1-year prevalence).5 This prevalence may be even higher in subgroups of adult laborers and military personnel involved in training exercises.4 Despite the common prevalence, most individuals with LBP do not seek medical care for this problem specifically. Approximately 10% to 15% of physically active adults with LBP may expect a serious episode of LBP each year. Most of these individuals apparently experience significant resolution of their symptoms within 1 month without formal medical intervention.6 Recurrences of back symptoms are common in this population, however, and can continue to be intermittently bothersome for years after the first event has passed. Despite the large proportion of adults who experience an episode or more of LBP, large population studies prospectively examining LBP symptoms over 5 years show that only a small proportion of respondents reported serious or persistent disability. The diagnostic challenge is the early identification and treatment of the few patients who either have serious disease (e.g., tumor, infection, fracture) or, in 617

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Table 41-1  Magnetic Resonance Imaging Findings   in Asymptomatic Subjects Radiographic Abnormality

Asymptomatic Patients with Abnormal Finding (%)

High intensity zone

14-33

Degenerative disk disease

25-70

Disk protrusion

25-50

the absence of clear radiographic or physical findings, might benefit from interventions to alter the course of common nonspecific LBP. The utility (and wisdom) of ordering imaging studies early in the course of LBP illness is not supported by clinical evidence. Nonetheless, numerous patients who see a clinician receive imaging modalities, such as radiographs or magnetic resonance imaging (MRI) scans, and are found to have radiographically identifiable “abnormalities.” The findings uncovered in such studies usually are nonspecific age-related changes (disk desiccation, Modic end plate changes, annular fissures). Whether these common findings have much to do with the patients’ chief complaints is unclear. Data from cross-sectional population studies of subjects who are asymptomatic for LBP show all of these findings can be seen commonly in individuals with little or no back problems (Table 41-1).7-9 Researchers also have examined patients who have had baseline MRI scans before developing any serious LBP problems and later went on to have a serious LBP episode. When a subject in this study experienced a serious episode of LBP and was reimaged in an attempt to identify new ­spinal pathology, the new MRI scan was compared with baseline images. In less than 5% of cases, there was a discrete new imaging finding compared with baseline studies.10 In prospective studies, investigators attempting to correlate ­baseline MRI findings in asymptomatic patients with future LBP problems found these baseline common changes could not predict with accuracy which patients would experience disabling LBP symptoms at any point in the future.11-14 Studies have shown that certain specific comorbidities are associated with risk of developing persistent, disabling LBP. These conditions include preexisting psychological distress, disputed compensation issues, chronic pain from other (nonlumbar) anatomic sites, and job dissatisfaction.13-16 Additionally, as noted earlier, common degenerative findings on imaging studies have been identified in large proportions of healthy, otherwise asymptomatic patients, complicating ­further the task of identifying appropriate treatments for pain that may or may not be emanating from a specific anatomic structure.7-9

DIAGNOSTIC METHODS HISTORY Paramount in the evaluation of patients with LBP is a thorough history and physical examination. The small percentage of patients with serious disease causing back pain (e.g., tumor, infection, inflammatory disease) generally can be suggested by the history and sometimes can be confirmed by specific physical signs. Imaging modalities generally should

be reserved (although they rarely are) as confirmatory, rather than diagnostic tests. A primary care clinician typically performs the initial evaluation of a patient with LBP. The initial clinical ­determination involves two decision points: (1) Does the patient have a significant risk of a serious underlying illness (Fig. 41-1)? (2) Is the back pain accompanied by a specific pattern of pain radiation to the legs suggesting neurogenic claudication or sciatic-type syndromes (radicular pain, numbness, or tingling down one or both lower extremities)? In working up the subset of patients with LBP and radicular symptoms in the absence of identifiable trauma, the ­physician must keep in mind that young individuals generally experience disk herniations, and elderly patients are more likely to have spinal stenosis. These two very different sources of combined radicular and back pain, although occasionally similar in presenting symptoms, require markedly different treatment strategies. This chapter focuses primarily on the evaluation of nonradicular LBP. PHYSICAL EXAMINATION Although patients with neurogenic claudication and radiculopathy present with classic findings, typically LBP patients without neurologic involvement exhibit few characteristic findings on examination. The goal of the initial assessment should always be to rule out the so-called red flags heralding diagnoses, including tumor, infection, and fracture (Table 41-2). Generally, if after a thorough history and physical examination, no serious abnormalities are identified (weakness, ataxia, point tenderness over the spine, numbness in a dermatomal pattern), patients should be reassured that the situation is not likely dangerous, and that these types of pain usually are self-limited. For persistent LBP lasting more than 4 to 6 weeks, imaging studies of the lumbar spine or blood tests (erythrocyte sedimentation rate or C-reactive protein) may be warranted to exclude serious structural disease. The utility of specific laboratory tests and imaging studies, which have low specificity, is to help rule out compression fractures and other destructive bony pathology, including neoplasm, and to allow a more aggressive rehabilitation plan. Patients should understand before obtaining radiographs that common degenerative findings (e.g., spurring, disk height loss, disk protrusion) are expected. IMAGING STUDIES A history of cancer, pain awakening the patient from sleep, recent weight loss, lethargy, or other constitutional symptoms suggested by the red flag survey (see Table 41-2) warrant appropriate workup for neoplasm, infection, or inflammatory conditions. Such a history, along with ­associated ­neurologic findings, warrants use of MRI early in the course of an LBP episode. Robertson and coworkers17 addressed the debate over the use of MRI as a screening tool in the evaluation of LBP. They showed that a rapid, twoplane, single echo, fast spin-echo sequence protocol alone is adequate to detect potentially significant degenerative ­disease of the lumbar spine. The significant time savings in the scanner (2.5 ­minutes versus 28 minutes) for conventional ­protocols ­compared with rapid sequence and the attendant cost savings may lead to re-evaluation of the role of MRI as

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Adults with low back pain (not for back pain associated with major trauma, nonspinal back pain or back pain due to systemic illness)

Perform a focused history and physical, evaluating: Duration of symptoms Risk factors for potentially serious conditions (e.g., tumor, infection, cauda equina syndrome) Symptoms suggesting radiculopathy or spinal stenosis Presence and severity of neurologic deficits Psychosocial risk factors

Cancer, infection, or cauda equina syndrome strongly suspected, or severe/progressive neurologic deficit?

Yes

No Cancer, infection, vertebral compression fracture, or other specific underlying condition not strongly suspected, but one or more risk factors present?

Yes

No Do not routinely obtain imaging or other diagnostic tests Provide infomation and self-care advice to all patients Provide information on expected course and effective self-care options Recommend continuing normal activities as much as possible Review indications for reassessment and for diagnostic testing

Back pain mild and no significant functional deficits?

MRI or CT Specialist consultation Consider imaging with initial plain radiography in most cases Consider ESR for evaluation of cancer or infection If only weak risk factors for cancer, consider trial of therapy

Specific condition present? Yes

No

Evaluate and treat appropriately

Continue self-care Review indications for reassessment

Yes

No Consider pharmacologic or nonpharmacologic, noninvasive therapy for initial treatment Pharmacologic options: acetaminophen, NSAIDs, opioids, tramadol, benzodiazepines, skeletal muscle relaxants (for acute LBP), and tricyclic antidepressants (for chronic LBP) Nonpharmacologic options for chronic LBP: acupuncture, exercise, massage, yoga, behavorial therapy, spinal manipulation (also for acute LBP), and interdisciplinary rehabilitation

Patient accepts risks and benefits of therapy?

Yes

Initiate time-limited trial of therapy Assess response to treatment

No Continue self-care Reassess patient (within 1 month for acute low back pain)

Back pain resolved or improved with no significant functional deficits?

Yes

Continue self-care Review indications for re-assessment

Figure 41-1  Algorithm for evaluation of a patient with low back pain. CT, computed tomography; ESR, erythrocyte sedimentation rate; LBP, low back pain; MRI, magnetic resonance imaging; NSAIDs, nonsteroidal anti-inflammatory drugs.

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Table 41-2  Red Flags in the Evaluation of Low   Back Pain Symptom

Potential Causes

Night pain

Tumor, infection

Recent weight loss

Malignancy

Lytic lesion on imaging studies

Malignancy/infection

Bowel/bladder incontinence

Cauda equina syndrome

Progressive, unrelenting pain

Malignancy/infection

Pain unrelieved by rest

Malignancy

a screening tool for LBP. Typical laboratory tests consist of C-reactive protein, erythrocyte sedimentation rate, and serum or urine protein electrophoresis. Additional laboratory work may include complete blood count, serum creatinine, and serum calcium if myeloma is suspected. Persistent, debilitating LBP lasting more than 4 to 6 weeks should be assessed carefully and possibly referred to the care of a spine specialist for secondary evaluation. Early in the evaluation, a consideration of psychosocial impediments to recovery should be considered. As ­discussed ­previously, these psychosocial and other comorbid conditions may be more important in predicting recovery than imaging results. Neither MRI nor plain radiographs obtained early in the course of LBP evaluation improves clinical outcome, ­predicts recovery course, or reduces the overall cost of care.18 If the patient has not already obtained further imaging studies at the time of referral to a spine specialist and his or her pain has persisted after 4 to 8 weeks of conservative care, a rapid-sequence MRI study may be warranted. It should be reiterated to the patient that common degenerative ­ findings (e.g., Schmorl’s nodes, end plate changes, disk desiccation) are fully expected and are most commonly unrelated to symptoms. PROVOCATIVE TESTING Further attempts at identifying a single pain-causing structure, the so-called pain generator hypothesis, have focused primarily on the intervertebral disks and facet joints. In recent years, strategies aimed at sorting out specifically the level of degenerative disk or facet joint most likely ­responsible for a patient’s discomfort have been presented. Provocative discography is aimed at identifying primary discogenic pain as the sole or major cause of LBP illness. In a typical discography procedure, a patient is lightly sedated, and radiopaque dye is injected under fluoroscopic guidance into several intervertebral disks in sequence. The patient’s pain responses are noted at each level. A concordant pain response (i.e., one reproducing the patient’s usual pain) at one level combined with a “negative” injection at an ­adjacent level is thought by proponents to be diagnostic for “discogenic pain.” Advocates of the technique interpret the data from such a “positive discogram” as defining the disk itself as the primary or sole cause of LBP illness in that patient, and suggest that eliminating the pain-generating disk (via spinal fusion, disk arthroplasty, or percutaneous intervention) would eliminate a patient’s symptoms. Provocative discography has not been validated by standard methods of determining the accuracy of diagnostic testing. Numerous reports have shown that injections into

disks can yield pain of a typical character and anatomic location, although the actual cause of the patient’s LBP is known not to originate from the disk in question.19 Additionally, currently asymptomatic subjects who previously had undergone disk surgery, patients with psychological distress, and individuals with disputed compensation claims or remote chronic pain issues experienced pain with disk injection 80% of the time.20,21 Many LBP patients who are evaluated with discography fall into one or more of the aforementioned categories, increasing the likelihood of a false-positive test. The ideal candidate for back surgery after positive discography may be one with an annular disruption and advanced disk degeneration on imaging studies, negative adjacent disk pathology, low pressures on injection, no complicating compensation claims, and normal psychometric testing. Studies focusing on patients with these “ideal” parameters show low rates of highly successful outcomes (<50% of subjects), even in the presence of radiographically solid interbody fusion. In the same group of model patients using high-grade relief of LBP symptoms after fusion as the “gold standard” for confirmed diagnosis, the positive predictive value of an injection was at best only 50% to 60%.22 Whether using discography improves the outcomes of individuals seeking surgery for LBP illness is unclear. In the best evidence study to date, lumbar fusions performed on individuals for positive discographic findings were no more successful at reducing back pain than fusions performed on patients selected for fusion surgery without discography.23 Investigators also have experimented with anesthetic blockade of the facet medial branch nerves and sacroiliac joints. An injection’s success is gauged by the patient’s ­subjective perception of pain before and immediately after the procedure. Although these modalities have shown anecdotal benefit, their validity remains questionable without a histopathologic “gold standard” against which other treatment modalities can be compared.24-26 Although using such blocks to predict the outcome of specific neuroablative ­procedures of the lumbar facet joints has shown promise in one study,27 the predominant interest to date of this intervention is with disk arthroplasty candidates to rule out facetmediated pathology as the source of back pain. The degree of success of facet and sacroiliac joint injections seems not to correlate with the actual presence of or degree of local pathology as seen on radiography or MRI.

NONSURGICAL INTERVENTIONS PHARMACOLOGIC THERAPY Treatment of LBP with narcotic pain medicines over the long-term is usually discouraged.28,29 In addition to the dependency issues that patients taking long-term narcotics may develop, habituation to the analgesic effects of narcotics can complicate postoperative pain control should ­surgery become necessary. Patients often are troubled by the ­gastrointestinal and sedative side effects of analgesic effects of high-dose narcotics, and some patients require progressively higher doses to achieve the same level of analgesia. Classically, first-line pharmacologic treatment of LBP in the absence of contraindications has been the ­nonsteroidal

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Table 41-3  Pharmacologic Treatment of Low Back Pain Drug Name

Mechanism of Action

Anti-inflammatory Effects

Side Effects

Acetaminophen

Inhibits prostaglandin E synthesis

+/−

Hepatotoxic at high doses

NSAIDs

Reversible inhibition of COX isoenzymes   blocking conversion of arachidonic   acid to prostaglandin

+++

Gastrointestinal damage;   renal failure at high dose

COX-2 inhibitors

Selective inhibition of COX-2 isoform;   blocks conversion of arachidonic   acid to prostaglandin

+++

Increased risk of cardiovascular events

Muscle relaxants

Inhibition of polysynaptic neuronal   events

−

Sedation

Opioids

Binds μ opioid receptors

−

Constipation, nausea,   somnolence, dry mouth

Corticosteroids

Inhibits phospholipase A2, preventing   leukotriene-mediated and   prostaglandin-mediated   inflammatory response

++++

Long-term use can lead to ­immunosuppression, aseptic ­necrosis of bone, impaired wound healing, osteoporosis, suppression of hypothalamic­pituitary-adrenal axis

Tricyclic   antidepressants

Unknown

−

Dry mouth, cardiac effects, ­sedation

COX, cyclooxygenase; NSAIDs, nonsteroidal anti-inflammatory drugs.

anti-inflammatory drug (NSAID) class of medications (Table 41-3). A more recent Cochrane analysis has pointed out the limited effect size of these medications in the treatment of LBP. Studies suggest that the effects of NSAIDs compared with placebo are quite small.28 In a month-long trial with patients experiencing acute flare-up of previously diagnosed LBP, pain scores improved an average of 40 points on a 100-point scale with cyclooxygenase-2 inhibitors compared with an average improvement of 30 points with placebo. Although not directly compared, acetaminophen alone may have a comparable effect at a much lower cost and risk of complications. Cyclooxygenase-2 inhibitors may limit some of the gastrointestinal risks of NSAIDs, but are considerably more expensive. Given their association with an increased risk of cardiovascular events,30,31 long-term control of chronic LBP with cyclooxygenase-2 inhibitors should be carefully considered. Adjuncts in the pharmacologic arsenal include muscle relaxants, but the evidence for their use is limited as well.28 Two randomized trials with a combined 222 patients ­compared treatment of LBP with 150 mg of the muscle relaxant tetrazepam (divided dosing three times daily) with placebo. The effect of tetrazepam, although statistically ­ significant, was clinically only of marginal benefit in ­alleviating symptoms.29 Only one other type of pharmacologic intervention has consistently shown reproducible clinical benefits in the treatment of LBP. The tricyclic and the tetracyclic classes of antidepressants have been proved in randomized clinical trials to be effective treatments for LBP in patients ­without preexisting clinical depression. The selective serotonin reuptake inhibitors and trazodone were no more effective at treating LBP than placebo in the trials, whereas over 4 to 8 weeks, patients taking the tricyclics or tetracyclics experienced a 20% to 40% greater reduction in pain than their placebocontrolled counterparts.32 Although subjects’ pain scores improved, their functional capabilities did not. In addition, the use of antidepressant ­ pharmacologic ­ intervention is

not without risk. Greater than 20% of ­subjects ­experienced some form of side effects while in the study.33 PHYSICAL MODALITIES An important aspect in trying to prevent or reverse the debilitating physical and mental effects of LBP is a patient’s willingness to engage in physical and social activities despite low back discomfort.34 Patients with high “fear avoidance” characteristics (a disproportionate predilection to avoid activities or situations that may produce discomfort) have poorer outcomes and are at increased risk for developing chronic LBP illness than patients who remain active despite their pain.13,14,16,35 Exercise, no matter what type of regimen, seems to hasten patients’ return to usual lifestyle activities. In addition to the natural analgesic effects of endorphins produced in the body with exercise, the preservation of joint mobility and a more positive mental outlook seems to be helpful in dealing with LBP. A Cochrane review of randomized trials of numerous exercise programs, including generalized stretching, the McKenzie method of passive end-range stretching, conventional physical therapy, and strengthening, showed equivalence among interventions. All the programs seemed to offer some benefit over the usual care given by primary care physicians.36 Of exercise programs, massage, physical therapy, low-impact aerobics, osteopathic or chiropractic manipulation, and classroom-style education (so-called back school) on proper back mechanics, none have proven superior to another.35,37-39 Concomitant medical and ­ physical treatments seem to have better outcomes with respect to pain and disability than medical treatment alone.35,40 Armed with this information, a more recent strategy for the treatment of patients with severe LBP impairments or psychosocial risk factors inhibiting recovery emphasizes a functional restoration type of approach. This ­multifaceted approach to LBP blends medical treatment strategies with physical exercises and a cognitive behavioral scheme

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f­ocusing the patient’s efforts on achieving specific functional goals (e.g., walking a set distance, ascending a certain ­number of stairs, lifting a set amount of weight a specific number of repetitions). Compared with usual care scenarios, these attempts at functional restoration also seem to achieve superior results and minimize the amount of sick leave taken.41-45 The long-term benefits of all back pain rehabilitation programs are unproven, however.46

SURGICAL INTERVENTIONS The surgical treatment of LBP in the absence of structural findings is as varied as the clinicians advocating treatment. Ranging from injections to neuroablation techniques to fusion to disk arthroplasty, the procedures performed today for the treatment of chronic LBP vary by surgical training, familiarity with a specific treatment, and even geographic region. PERCUTANEOUS TECHNIQUES Injections into facet joints, into sacroiliac joints, into the lumbar epidural space, around nerve roots, and into trigger points are frequently used in the treatment of LBP syndromes, although there is no compelling evidence that injections are effective in the absence of primary radicular pain. Frequent corticosteroid injections (more than three or four a year) may be associated with systemic or local side effects. In randomized clinical trials, lumbar epidural ­steroid injections, facet blocks, trigger point injections, and intradiscal anesthetics have not shown improvement in the outcomes of LBP patients who lack discrete radicular ­symptoms.47-49 Sclerotherapy, sometimes called ­ prolotherapy, involves injecting solutions of dextrose 12.5%, glycerin 12.5%, phenol 1.25%, or lidocaine 0.25% into the spinal ligaments or lumbodorsal fascia. The theory of prolotherapy stems from the belief that LBP is generated from weakened or damaged spinal ligaments. Repeatedly injecting these “damaged” structures with irritant solutions is purported to strengthen the ligaments, reducing pain and disability.50 There is conflicting evidence in the literature, however, with regard to the ability of sclerosing agents to eliminate patients’ chronic LBP and disability. Of some 200 articles authored on the topic, only 4 met criteria for scientific validity, consisting of a total of 344 subjects. Confounding variables exist in terms of clinical heterogeneity among studies and by the presence of cointerventions that differed greatly among studies. In the end, there was no clear evidence that ­prolotherapy injections were more effective than control injections alone.51-53 Radiofrequency ablation of the afferent medial branch nerves to the facet joints was examined as a treatment for facet-mediated pain. According to this hypothesis, facets are sometimes thought to act as the pain generator in the absence of obvious facet pathology. Neurotomy was found to be marginally effective in the short-term (lasting 4 weeks) in one study,54 whereas another randomized trial showed the intervention to be ineffective.55 In a small subset of patients with suspected facet-mediated pain that seemed to respond well to placebo-controlled anesthetic blockade of the joint, observational studies (without controls) have suggested relatively good outcomes.56,57

Various percutaneous technologies aimed at the alteration of intradiscal biomechanics and nociception have been advocated by some clinicians. The two most commonly employed treatments, intradiscal electrothermal treatment and percutaneous neuromodulation therapy, met with skepticism by some clinicians who believed that the use of radiofrequency energy or heat around sensitive nerve structures was an ill-conceived idea. Intradiscal electrothermal treatment involves the percutaneous insertion of a navigable wire catheter into the disk space. Thermal energy is delivered with the aim of decreasing the nociceptive response to degenerative changes within the intervertebral disk. The improvement in pain response effected by intradiscal electrothermal treatment is thought to occur through shrinkage of collagen fibers leading to remodeling, cauterization of granulation tissue, and thermocoagulation of nervous tissue resulting in denervation of nociceptive nerve fibers within the disk.58 Randomized trials have shown either no effect59,60 or a very small treatment effect, but only in narrowly tailored cohorts.61 Additionally, in a more recent study, the investigators failed to show any correlation of the theoretically critical position of the ablative catheter with patient outcomes.62 Percutaneous neuromodulation therapy is best likened to acupuncture, wherein 10 needle probes are inserted to various depths within the paraspinal musculature through which an electric current is passed. By activating dermatomal sensory, myotomal sensorimotor, sclerotomal, and sympathetic sensory nerves in the dermatomal distribution of the pain, the postulated mechanism of action is a recal­ ibration of one or more of the neuronal feedback systems involved in the regulation and maintenance of pain. There are very few clinical studies and no long-term outcome studies on percutaneous neuromodulation therapy. OPEN SURGICAL TECHNIQUES Open surgical treatment of LBP is at the heart of a long and continuing controversy. There is no doubt that open surgical management of some spinal fractures, infections, neoplasm, or progressive instability can be enormously helpful. The usefulness of spinal fusion or decompression in patients with back pain and only common degenerative changes on imaging studies is unclear, however. Shortly after the discovery that decompressive laminectomy seemed to be a highly effective treatment for sciatica, many surgeons attempted to expand the ­indications to LBP without radicular symptoms. Although many surgeons reported anecdotal successes with the application of decompressive laminotomy for degenerative changes, the more common observation was little, if any, symptom ­improvement. Today, laminectomy as a treatment for degenerative disk disease in the absence of neurologic ­symptoms has been all but abandoned.63 Contemporary strategies to address surgically degenerative spinal changes without structural or neurologic compromise include lumbar spinal fusion, nonfusion technologies such as disk arthroplasty and dynamic stabilization, and the above-described percutaneous ­modalities. Lumbar fusion as a treatment for LBP caused by a severe structural deficiency is extremely effective. In the presence of certain fracture types, spinal infections, ­spondylolisthesis,

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and increasing coronal or sagittal imbalance, lumbar fusion may have a dramatic effect in alleviating pain. Studies place the success rate of lumbar fusion surgery in patients with discrete and clear pathology at 70% to 90%,22,64 but in patients who have had fusion for backache and common ­degenerative changes alone, outcomes lag far behind.65 There have been no randomized clinical trials of spinal fusion versus nonsurgical care to date in the United States. In two of three European randomized clinical trials comparing fusion and nonoperative treatments, a cognitive behavioral model seems to be more beneficial than usual treatment as far as nonoperative modalities are concerned.66,67 The cognitive behavioral therapy group also seemed to have improved coping strategies, fewer complications, and possibly even improved occupational outcomes compared with the fusion group (as measured by Oswestry disability indices). The third study showed small, yet statistically significant differences in the fusion group over unstructured nonsurgical modes of therapy. It is important to realize, however, that neither group did exceedingly well, with only 16% of the fusion patients and 6% of the nonoperated group rating their overall result as “excellent.”68 Cohort studies in which lumbar fusion was undertaken for a diagnosis of nonspecific degenerative disk disease or internal disk derangement show small functional improvements. In reviews of the literature on spinal fusion for nonspecific MRI changes along with presumed discogenic pain based on discography, Carragee and colleagues showed that ODI improvements were in the 6- to 15-point range (close to the minimal detectable difference),68a and in another similar study of workers’ compensation patients, satisfactory outcomes were rarely observed.69 The role of artificial disk replacement (ADR) in the treatment of LBP is unclear. The success of total joint arthroplasty in the knee and hip has led to the hope that similarly positive outcomes could be realized with joint replacement in the spine. In contrast to hips or knees, however, a spinal motion segment comprises three discrete articular surfaces—two facet joints and the intervertebral disk space. Arthroplasty of the spine addresses only one of the three surfaces, leaving facet arthrosis untreated. The cause of the severe impairment in hip and knee arthrosis is usually well ­correlated with the degree of arthritic change, whereas this is not the case in LBP: Severe pain and disability are sometimes reported with minimal changes in the spine, or minimal LBP can be reported with severe ­arthrosis. Hip arthrodesis (which hip replacement supplanted) was an effective painrelieving operation for hip arthrosis, whereas spinal fusion, as described previously, is only marginally effective. Shortterm trials to date have shown little ­­difference in outcome between spinal fusion versus disk replacement surgery. In theory, preserving motion segments in the spine may decrease the rate at which adjacent segments degenerate. Whether or not this benefit over fusion makes a clinical difference remains to be shown by carefully controlled clinical assessment. The progressive disk degeneration is frequently asymptomatic in patients with adjacent segment disease. Current ADR instrumentation is widely inhomogeneous with regard to mechanism of constraint, materials, and mobility. It has taken several decades of clinical research to arrive at the current successful outcomes with total joint

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a­ rthroplasty. In an elderly patient population, joint replacements in the hip and knee now can be reliably predicted to last 15 to 20 years from a purely materials standpoint. The data on ADR, by comparison, are still in their infancy. Early follow-up data show that potential problems of osteolysis and aseptic loosening in ADR are infrequently encountered in the first 5 years after implantation. Clinical outcome comparisons between fusion and ADR for nonspecific LBP have been equivocal. In terms of postoperative functionality, narcotic use, pain scores, and occupational disability, there do not seem to be large differences between the two groups.70,71 Trials in the United States and United Kingdom show clinical failure in half of the patients who underwent ADR. This fact is especially surprising given the narrowly tailored entry criteria for the initial ADR studies.70,72 Pioneering work on ADR was performed in Europe with the Charité disk (Depuy, Warsaw, Ind). Long-term data from the Charité experience show questionable preservation of motion at operated levels. The data also call into question the clinical benefit of preserving motion segments and the relationship to improving pain.73

PUBLIC HEALTH CAMPAIGNS The immense public health cost of LBP to society has prompted some governmental agencies to get involved. Buchbinder and Jolley74 examined the long-term effects of an Australian media campaign aimed at altering negative beliefs about LBP, decreasing lost work time, and decreasing medical use by individuals with LBP. Over the course of 2 years, media advertisements encouraging Australians to remain active and in the workforce despite having LBP proved significantly effective at altering physicians’ and patients’ perceptions regarding back pain. Workers’ compensation claims for LBP were significantly reduced for the 2 years during which the ads ran, with an effect that persisted for at least 3 years after the campaign. This lasting effect suggests the potential effectiveness of primary prevention strategies in altering the negative way in which LBP is perceived in the medical and the lay communities.

CONCLUSION Compared with many areas of our current fund of orthopaedic knowledge, the spine remains a comparative “black box” in terms of understanding of certain specific disorders. What is clear from the data is that an effective treatment for chronic persistent and disabling LBP must focus on a multifaceted approach. The answer at present seems to lie in a combination of medical and physical modalities, although current strategies for non-neurogenic back disorders remain as varied as the physicians who provide them. Current guidelines from numerous spine professional groups agree that an early, gradual return to activities of daily living represents a good strategy for coping with nonspecific LBP. Identification of psychological risk factors may aid significantly in identifying patients who may not respond well to surgical interventions. In the presence of certain structural findings that are not well delineated in their recommendations, the North American Spine Society currently recommends a 2- to 4-month trial of nonoperative modalities before attempting a surgical treatment for LBP.

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Surgical treatments have not been found to be highly effective. The assessment of LBP is best done on an individual basis, taking into account the complex interconnectedness of each patient’s specific physical demands, expectations for recovery, psychosocial makeup, social and occupational demands, and objective physical examination and radiographic findings. REFERENCES   1. Anderson GB: Epidemiological features of low-back pain Lancet 354:581-585, 1999.   2. U.S. Department of Health and Human Services: Summary Health Statistics for U.S. Adults: National Health Interview Survey, 2002. Vital and Health Statistics Series 10, No. 222 [DHHS Publication No. (PHS) 2004-1550]. Hyattsville, Md, U.S. Department of Health and Human Services, 2004. Available at: www.cdc.gov/nchs/data/series/ sr_10/sr10_222.pdf. Accessed January 8, 2007.   3. National Academy of Sciences and Institute of Medicine: Musculoskeletal Disorders and the Workplace. Washington, DC, National ­Academy Press, 2001.   4. Skovron ML, Szpalski M, Nordin M, et al: Sociocultural factors and back pain: A population-based study in Belgian adults. Spine 19: 129-137, 1994.   5. Cassidy JD, Carroll LJ, Cote P: The Saskatchewan Health and Back Pain Survey: The prevalence of low back pain and related disability in Saskatchewan adults. Spine 23:1860-1866, 1998.   6. Carragee E, Cohen S: Reliability of LBP history in asymptomatic ­subjects? The prevalence and incidence of reported back pain correlates with surveillance frequency. In Proceedings of the 19th Annual Meeting of the North American Spine Society, Chicago, October 26-30, 2004, p 216 (abstract).   7. Carragee EJ, Paragioudakis SJ, Khurana S: 2000 Volvo Award ­winner in clinical studies: Lumbar high-intensity zone and discography in ­subjects without low back problems. Spine 25:2987-2992, 2000.   8. Boden S, Davis D, Dina T, et al: Abnormal magnetic resonance scans of the lumbar spine in asymptomatic subjects: A prospective investigation. J Bone Joint Surg Am 72:403-408, 1990.   9. Jensen M, Brant-Zawadzki M, Obuchowski N, et al: Magnetic ­resonance imaging of the lumbar spine in people without back pain. N Engl J Med 331:69-73, 1994. 10. Carragee E, Alamin T, Cheng I, et al: Are first-time episodes of serious LBP associated with new MRI findings? Spine J 6:624-635, 2006. 11. Jarvik JJM, Hollingworth W, Heagerty P, et al: The ­ Longitudinal Assessment of Imaging and Disability of the Back (LAIDBack) study—baseline data. Spine 26:1158-1166, 2001. 12. Borenstein DG, O’Mara JW Jr, Boden SD, et al: The value of magnetic resonance imaging of the lumbar spine to predict low-back pain in asymptomatic subjects: A seven-year follow-up study. J Bone Joint Surg Am 83:1306-1311, 2001. 13. Carragee EJ, Alamin TF, Miller JL, et al: Discographic, MRI, and ­psychosocial determinants of low back pain disability and remission: A prospective study in subjects with benign persistent back pain. Spine J 5:24-35, 2005. 14. Boos N, Semmer N, Elfering A, et al: Natural history of individuals with asymptomatic disc abnormalities in magnetic resonance ­imaging: Predictors of low back pain-related medical consultation and work incapacity. Spine 25:1484-1492, 2000. 15. Bigos SJ, Battie MC, Spengler DM, et al: A prospective study of work perceptions and psychosocial factors affecting the report of back injury [erratum in Spine 16:688, 1991]. Spine 16:1-6, 1991. 16. Burton AK, Tillotson KM, Main CJ, et al: Psychosocial predictors of outcome in acute and subacute low back trouble. Spine 20:722-728, 1995. 17. Robertson WD, Jarvik JG, Tsuruda JS, et al: The comparison of a rapid screening MR protocol with a conventional MR protocol for lumbar spondylosis. AJR Am J Roentgenol 166:909-916, 1996. 18. Gilbert FJ, Grant AM, Gillan MG, et al: Low back pain: Influence of early MR imaging or CT on treatment and outcome—multicenter randomized trial. Radiology 231:343-351, 2004. 19. Carragee EJ, Tammer CM, Yang B, et al: False-positive findings on lumbar discography: Reliability of subjective concordance assessment during provocative disc injection. Spine 24:2542-2547, 1999.

20. Carragee EJ, Chen Y, Tanner CJ, et al: Provocative diskography in patients after limited lumbar diskectomy: A controlled, randomized study of pain response in symptomatic and asymptomatic subjects. Spine 25:3065-3071, 2000. 21. Carragee EJ, Tanner CM, Khurana S, et al: The rates of false-­positive lumbar discography in select patients without low back symptoms. Spine 25:1373-1380, 2000. 22. Carragee EJ, Lincoln T, Parmar VS, et al: A gold standard evaluation of the “discogenic pain” diagnosis as determined by provocative ­discography. Spine 31:2115-2123, 2006. 23. Madan S, Gundanna M, Harley JM, et al: Does provocative ­diskography screening of discogrnic back pain improve surgical outcome? J Spinal Disord Tech 15:245-251, 2002. 24. Reid M, Lachs M, Feinstein A: Use of methodological standards in diagnostic test research: Getting better but still not good. BMJ 274:645-651, 1995. 25. Sackett DL, Rosenberg WM, Gray JA, et al: Evidence based medicine: What it is and what it isn’t. BMJ 312:71-72, 1996. 26. Greenhalgh T: Education and debate: Papers that report diagnostic or screening tests. BMJ 315:1-12, 1997. 27. Dreyfuss P, Halbrook B, Pauza K, et al: Efficacy and validity of ­radiofrequency neurotomy for chronic lumbar zygoapophyseal joint pain. Spine 25:1270-1277, 2000. 28. van Tulder MW, Scholten RJ, Koes BW, et al: Nonsteroidal antiinflammatory drugs for low back pain: A systematic review within the framework of the Cochrane Collaboration Back Review Group. Spine 25:2501-2513, 2000. 29. Van Tulder MW, Touray T, Furlan AD, et al: Muscle relaxants for nonspecific low back pain. Cochrane Database Syst Rev 2:CD004252, 2003. 30. Nussmeier NA, Whelton AA, Brown MT, et al: Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 352:1081-1091, 2005. 31. Ostelo R, Tulder M, Vlaeyen J, et al: Behavioral treatment for chronic low back pain. Cochrane Database Syst Rev 1:CD002014, 2005. 32. Staiger TO, Gaster B, Sullivan MD, et al: Systematic review of ­antidepressants in the treatment of chronic low back pain. Spine 28:2540-2545, 2003. 33. Salerno SM, Browning R, Jackson JL: The effect of antidepressant treatment on chronic back pain: A meta analysis. Arch Intern Med 162:19-24, 2002. 34. Deyo RA, Diehl AK, Rosenthal M: How many days of bed rest for acute low back pain? A randomized clinical trial. N Engl J Med 315:1064-1070, 1986. 35. Hurwitz EL, Morganstern H, Harber P, et al: A randomized trial of medical care with and without physical therapy and chiropractic care with and without physical modalities for patients with low back pain: 6 month follow-up outcomes from the UCLA low back pain study. Spine 27:2193-2204, 2002. 36. Van Tulder MW, Malmivaara A, Esmail R, et al: Exercise therapy for low back pain. Cochrane Database Syst Rev 2:CD000335, 2000. 37. Cherkin DC, Sherman KJ, Deyo RA, et al: A review of the evidence for the effectiveness, safety, and cost of acupuncture, massage therapy, and spinal manipulation for back pain. Ann Intern Med 138:898-906, 2003. 38. Assendelft WJ, Morton SC, Yu EI, et al: Spinal manipulative therapy for low back pain: A meta-analysis of effectiveness relative to other therapies. Ann Intern Med 138:871-881, 2003. 39. Mannion AF, Muntener M, Taimela S, et al: A randomized ­clinical trial of three active therapies for chronic low back pain. Spine 24: 2435-2448, 1999. 40. Niemisto L, Lahtinen-Soupanki T, Rissanen P, et al: A randomized trial of combined manipulation, stabilizing exercises and physician consultation alone for chronic low back pain. Spine 28:2185-2191, 2003. 41. Schonstein E, Kenny DT, Keating J, et al: Work conditioning, work hardening and functional restoration for workers with back and neck pain. Cochrane Database Syst Rev 1:CD001822, 2003. 42. Guzman J, Esmail R, Karjalainen K, et al: Multidisciplinary bio­psycho-social rehabilitation for chronic low-back pain. Cochrane Database Syst Rev 1:CD000963, 2002. 43. Fairbank J, Frost H, MacDonald J, et al: The MRC Spine Stabilization Trial: A randomized controlled trial comparing surgical stabilization of the lumbar spine with intensive rehabilitation in patients with chronic low back pain. In Proceedings of the 31st Annual Meeting of the International Society for the Study of the Lumbar Spine, Porto, Portugal, May 31-June 5, 2004, p 38 (abstract).

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44. Ivar Brox J, Sorensen R, Friis A, et al: Randomized clinical trial of lumbar instrumentated fusion and cognitive intervention and ­exercises in patients with chronic low back pain and disc degeneration. Spine 28:1913-1921, 2003. 45. Van Tulder MW, Ostelo R, Vlaeyen JW, et al: Behavioral treatment for chronic low back pain: A systematic review within the framework of the Cochrane Collaboration Back Review Group. Spine 26: 270-281, 2001. 46. Ostelo R, Tulder M, Vlaeyen J, et al: Behavioral treatments for chronic low back pain. Cochrane Database Syst Rev 1:CD002014, 2005. 47. Carette S, Marcoux S, Truchon R, et al: A controlled trial of corticosteroid injections into facet joints for chronic low back pain. N Engl J Med 325:1002-1007, 1991. 48. Nelemans PJ, deBie RA, deVet HC, et al: Injection therapy for ­subacute and chronic benign low back pain. Spine 26:501-515, 2001. 49. Khot A, Bowditch M, Powell J, et al: The use of intradiscal steroid therapy for lumbar spinal discogenic pain: A randomized controlled trial. Spine 29:833-836, 2004. 50. Dagenais S, Haldeman S, Wooley JR: Intraligamentous injection of sclerosing solutions (prolotherapy) for spinal pain: A critical review of the literature. Spine J 5:310-328, 2005. 51. Dechow E, Davies RK, Carr AJ, et al: A randomized, double-blind, placebo-controlled trial of sclerosing injections in patients with chronic low back pain. Rheumatology (Oxf) 38:1255-1259, 1999. 52. Yelland MJ, Glasziou PP, Bogduk N, et al: Prolotherapy injections, saline injections, and exercises for chronic low-back pain: a randomized trial. Spine 29:9-16, 2004. 53. Yelland MJ, Mar C, Pirozzo S, et al: Prolotherapy injections for chronic low-back pain. Cochrane Database Syst Rev 2:CD004059, 2004. 54. Van Kleef M, Barendse GA, Kessels A, et al: Randomized trial of radiofrequency lumbar facet denervation for chronic low back pain. Spine 24:1937-1942, 1999. 55. Leclaire R, Fortin L, Lambert R, et al: Radiofrequency facet joint denervation in the treatment of low back pain: A placebo-controlled clinical trial to assess efficacy. Spine 26:1411-1416, 2001. 56. Dreyfuss P, Halbrook B, Pauza K, et al: Efficacy and validity of radiofrequency neurotomy for chronic lumbar zygoapophyseal joint pain. Spine 25:1270-1277, 2000. 57. Van Kleef M, Weber WE, Kessels A, et al: Re: Efficacy and validity of radiofrequency neurotomy for chronic lumbar zygoapophyseal joint pain (Spine 25:1270-1277, 2000). 58. Saal JA, Saal JS: Management of chronic discogenic low back pain with intradiscal thermal catheter Spine 25:382-388, 2000. 59. Barendse GA, van den Berg SG, Kessels AH, et al: Randomized controlled trial of percutaneous intradiscal radiofrequency thermocoagulation for chronic discogenic back pain: Lack of effect from a 90-second 70 C lesion. Spine 26:287-292, 2001. 60. Freeman BJ, Fraser RD, Cain CM, et al: A randomized double-blind controlled efficacy study: Intradiscal Electrothermal Therapy (IDET) versus placebo. J Bone Joint Surg Br 86:484-485, 2004.

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61. Pauza KJ, Howell S, Dreyfuss P, et al: A randomized, placebo­controlled trial of intradiscal electrothermal therapy for the treatment of discogenic low back pain. Spine J 4:27-35, 2004. 62. Freeman BJ, Fraser RD, Cain CM, et al: A randomized, double-blind, controlled trial: Intradiscal electrothermal therapy versus placebo for the treatment of chronic discogenic low back pain Spine 30: 2369-2377, 2005. 63. Allan DB, Waddell G: An historical perspective on low back pain and disability. Acta Orthop Scand 234S:1-23, 1989. 64. Swan J, Hurwitz E, Malek F, et al: Surgical treatment for unstable low grade isthmic spondylolisthesis in adults: A prospective ­controlled study of posterior instrumented fusion compared with combined ­anterior-posterior fusion. Spine J 6:606-614, 2006. 65. Gibson JN, Waddell G: Surgery for degenerative lumbar spondylosis: Updated Cochrane Review. Spine 30:2312-2320, 2005. 66. Ivar Brox J, Sorensen R, Friis A, et al: Randomized clinical trial of lumbar instrumented fusion and cognitive intervention and exercises in patients with chronic low back pain and disc degeneration. Spine 28:1913-1921, 2003. 67. Fairbank J, Frost H, Wilson-Macdonald J, et al: Randomised ­controlled trial to compare surgical stabilization of the lumbar spine with an intensive rehabilitation programme for patients with chronic low back pain: The MRC spine stabilization trial. BMJ 330:1233, 2005. 68. Fritzell P, Hagg O, Wessberg P, et al: Group SLSS: 2001 Volvo Award winner in clinical studies: Lumbar fusion versus nonsurgical treatment for chronic low back pain: A multicenter randomized controlled trial from the Swedish Lumbar Spine Study Group. Spine 26:2521-2532, 2001. 68a. Don AS, Carragee E: A brief overview of evidence-informed management of chronic low back pain with surgery. Spine J 8(1):258-265, 2008. 69. DeBerard MS, Masters KS, Colledge AL, et al: Outcomes of posterolateral lumbar fusion in Utah patients receiving workers’ compensation: A retrospective cohort study. Spine 26:738-746; discussion 747, 2001. 70. Freeman BJ, Davenport J: Total disc replacement in the lumbar spine: A systematic review of the literature. Eur Spine J 15:439-447, 2006. 71. Delamarter RB, Bae HW, Pradhan BB: Clinical results of ProDisc-II lumbar total disc replacement: Report from the United States clinical trial. Orthop Clin North Am 36:301-313, 2005. 72. Blumenthal S, McAfee PC, Guyer RD, et al: A prospective, randomized, multicenter Food and Drug Administration investigational device exemptions study of lumbar total disc replacement with the CHARITE artificial disc versus lumbar fusion, part I: Evaluation of clinical outcomes. Spine 30:1565-1575; discussion E387-E391, 2005. 73. Putzier M, Funk JF, Schneider SV, et al: Charite total disc replacement—clinical and radiographical results after an average follow-up of 17 years. Eur Spine J 15:183-195, 2006. 74. Buchbinder R, Jolley D: Population based intervention to change back pain beliefs: Three year follow up population survey. BMJ 328:321, 2004.

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Hip and Knee Pain James I. Huddleston  •  Stuart B. Goodman

KEY POINTS The clinician should be able to narrow the differential diagnosis of hip and knee pain down to two to three diagnoses after the history and physical examination. Imaging studies should be used to confirm the diagnosis. Conventional radiographs should be the initial imaging study ordered. Many vital structures in the knee can be palpated easily or examined with provocative tests. A knee effusion usually is associated with internal derangement. The clinician should suspect a torn meniscus if a patient has an effusion, joint line tenderness, and pain with hyperextension and with hyperflexion. Patients with osteoarthritis often complain of stiffness and pain with activity. Inflammatory arthritis should be considered when a patient continues to experience pain despite resting the joint. Groin pain with internal rotation of the hip is due to hip pathology until proved otherwise. Concurrent hip and lumbosacral pathology are common.

It is estimated that musculoskeletal pain affects one third to one half of the general population.1,2 A substantial increase in the burden of musculoskeletal disease is expected in the next decade as the “Baby Boomers” reach middle age and beyond. Hip and knee replacement operations already have increased in prevalence; operations increased by 16.2% to 884,400 procedures annually in the United States between 2002 and 2004.3 The prevalence of total knee and total hip arthroplasty is expected to double by 2016 (for total knee arthroplasty) and 2026 (for total hip arthroplasty).4 The hip and knee joints are two of the most commonly affected sites of musculoskeletal pain, with the prevalence of hip pain ranging from 8% to 30% in individuals 60 years old and older,5,6 and the prevalence of knee pain ranging from 20% to 52% in individuals 55 years old and older. Women generally experience more musculoskeletal pain than men.7 Geographic and ethnic variations in the rates of hip and knee pain also exist. There tends to be significantly less hip and knee pain as latitude decreases and significantly less hip pain and osteoarthritis in China than in the United States.8-15 When evaluating complaints of knee or hip pain, knowledge of the anatomy of these joints is necessary for formulating a differential diagnosis. Given the thin soft tissue envelope around the knee, and the fact that knee pain is

rarely referred, the pain generators around the knee often can be elucidated with a complete history and thorough physical examination. Diagnosis of hip pain may be more challenging because the joint is deeper, and the region is frequently the site of referred pain from the spine. An understanding of the basic biomechanics of these joints also is important in formulating a differential diagnosis because certain activities are likely to cause specific injuries.

KNEE PAIN HISTORY A detailed history is perhaps the most important step in accurately diagnosing the cause of knee pain. Knee complaints generally fall into two broad categories—pain or instability. Pain may arise from injury to the articular surfaces (e.g., osteoarthritis, inflammatory arthritis, osteochondral defects, and osteochondritis dissecans), torn menisci, quadriceps and patella tendon tears, bursitis, nerve damage, fractures, neoplasia, or infection. Instability is usually episodic and stems from injuries to the quadriceps–patellar extensor mechanism, collateral ligaments, or cruciate ligaments. It is important to distinguish true instability from the common complaint of “giving way” because the latter is usually due to a robust pain response, rather than to specific structural pathology. Patients in certain age groups tend to experience similar injuries. In patients younger than 40 years, ligament injuries, acute meniscus tears, and patellofemoral problems are frequently encountered. In contrast, degenerative conditions, such as osteoarthritis and degenerative meniscal lesions, tend to occur more frequently in older patients. The location and character of the pain are particularly important when evaluating knee pain. It is useful to conceptualize the knee as three separate compartments—medial, lateral, and patellofemoral. Each compartment should be examined separately. The patient should be able to point to the exact area where the pain is most severe. The onset of the pain should be determined. Osteoarthritis and inflammatory arthritis tend to have an insidious onset, whereas injuries to menisci and ligaments usually are associated with a traumatic event. Knowing the details of a traumatic event is helpful. A twisting injury, especially one sustained with a flexed knee, suggests a meniscus tear, whereas a noncontact knee injury associated with change of direction is more likely to produce a tear of the anterior cruciate ligament. Pain from degenerative arthritis tends to be associated with stiffness; is generally worse with ongoing activity during the day; and is exacerbated by exercise, stair climbing, getting up from a chair, or getting in and out of a car. 627

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The presence or absence of knee swelling is an important part of the history because knee effusions usually accompany internal derangement. An effusion also may be present with synovitis, osteoarthritis, inflammatory arthritis, fractures, infection, and neoplasm. Distinguishing between soft tissue swelling around the knee, synovial thickening, and a true knee effusion is crucial (see later). The timing or onset of the swelling also is important for determining the diagnosis. An acute cruciate or collateral ligament injury or osteochondral fracture usually manifests with an acute hemarthrosis (occurring within 1 hour), whereas an effusion associated with arthritis tends to be more insidious in its development. Complaints of “locking” are common. In a younger patient, locking may be due to a displaced meniscal tear. In older patients with degenerative arthritis, complaints of locking are often due to loose bodies. It is important to distinguish between true locking and diminished range of motion owing to pain (so-called pseudolocking); this distinction determines which imaging studies are most appropriate. Timing of the pain with activity also is important for making the correct diagnosis. Meniscus tears and ligament injuries leading to instability are particularly troublesome with activities such as walking on uneven surfaces, walking up or down stairs, movements requiring knee flexion, and pivoting. Osteoarthritis tends to be exacerbated by all load bearing activities and is relieved by rest. The clinician also should explore the patient’s exercise tolerance and ability to perform activities of daily living. Important details of the patient’s story include the use of ambulatory assist devices (cane, crutches, walker, brace, and wheelchair), walking tolerance, and capability for other exercises (physical therapy). A history of any previous treatment should be recorded. The response to physical therapy, analgesics, nonsteroidal antiinflammatory drugs, nutritional supplements (e.g., glucosamine and chondroitin), intra-articular injections of corticosteroids

Figure 42-1  Assessment of coronal alignment.

or hyaluronic acid derivatives, and any operative treatments lends further insight into the accurate diagnosis and has implications for treatment when the diagnosis has been confirmed. At the end of taking a detailed history, the clinician should be able to formulate a differential diagnosis with a short list of potential conditions. PHYSICAL EXAMINATION General After a brief overall assessment of the patient, the physical examination should begin with observation of the patient’s lower extremity coronal alignment and leg lengths. It is preferable to have the patient stand with legs slightly apart while facing the examiner (Fig. 42-1). A goniometer is used to measure the varus/valgus alignment of the knees. Evaluation of leg lengths should be performed with step blocks of known sizes. The total height of the blocks needed to make the iliac crests level with the floor is equivalent to the leglength discrepancy (Fig. 42-2). Gait is examined next. Although a comprehensive discussion of gait analysis is beyond the scope of this chapter, there are a few basic observations that all clinicians should make routinely when evaluating a patient with a knee problem. Antalgic gaits (shortened stance phase) and thrusts are commonly seen. Any disorder that causes lower extremity pain may cause an antalgic gait. Seen in the stance phase of gait, thrusts may be due to a progressive angular deformity secondary to degenerative changes or chronic ligamentous instability. Medial thrusts result from medial collateral ligament laxity, posteromedial capsular laxity or both. Lateral thrusts arise from lateral collateral ligament or posterolateral corner laxity (Fig. 42-3). Patients also may thrust into

Figure 42-2  The total height of the blocks needed to make the iliac crests level is equal to the length discrepancy.

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Figure 42-3  A and B, The femur shifts medially during a medial thrust (A) and laterally during a lateral thrust (B).

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C

Figure 42-5  Small effusions can be appreciated by the “milking” of fluid into the suprapatellar pouch and then pressing it down, producing a “bulge sign“ below the medial edge of the patella.

to the patella (Fig. 42-5). The active and passive range of motion of both knees should be recorded, preferably by use of a goniometer. The examiner should proceed with palpation of all structures of the knee. Palpation should be gentle, but firm enough to detect subtle pathology. Structures to be palpated include the quadriceps tendon, the patella (superior and inferior poles), the pes anserinus bursa, the medial (Fig. 42-6A) and lateral (Fig. 42-6B) joint lines, the origins and insertions of the collateral ligaments, the tibial tubercle, and the popliteal fossa. Ligaments

Figure 42-4  A-C, Large effusions can be detected by “ballotting” the patella with the knee in extension.

recurvatum (so-called back-knee deformity) secondary to posterior capsular laxity or quadriceps weakness. The patient should transfer to the examination table for evaluation in a supine position. A pillow should be placed under the knee if full extension is impossible because of pain (e.g., fractures, displaced meniscus tears, or large effusion). If it is not symptomatic, the contralateral knee can serve as an adequate control. The lower extremity should be inspected for any skin lesions, areas of ecchymosis, or surgical scars. Quadriceps atrophy should be noted, and a tape measure should be used to record thigh circumference at the same distance from the patella or joint line in each knee. The presence of an effusion should be noted. Effusion is seen as fullness or swelling in the suprapatellar pouch. The effusion should be confirmed by ballottement of the patella (Fig. 42-4). Small effusions require “milking” of the fluid upward into the suprapatellar pouch and expressing it down with the examiner’s fingers to appear as a “bulge” medial

Injuries to the collateral or cruciate ligaments may lead to knee instability. For each translational and rotational motion of the knee, there are primary and secondary restraints. When a primary restraint is disrupted, motion is limited by the secondary restraint. If a secondary restraint is injured, and the primary restraint remains intact, motion is not abnormal. The anterior cruciate ligament is the primary restraint to anterior translation of the tibia, whereas the medial meniscus is the secondary restraint. Anterior cruciate ligament disruption leads to a significant increase in anterior tibial translation. This translation is increased if the patient had a prior medial menisectomy.16 The collateral ligaments can be examined with stress applied in the coronal plane and should be examined in full extension and in 30 degrees of flexion to remove the influence of the cruciate ligaments and the capsular restraints. With the patient in a supine position, a varus force is applied across the knee to test the lateral collateral ligament, and a valgus force is applied across the knee to evaluate the medial collateral ligament. The anterior cruciate ligament is one of the most frequently injured structures in the knee. Anterior cruciate ligament insufficiency also is common in advanced osteoarthritis. Common mechanisms of injury include a direct blow to the lateral side of the knee (the “clipping” injury in football causing the triad of medial collateral ligament, anterior cruciate ligament, and medial meniscus injuries17) and

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A Figure 42-7  The anterior drawer test is performed by subluxating the tibia anteriorly with the knee in 90 degrees of flexion. The amount of anterior translation (mm) is noted. The end point is characterized as “soft” or “hard.”

B Figure 42-6  A and B, Palpation of the medial (A) and lateral (B) joint lines.

noncontact injuries that occur during cutting, pivoting, and jumping.18 Patients often report an audible “pop” accompanied by the acute onset of knee swelling. Multiple tests have been described to evaluate the anterior cruciate ligament. The most sensitive tests for diagnosis of an anterior cruciate ligament injury include the anterior drawer, Lachman,19 and pivot-shift tests.20,21 All three tests are performed with the patient in the supine position. The anterior drawer test is performed with the knee flexed to 90 degrees. The examiner places his or her hands on the posterior surface of the proximal tibia and subluxates the tibia anteriorly (Fig. 42-7). Any gross movement of the tibia that is different from the contralateral side is considered abnormal. The Lachman test is performed with the knee in 30 degrees of flexion (to remove the contribution of secondary restraints). The examiner applies an anterior force on the tibia while stabilizing the femur with his or her contralateral hand. Any increase in anterior tibial translation relative to the contralateral side is considered abnormal (Fig. 42-8). The pivot-shift test is performed with the knee in extension. The examiner holds the tibia in slight internal rotation and applies a valgus stress while the knee is slowly flexed. This combination of forces should cause the tibia to subluxate anteriorly if the anterior cruciate ligament is injured. The test is positive if the tibia reduces with a “clunk” or a “glide” at 20 to 40 degrees of flexion.

Figure 42-8  The Lachman test is performed by applying an anterior force on the tibia while stabilizing the femur with the knee in 30 degrees of flexion.

The posterior cruciate ligament is the strongest ligament in the knee,22,23 and injuries to the posterior cruciate ligament are usually a result of significant knee trauma. The “dashboard” injury is a common mechanism for posterior cruciate ligament injury and occurs during a motor vehicle accident when the tibia with the knee flexed strikes the dashboard (Fig. 42-9). The posterior cruciate ligament can be evaluated with the posterior drawer, posterior sag, and quadriceps active tests. All tests are performed with the patient in the supine position. The posterior drawer test is performed with the knee in 90 degrees of flexion. The examiner applies a posteriorly directed force to the tibia. Placement of one’s thumb tips at the anterior joint line allows for quantification of any abnormal translation (Fig. 42-10). The posterior sag test is positive when the tibia subluxates posteriorly with the knee at 90 degrees of flexion. Loss of the medial tibial step-off at the joint line should alert the examiner to a posterior cruciate ligament injury (Fig. 42-11).22 This test is usually

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Figure 42-11  The posterior sag test is positive when the tibia subluxates posteriorly with the knee in 90 degrees of flexion. Figure 42-9  An injury to the posterior cruciate ligament can occur when the tibia strikes the dashboard, causing the tibia to subluxate posteriorly on the femur.

The posterolateral corner structures restrain external rotation at 30 degrees of flexion, whereas the posterior cruciate ligament restrains external rotation at 90 degrees of flexion. An increase of external rotation at 90 degrees of flexion without an increase in external rotation at 30 degrees of flexion suggests an isolated posterior cruciate ligament injury. An increase of external rotation at 30 degrees of flexion without an increase at 90 degrees of flexion suggests an isolated injury to the posterolateral corner. Increased external rotation at 30 degrees and 90 degrees of flexion suggests combined posterior cruciate ligament and posterolateral corner injuries. Menisci

Figure 42-10  The posterior drawer test is performed by subluxating the tibia posteriorly with the knee in 90 degrees of flexion. The amount of posterior translation (mm) is noted. The end point is characterized as “soft” or “hard.”

positive in the setting of chronic pathology or under anesthesia in the setting of acute injury. The quadriceps active test is performed with the knee in 60 degrees of flexion. The patient is asked to extend the knee while keeping his or her foot on the examination table. One sees reduction of the tibia in a positive test.24 Injuries to the posterior cruciate ligament are often accompanied by injuries to the “posterolateral corner,” a complex structure that functions as a static and a dynamic stabilizer of the knee.23 The posterolateral corner comprises the lateral collateral ligament, the popliteofibular ligament, the popliteomeniscal attachment, the arcuate ligament, and the popliteus tendon and muscle.25 Injuries to the posterolateral corner, the posterior cruciate ligament or both can be examined with the “dial test” (Fig. 42-12).

Traumatic and degenerative meniscal injuries are among the most common knee injuries. The menisci are considered the “shock absorbers” in the knee. They also provide rotational and translational restraint. The medial meniscus is beanshaped and is larger and less mobile than the lateral meniscus. The lateral meniscus is more C-shaped. Meniscal tears usually occur with rotation of the flexed knee as it moves into extension. Tears of the medial meniscus are more common than tears of the lateral meniscus, likely owing to the relative lack of mobility of the medial meniscus.26 Patients frequently complain of “locking” and “clicking” or of something not being “right” with the knee, and this usually results from displacement of the torn meniscus during motion. Common physical findings include pain with hyperflexion and with hyperextension, joint line tenderness, and an effusion. Many provocative tests have been described to diagnose meniscal tears. The McMurray27 and Apley compression28 tests are performed frequently, although they do lack sensitivity and specificity. The flexion McMurray test is performed with the patient supine and the hip and knee flexed to 90 degrees. A compressive and rotational force is applied to the knee as it is moved from a flexed to an extended position. The test is positive if the patient complains of pain (Fig. 42-13). The Apley compression test is performed with

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Figure 42-12  A and B, The degree of tibial external rotation is measured in the “dial” test.

B

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B Figure 42-14  A and B, Images taken during knee arthroscopy reveal a tear in the posterior horn of the medial meniscus before (A) and after  (B) débridement. Figure 42-13  A positive flexion McMurray test may indicate a torn  meniscus.

the patient prone and the knee flexed to 90 degrees. In a positive test, the patient complains of pain with rotation of the tibia. The images in Figure 42-14 show a tear in the posterior horn of the medial meniscus. Quadriceps Tendon Injuries to the quadriceps tendon are most common in the sixth and seventh decades of life. Patients with systemic lupus erythematosus, renal failure, endocrinopathies, diabetes, and

various other systemic inflammatory and metabolic diseases are at a higher risk for these injuries. Quadriceps tendon rupture after total knee arthroplasty is a rare (0.1%) but devastating complication.29 Patients usually present with intense anterior knee pain after experiencing an eccentric quadriceps contraction during a fall or twisting injury. Physical examination reveals a palpable defect in the tendon, an effusion owing to hemarthrosis, and hypermobility of the patella. Patients usually are unable to extend their knee fully (Fig. 42-15).

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Figure 42-15  An extensor lag resulting from a complete tear in the quadriceps tendon.

Patella Tendon Problems with the infrapatellar tendon include tendinitis and rupture. Tendinitis is usually an overuse injury and is often associated with jumping, changes in activity level, and eccentric contractions during falls. Patients exhibit tenderness at the tibial tubercle or at the inferior pole of the patella. Rupture of the patella tendon usually occurs in patients younger than 40 years old and is associated with chronic patella tendinitis. Patients usually present with anterior knee pain and the inability to extend the knee. Patellofemoral Pain Anterior knee pain is a common complaint and is more common in women; it accounts for 25% of all sports-related knee injuries.30 A variety of factors contribute to the biomechanics of the patellofemoral joint, including overuse, the depth of the trochlea, the shape of the patella, quadriceps strength, the line of pull of the quadriceps relative to the patella tendon (the Q angle), the length of the patella tendon, the shape of the femoral condyles, and the articular cartilage. Abnormalities of any of these factors may contribute to this pain syndrome, and successful treatment is possible only with correct identification of any contributing factors. Physical examination of the patellofemoral joint begins with an analysis of coronal alignment of the knee because any valgus deformity may contribute to lateral subluxation. The height of the patella relative to the tibial tubercle should be noted (patella alta or baja). The J sign is present when the patella slides laterally at terminal extension, indicating excessive pull of the vastus lateralis. The vastus medialis obliquus is the primary stabilizer against lateral pull by the vastus lateralis. With the knee extended and the quadriceps relaxed, the examiner should make note of any patellar tilt. Any audible or palpable crepitus should be noted as well. Crepitus is common in osteoarthritis. A Q angle greater than 15 degrees in women and greater than 8 to 10 degrees in men is considered abnormal.30 Patellar mobility should be assessed using a quadrant system for passive mediolateral displacement of the patella relative to the trochlear groove. The normal patella should not be displaced medially or laterally

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Figure 42-16  The apprehension test is positive when subluxation of the patella causes pain.

beyond the second quadrant. Any abnormality in mobility may stem from changes in the tightness of the retinaculum. The apprehension test is performed by attempting to subluxate the patella with the knee in extension. The test is positive when it elicits pain and an unwillingness to allow the examiner to move the patella laterally (Fig. 42-16). At the conclusion of the history and physical examination, the astute clinician should have formulated a short list of possible diagnoses. With this list in mind, the imaging studies, if appropriate, can now be obtained. The goal of the initial imaging studies should be to confirm the diagnosis with the most appropriate and least expensive study. Advanced imaging studies should not replace a thorough history and physical examination. IMAGING Conventional Radiographs Conventional radiographs are usually the first study obtained after knee injury and should be read in a systematic manner. Soft tissues should be evaluated before examining the bony structures. Findings should be described in terms of radiolucent and radiopaque lines. Only after the findings have been described should the interpretation phase begin because it is the natural tendency to bypass the description and proceed directly to interpretation. If this is done, certain findings are likely to be missed or dismissed prematurely. The basic radiographic evaluation of the symptomatic knee consists of standing anteroposterior weight-bearing, lateral, and Merchant’s views. The anteroposterior view allows for evaluation of coronal alignment and height of the tibiofemoral joint spaces. The normal coronal alignment of the knee should be 5 to 7 degrees of anatomic (tibiofemoral) valgus. The lateral tibiofemoral joint space should be wider than the medial tibiofemoral joint space in a normal knee. Marginal osteophytes, joint space narrowing, subchondral sclerosis, and cystic change are seen in the presence of osteoarthritis (Fig. 42-17). Periarticular osteopenia, concentric joint space narrowing, and a paucity of osteophytes are commonly seen in inflammatory arthritis (Fig. 42-18). The lateral x-ray allows for evaluation of an effusion, patella

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B C Figure 42-17  A-C, Standing anteroposterior (A), lateral (B), and Merchant’s (C) views of an osteoarthritic knee.

tendon length, and the quadriceps tendon. Merchant’s view is taken tangential to the patellofemoral joint.31 It allows for detection of patellofemoral arthritis and malalignment and should be obtained only when indicated for symptoms or findings. The posterior femoral condyles can be evaluated for joint space narrowing with a posteroanterior standing view with the knees flexed approximately 45 degrees, the tunnel or intercondylar notch view, and the 36-inch anteroposterior standing view of bilateral lower extremities.32 The flexed posteroanterior standing view is taken with the radiographic beam directed 10 degrees caudad from anterior to posterior. The tunnel view is obtained with the knee flexed and the radiographic beam directed inferiorly at an angle perpendicular to the tibial plateau. It is useful in detecting posterior tibiofemoral joint space narrowing, tibial spine fractures, loose bodies, and osteochondral lesions on the medial aspect of the femoral condyles. The 36-inch standing view is used to determine the mechanical axis of the lower extremity and to evaluate any deformity that may be present. The normal mechanical axis is a straight line joining the center of the hip, knee, and ankle joints. Surgeons use it for preoperative planning and postoperative evaluation in total knee arthroplasty and for the planning of distal femoral and proximal tibia osteotomies in arthritis surgery. Computed Tomography Computed tomography (CT) has largely been replaced by magnetic resonance imaging (MRI) in evaluation of knee pathology. CT is now used primarily for detection of bony tumors, in the trauma setting for detection of subtle fractures that are not easily visualized with conventional radiographs, and for a more thorough evaluation of intraarticular fractures. In cases of distal femoral or proximal tibia fractures, CT is used to help the surgeon plan operative

treatment and to assess axial alignment of the femoral and tibial components in patients with a painful total knee arthroplasty.33,34 Ultrasound The use of ultrasound has become more common in the diagnosis of knee disorders as a result of more recent improvements in transducer technology. Ultrasound is an attractive imaging modality because of its low cost, real-time capabilities, and portability. The ability to perform provocative maneuvers during sonography is particularly appealing. Ultrasound can easily and reliably detect joint effusions and quadriceps and patella tendon disruptions. It has been reported that ultrasound can detect a 1-mm increase in joint fluid.35 Nuclear Scintigraphy Nuclear scintigraphy is sensitive, but not specific, and it is used to detect areas of increased osseous remodeling. It requires clinical correlation and should be used in conjunction with other imaging modalities. Technetium phosphate compounds are injected intravenously. Approximately 50% of the tracer is excreted by the kidneys, and the remainder is taken up in areas of increased osseous turnover. Imaging of the skeleton is typically performed 2 to 3 hours after injection because this allows for maximal contrast between the soft tissues and the skeletal structures, while still providing for an adequate photon count.36 Three-phase bone scanning can yield additional information. The three phases include an angiographic pool, a blood pool, and bone imaging. The angiographic phase allows for detection of regional hyperemia. This technique has been reported to have greater specificity and can be used in cases of suspected osteomyelitis, osteonecrosis, stress fracture, and

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Figure 42-18  A-C, Standing anteroposterior (A), lateral (B), and Merchant’s (C) views of the knee in a patient with rheumatoid arthritis.

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implant loosening.36 It has been reported that increased radionuclide uptake can be seen for 12 to 18 months after total knee arthroplasty. Asymmetric uptake in one area around the prosthesis should raise the question of loosening or periprosthetic fracture (Fig. 42-19).37,38 Addition of labeled leukocytes to technetium-99m sulfur colloid yields 80% sensitivity and 100% specificity for diagnosing infection.39

tears) and 77% and 89% (lateral tears). This translates to a positive predictive value of 91% to 94% for medial meniscus tears and 83% to 96% for lateral meniscus tears.40 COMMON DISORDERS IN THE DIFFERENTIAL DIAGNOSIS OF KNEE PAIN General

Magnetic Resonance Imaging MRI has supplanted many imaging modalities because of its direct multiplanar capabilities and superior soft tissue contrast. Although conventional radiographs remain the “gold standard” for defining osseous structures, MRI provides excellent visualization of articular cartilage, the cruciate ligaments, the collateral ligaments, the patella tendon, the quadriceps tendon, and the menisci (Fig. 42-20). It also is highly sensitive for detecting bone marrow edema (contusion), stress fractures, and mass lesions. Use of the “two-slice touch” rule has improved the sensitivity and specificity of MRI in accurately diagnosing meniscal tears. This rule classifies a meniscus as torn if there are two or more MR images with abnormal findings and as possibly torn if there is only one MR image with an abnormal finding. Using fast spinecho imaging, the sensitivity and specificity for diagnosing medial and lateral meniscal tears were 95% and 85% (medial

Although there are many diseases that may involve the knee, only a few are common. In evaluating the complaint of knee pain, the clinician should be familiar with osteoarthritis; rheumatoid arthritis; inflammatory arthritis associated with the seronegative spondyloarthropathies; tears of the menisci, ligaments, and tendons; osteochondritis dissecans; osteochondral fractures; fractures; referred pain from the hip (e.g., with slipped capital femoral epiphysis in adolescents); vascular claudication; neurogenic claudication; complex regional pain syndrome; sarcoma; metastases; and infection. Bursitis The prepatellar bursa lies between the retinaculum and the subcutaneous fat and runs from the patella to the tibial tubercle. The bursa may become inflamed and fill with fluid

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Figure 42-19  A bone scan reveals increased uptake of radiotracer around the distal femur in a patient with an infected total knee arthroplasty and septic loosening of the femoral component.

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when exposed to a direct blow or repetitive microtrauma (kneeling). Patients with prepatellar bursitis present with anterior knee pain on flexion and a fluctuant mass over the anterior knee. If the area becomes warm, tender to palpation, and erythematous, septic bursitis should be ruled out by aspiration and culture. The pes anserinus bursa, located over the insertions of the sartorius, gracilis, and semitendinosus muscles on the proximal medial tibia, also can be a source of knee pain when it is inflamed. Neoplasia Tumors around the knee are often diagnosed after trauma prompts medical evaluation. Pain at night, pain at rest, and constitutional symptoms should alert the clinician to consider the appropriate workup. Some benign tumors seen around the knee include enchondroma, pigmented villo­ nodular synovitis, osteochondromatosis, and giant cell tumor. Malignant tumors seen around the knee include, but are not limited to, metastases, osteosarcoma, Ewing’s sarcoma, chondrosarcoma, and malignant fibrous histiocytoma. Popliteal Cysts A popliteal cyst, originally called Baker’s cyst, is a synovial fluid–filled mass located in the popliteal fossa. The most common synovial popliteal cyst is considered to be a distention of the bursa located beneath the medial head of the gastrocnemius muscle. Usually, in an adult patient, an underlying intra-articular disorder (osteoarthritis or rheumatoid arthritis) is present. In children, the cyst can be isolated, and the knee joint can be normal. Patients usually present with episodic posterior knee pain.41 The diagnosis is made by ultrasonography or MRI. Treatment options include benign neglect, aspiration, surgical excision, and removal of

Figure 42-20  Sagittal MRI shows linear signal change extending to the meniscal surface consistent with a tear in the posterior horn of the medial meniscus.

the underlying pathology (arthritis) with knee arthroplasty. Popliteal pain and edema of the lower leg caused by a popliteal cyst can mimic thrombophlebitis, and anticoagulation in such cases is not indicated.

HIP PAIN HISTORY Generally, more conditions should be considered in the differential diagnosis for hip pain than for knee pain because the hip is a common site for referred pain from lumbosacral and intrapelvic pathology. A detailed, comprehensive history directs the clinician to a focused ­physical examination.

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Most patients who present with hip pathology complain of pain. It is important to define the exact location of the pain because “hip” pain may refer to discomfort in the groin, lateral thigh, or buttock. Pain in the groin or medial thigh region is most often due to hip disease and is believed to arise from irritation of the capsule or synovial lining or both.42 Pain generated, the lumbosacral spine may be referred to the buttocks, lateral thigh, or groin.43 Lateral thigh pain may stem from so-called trochanteric bursitis (usually abductor tendinitis). Activities or positions that aggravate and relieve the pain and the severity, frequency, and patterns of radiation should be explored. It is common for knee pain to be referred from the hip joint. Metastatic and primary tumors that occur in the pelvic and proximal thigh regions and intrapelvic pathology from the prostate, seminal vesicles, hernias, ovaries, gastrointestinal system, and vasculature always should be included in the differential diagnosis.44,45 Knowledge of the patient’s general level of functioning is important because this lends insight into the severity of disease and may influence treatment. Patients with hip pathology may have difficulty trimming their toenails, donning shoes and socks, and using stairs. Walking tolerance and use of assist devices also should be recorded. The Harris Hip Score and WOMAC Osteoarthritis Index are two rating scales that are widely used to assess function in this patient population.46,47 The patient should be asked about any hip problems and their treatment that he or she encountered in childhood. Diseases such as developmental dysplasia, slipped capital femoral epiphysis, Legg-Calvé-Perthes disease, polio, and trauma may lead to osteoarthrosis later in life.48-50 Osteoarthritis and inflammatory arthritis are two common causes of hip pain. Generally, pain from osteoarthritis is exacerbated by activity and relieved by rest. Mild arthritis of the hip may not become symptomatic until a certain activity level is reached. Stiffness (usually from synovitis) also is a common complaint with degenerative and inflammatory arthritis. When the hip pain continues despite a trial of rest, an underlying inflammatory or infectious process should be considered. Any previous treatments for hip pain should be discussed. The patient’s response to nonsteroidal anti-inflammatory drugs, nutritional supplements (e.g., chondroitin and glucosamine), physical therapy, corticosteroid injections, local anesthetic injections, hyaluronic acid injections, ultrasound, and operative interventions should be recorded. Finally, a more general medical history should be explored. The physician should always consider alcoholism, fibromyalgia, neuromuscular disorders, and smoking history as complicating factors in these patients. PHYSICAL EXAMINATION The physical examination of a patient with hip pain begins as the clinician watches the patient for the first time. Ease of chair rise, postures, and walking speed all provide insight into the extent of a patient’s disability. A general evaluation of the patient’s spine, lower extremity alignment, and leg lengths comes next. With the examiner behind the patient, the spine is examined for coronal and sagittal balance. The patient is asked to touch his or her toes. A rib hump indicates the presence of scoliosis. Any gross deformity of the

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spine alerts the examiner to the potential of a pelvic obliquity and resultant apparent leg-length discrepancy. The overall coronal alignment of the lower extremities is evaluated next. If a leg-length discrepancy is detected, blocks can be used, as discussed previously, to determine the amount of inequality. If the leg-length discrepancy is due to a fixed pelvic obliquity from lumbosacral disease, blocks may not be able to level the pelvis. Palpation of the bony landmarks (iliac crest, anterior superior iliac spine, posterior superior iliac spine, ischial tuberosity, coccyx, spinous processes, and greater trochanter) should be performed (Fig. 42-21). The femoral neck is located approximately three fingerbreadths below the anterior superior iliac spine. A basic evaluation of gait is useful. Although gait analysis is a complex science, all clinicians should feel comfortable evaluating for common abnormalities. A patient with hip pain may present with an antalgic gait. The severity of the limp should be classified as mild, moderate, or severe. Mild limps can be detected only by trained observers. Moderate limps are noticed by the patient. A severe limp is readily apparent and has a significant impact on speed of ambulation. Common causes of limp include pain and abductor (gluteus medius and gluteus minimus) muscle weakness. Differentiating between these two etiologies is an important part of the physical examination. A patient with abductor dysfunction is likely to have an abductor, or Trendelenburg, lurch.51 With a Trendelenburg lurch, the patient compensates for abductor dysfunction by leaning over the involved hip to shift the body’s center of gravity in that direction (Fig. 42-22). If the patient has a Trendelenburg lurch, we proceed to evaluate for a Trendelenburg sign. A positive Trendelenburg sign occurs when the pelvis tilts toward the unsupported side during one-legged stance when viewed with the examiner behind the patient. Causes of abductor weakness are numerous and may include a contracted or shortened gluteus medius, coxa vara, fracture, dysplasia, neurologic conditions (e.g., superior gluteal nerve injury, radiculopathy, poliomyelitis, myelomeningocele, spinal cord lesions), and slipped capital femoral epiphysis. The patient is then asked to lay supine on the examination­ table. The range of motion of both hips should be evaluated by recording flexion, extension, adduction, abduction, internal rotation in extension, and external rotation in extension. Hip extension is best evaluated with the patient in the prone position. Normal range of motion values include 100 to 135 degrees for flexion (knee should be flexed to relax the hamstrings), 15 to 30 degrees for extension, 15 to 30 degrees for adduction, 20 to 40 degrees for abduction, 20 to 40 degrees for internal rotation, and 15 to 60 degrees for external rotation. Motion is often limited in cases of deformity (e.g., limited internal rotation in slipped capital femoral epiphysis) and advanced osteoarthritis. Internal rotation and abduction are usually the first motions to be limited in osteoarthritis. Motion also is painful in patients with synovitis. Areas that are painful should be palpated. A series of special tests can be performed to evaluate for subtle muscle contractures and limitation of motion. The presence of a hip flexion contracture is common in patients with moderate-to-severe hip pathology and can be quantified with the Thomas test (Fig. 42-23).52 This test is performed by having the patient bring his or her thighs to the

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Figure 42-21  Diagram of the bony landmarks on the pelvis that can be palpated during physical examination.

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Figure 42-22  Physical examination of abductor function. A, Normal single-legged stance. B, Positive Trendelenburg lurch and negative Trendelenburg sign. C, Positive Trendelenburg lurch with pelvic obliquity and leaning over the involved hip to shift the body’s center of gravity.

chest while in the supine position. This allows for flattening of the spine, and the hip to be evaluated is allowed to extend to neutral. If the patient is unable to reach neutral, the amount of flexion contracture is recorded. The Ober test measures tightness of the iliotibial band. The patient lies on the unaffected side, and the examiner helps the patient abduct the hip with the hip extended and the knee flexed to 90 degrees. The leg is slowly released from abduction to neutral, and the hip remains abducted if there is contracture of the iliotibial band. Ely’s test detects a tight rectus femoris muscle. The knee is passively flexed with the patient in the prone position. If the rectus femoris is tight, the ipsilateral hip spontaneously flexes. If the rectus femoris is normal, the hip remains flush with the examination table. Patients occasionally complain of a “snapping” sensation in their hip. Although it may be difficult for the clinician to

Figure 42-23  In the Thomas test, a hip flexion contracture is measured by flexing the contralateral hip to eliminate compensatory lumbar lordosis. The ipsilateral hip is allowed to extend with gravity. The angle between the examination table and the thigh is the degree of flexion contracture.

reproduce snapping, patients may be able to demonstrate this by flexing and internally rotating their hip. Extra-articular causes of hip snapping include a thickened iliotibial band snapping over the greater trochanter, the iliopsoas tendon gliding over the iliopectineal eminence, the long head of the biceps tendon rubbing on the ischial tuberosity, and the iliofemoral ligament rubbing on the femoral head. Intra-articular causes of snapping hip syndrome include loose bodies and large labral tears. In addition to using blocks with the patient standing, leg lengths can be measured while the patient is in the supine position (Fig. 42-24). The apparent leg length is the distance from the umbilicus to the medial malleolus. The true leg length is measured from the anterior superior iliac spine to the medial malleolus. Pelvic obliquity and abduction/adduction of the hip create an apparent leg-length discrepancy. Sacroiliac disease should be included in the differential diagnosis of hip pain. Although multiple provocative tests have been described to elicit sacroiliac disease, the FABER test (also known as Patrick’s test) can help distinguish between hip and sacroiliac joint pathology. With the patient supine, the clinician has the patient place his or her hip in the flexion, abduction, and externally rotated positions. The clinician presses the flexed knee and the contralateral anterior superior iliac spine toward the floor. Pain in the buttocks suggests sacroiliac joint disease, whereas pain in the groin points to hip pathology. If the sacroiliac joint is implicated, it is recommended that multiple other provocative tests be performed. It has been shown that by using a combination of the distraction, thigh thrust, compression, sacral thrust, Gaenslen’s, and FABER tests, sacroiliac joint pathology is the likely pain generator when three or more of the tests are positive.53,54 The acetabular labrum is drawing attention as a previously underappreciated cause of hip pain. Clinical presentation of a labral tear of the acetabulum may vary, and the diagnosis is often delayed. Patients usually see multiple providers before the diagnosis is confirmed. In a series of 66 patients with

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Figure 42-24  Measurement of leg lengths. A, The apparent leg length is the distance from the umbilicus to the medial malleolus. B, Pelvic obliquity causing an apparent leg-length discrepancy. C, The true leg length is the distance from the anterior superior iliac spine to the medial malleolus.

arthroscopically confirmed tears of the acetabular labrum, 92% of the patients complained of groin pain, 91% of the patients had activity-related pain, 71% of the patients complained of night pain, 86% of the patients described the pain as moderate to severe, and 95% of the patients had a positive impingement sign. The authors recommended that a diagnosis of acetabular labral tear be suspected in young, active patients complaining of groin pain with or without trauma.55 The positive impingement test helps confirm the diagnosis of labral tear. The test is positive if the patient experiences groin pain with the hip flexed, adducted, and internally rotated. A thorough evaluation of the neurovascular system should be completed after the musculoskeletal portion of the physical examination for the hip or knee is completed. This should include palpation or Doppler evaluation of the femoral, popliteal, dorsalis pedis, and posterior tibial arteries, as indicated. Strength testing with resisted isometric movements for each muscle in the lower extremity is performed, with a score of 5 being normal strength, 4 being full motion against gravity and against some resistance, 3 being fair motion against gravity, 2 being movement only with gravity eliminated, 1 being evidence of muscle contraction but no joint motion, and 0 being no evidence of contractility. Sensation in the lower extremity should be evaluated by assessing for light touch or appreciation of pin prick in a dermatomal distribution. Patellar and ankle reflexes should be tested. The examiner should test for any abnormal clonus and Babinski’s reflexes as indicated. IMAGING Conventional Radiographs Plain radiographs remain the primary diagnostic imaging tool for the evaluation of hip pathology. All other imaging modalities should be viewed as complementary to conventional radiographs. Our standard screening series includes

Figure 42-25  Anteroposterior radiograph of the pelvis shows the characteristic joint space narrowing, cystic changes, and osteophytes seen in osteoarthritis.

a low anteroposterior pelvis view (Fig. 42-25), an anteroposterior hip view (Fig. 42-26), a frog-lateral view, and a cross-table lateral view. The frog-lateral view provides a lateral view of the proximal femur and is useful for detecting femoral head collapse (as seen in osteonecrosis) (Fig. 42-27). There are numerous other special radiographs of the hip; some of these include Judet 45-degree oblique views and the false profile view. Judet views allow for easier visualization of the anterior (obturator oblique) and posterior (iliac oblique) columns. The false profile view allows for evaluation of anterior bony coverage of the femoral head in cases of acetabular dysplasia. Developmental dysplasia of the hip is common, and we do not recommend the routine use of any special views before referral to an orthopaedic surgeon (Fig. 42-28).

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Figure 42-26  Anteroposterior radiograph of the hip shows the characteristic concentric joint space narrowing, paucity of osteophytes, and periarticular osteopenia seen in rheumatoid arthritis.

Figure 42-28  Anteroposterior radiograph of the hip shows osteoarthrosis from developmental dysplasia. The up-sloping lateral edge of the acetabulum is characteristic for developmental dysplasia of the hip.

imaging modalities because of its limited specificity (Fig. 42-29). Magnetic Resonance Imaging

Figure 42-27  Frog-lateral radiograph shows femoral head collapse from osteonecrosis.

Computed Tomography CT is used for assessment of acetabular fractures, acetabular nonunions, femoral head fractures, subtle femoral neck fractures, neoplasia, and bone stock in the setting of revision total hip arthroplasty. Owing to its limited soft tissue contrast, CT has largely been replaced by MRI for detailed evaluation of the soft tissues around the hip. Nuclear Scintigraphy The role of bone scanning in the evaluation of hip pathology is similar to its role in the assessment of knee pain. It should always be used in conjunction with other

MRI provides unprecedented detail of the soft tissues around the hip joint. Its use is now common for diagnosis of osteonecrosis, labral pathology, neoplasia, effusion, synovitis, loose bodies, tendinitis, transient osteoporosis of the hip, occult femoral neck fractures, bone edema, gluteus medius tendon avulsions, and nerve injury. Magnetic resonance arthrography of the hip joint is useful for identifying gluteus medius tendon avulsion after total hip arthroplasty (Fig. 42-30) and for detecting labral tears. One study showed a 92% sensitivity for the detection of labral tears using magnetic resonance arthrography.56 Delayed gadolinium-enhanced MRI of cartilage, a technique designed to measure early arthritis in the hip joint, is now being used clinically in the management of hip dysplasia.57 Despite the tremendous diagnostic capabilities of MRI, its ability to detect bony pathology is limited. As such, conventional radiographs remain the imaging modality of choice for screening. Hip Arthrography Hip arthrography is useful for detecting avulsions of the gluteus medius tendon from the greater trochanter and for differentiating intra-articular hip pathology from lumbosacral disease. In one study, intra-articular anesthetic injection was 90% accurate in predicting intra-articular pathology as confirmed by hip arthroscopy.58 Anesthetic arthrogram of the hip has shown a 95% positive predictive value and a 67% negative predictive value for pain relief after total hip arthroplasty in patients with concurrent hip and lumbar osteoarthritis.59

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Figure 42-29  Bone scan shows increased radiotracer uptake at the proximal femur. The patient presented with activity-related thigh pain 1-year status post primary cementless total hip arthroplasty. History, physical examination, and  conventional radiographs suggested failure of osseointegration. At the time of surgery, the femoral component was found to be grossly loose.

of the acetabular labrum, transient osteoporosis of the proximal femur, infection, snapping hip syndrome, osteitis pubis, neoplasia (osteosarcoma, chondrosarcoma, pigmented villonodular synovitis, osteochondromatosis, malignant fibrous histiocytoma, or metastases), inguinal hernia, or referred pain (lumbosacral spine, sacroiliac joint, prostate, seminal vesicles, uterus, ovaries, or lower gastrointestinal tract). This list can be efficiently narrowed down by taking a detailed history, performing a comprehensive examination of the musculoskeletal and neurovascular systems, and obtaining the appropriate imaging studies. REFERENCES

Figure 42-30  Short tau inversion recovery coronal MRI shows complete avulsion of the gluteus medius tendon from its insertion on the greater trochanter. Note the signal change along the lateral aspect of the greater trochanter, consistent with accumulation of intra-articular gadolinium at the site where the gluteus medius tendon should be.

COMMON DISORDERS IN THE DIFFERENTIAL DIAGNOSIS OF HIP PAIN A detailed discussion of the numerous common causes of hip pain is beyond the scope of this chapter. The differential diagnosis of hip pain should include osteoarthrosis (most frequently from developmental dysplasia, Legg-Calvé-Perthes disease, or slipped capital femoral epiphysis), inflammatory arthritis, osteonecrosis, fractures (acetabulum, femoral head, femoral neck, intertrochanteric, or subtrochanteric), trochanteric bursitis, femoroacetabular impingement, tears

  1. Mallen CD, Peat G, Thomas E, et al: Is chronic musculoskeletal pain in adulthood related to factors at birth? A population-based case-control study of young adults. Eur J Epidemiol 21:237-243, 2006.   2. Peat G, McCarney R, Croft P: Knee pain and osteoarthritis in older adults: A review of community burden and current use of primary health care. Ann Rheum Dis 60:91-97, 2001.   3. Mendenhall S: Mix shifts toward high-demand implants. OR Manager 21:13, 2005.   4. Ong KL, Mowat FS, Chan N, et al: Economic burden of revision hip and knee arthroplasty in Medicare enrollees. Clin Orthop 446:22-28, 2006.   5. Aoyagi K, Ross PD, Huang C, et al: Prevalence of joint pain is higher among women in rural Japan than urban Japanese-American women in Hawaii. Ann Rheum Dis 58:315-319, 1999.   6. Jacobsen S, Sonne-Holm S, Soballe K, et al: Radiographic case definitions and prevalence of osteoarthrosis of the hip: A survey of 4 151 subjects in the Osteoarthritis Substudy of the Copenhagen City Heart Study. Acta Orthop Scand 75:713-720, 2004.   7. Helme RD, Gibson SJ: The epidemiology of pain in elderly people. Clin Geriatr Med 17:417-431, 2001.   8. Chen J, Devine A, Dick IM, et al: Prevalence of lower extremity pain and its association with functionality and quality of life in elderly women in Australia. J Rheumatol 30:2689-2693, 2003.   9. Felson DT: Epidemiology of hip and knee osteoarthritis. Epidemiol Rev 10:1-28, 1988. 10. Felson DT: An update on the pathogenesis and epidemiology of osteoarthritis. Radiol Clin North Am 42:1-9, 2004. 11. Felson DT, Nevitt MC: Epidemiologic studies for osteoarthritis: New versus conventional study design approaches. Rheum Dis Clin North Am 30:783-797, 2004.

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12. Gelber AC, Hochberg MC, Mead LA, et al: Joint injury in young adults and risk for subsequent knee and hip osteoarthritis. Ann Intern Med 133:321-328, 2000. 13. Horvath G, Than P, Bellyei A, et al: [Prevalence of musculoskeletal symptoms in adulthood and adolescence (survey conducted in the Southern Transdanubian region in a representative sample of 10.000 people]. Orv Hetil 147:351-356, 2006. 14. Leveille SG, Zhang Y, McMullen W, et al: Sex differences in musculoskeletal pain in older adults. Pain 116:332-338, 2005. 15. Zeng QY, Westermark SQ, Rasmussen-Lestander A, et al: Low prevalence of knee and back pain in southeast China: The Shantou COPCORD study. J Rheumatol 31:2439-2443, 2004. 16. Butler DL, Noyes FR, Grood ES: Ligamentous restraints to anterior-posterior drawer in the human knee: A biomechanical study. J Bone Joint Surg Am 62:259-270, 1980. 17. O’Donoghue DH: Surgical treatment of fresh injuries to the major ligaments of the knee. J Bone Joint Surg Am 32:721-738, 1950. 18. Griffin LY, Agel J, Albohm MJ, et al: Noncontact anterior cruciate ligament injuries: Risk factors and prevention strategies. J Am Acad Orthop Surg 8:141-150, 2000. 19. Torg JS, Conrad W, Kalen V: Clinical diagnosis of anterior cruciate ligament instability in the athlete. Am J Sports Med 4:84-93, 1976. 20. Bach BR Jr, Warren RF, Wickiewicz TL: The pivot shift phenomenon: Results and description of a modified clinical test for anterior cruciate ligament insufficiency. Am J Sports Med 16:571-576, 1988. 21. Noyes FR, Grood ES, Cummings JF, et al: An analysis of the pivot shift phenomenon: The knee motions and subluxations induced by different examiners. Am J Sports Med 19:148-155, 1991. 22. Harner CD, Hoher J: Evaluation and treatment of posterior cruciate ligament injuries. Am J Sports Med 26:471-482, 1998. 23. Harner CD, Xerogeanes JW, Livesay GA, et al: The human posterior cruciate ligament complex: An interdisciplinary study: Ligament morphology and biomechanical evaluation. Am J Sports Med 23:736-745, 1995. 24. Fanelli GC: Posterior cruciate ligament injuries in trauma patients. Arthroscopy 9:291-294, 1993. 25. Watanabe Y, Moriya H, Takahashi K, et al: Functional anatomy of the posterolateral structures of the knee. Arthroscopy 9:57-62, 1993. 26. Andrews JR, Norwood LA Jr, Cross MJ: The double bucket handle tear of the medial meniscus. J Sports Med 3:232-237, 1975. 27. McMurray T: The semilunar cartilages. Br J Surg 29:407, 1941. 28. Apley A: The diagnosis of meniscus injuries: Some new clinical methods. J Bone Joint Surg Br 29:78, 1929. 29. Dobbs RE, Hanssen AD, Lewallen DG, et al: Quadriceps tendon rupture after total knee arthroplasty: Prevalence, complications, and outcomes. J Bone Joint Surg Am 87:37-45, 2005. 30. Fredericson M, Yoon K: Physical examination and patellofemoral pain syndrome. Am J Physical Med Rehabil 85:234-243, 2006. 31. Merchant AC: Classification of patellofemoral disorders. Arthroscopy 4:235-240, 1988. 32. Messieh SS, Fowler PJ, Munro T: Anteroposterior radiographs of the osteoarthritic knee. J Bone Joint Surg Br 72:639-640, 1990. 33. Barrack RL, Schrader T, Bertot AJ, et al: Component rotation and anterior knee pain after total knee arthroplasty. Clin Orthop 392:46-55, 2001. 34. Berger RA, Rubash HE: Rotational instability and malrotation after total knee arthroplasty. Orthop Clin North Am 32:639-647, 2001. 35. van Holsbeeck M, Introcaso JH: Musculoskeletal ultrasonography. Radiol Clin North Am 30:907-925, 1992. 36. Palmer EL, Scott JA, Strauss HW: Bone imaging. In Practical Nuclear Medicine. Philadelphia, WB Saunders, 1992, pp 121-183.

37. Duus BR, Boeckstyns M, Kjaer L, et al: Radionuclide scanning after total knee replacement: Correlation with pain and radiolucent lines: A prospective study. Invest Radiol 22:891-894, 1987. 38. Kantor SG, Schneider R, Insall JN, et al: Radionuclide imaging of asymptomatic versus symptomatic total knee arthroplasties. Clin Orthop 260:118-123, 1990. 39. Palestro CJ, Swyer AJ, Kim CK, et al: Infected knee prosthesis: Diagnosis with In-111 leukocyte, Tc-99m sulfur colloid, and Tc-99m MDP imaging. Radiology 179:645-648, 1991. 40. De Smet AA, Tuite MJ: Use of the “two-slice-touch” rule for the MRI diagnosis of meniscal tears. AJR Am J Roentgenol 187:911-914, 2006. 41. Fritschy D, Fasel J, Imbert JC, et al: The popliteal cyst. Knee Surg Sports Traumatol Arthrosc 14:623- 628, 2006. 42. Kellgren JH: The sensitivity and innervation of the articular capsule. J Bone Joint Surg Br 32:84, 1950. 43. Offierski CM, MacNab I: Hip-spine syndrome. Spine 8:316-321, 1983. 44. Dewolfe VG, Lefevre FA, Humphries AW, et al: Intermittent claudication of the hip and the syndrome of chronic aorto-iliac thrombosis. Circulation 9:1-16, 1954. 45. Leriche R, Morel A: The syndrome of thrombotic obliteration of the aortic bifurcation. Am Surg 127:193, 1948. 46. Bellamy N, Buchanan WW, Goldsmith CH, et al: Validation study of WOMAC: A health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 15: 1833-1840, 1988. 47. Harris WH: Traumatic arthritis of the hip after dislocation and acetabular fractures: Treatment by mold arthroplasty: An end-result study using a new method of result evaluation. J Bone Joint Surg Am 51:737-755, 1969. 48. Harris WH: Etiology of osteoarthritis of the hip. Clin Orthop 213: 20-33, 1986. 49. Millis MB, Murphy SB, Poss R: Osteotomies about the hip for the prevention and treatment of osteoarthrosis. Instr Course Lect 45: 209-226, 1996. 50. Millis MB, Poss R, Murphy SB: Osteotomies of the hip in the prevention and treatment of osteoarthritis. Instr Course Lect 41:145-154, 1992. 51. Trendelenburg F: Dtsch Med Wschr (RSM translation) 21:21-24, 1895. 52. Thomas H: Hip, Knee and Ankle. Liverpool, Dobbs, 1976. 53. Laslett M: Pain provocation tests for diagnosis of sacroiliac joint pain. Aust J Physiother 52:229, 2006. 54. Laslett M, Aprill CN, McDonald B: Provocation sacroiliac joint tests have validity in the diagnosis of sacroiliac joint pain. Arch Phys Med Rehabil 87:874; author reply 874-875, 2006. 55. Burnett RS, Della Rocca GJ, Prather H, et al: Clinical presentation of patients with tears of the acetabular labrum. J Bone Joint Surg Am 88:1448-1457, 2006. 56. Toomayan GA, Holman WR, Major NM, et al: Sensitivity of MR arthrography in the evaluation of acetabular labral tears. AJR Am J Roentgenol 186:449-453, 2006. 57. Cunningham T, Jessel R, Zurakowski D, et al: Delayed gadoliniumenhanced magnetic resonance imaging of cartilage to predict early failure of Bernese periacetabular osteotomy for hip dysplasia. J Bone Joint Surg Am 88:1540-1548, 2006. 58. Byrd JW, Jones KS: Diagnostic accuracy of clinical assessment, magnetic resonance imaging, magnetic resonance arthrography, and intraarticular injection in hip arthroscopy patients. Am J Sports Med 2004; 32(7):1668-1674, 2004. 59. Illgen RL 2nd, Honkamp NJ, Weisman MH, et al: The diagnostic and predictive value of hip anesthetic arthrograms in selected patients before total hip arthroplasty. J Arthroplasty 21:724-730, 2006.

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Foot and Ankle Pain Mark D. Price  • Christopher P. Chiodo

KEY POINTS The differential diagnosis for foot and ankle pain is vast. Localizing symptoms by anatomic region helps to narrow this differential. On physical examination, most structures in the foot and ankle are immediately subcutaneous and readily palpable. Beyond medications, useful nonoperative treatments include bracing, shoewear modification, orthoses, and physical therapy. Most surgical procedures in foot and ankle surgery fall into one of the following categories: arthrodesis, arthroplasty, corrective osteotomy, ostectomy, tendon débridement and transfer, and synovectomy. Patient compliance and soft tissue integrity are important factors when considering surgery. Advances in medical management now make joint-sparing procedures possible in many patients with inflammatory arthritis who previously would have required arthrodesis.

Rheumatoid arthritis (RA) and other inflammatory arthritides are potentially devastating systemic diseases that often affect the foot and ankle. Foot and ankle pain is the presenting complaint in approximately 15% to 20% of patients newly diagnosed with RA.1 Of patients already diagnosed with RA, the prevalence of foot and ankle involvement has been estimated to be greater than 90%.2 Nevertheless, many patients with RA have foot and ankle pain secondary to a noninflammatory process, and many rheumatologists often see patients without inflammatory arthritis. This chapter provides a broad overview of foot and ankle pain, regardless of etiology. The evaluation of any patient with foot and ankle pain begins with a thorough history and physical examination. The location, timing, and duration of symptoms can help establish a specific diagnosis and help guide the subsequent course of treatment. Radiographs and advanced imaging modalities provide useful adjuncts in the evaluation of specific foot and ankle pathologies. The treatment of any disorder of the foot and ankle is aimed at alleviating pain and preserving function (i.e., maintaining the ambulatory status of the patient). Initial nonoperative treatment options include medical management, physical therapy, shoewear modification, orthoses, and bracing. These measures provide substantial relief for many individuals. For recalcitrant symptoms, surgical intervention may be necessary. Most surgical procedures fall into one of the following general categories: arthrodesis (joint fusion), arthroplasty (joint replacement), corrective osteotomy, ostectomy, tendon débridement and transfer, and synovectomy (joint or tendon).   Video available on the Expert Consult Premium Edition website.

FUNCTIONAL ANATOMY AND BIOMECHANICS The ankle, or tibiotalar, joint comprises the articulation between the foot (talus) and the lower leg (distal tibia and fibula). Its primary motion is plantar flexion and dorsiflexion in the sagittal plane. In addition, the articulation between the distal tibia and fibula allows a lesser degree of internal and external rotation to occur in the axial, or transverse, plane. The foot may be loosely divided into three anatomic regions: the forefoot, the midfoot, and the hindfoot. The forefoot consists of the toes and metatarsal bones, along with the metatarsophalangeal (MTP) and interphalangeal joints. The tarsometatarsal (TMT) joints connect the forefoot to the midfoot, which comprises the three cuneiform bones, the navicular, and the cuboid. Finally, the hindfoot, located below the ankle, consists of the talus and calcaneus. The joints of the hindfoot include the talocalcaneal (subtalar), talonavicular, and calcaneocuboid articulations. Forefoot and midfoot motion is primarily plantar flexion and dorsiflexion in the sagittal plane, with some secondary pronation and supination in the coronal plane and abduction/adduction in the axial plane. Motion in the hindfoot consists primarily of inversion/eversion in the coronal plane, with secondary internal/external rotation in the axial plane and plantar flexion/dorsiflexion in the sagittal plane. Rheumatoid arthritis affects the joints and the tendons of the foot and ankle. Articular synovial disease results in loss of cartilage and erosion of subchondral bone. In addition, such articular disease also leads to attenuation of the joint capsule and supporting collateral ligaments. As a result of these combined structural insults, rheumatoid arthritis often results in substantial deformity.

DIAGNOSTIC EVALUATION PHYSICAL EXAMINATION A thorough physical examination of the foot and ankle begins with gait analysis, which is done by observing the patient enter the examination room. Normal human gait is classically divided into four segments and two phases. The four segments are heel-strike, foot-flat, toe-off, and swing. Stance phase is the weight-bearing portion of the gait cycle. It extends from heel-strike to toe-off and constitutes roughly 60% of the cycle. Meanwhile, the swing phase of gait extends from toe-off to heel-strike and constitutes the remaining 40% of the gait cycle. Patients with an antalgic gait pattern have a shortened stance phase on the side of the affected limb, as they 643

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attempt to transfer their weight quickly to the nonpainful limb. In addition to an antalgic gait, foot and ankle pain often results in the avoidance of ground contact with the painful part of the foot. A further problem noted in stance phase is dynamic collapse of the medial longitudinal arch, most apparent at foot-flat and toe-off. After gait analysis, the foot and ankle are inspected with the patient sitting and standing. The location of swelling is usually well correlated with the joints involved (e.g., ankle versus talocalcaneal joint). Deformity also should be noted. Common foot and ankle deformities include hallux valgus, or bunion (Fig. 43-1), hammer toes, and flatfoot deformity (characterized by hindfoot valgus/forefoot abduction). Callosities develop over regions of increased pressure and are associated with deformity and fat pad atrophy. Rheumatoid nodules can appear anywhere on the foot, but are often found in areas of repetitive trauma (i.e., at the site of irritation from a tight shoe counter). Similarly, ulcerations appear in areas of repeated injury, such as those found in tight-fitting shoes. Finally, wear patterns on shoes should be noted. As Hoppenfeld3 observed, “A deformed foot can deform any good shoe; in fact, in many cases the shoe is a literal showcase for certain disorders.” After inspection, the foot and ankle are thoroughly palpated. The dorsum of the foot and ankle has little overlying musculature. Many of the bones and tendons are immediately subcutaneous, and a great deal of information can be gained from palpating these structures. It is helpful to palpate the foot and ankle by anatomic location (i.e., forefoot, midfoot, hindfoot, anterior and posterior ankle). In the forefoot, the first metatarsal head and MTP joint can be palpated at the base of the hallux (great toe), at the medial aspect of the “ball” of the foot. Proceeding laterally, the lesser metatarsal heads and MTP joints can be sequentially palpated. In patients with RA or nonarthritic metatarsalgia, such palpation often reveals tenderness, synovitis, and swelling. In the second and third MTP joints, sagittal

Figure 43-1  Clinical photograph of hallux valgus deformity.

plane instability often results from attenuation of the plantar joint capsule. This can be appreciated by gently translating the second and third toes dorsally. In the hindfoot, the calcaneus is readily palpable, and its various parts can be palpated individually. Tenderness over the posterior aspect of this bone may indicate Achilles tendinitis, whereas pain over the medial tubercle (palpable on the medial plantar surface) may indicate plantar fasciitis. Tenderness over sinus tarsi of the hindfoot (located laterally, just anterior and distal to the tip of the fibula) indicates talocalcaneal joint pathology. In the ankle joint proper, tenderness over the anterior joint line usually correlates with ankle joint pathology. After inspection and palpation, range of motion analysis is performed. Passive range of motion of the ankle is normally 10 to 20 degrees of dorsiflexion and 40 to 50 degrees of plantar flexion. Normal hindfoot inversion and eversion are each approximately 5 degrees. The first MTP joint should have approximately 45 degrees of plantar flexion (flexion) and 70 to 90 degrees of dorsiflexion (extension). Deviations from these norms should be noted as part of the standard workup. IMAGING Despite the abundant availability of advanced imaging modalities such as magnetic resonance imaging (MRI) and computed tomography (CT), radiographs remain the imaging mainstay in the evaluation of foot and ankle pain. Weight-bearing images should be obtained whenever possible because joint space narrowing and deformity may not be apparent in non–weight-bearing images. Standard images consist of weight-bearing anteroposterior, lateral, and oblique views of the foot and anteroposterior, mortise, and lateral views of the ankle. MRI provides reliable imaging of soft tissue structures and is integral to the evaluation of foot and ankle pain. MRI is especially crucial in the evaluation of synovitis, tendinitis, tendinosis, and bursitis (Fig. 43-2).4 CT scan5 and nuclear

Figure 43-2  Axial MR image of ankle showing posterior tibial tendon degeneration and synovitis.

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scintigraphy6 also are used in the evaluation of foot and ankle pain. Either method is helpful in delineating arthritis and postoperatively evaluating the results of joint fusion surgery. Ultrasonography is gaining popularity in some centers, especially when used to evaluate tendon integrity. The results are largely technique dependent, however, with minimization of artifacts being a concern. Ultrasound is difficult to use in preoperative planning because important landmarks are often not well imaged.7 Anesthetic arthrograms can be extremely useful adjuncts in diagnosing foot and ankle pain in patients with degenerative and inflammatory arthritis. Given the complex and crowded anatomy of the foot and ankle, it is sometimes difficult to determine precisely which joint is symptomatic, or if more than one joint is diseased. With an anesthetic arthrogram, a mixture composed of a steroid, anesthetic, and contrast material is injected under fluoroscopic guidance into a joint. This allows the clinician to determine more precisely whether or not the injected joint is a significant pain generator.8

COMMON CAUSES OF ANKLE PAIN From a diagnostic standpoint, it is useful for the clinician to conceptualize ankle pain based on anatomic location. This approach applies to patients with and without arthritis and helps to make a long differential list more manageable. Conditions affecting the foot and ankle and their correlation with anatomic location are summarized in Table 43-1. ANTERIOR AND CENTRAL ANKLE PAIN Anterior and central ankle pain is often the result of intraarticular pathology. The reason for this is that anteriorly the ankle joint is not shielded by the malleoli and is immediately subcutaneous. With the exception of the anterior tibial tendon, the extensor tendons that cross the joint are not prone to the development of tendinitis and tendinosis. Spur and osteophyte formation are often seen in the anterior ankle and localized to the superior talar neck and anterior distal tibia. Nonarthritic spurs do occur in the absence of degenerative and inflammatory arthritis, especially in active individuals who have a history of chronic ankle instability. Clinically, anterior spurs and osteophytes may result in symptoms of “impingement,” with anterior joint line pain, swelling, and tenderness. Patients specifically note pain with ankle dorsiflexion, such as when they walk up stairs or an incline. On physical examination, there may be anterior tenderness or pain or both with terminal passive dorsiflexion. Patients with more advanced global ankle arthritis, whether degenerative or inflammatory, typically present with either anterior or central pain. “Start-up” symptoms are common. Radiographs are essential to differentiate between anterior impingement and more global arthritis. Two other bony causes of central ankle pain, stress fracture and osteochondral defect, should always be considered. Stress fractures are commonly seen in patients with inflammatory arthropathy secondary to periarticular and generalized osteopenia. An osteochondral defect is a focal defect in the articular cartilage and subchondral bone. These lesions are encountered more commonly in younger

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Table 43-1  Differential Diagnosis of Foot   and Ankle Pain Based on Anatomic Location Location

Differential Diagnosis

Hallux and first MTP joint

Arthritis, hallux valgus, hallux rigidus, sesamoid disorders

Lesser toes and MTP joints

Lesser toe deformities, MTP instability, metatarsalgia, Morton’s neuroma, bunionette

Midfoot

Arthritis, accessory navicular,   osteonecrosis, peroneal tendinitis, posterior tibial tendinitis, fifth metatarsal stress fracture

Hindfoot

Arthritis, posterior tibial tendinitis and dysfunction

Heel

Plantar fasciitis, Achilles tendinitis, nerve entrapment, calcaneal stress fracture

Anterior ankle

Arthritis, impingement,   osteochondral defect

Posterior ankle

Achilles tendinitis/tendinosis, bursitis

Posterolateral ankle

Stress fracture, peroneal tendon pathology (tendinitis, tear, instability)

Posteromedial ankle

Posterior tibial tendinitis/  dysfunction, FHL/FDL tendinitis, tarsal tunnel syndrome

FHL/FDL, flexor hallucis longus/flexor digitorum longus; MTP, metatar­ sophalangeal.

patients ­without inflammatory arthritis. Although a history of trauma is often present, many osteochondral defects are idiopathic or attributed to the ill-defined concept of “repetitive microtrauma.” Of the tendons that cross the front of the ankle joint, the anterior tibial tendon is the most prone to developing tendinitis or tendinosis. Nevertheless, the incidence of anterior tibial tendon pathology is much lower compared with other tendons such as the Achilles. With anterior tibial tendinitis or tendinosis, a visible fullness is usually present. Tendon dysfunction or rupture may result in a foot-slap or steppage gait pattern. POSTERIOR JOINT PAIN Posterior ankle pain usually originates from the Achilles tendon, its insertion onto the calcaneal tuberosity, and two associated bursae in this region. The Achilles tendon is the largest tendon in the body. It lacks a true synovial lining. Isolated Achilles tendinitis is uncommon. In most instances, Achilles pain results from degenerative tendinosis, with or without an overlying tendinitis. Although associated intratendinous spur formation is common, Achilles spurs are a manifestation of associated tendon degeneration. Spur excision also frequently entails tendon débridement, reconstruction, and transfer. The Achilles tendon is protected by two distinct bursae. A more superficial bursa is immediately subcutaneous and becomes inflamed primarily with irritation from ill-fitting shoes with a tight counter (“pump bump”). The “retrocalcaneal” bursa is a larger structure that lies deep to the Achilles tendon. Inflammation of this structure often accompanies

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Achilles tendinitis/tendinosis. It also may be irritated by an enlarged posterior superior calcaneal tuberosity, sometimes referred to as a Haglund’s deformity. MEDIAL AND LATERAL ANKLE PAIN As with anterior, central, and posterior ankle pain, the origin of medial or lateral ankle pain also is anatomically based. On the medial side, pain directly over the medial malleolus should alert the clinician to the possibility of a stress fracture. Pain anterior to the medial malleolus is usually articular in nature. Pain posterior to the medial malleolus is often caused by inflammation or degeneration (or both) of the posteromedial flexor tendons, including the posterior tibial tendon and the flexor hallucis longus and flexor digitorum longus tendons. The posterior tibial tendon is the largest and strongest of the posteromedial flexor tendons. Its primary function is to invert the hindfoot and support the medial longitudinal arch of the foot. Longstanding synovitis and dysfunction of this tendon ultimately may lead to collapse of the arch and the development of an acquired flatfoot deformity. Finally, tarsal tunnel syndrome is another cause of posteromedial ankle pain. This disorder is believed to represent an entrapment neuropathy of the tibial nerve in the tarsal tunnel. Patients typically complain of pain that radiates into the plantar foot. On examination, percussion of the tarsal tunnel reproduces these symptoms (Tinel’s sign). On the lateral side of the ankle, pain directly over the lateral malleolus may be caused by a stress fracture. Similar to the medial side, pain anterior to the lateral malleolus is usually articular in nature. Finally, pain posterior to this lateral malleolus usually indicates peroneal tendon pathology. In patients with and without inflammatory arthritis, the peroneal tendons may be affected by tenosynovitis, longitudinal “split” tears, and chronic tendon instability. With the last-mentioned, the tendons sublux over the posterolateral edge of the fibula, causing pain and attritional tearing.

COMMON CAUSES OF FOOT PAIN FOREFOOT PAIN The forefoot region is a common location of foot pain. Patients with RA are particularly prone to symptoms9 because inflammation and progressive MTP synovitis eventually lead to capsular distention and destruction.10 Eventually, there may be loss of collateral ligament stability and, finally, destruction of the articular cartilage and bone (Fig. 43-3). It is helpful to subdivide the forefoot further into two regions: (1) the hallux and first MTP joint and (2) the “lesser” (i.e., second through fifth) toes and MTP joints. Several disorders frequently affect the hallux and first MTP joint. The hallux valgus deformity, or bunion, is commonly encountered in patients with and without inflammatory arthritis (see Fig. 43-1). In RA, where the incidence of hallux valgus has been estimated to be 70%,9 progression of this deformity may be accelerated further by loss of support from the adjacent lesser MTP joints. Hallux pain without deformity may be caused by degenerative arthritis, commonly referred to as hallux rigidus. Alternatively, it may be caused

by one of several sesamoid disorders, including sesamoiditis, osteonecrosis, fracture, and arthritis. In the lesser toes, three common deformities can cause pain: claw toes, hammer toes, and mallet toes. Potential etiologies of these deformities include arthritis, trauma, nerve/ muscle imbalance, and chronic use of shoes with inadequate toe boxes. In the lesser MTP joints, instability may result from mechanical causes or inflammatory disease. A particularly common mechanical cause of MTP instability is a relatively long second metatarsal, which increases the cyclical loads of the MTP joint. With MTP instability, dorsiflexion forces at toe-off can lead to progressive subluxation and dorsal dislocation. With this, the metatarsal head is prone to forming keratotic skin lesions that can ulcerate. Lesser MTP joint subluxation has been reported to be 70% with a concomitant incidence of pressure sores in approximately 30% of those patients.10 Metatarsalgia is a general term used to denote pain under the lesser metatarsal heads. There are several causes of metatarsalgia. With a gastrocnemius contracture or tight Achilles tendon, the forefoot is prematurely loaded during the stance phase of gait. Alternatively, hammer toes and mallet toes can result in downward pressure on the metatarsal heads, leading to metatarsalgia. In elderly patients and patients with inflammatory arthritis, atrophy of the plantar fat pad of the forefoot also can result in metatarsalgia. In the lateral forefoot, two common causes of pain include Morton’s neuroma and bunionette. Morton’s neuroma typically occurs in between the third and fourth metatarsal heads and manifests with burning, aching, or shooting pain in this region. Symptoms are especially exacerbated with tight shoes. A bunionette is an angular deformity of the fifth toe, typically causing pain over the lateral aspect of the fifth metatarsal head. MIDFOOT PAIN In the midfoot, the most common cause of foot pain is arthritis at the TMT joints, and most frequently the first TMT joint on the medial side of the foot. If there is associated instability of the first TMT joint, repetitive stress can lead to dorsiflexion of the first metatarsal. Alternatively, midfoot arthritis can lead to an abduction deformity of the foot, where the forefoot and metatarsals deviate outward.9 Arthritis of the lateral (fourth and fifth) TMT joints is often asymptomatic. More commonly, lateral midfoot pain results from insertional peroneal tendinitis or a stress fracture of the fifth metatarsal. Simple palpation of these structures should allow one to distinguish readily between the two diagnoses. On the medial side of the midfoot, pain not due to arthritis may instead be secondary to an accessory navicular bone, osteonecrosis of the native navicular bone, and insertional posterior tibial tendinitis. HINDFOOT PAIN The three joints of the hindfoot (talonavicular, talocalcaneal, and calcaneocuboid) all may be affected by degenerative and inflammatory arthritis. In patients with RA, the overall prevalence of hindfoot involvement is 21% to 29%.5 The talonavicular joint is most often affected, followed by the talocalcaneal and calcaneocuboid joints. The incidence

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of hindfoot deformity in patients with RA of less than 5 years’ duration has been estimated to be 8% and increases to 25% in patients with RA longer than 5 years.11 Clinically, patients with talocalcaneal or calcaneocuboid arthritis complain of lateral hindfoot pain. Patients with arthritis and synovitis of the talonavicular joint complain of dorsal or medial pain. A common source of medial hindfoot pain in the general population and patients with inflammatory arthritis is posterior tibial tendinitis and dysfunction. The posterior tibial tendon runs along the posteromedial ankle and hindfoot and stabilizes the medial longitudinal arch. Inflammation, degeneration, and dysfunction of this tendon typically result in medial ankle and hindfoot pain. An associated flatfoot deformity, characterized by heel valgus and forefoot ­abduction, may be noted. HEEL PAIN Most heel pain can be attributed to one of four causes: plantar fasciitis, Achilles tendinosis, nerve entrapment, or calcaneal stress fracture. Plantar fasciitis typically causes inferior heel pain, worse when first getting up in the morning or getting up after sitting for a long time. Insertional Achilles tendinosis usually results in posterior heel pain, worse during or after exercise. Finally, entrapment of the first branch of the lateral plantar nerve (Baxter’s nerve) can be a source of medial heel pain and tenderness, whereas calcaneal stress fracture can produce medial and lateral symptoms. Calcaneal stress fracture usually can be distinguished by a positive “squeeze test,” with compression of both sides of the heel.

NONOPERATIVE TREATMENT Medical management is the cornerstone of treatment for most foot and ankle disorders. With RA, many of the current recommendations for operative treatment may soon

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Figure 43-3  A and B, Preoperative (A) and postoperative (B) anteroposterior radiographs of hallux valgus deformity with lesser metatarsophalangeal joint erosions treated by fusion and lesser metatarsal head resections.

be modified given the alteration of disease progression with current medical regimens.12 The most common medical management still consists of nonsteroidal anti-inflammatory drugs, steroids, and disease-modifying antirheumatic drugs. Although each of these drug classes has done much to alleviate patient suffering, they have an impact on the surgical management of rheumatic disease. There is concern about lower fusion rates in the setting of nonsteroidal antiinflammatory drugs and increased infection rates in the setting of steroids or disease-modifying antirheumatic drugs.13,14 Patients who have been on long-term steroids are at risk for postoperative adrenal insufficiency and may require perioperative corticosteroids.15 Close communication and collaboration between the rheumatologist and surgeon is essential to good outcomes. Beyond medications, shoewear modification should not be overlooked because it often has profound benefits for patients with foot and ankle pain. Shoes should be examined in the clinic to ensure that they can accommodate a patient’s deformity. Patients often feel best in shoes with a deep, wide toe box, a firm heel counter, and soft heel. Wellconstructed walking or jogging shoes usually provide sufficient room for mild-to-moderate deformities. It is helpful to provide patients with a list of suitable manufacturers when making such recommendations. Often it is necessary to prescribe a custom orthotic insert for patients with more moderate deformities. It is typically necessary to remove the insole of the shoe to make room for the orthotic insert. Most walking or jogging shoes suffice. Generally, custom orthoses can be divided into rigid, semirigid, and softer accommodative devices. Rigid and semirigid orthoses usually are used to correct supple deformities and should be used with caution in patients with arthritis.16 More commonly, these patients, especially if they have RA, benefit from accommodative orthoses (i.e., orthoses made of softer material that can be molded to “accommodate” a deformity).17 Accommodative orthoses can be modified

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f­urther by incorporating a “relief” under a deformity, further unloading it. When sending patients for orthoses, it is best to provide the orthotist with a prescription that includes the patient’s precise diagnosis (e.g., metatarsalgia) and the type of orthosis and any modifications desired (e.g., a “custom accommodative orthosis with a relief under the lesser metatarsal heads”).18 Injections of a mixture of anesthetic and corticosteroid to areas of inflammation or bursitis are useful in the treatment of inflammatory and noninflammatory conditions affecting the foot and ankle. In the foot and ankle, such injections must be judiciously employed, however. Most importantly, injections into and around tendons should be avoided. Because of the forces associated with weight bearing and ambulation, these tendons are under substantial load. The injection of a corticosteroid near or directly into a tendon can adversely affect the biomechanical properties of the tendon, ultimately leading to rupture.19 A further precaution is to avoid corticosteroid injections into the lesser MTPs when there is evidence of joint instability (manifested by deviation on radiographs or instability on physical examination). Such injections can lead to further attenuation of the joint capsule and result in frank joint dislocation.

OPERATIVE TREATMENT If symptoms persist despite nonoperative management, surgical intervention should be considered. Two important factors must be taken into account when deciding whether or not to proceed with surgery. First, the soft tissues and vascular status must be assessed carefully. Both may be compromised and negatively affect outcome. Second, the ability of patients to comply with the postoperative regimen (e.g., being able to use crutches and remain non–weight bearing if necessary) must be considered. Even limited noncompliance can lead to a poor outcome, especially in fusion surgery. As noted earlier, most surgical procedures fall into one of the following categories: arthrodesis (joint fusion), arthroplasty (joint replacement), corrective osteotomy, ostectomy, tendon débridement and transfer, and synovectomy (joint or tendon). Arthrodesis is a surgical cornerstone for arthritis of the foot and ankle. With an arthrodesis procedure, the two sides of the joint are roughened with a burr or small chisel. Next, the two bones to be fused are compressed and fixed together, usually with one or more screws (see Fig. 43-3B). In the weeks and months after surgery, the body is “tricked” into thinking that there is a fracture present at the fusion site and heals this with bone. The two bones become one and are considered fused. Fusion surgery offers reliable pain relief in most patients. One concern with fusion surgery is the loss of motion. For the patient, however, this usually results in only mild functional compromise. To the untrained eye, there is remarkably little change in gait. Commonly performed fusions include ankle arthro­ desis, isolated hindfoot fusions, triple arthrodesis, midfoot arthrodesis, and arthrodesis of the first MTP joint. A triple arthrodesis involves fusion of the talocalcaneal, talonavicular, and calcaneocuboid joints. Together, these joints allow coronal plane motion and are most important when walking on uneven ground. Fusion remains the “gold standard” for patients with degenerative and inflammatory ankle arthritis. If there is

minimal deformity and no loss of bone stock, ankle fusion surgery may be performed arthroscopically or through a mini-open approach. These techniques involve less soft tissue dissection and stripping, minimizing loss of bony perfusion. Nevertheless, the time period for which the patient must remain non–weight bearing (6 to 12 weeks) remains the same. The success rate of ankle fusion surgery in patients with RA is generally 85% or greater. Although the osteopenia associated with the disease can compromise fixation, it also theoretically can enhance fusion because there is less sclerotic subchondral bone. In the hindfoot, fusion surgery may be performed on one or more of the three joints of this part of the foot (i.e., the talocalcaneal, talonavicular, and calcaneocuboid joints). If only one of these joints is diseased, an isolated fusion of this joint is acceptable.20 This procedure reduces surgical morbidity and the extent of the procedure. Nevertheless, with fusion of just one of the joints of the hindfoot, motion in the other joints is reduced.21 If more than one joint is diseased, a double or triple arthrodesis is necessary. In the midfoot, fusion surgery results in negligible loss of motion because the joints of the midfoot normally have less than 10 degrees of motion. With osteoarthritis and inflammatory arthritis, symptoms most often are limited to the medial (first through third) TMT joints. The lateral (fourth and fifth) TMT joints are infrequently symptomatic, even in the setting of advanced radiographic changes. In the forefoot, fusion surgery is indicated only for the first MTP joint. This procedure is used for arthrosis and advanced hallux valgus (bunion) deformities. When the first MTP joint is fused, it is positioned in a slightly dorsiflexed position to facilitate ambulation. With MTP fusion in 47 feet, Coughlin22 reported 96% good-to-excellent results and 100% fusion at an average 6.2-year follow-up. Fusion surgery generally provides reliable pain relief and a stable, plantigrade foot. Nevertheless, the loss of motion of the fused joint can lead to increased motion and altered biomechanics at adjacent joints. This alteration ultimately may lead to arthritic changes in these joints.23 Fusion surgery may lead to subtle, albeit real changes in gait.24 Finally, the minimal ramifications of fusing just one joint may become much greater in the setting of a subsequent fusion in either the ipsilateral or the contralateral limb. Such concerns drive many researchers to work toward improving joint replacement surgery (arthroplasty) in the foot and ankle. Most notably, total ankle replacement surgery continues to evolve and remains a controversial topic among orthopaedic surgeons. Although many orthopaedic surgeons perform ankle replacement surgery, many do not or do so on a limited basis. To this end, the U.S. Food and Drug Administration currently approves only two ankle prostheses for implantation. Long-term survival data as published for hip and knee arthroplasty are not yet available. The main advantage of ankle arthroplasty is preservation of motion. Its main two disadvantages are technical complexity and the difficulty with subsequent fusion if the procedure fails. Generally, ankle replacement surgery is indicated for late middle-age and elderly individuals with low functional demands and minimal deformity. Bilateral disease and concomitant ipsilateral hindfoot fusion increase the benefits afforded by arthroplasty. The paradox of ankle replacement surgery remains as follows: Ankle replacement

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is contraindicated in young patients for whom preservation of motion is most important. Arthroplasty is more commonly performed in older patients for whom preservation of motion is less important, and who would do well with a fusion. Nevertheless, total ankle replacement surgery continues to evolve, and reported success rates with modern designs continue to improve (Fig. 43-4).25 In the foot, arthroplasty is performed by some surgeons for the first MTP joint. The relevant literature is still conflicted, however. Although there were some encouraging early results with arthroplasty, other studies have shown high rates of implant failure and loosening secondary to synovitis from Silastic particle wear.25-27 Advanced deformity, often present in patients with RA and inflammatory arthritis, is considered to be a relative contraindication to first MTP joint arthroplasty. Nevertheless, new implant designs may hold increased promise. Generally, these implants are lower profile and resect less bone, which also makes it easier to perform a subsequent fusion, if necessary. Corrective osteotomies are used primarily for two reasons in the treatment of arthritis: to correct deformity and to redistribute forces on a joint or the terminal aspect of a bone. Examples of osteotomies to correct deformity include calcaneal osteotomies for pes planovalgus and metatarsal osteotomies for hallux valgus. Previously, patients with RA and concomitant pes planovalgus or hallux valgus underwent fusion surgery. With advances in medical management of the disease, however, it is reasonable to attempt joint preservation surgery in patients who have mild-to-moderate disease, good soft tissues, and flexible deformities. Examples of osteotomies to redistribute forces include tibial osteotomies in the setting of eccentric ankle arthritis and metatarsal osteotomies in the setting of metatarsalgia. Patients requiring surgery for ankle RA previously underwent fusion surgery only, and patients requiring surgery

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for metatarsalgia underwent metatarsal head resection. Advances in medical management of the disease allow joint preservation osteotomies to be considered, however. This is especially the case for metatarsalgia, which is common in patients with RA, yet increasingly does not entail frank dislocation or articular erosion. Some patients with early arthritis or chronic ankle instability may present with symptoms of mechanical impingement from anterior ankle spurs or osteophytes. In cases without global joint destruction, surgical resection of the spurs, or cheilectomy, is a reasonable treatment. Although no studies have examined cheilectomy in RA specifically, patients with less severe erosive changes tend to be more satisfied with the results of cheilectomy.28 Some clinicians believe that early synovectomy of either the affected joint or the tendon may help halt the progress of joint destruction in RA. For patients whose symptoms persist despite nonoperative treatment, synovectomy can provide substantial pain relief.29 When considering synovectomy of an arthritic joint, there should be preservation of the articular cartilage. Similarly, tenosynovectomy is most reliable when performed on tendons with little or no underlying tendinosis.

SUMMARY Foot and ankle pain is a prevalent and potentially debilitating problem for many patients with and without inflammatory arthritis. A proper history and physical examination, performed in conjunction with appropriate imaging modalities, are essential for establishing an ­accurate diagnosis. Conceptualizing the various causes of foot and ankle pain according to anatomic location narrows the differential diagnosis and allows the clinician to take a categorical approach to the diagnostic process. Nonoperative modalities, such as medications, bracing, ­physical therapy, orthoses, and shoewear modification, relieve pain and maintain function for many individuals. For ­ recalcitrant symptoms, substantial relief may be afforded by ­surgical intervention. REFERENCES

Figure 43-4  Anteroposterior ankle radiograph of a total ankle arthroplasty.

  1. Vanio E: Rheumatoid foot: Clinical study with pathological and roentgenological comments. Ann Chir Gynaecol Fenniae 45(S): 1-107, 1956.   2. Flemming A, Crown JM, Corbett M: Early rheumatoid disease, I: Onset. Ann Rheum Dis 35:357-360, 1976.   3. Hoppenfeld S: Physical Examination of the Spine and Extremities. Norwalk, Conn, Appleton & Lange, 1976.   4. Boutry N, Flipo RM, Cotten A: MR imaging appearance of rheumatoid arthritis in the foot. Semin Musculoskelet Radiol 9:199-209, 2005.   5. Seltzer SE, Weismann BN, Braunstein EM, et al: Computed tomography of the hindfoot with rheumatoid arthritis. Arthritis Rheum 28:1234-1242, 1985.   6. Groshar D, Gorenberg M, Ben-Haim S, et al: Lower extremity scintigraphy: The foot and ankle. Semin Nucl Med 28:62-77, 1998.   7. Riente L, Delle Sedie A, Iagnocco A, et al: Ultrasound imaging for the rheumatologist, V: Ultrasonography of the ankle and foot. Clin Exp Rheumatol 24:493-498, 2006.   8. Khoury NK, el-Khoury GY, Saltzman CL, et al: Intraarticular foot and ankle injections to identify source of pain before arthrodesis. AJR Am J Roentgenol 167:669-673, 1996.   9. Vidigal E, Jacoby RK, Dixon AS, et al: The foot in chronic rheumatoid arthritis. Ann Rheum Dis 34:292-297, 1975.

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10. Jaakkola JI, Mann RA: A review of rheumatoid arthritis affecting the foot and ankle. Foot Ankle Int 25:866-874, 2004. 11. Spiegel TM, Spiegel JS: Rheumatoid arthritis in the foot and ankle— diagnosis, pathology and treatment. Foot Ankle 2:318-324, 1982. 12. Matteson EL: Current treatment strategies for rheumatoid arthritis. Mayo Clin Proc 75:69-74, 2000. 13. Conn DL, Lim SS: New role for an old friend: Prednisone is a diseasemodifying agent in early rheumatoid arthritis. Curr Opin Rheumatol 15:192-196, 2003. 14. Mohan AK, Cote TR, Siegel JN, et al: Infectious complications of biologic treatment of rheumatoid arthritis. Curr Opin Rheumatol 15: 179-184, 2003. 15. Coursin DB, Wood KE: Corticosteroid supplementation for adrenal insufficiency. JAMA 287:236-240, 2002. 16. Clark H, Rome K, Plant M, et al: A critical review of foot orthoses in the rheumatoid arthritic foot. Rheumatology 45:239-245, 2006. 17. Woodburn J, Barker S, Helliwell PS: A randomised controlled trial of foot orthoses in rheumatoid arthritis. J Rheumatol 29:13771383, 2002. 18. Magalhaes E, Davitt M, Filho DJ, et al: The effect of foot orthoses in rheumatoid arthritis. Rheumatology 45:449-453, 2006. 19. Hugate R, Pennypacker J, Saunders M, et al: The effects of intratendinous and retrocalcaneal intrabursal injections of corticosteroid on the biomechanical properties of rabbit Achilles tendons. J Bone Joint Surg Am 86:794-801, 2004.

20. Chiodo CP, Martin T, Wilson MG: A technique for isolated arthro­ desis for inflammatory arthritis of the talonavicular joint. Foot Ankle Int 21:307-310, 2000. 21. Astion DJ, Deland JT, Otis JC, et al: Motion of the hindfoot after simulated arthrodesis. J Bone Joint Surg Am 79:241-246, 1997. 22. Coughlin M: Rheumatoid forefoot reconstruction: A long term followup study. J Bone Joint Surg Am 82:322-341, 2000. 23. Coester LM, Saltzman CL, Leupold J, et al: Long-term results following ankle arthrodesis for post-traumatic arthritis. J Bone Joint Surg Am 83:219-228, 2001. 24. Thomas R, Daniels TR, Parker K: Gait analysis and functional outcomes following ankle arthrodesis for isolated ankle arthritis. J Bone Joint Surg Am 88:526-535, 2006. 25. Deheer PA: The case against first metatarsal phalangeal joint implant arthroplasty. Clin Podiatr Med Surg 23:709-723, 2006. 26. Bommireddy R, Singh SK, Sharma P, et al: Long term followup of Silastic joint replacement of the first metatarsophalangeal joint. Foot 12:151-155, 2003. 27. Shankar NS: Silastic single-stem implants in the treatment of hallus rigidus. Foot Ankle Int 16:487-491, 1995. 28. Hattrup SJ, Johnson KA: Subjective results of hallux rigidus treatment with cheilectomy. Clin Orthop 226:182-191, 1988. 29. Aho H, Halonen P: Synovectomy of the MTP joints in rheumatoid arthritis. Acta Orthop Scand Suppl 243:1, 1991.

44

Hand and Wrist Pain CARRIE R. SWIGART

KEY POINTS

DeQuervain’s disease, inflammation of the extensor pollicis brevis and abductor pollicis longus tendons in the first dorsal extensor compartment, is common in women and is associated with repetitive hand activities, such as caring for an infant.

similar symptom patterns despite varying pathologies. A precise knowledge of the anatomy of the hand and wrist often eliminates several diagnostic considerations on the basis of the physical examination alone. The history of the illness and the examination also help to narrow further investigation by enabling the physician to choose appropriate additional diagnostic tests better. Several common sites of pain in the hand and wrist and their corresponding leading diagnoses are illustrated in Figure 44-1. Pain in one location can have multiple etiologies depending on the patient profile and the history of the problem. A thorough review of the pertinent regional ­anatomy is important to help differentiate successfully the many possible causes of hand and wrist pain.

Painful osteoarthritis involving the carpometacarpal joint of the thumb usually can be treated successfully by splinting.

HISTORY

Patients with carpal tunnel syndrome typically present with nocturnal paresthesias associated with intermittent pain or paresthesia during the day. Ganglia are mucin-filled cysts arising from joint capsules or tendon sheaths. If they are particularly symptomatic, ­corticosteroid injections may be tried, but surgical excision may be necessary to effect a cure. Tendinitis of the extensor pollicis longus tendon can be ­particularly dangerous because of the risk of tendon rupture.

Trigger fingers, caused by thickening of the A1 retinacular pulley in the palm, usually can be treated by corticosteroid injections and splinting.

The multiple functions that the hand performs in daily life are usually taken for granted until they become affected by disease or injury. Depending on the nature of the disorder, patients have different capacities to adapt. Patients presenting with pain and dysfunction of the hand or wrist or both represent a wide spectrum, diverse in age, occupations, and avocations. These patients have a broad range of medical conditions that may or may not be related to their current problem. Each patient has a different story to tell about his or her hand and wrist and why he or she is seeking treatment. It is up to the clinician to sort out these various factors, some of which may seem confounding, and determine the most appropriate diagnosis and course of treatment. This chapter presents guidelines that are useful in the evaluation of patients presenting with hand and wrist pain. Complete coverage of all of the various conditions that can affect the hand and wrist is beyond the scope of this chapter. Instead, the conditions discussed include the most common pathologies seen by general practitioners and hand surgeons. The conditions are grouped by their anatomic area to include pain localized to the volar, dorsal, radial, or ulnar wrist; the base of the thumb; and the palm and digits.

PATIENT EVALUATION ANATOMY The complex anatomy of the hand and wrist involves many structures interacting in close proximity to one another. ­ Several different diagnoses can manifest with

Important patient factors include age, sex, hand dominance, occupation, and hobbies or sports. When determining the history of the problem, a history of recent or distant trauma should be sought, and an estimation of the severity of the trauma should be noted. Next, questions about the duration and frequency of the pain and the intensity and quality should be addressed. The pain of degenerative arthritis is often described as a localized “toothache”-type pain, which is always present at a low level and increases with activity, whereas the pain of tendinitis may be sharp, poorly localized, and present only with activity. Rheumatoid arthritis manifests initially with hand and wrist involvement in 25% of patients and is characterized by joint effusion, with bilateral hand and wrist involvement and morning stiffness. Nighttime symptoms of a burning-type pain in the hand and wrist that are exacerbated by arm position are often associated with nerve entrapment syndromes. Specific activities that either cause pain or alleviate it also should be noted. Arthritis at the base of the thumb, or first carpometacarpal joint, is often aggravated by such activities as opening jars, turning doorknobs, and doing needlework or other hobbies. PHYSICAL EXAMINATION A thorough examination of the involved extremity and comparison with the uninvolved extremity are essential. Attention should be paid to abnormalities of the more proximal joints of the elbow and shoulder and the cervical spine. As the differential diagnosis narrows, the examination should be tailored as needed to include or eliminate any possible systemic etiologies. As with other musculoskeletal examinations, a complete record of the range of motion of the involved joints and comparison measurements of the opposite side should be made. Any difference between active and 651

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Carpal tunnel syndrome Ulnar nerve entrapment FCR/FCU tendinitis Hamate fracture TFCC injury/ulnar impaction syndrome ECU tendinopathy Lunotriquetral ligament injury Pisotriquetral arthritis

A

B

Ganglion Carpal boss Extensor tendinopathies .. Kienbock’s disease Scapholunate interosseous ligament injury Gout and inflammatory arthritis DeQuervain’s disease and intersection syndrome Basal joint pathology Volar ganglia Scaphoid fracture/nonunion Figure 44-1  A, Palmar and ulnar view of the hand and wrist with areas of pain and tenderness marked with their corresponding leading differential diagnoses. B, Dorsal and radial view of the hand and wrist with areas of pain and tenderness marked with their corresponding leading differential diagnoses. ECU, extensor carpi ulnaris; FCR/FCU, flexor carpi radialis/flexor carpi ulnaris; TFCC, triangular fibrocartilage complex.

passive motion should be noted. Careful palpation for the site of maximal tenderness is important in differentiating the source of pain and is particularly important when trying to exclude possible factors of secondary gain. Measurements of grip and pinch strength also are helpful in many situations as a diagnostic aid and a baseline measurement to follow for improvement. Many provocative maneuvers are useful in differentiating etiologies; these are discussed with the specific pathology with which they are associated. IMAGING STUDIES Technologic advances have increased the availability of imaging studies for the hand and wrist. Improvements in magnetic resonance imaging (MRI) resolution using small joint coils allow more precise imaging of small structures in the hand and wrist. Advancements in ultrasound technology have allowed this tool to be increasingly used in the diagnosis of musculoskeletal complaints. With the multitude of ancillary studies available, it is important to be selective in using these to establish or refute diagnostic possibilities. In this era of cost containment, imaging studies should be

used most often to confirm a diagnosis rather than to find one. An understanding of the advantages and limitations of each study is necessary to enable using them to their fullest potential. Plain radiographs are the easiest and most readily available study that can be obtained in most offices. A routine hand or wrist series, including anteroposterior, lateral, and oblique views, is a useful screening tool, but often lacks the specificity required. Depending on the suspected diagnosis, there are many available special views. These are discussed with the specific diagnoses to which they pertain later in this chapter. If further detail of the bony anatomy is required, computed tomography (CT) is the best available tool today. The most common uses for CT in the hand and wrist include evaluation of intra-articular fractures of the distal radius and metacarpals, scaphoid fractures and nonunions, and intraosseous cysts or tumors.1,2 Advances in ultrasound and MRI technology have enhanced the ability to evaluate the soft tissue structures of the hand and wrist. Smaller ultrasound probes with higher resolution have made it possible to visualize and differentiate structures such as flexor tendons, ganglion cysts, and ligaments. Doppler ultrasound can help to differentiate vascular disorders of the hand. MRI technology is constantly improving and allowing for new uses in the hand and wrist. By altering the parameters of this test, information about anatomy and physiology can be obtained.3 Specific uses of these tests and others such as arthrography and bone scans are addressed with the diagnoses for which they are most useful. ADDITIONAL DIAGNOSTIC TESTS Neurodiagnostic Tests Neurodiagnostic tests, including nerve conduction studies and electromyography, are useful in the diagnosis of suspected neurologic disorders of the upper extremity. Specifying the type and nature of examination required enhances the information gained by these studies. If a nerve compression syndrome such as carpal or cubital tunnel syndrome is suspected, nerve conduction studies may be sufficient without the added cost and patient discomfort of formal electromyography testing. Nerve conduction studies evaluate the speed of conduction of motor and sensory nerves across a set distance at a specific location and compare this with established normal values. A decrease in the speed of nerve conduction, as evidenced by an increase in the latency, is seen with localized nerve compression and is shown in several different nerves concomitantly in demyelinating diseases, such as multiple sclerosis. When more severe nerve injuries are suspected, or if there is clinical evidence of muscle weakness or atrophy, an electromyogram can be useful to delineate better the extent of the process or rule out a myopathic process.4 Injections and Aspirations The use of injections and aspirations can be therapeutic and diagnostic. A so-called lidocaine challenge can be used to discriminate between different diagnoses when placed

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precisely in one joint or painful area. Corticosteroids can be given selectively in conjunction with the local anesthetic for more lasting relief and in some cases can be curative.5-11 Some of the most common sites for injection are the A1 pulley region of the finger for trigger finger, the carpal canal for carpal tunnel syndrome, and the first dorsal compartment of the wrist for deQuervain’s disease. Aspiration of joints or other fluid collections such as ganglia can yield vital diagnostic information and can be therapeutic. If infection is suspected, aspiration should be used to obtain a sample of joint fluid for Gram stain, cell count, and culture. Diagnoses such as gout and pseudogout can be confirmed by crystal analysis under polarized light. Many ganglia and retinacular cysts can be treated temporarily or permanently with simple aspiration.12,13 Arthroscopy Direct visualization of a joint via arthroscopy can be an invaluable diagnostic tool. Despite the increasing sensitivity of imaging techniques such as MRI, arthroscopy provides a dynamic evaluation that static imaging cannot provide.14 Since the first published report of a series of cases by Roth and colleagues in 1988,15 it has become the “gold standard” for evaluation of chronic wrist pain.16-18 With new surgical techniques being developed, surgeons often can proceed directly to the definitive treatment using arthroscopy entirely or in part.19-24

COMMON ETIOLOGIES FOR HAND AND WRIST PAIN WRIST PAIN—PALMAR Carpal Tunnel Syndrome Carpal tunnel syndrome is the most commonly diagnosed compression neuropathy in the upper extremity. It usually occurs as an isolated phenomenon, but symptoms of carpal tunnel syndrome can accompany many systemic diseases, such as congestive heart failure, multiple myeloma, and tuberculosis.25-28 More commonly, carpal tunnel syndrome is associated with conditions such as pregnancy, diabetes, obesity, rheumatoid arthritis, and gout.29-39 The classic constellation of symptoms consists of weakness or clumsiness of the hand; paresthesias or hypesthesias in the thumb, index, and long fingers; and nocturnal paresthesias in the affected digits. Patients often may complain of forearm and elbow pain that is aggravated by activities, but is poorly localized and aching in nature. Occasionally, more proximal symptoms, such as shoulder pain, are the main presenting complaint.40 Past reports have indicated a 3:1 prevalence of carpal tunnel syndrome in women. Approximately half of patients are 40 to 60 years old, although carpal tunnel syndrome occasionally has been diagnosed in children.41,42 The diagnosis of carpal tunnel syndrome is usually clinical. Tinel’s sign, shown by radiating paresthesias in the median nerve distribution with gentle percussion over the volar wrist, indicates nerve irritation. Reproduction of symptoms with wrist flexion, as described by Phalen,43 and with the carpal compression test, as described by Durkan,44 has been shown to be more specific.45 Decreased sensibility and thenar atrophy are late signs seen in advanced median

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nerve entrapment. Bilateral electrodiagnostic tests, specifically nerve conduction velocity testing, should be used to confirm the diagnosis, particularly in patients claiming a compensable injury or in patients with atypical signs or symptoms. Prolonged motor and sensory latencies across the carpal canal confirm pathologic compression of the median nerve.46-48 In patients with classic clinical findings, a study found that carpal tunnel syndrome could be diagnosed with a high degree of accuracy on clinical grounds alone, and that the addition of electrodiagnostic tests did not increase the accuracy.49 When attempting to differentiate carpal tunnel syndrome from more proximal nerve entrapments such as cervical root compression or thoracic outlet syndrome, the addition of electromyography of the cervical paraspinal muscles and proximal conduction tests (H reflex, f waves) can be useful.50 Conservative treatment for carpal tunnel syndrome consists of splinting of the wrist in neutral position and consideration of oral nonsteroidal anti-inflammatory drugs (NSAIDs) for pain control. Splinting should be used sparingly during the workday to prevent secondary muscle weakness and fatigue, but is best prescribed to prevent provocative wrist positioning at night. The splint should not hold the wrist in extension beyond 10 degrees. Although splinting may be beneficial for relief of symptoms in cases of mild compression, its long-term effectiveness is limited.51 The use of vitamin B6 (100 to 200 mg/day) has been helpful in some cases, but its efficacy has not been confirmed in a randomized trial. The popularity of injections of corticosteroid in the treatment of carpal tunnel syndrome has waxed and waned over the last half century. Although it has been shown to be quite effective in the short-term, the long-term efficacy is mixed.52-54 Also, injections have been associated with exacerbation of the condition and permanent median nerve injury if performed incorrectly.55,56 For these reasons, injections are most often indicated in cases when the condition is thought to be temporary, such as with pregnancy, or if surgery has to be deferred because of a medical condition or major life event. Surgical release is indicated for patients with confirmed carpal tunnel syndrome who have failed a course of conservative treatment. In patients who exhibit late findings of objective sensory loss or thenar atrophy, early surgery should be recommended. Ulnar Nerve Entrapment—Cubital Tunnel Syndrome Entrapment of the ulnar nerve as it passes through the cubital tunnel just posterior to the medial epicondyle of the elbow can manifest with symptoms localized to the ulnar border of the hand. There also may be associated medial forearm pain and irritability of the ulnar nerve at the elbow. Presenting symptoms usually consist of paresthesias or numbness or both in the small and ring fingers. Percussion of the nerve in the cubital tunnel elicits Tinel’s sign. Prolonged elbow flexion reproduces the symptoms. In contrast to carpal tunnel syndrome, it is not unusual for patients to present with early atrophy of the intrinsics, most easily appreciated in the first dorsal interosseous muscle. Electrodiagnostic studies can help to confirm the diagnosis and differentiate cubital tunnel syndrome from more distal compression of the ulnar nerve in Guyon’s canal

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(see later). If malalignment of the elbow is present, or the patient relates a history of childhood trauma, radiographs should be obtained to rule out a supracondylar or epicondylar malunion. So-called tardy ulnar nerve palsy can develop years after a supracondylar fracture of the elbow.57 Conservative treatment includes strategies to help the patient avoid having the elbow flexed for prolonged periods, particularly at night. Soft, or semirigid, elbow splints prevent elbow flexion beyond 50 to 70 degrees. Medial elbow pads can be used if the patient’s job or hobbies requires resting the medial elbow on a hard surface. NSAIDs can be beneficial in acute or traumatic cases. Surgical decompression of the nerve is indicated if a patient fails to obtain relief from splinting and activity modification, or if there is clinical or electrodiagnostic evidence of muscle denervation. Ulnar Nerve Entrapment—Guyon’s Canal In 1861, Guyon58 published a description of the contents of an anatomic canal at the wrist. The distal branches of the ulnar nerve and the ulnar artery pass through this space. As it exits the canal, the ulnar nerve divides into its sensory and motor branches. Compression of the nerve within or proximal to the canal usually manifests with a combination of sensory and motor symptoms in the ulnar nerve distribution. Patients complain of numbness and paresthesias of the palmar aspect of the ring and small fingers. Motor symptoms usually are described as a cramping weakness with grasping and pinching. As with median neuropathy, atrophy of the intrinsics and objective sensory loss are late findings. In contrast to carpal tunnel syndrome, in which patients usually have an ill-defined onset of symptoms, ulnar nerve compression in the canal of Guyon is often of more acute onset. It can be associated with repeated blunt trauma,59,61 a fracture of the hamate or the metacarpal bases, or occasionally a fracture of the distal radius.62,63 Space-occupying lesions, such as a ganglion, lipoma, or anomalous muscle, also can cause compression.64-68 Because of the difference in etiology, this nerve entrapment syndrome is often not amenable to conservative treatment. If there is an anatomic lesion, such as a fracture or a mass, this must be addressed. If repetitive blunt trauma is the cause, without associated fracture or arterial thrombosis, splinting and activity modification can alleviate the symptoms.

calcific tendinitis and is most commonly seen around the flexor carpi ulnaris tendon.70,71 Hamate Fracture An uncommon and underdiagnosed etiology of palmar pain in young, active individuals is a fracture of the hook of the hamate. These fractures can occur from a fall on an extended wrist, a “dubbed” golf shot, or from forcefully striking a ball with a club or bat. Plain radiographs of the wrist are usually read as normal. The condition should be established and treated expeditiously because it may lead to ulnar nerve entrapment, ulnar artery thrombosis, or rupture of flexor tendons.72 Pain in the base of the palm overlying the hamate is the most common presenting symptom. Often, the pain is present only with the activity that caused the fracture, such as driving a golf ball or swinging a bat. Because of the proximity of the ulnar nerve, patients also can have sensory and motor symptoms of distal ulnar neuropathy. Occasionally, in the acute setting, vascular complaints, such as cold intolerance or frank ischemia, from ulnar artery thrombosis can be the presenting condition. A carpal tunnel view, obtained with the wrist in a hyperextended position, may show the fracture (Fig. 44-2A). Alternatively, a selective CT scan through the hamate is a more accurate way to confirm the diagnosis (Fig. 44-2B).73 If diagnosed within 2 to 3 weeks of injury, casting should be attempted to allow the fracture to heal.74 If this fails, or if the fracture is diagnosed late, surgical treatment is indicated, and most authors favor excision of the hook followed by a gradual return to activities.75-78

A

Flexor Carpi Radialis and Flexor Carpi Ulnaris Tendinitis Similar to other tendinopathies around the wrist, irritation of the wrist flexors occurs with stress of the wrist in a particular position. Activities that require forced wrist flexion for prolonged periods or with repetition put patients at risk for inflammation around the flexor carpi radialis tendon69 or the flexor carpi ulnaris tendon or both. The condition manifests with tenderness along the course of the tendon, especially near its insertion. Wrist flexion against resistance with radial or ulnar deviation reproduces the symptoms. Treatment consists of splinting and rest, elimination of activities that cause pain, and oral NSAIDs. Injection of corticosteroid into the flexor carpi radialis or flexor carpi ulnaris sheath may be curative. Sharp pain, associated with an intense inflammatory localized reaction, is suggestive of

B Figure 44-2  A, Carpal tunnel view radiograph showing a hamate hook fracture (arrow). B, Coronal CT scan showing the same hamate hook ­fracture.

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WRIST PAIN—DORSAL Ganglion Ganglia account for 50% to 70% of all soft tissue tumors of the hand and wrist. Of these, 60% to 70% occur around the dorsal wrist. These mucin-filled cysts usually arise from an adjacent joint capsule or tendon sheath. The most common site of origin is the scapholunate ligament, and the main body of the cyst may be located elsewhere on the dorsum of the wrist and attached to this ligament by a long pedicle. Although most ganglia occur as a well-circumscribed and obvious soft mass, some are subtler and are evident only with the wrist in marked volar flexion. As a result of their characteristic appearance, ganglia are not often misdiagnosed, but should be differentiated from the less well-demarcated swelling of extensor tenosynovitis, lipomas, and other hand tumors. Plain radiographs are usually normal, but occasionally show an intraosseous cyst or an osteoarthritic joint. Some ganglia may not be clinically apparent and are known as “occult” ganglia. Ultrasound and MRI have been shown to be useful in the diagnosis of these ganglia.79,80 Not all ganglia are painful, and the tendency is for smaller ganglia to be more painful. Patients may present with complaints of wrist weakness or simply because of the cosmetic appearance of the cyst. In approximately 10% of cases, there is evidence of associated trauma to the wrist. The ganglia may appear suddenly or develop over many months. Intermittent complete resorption followed by reappearance months or years later is common. Most conservative measures, such as splinting and rest, have only a temporary effect on ganglia. They tend to diminish in size with rest and enlarge with increased activity. Spontaneous rupture is common, and at one time attempting to rupture the cyst with a heavy object, such as a large book, was recommended as treatment. Aspiration can be performed, but has mixed results because of the thick gelatinous nature of the fluid within the cyst. Even if adequate decompression of the cyst can be achieved, reaccumulation of the fluid usually occurs. Aspiration in conjunction with irrigation or injection of corticosteroids can be effective in alleviating the symptoms for varying periods of time.12,13,81 Occasionally, a ganglion can become so large that it can interfere with the function of the wrist by limiting the motion, especially in extension. Pressure of the mass on the terminal branches of the posterior interosseous nerve may be painful. Excision is generally curative, but may result in short-term stiffness and some loss of terminal flexion secondary to surgical scarring. Occasionally, a patient desires excision of the cyst for cosmetic reasons. With proper excision, recurrence is less than 10%,82-84 but if the dissection is incomplete and fails to identify the origin of the cyst, recurrence rates can be 50%. Arthroscopic resection has been shown to be a safe and effective method of treating dorsal wrist ganglia.23,24 Carpal Boss Often confused with a dorsal ganglion, the carpal boss is a bony, nonmobile prominence on the dorsum of the wrist. It is an osteoarthritic spur that forms at the second or third carpometacarpal joints.85 The boss is most evident with the wrist in volar flexion. Patients usually present with pain and

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localized tenderness over the prominence. The condition is twice as common in women as in men, and most patients are in their 20s to 30s. It is not unusual for a small ganglion to be associated with the boss. Radiographs are best taken with the hand and wrist in 30 to 40 degrees of supination and 20 to 30 degrees of ulnar deviation to put the bony prominence on profile (the “carpal boss view”).86 Conservative treatment consists of rest, immobilization, NSAIDs, and occasionally injection with corticosteroids. If persistently painful despite these measures, surgical excision of the boss may be necessary, but is associated with a prolonged recovery and continued symptoms in a high percentage of patients. Extensor Tendinopathies The extensor pollicis longus (EPL) tendon can be irritated as it passes around Lister’s tubercle. This condition, in contrast to other tendinopathies around the wrist, carries a significant risk of tendon rupture. Early diagnosis and sometimes urgent operative treatment are necessary to prevent this complication. Localized pain, swelling, and tenderness are the hallmarks of this condition, and similar to other tendinopathies, initial treatment consists of decreased activity and splinting. A short course of oral anti-inflammatory medication can be useful in decreasing symptoms. Diagnostic injections with lidocaine can help to differentiate the condition from other causes of wrist pain, but corticosteroid injections are not routinely used in this condition because of a propensity for the EPL to rupture in chronic cases. A patient commonly may present with a rupture of the EPL without antecedent pain or swelling. There is a wellknown association of EPL rupture with fractures of the distal radius that likely occurs owing to a relative “watershed zone” of vascular supply within its tight retinacular sheath. Tendon rupture most often occurs with minimally displaced or nondisplaced fractures and can occur several weeks or months after the original injury.87-90 Individuals with rheumatoid arthritis and systemic lupus erythematosus are especially prone to rupture of the EPL and other tendons. Kienböck’s Disease Kienböck’s disease is so named for Kienböck,91 who first described in 1910 what he postulated were avascular changes in the lunate. Nearly a century later, the cause of this disease remains unclear; it is likely multifactorial. Kienböck’s disease should be suspected when a young adult presents with pain and stiffness of the wrist and swelling and tenderness around the region of the dorsal lunate. There is an increased propensity of the disease among patients with an ulna that is anatomically shorter than the radius (so-called ulnar negative variance). Radiographs are needed to confirm and stage the process. Kienböck’s disease is staged by the degree of fragmentation and collapse of the lunate, associated osteoarthritis, and carpal collapse in a system originally proposed by Stahl.92 In this system, the earliest sign of the disease is a linear or compression fracture in the lunate. Later stages show sclerosis of the lunate, followed by lunate collapse and a loss of carpal height. In the final stage, the carpus shows signs of diffuse osteoarthritis with complete collapse and fragmentation of the lunate (Fig. 44-3). With the increased sensitivity of MRI, it is possible to identify avascular changes within

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Figure 44-3  Advanced Kienböck’s disease, showing carpal collapse, intercarpal and radiocarpal arthrosis, and fragmentation of the lunate. A, Posteroanterior view. B, Lateral view.

A

the lunate before they become evident on plain radiographs. This is referred to as “stage zero” Kienböck’s disease. The treatment for Kienböck’s disease is largely surgical. Depending on the stage of the disease and the postulated etiology, several surgical procedures have been described. In early stages of the disease, when there is little lunate collapse and no osteoarthritis, the goal of surgery is to “unload” the lunate by redistributing articular contact forces and allow it to revascularize.93-96 The most common procedure is a radial shortening osteotomy, performed to neutralize ulnar variance. In later stages, various intercarpal arthrodeses have been used to readjust and maintain carpal height and alignment.97-99 Microsurgical techniques have been used more recently to revascularize the lunate with promising early results.100 Scapholunate Interosseous Ligament Injury The interosseous ligament between the scaphoid and the lunate is a stout structure, especially dorsally, and usually requires a significant force to cause disruption. The typical mechanism of injury is a fall onto the outstretched hand with the wrist extended. Early diagnosis is essential to prevent the late sequelae of carpal collapse. The key radiographic features of scapholunate dissociation (scapholunate interval widening) are shown in Figure 44-4. The anteroposterior view shows the scapholunate interval better than the posteroanterior view.101 Early surgical intervention is recommended with the goal of maintaining carpal alignment and prevention of an otherwise inevitable progression to carpal collapse and degenerative arthritis. Gout and Inflammatory Arthritis All of the inflammatory arthritides, including the crystalline arthropathies, can manifest as dorsal wrist pain. Approximately 25% of patients with a diagnosis of rheumatoid arthritis present initially with hand and wrist symptoms. The reader is referred to Chapters 87 and 88 for further details.

B

WRIST PAIN—ULNAR Triangular Fibrocartilage Complex Injury and Ulnocarpal Impaction Syndrome One of the most complex and confusing areas of the wrist from a diagnostic standpoint is the articulation of the ulna with the carpus. The triangular fibrocartilage complex (TFCC), so named by Palmer and Werner,102 comprises the articular disk itself and the immediately surrounding ulnocarpal ligaments. It can be injured by a variety of acute and chronic mechanisms. Hyperpronation and hypersupination of the carpus during forceful activities are the usual causes of acute injuries, whereas repetitive pronation and supination more often cause attritional changes in the TFCC. Careful physical examination is important to determine the origin of the pain and to try to discover the maneuver or wrist position that most closely reproduces the symptoms. The radius and ulna must remain congruent through a 190-degree arc.103 Limitation of motion and pain with pronation and supination are consistent with a tear of the supporting ligaments and resultant distal radioulnar joint (DRUJ) instability. If a sufficient portion of the stability has been lost, the ulna appears clinically dislocated or subluxated, and there is severe limitation of forearm rotation. Lateral radiographs of the wrist in neutral and full pronation and supination are not generally specific enough to confirm ulnar subluxation. To evaluate better the congruency of the DRUJ through its range of motion, and to assess for subtle subluxations, CT can be performed on both wrists simultaneously in positions of neutral, full pronation, and full supination.104-107 Tears of the TFCC may manifest with painful clicking during wrist rotation. Patients generally have localized tenderness on the midaxial border of the wrist and directly beneath the extensor carpi ulnaris tendon. If forced ulnar deviation of the wrist or gripping or both reproduce the patient’s symptoms, a degenerative tear of the central portion of the TFCC is more likely. The degenerative tear is

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Figure 44-4  Anteroposterior radiograph of the wrist showing scapholunate interosseous space widening, scaphoid foreshortening, and the cortical ring sign associated with scapholunate interosseous ligament disruption.

Figure 44-5  Posteroanterior radiograph of the wrist in neutral forearm rotation showing the method of measuring ulnar variance by drawing tangential lines to the distal ulna and distal radius. The space between these lines in millimeters is the ulnar variance. A positive value indicates the ulnar length is greater than the radial length.

frequently a component of the ulnocarpal impaction syndrome, a condition associated with higher than normal loads on the ulnar carpus secondary to a congenitally positive ulnar variance. Plain radiographs are most useful in determining ulnar variance and for ruling out fractures or arthritis as a cause of ulnar wrist pain. Because of the variable relationship of the radius and ulna depending on forearm rotation, it is important to take standardized films when measuring ulnar variance.108,109 A posteroanterior view of the wrist with the shoulder abducted to 90 degrees and the elbow flexed to 90 degrees shows the DRUJ in neutral forearm rotation and is easily reproducible (Fig. 44-5). Because the ulna lengthens relative to the radius during power grip, a radiograph in the same position during maximal grip best shows impaction of the ulna on the carpus. Ancillary studies for TFCC tears include three-compartmental arthrography and MRI. In arthrography, sequential injections of radiopaque dye are performed into the carpal joint, midcarpal joint, and DRUJ. The test is considered positive when the dye is seen leaking from one compartment to another. The site of the leak determines the location of the torn structure.110 Several studies have shown, however, that there are age-related attritional tears, which occur in the TFCC and other ligamentous structures of the wrist.111-113 Technologic advancements in MRI have improved the ability to visualize and diagnose abnormalities in the TFCC. MRI can be combined with arthrography in an MRI arthrogram to visualize better the TFCC and the intrinsic wrist ligaments. Peripheral detachments and central degenerative tears of the TFCC can be visualized. MRI remains highly operator-dependent and technique-dependent, and the studies should be interpreted in the context of the findings on physical examination.114 Patients presenting with pain localized to the ulnar side of the wrist often respond to simple splinting and rest. This conservative treatment and NSAIDs can be used effectively

while a workup is in progress. A course of rest and splinting, followed by a gradual return to activities, may completely alleviate ulnar-sided symptoms. Despite the advancements in imaging techniques, there is often no substitute for direct visualization of the ulnocarpal joint or DRUJ or both. Arthroscopy has become an invaluable diagnostic and surgical tool. Tears of the TFCC can be visualized and their clinical significance better determined. Arthroscopy, done in conjunction with fluoroscopy, can assess for instability of the DRUJ or intercarpal joints or both. Several surgical procedures can now be performed entirely or in part through the arthroscope.115,116 Extensor Carpi Ulnaris Tendinitis and Subluxation The extensor carpi ulnaris tendon can become irritated with forced pronation/supination activities, such as putting topspin on a tennis ball. In severe cases, the tendon can begin to sublux around the ulnar head as its restraining dorsal retinaculum becomes increasingly lax. Patients complain of pain with forceful rotation of the forearm, and sometimes there is an associated snapping of the extensor carpi ulnaris tendon. Early treatment consists of immobilization of the wrist and forearm to prevent rotation. Anti-inflammatory medication can help to decrease the inflammation more quickly. After an adequate period of rest, if the acute inflammation resolves, but the extensor carpi ulnaris tendon continues to be unstable, surgery may be indicated to reconstruct or release the sheath at the wrist. Lunotriquetral Ligament Injury Tears in the short, stout intraosseous ligament connecting the lunate and the triquetrum are uncommon and often difficult to diagnose. As with the aforementioned diagnoses, patients present with ulnar-sided wrist pain usually worsened by either pronation or supination. Forceful translation

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of the triquetrum against the lunate causes pain in affected individuals. If diagnosed within 3 to 4 weeks of injury, a short arm cast allows healing and eliminates symptoms. Chronic tears may lead to advanced carpal instability and collapse. MRI or wrist arthroscopy or both may be necessary to make the diagnosis. Treatment is predicated on the staging of instability and ranges from simple casting for acute instability to ligament reconstruction or intercarpal fusion for more advanced cases. Pisotriquetral Arthritis Degenerative changes in the pisotriquetral articulation usually are post-traumatic in nature. Patients may recall a fall onto the extended wrist with direct trauma to the ulnar side of the palm. Affected patients present with pain during passive wrist hyperextension and exacerbation with flexion against resistance. With palpation of the pisotriquetral joint, there is tenderness and often crepitus. As with many joints, splinting, NSAIDs, and occasionally injection with corticosteroid and lidocaine are the mainstays of conservative treatment. If this is inadequate to control the symptoms, surgical resection of the pisiform is indicated. WRIST PAIN—RADIAL AND BASE OF THUMB de Quervain’s Disease and Intersection Syndrome One of the most common sites of tendon irritation around the wrist is in the first dorsal extensor compartment, a phenomenon known as de Quervain’s disease. The tendons involved are the extensor pollicis brevis and the abductor pollicis longus. At the level of the radial styloid, these two tendons pass through an osteoligamentous tunnel composed of a shallow groove in the radius and an overlying ligament. Anatomic studies have shown that a high percentage of patients have a divided first dorsal compartment, and this can account for failure of conservative treatment and injections.117-119 Patients with de Quervain’s disease are typically women in their 30s and 40s, although men and women can develop the condition at any age. This is the most common tendinopathy to develop in women in the postpartum period because of the specific hand and wrist position requirements in the care of an infant. Any activity requiring repeated thumb abduction and extension in combination with wrist radial and ulnar deviation can aggravate this problem. Patients complain of pain along the course of these tendons with grasping activities. Clinically, there is tenderness along the affected compartment, and there may be swelling over the radial styloid. In severe cases, a creaking sound can be elicited with movement of the involved tendons. Finkelstein’s test of forced ulnar deviation of the wrist with the thumb clasped in the fisted palm is pathognomonic of the condition120,121 A less common condition that may occur in the same general location in the wrist is intersection syndrome. Although initially attributed to friction between the first and second dorsal compartment tendons, Grundberg and Reagan122 subsequently showed that the condition represented a tendinopathy of the radial wrist extensors within the second dorsal compartment.

The primary treatment for de Quervain’s disease and inter­ section syndrome is rest with splinting. For de Quervain’s disease, the wrist should be held in slight extension and the thumb abducted in a thumb spica splint to the level of the interphalangeal joint. Immobilization of the wrist alone, in approximately 15 degrees of extension, is usually adequate for intersection syndrome. The addition of a 2- to 4-week course of anti-inflammatory medication also can be helpful. Phonophoresis with a cortisone cream and injection of the compartment with cortisone are second-line treatments if immobilization alone fails to give adequate relief. Injection of corticosteroid into the affected first dorsal compartment is curative for de Quervain’s disease in approximately 75% of patients.123 Surgery may be indicated for patients who do not respond to a course of conservative treatment. For de Quervain’s disease and intersection syndrome, surgery consists of releasing the stenotic retinacular sheath of the involved compartment. Basal Joint Arthropathy Inflammation and pain related to the carpometacarpal joint of the thumb are common and can occur at any age. In younger patients, instability secondary to ligamentous laxity is associated with joint subluxation and abnormal cartilage wear and may lead to pain with mechanical activities. In women older than 45 years, studies show 25% have radiographic evidence of degeneration of the basal joint.124,125 Patients generally present with pain at the base of the thumb, worsened by pinch and highly dexterous activities. They often report difficulty with tasks such as opening jars and bottles, turning doorknobs and keys, and other activities of daily living. The thumb carpometacarpal joint may be swollen and subluxed and is generally tender to palpation. The joint should be assessed for the presence of increased laxity by manual subluxation of the base of the metacarpal out of the trapezial “saddle” with radial and volar force. With advanced degenerative disease, crepitus is sometimes appreciated. Radiographs should be obtained to determine the stage of the disease. The addition of a basal joint posteroanterior stress film, in which the patient presses the tips of the thumbs together firmly with the nail plates facing up, is helpful in assessing joint subluxation (Fig. 44-6). The most commonly

Figure 44-6  “Basal joint stress” radiograph showing stage three  degeneration of the left thumb and stage four degeneration of the right thumb.

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used staging system was developed by Eaton and Glickel126 and is based on the degree of involvement of the trapeziometacarpal joint and whether or not the scaphotrapezial joint is involved.126 Advancing stages show increased subluxation of the basal joint, with development of joint space narrowing, osteophytes, and subchondral cysts. Stage 4 implies the presence of pantrapezial ­degenerative ­disease. Regardless of the stage of the disease, the first line of treatment is immobilization of the thumb metacarpal, leaving the interphalangeal joint free. Splinting has been shown to alleviate the symptoms of carpometacarpal joint inflammation in more than 50% of patients.127 NSAIDs can be a useful adjunct. Injections of corticosteroid and local anesthetic mixture are quite effective, but usually for a limited time. Although therapy for thenar muscle strengthening has been advocated, especially in early stages, its benefits are minimal, and it can occasionally aggravate the ­problem. Many patients are able to manage their symptoms with a combination of splinting, medications, corticosteroid injections, and activity modification. If this combination is insufficient, surgery may be indicated in young patients to reconstruct the ligaments that stabilize the metacarpal base. In patients with advanced degenerative changes and whose symptoms continue to interfere sufficiently with their daily activities, surgery is indicated to replace the joint with a prosthetic device or to excise the trapezium and reconstruct the soft tissue supports. Volar Ganglion Another common location for ganglia is the radial side of the volar wrist. Ganglia typically originate from the scaphotrapezial joint, but become superficial and are clinically evident at or near the distal wrist crease over the flexor carpi radialis tendon. Volar ganglia can occur in close proximity to the radial artery and should be differentiated from a radial artery aneursym. Aspiration, if attempted, should be performed carefully to avoid vascular injury, and surgery should be preceded by performance of an Allen test to document patent ulnar arterial flow. Volar ganglia are associated with a higher recurrence rate and a higher complication rate than their dorsal ­counterparts.128 Scaphoid Fracture and Nonunion Occasionally, a young or middle-aged patient presents with a nonunited scaphoid fracture without recollection of a traumatic incident. When evaluating a relatively young patient with pain at the base of the thumb, wrist swelling in the region of the anatomic snuffbox, and a decreased range of motion of the wrist, plain radiographs and a specialized ulnar-deviation “navicular” x-ray should be obtained to rule out scaphoid pathology. In patients in whom a scaphoid nonunion has been present for a significant period, secondary changes in carpal alignment and joint degeneration have usually occurred. Although splint or cast immobilization can be tried, surgical repair of the scaphoid or other wrist salvage procedure is usually required.

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PALM Trigger Finger Painful clicking and locking of the digits in flexion is one of the most common causes of pain in the hand. This condition, caused by a thickening of the A1 retinacular pulley in the palm, is commonly known as trigger finger. The thumb is the most commonly affected digit, followed by the ring and long fingers.129 Patients may present with isolated activityrelated pain in the proximal interphalangeal joint without frank clicking or locking. Early clicking is felt as a snapping sensation during digital motion and is frequently worst on awakening. As the condition progresses, the digital range of motion can be reduced and secondary proximal interphalangeal joint contractures develop. The final stage is a locked trigger finger that cannot be straightened actively. Primary trigger finger is the most common type, found most often in middle-aged individuals. Triggering of the thumb is four times more frequent in women than in men.5 Secondary triggering is seen in association with such diseases as rheumatoid arthritis, diabetes, and gout. In this type, trigger fingers are often multiple and can coexist with other stenosing tendinopathies, such as de Quervain’s disease or carpal tunnel syndrome. Congenital or developmental triggering can be identified in children and is much less common. Similar to in adults, the thumb is most commonly affected, but in contrast to adults, these often present with the interphalangeal joint locked in flexion. Nonoperative treatment of this condition consists primarily of splinting and local steroid injections. In adults, injection of steroid into the tendon sheath has been shown to be quite effective.5,6,130 Injection is used infrequently in infants or children. When nonoperative treatments fail to give lasting relief, surgical treatment consists of longitudinal division of the A1 pulley at the level of the metacarpal head. It is a simple procedure that yields reliable and permanent results with few complications. Retinacular Cysts Retinacular ganglion cysts can occur in conjunction with a triggering digit or in isolation. They are located at the base of the digit over the A1 pulley as a discrete, firm, pea-sized nodule. They originate from the flexor tendon sheath or annular pulleys and contain synovial fluid. Patients usually complain of pain with gripping objects or with direct pressure over the cyst. A retinacular cyst is most easily treated initially by needle decompression, with care to avoid injury to the sensory nerves that lie immediately adjacent to the flexor tendon and associated cyst. Approximately 50% recur after aspiration, and surgical resection may be required. DIGITS Mallet Finger Mallet finger refers to a loss of terminal extension of the distal interphalangeal joint of the digit and can be classified as bony or soft tissue depending on where the disruption in the extensor mechanism occurred. Mallet fingers can occur with minimal trauma, such as tucking in bed sheets, and may not be recalled by the patient. This sometimes leads to a delay

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in diagnosis and treatment. When a patient presents with a digit that droops at the distal interphalangeal joint and cannot be actively extended, but has full passive motion, a radiograph should be obtained to determine if there is an associated fracture of the distal phalanx. An extension splint is the treatment of choice for bony and soft tissue mallet fingers. The distal interphalangeal joint should be held in full extension, and care should be taken not to force the distal interphalangeal joint into hyperextension to prevent dorsal skin ischemia and necrosis. Splinting is employed full time for 6 weeks. The patient should not remove the splint for showering or any other activity, but may change the splint carefully for skin care, provided that the joint is maintained in extension throughout. Proximal interphalangeal flexion exercises are initiated from the outset and are important to help reset the tension in the extensor mechanism. Gentle distal interphalangeal flexion exercises are begun at 6 weeks, and splinting is decreased to nighttime between 6 and 8 weeks. Patients usually can expect a small extension lag, on the order of 5 degrees, and a return of most of their flexion.

Figure 44-7  Dorsal view of a digit with an as yet clinically inapparent mucous cyst and the corresponding groove deformity of the nail plate.

Osteoarthritis of the Digits Osteoarthritis of the interphalangeal joints is extremely common in older patients and is most often manifested as Heberden’s nodes of the distal interphalangeal joint. Despite gross deformities, pain and dysfunction may be minimal. A mucous cyst may appear in association with degenerative arthritis. Mucous cysts appear on the dorsum of the joint and can cause nail growth deformities owing to pressure on the germinal matrix (Fig. 44-7). The changes in nail growth may precede clinical detection of the cyst. These cysts should not be aspirated with a needle because of the close proximity of the distal interphalangeal joint and the risk of secondary joint infection. Treatment consists of distal interphalangeal joint immobilization to control symptoms or surgical excision of the cyst and in particular the underlying osteophytic spurs. Tumors Benign bone tumors, such as simple bone cysts and enchondromas, are common in the phalanges. These usually cause no symptoms and frequently are diagnosed as incidental findings on routine hand radiographs. Enchondromas are most commonly located in the metaphysis of the proximal phalanx and may lead to fracture with minimal trauma as a result of weakening of the bone structure. If a pathologic fracture occurs, nonoperative treatment is indicated until the fracture heals. The bone tumor subsequently can be addressed with curettage and bone grafting. Occasionally, because of malalignment, earlier surgical intervention becomes necessary. Many soft tissue tumors can occur in the hand and digits. Some common benign tumors are giant cell tumors of the tendon sheath, lipomas, and glomus tumors. Lipomas and giant cell tumors of the tendon sheath manifest clinically as painless, slow-growing masses in the palm and digits. Surgical excision is necessary for diagnosis. Glomus tumors arise from the pericytes in the fingertip or subungual area and typically present with intermittent sharp pain in the

fingertip. These vascular tumors become intensely symptomatic when the hand is exposed to cold temperatures, owing to abnormal arteriovenous shunting through the hypertrophic glomus system. Surgical excision is generally curative and should be preceded by MRI to rule out multifocal sites. Infection The most common infection in the hand is the paronychia. It involves the fold of tissue surrounding the fingernail. Staphylococcus aureus is the usual pathogen, introduced by a hangnail, a manicure instrument, or nail biting. Patients present with an exquisitely painful and erythematous swelling involving a part of the nail fold. Occasionally, the infection can progress to surround the nail in a horseshoe fashion and undermine the nail plate. If seen early, within the first 24 to 48 hours, oral antibiotics and local treatment of the finger with warm soaks can be effective. Superficial abscesses can be drained with a sharp blade through the thin skin without requiring local anesthesia. Larger or more chronic infections require surgical drainage. An infection of the distal pulp of the fingertip, known as a felon, is a particular problem in diabetic patients. This infection differs from other subcutaneous infections because of the vertical fibrous septa that divide and stabilize the pulp of the fingertip. Often patients have had some recent penetrating injury in the area. Because of the tightly constrained area of the infection, patients present with an intensely painful fingertip. There may be an area of “pointing” over the abscess. Surgical drainage is required followed by soaks and oral antibiotics, and intravenous antibiotics are generally recommended in diabetic patients. Although similar in appearance to a paronychia, herpetic whitlow is caused by herpes simplex virus and must be differentiated from other fingertip infections because of a radically different treatment protocol.131,132 Whitlow was common among dental hygienists before the widespread use of gloves for all health care workers. As with bacterial ­infections, the

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area becomes painful and erythematous; local tenderness is much less severe, however. Diagnosis is by clinical presentation and history. If seen early, vesicles can be ruptured for fluid analysis and viral culture. Nonoperative treatment with oral antiviral agents is recommended. Other hand and digit infections, such as suppurative flexor tenosynovitis, deep space infections of the palm, pyogenic arthritis, infections from bite wounds, and osteomyelitis, should be evaluated initially with radiographs of the hand and appropriate blood work. If possible, antibiotics should be withheld until definitive cultures are obtained from the affected area. Antibiotics should be administered intravenously, and the hand and wrist should be immobilized. Most infections require surgical drainage for definitive treatment. REFERENCES   1. Metz VM, Gilula LA: Imaging techniques for distal radius fractures and related injuries. Orthop Clin North Am 24:217-228, 1993.   2. Larsen CF, Brondum V, Wienholtz G, et al: An algorithm for acute wrist trauma: A systematic approach to diagnosis. J Hand Surg (Am) 18:207-212, 1993.   3. Schreibman KL, Freeland A, Gilula LA, et al: Imaging of the hand and wrist. Orthop Clin North Am 28:537-582, 1997.   4. Kaufman MA: Differential diagnosis and pitfalls in electrodiagnostic studies and special tests for diagnosing compressive neuropathies. Orthop Clin North Am 27:245-252, 1996.   5. Marks MR, Gunther SF: Efficacy of cortisone injection in treatment of trigger fingers and thumbs. J Hand Surg (Am) 14:722-727, 1989.   6. Newport ML, Lane LB, Stuchin SA: Treatment of trigger finger by steroid injection. J Hand Surg 15:748-750, 1990.   7. Freiberg A, Mulholland RS, Levine R: Nonoperative treatment of trigger fingers and thumbs. J Hand Surg (Am) 14:553-558, 1989.   8. Gelberman RH, Aronson D, Weisman MH: Carpal tunnel syndrome: Results of a prospective trial of steroid injection and splinting. J Bone Joint Surg 62:1181-1184, 1980.   9. Avci S, Yilmaz C, Sayli U: Comparison of nonsurgical treatment measures for de Quervain’s disease of pregnancy and lactation. J Hand Surg (Am) 27:322-324, 2002. 10. Lane LB, Boretz RS, Stuchin SA: Treatment of de Quervain’s disease: Role of conservative management. J Hand Surg (Am) 26:258-260, 2001. 11. Taras JS, Raphael JS, Pan WT, et al: Corticosteroid injections for trigger digits: Is intrasheath injection necessary? J Hand Surg (Am) 23:717-722, 1998. 12. Esteban JM, Oertel YC, Mendoza M, et al: Fine needle aspiration in the treatment of ganglion cysts. South Med J 79:691-693, 1986. 13. Richman JA, Gelberman RH, Engber WD, et al: Ganglions of the wrist and digits: Results of treatment by aspiration and cyst wall puncture. J Hand Surg (Am) 12:1041-1043, 1987. 14. Easterling KJ, Wolfe SW: Wrist arthroscopy: An overview. Contemp Orthop 24:21-30, 1992. 15. Roth JH, Poehling GG, Whipple TL: Arthroscopic surgery of the wrist. Instr Course Lect 37:183-194, 1988. 16. Adolfsson L: Arthroscopy for the diagnosis of post-traumatic wrist pain. J Hand Surg (Am) 17:46-50, 1992. 17. Koman LA, Poehling GG, Toby EB, et al: Chronic wrist pain: Indications for wrist arthroscopy. Arthroscopy 6:116-119, 1990. 18. Terrill RQ: Use of arthroscopy in the evaluation and treatment of chronic wrist pain. Hand Clin 10:593-603, 1994. 19. DeSmet L, Dauwe D, Fortems Y, et al: The value of wrist arthroscopy: An evaluation of 129 cases. J Hand Surg (Am) 21:210-212, 1996. 20. Kelly EP, Stanley JK: Arthroscopy of the wrist. J Hand Surg 15:236-242, 1990. 21. Poehling GP, Chabon SJ, Siegel DB: Diagnostic and operative arthroscopy. In Gelberman RH (ed): The Wrist: Master Techniques in Orthopedic Surgery. New York, Raven Press, 1994 pp 21-45. 22. Bienz T, Raphael JS: Arthroscopic resection of the dorsal ganglia of the wrist. Hand Clin 15:429-434, 1999. 23. Luchetti R, Badia A, Alfarano M, et al: Arthroscopic resection of dorsal wrist ganglia and treatment of recurrences. J Hand Surg (Am) 25B:38-40, 2000.

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24. Ho PC, Griffiths J, Lo WN, et al: Current treatment of ganglion of the wrist. Hand Surg 6:49-58, 2001. 25. Arnold AG: The carpal tunnel syndrome in congestive cardiac failure. Postgrad Med J 53:623, 1977. 26. Doll DC, Weiss RB: Unusual presentations of multiple myeloma. Postgrad Med 61:116-121, 1977. 27. Klofkorn RW, Steigerwald JC: Carpal tunnel syndrome as the initial manifestation of tuberculosis. Am J Med 60:583, 1976. 28. Mayers LB: Carpal tunnel syndrome secondary to tuberculosis. Arch Neurol 10:426, 1964. 29. Champion D: Gouty tenosynovitis and the carpal tunnel syndrome. Med J Aust 1:1030, 1969. 30. Gould JS, Wissinger HA: Carpal tunnel syndrome in pregnancy. South Med J 71:144-145, 1978. 31. Green EJ, Dilworth JH, Levitin PM: Tophacceous gout: An unusual cause of bilateral carpal tunnel syndrome. JAMA 237:2747-2748, 1977. 32. Leach RE, Odom JA: Systemic causes of the carpal tunnel syndrome. Postgrad Med 44:127-131, 1968. 33. Massey EW: Carpal tunnel syndrome in pregnancy. Obstet Gynecol Surg 33:145, 1978. 34. Michaelis LS: Stenosis of carpal tunnel, compression of median nerve, and flexor tendon sheaths, combines with rheumatoid arthritis elsewhere. Proc R Soc Med 43:414, 1950. 35. O’Hara LJ, Levin M: Carpal tunnel syndrome and gout. Arch Intern Med 120:180, 1967. 36. Phillips RS: Carpal tunnel syndrome as manifestation of systemic disease. Ann Rheum Dis 26:59, 1967. 37. Stallings SP, Kasdan ML, Soergel TM, et al: A case-control study of obesity as a risk factor for carpal tunnel syndrome in a population of 600 patients presenting for independent medical examination. J Hand Surg (Am) 22:211-215, 1997. 38. Karpitskaya Y, Novak CB, Mackinnon SE: Prevalence of smoking, obesity, diabetes mellitus, and thyroid disease in patients with carpal tunnel syndrome. Ann Plast Surg 48:269-273, 2002. 39. Mondelli M, Giannini F, Giacchi M: Carpal tunnel syndrome incidence in a general population. Neurology 58:289-294, 2002. 40. Kummel BM, Zazanis GA: Shoulder pain as the presenting complaint in carpal tunnel syndrome. Clin Orthop 83:41-47, 1972. 41. Lettin AWF: Carpal tunnel syndrome in childhood. J Bone Joint Surg 47:556-559, 1965. 42. al-Qattan MM, Thomson HG, Clarke HM: Carpal tunnel syndrome in children and adolescents with no history of trauma. J Hand Surg (Am) 21B:108-111, 1996. 43. Phalen GS: Spontaneous compression of the median nerve at the wrist. JAMA 145:1128, 1951. 44. Durkan JA: A new diagnostic test for carpal tunnel syndrome. J Bone Joint Surg 73:535-538, 1991. 45. Gonzalez del Pino J, Delgado-Martinez AD, Gonzalez Gonzalez I, et al: Value of the carpal compression test in the diagnosis of carpal tunnel syndrome. J Hand Surg (Am) 22:38-41, 1997. 46. Kemble F: Electrodiagnosis of the carpal tunnel syndrome. J Neurol Neurosurg Psychiatry 31:23, 1968. 47. Ludin HP, Lutschg J, Valsangiacomo F: Comparison of orthodromic and antidromic sensory nerve conduction, 1: Normals and patients with carpal tunnel syndrome. EEG EMG 8:173, 1977. 48. Richier HP, Thoden U: Early electroneurographic diagnosis of carpal tunnel syndrome. EEG EMG 8:187, 1977. 49. Szabo RM, Slater RR Jr, Farver TB, et al: The value of diagnostic testing in carpal tunnel syndrome. J Hand Surg (Am) 24:704-714, 1999. 50. Melvin JL, Schuckmann JA, Lanese RR: Diagnostic specificity of motor and sensory nerve conduction variables in the carpal tunnel syndrome. Arch Phys Med Rehabil 54:69, 1973. 51. Gerritsen AAM, deVet HCW, Scholten RJPM, et al: Splinting vs surgery in the treatment of carpal tunnel syndrome: A randomized controlled trial. JAMA 288:1245-1251, 2002. 52. Gonzalez MH, Bylak J: Steroid injection and splinting in the treatment of carpal tunnel syndrome. Orthopedics 24:479-481, 2001. 53. Irwin LR, Beckett R, Suman RK: Steroid injection for carpal tunnel syndrome. J Hand Surg (Am) 21B:355-357, 1996. 54. Irwin LR, Beckett R, Suman RK: Steroid injection for carpal tunnel syndrome. J Hand Surg (Am) 21:355-357, 1996. 55. Linskey ME, Segal R: Median nerve injury from local steroid injection for carpal tunnel syndrome. Neurosurgery 26:512-515, 1990.

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56. Tavares SP, Giddins GE: Nerve injury following steroid injection for carpal tunnel syndrome: A report of two cases. J Hand Surg (Am) 21:208-209, 1996. 57. Ogino T, Minami A, Fukada K: Tardy ulnar nerve palsy caused by cubitus varus deformity. J Hand Surg (Am) 11:352-356, 1986. 58. Guyon F: Note sur une disposition anatomique proper a la face anterieure do la region du poignet et non encores decritie par la docteur. Bull Soc Anat Paris 36:184-186, 1861. 59. Blunden R: Neuritis of deep branch of the ulnar nerve. J Bone Joint Surg 40:354, 1958. 60. Eckman PB, Perlstein G, Altrocchi PH: Ulnar neuropathy in bicycle riders. Arch Neurol 32:130-131, 1975. 61. Uriburu IJF, Morchio FJ, Marin JC: Compression syndrome of the deep branch of the ulnar nerve (piso-hamate hiatus syndrome). J Bone Joint Surg 58:145-147, 1976. 62. Poppi M, Padovani R, Martinelli P, et al: Fractures of the distal radius with ulnar nerve palsy. J Trauma 18:278-279, 1978. 63. Vance RM, Gelberman RH: Acute ulnar neuropathy with fractures at the wrist. J Bone Joint Surg 60:962-965, 1978. 64. Jeffery AK: Compression of the deep palmar branch of the ulnar nerve by an anomalous muscle. J Bone Joint Surg 53:718-723, 1971. 65. Kalisman M, Laborde K, Wolff TW: Ulnar nerve compression secondary to ulnar artery false aneurysm at the Guyon’s canal. J Hand Surg (Am) 7:137-139, 1982. 66. McFarland GB, Hoffer MM: Paralysis of the intrinsic muscles of the hand secondary to lipoma in Guyon’s canal. J Bone Joint Surg 53:375-376, 1971. 67. Richmond DA: Carpal ganglion with ulnar nerve compression. J Bone Joint Surg 45:513-515, 1963. 68. Toshima Y, Kimata Y: A case of ganglion causing paralysis of intrinsic muscles innervated by the ulnar nerve. J Bone Joint Surg 43:153, 1961. 69. Bishop AT, Gabel G, Carmichael SW: Flexor carpi radialis tendonitis, part I: Operative anatomy. J Bone Joint Surg 76:1009-1014, 1994. 70. Carroll RE, Sinton W, Garcia A: Acute calcium deposits in the hand. JAMA 157:422-426, 1955. 71. Moyer RA, Bush DC, Harrington TM: Acute calcific tendonitis of the hand and wrist: A report of 12 cases and a review of the literature. J Rheum 16:198-202, 1989. 72. Yang SS, Kalainov DM, Weiland AJ: Fracture of the hook of hamate with rupture of the flexor tendons of the small finger in a rheumatoid patient: A case report. J Hand Surg (Am) 21:916-917, 1996. 73. Kato H, Nakamura R, Horii E, et al: Diagnostic imaging for fracture of the hook of the hamate. Hand Surg 5:19-24, 2000. 74. Whalen JL, Bishop AT, Linscheid RL: Nonoperative treatment of acute hamate hook fractures. J Hand Surg (Am) 17:507-511, 1992. 75. Bishop AT, Bechenbaugh RD: Fracture of the hamate hook. J Hand Surg (Am) 13:863-868, 1988. 76. Carter PR, Eaton RG, Littler JW: Ununited fracture of the hook of the hamate. J Bone Joint Surg (Am) 59:583-588, 1977. 77. Stark HH, Chao EK, Zemel NP, et al: Fracture of the hook of the hamate. J Bone Joint Surg 71:1202-1207, 1989. 78. Stark HH, Jobe FW, Boyes JH, et al: Fracture of the hook of the hamate in athletes. J Bone Joint Surg 59:575-582, 1977. 79. Cardinal E, Buckwalter KA, Braunstein EM, et al: Occult dorsal carpal ganglion: Comparison of US and MR imaging. Radiology 193:259-262, 1994. 80. Vo P, Wright T, Hayden F, et al: Evaluating dorsal wrist pain: MRI diagnosis of occult dorsal wrist ganglion. J Hand Surg (Am) 20: 667-670, 1995. 81. Zubowicz VN, Ishii CH: Management of ganglion cysts of the hand by simple aspiration. J Hand Surg (Am) 12:618-620, 1987. 82. Angelides AC, Wallace PF: The dorsal ganglion of the wrist: Its pathogenesis, gross and microscopic anatomy, and surgical treatment. J Hand Surg (Am) 1:228-235, 1976. 83. Clay NR, Clement DA: The treatment of dorsal wrist ganglia by radical excision. J Hand Surg (Am) 13:187-191, 1988. 84. Janzon L, Niechajev IA: Wrist ganglia: Incidence and recurrence rate after operation. Scand J Plast Reconstr Surg 15:53-56, 1981. 85. Angelides AC: Ganglions of the hand and wrist. In Green DP (ed): Operative Hand Surgery. New York, Churchill Livingstone, 1993. 86. Cuono CB, Watson HK: The carpal boss: Surgical treatment and etiological considerations. Plast Reconstr Surg 63:88-93, 1979. 87. Bonatz E, Dramer TD, Masear VR: Rupture of the extensor pollicis longus tendon. Am J Orthop 25:118-122, 1996.

  88. Stahl S, Wolff TW: Delayed rupture of the extensor pollicis longus tendon after nonunion of a fracture of the dorsal radial tubercle. J Hand Surg (Am) 13:338-341, 1988.   89. Hove LM: Delayed rupture of the thumb extensor tendon: A 5-year study of 18 consecutive cases. Acta Orthop Scand 65:199-203, 1994.   90. Dawson WJ: Sports-induced spontaneous rupture of the extensor pollicis longus tendon. J Hand Surg (Am) 17:457-458, 1992.   91. Kienbock R: Uber Traumatische Malazie des Mondbeins und Kompression Fracturen. Fortschr Roentgenstrahlen 16:77-103, 1910.   92. Stahl F: On lunatomalacia (Keinbock’s disease): Clinical and roentgenological study, especially on its pathogenesis and late results of immobilization treatment. Acta Chir Scand 126(suppl):1-133, 1947.   93. Wada A, Miura H, Kubota H, et al: Radial closing wedge osteotomy for Kienbock’s disease: An over 10 year clinical and radiographic follow-up. J Hand Surg (Am) 27B:175-179, 2002.   94. Wintman BI, Imbriglia JE, Buterbaugh GA, et al: Operative treatment with radial shortening in Kienbock’s disease. Orthopedics 24:365-371, 2001.   95. Quenzer DE, Dobyns JH, Linscheid RL, et al: Radial recession osteotomy for Kienbock’s disease. J Hand Surg (Am) 22:386-395, 1997.   96. Nakamura R, Imaeda T, Miura T: Radial shortening for Kienbock’s disease: Factors affecting the operative result. J Hand Surg (Am) 15:40-45, 1990.   97. Oishi SN, Muzaffar AR, Carter PR: Treatment of Kienbock’s disease with capitohamate arthrodesis: Pain relief with minimal morbidity. Plast Reconstr Surg 109:1293-1300, 2002.   98. Watson HK, Monacelli DM, Milford RS, et al: Treatment of Kienbock’s disease with scaphotrapezio-trapezoid arthrodesis. J Hand Surg (Am) 21:9-15, 1996.   99. Chuinard RG, Zeman SC: Kienbock’s disease: An analysis and rationale for treatment by capitate-hamate fusion. Orthop Trans 4:18, 1980. 100. Kakinoki R, Matsumoto T, Suzuki T, et al: Lunate plasty for Kienbock’s disease: Use of a pedicled vascularised radial bone graft combined with shortening of the capitate and radius. Hand Surg 6:145-156, 2001. 101. Thompson TC, Campbell RD Jr, Arnold WD: Primary and secondary dislocation of the scaphoid bone. J Bone Joint Surg 46:73-82, 1964. 102. Palmer AK, Werner FW: The triangular fibrocartilage complex of the wrist: Anatomy and function. J Hand Surg (Am) 6:153-161, 1981. 103. King GJ, McMurtry RY, Rubenstein JD, et al: Kinematics of the distal radioulnar joint. J Hand Surg (Am) 11:798-804, 1986. 104. Burk DL Jr, Karasick D, Wechsler RJ: Imaging of the distal radioulnar joint. Hand Clin 7:263-275, 1991. 105. King GJ, McMurtry RY, Rubenstein JD, et al: Computerized tomography of the distal radioulnar joint: Correlation with ligamentous pathology in a cadaveric model. J Hand Surg (Am) 11:711-717, 1986. 106. Mino DE, Palmer AK, Levinsohn EM: The role of radiography and computerized tomography in the diagnosis of subluxation and dislocation of the distal radioulnar joint. J Hand Surg (Am) 8:23-31, 1983. 107. Mino DE, Palmer AK, Levinsohn EM: Radiography and computerized tomography in the diagnosis of incongruity of the distal radio-ulnar joint: A prospective study. J Bone Joint Surg 67:247-252, 1985. 108. Steyers CM, Blair WF: Measuring ulnar variance: A comparison of techniques. J Hand Surg (Am) 14:607-612, 1989. 109. Epner RA, Bowers WH, Guilford WB: Ulna variance: The effect of wrist positioning and roentgen filming technique. J Hand Surg (Am) 7:298-305, 1982. 110. Gilula LA, Hardy DC, Totty WG: Distal radioulnar joint arthrography. AJR Am J Roentgeol 150:180-189, 1988. 111. Mikic ZD: Age changes in the triangular fibrocartilage of the wrist joint. J Anat 126:367-384, 1978. 112. Mikic ZD: Arthrography of the wrist joint: An experimental study. J Bone Joint Surg 66:371-378, 1984. 113. Palmer AK, Levinsohn EM, Kuzma GR: Arthrography of the wrist. J Hand Surg (Am) 8:18-23, 1983. 114. Potter HG, Asnis-Ernberg L, Weiland AJ, et al: The utility of highresolution magnetic resonance imaging in the evaluation of the triangular fibrocartilage complex of the wrist. J Bone Joint Surg 79:1675-1684, 1997. 115. Feldon P, Terronon AL, Belsky MR: The wafer procedure: Partial distal ulnar resection. Clin Orthop 275:124-129, 1992. 116. de Araujo W, Poehling GG, Kuzma GR: New Tuohy needle technique for triangular fibrocartilage complex repair: Preliminary studies. Arthroscopy 12:699-703, 1996.

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117. Lacey T II, Goldstein LA, Tobin CE: Anatomical and clinical study of the variations in the insertions of the abductor pollicis longus tendon, associated with stenosing tendovaginitis. J Bone Joint Surg 33:347-350, 1951. 118. Leao L: De Quervain’s disease: A clinical and anatomical study. J Bone Joint Surg 40:1063-1070, 1958. 119. Strandell G: Variations of the anatomy in stenosing tenosynovitis at the radial styloid process. Acta Chir Scand 113:234-240, 1957. 120. F  inkelstein H: Stenosing tendovaginitis at the radial styloid process. J Bone Joint Surg 12:509-540, 1930. 121. Pick RY: De Quervain’s disease: A clinical triad. Clin Orthop 143:165-166, 1979. 122. Grundberg AB, Reagan DS: Pathologic anatomy of the forearm: Intersection syndrome. J Hand Surg (Am) 10:299-302, 1985. 123. Weiss AP, Akelman E, Tabatabai M: Treatment of de Quervain’s disease. J Hand Surg (Am) 19:595-598, 1994. 124. Kelsey JL, Pastides H, Kreiger N, et al: Arthritic Disorders, Upper Extremity Disorders: A Survey of Their Frequency and Cost in the United States. St. Louis, CV Mosby, 1980.

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125. Armstrong AL, Hunter JB, Davis TRC: The prevalence of degenerative arthritis of the base of the thumb in post-menopausal women. J Hand Surg (Am)19:340-341, 1994. 126. Eaton RG, Glickel SZ: Trapeziometacarpal osteoarthritis: Staging as a rationale for treatment. Hand Clin 3:455-469, 1987. 127. Swigart CR, Eaton RG, Glickel SZ, et al: Splinting in the treatment of trapeziometacarpal joint arthritis. J Hand Surg (Am) 24:86-91, 1999. 128. Gundes H, Cirpici Y, Sarlak A, et al: Prognosis of wrist ganglion operations. Acta Orthop Belg 66:363-367, 2000. 129. Bonnici AV, Spencer JD: A survey of ‘trigger finger’ in adults. J Hand Surg (Am) 13:202-203, 1988. 130. Murphy D, Failla JM, Koniuch MP: Steroid versus placebo injection for trigger finger. J Hand Surg (Am) 20:628-631, 1995. 131. Fowler JR: Viral infections. Hand Clin 5:533-552, 1989. 132. LaRossa D, Hamilton R: Herpes simplex infections of the digits. Arch Surg 102:600-603, 1971.

45

Temporomandibular Joint Pain Daniel J. Laskin

Key Points Temporomandibular joint (TMJ) pain must be distinguished from the pain that more commonly arises from the muscles of mastication (myofascial pain), which can produce similar signs and symptoms. TMJ pain also must be distinguished from pain coming from the ear or parotid gland. TMJ and masticatory muscle pain generally are accompanied by limitation of mouth opening, but not pain arising from the ear or parotid gland. All the forms of arthritis that involve other joints in the body also involve the TMJ and may give rise to pain and limited jaw movement. Displacement of the intra-articular disk in the TMJ produces pain that is accompanied by a clicking or popping sound or sudden onset of jaw locking.

Pain in the temporomandibular joint (TMJ) region, a commonly encountered symptom, affects more than 10 million Americans. Because of its diverse etiology, however, there is often considerable difficulty in proper diagnosis and treatment. Owing to the proximity of the ear and parotid gland and the similar nature of pain in these areas, pathologic conditions involving these structures are often confused with conditions arising in the TMJ. Pain occurring in the adjacent muscles of mastication, also a frequently encountered situation, not only is similar to TMJ pain in character and location, but also is associated with jaw dysfunction, a common finding with painful conditions directly involving the TMJ. For these reasons, a knowledge of the various painful conditions occurring in the TMJ region is essential in establishing a correct diagnosis. Because patients with primary TMJ disease often have secondary myofascial pain in the muscles of mastication, and patients with primary myofascial pain problems in the masticatory muscles can develop secondary TMJ disease, the generally accepted term used to describe this overlapping group of conditions is temporomandibular disorders. These conditions are subdivided for purposes of diagnosis and treatment into conditions that primarily involve the TMJ (TMJ problems) and conditions that primarily involve the muscles of mastication (myofascial pain and dysfunction [MPD], masticatory myalgia). From a diagnostic standpoint, it also is important to consider the numerous conditions that mimic the temporomandibular disorders or MPD by producing similar signs and symptoms (Tables 45-1 and 45-2). Table 45-3 lists the various pathologic entities that commonly involve the TMJ. Although there are a variety of

conditions, only three types commonly are considered to produce pain: the various arthritides, derangements of the intra-articular disk, and certain neoplasms.

ARTHRITIS OF THE TEMPOROMANDIBULAR JOINT Arthritis is the most common condition affecting the TMJ, just as it is in other joints. Although degenerative arthritis and rheumatoid arthritis are encountered most frequently, cases of infectious arthritis, metabolic arthritis, and the spondyloarthropathies also have been reported. Traumatic arthritis is another common occurrence. Degenerative Arthritis (Osteoarthritis) Degenerative arthritis is the most common type of arthritis involving the TMJ and the most frequent cause of pain in that region. Clinical symptoms of the disease have been reported in 16% of the general population,1 but radiographic evidence has been found in 44% of asymptomatic individuals.2 Although the TMJ is not a weight-bearing joint in the same sense as the joints of the long bones, the stresses associated with such parafunctional habits as clenching and grinding of the teeth are sufficient to contribute to similar degenerative changes in some patients.3 Acute and chronic trauma and derangements of the intra-articular disk also are common causes of secondary degenerative arthritis. Clinical Findings Primary degenerative arthritis, which usually is seen in older individuals, is insidious in its onset; it generally produces only mild discomfort, and individuals rarely complain about the condition. Secondary degenerative arthritis usually occ­ urs in younger patients (20 to 40 years old) and tends to be painful. In contrast to primary degenerative joint disease and rheumatoid arthritis, it often is limited to only one TMJ, although it may become bilateral in the late stages, and involvement of other joints is uncommon. The condition is characterized by TMJ pain that is increased by function, joint tenderness, limitation of mouth opening, and occasional clicking and popping sounds. In the late stages, there may be crepitation in the joint. Imaging Findings The earliest radiologic feature of degenerative arthritis of the TMJ, whether primary or secondary, is subchondral sclerosis in the mandibular condyle. If the condition progresses, 665

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Table 45-1  Differential Diagnosis of Nonarticular Conditions Mimicking Temporomandibular Joint Pain   or Myofascial Pain in the Masticatory Muscles Disorder

Jaw Limitation

Muscle Tenderness

Diagnostic Features

Pulpitis

No

No

Mild-to-severe ache or throbbing; intermittent or constant; aggravated by thermal change; eliminated by dental anesthesia; positive radiographic findings

Pericoronitis

Yes

Possible

Persistent mild-to-severe ache; difficulty swallowing; possible fever; local inflammation; relieved with dental anesthesia

Otitis media

No

No

Moderate-to-severe earache; pain constant; fever; usually history of upper respiratory infection; no temporomandibular joint tenderness

Parotitis

Yes

No

Constant aching pain, worse when eating; pressure feeling; absent salivary flow; ear lobe elevated; suppuration from duct

Sinusitis

No

No

Constant aching or throbbing; worse with change of head position; nasal discharge; often maxillary molar pain not relieved by dental anesthesia

Trigeminal neuralgia

No

No

Sharp stabbing pain of short duration; trigger zone; pain follows nerve pathway; older age group; often relieved by dental anesthesia

Atypical (vascular) ­neuralgia

No

No

Diffuse throbbing or burning pain of long duration; often associated autonomic symptoms; no relief with dental anesthesia

Temporal arteritis

No

No

Constant throbbing preauricular pain; artery prominent and tender;   low-grade fever; may have visual problems; elevated erythrocyte   sedimentation rate

Trotter’s syndrome

Yes

No

Aching pain in ear, side of face, and lower jaw; deafness; nasal obstruction; cervical lymphadenopathy

Eagle’s syndrome

No

No

Mild-to-sharp stabbing pain in ear, throat, and retromandible; provoked by swallowing, turning head, carotid compression; usually post-tonsillectomy; styloid process >2.5 cm

Modified from Laskin DM, Block S: Diagnosis and treatment of myofascial pain dysfunction (MPD) syndrome. J Prosthet Dent 56:75-84, 1986.

Table 45-2  Differential Diagnosis of Nonarticular Conditions Producing Limitation of Mandibular Movement Disorder

Pain

Muscle Tenderness

Diagnostic Features

Odontogenic infection

Yes

Yes

Fever; swelling; positive radiographic findings; tooth tender to percussion; pain relieved and movement improved with dental anesthesia

Nonodontogenic   infection

Yes

Yes

Fever; swelling; negative dental findings on radiograph; dental anesthesia may not relieve pain or improve jaw movement

Myositis

Yes

Yes

Sudden onset; jaw movement associated with pain; areas of muscle tenderness; usually no fever

Myositis ossificans

No

No

Palpable nodules seen as radiopaque areas on radiograph; involvement of nonmasticatory muscles

Neoplasia

Possible

Possible

Palpable mass; regional nodes may be enlarged; may have paresthesia; radiograph may show bone involvement

Scleroderma

No

No

Skin hard and atrophic; masklike facies; paresthesias; arthritic joint pain; widening of periodontal ligament

Hysteria

No

No

Sudden onset after psychological trauma; no physical findings; jaw opens easily under general anesthesia

Tetanus

Yes

No

Recent wound; stiffness of neck; difficulty swallowing; spasm of facial muscles; headache

Extrapyramidal   reaction

No

No

Patient on antipsychotic drug or phenothiazine tranquilizer; hypertonic movement; lip smacking; spontaneous chewing motions

Depressed zygomatic   arch

Possible

No

History of trauma; facial depression; positive radiographic findings

Osteochondroma   coronoid

No

No

Gradual limitation; jaw may deviate to unaffected side; possible ­clicking sound on jaw movement; positive radiograph findings

From Laskin DM, Block S: Diagnosis and treatment of myofascial pain dysfunction (MPD) syndrome. J Prosthet Dent 56:75-84, 1986.

condylar flattening and marginal lipping may be noted. In the later stages, erosion of the cortical plate, osteophyte ­formation, or both may occur. There also occasionally may be breakdown of the subcortical bone resulting in the formation of bone cysts. Although the changes in the ­articular

fossa generally are not as severe as the changes in the condyle, cortical erosion sometimes can be seen. Narrowing of the joint space also occurs in the late stages, and this is indicative of concomitant degenerative changes in the intraarticular disk. Although the changes in the TMJ ­usually can

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Table 45-3  Differential Diagnosis of Temporomandibular Joint Diseases Disorder

Pain

Jaw Limitation

Diagnostic Features

Agenesis

No

Yes

Congenital; usually unilateral; mandible deviates to affected side; unaffected side long and flat; severe malocclusion; often ear abnormalities; radiograph shows condylar deficiency

Condylar hypoplasia

No

No

Congenital or acquired; affected side has short mandibular body and ramus, fullness of face, deviation of chin; body of mandible elongated and face flat on unaffected side; malocclusion; radiograph shows condylar deformity, antegonial notching

Condylar hyperplasia

No

No

Facial asymmetry with deviation of chin to unaffected side; cross-bite malocclusion; prognathic appearance; lower border of mandible often convex on affected side; radiograph shows symmetric enlargement of condyle

Neoplasia

Possible

Yes

Mandible may deviate to affected side; radiographs show enlarged, irregularly shaped condyle or bone destruction, depending on type of tumor; unilateral condition

Infectious arthritis

Yes

No

Signs of infection; may be part of systemic disease; radiograph may be normal early, later can show bone destruction; fluctuance may be present; pus may be obtained on aspiration; usually unilateral

Rheumatoid arthritis

Yes

Yes

Signs of inflammation; findings in other joints (hands, wrists, feet, elbows, ankles); positive laboratory test results; retarded mandibular growth in children; anterior open bite; radiograph shows bone destruction; usually bilateral

Spondyloarthropathies Psoriatic arthritis

Yes

Yes

Yes

Yes

Presence of cutaneous psoriasis; nail dystrophy; involvement of distal interphalangeal joints; radiograph shows condylar erosion; negative for rheumatoid factor Frequent involvement of the spine and sacroiliac joint; extra-articular manifestations of spondylitis include iritis, anterior uveitis, aortic insufficiency, and conduction defects; erosive condylar changes; TMJ ankylosis may occur

Metabolic arthritis Gout

Yes

Yes

Pseudogout

Yes

Yes

Traumatic arthritis

Yes

Yes

History of trauma; radiograph normal except for possible widening of joint space; local tenderness; usually unilateral

Degenerative arthritis

Yes

Yes

Unilateral joint tenderness; often crepitus; TMJ may be only joint involved; radiograph may be normal or show condylar flattening, lipping, spurring, or erosion

Ankylosis

No

Yes

Usually unilateral, but can be bilateral; may be history of trauma; young patient may show retarded mandibular growth; radiographs show loss of normal joint architecture

Internal disk degeneration

Yes

Yes

Pain exacerbated by function; clicking on opening or opening limited to <25 mm with no click; positive magnetic resonance imaging findings; may be history of trauma; usually unilateral

Ankylosing spondylitis

Usually sudden onset; often monarticular; commonly involves great toe, ankle, and wrist; joint swollen, red, and tender; increased serum uric acid; late radiographic changes Generally unilateral; TMJ may be only joint involved; joint frequently swollen; presence of intra-articular calcification; may be a history of trauma

TMJ, temporomandibular joint. Modified from Laskin DM, Block S: Diagnosis and treatment of myofascial pain dysfunction (MPD) syndrome. J Prosthet Dent 56:75-84, 1986.

be seen on plain radiographs, sagittal and coronal computed tomography (CT) scans are the preferred modality for imaging the bony structures. Diagnosis The diagnosis of degenerative arthritis is based on the patient’s history and clinical and radiographic findings. There is often a history of trauma or parafunctional oral habits. The involvement is generally unilateral, and there are no significant changes in any of the other joints. The pain tends to be well localized, and the TMJ is often tender to palpation. Treatment The treatment of degenerative arthritis of the TMJ is usually medical, just as in other joints in the body. It involves the use of nonsteroidal anti-inflammatory drugs, application of

heat, eating a soft diet, limitation of jaw function, and use of a bite appliance to control parafunction if the patient has a chronic habit of clenching or grinding the teeth. Physical therapy with thermal agents, ultrasound, and iontophoresis also can be beneficial, and isotonic and isometric exercises are used to improve joint stability after the acute symptoms have subsided. The use of intra-articular steroid injections is controversial, and they should be used only in patients with acute symptoms that do not respond to other forms of medical management. Because of the potential damaging effects of long-acting steroids,4 they should be limited to no more than three or four single injections given at 3-month intervals. Intra-articular injection of high-molecular-weight sodium hyaluronate given twice, 2 weeks apart, has been shown to have essentially the same therapeutic effect as a steroid injection, without the potential adverse side effects.5 When the acute symptoms have been controlled, therapy is directed toward control of the factors possibly contributing to the degenerative process. Unfavorable loading of the joint

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is eliminated by replacement of missing teeth to establish a good, functional occlusion; by correction of any severe dental malrelationships through orthodontics or orthognathic surgery; and by continued use of a bite appliance at night to control any teeth-clenching or teeth-grinding habits.6 In patients in whom medical management for 3 to 6 months fails to relieve the symptoms, surgical management may be indicated. Surgery involves removal of only the minimal amount of bone necessary to produce a smooth articular surface. The unnecessary removal of the entire cortical plate, as occurs with the so-called condylar shave procedure or high condylotomy, can lead to a continuation of the resorptive process in some instances and should be avoided if possible. Rheumatoid Arthritis Of patients with rheumatoid arthritis, 50% have involvement of the TMJ. Although the TMJ may be affected early in the course of the disease, other joints in the body usually are involved first. Children and adults are affected, with a femaleto-male ratio of 3:1. In children, destruction of the mandibular condyle by the disease process results in growth retardation and facial deformity characterized by a severely retruded chin. Fibrous or bony ankylosis is a possible sequela at all ages. Clinical Findings Patients with rheumatoid arthritis of the TMJ have bilateral pain, tenderness, swelling in the preauricular region, and limitation of mandibular movement. These symptoms are characterized by periods of exacerbation and remission. Joint stiffness and pain are usually worse in the morning and decrease during the day. The limitation in mandibular movement worsens as the disease progresses; the patient also may develop an anterior open bite.

prevent excessive loss of motion when the acute symptoms subside. In severe cases, disease-modifying drugs, such as methotrexate, etanercept, infliximab, adalimumab, abatacept, and rituximab, also are used. Surgery may be necessary in patients with an anterior open bite after the disease goes into remission or in paients in whom ankylosis develops. Spondyloarthropathies In addition to the adult and juvenile forms of rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis also can involve the TMJ.8-10 Psoriatic Arthritis Psoriatic arthritis occurs in a small percentage of patients who have long-standing cutaneous psoriasis. It can have a sudden onset, can be episodic in nature, and may show spontaneous remission.9 Often only one TMJ is involved. Symptoms include TMJ pain and tenderness, restricted jaw movement, and crepitation, mimicking the symptoms of rheumatoid arthritis.9 The radiographic changes are nonspecific and cannot be distinguished easily from other types of arthritis, particularly rheumatoid arthritis and ankylosing spondylitis.10 They usually involve erosive changes in the condyle and glenoid fossa associated with extreme narrowing of the joint space.11 In severe cases, ankylosis may develop.12 The diagnosis usually is based on the triad of psoriasis, radiographic evidence of erosive arthritis, and a negative serologic test for rheumatoid factor. Even in the presence of a rash, however, the diagnosis cannot be absolutely confirmed. The differential diagnosis always should include rheumatoid arthritis, Reiter’s syndrome, ankylosing spondylitis, and gout. The treatment of psoriatic arthritis of the TMJ is similar to that of rheumatoid arthritis, involving the use of diseasemodifying drugs.13 Surgery is necessary if ankylosis occurs.

Imaging Findings Although there may not be any radiographic changes in the early stages of the disease, about 50% to 80% of patients show bilateral evidence of demineralization, condylar flattening, and bone erosion as the disease progresses, so the articular surface appears irregular and ragged. Erosion of the glenoid fossa also is seen sometimes. As a result of destruction of the intra-articular disk, there also is narrowing of the joint space. With continued destruction of the condyle, the loss of ramus height can lead to contact of only the posterior teeth and an anterior open bite.

Ankylosing Spondylitis

Rheumatoid arthritis is diagnosed on the basis of the clinical and radiographic findings and confirmatory laboratory tests. The distinguishing features for rheumatoid arthritis and degenerative arthritis of the TMJ are shown in Table 45-3.

About one third of patients with ankylosing spondylitis develop TMJ involvement several years after the onset of the disease. Pain and limitation of jaw movement are the most common symptoms, and ankylosis can develop in ­adv­anced cases.8,14 On radiographic examination, about 30% of patients show erosive changes in the condyle and fossa and narrowing of the joint space.15 In long-standing cases, there is sometimes a more florid osteophytic response during quiescent periods. The severity of the changes seems to be related to the severity of the disease. The treatment of ankylosing spondylitis of the TMJ is generally medical and is part of the total management of the patient. Physical therapy is used to improve jaw mobility, and bite appliances are used, when indicated, to reduce parafunctional stress on the joint. If ankylosis develops, ­surgery is the treatment of choice.

Treatment

Traumatic Arthritis

The treatment of rheumatoid arthritis of the TMJ is similar to that for other joints.7 Anti-inflammatory drugs are used during the acute phases, and mild jaw exercises are used to

Acute trauma to the mandible that does not result in a fracture still can produce injury to the TMJ. When this occurs in a child, it is essential to warn the parents about

Diagnosis

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the possibility of future retardation of mandibular growth and associated facial deformity resulting from damage to the articular cartilage, which is an important growth site.16 Traumatic arthritis is characterized by TMJ pain and tenderness and limitation of jaw movement. The resultant inflammation and occasional hemarthrosis also can result in loss of tooth contact on the affected side. Frequently, there are bruises or lacerations at the site of the initial injury. No radiographic changes may be seen, or there may be widening of the joint space owing to intra-articular edema or hemorrhage. In some instances, radiographs may show an intracapsular fracture that was not recognized on clinical examination. The treatment of traumatic arthritis consists of the use of nonsteroidal anti-inflammatory drugs, application of heat, a soft diet, and initial restriction of jaw movement. When the acute symptoms subside, range-of-motion exercises should be used to avoid fibrous ankylosis. Infectious Arthritis Infectious arthritis rarely involves the TMJ. Although it can affect the joint as part of such systemic diseases as gonorrhea, syphilis, tuberculosis, and Lyme disease,17,18 the most common way is by direct extension of an adjacent infection of dental, parotid gland, or otic origin. 19 Occasionally, it also may occur from the localization of blood-borne organisms in the joint after a traumatic injury or by direct involvement through a penetrating wound.20 Clinical Findings Infectious arthritis generally results in unilateral pain, tenderness, swelling, and redness in the region of the TMJ. Chills, fever, sweating, and systemic findings characteristic of the specific type of infection also are present. There is often an inability to occlude the teeth because of the swelling within the joint. In pyogenic forms of infectious arthritis, fluctuation may be present in the joint region. Patients with Lyme disease show characteristic skin lesions.18 Imaging Findings The radiographic findings are usually normal in the early stages of the disease because of the lack of bony involvement, but the intra-articular accumulation of pus or inflammatory exudate may cause separation of the articulating surfaces, which can be detected on magnetic resonance imaging (MRI). Later, depending on the severity and chronicity of the infection, varying degrees of bony destruction, ranging from damage to the articular surface of the mandibular condyle to extensive osteomyelitis, may be seen. In the late stages, fibrous or bony ankylosis may occur. In children, infectious arthritis can affect the growth of the condyle and result in facial asymmetry.

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may require aspiration, incision and drainage, or sequestrectomy. When there has been extensive bone loss, reconstructive procedures may be necessary. In children in whom mandibular growth has been affected, a costochondral graft can be used to correct the facial asymmetry and re-establish growth of the mandible. Metabolic Arthritis Metabolic arthritis, which can accompany gout or pseudo­ gout (calcium pyrophosphate dehydrate arthropathy), is rare in the TMJ.21 Gout Gouty arthritis of the TMJ occurs most frequently in men older than 40 years and usually is preceded by involvement of one or more joints of the feet or hands. The attack usually occurs suddenly, and the joint becomes swollen, painful, red, and tender. Recovery may occur in a few days, and remission can last for months to years. When the attacks are infrequent, there may not be any radiographic changes for a long time. Because there have been so few cases reported, the precise radiographic changes that occur have not been well documented. Calcified areas in the disk, destruction of the hard tissues of the joint, condylar exostoses and spurring, and the presence of tophi have been described.21 The initial approach to treatment of gout involving the TMJ is medical. If the symptoms are not controlled, however, surgical débridement of the joint and arthroplasty may be indicated. Pseudogout Calcium pyrophosphate dehydrate arthropathy (pseudo­ gout) in the TMJ clinically mimics gout, and the mandibular condyle may show degenerative and erosive changes radiographically. In the primary form, which usually is seen in older patients, there is intra-articular calcification (chondrocalcinosis), and diffuse calcification occurs in the intra-articular disk.21-25 Similar changes are seen in the secondary form, but it occurs in younger patients and is frequently preceded by a history of trauma. Just as in gout of the TMJ, the initial treatment of pseudogout is medical, and surgery is reserved for patients in whom such treatment is ineffective.

INTERNAL DERANGEMENTS Internal derangements are a common cause of pain in the TMJ. They represent a disturbance in the normal anatomic relationship between the intra-articular disk and the condyle, resulting in an interference with the smooth movement of the joint. Clinical Findings

Treatment The treatment of infectious arthritis includes the use of appropriate antibiotics, proper hydration, control of pain, and limitation of jaw movement. Suppurative infections

There are three stages of internal derangement: a painless incoordination phase, in which there is a momentary catching sensation during mouth opening; anterior disk displacement with reduction into the normal position during

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mouth opening, which is characterized by a clicking or popping sound (Fig. 45-1); and anterior disk displacement without reduction on attempted mouth opening, which is characterized by a restriction of jaw movement, or locking (Fig. 45-2). The joint pain in patients with anterior disk displacement, with or without reduction, is caused by condylar compression of the highly innervated retrodiskal tissue that occupies the glenoid fossa as the intra-articular disk assumes a more forward position, and by the accompanying inflammation. ETIOLOGY The three main causes of internal derangement of the intraarticular disk are trauma, abnormal functional loading of the joint, and degenerative joint disease.26 It also has been suggested that spasm in the lateral pterygoid muscle, a portion of which attaches to the anterior aspect of the disk, can lead to a disk derangement, but the evidence for this theory is circumstantial. Although some clinicians believe that occlusal factors also play a role in causing internal derangements, no conclusive studies have shown such a relationship. Acute macrotrauma is probably the most common cause of internal derangement. Among the incidents that have been implicated are a blow to the jaw, endotracheal intubation, cervical traction, and iatrogenic stretching of the joint during dental or oral surgical procedures. Although whiplash injuries frequently have been implicated in the etiology of internal derangement, a study of 155 patients with this type of injury showed that only one developed clicking in the TMJ immediately after the automobile accident.27 At 1 month of follow-up, two additional patients of the 129 A

contacted experienced clicking, but at 1 year, no additional patients of the 104 contacted had developed clicking. Although internal derangements of the TMJ can be caused by a whiplash injury, the incidence seems to be low. Whether a patient merely develops alterations in the articular surface leading to a catching or binding sensation, anterior disk displacement with reduction on mouth opening (clicking or popping), or anterior disk displacement without reduction during mouth opening (locking) after trauma to the TMJ depends on the severity of the injury. Although the associated traumatic arthritis causes pain during function in each of these instances, the pain is more severe in the last two conditions because of compression of the retrodiskal tissue, which is now located in the articular zone. The functional overloading of the TMJ associated with the habit of chronic teeth clenching is another frequent cause of internal derangements. Although the TMJ is constructed for eccentric movements, it is not constructed for the constant isometric loading and unloading that occurs during this activity. Such parafunction affects the lubrication of the joint, introducing friction between the disk and the condyle that leads to degenerative changes in the articular surfaces and results in gradual anterior displacement of the disk.26,28 Degenerative joint disease may precede the development of an internal derangement, or it may occur after the development of an internal derangement. In the first instance, the changes in the character of the articulating surfaces result in an inability of the parts to glide smoothly over each other, gradually leading to a forward displacement of the disk, which normally rotates posteriorly during mouth opening. In the second instance, the displaced disk results in an altered relationship between the articulating components of the joint, which leads to the degenerative changes in these structures. In patients in whom the condition causing the

Closing click

F

A

B

Opening click

E B

E

C

D Figure 45-1  Anterior displacement of the intra-articular disk with reduction on opening of the mouth. A clicking or popping sound occurs as the disk returns to its normal position in relation to the condyle. During closure, the disk again becomes anteriorly displaced, sometimes accompanied by a second sound (reciprocal click). (Modified from McCarty W: Diagnosis and treatment of internal derangements of the articular disc and mandibular condyle. In Solberg WK, Clark GT [eds]: Temporomandibular Joint Problems: Biologic Diagnosis and Treatment. Chicago, Quintessence, 1980, p 155.)

D

C

Figure 45-2  Anterior displacement of the intra-articular disk without reduction on attempted mouth opening. The displaced disk acts as a barrier and prevents full translation of the condyle. (Modified from McCarty W: Diagnosis and treatment of internal derangements of the articular disc and mandibular condyle. In Solberg WK, Clark GT [eds]: Temporomandibular Joint Problems: Biologic Diagnosis and Treatment. Chicago, Quintessence, 1980, p 151.)

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DIFFERENTIAL DIAGNOSIS OF REGIONAL MUSCULOSKELETAL PAIN

Management of internal derangements of the TMJ Clicking

Locking

Analgesics Soft diet Limited jaw function Bite appliance

Arthrocentesis or arthroscopic lysis and lavage Bite appliance patients with parafuction

Pain continues

Pain relieved

Diskoplasty

Continue bite appliance in patients with parafunction Periodic follow-up

Pain continues Diskoplasty or diskectomy

Pain relieved Continue bite appliance Periodic follow-up

Figure 45-3  Management of internal derangements of the temporomandibular joint. Patients with painful clicking or locking are treated medically initially, whereas patients with locking require surgical intervention.

degenerative joint disease is still active, whether primarily or secondarily, it—and the disk derangement—must be treated to resolve the problem completely.

671

with a history of clicking treated by such conservative non­ surgical modalities, which are not directed specifically to the problems of joint noise or disk displacement, showed that the condition worsened in only 1%, indicating that it is permissible to observe individuals with painless clicking as long as they remain otherwise asymptomatic.30 In patients with pain and clicking in the TMJ that is unresponsive to nonsurgical management, the disk should be repositioned arthroscopically or by open surgery (diskoplasty). Patients with parafunctional habits should continue the use of a bite appliance when sleeping. In patients with locking (anterior disk displacement without reduction), whether painful or not, treatment is urgent because if the condition is left untreated for a long time, the subsequent management can be complicated by further degenerative changes in the disk and condyle that make disk salvage (diskoplasty) impossible. The initial treatment involves joint lavage and lysis of adhesions either arthroscopically or by arthrocentesis. The latter involves establishing inlet and outlet portals in the upper joint space with hypodermic needles, irrigation with lactated Ringer’s solution to remove inflammatory tissue breakdown products and cytokines, and lysis of adhesions by hydraulic distention and manual manipulation of the joint (Fig. 45-4).31 The results of arthrocentesis parallel the results achieved with arthroscopic lysis and lavage, and the procedure is less invasive. Although neither of these procedures restores the disk to its normal position, they do restore disk and joint

Imaging Findings Depending on the cause of the internal derangement and its duration, the radiographs may or may not show any evidence of degenerative joint disease. Magnetic resonance imaging shows anterior disk displacement in the closed mouth position, however, and a return to a normal disk relationship during mouth opening in patients with clicking and popping; in patients with locking, the disk remains in the anterior position on attempted mouth opening, and there is limited movement of the condyle. There also is a small group of patients with locking who show the intra-articular disk in normal position when the teeth are in occlusion, rather than anteriorly displaced, and there is no change in disk position when the patient attempts to open the mouth.29 In such cases, there is adhesion of the disk to the articular eminence preventing translation of the condyle. These patients differ from patients with anteriorly displaced, nonreducing disks in that they do not have a history of TMJ clicking preceding the sudden onset of locking.

A

Treatment The initial treatment of patients with painful clicking or popping in the TMJ consists of a nonsteroidal antiinflammatory drug; a soft, nonchewy diet; and the use of a bite-opening appliance to reduce compression of the retrodiskal tissue (Fig. 45-3). A muscle relaxant drug can be added to the regimen if the patient has associated myofascial pain. When the pain has stopped, no further treatment is necessary, although the joint noise still may be present. A long-term follow-up study (1 to 15 years) of 190 patients

B Figure 45-4  Temporomandibular joint arthrocentesis. A, Hypodermic needles inserted into the upper joint space to allow lavage of the joint.  B, Joint being irrigated with lactated Ringer’s solution.

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mobility, and reduce pain and improve function in most patients.32,33 In these patients, the retrodiskal tissue within the joint undergoes fibrosis and acts as a pseudodisk. It is important that patients who have teeth-grinding or teethclenching habits are prescribed a bite appliance postoperatively to wear while sleeping. In patients who do not respond favorably to arthroscopy or arthrocentesis, repositioning of the displaced disk by an open operation should be done. If the disk is extremely deformed and cannot be repositioned, or if there is a large, nonreparable perforation in the disk or tear in the retrodiskal tissue, the disk should be removed. Although autogenous auricular cartilage or dermal grafts, or temporalis muscle flaps, have been used as a disk replacement, the results have been unpredictable.31 More recent long-term studies have shown that most patients can tolerate a diskless joint.34 Currently, there are no acceptable alloplastic substitutes for the disk.

NEOPLASMS Although primary neoplasms involving the TMJ are uncommon, they still need to be considered in the differential diagnosis of painful conditions affecting this region.35,36 Chondroma, osteochondroma, and osteoma are the most frequently encountered benign tumors, but isolated cases of fibro-osteoma, myxoma, fibrous dysplasia, giant cell reparative granuloma, aneurysmal bone cyst, synovioma, synovial chondromatosis, chondroblastoma, osteoblastoma, glomus tumor, and synovial hemangioma have been reported. ­Mali­gnant tumors of the TMJ are even rarer, with infrequent reports of fibrosarcoma, chondrosarcoma, synovial fibrosarcoma, osteosarcoma, malignant fibrous histiocytoma, malignant schwannoma, leiomyosarcoma, and multiple myeloma. The TMJ also can be invaded by neoplasms from the cheek, the parotid gland, the external auditory canal, and the adjacent ramus of the mandible. Metastasis to the condyle from distant neoplasms in the breast, lung, prostate, colon, and thyroid gland also has been described. Tumors of the TMJ can cause pain, limitation of jaw movement, deviation of the mandible to the affected side on attempted mouth opening, and difficulty in occluding the teeth. Depending on the nature of the condition, the radiographs may show bony deformation, apposition, or resorption. A biopsy is necessary to establish the definitive diagnosis.

Etiology Stress seems to be an important factor in the development of MPD.39 It is hypothesized that centrally induced increases in muscle activity, frequently combined with the presence of parafunctional habits such as clenching or grinding of the teeth, result in the associated muscle fatigue, pain, and dysfunction.40 Similar symptoms also occasionally can result, however, from muscle overextension, muscle overcontraction, or trauma (Fig. 45-5). Clinical Findings Pain of unilateral origin is the most common symptom of MPD. In contrast to the pain associated with joint disease, which is well localized, the pain of muscle origin is more diffuse. The patient generally is unable to identify accurately the specific site involved, which can serve as an important diagnostic criterion in distinguishing between muscle and joint disorders. Depending on the muscle involved, the pain associated with MPD may be described by the patient in various ways. The masseter is the most frequent muscle involved, and the patient usually refers to the pain as a jaw ache. The temporalis is the next most commonly involved muscle, and it produces pain on the side of the head and is interpreted by the patient as a headache. Involvement of the lateral pterygoid muscle produces earache or a deep pain behind the eye, whereas medial pterygoid involvement causes discomfort on swallowing and the feeling of a painful, swollen gland beneath the angle of the mandible. Medial pterygoid involvement also can cause stuffiness or a full feeling in the ear. The pain associated with MPD is usually constant, but it is often more severe on arising in the morning or may worsen gradually as the day progresses. Pain generally is exacerbated by jaw function, especially during such activities as eating and excessive talking. Myofascial pain tends to be regional rather than local, and patients with a long-standing problem may complain that the pain in the facial region has spread to the cervical area and later to the shoulders and back. Stress

Muscular overextension

Muscular hyperactivity

“Dental irritation”

Muscular fatigue

Muscular overcontraction

MYOFASCIAL PAIN AND DYSFUNCTION MPD, or masticatory myalgia, is a psychophysiologic disease that primarily involves the muscles of mastication and not the TMJ. Women are affected more frequently than men; the ratio in various reports ranges from 3:1 to 5:1. Although the condition can occur in children, the greatest incidence seems to be in adults 20 to 40 years old. MPD frequently is confused with painful conditions affecting the TMJ, such as degenerative arthritis or internal derangements, because patients with primary MPD can develop these diseases secondarily, and patients with primary joint disease can develop secondary MPD. Better understanding of the causes and pathogenesis of this condition now makes its diagnosis easier, however, and its treatment more effective.37,38

Myofascial pain-dysfunction

Contracture

Internal Occlusal disharmony derangement

Degenerative arthritis

Altered chewing pattern Figure 45-5  Causes of myofascial pain and dysfunction. Although the diagram shows three pathways, the one involving psychological stress is most common. The mechanism by which stress leads to myofascial pain and dysfunction is termed the psychophysiologic theory. (Modified from Laskin DM: Etiology of the pain-dysfunction syndrome. J Am Dent Assoc 79:147-153, 1969. Copyright © 1969 American Dental Association. Reprinted by permission of ADA Publishing Co., Inc.)

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Tenderness in the muscles of mastication is another common finding, and the presence of tenderness can be used to confirm the source of the pain in muscles that are accessible to palpation (masseter, temporalis, and medial pterygoid). Although muscle tenderness usually is not reported by the patient, this symptom can be elicited easily by the examiner. The most frequent sites of tenderness are near the angle of the mandible, in the belly and posterosuperior aspect of the masseter, in the anterior temporal region, and over the temporal crest on the anterior aspect of the coronoid process. The location of some of the tender areas suggests that the tendons also may be a source of the pain and tenderness. Limitation of mandibular movement is the third cardinal symptom of MPD. It manifests as an inability to open the mouth as wide as usual and as a deviation of the mandible to the affected side when mouth opening is attempted. Lateral excursion to the unaffected side also is reduced. The limitation of mandibular movement usually is correlated with the amount of pain present. A clicking or popping sound in the TMJ is another finding in some patients with MPD. This is not a cardinal sign, however, because it occurs only in patients with a chronic teeth-clenching habit, which gradually produces frictional changes in the joint and subsequent disk displacement.26 The presence of joint sounds alone is insufficient to make a diagnosis of MPD. The joint sounds must be accompanied by myofascial pain and tenderness in the masticatory muscles that began before the onset of the joint noise. Such patients must be distinguished from patients with a primary internal derangement, in whom muscle splinting produces myofascial pain and tenderness after the onset of the joint noise. The history and the difference in physical findings are helpful in making this distinction. In addition to having the three cardinal symptoms of pain, muscle tenderness, and limitation of mouth opening, patients with MPD usually have no clinical or radiographic evidence of pathologic changes in the TMJ. These negative characteristics are important in establishing the diagnosis because they confirm that the primary site of the problem is not the articular structures. Diagnosis Because the cardinal signs and symptoms of MPD are similar to those produced by such organic problems involving the TMJ as degenerative joint disease and internal disk derangement and by a variety of nonarticular conditions (see Tables 45-1 and 45-2), the diagnosis of this condition can be difficult, requiring a careful history and a thorough clinical evaluation. Periapical radiographs of the teeth and screening radiographs (transcranial, transpharyngeal, or panoramic) of the TMJs can be helpful in eliminating dental problems or gross joint disease. If the screening views of the TMJs show some abnormality, CT scans are usually advisable for confirmation. MRI also can be useful in determining the position of the disk when an internal derangement of the TMJ is being considered. Depending on the suspected condition, other radiographic views of the head and neck and scintigraphy may be needed to establish a final diagnosis. Certain laboratory tests may be helpful in some instances. These include a complete blood cell count if an infection is

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Table 45-4  Distinguishing Features of Myofascial   Pain and Fibromyalgia Myofascial Pain

Fibromyalgia

Age distribution

20-40 years

20-50 years

Gender distribution

Mainly women

Mainly women

Distribution of pain

Localized; usually unilateral

Generalized; bilaterally symmetric

Tender points

Few

Multiple

Trigger points

Uncommon

Common

Fatigue

Localized muscle fatigue

Generalized fatigue

Sleep disturbance

Common

Common

suspected; serum calcium, phosphorus, and alkaline phosphatase measurements for possible bone disease; serum uric acid determination for gout; serum creatinine and creatinine kinase levels as indicators of muscle disease; and erythrocyte sedimentation rate, rheumatoid factor, latex fixation, and antinuclear antibody tests for suspected rheumatoid arthritis. Electromyography can be used to evaluate muscle function. Psychological evaluation and psychometric testing are good research tools, but have little diagnostic value other than for determining the presence of any associated abnormal behavioral characteristics. A condition that sometimes is confused with myofascial pain is fibromyalgia, particularly when MPD involves several regions in addition to the face. Although a small subset of patients with MPD eventually may develop fibromyalgia, they are probably distinct conditions.41 Table 45-4 lists the distinguishing characteristics of myofascial pain versus fibromyalgia. Treatment The treatment of MPD is divided into four phases.42 When a definitive diagnosis is made, phase I therapy should be started (Fig. 45-6). Phase I therapy initially involves providing the patient with some understanding of the problem. Because patients often have difficulty accepting a psychophysiologic explanation for their condition, the discussion should deal with the issue of muscle fatigue as the cause of the pain and dysfunction, delaying consideration of the role of stress and psychological factors until the symptoms have improved, and the patient’s confidence has been gained. Relating the symptoms to the specific masticatory muscles from which they arise helps the patient understand the reason for the type and location of the pain—headache from the temporalis muscle, jaw ache from the masseter muscle, discomfort on swallowing and stuffiness in the ear from the medial pterygoid muscle, and earache and pain behind the eye from the lateral pterygoid muscle. In addition to the initial explanation, the patient should be counseled regarding home therapy; this includes recommendations about avoidance of clenching and grinding of the teeth, eating a soft diet, use of moist heat and massage on the masticatory muscles, and limitation of jaw movement. A nonsteroidal anti-inflammatory drug should be prescribed for the pain. In patients who have problems sleeping, a small dose of amitriptyline at bedtime is helpful in improving sleep and reducing parafunction.

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About 50% of these patients experience resolution of their symptoms within 2 to 4 weeks with phase I therapy. For patients whose symptoms persist, phase II therapy is initiated. Home therapy and medications are continued, and a bite appliance is made for the patient. Although numerous types have been used, the Hawley-type maxillary appliance is probably most effective because it prevents contact of the posterior teeth and prevents most forms of parafunctional activity (Fig. 45-7).43 The appliance generally is worn at

Management of Myofascial Pain and Dysfunction Phase I Therapy (2-4 weeks) Initial explanation of the problem Home therapy Medication for pain and sleep Symptoms eliminated

Symptoms persist

Phase II Therapy (2-4 weeks) Reevaluate diagnosis Check for compliance

Phase out therapy Symptoms eliminated

Continue home therapy and medications Prescribe a bite appliance

Final explanation of problem Instructions for self-management Follow-up appointments

Symptoms persist

Phase III Therapy (4-6 weeks)

Symptoms eliminated

Continue home therapy and medications Reevaluate the bite appliance Initiate physical therapy or relaxation therapy Symptoms persist

Phase IV Therapy Consultation

Pain center

Psychological counseling Figure 45-6  Management of myofascial pain and dysfunction. The treatments are divided into four phases. If the symptoms are eliminated in any of the first three phases, the ongoing therapy is gradually phased out, and the patient is instructed in continued self-management of the condition. (Modified from Laskin DM, Block S: Diagnosis and treatment of myofascial pain dysfunction [MPD] syndrome. J Prosthet Dent 56:75-84, 1986.)

Figure 45-7  Hawley-type maxillary bite appliance. Only the anterior teeth contact the appliance, and there is space between the posterior teeth (arrow).

night, but it can be worn for 5 to 6 hours during the day, if necessary. The appliance should not be worn continuously, however, because the posterior teeth may supraerupt in some patients. With phase II therapy, another 20% to 25% of patients become symptom-free in 2 to 4 weeks. When the patient becomes symptom-free, the medications are stopped first, and wearing the bite appliance is discontinued next. If the patient has a return of symptoms, and the appliance is worn only at night, its use can be continued indefinitely. Patients who do not respond to the use of a bite appliance are entered into phase III treatment for 4 to 6 weeks. In this phase, either physical therapy (heat, massage, ultrasound, electrogalvanic stimulation) or relaxation therapy (electromyographic biofeedback, conditioned relaxation) is added to the regimen. There is no evidence to show that one form of treatment is better than the other, and either can be used first. If one is unsuccessful, the other can be tried. Phase III therapy usually helps another 10% to 15% of the patients. If all of these approaches fail, and there is no question about the correctness of the diagnosis, psychological counseling is recommended. This counseling involves helping patients identify possible stresses in their lives and learning to cope with such situations. If the diagnosis is in doubt, the patient should be referred first for appropriate dental and neurologic consultation and re-evaluation. Another alternative is to refer patients with recalcitrant MPD to a TMJ center or pain clinic because such patients generally require a multidisciplinary approach for successful treatment.

SUMMARY The successful management of patients with temporomandibular disorders depends on establishing an accurate diagnosis and using proper therapy based on an understanding of the etiology of the condition being treated. Of particular importance is separating patients with MPD,

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who constitute the major group encountered and who are not surgical candidates, from patients with TMJ disease, who frequently require surgical treatment. Even in the latter group, many commonly encountered conditions, such as arthritis and internal disk derangements, often respond to nonsurgical therapy, and this type of treatment should be given a fair trial before more aggressive management is considered. REFERENCES   1. Merjersjo C: Therapeutic and prognostic considerations in TMJ osteoarthrosis: A literature review and a long-term study in 11 subjects. J Craniomandib Pract 5:70, 1987.   2. Madsen B: Normal variations in anatomy, condylar movements and arthrosis frequency of the TMJs. Acta Radiol 4:273, 1966.   3. Milam SB, Zardeneta G, Schmitz JP: Oxidative stress and degenerative temporomandibular joint disease. J Oral Maxillofac Surg 56:214, 1998.   4. Haddad IK: Temporomandibular joint osteoarthritis: Histopathological study of the effects of intra-articular injection of triamcinolone acetonide. Saudi Med J 21:675, 2000.   5. Bjornland T, Gjaerum AA, Moystad A: Osteoarthritis of the temporomandibular joint: An evaluation of the effects and complications of corticosteroid injection compared with injection with sodium hyaluronate. J Oral Rehabil 34:583, 2007.   6. Abubaker AO, Laskin DM: Nonsurgical management of arthritis of the temporomandibular joint. Oral Maxillofac Surg Clin N Am 7:1, 1995.   7. Zide MF, Carlton D, Kent JH: Rheumatoid arthritis and related arthropathies: Systemic findings, medical therapy, and peripheral joint surgery. Oral Surg Oral Med Oral Pathol 61:119, 1986.   8. Davidson C, Wojtulewsky JA, Bacon PA, et al: Temporomandibular joint disease in ankylosing spondylitis. Ann Rheum Dis 34:87, 1975.   9. Wilson A, Braunwald E, Issilbacker KJ: Psoriatic arthropathy of the temporomandibular joint. Oral Surg Oral Med Oral Pathol 70:555, 1990. 10. Kononen M: Radiographic changes in the condyle of the temporomandibular joint in psoriatic arthritis. Acta Radiol 28:185, 1987. 11. Koorbusch GF, Zeitler DL, Fotos PG, et al: Psoriatic arthritis of the temporomandibular joint with ankylosis. Oral Surg Oral Med Oral Pathol 71:267, 1991. 12. Miles DA, Kaugers GA: Psoriatic involvement of the temporomandibular joint: Literature review and report of two cases. Oral Surg Oral Med Oral Pathol 71:770, 1991. 13. Wenneberg B: Inflammatory involvement of the temporomandibular joint: Diagnostic and therapeutic aspects and a study of individuals with ankylosing spondylitis. Swed Dent J Suppl 20:1, 1983. 14. Salvarini C, Cantini F, Olivieri I: Disease-modifying antirheumatic drug therapy for psoriatic arthritis. Clin Exp Rheumatol 20(Suppl 28):S71, 2002. 15. Wenneberg B, Hollender L, Kopp S: Radiographic changes in the temporomandibular joint in ankylosing spondylitis. Dentomaxillofac Radiol 12:25, 1983. 16. Harris S, Rood JP, Testa HJ: Post-traumatic changes of the temporomandibular joint by bone scintigraphy. Int J Oral Maxillofac Surg 17:173, 1988. 17. Hanson TL: Pathological aspects of arthritides and derangements. In Sarnat BG, Laskin DM (eds): The Temporomandibular Joint: A Biological Basis for Clinical Practice, 4th ed, Philadelphia, WB Saunders, 1992, pp 165-182. 18. Lesnicar DG, Zerdoner D: Temporomandibular joint involvement caused by Borrelia burgdorferi. J Craniomaxillofac Surg 35:397, 2007. 20. Leighly SM, Spach DH, Myall RW, et al: Septic arthritis of the temporomandibular joint: Review of the literature and report of two cases in children. Int J Oral Maxillofac Surg 22:292, 1993. 21. Gross BD, Williams RB, DiCosimo CT, et al: Gout and pseudogout of the temporomandibular joint. Oral Surg Oral Med Oral Pathol 63:551, 1987. 22. Nakagawa Y, Ishibashi K, Kobayoshi K, et al: Calcium phosphate deposition disease in the temporomandibular joint: Report of two cases. J Oral Maxillofac Surg 57:1357, 1999.

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23. Chuong R, Piper MA: Bilateral pseudogout of the temporomandibular joint: Report of a case and review of the literature. J Oral Maxillofac Surg 53:691, 1995. 24. Aoyama S, Kino K, Amagosa T, et al: Differential diagnosis of calcium pyrophosphate dihydrate deposition of the temporomandibular joint. Br J Oral Maxillofac Surg 38:550, 2000. 25. Ascani G, Pieramici MD, Fiosa A, et al: Pseudogout of the temporomandibular joint: A case report. J Oral Maxillofac Surg 66:386, 2008. 26. Laskin DM: Etiology and pathogenesis of internal derangements of the temporomandibular joint. Oral Maxillofac Surg Clin N Am 6:217, 1994. 27. Heise AP, Laskin DM, Gervin AS: Incidence of temporomandibular joint symptoms following whiplash injury. J Oral Maxillofac Surg 50:825, 1992. 28. Nitzan DW: The process of lubrication impairment and its involvement in temporomandibular disk displacement: A theoretical concept. J Oral Maxillofac Surg 59:36, 2001. 29. Nitzan DW, Samson B, Better H: Long-term outcome of arthrocentesis for sudden-onset persistent, severe closed lock of the temporomandibular joint. J Oral Maxillofac Surg 55:151, 1997. 30. Greene CS, Laskin DM: Long-term status of TMJ clicking in patients with myofascial pain and dysfunction. J Am Dent Assoc 117:461, 1988. 31. Laskin DM: Surgical management of internal derangements. In Laskin DM, Greene CS, Hylander WL (eds): Temporomandibular Disorders: An Evidence-Based Approach to Diagnosis and Treatment. Chicago, Quintessence, 2006, pp 469-481. 32. Dimitroulis G: A review of 55 cases of chronic closed lock treated with temporomandibular joint arthroscopy. J Oral Maxillofac Surg 60:519, 2002. 33. Carvajal W, Laskin DM: Long-term evaluation of arthrocentesis for treatment of internal derangement of the temporomandibular joint. J Oral Maxillofac Surg 58:852, 2000. 34. Eriksson L, Westesson PL: Discectomy as an effective treatment for painful temporomandibular joint internal derangement: A 5 year clinical and radiographic follow-up. J Oral Maxillofac Surg 59:750, 2001. 35. Stern D: Benign and malignant tumors. In Laskin DM, Greene CS, Hylander WL (eds): Temporomandibular Disorders: An EvidenceBased Approach to Diagnosis and Treatment. Chicago, Quintessence, 2006, pp 319-333. 36. Clayman L: Surgical management of benign and malignant neoplasms. In Laskin DM, Greene CS, Hylander WL (eds): Temporomandibular Disorders: An Evidence-Based Approach to Diagnosis and Treatment. Chicago, Quintessence, 2006, pp 509-532. 37. Laskin DM: Diagnosis and etiology of myofascial pain and dysfunction. Oral Maxillofac Surg Clin N Am 7:73, 1995. 38. Clark GT: Treatment of myogenous pain and dysfunction. In Laskin DM, Greene CS, Hylander WL (eds): Temporomandibular Disorders: An Evidence-Based Approach to Diagnosis and Treatment. Chicago, Quintessence, 2006, pp 483-500. 39. Dworkin SF: Psychological and psychosocial assessment. In Laskin DM, Greene CS, Hylander WL (eds): Temporomandibular Disorders: An Evidence-Based Approach to Diagnosis and Treatment. Chicago, Quintessence, 2006, pp 203-217. 40. Laskin DM: Etiology of the pain-dysfunction syndrome. J Am Dent Assoc 59:147, 1969. 41. Cimino R, Michelotti A, Stradi R, et al: Comparison of the clinical and psychologic features of fibromyalgia and masticatory myofascial pain. J Orofac Pain 12:35, 1998. 42. Laskin DM, Block S: Diagnosis and treatment of myofascial paindysfunction (MPD) syndrome. J Prosthet Dent 56:75, 1986. 43. Clark GT, Minakuchi H: Oral appliances. In Laskin DM, Greene CS, Hylander WL (eds): Temporomandibular Disorders: An EvidenceBased Approach to Diagnosis and Treatment. Chicago, Quintessence, 2006, pp 377-390. Internet Links 1. www.nicdr.nih.gov. General information, clinical trials, and sponsored research in TMJ and related areas 2. www.aaoms.org. General information about TMJ surgery 3. www.tmj.org. Advocate group that provides general information for patients

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The Eye and Rheumatic Diseases James T. Rosenbaum

Key Points The symptoms of uveitis vary widely based on the location of the inflammation within the eye and the suddenness of onset. Ankylosing spondylitis is the systemic disease most often associated with uveitis in North America and Europe. During a lifetime, about 40% of patients with ankylosing spondylitis develop acute anterior uveitis. The uveitis associated with HLA-B27 tends to be unilateral, recurrent, and sudden in onset. Recurrences sometimes affect the opposite eye. Sarcoidosis frequently manifests as a uveitis. Most patients with retinal vasculitis do not have a systemic vasculitis. Many patients with scleritis have a systemic disease, such as rheumatoid arthritis. Antineutrophilic cytoplasmic antibody testing helps to ­identify a subset of patients with severe scleritis. Wegener’s granulomatosis is the rheumatic disease that most frequently involves the orbit. Anterior ischemic optic neuropathy is the most common ocular manifestation of temporal arteritis. Most patients with visual loss secondary to optic nerve ­ischemia do not have arteritis.

Virtually all of the systemic inflammatory diseases that require rheumatologic care tend to affect the eye or its surrounding structures. Table 46-1 presents the prototypic ocular manifestations of rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, spondyloarthropathies, vasculitides including Wegener’s granulomatosis and temporal arteritis, scleroderma, Behçet’s syndrome, relapsing polychondritis, and dermatomyositis. Each of these diseases is addressed elsewhere in this text; this chapter focuses on specific ocular structures—the uvea, cornea, orbit, and optic nerve—and illustrates how inflammation of each might relate to an autoimmune or inflammatory process.

OCULAR ANATOMY AND PHYSIOLOGY A diagram of the eye is shown in Figure 46-1. The eye is a tiny, but elegantly complex structure. The anterior segment of the eye includes the cornea, which is avascular and transparent when healthy. The lens also is an avascular structure. The anterior chamber is filled with aqueous humor, which has homology to cerebrospinal fluid. When the blood­aqueous barrier is intact, the aqueous humor contains no

leukocytes and very little protein. The blood-aqueous barrier, which resembles the blood-synovial barrier, is disrupted in anterior uveitis. In this case, a routine, noninvasive biomicroscopic or slit lamp examination would reveal leukocytes and increased protein in the anterior chamber. An ophthalmologist has the opportunity to observe two universal hallmarks of inflammation noninvasively. The term uvea derives from the Latin word for “grape.” The anterior uvea includes the iris and the ciliary body. The aqueous humor is synthesized by the ciliary body. The posterior portion of the uvea is the choroid, which is a highly vascular tissue just posterior to the retina. Any portion of the uveal tract could become inflamed; adjacent tissue also is frequently inflamed. Anatomic subsets of uveitis include anterior uveitis, which includes iritis or iridocyclitis (ciliary body inflammation); intermediate uveitis, in which leukocytes are present within the vitreous humor; and posterior uveitis, in which the choroid and retina are inflamed. A panuveitis means that all portions of the uveal tract are inflamed. An attempt has been made to standardize the nomenclature used to describe uveitis by the Standardization of Uveitis Nomenclature working group,1 although ambiguities still persist because not all ophthalmologists follow these definitions as yet. Signs and symptoms of uveitis depend on the portion of the uveal tract that is affected. An anterior uveitis, especially if it begins suddenly, is associated with redness, pain, and photophobia. Visual loss varies and is often due to macular edema if present (Figs. 46-2 and 46-3). An intermediate uveitis usually causes floaters owing to the leukocytes that enter the visual axis, although most floaters are due to aging or other changes within the vitreous humor. A posterior uveitis by itself does not usually produce pain or ­redness. Visual loss depends on the location and extent of the inflammatory process. The outer tunic of the eye is known as the sclera. At the front of the eye, the sclera meets the cornea at a tissue known as the limbus. The most interior layer of the eye is an extension of the brain that responds to visual signals, the retina. The eye shares some common features with the joint, including the presence of hyaluronic acid primarily in the vitreous humor and the presence of type II collagen, although ocular inflammation is not a reported accompaniment of collagen-induced arthritis.

OCULAR IMMUNE RESPONSE The eye generally is regarded as an immune privileged site.2 From a teleologic perspective, many scientists believe that the eye has evolved mechanisms to avoid becoming inflamed because of the consequences this has for visual acuity.

  Supplemental images available on the Expert Consult Premium Edition website.

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Table 46-1  Most Characteristic Ocular Findings   of Selected Rheumatic Diseases Disease

Most Characteristic Eye Findings

Rheumatoid arthritis

Sicca Scleritis

Systemic lupus   erythematosus

Sicca Cotton-wool spots

Sjögren’s syndrome

Sicca

Spondyloarthritis

Acute anterior uveitis

Wegener’s granulomatosis

Scleritis Orbital inflammation

Temporal arteritis

Anterior ischemic optic neuropathy

Scleroderma

Sicca

Behçet’s disease

Uveitis, retinal arteritis

Relapsing polychondritis

Scleritis, episcleritis, uveitis

Dermatomyositis

Heliotrope eyelids Figure 46-2  Fluorescein angiogram. The normal macula is avascular and does not stain with the fluorescein dye. This patient has macular edema indicated by the donut-shaped pattern of dye in the center of the photo. The optic nerve is at the 3-o’clock position in the photo. Macular edema can complicate uveitis, even an anterior uveitis.

Retina Macula Cornea

Optic nerve

Lens

Figure 46-1  Diagram of the eye.

­ imilar to the brain, the internal portion of the eye has no S lymphatics, although the conjunctiva on the ocular surface has lymphatic drainage. Portions of the eye are avascular— the cornea and lens. The aqueous humor contains several factors that are known to be immunosuppressive, including transforming growth factor-β and α-melanocyte-stimulating hormone. Several tissues within the eye express ligands that promote apoptosis, including TRAIL and Fas ligand. If a soluble antigen is injected into the anterior chamber, a cellular immune response is suppressed. This phenomenon is known as ACAID, anterior chamber–associated immune deviation. These factors are important to consider in the effort to understand why the eye is sometimes targeted as part of an immune or inflammatory disease.

UVEITIS Rheumatologists may be consulted to identify a systemic disease in a patient with uveitis, and a rheumatologist often is asked to assist in the management of immunosuppression in selected patients with uveitis. In some referral practices for patients with uveitis, 40% of patients might have an associated systemic illness. Table 46-2 lists the differential diagnoses of uveitis. The immunologic diseases most likely to be associated with uveitis are listed in Table 46-3.

Figure 46-3  Ocular coherence tomography produces precise imaging of retinal structure. The ovoid black hole in the center of the image is due to macular edema, a major cause of visual loss in patients with uveitis.

Table 46-2  Differential Diagnosis of Uveitis Infections—toxoplasmosis, syphilis, herpes simplex, herpes zoster, and cytomegalovirus Systemic, immune-mediated diseases Masquerade syndromes such as lymphoma Syndromes confined to the eye, such as pars planitis, birdshot   chorioretinopathy, and serpiginous choroiditis

The most common systemic illness associated with uveitis in most North American practices is ankylosing spondylitis. From an epidemiologic perspective, anterior uveitis is more common than posterior or intermediate uveitis.3 About 50% of individuals who develop an anterior uveitis are HLAB27+.4 The uveitis associated with HLA-B27 is almost always unilateral, is recurrent, is of relatively short duration (<3 months per attack), resolves completely between attacks, and is associated with reduced intraocular pressure (in contrast to herpes simplex, which can cause a recurrent anterior uveitis associated with increased ­ intraocular pressure).5 Hypopyon or pus in the anterior chamber is sometimes present in patients with HLA-B27–associated uveitis (Fig. 46-4). Recurrent episodes can affect the contralateral eye, but simultaneous bilateral involvement is rare.

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Table 46-3  Immune-Mediated Diseases Most Often   Associated with Uveitis Ankylosing spondylitis Behçet’s disease Drug/hypersensitivity reactions Familial granulomatosus synovitis Inflammatory bowel disease Interstitial nephritis Juvenile idiopathic arthritis Multiple sclerosis Neonatal onset multisystem inflammatory disease Psoriatic arthritis Reactive arthritis Sarcoidosis Sweet’s syndrome Systemic lupus erythematosus Vasculitis, especially Cogan’s syndrome and Kawasaki disease Vogt-Koyanagi-Harada syndrome

Figure 46-4  The creamy material at the bottom of the pupil is an a­ ccumulation of leukocytes or hypopyon.

Many studies have tried to address the question of how frequently a patient with HLA-B27–associated anterior uveitis has an associated spondyloarthropathy. A wide range of answers have been suggested, and the percentage depends on the definition of spondyloarthropathy, but one reasonable estimate is that 80% of HLA-B27+ patients with acute anterior, unilateral uveitis have associated spondyloarthropathy.5 The uveitis associated with reactive arthritis is indistinguishable from the uveitis associated with ankylosing spondylitis. In either of these entities, about 40% of patients develop acute anterior uveitis during a lifetime. Although conjunctivitis is part of the classic triad of reactive arthritis (in association with arthritis and nongonococcal urethritis), conjunctivitis is uncommon. A genome-wide screen for susceptibility genes for acute anterior uveitis identified loci that also predispose to ankylosing spondylitis and loci that seem to be unassociated with susceptibility to ankylosing spondylitis.6 Approximately 5% of patients with inflammatory bowel disease and 7% of patients with psoriatic arthritis also

Figure 46-5  Keratic precipitates. The white dots result from concretions of cells depositing against the corneal endothelium. These keratic precipitates are large and usually described as granulomatous even though a granuloma is not present histologically.

develop uveitis. Although some of these patients have disease that is unilateral, anterior, and recurrent, many have disease that is bilateral, chronic in duration, and posterior to the lens.7,8 About half of all patients with Crohn’s disease or psoriatic arthritis and uveitis are HLA-B27+. Sarcoidosis is the second most common systemic disease associated with uveitis, at least in North America, and in some geographic areas it might be more common than spondyloarthritis. Sarcoidosis is promiscuous within the eye, meaning that it can affect a wide range of structures, including the orbit, lacrimal gland, anterior uvea, vitreous humor, choroid, retina, or optic nerve. The ocular inflammation with sarcoidosis frequently is termed granulomatous because large collections of cells deposit on the back of the cornea (Fig. 46-5). A retinal vasculitis is frequently a prominent feature of sarcoidosis, even though systemic vasculitis is not a typical systemic feature of the disease; this results partly from the manner in which vasculitis is diagnosed in the retina. Histologic evidence of vessel wall destruction is rarely obtained because of the morbidity of a retinal biopsy. Instead, a retinal vasculitis is diagnosed on the basis of perivascular sheathing along a vessel as seen on funduscopic examination (Fig. 46-6), intraretinal hemorrhages that must be secondary to vascular injury, and fluorescein angiography indicating increased vascular permeability.9 The term retinal vasculitis is misleading to most rheumatologists because the classic systemic vasculitides, such as polyarteritis nodosa and Wegener’s granulomatosis, rarely are associated with retinal vasculitis. Sarcoidosis frequently manifests initially as an ocular problem.10 An ocular symptom is the initial manifestation almost as frequently as a lung symptom. Sarcoidosis frequently involves the conjunctiva, which is an accessible tissue for biopsy confirmation of the diagnosis. In most series of patients with uveitis, about 30% of the patients have uveitis that defies placement within a diagnostic category.11 Many of these patients may have sarcoidosis that is difficult to find outside the eye. The sensitivity and specificity of studies such as a serum angiotensin-converting enzyme level or gallium scan for sarcoid that is primarily ocular are unknown. The author routinely obtains a chest computed tomography

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Figure 46-6  Retinal vasculitis. Arrows indicate areas of vascular sheathing or occlusion.

Figure 46-7  Band keratopathy is illustrated by the calcific patches stretching across the cornea.

(CT) scan to look for symmetric hilar adenopathy in any patient who has a uveitis of unknown etiology.12 Juvenile idiopathic arthritis comprises several ­ different diseases. Patients with juvenile ankylosing spondylitis resemble their adult counterparts in that they can develop a sudden-onset, unilateral anterior uveitis. The subset of juvenile idiopathic arthritis that is most classically associated with uveitis tends to be girls with the onset of arthritis between 2 and 8 years old.13 The joint disease is pauciarticular, and most patients are antinuclear antibody positive. The uveitis tends to have an insidious onset such that pain and redness are almost always absent. The joint disease can be minimal as well, so that some patients are not diagnosed until a visual screening examination is performed when starting school. The eye disease is usually bilateral and very persistent, although remissions are now well described. Band keratopathy, which is the deposition of calcium superficially in the cornea, is a well-known and frequent complication of this form of uveitis (Fig. 46-7). Patients also may develop glaucoma and posterior synechiae, a term that describes adhesions of the iris to the lens. Other forms of uveitis associated with joint disease include Behçet’s syndrome, relapsing polychondritis, and vasculitis such as Cogan’s syndrome and Kawasaki disease. In Behçet’s syndrome, uveitis is often the symptom that “drives” the therapy; that is, it is often the manifestation that most requires systemic immunotherapy.14 Eye inflammation is usually bilateral and recurrent. In contrast to the recurrences typical of ankylosing spondylitis, recurrences of uveitis with Behçet’s syndrome usually do not have complete resolution between attacks. A hallmark of Behçet’s syndrome–associated uveitis is a retinal vasculitis. Retinal arteries are especially prone to be affected. The visual prognosis with Behçet’s syndrome can be grim, and blindness is a frequent concomitant of untreated ocular disease. Relapsing polychondritis can have an impact on almost any portion of the eye, including the episclera, sclera, and uveal tract.15 Ocular inflammation is common. Cogan’s syndrome is classically defined as sensorineural hearing loss with corneal disease, especially an interstitial keratitis. This definition is usually broadened to include any ocular inflammatory process, such as uveitis or scleritis. Although uveitis can occur with polyarteritis or Wegener’s

granulomatosis, scleral disease is more typical. In contrast, anterior uveitis in association with conjunctivitis is present in most patients with Kawasaki’s disease. Uveitis and arthritis occasionally can result from an infection such as Whipple’s disease or Lyme disease. Uveal involvement with Lyme disease is described, but extremely rare. Some autoinflammatory diseases are associated with uveitis. Autoinflammatory diseases are characterized by widespread inflammation in the absence of detectable autoantibodies. Many autoinflammatory syndromes respond dramatically to inhibition of interleukin-1. Blau syndrome, which also is known as familial granulomatous synovitis, results from a single base change in the nucleotide binding domain of the CARD15 gene, which is also known as NOD2.16 Polymorphisms elsewhere in this same gene predispose to Crohn’s disease. Blau syndrome is characterized by the childhood onset of uveitis, arthritis, and dermatitis. Inflammation in additional organ systems also has been described. The disease is autosomal dominant. The histopathology of affected skin or joint can show noncaseating granuloma as in sarcoidosis. Lung involvement has not been described in Blau syndrome, however. Many patients thought to have so-called early-onset sarcoid have now been shown by gene sequencing to have new mutations in the NOD2 gene.17 Neonatal-onset multisystem inflammatory disease (NOMID), which also is known as chronic infantile neurologic cutaneous articular syndrome, is an autosomal dominant autoinflammatory syndrome. Ocular involvement in NOMID is more variable than in Blau syndrome. Characteristic findings include papilledema and uveitis.18 The therapy of uveitis depends on multiple factors, such as severity, location within the eye, patient preference, and the specific diagnosis (e.g., Behçet’s syndrome might be especially responsive to either infliximab19 or interferon alfa20). For noninfectious causes of uveitis that involve the anterior portion of the eye, treatment usually begins with topical corticosteroids and often dilating drops to prevent posterior synechiae and to relieve spasm of the ciliary muscle. Periocular corticosteroid injections, usually with triamcinolone, are given for inflammation posterior to the lens that is not responding to topical medication. Local corticosteroids can increase intraocular pressure, induce cataracts, interfere

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Figure 46-8  Scleral nodule. Active scleritis is present superior to the limbus. In this patient, the scleritis has taken on a nodular configuration.

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Figure 46-10  Corneal melt. The white light of the slit lamp beam narrows over the peripheral cornea where the tissue is thin.

all of these options in the therapeutic armamentarium of a uveitis clinic.

SCLERITIS AND CORNEAL MELT

Figure 46-9  Scleromalacia has resulted in a bluish ulceration in the sclera.

with the response to infection, and delay wound healing. A long-lasting corticosteroid implant containing fluocinolone has been approved by the Food and Drug Administration.21 All patients who elect this type of therapy develop a cataract if the lens has not already been surgically removed, and most patients develop glaucoma, many requiring surgery to control the intraocular pressure. Systemic immunosuppressive therapy generally is reserved for patients with active, noninfectious causes of inflammation. For systemic immunosuppression to be indicated, usually the inflammation is bilateral and severe enough to interfere with activities of daily living. A variety of immunomodulatory medications have been tried to treat intraocular inflammation, including azathioprine, chlorambucil, cyclophosphamide, cyclosporine, daclizumab, infliximab, methotrexate, mycophenolate mofetil, and tacrolimus. The optimal choice depends on many factors, not the least of which is the empiric result of any therapeutic approach. Maintaining a treatment for uveitis usually requires some efficacy in association with good tolerability. In this regard, at least one study found methotrexate to be superior to other antimetabolites.22 Because of the range of diseases being treated and the range of clinical response, there is room for

Scleritis often is divided into five categories: diffuse anterior, nodular, necrotizing, scleromalacia perforans, and posterior (Fig. 46-8). The first three categories each result in a red, painful eye. Pain is more variable in scleromalacia perforans, in which a nodule pathologically similar to a rheumatoid nodule forms in the sclera (Fig. 46-9). Pain also varies with posterior scleritis, and because the sclera extends back to the optic nerve, posterior scleritis can occur in a localized fashion such that the eye is not red. Because of the risk of perforation, the sclera is not normally biopsied, but biopsy studies have shown that scleritis is often a granulomatous inflammation of scleral tissue.23 Patients with scleritis can develop complications within the eye, including uveitis, glaucoma, optic nerve edema, and retinal or choroidal distortion. A corneal melt or peripheral thinning of the cornea sometimes develops in individuals with severe scleritis and represents a potentially blinding complication of the disease (Fig. 46-10). About 50% of patients with scleritis have an associated systemic illness.24 The most common such illness is rheumatoid arthritis. Generally, this is long-standing, seropositive rheumatoid arthritis. These patients may have associated nodules, vasculitis, or pleuropericarditis. They have a shortened life expectancy compared with other patients with rheumatoid arthritis.25 It is unusual for scleritis to be an initial manifestation of rheumatoid arthritis. Wegener’s granulomatosis is probably the second most common disease associated with scleritis. In contrast to rheumatoid arthritis, scleritis can be the initial manifestation of Wegener’s granulomatosis, and our routine is to obtain antineutrophilic cytoplasmic antibody serology on any patient who presents with scleritis without an obvious systemic disease association. Other systemic associations with scleritis include inflammatory bowel disease, relapsing polychondritis, other vasculitides including temporal arteritis, and ankylosing spondylitis. Infections are a rare but possible cause of scleritis. Tophaceous gout also has been reported as a rare cause of scleritis.

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Scleritis tends to be a painful and persistent disease that often lasts for years. In contrast, episcleritis involves more superficial tissue and is usually transient. Episcleritis may be a feature of rheumatoid arthritis, although many patients with episcleritis may not have any associated systemic illness. Complications within the eye, such as glaucoma or uveitis, are absent. Mild discomfort, rather than frank pain, is the usual presenting symptom. In contrast to scleritis, patients with episcleritis have vessels that constrict completely after 2.5% phenylephrine (Neo-Synephrine) is placed on the surface of the eye. Some patients with scleritis, especially patients who do not have an associated systemic illness, are treated adequately by an oral nonsteroidal anti-inflammatory drug. Some experts treat scleritis with locally injected corticosteroids, but this should be avoided if the sclera is thin (necrotizing disease). In addition, corticosteroid has the theoretical risk of promoting thinning. The usual option for patients who do not respond to nonsteroidal anti-inflammatory drugs is oral prednisone. Some patients can be maintained on low doses of prednisone, but many require the addition of an antimetabolite as a steroid-sparing drug. A substantial subset of patients with scleritis, especially patients who are positive for antineutrophilic cytoplasmic antibody, are best managed with an alkylating agent, such as cyclophosphamide. Because of the risk of this therapeutic approach, this drug is often given until the disease is in remission for several months, and then the therapy is switched to an antimetabolite to maintain the disease-free state.

ORBITAL DISEASE Graves’ disease is the most common orbital inflammatory disease and generally results in an orbital myositis that can be identified on imaging such as CT, ultrasound, or magnetic resonance imaging (MRI). From a rheumatologic perspective, Wegener’s granulomatosis is the disease that most commonly affects the orbit. The inflammation can be extremely painful and may result in blindness. Inflammation is sometimes more recalcitrant to therapy than other aspects of Wegener’s granulomatosis. A small series suggested that rituximab may be efficacious in patients with Wegener’s granulomatosis, including patients with orbital involvement.26 Orbital pseudotumor, or nonspecific orbital inflammatory disease, is a diagnosis of exclusion that is made on the basis of objective orbital swelling as documented by imaging and a biopsy showing an inflammatory process that cannot be ascribed to another process such as Graves’ disease. A biopsy specimen of the orbit is not always obtained, but it can be useful in ruling out lymphoma or a metastatic malignancy as the cause of the proptosis. Methotrexate is a therapeutic option to treat nonspecific orbital inflammation.27 Other systemic diseases that affect the orbit commonly include sarcoidosis.

disease that most commonly affects the optic nerve is ­multiple sclerosis. This demyelinating condition generally starts suddenly in one eye with pain, an afferent pupillary defect, a loss in color vision, and visual field loss typical of optic nerve disease. Initially, the optic nerve may show papilledema, or it may appear normal if the inflammation is retrobulbar. Over several weeks, the affected nerve usually becomes pale. Demyelinating disease affecting the optic nerve generally is not treated by a rheumatologist, but a rare patient with optic nerve disease has inflammation that might require long-term immunosuppression. These patients carry a diagnosis labeled variously as autoimmune optic neuropathy or sometimes steroid-sensitive optic neuropathy. This diagnosis is clinically distinct from optic neuritis associated with multiple sclerosis in that MRI of the head should not indicate a demyelinating process, the disease is often bilateral, the kinetics of the inflammation are different from multiple sclerosis, and the disease usually responds to oral corticosteroids. In most centers, a neuro-ophthalmologist would be involved in establishing this diagnosis. Systemic lupus erythematosus and sarcoidosis may affect the optic nerve in this way, but many patients with this diagnosis do not have an associated systemic illness. Either alkylating agent therapy or an antimetabolite can be beneficial for many patients with this entity.28 Sudden blindness is arguably the most feared consequence of temporal arteritis. This disease is characterized by granulomatous inflammation of multiple vessels above the waist. These frequently include the temporal artery and the posterior ciliary arteries. Inflammation in these latter vessels leads to anterior ischemic optic neuropathy (AION), which is ischemia of the optic nerve that manifests as sudden visual loss (Fig. 46-11). Temporal arteritis also can affect the central retinal artery, which may result in blindness. For this condition, the funduscopic appearance of the eye shows markedly reduced arteriolar flow and a cherry-red spot in the macula. Temporal arteritis can cause diplopia by affecting circulation to extraocular muscles. The visual loss associated with temporal arteritis is frequently labeled arteritic AION to distinguish it from the more common nonarteritic AION that is usually ­attributable

OPTIC NEURITIS Optic nerve disease can result from many insults, including toxins (some of which are medications), vascular insufficiency as occurs from atherosclerotic disease or giant cell arteritis, and immunologic attack. The immune-mediated

Figure 46-11  Anterior ischemic optic neuropathy resulting from  giant cell arteritis. The optic nerve is swollen, and there are surrounding  hemorrhages.

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to small vessel atherosclerosis. Patients with arteritic AION are typically older than 50 years and have an erythrocyte sedimentation rate greater than 50 mm/hr. Many patients with arteritic AION have associated symptoms of polymyalgia rheumatica, jaw claudication, scalp tenderness, or temporal artery tenderness. The biopsy specimen of the temporal artery shows vasculitis in about 80% of patients with temporal arteritis if an adequate length of vessel is sampled. Twenty percent of patients with temporal arteritis might have a biopsy specimen of the artery that is negative because it either has spared this vessel or has affected it in a sufficiently patchy distribution such that the biopsy specimen did not reveal the pathology. Patients with nonarteritic AION tend to have small optic nerve cups.

SUMMARY In some ways, from a rheumatologist’s perspective, the eye is a microcosm of the body. Its complex structures frequently reflect inflammation elsewhere in the body. The treatment of many forms of ocular inflammation requires collaboration between a rheumatologist and an ophthalmologist. REFERENCES   1. Jabs DA, Nussenblatt RB, Rosenbaum JT: Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 140:509-516, 2005.   2. Niederkorn JY: See no evil, hear no evil, do no evil: the lessons of immune privilege. Nat Immunol 7:353-359, 2006.   3. Gritz DC, Wong IG: Incidence and prevalence of uveitis in Northern California; the Northern California Epidemiology of Uveitis Study. Ophthalmology 111:491-500, 2004.   4. Brewerton DA, Caffrey M, Nicholls A, et al: Acute anterior uveitis and HL-A 27. Lancet 2:994-996, 1973.   5. Rosenbaum JT: Characterization of uveitis associated with spondyloarthritis. J Rheumatol 16:792-796, 1989.   6. Martin TM, Zhang G, Luo J, et al: A locus on chromosome 9p predisposes to a specific disease manifestation, acute anterior uveitis, in ankylosing spondylitis, a genetically complex, multisystem, inflammatory disease. Arthritis Rheum 52:269-274, 2005.   7. Paiva ES, Macaluso DC, Edwards A, et al: Characterisation of uveitis in patients with psoriatic arthritis. Ann Rheum Dis 59:67-70, 2000.   8. Lyons JL, Rosenbaum JT: Uveitis associated with inflammatory bowel disease compared with uveitis associated with spondyloarthropathy. Arch Ophthalmol 115:61-64, 1997.

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  9. Rosenbaum JT, Robertson JE, Watzke RC: Retinal vasculitis: A primer. West J Med 154:182-185, 1991. 10. Obenauf CD, Shaw HE, Sydnor CF, et al: Sarcoidosis and its ophthalmic manifestations. Am J Ophthalmol 86:648-655, 1978. 11. Rosenbaum JT: Uveitis: An internist’s view. Arch Intern Med 149:1173-1176, 1989. 12. Kaiser PK, Lowder CY, Sullivan P, et al: Chest computerized tomography in the evaluation of uveitis in elderly women. Am J Ophthalmol 133:499-505, 2002. 13. Petty RE, Smith JR, Rosenbaum JT: Arthritis and uveitis in children: A pediatric rheumatology perspective. Am J Ophthalmol 135: 879-884, 2003. 14. Yazici H, Pazarli H, Barnes CG, et al: A controlled trial of azathioprine in Behçet’s syndrome. N Engl J Med 322:281-285, 1990. 15. Isaak BL, Liesegang TJ, Michet CJJ: Ocular and systemic findings in relapsing polychondritis. Ophthalmology 93:681-689, 1986. 16. Miceli-Richard C, Lesage S, Rybojad M, et al: CARD15 mutations in Blau syndrome. Nat Genet 29:19-20, 2001. 17. Rose CD, Wouters CH, Meiorin S, et al: Pediatric granulomatous arthritis: An international registry. Arthritis Rheum 54:3337-3344, 2006. 18. Dollfus H, Hafner R, Hofmann HM, et al: Chronic infantile neurological cutaneous and articular/neonatal onset multisystem inflammatory disease syndrome: Ocular manifestations in a recently recognized chronic inflammatory disease of childhood. Arch Ophthalmol 8:386-392, 2000. 19. Sfikakis PP, Theodossiadis PG, Katsiari CG, et al: Effect of inflix­ imab on sight-threatening panuveitis in Behçet’s disease. Lancet 358:295-296, 2001. 20. Kotter I, Zierhut M, Eckstein AK, et al: Human recombinant interferon alfa-2a for the treatment of Behçet’s disease with sight threatening posterior or panuveitis. Br J Ophthalmol 87:423-431, 2003. 21. Lim LL, Smith JR, Rosenbaum JT: Retisert (Bausch & Lomb/Control Delivery Systems). Curr Opin Investig Drugs 6:1159-1167, 2005. 22. Baker KB, Spurrier NJ, Watkins AS, et al: Retention time for corticosteroid-sparing systemic immunosuppressive agents in patients with inflammatory eye disease. Br J Ophthalmol 90:1481-1485, 2006. 23. Riono WP, Hidayat AA, Rao NA: Scleritis: A clinicopathologic study of 55 cases. Ophthalmology 106:1328-1333, 1999. 24. Akpek EK, Thorne JE, Qazi FA, et al: Evaluation of patients with scleritis for systemic disease. Ophthalmology 111:501-506, 2004. 25. Foster CS, Forstot SL, Wilson LA: Mortality rate in rheumatoid arthritis patients developing necrotizing scleritis or peripheral ulcerative keratitis. Ophthalmology 91:1253-1263, 1984. 26. Keogh KA, Wylam ME, Stone JM, et al: Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 52:262-268, 2005. 27. Smith JR, Rosenbaum JT: A role for methotrexate in the management of non-infectious orbital inflammatory disease. Br J Ophthalmol 85: 1220-1224, 2001. 28. Myers TD, Smith JR, Wertheim MS, et al: Use of corticosteroid sparing systemic immunosuppression for treatment of corticosteroid dependent optic neuritis not associated with demyelinating disease. Br J Ophthalmol 88:673-680, 2004.

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The Skin and Rheumatic Diseases LELA A. LEE  •  VICTORIA P. WERTH

KEY POINTS Many systemic rheumatologic conditions present with skin findings. The differential diagnosis for skin findings may require a skin biopsy for clinical-pathologic correlation. Systemic steroids should be avoided in psoriasis, because ­flaring may occur with tapering of systemic glucocorticoids. New biologic therapies have substantially improved the care of patients with severe and resistant psoriasis. The neutrophilic dermatoses are a group of inflammatory diseases, including pyoderma gangrenosum and Sweet’s ­syndrome, that can be associated with autoimmune diseases. Patients with lupus erythematosus can have a wide variety of lupus-specific and -nonspecific skin lesions. Lupus-nonspecific skin lesions are more frequently seen in patients with systemic lupus erythematosus. Patients with dermatomyositis frequently have pathognomonic skin lesions that may be seen in the absence of muscle disease. Antimalarials may be of benefit in patients with morphea.

THE DIAGNOSIS OF SKIN LESIONS ASSOCIATED WITH RHEUMATIC DISEASES The skin is a highly visible organ that is frequently affected in rheumatic diseases, and the presence of skin lesions may be helpful diagnostically. However, certain caveats must be considered before proceeding to a more specific discussion of these diseases. First, a major pitfall for the nondermatologist is incomplete knowledge of the entities in the differential diagnosis. For example, malar erythema occurs frequently in patients with systemic lupus erythematosus (SLE), but the differential diagnosis for malar erythema is rather extensive and includes both conditions that are much more prevalent than lupus (e.g., rosacea) and those that are far less prevalent (e.g., Rothmund-Thomson syndrome). Patients frequently have more than one skin condition, which often makes the diagnosis more challenging. Another caveat has to do with skin biopsy. Being able to determine when a skin biopsy is likely to be diagnostically useful often requires specialized knowledge, as does the interpretation of pathology reports. With inflammatory skin conditions, the microscopic findings are often less diagnostically specific than is the clinical examination. Unfortunately, it is common for a pathology report to list a diagnosis without indicating how definitive the findings were. For example, a skin biopsy report may list psoriasis as the final diagnosis, but, depending on the specific case,

other unstated possibilities may include nummular dermatitis, atopic dermatitis, seborrheic dermatitis, lichen simplex chronicus, dermatophytosis, and drug eruption. Thus, a working knowledge of both dermatopathology and dermatology, and the ability to place the histologic findings in the context of the clinical presentation, may be necessary to arrive at the correct diagnosis. These considerations notwithstanding, it is clearly useful for the physician caring for patients with rheumatic diseases to be well versed in their cutaneous manifestations. In this chapter, we provide an overview of these manifestations, as well as a perspective on their diagnosis and differential diagnosis. Therapy is discussed briefly when the treatment may be specifically directed toward the skin lesions. Etiology and pathogenesis of these diseases are covered elsewhere in this text.

PSORIASIS Psoriasis is one of the most common inflammatory skin diseases, affecting about 2% of the general population. There is a wide range of severity, from a few relatively asymptomatic plaques to extensive, disabling disease. The onset may occur ar any time during life. Once the disease is present, there may be exacerbations and remissions, but it does not tend to resolve permanently. In general, onset in childhood portends more severe disease. The characteristic skin lesions of psoriasis are sharply demarcated plaques with underlying erythema and silvery scales, although there may be a paucity of scales if the lesions have been partially treated or if they occur in intertriginous areas. When the scale is removed, pinpoint bleeding may be observed (Auspitz sign). Lesions may occur in areas of trauma (Koebner’s phenomenon), such as in surgical scars. In some cases, lesions contain small pustules. General phenotypes of psoriasis are chronic plaque, guttate, localized pustular, generalized pustular, and erythroderma.1 Chronic plaque and guttate psoriasis are the most common; generalized pustular psoriasis and erythroderma are typically the most disabling and even life threatening. Chronic plaque psoriasis lesions are often relatively large in diameter and occur preferentially on the elbows, knees, scalp, genitalia, lower back, and gluteal cleft, although they may occur at many other locations. It is quite common for only one area of skin, such as the scalp, to be affected. Guttate lesions are relatively small in diameter and usually quite numerous, distributed preferentially on the trunk and proximal extremities (Fig. 47-1). Guttate psoriasis occurs relatively commonly in children and young adults, often manifesting a few weeks after a ­streptococcal infection.

  Supplemental images available on the Expert Consult Premium Edition website.

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Figure 47-1  Guttate psoriasis resembles “drops” of discrete scaly ­ apules with erythema, often on the trunk. (Courtesy of Dr. Nicole Rogers, p ­Tulane University Department of Dermatology, New Orleans.)

Nail changes are common, occurring in about half of patients, and are often mistaken for fungal infection. Charac­ teristic changes include pitting, onycholysis (“oil spots”), dystrophy of nails, and loss of the nail plate. These changes are not specific for psoriasis. Notably, pitting may occur as a result of trauma, and the finding of a few pits in the nails may not be helpful diagnostically. Nail changes are more frequent in patients with arthritis of the distal interphalangeal joints.2 Arthritis occurs more often in patients with severe cutaneous disease, but cutaneous disease need not be present at all. Remissions and exacerbations of arthritis do not correlate well with remissions and exacerbations of skin disease. The presence of psoriatic skin lesions may be helpful in supporting a diagnosis of psoriatic arthritis, although many patients with psoriasis have joint disease unrelated to psoriasis. The diagnosis of psoriatic skin disease is usually made on clinical grounds alone, based in large part on the morphology and distribution of lesions. The differential diagnosis may be extensive and includes in selected cases nummular eczema, seborrheic dermatitis, candidiasis (in intertriginous areas), pityriasis rubra pilaris, Bowen’s disease or Paget’s disease (for isolated plaques), drug eruption, pityriasis rosea, pityriasis lichenoides, dermatophytosis, lichen planus, secondary syphilis, parapsoriasis, cutaneous lupus (especially subacute cutaneous lupus), and dermatomyositis. In cases in which the diagnosis is not clear-cut, biopsy may be helpful. The histologic findings may range from virtually diagnostic for psoriasis to merely consistent with but not diagnostic. Histologically, psoriasis generally cannot be distinguished from Reiter’s syndrome. Common topical therapies include corticosteroids, tar, anthralin, calcipotriene, and tazarotene.3 Phototherapy using sunlight, broad-band ultraviolet B (UVB), narrowband UVB, or psoralen plus ultraviolet A (PUVA) is still a mainstay for many patients. Common systemic therapies include methotrexate, acitretin, cyclosporine, and the relatively new biologic agents. Although topical corticosteroids are an acceptable treatment for many patients, systemic corticosteroids are avoided for the treatment of cutaneous ­disease because of the severe flaring of psoriasis that can occur following their withdrawal.

The diagnosis of Reiter’s syndrome may be rather straightforward in a young male who develops urethritis, conjunctivitis, and arthritis following an episode of nongonococcal urethritis. However, in many cases, the clinical features are not fully expressed, and cutaneous lesions may be helpful in establishing the diagnosis.4 Circinate balanitis is the most common of the characteristic mucocutaneous lesions. Small erythematous papules and pustules coalesce to form serpiginous erosive or crusted plaques on the glans penis. In uncircumcised men, the appearance is often that of erosion rather than crust, because the moisture and trauma minimize the formation of crust. In circumcised men, crusting may be more obvious than erosion. The palms and, particularly, the soles may develop lesions that are initially similar to the small erythematous papules and pustules of the genital region. With time, these lesions, termed keratoderma blennorrhagica, tend to become markedly hyperkeratotic (Fig. 47-2). They may coalesce into large plaques or generalized hyperkeratosis involving the entire plantar surface, or they may remain discrete, erythematous, hyperkeratotic papules a few millimeters in diameter. Erythematous, scaly plaques indistinguishable from psoriasis may appear elsewhere on the skin, including the scalp, elbows, and knees. When lesions occur around the nails, it is common for there to be hyperkeratosis underneath the nails. Pitting is not typical of Reiter’s syndrome, but thickening, ridging, or shedding of the nail plate may occur. Erosions of the oral mucosa are relatively common on the tongue, buccal mucosa, and palate. The cutaneous lesions are usually diagnosed on a clinical basis. Skin biopsy may be helpful in excluding many entities in the differential diagnosis but generally cannot exclude psoriasis—the major condition in the differential ­diagnosis. One somewhat distinguishing feature is that the older lesions of keratoderma blennorrhagica may have a considerably thickened stratum corneum, corresponding to the markedly hyperkeratotic papules seen grossly.

Figure 47-2  Reiter’s syndrome with keratoderma blennorrhagica of the feet.

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For the genital lesions, conditions to consider in the differential diagnosis may include candidiasis, psoriasis, dermatitis, Bowen’s disease, Paget’s disease, squamous cell carcinoma, Zoon’s balanitis, erosive lichen planus, lichen sclerosus (balanitis xerotica obliterans), aphthosis, fixed drug eruption, and certain infectious diseases. The differential diagnosis for lesions on the soles and palms may include psoriasis, hereditary or acquired hyperkeratosis of the palms and soles, pustular eruption of the palms and soles, pompholyx, scabies, and dermatophytosis. The differential diagnosis for oral lesions may include geographic tongue, lichen planus, candidiasis, aphthae, and autoimmune bullous ­diseases. The approach to the treatment of skin lesions is similar to that for psoriasis, particularly in cases in which the lesions are persistent. Choice of topical therapies may be somewhat limited owing to the sites involved. It is difficult to deliver medication topically to the oral mucosa, and the genital area may develop irritant reactions to certain topical medications. Often, topical corticosteroids are preferred for both these areas because of the low potential for irritation and the availability of topical preparations specifically designed for these sites. In the genital area, suprainfection with Candida may occur, and concurrent therapy with a topical or systemic anticandidal medication may be needed.

RHEUMATOID ARTHRITIS The major skin manifestations associated with rheumatoid arthritis (RA) can generally be divided into granulomatous lesions, exemplified by the rheumatoid nodule, and neutrophilic lesions, exemplified by vasculitis and pyoderma gangrenosum. Rheumatoid nodules are the most common cutaneous manifestations of RA.5 They occur more often in seropositive patients and correlate somewhat with higher rheumatoid factor titers, more severe arthritis, and increased risk for vasculitis. Nodules are usually relatively deep, firm, and painless, and they tend to develop over areas of pressure and trauma, such as the extensor forearms, fingers, olecranon processes, ischial tuberosities, sacrum, knees, heels, and posterior scalp (Fig. 47-3). In patients who wear glasses, nodules may develop under the bridge or nosepiece. In most cases, rheumatoid nodules are in the subcutaneous tissue or deep dermis, but they occasionally occur more deeply or more superficially. Clinically, depending on the presentation, numerous entities may be considered in the differential diagnosis, including infections, inflammatory disorders, and benign tumors. If necessary, biopsy of a nodule may be quite helpful in establishing the diagnosis. Rheumatoid nodules exhibit a distinctive histologic finding called necrobiosis, a fibrinoid degeneration of the connective tissue, surrounded by palisaded histiocytes. Necrobiosis is also a characteristic feature of granuloma annulare and necrobiosis lipoidica diabeticorum. Although necrobiosis lipoidica diabeticorum is easily distinguished from rheumatoid nodule clinically, the subcutaneous variant of granuloma annulare may be difficult to distinguish both clinically and histologically. The term rheumatoid nodulosis has been used to describe an entity characterized by subcutaneous rheumatoid nodules, cystic bone lesions, rheumatoid factor positivity, and arthralgias in patients with little or no evidence of

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Figure 47-3  Rheumatoid nodule over the extensor tendon of the distal interphalangeal joint.

systemic manifestations of RA or erosive joint disease.6 Older males are preferentially affected. The development of new nodules in RA patients undergoing treatment with methotrexate has been noted by several observers and termed accelerated rheumatoid nodulosis.7 The nodules occur preferentially on the hands. There are also case reports of the phenomenon in RA patients treated with etanercept. The other major type of cutaneous lesion associated with RA is neutrophil predominant. Rheumatoid vasculitis occurs more frequently in patients who are seropositive and have rheumatoid nodules, and it often occurs relatively late in the course of the disease.8 Vessels of any size may be affected. In the skin, vasculitis may appear as purpuric papules and macules, nodules, ulcerations, or infarcts. Bywaters’ lesions are periungual or digital pulp purpuric papules representing a small vessel vasculitis; they are not necessarily associated with vasculitic lesions elsewhere. The differential diagnosis of purpuric or petechial lesions may include stasis dermatitis, Schamberg’s purpura, platelet dysfunction, petechial drug eruptions, viral exanthems, emboli, thromboses, and sludging. Of these, Schamberg’s purpura, a relatively common condition unassociated with systemic disease, is probably most frequently confused with small vessel vasculitis. Skin biopsy may be quite helpful in establishing the diagnosis of vasculitis, particularly if an early lesion is sampled, although rheumatoid vasculitis cannot be distinguished histologically from many other causes of small vessel vasculitis. Immunofluorescent examination of an early lesion may be helpful in ruling out immunoglobulin (Ig) A–predominant vasculitis. The differential diagnosis of ulcers and infarcts is extensive. Biopsy is often unrewarding, because nonspecific changes present in established lesions may make interpretation difficult. On occasion, however, biopsy of ulcers or infarcts may result in a definitive diagnosis of vasculitis. The neutrophilic dermatoses are a group of diseases that are inflammatory rather than infectious in origin, typified by pyoderma gangrenosum and Sweet’s syndrome. These conditions have been associated with a variety of extracutaneous diseases, including RA. The classic pyoderma gangrenosum lesion is a very rapidly appearing large, destructive ulcer in which the border is undermined. The classic lesion

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of Sweet’s syndrome is an erythematous, edematous plaque with a surface that is often described as mammillated, pseudovesicular, or microvesicular. Intermediate clinical appearances between these two entities have been described. For pyoderma gangrenosum, the differential diagnosis usually includes conditions causing leg ulcers, and the diagnosis is mainly clinical; biopsy serves primarily to exclude some of the other entities under consideration. For Sweet’s syndrome, the differential diagnosis may include infections, halogenoderma, and other neutrophilic dermatoses; biopsy often provides helpful supporting evidence. The mainstay of therapy for acute lesions of both conditions is systemic corticosteroids. For more persistent lesions, a variety of options may be considered; cyclosporine and infliximab are two of the more common. Colchicine or potassium iodide may be useful therapies for Sweet’s syndrome, particularly in patients with infections or contraindications to corticosteroids. The term rheumatoid neutrophilic dermatitis has been used to describe chronic, erythematous, urticaria-like plaques that occur primarily on the distal arms.9 Clinically and histologically, rheumatoid neutrophilic dermatitis is quite similar to Sweet’s syndrome and may be a variant of it. Palisaded neutrophilic and granulomatous dermatitis of connective tissue disease is an unusual condition or set of conditions for which consistent terminology is still evolving. As the name implies, the major bases for diagnosis of this entity are the histologic appearance and the occurrence in a patient with connective tissue disease, often RA.10 The clinical appearance ranges from erythematous or flesh-­colored papules that appear primarily on the fingers and elbows to erythematous or flesh-colored linear cords on the trunk. Some authors classify the latter as interstitial granulomatous dermatitis with cutaneous cords or interstitial granulomatous dermatitis with arthritis. Treatment can be challenging. Palisaded neutruophilic and granulomatous dermatitis may respond to dapsone or sulfapyridine. Interstitial granulomatous dermatits with arthritis can be treated with antimalarials or immunosuppressives; however, this is both a newly described and a relatively infrequent condition, and all evidence is based on case reports and small case series. Patients can progress to a severe deforming arthritis. In some cases, granuloma annulare and rheumatoid nodule may be in the differential diagnosis.

JUVENILE RHEUMATOID ARTHRITIS AND STILL’S DISEASE The majority of patients with classic Still’s disease manifest an exanthematous eruption coincident with daily fever spikes.11 The lesions are evanescent, usually nonpruritic, erythematous macules occurring over the trunk, extremities, and face. The differential diagnosis includes viral exanthem, drug eruption, familial periodic fever syndromes, and rheumatic fever. It is not unusual for exanthems of any type to be more prominent during fevers, but viral exanthems and drug eruptions would not be expected to clear completely between fever spikes. However, it should be noted that the eruption of erythema infectiosum (fifth disease) due to parvovirus B19 may resolve completely but reappear when the skin temperature rises, such as during warm baths or exercise. Skin biopsy is unlikely to be helpful in ­establishing the

diagnosis of Still’s disease or in excluding other entities in the differential diagnosis. Adult-onset Still’s disease is also typified by an evanescent, erythematous, sometimes salmoncolored eruption over the trunk and extremities, associated with high fever. Subcutaneous nodules may develop in both juvenileonset and adult-onset Still’s disease. The lesions tend to occur at the same sites as the rheumatoid nodules in RA, but histologically, they appear similar to the nodules of rheumatic fever.

LUPUS ERYTHEMATOSUS The skin becomes involved during the course of the disease in the majority of patients with lupus erythematosus (LE), and skin lesions may be important in establishing the diagnosis. Some skin lesions are highly likely to be associated with systemic (i.e., extracutaneous) disease, whereas others may or may not be associated with extracutaneous disease. The phenomenon of lupus skin lesions in the absence of systemic disease was previously termed discoid lupus by some; however, discoid lupus is a term used by dermatologists to denote a specific type of skin lesion, regardless of the presence or absence of systemic disease. We use the latter meaning in this chapter. LUPUS-SPECIFIC SKIN LESIONS Gilliam classified cutaneous lesions as being specific or nonspecific for lupus, with discoid lupus lesions being an example of the former, and palpable purpura being an example of the latter.12 Although this division is quite useful, a lupusspecific lesion sometimes occurs in a patient whose primary autoimmune disease is something other than LE. For example, subacute cutaneous lupus lesions may occur in patients whose primary condition is Sjögren’s syndrome, and discoid lesions may be seen in a variety of conditions, including mixed connective tissue disease. Many of the lupus-specific skin lesions can occur in patients who have no evidence of extracutaneous disease. The characteristic morphologies of the various lupusspecific skin lesions are in large part a function of the depth and intensity of the inflammatory infiltrate, presence or absence of epidermal basal cell damage, involvement of hair follicles, abundance of dermal mucin, and tendency to scar. In practice, these features may overlap, and a patient may have more than one type of lesion, making classification difficult. Because therapy for most of the lupus-specific lesions is similar, it is not always important to distinguish among the various types of lesions. However, it can be useful to identify conditions that are more likely to scar, and thus warrant more aggressive therapy, and to identify conditions that are highly likely or highly unlikely to be associated with systemic disease. Acute cutaneous lupus erythematosus (ACLE) lesions are typified by malar erythema, the classic butterfly rash (Fig. 47-4). The inflammation tends to be superficial, with little propensity to scar. Precipitation or exacerbation of lesions by sun exposure is common, and lesions tend to be distributed on the sun-exposed face, neck, extensor arms, and dorsal hands, where the skin over the knuckles is relatively spared. Often the lesions are transient, but they may

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Figure 47-4  Acute malar rash in a butterfly distribution in systemic l­upus erythematosus.

be ­ persistent. When the face is severely affected, facial edema may be prominent. Oral lesions are often present concurrently. Acute eruptions with considerable focal basal cell damage can result in erythematous papules with dusky centers that clinically mimic erythema multiforme. The major importance of recognizing ACLE is its strong association with systemic disease. The differential diagnosis of malar rash may include several conditions. In some cases, the facial rash of ACLE may be difficult to distinguish from rosacea. Seborrheic dermatitis, atopic dermatitis, and photosensitive eruptions such as polymorphous light eruption and drug-induced photosensitivity should also be considered. Dermatomyositis may cause a photosensitive facial erythema with edema very similar to ACLE, although the erythema tends to be more violaceous. Persistent lesions on the neck and arms may be indistinguishable from subacute cutaneous lupus erythematosus (SCLE). Discoid lupus lesions occasionally appear in a butterfly distribution, and they can result in disfiguring scarring. Skin biopsy is usually not performed on malar erythema because of its transient character, the scar resulting from biopsy, and the availability of other means of establishing the diagnosis of SLE. If a biopsy is done, it should be noted that dermatomyositis and SCLE cannot be distinguished from ACLE by histology, and skin biopsy findings are sometimes nonspecific. SCLE is a photosensitive eruption usually associated with anti-Ro/SS-A autoantibodies.13 Lesions are of two main types: annular erythematous plaques and scaly erythematous psoriatic plaques. They are distributed over the sun-exposed skin of the arms, upper trunk, neck, and sides of the face (Fig. 47-5). Inexplicably, the midfacial area is usually uninvolved. Fair-skinned individuals are preferentially affected. Lesions may resolve with hypopigmentation or even depigmentation, but they rarely scar. Several drugs, particularly hydrochlorothiazide, have been reported to induce SCLE.14 The risk for developing systemic disease is not fully known, but perhaps 15% of patients with SCLE have or will develop significant systemic disease—often SLE, Sjögren’s syndrome, or an overlap. Depending on the morphology of the lesions and the clinical presentation, the differential diagnosis may include psoriasis, tinea, polymorphous light eruption, reactive erythema, and erythema

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Figure 47-5  Subacute cutaneous lupus erythematosus—annularpolycyclic type.

multiforme. Skin biopsy for routine histology is often helpful in establishing the diagnosis. The characteristic finding of skin biopsy for immunofluorescence is a particulate deposition of IgG in the epidermis of both lesions and uninvolved skin (Fig. 47-6).15 This pattern can be reproduced in animal models by infusing anti-Ro; thus, immunofluorescence provides information that duplicates serologic testing for antiRo.16 The particulate epidermal pattern seen in normal skin does not carry the same implication for an increased risk of SLE as does the finding of granular deposits of IgG at the dermal-epidermal junction (the nonlesional lupus band test). It should be noted that many immunofluorescence laboratories do not routinely report epidermal findings. Discoid lupus erythematosus (DLE) lesions are the most common of the persistent lupus-specific skin lesions. Active lesions are erythematous papules and plaques that feel indurated to palpation because of the substantial numbers of inflammatory cells infiltrating the dermis. Involvement of hair follicles may be grossly evident as follicular plugs and scarring alopecia. Dyspigmentation is common, often with hypopigmentation or even depigmentation in the center and hyperpigmentation at the periphery (Fig. 47-7). Visible scale is common; it is occasionally pronounced in a clinical variant called hypertrophic DLE. In established

Figure 47-6  Direct immunofluorescence (lupus band test).

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Figure 47-7  Discoid lupus erythematosus of the scalp, with scarring alopecia and central hypopigmentation. (Courtesy of Dr. Nicole Rogers, Tulane University School of Medicine, New Orleans.)

lesions, ­ scarring may be disfiguring. Lesions tend to occur on the scalp, ears, and face, but they may be widespread and occasionally involve mucosal surfaces. It is unusual to have lesions below the neck in the absence of lesions above the neck.17 Sun exposure may exacerbate DLE in some cases, but the presence of lesions in sun-protected areas of the scalp and ears and the frequent absence of a history of photosensitivity indicate that sun exposure is probably not a trigger in every instance. There are case reports of squamous cell carcinoma developing in established DLE lesions. In a patient who presents with DLE lesions, the risk for developing SLE is probably about 5% to 10%, although mild systemic symptoms such as arthralgias are relatively common. The differential diagnosis of DLE lesions often consists of conditions exhibiting intense lymphocytic or granulomatous infiltrates, such as sarcoid, Jessner’s lymphocytic infiltrate, granuloma faciale, polymorphous light eruption, lymphocytoma cutis, and lymphoma cutis. In the scalp, lichen planopilaris and other scarring alopecias may be considered. Skin biopsy for routine histology often establishes the diagnosis definitively. In more difficult cases, biopsy for immunofluorescence may provide additional supporting diagnostic information. Lesions are expected to have granular deposits of immunoglobulins at the dermal-epidermal junction. Unless there is concomitant systemic disease, normal skin would not be expected to have immunoglobulin deposits. Tumid lupus erythematosus (TLE) skin lesions are similar to DLE lesions, in that they are erythematous, indurated papules and plaques with a substantial lymphocytic infiltrate. Unlike DLE, however, the lesions do not exhibit epidermal abnormalities, follicular involvement, or scarring. Considerable mucin is present in the dermis, giving the lesions a somewhat boggy look and feel. In some reports, lesions are most common on the face and may be reproduced by phototesting.18 The risk for SLE appears to be very low, and immunoglobulin deposits are not generally present in skin biopsies. Jessner’s lymphocytic infiltrate and other lymphocytic and granulomatous infiltrative conditions (noted earlier) are included in the differential diagnosis. Skin biopsy for routine histology is valuable in establishing the diagnosis, with the exception of reliably distinguishing TLE from Jessner’s ­lymphocytic ­infiltrate.

Some believe that Jessner’s lymphocytic infiltrate and TLE are the same entity, and it might reasonably be argued that TLE should not be classified as a form of chronic cutaneous LE. However, the presence of TLE lesions in some patients with lupus is evidence to the contrary. Lupus erythematosus panniculitis (LEP) lesions have inflammation in the subcutaneous tissue, resulting in deep, indurated plaques that become disfiguring, depressed areas (Fig. 47-8). Usual sites of involvement are the face, upper trunk, breasts, upper arms, buttocks, and thighs. The risk for SLE is not known precisely, but it is clear that some patients with LEP have or will develop SLE. The differential diagnosis is that of the panniculitides, but the distribution exhibited in LEP is unusual for most other conditions that cause panniculitis. The combination of clinical presentation and skin biopsy for histology usually establishes the diagnosis. Some unusual variants of cutaneous lupus are chilblain lupus (red or dusky plaques on colder areas of skin such as the fingers, toes, nose, elbows, knees, and lower legs), cutaneous lupus–lichen planus overlap, and a bullous eruption due to autoantibodies to type VII collagen or other basement membrane zone proteins. Not all bullae related to lupus are due to autoantibodies to basement membrane proteins, however. It is not unusual to develop bullae simply from intensive destruction of the basal cell layer in ACLE, SCLE, or, rarely, DLE. Treatment of the lupus-specific lesions is similar for most of the subtypes, with some exceptions and modifications. Sun protection is critical for lesions that are initiated or exacerbated by sun exposure. Many or most patients underestimate the amount of sunscreen that should be applied, the potential damage of seemingly minimal exposure during the course of day-to-day activities, and the value of protective clothing. Topical therapy is often used to avoid the side effects of systemic medications or to provide adjunctive therapy, although topical agents are unlikely to be beneficial if the disease process is deep, as in panniculitis. Topical or intralesional corticosteroids are the most commonly used local therapy, but there are some reports that topical calcineurin inhibitors (e.g., tacrolimus) and topical ­ retinoids are beneficial.19,20 The first-line systemic medication for

Figure 47-8  Lupus profundus (panniculitis) with extensive atrophy.

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c­ utaneous lupus is antimalarial therapy. Several reports indicate that smoking tobacco decreases the likelihood of a response to antimalarials.21 For antimalarial-resistant skin disease, a wide variety of medications have been used, but there is no clear second choice when antimalarials do not work. Although dapsone is arguably not helpful in most types of cutaneous lupus, it may be helpful in neutrophilpredominant bullous eruptions.22 Measures to keep the skin warm may be useful for chilblain lupus.

no scale, unlike the annular lesions of tinea. In areas where there is intense destruction of the basal cell layer, lesions may be crusted and look similar to bullous impetigo. Treatment of skin lesions consists largely of sun protection and mild topical steroids. The pathogenesis of lupus is covered elsewhere, but it is noteworthy that SCLE-like, anti-Ro/SS-A–associated skin lesions may occur in neonates; however, other lupus-specific skin lesions do not appear to be maternally transmissible.

NONSPECIFIC CUTANEOUS LESIONS

SJÖGREN’S SYNDROME

A wide variety of lupus-nonspecific skin lesions have been reported. Many of these, such as vasculitic lesions, are cutaneous clues to the possibility of extracutaneous disease. Noteworthy in this regard is livedo reticularis. The netlike erythema of livedo reticularis is a vascular phenomenon caused by reduced oxygenation at the periphery of the area supplied by a particular vessel. This might simply be due to vasoconstriction, such as occurs in a cold environment, in which case it is a benign finding. If livedo is more prominent than usual, not corrected by warming, and persistent, it can be an indication of decreased flow due to pathology such as vasculitis, atherosclerotic disease, or sludging. In lupus, livedo reticularis may be a sign of the presence of antiphospholipid antibodies.23 Other nonspecific skin lesions include Raynaud’s phenomenon, palmar erythema, periungual telangiectasia, alopecia, erythromelalgia, papulonodular mucinosis, and anetoderma. Sclerodactyly, calcinosis, and rheumatoid nodules have been reported but may be more likely in overlap syndromes than in SLE.

The most common mucocutaneous findings of Sjögren’s syndrome are related to glandular dysfunction. Lacrimal gland dysfunction causes dryness and irritation of the eyes and can lead to keratitis and corneal ulceration. Salivary gland dysfunction causes dry mouth and may result in angular cheilitis and numerous dental caries. Vaginal xerosis may cause burning and dyspareunia. The skin may be dry, cracked, and pruritic. Mildly dry mucous membranes and even severely dry skin may be present in a substantial percentage of normal individuals who live in dry climates, so the findings should be interpreted in the context of the setting. In Japanese patients with Sjögren’s syndrome, an annular erythema has been described that is somewhat reminiscent of annular SCLE or the annular lesions of neonatal lupus, although they are more indurated.26 Vasculitis is a relatively common finding. In one series of 558 patients with primary Sjögren’s syndrome, 52 had vasculitis, typically involving small vessels. In most cases, lesions were purpuric, but in some, urticarial vasculitis was the clinical presentation. Patients with cutaneous evidence of vasculitis generally had more severe systemic disease.27

NEONATAL LUPUS SYNDROME Neonatal lupus erythematosus (NLE) is associated with maternal IgG autoantibodies to Ro/SS-A and La/SS-B.24 Affected children may have cutaneous lesions, cardiac disease (complete heart block, cardiomyopathy, or both), hepatobiliary disease, or hematologic cytopenias. Most children have only one or two features of the disease. Similar to the anti-Ro/SS-A–associated SCLE of adults, the skin lesions are often photosensitive, have relatively superficial inflammatory infiltrates, and do not tend to scar. The lesions usually appear at a few weeks of age but have been noted at birth in several cases. The natural history of the skin disease is that the lesions last for weeks or months and resolve spontaneously, usually leaving no residuum. In a few cases, persistent telangiectasias have been noted. Individual lesions appear as erythematous annular papules or plaques. Lesions are usually more numerous and more intensely inflamed on the face and scalp but may also occur on the trunk and extremities. Confluent periorbital erythema, giving the appearance of an erythematous mask, is common and diagnostically helpful. Even though the skin disease resolves and most children without extracutaneous involvement remain otherwise healthy, there is a possibility that children who have had NLE are at increased risk for the development of autoimmune disease later in childhood.25 Differential diagnosis of the skin lesions may include reactive erythema, drug eruption, erythema multiforme, and urticaria. Annular NLE lesions usually have little or

DERMATOMYOSITIS The current American College of Rheumatology criteria for dermatomyositis (DM) do not recognize the existence of amyopathic dermatomyositis (ADM). This has led to a problem in diagnosing patients with predominantly skin involvement. ADM, or dermatomyositis sine myositis, refers to classic cutaneous manifestations of DM without evidence of inflammatory myopathy. ADM has also been defined as the presence of biopsy-proven cutaneous findings of classic DM for 6 months or longer without any clinical evidence of proximal muscle weakness, serum muscle enzyme abnormalities, or abnormal muscle testing. This latter definition excludes any patient treated with systemic immunosuppressive therapy for 2 or more consecutive months during the first 6 months of cutaneous manifestations of DM, because such therapy could suppress clinically significant myositis, or any patient using drugs that are associated with DM-like skin changes (e.g., hydroxyurea).28 The most common cutaneous manifestations of active DM include Gottron’s papules (Fig. 47-9) and Gottron’s sign, which are pathognomonic of DM. Other characteristic findings of DM include heliotrope rash of the periorbital and upper eye area (Fig. 47-10), V- or shawl-shaped macular erythema over the chest and back, cuticular overgrowth, and periungual telangiectasias. Patients with active disease can have widespread erythema over the trunk and ­extremities, with accentuation on the extensor arms and legs and the

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lateral thighs. Erythema and scale of the scalp can result in extensive alopecia. Hyperkeratosis of the palmar and lateral surfaces of the fingers, called mechanic’s hands, can be associated with anti-Jo-1 autoantibodies and interstitial lung disease. Rarely, patients can have a panniculitis. Vasculopathy, with livedo reticularis and ulceration, can occur. Itching can result in excoriations and lichenification. Damage from lesions includes postinflammatory hyperpigmentation, poikiloderma, calcinosis, lipoatrophy, and depressed scars.29 Poikiloderma is a descriptive term for a pattern of finely mottled white areas and brown pigmentation, telangiectasia, and atrophy. Skin biopsy from a patient with cutaneous DM is identical to that seen with cutaneous lupus erythematosus. A diagnosis of DM is made by clinical-pathologic correlation and need not include muscle disease. In the absence of clinical muscle findings, the workup for DM should include muscle enzyme testing, pulmonary function testing, chest radiograph, electrocardiogram, and evaluation for underlying malignancy. There has been an increased association between DM, including ADM, and underlying malignancy. The most frequent malignancies are lung, ovarian, pancreatic, stomach, colorectal, and non-Hodgkin’s lymphoma.30 An increased risk of malignancy is present for at least 5 years after the diagnosis of DM, so patients should receive routine cancer screening during that time.31 Patients with DM frequently experience a delay in diagnosis, and the presence of photosensitivity, malar rash, oral ulcers, and a positive antinuclear antibody test means that they are frequently misdiagnosed as having SLE, having met the current criteria for that disease. In patients with both skin and muscle disease, the muscle disease frequently resolves with aggressive treatment with glucocorticoids, with or without immunosuppressives. Patients are sometimes treated with intravenous immunoglobulin (IVIG), cyclosporine, or tacrolimus. Patients with AMD or residual skin disease after treatment often benefit from hydroxychloroquine. Patients who do not improve on a single antimalarial can benefit from the addition of quinacrine or a switch from hydroxychloroquine to chloroquine.32 Immunosuppressives such as methotrexate, azathioprine, or mycophenolate mofetil can be of additional benefit in patients with resistant skin disease. IVIG can be of benefit for the skin disease of DM, and studies related to the role of biologics are ongoing.33

Figure 47-9  Gottron’s papules over the interphalangeal joints in dermatomyositis.

Figure 47-10  Heliotrope eruption of dermatomyositis, with characteristic edema.

SCLERODERMA AND OTHER SCLEROSING CONDITIONS MORPHEA Scleroderma can occur as localized or systemic disease. The localized form of the disease occurs as localized or generalized morphea, linear scleroderma, or facial hemiatrophy, otherwise known as Parry-Romberg syndrome. Linear scleroderma can occur over the forehead in a variant called en coup de sabre (Fig. 47-11). Morphea is seen more commonly in adults, with an increased incidence with advancing age; linear scleroderma occurs more frequently in children and adolescents.34 Although remissions are reported to occur in 3 to 5 years, ongoing clinical activity or reactivation is not unusual. Localized scleroderma patients typically lack sclerodactyly, Raynauds’ phenomenon, or internal organ involvement. The level of involvement in localized scleroderma can be in the dermis (morphea), fat (subcutaneous morphea), fat and fascia (morphea profundus), and fascia (eosinophilic fasciitis). Morphea typically has round or oval, irregular plaques that are initially dull red or violaceous, smooth, and indurated. They frequently progress to chalky white, atrophic lesions, although some patients have residual hyperpigmentation overlying the lesions. Morphea can have different presentations. When it overlaps with lichen sclerosus et atrophicus, flat-topped papules coalesce to form a white plaque, sometimes combined with a deeper morphea lesion. Some lesions are small and oval, known as guttate morphea. There are many mimickers of morphea, including radiationinduced morphea, injection-induced morphea-like lesions, morphea-like Lyme disease (seen in Europe), eosinophiliamyalgia syndrome, toxic oil syndrome, and, more recently, nephrogenic fibrosing dermopathy. Linear scleroderma is frequently located on the lower limbs, upper limbs, frontal head area, and anterior trunk. It is frequently unilateral and can result in joint deformity, joint contractures, and limb atrophy. Some cases are associated with seizures or other focal neurologic symptoms. Parry-Romberg syndrome can occur in the first or second decade of life and leads to unilateral facial atrophy in 95% of cases. Half of patients start as en coup de sabre and progress

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elsewhere. There are reports that bosentan, an endothelin receptor antagonist, and phosphodiesterase inhibitors such as sildenafil have been helpful in the treatment of skin ulcers.42,43 Patients who have pruritus may benefit from systemic ­antihistamines. EOSINOPHILIC FASCIITIS

Figure 47-11  Linear scleroderma of the forehead. (Courtesy of Dr. Victoria Werth, University of Pennsylvania Department of Dermatology and Philadelphia VAMC, Philadelphia.)

to soft tissue involvement in the upper face. Patients can have seizures, headaches, visual changes, and atrophy of the salivary glands and hemiatrophy of the tongue on the same side as the facial atrophy. Any reparative surgical treatment should be timed to occur no sooner than 1 year after cessation of the ongoing atrophic process. Treatment of localized scleroderma includes protection from trauma and cold, antimalarials (hydroxychloroquine [Plaquenil] alone, hydroxychloroquine and quinacrine together, or chloroquine with or without quinacrine), lowdose prednisone for eosinophilic fasciitis, topical calcipotriene, and methotrexate.35 Phototherapy with narrow-band UVB, UVA1, and PUVA and topical photodynamic therapy have also been used.36,37 SYSTEMIC SCLERODERMA Patients with early limited cutaneous scleroderma have ­Raynaud’s phenomenon for many years, minimal constitutional symptoms, puffy fingers, limited skin thickening, and anticentromere antibody. Patients with early diffuse cutaneous scleroderma frequently have delayed Raynaud’s phenomenon, acute onset, many constitutional symptoms, arthralgias, tendon friction rubs, swollen puffy hands, and early diffuse skin thickening; they may have anti-Scl-70 antibody as well as anti-RNA polymerase III. The major and minor criteria for diffuse cutaneous scleroderma include many skin findings. Major criteria include proximal scleroderma. Minor criteria include sclerodactyly (Fig. 47-12), digital pitting and scars of the fingertips, loss of substance of the finger pad, and ­bibasilar pulmonary fibrosis.38 Ischemia and skin changes in systemic scleroderma can result in skin ulcers. Therapies used in the cutaneous treatment of systemic scleroderma include D-penicillamine, methotrexate, cyclophosphamide, photopheresis, and bone marrow transplantation.39-41 Treatment of Raynaud’s phenomenon is covered

Eosinophilic fasciitis (EF) involves inflammation of the fascia overlying muscle and results in swelling of the extremities, followed by fibrosis and contractures. The digits are typically spared. There is often a rapid onset of disease activity, particularly following physical exertion. A contaminant of l-tryptophan was associated with an EF-like disease in the early 1990s.44 Approximately 30% of EF patients have morphea concurrently. Occasionally, localized scleroderma overlaps with other autoimmune diseases, such as SLE. Diagnosis is based on a deep, usually excisional biopsy of the skin that includes fascia. There are inflammatory cells among collagen bundles, thickening of collagen, sclerosis of the dermis and fat or fascia, and absent sweat glands and hair. Antinuclear antibodies are positive 46% of the time in localized scleroderma; this correlates with disease severity.45 A peripheral eosinophilia and hypergammaglobulinemia can be seen. POEMS SYNDROME POEMS syndrome includes polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. Polyneuropathy and a monoclonal plasma proliferative disorder must be present, along with one other minor criterion, including sclerotic bone lesions, Castleman’s disease, organomegaly, edema, endocrinopathy, papilledema, or skin changes. Other associated findings may include ascites, pleural effusions, thrombocytosis, fingernail clubbing, and white nails. The sensorimotor polyneuropathy has both demyelinating and axonal features and is slowly progressive and debilitating in most cases. Organomegaly may consist of hepatosplenomegaly or lymph node enlargement. Endocrinopathies include diabetes, impotence, gynecomastia, and hypothyroidism. The monoclonal (M) protein abnormality consists of IgA or IgG heavy chains with λ light chains. The

Figure 47-12  Sclerodactyly with flexion contractures.

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skin changes may consist of hyperpigmentation, hypertrichosis, hyperhidrosis, skin thickening, telangiectasia, and glomeruloid hemangiomas.46 Treatment with corticosteroids, low-dose alkylators, high-dose melphalan, and autologous peripheral blood stem cell transplantation has been reported to be successful.47,48 SCLEROMYXEDEMA Scleromyxedema is a rare disorder frequently characterized by a dysproteinemia and widespread skin changes. The paraprotein has been shown to stimulate fibroblast production of mucin, suggesting a causal role and a rationale for lowering it. Patients have waxy papules on the face, neck, upper trunk, forearms, hands, and thighs that become confluent and occur in association with underlying sclerosis, which can lead to joint contractures, sclerodactyly, and carpal tunnel syndrome. Common extracutaneous manifestations include upper gastrointestinal dysmotility, muscle weakness, joint contractures, and neurologic symptoms such as seizures, encephalopathy, coma, and obstructive or restrictive pulmonary disease. Eighty percent of patients have a monoclonal gammopathy, most frequently IgG-λ, but occasionally IgG-κ. Skin biopsy shows mucin deposition and a proliferation of fibroblasts in the upper dermis. Treatment has included prednisone, IVIG, PUVA, systemic retinoids, thalidomide, interferon-α, plasmapheresis, photopheresis, low-dose melphalan, and high-dose dexamethasone.49,50 Chemotherapeutic agents such as melphalan, cyclosporine, cladribine, cyclophosphamide, methotrexate, and chlorambucil have been used. Successful remission after autologous stem cell transplantation has been reported.51 NEPHROGENIC FIBROSING DERMOPATHY Nephrogenic fibrosing dermopathy (NFD) is a relatively new illness that occurs in patients with renal disease; most patients have undergone dialysis for renal failure.52 NFD presents as either a morphea-like disease or a more diffuse acral sclerosois. Morphea-like presentations include ill-defined indurated plaques, with islands of sparing and finger-like projections, that involve the lower more than the upper extremities. More diffuse confluent acral sclerosis, sometimes with trunk involvement, can occur. There are often yellow plaques on the conjunctiva. Patients may experience pain, severe itching, joint contractures, and fibrosis and calcification of the skin, subcutaneous tissue, fascia, muscle, myocardium, lung, renal tubule, and testis. Patients typically do not have Raynaud’s phenomenon. Skin biopsy is identical to that seen with scleromyxedema, with stellate fibroblasts, glycosaminoglycans, and thickening of collagen.53 Transforming growth factor-β is increased in lesional skin.54 There is no proven effective therapy, and prognosis depends on the extent and rapidity of skin involvement and the severity of systemic disease.54 Treatments with potential benefit include plasmapheresis, IVIG, immunosuppressives, glucocorticoids, interferonα, thalidomide, PUVA, UVA1, and photopheresis.55 The critical issue is to determine the inciting agent in this disease.

PRIMARY NECROTIZING VASCULITIS INVOLVING THE SKIN In cutaneous diseases, vasculitis is a term typically reserved for lesions characterized by damage to vessel walls and a neutrophilic or granulomatous infiltrate. Classification, pathogenesis, diagnostic evaluation, and therapy are covered elsewhere. Here, the focus is on the skin findings and differential diagnosis. The primary determinant of the appearance is the size of the vessel affected. LEUKOCYTOCLASTIC SMALL VESSEL VASCULITIS AND ITS VARIANTS Leukocytoclastic small vessel vasculitis is a rather common condition with characteristic histologic findings of fibrinoid necrosis of vessel walls, a neutrophil-predominant infiltrate, and leukocytoclasis (i.e., fragmented nuclei resulting from the degeneration of neutrophils).56 In the skin, the vessels involved are in the dermis, and damage to these vessels results in lesions of a characteristic size. The lesions are both erythematous and purpuric and are distinctly palpable if there are sufficient numbers of neutrophils in the lesion. The usual diameter of the purpuric papules is about 0.3 to 0.6 cm, although smaller and larger lesions may be observed (Fig. 47-13). Discrete lesions have a round shape. The center may look dusky, pustular, or ulcerated, or it may appear as a hemorrhagic vesicle. Larger ulcerations may occur when lesions coalesce. Particularly in larger lesions, the devitalized tissue may be a focus for secondary bacterial infection. Lesions tend to occur in dependent areas. Thus, for ambulatory patients, lesions are most numerous on the lower legs. Koebnerization—the appearance of lesions along lines of trauma, such as scratches—is sometimes observed. As mentioned under the discussion of rheumatoid ­vasculitis, the differential diagnosis of purpuric or petechial lesions may include stasis dermatitis, Schamberg’s purpura, platelet dysfunction, petechial drug eruptions, viral exanthems, emboli, thromboses, and sludging. Skin biopsy is often helpful in establishing the diagnosis of small vessel vasculitis, especially if an early lesion is sampled.

Figure 47-13  Leukocytoclastic vasculitis demonstrating nonblanch­ ing, purpuric macules.

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Immunofluorescence of an early lesion may establish whether the vasculitis is IgA predominant. Small vessel vasculitis unassociated with connective tissue disease and not IgA predominant is sometimes called hypersensitivity vasculitis. It is often apparently confined to the skin and therefore has a good prognosis. In some cases, infections or drugs may be implicated, but often, the initiating event is unknown. Therapy is directed first toward treating the underlying cause, if one is found. If there is no significant extracutaneous disease, treatment is often symptomatic. Leg elevation, compression stockings, and reduction of activity may be helpful. Nonsteroidal antiinflammatory agents or antihistamines are sometimes used. Systemic corticosteroids are not routinely indicated for skinlimited disease. For patients with persistent disease confined to the skin, colchicine and dapsone have each been used with some success.57 A common variant of small vessel vasculitis is HenochSchönlein (HS) purpura. HS purpura occurs commonly in children and is often associated with extracutaneous findings of gastrointestinal or renal involvement. The typical lesion of IgA-predominant small vessel vasculitis is an erythematous or urticarial macule or papule that evolves rapidly into palpable purpura. It has been noted that IgApredominant vasculitis in particular may display superficial plaques of palpable purpura or a retiform configuration of lesions.58 The most reliable means of establishing that the vasculitis is IgA predominant is biopsy for immunofluorescence. IgA-predominant vasculitis is not unusual in adults. Compared with the presentation in children, there is a lower association with a preceding upper respiratory infection and a higher association with medication use. Mixed cryoglobulinemia can present as a small vessel vasculitis. Additional skin findings include livedo reticularis, urticarial papules, cold urticaria, Raynaud’s phenomenon, acrocyanosis, leg ulcers, and digital ulceration or gangrene. Hepatitis C is a frequent association. Patients with type I monoclonal cryoglobulinemia may have purpura due to cryogelling rather than a true vasculitis. A distinct subset of patients with small vessel vasculitis has lesions that are primarily urticarial rather than purpuric. The main clinical entity in the differential diagnosis is urticaria. Individual lesions of urticaria tend to be short-lived, usually lasting less than 24 hours, whereas individual lesions of urticarial vasculitis tend to last for several days. Additional skin findings may include angioedema, livedo reticularis, nodules, and bullae. In some lesions, foci of purpura may be observed. Urticarial vasculitis has been classified into two groups: normocomplementemic and hypocomplementemic. Extracutaneous disease is more likely to occur in the hypocomplementemic group, and some of these patients have underlying SLE. It has been proposed that there is a distinct subset of the hypocomplementemic group characterized by IgG antibodies to C1q, angioedema, ocular inflammation, arthritis, obstructive pulmonary disease, and renal disease. The pulmonary disease tends to be severe and life threatening. This entity has been termed hypocomplementemic ­urticarial vasculitis syndrome.59,60 Erythema elevatum diutinum is an unusual form of small vessel vasculitis that is characterized by erythematous or violaceous papules, plaques, and nodules over the dorsal hands, ears, knees, heels, and buttocks. In the clinical differential

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diagnosis are Sweet’s syndrome, multicentric reticulohistiocytosis, sarcoidosis, and lymphoma, among others. With time, fibrosis often occurs. Established lesions may be disfiguring and may have an appearance somewhat reminiscent of keloids. Although significant extracutaneous involvement is not expected, and many patients are otherwise well, erythema elevatum diutinum has been reported in association with various autoimmune, infectious, and hematologic conditions, including streptococcal infection, paraproteinemia, inflammatory bowel disease, RA, SLE, and HIV. For active skin lesions, dapsone is the usual treatment.61 Intralesional corticosteroids are sometimes used for fibrotic lesions. Acute hemorrhagic edema of childhood is an uncommon but generally benign and self-limited form of vasculitis usually occurring in children younger than 2 years, commonly preceded by an upper respiratory infection or medication.62 The clinical appearance may be dramatic, with large purpuric plaques on the face, ears, and extremities. Based on the appearance of the skin lesions, meningococcemia is sometimes suspected, but a child with acute hemorrhagic edema appears relatively healthy. Generally, there is no extracutaneous involvement. Treatment is symptomatic. GRANULOMATOUS VASCULITIDES Skin lesions are occasionally the presenting feature of Wegener’s granulomatosis.63 The most common type of lesion is palpable purpura, with or without necrosis. Many other types of lesions have been noted, including papules, ecchymoses, hemorrhagic bullae, necrotic papules, subcutaneous nodules, and ulcers. Ulcerative lesions may be similar in appearance to pyoderma gangrenosum, though they lack an undermined border. Oral ulcers are relatively common but nonspecific in appearance. A more specific oral finding is hypertrophic gingival inflammation with petechiae. Skin biopsy is sometimes helpful diagnostically, but unfortunately, biopsies are often nonspecific or show leukocytoclastic vasculitis. True granulomatous vasculitis is not often observed in skin specimens. Extravascular granulomatous inflammation is sometimes noted and may be more likely in nonpurpuric papules or nodules than in palpable purpura. Differential diagnosis of the skin lesions includes other small vessel vasculitides, particularly when cutaneous lesions consist of palpable purpura and the biopsy finding is leukocytoclastic vasculitis. If granulomatous inflammation is observed, the differential diagnosis may include ChurgStrauss syndrome, polyarteritis nodosa, microscopic polyangiitis, RA, SLE, infection, lymphoproliferative disorders, chronic active hepatitis, erythema nodosum, granuloma annulare, and inflammatory bowel disease. Patients with Churg-Strauss syndrome characteristically present with respiratory symptoms, but skin lesions are common during the vasculitic phase of the disease.64 Hemorrhagic lesions ranging from petechiae to palpable purpura to ecchymoses, cutaneous nodules with or without ulceration, subcutaneous nodules, and nonspecific erythematous eruptions are most common. As with Wegener’s granulomatosis, hemorrhagic lesions tend to show small vessel vasculitis on biopsy, and nodules are more likely to demonstrate granulomas. The clinical and histologic differential diagnosis often includes polyarteritis nodosa, Wegener’s granulomatosis,

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and microscopic polyangiitis. As alluded to earlier, the histologic finding of Churg-Strauss granuloma is not specific and may be seen in several entities. Large numbers of eosinophils in the biopsy may be diagnostically helpful but not definitive. Hypereosinophilic syndrome may share clinical and laboratory features with Churg-Strauss syndrome, but vasculitis is not characteristic. POLYARTERITIS NODOSA AND RELATED CONDITIONS Historically, classic polyarteritis nodosa (PAN) and microscopic polyangiitis were classified together as PAN, but they appear to be distinct conditions distinguishable in part by the size of the vessels affected. Classic PAN involves medium-sized vessels, whereas microscopic polyangiitis involves primarily vessels ranging in size from capillaries to arterioles. Cutaneous findings of classic PAN represent damage downstream of the affected vessel and consist of ulceration, digital gangrene, ecchymoses from vessel rupture, livedo reticularis, and subcutaneous nodules that may follow the course of arteries. Because the affected vessel is proximal to the skin, skin biopsy is likely to show nonspecific findings. The skin findings of microscopic polyangiitis reflect the smaller size of the vessels affected. Petechiae, palpable purpura, purpuric plaques, erythematous nodules, and ulcerations may be observed. There have also been some reports of livedo reticularis. The cutaneous pathology is that of a leukocytoclastic vasculitis, but in contrast to many of the small vessel vasculitides previously discussed, small arterioles may be involved. The differential diagnosis is mainly other small vessel vasculitides. The size of affected vessels, antineutrophil cytoplasmic autoantibody (ANCA) positivity, paucity or absence of antibody deposits in vessels, and spectrum of extracutaneous involvement aid in distinguishing microscopic polyangiitis from other vasculitides. There is a variant of PAN termed benign cutaneous PAN or, perhaps more accurately, primarily cutaneous PAN. In this condition, arterioles in the subcutaneous fat and lower dermis are affected, and the presentation is often that of tender subcutaneous nodules and livedo reticularis. Associations with Crohn’s disease, hepatitis B, and hepatitis C have been reported. Clinically, panniculitides such as erythema nodosum and erythema induratum may be considered, although livedo reticularis is not expected. Biopsy for diagnosis should include subcutaneous fat. Even after biopsy, microscopic polyangiitis may be difficult to exclude. Although relatively little information is available concerning ANCA in cutaneous PAN, a negative ANCA is more consistent with cutaneous PAN than with microscopic polyangiitis. Although the outcome is benign, the course is often chronic and relapsing. Therapy is typically conservative and may consist of intralesional corticosteroids, nonsteroidal anti-inflammatory drugs, low-dose methotrexate, dapsone, or, occasionally, systemic corticosteroids. Kawasaki’s disease is considered a PAN variant due to the involvement of coronary arteries. Skin findings ­ constitute several of the criteria for diagnosis. None of the findings is specific for Kawasaki’s disease, but the constellation of findings establishes the diagnosis. Kawasaki’s disease usually affects young children but has been reported in adults.

Criteria for diagnosis are otherwise unexplained fever for at least 5 days and four of the following five ­ findings: (1) bilateral nonexudative conjunctivitis; (2) injected pharynx, strawberry tongue, or injected or fissured lips; (3) erythema of palms or soles, hand and foot edema, and, in the convalescent phase, desquamation; (4) erythematous, polymorphous, generalized skin eruption; and (5) cervical lymphadenopathy. In addition, erythema of the perineal region is quite common, and transverse lines across the fingernail beds have been noted in a few cases. LARGE VESSEL VASCULITIS Skin findings of temporal arteritis (giant cell arteritis) consist mainly of palpable temporal arteries, skin tenderness in the area, and scalp nodules or ulcerations. Skin lesions in patients with Takayasu’s arteritis may include Raynaud’s phenomenon, livedo reticularis, ulcerated nodules, subcutaneous nodules, and pyoderma gangrenosum–like ulcers. Skin biopsy is generally not performed in these conditions.

INFECTIONS There are many infectious diseases that present with both skin and rheumatologic findings.65 This section highlights a few examples. LYME BORRELIOSIS Borrelia burgdorferi, the causative agent of Lyme disease in North America, is associated with erythema migrans (EM). In Europe, the related genospecies Borrelia afzelii is associated with both EM and acrodermatitis chronica atrophicans (ACA), and several European studies have found compelling evidence of B. afzelii infection in patients with morphea. There is no similar association between Borrelia and morphea in the United States.66 Hematogenous dissemination from the initial skin site is believed to cause secondary skin lesions and extracutaneous manifestations, and only certain subtypes of B. burgdorferi are associated with dissemination. EM is the first manifestation of Lyme disease in 60% to 80% of people and occurs at the site of the tick bite.67 At the time of the skin lesion, which occurs within a few days to a month after the bite, the spirochetes enter the circulation and disseminate. The skin findings may be associated with fever, chills, fatigue, headache, neck stiffness, myalgias, arthralgias, conjunctivitis, erythematous throat, and regional or generalized lymphadenopathy. The lesions of EM begin as red macules that become papular and then expand into an erythematous, annular plaque (Fig. 47-14). There are two forms of EM. In one, there is an expanding red plaque with varying intensities of redness within the plaque. In the second, there is a target-like appearance, with a central red plaque surrounded by normal-appearing skin, which in turn is surrounded by another band of erythema. The lesions can enlarge very rapidly, and multiple lesions due to hematogenous spread are seen in 17% of cases. As the lesion enlarges, the central erythema may fade. The central portion of the lesion may be edematous, vesicular, urticarial, or crusted. Triangular and elongated oval lesions have been described, but circular lesions are most frequent.

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after penetrating injuries to the fingers and hands. This is an indolent disease consisting of nodules or ulcerated plaques, occasionally with extension to deep tissue. Common areas of involvement are the fingers, dorsum of the hands, and knees. The lesions can be localized or sporotrichoid (25%), with dissemination 2% of the time.

PANNICULITIS

Figure 47-14  Lyme disease with characteristic erythematous, annular plaques. (Courtesy of Dr. Joshua Levin, University of Pennsylvania Department of Dermatology, Philadelphia.)

The most common locations are the inguinal region, axillae, abdomen, and behind the knees. EM lesions are usually ­asymptomatic but can be pruritic or painful. Untreated EM lesions resolve in a median of 28 days, with a range from 1 day to 14 months. Resolution occurs within a few days after treatment with antibiotics such as doxycycline or peni­ cillin. ACA is associated with late Lyme disease. It occurs mainly in women between 40 and 70 years old. The lesions begin on an extremity, usually the lower leg or foot, as a bluish red edematous plaque. Fibrous bands may develop, especially in the ulnar and tibial regions, and fibrous nodules may form near joints. Regional lymphadenopathy is often present. Over many years, the skin becomes atrophic.68 B. burgdorferi has been isolated from the skin of patients with ACA.69 PARVOVIRUS Presentation of parvovirus B19 includes an erythematous “slapped cheeks” appearance; a lacy, reticulated proximal extremity rash; a febrile petechial eruption; and papularpurpuric gloves and socks syndrome. The infection is self­limited and generally resolves spontaneously within 1 to 2 weeks. Laboratory findings may include mild or severe leukopenia, transient neutropenia or relative neutrophilia, eosinophilia, and mild thrombocytopenia. Adults often contract the virus from infected children and commonly present with systemic disease, including arthropathy and a flulike illness.70 ATYPICAL INFECTIONS: MycoBACTERIUM MARINUM There are many types of mycobacterial, atypical mycobacterial, and deep fungal infections that can affect the skin and joints. Mycobacterium marinum is one example; it can be acquired through exposure to fresh water, salt water, fish tanks, swimming pools, fish or other aquatic organisms, timber cuts, or splinters. The incubation period is usually about 3 weeks, although much longer periods are possible. The disease often occurs after inoculation into abrasions or

Panniculitis refers to a group of diseases that manifest as inflammation or alterations in the subcutaneous fat. The complexity of causes for even one form of panniculitis, such as erythema nodosum; the relative rarity of most forms of panniculitis; and the number of different panniculitides has slowed the acquisition of scientific knowledge. The causes of many panniculitides are still poorly understood. Panniculitis may be primary, without an identifiable cause, or secondary. Common secondary causes of panniculitis include infection, trauma, pancreatic disease, immunodeficiency states, malignancies, and connective tissue disease. Erythema nodosum is the most common form of panniculitis, and although there is a long list of diseases and medications that have been associated with it, there is often no identifiable underlying condition. Underlying conditions that have been associated with erythema nodosum include inflammatory bowel disease, sarcoidosis, malignancies such as leukemia and lymphoma, infections (bacterial, Yersinia, rickettsial, chlamydial, spirochetal, and protozoal disease), pregnancy, drugs (sulfonamides, contraceptives), and autoimmune diseases such as Behçet’s disease, Sjögren’s syndrome, Reiter’s syndrome, and SLE.71 As the understanding of lobular panniculitis has expanded, cases that were once grouped under the catchall of Weber-Christian disease are now recognized to be clearly definable and separate entities such as lupus panniculitis, cytophagic histiocytic panniculitis, α1-antitrypsin deficiency, factitial panniculitis, traumatic panniculitis, and calciphylaxis.72-74 Infections are recognized as a trigger of panniculitis, as exemplified by erythema nodosum due to streptococcal infection, hepatitis B or C associated with PAN, infectious panniculitides in immunocompromised hosts, and, most recently, some cases of erythema induratum or nodular ­vasculitis associated with Mycobacterium tuberculosis. In addition, atypical infections can cause lesions that look like panniculitis. An understanding of the heterogeneity of lymphomas that involve the fat is still evolving, but advances are being made in differentiating various histologic and clinical outcomes.75 For example, some patients thought to have lupus panniculitis based on cytopenia and laboratory tests were found to actually have subcutaneous lymphoma, after a careful review of their pathology. Patients with panniculitis frequently have erythematous tender nodules, and the clinical presentation is seldom specific enough to allow a determination of the exact subtype of panniculitis without a biopsy. Patients with panniculitis can have associated symptoms such as low-grade fever, fatigue, arthralgia, and myalgias. An adequate skin biopsy, often involving an elliptical excision, is essential to properly diagnose the various entities that fall under the category of panniculitis (Table 47-1).

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Table 47-1  Classification of Panniculitis I.  Without prominent vasculitis   A.  Septal inflammation     1.  Lymphocytic and mixed: erythema nodosum and variants     2. Granulomatous: palisaded granulomatous diseases, sarcoidosis, subcutaneous infection (tuberculosis, syphilis)     3. Sclerotic: scleroderma, eosinophilic fasciitis, lipodermatosclerosis, toxins   B.  Lobular inflammation     1. Neutrophilic: infection, ruptured folliculitis and cysts, pancreatic fat necrosis     2. Lymphocytic: lupus panniculitis, poststeroid panniculitis, lymphoma, leukemia     3. Macrophagic: histiocytic cytophagic panniculitis     4. Granulomatous: erythema induratum, nodular vasculitis, palisaded granulomatous diseases, sarcoidosis, Crohn’s disease     5. Mixed inflammation with many foam cells: α1-antitrypsin deficiency, Weber-Christian disease, traumatic fat necrosis     6. Eosinophilic: eosinophilic panniculitis, arthropod bites,  parasites     7.  Enzymatic fat necrosis: pancreatic enzyme panniculitis     8. Crystal deposits: sclerema neonatorum, subcutaneous fat necrosis of the newborn, gout, oxalosis     9.  Embryonic fat pattern: lipoatrophy, lipodystrophy II.  With prominent vasculitis (septal or lobular)   A. Neutrophilic: leukocytoclastic vasculitis, subcutaneous polyarteritis nodosa, thrombophlebitis, erythema nodosum leprosum (ENL)   B. Lymphocytic: nodular vasculitis, perniosis, angiocentric lymphomas   C. Granulomatous: nodular vasculitis, erythema induratum, ENL, Wegener’s granulomatosis, Churg-Strauss allergic granulomatosis III. Mixed patterns

Panniculitis is typically divided into four main subgroups: septal, lobular, mixed, and panniculitis with vasculitis. Determining the exact nature of the cellular infiltrate also contributes to arriving at a proper diagnosis. There is no question that these categorizations help narrow the differential diagnosis in any given case, but there may be overlapping features or reaction patterns that do not allow a specific diagnosis. Clinical-pathologic correlation is important, as emphasized by a published review that includes an expanded and useful classification of panniculitis.76 There are anecdotal reports of the efficacy of combination antimalarials such as hydroxychloroquine and quinacrine in treating subcutaneous sarcoid, but no studies exist, so definitive recommendations cannot be made. Reports about the use of mycophenolate mofetil and thalidomide to treat inflammatory causes of panniculitis, such as nodular panniculitis and erythema nodosum, have already been published, indicating that newer drugs will likely evolve for the treatment of these conditions.77,78 The efficacy of these and more established drugs, such as nonsteroidal anti-inflammatory agents, antimalarials, and methotrexate, needs to be studied, and it is hoped that outcomes will be more systematically evaluated.

RELAPSING POLYCHONDRITIS The diagnosis of relapsing polychondritis is based on the typical clinical manifestations, with auricular findings seen in 90% of patients. Nasal and respiratory tract ­ chondritis can occur, along with nonerosive inflammatory arthritis,

cardiac valvular insufficiency, vasculitis, and eye and audiovestibular involvement. The estimated prevalence of 3.5 per million makes controlled trials nearly impossible. The cause is unknown, but the pathogenesis appears to be mediated by an immune reaction to type II collagen. Clinical skin manifestations include inflammation of the ear, with sparing of the earlobe. Diagnosis includes the presence of a positive serum antibody test to type II collagen and a wedge biopsy that shows cartilage necrosis and perichondral inflammation with lymphocytes and histiocytes. Involvement of other cartilage areas, including the upper airway, should be assessed. Glucocorticoids are the therapeutic choice for reducing the inflammatory process in patients with relapsing polychondritis. For patients with sustained disease, many immunosuppressive drugs have been used as steroid-sparing agents. There have been reports of response to tumor necrosis factor-α (TNF-α) inhibitors in patients ­otherwise refractory to therapy.79

INFILTRATIVE DISEASES AMYLOID Type AL amyloidosis is rare, with an incidence of less than 1 per 100,000. Skin lesions may occur in up to 40% of these patients. Skin lesions can be an early sign of the disease and include purpura, petechiae, and ecchymoses due to infiltration of blood vessels by amyloid. Other skin findings include alopecia, plaques, and nodules, often found on flexor surfaces, the face, or the buccal mucosa. Bullae and nail dystrophy are occasionally seen. Diagnosis is confirmed by biopsy of lesional or nonlesional skin, along with urine and serum immunoelectrophoresis to confirm the presence of a circulating monoclonal protein. Skin biopsy shows Congo red–­positive, homogeneous, hyaline, fibrillary deposits. Treatment includes autologous stem cell transplantation, with approximately 50% of patients achieving prolonged remission with such therapy. Other effective therapies include the combination of melphalan with high-dose dexamethasone or the use of thalidomide.80 The prognosis depends on the stage at the time of diagnosis, emphasizing the importance of recognizing the disease. SARCOIDOSIS Cutaneous involvement occurs in 20% to 25% of cases of sarcoidosis and is most likely to be seen early in the disease. Cutaneous lesions can be classified as nonspecific, typically erythema nodosum, and specific or granulomatous. Erythema nodosum occurs frequently as part of Löfgren’s syndrome, with bilateral hilar lymphadenopathy and acute iridocyclitis. This variant has a good ­prognosis and resolves in 80% of patients within 2 years. The skin lesions of sarcoidosis generally have no prognostic significance or ­ correlation with disease activity. Skin involvement has no effect on the course of the disease, and the number of skin lesions does not correlate with systemic disease. Skin plaques tend to be more persistent and commonly associated with chronic forms of the disease. Lupus pernio (Fig. 47-15), with violaceous plaques on the nose, ears, cheeks, lips, and fingers, is often seen in long-standing sarcoidosis and is associated with upper

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2 mm in diameter at 24 to 48 hours. A diagnosis is made if patients have recurrent oral ulcerations plus at least two of the other findings without other clinical explanations. Skin lesions include erythema nodosum, pseudofolliculitis, and papulopustular lesions or acneiform nodules in postadolescents. Oral ulcers are painful and occur on the gingiva, tongue, and buccal and labial mucosa. Genital ulcers, usually larger and deeper than oral ulcers, are typically on the scrotum and penis in men and the vulva in women. Venous involvement, including superficial thrombophlebitis and deep venous thrombosis, can occur. On skin biopsy, small vessel vasculitis is common. Ulcer treatment includes topical corticosteroids, colchicine, and thalidomide. Systemic corticosteroids are prescribed for unresponsive erythema nodosum. FAMILIAL MEDITERRANEAN FEVER

Figure 47-15  Sarcoidosis with “apple-jelly” plaques on the face and lupus pernio, or nasal rim lesions.

airway involvement and pulmonary fibrosis.81 Other forms of cutaneous sarcoidosis include papules, follicular papules, subcutaneous nodules, ulcerative lesions, alopecia, and icthyosis. Cutaneous sarcoid can arise in scars. Because of the many different presentations, diagnosis can be challenging, and a skin biopsy is necessary to confirm the clinical suspicion. Mimickers of papules include xanthelasma, rosacea, trichoepithelioma, syphilis, lupus erythematosus, and granuloma annulare. Plaques can resemble lupus vulgaris, necrobiosis lipoidica, morphea, leprosy, leishmaniasis, or lupus erythematosus. Nodules can resemble lymphoma or other types of panniculitis. Treatment of cutaneous sarcoidosis depends on the degree of systemic involvement. Clearly, patients who need prednisone for systemic disease often experience improvement of their cutaneous sarcoid. Patients with isolated skin disease or systemic disease not requiring aggressive therapy can benefit from topical or intralesional corticosteroids, topical tacrolimus, hydroxychloroquine, combination antimalarials with hydroxychloroquine and quinacrine, or chloroquine. If antimalarials are not adequate, methotrexate or oral retinoids can be used. There have been case reports and small case series of successful therapy with thalidomide and TNF-α inhibitors, as well as laser remodeling of lupus pernio.82,83 There is some concern that ­interferon-α therapy may induce sarcoidosis.

MISCELLANEOUS SKIN DISEASES AND ARTHRITIS BEHÇET’S DISEASE The criteria for Behçet’s disease include recurrent oral and genital ulcers, eye lesions (uveitis or retinal vasculitis), characteristic skin lesions, and a positive pathergy test.84 The pathergy test involves using a sterile needle to prick the forearm. The results are positive when the puncture causes an aseptic erythematous nodule or pustule that is more than

Familial Mediterranean fever is an autosomal recessive disease that tends to affect certain ethnic groups, including Sephardic Jews, Arabs, Armenians, and Turks. There is a mutation on the short arm of chromosome 16, and the mutant protein pyrin likely plays an inhibitory role in the control of inflammation.85,86 The disease is characterized by recurrent, self-limited attacks of peritonitis, pleuritis, and synovitis. Erysipelas-like erythema is the pathognomonic skin manifestation. This is characterized by tender, erythematous, well-demarcated plaques, usually located on the lower legs.87 They may be triggered by physical effort and subside spontaneously within 48 to 72 hours of bed rest. Fever and leukocytosis may accompany this condition. Other associated skin findings include HS purpura; nonspecific purpura; erythema of the face, trunk, or palm; angioneurotic edema; Raynaud’s phenomenon; pyoderma; and subcutaneous nodules. Secondary generalized amyloidosis may lead to chronic renal failure and death if not recognized. Skin biopsy shows edema of the superficial dermis and sparse perivascular infiltrate composed of a few lymphocytes, neutrophils, and nuclear dust, without vasculitis. Direct immunofluorescence shows deposits of C3 in the wall of small superficial vessels. Early treatment with colchicine, which prevents or diminishes the frequency and severity of inflammatory episodes, can be beneficial. MULTICENTRIC RETICULOHISTIOCYTOSIS Multicentric reticulohistiocytosis is a rare condition of unknown cause that most frequently occurs in Caucasian women in the fifth and sixth decades of life. There is destructive symmetric arthritis, with arthritis mutilans developing in about 45% of cases, associated with cutaneous papulonodular lesions. Skin findings include cutaneous red to brown papules or nodules, typically on the face, on the dorsum of the fingers, and over the proximal and distal ­interphalangeal joints, but they can occur in a more generalized distribution. A rarer presentation includes photodistributed erythema, often with targeting over joints, that masquerades as DM.88 Diagnosis is made by skin biopsy, which shows infiltration of histiocytes and multinucleated giant cells. These changes can be seen in a variety of ­tissues, including the heart, lungs, skeletal muscle, and gastrointestinal tract. The differential diagnosis of the skin disease

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includes other infiltrative processes such as sarcoidosis and even leprosy. Treatment recommendations, based mostly on small case reports, include glucocorticoids and methotrexate, with the use of cyclophosphamide and finally chlorambucil if the condition is unresponsive.89 Cyclosporine, TNF inhibitors, and bisphosphonates have also been used with reported benefit.90 In about one third of patients, multicentirc reticulohistiocytosis may precede or follow an underlying malignancy. Reported associated malignancies include cancer of the breast, cervix, colon, stomach, lung, larynx, and ovary; lymphoma; leukemia; sarcoma; melanoma; mesothelioma; and metastatic cancer of unknown primary source. CHRONIC INFANTILE NEUROLOGIC CUTANEOUS AND ARTICULAR SYNDROME Mutations in cryopyrin (CIAS1, NALP3, PYPAF1), associated with increased proinflammatory cytokines, especially interleukin-1β, have been found in about 50% of patients with chronic infantile neurologic cutaneous and articular (CINCA) syndrome.91,92 CINCA syndrome is characterized by a neonatal urticarial eruption, fever, and arthritis, and leukocytosis. Other findings include chronic meningitis, papilledema, hearing loss, and growth retardation. Recent isolated reports suggest that TNF-α inhibitors, anakinra, and thalidomide may be beneficial in these patients. Acknowledgments The authors want to acknowledge Dr. Nicole Rogers for her assistance with the figures.

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38. Masi AT, Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee: Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 5:581-590, 1980. 39. Zandman-Goddard G, Tweezer-Zaks N, Shoenfeld Y: New therapeutic strategies for systemic sclerosis—a critical analysis of the literature. Clin Dev Immunol 12:165-173, 2005. 40. DeMarco PJ, Weisman MH, Seibold JR, et al: Predictors and outcomes of scleroderma renal crisis: The high-dose versus low-dose Dpenicillamine in early diffuse systemic sclerosis trial. Arthritis Rheum 46:2983-2989, 2002. 41. Tashkin DP, Elashoff R, Clements PJ, et al: Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 354:2655-2666, 2006. 42. Chung L, Fiorentino D: Digital ulcers in patients with systemic sclerosis. Autoimmun Rev 5:125-128, 2006. 43. Korn JH, Mayes M, Matucci Cerinic M, et al: Digital ulcers in systemic sclerosis: Prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 50:3985-3993, 2004. 44. Mayeno AN, Lin F, Foote CS, et al: Characterization of “peak E,” a novel amino acid associated with eosinophilia-myalgia syndrome. Science 250:1707-1708, 1990. 45. Falanga V, Medsger TA Jr, Reichlin M, et al: Linear scleroderma: Clinical spectrum, prognosis, and laboratory abnormalities. Ann Intern Med 104:849-857, 1986. 46. Chan JK, Fletcher CD, Hicklin GA, et al: Glomeruloid hemangioma: A distinctive cutaneous lesion of multicentric Castleman’s disease associated with POEMS syndrome. Am J Surg Pathol 14:1036-1046, 1990. 47. Dispenzieri A, Gertz MA: Treatment options for POEMS syndrome. Exp Opin Pharmacother 6:945-953, 2005. 48. Dispenzieri A, Moreno-Aspitia A, Suare GA, et al: Peripheral blood stem cell transplantation in 16 patients with POEMS syndrome, and a review of the literature. Blood 104:3400-3407, 2004. 49. Kreuter A, Altmeyer P: High-dose dexamethasone in scleromyxedema: Report of 2 additional cases. J Am Acad Dermatol 53:739-740, 2004. 50. Sansbury JC, Cocuroccia B, Jorizzo JL, et al: Treatment of recalcitrant scleromyxedema with thalidomide in 3 patients. J Am Acad Dermatol 51:126-131, 2004. 51. Donato ML, Feasel AM, Weber DM, et al: Scleromyxedema: Role of high-dose melphalan with autologous stem cell transplantation. Blood 107:463-466, 2006. 52. Cowper SE, Su L, Robin H, et al: Nephrogenic fibrosing dermopathy. Am J Dermatopathol 23:383-393, 2001. 53. Kucher C, Xu X, Pasha T, et al: Histopathologic comparison of nephrogenic fibrosing dermopathy and scleromyxedema. J Cutan Pathol 32:484-490, 2005. 54. Mendoza FA, Artlett CM, Sandorfi N, et al: Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum 35:238-249, 2006. 55. Kafi R, Fisher GJ, Quan T, et al: UV-A1 phototherapy improves nephrogenic fibrosing dermopathy. Arch Dermatol 140:1322-1324, 2004. 56. Piette WW: Primary systemic vasculitis. In Provost TT, Sontheimer RD (eds): Cutaneous Manifestations of Rheumatic Diseases, 2nd ed. Philadelphia, Lippincott Williams & Wilkins, 2004, pp 159-196. 57. Callen JP: Colchicine is effective in controlling chronic cutaneous leukocytoclastic vasculitis. J Am Acad Dermatol 13:193-200, 1985. 58. Piette WW, Stone MS: A cutaneous sign of IgA-associated small dermal vessel leukocytoclastic vasculitis in adults (Henoch-Schonlein purpura). Arch Dermatol 125:53-56, 1989. 59. Wisnieski JJ, Baer AN, Christensen J, et al: Hypocomplementemic urticarial vasculitis syndrome: Clinical and serologic findings in 18 patients. Medicine 74:24-41, 1995. 60. Mehregan DR, Hall MJ, Gibson LE: Urticarial vasculitis: A histopathologic and clinical review of 72 cases. J Am Acad Dermatol 26:441-448, 1992. 61. Katz SI, Gallin JI, Hertz KC, et al: Erythema elevatum diutinum: Skin and systemic manifestations, immunologic studies, and successful treatment with dapsone. Medicine 56:443-455, 1977. 62. Dubin BA, Bronson DM, Eng AM: Acute hemorrhagic edema of childhood: An unusual variant of leukocytoclastic vasculitis. J Am Acad Dermatol 23:347-350, 1990. 63. Frances C, Du LT, Piette JC, et al: Wegener’s granulomatosis: Dermatological manifestations in 75 cases with clinicopathologic correlation. Arch Dermatol 130:861-867, 1994.

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64. Lanham JG, Elkon KB, Pusey CD, et al: Systemic vasculitis with asthma and eosinophilia: A clinical approach to the Churg-Strauss syndrome. Medicine 63:65-81, 1984. 65. Khan-Sabir SM, Werth VP: Infectious diseases that affect the skin and joint. In Sontheimer RD, Provost TT (eds): Cutaneous Manifestations of Rheumatic Diseases, 2nd ed. Philadelphia, Lippincott Williams & Wilkins, 2004, pp 242-264. 66. Fujiwara H, Fujiwara K, Hashimoto K, et al: Detection of Borrelia burgdorferi DNA (B garinii or B afzelii) in morphea and lichen sclerosus et atrophicus tissues of German and Japanese but not of US patients. Arch Dermatol 133:41-44, 1997. 67. Steere A: Lyme disease. N Engl J Med 345:115-125, 2001. 68. Asbrink E, Hovmark A: Successful cultivation of spirochetes from skin lesions of patients with erythema chronicum migrans afzelius and acrodermatitis chronica atrophicans. Acta Pathol Microbiol Immunol Scand B Microbiol 93:161-163, 1985. 69. Aberer E, Breier F, Stanek G, et al: Success and failure in the treatment of acrodermatitis chronica atrophicans. Infection 24:85-87, 1996. 70. Woolf AD: Clinical manifestations of human parvovirus B19 in adults. Arch Intern Med 149:1153-1156, 1989. 71. Psychos DN, Voulgari PV, Skopouli FN, et al: Erythema nodosum: The underlying conditions. Clin Rheumatol 19:212-216, 2000. 72. White JW Jr, Winkelmann RK: Weber-Christian panniculitis: A review of 30 cases with this diagnosis. J Am Acad Dermatol 39:56-62, 1998. 73. Nakane S, Kawabe Y, Eguchi K, et al: A case of cytophagic histiocytic panniculitis: Successful treatment of recurrent attacks with steroid pulse therapy and oral cyclosporin A. Clin Rheumatol 16:417-421, 1997. 74. Panush RS, Yonker RA, Dlesk A, et al: Weber-Christian disease: Analysis of 15 cases and review of the literature. Medicine 64:181-191, 1985. 75. Salhany KE, Macon WR, Choi JK, et al: Subcutaneous panniculitislike T-cell lymphoma: Clinicopathologic, immunophenotypic, and genotypic analysis of alpha/beta and gamma/delta subtypes. Am J Surg Pathol 22:881-893, 1998. 76. Peters MS, Su WP: Panniculitis. Dermatol Clin 10:37-57, 1992. 77. Enk AH, Knop J: Treatment of relapsing idiopathic nodular panniculitis (Pfeifer-Weber-Christian disease) with mycophenolate mofetil. J Am Acad Dermatol 39:508-509, 1998. 78. Calderon P, Anzilotti M, Phelps R: Thalidomide in dermatology: New indications for an old drug. Int J Dermatol 36:881-887, 1997. 79. Saadoun D, Deslandre CJ, Allanore Y, et al: Sustained response to infliximab in 2 patients wtih refractory relapsing polychondritis. J Rheumatol 30:1394-1395, 2003. 80. Rajkumar SV, Dispenzieri A, Kyle RA: Monoclonal gammopathy of undetermined significance, Waldenstrom macroglobulinemia, AL amyloidosis, and related plasma cell disorders: Diagnosis and treatment. Mayo Clin Proc 81:693-703, 2006. 81. Mana J, Marcoval J, Graells J, et al: Cutaneous involvement in sarcoidosis: Relationship to systemic disease. Arch Dermatol 133: 882-888, 1997. 82. Oliver SJ, Kikuchi T, Krueger JG, et al: Thalidomide induces granuloma differentiation in sarcoid skin lesions associated with disease improvement. Clin Immunol 102:225-236, 2002. 83. Malbriss L, Ljungberg MA, Hedblad P, et al: Progressive cutaneous sarcoidosis responding to anti-tumor necrosis factor-alpha therapy. J Am Acad Dermatol 48:290-293, 2003. 84. International Study Group for Bechet’s Disease: Criteria for diagnosis of Behçet’s disease. Lancet 335:1078-1080, 1990. 85. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell 90:797-807, 1997. 86. Pras E, Aksentijevich I, Gruberg L, et al: Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. N Engl J Med 326:1509-1513, 1992. 87. Azizi E, Fisher BK: Cutaneous manifestations of familial Mediterranean fever. Arch Dermatol 112:364-366, 1976. 88. Hsiung SH, Chan EF, Elenitsas R, et al: Multicentric reticulohistiocytosis presenting with clinical features of dermatomyositis. J Am Acad Dermatol 48:S11-S14, 2003. 89. Liang GC, Granston AS: Complete remission of multicentric reticulohistiocytosis with combination therapy of steroid, cyclophosphamide, and low-dose pulse methotrexate: Case report, review of the literature, and proposal for treatment. Arthritis Rheum 39:171-174, 1996.

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90. Goto H, Inaba M, Kobayashi K, et al: Successful treatment of multicentric reticulohistiocytosis with alendronate: Evidence for a direct effect of bisphosphonate on histiocytes. Arthritis Rheum 48:3538-3541, 2003. 91. Bihl T, Vassina E, Boettger MK, et al: The T348M mutated form of cryopyrin is associated with defective lipopolysaccharide-induced interleukin 10 production in CINCA syndrome. Ann Rheum Dis 64:1380-1381, 2005.

92. Neven B, Callebaut I, Prieur AM, et al: Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/NOMID, MWS, and FCU. Blood 103:2809-2815, 2004.

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Synovial Fluid Analysis, Synovial Biopsy, and Synovial Pathology , HANI S. EL-GABALAWY

KEY POINTS Analysis of synovial fluid samples by leukocyte count, cytology, polarized microscopy, Gram stain, and culture provides key diagnostic information, particularly in acute monarthritis. Synovial biopsy performed using either closed needle techniques or arthroscopy may provide valuable diagnostic information, particularly in persistent monarthritis. Although the histopathologic features of synovitis are nonspecific, specific synovial pathologies can be diagnosed on small synovial tissue biopsy samples. Analysis of synovial tissue using immunohistology and other molecular techniques has been valuable in understanding the mechanisms of synovitis. Sequential analysis of synovial tissue samples in the context of therapeutic trials provides unique information regarding the effects of treatment on the target organ.

The analysis of synovial fluid and synovial tissue obtained from diseased joints provides important diagnostic information in specific clinical settings and is valuable in addressing a spectrum of research questions aimed at enhancing the understanding of the pathogenesis and mechanisms of rheumatic diseases. Many peripheral joints are readily accessible to sampling of synovial fluid effusions and synovial tissue, although the knee is the most frequently sampled joint. The techniques used to obtain and analyze synovial fluid and tissue samples are discussed in this chapter.

SYNOVIAL FLUID ANALYSIS SYNOVIAL FLUID IN HEALTH Under normal conditions, a small volume of synovial fluid is present in each joint, forming a thin interface between the surfaces of the articular cartilage, and providing for friction-free movement of these surfaces. In a large joint, such as the knee, the volume of synovial fluid is estimated to be less than 5 mL. The intra-articular pressure is typically subatmospheric. Compositionally, normal synovial fluid is an

ultrafiltrate of plasma to which proteins and proteoglycans are added by fibroblast-like synoviocytes in the lining layer. Most of the small-molecular-weight solutes, such as oxygen, carbon dioxide, lactate, urea, creatinine, and glucose, diffuse freely through the fenestrated endothelium of the synovium and are normally present at comparable levels to plasma. There is evidence for active transport of glucose. The total protein concentration of normal synovial fluid is 1.3 g/dL. The concentration of individual plasma proteins is inversely proportional to the molecular size, with small proteins, such as albumin, being present at approximately 50% of plasma levels, and large proteins, such as fibrinogen, macroglobulins, and immunoglobulins, being present at low levels. In contrast to this selective entry on the basis of size, the clearance of synovial fluid proteins through the synovial lymphatics is unrestricted by size. Hyaluronan is the major proteoglycan synthesized by synovial cells and secreted into synovial fluid. Hyaluronan is highly polymerized and reaches molecular weights exceeding 1 million D, giving this fluid its characteristic viscosity. The hyaluronan also acts to retain small molecules in the synovial fluid. The lubricating capacity of the synovial fluid is attributed to a glycoprotein called lubricin.1 This molecule has been fully characterized on the basis of studying individuals with mutations of the PRG4 gene, which encodes for its production.2 These mutations result in an autosomal recessive loss-of-­function disorder called the camptodactyly–arthropathy–coxa vara– ­pericarditis syndrome, which features a progressive, noninflammatory arthropathy characterized by severe cartilage destruction associated with proliferation of the synovial lining cells. The role of lubricin in maintaining the health of the cartilage has been shown further in a murine knockout model.3 ACCUMULATION OF SYNOVIAL EFFUSIONS Synovial fluid and its contents are cleared through the synovial lymphatics, a process that is aided by joint motion. Excess fluid can accumulate in any diarthrodial joint as a result of a broad range of processes, including noninflammatory, inflammatory, and septic disorders. In addition, overt hemarthroses can result from traumatic and nontraumatic

  Supplemental images available on the Expert Consult Premium Edition website.   Video available on the Expert Consult Premium Edition website.

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disorders. The most important mechanism contributing to the accumulation of joint effusions is an increase in synovial microvascular permeability. This mechanism allows for an increase in the efflux of plasma proteins, particularly larger proteins, which increases the osmotic pressure and contributes to the effusion. Leukocytes accumulate in the fluid after transmigration through the endothelium, stimulated by chemokines produced in the synovium. The capacity of synovial lymphatics to clear proteins, cells, and debris is rapidly exceeded, which contributes to their accumulation in the synovial compartment.

After obtaining aspirated synovial fluid samples, it is important to analyze the samples as quickly as possible to avoid spurious results. In particular, leukocyte count and differential should be performed on fresh specimens. If the specimen cannot be analyzed quickly, and short-term storage is needed, the specimen should be kept at 4°C, and an aliquot preferably should be placed in ethylenediamine tetraacetic acid to prevent clotting. Delays in analysis beyond 48 hours should be avoided. Figure 48-1 is a simplified algorithm for analyzing synovial fluid samples. GROSS EXAMINATION

ARTHROCENTESIS Most peripheral joints are readily accessible to diagnostic arthrocentesis, and the procedure can be performed in almost any ambulatory care setting equipped for sterile procedures. Joints that are less accessible because of a deeper location, such as the hip, may require an imaging technique using fluoroscopy or ultrasound to guide the needle and ensure accurate placement. The techniques used for arthrocentesis are described in detail in Chapter 49. Because the ease with which joint fluid is aspirated depends on the gauge of the needle being used, it is important to attempt arthrocentesis with a needle of adequate gauge, particularly in the larger joints. High suction gradients created by large syringes should be avoided because this may reduce the capacity to aspirate synovial fluid successfully. Difficulty in aspirating synovial fluid may relate to numerous intra-articular factors, including viscosity, presence of debris such as rice bodies, and loculation of the fluid into inaccessible areas. Instillation of a small amount of sterile saline may assist in obtaining enough fluid for culture in situations in which infection is highly suspected, yet direct aspiration is difficult.

The first impressions regarding the nature of the synovial fluid occur as the fluid enters the syringe during the arthrocentesis procedure itself. The viscosity of the fluid is readily appreciated during this step. As mentioned previously, normal synovial fluid is highly viscous because of its hyaluronan content and forms a long string when a drop is expressed from the end of the needle. With increasing levels of ­inflammation associated with the recruitment and activation of leukocytes in the synovial cavity, the hyaluronan is digested, resulting in a loss of viscosity that is appreciated as a reduction in the “stringiness” of the fluid. Large pieces of debris, such as rice bodies, thought to arise from detached ischemic synovial villi, may be visible as they are aspirated. These pieces of debris can cause sudden arrests in the flow of fluid into the syringe, requiring manipulation and redirection of the needle placement. Inspection of the aspirated synovial fluid can yield other important diagnostic information. Floridly purulent fluid is completely opaque on the basis of the high number of leukocytes present, whereas synovial fluid that is transparent, to the point where printed text can be read through it, is seen in noninflammatory settings. Inflammatory synovial fluid,

Synovial fluid analysis WBC, Gram stain, polarizing microscopy

– –

+

Organisms on Gram stain?

WBC

<3000

3000-50,000

Noninflammatory

Inflammatory

NSAIDs, analgesics

Crystals on polarizing microscopy?

Birefringence negative, Birefringence positive, rhomboid-shaped needle-shaped

>50,000

– NSAIDs, intra-articular steroids treat systemic disease

+

Assume septic, appropriate empiric antibiotics

Cultures positive?

+

Urate

CPPD

NSAIDs, intra-articular steroids, colchicine

Appropriate specific antibiotics

Figure 48-1  Simplified algorithm for analyzing synovial fluid samples and initiating a plan of management. CPPD, calcium pyrophosphate dehydrate; NSAID, nonsteroidal anti-inflammatory drug; WBC, white blood cell count.

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as would be aspirated from an individual with active rheumatoid arthritis (RA), appears cloudy and translucent, with the degree of translucency depending on the intensity of the inflammatory response and the concentration of leuckocytes in the sample. Synovial fluid from patients with ochronosis may have a speckled appearance, and particulate debris from joint prostheses may be visible on gross inspection. During the arthrocentesis procedure, an important challenge may be to determine whether the presence of blood in the aspirated synovial fluid indicates a hemarthrosis, or alternatively is a result of trauma from the procedure itself. In the latter case, the blood may remain unmixed with the synovial fluid, appearing as red streaks in an otherwise yellow fluid, whereas in the case of hemarthroses the synovial fluid is generally homogeneously bloody and does not form a clot. The causes of frank hemarthrosis vary and include trauma; pigmented villonodular synovitis; tumors; hemophilia, other bleeding disorders, or anticoagulant therapy; Charcot joint; and occasionally intense inflammation from a chronic arthropathy, such as RA or psoriatic arthritis. LEUKOCYTE COUNT Analysis of leukocyte counts and cytology provides important diagnostic information regarding the cause of a synovial effusion (Table 48-1). A fresh specimen should be placed in a heparinized tube for rapid analysis, and if the fluid is particularly viscous, it may need to be diluted in normal saline before counting. Normal synovial fluid contains less than 180 nucleated cells/mm3, most of which originate as desquamated synovial lining cells. The leukocyte count broadly classifies synovial fluids as noninflammatory (>3000 cells/ mm3), inflammatory (3000 to 50,000 cells/mm3), and septic (>50,000 cells/mm3). These definitions are broad guidelines to help narrow the differential diagnosis, rather than being inherent biologic properties of the fluid. The most common causes of noninflammatory synovial fluids are mechanical derangements of the joint and osteoarthritis. Other causes include endocrinopathies, such as

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acromegaly and hyperparathyroidism; inherited disorders, such as ochronosis, hemachromatosis (which also can manifest with hemarthrosis), Ehlers-Danlos syndrome, Wilson’s disease, and Gaucher’s disease; acquired disorders, such as Paget’s disease, avascular necrosis, and osteochondritis dissecans, and an uncommon condition called intermittent hydrarthrosis, in which joints accumulate effusions in a cyclical manner. At the other extreme, leukocyte counts of 50,000 to 300,000 cells/mm3 are most commonly associated with septic arthritis and should prompt the clinician to treat the individual empirically for septic arthritis until this diagnosis is excluded with a high degree of certainty, which typically requires definitive culture results and possibly repeat aspiration. Leukocyte counts exceeding 50,000 cells/mm3 also are commonly seen in acute crystal-induced arthritis, particularly gout. Inflammatory cell counts of 3000 to 50,000 cells/mm3 are seen in a wide spectrum of articular disorders, including many cases of septic arthritis. Most patients with acute attacks of gout and pseudogout, active RA, reactive arthritis, and psoriatic arthritis and patients with gonococcal arthritis and other nonpyogenic forms of septic arthritis all typically present with synovial fluid cell counts in this range (see Table 48-1). SYNOVIAL FLUID CYTOLOGY Characterization of the cells present in the synovial fluid is an important diagnostic step, and this can be achieved initially by performing cytology on a wet mount of the synovial fluid. To perform the wet mount analysis, one drop of synovial fluid is placed on a clean glass slide, which is covered by a coverslip and is examined under low-power and high-power light microscopy. In addition to leukocytes, and in the case of traumatic taps or hemarthroses, and large numbers of erythrocytes, the wet mount may show clumps of fibrin and crystals, cartilage and synovium fragments, and lipid droplets. These all can appear as amorphous material, and care should be given in assuming their composition without further characterization.

Table 48-1  Characteristics of Synovial Fluid Appearance

Viscosity

Cells per mm3

% PMN

Crystals

Culture

Normal

Transparent

High

<180

<10%

Negative

Negative

Osteoarthritis

Transparent

High

200-2000

<10%

Occasional calcium pyrophospate and hydroxyapatite crystals

Negative

Rheumatoid arthritis

Translucent

Low

2000-50,000

Variable

Negative

Negative

Psoriatic arthritis

Translucent

Low

2000-50,000

Variable

Negative

Negative

Reactive arthritis

Translucent

Low

2000-50,000

Variable

Negative

Negative

Gout

Translucent to cloudy

Low

200->50,000

>90%

Needle-shaped, negatively birefringent monosodium urate monohydrate   crystals

Negative

Pseudogout

Translucent to cloudy

Low

200-50,000

>90%

Rhomboid, positively birefringent calcium pyrophosphate crystals

Negative

Bacterial arthritis

Cloudy

Variable

2000->50,000

>90%

Negative

Positive

PVNS

Hemorrhagic or brown

Low

—

—

Negative

Negative

Hemarthrosis

Hemorrhagic

Low

—

—

Negative

Negative

PMN, polymorphonuclear neutrophil; PVNS, pigmented villonodular synovitis.

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Characterization of the synovial fluid leukocytes is best achieved by staining a dried smear of the fluid. Wright’s stain is the most commonly used for this purpose. The phenotype and morphology of the leukocytes can be assessed under high power using oil immersion. Septic range synovial fluid containing greater than 50,000 cells/mm3 is almost always associated with a high preponderance of polymorphonuclear neutrophils, often greater than 90%. Monocytes and lymphocytes predominate in the synovial fluid of patients with viral arthritis, lupus, and other connective tissue diseases. Synovial fluid samples from patients with active RA, reactive arthritis, psoriatic arthritis, and acute attacks of crystal-induced arthritis all typically show a preponderance of polymorphonuclear neutrophils, although early RA fluids may have a low leukocyte count with primarily mononuclear cells. The presence of numerous “ragocytes,” which are granulocytes that have phagocytized immune complexes, is associated with active RA, and their presence may indicate an unfavorable prognosis in this disease.4 Reiter’s cells represent cytophagocytic mononuclear cells that have phagocytized apoptotic polymorphonuclear neutrophils, this possibly representing a pathway by which autolysis and release of damaging mediators from the latter cells is avoided.5 The presence of Reiter’s cells is not specific for reactive arthritis or spondyloarthropathies in general. Occasionally, eosinophils predominate in the synovial fluid; this may be associated with parasitic infections, urticaria, or hypereosinophilic syndrome. It has been suggested that cytocentrifugation of synovial fluid is the optimal method for performing cytopathology, although the cost-effectiveness of this technique is questionable in most clinical settings. WET SMEAR ANALYSIS BY POLARIZED MICROSCOPY A search for crystals using polarized microscopy is particularly valuable in the diagnosis of acute monarthritis or oligoarthritis, where gout and pseudogout are often on the differential diagnosis. In such a clinical situation, if the absence of pathogenic crystals in the synovial fluid can be established, the likelihood of septic arthritis increases, prompting the initiation of intravenous antibiotics and potentially necessitating a hospital admission. The rapid and accurate diagnosis of a crystal-induced process can prevent a costly and unnecessary sequence of events. It is quite helpful if the individual or team that performs the

A

arthrocentesis is also in a position to examine the ­specimen rapidly by polarized microscopy; this requires the availability of a functional polarizing microscope and having adequate experience in the identification of crystals using this technique. This is particularly important in the case of calcium pyrophosphate dihydrate (CPPD) crystals, which are notoriously difficult to detect. Care should be taken to ensure the slide and coverslip are free of dust, talc, and other particulate matter. Crystals present in the specimen rotate the light such that it appears as bright objects in the otherwise dark field. There is frequently birefringent debris scattered throughout the slide, and this should not be mistaken for crystals. The first order red compensator is usually inserted immediately below the upper filter and blocks out green light. Birefringent material in the specimen appears as a bright yellow or blue color in the red field generated by the first order compensator. As the birefringent crystals are rotated relative to the axis of the first order compensator, the color changes from yellow to blue or vice versa. Crystals that are yellow when oriented parallel to the axis of the compensator are negatively birefringent, whereas crystals that are blue are positively birefringent. Identification of crystals in synovial fluid is greatly facilitated by a detailed examination of the specimen, under low and high power, using the approach described earlier. A combination of morphology and birefringence serves to identify the crystals. Monosodium urate crystals, shown in Figure 48-2, are the easiest to identify because the crystal load is typically quite high during an acute attack of gout. There is a good degree of concordance between laboratories in the identification of monosodium urate crystals.6-8 These crystals appear as strongly negatively birefringent needle-shaped objects, many of which are intracellular, having been phagocytosed by the synovial fluid leukocytes. In contrast, CPPD crystals seen during attacks of pseudogout tend to be smaller, rhomboid-shaped objects that are weakly positively birefringent (Fig. 48-3). Because the CPPD crystal load during an attack of pseudogout tends to be relatively low, and because the CPPD crystals are only weakly birefringent, it is important to examine all areas of the specimen on the microscope slide, and possibly to prepare a second wet mount to exclude or confirm this

B

Figure 48-2  A, Urate crystals in a tophus from a patient with gouty arthritis. The crystals are negatively birefringent and needle-shaped.  B, Intracellular urate crystal as seen on a Wright stain. (Courtesy of H. Ralph Schumacher, Jr.)

Figure 48-3  Calcium pyrophosphate crystals in synovial fluid from a patient with pseudogout. The crystals are positively birefringent and rhomboid-shaped. (Courtesy of H. Ralph Schumacher, Jr.)

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diagnosis. The concordance between laboratories in the recognition of CPPD has been shown to be substantially lower than in the case of monosodium urate crystals.6-8 A challenging situation arises when intracellular crystals cannot be identified, yet birefringent extracellular objects resembling crystals are seen scattered throughout the slide. This situation may be caused by powder from gloves or dirt on the slides. As with other analyses performed on the synovial fluid, wet mount preparation and analysis should be performed as quickly as possible, although identification of crystals still can be successful after prolonged storage of specimens. The crystal load decreases substantially as the acute inflammatory attack subsides, making a specific diagnosis more difficult as the attack begins to subside. Urate crystals have been detected in synovial fluid in between attacks of gout. Deposits of hydroxyapatite or basic calcium phosphate are present within the joint and in periarticular locations, such as around the shoulder area, and are associated with osteoarthritis. These crystals have been incriminated in a particularly destructive syndrome that has been named Milwaukee shoulder.9 Hydroxyapatite can be detected in synovial fluid, but because these crystals are generally nonbirefringent, it is impossible to detect them by polarized microscopy. A ­useful and rapid method with which to detect hydroxyapatite and other calcium-containing crystals, such as octacalcium and tricalcium phosphate, is to stain the fluid with alizarin red S stain and look for clumps of crystals under routine light microscopy (Fig. 48-4). These crystals also have been identified using electron microscopy, although this is rarely available to practicing clinicians. Synovial cholesterol crystals appear as flat, platelike structures with notched corners (Fig. 48-5), and lipid crystals have the appearance of Maltese crosses. Both can be strongly negatively and positively birefringent. Corticosteroid crystals can be highly birefringent and mimic urate or CPPD crystals. Large amounts of lipid in the synovial fluid can be visible on gross examination. The significance of these crystals in synovial fluid is unclear, but it is unlikely that they are pathogenic in most cases.

Figure 48-4  Clumps of calcium hydroxyapatite crystals shown using alizarin red staining. The crystals are nonbirefringent. (Courtesy of H. Ralph Schumacher, Jr.)

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DETECTION OF MICROORGANISMS BY GRAM STAIN, CULTURE, AND POLYMERASE CHAIN REACTION ANALYSIS OF SYNOVIAL FLUID A wide spectrum of organisms can cause septic arthritis, although the most common pathogens are gram-positive bacteria, such as staphylococci and streptococci. Because septic arthritis causes rapid destruction of the joint, can spread hematogenously to other areas, and is associated with significant mortality, it is imperative that a specific diagnosis be made as quickly as possible, and that empiric therapy with broad-spectrum antibiotics be instituted until this diagnosis can be confirmed or excluded. A Gram stain performed on fresh synovial fluid identifies an organism in an estimated 50% of cases of septic arthritis,10 with the sensitivity being highest for grampositive organisms. The specificity of a positive Gram stain approaches 100%; this indicates that the positive predictive value for the Gram stain is very high, whereas the negative predictive value is substantially lower. The “gold standard” for diagnosing septic arthritis is bacteriologic culture, which has a sensitivity of 75% to 95% and a specificity of 90% in cases of nongonococcal septic arthritis.11,12 It also has been shown that the use of blood culture bottles increases further the yield of positive synovial cultures.13 The bacteriologic cultures are the only studies to provide a guide for specific antimicrobial therapy. Because the sensitivity of the bacteriologic cultures declines dramatically after institution of antibiotic therapy, it is important to perform the arthrocentesis before the administration of any antibiotics. Cultures should be performed even when uric acid or other crystals are shown in the synovial fluid because gout and septic arthritis can coexist.14 In the case of gonococcal arthritis, the sensitivity of bacteriologic culture, even if performed on a sample collected using appropriate media, is quite low and estimated to be less than 10%.

Figure 48-5  Cholesterol crystals in a synovial fluid sample. (Courtesy of H. Ralph Schumacher, Jr.)

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The use of polymerase chain reaction (PCR) has a high degree of sensitivity and specificity for the detection of microorganisms in the synovial fluid and tissue, even in individuals who are culture negative.15 Most bacteria can be detected on the basis of amplifying specific sequences in their ribosomal RNA (16S rRNA). PCR is the procedure of choice for making the diagnosis of gonoccocal arthritis16,17 and is a highly sensitive and specific method of detecting tuberculous arthritis, although as discussed subsequently, the analysis of synovial tissue is better than analysis of synovial fluid for making this diagnosis.18,19 PCR also has been proposed as a method of verifying the successful elimination of the offending organism in cases of septic arthritis.20,21 The sensitivity and specificity of PCR in detecting synovial microorganisms need to be balanced against the biologic significance of a positive test. Contaminants are detected easily using this method, and highly stringent conditions for sample collection are required to prevent false-positive tests. PCR studies of synovial fluid and tissue from a spectrum of chronic forms of arthritis, including RA, osteoarthritis, reactive arthritis, and undifferentiated arthritis, have indicated the presence of microorganisms in numerous specimens.22,23 The biologic significance of these findings and the potential role of bacterial DNA or cell wall fragments in the pathogenesis of these arthropathies are unclear. BIOCHEMICAL ANALYSIS OF SYNOVIAL FLUID Numerous widely available biochemical tests may add to the diagnostic impression of aspirated synovial fluid samples, although the lack of specificity of these biochemical analyses tends to limit their value.12,24 Testing for synovial fluid glucose, protein, and lactate dehydrogenase has long been included in routine practice, and if these are tested, they should be compared with the serum values. Samples from septic arthritis typically exhibit very low glucose, low pH, and high lactate levels—all of these being indicative of a switch to anaerobic metabolism. Highly inflammatory synovial fluids from RA patients exhibit a similar profile, along with high protein and lactate dehydrogenase levels. A prospective study evaluating these tests in a spectrum of inflammatory and noninflammatory disorders showed considerable variability in each diagnostic category, which limits their clinical utility.24 Serologic testing of synovial fluid to detect rheumatoid factor, antinuclear antibodies, and complement levels has been suggested in the past for confirming a diagnosis of RA or other connective tissue diseases. In particular, RA synovial fluids may be positive for rheumatoid factor, even when the serum is not,25 and complement levels are typically quite low as a result of consumption by immune complexes. These findings are of insufficient sensitivity and specificity to be valuable on a routine clinical basis. SYNOVIAL FLUID ANALYSIS IN ARTHRITIS RESEARCH The ease with which synovial fluid is aspirated from effused joints has allowed for a wide spectrum of research studies to be conducted on this biologic material. In research settings, the cells in the synovial fluid samples are typically separated by centrifugation, and the cellular and noncellular

c­ omponents of the fluid are analyzed separately. Detailed analysis of the phenotype and functional properties of synovial fluid leukocytes has been particularly informative in RA and reactive arthritis research, where immunophenotyping of lymphocyte subpopulations has provided important clues to the pathogenesis of these diseases. In the case of reactive arthritis, where triggering organisms often can be identified, the proliferative and cytokine responses of synovial fluid lymphocytes to antigens derived from Chlamydia, Yersinia, and other pathogens have been elucidated.26,27 Generally, synovial fluid T cells from patients with reactive arthritis are biased toward production of T helper type 2 (Th2) cytokines, such as interleukin (IL)-10 and IL-4, whereas synovial fluid T cells from RA patients are Th1 biased and exhibit defects in Th2 differentiation.28-30 Analysis of the noncellular portion of synovial fluid has provided important information regarding a spectrum of soluble molecules, including cytokines and growth factors,31 extracellular matrix proteins, autoantibodies, and therapeutic drug levels. Broad-based proteomic studies of synovial fluid using fractionation techniques and mass spectrometry are beginning to provide novel approaches to understanding pathogenesis and prognosis in arthropathies such as RA.32

SYNOVIAL BIOPSY Sampling of synovial tissue is a direct approach to defining the pathologic processes that cause joints to be swollen and painful. In clinical settings, synovial tissue sampling can be particularly valuable in evaluating an undiagnosed persistent monarthritis when other investigations, including synovial fluid analysis, have failed to provide a specific diagnosis. In research settings, analysis of synovial tissue samples has dramatically improved the understanding of the pathogenetic mechanisms underlying RA, spondyloarthropathies, and other chronic articular disorders. More recently, synovial biopsy has been explored as a method for defining the target tissue response to therapeutic agents, particularly targeted biologic therapies. BLIND PERCUTAENOUS SYNOVIAL BIOPSY Percutaneous needle biopsy is most commonly performed using the method originally described by Parker and Pearson,33,34 using a biopsy needle that now carries their name. Percutaneous synovial biopsy is most often performed on the knee joint, although the technique can be adapted for use in other joints, such as the wrist, elbow, ankle, or shoulder. A modification of the original Parker-Pearson needle has facilitated synovial biopsy of small hand joints, such as metacarpophalangeal and proximal interphalangeal joints.35 The technique for Parker-Pearson synovial biopsy uses a 14-gauge needle with a lateral aperture just proximal to the inserted end of the needle. This lateral opening features a sharp cutting edge for severing trapped synovial tissue that is captured by applying suction with a 3- to 5-cc syringe. Using this approach, multiple 1- to 3-mm sized samples are obtained by angling the trochar in several directions. This approach also minimizes the sampling error involved. Synovial samples are typically pink in color and are easily removed with a slight twisting motion. Because of the blind

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nature of the procedure, samples of fat, muscle, or fibrous tissue may be obtained and need to be separated from true synovial samples. Percutaneous synovial biopsy is easily performed in most ambulatory care settings using relatively inexpensive equipment. The overall morbidity of the procedure is quite low and is comparable to arthrocentesis, with perhaps a slightly higher rate of hemarthrosis. Hemarthrosis can be minimized if the patient avoids weight bearing for a few hours after the procedure. The main disadvantage of the procedure is its blind nature. Compared with visually guided arthroscopy, there is an underrepresentation of samples derived from the interface between synovium and adjacent cartilage using the blind procedure.36,37 As discussed subsequently, this drawback is particularly relevant to many research questions. ARTHROSCOPICALLY GUIDED SYNOVIAL BIOPSY Arthroscopy is widely used by orthopedic specialists for the diagnosis and treatment of a variety of articular disorders, particularly mechanical derangements of intra-articular structures, such as cruciate ligaments and menisci. The arthroscopic procedure has been adapted for acquiring diagnostic synovial biopsy specimens in settings that do not require a fully equipped operating theater and general anesthetic. In most cases, intra-articular local anesthesia suffices for the procedure, although conscious sedation may be required in some individuals. The procedure is well tolerated and associated with low morbidity, although the risk of hemarthrosis and infection after the procedure is slightly higher than that of percutaneous needle biopsy. The patient should be instructed to minimize weight bearing for 24 to 48 hours after the procedure. The primary advantage of arthroscopy is the ability to guide the biopsy procedure visually. This guidance allows for a macroscopic evaluation of the synovium and for sampling of areas that appear to be particularly severely affected by the pathologic process, and allows for sampling of the interface between the inflamed synovium and the adjacent cartilage, this being an area of particular interest for understanding the pathogenesis of destructive arthropathies such as RA.36 As with the samples obtained by percutaneous synovial biopsy, individual samples are allocated for specific laboratory studies depending on the clinical or the research question being addressed. PROCESSING SYNOVIAL TISSUE SAMPLES In all cases, an adequate number of individual synovial specimens need to be allocated for routine light microscopy using formalin fixation and paraffin embedding. This allocation provides the highest quality sections for hematoxylin and eosin histologic analysis and allows for the most accurate delineation of pathologic processes in the tissue. Although formalin-fixed sections also can be used in some cases for immunohistology, formalin fixation alters the conformation of many protein antigens, making them inaccessible for specific identification by immunohistology. Many of the molecular markers used to analyze diseased synovium, including cell surface markers, cytokines, adhesion molecules, and proteases, require that the tissue samples are snap frozen in a suitable

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mounting medium such as OCT (optimal cutting temperature) compound, and then sectioned using a cryostat. The sections can be processed using antigen-specific monoclonal or polyclonal antibodies and color development achieved by one of many immunofluorescence or immunoperoxidase methods available. Typically, a nuclear counterstain also is used to assist in orientation of the tissue, this being hematoxylin in the case of immunoperoxidase studies. If only formalin-fixed, paraffin-embedded tissue is available, an alternative method for detecting antigens that are sensitive to formalin fixation is antigen retrieval. Several antigen retrieval methods are available, including enzymatic and thermal methods.38 These methods have been used to retrieve a spectrum of antigens successfully from archival synovial tissue samples for immunohistologic studies, although the quality of the tissue sections often deteriorates after antigen retrieval. Numerous double-staining immunohistology techniques also have been developed to evaluate simultaneously the expression of two markers in the same tissue section, although these techniques are labor intensive and often require a considerable amount of experimentation to generate good stains.39 The sensitivity and specificity of molecular DNA and RNA techniques provide unprecedented opportunities for understanding the pathogenesis of synovial disorders. Although these studies can be done on very small quantities of tissue, great care needs to be taken in the handling and processing of the tissue samples to prevent the degradation of the nucleic acids, particularly in the case of RNA, where RNAase enzymes are ubiquitous and can rapidly degrade the small quantity of RNA present in a tissue sample. As discussed subsequently, a search for microbial DNA and RNA has been of particular interest in attempting to understand the etiology and pathogenesis of reactive arthritis, RA, and other forms of chronic synovitis of unknown cause. Techniques for analyzing human gene expression in small tissue samples have improved rapidly. This improvement has allowed for the detection and quantitation of multiple mRNA transcripts in very small quantities of biopsy material, in many cases without the need for amplification.40,41

SYNOVIAL PATHOLOGY SYNOVIAL MEMBRANE IN HEALTH A detailed description of the composition of normal synovium is provided in Chapter 2. Histologically, the normal synovial lining layer is one to three cells thick and is composed of closely associated macrophage-like (type A) and fibroblast-like synoviocytes (type B) that are not separated from the underlying stroma by a basement membrane, as is the case with a true epithelium. In many areas, there are visible gaps in this lining layer allowing small molecules to diffuse easily through the extracellular matrix into the synovial fluid. The two types of lining layer synoviocytes are distinct and can be differentiated on the basis of ultrastructural and immunohistologic features. Macrophage-like synoviocytes are myeloid in origin because they exhibit the morphologic characteristics of phagocytic cells and express macrophage markers such as CD68, CD14, and FcγRIIIa. Fibroblast-like synoviocytes are synthetic cells of mesenchymal origin that are

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Figure 48-6  Normal synovium.  A, There is a one- to two-cell deep lining layer composed of macrophage-like synoviocytes (type A) and fibroblast-like synoviocytes (type B). B, Normal synovium stained for the enzyme uridine diphosphoglucose dehydrogenase and indicator of  hyaluronan synthesis by the fibroblast-like synoviocytes.

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the primary source of hyaluronan and other proteoglycans found in normal synovial fluid. They express CD55 (decay accelerating factor), high levels of the adhesion molecule VCAM-1, and the enzyme urodine diphosphoglucose dehydrogenase, which is involved in the synthesis of hyaluronan and which has been detected by cytochemical methods (Fig. 48-6). Fibroblast-like synoviocytes express cadherin 11, a specialized adhesion molecule that is involved in homotypic aggregation of these cells and contributes to maintaining the integrity of the synovial lining layer.42 Most of the cells in the normal synovial lining layer are the synthetic type B cells. The underlying stroma features a rich network of capillaries with fenestrated endothelium in the immediate sublining area that maintain the health and viability of the adjacent cartilage. Larger arterioles and venules can be found deeper in the synovial stroma. The synovial microvasculature is surrounded by loose connective tissue, which also incorporates the synovial lymphatics that drain this tissue. The synovium of completely asymptomatic individuals commonly exhibits a modest infiltrate of T lymphocytes that are occasionally

Figure 48-7  A, Synovial pathology of gonococcal arthritis. There is a marked infiltrate with polymorphonuclear neutrophils and vascular congestion. B, Synovial pathology of scleroderma showing loss of lining layer with surface fibrin deposition and mononuclear inflammation in the sublining areas. C, Pigmented nodular synovitis with hemosiderin deposits and foamy cells. D, Amyloidosis with deposits on the synovial surface, Congo red stain. (Courtesy of H. Ralph Schumacher, Jr.)

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organized in perivascular aggregates, although B cells were not seen.43 SYNOVIAL HISTOPATHOLOGY IN THE EVALUATION OF MONARTHRITIS Pathologic analysis of synovial tissue samples can be of considerable value in certain clinical settings. Having said this, it should be kept in mind that the histopathologic interpretation of synovial biopsy specimens is often nondiagnostic and lacking in specificity.44 Pathologic analysis of synovial samples from patients with undiagnosed monarthritis may be of particular value. The presence of large numbers of neutrophils in the synovial tissue stroma is highly suggestive of septic arthritis, and in such cases Gram stain may reveal bacteria in the tissue. Because septic arthritis is usually quite acute in onset, synovial biopsy is rarely required, and the diagnosis can be made by analyzing synovial fluid as described earlier. Gonococcal arthritis may require synovial biopsy for diagnosis (Fig. 48-7). A mononuclear cell infiltrate is more consistent with a chronic inflammatory process and has a wide ­ differential

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diagnosis as described subsequently. The presence of ­granulomas supports a diagnosis of tuberculous arthritis or sarcoidosis, both of which cause a chronic monarthritis. The synovial granulomas of tuberculosis may be caseating or noncaseating, and staining of the tissue for acid-fast bacilli, culture, and molecular probing can yield a definitive diagnosis in an estimated 50% of cases. A spectrum of fungal infections can be diagnosed using similar approaches, but may require special stains, such as Gomori. The diagnosis of sarcoid arthropathy is suspected in synovial specimens with noncaseating granulomas in which mycobacterial or fungal infection has been excluded. Pigmented villonodular synovitis is a common cause of monarthritis in a large joint, such as the knee or hip. This disorder has a characteristic magnetic resonance imaging appearance resulting from hemosiderin deposits in the synovium and large cystic lesions in the adjacent bone. Histopathologic analysis of the synovium can confirm this diagnosis and shows a diffusely hypervascular proliferative lesion with mononuclear cells of the monocyte/macrophage lineage, foamy multinucleated cells resembling osteoclasts, and hemosiderin deposits (see Fig. 48-7).45 Synovial sarcomas are rare tumors that need to be diagnosed on the basis of synovial pathology. SYNOVIAL HISTOPATHOLOGY IN THE EVALUATION OF POLYARTHRITIS In current clinical practice, the availability of well-validated diagnostic criteria and specific serologic tests, combined with a relative lack of specificity in the synovial histopathologic features, limits the clinical utility of synovial pathology in the differential diagnosis of oligoarthritis and polyarthritis.

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Analysis of synovial tissue samples obtained in the context of research studies from patients with RA and various spondyloarthropathies has dramatically enhanced understanding of the cellular and molecular mechanisms of these disorders; this is reflected in a large body of literature published over the past 3 decades.36,46 RA synovium has been the most extensively studied histopathologically. The two characteristic features seen in RA synovitis are hyperplasia of the lining layer and infiltration of the sublining stroma with mononuclear cells (Fig. 48-8). The surface of the lining layer is often covered with fibrin deposits generated from activation of the fibrinolytic system in the inflammatory synovial fluid. Occasionally, the synovial lining layer is completely denuded and replaced by a dense fibrin cap. In highly inflamed tissues, the fibrin deposits extend deeply into the sublining stroma, which may be edematous because of the marked increase in vascular permeability. The microvasculature is abnormal appearing, and vessels may be completely occluded or the walls disrupted, although frank vasculitis is uncommon. The earliest synovial changes in RA seem to feature microvascular abnormalities,47 and mononuclear cell infiltrates have been detected in asymptomatic joints of RA patients.48,49 These features are nonspecific and are seen in the synovium of acutely inflamed joints from a spectrum of disorders, including reactive arthritis and psoriatic arthritis. Fassbender, one of the pioneers of synovial pathology, stated that proliferation of the stromal mesenchymal elements is relatively specific to RA synovitis. This has been termed mesenchymoid transformation, although as discussed subsequently, the absence of suitable immunohistologic markers for mesenchymal stromal cells has hindered a better understanding of this process.49a

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Figure 48-8  Histopathology of  rheumatoid arthritis synovitis.  A, Lymphoid aggregate. B, Diffuse lymphocyte infiltrate. C, Hyperplasia of the lining layer. D, Fibrin cap replacing a denuded lining layer.

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High endothelial venule

Transitional zone Lymphoblasts Dendritic cells Macrophages

Lymphocyte zone T cells, B cells

Figure 48-9  Microarchitecture of rheumatoid arthritis synovial l­ymphoid aggregates.

Figure 48-10  Multinucleated giant cell in a patient with rheumatoid arthritis.

In RA, the mononuclear cell infiltrate in the sublining stroma can be diffuse, but more commonly is arranged in perivascular aggregates resembling lymphoid follicles (see Fig. 48-8). In a few cases in which these lymphoid follicles are large and well developed, true germinal centers may be identifiable. The lymphoid follicles are typically located near vessels with tall endothelium, which are termed high endothelial venules; these vessels specialize in the recruitment of lymphocytes (Fig. 48-9). Multinucleated giant cells are occasionally seen in RA synovium (Fig. 48-10), with some tissues showing granuloma formation. Based on a detailed study that coupled histopathology with molecular analysis, it has been proposed that three distinct synovial pathology patterns are seen in RA. The patterns were based on whether the mononuclear cell infiltrate was diffuse, formed lymphoid aggregates with germinal centers, or was granulomatous.50 Granulomatous synovitis was the most closely associated with extra-articular features, such as nodules, whereas diffuse synovitis was associated with seronegative RA. It is proposed further that these pathologic features are associated with distinct cytokine and chemokine profiles and were a characteristic and consistent feature of each RA patient’s synovitis. Although this notion has been challenged, and revised to some extent, it does suggest that the immunopathologic mechanisms underlying what is clinically referred to as RA are likely heterogeneous. Finally, synovial tissue obtained at the time of joint arthroplasty often exhibits extensive fibrosis and may be indistinguishable from arthroplasty samples obtained from osteoarthritis patients. The synovial histopathologies of psoriatic arthritis, ankylosing spondylitis, and reactive arthritis have been compared with that of RA.51 In all cases, a similar spectrum of inflammatory cell populations has been identified, but many subtle and potentially important differences have been observed. Comparative studies have suggested that the synovial lesions in psoriatic arthritis are more vascular than the lesions of RA, with more tortuosity of the synovial microvasculature.52 This is evident macroscopically and microscopically. Studies of synovium from the peripheral joints of ankylosing spondylitis patients have revealed intense infiltrates of lymphocytes, plasma cells, and lymphocytic aggregates.53,54 Comparisons made between the synovial lesions seen in

reactive arthritis and those seen in early RA of similar disease duration suggest that reactive arthritis synovia are less infiltrated with B lymphocytes, plasma cells, and macrophages.55,56 Synovium from patients with osteoarthritis often has lymphocyte aggregates, although these tend to be small and less well developed than those seen in RA. The synovium of lupus patients showed synovial hyperplasia, inflammatory infiltrates, vascular proliferation, edema and congestion, fibrinoid necrosis and intimal fibrous hyperplasia of blood vessels, and superficial fibrin deposits, although these changes were quantitatively modest compared with RA.57 In early scleroderma, the lining layer was seen to be thin with deposits of fibrin and stromal lymphocytes and plasma cells,58 and similar changes were seen in patients with dermatomyositis and polymyositis (see Fig. 48-7).59 In patients with chronic crystal arthropathies, large deposits of birefringent material can be detected in the synovium.60 Amyloid arthropathy can be diagnosed by showing amyloid deposits in the synovium using Congo red staining (see Fig. 48-7). The synovium in ochronosis contains brownish shards of cartilage.61 Multicentric reticulohistiocytosis can be diagnosed pathologically by the presence of large foamy cells and multinucleated cells in the synovium. In arthritis of hemochromatosis, the synovium exhibits brown hemosiderin deposits in the lining cells, and CPPD crystals can be found.62

SYNOVIAL IMMUNOHISTOLOGY SAMPLING AND QUANTITATIVE ANALYSIS Immunohistology uses specific monoclonal or polyclonal antibodies with well-defined molecular targets and is an effective tool for analyzing the cellular and molecular features of the synovium. As the field has progressed, it has become clear that algorithms for generating reproducible quantitative data from immunohistologically stained sections are required. Approaches need to be developed for minimizing the sampling bias that is inherent in biopsybased studies.63 Studies have suggested that if six or more individual specimens from different parts of the joint are examined, this reduces the variance to less than 10% for

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T cell and activation markers.64 It has been shown that the synovial inflammatory features are similar in areas adjacent to and distant from the pannus-cartilage junction, with the possible exception of macrophage numbers, which tend to be higher in the adjacent areas.65,66 Numerous methods have been proposed to generate quantitative data for immunohistologically stained synovial tissue sections.67,68 The easiest and least costly method is to generate semiquantitative scores of staining intensity (e.g., on a 0-to-3 scale) from multiple areas of the tissue; from these an average score is generated for the entire tissue. The reliability and reproducibility of this method are increased if two observers score the tissue sections independently, and a final average of the scores is generated. Computer-assisted image analysis involves capturing images from multiple areas of the tissue samples, to which colorspecific quantitative software algorithms are then applied. This method generates the most reproducible data, but requires expensive equipment with a certain level of operator skill. Differences in the background staining intensity of individual sections can make this type of analysis technically difficult. SYNOVIAL LINING CELL LAYER Compared with normal synovium, in RA the lining layer is often hyperplasic resulting from an increase in type A and type B cells as indicated by an increase in CD68 and CD55 staining (Fig. 48-11). It is assumed that the macrophagelike synoviocytes are recruited from the blood, after which they migrate through the synovial stroma and ultimately are retained in the lining layer in close association with fibroblast-like synoviocytes. The increase in fibroblast-like

Figure 48-11  Immunoperoxidase   staining of normal synovium (A and B) and rheumatoid arthritis synovium (C and D). (A and C are stained for CD55 [fibroblast-like synoviocytes] and B and D are stained for CD68 [macrophage-like synoviocytes]). Both subsets of lining cells are increased in the hyperplastic lining layer of rheumatoid arthritis synovium.

synoviocytes may be more related to defects in apoptosis than to recruitment or local proliferation. Expression of several families of adhesion molecules by both types of lining cells results in their close association and modulates their activation status. This includes β1 and β2 integrins and their respective immunoglobulin supergene family ligands, particularly ICAM-1 and VCAM-1.69-71 Cadherin 11 expressed by the fibroblast-like cells likely plays a key role in the adhesive interactions that sustain the lining layer hyperplasia.42 The relationship between fibroblast-like synoviocytes in the lining layer and other populations of mesenchymal cells in the sublining stroma is uncertain. Immunohistology indicates that the expression of CD55, VCAM-1, and cadherin 11 is primarily seen in the lining cell layer with minimal evidence of expression in sublining fibroblast populations. ­ Similarly, there is an incomplete understanding of the relationship between the lining layer macrophagelike cells and sublining macrophages, both of which express widely used macrophage markers such as CD68 and CD14. Work from Edwards and colleagues72 suggested that the macrophage-like lining cells preferentially express FcγRIIIa receptors, which might localize immune complexes to the synovium. Functionally, the lining cell layer in RA is highly activated. HLA-DR is expressed, particularly by the macrophage-like cells, which may suggest a role for these cells in antigen presentation.73 Several studies have indicated that cells in the RA lining layer are the principal source of cartilage degrading proteases, particularly MMP-1 and MMP-3 (Fig. 48-12).74,75 Although both types of lining cells produce these proteases, in vitro studies of cultured synovial cells indicate that the fibroblast-like synoviocytes

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Figure 48-12  Immunoperoxidase staining of rheumatoid arthritis synovium. A, CD3 (T lymphocytes).  B, CD20 (B lymphocytes). C, MMP-1. D, αvβ3 ­integrin (angiogenic ­vessels).

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are likely the major source. The macrophage-like cells are the major source of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and IL-1, which stimulate protease production. The lining layer is generally less hyperplastic in spondyloarthropathies, such as psoriatic arthritis and reactive arthritis, compared with RA.54,76 Less is known about the functional state of the lining cells in these disorders, although it is likely that differences compared with RA are quantitative rather than qualitative. SYNOVIAL LYMPHOCYTES AND PLASMA CELLS In the synovial tissues of RA and spondyloarthropathy patients, there is a predominance of CD3+ T cells, and the CD4-to-CD8 ratio is 4:1 or more in the lymphocytic aggregates, but is lower in more diffuse infiltrates. The phenotype of the T cells has been delineated further and is consistent with a preponderance of memory T helper cells exhibiting CD45Ro. The CD4 cells in the aggregates also express CD27,77 which facilitates B cell help. Considerable attention has been directed toward determining whether the infiltrating T cells in RA and other arthropathies are primarily Th1 (interferon-γ producing) or Th2 (IL-4 producing) biased, but the data in this area have been inconsistent. Until more recently, it was suggested that the T cells in RA and psoriatic arthritis are more Th1 biased, whereas T cells in reactive arthritis are Th2 biased. The identification of a third subset of T helper cells expressing IL-17 and playing a central role in chronic inflammatory disorders has necessitated a revision in the role that T cells play in synovitis.78,79 The presence of IL-17, IL-1β, and TNF-α in RA synovium is predictive of progressive damage.80

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A subset of CD4 T cells expressing CD25 and the gene FoxP3, so called T-regulatory (T-regs), are now known to play a regulatory role in antigen-specific T cell expansion. Although T-regs are readily detected in the joints of patients with RA and other inflammatory arthropathies, their suppressor function seems to be defective in this microenvironment.81-84 CD8 T cells might be needed to maintain the structure of the ectopic lymphoid-like structures in RA synovium, although the numbers of these T cells are typically substantially lower than CD4+ cells.85 B cells are identified by the expression of CD19 and CD20 and are particularly abundant in tissues exhibiting large lymphoid aggregates with germinal centers. B cells typically are found in close association with CD4+ T cells in these aggregates (see Figs. 48-9 and 48-12). Experiments in SCID mice suggest that B cells may be crucial for maintaining the microarchitecture of the synovial lymphoid follicles and for T cell activation.86 Memory B cells are efficient antigen presenting cells, and rheumatoid factor–producing B cells are well suited for capturing a wide spectrum of antigens in immune complexes. In RA synovium in particular, areas surrounding the lymphoid aggregates are often densely infiltrated with sheets of CD38+ plasma cells. Analysis of V gene variants and rearrangements in B cells and plasma cells in RA and reactive arthritis synovium indicated that plasma cells from a particular aggregate are clonally related, suggesting that their terminal differentiation occurred in the synovial microenvironment.87 Synovial plasma cells actively synthesize immunoglobulin, some of which has been shown to result in the production of autoantibodies, such as anticitrulline antibodies, which recognize local citrullinated antigens.88-90 As has been stated previously, plasma cell infiltrates also are seen in psoriatic arthritis,

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ankylosing spondylitis, and reactive arthritis synovium, although a systematic analysis of synovial samples from patients with early arthritis has suggested that their presence is most suggestive of RA.55 The areas immediately adjacent to the dense lymphoid aggregates, which comprise primarily CD4+ T cells and B cells, have been called “transitional zones” (see Fig. 48-9).91,92 These areas feature a lower CD4/CD8 ratio and seem to be particularly active immunologically. Transitional areas are rich in macrophages and interdigitating dendritic cells, both highly efficient antigen presenting cells. Lymphoblasts, in particular CD8+ T cells, are present in close proximity to antigen presenting cells. Natural killer cells can be identified by cell surface markers, expression of granzymes, and functional assays. Several studies have suggested an expansion of subsets of natural killer cells in RA synovial tissue and synovial fluids.93-95 Mast cells are ­ abundant in RA synovium and colocalize with inflammatory mediators and proteases in the synovial microenvironment.96,97 SYNOVIAL SUBLINING MACROPHAGES AND DENDRITIC CELLS Macrophages are especially abundant in the sublining stroma of RA synovium. When markers such as CD68 and CD14 are used to study highly inflamed tissues, there is no clear distinction between the sublining macrophage population and the macrophage-like synoviocytes present in the hyperplastic lining layer. Studies using numerous macrophage markers suggest that recently migrated macrophages in the perivascular areas express CD163 brightly, in addition to expressing CD68 and CD14, whereas macrophages in large lymphocytic aggregates and in the ­lining layer were less likely to express CD163. The functional correlates of these phenotypic differences are unclear.98,99 It has been shown that the number of macrophages in RA synovium correlates well with the destructive potential of the synovitis as evidenced by erosive radiographic damage.100-102 This correlation may reflect the highly activated status of these cells, these being the principal source of synovial TNF-α and IL-1β. A body of evidence has suggested that populations of synovial macrophages serve as osteoclast precursors that mature in the synovial microenvironment and directly mediate the erosive damage to the adjacent bone.103,104 Mature dendritic cells are the most efficient and potent antigen presenting cells and are found abundantly in RA synovium in close contact with T lymphocytes.105,106 They can be identified by immunohistology as stellate cells with dendrites expressing high levels of HLA-DR and costimulatory molecules such as CD80 and CD86, and myeloid dendritic cells also express the β2 integrin CD11c. These phenotypic characteristics are useful in differentiating immature dendritic cells from ones that have been exposed to antigen and are efficient at antigen presentation. Detailed studies that have used these markers and examined the expression of chemokines involved in dendritic cell migration and recruitment suggest that a substantial proportion of the dendritic cells in synovium arrive in an immature state and subsequently undergo maturation within the synovial microenvironment in T cell–rich

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areas.105,106 ­Follicular dendritic cells in the germinal centers of large lymphocytic aggregates express the markers CD16, FDC, and VCAM-1. SYNOVIAL MICROVASCULATURE, ENDOTHELIUM, AND STROMAL MESENCHYMAL CELLS The stromal elements in synovitis are often expanded in parallel with the inflammatory cell infiltration. The microvasculature seems to be markedly increased, particularly in the deep sublining areas, and this expansion is presumed to relate to the local stimulation of angiogenesis (see Fig. 48-12). ­ Morphometric studies have suggested that the number of vessels immediately adjacent to the lining layer is reduced compared with normal.107 This situation, combined with the metabolic demands of this tissue, may produce a relatively ischemic and hypoxic environment, which is reflected in the biochemical properties of synovial fluid.108 Immunohistologic studies also have indicated that the molecular consequences of hypoxia, particularly the expression of hypoxia inducible factor-1a, a key regulator of the cellular hypoxic response, are increased in RA synovitis.109,110 The synovial endothelium in RA and other inflammatory arthropathies is activated by proinflammatory mediators in the microenvironment to express adhesion molecules such as E-selectin, ICAM-1, and VCAM-1 that are involved in the recruitment of inflammatory cells.111 RA synovial samples may show an increase in the number of mesechymal stromal cells, or “mesenchymoid transformation.” These stromal cells show an activated phenotype with large pale nuclei and multiple nucleoli. The sequence of events involved in generating transformed mesenchymal cells in RA is incompletely understood.112 Although attempts have been made to characterize these cells, better understanding is hindered by the current lack of appropriate immunohistologic markers with which to phenotype these cells.113 It is presumed that the pathologic finding of synovial chondromatosis, which features the development of islands of chondrocytes in the synovium, results from chondroblastic differentiation of the synovial mesenchymal stem cells. SYNOVIAL-CARTILAGE-BONE INTERFACE The interface between inflamed synovium and the adjacent cartilage and bone in chronic arthropathies is a site of particular interest because much of the articular damage occurs in these areas. In RA, this destructive synovial tissue is called pannus and may spread to cover most of the surface of the cartilage and invade the bone in bare areas at the joint margin (Fig. 48-13). Pannus has been pathologically characterized primarily from samples obtained at the time of joint arthroplasty, although arthroscopic studies at earlier stages of the disease have attempted to characterize synovial samples adjacent to this area. Immunohistology suggests that synovial macrophages and fibroblasts are abundant at the pannus-cartilage interface, and that high levels of proteases are expressed by these cells. At the interface between pannus and bone, substantial numbers of multinucleated osteoclasts can be identified morphologically and by specific markers, such as calcitonin receptors, ­cathepsin

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Figure 48-13  Interface between pannus tissue and bone in a ­patient with rheumatoid arthritis. A, The synovium lesion is invading the ­adjacent bone (circled area). B, Staining for tartrate-­resistant acid phosphatase shows the presence of osteoclasts.

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K, and staining for tartrate-resistant acid phosphatase (see Fig. 48-13).114 Expression of RANKL, a key cytokine in osteoclastogenesis, was prominent in these areas.115 SYNOVIAL BIOPSY AND PATHOLOGY AS TOOLS FOR PREDICTING AND ASSESSING RESPONSE TO THERAPY IN INFLAMMATORY ARTHRITIS Numerous academic rheumatology centers have focused on using serial arthroscopic biopsy and quantitative immunohistology as tools with which to assess the impact of therapeutic interventions on the synovial lesions in RA. These studies have been particularly valuable in evaluating the effects of targeted biologic therapies, where the molecular target and biologic basis of the mechanism of action are well defined.116,117 It has been proposed that synovial biopsy–based studies, which are relatively small and inexpensive to undertake, might offer a unique opportunity to assess the impact of novel therapeutic agents on the target tissue at an early stage of pharmaceutical drug development. On the basis of these studies, it may be possible to make important decisions regarding the future development of a particular agent. This appealing proposition is currently hindered by numerous important considerations. First, the arthroscopic equipment, expertise, and infrastructure to undertake these studies remain limited to a few centers. Second, there has been considerable concern regarding the issue of sampling bias in these studies, particularly because serial biopsy samples are compared in the same individual. As discussed previously, many approaches are used to minimize this bias, including systematic sampling of the same areas of the joint, computerized image analysis of multiple representative ­ tissue samples, quantification of an adequate number of microscopic fields, and use of quantitative PCR and proteomic techniques to assess the overall levels of specific molecules. Finally, and most importantly, has been the lack of a synovial biomarker with which to evaluate ­ outcome reproducibly across the various studies. The number of ­macrophages in the tissue has been proposed as a good ­candidate biomarker, although this remains to be systematically tested.118

SUMMARY The analysis of synovial fluid and tissue samples provides valuable diagnostic information in specific clinical settings. In cases in which septic or crystal-induced arthritis

B

is ­ suspected, such as an acute monarthritis, synovial fluid analysis is crucial for making the diagnosis. In cases of undiagnosed chronic monarthritis, synovial biopsy may provide definitive evidence of conditions such as tuberculosis, sarcoidosis, and pigmented villonodular synovitis. The systematic analysis of synovial tissue in RA and other forms of inflammatory arthritis, particularly using immunohistology, has provided a wealth of information concerning the cellular and molecular mechanisms that sustain the synovial lesions. Research protocols are currently exploring the utility of synovial biopsy in predicting response to antirheumatic therapies. REFERENCES   1. Swann DA, Slayter HS, Silver FH: The molecular structure of lubricating glycoprotein-I, the boundary lubricant for articular cartilage. J Biol Chem 256:5921-5925, 1981.   2. Marcelino J, Carpten JD, Suwairi WM, et al: CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-­arthropathycoxa vara-pericarditis syndrome. Nat Genet 23:319-322, 1999.   3. Rhee DK, Marcelino J, Baker M, et al: The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth. J Clin Invest 115:622-631, 2005.   4. Davis MJ, Denton J, Freemont AJ, et al: Comparison of serial synovial fluid cytology in rheumatoid arthritis: Delineation of subgroups with prognostic implications. Ann Rheum Dis 47:559-562, 1988.   5. Jones ST, Denton J, Holt PJ, et al: Possible clearance of effete polymorphonuclear leucocytes from synovial fluid by cytophagocytic mononuclear cells: Implications for pathogenesis and chronicity in inflammatory arthritis. Ann Rheum Dis 52:121-126, 1993.   6. von Essen R, Holtta AM: Quality control of the laboratory diagnosis of gout by synovial fluid microscopy. Scand J Rheumatol 19:232-234, 1990.   7. Schumacher HR Jr, Sieck MS, Rothfuss S, et al: Reproducibility of synovial fluid analyses: A study among four laboratories. Arthritis Rheum 29:770-774, 1986.   8. Hasselbacher P: Variation in synovial fluid analysis by hospital laboratories. Arthritis Rheum 30:637-642, 1987.   9. Garancis JC, Cheung HS, Halverson PB, et al: “Milwaukee ­shoulder”— association of microspheroids containing hydroxyapatite crystals, active collagenase, and neutral protease with rotator cuff defects, III: Morphologic and biochemical studies of an excised synovium showing chondromatosis. Arthritis Rheum 24:484-491, 1981. 10. Faraj AA, Omonbude OD, Godwin P: Gram staining in the diagnosis of acute septic arthritis. Acta Orthop Belg 68:388-391, 2002. 11. Shmerling RH: Synovial fluid analysis: A critical reappraisal. Rheum Dis Clin N Am 20:503-512, 1994. 12. Swan A, Amer H, Dieppe P: The value of synovial fluid assays in the diagnosis of joint disease: A literature survey. Ann Rheum Dis 61:493-498, 2002. 13. von Essen R, Holtta A: Improved method of isolating bacteria from joint fluids by the use of blood culture bottles. Ann Rheum Dis 45: 454-457, 1986.

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14. Yu KH, Luo SF, Liou LB, et al: Concomitant septic and gouty ­arthritis— an analysis of 30 cases. Rheumatology (Oxf) 42:1062-1066, 2003. 15. Jalava J, Skurnik M, Toivanen A, et al: Bacterial PCR in the diagnosis of joint infection. Ann Rheum Dis 60:287-289, 2001. 16. Muralidhar B, Rumore PM, Steinman CR: Use of the polymerase chain reaction to study arthritis due to Neisseria gonorrhoeae. Arthritis Rheum 37:710-717, 1994. 17. Liebling MR, Arkfeld DG, Michelini GA, et al: Identification of Neisseria gonorrhoeae in synovial fluid using the polymerase chain reaction. Arthritis Rheum 37:702-709, 1994. 18. van der Heijden IM, Wilbrink B, Schouls LM, et al: Detection of mycobacteria in joint samples from patients with arthritis using a genus-specific polymerase chain reaction and sequence analysis. Rheumatology (Oxf) 38:547-553, 1999. 19. Titov AG, Vyshnevskaya EB, Mazurenko SI, et al: Use of polymerase chain reaction to diagnose tuberculous arthritis from joint tissues and synovial fluid. Arch Pathol Lab Med 128:205-209, 2004. 20. Canvin JM, Goutcher SC, Hagig M, et al: Persistence of Staphylococcus aureus as detected by polymerase chain reaction in the synovial fluid of a patient with septic arthritis. Br J Rheumatol 36:203-206, 1997. 21. van der Heijden IM, Wilbrink B, Vije AE, et al: Detection of bacterial DNA in serial synovial samples obtained during antibiotic treatment from patients with septic arthritis. Arthritis Rheum 42:2198-2203, 1999. 22. Wilkinson NZ, Kingsley GH, Jones HW, et al: The detection of DNA from a range of bacterial species in the joints of patients with a variety of arthritides using a nested, broad-range polymerase chain reaction. Rheumatology (Oxf) 38:260-266, 1999. 23. van der Heijden IM, Wilbrink B, Tchetverikov I, et al: Presence of bacterial DNA and bacterial peptidoglycans in joints of patients with rheumatoid arthritis and other arthritides. Arthritis Rheum 43:593598, 2000. 24. Shmerling RH, Delbanco TL, Tosteson AN, et al: Synovial fluid tests: What should be ordered? JAMA 264:1009-1014, 1990. 25. Lettesjo H, Nordstrom E, Strom H, et al: Autoantibody patterns in synovial fluids from patients with rheumatoid arthritis or other arthritic lesions. Scand J Immunol 48:293-299, 1998. 26. Thiel A, Wu P, Lauster R, et al: Analysis of the antigen-specific T cell response in reactive arthritis by flow cytometry. Arthritis Rheum 43:2834-2842, 2000. 27. Mertz AK, Ugrinovic S, Lauster R, et al: Characterization of the synovial T cell response to various recombinant Yersinia antigens in Yersinia enterocolitica-triggered reactive arthritis: Heat-shock protein 60 drives a major immune response. Arthritis Rheum 41:315-326, 1998. 28. Davis LS, Cush JJ, Schulze-Koops H, et al: Rheumatoid synovial CD4+ T cells exhibit a reduced capacity to differentiate into IL-4producing T-helper-2 effector cells. Arthritis Res 3:54-64, 2001. 29. Yin Z, Braun J, Neure L, et al: Crucial role of interleukin-10/interleukin-12 balance in the regulation of the type 2 T helper cytokine response in reactive arthritis. Arthritis Rheum 40:1788-1797, 1997. 30. Dolhain RJ, van der Heiden AN, ter Haar NT, et al: Shift toward T lymphocytes with a T helper 1 cytokine-secretion profile in the joints of patients with rheumatoid arthritis. Arthritis Rheum 39:19611969, 1996. 31. Raza K, Falciani F, Curnow SJ, et al: Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res Ther 7:R784-R795, 2005. 32. Liao H, Wu J, Kuhn E, et al: Use of mass spectrometry to identify protein biomarkers of disease severity in the synovial fluid and serum of patients with rheumatoid arthritis. Arthritis Rheum 50:3792-3803, 2004. 33. Parker RH, Pearson CM: A simplified synovial biopsy needle. Arthritis Rheum 6:172-176, 1963. 34. Schumacher HR Jr, Kulka JP: Needle biopsy of the synovial membrane—experience with the Parker-Pearson technic. N Engl J Med 286:416-419, 1972. 35. Arayssi TK, Schumacher HR Jr: Evaluation of a modified needle for small joint biopsies. J Rheumatol 25:876-878, 1998. 36. Tak PP, Bresnihan B: The pathogenesis and prevention of joint damage in rheumatoid arthritis: Advances from synovial biopsy and tissue analysis. Arthritis Rheum 43:2619-2633, 2000. 37. Youssef PP, Kraan M, Breedveld F, et al: Quantitative microscopic analysis of inflammation in rheumatoid arthritis synovial membrane samples selected at arthroscopy compared with samples obtained blindly by needle biopsy. Arthritis Rheum 41:663-669, 1998.

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38. Shi SR, Cote RJ, Taylor CR: Antigen retrieval techniques: Current perspectives. J Histochem Cytochem 49:931-937, 2001. 39. van der Loos CM, Becker AE, van den Oord JJ: Practical suggestions for successful immunoenzyme double-staining experiments. Histochem J 25:1-13, 1993. 40. Devauchelle V, Marion S, Cagnard N, et al: DNA microarray allows molecular profiling of rheumatoid arthritis and identification of pathophysiological targets. Genes Immun 5:597-608, 2004. 41. van der Pouw Kraan TC, van Gaalen FA, Kasperkovitz PV, et al: Rheumatoid arthritis is a heterogeneous disease: Evidence for differences in the activation of the STAT-1 pathway between rheumatoid tissues. Arthritis Rheum 48:2132-2145, 2003. 42. Lee DM, Kiener HP, Agarwal SK, et al: Cadherin-11 in synovial lining formation and pathology in arthritis. Science 315:1006-1010, 2007. 43. Singh JA, Arayssi T, Duray P, et al: Immunohistochemistry of normal human knee synovium: A quantitative study. Ann Rheum Dis 63:785-790, 2004. 44. Bresnihan B: Are synovial biopsies of diagnostic value? Arthritis Res Ther 5:271-278, 2003. 45. Darling JM, Goldring SR, Harada Y, et al: Multinucleated cells in pigmented villonodular synovitis and giant cell tumor of tendon sheath express features of osteoclasts. Am J Pathol 150:1383-1393, 1997. 46. Bresnihan B, Tak PP, Emery P, et al: Synovial biopsy in arthritis research: Five years of concerted European collaboration. Ann Rheum Dis 59:506-511, 2000. 47. Schumacher HR, Kitridou RC: Synovitis of recent onset: A clinicopathologic study during the first month of disease. Arthritis Rheum 15:465-485, 1972. 48. Kraan MC, Versendaal H, Jonker M, et al: Asymptomatic synovitis precedes clinically manifest arthritis. Arthritis Rheum 41:1481-1488, 1998. 49. Soden M, Rooney M, Cullen A, et al: Immunohistological features in the synovium obtained from clinically uninvolved knee joints of patients with rheumatoid arthritis. Br J Rheumatol 28:287-292, 1989. 49a. Fassbender HG: Pathology of Rheumatic Diseases. New York, Oxford, 1975. 50. Klimiuk PA, Goronzy JJ, Bjor NJ, et al: Tissue cytokine patterns distinguish variants of rheumatoid synovitis. Am J Pathol 151:13111319, 1997. 51. Baeten D, Kruithof E, De Rycke L, et al: Diagnostic classification of spondylarthropathy and rheumatoid arthritis by synovial histopathology: A prospective study in 154 consecutive patients. Arthritis Rheum 50:2931-2941, 2004. 52. Reece RJ, Canete JD, Parsons WJ, et al: Distinct vascular patterns of early synovitis in psoriatic, reactive, and rheumatoid arthritis. Arthritis Rheum 42:1481-1484, 1999. 53. Voswinkel J, Weisgerber K, Pfreundschuh M, et al: B lymphocyte involvement in ankylosing spondylitis: The heavy chain variable segment gene repertoire of B lymphocytes from germinal center-like foci in the synovial membrane indicates antigen selection. Arthritis Res 3:189-195, 2001. 54. Cunnane G, Bresnihan B, FitzGerald O: Immunohistologic analysis of peripheral joint disease in ankylosing spondylitis. Arthritis Rheum 41:180-182, 1998. 55. Kraan MC, Haringman JJ, Post WJ, et al: Immunohistological analysis of synovial tissue for differential diagnosis in early arthritis. Rheumatology (Oxf) 38:1074-1080, 1999. 56. Smeets TJ, Dolhain RJ, Breedveld FC, et al: Analysis of the cellular infiltrates and expression of cytokines in synovial tissue from patients with rheumatoid arthritis and reactive arthritis. J Pathol 186:75-81, 1998. 57. Natour J, Montezzo LC, Moura LA, et al: A study of synovial membrane of patients with systemic lupus erythematosus (SLE). Clin Exp Rheumatol 9:221-225, 1991. 58. Schumacher HR Jr: Joint involvement in progressive systemic sclerosis (scleroderma): A light and electron microscopic study of synovial membrane and fluid. Am J Clin Pathol 60:593-600, 1973. 59. Schumacher HR, Schimmer B, Gordon GV, et al: Articular manifestations of polymyositis and dermatomyositis. Am J Med 67:287-292, 1979. 60. Beutler A, Rothfuss S, Clayburne G, et al: Calcium pyrophosphate dihydrate crystal deposition in synovium: Relationship to collagen fibers and chondrometaplasia. Arthritis Rheum 36:704-715, 1993. 61. Schumacher HR, Holdsworth DE: Ochronotic arthropathy, I: Clinicopathologic studies. Semin Arthritis Rheum 6:207-246, 1977.

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62. Schumacher HR Jr: Ultrastructural characteristics of the synovial membrane in idiopathic haemochromatosis. Ann Rheum Dis 31:465-473, 1972. 63. Lindblad S, Hedfors E: Intraarticular variation in synovitis: Local macroscopic and microscopic signs of inflammatory activity are ­significantly correlated. Arthritis Rheum 28:977-986, 1985. 64. Dolhain RJ, ter Haar NT, De Kuiper R, et al: Distribution of T cells and signs of T-cell activation in the rheumatoid joint: Implications for semiquantitative comparative histology. Br J Rheumatol 37:324330, 1998. 65. Smeets TJ, Kraan MC, Galjaard S, et al: Analysis of the cell infiltrate and expression of matrix metalloproteinases and granzyme B in paired synovial biopsy specimens from the cartilage-pannus junction in patients with RA. Ann Rheum Dis 60:561-565, 2001. 66. Kirkham B, Portek I, Lee CS, et al: Intraarticular variability of ­synovial membrane histology, immunohistology, and cytokine mRNA expression in patients with rheumatoid arthritis. J Rheumatol 26:777-784, 1999. 67. Cunnane G, Bjork L, Ulfgren AK, et al: Quantitative analysis of synovial membrane inflammation: A comparison between automated and conventional microscopic measurements. Ann Rheum Dis 58:493-499, 1999. 68. Youssef PP, Smeets TJ, Bresnihan B, et al: Microscopic measurement of cellular infiltration in the rheumatoid arthritis synovial membrane: A comparison of semiquantitative and quantitative analysis. Br J Rheumatol 37:1003-1007, 1998. 69. El-Gabalawy H, Canvin J, Ma GM, et al: Synovial distribution of alpha d/CD18, a novel leukointegrin: Comparison with other integrins and their ligands. Arthritis Rheum 39:1913-1921, 1996. 70. El-Gabalawy H, Gallatin M, Vazeux R, et al: Expression of ICAM-R (ICAM-3), a novel counter-receptor for LFA-1, in rheumatoid and nonrheumatoid synovium: Comparison with other adhesion molecules. Arthritis Rheum 37:846-854, 1994. 71. El-Gabalawy H, Wilkins J: Beta 1 (CD29) integrin expression in rheumatoid synovial membranes: An immunohistologic study of distribution patterns. J Rheumatol 20:231-237, 1993. 72. Edwards JC, Blades S, Cambridge G: Restricted expression of Fc gammaRIII (CD16) in synovium and dermis: Implications for tissue targeting in rheumatoid arthritis (RA). Clin Exp Immunol 108:401-406, 1997. 73. Iguchi T, Kurosaka M, Ziff M: Electron microscopic study of HLADR and monocyte/macrophage staining cells in the rheumatoid synovial membrane. Arthritis Rheum 29:600-613, 1986. 74. Firestein GS, Paine MM, Littman BH: Gene expression (collagenase, tissue inhibitor of metalloproteinases, complement, and HLA-DR) in rheumatoid arthritis and osteoarthritis synovium: Quantitative analysis and effect of intraarticular corticosteroids. Arthritis Rheum 34:1094-1105, 1991. 75. Cunnane G, FitzGerald O, Hummel KM, et al: Collagenase, cathepsin B and cathepsin L gene expression in the synovial membrane of patients with early inflammatory arthritis. Rheumatology (Oxf) 38:34-42, 1999. 76. Veale D, Yanni G, Rogers S, et al: Reduced synovial membrane macrophage numbers, ELAM-1 expression, and lining layer hyperplasia in psoriatic arthritis as compared with rheumatoid arthritis. Arthritis Rheum 36:893-900, 1993. 77. Tak PP, Hintzen RQ, Teunissen JJ, et al: Expression of the activation antigen CD27 in rheumatoid arthritis. Clin Immunol Immunopathol 80:129-138, 1996. 78. Lundy SK, Sarkar S, Tesmer LA, et al: Cells of the synovium in rheumatoid arthritis: T lymphocytes. Arthritis Res Ther 9:202, 2007. 79. Chabaud M, Durand JM, Buchs N, et al: Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum 42:963-970, 1999. 80. Kirkham BW, Lassere MN, Edmonds JP, et al: Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: A two-year prospective study (the DAMAGE study cohort). Arthritis Rheum 54:1122-1131, 2006. 81. Ruprecht CR, Gattorno M, Ferlito F, et al: Coexpression of CD25 and CD27 identifies FoxP3+ regulatory T cells in inflamed synovia. J Exp Med 201:1793-1803, 2005. 82. van Amelsfort JM, Jacobs KM, Bijlsma JW, et al: CD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: Differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum 50:2775-2785, 2004.

83. de Kleer IM, Wedderburn LR, Taams LS, et al: CD4+CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J Immunol 172:6435-6443, 2004. 84. Cao D, Malmstrom V, Baecher-Allan C, et al: Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur J Immunol 33:215-223, 2003. 85. Kang YM, Zhang X, Wagner UG, et al: CD8 T cells are required for the formation of ectopic germinal centers in rheumatoid synovitis. J Exp Med 195:1325-1336, 2002. 86. Takemura S, Klimiuk PA, Braun A, et al: T cell activation in rheumatoid synovium is B cell dependent. J Immunol 167:47104718, 2001. 87. Kim HJ, Krenn V, Steinhauser G, et al: Plasma cell development in synovial germinal centers in patients with rheumatoid and reactive arthritis. J Immunol 162:3053-3062, 1999. 88. Masson-Bessiere C, Sebbag M, Girbal-Neuhauser E, et al: The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the alpha- and betachains of fibrin. J Immunol 166:4177-4184, 2001. 89. Masson-Bessiere C, Sebbag M, Durieux JJ, et al: In the rheumatoid pannus, anti-filaggrin autoantibodies are produced by local plasma cells and constitute a higher proportion of IgG than in synovial fluid and serum. Clin Exp Immunol 119:544-552, 2000. 90. Girbal-Neuhauser E, Durieux JJ, Arnaud M, et al: The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues. J Immunol 162:585-594, 1999.   91. Kurosaka M, Ziff M: Immunoelectron microscopic study of the distribution of T cell subsets in rheumatoid synovium. J Exp Med 158:1191-1210, 1983.   92. Ishikawa H, Ziff M: Electron microscopic observations of immunoreactive cells in the rheumatoid synovial membrane. Arthritis Rheum 19:1-14, 1976.   93. Dalbeth N, Callan MF: A subset of natural killer cells is greatly expanded within inflamed joints. Arthritis Rheum 46:1763-1772, 2002.   94. Tak PP, Kummer JA, Hack CE, et al: Granzyme-positive cytotoxic cells are specifically increased in early rheumatoid synovial tissue. Arthritis Rheum 37:1735-1743, 1994.   95. Goto M, Zvaifler NJ: Characterization of the natural killer-like lymphocytes in rheumatoid synovial fluid. J Immunol 134:1483-1486, 1985.   96. Woolley DE, Tetlow LC: Mast cell activation and its relation to proinflammatory cytokine production in the rheumatoid lesion. Arthritis Res 2:65-74, 2000.   97. Tetlow LC, Woolley DE: Mast cells, cytokines, and metalloproteinases at the rheumatoid lesion: Dual immunolocalisation studies. Ann Rheum Dis 54:896-903, 1995.   98. Kinne RW, Brauer R, Stuhlmuller B, et al: Macrophages in rheumatoid arthritis. Arthritis Res 2:189-202, 2000. 99. Fonseca JE, Edwards JC, Blades S, et al: Macrophage subpopulations in rheumatoid synovium: Reduced CD163 expression in CD4+ T lymphocyte-rich microenvironments. Arthritis Rheum 46:12101216, 2002. 100. Cunnane G, FitzGerald O, Hummel KM, et al: Synovial tissue protease gene expression and joint erosions in early rheumatoid arthritis. Arthritis Rheum 44:1744-1753, 2001. 101. Mulherin D, FitzGerald O, Bresnihan B: Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. Arthritis Rheum 39:115-124, 1996. 102. Yanni G, Whelan A, Feighery C, et al: Synovial tissue macrophages and joint erosion in rheumatoid arthritis. Ann Rheum Dis 53:39-44, 1994. 103. Schett G: Cells of the synovium in rheumatoid arthritis: Osteoclasts. Arthritis Res Ther 9:203, 2007. 104. Gravallese EM, Manning C, Tsay A, et al: Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum 43:250-258, 2000. 105. Page G, Miossec P: Paired synovium and lymph nodes from rheumatoid arthritis patients differ in dendritic cell and chemokine expression. J Pathol 204:28-38, 2004. 106. Page G, Lebecque S, Miossec P: Anatomic localization of immature and mature dendritic cells in an ectopic lymphoid organ: Correlation with selective chemokine expression in rheumatoid synovium. J Immunol 168:5333-5341, 2002.

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107. Stevens CR, Blake DR, Merry P, et al: A comparative study by morphometry of the microvasculature in normal and rheumatoid synovium. Arthritis Rheum 34:1508-1513, 1991. 108. Hitchon CA, El-Gabalawy HS: Oxidation in rheumatoid arthritis. Arthritis Res Ther 6:265-278, 2004. 109. Hitchon C, Wong K, Ma G, et al: Hypoxia-induced production of stromal cell-derived factor 1 (CXCL12) and vascular endothelial growth factor by synovial fibroblasts. Arthritis Rheum 46:2587-2597, 2002. 110. Hollander AP, Corke KP, Freemont AJ, et al: Expression of hypoxiainducible factor 1alpha by macrophages in the rheumatoid synovium: Implications for targeting of therapeutic genes to the inflamed joint. Arthritis Rheum 44:1540-1544, 2001. 111. Szekanecz Z, Koch AE: Cell-cell interactions in synovitis: Endothelial cells and immune cell migration. Arthritis Res 2:368-373, 2000. 112. Li X, Makarov SS: An essential role of NF-kappaB in the “tumorlike” phenotype of arthritic synoviocytes. Proc Natl Acad Sci U S A 103:17432-17437, 2006. 113. Marinova-Mutafchieva L, Taylor P, Funa K, et al: Mesenchymal cells expressing bone morphogenetic protein receptors are present in the rheumatoid arthritis joint. Arthritis Rheum 43:2046-2055, 2000.

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114. Gravallese EM, Harada Y, Wang JT, et al: Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis. Am J Pathol 152:943-951, 1998. 115. Pettit AR, Walsh NC, Manning C, et al: RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis. Rheumatology (Oxf) 45:10681076, 2006. 116. Vos K, Thurlings RM, Wijbrandts CA, et al: Early effects of rituximab on the synovial cell infiltrate in patients with rheumatoid arthritis. Arthritis Rheum 56:772-778, 2007. 117. Haringman JJ, Gerlag DM, Smeets TJ, et al: A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis. Arthritis Rheum 54:2387-2392, 2006. 118. Haringman JJ, Gerlag DM, Zwinderman AH, et al: Synovial tissue macrophages: A sensitive biomarker for response to treatment in patients with rheumatoid arthritis. Ann Rheum Dis 64:834-838, 2005.

49

Arthrocentesis and Injection of Joints and Soft Tissue Christopher M. Wise

Key Points Arthrocentesis with joint injection is a simple, low-risk, officebased procedure that can be extremely useful diagnostically and therapeutically. Diagnostic arthrocentesis is indicated in patients with effusion without a known diagnosis or if a new diagnosis is suspected, and can be definitive for infection or crystal-induced disease. Therapeutic corticosteroid injection potentially can provide clinical benefit for almost any painful joint or periarticular structure. Most forms of noninfectious inflammatory arthritis respond to local injection. Clinical trials of injection in osteoarthritis of the knee show benefit compared with placebo, but duration varies. Evidence for efficacy of corticosteroid injection for nonarticular conditions is best for painful shoulders, but many other ­conditions have been shown to respond in small trials or anecdotal reports.

Arthrocentesis and injection of joints are safe and simple procedures that can be performed routinely at an outpatient visit.1 With analysis of synovial fluid, few procedures in medical practice have the potential to be as diagnostically definitive as arthrocentesis, and few modalities can be as effective in achieving symptomatic relief of painful or swollen articular structures as the injection of corticosteroids. For these reasons, one out of five visits to a rheumatology practice include aspiration or injection of a joint or periarticular structure.2 Surveys have estimated, however, that 60% to 70% of internists finishing their residency training believe they need more training in these important, safe, and effective procedures, and that most injections performed in primary care settings are done by a small ­percentage (5%) of practitioners with experience and comfort with the ­procedure.3,4 Paracelsus is credited with the first descriptions, in the early 16th century, of the viscous fluid present within synovial cavities, but aspiration of synovial fluid for analysis and aid in diagnosis did not become a topic of increasing interest until the first half of the 20th century. Numerous studies of synovial fluid components and techniques used to obtain this fluid appear in a 1935 textbook by Pemberton.5 An early description of arthrocentesis technique can be found in the classic book by Ropes and Bauer6 on synovial fluid analysis, published in 1953, which used data collected over a 20-year period. During this era, swollen, distended joints were often aspirated for relief of discomfort. In most   Video available on the Expert Consult Premium Edition website.

instances, the prompt reaccumulation of fluid and concerns about ­infection from repeated aspirations limited the usefulness of aspiration for the relief of symptoms of arthritis. A wide variety of substances were injected into joints throughout the early 20th century, including formalin and glycerin, lipiodol, lactic acid, petroleum jelly, and liquefied oil prepared from the patient’s own subcutaneous fat.7,8 Most of these therapies were apparently abandoned, and the most therapeutic injections discussed in arthritis textbooks from the 1940s related to temporary relief via injections of procaine for osteoarthritic knees and bursitis of the shoulder.9 In 1951, after observations on the efficacy of topical cortisone for ocular inflammation, Hollander first reported a minimal, transient improvement in 25 knees of patients with rheumatoid arthritis when injected with cortisone. In subsequent years, Hollander injected hydrocortisone acetate with a much better response, providing further evidence that this was the active anti-inflammatory metabolite of cortisone.10 Further reports of benefit from injectable corticosteroids appeared in the 1950s. During this period, studies showed that more stable and less soluble compounds in the form of esterified crystalline hydroxycortisone and its analogues were even more effective and had longer duration of anti-inflammatory effects.11 By the early 1960s, Hollander had reported a series of more than 100,000 injections of joints, bursae, and tendon sheaths in 4000 patients with a variety of conditions.12 In rheumatology practice since then, aspiration and therapeutic injection of joints and periarticular tissues have become common and essential procedures.

INDICATIONS AND CLINICAL EVIDENCE ARTHROCENTESIS Aspiration of synovial fluid may be indicated in any joint with detectable effusion or may be attempted in joints without detectable effusions when diagnosis is in doubt (Table 49-1). In patients in whom a diagnosis is uncertain, synovial fluid analysis usually provides important information regarding the inflammatory or noninflammatory nature of the process within the affected joint and may be definitive in patients with crystal-induced or infectious arthritis. In patients with recently diagnosed bacterial arthritis, repeated aspiration of accumulated fluid is often an important adjunct to antibiotic therapy. Joints with detectable effusions may be aspirated for relief of discomfort, with or without a subsequent injection of corticosteroid. In some patients, aspiration alone, without steroid injection, may be particularly effective for noninflammatory effusions or selflimited conditions. 721

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Table 49-1  Indications for Arthrocentesis

Table 49-2  Indications for Therapeutic Injection

Undiagnosed Arthritis with Effusion

Inflammatory Arthritis

Characterize type of arthritis   Noninflammatory (WBC <2000/mm3)   Inflammatory (WBC >2000/mm3)   Septic (WBC >50,000/mm3) Definitive diagnosis   Gout (urate crystals)   Pseudogout (CPPD crystals)   Septic arthritis (Gram stain [rare] or culture)

Rheumatoid arthritis—almost always effective; duration varies; should be used as an adjunct to an overall regimen of diseasemodifying therapy Crystal-induced arthritis—few published studies; effective in   24-48 hr Undiagnosed early inflammatory oligoarthritis—complete response in 2 wk in 57%; predictor of good outcome Spondyloarthropathies   Peripheral joints respond as in rheumatoid arthritis   Sacroiliac joint injections under fluoroscopy Juvenile rheumatoid arthritis—particularly useful in oligoarticular form; may be “disease modifying” Miscellaneous diseases (anecdotal)   Sarcoidosis   Systemic lupus erythematosus

Undiagnosed Arthritis without Effusion May be definitive in gout (knee, first MTP joint) Patient with Known Diagnosis Septic arthritis (repeated taps for adequate drainage) Other types of arthritis for symptomatic relief (with or without ­injection)* *Most studies show improved effect if fluid aspirated before injection, CPPD, calcium pyrophosphate dihydrate; MTP, metarsophalangeal; WBC, white blood cells.

THERAPEUTIC INJECTION Inflammatory Arthritis Therapeutic injection of corticosteroids is generally believed to be most effective in joints affected by inflammatory arthritis (Table 49-2). Most of the experience in this area has been with common conditions, such as rheumatoid arthritis, juvenile rheumatoid arthritis, crystal-induced arthritis, psoriatic arthritis, and reactive arthritis. Anecdotal experience has been reported in less common conditions, such as systemic lupus erythematosus and sarcoidosis. In self-limited conditions, such as gout, injections generally lead to more prompt resolution of exacerbations. In rheumatoid arthritis, injections are used frequently to suppress inflammation in individual joints. Such injections generally are considered to be adjunctive to disease­modifying drug therapy and are not believed to affect overall outcomes. The efficacy of individual joint injections in rheumatoid arthritis is supported by many large, uncontrolled case series dating back to the 1950s. Most of ­ Hollander’s early reports suggested long-lasting relief in most joints injected, with improvement lasting several months in most patients.12,13 This long-lasting relief has been confirmed in several series of patients in subsequent years. In 1972, McCarty14 reported that 88% of patients attained remission for an average of 22 months in small joints of the hands and wrists, much better than comparable joints not injected in the opposite hands of the same patients. In a subsequent report on 956 injections in 140 patients followed for an average of 7 years, 75% of injected joints remained in remission.15 In this series, patients received about two injections during the first year of treatment and averaged 0.6 injection per patient-year for the next 15 years. The authors of this report used a regimen that emphasized 3 weeks of splinting for upper extremity joints and 6 weeks of crutch walking for lower extremity joints. Removal of fluid before aspiration increases the efficacy of steroid injections in most patients with inflammatory arthritis. One study of 191 knee injections in patients with rheumatoid arthritis showed that aspiration of fluid

Noninflammatory Arthritis Osteoarthritis   Knees—60%-80% response in 1-6 wk versus placebo; no difference at 12 wk   Hips—anecdotal reports; require fluoroscopy; usually avoided   Hyaluronic acid derivatives (Hyalgan, Synvisc) weekly for 3-5 wk,     moderately better than placebo Hemophilic arthropathy—reported, but rarely used Nonarticular Conditions (Tendinitis, Bursitis, Myofascial Pain) Trigger point injections—done frequently; not supported by studies Painful shoulder (rotator cuff tendinitis, frozen shoulder)—efficacy compared with placebo; lasting 4-6 mo Lateral epicondylitis (tennis elbow)—efficacy for 1-2 mo versus placebo; less in some studies Carpal tunnel syndrome—90% short-term response; variable at 6-12 mo; good response to injection may be predictor of surgical response de Quervain’s tenosynovitis—70%-90% improved with 1-2   injections, relapse in 30% at 1 yr Trochanteric pain of hip (bursitis, tendinitis)—60%-70% at 6 mo (uncontrolled) Knee pain syndromes   Anserine bursitis   Patellofemoral pain syndromes   Synovial plica   Popliteal cyst (usually treated with intra-articular knee injection) Plantar fasciitis—variable; probably better for 1-3 mo Morton’s neuroma—response often prolonged (no controls) Tarsal tunnel syndrome—rarely reported; usually only temporary Achilles tendinitis, bursitis—usually avoided Cervical girdle, lumbar areas, posterior hip—uncertain what structure injected (without fluoroscopic facet block); efficacy not proved

reduced the rate of relapse from 47% to 23% within a 6-month period after injection compared with joints not aspirated.16 More recently, multiple intra-articular injections in inflamed joints have been shown to be a useful part of an overall regimen of disease-modifying therapy in rheumatoid arthritis, resulting in improvement superior to similar doses of systemic steroids, and helpful in obtaining clinical remission and reducing radiographic progression of disease.17,18 Corticosteroid injection is considered to be a safe and effective option for prompt relief of acute crystal-induced arthritis in gout and pseudogout. Steroid injections are so widely accepted as an effective treatment that few reports have attempted to address the degree or duration of efficacy for injections in these conditions. Many of the patients described in early reports of steroid injections were being

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treated for acute crystal-induced arthritis, with prompt relief being almost uniform. In a more recent report, small doses of intra-articular steroids were successful in ­relieving pain and swelling completely in all patients within 48 hours, and no relapses were noted in 20 patients over a 3-month period.19 In patients with recent onset of inflammatory oligoarthritis, without definitive diagnosis, corticosteroids can be used to relieve symptoms of swelling in individual joints, and the response to these injections can be used as a prognostic marker. In a series of 51 patients with recent-onset inflammatory arthritis involving five or fewer joints, a strategy of injecting all joints with clinical synovitis resulted in improvement in all patients, and a complete resolution of synovitis after 2 weeks in 57% of patients. The response at 2 weeks was the best predictor of continued improvement persisting for 26 weeks and 52 weeks.20 A trial of ­steroid injection may be used for symptomatic relief in such patients, and a complete response at 2 weeks can be used as a prognostic indicator for a better outcome. Patients with refractory sacroiliac joint pain related to ankylosing spondylitis or other spondyloarthropathies may benefit from injection of the sacroiliac joints.21,22 Because of the anatomy of this joint, such injections often require radiographic confirmation of needle placement in the joint space, and use of fluoroscopy-guided, computed tomography (CT)–guided, and magnetic resonance imaging (MRI)– guided injections has been reported. In uncontrolled studies, a good response has been reported in about 80% of injections, with an average time of improvement of 6 to 9 months. At least one controlled study in a small group of patients showed slight benefit of steroid compared with placebo injection. The degree of improvement seen after sacroiliac injections has not been consistent among studies to date, however, probably because of a lack of uniformity of patient selection and outcomes assessed. Joint injection has been used with increasing frequency in recent years in patients with juvenile rheumatoid arthritis.23,24 The use of injections has become more common particularly in the pauciarticular variant of the disease, in which only a few joints are involved, and potentially toxic systemic therapy can be avoided. Complete remission lasting more than 6 months has been reported in approximately 65% to 80% of joints injected in this condition, most commonly in the knees. Benefit also has been shown in smaller numbers of ankles, wrists, shoulders, and elbows, with most children being able to stop oral medications, and correction of joint contracture being noted in most as well.25,26 A median duration of improvement of approximately 74 weeks has been documented in another large study.27 Joint lavage before injection may be useful in prolonging response in patients with a poor response to previous injection.28 One study showed a significant decrease in leg-length discrepancy in children treated with repeated injections (average of 3.25 injections per child over 42 months) compared with children in another center who were not injected.29 A more recent study specifically addressed the efficacy and safety of steroid injections in the hip in juvenile rheumatoid arthritis.30 In this prospective study of 67 hip injections, 58% of hips remained in remission for 2 years after a single injection; another 18% required a second injection to maintain remission. Only two cases of avascular necrosis were seen in this group, and both of these were in patients

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receiving systemic steroids, suggesting no role for local steroid injections in the development of avascular necrosis in this population. Noninflammatory Arthritis Corticosteroid injection is used frequently in common noninflammatory articular conditions, such as osteoarthritis, internal derangements, and post-traumatic arthritis. Clinical studies that support efficacy are less convincing and suggest a less predictable and smaller degree of response in these conditions than is seen in inflammatory arthritis. Most studies of steroid injections in osteoarthritis have studied patients undergoing knee injections.31,32 Early uncontrolled studies suggested improvement in approximately 60% to 80% of patients.11,13 In controlled studies, most benefit, compared with placebo, seems to last 1 to 6 weeks, with return to the same pain levels seen in placebo groups by around 12 weeks after injection.33-41 Factors associated with a better response to steroid injections have included less severe radiographic changes, the presence of effusion at the time of injection, and successful aspiration of fluid at the time of injection. The theoretical concern about the potential for negative effects of injected steroids on cartilage (discussed in the following section) is often sited as a reason to limit injections in osteoarthritis and other forms of noninflammatory arthritis. A more recent trial in 68 patients comparing corticosteroid injections every 3 months with saline injections showed no worsening of radiographic changes, however, after 2 years of repeated steroid injection, along with significant improvement in symptoms during the period of study.42 Injections usually are not performed in patients with osteoarthritis of the hip, partly because of the technical difficulty of accurate needle placement. Some relief can be obtained, however, in patients with less severe disease or in a rare patient with more severe involvement. A prospective, open study of intra-articular steroid in 45 patients with hip arthritis, 27 of whom had osteoarthritis, found a significant reduction in pain at 2 weeks and 12 weeks, although the effect was lost by 26 weeks.43 In a report of 510 patients treated with a single injection done under fluoroscopic guidance, pain relief that persisted 8 weeks was seen in 90% of patients with mild disease, 58% of patients with moderate disease, and 9% of patients with severe hip osteoarthritis; improved range of motion was shown in most of the patients responding.44 Controlled trials have shown that steroid injection provides modest benefit compared with placebo for 2 to 12 weeks, and the benefit was no longer apparent at 3 months.45,46 Steroid injection followed by non–weight bearing was not helpful in reducing the need for hip replacement in a retrospective study of patients with rapidly progressive osteoarthritis of the hip.47 In patients with osteoarthritis of the thumb, local steroid injection may be helpful for 1 year in a few patients (about 20%), but most patients are improved for 1 to 3 months at the most.48 Local steroid injection may be a useful adjunct in managing patients with hemophilic arthropathy.49 In an open trial of 19 injections, 79% of joints improved within 24 hours; this improvement persisted for 8 weeks in 58% of joints. A decrease in need for clotting factor was shown in this small group.

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Injectable hyaluronic acid derivatives have been studied extensively and are now approved for use in the United States and Canada for injection into osteoarthritic knees. A series of three to five weekly injections has been shown to provide more pain relief than placebo in most studies. The degree and duration of improvement in these studies have varied, however, and the optimal role for hyaluronic acid injections in the management of arthritis has yet to be determined (see Chapter 93).50-52 Nonarticular Conditions Patients with various forms of tendinitis, bursitis, myofascial pain, and nerve entrapment syndromes frequently are treated with local injections of corticosteroids.53 In many of these conditions, uncontrolled clinical experience suggests a high response rate, and in many others, controlled trials show variable levels of benefit, often depending on whether short-term or long-term outcomes are considered. The injection of trigger points for pain relief has been used by many practitioners over the past several decades, but few controlled studies to support efficacy have been published. Cummings and White54 reviewed 23 publications dealing with trigger point injections and concluded that none of the trials were of sufficient quality to demonstrate or refute the efficacy of any needling technique beyond placebo in the treatment of myofascial pain. Steroid injections frequently are used in the management of rotator cuff tendinitis, frozen shoulder, and other causes of shoulder pain. Most controlled studies have shown significant short-term improvement from steroid injection compared with placebo injection, usually lasting 4 to 6 months.55,56 In most such trials, short-term treatment success of 75% to 80% is usually reported in steroid-treated groups compared with 40% to 50% in placebo groups. Most, but not all, controlled studies have shown that steroid injections are superior to physical therapy without injection, and that combining steroid injection with physical therapy has an additive benefit.57-59 Lateral epicondylitis also is commonly treated by local injections. Pain may worsen for 1 or 2 days after injection, but usually is improved after 4 to 5 days.60 Longer controlled studies typically document improvement of 90% compared with 50% in placebo treatment in the first 1 or 2 months after injection, but outcomes at 6 to 12 months usually are not affected.61,62 Local injection of botulinum toxin has been shown to be beneficial compared with placebo for epicondylitis in small trials.63 In femoral trochanteric pain syndromes (i.e., bursitis), the response rate to locally injected steroids has been reported to be 60% to 100%, but no placebo-controlled studies have been done. A prospective study reported significant improvement after a single injection in 77% of patients at 1 week; this number decreased to 69% at 6 weeks and 61% at 26 weeks.64 Patients receiving larger amounts of locally injected steroid (24 mg of betamethasone) were more likely to have sustained improvement. Around the knee, anecdotal and retrospective studies have shown that most patients with anserine bursitis respond to local steroid injection.65 Local steroid injection may be a useful nonsurgical therapy for carpal tunnel syndrome. Most studies report

90% short-term relief of symptoms from a single injection; longer term relief is 20% to 90%, and surgery is eventually required in about half of patients treated with injection. Controlled trials comparing local steroid injection with ­surgical ­decompression have shown variable results, suggesting that injection may provide better relief within the first 3 to 6 months, but that more patients benefit from surgery when followed for 6 to 12 months.66,67 A good response to local injection is sometimes useful as a diagnostic test and is a predictor of good surgical response. As noted later, care should be taken to avoid injection into the body of the median nerve.68,69 Most patients with de Quervain’s tenosynovitis involving the tendons at the base of the thumb respond to local steroid injection.70 In three prospective studies, 60% to 76% of patients with this condition had their symptoms adequately controlled with a single injection, and another 10% to 33% required a second injection.71-73 About 30% had exacerbations an average of 1 year later, but overall, only 10% to 17% of patients were not controlled and required surgical release. Another small controlled study showed that injection was much better than splinting.74 Similar success rates have been reported in patients with flexor tenosynovitis75,76 and ganglion cysts.77 In the ankle and foot area, injection therapy has been used to treat plantar fasciitis, tarsal tunnel syndrome, Achilles tendinitis or bursitis, and interdigital neuroma (­Morton’s neuroma). Most of the data about efficacy for these conditions are anecdotal and uncontrolled. ­ Generally, the response in tarsal tunnel syndrome is temporary, whereas the response in Morton’s neuroma is more often prolonged.78,79 Reported response rates for plantar fasciitis vary, but one controlled trial showed a significant improvement at 1 month compared with placebo, but results no different from placebo at 3 months.80,81 Local injections for neck pain and low back pain have been used for many years, with anecdotal reports of improvement, but controlled or prospective studies have shown variable results, depending on patient selection and methodology. Few controlled studies have assessed local trigger point or other soft tissue injections in the paracervical or paralumbar areas. Most studies of radiographically assisted facet joint injection of steroids in the lumbar or cervical areas show no difference compared with placebo, facet block, or local paraspinous injections.82-85 Injections of the sacroiliac joint in patients with noninflammatory pain have shown a slight benefit from steroids compared with lidocaine alone.86

PREPARATIONS CORTICOSTEROIDS All hydroxycorticosteroid preparations are effective for intra-articular and periarticular injections (Table 49-3). The originally injected hydroxycortisone acetate is still available, widely used, and inexpensive. Triamcinolone hexacetonide is one of the least soluble agents with the presumed most prolonged effect. Not all preparations are equivalent in efficacy or duration of effect, but few studies have been done to compare the efficacy of the various preparations. More recent reports suggest a more prolonged

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Table 49-3  Injectable Preparations for Intra-Articular Injection Corticosteroids

Prednisone Equivalent (mg)

Betamethasone sodium   ­phosphate (6 mg/mL)

50

Dexamethasone sodium   (4 mg/mL)

40

Dexamethasone acetate   (8 mg/mL)

80

Hydrocortisone acetate   (24 mg/mL)

5

Methylprednisolone acetate   (40 mg/mL)

50

Prednisolone terbutate   (20 mg/mL)

20

Triamcinolone acetonide   (40 mg/mL)

50

Triamcinolone hexacetonide   (20 mg/mL)

25

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Table 49-4  Contraindications to Arthrocentesis and Joint Injection Contraindication

Comment

Established infection in nearby structures (e.g., cellulitis, septic bursitis)

Sometimes gout mimics cellulitis, creating a confusing picture

Septicemia (theoretical risk of ­introducing organism into joint)

Need to tap suspected septic joints in septic patients

Disrupted skin barrier   (e.g., psoriasis)

Do not tap through lesions

Bleeding disorder (not absolute, Risk of bleeding very low, even in but use more care) patients taking warfarin Septic joint

Steroid injection contraindicated

Prior lack of response

Relative contraindication

Difficult-to-access joint

Relative contraindication without imaging aid

Hyaluronic Acid (indicated in osteoarthritis of knee) Euflexxa—inject 20 mg (2 mL)   once weekly for 3 wk Hyalgan—inject 20 mg (2 mL)   once weekly for 5 wk; some   may benefit with a total of   3 injections Orthovisc—inject 30 mg (2 mL)   once weekly for 3-4 wk Supartz—inject 25 mg (2.5 mL)   once weekly for 5 wk Synvisc—inject 16 mg (2 mL)   once weekly for 3 wk (total   of 3 injections)

response from triamcinolone hexacetonide compared with triamcinolone acetonide, and both of these were more effective than hydrocortisone.87-89 Most clinicians have become familiar with certain preparations and have continued to use these with efficacy for years. Some clinicians prefer to inject combinations of short-acting and long-acting preparations. Steroid preparations are often mixed with local anesthetics, particularly for injecting small joints, tendon sheaths, and periarticular structures. Mixing with a local anesthetic reduces the local discomfort of injection into a confined space and dilutes the concentration of the locally injected steroid and reduces the risk of soft tissue atrophy. Guidelines for the dosage of steroid injected into given joints are based roughly on the size of the joint injected. Although no consensus exists regarding these amounts, most experts suggest injecting 1 mL of steroid preparation into large joints, with smaller amounts into smaller joints. OTHER INJECTABLE PRODUCTS Over the years, many other agents have been injected into joints, including salicylates, phenylbutazone, gold, orgotein, progesterone, glycosaminoglycan polysulfate, and various antibiotics, but most have been abandoned because of lack of efficacy or local reactions. Various cytotoxic agents have been used sporadically or in small numbers of patients for intrasynovial tumors and refractory proliferative synovitis,

including nitrogen mustard, osmic acid, methotrexate, and radioactive preparations (yttrium-90, colloidal P32 chromic phosphate, dysprosium-165-ferric hydroxide). More recently, biologic agents used as systemic therapy for rheumatoid arthritis (infliximab, anakinra) have been shown to be beneficial when injected locally in a few patients with osteoarthritis and inflammatory arthritis.90-92 Intra-­articular hyaluronic acid preparations have been in use for many years in Europe and have been approved for clinical use in Canada and the United States more recently. Several preparations of hyaluronic acid are approved for the treatment of osteoarthritis of the knee and seem to be superior to placebo injections in most clinical trials, although no evidence for long-term efficacy or disease modification has been reported.50-52,93,94 These preparations are given weekly in a series of three to five injections. Studies of hyaluronic acid preparations in other osteoarthritic joints are inconclusive or small.45,95

CONTRAINDICATIONS There are few contraindications to diagnostic arthrocentesis (Table 49-4). Established infection, such as cellulitis, in periarticular structures is generally considered to be an absolute contraindication to inserting a needle into a joint. If inflammation in an underlying joint or bursa is thought to be the cause of the appearance of infection, however, aspiration of the joint or bursa should be attempted. Septicemia carries the theoretical risk of introducing blood-borne bacteria into a joint, but such complications are not well documented, and joints suspected of being infected should be aspirated regardless of the presence of septicemia. Arthrocentesis through an area of irregular or disrupted skin, as seen in psoriasis, should be avoided because of the increased numbers of colonizing bacteria in these areas. Caution should be exercised in patients with bleeding disorders or patients taking anticoagulants, owing to the theoretical risk of inducing hemarthrosis. The risk of significant hemarthrosis after arthrocentesis is low, however, even in patients on regular warfarin therapy with international normalized ratios of 4.5.96

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COMPLICATIONS Iatrogenic infection is the most serious, but least common, complication of arthrocentesis and joint injection (Table 49-5). In Hollander’s large series,13 an incidence of infection of 0.005% was reported in a series of 400,000 injections. Gray and colleagues97 reported an incidence of 0.001% several years later. A more recent publication noted an infection ratio of 1:2000 to 1:10,000 in patients with rheumatoid arthritis.98 In this series, infections occurred almost exclusively in debilitated patients on immunosuppressive therapy. Few other prospective or systematic studies of infection after arthrocentesis have been published, but most reported anecdotal experience has noted a similar rare incidence of this serious complication.99 An arthroscopic study showed that a small fragment of skin stained with surgical marking pen could be identified within the joint space after most percutaneous insertions of a needle into the joint space, with identifications of bacterial nucleic acid by polymerase chain reaction in about one third of these.100 Considering the rarity of joint infection after arthrocentesis,

Table 49-5  Potential Complications of Arthrocentesis and Joint Injection Complication

Comment

Iatrogenic infection

<1/10,000; may be higher in RA patients

Postinjection “flare”

1%-6%; lasting 48 hr; may be related to preparation

Local soft tissue

May occur 1-6 mo later; pigment change

Local nerve damage

In structures near prominent nerves (e.g., carpal tunnel syndrome)

Tendon rupture or weakening

Case reports; animal studies show highest risk in Achilles tendon and plantar fascia

Systemic steroid absorption

Inevitable; usually subclinical Hypothalamic-pituitary ­sup­pression 2-7 days; changes in bone formation 14 days Flushing; facial warmth; ­diaphoresis Transient elevation of blood glucose; lymphopenia; ­eosinopenia

Avascular necrosis of bone

Controversial; reported but ­usually explained by ­underlying disease or systemic steroids in same patient (ischemic necrosis)

Negative effects on cartilage

Controversial Found in animal models of normal cartilage, but not in primates Case reports in humans receiving multiple injections Some animal models of arthritis are better with steroid ­injections Large human observational studies have not documented more problems than expected (osteoarthritis, RA, juvenile RA)

RA, rheumatoid arthritis.

these findings suggest that bacteria introduced at the time of arthrocentesis either are not viable or are quickly cleared in almost all cases. The most common complications of local steroid injections are related to local irritation of synovial and subcutaneous tissues and atrophy of soft tissues. Postinjection “flare” may develop in 1% to 6% of patients a few hours after ­ injection and may last 48 hours, sometimes mimicking iatrogenic infection.13,15,101 These flares are reportedly more common with needle-shaped crystals and are believed to be similar to the acute arthritis related to other crystals phagocytosed by leukocytes, but they also may be caused by preservatives in some steroid suspensions. Weakening of tendons and tendon rupture also have been reported as a result of locally injected steroids,102,103 emphasizing the importance of avoiding direct injection of steroids into the body of tendons. Most reports of tendon rupture have been anecdotal and described in patients involved in athletic activities or with rheumatoid arthritis. The risk of tendon rupture has not been adequately determined, but it seems to be quite low in the hands and wrists, where no ruptures were seen in a series of more than 200 injections,104 and only 2 were seen in another series of 956 injections.15 Areas believed to be at highest risk for rupture include the Achilles tendon, bicipital tendon, and plantar fascia, where the risk of rupture has been estimated to be 10%.105,106 Systemic absorption occurs with locally injected depot corticosteroids. Since the earliest intra-articular injections of steroids, an anti-inflammatory effect has been shown not only in the injected joint, but also in other joints in the same patient.10 Subsequent studies have documented decrease in plasma cortisol and suppression of the hypothalamic­pituitary axis lasting 2 to 7 days after a single injection.107 The degree and duration of adrenal suppression from a single intra-articular dose of depot steroid is less pronounced than that seen from an equal intramuscular dose.108 The effect of the systemic absorption of locally injected steroid on bone metabolism also has been studied. In a study of markers of bone turnover, a single injection of triamcinolone in knees of rheumatoid arthritis patients resulted in no change in bone resorption markers, but yielded a drastic reduction in markers of bone formation within 1 day, which returned to normal levels in 14 days.109 Some patients experience prominent erythema, warmth, and diaphoresis of the face and torso within minutes to hours after steroid injections.103,107 This reaction is most likely related to systemic absorption, but idiosyncratic reaction to preservatives in steroid preparations also has been implicated. Similarly, some patients may experience other typical metabolic effects of systemic steroids, such as transient increases in blood glucose or decreases in peripheral blood eosinophil or lymphocyte counts. Avascular necrosis of bone (ischemic necrosis) has long been considered a potential complication of intra-articular steroids, with a reported prevalence of this complication in injected joints ranging from less than 0.1% to 3%.13,24,30 Most studies have suggested, however, that the occurrence of this complication is related more to the severity of the associated disease or systemic steroid therapy and is unrelated to local injections. The potential for negative effects of locally injected corticosteroids on cartilage metabolism has been a controversial

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area of study for several decades. Anecdotal reports of Charcot-like arthropathy attributed to intra-articular steroids first appeared in the late 1950s and 1960s, often occurring in patients having more than 10 (and sometimes hundreds) joint injections over many months or years.110-112 Several studies in the 1960s and 1970s showed that locally injected steroids caused destructive changes, catabolic effects, or both in normal animal cartilage.113-115 These included findings of decreased protein and matrix synthesis with degenerative cellular changes in chondrocytes, and fissures and decreased proteoglycan content in cartilage matrix. Similar studies done in primate joints failed to show any negative effects from intra-articular corticosteroids, however.116 Studies done in subsequent years have shown protective effects on cartilage lesions and reduction in osteophyte development in animal models of experimentally induced osteoarthritis, and associated reduction in metalloprotease levels in cartilage and increase in lubricating synovial surfactant.117-120 In humans with osteoarthritis, intra-articular steroids have been shown to decrease macrophage infiltration of the synovial lining, but no change was noted in metalloprotease levels.121 Observations in humans treated with frequent corticosteroid injections have yielded conflicting information regarding changes in articular cartilage. More recent observations in patients with oligoarticular juvenile rheumatoid arthritis, mentioned previously, suggest that frequent steroid injections have the potential to help protect cartilage from the destructive process of the underlying disease process and are not associated with ­negative effects on articular cartilage.25-27,29,30 In addition, a study of patients with rheumatoid arthritis has shown no increase in the need for subsequent joint replacement ­surgery in the joints receiving four or more injections in a 1-year period.122

GENERAL ARTHROCENTESIS TECHNIQUES MATERIALS Most practitioners find that an arthrocentesis tray containing needed items allows more flexibility in preparing for aspirating or injecting joints or other articular structures. Syringes greater than 20 mL are not needed for most procedures, but a swollen knee occasionally may contain 60 mL or more of fluid, and it is reasonable to have at least one syringe of this size in a tray, with others available for rare patients with effusions greater than 100 to 200 mL in volume. Heparinized or citrated tubes to prevent coagulation of inflammatory fluids for accurate cell counts and crystal analysis, plain tubes for chemistry evaluations, and sterile tubes for transporting fluid to a microbiology laboratory for culture should be included. In joints being aspirated for the presence of bacteria and crystals, small amounts of fluid or debris may be present in the bore of the needle, even when no obvious fluid is obtained. In such situations, it is best to have clean microscope slides and coverslips available at the bedside for microscopic examination for cellularity, Gram stain, and crystals. A hemostat is helpful for changing syringes after aspiration to inject corticosteroid. The size and length of needles used depend on anticipated amount of fluid to be obtained from a joint and the size of the involved joint. A 20-gauge to

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22-gauge needle is usually sufficient to aspirate most detectable effusions, but large effusions with large amounts of debris, as seen in septic joints, may require larger bore needles. In small joints, a 23-gauge to 27-gauge needle may be used, particularly when no fluid appears to be present, and only therapeutic injection is being considered. A needle 1½ inches in length is adequate for almost all procedures, but a 3-inch spinal needle may be needed occasionally for a large knee or hip. SITE PREPARATION AND TECHNIQUE Sterile technique designed to avoid the introduction of skin bacteria into the joint should be observed in all procedures, although precautions taken to avoid infection in clinical practice vary widely.99 After careful examination and identification of the specific point of aspiration, this point may be marked by the end of a ballpoint pen with writing point retracted. The area should be carefully cleaned with one or two layers of iodine followed by alcohol. These precautions are sufficient to minimize the risk of infection to no more than 1 in 10,000 in most studies, although a single “swipe” of isopropyl alcohol has been shown to provide a similar level of protection.123 A physician experienced in arthrocentesis may elect not to use topical anesthesia in many patients because the amount of pain is often no more than that experienced from phlebotomy. In an anxious patient or when small joints or joints with minimal fluid are being aspirated, topical anesthesia may be attained by the use of spray coolant (ethyl chloride) or an intradermal wheal and subcutaneous infiltration of lidocaine. Spray coolant may be applied after sterile preparation and has been shown not to contaminate the field.124 In pediatric patients, particularly when multiple joints are injected, sedation or general anesthesia may be required for safe and accurate injections.125 Topical anesthetic cream does not seem to offer much overall benefit in pediatric patients undergoing joint injection.126 Nonsterile gloves should be worn by the operator to avoid contamination with the patient’s synovial fluid or blood. Drapes and sterile gloves are unnecessary, but the gloved hand should not touch the prepared site. A joint usually is entered at a 90-degree angle to the skin, slowly and evenly, and negative pressure should be applied to the syringe when the needle has been advanced ½ to 1 inch (in a large joint). If the needle’s course is obstructed by bone, the needle should be withdrawn slightly and redirected at a slightly different angle. If no fluid is obtained, the needle should be slowly advanced and negative pressure continued. If fluid flows initially and then stops, the needle may be advanced or retracted slightly or rotated in case it is blocked by an intra-articular structure or synovial tissue. After an adequate amount of fluid is obtained, a hemostat may be used to secure the needle, the syringe may be removed, and a new syringe with injectable steroid may be attached if injection is indicated. Alternatively, a three-way stopcock is preferred by some practitioners when aspiration and injection are performed in the same setting.127 After injection, the needle and syringe should be removed and pressure applied over the site until a bandage is applied. When synovial fluid is to be examined for crystals, care should be taken not to replace the needle used for steroid injection on the syringe with synovial fluid because the ­contamination

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of fluid with steroid crystals would make accurate identification of urate and calcium pyrophosphate crystals more difficult. In some situations, positioning the barrel of the syringe and simultaneous aspiration may result in difficulty controlling needle position, and a newly available one-handed reciprocating syringe may allow for better operator control of the syringe in more difficult ­aspirations.128 POSTPROCEDURE INSTRUCTIONS AND CARE After the procedure, patients should be reminded about the risk for postinjection “flare” within 24 to 48 hours after local steroid injection. If pain, redness, or swelling progress after this, are particularly severe, or are accompanied by fever, the patient should be instructed to call and be re-evaluated for the remote possibility of iatrogenic infection. Patients also should be reminded about the soft tissue atrophy and hypopigmentation that may occur weeks to months after the procedure, particularly when structures close to the skin are injected. For patients in whom tendon sheaths are injected, heavy activities using the involved tendons should be avoided for several days. After injection of joints, particularly weight-bearing joints, activities should be limited owing to evidence that activity restriction prolongs the effect of the injected steroid. In a large series reported in 1995, McCarty and colleagues15 used a regimen that emphasized 3 weeks of splinting for upper extremity joints and 6 weeks of crutch walking for lower extremity joints, suggesting that rest after the injection was important in prolonging the effect of injections. Several other retrospective studies and anecdotal observations have suggested a role for strict rest or non–weight bearing after injection to improve duration of efficacy.34,129 One small controlled study showed that rest provided no advantage over regular activities in regard to short-term or long-term outcomes.130 In a larger prospective controlled trial of knees in patients with rheumatoid arthritis, a 24-hour period of strict bed rest after injection resulted in a more prolonged improvement, however, compared with patients who were not restricted.131 Most practitioners advise restricted activities after steroid injections, particularly in weight-bearing joints, but opinions on the relative importance of rest after injections still vary, and no specific regimen of rest would be considered standard practice among physicians.132

SPECIFIC REGIONAL ARTHROCENTESIS TECHNIQUES CERVICAL SPINE AREA Most injections in the region of the cervical spine, trapezius, and scapular areas are best considered to be myofascial or trigger point injections. The point of injection is usually determined by palpating for the areas of most tenderness, and few reliable landmarks are available for localization of anatomic structures. Using a 22-gauge to 25-gauge needle, a combination of 0.5 mL of steroid and 0.5 to 2 mL of lidocaine can be injected into areas in the paracervical muscles or other areas where tenderness can be elicited. Some of the injections done in these areas are likely to be close enough to the posterior cervical facet joints to reduce inflammation in the joints themselves, whereas others probably reduce

inflammation in ligaments, tendons, or bursal structures. More precise injection of posterior cervical facet joints may be accomplished under fluoroscopic visualization.85 ANTERIOR CHEST WALL The anterior chest area occasionally may be the site of inflammatory disease of the sternoclavicular joints. It is usually difficult to obtain much fluid for diagnostic purposes from this joint, but a few drops for microscopic analysis and culture may be available in some patients. The point of aspiration should be dictated by the point of maximal swelling near the surface. Aspiration should be attempted with caution, using as short and small a needle as possible to avoid damage to nearby vascular structures, lung, or airway. A small amount of steroid (0.1 to 0.5 mL) may be injected in this joint, as long as the suspicion of infection is low. In Tietze’s syndrome, one or more of the anterior costochondral junctions may be swollen, but such areas do not contain fluid for analysis and should be approached with caution for injection of small amounts of steroid and lidocaine. Inflammation of the manubriosternal joint in patients with spondyloarthropathy may be improved by fluoroscopically guided injection.133 TEMPOROMANDIBULAR JOINT The temporomandibular joint may be involved in patients with rheumatoid arthritis, spondyloarthropathies, or osteoarthritis, and internal derangement of this joint may be a source of discomfort usually treated by oral surgeons.134 This joint is palpated as a depression just below the zygomatic arch about 1 to 2 cm anterior to the tragus. The depression is usually more easily palpated by having the patient open and close the mouth. After a mark is made over the area, a 22-gauge to 25-gauge needle is inserted perpendicular to the skin and directed slightly posteriorly and superiorly; 0.1 to 0.25 mg of steroid preparation can be injected. This joint seldom has enough fluid for diagnostic aspiration. SHOULDER Numerous structures in and around the shoulder may be involved in systemic processes, injury, or overuse ­syndromes, and each has the potential to benefit from local steroid injection. Ideally, injections should be directed toward specific anatomic sites based on clinical findings. For practical purposes, injections into the glenohumeral joint or subacromial bursal space are often beneficial for pain related to other nearby structures, such as the rotator cuff tendons or bicipital tendon. Glenohumeral Joint The glenohumeral joint may be entered from an anterior or posterior approach. For an anterior approach, the patient should be in a sitting position with the shoulder externally rotated (Fig. 49-1). A mark is made just medial to the head of the humerus and slightly inferiorly and laterally to the coracoid process. A 20-gauge to 22-gauge, 1½-inch needle is directed posteriorly and slightly upward and laterally. For a posterior approach, the upper arm should be against the lateral chest and forearm across the chest. A mark should be

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Figure 49-1  Shoulder (glenohumeral) joint arthrocentesis: anterior approach. With the shoulder externally rotated, the needle is inserted at a point just medial to the head of the humerus, slightly inferior and lateral to the coracoid process (marked in black), which is just inferior to the lateral aspect of the clavicle (marked in black above).

Figure 49-3  Elbow arthrocentesis. With the elbow flexed 90 degrees, the needle is inserted into the recess just below the lateral epicondyle (black circle) and radial head (black line) and is directed parallel to the shaft of the radius.

made about 2 inches inferior to the acromion. One should be able to feel the needle enter the joint space, but if bone is hit, the needle should be pulled back and redirected at a slightly different angle. When the joint is entered, fluid should be aspirated, if present, and the joint should be injected with 1 mL of steroid preparation, with or without 1 to 3 mL of lidocaine.

1 inch or less. After an attempt to obtain fluid, 0.25 to 0.5 mL of steroid preparation may be injected.

Acromioclavicular Joint The acromioclavicular joint, similar to the sternoclavicular joint, is composed of fibrocartilage and rarely contains fluid. The joint is palpated as a groove at the lateral end of the clavicle, just medial to the tip of the acromion, and may display some degree of soft tissue swelling or bony prominence, depending on the underlying disease process. To enter the joint with a needle, a mark should be made over the groove, and a 22-gauge to 25-gauge needle should be introduced

Rotator Cuff Tendon and Subacromial Bursa The rotator cuff tendon and subacromial bursa area may be entered using a 22-gauge to 25-gauge needle, usually 1½ inches in length (Fig. 49-2). Over the lateral or posterolateral aspect of the shoulder, the groove between the acromion and humerus should be palpated and marked. The needle is inserted at this point and advanced in a horizontal plane medially, usually 1 to 1½ inches. It is unusual to obtain fluid from this space. In most cases, the area is injected ­without aspiration; usually 1 mL of steroid preparation with 1 to 3 mL of lidocaine is injected to allow wider distribution of medication in this area. Bicipital Tendon Bicipital tendinitis may be treated by injecting the shoulder joint or the tendon sheath itself. If the tendon is to be injected, it can be palpated over the anterior aspect of the shoulder in the bicipital groove of the shoulder; it is usually tender and can be rolled under the examiner’s finger. A 22-gauge, 1½-inch needle should be inserted in the sheath, and portions of the steroid and lidocaine preparation should be injected directly, and then superiorly and inferiorly, along the course of the tendon after redirecting the needle in each direction. Discretion is advised, however, when considering injection of this tendon sheath because there may be increased risk of tendon rupture in this area. ELBOW

Figure 49-2  Rotator cuff tendon/subacromial bursa injection: lateral approach. Over the lateral aspect of the shoulder, the groove between the acromion (marked in black) and humerus is palpated and marked (spot). The needle is inserted at this point and advanced in a horizontal plane medially.

Elbow Joint The elbow is best entered by insertion of the needle into the area over the lateral elbow where a bulge can be palpated if fluid is present within the joint (Fig. 49-3); this is best

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processes, but a larger gauge (20-gauge) is often needed for bursal effusions related to rheumatoid arthritis or gout. After preparation, the needle should be inserted under the skin into the easily palpable area of fluid, and as much fluid as possible should be aspirated. For noninfectious processes, 0.5 to 1 mL of steroid can be injected into the space. Subcutaneous nodules in this area, or at other locations around the body, may be aspirated for diagnostic purposes, usually to differentiate rheumatoid nodules from tophi. For this type of aspiration, an 18-gauge to 20-gauge needle is inserted into the nodule and rotated, retracted to near the surface, and then reinserted and rotated, with negative pressure applied on the syringe. After removal, the contents of the syringe should be expelled onto a microscope slide and may be examined for cellular content and crystals. Figure 49-4  Lateral epicondyle (tennis elbow) injection. With the ­ lbow flexed and pronated, the needle is inserted at the most tender e area over the bony prominence on the anterolateral aspect of the lateral humerus, which is proximal to radial head (black line). A combination of steroid and local anesthetic is injected into the subcutaneous tissues at the attachment of the extensor muscles to the epicondyle.

d­ etermined with the elbow flexed at 90 degrees. A mark should be made just below the lateral epicondyle in the groove just proximal to the head of the radius and above the olecranon process of the ulna. After preparation, a 20-gauge to 22-gauge needle held perpendicular to the skin is inserted approximately 1 inch, and the joint is aspirated, followed by injection if indicated. Medial and Lateral Epicondyle The areas of the medial and lateral epicondyle are commonly affected by overuse syndromes involving the origins of ­muscle groups of the forearm, particularly the lateral ­ epicondyle, which is the area of inflammation in tennis elbow (Fig. 49-4). With the elbow flexed, the area of tenderness over the anterolateral surface of the external condyle of the humerus should be marked. After preparation, a 22-gauge to 25gauge needle 1 to 1½ inches long should be inserted about 1 to 2 cm distal to the mark; 0.5 mL of steroid preparation mixed with 1 to 3 mL of lidocaine is administered in several small doses after partially withdrawing and redirecting the needle and reinjecting in two to three passes of the needle in the area. Injections in this area often deliver steroids to subcutaneous tissues close to the skin, and patients should be advised about the likelihood of subcutaneous atrophy and pigment changes that may occur weeks or months after the injection. The medial epicondyle is injected in a similar fashion, with more care required to avoid inadvertent injection of steroids into the area of the ulnar groove just behind the bony prominence of the epicondyle.

WRIST AND HAND Radiocarpal Joint The wrist joint is complex, but most of the intercarpal spaces communicate with the radiocarpal joint, which may be entered from a dorsal approach. A mark should be made just distal to the radius and just ulnar to the “anatomic snuffbox” (Fig. 49-5). A 22-gauge to 25-gauge needle, ½ to 1 inch long is usually adequate. Occasionally, 3 to 5 mL of fluid may be obtained from the wrist by aspiration, and, if indicated, 0.5 mL of steroid may be injected into the space. Dorsal Wrist Tendons The extensor tendon sheaths over the dorsal wrist may become inflamed and swollen secondary to numerous in­ flammatory processes, most commonly rheumatoid arthritis, but occasionally crystal-induced arthritis or infectious processes. The areas of swelling are well defined and close to the surface, and they are entered easily with a direct aspiration, usually at a 30-degree to 45-degree angle, with the needle directed along the course of the swollen tendon. Fluid is often easily obtained, but in some patients, in particular, patients with rheumatoid arthritis, proliferative synovial

Olecranon Bursa and Nodules The area of the olecranon bursa and nodules is located just under the skin over the tip of the olecranon process at the posterior aspect of the elbow. Swelling in this area is detected easily as a localized collection of fluid and can be easily aspirated and injected if fluid is present. A smaller gauge needle (22-gauge to 23-gauge) may be used for ­ noninflammatory

Figure 49-5  Wrist (radiocarpal) arthrocentesis. The needle is inserted just distal to the radius (marked in black) at a point just ulnar to the anatomic snuffbox. It is directed perpendicular to the skin and advanced until fluid is obtained or the needle is advanced 1 to 1.5 inches.

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tissue limits the amount of fluid that can be aspirated. After aspiration, the area can be injected with 0.5 mL of corticosteroid mixed with 0.5 to 1 mL of lidocaine, if indicated. de Quervain’s Tenosynovitis de Quervain’s tenosynovitis, a common overuse syndrome involving the tendons at the radial aspect of the anatomic snuffbox, is often helped by local injection of the tendon sheath. After examination, the area of greatest tenderness along the course of the tendon should be marked, and the needle should be inserted almost parallel to the skin, either proximally or distally (Fig. 49-6). As the needle is advanced, 0.5 mL of steroid with 0.5 to 2 mL of lidocaine can be injected along the sheath of the tendon, and a palpable bulge is usually felt along the tendon. Care should be taken to avoid injection of steroid into the body of the tendon by moving the needle slightly if resistance to injection is noted. Carpal Tunnel Syndrome Inflammation with swelling in the many flexor tendons in the carpal tunnel area may result in median nerve compression, and injection in this area has the potential to relieve symptoms by reducing this inflammation (Fig. 49-7). This area should be injected by making a mark on the volar aspect of the wrist along the flexor carpi radialis tendon (on the radial side of the long palmar tendon), approximately 1 to 2 cm proximal to the distal wrist crease.135,136 A 22-gauge to 26-gauge needle may be introduced perpendicular to the skin, or, alternatively, at a 30-degree to 45-degree angle, directing the needle proximally or distally along the course of the tendon. The needle should be introduced about ½ to 1 inch, and the area is injected with 0.5 mL of steroid with 0.5 to 1 mL of lidocaine. If the needle meets obstruction, or if the patient experiences paresthesias, the needle should be withdrawn and redirected

Figure 49-7  Injection for carpal tunnel syndrome. To begin an injection in this area, the clinician should make a mark on the volar aspect of the wrist along the flexor tendons, on the radial side of the long palmar tendon, and approximately 1 inch proximal to the distal volar skin crease at the wrist (black marking). A 22-gauge to 26-gauge needle is introduced at a 30-degree to 45-degree angle and is directed proximally or distally along the course of the tendon. The needle should be introduced about ½ to 1 inch. If the needle meets obstruction, or if the patient experiences paresthesias, the needle should be withdrawn and redirected slightly to avoid injecting into the body of a tendon or into the median nerve itself.

slightly to avoid injecting into the body of a tendon or into the median nerve itself. Ganglia Small, often hard, nodular structures known as ganglia are frequently present around the hands and wrists, and they may occur in many other areas near joints or tendons. These structures usually contain a thick, gelatinous substance that is difficult to aspirate. In cases in which pain, tendon dysfunction, or nerve entrapment symptoms are bothersome to the patient, aspiration may be attempted, usually with an 18-gauge to 20-gauge needle. Even if no fluid is obtained, the process of puncture occasionally causes the structure to dissipate its contents, and symptoms are relieved. A small amount (0.2 to 0.5 mL) of steroid with lidocaine may be injected in an attempt to prevent reaccumulation of fluid. Thumb Carpometacarpal Joint

Figure 49-6  Injection for de Quervain’s tenosynovitis. The needle is inserted along the course of the tendons (black line), proximal to the thumb carpometacarpal joint (spot), at the radial aspect of the anatomic snuffbox. The needle is directed almost parallel to the skin either proximally or distally. As the needle is advanced, a mixture of steroid and anesthetic is injected along the sheath of the tendon, and a palpable bulge is usually felt along the tendon. Care should be taken to avoid injection of steroid into the body of the tendon.

Aspiration of fluid from this joint is seldom possible and rarely indicated. This joint is commonly involved in osteoarthritis, however, and may be a source of localized pain amenable to local injection (Fig. 49-8). The joint space is narrowed and often surrounded by osteophytes, but it may be entered accurately by flexing the thumb across the palm and making a mark at the base of the thumb metacarpal away from the border of the snuffbox.137 A 22-gauge to 25-gauge needle should be inserted ½ to 1 inch at this mark and directed away from the radial artery; 0.2 to 0.5 mL of steroid may be injected. Metacarpophalangeal and Interphalangeal Joints Inflammation in the small joints of the hands usually causes the synovium to bulge dorsally. Occasionally, these small joints may have enough swelling for a drop or two of fluid

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posterior lumbar facet or upper sacroiliac joints to reduce inflammation in the joints themselves, whereas others probably reduce inflammation in ligaments, tendons, or bursal structures. More precise injection of posterior lumbar facet or sacroiliac joints requires radiographic guidance, with fluoroscopy, CT, or MRI.82,83 PELVIC GIRDLE Ischiogluteal Bursitis

Figure 49-8  Injection of the thumb carpometacarpal joint. The procedure begins by flexing the thumb across the palm and making a mark at the base of the thumb metacarpal distal to the radial tendons of the snuffbox (black). A 22-gauge to 25-gauge needle is inserted ½ to 1 inch at this mark and directed away from the radial artery; 0.2 to 0.5 mL of steroid may then be injected.

The bursa over the ischial tuberosity is located by direct palpation in the buttock while the patient lies on the opposite side with knees fully flexed. The prominence is more easily palpated as the gluteus muscles are displaced from the area. After marking the area of tenderness over the prominence, a 3-inch needle should be inserted horizontally until bone is hit, and 1 mL of steroid with 1 to 2 mL of lidocaine is instilled. Care should be taken to avoid the sciatic notch medially. Trochanteric Pain Syndrome (Bursitis)

to be obtained for crystal analysis, culture, or both. In most cases, arthrocentesis is performed for symptom relief; 0.1 to 0.2 mL of corticosteroid is injected, with or without local anesthetic. A 24-gauge to 27-gauge, ½- to 1-inch needle can be inserted on either side of the joint at a mark made at the joint line, just under the extensor tendon mechanism. Some physicians prefer to have the joint slightly flexed to improve the chances for entry into the joint space itself.

Trochanteric pain syndrome is diagnosed by physical findings of normal hip joint motion and a reproducible tender area in the region of the greater trochanter where the gluteal muscles insert (Fig. 49-9). This area can be injected easily after marking the area of tenderness with the patient lying on the opposite side. A 1- to 3-inch needle should be inserted perpendicular to the skin of the bony prominence, and 1 mL of steroid with 2 to 4 mL of local anesthetic is injected into the area.

Flexor Tenosynovitis (Trigger Fingers) The pathologic process in this condition usually involves the tendon at the level of the metacarpophalangeal joint in the palm. Usually, a localized swelling that moves with the tendon sheath may be palpated in this area. After a mark has been made at this area, a 22-gauge to 27-gauge needle may be introduced at a 30-degree to 45-degree angle, directing the needle proximally or distally along the course of the tendon. The needle should be introduced about ½ inch, and the area may be injected with 0.5 mL of steroid with 0.5 mL of lidocaine. Lack of resistance during injection indicates proper needle placement, as is the case with other tendon sheath injections.

Hip (Acetabular) Joint The hip is a difficult joint to aspirate and inject, and synovial fluid is seldom obtained from the hip in clinical practice. Two approaches can be attempted—either an anterior or a lateral approach—but accuracy of each varies. A cadaver study

LUMBOSACRAL SPINE AREA Back pain is difficult to explain anatomically in most pa­ tients, but many patients with back pain have areas tender to deep palpation, particularly in the presacral area and paraspinous muscles. As is the case in the cervical spine area, most injections in this region are best considered to be myofascial or trigger point injections. The point of injection usually is determined by palpating for the areas of most tenderness, with few reliable landmarks available for localization of anatomic structures. Using a 22-gauge to 25-gauge needle, a combination of 0.5 to 1 mL of steroid and 0.5 to 2 mL of lidocaine can be injected into areas of the paraspinous muscles or other tender areas. Some of the injections performed in these areas are likely to be close enough to the

Figure 49-9  Injection for trochanteric pain syndrome. This area is easily injected after marking the area of tenderness over the bony prominence of the lateral hip with the patient lying on the opposite side. A 1- to 3-inch needle is inserted perpendicular to the skin over the bony prominence, and 1 mL of steroid with 2 to 4 mL of local anesthetic is injected into the area. (Anterior superior iliac spine is marked in black for reference.)

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Figure 49-10  Hip arthrocentesis: lateral approach. With the hip internally rotated, the needle is inserted just anterior to the greater trochanter (black) and directed toward a point slightly below the inguinal ligament (anterior superior iliac spine is for reference). As noted in the text, accuracy of any approach to the hip joint is limited, and radiographic guidance should be considered unless synovial fluid is easily obtained using this approach.

found the rate of correct needle placement was only 60% with the anterior approach and 80% with the lateral approach, and the anterior approach frequently resulted in needle placement in the vicinity of the femoral nerve.138 In situations where synovial fluid analysis is essential to patient management, particularly when infection is suspected, fluoroscopic guidance is necessary to obtain fluid for culture and other studies. If aspiration without fluoroscopic guidance is attempted, a 20-gauge, 3-inch needle should be used. For the anterior approach, the patient should be supine with the hip fully extended and externally rotated. A mark should be made 2 to 3 cm below the anterior superior iliac spine and 2 to 3 cm lateral to the femoral pulse. The needle is inserted at a 60-degree angle and directed posteriorly and medially until bone is hit. The needle is withdrawn slightly, and an attempt should be made to aspirate fluid. Injection of 1 mL of steroid with lidocaine may follow if indicated. For a lateral approach (Fig. 49-10), the patient should be supine and the hips rotated internally with knees apart and toes touching. A mark should be made just anterior to the greater trochanter, and the needle should be inserted and directed medially and slightly cephalad toward a point slightly below the middle of the inguinal ligament. Often, the clinician can feel the tip of the needle slide into the joint, and aspiration can be attempted.

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Figure 49-11  Knee arthrocentesis: medial approach. With the patient supine, a mark is made in the recess (or where there is a fluid bulge) behind the medial portion of the patella (black), approximately at the midline. The needle should be advanced 1.5 inches or more until fluid is obtained (patellar tendon is for reference).

where a bulge or “fluid wave” can be detected on physical examination if fluid is present (Figs. 49-11 and 49-12). An 18-gauge to 22-gauge needle should be directed posteriorly and slightly inferiorly, and fluid can be aspirated after advancing the needle ½ to 1½ inches into the joint space. A lateral approach is preferred by some clinicians because more fluid can be removed from this side in many patients.139 In patients with rheumatoid arthritis or septic arthritis, synovial debris or proliferative synovial tissue may occlude the needle, and it may be necessary to rotate the needle to facilitate aspiration. In some patients, the knee can be aspirated and injected with the patient in a sitting position with the knee flexed. A mark can be made just below the distal border of the patella in the recess on either side of the infrapatellar tendon. One more recent study showed that a lateral midpatellar approach had a higher accuracy rate than the anteromedial or anterolateral approaches done in a sitting position.140

KNEE Knee Joint The knee is the easiest joint to enter with certainty by arthrocentesis and is the joint most frequently aspirated for synovial fluid analysis in clinical practice. The knee may be aspirated with the patient in the supine or sitting position and from medial, lateral, or anterior aspects. Aspiration usually is considered to be easiest with the patient in the supine position with the knee almost fully extended. A mark should be made just posterior to the medial or lateral aspect of the patella in the recess behind the patella,

Figure 49-12  Knee arthrocentesis: lateral approach. With the patient supine, a mark is made in the recess (or where there is a fluid bulge) behind the lateral portion of the patella (black), approximately at the midline. The needle should be advanced 1.5 inches or more until fluid is obtained (patellar tendon is for reference).

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In some patients, the suprapatellar bursa may become distended with fluid. Because this space is an extension of the knee joint, either the knee joint or the suprapatellar bursa may be aspirated directly to remove fluid from this area. In some patients with large effusions, compression of the suprapatellar area allows more fluid to be obtained by arthrocentesis from the knee joint itself. In other patients, a popliteal cyst may form in the area behind the knee joint, and there may often be a ball-valve leakage of fluid from the knee joint.141 The cyst may be difficult to aspirate sometimes because of its location or lack of distinct borders. Injection of corticosteroid into the knee joint usually results in the passage of medication into the cyst with a therapeutic effect. Periarticular Knee Pain Syndromes Pain related to the anserine bursa, located over the medial aspect of the tibia just below the joint line, can be treated with a local injection into this area. In addition, some patients may have an area of localized soft tissue tenderness above the joint line over the medial and lateral condyles, often believed to be related to an irritated iliotibial band (lateral) or infrapatellar plica (medial). In each of these conditions, the area of tenderness should be marked, and a 22-gauge needle should be introduced to the bone and withdrawn slightly, and the area should be injected with 0.5 mL of steroid with 1 to 3 mL of local anesthetic. Prepatellar bursitis may result in swelling in the soft tissues anterior to the patella and should be distinguishable from a knee effusion. Similar to olecranon bursitis at the elbow, this area may be aspirated directly at the point of maximal swelling, and the area may be injected with 0.5 mL of corticosteroid preparation if indicated. ANKLE AND FOOT Tibiotalar Joint The tibiotalar joint is best aspirated with the patient in a supine position with the leg-foot angle at 90 degrees (Fig. 49-13). A mark is made just medial to the tibialis anterior tendon and lateral to the medial malleolus. A 20-gauge to 22-gauge, 1½-inch needle is directed posteriorly and should enter the joint space without striking bone. If resistance is felt, and no fluid is obtained, the needle should be withdrawn to close to the surface and redirected slightly while aspirating for fluid. After aspiration, the area may be injected with 0.5 mL of corticosteroid, with or without ­lidocaine.

Figure 49-13  Ankle arthrocentesis: anterior approach (tibiotalar joint). With the ankle at a 90-degree angle to the lower leg, the needle is ­inserted at a point just lateral to the medial malleolus (black marking)  and just medial to the tibialis anterior tendon. The needle is directed  posteriorly, perpendicular to the shaft of the tibia.

Achilles Tendon Area Generally, the area around the insertion of the Achilles tendon on the calcaneus should not be approached with a needle. In some patients, an area of swelling may be detected, however, in the subcutaneous Achilles bursa between the skin and tendon or in the retrocalcaneal bursa between the tendon and calcaneus. In either case, the area may be aspirated for fluid analysis, using a lateral or medial approach for the deeper area, to avoid inserting the needle through the Achilles tendon. In rare patients, these areas or the sheath of the Achilles tendon itself may be injected with 0.25 to 0.5 mL of steroid preparation with lidocaine. As noted previously, any injection in this area should be undertaken with extreme care to avoid injection within the body of the Achilles tendon, owing to the risk and potential consequences of rupture.

Subtalar Joint Swelling from the subtalar joint usually is detected by swelling beneath the lateral malleolus. A mark is made just inferior to the tip of the lateral malleolus, usually over the area of swelling. A 20-gauge to 22-gauge needle should be directed perpendicular to the skin, and the area should be aspirated as the needle is advanced (Fig. 49-14). The needle may be withdrawn partially and advanced again if no fluid is obtained with the first pass, and 0.5 mL of corticosteroid may be injected after fluid is aspirated, if indicated.

Figure 49-14  Subtalar (lateral) ankle arthrocentesis. The needle is inserted into the recess just inferior to the tip of the lateral malleolus (black marking) and directed perpendicularly. A bulge is often easily palpated here if fluid is present in this joint.

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Tarsal Tunnel Syndrome Tarsal tunnel syndrome, an uncommon condition, is sometimes amenable to local steroid injection, although the optimal approach to therapy in this condition is uncertain. The skin should be marked just inferior and posterior to the medial malleolus. The tendon sheaths in this area may be injected with a 22-gauge to 25-gauge needle with 0.5 mL of steroid and 0.5 to 1 mL of lidocaine. Care should be taken not to inject the nerve. Plantar Fascia Tenderness is usually elicited along the course of the plantar fascia and at its insertion at the calcaneus. This area may be injected by inserting a 22-gauge to 25-gauge, 1½-inch needle from the lateral or medial aspect of the heel and directing it through the tissues of the heel pad toward the area of tenderness. About 0.5 mL of corticosteroid with 0.5 to 1 mL of lidocaine can be injected. Repeated injections in this area should be avoided because of the risk of plantar fascia rupture.105,106 Metatarsophalangeal Joints The small joints of the toes are aspirated and injected using techniques similar to those of the small joints of the hands. The metatarsophalangeal joint of the great toe is an area of particular interest because this joint is involved so often in gout. This joint may be aspirated in patients with a history suggestive of gout, even between attacks, and may yield enough fluid sometimes to allow a diagnosis of gout to be confirmed by microscopic analysis. A small mark can be made at the joint line over the medial aspect of this joint, a 22-gauge to 25-gauge needle can be inserted, and the area can be aspirated. Care should be taken to express the tiny amount of fluid often found in the needle hub onto a microscope slide. These joints can be injected for therapeutic benefit, usually with 0.1 to 0.25 mL of steroid. Interdigital Neuroma Interdigital neuroma causes pain between the metatarsal heads in the foot, usually between the second and third or third and fourth toes (Fig. 49-15). Injection into this space may reduce inflammation and relieve symptoms of nerve compression between the metatarsal heads. The area is injected most easily from the dorsal aspect. The area of tenderness should be marked, a 22-gauge to 27-gauge needle should be inserted ½ to 1 inch, and 0.25 to 0.5 mL of steroid with equal volume of anesthetic should be injected.

CURRENT AND FUTURE TRENDS IN ARTHROCENTESIS AND JOINT INJECTION In recent years, ultrasound guidance has been the subject of numerous studies as a means to increase accuracy for needle placement for arthrocentesis and therapeutic steroid injection in joints and tendon sheaths, particularly in Europe.142 One comparative study showed that ultrasound guidance increased the ability to obtain synovial fluid from

Figure 49-15  Injection for interdigital (Morton’s) neuroma. The area is most easily injected from the dorsal aspect, usually between the metarsal heads of the third and fourth toes. The area of tenderness is marked, the needle is inserted ½ to 1 inch, and steroid with anesthetic is injected.

joints to 97% of patients compared with 32% when using conventional techniques without ultrasound.143 Ultrasound has been shown to improve response to injection in painful shoulders, fingers, and ankles compared with injections using traditional anatomic landmarks.144-146 Ultrasound can be employed by having the area to be aspirated marked by the ultrasonographer or by having concurrent ultrasound monitoring while the needle is inserted into the joint or tendon sheath area. The latter approach has the potential to be particularly helpful in areas difficult to assess, but it is more cumbersome and requires the use of sterile components for the ultrasound machine and ­sterile ultrasound gel. Cost and time constraints would probably limit the widespread use of ultrasonography in routine clinical rheumatology practice, but increased use of this procedure has the potential to improve outcomes in individual patients with pain associated with difficult-to-access ­periarticular structures. The irrigation of joints in osteoarthritis with large volumes of saline, known as tidal irrigation, had been a subject of controversy during the period from 1992 to 2002. Based on observations that some patients undergoing arthroscopy seemed to improve from the process of lavage that accompanies the procedure, subsequent studies suggested that irrigation of the joint was superior to medical management and comparable to local steroid injection.38,147-149 A more recent study using a “sham” irrigation as control showed no benefit, however, in patients receiving tidal irrigation, suggesting that most of the previously noted response was related to placebo effect.150 Advances in understanding of the underlying biologic processes in rheumatoid arthritis and osteoarthritis in re­ cent years have raised hopes that intrasynovial therapy with biologic agents might have a role in the treatment of various forms of arthritis. Potential intrasynovial therapies might include agents that suppress inflammation and bone destruction (e.g., interleukin-1 receptor antagonist, interleukin-4, tumor necrosis factor inhibitors, bisphosphonates, caspase inhibitors) or agents that promote cartilage growth (e.g., dehydroepiandrosterone, insulin-like growth factor, transforming growth factor-β).151-154 The ability to transfer

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genes to synoviocytes in vivo and ex vivo has led to speculation that the delivery of genes directly to the joints might lead to reduced inflammation and cartilage degradation in rheumatoid arthritis and osteoarthritis. In the past decade, further investigations have attempted to identify viral vectors with potential to deliver genes directly to synovial cells. Numerous strategies have been outlined to investigate further the possibility of intrasynovial gene therapy for rheumatoid arthritis, osteoarthritis, and other diseases of the joints.155,156 The role of such therapies in the future will most likely depend on the ability to find safe and effective vectors that can deliver genetic material that persists in synovial tissues for long periods at a reasonable cost. REFERENCES   1. Courtney P, Doherty M: Joint aspiration and injection. Best Pract Res Clin Rheumatol 19:345-369, 2005.   2. Committee on Rheumatology Care: Benchmarks in Rheumatology Practice: Data from the 1999 American College of Rheumatology Economic Survey. Atlanta, American College of Rheumatology, 1999.   3. Nelson RL, McCaffrey LA, Nobrega FT, et al: Altering residency curriculum in response to a changing practice environment: Use of the Mayo internal medicine residency alumni survey. Mayo Clin Proc 65:809-817, 1990.   4. Gormley GJ, Corrigan M, Steele WK, et al: Joint and soft tissue injections in the community: Questionnaire survey of general practitioners’ experiences and attitudes. Ann Rheum Dis 62:61-64, 2003.   5. Pemberton R: Arthritis and Rheumatoid Conditions: Their Nature and Treatment. Philadelphia, Lea & Febiger, 1935.   6. Ropes MW, Bauer W: Synovial Fluid Changes in Joint Disease. Cambridge, Mass, Harvard University Press, 1953.   7. Woolf AEM: A surgical method of relief for intractable pain in osteoarthritis of the knee. Br J Rheumatol 1:97-108, 1938.   8. Waugh WG: Mono-articular osteo-arthritis of the hip: Treatment by acid injection. BMJ 1:873-874, 1945.   9. Comroe BI: Arthritis and Allied Conditions. Philadelphia, Lea & Febiger, 1949. 10. Hollander JL: Hydrocortisone and cortisone injected into arthritic joints: Comparative effects of and use of hydrocortisone as a local antiarthritic agent. JAMA 147:1629, 1951. 11. Hollander JL: Local anti-rheumatic effectiveness of higher esters and analogues of hydrocortisone. Ann Rheum Dis 13:297, 1954. 12. Hollander JL: Intrasynovial corticosteroid therapy: A decade of use. Bull Rheum Dis 11:239-240, 1961. 13. Hollander JL: Intrasynovial corticosteroid therapy in arthritis. Md State Med J 19:62-66, 1970. 14. McCarty DJ: Treatment of rheumatoid joint inflammation with triamcinolone hexacetonide. Arthritis Rheum 15:157-173, 1972. 15. McCarty DJ, Harman JG, Grassanovich JL, et al: Treatment of rheumatoid joint inflammation with intrasynovial triamcinolone hexacetonide. J Rheumatol 22:1631-1635, 1995. 16. Weitoft T, Uddenfeldt P: Importance of synovial fluid aspiration when injecting intra-articular corticosteroids. Ann Rheum Dis 59:233-235, 2000. 17. Furtado RN, Oliveira LM, Natour J: Polyarticular corticosteroid injection versus systemic administration in treatment of rheumatoid arthritis patients: A randomized controlled study. J Rheumatol 32:1691-1698, 2005. 18. Hetland ML, Stengaard-Pedersen K, Junker P, et al: Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: An ­investigatorinitiated, multicenter, randomized, double-blind, parallel-group, ­placebo-­controlled study. Arthritis Rheum 54:1401-1409, 2006. 19. Fernandez C, Noguera R, Gonzalez JA, et al: Treatment of acute attacks of gout with a small dose of intraarticular triamcinolone acetonide. J Rheumatol 26:2285-2286, 1999.

20. Green M, Marzo-Ortega H, Wakefield RJ, et al: Predictors of outcome in patients with oligoarthritis: Results of a protocol of intraarticular corticosteroids to all clinically active joints. Arthritis Rheum 44:1177-1183, 2001. 21. Maugars Y, Mathis C, Berthelot JM, et al: Assessment of the efficacy of sacroiliac corticosteroid injections in spondylarthropathies: A double-blind study. Br J Rheumatol 35:767-770, 1996. 22. Hanly JG, Mitchell M, MacMillan L, et al: Efficacy of sacroiliac corticosteroid injections in patients with inflammatory spondyloarthropathy: Results of a 6 month controlled study. J Rheumatol 27:719-722, 2000. 23. Allen RC, Gross KR, Laxer RM, et al: Intraarticular triamcinolone hexacetonide in the management of chronic arthritis in children. Arthritis Rheum 29:997-1001, 1986. 24. Sparling M, Malleson P, Wood B, et al: Radiographic followup of joints injected with triamcinolone hexacetonide for the management of childhood arthritis. Arthritis Rheum 33:821-826, 1990. 25. Ravelli A, Manzoni SM, Viola S, et al: Factors affecting the efficacy of intraarticular corticosteroid injection of knees in juvenile idiopathic arthritis. J Rheumatol 28:2100-2102, 2001. 26. Padeh S, Passwell JH: Intraarticular corticosteroid injection in the management of children with chronic arthritis. Arthritis Rheum 41:1210-1214, 1998. 27. Breit W, Frosch M, Meyer U, et al: A subgroup-specific evaluation of the efficacy of intraarticular triamcinolone hexacetonide in juvenile chronic arthritis. J Rheumatol 27:2696-2702, 2000. 28. Sornay-Soares C, Job-Deslandre C, Kahan A: Joint lavage for treating recurrent knee involvement in patients with juvenile idiopathic arthritis. Joint Bone Spine 71:296-299, 2004. 29. Sherry DD, Stein LD, Reed AM, et al: Prevention of leg length discrepancy in young children with pauciarticular juvenile rheumatoid arthritis by treatment with intraarticular steroids. Arthritis Rheum 42:2330-2334, 1999. 30. Neidel J, Boehnke M, Kuster RM: The efficacy and safety of intraarticular corticosteroid therapy for coxitis in juvenile rheumatoid arthritis. Arthritis Rheum 46:1620-1628, 2002. 31. Towheed TE, Hochberg MC: A systematic review of randomized controlled trials of pharmacological therapy in osteoarthritis of the knee, with an emphasis on trial methodology. Semin Arthritis Rheum 26:755-770, 1997. 32. Schumacher HR, Chen LX: Injectable corticosteroids in treatment of arthritis of the knee. Am J Med 118:1208-1214, 2005. 33. Miller JH, White J, Nortan TH: The value of intra-articular corticosteroids for osteoarthritis of the knee. J Bone Joint Surg Br 40:636, 1958. 34. Dieppe PA, Sathapatayavongs B, Jones HE, et al: Intra-articular steroids in osteoarthritis. Rheumatol Rehabil 19:212-217, 1980. 35. Friedman DM, Moore ME: The efficacy of intraarticular steroids in osteoarthritis: A double-blind study. J Rheumatol 7:850-856, 1980. 36. Jones A, Doherty M: Intra-articular corticosteroids are effective in osteoarthritis but there are no clinical predictors of response. Ann Rheum Dis 55:829-832, 1996. 37. Gaffney K, Ledingham J, Perry JD: Intra-articular triamcinolone hexacetonide in knee osteoarthritis: Factors influencing the clinical response. Ann Rheum Dis 54:379-381, 1995. 38. Ravaud P, Moulinier L, Giraudeau B, et al: Effects of joint lavage and steroid injection in patients with osteoarthritis of the knee: Results of a multicenter, randomized, controlled trial. Arthritis Rheum 42: 475-482, 1999. 39. Godwin M, Dawes M: Intra-articular steroid injections for painful knees: Systematic review with meta-analysis. Can Fam Physician 50:241-248, 2004. 40. Arroll B, Goodyear-Smith F: Corticosteroid injections for osteoarthritis of the knee: Meta-analysis. BMJ 3232:869, 2004. 41. Bellamy N, Campbell J, Robinson V, et al: Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane ­Database Syst Rev 2:CD005328, 2005. 42. Raynauld JP, Buckland-Wright C, Ward R, et al: Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: A randomized, double-blind, placebo-controlled trial. Arthritis Rheum 48:370-377, 2003. 43. Plant MJ, Borg AA, Dziedzic K, et al: Radiographic patterns and response to corticosteroid hip injection. Ann Rheum Dis 56:476-480, 1997. 44. Margules KR: Fluoroscopically directed steroid instillation in the treatment of hip osteoarthritis: Safety and efficacy in 510 cases. Arthritis Rheum 44:2449-2450, 2455-2456, 2001.

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45. Qvistgaard E, Christensen R, Torp-Peterson S, et al: Intra-articular treatment of hip osteoarthritis: A randomized trial of hyaluronic acid, corticosteroid, and isotonic saline. Osteoarthritis Cartilage 14: 163-170, 2006. 46. Kullenberg B, Runesson R, Tuvhag R, et al: Intraarticular corticosteroid injection: Pain relief in osteoarthritis of the hip? J Rheumatol 31:2265-2268, 2004. 47. Villoutreix C, Pham T, Tubach F, et al: Intraarticular glucocorticoid injections in rapidly destructive hip osteoarthritis. Joint Bone Spine 73:66-71, 2006. 48. Joshi R: Intraarticular corticosteroid injection for first carpometacarpal osteoarthritis. J Rheumatol 32:1305-1306, 2005. 49. Shupak R, Teitel J, Garvey MB, et al: Intraarticular methylprednisolone therapy in hemophilic arthropathy. Am J Hematol 27:26-29, 1988. 50. Felson DT, Anderson JJ: Hyaluronate sodium injections for osteoarthritis: Hope, hype, and hard truths. Arch Intern Med 162:245-247, 2002. 51. Aggarwal A, Sempowski IP: Hyaluronic acid injections for knee osteoarthritis: Systematic review of the literature. Can Fam Physician 50:249-256, 2004. 52. Lo GH, LaValley M, McAlindon T, et al: Intra-articular hyaluronic acid in treatment of knee osteoarthritis: A meta-analysis. JAMA 290:3115-3121, 2003. 53. Ines LP, da Silva JA: Soft tissue injections. Best Pract Res Clin Rheumatol 19:503-527, 2005. 54. Cummings TM, White AR: Needling therapies in the management of myofascial trigger point pain: A systematic review. Arch Phys Med Rehabil 82:986-992, 2001. 55. Green S, Buchbinder R, Glazier R, et al: Systematic review of ­randomised controlled trials of interventions for painful shoulder: Selection criteria, outcome assessment, and efficacy. BMJ 316: 354-360, 1998. 56. van der Windt DA, Koes BW, Deville W, et al: Effectiveness of corticosteroid injections versus physiotherapy for treatment of painful stiff shoulder in primary care: Randomised trial. BMJ 317:1292-1296, 1998. 57. Thomas E, van der Windt DA, Hay EM, et al: Two pragmatic trials of treatment for shoulder disorders in primary care: Generalisability, course, and prognostic indicators. Ann Rheum Dis 64:1056-1061, 2005. 58. Hay EM, Mullis R, Lewis M, et al: Comparison of physical treatments versus a brief pain-management programme for back pain in primary care: A randomised clinical trial in physiotherapy practice. Lancet 365:2024-2030, 2005. 59. Buchbinder R, Green S, Forbes A, et al: Arthrographic joint ­distension with saline and steroid improves function and reduces pain in patients with painful stiff shoulder: Results of a randomised, double blind, placebo controlled trial. Ann Rheum Dis 6:302-309, 2004. 60. Lewis M, Hay EM, Paterson SM, et al: Local steroid injections for tennis elbow: Does the pain get worse before it gets better? Results from a randomized controlled trial. Clin J Pain 21:330-334, 2005. 61. Hay EM, Paterson SM, Lewis M, et al: Pragmatic randomised controlled trial of local corticosteroid injection and naproxen for treatment of lateral epicondylitis of elbow in primary care. BMJ 319:964-968, 1999. 62. Smidt N, van der Windt DA, Assendelft WJ, et al: Corticosteroid injections, physiotherapy, or a wait-and-see policy for lateral epicondylitis: A randomised controlled trial. Lancet 359:657-662, 2002. 63. Wong SM, Hui AC, Tong PY, et al: Treatment of lateral e­picondylitis with botulinum toxin: A randomized, double-blind, placebo­controlled trial. Ann Intern Med 143:793-797, 2005. 64. Shbeeb MI, O’Duffy JD, Michet CJ Jr, et al: Evaluation of glucocorticosteroid injection for the treatment of trochanteric bursitis. J ­Rheumatol 23:2104-2106, 1996. 65. Larsson LG, Baum J: The syndrome of anserina bursitis: An overlooked diagnosis. Arthritis Rheum 28:1062-1065, 1985. 66. Ly-Pen D, Andreu JL, de Blas G, et al: Surgical decompression ­versus local steroid injection in carpal tunnel syndrome: A oneyear, ­ prospective, randomized, open, controlled clinical trial. Arthritis Rheum 52:612-619, 2005. 67. Hui AC, Wong S, Leung CH, et al: A randomized controlled trial of surgery vs steroid injection for carpal tunnel syndrome. Neurology 64:2074-2078, 2005. 68. Green DP: Diagnostic and therapeutic value of carpal tunnel injection. J Hand Surg Am 9:850-854, 1984.

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69. Dammers JW, Veering MM, Vermeulen M: Injection of methylprednisolone proximal to the carpal tunnel: Randomised double blind trial. Br Med J 319:884-886, 1999. 70. Neustadt DH: Local corticosteroid injection therapy in soft tissue rheumatic conditions of the hand and wrist. Arthritis Rheum 34: 923-926, 1991. 71. Anderson BC, Manthey R, Brouns MC: Treatment of de Quervain’s tenosynovitis with corticosteroids: A prospective study of the response to local injection. Arthritis Rheum 34:793-798, 1991. 72. Harvey FJ, Harvey PM, Horsley MW: De Quervain’s disease: Surgical or nonsurgical treatment. J Hand Surg Am 15:83-87, 1990. 73. Lane LB, Boretz RS, Stuchin SA: Treatment of de Quervain’s disease: Role of conservative management. J Hand Surg Br 26:258-260, 2001. 74. Avci S, Yilmaz C, Sayli U: Comparison of nonsurgical treatment measures for de Quervain’s disease of pregnancy and lactation. J Hand Surg Am 27:322-324, 2002. 75. Marks MR, Gunther SF: Efficacy of cortisone injection in treatment of trigger fingers and thumbs. J Hand Surg Am 14:722-727, 1989. 76. Fauno P, Andersen HJ, Simonsen O: A long-term follow-up of the effect of repeated corticosteroid injections for stenosing tenovaginitis. J Hand Surg Br 14:242-243, 1989. 77. Lapidus PW, Guidotti FP: Report on the treatment of one hundred and two ganglions. Bull Hosp Jt Dis 28:50-57, 1967. 78. Kaplan PE, Kernahan WT Jr: Tarsal tunnel syndrome: An electrodiagnostic and surgical correlation. J Bone Joint Surg Am 63:96-99, 1981. 79. Strong G, Thomas PS: Conservative treatment of Morton’s neuroma. Orthop Rev 16:343-345, 1987. 80. Crawford F, Atkins D, Young P, et al: Steroid injection for heel pain: Evidence of short-term effectiveness—a randomized controlled trial. Rheumatology (Oxf) 38:974-977, 1999. 81. Buchbinder R: Clinical practice: Plantar fasciitis. N Engl J Med 350:2159-2166, 2004. 82. Marks RC, Houston T, Thulbourne T: Facet joint injection and facet nerve block: A randomised comparison in 86 patients with chronic low back pain. Pain 49:325-328, 1992. 83. Lilius G, Harilainen A, Laasonen EM, et al: Chronic unilateral lowback pain: Predictors of outcome of facet joint injections. Spine 15:780-782, 1990. 84. Carette S, Marcoux S, Truchon R, et al: A controlled trial of corticosteroid injections into facet joints for chronic low back pain. N Engl J Med 325:1002-1007, 1991. 85. Barnsley L, Lord SM, Wallis BJ, et al: Lack of effect of intraarticular corticosteroids for chronic pain in the cervical zygapophyseal joints. N Engl J Med 330:1047-1050, 1994. 86. Luukkainen RK, Wennerstrand PV, Kautiainen HH, et al: Efficacy of periarticular corticosteroid treatment of the sacroiliac joint in non-spondylarthropathic patients with chronic low back pain in the region of the sacroiliac joint. Clin Exp Rheumatol 20:52-54, 2002. 87. Blyth T, Hunter JA, Stirling A: Pain relief in the rheumatoid knee after steroid injection: A single-blind comparison of hydrocortisone succinate, and triamcinolone acetonide or hexacetonide. Br J ­Rheumatol 33:461-463, 1994. 88. Zulian F, Martini G, Gobber D, et al: Triamcinolone acetonide and hexacetonide intra-articular treatment of symmetrical joints in juvenile idiopathic arthritis: A double-blind trial. Rheumatology (Oxf) 43:1288-1291, 2004. 89. Eberhard BA, Sison MC, Gottlieb BS, et al: Comparison of the intraarticular effectiveness of triamcinolone hexacetonide and triamcinolone acetonide in treatment of juvenile rheumatoid arthritis. J Rheumatol 31:2507-2512, 2004. 90. Conti F, Priori R, Chimenti MS, et al: Successful treatment with intraarticular infliximab for resistant knee monarthritis in a patient with spondylarthropathy: A role for scintigraphy with 99m Tc-­infliximab. Arthritis Rheum 52:1224-1226, 2005. 91. Chevalier X, Giraudeau B, Conrozier T, et al: Safety study of intraarticular injection of interleukin 1 receptor antagonist in patients with painful knee osteoarthritis: A multicenter study. J Rheumatol 32:1317-1323, 2005. 92. Schatteman L, Gyselbrecht L, De Clerq L, et al: Treatment of refractory inflammatory monoarthritis in ankylosing spondylitis by intraarticular injection of infliximab. J Rheumatol 33:82-85, 2006. 93. Brandt K, Smith G, Simon L: Review: Intraarticular injection of hyaluronan as treatment for knee osteoarthritis: What is the evidence? Arthritis Rheum 43:1192-1203, 2000.

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94. Petrella RJ, DiSilvestro MD, Hildebrand C: Effects of hyaluronate sodium on pain and physical functioning in osteoarthritis of the knee: A randomized, double-blind, placebo-controlled clinical trial. Arch Intern Med 162:292-298, 2002. 95. Schumacher HR, Meador R, Sieck M, et al: Pilot investigation of hyaluronate injections for first metacarpal-carpal (MC-C) osteoarthritis. J Clin Rheumatol 10:59-62, 2004. 96. Thumboo J, O’Duffy JD: A prospective study of the safety of joint and soft tissue aspirations and injections in patients taking warfarin sodium. Arthritis Rheum 41:736-739, 1998. 97. Gray RG, Tenenbaum J, Gottlieb NL: Local corticosteroid injection treatment in rheumatic disorders. Semin Arthritis Rheum 10:231254, 1981. 98. Ostensson A, Geborek P: Septic arthritis as a non-surgical complication in rheumatoid arthritis: Relation to disease severity and therapy. Br J Rheumatol 30:35-38, 1991. 99. Charalambous CP, Tryfonidis M, Sadiq S, et al: Septic arthritis following intra-articular steroid injection of the knee—a survey of current practice regarding antiseptic technique used during intra-articular steroid injection of the knee. Clin Rheumatol 22:386-390, 2003. 100. Glaser DL, Schildhorn JC, Bartolozzi AR, et al: Do you really know what is on the tip of your needle? The inadvertent introduction of skin into the joint. Arthritis Rheum 43:S149, 2000 (abstract). 101. McCarty DJ, Hogan JM: Inflammatory reaction after intrasynovial injection of microcrystalline adrenocorticosteroid esters. Arthritis Rheum 7:359, 1964. 102. Sweetnam R: Corticosteroid arthropathy and tendon rupture. J Bone Joint Surg Br 51:397-398, 1969. 103. Gottlieb NL, Riskin WG: Complications of local corticosteroid injections. JAMA 243:1547-1548, 1980. 104. Gray RG, Kiem IM, Gottlieb NL: Intratendon sheath corticosteroid treatment of rheumatoid arthritis-associated and idiopathic hand flexor tenosynovitis. Arthritis Rheum 21:92-96, 1978. 105. Sellman JR: Plantar fascia rupture associated with corticosteroid injection. Foot Ankle Int 15:376-381, 1994. 106. Acevedo JI, Beskin JL: Complications of plantar fascia rupture associated with corticosteroid injection. Foot Ankle Int 19:91-97, 1998. 107. Koehler BE, Urowitz MB, Killinger DW: The systemic effects of intra-articular corticosteroid. J Rheumatol 1:117-125, 1974. 108. Lazarevic MB, Skosey JL, Djordjevic-Denic G, et al: Reduction of cortisol levels after single intra-articular and intramuscular steroid injection. Am J Med 99:370-373, 1995. 109. Emkey RD, Lindsay R, Lyssy J, et al: The systemic effect of intraarticular administration of corticosteroid on markers of bone formation and bone resorption in patients with rheumatoid arthritis. Arthritis Rheum 39:277-282, 1996. 110. Chandler G, Wright V: Deleterious effect of intra-articular hydrocortisone. Lancet 2:661, 1958. 111. Alarcon-Segovia D, Ward LE: Marked destructive changes occurring in osteoarthric finger joints after intra-articular injection of corticosteroids. Arthritis Rheum 9:443-463, 1966. 112. Bentley G, Goodfellow JW: Disorganisation of the knees following intra-articular hydrocortisone injections. J Bone Joint Surg Br 51: 498-502, 1969. 113. Mankin HJ, Conger KA: The acute effects of intra-articular hydrocortisone on articular cartilage in rabbits. J Bone Joint Surg Am 48: 1383-1388, 1966. 114. Behrens F, Shepard N, Mitchell N: Alterations of rabbit articular cartilage by intra-articular injections of glucocorticoids. J Bone Joint Surg Am 57:70-76, 1975. 115. Moskowitz RW, Davis W, Sammarco J, et al: Experimentally induced corticosteroid arthropathy. Arthritis Rheum 13:236-243, 1970. 116. Gibson T, Burry HC, Poswillo D, et al: Effect of intra-articular corticosteroid injections on primate cartilage. Ann Rheum Dis 36:74-79, 1977. 117. Williams JM, Brandt KD: Triamcinolone hexacetonide protects against fibrillation and osteophyte formation following chemically induced articular cartilage damage. Arthritis Rheum 28:1267-1274, 1985. 118. Pelletier JP, Martel-Pelletier J: Protective effects of corticosteroids on cartilage lesions and osteophyte formation in the Pond-Nuki dog model of osteoarthritis. Arthritis Rheum 32:181-193, 1989. 119. Pelletier JP, Mineau F, Raynauld JP, et al: Intraarticular injections with methylprednisolone acetate reduce osteoarthritic lesions in parallel with chondrocyte stromelysin synthesis in experimental osteoarthritis. Arthritis Rheum 37:414-423, 1994.

120. Hills BA, Ethell MT, Hodgson DR: Release of lubricating synovial surfactant by intra-articular steroid. Br J Rheumatol 37:649-652, 1998. 121. Young L, Katrib A, Cuello C, et al: Effects of intraarticular glucocorticoids on macrophage infiltration and mediators of joint damage in osteoarthritis synovial membranes: Findings in a double-blind, placebo-controlled study. Arthritis Rheum 44:343-350, 2001. 122. Roberts WN, Babcock EA, Breitbach SA, et al: Corticosteroid injection in rheumatoid arthritis does not increase rate of total joint arthroplasty. J Rheumatol 23:1001-1004, 1996. 123. Cawley PJ, Morris IM: A study to compare the efficacy of two ­methods of skin preparation prior to joint injection. Br J Rheumatol 31: 847-848, 1992. 124. Abeles M, Garjian P: Do spray coolant anesthetics contaminate an aseptic field? Arthritis Rheum 29:576, 1986. 125. Cleary AG, Ramanan AV, Baildam E, et al: Nitrous oxide analgesia during intra-articular injection for juvenile idiopathic arthritis. Arch Dis Child 86:416-418, 2002. 126. Uziel Y, Berkovitch M, Gazarian M, et al: Evaluation of eutectic lidocaine/prilocaine cream (EMLA) for steroid joint injection in children with juvenile rheumatoid arthritis: A double blind, randomized, placebo controlled trial. J Rheumatol 30:594-596, 2003. 127. Simkin PA, Gardner GC: The 3-way stopcock: A useful adjunct in the practice of arthrocentesis. Arthritis Rheum 53:627-628, 2005. 128. Sibbitt W Jr, Sibbitt RR, Michael AA, et al: Physician control of needle and syringe during aspiration-injection procedures with the new reciprocating syringe. J Rheumatol 33:771-778, 2006. 129. Neustadt DH: Intra-articular therapy for rheumatoid synovitis of the knee: Effects of the postinjection rest regimen. Clin Rheumatol Pract 3:65-68, 1985. 130. Chatham W, Williams G, Moreland L, et al: Intraarticular corticosteroid injections: Should we rest the joints? Arthritis Care Res 2:70-74, 1989. 131. Chakravarty K, Pharoah PD, Scott DG: A randomized controlled study of post-injection rest following intra-articular steroid therapy for knee synovitis. Br J Rheumatol 33:464-468, 1994. 132. Alarcon GS: Treatment of rheumatoid joint inflammation with intrasynovial triamcinolone. J Rheumatol 24:1849-1850, 1997. 133. Golder W, Karberg W, Sieper J: Fluoroscopy-guided application of corticosteroids for local control of manubriosternal joint pain in patients with spondyloarthropathies. Clin Rheumatol 23:481-484, 2004. 134. Nitzan DW, Price A: The use of arthrocentesis for the treatment of osteoarthritic temporomandibular joints. J Oral Maxillofac Surg 59:1154-1159, 1160, 2001. 135. Minamikawa Y, Peimer CA, Kambe K, et al: Tenosynovial injection for carpal tunnel syndrome. J Hand Surg Am 17:178-181, 1992. 136. Racasan O, Dubert T: The safest location for steroid injection in the treatment of carpal tunnel syndrome. J Hand Surg Br 30:412-414, 2005. 137. Mandl LA, Hotchkiss RN, Adler RS, et al: Can the carpometacarpal joint be injected accurately in the office setting? Implications for therapy. J Rheumatol 33:1137-1139, 2006. 138. Leopold SS, Battista V, Oliverio JA: Safety and efficacy of intraarticular hip injection using anatomic landmarks. Clin Orthop 1:192197, 2001. 139. Roberts WN, Hayes CW, Breitbach SA, et al: Dry taps and what to do about them: A pictorial essay on failed arthrocentesis of the knee. Am J Med 100:461-464, 1996. 140. Jackson DW, Evans NA, Thomas BM: Accuracy of needle placement into the intra-articular space of the knee. J Bone Joint Surg Am 84:1522-1527, 2002. 141. Handy JR: Popliteal cysts in adults: A review. Semin Arthritis Rheum 31:108-118, 2001. 142. Conaghan PG: Musculoskeletal ultrasonography: Improving our senses. Arthritis Rheum 53:639-642, 2005. 143. Balint PV, Kane D, Hunter J, et al: Ultrasound guided versus ­conventional joint and soft tissue fluid aspiration in rheumato­logy practice: A pilot study. J Rheumatol 29:2209-2213, 2002. 144. d’Agostino MA, Aryal X, Baron G, et al: Impact of ultrasound imaging on local corticosteroid injections of symptomatic ankle, hind-, and mid-foot in chronic inflammatory diseases. Arthritis Rheum 53:284-292, 2005. 145. Naredo E, Cabero F, Beneyto P, et al: A randomized comparative study of short term response to blind injection versus sonographicguided injection of local corticosteroids in patients with painful shoulder. J Rheumatol 31:308-314, 2004.

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146. Raza K, Lee CY, Pillling D, et al: Ultrasound guidance allows accurate needle placement and aspiration from small joints in patients with early inflammatory arthritis. Rheumatology (Oxf) 42:976-979, 2003. 147. Ike RW, Arnold WJ, Rothschild EW, et al: Tidal irrigation versus conservative medical management in patients with osteoarthritis of the knee: A prospective randomized study. Tidal Irrigation Cooperating Group. J Rheumatol 19:772-779, 1992. 148. Chang RW, Falconer J, Stulberg SD, et al: A randomized, controlled trial of arthroscopic surgery versus closed-needle joint lavage for patients with osteoarthritis of the knee. Arthritis Rheum 36:289-296, 1993. 149. Frias G, Caracuel MA, Escudero A, et al: Assessment of the efficacy of joint lavage versus joint lavage plus corticoids in patients with osteoarthritis of the knee. Curr Med Res Opin 20:861-867, 2004. 150. Bradley JD, Heilman DK, Katz BP, et al: Tidal irrigation as treatment for knee osteoarthritis: A sham-controlled, randomized, double-blinded evaluation. Arthritis Rheum 46:100-108, 2002.

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151. Cocco R, Tofi C, Fioravanti A, et al: Effects of clodronate on synovial fluid levels of some inflammatory mediators, after intra-articular administration to patients with synovitis secondary to knee osteoarthritis. Boll Soc Ital Biol Sper 75:71-76, 1999. 152. Jo H, Ahn HJ, Kim EM, et al: Effects of dehydroepiandrosterone on articular cartilage during the development of osteoarthritis. Arthritis Rheum 50:2531-2538, 2004. 153. Gelse K, Von Der Mark K, Aigner T, et al: Articular cartilage repair by gene therapy using growth factor-producing mesenchymal cells. Arthritis Rheum 48:430-441, 2003. 154. D’Lima D, Hermida J, Hashimoto S, et al: Caspase inhibitors reduce severity of cartilage lesions in experimental osteoarthritis. Arthritis Rheum 54:1814-1821, 2006. 155. Evans CH, Ghivizzani SC, Robbins PD: Gene therapy for arthritis: What next? Arthritis Rheum 54:1714-1729, 2006. 156. Evans CH, Robins PD, Ghivizzani, et al: Gene transfer to human joints: Progress toward a gene therapy of arthritis. Proc Natl Acad Sci U S A 102:8698-8703, 2005.

50

Antinuclear Antibodies Stanford L. Peng  •  JoSEPH E. Craft

KEY POINTS The presence of clinically detectable antinuclear antibodies (ANAs) is characteristic of systemic lupus erythematosus (SLE), systemic sclerosis, inflammatory myositis, and Sjögren’s syndrome, and is required for the diagnosis of some syndromes, such as mixed connective tissue disease or drug-induced lupus. Fluorescent ANA testing, as a first screening step, is appropriate for patients in whom such diseases are clinically suspected. Testing of individual ANA specificities should be performed only in the context of clinical signs that correlate with ­antibody-disease associations (e.g., anti-DNA or anti-Sm in the suspicion of systemic lupus erythematosus). Key ANA specificities in SLE include anti–double-stranded DNA, which corresponds to renal disease and overall disease activity; anti–ribosomal P, which corresponds to neuropsychiatric manifestations and renal disease; anti-Ro and anti-La, which are associated with cutaneous and neonatal lupus; and anti-Sm, which is considered SLE specific without clear clinical disease manifestation correlation. Key ANA specificities in systemic sclerosis include antikinetochore (anticentromere), which corresponds to CREST manifestations; anti-Scl-70 (topoisomerase I) and anti–RNA polymerase III, which are associated with diffuse cutaneous disease and pulmonary fibrosis; and anti-PM-Scl (exosome), which is found in myositis–systemic sclerosis overlap. Key ANA specificities in inflammatory myositis include ­antihistidyl tRNA synthetase (e.g., Jo-1), which is associated with the poor-prognosis antisynthetase syndrome, and anti-Mi-2 (nucleosome remodeling-deacetylase complex), which is associated with dermatologic manifestations. Key ANA specificities in Sjögren’s syndrome include anti-Ro and anti-La, found in mothers of children with neonatal lupus, and antifodrin, which does not seem to have well-documented prognostic ramifications, but, similar to anti-Ro and anti-La, is observed at high frequency in the disease. Although many ANA specificities are generally considered disease or manifestation specific, exceptions have often ­appeared in the literature, confounded by the observation that many autoantibodies are present at low frequencies in normal individuals. In clinical use, ANA testing is insufficient to establish or refute diagnoses. Rather, such results add weight to diagnoses that throughout the evaluation should rely heavily on other ­clinical information.

OVERVIEW In the strictest sense, antinuclear antibodies (ANAs) are autoantibodies directed against nuclear specificities, such as DNA or small nuclear ribonucleoproteins (snRNPs), but since the advent of the now widely used fluorescent ­antinuclear antibody test (FANA), which can detect ­autoantigens throughout the entire cell, the spectrum of ANAs has expanded to include a diverse spectrum of nuclear and cytoplasmic specificities.1 The ANA diseases (Table 50-1) include syndromes that are characterized by an unusually high prevalence of ANA activity, such as systemic lupus erythematosus (SLE), systemic sclerosis, and mixed connective tissue disease. The prevalence of ANAs in polymyositis, dermatomyositis, and Sjögren’s syndrome has been reported to be lower than in the other ANA diseases, but they are often grouped together because they share similar target antigens and, presumably, similar etiologies. For decades, ANAs have remained important diagnostic and prognostic tools for these connective tissue diseases and have become routine assays in the evaluation of patients with suspected rheumatic diseases. These autoantibodies also arise in a variety of infectious, inflammatory, and neoplastic diseases, however, and in normal individuals. This chapter describes common ANA specificities, outlining their history, methods of detection, clinical disease associations, and the molecular biology of their target autoantigens, in an effort to delineate clearly the clinical efficacy of testing for these specificities.

HISTORY ANAs have long cultivated a collaboration between c­ linical immunology and molecular biology.1 In the first formal description of an ANA-related phenomenon in 1948, SLE bone marrow specimens were found to contain lupus erythematosus (LE) cells, which were subsequently used to diagnose SLE, drug-induced lupus, Sjögren’s syndrome, and rheumatoid arthritis (RA).2 LE cells were soon discovered to be due to a plasma factor, autoantibody against deoxyribonucleoprotein, which opsonized or induced apoptosis in free-cell nuclei, resulting in antibody sensitization and phagocytosis by phagocytic cells. In 1957, indirect immunofluorescence allowed the development of FANA as a more sensitive assay for SLE and related diseases.3 Finer distinction of autoantibody reactivities led to the description of Smith (Sm), nuclear ribonucleoprotein (nRNP), Ro/SS (SS-A), and La/SS-B specificities, which later gained further biologic prominence when it was shown that their autoantigens play prominent roles in cellular homeostasis (e.g., snRNPs, targets of anti-Sm and anti-nRNP, regulate pre–messenger RNA splicing).4 741

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Table 50-1  Antinuclear Antibody Diseases   and Related Conditions Condition

Patients with ANAs (%)

Diseases for Which ANA Testing Is Helpful for Diagnosis Systemic lupus erythematosus Systemic sclerosis Polymyositis/dermatomyositis Sjögren’s syndrome

99-100 97 40-80 48-96

Diseases for Which ANA Is Required for Diagnosis Drug-induced lupus Mixed connective tissue disease Autoimmune hepatitis

100 100 100

Diseases for Which ANA May Be Useful for Prognosis Juvenile rheumatoid arthritis Antiphospholipid antibody syndrome Raynaud’s phenomenon

20-50 40-50 20-60

Diseases for Which ANA Is Typically not Useful Discoid lupus erythematosus Fibromyalgia Rheumatoid arthritis Relatives of patients with autoimmune diseases Multiple sclerosis Idiopathic thrombocytopenic purpura Thyroid disease Patients with silicone breast implants Infectious diseases Malignancies

5-25 15-25 30-50 5-25 25 10-30 30-50 15-25 Varies widely Varies widely

Normal Individuals ≥1:40 ≥1:80 ≥1:160 ≥1:320

20-30 10-12 5 3

ANA, antinuclear antibody. Adapted from Kavanaugh A, Tomar R, Reveille J, et al: Guidelines for ­clinical use of the antinuclear antibody test and tests for specific ­autoantibodies to nuclear antigens. American College of Pathologists. Arch Pathol Lab Med 124:71-81, 2000.

Subsequent investigations have revealed many autoantigens (Table 50-2), many still largely uncharacterized. ANAs not only serve as diagnostic markers in autoimmunity, but also have greatly aided studies on intracellular metabolism.

METHODS OF DETECTION IMMUNOFLUORESCENCE FANA provides a rapid, yet highly sensitive screening method for ANA detection. Test sera at varying dilutions (typically serially increasing by twofold) are incubated with substrate cells, and bound antibodies are detected by fluorescein-conjugated anti–human IgG, followed by visualization via a fluorescence microscope. Results typically are reported by two parameters—pattern and titer— with any pattern of reactivity at a titer of 1:40 or greater being considered positive.5 The former includes one or more morphologic descriptors that reflect the localization of the respective autoantigen (Figs. 50-1 and 50-2; see Table 50-2); its clinical utility has been largely supplanted by tests for individual specificities, such as ­ autoantigenspecific enzyme-linked immunosorbent assays (ELISA) (see later). Titer is generally reported as the last ­dilution

at which an ANA pattern is detectable, but such an ­assessment has been considered imprecise and subjective, and interlaboratory standardization has not been widely instituted: Attempts to standardize the protocol have included computer-based fluorescent image quantification, subjective optical scales, and the use of standardized sera to define international units (IU/mL).1 FANA provides only a semiquantitative and partially specific screening assay for the presence of rheumatic disease–related autoantibodies. FANA results always must be interpreted in light of the particular method used by individual clinical laboratories. The substrate used for assessment may vary from frozen sections of rodent liver or kidney to cultured proliferating cell lines, most commonly the human epithelial tumor line HEp-2. Although tissue sections possess the advantage of eliminating interference from blood group antibodies, heterophil antibodies, or passenger viruses, cultured cell lines remain a common substrate because of their higher concentration of nuclear and cytoplasmic antigens and standardization of use.5,6 Different ANA test substrates are usually comparable in their ability to detect common ANAs, but differ substantially in the quantitation of antibody titer, such that HEp-2 substrates often yield higher sensitivities in the detection of ANA-associated diseases at the cost of lower specificity. Additional variables include quality of reagents, such as the fluorescein-conjugated anti-human IgG, and the microscope. Several laboratory practices have been recommended:5,7 (1) performance of the test on serum stored at 4°C for 72 hours or at −20°C or less indefinitely; (2) use of acetone-fixed HEp-2 cells as substrate because ethanol and methanol fixation may remove Ro/SS-A, and mouse or rat tissues contain little Ro/SS-A and do not reveal antibodies to several organelles characteristic of proliferating cells, such as centromeres (kinetochores); (3) use of IgG-specific anti-Ig fluorescein isothiocyanate (FITC) conjugates with a FITC-to-protein ratio of approximately 3, antibody-to-protein ratio of ≥0.1, specific antibody content of 30 to 60 μg/mL, and working dilution determined by titration of reference sera with known patterns and end point titers; and (4) use of reference sera, as set by the World Health Organization or Centers for Disease Control and Prevention. Normal individuals, usually older and female, or ­relatives of individuals with connective-tissue diseases, produce positive FANAs at a frequency of 30% (see Table 50-1).8 These patients often possess titers of less than 1:320 with homogeneous staining patterns, although several patients possess higher titers yet remain clinically asymptomatic for years. Conversely, rare SLE patients may have negative FANAs (e.g., if the patient possesses isolated anti-Ro or anti–single-stranded DNA [ssDNA] antibodies, or the test uses rat or mouse tissues).9,10 Such occurrences reiterate that the FANA, although an effective screening test, requires ­clinical correlation. ENZYME-LINKED IMMUNOSORBENT ASSAY ELISAs provide highly sensitive and rapid techniques for the detection of ANAs and determination of antibody specificity. Test sera are incubated in wells precoated with purified target antigen; bound antibodies are detected via an

Ro (Ribosomal RNA processing) La (Ribosomal RNA processing) NuRD complex (Transcription regulation) Coiled bodies Mitotic apparatus

dsDNA ssDNA, dsDNA ssDNA Nucleosome structure H1, H2A/B, H3, H4 H3 CENP-A, CENP-B, CENP-C, CENP-D (Mitotics spindle apparatus) Regulatory subunit (Ku70/80) of DNA-dependent protein kinase (DNA break repair) PCNA (DNA scaffold) (Splicing of pre-mRNA) Sm core B′/B, D, E, F, G U1 snRNP 70K, A, C U2 snRNP U4/U6 snRNP U5 snRNP U7 snRNP U11 snRNP SR

Target Autoantigens (Function)

ID, ELISA, IB, IPP ID, ELISA, IB, IPP ID, IPP

ID, ELISA, IB, IPP ID, ELISA, IB, IPP ID, ELISA, IB, IPP ID, ELISA, IB, IPP ID, ELISA, IB, IPP ID, ELISA, IB, IPP ID, ELISA, IB, IPP ELISA, IB, IPP

Speckled Speckled Speckled Speckled Speckled Speckled Speckled Speckled Speckled or negative† Speckled Homogeneous Speckled Speckled*

ELISA, ID, IB, IPP

ID, IPP, IB

IF, ELISA

RIA, ELISA, CIF, Farr RIA, ELISA, CIF ELISA ELISA B, RIA, ELISA

Other Tests

Nuclear/nucleolar speckles*

Diffuse-speckled nuclear or nucleolar*

Rim, homogeneous Rim, homogeneous Undetectable Homogeneous, rim Homogeneous, rim Large speckles Speckles*

ANA Patterns

Continued

SS, SCLE, NLE, SLE, PBC, SSc SS, SCLE, NLE, SLE DM SS SS, SSc

SLE SLE, MCTD SLE, MCTD, overlap SS, SSc SLE, MCTD SLE SSc SLE

SLE

SLE, PM/SSc overlap

SLE SLE SLE, DIL, RA SLE SLE, DIL, RA, SSc SLE, UCTD SSc, SLE, SS

Primary Rheumatic ­Disease Associations

| 

Other ribonucleoproteins   Ro/SS-A   La/SS-B/Ha   Mi-2   p80-coilin   MA-I

  PCNA/Ga/LE-4 Spliceosome components   Sm   RNP, nRNP

  Ku

  Kinetochore (centromere)

  Histone

Chromatin-associated antigens   DNA

Nuclear

Specificity

Table 50-2  Diagnostic Characteristics of Antinuclear Antibodies

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(Translational machinery) tRNAHis tRNAThr tRNAAla tRNAGly tRNAIle tRNAAsn tRNA[Ser]Sec α-fodrin, β-fodrin (Cytoskeletal component) Signal recognition particle (Transmembrane protein handling) Translational apparatus Elongation factor 1α (Protein translation)

(RNA transcription) RNAP I RNAP II RNAP III Ribosomal RNPs (Protein translation) Topoisomerase I (DNA gyrase) Topoisomerase II (DNA gyrase) U3 snoRNP (Ribosomal RNA processing) RNase MRP (Mitochondrial RNA processing) hUBF (Ribosomal RNA transcription) Exosome (RNA processing/degradation) Nucleobindin-2

? ?

Diffuse Diffuse Diffuse Diffuse Diffuse Diffuse ? Diffuse subplasmalemmal ?

Punctate Nucleolar Nuclear/nucleolar‡ Nuclear/nucleolar‡ Nucleolar, cytoplasmic Diffuse, grainy, nuclear or nucleolar ? Clumpy Diffuse with sparse nuclear 10-20 discrete spots or nuclear* Homogeneous nuclear or nucleolar ?

ID, IB IPP

ID, IPP, IB, ELISA, AAI ID, IPP, IB, ELISA, AAI ID, IPP, IB, ELISA, AAI ID, IPP, IB, ELISA, AAI ID, IPP, IB, ELISA, AAI ID, IPP, IB, ELISA, AAI IPP ELISA IPP, IB

ID, IB, IPP, ELISA ID, IB, ELISA ELISA, IB IB, IPP IPP IB, IPP ID, IPP, IB ELISA

IPP, IB

Other Tests

Myositis Myositis

PM, DM PM, DM PM, DM PM, DM PM, DM UCTD, ? Myositis SS PM

SSc SSc, SLE, overlap SSc SLE SSc SSc SSc SSc SSc PM, DM, SSc, overlap SSc, SLE, PM/DM

Primary Rheumatic ­Disease Associations

*Cell cycle dependent. † In cell studies, Ro RNP associates with cytoplasmic fractions.82 ‡ May also stain nucleoli because of an association with antibodies to RNA polymerase I. AAI, aminoacylation inhibition; ANA, antinuclear antibody; CIE, counterimmunoelectrophoresis; CIF, Crithidia luciliae immunofluorescence; DIL, drug-induced lupus erythematosus; DM, dermatomyositis; dsDNA, double-stranded DNA; ELISA, enzyme-linked immunosorbent assay; Farr, Farr radioimmunoassay; hUBF, human upstream binding factor; IB, immunoblot; ID, immunodiffusion; IPP, immunoprecipitation; MCTD, mixed connective tissue disease; NLE, neonatal lupus erythematosus; NOR, nuclear organizer region; NuRD, nucleosome remodeling-deacetylase; overlap, overlap syndromes; PBC, primary biliary cirrhosis; PCNA, proliferating cell nuclear antigen; PM, polymyositis; RA, rheumatoid arthritis; RIA, radioimmunoassay; RNAP, RNA polymerase; RNP, ribonucleoprotein; SSc, systemic sclerosis; SCLE, subacute cutaneous lupus erythematosus; SLE, systemic lupus erythematosus; SS, Sjögren’s syndrome; ssDNA, single-stranded DNA; tRNA, transfer RNA; UCTD, undifferentiated connective tissue disease. Adapted from Fritzler MJ: Immunofluorescent antinulear antibody test. In Rose NR, De Macario EC, Fahey JL, et al (eds): Manual of Clinical Laboratory Immunology. Washington, DC, American Society for Microbiology, 1992, pp 724-729.

KJ   Elongation factor 1α (Fer)

tRNA synthetases   Jo-1   PL-7   PL-12   EJ   OJ   KS   Mas Fodrin Signal recognition particle

Cytoplasmic

Ribosomal RNP Topoisomerase I (Scl-70) Topoisomerase II U3 snoRNP (fibrillarin) Th snoRNP (RNase MRP) NOR 90 (hUBF) PM-Scl (PM-1) Nucleobindin-2 (Wa)

RNA polymerases (RNAP)

Nucleolar

ANA Patterns

| 

Target Autoantigens (Function)

PENG 

Specificity

Table 50-2  Diagnostic Characteristics of Antinuclear Antibodies—cont’d

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B

C

D

A

B

C

| 

D

Figure 50-1  Fluorescent antinuclear antibody test: specificities of systemic lupus erythematosus. A, Speckled nuclear pattern of anti-Sm antibodies. B, Nuclear rim pattern of anti-DNA antibodies. C, Homogeneous nuclear pattern of anti-DNA antibodies. D, Discrete cytoplasmic and nucleolar pattern of antiribosome antibodies.

Figure 50-2  Fluorescent antinuclear antibody test: specificities of systemic sclerosis. A, Discrete speckled nuclear pattern of antikinetochore (centromere) antibodies. B, Grainy nuclear and nucleolar pattern of anti– topoisomerase I (Scl-70) antibodies. C, Diffuse nucleolar and sparse nucleoplasmic pattern of anti-Th (RNase MRP, 7-2) antibodies. D, Punctate nucleolar staining of anti–RNA polymerase antibodies. (A from Clinical Slide Collection on the Rheumatic Diseases, copyright 1991; used by permission of the American College of Rheumatology.)

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enzyme-conjugated anti–human immunoglobulin antibody, followed by color visualization with the appropriate enzyme substrate. Although these assays require a source of antigen, many clinical laboratories have incorporated ELISAs in the routine determination of ANA specificity after positive FANA results. Their popularity has resulted further from the commercial availability of ELISA kits for the detection of specific autoantibodies and the cloning and bacterial overexpression of recombinant autoantigens, such as Sm, U1 snRNP, Ro, La, tRNA synthetases, and topoisomerase I. Because the ELISA technique can denature autoantigens, ELISAs can produce some false-positive results, and confirmation sometimes requires further testing. Nonetheless, because of their ease of use, ELISAs continue to play a prominent clinical role. ANTI-DNA ANTIBODY TESTS Anti-DNA antibodies warrant special consideration because of their wide range of autoantigenic epitopes and their assay difficulties.11 Antibodies that recognize denatured ssDNA bind the free purine and pyrimidine base sequences; SLE­specific antibodies that recognize native, double-stranded DNA (dsDNA) bind the deoxyribose phosphate backbone or the rarer, conformation-dependent, left-handed helical Z-form. Two methods to ensure the use of native dsDNA in anti-DNA tests include digestion with S1 nuclease, which removes overhanging ssDNA ends, and chromatography on a hydroxyapatite column, which separates single-stranded segments from dsDNA. Despite such efforts, native DNA may denature spontaneously, especially when bound to plastic ELISA plates; this may account for the results of several reports that revealed a relative lack of specificity of antidsDNA antibodies for SLE. Reliable assays must ensure the integrity of dsDNA. Two assays offer greater assurance for anti-dsDNA ­testing. The Farr radioimmunoassay involves the ­binding of autoantibodies to radiolabeled dsDNA in ­solution. ­Precipitation of the antibody-DNA complexes by ­ ammonium sulfate allows a quantification of the ­percentage of incorporated (antibody-bound) ­radioactive dsDNA. Normal sera typically bind a small fraction of added DNA (usually <20%), whereas SLE sera often bind nearly 100% of added DNA. The specificity of this assay still depends, however, on the quality of dsDNA and the removal of contaminating ssDNA. Because the assay requires antibody-antigen binding in solution, the Farr assay is generally considered the “gold standard” for anti-dsDNA analysis. A second test, the Crithidia test, provides an inherently reliable dsDNA substrate. In this assay, the hemoflagellate Crithidia luciliae serves as a substrate for indirect immunofluorescence. Its kinetoplast, a modified giant mitochondrion, contains a concentrated focus of stable, circularized dsDNA, without contaminating RNA or nuclear proteins, providing a sensitive and specific immunofluorescence substrate by which to establish anti-dsDNA activity. Many ­laboratories have adopted the Crithidia ­immunofluorescence test for ­ routine use. ELISAs, Farr assays, and C. luciliae immunofluorescence tests provide effective, complementary ­ mechanisms to distinguish anti-ssDNA and antidsDNA.

OTHER ASSAYS Several additional assays for the determination of ANA specificity have been employed in clinical and basic ­science studies.1 Such techniques include the immunodiffusion and counterimmunoelectrophoresis techniques, two relatively insensitive assays used in many clinical ­studies associating ANA specificities (especially extractable nuclear antigens) with disease manifestations and outcome; immunoprecipitation and immunoblot, two sensitive and specific assays predominantly confined to research settings; and enzyme inhibition assays (e.g., inhibition of topoisomerase I by antiScl70, inhibition of RNA splicing by anti-snRNP), which include highly specialized techniques to characterize ANAs functionally. Such assays have not achieved widespread use in diagnostic laboratories, however, because of their cumbersome or highly specialized natures.

DISEASES ASSOCIATED WITH ANTINUCLEAR ANTIBODIES SYSTEMIC LUPUS ERYTHEMATOSUS ANAs remain a hallmark of SLE. Although past studies have reported FANA frequencies of 90%, the test is positive in more than 99% of patients using current methods.12 SLE often evokes autoantibodies against a seemingly endless range of antigens in many cellular locations, but most SLE autoantigens reside in the nucleus and may be broadly categorized into chromatin-­associated versus RNP antigens (Table 50-3; see Table 50-2), which may facilitate disease subclassification and prognosis.13 Chromatin-Associated Antigens Anti-DNA. Although antibodies against DNA remain one of the most widely recognized specificities in SLE, antibodies against its more physiologic forms, such as nucleosomes or chromatin, are more prevalent in and probably relevant to pathogenesis.11 Nonetheless, most clinical literature remains linked to classic anti-DNA antibodies (see anti-DNA antibody tests earlier): Many diseases exhibit anti-ssDNA activity, but only SLE sera characteristically possess high-titer anti-dsDNA or anti-Z-DNA activity, as characterized by positive Farr or Crithidia assays, seen in approximately 73% of patients, in contrast to low titers seen much less often in Sjögren’s syndrome, RA, and other disorders and in normal individuals.14,15 In SLE, anti-DNA antibodies strongly correlate with nephritis and disease activity, in contrast to other ANA specificities, and likely contribute directly to renal disease by immune complex formation, complement fixation, renal antigen cross-reactivity, or direct cellular toxicity on intracellular penetration.11,14 In some settings, drug-induced anti-DNA is observed, such as during therapy with some tumor necrosis factor inhibitors, although they do not correlate with clinical manifestations of connective tissue disease.16 Nonetheless, some anti-DNA antibodies may crossreact with other autoantigens, explaining correlation with other end-organ manifestations, such as the ­neuronal N-methyl-d-aspartate receptor or ribosomal P antigens for central nervous system disease.17,18 Such findings suggest that the immunologically relevant

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Table 50-3  Antinuclear Antibodies in Systemic Lupus Erythematosus* Antibody Specificity

Prevalence (%)

SLE Specific?

Major Disease Associations

80-90 70-80 50-70 H1, H2B > H2A > H3 > H4 20-40 9-14 6 3-6

In high titer In high titer No

Renal LE, overall disease activity Drug-induced lupus, anti-DNA

snRNPs   Sm core   U1 snRNP   U2 snRNP   U5 snRNP   U7 snRNP Ro/SS-A

20-30 30-40 15 ? ? 40

Yes No

La/SS-B

10-15

No

Ribosomes   P0, P1, P2 protein   28S rRNA   S10 protein   L5 protein   L12 protein SR proteins Proteasome RNA Ki-67

10-20 ? ? ? ? 50-52 58 ? ?

Yes

Chromatin-Associated Antigens Chromatin dsDNA Histone Ku RNA polymerase II Kinetochore PCNA

No Relatively (SLE and overlap) No No

Overlap

Ribonucleoprotein Components

No

Cutaneous LE, neonatal LE, and CHB Neonatal LE, secondary Sjögren’s syndrome Neuropsychiatric LE

*Shown are major antinuclear antibody specificities described in SLE, along with estimated prevalences and disease associations (bold indicates data supported by multiple studies). See text for details. CHB, congenital heart block; dsDNA, double-stranded DNA; LE, lupus erythematosus; PCNA, proliferating cell nuclear antigen; SLE, systemic lupus erythematosus; snRNP, small nuclear ribonucleoprotein.

antigen for anti-DNA antibodies may not be DNA.19 As a result, the presence of anti-DNA activity should always prompt consideration of renal disease, but the presence of anti-DNA activities does not always indicate lupus nephritis, and vice versa. Antihistone (Nucleosome). Antihistone antibodies target the protein components of nucleosomes, the DNA-protein complexes that form the substructure of transcriptionally inactive chromatin. They are common in SLE, are associated with anti-dsDNA, and are particularly characteristic of and sensitive for drug-induced lupus, where they associate with anti-ssDNA. Antihistone antibodies are commonly seen in other rheumatic diseases, however, including myositis and systemic sclerosis, and chronic infections, such as EpsteinBarr virus,1 such that clinical correlations for antihistone antibodies have been inconsistent. Other Chromatin-Associated Autoantigens. Other chromatin-associated autoantigens in SLE include several specificities also observed in other rheumatic and nonrheumatic diseases with unclear clinical significance. Autoantibodies against the p70 and p80 proteins of Ku, the catalytic subunit of the DNA-dependent protein kinase implicated in DNA repair and V(D)J recombination, have been associated with RNA polymerase II antibodies, and one study has associated them with Raynaud’s ­ phenomenon, arthralgia, skin thickening, and esophageal reflux20; however, other

studies suggest that Ku subunit specificity may be more relevant, with anti-p70 antibodies correlating with features of systemic sclerosis–polymyositis ­ overlap, and anti-p80 antibodies correlating with features of ­ systemic sclerosis or SLE.21 Other chromatin-associated autoantigens include proliferating cell nuclear antigen, which participates in a scaffold to facilitate DNA replication, recombination, and repair, and RNA polymerase II, which transcribes some small nuclear RNA genes and all protein-encoding genes— both of which remain of uncertain clinical correlation.1 Ribonucleoproteins Anti–Small Nuclear Ribonucleoproteins. In SLE, the most well-described snRNP autoantibodies include the Sm and U1 RNP specificities, which target the RNAs or proteins of the spliceosome, a complex of RNP particles involved in the pre–messenger RNA splicing. These particles include the U1, U2, U4/U6, U5, U7, U11, and U12 snRNPs, each of which consists of its respective uridine-rich (thus U) small nuclear RNA (snRNA) and a set of polypeptides, including a common core of “Sm” polypeptides (B/B′, D1, D2, D3, E, F, and G) and particle-specific polypeptides.22 Anti-Sm antibodies, which target proteins of the Sm core, the B/B′, and one of the D polypeptides and the Sm-like LSm4, appear in only 20% to 30% of SLE patients, but are considered specific for the diagnosis23; however, their presence has been associated inconsistently with specific disease activity or prognosis

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or both. In contrast, anti-U1 snRNP (nRNP, nuclear RNP, or U1 RNP) autoantibodies, which target the 70 K, A, or C polypeptides specific to the U1 snRNP, occur in 30% to 40% of SLE patients, but are not specific for SLE and likewise have been only variably associated with disease activity, ­myositis, esophageal hypomotility, Raynaud’s phenomenon, leukopenia, lack of nephritis, arthralgias or arthritis, sclerodactyly, and interstitial changes on chest radiographs.1 Several other snRNP antibodies have been described in SLE, often in overlap syndromes (e.g., U2, U5, or U7 snRNP specific), although their clinical importance also remains uncertain.22 Anti-Ro/SS-A and La/SS-B. Anti-Ro/SS-A and La/SS-B, two RNP particles that are part of a macromolecular complex that predominantly processes RNA polymerase III transcripts, have been associated often with Sjögren’s syndrome and the neonatal lupus syndrome and ANA-negative SLE (especially anti-Ro; see FANA, earlier)—although some, but not all, studies have indicated that anti-Ro may segregate among rheumatic diseases based on subunit specificities, with Ro52 without Ro60 specificities correlating with Sjögren’s syndrome, and Ro60 with or without Ro52 specificities correlating with other connective tissue diseases, including SLE.24 In SLE, anti-Ro is associated with several manifestations, especially skin disease (cutaneous lupus, chilblains, photosensitivity) and sicca symptoms, but also the neonatal lupus syndrome, including congenital heart block, anti-La, rheumatoid factor, pulmonary disease, complement (especially C4) deficiencies, thrombocytopenia, lymphopenia, and cardiac fibroelastosis.1,25,26 In comparison, anti-La correlates with late-onset SLE, secondary Sjögren’s syndrome, neonatal lupus syndrome, and protection from anti-Ro–associated nephritis.27 Antiribosomes The most well-studied antiribosome antibodies in SLE, antiribosomal P protein (anti-P), target the P0, P1, and P2 proteins of the large 60S ribosome subunit. Although they occur in only a few patients, they are considered highly specific for SLE and particularly specific for neuropsychiatric lupus, classically psychosis.28 Correlations with active disease; renal, liver, and hematologic disease; alopecia; and anti-Sm, anti-DNA, and anticardiolipin antibodies also have been reported.29 Other, less prevalent antiribosomal antibodies target rRNA, such as the 28S rRNA, or other ribosomal proteins, such as the S10, L5, and L12 subunit proteins, although their clinical significance is unclear.30 Other Antinuclear Antibodies in Systemic Lupus Erythematosus Many other SLE ANA specificities have been described, some apparently quite prevalent, such as the SR splicing factors31 and proteasome32 specificities. Many specificities continue to lack clear clinical context, although preliminary analyses indicate some correlation, such as Ki-67 with sicca33 or RNA with overlap syndromes. Other specificities remain of interest because of their connection with other diseases, such as perinuclear antineutrophil cytoplasmic antigens (pANCAs), topoisomerase I, or kinetochore specificities.1

SYSTEMIC SCLEROSIS (SCLERODERMA) ANAs against nucleolar antigens characterize the autoantibody response in systemic sclerosis. Positive FANAs, sometimes speckled in appearance, appear in 97% of sera, although percentages vary depending on the substrate used for detection. In contrast to SLE sera, systemic sclerosis sera usually contain monospecific autoantibody specificities, targeting such structures as the kinetochore, topoisomerase I, or RNA polymerases (Table 50-4; see Table 50-2).34 Antikinetochore (Centromere) and Anti–Topoisomerase I Antikinetochore (centromere) and anti–topoisomerase I specificities constitute major diagnostic tools in the subclassification of systemic sclerosis. Originally named anticentromere, antikinetochore targets at least four centromere (kinetochore) antigens (CENPs) of the mitotic spindle apparatus that promotes chromosome separation during mitosis: CENP-B (the predominant kinetochore autoantigen), CENP-A, CENP-C, and CENP-D. These specificities require mitotically active cells for robust detection, accounting for some ANA-negative systemic sclerosis findings (see FANA, earlier). Their clinical significance has been ­extensively studied and heavily associated with Raynaud’s phenomenon and limited scleroderma, or CREST (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias), in which 98% of patients have antikinetochore antibodies.35 Other associations include limited skin involvement, matlike telangiectasias, pulmonary or vascular disease, and increased malignancy risk.36 In contrast, anti–topoisomerase I (Scl-70) autoantibodies, which predominantly target the catalytic region of DNA helicase topoisomerase I, generally predict diffuse cutaneous disease with proximal skin involvement, pulmonary fibrosis and other pulmonary abnormalities,35 longer disease duration, association with cancer, digital pitting scars, and cardiac involvement and disease activity37—perhaps by a direct pathogenic role of the antibodies on fibroblast activation.38 Approximately 40% of all patients with systemic sclerosis lack either antibody,39 however, and a few (<1%) possess both antibodies, such that, although clinically useful for ­ disease classification and prognosis, they may not be used for definitive diagnoses.40 Anti-RNA Polymerases Anti-RNA polymerase (RNAP) antibodies, which ­target the eukaryotic RNA polymerases (see section on SLE and anti-RNAP), are associated with diffuse cutaneous involvement.41 Although anti–RNAP II antibodies appear in other diseases, such as SLE or overlap syndrome, and may be associated with other autoantibody specificities against Ku or RNPs, anti–RNAP I and anti–RNAP III antibodies are specific for systemic sclerosis, in which they may be useful for the prediction of renal crisis.42 RNAP III antibodies in particular may predict diffuse cutaneous systemic sclerosis, including higher skin score and tendon friction rubs.43

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Table 50-4  Antinuclear Antibodies in Systemic Sclerosis* Antibody Specificity

Prevalence (%)

Systemic Sclerosis Specific?

Mutually Exclusive?

Major Disease Associations

Kinetochore (centromere)

22-36

Relatively

Yes

Limited cutaneous disease (CREST)

Topoisomerase I

22-40

Relatively

Yes

Diffuse cutaneous disease Pulmonary fibrosis

Topoisomerase II   RNA polymerases   RNA polymerases I   RNA polymerase II   RNA polymerases III

22 4-23 Relatively No Relatively

Yes

Renal crisis Overlap Renal crisis, diffuse disease

B23 nuclear   phosphoprotein

11

U3 snoRNP (fibrillarin)

6-8

Th snoRNP (RNase   MRP, 7-2 RNA)

4-16

PM-Scl

2-5

Yes

Limited cutaneous disease Myositis-SSc overlap

No

Sp1

?

No

NOR 90 (hUBF)

?

No

*Shown are major antinuclear antibody specificities described in SSc, along with estimated prevalences and disease associations (bold indicates data supported by multiple studies). Antinuclear antibody specificities whose incidences are thought to be “mutually exclusive” of each other in SSc are indicated. See text for details. hUBF, human upstream binding factor; NOR, nucleolar organizer region; snoRNP, small nucleolar ribonucleoprotein; SSc, systemic sclerosis.

Anti–Polymyositis-Scleroderma Anti–polymyositis-scleroderma (PM-Scl) antibodies target the PM-Scl-75 and PM-Scl-100 components of the exosome, an exoribonuclease complex that regulates ribosomal RNA.44 The presence of the exosome is associated with ­myositis–systemic sclerosis overlap without SLE ­ features: 50% of anti-PM-Scl antibody–positive patients have the overlap, whereas 25% of overlap patients have the antibody.45 Also, anti-PM-Scl appears in association with arthritis and skin lesions of dermatomyositis, calcinosis, mechanic’s hands, and eczema,46 and seems to increase the incidence of muscle, tendon, and renal disease.1 Other Systemic Sclerosis–Related Antinuclear Antibodies Several other specificities have been described in systemic sclerosis with possible prognostic implications, including antifibrillarin, which targets a component of the U3 small nucleolar RNP and may be associated with diffuse ­disease, including internal organ involvement47; anti– topoisomerase II, which appears in association with pulmonary hypertension and localized scleroderma48,49; antiTh (Th snoRNP, mitochondrial RNA processing RNase MRP), which may predict pulmonary hypertension, limited cutaneous disease, puffy fingers, small bowel involvement, hypothyroidism, and reduced arthritis or arthralgias1,50; antibodies against the nuclear phosphoprotein B23, which appear in association with pulmonary hypertension and antifibrillarin antibodies51; antibodies against the RNAP II transcription activator Sp1, which seem to correlate with Raynaud’s phenomenon and other signs of undifferentiated connective tissue diseases52; and anti–nucleolar organizer region (NOR) 90 (human upstream binding factor). Other ANAs described in systemic sclerosis include several specificities characteristically observed in other ­connective

tissue ­ diseases, such as histone, Ku, Ro, tRNA, snRNP, and ANCA, although their clinical relevance in systemic ­sclerosis is unclear.34 INFLAMMATORY MUSCLE DISEASES Inflammatory muscle diseases constitute a diverse group of illnesses often characterized by autoantibody responses against cytoplasmic antigens. Although 40% to 80% of polymyositis/dermatomyositis patients have positive ANA, 90% of patients with all types of inflammatory muscle diseases have autoantibodies to cellular antigens.53,54 Myositis ­autoantibodies are generally categorized into myositis-specific autoantibodies (MSAs), which are considered ­exclusive to inflammatory myositis, and autoantibodies associated with overlap syndromes that include myositis (Table 50-5; see Table 50-2). Myositis-Specific Autoantibodies The most well-characterized MSAs include the antisynthetases, which target different aminoacyl-tRNA synthetases. Some of these antibodies target the tRNA anticodon loop, enabling them to inhibit enzymatic activity. The individual prevalences of these antibodies vary, but their clinical associations remain similar: Although polymyositis occurs more commonly with anti-Jo-1 (anti-histidyl tRNA synthetase), and dermatomyositis is more common with the other synthetases, these specificities together correlate with the “antisynthetase syndrome,” which includes interstitial lung disease, arthritis, Raynaud’s phenomenon, mechanic’s hands, hyperkeratotic lines, sclerodactyly, facial telangiectasia, calcinosis, and sicca, generally with a poor prognosis.55,56 Nonetheless, other disease associations have been reported, distinct from the antisynthetase syndrome: One study has associated anti–threonyl-tRNA synthetase

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Table 50-5  Antinuclear Antibodies in Inflammatory Muscle Diseases* Antibody Specificity

Prevalence (%)

Disease Specificity

Major Disease Associations

Anti-tRNA synthetases   Histidyl (Jo-1)   Threonyl (PL-7)   Alanyl (PL-12)   Glycyl (EJ)   Isoleucyl (OJ)   Asparaginyl (KS)   Selenocysteinyl (Mas)

20-30 1-5 1-5 1-5 1-5 ? 1-2

Myositis Myositis Myositis Myositis Myositis Overlap Myositis†

?

Mi-2

8 (15-20% of DM)

Myositis‡

Dermatologic involvement

Signal recognition particle

4

No

KJ

<1

Myositis‡

Proteasome

62

No

Histone

17

No

RNPs   U1 snRNP   U2 snRNP   Ro   La

12 3 10 ?

PM-Scl

8

Overlap

Elongation factor 1α (Fer)

1

No

Histone

?

No

Antisynthetase syndrome

No MCTD features

Ku

?

Overlap

U3 snoRNP

?

Overlap

Overlap

*Shown are major antinuclear antibody specificities described in inflammatory myositis, along with estimated prevalences and disease associations (bold indicates data supported by multiple studies). See text for details. † Considered a myositis-specific autoantibody despite recent findings in autoimmune hepatitis.83 ‡ Often referred to as myositis-specific autoantibodies. DM, dermatomyositis; MCTD, mixed connective tissue disease; RNP, ribonucleoprotein; snRNP, small nuclear ribonucleoprotein; snoRNP, small nucleolar ribonucleoprotein; tRNA, transfer RNA.

antibodies with fetal loss and severe relapsing myositis,57 and a relatively rare activity, anti-KS, has been described against the asparaginyl-tRNA synthetase in a few patients with interstitial lung disease and inflammatory arthritis or undifferentiated connective tissue disease.58 Other MSAs include specificities against Mi-2, a component of the nucleosome remodeling-deacetylase (NuRD) complex involved in chromatin remodeling and transcription regulation, which associates with dermatomyositis and dermatologic manifestations such as the “shawl” and “V” signs, and Mas, a UGA suppressor serine tRNA that carries selenocysteine (tRNA[Ser]Sec). Antibodies against the signal recognition particle, the cytoplasmic RNP that translocates nascent proteins across the endoplasmic reticulum, have been reported to be MSAs that are associated with acute, severe, treatment-resistant disease; however, more recent studies are conflicting.59

snRNP is associated with myositis and sclerodactyly, sometimes with SLE, and usually without interstitial lung disease.22 Anti-PM-Scl antibodies associated with myositis–systemic sclerosis overlap without SLE features (50% of anti-PMScl antibody–positive patients have overlap, whereas 25% of overlap patients have the antibody), and with arthritis, dermatomyositis skin lesions, calcinosis, mechanic’s hands, and eczema.45,46 Other antibodies associated with myositis in overlap syndromes include several specificities found in other diseases, such as Ku, found more commonly in SLE and systemic sclerosis, and U3 small nucleolar RNP (fibrillarin), associated with myositis in systemic sclerosis, especially of the diffuse type. Several other specificities have been described in inflammatory myositis, although their clinical significance remains largely undefined (see Table 50-5).1 SJÖGREN’S SYNDROME

Myositis Overlap Autoantibodies The most well-described, myositis overlap–associated ANAs include snRNP and PM-Scl specificities. In myositis, anti-snRNP antibodies typically target U1 snRNP, although a few anti-Sm and anti-U2 snRNP specificities have been described (see SLE anti-snRNP). The former tend to be associated with features of mixed connective tissue disease, including SLE-myositis overlap, myositis–systemic sclerosis overlap, and undifferentiated features (Raynaud’s phenomenon, puffy fingers, arthritis) later progressing to myositis, possibly responding to corticosteroids,60 whereas anti-U2

In Sjögren’s syndrome, reported incidences of positive FANAs range widely, reflecting differences in study populations and disease criteria, and depend heavily on the inclusion or exclusion of secondary, connective tissue disease–related disease, which increases the likelihood and amplitude of positive tests.6 Although 40% ANA positivity has been reported, many studies report frequencies of 90% to 96%,61 with a diverse range of autoantibodies including ubiquitous (Table 50-6; see Table 50-2) and tissue-specific reactivities, such as antithyroid, gastric parietal cell, and muscarinic receptor. Such issues hinder interpretation of

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Table 50-6  Antinuclear Antibodies in Sjögren’s Syndrome* Antibody Specificity

Prevalence (%)

Sjögren’s Syndrome Specific?

Major Disease Associations

Ro/SS-A

40-95

No

Neonatal LE and CHB

La/SS-B

80-90

No

Neonatal LE

Fodrin   α-fodrin   β-fodrin

64-100 64-67 (100 in pediatric?) 70

Possibly

Proteasome

39

No

Pyruvate dehydrogenase

27

No

p-ANCA

11-40

No

MA-I

8

Possibly

Mitochondrial

6.6

No

pp75 (Ro-associated protein)

6

No

Kinetochore

4

No

p80-coilin

4

Possibly

*Shown are major antinuclear antibody specificities described in Sjögren’s syndrome, along with estimated prevalences and disease associations (bold indicates data supported by multiple studies). See text for details. CHB, congenital heart block; LE, lupus erythematosus; p-ANCA, peripheral antineutrophil cytoplasmic antibody.

disease associations and disease specificities of ANAs in Sjögren’s syndrome. Of the Sjögren’s syndrome ANA specificities, the most well-characterized are Ro (SS-A) and La (SS-B), two nuclear RNPs involved in RNA metabolism (see SLE anti-Ro/SS-A and anti-La/SS-B), and the more recently described fodrin (nonerythroid spectrin), a cytoskeletal heterodimer composed of α and β subunits structurally and functionally similar to erythroid spectrin. Anti-Ro antibodies occur in approximately 40% to 95% of Sjögren’s syndrome patients; are associated with numerous extraglandular manifestations, including serologic association with anti-La and rheumatoid factor; and may result from genetically linked alternative mRNA processing of Ro.62 Similarly, anti-La antibodies occur in 87% of Sjögren’s syndrome patients and are associated with extraglandular manifestations and serologic association with anti-Ro and rheumatoid factor.1 Antibodies against α-fodrin have been detected in 64% to 67% of patients63 and in 100% of patients in small pediatric series,64,65 but they are uncommon in other connective tissue diseases such as SLE. Preliminary analyses suggest some extraglandular and serologic associations. In contrast, antibodies against β-fodrin have been described in 70% of patients, but clinical associations have not been reported.66 Several other specificities have been reported in Sjögren’s syndrome in a significant proportion (>3%) of patients, including antibodies against MA-I, a 200-kD protein localized to the mitotic apparatus in dividing cells (which may be identical to NuMA67); p80-Coilin, an 80-kD protein associated with nuclear coiled bodies (although this antibody might not be connective tissue disease specific)68; and specificities characteristically found in other rheumatic ­diseases, such as kinetochore pANCAs, although their clinical importance is uncertain (see Table 50-6).69 MIXED CONNECTIVE TISSUE DISEASE AND OVERLAP SYNDROMES Although overlap syndromes of connective tissue disease remain matters of nosologic debate, virtually all investigators concur that ANAs are universal in these conditions.70 Since

the initial formal description of mixed connective tissue disease in 1972, the presence of anti-U1 snRNP antibodies has been consistently required for classification and diagnosis, with associated ANA titers typically exceeding 1:1000 and often 1:10,000.71 Several investigations have noted, however, that many of such patients develop clinical and serologic manifestations that allow the diagnosis of a defined connective tissue disease, such as SLE, RA, systemic sclerosis, or polymyositis/dermatomyositis,72,73 and the accuracy of specific clinical associations of specific ANAs in overlap settings is hindered by issues of disease classification. In such instances, it seems most reasonable to base the importance of individual autoantibody specificities on their primary disease association, despite the lack of definitive, well-codified evidence (e.g., anti–topoisomerase I as predictive of eventual diffuse systemic sclerosis–like skin disease or pulmonary fibrosis, or anti-dsDNA for lupus-like glomerulonephritis). OTHER DISEASES In contrast to the traditional ANA diseases, the presence of a positive ANA in other diseases is largely unhelpful for diagnosis, although in Raynaud’s phenomenon, juvenile rheumatoid arthritis, and antiphospholipid antibody syndrome, it can aid prognosis (see Table 50-1). In Raynaud’s phenomenon, a positive result increases the likelihood, from 19% to 30%, of the development of a systemic rheumatic disease, including SLE, RA, and systemic sclerosis, whereas a negative result decreases the likelihood to approximately 7%, which is often helpful for patient reassurance.74 In juvenile rheumatoid arthritis, ANA positivity may predict the development of uveitis75; in antiphospholipid antibody syndrome, it may predict the development or presence of underlying SLE.76 Other conditions in which ANAs have been found include other rheumatic diseases, such as the vasculitides or sarcoidosis; autoimmune diseases, such as multiple sclerosis or inflammatory bowel disease; and an ever-growing list of additional conditions, including dermatologic, infectious, psychiatric, neurologic, and cardiovascular diseases.1 The more recently characterized ANA antigen DFS70 (dense fine speckles 70, lens epithelium-derived

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Antinuclear Antibodies Suspect ANA disease: Obtain FANA LOW-TITER

NEGATIVE

Low clinical suspicion

SLE Consider:

anti-Ro/SS-A

anti-tRNA synthetases (anti-Jo-1, etc.)

antiphospholipid Figure 50-3  Algorithm for the use of antinuclear antibodies (ANAs) in the diagnosis of connective tissue disorders. See text for details. FANA, fluorescent antinuclear antibody test; MCTD, mixed connective tissue disease; SLE, systemic lupus erythematosus. (Modified from Peng SL, Craft J: Antinuclear antibodies. In Harris ED, Budd RC, Firestein GS, et al (eds): Kelley’s Textbook of Rheumatology. Philadelphia, WB Saunders, 2005, pp 311-331.)

Druginduced lupus

POSITIVE High clinical suspicion

anti-dsDNA anti-U1 snRNP anti-Sm anti-Ro/SS-A

antihistones

Drug exposure

anti-scl 70 anti-RNA polymerase anticentromere anti-U1 snRNP anti-tRNA synthetase (anti-Jo-1, etc.)

Raynaud's sclerodactyly Myositis Telangiectasias Esophageal dysfunction Lung disease

Systemic sclerosis

MCTD

Polymyositis/ Dermatomyositis Sjögren's syndrome

Skin ± joint involvement

anti-Ro/SS-A anti-La/SS-B

Sicca symptoms

Hypercoagulable state

growth factor) seems to correlate with nonrheumatic diseases, suggesting that its presence may predict the absence of ­connective tissue disease.77 In general, the studies describing such associations lack comprehensive analyses regarding the significance of ANAs, such that the use of the ANA outside of the rheumatic diagnoses indicated here (see Table 50-1) remains still largely exploratory.

CLINICAL UTILITY OF ANTINUCLEAR ANTIBODIES The ANAs encompass an ever-widening range of nuclear, nucleolar, and cytoplasmic autoantigen specificities. Within the ANA diseases, including SLE, systemic sclerosis, polymyositis/dermatomyositis, Sjögren’s syndrome, and mixed connective tissue disease, many autoantibodies possess unique rheumatologic associations, but the specificity of these associations has diminished as the sensitivity of clinical studies has increased the detection of these specificities in rheumatic and nonrheumatic diseases. Consequently, tests for ANAs can aid greatly in the clinical evaluation of patients in the context of their particular disease associations, but these studies retain only an adjunct role in rheumatologic diagnosis. Figure 50-3 is an algorithm for the rheumatologic evaluation of a patient for ANAs. In most clinical laboratories, FANA serves as a screening test, with a positive result often prompting “cascade” testing by the laboratory, ordering physician, or both consisting of ELISAs or other assays for specific

autoantibody specificities, such as anti-ds-DNA, anti-Ro, anti-La, anti-RNP, and anti-Sm.5,6 A negative or low-titer FANA in the setting of a low clinical suspicion of rheumatic disease usually indicates the absence of significant ANAs and argues against the diagnosis of one of the ANA diseases (see Table 50-1)78; however, if the clinical picture strongly suggests connective tissue disease, further investigation may involve specific assays for antigens that are often FANA-negative, such as Ro, Jo-1, or phospholipids. Because some specific ANAs possess diagnostic significance, positive FANA results usually warrant follow-up with specialized assays—but only in the setting of strong clinical suspicion as the positive predictive value of an ANA in the absence of other clinical signs of connective tissue disease is low, in part because ANAs may precede clinical disease by many years,79 and in part because of the high incidence of ANA in normal individuals.8 If SLE features are present, further work may focus on anti-DNA, anti-Sm, anti-U1 snRNP, and anti-Ro antibodies. Similarly, if mixed connective tissue disease, Sjögren’s syndrome, systemic sclerosis, or polymyositis is suspected, the serum may be tested for anti-U1 snRNP; anti-Ro or anti-La; anti–topoisomerase I, anticentromere, or antinucleoli; or anti–tRNA synthetases. If these tests are negative in the setting of high clinical suspicion, repeat testing at a later date may be warranted because titers of such autoantibodies can fluctuate over time, regardless of disease course.80 Positive results in these more specialized assays alone do not signify specific diseases, but rather add weight to diagnoses that throughout the evaluation should

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rely heavily on other clinical information. Many clinical and research studies on which autoantibody-disease associations have been developed often used highly refined ­ detection methods, such as immunoprecipitation or ­immunoblot, and different laboratories often vary in technique and test reproducibility. The relevance of many antibody test results in specific clinical settings requires careful, individualized interpretation by the referring physician.81 REFERENCES   1. Peng SL, Craft J: Antinuclear antibodies. In Harris ED, Budd RC, Firestein GS, et al (eds): Kelley’s Textbook of Rheumatology. Philadelphia, WB Saunders, 2005, pp 311-331.   2. Tan EM: The L.E. cell and its legacy. 1948. Clin Exp Rheumatol 16:652-658, 1998.   3. Friou GJ: Clinical application of lupus serum nucleoprotein reaction using fluorescent antibody technique. J Clin Invest 36:890, 1957.   4. Lerner MR, Steitz JA: Antibodies to small nuclear RNAs complexed with proteins are produced by patients with systemic lupus erythematosus. Proc Natl Acad Sci U S A 76:5495-5499, 1979.   5. Kavanaugh A, Tomar R, Reveille J, et al: Guidelines for clinical use of the antinuclear antibody test and tests for specific autoantibodies to nuclear antigens. American College of Pathologists. Arch Pathol Lab Med 124:71-81, 2000.   6. Solomon DH, Kavanaugh AJ, Schur PH, et al: Evidence-based guidelines for the use of immunologic tests: Antinuclear antibody testing. Arthritis Rheum 47:434-444, 2002.   7. Nakamura RM: Quality Assurance for the Indirect Immuno­ fluorescence Test for Autoantibodies to Nuclear Antigen (IF-ANA): Approved Guideline. Wayne, Penn, National Committee for ­Clinical Laboratory Standards, 1996.   8. Tan EM, Feltkamp TE, Smolen JS, et al: Range of antinuclear antibodies in “healthy” individuals. Arthritis Rheum 40:1601-1611, 1997.   9. Maddison PJ, Provost TT, Reichlin M: Serological findings in patients with “ANA-negative” systemic lupus erythematosus. Medicine 60: 87-94, 1981. 10. Davis JM III, Moder KG, Homburger HA, et al: Clinical features of 39 patients with antibodies to extractable nuclear antigens despite negative antinuclear antibodies: Evidence for autoimmunity including neurologic and connective tissue diseases. Medicine 84:208-217, 2005. 11. Hahn BH: Antibodies to DNA. N Engl J Med 338:1359-1368, 1998. 12. Cross LS, Aslam A, Misbah SA: Antinuclear antibody-negative lupus as a distinct diagnostic entity—does it no longer exist? QJM 97: 303-308, 2004. 13. To CH, Petri M: Is antibody clustering predictive of clinical subsets and damage in systemic lupus erythematosus? Arthritis Rheum 52:4003-4010, 2005. 14. Kavanaugh AF, Solomon DH, American College of Rheumatology Ad Hoc Committee on Immunologic Testing G: Guidelines for immunologic laboratory testing in the rheumatic diseases: AntiDNA antibody tests. Arthritis Rheum 47:546-555, 2002. 15. Haugbro K, Nossent JC, Winkler T, et al: Anti-dsDNA antibodies and disease classification in antinuclear antibody positive patients: The role of analytical diversity. Ann Rheum Dis 63:386-394, 2004. 16. De Rycke L, Baeten D, Kruithof E, et al: Infliximab, but not etanercept, induces IgM anti-double-stranded DNA autoantibodies as main antinuclear reactivity: Biologic and clinical implications in autoimmune arthritis. Arthritis Rheum 52:2192-2201, 2005. 17. DeGiorgio LA, Konstantinov KN, Lee SC, et al: A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nature Med 7:1189-1193, 2001. 18. Takeda I, Rayno K, Movafagh FB, et al: Dual binding capabilities of anti-double-stranded DNA antibodies and anti-ribosomal phosphoprotein (P) antibodies. Lupus 10:857-865, 2001. 19. Reichlin M, Martin A, Taylor-Albert E, et al: Lupus autoantibodies to native DNA cross-react with the A and D SnRNP polypeptides. J Clin Invest 93:443-449, 1994. 20. Cooley HM, Melny BJ, Gleeson R, et al: Clinical and serological associations of anti-Ku antibody. J Rheumatol 26:563-567, 1999. 21. Reeves WH: Antibodies to the p70/p80 (Ku) antigens in systemic lupus erythematosus. Rheum Dis Clin N Am 18:391-414, 1992. 22. Peng SL, Craft J: Spliceosomal snRNPs autoantibodies. In Peter JB, Shoenfeld Y (eds): Autoantibodies. Amsterdam, Elsevier, 1996, pp 744-782.

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23. Benito-Garcia E, Schur PH, Lahita R, et al: Guidelines for immunologic laboratory testing in the rheumatic diseases: Anti-Sm and anti-RNP antibody tests. Arthritis Rheum 51:1030-1044, 2004. 24. Lopez-Longo FJ, Rodriguez-Mahou M, Escalona M, et al: Heterogeneity of the anti-Ro(SSA) response in rheumatic diseases. J Rheumatol 21:1450-1456, 1994. 25. Sibilia J: Ro(SS-A) and anti-Ro(SS-A): An update. Rev Rhum 65: 45-57, 1998. 26. Costedoat-Chalumeau N, Amoura Z, Villain E, et al: Anti-SSA/Ro antibodies and the heart: More than complete congenital heart block? A review of electrocardiographic and myocardial abnormalities and of treatment options. Arthritis Res Ther 7:69-73, 2005. 27. St Clair EW: Anti-La antibodies. Rheum Dis Clin N Am 18:359-376, 1992. 28. Karassa FB, Afeltra A, Ambrozic A, et al: Accuracy of anti-ribosomal P protein antibody testing for the diagnosis of neuropsychiatric systemic lupus erythematosus: An international meta-analysis. Arthritis Rheum 54:312-324, 2006. 29. do Nascimento AP, dos Santos Trindade Viana VS, de Abreu ­Testagrossa LA, et al: Antibodies to ribosomal P proteins: A potential serologic marker for lupus membranous glomerulonephritis. Arthritis Rheum 54:1568-1572, 2006. 30. Elkon KB, Bonfa E, Brot N: Antiribosomal antibodies in systemic lupus erythematosus. Rheum Dis Clin N Am 18:377-390, 1992. 31. Neugebauer KM, Merrill JT, Wener MH, et al: SR proteins are autoantigens in patients with systemic lupus erythematosus: Importance of phosphoepitopes. Arthritis Rheum 43:1768-1778, 2000. 32. Feist E, Dorner T, Kuckelkorn U, et al: Diagnostic importance of antiproteasome antibodies. Int Arch Allergy Immunol 123:92-97, 2000. 33. Yamanaka K, Takasaki Y, Nishida Y, et al: Detection and quantification of anti-Ki antibodies by enzyme-linked immunosorbent assay using recombinant Ki antigen. Arthritis Rheum 35:667-671, 1992. 34. Cepeda EJ, Reveille JD: Autoantibodies in systemic sclerosis and fibrosing syndromes: Clinical indications and relevance. Curr Opin Rheumatol 16:723-732, 2004. 35. Reveille JD, Solomon DH: American College of Rheumatology Ad Hoc Committee of Immunologic Testing G: Evidence-based guidelines for the use of immunologic tests: Anticentromere, Scl-70, and nucleolar antibodies. Arthritis Rheum 49:399-412, 2003. 36. Weiner ES, Hildebrandt S, Senecal JL, et al: Prognostic significance of anticentromere antibodies and anti-topoisomerase I antibodies in Raynaud’s disease: A prospective study. Arthritis Rheum 34:68-77, 1991. 37. Hu PQ, Fertig N, Medsger TA Jr, et al: Correlation of serum antiDNA topoisomerase I antibody levels with disease severity and activity in systemic sclerosis. Arthritis Rheum 48:1363-1373, 2003. 38. Henault J, Robitaille G, Senecal JL, et al: DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti-topoisomerase I autoantibodies from systemic sclerosis patients. Arthritis Rheum 54:963-973, 2006. 39. Spencer-Green G, Alter D, Welch HG: Test performance in systemic sclerosis: Anti-centromere and anti-Scl-70 antibodies. Am J Med 103:242-248, 1997. 40. Dick T, Mierau R, Bartz-Bazzanella P, et al: Coexistence of antitopoisomerase I and anticentromere antibodies in patients with systemic sclerosis. Ann Rheum Dis 61:121-127, 2002. 41. Kuwana M, Kaburaki J, Mimori T, et al: Autoantibody reactive with three classes of RNA polymerases in sera from patients with systemic sclerosis. J Clin Invest 91:1399-1404, 1993. 42. Phan TG, Cass A, Gillin A, et al: Anti-RNA polymerase III antibodies in the diagnosis of scleroderma renal crisis sine scleroderma. J Rheumatol 26:2489-2492, 1999. 43. Kuwana M, Okano Y, Pandey JP, et al: Enzyme-linked immunosorbent assay for detection of anti-RNA polymerase III antibody: Analytical accuracy and clinical associations in systemic sclerosis. Arthritis Rheum 52:2425-2432, 2005. 44. Raijmakers R, Renz M, Wiemann C, et al: PM-Scl-75 is the main autoantigen in patients with the polymyositis/scleroderma overlap syndrome. Arthritis Rheum 50:565-569, 2004. 45. Oddis CV, Okano Y, Rudert WA, et al: Serum autoantibody to the nucleolar antigen PM-Scl: Clinical and immunogenetic associations. Arthritis Rheum 35:1211-1217, 1992. 46. Marguerie C, Bunn CC, Copier J, et al: The clinical and immunogenetic features of patients with autoantibodies to the nucleolar antigen PM-Scl. Medicine 71:327-336, 1992.

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47. Yang JM, Hildebrandt B, Luderschmidt C, et al: Human scleroderma sera contain autoantibodies to protein components specific to the U3 small nucleolar RNP complex. Arthritis Rheum 48:210-217, 2003. 48. Grigolo B, Mazzetti I, Meliconi R, et al: Anti-topoisomerase IIa autoantibodies in systemic sclerosis—association with pulmonary hypertension and HLA-B35. Clin Exp Immunol 121:539-543, 2000. 49. Hayakawa I, Hasegawa M, Takehara K, et al: Anti-DNA topoisomerase IIa autoantibodies in localized scleroderma. Arthritis Rheum 50:227-232, 2004. 50. Mitri GM, Lucas M, Fertig N, et al: A comparison between anti-Th/ To- and anticentromere antibody-positive systemic sclerosis patients with limited cutaneous involvement. Arthritis Rheum 48:203-209, 2003. 51. Ulanet DB, Wigley FM, Gelber AC, et al: Autoantibodies against B23, a nucleolar phosphoprotein, occur in scleroderma and are associated with pulmonary hypertension. Arthritis Rheum 49:85-92, 2003. 52. Spain TA, Sun R, Gradzka M, et al: The transcriptional activator Sp1, a novel autoantigen. Arthritis Rheum 40:1085-1095, 1997. 53. Reichlin M, Arnett FC Jr: Multiplicity of antibodies in myositis sera. Arthritis Rheum 27:1150-1156, 1984. 54. Love LA, Leff RL, Fraser DD, et al: A new approach to the classification of idiopathic inflammatory myopathy: Myositis-specific autoantibodies define useful homogeneous patient groups. Medicine 70:360-374, 1991. 55. Imbert-Masseau A, Hamidou M, Agard C, et al: Antisynthetase syndrome. Joint Bone Spine 70:161-168, 2003. 56. Spath M, Schroder M, Schlotter-Weigel B, et al: The long-term outcome of anti-Jo-1-positive inflammatory myopathies. J Neurol 251:859-864, 2004. 57. Satoh M, Ajmani AK, Hirakata M, et al: Onset of polymyositis with autoantibodies to threonyl-tRNA synthetase during pregnancy. J Rheumatol 21:1564-1566, 1994. 58. Hirakata M, Suwa A, Nagai S, et al: Anti-KS: Identification of autoantibodies to asparaginyl-transfer RNA synthetase associated with interstitial lung disease. J Immunol 162:2315-2320, 1999. 59. Kao AH, Lacomis D, Lucas M, et al: Anti-signal recognition particle autoantibody in patients with and patients without idiopathic inflammatory myopathy. Arthritis Rheum 50:209-215, 2004. 60. Lundberg I, Nennesmo I, Hedfors E: A clinical, serological, and histopathological study of myositis patients with and without anti-RNP antibodies. Semin Arthritis Rheum 22:127-138, 1992. 61. Harley JB, Alexander EL, Bias WB, et al: Anti-Ro (SS-A) and antiLa (SS-B) in patients with Sjögren’s syndrome. Arthritis Rheum 29: 196-206, 1986. 62. Nakken B, Jonsson R, Bolstad AI: Polymorphisms of the Ro52 gene associated with anti-Ro 52-kd autoantibodies in patients with primary Sjögren’s syndrome. Arthritis Rheum 44:638-646, 2001. 63. Haneji N, Nakamura T, Takio K, et al: Identification of α-fodrin as a candidate autoantigen in primary Sjogren’s syndrome. Science 276:604-607, 1997. 64. Kobayashi I, Kawamura N, Okano M, et al: Anti-α-fodrin autoantibody is an early diagnostic marker for childhood primary Sjogren’s syndrome. J Rheumatol 28:363-365, 2001. 65. Maeno N, Takei S, Imanaka H, et al: Anti-α-fodrin antibodies in Sjogren’s syndrome in children. J Rheumatol 28:860-864, 2001.

66. Kuwana M, Okano T, Ogawa Y, et al: Autoantibodies to the aminoterminal fragment of β-fodrin expressed in glandular epithelial cells in patients with Sjogren’s syndrome. J Immunol 167:5449-5456, 2001. 67. Yang CH, Lambie EJ, Snyder M: NuMA: An unusually long coiledcoil related protein in the mammalian nucleus. J Cell Biol 116: 1303-1317, 1992. 68. Goto N, Sugiura K, Ogawa Y, et al: Anti-p80 coilin autoantibodies react with a conserved epitope and are associated with anti-DFS70/ LEDGF autoantibodies. J Autoimmun 26:42-51, 2006. 69. Ramos-Casals M, Nardi N, Brito-Zeron P, et al: Atypical autoantibodies in patients with primary Sjogren syndrome: Clinical characteristics and follow-up of 82 cases. Semin Arthritis Rheum 35:312-321, 2006. 70. Smolen JS, Steiner G: Mixed connective tissue disease: To be or not to be? Arthritis Rheum 41:768-777, 1998. 71. Greidinger EL, Hoffman RW: Autoantibodies in the pathogenesis of mixed connective tissue disease. Rheum Dis Clin N Am 31:437-450, 2005. 72. Nimelstein SH, Brody S, McShane D, et al: Mixed connective tissue disease: A subsequent evaluation of the original 25 patients. Medicine 59:239-248, 1980. 73. van den Hoogen FH, Spronk PE, Boerbooms AM, et al: Long-term follow-up of 46 patients with anti-(U1)snRNP antibodies. Br J Rheumatol 33:1117-1120, 1994. 74. Spencer-Green G: Outcomes in primary Raynaud phenomenon: A meta-analysis of the frequency, rates, and predictors of transition to secondary diseases. Arch Intern Med 158:595-600, 1998. 75. Ravelli A, Felici E, Magni-Manzoni S, et al: Patients with antinuclear antibody-positive juvenile idiopathic arthritis constitute a homogeneous subgroup irrespective of the course of joint disease. Arthritis Rheum 52:826-832, 2005. 76. Petri M: Diagnosis of antiphospholipid antibodies. Rheum Dis Clin N Am 20:443-469, 1994. 77. Ganapathy V, Casiano CA: Autoimmunity to the nuclear autoantigen DFS70 (LEDGF): What exactly are the autoantibodies trying to tell us? Arthritis Rheum 50:684-688, 2004. 78. Thomson KF, Murphy A, Goodfield MJ, et al: Is it useful to test for antibodies to extractable nuclear antigens in the presence of a negative antinuclear antibody on Hep-2 cells? J Clin Pathol 54:413, 2001. 79. Arbuckle MR, McClain MT, Rubertone MV, et al: Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 349:1526-1533, 2003. 80. Faria AC, Barcellos KS, Andrade LE: Longitudinal fluctuation of antibodies to extractable nuclear antigens in systemic lupus erythematosus. J Rheumatol 32:1267-1272, 2005. 81. Illei GG, Klippel JH: Why is the ANA result positive? Bull Rheum Dis 48:1-4, 1999. 82. O’Brien CA, Wolin SL: A possible role for the 60-kD Ro autoantigen in a discard pathway for defective 5S rRNA precursors. Genes Dev 8:2891-2903, 1994. 83. Gelpi C, Sontheimer EJ, Rodriguez-Sanchez JL: Autoantibodies against a serine tRNA-protein complex implicated in cotranslational selenocysteine insertion. Proc Natl Acad Sci U S A 89:9739-9743, 1992.

51

Key Points Rheumatoid factors (RFs) are autoantibodies that bind to the Fc portion of Ig. Low-affinity RF can be present in health and may be part of the normal immune response. The presence of more than one RF isotype is highly specific for rheumatoid arthritis (RA). IgA and IgG RFs are associated with systemic manifestations, such as vasculitis. Anticitrullinated protein (anti-CCP) binds to modified arginine residues that are reconverted to citrulline. Anti-CP antibodies are proposed to have greater diagnostic utility in early RA. Anti-CP-positive patients who are RF seronegative have increased radiographic progression and poorer functional outcomes.

Rheumatoid Factors and Other Autoantibodies in Rheumatoid Arthritis Carl S. Goodyear  •  Helen Tighe  •  Iain B. McInnes

greater specificity for RA. These antibodies recognize the enzymatic post-translational modification of arginine to citrulline (Fig. 51-2), and this modification is found in numerous proteins, including filaggrin,8 vimentin,9 α and β fibrin,10 α-enolase,11 and peptides of collagens I and II.12,13 This reactivity, albeit under a different guise, was first discovered in 1964 by the Dutch group of Nienhuis and Mandema,14 who described the reactivity of a serum factor against the antiperinuclear factor in RA patients. In 1979, Young and colleagues described reactivity of RA serum to keratin.14a These findings were finally clarified by Schellekens and colleagues,8 who illustrated that the epitopes seen by both of these RA-specific autoantibodies were arising from the citrullination of self-proteins.

DIAGNOSTIC TESTS FOR RHEUMATOID FACTOR AND ANTICITRULLINATED PEPTIDE AUTOANTIBODIES

Autoimmunity is a cardinal feature of rheumatoid arthritis (RA) best exemplified in the detection of high titers of plasma autoantibodies. The advent of B cell–targeting therapeutics has elevated further the potential role for autoantibody-producing B cell clones in disease pathogenesis. Although numerous specificities have been described, rheumatoid factor (RF) autoantibodies directed against antigenic determinants on the fragment crystallizable (Fc) portion of IgG molecules are best characterized (Fig. 51-1). The presence of RFs has been used for several decades, in concert with other clinical features, to diagnose RA. RFs are not uniquely expressed in RA—they can be present in normal individuals (particularly after antigenic challenge) and are elevated in some patients with a variety of other diseases, including other rheumatic diseases; viral infections; acute and chronic inflammatory diseases; and lymphoproliferative diseases, such as chronic lymphocytic leukemia, Waldenström’s macroglobulinemia, and mixed cryoglobulinemia.1-7 RFs associated with other diseases are frequently polyspecific, of lower affinity, and of the IgM isotype (Table 51-1). In recent years, anticitrullinated protein (anti-CP) autoantibodies have come to the forefront in diagnostic algorithms, although they have not yet replaced RFs in many routine clinical practices. In general terms, anti-CP ­autoantibodies have a similar sensitivity to RFs, but offer

The emergence of new biologic therapies (see Chapters 58 and 59) in recent years has changed the approach to treatment of RA and in particular has revised acceptable outcomes. Practitioners now are aiming at achieving remission, halting or healing destruction, reversing disability, and giving patients a normal life expectancy. To achieve these aims, it is necessary to predict disease course better, in particular, to identify aggressive disease prone to rapid erosive progression with attendant irreversible loss of disability. Similarly, biomarkers that can predict response to therapy are urgently needed. In clinical practice, there are currently only two autoantibody biomarkers deemed to be of significant sensitivity (i.e., detect a high percentage of patients) and specificity (i.e., limited false-positive results) to be considered clinically useful in the diagnosis of RA—the RF and antiCP autoantibodies. Other autoantibodies remain under investigation. Although it was shown previously that autoantibodies specific for the immunoglobulin-binding protein (BiP) may provide sufficient sensitivity and specificity,15 no clinical test is routinely available or validated for widespread use. RHEUMATOID FACTOR The detection of RF, usually in patient serum, is by the agglutination of sensitized sheep cells, by IgG-coated particles (latex beads or tanned erythrocytes), or by more 755

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H+3N +H3N

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Rheumatoid Factors and Other Autoantibodies in Rheumatoid Arthritis

Fab

Fc

H

Vκ

VH

R

C

N

CH23

Cκ CH3

CH2

CH1

H Chain

R

R

C

+H

C 2N

Arginine

Pepsin Papain

R

C

CH23 NH3

PAD

NH3

C

N

H2O

NH3

COOCOO-

O

H

O

NH3

C

H2N

O

Citrulline (deiminated arginine)

Figure 51-2  The deimination of arginine to citrulline. The peptidylarginine deiminase (PAD) enzymes deiminate the arginine residues in numerous proteins resulting in citrulline residues that are implicated in the pathogenesis of rheumatoid arthritis. (Modified from Molberg O, Sollid LM: A gut feeling for joint inflammation—using coeliac disease to understand rheumatoid arthritis. Trends Immunol 27:188-194, 2006.)

+H3N +H3N Figure 51-1  Structure of an IgG molecule of the G1 subclass containing κ light chains. The antigens reacting with rheumatoid factor are in the fragment crystallizable (Fc) region.

Table 51-1  Comparison of Rheumatoid Factors   of IgM and IgG Classes Property

IgM Rheumatoid Factor

IgG Rheumatoid Factor

Effective valence for IgG

5

2

Intrinsic affinity for   antigen (L/mol)

104-106

104-106

Agglutination of   IgG-­coated latex   particles

Strong

Weak

Enhanced binding to   ­aggregated IgG

Marked

Moderate

Usual ­sedimentation   ­constants in ­  ultracentrifuge

19S-22S

10S-18S

Self-association

No

Yes

Binding to IgG after ­  treatment with   reducing agents

Decreased

Unchanged

Binding to IgG after ­  treatment with   pepsin

Decreased

Unchanged or increased

q­ uantitative assays that measure either formation of ­complexes between RF and IgG by nephelometry or the capture of RF on IgG-coated plastic wells using enzymelinked immunosorbent assay (ELISA). In the case of the agglutination method, the reported value is simply the dilution of test serum that can cause agglutination (normal values generally are <1:80 titer), whereas nephelometry and ELISA are usually reported in international standard units using standardized reagents. ELISA has the added advantage of being able to discriminate between IgM, IgG, and IgA RFs. Normal ranges are provided by individual laboratories and should not be generalized.

ANTI–CYCLIC CITRULLINATED PEPTIDE ­ENZYME-LINKED IMMUNOSORBENT ASSAY The presence of anti-CP autoantibodies is determined via an ELISA that detects reactivity to cyclic citrullinated peptides (CCPs). The initial clinical test was based on the reactivity to a citrullinated filaggrin-based cyclic peptide because it was found that cyclization of the citrullinated peptide more closely emulated the natural conformational epitopes, increasing the performance of the assay.16 This test has now been replaced by a better performing second-generation assay,17 CCP2 ELISA, which uses proprietary (undisclosed) citrullinated peptides that were derived from screening a large library of citrullinated peptides. These anti-CCP assays use a standardized set of reagents to generate a standard unit of reactivity. More recently, a third-­generation antiCCP3 ELISA has been developed. Although the sensitivity for the diagnosis of RA seems to be increased, it has been shown more recently that specificity is decreased owing to reactivity in patients with calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia (CREST) syndrome.18

INCIDENCE RHEUMATOID FACTOR The exact incidence of RF in a population depends on the assay system used and the titer chosen to separate positive and negative reactors. Table 51-2 is a partial list of diseases in which an increased incidence of RF has been reported. The titer of RF in a population, whether measured by the sensitized sheep cell agglutination test or by latex fixation, usually behaves as a continuous variable, but differs among various ethnic groups.2,3,19 With increasing age, the percentage of individuals with a particular titer and the mean titer of a population as a whole increase.20 Some studies have shown that the prevalence of RFs and other autoantibodies in the general population tends to decline beyond the age of 70 to 80 years.19 This decrease may be related to an increased mortality among autoantibody-positive individuals.

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Table 51-2  Diseases Commonly Associated   with ­Rheumatoid Factor Rheumatic diseases

Rheumatoid arthritis, ­systemic   lupus erythematosus, ­  scleroderma, mixed ­connective   tissue disease, Sjögren’s   syndrome

Viral infections

Acquired immunodeficiency ­syndrome, mononucleosis,   hepatitis, influenza; after   vaccination (may yield falsely   elevated titers of antiviral ­antibodies)

Parasitic infections

Trypanosomiasis, kala-azar,   ­malaria, schistosomiasis,   filariasis

Chronic bacterial   infections

Tuberculosis, leprosy, yaws, ­  syphilis, brucellosis, sub­­­­acute   bacterial endocarditis, ­salmonellosis

Neoplasms

Lymphoproliferative diseases

Other hyperglobulinemic   states

Hypergammaglobulinemic   ­purpura, cryoglobulinemia,   chronic liver disease, sarcoidosis, other chronic pulmonary   diseases

In most, but not all, nonrheumatic conditions, titers of RF are lower than in RA. The specificity of the RF reaction for RA increases with serum titer.3 At a dilution of serum at which 95% of the normal population would be RF negative, 70% of patients with RA (as diagnosed by other criteria) assay RF positive by latex agglutination. This number increases to 90% when the more sensitive ELISA is used.21 The remaining patients are considered seronegative (i.e., having RF titers falling within the normal range). Some of the latter sera, particularly from patients with juvenile RA, may contain hidden IgM RFs,19,22,23 which are IgM RFs whose detection is masked by nonspecifically aggregated IgG in improperly treated sera or specific immune complexes. A few have IgG RFs in the absence of IgM. Some seronegative patients, on repeated testing, convert to seropositivity, perhaps reflecting pathogenetic disease progession. Although high titers of RF are generally associated with RA, elevation of more than one RF isotype, particularly in the joint, is considered highly specific for RA and is rarely found in other rheumatic diseases.21 High levels of serum RF are associated with a worse prognosis in RA.23 IgG RFs are abundant in the sera, and particularly the synovial fluids, of many patients with severe RA.24-26 The presence of IgA RFs in RA patients is associated with rapidly progressive, more severe disease and bone erosion, and IgG and IgA RFs are associated with systemic manifestations such as vasculitis.20,27-30 The presence of IgE RF, as measured by ELISA, also correlates with extra-articular manifestations in RA patients.20,21,31 In general, the specificity of RF for the diagnosis of RA is increased by showing a positive RF test on two or more consecutive occasions, by high titer, by reactivity with human and rabbit IgG, and by association with IgM, IgG, and IgA isotypes. Serial measurements of IgM RF modestly correlate with disease activity, but they are far less useful

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than ­ erythrocyte sedimentation rate or measurement of C-reactive protein in this respect.32 Increasingly, composite measures of disease activity (e.g., DAS28) fulfill this role in practice. Asymptomatic individuals with persistently elevated RFs have greatly increased risk of developing RA, suggesting that dysregulation of RF production is a predisposing factor in the development of RA.33 Although elevated expression of RF may have significant effects on immune regulation through the production of immune complexes and complement activation, its absence in patients with seronegative RA argues against it being a causative, or at least nonredundant, factor in joint disease. This argument is also supported by the finding of elevated RF titers in other diseases, such as congenital human immunodeficiency virus infection, in which the infected children do not manifest clinical rheumatic disease despite the presence of high levels of circulating IgA RF in 50% of cases.6 ANTICITRULLINATED PROTEIN In a concise review of the diagnostic and predictive literature by Avouac and coworkers,34 of 107 studies identified, 68 were analyzed further (58 for the diagnostic and 14 for the predictive ability of anti-CP autoantibodies). Depending on the generation of test used, the sensitivity ranged from 53% ± 10% (anti-CCP1) to 68% ± 15% (anti-CCP2), and the specificity ranged from 96% ± 3% (anti-CCP1) to 95% ± 5% (anti-CCP2). In the same series of studies, the RF values also were evaluated revealing a sensitivity of 60% ± 18% and a specificity of 79% ± 15%, illustrating that the second generation of the anti-CCP ELISA has comparable sensitivity to that of RF, but potentially offers a much higher specificity for RA. The predictive ability of anti-CP autoantibodies in patients with early undifferentiated arthritis gave an odds ratio of 20 (95% confidence interval 14 to 31) for anti-CCP1 and 25 (95% confidence interval 18 to 35) for anti-CCP2, whereas for healthy subjects the odds ratio was 64.5 (95% confidence interval 8.5 to 489) for anti-CCP1 and 28 (95% confidence interval 8 to 95) for anti-CCP2. In several subsequent studies, it has been proposed that antiCP antibodies are of greater diagnostic utility in early RA than any other single biomarker.35-37 The combination of anti-CP antibodies and RF may provide a better indication of the subsequent course of disease. It is debated at this time, however, as to whether anti-CP should replace RF altogether in routine clinical practice. In terms of disease severity and erosive potential, antiCP antibodies (and their titer) are associated with erosive and deforming disease in established RA patients38 and patients who had autoantibodies before39 or at disease onset.40 Patients who at disease presentation, or with established disease, were seronegative for RF, but were anti-CP positive have an increased radiographic progression and poorer functional outcomes.41 Conversely, patients who present with anti-CP reactivity alone have less association with extra-articular disease compared with RF; this might indicate that patients who have anti-CP and RF are more likely to have extra-articular disease.42 The incidence of anti-CP antibodies in other rheumatic diseases, as indicated by the specificity, is minimal34 with the most being seen in palindromic rheumatism (44%).43

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BIOCHEMICAL AND IMMUNOCHEMICAL PROPERTIES RHEUMATOID ANTIGEN SPECIFICITY Numerous studies have analyzed the fine antigen specificity of RFs derived from patients with RA and compared them with RFs from normal immunized volunteers and with monoclonal IgM RFs from patients with Waldenström’s macroglobulinemia. Specificities for the IgG1, IgG2, and IgG4 subclasses (termed the Ga specificity) were associated with RFs derived from all sources, whereas RFs from RA patients were relatively enriched for reactivity with IgG3.7,44 RFs derived from rheumatoid synovial membrane exhibit higher binding activity with IgG3 than serum RFs, which mainly react with IgG1, IgG2, and IgG4 subclasses.28 Consequently, the IgG3 binding specificity of RFs seems to be disease associated. The antigenic determinant recognized by IgM RFs seems to be primarily localized to the Fc portion of the IgG molecule in the CH2 and CH3 domains (see Fig. 51-1).44-46 Analysis of the crystal structure of a complex of a human RA synovial RF with the Fc portion of IgG confirms contacts with the CH2/CH3 cleft. This study also shows that the ratio of Fab to Fc fragments within the crystal is 2:1, implying that monomeric IgG can cross-link two RF molecules.47,48 A crystallographic study of a higher affinity IgM RF revealed, however, that this somatically mutated antibody bound to the CH3/CH3 C-terminal interface through five of the six complementarity determining regions, providing evidence that alternative sites can be recognized by RF, and that they do undergo affinity maturation.49 ANTICITRULLINATED PROTEIN ANTIGEN SPECIFICTY Compared with the extensive volume of information concerning the biochemical properties of RF, the anti-CP literature is in its infancy. Although various studies have looked at the polyclonal response to citrullinated proteins,8-14 there are no data as yet elucidating fine specificity. One study has investigated the antibody response using recombinant phage display50 and in essence the reactivity of monoclonal antibodies. This technique does not lend itself, however, to the analysis of the in vivo variable heavy chain (VH) and variable light chain (VL) pairing (see Fig. 51-1). It nevertheless provides an insight into the overall VH usage and a glimpse of the in vivo repertoire. Among several RA patients, there was restriction of the VH gene usage in anti-CP antibodies, which implied some altered immune response perhaps attributable to some type of genetic predisposition. Further studies need to be done to understand the immune response to citrullinated proteins, and how the autoantibodies interact with target proteins.

RELATIONSHIP TO PATHOGENESIS AND DISEASE EVOLUTION It has been known for some time that autoantibodies of specific reactivity, such as RF and more recently anti-CP, can be found in patients before disease onset. It is unclear,

however, why the presence of these autoantibodies does not cause overt clinical disease. By ­implication, the transition factors that lead to the eventual clinical emergence of detectable RA (i.e., synovitis and attendant diagnostic clinical sequelae) may be distinct from the factors that predispose to initial breach of self-tolerance and development of self-reactive antibody responses. We still must answer several questions: Why is there a period of time in which no disease is observed? Are these autoreactive antibodies an epiphenomenon signaling some other crucial alteration in self-tolerance maintenance? Are IgM RF (and possibly IgM anti-CP) natural antibodies that provide housekeeping functions that can help prime and regulate the immune response to foreign antigens? Why does isotype switching and somatic mutation of RFs occur in RA? Are the RF or anti-CP antibodies truly pathogenic? Does the alteration in RF isotype subsequently lead to the production of other autoreactive antibodies as a result of some form of epitope spreading? How is autoantibody formation regulated by and dependent on subtle factors in the genome and subsequent gene environmental interactions, such as smoking, which are increasingly recognized? RHEUMATOID FACTOR IN HEALTH AND NONRHEUMATOLOGIC DISEASE To understand why autoantibodies might be associated with the evolution of disease, we first must focus on the presence of autoantibodies in health and nonrheumatologic disease states. In individuals, it is common to observe low-affinity RFs,51,52 which are generally polyreactive with a wide variety of self-antigens and exogenous antigens.51-56 The IgM RFs are thought to have several physiologic functions in health (Table 51-3). It has been proposed that there are at least three potential triggers for the activation and generation of these RFs: (1) antigen-antibody complexes forming during the secondary phase (recall) of an immune response,57-59 (2) polyclonal B cell activation,60,61 and (3) chronic viral infection.62-64 When generated, RFs and their source B cells may play roles throughout the generation and regulation of a given immune response. RF-producing B cells may provide multifaceted functions, including in particular the ability to act as efficient antigen-presenting cells,65 whereas soluble RFs likely can enhance the clearance of immune complexes.66 In an attempt to put these functions in some mechanistic context, studies have shown that after secondary immunization or infection, there is an increase in the production of IgM RFs. The activation of RF B cells and subsequent IgM RF production depends on the presence of immune­complexed antigen and T cells specific for the antigen present in the immune complex.57,58,67,68  able 51-3  Physiologic Functions of IgM   T Rheumatoid Factor Cell-associated rheumatoid   factor

Antigen processing and   presentation

Secreted rheumatoid factor

Stabilization of low-affinity IgG antigen complexes Immune complex clearance Enhancement of opsonization

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RF production in normal individuals, in contrast to RA patients, is transient and efficiently regulated with no evidence of affinity maturation.69,70 The transient nature of the RF is best exemplified by studies of subacute bacterial endocarditis, in which elimination of bacteria by antibiotics leads to a subsequent decline in RF titers.71,72 These data imply that, under normal circumstances, there are efficient peripheral mechanisms that provide tight regulation of higher affinity, potentially pathologic RFs. It is likely that early in a secondary immune response, when very small amounts of antigen are available, most of the antigen arrives in the draining lymph nodes in the form of an immune complex. Low levels of immune-complexed antigen may not bind efficiently to conventional antigen-presenting cells. The interaction of IgG with Fc receptors on B cells may inhibit antigen presentation.73 Under these circumstances, IgM RF–expressing B cells may act as highly efficient antigen-presenting cells for immunecomplexed antigen, stimulating and amplifying antipathogen responses.65 This unique method of antigen presentation enhances the antigen-specific T cell expansion early in a secondary immune response. This non–B cell receptor–specific antigenic presentation by the RF B cell is not just a one-way signal, and it is feasible that the activated T cell would provide secondary signals to the already B cell receptor–stimulated B cells, which results in further activation, expansion, differentiation and potentially somatic mutation, and affinity maturation of the RF B cell immunoglobulin receptor such that it may now be able to bind soluble and immune-complexed IgG. When the infection is cleared, T cell helper and other B cell survival signals, such as B lymphocyte stimulator (BLyS), are limited, and high-affinity, disease-associated RF B cells that are now receiving B cell receptor signals, possibly by the engagement of soluble IgG, are deleted by Fas/Fas ligand–independent mechanisms.74-77 This deletion would leave only RF B cell clones whose somatic mutations have not resulted in substantially increased affinities, accounting for the type of RFs detected in healthy immunized donors.69,70 Many of these checks and balances may be perturbed in RA—we address how they may modulate disease initiation and progression in the next section. RHEUMATOID FACTOR IN RHEUMATOID ARTHRITIS The roles that RF B cells, and their product, the soluble RFs, play in the pathogenesis of RA are poorly understood. It is hypothesized that they contribute through their role either in the afferent arm of immune synovitis functioning as antigen-presenting cells65,78 or in the efferent arm of the response (e.g., by synthesizing inflammatory cytokines directly or via pathogenic antibody-dependent pathways). As efficient antigen-presenting cells, RF B lymphocytes may increase the chance of T cell autosensitization to self­components that are released from damaged articular tissues, such as collagen, proteoglycans, and heat shock ­ proteins. In this way, the abnormal accumulation of activated RF B cells at synovial sites could create a vicious cycle that promotes T cell–dependent joint inflammation through a variety of mechanisms. Secreted RFs can play a role in the efferent arm of immune synovitis by complement fixation and through cytokine induction (e.g., tumor necrosis

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factor-α or interleukin-6) via IgG RF complexes binding to Fc receptors (FcγRIIIa) on macrophages, mast cells, and even other B cells.79 To get to a point where RFs can perform some of these functions, there presumably has to be a transition of non– RA-associated RF to the pathogenic RA-associated RF— why this occurs is not understood. Data indicate that RFs in RA have undergone antigen-induced expansion and affinity maturation, together with recruitment of new clones of B cells. Studies of IgG RFs derived from RA patients support this conclusion. Some IgG RFs use the same V genes as IgM RFs, but exhibit a much greater degree of somatic mutation than IgM RFs, indicating a further affinity maturation of the autoantibody response.80,81 Sequencing of synovial RFs indicates that class switching and subsequent somatic mutation occur within the synovium, supporting the view that synovial tissue becomes a type of secondary lymphoid tissue containing germinal center–like lymphoid aggregates.82 Consequently, the synovium becomes a major source of the RFs, which appear in copious amounts in the circulation of RA patients, although lymphoid tissues such as bone marrow also produce the autoantibody.83 How do the “asymptomatic” autoantibodies convert to pathogenic autoantibodies? To propose a linear mechanism for this conversion is probably naive—however, for exemplary purposes, let us propose that an environmental trigger (i.e., an infection) or some random intrinsic process or both occur in an otherwise healthy subject with some form of genetic predisposition (e.g., HLA class II, stat4, ptpn22 polymorphisms associated with RA) and who has low-affinity IgM- RF a priori or generated early within this infectious event. The immune response to infection (as discussed earlier) would result in antibodies to foreign antigens and the generation of immune complexes. These complexes would be bound by the low-affinity IgM RF B cells allowing the uptake and processing of the nonself antigens and the subsequent presentation to nonautoreactive T cells, allowing the already B cell receptor–stimulated RF B cells mistakenly to receive T cell help (Fig. 51-3).65 This T cell help would result in the further activation, differentiation, and affinity maturation of the RF B cells. Infections also are associated with numerous innate activators, such as the Toll-like receptor (TLR) ligands (e.g., bacterial DNA and proteoglycans) and intracellular nucleotide­binding oligomerization domains (NOD) ligands (e.g., muramyl dipeptide (MBP). In parallel, or independently of the T cell phenomenon, the generation of immune complexes that contain RF, TLR ligands, and other immunoglobulins of varying specificity could lead to the activation of complement and the recruitment of inflammatory cells into the inflamed tissue. Such complement activation undoubtedly contributes to joint inflammation, and there is evidence for selective enrichment of high-affinity RF clones in the synovium.84 The RF B cells also have the ability to interact directly with immune complexes containing TLR ligands, providing a B cell receptor and TLR signal to the RF B cell promoting longer term breach of self-tolerance. Intriguing data suggest that this interaction can occur in certain settings. RF B cells can be activated to proliferate by dual engagement of surface immunoglobulin and TLRs by IgG-chromatin immune complexes providing an alternative pathway for RF B cell expansion.85-87 TLR9 primarily recognizes unmethylated

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T cell RF B cell

T cell

Activation, differentiation and affinity maturation Figure 51-3  Model of the generation of pathogenic rheumatoid factor (RF) and anticitrulline antibodies via the presentation of foreign antigen or citrullinated epitopes in rheumatoid arthritis. In the rheumatoid synovium, bacterial products (blue) taken up by antigen-presenting cells (APC) (green) can be presented to specific T cells leading to their activation. In parallel, immune complexes of bacterial products can interact with RF B cells and be processed for their presentation to specific T cells. This  ultimately results in the RF B cells receiving cognate help that allows their further activation, differentiation, and affinity maturation. The RF B cells also are able to interact with immune complexes containing citrullinated proteins. These HLA-DR4+ RF B cells present the citrullinated peptides to DR4-restricted citrulline-specific T cells resulting in their activation. The initial generation of these citrulline-specific T cells is due to the deimination of native proteins (white) by peptidylarginine deiminase (PAD) enzymes and the resulting citrullinated proteins or peptide fragments (orange) being presented by APCs. This allows the expansion of anti­ci­trulline B cells (anti-CP) through further uptake and presentation of antigen and cognate T cell help. (Modified from Molberg O, Sollid LM: A gut feeling for joint inflammation—using coeliac disease to understand rheumatoid arthritis. Trends Immunol 27:188-194, 2006.) Anti-CP B cell

cyotsine guanine dinucleotide (CpG) motifs common in pathogen DNA,88 but these motifs also can occur in certain regions of mammalian DNA. More recently, a study has shown that RF can bind directly to B cell stimulatory CpG, and that hypomethylated mitochondrial DNA is capable of activating RF B cells.89 Consequently, the need for T cell help is bypassed and substituted for by stimulation of TLR9 and simultaneous activation of surface RF by IgG-DNA complexes or even DNA alone. These data may provide an explanation for the production of non–RAassociated RF during acute bacterial infections,71,72 but would this be enough to overcome all of the control mechanisms that suppress the production of pathogenic RF? Studies of transgenic mice expressing high-affinity RFs have shown that an encounter with soluble IgG results in deletion of the autoreactive B cell in the absence of T cell help.74-77 In the presence of alloimmune-specific T cell help, high-affinity RF B cells differentiate and secrete RF in response to soluble IgG and do not require immunecomplexed antigen.75 The presence of two binding sites for RF on the Fc portion of IgG is presumably sufficient to crosslink surface RF.48 Consequently, it is interesting that RA patients were reported several years ago to have T cells responsive to autologous macrophages and other antigenpresenting cells.90-92 Potentially, this weak T cell responsiveness may be sufficient to promote RF B cell survival within the environment of the rheumatoid joint, where adhesion molecules are abundant, and accumulation and ectopic aggregation of cells delays migration.

In the confined environment of the rheumatoid joint, the relative proportion of complexed to soluble IgG is increased. In this situation, T cell help may be supplied by a localized, weak graft-versus-host reaction. Alternatively, it has been shown in several studies that B cell survival factors, such as BLyS and APRIL, are upregulated in the sera and synovial fluid of RA patients.93,94 Consequently, it has been shown that autoreactive B cells are more dependent on survival signals such as BLyS. Compared with the healthy environment where BLyS might be a limiting fact, if enough survival factor is present, it potentially can overcome the intrinsic death signal that disseminates from the B cell receptor through the Bcl-2 family member Bim,95 which ultimately would lead to the death of the autoreactive B cells. The inflamed rheumatoid synovium contains all the prerequisites for sustained RF synthesis, and it is not surprising that RF synthesis primarily occurs within the joints. Although not solely responsible for causing disease, RFs exacerbate joint inflammation and promote immune dysregulation through a variety of mechanisms. This finding is commensurate with emerging clinical data showing the beneficial effects of B cell depletion and of preferential reduction in circulating RF titers in responding patients (see Chapter 59). ANTICITRULLINATED PROTEIN IN RHEUMATOID ARTHRITIS The events leading to the evolution of the anti-CP reactive antibodies that are observed in RA are currently unclear. Various genetic and environmental associations have been made with the anti-CP antibodies, which include the shared epitope (HLA-DR4), polymorphisms in the PADI-4 and PTPN22 genes (see Chapter 18),96-100 and smoking,40,101,102 but whether or not these are involved in the actual generation of these antibodies is undetermined. The generation of the reactive epitope in various proteins, such as filaggrin,8 fibrin,10 and vimentin,9 is by the deimination of the arginine to the atypical citrulline residue (see Fig. 51-2). This enzymatic modification is catalyzed by one (or more) of the four known mammalian isoforms of the peptidylarginine deiminase enzymes.103 Smoking has been shown to give rise to the presence of citrullinated peptides in bronchoalveolar lavage fluid102 and to increase the expression of PADI-2 and potentially to increase the presence of citrullinated peptides, which in all likelihood can be presented by the shared epi­ tope to the immune repertoire. More recent studies have shown that citrulline residues are present in the lungs104 and the synovium.105 Whether or not this has any relevance to the production of anti-CP antibodies has not been determined, but it has been shown that the presence of citrullinated proteins in the synovial fluid is not specific for RA.106 A potential mechanism (see Fig. 51-3) for the generation of the anti-CP antibodies could entail the peptidylarginine deiminase–mediated deimination of various proteins in the lung or synovium. These proteins could be taken up by specialized antigen-presenting cells or by RF B cells in the form of immune complexes, leading to presentation of citrullinated peptides to T cells, which provide cognate help to anti-CP reactive B cells. New insights in the collagen-induced arthritis mouse model provide a novel perspective to the mechanism for the

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induction of anti-CP antibodies. The first surprising finding was that before any manipulation, DBA/1 mice (the most susceptible in bred mouse strains for induction of type II collagen–induced arthritis) had IgM anti-CP antibodies,107 suggesting that these antibodies, similar to the IgM RF, could emerge from a natural antibody pool that may have some housekeeping function. The immunization of these mice with collagen type II resulted in the emergence of IgG anti-CP antibodies that were shown to have pathogenic capabilities such that they could increase the severity of collagen antibody-induced arthritis.107 With these data and the work of Koivula and colleagues,12 which shows the presence of autoantibodies to citrullinated telopeptides of type II collagen in RA patients, one can generate a hypothesis to explain how these events are promoted. It is feasible that in collagen-induced arthritis, anti–collagen-specific B cells interact with citrullinated collagen and are able to present these peptides to T cells, which can provide cognate help to anti-CP B cells. By this means, a positive feedback loop is created that overwhelms normal T and B cell regulatory loops, leading to persistence. Future studies that explore this and related possibilities should prove insightful to RA disease pathogenesis.

OTHER AUTOANTIBODIES IN RHEUMATOID ARTHRITIS The search for autoantibodies with new reactivities, in various autoimmune diseases, is ongoing. New techniques are constantly being employed to discover and analyze the antibodies, such as recombinant phage display108 and antigen microarrays.109 This section provides examples of some of the reactivities that have been investigated in relation to RA. Generally, all of the listed antigen reactivities require further studies to assess their utility as diagnostic and prognostic biomarkers for RA. These studies may be more informative in elucidating mechanisms subserving breach of tolerance in disease progression. IMMUNOGLOBULIN BINDING PROTEIN BiP is an endoplasmic reticulum chaperone and stress protein belonging to the Hsp70 family. The anti-BiP reactivity initially was shown in experimental arthritis, where BiP itself could tolerize effector responses in the model110,111; this was followed up by studies showing that anti-BiP antibodies were present in RA patient sera. In established RA, the specificity is 71% with a sensitivity of 73%, whereas in early RA the specificity is 65%, and the sensitivity is 66%.15 Apart from being a target for autoantibodies, BiP itself has immunomodulatory properties—it can stimulate human CD4 and CD8 T cells and monocytes to produce interleukin-10.112,113 Current data suggest that the dual functions in the induction (immunomodulatory) and maintenance (autoantigen) of RA might make BiP a good candidate for immunotherapy. GLUCOSE-6-PHOSPHATE ISOMERASE The initial observation of anti–glucose-6-phosphate isomerase (GPI) reactivity came from the K/BxN mouse model (see Chapter 25), in which T cell receptor transgenic mice

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(KRN) crossed onto the NOD background spontaneously developed an inflammatory arthritis associated with the development of anti-GPI antibodies.114 The passive transfer of these autoreactive antibodies confers disease.114 The relevance of the anti-GPI reactivity in human RA is controversial, however. Schaller and associates115 showed the presence of anti-GPI antibodies in the serum of 64% of RA patients,115 with increased soluble GPI in the sera and synovial fluid of RA patients. They also were able to detect the presence of anti-GPI/GPI immune complexes.115,116 In other cohorts, these data have not been reproduced, such that reactivity to GPI has been seen only in a few cases of RA.117,118 In the Japanese population, it was shown that only 12% of RA patients were positive for anti-GPI reactivity; anti-GPI antibodies also were found in 8% of patients with systemic lupus erythematosus and 4% of healthy controls.119 Follow-up studies indicate that anti-GPI antibodies are present in the synovial fluid of RA patients.120,121 To investigate the pathogenic potential of the anti-GPI antibodies, patient sera positive for GPI were fractionated, and the IgG anti-GPI antibodies were injected into the metacarpophalangeal joints of macaques. Sixteen days after injection, the joints were examined, and synovitis was observed.122 These data, together with the extensive and elegant studies of the group of Mathis and Benoist in the above-noted rodent K/ BxN model,114 suggest that anti-GPI antibodies, if present in a subset of patients, could have a pathogenic role in RA. TYPE II COLLAGEN Collagen-induced arthritis and collagen antibody–induced arthritis mouse models are well established for the investigation of murine arthritis.123 The reactivity of antibodies to type II collagen in humans is an insensitive measure of RA (approximately 24% sensitivity); however, if the reactivity for the CB10 peptide is evaluated in the same sera, the sensitivity for RA is increased to approximately 88%.124 The work by Koivula and colleagues12 also has shown that autoantibodies to citrullinated telopeptides of type II collagen are present in RA patients. Further studies are required to explore the potential role of collagen-reactive autoantibodies because the antigen is abundant in the articular environment, and it represents a plausible cartilage-derived disease target. MANNOSE-BINDING LECTIN In the Indian population, it has been shown that a polymorphism of a mannose-binding lectin (MBL2) is associated with susceptibility and progression of RA.125 MBL has a significant immune modulatory role in the inflammatory response to various autoimmune and infectious diseases.125,126 In preliminary studies to investigate the occurrence of anti-MBL antibodies in RA, Gupta and coworkers126 observed a reactivity to MBL in approximately 61% of RA patients compared with approximately 1.7% of healthy subjects. Further studies are needed to evaluate the diagnostic utility of this reactivity and its ability to predict the onset and severity of RA. Similarly, such antibodies may have a pathogenic role based on the modulation of the immune regulatory function of MBL itself.

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FERRITIN In an attempt to identify novel antigens, Mewar and colleagues108 screened phage-display complementary DNA libraries with IgG obtained from patients with early RA. They detected reactivity to the ferritin heavy chain. The reactivity was observed in 16% of established RA patients and 19% of early RA patients, with about 2% seen in healthy subjects or osteoarthritis and systemic lupus erythematosus patients. This reactivity also was associated with increased joint damage over time. Further studies are needed to determine the diagnostic and prognostic utility of this reactivity in RA. RA 33 The autoantibody reactivity defined as anti–RA 33 is to a component of the splicosome—the heterogeneous ribonucleoprotein complex 33-kD A2 protein. This autoantibody is not specific for RA and can be found in mixed connective tissue disease and systemic lupus erythematosus.127 The reactivity in sera has no predictive value for disease severity or progression. The anti–RA 33 antibodies can be found in the tumor necrosis factor–transgenic mice that develop spontaneous arthritis,128 however, implicating them perhaps in effector pathogenetic mechanisms in a nonspecific manner.

CONCLUSION B cell depletion in RA has refocused interest on the utility of autoantibodies not only as diagnostic and prognostic biomarkers, but also as effector pathways in the disease. New technologies will allow progressively more detailed information to emerge concerning the precise specificity of the B cell response in RA, and with this should come improved understanding of their pathogenic role. This improved understanding of pathogenesis should lead to newer, more specific therapies that need not rely on depletion of large parts of the B cell compartment. New autospecificities are likely to emerge that will refine further the identification of RA disease subsets that, it is hoped, would be amenable to remission induction therapeutics. It is salutary, however, that the autoantibody discovered half a century before— RF—remains such a useful and clinically dominant tool in current practice and theories of disease pathogenesis. REFERENCES   1. Kunkel HG, Simon HJ, Fudenberg H: Observations concerning positive serologic reactions for rheumatoid factor in certain patients with sarcoidosis and other hyperglobulinemic states. Arthritis Rheum 1:289-296, 1958.   2. Mikkelsen WM, Dodge HJ, Duff IF, et al: Estimates of the prevalence of rheumatic diseases in the population of Tecumseh, Michigan, 1959-60. J Chron Dis 20:351-369, 1967.   3. Lawrance JS: Rheumatism in Populations. London, William Heinemann, 1977.   4. Procaccia S, Lazzarin A, Colucci A, et al: IgM, IgG and IgA rheumatoid factors and circulating immune complexes in patients with AIDS and AIDS-related complex with serological abnormalities. Clin Exp Immunol 67:236-244, 1987.

  5. Jarvis JN, Taylor H, Iobidze M, et al: Rheumatoid factor expression and complement activation in children congenitally infected with human immunodeficiency virus. Clin Immunol Immunopathol 67:50-54, 1993.   6. Chen PP, Carson DA: New insights on the physiological and pathological rheumatoid factors in humans. In Coutinho A, Kazatchkine M (eds): Autoimmunity: Physiology and Disease. New York: WileyLiss, 1994, pp 247-266.   7. Bonagura VR, Agostino N, Borretzen M, et al: Mapping IgG epitopes bound by rheumatoid factors from immunized controls identifies disease-specific rheumatoid factors produced by patients with rheumatoid arthritis. J Immunol 160:2496-2505, 1998.   8. Schellekens GA, de Jong BA, van den Hoogen FH, et al: Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest 101:273-281, 1998.   9. Menard HA, Lapointe E, Rochdi MD, et al: Insights into rheumatoid arthritis derived from the Sa immune system. Arthritis Res 2:429432, 2000. 10. Masson-Bessiere C, Sebbag M, Girbal-Neuhauser E, et al: The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the alpha- and beta-chains of fibrin. J Immunol 166:4177-4184, 2001. 11. Kinloch A, Tatzer V, Wait R, et al: Identification of citrullinated alpha-enolase as a candidate autoantigen in rheumatoid arthritis. Arthritis Res Ther 7:R1421-R1429, 2005. 12. Koivula MK, Heliovaara M, Ramberg J, et al: Autoantibodies binding to citrullinated telopeptide of type II collagen and to cyclic citrullinated peptides predict synergistically the development of seropositive rheumatoid arthritis. Ann Rheum Dis 66:1450-1455, 2007. 13. Koivula MK, Aman S, Karjalainen A, et al: Are there autoantibodies reacting against citrullinated peptides derived from type I and type II collagens in patients with rheumatoid arthritis? Ann Rheum Dis 64:1443-1450, 2005. 14. Nienhuis RL, Mandema E: A new serum factor in patients with ­rheumatoid arthritis: The antiperinuclear factor. Ann Rheum Dis 23:302-305, 1964. 14a. Young BJ, Mallya RK, Leslie RD, et al: Anti-keratin antibodies in rheumatoid arthritis. BMJ 2:97-99, 1979. 15. Bodman-Smith MD, Corrigall VM, Berglin E, et al: Antibody response to the human stress protein BiP in rheumatoid arthritis. Rheumatology (Oxf) 43:1283-1287, 2004. 16. Schellekens GA, Visser H, de Jong BA, et al: The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 43:155-163, 2000. 17. van Gaalen FA, Visser H, Huizinga TW: A comparison of the diagnostic accuracy and prognostic value of the first and second anticyclic citrullinated peptides (CCP1 and CCP2) autoantibody tests for rheumatoid arthritis. Ann Rheum Dis 64:1510-1512, 2005. 18. Wu R, Shovman O, Zhang Y, et al: Increased prevalence of antithird generation cyclic citrullinated peptide antibodies in patients with rheumatoid arthritis and CREST syndrome. Clin Rev Allergy Immunol 32:47-56, 2007. 19. Hooper B, Whittingham S, Mathews JD, et al: Autoimmunity in a rural community. Clin Exp Immunol 12:79-87, 1972. 20. Pai S, Pai L, Birkenfeldt R: Correlation of serum IgA rheumatoid factor levels with disease severity in rheumatoid arthritis. Scand J Rheumatol 27:252-256, 1998. 21. Jonsson T, Steinsson K, Jonsson H, et al: Combined elevation of IgM and IgA rheumatoid factor has high diagnostic specificity for rheumatoid arthritis. Rheumatol Int 18:119-122, 1998. 22. Nykanen M, Palosuo T, Aho K, et al: Improved immunoturbidimetric method for rheumatoid factor testing. J Clin Pathol 46:10651066, 1993. 23. Masi AT, Maldonado-Cocco JA, Kaplan SB, et al: Prospective study of the early course of rheumatoid arthritis in young adults: Comparison of patients with and without rheumatoid factor positivity at entry and identification of variables correlating with outcome. Semin Arthritis Rheum 4:299-326, 1976. 24. Winchester RJ, Kunkel HG, Agnello V: Occurrence of γ-globulin complexes in serum and joint fluid of rheumatoid arthritis patients: Use of monoclonal rheumatoid factors as reagents for their demonstration. J Exp Med 134:286s-295s, 1971.

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25. Winchester RJ, Agnello V, Kunkel HG: Gamma globulin complexes in synovial fluids of patients with rheumatoid arthritis: Partial characterization and relationship to lowered complement levels. Clin Exp Immunol 6:689-706, 1970. 26. Hannestad K: Presence of aggregated gamma-globulin in certain rheumatoid synovial effusions. Clin Exp Immunol 2:511-529, 1967. 27. Scott DG, Bacon PA, Allen C, et al: IgG rheumatoid factor, complement and immune complexes in rheumatoid synovitis and vasculitis: Comparative and serial studies during cytotoxic therapy. Clin Exp Immunol 43:54-63, 1981. 28. Houssien DA, Jonsson T, Davies E, et al: Rheumatoid factor isotypes, disease activity and the outcome of rheumatoid arthritis: Comparative effects of different antigens. Scand J Rheumatol 27:46-53, 1998. 29. Westedt ML, Herbrink P, Molenaar JL, et al: Rheumatoid factors in rheumatoid arthritis and vasculitis. Rheumatol Int 5: 209-214, 1985. 30. Arnason JA, Jonsson T, Brekkan A, et al: Relation between bone erosions and rheumatoid factor isotypes. Ann Rheum Dis 46: 380-384, 1987. 31. Gioud-Paquet M, Auvinet M, Raffin T, et al: IgM rheumatoid factor (RF), IgA RF, IgE RF, and IgG RF detected by ELISA in rheumatoid arthritis. Ann Rheum Dis 46:65-71, 1987. 32. Wolfe F: A comparison of IgM rheumatoid factor by nephelometry and latex methods: Clinical and laboratory significance. Arthritis Care Res 11:89-93, 1998. 33. Halldorsdottir HD, Jonsson T, Thorsteinsson J, et al: A prospective study on the incidence of rheumatoid arthritis among people with persistent increase of rheumatoid factor. Ann Rheum Dis 59:149151, 2000. 34. Avouac J, Gossec L, Dougados M: Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: A systematic literature review. Ann Rheum Dis 65:845-851, 2006. 35. Silveira IG, Burlingame RW, von Muhlen CA, et al: Anti-CCP antibodies have more diagnostic impact than rheumatoid factor (RF) in a population tested for RF. Clin Rheumatol 26:1883-1889, 2007. 36. Matsui T, Shimada K, Ozawa N, et al: Diagnostic utility of anticyclic citrullinated peptide antibodies for very early rheumatoid arthritis. J Rheumatol 33:2390-2397, 2006. 37. Kudo-Tanaka E, Ohshima S, Ishii M, et al: Autoantibodies to cyclic citrullinated peptide 2 (CCP2) are superior to other potential diagnostic biomarkers for predicting rheumatoid arthritis in early undifferentiated arthritis. Clin Rheumatol 26:1627-1633, 2007. 38. Agrawal S, Misra R, Aggarwal A: Autoantibodies in rheumatoid arthritis: Association with severity of disease in established RA. Clin Rheumatol 26:201-204, 2007. 39. Berglin E, Johansson T, Sundin U, et al: Radiological outcome in rheumatoid arthritis is predicted by presence of antibodies against cyclic citrullinated peptide before and at disease onset, and by IgARF at disease onset. Ann Rheum Dis 65:453-458, 2006. 40. Forslind K, Ahlmen M, Eberhardt K, et al: Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: Role of antibodies to citrullinated peptides (anti-CCP). Ann Rheum Dis 63: 1090-1095, 2004. 41. Quinn MA, Gough AK, Green MJ, et al: Anti-CCP antibodies measured at disease onset help identify seronegative rheumatoid arthritis and predict radiological and functional outcome. Rheumatology (Oxf) 45:478-480, 2006. 42. De Rycke L, Peene I, Hoffman IE, et al: Rheumatoid factor and anticitrullinated protein antibodies in rheumatoid arthritis: Diagnostic value, associations with radiological progression rate, and extraarticular manifestations. Ann Rheum Dis 63:1587-1593, 2004. 43. Salvador G, Gomez A, Vinas O, et al: Prevalence and clinical significance of anti-cyclic citrullinated peptide and antikeratin antibodies in palindromic rheumatism: An abortive form of rheumatoid arthritis? Rheumatology (Oxf) 42:972-975, 2003. 44. Artandi SE, Canfield SM, Tao MH, et al: Molecular analysis of IgM rheumatoid factor binding to chimeric IgG. J Immunol 146:603-610, 1991. 45. Natvig JB, Gaarder PI, Turner MW: IgG antigens of the C gamma 2 and C gamma 3 homology regions interacting with rheumatoid factors. Clin Exp Immunol 12:177-184, 1972. 46. Williams RC Jr, Malone CC: Rheumatoid-factor-reactive sites on CH2 established by analysis of overlapping peptides of primary sequence. Scand J Immunol 40:443-456, 1994.

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47. Corper AL, Sohi MK, Bonagura VR, et al: Structure of human IgM rheumatoid factor Fab bound to its autoantigen IgG Fc reveals a novel topology of antibody-antigen interaction. Nat Struct Biol 4:374-381, 1997. 48. Sohi MK, Corper AL, Wan T, et al: Crystallization of a complex between the Fab fragment of a human immunoglobulin M (IgM) rheumatoid factor (RF-AN) and the Fc fragment of human IgG4. Immunology 88:636-641, 1996. 49. Duquerroy S, Stura EA, Bressanelli S, et al: Crystal structure of a human autoimmune complex between IgM rheumatoid factor RF61 and IgG1 Fc reveals a novel epitope and evidence for affinity maturation. J Mol Biol 368:1321-1331, 2007. 50. Raats JM, Wijnen EM, Pruijn GJ, et al: Recombinant human monoclonal autoantibodies specific for citrulline-containing peptides from phage display libraries derived from patients with rheumatoid arthritis. J Rheumatol 30:1696-1711, 2003. 51. Burastero SE, Casali P, Wilder RL, et al: Monoreactive high affinity and polyreactive low affinity rheumatoid factors are produced by CD5+ B cells from patients with rheumatoid arthritis. J Exp Med 168:1979-1992, 1988. 52. Chen PP, Silverman GJ, Liu MF, et al: Idiotypic and molecular characterization of human rheumatoid factors. Chem Immunol 48:63-81, 1990. 53. Nakamura M, Burastero SE, Notkins AL, et al: Human monoclonal rheumatoid factor-like antibodies from CD5 (Leu-1)+ B cells are polyreactive. J Immunol 140:4180-4186, 1988. 54. Hardy RR: Variable gene usage, physiology and development of Ly1+ (CD5+) B cells. Curr Opin Immunol 4:181-185, 1992. 55. Riboldi P, Kasaian T, Mantovanni L, et al: Natural antibodies. In Bona CA, Siminovitch KA, Zanetti M, Theofilopoulos AN, et al (eds): The Molecular Pathology of Autoimmune Diseases. Philadelphia, Harwood Academic, 1993, pp 45-64. 56. Casali P, Burastero SE, Nakamura M, et al: Human lymphocytes making rheumatoid factor and antibody to ssDNA belong to Leu-1+ B-cell subset. Science (NY) 236:77-81, 1987. 57. Nemazee DA, Sato VL: Induction of rheumatoid antibodies in the mouse: Regulated production of autoantibody in the secondary humoral response. J Exp Med 158:529-545, 1983. 58. Van Snick J, Coulie P: Rheumatoid factors and secondary immune responses in the mouse, I: Frequent occurrence of hybridomas secreting IgM anti-IgG1 autoantibodies after immunization with protein antigens. Eur J Immunol 13:890-894, 1983. 59. Welch MJ, Fong S, Vaughan J, et al: Increased frequency of rheumatoid factor precursor B lymphocytes after immunization of normal adults with tetanus toxoid. Clin Exp Immunol 51:299-304, 1983. 60. Slaughter L, Carson DA, Jensen FC, et al: In vitro effects of Epstein-Barr virus on peripheral blood mononuclear cells from patients with rheumatoid arthritis and normal subjects. J Exp Med 148:1429-1434, 1978. 61. Izui S, Eisenberg RA, Dixon FJ: IgM rheumatoid factors in mice injected with bacterial lipopolysaccharides. J Immunol 122: 2096-2102, 1979. 62. Tsuchiya N, Williams RC Jr, Hutt-Fletcher LM: Rheumatoid factors may bear the internal image of the Fc gamma-binding protein of herpes simplex virus type 1. J Immunol 144:4742-4748, 1990. 63. Ramos-Casals M, Cervera R, Yague J, et al: Cryoglobulinemia in primary Sjögren’s syndrome: Prevalence and clinical characteristics in a series of 115 patients. Semin Arthritis Rheum 28:200-205, 1998. 64. Pileri P, Uematsu Y, Campagnoli S, et al: Binding of hepatitis C virus to CD81. Science (NY) 282:938-941, 1998. 65. Roosnek E, Lanzavecchia A: Efficient and selective presentation of antigen-antibody complexes by rheumatoid factor B cells. J Exp Med 173:487-489, 1991. 66. Hogben DN, Devey ME: Studies on rheumatoid factor, I: The effect of rheumatoid factor on the clearance of preformed immune complexes in mice. Clin Exp Immunol 66:648-653, 1986. 67. Coulie PG, Van Snick J: Rheumatoid factor (RF) production during anamnestic immune responses in the mouse, III: Activation of RF precursor cells is induced by their interaction with immune complexes and carrier-specific helper T cells. J Exp Med 161:88-97, 1985. 68. Nemazee DA: Immune complexes can trigger specific, T celldependent, autoanti-IgG antibody production in mice. J Exp Med 161:242-256, 1985. 69. Borretzen M, Chapman C, Natvig JB, et al: Differences in mutational patterns between rheumatoid factors in health and disease are related to variable heavy chain family and germ-line gene usage. Eur J Immunol 27:735-741, 1997.

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70. Borretzen M, Randen I, Zdarsky E, et al: Control of autoantibody affinity by selection against amino acid replacements in the complementarity-determining regions. Proc Natl Acad Sci U S A 91:1291712921, 1994. 71. Williams RC Jr, Kunkel HG: Rheumatoid factor, complement, and conglutinin aberrations in patients with subacute bacterial endocarditis. J Clin Invest 41:666-675, 1962. 72. Carson DA, Bayer AS, Eisenberg RA, et al: IgG rheumatoid factor in subacute bacterial endocarditis: Relationship to IgM rheumatoid factor and circulating immune complexes. Clin Exp Immunol 31: 100-103, 1978. 73. Phillips NE, Parker DC: Fc-dependent inhibition of mouse B cell activation by whole anti-mu antibodies. J Immunol 130:602-606, 1983. 74. Tighe H, Heaphy P, Baird S, et al: Human immunoglobulin (IgG) induced deletion of IgM rheumatoid factor B cells in transgenic mice. J Exp Med 181:599-606, 1995. 75. Tighe H, Warnatz K, Brinson D, et al: Peripheral deletion of rheumatoid factor B cells after abortive activation by IgG. Proc Natl Acad Sci U S A 94:646-651, 1997. 76. Wang H, Shlomchik MJ: High affinity rheumatoid factor transgenic B cells are eliminated in normal mice. J Immunol 159:1125-1134, 1997. 77. Warnatz K, Kyburz D, Brinson DC, et al: Rheumatoid factor B cell tolerance via autonomous Fas/FasL-independent apoptosis. Cell Immunol 191:69-73, 1999. 78. Tighe H, Chen PP, Tucker R, et al: Function of B cells expressing a human immunoglobulin M rheumatoid factor autoantibody in transgenic mice. J Exp Med 177:109-118, 1993. 79. Edwards JC, Cambridge G: Rheumatoid arthritis: The predictable effect of small immune complexes in which antibody is also antigen. Br J Rheumatol 37:126-130, 1998. 80. Randen I, Pascual V, Victor K, et al: Synovial IgG rheumatoid factors show evidence of an antigen-driven immune response and a shift in the V gene repertoire compared to IgM rheumatoid factors. Eur J Immunol 23:1220-1225, 1993. 81. Deftos M, Olee T, Carson DA, et al: Defining the genetic origins of three rheumatoid synovium-derived IgG rheumatoid factors. J Clin Invest 93:2545-2553, 1994. 82. Williams DG, Moyes SP, Mageed RA: Rheumatoid factor isotype switch and somatic mutation variants within rheumatoid arthritis synovium. Immunology 98:123-136, 1999. 83. Panush RS, Bittner AK, Sullivan M, et al: IgM rheumatoid factor elaboration by blood, bone marrow, and synovial mononuclear cells in patients with rheumatoid arthritis. Clin Immunol Immunopathol 34:387-391, 1985. 84. Hakoda M, Ishimoto T, Hayashimoto S, et al: Selective infiltration of B cells committed to the production of monoreactive rheumatoid factor in synovial tissue of patients with rheumatoid arthritis. Clin Immunol Immunopathol 69:16-22, 1993. 85. Rifkin IR, Leadbetter EA, Beaudette BC, et al: Immune complexes present in the sera of autoimmune mice activate rheumatoid factor B cells. J Immunol 165:1626-1633, 2000. 86. Leadbetter EA, Rifkin IR, Hohlbaum AM, et al: Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416:603-607, 2002. 87. Viglianti GA, Lau CM, Hanley TM, et al: Activation of autoreactive B cells by CpG dsDNA. Immunity 19:837-847, 2003. 88. Bernasconi NL, Onai N, Lanzavecchia A: A role for Toll-like receptors in acquired immunity: Up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells. Blood 101:4500-4504, 2003. 89. Skriner K, Schumann F, Naddaf G, et al: Rheumatoid factors bind to B cell stimulatory CpG “K” cluster oligos-possible involvement of toll-like-receptors. Ann Rheum Dis 66:S159, 2007. 90. Duke O, Gordon Y, Panayi GS: Synovial fluid mononuclear cells exhibit a spontaneous HLA-DR driven proliferative response. Clin Exp Immunol 70:10-17, 1987. 91. Hazelton RA, Morrison JJ, Vedam R, et al: Analysis of the responding and stimulating cells in the AMLR of patients with rheumatoid arthritis using limiting dilution. Clin Exp Immunol 74:94-99, 1988. 92. Duke-Cohan JS, Rubinow A, Hirt R, et al: The reaction against autologous lymphoblasts as an indicator of lymphocyte hyperreactivity in rheumatoid arthritis. Clin Immunol Immunopathol 54:298308, 1990.

93. Pers JO, Daridon C, Devauchelle V, et al: BAFF overexpression is associated with autoantibody production in autoimmune diseases. Ann N Y Acad Sci 1050:34-39, 2005. 94. Tan SM, Xu D, Roschke V, et al: Local production of B lymphocyte stimulator protein and APRIL in arthritic joints of patients with inflammatory arthritis. Arthritis Rheum 48:982-992, 2003. 95. Lesley R, Xu Y, Kalled SL, et al: Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity 20:441-453, 2004. 96. Cha S, Choi CB, Han TU, et al: Association of anti-cyclic citrullinated peptide antibody levels with PADI4 haplotypes in early rheumatoid arthritis and with shared epitope alleles in very late rheumatoid arthritis. Arthritis Rheum 56:1454-1463, 2007. 97. Kaltenhauser S, Pierer M, Arnold S, et al: Antibodies against cyclic citrullinated peptide are associated with the DRB1 shared epitope and predict joint erosion in rheumatoid arthritis. Rheumatology (Oxf) 46:100-104, 2007. 98. Johansson M, Arlestig L, Hallmans G, et al: PTPN22 polymorphism and anti-cyclic citrullinated peptide antibodies in combination strongly predicts future onset of rheumatoid arthritis and has a specificity of 100% for the disease. Arthritis Res Ther 8:R19, 2006. 99. Berglin E, Padyukov L, Sundin U, et al: A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res Ther 6:R303-R308, 2004. 100. Kokkonen H, Johansson M, Innala L, et al: The PTPN22 1858C/ T polymorphism is associated with anti-cyclic citrullinated peptide antibody positive early rheumatoid arthritis in northern Sweden. Arthritis Res Ther 9:R56, 2007. 101. Lee HS, Irigoyen P, Kern M, et al: Interaction between smoking, the shared epitope, and anti-cyclic citrullinated peptide: A mixed picture in three large North American rheumatoid arthritis cohorts. Arthritis Rheum 56:1745-1753, 2007. 102. Klareskog L, Stolt P, Lundberg K, et al: A new model for an etiology of rheumatoid arthritis: Smoking may trigger HLA-DR (shared epi­ tope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 54:38-46, 2006. 103. Rus’d AA, Ikejiri Y, Ono H, et al: Molecular cloning of cDNAs of mouse peptidylarginine deiminase type I, type III and type IV, and the expression pattern of type I in mouse. Eur J Biochem FEBS 259: 660-669, 1999. 104.   Bongartz T, Cantaert T, Atkins SR, et al: Citrullination in extraarticular manifestations of rheumatoid arthritis. Rheumatology (Oxf) 46:70-75, 2007. 105. Makrygiannakis D, af Klint E, Lundberg IE, et al: Citrullination is an inflammation-dependent process. Ann Rheum Dis 65:1219-1222, 2006. 106. Vossenaar ER, Smeets TJ, Kraan MC, et al: The presence of citrullinated proteins is not specific for rheumatoid synovial tissue. Arthritis Rheum 50:3485-3494, 2004. 107. Kuhn KA, Kulik L, Tomooka B, et al: Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J Clin Invest 116:961-973, 2006. 108. Mewar D, Moore DJ, Young-Min S, et al: Antiferritin antibodies discovered by phage display expression cloning are associated with radiographic damage in rheumatoid arthritis. Arthritis Rheum 52:3868-3872, 2005. 109.  Hueber W, Kidd BA, Tomooka BH, et al: Antigen microarray profiling of autoantibodies in rheumatoid arthritis. Arthritis Rheum 52:2645-2655, 2005. 110. Corrigall VM, Bodman-Smith MD, Fife MS, et al: The human endoplasmic reticulum molecular chaperone BiP is an autoantigen for rheumatoid arthritis and prevents the induction of experimental arthritis. J Immunol 166:1492-1498, 2001. 111. Brownlie RJ, Myers LK, Wooley PH, et al: Treatment of murine collagen-induced arthritis by the stress protein BiP via interleukin4-producing regulatory T cells: A novel function for an ancient protein. Arthritis Rheum 54:854-863, 2006. 112. Bodman-Smith MD, Corrigall VM, Kemeny DM, et al: BiP, a putative autoantigen in rheumatoid arthritis, stimulates IL-10-producing CD8-positive T cells from normal individuals. Rheumatology (Oxf) 42:637-644, 2003. 113. Corrigall VM, Bodman-Smith MD, Brunst M, et al: Inhibition of antigen-presenting cell function and stimulation of human peripheral blood mononuclear cells to express an antiinflammatory cytokine profile by the stress protein BiP: Relevance to the treatment of inflammatory arthritis. Arthritis Rheum 50:1164-1171, 2004.

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114. Matsumoto I, Staub A, Benoist C, et al: Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme. Science (NY) 286:1732-1735, 1999. 115. Schaller M, Burton DR, Ditzel HJ: Autoantibodies to GPI in rheumatoid arthritis: Linkage between an animal model and human disease. Nat Immunol 2:746-753, 2001. 116. Schaller M, Stohl W, Benoit V, et al: Patients with inflammatory arthritic diseases harbor elevated serum and synovial fluid levels of free and immune-complexed glucose-6-phosphate isomerase (G6PI). Biochem Biophys Res Commun 349:838-845, 2006. 117. Schubert D, Schmidt M, Zaiss D, et al: Autoantibodies to GPI and creatine kinase in RA. Nat Immunol 3:411; author reply 412-413, 2002. 118. Kassahn D, Kolb C, Solomon S, et al: Few human autoimmune sera detect GPI. Nat Immunol 3:411-412; author reply 412-413, 2002. 119. Hayashi T, Matsumoto I, Muraki Y, et al: Clinical characteristics of anti-glucose-6-phosphate isomerase antibody-positive Japanese patients with rheumatoid arthritis. Mod Rheumatol Japan Rheumatism Assoc 15:258-263, 2005. 120. Cha HS, Kim TJ, Kim JY, et al: Autoantibodies to glucose6-­phosphate isomerase are elevated in the synovial fluid of rheumatoid arthritis patients. Scand J Rheumatol 33:179-184, 2004. 121. Schaller M, Stohl W, Tan SM, et al: Raised levels of antiglucose-6-phosphate isomerase IgG in serum and synovial fluid from patients with inflammatory arthritis. Ann Rheum Dis 64:743-749, 2005.

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122. Suzuki T, Muraki Y, Yasukochi T, et al: Immunoglobulin G from anti-glucose-6-phosphate isomerase antibodies positive patient with rheumatoid arthritis induces synovitis in cynomolgus monkeys. Autoimmun Rev 4:475-478, 2005. 123. Trentham DE, Townes AS, Kang AH: Autoimmunity to type II collagen an experimental model of arthritis. J Exp Med 146:857-868, 1977. 124. Cook AD, Gray R, Ramshaw J, et al: Antibodies against the CB10 fragment of type II collagen in rheumatoid arthritis. Arthritis Res Ther 6:R477-R483, 2004. 125. Gupta B, Agrawal C, Raghav SK, et al: Association of mannose­binding lectin gene (MBL2) polymorphisms with rheumatoid arthritis in an Indian cohort of case-control samples. J Hum Genet 50:583-591, 2005. 126. Gupta B, Raghav SK, Agrawal C, et al: Anti-MBL autoantibodies in patients with rheumatoid arthritis: Prevalence and clinical significance. J Autoimmun 27:125-133, 2006. 127. Hassfeld W, Steiner G, Studnicka-Benke A, et al: Autoimmune response to the spliceosome: An immunologic link between rheumatoid arthritis, mixed connective tissue disease, and systemic lupus erythematosus. Arthritis Rheum 38:777-785, 1995. 128. Hayer S, Tohidast-Akrad M, Haralambous S, et al: Aberrant expression of the autoantigen heterogeneous nuclear ribonucleoprotein-A2 (RA33) and spontaneous formation of rheumatoid arthritis-­associated anti-RA33 autoantibodies in TNF-alpha transgenic mice. J Immunol 175:8327-8336, 2005.

52

Acute-Phase Reactants and the Concept of Inflammation IRVING KUSHNER  •  STANLEY P. BALLOU

KEY POINTS Inflammation comprises a complex and highly variable set of processes that represents a response to tissue injury or ­metabolically distressed cells. The acute-phase response is a major accompaniment of inflammation, is induced by inflammation-associated ­cytokines, and includes reorchestration of acute-phase ­protein synthesis by the liver. The quintessential acute-phase protein, C reactive-protein (CRP), plays a role in host defense by recognition of biologic substrates, activation of the complement pathway, and binding to leukocytes. The erythrocyte sedimentation rate (ESR), the most commonly employed measure of inflammation, depends on numerous poorly understood physical and chemical characteristics of blood, many of which are not related to inflammation. Cytokines, chemokines, adhesion molecules, and other products of activated inflammatory cells are secreted during and play roles in the inflammatory response, but several problems limit the clinical usefulness of their quantitation for routine clinical purposes. CRP and ESR may reflect disease activity and may correlate with disease prognosis in rheumatoid arthritis, but are generally not helpful for differential diagnosis. Either CRP or ESR is elevated in greater than 80% of patients with polymyalgia rheumatica and in about 95% of patients with giant cell arteritis, and both are useful for disease follow-up, but their imperfect correlation with disease activity indicates that these measures cannot supplant sound clinical judgment. Although CRP and ESR correlate with clinical activity in many inflammatory rheumatic diseases, the absent or only modest CRP response seen in some patients with active systemic lupus erythematosus remains unexplained. Minor “elevations” of CRP, within the normal population reference range, are associated with increased risk of ­myocardial infarction, but are a nonspecific finding (especially in patients with rheumatic diseases). Minor CRP elevation is associated with all of the well-recognized risk factors for ­cardiovascular disease, which may explain its predictive value.

A major problem in using laboratory tests to quantitate the severity and extent of inflammation stems from ambiguity associated with the concept of inflammation.1 It is difficult to arrive at a precise definition of inflammation because understanding of it has continued to evolve. For centuries, inflammation has been recognized by the clinical findings of redness, swelling, heat, and pain. The first three of these reflect vascular dilation and altered capillary permeability. The introduction of light microscopy led to a histologic

criterion: infiltration by inflammatory cells. In the modern era, inflammation has increasingly been described in biochemical, ultrastructural, and molecular terms. Amid the complexity of inflammatory processes, the classic definition of inflammation has been imprecise: the local response to tissue injury. Such a vague definition highlights the difficulty of evaluating inflammation by a laboratory test. Two points are inadequately appreciated: (1) Inflammation is not a single process; inflammation may be acute or chronic, and different stimuli (e.g., staphylococci, schistosomes, allergens, urate crystals, myocardial infarction, tubercle bacilli) induce different types of inflammatory responses. (2) Each type of inflammatory response represents a complex, highly orchestrated set of interactions between cells, soluble mediators, and tissue matrix. It is unreasonable to expect a single laboratory test to reflect all of these diverse processes accurately, and a single systemic marker (e.g., any constituent of blood) may not reflect local inflammatory processes accurately. In addition, the various stimuli capable of inducing different clinical types of inflammation (e.g., acute or chronic) can be associated with distinct patterns of laboratory abnormalities. Acute gout and active rheumatoid arthritis (RA) entail inflammation and are associated with elevation of the erythrocyte sedimentation rate (ESR); leukocytosis is more frequently associated with gout, however, whereas anemia of chronic disease is more characteristic of RA. Despite these problems, physicians have exploited the acute-phase response to obtain objective but imperfect information about the extent or degree of inflammation. During the past 75 years, this role has largely been filled by measurement of the ESR and, more recently, the serum C-reactive protein (CRP) concentration. Several new inflammatory markers have been recognized in recent years, but none has yet proved substantially more helpful in the clinical setting. Although acute-phase reactants traditionally have been regarded as markers of inflammation, more recent reports of minor elevation of CRP in conditions in which classic signs of inflammation are not clinically apparent have caused this belief to be revisited. As discussed later in this chapter, these observations suggest that such minor acute-phase responses may reflect a form of tissue injury—the presence of distressed cells—in the absence of a clinically apparent inflammatory response. The inflammatory response to tissue injury and infection is a defensive and reparative mechanism that represents a sort of calculated risk on the body’s part. Among its components are cells and molecules that have the potential, if excessive or not controlled, to harm the host; usually, no harm results. Conditions such as RA, systemic inflammatory 767

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response syndrome (SIRS) resulting from marked multiple cytokine release (cytokine storm),2 and the deadly influenza epidemic of 19183 represent circumstances in which the inflammatory response is not sufficiently restrained, with consequent deleterious effects.

ACUTE-PHASE RESPONSE Numerous systemic and metabolic changes, collectively referred to as the acute-phase response, begin to occur within minutes to hours after tissue injury.4,5 Genome-wide analyses reveal that 7% of mouse genes undergo significant changes in expression during inflammatory states.6 Many elements of the acute-phase response presumably represent early defensive mechanisms or adaptations to the stress of an inflammatory stimulus and can be regarded as participants in the innate immune response.7 A major component of the acute-phase response is alteration of synthesis of plasma proteins by hepatocytes. These “acute-phase proteins” display variable changes in plasma concentration and kinetics after tissue injury (Fig. 52-1). Concentrations of some, such as ceruloplasmin and complement proteins, increase about 50% above normal; others, such as α1-acid glycoprotein, α1-proteinase inhibitor, haptoglobin, and fibrinogen, can increase severalfold. The two major acute-phase proteins in humans, CRP and serum amyloid A (SAA), often increase to levels several hundred times above the trace levels normally present in healthy states and may increase more than 1000-fold in severe inflammatory states, usually infections. In contrast,

30,100 30,000

Plasma concentration (% change)

700 C-reactive protein

600 500

Serum amyloid A

400 300

Haptoglobin

200 100

Fibrinogen

C3

0 Albumin 0 Inflammatory stimulus

Transferrin 7

14

21

Days

Figure 52-1  Typical plasma acute-phase protein changes after a moderate inflammatory stimulus. Several patterns of response are seen:  major acute-phase protein, increase 100-fold (e.g., C-reactive protein and serum amyloid A); moderate acute-phase protein, increase 2-fold to  4-fold (e.g., fibrinogen, haptoglobin); minor acute-phase protein, increase 50% to 100% (e.g., complement C3); and negative acute-phase protein, decrease (e.g., albumin, transferrin). (Adapted from Gitlin JD, Colten HR: Molecular biology of the acute-phase plasma proteins. In Pick E, Landy M [eds]: Lymphokines, Vol 14. San Diego, Academic Press, 1987, pp 123-153.)

concentrations of several negative acute-phase proteins, such as albumin, may decrease. Acute-phase protein synthesis by hepatocytes is induced largely by the cytokines that are released by activated monocytes, macrophages, and certain other cells after tissue injury, and that participate in the local inflammatory response. Interleukin (IL)-6 is the major inducer of acute-phase protein changes. Other cytokines, such as IL-1 and tumor necrosis factor (TNF)-α, play more limited roles. These effects also are influenced by modulators of cytokine function, such as IL-1 receptor antagonist and soluble cytokine receptors, and by other humoral molecules.4 Acute-phase protein levels do not always change uniformly, suggesting independently coordinated mechanisms for regulation of their synthesis, probably involving different combinations and interactions of cytokines and their modulators in varying circumstances. Teleologic considerations suggest that changes in concentration of the acute-phase proteins lead to improved functional capacity to cope with the consequences of tissue injury or infection. Functional activities that have been attributed to acute-phase proteins include direct involvement in host defense (e.g., by activation of the complement pathway), proteinase inhibition, and antioxidant activity.5,8 Some of the described in vitro effects of acutephase proteins may not be relevant to in vivo phenomena, however. C-REACTIVE PROTEIN C-reactive protein is present in trace concentrations in the plasma of all humans. It is a pentamer consisting of five identical, noncovalently linked 23-kD subunits that has been highly conserved over hundreds of millions of years of evolution; a homologous protein is found in the ancient organism Limulus polyphemus, the horseshoe crab. In contrast to immunoglobulins and complement components, other molecules involved in host defense, CRP deficiency in humans has not been described. Although the precise function of CRP is unknown, it exhibits important recognition and activation capabilities.9 Among the major biologic ligands recognized by CRP are phosphocholine and histone proteins. These constituents of cell membranes and nuclei are exposed at sites of tissue damage, and by apoptotic cells, and CRP may target them for clearance. Major activation functions of CRP include activation of the classic complement pathway after interaction with many of its biologic ligands, and interaction with cells of the immune system by binding to Fcγ receptors.10,11 It bridges the gap between innate and adaptive immunity and can promote an early, effective inflammatory response. Other CRP functions seem to be anti-inflammatory, suggesting that CRP may play many pathophysiologic roles during the course of the inflammatory process.8,12 Following acute inflammatory stimuli, the concentration of CRP rapidly increases for 2 or 3 days to peaks that generally reflect the extent of tissue injury. In the absence of continuing stimulus, serum CRP levels then decrease rapidly, with a half-life of about 19 hours.13 Persistently elevated serum CRP concentrations are often seen in chronic inflammatory states, however, such as active RA or pulmonary tuberculosis, or in the presence of extensive malignant disease.

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Serum levels of CRP can be accurately quantitated by immunoassay or laser nephelometry at modest cost. Most apparently healthy adults have serum CRP levels less than 0.3 mg/dL, although concentrations of 1 mg/dL are not unusual. (The significance of such minor CRP elevation is discussed subsequently.) It is generally accepted that concentrations greater than 1 mg/dL reflect clinically significant inflammatory disease.14,15 Concentrations of 1 to 10 mg/dL can be considered moderate increases, and concentrations greater than 10 mg/dL can be considered marked increases. Most patients with extremely high levels (e.g., >15 to 20 mg/dL) have bacterial infections; a study found that infections accounted for 88% of episodes in which CRP concentrations exceeded 50 mg/dL.16 Clinical conditions associated with CRP elevations of varying degrees are listed in Table 52-1, and the range of CRP concentrations generally seen in many rheumatologic diseases is shown in Figure 52-2. Several additional caveats regarding clinical interpretation of CRP levels are in order. There is no uniformity in reporting CRP concentrations; some laboratories report CRP as mg/L or μg/mL, and some use mg/dL. Also, population studies of CRP reveal a skewed rather than normal distribution, rendering parametric statistical tests

inappropriate for interpretation of CRP data. Finally, the elevation of CRP levels that occurs with aging17 may reflect age-related disorders whose pathogenesis may involve low-grade inflammatory processes. CRP levels in the U.S. population also differ between the sexes and among racial groups.17 SERUM AMYLOID A SAA consists of a family of proteins, some of which are constitutively expressed, whereas others display marked acute-phase behavior.18 Although largely produced by hepatocytes, more recent studies show that SAA is produced by adipocytes as well, and its serum concentration is associated with body mass index.19 In plasma, SAA is associated with high-density lipoproteins. The function of SAA is unclear. Studies indicate that SAA may function as a chemoattractant,20 induce secretion of a variety of cytokines,19,21 and promote export of macrophage cholesterol.22,23 Presumably, these activities subserve a role in the inflammatory process. Similar to CRP, levels of acute-phase SAA increase within hours after stimulus, and the magnitude of increase may be greater than that of CRP. Relatively trivial inflammatory stimuli can lead to SAA responses.24 Clinical studies have shown correlation of SAA levels with disease activity in a variety of inflammatory disorders. It has been suggested that SAA levels correlate better with disease activity in early inflammatory joint disease than do ESR and CRP.25 The normal level of SAA in healthy adults is less than 10 mg/L, with a median value of 3 mg/L in a European population.26 Reliable testing for acute-phase SAA is not yet widely available, and data about levels expected in disease are limited.

Table 52-1  Conditions Associated with Various   C-Reactive Protein Levels Normal or Minor Moderate Elevation Marked Elevation Elevation (<1 mg/dL) (1-10 mg/dL) (>10 mg/dL) Vigorous   exercise Common cold Pregnancy Gingivitis Seizures Depression Insulin resistance   and diabetes Several genetic   polymorphisms Obesity

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Acute bacterial   Myocardial   infarction infection (80%-85%) Malignancies Major trauma Pancreatitis Systemic vasculitis Mucosal infection (bronchitis, cystitis) Most connective   tissue diseases Rheumatoid arthritis

OTHER ACUTE-PHASE PROTEINS Measurement of other acute-phase proteins has limited value for clinical assessment of inflammation because their responses to tissue injury are slower, and the magnitudes of change in concentrations are smaller than those of CRP and SAA. Serum levels of ferritin, a moderate acute-phase

SERUM CRP LEVELS (mg/dL) 0.1

0.2

0.5

1.0

2.0

5.0

10

20

50

100

Normal Osteoarthritis Rheumatoid arthritis Gout Lupus without serositis Lupus with serositis Spondylitis Vasculitis Adult Still’s

Figure 52-2  Range of C-reactive protein (CRP) levels in rheumatic diseases. Authors’ estimates of expected levels of CRP (mg/dL) in certain rheumatic diseases.

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Table 52-2  Markers of Inflammation   That Are Not Acute-Phase Proteins Cytokines and Related Molecules

Products of Inflammatory and Endothelial Cells

Cytokines   IL-1   IL-6

Calprotectin von Willebrand’s factor Adhesion molecules (e.g., vascular cell adhesion molecule-1) Hyaluronic acid Collagen and aggrecan   degradation products Osteocalcin

  IL-12   Interferon-α   Tumor necrosis factor-α Granulocyte-macrophage   colony-stimulating factor IL-1 receptor antagonist IL, interleukin.

r­ eactant, may be extremely high in adult-onset Still’s disease (see later) and may reflect disease activity in lupus erythematosus,27 but are also influenced by total body iron stores. CYTOKINES Although not acute-phase proteins in the classic sense (i.e., not secreted by hepatocytes), cytokines display the most striking acute-phase behavior of any circulating proteins. IL-6 may respond dramatically to tissue injury, with changes that are faster and greater than changes of CRP and SAA. Acute and chronic inflammation and trauma have been associated with increases in IL-6, and serum levels of this cytokine have been correlated with the severity and course of disease in RA, juvenile arthritis, ankylosing spondylitis, and polymyalgia rheumatica (PMR).28,29 Increased levels of several other cytokines and circulating cytokine receptors also have been associated with inflammation or disease activity in such conditions (Table 52-2).30,31 Different patterns of cytokine responses have been reported in different diseases, suggesting that cytokine determinations ultimately may have diagnostic value,32,33 as does a report that IL-6 is more sensitive than ESR for detecting disease activity in giant cell arteritis (GCA).34 Although plasma concentrations of such cytokines and cytokine receptors are potentially useful clinically, their quantitation presents several problems related to their short plasma half-lives, the presence of blocking factors and natural inhibitors, and other technical considerations.35 At present, the high cost, limited availability, and absence of standardization discourage measurement of plasma cytokines and their receptors in clinical practice.

ERYTHROCYTE SEDIMENTATION RATE Over many years, the ESR has been the most widely used marker of the acute-phase response. Elevation of the ESR was recognized as a correlate of illness by the ancient Greeks. In this test, anticoagulated blood is placed in a vertical tube, and the rate of fall of erythrocytes is measured. The ESR is an indirect way of screening for elevated concentrations of the acute-phase plasma proteins, particularly fibrinogen, that result in increased aggregation of erythrocytes (rouleaux formation), causing them to fall more rapidly. Many of the complex physicochemical factors that affect the ESR still are unknown.36 The ESR is known to be influenced by changes in concentrations of plasma proteins and

the number and morphology of red blood cells. Two types of changes in plasma proteins commonly lead to elevation of the ESR. First, an increase in concentration of asymmetric charged proteins decreases the natural tendency of erythrocytes to repel each other, leading to red blood cell aggregation and rouleaux formation. Fibrinogen, a moderate acute-phase reactant, is the most prevalent of the asymmetric acutephase proteins in plasma and has the greatest effect on the ESR. Second, a major increase in concentration of a single molecular species, such as the monoclonal immunoglobulin elevations that occur in multiple myeloma, may lead to ESR elevation; such changes do not reflect inflammatory states. In addition, anemia and polycythemia may affect the ESR, and alterations in size and shape of ­erythrocytes may physically interfere with rouleaux formation. It is impossible to correct accurately for alterations in size, shape, or concentration of erythrocytes. The ESR is elevated in obesity, as is CRP, presumably as a result of IL-6 secretion by adipocytes.37 The International Committee for Standardization in Hematology has recommended that the Westergren technique be designated as the preferred method of ESR determination.38 The generally accepted upper limits of normal are 15 mm/hr for males and 20 mm/hr for females, but the ESR progressively increases with aging, resulting in great uncertainty about “normal” levels, particularly in the elderly. Values of 40 mm/hr are common in apparently healthy elderly individuals. A simple formula for calculating maximal normal ESR at any age was proposed in the early 1980s.39 A racial difference in ESR has been reported, further rendering “normal” values unreliable.40 Similar to CRP levels, the population distribution of ESR determinations is nongaussian. Other problems with the ESR are listed in Table 52-3. The ESR has retained an important place in medical practice, probably because the test is easy to perform and inexpensive, and because a wealth of information about its clinical significance has accumulated over many years. Many experienced physicians believe, rightly or wrongly, that they know how to compensate for its flaws, but the relative virtues of CRP determination are propelling it to a more important role in clinical practice.

ACUTE-PHASE REACTANTS IN MANAGEMENT OF RHEUMATIC DISEASES Measurement of ESR and CRP can be clinically helpful in three ways: (1) in evaluating the extent or severity of inflammation, (2) in monitoring changes in disease activity over time, and (3) in assessing prognosis. Because neither test possesses diagnostic specificity, results cannot be used to confirm or exclude definitely any particular disease—even PMR and GCA (see later). RHEUMATOID ARTHRITIS ESR and CRP have no role in the differential diagnosis of RA, osteoarthritis, systemic lupus erythematosus (SLE), or other inflammatory arthropathies. A more appropriate application of these tests in RA is for monitoring disease activity and response to therapy. Although ESR traditionally has been more widely used for these purposes, many more recent studies have suggested that CRP levels correlate

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Table 52-3  Advantages and Disadvantages   of Erythrocyte Sedimentation Rate and C-Reactive   Protein Determination Erythrocyte Sedimentation Rate Advantages

C-Reactive Protein

Much clinical information   Rapid response to inin the literature flammatory stimuli May reflect overall health Wide range of clinically status relevant values are detectable Unaffected by age and gender Reflects value of a single acute-phase protein Can be measured on stored sera Quantitation is   precise and   reproducible

Disadvantages Affected by age and   None gender Affected by red blood cell morphology Affected by anemia and   polycythemia Reflects levels of many   plasma proteins, not all of which are acute-phase proteins Responds slowly to   inflammatory stimuli Requires fresh sample May be affected by drugs

better with disease activity.41 CRP levels average 2 to 3 mg/dL in adult RA patients with moderate disease activity.42 There is considerable variation: At least 5% to 10% of patients have values in the normal range, whereas a few patients with severe disease activity have levels greater than 10 mg/dL. ESR values have been found to remain stable over the years.43 ESR and CRP have long been employed to follow the response to therapy; in general, effective disease-modifying antirheumatic drug therapy decreases CRP levels by about 40%. Inhibition of joint damage by these agents usually is accompanied by marked improvement in acute-phase reactants. Progression of joint damage can occur, however, despite decreases in ESR and CRP on therapy.44 Even more striking improvement has been seen with the biologic agents introduced since the 1990s, providing objective laboratory support for the encouraging clinical responses observed. In early reports of anti-TNF-α therapy, CRP and SAA levels declined by 75% and 85% in about 1 week.45 In one study, failure to suppress CRP levels 2 weeks after initiation of infliximab therapy identified most patients who would prove to be clinical nonresponders after 12 weeks.46 In contrast to traditional disease-modifying antirheumatic drugs, TNF inhibitors have been found to inhibit joint damage even while clinical activity, reflected by CRP levels, remains high.47 The ESR and CRP also have value as prognostic indicators in RA. Elevated acute-phase reactant levels are associated with early synovitis and erosions as detected by magnetic resonance imaging,48 with inflammatory cellular infiltrates in synovium,49 and with osteoclastic

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activation and reduced bone mineral density.50 CRP predicts radiographic progression,51,52 as does ESR53 and the matrix metalloproteinases MMP-3 and MMP-1.54 Finally, and perhaps most importantly, acute-phase reactants correlate with work disability on long-term follow-up.55 As in the normal population, CRP levels are associated with death from cardiovascular disease.56 In RA patients who developed heart failure, ESR was higher during the 6-month period immediately preceding the onset of heart failure than earlier in their course.57 Serum or synovial fluid levels of many other tissue products (see Table 52-2) have been correlated with clinical measures of disease activity, severity, and radiographic damage. More recent interest has focused on MMP-3, pro-MMP-3, and E-selectin. Serum levels of these markers generally correlate with CRP levels.54,58 SYSTEMIC LUPUS ERYTHEMATOSUS Although serum CRP and ESR levels are elevated in numerous patients with active SLE, many do not show even mild elevation of CRP. Lupus patients with acute serositis59 or chronic synovitis60 are most likely to have substantially elevated levels of CRP, whereas patients with other manifestations of lupus, such as nephritis, may have only modest or no elevation. Intuitively, this finding may not be surprising because tissue damage, the major proximate cause of CRP elevation, is not obvious in manifestations such as psychosis or immune thrombocytopenia. In contrast to CRP, ESR correlates with disease activity and accrued tissue damage in SLE.61 Data are insufficient to evaluate the potential use of some of the other newer markers described previously, but many SLE patients with normal CRP levels show elevated IL-6 concentrations.62 It is unclear whether antibodies to CRP, detected in some SLE patients, explain the relatively lower CRP levels in such patients.63,64 Substantial CRP elevation in SLE patients is more likely to result from superimposed infection than from activation of lupus. CRP levels greater than 6 mg/dL in these patients should serve as an impetus to exclude the possibility of infection, just as it should in other diseases.14 Such levels should not be regarded as proof of infection, however; as indicated earlier, marked CRP elevation related to active SLE can be seen in the absence of infection. Basal levels of CRP are influenced by two genetic polymorphisms at the CRP locus, and one of these polymorphisms, associated with reduced basal CRP, also was associated with the development of SLE and antinuclear autoantibody production.65 Carotid plaque and intima-media wall thickness, correlates of atherosclerotic vascular disease, have been found in association with minor CRP elevation in women with SLE,66 as they have in patients with RA.67 POLYMYALGIA RHEUMATICA AND GIANT CELL ARTERITIS The diagnosis of PMR or GCA is supported by an elevated ESR, often greater than 100 mm/hr. Such an elevation is no longer regarded as a sine qua non of these disorders; continuing reports suggest that 10% to 20% of patients with PMR can have “normal” ESRs, depending on which value

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(30 mm/hr, 40 mm/hr, or 45 mm/hr) is taken as the limit of normal. Such patients tend to have fewer systemic symptoms and less severe, and less frequent, anemia.68 They have the same frequency of positive temporal artery biopsy results, however, as patients with elevated ESR.69,70 Only about 5% of patients with GCA had ESR values less than 40 mm/hr; these patients had fewer visual and systemic symptoms than patients with higher ESR values.71 In contrast to these findings, ESR and CRP were found to be significantly lower in patients with permanent visual loss,72 and patients with ESR greater than 100 mm/hr had decreased incidence of visual ischemic events.73 In PMR and GCA, CRP and ESR have been regarded in the past as equally valuable in assessing disease activity. More recent reports suggest, however, that CRP is more sensitive for both conditions and should be included routinely in the diagnostic workup.70,74,75 In addition, the uncertainty as to what ESR values are “normal” in elderly patients suggests that CRP may be more valuable in this population. The report that IL-6 is more sensitive than ESR for indicating disease activity in GCA is of particular interest.34 Persistently elevated CRP levels are associated with risk of relapse or recurrence of PMR.76 Clinical manifestations of disease, even in the presence of a normal ESR or CRP level, should not be ignored. Extreme elevation of the ESR in the absence of symptoms of PMR or GCA should raise suspicion of other disorders, such as infection, malignancy, or renal disease. Numerous markers of endothelial perturbation, not acute-phase reactants in the strict sense, are elevated in plasma in various inflammatory disorders of vessels, particularly PMR, GCA, and other vasculitides.77 These molecules include von Willebrand’s factor, thrombomodulin, some vasoactive prostanoids, and a variety of adhesion molecules, such as vascular cell adhesion molecule-1. ADULT-ONSET STILL’S DISEASE Markedly elevated concentrations of ferritin, disproportionately high compared with other acute-phase reactants, have long been noted in adult-onset Still’s disease,78 but are not specific. Only a low percentage—commonly less than 20%—of ferritin is glycosylated in adult-onset Still’s disease,79 a criterion included in a more recently proposed set of classification criteria for this condition.80 Extremely elevated ferritin levels have been found in macrophage activation syndrome,81 and 40% of individuals with this condition meet the criteria for adult-onset Still’s disease, suggesting to some that macrophage activation syndrome and Still’s disease are not distinct entities.82,83 Concentrations of serum IL-18 were extremely elevated in patients with active adultonset Still’s disease compared with patients with other connective tissue diseases or with healthy individuals and were correlated with serum ferritin values and disease severity.84 It has been suggested that interferon-α may be responsible for the hyperferritinemia of adult-onset Still’s disease.78 CRP levels also are usually markedly elevated in this disease. ANKYLOSING SPONDYLITIS Ankylosing spondylitis ordinarily does not lead to a substantial increase in CRP or ESR. Median CRP levels are 1.6 mg/dL in patients with spinal involvement only and

2.5 mg/dL in patients with peripheral involvement or associated inflammatory bowel disease. Median ESR is 13 mm/hr in patients with spinal involvement only and 21 mm/hr in patients with peripheral involvement or associated inflammatory bowel disease.85 Infliximab treatment of ankylosing spondylitis patients led to an average decrease of 75% in CRP concentration after 12 weeks. Patients with lower CRP levels showed little improvement, however, raising the possibility that patients with higher CRP values show better responses to anti-TNF treatment than do patients with lower CRP levels.86,87 It has been reported that IL-8 levels may reflect clinical activity in spondyloarthropathies.88 OSTEOARTHRITIS Minor CRP elevations of 0.3 to 1.0 mg/dL have been reported in patients with knee osteoarthritis, particularly patients with progressive joint damage. One study has failed to confirm this finding,89 however, whereas others cast doubt on the clinical usefulness of this association because of the association between CRP levels and obesity, a common accompaniment of osteoarthritis of the knee.90 CRP levels are higher in patients with erosive osteoarthritis of the hand than in patients with nonerosive osteoarthritis.91

PRACTICAL USE OF ACUTE-PHASE REACTANTS When surveyed in the 1990s, rheumatologists were found to employ the ESR more than twice as frequently as they did CRP levels.92 The ESR reflects many complex, poorly understood changes in the physical and chemical characteristics of blood, however, not associated with inflammation. As indicated earlier, it is a mistake to take the reference normal values for ESR seriously. It is well established that mean ESR values increase substantially with age; normal at age 20 years is different from normal at age 70. Normal values also differ between men and women. The vagaries associated with interpretation of the ESR, its uncertain “normal” value, and increasing positive clinical experience with CRP all suggest that rheumatologists should rely more on CRP than ESR testing.93 There is no single ideal test to evaluate the acute-phase response, however. The relative virtues of these tests in following patients with RA have been discussed more recently.94 Discrepancies between ESR and CRP may result from the effects of blood constituents that are not related to inflammation, but that can influence the ESR, as discussed earlier. In addition, patterns of acute-phase protein changes differ in different conditions.4 ESR may be markedly elevated in many patients with active SLE, whereas CRP is normal. Undoubtedly numerous other clinical situations exist in which similar discrepancies occur. Although many noninflammatory physicochemical causes for falsely high ESR exist (some known, and many unknown), CRP values greater than 1 mg/dL almost invariably reflect a clinically significant inflammatory process. In light of these considerations, many authors believe that several tests, rather than a single test, should be performed and interpreted in their clinical context. It has been suggested that ESR, which is associated with anemia and immunoglobulin levels, may reflect “general severity” in RA, whereas CRP is a better test of active inflammation per se.95

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C-REACTIVE PROTEIN AND HEALTH: ASSOCIATION WITH NONRHEUMATOLOGIC CONDITIONS Although most ostensibly healthy individuals have CRP concentrations of 0.3 mg/dL or less, some have concentrations of 1 mg/dL or greater. Such minor CRP elevation has long been attributed to trivial tissue injury or to minimal inflammatory processes, such as gingivitis. More recent data indicate, however, that CRP concentrations between 0.3 and 1 mg/dL have clinical relevance. Employing a highsensitivity CRP assay, it has been well established that serum CRP levels greater than 3 mg/dL indicate increased relative risk of future myocardial infarction.96 The primary unanswered question has remained: Why does CRP predict myocardial infarction? Is such minor elevation of CRP a marker of the inflammatory response to tissue injury, as classically recognized— altered capillary permeability, vasodilation, and leukocyte infiltration? The observation that CRP is associated with many noninflammatory conditions, such as low levels of physical activity, low intake of fruits and vegetables, a variety of other “unhealthy” diets, sleep deprivation, and low alcohol intake,97 indicates that classic inflammation does not invariably underlie a CRP response. Many of these CRP-associated conditions are known to be associated with ill health, suggesting that CRP may not reflect inflammation, but can be produced in response to the presence of distressed, metabolically disturbed cells.97 In this scenario, the presence of such cells represents tissue injury that is sufficient to lead to production of inflammatory mediators and cytokines sufficient to elicit a minor acute-phase response in hepatocytes, but not enough to induce a local inflammatory response. Some authors have called this response subclinical inflammation or microinflammation. Whether to call this response inflammation or not becomes a semantic issue,1 but one that has significant therapeutic consequences: Does one attempt to reduce the distress of cells, or does one suppress inflammation with anti-inflammatory agents? Numerous studies have shown that minor CRP elevation provides little prognostic information about future coronary events beyond that afforded by “traditional” risk factors.98,99 This issue has been eludicated by the INTERHEART study,100 in which putative risk factors were evaluated in more than 12,000 cases of myocardial infarction in 52 countries. Only nine risk factors accounted for 90% of the population-attributable risk globally, and greater than 98% of the risk in North America. All of these risk factors have been reported to be associated with CRP,97 suggesting that CRP predicts myocardial infarction simply because it is associated with all of the major risk factors for myocardial infarction. These findings support the view that CRP is a reflector rather than an effector, especially because many other acute-phase reactants similarly predict coronary events.101 This conclusion argues against identifying CRP as a therapeutic target to prevent myocardial infarction and argues against describing CRP as an “independent” risk factor. At present, it is unclear whether high-sensitivity CRP screening offers any advantage over thorough evaluation of traditional risk factors in identifying individuals at risk for atherosclerosis. Because of the high prevalence of

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underlying chronic inflammation in rheumatologic patients, it is unlikely that this screening strategy would be of much value in such patients. Evidence has been presented supporting the view that CRP is not merely a risk factor, but may participate in atherogenesis.102 The proatherogenic effects attributed to CRP may have been caused by contaminants in commercial CRP preparations, however, and not by CRP.103 Individuals who have high CRP levels on a genetic basis were not found to be at increased risk for coronary events in mendelian randomization studies,104 casting further doubt on a causal role for CRP in atherosclerosis. Epidemiologic studies describing an association of CRP levels with morbidity and mortality in many chronic diseases and even in normal aging have become a “cottage industry.” It is important to remember that these are merely population studies. Although such associations may have broad and intriguing implications, particularly at a societal level, they merely reflect probabilities, which limit their clinical value when dealing with the individual patient. REFERENCES   1. Kushner I: Semantics, inflammation, cytokines and common sense. Cytokine Growth Factor Rev 9(3-4):191-196, 1998.   2. Suntharalingam G, Perry MR, Ward S, et al: Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355:1018-1028, 2006.   3. Kash JC, Goodman AG, Korth MJ, et al: Hijacking of the host-cell response and translational control during influenza virus infection. Virus Res 119:111-120, 2006.   4. Gabay C, Kushner I: Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 340:448-454, 1999.   5. Kushner I, Rzewnicki D: Acute-phase response. In Galin J, ­Snyderman R (eds): Inflammation: Basic Principles and Clinical Correlates, 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 1999, pp 317-330.   6. Desiderio S, Yoo JY: A genome-wide analysis of the acute-phase response and its regulation by Stat3beta. Ann N Y Acad Sci 987:280284, 2003.   7. Yoo JY, Desiderio S: Innate and acquired immunity intersect in a global view of the acute-phase response. Proc Natl Acad Sci U S A 100:1157-1162, 2003.   8. Volanakis JE: Human C-reactive protein: Expression, structure, and function. Mol Immunol 38:189-197, 2001.   9. Black S, Kushner I, Samols D: C-reactive protein. J Biol Chem 279:48487-48490, 2004. 10. Marnell L, Mold C, Du Clos TW: C-reactive protein: Ligands, receptors and role in inflammation. Clin Immunol 117:104-111, 2005. 11. Du Clos TW, Mold C: C-reactive protein: An activator of innate immunity and a modulator of adaptive immunity. Immunol Res 30:261-277, 2004. 12. Mortensen RF: C-reactive protein, inflammation, and innate immunity. Immunol Res 24:163-176, 2001. 13. Vigushin DM, Pepys MB, Hawkins PN: Metabolic and scintigraphic studies of radioiodinated human C-reactive protein in health and disease. J Clin Invest 91:1351-1357, 1993. 14. Morley JJ, Kushner I: Serum C-reactive protein levels in disease. Ann N Y Acad Sci 389:406-418, 1982. 15. Macy EM, Hayes TE, Tracy RP: Variability in the measurement of C-reactive protein in healthy subjects: Implications for reference intervals and epidemiological applications. Clin Chem 43:52-58, 1997. 16. Vanderschueren S, Deeren D, Knockaert DC, et al: Extremely elevated C-reactive protein. Eur J Intern Med 17:430-433, 2006. 17. Woloshin S, Schwartz LM: Distribution of C-reactive protein values in the United States. N Engl J Med 352:1611-1613, 2005. 18. O’Brien KD, Chait A: Serum amyloid A: The “other” inflammatory protein. Curr Atheroscler Rep 8:62-68, 2006. 19. Yang RZ, Lee MJ, Hu H, et al: Acute-phase serum amyloid A: An inflammatory adipokine and potential link between obesity and its metabolic complications. PLoS Med 3:e287, 2006.

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20. Su SB, Gong W, Gao JL, et al: A seven-transmembrane, G proteincoupled receptor, FPRL1, mediates the chemotactic activity of serum amyloid A for human phagocytic cells. J Exp Med 189:395-402, 1999. 21. He R, Shepard LW, Chen J, et al: Serum amyloid A is an endogenous ligand that differentially induces IL-12 and IL-23. J Immunol 177:4072-4079, 2006. 22. Tam SP, Flexman A, Hulme J, et al: Promoting export of macrophage cholesterol: The physiological role of a major acute-phase protein, serum amyloid A 2.1. J Lipid Res 43:1410-1420, 2002. 23. Manley PN, Ancsin JB, Kisilevsky R: Rapid recycling of cholesterol: The joint biologic role of C-reactive protein and serum amyloid A. Med Hypotheses 66:784-792, 2006. 24. Chambers RE, Hutton CW, Dieppe PA, et al: Comparative study of C reactive protein and serum amyloid A protein in experimental inflammation. Ann Rheum Dis 50:677-679, 1991. 25. Cunnane G, Grehan S, Geoghegan S, et al: Serum amyloid A in the assessment of early inflammatory arthritis. J Rheumatol 27:58-63, 2000. 26. Wilkins J, Gallimore JR, Tennent GA, et al: Rapid automated enzyme immunoassay of serum amyloid A. Clin Chem 40(7 Pt 1):1284-1290, 1994. 27. Nishiya K, Hashimoto K: Elevation of serum ferritin levels as a marker for active systemic lupus erythematosus. Clin Exp Rheumatol 15: 39-44, 1997. 28. Tutuncu ZN, Bilgie A, Kennedy LG, et al: Interleukin-6, acute phase reactants and clinical status in ankylosing spondylitis. Ann Rheum Dis 53:425-426, 1994. 29. Uddhammar A, Sundqvist KG, Ellis B, et al: Cytokines and adhesion molecules in patients with polymyalgia rheumatica. Br J Rheumatol 37:766-769, 1998. 30. Luqmani R, Sheeran T, Robinson M, et al: Systemic cytokine measurements: Their role in monitoring the response to therapy in patients with rheumatoid arthritis. Clin Exp Rheumatol 12:503-508, 1994. 31. Pountain G, Hazleman B, Cawston TE: Circulating levels of IL1beta, IL-6 and soluble IL-2 receptor in polymyalgia rheumatica and giant cell arteritis and rheumatoid arthritis. Br J Rheumatol 37: 797-798, 1998 (letter). 32. Gabay C, Cakir N, Moral F, et al: Circulating levels of tumor necrosis factor soluble receptors in systemic lupus erythematosus are significantly higher than in other rheumatic diseases and correlate with disease activity. J Rheumatol 24:303-308, 1997. 33. Gabay C, Gay-Croisier F, Roux-Lombard P, et al: Elevated serum levels of interleukin-1 receptor antagonist in polymyositis/dermatomyositis: A biologic marker of disease activity with a possible role in the lack of acute-phase protein response. Arthritis Rheum 37:17441751, 1994. 34. Weyand CM, Fulbright JW, Hunder GG, et al: Treatment of giant cell arteritis: Interleukin-6 as a biologic marker of disease activity. Arthritis Rheum 43:1041-1048, 2000. 35. Barnes A: Measurement of serum cytokines. Lancet 352:324-325, 1998 (letter). 36. Bedell SE, Bush BT: Erythrocyte sedimentation rate: From folklore to facts. Am J Med 78(6 Pt 1):1001-1009, 1985. 37.  Bastard JP, Maachi M, Van Nhieu JT, et al: Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. J Clin Endocrinol Metab 87:2084-2089, 2002. 38. International Council for Standardization in Haematology (Expert Panel on Blood Rheology): ICSH recommendations for measurement of erythrocyte sedimentation rate [published erratum appears in J Clin Pathol 46(5):488, 1993]. J Clin Pathol 46: 198-203, 1993. 39. Miller A, Green M, Roberson D: Simple rule for calculating normal erythrocyte sedimentation rate. BMJ 286:266, 1983. 40. Gillum RF: A racial difference in erythrocyte sedimentation. J Natl Med Assoc 85:47-50, 1993. 41. Cohick CB, Furst DE, Quagliata S, et al: Analysis of elevated serum interleukin-6 levels in rheumatoid arthritis: Correlation with erythrocyte sedimentation rate or C-reactive protein. J Lab Clin Med 123:721-727, 1994. 42. Aletaha D, Smolen JS: The rheumatoid arthritis patient in the clinic: Comparing more than 1300 consecutive DMARD courses. Rheumatology (Oxf) 41:1367-1374, 2002.

43. Wolfe F, Pincus T: The level of inflammation in rheumatoid arthritis is determined early and remains stable over the longterm course of the illness. J Rheumatol 28:1817-1824, 2001. 44. Sanmarti R, Gomez A, Ercilla G, et al: Radiological progression in early rheumatoid arthritis after DMARDS: A one-year follow-up study in a clinical setting. Rheumatology (Oxf) 42:1044-1049, 2003. 45. Charles P, Elliott MJ, Davis D, et al: Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis. J Immunol 163:1521-1528, 1999. 46. Buch MH, Seto Y, Bingham SJ, et al: C-reactive protein as a predictor of infliximab treatment outcome in patients with rheumatoid arthritis: Defining subtypes of nonresponse and subsequent response to etanercept. Arthritis Rheum 52:42-48, 2005. 47. Smolen JS, Van Der Heijde DM, St Clair EW, et al: Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: Results from the ASPIRE trial. Arthritis Rheum 54:702-710, 2006. 48. Graudal N, Tarp U, Jurik AG, et al: Inflammatory patterns in rheumatoid arthritis estimated by the number of swollen and tender joints, the erythrocyte sedimentation rate, and hemoglobin: Longterm course and association to radiographic progression. J Rheumatol 27:47-57, 2000. 49. Fujinami M, Sato K, Kashiwazaki S, et al: Comparable histological appearance of synovitis in seropositive and seronegative rheumatoid arthritis. Clin Exp Rheumatol 15:11-17, 1997. 50. Gough A, Sambrook P, Devlin J, et al: Osteoclastic activation is the principal mechanism leading to secondary osteoporosis in rheumatoid arthritis. J Rheumatol 25:1282-1289, 1998. 51. Machold KP, Stamm TA, Nell VP, et al: Very recent onset rheumatoid arthritis: Clinical and serological patient characteristics associated with radiographic progression over the first years of disease. Rheumatology (Oxf) 46:342-349, 2007. 52. Symmons DP, Silman AJ: Aspects of early arthritis: What determines the evolution of early undifferentiated arthritis and rheumatoid arthritis? An update from the Norfolk Arthritis Register. Arthritis Res Ther 8:214, 2006. 53. Combe B, Dougados M, Goupille P, et al: Prognostic factors for radiographic damage in early rheumatoid arthritis: A multiparameter prospective study. Arthritis Rheum 44:1736-1743, 2001. 54. Green MJ, Gough AK, Devlin J, et al: Serum MMP-3 and MMP-1 and progression of joint damage in early rheumatoid arthritis. Rheumatology (Oxf) 42:83-88, 2003. 55. Wolfe F, Sharp JT: Radiographic outcome of recent-onset rheumatoid arthritis: A 19-year study of radiographic progression. Arthritis Rheum 41:1571-1582, 1998. 56. Goodson NJ, Symmons DP, Scott DG, et al: Baseline levels of Creactive protein and prediction of death from cardiovascular disease in patients with inflammatory polyarthritis: A ten-year followup study of a primary care-based inception cohort. Arthritis Rheum 52: 2293-2299, 2005. 57. Maradit-Kremers H, Nicola PJ, Crowson CS, et al: Raised erythrocyte sedimentation rate signals heart failure in patients with rheumatoid arthritis. Ann Rheum Dis 66:76-80, 2007. 58. Posthumus MD, Limburg PC, Westra J, et al: Serum matrix metalloproteinase 3 levels in comparison to C-reactive protein in periods with and without progression of radiological damage in patients with early rheumatoid arthritis. Clin Exp Rheumatol 21:465-472, 2003. 59.  ter Borg EJ, Horst G, Limburg PC, et al: C-reactive protein levels during disease exacerbations and infections in systemic lupus erythematosus: A prospective longitudinal study. J Rheumatol 17:1642-1648, 1990. 60. Moutsopoulos HM, Mavridis AK, Acritidis NC, et al: High C-reactive protein response in lupus polyarthritis. Clin Exp Rheumatol 1:53-55, 1983. 61. Vila LM, Alarcon GS, McGwin G Jr, et al: Systemic lupus erythematosus in a multiethnic cohort (LUMINA): XXIX. Elevation of erythrocyte sedimentation rate is associated with disease activity and damage accrual. J Rheumatol 32:2150-2155, 2005. 62. Gabay C, Roux-Lombard P, de Moerloose P, et al: Absence of correlation between interleukin 6 and C-reactive protein blood levels in systemic lupus erythematosus compared with rheumatoid arthritis. J Rheumatol 20:815-821, 1993. 63. Figueredo MA, Rodriguez A, Ruiz-Yague M, et al: Autoantibodies against C-reactive protein: Clinical associations in systemic lupus erythematosus and primary antiphospholipid syndrome. J Rheumatol 33:1980-1986, 2006.

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64. Sjowall C, Eriksson P, Almer S, et al: Autoantibodies to C-reactive protein is a common finding in SLE, but not in primary Sjogren’s syndrome, rheumatoid arthritis or inflammatory bowel disease. J Autoimmun 19:155-160, 2002. 65. Russell AI, Cunninghame Graham DS, Shepherd C, et al: Polymorphism at the C-reactive protein locus influences gene expression and predisposes to systemic lupus erythematosus. Hum Mol Genet 13: 137-147, 2004. 66. Selzer F, Sutton-Tyrrell K, Fitzgerald SG, et al: Comparison of risk factors for vascular disease in the carotid artery and aorta in women with systemic lupus erythematosus. Arthritis Rheum 50:151-159, 2004. 67. Pahor A, Hojs R, Gorenjak M, et al: Accelerated atherosclerosis in pre-menopausal female patients with rheumatoid arthritis. Rheumatol Int 27(2):119-123, 2006. 68. Gonzalez-Gay MA, Rodriguez-Valverde V, Blanco R, et al: Polymyalgia rheumatica without significantly increased erythrocyte sedimentation rate: A more benign syndrome. Arch Intern Med 157:317-320, 1997. 69. Proven A, Gabriel SE, O’Fallon WM, et al: Polymyalgia rheumatica with low erythrocyte sedimentation rate at diagnosis. J Rheumatol 26:1333-1337, 1999. 70. Cantini F, Salvarani C, Olivieri I, et al: Erythrocyte sedimentation rate and C-reactive protein in the evaluation of disease activity and severity in polymyalgia rheumatica: A prospective follow-up study. Semin Arthritis Rheum 30:17-24, 2000. 71. Salvarani C, Hunder GG: Giant cell arteritis with low erythrocyte sedimentation rate: Frequency of occurence in a population-based study. Arthritis Rheum 45:140-145, 2001. 72. Salvarani C, Cimino L, Macchioni P, et al: Risk factors for visual loss in an Italian population-based cohort of patients with giant cell arteritis. Arthritis Rheum 53:293–299, 2005. 73. Gonzalez-Gay MA, Lopez-Diaz MJ, Barros S, et al: Giant cell arteritis: Laboratory tests at the time of diagnosis in a series of 240 patients. Medicine (Baltimore) 84:277-290, 2005. 74. Larrosa M, Gratacos J, Sala M: Polymyalgia rheumatica with low erythrocyte sedimentation rate at diagnosis. J Rheumatol 27: 1815-1816, 2000. 75. Liozon E, Jauberteau-Marchan MO, Ly K, et al: Giant cell arteritis with a low erythrocyte sedimentation rate: Comments on the article by Salvarani and Hunder. Arthritis Rheum 47:692-693; author reply 693-694, 2002. 76. Salvarani C, Cantini F, Niccoli L, et al: Acute-phase reactants and the risk of relapse/recurrence in polymyalgia rheumatica: A prospective followup study. Arthritis Rheum 53:33-38, 2005. 77. Pearson JD: Markers of endothelial perturbation and damage. Br J Rheumatol 32:651-652, 1993. 78. Stam TC, Swaak AJ, Kruit WH, et al: Regulation of ferritin: A specific role for interferon-alpha (IFN-alpha)? The acute phase response in patients treated with IFN-alpha-2b. Eur J Clin Invest 32(Suppl 1): 79-83, 2002. 79. Fautrel B, Le Moel G, Saint-Marcoux B, et al: Diagnostic value of ferritin and glycosylated ferritin in adult onset Still’s disease. J Rheumatol 28:322-329, 2001. 80. Fautrel B, Zing E, Golmard JL, et al: Proposal for a new set of classification criteria for adult-onset Still disease. Medicine (Baltimore) 81:194-200, 2002. 81. Emmenegger U, Frey U, Reimers A, et al: Hyperferritinemia as indicator for intravenous immunoglobulin treatment in reactive macrophage activation syndromes. Am J Hematol 68:4-10, 2001. 82. Emmenegger U, Reimers A, Frey U, et al: Reactive macrophage activation syndrome: A simple screening strategy and its potential in early treatment initiation. Swiss Med Wkly 132(17-18):230-236, 2002.   83. Grom AA: Natural killer cell dysfunction: A common pathway in systemic-onset juvenile rheumatoid arthritis, macrophage activation syndrome, and hemophagocytic lymphohistiocytosis? Arthritis Rheum 50:689-698, 2004.

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  84. Kawashima M, Yamamura M, Taniai M, et al: Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still’s disease. Arthritis Rheum 44:550-560, 2001.   85. Spoorenberg A, van der Heijde D, de Klerk E, et al: Relative value of erythrocyte sedimentation rate and C-reactive protein in assessment of disease activity in ankylosing spondylitis. J Rheumatol 26:980-984, 1999.   86. Braun J, Brandt J, Listing J, et al: Treatment of active ankylosing spondylitis with infliximab: A randomised controlled multicentre trial. Lancet 359:1187-1193, 2002.   87. Stone MA, Payne U, Pacheco-Tena C, et al: Cytokine correlates of clinical response patterns to infliximab treatment of ankylosing spondylitis. Ann Rheum Dis 63:84-87, 2004.   88. Sonel B, Tutkak H, Duzgun N: Serum levels of IL-1 beta, TNF-alpha, IL-8, and acute phase proteins in seronegative spondyloarthropathies. Joint Bone Spine 69:463-467, 2002.   89. Nevitt M, Felson D, Peterfy C, et al: Inflammation markers (CRP, TNF-a, IL-6) are not associated with radiographic or MRI findings of knee OA in the elderly: The health ABC study. Arthritis Rheum 46(9 Suppl):S372, 2002.   90. Sowers M, Jannausch M, Stein E, et al: C-reactive protein as a biomarker of emergent osteoarthritis. Osteoarthritis Cartilage 10: 595-601, 2002.   91. Punzi L, Ramonda R, Oliviero F, et al: Value of C reactive protein in the assessment of erosive osteoarthritis of the hand. Ann Rheum Dis 64:955-957, 2005.   92. Donald F, Ward MM: Evaluative laboratory testing practices of United States rheumatologists. Arthritis Rheum 41:725-729, 1998.   93. Giacomello A, Quaratino CP, Zoppini A: Erythrocyte sedimentation rate within rheumatic disease clinics. J Rheumatol 24:2263-2265, 1997 (letter; comment).   94. Paulus HE, Brahn E: Is erythrocyte sedimentation rate the preferable measure of the acute phase response in rheumatoid arthritis? J Rheumatol 31:838-840, 2004.   95. Wolfe F: Comparative usefulness of C-reactive protein and erythrocyte sedimentation rate in patients with rheumatoid arthritis. J Rheumatol 24:1477-1485, 1997.   96. Danesh J, Wheeler JG, Hirschfield GM, et al: C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 350:1387-1397, 2004.   97. Kushner I, Rzewnicki D, Samols D: What does minor elevation of C-reactive protein signify? Am J Med 119:166 e117-e128, 2006. 98. Lloyd-Jones DM, Liu K, Tian L, et al: Narrative review: Assessment of C-reactive protein in risk prediction for cardiovascular disease. Ann Intern Med 145:35-42, 2006.   99. Folsom AR, Chambless LE, Ballantyne CM, et al: An assessment of incremental coronary risk prediction using C-reactive protein and other novel risk markers: The atherosclerosis risk in communities study. Arch Intern Med 166:1368-1373, 2006. 100. Yusuf S, Hawken S, Ounpuu S, et al: Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study. Lancet 364:937-952, 2004. 101. Danesh J, Collins R, Appleby P, et al: Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: Meta-analyses of prospective studies. JAMA 279:1477-1482, 1998. 102. Verma S, Devaraj S, Jialal I: Is C-reactive protein an innocent bystander or proatherogenic culprit? C-reactive protein promotes atherothrombosis. Circulation 113:2135-2150; discussion 2150, 2006. 103. Lowe GD, Pepys MB: C-reactive protein and cardiovascular disease: Weighing the evidence. Curr Atheroscler Rep 8:421-428, 2006. 104. Casas JP, Shah T, Cooper J, et al: Insight into the nature of the CRP-coronary event association using Mendelian randomization. Int J Epidemiol 35:922-931, 2006.

53

Imaging Modalities in Rheumatic Disease LEYLA ALPARSLAN  •  BARBARA N. WEISSMAN

In recent years, imaging techniques available for use in evaluation of rheumatologic diseases have greatly expanded beyond the conventional radiographic studies. This chapter provides an introduction to the general principles of various imaging modalities to emphasize the strengths and weaknesses of each of these techniques and their musculoskeletal applications. Characteristic imaging findings of several arthritic diseases and related conditions are discussed by integrating the findings of conventional radiography with the findings of more advanced imaging techniques, including magnetic resonance imaging (MRI), computed tomography (CT), ultrasound, and scintigraphy.

OVERVIEW OF IMAGING MODALITIES CONVENTIONAL RADIOGRAPHY Conventional radiographic examination is traditionally the first step in the radiologic evaluation of patients with suspected arthritis. In addition to its role in diagnosing and confirming the presence of arthritis, conventional radiography has been used for monitoring the progression of the disease and the efficacy of treatment. Assessment of radiographic changes in rheumatoid arthritis (RA), using several scoring methods, is one of the pivotal measures in clinical trials. Conventional radiography has major deficiencies in imaging arthritis, however. Its poor sensitivity to soft tissue contrast does not allow direct visualization of inflamed synovial tissues, articular cartilage, bone marrow edema, menisci, ligaments, and periarticular tendons. Conventional radiography can detect only the osseous erosions and joint space narrowing that are the late irreversible sequelae of preceding synovitis. It provides limited information about disease activity. Despite its limitations, conventional radiography is inexpensive and universally available, and remains the mainstay in the basic imaging of arthritis. ARTHROGRAPHY In arthrography, radiopaque contrast material is injected into the joint, occasionally with air (double-contrast arthrography), to delineate the intra-articular structures and joint capsule. In the past, arthrography was frequently used to evaluate injuries of the articular cartilage, menisci, ligaments, and rotator cuff, and to investigate monarticular arthritis (Fig. 53-1). More recently, these procedures have been replaced by other imaging modalities, particularly MRI.

The primary indication for an aspiration arthrogram is to diagnose a septic joint. Aspiration arthrography also is helpful in the evaluation of patients with painful joint arthroplasty to differentiate between infection and aseptic loosening of the prosthesis. Other uses of arthrography include diagnosis and treatment of adhesive capsulitis. Joint distention during arthrography, the “brisement procedure,” may aid in the treatment of this condition.1 Corticosteroid or long-acting anesthetic may be injected into the joints to provide pain relief. Arthrography combined with MRI can provide better visualization of loose bodies, fibrocartilaginous and labrocapsular abnormalities, and osteochondral lesions. COMPUTED TOMOGRAPHY Technical Considerations Since its development in the early 1970s, CT has had wide applications in almost all the subspecialties of radiology and has effectively replaced conventional tomography. In CT, a collimated x-ray beam is passed through the body from multiple directions, and the exiting attenuated x-ray is measured by detectors. The data obtained from the detectors with each set of exposures are transferred to the computer for image reconstruction.2 With few exceptions, CT generally is performed in the axial plane. It is possible, however, to reformat images in other planes. The CT images are formed in arrays of individual picture elements (pixels), each of which is assigned a CT number known as a Hounsfield unit (HU). These attenuation values are expressed on an arbitrary scale, with water density being 0 HU, bone density being +1000 HU, and air density being −1000 HU. To visualize a specific tissue optimally, the range and level of densities to be displayed can be adjusted on monitors. For musculoskeletal scans, the images are reviewed in bone and soft tissue settings. There are two methods of CT scanning: conventional (nonspiral) and volumetric (spiral or helical) acquisition. In conventional CT systems, images are acquired sequentially with a delay of a few seconds between each exposure. In spiral (helical) CT scans, the data are collected continuously. When a volume of data is acquired with spiral CT, images can be reconstructed at any desired increments from this volumetric dataset. The advantages of spiral CT are significant reduction of scan time, contiguous slices eliminating gaps from respiratory misregistration, and superior multiplanar reformation.3 777

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B

S

Figure 53-1  Rotator cuff tear shown on single-contrast arthrography. Anteroposterior radiograph after injection of iodinated contrast material into the joint shows filling of the normal shoulder joint and subscapularis recess (S). The contrast material has filled the subacromial-subdeltoid bursa (B), indicating a full-thickness rotator cuff tear, and has extended into the acromioclavicular joint. The acromioclavicular joint distention may be palpable.

More recently, the introduction of multidetector (multislice) spiral CT technology has led to faster and better quality images with high spatial resolution (Fig. 53-2). In these new scanners, the data are collected with two or more parallel arcs of detectors that enable the coverage of long anatomic segments within seconds. Multidetector CT scanning also improves imaging of obese patients and patients with metal hardware.4,5 Clinical Application The main advantages of CT scanning over conventional radiography are greater contrast resolution, cross-sectional display of the acquired images, and the capability of reformatting images in different planes. The tomographic nature of CT allows better visualization of the joints that have complex anatomy and joints obscured by overlying structures, such as sacroiliac, subtalar, and sternoclavicular joints. The role of CT in evaluation of sacroiliac joint disorders has been investigated in several studies. CT images of sacroiliac joints generally are considered to be more consistently interpretable and sensitive for early pathologic changes than conventional radiography.6-9 CT also can provide guidance for aspiration of the sacroiliac joints and intra-articular injection of corticosteroids. Although CT offers high contrast between bone and adjacent soft tissues and is excellent for evaluation of osseous structures and calcification, its sensitivity for soft tissue contrast is poor and insufficient to visualize intra-articular structures. The limited contrast resolution of CT for evaluation of articular cartilage, synovial tissue, and ligaments can be overcome to some extent by injection of iodinecontaining contrast material, air, or both into the joint (CT arthrography). In more recent studies, it has been reported that dual-detector spiral CT arthrography of the knee

Figure 53-2  Coronal reformatted image of the knee acquired by multidetector CT after intra-articular injection of iodinated contrast material. Excellent spatial resolution can be achieved with multidetector CT for reformatted images by using submillimeter reconstruction increments.

enables accurate detection of meniscal tears and open cartilage lesions.10,11 Another application of CT in rheumatologic imaging is preoperative evaluation of arthritic patients who are candidates for various surgical procedures.12 In surgical planning of total shoulder and hip arthroplasties, CT can be used to assess the glenoid body angle, bone stock, and protrusio acetabuli. CT also is helpful in evaluating many congenital diseases, including tarsal coalition, patellar tracking abnormalities, femoral anteversion, and tibial torsion. MAGNETIC RESONANCE IMAGING MRI produces high-quality tomographic images of the body in any plane by portraying the distribution of hydrogen nuclei within the tissue imaged. MRI does not involve ionizing radiation; it uses radiofrequency pulses and a strong magnetic field to create images. When the patient is placed in a strong magnetic field, the hydrogen nuclei (protons) in the body align with the axis of the external magnetic field. Radiofrequency pulses are applied to change the orientation of aligned protons. After the cessation of the radiofrequency pulses, the excited protons relax and return to their initial state by emitting electromagnetic energy. The emitted electromagnetic energy is detected by, localized by, and ultimately converted into the MR image.13,14 The MRI signal intensity (brightness) of a particular ­tissue depends on the number of the mobile hydrogen nuclei and on two relaxation times: T1 and T2. Tissues or materials with low proton density, such as calcium, air, cortical bone, tendons, menisci, and ligaments, exhibit low or no signal intensity in all pulse sequences. Fat, fluid, and edematous tissues containing high proton density have a variable appearance, depending on the pulse sequence.13

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D

*

* IS

*

A

B

Figure 53-3  MRI of inflammatory arthritis. A and B, Oblique coronal fast spin echo proton density images from an MRI-arthrogram of the shoulder of a patient with ankylosing spondylitis shows frondlike synovitis (stars). Erosions (arrowheads) at the superior aspect of the humeral head give the appearance of hatchet deformity. There is thinning or partial tear of the rotator cuff without evidence of a full-thickness tear. The infraspinatus (IS) and deltoid (D) muscles are atrophic.

Relaxation time refers to the time required for tissue magnetization to return to equilibrium conditions after the radiofrequency pulse is turned off. T1 relaxation time represents the time the hydrogen protons take to return to the axis of the external magnetic field; T2 relaxation time depends on the time the protons take to dephase. T1 and T2 values, expressed in milliseconds, are constant for a particular type of tissue. An MR image is said to be T1-weighted if image contrast is based on T1 differences between tissues. Similarly, image contrast on a T2-weighted image is based on different T2 relaxation times of tissues.15 The type of MRI is determined by altering (1) the repetition time (TR), the time that elapses between applying sequential radiofrequency pulses to the patient, or (2) the echo time (TE), the time interval between the incident radiofrequency pulse and when the signal is recorded. A T1-weighted imaging sequence uses short TR and TE, and T2-weighted images are produced with long TR and TE. A third type of image is a proton density or intermediate-weighted image with long TR and short TE. A typical MRI examination includes series of different types of imaging sequences; T1-weighted and proton density–weighted images provide anatomic information, and T2-weighted and inversion recovery images are sensitive to fluid and to pathologic ­processes. Although MRI provides great inherent soft tissue contrast, intravenous contrast agents may be used to enhance further the contrast difference between normal and pathologic or vascular tissues. The most widely used agents are gadolinium compounds, which have a T1-shortening effect on nearby water protons. This effect results in increased signal intensity on T1-weighted images.16 Uptake depends

on tissue vascularity and capillary permeability. Gadolinium also is used in dilute solution as an MRI arthrographic contrast agent, although it has not been approved by the U.S. Food and Drug Administration for this use. Clinical Application MRI is the only available imaging modality that can directly display the osseous, cartilaginous, and soft tissue components of the joint simultaneously. This uniqueness of MRI derives from its excellent soft tissue contrast. Application of MRI in the assessment of arthritis has increased rapidly in clinical practice and research. Many factors have contributed to this increase, including better access to scanners, improved resolution of scanners, and development of new MRI sequences for evaluating different tissues.17 MRI offers several distinct advantages over conventional radiography and clinical examination in evaluating early RA. MRI is capable of showing inflammatory synovitis with or without contrast enhancement (Fig. 53-3). MRI detects bone erosions in early RA before they appear on plain radiographs. Bone marrow edema is another important MRI finding associated with inflammatory arthritis and is thought to be a forerunner of erosion. This valuable information provided by MRI may be used to improve diagnostic accuracy, predict prognosis, and monitor the effectiveness of therapies in clinical practice.18-20 In the near future, MRI is likely to play a major role as a prognostic marker and as an outcome measure in the management of RA. To achieve these goals, further development is required in terms of longitudinal studies and ­standardization of MRI scanning protocols, nomenclature, and scoring systems to make them reproducible and

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C

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Figure 53-4  MRI of occult insufficiency fractures. A and B, Anteroposterior (A) and lateral (B) radiographs of a patient with rheumatoid arthritis show no visible fracture. C and D, Coronal short tau inversion recovery (STIR) (C) and sagittal fast spin echo proton density (D) MR images show a linear area of low signal in the medial tibial condyle, indicating a fracture. The surrounding bone marrow edema is evident as diffuse increased signal on the STIR image (C).

r­ eliable.21 In addition to the potential applications of MRI mentioned previously, the most widely accepted, practical application of MRI in inflammatory arthritis is in evaluation of some of the complications that may arise because of the disease or its treatment, such as tendon tears, insufficiency fractures, osteonecrosis, and brainstem and spinal cord compression (Fig. 53-4). At present, the main drawbacks of MRI are its high cost and limited availability. MRI requires a longer scan time compared with most imaging modalities. Patients have to stay still during the scanning procedure because motion

often degrades the image. MRI is contraindicated in patients with cardiac pacemakers, certain types of aneurysm clips, cochlear implants, and intraocular metallic foreign bodies. ULTRASOUND Technical Considerations Ultrasound imaging is based on detection and display of sound waves reflected from various interfaces within the body. Sound waves are produced and transmitted by

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t­ ransducers, which convert electric energy to sound energy. The transducers also are receivers. Returning ultrasound signals are displayed in gray scale; images are produced in a black-and-white format, and each gray dot represents a reflected sound wave of a particular intensity. Transducers are described in megahertz (MHz), indicating their sound wave frequencies. High-resolution linear transducers are best applied to musculoskeletal examination. Superficial structures are imaged with 7.5- to 15-MHz transducers, whereas deeper structures, such as the hip joint, require low-frequency transducers.22 Doppler ultrasound is a technique developed for evaluation of blood flow. Doppler information can be displayed as color maps simultaneously with a standard ultrasound image. Power Doppler ultrasound is a more recent development in Doppler imaging that offers greater sensitivity for detection of low-velocity blood flow and small vessels than conventional color Doppler ultrasound.23,24 The addition of microbubble-based ultrasound contrast agents increases Doppler signal intensity and improves the detection of lowvolume and low-velocity blood flow and deeply located vessels.25 Clinical Application More recent developments in ultrasound technology have expanded the application of ultrasound in the musculo­ skeletal system. Introduction of high-resolution linear transducers has allowed excellent panoramic imaging of tendons, muscles, and vessels. Three-dimensional imaging permits multiplanar reformatting, enabling visualization of the optimal image plane, which may or may not be directly accessible.26,27 Advantages of ultrasound include its noninvasiveness, portability, low cost, and lack of ionizing radiation. The major weakness of ultrasound is that the ultrasound waves cannot penetrate bones; for this reason, the bones and structures deep to bones are obscured. Likewise, evaluation of intra-articular structures is limited, depending on their accessibility by the sonographic beam; only portions of articular cartilage, synovial tissue, and intra-articular ligaments can be examined. A widely accepted application of musculoskeletal ultrasound is evaluation of rotator cuff tears. Any tendon that is located in a site accessible by the ultrasound beam can be examined for tear, tenosynovitis, and subluxation or dislocation. The real-time capability of ultrasound permits dynamic evaluation of tendons. Because fluid is a good conductor of sound, fluid collections such as Baker’s cysts, bursitis, and ganglions can be readily identified by ultrasound. Ultrasound also can provide easy guidance for aspiration, biopsy, and intra-articular anesthetic or steroid injections. Potential applications of ultrasound in the evaluation of RA are under investigation. Preliminary data have suggested that Doppler ultrasound with or without contrast agent is a potential method for assessing the activity of synovitis in RA by measuring alterations in the vascularity of the synovial membrane.28-31 Also, in more recent studies, the diagnostic efficacy of high-resolution ultrasound for detecting osseous erosions of small joints in early RA has been reported.32,33

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RADIONUCLIDE SCINTIGRAPHY In contrast to other imaging modalities, nuclear medicine imaging provides physiologic and metabolic information about the tissues using gamma ray–emitting radioisotopes. Scintigraphic images are obtained by mapping the spatial distribution and concentration of radioisotopes administered into the body. Scintigraphy tends to produce images with less detail and more noise than other modalities; this is due to the relatively few photons used to generate scintigraphic images. Conventional scintigraphic images are projectional and subject to superimposition. Single photon emission computed tomography (SPECT), a tomographic technique analogous to CT and performed with a rotating camera, provides better lesion localization because of its ability to separate normal overlying activity from target activity. The most commonly used compounds in imaging of bone disorders and articular disease are Tc 99m methylene diphosphonate and Tc 99m hydroxymethylene diphosphonate. Although the exact mechanism of uptake of the radiolabeled diphosphonates is not well understood, it has been suggested that these compounds label bone by adsorption to the hydroxyapatite crystal. The amount of tracer uptake depends on local osteoblastic activity and blood flow. Tc 99m methylene diphosphonate scintigraphy is highly sensitive for changes in physiology, but the information provided is nonspecific. A large variety of bone disorders, such as infection, arthritis, neoplasms, and trauma, lead to increased bone metabolism and elevated blood flow with resultant increased uptake. A positive bone scan finding requires close correlation with other imaging modalities and clinical information to establish a correct diagnosis. Other radiotracers used as markers of inflammatory proc­ esses are gallium citrate Ga 67 and indium In 111 chloride. These radiotracers are iron analogues and attach to iron-carrying proteins, particularly transferrin. The tracer deposition at sites of inflammation may occur by several mechanisms, including passage of the tracer through leaky capillaries and binding to transferrin receptors of dendritic and T cells in inflammatory arthritis. The suboptimal physical characteristics and high radiation dose are major drawbacks of these radiotracers.13,34 Clinical Application The role of scintigraphy in the evaluation of arthritides has been limited. Scintigraphy with Tc 99m diphosphonates seems to be a more sensitive method for detecting inflammatory joint disease than conventional radiographs. Negative bone scintigraphy accurately excludes active arthritis in patients with persistent polyarthralgia. In addition, scintigraphy is a convenient way of surveying the entire skeleton for the extent and distribution of the arthritic involvement. Its major disadvantages are that Tc 99m methylene diphosphonate bone scan remains positive for a long time after synovitis subsides, and the information it provides is nonspecific.35 Several new scintigraphic techniques, such as radiolabeled cell determinant 4 (CD4), E-selectin antibodies, cytokines, and somatostatin receptor imaging, and Tc 99m IgG scintigraphy, are under investigation for assessment of disease

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activity in arthritis. It has been reported that compared with conventional bone scan, Tc 99m IgG scintigraphy is a more specific method of detecting synovitis activity and differentiating between the various degrees of activity in RA.36,37 Bone scan has been widely used for assessment of insufficiency fractures and osteonecrosis associated with arthritides. MRI has been shown to be a more sensitive and specific modality in detecting these complications, however.38 POSITRON EMISSION TOMOGRAPHY Technical Considerations Positron emission tomography (PET) is a functional imaging technique that enables metabolic mapping of the tissues in vivo with positron-emitting radionuclides. Fludeoxyglucose F 18 (18FDG) is the most commonly used radiopharmaceutical in PET because of its availability, favorable 110-minute half-life, and high uptake in most cancers.39,40 When injected into the body, 18FDG is a tracer of glucose metabolism; 18FDG is transported into the cells by glucose-specific transporters and then phosphorylated to FDG-6-phosphate. FDG-6-phosphate is not metabolized any further, and there is little diffusion out of the cell, which allows time for imaging. The degree of cellular uptake of 18FDG is proportional to cellular metabolism.41 PET scanners collect data in two or three dimensions and display images in thin (3 to 4 mm) tomograms in any plane (mostly coronal, transverse, and sagittal planes). Wholebody or single-organ studies can be obtained. Introduction of integrated PET/CT scanners in the late 1990s allowed precise localization of 18FDG-positive lesions, greatly facilitating image interpretation. In addition to offer­ ing an aligned functional and anatomic image, the CT component of PET/CT provides fast PET attenuation correction for accurate radiotracer uptake quantitation.42 The goal of CT scanning is to generate a map for PET images; CT images obtained during PET/CT usually are limited to some degree compared with routine diagnostic CT scans performed with intravenous contrast material and thinner slices. Clinical Application Greater than 80% of clinical PET is currently used for oncology patients. PET is of proven benefit for staging of certain cancers and lymphoma and in monitoring the effects of therapy.43-45 18FDG shows high target activity in many neoplasms, where regionally increased blood flow and increased glucose metabolism are present. Labeled 18FDG is not, however, a specific marker for cancer; similarly activated macrophages and neutrophils at the sites of infection and inflammation also show high tracer uptake.46 Several publications have shown the feasibility of 18FDGPET in the evaluation of patients with suspected prosthetic infection, chronic osteomyelitis, fever of unknown origin, and large vessel vasculitis.46-49 Polisson and Palmer and their colleagues50,51 first reported the application of 18FDGPET imaging in the evaluation of inflammatory arthritis in 1995. The authors showed strong correlation between the standardized 18FDG uptake value in inflamed joints and volume of enhancing synovitis estimated with MRI. Beckers and coworkers52 reported similar findings showing that

18FDG-PET

imaging can assess the metabolic activity of synovitis and measure the disease activity in RA. Standardized uptake values were highly correlated with the synovial thickness measured by ultrasonography.52 Later, the same group conducted a study on patients with active RA who were imaged before and 4 weeks after initiation of anti– tumor necrosis factor-α treatment, which showed changes in standardized uptake values of PET imaging correlating with changes of serum C-reactive protein and matrix metalloproteinase-3 levels.53,54 These results are promising for 18FDG-PET imaging in quantifying the disease activity in inflammatory arthritides and effectiveness of antirheumatic therapy. The potential clinical utility of these measures remains to be defined, however.

CONDITIONS PRIMARILY AFFECTING PERIPHERAL JOINTS INFLAMMATORY CONDITIONS Rheumatoid Arthritis General Imaging Features Symmetry. The hallmark of RA is the symmetric involvement of synovial joints. Osteoporosis. Osteoporosis is a characteristic feature of RA. Early in RA, it tends to be localized to the juxta-articular region of the small peripheral joints. Later, generalized osteoporosis may be present in the axial and appendicular skeleton, often exacerbated by medications (e.g., steroids) and disuse. Soft Tissue Changes. One of the earliest radiographic changes seen in the hands and feet is symmetric soft tissue swelling around the involved joints. Soft tissue swelling is caused by a summation of joint effusion, synovial proliferation, and periarticular soft tissue edema. Occasionally, joint effusion and edema may produce transient, subtle joint space widening in the small joints of the hand early in the disease.55 Displacement of the fat pads in the elbow, knee, and ankle is an indirect sign of the presence of joint distention on radiographs. Swelling around the joints also may occur as a result of bursitis or tenosynovitis and is usually eccentric. Rheumatoid nodules appear as noncalcified, eccentric, lobular subcutaneous masses on radiographs (Fig. 53-5). Typical locations include the olecranon, heel, Achilles tendon region, and areas around the femoral trochanters and ischial tuberosities—sites that are subjected to pressure. On MRI, nodules exhibit low signal intensity on T1-weighted and heterogeneous low and high signal intensity on T2weighted images.56 Bony Erosions. Erosive changes indicate the aggressiveness of the arthritis. Erosions appear first in the “bare areas” of the joints where the articular cartilage is absent or thinnest. These marginal erosions may be subtle and first appear as disruption of the white cortical line, especially at the radial aspect of the metacarpal heads under the collateral ligaments. In addition to marginal erosions, two other types of erosions have been described in RA. Compressive erosions refer to remodeling of osteoporotic bone with gradual invagination of one bone into another or the effect of muscular forces acting on osteoporotic bone.

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Figure 53-5  Rheumatoid nodules appearing as lobulated subcutaneous soft tissue swellings (arrows) at the extensor surface of the elbow and forearm.

The most characteristic site of compressive erosion is the hip, where protrusio acetabuli may be identified. Other sites are at the metacarpophalangeal joints, where chronic subluxation leads to remodeling of the base of a proximal phalanx by the adjacent metacarpal head. The third type of erosion seen in RA is surface resorption, usually resulting from inflammation of an adjacent tendon sheath. The typical location of this kind of erosion is at the outer margin of the ulnar styloid process secondary to extensor carpi ulnaris tenosynovitis.57 Joint Space Narrowing. Progressive destruction of articular cartilage leads to joint space narrowing. Joint space narrowing in RA tends to be diffuse, and this feature may allow differentiation from the focal or asymmetric type of joint space loss that occurs in osteoarthritis. With continuing cartilage damage, the joint space may become partially or completely obliterated by fibrous ankylosis. In end-stage disease, bony ankylosis eventually may develop, characteristically in the wrist and midfoot. Bone Cysts. Subchondral cysts are almost invariably described as radiographic features of RA. These subchondral radiolucent areas are referred to as cysts, geodes, or pseudocysts. They may develop as a result of intraosseous extension of pannus, nutritional, and metabolic injury to the bone or true intraosseous rheumatoid nodules. Mechanical factors also may accentuate the development of cystic lesions. A cystic pattern of RA has been described in the hands and wrists of patients who maintain high physical activity and is called RA of robust reaction type.58 Occasionally, very large cystic lesions may be encountered in the elbow (olecranon process of ulna, distal humerus),

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Figure 53-6  Ulnar deviation in rheumatoid arthritis. Severe ulnar deviation is present at the metacarpophalangeal joints with extensive erosions. Pancompartmental bony ankylosis and erosion also are seen in the wrist.

femoral neck, or knee (distal femur, proximal tibia, patella); these have been described as pseudocystic RA. These large cysts may lead to pathologic fractures. Deformities and Instabilities. Joint malalignment and deformities are due to capsular, ligamentous, and tendinous laxity and disruption, and associated muscular contraction. The deformities are most characteristic in the wrist; the metacarpophalangeal, metatarsophalangeal, and interphalangeal joints of the hand and foot; and the atlantoaxial region. The cartilage and bone loss also may lead to deformity, such as is seen in protrusio acetabuli. Malalignments may be reduced when positioning for the radiographs. Abnormalities in Specific Sites Hand and Wrist. The usual sites of involvement in the hands are the metacarpophalangeal and proximal interphalangeal joints. The early changes consist of fusiform soft tissue swelling, juxta-articular osteoporosis, diffuse joint space loss, and marginal erosions. These changes tend to be bilaterally symmetric in involved joints. Cartilage loss may occur without bone erosions. With progression of the disease, large erosions and complete obliteration of joint spaces appear. Finger deformities, such as swan neck and boutonnière deformities and ulnar deviation at the metacarpophalangeal joints, are common findings (Fig. 53-6). In the end stage of the disease, fibrous ankylosis may occur in the affected joints of the hand, and eventually arthritis mutilans may develop. RA involves all the compartments of the wrist, with relative sparing of the first carpometacarpal compartment. The distal ulna is a characteristic target area with surface erosions along the outer surface of the ulnar styloid secondary to tenosynovitis of the extensor carpi ulnaris. ­Inflammatory

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changes in the prestyloid recess and inferior radioulnar compartment may produce erosions at the tip and base of the ulnar styloid. Early erosions may be encountered in any carpal bone, typically at the radial styloid, the waist of the scaphoid, triquetrum, and pisiform (Fig. 53-7). As the disease progresses, greater amounts of cartilage and bone are destroyed, leading to bony ankylosis and carpal collapse. Drift of the entire carpus in an ulnar direction, volar direction, or both and scapholunate dissociation are frequently encountered deformities. Elbow. Elbow involvement occurs in at least half of patients with RA. The earliest changes are soft tissue abnormalities, including joint effusion identified by elevation of the anterior and posterior fat pads, olecranon bursitis, and rheumatoid nodules along the extensor surface of the elbow. Diffuse cartilage loss and erosive changes occur in all compartments. Eventually, extensive osteolysis of the bones can simulate a neuropathic osteoarthropathy. Large intramedullary cystic erosions of the distal humerus and olecranon may predispose to pathologic fracture.59 Shoulder. At the shoulder, the glenohumeral and acromioclavicular joints are involved. Cartilage loss in the glenohumeral joint is an early finding. Erosions typically are seen at the superolateral aspect of the humeral head, resembling Hill-Sachs fracture associated with anterior shoulder dislocation. The subacromial-subdeltoid bursa may be distended owing to bursitis. Involvement of the acromioclavicular joint may lead to resorption of the distal clavicle and joint widening. Rotator cuff tear or atrophy is common with resultant superior migration of the humeral head and pressure erosion of the undersurface of the acromion (Fig. 53-8). Foot. Involvement of the foot in RA is about as common as involvement of the hand. In the forefoot, early erosions

Figure 53-7  Rheumatoid arthritis. Typical sites of osseous erosion of a rheumatoid wrist shown here include triquetrum, pisiform, scaphoid, and radius. There also are erosions at the ulnar aspect of the distal radius and the ulnar styloid process secondary to involvement of the inferior radioulnar compartment. Diffuse cartilage loss also is evident in the radiocarpal compartment.

occur at the lateral aspect of the fifth and medial aspect of the first metatarsal heads. With progression, diffuse cartilage loss and larger erosions may be seen in all metatarsophalangeal joints, leading to forefoot deformities. These include hallux valgus, hammer toes, and “cock up” deformity of the metatarsophalangeal joints; fibular deviation of the toes; and plantar subluxation of the metatarsal heads. In long-standing RA, bony ankylosis of the midfoot is common. Subluxation at the talonavicular joint may indicate posterior tibialis tendon rupture. In the heel, soft tissue findings are commonly encountered, including retrocalcaneal bursitis, Achilles tendinosis, peritendinitis, plantar fasciitis, and rheumatoid nodules. Erosive changes may develop at the posterior and plantar surface of the calcaneus as a result of synovitis of the adjacent bursae. Ankle. Approximately 60% of patients with long-standing RA have significant ankle involvement. The radiographic changes in the tibiotalar joint include joint effusion, diffuse cartilage loss, and erosions. A scalloped erosion along the medial border of the distal fibula is a characteristic finding and is called the fibular notch sign (Fig. 53-9).60 Progressive osteoporosis may be complicated by an insufficiency fracture in the distal tibial metaphysis or calcaneus. Knee. The knee is frequently affected in RA. Distention of the suprapatellar pouch of the knee joint by effusion, synovial hypertrophy, or both is identifiable on the lateral projection. Cartilage loss is uniform involving patellofemoral and femorotibial articulations. Erosions develop usually at the periphery of the articular margins. Subchondral cysts may be seen in the femoral condyles or proximal tibia and

Figure 53-8  Abnormalities of the shoulder in rheumatoid arthritis. Grashey posterior oblique view of a shoulder shows severe glenohumeral  joint space narrowing with a marginal erosion and cystic change of the humeral head adjacent to the greater tuberosity (curved arrow). Elevation of the humeral head with respect to the glenoid indicates chronic rotator cuff tear. There also is tapering of the distal end of the clavicle and widening of the acromioclavicular joint (straight arrow).

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may lead to bony collapse. Varus or valgus deformity of the knee joint may be present. Rupture of the quadriceps or patellar tendon may occur with corresponding soft tissue abnormalities. Baker’s cysts are a well-known manifestation of RA. They can extend far down the calf and cause compartment syndrome. They also can rupture with resultant inflammation, mimicking deep vein thrombosis clinically. Hip. Hip involvement in RA is less common than knee involvement. Radiographic abnormalities of the hip are generally bilateral and symmetric in distribution. The hip joints show concentric loss of articular space with axial migration of the femoral head, which may lead to protrusio acetabuli (Fig. 53-10). Insufficiency fractures of the femoral neck and osteonecrosis of the head may be encountered, usually associated with steroid therapy. Occasionally, large cystic changes of the femoral neck occur and predispose to pathologic fracture. Other Sites. Asymptomatic erosive changes are reported to be common in sacroiliac joints. Other synovial joints that may be involved include the temporomandibular and sternoclavicular joints. Cartilaginous articulations, such as the sternomanubrial joint and symphysis pubis, may show erosive changes. Magnetic Resonance Imaging in Rheumatoid Arthritis. The superior soft tissue contrast of MRI offers greater sensitivity for detection of early changes of RA than conventional radiography. MRI has proved to be useful in determining the

Figure 53-9  Rheumatoid arthritis of the ankle. There is diffuse loss of cartilage space with erosions of the fibula (arrow and arrowhead). The scalloping along the medial border of the distal fibula (arrow) is called the fibular notch sign and is a characteristic finding in rheumatoid arthritis. The hindfoot is in valgus alignment.

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extent of the inflammatory and structural changes in early stages of the disease. MRI also has the potential to monitor patients’ response to therapy. Perhaps the most frequent application of MRI in RA is in diagnosis of various complications encountered during the course of the disease and its treatment. Inflammatory changes characterized by joint effusion, acute synovitis, pannus, and synovial sheath effusions can be recognized on MR images. The conspicuity of inflammatory synovial ­tissue in contrast to joint effusion seems to vary depending on the nature of the tissue and the MRI sequence. Differentiation of inflamed synovium and joint effusion on non– contrast-enhanced standard spin echo T1-weighted and T2weighted (TE <80 msec) sequences may not always be possible. Fast spin echo with heavily T2-weighted sequences (80 to 180 msec) allow excellent contrast between the hyperintense fluid and hypointense pannus (Fig. 53-11). Newer MRI sequences, such as fat-suppressed, T1-weighted, three-dimensional spoiled-gradient echo imaging or magnetization transfer contrast sequences, also may allow differentiation of inflamed synovium and joint fluid.61-63 Contrast-enhanced MRI has been proposed by several authors for evaluation of inflammatory synovial tissue.64-66 After the intravenous administration of contrast agent, correct timing of aquisition of MR images is necessary to differentiate inflamed synovial tissue from joint fluid.67,68 Because the synovial intima has no tight junction or basement membrane, gadolinium compounds can diffuse into the synovial fluid on delayed images. The images must be obtained immediately after the injection of contrast agent to display only the synovial enhancement. The enhancement of inflamed synovial tissue may vary. An active proliferative pannus is hypervascular and shows rapid enhancement after intravenous injection of gadolinium­containing agents.69 In long-standing “burned out” cases of RA, the hypervascular pannus changes into more fibrotic tissue, which is accompanied by a gradual loss of ­vascularization. Quantitative MRI has been suggested to estimate the volume of enhancing pannus before and after treatment to monitor treatment efficacy. Ostergaard and colleagues71 also

Figure 53-10  Bilateral protrusio acetabuli in rheumatoid arthritis. The medial acetabular margins protrude into the pelvis. There is severe accompanying cartilage loss.

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injury, which may be due to erosion from invasion by pannus or partial tear. Partial tear also may result in thickening or thinning of the tendon. Tendon discontinuity indicates complete tear. Tenosynovitis appears as fluid and hyperplastic synovium distending the tendon sheath.62 Juvenile Chronic Arthritis

Figure 53-11  MRI in rheumatoid arthritis. Sagittal fast spin echo  T2-weighted (TR 3625/TE133), fat-suppressed MR image allows excellent contrast between intermediate (gray) signal intensity, pannus, and (white) joint fluid.

have proposed that MRI-determined synovial membrane volume may prove to be useful as a marker of joint disease activity and a predictor of progressive joint destruction. Synovial membrane volume can be estimated using manual or semiautomated volume measures with MRI.70-76 MRI is convincingly more sensitive than conventional radiography in detection of early structural changes of RA, including cartilage damage, meniscal degeneration, subchondral cysts, and erosions.18,77-80 Erosions appear as subcortical areas of dark signal on T1-weighted images in the marrow adjacent to the bony margin or beneath the chondral surface. The content of the erosions or bone cysts may exhibit fluid-like bright signal on T2-weighted images, synovium-like intermediate signal, or both. In more recent studies, the bone marrow edema detected on MRI is found to be a strong predictor of erosions in the wrist.18 MRI is the preferred method of imaging of the musculoskeletal complications of RA, such as tendon ruptures, ischemic necrosis, insufficiency fractures, and cord compression in cervical spine. Rheumatoid synovitis may invade ligaments and tendons directly and eventually may lead to their disruption (Fig. 53-12). Tendon injury and rupture most frequently affect the wrist, shoulder, foot, and knee in patients with RA, specifically the posterior tibialis tendon, rotator cuff tendons, quadriceps tendon, and extensor tendons of the wrist, in particular, the extensor carpi ulnaris. MRI is sensitive for diagnosis of tenosynovitis and subclinical tendon ruptures.80 Normal tendons have smooth margins and show homogeneously low signal intensity in all MRI sequences. Increased signal intensity on proton ­density and T2-weighted spin echo images indicates tendon

The term juvenile chronic arthritis describes a heterogeneous group of chronic inflammatory arthritides that begin in childhood. Juvenile chronic arthritis is used synonymously with juvenile RA and juvenile idiopathic arthritis.81,82 Table 53-1 summarizes a new classification of juvenile chronic arthritis.82 The radiologic changes in juvenile chronic arthritis are largely determined by the age of onset and type of arthritis. The types of arthritis according to the onset of the disease have been recognized as follows: 1. Systemic illness that is not usually associated with radiologic changes 2. Oligoarticular disease where growth anomalies are frequent 3. Generalized polyarthritis in which osteoporosis and periostitis occur early with subsequent development of cartilage loss and bone erosion83 Although the radiographic appearance of each specific type of juvenile chronic arthritis has some distinctive features, most of them share common radiographic changes. General Imaging Features Osteopenia. Regional or diffuse osteopenia is characteristically present. Regional osteopenia may be juxta-articular or may appear as bandlike metaphyseal lucent zones, particularly in the distal end of the femur; proximal portion of the tibia; and distal ends of the radius, tibia, and fibula. These lucent bands are similar to the bands seen in childhood leukemia. In these regions, subsequent development of transverse radiodense “growth recovery” lines has been noted.84 Osteoporosis may lead to compression fractures of the epiphysis, fractures of the tubular bones, and compression fractures of the vertebral bodies. Joint Space Abnormalities. Joint space narrowing is usually a late finding in juvenile chronic arthritis, as opposed to adult-onset RA. In the later stages of the disease, intraarticular bony ankylosis ultimately can develop, especially affecting small joints of the hands, wrists, and feet and apophyseal joints of the cervical spine. Bone Erosion. The development of bone erosions also is a late finding in juvenile chronic arthritis. The erosions may occur at the margins of the joint or along the entire articular surface of the bone. Periostitis. One of the most common findings of all types of juvenile chronic arthritis on presentation is periostitis with soft tissue swelling and osteoporosis. It is most frequent in the phalanges, metacarpals, and metatarsals and occasionally is seen along the metaphyses and diaphyses of long tubular bones. In some cases, the extensive periosteal proliferation may produce an enlarged, rectangular appearance of the tubular bones of the hands and feet. Growth Disturbance. Growth disturbance is a striking feature of juvenile chronic arthritis. Overgrowth of epiphysial centers as a result of hyperemia may result in deformity and

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Figure 53-12  Enlargement and disruption of flexor carpi radialis tendon secondary to invasion by rheumatoid synovitis. A, Radiograph of the wrist of a patient with long-standing rheumatoid arthritis shows carpal ankylosis with carpal collapse. A lobulated soft tissue mass (arrowhead) is seen at the lateral aspect of the distal radius. B and C, T1-weighted coronal (B) and axial (at the level of the dashed line) (C) MR images show heterogeneous signal distending the extensor carpi radialis tendon consistent with rheumatoid synovitis (stars).

premature fusion of epiphysis. Commonly affected locations include metacarpals, metatarsals, carpal and tarsal bones, proximal and distal femur, proximal tibia, and radial head. Asymmetric growth of paired bones may cause discrepancy of the lengths of fibula and radius. Epiphyseal Compression Fractures. Deformity and flattening of the epiphyseal centers secondary to epiphyseal compression fractures are encountered frequently in juvenile chronic arthritis. These changes develop as a result of abnormal

stress on weakened osteoporotic bone. In a similar way, cupping of the ossification centers of the proximal phalanges in response to compression by metacarpal and metatarsal heads may be encountered.85 Abnormalities in Specific Sites Hand and Wrist. In early cases of generalized polyarthritis, radiologic abnormalities are shown most frequently in the wrist and consist of squaring of carpal ossification centers,

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Table 53-1  International League of Associations   for Rheumatology Classification of Juvenile Chronic   Arthritis (Juvenile Idiopathic Arthritis) 1.  Systemic arthritis 2. Oligoarthritis Persistent—≤4 joints throughout the disease course Extended—affects cumulative total of ≥5 joints after first 6 mo of disease 3.  Polyarthritis (rheumatoid factor–negative) 4.  Polyarthritis (rheumatoid factor–positive) 5.  Psoriatic arthritis 6. Enthesitis-related arthritis 7. Other arthritis

followed by loss of joint space. Ultimately, bony ankylosis can develop (Fig. 53-13). Any joint of the hand can be affected, typically in an asymmetric fashion. Early radiographic changes of the hands are soft tissue swelling and periarticular osteoporosis and periostitis of the metacarpal and phalangeal shafts. Joint space narrowing and bone erosions tend to occur late. Epiphyseal deformity, growth disturbance, and a variety of finger deformities are characteristic changes appearing during the course of the disease. Foot and Ankle. The radiologic changes in the tarsus are similar to those observed in the carpus, with initial enlargement and irregularity of the tarsal bones, which may fuse and show premature osteoarthritic changes. Deformities secondary to growth disturbance around the metatarsophalangeal joints are common. Late deformities include clawing of the toes, hammer toes, hindfoot and valgus, pes cavus, and hallux valgus (Fig. 53-14). Knee. Characteristic radiographic abnormalities of the knee related to disturbance of growth usually become obvious within 1 year of involvement and consist of “ballooning” of the distal femoral and proximal tibial epiphyses, flattening of femoral condyles, widening of the intercondylar notch, and squaring of the patella (Fig. 53-15). Other radiographic findings are diffuse narrowing of the joint space and marginal and central osseous erosions. Hip. Involvement of the hip is common and can be recognized radiologically in 40% of patients 10 years after disease onset. Overgrowth of the femoral capital epiphysis is a characteristic initial radiologic finding, followed by premature fusion and failure of growth of the femoral neck. Coxa valga and protrusio acetabuli deformities are common. Intra-articular bony ankylosis of the hip occasionally can be encountered. Development of iliac bones also is impaired, especially in younger children. Rarely, improvement in hip cartilage space is seen. Sacroiliac Joints. Radiographic findings of sacroiliitis in juvenile-onset ankylosing spondylitis can become evident usually several years after onset. Early sacroiliac joint changes may be overlooked because of difficulty in radiographic analysis of the sacroiliac joints in children. Conventional radiographs of the sacroiliac joints are of limited value in patients 8 to 16 years old because widened articular joint spaces and indistinct subchondral bone are normal findings in this age group.86 Sacroiliac joint changes in juvenile-onset ankylosing spondylitis initially may be unilateral or asymmetric in distribution; however, they soon become bilateral and symmetric.

Figure 53-13  Juvenile chronic arthritis. Severe abnormalities of the hand and wrist include ankylosis of carpal bones, growth disturbance of the distal radius and ulna, erosion, compression and flexion deformities of the proximal interphalangeal joints, and periosteal bone formation along the proximal phalanges.

Joint space widening, indistinct joint margins, erosions, sclerosis, and eventually bony ankylosis can be detected. Bollow and coworkers87 reported that contrast-enhanced MRI is superior to conventional radiography for detection of sacroiliitis in children. In their study, unenhanced MRI alone also was more sensitive than conventional radiography in identifying sacroiliitis. Cervical Spine. As in adult disease, juvenile chronic arthritis affects, in particular, the cervical spine, sparing the thoracic and lumbar regions. Ankylosis may result in growth disturbance with underdeveloped vertebral bodies. Ankylosis affects intervertebral and apophyseal joints. Growth disturbances of the vertebral bodies occur at the levels of apophyseal joint ankylosis and consist of decreased vertical and anteroposterior diameters (Fig. 53-16). Atlantoaxial subluxation occurs most frequently in juvenile-onset adult-type RA. Underdevelopment of the mandible with antegonial notching and articular involvement of the temporomandibular joints are additional radiographic findings in juvenile chronic arthritis. Adult-Onset Still’s Disease Rarely, an adult patient may be encountered with a febrile illness identical to classic Still’s disease. The radiographic changes involve the hands, wrists, knees, and hips. Bony erosions are unusual. Predilection for narrowing and ankylosis of carpometacarpal joints, especially the second and third metacarpal bones and the intercarpal joints in a pericapitate distribution, are characteristic.88

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Figure 53-14  Foot abnormalities of juvenile chronic arthritis. A and B, Lateral (A) and oblique (B) views of the foot show diffuse osteopenia, bony ankylosis of intertarsal and tarsometatarsal joints with preservation of the talonavicular and calcaneocuboid joints, secondary osteoarthritis of the ankle, and growth disturbance of the metatarsals with erosive changes in the metatarsophalangeal joints. There is a hallux valgus deformity.

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Figure 53-15  Juvenile chronic arthritis. A, Anteroposterior view of the knee shows overgrowth of the femoral epiphysis, constriction of epiphysis at the joint, and widening of the intercondylar notch (arrow). Old corticated, marginal erosions (arrowheads) are present. B, The square shape of the patella is visible on the lateral view.

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Figure 53-16  Cervical spine abnormalities in juvenile chronic arthritis. Segmental fusion is present at various levels, including vertebral bodies and posterior elements. The involved vertebral bodies are hypoplastic. Antegonial notching (arrow) of the mandible, a manifestation of juvenile chronic arthritis, is secondary to growth disturbance of the mandible and altered muscle pull.

Psoriatic Arthritis The radiologic manifestations of psoriatic arthritis can be seen in the synovial and cartilaginous joints and at the osseous attachment sites of tendons and ligaments, involving the axial and the appendicular skeleton. At least five patterns of clinical presentation have been described in psoriatic arthritis, as follows: 1. Polyarthritis with distal interphalangeal joint involvement 2. Symmetric seronegative polyarthritis simulating RA 3. Arthritis mutilans 4. Monarthritis or asymmetric oligoarthritis 5. Spondyloarthropathy Of these, asymmetric or unilateral polyarthritis seems to be the most common presentation.89 Psoriatic arthritis affects mainly the interphalangeal joints of the hands and feet, the metacarpophalangeal, and metatarsophalangeal joints. The knees, ankles, elbows, and wrists, and manubriosternal and sternoclavicular joints are other sites of involvement. In the axial skeleton, sacroiliac joint and spinal abnormalities predominate. Involvement of the hip and shoulder is uncommon in psoriatic arthritis. General Imaging Features General radiographic abnormalities typically seen in the affected peripheral joints of the upper and lower extremities are soft tissue swelling, joint space widening or narrowing,

Figure 53-17  Psoriatic arthritis. Classic radiographic findings around the distal interphalangeal joints include soft tissue swelling, erosions with accompanying bone proliferation, and lack of osteoporosis.

erosions, bone proliferation, malalignment, and ankylosis. The findings in large joints are less distinctive and are similar to those of RA. Bone proliferation is a characteristic feature of psoriatic arthritis, accompanying the bone erosions as a healing response. Bone proliferation also occurs at sites of tendon and ligament insertion. Absence of osteoporosis is a useful sign in differentiating psoriatic arthritis from RA. Abnormalities in Specific Sites Hand and Foot. The radiographic changes in the hands and feet are highly distinctive. At these sites, bilateral symmetric, asymmetric, or unilateral involvement of interphalangeal, metacarpophalangeal, and metatarsophalangeal joints is observed. Sometimes involvement occurs along a digit (the “ray distribution”). An early soft tissue finding of psoriatic arthritis is periarticular soft tissue swelling or diffuse fusiform swelling of an entire digit, the so-called sausage digit. Fingernail thickening and irregularity sometimes may be discernible. Initial erosions occur at the joint margins and proceed centrally. Fluffy new bone formation associated with marginal erosions produces a “whiskered” appearance (Fig. 53-17). Further destruction of the articular surfaces may lead to apparent widening of the joint space, a “pencil-and-cup” appearance, and opera glass (main en lorgnette) deformities. The pencil-and-cup appearance describes the deformity created by protrusion of one articular surface into its opposing articular counterpart (Fig. 53-18). Proliferative bone changes may result in sclerosis of an entire phalanx, which is termed an ivory phalanx. This

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The most characteristic sites of abnormality are the small joints of the feet, calcaneus, ankles, and knees. The upper extremity joints are less frequently affected, in contrast to psoriatic arthritis. In the axial skeleton, the sacroiliac joints, spine, symphysis pubis, and manubriosternal joints are frequently involved. General Imaging Features The general radiologic findings are soft tissue swelling, erosions, joint space narrowing, and bone proliferation. Osteopenia is not a prominent finding, although periarticular osteopenia may accompany acute episodes of arthritis.

Figure 53-18  Arthritis mutilans resulting from psoriatic arthritis with destructive changes and joint deformity of the hand and pancompartmental ankylosis of the wrist.

sclerosis is seen most frequently in the terminal phalanx of the great toe. Intra-articular osseous fusion is another manifestation of bone proliferation, and it particularly affects the interphalangeal joints. Resorption of the tufts (acro-osteolysis) and of the distal phalanges of the hands and feet is also a characteristic finding of psoriatic arthritis.90,91 Bony proliferation with erosions at the posterior and plantar aspects of the calcaneus is common in psoriatic arthritis as in the other seronegative spondyloarthropathies. Retrocalcaneal bursitis, thickening of the adjacent Achilles tendon, and poorly defined enthesophytes at the attachment sites of the plantar aponeurosis and the Achilles tendon are associated abnormalities.92 New bone production along the malleoli may indicate adjacent tenosynovitis. Sacroiliac Joints. Radiographic changes of the sacroiliac joints are observed in approximately 30% to 50% of patients with psoriatic arthritis. Bilateral abnormalities are much more frequent than unilateral changes. The changes in the sacroiliac joints may or may not be symmetric. Radiographic changes include erosions and sclerosis, predominantly on the iliac side, and widening and subsequent narrowing of the articular space. In contrast to ankylosing spondylitis, the disease rarely progresses to complete joint fusion. Sacroiliitis can appear without spondylitis. Reactive Arthritis (Reiter’s Syndrome) The radiographic features of articular involvement of reactive arthritis are similar to those of the other seronegative spondyloarthropathies. Reactive arthritis produces asymmetric arthritis with predilection for the lower extremity.

Abnormalities in Specific Sites Foot and Ankle. The most frequently affected joints in the foot are the metatarsophalangeal and interphalangeal joints. Radiographic changes include joint space loss, marginal erosions with adjacent bony proliferation, and periostitis of the shafts of affected metatarsals and phalanges. Joint ankylosis is less common than in psoriatic arthritis. Occasionally, severe destruction and dorsolateral subluxation of the metatarsophalangeal joints are observed. Such deformity associated with Reiter’s syndrome has been called Launois’ deformity.93,94 The most characteristic radiographic feature of reactive arthritis is exuberant, fluffy bone proliferation. The calcaneus is a target site for such proliferative new bone formation. Bone proliferation and poorly defined erosions usually develop on the plantar and posterior aspects of the calcaneus. Retrocalcaneal bursitis can be observed, as can thickening of the Achilles tendon (Fig. 53-19). Heel changes may be the sole or predominant radiographic finding of Reiter’s syndrome.92 Radiographic changes in the ankles include soft tissue swelling, joint space narrowing, and periostitis along the malleoli. Erosions are infrequently encountered. Knee. Radiographic abnormalities of the knee are apparent in 25% to 40% of patients. The most common abnormality is joint effusion, although osteoporosis, joint space narrowing, and periostitis of the distal femur or proximal tibia and shallow erosions can be detected. Sacroiliac Joints. Sacroiliac joint changes are usually bilateral, but often can be persistently asymmetric. Sacroiliitis has radiographic features similar to ankylosing spondylitis and psoriatic arthropathy, although bony ankylosis is less frequent in reactive arthritis (Fig. 53-20). Enteropathic Arthropathies The rheumatologic manifestations of inflammatory bowel disease are sacroiliitis; spondylitis; and nondestructive, asymmetric, and usually transient arthritis of peripheral joints. The radiographic features of the sacroiliac joint and spinal abnormalities are virtually indistinguishable from the radiographic features in ankylosing spondylitis. Sacroiliac joint changes are usually bilateral and symmetric. Peripheral joint involvement is usually monarticular or pauciarticular in distribution, although it can be polyarticular. The knees are involved most commonly, followed by the ankles, elbows, wrists, shoulders, and small joints of the hands and feet. The radiographic findings at these sites are nonspecific. Soft tissue swelling and regional osteoporosis may be observed; cartilage loss and bone erosions are rare.

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Figure 53-19  Radiographic findings of the foot in reactive arthritis. A, Anteroposterior view of the foot reveals erosions and bony proliferation of the first through fourth metatarsophalangeal joints with subluxation. Fluffy bony proliferation is noted along the medial malleolus, midfoot, and sesamoid bones of the first metatarsal head (arrows). B, Lateral view of the hindfoot shows ill-defined plantar calcaneal enthesophytes (arrowhead), periosteal new bone formation along the posterior aspect of the distal tibia (arrow), retrocalcaneal bursitis and thickening of the Achilles tendon (star), and erosions at the subjacent calcaneus.

Figure 53-20  CT scanning in reactive arthritis. Oblique axial image through the sacroiliac joints shows erosions with associated new bone formation predominating in the iliac bones.

Septic Arthritis In all varieties of septic arthritis, the earliest radiographic change is symmetric soft tissue swelling around the joint secondary to soft tissue edema, hypertrophied synovium, and joint effusion. The synovial hyperemia and early disuse atrophy may result in periarticular osteopenia. Joint effusions may be identified in elbow, wrist, hip, knee, or ankle by displacement of the capsular fat planes. Initially, edema and joint effusion may produce widening of the joint space, a finding seen commonly in the pediatric septic hip. The next radiographic finding is marginal erosions. These erosions occur at the synovium-bone interface where the

cartilage is lacking and are indistinguishable from the erosion of inflammatory arthritides. As the infection progresses, the pannus extends between cartilage and bone, leading to destruction of central cartilage and subchondral cortex. Radiographically, these pathologic changes are identified as central erosion with disruption of the white line of the articular cortex (a finding strongly suggesting septic arthritis) (Fig. 53-21). Further destruction of cartilage results in narrowing of the joint space. In late stages, ankylosis of the joint may be seen.95 In chronic septic arthritis, the adjacent bones may show signs of osteomyelitis with periostitis and bone destruction. Early diagnosis is the most important prognostic factor in septic arthritis. When there is clinical suspicion of septic arthritis, a joint aspiration should be performed without delay to avoid irreversible articular damage. Instillation of a radiographic contrast agent during arthrocentesis helps to confirm the site of fluid sampling, show the extent of articular and periarticular destruction, and define any cavities or fistulas.96 Although the radiologic abnormalities in septic arthritis are not specific for the offending organism, certain generalizations apply. Bacterial arthritis is characterized by rapid destruction of bone and articular cartilage. The bone mineralization is preserved. In tuberculous arthritis, a triad of radiographic findings (Phemister’s triad) is characteristic and consists of juxtaarticular osteoporosis, marginal erosions, and absent or mild joint space narrowing. Sequestra at articular margins may be identified. Periostitis and bone production are not as prominent as in bacterial arthritis. The eventual outcome of tuberculous arthritis is a fibrous ankylosis of the affected joint. Bony ankylosis is seen occasionally, but is more

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Figure 53-21  Septic arthritis of the right sacroiliac joint. A, Anteroposterior view of the sacroiliac joints shows destruction of the right sacroiliac joint. B, In a different patient, short tau inversion recovery coronal MR image through sacroiliac joints shows erosive changes in the right sacroiliac joint with extensive bone marrow edema.

frequently observed with bacterial arthritis. The radiographic manifestations of fungal arthritis are similar to the manifestations of tuberculosis.97 The MRI appearance of septic arthritis is nonspecific, and similar findings can be observed in inflammatory arthropathies and evolving neuropathic joints. MRI may be helpful in diagnosing complications of septic arthritis, such as abscesses and osteomyelitis. Differentiation of osteomyelitis from nonspecific reactive bone marrow edema may not always be possible in the early stages of the disease and may lead to a false-positive MRI diagnosis of osteomyelitis.98-100 In septic arthritis, the three-phase bone scan shows increased periarticular uptake in the distribution of the synovium, soft tissues, or both during blood flow and blood pooling phases. The delayed phase reveals minimal increased uptake in the underlying bone. Bone scintigraphy, although sensitive, is not specific in differentiating septic from inflammatory arthritis. Generally, bone scintigraphy is used to rule out concomitant osteomyelitis.101 DEGENERATIVE JOINT DISEASE Osteoarthritis The most characteristic sites of osteoarthritis include the proximal and distal interphalangeal joints of the hand, first carpometacarpal and trapezioscaphoid joints of the wrist, acromioclavicular and sacroiliac joints, hips, knees, and first metatarsophalangeal joints. Degenerative joint disease also may affect cartilaginous joints (e.g., manubriosternal joint and symphysis pubis) and tendinous and ligamentous attachments to bone (e.g., in the pelvis, patella, and calcaneus). Degenerative disease of the spine is discussed separately. General Imaging Features. Despite diversity of etiologies of osteoarthritis, certain common radiographic characteristics allow a confident diagnosis in most instances. Joint space narrowing is a key diagnostic feature of the disease (Fig. 53-22).

Figure 53-22  Osteoarthritis of the hip. Anteroposterior view of the hip shows complete cartilage space loss superiorly. There is osteophytic lipping from the femoral head, especially medially (thin arrow), and buttressing bone (open arrow) is present along the femoral neck.

In contrast to the inflammatory arthropathies, in which diffuse joint space ­narrowing of an involved articulation is expected, the joint space loss in osteoarthritis tends to involve the portion of the joint exposed to the greatest stress (i.e., the lateral aspect of the hip, the medial compartment of the knee). Subchondral bone abnormalities also are characteristic of osteoarthritis and include sclerosis and cyst formation, both of which predominate in the most stressed area of the articulation. Subchondral eburnation results from cartilage denudation and subsequent bone-to-bone contact. The origin

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of subchondral cysts is debated; joint fluid may intrude into the subchondral bone through a cartilaginous defect, or necrosis of subchondral bone may become cystic. Osteophytes are the most characteristic abnormality in osteoarthritis.102 They tend to arise from endochondral ossification in areas of low stress where islands of cartilage are preserved, most commonly at the joint margins (Fig. 53-23; see Fig 53-22). The presence of tibial spine or intercondylar osteophytes alone, however, may not indicate osteoarthritis as cartilage space narrowing or pain do not necessarily ­follow osteophyte formation in these locations.103 Articular Cartilage MRI allows direct assessment of the thickness, surface contour, and internal architecture of articular cartilage and the changes in these areas that may accompany osteoarthritis or other conditions.104-107 Direct imaging of articular cartilage would be extremely helpful in staging and following osteoarthritis. Detailed cartilage imaging protocols are still being developed. Cartilage imaging requires high spatial resolution, while examination times must remain reasonable to avoid motion artifact. The signal intensities of the articular structures must be manipulated to allow articular cartilage to be differentiated from subjacent bone and from adjacent joint fluid. Imaging after intravenous contrast administration (indirect arthrography) is used in specific circumstances, such as after cartilage repair surgery.105 Waldschmidt and coworkers108 have found normal articular cartilage to consist of three laminae: a superficial hypointense lamina, a deeper hyperintense lamina, and a heterogeneous deep zone. These laminae seem to correspond to the histologic structure of articular cartilage. Eckstein and colleagues107 found MRI to provide accurate assessment of articular cartilage volume and thickness in cadaver knees. The presence of cartilage erosion, fissuring, thinning, signal change, and changes in cartilage volume can be determined.

Figure 53-23  Osteoarthritis of the shoulder. There is osteophytic lipping (open arrow) from the humeral head, including new bone formation deep to the cartilage (thin arrow).

Patients otherwise thought to have bicompartmental osteoarthritis have been found on MRI to have tricom­ partmental disease, making this a useful technique for surgical planning.109 MRI generally allows detection of only intermediate-to-advanced osteoarthritic change in clinical cases however.110 More recent investigations use MRI techniques such as T2 relaxation mapping, T1 rho relaxation mapping, and delayed gadolinium-enhanced MRI of cartilage to provide molecular information about articular cartilage.110a The delayed gadolinium-enhanced MRI of cartilage technique uses MRI examination after intravenously administered gadolinium injection to image noninvasively the glycosaminoglycan concentration of articular cartilage. This technique is possible because glycosaminoglycan has a negative fixed charge density, and gadolinium DTPA (Magnevist; Berlex, Wayne, NJ) is a divalent anion. Glycosaminoglycan concentration is related to the mechanical properties of cartilage and is decreased in diseased cartilage. Ultrasound also has been used for evaluation of articular cartilage, which is seen as a hypoechoic band with sharp margins.111 Evaluation of articular cartilage by ultrasonography is of limited use because the weight-bearing knee articular cartilage and patellar cartilage cannot be assessed. Abnormalities in Specific Sites Hand and Wrist. The interphalangeal joints of the hand are frequent targets of osteoarthritis (Fig. 53-24). The appearance of articular space narrowing with closely apposed interdigitating bony surfaces and marginal osteophytes is characteristic. Metacarpophalangeal joint involvement may occur, but not as an isolated event; rather, such involvement is associated with alterations at interphalangeal

Figure 53-24  Osteoarthritis of the hands. There is asymmetric cartilage space narrowing at the proximal and distal interphalangeal joints, the thumb carpometacarpal joints, and the scaphoid trapezium trapezoid articulations. Subluxation at the thumb carpometacarpal joints and secondary hyperextension at the metacarpophalangeal joints (MCPs) are characteristic deformities of osteoarthritis. Some secondary signs of osteoarthritic changes are noted at the thumb MCPs, but the other MCPs show only minimal cartilage narrowing. The osteoarthritic changes of the right radioulnar joint are likely post-traumatic.

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articulations and consists of cartilage space narrowing as the predominant abnormality. Osseous erosions are not ­radiographic features of osteoarthrits. The first carpometacarpal (trapeziometacarpal) joint is the characteristic site of degenerative abnormalities in the wrist. Joint space narrowing with bony eburnation, subchondral cysts, and osteophyte formation is typical. Radial subluxation of the first metacarpal base is common. The trapezioscaphoid cartilage space is the only other common site of osteoarthritis in the wrist; involvement at this site generally is combined with involvement at the first carpometacarpal joint. Trapezio­ scaphoid joint disease in the absence of first carpometacarpal joint involvement should suggest another diagnosis, especially calcium pyrophosphate dihydrate (CPPD) crystal deposition disease. Similarly, a degenerative arthropathy elsewhere in the wrist, especially at the radiocarpal joint, in the absence of significant occupational or accidental trauma, generally is related to a disease other than primary osteoarthritis. Sacroiliac Joint. Osteoarthritis of the sacroiliac joint is extremely common in elderly patients. Joint space narrowing with a thin, well-defined band of subchondral sclerosis, especially in the ilium, is typically present. Osteophyte formation is most common at the superior and inferior margins of the synovial portion of the joint. At the former location, these osteophytes may appear as localized radiodensities projected over the joint in the anteroposterior radiographic projection. Bony erosion and intra-articular osseous fusion are not features of sacroiliac joint osteoarthritis. Hip. Osteoarthritis of the hip is common and may lead to significant disability. In the typical case, cartilage loss is focal, involves the superolateral aspect of the joint, and leads to upward migration of the femoral head (see Fig. 53-22).112 Osteophyte formation is most prominent at the lateral acetabular and medial femoral margins, often in combination with thickening (buttressing) of the cortex along the medial aspect of the femoral neck. Subchondral sclerosis and cyst formation on both sides of the joint space may be marked. Focal loss of cartilage on the medial aspect of the articulation occurs in approximately 20% of patients with osteoarthritis. Diffuse loss of cartilage with axial migration of the femoral head (along the axis of the femoral neck) is uncommon in primary osteoarthritis. This latter feature is important in the differentiation of primary osteoarthritis from inflammatory arthropathies such as RA and in identifying secondary osteoarthritis, such as may be due to underlying CPPD crystal deposition disease in which axial migration may occur. Abnormal juxta-articular bone, as seen in Paget’s disease, increases the incidence of osteoarthritis. Knee. The knee is a common site of osteoarthritis. The most characteristic pattern of disease is involvement of the medial femorotibial compartment with joint space narrowing, osseous eburnation, subchondral cysts, and marginal osteophytes (Fig. 53-25).113 Women often have lateral femorotibial disease. A true assessment of cartilage thinning may be impossible on standard supine anteroposterior radiographs; it is better provided on radiographs obtained either in the tunnel projection (Fig. 53-26) or with the patient standing in a weight-bearing position.114 Boegard and Jonsson103 and others suggest obtaining weight-bearing radiographs with

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the knee flexed, although the correct degree of flexion for a specific individual depends on the location of cartilage loss, which is not known a priori. Cartilage space narrowing is documented in standing, not flexed, views if the joint space width is less than 3 mm, is narrower than half the width of the other articulation in the same knee or the same articulation in the other knee, or decreases on weight-bearing compared with non–weight-bearing radiographs.103 Although joint space width has been shown to correlate with cartilage thickness, a study by Hunter and associates revealed that decrease in the joint space also may occur as a result of meniscal degeneration or extrusion.114a Varus angulation of the knee is the most common deformity in osteoarthritis, reflecting the more severe involvement of the medial femorotibial compartment compared with the lateral one. Standing views of the lower extremities from hips to ankles show knee alignment in relation to the mechanical axis of the leg. Symmetric medial and lateral femorotibial compartment disease is unusual. Osteoarthritis changes in the patellofemoral compartment are common, either in isolation or accompanying medial femorotibial compartment disease. Osseous or cartilaginous debris may be present as intraarticular bodies, either free within the joint cavity or attached to the synovial membrane. Degeneration of the fibrocartilaginous menisci is a typical feature of advanced osteoarthritis. Degenerative tears are most common in the posterior horn of the medial meniscus. On an MRI examination, grade 3 signal (linear signal reaching the articular surface of the meniscus) has been found in 76% of asymptomatic subjects and 91% of patients with symptomatic osteoarthritis. Also, if osteoarthritis is present, it, rather than the meniscal tear, may be the cause of symptoms. Foot. Osteoarthritis in the foot typically affects the first metatarsophalangeal joint. Articular space narrowing, bony eburnation, osteophyte formation, and subchondral cysts are common. Hallux rigidus is a specific pattern of osteoarthritis characterized by painful restriction of dorsiflexion at the first metatarsophalangeal joint. Dorsal osteophytes are characteristic; sclerosis, cyst formation, and osteophytes on the medial aspect of the metatarsal head also are seen. Other Locations. Typical osteoarthritis changes in the elbows, acromioclavicular and glenohumeral joints, and ankles may be encountered, usually in patients with a history of trauma or preexisting disease. Generally, without such a history, a radiographic pattern consistent with osteoarthritis103 at an unusual site should suggest another process, such as acromegaly, CPPD crystal deposition disease, hydroxyapatite deposition disease, ochronosis, or epiphyseal dysplasia. Inflammatory Osteoarthritis. Inflammatory osteoarthritis is a disorder occurring most commonly in middle-aged women. It is characterized by acute episodic inflammation of interphalangeal joints of the hand. On radiographs, typical marginal osteophytes with or without bony erosions are seen. The erosions are first evident in the central portion of the subchondral bone, appearing as sharply marginated defects eventually producing a “gull wing” deformity (Fig. 53-27).103 Intra-articular bony ankylosis may result. High­resolution MRI has shed new light on this condition. In a study of 15 patients with osteoarthritis of the small joints of the hand, MRI using a 23-mm microscopy surface coil revealed erosions, synovitis, and bone marrow edema

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Figure 53-25  MRI of osteoarthritis of the knee. A, T1-weighted coronal MR image of the knee. Osteophytes are at the joint margins. There are discrete areas of low signal replacing the subchondral fat (arrow) and more diffuse low signal extending into the tibial metaphysis. B, Inversion recovery image of the knee shows that most of the low signal area has become bright and is poorly marginated, consistent with edema. Bright joint fluid is adjacent to the bone medially, documenting complete absence of cartilage.  C, Coronal short tau inversion recovery image in another patient shows a focal cartilage defect at the weight-bearing surface of the lateral femoral condyle with fissuring and flap formation (arrow). There is associated subchondral bone marrow edema.

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i­dentical to the changes seen in inflammatory arthritis in 80% of joints. This study suggests that erosive osteoarthritis may be part of the spectrum of osteoarthritis, rather than a separate entity. Radiographs were not as sensitive as MRI for the identification of erosion.114b Magnetic Resonance Imaging in Osteoarthritis.  MRI in patients with osteoarthritis reflects the underlying pathologic changes. Osteophytes are well seen on MRI at the joint margins and beneath the articular cartilage. Often the osteophytes are seen better on MRI than on radiographs owing to the tomographic nature of MRI.110 As in radiographs, the cortex of the osteophyte and the marrow are continuous from the host bone to the osteophyte. Subchondral changes consist of edema, sclerosis, and cyst formation. Edema results from venous congestion and microfracture (see Fig. 53-25).110 These areas exhibit inhomogeneous, intermediate to low signal on T1-weighted or intermediate-weighted images and bright signal on fluid-sensitive sequences. Subchondral fibrosis and trabecular thickening replacing normal marrow result in hemispherical subchondral areas that are intermediate in signal on T1-weighted images and intermediate to low in signal on T2-weighted images.115 Cystic changes

may occur within the areas of subchondral sclerosis and produce well-defined lesions, usually with internal fluid signal.111 Synovial hypertrophy occurs in osteoarthritis to a lesser degree than in RA, but may be visible on MRI.116 Investigation of the knees of patients with idiopathic osteoarthritis by Fernandez-Madrid and colleagues117 showed synovial thickening in nearly three quarters of the patients. The synovial change was unusual in that it appeared as nodules or grapelike clusters in the intercondylar region, around the cruciate ligaments; involved the infrapatellar fat pad with extension to the anterior horn of the lateral meniscus; or appeared as extensive involvement.118 Synovial volume can be quantified.119 Correlative clinical and MRI studies have shown relationships between pain and large effusion, patellofemoral osteophyte or more than four osteophytes in the knee, and bone marrow lesions.119a-c Crystal-Related Arthropathies A variety of microcrystals can deposit in and around the joints and induce an inflammatory response. The crystals most frequently associated with arthropathy are monosodium urate, CPPD, and calcium hydroxyapatite. The other

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Figure 53-26  Osteoarthritis with medial compartment cartilage narrowing shown to advantage on tunnel view.

entities that may be included in this group are hemochromatosis, ochronosis, and Wilson’s disease. Gout. The radiologic findings in acute gouty arthritis are nonspecific and include soft tissue swelling, joint effusion, and periarticular osteopenia. When the acute arthritic attack subsides, the bone remineralizes, and more chronic, slowly progressive bony changes may develop.

Figure 53-27  Gull wing deformities in erosive arthritis. Cartilage loss and bone remodeling at the middle and ring finger proximal interphalangeal joints produce a gull wing appearance.

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Figure 53-28  Radiographic forefoot abnormalities in tophaceous gout. Extensive bone destruction is seen at the great toe metatarsophalangeal joint with overhanging edges (arrowhead) and soft tissue swelling. Smaller erosions are present involving the first tarsometatarsal and second metatarsophalangeal joints (arrows).

Chronic tophaceous gout manifests as an asymmetric, erosive, polyarticular disease, especially involving the feet, hands, wrists, elbows, and knees. The most common site of involvement is the first metatarsophalangeal joint. The shoulders, ankles, hips, sacroiliac joints, and spine are uncommon sites of involvement. The radiologic changes in long-standing gout are related to tophi and their effect on soft tissue and bone. Tophi appear as eccentric, nodular soft tissue masses around the joints. They may have an amorphous increased density or patchy calcification.120 Intraosseous tophi may form, and these are usually recognized as small, well-marginated subchondral cystic lucencies. Calcification of urate deposits may produce intraosseous calcifications, similar to calcifications of enchondromas and bone infarcts.121 The enlarging tophi can erode the adjacent bone or destroy bone from within, finally breaking out to produce erosions. The erosions may be intra-articular, para-articular, or remote from the joint. These erosions are usually well defined and round or oval, with sclerotic borders. The overhanging margin of bone is a characteristic feature of gout (Fig. 53-28).122 This new bone develops at the margin of the erosion and forms as a result of stimulated periosteal bone apposition partially covering a tophus. The preservation of joint space and bone density is characteristic of gouty arthritis until the destructive erosive changes lead to secondary osteoarthritis and disuse osteopenia. Extensive destructive changes occasionally produce a mutilating arthritis. Bony ankylosis also has been described.123 Bursal inflammation commonly produces soft tissue swelling

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around the olecranon and in a prepatellar location. Adjacent tophi are frequently present, as are adjacent bony erosions. Chondrocalcinosis occasionally is detected in patients with gout, usually localized in knees, symphysis pubis, and wrists, predominantly involving fibrocartilage. MRI and CT characteristics of gouty tophi have been described in several reports.124-127 CT attenuation of tophi has been shown to measure about 160 HU, corresponding to the attenuation of monosodium crystal deposits measured in vitro (Fig. 53-29). On MRI, the tophi appear as masses of low-to-intermediate signal on T1-weighted and T2-weighted images and show variable enhancement, including peripheral enhancement, after the intravenous administration of gadolinium. MRI may prove to be useful in the evaluation of various complications of gout, such as osteonecrosis, dissecting popliteal cysts, carpal tunnel syndrome, tendon ruptures, and spinal cord and nerve root compression.127 Calcium Pyrophosphate Dihydrate Crystal Deposition Disease. The general term CPPD crystal deposition disease includes asymptomatic CPPD crystal deposition, pseudogout, pyrophosphate arthropathy, and other, less frequent presentations, such as pseudo-RA and pseudoneuropathic joints. Chondrocalcinosis refers to calcification of cartilage within one or more joints, regardless of its etiology. These calcium compounds may consist of CPPD, dicalcium phosphate dihydrate, or hydroxyapatite crystals.128 During acute attacks of pseudogout, the usual radiographic findings are soft tissue swelling and joint effusion. Chondrocalcinosis may or may not be present. The radiologic changes in pyrophosphate arthropathy are joint space narrowing, sclerosis, and subchondral cysts, similar to osteoarthritis, with or without radiographically detectable intra-articular or periarticular calcifications. ­ Intra-articular calcifications can occur in fibrocartilage and hyaline cartilage. Fibrocartilaginous calcifications are observed most frequently in the menisci of the knee, ­triangular fibrocartilage of the wrist, acetabular labrum, ­symphysis pubis, and anulus fibrosus of the intervertebral disk. Calcifications also may be deposited in bursae, synovium, ligaments, and tendons (Fig. 53-30). MRI detects calcification of hyaline cartilage as an area of low signal intensity, especially on gradient echo images; meniscal chondrocalcinosis exhibits increased signal on T1-weighted and proton density images and may simulate meniscal degeneration or tear (Fig. 53-31).129,130 The subchondral cystic changes are one of the hallmarks of this arthropathy. They may have a distinctive radiologic appearance not usually observed in ordinary osteoarthritis. These cysts appear as clusters of coalescent lucencies, varying in size and shape, with slightly sclerotic, smudged, and indistinct margins.131 The patellofemoral, radiocarpal, and metacarpophalangeal joints (especially the second and third metacarpophalangeal joints) are typical sites of involvement in pyrophosphate arthropathy. The distribution is usually bilateral and often symmetric. In addition to the usual target sites, arthritic changes may be observed in the hip, elbow, shoulder, and sacroiliac joints.132 In the wrist, the radiocarpal compartment is the most common site of involvement. CPPD crystal deposition within the scapholunate ligament may predispose to its disruption with consequent scapholunate dissociation and carpal

i­nstability. Characteristic findings of scapholunate advanced collapse wrist may be observed with narrowing of the radioscaphoid joint and proximal migration of the capitate133 (Fig. 53-32). Narrowing of the capitolunate joint space also is common, as is involvement of the trapezioscaphoid joint with or without involvement of the first ­ carpometacarpal

N

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Figure 53-29  CT scan shows hyperdense gouty tophus around the extensor digitorum muscle (arrowhead), with smaller deposits around the other extensor tendons. C, calcaneus; N, navicular.

Figure 53-30  Calcium pyrophosphate dihydrate crystal deposition disease. Cartilaginous and capsular calcifications (arrows) are seen within the second through fourth metatarsophalangeal joints. A nondisplaced fracture of the fourth metatarsal neck is noted.

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Figure 53-32  Scapholunate advanced collapse wrist secondary to calcium pyrophosphate dihydrate arthropathy. Posteroanterior view of the wrist shows widening of the scapholunate distance (arrowhead) with proximal migration of the capitate and calcification of hyaline cartilage, triangular fibrocartilage (arrow), and interosseous lunotriquetral ligament. Subchondral cysts also are seen in the carpal bones and at the base of the fifth metacarpal.

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Figure 53-31  Calcium pyrophosphate dihydrate crystal deposition disease producing chondrocalcinosis. A, Linear calcification is present within the lateral meniscus. B, Sagittal fast spin echo proton density MR image of the same patient shows increased signal within the lateral meniscus corresponding to chondrocalcinosis.

joint. Calcification of the triangular cartilage, intercarpal ligaments, or articular cartilage also may be encountered. Although the structural joint changes superficially resemble osteoarthritis, the distribution of joints or components of joints in pyrophosphate arthropathy differs from that of osteoarthritis. Non–weight-bearing joints, such as the wrist, elbow, and shoulder, are commonly affected in pyrophosphate arthropathy in contrast to osteoarthritis. The preferential involvement of the radiocarpal joint of the wrist and patellofemoral compartment of the knee are distinctive features of pyrophosphate arthropathy. The anterior talocalcaneonavicular joint is selectively affected when CPPD crystal deposition disease involves the foot.132 Pyrophosphate arthropathy may be associated with extensive and rapid subchondral bone collapse and fragmentation with intra-articular loose bodies, resembling ­neuropathic osteoarthropathy. Tumorous CPPD ­ crystal deposits that resemble gouty tophi are observed occasionally, most frequently in digits, and are referred to as tophaceous pseudogout.134 The most common spine abnormalities of CPPD crystal deposition disease are intervertebral disk and ligamentous calcifications. In the cervical spine, CPPD crystals may deposit around the odontoid process in the region of the transverse ligament and produce cord compression and bone erosion, which may result in spontaneous fracture of the odontoid process.135 Calcium Hydroxyapatite Crystal Deposition Disease. Hydroxyapatite deposition disease is associated with a spectrum of abnormalities from monarticular periarthritis to destructive arthropathy, depending largely on the periarticular or intra-articular location of crystal deposition.

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Figure 53-33  Calcific tendinitis of the supraspinatus tendon. A, Grashey view shows amorphous calcifications (arrowhead) at the site of insertion of the supraspinatus tendon on the greater tuberosity. B, On corresponding MR arthrography, calcification appears as an area of low signal intensity  (arrowhead) within the supraspinatus tendon and is less conspicuous.

Periarticular calcium hydroxyapatite deposits generally appear as amorphous and fluffy calcifications without internal trabeculation. These deposits develop within tendons, ligaments, joint capsules, bursae, and periarticular soft tissues. Calcification may change in size over time, becoming larger, smaller, or disappearing completely. Hydroxyapatite deposition disease is most commonly identified in the supraspinatus tendon of the rotator cuff (Fig. 53-33). Other sites include the longus colli muscle in the neck, the gluteal insertion around the proximal femur, and the flexor carpi ulnaris tendon in the wrist.136 Osseous erosion may develop adjacent to the involved tendon or ligament insertion site. On MRI, the calcification itself is difficult to appreciate with most sequences, unless it is large. The calcific deposits are of low signal intensity on all sequences. The surrounding inflamed and edematous soft tissues and muscles show high signal on T2-weighted images. Calcifications and the bone erosions beneath the calcified tendons are best shown on CT scan.137,138 Intra-articular hydroxyapatite deposition disease may be seen in association with osteoarthritis or destructive arthropathy. When the accumulation of hydroxyapatite crystal is sufficient, amorphous or cloudlike radiodense areas within the joint can be detected; this may be accompanied by calcification in the synovial membrane and joint capsule. Structural joint changes include bone destruction, loss of cartilage, and joint deformity. The small joints of the hand are most frequently affected.139 Hydroxyapatite-associated destructive arthritis of the shoulder has been described as Milwaukee shoulder syndrome. The radiographic findings include bone destruction,

intra-articular osseous debris, joint disorganization, and massive joint and bursal effusion. Osteophyte and subchondral cyst formation are infrequent. Associated massive rotator cuff tear results in superior displacement of the humeral head so that it articulates with the undersurface of the acromion. Although shoulder involvement predominates, knees and hips also may be affected.140 Hemochromatosis. The radiologic features of the arthropathy of hemochromatosis include signs of degenerative joint disease, chondrocalcinosis, and diffuse osteoporosis. Radiologic evidence of osteoarthritis is present in approximately 50% of patients with hemochromatosis, and chondrocalcinosis is present in approximately 30% of patients.141,142 The metacarpophalangeal joints, particularly the second and third joints, are the most frequently affected. The proximal interphalangeal and carpal joints, and large joints such as the hip, knee, shoulder, ankle, and elbow are other sites of involvement. The spine also may be affected.143 The typical radiologic findings of the metacarpophalangeal joints in hemochromatosis are uniform joint space narrowing, osteophytes, sharply marginated subchondral cysts, and subchondral sclerosis. Beaklike osteophytes arising from the radial aspect of the metacarpal heads are characteristic of this disorder (Fig. 53-34). Wrist abnormalities, consisting of joint space narrowing, sclerosis, and cystic changes, are seen in 30% to 50% of patients. The arthropathy of hemochromatosis has similar radiographic findings to CPPD crystal deposition disease. The presence of distinctive beaklike osteophytes of the metacarpal heads and osteoporosis may facilitate the differential diagnosis. The radiocarpal joint

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Figure 53-34  Hemochromatosis. Hooklike osteophyte (arrowhead) at the third metacarpal head with cartilage loss at metacarpophalangeal  joints (star) and chondrocalcinosis of triangular fibrocartilage (bent arrow) are typical features of hemochromatosis.

involvement and scapholunate dissociation are less frequent in hemochromatosis than in CPPD arthritis. The arthropathy of the hemochromatosis is usually slowly progressive, in contrast to idiopathic pyrophosphate arthropathy, in which a rapidly progressive arthropathy may be seen.144 MRI in hemochromatosis shows the presence of hepatic iron overload as decreased signal intensity on T1-weighted and T2-weighted images owing to the paramagnetic effect of iron. To date, MRI has not proved to be reliable in the detection of intra-articular iron, however.145 Wilson’s Disease. The radiographic features of Wilson’s disease include osteopenia, arthropathy, and chondrocalcinosis. Osteopenia is most apparent in the hands, feet, and spine. Osteomalacia and rickets have been reported in patients with Wilson’s disease. In these patients, radiologic signs of rickets, retardation of skeletal maturation, and pseudofractures may be observed. Articular abnormalities described in Wilson’s disease are subchondral bone fragmentation, cyst formation, and cortical irregularities, most commonly identified in the wrist, hand, foot, hip, shoulder, elbow, and knee. Irregularity and indistinctness of the subchondral bone may form a characteristic “paintbrush” appearance (Fig. 53-35). Additional characteristic radiographic findings are small, distinctly corticated ossicles around the affected joint and periosteal bone formation at the attachment sites of tendons and ligaments. Chondrocalcinosis is rare, usually limited to the knees.146,147 Ochronosis (Alkaptonuria). The radiologic manifestations of skeletal involvement in alkaptonuria can be divided into spinal and extraspinal abnormalities. Spinal abnormalities

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Figure 53-35  Wilson’s disease. Lateral radiograph of the knee shows brushlike calcifications (arrow) along the articular surface.

include calcification and ossification of intervertebral disks, disk space narrowing with vacuum phenomena, and osteoporosis (Fig. 53-36). Disk calcifications usually are distributed diffusely throughout the spine in a wafer-like configuration. The lumbar spine is affected first, followed by the dorsal and cervical spine. Calcifications are found predominantly in the inner fibers of the anulus fibrosus. Progressive ossification of disks and peripheral bony bridges may produce variable degrees of fusion of the vertebral bodies, simulating the “bamboo spine” appearance of ankylosing spondylitis. Osteoporosis may be associated with vertebral collapse.148 Extraspinal sites of calcification and ossification include the symphysis pubis, costal cartilage, helix of the ear, and peripheral tendons and ligaments. In the peripheral skeleton, the knees, hips, and shoulders are most commonly involved; more peripheral joint changes are rare. In these locations, radiologic changes resemble those of osteoarthritis; however, osteophytes and subchondral cysts are not prominent in ochronosis. Occasionally, a rapidly progressing destructive peripheral arthropathy characterized by fragmentation of articular surfaces may be observed.149 HEMATOLOGIC AND VASCULAR DISORDERS Hemophilia The arthropathy of hemophilia is related to destructive changes associated with repeated episodes of intra-articular hemorrhage (hemarthrosis) and the subsequent inflammatory reaction.150 Any joint may be involved, but changes in the knee, ankle, and elbow are most frequent. The joint lining becomes thickened and brown, with hemosiderin present as fine particles within phagocytic cells.151 The earliest radiographic findings are due to the large intra-articular

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Figure 53-36  Alkaptonuria. Spinal abnormalities; widespread disk space narrowing, disk calcification, and osteoporosis are typical features of this disorder.

effusions. Chronic effusions may appear dense because of the presence of hemosiderin (Fig. 53-37). This development is followed by osteoporosis and, in the immature skeleton, by epiphyseal overgrowth (Fig. 53-38). Subchondral cysts and bony erosions appear with subsequent cartilage destruction and joint space narrowing. Late abnormalities include complete joint destruction with obliteration of the articular space, large bony erosions, and joint instability. In the knee, radiographic features of hemophilia include widening of the intercondylar notch of the distal femur and squaring of the inferior pole of the patella. The radiographic features of hemophilia may be difficult to differentiate from the features of juvenile chronic arthritis. MRI may help to assess the degree of damage present in patients with hemophilia. The hemarthrosis is not distinguishable from other types of joint effusion on MRI examination, however. Cyst formation and synovitis are more apparent on MRI than on radiographs. The synovitis in patients with hemophilia typically shows fronds of tissue with low-to-intermediate signal on all pulse sequences owing to its hemosiderin content (Fig. 53-39). MRI signal within the cysts varies depending on the content (e.g., low signal contents on T1-weighted images and bright signal intensity on T2-weighted images suggest blood-filled or fluid-filled cysts).152 Osteonecrosis (Avascular Necrosis) Osteonecrosis of the femoral head is the end result of many conditions that interrupt the blood supply to the femoral head. These conditions include traumatic disruption (e.g., femoral

Figure 53-37  Hemophilia. Lateral view of the ankle shows ankle joint distention (arrows). The effusion appears more dense than the other soft tissues, consistent with hemosiderin deposition.

Figure 53-38  Hemophilia. Anteroposterior radiograph of the knee shows severe cartilage space loss and secondary osteoarthritis with marginal osteophytes. There is widening of the intercondylar notch of the femur.

neck fractures, hip dislocations), vascular occlusion (e.g., sickle cell anemia, caisson disease), vessel wall abnormalities (vasculitis), joint distention (e.g., sepsis) and other conditions including corticosteroid treatment and pancreatitis.

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H

R R

Figure 53-39  Hemophilia of the elbow with low signal synovial tissue on MRI. Two coronal T1-weighted images of the elbow, the left more anterior, show the low signal tissue (arrows). H, humerus; R, radius.

Radiographs are insensitive indicators of osteonecrosis in early stages (Fig. 53-40). Radiographic staging, usually a modification of the Ficat and Arlet classification,153 is summarized in Table 53-2. MRI is more sensitive than radiographs, CT scan, or bone scanning for the identification of osteonecrosis, although occasional cases of osteonecrosis that are normal on MRI but abnormal on bone scintigraphy have been documented. Sensitivity of 97% and specificity of 98% have been reported for the MRI diagnosis of osteonecrosis.154 MRI findings depend on the replacement of normal bone marrow signal by abnormal signal resulting from cell death and the ensuing repair process. In adults, the femoral epiphyses are filled with yellow (fatty) marrow. After vascular occlusion, cell death occurs, with hematopoietic cells dying within 6 to 12 hours, osteocytes dying within 12 to 48 hours, and fat cells dying 2 to 5 days after the insult.154 After the fat cells die, the normal fat signal of the femoral head is altered.153 Theoretically, MRI findings could be abnormal within the first week after infarction. Healing proceeds from the periphery of the affected area centrally, with a hyperemic zone and granulation tissue developing around the infarcted area.

A

B

The signal abnormalities present on MRI in the center of femoral head lesions vary and have been characterized by Mitchell and coworkers155 as follows: Class A (fatlike lesions)—the center of the lesion shows the signal characteristics of fat Class B (bloodlike lesions)—the center of the lesion exhibits high signal on T1-weighted and T2-weighted images Class C (fluid-like lesions)—the center of the lesion has fluid-type signal, low on T1-weighted images and high on T2-weighted images Class D (fibrous lesions)—the center of the lesion shows low signal on T1-weighted and T2-weighted images Generally, class A lesions are early and class D lesions are the most chronic. Many lesions exhibit mixed signal. As healing occurs, the periphery of the infarcted area becomes delimited by a low signal rim on T1-weighted images. On T2-weighted images, the inner portion of this rim exhibits bright signal, producing an appearance known as the double line sign (Fig. 53-41).154 The inner bright zone most likely corresponds to granulation tissue, and the outer rim corresponds to sclerosis. Chemical shift artifact may accentuate the low signal rim. This doubleline sign is

Figure 53-40  Osteonecrosis (avascular necrosis). A, Frog leg lateral view of the hip shows a lucency (crescent sign [arrows]) between the living subchondral bone and the dead bone of the femoral head. B, Late osteonecrosis is present with flattening of the articular surface. The area of infarcted bone appears largely lucent in this case with a rim of sclerosis (arrows) at the junction with the living bone.

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Table 53-2  Staging Osteonecrosis Magnetic Resonance Imaging Findings

Stage

Symptoms

Radiographic Findings

Bone Scintigraphic Findings

0

None

Normal

± Decreased flow

± Low signal in head and focal marrow edema

I

Pain

Normal, ± osteopenia

Decreased flow, increased uptake in   reactive zone at edge of infarct

—

II

Pain

Osteopenia and sclerosis

Larger area, increased uptake

Larger nonhomogeneous decreased signal on   T1-weighted and T2weighted images

III

Pain

Crescent sign (fracture)

Focal cold area with surrounding   increased activity

Heterogeneous marrow abnormalities

IV

Pain

Flattening

Same as III

Femoral head flattening

V

Pain

Osteoarthritis

Same as III

Osteoarthritis

Adapted from Conway WF, Totty WG: Hip. In Stark DD, Bradley JR (eds): MR Imaging. St. Louis, Mosby, 1999, pp 795-810.

diagnostic of osteonecrosis and is seen in 80% of cases.154 Other findings present in patients with osteonecrosis include premature conversion of intertrochanteric femoral hematopoietic marrow to fatty marrow, joint effusion, and a complete (“sealed off”) epiphyseal scar.156 MRI may help determine the prognosis of osteonecrosis. In one series, involvement of less than 25% of the femoral head was unlikely to be associated with collapse of the femoral head, whereas when involvement of more than half of the head was seen, collapse was common.157 As emphasized by Conway and Totty,153 MRI abnormalities occurring in the absence of clinical findings do not predict subsequent clinical osteonecrosis.153 In the knee, a particular form of “spontaneous” osteonecrosis is seen, most commonly involving the medial femoral condyle. The condition affects elderly individuals, and the onset is abrupt. Radiographic changes are delayed, but eventually sclerosis, flattening, and irregularity of the femoral surface occur (Fig. 53-42). MRI is able to show marrow changes before radiographic abnormalities. Bone Marrow Edema. Bone marrow edema may be an early feature of osteonecrosis or a finding accompanying a variety of disorders, including stress fracture, osteomyelitis, tumor, transient osteoporosis, or transient marrow edema syndrome.158 The MRI features of the edema pattern consist

of poorly defined, diffusely abnormal signal intensity in the femoral head that extends to some degree into the femoral neck and intertrochanteric regions. The normal marrow signal is replaced by fluid signal, which is low on T1-weighted images and bright on T2-weighted images (Fig. 53-43). Distinguishing patients with early osteonecrosis from patients with transient osteoporosis and patients with transient bone marrow edema syndrome may be problematic. In transient osteoporosis, marked osteopenia is noted on radiographs, sometimes with the loss of the subchondral bone, but with preservation of cartilage space. Infection must be excluded in these cases. Transient osteoporosis resolves spontaneously. The distinction between bone marrow edema and osteonecrosis also is difficult. Radiographs are normal in the transient marrow edema syndrome and in early osteonecrosis. Conway and Totty153 suggest that if no osteopenia is present on radiographic follow-up at 4 to 6 weeks, patients should be evaluated clinically and with MRI; patients with high risk factors for osteonecrosis should be considered for early surgical intervention, and patients without risk factors should be carefully followed clinically and with radiographs and MRI. Vande Berg and coworkers159 found that analysis of subchondral signal was helpful. The absence of any signal abnormality in the subchondral region (besides the edema) on T2-weighted or contrast-enhanced T1-weighted images

* Figure 53-41  Osteonecrosis of the humeral head. A, T1-weighted spin echo MR image shows a black demarcation zone (arrows) between the avascular portion of the humeral head and the viable bone distally.  B, T1-weighted image shows the double line sign with an area of bright signal intensity (asterisks). The brighter signal region corresponds to granulation tissue.

A

B

*

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B

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C

was evidence of a transient lesion rather than osteonecrosis in all cases. Neuropathic Osteoarthropathy Neuropathic osteoarthropathy (Charcot joint) is a progressive destructive arthropathy associated with numerous diseases that produce loss of pain sensation and proprioception. Most cases of neuropathic osteoarthropathy occur in patients with diabetes; less frequent causes are syringomyelia, syphilis, congenital insensitivity to pain, myelomeningocele, and alcohol abuse. Two different hypotheses have been proposed for the pathogenesis of neuroarthropathy. The “neurotraumatic” theory postulates that the loss of joint sensation, unperceived repetitive trauma, ligamentous laxity, and continued joint use all lead to permanent damage to the bone

Figure 53-42  Spontaneous osteonecrosis. A, Initial radiograph shows mild medial cartilage space narrowing. Questionable subchondral lucency of the medial femoral condyle is noted. B, T1-weighted coronal MR image shows a prominent focal area of low signal intensity in the medial femoral condyle (arrow). C, Radiograph obtained months later shows diagnostic features of osteonecrosis with a subchondral area of lucency surrounded by sclerosis (open arrow) and a depressed cortical bone fragment (thin arrow). The medial cartilage space is slightly narrow, and there are tiny osteophytes.

and articular structures. The second mechanism, known as the “neurovascular” theory, postulates a neurovascular reflex with regional hyperemia causing osteoclastic stimulation and active bone resorption. It seems likely that both mechanisms play a role, and the resultant hypertrophic and resorptive appearance of the joint reflects the final balance of the two.160 The radiographic abnormalities of neuropathic osteoarthropathy have been subdivided into hypertrophic and atrophic types. The earliest radiographic findings are joint effusion and soft tissue swelling. At this stage, the bony contours may remain well defined. Abnormal joint alignment from subluxation may be found before any bony changes are visible. Subsequently, fragmentation of the articular surfaces occurs leading to disorganization of the joint with large amounts of intra-articular and extra-articular osseous and calcified debris. Osseous proliferation in the form of

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B

Figure 53-43  Bone marrow edema. A, T1-weighted MR image shows replacement of normal left proximal femoral marrow fat by intermediate signal (arrow). B, Short tau inversion recovery image shows poorly defined increased signal in the proximal femur consistent with edema.

p­ eriosteal new bone formation, sclerosis, and osteophytes also is a characteristic finding. These findings are referred to as the “D’s” of neuropathic arthropathy—debris, destruction, dislocation, and no demineralization (Fig. 53-44). Fractures of the neighboring bones are often shown in neuropathic arthropathy. These fractures may occur spontaneously or with minor trauma and tend to be transverse, in contrast to the fractures associated with trauma, which are often spiral or oblique. In the atrophic form, the affected joint has sharp edges, resembling surgical amputation with little or absent bone repair (Fig. 53-45). Diabetes Mellitus. Diabetes mellitus is the most common cause of neuropathic osteoarthropathy. The joints involved

Figure 53-44  Severe neuropathic changes in the ankle of a diabetic patient. Complete destruction of the joint with sclerosis and fragmentation of the joint margins is noted.

are almost always in the lower extremity, especially the feet. The tarsal, tarsometatarsal, and metatarsophalangeal joints are most commonly affected. Arthropathy of the ankle and knee also is seen. Spinal, elbow, and wrist involvement also have been reported.161-163 The most common radiographic finding is a long-standing Lisfranc fracture-dislocation with eburnation and fragmentation of the tarsometatarsal joints. Calcaneal fractures, talocalcaneal joint dissolution, collapse of the talus, talar angulation within the ankle mortise, and distal fibular fractures also are encountered. In the forefoot, osseous ­resorption may result in tapering or sharpening of metatarsal and phalangeal shafts.164 Neuropathic joint changes and infection may coexist in the affected foot in diabetes. The radiologic changes of neuropathic joint make the diagnosis of superimposed ­infection

Figure 53-45  Atrophic neuropathic osteoarthropathy of the right hip, secondary to spinal dysraphism.

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B

Figure 53-46  Early changes of neuropathic osteoarthropathy involving the talonavicular joint in a diabetic patient. A, Lateral view reveals calcific debris at the dorsal aspect of the talonavicular joint (arrow), which shows subtle incongruity. B, Sagittal short tau inversion recovery MR image shows extensive bone marrow edema in the tarsal bones and soft tissue edema. Subluxation of the talonavicular joint appears more conspicuous. The calcific debris detected on plain film appears as material of inhomogeneous signal outlined by bright joint fluid around the talonavicular joint.

a diagnostic challenge. The presense of fuzzy bone margins and osteoporosis may suggest infection. Scintigraphy is sensitive, but not specific; Tc 99m methylene diphosphonate–labeled, gallium citrate Ga 67–labeled, and indium In 111 chloride–labeled white blood cell scans cannot reliably distinguish between osteomyelitis and neuropathic arthropathy because of extensive bone remodeling and inflammation, which are present in both conditions.165 MRI may play a role in evaluation of the neuropathic joint.98,166-168 On MRI, marrow and soft tissue edema, joint effusion, articular destruction with fragmentation, and malalignment characterize neuropathic osteoarthropathy (Fig. 53-46). If the bone marrow changes around the affected joint exhibit decreased signal intensity on T1-weighted and T2-weighted images, superimposed infection can be virtually excluded. If bone marrow has decreased signal intensity on T1-weighted images and increased signal intensity on T2-weighted images, and similar changes of signal intensity in the adjacent soft tissues, it may represent acutely evolving neuropathic arthropathy with or without concomitant infection. Evaluation of adjacent soft tissue for ulceration and underlying cortical destruction is helpful in suggesting osteomyelitis. Syringomyelia. Approximately 20% to 25% of patients with syringomyelia develop neuroarthropathy. There is a distinct predilection for the joints of the upper extremity, especially the glenohumeral joint, elbow, and wrist. Lower extremity or spinal alterations also may occur. Tabes Dorsalis. Five percent to 10% of patients with tabes dorsalis have neuroarthropathy. The joints of the lower extremity are most affected, with the knee and hip being the most frequent target sites. Involvement of the axial skeleton is common in tabes dorsalis. The thoracolumbar junction

and lumbar spine are most frequently affected, and one or more vertebral segments may be involved. The radiologic appearance of spinal neuroarthropathy may be similar to that of severe degenerative disease, spinal infection, or metastatic disease. CT and MRI findings, such as the presence of vacuum disk, facet involvement, spondylolisthesis, joint disorganization, and debris, and gadolinium enhancement in the periphery of the disk, help to differentiate spinal neuropathic arthropathy from infection, favoring the former.169,170

CONNECTIVE TISSUE DISORDERS PROGRESSIVE SYSTEMIC SCLEROSIS (SCLERODERMA) Soft tissue or bony involvement in progressive systemic sclerosis is common. The radiographic abnormalities can be divided into four main categories:171 (1) soft tissue resorption, (2) soft tissue calcification, (3) osteolysis, and (4) erosive articular disease. Soft tissue resorption is most commonly noted in the fingertips in association with Raynaud’s phenomenon (Fig. 53-47). Early changes can be identified by noting a reduction in the normal distance between the phalangeal tips and the skin (the normal distance is approximately 20% of the transverse diameter of the base of the same phalanx).172 In time, the fingertip assumes a conical shape, and soft tissue calcification is often present. Soft tissue calcification is most common in the hand, but may occur at virtually any site.173,174 Calcification may be present in subcutaneous tissue, joint capsule, tendons, or ligaments. The calcification typically is composed of hydroxyapatite crystals and has a cloudlike radiographic appearance. Occasionally, large tumoral collections may be

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Figure 53-47  Scleroderma. Posteroanterior radiograph shows flexion of the fingers, loss of the tufts of the index finger and middle finger distal phalanges, and calcification including finger tip calcification.

present adjacent to a joint. Intra-articular or intraosseous calcification also may be noted. Extra-articular osteolysis is frequently a manifestation of progressive systemic sclerosis. The most common sites are the tufts of the distal phalanges of the hand, or occasionally of the foot, usually in association with Raynaud’s phenomenon and soft tissue calcification. The earliest change is in the volar aspect of the tuft with continuing resorption, leading to a “sharpened” appearance of the phalanx. Elsewhere, thickening of the periodontal membrane around the roots of the teeth175 or localized mandibular osteolysis may be seen, the latter predisposing to pathologic fracture. Localized osteolysis involving the ribs, acromion, clavicle, radius, ulna, and cervical spine also has been reported.176-179 A severe articular disease consisting of joint space narrowing, marginal and central osseous erosions, and deformity may occur.180 There is a tendency toward involvement of the first carpometacarpal joint.181 Bilateral destructive changes of the first carpometacarpal articulation with joint subluxation should arouse suspicion of progressive systemic sclerosis. Other common sites of joint involvement in progressive systemic sclerosis include the distal interphalangeal, proximal interphalangeal, distal radioulnar, and metatarsophalangeal joints. Patients with scleroderma may exhibit a spectrum of muscle disease ranging from fatigue, most likely without objective findings, to an inflammatory myositis resembling dermatomyositis.182 MRI is useful for evaluating the presence and extent of inflammatory muscle disease.

B Figure 53-48  Systemic lupus erythematosus. A, Posteroanterior view of the hands and wrists shows hyperextension of the thumb interphalangeal joints. There are small calcifications at the radial aspect of the right wrist. B, Posteroanterior view of the hands and wrists shows multiple finger deformities. No erosions are present. (From Weissman BN, Rappoport AS, Sosman JL, et al: Radiographic findings in patients with systemic lupus erythematosus. Radiology 126:313, 1978.)

SYSTEMIC LUPUS ERYTHEMATOSUS The radiographic changes of systemic lupus erythematosus (SLE) include symmetric polyarthritis, deforming nonerosive arthropathy, spontaneous tendon rupture (Fig. 53-48), osteonecrosis, soft tissue calcification, acral sclerosis, and tuft resorption.183-191 The radiographic changes of polyarthritis in SLE are nonspecific and consist of soft tissue swelling and periarticular osteoporosis.183,184 Joint space narrowing and bony erosions are unusual. Deforming nonerosive arthropathy is seen in 5% to 40% of patients with SLE. Symmetric involvement of the hands is typical. The specific type of deformity varies.183-185 Swan neck or boutonnière deformity may be evident. Other deformities include hyperextension of the interphalangeal joint of the thumb, ulnar drift at the metacarpophalangeal joints, and subluxation of the first carpometacarpal joint. The prominent thumb deformity is especially characteristic of lupus arthropathy (see Fig. 53-48). Although bony and cartilaginous abnormalities are generally not present, joint space narrowing, “hooklike” erosions of the radial and volar aspects of the metacarpal heads, and subchondral cyst formation are occasionally encountered. Linear and nodular calcific deposits in the subcutaneous tissues, particularly in the lower extremities, occasionally may be seen in SLE.189 Sclerosis (acrosclerosis) or resorption

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of the tufts of the terminal phalanges also is occasionally ­evident in SLE.191 The prevalence and severity of osteonecrosis in SLE patients on glucocorticoid treatment are reported to be higher than in patients without SLE.192 Osteonecrosis in SLE patients may affect small bones. MRI prognostication of osteonecrosis in SLE patients with normal radiographs was performed by Sugano and coworkers,193 who concluded that the location and size of osteonecrosis were major elements of prognosis. This study also showed that if the MRI findings were normal 1 year after treatment, progression to femoral head collapse was unlikely. DERMATOMYOSITIS AND POLYMYOSITIS Articular abnormalities in dermatomyositis and polymyositis are usually without radiographic manifestations, although periarticular soft tissue swelling and osteoporosis are noted occasionally.194 More dramatic radiographic changes occur in the skeletal musculature, especially the large proximal muscle groups of the thorax, arm, forearm, thigh, and calf. Initial inflammation produces increased bulk and radiodensity of muscles with loss of the normal intermuscular fat planes.195 In later stages, muscle atrophy or contractures may be prominent. The most characteristic soft tissue abnormality is calcification in subcutaneous tissue, intermuscular fascia, tendons, or fat (Fig. 53-49). Subcutaneous calcific deposits simulate those of progressive systemic sclerosis, but the presence of marked linear calcification favors the diagnosis of polymyositis or dermatomyositis. MRI of patients with polymyositis or dermatomyositis lesions has shown abnormal muscle signal consisting of either isointense signal on T1-weighted images with hyperintense signal on T2-weighted images (suggesting inflammation or edema) or fatty atrophy (Fig. 53-50). Inflammatory changes

Figure 53-49  Dermatomyositis. Extensive soft tissue calcification is present.

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usually involve the entire muscle, whereas fatty atrophy often begins at the distal myotendinous junction. Muscle involvement may be asymmetric, and distal and proximal leg muscles are often involved. Inflammatory changes on MRI mirror clinical findings.196 MRI may be used to select a biopsy site and to follow the inflammatory response after treatment.197

CONDITIONS PRIMARILY AFFECTING THE SPINE INFLAMMATORY DISORDERS Rheumatoid Arthritis Cervical spine involvement occurs in approximately two thirds of patients with RA.198 In contrast to the frequency of cervical spine involvement, changes in thoracic and lumbar spine are uncommon in this disease. The radiographic findings include osteoporosis, atlantoaxial and subaxial subluxations, erosions involving the vertebral end plates, apophyseal joints and spinous processes, intervertebral disk space narrowing, and, rarely, bony ankylosis of the apophyseal joints. Although any segment of the cervical spine may be affected, the destructive changes at the occipitoatlantoaxial junction predominate. Erosive synovitis involving the atlantoaxial, atlanto-odontoid, and atlanto-occipital joints causes atlantoaxial subluxation. Atlantoaxial subluxation can be anterior, posterior, vertical, lateral, rotational, or a combination of these. Anterior atlantoaxial subluxation is the most common type of subluxation and is due to weakening and destruction of the transverse, alar, and apical ligaments. Resultant anterior displacement of the atlas narrows the spinal canal and eventually causes spinal cord compression (Fig. 53-51). On lateral radiographs of the cervical spine, an anterior atlantodental interval greater than 2.5 mm is considered abnormal in adults. The measurement is made from the posteroinferior arch of the atlas to the anterior surface of the odontoid. Radiographs should be obtained in the flexion and extension positions because radiographs taken in the neutral position may miss 48% of cases of anterior atlantoaxial subluxation, and subluxation may reduce extension.199 Vertical subluxation, also known as atlantoaxial impaction and cranial settling, is the least common, but clinically most dangerous, form of instability. Destruction of

Figure 53-50  Dermatomyositis. Axial short tau inversion recovery MR image through the thighs shows scattered muscle involvement as increased signal in the involved muscles.

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O

**

**

O

A

B

Figure 53-51  Rheumatoid arthritis of cervical spine. A, Lateral radiograph in flexion shows severe anterior atlantoaxial subluxation with a wide anterior  atlantodental interval (asterisks) and decreased posterior atlantodental interval (arrow). B, Almost complete reduction of subluxation is noted on the lateral view in extension. There also is subaxial subluxation at the level of C4-C5 (arrowhead) with erosive changes in various facet joints. O, odontoid.

a­ tlantoaxial and atlanto-occipital joints leads to superior migration of the odontoid and surrounding pannus through the foreman magnum, impinging on the brainstem and spinal cord (Fig. 53-52). Posterior atlantoaxial subluxation may occur in the setting of pathologic fracture or severe erosion of the odontoid. Asymmetric bony erosion and collapse of the lateral masses of C1 and C2 may lead to lateral atlantoaxial subluxation. Lateral subluxation is defined as more than 2 mm offset of the lateral masses of C1 and C2. Rotational deformity usually accompanies it. Clinically, these patients reveal fixed head tilt toward the side of osseous collapse and rotation of the face toward the opposite site. In the lower cervical spine, involvement of apophyseal and uncovertebral joints, intervertebral disks, and interspinous ligaments results in subaxial subluxations and disko­ vertebral joint abnormalities (see Fig. 53-51). Subaxial subluxations tend to occur at multiple levels, giving the “stepladder” appearance of the cervical vertebral bodies. The radiologic examination plays a key role in identifying patients who are at increased risk of developing neurologic sequelae. On the basis of plain radiographs, anterior atlantoaxial subluxation greater than 9 mm and the presence of atlantoaxial impaction have been defined as risk factors for cord compression.200 More recent literature suggests that the posterior atlantodental interval, the distance measured between the posterior surface of the odontoid and the anterior margin of the posterior ring of atlas, is a better method of assessing anterior atlantoaxial subluxation than the anterior atlantodental interval. A minimum distance of 14 mm for the posterior atlantodental interval is required to avoid cord compression.201

MRI is the preferred method for evaluation of spinal cord and brainstem compression. MRI has been recommended for patients who have progressive and severe subluxations, intractable cervical or suboccipital pain, symptoms or signs of spinal cord or brainstem compression, and signs of vertebral artery compromise.202 MRI allows direct visualization of periodontoid pannus, subarachnoid space, spinal cord, and brainstem (Fig. 53-53). Distortion of the spinal cord (cervicomedullary angle <135 degrees) correlates with clinical evidence of cervical myelopathy.203 Internal spinal cord damage resulting from cord compression is best shown on T2-weighted images as an area of increased signal. This increased signal may represent myelomalacia or cord gliosis, with or without associated edema, and correlates with a poor response to conservative and surgical treatment.204 MRI obtained in neck flexion may show better the degree of spinal cord compromise, but the necessity and safety of this maneuver are debated. SERONEGATIVE SPONDYLOARTHROPATHIES Ankylosing Spondylitis Synovial and cartilaginous joints and sites of tendon and ligament insertion (entheses) may be involved in ankylosing spondylitis and other seronegative spondyloarthropathies.205,206 Axial skeletal involvement is characteristic, with predilection for the sacroiliac, apophyseal, diskovertebral, and costovertebral articulations. The initial sites of involvement are the sacroiliac joints and the lumbosacral and thoracolumbar vertebral junctions. Subsequently, ascending and descending spinal disease may be encountered.207,208

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P

*

^^

Figure 53-52  Vertical subluxation of C1 on C2. Lateral tomogram shows protrusion of odontoid (asterisk) through the foramen magnum.

Peripheral joint involvement, although common (50%), is usually mild.209 The hips and glenohumeral joints are the most common extraspinal locations of disease. Sacroiliac Joints. Involvement of the sacroiliac joints is the hallmark of ankylosing spondylitis, and it is difficult to verify the diagnosis of this disease in the absence of sacroiliac joint involvement. Sacroiliitis occurs early in ankylosing spondylitis and is characteristically bilateral and symmetric in its distribution.208,210-212 Occasionally, initial unilateral or asymmetric sacroiliac joint changes are observed, and, rarely, spinal disease occurs in the absence of significant sacroiliac joint abnormality. Changes occur in the synovial and the ligamentous portions of the joint, with the abnormalities being more prominent on the iliac side of the articulation. Osteoporosis, subchondral bony resorption with loss of definition of the articular margins, and superficial osseous erosions are interspersed with focal areas of bony sclerosis. Radiographically, in this stage, the articulation may appear widened. With progression of the disease, a wide, ill-defined band of sclerosis is seen on the iliac side of the joint with larger subchondral erosions (Fig. 53-54). In the late proliferative stage, bony bridges traverse the joint space, initially isolating islands of intact cartilage. Such segmental ankylosis may be followed by complete intra-articular bony fusion and disappearance of the periarticular sclerosis. The ligamentous (syndesmotic) portions of the sacroiliac joint also may be affected, leading to bony erosions and proliferation. CT and MRI delineate better the complex anatomy of the sacroiliac joints than conventional radiographs. Good indicators of sacroiliitis on CT include increased subchondral sclerosis in patients younger than 40 years, unilateral or bilateral diffuse joint space loss (<2 mm), erosions, and

Figure 53-53  Rheumatoid arthritis of cervical spine. T2-weighted sagittal MR image shows low signal periodontoid pannus (P). Odontoid process appears irregular secondary to erosions (arrow). The atlantodental distance shows mild widening (solid line). There also is vertical subluxation without signs of cord compression. The anterior subarachnoid space is compromised by disk protrusions at multiple levels. Erosions  (arrowheads) are seen at the vertebral end plates at the C6-C7 level.

intra-articular ankylosis. The superiority of CT over plain films in the study of sacroiliitis is controversial. In most patients with clinical signs of sacroiliitis, high-quality radiographs of the sacroiliac joints are diagnostic. When CT is used, it may reveal, however, that the disease is more advanced than had been suspected. In cases of ankylosing spondylitis not responding to conventional therapy, intra-articular corticosteroid injection can be guided by CT (or fluoroscopy). MRI allows detection of sacroiliitis before conventional radiography or CT. This sensitivity is due to the ability of MRI to detect bone marrow edema on fluid-sensitive sequences. Contrast-enhanced MRI studies increase further the sensitivity for detecting early sacroiliitis.213 Cartilage

Figure 53-54  Sacroiliitis in ankylosing spondylitis. There is sclerosis along the iliac sides of the sacroiliac joints and loss of portions of the iliac subchondral bone indicating erosion. Small linear bony bridges or residual bone are noted overlying the cartilage space.

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Figure 53-55  Ankylosing spondylitis with shining corners and vertebral squaring. A, There has been marked erosion at the vertebral margins producing straight or slightly convex anterior vertebral surfaces. New bone  formation has resulted in shining corners (arrows). The facet joints are fused. B, Sagittal fast spin echo T2-weighted MR image in another patient shows bone marrow edema–like signal at the anterosuperior corners of the vertebral bodies (arrows) corresponding to early osteitis.

A

abnormalities may be visible on MRI with the normal thin band of intermediate signal intensity representing cartilage on T1-weighted images replaced by areas of inhomogeneous, mixed signal intensity. Spine. The initial sites of spinal involvement, especially in men, are the lumbosacral and thoracolumbar junctions. In women, the cervical spine may be affected at an early stage of disease. Osteitis is an initial finding, related to inflammation of the anterior portion of the diskovertebral junction. Erosions at the anterosuperior and anteroinferior vertebral margins lead to loss of the normal concavity of the anterior aspect of the vertebral body, resulting in a “squared” vertebral configuration on the lateral radiographic projection. This appearance is more easily identified in the lumbar spine because the thoracic vertebral bodies may normally have a straight, squared appearance. In ankylosing spondylitis, bony sclerosis adjacent to the sites of erosion produces a “shining corner” sign on radiographs (Fig. 53-55). Syndesmophytes are vertically oriented bony excrescences that represent ossification of the outer fibers of the anulus fibrosus of the intervertebral disk.214 They predominate on the anterior and lateral aspects of the spine and eventually bridge the intervertebral disk (Fig. 53-56). In the late stages of the disease, extensive syndesmophyte formation produces a smooth, undulating spinal contour termed bamboo spine. It is important to differentiate the syndesmophytes that characterize ankylosing spondylitis (and enteropathic spondyloarthritis) from other spinal and paraspinal bony excrescences. Vertebral excrescences in spondylosis deformans arise several millimeters from the diskovertebral junction, are

B

triangular in shape, and have a horizontally oriented segment of variable length at their point of origin. In diffuse idiopathic skeletal hyperostosis (DISH), bone formation in the anterior longitudinal ligament results in a flowing pattern of ossification, thicker than that seen in ankylosing spondylitis.

Figure 53-56  Syndesmophytes of ankylosing spondylitis. Bony bridging (arrows) extends from the edge of one vertebral body to the next.

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Such ossification is best shown on lateral spine ­radiographs. In DISH, there is absence of erosion and widespread bony ankylosis of the sacroiliac joints. The paravertebral ossifications that characterize psoriatic arthritis and Reiter’s syndrome arise, asymmetrically, in the soft tissues adjacent to the outer layer of anulus fibrosus. Initially, they are unattached to the vertebral bodies, but with time, they fuse with the margins of the vertebral body at a point several millimeters from the diskovertebral junction. Bridging identical to that observed in ankylosing spondylitis may occur, however, in psoriatic arthritis or Reiter’s syndrome. Disk calcification may occur at levels of ankylosis in all these conditions. Erosions at one or more diskovertebral junctions can be prominent radiographic findings in ankylosing spondylitis. These erosions may be classified as focal or diffuse.215 Focal lesions may relate to intraosseous protrusion of disk material (cartilaginous or Schmorl’s node) or enthesis. Diffuse destruction of the diskovertebral junction may be related to a pseudarthrosis that follows a fracture in a previously ankylosed spine (Fig. 53-57). Early alterations in the apophyseal joints in the lumbar, thoracic, and cervical segments consist of ill-defined erosions accompanied by reactive sclerosis. Capsular ossification or intra-articular bony ankylosis may occur subsequently. On frontal radiographs of the spine, such ossifications produce vertically oriented, parallel radiodense bands, which when combined with a central radiodense band related to ossification of the interspinous and supraspinous ligaments, lead to the “trolley-track” sign (Fig. 53-58). Erosions of the odontoid process and sclerosis of the odontoid process and atlantoaxial subluxation may be observed in ankylosing spondylitis, although with less frequency than in RA.210,216 Ankylosis of the atlantoaxial articulation, either in its normal position or in a position of subluxation, may be noted occasionally. At other levels in the cervical spine, the changes, when present, are identical to those in the thoracolumbar spine.

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Figure 53-57  Ankylosing spondylitis with pseudarthrosis. There is marked bone resorption from vertebral bodies and posterior elements at the site of pseudarthrosis (arrow). In this patient, syndesmophytes were not prominent.

MRI can be used to detect spinal involvement, even before the onset of clinical symptoms related to the spine or before changes detectable by other imaging modalities, such as radiographs or bone scans. On MRI, the low signal at the affected enthesis enhances after intravenous gadolinium on T1-weighted images with fat saturation, and there is a high signal on T2-weighted images. These findings correspond to

Figure 53-58  Ankylosing spondylitis. A, Fusion of the facet joints and ossification of the adjacent soft tissue has produced a trolley track appearance (thin arrows). The sacroiliac joints are fused. Syndesmophytes (open arrow) are present. B, In another patient, there is a prominent fusion of the interspinous ligaments producing a saber sheath appearance.

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Figure 53-59  Fracture in ankylosing spondylitis. A, Radiograph shows disruption of the previously fused C6-C7 facet joints and slight anterior subluxation. B, Sagittal T2weighted MR image confirms a high signal fracture line (arrow) through the superior aspect of C7.

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hypervascularity and inflammation of the subchondral bone at the involved enthesis. Spinal complications include functional limitation from severe kyphosis, acute fracture of the ankylosed spine, pseudarthrosis after spinal fracture (usually from minor trauma), and cauda equina syndrome. Detection of pseudarthrosis or of acute spinal fracture may be difficult (Fig. 53-59). CT with reformatted images may detect spinal fracture that is not apparent on radiographs or on axial CT images. In patients who develop pseudarthrosis, MRI helps differentiate this condition from other causes of diskovertebral destruction, such as infection or tumor. Spinal cord compression also can be delineated with MRI, enabling early intervention to prevent catastrophic consequences. CT examination of the lumbar region in patients with ankylosing spondylitis who have cauda equina syndrome may reveal enlargement of the spinal canal with multiple scalloped erosions involving the adjacent bone (Fig. 53-60). Extraspinal Locations. The hip is the most commonly involved peripheral articulation in ankylosing spondylitis, and the changes are most frequently bilateral and symmetric in distribution.217 Concentric joint space narrowing with axial migration of the femoral head and marginal osteophyte formation is characteristic (Fig. 53-61). Osteophytes are first observed at the lateral margin of the femoral head-neck junction and, with progression, proliferate circumferentially to produce a “ring osteophyte.”217,218 Subchondral cysts and erosions and intra-articular bony ankylosis may be seen. Surgical intervention may be required, but patients with ankylosing spondylitis who undergo total hip replacement are prone to develop exuberant heterotopic bone, which may restrict postoperative motion. The shoulder is the second most common site of peripheral involvement in ankylosing spondylitis.209 Bilateral

B

involvement is common; changes are osteoporosis, joint space narrowing, bony erosions, and rotator cuff disruption. A characteristic large destructive abnormality involving the superolateral aspect of the humeral head in this disease is called the hatchet sign.219 Changes in other peripheral joints occur with variable frequency. Generally, these changes, which are similar to, but less extensive than, the changes in the other seronegative

Figure 53-60  Cauda equina syndrome in ankylosing spondylitis. Ankylosing spondylitis and thecal diverticula. CT scan of a lumbar vertebra shows scalloped erosions of the posterior elements. (From Resnick D, Niwayama G: Diagnosis of Bone and Joint Disorders. Philadelphia, WB Saunders, 1988.)

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Figure 53-61  Ankylosing spondylitis involving the hips. Bilateral cartilage space narrowing is present. A ring of osteophytes is noted at the capsular insertion (arrows) on each femoral head. The sacroiliac joints are fused.

spondyloarthropathies, include soft tissue swelling, mild osteoporosis, joint space narrowing, bony erosions, and osseous proliferation.206 The erosions tend to be less prominent than in RA. The presence of bone proliferation (whiskering) and periostitis in ankylosing spondylitis (and the other seronegative spondyloarthropathies) is another helpful diagnostic feature. Inflammation with bony proliferation at sites of tendon and ligament insertion (enthesitis) is prominent in ankylosing spondylitis (and in the other seronegative spondyloarthropathies). Plantar and posterior calcaneal enthesophytes are common and may be either well defined or indistinct with feathery margins, representing the combination of erosive and proliferative change. Erosions of the posterior calcaneal margin secondary to inflammation in the retrocal­ caneal bursa and thickening of the Achilles tendon may be present.220 The inflammatory enthesopathy of the sero­ negative spondyloarthropathies221 differs from the degenerative enthesopathy seen in DISH. In DISH, bony outgrowths (enthesophytes) are sharply marginated and well defined. Other sites of involvement in ankylosing spondylitis include the symphysis pubis and manubriosternal, temporomandibular, and sternoclavicular joints.

Figure 53-62  Psoriatic spondylitis. Note the thick asymmetric paravertebral ossification (arrows). These lesions, which are best shown in the anteroposterior projection of the spine, are characteristic of psoriatic spondylitis and Reiter’s syndrome. (From Resnick D, Niwayama G: Diagnosis of Bone and Joint Disorders. Philadelphia, WB Saunders, 1988.)

Cervical spine changes in psoriatic arthritis may be dramatic, even in patients with minimal thoracolumbar spinal involvement.223,224 Diskovertebral joint irregularity with extensive bony proliferation around the anterior aspect of the vertebra and extensive apophyseal joint erosion and narrowing may be seen. Atlantoaxial subluxation may occur. Spinal involvement is less frequent in reactive arthritis than in ankylosing spondylitis and psoriatic arthritis. Although in some instances the changes may be identical to the changes of ankylosing spondylitis, a more characteristic finding consists of asymmetrically distributed paravertebral ossifications involving the thoracolumbar spine.225 Cervical spine involvement is unusual, and atlantoaxial subluxation is rare.

Psoriatic Arthritis and Reactive Arthritis

Infectious Spondylitis

The characteristic spinal lesion of psoriatic arthritis (and reactive arthritis) is paravertebral ossification.222 These ossifications initially appear as either thick and irregular or thin and curvilinear densities, asymmetrically distributed parallel to the lateral surface of the intervertebral disk and vertebral body (Fig. 53-62). At this stage, the outgrowths are unattached to the vertebral body, although in later stages, the ossific densities merge with the lateral margins of the vertebral body several millimeters from the diskovertebral junction. Occasionally, syndesmophytes identical to those in ankylosing spondylitis occur in psoriatic arthritis and reactive arthritis; however, in most cases, they are interspersed with the more characteristic paravertebral ossifications. “Corner osteitis,” vertebral body “squaring,” and apophyseal joint ankylosis are less common than in ankylosing spondylitis.

Infectious spondylitis represents 2% to 7% of all cases of osteomyelitis.226 Pathogenic organisms reach the spine by hematogenous or contiguous spread or direct inoculation from penetrating wounds or diagnostic or surgical procedures. The most common offending organism is Staphylococcus aureus. Other organisms include streptococci, gram-negative organisms, and mycobacteria. In adults, the infection almost always starts at the vertebral body, and involvement of disk is secondary. The initial radiographs are often normal in early infection. There is usually 2 to 3 weeks’ delay between the onset of clinical symptoms and detection of radiographic changes. The earliest radiographic findings include blurring of end plates of the involved vertebral bodies followed by narrowing of intervertebral disk height and gradual development of

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P

A

P

B

Figure 53-63  Tuberculous spondylitis. A, Lateral view of the lumbar spine shows disk space narrowing at L3-L4 level with destructive changes involving the superior end plate of the L4 vertebral body (arrow). B, Coronal short tau inversion recovery MR image of the lumbar spine of the same patient confirms focal destruction of the L4 vertebral body (arrow). Enlargement of both psoas muscles (P) with increased signal is noted, owing to paraspinal extension of the infection.

destruction of the vertebral end plates. Depending on host resistance and the virulence of the organism, the destruction may progress to vertebral collapse. Reparative sclerosis with new bone formation ensues at about 10 to 12 weeks. Bony bridging between the involved vertebral bodies or complete bony ankylosis can be the late sequela of infectious spondylitis.227 In tuberculous spondylitis, the lower thoracic and upper lumbar vertebrae are most frequently affected. The infection typically starts at the anterior part of the vertebral body near the end plate and spreads by subligamentous extension with multilevel involvement and skip levels. Initially, the vertebral end plates are often focally destroyed with little or no reactive sclerosis (Fig. 53-63). With progression of destruction, collapse and anterior wedging of vertebral bodies can occur, leading to characteristic sharp angulation and gibbus deformity. Large calcified paravertebral abscesses are characteristic findings in tuberculous spondylitis. On MRI, intraosseous abscesses with ringlike, peripheral enhancement and meningeal involvement can be shown on postcontrast images. Although there is an overlap in the radiologic appearances of tuberculous and pyogenic spondylitis, involvement of multiple levels, a delay in destruction of the intervertebral disks, and the presence of large calcified paravertebral abscesses favor tuberculous spondylitis.228,229 Bone scintigraphy is positive in spinal infection well before bone destruction becomes obvious on radiographs. The combined accuracy of technetium and gallium scans

has been reported to be 94%. For follow-up studies, gallium scan alone is recommended. During the healing phase, the technetium scan remains abnormal despite the resolution of infection owing to its sensitivity for bone remodeling and repair; the gallium scan returns to normal, however, when the infection is eradicated.230,231 CT with reformatted images in the sagittal and coronal planes may play a role in the assessment of spinal infection. CT scans allow better definition of the extent of bone destruction and spinal canal compromise than radiographs. Paravertebral and epidural abscesses are easily identified after contrast administration. CT also facilitates guidance for percutaneous biopsy. MRI has become the imaging modality of choice for the diagnosis and evaluation of the extent and complications of infectious spondylitis. The reported sensitivity, specificity, and accuracy of MRI in the diagnosis of infectious spondylitis are 96%, 92%, and 94%.232 The appearance of pyogenic spondylitis on MRI has been characterized as (1) decreased signal intensity on T1-weighted images with corresponding increased signal on T2-weighted and short tau inversion recovery images in the involved vertebral body, (2) abnormal increased signal of the intervertebral disk with obliteration of the normal low signal central cleft on T2-weighted images, and (3) increased signal of the vertebral end plates at the abnormal disk level on T2-weighted images.232 Gadolinium-enhanced images are helpful in precise characterization and delineation of any paravertebral and epidural extension of the infection. On postcontrast

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images, a phlegmon shows uniform enhancement, whereas an abscess shows rim enhancement.233,234 MRI also is helpful in monitoring the efficacy of conservative treatment. Resolution of soft tissue inflammation, reduced enhancement of tissues, and quiescence of signal changes within the intervertebral disk and adjacent bone marrow reflect a favorable response to treatment.235,236

the anulus fibrosus and adjacent apophyses and is characterized by anterior and lateral marginal osteophytes with normal and or slightly narrowed disk spaces, or intervertebral osteochondrosis, which affects mainly the nucleus pulposus and the vertebral body end plates, but also includes extensive fissuring of the anulus fibrosus. Osteochondrosis leads to significant disk space narrowing, vacuum phenomenon, reactive changes of the vertebral bodies, and development of posterior osteophytes, which is an important factor in pathogenesis of spinal canal stenosis.239 In contrast to spondylosis deformans, which may represent in part aging, intervertebral osteochondrosis is a clearly pathologic process, although not symptomatic.240 On MRI, the earliest appearance of disk aging or degeneration is desiccation, manifest as low signal intensity on T2-weighted images instead of the high signal intensity of normally hydrated disks.241,242 The degenerating anulus fibrosus may develop frank tear of the collagen fibers. Annular tears, also called annular fissures, are depicted as foci of bright signal on T2-weighted MR images, defined as a highintensity zone (Fig. 53-64A).243 Loss of disk height usually accompanies the disk dehydration. Degenerative changes involving the intervertebral disks may lead to extension of disk material outside of the normal disk space in the axial plane. Although there is no universally accepted classification system describing degenerative disk disease, a multispecialty task force proposed a nomenclature for lumbar disk pathology in 2001.244 This group has defined bulge as smooth circumferential extension of the disk margin beyond the boundary of the adjacent vertebral end plates in greater than 50% of the disk circumference. Herniation is defined as a localized (<50% of the circumference of the disk) displacement of disk material beyond the limits of the intervertebral disk space. Herniated disks may

DEGENERATIVE DISEASE OF THE SPINE The general term degenerative disease of the spine is used to describe a wide spectrum of degenerative abnormalities involving intervertebral disk, bony structures, and supportive soft tissues. MRI is currently the imaging technique of choice for evaluation of the degenerative changes of the spine. CT or CT myelography is useful for patients who cannot enter the MRI scanner or patients whose MRI findings do not correlate with clinical symptoms. CT or CT myelography can provide additional information for presurgical planning by identifying ossific or calcific pathologic changes (e.g., calcified disk herniation, osteophytes). Radiographs are valuable for initial evaluation, but limited in assessment of spinal stenosis. Degenerative Disk Disease The term degeneration includes any or all of the following: disk desiccation, fibrosis, narrowing of the disk space, diffuse bulging of the anulus beyond the disk space, extensive fissuring and mucinous degeneration of the anulus, defects and sclerosis of the end plates, and osteophytes at the vertebral apophyses.237,238 A disk exhibiting one or more of these degenerative changes can be qualified further into two subcategories: spondylosis deformans, which affects essentially

L4 L5 L5 S1

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B

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Figure 53-64  Disk degeneration and herniation. A, Disk degeneration and annular fissure. Sagittal fast spin echo T2weighted MR image shows loss of normal bright signal of L5-S1 disk representing disk desiccation. The high signal intensity in anulus fibrosus, posteriorly, represents an annular fissure (arrowhead). B, Disk herniation. Sagittal fast spin echo T2-weighted image shows marked loss height of disk at L4-L5 level with mildly cranially migrated disk extrusion, deforming the thecal sac.

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take the form of protrusion or extrusion, based on the shape of the displaced material. Protrusion is present if the base of the herniated material is broader than the herniation itself. Disk extrusion is a larger herniation of disk contents where the diameter of the disk material beyond the disk space is greater than the distance between the edges of the base (Fig. 53-64B). A free (sequestered) disk fragment is an extrusion that is no longer contiguous with the parent disk. Bone marrow signal changes of the end plates adjacent to the degenerated disks are a common observation on MR images. Three types have been described.245,246 Type I changes, which correspond to active inflammation, show decreased signal on T1-weighted images and increased signal T2-weighted sequences. Type II changes occur in a more chronic phase, when yellow (fatty) marrow infiltration replaces acute inflammation of the end plates. Type II changes are characterized by increased signal on T1weighted and T2-weighted images. Type III changes are represented by decreased signal intensity on T1-weighted and T2-weighted images and correlate with sclerosis on radiographs.

subchondral sclerosis of the articular surfaces, subchondral cyst formation, and osteophytes. Soft tissue findings include thickening of the ligamentum flavum and capsular laxity. Radiographs with oblique views are useful in screening for facet osteoarthritis of the lumbar spine, but are insensitive compared with CT.249 The findings of facet joint degeneration are readily detected with CT or MRI, however; osseous alterations are better shown and graded on CT (Fig. 53-65A).250 Facet joint degeneration may lead to synovial cyst formation. The synovial cysts are presumably related to herniation of synovium through capsular tears. Synovial cysts protruding into the spinal canal appear as posterolateral epidural masses adjacent to a facet joint, most commonly at L4-L5 level, and may cause neurologic symptoms.251 The cysts may contain clear, mucinous, or hemorrhagic fluid and gas. On MRI, the cysts are typically of high signal intensity on T2-weighted images (Fig. 53-65B). Synovial cysts may show a peripheral rim of low signal intensity, corresponding to calcifications or hemosiderin. After administration of intravenous contrast agent, enhancement of the cyst wall may be seen owing to its vascularity.252

Facet Joint Osteoarthritis Degenerative disease of the facet joints typically occurs in combination with degenerative disk disease. Facet osteoarthritis can result in narrowing of the central canal, lateral recesses, and foramina and is an important component of spinal stenosis. It has been proposed, however, that facet arthrosis may occur independently and be a source of symptoms on its own.247,248 The imaging findings are identical to those of osteoarthritis of other synovial joints with joint space narrowing,

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Spinal Stenosis Spinal stenosis refers to narrowing of the central spinal canal, lateral recesses, or neural foramina or any combination of these anatomic regions.253 Spinal stenosis may be developmental (congenital) or acquired. The most common cause of acquired spinal stenosis is degenerative disease of intervertebral disks, facet joints, thickened ligamentum flavum, and osteophytes; congenital short pedicles are important components of symptomatic ­spinal

B

Figure 53-65  Facet osteoarthritis and synovial cyst. A, Axial CT scan shows severe osteoarthritis of facet joints with osteophyte formation, joint space narrowing, subchondral cysts, and vacuum phenomena. B, Axial T2-weighted MR image through L4-L5 level shows a synovial cyst (arrowhead) adjacent to the degenerated right facet joint resulting in central spinal and right lateral recess stenosis. Thickening and redundancy of flaval ligaments and disk bulging contribute to spinal stenosis.

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stenosis in patients with otherwise mild degenerative changes.249 Other, less common causes of acquired spinal canal stenosis include ossification of the posterior longitudinal ligament or ligamentum flavum or both and epidural lipomatosis.240 The lateral recess is bordered anteriorly by the posterior aspect of the vertebral body and disk, laterally by the pedicle, and posteriorly by the superior articular facet. The nerve root descends obliquely downward through the lateral recess before it exits the neural foramen. Lateral recess stenosis is caused by degenerative changes of facet joints, disk bulging or herniation, or, less commonly, a synovial cyst or postoperative fibrosis. Neural foraminal stenosis occurs from osteophyte formation of the facet joints or of the uncovertebral joints of the cervical spine, foraminal disk herniation, or disk bulge. Reduction in foraminal height owing to loss of disk height or spondylolisthesis or both also results in neural foraminal stenosis. MRI accurately depicts the cause and extent of the spinal stenosis. MRI also can identify the degree of cord compression and intramedullary changes of the spinal cord. In compressive myelopathy, increased intramedullary signal intensity on T2-weighted images may represent edema, transient ischemia, or myelomalacia/gliosis of the spinal cord. Corresponding low-intensity areas on T1-weighted images seem to indicate a poor prognosis.254,255 Diffuse Idiopathic Skeletal Hyperostosis DISH is a common degenerative enthesopathy and has been described with a variety of terms,256-259 including Fores­ tier’s disease, spondylitis ossificans ligamentosa, spondylosis hyperostotica, and ankylosing hyperostosis of the spine. Although radiographic changes are evident in the axial and the appendicular skeleton, the diagnosis of DISH is based on the presence of characteristic spinal alterations. Resnick and Niwayama258 have advocated that three criteria must be present before a diagnosis of DISH can be made: (1) the presence of flowing calcification or ossification along the anterolateral aspect of at least four contiguous vertebral levels; (2) relative preservation of intervertebral disk heights in the involved vertebral segments without the extensive changes of primary degenerative disk disease; and (3) the absence of apophyseal joint ankylosis or sacroiliac joint ­erosions, sclerosis, or widespread intra-articular bony ankylosis.258 The most characteristic radiographic abnormality of DISH is calcification and ossification of the anterior longitudinal ligament of the spine.258 This finding is most commonly identified in the midthoracic spine, but also is evident in the cervical and lumbar levels. Early in the disease, an undulating radiodense band forms along the anterolateral aspect of the spine and is separated from the anterior aspect of the vertebral body by a thin radiolucent line (Fig. 53-66); with progression of the disease, the lucency may disappear. These changes, which are best shown in the lateral radiographic projection of the thoracic spine, may resemble the bamboo spine of ankylosing spondylitis, but several important differentiating features exist. Syndesmophytes arise from anterosuperior and anteroinferior margins of the vertebral body, whereas the ossification in DISH attaches to the vertebral body several millimeters from these margins. In addition,

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syndesmophytes may be best seen in the frontal projection, in contrast to DISH, in which changes are most prominent on the lateral radiographic projection. The presence of sacroiliac joint erosions and extensive intra-articular bony ankylosis of the sacroiliac and apophyseal joints in ankylosing spondylitis constitute another important differential point. In the cervical spine, bony outgrowths characteristically appear at the anteroinferior margin of the vertebral body and extend inferiorly around the disk space. With progression, a thick, armor-like mass bridges the intervertebral disk, leading to markedly diminished cervical motion and, in some cases, dysphagia. Linear or Y-shaped radiolucencies in the bony mass may be noted at the level of the intervertebral disk space, owing to displacement of disk material into the ossific mass. Ossification adjacent to the posterior margin of the posterior longitudinal ligament may be seen as a distinct entity, but occurs with increased frequency in patients with DISH (Fig. 53-67).260 DISH-like changes also occur in a rare syndrome, sternoclavicular hyperostosis, in which extensive ossification of the soft tissues is evident between the anterior ribs, medial clavicle, and sternum. Extraspinal manifestations of DISH261 are especially common in the pelvis. Bony proliferation at sites of ligamentous and tendinous attachment (enthesopathy) results in the formation of coarse, well-marginated bony excrescences, in contrast to the finely spiculated, ill-defined bony proliferative changes of the seronegative spondyloarthropathies (Fig. 53-68). Calcification of the iliolumbar and sacrotuberous ligaments is an additional characteristic feature.

Figure 53-66  Diffuse idiopathic skeletal hyperostosis. There is bone formation along the anterior aspects of more than four vertebral bodies. The disk spaces are maintained, and the sacroiliac joints were normal.

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Figure 53-67  Ossification of the posterior longitudinal ligament. In a patient with diffuse idiopathic skeletal hyperostosis, there is flowing ossification along the anterior margins of the vertebral bodies. Ossification of the posterior longitudinal ligament also is present (arrowheads) just behind the C2 to C5 vertebral bodies.

Para-articular osteophytes are commonly noted around the hip and along the inferior aspect of the sacroiliac joints. Other extraspinal sites of prominent bony proliferation include the patellar poles, calcaneus, and olecranon proc­ ess of the ulna. The “spurs” that form at these sites may be identical in appearance to localized degenerative changes in otherwise normal individuals, but they show a tendency toward increased size and multiplicity. In the hand, hyperostotic changes of the metacarpal and phalangeal heads, with proliferation in the terminal tufts, may be noted. Irregular excrescences also may be seen at the femoral trochanters, deltoid tuberosity of the humerus, anterior tibial tuberosity, and interosseous membranes of the forearm and leg. Sacral Insufficiency Fractures Insufficiency fractures occur when normal stress is applied to a bone with deficient elastic resistance, typically in elderly osteoporotic patients. The most common presenting symptom is low back pain, accompanied by hip and buttock pain. The fractures may go unrecognized on plain radiographs, until visible areas of linear sclerosis are seen in the sacral alae. Radionuclide bone scan shows intense uptake along one or both sacral ala, and, occasionally, if the fracture crosses from one side to the other, it produces characteristic H-shaped uptake (Honda sign). CT may be used to confirm the diagnosis. It has been reported that the presence of vacuum phenomena at the fracture site on CT scan can be a clue for the diagnosis of insufficiency fracture.262 MRI is the most sensitive and specific tool to detect occult fractures. MRI shows fractures as linear low signal intensity paralleling the sacroiliac joints on T1-weighted and

Figure 53-68  Extraspinal manifestation of diffuse idiopathic skeletal hyperostosis. The degenerative enthesopathy of diffuse idiopathic skeletal hyperostosis is well shown with coarse bony excrescences arising from sites of ligament and tendon insertion along the lateral aspect of the ilium, superior acetabular margin, and lesser trochanter (arrows). This appearance differs from that of the finely spiculated inflammatory enthesopathy of the seronegative spondyloarthropathies. (From Resnick D, Niwayama G: Diagnosis of Bone and Joint Disorders. Philadelphia, WB Saunders, 1988.)

T2-weighted images with surrounding bone marrow edema (Fig. 53-69).38,263

MISCELLANEOUS DISORDERS PIGMENTED VILLONODULAR SYNOVITIS Pigmented villonodular synovitis is a proliferative synovitis of unknown cause. It may be intra-articular or extra-articular in location and diffuse or localized in distribution. The extra-articular form, sometimes known as giant cell tumor of tendon sheath, is most often seen in the fingers and is usually localized. The intra-articular form is usually present in the knee, hip, or ankle and is usually diffuse.151 Pathologic examination reveals nodular or villous enlargement of the synovial lining, which appears red, brown, or yellow. Histiocytic cells and lipid-laden foam cells are present in fibrous stroma. Intracellular and extracellular hemosiderin is present. The joint fluid is typically brown or red-brown. Radiographic examination may suggest the diagnosis. Only one joint is involved in nearly all cases. Erosions and cysts on both sides of the joint are seen with normal bone density and cartilage space (Fig. 53-70).264-266 During arthrography, nodular soft tissue masses may be shown, and aspiration of joint fluid yields the characteristic “rusty” fluid.

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A

Figure 53-70  Pigmented villonodular synovitis. Anteroposterior and mortise radiographs of the ankle show the classic, but not entirely specific features of pigmented villonodular synovitis: erosion on both sides of the joint (arrows), preservation of the cartilage space, and normal bone density. The location at the tibiofibular joint recess is unusual.

PRIMARY SYNOVIAL OSTEOCHONDROMATOSIS

B Figure 53-69  Sacral insufficiency fracture shown on MRI. A, T1-weighted MR image of the posterior portion of the pelvis in an elderly woman with pain shows a band of low signal in the left side of the sacrum (arrow). B, Short tau inversion recovery image shows a linear area of very bright signal intensity with adjacent high signal in the left sacral ala.

MRI signal characteristics can be highly suggestive of nodular or diffuse pigmented villonodular synovitis, but are not always specific enough to differentiate it from other forms of synovitis associated with hemosiderin deposition or caused by amyloid (Table 53-3). The MRI signal characteristics reflect the fat, fibrous tissue, and iron present in the tissues; iron appears dark on all pulse sequences, and the size of the lesion may appear slightly larger on T2-weighted images (the blooming effect). Pigmented villonodular synovitis deposits usually display intermediate signal intensity on T1-weighted or intermediate-weighted images with some low signal regions, and show very dark signal intensity on T2-weighted sequences (Fig. 53-71).151 These deposits are enhanced with intravenous gadolinium administration. Bright regions on T2-weighted sequences are noted and may represent trapped fluid within the synovial membrane.267 MRI must include the entire joint to evaluate the extent and location of intra-articular and periarticular masses for surgical removal. Post-treatment recurrence also can be assessed on MRI.

Primary synovial osteochondromatosis is due to metaplasia of the synovial lining with the formation of hyaline cartilage nodules that may protrude into the joint and eventually detach to form loose bodies. Calcification or ossification of these nodules may occur. Primary synovial osteochondromatosis is the term used when no underlying cause of loose body formation, such as osteoarthritis, can be identified. Joints, tendon sheaths, or bursae may be affected. The disorder is monarticular. The typical radiographic picture of synovial osteochondromatosis is that of numerous calcific (or ossific) densities confined to the joint cavity (Fig. 53-72). The calcified bodies are fairly uniform in size. Pressure erosions of adjacent bony surfaces may be seen and may predispose to fracture. Osteoporosis and joint space narrowing are generally not prominent. In cases in which the bodies are not calcified, MRI may confirm the diagnosis. MRI appearances may be diagnostic, even when no calcification is present, because uncalcified cartilage nodules exhibit a characteristic lobulated appearance and are isointense or slightly brighter in signal intensity than muscle on T1-weighted and T2-weighted images.151 Low signal fibrous Table 53-3  Intra-articular and Periarticular Conditions Producing Low Signal Intensity Masses on T2-Weighted Magnetic Resonance Imaging Chronic rheumatoid arthritis Pigmented villonodular synovitis Chronic hemarthrosis Amyloidosis Calcified loose bodies Benign fibroblastic tumors Gouty tophus

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Figure 53-71  Pigmented villonodular synovitis shown on MRI. A and B, Sagittal fast spin echo proton density (A) and fat saturation proton density  (B) images show diffuse intermediate to low signal intensity synovial masses compatible with pigmented villonodular synovitis involving the suprapatellar recess, infrapatellar fat pad, and posterior joint with large posterior extra-articular extension. Fluid signal intensity areas within the posterior periarticular mass likely represent trapped fluid. Erosive changes are noted at the articular surfaces of the patella, femur, and tibia.

T

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Figure 53-72  Synovial osteochondromatosis. Multiple calcified bodies that are uniform in size are noted within a distended iliopsoas bursa and the hip joint. The cartilage space is not narrowed, and bone density is normal; these features are typical of synovial osteochondromatosis.

septa separate the cartilage nodules and aid in the differentiation of the nodules from joint effusion, which has similar signal characteristics on these sequences. Arclike enhancement around the nodules may be seen within the cartilage. Ossification is identified by its peripheral low signal calcified rim and central fat signal marrow (Fig. 53-73).

B

Figure 53-73  Synovial osteochondromatosis shown on MRI. A, Oblique axial proton density MR image of the ankle shows multiple, fairly uniformly sized bodies (arrow) with low signal rims and intermediate signal centers. B, Corresponding T2-weighted image shows the periphery of the nodules to remain dark, consistent with calcification or bone, and the centers of the nodules to remain intermediate in signal intensity. The joint fluid is very bright on the T2-weighted image. C, calcaneus; T, talus.

β2-MICROGLOBULIN AMYLOIDOSIS β2-Microglobulin amyloid arthropathy is a sequela of long-term hemodialysis, but also may occur in patients on peritoneal dialysis or with uremia without dialysis treatment.151,268,269 β2-Microglobulin amyloidosis is found in synovial tissue, joint capsules, periarticular tissues, articular cartilage, and bone—the last likely by extension from the adjacent soft tissue deposits.270-273 The wrists, shoulders,

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hips, and knees are involved most often. Carpal tunnel syndrome and large joint arthralgias are the most common clinical complaints.274 Pathologic fracture of the femur may follow cystic bone changes.270-272 A peripheral arthropathy is seen in hemodialyzed patients, but its relationship to amyloid is uncertain.274 A destructive spondyloarthropathy may occur that usually involves the cervical spine, often the atlantoaxial region.269,275 Radiographically, juxta-articular cysts or erosions are present with preserved articular cartilage spaces. In contrast to pigmented villonodular synovitis, multiple joints may be involved, and osteopenia is usually present. Nodular soft tissue swelling may be seen. The wrists, hips, and shoulders are often involved. Hip erosion seems to favor the anterosuperior aspect of the femoral necks.276 The spondyloarthropathy may be rapidly progressive with vertebral collapse, end plate erosion, disk narrowing, and subluxation.279 Ultrasonography has been particularly helpful around the shoulder in identifying the echogenic nature of the amyloid deposits.277 MRI of β2-microglobulin amyloidosis typically shows masses of tissue in joints and bursae that are intermediate to low in signal intensity on T1-weighted images and usually low in signal intensity on T2-weighted images (Fig. 53-74). MRI can distinguish amyloid deposition from inflammatory conditions or tumors, which usually show high signal on

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T2-weighted images.151,278,279 Tendon and capsular thickening is noted particularly in the supraspinatus tendon and the iliofemoral portion of the hip capsule. The masses of amyloid extend into the bone defects, although the signal of bone lesions seems more variable, possibly because of the presence of fluid in some of the erosions.271 As in other erosive processes, MRI is able to show erosions that are invisible on radiographs.271 Amyloid deposition may be documented on MRI even in asymptomatic subjects, but is more marked when symptoms are present.271 LIPOMA ARBORESCENS Lipoma arborescens is a rare disorder in which collections of fat develop beneath the synovial lining.280 Their large size and frondlike configuration distinguish them from other intrasynovial collections of fat. The condition is usually unilateral, but may be bilateral or may involve multiple joints,280 with the knee most often affected. Painless swelling of the joint over many years occurs with periodic effusions.281 Occasionally, the fatty deposits are visible on standard radiographs. CT and MRI are better able to establish the specific diagnosis, however, because the villous fatty nature of the lesion and the accompanying effusions are well seen with these modalities.280,282,283 The lesion does not enhance after intravenous gadolinium injection (Fig. 53-75).283 SILICONE SYNOVITIS

A

Silicone synovitis or prosthetic synovitis is a form of chronic foreign body synovitis caused in response to shedding of silicone particles from damaged silicone polymer prostheses. Silicone synovitis has been reported most frequently in cases with carpal implants. The interval between surgical implantation and the complication of synovitis ranges from 1 to 9 years with a mean of 5.5 years. The most common clinical features are local pain, limitation of motion, and swelling.284,285 Radiologic changes in silicone synovitis, when present, include nodular soft tissue swelling and well-defined subchondral lytic lesions (Fig. 53-76). These lytic lesions vary in size and may or may not have a sclerotic rim.286 The cartilage space is preserved. The prosthesis is often fragmented, deformed, or subluxed. On MRI, the lytic lesions show intermediate to mildly increased signal on proton density and T2weighted images, which are not typical of fluid-filled cysts. The internal signal characteristic of these lytic lesions is consistent with the presence of inflammatory and fibrous tissue. Disintegrated silicone fragments appear as hypointense regions on all sequences, as does the prosthesis itself.287 IMPINGEMENT SYNDROME AND ROTATOR CUFF TEARS

B Figure 53-74  β2-Microglobulin amyloid in a renal transplant recipient. A, Proton density MR image shows low signal material filling the hip joints bilaterally (arrows). There is erosion of the right femoral head-neck junction (arrowhead). B, T2-weighted image shows the material around the femoral head and within the erosions of the right hip to remain low in signal, typical of amyloidosis.

The impingement syndrome is a well-recognized clinical entity, defined as painful compression of the supraspinatus tendon, subacromial bursa, and long head of the biceps tendon between the humeral head and the coracoacromial arch. The coracoacromial ligament, anterior third of acromion, and acromioclavicular joint make up the coraco­ acromial arch.288

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B Figure 53-75  Lipoma arborescens. A and B, Proton density (A) and T2weighted (B) MR images show frondlike collections of fat (arrows) within the joint separated by synovial fluid (F).

Impingement syndrome produces a spectrum of rotator cuff tendon abnormalities, beginning with degenerative tendinopathy and eventually progressing to a full-thickness tear. Many causes have been proposed for impingement of subacromial soft tissues.288,289 These factors can be classified as extrinsic and intrinsic. The extrinsic causes include abnormal shape and slope of the acromion, subacromial spur formation, thickened coracoacromial ligament, and degenerative changes of the acromioclavicular joint. Rotator cuff disease also may occur as a result of repetitive microtrauma (overuse syndrome) without morphologic abnormalities of the coracoacromial arch. Intrinsic causes, such as aging and decreased vascularity of the tendons, are other contributing factors.

Figure 53-76  Silicon synovitis. Posteroanterior view of the wrist shows a silicone implant of the lunate for the treatment of Kienböck’s disease. Multiple periarticular subchondral lytic lesions involving the carpal bones and distal ulna and radius are typical features of silicone synovitis. The prosthesis shows medial migration with a deformed and eroded proximal surface. There also is rotary subluxation of the scaphoid.

Radiographic findings suggesting subacromial impingement include osteophytes around the acromioclavicular joint and spur formation of the anterior acromion (Fig. 53-77) with corresponding areas of sclerosis and subchondral cysts of the greater tuberosity. An unfused acromial apophysis at the anterior aspect of the acromion (os acromiale), best seen on axillary view, may also predispose to subacromial impingement.290 An outlet view is helpful to evaluate the shape of the acromion. Rotator cuff tears generally are not apparent on radiographs, but chronic rotator cuff tear may be suggested on radiographs when there is superior migration of the humeral head in relation to the glenoid and an acromiohumeral distance less than 7 mm. MRI findings used in diagnosing rotator cuff impingement and tear have been described in several reports.291-296 The normal rotator cuff tendons appear uniformly low in signal intensity on all sequences. In early stages of impingement, the supraspinatus tendon shows thickening and inhomogeneous increased signal, representing degenerative tendinopathy or tendinosis. There may be associated subacromial-subdeltoid bursitis. Further damage to the tendon results in partial tear as manifested on MRI by the presence of focal fluid signal intensity through a portion of the tendon on T2-weighted images. Partial rotator cuff tears can be seen inferiorly at the articular surface, superiorly at the bursal surface, or within the tendon substance. Partial tears can be mistaken for full-thickness tears or tendinopathy with MRI. MRI arthrography has been shown to be more

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accurate than conventional MRI for evaluation of partial tears, especially for articular surface tears.297 Full-thickness rotator cuff tear is characterized on MRI by a fluid-filled gap in the tendon, with or without tendon retraction (Fig. 53-78). Ten percent of the tears may not show high signal intensity on T2-weighted images, however294; this may be due to replacement of the chronic tears with fibrous or granulation tissue that is low on T2-weighted images. Indirect signs of rotator cuff tears include a highriding humeral head, fluid in subacromial-subdeltoid bursa, obliteration of the peribursal fat stripe, and joint effusion in the glenohumeral joint.298 Overall reported sensitivity of MRI for identification of rotator cuff tears is 90% to 100%, and specificity is 80% to 95%.291-293,299,300 Ultrasound also is an effective tool for the evaluation of rotator cuff tears, when performed by experienced sonographers. The tendons of a normal rotator cuff appear as hyperechoic, fibrillar structures on ultrasound. A large

Figure 53-77  Frontal radiograph of the shoulder shows a large spur (arrow) projecting from the inferior, anterior acromion process. Subsequent MRI showed full-thickness tears of the supraspinatus and infraspinatus tendons.

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retracted tear is diagnosed when there is nonvisualization of the supraspinatus tendon, and the deltoid muscle is directly apposed to the humeral cortex. A focal full-thickness tear is visualized as a hypoechoic or anechoic area extending through the rotator cuff with subacromial bursal fluid supporting the diagnosis. Ultrasound is less sensitive in diagnosing partial-thickness tears that may appear hypoechoic or of mixed echogenicity if the hyperechoic free edges of the torn tendon are surrounded by hypoechoic fluid or granulation tissue.288,301 CARPAL TUNNEL SYNDROME Carpal tunnel syndrome is the most common peripheral entrapment neuropathy, caused by pressure on the median nerve as it passes through the carpal tunnel. The nerve compression may result from a decrease in the volume of the canal (e.g., malalignment, fractures of the distal radius or carpal bones) or from an increase in the size of the soft tissues within the canal (e.g., tenosynovitis, soft tissue masses, persistent median artery, anomalous lumbrical muscles, amyloid deposition, excessive fat, hemorrhage). In most cases, carpal tunnel syndrome can be diagnosed with clinical examination and confirmed by nerve conduction studies302; generally, imaging is unnecessary. MRI is reserved for patients with atypical clinical presentation and inconclusive electrophysiologic tests. MRI findings of carpal tunnel syndrome, regardless of the underlying etiology, are diffuse or segmental enlargement of the median nerve, increased signal intensity of the median nerve on T2-weighted images, bowing of the flexor retinaculum, and flattening of the nerve (Fig. 53-79).303,304 MRI also may be helpful in evaluating patients with recurrent or persistent symptoms after surgical division of the flexor retinaculum by showing incomplete release of the flexor retinaculum, postsurgical fibrosis around the median nerve, or a mass lesion within the carpal tunnel.305 Morphologic changes of the median nerve in carpal tunnel syndrome also have been described with ultrasound.306,307 When the cross-sectional area of median nerve exceeds 10 to 15 mm2, it is considered abnormal. Tenosynovitis and a ganglion are causes of carpal tunnel syndrome that can be evaluated with sonography.

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Figure 53-78  Rotator cuff tear with retraction. A, T1-weighted oblique coronal MR image of the shoulder shows elevation of the humeral head (H) in relation to the glenoid (G). There is narrowing of the distance between the humeral head and the acromion. The supraspinatus is atrophic and infiltrated with fat. The dark tendon (arrow) is seen retracted proximally. B, Oblique coronal T2-weighted image shows better the torn, retracted edge of the supraspinatus tendon (arrow). The joint fluid (F) is bright on this sequence and communicates through the rotator cuff defect with the subacromial subdeltoid bursal fluid.

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Figure 53-79  Carpal tunnel syndrome. A, Fast spin echo proton density axial MR image at the level of the distal radius. The median nerve (arrows) has normal size before entering the carpal tunnel. B, Fast spin echo proton density axial image at the level of pisiform. The median nerve (arrows) shows enlargement and high signal.

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88. Medsger TA Jr, Christy WC: Carpal arthritis with ankylosis in lateonset Still’s disease. Arthritis Rheum 19:232, 1976. 89. Moll JHM, Wright V: Psoriatic arthritis. Semin Arthritis Rheum 3:55-78, 1973. 90. Porter GG: Psoriatic arthritis: Plain radiology and other imaging techniques. Bailliere Clin Rheumatol 8:465-482, 1994. 91. Resnick D: Psoriatic arthritis. In Resnick D (ed): Diagnosis of Bone and Joint Disorders, 4th ed. Philadelphia, WB Saunders, 2002, pp 1082-1109. 92. Resnick D, Feingold ML, Curd J, et al: Calcaneal abnormalities in articular disorders: Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and Reiter’s syndrome. Radiology 125:355-366, 1977. 93. Sholkoff SD, Glickman MG, Steinbach HL: Roentgenology of Reiter’s syndrome. Radiology 97:497-503, 1970. 94. Resnick D: Reiter’s syndrome. In Resnick D (ed): Diagnosis of Bone and Joint Disorders, 4th ed. Philadelphia, WB Saunders, 2002, pp 1010-1126. 95. Mitchell M, Howard B, Haller J, et al: Septic arthritis. Radiol Clin North Am 26:1295-1313, 1988. 96. Goldman AB: Arthrography for rheumatic disease: When, why and for whom: Imaging of rheumatic diseases. Rheum Dis Clin N Am 17:505-542, 1991. 97. Resnick D: Osteomyelitis, septic arthritis and soft tissue infection: organisms. In Resnick D (ed): Diagnosis of Bone and Joint Disorders, 4th ed. Philadelphia, WB Saunders, 2002, pp 2510-2624. 98. Brower A: Septic arthritis. Radiol Clin North Am 34:293-309, 1996. 99. Graif M, Schweitzer ME, Deely D, et al: The septic versus nonseptic inflamed joint: MRI characteristics. Skeletal Radiol 28:616-620, 1999. 100. Learch TJ, Farooki S: Magnetic resonance imaging of septic arthritis. J Clin Imaging 24:236-342, 2000. 101. Tumeh SS, Tohmeh A: Nuclear medicine techniques in septic arthritis and osteomyelitis. Rheum Clin Rheumatol 17:559-583, 1991. 102. Resnick D, Niwayama G: Degenerative disease of extraspinal locations. In Resnick D, Niwayama G (eds): Diagnosis of Bone and Joint Disorders. Philadelphia, WB Saunders, 1981, p 1270. 103. Boegard T, Jonsson K: Radiography in osteoarthritis of the knee. Skeletal Radiol 28:605, 1999. 104. Marshall KW, Mikulis DJ, Gunthrie BM: Quantitation of articular cartilage using magnetic resonance imaging and three-dimensional reconstruction. J Orthop Res 13:184, 1995. 105. Drape JL, Pessis E, Auleley GR, et al: Quantitative MR imaging evaluation of chondropathy in osteoarthritis knees. Radiology 208:49, 1998. 106. Reddy R, Insko EK, Noyszeski EA, et al: Sodium MRI of human cartilage in vivo. Magn Reson Med 39:697, 1998. 107. Eckstein F, Schnier M, Haubner M, et al: Accuracy of cartilage volume and thickness measurements with magnetic resonance imaging. Clin Orthop 352:137, 1998. 108. Waldschmidt JG, Rilling RJ, Kajdacsy-Balla AA, et al: In vitro and in vivo MR imaging of hyaline cartilage: Zonal anatomy, imaging pitfalls, and pathologic conditions. RadioGraphics 17:1387, 1997. 109. Chan WP, Lang P, Stevens MP, et al: Osteoarthritis of the knee: Comparison radiography, CT and MR imaging to assess extent and severity. AJR Am J Roentgenol 157:799, 1991. 110. Waldschmidt JG, Braunstein EM, Buckwalter KA: Magnetic resonance imaging of osteoarthritis. Rheum Dis Clin North Am 25:451, 1999. 110a. Gray ML, Burstein D, Kim YJ, et al: Magnetic resonance imaging of cartilage glycosaminoglycan: basic principles, imaging technique, and clinical applications. J Orthop Res 26(3):281-291, 2008. 111. Ostegaard M, Court-Payan M, Gideon P, et al: Ultrasonography in arthritis of the knee: A comparison with MR imaging. Acta Radiol 36:19, 1995. 112. Resnick D: Patterns of migration of the femoral head in osteoarthritis of the hip: Roentgenographic-pathologic correlation and comparison with rheumatoid arthritis. AJR Am J Roentgenol 124:62, 1975. 113. Thomas RH, Resnick D, Alazraki NP, et al: Compartmental evaluation of osteoarthritis of the knee: A comparative study of available diagnostic modalities. Radiology 116:585, 1975.

114. Leach RE, Grett T, Ferris JS: Weight-bearing radiography in osteoarthritis of the knee. Radiology 97:265, 1970. 114a. Hunter DJ, Zhang YQ, Tu X, et al: Change in joint space width: hyaline articular cartilage loss or alteration in meniscus? Arthritis Rheum 54(8):2488-2495, 2006. 114b. Grainger AJ, Farrant JM, O’Connor PJ, et al: MR imaging of erosions in interphalangeal joint osteoarthritis: Is all osteoarthritis erosive? Skeletal Radiol 36(8):737-745, 2007. 115. Bergman AG, Willen HK, Lindstran AL, et al: Osteoarthritis of the knee: Correlation of subchondral MR signal abnormalities with histopathologic and radiographic features. Skeletal Radiol 23:445, 1994. 116. Ostegaard M, Soltenberg M, Lovgreen-Nielson P, et al: Magnetic resonance imaging: Determined synovial membrane and joint effusion volumes in rheumatoid arthritis and osteoarthritis: Comparison of the macroscopic and microscopic appearance of the synovium. Arthritis Rheum 40:1856, 1997. 117. Fernandez-Madrid F, Karvonen RL, Teitge RA, et al: MR features of osteoarthritis of the knee. Magn Reson Imaging 12:703, 1994. 118. Fernandez-Madrid F, Karvonen RL, Teitge RA, et al: Synovial thickening detected by MR imaging in osteoarthritis of the knee confirmed by biopsy as synovitis. Magn Reson Imaging 13:177, 1995. 119. Ostegaard M: Different approaches to synovial membrane volume determination by magnetic resonance imaging: Manual versus automated segmentation. Br J Rheum 36:1166, 1997. 119a. Kornaat PR, Bloem JL, Ceulemans RY, et al: Osteoarthritis of the knee: association between clinical features and MR imaging findings. Radiology 239(3):811-817, 2006. 119b. Hill CL, Hunter DJ, Niu J, et al: Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis. Ann Rheum Dis 66(12):1599-1603, 2007. 119c. Felson DT, Chaisson CE, Hill CL, et al: The association of bone marrow lesions with pain in knee osteoarthritis. Ann Intern Med 134(7):541-549, 2001. 120. Cornelius R, Schneider HJ: Gouty arthritis in the adult. Radiol Clin North Am 26:1267-1276, 1988. 121. Resnick D, Broderick TW: Intraosseous calcifications in tophaceous gout. AJR Am J Roentgenol 137:1157-1161, 1981. 122. Martel W: The overhanging margin of bone: A roentgenologic manifestation of gout. Radiology 91:755-756, 1968. 123. Good AE, Rapp R: Bony ankylosis: A rare manifestation of gout. J Rheumatol 5:335-337, 1978. 124. Chen KHC, Yeh LR, Pan HB, et al: Intraarticular gouty tophi of the knee: CT and MR imaging in 12 patients. Skeletal Radiol 28:75-80, 1999. 125. Gerster JC, Landry M, Dufresne L, et al: Imaging of tophaceous gout: Computed tomography provides images compared with magnetic resonance imaging and ultrasonography. Ann Rheum Dis 61:52-54, 2002. 126. Yu JS, Chung C, Recht M, et al: MR imaging of tophaceous gout. AJR Am J Roentgenol 168:523-527, 1997. 127. King JG, Nicholas CN: Gouty arthropathy of the lumbar spine. Spine 22:2309-2312, 1997. 128. Jensen PS: Chondrocalcinosis and other calcifications. Radiol Clin North Am 26:1315-1325, 1988. 129. Beltran J, Marthy-Delfault E, Bencardino J, et al: Chondrocalcinosis of the hyaline cartilage of the knee: MRI manifestation. Skeletal Radiol 27:369-374, 1998. 130. Kaushik S, Erickson JK, Palmer WE, et al: Effect of chondrocalcinosis on the MR imaging of knee menisci. AJR Am J Roentgenol 177:905-909, 2001. 131. Martel W, McCarter DK, Solsky MA, et al: Further observations on the arthropathy of calcium pyrophosphate deposition disease. Radiology 141:1-15, 1981. 132. Steinbach LS, Resnick D: Calcium pyrophosphate dihydrate crystal deposition disease revisited. Radiology 200:1-9, 1996. 133. Helfgott SM, Skoff H: Scapholunate dissociation associated with crystal induced synovitis. J Rheumatol 19:485-487, 1992. 134. Ishida T, Dorfman HD, Bullough PG: Tophaceous pseudogout tumoral calcium pyrophosphate dihydrate crystal deposition. Hum Pathol 26:587-593, 1995. 135. Kakisubata Y, Boutin RD, Theodorou DJ, et al: Calcium pyrophosphate crystal deposition in and around atlantoaxial joint: Association with type 2 fractures in nine patients. Radiology 216:213-219, 2000.

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136. Holt PD, Keats TE: Calcific tendinitis: A review of the usual and unusual. Skeletal Radiol 22:1-9, 1993. 137. Resnick D: Calcium hydroxyapatite crystal deposition disease. In Resnick D (ed): Diagnosis of Bone and Joint Disorders, 4th ed. Philadelphia, WB Saunders, 2002, pp 1619-1657. 138. Kraemer EJ, El-Khoury GY: Atypical calcific tendinitis with cortical erosions. Skeletal Radiol 29:690-696, 2000. 139. Uri DS, Dalinka MK: Crystal disease. Radiol Clin North Am 34: 359-374, 1996. 140. Nguyen VD: Rapid destructive arthritis of the shoulder. Skeletal Radiol 25:107-112, 1996. 141. Jensen PS: Hemachromatosis: A disease often silent but not visible. AJR Am J Roentgenol 126:343-351, 1976. 142. Dymock IW, Hamilton EBD, Laws JW, et al: Arthropathy of hemochromatosis: Clinical and radiological analysis of 63 patients with iron overload. Ann Rheum Dis 29:469-476, 1970. 143. Hirsch JH, Killien FC, Troupin RH: The arthropathy of hemochromatosis. Radiology 118:591-596, 1976. 144. Adamson TC, Resnik CS, Guerra J, et al: Hand and wrist arthropathies of hemochromatosis and calcium pyrophosphate deposition disease: Distinct radiologic features. Radiology 147:377-381, 1983. 145. Eustace S, Buff B, McCarthy C, et al: Magnetic resonance imaging of hemochromatosis arthropathy. Skeletal Radiol 23:547-549, 1994. 146. Mindelzun R, Elkin M, Scheinberg IH, et al: Skeletal changes in Wilson’s disease. Radiology 94:127-132, 1970. 147. Resnick D: Hemochromatosis and Wilson’s disease. In Resnick D (ed): Diagnosis of Bone and Joint Disorders, 4th ed. Philadelphia, WB Saunders, 2002, pp 1658-1677. 148. Cervenansky J, Sitaj S, Urbanek T: Alkaptonuria and ochronosis. J Bone Joint Surg Am 41A:1169-1182, 1959. 149. Resnick D: Alkaptonuria. In Resnick D (ed): Diagnosis of Bone and Joint Disorders, 4th ed. Philadelphia, WB Saunders, 2002, pp 16781691. 150. Pettersson H, Ahlberg A, Nilsson IM: A radiologic classification of hemophilic arthropathy. Clin Orthop 149:153, 1980. 151. Winalski CS, Foldes K, Gravallese EM, et al: Synovial membrane disorders. Magn Reson Imaging 2:1079-1096, 1999. 152. Idy-Peretti I: MR imaging of hemophilic arthropathy of the knee: Classification and evolution of the subchondral cysts. Magn Reson Imaging 10:67, 1992. 153. Conway WE, Totty WG: Hip in Magnetic Resonance Imaging, 3rd ed. St. Louis, Mosby, 1999. 154. Zurla JV: The double line sign. Radiology 212:541, 1999. 155. Mitchell DG, Rao JM, Dalinka MK, et al: Femoral head avascular necrosis: Correlation of MR imaging, radiographic staging, radionuclide imaging, and clinical findings. Radiology 162:709, 1987. 156. Jiang CC, Shih TTF: Epiphyseal scar of the femoral head: Risk factor of osteonecrosis. Radiology 191:409, 1994. 157. Beltran J, Herman IJ, Burk JM, et al. Femoral head avascular necrosis: MRI with clinical-pathologic correlation. Radiology 166:215, 1988. 158. Hayes CW, Conway WF, Daniel CW: MR imaging of bone marrow edema pattern: Transient osteoporosis, transient bone marrow edema syndrome, or osteonecrosis. RadioGraphics 13:1001, 1993. 159. Vande Berg BC, Malghem JJ, Lecouvert FE, et al: Idiopathic bone marrow lesions of the femoral head: Predictive value of MR imaging findings. Radiology 212:527, 535. 160. Brower AC, Almann RM: Pathogenesis of the neurotrophic joint: Neurotraumatic versus neurovascular. Radiology 139:349-354, 1981. 161. Phillips S, Williams AL, Peters JR: Neuropathic arthropathy of the spine in diabetes. Diabetes Care 18:867-869, 1995. 162. Feldman MJ, Becker KL, Reefe WE, et al: Multiple neuropathic joints, including wrist, in a patient with diabetes mellitus. JAMA 209:1690-1692, 1969. 163. Deirmengian CA, Lee SG, Jupiter JB: Neuropathic arthropathy of the elbow: A report of five cases. J Bone Joint Surg Am 83A: 839-844, 2001. 164. Reinhardt K: The radiological residue of healed diabetic arthropathies. Skeletal Radiol 7:167-172, 1981. 165. Seabold JE, Flicker FW, Kao SC, et al: Indium-111-leukocyte/technetium-99m-MDP bone and magnetic resonance imaging: Difficulty of diagnosing osteomyelitis with neuropathic osteoarthropathy. J Nucl Med 31:549-556, 1990.

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166. Beltran J, Campanini DS, Knight C, et al: The diabetic foot: Magnetic resonance imaging evaluation. Skeletal Radiol 19:37-41, 1990. 167. Yu J: Diabetic foot and neuroarthropathy: Magnetic resonance imaging evaluation. Top Magn Reson Imaging 9:295-310, 1998. 168. Greenstein AS, Marzo-Ortega H, Emery P, et al: Magnetic resonance imaging as a predictor of progressive joint destruction in neuropathic disease. Arthritis Rheum 46:2814-2815, 2002. 169. Park YH, Taylor JAM, Szollar SM, et al: Imaging findings in spinal neuropathy. Spine 13:1499-1504, 1994. 170. Wagner SC, Schweitzer ME, Morrison WB, et al: Can imaging findings help differentiate spinal neuropathic arthropathy from disk space infection? Initial experience. Radiology 214:693-699, 2000. 171. Resnick D: Scleroderma (progressive systemic sclerosis). In Resnick D, Niwayama G (eds): Diagnosis of Bone and Joint Disorders. Philadelphia, WB Saunders, 1981, p 1204. 172. Poznanski AK: The Hand in Radiologic Diagnosis. Philadelphia, WB Saunders, 1974. 173. Thibierge G, Weissenbach RJ: Concretions calcare souscutanees et sclerodermie. Ann Dermatol Syph 2:129, 1911. 174. Muller SA, Brunsting LA, Winkelmann RK: Calcinosis cutis: Its relationship to scleroderma. Arch Dermatol Venereal 80:15, 1959. 175. Rowell NR, Hopper FE: The periodontal membrane in systemic lupus erythematosus. Br J Dermatol 93(Suppl):23, 1975. 176. Mezarsos WT: The regional manifestations of scleroderma. Radiology 70:313, 1958. 177. Kemp Harper RA, Jackson DC: Progressive systemic sclerosis. Br J Radiol 38:825, 1965. 178. Keats TE: Rib erosions in scleroderma. AJR Am J Roentgenol 100:530, 1967. 179. Seifert MH, Steigerwald JC, Cliff MM: Bone resorption of the mandible in progressive systemic sclerosis. Arthritis Rheum 18:507, 1977. 180. Haverbush TJ, Wilde AH, Hawk WA Jr, et al: Osteolysis of the ribs and cervical spine in progressive systemic sclerosis (scleroderma): A case report. J Bone Joint Surg Am 56A:637, 1974. 181. Lovell CR, Jayson MIV: Joint involvement in systemic sclerosis. Scand J Rheumatol 8:154, 1979. 182. Olsen NJ, King LE, Park JH: Muscle abnormalities in scleroderma. Scleroderma 22:783, 1996. 183. Labowitz R, Schumacher H: Articular manifestations of systemic lupus erythematosus. Ann Intern Med 74:911, 1971. 184. Weissman BN, Rappoport AS, Sosman JL, et al: Radiographic findings in the hands in patients with systemic lupus erythematosus. Radiology 126:313, 1978. 185. Bleifield CJ, Inglis AE: The hand in systemic lupus erythematosus. J Bone Joint Surg Am 56A:1207, 1974. 186. Bywaters EGL: Jaccoud’s syndrome: A sequel to the joint involvement in systemic lupus erythematosus. Clin Rheum Dis 1:125, 1975. 187. Twinning RH, Marcus WY, Carey JL: Tendon rupture in systemic lupus erythematosus. JAMA 189:377, 1964. 188. Klippel JH, Gerber LH, Pollack L, et al: Avascular necroses in systemic lupus erythematosus: Silent symmetric osteonecrosis. Am J Med 67:83, 1979. 189. Budin JA, Feldman F: Soft tissue calcifications in systemic lupus erythematosus. AJR Am J Roentgenol 124:358, 1975. 190. Staples PJ, Gerding DN, Decker JL, et al: Incidence of infection in systemic lupus erythematosis. Arthritis Rheum 17:1, 1971. 191. Goodman N: The significance of terminal phalangeal osteosclerosis. Radiology 89:709, 1967. 192. Houssiau FA, N’Zeusseu Toukap A, Depresseux G, et al: Magnetic resonance imaging-detected avascular osteonecrosis in systemic lupus erythematosus: Lack of correlation with antiphospholipid antibodies. Br J Rheumatol 37:448, 1998. 193. Sugano N, Ohzono K, Masuhara K, et al: Prognostication of osteonecrosis of the femoral head in patients with systemic lupus erythematosus by magnetic resonance imaging. Clin Orthop 305:190, 1994. 194. Schumacher HR, Schimmer B, Gordon GV, et al: Articular manifestations of polymyositis and dermatomyositis. Arthritis Rheum 23:491, 1980. 195. Ozonoff MB, Flynn FJ Jr: Roentgenologic features of dermatomyositis of childhood. AJR Am J Roentgenol 118:206, 1973.

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196. Fujitake J, Ishikawa Y, Fujii H, et al: Magnetic resonance imaging of skeletal muscles in polymyositis. Muscle Nerve 20:1463, 1997. 197. Fleckenstein JL, Reimers CD: Inflammatory myopathies. Radiol Clin North Am 34:427, 1996. 198. Park WM, O’Neil M, McCall IW: The radiology of rheumatoid involvement of the cervical spine. Skeletal Radiol 4:1-7, 1979. 199. Kauppi M, Neva MH: Sensitivity of lateral view taken in the neutral view position in atlantoaxial subluxation in rheumatic disease. Clin Rheumatol 17:511-514, 1998. 200. Weissman BN, Aliabadi P, Weinfeld MS, et al: Prognostic features of atlantoaxial subluxation in rheumatoid arthritis patients. Radiology 144:745-751, 1982. 201. Boden S, Dodge L, Bohlman H, et al: Rheumatoid arthritis of cervical spine: A long-term analysis with predictors of paralysis and recovery. J Bone Joint Surg Am 75:1282-1297, 1993. 202. Kramer J, Jolesz F, Kleefield J: Rheumatoid arthritis of the cervical spine. Rheum Dis Clin N Am 17:757-772, 1991. 203. Bundschuh C, Modic MT, Kearney F, et al: Rheumatoid arthritis of the cervical spine: Surface coil MR imaging. AJNR Am J Neuroradiol 9:565-571, 1988. 204. Takahashi M, Yamashita Y, Sakamoto Kojima R, et al: Chronic cervical cord compression: Clinical significance of increased signal intensity on MR images. Radiology 173:219-224, 1989. 205. Bluestone R: Histocompatibility antigens and rheumatic disease. In: Current Concepts. Kalamazoo, Mich, Upjohn, 1978, p 17. 206. Resnick D, Niwayama G: Ankylosing spondylitis. In Resnick D, Niwayama G (eds): Diagnosis of Bone and Joint Disorders. Philadelphia, WB Saunders, 1981, p 1040. 207. Kleinman P, Rivelas M, Schneider R, et al: Juvenile ankylosing spondylitis. Radiology 125:775, 1977. 208. Rosen PS, Graham DC: Ankylosing (Strumpell-Marie) spondylitis: A clinical review of 128 cases. AJR Am J Roentgenol 5:158, 1962. 209. Resnick D: Patterns of peripheral joint disease in ankylosing spondylitis. Radiology 110:523, 1977. 210. Wilkinson M, Bywaters EGL: Clinical features and course of ankylosing spondylitis as seen in a follow-up referred case. Ann Rheum Dis 17:209, 1958. 211. Berens DL: Roentgen features of ankylosing spondylitis. Clin Orthop 74:20, 1971. 212. Resnick D, Niwayama G, Goergen TG: Comparison of radiographic abnormalities of the sacroiliac joint in degenerative joint disease and ankylosing spondylitis. AJR Am J Roentgenol 128:189, 1977. 213. Bollow M, Braun J, Biederman T, et al: Use of contrast-enhanced MR imaging to detect sacroiliitis in children. Skeletal Radiol 27:606, 1998. 214. Forestier J, Jacqueline F, Rotes-Querol J: Ankylosing Spondylitis. Springfield, Ill, Charles C Thomas, 1956. 215. Cawley MID, Chalmers TM, Kellgren JH, et al: Destructive lesions of vertebral bodies in ankylosing spondylitis. Ann Rheum Dis 13:345, 1972. 216. Martel W: The occipito-atlanto-axial joints in rheumatoid arthritis and ankylosing spondylitis. AJR Am J Roentgenol 86:223, 1961. 217. Dwosh IL, Resnick D, Becker MP: Hip involvement in ankylosing spondylitis. Arthritis Rheum 19:683, 1976. 218. Glick EN: A radiological comparison of the hip in rheumatoid arthritis and ankylosing spondylitis. Proc R Soc Med 59:1229, 1976. 219. Rosen PS: A unique shoulder lesion in ankylosing spondylitis: Clinical comment. J Rheumatol 7:109, 1980. 220. Bywaters EGL: Heel lesions in rheumatoid arthritis. Ann Rheum Dis 13:42, 1954. 221. Ball J: Enthesopathy of rheumatoid and ankylosing spondylitis. Ann Rheum Dis 30:213, 1971. 222. Sundaram M, Patton JT: Paravertebral ossification in psoriasis and Reiter’s disease. Br J Radiol 48:628, 1975. 223. Killebrew K, Gold RH, Sholkoff SD: Psoriatic spondylitis. Radiology 108:9, 1973. 224. Kaplan D, Plotz CM, Nathanson L, et al: Cervical spine in psoriasis and psoriatic arthritis. Ann Rheum Dis 23:50, 1964. 225. Cliff JM: Spinal bony bridging and carditis in Reiter’s disease. Ann Rheum Dis 30:171, 1971. 226. Currier BL, Eismont FJ: Infection of spine. In Rothman RH, Simone FA (eds): The Spine, 3rd ed. Philadelphia, WB Saunders, 1992. 227. Stabler A, Reiser MF: Imaging of spinal infection. Radiol Clin North Am 39:115-135, 2001.

228. Yao DC, Sartoris D: Musculoskeletal tuberculosis. Radiol Clin North Am 33:679-688, 1995. 229. Moore SL, Rafii M: Imaging of musculoskeletal and spinal tuberculosis. Radiol Clin North Am 39:329-342, 2001. 230. Varma R, Lander P, Assat A: Imaging of pyogenic infectious spondylodiskites. Radiol Clin Radiol 39:203-213, 2001. 231. Hadjipavlou AG, Cesani-Vazquez F, Villaneuva-Meyer, et al: The effectiveness of gallium citrate 67 radionuclide imaging in vertebral osteomyelitis revisited. Am J Orthop 27:179-183, 1998. 232. Modic MT, Feiglin DH, Piraino DW, et al: Vertebral osteomyelitis: Assessment using MR. Radiology 157:157-166, 1985. 233. Thrush A, Enzmann D: MR imaging of infectious spondylitis. AJNR Am J Neuroradiol 11:1171-1180, 1990. 234. Dagirmanjian A, Schils J, McHenry MC: MR imaging of spinal infections. Magn Reson Imaging Clin N Am 7:525-538, 1999. 235. Gilliams AR, Chadda B, Carter AP: ME appearance of the temporal evaluation and resolution of infectious spondylitis. AJR Am J Roentgenol 166:903-907, 1996. 236. Tyrrell PN, Cassar-Pullicino VN, McCall IW: Spinal infection. Eur Radiol 9:1066-1077, 1999. 237. Modic MT, Ross JS: Lumbar degenerative disk disease. Radiology 1:43-61, 2007. 238. Milette PC: Reporting lumbar disk abnormalities: At last, consensus! AJNR Am J Neuroradiol 22:428-429, 2001. 239. Resnick D, Niwayama G: Degenerative disease of the spine. In Res­ nick D (ed): Diagnosis of Bone and Joint Disorders, 3rd ed. Philadelphia, WB Saunders, 1995, pp 1372-1462. 240. Rumboldt Z: Degenerative disorders of the spine. Semin Roentgenol 41:327-362, 2006. 241. Sether LA, Yu S, Haughton VM, et al: Intervertebral disk: Normal age-related changes in MR signal intensity. Radiology 177:385-388, 1990. 242. Luoma K, Riihimaki H, Luukkonen R, et al: Low back pain in relation to lumbar disc degeneration. Spine 25:487-492, 2000. 243. Schellhas KP, Pollei SR, Gundry CR, et al: Lumbar disc highintensity zone: Correlation of magnetic resonance imaging and discography. Spine 121:79-86, 1996. 244. Fardon DF, Milette PC: Nomenclature and classification of lumbar disc pathology: Recommendation of the combined task forces of the North American Spine Radiology, American Society of Spine Radiology and American Society of Neuroradiology. Spine 26:93-113, 2001. 245. Modic MT, Steinberg PM, Ross JS, et al: Degenerative disc disease: Assessment of changes in vertebral body marrow MR imaging. Radiology 166:193-199, 1988. 246. Modic MT: Degenerative disorders of the spine. In Modic MT, Masaryk TJ, Ross JS (eds): Magnetic Resonance Imaging of the Spine, 2nd ed. St. Louis, Mosby, 1994, pp 80-150. 247. Harris RI, MacNab I: Structural changes in the lumbar intervertebral discs: Their relationship to low back pain and sciatica. J Bone Joint Surg Br 36B:304-322, 1954. 248. Schellinger D, Wener L, Ragsdale BD, et al: Facet joint disorders and their role in the production of back pain and sciatica. RadioGraphics 7:923-944, 1987. 249. Pathria M, Sartoris DJ, Resnick D: Osteoarthritis of the facet joints: Accuracy of oblique radiographic assessment. Radiology 164: 227-230, 1987. 250. Weishaupt D, Zanetti M, Boos N, et al: MR imaging and CT in osteoarthritis of the lumbar facet joints. Skeletal Radiol 28:215-219, 1999. 251. Howington JU, Connoly ES, Voorhies RM: Intraspinal synovial cyts: 10-year experience at the Ochsner Clinic. J Neurol 91: 193-199, 1999. 252. Silbergleit R, Gebarski SS, Brunberg JA, et al: Lumbar synovial cysts: Correlation of myelographic, CT, MR and pathologic findings. AJNR Am J Neuroradiol 11:777-779, 1990. 253. Amundsen T, Weber H, Lilleås F, et al: Lumbar spinal stenosis: Clinical and radiologic features. Spine 20:1178-1186, 1995. 254. Chen C, Lyu R, Lee S, et al: Intramedullary high signal intensity on T2-weighted MR images in cervical spondylotic myelopathy: Prediction of prognosis with type of intensity. Radiology 221:789-794, 2001. 255. Takahashi M, Sakamoto Y, Miyawaki M, et al: Increased MR signal intensity secondary to chronic cervical cord compression. Neuroradiology 29:550-556, 1987.

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256. Oppenheimer A: Calcification and ossification of vertebral ligaments. Radiology 38:160, 1940. 257. Forestier J, Rotes-Querol J: Senile ankylosing hyperostosis of the spine. Ann Rheum Dis 9:321, 1950. 258. Resnick D, Niwayama G: Radiographic and pathologic features of spinal involvement in diffuse idiopathic skeletal hyperostosis (DISH). Radiology 119:559, 1976. 259. Resnick D, Niwayama G: Diffuse idiopathic skeletal hyperostosis (DISH): Ankylosing hyperostosis of Forestier and Rotes-Querol. In Resnick D, Niwayama G (eds): Diagnosis of Bone and Joint Disorders. Philadelphia, WB Saunders, 1981, p 1416. 260. Resnick D, Guerra J Jr, Robinson CA, et al: Association of diffuse idiopathic skeletal hyperostosis (DISH) and calcification and ossification of posterior longitudinal ligament. AJR Am J Roentgenol 131:1049, 1978. 261. Resnick D, Shaul SR, Robins JM: Diffuse idiopathic skeletal hyperostosis (DISH): Forestier’s disease with extraspinal manifestations. Radiology 115:513, 1975. 262. Stabler A, Beck R, Bartl R, et al: Vacuum phenomena in insufficiency fractures of the sacrum. Skeletal Radiol 24:31-35, 1995. 263. Kursunoglu Brahme S, Cervillo V, Vint V, et al: Magnetic resonance appearance of sacral insufficiency fractures. Skeletal Radiol 19: 489-493, 1990. 264. Resnick D: Tumors and tumor-like lesions in or about joints. In Resnick D, Niwayama G (eds): Diagnosis of Bone and Joint Disorders. Philadelphia, WB Saunders, 1981, pp 2638. 265. Prager RJ, Mall JC: Arthrographic diagnosis of synovial chondromatosis. AJR Am J Roentgenol 127:344, 1976. 266. Breimer CW, Freiberger RH: Bone lesions associated with villo­ nodular synovitis. AJR Am J Roentgenol 79:618, 1958. 267. Weissman BN: Imaging of arthritis. Syllabus: A categorical course in musculoskeletal radiology. Advanced imaging of joints: Theory and practice. Presented at the 79th Scientific Assembly of Annual Meeting of the Radiological Society of North America, Chicago, IL; 1993, pp 37-50. 268. Cornelis F, Bardin T, Faller B, et al: Rheumatic syndromes and beta 2-microglobulin amyloidosis in patients receiving long-term peritoneal dialysis. Arthritis Rheum 32:785, 1989. 269. Goldman AB, Bansal M: Amyloidosis and silicone synovitis updated classification, updated pathophysiology, and synovial articular abnormalities. Imaging Arthrop 34:375, 1996. 270. Campistol JM, Sole M, Munoz-Gomez J, et al: Pathological fractures in patients who have amyloidosis associated with dialysis. J Bone Joint Surg Am 72A:568, 1990. 271. Escobedo EM: Magnetic resonance imaging of dialysis-related amyloidosis of the shoulder and hip. Skeletal Radiol 25:41, 1996. 272. Kokubo T: MR demonstration of intraosseous beta 2-microglobulin amyloidosis. J Comput Assist Tomogr 14:1030, 1990. 273. Claudon M: MR patterns of dialysis arthropathy. J Comput Assist Tomogr 14:968, 1990. 274. Friman C, Pettersson T: Amyloidosis. Curr Opin Rheumatol 8:62, 1996. 275. Orzincolo C, Bedani PL, Scutellari PN, et al: Destructive spondyloarthropathy and radiographic follow-up in hemodialysis patients. Skeletal Radiol 19:483, 1990. 276. Naito M, Ogata K, Shiota E, et al: Amyloid bone cysts of the femoral neck. Br J Bone Joint Surg 76:922, 1994. 277. Kaye J, Benson CB, Lester S, et al: Utility of high-resolution ultrasound for the diagnosis of dialysis-related amyloidosis. Arthritis Rheum 35:926, 1992. 278. Bernageau J, Bardin T, Goutallier D, et al: Magnetic resonance imaging findings in shoulders of hemodialyzed patients. Clin Orthop 304:91, 1994. 279. Cobby MJ, Adler RS, Swartz R, et al: Dialysis-related amyloid arthropathy: MR findings in four patients. AJR Am J Roentgenol 157:1023, 1991. 280. Armstrong SJ, Watt I: Lipoma arborescens of the knee. Br J Radiol 62:178, 1989. 281. Hallel T, Lew S, Bansal M: Villous lipomatous proliferation of the synovial membrane (lipoma arborescens). Am J Bone Joint Surg 70:264, 1988.

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282. Laorr A, Peterfy CG, Tirman PFJ, et al: Lipoma arborescens of the shoulder: Magnetic resonance imaging findings. Can Assoc Radiol J 46:311, 1995. 283. Chaljub G, Johnson PR: In vivo MRI characteristics of lipoma arborescens utilizing fat suppression and contrast administration. J Comput Assist Tomogr 20:85, 1996. 284. Shergy WJ, Urbaniak JR, Polisson RP, et al: Silicone synovitis: Clinical, radiologic and histologic features. South Med J 82:1156-1158, 1989. 285. Goldman AB, Bansal M: Amyloidosis and silicone synovitis. Radiol Clin North Am 34:375-394, 1996. 286. Rosenthal DI, Rosenberg AE, Schiller AL, et al: Destructive arthritis due to silicone: A foreign body reaction. Radiology 149:69-72, 1983. 287. Man-Kwong C, Prathana C, Workman T, et al: Silicone synovitis: MR imaging in five patients. Skeletal Radiol 27:13-17, 1999. 288. Bigliani LU, Levine WN: Subacromial impingement syndrome. J Bone Joint Surg Am 79A:1854-1868, 1997. 289. Neer CS II: Anterior acromioplasty for chronic impingement syndrome in shoulder: A preliminary report. J Bone Joint Surg Am 54A:41-50, 1972. 290. Neer CS: Rotator cuff tears associated with os acromiale. J Bone Joint Surg Am 66A:1320-1321, 1984. 291. Kneeland BJ, Middleton WD, Carrera GF, et al: MR imaging of shoulder: Diagnosis of rotator cuff tears. AJR Am J Roentgenol 149:333-337, 1987. 292. Reeder JD, Andelman S: The rotator cuff tear: MR evaluation. Magn Reson Imaging 5:331-338, 1987. 293. Seeger LL, Gold RH, Bassett LW, et al: Shoulder impingement syndrome: MR findings in 53 shoulders. AJR Am J Roentgenol 150: 343-347, 1988. 294. Rafii M, Firooznia H, Sherman O: Rotator cuff lesions: Signal patterns at MR imaging. Radiology 177:817-823, 1990. 295. Buirski G: Magnetic resonance imaging in acute and chronic rotator cuff tears. Skeletal Radiol 19:109-111, 1990. 296. Farley TE, Neumann CH, Steinbach LS, et al: Full-thickness tears of the rotator cuff of the shoulder: Diagnosis with MR imaging. AJR Am J Roentgenol 158:347-351, 1992. 297. Flannigan B, Kursunoglu-Brahme S, Snyder S, et al: MR arthropathy of the shoulder: Comparison with conventional MR imaging. AJR Am J Roentgenol 155:829-832, 1990. 298. Liou JTS, Wilson AJ, Totty WG, et al: The normal shoulder: Common variations that simulate pathologic conditions at MR imaging. Radiology 186:435-441, 1993. 299. Zlatkin MB, Iannotti JP, Roberts MC, et al: Rotator cuff tears: Diagnostic performance of MR imaging. Radiology 172:223-229, 1989. 300. Burk DL Jr, Karasick D, Kurtz AB, et al: Rotator cuff tears: Prospective comparison of MR imaging with arthroscopy, sonography, and surgery. AJR Am J Roentgenol 153:87-92, 1989. 301. Jacobsen JA, van Holsbeeck MT: Musculoskeletal ultrasonography. Orthop Clin North Am 29:135-167, 1998. 302. Omer GE Jr: Median nerve compression at the wrist. Hand Clin 8:317-324, 1992. 303. Middleton WD, Kneeland JB, Kellman GM, et al: MR imaging of the carpal tunnel: Normal anatomy and preliminary findings in the carpal tunnel syndrome. AJR Am J Roentgenol 148:307-316, 1987. 304. Mesgarahzade M, Schneck CD, Bonakdarpour A: Carpal tunnel MR imaging, part II: Carpal tunnel syndrome. Radiology 171:749-754, 1989. 305. Murphy RX Jr, Chernofsky MA, Osborne MA, et al: Magnetic resonance imaging in the evaluation of persistent carpal tunnel syndrome. J Hand Surg 18:113-120, 1993. 306. Lee D, van Holsbeeck MT, Janevski PK, et al: Diagnosis of carpal tunnel syndrome: Ultrasound versus electromyography. Radiol Clin North Am 37:859-872, 1999. 307. Chen P, Maklad N, Redwine M, et al: Dynamic high-resolution sonography of carpal tunnel. AJR Am J Roentgenol 168:533-537, 1997.

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54

Nonsteroidal Anti-inflammatory Drugs Leslie R. Ballou  •  Benjamin W. E. Wang

Key Points Nonsteroidal anti-inflammatory drugs (NSAIDs) and coxibs are effective anti-inflammatory, antipyretic, and analgesic compounds. Evidence suggests that there is little difference in the efficacy of the various NSAIDs and COX-2 inhibitors in the treatment of pain and inflammation. Awareness of patient risk factors for gastrointestinal ulceration is crucial to minimize ulcer complications resulting from NSAID or coxib therapy. Rates of gastrointestinal ulceration may be reduced with the use of a cyclooxygenase-2 selective inhibitor or the concomitant use of an NSAID with a proton-pump inhibitor. There is evidence that all currently available NSAIDs and coxibs are associated with an increased incidence of cardiovascular disease. Awareness of cardiovascular risk factors is crucial to minimize cardiovascular adverse effects resulting from NSAIDs and coxibs. Periodic monitoring of blood pressure, renal function, and liver enzymes should be considered in all patients taking NSAIDs and coxibs. Practitioners should be aware of the shared toxicities of all drugs in this class. Practitioners must approach simultaneous use of NSAIDs or coxibs with other antiplatelet agents, anticoagulants, and corticosteroids with caution. The incidence of adverse effects increases in the elderly. This population requires special attention to minimize ­adverse effects.

Traditionally, nonsteroidal anti-inflammatory drugs (NSAIDs) have been extensively used by physicians (prescription) and the general public (over-the-counter) as anti-inflammatory, analgesic and antipyretic agents because of their effectiveness coupled with few adverse side effects. Although the NSAIDs are structurally different, they share the ability to block the synthesis of prostaglandins (PGs). This ability is the underlying biochemical mechanism by which all NSAIDs exert their anti-inflammatory, analgesic, and antipyretic properties. Because some patients may respond well to one NSAID and not to another, however, other biochemical and

p­ harmacologic factors are likely involved. The inhibition of PG production occurs at the molecular level by inhibiting the enzyme involved in PG biosynthesis, PGH synthase, more commonly referred to as cyclooxygenase (COX). COX exists in at least two isoforms, COX-1 and COX-2 (for a complete review, see Simmons and colleagues1). The discovery of the second COX isoform (COX-2) increased understanding of the many, varied clinical effects elicited by the NSAIDs. The COX-2 isoform, whose expression is primarily increased during inflammation, has enabled better understanding of the PG biosynthetic pathway in the context of two, independently regulated COX isoforms: COX-1, a constitutively active isoform, and COX-2, an inducible isoform most commonly expressed in response to inflammatory stimuli. The development of COX-2-selective NSAIDs (coxibs) facilitated inhibition of PG production during inflammation in certain tissues, while leaving intact the ability of COX-1 to produce PGs in the tissues not directly involved in inflammation, most notably platelets and gastroduodenal mucosa. The therapeutic and adverse effects of the nonselective NSAIDs compared with the coxibs could be directly linked to the biosynthesis and biologic actions of PGs produced by two distinct COX isoforms. COX-2 also is constitutively expressed in some tissues (e.g., brain, kidney, and endothelium), and its inhibition therein may underlie at least some of the adverse effects of coxib use. NSAIDs are in widespread use in treating patients with rheumatoid arthritis (RA) or osteoarthritis, and they are extensively used to treat the symptoms of a variety of other rheumatic diseases most often characterized by chronic musculoskeletal pain and a wide range of acute pain manifestations, such as headache, dysmenorrhea, injury, and postoperative pain. Millions of people currently use aspirin (acetylsalicylic acid [ASA]) for the prevention of cardiovascular thrombosis. The potential uses of NSAIDs as chemopreventive agents against diseases ranging from Alzheimer’s disease to cancer are currently under intense investigation. Because the use of NSAIDs has become so widespread for the treatment of common diseases and ailments directly associated with the aging population, it is crucial to understand their underlying mechanisms of action, potential for adverse reactions, and interactions with other drugs. This chapter discusses the class-specific characteristics of the traditional, nonselective NSAIDs and newer COX-2-selective 833

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Nonsteroidal Anti-inflammatory Drugs

coxibs, focusing on the underlying biochemical mechanisms associated with mediating the therapeutic and adverse actions of these drugs, especially the more recently observed cardiovascular events associated with coxib use.

HISTORY The earliest treatments for “rheumatism,” developed over thousands of years, involved the use of extracts of plants such as willow bark and leaves.2 Many of these plant materials contained a compound later identified as salicin in the 1820s, although its effects were first noted in the Ebers papyrus some 3500 years ago. Ten centuries later, Hippocrates, Celsus, Pliny the Elder, Dioscorides, and Galen all prescribed willow extracts containing salicin for the treatment of rheumatic pain. Extracts of the autumn crocus, containing colchicine, were used to treat acute gout in the 6th century a.d. In the first “clinical trial” of willow bark, the Reverend Edward Stone gathered a pound of bark, which was dried, pulverized, and put into the tea, beer, or water of 50 people with fever; he found that one dose (1 dram = 1.8 g) cured their fever. In 1763, Stone wrote, “I have no other motives for publishing this valuable specific, than that it may have a fair and full trial in all its variety of circumstances and situations, and that the world may reap the benefits accruing from it.”3 In 1829, Leroux purified the active substance in willow bark that was later identified as salicylic acid.2 In 1853, Gerhardt neutralized salicylic acid by buffering it with sodium and acetyl chloride, creating ASA. Gerhardt’s product worked, but he had no desire to market it and abandoned his discovery. In 1860, the German chemist Kolbe chemically synthesized salicylic acid, which led to its widespread use as an external antiseptic, antipyretic, and analgesic. In 1860, Hoffman, working at Bayer, synthesized ASA in response to complaints from his father regarding the bitter taste of the salicylate he was taking for his severe rheumatism. Bayer’s Research Director, Dr. Heinrich Dreser, tested ASA in animals and found it to be antipyretic, analgesic, and anti-inflammatory. He recognized the importance of this new drug and introduced it to the market as a powder in 1899. About 50,000 tons of ASA is produced annually, and an average person takes 80 tablets per year, making ASA the most widely used drug in the world. In 1949, phenylbutazone was introduced into clinical practice and was followed by indomethacin, ibuprofen, fenamates, naproxen, and a variety of other ASA-like drugs. Even with their dissimilar chemical structures, all of these drugs shared the same potential for adverse effects involving gastrointestinal ulcers and bleeding, hypertension, edema, and renal damage as occurred with ASA itself. This observation led Vane to speculate, “When a chemically diverse group of drugs all share the same therapeutic qualities and the same side-effects, it is fairly certain that the actions of those drugs are based on a single biochemical intervention.”2 In 1971, speculation became fact when he showed that these drugs all acted via the same biochemical mechanism, the inhibition of PG biosynthesis. This demonstration provided the first, unifying mechanism explaining how these drugs elicited their therapeutic and their adverse effects.2 One major question remained unanswered: Why, at therapeutic concentrations, did all of these drugs, presumably acting via a common basic pathway, exhibit such wide variation in the severity of their side effects? Could there be more than

one COX enzyme? In the early 1970s, several groups speculated that there must be a second COX enzyme.4,5 In1990, Needleman reported that bacterial lipopolysaccharide (LPS) increased PG synthesis in human monocytes in vitro and in mouse peritoneal macrophages in vivo.6 The LPS-induced increase, but not the basal activity of the enzyme, was inhibited by dexamethasone and required the de novo synthesis of “new” COX protein. This observation was the foundation of the concept for “constitutive” and “inducible” forms of COX. Soon thereafter in 1991, Simmons and colleagues, during studies of early response genes in chicken embryogenesis, discovered an inducible second form of COX encoded by a 4.1kb mRNA.7,8 They went on to clone the gene and deduced its structure. They found the gene product was homologous to COX, but to no other known protein. Several groups made similar observations, defining two enzyme isoforms.9-13 Both enzymes had a molecular weight of 71 kD, and the amino acid sequence of the complementary DNA for COX-2 showed 60% homology with COX-1 complementary DNA; COX-2 mRNA was 4.5 kb, whereas that of COX-1 was 2.8 kb. The observation that glucocorticoids regulated the expression of COX-2 represented an activity that could be directly associated with the anti-inflammatory actions of the corticosteroids. The concept that inducible COX-2 expression was regulated by inflammatory stimuli indicated that specific inhibition of COX-2 might block PG production directly associated with the inflammatory response, while sparing the PGs synthesized by constitutive COX-1 involved in homeostasis, eliminating the adverse side effects produced by NSAIDs that inhibited COX-1. This intriguing hypothesis provoked an intense effort to design and develop drugs that could specifically or selectively inhibit COX-2. This task was quickly accomplished using a strategy involving the testing of existing NSAIDs for their relative ability to inhibit COX-1 or COX-2. Resolving the crystal structures for these enzymes facilitated this process—differences in crystal structure revealed specific protein regions that could be targeted and on which new drug designs could be based and tested.14,15 Within 10 years, two highly selective COX2 inhibitors were developed: celecoxib (Celebrex) and rofecoxib (Vioxx). In clinical trials, it seemed that both of these drugs were far superior to the nonselective NSAIDs in terms of their safety profiles; the Food and Drug Administration (FDA) subsequently approved both drugs for treatment of arthritis and pain. As clinical trials continued, however, adverse clinical events involving coxibs began to occur. This situation resulted in the voluntary withdrawal of Vioxx and several other coxibs from the market as a result of safety and efficacy issues related to coxib use that had been previously underappreciated by the clinical and scientific community.

BIOCHEMISTRY, BIOLOGY, AND STRUCTURE OF CYCLOOXYGENASE-1 AND CYCLOOXYGENASE-2 COX function and structure best elucidate the potential for therapeutic and adverse effects of NSAIDs. The primary substrate for the biosynthesis of PGs is arachidonic acid (AA) (Fig. 54-1). AA is a 20:4 polyunsaturated fatty acid commonly found at the sn-2 position of cell membrane glycerophospholipids that is enzymatically cleaved from the cell membrane by one of several different

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MODALITIES OF THERAPY IN RHEUMATIC DISEASE

835

11-, 12- or 15-HETE COOH

LTB4

11-, 12- or 15-HpETE Arachidonic acid

11-, 12- or 15Lipoxygenase

LTA4

5-HpETE 5-Lipoxygenase

NSAIDs

COX-1 or COX-2

LTC4

Aspirin AA Lipoxins

LTD4

COOH

O

LTE4

O OOH PGG2 COX-1 or COX-2 COOH

O O COOH

OOH

PGI synthase

O

TXA synthase

PGH2

COOH

O O

HO

OH

OH TXA2

PGI2 (prostacyclin) HO

OH

O

COOH

COOH HO HO

OH

PGD synthase

6-keto-PGF1G HO

HO

OH PGE synthase

PGF synthase

COOH O

OH PGD2

O

TXB2 O

COOH

HO

COOH

HO

OH PGF2 (9α, 11α-PGF2α)

OH PGE2

Figure 54-1  The arachidonic acid cascade. The fate of arachidonic acid in cells as it is metabolized by lipoxygenases to hydroxyeicosatetraenoic acids (HETEs) and hydroperoxyeicosatetraenoic acids (HPETEs), then to leukotrienes (LT), or by cyclooxygenases (COXs) to prostaglandin (PG) H2 via the shortlived hydroperoxyl-containing intermediate PGG2. Nonsteroidal anti-inflammatory drugs (NSAIDs) block the synthesis of PGG2. PGH2 spontaneously rearranges or is enzymatically isomerized, oxidized, or reduced to yield bioactive prostaglandin isomers, some of which are shown. Aspirin modifies COX-2 activity to yield lipoxins from arachidonic acid via transcellular metabolism. (Modified from Vane JR, Botting R, Emery P, et al [eds]: Clinician’s Manual on COX-2 Inhibition, 2nd ed. London, Science Press, 2002.)

phospholipase A2 enzymes.16 There are several possible fates for released AA in cells; it can be metabolized by lipoxygenases to hydroxyeicosatetraenoic acids, hydroperoxyeicosatetraenoic acids, and leukotrienes or by COXs to PGH2 by way of an unstable hydroperoxyl-containing intermediate, PGG2. NSAIDs inhibit the synthesis of PGG2. PGH2

spontaneously rearranges or is enzymatically isomerized via PG synthases, oxidized, or reduced to produce biologically active PGs, of which there are many isomers.1 Generally, although phospholipase A2 activity is required to initiate PG synthesis, the overall regulation of the type and amount of PG produced is determined by the expression levels of

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COX-1, COX-2, and the cell-specific terminal PG synthase enzymes. An exception is the platelet, in which COX-1 is constitutively expressed, and thromboxane production is regulated by substrate availability. There also are some newly discovered effects of ASA on COX-2 resulting in the biosynthesis of novel anti­inflammatory metabolites from AA, or from alternative substrates such as docosahexaenoic acid or eicosapentaenoic acid.17-20 The discovery of such pathways has shed light on the mechanisms by which ASA may elicit its “protective” effects with respect to cardiovascular and cancer-related diseases and the importance of an intrinsic role for COX-2 in the “resolution” of inflammation.21 ARACHIDONIC ACID CASCADE AND PROSTAGLANDIN BIOSYNTHESIS AND ACTION PGs can function as paracrine and autocrine mediators. Their effects most often occur near the cellular sites of their synthesis. All of the enzymatic machinery necessary for the synthesis of a specific PG is restricted to its site of action, including the PG receptors that are responsible for transducing the specific signals inherent to each PG.22 The actions of PGs are extremely diverse largely as a result of the numerous different PG isomers that can be synthesized from AA. Most cell types are typically unable to synthesize more than a few PGs, however, a process limited by the types of terminal PG synthases that are expressed in a specific cell type.23 PGE2, whose synthesis is greatly increased at sites of inflammation, is produced by many different cell types and is regulated by the activity of multiple, differentially expressed PGE synthases.24-26 One of these synthases, microsomal PGE synthase-1, is an inducible enzyme that exhibits a pattern of expression comparable to COX-2 and plays a central role in the increased production of PGE2 at sites of inflammation27; as such, microsomal PGE synthase-1 activity also may be a potential therapeutic target.28 The facilitated transport of PGs occurs by means of a member of the organic anion transporter polypeptide family and perhaps others.29-31 The fact that PG action is limited to sites of its synthesis can be explained by its ephemeral nature and predisposition to metabolic inactivation as a means of regulating its potent biologic activities. PGs mediate their effects by signaling through specific cell surface G protein–coupled receptors.32 There are multiple PG receptor subtypes and splice variants,33 which all belong to three clusters within three different subfamilies of the G protein–coupled receptor superfamily; an exception to this is one of the PGD2 receptors (DP2), which is a member of the chemokine receptor subfamily.32 The prostacyclin receptors, PGD2 (DP1) and PGE2 (EP2 and EP4) “relaxant receptors,” signal via Gs-mediated increases in intracellular cyclic adenosine monophosphate (cAMP).32 This increase in cAMP upregulates COX-2 transcriptional activity via a cAMPresponsive element in the COX-2 promoter region.34 The contractile receptors for thromboxane A2 (TP), PGF2a (FP), and PGE2 (EP1) use Gq-mediated increases in intracellular calcium for signal transduction. The EP3 receptor for PGE2 transduces inhibitory signals through Gs-mediated decreases in cAMP levels. Given the great diversity of PG isomers and the identification of a growing number of PG

receptors expressed by different cell types, PG signaling pathways constitute an enormously complex network controlling many biologic actions. Much work remains to understand fully all of the cellular signaling mechanisms by which PGs and their receptors elicit their respective biologic actions. CYCLOOXYGENASE VARIANTS COX variants arise primarily via alternative splicing. Diaz and colleagues35 discovered the first COX-1 splice variant, in which the last 111 base pairs of exon 9 were removed, eliminating the N-glycosylation site at residue 409, a site required for proper protein folding and activity. More recently, brainspecific splice variants were discovered in dogs.36 One of these variants, COX-3, was identical to COX-1 mRNA, but retained intron 1. COX-3 was expressed in insect cells and was active, although less so than COX-1, and was inhibited differently by NSAIDs than COX-1. Detailed analysis of COX-3 has shown that the retained intron 1 of COX-3 is not in proper reading frame in all species, most notably in humans and rodents, which would require additional editing mechanisms to produce a functional enzyme.36,37 Several PCOX (partial COX-1) proteins36 also have been ­identified, but they lack enzymatic activity, and their functions are unknown. There are many alternatively polya­ denylated transcripts of COX-138 and COX-239; numerous single nucleotide polymorphisms also exist.40 Given the central roles of the COXs in normal physiology and pathophysiology, it is likely that single nucleotide polymorphisms would play a role in altered susceptibility to diseases.41 COMPENSATION The concept of compensation with respect to the expression of COXs and the use of NSAIDs to inhibit them is physiologically significant. All one needs to do is look at the complexity of the AA cascade and consider what would happen if COX-1, COX-2, or both enzymes were to become inactive. Substrate (AA) that is not being used by the enzymes whose activity is altered would be potentially free to be used by other enzymes in the pathway (e.g., lipoxygenase), and this could alter the balance between PG and leukotriene biosynthesis. Ballou and others42-44 have shown that in mice or cells genetically deficient in either COX-1 or COX-2, there is a “compensatory” upregulation of the alternative COX isoform, cytosolic phospholipase A2, and lipoxyge­ nase expression resulting in altered patterns of PG and leu­ kotriene production. Such shifts in the pathways of the AA cascade conceivably could arise from the use of NSAIDs (especially long-term) and potentially could explain some of the effects of NSAIDs not directly linked to the inhibition of PG production. RESOLUTION OF INFLAMMATION AND THE CYCLOOXYGENASE-2-MEDIATED PRODUCTION OF NATURAL ANTI-INFLAMMATORY PRODUCTS In the early 1930s, the Burrs45 reported that certain polyunsaturated fatty acids were “essential” for the health of mammals, but why? First, the essential fatty acids, including AA and eicosapentaenoic acid, could not be synthesized by mammals de novo, but had to be supplied in the diet.

PART 8 

These fatty acids were substrates for conversion to PGs by the COXs.46 Eicosapentaenoic acid (high levels in fish oil) is not nearly as good a substrate as AA for COX, however, and is a competitive inhibitor of AA oxidation by COX; this was thought to be the main reason why diets high in fish were associated with reduced inflammatory and cardiovascular diseases.47 More recently, Serhan17 showed that although ASA inhibits COX-1, it possesses the capacity to “alter” COX-2 activity such that an “ASA-triggered” catalytic cascade involving endothelial cell COX-2 and leukocyte-5-lipoxygenase can mediate the “transcellular” synthesis of anti-inflammatory products, such as resolvins and lipoxins.20 Anti-inflammatory products can be generated from AA, eicosapentaenoic acid, and docosahexaenoic acid via ASA-dependent or ASA-independent pathways as shown in Figure 54-2.18,21,48 COX-2 activity also has been shown to play an important role in the natural “resolution” of inflammation. Evidence indicates that the inhibition of COX-2 may have a negative effect on this process and in some instances may explain some of the adverse effects of coxibs relative to its ability to limit inflammatory responses in vivo naturally.49 CYCLOOXYGENASE BIOCHEMISTRY AND STRUCTURE The PGs are potent bioactive lipid metabolites derived from AA. Goldblatt50 and von Euler51 were the first to isolate these metabolites from semen, prostate, and seminal

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vesicles in the 1930s, establishing their nomenclature. The first PG isomers were identified and purified by Bergstrom and colleagues during the 1950s and 1960s; van Dorp and colleagues52 and Bergstrom and colleagues46 independently discovered that PGs arose from the metabolism of AA, a 20carbon tetraenoic fatty acid (C20:4). It was not until 1973, however, that Hamberg and Samuelsson53 identified the enzymatic reaction that converted AA to PGs; the enzyme was named cyclooxygenase based on its ability to cyclize and oxygenate AA to form an endoperoxide-containing intermediate, PGG2. COX also reduces the hydroperoxyl group in PGG2 to a hydroxyl to yield PGH2, via a separate peroxidase active site. Isomerases and oxidoreductases catalyze the formation of the many different PG isomers using PGH2 as substrate. Smith and Lands5 identified COX, also referred to as PGH synthase or prostaglandin endoperoxide synthase (E.C.1.14.99.1), as the main enzyme in the conversion of AA to PGG2 to PGH2. Purification to homogeneity was first achieved by Hemler and Lands in 197654 with a molecular weight of about 70 kD; its COX and peroxidase activities were later found to reside at distinct sites within the molecule.55 In 1971, Vane56 showed that ASA, indomethacin, and salicylate, commonly used NSAIDs, were COX inhibitors, elucidating the mechanism by which these drugs acted, a discovery that earned him a share of the Nobel Prize in Medicine in 1982. COX-1 and COX-2 possess identical enzymatic activities, and both are integral membrane proteins located within the inner leaflet of the lipid bilayer of

Arachidonic acid C20:4

Eicosanoids Aspirin

Aspirin:COX-2 Proinflammatory mediators

Prostaglandins Leukotrienes

Anti-inflammatory proresolution

Eicosapentanoic acid C20:5 Resolvins E series

Docosanoids

A

18R-H(p)EPE

EPA

LOX

RvE1

P450

EETs P450 Lipoxins

Docosahexanoic acid C22:6

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Protectins neuroprotectins

NPD1 Epoxidation

Aspirin:COX-2 (acetylated) Resolvins D series Protectins Neuroprotectin D1

RvD1 17-H(p)DHA

DHA LOX

LOX

RvD2 RvD3 RvD4

17S-resolvin D series

B

Figure 54-2  Function of essential polyunsaturated fatty acids in the production of families of bioactive lipid mediators. A, Arachidonic acid is the precursor of metabolites that function as proinflammatory mediators. Prostaglandins and leukotrienes play pivotal roles in the progression of inflammation. Through cell-cell interactions, exemplified by platelet leukocytes in the vasculature, or polymorphonuclear cell-mucosa interactions, or both, lipoxins are generated that serve as “stop signals” and promote resolution and serve as endogenous anti-inflammatory mediators self-limiting the course of inflammation. The essential omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid (C20:5 and C22:6) are converted to new families of lipid mediators that are pivotal in promoting resolution (as in B). Resolvins of the E series, such as RvE1, are generated from eicosapentaenoic acid, and resolvins of the D series, such as RvD1 and the protectins such as neuroprotectin D1 (NPD1), are generated from docosahexaenoic acid, for which neural systems are enriched. B, Aspirin affects the formation of resolvin E1 by acetylating cyclooxygenase (COX)-2 in vascular endothelial cells, which, in a “stereoselective” way, can generate 18R-H(p)EPE (hydroperoxyeicosapentaenoic acid) that is picked up through transcellular metabolism by leukocytes and converted by a lipoxygenase (LOX)-like mechanism to resolvin E1. Aspirin also affects the formation of D-series resolvins and catalytically switches COX-2 to a 17R-LOX-like mechanism that serves to generate 17R-series resolvin D. Aspirin also affects the formation of protectins and neuroprotectins by a similar mechanism and generates compounds carrying the 17R epimer at the alcohol at carbon-17 in neuroprotectin D1 and other protectins. DHA, docosahexaenoic acid; H(p)DHA, hydroperoxydocosahexaenoic acid. (Modified from Serhan CN, Savill J: Resolution of inflammation: the beginning programs the end. Nat Immunol 6:1191-1197, 2005.)

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A

B COX-1 homodimer

COX-2 homodimer

Figure 54-3  Cyclooxygenase (COX)-1 and COX-2 crystal structure. A and B, Crystallographic structures of COX-1 (A, ovine) and COX-2 (B, murine) homodimers. The crystallographic structure of ovine COX-1 was taken from Protein Data Bank file1PRH, and the murine COX-2 structure was taken from file COX5 from the same source. Functional domains are as follows: (1) membrane binding domain (yellow), (2) dimerization domain (green), (3) catalytic domain (blue), and (4) heme domain (red). The open cleft of the peroxidase active site can be seen at the top of each monomer. Glycosyl residues are not shown. (From Simmons DL, Botting RM, Hla T: Cyclooxygenase isozymes: The biology of prostaglandin synthesis and inhibition. Pharmacol Rev 56:387-437, 2004.)

the ­intracellular phospholipid membranes of the nuclear envelope and the endoplasmic reticulum. Seminal studies by Picot and associates in 199457 elucidated the structure of COX-1, and studies in the early 1970s showed the distinct domains of COX-1 for dimerization, membrane binding, and catalysis. A fourth domain, an N-terminal signal peptide, present in the primary structure of COX-1, is cotranslationally cleaved and not seen as part of its crystal structure. As shown in Figure 54-3, COX-1 and COX-2 crystal structures are strikingly similar.15 All known COXs are homodimers sharing the same functional domains: The N-terminal, epidermal growth factor–like domain is involved in dimerization via hydrophobic interactions; the membrane-binding domain is composed of four amphi­ pathic α-helices lodged into half of the lipid bilayer to form a hydrophobic channel in the center of the large, catalytic domain that contains the COX and peroxidase active sites and that constitutes about 80% of the protein. The catalytic domain is globular with two distinct intertwining lobes. The interface of these lobes creates a shallow cleft on the upper surface of the enzyme where the peroxidase active site is located and where heme is bound. The COX active site is a long, narrow, dead-end, hydrophobic  channel whose entrance is framed by the four amphipathic helices of the membrane-binding domain (Fig. 54-4). The channel extends into the globular catalytic domain and is about 8 Å wide, but significant narrowing of the channel occurs where arginine 120 protrudes into the channel and forms a hydrogen-bonded network with glutamate 524 and tyrosine 355. Arginine 120 is essential for binding substrates and carboxylate-containing NSAIDs in COX-1. In contrast, this residue is unessential in binding substrate in COX-2,58 whereas it seems to be essential for binding of carboxylate-containing NSAIDs.59 Generally, NSAIDs act by blocking access of AA to the COX active site within the hydrophobic channel. The upper part of the channel, the catalytic pocket, contains tyrosine 385, which is essential for the cyclization/ oxygenation reaction. Ser530, the residue transacetylated

by ASA, along with valine 349, seems to govern the stereochemistry of the pocket such that AA is sterically blocked from a functional interaction with the catalytic domain.60 A crucial structural difference between COX-1 and COX-2 is a substitution of isoleucine523 of COX-1 for a valine in COX-2 that opens a hydrophobic area in COX-2 that can be accessed by some coxibs.15 COX-2 seems to have a wider and more flexible hydrophobic substrate-binding channel, a structural feature that has been exploited with respect to the development of coxibs, as shown in Figure 54-4.61 MOLECULAR BIOLOGY Although there are few structural and catalytic differences between COX-1 and COX-2, there are physiologically relevant differences with respect to their expression and regulation.1 Generally, COX-1 is a constitutively expressed gene in most cell types, and its expression is not modulated by inflammatory stimuli. The promoter region of COX-1 exhibits several traits consistent with a gene that is continuously transcribed and stably expressed. COX-1 activity is regulated by substrate (AA) availability. When there is an increase in substrate mobilization via phospholipase A2 activation, there is a concordant increase in PG synthesis mediated by COX-1.1 Of physiologic significance, COX-1 is the only isoform expressed in mature platelets, is the most highly expressed isoform in normal gastroduodenal mucosa,62 is inhibited by most NSAIDs, and may explain the adverse effects (gastrointestinal ulceration and bleeding) of these drugs in vasculature and gastrointestinal tissues. In contrast to COX-1 promoter structure, the COX-2 promoter exhibits characteristics of a highly inducible gene product containing binding sites for numerous regulatory transcription factors, such as nuclear factor кB (NFкB), activating protein-1, and cAMP-responsive element, which mediate the rapid increase in transcription of COX-2 in response to inflammatory signals.62 COX-2 expression is predictably increased in response to proinflammatory cytokines such as interleukin-1β and tumor necrosis factor-α,

PART 8 

A

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MODALITIES OF THERAPY IN RHEUMATIC DISEASE

839

COX-2

COX-1

IIe532 IIe434

His513

Val434

Val532

N N

N

O

N Arg513

Active site

Arg120

N N

Arg120

N

N

N

O

N

N

OH

Active site

OH

O Nonselective COX inhibitor

OH

B

COX-1

COX-2

IIe532

IIe434

Val434

Val532

Active site His513

R

N

Arg513 N

N N

Arg120

N

N

O

N

N

N N

O

Active site

Arg120

N

R O O

COX-2 selective inhibitor

Figure 54-4  Cyclooxygenase (COX)-1 and COX-2 substrate-binding channels. Schematic depiction of the structural differences between the substrate-binding channels of COX-1 and COX-2 that allowed the design of selective inhibitors. The amino acid residues, Val434, Arg513, and Val523, form a side pocket in COX-2 that is absent in COX-1. A, Nonselective inhibitors have access to the binding channels of both isoforms. B, The more voluminous residues in COX-1, Ile434, His513, and Ile532, obstruct access of the bulky side chains of the coxibs. (From Grosser T, Fries S, FitzGerald GA: Biological basis for the cardiovascular consequences of COX-2 inhibition: Therapeutic challenges and opportunities. J Clin Invest 116:4-15, 2006.)

microbial products such as LPS, and mitogens such as phorbol esters and growth factors.62 COX-2 transcriptional activation can occur in a few minutes based on mRNA levels, and protein levels usually increase within a few hours. As is the case in the synthesis of many inflammatory proteins, glucocorticoids suppress COX-2 expression.23,63 COX-2 mRNA stability is a key regulator of COX-2 levels. The potential for instability of the COX-2 message is due to the presence of multiple AUUUA instability sequences in

the 3′ region that mediate a rapid degradation of mRNA, which ultimately suppresses COX-2 protein synthesis and PG production; conversely, some stimuli (e.g., interleukin1β) may interfere with autodegradation and increase COX2 levels and PG production.64 COX-1 and COX-2 can be post-translationally modified65; COX-1 is glycosylated at three asparagines involved in proper protein folding of the enzyme,66 whereas COX-2 can be glycosylated at four asparagines with as yet unknown

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effects. The generalization that COX-1 expression is constitutive and COX-2 expression is inducible has its limitations, given the more recent findings showing the physiologic importance of “constitutive COX-2” that is responsible for basal COX-2 expression in the brain, kidney, pancreas, and blood vessels.61,67,68 COX-2 is required for normal reproductive, renal, cardiovascular, and skeletal physiology.1,69

MOLECULAR BASIS OF CYCLOOXYGENASE INHIBITION All of the NSAIDs are synthetic inhibitors of the COX active site, but subtle mechanistic differences in the manner in which individual NSAIDs interact and bind with the active site are responsible for the differences in their pharmacologic characteristics.70 The primary differences between NSAIDs and the mechanisms by which they inhibit COX are reflected by how they modify or interact with the COX active site. ASA is the only covalent, irreversible modifier (I) of COX-1 and COX-2, whereas all of the other NSAIDs are competitive inhibitors (II), competing with substrate (AA) for binding in the active site. The competitive inhibitors are subdivided further based on whether they bind to the COX active site in a time-dependent or time-independent manner. ASPIRIN Crystallographic studies have shown how ASA effectively acetylates Ser530 of COX-1. Similar to other NSAIDs, ASA diffuses into the COX-1 active site at the mouth of the channel and travels to the constriction created by Arg120, Tyr355, and Glu524, where it is in the best orientation to transacetylate Ser530 of COX-1.71 Acetylation of the Ser530 of COX-1 results in the complete and irreversible inhibition of PG production. In COX-2, the channel of the active site is larger than COX-1, the orientation of ASA for Ser530 attack is not as good, and transacetylation efficiency for COX-2 is 10-fold to 100-fold less than for COX-1. As mentioned earlier, ASA also can “trigger” COX-2 to alter its catalytic activity to produce substrate for the transcellular synthesis of anti-inflammatory metabolites, such as lipoxins.

COX channel). This orientation may involve a change in conformation of the constriction site, to the “open state” to allow the drug to access the upper part of the COX catalytic site.74 The binding of COX-1 to time-dependent or nondependent NSAIDs does not alter its conformation.75 CARBOXYLATE-CONTAINING NONSTEROIDAL ANTI-INFLAMMATORY DRUGS Drugs such as flurbiprofen and indomethacin form a saltbridge between the carboxylate moiety of the NSAID and the guanidinium moiety of Arg120 in COX-1.71 Hydrophobic interactions between the aromatic rings and the hydrophobic amino acids in the channel aid binding. Such interactions at the constriction point of the channel completely block the entry of substrate to the active site.76 SELECTIVE CYCLOOXYGENASE-2 INHIBITORS (COXIBS) In 1999, celecoxib and rofecoxib were marketed as the first NSAIDs specifically developed to inhibit COX-2 selectively, while leaving COX-1 to function normally. Earlier NSAIDs, such as meloxicam (Mobic), nimesulide, and etodolac (Lodine), were marketed as “safer” NSAIDs in Europe and the United States, but it was not until after the discovery of COX-2 that it was determined that these drugs were “preferential” COX-2 inhibitors. Subsequently, numerous even more selective COX-2 inhibitors were developed, including valdecoxib (Bextra), etoricoxib and lumiracoxib. Celecoxib and rofecoxib are diaryl compounds containing a sulfonamide (celecoxib) and methylsulfone (rofecoxib) rather than a carboxyl group. Both drugs are weak time-independent inhibitors of COX-1, but strong time-dependent inhibitors of COX-2 that require their entry into, and stabilized binding in, the catalytic pocket. Because these drugs lack a carboxyl group, Arg120 is not involved, but rather, multiple sites of hydrogen and hydrophobic binding stabilize the coxib at the catalytic site. The sulfur-containing phenyl ring of these drugs plays a pivotal role in binding stability by occupying the hydrophobic outpocketing characteristic of the COX-2 catalytic site. If this outpocket is removed by mutagenesis, all isozyme selectivity is lost.15

TIME DEPENDENCE AND COMPETITIVE NONSTEROIDAL ANTI-INFLAMMATORY DRUG INHIBITION

ASSESSING CYCLOOXYGENASE ISOFORM SELECTIVITY

The time it takes for an NSAID to bind to the COX active site relative to how long it takes for it to leave the COX channel is a crucial factor in the inhibition of COX.72,73 Drugs such as ibuprofen exhibit such rapid on and off rates that they essentially inhibit COX instantly and can be removed from the COX active site just as quickly when drug levels decrease. Conversely, indomethacin and diclofenac are timedependent inhibitors and require seconds to minutes to bind to the COX active site. These NSAIDs exhibit slow off rates, often needing hours to leave the COX active site. Initially, time-dependent NSAIDs form a loose complex with the COX active site before a stronger interaction is established. This complex is limited by the time it takes the drug to become properly oriented within the COX channel at Arg120, Tyr355, and Glu524 (the constriction site in the

Generally, most of the NSAIDs have effects on COX-1 and COX-2 except for ASA, which is predominately COX-1 selective, and all of the coxibs, which are COX-2 selective. COX isozyme selectivity is defined most commonly using an IC50, the concentration of drug required to inhibit PG production by 50% in a particular assay system. Ratios using values obtained for COX-1 IC50s compared with COX-2 IC50s can be calculated and used as a standard measure for comparing the degrees of selectivity of a particular NSAID for one or the other COX isoform.77 PG assay systems can vary widely, however, making it difficult to compare directly results from studies using different assay systems. To circumvent such  problems, most  clinicians have accepted the use of the in vitro whole-blood assay to compare NSAID selectivities. In this system, COX-1 inhibition

PART 8 

is assessed as a function of the reduction of thromboxane made by platelets after clot formation. Inhibition of COX-2 is based on the inhibition of PGE2 production in a heparinized blood sample after LPS stimulation. By definition, a COX-2 selective inhibitor lacks inhibitory effect on platelet COX-1 at concentrations at or above those that maximally inhibit COX-2.78,79 The modified William Harvey whole-blood assay uses cultured A549 cells, instead of blood monocytes, incubated with IL-1 and added to human blood for estimation of activity against COX-2.80 ANALGESIC AND ANTIPYRETIC DRUGS Acetaminophen and dipyrone relieve pain and fever, but they are not anti-inflammatory; in other words, neither acetaminophen nor dipyrone is a good COX inhibitor. The precise mechanisms by which these drugs elicit their effects remain unclear to this day, even though acetaminophen is older than ASA and still in widespread use. In the 1970s, it was proposed that acetaminophen worked by means of a “central” action by inhibiting COX activity primarily in the brain and not in peripheral tissues because they were not acidic and could cross the blood-brain barrier.81 This hypothesis still does not fully explain acetaminophen’s mechanism of action, however, because it remains a poor inhibitor of purified COX enzymes.82 With the discovery of a variant of COX-1, COX-3, and studies showing that it is highly expressed in brain and more sensitive to inhibition by acetaminophen than in peripheral tissues,36 Botting and Ayoub83,84 proposed that acetaminophen’s analgesic and antipyretic actions could be mediated by its ability to inhibit COX-3 in brains of at least some species. Salicylate has analgesic, antipyretic, and anti-inflammatory activity, but similar to acetaminophen and in contrast to ASA, is a poor COX inhibitor. Acetaminophen85 and salicylate86 have been shown to inhibit COX activity if substrate levels are low, suggesting that both drugs may inhibit COX by redox-related mechanisms.87

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841

at best. Some NSAIDs inhibit phosphodiesterase associated with the metabolism of cAMP leading to increased intracellular cAMP levels and the subsequent general inhibition of peripheral blood lymphocyte responses to mitogen stimulation, monocyte and neutrophil migration, and neutrophil aggregation.89 NSAIDs scavenge free radicals, inhibit superoxide production by polymorphonuclear neutrophils, reduce mononuclear cell phospholipase C activity, and inhibit inducible nitric oxide synthase activity.90 Sodium salicylate and ASA inhibit NFкB activation,91 as do certain inactive enantiomers of flurbiprofen.92 NSAIDs may affect cell signaling by modulating the activity of mitogen-activated protein kinases and the transcription factor activating protein-1.92 Peroxisome proliferator–activated receptors, which transduce anti-inflammatory signals, may be a target of some NSAIDs.93 There also is evidence indicating that some coxibs may affect apoptosis and angiogenesis independent of their effects on COX.94

PHARMACOLOGY CLASSIFICATION

Colchicine seems to inhibit primarily the participation of neutrophils in the inflammatory cascade by interfering with fibrillar microtubular organization, disrupting neutrophil motility and chemotaxis. Colchicine also seems to reduce the production of chemotactic factors (e.g., leukotrienes), digestive vacuole formation, and lysosomal degranulation.88 These effects of colchicine combine to disrupt the ability of neutrophils to migrate to sites of inflammation and inhibit the activation of resident neutrophils. Colchicine helps to abrogate the inflammatory processes associated with gout and other neutrophil-mediated acute inflammatory diseases.

NSAIDs generally are grouped according to their chemical structures, plasma half-life, and COX-1 versus COX2-selectivity (Table 54-1 and Fig. 54-5). Structurally, most NSAIDs are organic acids with low pKa values that lend themselves to their accumulation at sites of inflammation, areas that often exhibit lower pHs than uninvolved sites.89 Most often, there is a direct relationship between low pKa and short-half life, but there are exceptions, such as nabumetone, which is nonacidic and anti-inflammatory. Classifying NSAIDs based on plasma half-life can be problematic given the fact that these drugs tend to accumulate in synovial fluid, where the concentration of drug may remain more stable than in the plasma. Short half-life NSAIDs potentially could be given less frequently than indicated by their plasma half-life. Table 54-1 presents a representative compilation of common NSAIDs, formulations, dosages, halflives, and precautions. NSAIDs exhibiting longer half-lives require more time to reach steady-state plasma levels. Drugs with a half-life greater than 12 hours can be given once or twice a day, and plasma levels increase for a few days to several weeks (depending on the specific half-life), but then tend to remain constant between doses. NSAIDs with longer half-lives enable drug concentrations to equilibrate between the plasma and the synovial fluid. Total bound and unbound drug levels are usually lower in synovial fluid because there is less albumin in synovial fluid than in plasma. NSAID classification schemes based on COX-isozyme selectivity can be useful in terms of predicting potential adverse events (e.g., gastrointestinal ulceration, bleeding, cardiovascular effects).

CYCLOOXYGENASE-INDEPENDENT EFFECTS OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

NONSTEROIDAL ANTI-INFLAMMATORY DRUG METABOLISM

At high, nonphysiologic concentrations, some NSAIDs seem to elicit effects on cellular pathways in vitro that do not involve the inhibition of COX. Because of the high doses of drug required, and the use of in vitro systems, the relevance of these effects to in vivo activity are uncertain

Regardless of the dosage form, most NSAIDs are absorbed via the gastrointestinal tract, and greater than 90% of the drug ultimately becomes bound to plasma proteins. When plasma proteins become saturated with drug, active free drug concentrations increase rapidly compared with total drug

COLCHICINE

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Table 54-1  Common Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Coxibs Brand Name

Available Formulations (mg)

Maximal Daily Dose (mg)

Tmax (hr)

Half-life (hr)

Dose Adjustment or Special Precautions

Acetylsalicylic acid

Aspirin

3000

0.5

4-6

Decrease dose by 50% in renal failure patients and patients with hepatic insufficiency

Salsalate

Disalcid Amigesic Salflex Dolobid

Tablets: 81,165, 325,   500, 650 Children’s: 81 Suppository: 120, 200, 300, 600 Capsule: 500 Tablet: 500, 750

3000

1.4

1

Tablets: 250, 500

1500

2-3

7-15

Decrease dose by 50% in renal failure

Voltaren

Tablets: 25, 50, 75

225

1-2

2

Incidence of increased transaminase levels higher than with other NSAIDs

Voltaren XR Cataflam Arthrotec

Extended release: 100 200

1-2

2

200

1-4

2-13

Incidence of increased transaminase levels higher than with other NSAIDs Approved for treatment of patent ductus arteriosus

400

2-4

16

Drug Salicylic Acids

Diflunisal Acetic Acids Diclofenac

Diclofenac + misoprostol Indomethacin

Indocin Indocin SR

Tablets: 50 or 75 plus misoprostol 200 μg Caps: 25, 50

Sulindac

Clinoril

Sustained release: 75 Oral suspension:   25 mg/5 mL Suppositories: 50 Tablets: 150, 200

Ketorolac

Toradol

IM/IV: 15 or 30 mg/mL

120 IV/IM

0.3-1

4-6

Tolmetin

Tolectin

40 mg PO 1800

0.5-1

1-1.5

Etodolac

Lodine Lodine XL

Tablets: 10 Tablets: 200, 600 Caps: 400 Caps: 200, 300 Tablets: 400 Extended release: 400, 500, 600

1200

1-2

6-7

3200

1-2

2

Avoid in severe hepatic disease

Tablets: 125 (OTC), 250, 1500 375, 500 Sustained release: 375,   500 Suspension: 125 mg/5 mL

2-4

12-15

Decrease dose in renal disease, liver disease, and elderly patients

Fenoprofen

Anaprox EC-Naprosyn Naprelan Nalfon Caps: 200, 300, 600

3200

1-2

2-3

Ketoprofen

Orudis

Tablets: 12.5 (OTC)

300

0.5-2

2-4

Idiosyncratic nephropathy more frequent than with other NSAIDs Decrease dose in severe renal disease, hepatic disease, and elderly patients

Oruvail

Caps: 25, 50, 75 Sustained release: 100, 150, 200 Tablets: 50, 100 Tablets: 600

300 1800 or 26 mg/ kg/day

1.5-2 3-6

3-4 49-60

Caps: 50, 100

400

0.5

2-3

Prodrug metabolized to active compound Decrease dose in renal disease, liver disease, and elderly patients Decrease dose by 50% in renal failure and elderly patients Do not use >5 days

Propionic Acids Ibuprofen

Motrin

Naproxen

Advil Nupren Rufen Naprosyn Aleve

Flurbiprofen Oxaprozin

Ansaid Daypro

Tablets: 200 (OTC), 300, 400, 600, 800

Decrease dose in renal failure patients and patients <50 kg

Fenamic Acids Meclofenamate Meclomen Oxicams Piroxicam

Feldene

Caps: 10, 20

20

2-5

3-86

Meloxicam

Mobic

Tab: 7.5, 15

15

5-6

20

IM/IV, intramuscular/intravenous; OTC, over-the-counter; PO, oral.

Decrease dose in hepatic disease and elderly patients

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843

Table 54-1  Common Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Coxibs­—cont’d Brand Name

Drug

Available Formulations (mg)

Maximal Daily Dose (mg)

Tmax (hr)

Half-life (hr)

Dose Adjustment or Special Precautions

Tablets: 500, 750

2000

3-6

24

Food increases peak concentration Reduce dose in renal disease Avoid in severe liver disease Limit dose to 1 g/day in elderly patients

3

11

Contraindicated with sulfonamide allergy

1-1.5

22

Contraindicated in severe renal or liver   disease patients Caution in mild-to-moderate disease Caution in renal failure and severe hepatic dysfunction Contraindicated with sulfonamide   allergy Caution in severe renal and liver disease Prodrug metabolized to valdecoxib   in <1 hr Contraindicated with sulfonamide allergy

Nonacidic Compounds Nabumetone

Relafen

COX-2 Selective Inhibitors (Coxibs) Celecoxib

Celebrex

Caps: 100, 200, 400

Etoricoxib*

Arcoxia

Tablets: 60, 90, 120

400 (800 mg   in FAP) 120

Lumiracoxib*

Prexige

Tablets: 200, 400

400

2-3

3-6

Valdecoxib†

Bextra

Tablets: 10, 20

20

1-3

8-11

<1-2.5

8

Parecoxib*

IM/IV

*Not approved by U.S. Food and Drug Administration. †Withdrawn from market. Data from MICROMEDEX Healthcare Series 2008. Greenwood Village, Colo. www.micromedex.com. Accessed February 2008.

Carboxylic acids

Acetic acids

Salicylic acids

*Aspirin Difunisal Trisalicylate Salsalate Sodium salicylate

Phenylacetic acids

Carbo-and heterocyclic acids

*Diclofenac

*Etodolac Indomethacin Sulindac Tolmetic Ketorolac

Cl

H N O

Cl

O

Na

-

+

Propionic acids

Fenamic acids

Pyrazolones

Oxicams

Flurbiprofen Ketoprofen Oxaprozin *Ibuprofen Naproxen Fenoprofen

*Mefanamic

*Phenylbutazone

Piroxicam *Meloxicam

COOH N

O

O

CH3O

NH S

N H N S

N

O

O

N

O

O

O OH

O

O

*Nabumetone

OH

N H OH O

COOH

CH3CH2CH2CH2

O

O

Nonacidic compounds

Enolic acids

COX-2-selective inhibitors (Coxibs)

CH3

CH3

N

CF3 N

*Celecoxib Rofecoxib Meloxicam Nimesulide Paracoxib

Etodolac Lumiracoxib Valdecoxib Deracoxib Etoricoxib

NH2SO2

Figure 54-5  Classification and representative structures of the traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and coxibs. *Selected NSAID structure from each subclass. (Modified from Harris E, Budd R, Firestein G, et al [eds]: Kelley’s Textbook of Rheumatology, 7th ed. Philadelphia, WB Saunders, 2005.)

concentrations. NSAID clearance occurs via hepatic metabolism, and inactive metabolites are excreted in the bile and urine. Microsomal cytochrome P-450–containing, mixedfunction oxidases (e.g., CYP3A, CYP2C9) and other cytosolic hepatic enzymes mediate the metabolism of NSAIDs.

SALICYLATES Acetylated salicylate (e.g., ASA) is rapidly deacylated to salicylate (spontaneously and enzymatically); the nonac­ etylated salicylates (e.g., sodium salicylate, salicylsalicylic

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acid), weak COX inhibitors that are able to reduce inflammation, are excreted in the urine. Differences in formulation affect absorption rather than bioavailability; buffered ASA contains antacids that increase pH, whereas enteric coatings slow absorption. Salicylates primarily bind to albumin and rapidly diffuse into most body fluids. Salicylate serum levels usually do not correlate well with dosage, however, and small increases in dosage may result in disproportionate increases in serum levels. The drug clearance rate is a function of serum concentration. The primary factors regulating serum salicylate levels are urinary pH and metabolic enzyme activity. MOLECULAR BASIS OF PHARMACOLOGIC VARIABILITY Different patients can respond to the same NSAID in a variety of ways; the basis for this is unclear. Pharmacologic variables include plasma half-life, dose response, stereochemical (enantiomeric) conversion, excretion rates, and pharmacodynamic variability,95 including protein binding and metabolic profile. Certain propionic acid–derivative NSAIDs, such as ibuprofen, ketoprofen, and flurbiprofen, exist as mixtures of enantiomers (R, inactive, and S, active). Metabolism from the inactive to active form occurs in vivo, and the variability in conversion rates forms the basis of patient responsiveness to such drugs. Genetic differences in the ability of individuals or groups to metabolize drugs also can explain pharmacologic variability. As one might expect, pharmacokinetic variability can be affected by an individual’s general health, in particular, hepatic or renal disease, and old age.

PRIMARY THERAPEUTIC EFFECTS OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

prevent tophus formation in the absence of the usual clinical symptoms associated with acute gout. Colchicine also may be useful to treat acute pseudogout and crystal-induced arthritis. The maximal cumulative dose is 6 mg orally in patients with normal hepatic and renal function, and adverse gastrointestinal effects, such as nausea, vomiting, diarrhea, cramping, and pain, limit the dosage. The use of intrave­nous colchicine is generally avoided because of cardiac toxicity, especially in patients with compromised renal function. Daily colchicine (1.2 to 1.8 mg) is the primary treatment for familial Mediterranean fever by preventing acute attacks and amyloidosis.96 Daily colchicine also may reduce attacks in patients with tumor necrosis factor receptor–associated periodic syndromes. Colchicine has been used to treat periodic fevers such as hyperimmunoglobulinemia D and Muckle-Wells syndrome with mixed results.96 Colchicine also has been used empirically to treat Behçet’s disease, sarcoidosis, calcific tendinitis, amyloidosis, cutaneous necrotizing vasculitis, and Sweet’s syndrome.89 NONSTEROIDAL ANTI-INFLAMMATORY DRUGS BEFORE THE DISCOVERY OF CYCLOOXYGENASE-2 AND THE NEED FOR REDUCED GASTROINTESTINAL TOXICITY Before the discovery of COX-2, there was a clear need for the development of NSAIDs that were less damaging to the gastric mucosa. During the 1980s, three drugs—nimesulide, etodolac, and meloxicam—were developed that were effective anti-inflammatory agents that exhibited little, if any, effect on the production of PGs in the gastrointestinal tract. COX-isozyme selectivity tests of these drugs after the discovery of COX-2 showed them to be COX-2-selective inhibitors, allowing for the COX-1-mediated production of PGs in the gastric mucosa, reducing gastrointestinal toxicity.

ANTI-INFLAMMATION The inhibition of PG production is the primary mechanism of action of the NSAIDs. As a class, the ability of NSAIDs to inhibit PG synthesis makes them the drugs of choice for the treatment of diseases characterized by chronic inflammation and pain, such as osteoarthritis, RA, systemic lupus erythematosus, and other inflammatory syndromes (e.g., gout), all of which are characterized to some degree by the overproduction of PGs. The NSAIDs also are effective in the treatment of Reiter’s syndrome, psoriatic arthritis, acute and chronic bursitis, and tendinitis, which have a similar pathogenic relationship with PG levels. Although these drugs are effective in reducing the pain and inflammation associated with these diseases, their effects are only palliative. There is no evidence that these drugs exhibit any disease-modifying properties as judged by radiographic evidence. NSAIDs have been shown, in double-blind, randomized clinical trials, to be effective in the treatment of inflammatory arthritis using primary outcome measures, such as the American College of Rheumatology (ACR)-20, among others. In gouty arthritis, colchicine is the anti-inflammatory agent of choice to treat acute attacks. The prophylactic use of colchicine reduces the frequency and severity of attacks, but should be used only when hyperuricemia is controlled to

ACTIONS OF NIMESULIDE, ETODOLAC, AND MELOXICAM Nimesulide Early animal studies showed that at anti-inflammatory doses, nimesulide had no effect on gastric PG levels and did not cause bleeding of the gastric mucosa.97 In the human whole-blood assay,98 nimesulide was 20 times more potent in inhibiting COX-2 in monocytes than COX-1 in platelets (IC50 for COX-2 = 0.5 μM; IC50 for COX-1 = 9 μM). Comparing gastrointestinal damage with nimesulide or naproxen showed a highly significant difference in favor of nimesulide (P < .0001).99 Another factor contributing to the lack of gastrointestinal toxicity with nimesulide could be its short half-life (1.8 to 4.7 hours), which might allow PG levels in the gastric mucosa to return to normal levels before their protective effect has worn off. The therapeutic efficacy of nimesulide was shown in clinical trials for inflammation and pain including osteoarthritis,100 RA, musculoskeletal inflammation, headache, dysmenorrhea, postsurgical and cancer pain, vascular diseases, upper respiratory tract diseases, and airway inflammation.101 Of 200 million patients treated with nimesulide

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since 1985, only 1212 adverse events were reported through 1999.102 In March 2002, nimesulide was withdrawn from the Finnish market, however, because of hepatotoxicity, and in May 2002, it was withdrawn from the Spanish market over similar concerns.103 Perhaps this situation was a harbinger of things to come with respect to the safety of coxibs—greater gastrointestinal safety, but other potentially more serious adverse side effects. Etodolac Etodolac has been available for clinical use in Europe and North America for many years, and, similar to nimesulide, it exhibits anti-inflammatory effects without gastrointestinal damage.104 Etodolac had an 11-fold greater potency for inhibition of COX-2 than for COX-1 using purified enzymes and an 8-fold selectivity for COX-2 over COX-1 in the human whole-blood assay.105 In numerous randomized double-blind clinical trials, etodolac was as effective as naproxen, piroxicam, and diclofenac in osteoarthritis patients over 6 to 12 weeks. Longer term (3 years) etodolac treatment (300 mg/day or 1000 mg/day) was comparable to ibuprofen (2400 mg/day) in 1446 RA patients for effectiveness; the cumulative incidence of gastrointestinal bleeds or ulcers was 2 patients from each etodolac dosage group (0.43% and 0.67%) and 9 taking ibuprofen (4.74%).106 Safety data from the Arthritis, Rheumatism and Aging Medical Information System (ARAMIS) indicate that etodolac (on the basis of data for 88 patient-years) and nabumetone (based on data for 221 patient-years) are the only two established NSAIDs that are not associated with serious gastrointestinal bleeds or other significant events requiring hospitalizations. Meloxicam Meloxicam, another of the anti-inflammatory drugs with low gastrointestinal toxicity, was registered in 1995 and marketed in many countries for osteoarthritis, RA, and ankylosing spondylitis. Meloxicam has a 10-fold selectivity for COX-2 compared with COX-1 in the human whole-blood assay and 25-fold selectivity in the William Harvey wholeblood assay.80 It exhibited potent anti-inflammatory activity while sparing PGE2 production in the stomach and kidneys compared with standard NSAIDs. Clinical trials showed that meloxicam was as effective as diclofenac or piroxicam for patients with osteoarthritis and RA. A systematic review of published clinical trials covering all treatments showed significant reductions in risk of gastrointestinal adverse events by 36%, withdrawals because of gastrointestinal adverse events by 41%, and dyspepsia by 27% for meloxicam relative to comparator NSAIDs.107 NONSTEROIDAL ANTI-INFLAMMATORY DRUG DESIGN AFTER DISCOVERY OF CYCLOOXYGENASE-2 AND DEVELOPMENT OF HIGHLY SELECTIVE CYCLOOXYGENASE-2 INHIBITORS (COXIBS) After COX-2 was cloned, second-generation coxibs with much greater COX-2 selectivity were developed. The prevailing concept was that the more selective the drug could

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be for COX-2, the less adverse reactions resulting from the inhibition of COX-1 (as is the case with most of the nonselective NSAIDs). The two drugs to be marketed first in the United States were celecoxib and rofecoxib. Celecoxib Celecoxib was developed by Monsanto/Searle (St. Louis, Mo) after the cloning of COX-2 in 1991, specifically for its inhibitory activity against COX-2, when it became clear that inhibition of COX-1 resulted in removal of protective PGs and injury to the gastric mucosa. Celecoxib is 155-fold to 3200-fold selective for COX-2 depending on the assay system used.108 On the basis of extensive clinical trials, celecoxib was approved by the FDA in 1998 for osteoarthritis and RA, and in 2001 it was approved for acute pain. All doses of celecoxib tested (100 to 400 mg twice daily) were found to be equally effective as naproxen in reducing the symptoms of RA.109 The analgesic properties of celecoxib were confirmed in a double-blind study of postorthopaedic pain comparing 200 mg of celecoxib with 10 mg of hydrocodone/1000 mg of acetaminophen; both were effective analgesics, but fewer doses of celecoxib were required for pain relief.110 Gastrointestinal toxicity historically has been a major adverse effect linked with the use of nonselective NSAIDs. One of the primary motivations for the development of highly selective COX-2 inhibitors was to abrogate gastrointestinal toxicity, while retaining anti-inflammatory, analgesic, and antipyretic function. To put gastrointestinal toxicity in perspective, more than 100,000 patients in the United States have NSAID-induced upper ­gastrointestinal tract perforations, ulcerations, or bleeding each year, of which 16,500 die.111 Coxibs have been tested extensively to establish their enhanced gastrointestinal safety compared with nonselective NSAIDs. To accomplish this, doses twofold to fourfold higher than the maximal clinically effective doses for RA and osteoarthritis were tested. The incidence of upper gastrointestinal ulceration was assessed endoscopically after 24 weeks, and the higher does of celecoxib did not induce more ulcers than placebo.109 The Celecoxib Long-Term Arthritis Safety Study (CLASS) was a 6-month trial comparing the incidence of upper gastrointestinal ulcers in arthritis patients receiving celecoxib (400 mg twice daily), ibuprofen (800 mg three times daily), or diclofenac (75 mg twice daily); low-dose ASA therapy was allowed during the study.112 Upper gastrointestinal ulcer incidence alone or combined with symptoms comparing celecoxib with conventional NSAIDs was 0.76% or 1.45% (P = .092) for celecoxib and 2.08% or 3.54% (P = .023) for conventional NSAIDs. In patients taking ASA, the beneficial effects of celecoxib on gastrointestinal safety were reversed (2.01% versus 2.12% [P = .92] and 4.70% versus 6.00% [P = .49]). COX-2 also is constitutively expressed in certain tissues (e.g., brain, kidney, and endothelium), and its inhibition may underlie the adverse effects of long-term coxib use. When extended to 1 year, CLASS results showed that ulcer complications from celecoxib, with or without concomitant ASA, were the same as diclofenac. Patients taking cardioprotective doses of ASA and celecoxib developed more ulcer complications than patients taking ASA and ibuprofen (FDA celecoxib hearing, July 2, 2001). As expected,

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celecoxib did not affect platelet function113 and exhibited less renal toxicity114 and hepatic adverse events115 than conventional nonselective NSAIDs. Concerns that the inhibition of endothelial COX-2 potentially could upset the balance between the synthesis of prostacyclin (antithrombotic) and thromboxane A2 (prothrombotic) and could result in increased cardiovascular adverse events116 seemed to be allayed, at least temporarily, because the CLASS trial showed no increase in myocardial infarction with celecoxib than with conventional NSAIDs.112 Rofecoxib Rofecoxib was developed by Merck Frosst (Montreal, Quebec, Canada) in the early 1990s. It seemed to be more COX-2 selective than celecoxib (77-fold versus 8-fold preference for COX-2) in the human whole-blood assay. Similar to celecoxib, rofecoxib exhibited a better gastrointestinal safety profile than conventional NSAIDs in the Vioxx Outcomes Research Study (VIGOR)117 and was approved by the FDA in May 1999 for the treatment of acute and osteoarthritis pain. The incidence of myocardial infarction among subjects in the rofecoxib group was higher, however, than in the naproxen group (0.4% versus 0.1%; relative risk 0.2; 95% confidence limits 0.1 to 0.7), although mortality rates did not differ between groups. This finding raised the issue of possible adverse cardiovascular events resulting from the inhibition of endothelial COX-2 and prostacyclin production. Other nonclass properties of rofecoxib, including fluid retention and hypertension, may have contributed, however. Since the approval of rofecoxib in the United States in 1999, 83 million prescriptions have been written. In ­September 2004, rofecoxib was voluntarily withdrawn from the market, however, based on an increased risk of serious cardiovascular side effects observed in a long-term study, Adenomatous Polyp Prevention On Vioxx (APPROVe) trial, undertaken because ASA had been shown to protect against colorectal adenomas.118 As mentioned previously, the VIGOR study also indicated potential cardiovascular risk several years before the APPROVe trial. Results from the CLASS trial supporting gastrointestinal safety after 6 months of use of celecoxib were not supported by data obtained after 12 months of use. The CLASS trial was criticized for the manner in which these results were reported, further raising concerns over the safety of the COX-2 selective inhibitors.119 Perhaps the most important message that can be taken from the VIGOR, CLASS, and APPROVe trials is the issue of a potential adverse cardiovascular “class effect” that could be an inherent property of all coxibs.120 This is a very important point given the development of many “second-generation,” even more selective COX-2 inhibitors, such as valdecoxib, heir apparent to celecoxib, and etoricoxib (Arcoxia), the planned successor of the withdrawn rofecoxib. Much experimental work is required before the coxibs can regain their reputation as a major pharmacologic advance over the more conventional NSAIDs for the treatment of arthritis and pain. Greater selectivity may not translate into greater efficacy and safety when considering the important role of COX-2 in the maintenance of normal physiologic function.

ANALGESIA Generally, NSAIDs are more effective analgesics than antiinflammatory agents based on doses of drug required to relieve pain compared with the suppression of inflammation. As is the case with all NSAIDs, their analgesic effects are mediated via their ability to inhibit PG synthesis in the periphery and in the central nervous system. PGs do not induce pain per se, but synergistically enhance the pain produced by mediators, such as bradykinin or histamine.121 PGs are “hyperalgesic.” This effect is mediated by sensitizing peripheral chemical receptors on primary afferent nerve terminals. PGs released during inflammation or other trauma lower the activation threshold of tetrodotoxin-resistant sodium channels on sensory neurons.122 In the central nervous system, PGs also play an important role in neuronal sensitization, especially those produced by COX-2. COX-2 is constitutively expressed in the dorsal horn of the spinal cord, and its expression is increased during inflammation.123 The analgesic activity of coxibs can be directly correlated with a decrease in PG levels in the cerebrospinal fluid. Acetaminophen is analgesic, but not anti-inflammatory, suggesting its effects are restricted to the central nervous system. Evidence also suggests that acetaminophen (paracetamol) inhibits the activity of the COX variant, COX-3, in some animal models,84 and this may help explain why its analgesic activity is more central than peripheral. COX-1 plays a key role in nociception as shown by Ballou and colleagues,124 who showed that COX-1-null mice experienced less peripheral pain than COX-2-null or normal mice. ANTIPYRESIS Fever results from the production of PGs, primarily PGE2, from endothelial cells lining the blood vessels of the hypothalamus125 in response to inflammatory mediators, such as interleukin-1 (endogenous pyrogen) or LPS (exogenous pyrogen). COX-2 plays an important role in fever genesis. Li and coworkers126 showed that mice lacking functional COX-2 were unable to develop fever in response to many endogenous and exogenous pyrogens, although nonselective and COX-2-selective NSAIDs seem to exhibit equally potent antipyretic activity. The NSAIDs and acetaminophen suppress fever by virtue of their ability to inhibit PG production, most likely in the thermoregulatory center of the preoptic area of the anterior hypothalamus. Although COX-2 is primarily involved in the fever response to LPS, other components of the febrile response depend on COX1.127 One caveat is that ASA should not be given in fever related to viral infections especially in children, owing to the increased potential for the development of Reye’s ­syndrome.128

OTHER PHYSIOLOGIC EFFECTS OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS: BALANCING THERAPEUTIC AND ADVERSE EFFECTS NSAIDs exhibit many shared toxicities (Table 54-2). Although the frequency of certain side effects varies with the type of drug, particular attention should be paid to the

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Table 54-2  Shared Toxicities of Nonsteroidal   Anti-inflammatory Drugs (NSAIDs) and Coxibs Organ System

Toxicity

Gastrointestinal

Dyspepsia Gastroduodenal ulcers* Ulcer complications (bleeding, perforation, obstruction)* Gastrointestinal bleeding   (upper and lower)* Exacerbates colitis

Renal

Sodium retention Weight gain and edema Hypertension Type IV renal tubular acidosis and hyperkalemia Acute renal failure Papillary necrosis Acute interstitial nephritis Accelerated chronic renal failures

Hepatic

Elevated transaminases Reye’s syndrome

Asthma/allergic

Exacerbates ASA-exacerbated respiratory disease*

Cutaneous

Hypersensitivity dermatitis Stevens-Johnson syndrome Toxic epidermal necrolysis

Hematologic Nervous

Cytopenias Dizziness, confusion, drowsiness Seizures Aseptic meningitis

Cardiovascular

Hypertension Thrombosis Myocardial infarction

Skeletal

Reduced fracture healing*

Reproductive

Infertility†

*Reduced with cyclooxygenase-2-specific NSAIDs. †Speculative. ASA, acetylsalicylic acid.

toxicities inherent to organ systems, including the gastrointestinal tract, kidney, liver, and cardiovascular system. GASTROINTESTINAL TRACT PGs are synthesized in virtually all regions of the gastrointestinal tract. One of their most important functions is to “protect” against gastric damage from internal and external stimuli. In this context, gastrointestinal complications are one of the primary adverse side effects of NSAID therapy, and the mechanisms by which NSAIDs induce such effects are significant. PG-mediated protection of the gastrointestinal system is complex and involves many factors. First, PGE2 and PGI2 reduce gastric acid secretion in the stomach. Second, PGE2 and PGI2 act as vasodilators that function to maintain the overall health of gastrointestinal tissues. Third, PGE2 stimulates the release of viscous mucus that functions as a defensive barrier against mucosal damage by gastric acid; PGE2 also stimulates bicarbonate secretion to neutralize gastric acid. Paradoxically, animals lacking functional COX-1 did not develop spontaneous stomach ulcers129 as one might expect. Possible explanations are that other PGindependent protective pathways are invoked in the gastrointestinal tract in the complete absence of COX-1, or that

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Table 54-3  Risk Factors Associated with Increased   Incidence of Nonsteroidal Anti-inflammatory Drug (NSAID)–Related Gastrointestinal Adverse Events Advanced age (substantial risk >65 years old) History of peptic ulcer or ulcer complications, with or without prior NSAID use Prolonged use of maximal dose nonselective NSAIDs, including ASA Concomitant use of steroids and anticoagulants Significant comorbidity (e.g., cardiovascular, renal, or hepatic   disease; diabetes; hypertension) Probable risk factors—cigarette smoking, alcohol consumption, Helicobacter pylori infection ASA, acetylsalicylic acid. Adapted from Osteoarthritis and Rheumatoid Arthritis—COX II Inhibitors: Guidance. London, National Institute for Health and Clinical Excellence, 2005; and Wolfe MM, Lichtenstein DR, Singh G: Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 340:1888-1899, 1999.

COX-1 and COX-2 are involved in mucosal defense, as was later suggested by evidence from the same group.130 The gastrointestinal adverse effects of NSAIDs are well documented and common. Because of the sheer number of individuals taking NSAIDs, particularly the elderly, who are more at risk of toxicity, the gastrointestinal side effects are of particular importance from a public health perspective. Annual costs associated with these complications were conservatively estimated in 1999 to exceed $2 billion.131 Because the inhibition of PGs occurs throughout the gastrointestinal tract, upper and lower gastrointestinal adverse effects are possible, regardless of drug and route of administration. It is recognized that annually 1% to 4% of individuals taking NSAIDs develop serious gastrointestinal complications, including bleeding, perforation, and obstruction.112,117 The risk of serious gastrointestinal complications is threefold to fivefold greater in NSAID users versus nonusers.132 These complications include predominantly upper gastrointestinal events, but lower gastrointestinal morbidity may account for 20% of all cases.133 Asymptomatic but endoscopically detectable gastric or duodenal ulcers can be found in 30% of long-term NSAID users.117 It is estimated that more than 100,000 people are hospitalized for upper gastrointestinal events associated with NSAID use, and that 7500 to 16,500 die.131,134 All classes of NSAIDs, including nonselective NSAIDs, COX-2 inhibitors, and ASA, have a linear, dose-response relationship with respect to gastrointestinal ­toxicity.134 Dyspepsia not associated with mucosal ulceration is the most common adverse event associated with the use of traditional NSAIDs and coxibs. At least 10% to 20% of patients taking these drugs report dyspepsia. There is a poor correlation between the development of dyspepsia and more serious gastrointestinal complications; most serious gastrointestinal events are not preceded by symptoms.111,135 Knowledge of a patient’s risks of therapy is crucial in clinical management because the incidence of NSAIDrelated gastrointestinal adverse effects increases with several known risk factors (Table 54-3), including older age (risks increase approximately 4% per year136), prolonged NSAID use, previous ulcer history (relative risk 13.5137), the presence of comorbidities, and use of medications that increased

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gastrointestinal bleeding risk.138,139 Patients who have one or more of these risk factors should be considered at higher risk for NSAID-related gastrointestinal adverse effects, and appropriate gastrointestinal protective measures should be undertaken. The possibility of exacerbating diseases such as ulcerative colitis and Crohn’s disease with NSAID use also must be considered. The need to reduce NSAID-related gastrointestinal events motivated the development of selective COX-2 inhibitors. These agents were proven to have similar analgesic efficacy for arthritis pain as traditional NSAIDs, but were associated with significantly reduced serious gastrointestinal complications. These agents, in addition to the campaign to eradicate Helicobacter pylori and perhaps the widespread use of proton-pump inhibitors, are thought to be responsible for a substantial decrease in hospitalizations for gastrointestinal complications since 1994.140,141 The VIGOR trial117 involving 8076 participants confirmed a decreased risk of developing upper gastrointestinal complications with the use of rofecoxib at a dose of 50 mg/ day (higher than the dose eventually approved—25 mg/ day—for the treatment of osteoarthritis and RA) compared with a dose of naproxen of 500 mg twice daily. The risk of developing confirmed, complicated upper gastrointestinal events, such as perforation, obstruction, or severe upper gastrointestinal bleeding, was 0.4 for rofecoxib compared with naproxen. A significant reduction in all confirmed gastrointestinal events (also including symptomatic ulcers) was found, with a relative risk of 0.5 for rofecoxib versus naproxen. In VIGOR, patients taking low-dose ASA for cardioprotection were excluded. In the CLASS trial of 8059 subjects,112 the primary end point was the incidence of symptomatic gastrointestinal ulcers using supratherapeutic doses of celecoxib (400 mg twice daily) versus ibuprofen, 800 mg three times daily, or diclofenac, 75 mg twice daily. The secondary end point was the incidence of ulcer complications of perforation, obstruction, or severe bleeding. For the primary end point of sympto­ matic ulcers, the relative risk for all patients with celecoxib was 0.53 compared with NSAID users. For the second end point of symptomatic gastrointestinal ulcers plus gastrointestinal complications, the relative risk was 0.59. Users of low-dose ASA were included in the CLASS trial (21% of patients took 75 to 325 mg/day), and analysis of subjects taking concomitant low-dose ASA showed no significant difference between the celecoxib arm and the NSAID arm in the incidence of symptomatic ulcers and complicated ulcers (2.01% versus 2.12% for symptomatic ulcers and 4.70% versus 6.00% for complicated ulcers). Patients ­taking ­celecoxib also had an overall lower incidence of endoscopically detectable gastroduodenal ulcers, gastrointestinal bleeding, blood loss, and gastrointestinal-related drug withdrawal compared with users of traditional NSAIDs in a more recent syste­ matic review142 and meta-analysis.135 Valdecoxib was associated with fewer gastrointestinal complications compared with traditional NSAIDs, as shown in a systematic review of randomized trials comparing valdecoxib with placebo or NSAIDs.143 A similar finding was described with etoricoxib in a randomized trial,144 suggesting that the use of a COX-2 selective inhibitor decreases (but does not eliminate) the risk of upper gastrointestinal complications compared with traditional NSAIDs.

As suggested in the CLASS trial data, however, the use of concomitant low-dose ASA may negate the benefit of lower gastrointestinal complications seen with the coxibs. It seems that there is no safe dose of ASA because even cardioprotective doses (≤325 mg/day) have been associated with an increased rate (7.3%) of endoscopically detectable ulcers with 3 months’ use.145 This number increased to nearly half of all users when low-dose ASA was used for more than 3 months.146 When ASA and NSAIDs are used together, the risk of gastrointestinal bleeding increases more than 10-fold compared with either agent alone.147 Other measures to reduce the risk of gastrointestinal complications arising from NSAID therapy are discussed later in the section on selecting NSAID therapy. CARDIOVASCULAR SYSTEM: RISKS OF COXIBS AND TRADITIONAL NONSTEROIDAL ANTI-INFLAMMATORY DRUGS An accumulation of evidence in the years immediately preceding the market withdrawal of the COX-2 inhibitor rofecoxib in September 2004 has been retraced by Hawkey and Fortun.148 Since then, a growing body of evidence has implicated not only the entire COX-2 class of drugs, but also the traditional NSAIDs as bearing an increased risk of cardiovascular complications. The seminal VIGOR trial117 showed that rofecoxib, 50 mg daily, was associated with fewer gastrointestinal complications compared with naproxen, 500 mg twice daily, in patients with RA. In this study, patients were not permitted to take cardioprotective doses of ASA (81 to 325 mg), even though about half of the patients had some form of cardiovascular disease and were candidates for ASA use. Patients who had cardiovascular events such as myocardial infarction or coronary bypass surgery in the year preceding the study, stroke in the past 2 years, and morbid obesity were excluded. In addition to the observed gastrointestinal benefit of rofecoxib in this study, it was noted that fewer patients in the naproxen group had a nonlethal myocardial infarction during the trial than patients in the rofecoxib arm, with a relative risk for naproxen versus rofecoxib of 0.2. This finding may have been due to the fact that low-dose ASA was not permitted, removing a protective effect in patients at risk. Investigators theorized that naproxen might have had a cardioprotective role, a finding not supported by subsequent studies.149-151 The relative risk associated with rofecoxib treatment was 2.38 for serious cardiovascular adverse events, including myocardial infarction, venous thromboembolism, and cerebrovascular accident (2.5% for patients receiving rofecoxib, 1.1% for patients receiving naproxen). For patients in whom cardioprotective ASA was indicated, the relative risk of developing a serious cardiovascular event while taking rofecoxib compared with naproxen was 4.89; for patients who did not require ASA, the relative risk was 1.89. This study represented an early signal of the potential cardiovascular toxicity of rofecoxib, a matter that received subsequent study and debate in the literature.82,152-155 It also prompted consideration that the entire coxib class of drugs possessed this potential adverse effect. The withdrawal of rofecoxib from the market was prompted further by the finding from a clinical trial designed

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to assess the effect of rofecoxib for the prevention of recurrent adenomatous colonic polyps over 3 years.156 The APPROVe study found an increased absolute risk of 1.6% for cardiovascular events in subjects receiving rofecoxib, 25 mg/day, versus placebo. Events included cardiovascular death, myocardial infarction, stroke, heart failure, coronary revascularization, and venous thromboembolism. Patients were excluded if they would require long-term NSAID therapy during the trial, as were patients who had uncontrolled hypertension, angina, unstable angina, or congestive heart failure. The study was terminated prematurely because of a significant difference in the incidence of cardiovascular events among patients receiving rofecoxib. The absolute risk of cardiovascular events was 3.5% for patients taking rofecoxib and 1.9% for patients taking placebo, ­corresponding to an approximately twofold increase in relative risk.157 These data caused the FDA to recommend withdrawing rofecoxib from the market. In addition, the Advisory Committee mandated labeling changes for COX-2 inhibitors and traditional NSAIDs to include potential cardiovascular risk.158 Although the cardiovascular data from CLASS112 showed a favorable effect of celecoxib in terms of gastrointestinal complications, the cardiovascular data showed no difference in events among patients treated with high-dose celecoxib versus the traditional NSAIDs, whether or not patients were taking concomitant cardioprotective doses of ASA. Approximately 40% of the patients in this study had a history of cardiovascular disease or its risk factors, and 21% were taking low-dose ASA; these were included in the study population. The rate of serious thromboembolic adverse events for the celecoxib and comparison NSAID groups was slightly increased, but not statistically significant.112 The Adenoma Prevention with Celecoxib (APC) trial showed that high-dose celecoxib use (400 mg twice daily) was associated with an increase in cardiac events; the risk was not significantly elevated at usual therapeutic doses.159 The COX-2 selective inhibitor valdecoxib was associated with increased risk of myocardial infarction in subjects having recent cardiovascular surgery.160,161 A study of a population similar to the VIGOR and CLASS populations showed that the incidence of cardiovascular events with valdecoxib use was not significantly increased versus comparator groups using traditional NSAIDs.155,162 Nonetheless, valdecoxib was voluntarily withdrawn from the market in 2005 because of an absence of conclusive data to confirm definite cardiovascular safety, in addition to the fact that rare yet severe adverse skin reactions such as Stevens-Johnson syndrome were being observed with this drug more frequently than with other NSAIDs or coxibs.158 Studies examining the gastrointestinal safety of the new COX-2 inhibitor lumiracoxib (Prexige) have not shown an excess of cardiovascular adverse effects, although it is argued that the TARGET trial163,164 with 18,500 subjects enrolled is still too small to detect an effect with adequate statistical power. No interference of lumiracoxib on the COX-1-­mediated antiplatelet effect has been observed.165 Etoricoxib is currently undergoing extensive evaluation in three large multinational trials of 40,000 patient-years of observation specifically designed to “provide a precise estimate of the relative cardiovascular event rates with

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e­ toricoxib ­ compared to the traditional NSAID diclofenac in patients with ­osteoarthritis and RA.”166 Population-based epidemiologic studies also have shed light on the potential for cardiovascular risk with coxibs and the nonselective NSAIDs. Because the older NSAIDs were not subjected to randomized trials examining cardiovascular effects specifically, much of the data for cardiotoxicity are derived from studies of observational design. A study using the Medicare databases in Pennsylvania and New Jersey of 54,475 patients 65 years old and older showed that celecoxib was not associated with an elevated risk of acute myocardial infarction compared with non-NSAID use, naproxen, ibuprofen, or other NSAIDs. Rofecoxib was associated with increased relative risk of acute myocardial infarction compared with celecoxib or no NSAID use. The magnitude of relative risk was higher at doses greater than 25 mg/day, with adjusted odds ratios for acute myocardial infarction with rofecoxib compared with celecoxib or other NSAIDs of 1.14 to 1.24.167 Time relationships between the administration of rofecoxib or celecoxib and acute myocardial infarction were studied, and it was concluded that rofecoxib used for the first 30 days elevated the odds ratio for such events to 1.43, and that this elevation persisted through 90 days of observation.168 The risk returned to normal, however, after 90 days of treatment. Rofecoxib also was found to have an elevated risk of cardiovascular events in a large study examining 1.4 million patients in the Kaiser-Permanente health care system.169 This nested case-control study of 40,405 patients showed that an increased risk of acute myocardial infarction existed with treatment with rofecoxib versus celecoxib or remote NSAID use, and that the risk was greatest at doses of greater than 25 mg/day (adjusted odds ratio 3.58, P < .02). Also, traditional NSAID users exhibited a small but statistically significant increased risk of myocardial infarction compared with control groups (nonuse or remote NSAID use). A study from the United Kingdom in June 2005 evaluated the risk of myocardial infarction in patients taking either coxibs or traditional NSAIDs.149 Of the 9218 cases identified, it was found that a significantly increased risk from myocardial infarction existed with the current use of rofecoxib, in addition to diclofenac, ibuprofen, and naproxen. Although the investigators did not report dose information, this study lent support to the idea that traditional NSAIDs also were associated with increased cardiovascular risk compared with nonusers. In one study examining patients 65 years old and older, the number needed to harm (i.e., the number of patients to whom the treatment must be given to produce harm in one patient) for acute myocardial infarction with ibuprofen was 1005.167 A Canadian population-based study of more than 30,000 patients using administrative data examined the safety of NSAIDs in a cohort of patients 66 years old and older who were newly treated with celecoxib, rofecoxib, naproxen, and other traditional NSAIDs, compared with a randomly selected control cohort not exposed to NSAIDs (100,000 patients).170 No short-term risk of acute myocardial infarction was seen in new users of any of the drugs. Drug doses were not reported, and higher than usual doses of drugs such as rofecoxib were not analyzed separately. Synthetic research studies, such as systematic reviews and meta-analyses, also have shown the potential ­cardiovascular

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risk of coxibs and traditional NSAIDs. A meta-analysis by Singh and associates,171 examining studies containing data from population databases, showed that nonselective NSAIDs as a class were associated with an overall increased risk of acute myocardial infarction of 1.19. This association was especially evident with diclofenac and ibuprofen, with risks of 1.38 and 1.11. The effect was not observed with naproxen, however. The risk of diclofenac in particular also was elevated in several of the large trials involving coxibs.172 Celecoxib had shown at most small, statistically nonsignificant increases in cardiovascular adverse effects in several clinical trials. A systematic review and meta-analysis of randomized double-blind clinical trials of celecoxib of at least 6 weeks’ duration173 found that the odds ratio of myocardial infarction with celecoxib compared with placebo was increased to 2.26. In a secondary meta-analysis of six studies involving 12,780 patients, a similar finding of increased risk for celecoxib and myocardial infarction (odds ratio 1.88) was present.173 Edwards and colleagues162 also showed that the efficacy and safety of valdecoxib were not excessive in terms of cardiovascular disease; however, the results were not definitive given the relatively small numbers of studies and patients enrolled in them. No recent studies—primary clinical trials, observational studies, systematic reviews, or meta-analyses—have shown a decreased risk of cardiovascular events with the use of coxibs or traditional NSAIDs compared with nonusers. FitzGerald and others61,174,175 have taken the lead with respect to determining the molecular mechanisms by which the inhibition of COX-2 could increase the incidence of myocardial infarction and stroke. In retrospect, it should have been no surprise to find that COX-2 selective inhibitors had cardiovascular effects given the fact that vascular tissues produce, secrete, and respond to a variety of PGs. Perhaps most importantly, endothelial cell COX-2 produces significant levels of PGI2 that bind to prostacyclin receptors on vascular smooth muscle cells, which functions to block vessel contraction.176 At the same time, PGI2 blocks platelet aggregation and thrombosis, making PGI2 a central player regulating antithrombotic activity. PGE2 also functions as a potent vasodilator, increasing blood flow ­ especially in inflamed tissues, leading to edema. Platelets express COX-1 only, the major function of which is to mediate the formation of thromboxane A2, an extremely potent inducer of platelet aggregation and vasoconstriction. In the 1970s, Moncada and coworkers177 suggested that PGI2 and thromboxane A2 were likely to be the opposing forces of a homeostatic mechanism for cardiovascular homeostasis in vivo. Vascular smooth muscle cells and endothelial cells express COX-1 and COX-2,178 and COX-2 expression seems to increase in response to stress. COX-1 is more highly expressed in normal vascular tissues, whereas COX-2 is more highly expressed during periods of vascular tissue activation and proliferation, in atherosclerotic lesions, and in inflammation. Vessel tone and thrombosis are largely regulated by interactions between PGI2 and thromboxane A2. ASA rapidly inhibits platelet COX-1 and endothelial cell COX-1, but platelets are unable to resynthesize the enzyme, whereas endothelial cells do have the capacity to synthesize rapidly (about 6 hours) COX-1 de novo. Vascular cells recover their

ability to produce PGI2 much more effectively than platelets resume the production of thromboxane A2, explaining the success of ASA for use as an antithrombotic agent. Nonselective NSAIDs also inhibit platelet COX-1 to varying degrees, but in contrast to ASA, the inhibition is ­reversible. Low-dose (81 mg) ASA can affect platelet aggregation for 4 to 6 days and is indicated for secondary prevention of cardiovascular disease, but its value in preventing cardiovascular disease in patients previously without such disease is less clear. It is suggested, however, that patients with increased risk for coronary artery disease are likely to obtain more benefit than harm from low-dose ASA.179 Although nonselective NSAIDs other than ASA do inhibit platelet COX-1, it is unclear whether they are effective in reducing the risk for adverse cardiovascular events. Some NSAIDs, such as ibuprofen, may interfere with the protective effects of ASA.180 Hypertension caused by NSAIDs and coxibs also may be an important mechanism contributing to the cardiovascular toxicity of these agents.181 Supine blood pressure was seen to increase by an average of 5 mm Hg in patients receiving NSAIDs, according to one meta-analysis.182 Coxibs were associated with a 2% rate of hypertension and peripheral edema in the CLASS trial.112 Hypertension induced by COX-2 agents, in particular rofecoxib, also was seen in prospective studies of ambulatory blood pressure ­monitoring.183 Cardiovascular Benefits of Aspirin Based on accumulated data showing its benefits, the FDA has approved ASA for use in the secondary prevention of cardiovascular disease in patients with suspected myocardial infarction and in patients with known coronary artery disease. Major trials have shown that meaningful decreases in nonfatal myocardial infarction, nonfatal stroke, and death all can be realized by daily administration of ASA of 75 to 325 mg. Major vascular events can be reduced by 10 to 20 events for every 1000 patients treated, at a cost of one to two major gastrointestinal bleeds.184 Similar effects have been observed with other antiplatelet therapies, such as ticlopidine and ­clopidogrel.185,186 There was no benefit in rates of myocardial infarction observed with the use of ASA, 100 mg every other day, in the Nurses Health Study of primary prevention of major vascular events, and rates of gastrointestinal bleeding were increased. Stroke rates were significantly reduced on this regimen, however.187 Results from a meta-analysis suggest that the use of low-dose ASA is beneficial as primary prevention only if the patient’s annual coronary risk is 1.5% or more.188 Aspirin in Combination with Nonsteroidal Anti-inflammatory Drugs and Coxibs Because of the potential of cardiovascular toxicity related to NSAID and coxib use, the concomitant use of low-dose ASA has been considered in patients at high cardiac risk. These combinations have not been studied in randomized trials, but available data from subgroup analyses and metaanalyses suggest that gastrointestinal complications increase

PART 8 

for NSAIDs and COX-2 selective agents with ASA, and that the protective effect of the coxibs may be attenuated by ASA. In the CLASS trial, gastrointestinal complications were not reduced in patients taking celecoxib with concomitant low-dose ASA,112 although the incidence of endoscopic ulcers was substantially less in patients taking celecoxib with ASA than in patients taking traditional NSAIDs plus ASA, according to two meta-analyses.135,189 Nonetheless, ASA use with NSAIDs and coxibs increased the rate of gastrointestinal events twofold to fivefold.189 The presence of an NSAID (ibuprofen has been specifically studied) may reduce the antiplatelet effect of ASA, leading to an increased risk of cardiovascular events.180,190 Closure of the Ductus Arteriosus The maintenance of an open ductus arteriosus and its closure during the postnatal period are regulated by PG levels.191,192 This point is emphasized by the fact that indomethacin is used clinically to induce closure of the ductus, and that COX-1 and COX-2–null mice die from neonatal circulatory failure because the ductus arteriosus remains open. PG receptor (EP4)–null mice experience the same fate, further supporting a role for PGs in this process. It is inadvisable for pregnant women to take ASA, NSAIDs, or coxibs during the last trimester of pregnancy because of the risk of a persistently patent ductus arteriosus and to minimize the risk of peripartum hemorrhage. RENAL SYSTEM PGs responsible for the regulation of vasodilation are crucial for the maintenance of kidney function in animal models of disease and in patients with heart failure, liver cirrhosis, or renal insufficiency. Such patients taking NSAIDs that reduce PG production are at risk of renal ischemia.67 Catella-Lawson and coworkers114 compared the effects of a nonselective NSAID (indomethacin) with a coxib (rofecoxib) on renal function in healthy older adults over a 2-week period. Initially, both drugs induced a transient decrease in urinary sodium excretion, but the glomerular filtration rate was decreased only by indomethacin, and not rofecoxib, suggesting that glomerular filtration rate suppression is a function of COX-1, whereas acute sodium retention is mediated by COX-2. Mice deficient in COX-2 exhibited disrupted kidney development leading to early death and seemed to have resided primarily with aberrant renal cortical development; this developmental abnormality also could be produced by coxibs when given to pregnant females and to pups until weaning.193 This phenomenon seems to be strain-specific, however, owing to the effects of modifier genes on COX-2 and the regulation of kidney development.194 PGs increase sodium resorption via their ability to inhibit active transport of sodium in the thick ascending limb and the collecting duct, and to increase renal water excretion by blunting the actions of vasopressin.195 Sodium retention occurs in 25% of NSAID-treated patients and may be particularly apparent in patients who have preexisting avidity for sodium, such as patients with mild heart failure or liver disease.196 PGs stimulate renin release, which increases secretion of aldosterone, subsequently causing sodium retention and potassium secretion by the distal nephron. NSAID-treated

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patients may develop hyporeninemic hypoaldosteronism that manifests as a type IV renal tubular acidosis and hyperkalemia. The degree of hyperkalemia is generally mild; however, patients with renal insufficiency or patients who may otherwise be prone to hyperkalemia, such as patients with diabetes mellitus and patients receiving angiotensin-converting enzyme inhibitors or potassium-sparing diuretics, may be at greater risk.197 In addition, COX-2 inhibition may be a predisposing factor for papillary necrosis, likely secondary to a marked reduction in medullary blood flow resulting from apoptosis of medullary interstitial cells.198 Acute interstitial nephritis and hypersensitivity phenomena, such as fever, rash, and eosinophilia, have been described with most traditional NSAIDs.199 Decreased sodium excretion may lead to weight gain and peripheral edema. This effect may be sufficiently important to cause clinically important exacerbations of congestive heart failure. In addition to sodium retention, NSAIDs and coxibs affect blood pressure. In a large (n = 51,630) prospective cohort of women 44 to 69 years old without hypertension in 1990, incident hypertension over the following 8 years was significantly more likely in frequent users of ASA, acetaminophen, and NSAIDs.200 NSAIDs can attenuate the effects of antihypertensive agents, including diuretics, angiotensin-converting enzyme inhibitors, and β-blockers, interfering with blood pressure control. In a case-control, population-based study of 17,844 patients with no history of hypertension, it was found that 3915 patients were diagnosed with hypertension. Patients taking rofecoxib had a significantly increased risk of developing hypertension compared with controls and with patients taking traditional NSAIDs or celecoxib.201 The Successive Celecoxib Efficacy and Safety Study trials (SUCCESS VI and VII) were conducted in patients with known osteoarthritis requiring anti-inflammatory therapy and who were receiving stable treatment for hypertension.202,203 Among the approximately 2000 patients enrolled, clinically meaningful systolic blood pressure elevations were observed in 17% of patients treated with rofecoxib, 25 mg/day, and in 11% of patients treated with celecoxib, 200 mg once daily (P = .03). CENTRAL NERVOUS SYSTEM Elderly patients taking NSAIDs may be particularly susceptible to developing cognitive dysfunction and other central nervous system effects, including severe headaches, dizziness, confusion, depression, hallucinations, and seizures. Recurrent aseptic meningitis also has been described, but is not related to hypersensitivity. More recent evidence is pointing away from an antigen-specific immune response.204 One study reports recurring aseptic meningitis in a patient exposed to three different NSAIDs including rofecoxib.205 Acute aseptic meningitis has been reported in patients with various connective tissue diseases treated with a variety of NSAIDs, including ibuprofen, sulindac, tolmetin, and naproxen. Alzheimer’s Disease Although prospective trials of NSAIDs in Alzheimer’s disease have been disappointing, epidemiologic data suggest that such drugs could play a role in reducing the risk of developing Alzheimer’s disease.206 Most of the ­epidemiologic data come

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from studies of arthritis patients who often take NSAIDs for long periods to control their symptoms. This population could in large part explain the disappointing results from clinical trials. In most cases, arthritis patients likely would start taking NSAIDs before any clinical manifestations of Alzheimer’s disease are evident, whereas therapeutic studies are focused on patients already showing clinical signs of the disease. The possibility exists that NSAIDs may be more effective when given before the clinical onset of disease.207 There is a significant inflammatory component associated with Alzheimer’s disease and the deposition of amyloid fibrillar sheets.208 This association is evident by the presence of high levels of inflammatory mediators in senile plaques of Alzheimer’s disease brains and elevated COX-2 expression in Alzheimer’s disease cortex. The role of COX-2 in neuron function is poorly understood, and the physiologic ramifications of its inhibition are unclear. The primary question is whether COX-2 is protective209 or induces210 apoptosis after neuronal damage. In animal studies, using the Tg2576 mouse that exhibits an Alzheimer’s disease–like syndrome, ibuprofen decreases not only PG production, but also inflammatory cytokine levels, amyloid plaque deposition, and dystrophic neuritis.211 With respect to COX selectivity and Alzheimer’s disease, the nonselective or COX-1-selective NSAIDs, particularly ASA, have been shown to slow the cognitive decline in Alzheimer’s disease patients. Some evidence points to the importance of COX-2 in Alzheimer’s disease. COX-2 is elevated in other neurodegenerative diseases, such as amyotrophic lateral sclerosis. In mice, COX-2 deletion reduces ischemic brain injury, whereas COX-2 overexpression increases amyloid-induced neuron injury.212 The precise roles of COX-1 and COX-2 in Alzheimer’s disease must be clearly established before the mechanisms of action of NSAIDs in slowing the development of Alzheimer’s disease can be determined, although most data seem to suggest that low-dose, nonselective NSAIDs are effective. ASA seems to exhibit protective effects in Alzheimer’s disease, but some data suggest that competitive COX inhibitors may be more effective. The precise types of brain cells that express COX-1, COX-2, or both and are affected by NSAID treatment also must be identified. Given the protective effects seen with ASA, an alternative mechanism for NSAIDs in Alzheimer’s disease could be mediated via ASA effects on the cardiovascular system (e.g., platelets and endothelial cells). BONE PGs produced by osteoblasts are directly involved in bone turnover. PGE2 is a potent stimulator of bone resorption and osteoclastogenesis. In vitro, deletion of the COX-2 gene or the use of coxibs partially blocked formation of osteoclasts induced by parathyroid hormone or 1,25-hydroxyvitamin D. This blockage may be related to reduction of receptor activator NFкB and bone marrow stromal cells when COX-2 is inhibited. In vivo, the skeletal development of mice that lack functional COX-2 gene expression also is inhibited.213 Under experimental conditions, NSAIDs can inhibit fracture healing and the production of heterotopic bone.214 This effect is largely mediated through inhibition of COX-2 because it is crucial for lamellar bone formation elicited by

mechanical strain.215 In animal models, coxibs can impair fracture healing.216 It is prudent to avoid use of traditional NSAIDs and COX-2-specific inhibitors during periods of bone healing. Studies generally have failed to show a significant effect of either COX-1 or COX-2 inhibition on bone mineral density in humans. In one study examining 2853 adults with a mean age of 74 years, it was found that bone mineral density was higher at the total body and total hip in current users of COX-2-selective NSAIDs and ASA. These data suggest that the combination of COX-2-selective NSAIDs and ASA is associated with higher bone mineral density at multiple skeletal sites in men and women.217 The Rancho Bernardo study showed that bone mineral density was ­significantly higher in users of propionic acid NSAIDs, but not in users of acetic acid NSAIDs.218 Levels of bone turnover markers such as N-telopeptide were not reduced by the use of regular NSAIDs or ASA in another prospective study.219 In a COX-1-deficient or COX-2-deficient mouse model, bone mineral density was significantly reduced, however, in COX-2-deficient mice compared with either normal or COX-1-deficient mice.213 HEPATIC SYSTEM Serum alanine aminotransferase and aspartate aminotransferase should be periodically monitored in individuals taking NSAIDs and coxibs. Fifteen percent of patients have elevations of one or both of the liver enzymes three times more than the upper limit of normal. Patients are usually asymptomatic, and discontinuation or dosage reduction usually results in normalization of laboratory values. Although rare, fatal hepatic side effects have been reported with almost all NSAIDs. The most likely to be associated with severe liver adverse effects are sulindac and diclofenac. IMMUNE SYSTEM Virtually all cell types composing the immune system produce and respond to PGs. PGs are typically immunosuppressive, and treatment with NSAIDs would reverse their immunosuppressant effects. Removal of immunosuppression may be one of the factors responsible for the cancer-inhibiting action of the NSAIDs. Also, suppression of the immune response by PGs may enhance the cartilage breakdown often observed with NSAID treatment.220 Myers and colleagues221 showed in a mouse model of arthritis that mice lacking COX-2 gene expression were unable to produce sufficient antibodies to type II collagen to develop arthritis, implicating COX-2 as a regulator of B cell function. More recently, Ryan and associates222 confirmed this observation by showing that human peripheral blood lymphocytes express inducible COX-2, and that inhibition of this enzyme abrogates the ability of these cells to produce antibodies. The regulatory effects of COX-2 on B cell function potentially could have wide-ranging implications for new therapeutic interventions in the treatment of rheumatic diseases given more recent successes with treatments targeting B cells in RA and other autoimmune diseases (e.g., rituximab). T cells express COX-2, which may play a role in the differentiation of T regulatory cells by modulating the expression of FOXP3.223

PART 8 

Cancer Chemoprevention Large-scale epidemiologic studies have long indicated that long-term NSAID use reduces the incidence of a variety of cancers, including colon, intestinal, gastric, breast, and bladder, 40% to 50%.224 Given the ability of the NSAIDs to inhibit COX and PG production, the COX pathway immediately becomes implicated as playing an important role in the pathogenic process. It is well recognized that growth factors, tumor promoters, and oncogenes stimulate PG production via the induction of COX-2,225 and that human tumorigenic tissues exhibit increased COX activity compared with their normal, nontumorigenic counterparts. Such tumor-derived PGs are likely involved in a network of complex regulatory functions, including angiogenesis, tumor proliferation, immunosuppression, and apoptosis. Most cancers express COX-1 and COX-2. Evidence implicates both isozymes in the chemopreventive roles of NSAIDs. In general, COX-2 is overexpressed in 80% of colorectal cancer tissues.226 ASA, a preferential COX-1 inhibitor, has been shown in three randomized placebocontrolled trials to be “moderately effective” in preventing sporadic colorectal adenomas in patients with a history of these tumors.118,227,228 COX-2-selective drugs also have been shown to reduce adenoma incidence and to mediate tumor regression in patients with familial polyposis.229,230 Duodenal adenomas, which are otherwise untreatable, show some reduction by treatment with celecoxib.230 With the development of coxibs came many studies with respect to their effects on carcinogenesis in a variety of animal models. Coxibs generally were shown to be effective in reducing the incidence of carcinogen-induced tumors. Paradoxically, nonselective NSAIDs, including some analogues unable to inhibit COX (sulindac sulfone), were equally effective, raising the question as to the precise role of the COX pathway in tumorigenesis. Other lines of evidence indicate that NSAIDs (usually only at high doses) can affect pathways other than COX that potentially may affect carcinogenesis. One of the most definitive examples showing an absolute requirement of COX-2 in tumorigenesis are the studies of Oshima and coworkers231 using COX-2 gene knockouts and a COX-2 inhibitor on Apc/delta716 knockout mice, a model of human familial adenomatous polyposis. The COX-2 mutation dramatically reduced the number and size of intestinal polyps. Treating Apc/delta716 mice with a coxib reduced polyp numbers more significantly than did sulindac, which inhibits both isoenzymes. This study provides direct genetic evidence that COX-2 plays a key role in tumorigenesis and indicates that coxibs can be used as therapeutic agents for colorectal polyposis and cancer. Other investigators have shown that COX-1 gene deletion blocks polyp formation,232 emphasizing roles for COX-1 and COX-2 in tumorigenesis. It has been suggested that COX-1 expressed in intestinal stromal cells provides only enough PG to initiate polyp growth, and PG levels increase enough to support significant increases in growth and differentiation only when COX-2 is induced.233 The role of COX-2 in the regulation of apoptosis is an important consideration with respect to cancer because dysregulated apoptosis is a hallmark of tumorigenesis. Generally, COX-2 overexpression inhibits apoptosis, whereas COX-2

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inhibition increases apoptosis. Han and colleagues234 showed that the activation of the tumor suppressor, p53, directly induces the expression of COX-2 and counteracts p53-mediated apoptosis in a variety of cell types. Such an antiapoptotic effect of COX-2 may be an important mechanism in regulating cellular stresses associated with the induction of p53. Treatment of cells with coxibs similarly increases apoptosis compared with untreated cells, suggesting another mechanism by which NSAIDs may exert their chemoprotective effects. Studies designed to determine the precise molecular effects of NSAIDs on different types of cancers are currently in progress in an effort to identify the NSAIDs most useful as chemopreventive agents. Asthma and Allergy Of general asthmatic patients, especially individuals with the triad of vasomotor rhinitis, nasal polyposis, and asthma, 10% to 20% are hypersensitive to ASA. In these patients, ingestion of ASA and nonspecific NSAIDs leads to severe exacerbations of asthma with naso-ocular reactions. The condition was formerly known as ASA-sensitive asthma, but these patients are now characterized as having ASAexacerbated respiratory disease because they have chronic upper and lower respiratory mucosal inflammation, sinusitis, nasal polyposis, and asthma independent of their hypersensitivity reactions. It is now thought that production of protective PGs in the setting of ASA-exacerbated respiratory disease is derived from COX-1. Numerous studies have been reported showing that the coxibs rofecoxib and celecoxib fail to trigger asthma exacerbation or naso-ocular symptoms in patients with ASA-exacerbated respiratory disease.235-237 Nevertheless, these studies were performed as challenge tests, rather than long-term placebo-controlled trials, and caution is advised. The fact that specific COX-2 inhibitors seem safe in ASA-exacerbated respiratory disease does not imply that other hypersensitivity reactions do not occur. Allergic Reactions A wide variety of cutaneous reactions have been associated with NSAIDs. Almost all the NSAIDs have been associated with cutaneous vasculitis, erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis. NSAIDs also are associated with urticaria/angioedema, and ­anaphylactoid or anaphylactic reactions. Celecoxib and valdecoxib contain an active sulfonamide group and should not be given to patients who report allergy to sulfa-containing drugs. Rofecoxib also contained a sulfonamide, though it was hidden within the molecule and was not a antigenic site. HEMATOLOGIC EFFECTS Aplastic anemia, agranulocytosis, and thrombocytopenia rarely are associated with NSAIDs, but they are prominent among the causes of deaths attributed to these drugs. Because of the risk of hematologic effects, phenylbutazone is no longer recommended for use in any condition in the United States and has been taken off the market, although it still may be obtained by special compounding by a pharmacist. The adverse hematologic effects of phenylbutazone were observed even in young individuals with normal renal function.

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EFFECTS ON OVARIAN AND UTERINE FUNCTION PGs derived from COX-2 have been implicated as mediators in multiple stages of the female reproductive cycle. Induction of COX-2 immediately after the luteinizing hormone surge was the first observation involving the isoenzyme during a normal physiologic event. It has been suggested that COX-2-derived PGs may be an important signal that sets the time of ovulation in mammals.238 Studies using COX-2–null mice show reproductive failure at ovulation, fertilization, implantation, and decidualization.239 COX2-dependent PG production probably leads to the generation of proteolytic enzymes that rupture the follicles. After fertilization, COX-2 also plays a role in embryo implantation in the myometrium.240 PGs are important for inducing uterine contractions during labor. Murine studies have shown that the mechanism of uterine contraction involves fetal release of PGF2, a compound that induces luteolysis. This pathway leads to reduced maternal progesterone levels, induction of oxytocin receptors in the myometrium, and parturition. Based on these observations in animals, one could hypothesize that NSAIDs may have an influence on fertility. Studies suggest that luteinized unruptured follicle syndrome as a cause of reversible infertility can be related to ingestion of NSAIDs.143 For this reason, women should be cautioned that long-term NSAID use may impair fertility.

SELECTING ANTI-INFLAMMATORY THERAPY PATIENT RISK ASSESSMENT As with any area of pharmacotherapy, the selection of antiinflammatory therapy is as much based on contraindications as it is on indications. Other factors, such as cost and patient preference for dosing regimens, should be considered. It is well established that NSAIDs and coxibs are valuable agents in the treatment of pain, fever, and inflammation, whereas low-dose ASA has been shown to be effective for secondary and, in some situations, primary prevention of cardiovascular diseases. NSAIDs and coxibs may have a role in the prevention of various cancers and Alzheimer’s disease. These risks must be balanced with the individual patient’s status, however, taking into account the various risk factors and comorbidities placing the patient at higher risk of toxicity related to NSAIDs and coxibs. More recent information regarding the gastrointestinal and cardiovascular toxicities of NSAIDs and COX-2 inhibitors makes navigating treatment choices more difficult. This information, in addition to other established adverse effects, including hypertension, edema, renal insufficiency, and allergic responses, should prompt the clinician to consider the whole patient when selecting therapy. Assessment of cardiovascular risk factors, especially traditional Framingham risk factors, and calculation of the patient’s annual cardiovascular risk score using online calculators such as that from the National Cholesterol Education Initiative (http://hp2010.nhlbihin.net/atpiii/calculator.asp) should be undertaken. This assessment requires knowledge of the patient’s blood pressure, glycemic status, lipid profile, smoking status, and family history. Although few data

describe the effect of these risk factors on the cardiovascular risk of NSAIDs and coxibs, these should be optimized as a general principle. Knowledge of risk factors for gastrointestinal toxicity also is required, the most established of which are presented in Table 54-3. GENERAL THERAPEUTIC CONSIDERATIONS Several general considerations apply to every patient to minimize risk, even before deciding on a specific choice of therapy. First, the use of nonpharmacologic or non-NSAID treatment, or both, should be considered, particularly if potential NSAID-related or coxib-related risk is considered high.241 Acetaminophen is commonly used as an alternative to NSAIDs; however, it may be associated with hepatic, renal, and blood pressure changes with long-term use, and its use also should be monitored.242-244 The dose and duration of treatment should be minimized, if possible, because complications have been well correlated with dose and duration of exposure. Combination NSAID therapy is common, although often inadvertent and intermittent, and should be recognized. The simultaneous use of a prescription and over-the-counter NSAID, or the combination of NSAID/coxib with ASA, may have cumulative toxicity, or negate the potential benefits of these drugs, or both. Combinations with other antiplatelet agents, anticoagulants, or corticosteroids are relatively contraindicated. Attempts to stratify the potential toxicity of NSAIDs have been made.245 In general, agents such as ibuprofen, etodolac, and coxibs have lower gastrointestinal toxicity, whereas more recent evidence seems to associate traditional NSAIDs and coxibs with an increased cardiovascular risk. Guidelines, such as those presented by the American Gastroenterological Association246 and the National Institute for Health and Clinical Excellence (http://www.nice.org. uk/guidance/TA27/?c=91524),138 assist the clinician to determine the optimal form of treatment best suited for a particular patient’s risk profile. Historically, specific NSAIDs have been preferentially used for certain arthritic diseases, such as the use of phenylbutazone for gout and ankylosing spondylitis and the preference for indomethacin in ankylosing spondylitis. The choice of agents may be related to their purported clinical potency in reducing inflammatory symptoms, although no studies have shown the superior efficacy of one NSAID over another. Clinical potency may roughly parallel the agent’s specificity for COX-1 inhibition, as seen with agents such as indomethacin, piroxicam, and aspirin, but also is matched with a higher propensity for gastrointestinal toxicity. Given the lack of evidence for the use of specific agents in specific diseases, the selection of NSAID or coxib therapy from the standpoint of clinical efficacy is largely empiric, and overall is still strongly dictated by the need to avoid toxicity. MINIMIZING GASTROINTESTINAL RISK Apart from NSAID use, infection with Helicobacter pylori is the most commonly identified risk factor for ulcer bleed.132 Eradication of H. pylori has been associated with a lower recurrence rate of ASA-related gastrointestinal bleeding,247 and endoscopic studies show that individuals starting on NSAID therapy have lower rates of bleeding if ­ successful

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Table 54-4  Guidelines for Selecting Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Coxib Therapy Patient Risk Factor Low cardiovascular risk:   Low-dose ASA not indicated Moderate to high cardio­vascular risk: Low-dose ASA indicated Potential for NSAID interference with low-dose ASA

Low Gastrointestinal Bleeding Risk Options (No Risk Factors)

Moderate Gastrointestinal Bleeding Risk

High Gastrointestinal Bleeding Risk Coxib with gastroprotective agent

1

Traditional NSAID

2

COX-2 inhibitor

Coxib with or without gastro­ protective agent NSAID with gastroprotective agent

1

Avoid COX-2 inhibitors

Avoid coxibs

Avoid NSAID and coxibs

2

NSAID with or without ­gastroprotective agent

NSAID with gastroprotective agent

Cautious use of NSAID with gastro­ protective agent Consider gastroprotective agent with low-dose ASA

3

Consider gastroprotective agent   with low-dose ASA

NSAID with gastroprotective agent

Adapted from Osteoarthritis and Rheumatoid Arthritis—COX II Inhibitors: Guidance. London, National Institute for Health and Clinical Excellence, 2005; and Wolfe MM, Lichtenstein DR, Singh G: Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 340:1888-1899, 1999. ASA, acetylsalicylic acid; COX-2, cyclooxygenase-2.

eradication has occurred.248 This effect is not as strong in patients with a previous ulcer history, however.249 All patients with known H. pylori infection should be given eradication treatment when initiating NSAID therapy, and patients at higher risk for gastrointestinal complications should be tested and treated for H. pylori infection. There is insufficient evidence to recommend testing in average-risk patients starting NSAID therapy.246 The addition of misoprostol, a PGE1 analogue, has been shown to reduce the incidence of ulcer bleeding and complications in NSAID users by 40%.137 It is most effective at higher doses (>600 μg/day),249 where diarrhea is the most limiting side effect, occurring in 20% of patients. If tolerated, misoprostol represents a viable way of adding gastrointestinal protection for moderate-risk to high-risk patients. Although shown to reduce the incidence of NSAIDrelated dyspepsia, histamine H2-receptor blockers are inadequate to reduce endoscopic gastric and duodenal ulceration induced by NSAIDs unless taken at twice the usual dose. Even at high doses, ulcer complications were not reduced,249 however, and H2-receptor blockers cannot be recommended as prophylactic therapy to prevent ulcer complications. The proton-pump inhibitors are well tolerated and have received considerable attention as protective therapy against NSAID-induced gastrointestinal complications, although no long-term outcomes study as yet exists. Esomeprazole, 20 mg/day or 40 mg/day, has been shown to be effective at reducing ulcer rates in at-risk patients with an ulcer history or older than age 60 or both taking either NSAIDs or coxibs.250 The use of esomeprazole248,251 has been shown to reduce the risk of recurrent ulcer bleed in users of NSAIDs (diclofenac) and confers a similar degree of gastrointestinal protection as the use of celecoxib. The use of proton-pump inhibitors in tandem with NSAIDs has been widely adopted as preventive therapy.

their individual risk analysis. In other situations of lesser cardiac risk, depending on concomitant gastrointestinal risks, it may be acceptable to add low-dose ASA to a regimen of NSAIDs or coxibs, bearing in mind the following points: (1) The addition of low-dose ASA may increase gastrointestinal risk to unacceptable levels,112,189 and (2) certain NSAIDs may abrogate the antiplatelet effect of ASA.180 These matters await further evaluation through randomized trials. The use of a gastrointestinal protective agent (misoprostol or a proton-pump inhibitor) is recommended even with low-dose cardioprotective ASA in patients with moderate to high gastrointestinal risk given its ulcerogenic potential. For patients with cardiovascular risk factors requiring antiplatelet therapy, the use of the nonsalicylate antiplatelet agent clopidogrel does not seem to reduce the rate of recurrent ulcer bleed first induced by ASA. A prospective trial examined the incidence of recurrent upper gastrointestinal bleed in patients with a history of ischemic heart disease or stroke taking cardioprotective ASA and who presented with ulcer bleeding.247 After ulcer healing, patients were randomly assigned to clopidogrel or ASA plus esomeprazole. In this study, patients taking clopidogrel had a significantly higher incidence of recurrent upper gastrointestinal bleed (8.6% versus 0.7%; P = .001) than patients taking ASA plus esomeprazole. The effect of PPI added to clopidogrel on recurrent bleeding is unknown. The antiplatelet agent ticlopidine caused endoscopic mucosal injury nearly as frequently as NSAIDs in one ­casecontrol study.252 Patients with significant comorbidities should avoid the use of NSAIDs and coxibs. The quantification of risk, especially from gastrointestinal and cardiovascular aspects, is crucial to guide the selection of a therapeutic regimen that minimizes overall risk. Various schemes have been proposed to guide the clinician (Table 54-4).

MINIMIZING CARDIOVASCULAR RISK

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND THE FUTURE

Given more recent data regarding the cardiotoxicity of coxibs and some traditional NSAIDs, these drugs should be avoided in patients with the greatest cardiac risk and used with caution in patients at lesser degrees of risk, based on

NSAIDs have been used effectively over the years to treat inflammation, pain, and fever with the primary adverse side effect being gastrointestinal toxicity. Other potentially beneficial side effects of the NSAIDs have led to their

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widespread usage as chemopreventive agents with respect to reducing gastrointestinal cancer risk and Alzheimer’s disease. Because NSAIDs cause tumor regression, they also may be useful as adjunct therapy in the treatment of certain cancers. As a result of the discovery of a second, inducible COX isozyme, COX-2, and the clear association of gastrointestinal toxicity with COX-1 inhibition, the idea of developing a COX-2-selective class of NSAID possessing all of the analgesic, anti-inflammatory, and antipyretic properties, without the gastrointestinal toxicity of the earlier nonselective NSAIDs, became paramount. In a remarkably short time, such coxibs as celecoxib, valdecoxib, and rofecoxib were developed, tested, and marketed, and many more, with even higher COX-2 selectivities, have been and are currently being developed. Although the new coxibs cannot be considered more effective than the older NSAIDs, they are not merely “superaspirins”; they have the advantage of greatly reducing the adverse gastrointestinal effects associated with nonselective NSAIDs. More recently, evidence from VIGOR suggested that coxibs, when used long-term, could increase the incidence of myocardial infarction. Data from APPROVe further implicated coxibs in adverse cardiovascular events, and rofecoxib and valdecoxib ultimately were withdrawn from the market. Celecoxib remains available, but with stronger label warnings relative to the potential for adverse cardiovascular events. Many factors contribute to the adverse effects encountered with the long-term use of coxibs, including pressure for “fast-track” approval of a drug within a class of drugs (NSAIDs) well known for their safety and efficacy for a long time. There was significant direct marketing of these new drugs to the public emphasizing the fact that they should be considered as safe as many of the over-the-counter NSAIDs without the gastrointestinal effects. This marketing may have led to overprescribing (number and duration of treatment) and a general sense that these drugs were completely safe because they affected only the COX-2 enzyme, associated with pathogenic processes, while the homeostatic COX-1 enzyme was spared. This kind of thinking was a significant oversimplification of the pharmacologic realities of inhibiting an enzyme as centrally important as COX-2, an enzyme that is involved in many basic physiologic activities, the inhibition of which can result in serious, adverse side effects. A major question still remaining is whether the cardiovascular adverse effects of rofecoxib exemplify a “class effect” intrinsic to all coxibs, or whether it is a rofecoxib-specific property, inherent in its structure and mechanism of action. Further studies are needed to resolve this important question. Perhaps the use of coxibs in combination with other drugs to maintain cardiovascular integrity while providing the beneficial effects of COX-2-selectivity may be developed. Perhaps greater specificity could be attained by developing PG synthase inhibitors to block the synthesis of specific PG isomers downstream of PGG2/PGH2, rather than blocking the synthesis of the entire repertoire of PGs, as is the case with nonselective NSAIDs or of the PGs derived via COX-2 activity in the case of the coxibs.

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145. Wilcox CM, Shalek KA, Cotsonis G: Striking prevalence of overthe-counter nonsteroidal anti-inflammatory drug use in patients with upper gastrointestinal hemorrhage. Arch Intern Med 154:42-46, 1994. 146. Weil J, Colin-Jones D, Langman M, et al: Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ 310:827-830, 1995. 147. Lanas A: Gastrointestinal injury from NSAID therapy: How to reduce the risk of complications. Postgrad Med 117:23-28, 31, 2005. 148. Hawkey CJ, Fortun PJ: Cyclooxygenase-2 inhibitors. Curr Opin Gastroenterol 21:660-664, 2005. 149. Hippisley-Cox J, Coupland C: Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional nonsteroidal anti-inflammatory drugs: Population based nested casecontrol analysis. BMJ 330:1366, 2005. 150. Johnsen SP, Larsson H, Tarone RE, et al: Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: A population-based case-control study. Arch Intern Med 165:978-984, 2005. 151. Graham DJ, Campen D, Hui R, et al: Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclooxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: Nested case-control study. Lancet 365:475-481, 2005. 152. Catella-Lawson F, Crofford LJ: Cyclooxygenase inhibition and thrombogenicity. Am J Med 110(Suppl 3A):28S-32S, 2001. 153. Konstam MA, Weir MR, Reicin A, et al: Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib. Circulation 104:2280-2288, 2001. 154. Mukherjee D, Nissen SE, Topol EJ: Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 286:954-959, 2001. 155. Strand V, Hochberg MC: The risk of cardiovascular thrombotic events with selective cyclooxygenase-2 inhibitors. Arthritis Rheum 47:349-355, 2002. 156. Bresalier R, Sandler R, Quan H, et al: Adenomatous Polyp Prevention on Vioxx. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. APPROVe Trial Investigators. N Engl J Med 352:1092-1102, 2005. 157. Bresalier RS, Friedewald VE Jr, Rakel RE, et al: The Editor’s roundtable: Cyclooxygenase-2 inhibitors and cardiovascular risk. Am J Cardiol 96:1589-1604, 2005. 158. Fendrick AM: FDA announces series of changes to the class of marketed non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitor use after Vioxx: Careful balance or end of the rope? Am J Manag Care 10:740-741, 2004. 159. Solomon S, McMurray J, Pfeffer M, et al: Adenoma Prevention with Celecoxib APC Study Investigators: Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352:1071-1080, 2005. 160. Ott E, Nussmeier NA, Duke PC, et al: Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thoracic Cardiovasc Surg 125:1481-1492, 2003. 161. Nussmeier NA, Whelton AA, Brown MT, et al: Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 352:1081-1091, 2005. 162. Edwards JE, McQuay HJ, Moore RA: Efficacy and safety of valdecoxib for treatment of osteoarthritis and rheumatoid arthritis: Systematic review of randomized controlled trials. Pain 111:286-296, 2004. 163. Schnitzer TJ, Burmester GR, Mysler E, et al: Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: Randomized controlled trial. Lancet 364: 665-674, 2004. 164. Farkouh ME, Kirshner H, Harrington RA, et al: Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: Randomized controlled trial. Lancet 364:675-684, 2004. 165. Jermany J, Branson J, Schmouder R, et al: Lumiracoxib does not affect the ex vivo antiplatelet aggregation activity of low-dose aspirin in healthy subjects. J Clin Pharmacol 45:1172-1178, 2005. 166. Cannon CP, Curtis SP, Bolognese JA, et al: Clinical trial design and patient demographics of the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) study program: Cardiovascular outcomes with etoricoxib versus diclofenac in patients with osteoarthritis and rheumatoid arthritis. Am Heart J 152:237-245, 2006.

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167. Solomon DH, Schneeweiss S, Glynn RJ, et al: Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 109:2068-2073, 2004. 168. Levesque LE, Brophy JM, Zhang B: Time variations in the risk of myocardial infarction among elderly users of COX-2 inhibitors. Can Med Assoc J 174:1563-1569, 2006. 169. Graham D, Campen D, Hui R, et al: Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclooxygenase 2 selective and nonselective non-steroidal anti-inflammatory drugs: Nested case-control study. Lancet 365:475-481, 2005. 170. Mamdani M, Rochon P, Juurlink DN, et al: Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly. Arch Intern Med 163:481-486, 2003. 171. Singh G, Wu O, Langhorne P, et al: Risk of acute myocardial infarction with non-selective non-steroidal anti-inflammatory drugs: A meta-analysis. Arthritis Res Ther 8:R153, 2006. 172. McGettigan P, Han P, Henry D: Cyclooxygenase-2 inhibitors and coronary occlusion-exploring dose-response relationships. Br J Clin Pharmacol 62:358-365, 2006. 173. Caldwell B, Aldington S, Weatherall M, et al: Risk of cardiovascular events and celecoxib: A systematic review and meta-analysis. J R Soc Med 99:132-140, 2006. 174. Cheng JW: Use of non-aspirin nonsteroidal antiinflammatory drugs and the risk of cardiovascular events. Ann Pharmacother 40: 1785-1796, 2006. 175. Cheng Y, Wang M, Yu Y, et al: Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function. J Clin Invest 116:1391-1399, 2006. 176. FitzGerald GA, Pedersen AK, Patrono C: Analysis of prostacyclin and thromboxane biosynthesis in cardiovascular disease. Circulation 67:1174-1177, 1983. 177. Moncada S, Needleman P, Bunting S, et al: Prostaglandin endope­ roxide and thromboxane generating systems and their selective inhibition. Prostaglandins 12:323-335, 1976. 178. Hla T, Neilson K: Human cyclooxygenase-2 cDNA. Proc Natl Acad Sci U S A 89:7384-7388, 1992. 179. Hayden M, Pignone M, Phillips C, et al: Aspirin for the primary prevention of cardiovascular events: A summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 136:161-172, 2002. 180. Catella-Lawson F, Reilly MP, Kapoor SC, et al: Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 345:1809-1817, 2001. 181. Collins R, Peto R, MacMahon S, et al: Blood pressure, stroke, and coronary heart disease, part 2: Short-term reductions in blood pressure: Overview of randomized drug trials in their epidemiological context. Lancet 335:827-838, 1990. 182. Johnson DL, Hisel TM, Phillips BB: Effect of cyclooxygenase-2 inhibitors on blood pressure. Ann Pharmacother 37:442-446, 2003. 183. Sewers J, White W, Pitt B, et al: CRESCENT Investigators: The effects of cyclooxygenase-2 inhibitors and nonsteroidal antiinflammatory therapy on 24-hour blood pressure in hypertensive patients with osteoarthritis and type 2 diabetes mellitus. Arch Intern Med 165:161-168, 2005. 184. Antithrombotic Trialists C: Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high-risk patients. BMJ 324:71-86, 2002. 185. Behan MW, Storey RF: Antiplatelet therapy in cardiovascular disease. Postgrad Med J 80:155-164, 2004. 186. Bhatt DL, Fox KA, Hacke W, et al: Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 354:1706-1717, 2006. 187. Ridker PM, Cook NR, Lee IM, et al: A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 352:1293-1304, 2005. 188. Sanmuganathan PS, Ghahramani P, Jackson PR, et al: Aspirin for primary prevention of coronary heart disease: Safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials. Heart 85:265-271, 2001. 189. Derry S, Loke YK: Risk of gastrointestinal hemorrhage with long term use of aspirin: Meta-analysis. BMJ 321:1183-1187, 2000. 190. MacDonald TM, Wei L: Effect of ibuprofen on cardioprotective effect of aspirin. Lancet 361:573-574, 2003.

191. Coceani F, Barogi S, Brizzi F, et al: Cyclooxygenase isoenzymes and patency of ductus arteriosus. Prostaglandins Leukot Essent Fatty Acids 72:71-77, 2005. 192. Loftin CD, Trivedi DB, Tiano HF, et al: Failure of ductus arteriosus closure and remodeling in neonatal mice deficient in cyclooxygenase-1 and cyclooxygenase-2. Proc Natl Acad Sci U S A 98: 1059-1064, 2001. 193. Komhoff M, Wang JL, Cheng HF, et al: Cyclooxygenase-2-selective inhibitors impair glomerulogenesis and renal cortical development. Kidney Int 57:414-422, 2000. 194. Laulederkind SJ, Wall BM, Ballou LR, et al: Renal pathology resulting from PGHS-2 gene ablation in DBA/B6 mice. Prostaglandins Other Lipid Mediat 70:161-168, 2002. 195. Harris RCMD: COX-2 and the kidney. J Cardiovas Pharm 47(Suppl): S37-S42, 2006. 196. Brater DC: Anti-inflammatory agents and renal function. Semin Arthritis Rheum 32:33-42, 2002. 197. Brater DC, Harris C, Redfern JS, et al: Renal effects of COX-2selective inhibitors. Am J Nephrol 21:1-15, 2001. 198. Harris RC, Breyer MD: Physiological regulation of cyclooxygenase-2 in the kidney. Am J Physiol Renal Physiol 281:F1-F11, 2001. 199. Akhund L, Quinet RJ, Ishaq S: Celecoxib-related renal papillary necrosis. Arch Intern Med 163:114, 2003. 200. Dedier J, Stampfer M, Hankinson S, et al: Non-narcotic analgesic use and the risk of hypertension in US women. Hypertension 40:604, 2002. 201. Solomon D, Schneeweiss S, Levin R, et al: Relationship between COX-2 specific inhibitors and hypertension. Hypertension 44: 140-145, 2004. 202. Whelton A, Fort JG, Puma JA, et al: Cyclooxygenase-2-specific inhibitors and cardiorenal function: A randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Am J Ther 8:85-95, 2001. 203. Whelton A, White W, Bello A, et al: SUCCESS-VII Investigators: Effects of celecoxib and rofecoxib on blood pressure and edema in patients >65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol 90:959-963, 2002. 204. Periard D, Mayor C, Aubert V, et al: Recurrent ibuprofen-induced aseptic meningitis: Evidence against an antigen-specific immune response. Neurology 67:539-540, 2006. 205. Ashwath ML, Katner HP: Recurrent aseptic meningitis due to different non-steroidal anti-inflammatory drugs including rofecoxib. Postgrad Med J 79:295-296, 2003. 206. McGeer PL: Cyclooxygenase-2 inhibitors: Rationale and therapeutic potential for Alzheimer’s disease. Drugs Aging 17:1-11, 2000. 207. Pasinetti GM: Cyclooxygenase and Alzheimer’s disease: Implications for preventive initiatives to slow the progression of clinical dementia. Arch Gerontol Geriatr 33:13-28, 2001. 208. Halliday G, Robinson SR, Shepherd C, et al: Alzheimer’s disease and inflammation: A review of cellular and therapeutic mechanisms. Clin Exp Pharmacol Physiol 27:1-8, 2000. 209. Kunz T, Oliw EH: The selective cyclooxygenase-2 inhibitor rofecoxib reduces kainate-induced cell death in the rat hippocampus. Eur J Neurosci 13:569-575, 2001. 210. Iadecola C, Niwa K, Nogawa S, et al: Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice. Proc Natl Acad Sci U S A 98:1294-1299, 2001. 211. Lim GP, Yang F, Chu T, et al: Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. J Neurosci 20:5709-5714, 2000. 212. Kelley KA, Ho L, Winger D, et al: Potentiation of excitotoxicity in transgenic mice over-expressing neuronal cyclooxygenase-2. Am J Pathol 155:995-1004, 1999. 213. Myers LK, Bhattacharya SD, Herring PA, et al: The isozyme-specific effects of cyclooxygenase-deficiency on bone in mice. Bone 39: 1048-1052, 2006. 214. Einhorn T: Do inhibitors of cyclooxygenase-2 impair bone healing? J Bone Miner Res 17:977, 2002. 215. Forwood M: Inducible cyclooxygenase (COX-2) mediates the induction of bone formation by mechanical loading in vivo. J Bone Miner Res 11:1688, 1996. 216. Simon AM, Manigrasso MB, O’Connor JP: Cyclooxygenase 2 function is essential for bone fracture healing. J Bone Miner Res 17: 963-976, 2002.

PART 8  217. Carbone LD, Tylavsky FA, Cauley JA, et al: Association between bone mineral density and the use of nonsteroidal anti-inflammatory drugs and aspirin: Impact of cyclooxygenase selectivity. J Bone Miner Res 18:1795-1802, 2003. 218. Morton DJ, Barrett-Connor EL, Schneider DL: Nonsteroidal antiinflammatory drugs and bone mineral density in older women: The Rancho Bernardo study. J Bone Miner Res 13:1924-1931, 1998. 219. Lane NE, Bauer DC, Nevitt MC, et al: Aspirin and nonsteroidal antiinflammatory drug use in elderly women: Effects on a marker of bone resorption. The Study of Osteoporotic Fractures Research Group. J Rheumatol 24:1132-1136, 1997. 220. Desa FM, Chander CL, Moore AR, et al: The effect of indomethacin on cartilage breakdown. Agents Actions 27:485-487, 1989. 221. Myers LK, Kang AH, Postlethwaite AE, et al: The genetic ablation of cyclooxygenase 2 prevents the development of autoimmune arthritis. Arthritis Rheum 43:2687-2693, 2000. 222. Ryan EP, Pollock SJ, Murant TI, et al: Activated human B lymphocytes express cyclooxygenase-2 and cyclooxygenase inhibitors attenuate antibody production. J Immunol 174:2619-2626, 2005. 223. Mahic M, Yaqub S, Johansson CC, et al: FOXP3+CD4+CD25+ adaptive regulatory T cells express cyclooxygenase-2 and suppress effector T cells by a prostaglandin E2-dependent mechanism. J Immunol 177:246-254, 2006. 224. Thun MJ, Henley SJ, Patrono C: Nonsteroidal anti-inflammatory drugs as anticancer agents: Mechanistic, pharmacologic, and clinical issues. J Natl Cancer Inst 94:252-266, 2002. 225. Dubois RN, Abramson SB, Crofford L, et al: Cyclooxygenase in biology and disease. FASEB J 12:1063-1073, 1998. 226. Sano H, Kawahito Y, Wilder RL, et al: Expression of cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res 55:3785-3789, 1995. 227. Baron JA: Epidemiology of non-steroidal anti-inflammatory drugs and cancer. Prog Exp Tumor Res 37:1-24, 2003. 228. Benamouzig R, Deyra J, Martin A, et al: Daily soluble aspirin and prevention of colorectal adenoma recurrence: One-year results of the APACC trial. Gastroenterology 125:328-336, 2003. 229. Higuchi T, Iwama T, Yoshinaga K, et al: A randomized, double- blind, placebo-controlled trial of the effects of rofecoxib, a selective cyclooxygenase-2 inhibitor, on rectal polyps in familial adenomatous ­polyposis patients. Clin Cancer Res 9:4756-4760, 2003. 230. Phillips RK, Wallace MH, Lynch PM, et al: A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut 50:857-860, 2002. 231. Oshima M, Dinchuk JE, Kargman SL, et al: Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87:803-809, 1996. 232. Langenbach R, Loftin CD, Lee C, et al: Cyclooxygenase-deficient mice: A summary of their characteristics and susceptibilities to inflammation and carcinogenesis. Ann N Y Acad Sci 889:52-61, 1999. 233. Takeda H, Sonoshita M, Oshima H, et al: Cooperation of cyclooxygenase 1 and cyclooxygenase 2 in intestinal polyposis. Cancer Res 63:4872-4877, 2003. 234. Han JA, Kim JI, Ongusaha PP, et al: P53-mediated induction of COX-2 counteracts p53- or genotoxic stress-induced apoptosis. Embo J 21:5635-5644, 2002. 235. Bianco S, Robuschi M, Petrigni G, et al: Efficacy and tolerability of nimesulide in asthmatic patients intolerant to aspirin. Drugs 46(Suppl 1):115-120, 1993.

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236. Stevenson D, Simon R: Lack of cross-reactivity between rofecoxib and aspirin in aspirin-sensitive patients with asthma. J Allergy Clin Immunol 108:47, 2001. 237. Woessner K, Simon R, Stevenson D: The safety of celecoxib in patients with aspirin-sensitive asthma. Arthritis Rheum 46:2201, 2002. 238. Sirois J, Sayasith K, Brown KA, et al: Cyclooxygenase-2 and its role in ovulation: A 2004 account. Hum Reprod Update 10:373-385, 2004. 239. Davis BJ, Lennard DE, Lee CA, et al: Anovulation in cyclooxygenase-2-deficient mice is restored by prostaglandin E2 and interleukin1β. Endocrinology 140:2685-2695, 1999. 240. Lim H, Paria B, Das S, et al: Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell 91:197, 1997. 241. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines: Recommendations for the medical management of osteoarthritis of the hip and knee—2000 update. Arthritis Rheum 43: 1905, 2000. 242. Curhan GC, Knight EL, Rosner B, et al: Lifetime nonnarcotic analgesic use and decline in renal function in women. Arch Intern Med 164:1519-1524, 2004. 243. Forman JP, Stampfer MJ, Curhan GC: Non-narcotic analgesic dose and risk of incident hypertension in US women. Hypertension 46:500-507, 2005. 244. Perneger TV, Whelton PK, Klag MJ: Risk of kidney failure ­associated with the use of acetaminophen, aspirin, and nonsteroidal anti­ inflammatory drugs. N Engl J Med 331:1675-1679, 1994. 245. Fries JF, Williams CA, Bloch DA: The relative toxicity of nonsteroidal antiinflammatory drugs. Arthritis Rheum 34:1353-1360, 1991. 246. Wilcox CM, Allison J, Benzuly K, et al: Consensus development conference on the use of nonsteroidal anti-inflammatory agents, including cyclooxygenase-2 enzyme inhibitors and aspirin. Clin Gastroenterol Hepatol 4:1082-1089, 2006. 247. Chan FK: NSAID-induced peptic ulcers and Helicobacter pylori infection: Implications for patient management. Drug Saf 28:287-300, 2005. 248. Chan FK, Hung LC, Suen BY, et al: Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 347:2104-2110, 2002. 249. Rostom A, Dube C, Wells G, et al: Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev CD002296, 2002. 250. Scheiman JM, Yeomans ND, Talley NJ, et al: Prevention of ulcers by esomeprazole in at-risk patients using non-selective NSAIDs and COX-2 inhibitors. Am J Gastroenterol 101:701-710, 2006. 251. Chan FK, Chung SC, Suen BY, et al: Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med 344: 967-973, 2001. 252. Sheikh RA, Romano PS, Prindiville TP, et al: Endoscopic evidence of mucosal injury in patients taking ticlopidine compared with patients taking aspirin/nonsteroidal antiinflammatory drugs and controls. J Clin Gastroenterol 34:529-532, 2002. 253. Wolfe MM, Lichtenstein DR, Singh G: Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 340:1888-1899, 1999. 254. Chan FK: Primer: Managing NSAID-induced ulcer complications— balancing gastrointestinal and cardiovascular risks. Nat Clin Pract Gastroenterol Hepatol 3:563-573, 2006.

55

Glucocorticoid Therapy JOHANNES W. G. JACOBS  •  JOHANNES W. J. BIJLSMA

Key Points Standard terminology to describe glucocorticoid dosages is recommended. Mode of action of glucocortocoids is genomic (via ­glucocorticoid receptor) and, in high dosages, nongenomic. Glucocorticoids differ considerably in potency and biologic half-life. Cortisone and prednisone are biologically inactive and are converted in the liver into biologically active cortisol and prednisolone. Glucocorticoids have disease-modifying and joint-sparing properties in rheumatoid arthritis.

Nevertheless, because glucocorticoids can be considered the most effective anti-inflammatory and immunosuppressive substances currently known,2 they have become a cornerstone of therapy of many rheumatic disorders, including systemic lupus erythematosus (SLE), vasculitis, polymyalgia rheumatica, and myositis.3 Careful administration of glucocorticoids to patients with RA also has become accepted. During the past decades, knowledge about glucocorticoids has increased, but there is still much to learn about the modes of actions of these drugs in rheumatic autoimmune disorders. It is hoped that the unraveling of these mechanisms eventually may lead to new classes of therapy.4

The risk of adverse effects of a glucocorticoid is dose and time dependent.

CHARACTERISTICS OF GLUCOCORTICOIDS

The risk of adverse effects of low-dose glucocorticoids ­generally is overestimated.

STRUCTURE AND CLASSIFICATION

The risk of bacterial infection after local injection of a ­glucocorticoid is very small. Low and low-to-moderate doses of prednisolone in ­pregnancy seem to be safe.

Glucocorticoids are widely used for the treatment of patients with rheumatic diseases. The first to be isolated, in 1935, was the naturally occurring corticosteroid hormone, cortisone. It was synthesized in 1944 and subsequently became available for clinical use. In 1948, cortisone (then called compound E) was administered by the American rheumatologist Hench to a 29-year-old woman with active rheumatoid arthritis (RA) of more than 4 years’ duration. Her joints were so painful she could “hardly get out of bed.” After 2 days of treatment with 100 mg of intramuscular compound E daily, “she rolled over in bed with ease, and noted much less muscular soreness.” The next day, she was able to walk with “only a slight limp.” Hench published this case of dramatic improvement in 19491 and won the 1950 Nobel Prize in Physiology or Medicine for his research, which he shared with colleagues at the Mayo Clinic Foundation. Later on, by chemical modification of natural steroids, different synthetic glucocorticoids were produced, some of which have proved to be very effective anti-inflammatory and immunosuppressive substances with rapid, sometimes instant, effects. Initially, there was considerable enthusiasm about glucocorticoids because of the striking relief of symptoms seen in patients treated with supraphysiologic dosages. When the wide array of potentially serious adverse side effects became apparent, however, the use of glucocorticoids decreased.

The main precursor molecule of all steroid hormones is cholesterol. Steroid hormones and cholesterol are characterized by a sterol skeleton, formed by three six-carbon hexane rings and one five-carbon pentane ring. The carbon atoms of this sterol nucleus are numbered in a specific sequence; the term steroid refers to this basic sterol nucleus (Fig. 55-1). Steroid hormones can be classified on the basis of their main function into sex hormones (male and female), mineralocorticoids, and glucocorticoids. Sex hormones are synthesized mainly in the gonads, but also in the adrenal cortex. Mineralocorticoids and glucocorticoids are synthesized only in the adrenal cortex; the terms corticosteroid and corticoid for these hormones refer to the adrenal cortex. Some glucocorticoids also have a mineralocorticoid effect and vice versa. The main natural mineralocorticoid is aldosterone, and the main natural glucocorticoid is cortisol (hydrocortisone). Although the separation of corticoids into the classes mineralocorticoids and glucocorticoids is not absolute, it is better (more precise) to use the term glucocorticoid than the term corticosteroid when referring to one of these compounds.5 The importance of standardized nomenclature is illustrated by the knowledge that an electronic literature search can be complicated by multiple synonyms. In the 1950s, chemical modification of natural steroids revealed numerous structural features essential for specific biologic activities. Synthetic steroid hormones more potent than natural steroid hormones and steroid hormones with altered biologic activity were developed. These studies proved that the 17-hydroxy, 21-carbon steroid configuration (see Fig. 55-1) is required for glucocorticoid activity through binding to the glucocorticoid receptor. Glucocorticoids with an 11-keto, instead of an 11-hydroxy, group, such as cortisone and prednisone, are prohormones 863

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JACOBS 

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Glucocorticoid Therapy

OH

1

17

12 11

13

16

14

15

9 8

10

2 3

Basic sterol nucleus

Cholesterol

7 6

5

OH

21 CH2OH

4

20 C

19

OH

17

12 11

1

C

O

18

O

CH2OH

13

16

14

15

OH

OH

9 8

10

2 3

Cortisol (hydrocortisone)

Cortisone

7 5

O

6

O

CH2OH

4

C

CH2OH C

O OH

O

O

OH

Prednisolone O

CH2OH C

O

OH

Prednisone

CH2OH C

O OH

OH

O OH

OH

OH

F

Methylprednisolone

Triamcinolone

O

O CH3

CH2OH C

CH2OH

O

C OH

OH

O OH

OH

CH3

F O

O

CH3

F

Dexamethasone

Betamethasone

O

Figure 55-1  Basic steroid configuration and structure of cholesterol and of natural and some synthetic glucocorticoids. Structural differences  compared to cortisol, the natural active glucocorticoid, are shown in red.

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injection site than dexamethasone acetate. If an immediate effect is required, dexamethasone sodium phosphate given intravenously is more effective than the same preparation given intramuscularly; the least rapidly active is intramuscular dexamethasone acetate. For local use, less solubility means longer duration of the local effect, which generally is beneficial.

that must be reduced in the liver to their 11-hydroxy configurations. Cortisone is converted by hepatic pathways to cortisol, and prednisone is converted to prednisolone, to become biologically active.6 Practically speaking, in patients with severe liver disease, it is rational to prescribe prednisolone instead of prednisone. There are no qualitative differences between the glucocorticoid effect of endogenous cortisol and exogenously applied synthetic glucocorticoids because these effects are, except for higher doses, predominantly genomic (i.e., mediated through the glucocorticoid receptor).5,7 There are quantitative differences, however. The potency and other biologic characteristics of the glucocorticoids depend on structural differences in the steroid configuration. The introduction of a double bond between the 1 and 2 positions of cortisol yields prednisolone, which has about four times more glucocorticoid activity than cortisol (Table 55-1).6 Addition of a six-methyl group to prednisolone yields methylprednisolone, which is about five times more potent than cortisol. All the aforementioned glucocorticoids also have a mineralocorticoid effect. The synthetic glucocorticoids triamcinolone and dexamethasone have negligible mineralocorticoid activity, however.

PHARMACOKINETICS AND PHARMACOLOGY Water insolubility does not impair absorption in the digestive tract. Most orally administered glucocorticoids, whether in free form or as an ester or salt, are absorbed readily, probably within about 30 minutes.6 Bioavailability of prednisone and prednisolone is high. Commercially available oral and rectal prednisone and prednisolone preparations are considered approximately bioequivalent. The affinity of the different glucocorticoids for various plasma proteins varies (see Table 55-1). Of cortisol in plasma, 90% to 95% is bound to plasma proteins, primarily transcortin (also called corticosteroid-binding globulin) and, to a lesser degree, albumin. Protein-bound cortisol is not biologically active, but the remaining 5% to 10% of free cortisol is. Prednisolone has—in contrast to methylprednisolone, dexamethasone, and triamcinolone—a high affinity for transcortin and competes with cortisol for this binding protein. The synthetic glucocorticoids, other than prednisolone, with little or no affinity for transcortin are two thirds bound (weakly) to albumin, and about one third circulates as free glucocorticoid.6 Because only unbound glucocorticoids are pharmacologically active, patients with low levels of plasma protein, such as albumin (e.g., because of liver diseases or chronic active inflammatory diseases), are more susceptible to effects and side effects of glucocorticoids. Dosage adjustment should be considered in these patients. In liver disease, an additional argument for dosage adjustment is reduced clearance of glucocorticoids (see later). Glucocorticoids have biologic half-lives 2 to 36 times longer than their plasma half-lives (see Table 55-1). With a plasma half-life of about 3 hours, prednisolone can be dosed once daily for most diseases. Maximal effects of ­glucocorticoids lag behind peak serum concentrations.

BIOLOGIC CHARACTERISTICS AND THERAPEUTIC CONSEQUENCES Apart from the steroid configuration, biologic characteristics of glucocorticoids also depend on whether they are in free form (as an alcohol) or chemically bound (as an ester or salt). In their free form, glucocorticoids are virtually insoluble in water, so they can be used in tablets, but not in parenteral preparations. For that reason, synthetic glucocorticoids are formulated as either organic esters or as salts. Esters, such as (di)acetate and (hex)acetonide, are lipid soluble, but have limited water solubility and are suitable for oral use and intramuscular, intralesional, and intraarticular injection. Salts, such as sodium phosphate and sodium succinate, are generally more water soluble and also suitable for intravenous use. Dexamethasone sodium phosphate can be used intravenously, whereas dexamethasone acetate cannot. When given intramuscularly, dexamethasone sodium ­ phosphate is absorbed much faster from the

Table 55-1  Pharmacodynamics of Glucocorticoids Used in Rheumatology Equivalent Glucocorticoid Dose (mg)

Relative Glucocorticoid Activity

Relative Mineralocorticoid Activity*

Protein Binding

Half-Life in Plasma (hr)

Biologic Half-Life (hr)

25 20

0.8 1

0.8 1

− ++++

0.5 1.5-2

8-12 8-12

4 5 5 4

5 4 4 5

0.5 0.6 0.6 0

− ++ +++ ++

>3.5 2.1-3.5 3.4-3.8 2->5

18-36 18-36 18-36 18-36

0.75 0.6

20-30 20-30

0 0

++ ++

3-4.5 3-5

36-54 36-54

Short-Acting Cortisone Cortisol Intermediate-Acting Methylprednisolone Prednisolone Prednisone Triamcinolone Long-Acting Dexamethasone Betamethasone

*Clinically; sodium and water retention, potassium depletion. Symbols: – = none; ++ = high; +++ = high to very high; ++++ = very high.

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Glucocorticoid Therapy

Transcortin binds these compounds more strongly than does albumin. The plasma elimination of glucocorticoids bound to transcortin is slower than that of glucocorticoids that do not bind. Transcortin binding is not a major determinant of biologic half-lives of glucocorticoids, however, in contrast to distribution to different compartments of the body and binding to the cytosolic glucocorticoid receptor. Synthetic glucocorticoids have lower affinity for transcortin, but higher affinity for the cytosolic glucocorticoid receptor than does cortisol (see later). The affinity of prednisolone and triamcinolone for the glucocorticoid receptor is approximately two times higher, and for dexamethasone it is seven times higher. Prednisone and cortisone have negligible glucocorticoid bioactivity before they have been chemically reduced because of their very low affinity for the glucocorticoid receptor. Another important factor determining biologic half-lives of glucocorticoids is the rate of metabolism. Synthetic glucocorticoids are subject to the same reduction, oxidation, hydroxylation, and conjugation reactions as cortisol. Pharmacologically active glucocorticoids are metabolized primarily in the liver into inactive metabolites and are excreted by the kidneys; only small amounts of unmetabolized drug also are excreted in the urine.6 There is an inverse correlation between prednisolone clearance and age, which means that a given dose may have a greater effect in older individuals.8 Prednisolone clearance also is slower in African-Americans compared with whites.9 Serum half-life of prednisolone is 2.5 to 5 hours, but it is increased in patients with renal disease and liver cirrhosis, and in the elderly. Prednisolone can be removed by hemodialysis, but overall, the amount removed does not require dosage adjustment in patients on hemodialysis. In patients with cirrhosis of the liver, the clearance of unbound steroid is about two thirds of normal, a difference that should be taken into account with dosing. DRUG INTERACTIONS Certain drugs (e.g., barbiturates, phenytoin, rifampin)10 increase the metabolism of synthetic and natural glucocorticoids, particularly by increasing hepatic hydroxylase activity by inducing cytochrome P-450 isoenzyme 3A4 and thus reducing glucocorticoid concentrations (Fig. 55-2).6 Rifampin-induced nonresponsiveness to prednisone in inflammatory diseases has been described,10-12 as has rifampin-induced adrenal crisis in patients on glucocorticoid replacement therapy.13 Clinicians should consider increasing the dosage of glucocorticoids in patients who are cotreated with these medications. Conversely, drugs that inhibit cytochrome P-450 3A4, such as ketoconazole, decrease glucocorticoid clearance and lead to higher concentrations of glucocorticoids and increased risk of side effects. Concomitant administration of prednisolone and cyclosporin may result in increased plasma concentrations of the former drug; concomitant administration of methylprednisolone and cyclosporin may result in increased plasma concentrations of the latter drug. The mechanism of this probably is competitive inhibition of microsomal liver enzymes.6 Antibiotics such as erythromycin may increase plasma concentrations of glucocorticoids. Synthetic estrogens in oral contraceptives increase the level of transcortin and thus total (sum of bound and unbound) glucocorticoid levels. Therefore, in women taking oral

Serum prednisolone concentraton (ng/nl)

866

800

600

Without rifampin

400 With rifampin 200

0

0

6

12 Time (h)

18

24

Figure 55-2  Serum prednisolone concentration in time in one patient, after 0.9 mg/kg prednisone orally daily, in the presence and absence of therapy with rifampin. Curve with rifampin, during a period of continuous administration of both drugs. Curve without rifampin, after a washout of  rifampin of 4 weeks. Rifampin shows a reduced area under the curve, indicating reduced biovailability.

c­ ontraceptives, care is required in the interpretation of cortisol measurements. Adrenal insufficiency might be present even if total cortisol levels are within the normal range.14 PREGNANCY AND LACTATION In pregnancy, two mechanisms protect the fetus from exogenous glucocorticoids. First, glucocorticoids bound to transport proteins cannot pass the placenta, in contrast to unbound glucocorticoids. Second, the enzyme 11β-hydroxysteroid dehydrogenase in the placenta, which catalyzes the conversion of active cortisol, corticosterone, and prednisolone into the inactive 11-dehydro-prohormones (cortisone, 11-dehydrocorticosterone, and prednisone), protects the fetus from glucocorticoids in the blood of the mother. The maternal-to-fetal prednisolone blood concentration ratio is about 10:1, owing to these mechanisms. In contrast, dexamethasone has little or no affinity for transport proteins and is poorly metabolized by 11β-hydroxysteroid dehydrogenase in the placenta; the maternal-to-fetal dexamethasone blood concentration ratio is about 1:1. When a pregnant woman has to be treated with glucocorticoids, prednisone, prednisolone, and methylprednisolone would be good choices; if the unborn child has to be treated, fluorinated glucocorticoids, such as betamethasone or dexamethasone, would be indicated. There is concern, however, about antenatal glucocorticoid therapy, especially in repeated courses and high doses; adverse effects later in life could include reduced growth and negative effects on psychomotor development.15-17 Because of an increased risk of an oral cleft, high doses (1 to 2 mg/kg prednisone equivalent) should be avoided in the first trimester.18,19 Prednisolone and prednisone are excreted in small quantities in breast milk. Breastfeeding is considered safe for an infant whose mother is taking these drugs.20,21 Because curves of milk and serum concentrations for prednisolone are virtually parallel in time, the exposure of the infant is minimized if breastfeeding is avoided during the first 4 hours after the intake of prednisolone.22

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867

receptor–glucocorticoid complex is rapidly translocated into the nucleus, where it binds to specific consensus sites in the DNA (glucocorticoid-responsive elements) regulating the transcription of a large variety of target genes. This process is termed transactivation. Binding to glucocorticoid-responsive elements results in either stimulation or suppression of transcription of these target genes.25 Suppression of genes also may be mediated by mechanisms involving the interaction of the glucocorticoid receptor with transcriptional factors, such as activator protein-1 and nuclear factor κB. This process is termed transrepression (Fig. 55-3).10 The nature and availability of these transcription factors may be pivotal in determining the differential sensitivity of different tissues to glucocorticoids,26 because they play a crucial role in regulating the expression of a wide variety of proinflammatory genes induced by cytokines. The binding of transcriptional factors to DNA is inhibited by glucocorticoids, resulting in depressed expression of these genes and inhibition of their amplifying role in inflammation. Activated glucocorticoid receptors also may inhibit protein synthesis by decreasing the stability of mRNA through the induction of ribonucleases. This mechanism has been proposed to mediate glucocorticoid-induced inhibition of the synthesis of interleukin (IL)-1, IL-6, granulocyte-­macrophage colony-stimulating factor, and inducible cyclooxygenase (COX)-2.27 There is increasing acceptance of the hypothesis that side effects of glucocorticoids, such as diabetes mellitus, osteoporosis, skin atrophy, growth retardation, and cushingoid appearance, may be due predominantly to transactivation of genes after binding of glucocorticoid receptor dimers to

BASIC MECHANISMS OF GLUCOCORTICOIDS GENOMIC AND NONGENOMIC EFFECTS Glucocorticoids at any therapeutically relevant dosage exhibit pharmacologic effects via classic genomic mechanisms. The lipophilic glucocorticoid passes across the cell membrane, attaches to the cytosolic glucocorticoid receptor and heat shock protein, then binds to glucocorticoidresponsive elements on genomic DNA, and interacts with nuclear transcription factors. This process takes time. When acting through genomic mechanisms, it takes at least 30 minutes before the clinical effect of a glucocorticoid begins to show.23 Only when high doses are given, such as in pulse therapy, can glucocorticoids act within minutes by nongenomic mechanisms; this occurs either via specific receptormediated activity or via nonspecific membrane-associated physicochemical activity.7 The response to high-dose pulse methylprednisolone therapy may be biphasic, with an early, rapid, nongenomic effect and a delayed and more sustained classic genomic effect.24 Clinically, genomic and nongenomic effects cannot be separated. GENOMIC MECHANISMS Most of the effects of glucocorticoids are exerted via genomic mechanisms by binding to the glucocorticoid receptor located in the cytoplasm of the target cells. Only one type of glucocorticoid receptor, common in all target tissues, binds all types of glucocorticoids. The activated glucocorticoid

CH2OH C HO

O

Cortisol

O OH

Glucocorticoidresponsive element Cell membrane Cytoplasm DNA

Glucocorticoid receptor

Nuclear membrane

Nucleus mRNA

Synthesis of metabolic and endocrine peptides

Transactivation

Transrepression p50 Transcription factor NFκB

p65 DNA

No mRNA Less synthesis of proinflammatory cytokines

NFκB-responsive element

Figure 55-3  Genomic action of cortisol, as example for glucocorticoids. Cortisol binds to the glucocorticoid receptor in the cytoplasm. This complex migrates into the nucleus, where transactivation and transrepression follow. Transactivation leads to transcription of DNA and is the key mechanism of metabolic and endocrine adverse effects of glucocorticoids. Transrepression means inhibition of transcription of DNA and is the key mechanism of the anti-inflammatory mechanism of glucocorticoids. Glucocorticoid-responsive element indicates the region of DNA bound and activated by the glucocorticoid receptor–glucocorticoid complex. NFκB-responsive element indicates the region of DNA bound and activated by the transcription factor nuclear factor κB, which consists of protein 50 (p50) and protein 65 (p65). Glucocorticoids also inhibit other transcription factors. (Adapted from Huisman AM, Jacobs JW, Buttgereit F, et al: [New developments in glucocorticoid therapy: Selective glucocorticoid receptor agonists, nitrosteroids and liposomal glucocorticoids]. Ned Tijdschr Geneeskd 150:476-480, 2006.)

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DNA, whereas the anti-inflammatory effects may be mostly due to the binding of a single glucocorticoid receptor to transcription factors or coactivators, resulting in gene repression (transrepression).28 Further unraveling of molecular mechanisms of these processes may lead to development of novel glucocorticoids, such as selective glucocorticoid receptor agonists,29 with a more favorable balance of transactivation and transrepression and, clinically, to a more favorable balance of metabolic and endocrine side effects and therapeutic effects.30 GLUCOCORTICOID EFFECTS ON THE IMMUNE SYSTEM Glucocorticoids reduce activation, proliferation, differentiation, and survival of a variety of inflammatory cells, including macrophages and T lymphocytes, and promote apoptosis, especially in immature and activated T cells. This activity is mainly mediated by changes in cytokine production and secretion. In contrast, B lymphocytes and neutrophils are less sensitive to glucocorticoids, and their survival may be increased by glucocorticoid treatment. The main effect of glucocorticoids on neutrophils seems to be inhibition of adhesion to endothelial cells. Glucocorticoids inhibit not only the expression of adhesion molecules, but also the secretion of complement pathway proteins and prostaglandins. At supraphysiologic concentrations, glucocorticoids suppress fibroblast proliferation and IL-1 and tumor necrosis factor (TNF)-α–induced metalloproteinase synthesis. By these effects, glucocorticoids may retard bone and cartilage destruction.31 Leukocytes Administration of glucocorticoids leads to an increase in the total leukocyte count owing to an increase in neutrophils in the blood, although the number of other leukocytes in blood decreases. Table 55-2 summarizes the effects of glucocorticoids on specific leukocytes. The redistribution of lymphocytes, which is maximal 4 to 6 hours after administration of a single high dose of prednisone and returns to normal within 24 hours, has no clinical consequences; B cell function and immunoglobulin production are hardly affected. The effects of glucocorticoids on monocytes and macrophages may increase susceptibility to infection, however.32 Cytokines The influence of glucocorticoids on cytokine production and action represents one of the major mechanisms for glucocorticoid action in chronic inflammatory diseases, such as RA. Glucocorticoids exert potent inhibitory effects on the transcription and action of a large variety of cytokines with pivotal importance in the pathogenesis of RA. Most proinflammatory, T helper type 1 (Th1) cytokines are inhibited by glucocorticoids, including IL-1β, IL-2, IL-3, IL-6, TNF-α, interferon-γ, and granulocyte-macrophage colonystimulating factor. In RA, these cytokines are considered responsible for synovitis, cartilage degradation, and bone erosion. Conversely, the production of Th2 cytokines, such as IL-4, IL-10, and IL-13, is either stimulated or not affected by glucocorticoids.33 These cytokines have been related to

Table 55-2  Anti-inflammatory Effects of ­Glucocorticoids  on Immunomodulatory Cells Cell Type

Effects

Neutrophils

Increased blood count, decreased trafficking, relatively unaltered functioning

Macrophages and monocytes

Decreased blood count, decreased trafficking, and decreased phagocytosis and bactericidal effects, inhibited antigen presentation, decreased cytokine and eicosanoid release

Lymphocytes

Decreased blood count, decreased trafficking, decreased cytokine production, decreased proliferation and impaired activation, little effect on immunoglobulin synthesis

Eosinophils

Decreased blood count, increased apoptosis

Basophils

Decreased blood count, decreased release of mediators of inflammation

the extra-articular features of erosive RA associated with B cell overactivity, such as immune complex formation and vasculitis. Activation of Th2 cells can inhibit rheumatoid synovitis and joint destruction through the release of IL-4 and IL-10, which inhibit Th1 activity and downregulate monocyte and macrophage functions.34 Inflammatory Enzymes An important part of the inflammatory cascade is arachidonic acid metabolism, leading to the production of prostaglandins and leukotrienes, most of which are strongly proinflammatory. Through the induction of lipocortin (an inhibitor of phospholipase A2), glucocorticoids inhibit the formation of arachidonic acid metabolites. Glucocorticoids also have been shown to inhibit the production of COX-2 and phospholipase A2 induced by cytokines in monocytes and other inflammatory cells. In addition, glucocorticoids are potent inhibitors of the production of metalloproteinases in vitro and in vivo, especially collagenase and stromelysin, which are the main effectors of cartilage degradation induced by IL-1 and TNF-α.35 Adhesion Molecules and Permeability Factors Pharmacologic doses of glucocorticoids dramatically inhibit exudation of plasma and migration of leukocytes into inflammatory sites. Adhesion molecules play a central role in chronic inflammatory diseases by controlling the trafficking of inflammatory cells into sites of inflammation. Glucocorticoids reduce the expression of adhesion molecules through the inhibition of proinflammatory cytokines and by direct inhibitory effects on the expression of adhesion molecules, such as intercellular adhesion molecule-1 and E-selectin.36 Chemotactic cytokines attracting immune cells to the inflammatory site, such as IL-8 and macrophage ­chemoattractant proteins, also are inhibited by glucocorticoids. Nitric oxide production in inflammatory sites is increased by proinflammatory cytokines and results in an increased blood flow, exudation, and probably amplification of the inflammatory response. The inducible form of nitric oxide synthase by cytokines is potently inhibited by glucocorticoids.37

PART 8 

HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

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MODALITIES OF THERAPY IN RHEUMATIC DISEASE

Inflammation

Proinflammatory cytokines, such as IL-1 and IL-6, and eicosanoids, such as prostaglandin E2, and endotoxins all activate corticotropin-releasing hormone (CRH) at the hypothalamic level. This activation stimulates the secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland and of glucocorticoids by the adrenal glands. In otherwise healthy individuals with severe infections or other major physical stress, cortisol production may increase to six times the normal amount.14 In patients with active RA (or other chronic inflammatory diseases), the increase of cortisol driven by elevated cytokines might be inappropriately low,4 meaning that cortisol levels—although normal or elevated in the absolute sense—are insufficient to control the inflammatory response. This is the concept of relative adrenal insufficiency.14,38,39 Endogenous and exogenous glucocorticoids exert negative feedback control on the hypothalamic-pituitary-adrenal axis directly by suppressing secretion of pituitary ACTH and indirectly on the level of corticotropin-releasing hormone by suppression of release from inflammatory tissues of proinflammatory cytokines (Fig. 55-4). This latter counterregulation mechanism is possibly also less effective in RA.40 ACTH is secreted in brief, episodic bursts, resulting in sharp increases in plasma concentrations of ACTH and cortisol followed by slower declines in cortisol levels—the normal diurnal rhythm in cortisol secretion. The secretory ACTH episodic bursts increase in amplitude but not in frequency after 3 to 5 hours of sleep, reach a maximum in the hours before and the hour after awakening, decline throughout the morning, and are minimal in the evening. Cortisol levels are highest at about the time of awakening in the morning, are low in the late afternoon and evening, and reach their lowest level some hours after falling asleep (see Fig. 55-4). Glucocorticoids are not stored in the adrenal glands in significant amounts. Continuing synthesis and release are required to maintain basal secretion or to increase blood levels during stress. The total daily basal secretion of cortisol in humans has been estimated at 5.7 mg/m2/ day.41 This low daily cortisol production rate may explain the cushingoid symptoms that are sometimes observed in patients with adrenal insufficiency using glucocorticoids at a dose previously regarded to be a normal replacement dose. Effects of Glucocorticoids on the Hypothalamic-Pituitary-Adrenal Axis Chronic suppression of the hypothalamic-pituitary-adrenal axis by pathologically increased endogenous glucocorticoid secretion or administration of exogenous glucocorticoids leads to adrenal atrophy and loss of cortisol secretory capability. Patients have a failure of pituitary ACTH release and adrenal responsiveness to ACTH. Serum cortisol and ACTH levels are low. Glucocorticoid-induced secondary adrenal insufficiency is characterized by a selective ACTH deficit, whereas other hypopituitary axes are normal. The time required to achieve suppression depends on the dosage and the serum half-life of the glucocorticoid used, but it also varies among patients, probably because of individual differences in rates of glucocorticoid metabolism and

Circadian regulation

Cytokines

Pathophysiology

869

+ Hypothalamus CRH

+

-

Pituitary

+

Cortisol

ACTH

Adrenal

Peak

Nadir

23

2

5

8

11

13

Time of day Plasma cortisol levels† Plasma prednisolone levels‡ Figure 55-4  Simplified scheme showing the hypothalamic-hypopituitary-adrenal axis, plasma cortisol levels in rheumatoid arthritis, and plasma prednisolone levels after an oral dose at 8 o’clock. Negative feedback loops of cortisol and exogenous glucocorticoids via pituitary (fast, major determinant serum half-life) and via inflammation (slow, major determinant biologic half-life). †Scheme for control subjects. Probably, induced by cytokines, circadian rhythms are changed in rheumatoid arthritis, with a shift to an earlier cortisol peak (about 1.5 hours earlier). ‡Oral administration of prednisolone at 8 o’clock, peak plasma concentration in 1 to  3 hours, plasma half-life 2 to 3.5 hours, biological half-life 6 hours. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone.

in ­ glucocorticoid sensitivity. Prediction with certainty of chronic suppression of the hypothalamic-pituitary-adrenal axis and adrenal insufficiency is impossible. The duration of anti-inflammatory effect of one dose of a glucocorticoid approximates the duration of hypothalamicpituitary-adrenal suppression. After a single oral dose of 250 mg of hydrocortisone or cortisone, 50 mg of prednisone or prednisolone, and 40 mg of methylprednisolone, suppression for 1.25 to 1.5 days has been described. Duration of suppression after 40 mg of triamcinolone and 5 mg of ­dexamethasone was 2.25 and 2.75 days.6 After intramuscular administration of a single dose of 40 to 80 mg of triamcinolone acetonide, duration of hypothalamic-pituitary-adrenal suppression is 2 to 4 weeks, and after 40 to 80 mg of methylprednisolone, suppression lasts 4 to 8 days.6 In the case of long-term therapy, for patients who have had less than 10 mg of prednisone or its equivalent per day in one dose in the morning, the risk of clinical (­symptomatic) adrenal insufficiency is not high, but neither is it negligible.

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A review of adrenal insufficiency stated that if the daily dose is 7.5 mg of prednisolone or equivalent or more for at least 3 weeks, adrenal hypofunction should be anticipated, and acute cessation of glucocorticoid in this situation could lead to problems.14 Patients who have received glucocorticoids for less than 3 weeks or have been treated with alternateday prednisolone therapy do not have zero risk of suppression of the hypothalamic-pituitary-adrenal axis,42,43 but the risk depends on the dose. After 5 to 30 days of at least 25 mg of prednisone or equivalent daily, suppression of adrenal response (measured by a low-dose corticotropin test) was present in 34 of 75 patients studied (45%).44 In these patients, a basal plasma cortisol concentration less than 100 nmol/L was highly suggestive of adrenal suppression, whereas levels of basal cortisol greater than 220 nmol/L predicted a normal adrenal response in most, but not all, patients. It seems prudent to treat each of these patients as having secondary adrenal insufficiency.

first glance. In systemic sclerosis, glucocorticoids, especially in high doses, are contraindicated because of the risk of scleroderma renal crisis,45 but they may be useful for myositis or interstitial lung disease. Glucocorticoids are a basic part of the therapeutic strategy in myositis, polymyalgia rheumatica, and systemic vasculitis. For other diseases, glucocorticoids are adjunctive therapy or are not used at all. In osteoarthritis, glucocorticoids are not given except for intra-articular injection when there are signs of synovitis of the osteoarthritic joint.46 For generalized soft tissue disorders, glucocorticoids are not indicated, and for localized soft tissue disorders, they should be used only for intralesional injection. GLUCOCORTICOID THERAPY IN RHEUMATOID ARTHRITIS Signs and Symptoms As can be seen in Table 55-4, RA is the only disease in which glucocorticoid therapy is often started and maintained at a low dose as additional therapy.47 The rationale for this therapy is a probable insufficiency of the adrenal gland in patients with RA.38,39 Glucocorticoids are highly effective

TREATMENT WITH GLUCOCORTICOIDS Glucocorticoids are widely used for several rheumatic diseases in various dosages. Often it is unclear what is meant by the semiquantitative terms used for dosages, such as low or high. Based on pathophysiologic and pharmacokinetic data, standardization has been proposed to minimize problems in interpretation of these generally used terms (Table 55-3).5

Table 55-3  Terminology of Dosages of Glucocorticoids   for Use in Rheumatology Low dose

INDICATIONS For each disease, indications for glucocorticoid therapy are discussed in the specific chapters. An overview is given here (Table 55-4), which summarizes only the general use and dosages of glucocorticoids. Without detailed description, some of the indications could be considered questionable at

≤7.5 mg prednisone or equivalent per day

Medium dose

>7.5 mg, but ≤30 mg prednisone or equivalent per day

High dose

>30 mg, but ≤100 mg prednisone or equivalent per day

Very high dose

>100 mg prednisone or equivalent per day

Pulse therapy

≥250 mg prednisone or equivalent per day for   1 day or a few days

Table 55-4  Use of Glucocorticoids in Rheumatology in the General Patient, Excluding Exceptional Clinical Situations Low†

Medium†

High†

Intravenous, Very High Dose† or Pulse

Intraarticular Injection

− − − − − − − 2

− 1 − − 1 − 1 2

− 1 − − − − 1 1

− − − − − − − 1

2 1 1 2 2 1 − 2

− − − − − −

− 1 3 − 2 1

3 − − 1 1 −

1 1 1 − 1 −

− 1 − − − −

−

−

3

1

−

Initial Oral Dose*

Arthritides Gouty arthritis, acute Juvenile idiopathic arthritis Osteoarthritis Pseudogout Psoriatic arthritis Reactive arthritis, Reiter’s syndrome Rheumatic fever Rheumatoid arthritis Collagen Disorders Dermatomyositis, polymyositis Mixed connective tissue disease Polymyalgia rheumatica Sjögren’s syndrome, primary Systemic lupus erythematosus Systemic sclerosis Systemic Vasculitides In general

*Initial dose is the dose at the start of therapy and often is decreased in time depending on disease activity. †Dose in prednisone equivalents per day: low, ≤7.5 mg; medium, >7.5 but ≤30 mg; high, >30 but ≤100 mg; very high, >100 mg. Symbols: −, rare use; 1, infrequent use or use for therapy-resistant disease, complications, severe flare, and major exacerbation; 2, frequently added to the basic therapeutic strategy; 3, basic part of therapeutic strategy.

PART 8 

for relieving symptoms in patients with active RA in doses of less than 10 mg/day. Many patients become functionally dependent on this therapy, however, and continue it longterm.48 A review of seven studies (253 patients) concluded that glucocorticoids, when administered for approximately 6 months, are effective for the treatment of RA.49 After 6 months of therapy, the beneficial effects of glucocorticoids seem to diminish.50-52 If this therapy then is tapered off and stopped, however, patients often—during some months— experience aggravation of symptoms. More patients are given glucocorticoids in the United States than in Europe. In the European leflunomide study, 27% of the patients used concomitant glucocorticoids,53 whereas in the U.S. leflunomide study, 54% did.54 Radiologic Joint Damage In 1995, joint-preserving effects of 7.5 mg of prednisolone daily for 2 years in patients with RA of short and intermediate duration who also were treated with disease-modifying antirheumatic drugs (DMARDs) were described. The group of RA patients participating in this randomized, placebocontrolled trial was heterogeneous, not only with respect to disease duration, but also to stages of the disease and the kind and dosages of DMARDs.52 In another trial published in 1997, patients with early RA were randomly assigned to either step-down therapy with two DMARDs (sulfasalazine and methotrexate) and prednisolone (start 60 mg/day, tapered in six weekly steps to 7.5 mg/day and stopped at 34 weeks) or sulfasalazine alone. In the combined drug strategy group, a statistically significant and clinically relevant effect in retarding joint damage was shown compared with the effect of sulfasalazine alone.55 In an extension of this study, long-term (4 to 5 years) beneficial benefits also were shown regarding radiologic damage after the combination strategy.56 It has been hypothesized that the superior effect of the combination therapy in this trial can be ascribed to the prednisolone because in three double-blind, randomized trials, the effect of the combination of methotrexate and sulfasalazine was not superior to that of either drug alone.57-59 In a study, 200 patients with early RA were treated with methotrexate or intramuscular gold and were randomly assigned for additional treatment with 5 mg of prednisolone or placebo. After 2 years, progression of radiologic damage proved to be less in the prednisolone-treated patients than in the patients treated with placebo.60 In 2002, the results of the Utrecht study, a placebo-controlled trial on the effects of prednisolone in DMARD-naive patients with early RA, were published. The progression of radiologic joint damage was inhibited by 10 mg of prednisolone daily in these patients (who received DMARD therapy only as rescue).51 The Utrecht study reported a 40% decreased need for intra-articular glucocorticoid injections, 49% decreased need for acetaminophen use, and 55% decreased need for nonsteroidal anti-inflammatory drugs (NSAIDs) in the prednisolone group compared with the placebo group. This indicates that in clinical trials evaluating the clinical effect of DMARDs or ­ glucocorticoids, additional therapies should be taken into account. In an extension of this study, at 3 years after the end of the study and

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MODALITIES OF THERAPY IN RHEUMATIC DISEASE

871

100

75

50

25

0

0

1

2

5

Figure 55-5  Radiologic joint damage according to the van der Heijde modification of the Sharp method. Means (standard errors) of total scores for erosions and joint space narrowing in hands and feet. On the y-axis is displayed the total Sharp score; on the x-axis, the time, in years. The data of the original study of 2 years’ duration and data from follow-up 3 years after the end of that study are shown. From 12 months on, joint damage is significantly less among patients treated with prednisone compared with patients taking placebo; the positive effects on radiographic damage extended after the end of the 2-year trial,51 after which the prednisone therapy was tapered down and stopped (5-year data).61

2 years after tapering off and stopping the prednisolone therapy, beneficial radiologic benefits of prednisolone were still present (Fig. 55-5).61 In another 2-year study in 250 patients with early RA, 7.5 mg/day of prednisolone added to DMARD therapy also retarded joint damage and increased the remission rate compared with placebo added to DMARDs.62 There also are negative studies on the effect of glucocorticoids on radiologic damage,50,63,64 but in early RA, evidence of joint-sparing properties of glucocorticoids seems convincing, classifying glucocorticoids as DMARDs. It is still unknown, however, whether or not glucocorticoids also can inhibit progression of erosions in RA of longer duration. It could be that there is a socalled window of opportunity in the treatment of RA.65 If this window exists, effective treatment of early RA with ­glucocorticoids and DMARDs may result in an effect that lasts for a long time, whereas if effective treatment starts later, this opportunity may be lost, and erosive progression may continue. Most studies on glucocorticoids and radiologic damage employed a dose of 5 to 10 mg/day of prednisone ­equivalent during 2 years, but a scheme starting with 60 mg/day tapered off and stopped within 34 weeks also was effective. In addition, because glucocorticoid-induced ­osteoporosis and peptic ulcer complications (if glucocorticoids are combined with NSAIDs) can be prevented much more effectively now than some decades ago, the joint-protective effect of prednisolone in early RA is a ­relevant finding. A toxicity index score for DMARDs has been published (based on symptoms, laboratory abnormalities, and hospitalization data), evaluating 3000 patients with more than 7300 patient-years from the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) database. Although this score is not yet validated and is influenced by

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confounding by indication, it gives an impression of the relative toxicity of glucocorticoids.66 It is comparable with that of other immunosuppressive medications used in RA, such as methotrexate and azathioprine. Also, a review showed that the incidence, severity, and impact of adverse effects of low-dose glucocorticoid therapy in RA trials were modest and suggested that probably many of the well-known adverse effects of glucocorticoids are predominantly associated with high-dose treatment.67 Because many questions remain to be answered, such as how the effect of glucocorticoids compares with that of high dosages of methotrexate or that of TNF-α blockers, and for how long glucocorticoids should be prescribed and in what dosages, the final place of glucocorticoid therapy in RA still has to be determined. Presently, guidelines on how to use glucocorticoids as a DMARD and how to monitor glucocorticoid therapy are being developed (see Chapter 67).3 CHRONOBIOLOGY The rheumatoid inflammatory process and symptoms have a diurnal rhythm. Early in the morning, patients experience the most extensive joint stiffness and other symptoms and signs; this is due to the long rest period during the night that facilitates edema formation around inflamed joints and the circadian rhythm of cortisol (see Fig. 55-4).68 In patients with RA with low or medium disease activity, serum cortisol maximum and minimum shift to earlier times of the day and night, whereas in patients with high disease activity, the circadian rhythm is markedly reduced or even lost. The timing of glucocorticoid administration may be important for efficacy and side effects. Data in the literature are equivocal in their findings, however. In one study, administration of low doses of prednisolone at 2:00 a m. had favorable effects on more of the clinical variables than administration at 7:30 a.m. The difference in the time period from the last dose of prednisolone to assessment could have been a bias, however.69 In another study, 12 patients with RA took low-dose prednisolone (mean 5.6 mg daily) at 8:00 a.m., 1:00 p.m., or 11:00 p m. in a doubleblind, within-patient controlled fashion. Subjective and objective assessments showed no differences in effectiveness among the three times of administration of prednisolone. Urinary excretion patterns of 11-­hydroxycorticosteroids provided no evidence of adrenocortical suppression at the dose levels studied, even when this dose was taken in the evening. It was concluded in this study that it is reasonable to administer therapy in the morning to diminish as much adrenopituitary suppression as possible.70 ALTERNATE-DAY REGIMENS For oral, long-term use of glucocorticoid therapy, alternateday regimens have been devised in an attempt to alleviate the undesirable side effects, such as hypothalamic-pituitaryadrenal axis suppression. Alternate-day therapy uses a single dose administered every other morning, which is usually equivalent to, or higher than, twice the usual or pre-established daily dose. The rationale of this regimen is that the body, including the hypothalamic-pituitary-adrenal axis, is exposed to exogenous glucocorticoid only on alternate days. This rationale makes sense only in cases of usage of

a class and dosage of a glucocorticoid that suppresses the hypothalamic-pituitary-adrenal axis activity for less than 36 hours after a single dose.71 The patient should have a responsive hypothalamic-pituitary-adrenal axis. The alternate-day sched­ule does not work in patients on long-term medium- or high-dose glucocorticoids. Alternate-day therapy is unsuccessful in most patients who require glucocorticoids. Patients with RA often experience exacerbation of symptoms on the second day. This experience is in line with the clinical impression that a single dose of glucocorticoids daily is less effective in RA than half that dose, given twice daily. In giant cell arteritis, alternate-day glucocorticoid therapy also is less effective than daily administration.72,73 Generally, alternate-day regimens are used rarely in rheumatology today except in patients with juvenile idiopathic arthritis, in whom alternate-day glucocorticoid usage results in less inhibition of body growth than does daily usage. If treatment has been initiated with daily administration, the change to alternateday therapy preferably should be made after the disease has stabilized. GLUCOCORTICOID SENSITIVITY AND RESISTANCE A small proportion of patients does not react favorably to glucocorticoids or even fails to respond to high doses. Also, the susceptibility to adverse effects of glucocorticoids varies widely. Several different factors are involved in the variability of glucocorticoid sensitivity in patients with rheumatic diseases, and understanding of the mechanisms involved might eventually allow their modulation. Hereditary glucocorticoid resistance (rare) and increased susceptibility to glucocorticoids have been related to specific polymorphisms of the glucocorticoid receptor gene.74 The glucocorticoid receptor exists as an α and β isoform, but only the α isoform binds glucocorticoids. The β isoform functions as an endogenous inhibitor of glucocorticoids and is expressed in several tissues. Glucocorticoid resistance has been associated with an enhanced expression of this β receptor.75 The protein lipocortin-1 (or annexin-1) inhibits eicosanoid synthesis. Glucocorticoids are thought to stimulate lipocortin-1. In patients with RA, autoantibodies to ­ lipocortin-1 have been described. The titers in these patients correlate with the height of maintenance doses of glucocorticoids, suggesting that these antibodies also may lead to glucocorticoid resistance.76 Although glucocorticoids exert most of their immunosuppressive actions through inhibition of cytokine production, high concentrations of cytokines, especially IL-2, antagonize the suppressive effect of glucocorticoids in a dose-dependent manner.77 The balance is usually in favor of glucocorticoids, but high local concentrations of cytokines may result in a localized glucocorticoid resistance that cannot be overridden by exogenous glucocorticoids. Also, migration inhibitory factor may play a role in steroid resistance in RA. Migration inhibitory factor is a proinflammatory cytokine whose involvement in TNF-α synthesis and T cell activation suggests a role in the pathogenesis of RA. Migration inhibitory factor is suppressed by higher concentrations of glucocorticoids, but it is induced by low concentrations, leading to stimulation of inflammation.78

PART 8 

GLUCOCORTICOID WITHDRAWAL REGIMENS Because of potential side effects, glucocorticoids usually are tapered off as soon as the disease being treated is under control. Tapering must be done carefully to avoid recurrent activity of the disease and, infrequently, cortisol deficiency resulting from chronic hypothalamic-pituitary-adrenal axis suppression. Gradual tapering permits recovery of the adrenal function. There is no best scheme based on controlled, comparative studies for tapering glucocorticoids. Tapering depends on the individual’s disease, the disease activity, doses and duration of therapy, and clinical response, which also depends on each individual’s glucocorticoid sensitivity. Only generic guidelines can be offered. To taper the dose of prednisone, decrements of 5 to 10 mg every 1 to 2 weeks can be used when the prednisone dose is more than 40 mg/day, followed by 5-mg decrements every 1 to 2 weeks at a dose between 40 and 20 mg/day, and finally 1- to 2.5-mg/day decrements every 2 to 3 weeks at a prednisone dose of less than 20 mg/day. Another scheme is to taper 5 to 10 mg every 1 to 2 weeks down to 30 mg/day of prednisone, and when the dose is less than 20 mg/day, to taper 2.5 to 5 mg every 2 to 4 weeks down to 10 mg/day; thereafter, dose is tapered 1 mg each month or 2.5 mg (half a 5-mg tablet of prednisolone) each 7 weeks. For tapering every 7 weeks or longer periods, a printed schedule can be given to the patient, such as the one shown in Table 55-5. ADAPTATIONS OF GLUCOCORTICOID DOSES, STRESS REGIMENS, AND PERiOPERATIVE CARE Patients on long-term low-dose glucocorticoid medication have suppressed adrenal activity and should be advised to double their daily glucocorticoid dose, or increase the dose to 15 mg prednisolone or equivalent if they develop fever attributed to infection and to seek medical help. In case of major surgery, given the unreliable prediction of adrenal suppression on the basis of duration and dose of glucocorticoid therapy (see the section on effects of glucocorticoids on the hypothalamic-pituitary-adrenal axis), many physicians recommend “stress doses” of glucocorticoids for patients with a low risk of adrenal suppression. The scheme of 100 mg of hydrocortisone intravenously just before the operation, followed by an additional 100 mg every 6 hours for 3 days, is not always necessary. A scheme with a lower dose, possibly reducing the risk of postoperative bacterial infectious

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complications, is to infuse continuously 100 mg of hydrocortisone intravenously the first day of surgery, followed by 25 to 50 mg of hydrocortisone every 8 hours for 2 or 3 days. Another option is to administer the usual dose of oral glucocorticoid orally or (the equivalent) parenterally on the day of surgery, followed by 25 to 50 mg of hydrocortisone every 8 hours for 2 or 3 days. In cases of minor surgery, it is probably sufficient to double the oral dose or to increase the dose to 15 mg of prednisolone or equivalent for 1 to 3 days. No comparative randomized studies on different perioperative glucocorticoid stress schemes have been published, however. Because in glucocorticoid-induced loss of adrenal responsiveness aldosterone secretion is preserved, mineralocorticoid therapy is unnecessary. GLUCOCORTICOID-SPARING AGENTS For most inflammatory rheumatic diseases, including SLE, vasculitis, RA, and myositis, other immunomodulatory drugs are often added to therapy with glucocorticoids, such as azathioprine and methotrexate, and, especially in case of systemic vasculitis, cyclophosphamide. An exception is polymyalgia rheumatica, which is managed with glucocorticoids alone. Combination therapy is applied early in the disease when the disease is one for which it is known that the effect of the combination is better than that of glucocorticoids alone (e.g., in the case of systemic vasculitis) or if the disease (e.g., inflammatory myositis) seems resistant to the high initial doses of glucocorticoids. If in a later stage of the disease immunomodulatory drugs are added to therapy with glucocorticoids to enable further reduction of the dose to decrease the risk of side effects, these immunomodulatory drugs are termed ­ glucocorticoidsparing agents. For this purpose, azathioprine and methotrexate are often used. GLUCOCORTICOID PULSE THERAPY Glucocorticoid pulse therapy is used in rheumatology, especially for disease induction or treatment of flares of collagen disorders and vasculitides (see Table 55-4). In RA, pulse therapy is applied to treat serious complications of the disease and to induce remission in active disease, often in the initiation phase of second-line antirheumatic treatment. In the latter patients, pulse therapy with schemes of 1000 mg

Table 55-5  Glucocorticoid Tapering Scheme to Hand Out to Patients* Monday

Tuesday

Wednesday

Thursday

Friday

Saturday

Sunday

Period 1

High

High

High

High

Low

High

High

Period 2

High

Low

High

High

High

Low

High

Period 3

High

Low

High

Low

High

Low

High

Period 4

Low

High

Low

High

Low

High

Low

Period 5

Low

High

Low

Low

Low

High

Low

Period 6

Low

Low

Low

High

Low

Low

Low

Period 7

Low

Low

Low

Low

Low

Low

Low

*At each consecutive period (e.g., 1 week or some weeks), the number of days during which a low dose should be taken increases by 1. After completion of period 7, the next step in tapering can be taken; the dose called “low” during the previous 7 periods now is “high,” and so on. In case of aggravation of symptoms, the patient should not diminish the dose, and should contact the specialist.

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of methylprednisolone intravenously has been proven to be effective in many studies. The beneficial effect generally lasts about 6 weeks, with a large variation in the duration of the effect.79 It does not seem sensible to apply pulse therapy in active RA, unless there is also a change in the therapeutic strategy (e.g., with second-line antirheumatic treatment) aimed to stabilize in the long-term the remission induced by the pulse therapy. The short-term effects of pulse therapy in patients with established, active RA on various dimensions of health status closely resemble the long-term effects of effective conventional DMARD therapy, such as methotrexate, in patients with early RA.80 The risk of adverse effects of pulse therapy is not the same for all rheumatic disorders. In SLE, osteonecrosis and psychosis seem to be more frequent side effects of pulse therapy compared with patients with RA.80 Osteonecrosis and psychosis also can be complications of SLE itself, ­however. INTRALESIONAL AND INTRA-ARTICULAR GLUCOCORTICOID INJECTIONS Injections with glucocorticoids are widely used for arthritis (see Table 55-4), tenosynovitis, bursitis, enthesitis, and compression neuropathies such as carpal tunnel syndrome (see also Chapter 44). Generally, the effect occurs within days, but if the underlying disease is active, the effect is temporary. Administration of a local anesthetic concurrently with intra-articular or soft tissue injection of a glucocorticoid may provide immediate pain relief. Soluble glucocorticoids (e.g., phosphate salts) have a more rapid onset of action with probably less risk of subcutaneous tissue atrophy and depigmentation of the skin when given intralesionally. Insoluble glucocorticoids are longer acting and might decrease the soft tissue fibrous matrix more, so they should be used with caution in places with thin skin, especially in elderly patients and patients with peripheral vascular disease. Insoluble glucocorticoids are more safely given into deep sites. Short-acting soluble glucocorticoids can be mixed with long-acting insoluble glucocorticoids to combine rapid onset with long-acting effect. The effect of intra-articular glucocorticoid injection probably depends on several factors: the underlying disease (e.g., RA or osteoarthritis), the treated joint (size, weight bearing or non–weight bearing), the activity of arthritis, the volume of synovial fluid of the treated joint,46 the application of arthrocentesis (synovial fluid aspiration) before injection, the choice and dose of the glucocorticoid preparation, the application of rest to the injected joint, and the injection technique. The effect of injections seems to be less favorable in osteoarthritis compared with RA. In a retrospective study, especially knee joints in osteoarthritis often required at least one additional injection.81 Arthrocentesis before injecting the glucocorticoid preparation reduces the risk for relapse of arthritis.82 Triamcinolone hexacetonide, which among the injectable glucocorticoids is the least soluble preparation, shows the longest effect.81,83,84 Theoretically, rest of the injected joint minimizes leakage of the injected glucocorticoid preparation to the systemic circulation (via the hyperemic, inflamed synovium by enhanced pressure in the joint during activity), minimizes the risk of cartilage damage, and provides rest for repair

of inflammatory tissue damage. Advice and procedures for the postinjection period in terms of activity vary from no restrictions, to minimal activity of the injected joint for a couple of days, to bed rest for 24 hours after injection of a knee joint or splinting of injected joints.81,85,86 Based on the literature, no definite evidence-based recommendation can be made, but it seems prudent to rest and not to overuse the injected joint for several days, even if pain is relieved. It is recommended that intra-articular glucocorticoid injections be repeated no more often than once every 3 weeks and be given no more frequently than three times a year in a weight-bearing joint (e.g., the knee) to minimize glucocorticoid-induced joint damage. This recommendation also seems sensible, but there is no definite clinical evidence to support it. As one would expect, accuracy of steroid placement influences the clinical outcome of glucocorticoid injections into the shoulder and probably into other joints as well.87 This is important because it is estimated that a little more than half of shoulder injections are inaccurately placed.87,88 The reported infection rate of joints after local injections with glucocorticoids is low, ranging from 1 case in 13,900 to 77,300 injections.89-91 Introduction of disposable needles and syringes has helped to reduce the risk. In a 3-year prospective study in an urban area of 1 million people in the Netherlands, bacterial infections were detected in 214 joints (including 58 joints with a prosthesis or osteosynthetic material) of 186 patients; only 3 of these joint infections were attributed to an intra-articular injection.92 Other adverse effects of local glucocorticoid injections are systemic adverse effects of the glucocorticoid, such as disturbance of the menstrual pattern,93 hot flush–like symptoms the day of or the day after injection,94 and hyperglycemia in diabetes mellitus.95 Local complications include subcutaneous fat tissue atrophy (especially after improper local injection),96 local depigmentation of the skin,97 tendon slip and rupture,81,98 and lesions to local nerves.99

ADVERSE EFFECTS AND MONITORING Given the diversity of their mechanisms and sites of action, it is not surprising that glucocorticoids can cause a wide array of adverse effects (Table 55-6). Most of these side effects cannot be avoided. The risk of most complications is dosage and time dependent; minimizing the amount of glucocorticoids minimizes the risk of complications. It is a striking clinical observation that some patients develop severe adverse effects after small doses of glucocorticoids, although other patients receive high doses without serious adverse effects. The apparent individual susceptibility to adverse effects does not seem to parallel the individual susceptibility to beneficial effects. SKELETAL ADVERSE EFFECTS Osteoporosis Osteoporosis is a well-known adverse effect of glucocorticoids, which can be prevented to a large degree. Internationally accepted guidelines have been developed to minimize the occurrence of glucocorticoid-induced osteoporosis.100

PART 8 

Table 55-6  Common Adverse Effects of Glucocorticoids System

Adverse Effect

Skeletal

Osteoporosis, osteonecrosis, myopathy

Gastrointestinal

Peptic ulcer disease (in combination with NSAIDs), pancreatitis, fatty liver

Immunologic

Predisposition to infections, suppressed delayed hypersensitivity (Mantoux test)

Cardiovascular

Fluid retention, hypertension, accelerated arteriosclerosis, arrhythmias

Ocular

Glaucoma, cataract

Cutaneous

Skin atrophy, striae, ecchymoses, impaired wound healing, acne, buffalo hump, hirsutism

Endocrine

Cushingoid appearance, diabetes mellitus, changes in lipid metabolism, enhanced appetite and weight gain, electrolyte abnormalities, HPA axis suppression, suppression of gonadal hormones

Behavioral

Insomnia, psychosis, emotional instability, cognitive effects

HPA, hypothalamic-pituitary-adrenal; NSAIDs, nonsteroidal anti-inflam­ matory drugs.

Preventive and therapeutic management of glucocorticoidinduced osteoporosis is discussed in detail in Chapter 90. Osteonecrosis High-dose (>30 mg prednisone or equivalent) glucocorticoids are implicated as a cause for osteonecrosis, especially in children and patients with SLE. Vascular mechanisms seem to be involved. Ischemia possibly may be caused by microscopic fat emboli or impingement of the sinusoidal vascular bed by increased intraosseous pressure owing to fat accumulation.101 An early symptom is diffuse pain, which becomes persistent and increases with activity. Most frequently, hip or knee joints are involved; ankle and shoulder joints are involved less frequently. For early assessment, magnetic resonance imaging is the most sensitive investigation. Radionuclide bone scans give less specific information. Plain radiographs are adequate only for follow-up. Treatment in the early stage includes immobilization and decreased weight bearing. Surgical decompression, joint replacement, or both follow this if needed. Prevention is impossible; awareness is the most important factor in early detection. Myopathy Weakness in proximal muscles, especially of the lower extremities, occurring within weeks to months after the onset of treatment with glucocorticoids, or after an increase in the dosage, may indicate steroid myopathy. It is often suspected, but infrequently found, and when it is found, it occurs almost exclusively in patients treated with high dosages (>30 mg/day prednisone or equivalent). Diagnosis can be made by a muscle biopsy specimen that reveals atrophy of type II fibers with a lack of inflammation. In the blood, there is no elevation of muscle enzymes.102 Treatment is withdrawal of the steroids. If this is possible, quite often there is a prompt improvement of symptoms. A rare syndrome of

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rapid-onset, acute steroid myopathy, occurring within days of the start of high-dose glucocorticoids or pulse therapy, has been described; muscle biopsy specimens show necrosis with atrophy of all muscle fibers. GASTROINTESTINAL ADVERSE EFFECTS Peptic Ulcer Disease Data from literature on upper gastrointestinal safety of oral glucocorticoids are inconclusive. The fact that glu­ cocorticoids inhibit the production of COX-2 without hampering the production of COX-1 supports the studies that found no increased risk. In other studies, a relative risk of serious upper gastrointestinal peptic complications of about 2 was found.103 When glucocorticoids are used in combination with NSAIDs, the relative risk of peptic ulcer disease and associated complications is about 4.104 In patients treated with glucocorticoids without concomitant use of NSAIDs, there is no indication for gastrointestinal protective agents if there are no (other) risk factors for ­peptic complications. Other Gastrointestinal Adverse Effects Although glucocorticoids usually are listed as one of the many potential causes of pancreatitis, evidence for such an association is weak and difficult to separate from the underlying disease, such as SLE or vasculitis.105 Asymptomatic and symptomatic colonization of the upper gastrointestinal tract with Candida albicans is increased in patients treated with glucocorticoids, especially when other risk factors are present, such as advanced age, diabetes mellitus, and concomitant use of other immunosuppressive agents. Glucocorticoids may mask symptoms and signs usually associated with the occurrence of intra-abdominal complications, such as perforation of the intestine and peritonitis, and can lead to a delay in diagnosis with increased morbidity and mortality. IMMUNOLOGIC ADVERSE EFFECTS At high doses, glucocorticoids diminish neutrophil phagocytosis and bacterial killing in vitro, whereas in vivo, normal bactericidal and phagocytic activities are found. Monocytes are more susceptible; during treatment with medium to high doses of glucocorticoids, bactericidal and fungicidal activity in vivo and in vitro is reduced. These factors may influence the risk of infection. From epidemiologic studies, treatment with a daily dose of less than 10 mg of prednisone or equivalent seems to lead to no or only a slightly increased risk of infection, however, whereas if doses of 20 to 40 mg daily are used, an increased risk of infection is found (relative risk 1.3 to 3.6).106 This risk increases with increase of dose and duration of treatment. In a meta-analysis of 71 trials involving more than 2000 patients with different diseases and different doses of glucocorticoids, an increased relative risk of infection of 2 was found. The risk varied according to the type of disease being treated. Five of these trials involved patients with rheumatic diseases and showed no increased risk (relative risk 1).106 The same was found in a double blind, placebo-controlled,

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2-year trial in patients with early RA, in which the effect of 10 mg of prednisone daily was compared with that of placebo.51 In patients treated with glucocorticoids, especially at high doses, clinicians should anticipate infections with usual and unusual organisms, realizing that glucocorticoids may blunt classic clinical features and delay diagnosis. CARDIOVASCULAR ADVERSE EFFECTS Mineralocorticoid Effects Some glucocorticoids have clear mineralocorticoid actions (see Table 55-1), including reduced excretion of sodium and chloride and increased excretion of potassium, calcium, and phosphate. This activity may lead to edema, weight gain, increased blood pressure, and heart failure (owing to reduced excretion of sodium and chloride); cardiac arrhythmia (owing to increased excretion of potassium); or tetany and electrocardiographic changes (owing to hypocalcemia). There are no direct effects of glucocorticoids on the kidneys or on renal function. Doses of less than 10 mg of prednisolone or equivalent per day have only minor effects on blood pressure and are not a relevant cause of hypertension.107 No formal studies addressing the effects of glucocorticoids in previously hypertensive patients have been reported. Detrimental effects of glucocorticoids on cardiac function in patients with congestive heart failure are to be expected, but have not been documented. Two randomized, controlled studies in patients with myocarditis and idiopathic cardiomyopathy showed no differences between placebo-treated or ­glucocorticoid-treated groups after 1 year or in survival at 2 and 4 years.108,109 Atherosclerosis Accelerated atherosclerosis has been reported in patients with SLE and in patients with RA.110 In the pathogenesis of this complication, the use of glucocorticoids has been directly and indirectly implicated through alterations in serum lipoproteins, blood pressure, and vascular effects.111 Atherosclerosis itself has now been recognized as an inflammatory disease, for which glucocorticoids may be theoretically effective.112 Although the use of glucocorticoids has been found to be an independent risk factor for coronary artery disease in SLE, it is difficult to eliminate the confounding factor of the underlying inflammatory ­disease.113 OCULAR ADVERSE EFFECTS Cataract Glucocorticoids tend to stimulate the formation of posterior subcapsular cataract especially,114 but the risk of cortical cataract also seems increased, with an odds ratio of 2.6.115 To some extent, the likelihood or severity of this cataract’s formation depends on dose and duration of treatment.116 In patients treated long-term with glucocorticoids at a dosage of 15 mg or more of prednisone daily for 1 year, cataract is observed frequently; in patients receiving long-term therapy with less than 10 mg of prednisone daily, the percentage of cataract is less, approximately 10%. Posterior ­subcapsular

cataract may develop in only 2 years on 5 mg/day of prednisone. These cataracts are usually bilateral, but progress slowly. They may cause glare disturbance, but usually cause little visual impairment except for end stages. Glaucoma By increasing intraocular pressure, glucocorticoids may cause or aggravate glaucoma. Patients with a familial propensity to develop open-angle glaucoma are prone to develop this adverse effect; they need to be treated with medications that reduce intraocular pressure, often for a prolonged period after stopping the glucocorticoid.117 Topical application of glucocorticoids in the eye has much more of an effect on the intraocular pressure than do systemic glucocorticoids.118 A family history of glaucoma or high doses of glucocorticoids demand occasional pressure checks for patients receiving long-term systemic glucocorticoids. DERMATOLOGIC ADVERSE EFFECTS Clinically relevant adverse effects of glucocorticoids on skin include cushingoid appearance, easy bruising, ecchymoses, skin atrophy, striae, disturbed wound healing, acne, perioral dermatitis, hyperpigmentation, facial redness, and increased hair growth (excluding scalp hair).119 The physician often considers these changes to be of minor clinical importance, but they may be disturbing to the patient. No reliable data on the occurrence of these adverse effects are available, but many physicians recognize immediately the skin of a patient who has been taking glucocorticoids longterm. ENDOCRINE ADVERSE EFFECTS Glucose Intolerance and Diabetes Mellitus Glucocorticoids increase hepatic glucose production and induce insulin resistance by inhibiting insulin-stimulated glucose uptake and metabolism by peripheral tissues.120 Glucocorticoids probably also have a direct effect on the beta cells of the pancreas, resulting in enhanced insulin secretion during glucocorticoid therapy.121 It may take only a few weeks before glucocorticoid-induced hyperglycemia occurs. One case-control, population-based study suggested, in previously nondiabetic subjects, an odds ratio of 1.8 for the need to initiate antihyperglycemic drugs during glucocorticoid therapy in doses of ≤10 mg of prednisone or equivalent per day.122 This risk increased with higher daily doses of glucocorticoids. The odds ratio was 3 for 10 to 20 mg, 5.8 for 20 to 30 mg, and 10.3 for 30 mg or more of prednisone or equivalent per day. It is likely that the risk is increased further in patients with other risk factors for diabetes mellitus, such as a family history of the disease, advanced age, obesity, and previous gestational diabetes. Postprandial hyperglycemia and only mildly elevated fasting glucose concentrations are characteristic of glucocorticoid-induced diabetes mellitus.123 Worsening of glycemic control in patients with established glucose intolerance or diabetes mellitus can be expected. Usually, glucocorticoid-induced diabetes is reversible when the drug is discontinued.

PART 8 

Fat Redistribution and Body Weight One of the most notable effects of long-term endogenous or exogenous glucocorticoid excess is the redistribution of body fat. A centripetal fat accumulation with sparing of the extremities is a characteristic feature of patients exposed to long-term high-dose glucocorticoids. Potential mechanisms include increased conversion of cortisone to cortisol in visceral adipocytes, hyperinsulinemia, and a change in expression and activity of adipocyte-derived hormones and cytokines, such as leptin and TNF-α.124 Protein loss resulting in muscle atrophy also contributes to the change in body appearance. Increased appetite and energy intake influence body weight during glucocorticoid therapy. More recent trials in patients with RA given low-dose glucocorticoids for a prolonged period showed only minor effects in fat redistribution and body weight.51,60 Dyslipidemia Long-term treatment with glucocorticoids increases plasma levels of low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, total cholesterol, and triglycerides—the so-called dyslipidemia of glucocorticoid therapy. These changes are likely mediated by increased plasma insulin levels, impaired lipid catabolism, and increased lipid production in the liver. The ensuing increased plasma level of low-density lipoprotein is one of the most important risk factors for the development of atherosclerosis, next to ­glucocorticoid-induced hypertension. The association of RA with a higher risk of cardiovascular disease may be due to the direct deleterious impact of prolonged inflammation on vessel walls. Glucocorticoids have been found to inhibit macrophage accumulation in injured arterial wall in vitro, possibly resulting in attenuation of the local inflammatory response.125 Because dyslipidemia and increased cardiovascular risk are found mainly during long-term and high-dose glucocorticoid therapy, it is possible that the use of low-dose glucocorticoids, especially when initiation of this therapy prompts the physician to check for the presence of (preexisting) dyslipidemia, could decrease the incidence of atherosclerosis in patients with RA. Suppression of the Hypothalamic-Pituitary-Adrenal Axis In the section on effects of glucocorticoids on the hypothalamic-pituitary-adrenal axis, mechanisms of chronic suppression of the hypothalamic-pituitary-adrenal axis by administration of exogenous glucocorticoids are described. In such a situation, acute discontinuation of glucocorticoid therapy may lead to acute adrenal insufficiency with possible circulatory collapse and death.126 About 10 years after glucocorticoid therapy became available, the first well­documented case of adrenal insufficiency after withdrawal of exogenous glucocorticoid was reported.127 Acute cessation of glucocorticoid therapy without tapering is indicated for corneal ulceration by herpesvirus, which can lead rapidly to perforation of the cornea, and glucocorticoid-induced acute psychosis. In these patients, assessment of the adrenal responsiveness on a corticotropin test seems prudent. Not all patients with a blunted cortisol response have signs or symptoms of adrenal insufficiency, however.

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Clinical signs and symptoms of chronic adrenal hypofunctioning are nonspecific and include fatigue and weakness, lethargy, orthostatic hypotension, nausea, loss of appetite, vomiting, diarrhea, arthralgia, and myalgia. These symptoms partially overlap glucocorticoid withdrawal symptoms, such as fatigue, arthralgia, and myalgia. When in doubt, measurements of serum cortisol levels and the corticotropin stimulation test are indicated. The glucocorticoid withdrawal symptoms also are difficult sometimes to discriminate from the symptoms of the primary disease, such as polymyalgia rheumatica. Because mineralocorticoid secretion remains intact via the renin-angiotensin-aldosterone axis, hypokalemia is uncommon.14 ADVERSE BEHAVIORAL EFFECTS Glucocorticoid treatment is associated with a variety of behavioral symptoms. Although most attention has been directed toward specific dramatic disturbances collectively described under the term glucocorticoid psychosis, less florid effects also occur that may cause distress to a patient and warrant medical attention. Similar manifestations may occur on withdrawal of glucocorticoids. Steroid Psychosis Overt psychosis is rare and usually is associated with highdose glucocorticoids or glucocorticoid pulse therapy, especially in patients with SLE, but psychosis also is a complication of this disease itself. This fact makes it difficult to distinguish in the individual SLE patient whether the psychosis is a complication of the disease, the therapy, or both. Isolated psychosis represents about 10% of ­glucocorticoidrelated cases, but in most patients, affective disorders are present as well. Around 40% of cases of glucocorticoidinduced psychosis manifest as depression, whereas mania, often dominated by irritability, is predominant in 30% of cases.128 Psychotic symptoms usually start just after initiation of treatment (60% within the first 2 weeks, 90% within the first 6 weeks), and remission after drug dose reduction or withdrawal follows the same pattern. Although the data are largely anecdotal, individuals developing steroid psychosis frequently have had prior evidence of some dissociative symptoms. Occasionally, remission occurs without dose reduction. Minor Mood Disturbances Glucocorticoids have been associated with a wide variety of low-grade disturbances, such as depressed or elated mood (euphoria), irritability, emotional instability, anxiety, insomnia, memory failure, and cognition impairments. Although the symptoms may not become severe enough for a specific diagnosis, they warrant attention—not only because they cause distress to the patient, but also because they may interfere with evaluation and treatment of the underlying disease. Most physicians recognize the occurrence of such symptoms in many glucocorticoid-treated patients; these symptoms can occur in varying degrees in 50% of treated patients within the first week. The exact incidence in rheumatic patients exposed to the usual doses of glucocorticoids is unknown: most series dedicated to mood

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Table 55-7  Risk and Monitoring for Adverse Effects   of Glucocorticoid Therapy* Screen before Treatment Is Started Blood pressure, check for peripheral edema and cardiac insufficiency Risk factors for osteoporosis Comedication, especially NSAIDs History of peptic ulcer Family history of glaucoma Serum lipids Urine glucose Screen during Treatment (Frequency Depends on Individual Patient’s Risk and Glucocorticoid Dose) Blood pressure, check for peripheral edema and cardiac insufficiency Serum lipids Urine glucose Ocular pressure (in patients with a family history of glaucoma or on a high dose of glucocorticoids) Preventive Measures Always provide calcium and vitamin D supplementation and bisphosphonates on indication (see international guidelines) In case of comedication with NSAIDs, consider comedication with a proton-pump inhibitor or prescribe a cyclooxygenase-1–sparing NSAID *International guidelines do not yet exist for monitoring. NSAIDs, nonsteroidal anti-inflammatory drugs.

disturbances studied high doses.129 It is also important to inform patients about these minor mood disturbances before starting glucocorticoid therapy. MONITORING Monitoring for adverse effects should include assessments even before therapy is started. Indications for what and how to monitor are presented in Table 55-7. The discovery of glucocorticoids as a therapeutic tool still stands as one of the most significant advances in clinical medicine of the 20th century. Because of their many adverse effects, however, glucocorticoids need to be applied prudently.

Future Directions Glucocorticoid analogues with dissociated effects on transactivation and transrepression, such as selective glucocorticoid receptor agonists, are being developed, which could have a more favorable balance of clinical effects and adverse effects than do conventional glucocorticoids.29 Another promising future development is targeting of glucocorticoids to inflammatory sites using polyethylene glycol liposomes as vector, reducing systemic concentrations of glucocorticoids and adverse effects while leading to high local therapeutic concentrations.130 Glucocorticoid–nitric oxide ­compounds ­releasing nitric oxide might have enhanced anti-­inflammatory properties at lower systemic ­ concentrations of glucocorticoid,131 but these drugs too are still in an early test phase.

REFERENCES   1. Hench PS, Kendall EC, Slocumb CH, et al: The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone: compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis: preliminary report. Proceedings Staff Meetings Mayo Clinic 24:181-197, 1949.

  2. Bijlsma JW, Straub RH, Masi AT, et al: Neuroendocrine immune mechanisms in rheumatic diseases. Trends Immunol 23:59-61, 2002.   3. Moreland LW, O’Dell JR: Glucocorticoids and rheumatoid arthritis: Back to the future? Arthritis Rheum 46:2553-2563, 2002.   4. Neeck G: Fifty years of experience with cortisone therapy in the study and treatment of rheumatoid arthritis. Ann N Y Acad Sci 966:28-38, 2002.   5. Buttgereit F, da Silva JA, Boers M, et al: Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: Current questions and tentative answers in rheumatology. Ann Rheum Dis 61:718-722, 2002.   6. AHFS Drug Information. Bethesda, Md, American Society of HealthSystem Pharmacists, Inc, 2001.   7. Buttgereit F, Wehling M, Burmester GR: A new hypothesis of modular glucocorticoid actions: Steroid treatment of rheumatic diseases revisited. Arthritis Rheum 41:761-767, 1998.   8. Tornatore KM, Logue G, Venuto RC, et al: Pharmacokinetics of methylprednisolone in elderly and young healthy males. J Am Geriatr Soc 42:1118-1122, 1994.   9. Tornatore KM, Biocevich DM, Reed K, et al: Methylprednisolone pharmacokinetics, cortisol response, and adverse effects in black and white renal transplant recipients. Transplantation 59:729-736, 1995. 10. Carrie F, Roblot P, Bouquet S, et al: Rifampin-induced nonresponsiveness of giant cell arteritis to prednisone treatment. Arch Intern Med 154:1521-1524, 1994. 11. Kawai S, Ichikawa Y, Homma M: [Rifampicin-induced resistance to prednisolone treatment in collagen disease: A pharmacokinetic study]. Ryumachi 24:32-37, 1984. 12. McAllister WA, Thompson PJ, Al Habet SM, et al: Rifampicin reduces effectiveness and bioavailability of prednisolone. BMJ (Clin Res Ed) 286:923-925, 1983. 13. Kyriazopoulou V, Parparousi O, Vagenakis AG: Rifampicin-induced adrenal crisis in addisonian patients receiving corticosteroid replacement therapy. J Clin Endocrinol Metab 59:1204-1206, 1984.   14. Cooper MS, Stewart PM: Corticosteroid insufficiency in acutely ill patients. N Engl J Med 348:727-734, 2003. 15. Lamer P: Current controversies surrounding the use of repeated courses of antenatal steroids. Adv Neonatal Care 2:290-300, 2002. 16. Bertram CE, Hanson MA: Prenatal programming of postnatal endocrine responses by glucocorticoids. Reproduction 124:459-467, 2002. 17. Sloboda DM, Challis JR, Moss TJ, et al: Synthetic glucocorticoids: Antenatal administration and long-term implications. Curr Pharm Des 11:1459-1472, 2005. 18. Ostensen M: Disease specific problems related to drug therapy in pregnancy. Lupus 13:746-750, 2004. 19. Park-Wyllie L, Mazzotta P, Pastuszak A, et al: Birth defects after maternal exposure to corticosteroids: Prospective cohort study and metaanalysis of epidemiological studies. Teratology 62:385-392, 2000. 20. Rayburn WF: Glucocorticoid therapy for rheumatic diseases: Maternal, fetal, and breast-feeding considerations. Am J Reprod Immunol 28:138-140, 1992. 21. American Academy of Pediatrics: Transfer of drugs and other chemicals into human milk. Pediatrics 108:776-789, 2001. 22. Ost L, Wettrell G, Bjorkhem I, et al: Prednisolone excretion in human milk. J Pediatr 106:1008-1011, 1985. 23. Barnes PJ: Anti-inflammatory actions of glucocorticoids: Molecular mechanisms. Clin Sci (Lond) 94:557-572, 1998. 24. Lipworth BJ: Therapeutic implications of non-genomic glucocorticoid activity. Lancet 356:87-89, 2000. 25. Truss M, Beato M: Steroid hormone receptors: Interaction with deoxyribonucleic acid and transcription factors. Endocr Rev 14: 459-479, 1993. 26. da Silva JA, Bijlsma JW: Optimizing glucocorticoid therapy in rheumatoid arthritis. Rheum Dis Clin N Am 26:859-880, 2000. 27. Ristimaki A, Narko K, Hla T: Down-regulation of cytokine-induced cyclo-oxygenase-2 transcript isoforms by dexamethasone: Evidence for post-transcriptional regulation. Biochem J 318(Pt 1):325-331, 1996. 28. Belvisi MG, Brown TJ, Wicks S, et al: New glucocorticosteroids with an improved therapeutic ratio? Pulm Pharmacol Ther 14:221-227, 2001. 29. Rhen T, Cidlowski JA: Antiinflammatory action of glucocorticoids— new mechanisms for old drugs. N Engl J Med 353:1711-1723, 2005. 30. Resche-Rigon M, Gronemeyer H: Therapeutic potential of selective modulators of nuclear receptor action. Curr Opin Chem Biol 2: 501-507, 1998.

PART 8  31. Boumpas DT, Chrousos GP, Wilder RL, et al: Glucocorticoid therapy for immune-mediated diseases: Basic and clinical correlates. Ann Intern Med 119:1198-1208, 1993. 32. Leonard JP, Silverstein RL: Corticosteroids and the haematopoietic system. In Lin AN, Paget SA (eds): Principles of Corticosteroid Therapy. New York, Arnold, 2002, pp 144-149. 33. Verhoef CM, van Roon JA, Vianen ME, et al: The immune suppressive effect of dexamethasone in rheumatoid arthritis is accompanied by upregulation of interleukin 10 and by differential changes in interferon gamma and interleukin 4 production. Ann Rheum Dis 58: 49-54, 1999. 34. Morand EF, Jefferiss CM, Dixey J, et al: Impaired glucocorticoid induction of mononuclear leukocyte lipocortin-1 in rheumatoid arthritis. Arthritis Rheum 37:207-211, 1994. 35. DiBattista JA, Martel-Pelletier J, Wosu LO, et al: Glucocorticoid receptor mediated inhibition of interleukin-1 stimulated neutral metalloprotease synthesis in normal human chondrocytes. J Clin Endocrinol Metab 72:316-326, 1991. 36. Cronstein BN, Kimmel SC, Levin RI, et al: A mechanism for the antiinflammatory effects of corticosteroids: The glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1. Proc Natl Acad Sci U S A 89:9991-9995, 1992. 37. Di Rosa M, Radomski M, Carnuccio R, et al: Glucocorticoids inhibit the induction of nitric oxide synthase in macrophages. Biochem Biophys Res Commun 172:1246-1252, 1990. 38. Gudbjornsson B, Skogseid B, Oberg K, et al: Intact adrenocorticotropic hormone secretion but impaired cortisol response in patients with active rheumatoid arthritis: Effect of glucocorticoids. J Rheumatol 23:596-602, 1996. 39. Chikanza IC, Petrou P, Kingsley G, et al: Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis. Arthritis Rheum 35:1281-1288, 1992. 40. Bijlsma JW, Cutolo M, Masi AT, et al: The neuroendocrine immune basis of rheumatic diseases. Immunol Today 20:298-301, 1999. 41. Esteban NV, Loughlin T, Yergey AL, et al: Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry. J Clin Endocrinol Metab 72:39-45, 1991. 42. Ackerman GL, Nolsn CM: Adrenocortical responsiveness after ­alternate-day corticosteroid therapy. N Engl J Med 278:405-409, 1968. 43. Schlaghecke R, Kornely E, Santen RT, et al: The effect of long-term glucocorticoid therapy on pituitary-adrenal responses to exogenous corticotropin-releasing hormone. N Engl J Med 326:226-230, 1992. 44. Henzen C, Suter A, Lerch E, et al: Suppression and recovery of adrenal response after short-term, high-dose glucocorticoid treatment. Lancet 355:542-545, 2000. 45. DeMarco PJ, Weisman MH, Seibold JR, et al: Predictors and outcomes of scleroderma renal crisis: The high-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial. Arthritis Rheum 46:2983-2989, 2002. 46. Gaffney K, Ledingham J, Perry JD: Intra-articular triamcinolone hexacetonide in knee osteoarthritis: Factors influencing the clinical response. Ann Rheum Dis 54:379-381, 1995. 47. Buchanan WW, Stephen LJ, Buchanan HM: Are ‘homeopathic’ doses of oral corticosteroids effective in rheumatoid arthritis? Clin Exp Rheumatol 6:281-284, 1988. 48. ACR Subcommittee on Rheumatoid Arthritis Guidelines: Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum 46:328-346, 2002. 49. Criswell LA, Saag KG, Sems KM, et al: Moderate-term, low-dose corticosteroids for rheumatoid arthritis. Cochrane Database Syst Rev CD001158, 2000. 50. Hansen M, Podenphant J, Florescu A, et al: A randomised trial of differentiated prednisolone treatment in active rheumatoid arthritis: Clinical benefits and skeletal side effects. Ann Rheum Dis 58: 713-718, 1999.   51. Van Everdingen AA, Jacobs JW, Siewertsz Van Reesema DR, et al: Low-dose prednisone therapy for patients with early active rheumatoid arthritis: Clinical efficacy, disease-modifying properties, and side effects. A randomized, double-blind, placebo-controlled clinical trial. Ann Intern Med 136:1-12, 2002.   52. Kirwan JR: The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group. N Engl J Med 333:142-146, 1995.

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53. Smolen JS, Kalden JR, Scott DL, et al: Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: A double-blind, randomised, multicentre trial. European Leflunomide Study Group. Lancet 353:259-266, 1999. 54. Weinblatt ME, Kremer JM, Coblyn JS, et al: Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis. Arthritis Rheum 42:1322-1328, 1999.   55. Boers M, Verhoeven AC, Markusse HM, et al: Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 350:309-318, 1997. 56. Landewe RB, Boers M, Verhoeven AC, et al: COBRA combination therapy in patients with early rheumatoid arthritis: Long-term structural benefits of a brief intervention. Arthritis Rheum 46:347-356, 2002. 57. Haagsma CJ, van Riel PL, de Jong AJ, et al: Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: A randomized, controlled, double-blind, 52 week clinical trial. Br J Rheumatol 36:1082-1088, 1997. 58. Dougados M, Combe B, Cantagrel A, et al: Combination therapy in early rheumatoid arthritis: A randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components. Ann Rheum Dis 58:220-225, 1999.   59. Goekoop-Ruiterman YP, Vries-Bouwstra JK, Allaart CF, et al: Clinical and radiographic outcomes of four different ­ treatment strategies in patients with early rheumatoid arthritis (the BeSt study): A randomized, controlled trial. Arthritis Rheum 52:3381-3390, 2005.   60. Wassenberg S, Rau R, Steinfeld P, et al: Very low-dose ­prednisolone in early rheumatoid arthritis retards radiographic progression over two years: A multicenter, double-blind, placebo-controlled trial. Arthritis Rheum 52:3371-3380, 2005. 61. Jacobs JW, Van Everdingen AA, Verstappen SM, et al: Followup radiographic data on patients with rheumatoid arthritis who participated in a two-year trial of prednisone therapy or placebo. Arthritis Rheum 54:1422-1428, 2006. 62. Svensson B, Boonen A, Albertsson K, et al: Low-dose prednisolone in addition to the initial disease-modifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: A two-year randomized trial. Arthritis Rheum 52:3360-3370, 2005. 63. Paulus HE, Di Primeo D, Sanda M, et al: Progression of radiographic joint erosion during low dose corticosteroid treatment of rheumatoid arthritis. J Rheumatol 27:1632-1637, 2000. 64. Capell HA, Madhok R, Hunter JA, et al: Lack of radiological and clinical benefit over two years of low dose prednisolone for rheumatoid arthritis: Results of a randomised controlled trial. Ann Rheum Dis 63:797-803, 2004. 65. O’Dell JR: Treating rheumatoid arthritis early: A window of opportunity? Arthritis Rheum 46:283-285, 2002. 66. Fries JF, Williams CA, Ramey D, et al: The relative toxicity of ­diseasemodifying antirheumatic drugs. Arthritis Rheum 36:297-306, 1993. 67. da Silva JAP, Jacobs JWG, Kirwan JR, et al: Safety of low dose glucocorticoid treatment in rheumatoid arthritis: Published evidence and prospective trial data. Ann Rheum Dis 65:285-293, 2006. 68. Neeck G, Federlin K, Graef V, et al: Adrenal secretion of cortisol in patients with rheumatoid arthritis. J Rheumatol 17:24-29, 1990. 69. Arvidson NG, Gudbjornsson B, Larsson A, et al: The timing of glucocorticoid administration in rheumatoid arthritis. Ann Rheum Dis 56:27-31, 1997. 70. Kowanko IC, Pownall R, Knapp MS, et al: Time of day of prednisolone administration in rheumatoid arthritis. Ann Rheum Dis 41: 447-452, 1982. 71. Fauci AS: Alternate-day corticosteroid therapy. Am J Med 64: 729-731, 1978. 72. Bengtsson BA, Malmvall BE: An alternate-day corticosteroid regimen in maintenance therapy of giant cell arteritis. Acta Med Scand 209:347-350, 1981. 73. Hunder GG, Sheps SG, Allen GL, et al: Daily and alternate-day corticosteroid regimens in treatment of giant cell arteritis: Comparison in a prospective study. Ann Intern Med 82:613-618, 1975. 74. Huizenga NA, Koper JW, De Lange P, et al: A polymorphism in the glucocorticoid receptor gene may be associated with an increased ­sensitivity to glucocorticoids in vivo. J Clin Endocrinol Metab 83:144-151, 1998.

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75. Chikanza IC: Mechanisms of corticosteroid resistance in rheumatoid arthritis: A putative role for the corticosteroid receptor beta isoform. Ann N Y Acad Sci 966:39-48, 2002. 76. Podgorski MR, Goulding NJ, Hall ND, et al: Autoantibodies to ­lipocortin-1 are associated with impaired glucocorticoid responsiveness in rheumatoid arthritis. J Rheumatol 19:1668-1671, 1992. 77. Molijn GJ, Spek JJ, van Uffelen JC, et al: Differential adaptation of glucocorticoid sensitivity of peripheral blood mononuclear leukocytes in patients with sepsis or septic shock. J Clin Endocrinol Metab 80:1799-1803, 1995. 78. Leech M, Metz C, Hall P, et al: Macrophage migration inhibitory factor in rheumatoid arthritis: Evidence of pro-inflammatory function and regulation by glucocorticoids. Arthritis Rheum 42:1601-1608, 1999. 79. Weusten BL, Jacobs JW, Bijlsma JW: Corticosteroid pulse therapy in active rheumatoid arthritis. Semin Arthritis Rheum 23:183-192, 1993. 80. Jacobs JW, Geenen R, Evers AW, et al: Short term effects of corticosteroid pulse treatment on disease activity and the well-being of patients with active rheumatoid arthritis. Ann Rheum Dis 60:61-64, 2001. 81. McCarty DJ, Harman JG, Grassanovich JL, et al: Treatment of rheumatoid joint inflammation with intrasynovial triamcinolone hexacetonide. J Rheumatol 22:1631-1635, 1995. 82. Weitoft T, Uddenfeldt P: Importance of synovial fluid aspiration when injecting intra-articular corticosteroids. Ann Rheum Dis 59:233-235, 2000. 83. Blyth T, Hunter JA, Stirling A: Pain relief in the rheumatoid knee after steroid injection: A single-blind comparison of hydrocortisone succinate, and triamcinolone acetonide or hexacetonide. Br J Rheumatol 33:461-463, 1994. 84. Gray RG, Gottlieb NL: Intra-articular corticosteroids: An updated assessment. Clin Orthop 177:235-263, 1983. 85. Chatham W, Williams G, Moreland L, et al: Intraarticular corticosteroid injections: Should we rest the joints? Arthritis Care Res 2:7074, 1989. 86. Chakravarty K, Pharoah PD, Scott DG: A randomized controlled study of post-injection rest following intra-articular steroid therapy for knee synovitis. Br J Rheumatol 33:464-468, 1994. 87. Eustace JA, Brophy DP, Gibney RP, et al: Comparison of the accuracy of steroid placement with clinical outcome in patients with shoulder symptoms. Ann Rheum Dis 56:59-63, 1997. 88. Jones A, Regan M, Ledingham J, et al: Importance of placement of intra-articular steroid injections. BMJ 307:1329-1330, 1993. 89. Hollander JL: Intrasynovial corticosteroid therapy in arthritis. Md State Med J 19:62-66, 1970. 90. Gray RG, Tenenbaum J, Gottlieb NL: Local corticosteroid injection treatment in rheumatic disorders. Semin Arthritis Rheum 10: 231-254, 1981. 91. Seror P, Pluvinage P, d’Andre FL, et al: Frequency of sepsis after local corticosteroid injection (an inquiry on 1,160,000 injections in rheumatological private practice in France). Rheumatology (Oxf) 38:1272-1274, 1999.   92. Kaandorp CJ, Krijnen P, Moens HJ, et al: The outcome of bacte­rial arthritis: A prospective community-based study. Arthritis Rheum 40:884-892, 1997. 93. Mens JM, Nico DW, Berkhout BJ, et al: Disturbance of the menstrual pattern after local injection with triamcinolone acetonide. Ann Rheum Dis 57:700, 1998. 94. DeSio JM, Kahn CH, Warfield CA: Facial flushing and/or generalized erythema after epidural steroid injection. Anesth Analg 80:617-619, 1995. 95. Black DM, Filak AT: Hyperglycemia with non-insulin-­dependent diabetes following intraarticular steroid injection. J Fam Pract 28:462-463, 1989. 96. Di Stefano V, Nixon JE: Skin and fat atrophy complications of local steroid injection. Pa Med 77:38, 1974. 97. Stapczynski JS: Localized depigmentation after steroid injection of a ganglion cyst on the hand. Ann Emerg Med 20:807-809, 1991. 98. Kleinman M, Gross AE: Achilles tendon rupture following steroid injection: Report of three cases. J Bone Joint Surg Am 65:1345-1347, 1983. 99. Linskey ME, Segal R: Median nerve injury from local steroid injection in carpal tunnel syndrome. Neurosurgery 26:512-515, 1990. 100. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis: Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. Arthritis Rheum 44:1496-1503, 2001.

101. Lukert BP: Glucocorticoid-induced osteoporosis. In The American Society for Bone and Mineral Research (eds): Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Philadelphia, Lippincott Williams & Wilkins, 1999, pp 292-296. 102. Dekhuijzen PN, Decramer M: Steroid-induced myopathy and its significance to respiratory disease: A known disease rediscovered. Eur Respir J 5:997-1003, 1992. 103. Garcia Rodriguez LA, Hernandez-Diaz S: The risk of upper gastrointestinal complications associated with nonsteroidal anti-­inflammatory drugs, glucocorticoids, acetaminophen, and combinations of these agents. Arthritis Res 3:98-101, 2001. 104. Piper JM, Ray WA, Daugherty JR, et al: Corticosteroid use and peptic ulcer disease: Role of nonsteroidal anti-inflammatory drugs. Ann Intern Med 114:735-740, 1991. 105. Saab S, Corr MP, Weisman MH: Corticosteroids and systemic lupus erythematosus pancreatitis: A case series. J Rheumatol 25:801-806, 1998. 106. Stuck AE, Minder CE, Frey FJ: Risk of infectious complications in patients taking glucocorticosteroids. Rev Infect Dis 11:954-963, 1989. 107. Jackson SH, Beevers DG, Myers K: Does long-term low-dose corticosteroid therapy cause hypertension? Clin Sci (Lond) 61(Suppl 7): 381S-383S, 1981. 108. Mason JW, O’Connell JB, Herskowitz A, et al: A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial investigators. N Engl J Med 333:269-275, 1995. 109. Latham RD, Mulrow JP, Virmani R, et al: Recently diagnosed idiopathic dilated cardiomyopathy: Incidence of myocarditis and efficacy of prednisone therapy. Am Heart J 117:876-882, 1989. 110. Van Doornum S, McColl G, Wicks IP: Accelerated atherosclerosis: An extraarticular feature of rheumatoid arthritis? Arthritis Rheum 46:862-873, 2002. 111. Maxwell SR, Moots RJ, Kendall MJ: Corticosteroids: Do they damage the cardiovascular system? Postgrad Med J 70:863-870, 1994. 112. Ross R: Atherosclerosis is an inflammatory disease. Am Heart J 138:S419-S420, 1999. 113. Petri M, Perez-Gutthann S, Spence D, et al: Risk factors for coronary artery disease in patients with systemic lupus erythematosus. Am J Med 93:513-519, 1992. 114. Carnahan MC, Goldstein DA: Ocular complications of topical, peri-ocular, and systemic corticosteroids. Curr Opin Ophthalmol 11: 478-483, 2000. 115. Klein BE, Klein R, Lee KE, et al: Drug use and five-year incidence of age-related cataracts: The Beaver Dam Eye Study. Ophthalmology 108:1670-1674, 2001. 116. Urban RC Jr, Cotlier E: Corticosteroid-induced cataracts. Surv Ophthalmol 31:102-110, 1986. 117. Garbe E, LeLorier J, Boivin JF, et al: Risk of ocular hypertension or open-angle glaucoma in elderly patients on oral glucocorticoids. Lancet 350:979-982, 1997. 118. Tripathi RC, Parapuram SK, Tripathi BJ, et al: Corticosteroids and glaucoma risk. Drugs Aging 15:439-450, 1999. 119. Cooper C, Kirwan JR: The risks of local and systemic corticosteroid administration. Baillieres Clin Rheumatol 4:305-332, 1991. 120. Tayek JA, Katz J: Glucose production, recycling, Cori cycle, and gluconeogenesis in humans: Relationship to serum cortisol. Am J Physiol 272:E476-E484, 1997. 121. Delaunay F, Khan A, Cintra A, et al: Pancreatic beta cells are important targets for the diabetogenic effects of glucocorticoids. J Clin Invest 100:2094-2098, 1997. 122. Gurwitz JH, Bohn RL, Glynn RJ, et al: Glucocorticoids and the risk for initiation of hypoglycemic therapy. Arch Intern Med 154:97-101, 1994. 123. Hirsch IB, Paauw DS: Diabetes management in special situations. Endocrinol Metab Clin N Am 26:631-645, 1997. 124. Stewart PM, Tomlinson JW: Cortisol, 11 beta-hydroxysteroid dehydrogenase type 1 and central obesity. Trends Endocrinol Metab 13:94-96, 2002. 125. Poon M, Gertz SD, Fallon JT, et al: Dexamethasone inhibits macrophage accumulation after balloon arterial injury in cholesterol fed rabbits. Atherosclerosis 155:371-380, 2001. 126. Oelkers W: Adrenal insufficiency. N Engl J Med 335:1206-1212, 1996. 127. Sampson PA, Brooke BN, Winstone NE: Biochemical conformation of collase due to adrenal failure. Lancet 1:1377, 1961.

PART 8  128. Patten SB, Neutel CI: Corticosteroid-induced adverse psychiatric effects: Incidence, diagnosis and management. Drug Saf 22:111-122, 2000. 129. Naber D, Sand P, Heigl B: Psychopathological and neuropsychological effects of 8-days’ corticosteroid treatment: A prospective study. Psychoneuroendocrinology 21:25-31, 1996. 130. Koning GA, Schiffelers RM, Wauben MH, et al: Targeting of angiogenic endothelial cells at sites of inflammation by dexamethasone phosphate-containing RGD peptide liposomes inhibits experimental arthritis. Arthritis Rheum 54:1198-1208, 2006.

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131. Paul-Clark M, Del Soldato P, Fiorucci S, et al: 21-NO-prednisolone is a novel nitric oxide-releasing derivative of prednisolone with enhanced anti-inflammatory properties. Br J Pharmacol 131: 1345-1354, 2000.

56

KEY POINTS Methotrexate is one of the most durable and frequently used disease-modifying antirheumatic drugs (DMARDs) in monotherapy and is the cornerstone of combination therapy for rheumatoid arthritis (RA). Leflunomide, sulfasalazine, and hydroxychloroquine are effective therapies in RA and are commonly employed in combination therapy. Although the precise mechanisms of action of the traditional DMARDs are incompletely understood, most have antiinflammatory and immunomodulatory actions. Choice of DMARD therapy should be tailored to the individual patient, with attention given to age, fertility plans, concomitant medications, and comorbidities. Toxicity from DMARD therapy can cause significant morbidity and mortality; appropriate dosing and monitoring for toxicity are essential. Combination therapy in RA has been shown to be more effective than monotherapy with one DMARD in groups of patients with early and established RA. Future research is needed to clarify the appropriate timing and combinations of DMARD therapy in individual patients.

METHOTREXATE It would be difficult to overstate the importance of ­methotrexate (MTX) in the contemporary management of ­rheumatic disease and, in particular, rheumatoid ­ arthritis (RA). MTX was introduced more than 50 years ago to treat ­cancer because of its antiproliferative effects. Since the early 1980s, it has become the disease-modifying antirheumatic drug (DMARD) of choice in the treatment of RA and is used in many other rheumatic diseases as well. CHEMICAL STRUCTURE MTX is a structural analogue of folic acid and has ­substitutions in the pteridine group and para-aminobenzoic acid structure (Fig. 56-1). The structure of folic acid (pteroylglutamic acid) consists of three elements: (1) a multiring pteridine group, linked to (2) a para-aminobenzoic acid, which is connected to (3) a terminal glutamic acid residue. ACTIONS OF METHOTREXATE Because MTX is a folate analogue, it enters cells via a reduced folate carrier. Leucovorin competes with MTX for uptake using the same reduced folate carrier; however, folic acid

Methotrexate, Leflunomide, Sulfasalazine, Hydroxychloroquine, and Combination Therapies AMY C. CANNELLA  • JAMES R. O’DELL enters cells via another group of transmembrane ­receptors called folate receptors.1 Folate receptors may be upregulated in cells with increased metabolic activity, including synovial macrophages, and serve as a second conduit for MTX influx.2,3 MTX efflux occurs via members of the adenosine triphosphate–binding cassette (ABC) family of transporters, specifically ABCC1-4 and ABCG2.4 Genetic polymorphisms may affect MTX transporter proteins (influx and efflux) and can result in a variable MTX response and toxicity profile.4 Multidrug resistance proteins have been identified that transport MTX, folic acid, and leucovorin out of cells, leading to MTX resistance.5 When inside the cell, naturally occurring folates and MTX undergo polyglutamation by the enzyme folyl-polyglutamyl synthetase. Polyglutamation of MTX is essential to prevent efflux of MTX, which easily occurs in the monoglutaminated state. Polyglutamated MTX has several key inhibitory effects on intracellular enzymes, which result in its postulated anti-inflammatory and antiproliferative (immunosuppressive) actions: (1) Inhibition of aminoimidazole carboxamide ribonucleotide (AICAR) transformylase (ATIC) results in increased intracellular and extracellular adenosine, (2) inhibition of thymidylate synthetase results in decreased pyrimidine synthesis, and (3) inhibition of dihydrofolate reductase results in inhibition of transmethylation reactions essential for cellular functioning (Fig. 56-2). Inhibition of ATIC by polyglutamated MTX leads to accumulation of AICAR and ultimately to increased levels of adenosine (see Fig. 56-2). Three possible mechanisms are postulated and likely work in combination: (1) AICAR inhibition of adenosine monophosphate (AMP) deaminase leads to excess production of adenosine from AMP; (2) AICAR inhibition of adenosine deaminase (ADA) leads to decreased breakdown of adenosine to inosine; and (3) AICAR stimulation of the ecto-5′-nucleotidase converts extracellular AMP to adenosine (Fig. 56-3).6-8 Adenosine, a purine nucleoside, has been called a “retaliatory metabolite” because of its tissue-protective functions after stressful injurious stimuli.9 Adenosine is a potent inhibitor of inflammation9 and induces vasodilation.10 Adenosine’s anti-inflammatory effects include regulation of endothelial cell inflammatory functions, including cell trafficking,11,12 counterregulation of neutrophils and dendritic cells,9,13 and cytokine modulation of monocytes and 883

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macrophages.9 Adenosine receptor ligation on monocytes and macrophages suppresses interleukin (IL)-12, a strong proinflammatory cytokine.14 Adenosine also suppresses the proinflammatory mediators tumor necrosis factor (TNF)-α, IL-6, IL-8, macrophage inflammatory protein–1α, leukotriene B4, and nitric oxide, and enhances production of the anti-inflammatory mediators IL-10 and IL-1 receptor antagonist.15-20 Adenosine receptor–mediated processes result in inhibition of the synthesis of collagenase.21 Adenosine seems to promote a self-limiting, healthy immune response, hastening the transition from neutrophil-mediated inflammation to a more efficient and highly specific dendritic cell–mediated response. Ultimately, adenosine leads to the resolution of inflammation by downregulating macrophage activation and promoting a shift from a T helper type 1 to a T helper type 2 response.9 Pterin structure H2N

N N

N N

HO

H

N

CONH

Pteroic acid

CO2H CH2 CH2 CH CO2H Glutamic acid

FOLIC ACID (Pteroylglutamic acid)

H 2N

N N

N N

NH2

N

CONH

CH3

CO2H CH2 CH2 CH CO2H

METHOTREXATE (Amethopterin)

Figure 56-1  Chemical structure of folic acid and methotrexate.

In vitro and animal studies have accumulated evidence that the anti-inflammatory effects of MTX are mediated through adenosine.22 Because of adenosine’s short blood half-life of 2 seconds and MTX’s long latent period for active metabolites that modulate adenosine, it has been difficult to show changes in blood adenosine levels directly related to MTX.23 Evidence using forearm blood flow as a surrogate marker for adenosine release in RA patients treated with MTX showed that MTX inhibits deamination of adenosine and potentiates adenosine-induced vasodilation.24 Altered adenosine kinetics shown in patients treated with MTX coupled with adenosine’s known anti-inflammatory effects lends further credence to the hypothesis that MTX increases extracellular adenosine, which likely mediates some of the anti-inflammatory effects of MTX. In addition to vasodilation, adenosine’s cardiovascular effects include negative inotropic and chronotropic cardiac effects, inhibition of vascular smooth muscle cell proliferation, presynaptic inhibition of sympathetic neurotransmitter release, and inhibition of thrombocyte aggregation.10 RA patients have a higher incidence of cardiovascular ­disease than the general population,25 and it may be because of adenosine modulation that MTX has been suggested to have a preferentially beneficial effect on cardiovascular mortality compared with other DMARDs.26 Anti-inflammatory and antiproliferative effects of MTX may be mediated through its inhibition of transmethylation reactions (see Fig. 56-2). MTX and polyglutamated MTX inhibit dihydrofolate reductase, resulting in diminution of tetrahydrofolate. Tetrahydrofolate acts as a proximal methyl donor for several reactions by donating the methyl group for the conversion of homocysteine to methionine. Methionine is converted to S-adenosylmethionine (SAM), which acts as a methyl donor for the methylation of RNA, DNA, amino acids, proteins, and phospholipids and the synthesis of the polyamines spermidine and spermine. On demethylation of SAM to S-adenosylhomocysteine (SAH), SAH is converted to adenosine and homocysteine. The methylation products that depend directly on SAM and indirectly on DHFR to generate THF are required for cellular survival and function, although specific cellular dependence on each varies (see Fig. 56-3).18 Folic acid MTX

Leucovorin

FR

ABC

RFC

MTX

Figure 56-2  Methotrexate (MTX) enters cells ­primarily via the reduced folate carrier (RFC), but can use the folate receptor (FR). When inside the cell, MTX becomes polyglutamated and can ­interfere with several cellular enzymes, including AICAR (aminoimidazole carboximide ribonucleotide) transformylase (ATIC), thymidylate synthetase (TYMS), and dihydrofolate reductase (DHFR). ABC, adenosine triphosphate–binding cassette transporters; FPGH, folylpolyglutamate hydrolase; FPGS, ­folylpolyglutamate synthetase; MTXPG, polyglutamated methotrexate.

FPGH

ATIC

FPGS

MTX - PG

-

DHFR

TYMS Adenosine

Pyrimidine synthesis

Inhibition of transmethylation reactions

Plasma membrane

PART 8 

The role of polyamines warrants further discussion. Spermine and spermidine have been shown to accumulate in the urine,27 peripheral blood mononuclear cells,28 and synovial fluid and tissue29 in patients with RA. Metabolism of polyamines by mononuclear cells gives rise to toxic agents, including ammonia and hydrogen peroxide, which may impair lymphocyte function.30,31 Additionally, accumulation of polyamines in B cells is associated with enhanced production of rheumatoid factor in vitro, and incubation of these cells with methotrexate ­ diminishes their ability to secrete immunoglobulin and rheumatoid factor.18 These effects are seen with high in vitro ­concentrations of MTX and may not translate into in vivo effects of MTX. MTX inhibits methylation of deoxyuridine monophosphate into deoxythymidine monophosphate by thymidylate synthetase, resulting in a further mechanism for disruption of DNA synthesis and proliferation of anti-inflammatory cells (see Fig. 56-2). This effect has been shown in vitro in human peripheral blood mononuclear cells incubated with low concentrations of MTX.32 Cell cycle disruption may lead to apoptosis of mononuclear cells via CD95 (APO-1/ Fas) ligand–dependent33 and independent mechanisms.34 Therefore inhibition of transmethylation reactions may lead to MTX efficacy via antiproliferative and anti-inflammatory mechanisms. Disruption of DNA, RNA, amino acid, and phospholipid synthesis results in its antiproliferative effect, which may be mediated via cellular apoptosis. Decreased levels of polyamines may downregulate the production of toxic agents and rheumatoid factor secretion, leading to anti-inflammatory effects. Theoretically, the aforementioned anti-inflammatory and antiproliferative properties of MTX should make it a potent inhibitor of the immune response that characterizes many rheumatic diseases. MTX has become the cornerstone

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MODALITIES OF THERAPY IN RHEUMATIC DISEASE

of therapy for RA and is efficacious in many other rheumatic diseases. Direct in vitro and in vivo evidence for the ­immunomodulatory effects of MTX exists. Treatment with MTX has been shown to modulate monocytic and lymphocytic cytokines and their inhibitors. MTX has been shown to inhibit proinflammatory cytokine IL-1 secretion and to induce the IL-1 receptor antagonist, effectively inhibiting cellular responses to IL-1.35,36 Soluble TNF-α receptor (sTNFR p75) synthesis upregulation also has been shown as a result of MTX treatment from cultured monoblastic leukemia cells, which results in a diminished TNF-α inflammatory effect.37 MTX also inhibits the production and the secretion of the proinflammatory cytokine IL-6 by cultured human moncytes.38,39 Reverse-transcriptase polymerase chain reaction has been used to study the effects of MTX on gene expression for lymphocytic cytokines.40,41 MTX increases anti-inflammatory T helper type 2 cytokine (IL-4 and IL-10) gene expression and decreases proinflammatory T helper type 1 cytokine (IL-2 and ­ interferon-γ) gene expression in peripheral blood mononuclear cells of patients with RA.41 Prostaglandins and leukotrienes are important mediators of joint destruction in RA. MTX has been shown to modulate the inflammatory enzymes cyclooxygenase and lipoxygenase and their products, prostaglandins and leukotrienes. Thromboxane B2 activity and prostaglandin E2 activity were reduced in the whole blood of RA patients treated with MTX compared with healthy controls.42 MTX also reduces leukotriene B4 synthesis by neutrophils and resulted in a decrease in total plasma leukotriene B4 levels in patients with RA treated with weekly MTX.43 In addition to possible direct effects on cyclooxygenase and lipoxygenase, MTX has been shown to exert an inhibitory effect on neutrophil chemotaxis, which may result in a further reduction of these enzymes in sites of inflammation.44 Intracellular

ATIC

– MTX-PG

FAICAR

IMP –

AMP Deaminase

FGAR GAR

Inosine DHF – MTX-PG DHFR THF

–

ADA

Extracellular

ATP

ATP

ADP

ADP

AMP

AMP +

1 2

AICAR

885

5 NT Adenosine

3

AICAR

Adenosine

Homocysteine MeTHF Methionine SAM Polyamines

SAH

Methylation of phospholipids proteins, RNA, DNA

Figure 56-3  Simplified schema of the effects of polyglutamated methotrexate (MTX-PG) on intracellular and extracellular adenosine production and interference with intracellular transmethylation reactions. ADA, adenosine deaminase; ADP, adenosine diphosphate; AICAR, aminoimidazole carboximide ribonucleotide; AMP, adenosine monophosphate; ATIC, AICAR transformylase; ATP, adenosine triphosphate; DHF, dihydrofolate; DHFR, dihydrofolate reductase; FAICAR, 10-formylaicar; GAR, glycinamide ribonucleotide; IMP, inosine monophosphate; 5′NT, 5′nucleotidase; RNA, ribonucleic acid; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; THF, tetrahydrofolate.

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Methotrexate, Leflunomide, Sulfasalazine, Hydroxychloroquine, and Combination Therapies

Tissue destruction at sites of inflammation is thought to be related to increased synthesis and activity of proteolytic enzymes released by inflammatory cells, particularly in RA. MTX treatment has been shown to reduce gene expression of collagenase, metalloproteinase-1 (MMP-1) and stromelysin, and to upregulate expression of tissue inhibitor of metalloproteinase-1 (TIMP-1).45 MTX may exert direct effects on mRNA for certain enzymes, such as collagenase. MTX also likely exerts indirect effects on gene expression via upstream cytokine modulation (IL-1 and IL-6) in the case of MMP-1 and TIMP-1.46 PHARMACOLOGY Absorption and Bioavailability At low doses, MTX can be administered orally or ­parenterally (subcutaneous or intramuscular), and absorption is rapid, peaking at 1 to 2 hours (oral administration) and 0.1 to 1 hour (parenteral administration). The absorption rates of low-dose oral and parenteral MTX (<15 mg/wk) are roughly equivalent, but when the oral dose exceeds 15 mg/wk, absorption diminishes by 30%.47 Absorption is not reduced by concomitant food intake except for milk, which may be inhibitory,48 but absorption may be reduced in the setting of intestinal pathology, such as inflammatory bowel disease or malabsorptive conditions. Orally administered MTX is absorbed via the gastrointestinal tract and passes through the liver via the portal vein, whereas parenterally administered MTX passes through the liver via the hepatic artery. Although not prospectively studied in RA patients receiving long-term MTX treatment, the parenteral route should have diminished potential for hepatotoxicity, and this effect has been seen in a retrospective study, in which there were more elevations in transaminases when oral MTX was administered to the same patients versus when given parenterally.49 Forty-one RA patients who received 10 mg/m2 of oral MTX had a mean bioavailability of 70% (range, 40% to 100%).50 The mean absorption time was 1.2 hours. Synovial fluid concentrations equal serum levels 4 hours after MTX administration.50 A study of high-dose oral MTX (median dose, 30 mg/wk) showed that mean bioavailability is improved by splitting the dose by 8 hours compared with one single dose (90% versus 76%).51 The pharmacokinetics of subcutaneous MTX are equivalent to intramuscular MTX; maximal serum concentration is attained within 2 hours of injection by either route.52 There also is equivalent bioavailability between tablets and orally administered parenteral solution.53 Distribution and Half-Life MTX is 50% to 60% bound to plasma proteins and has a halflife of approximately 6 hours.50 An increase in free MTX as a result of displacement from albumin by more highly proteinbound drugs, such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and sulfonamides, can occur. This is generally of limited clinical significance with low MTX doses because the increase in free MTX is usually only modest. MTX accumulates in third-space fluids, which can serve as a reservoir for redistribution into the circulation long

after the last dose is administered.54 Caution should be used when administering MTX to patients with pleural effusions or ascites. Unexpectedly high levels of MTX have been seen in patients with bladder cancer who have undergone ileal conduit surgery as a result of enhanced intestinal absorption through the newly fashioned conduit.55 Elimination Most MTX is excreted in the urine within the first 12 hours after administration except for the MTX that has been intracellularly polyglutaminated. MTX undergoes some hepatic metabolism by the enzyme aldehyde oxidase to the 7-hydroxymethotrexate metabolite; this metabolite has unknown significance in RA. MTX and metabolites are excreted by the kidney by glomerular filtration and proximal tubular secretion, but also undergo distal tubular ­reabsorption. Indications Rheumatoid Arthritis. The efficacy of MTX in RA has been clearly established. Four well-designed, blinded, placebo-controlled trials56-59 published in 1984 and 1985 had a tremendous impact on the treatment of RA. These trials varied in design and duration: Two trials used oral MTX, and two used intramuscular MTX; two had a crossover, and two were parallel; and the duration of treatment varied from 6 to 28 weeks. Although the design and duration of therapy in these trials varied, the conclusions did not; all showed MTX to be superior to placebo in the short-term treatment of RA. A meta-analysis of these trials by Tugwell and coworkers60 showed that MTX-treated patients experienced a 37% greater improvement in swollen joint and tender joint scores, a 39% greater improvement in joint pain, and a 46% greater improvement in morning stiffness. MTX was generally well tolerated in these trials; withdrawal rates ranged from 0% to 32% and were mostly for minor toxicities (i.e., stomatitis, nausea). Taken together, the results of these trials firmly established MTX as an effective therapy for the treatment of RA, at least in the short-term. Numerous trials have been done comparing MTX with other DMARDs. A meta-analysis done by Felson and coworkers61 showed that MTX was superior to placebo, auranofin, and probably hydroxychloroquine (HCQ), and comparable to penicillamine, sulfasalazine (SSZ), and intramuscular gold. Notably, no trial has ever suggested that any other synthetic DMARD is superior to MTX. There is accumulating evidence that the short-term benefit of most DMARDs is not sustained, and few patients continue to take these drugs after 3 years.62,63 MTX seems to have the best durability. Pincus and colleagues62 showed that 60% of patients continued MTX at 5 years compared with less than 25% for penicillamine, gold, HCQ, and azathioprine. Of all the DMARDs, MTX seems to have the best efficacy-to-toxicity ratio.61 Despite all the favorable efficacy reports, MTX alone rarely induces remissions of RA; however, it has become the cornerstone of combinations of DMARD therapies, as discussed subsequently.64,65 Rheumatoid Arthritis–Related Conditions. MTX has been used successfully in treating Felty’s syndrome66 and large granulocytic lymphocyte syndrome when it is found in

PART 8 

patients with RA.67 Improvement in neutrophil count occurs within 4 to 8 weeks of MTX initiation in both cases. MTX has been used successfully in adult-onset Still’s disease68 and for cutaneous vasculitis in RA.69 Juvenile Idiopathic Arthritis. MTX is efficacious in juvenile idiopathic arthritis. A definitive, randomized, placebocontrolled trial showed that MTX at a dose of 10 mg/m2 was superior to 5 mg/m2 or placebo.70 Of children who received the higher dose (10 mg/m2) of MTX, 63% improved compared with 32% in the lower dose group (5 mg/m2) and 36% in the placebo group. Psoriatic Arthritis. Numerous prospective and retrospective cohort trials have shown a benefit for MTX in psoriatic arthritis.71 The largest double-blind, randomized trial compared weekly oral MTX with placebo and showed statistically significant results only for physician global assessment of arthritis activity and the amount of affected skin surface area; however, this study was small and may have been underpowered to detect differences in joint count, pain, and swelling.72 Despite the paucity of randomized controlled trial data, MTX remains a commonly used systemic agent in the treatment of psoriatic arthritis. Systemic Lupus Erythematosus. MTX has been shown to be efficacious in controlling cutaneous and articular manifestations of systemic lupus erythematosus (SLE), particularly in disease resistant to antimalarials or requiring high doses of systemic steroids.73 Concomitant folic acid should be administered to abrogate the elevated levels of homocysteine that may be a side effect of MTX therapy, and is considered a risk factor for cardiovascular disease in SLE. The role of MTX in treating more severe SLE involvement, including renal, hematologic, or central nervous system disease, has not yet been established.74 Extreme caution should be employed in patients with renal disease. Vasculitis. MTX in conjunction with corticosteroids has shown efficacy in treating early and non–life-threatening Wegener’s granulomatosis, including upper airway disease and mild renal disease.75-78 In addition to induction of remission, MTX has been shown to maintain remission in Wegener’s granulomatosis, although vigilance for relapse is warranted.79 Despite a lack of well-designed studies, MTX has been shown to be efficacious in corticosteroid-resistant Takayasu’s arteritis80 and relapsing polychondritis.81 The use of MTX for polymyalgia rheumatica and giant cell arteritis has been controversial. Multiple open label studies have shown differing results. Randomized, placebocontrolled trials of MTX in addition to corticosteroids in polymyalgia rheumatica and giant cell arteritis have shown conflicting results.82-85 The routine use of MTX in either polymyalgia rheumatica or giant cell arteritis has not been adopted, but some authors advocate for its use in an effort to taper corticosteroid more rapidly in patients with intolerant side effects. Inflammatory Myopathies. A review of the published reports of MTX and the inflammatory myopathies, polymyositis and dermatomyositis, shows overall positive results.86 Despite the frequent use of MTX in the inflammatory

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MODALITIES OF THERAPY IN RHEUMATIC DISEASE

887

mypoathies, a Cochrane database review reveals a paucity of well-designed trials.87 Other Rheumatic Diseases. MTX has been used in systemic sclerosis. One randomized controlled trial looking at MTX use in early systemic sclerosis showed a trend in benefit for skin scores and pulmonary diffusion capacity and a significant benefit for physician global assessment.88 A second randomized controlled trial in established systemic sclerosis showed significant benefit for skin scores and total creatinine clearance.89 In addition, prospective trials have shown that MTX is efficacious in treatment of corticosteroid-resistant multisystem sarcoidosis,90,91 and a more recent randomized controlled trial showed that if initiated early in sarcoidosis, MTX is an effective steroid-sparing agent.92 MTX also has been shown to be effective as primary treatment and as a corticosteroid-sparing agent in inflammatory ocular disease.93,94 Finally, MTX in combination with corticosteroids is also effective in the treatment of multicentric reticulohistiocytosis.95 DOSE AND DRUG ADMINISTRATION MTX is available as 2.5-mg, 5-mg, 10-mg, and 15-mg tablets, and as a solution of 25 mg/mL, for subcutaneous or intramuscular injection. The starting dose is usually 5 to 10 mg given as a single weekly dose. More frequent administration is associated with a significantly increased risk of liver toxicity,96 but occasionally, to improve tolerability, the MTX dose may be divided into two doses and each half given 8 to 12 hours apart. The dosage of MTX can be titrated, usually every 4 to 8 weeks to 25 mg/wk, to achieve the desired clinical response. MTX may be administered orally via tablet or parenteral solution, the latter being less costly. Because the bioavailability varies and seems to decrease at higher doses, a trial of parenteral MTX is generally recommended if patients have active disease despite oral doses of approximately 20 mg/wk. Concomitant administration of folic acid (1 to 3 mg/day) decreases the frequency of toxicities, including mucositis, nausea, hematologic abnormalities, and liver enzyme elevations, without seemingly interfering with the clinical efficacy.97,98 Folic acid administration also decreases the hyperhomocystinemia that patients on MTX therapy may develop, and this may be important to help decrease the already high cardiovascular risk of patients with RA. Low-dose folinic acid also has been used and can markedly reduce MTX toxicity in rheumatic disease therapy without interfering with efficacy if given in doses of 2.5 to 5 mg/wk and not administered until 24 hours after the MTX dose. Because folic acid is widely available and less expensive, it is preferred by most clinicians. Geriatric Patients Patients older than 65 years represent a special subset of patients receiving pharmacotherapy. Pharmacokinetic profiles are changed in the elderly, including drug distribution owing to decreases in end-organ blood flow and lean body mass, decreased hepatic drug metabolism, and decreased renal drug excretion. Elderly patients are more likely to have multiple comorbidities, polypharmacy, noncompliance,

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Methotrexate, Leflunomide, Sulfasalazine, Hydroxychloroquine, and Combination Therapies

Table 56-1  Special Considerations with Use of Methotrexate, Leflunomide, Sulfasalazine, and Hydroxychloroquine Methotrexate

Leflunomide

Sulfasalazine

Hydroxychloroquine

Fertility

Pregnancy

Lactation

Elderly

Women—no effect

Contraindicated

Contraindicated

Men—reversible   sterility Stop 3 mo before   conception

FDA category X

Present in breast milk

Lower initial dose   (5-7.5 mg/wk) Dose based on creatinine clearance

No effect

Contraindicated

Contraindicated

Test levels before  conception May require washout

FDA category X

Unknown concentrations in breast milk

Women—no effect

Relatively safe

Abortifacient Teratogenic No dosage adjustment required

Embryolethal Teratogenic Relatively safe

Men—reversible sterility

FDA category B, C

Present in breast milk

No effect

Relatively safe FDA category C

Relatively safe Present in breast milk

No dosage adjustment required No dosage adjustment required

FDA, Food and Drug Administration.

increased risk for dosage errors, and limited access to medication for financial reasons.99 In practice, recommended doses should be reduced when initiating therapy and adjusted for renal function based on creatinine clearance.100 The serum creatinine may be a misleading measure of renal function in older patients because of an overall reduction in lean muscle mass. Dosing recommendations are as follows: Initial doses should be around 5 to 7.5 mg/wk and should not exceed 20 mg/wk. Dosage adjustments for creatinine clearance are as follows: When creatinine clearance is 61 to 80 mL/min, dose is reduced by 25%; 51 to 60 mL/min, dose is reduced by 30%; 10 to 50 mL/min, dose is reduced by 50% to 80%; and less than 10 mL/min, use of MTX should be avoided (Table 56-1).101 TOXICITY Despite initial concerns, when given once a week in the doses used for rheumatic diseases and monitored correctly, MTX is well tolerated. Some toxicities of MTX (stomatitis, nausea, bone marrow depression) are dose dependent, seem to be related to folate deficiency, and respond to folate replacement. Other toxicities seem to be idiosyncratic or allergic and in most cases require discontinuation of MTX (e.g., pneumonitis). Still other toxicities, such as liver fibrosis and cirrhosis, seem to be multifactorial and may depend on the presence of concomitant risk factors, total dose, and frequency of administration. Gastrointestinal and Hepatic Side Effects Gastrointestinal symptoms, including dyspepsia, nausea, and anorexia, are common, occurring in 20% to 70% of patients within the first year of therapy.102 These symptoms may be attenuated by the addition of folic acid or by changing to a parenteral dosing regimen.

The risk of significant liver toxicity seems to be low when MTX is given once weekly to patients who abstain from alcohol consumption and are monitored carefully, and is on the order of 1 case per 1000 after 5 years of use.103 Alcohol consumption, α1-antitrypsin deficiency, morbid obesity, diabetes, and chronic hepatitis B or C all have been implicated as possible risk factors for MTX toxicity.104 Hematologic Side Effects Bone marrow toxicity, in most cases, is dose dependent and responds to folic acid administration. Pancytopenia, leukopenia, anemia, and thrombocytopenia can occur, but are rare. In a review by Gutierrez-Urena and colleagues,105 it was found that clinically significant pancytopenia may develop in 1% to 2% of RA patients on MTX therapy. Severe, life-threatening bone marrow toxicity can be treated with folinic acid (leucovorin) and, if necessary, granulocyte colony-stimulating factor. Because the elimination of MTX depends on the kidney, decreases in renal function may precipitate bone marrow toxicity in patients who have been previously stable. Additional risk factors include hypoalbuminemia, dosing errors, and concomitant use of trimethoprim-sulfamethoxazole. Pulmonary Side Effects Five clinical pulmonary syndromes have been associated with MTX treatment: acute interstitial pneumonitis (hypersensitivity pneumonitis), interstitial fibrosis, noncardiogenic pulmonary edema (seen in high-dose treatment for malignancy with rare reports in RA), pleuritis and pleural effusions, and pulmonary nodules.106 Time lapse from initiation of therapy and cumulative dose before the onset of pulmonary toxicity varies from 1 to 480 weeks and 7.5 to 3600 mg of MTX.106 MTX-induced pulmonary disease is rare and difficult to quantify, but estimates suggest an

PART 8 

incidence of 3.9 cases per 100 patient-years of MTX exposure and a prevalence of 2.1% to 5.5%.107,108 Patients with pneumonitis generally present with shortness of breath, tachypnea, dry cough, and fevers. Chest radiographs typically show a bilateral interstitial infiltrate (although this varies). Infectious causes, including opportunistic organisms, must always be ruled out. If routine evaluations for infection, including sputum studies, and for other medical conditions fail to explain the pulmonary symptoms, bronchoscopy with bronchoalveolar lavage and transbronchial biopsy is recommended. If MTX pulmonary toxicity is suspected, MTX should be discontinued, and supportive treatment should be initiated, with the use of corticosteroids in more severe cases. Some patients with pulmonary toxicity have been successfully restarted on MTX,109 but some clinicians have reported mortality in 50% of retreated patients.110 Factors that seem to predispose to MTX lung toxicity include age, blue-collar occupation, smoking (in women), diabetes, pleuropulmonary rheumatoid disease, and skin rashes from MTX.111 Mucocutaneous Side Effects The mucocutaneous toxicities of MTX, which have been reported to occur in one third of patients, are dose dependent and respond to folate replacement. Patients generally complain of fairly minor oral ulcerations, but severe ulceration of the mouth, esophagus, bowel, and vagina can occur, especially at higher doses. Malignancies The induction of malignancies by MTX is a concern, and several studies have examined this question with conflicting conclusions. Some reports of lymphoma in MTX-treated RA patients have appeared more recently. Because the incidence of lymphoma is increased in RA patients anyway,112 these reports are difficult to interpret. The case for a causative role of MTX has been strengthened, however, because many of these cases have been B cell lymphomas of the type commonly seen in association with immunosuppression and that regress after the discontinuation of MTX.113,114 ­Subsequently, a lack of a causal relationship between MTX treatment and the development of lymphoma has been seen in two large series of RA patients, one prospective study112 and one retrospective study.115 The potential benefits of MTX for most RA patients far outweigh these statistically small risks.116 Miscellaneous Methotrexate Flu. Patients taking MTX may describe flulike symptoms shortly after taking their weekly dose. Nausea, low-grade fevers, myalgias, and chills are the most common signs of so-called methotrexate flu. These side effects usually respond to supplementing with folic acid, decreasing the dose, switching from oral to parenteral administration, or changing the time of the dose (so that the patient takes MTX right before going to bed). Nodulosis. The development of, or increase in, the number or size of rheumatoid nodules has been reported to occur in

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MODALITIES OF THERAPY IN RHEUMATIC DISEASE

889

RA patients treated with MTX with a prevalence of 8%.117 Nodulosis may occur in rheumatoid factor–negative patients and when the synovitis is under excellent control. The mechanism of this nodule formation has been suggested to be due to an increase in adenosine, which seems to promote nodule formation.118 Conversely, nodules also have been reported to decrease during MTX therapy. Vasculitis. Despite efficacy in the treatment of the cutaneous vasculitis associated with RA, leukocytoclastic vasculitis also has been attributed to MTX therapy.119 Fertility, Pregnancy, and Lactation MTX does not seem to affect female fertility adversely, but can cause reversible sterility in men.120 Women and men should discontinue MTX for at least 3 months before attempting to conceive because of its large distribution and long half-life in the liver. Folic acid supplementation is essential before conception. MTX is in Food and Drug Administration (FDA) pregnancy category X and is contraindicated in pregnancy. Women of childbearing age who are considered for MTX therapy should have extensive counseling regarding teratogenic risk and be placed and maintained on adequate contraception before initiation of therapy. Toxicities include fetal abnormalities, including “aminopterin syndrome” (multiple craniofacial, limb, and central nervous system abnormalities), embryonic loss, or fetal loss. MTX at high doses (1 mg/kg) is an effective abortifacient. MTX also is contraindicated during lactation because small amounts are excreted in breast milk (see Table 56-1). Toxicity Monitoring A set of guidelines published by the American College of Rheumatology (ACR) provides excellent recommendations for starting and monitoring MTX therapy.121 Toxicities that require monitoring include myelosuppression, hepatotoxicity, and pulmonary toxicity. Baseline evaluation should include a complete blood count with platelets, chest radiograph within the past year, hepatitis B and C serology in high-risk patients, aspartate aminotransferase (AST) or alanine aminotransferase (ALT), albumin, and creatinine. Liver biopsy before initiating MTX is not routinely recommended. In the rare patient whom the clinician wants to treat with MTX despite abnormalities in screening laboratory or other significant risk factors, liver biopsy may be required before starting MTX. In addition, biopsy is recommended only in patients who continue to have enzyme abnormalities and for whom continuation of MTX therapy is contemplated. Monitoring for toxicity should be done every 4 to 8 weeks. Systems review and physical examination should include monitoring for symptoms or signs of myelosuppression (fever, infection, bruising, and bleeding), pulmonary toxicity (shortness of breath, cough, rales), gastrointestinal intolerance (nausea, vomiting, diarrhea), and lymphadenopathy. Laboratory parameters that should be followed are a complete blood count with platelets, AST or ALT, albumin, and creatinine. It is important to consider vaccination status in any patient who is going to use MTX. RA patients have an increased incidence of death from pneumonia,122 and MTX may

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reduce the immune response to pneumococcal antigen.123 Any patient in whom MTX is going to be used should first receive the pneumococcal vaccination. Any patient already on MTX should not receive live virus vaccinations because they are at increased risk for vaccine-induced infections. DRUG INTERACTIONS AND CONTRAINDICATIONS Drug Interactions Drugs that are known hepatotoxins, such as SSZ, leflunomide, and azathioprine, may potentiate liver toxicity when used in combination. Organic acids, such as sulfonamides, salicylates, NSAIDs, penicillin G, piperacillin, and probenecid, competitively inhibit tubular secretion, which delays MTX clearance.124 MTX also undergoes distal tubular reabsorption, which may be enhanced by the addition of HCQ125 and blocked by the addition of folic acid.21,124 Drugs that affect renal function should be used with caution because of the renal clearance of MTX and the increased risk of MTX toxicity that could occur because of decreased clearance. Several of the aforementioned drugs warrant special mention. Trimethoprim-sulfamethoxazole should be avoided or used with extreme caution because of possible hematologic toxicity with MTX. Mechanisms for this toxicity include an additive antifolate effect from trimethoprim, decreased MTX clearance owing to inhibition of tubular secretion by sulfamethoxazole, and altered MTX plasma protein binding. NSAIDs are commonly used in RA patients as adjunctive therapy. NSAIDs may increase MTX levels by displacing MTX from plasma proteins and limiting tubular secretion. Despite lack of a significant pharmacokinetic or clinical interaction between low-dose MTX and a variety of NSAIDs,126 vigilance for MTX toxicity should increase whenever NSAID dosages are changed in patients on stable weekly doses of MTX. Low doses of aspirin used for cardiovascular prophylaxis are not likely to be concerning. Probenecid should be avoided because it inhibits tubular secretion of MTX. Contraindications MTX should not be used in severe renal, pulmonary, or hepatic impairment; preexisting bone marrow suppression; alcoholic liver disease; acquired immunodeficiency syndrome (AIDS); and pregnancy or breastfeeding. In most cases, patients who desire to continue drinking alcohol should not be treated with MTX. Mild-to-moderate renal insufficiency is a relative contraindication, and use of MTX in these patients may require more vigilant toxicity ­monitoring.

LEFLUNOMIDE Leflunomide is a synthetic DMARD approved for the treatment of RA. It emerged from a specific anti-inflammatory drug development program and has potent immunomodulatory effects. CHEMICAL STRUCTURE Leflunomide is a low-molecular-weight isoxazole compound and is chemically unrelated to any previous immunosuppressant. Leflunomide is a prodrug and is rapidly and completely

Leflunomide

CO

NH

CF3

N O

CH3 OH– O NH

F 3C

C

C

C

CH3

N

OH

Active metabolite-A77 1726 Figure 56-4  Leflunomide is rapidly and completely metabolized to its active metabolite, A77 1726.

converted to its active metabolite, malononitriloamide A77 1726 (Fig. 56-4). ACTIONS OF LEFLUNOMIDE Similar to MTX, the precise mechanism of action of leflunomide in rheumatic disease is not completely understood.127 Leflunomide is immunomodulatory with the net effect being a reduction in activated T lymphocytes. Its two in vitro mechanisms of action vary depending on concentration: (1) At the concentration of the active metabolite (A77 1726) achieved in patients, its major effect seems to be a reversible inhibition of the enzyme dihydroorotate dehydrogenase (DHODH), which results in inhibition of pyrimidine synthesis; (2) at higher concentrations, A77 1726 also inhibits tyrosine kinases, interfering with cell signal transduction.128 Activation of T cells results in a progression from the resting phase (G0) to the G1 phase, where ribonucleotides are synthesized, and then to the S phase, where cellular DNA is replicated in preparation for mitosis. T cell activation requires significant increases in de novo pyrimidine and purine biosynthesis. There are sensors, such as protooncogenes (p53), and checkpoints (cyclins C and D), in this pathway that monitor the level of nucleotide pools and prevent damaged cells from replicating.128 Uridine monophosphate (rUMP) is a precursor for the formation of pyrimidine nucleotides and is essential for RNA and DNA synthesis. The steps in de novo rUMP synthesis are shown in Figure 56-5. A crucial step in this pathway is the generation of dihydroorotate in the cytoplasm with subsequent diffusion into the mitochondria where the enzyme DHODH is located. DHODH converts dihydroorotate to orotate, and the latter diffuses back into the cytoplasm and is subsequently converted to rUMP and ultimately to RNA and DNA.

PART 8 

ATP + Glutamine Carbamyl phosphate synthetase II Carbamoyl phosphate

| 

MODALITIES OF THERAPY IN RHEUMATIC DISEASE

RNA

DNA

rCTP

dTMP

rUTP

dUMP

891

rUMP

Carbamoyl aspartate

Orotidine monophosphate

Dihydroorotate

A77 1726 Dihydroorotate dehydrogenase Dihydroorotate

Orotate Coenzyme Q

Figure 56-5  Leflunomide’s active metabolite, A77 1726, blocks the conversion of dihydroorotate to orotate within the mitochondria.

MITOCHONDRIA

The first postulated mechanism of action of leflunomide is that inhibition of DHODH by A77 1726 reduces orotate levels and leads to a decrease in rUMP and subsequent nucleotide synthesis, resulting in T cell cycle arrest. This mechanism of action has been substantiated by experimental evidence. In vitro mitogen-stimulated activation of T cells is blocked by levels of A77 1726 that inhibit DHODH, and this inhibition can be reversed by the addition of uridine, suggesting that A77 1726 works by disruption of pyrimidine biosynthesis. 129,130 The only enzyme inhibited by A77 1726 in this pathway, at concentration obtained in vivo, is DHODH.131 Evidence also exists to support that inhibition of DHODH produces an arrest of lymphocytes in the G1 phase of the cell cycle.132 If the level of ribonucleotides, including rUMP, decreases below a critical point, cytoplasmic p53 activation occurs, and p53 translocates to the nucleus and initiates cellular arrest by ultimately preventing transcription of cyclins D and E. In cultures of human T cells, A77 1726 depletes rUMP pools and results in an accumulation of nuclear p53 with resultant cell cycle arrest.133 In comparison, treatment of cell lines lacking p53 with A77 1726 does not cause a G1 phase arrest.134 Resting lymphocytes maintain ribonucleotide requirements largely through salvage pathways and are essentially unaffected by leflunomide.135 Active, or autoimmune, lymphocytes rely on the de novo pathway and are affected by leflunomide. Over the course of treatment with this slow-acting agent, autoimmune lymphocytes should be progressively removed.128 At higher concentrations, A77 1726 inhibits phosphorylation of tyrosine kinases that are crucial for cell growth and differentiation of activated cells.136,137 This inhibition has been proposed to explain partially or completely leflunomide’s antiproliferative effects; however, it is unclear whether concentrat­ ions sufficient to achieve this effect are obtained in vivo.

Several other additional anti-inflammatory properties of leflunomide have been noted. Leflunomide has the ability to block the activation of nuclear factor κB (NFκB),138 which regulates the expression of genes important in inflammatory processes, including genes seen in inflammatory arthritis.139 Ex vivo and in vitro studies in humans have shown that leflunomide and MTX inhibit neutrophil chemotaxis, which may decrease the recruitment of inflammatory cells into the joints.44 Leflunomide also has been shown to decrease the ratio of MMP-1 to TIMP-1.44 Finally, leflunomide alters the synthesis of cytokines by augmenting the immunosuppressive cytokine transforming growth factor-β1 and suppressing the immunostimulatory cytokine IL-2.140 PHARMACOLOGY Absorption and Bioavailability The gastrointestinal tract and liver rapidly and completely convert ingested leflunomide into A77 1726. Food does not interfere with absorption. Circulating A77 1726 is highly bound (>99%) to plasma proteins, predominantly albumin. Its plasma concentration is linearly correlated with a single oral dose over a range of 5 to 25 mg; steady state is reached in 7 weeks after daily dosing.141 Distribution and Half-Life A77 1726 has a half-life of approximately 2 weeks (mean 15.5 days), with a low apparent volume of distribution.141 A77 1726 undergoes enterohepatic recirculation. In healthy subjects, 90% of leflunomide is excreted by 28 days,141 but some may be present for much longer periods.

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Elimination In healthy subjects, the proportions excreted by the kidney and gut are nearly equal. Because detectable A77 1726 may be present in the body months or years later, the ability to eliminate A77 1726 rapidly and effectively with cholestyramine is important. Oral administration of cholestyramine, 8 g three times daily, can reduce the apparent half-life of A77 1726 to 1 to 2 days.142 Activated charcoal, 50 g every 6 hours, can reduce plasma levels by 50% within 24 hours.142 Indications Rheumatoid Arthritis. Leflunomide was first shown to be safe and effective in treating RA in a placebo-controlled, dose-ranging, 6-month trial.141 Two pivotal trials, one in Europe and one in the United States, have been done comparing leflunomide with SSZ and MTX. The European trial had three arms: leflunomide, 20 mg/day after a loading dose; SSZ, escalated to 2 g/day; and placebo.143 In this trial, leflunomide and SSZ were superior to placebo in terms of swollen and tender joint counts and physicians’ and patients’ overall assessment. The leflunomide and SSZ groups reported significant effects on slowing radiographic progression of disease compared with placebos. The U.S. trial compared patients treated with leflunomide, 20 mg/day after a loading dose; MTX, 7.5 to 15 mg/wk; or placebo.144 Both active drugs were found to be superior to placebo, but not different from each other. Leflunomide and MTX also slowed radiographic progression of disease compared with the placebo group. Another trial compared leflunomide, 20 mg/day with loading, with MTX, 10 to 15 mg/wk, in a 1-year trial with a 1-year extension (Table 56-2).145 In this trial, MTX was shown to be statistically superior to leflunomide for the clinical outcomes measured and the rate of radiographic progression after 2 years. Other Rheumatic Diseases. Leflunomide has been reported to be efficacious in SLE. In a randomized controlled trial, leflunomide was more effective than placebo in improving markers of SLE disease activity and was safe and well tolerated.146 A subsequent small, prospective, open label trial of patients with lupus nephritis unresponsive to conventional therapy showed that leflunomide was efficacious and well tolerated.147 Leflunomide has been shown to be effective in treating psoriatic arthritis and psoriasis compared with placebo.148 In an open label trial of ankylosing spondylitis, leflunomide was shown to be effective in treating peripheral arthritis, but axial symptoms did not improve.149 An open label150 and a randomized controlled clinical trial151 have shown leflunomide’s efficacy in ­ maintaining Table 56-2  Leflunomide Trial Withdrawals   for Adverse Event No. Patients

Withdrawals

Leflunomide

816

154 (19%)

Methotrexate

680

  94 (14%)

Sulfasalazine

133

  25 (19%)

Placebo

210

  16 (8%)

remission in Wegener’s granulomatosis after successful induction with cyclophosphamide. In the latter trial, leflunomide was superior to MTX in preventing relapse.151 DOSE AND DRUG ADMINISTRATION Leflunomide is available in oral tablets at doses of 10 mg, 20 mg, and 100 mg. Oral leflunomide is metabolized rapidly to A77 1726, which has a very long half-life; the standard recommendation is to start therapy with a loading dose of 100 mg daily for 3 days, then switch to the standard maintenance dose of 20 mg daily. Despite this recommendation, most clinicians no longer prescribe a loading dose because it is believed to increase the drug’s gastrointestinal toxicity.152 Also, it is common practice to decrease the dose to 10 mg daily if toxicity occurs, or if complete control of the disease can be maintained. Because of its long half-life, some clinicians give leflunomide less often (three to five times per week). Geriatric Patients No pharmacokinetic studies specific to geriatric patients have been done for leflunomide. Dosing recommendations are the same as for the general population. There is no clinical experience in patients with renal insufficiency, so such patients should be monitored carefully. TOXICITY For the major controlled trials that have used leflunomide at the dose of 20 mg/day, the incidence of adverse events that resulted in trial withdrawal are shown in Table 56-2. Leflunomide-associated withdrawals (19%) were more frequent than withdrawals associated with MTX (14%), were similar in frequency to withdrawals associated with SSZ (19%), but more frequent than withdrawals associated with placebo treatment (8%). Gastrointestinal and Hepatic Side Effects The most common side effect that limits the use of leflunomide is diarrhea, which responds to dose reduction and may be less common if the loading dose is not used.153 Abdominal pain, dyspepsia, and nausea from leflunomide seem to be slightly increased over placebo rates. It is apparent from more recent reports that liver toxicity, although rare, does occur in association with leflunomide administration. The incidence of elevations of transaminase levels out of the normal range in clinical trials is not published; some studies report information on levels that are two or three times the upper limits of normal. There also is a paucity of data from clinical trials on liver biopsies in leflunomide-treated patients. The European Agency for Evaluation of Medicinal Products reported 296 cases of hepatic abnormalities and 15 patients with liver failure and death while taking leflunomide154; additional cases of liver toxicity in patients taking leflunomide have been reported in Australia.155 Most patients with hepatotoxicity have risk factors, including concomitant administration of another hepatotoxic agent or underlying liver disease or other comorbidities. Conversely, data from a large U.S. RA database failed to show any difference in liver abnormalities

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in patients receiving leflunomide compared with patients treated with MTX.156 Until further information is available, it seems prudent to follow transaminase levels and adjust the dose of leflunomide for any elevations, as is done for MTX.

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should undergo the same washout procedure as women and should wait an additional 3 months after the second drug plasma level is verified less than 0.02 mg/L. Toxicity Monitoring

Cardiovascular Side Effects Hypertension has consistently been reported to occur more frequently in leflunomide-treated patients compared with placebo-treated patients.143,144 Additionally, elevation of cholesterol levels has been reported in association with leflunomide use.157 Both of these effects should be monitored because of the excess cardiovascular mortality in patients with RA. Miscellaneous Dermatologic. Skin rashes have been reported, most commonly occurring between the second and fifth month, and necessitate discontinuation of the drug. Severe skin reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis, require leflunomide washout with cholestyramine. An increased incidence of alopecia has been reported in clinical trials in association with leflunomide. Pulmonary. There have been rare postmarketing reports of interstitial lung disease, including interstitial pneumonitis and pulmonary fibrosis. Hematologic. Rare cases of pancytopenia have been reported in postmarketing surveillance, primarily in patients with known risk factors for blood dyscrasias. There has not been an increased risk of lymphoproliferative disorders with leflunomide. Weight Loss. Significant weight loss also has been reported to occur with leflunomide.158 Fertility, Pregnancy, and Lactation Leflunomide is rated FDA pregnancy category X. Animal studies have shown substantial teratogenic and embryolethal effects with small doses of leflunomide. Women of childbearing potential should be strongly counseled about this, and leflunomide should not be prescribed for women who are not practicing reliable birth control methods. A pregnancy test should be considered before initiation of therapy. Leflunomide excretion in milk is unknown; nursing mothers should not receive leflunomide (see Table 56-1). Leflunomide’s active metabolite, A77 1726, may remain in the body for years, largely because of its enterohepatic circulation. If a woman who has previously received leflunomide desires to become pregnant, A77 1726 levels should be measured. Active elimination of leflunomide from the body should be considered for levels greater than 0.02 mg/L. Elimination can be achieved by the oral administration of cholestyramine for 11 days (8 g three times daily).159 Before attempting pregnancy, levels less than 0.02 mg/L should be confirmed on two separate occasions, at least 14 days apart, and women should wait an additional three full menstrual cycles.160 Patients may require more than one course of cholestyramine to achieve this level. Although no data exist, men wishing to father children

Patients taking leflunomide should have a baseline complete blood count and liver enzyme monitoring, including AST, ALT, and albumin. Serum creatinine is important because leflunomide is partially eliminated by the kidney. The complete blood count and liver tests should be repeated monthly for the first 6 months and then every 6 to 8 weeks thereafter, with dosage adjustments for abnormal test results. More frequent monitoring may be warranted if concomitant immunosuppressive agents, such as MTX, are given. If patients experience a significant toxicity, a washout procedure is indicated to eliminate the drug more rapidly. Live vaccinations should be avoided in patients on leflunomide. DRUG INTERACTIONS AND CONTRAINDICATIONS Drug Interactions Cholestyramine interferes with enterohepatic recycling of leflunomide and results in lower serum concentrations. Concomitant use with hepatotoxic agents, including MTX, increases the risk of liver toxicity, and such use must be approached with caution and monitored judiciously. Rifampin may increase the serum concentration of A77 1726. Leflunomide may potentiate warfarin therapy. Contraindications Leflunomide should not be used in patients with impaired liver function, severe renal impairment, bone marrow dysplasia, severe immunodeficiency, severe hypoproteinemia, or known hypersensitivity to the drug. The liver is involved in enterohepatic recirculation and biliary excretion; leflunomide use in liver disease is contraindicated. In renal insufficiency, the levels of circulating A77 1726 do not seem to be increased, but the component of free A77 1726 is. Leflunomide is contraindicated in the setting of serious infection and should be discontinued in patients with new or ­worsening pulmonary symptoms or rash. Leflunomide is absolutely contraindicated in pregnancy.

SULFASALAZINE In 1938, SSZ was the first agent to be synthesized specifically for rheumatoid arthritis by Svartz in Stockholm, in collaboration with the Swedish pharmaceutical company Pharmacia. The prevailing notion at that time was that RA was caused by an infection, and SSZ was designed with antiinflammatory and antibacterial properties. CHEMICAL STRUCTURE Salazosulfapyridine (SASP), now known as sulfasalazine, is a conjugate of the anti-inflammatory 5-aminosalicylic acid (5-ASA or mesalamine) and the antibacterial sulfapyridine joined by an azo bond (Fig. 56-6). The abbreviation SASP is still in use as an alternative to SSZ.

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HOOC HO

N

N

SO2

NH N

Colonic bacteria

HOOC HO

NH2

H2N

SO2

NH N

5-Aminosalicylic acid

Sulfapyridine

Figure 56-6  Sulfasalazine and its major metabolites.

ACTIONS OF SULFASALAZINE Despite more than 7 decades of use, the mechanism of action of SSZ in rheumatic disease is still not fully elucidated. When SSZ was designed, its antimicrobial properties were thought to be fundamentally important in its successful treatment in RA, which was postulated to be an enteropathic arthropathy.161 By alteration of gut flora, SSZ may downregulate the immune response leading to inflammatory arthritis. Although this hypothesis has never been disproved, this mechanism of action has fallen out of favor for several reasons, as follows: To date, there is no conclusive evidence for an infectious etiology for RA; other sulfonamides have failed to result in clinical improvement; and a relationship between gut flora and clinical response to SSZ is lacking.162 Currently, SSZ is presumed to work via anti-inflammatory and immunomodulatory effects. SSZ has been shown in vitro to possess multiple antiinflammatory properties. First, SSZ weakly inhibits the ­proinflammatory effects of the arachidonic acid cascade, with a slight inhibitory effect on prostaglandin E2 synthetase ­activity163 and lipoxygenase products.164 SSZ also downregulates neutrophil chemotaxis, migration, proteolytic enzyme production, and degranulation,165,166 and has been shown to inhibit neutrophil activation by decreasing the flux of second messengers involved in intracellular signal transduction.167 Neutrophil migration to sites of inflammation can be downregulated by adenosine. It has been shown that SSZ inhibits folate-dependent enzymes, including ATIC and dihydrofolate reductase, resulting in increased adenosine release into the extracellular milieu.168 Gadangi and coworkers169 confirmed that SSZ, similar to MTX, modulates inflammation via increased adenosine release. This effect seems to be due solely to SSZ because sulfapyridine and 5-ASA are inactive. SSZ is a more potent inhibitor of ATIC than MTX.170 SSZ also has been shown to possess multiple immunomodulatory properties. In vitro, SSZ inhibits T cell proliferation, natural killer cell activity, and B cell activation, with resultant declines in immunoglobulin synthesis and rheumatoid factor production.162 In all of these systems, sulfapyridine and 5-ASA are less active than SSZ. Cytokine profiles also are altered by SSZ, resulting in inhibition of the

T cell cytokines IL-2171 and interferon-γ,172 and the monocyte/macrophage cytokines IL-1, TNF-α, and IL-6.173 NFκB is a key transcription factor that when active mediates the transcription of key cytokines, adhesion molecules, and chemokines essential to mounting an immune response. In vitro, SSZ, but not sulfapyridine or 5-ASA, inhibits NFκB translocation to the nucleus.174 SSZ, more so than sulfapyridine, inhibits endothelial cell proliferation and angiogenesis, which likely contribute to the synovitis of RA.175 The synovial fibroblast also plays a key role in the pathogenesis of RA, and SSZ inhibits fibroblast proliferation and metalloproteinase synthesis.176 Finally, SSZ has been shown to inhibit the formation of osteoclasts and may be antiresorptive in RA.177 The active moiety of SSZ is controversial. The parent compound, SSZ, seems to have the most biologic activity compared with sulfapyridine and 5-ASA. The SSZ levels needed in vitro to see the anti-inflammatory and immunomodulatory effects are far greater, however, than the levels obtained in vivo. A demonstrable relationship between plasma SSZ, sulfapyridine, or 5-ASA levels that correlate with clinical efficacy has not been shown, so serum levels may be irrelevant.162 In an open, nonrandomized study comparing two groups of patients who received either sulfapyridine or 5-ASA in doses that would represent the molar equivalent of 2 g of SSZ, the group receiving sulfapyridine had significant improvements in erythrocyte sedimentation rate and some clinical parameters, including grip strength and joint circumference.178 Taken together, SSZ and sulfapyridine both seem to have a role in the therapeutic efficacy seen in RA. One potential site of action for SSZ that may explain its systemic action despite its low serum levels is the mucosa-associated lymphoid tissue (MALT) in the small bowel.162 In the gut lumen, the therapeutic concentration of SSZ is at least two times greater than in the serum, and drug concentration in the surrounding mucosal tissue is likely also high. The gut immune system is extensive, and active communication with the rest of the body occurs via migration and recirculation of activated lymphocytes.162 A link between MALT and the joints has been ­suggested.179 ­Evidence that some of the efficacy of SSZ may be mediated via MALT is as follows: Treatment with SSZ has been shown to decrease circulating IgA-producing cells and serum levels of IgA, correlating with disease improvement,180 SSZ has been shown to reduce gut mucosa lymphocytes in treated patients,181 and SSZ has been shown to modulate an immune response elicited by an oral antigen in mice and healthy volunteers.182 PHARMACOLOGY Absorption and Bioavailability Less than 30% of SSZ is absorbed by the small bowel, and most undergoes enterohepatic circulation and is secreted unchanged in the bile, with a resulting bioavailability of 10%.162 The steady-state serum concentration of SSZ is 5 μg/ mL after an oral dose of 2 g/day. Most SSZ reaches the colon where intestinal bacteria reduce the azo bond and release the two active components, sulfapyridine and 5-ASA.183 Most of the sulfapyridine is absorbed from the colon (>90%) and appears in plasma 4 to 6 hours after an oral dose (steady-state

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Table 56-3  Methotrexate, Leflunomide, Sulfasalazine, and Antimalarials: Summary of Mechanism of Action,   Efficacy, and Toxicity Methotrexate

Proposed Mechanism of Action

Efficacy

Toxicity

Inhibition of ATIC → ↑ Adenosine

RA LGL syndrome and Felty’s   syndrome JIA Psoriatic arthritis SLE Vasculitis

Nausea Hepatotoxicity

Inhibition of TYMS → ↓ Pyrimidine synthesis Inhibition of DHFR → ↓ Transmethylation reactions

Bone marrow suppression Pneumonitis Methotrexate flu

Leflunomide

Inhibition of DHODH → ↓ Pyrimidine synthesis Inhibition of tyrosine kinase → ↓ cell signal transduction

RA SLE Psoriatic arthritis

Hepatotoxicity Diarrhea Weight loss

Sulfasalazine

Inhibition of arachidonic acid   cascade Inhibition of ATIC → ↑ Adenosine Multiple cellular effects Systemic effects via MALT

RA JIA

Nausea Headache

Ankylosing spondylitis Psoriatic arthritis Reactive arthritis

Leukopenia Rash

RA SLE

Nausea Rash

Discoid lupus Antiphospholipid syndrome Sjögren’s syndrome

Neuromyopathy Retinopathy

Antimalarials— Hydroxychloroquine, Chloroquine

↑ pH of subcellular vesicles →  interference with antigen   processing and cell-mediated ­cytotoxicity

ATIC, AICAR (aminoimidazole carboximide ribonucleotide) transformylase; DHFR, dihydrofolate reductase; DHODH, dihydroorotate dehydrogenase; JIA, juvenile idiopathic arthritis; LGL, large granulocytic lymphocyte; MALT, mucosa-associated lymphoid tissue; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; TYMS, thymidylate synthetase.

serum concentration of 30 μg/mL after 2 g/day dose). Most of the 5-ASA (80% to 90%) remains in the bowel.162 Sulfapyridine and SSZ are likely the active components in rheumatic disease, whereas 5-ASA is the active component in ulcerative colitis.184 The bioavailability of standard and enteric-coated SSZ is similar.185 Administration of SSZ with food decreases the blood concentration of SSZ and sulfapyridine.186 Distribution and Half-Life SSZ and sulfapyridine are widely distributed in the body with greater than 99% and 50% to 70% plasma protein binding.162,186 Serum and synovial concentrations are comparable.187 The half-life of SSZ is 6 to 17 hours with the upper range values reflecting older patients. The half-life of sulfapyridine is 8 to 21 hours with upper range values reflecting slow acetylators.188 Elimination Sulfapyridine is extensively metabolized in the liver by N-acetylation and ring hydroxylation with subsequent glucuronidations,189 and as a result of genetic variation in acetylator phenotype, there is wide variability among individuals.188 Slow acetylators have a reduced clearance rate and higher serum sulfapyridine concentrations. Sulfapyridine is excreted in the urine, whereas 5-ASA is eliminated primarily in the feces. The small portion of 5-ASA that is absorbed is excreted in the urine as N-acetylmesalamine (Table 56-3).190

Indications Rheumatoid Arthritis. Multiple published trials have been performed since the early 1980s showing significant benefit in clinical and laboratory parameters for SSZ (2 to 3 g daily) versus placebo in the treatment of RA.191 A meta-analysis of randomized controlled clinical trials of SSZ for the treatment of RA was published in 1999.192 In this analysis, SSZ was compared with placebo and other single DMARD therapies, including HCQ, d-penicillamine, and gold sodium thiomalate or aurothioglucose. In the trials looking at SSZ versus placebo, SSZ was shown to be superior to placebo for improvement in multiple clinical parameters. The withdrawal rate owing to lack of efficacy was significantly greater in the placebo group than the SSZ group; however, more patients in the SSZ group withdrew because of adverse effects compared with the placebo group (P < .0001). No one DMARD emerged as clinically superior in this metaanalysis. Subsequent studies showed equivalent clinical efficacy with SSZ and MTX193,194 and with SSZ and leflunomide,143 although a 2-year extension trial did show that the beneficial effects are sustained to a greater extent with leflunomide over SSZ.195 Spondyloarthropathies Psoriatic Arthritis.  A systematic review of therapies for psoriatic arthritis looked at six randomized controlled trials comparing SSZ with placebo in psoriatic arthritis.196 The results showed that SSZ is efficacious in treating the peripheral arthritis of psoriatic arthritis, but does not seem to influence the axial manifestations.197

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Few data are available on prevention of radiographic progression. Ankylosing Spondylitis.  A meta-analysis reviewed 11 trials with 895 patients with ankylosing spondylitis treated with SSZ or placebo.198 Across all patients with ankylosing spondylitis, SSZ showed some benefit in reducing erythrocyte sedimentation rate and easing spinal stiffness. The authors concluded that SSZ may benefit patients at an early disease stage, with a higher erythrocyte sedimentation rate and peripheral arthritis. This finding is in agreement with Clegg and associates,197 who found a significant benefit for SSZ for the peripheral arthritis, but not the axial arthritis in ankylosing spondylitis. Reactive Arthritis.  Many cases of reactive arthritis resolve spontaneously, whereas others become chronic with peripheral or axial arthritis. In a randomized controlled trial of 134 male veterans with reactive arthritis (predominantly peripheral arthritis) unresponsive to NSAIDs, SSZ was more effective than placebo.199 Inflammatory Bowel–Associated Arthritis.  SSZ has been used effectively to treat ulcerative colitis and distal Crohn’s disease. There are no randomized controlled trials of SSZ in the peripheral or axial arthritis manifestations of these diseases, although SSZ is used in clinical practice for the peripheral arthritis. Juvenile Inflammatory Arthritis. SSZ has been shown to be effective in polyarticular and pauciarticular juvenile inflammatory arthritis. A literature review by Brooks200 in 2001 found reports of 550 patients with juvenile inflammatory arthritis (half with polyarticular and one third with pauciarticular disease) treated with SSZ. The results showed at least some drug-associated benefit in all subtypes, with the best response in late-onset pauciarticular disease and the least benefit in systemic-onset disease. Toxicity and intolerance were similar to those seen with adult use of SSZ except for a substantial incidence of serum sickness in patients with systemic-onset disease.

effects include gastrointestinal effects, headache, dizziness, and rash.186 Gastrointestinal and Hepatic Nausea and upper abdominal discomfort are the most common adverse effect with SSZ. Nausea frequently occurs with central nervous system effects, including dizziness and headache. In one large cohort of 1382 RA patients, gastrointestinal and central nervous system effects were reported as transient in 8% of patients, and SSZ was continued, and in another 18% led to discontinuation of therapy.202 Nausea is more common in patients who achieve higher sulfapyridine levels and in slow acetylators.203 Diarrhea can occur, usually in the first several months. Gastrointestinal effects may be decreased by administration of enteric-coated preparations. Elevations in liver transaminases may occur and are usually transient. They may be accompanied by fever, rash, hepatomegaly, and possibly eosinophilia.201 Hematologic Hematologic disturbances are rare, occurring in less than 3% of patients. They usually occur within the first 3 months.186 The most common abnormality includes leukopenia, which usually reverses on cessation of the drug, although some cases of fatal agranulocytosis have been reported, warranting continued surveillance.204 Macrocytosis and hemolysis have been reported with SSZ, and its use should be avoided in patients with glucose-6-phosphate dehydrogenase deficiency. Folic acid supplementation may be reasonable because of effects of SSZ on folate metabolism. Thrombocytopenia is rare. Dermatologic

SSZ is available in regular and enteric-coated tablets of 500 mg or in a suspension of 50 mg/mL. To minimize side effects, most clinicians prescribe 500 mg daily and escalate by 500 mg/day every week to the standard dose of 1500 to 3000 mg divided daily. Dose reduction may ameliorate side effects.

Rashes occur in less than 5% of patients, usually in the first 3 months of therapy.202 Rashes are usually maculopapular, pruritic, and generalized, although some patients develop urticaria. Desensitization to SSZ has been reported.205 ­Anecdotally, erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome have been rarely reported, but were not seen in the major clinical trials. Photosensitivity also has been reported. Patients who develop a rash on SSZ should be cautioned to avoid other sulfonamide-containing agents, such as thiazide diuretics, celecoxib, and antibiotics.

Geriatric Patients

Pulmonary

Dosing recommendations for SSZ in geriatric patients are the same as for the general adult population.101 Studies of pharmacokinetics in the elderly have shown that although the elimination half-life is longer, it is primarily dependent on acetylator phenotype; however, the dose should be reduced for renal insufficiency.99

Pulmonary toxicity from SSZ is rare and manifests as reversible infiltrates with peripheral eosinophilia, cough, dyspnea, fever, and weight loss.206 Pathology reveals an eosinophilic pneumonia with interstitial infiltrates with or without fibrosis. Most cases resolve with discontinuation of SSZ with or without corticosteroids.

TOXICITY

Miscellaneous

In general, most adverse effects from SSZ occur within the first several months of treatment and decrease with continued use.201 The most common early adverse

Minor reactions, such as irritability, anxiety, headache, and difficulty sleeping, may occur.201,202 Rare cases of druginduced lupus,207 hypogammaglobulinemia,207 and aseptic

DOSING

PART 8 

meningitis have been reported.208 Patients should be advised that they may develop orange discoloration of their urine, sweat, and tears. Fertility, Pregnancy, and Lactation There are no reports of diminished fertility in women taking SSZ; however, men can have oligospermia, impaired sperm motility, and abnormal sperm morphology,209 which returns to normal 2 to 3 months after cessation of drug. SSZ is considered FDA category B, C for pregnancy. SSZ and sulfapyridine cross the placenta, and fetal concentrations are equivalent to maternal concentrations; however, SSZ does not seem to cause or increase fetal abnormalities or spontaneous abortions, and may be one of the DMARDs of first choice in treating rheumatic disease in women of childbearing age who are or wish to become pregnant.120 Sulfapyridine is excreted into breast milk, and there is one report of a child developing bloody diarrhea, which led the American Academy of Pediatrics to classify SSZ as a drug that must be given with caution to nursing women (see Table 56-1).120

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MODALITIES OF THERAPY IN RHEUMATIC DISEASE

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CHEMICAL STRUCTURE HCQ and CQ are very similar in their chemical structure, ­differing only by the substitution of a hydroxyethyl group for an ethyl group on the tertiary amino nitrogen of the side chain of CQ. Quinacrine includes the CQ structure, although it is not a 4-aminoquinolone derivative (Fig. 56-7). ACTIONS OF HYDROXYCHLOROQUINE Antimalarial agents have immunomodulatory and antiinflammatory properties, although their precise mechanism of action in rheumatic diseases is unknown. Because HCQ and CQ are weak bases, they can pass through cytoplasmic membranes into cytoplasmic vesicles and accumulate, increasing the vesicle pH from around 4.0 to 6.0, and interfere with acid-dependent subcellular functions. This increased pH has several postulated immunoregulatory effects, including stabilization of lysosomal membranes, attenuation of antigen processing and presentation, and inhibition of cell-mediated cytotoxicity.210,211

Toxicity Monitoring Most side effects from SSZ occur early in the course of treatment. At baseline, patients should have a complete blood count with platelets, AST, ALT, and creatinine and consideration for glucose-6-phosphate dehydrogenase. The complete blood count should be followed at 2- to 4-week intervals during the first 3 months of therapy. Long-term follow-up requires a complete blood count, creatinine, AST, and ALT every 3 to 6 months.121

N

CI

HN-R 4-AMINOQUINOLINE DERIVATIVES N

CI

DRUG INTERACTIONS AND CONTRAINDICATIONS Drug Interactions Few SSZ-drug interactions occur. SSZ may impair absorption of digoxin and decrease its bioavailability. Rarely, SSZ can increase the effects of oral hypoglycemics and the ­anticoagulant effects of warfarin. Broad-spectrum ­antibiotics may alter gut flora and decrease the bioavailablity of sulfapyridine and 5-ASA, owing to reduced cleavage of the azo bond.

HN

ANTIMALARIALS The aminoquinolones, including quinine, were first derived from the bark of the Peruvian cinchona tree and were originally used to treat malaria. To reduce toxicity, the 4-aminoquinolines, chloroquine (CQ) and hydroxychloroquine (HCQ), were developed. CQ and HCQ are the most common antimalarials prescribed, although quinacrine is occasionally used.

(CH2)3

N

CH3

C2H5 C2H5

CHLOROQUINE N

CI

HN

Contraindications Patients with hypersensitivity to any component of SSZ or a sulfonamide or salicylate allergy should not be prescribed SSZ. Patients with porphyria or gastrointestinal or genitourinary obstruction should not be prescribed SSZ.

CH

CH

(CH2)3 N

CH3

C2H4 OH C2H5

HYDROXYCHLOROQUINE CI

N OCH3 HN

CH(CH2)3N(C2H5)2 CH3

QUINACRINE

Figure 56-7  Chemical structures of antimalarial drugs used to treat rheumatic disease and the basic structure of 4-aminoquinolines. R represents the side chain.

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­ acrophages and monocytes require precise pH concenM trations for protein digestion and antigen processing, which is altered with an increased pH.212 Receptor assembly is disrupted, including the major histocompatibility complex (MHC) class II molecules, because a higher pH in the endoplasmic reticulum stabilizes the MHC protein with invariant chains and prevents their displacement by low-affinity autoantigens. This action combined with decreased membrane receptor recycling leads to downregulation of antigen presentation.210,212,213 Antimalarial treatment has been shown to decrease circulating immune complexes.214 Antimalarials also have inhibitory effects on proinflammatory cytokines. CQ inhibits IL-1 and interferon-γ production by monocytes and T cells.215 CQ also inhibits macrophage TNF-α mRNA transcription and endotoxininduced secretion of TNF-α, IL-1, and IL-6.216 Studies of HCQ have reported conflicting results in its ability to inhibit TNF-α, but HCQ has been shown to block IL-1, IL-6, and interferon-γ production by monocytes.217,218 Apoptosis or cell death plays an important role in the regulation of the immune system, and defects in apoptosis may allow for longevity and persistence of autoreactive lymphocyte clones and perpetuation of autoimmunity. CQ and HCQ have been shown to upregulate apoptosis and may downregulate autoimmunity by elimination of autoreactive lymphocytes.211 Antimalarials have been shown to inhibit the proliferative response of human lymphocytes and natural killer cell activity.219,220 Anti-inflammatory properties of the antimalarials include effects on the arachidonic acid cascade, by downregulation of phospholipase A2 and C, which contribute to the production of proinflammatory prostaglandins and lipid peroxidation.221-223 Lipid peroxidation is thought to play a role in apoptosis, particularly in response to ultraviolet A and ultraviolet B irradiation.224 Antimalarial agents also have antioxidant properties and may protect against tissue damage from free radicals.225 Antimalarials have several other beneficial effects relevant to rheumatic disease that warrant further discussion. First, they are photoprotective, and this is likely via locally induced anti-inflammatory effects.211 Second, HCQ and CQ inhibit platelet adhesion and aggregation leading to an antithrombotic effect.226,227 Third, HCQ and CQ favorably alter the lipid profile, with reductions in total cholesterol, triglycerides, very-low-density lipoproteins, and low-density lipoproteins, particularly in patients on concomitant corticosteroid therapy.211,228 Finally, HCQ and CQ have been reported to decrease plasma glucose levels, owing to inhibition of insulin degradation in the Golgi apparatus.211,229 PHARMACOLOGY Absorption and Bioavailability HCQ and CQ are administered orally and are absorbed rapidly and completely, with the peak plasma concentration for both occurring within 8 hours.230 There is considerable variability in blood concentrations among patients treated with the same dose, but higher plasma levels do not correlate with a better therapeutic response.211

Distribution and Half-Life Antimalarials accrue in different concentrations in various tissue compartments. Relatively small concentrations, similar to that seen in the plasma, are contained in the fat, bone, tendon, and brain. Increased concentrations are seen in the kidney, bone marrow, spleen, lungs, adrenal glands, and liver. The highest concentration occurs in melanin-containing cells, such as in the skin and retina.231 The skin can serve as a long-term reservoir whereby the drug can exert its effect, or toxicity, even after it has been stopped.211 The half-life of HCQ and CQ is 40 to 50 days, and plasma levels increase gradually and equilibrate after 3 to 4 months.232 Elimination Most of the absorbed drug is excreted in the urine unchanged, but some is metabolized to a desethyl derivative. The remainder is excreted in the feces.233 Indications Rheumatoid Arthritis. The efficacy of the antimalarial agents in RA is in their ability to control signs and symptoms of the disease60,61,234; however, they have not been shown to retard bone erosions.235 In a meta-analysis of antimalarials, HCQ was found to be less toxic, but also less effective than CQ.236 Compared with other DMARDs, symptomatic efficacy is equal to or slightly less than the other agents, and they have the slowest onset of action.237 Antimalarial agents are particularly suited for use in early, mild rheumatoid arthritis and in combination therapy. Systemic Lupus Erythematosus. Although antimalarials are inappropriate monotherapy for severe manifestations of SLE, they are used frequently for controlling constitutional symptoms, arthritis, fever, fatigue, and rash. The most convincing data supporting the efficacy of antimalarials in SLE come from studies in which the medication was discontinued in successfully treated patients. In one double-blind, placebo-controlled drug discontinuation study of 47 SLE patients in remission on HCQ, the risk of disease flare was increased by a factor of 2.5 in the placebo group.238 Antimalarials are particularly suited to treat SLE because of their photoprotective effects and are especially useful in dermatologic manifestations of SLE. Discoid Lupus. Antimalarials are effective in discoid lesions, with remission or major improvement in 60% to 90% of treated patients.220 When HCQ or CQ treatment alone is unsuccessful, the addition of quinacrine may be helpful, but long-term use may be limited by the development of yellowish skin pigmentation.239 Antiphospholipid Antibody Syndrome. HCQ use has been associated with a decreased incidence of thrombosis in patients with antiphospholipid antibodies.240 HCQ also has been shown to diminish thrombus size and time in mice injected with antiphospholipid antibodies and to reverse antiphospholipid antibody–mediated platelet activation.241,242 Although clinical trials are needed to establish efficacy further, it is reasonable to consider the use of HCQ

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in patients with antiphospholipid antibody syndrome, especially if the patients are unable to tolerate high levels of anticoagulation or develop thrombosis despite oral anticoagulation.

and HCQ also can cause corneal deposits, which can be associated with halos around lights and are benign and reversible.

Sjögren’s Syndrome. HCQ was shown to improve local eye and mouth symptoms, arthralgia, and myalgia in a prospective open label study of patients with Sjögren’s syndrome.243 In addition to the immunomodulatory and anti-inflammatory effects discussed earlier, HCQ may inhibit glandular cholinesterase activity and enhance salivary gland secretion.244

Rash is a common side effect leading to discontinuation of therapy. HCQ also may cause photosensitivity, alopecia, and depigmentation of hair.236

Dermatologic

Neuromuscular

Miscellaneous. Antimalarials have been reported to be efficacious in small and uncontrolled trials for the treatment of palindromic rheumatism,245 childhood SLE,246 childhood dermatomyositis,247 eosinophilic fasciitis,248 and erosive osteoarthritis.249 In a controlled trial of 17 patients, the arthritis of calcium pyrophosphate crystal deposition disease improved more in the HCQ group than in the ­placebo group.250

Common neuromuscular symptoms include headache, insomnia, nightmares, and irritability, which are mild and reversible with reduction of the daily dose. Tinnitus and deafness can occur. Neuromyotoxicity has been reported and manifests as insidious-onset proximal weakness with a normal creatine phosphokinase, which may be associated with a peripheral neuropathy and cardiac myotoxicity. Muscle biopsy specimens show curvilinear bodies and muscle fiber atrophy with vacuolar changes.254

DOSING

Cardiovascular

HCQ comes in 200-mg tablets, CQ is available in 250-mg and 500-mg tablets, and quinacrine is available from compounding pharmacies. To prevent ocular toxicity, HCQ should be maintained at a dose of 6.5 mg/kg or less for body weight or ideal body weight, whichever is less, and the dose of CQ should be 3 mg/kg or less.251 In practice, doses of HCQ rarely exceed 400 mg daily, in divided doses, and doses of CQ rarely exceed 250 mg, dosed daily.

Rarely, conduction disturbances and cardiomyopathy have been reported.255 Gastrointestinal Anorexia, nausea, vomiting, diarrhea, and abdominal cramping have been reported.236 Metabolic

Geriatric Patients There have been no specific pharmacokinetic studies of antimalarials in the elderly. Dosing recommendations are the same as for the general population.101 Elderly patients should be screened at baseline for preexisting ocular ­disease (see Table 56-1). TOXICITY Ophthalmologic Early eye symptoms can include defects in accommodation, conversion, or blurred vision, which resolve. Retinal toxicity is the most feared side effect, although it is rarely seen if proper dosage and monitoring protocols are followed. Less than 20 cases have been reported in the literature in more than 1 million patients prescribed the drug, and in a more recent review of six cases of retinal toxicity, all arose as a result of dosing above published guidelines.251,252 CQ has a higher risk of retinal toxicity than HCQ.253 Risk factors for retinopathy include high dosage, duration of use (>5 years), renal or liver disease, and age (>60 years old). HCQ or CQ retinopathy is described as bilateral bull’s eye maculopathy, with retinal pigment epithelial cell depigmentation in the central macula with sparing of a small foveal island. Testing of the paracentral visual field usually can show toxicity before retinal pigment epithelial cell changes are visible. When advanced, visual loss may be irreversible and continue despite cessation of the drug owing to its long half-life in the retina, so early detection is essential. CQ

HCQ can reduce blood glucose levels, so diabetic patients need to be cautioned to watch their blood glucose levels closely with initiation of HCQ and may need adjustments in their diabetic medications. Fertility, Pregnancy, and Lactation There are no reports of adverse effects on fertility. HCQ and CQ are considered FDA pregnancy category C.120 Because of the long half-life of HCQ, discontinuation of the drug at the time of pregnancy does not avoid fetal exposure. HCQ does cross the placenta, but there have been no reports of adverse outcomes or teratogenic effects in women who continue HCQ therapy during pregnancy.120 CQ also crosses the placenta and binds more tightly in tissue than HCQ, and there have been reports of fetal anomalies in women who took CQ during pregnancy.256 Quinacrine should not be used in pregnancy because it is mutagenic. Current recommendations are that HCQ may be continued throughout pregnancy, particularly in SLE, in which discontinuation could precipitate a flare, which would be more dangerous to the mother and the child.160 HCQ is found in low concentration in breast milk, but the American Academy of Pediatrics classifies it as compatible with breastfeeding.120 Toxicity Monitoring In 2002, the American Academy of Ophthalmology released an information statement on screening ­ recommendations for CQ and HCQ retinopathy.251 According to these

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­recommendations, all patients should have a baseline eye examination within the first year of therapy to document any ocular conditions and to establish a record of the fundus and visual fields. At a minimum, this should include a dilated eye examination, visual field testing with an Amsler grid or Humphrey 10-2 fields, and screening for color blindness in male patients. Because the risk of toxicity is low in the first 5 years, patients without risk factors, as mentioned previously, should follow American Academy of Ophthalmology guidelines based on age; however, most rheumatologists would favor annual screening or, at a minimum, every 2 years. For patients with risk factors, underlying ocular disease, or therapy duration more than 5 years, annual screening examinations are warranted. DRUG INTERACTIONS AND CONTRAINDICATIONS Drug Interactions HCQ should be used with caution in diabetic patients on hypoglycemic agents. HCQ has been shown to increase digoxin levels. CQ may increase cyclosporine levels and reduce MTX levels. CQ can interfere with cytochrome P-450 enzymes and should be used with caution when combined with other agents metabolized by this pathway. Contraindications Hypersensitivity to 4-aminoquinoline agents and previous retinal or visual field changes attributable to these agents are contraindications to further use.

COMBINATION DISEASE-MODIFYING ANTIRHEUMATIC DRUG THERAPY IN RHEUMATOID ARTHRITIS In the early 1990s, the use of combinations of DMARDs to treat RA was rare; now this strategy is employed by essentially all rheumatologists to treat more than one quarter of their patients.257 Currently, the timing of combination ­ therapy and the composition of combinations selected to treat RA are among the most important decisions clinicians face. Monotherapy with MTX is considered by most as the initial treatment of choice for early RA. Four major studies have shown the superiority of combinations of DMARDs over monotherapy in head-to-head comparisons.64,258-260 Trials with multiple conventional DMARDs and biologics have shown them to be more effective than placebo when added to the baseline MTX in patients who have active disease despite MTX therapy. With few exceptions, successful combination trials have included MTX, and it remains the cornerstone of combination therapy. HISTORY OF COMBINATION DISEASE-MODIFYING ANTIRHEUMATIC DRUG THERAPY Early combination DMARD studies were initiated in the late 1970s. The combination of cyclophosphamide, azathioprine, and HCQ produced substantial responses in a small group of patients; however, there were an unacceptably high number of malignancies.261 Early enthusiasm for combination therapy was limited. During the 1980s, inadequate dosing, the use of DMARDs with marginal efficacy, and

problematic trial design contributed to the mediocre results reported with combination therapy. In 1994, the first trial to show convincingly superior efficacy without increased toxicity of combination DMARD therapy in a head-tohead comparison with monotherapy with a DMARD was reported,64,262 and multiple trials showing the success of combination therapy have ensued. EARLY RHEUMATOID ARTHRITIS In the late 1990s, three pivotal trials showed the success of combination DMARD therapy in early RA. Researchers in the Netherlands reported success with a step-down approach: the COBRA (Combinatietherapie Bij Reumatoide Artritis) trial.258 In this trial, patients with early disease were randomly assigned to two groups: a combination of prednisolone, MTX, and SSZ versus SSZ alone. Prednisolone was started at 60 mg/day, rapidly tapered, and discontinued by week 28. MTX was given until week 40. The dose of SSZ was the same in both groups. At 28 weeks, the combination group was significantly better than the SSZalone group. As the prednisolone and MTX were tapered, the clinical responses became similar in the two groups; however, significant benefits in certain parameters existed in the combination group.263 Combination therapy was not more toxic. Subsequent data confirm that the radiographic benefits conferred by COBRA in the initial trial extend at least 5 years.263 The second important early RA study was the Fin-RA (Finland Rheumatoid Arthritis) trial.260 In this open trial, patients were randomly assigned to receive combination DMARD therapy (MTX, SSZ, HCQ, and low-dose prednisolone) or monotherapy with SSZ with optional prednisolone. The major end point of this trial was remission at 2 years. Significantly, patients who received combination therapy achieved more frequent remissions. A follow-up of this trial at 5 years showed that patients treated initially with the combination were less likely to have evidence of C1-C2 subluxation on cervical spine radiographs.264 In a third trial from Turkey, patients with early RA were randomly assigned to single DMARD therapy (MTX, SSZ, or HCQ), two-drug therapy (MTX and SSZ or MTX and HCQ), or three-drug therapy (MTX, SSZ, and HCQ), with remission at 2 years as the major outcome.259 For all end points measured, two drugs were shown to be statistically superior to monotherapy, and three drugs were statistically superior to the two-drug regimens. With the data provided from the COBRA trial,258,263 the Fin-RA trial,260,264 and the Turkish trial,259 a convincing case can be made to treat patients initially with combination therapy. Trials to define whether an approach that uses initial combinations is superior to a rapid step-up program are needed, however. PATIENTS WITH ACTIVE DISEASE DESPITE METHOTREXATE Combination DMARD therapy was first studied in groups of patients with active disease despite MTX therapy, or suboptimal MTX responders. The first study to show the advantage of combination therapy with MTX and another DMARD compared with continued therapy with MTX alone in this group of patients was the cyclosporine-MTX trial (Fig. 56-8).60

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80 71

71 66

Placebo 58

55 48

46

42 40

36

0

Weinblatt et al. Lipsky et al. (170) (171)

Cohen et al. Keystone et al. Tugwell et al. (172) (173) (166)

SSZ+HCQ

SSZ

20

HCQ

16

Cyclosporine

Adalimumab

Anakinra

15 Infliximab

20

23

20

Leflunomide

27

Etanercept

Responders (%)

60

O’Dell et al. Kremer et al. (265) (268)

*All patients were on baseline MTX.

Figure 56-8  Summary data taken from seven different clinical trials of therapies in patients with active disease despite methotrexate therapy.  ACR, American College of Rheumatology; HCQ, hydroxychloroquine; SSZ, sulfasalazine.

Therapy with the combination of MTX, SSZ, and HCQ, so-called triple therapy, has been shown by three different groups (four trials) not only to be well tolerated,64,259,260,265 but also to be more effective than MTX monotherapy,64,259 SSZ monotherapy,260 and, in an open trial of patients with early disease, more effective than the double combinations of MTX and SSZ or MTX and HCQ.259 In 1996, a 2-year, randomized, double-blind, parallel study of 102 established RA patients was done to compare triple-drug therapy (MTX, SSZ, and HCQ) versus double therapy (HCQ and SSZ) versus monotherapy with MTX.64 Significantly more patients receiving the triple-drug regimen achieved a modified Paulus 50% response266 compared with patients receiving MTX alone or double therapy. Triple therapy was well tolerated, with numerically fewer withdrawals in the combination group compared with the other two groups. This therapy also has been shown to be durable, with 62% of patients remaining on triple therapy for 5 years continuing to maintain a 50% efficacy response.267 In follow-up, a 2-year, double-blind trial on patients with moderately advanced disease was done in 2002, in which the triple combination was compared with two double combinations (MTX plus SSZ and MTX plus HCQ) in a head-to-head comparison.265 Patients were stratified for previous MTX use, and the previous users had to have active disease despite receiving 17.5 mg/wk. Patients in the triple therapy group and both double therapy groups tolerated their treatments well, with only 8% withdrawing for toxicities, which were mostly minor. Triple therapy was shown to be superior to either of the double ­combinations. A double-blind, placebo-controlled trial (see Fig. 56-8) has compared the addition of leflunomide or placebo to baseline MTX in suboptimal MTX responders.268 Leflunomide or placebo was added to MTX. The combination group was statistically superior to the MTX-placebo group for the ACR-20 criteria for clinical response. The combination

was reasonably well tolerated, but side effects, including diarrhea, nausea, and dizziness, were increased in the combination arm. Elevated ALT levels (>1.2 times normal) occurred more frequently in patients on combination therapy than in patients on MTX alone, with increases leading to withdrawal in 2.3% of patients who received the ­combination. CORTICOSTEROIDS IN DISEASE-MODIFYING ANTIRHEUMATIC DRUG COMBINATIONS Corticosteroids traditionally have not been considered DMARDs. They fulfill all the criteria for DMARDs, however, including retarding radiographic progression.269 Few clinicians who care for patients with RA dispute their efficacy. Corticosteroids have been used as baseline therapy for more than half of the patients included in the combination trials discussed previously. Prednisolone undoubtedly was a crucial component for the success of the COBRA protocol,258 and may have played a role in the success of the combination group in the Fin-RA trial.260 Kirwan and colleagues,269,270 report of the ability of prednisolone to retard significantly radiographic progression of RA compared with placebo is testament to the efficacy of steroids when used in combination with other DMARDs. Corticosteroids warrant further formal investigation as a component of combination therapy. The COBRA trial and the Kirwan data have raised another question: Should or could short courses of high-dose steroids be used as a form of induction therapy?271 BIOLOGIC AGENTS IN DISEASE-MODIFYING ANTIRHEUMATIC DRUG COMBINATIONS Biologic agents that block TNF-α (etanercept, infliximab, and adalimumab) and IL-1 (anakinra) have been studied in early and established RA in combination with MTX

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(see Fig. 56-8).166,170-173,265,268,272 These trials have shown superior improvements in clinical and radiographic end points in the combination groups.145,272 Two other biologic agents, rituximab, an anti-CD20 monoclonal antibody, and abatacept, a T cell costimulatory (CTLA-4) inhibitor, have been studied in combination with MTX.273,274 In the REFLEX trial, rituximab versus placebo was added to baseline MTX in RA patients who were suboptimal responders to MTX and had failed one or more TNF inhibitors.273 The results showed that the combination group had significant improvements in ACR-N responses. Abatacept versus placebo in addition to background MTX was studied in RA patients with a suboptimal response to MTX, and the results at 1 year showed significant improvements in clinical and radiographic end points.274 Concerns exist regarding the risk of infections and infusion reactions in combination therapy including biologic agents. SELECTING THE RIGHT PATIENTS FOR COMBINATION THERAPY Factors that predict a poor prognosis for patients with RA are well accepted and include rheumatoid factor, elevated erythrocyte sedimentation rate or C-reactive protein, the number of joints involved, erosions, and the presence of certain genetic markers. Unless these factors can be shown to predict response to certain therapies in a differential fashion, however, they are of limited therapeutic use. Patient characteristics recommending one therapeutic regimen over another remain to be fully elucidated. Genetic differences have been suggested to influence outcomes in a differential fashion. Until this observation can be corroborated and factors that predict response to other therapies elucidated, choices will remain largely empiric. Treatment of RA using MTX combinations should be the “gold standard” against which future therapies are compared. Available data show that a variety of combinations are more effective than MTX alone. Many questions remain to be answered regarding the appropriate timing of combination therapy and the optimal combinations for specific patients and for specific clinical situations (e.g., induction, maintenance therapy, and suboptimal response to MTX). Future research is needed to clarify the role of corticosteroids and, particularly, biologic response modifiers (specifically anti-TNF therapies) as components of and alternatives to MTX combination regimens. REFERENCES    1. Kremer J: Toward a better understanding of methotrexate. Arthritis Rheum 50:1370-1382, 2004.    2. Nakashima-Matsushita N, Homma T, Yu S, et al: Selective ­expression of folate receptor b and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis. Arthritis Rheum 42:1609-1616, 1999.    3. Turk M, Breur G, Widmer W, et al: Folate-targeted imaging of activated macrophages in rats with adjuvant-induced arthritis. Arthritis Rheum 46:1947-1955, 2002.    4. Ranganathan P, McLeod H: Methotrexate pharmacogenetics: The first step toward individualized therapy in rheumatoid arthritis. Arthritis Rheum 54:1366-1377, 2006.    5. Chen Z, Lee K, Walther S, et al: Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABC4): MRP4 is a component of the methothrexate efflux system. Cancer Res 62: 3144-3150, 2002.

   6. Bagott J, Vaughan W, Hudson B: Inhibition of 5-aminoimidazole4-carboxamide ribotide transformylase, adenosine deaminase and 5′-adenylate deaminase by polyglutamates of methotrexate and ­oxidized folates and by 5-aminoimidazole-4-carboxamide riboside and ribotide. Biochem J 236:193-200, 1986.    7. Ha T, Morgan S, Vaughan W, et al: Inhibition of adenosine deaminase and 5-adenosyl homocysteine hydrolase by 5-aminoimidazole4-carboxamide riboside. FASEB J 6:1210-1215, 1992.    8. Morabito L, Montesinos M, Schreibman D, et al: Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5′-nucleotidase-mediated conversion of adenine nucleotides. J Clin Invest 101:295-300, 1998.    9. Hasko G, Cronstein B: Adenosine: An endogenous regulator of innate immunity. Trends Immunol 25:33-39, 2004.   10. Rongen G, Floras J, Lenders J, et al: Cardiovascular pharmacology of purines. Clin Sci 92:13-24, 1997.   11. Bouma M, van den Wildenberg F, Buurman WA: Adenosine inhibits cytokine release and expression of adhesion molecules by activated human endothelial cells. Am J Physiol 270:C522-C529, 1996.   12. Feoktistov I, Goldstein A, Ryzhov S, et al: Differential expression of adenosine receptors in human endothelial cells: Role of A2B receptors in angiogenic factor regulation. Circ Res 90:531-538, 2002.   13. Cronstein B: Adenosine, an endogenous anti-inflammatory agent. J Appl Physiol 76:5-13, 1994.   14. Link A, Kino T, Worth J, et al: Ligand-activation of the adeno­ sine A2a receptors inhibits IL-12 production by human monocytes. J Immunol 164:436-442, 2000.   15. Hasko G, Szabo C, Nemeth Z, et al: Adenosine receptor agonists differentially regulate IL-10, TNF-alpha, and nitric oxide production in RAW 264.7 macrophages and in endotoxemic mice. J Immunol 157:4634-4640, 1996.   16. Szabo C, Scott G, Virag L: Suppression of macrophage inflammatory protein (MIP)-1alpha production and collagen-induced arthritis by adenosine receptor agonists. Br J Pharmacol 125:379-387, 1998.   17. Bouma M, Stad R, van den Wildenberg F, et al: Differential ­regulatory effects of adenosine on cytokine release by activted human monocytes. J Immunol 1:4159-4168, 1994.   18. Cronstein B: The mechanism of action of methotrexate. Rheum Dis Clin N Am 23:739-755, 1997.   19. Sajjadi F, Takabayashi K, Foster A, et al: Inhibition of TNF-alpha expression by adenosine: Role of A3 adenosine receptors. J Immunol 156:3435-3442, 1996.   20. Krump E, Lemay G, Borgeat D: Adenosine A2 receptor-induced inhibition of leukotriene B4 synthesis in whole blood ex vivo. Br J Pharmacol 117:1639-1644, 1996.   21. Boyle D, Sajjadi F, Firestein G: Inhibition of synoviocyte collagenase gene expression by adenosine receptor stimulation. Arthritis Rheum 39:923-930, 1996.   22. Cronstein B: Low-dose methotrexate: A mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev 57:163-172, 2005.   23. Cronstein B: Going with the flow: Methotrexate, adenosine, and blood flow. Ann Rheum Dis 65:421-422, 2006.   24. Risken N, Barrera P, van den Broek P, et al: Methotrexate modulates kinetics of adenosine in humans in vivo. Ann Rheum Dis 65: 465-470, 2006.   25. Turesson C, Jarenros A, Jacobsson L: Increased incidence of ­cardiovascular disease in patients with rheumatoid arthritis: Results from a community based study. Ann Rheum Dis 63:952-955, 2004.   26. Choi H, Hernan M, Seeger J: Methotrexate and mortality in patients with rheumatoid arthritis: A prospective study. Lancet 359: 1173-1177, 2002.   27. Furumitsu Y, Yukioka K, Kojima A, et al: Levels of urinary polyamines in patients with rheumatoid arthritis. J Rheumatol 20:1661-1665, 1993.   28. Nesker G, Moore T: The in vitro effects of methotrexate on ­peripheral blood mononuclear cells: Modulation by methyl donor and spermidine. Arthritis Rheum 33:954-959, 1990.   29. Yukioka K, Wakitani S, Yukioka M, et al: Polyamine levels in synovial tissues and synovial fluids of patients with rheumatoid arthritis. J Rheumatol 19:689-692, 1992.   30. Flescher E, Bowlin T, Ballester A, et al: Increased polyamines may downregulate interleukin 2 production in rheumatoid arthritis. J Clin Invest 83:1356-1362, 1989.   31. Flescher E, Bowlin T, Talal N: Regulation of IL-2 production by mononuclear cells from rheumatoid arthritis synovial fluids. Clin Exp Immunol 87:435-437, 1992.

PART 8    32. Hornung N, Stengaard-Pedersen K, Ehrnrooth E, et al: The effects of low-dose methotrexate on thymidylate synthase activity in human peripheral blood mononuclear cells. Clin Exp Rheumatol 18: 691-698, 2000.   33. Huschtascha L, Bartier W, Andersson Ross C, et al: ­Characteristics of cancer cell death after exposure to cytotoxic drugs in vitro. Br J Cancer 73:54-60, 1996.   34. Genestier L, Pailot R, Fournel S, et al: Immunosuppressive properties of methotrexate: Apoptosis clonal deletion of activated peripheral T cells. J Clin Invest 15:322-328, 1998.   35. Seitz M, Loetscher B, Dewald B: Methotrexate action in rheumatoid arthritis: Stimulation of cytokine inhibitor and inhibition of chemokine production by peripheral blood mononuclear cells. Br J ­Rheumatol 34:602-609, 1995.   36. Seitz M, Loetscher B, Dewald B: Interleukin-1 receptor antagonist, soluble tumor necrosis factor receptors, Il-1 and Il-8 markers of ­remission in rheumatoid arthritis during treatment with methotrexate. J Rheumatol 23:1512-1516, 1996.   37. Seitz M, Zwicker M, Loetscher B: Effects of methotrexate on ­differentiation of monocytes and production of cytokine inhibitors by monocytes. Arthritis Rheum 42:2023-2028, 1998.   38. Crilly A, McInness I, McDonald A, et al: Interleukin-6 (IL-6) and soluble IL-2 receptor levels in patients with rheumatoid arthritis treated with low-dose methotrexate. J Rheumatol 22: 224-229, 1995.   39. Straub R, Muller-Ladner U, Lichtinger T, et al: Decrease of interleukin 6 during the first 12 months is a prognostic marker of clinical outcome during 36 months treatment with disease-modifying ­antirheumatic drugs. Br J Rheumatol 36:1298-1303, 1997.   40. Cronstein B, Lounet-Lescoulie P, Lambert N: Antiinflammatory and immunoregulatory action of methotrexate in the treatment of rheumatoid arthritis. Arthritis Rheum 41:48-57, 1998.   41. Miossec P, Briolay J, Dechanet J, et al: Inhibition of the production of proinflammatory cytokines and immunoglobulins by interleukin4 in an ex vivo model of rheumatoid synovitis. Arthritis Rheum 35:874-883, 1992.   42. Mello S, Barros D, Silva A, et al: Methotrexate as a preferential cyclooxygenase 2 inhibitor in whole blood of patients with ­ rheumatoid arthritis. Rheumatology 39:533-536, 2000.   43. Leroux J, Damon M, Chavis C, et al: Effects of methotrexate on leukotriene and derivated lipoxygenase synthesis in polynuclear neutrophils in rheumatoid polyarthritis. Rev Rheum Mal Osteoartic 59:587-591, 1992.   44. Kraan M, Koster B, Elferink J, et al: Inhibition of neutrophil ­migration soon after initiation of treatment with leflunomide or methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 43:1488-1495, 2000.   45. Cutolo M, Sulli A, Pizzorni C, et al: Anti-inflammatory mechanisms of methotrexatee in rheumatoid arthritis. Ann Rheum Dis 60: 729-735, 2001.   46. Firestein G, Paine M, Boyle D, et al: Mechanism of methotrexate action in rheumatoid arthritis: Selective decrease in synovial collagenase gene expression. Arthritis Rheum 37:923-930, 1994.   47. Hamilton R, Kremer J: Why intramuscular methotrexate works ­better than oral drug in patients with rheumatoid arthritis. Br J Rheumatol 36:86-90, 1997.   48. Hamilton R, Kremer J: The effect of food on methotrexate absorption. J Rheumatol 22:2072-2077, 1995.   49. Wegrzyn J, Adeleine P, Miossec P: Better efficacy of methotrexate administered by intramuscular injections versus oral route in patients with rheumatoid arthritis. Ann Rheum Dis 63:1232-1234, 2004.   50. Herman R, Veng-Pedersen P, Hoffman J, et al: Pharmacokinetics of low-dose methotrexate in rheumatoid arthritis patients. J Pharm Sci 78:165, 1989.   51. Hoekstra M, Haagsma C, Neef C, et al: Splitting high-dose oral methotrexate improves the bioavailability: A pharmacokinetic study in patients with rheumatoid arthritis. J Rheumatol 33:481-485, 2006.   52. Brooks P, Spruill W, Parish R, et al: Pharmacokinetics of methotrexate administered by intramuscular and subcutaneous injections in patients with rheumatoid arthritis. Arthritis Rheum 33: 91-94, 1990.   53. Marshall P, Gertner E: Oral administration of an easily prepared solution of injectable methotrexate diluted in water: A comparison of serum concentrations vs methotrexate tablets and clinical utility. J Rheumatol 23:455-458, 1996.

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Methotrexate, Leflunomide, Sulfasalazine, Hydroxychloroquine, and Combination Therapies

177. Lee C, Lee E, Chung S, et al: Effects of disease-modifying antirheumatic drugs and antiinflammatory cytokines on human osteoclastogenesis through interaction with receptor activator of nuclear factor kappaB, osteoprotegerin, and receptor activator of nuclear factor kappaB ligand. Arthritis Rheum 50:3831-3843, 2004. 178. Bird H: Sulphasalazine, sulphapyridine or 5-aminosalicylic acid— which is the active moiety in rheumatoid arthritis? Br J Rheumatol 34(Suppl 2):16-19, 1995. 179. Sheldon P: Rheumatoid arthritis and gut-related lymphocytes: The iteropathy concept. Ann Rheum Dis 47:697-700, 1988. 180. Jorgensen C, Bolobna C, Anaya J, et al: Variations in the serum IgA concentration and the production of IgA in vitro in rheumatoid arthritis treated by sulfasalazine. Rheumatol Int 13:113-116, 1993. 181. Kanerud L, Scheynius A, Hafstrom I: Evidence of a local intestinal immunomodulatory effect of sulfasalazine in rheumatoid arthritis. Arthritis Rheum 37:1138-1145, 1994. 182. Sheldon P, Pell P: Comparison of the effect of oral sulphasalazine, sulphapyridine and 5-amino-salicylic acid on the in vivo antibody response to oral and systemic antigen. Br J Pharmacol 53:261-264, 1993. 183. Peppercorn M, Goldman P: The role of intestinal bacteria in the metabolism of salicylazosulfapyridine. J Pharm Exp Ther 181:555, 1972. 184. Pullara T, Hunter J, Capell H: Which component of sulphasalazine is active in rheumatoid arthritis? BMJ 290:1535, 1985. 185. Rains C, Noble S, Faulds D: Sulfasalazine: A review of its ­pharmacological properties and therapeutic efficacy in the treatment of ­rheumatoid arthritis. Drugs 50:137-156, 1995. 186. Plosker G, Croom K: Sulfasalazine: A review of its use in the management of rheumatoid arthritis. Drugs 65:1825-1849, 2005. 187. Farr A, Brodrick A, Bacon P: Plasma synovial fluid concentration of sulphasalazine and two of its metabolites in rheumatoid arthritis. Rheumatol Int 5:247-251, 1985. 188. Taggart A, McDermott B, Roberts S: The effect of age and acetylator phenotype on the pharmacokinetics of sulfasalazine in patients with rheumatoid arthritis. Clin Pharmacokinet 23:311-320, 1992. 189. Schroder H, Campbell D: Absorption, metabolism and excretion of salicylazo-sulfapyridine in man. Clin Pharmacol Ther 13:539, 1972. 190. Lauritsen K, Laursen LS, Rask-Madsen J: Clinical pharmacokinetics of drugs used in the treatment of gastrointestinal disease (part II). Clin Pharmacokinet 19:94-125, 1990. 191. Capell H: Clinical efficacy of sulphasalazine—a review. Br J Rheumatol 34(Suppl 2):35-39, 1995. 192. Weinblatt M, Reda D, Henderson W, et al: Sulfasalazine treatment for rheumatoid arthritis: A meta-analysis of 15 randomized trials. J Rheumatol 26:2123-2130, 1999. 193. Dougados M, Combe B, Cantagrel A, et al: Combination therapy in early rheumatoid arthritis: A randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components. Ann Rheum Dis 58:220-225, 1999. 194. Haagsma C, Van Riel P, De Jong A, et al: Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: A randomized, controlled, double-blind, 52 week clinical trial. Br J Rheumatol 36:1082-1088, 1997. 195. Scott D, Smolen J, Kalden J, et al: Treatment of active rheumatoid arthritis with leflunomide: Two year follow up of a double blind, placebo controlled trial versus sulfasalazine. Ann Rheum Dis 60: 913-923, 2001. 196. Soriano E, McHugh N: Therapies for peripheral joint disease in psoriatic arthritis: A systematic review. J Rheumatol 33:1422-1430, 2006. 197. Clegg D, Reda D, Abdellatif M: Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies. Arthritis Rheum 42:2325-2329, 1999. 198. Chen J, Liu C: Is sulfasalazine effective in ankylosing spondylitis? A systematic review of randomized controlled trials. J Rheumatol 33:722-731, 2006. 199. Clegg D, Reda D, Weisman M, et al: Comparison of sulfasalazine and placebo in the treatment of reactive arthritis (Reiter’s syndrome). Arthritis Rheum 39:2021-2027, 1996. 200. Brooks C: Sulfasalazine for the management of juvenile rheumatoid arthritis. J Rheumatol 28:845-853, 2001. 201. Amos R, Pullar T, Bax D, et al: Sulphasalazine for rheumatoid arthritis: Toxicity in 774 patients monitored for one to 11 years. BMJ 293:420-423, 1986. 202. Donvan S, Hawley S, MacCarthy J, et al: Tolerability of enteric-coated sulphasalazine in rheumatoid arthritis: Results of a co-operating clinics study. Br J Rheumatol 29:201-204, 1990.

203. Pullar T, Hunter J, Capell H: Effect of acetylator phenotype on efficacy and toxicity of sulphasalazine in rheumatoid arthritis. Ann Rheum Dis 44:831-837, 1985. 204. Canvin J, El-Gaalawy H, Chalmers I: Fatal agranulocytosis with sulfasalazine therapy in rheumatoid arthritis. J Rheumatol 20:909, 1993. 205. Farr M, Scott D, Bacon P: Sulphasalazine desensitization in rheumatoid arthritis. BMJ 284:118, 1982. 206. Parry S, Barbatzas C, Peel E, et al: Sulphasalazine and lung toxicity. Eur Respir J 19:756-764, 2002. 207. Chalmers I, Sitar D, Hunter T: A one-year, open, prospective study of sulfasalazine in the treatment of rheumatoid arthritis: Adverse reactions and clinical response in relating to laboratory variables, drug and metabolite serum levels and acetylator status. J Rheumatol 17:764, 1990. 208. Alloway J, Mitchell S: Sulfasalazine neurotoxicity: A report of aseptic meningitis and a review of the literature. J Rheumatol 20:409, 1993. 209. O’Morain C, Smethurst P, Dore C, et al: Reversible male infertility due to sulphasalazine: Studies in man and rat. Gut 25:1078-1084, 1984. 210. Fox R: Anti-malarial drugs: Possible mechanisms of action in auto-immune disease and prospects for drug development. Lupus 5(Suppl):4-10, 1996. 211. Wozniacka A, Carter A, McCauliffe D: Antimalarials in ­cutaneous lupus erythematosus: Mechanisms of therapeutic benefit. Lupus 11:71-81, 2002. 212. Gonzalez-Noriega A, Grubb J, Talkad V, et al: Chloroquine inhibits lysosomal enzyme pinocytosis and enhances lysosomal enzyme secretion by impairing receptor recycling. J Cell Biol 85:839-852, 1980. 213. Fox R, Kang H: Mechanism of action of antimalarial drugs: ­Inhibition of antigen processing and presentation. Lupus 2(Suppl):9, 1993. 214. Segal-Eiras A, Segura G, Babini J, et al: Effect of antimalarial ­treatment on circulating immune complexes in rheumatoid arthritis. J Rheumatol 12:87-89, 1985. 215. Salmeron G, Lipsky P: Immunosuppressive potential of antimalarials. Am J Med 18:19-24, 1983. 216. Karres I, Kremer J: Chloroquine inhibits proinflammatory cytokine release into human whole blood. Am J Physiol 274:1058-1064, 1998. 217. Sperber K, Quraishi H, Kalb T, et al: Selective regulation of ­cytokine secretion by hydroxychloroquine: Inhibition of interleukin 1 alpha (IL-1) and IL-6 in human monocytes and T cells. J Rheumatol 20:803-808, 1993. 218. van den Borne B, Kijkmans B, de Rooij H, et al: Chloroquine and hydroxychloroquine equally affect tumor necrosis factor, interleukin 6 and interferon production by peripheral blood mononuclear cells. J Rheumatol 24:55-60, 1997. 219. Ausiello C, Barbier P, Spagnoli C, et al: In vivo effects of ­chloroquine treatment on spontaneous and interferon-induced natural killer activities in rheumatoid arthritis patients. Clin Exp Rheumatol 1:225, 1986. 220. Gordon D, Klinkhoff A: Second-Line Agents. In Harris ED, Budd RC, Firestein GS, et al (eds): Kelley’s Textbook of Rheumatology, 7th ed. Philadelphia, WB Saunders, 2005. 221. Bondeson J, Sundler R: Antimalarial drugs inhibit phospholipase A2 activation and induction of interleukin 1β and tumor necrosis factor in macrophages: Implications for their mode of action in rheumatoid arthritis. Gen Pharmacol 30:357-366, 1998. 222. Chen X, Gresham A, Morrison A, et al: Oxidative stress mediates synthesis of cytosolic phospholipase A2 after UVB injury. J Biol Chem 111:693-695, 1996. 223. Ruzicka T, Printz M: Arachidonic acid metabolism in guinea pig skin: Effects of chloroquine. Agents Actions 12:527-529, 1982. 224. Ramakrishnan N, Kalinich J, McClain D: Ebselen inhibition of apoptosis by reduction of peroxides. Biochem Pharmacol 51: 1443-1451, 1996. 225. Miyachi Y, Yoshioka A, Imamura S, et al: Antioxidant action of antimalarials. Ann Rheum Dis 45:244-248, 1986. 226. Jancinova V, Nosal R, Petrikova M: On the inhibitory effect of chloroquine on blood platelet aggregation. Thromb Res 74:495-504, 1994. 227. Wallace D: Does hydroxychloroquine sulfate prevent clot formation in systemic lupus erythematosus? Arthritis Rheum 30: 1435-1436, 1987. 228. Rahman P, Gladman D, Urowitz M, et al: The cholesterol lowering effect of antimalarial drugs is enhanced in patients with lupus taking corticosteroid drugs. J Rheumatol 26:325-330, 1999. 229. Blazar B, Whitley C, Kitabchi A, et al: In vivo chloroquine-induced inhibition of insulin degradation in a diabetic patient with severe insulin resistance. Diabetes 33:1133-1136, 1984.

PART 8  230. Koranda F: Antimalarials. J Am Acad Dermatol 4:650-655, 1981. 231. Mackenzie A: Pharmacologic actions of the 4-aminoquinoline compounds. Am J Med 75:11-18, 1983. 232. Furste D: Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases. Lupus 5(Suppl):S11, 1996. 233. McChesney E, Conway W, Banks W, et al: Studies on the metabolism of some compounds of the 1-amino-7-chloroquinoline series. J Pharmacol Exp Ther 151:482, 1966. 234. Group HS: A randomized trial of hydroxychloroquine in early rheumatoid arthritis: The HERA Study. Am J Med 98:156-168, 1995. 235. Edmonds J, Scott K, Furst D: Antirheumatic drugs: A proposed new classification. Arthritis Rheum 36:336-339, 1993. 236. Avina-Zubieta J, Galindo-Rodriguez G, Newman S, et al: Long term effectiveness of antimalarial drugs in rheumatic diseases. Ann Rheum Dis 57:582-587, 1998. 237. Case J: Old and new drugs used in rheumatoid arthritis: A historical perspective. Am J Therap 8:123-143, 2001. 238. The Canadian Hydroxychloroquine Study Group: A randomized study of the effects of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. N Engl J Med 324:150, 1991. 239. Toubi E, Rosner I, Rosenbaum M, et al: The benefit of combining hydroxychloroquine with quinacrine in the treatment of SLE patients. Lupus 9:92, 2000. 240. Erkan D, Yazici Y, Peterson M, et al: A cross-sectional study of ­clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome. Rheumatology 41:924-929, 2002. 241. Edwards M, Pierangeli S, Liu X, et al: Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice. Circulation 96:4380-4384, 1997. 242. Espinola R, Pierangeli S, Harris E: Hydroxychloroquine reverses platelet activation induced by human IgG antiphospholipid ­antibodies. Thromb Haemost 87:518-522, 2002. 243. Fox R, Dixon R, Guarrasi V, et al: Treatment of primary Sjogren’s syndrome with hydroxychloroquine: A retrospective open-label study. Lupus 5(Suppl 1):S31-S36, 1996. 244. Dawson L, Caulfield V, Stanbury J, et al: Hydroxychloroquine therapy in patients with primary Sjogren’s syndrome may improve salivary gland hypofunction by inhibition of glandular cholinesterase. Rheumatology 44:449-455, 2005. 245. Youssef W, Yan A, Russell A: Palindromic rheumatism: A response to chloroquine. J Rheumatol 18:1, 1991. 246. Gladman D, Urowitz M, Senecal J, et al: Aspects of use of ­antimalarials in systemic lupus erythematosus. J Rheumatol 25:983, 1998. 247. Olson N, Lindsley C: Adjunctive use of hydroxychloroquine in childhood dermatomyositis. J Rheumatol 16:12, 1989. 248. Lakhanpal S, Ginsburg W, Michet C, et al: Eosinophilic fasciitis: Clinical spectrum and therapeutic response in 52 cases. Semin Arthritis Rheum 17:221, 1988. 249. Bryant L, DesRosier K, Carpenter M: Hydroxychloroquine in the treatment of erosive osteoarthritis. J Rheumatol 22:1527, 1995. 250. Rothschild B: Prospective six-month double-blind trial of plaquenil treatment of calcium pyrophosphate deposition disease (CPPD). Arthritis Rheum 37(Suppl 9):S414, 1994. 251. Marmor M, Carr R, Easterbrook M, et al: Information Statement: Recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 109:1377-1382, 2002. 252. Browning D: Hydroxychloroquine and chloroquine retinopathy: Screening for drug toxicity. Am J Ophthalmol 133:649-656, 2002. 253. Wallace D: Antimalarials—the “real” advance in lupus. Lupus 10:385-387, 2001. 254. Stein M, Bell M, Ang L: Hydroxychloroquine neuromyotoxicity. J Rheumatol 27:2927-2931, 2000. 255. Cervera A, Espinosa G, Cervera R, et al: Cardiac toxicity secondary to long term treatment with chloroquine. Ann Rheum Dis 60: 301-304, 2001.

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256. Petri M: Immunosuppressive drug use in pregnancy. Autoimmunity 36:51-56, 2003. 257. Mikuls T, O’Dell J: The changing face of rheumatoid arthritis. Arthritis Rheum 43:464, 2000. 258. Boers M, Verhoeven A, Marusse H, et al: Randomized comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 350:309-318, 1997. 259. Calguneri M, Pay S, Caliskener Z, et al: Combination therapy versus mono-therapy for the treatment of patients with rheumatoid arthritis. Clin Exp Rheum 17:699-704, 1999. 260. Mottonen T, Hannonsen P, Leiralalo-Repoo M, et al: Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: A randomized trial. Lancet 353:1568-1573, 1999. 261. Csuka M, Carrero G, McCarty D: Treatment of intractable rheumatoid arthritis with combined cyclophosphamide, azathioprine and hydroxychloroquine: A follow-up study. JAMA 255:2315, 1986. 262. O’Dell J, Haire C, Erickson N, et al: Triple DMARD therapy for rheumatoid arthritis: Efficacy. Arthritis Rheum 41:S295, 1994. 263. Landewe R, Boers M, Verhoeven A, et al: COBRA combination therapy in patients with early rheumatoid arthritis: Long-term structural benefits of a brief intervention. Arthritis Rheum 46:347-356, 2002. 264. Neva M, Dauppi M, Kautiainen H, et al: Combination drug therapy retards the development of rheumatoid atlantoaxial subluxations. Arthritis Rheum 11:2397-2401, 2000. 265. O’Dell J, Leff R, Paulsen G: Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine or a combination of three medications. Arthritis Rheum 46:1164-1170, 2002. 266. Paulus H, Egger M, Ward J, et al: Analysis of improvement in individual rheumatoid arthritis patients treated with disease-modifying antirheumatic drugs, based on the findings in patients treated with placebo. Arthritis Rheum 33:477-484, 1990. 267. O’Dell J, Paulsen G, Haire C, et al: Combination DMARD therapy with methotrexate (M)–sulfasalazine (S)–hydroxychloroquine (H) in rheumatoid arthritis (RA): Continued efficacy with minimal toxicity at 5 years. Arthritis Rheum 41(Suppl):S132, 1998. 268. Kremer J, Genovese M, Cannon G, et al: Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: A randomized, double-blind, placebo controlled trial. Ann Intern Med 137:726, 2002. 269. Kirwan J: The effect of glucocorticoid on joint destruction in rheumatoid arthritis. N Engl J Med 333:142-146, 1995. 270. Hickling P, Jacoby R, Kirwan J: Joint destruction after glucocorticoids are withdrawn early in rheumatoid arthritis. Br J Rheumatol 37:930, 1998. 271. O’Dell J: Treating rheumatoid arthritis early: A window of opportunity? Arthritis Rheum 46:283-285, 2002. 272. Klareskog L, Van der Heide A, de Jager F, et al: TEMPO (Trial of Etanercept and Methotrexate with radiographic Patient Outcomes) study investigators: Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: Double-blind randomised controlled trial. Lancet 363:675-681, 2004. 273. Cohen S, Emery P, Greenwald M, et al: Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 54:2793-2806, 2006. 274. Kremer J, Genant H, Moreland L, et al: Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: A randomized trial. Ann Intern Med 144:865-876, 2006.

57

Immunoregulatory Drugs C. MICHAEL STEIN  •  H. GUY TAYLOR

KEY POINTS Most immunoregulating drugs have a narrow therapeutic index and require careful monitoring and dosage adjustment. Cyclophosphamide toxicities include myelosuppression, infection, ovarian failure, bladder cancer, and malignancy. Many patients with severe azathioprine-induced myelosuppression have low or absent thiopurine methyltransferase (TPMT) activity. TPMT activity is affected by genetic polymorphism; individuals at risk can be identified by genetic screening. One of the most important, and potentially fatal, drug interactions in rheumatology is the ability of allopurinol, through inhibition of xanthine oxidase–mediated inactivation of mercaptopurine, to increase dramatically the cytotoxic effects of azathioprine and mercaptopurine. Two major factors determine cyclosporine disposition: P-glycoprotein (Pgp), a drug efflux pump, and the cytochrome P4503A (CYP3A) enzyme system. Pgp, by limiting drug uptake, and CYP3A4, by facilitating drug metabolism, act to limit the bioavailability of cyclosporine and contribute to its many drug interactions. If the serum creatinine level of a patient receiving cycylosporine increases more than 30% above the patient’s baseline (even within the normal range for serum creatinine), the dose of cyclosporine should be reduced.

Understanding of the complex cellular and subcellular mechanisms that regulate immune function is sophisticated, but understanding of the specific immunologic factors that trigger and sustain most inflammatory rheumatic diseases remains rudimentary. The immunologic triggers of rheumatic disease and the specific functionally important mechanisms of antirheumatic drugs are poorly characterized; until more recently, therapy has evolved empirically, rather than in a hypothesis-based, targeted fashion. This trial-and-error approach has led to the relatively slow evolution of immunoregulating treatment regimens, which are often based on clinical practice rather than controlled trials. Current regimens (Table 57-1) are not ideal because they have suboptimal efficacy and often substantial toxicity, but they continue to evolve. This chapter outlines the clinical pharmacology of the older cytotoxic agents, where the major advance has been an improved understanding of how to use the drugs, and newer immunoregulating drugs, where optimal clinical use remains to be defined. Methotrexate, leflunomide, and biologic agents are discussed elsewhere.

ALKYLATING AGENTS Alkylating agents, widely used as anticancer drugs, substitute alkyl radicals into DNA, resulting in cross-linking of DNA, impaired DNA synthesis, and cell death. Nitrogen mustard (mechlorethamine) was the alkylating agent first used in rheumatic diseases in the 1950s, but the requirement for intravenous administration and toxicity led to its replacement by cyclophosphamide and chlorambucil. CYCLOPHOSPHAMIDE Structure Cyclophosphamide is an oxazaphosphorine-substituted nitrogen mustard that was developed to be a less reactive drug, more selectively cytotoxic to neoplastic cells.1 The original concept that tumor cells would selectively activate cyclophosphamide, resulting in selective cytotoxicity to neoplastic cells, proved incorrect. Nevertheless, cyclophosphamide has a better therapeutic index than nitrogen mustard and is the alkylating agent of choice for most rheumatic disease requiring such therapy. Mechanisms of Action Cyclophosphamide is inactive. Its effects are mediated predominantly through phosphoramide mustard and, to a lesser extent, other active metabolites (Fig. 57-1). The primary mechanism of action is through the alkylation of DNA by active metabolites, such as phosphoramide mustard. These positively charged, reactive intermediates alkylate nucleophilic bases resulting in the cross-linking of DNA, breaks in DNA, decreased DNA synthesis, and apoptosis.1,2 The cytotoxicity of alkylating agents correlates with the amount of DNA cross-linking, but the relationship between cytotoxicity and immunoregulatory effects is unclear. The effects of cyclophosphamide are not limited to any particular cell type; however, sensitivity varies among cell populations. Several mechanisms of cellular resistance to alkylating agents have been proposed, including increased intracellular concentrations of glutathione and other thiols, increased activity of enzymes such as aldehyde dehydrogenase that produce inactive metabolites of cyclophosphamide, and increased DNA repair mechanisms.3 Cyclophosphamide has a marked effect not only on rapidly dividing cells, but also throughout the cell cycle, resulting in alterations of most humoral and cellular immune responses.4,5 The effects of cyclophosphamide include decreased numbers of T lymphocytes and B lymphocytes, decreased lymphocyte proliferation, decreased antibody production, and suppression of delayed hypersensitivity 909

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Table 57-1  Mechanism of Action of Immunoregulatory Drugs Drugs

Class

Mechanism of Action

Cyclophosphamide, chlorambucil

Alkylating cytotoxics

Active metabolites alkylate DNA

Azathioprine, mercaptopurine

Purine analogue cytotoxics

Inhibit purine synthesis

Cyclosporine, tacrolimus (FK506)

Calcineurin inhibitors

Inhibit calcium-dependent T cell activation and   interleukin-2 production

Sirolimus (rapamycin)

Non–calcineurin-binding macrolide   immunoregulator

Blocks interleukin-2–mediated and growth factor–  mediated signal transduction

Mycophenolate mofetil

Purine synthesis inhibitor

Mycophenolic acid inhibits inosine monophosphate dehydrogenase

Thalidomide

Glutamic acid derivative

Inhibition of tumor necrosis factor-α production and angiogenesis

Dapsone

Sulfone antimicrobial

Inhibition of neutrophil function

Cyclophosphamide Cytochrome P450 4-Hydroxycyclophosphamide Figure 57-1  The metabolism of cyclophosphamide. Cyclophosphamide is converted to 4-hydroxycyclophosphamide, in equilibrium with its tautomer aldophosphamide, by cytochrome P-450 enzymes. Subsequent nonenzymatic processes lead to the formation of phosphoramide mustard and acrolein. Oxidation of 4-hydroxycyclophosphamide and aldophosphamide through enzymes, including aldehyde dehydrogenase, result in inactive metabolites. Cytotoxic metabolites are shown in bold type.

Aldophosphamide

Oxidation

Oxidation

4-Ketocyclophosphamide

Carboxyphosphamide

Nonenzymatic Phosphoramide mustard + Acrolein

to new antigens with ­ relative ­ preservation of established delayed hypersensitivity.4,5 A marked effect on B lymphocyte function in resting and stimulated cells is thought to be an important component of the clinical mechanism of action of cyclophosphamide.5,6 Pharmacology Absorption and Distribution. Oral and intravenous admin­ istration of cyclophosphamide result in similar plasma concentrations.7 Peak plasma concentrations of cyclophosphamide occur 1 hour after oral administration, and formation of the active phosphoramide mustard is rapid.8 Protein binding of cyclophosphamide is low (20%), and it is widely distributed.1 Metabolism and Elimination. Cyclophosphamide, ­ itself inactive, is rapidly metabolized, largely by the liver, to active and inactive metabolites (see Fig. 57-1). The formation of the active 4-hydroxycyclophosphamide is mediated by several cytochrome P-450 (CYP) enzymes. CYP2B6 and CYP2C19 seem to contribute more than CYP2C9, CYP3A4, and CYP3A5, and genetic variations in the enzymes may affect responses to cyclophosphamide.9 The formation of 4-hydroxycyclophosphamide, which is ­ cytotoxic, but not at physiologic pH, allows ­entry of the drug into cells and subsequent formation of the active phosphoramide mustard. The elimination half-life of cyclophosphamide is 5 to 9 hours,10 and alkylating activity is undetectable in the plasma

of most patients 24 hours after a dose of 12 mg/kg.11 Plasma concentrations of cyclophosphamide are not clinically ­useful predictors of either efficacy or toxicity. Cyclophosphamide is eliminated predominantly in the urine, mostly as inactive metabolites. Ten percent to 20% is eliminated as unaltered cyclophosphamide, however, and some active metabolites, such as phosphoramide mustard and acrolein, are present in urine.1,10,11 Pharmacokinetic Considerations in Special Circumstances Liver Disease.  The half-life of cyclophosphamide is increased to 12 hours in patients with liver failure compared with 8 hours in controls.12 Toxicity is not increased, how­ ever, suggesting that exposure to cytotoxic metabolites is not incre­ased, and dose modification in liver disease is ­generally not required.1,10 Renal Impairment.  Some studies have shown little ­alteration in drug disposition with no increased toxicity in patients with impaired renal function.10 Small amounts of unchanged cyclophosphamide and its active metabolites are excreted by the kidneys, however, and some accumulation of these would be expected. In patients with autoimmune disease and a creatinine clearance of 25 to 50 mL/min and 10 to 25 mL/min, exposure to cyclophosphamide increased approximately 40% and 70%.13 In clinical practice, initial cyclophosphamide doses are decreased by approximately 30% in patients with moderate-to-severe renal impairment. Subsequent doses are titrated according to clinical response and effects on the leukocyte (white blood cell) count.14 Cyclophosphamide is removed by

PART 8 

­dialysis and is administered after dialysis,1 or, alternatively, dialysis can be initiated the day after cyclophosphamide ­administration.13 Dosage and Route of Administration Typical dosage regimens are presented in Table 57-2. In longterm studies in patients with systemic lupus erythematosus (SLE), monthly intravenous cyclophosphamide regimens preserve renal function better than oral cyclophosphamide or azathioprine-based regimens.15 More recent trends are to use shorter induction courses before switching to alternative maintenance agents to minimize cyclophosphamide toxicity. Also, in Europe particularly, more frequent administration of lower doses of cyclophosphamide has been studied. Six doses of 0.5 g of cyclophosphamide every 2 weeks and a more traditional monthly cyclophosphamide induction regimen, both followed by azathioprine maintenance, resulted in similar rates of the end points of end-stage renal disease or doubling of creatinine concentration with 6 years of follow-up.16 Cyclophosphamide pulses also can be effective in patients with other serious complications of SLE, including central nervous system involvement and thrombocytopenia, and interstitial lung disease associated with scleroderma and other autoimmune diseases.17-19 The use of cyclophosphamide for the treatment of Wegener’s granulomatosis and other forms of systemic vasculitis has evolved through careful observational studies. Oral daily cyclophosphamide regimens remain the standard against which other treatments are compared. Intravenous cyclophosphamide is less effective than oral cyclophosphamide for the treatment of Wegener’s granulomatosis, particularly in terms of inducing a sustained response to therapy,14,20

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although this opinion is not universal.21 As in lupus nephritis, shorter induction courses of cyclophosphamide have been reported to be effective in Wegener’s granulomatosis and microscopic polyangiitis.22 In rheumatoid arthritis (RA), oral cyclophosphamide is effective, but the benefit seldom justifies the risks.23 In rheumatoid vasculitis, intravenous cyclophosphamide improved the vasculitis, but did not improve the arthritis.23 The bioavailability of oral cyclophosphamide is excellent, and monthly oral pulse therapy with cyclophosphamide (0.5 to 1 g/m2) has been successful.24 Weekly low-dose (500 mg) intravenous cyclophosphamide infusions for 1 to 3 weeks have been used to initiate therapy to induce remission more rapidly in patients who otherwise would be treated with daily oral cyclophosphamide.25 Toxicity Hematologic. Reversible myelosuppression is common. The degree of leukopenia and neutropenia, and the consequent increased risk of infection, is related to the dose of cyclophosphamide administered. Platelet counts generally are not affected with pulse doses of less than 50 mg/kg, but with long-term oral use, a mild decrease in platelet count is common. After a single dose of cyclophosphamide, the approximate times to nadir and recovery of leukocyte counts are 8 to 14 days and 21 days.26 The white blood cell nadir is about 3000 cells/mm3 ­after a dose of 1 g/m2 (approximately 25 mg/kg) and 1500 cells/mm3 after a dose of 1.5 g/m2.8 With long-term use, there is increased sensitivity to the myelosuppressive effects of cyclophosphamide, and doses usually need to be decreased over time.

Table 57-2  Typical National Institutes of Health–Derived Protocols for the Management of Systemic Vasculitis   with Oral Cyclophosphamide and the Management of Lupus Nephritis with Intravenous Pulse Cyclophosphamide Wegener’s Granulomatosis Oral Cyclophosphamide Regimen

Lupus Nephritis Intravenous Cyclophosphamide Regimen

Glucocorticoid

Prednisone 1 mg/kg/day for 4 wk decreasing, if possible, to achieve a prednisone dose of approximately 60 mg alternate days at 3 mo

Prednisone 0.5-1 mg/kg/day for 4 wk decreasing the every-other-day dose each week, if possible, by 5 mg   to achieve a prednisone dose of 0.25 mg/kg on alternate days

Cyclophosphamide   (initial dose)

2 mg/kg/day by mouth; very ill patients receive 3-5 mg/kg/day for 2-3 days, then 2 mg/kg/day; decrease dosage   25-50% for renal impairment

0.5-0.75 g/m2 infused IV in saline over 30-60 min; decrease dosage by approximately 30% if glomerular filtration rate is less than one third normal

Cyclophosphamide   (subsequent dose)

Increase daily dose in 25-mg increments at 1-2 wk intervals if disease active; adjust dosage to avoid leukopenia (WBC <3000/mm3) and granulocytopenia

If WBC nadir 10-14 days after the previous dose is >4000/mm3, increase the dose 25% to a maximum of 1 g/m2; adjust dosage to avoid WBC nadir <2000/mm3; if WBC nadir <1500/mm3, decrease dosage by at least 25%

Adjunct treatment

Pneumocystis prophylaxis, particularly during “induction” phase

Optional mesna every 3 hr for 4 doses orally or IV;   each mesna dose approximately 20% of   cyclophosphamide dose Antiemetics: ondansetron 4-8 mg orally every 4 hr for 3-4 doses and 1 dose of dexamethasone 10 mg orally

Treatment plan

Taper cyclophosphamide after 1 yr of remission; alternatively, after remission induced, consider alternative maintenance therapy, such as methotrexate or azathioprine

Monthly cyclophosphamide for 6 mo, then a maintenance dose every 3 mo; continue maintenance   cyclophosphamide for 1 yr after remission, or consider alternative maintenance therapy, such as mycophenolate or azathioprine

IV, intravenously; WBC, white blood cell count. Data from references 28, 29, 30, 82, 84, 182, and 183.

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Infection. Infection with a range of common and opportunistic pathogens is a frequent complication. In 100 patients with SLE, infection occurred in 45 during treatment with a cyclophosphamide-based regimen and was the primary cause of death in 7 patients.27 In this study, infection was equally common in patients receiving oral or intravenous cyclophosphamide and was associated with a white blood cell nadir at some point in treatment of less than 3000/mm3 (55% infection rate versus 36%). At the time of infection, the average white blood cell count was normal, however.27 A higher maximal corticosteroid dose also was associated with increased risk of infection. Half of the infections occurred at prednisone doses of less than 40 mg/ day, and a quarter of the infections occurred at doses less than 25 mg/day. Lower rates of infection (25% to 30%) have been reported in patients with SLE receiving ­cyclophosphamide in National Institutes of Health protocols.28 Oral cyclophosphamide regimens generally pose a greater risk of infection than intravenous pulse regimens. Serious infections occurred in 41% and 70% of patients with Wegener’s granulomatosis treated with pulse intravenous and daily oral cyclophosphamide.20 These rates of infection are higher than rates reported in long-term National Institutes of Health protocols, in which 48% of 158 patients experienced 140 infections requiring hospitalization.29 The reported frequency of cyclophosphamide-associated infection varies, probably as a function of the stage and severity of the underlying disease, the degree of cyclophosphamideinduced immunosuppression, and variations in concomitant glucocorticoid regimens.20,30 Despite differences in clinical experience, infections are a common and potentially serious complication of all cyclophosphamide-based regimens. Pneumocystis jiroveci pneumonia has been recognized as a preventable, serious opportunistic infection that complicates treatment of systemic vasculitis with regimens using cyclophosphamide and methotrexate. The risk is highest during the initial “induction” phase and is greater with oral than intravenous cyclophosphamide regimens.20,31 Urologic. The bladder toxicities of cyclophosphamide, hemorrhagic cystitis, and bladder cancer are related to route of administration, duration of therapy, and cumulative cyclophosphamide dose. Pulse intravenous cyclophosphamide regimens in rheumatology, in contrast to high-dose oncology regimens, do not generally result in bladder toxicity. Bladder toxicity, a particular problem with long-term oral cyclophosphamide, is largely due to acrolein, a metabolite of cyclophosphamide.32 Bladder toxicity can be minimized in ­patients receiving pulse doses of intravenous cyclophosphamide by administering mesna, a sulfhydryl compound that binds ­acrolein in the urine and inactivates it.33 The short half-life of mesna renders it suboptimal for the prevention of bladder toxicity in patients at greatest risk—patients receiving daily oral cyclophosphamide—but oral mesna administered three times a day with daily oral cyclophosphamide decreased the incidence of bladder toxicity to 12% and may decrease the risk of bladder cancer.34 Nonglomerular hematuria, which may range from minor, microscopic blood loss to severe, macroscopic bleeding, is the most common manifestation of cyclophosphamide-induced cystitis.35 Nonglomerular hematuria occurred at some time in 50% of 145 patients treated with oral cyclophosphamide and was related to the duration of therapy and cumulative cyclophosphamide dose.35

The absolute risk of bladder cancer is difficult to quantify. In a large study, the risk of bladder cancer was increased 31-fold (95% confidence interval 13-fold to 65-fold), and 7 of 145 patients (5%) have developed bladder cancer to date.35 Cancer developed 7 months to 15 years after initiating therapy and was preceded by nonglomerular hematuria in all patients. Six of the seven patients had a cumulative dose of more than 100 g of cyclophosphamide and a duration of therapy of more than 2.7 years.35 Smokers are at increased risk of hemorrhagic cystitis and bladder cancer.35 Malignancy. In addition to the increased risk of bladder cancer, cyclophosphamide increases the risk of other malignancies twofold to fourfold.35,36 The absolute risk is difficult to quantify, however, because few patients have been studied long-term. In the largest study, 119 patients with RA who had been treated with oral cyclophosphamide were followed for 20 years. There were 50 cancers in 37 patients in the cyclophosphamide group compared with 26 cancers in 25 of 119 control RA patients.36 Bladder, skin, myeloproliferative, and oropharyngeal malignancies occurred more commonly in the cyclophosphamide group.36 The risk of bladder and other malignancies increased with the cumulative dose of cyclophosphamide, and 53% of patients who ­received more than 80 g of cyclophosphamide developed malignancy.36 Few malignancies have been reported in patients treated with pulse intravenous cyclophosphamide regimens. Current data do not allow quantification of the long-term risk of malignancy associated with pulse intravenous cyclophosphamide treatment, but it is likely to be substantially smaller than that associated with oral regimens. Reproductive. The adverse effects of alkylating agents on subsequent fertility in men and women who have undergone cancer chemotherapy are well recognized37; however, there was no increase in genetic disease in the offspring of adults who underwent cancer chemotherapy in childhood.38 Cyclophosphamide, as used in autoimmune disease, results in significant gonadal toxicity. The risk of sustained amenorrhea after cyclophosphamide therapy has ranged from 11% to 59%.39 The risk of ovarian failure may be lower with intravenous pulse cyclophosphamide regimens than with oral regimens, but the difference is not substantial. Ovarian failure occurred in 5 of 11 patients (45%) receiving intravenous pulse cyclophosphamide compared with 13 of 22 (59%) ­receiving oral cyclophosphamide for lupus nephritis.40 ­Regardless of the route of cyclophosphamide administration, the risk of ovarian failure increases with the age of the ­patient and the cumulative dose of cyclophosphamide.39,41,42 Patients younger than 25 years old receiving 6 pulses of intravenous cyclophosphamide had a very low frequency of ovarian failure (none of four patients), whereas patients older than 31 years receiving 15 to 24 pulses all had ovarian failure (four of four patients).41 In men undergoing chemotherapy with regimens that include an alkylating agent, the frequency of azoospermia has ranged from 50% to 90%.37,43 Less ­ information is available in autoimmune disease, but azoospermia or ­ severe oligospermia was found in 11 of 17 men receiving cyclophosphamide for Behçet’s syndrome.44 If the clinical situation allows, sperm or ova can be banked before starting treatment with cyclophosphamide to preserve future fertility in selected patients. Various ­strategies,

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usually involving suppression of luteinizing hormone and follicle-stimulating hormone, have been used to protect against cyclophosphamide-induced gonadal toxicity. Data are limited, however. A small study suggested that an oral contraceptive with a high dose of estrogen was protective, but in a retrospective cohort study, low-dose oral contraceptives were not.42 Preliminary findings in women treated with a gonadotropin-releasing hormone analogue while undergoing chemotherapy for lymphoma45 and SLE46 suggested a protective effect. In a nonrandomized study of women with lupus receiving monthly intravenous cyclophosphamide, ovarian failure occurred in 1 of 20 who received depot leuprolide acetate, a gonadotropin-releasing hormone agonist, compared with 6 of 20 matched controls.47 In men, a luteinizing hormone–releasing analogue was not protective,48 but testosterone (100 mg intramuscularly every 15 days) was protective in five patients.43 Pulmonary. Cyclophosphamide-induced pulmonary toxicity occurs in less than 1% of patients.26 Early-onset pneumonitis 1 to 6 months after exposure to cyclophosphamide may respond to withdrawal of the drug and treatment with corticosteroids. A more insidious, irreversible, late-onset pneumonitis and fibrosis with radiographic findings of diffuse reticular or reticulonodular infiltrates may occur after treatment with oral cyclophosphamide for 1 to 13 years.49 Miscellaneous. A varying degree of reversible alopecia can occur with daily oral and monthly pulse cyclophosphamide. Cardiotoxicity, a dose-limiting adverse effect in oncology, and water intoxication, owing to inappropriate antidiuretic hormone secretion, are rare.50 Unusual hypersensitivity reactions include urticaria and anaphylaxis,26,51 although the bladder protectant mesna is a more likely cause of allergic responses in patients receiving both drugs.52 Cyclophosphamide is teratogenic, particularly in the first trimester, and should be avoided in pregnancy.53,54 Strategies to Minimize Toxicity. Strategies to minimize toxicity include adjusting the dose of cyclophosphamide to avoid a significant degree of leukopenia (white blood cell count <3000/mm3 for daily oral therapy or a nadir of <2000/mm3 for pulse intravenous therapy) and granulocytopenia.30,55 The blood count is monitored initially at 1- to 2-week intervals and monthly thereafter in patients on stable oral doses. To decrease the risk of infection added by concomitant high-dose corticosteroids, the dose of corticosteroids should be reduced after a clinical response has been obtained, and alternate-day glucocorticoids can be considered in the maintenance phase. Oral cyclophosphamide is best administered as a single dose in the morning with the patient drinking plenty of fluids and emptying the bladder frequently to dilute the urinary concentration of acrolein and to minimize the time the bladder is exposed to it. Prophylaxis against Pneumocystis jiroveci pneumonia is often prescribed, particularly during the induction phase when doses of cyclophosphamide and corticosteroids are higher.30 Many clinicians administer mesna with intravenous cyclophosphamide (see Table 57-2) to decrease bladder toxicity, and limited data suggest it also may be beneficial with oral therapy.34 Urinalysis should be performed monthly, and nonglomerular hematuria should be evaluated by a urologist. All patients

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who receive cyclophosphamide, particularly patients who develop hemorrhagic cystitis, are at increased risk of developing bladder cancer, and lifelong surveillance is required with urinalysis, urine cytology, and, if indicated, cystoscopy.56 Lastly, drugs that are less toxic than cyclophosphamide, such as methotrexate, are an option for inducing remission in patients with less severe Wegener’s granulomatosis57 or for maintenance therapy in some patients after remission has been induced with cyclophosphamide and prednisone.58 Drug Interactions Cimetidine. Cimetidine inhibits the activity of several hepatic enzymes. Coadministration with cyclophosphamide results in increased exposure to alkylating metabolites in a rabbit model.59 Ranitidine60 and presumably other H2-receptor antagonists that have little effect on hepatic drug metabolism are not associated with increased ­cyclophosphamide toxicity. Allopurinol. Allopurinol increases the half-life of cyclophosphamide61 and the frequency of leukopenia.62 Succinylcholine. Cyclophosphamide decreases plasma pseudocholinesterase activity and can potentiate the effect of succinylcholine.63 Clinical Role Cyclophosphamide remains the drug of choice for most patients with systemic necrotizing vasculitis or Goodpasture’s syndrome, for many patients with organ-threatening SLE, and for some patients with autoimmune disease–associated interstitial lung disease and inflammatory eye disease. In other diseases, such as RA, unless complicated by vasculitis, less toxic and more effective drugs have replaced cyclophosphamide. High doses of cyclophosphamide, with or without stem cell rescue, are being studied as therapies for RA and SLE. Cyclophosphamide may be a lifesaving drug, but it also can induce life-threatening adverse effects. Meticulous monitoring and good clinical judgment are required to use it effectively. CHLORAMBUCIL Structure Chlorambucil (4(4-bis(2chloroethyl)aminophenyl)-butyric acid) is an alkylating agent widely used to treat lymphomas and other malignancies. It also has been used, usually as an alternative to cyclophosphamide, in rheumatologic diseases. Mechanism of Action The mechanism of action of chlorambucil is similar to that of cyclophosphamide, but slower. Pharmacology Chlorambucil is well absorbed (>70%) after oral administration with peak concentrations occurring within 2 hours.64 Chlorambucil is extensively metabolized by β-oxidation

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to a metabolite, phenylacetic acid mustard, which also is cytotoxic.64,65 Less than 1% of the oral dose of chlorambucil appears in the urine as unchanged drug.64 The plasma half-life of chlorambucil and the phenylacetic acid mustard metabolite is 30 to 180 minutes.64,65 Dosage Chlorambucil is moderately effective in RA, with approximately 70% of patients showing benefit in uncontrolled studies.66 Alternative, safer drugs are preferred for the treatment of RA. Chlorambucil is effective for some patients with inflammatory eye disease, including Behçet’s syndrome,67 and occasionally for refractory dermatomyositis.68 Chlorambucil is used as an alternative alkylating agent for patients unable to tolerate cyclophosphamide because of bladder toxicity or gastrointestinal intolerance. Chlorambucil does not seem to be as effective as cyclophosphamide, however, in the treatment of vasculitis or glomerulonephritis.69 Chlorambucil is often started at a dose of 0.1 mg/kg/day; the dose is increased or decreased according to clinical response and toxicity. Doses of 0.2 mg/kg/day or greater are associated with more frequent myelosuppression. Alternatively, a “start low, go slow” approach, with chlorambucil started at a dose of 4 mg/day and increased in 1-mg increments at 1- to 2-month intervals, if required, may be better tolerated. Even with this approach, 75% of patients discontinued therapy because of chlorambucil-related toxicity.66 Regular monitoring, particularly of the white blood cell count, at approximately 2-week intervals initially, and then monthly when stable, is required. Toxicity Hematologic. Myelosuppression is common and may be abrupt in onset. The degree of leukopenia and neutropenia is dose related, but there are considerable interindividual differences in sensitivity. The frequency of leukopenia in patients receiving chlorambucil for RA has ranged from 14% to 50%.66 Myelosuppression is usually reversible; however, it may take several months for the white blood cell count to return to the normal range, and some patients remain relatively leukopenic. Irreversible, fatal bone marrow suppression has been reported in patients receiving chlorambucil for rheumatic disease.66 Infection. The average frequency of herpes zoster infection is 13%. As is the case with cyclophosphamide, infections resulting from a wide range of bacterial and nonbacterial pathogens occur.66 Malignancy. Treatment with chlorambucil increases the risk of leukemia, particularly myeloid leukemia, and has been associated with a range of lymphomas.66,70 Various solid organ tumors have occurred in association with chlorambucil, but no causal relationship has been established.66 Miscellaneous. Other adverse effects of chlorambucil include azoospermia and amenorrhea, which are usually reversible. Pulmonary fibrosis, oral ulceration, hepatotoxicity, nausea, fever, and rashes are other adverse effects. Chlorambucil is teratogenic.

PURINE ANALOGUES AZATHIOPRINE AND MERCAPTOPURINE Structure Azathioprine, a prodrug, is an imidazolyl derivative of mercaptopurine, and is a purine analogue, cycle-specific antimetabolite that is widely used as an immunosuppressant for organ transplantation; the treatment of malignancy; and autoimmune diseases such as RA, SLE, and Behçet’s syndrome. Azathioprine has a better therapeutic index than mercaptopurine and has largely replaced it in the treatment of autoimmune disease. Azathioprine is rapidly converted to mercaptopurine in vivo by the removal of an imidazole group.71 The clinical pharmacology of azathioprine and mercaptopurine are similar, and the drugs are discussed together. Mechanisms of Action Azathioprine is converted to mercaptopurine and then to active intracellular thiopurine metabolites as discussed later. The exact mechanism of action of the active thiopurine metabolites of azathioprine and mercaptopurine in autoimmune disease is unknown. Thiopurine metabolites, such as thioguanine nucleotides, decrease the de novo synthesis of purine nucleotides by inhibiting amidotransferase enzymes and purine ribonucleotide interconversion and are incorporated into DNA and RNA.71 The incorporation of thioguanine nucleotides into the nucleic acids of cells is thought to mediate the cytotoxicity of azathioprine, whereas inhibition of purine synthesis may be more important in decreasing cellular proliferation.71 Leukopenia is unnecessary for immunosuppression. Azathioprine and mercaptopurine decrease the circulating lymphocyte count, suppress lymphocyte proliferation, inhibit antibody production, inhibit monocyte production, suppress natural killer cell activity, and inhibit cell-mediated and humoral immunity. Pharmacology Absorption and Distribution. After absorption, azathioprine is rapidly converted to mercaptopurine enzymatically by glutathione-S-transferase and nonenzymatically by sulfhydryl groups (Fig. 57-2).71 The bioavailability of azathioprine, measured as the concentrations of mercaptopurine achieved after oral administration, varies. In healthy volunteers, bioavailability ranged from 27% to 83% with an average of 47%.72 Mercaptopurine is widely distributed with a volume of distribution of 4 to 8 L/kg.72 Metabolism and Elimination. The metabolism of mercaptopurine is complex71,73 and has been simplified in Figure 57-2. Two enzymes, xanthine oxidase and thiopurine methyltransferase (TPMT), shunt mercaptopurine metabolites to relatively inactive compounds, whereas other enzymes, such as hypoxanthine-guanine-phosphoribosyl-transferase, lead to the formation of cytotoxic thiopurine nucleotides. Low TPMT activity or inhibition of xanthine oxidase by drugs such as allopurinol leads to decreased detoxification and increased formation of cytotoxic metabolites after the administration of azathioprine or mercaptopurine. Maximal concentrations of mercaptopurine occur 1 to 3 hours after ­ administration

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6-Methylmercaptopurine Thiopurine methyltransferase Azathioprine

Glutathione-S-transferase

6-MP

HGPRT

Thiopurine nucleotides

Xanthine oxidase 6-Methylthiouric acid

of azathioprine, and the half-life of mercaptopurine is 1 to 2 hours.72 The half-life of the intracellular, ­active 6-thioguanine nucleotides is estimated to be 1 to 2 weeks, however, and concentrations do not change over the 24-hour dose period in patients receiving daily azathioprine.74,75 At conventional rheumatologic doses, approximately 1% of mercaptopurine is excreted unchanged in the urine.74 Increased toxicity can occur with renal impairment, however, and a modest dose reduction is usually needed. The substantial interindividual variability in azathioprine disposition and TPMT activity are more important determinants of sensitivity to azathioprine than renal function.76 Azathioprine and mercaptopurine cross the placenta, but drug and metabolite concentrations are lower in the fetal circulation, suggesting placental metabolism.77,78 Studies in renal allograft recipients who received azathioprine during pregnancy generally have not found an increased frequency of birth defects.77 There are limited data in rheumatologic diseases; if possible, azathioprine is avoided in pregnancy, but it has been used with caution.79 Dosage Azathioprine is often started at a dose of 1 mg/kg daily, and if this is tolerated, the dose is increased to 2 to 2.5 mg/kg after 2 to 4 weeks. A gradual increase in dose is often better tolerated. The onset of immunomodulatory effects is relatively slow, over several weeks, presumably because the active thioguanine metabolites slowly accumulate intracellularly. Azathioprine is effective in the treatment of RA with a slow clinical response over several months,23 but it is not as effective as methotrexate. The combination of azathioprine and methotrexate has been reported to be effective in RA, but a controlled trial found no advantage of the combination compared with the individual drugs.80 The latter trial used lower doses in the combination arm, however, than individually. Azathioprine has been combined with infliximab as an alternative to methotrexate without unexpected adverse effects.81 Azathioprine is used to treat some patients with lupus nephritis, and although it is more effective than corticosteroids alone, it is not as effective as intravenous pulse cyclophosphamide.82,83 It is effective in maintenance therapy,84 even after low-dose cyclophosphamide induction.16 For other manifestations of SLE, including cutaneous disease, azathioprine is widely used as a corticosteroid-sparing agent.85 Azathioprine in combination with corticosteroids is useful in the treatment of a range of other autoimmune diseases, including inflammatory muscle disease. For refractory

Figure 57-2  Azathioprine is converted to mercaptopurine (6-MP) enzymatically by glutathione-S-transferase and nonenzymatic mechanisms. Xanthine oxidase and thiopurine methyltransferase metabolize 6-MP to the inactive metabolites 6-methylthiouric acid and 6-methylmercaptopurine. Hypoxanthine-guanine-phosphoribosyl-transferase (HGPRT) metabolizes 6-MP to active, cytotoxic thiopurine nucleotides.

myositis, the combination of azathioprine, methotrexate, and corticosteroids has been effective.86 Efficacy is reported in inflammatory eye disease, including Behçet’s syndrome,87 psoriatic arthritis,88 Reiter’s syndrome, and various forms of vasculitis.89 In systemic vasculitis, azathioprine is most often used as a steroid-sparing agent, and generally not to induce remission, being less effective than cyclophosphamide.22A small study has shown efficacy, however, of high-dose (1200to 1800-mg infusions) monthly azathioprine as initial treatment of Wegener’s granulomatosis and lupus nephritis.90 Toxicity Azathioprine is not as well tolerated as weekly methotrexate.80 Approximately 15% to 30% of patients discontinue azathioprine within 6 months, most often because of gastrointestinal adverse effects.91 Hematologic. Reversible myelosuppression is common, is dose related, and varies substantially among individuals. Lowdose azathioprine (1 to 2 mg/kg/day) resulted in leukopenia in 4.5% and thrombocytopenia in 2% of subjects.91 Pure red cell aplasia is rare. Severe myelosuppression is uncommon and until more recently has been thought to be an idiosyncratic response to azathioprine. It is now evident that many patients with severe azathioprine-induced myelosuppression have low or absent TPMT activity. Decreased TPMT activity leads to a decreased ability to detoxify mercaptopurine and results in increased formation of cytotoxic thioguanine metabolites and clinical toxicity. TPMT activity is affected by genetic polymorphism, and several point mutations are associated with impaired enzyme activity.92 TPMT activity in white Americans and African-Americans is similarly polymorphic with a trimodal distribution. ­ Approximately 90% of subjects show high activity, 10% show intermediate activity, and 0.3% (the subjects homozygous for the poorly functional polymorphisms) show very low activity.92,93 The median TPMT activity in African-Americans is approximately 17% lower than in white Americans.93 The 1 in 300 subjects with low or absent TPMT activity is at great risk of severe azathioprine-induced myelosuppression, which has a delayed but sudden onset, most commonly 4 to 10 weeks after azathioprine has been started.94 More than half of all cases of leukopenia in patients receiving azathioprine have a normal TPMT genotype and phenotype, however.95 Subjects with intermediate TPMT activity may have more frequent adverse effects, including early nausea and other gastrointestinal effects.73

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Gastrointestinal. In a cohort of patients with inflammatory bowel disease, nausea and vomiting requiring drug cessation occurred in 6%, and pancreatitis occurred in 7%96; however pancreatitis after azathioprine seems to be significantly more common in patients with inflammatory bowel disease than in patients with other conditions.97 Liver test abnormalities occur in 34%, but are seldom serious. ­Serious liver toxicity, severe cholestasis, hepatic veno-occlusive disease, and nodular regenerative hyperplasia and pancreatitis are rare. Malignancy. Data regarding the risk of malignancy in ­patients treated with azathioprine for rheumatologic disease are conflicting. Some studies found an increased risk, particularly of lymphoproliferative malignancies, whereas others did not.98 A 24-year retrospective study of 358 SLE patients found no difference in malignancy rates between patients who had received azathioprine and patients who had not, and there were no lymphomas in the azathioprine group.99 A meta-analysis of patients with inflammatory bowel disease showed a fourfold increased risk of lymphoma, however, in azathioprine-treated patients.100 Azathioprine Hypersensitivity. Acute hypersensitivity syndromes, usually occurring within 2 weeks of starting therapy, with a range of manifestations, including shock, fever, rash, pancreatitis, renal failure, and hepatitis, are rare.101 Others. Infection is less common with azathioprine than with alkylating agents; however, infections with a range of bacterial and nonbacterial pathogens, including herpes zoster and cytomegalovirus, may occur. The rate of infection when azathioprine is administered alone or with low doses of glucocorticoids is approximately 2.5 per 100 person-years of exposure.91 Maculopapular or urticarial rashes can occur. Eosinophilia and drug fever are rare. Strategies to Minimize Toxicity. Measurements of plasma concentrations of azathioprine or mercaptopurine are not useful predictors of efficacy or toxicity. Therapeutic monitoring using the red blood cell concentration of 6-thioguanine nucleotides has been attempted, but although there is a relationship between concentrations and efficacy and toxicity, the relationship does not seem to be clinically useful except at the extremes (i.e., noncompliance or severe toxicity).95 This is partly because red blood cells, in contrast to leukocytes, lack inosine monophosphate dehydrogenase to convert mercaptopurine to thioguanines, and concentrations reflect hepatic conversion rather than leukocyte concentrations. Tests to identify the 1 in 300 individuals with low or absent TPMT activity are now available from commercial and research laboratories and are prudent. TPMT activity (phenotype) can be measured directly in red blood cell membranes, or, alternatively, the known polymorphisms can be identified by polymerase chain reaction. The clinical utility and cost-effectiveness of genotyping for TPMT and modifying the dose of azathioprine accordingly (from the standard dose of 2.5 mg/kg to 1 mg/kg in heterozygotes and to 0.25 mg/kg in homozygotes) has been studied using a decision analysis model. Although this modeling predicts a modest cost savings and a marked reduction in morbidity,102 a small prospective controlled study in 29 patients found the

reverse.103 This finding is at least partly because the ­ ability to predict azathioprine toxicity from TPMT ­ activity is ­limited.104 In the absence of TPMT testing, a low initial dose and careful monitoring of the white blood cell count in patients starting azathioprine is required. Some authors suggest weekly monitoring during the first 15 weeks of ­ azathioprine treatment.94 When patients are on a ­stable dose of azathioprine, blood counts are monitored monthly, and liver function tests are monitored every 3 to 4 months. Drug Interactions Allopurinol. One of the most important, and potentially fatal, drug interactions in rheumatology is the ability of allopurinol, through inhibition of xanthine oxidase– mediated inactivation of mercaptopurine, to increase dramatically the cytotoxic effects of azathioprine and ­mercaptopurine.105 Various strategies have been employed to treat hyperuricemia and gout in patients receiving azathioprine, a common clinical problem after transplantation. Reduction of the dose of azathioprine by at least two thirds in patients who also are receiving allopurinol is advocated. Because myelosuppression still can occur after a 75% reduction in dose, however, careful monitoring is required.105 Alternatively, uricosurics, such as benzbromarone, have been effective and safe,105 and mycophenolate mofetil has been substituted for azathioprine as an alternative immunosuppressant.106 Sulfasalazine. Sulfasalazine is commonly used in ­combination with azathioprine or mercaptopurine for the ­ management of refractory inflammatory bowel disease. This combination may increase the frequency of myelosuppression, perhaps because sulfasalazine inhibits TPMT activity.107 Warfarin. Azathioprine has been associated with resistance to warfarin in case reports.108

CYCLOSPORINE, TACROLIMUS (FK506), AND SIROLIMUS (RAPAMYCIN) CYCLOSPORINE Structure Cyclosporine is a lipophilic endecapeptide derived from a fungus; it has revolutionized organ transplantation and more recently has become a therapeutic option for autoimmune diseases ranging from RA to autoimmune eye disease. Mechanism of Action Cyclosporine is a prototype drug that impairs production of interleukin-2 and other cytokines, reducing lymphocyte proliferation. Cyclosporine complexes with cyclophilin, one of a group of cytosolic-binding proteins known as immunophilins. This complex binds to and inhibits calcineurin, a serine/threonine phosphatase. Inhibition of calcineurin phosphatase activity prevents the translocation of cytosolic nuclear factor of activated T cells to the nucleus, a

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t­ ranslocation that is required for the transcription of genes for cytokines such as interleukin-2 and for T cell activation (Fig. 57-3).109,110 Pharmacology There are two formulations of cyclosporine for oral use: the older, oil-based Sandimmune formulation, and the newer, microemulsion Neoral formulation. The active drug, cyclosporine, is identical in both formulations, but the microemulsion formulation results in better bioavailability and less intersubject and intrasubject variability. Neoral or equivalent generic formulations are replacing the Sandimmune formulation of cyclosporine, which is no longer universally available. Absorption and Distribution. Cyclosporine is poorly and variably absorbed from the gut with a bioavailability of approximately 30%. A high-fat meal increases absorption. There is substantial interindividual (threefold) and intraindividual (twofold) variability in cyclosporine disposition.111 The time to peak concentration (1 to 8 hours) and the elimination half-life (3 to 20 hours) vary. Cyclosporine is lipophilic and widely distributed in body ­tissues, particularly in the lean body mass.111 Higher concentrations of cyclosporine are found in red blood cells than in plasma, and whole-blood concentrations are used for monitoring, although this is seldom required in autoimmune diseases. The time to maximal concentration is approximately 25% shorter, and the maximal cyclosporine concentration and area

Costimulatory signal

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under the concentration curve are increased by approximately 50% with the microemulsion formulation.112,113 Also, interindividual and intraindividual variability in cyclo­ sporine disposition is decreased by ­approximately 50% with the microemulsion formulation.112,113 Metabolism and Elimination. There are two major determinants of cyclosporine disposition. First, P-glycoprotein (Pgp), a drug efflux pump, pumps substrates such as cyclosporine out of cells. Pgp, the product of the multidrug resistance gene, is expressed on intestinal epithelial cells and in the liver. Second, cyclosporine is extensively metabolized by the CYP3A enzyme system, which is active not only in the liver, but also in intestinal epithelium. Pgp, by limiting drug uptake, and CYP3A4, by facilitating drug metabolism in the gut and liver, act to limit the bioavailability of cyclosporine and to determine its disposition.114 Cyclosporine is extensively metabolized to more than 20 metabolites. The rate-limiting step in the elimination of cyclosporine is the formation of metabolites, not their clearance. Cyclosporine elimination is not altered in renal failure; however, because of its nephrotoxicity, cyclosporine is avoided in patients with impaired renal function. Liver disease impairs the excretion of cyclosporine metabolites. Dosage Effective use of cyclosporine requires that appropriate patients be selected for treatment and monitored carefully (Table 57-3). The starting dosage of cyclosporine is

Antigen-presenting cell Antigenic signal

T cell receptor

Interleukin-2 receptor

ñ Ca Cy A

-

Sirolimus

2+

-

Activated calcineurin

Tacrolimus

De novo purine synthesis

Interleukin-2 P

G1

S Cell cycle

NFAT M

G2

-

MMF

-

Azathioprine

Steroid NFAT

-

+ Interleukin-2 gene promoter Figure 57-3  Stages of T cell activation. Multiple targets for immunosuppressive agents. Stimulation of the T cell receptor results in calcineurin ­activation, a process inhibited by cyclosporine (CyA) and tacrolimus. Calcineurin dephosphorylates nuclear factor of activated T cells (NFAT), enabling it to enter the nucleus and bind to interleukin (IL)-2 promoter. Corticosteroids inhibit cytokine gene transcription in lymphocytes and antigen-­presenting cells by several mechanisms. Costimulatory signals are necessary to optimize T cell IL-2 gene transcription, prevent T cell anergy, and inhibit T cell apoptosis. IL-2 receptor stimulation induces the cell to enter the cell cycle and proliferate. Signal 3 may be blocked by IL-2 receptor antibodies or by sirolimus, which inhibits second messenger signals induced by IL-2 receptor ligation. Following progression into the cell cycle, azathioprine and mycophenolate mofetil (MMF) interrupt DNA replication by inhibiting purine synthesis. (From Denton MD, Magee CC, Sayegh MH: Immunosuppressive strategies in transplantation. Lancet 353:1083-1091, 1999.)

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Table 57-3  Clinical Use of Cyclosporine   in Rheumatic Disease Select appropriate patients Contraindications Current or past malignancy other than basal call carcinoma, renal impairment, uncontrolled hypertension, hepatic dysfunction Cautions Elderly age, obesity, controlled hypertension, premalignant lesions, drugs that interact with cyclosporine, pregnancy Obtain ≥2 creatinine concentrations before starting cyclosporine, and average these to provide baseline creatinine value Start low—cyclosporine 2.5 mg/kg/day in divided doses Stay low—maximum 4 mg/kg/day (microemulsion formulation) Monitor blood pressure and creatinine initially every 2 wk for 3 mo, then monthly if stable If serum creatinine increases >30% above patient’s baseline, reduce dosage of cyclosporine by 1 mg/kg/day; recheck serum creatinine in 1-2 wk, and temporarily discontinue cyclosporine if creatinine remains >30% above baseline When creatinine level returns to within 15% of baseline, cyclosporine can be restarted at a lower dosage For Consensus Guidelines, see references 184 and 185.

2.5 mg/kg/day, usually administered in divided doses. In obese patients, dosage is based on the approximate ideal body weight. Clinical response is slow, occurring over 4 to 8 weeks, and may be only ­maximal after 12 weeks or more of treatment. To improve efficacy, the dosage can be increased by 0.5 mg/kg/day at 4- to 8-week intervals to a maximal dosage of 4 mg/kg/day of the ­microemulsion formulation. If there is no clinical response in 4 to 6 months, cyclosporine should be discontinued. In patients who are well controlled, the dosage of cyclosporine can be decreased by 0.5 mg/kg/ day at 4- to 8-week intervals to determine the minimal effective dose for the individual patient. In patients receiving the older Sandimmune ­formulation of cyclosporine who ­convert to the microemulsion formulation, a 1:1 dose conversion is generally used. Because of the greater and more predictable bioavailability of the microemulsion formulation, however, a greater exposure to cyclosporine is likely, and blood pressure and creatinine should be monitored initially at 2-week intervals after the conversion, and the dose of cyclosporine should be decreased if required. Cyclosporine is effective in the treatment of RA as a single agent and in combination with methotrexate115 or ­hydroxychloroquine. Cyclosporine has been shown to increase mean peak plasma methotrexate levels and area under the curve by about 20%116; this may contribute to the efficacy of the combination. Data comparing the efficacy and safety of cyclosporine with other disease-modifying antirheumatic drugs over long periods and in a large number of patients are limited. Cyclosporine is effective for the skin and joint manifestations of psoriasis.117 Less data are available regarding the use of cyclosporine in other rheumatic diseases. In uncontrolled, small studies in SLE,118 cyclosporine has been reported to improve disease activity; have a steroid-sparing effect; and to improve proteinuria, thrombocytopenia, and leukopenia. Cyclosporine also has been reported to be effective in small series of cases in many other autoimmune conditions, ­ including pyoderma gangrenosum, Behçet’s

d­ isease, ­maintenance therapy of antineutrophil cytoplasmic antibody–associated vasculitis, and macrophage-activation syndrome in juvenile RA.119 Toxicity In many clinical trials performed over 6 to 12 months, cyclosporine generally has been well tolerated with little serious toxicity. Gastrointestinal upset is common, but usually mild and transient. A few patients discontinue cyclosporine therapy for this reason, however. Other adverse effects that are common but usually of minor significance include hypertrichosis, gingival hyperplasia, tremor, paresthesia, breast tenderness, hyperkalemia, hypomagnesemia, and increase in serum uric acid.120 Cyclosporine may result in a clinically insignificant increase in alkaline phosphatase concentrations, but does not increase the frequency of abnormal transaminase concentrations in patients also receiving methotrexate.121 Hypertension. Hypertension occurs in approximately 20% of patients with autoimmune disease receiving cyclosporine. The hypertension is usually mild and can be controlled by reducing the dose of cyclosporine or by antihypertensive drug therapy.120 Nephrotoxicity. Virtually all patients who take cyclosporine have a small but measurable decrease in renal function that is reversible after cyclosporine is discontinued. Serum creatinine concentrations have increased approximately 20% in 6- to 12-month clinical trials, but few patients have had to withdraw because of this.122 Long-term data regarding renal function in RA patients treated with cyclosporine are limited. In one 12-month study, an increase in serum creatinine of more than 30% occurred in 50% of patients; half of these patients responded to cyclosporine dose reduction, and half did not, requiring discontinuation of the drug.120 The small increase in serum creatinine observed in most studies occurs mainly during the first 2 to 3 months of treatment, and then creatinine remains relatively stable over 12 months.120,122 Other data suggest, however, that over periods of treatment longer than 1 year, many patients, who over the first year had a stable, acceptable increase in creatinine concentration, subsequently have an increase in creatinine to more than 30% of baseline that is not controlled by cyclosporine dose reduction; such patients have to discontinue treatment.123 Preventable risk factors for cyclosporine-induced ­nephrotoxicity are a high dosage of cyclosporine (>5 mg/ kg/day) and an increase in serum creatinine ­concentration of more than 50% of the baseline value. The risk of ­cyclosporine nephropathy is low in patients treated ­according to the ­ clinical guidelines (see Table 57-3).124 Renal biopsy specimens in 11 patients with RA who received cyclosporine (average dosage 3.3 mg/kg/day) for 26 months and had an average increase in serum ­creatinine of 31% showed no significant cyclosporine-induced renal changes.125 Malignancy. In transplant recipients, cyclosporine use has been associated with an increased risk of skin cancer and lymphoma. The number of patients with RA treated with

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cyclosporine is too small, and the duration of treatment too short, to provide definitive data about the risks of ­malignancy. In 208 patients with RA treated with cyclosporine for an ­ average of 1.6 years, the incidence of malignancy and ­mortality was similar to that of RA controls.126 Epstein-Barr virus–induced B cell lymphoma, which may be reversible when ­cyclosporine is discontinued, has been reported in a few patients receiving cyclosporine for a variety of indications. Strategies to Minimize Toxicity. Because cyclosporine may increase liver enzymes, potassium, uric acid, and lipid concentrations, and decrease magnesium ­ concentrations, it is prudent to measure these before, and ­ occasionally ­after, initiating therapy. At least two, and preferably more, recent normal blood pressure and serum creatinine ­determinations should be obtained before starting treatment. Many patients with RA have low serum creatinine concentrations, and it is important not to overlook significant cyclosporine-induced elevations in serum creatinine, which may remain within the normal laboratory reference range. If a patient has a baseline creatinine level of 0.6 mg/dL that after cyclosporine increases to 0.9 mg/dL (still in the normal range), this represents a 50% increase above baseline and requires dose reduction. Monitoring and ­cyclosporine dose reduction should be performed as shown in Table 57-3. Cyclosporine concentrations are not useful predictors of efficacy or toxicity in rheumatic diseases and are not routinely performed. Cyclosporine trough concentrations, measured approximately 12 hours after the last dose, can be useful if there are concerns about compliance or unusual drug disposition in individual patients. Pregnancy outcomes in transplant recipients receiving cyclosporine-based and non–cyclosporine-based regimens are similar. Cyclosporine use in pregnancy is not recommended, however, unless the potential benefit exceeds the potential risk to the fetus. Breastfeeding should be avoided.

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Table 57-4  Clinically Important Drug Interactions   with Cyclosporine* Increased Cyclosporine Concentrations Erythromycin, clarithromycin Azole antifungals—ketoconazole, fluconazole, itraconazole Calcium channel antagonists—diltiazem, verapamil, amlodipine† Grapefruit juice Others—amiodarone, danazol, allopurinol, colchicine Decreased Cyclosporine Concentrations Inducers of hepatic enzymes—rifampicin, phenytoin, phenobarbitone, nafcillin, St. John’s wort Increased Cyclosporine Toxicity Increased renal toxicity with aminoglycosides, quinolone antibiotics, amphotericin B, (?) nonsteroidal anti-inflammatory drugs, (?) angiotensin-converting enzyme inhibitors Cyclosporine Increasing Toxicity of Another Drug Increased risk of myopathy and rhabdomyolysis with lovastatin and other statins Increased risk of colchicine neuromyopathy and toxicity Increased digoxin concentrations Increased risk of hyperkalemia with K+-sparing diuretics and K+ supplements *Most interactions with cyclosporine also likely apply to tacrolimus. † There are conflicting data that amlodipine does and does not increase cyclosporine concentrations.

isradipine and nitrendipine do not generally affect concentrations.131 It is controversial whether nonsteroidal anti-inflammatory drugs (NSAIDs) increase cyclosporine nephrotoxicity. In many clinical studies, cyclosporine and NSAIDs have been safely coadministered115,132; however, increased cyclosporine-associated nephrotoxicity with NSAIDs has been reported. Currently, many patients starting cyclosporine also take an NSAID. If the creatinine increases, in addition to decreasing the dose of cyclosporine, discontinuing the NSAID may be tried. TACROLIMUS (FK506)

Drug Interactions

Structure

Cyclosporine and tacrolimus, because of the influence of Pgp and CYP3A4 enzyme activity on their disposition, have many clinically important drug interactions (Table 57-4).127,128 Many drugs, such as erythromycin, azole antifungal drugs, and some calcium channel antagonists, that inhibit CYP3A4 (inhibiting the metabolism of cyclo­sporine) also inhibit Pgp. Drug interactions mediated by these dual mechanisms may result in a twofold to fivefold increase in cyclosporine concentrations. Azithromycin, in contrast to erythromycin and clarithromycin, seems unlikely to alter cyclosporine levels. The plasma concentrations and clinical toxicity of several statin lipid-lowering agents are increased substantially by cyclosporine, but the disposition of fluvastatin and pravastatin, because they are not metabolized primarily by CYP3A4, are altered less by cyclosporine.129 Nevertheless, the pravastatin area under the concentration curve, a measure of drug exposure, was five times higher in patients also receiving cyclosporine.130 Of the calcium channel antagonists, diltiazem, nicardipine, and verapamil increase cyclosporine concentrations; nifedipine and amlodipine have variable effects; and

Tacrolimus, previously known as FK506, is a macrolide derived from an actinomycete and is widely used in organ transplantation as an alternative to cyclosporine. Studies in autoimmune disease are less advanced. Mechanisms of Action Tacrolimus is about 100 times more potent than c­ yclosporine and, although structurally different, is also a calcineurin inhibitor. Tacrolimus binds to an ­intracellular binding protein (FK binding protein), and this drugimmunophilin complex, in association with calcineurin, suppresses transcription of cytokines, such as interleukin-2, inhibiting the early steps of T lymphocyte activation (see Fig. 57-3).110 Pharmacology Absorption of tacrolimus after oral administration is poor and highly variable (range 4% to 93%; average 25%).133 Tacrolimus is lipophilic, is widely ­distributed in tissues,

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and is almost completely metabolized with an ­elimination half-life of 5 to 16 hours.134 As with ­ cyclosporine, Pgp and CYP3A4 in liver and gut are important ­determinants of the metabolism and ­ disposition of tacrolimus. Drugs that inhibit CYP3A4 or Pgp can increase tacrolimus ­concentrations (see Table 57-4).133 Impaired hepatic ­function, but not impaired renal function, increases tacrolimus concentrations.134 The adverse effects of tacrolimus are dose related and include nephrotoxicity, hypertension, hyperkalemia, hyperuricemia, tremor, hyperglycemia, and gastrointestinal intolerance.133 Among RA patients taking 3 mg of tacrolimus daily for more than 1 year, 59% experienced a side effect, probably or possibly due to the drug, ­ including diarrhea (15%); nausea (10%); tremor (9%); headache (9%); abdominal pain (8%); increased ­creatinine (7%); ­hypertension (5%); and pneumonia, pancreatitis, ­hyperglycemia, and diabetes mellitus (all <1%). A creatinine increase of greater than 30% from baseline to end of study was found in 40%.135 Dosage Tacrolimus is effective in animal models of ­ arthritis, but data in humans are limited.136,137 In a 6-month phase II, randomized, double-blind, placebo-controlled ­monotherapy study, patients with RA received 2 mg or 3 mg of tacrolimus or placebo daily for 24 weeks. An American College of Rheumatology (ACR)-20 response was observed in 10.2% of patients receiving placebo and in 18.8% and 26.8% of patients receiving 2 mg and 3 mg of tacrolimus.137 A longer term study of 3 mg of ­tacrolimus in 896 rheumatoid patients with a median duration of treatment of 359 days yielded ACR-20, ACR-50, and ACR-70 responses of 38.4%, 18.6%, and 9%.135 Topical 1% tacrolimus has been used with moderate success in patients with resistant skin disease secondary to SLE, subacute cutaneous lupus erythematosus, and discoid lupus erythematosus.138 The potential efficacy of tacrolimus in treating RA and other autoimmune diseases and its tolerability, particularly compared with current immunomodulating agents, are unknown. SIROLIMUS (RAPAMYCIN) Sirolimus, isolated from an actinomycete, has been developed as an immunosuppressant for organ transplantation. Sirolimus, in contrast to cyclosporine and tacrolimus, does not act through calcineurin. It binds to FK binding protein and targets proteins variously known as targets of rapamycin (TOR) proteins or FK-rapamycin associated proteins (FRAP), blocking progression of the cell cycle from G1 to S phase by inhibiting several downstream signal transduction pathways.109 Clinical trials have shown efficacy in transplantation, and in transplant recipients who also had inflammatory arthritis there are positive and negative reports of its efficacy in controlling the arthritis. There are no clinical trials in RA or autoimmune disease. The mechanism of action of sirolimus distinguishes it from cyclosporine and tacrolimus. It has a different adverse effect profile and potentially a different efficacy profile in ­autoimmune ­disease.

MYCOPHENOLATE MOFETIL STRUCTURE Mycophenolate mofetil, a prodrug, is the inactive 2-morpholinoester of mycophenolic acid, which is ­hydrolyzed to the active mycophenolic acid (MPA), an antibiotic whose immunosuppressive effects have been ­recognized since the 1970s and used to treat psoriasis.139,140 MECHANISMS OF ACTION There are two pathways for the synthesis of guanine ­nucleotides: the de novo pathway and the salvage pathway. MPA reversibly inhibits inosine monophosphate dehydrogenase, a crucial enzyme for the de novo ­ synthesis of purines.140,141 Lymphocytes, in contrast to many other cells, are critically dependent on the de novo purine ­ synthesis pathway and are a relatively selective target for MPA, accounting for the ability of the drug to inhibit reversibly B cell and T cell proliferation without myelotoxicity.142 MPA results in decreased guanine synthesis and decreased DNA synthesis, decreased lymphocyte proliferation, and decreased antibody production.141-143 PHARMACOLOGY Mycophenolate mofetil is rapidly and completely absorbed and de-esterified to the active MPA, which is highly (98%) protein bound. Most MPA (>99%) is found in plasma, with very little in cells; most ­ glucuronidated to the poorly active, stable phenolic glucuronide, which is eliminated in the urine.144 Minor metabolites, some of which may be active, also have been described. Peak levels of MPA occur 1 to 2 hours after administration, and secondary peaks, thought to be due to ­enterohepatic circulation, can be seen. The half-life of MPA is 16 hours.144 MPA concentrations may vary fivefold to tenfold in ­ individuals receiving the same dose.145 A small amount of this variabilty may be due to genetic ­variation in uridine-glucuronosyltransferase enzymes.146 Renal disease and liver disease have relatively minor effects on the disposition of the active drug, MPA. Dosage ­adjustments generally are not required,144 but because free MPA ­concentrations are approximately doubled in patients with severe renal impairment (creatinine ­clearance <20 to 30 mL/min),147,148 they may be necessary sometimes. The major glucuronide metabolite of MPA ­ accumulates in patients with impaired renal ­ function and may cause increased gastrointestinal side effects. Because MPA is highly protein bound, it is not cleared by ­hemodialysis.149 TOXICITY Mycophenolate mofetil is well tolerated in transplant ­recipients, but data are limited in rheumatic diseases. Of 325 patients with RA who received mycophenolate mofetil daily, 16% withdrew for adverse events, most commonly ­gastrointestinal side effects, such as diarrhea, nausea, abdominal pain, and vomiting.150 Occasional infections, leukopenia, lymphocytopenia, and elevated liver enzymes occurred. Seven nonskin ­ malignancies, four skin malignancies, and

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seven deaths (three from pneumonia) were reported.150 Of 54 SLE patients treated with mycophenolate mofetil over a 3-year period, 16% withdrew because of adverse events, with 73% continuing treatment at 12 months.151 In patients with lupus nephritis, diarrhea was more common, and serious ­ infections were less common, with mycophenolate mofetil than with cyclophosphamide.152 Enteric-coated ­mycophenolate sodium and mycophenolate mofetil have similar rates of side effects.153 DOSAGE In renal transplantation, mycophenolate mofetil has been used in a standard dosage of 1 g twice a day; 3 g/day increased side effects without improving outcomes.154 In African-American renal allograft recipients, mycophenolate mofetil 3 g/day was more effective than 2 g/day, ­however.155 Gastrointestinal events and infections were the most common adverse events. In 71 patients with lupus nephritis, the intial dose was 1 g/day with a target of 3 g/day. The mean maximal dose was 2680 mg/day, and 63% of patients tolerated 3 g/day.152 Recognition that there is a fivefold to tenfold variability in drug concentrations among individuals has led to the consideration of therapeutic drug monitoring and individualized dosing. There is no information about such a strategy in patients with rheumatic diseases. Mycophenolate mofetil is currently undergoing clinical trials in several rheumatic diseases. There are controlled studies showing efficacy in patients with lupus ­nephritis152,156; preliminary reports from a controlled trial in RA150; and observational reports in vasculitis,157 myasthenia gravis, and inflammatory muscle disease.158 In a 24-week study in lupus nephritis, mycophenolate was more effective than monthly pulse cyclophosphamide with a failure rate (without complete or partial remission at 24 weeks, plus those who stopped treatment for any reason) of 34 of 71 (47.9%) compared with 48 of 69 in the cyclophosphamide group (69.6%; P = .01).152 In RA, the percentage of patients meeting the ACR criteria for a 20% improvement receiving 1 g twice daily (29.3%) and 2 g twice daily (37.1%) is modest and suggests that mycophenolate mofetil, as monotherapy, does not control RA in most patients.150 In seven patients with myositis, six had a good clinical and biochemical response to mycophenolate.159 Mycophenolate mofetil may be useful as an alternative immunosuppressant to azathioprine, particularly in patients with gout who require therapy with allopurinol because, in contrast to azathioprine, it does not seem to interact significantly with allopurinol.106,142 Further studies regarding the comparative efficacy and long-term safety of mycophenolate mofetil in SLE and vasculitis would be of interest. DRUG INTERACTIONS Because MPA is glucuronidated and not metabolized by CYP oxidation, there are few clinically significant drug interactions. Antacids reduce bioavailability by approximately 15%,160 and cholestyramine reduces bioavailability by approximately 40%. Rifampin treatment reduced MPA concentrations twofold to threefold.161 Coadministration with azathioprine is not recommended.

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THALIDOMIDE STRUCTURE Thalidomide is a racemic glutamic acid analogue that was introduced in the 1950s as a sedative and antiemetic.162 The recognition that thalidomide was a potent teratogen resulting in characteristic congenital malformations led to its withdrawal in 1961. The rediscovery of the immunomodulating effects of thalidomide has led to the cautious and closely regulated, but controversial, reintroduction of thalidomide for a specific indication: the treatment of erythema nodosum leprosum. Preliminary studies have explored other potential therapeutic roles. MECHANISMS OF ACTION Thalidomide has immunosuppressive effects in several transplant models.163 Multiple mechanisms have been ­proposed, the most plausible being the inhibition of ­angiogenesis and the inhibition of tumor necrosis factor-α production.164,165 PHARMACOLOGY Thalidomide is a derivative of glutamic acid and exists as a racemic compound that, in vivo, interconverts between isomers.163 Peak concentrations of thalidomide occur 2 to 4 hours after oral administration. The elimination half-life is approximately 5 hours, with elimination being virtually entirely through nonenzymatic hydrolysis.163,166 CYP2C19, a polymorphic enzyme, contributes to the formation of an active metabolite, 5-hydroxythalidomide.162 The pharmacokinetics of thalidomide are poorly characterized, and there is little information regarding drug interactions or use in patients with impaired renal or hepatic function. The sedative effects of other central depressants, such as barbiturates, are enhanced by thalidomide. DOSAGE Thalidomide is approved by the U.S. Food and Drug ­Administration only for the treatment of erythema nodosum leprosum. Prescription of thalidomide for this indication and its off-label use is very closely regulated. Thalidomide (200 mg/ day for 4 weeks) healed oral aphthous ulcers ­associated with human immunodeficiency virus (HIV) infection in approximately half the patients studied.167 Thalidomide (100 mg/day and 300 mg/day) for 24 weeks improved the ­mucocutaneous lesions of Behçet’s syndrome. Clinical response was lost rapidly, however, after discontinuation of the drug.168 Small, largely uncontrolled reports suggest possible benefit in graftversus-host disease, the skin manifestations of lupus, sarcoidosis, RA, Sjögren’s syndrome, ankylosing spondylitis, systemic onset juvenile RA, and pyoderma gangrenosum.162,169 TOXICITY The most serious, best-known, and preventable adverse effect of thalidomide is its ability to cause birth defects. In clinical studies, peripheral neuropathy has been the most common serious adverse effect. The reported incidence of peripheral neuropathy, usually manifesting as symmetric

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p­ aresthesias that may be painful, varies widely from 1% to more than 50%.163,170 Electrophysiologic changes precede clinical neuropathy, and most studies reporting higher rates of neuropathy have used this diagnostic technique. The neuropathy may become evident only after thalidomide has been discontinued and in most patients (75%) may not resolve completely.163 Other common adverse effects include sedation, skin rash, limb edema, and constipation. Neutropenia is less common. Ovarian failure171 and arterial and venous thromboses have been reported. Strategies to Minimize Toxicity Strategies to prevent fetal exposure to thalidomide are ­outlined in the System for Thalidomide Education and Prescribing Safety (STEPS) program developed by the drug’s manufacturer, Celgene, and in guidelines developed in the United Kingdom.172 Registration in the STEPS program is required before thalidomide is used. The program involves mandatory patient registration, education, surveys, and contraception for men and women. Electrophysiologic monitoring for thalidomide-induced neuropathy has been advocated172 and should be considered, particularly if longterm therapy is planned. Thalidomide should be discontinued if peripheral neuropathy occurs. The frequent side effects of thalidomide limit its potential for long-term use. Thalidomide’s side effects, its teratogenic effects, and the rapid relapse of autoimmune disease after ­discontinuation of thalidomide severely limit its therapeutic potential. Research is being directed toward safer analogues of ­thalidomide.

DAPSONE Dapsone, a sulfone antimicrobial, has been used for decades to treat leprosy and is a second-line component of regimens for prophylaxis against Pneumocystis and malaria. The antiinflammatory effects of dapsone have led to its use in a range of autoimmune disorders. MECHANISMS OF ACTION As with sulfonamides, the antimicrobial action of dapsone occurs through the inhibition of folate synthesis. The mechanisms of the anti-inflammatory effects of dapsone are poorly understood, but effects on neutrophil function are prominent. Inhibition of chemoattractant-induced signal transduction by dapsone may decrease neutrophil recruitment and neutrophil chemotaxis, inhibiting neutrophil function.173 PHARMACOLOGY Absorption and Distribution After oral administration of dapsone, 70% to 80% is absorbed with peak concentrations occurring 2 to 6 hours after administration.174 Dapsone is 70% to 90% protein bound, and its major circulating metabolite, monoacetyldiaminodiphenylsulfone (MADDS) is even more tightly protein bound (99%).174 Dapsone is widely distributed, crosses the placenta, and appears in breast milk.174

Metabolism and Elimination There are two major metabolic pathways: acetylation and hydroxylation. Dapsone is acetylated by hepatic N-acetyltransferases to form MADDS. There is substantial interindividual variability in acetylation activity, and in populations there is a polymorphic, bimodal distribution. Because deacetylation of MADDS back to dapsone takes place, however, and an equilibrium in this cycling exists, “slow acetylators” and “fast acetylators” show no differences in dapsone pharmacokinetics, therapeutic response, or toxicity.174 Dapsone also undergoes N-hydroxylation by the CYP system. The resulting hydroxylamine metabolite is the cause of the methemoglobinemia associated with dapsone. The half-life of dapsone is 20 to 30 hours. The major route of elimination from the body is renal, largely as conjugated metabolites. There is little information to guide the use of dapsone in individuals with impaired renal or hepatic function. Rifampin, through enzyme induction, decreases the half-life of dapsone.174 Probenecid reduces excretion of dapsone.174 TOXICITY Hematologic The most frequent adverse effects of dapsone are methemoglobinemia and hemolysis. The hematologic effects of dapsone are dose dependent, often detectable at dosages of 75 mg/day or greater, and are observed in almost all individuals receiving 250 mg/day.175,176 A mild degree of asymptomatic methemoglobinemia (2% to 5%) and hemolytic anemia, resulting in a decrease in hemoglobin concentration of 1 to 2 g/L, is common in patients receiving 100 mg/day of dapsone.176 The hemotoxic effects are often most marked in the first 6 weeks, then improve and stabilize, and are generally well tolerated.175 Individuals vary in their susceptibility to dapsone-induced methemoglobinemia and hemolysis. Subjects with glucose-6-phosphate dehydrogenase deficiency are particularly susceptible to the oxidative stress imposed by dapsone that results in lipid peroxidation, red blood cell membrane damage, and hemolysis.175,176 Agranulocytosis, which is reversible if dapsone is discontinued, may develop in 1 in 250 to 500 patients treated.177,178 The median time of onset of agranulocytosis is 6 to 8 weeks. Although it may occur suddenly, a gradual decrease in granulocyte count preceding agranulocytosis is often noted.177 Sulfone Syndrome A rare, potentially serious syndrome thought to be due to a hypersensitivity reaction, which manifests as fever, rash that may be exfoliative, jaundice with elevated liver enzymes, lymphadenopathy, and hemolytic ­anemia, may occur even after low doses (e.g., 50 mg/day) of ­dapsone.179 Miscellaneous Other adverse effects are uncommon and include rash, peripheral neuropathy, psychosis, hepatitis, headache, and insomnia.

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Strategies to Minimize Toxicity Screening patients for glucose-6-phosphate dehydrogenase deficiency before treatment with dapsone is prudent, particularly in population groups in which glucose-6-phosphate dehydrogenase deficiency is more frequent (i.e., African, Mediterranean, East Asian). Cimetidine, because it inhibits the formation of the toxic hydroxylamine metabolite of dapsone, has been used in subjects receiving high doses of dapsone to reduce the degree of methemoglobinemia and to improve ­tolerability.177 Regular monitoring of the blood count, initially weekly for 1 month, every 2 weeks for the next 2 months, and monthly thereafter, and intermittent monitoring of the liver function tests is recommended.175 Because of increased red blood cell turnover, folate supplementation may be required. DOSAGE Efficacy in Rheumatic Diseases There are few controlled clinical trials guiding the use of dapsone in rheumatology. In most clinical studies, the starting dosage of dapsone has been 50 mg/day for a few days, increasing rapidly to a maintenance dosage of 100 mg/day. A more gradual increase from a starting ­dosage of 25 mg twice daily to 50 mg twice daily over ­several months may be better tolerated, however.175 Higher ­dosages, up to 350 mg/day, have been used in ­ dermatologic conditions, but dose-related toxicity is limiting. Empiric use, often when standard therapies have failed, has evolved. Occasional efficacy has been reported in a few patients over a range of conditions, including pustular dermatoses, erythema elevatum diutinum, leukocytoclastic and urticarial vasculitis,180 cutaneous and bullous lupus erythematosus,181 orogenital ulceration in Behçet’s syndrome, and RA.175 In a few small, double-blind, randomized studies, dapsone (100 mg/day) was more effective than placebo and equal in efficacy to antimalarials in the treatment of RA.175 In cutaneous lupus erythematosus, an excellent response is estimated to occur in only about 25% of patients, and dapsone is seldom a drug of first choice.181 Dapsone, because of its dose-related toxicity and the limited efficacy data, has a limited role in rheumatology, usually as a drug that is tried in occasional patients when more standard therapies have failed.

CONCLUSION The use of immunoregulatory drugs for rheumatic diseases has evolved out of the use of glucocorticoids and the older anticancer alkylating and purine analogue cytotoxic drugs to include now a generation of noncytotoxic immunomodulators. The clinical use of immunomodulating drugs provides a therapeutic challenge unique to rheumatology. It often involves the selection of a drug, or combinations of drugs, based on inadequate data, a highly variable individual response to that therapy, long-term treatment with drugs that have potentially serious adverse effects, and the goal of halting or controlling a disease that can have an unpredictable clinical course.

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Immunoregulatory Drugs

119. Mouy R, Stephan JL, Pillet P, et al: Efficacy of cyclosporine A in the treatment of macrophage activation syndrome in juvenile arthritis: Report of five cases. J Pediatr 129:750-754, 1996. 120. Landewe RB, Goei TH, van Rijthoven AW, et al: Cyclosporine in common clinical practice: An estimation of the benefit/risk ratio in patients with rheumatoid arthritis. J Rheumatol 21:1631-1636, 1994. 121. Stein CM, Brooks RH, Pincus T: Effect of combination therapy with cyclosporine and methotrexate on liver function test results in rheumatoid arthritis. Arthritis Rheum 40:1721-1723, 1997. 122. Stein CM, Pincus T, Yocum D, et al: Combination treatment of severe rheumatoid arthritis with cyclosporine and methotrexate for forty-eight weeks: An open-label extension study. The Methotrexate-Cyclosporine Combination Study Group. Arthritis Rheum 40:1843-1851, 1997. 123. Yocum DE, Stein CM, Pincus T: Longterm safety of Cyclosporin/ Sandimmune alone and in combination with methotrexate in the treatment of active rheumatoid arthritis: Analysis of open label extension studies. Arthritis Rheum 41:S364, 1998. 124. Rodriguez F, Krayenbuhl JC, Harrison WB, et al: Renal biopsy findings and followup of renal function in rheumatoid arthritis patients treated with cyclosporin A: An update from the International Kidney Biopsy Registry. Arthritis Rheum 39:1491-1498, 1996. 125. Landewe RB, Dijkmans BA, van der Woude FJ, et al: Longterm low dose cyclosporine in patients with rheumatoid arthritis: Renal function loss without structural nephropathy. J Rheumatol 23:61-64, 1996. 126. van den Borne BE, Landewe RB, Houkes I, et al: No increased risk of malignancies and mortality in cyclosporin A-treated patients with rheumatoid arthritis. Arthritis Rheum 41:1930-1937, 1998. 127. Campana C, Regazzi MB, Buggia I, et al: Clinically significant drug interactions with cyclosporine: An update. Clin Pharmacokinet 30:141-179, 1996. 128. Page RL, Miller GG, Lindenfeld J: Drug therapy in the heart ­transplant recipient, part IV: Drug-drug interactions. Circulation 111:230-239, 2005. 129. Asberg A: Interactions between cyclosporin and lipid-­lowering drugs: Implications for organ transplant recipients. Drugs 63: 367-378, 2003. 130. Olbricht C, Wanner C, Eisenhauer T, et al: Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses. Clin Pharmacol Therap 62:311-321, 1997. 131. Baxter K (ed): Stockley’s Drug Interactions, 7th ed. London, Pharma­ ceutical Press, 2006. 132. Tugwell P, Ludwin D, Gent M, et al: Interaction between cyclosporin A and nonsteroidal antiinflammatory drugs. J Rheumatol 24:1122-1125, 1997. 133. Spencer CM, Goa KL, Gillis JC: Tacrolimus: An update of its pharmacology and clinical efficacy in the management of organ transplantation. Drugs 54:925-975, 1997. 134. Peters DH, Fitton A, Plosker GL, et al: Tacrolimus: A review of its pharmacology, and therapeutic potential in hepatic and renal transplantation. Drugs 46:746-794, 1993. 135. Yocum DE, Furst DE, Bensen WG, et al: Safety of tacrolimus in patients with rheumatoid arthritis: Long-term experience. Rheumatology (Oxf) 43:992-999, 2004. 136. Furst DE, Saag K, Fleischmann MR, et al: Efficacy of tacrolimus in rheumatoid arthritis patients who have been treated unsuccessfully with methotrexate: A six-month, double-blind, randomized, doseranging study. Arthritis Rheum 46:2020-2028, 2002. 137. Yocum DE, Furst DE, Kaine JL, et al: Efficacy and safety of tacrolimus in patients with rheumatoid arthritis: A double-blind trial. Arthritis Rheum 48:3328-3337, 2003. 138. Lampropoulos CE, Sangle S, Harrison P, et al: Topical tacrolimus therapy of resistant cutaneous lesions in lupus erythematosus: A possible alternative. Rheumatology (Oxf) 43:1383-1385, 2004. 139. Epinette WW, Parker CM, Jones EL, et al: Mycophenolic acid for psoriasis: A review of pharmacology, long-term efficacy, and safety. J Am Acad Dermatol 17:962-971, 1987. 140. Lipsky JJ: Mycophenolate mofetil. Lancet 348:1357-1359, 1996. 141. Ransom JT: Mechanism of action of mycophenolate mofetil. Therap Drug Monit 17:681-684, 1995.

142. Suthanthiran M, Strom TB: Immunoregulatory drugs: Mechanistic basis for use in organ transplantation. Pediatr Nephrol 11:651-657, 1997. 143. Smith KG, Isbel NM, Catton MG, et al: Suppression of the humoral immune response by mycophenolate mofetil. Nephrol Dial Transplant 13(1):160-164, 1998. 144. Bullingham RE, Nicholls AJ, Kamm BR: Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 34:429-455, 1998. 145. van Hest RM, Mathot RA, Vulto AG, et al: Within-patient ­variability of mycophenolic acid exposure: Therapeutic drug monitoring from a clinical point of view. Ther Drug Monit 28:31-34, 2006. 146. Kuypers DR, Naesens M, Vermeire S, et al: The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients. Clin Pharmacol Ther 78:351-361, 2005. 147. Meier-Kriesche HU, Shaw LM, Korecka M, et al: Pharmacokinetics of mycophenolic acid in renal insufficiency. Therap Drug Monit 22:27-30, 2000. 148. Gonzalez-Roncero FM, Gentil MA, Brunet M, et al: Pharmacokinetics of mycophenolate mofetil in kidney transplant patients with renal insufficiency. Transplant Proc 37:3749-3751, 2005. 149. Johnson HJ, Swan SK, Heim-Duthoy KL, et al: The pharma­ cokinetics of a single oral dose of mycophenolate mofetil in patients with varying degrees of renal function. Clin Pharmacol Therap 63:512-518, 1998. 150. Schiff M, Stein G, Leishman B: CellCept (mycophenolate mofetil), a new treatment for RA: A 9-month, randomized, double -blind trial comparing 1g bid and 2g bid. Arthritis Rheum 40(Suppl):S194, 1997. 151. Riskalla MM, Somers EC, Fatica RA, et al: Tolerability of mycophenolate mofetil in patients with systemic lupus erythematosus. J Rheumatol 30:1508-1512, 2003. 152. Ginzler EM, Dooley M A, Aranow C, et al: Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 353:2219-2228, 2005. 153. Behrend M, Braun F: Enteric-coated mycophenolate sodium: Tolerability profile compared with mycophenolate mofetil. Drugs 65:1037-1050, 2005. 154. van Gelder T: Mycophenolate mofetil: How to further improve using an already successful drug? Am J Transplant 5:199-200, 2005. 155. Neylan JF: Immunosuppressive therapy in high-risk transplant patients: Dose-dependent efficacy of mycophenolate mofetil in African-American renal allograft recipients. U.S. Renal ­Transplant Mycophenolate Mofetil Study Group. Transplantation 64:1277-1282, 1997. 156. Chan TM, Li FK, Tang CS, et al: Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong KongGuangzhou Nephrology Study Group. N Engl J Med 343:1156-1162, 2000. 157. Langford CA, Talar-Williams C, Sneller MC: Mycophenolate mofetil for remission maintenance in the treatment of Wegener’s granulomatosis. Arthritis Rheum 51:278-283, 2004. 158. Rowin J, Amato AA, Deisher N, et al: Mycophenolate mofetil in dermatomyositis: Is it safe? Neurology 66:1245-1247, 2006. 159. Majithia V, Harisdangkul V: Mycophenolate mofetil (CellCept): An alternative therapy for autoimmune inflammatory myopathy. Rheumatology (Oxf) 44:386-389, 2005. 160. Bullingham R, Shah J, Goldblum R, et al: Effects of food and antacid on the pharmacokinetics of single doses of mycophenolate mofetil in rheumatoid arthritis patients. Br J Clin Pharmacol 41:513-516, 1996. 161. Kuypers DR, Verleden G, Naesens M, et al: Drug interaction between mycophenolate mofetil and rifampin: Possible induction of uridine diphosphate-glucuronosyltransferase. Clin Pharmacol Ther 78:81-88, 2005. 162. Franks ME, Macpherson GR, Figg WD: Thalidomide. Lancet 363:1802-1811, 2004. 163. Tseng S, Pak G, Washenik K, et al: Rediscovering thalidomide: A review of its mechanism of action, side effects, and potential uses. J Am Acad Dermatol 35:969-979, 1996. 164. D’Amato RJ, Loughnan MS, Flynn E, et al: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 91:4082-4085, 1994.

PART 8  165. Sampaio EP, Sarno EN, Galilly R, et al: Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 173:699-703, 1991. 166. Eriksson T, Bjorkman S, Hoglund P: Clinical pharmacology of thalidomide. Eur J Clin Pharmacol 57:365-376, 2001. 167. Jacobson JM, Greenspan JS, Spritzler J, et al: Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. N Engl J Med 336:1487-1493, 1997. 168. Hamuryudan V, Mat C, Saip S, et al: Thalidomide in the ­treatment of the mucocutaneous lesions of the Behçet syndrome: A ­randomized, double-blind, placebo-controlled trial. Ann Intern Med 128:443-450, 1998. 169. Matthews SJ, McCoy C: Thalidomide: A review of approved and investigational uses. Clin Ther 25:342-395, 2003. 170. Gunzler V: Thalidomide in human immunodeficiency virus (HIV) patients: A review of safety considerations. Drug Saf 7:116-134, 1992. 171. Ordi J, Cortes F, Martinez N, et al: Thalidomide induces amenorrhea in patients with lupus disease. Arthritis Rheum 41:2273-2275, 1998. 172. Powell RJ, Gardner-Medwin JM: Guideline for the clinical use and dispensing of thalidomide. Postgrad Med J 70:901-904, 1994. 173. Debol SM, Herron MJ, Nelson RD: Anti-inflammatory action of dapsone: Inhibition of neutrophil adherence is associated with inhibition of chemoattractant-induced signal transduction. J Leukoc Biol 62:827-836, 1997. 174. Zuidema J, Hilbers-Modderman ES, Merkus FW: Clinical pharmacokinetics of dapsone. Clin Pharmacokinet 11:299-315, 1986. 175. Chang DJ, Lamothe M, Stevens RM, et al: Dapsone in rheumatoid arthritis. Semin Arthritis Rheum 25:390-403, 1996.

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176. Jollow DJ, Bradshaw TP, McMillan DC: Dapsone-induced hemolytic anemia. Drug Metab Rev 27(1-2):107-124, 1995. 177. Coleman MD: Dapsone toxicity: Some current perspectives. Gen Pharmacol 26:1461-1467, 1995. 178. Hornsten P, Keisu M, Wiholm BE: The incidence of agranulocytosis during treatment of dermatitis herpetiformis with dapsone as reported in Sweden, 1972 through 1988. Arch Dermatol 126:919-922, 1990. 179. Tomecki KJ, Catalano CJ: Dapsone hypersensitivity: The sulfone syndrome revisited. Arch Dermatol 117:38-39, 1981. 180. Holtman JH, Neustadt DH, Klein J, et al: Dapsone is an effective therapy for the skin lesions of subacute cutaneous lupus erythematosus and urticarial vasculitis in a patient with C2 deficiency. J Rheumatol 17:1222-1225, 1990. 181. Callen JP: Treatment of cutaneous lesions in patients with lupus erythematosus. Dermatol Clin 12:201-206, 1994. 182. McCune WJ, Golbus J, Zeldes W, et al: Clinical and ­immunologic effects of monthly administration of intravenous cyclophosphamide in severe systemic lupus erythematosus. N Engl J Med 318:1423, 1988. 183. Hellmich B, Lamprecht P, Gross WL: Advances in the therapy of Wegener’s granulomatosis. Curr Opin Rheumatol 18:25, 2006. 184. Panayi GS, Tugwell P: The use of cyclosporin A microemulsion in rheumatoid arthritis: Conclusions of an international review. Br J Rheumatol 36:808, 1997. 185. Cush JJ, Tugwell P, Weinblatt M, et al: US consensus guidelines for the use of cyclosporin A in rheumatoid arthritis. J Rheumatol 26: 1176-1186, 1999.

58

Anticytokine Therapies Zuhre Tutuncu  •  Arthur Kavanaugh

KEY POINTS Inhibition of a single key cytokine can be effective in autoimmune and inflammatory diseases. Most patients with rheumatoid arthritis (RA) respond to treatment with tumor necrosis factor (TNF) inhibitors, with significant improvements in signs and symptoms of disease. Maintaining clinical efficacy with TNF inhibitors usually requires continued therapy; that is, there is no induction of immune tolerance or “cure.” However, there may be a window of opportunity in early RA for inducing long-term remission. Treatment with TNF inhibitors significantly decreases radiographic damage (slowing disease progression), improves quality of life, and helps preserve functional status. There is guarded optimism regarding the long-term safety of TNF inhibitors. Combining a TNF inhibitor with methotrexate achieves additive benefits. TNF inhibitors have proved highly effective in treating ankylosing spondylitis, psoriatic arthritis, psoriasis, and Crohn’s disease. TNF inhibitors have been ineffective in patients with vasculitis (Wegener’s granulomatosis, temporal arteritis). Although interleukin (IL)-1 inhibition is generally less effective in RA than TNF inhibition, this approach can be highly effective in certain autoinflammatory conditions. Combination biologic therapy (TNF inhibitor plus IL-1 inhibitor, TNF inhibitor plus costimulatory molecule inhibitor) appears to increase the risk but not the benefit.

In recent years, discoveries delineating the immunopathophysiologic basis of various rheumatic diseases, combined with biopharmaceutical development, have allowed the introduction of biologic therapeutics. These agents target specific components of the immune response that are dysregulated and thought to be central to the cause and sustenance of the disease process. In the rheumatoid synovium, for example, there is substantial evidence of an upregulation of key proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and others.1,2 Agents targeting these key mediators, in particular TNF, have considerable efficacy in the treatment of patients with rheumatoid arthritis (RA) and other systemic inflammatory disorders. The ability of TNF inhibitors not only to substantially improve the signs and symptoms of disease but also to preserve functional status and quality of life and to inhibit disease progression has altered both physicians’ and patients’ expectations regarding antirheumatic ­treatment. Moreover,

their success has driven research into the targeting of other cytokines relevant to the pathogenesis of autoimmune disorders. In this chapter, we focus on therapeutic agents targeting TNF and IL-1 and briefly discuss IL-6. Agents currently in development that target other inflammatory cytokines, such as IL-6, IL-15, and IL-18, are reviewed elsewhere.

TUMOR NECROSIS FACTOR-α INHIBITORS TNF-α plays a central role in the pathogenesis of RA and other inflammatory disorders. Although it can be produced by numerous cell types, in inflammatory conditions such as RA, TNF-α is produced largely by activated macrophages. Human TNF-α is synthesized and expressed as a 26-kD transmembrane protein on the plasma membrane and is cleaved by a specific metalloproteinase (TNF-α converting enzyme). After proteolytic cleavage, TNF-α is converted to a 17-kD soluble protein, which oligomerizes to form the active homotrimer. The actions of TNF-α are mediated through two structurally distinct receptors: TNF-RI (55 kD; CD120a) and TNF-RII (75 kD; CD120b).3 The two receptors differ in their binding abilities, signaling properties, and primary functions.3,4 The binding of TNF-α to its receptor can initiate several signaling pathways. Signaling cascades include the activation of transcription factors (e.g., nuclear factor κB [NFκB]), protein kinases (intracellular enzymes that mediate cellular responses to inflammatory stimuli, such as c-Jun N-terminal kinase [JNK] and p38 MAP kinase), and proteases (enzymes that cleave peptide bonds, such as caspases). TNF-α may contribute to the pathogenesis of RA by myriad mechanisms, including induction of other proinflammatory cytokines (e.g., IL-1, IL-6) and chemokines (e.g., IL-8); enhancement of leukocyte migration, by increasing endothelial layer permeability and adhesion molecule expression and function; activation of numerous cell types; and induction of the synthesis of acute-phase reactants and other proteins, including tissue-degrading enzymes (matrix metalloproteinase enzymes) produced by synoviocytes or chondrocytes. The pivotal role of TNF-α in mediating such diverse inflammatory activities provided the rationale for targeting this cytokine in systemic inflammatory diseases.5 Initially, animal studies proved that the inhibition of TNF-α with monoclonal antibodies or soluble TNF-R constructs ameliorated the signs of inflammation and prevented joint destruction.6 Subsequently, studies in humans confirmed the substantial efficacy of these compounds. Currently, there are three anti–TNF-α agents available for clinical use: infliximab, a chimeric anti–TNF-α monoclonal antibody; etanercept, a soluble dimeric p75-TNF-R/Fc fusion construct; and adalimumab, a human anti–TNF-α 929

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Table 58-1  Clinical Trials with Infliximab Drug and ­Reference

Study Design

MTX Mean Dose

No. of Pts

Infliximab15

Single dose: 0, 1,   or 10 mg/kg

None

73

Infliximab13

DB wk: 0   (0, 5, 10,   20 mg/kg) OL wk: 12, 20, 28 (10 mg/kg)

10 mg/wk

28

Infliximab11

DBPCRCT: 1, 3,   7.5 mg/wk   or 10 mg/kg wk (some   0, 2, 6, 10, 14 groups)

Infliximab12 (ATTRACT)

Infliximab16 (ATTRACT)

DD (mean yr)

SJC/TJC at Entry

% Failed DMARDs (mean) Efficacy

 8

24/27   (mean)

3.2

Paulus 20: 79% (10 mg), 44%   (1 mg), 8% (placebo)

  6.2

21/31   (mean)

2.8

ACR-20 at 1 wk: 86% (5 mg/kg), 71%   (10 mg/kg), 86% (20 mg/kg), 14%   (placebo) ACR-20 at 40 wk: 28% (10 mg/kg)

101

10

18/26   2.4 (median)

Paulus 20 at 14 wk: 60%   (3 or 10 mg/kg ± MTX) Paulus 20 sustained at 26 wk in   3 or 10 mg/kg group + MTX

DBPCRCT:   15 mg/wk 1, 3, or 10 mg/kg every 4 or 8 wk

428

  8.4

20/30   2.6 (median)

ACR-20 at 30 wk: 52% (infliximab),   20% (placebo) ACR-50 at 30 wk: 28% (infliximab),   5% (placebo) ACR-70 at 30 wk: 12% (infliximab),   0% (placebo)

DBPCRCT: 3 or   16 mg/wk 10 mg/kg every   4 or 8 wk

428

 9

22/32

?

Radiograph at 54 wk: arrest of   progression of structural damage Sharp score median change: 0.0   (infliximab), +4.0 (placebo)

Infiliximab17 DB: infliximab   20 mg/wk (ASPIRE; 3 mg/kg + MTX, early RA) or infliximab   6 mg/kg + MTX,   or MTX alone

1049

  0.9

21.7/33.0

MTX naïve

ACR-N at 54 wk: 46.7%   (6 mg/kg + MTX), 38.9%   (3 mg/kg + MTX), 26.4% (MTX) ACR-20 at 54 wk: 66.2%   (6 mg/kg + MTX), 62.4%   (3 mg/kg + MTX), 53.6% (MTX) ACR-50 at 54 wk: 50.4% (6 mg/kg   + MTX), 45.6% (3 mg/kg + MTX), 32.1% (MTX) ACR-70 at 54 wk: 37.2% (6 mg/kg   + MTX), 32.5% (3 mg/kg + MTX), 21.2% (MTX)

ACR, American College of Rheumatology; DB, double blind; DBPCRCT, double-blind placebo-controlled randomized clinical trial; DD, disease duration; DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; OL, open label; Pts, patients; RA, rheumatoid arthritis; SJC, swollen joint count; TJC, tender joint count.

monoclonal antibody. Additional agents are in clinical development. For each agent, an initial assessment in open-label studies of patients with RA was followed by double-blind, placebo-controlled, randomized clinical trials. Typically, early studies included patients with very active disease that was relatively chronic and refractory. Driven by the success in the most difficult populations, studies of all TNF inhibitors have also been performed in patients with early RA (Tables 58-1 to 58-3). Most studies included patients whose disease remained active despite the concurrent use of methotrexate (MTX); some studies assessed a drug’s efficacy as monotherapy. Building on the efficacy achieved in RA, TNF inhibitors have been tested in other autoimmune arthritides, including psoriatic arthritis (Table 58-4) and ankylosing spondylitis (Table 58-5). Moreover, these agents have been studied in other autoimmune conditions, such as Crohn’s disease, ulcerative colitis, psoriasis, uveitis, and others. Although all three available agents are macromolecule TNF inhibitors, there are differences among them.7 The monoclonal antibodies infliximab and adalimumab are specific for TNF-α, whereas etanercept binds both TNF-α and lymphotoxin-α (LT-α; previously referred to as TNF-ß). Given intravenously, infliximab has a high peak concentration followed by steady-state elimination, whereas etanercept and adalimumab, because they are given subcutaneously, have “flatter” pharmacokinetic profiles. All agents are ­capable

of affecting Fc-mediated ­ functions, such as complementdependent cytolysis and antibody-dependent cell-mediated cytotoxicity, and all bind to both soluble and membrane forms of TNF, although there may be some relative differences in affinity. Other differences, such as effects on cytokine secretion, have been observed in some in vitro studies.8 Regarding apoptosis, the data have been somewhat discrepant. In patients with RA, both the anti–TNF-α monoclonal antibody infliximab and the soluble receptor construct etanercept are capable of inducing apoptosis in synovial macrophages.9 However, in patients with Crohn’s disease, etanercept was not clinically effective at the doses studied and did not induce apoptosis; in contrast, both anti–TNF-α monoclonal antibodies were clinically effective and were shown to induce apoptosis in highly activated lymphocytes.10 The extent to which these potential differences among TNF inhibitors correlate with any specific aspect of efficacy or toxicity remains to be established. INFLIXIMAB Structure Infliximab is a chimeric mouse-human monoclonal antibody composed of constant regions of human immunoglobulin (Ig) G1κ coupled to the variable regions of a high-affinity neutralizing murine anti–human TNF-α antibody. The resulting construct is approximately 70% human (Fig. 58-1).

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Table 58-2  Clinical Trials with Etanercept Drug and Reference

Study Design

Etanercept36 DBPCRCT:   0.25, 2, or   16 mg/m2 twice a wk

MTX Mean Dose

No. of DD SJC/TJC at Pts (mean yr) Entry

% Failed DMARDs (mean) Efficacy

None

180

5 ( > 77%) 24/32 (mean)

100

ACR-20 at 12 wk: 75% (16 mg), 46% (2 mg), 33% (0.25 mg), 14% (placebo) ACR-50 at 12 wk: 57% (16 mg), 22% (2 mg), 9% (0.25 mg), 7% (placebo)

Etanercept37 DBPCRCT: 10 or None 25 mg twice a wk

234

12

25/34 (mean)

3.2

ACR-20 at 24 wk: 59% (25 mg), 51% (10 mg), 11% (placebo) ACR-50 at 24 wk: 40% (25 mg), 24% (10 mg), 5% (placebo) ACR-70 at 24 wk: 15% (25 mg), 9% (10 mg), 1% (placebo)

89

13

19/28 (median)

2.7

ACR-20 at 24 wk: 71% (etanercept), 27% (placebo) ACR-50 at 24 wk: 39% (etanercept), 3% (placebo) ACR-70 at 24 wk: 15% (etanercept), 0% (placebo)

19 mg/wk (only Etanercept 39, 40 OL: 10 or   MTX group) 25 mg   (ERA, early etanercept RA) twice a wk, or oral MTX

512

1

24/31 (mean)

42

ACR-20 at 24 mo: 72% (25 mg), 61% (10 mg), 59% (MTX) ACR-50 at 24 mo: 49% (25 mg), 35% (10 mg), 42% (MTX) ACR-70 at 24 mo: 29% (25 mg), 19% (10 mg), 24% (MTX) Radiograph at 2 yr: Sharp score mean change: 1.3 (25 mg), 3.2 (MTX)

Etanercept43 DB: 25 mg/wk 17.2 (1st yr) (TEMPO) etanercept or 16.4 (2nd yr) MTX alone or etanercept + MTX combination

686

6.6

22.6/34.2 (mean)

2.3

ACR-20 at 2 yr: 86% (combo), 75% (etanercept), 71% (MTX) ACR-50 at 2 yr: 71% (combo), 54% (etanercept), 42% (MTX) ACR-70 at 2 yr: 49% (combo), 27% (etanercept), 21% (MTX) Radiograph at 2 yr: arrest of radiographic progression: 78% (combo), 68% (etanercept), 60% (MTX) Sharp score mean change in combination group: –0.56

Etanercept38 DBPCRCT:   25 mg twice a wk

19 mg/wk

ACR, American College of Rheumatology; DB, double blind; DBPCRCT, double-blind placebo-controlled randomized clinical trial; DD, disease duration; DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; OL, open label; Pts, patients; RA, rheumatoid arthritis; SJC, swollen joint count; TJC, tender joint count.

Pharmacokinetics Clinical pharmacology studies demonstrate that infliximab has a dose-dependent pharmacokinetic profile following infusions of 1 to 20 mg/kg. In combination therapy with MTX (7.5 mg once a week), serum infliximab concentrations tend to be slightly higher than when administered alone.11 Infliximab behaves in a consistent manner across different demographic groups (including pediatric versus adult patients) and among patients with different diseases of varied severity. It has been estimated that the half-life of infliximab is around 8 to 9.5 days at the 3 mg/kg dose, although longer values have been reported for higher doses.12 The volume distribution of infliximab at steady state (3 to 5 L) is independent of dose, suggesting a predominantly intravascular distribution.13,14 The concomitant use of MTX results in an increase in the area under the curve of infliximab of approximately 25% to 30%. Drug Dose The typical initial dose of infliximab in RA is 3 mg/kg given as an intravenous (IV) infusion in combination with MTX, followed by doses 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Some RA patients

have received infliximab in combination with diseasemodifying antirheumatic drugs (DMARDs) other then MTX or as monotherapy. For patients who have an incomplete response, dosing may be increased up to 10 mg/kg, or the drug may be administered as often as every 4 weeks. In the clinic, increasing the dose of infliximab or decreasing the interval of administration is not an uncommon practice; however, it is not clear to what extent such changes achieve clinical improvements. For patients with psoriatic arthritis and ankylosing spondylitis, the recommended dose is 5 mg/kg, with or without MTX, at 0, 2, and 6 weeks, then every 8 weeks. Efficacy Rheumatoid Arthritis. In the earliest controlled trials, the efficacy of single doses of 1, 5, 10, and 20 mg/kg of infliximab was demonstrated; however, disease activity recurred when therapy was discontinued.13,15 This, along with the growing safety record, provided the rationale for studies with longer durations of therapy. In a subsequent study, concurrent therapy with MTX, even at a relatively low dose of 7.5 mg/week, seemed to enhance the clinical response to infliximab and

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Table 58-3  Clinical Trials with Adalimumab and Anakinra Drug and Reference

Study Design

MTX Mean DD SJC/TJC at Dose No. of Pts (mean yr) Entry

% Failed DMARDs (mean) Efficacy

Adalimumab56 DBPCRCT: 20, None 40 mg every wk or every other wk

544

11

20/34 (median) 3.7

ACR-20 at 26 wk: 53% (40 mg qwk), 46% (40 mg qowk), 39% (20 mg qwk), 36% (20 mg qowk), 19% (placebo) ACR-50 at 26 wk: 35% (40 mg qwk), 22% (40 mg qowk), 21% (20 mg qwk), 19% (20 mg qowk), 8% (placebo)

Adalimumab57 DBPCRCT: 20, 16.8 mg/wk (ARMADA) 40, or 80 mg every other wk

271

12

17/29 (mean)

3.0

ACR-20 at 24 wk: 66% (80 mg), 66% (40 mg), 48% (20 mg), 15% (placebo) ACR-50 at 24 wk: 43% (80 mg), 54% (40 mg), 32% (20 mg), 8% (placebo) ACR-70 at 24 wk: 19% (80 mg), 27% (40 mg), 10% (20 mg), 5% (placebo) Radiograph at 52 wk: Sharp score mean change: 0.1 (40 mg), 0.8 (20 mg), 2.7 (placebo)

Adalimumab59 DBPCRCT:   16.7 mg/wk 40 mg every other wk   or 20 mg every wk

619

11

19/28 (mean)

2.4

ACR-20 at 24 wk: 60% (40 mg), 55% (20 mg), 24% (placebo) ACR-50 at 24 wk: 41.5% (40 mg), 38% (20 mg), 9.5% (placebo) ACR-70 at 24 wk: 23% (40 mg), 21% (20 mg), 4.5% (placebo) Radiograph at 52 wk: Sharp score change: 0.1 ± 4.8 (40 mg), 0.8 ± 4.9 (20 mg), 2.7 ± 6.8 (placebo)

Adalimumab62 DB: 40 mg every 16.6 mg/wk (PREMIER; early other wk or RA) MTX alone or adalimumab + MTX

799

  0.7

32.1/22.0

MTX naive ACR-50 at 1 yr: 62% (combo), 46% (MTX), 41% (adalimumab) Radiograph at 1 and 2 yr : Sharp score change: 1.3 and 1.9 (combo), 3.0 and 5.5 (adalimumab), 5.7 and 10.4 (MTX)

Anakinra104

DBPCRCT: 30, None 75 or 150 mg

472

  4.0

26/34 (mean)

75

ACR-20 at 24 wk: 43% (150 mg), 34% (75 mg), 39% (30 mg), 27% (placebo) Radiograph at 24 wk: Genant score: 47% reduction (anakinra)

Anakinra107

DBPCRCT:   17 mg/wk 0.04, 0.1, 0.4, 1.0, or 2.0 mg/  kg/day

419

  7.4

18/25 (mean)

1.9

ACR-20 at 24 wk: 35% (2 mg), 42% (1 mg), 23% (placebo)

ACR, American College of Rheumatology; DB, double blind; DBPCRCT, double-blind placebo-controlled randomized clinical trial; DD, disease duration; DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; OL, open label; Pts, patients; qowk, every other week; qwk, every week; RA, rheumatoid arthritis; SJC, swollen joint count; TJC, tender joint count.

also decrease its ­ immunogenicity.11 Almost all subsequent studies in RA have used such combination therapy. Multicenter double-blind, placebo-controlled, randomized clinical trials have evaluated the effects of multiple doses of infliximab over longer periods. In the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) trial, the addition of infliximab in patients with long-standing, refractory, active disease was significantly superior to treatment with MTX alone. The results were promising: substantial improvement in signs and symptoms of disease was noted soon after treatment and sustained though 54 weeks of follow-up.12,16 In addition to achieving substantial efficacy, as measured by American College of Rheumatology-20 (ACR-20) clinical response criteria, the use of infliximab was associated with significant improvement in functional status and quality of life.16 Perhaps most remarkably, patients receiving infliximab had a dramatic reduction in the progression of joint damage as assessed by radiographic change scores. The median change in the Sharp score at 1 year for infliximab-treated patients was 0.0 units (mean change, +0.55; baseline score, 50.5), indicating no significant progression. The median change in score for patients on MTX alone was +4.0 units (mean change, +7.0;

baseline score, 55.5); this amount of progression is roughly what would have been predicted given the disease severity.14,16 For patients who have an incomplete response, dosing may be increased up to 10 mg/kg, or the drug can be administered as often as every 4 weeks. Following the success achieved in patients with longstanding RA, this therapy was tested in patients with early RA ( <  3 years’ duration). In the ASPIRE trial, which compared the effects of infliximab plus MTX and MTX alone, the percentage of patients achieving an ACR-20 response was significantly higher in the infliximab group at 54 weeks (see Table 58-1). In addition, although a significant increase in radiographic destruction was observed in patients treated only with MTX, a reduction in disease progression was observed in the infliximab plus MTX groups.17 A detailed subanalysis of data from the ATTRACT study demonstrated that a significant radiographic benefit was achieved with infliximab plus MTX treatment even among patients who experienced no improvement in signs and symptoms of disease. This suggests that there may be an uncoupling among various outcomes and that treatment with TNF inhibitors might have disease-modifying activity even in the absence of a clinical response.18

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Table 58-4  Clinical Trials with Anti–TNF-α Agents in Patients with Psoriatic Arthritis Drug and Reference

No. of Pts D/P

MTX (% Pts) D/P

PsA Follow-up Duration (yr) (wk) D/P D/P

PsARC (%) D/P

DAS-28 (%) D/P

ACR-20 (%) D/P

ACR-50 (%) D/P

ACR-70 (%) D/P

PASI-50 (%) D/P

PASI75 (%) D/P

Infliximab 20 21, 22

52/52 100/100

63/79 47/45

11.7/11 8.4/7.5

16 14

75/21 77/27

89/25 —

65/10 58/11

46./0 36/3

29/0 15/1

100/0 82/9

68/0 64/2

Etanercept 44 46

30/30 101/104

47/47 42/43

9/9.5 9/9.2

12 12

87/23 72/31

— —

73/13 59/15

50/3 38/—

13/0 —

46.2/8.7 —

26.0 —

Adalimumab 62 151/162

51/50

9.8/9.2

12

62/26

—

58/14

36/4

17/1

72/15

49/4

ACR, American College of Rheumatology; DAS, disease activity score; D/P, drug/placebo; MTX, methotrexate; PASI, psoriatic arthritis severity index; PsA, psoriatic arthritis; PsARC, psoriatic arthritis response criteria; Pts, patients.

Table 58-5  Clinical Trials with Anti–TNF-α Agents in Patients with Ankylosing Spondylitis Drug and Reference

No. of Patients D/P

Infliximab 24 25 (OLEX)

35/35 69

26 (OLEX) 27 (OLEX) 29

52 46 201/78

Etanercept 44

20/20

47

138/139

48 (OLEX) 49

257 45/39

Adalimumab 60

208/107

BASDAI-50 (%) D/P

ASAS-20 (%) D/P

Partial Remission (%) D/P

  12   24   54 102 156   24

53/9 60 50 43 47 51/10.7

73/27 78 65 60 49 61.2/19.2

20/1 12 26 25 33 22.4/1.3

  16   24   12   24   72   12

— — — — — 71.1/25.6

68/24 78/80 59/28 57/22 48 60/23

— — — 17/4 — 24.4/10.3

  12   24

— —

48.6/13.1 44.7/12.1

20.7/3.3 22.1/5.6

Follow-up (wk)

ASAS-20, 20% improvement in 5 of 6 domains, without a 20% worsening in the sixth domain of the assessment in ankylosing spondylitis; BASDAI-50, 50% improvement in Bath ankylosing spondylitis disease activity index; D/P, drug/placebo; OLEX, open-label extension.

Chimeric anti-TNF- mAb

Infliximab

p75 TNF-receptor/IgG1 Fc construct

Etanercept

Human anti-TNF- α mAb

Adalimumab

Human

Mouse

Linker

Figure 58-1  Structure of infliximab, etanercept, and adalimumab. Ig, immunoglobulin; mAb, monoclonal antibody; TNF, tumor necrosis  factor.

In a safety-based study, a group of patients with active RA and disease more typical of clinic populations (i.e., patients with comorbidities were allowed to enroll) was treated with either 3 or 10 mg/kg of infliximab for 46 weeks, resulting in comparable efficacy to that found in earlier trials.19 However, there was an increase in serious infectious events in the 10 mg/kg group.

Psoriatic Arthritis. In the Infliximab Multinational Psoriatic Arthritis Controlled Trial 1 (IMPACT 1), 104 patients, 65% of whom were on background DMARDs (46% MTX), were randomized to receive either infliximab or placebo. Patients initially assigned to receive placebo crossed over after week 16; thereafter, all the patients received infliximab until week 50. The response to infliximab therapy defined by ACR-20 and psoriatic arthritis response criteria was evident as early as week 2, and improvement continued through week 50. Similar clinical response was achieved in the placebo group that began receiving infliximab after week 16. Significant improvements were also seen in skin psoriasis and in dactylitis and enthesitis assessments.20 In the phase III (IMPACT 2) trial, the placebo group was allowed early escape at week 16, and all patients received infliximab after week 24. Clinical improvement was seen very early in the treatment groups, and the response was maintained with continued treatment through the end of the study. Significant dermatologic improvement, defined by changes in the psoriasis area and severity index (PASI), was also reported in the infliximab group.21,22 In the same group of patients, infliximab inhibited radiographic progression as

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early as 24 weeks. Thus, the change in van de Heijde–Sharp score was –0.70 ± 2.53 versus 0.82 ± 2.62 at week 24 for infliximab- and placebo-treated patients, respectively. At week 54, these scores continued to improve: –0.94 versus 0.53 for infliximab and placebo crossover patients, respectively.23 In the same study, the effect of infliximab on healthrelated quality of life was assessed using the short form-36 (SF-36) at weeks 0, 14, and 24. Functional disability was assessed using the health assessment questionnaire (HAQ). The mean percentage improvement from baseline in the HAQ was 48.6% in the infliximab group, compared with a worsening of 18.4% in the placebo group at week 14. Overall, 58.6% of the infliximab group and 19.4% of the placebo group achieved a clinically meaningful improvement in HAQ at week 14.24 Ankylosing Spondylitis. The efficacy and safety of infliximab have been assessed in several multicenter clinical ­trials.24-27 In the initial double-blind, placebo-controlled, ­randomized part of one early study, disease activity measured by the Bath ankylosing spondylitis disease activity index (BASDAI), functional ability measured by the Bath ankylosing spondylitis functional index (BASFI), and mobility of the spine measured by the Bath ankylosing spondylitis ­metrology index (BASMI) significantly improved with 5 mg/ kg infliximab given at weeks 0, 2, 6, 12 compared with placebo.25 Of the patients who continued to receive infliximab every 6 weeks until week 102, a significantly higher percentage achieved 50% or greater improvement in the BASDAI.26,27 Importantly, at week 102, 25% of the completers were in partial remission according to the assessment in ankylosing spondylitis (ASAS) criteria. The clinical efficacy and the partial remission achieved in a substantial minority of patients were maintained through 3 years of treatment. In addition, the incidence of enthesitis and anterior uveitis significantly decreased during the third year of the treatment in comparison to baseline.28 This group was also analyzed for the clinical response and the time to relapse after discontinuation of anti-TNF therapy. Of note, after infliximab was stopped, all patients experienced a return of disease activity, with a mean time to relapse of 17.5 weeks. Re-treatment with infliximab was safe and resulted in clinical improvement in all patients to a state similar to that achieved previously.29 In another trial, 279 patients with ankylosing spondylitis were assigned to receive either 5 mg/kg infliximab or placebo at 0, 2, 6, and 12 weeks. Sixty-one percent of infliximab-treated patients reached ASAS-20 response criteria at week 24, in comparison to 19% in the placebo group. Efficacy was noted as early as 2 weeks after beginning therapy and was maintained throughout the 24-week observation period. At week 24, 22.4% of the patients in the infliximab group achieved ASAS partial remission, in comparison to 1.3% in the placebo group. In addition, patients receiving infliximab showed significant improvement in BASDAI, BASFI, and BASMI30 (see Table 58-5). To assess the effect of treatment on inflammation and structural damage, magnetic resonance images of the lumbar spine and sacroiliac joints were assessed. ­Spinal inflammation and clinical disease activity improved significantly from week 0 to week 30 in patients treated with infliximab plus MTX, in comparison to MTX alone.31 In one study, 2 years of continuous infliximab therapy resulted in persistent

improvement in spinal inflammation determined by both T1-weighted gadolinium-enhanced and short tau inversion recovery MRI sequences in all ankylosing spondylitis patients (n = 20).32 Of note, disease activity parameters did not directly correlate with MRI results. ETANERCEPT Structure Etanercept is formed by the linkage of two soluble p75 TNF-R extracellular domains to the Fc portion of human IgG1 (see Fig. 58-1). The resultant molecule binds both TNF-α and LT-ß with high affinity and specificity.33 The TNF-R domains in etanercept bind to two of the three receptor binding sites on the TNF trimer, thus blocking the ability of TNF to interact with cellbound TNF-R, a prerequisite for signal transduction.32 Pharmacokinetics When administered subcutaneously, etanercept is absorbed slowly, reaching a mean peak concentration approximately 50 hours after a single 25-mg dose. The Ig structure affords a halflife of 3 to 4.8 days. The volume of distribution suggests predominantly intravascular distribution.34 The route of clearance from the circulation is unclear, although it is ­presumed to be mediated through Fc binding by the reticuloendothelial ­system. Unlike with the anti-TNF monoclonal antibodies, the concomitant use of MTX does not alter the pK of etanercept. Drug Dose Etanercept is administered by subcutaneous injection in doses of 25 mg twice weekly or 50 mg once weekly in RA, psoriatic arthritis, and ankylosing spondylitis. Etanercept is approved for use either as monotherapy or in combination with MTX. In skin psoriasis, a higher dose (50 mg twice weekly) is commonly used for the first 12 weeks of therapy. As is true of all the available TNF inhibitors, in the clinic, etanercept has been used in combination with DMARDs other than MTX, for example, leflunomide, sulfasalazine, and others. Efficacy Rheumatoid Arthritis. Initial studies demonstrated the efficacy and tolerability of etanercept in both early and refractory disease and also established the optimal dose as 25 mg twice weekly.35-45 In addition to achieving substantial efficacy, as measured by ACR-20 clinical response criteria, the use of etanercept has been associated with significant improvement in functional status and quality of life. In one double-blind, placebo-controlled, randomized clinical trial, patients with active and long-standing RA who were refractory to DMARD therapy were treated with etanercept (10 or 25 mg twice weekly) for 6 months. Etanercept was effective in rapidly reducing disease activity.37 In another trial, the addition of etanercept in patients with active disease, despite concurrent MTX, was significantly superior to treatment with MTX alone. The addition of etanercept resulted in rapid and sustained improvement.38 At 6 months, disease activity was significantly reduced in the ­combination therapy group versus those who received only MTX. In the

PART 8 

open-label extension part of this study, the patients were able to sustain the improvement, and the majority of them were able to decrease their use of MTX, corticosteroid, or both. Following the success achieved in patients with refractory disease, the role of TNF-α inhibitors for the treatment of early disease was demonstrated in a large clinical trial in which two doses of etanercept (10 or 25 mg twice weekly) were compared to an accelerated dosing of MTX in MTXnaive RA patients with disease of less than 3 years’ duration.39,40 Clinical efficacy was achieved more quickly with the standard dose of etanercept than with either MTX or lower-dose etanercept. Moreover, radiographic assessments at 0, 6, 12, and 24 months showed that the rate of radiographic progression was significantly reduced with etanercept compared to MTX. In long-term, open-label follow-up studies of patients from the clinical trials, responses to etanercept therapy have been sustained over a number of years, with some patients at nearly a decade of treatment to date.41 Etanercept has also proved efficacious in patients with juvenile arthritis.42 In a study known as TEMPO, the effects of etanercept only, MTX only, and etanercept plus MTX in patients with relatively early disease were assessed. ACR-20, -50, and -70 responses, as well as rates of remission, were significantly higher in the combination therapy group compared with either monotherapy group. Similarly, improvement in disability based on HAQ was greater with combination therapy. The etanercept plus MTX group showed significantly less radiographic progression than did either group receiving monotherapy, and radiographic progression was significantly lower in the etanercept group compared with the MTX group. Because there is no pK interaction between etanercept and MTX, this study conclusively shows that there is an additive effect on various important outcomes with the combination of MTX and a TNF inhibitor43 (see Table 58-2). Different dosing of etanercept has been assessed in clinical trials. In RA patients, 50 mg etanercept once weekly resulted in similar efficacy to 25 mg twice weekly.44 Of note, etanercept monotherapy at a dose of 50 mg twice weekly did not result in increased efficacy in RA patients compared with 25 mg twice weekly.45 Psoriatic Arthritis. In the initial double-blind, placebocontrolled clinical trial, 60 patients with psoriatic arthritis were randomized to receive either etanercept or placebo for 12 weeks. Substantial improvements were observed in psoriatic arthritis response criteria, ACR-20 response criteria, and PASI dermatologic scores in the etanercept-treated patients. The median PASI improvement was 46% in the etanercept group, versus 9% in the placebo group.46 Subsequently, 205 patients with psoriatic arthritis were randomized to treatment with placebo or 25 mg etanercept twice weekly. At week 12, 59% of etanercept-treated patients met the ACR-20 criteria, compared with 15% of placebo patients. During the open-label extension through week 48, patients continuing with etanercept treatment maintained or improved their clinical responses, while those in the placebo group showed similar improvements once they began receiving etanercept. The primary radiographic end point was the annualized rate of change in the modified total Sharp score. The radiographic disease progression was inhibited in

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the etanercept group (–0.03 unit), compared with worsening (+ 1.00 unit) in the placebo group47 (see Table 58-4). Ankylosing Spondylitis. Similarly positive results were observed with etanercept therapy in patients with ankylosing splondylitis. In a double-blind, placebo-controlled, randomized clinical trial, significant improvement in clinical response (defined by ASAS-20) was demonstrated in etanercept-treated patients throughout the 24-week study.48 Sustained clinical response was maintained in the open-label extension of this study throughout 96 weeks of treatment. The patients who had received placebo in the preceding study but etanercept thereafter had similar responses.49 ­Recently, the impact of ankylosing spondylitis on patients’ health-related quality of life was assessed, and treatment with etanercept resulted in significant improvements.50 The extent of clinical response was similar in the subsequent clinical trials. In one multicenter trial, the improvement measured by ASAS-20 was noted as early as 2 weeks after etanercept was started, and the response was maintained throughout the trial.51 In a subsequent multicenter trial, significant improvements in the BASDAI, BASFI, and BASMI scores were achieved initially in the etanercept-treated group and later in all patients after the placebo group received etanercept as well. Relapses occurred at a mean of 6 weeks after cessation of etanercept.52 Recently, the same authors reported the results of readministration of etanercept in the same group of ­patients. Sixty percent of the patients showed a 50% improve­ ment in the BASDAI. Most patients (83%) were able to completely discontinue nonsteroidal anti-inflammatory drugs (NSAIDs)53 (see Table 58-5). As part of one clinical trial, magnetic resonance images of the lower thoracic and lumbar spine of 40 patients were evaluated. Spinal inflammation regressed by 54% in the etanercept group but worsened by 13% in the placebo group after 12 weeks of therapy. After switching to etanercept, the placebo patients experienced a similar improvement in spinal inflammation.54 Finally, it was demonstrated that continuous treatment with etanercept for 24 weeks reduced active spinal changes by 69% measured by different magnetic resonance imaging (MRI) sequences.55 ADALIMUMAB Structure Adalimumab is a human anti-TNF IgG1 monoclonal antibody generated through repertoire cloning. Adalimumab neutralizes the biologic activity of TNF-α by binding with high affinity to the soluble and transmembrane forms of TNF-α and inhibiting the binding of TNF-α with its receptors. Pharmacokinetics The peak serum adalimumab concentration and the area under the curve increase linearly with doses in the range of 0.5 to 10 mg/kg. Adalimumab appears to have a low clearance and distributes mainly in the vascular compartment. Its elimination half-life is comparable to that of native IgG1 (10 to 13.6 days). The concomitant use of MTX results in an approximate increase in the area under the curve of adalimumab of 25% to 30%.

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Drug Dose The recommended dosing for adalimumab in RA, psoriatic arthritis, and ankylosing spondylitis is 40 mg subcutaneously every other week. In patients who do not achieve an ­optimal response, it is possible to increase the dosing frequency to weekly. Adalimumab is approved for use as ­monotherapy or in combination with MTX. In the clinic, it has been used in combination with a number of DMARDs other than MTX. Efficacy Rheumatoid Arthritis. In a phase II trial, 283 patients were treated with placebo or one of three doses of adalimumab (20, 40, or 80 mg) via weekly subcutaneous injection for 12 months (placebo patients switched to active treatment at 3 months).56 Clinical results demonstrated the efficacy of adalimumab in comparison to placebo. ­Efficacy was comparable among the various doses. In a subsequent trial, adalimumab was given to patients with active RA despite long-term MTX therapy at doses of 20, 40, and 80 mg every other week. Adalimumab at all doses provided significant, rapid, and sustained improvement in disease activity over 24 weeks compared with MTX alone.57 Greater efficacy was observed with the two ­higher dose regimens, which were comparable. In a study known as ARMADA, combined treatment with adalimumab and MTX demonstrated sustained improvements in the signs and symptoms of RA as assessed by the ACR criteria, as well as notable improvement in functional status as assessed by HAQ scores.58 In a phase III multicenter trial, 619 patients with active RA and inadequate response to MTX were randomized to receive adalimumab 40 mg every other week, adalimumab 20 mg weekly, or placebo.59 Both adalimumab regimens were significantly more effective at reducing signs and symptoms (measured by the ACR-20 response) and in improving physical function in comparison to placebo. In addition, joint damage was assessed radiographically using Sharp scores; patients treated with adalimumab showed significantly smaller changes, and significantly fewer adalimumabtreated patients had new erosions and overall progression of damage compared with those taking placebo. A study evaluating the health-related quality of life in two clinical trials demonstrated that adalimumab plus MTX provides statistically significant improvements.60 Long-term follow-up of patients receiving open-label treatment following several controlled trials has demonstrated sustained improvement and good tolerability over several years.61 Following the efficacy noted in patients with refractory RA, adalimumab was assessed in patients with early disease. In a study known as PREMIER, adalimumab plus MTX was compared with adalimumab monotherapy and MTX monotherapy in MTX-naive patients with early RA (active disease   <  3 years’ duration). The combination of adalimumab and MTX was superior to either monotherapy at 1 year with respect to clinical efficacy. There was significantly less radiographic progression among patients in the combination group at both 1 year and 2 years in

comparison to the monotherapy groups, although ­progression was less with adalimumab monotherapy than with MTX monotherapy62 (see Table 58-3). Because this study was the first to include all three possible treatment arms (TNF inhibitor, MTX, and TNF inhibitor plus MTX), it definitively established that combination t­herapy with MTX and TNF inhibitor achieves the best ­outcomes in patients with early RA. Although TNF inhibitor monotherapy was superior to MTX alone in terms of ­ radiographic progression, clinical efficacy was comparable; both, however, were substantially less effective than the combination. Psoriatic Arthritis. Adalimumab given as 40-mg subcutaneous injections every other week has also been studied in patients with psoriatic arthritis. In a large placebo-controlled trial with 313 patients, 50% of the patients were on background MTX. A significantly higher percentage of ­patients from the adalimumab-treated group reached ACR-20, -50, and -70 response criteria compared with those ­ receiving placebo63 (see Table 58-4). Moreover, the rate of radiographic damage progression was significantly attenuated with adalimumab. As was true in studies of the other TNF inhibitors in psoriatic arthritis, MTX was permitted but not required for enrollment in the study. With this design, there seemed to be no difference in efficacy or toxicity between the combination of MTX plus adalimumab and adalimumab monotherapy. In addition to the improvements in various articular manifestations, dramatic improvements were noted in skin psoriasis with ­adalimumab treatment. Ankylosing Spondylitis. In the adalimumab trial evaluating its long-term efficacy and safety in ankylosing spondylitis (known as the ATLAS trial), a total of 315 patients received either 40 mg adalimumab or placebo every other week for 24 weeks. The number of subjects who met the ASAS partial remission criteria was significantly higher in the adalimumab group at weeks 12 and 24 in comparison to the placebo group. Subjects meeting the ASAS 5/6 criteria (20% improvement in five of six domains, without a 20% worsening in the sixth domain) at weeks 12 and 24 were also significantly higher in the adalimumab-treated patients.64 Significant improvement in health-related quality of life was also reported in this group of patients65 (see Table 58-5). The efficacy of these drugs was demonstrated not only by improved clinical indexes but also by spinal inflammation assessed by MRI. MECHANISM OF ACTION Several potential mechanisms of action may explain the e­ fficacy of TNF inhibitors in RA and other conditions (Table 58-6). Although there is some support for these ­varied mechanisms, the exact relationship between any particular mechanism and specific aspects of clinical ­efficacy remains to be delineated. However, downregulation of local and systemic proinflammatory cytokine production and reduction of lymphocyte activation and migration into the joint may be the most relevant ­mechanisms. It has been demonstrated, for example, that serum levels of IL-6 and IL-1 are significantly reduced after

PART 8 

Table 58-6  Potential Mechanisms of Action of TNF Inhibitors Downregulate production of other inflammatory mediators Cytokines (e.g., IL-1, IL-6, GM-CSF) Chemokines (e.g., IL-8) Degradative enzymes (e.g., MMPs) Other mediators (e.g., C-reactive protein) Alter vascular function; leukocyte traffic and activation Adhesion molecule expression and function Angiogenesis inhibition Modulate the function of immunocompetent cells T cells Normalize activation threshold for CD3–T cell receptor signaling Alter Th1/Th2 phenotype, cytokine secretion Increase regulatory T cell number and function Induce apoptosis (?) Monocytes and macrophages Modulate HLA-DR expression Induce apoptosis (?) GM-CSF, granulocyte-macrophage colony-stimulating factor; HLA, human leukocyte antigen; IL, interleukin; MMP, matrix metalloproteinase; Th, T helper.

the administration of anti–TNF-α monoclonal antibody.66, 67 The reduction in TNF-α and the consequent reduction in IL-1 would be expected to reduce the synthesis of matrix metalloproteinase (MMP) and the production of other degradative enzymes. Serial studies have shown that there is in fact a marked reduction in pro–MMP-3 and pro– MMP-1 after anti–TNF-α therapy.68-70 As noted, anti–TNFα therapy is also associated with a reduction of lymphocyte migration into the joints of patients with RA. Using radiolabeled granulocytes, it has been demonstrated that anti– TNF-α monoclonal antibody significantly reduces cell movement into the affected joints.71 In addition, posttreatment synovial biopsies show reduced cellular infiltrates, with fewer T cells and macrophages present.72 These effects are thought to be secondary to a reduction in the expression of endothelial adhesion molecules in the synovial tissue. Treatment with anti–TNF-α monoclonal antibody results in a dose-dependent decrease in soluble forms of intercellular adhesion molecule-1 (ICAM-1) and Eselectin (CD62E).71 Changes in soluble E-selectin, soluble ICAM-1, and circulating lymphocytes with anti–TNF-α therapy correlates with clinical outcome. Vascular endothelial growth factor (VEGF) is a potent endothelial cell– specific angiogenic factor. It is produced in the synovium and is an important regulator of neovascularization in the pannus. After anti–TNF-α therapy, VEGF serum levels are reduced in patients with RA. The decrease correlates significantly with the clinical benefit observed in these patients.73 Because angiogenesis is a prominent feature of rheumatoid synovium, the relationship between inflammation and angiogenesis has been investigated. Computerized image analysis of endothelium for multiple markers of endothelium (e.g., von Willebrand’s factor, CD31) and neovasculature (aνß3) has shown reduced vascularity after anti-TNF therapy. A number of other potential mechanisms of action have also been suggested to be operative for TNF inhibitors (see Table 58-6), although there is still some debate on these aspects.

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OTHER CONSIDERATIONS Treatment in Other Autoimmune Conditions The role of TNF inhibitors in the treatment of Crohn’s ­disease, juvenile idiopathic arthritis, and psoriasis has also been clearly defined. Based on promising results in these autoimmune conditions, these agents have been used in a variety of other disorders, including idiopathic and ­spondyloarthopathy-related anterior uveitis, sarcoidosis, Sjögren’s syndrome, Behçet’s syndrome, inflammatory my­opathies, and various types of vasculitis. Importantly, although there are a number of case reports or small, ­uncontrolled clinical trials in these conditions, there is a paucity of conclusive data from controlled trials. Perhaps the most notable clinical response has been in the treatment of anterior uveitis, especially with the anti-TNF ­monoclonal antibody constructs.74 On occasion, promising results in uncontrolled trials have been disproved in controlled trials. This was observed in a placebo-controlled trial of ­ etanercept given in addition to standard therapy for remission induction and maintenance in patients with Wegener’s granulomatosis. Despite ­ promising anecdotal evidence, the addition of the TNF inhibitor not only failed to achieve any clinical improvement but also resulted in a higher risk of solid malignancies beyond that observed with cyclophosphamide alone.75 Despite the evidence that anti-TNF agents can result in the development of certain autoantibodies and even lupuslike syndromes, the safety and efficacy of anti-TNF agents have been assessed in a small group of patients with systemic lupus erythamatosus (SLE). Patients with joint involvement experienced remission of arthritis, and there was a significant reduction in the level of proteinuria with infliximab. In this small study, TNF inhibitor therapy did not lead to adverse events suggestive of an increase in SLE activity; however, as might have been expected, autoantibodies to double-stranded DNA and cardiolipin did increase.76 Monitoring No specific laboratory monitoring is currently required by regulatory agencies during therapy with TNF-α ­ inhibitors. Nevertheless, because of the rare occurrence of myelo­ suppression and concern about the risk of infection, ­­clinicians typically assess the complete blood count (CBC) intermittently during therapy. Assiduous monitoring of patients for any sign or symptom of infection, demyelinating disease, and malignancy is requisite during treatment with all TNF-α inhibitors. Pregnancy and Breast-feeding Developmental toxicity studies in rats, rabbits, and mice have not revealed any maternal toxicity, embryo toxicity, or teratogenicity associated with TNF inhibition. Minimal human pregnancy information has been published for these medications, and the majority of data consists of isolated case reports, retrospective surveys, and uncontrolled ­studies. As the number of patients treated with TNF-α inhibitors increases, there will be a growing number of pregnancies among them.77 Outcome data based on anecdotal observations

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of small numbers of pregnant women treated with infliximab, etanercept, and adalimumab reveal that the ­relative rates of live births, miscarriages, and therapeutic terminations were comparable to rates in a national cohort of agematched healthy women. TNF inhibitors are classified as Food and Drug Administration pregnancy risk category B (animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no adequate and well-controlled studies in pregnant women). The use of anti-TNF agents in pregnancy is recommended only if such treatment is clearly needed. Because it is not currently known whether TNF-α blockers are excreted in human milk or whether they are absorbed systemically after ingestion, it is recommended that TNF-α blockers not be used by nursing mothers. Toxicity In clinical trials, etanercept, infliximab, and adalimumab have generally been well tolerated.12,16,35-37,56 Longer term follow-up of patients initially enrolled in clinical ­trials has provided additional safety data for these agents. ­However, TNF-α plays a key role not only in the ­ pathogenesis of autoimmune diseases but also in normal immune homeostasis. Therefore, there are a number of safety considerations, including the potential risk of infection and malignancy, that are germane to the optimal clinical use of these agents.78 Additional information concerning the adverse effects associated with these agents has been obtained through pharmacovigilance. Adverse events related to the use of TNF-α inhibitors can be grouped into those that are agent related and those that are target related (Table 58-7).79 Injection site and infusion reactions and ­immunogenicity and its sequelae vary, depending on the particular agent. A ­ potentially increased predisposition to infection, ­development of malignancy, and induction of autoimmune disorders and an association with ­demyelinating disorders, myelosuppression, and worse outcome with congestive heart failure might be considered target-related adverse events. Thus, any ­ clinically effective TNF-α inhibitor might be expected to be ­associated with such adverse events, although the relative risk among different agents may vary, depending on dose and other factors. Infusion and Injection Site Reactions. Infliximab has been associated with infusion reactions, the most common of which are headache (20%) and nausea (15%). These are rarely severe, are usually transient, and can typically be controlled by slowing the rate of infusion or by treatment with acetaminophen or antihistamines.12,16 With etanercept and adalimumab, cutaneous reactions at injection sites represent the most frequent administration-related side effect; ­however, they rarely cause the ­discontinuation of therapy.30,58 Injection site reactions typically consist of erythematous or urticarial lesions.. Although they can arise at sites of previous injections, these reactions seem to be limited to the skin and are not associated with other or systemic features of immediate hypersensitivity. Reactions typically occur close to treatment initiation and abate over time, even with continued dosing.

Table 58-7  Adverse Effects Potentially Associated   with TNF Inhibitors Target related Infections (including serious infections) Opportunistic infections (e.g., tuberculosis) Malignancies (skin cancer, lymphoma [?]) Demyelinating conditions Hematologic abnormalities Congestive heart failure Autoantibodies (antinuclear antibody, anti–double-stranded DNA) Hepatotoxicity Dermatologic reactions Agent related Administration reactions Immunogenicity

Antigenicity. As is true for any therapeutic agent ­(especially large protein molecules, some of which contain foreign ­sequences), antibodies to anti-TNF agents can develop. Although the clinical relevance of these antibodies is ­presently unclear, they can diminish the half-life of the therapeutic agent and consequently decrease its efficacy. Approximately 3% of etanercept-treated patients develop antibodies to the drug. In an early study, it was noted that antibodies to infliximab developed in 53%, 21%, and 7% of patients who were receiving 10, 3, and 1 mg/kg infliximab, respectively.12 RA trials of infliximab with or without concomitant MTX treatment revealed that immunogenicity was decreased by concomitant MTX, perhaps due in part to the increase in the half-life of infliximab associated with MTX use.12 A multicenter trial of infliximab therapy in Crohn’s disease demonstrated that the induction of these anti-infliximab antibodies might contribute to hypersensitivity reactions in some patients. Antibodies to adalimumab developed in about 12% of patients; the rate was reduced to 1% with concurrent MTX treatment.79 Although it is believed that there is a trend toward higher clearance of TNF inhibitors in the presence of antibodies to the construct, routine ­testing for antibodies to TNF inhibitors is not currently recommended. Infection. Given that TNF-α is a key mediator of inflammation, a major concern surrounding the use of TNF-α inhibitors is their potential to increase the risk for infection. Although inhibition of TNF-α in animals does not appear to increase their risk for infection with most pathogens, it does interfere with the ability to mount an inflammatory response against intracellular organisms. In experimental models, TNF-α blockade impaired resistance to infection with mycobacteria,80,81 Pneumocystis carinii,82 fungi,83 Listeria monocytogenes,84 and Legionella.85 In patients with RA, infection with these types of opportunistic organisms has been observed.78,79 However, confounding the attribution of infection to any therapeutic agent is the fact that infections occur more frequently and are important contributors to the accelerated morbidity of RA patients compared with the normal population.86,87 It is difficult to determine how much of this susceptibility relates to the disease itself and how much is caused by the effects of immunomodulatory drugs (e.g., steroids, cytotoxic drugs). The subset of RA patients with great susceptibility to infection (i.e., those with severe, active disease) is also the subset most commonly enrolled in trials of TNF-α inhibitors; this is also the group of patients for whom these agents have the greatest clinical utility.

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In RA trials with TNF inhibitors, a number of infections have occurred. In general, the most frequent infections have been those that occur most commonly among all persons, such as upper and lower respiratory tract infections and urinary tract infections. In most studies, a slightly greater propensity to develop infection was seen in patients receiving TNF inhibitors; however, this trend is common in most studies of effective therapies for RA. Importantly, the incidence of serious infection, defined as infection requiring hospitalization or treatment with parenteral antibiotics, among RA patients treated with TNF inhibitors was similar to that of the control groups in individual studies; it also approximated the incidence noted among RA patients before the anti-TNF era.88,89 In certain subgroups, such as patients with early RA, the overall incidence of infection was less than in patients with more long-standing disease, and ­ infections and serious infections were comparable among TNF inhibitor–treated patients and controls. It is worth noting, however, that there are several characteristics of clinical trials that affect the ability to extrapolate their safety data to the clinic. In general, patients enrolled in clinical trials tend to be healthier and therefore less likely to develop adverse effects such as infection, compared with the general population of RA patients in the clinic. Therefore, postmarketing data provide an important complement to safety data obtained from clinical trials. Also, clinical trials are powered to assess efficacy and therefore may not have sufficient numbers of patients to ascertain real but small differences in uncommon side effects. A systematic analysis that combined the results from nine clinical trials of TNF inhibitors has been performed.89 That analysis found an increased risk of serious infection among patients receiving TNF inhibitors compared with controls (3.6% versus 1.7%); however, it should be noted that a nonstandard definition of serious infection was used, and there was no attempt to control for the time of exposure, which was nearly always greater for patients receiving TNF inhibitors. In that same analysis, there was a nonsignificant trend toward a greater incidence of serious infection with higher doses of TNF inhibitor. In one of the only clinical trials having a primary outcome of safety, the use of a high-dose TNF inhibitor was also associated with a greater incidence of serious infection compared with a lower dose; the lower dose was no different from placebo in that regard.19 In postmarketing surveillance data, also known as pharmacovigilance, serious infections have certainly been observed among patients receiving TNF inhibitors.78 The relative impact of potentially confounding factors such as comorbidities and concomitant medications on the rate of serious infection remains incompletely defined. This important question has also been addressed using registries of RA patients.90,91 In a German registry, the rate of infection and serious infection among 858 RA patients receiving treatment with TNF inhibitors was compared with that among 601 patients receiving only DMARDs.90 The relative risk for infection (3.3 to 4.1) as well as serious infection (2.7 to 2.8) was significantly higher among patients receiving TNF inhibitors. However, those patients also had more severe and more active RA, thereby placing them at a greater risk of infection. When the investigators used propensity scoring methods to control for severity of disease as a ­confounder, the relative risks were reduced. The risk of infection

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decreased to 2.3 to 3.0, and that for serious infection became a nonsignificant trend of 2.1. In data from a British registry, 7644 RA patients treated with TNF inhibitors were compared with 1354 RA patients on DMARDs alone.91 In this analysis, the crude rate of serious infection was higher among TNF inhibitor–treated patients (1.28; 95% confidence interval 0.94 to 1.76), although this did not reach statistical significance. Further, when the rates were adjusted for age, sex, severity of RA, use of corticosteroids, and comorbidity, there was no difference between the groups (relative risk 1.03; 95% confidence interval 0.68 to 1.57). In summary, although treatment with TNF inhibitors can result in an increased risk of infection and serious infection, other factors such as the severity of RA, the use of other medications such as corticosteroids, and the presence of comorbidities are important contributors to these outcomes. Clinicians must monitor patients closely for signs and symptoms of infection, and it is worth noting that TNF inhibitor therapy itself can mask the initial signs and symptoms of infection. Opportunistic infections, particularly disseminated Mycobacterium tuberculosis, are of concern with the use of TNF-α inhibitors. Of note, more patients treated with TNF-α ­inhibitors have extrapulmonary and disseminated ­tuberculosis (TB), highlighting the specific role of TNF in controlling this infection.92 Rates of TB associated with the use of TNF-α antagonists are higher in geographic regions where TB is more prevalent in the general population.93 Most cases of TB observed in the early years after the ­ introduction of TNF inhibitors arose within the first few months after initiation of therapy and were probably related to the reactivation of latent TB. Interestingly, very few cases of TB were observed during clinical trials of the TNF inhibitors, highlighting the important role of pharmacovigilance in identifying safety signals with new therapies. For etanercept, no cases of TB occurred in clinical trials, but there were 38 cases of etanercept-associated TB worldwide among an estimated 150,000 patients exposed through December 2002. For infliximab, 441 cases of TB among the approximately 500,000 initially exposed patients were reported; only 6 cases of infliximabrelated TB were reported from clinical trials. Ninety-seven percent of the infliximab-related cases occurred within 7 months of treatment initiation, with a median time of onset of 12 weeks. The incidence of TB in clinical trials with adalimumab was higher in earlier ­clinical trials, related to a lack of screening, the location of the ­studies, and the higher dose used in early trials. The incidence dropped to 1% after adalimumab was reduced to its current dose and after screening for latent TB infection was instituted before therapy (21 cases in 2400 patients).94,95 This highlights the benefit of screening for and treating latent TB among patients being considered for TNF inhibitor therapy. However, because treated patients may acquire new cases of TB, and because cases of latent TB may be missed owing to false-negative screening tests, constant vigilance for TB is required during therapy with TNF inhibitors. The impact of screening for latent TB in patients receiving anti-TNF agents has been assessed in a Spanish registry; the rate of development of active TB among RA patients treated with anti-TNF agents dropped by 83% with use of the recommended guidelines96 Current U.S. guidelines recommend purified protein derivative (PPD) skin testing and

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a chest radiograph before ant–TNF-α therapy. If the PPD test is positive without evidence of active infection, treatment for latent TB with isoniazid is recommended. The ­recommended duration of therapy is 9 months. Recommendations concerning the timing of TNF inhibitor therapy and isoniazid prophylaxis for latent TB vary; however, concomitant initiation appears feasible.19 During anti-TB treatment, alanine aminotransferase (ALT) monitoring is recommended, especially for those who chronically consume alcohol and take hepatotoxic drugs. Treatment should be interrupted and a modified or alternative regimen chosen for those with ALT elevation more than three times the upper limit of normal in the presence of hepatitis symptoms or jaundice, or five times the upper limit of normal in the absence of symptoms.97 Malignancy. Anti–TNF-α drugs can also theoretically ­affect the host defense against malignancy. To date, the occurrence of malignancies in clinical trials and long-term follow-up of RA patients from clinical trials does not appear to exceed the rate that would be expected in this population. The overall rate of most malignancies in patients with RA is the same as the normal population. However, the risk of lymphoma and lung cancer appears to be ­increased in patients with RA. Although the ­actual reason is not known, the severity and duration of the disease and the use of immunomodulatory agents such as MTX seem to play a role in the increased risk of lymphoma in RA patients.98 Postmarketing analysis of the association between anti–TNF-α agents and lymphoma is inconclusive. In one populationbased analysis, standardized incidence ratios of lymphoma among patients receiving anti-TNF therapies were somewhat higher than those among RA controls; however, this analysis did not adjust for baseline differences between patients.98 In a more recent analysis in which age, sex, and disease duration adjustments were made, no increased risk of lymphoma was identified among RA patients treated with anti–TNF-α agents compared with those treated with other therapies.99 The systematic review of clinical trials of anti– TNF-α monoclonal antibodies demonstrated an increased risk of malignancies, including lymphomas and skin cancers, with treatment, although the longer time of exposure to TNF inhibitors was not accounted for.89 Given these uncertainties, caution is indicated when considering the use of anti–TNF-α agents in patients with a history of malignancy or in those at high risk of malignancy for other reasons. ­Longer term follow-up of larger numbers of patients will provide clinicians with a better idea of the safety of these agents in this regard. Autoimmune Disorders. Approximately 10% to 15% of patients treated with any TNF inhibitor develop antibodies to double-stranded DNA.78,100 However, few patients (0.2% to 0.4%) develop symptoms consistent with druginduced lupus. The mechanism and the significance of the development of antibodies are uncertain, although this adverse effect seems relatively specific for TNF inhibitors and is not noted with other biologic agents. Of note, patients with TNF inhibitor–related lupus generally do not develop life-threatening lupus involvement (e.g., nephritis, central nervous system lupus) and rarely develop the diversity of other autoantibodies characteristic of idiopathic SLE (e.g.,

anti-Sm/RNP, anti-Ro/La, anti-Scl70). A few patients have reportedly developed anticardiolipin antibodies, but they are mostly asymptomatic. Among those few patients who developed lupus-like symptoms while on TNF-α inhibition therapy, improvement has been seen upon discontinuation of therapy. Although the rare occurrence of ­autoimmune ­ disorders has not dissuaded most clinicians from using TNF-α inhibitors in patients with RA, some remain cautious about using these drugs in patients with a history of SLE. Demyelinating Syndromes. Several cases of multiple ­sclerosis (MS) or peripheral demyelinating disease have been ­reported with anti–TNF-α therapy in patients with RA, ­psoriatic arthritis, and Crohn’s disease.101 In addition, two studies of TNF-α inhibitors in MS patients showed worsening of MS-related symptoms and exacerbations in the treated group.102,103 Although there is some evidence that the incidence of MS may be increased in patients with RA, the association between anti–TNF-α therapy and MS remains unclear. The risk of developing a demylelinating disease is very small; however, many clinicians withhold anti–TNF-α therapy in patients with a history of demyelinating diseases or in those showing signs and symptoms of such disease during anti–TNF-α therapy. Congestive Heart Failure. Some data suggest that TNF-α may play a role in the pathogenesis of congestive heart ­failure (CHF), and inhibition of TNF was highly effective in ­ animal models of ischemic cardiomyopathy. However, in trials of TNF inhibitors in patients with stable but ­severe (class III or IV) CHF, no clinical benefit was observed, and in some treatment arms, higher incidences of mortality and hospitalization for worsening of CHF were reported. Thus, TNF inhibition has been largely abandoned as a ­therapeutic approach in patients with CHF. Encouragingly, in patients with RA, treatment with TNF inhibitors does not appear to result in an increased incidence of CHF.104 In fact, TNF inhibitor therapy may actually improve mortality associated with heart disease and overall mortality in RA patients.

INTERLEUKIN-1 Members of the IL-1 family include IL-1α, IL-1ß, and the naturally occurring IL-1 receptor antagonist (IL-1ra). Specific cellular proteases process IL-1α and IL-1ß to their 17kD mature forms. Pro–IL-1α precursor is active intracellularly. However, pro–IL-1ß is not active before cleavage with IL-1ß–converting enzyme. After, cleavage it is secreted and is fully functional. IL-1Ra is a naturally occurring antagonist protein with amino acid sequence homology to IL-1α and IL-1ß. Multiple forms of this protein exist. One is secreted and functions as a ­competitive inhibitor of IL-1α and IL-1ß, binding to the same ­counterreceptor but transducing no signal. The IL-1 polypeptides bind to two cell surface receptors: type I (IL-1RI) and type II (IL-1RII). IL-1RI is found on most cell types, whereas IL-1RII occurs mainly on the surface of ­neutrophils, monocytes, B cells, and bone marrow ­ progenitor cells. When IL-1 binds to IL-1RI, the signal transduction is mediated through the association of a second receptor unit,

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IL-1R accessory protein. The three members of the IL-1 family bind to IL-1RI with similar affinities. Binding of IL1 to IL-1RII does not lead to signal transduction. IL-1RII acts like a decoy receptor and competitive inhibitor. Soluble forms of IL-1RII inhibit IL-1 activity by competing with IL-1RI for IL-1 binding. IL-18 is another member of the IL-1 family of inflammatory cytokines. It is now recognized as an important regulator of innate and acquired immune responses. IL-18 is expressed at sites of chronic inflammation, in autoimmune diseases, in a variety of cancers, and in the context of numerous infectious diseases. IL-18 likely plays a role in RA, and strategies to block IL18 activity are under way in clinical trials.105 Like TNF-α , IL-1 is one of the key mediators of the inflammatory response. Studies in animal models of arthritis have demonstrated the therapeutic potential of IL-1 blockade. IL-1ß gene knockout mice show markedly reduced levels of inflammation following immunization with type II collagen. The use of genetically modified mice has also helped confirm the physiologic significance of IL-1ra: deletion of this gene in mice results in the spontaneous development of arthritis. ANAKINRA Structure and Mechanism of Action Anakinra is a recombinant, nonglycosylated homologue of IL-1R that differs from native human IL-1R by the addition of a single methionine residue at its amino terminus. Anakinra blocks the activity of IL-1 by competitively inhibiting IL-1 binding to the IL-1RI receptor.98-102 Levels of the naturally occurring IL-1R, which are elevated in the synovium and synovial fluid from RA patients, appear to be insufficient for the excess amount of locally produced IL-1. Pharmacokinetics In subjects with RA, maximum plasma concentrations of anakinra occur 3 to 7 hours after the subcutaneous administration of clinically relevant doses (1 to 2 mg/kg). The terminal half-life ranges from 4 to 6 hours. In RA patients, no unexpected accumulation of anakinra is observed after daily subcutaneous doses for up to 24 weeks. The estimated anakinra clearance increases with increasing creatinine clearance and body weight. Drug Dose The recommended dose of anakinra for the treatment of patients with moderate to severely active RA is 100 mg/day administered by subcutaneous injection. Anakinra can be used alone or in combination with MTX. Because of the potential for an increased risk of infection, it is not recommended for use in conjunction with TNF inhibitors.104 Efficacy Rheumatoid Arthritis. Preliminary clinical studies i­ ndicated that anakinra could be safely administered by subcutaneous injection.106 The efficacy of anakinra in the treatment of active RA was confirmed in a 24-week, phase

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II, placebo-controlled study in which 472 patients received daily subcutaneous injections of placebo or one of the three different doses of anakinra (30, 75, or 150 mg)(see Table 58-3).107 Improvements were observed in all individual clinical parameters, including swollen and ­ tender joint counts, pain score, duration of early-morning stiffness, and patient and physician assessment of disease ­activity. More patients on the higher dose of anakinra achieved improvement in ACR-20 criteria compared with the placebo group. However, the overall magnitude of the reduction in clinical symptoms and signs (20% to 30%) was relatively modest compared with that seen with TNF-α blocking agents (60% to 70%). Patients were allowed to go on to a non-placebo-controlled extension study with three different doses of anakinra after completing the 24-week double-blind study. On completion of the ­extension study, 55% of the patients who had previously received ­placebo achieved an ACR-20 response. Of the patients who continued receiving the same dose of anakinra, 49% maintained an ACR-20 response at 48 weeks. Analysis of hand radiographs by two different methods after 24 weeks of treatment showed a statistically significant decrease in the rate of progressive joint damage compared with ­placebo.108 Improvements in functional status and quality of life were also observed.109 Anakinra is a competitive inhibitor of IL-1 that must be continuously present in great excess to be effective, and it must be administered daily. It was hypothesized that the relatively modest clinical results seen with anakinra in RA patients (compared with those achieved by TNF inhibitors) might be related to the agent rather than the target. Interestingly, two lines of evidence appear to refute this hypothesis: the efficacy of anakinra in other autoimmune diseases, and the comparable clinical efficacy of other IL-1 inhibitors in RA. Other Autoimmune Diseases. Autoinflammatory ­ diseases are a group of conditions that include familial cold ­autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease (also known as chronic infantile neurologic, cutaneous, ­articular [CINCA] syndrome). These conditions, which share some clinical features, are associated with various mutations in the NALP3/CIAS1/PYPAF1 gene, which encodes the ­protein cryopyrin. Cryopyrin is a key component of the ­inflammasome; thus, the autoinflammatory syndromes may be related to abnormalities in IL-1 regulation. This was proved by the remarkable responses to anakinra reported in these syndromes.110,111 In addition, significant and rapid ­ response have been achieved using anakinra to treat ­patients with adult-onset Still’s disease. Improvement in various ­hematologic, biochemical, and other markers suggests that IL-1 plays a key role in this disease as well.112 IL-1 TRAP IL-1 Trap is a fusion protein consisting of the human IL-1 receptor extracellular domains and the Fc portion of human IgG1. It incorporates in a single molecule the extracellular domains of both receptor components required for IL-1 ­signaling: IL-1RI and the IL-1R accessory protein. IL-1 Trap has a very high binding affinity for IL-1 (dissociation ­constant ∼1 pM), and it is specific for IL-1ß and IL-1α.

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Based on early studies, the subcutaneous administration of IL-1 Trap in subjects with RA demonstrated evidence of its clinical and biologic activity. However, a double-blind, placebo-controlled clinical trial in patients with moderate to severe RA who were randomized to receive weekly injections of either placebo or several doses of IL-1 Trap for 12 weeks showed only modest efficacy.113 Trials of this agent in autoinflammatory diseases and other autoimmune conditions are under way. OTHER CONSIDERATIONS Toxicity Anakinra is generally well tolerated. Injection site reactions are the most frequently reported adverse event. In a randomized clinical trial, injection site reactions were reported in 25% of patients given placebo and in 50%, 73%, and 81% of patients given anakinra in doses of 30, 75, and 150 mg/day, respectively.107 These reactions were generally mild and transient. Infections were uncommon and occurred at a similar rate in the placebo and treatment groups. Infections that required antibiotic therapy occurred in 12% of the placebo-treated group and in 15% to 17% of the treatment group. The infections consisted primarily of bacterial events such as cellulitis and pneumonia. The incidence of pulmonary infection appeared to be higher among patients with underlying asthma. In placebo-controlled studies, up to 8% of patients receiving anakinra showed a reduction in the neutrophil count, compared with 2% of the placebo patients. Other adverse events reported were headache, nausea, diarrhea, sinusitis, influenza-like syndrome, and abdominal pain. Malignancy rate and incidences were similar to those expected for the populations studied. Long-term follow-up of patients on anakinra has proved the overall tolerability of therapy over several years.114 In animal studies, the combination of TNF inhibition and IL-1 inhibition achieved synergistic efficacy in arthritis models. However, when this approach was tested in RA patients, the combination did not achieve any additional clinical benefit but did result in greater ­toxicity— specifically, an increased incidence of infection and serious infection.115 Therefore, the combination of biologic therapy targeting TNF and IL-1 is currently not recommended. Monitoring Patients should be closely monitored for signs and symptoms of infection. Administration of anakinra must be discontinued if a patient develops serious infection. Neutrophil counts should be assessed before initiating anakinra treatment, as well as monthly during anakinra therapy for 3 months, and then every 4 months for up to 1 year. Pregnancy and Breast-feeding Reproductive studies have been performed only on rats and rabbits, and they have not revealed any evidence of harm to the fetus. However, there are no well-controlled studies in pregnant women. Therefore, anakinra should be used ­during pregnancy only if it is clearly needed. It is not known

whether anakinra is secreted in human milk, so it should be discontinued in nursing mothers.

SUMMARY Treatment of RA with inhibitors of the key proinflammatory cytokines TNF-α and IL-1 is a compelling example of effective targeted biologic therapy. Therapy with these agents, particularly TNF inhibitors, has substantially improved the signs and symptoms of disease; for many patients, quality of life has been improved, the progression of joint damage has been inhibited, and disability has been averted. The success of this approach has “raised the bar” for the goals of treating this pernicious disease and has reinvigorated research aimed at further refinements of therapy. It has also stimulated research into the potential utility of inhibitors of additional cytokines such as IL-6, IL-15, and IL-18 and other components of the immune system relevant to autoimmune diseases. A number of questions remain regarding the optimal use of these drugs. Longer term safety data will allow clinicians to more fully assess the risk-benefit ratio for individual patients. Given the uncertainties regarding these drugs’ long-term safety and the heterogeneity of clinical responses, research defining the populations of patients expected to derive the greatest benefit with the least toxicity is critical. For example, ongoing research assessing genetic polymorphisms or proteomic or glycomic differences among treated patients could optimize efficacy while minimizing toxicity. This is also relevant from a cost standpoint. Although the acquisition costs of these agents are relatively high, data supporting their cost-effectiveness, including gains in employment and reduced hospitalizations, are emerging.116 The success observed with these biologic therapies has raised additional clinical questions. For example, can very early treatment with highly effective therapy, such as the combination of TNF inhibitor and MTX, truly alter the disease course? What might the optimal treatment paradigms be for various rheumatic diseases? The success of the TNF inhibitors has also generated substantial interest in targeting this cytokine by alternative approaches, including inhibition of key regulatory factors, such as p38 MAP kinase and NFkB. Advances in biopharmaceuticals could generate agents that possess desirable characteristics in terms of pharmacokinetics, immunogenicity, adverse effects, ease of administration, and cost. These developments should eventually allow clinicians to maximize the use of these novel therapies and achieve clinical benefits that were previously ­considered unattainable.

INTERLEUKIN-6 Recent data suggest that IL-6 and other members of the IL-6-cytokine family have important effects on the ­inflammatory and immune responses. IL-6 is expressed by monocytes, T and B lymphocytes, and fibroblasts and is detectable at elevated levels in the serum and synovial tissue, together with its receptor components IL-6R and gp 130, in RA and psoriatic arthritis patients. Levels of IL-6 are proportional to levels of CRP and disease severity, strongly suggesting a central role in disease pathogenesis.

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IL-6 knockout mice are resistant to CIA and have reduced levels of serum TNF-α. IL-6 blockade might therefore be an attractive therapy for the treatment of RA and other ­autoimmune diseases. TOCILIZUMAB Previously referred to as MRA (myeloma receptor antibody), tocilizumab is a humanized IgGl mAb that binds with high affinity to soluble and membrane-bound forms of the 80-kDa component of the IL-6R. Treatment with this mAb inhibits IL-6-mediated interactions on cells constitutively expressing the IL-6R. Because soluble forms of the IL-6R can productively interact with the 130-kDa signaltransducing component gp130, which is expressed on a wide variety of cell types, treatment with tocilizumab inhibits a broad array of IL-6-driven processes. Efficacy The efficacy of tocilizumab as monotherapy was initially shown in several double-blind, placebo-controlled, randomized clinical trials in patients with active RA.117, 118 Sub­ stantial decreases in measures of the acute-phase response, including the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) concentration were consistently seen as early as 1 week and were largely sustained through 4 weeks. Larger phase II studies tested tocilizumab monotherapy, given at doses of 4 mg/kg and 8 mg/kg intravenously every 4 weeks over 3 months, in patients with relatively refractory and active RA. Most individual measures of arthritis activity significantly improved by week 4 and the extent of response continued to improve through 12 weeks. Sustained clinical responses were maintained for a consider­ able number of patients over 5 years of the open-label ­followup period.119 In a larger study known as CHARISMA, 359 RA patients with active disease despite the concomitant use of MTX were enrolled into one of seven treatment arms: tocilizumab 2 mg/kg, 4 mg/kg, or 8 mg/kg, as mono­ therapy, or tocilizumab at the same doses in combination with MTX; the seventh arm consisted of MTX with ­placebo.120 With tocilizumab monotherapy, doses of 4 mg/kg and 8 mg/kg were superior to MTX alone, whereas the lower dose of 2 mg/kg was not. However, among patients remaining on concomitant MTX, all three dosing groups achieved statistically significant improvement compared with MTX alone. The ability of treatment with tocilizumab to alter the progression of joint damage was assessed in patients with relatively early RA in a study called SAMURAI.121 Therapy with the anti-IL-6R mAb had a beneficial effect on the ­ progression of radiographic joint damage defined by total Sharp score in addition to improvements in clinical and functional status. Safety As is seen with almost all effective immunomodulatory therapies in RA, a slight increase in the prevalence of infections was seen in trials of tocilizumab. Other adverse effects included transient elevations in liver function and cholesterol and neutropenia. The implications of these effects are being studied in larger and longer-term analyses.

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  23. Van de Heijde D, Gladman DD, Kavanaugh A, et al: Infliximab inhibits progression of radiographic damage in patients with active psoriatic arthritis: 54 week result form IMPACT 2. Arthritis Rheum 52(Suppl 9):S281, 2005.   24. Kavanaugh A, Antoni C, Krueger GG, et al: Infliximab improves health related quality of life and physical function in patients with psoriatic arthritis. Ann Rheum Dis 65:471-477, 2006.   25. Braun J, Brandt J, Listing J, et al: Treatment of active ankylosing spondylitis with infliximab: A randomised controlled multicentre trial. Lancet 359:1187-1193, 2002.   26. Braun J, Brandt J, Listing J, et al: Long-term efficacy and safety of infliximab in the treatment of ankylosing spondylitis: An open, ­observational, extension study of a three-month, randomized, placebo-controlled trial. Arthritis Rheum 48:2224-2233, 2003.   27. Braun J, Brandt J, Listing J, et al: Two year maintenance of efficacy and safety of infliximab in the treatment of ankylosing spondylitis. Ann Rheum Dis 64:229-234, 2005.   28. Braun J, Baraliakos X, Brandt J, et al: Persistent clinical response to the anti-TNF-α antibody infliximab in patients with ankylosing spondylitis over 3 years. Rheumatology 44:670-676, 2005.   29. Baraliakos X, Listing J, Brandt J, et al: Clinical response to discontinuation of anti-TNF therapy in patients with ankylosing spondylitis after 3 years of continuous treatment with infliximab. Arthritis Res Ther 7:R439-R444, 2005.   30. Van der Heijde D, Dijkmans B, Geusens P, et al: Efficacy and safety of infliximab in patients with ankylosing spondylitis. Arthritis Rheum 52:582-591, 2005.   31. Marzo-Ortega H, Mcgonagle D, Jarrett S, et al: Infliximab in combination with methotrexate in active ankylosing spondylitis: A clinical and imaging study Ann Rheum Dis 64:1568-1575, 2005.   32. Sieper J, Baraliakos X, Listing J, et al: Persistent reduction of spinal inflammation as assessed by magnetic resonance imaging in patients with ankylosing spondylitis after 2 years of treatment with the anti-tumor necrosis factor agent infliximab. Rheumatology 44:1525-1530, 2005.   33. Mohler KM, Torrance DS, Smith CA, et al: Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endothexemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol 151:1548-1561, 1993.   34. Korth-Bradley JM, Abbe SR, Roberta KH, et al: The pharmacokinetics of etanercept in healthy volunteers. Ann Pharmacothrr 34:161164, 2000.   35. Moreland LW, Margolies G, Heck LW, et al: Recombinant soluble tumor necrosis factor receptor (p80) fusion protein: Toxicity and dose finding trial in refractory rheumatoid arthritis. J Rheumatol 23:18491855, 1996.   36. Moreland LW, Baumgartner SW, Schiff MH, et al: Treatment of rheumatoid arthritis with a recombinant human tumour necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 337:141147, 1997.   37. Moreland LW, Schiff MH, Baumgartner SW, et al: Etanercept therapy in rheumatoid arthritis: A randomized, controlled trial. Ann Intern Med 130:478-486, 1999.   38. Weinblatt ME, Kremer KM, Bankhurst AD, et al: A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 340:253-259, 1999.   39. Genovese MC, Bathon JM, Martin R, et al: Etanercept versus methotrexate in patients with early rheumatoid arthritis: Two year radiographic and clinical outcomes. Arthritis Rheum 46:1443-1450, 2002.   40. Bathon JM, Martin RW, Fleischmann RM, et al: A comparison of entanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 343:1586-1593, 2000.   41. Moreland LM, Cohen SB, Baumgartner SW, et al: Long-term safety and efficacy of etanercept in patients with rheumatoid arthritis. J Rheumatol 28:1238-1244, 2001.   42. Lovell DJ, Giannini EH, Reiff A, et al: Etanercept in children with polyarticular juvenile rheumatoid arthritis. N Engl J Med 342: 763-769, 2000.   43. Klareskog L, van der Heijde D, de Jager JP, et al: Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: Doubleblind randomized controlled trial. Lancet 363:675-681, 2004.   44. Keystone EC, Schiff MH, Kremer JM, et al: Once-weekly administration of 50 mg etanercept in patients with rheumatoid arthritis: Results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 50:353-363, 2004.

  45. Johnsen AK, Schiff MH, Mease PJ, et al: Comparison of 2 doses of etanercept (50 vs 100 mg) in active rheumatoid arthritis: A randomized double blind study. J Rheumatol 33:659-664, 2006.   46. Mease PJ, Goffe BS, Metz J, et al: Etanercept in the treatment of psoriatic arthritis and psoriasis: A randomised trial. Lancet 356:385-390, 2000.   47. Mease PJ, Kivitz AJ, Burch FX, et al: Etanercept treatment of psoriatic arthritis: Safety, efficacy, and effect on disease progression. Arthritis Rheum 50:2264-2272, 2004.   48. Davis JC, Van der Heijde D, Braun J, et al: Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: A randomized, controlled trial. Arthritis Rheum 48:3230-3236, 2003.   49. Davis JC, Van der Heijde D, Braun J, et al: Sustained durability and tolerability of etanercept in ankylosing spondylitis for 96 weeks. Ann Rheum Dis 64:1557-1562, 2005.   50.  Davis JC, Van der Heijde D, Dougados M, et al: Reductions in healthrelated quality of life in patients with ankylosing spondylitis and improvements with etanercept therapy. Arthritis Rheum 53:494-501, 2005.   51. Calin A, Dijkmans BAC, Emery P, et al: Outcomes of a multicentre randomised clinical trial of etanercept to treat ankylosing spondylitis. Ann Rheum Dis 63:1594-1600, 2004.   52. Brandt J, Khariouzov A, Listing J, et al: Six-month results of a doubleblind, placebo-controlled trial of etanercept treatment in patients with active ankylosing spondylitis. Arthritis Rheum 48:1667-1675, 2003.   53. Brandt J, Listing J, Haibel H, et al: Long-term efficacy and safety of etanercept after readministration in patients with active ankylosing spondylitis. Rheumatology 44:342-348, 2005.   54. Baraliakos X, Davis J, Tsuji W, et al: Magnetic resonance imaging examinations of the spine in patients with ankylosing spondylitis before and after therapy with the tumor necrosis factor α receptor fusion protein etanercept. Arthritis Rheum 52:1216-1223, 2005.   55. Rudwaleit M, Baraliakos X, Listing J, et al: Magnetic resonance imaging of the spine and the sacroiliac joints in ankylosing spondylitis and undifferentiated spondyloarthritis during treatment with etanercept. Ann Rheum Dis 64:1305-1310, 2005.   56. Van de Putte LBA, Rau R, Breedveld FC, et al: Efficacy and safety of the fully human anti-tumour necrosis factor antibody adalimumab (D2E7) in DMARD refractory patients with rheumatoid arthritis: A 12 week, phase II study. Ann Rheum Dis 62:1168-1177, 2003.   57. Weinblatt ME, Keystone EC, Furst DE, et al: Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate. Arthritis Rheum 48:35-45, 2003.   58. Weinblatt ME, Keystone EC, Furst DE, et al: Long term efficacy and safety of adalimumab plus methotrexate in patients with rheumatoid arthritis: ARMADA 4 year extended study. Ann Rheum Dis 65: 753-759, 2006.   59. Keystone E, Kavanaugh A, Sharp J, et al: Radiographic, clinical and functional outcomes of treatment with adalimumab (a human antitumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: A randomized placebo-controlled 52 week trial. Arthritis Rheum 50:1400-1411, 2004.   60. Torrance GW, Tugwell P, Amorosi S, et al: Improvement in health utility among patients with rheumatoid arthritis treated with adalimumab plus methotrexate. Rheumatology 43:712-718, 2004.   61. Schiff MH, Burmester GR, Kent JD, et al: Adalimumab is efficacious and safe: Safety analysis of adalimumab (Humira) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis. Ann Rheum Dis 65:889-894, 2006.   62. Breedveld FC, Weisman MH, Kavanaugh AF, et al: The ­PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 54:26-37, 2006.   63. Mease PJ, Gladman DD, Ritchlin CT, et al: Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: Result of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum 52:3279-3289, 2005.   64. Van der Heijde D, Kivitz A, Schiff M, et al: Efficacy and safety of adalimumab in patients with ankylosing spondylitis: Results of a multicenter, randomized double-blind, placebo-controlled trial. Arthritis Rheum 54:2136-2146, 2006.

PART 8    65. Van der Heijde D, Luo M, Matsumoto A, et al: Adalimumab improves health-related quality of life in patients with active ankylosing spondylitis: Rhe ATLAS trial. Arthritis Rheum 52(Suppl 9): S211, 2005.   66. den Broeder AA, Joosten LAB, Saxne T, et al: Long term ­ antitumour necrosis factor α monotherapy in rheumatoid arthritis: Effect on radiological course and prognostic value of markers of cartilage turnover and endothelial activation. Ann Rheum Dis 61:311-318, 2002.   67. Lorenz HM, Antoni C, Valerius T, et al: In vivo blockade of TNF-α by intravenous infusion of a chimeric monoclonal TNF-α antibody in patients with rheumatoid arthritis: Short term cellular and molecular effects. J Immunol 156:1646-1653, 1996.   68. Charles P, Elliott MJ, Davis D, et al: Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF alpha therapy in rheumatoid arthritis. J Immunol 163:1521-1528, 1999.   69. Brennan FM, Browne KA, Green PA, et al: Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid arthritis patients following anti-tumour necrosis factor-alpha (cA2) therapy. Br J Rheumatol 36:643-650, 1997.   70. Catrina AI, Lampa J, af Klint E, et al: Anti-tumour necrosis factor (TNF)-alpha therapy (etanercept) down-regulates serum matrix metalloproteinase (MMP)-3 and MMP-1 in rheumatoid arthritis. Rheumatology 41:484-489, 2002.   71. Paleolog EM, Hunt M, Elliot MJ, et al: Deactivation of vascular endothelium by monoclonal anti-tumor necrosis factor-α antibody in rheumatoid arthritis. Arthritis Rheum 39:1082-1091, 1996.   72. Tak PP, Taylor PC, Breedveld FC, et al: Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor α monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum 39:1077-1081, 1996.   73. Paleolog E, Young S, McClosekey RV, et al: Angiogenesis as a therapeutic target in rheumatoid arthritis: Serum vascular endothelial growth factor is decreased by anti-TNF α therapy. Clin Exp Rheumatol 16:232, 1998.   74. Atzeni F, Sarzi-Puttini P, Doria A, et al: Potential off-label use of infliximab in autoimmune and non-autoimmune diseases: A review. Autoimmun Rev 43:144-152, 2005.   75. Stone JH, Holbrook JT, Marriott MA, et al: Solid malignancies among patients in the Wegener’s Granulomatosis Etanercept Trial. Arthritis Rheum.54:1608-1618, 2006.   76. Aringer M, Graninger WB, Steiner G, Smolen JS: Safety and ­efficacy of tumor necrosis factor alpha blockade in systemic lupus erythematosus: An open-label study. Arthritis Rheum 50:31613169, 2004.   77. Chambers CD, Tutuncu ZN, Johnson D, Jones KL: Human pregnancy safety for agents used to treat rheumatoid arthritis: Adequacy of available information and strategies for developing post-marketing data. Arthritis Res Ther 14:215, 2006.   78. Olsen NJ, Stein CM: New drugs for rheumatoid arthritis. N Engl J Med 350:2167-2179, 2004.   79. Lee SJ, Kavanaugh A: Adverse events related to biologic agents. J Allergy Clin Immunol 116:900-905, 2005.   80. Bean AG, Roach DR, Briscoe H, et al: Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection. J Immunol 162:3504-3511, 1999.   81. Ehlers S, Benini J, Kutsch S, et al: Fatal granuloma necrosis despite intact antibacterial functions in TNFRp55-deficient mice chronically infected with M. avium. Infect Immun 67:3571-3579, 1999.   82. Chen W, Havell EA, Harmsen AG: Importance of endogeneous tumor necrosis factor and gamma interferon in host resistance against Pneumocystis carinii infection. Infect Immun 60:1279-1284, 1992.   83. Allendoerfer R, Deepe GS: Blockade of endogenous TNF-α exacerbates primary and secondary pulmonary histoplasmosis by differential mechanisms. J Immunol 160:6072-6082, 1998.   84. Rothe J, Lesslauer W, Lotscher H, et al: Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature 364:798-802, 1993.   85. Skerret SJ, Bagby GJ, Schmidt RA, Nelson S: Antibody-mediated depletion of tumour necrosis factor impairs pulmonary host defenses to Legionella pneumophila. J Infect Dis 176:1019-1028, 1997.

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  86. Wolfe F, Mitchell D, Sibley J: The mortality of rheumatoid arthritis. Arthritis Rheum 37:481-494, 1994.   87. Doran MF, Crowson CS, Pond GR, et al: Frequency of infection in patients with rheumatoid arthritis compared with controls. Arthritis Rheum 46:2287-2293, 2002.   88. Jeurissan ME, Boerbooms AM, van de Putte LB, et al: Methotrexate versus azathioprine in the treatment of rheumatoid arthritis: A forty week randomized, double blind trial. Arthritis Rheum 34:961-972, 1991.   89. Bongartz T, Suttin A, Sweetings MJ, et al: Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies. JAMA 295:2275-2285, 2006.   90. Listing J, Strangfeld A, Kary S, et al: Infections in patients with rheumatoid arthritis treated with biologic agents. Arthritis Rheum 52:3403-3412, 2005.   91. Dixon WG, Watson K, Lunt M, et al: Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: Results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 54:2368-2376, 2006.   92. Keane J, Gerson S, Wise RP, et al: Tuberculosis associated with in­fliximab, a tumor necrosis factor α-neutralizing agent. N Engl J Med 345:1098-1104, 2001.   93. Wolfe F, Michaud K, Anderson J, Urbansky K: Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum 50:372-379, 2004.   94. Keane J: TNF-blocking agents and tuberculosis: New drugs illuminate an old topic. Rheumatology 44:714-720, 2005.   95. Bieber J, Kavanaugh A: Consideration of the risk and treatment of tuberculosis in patients with rheumatoid arthritis receiving biologic treatments. Rheum Dis Clin North Am 30:257-270, 2004.   96. Carmona L, Gomez-Reino JJ, RodriguezValverde V, et al: Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum 52:1766-1772, 2005.   97. Saukkonen JJ, Cohn DL, Jasmer M, et al: An official ATS statement: Hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 174:935-952, 2006.   98. Wolfe F, Michaud K: Lymphoma in rheumatoid arthritis. Arthritis Rheum 50:1740-1751, 2004.   99. Askling J, Fored CM, Baeklung E, et al: Haematopoietic malignancies in rheumatoid arthritis: Lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists. Ann Rheum Dis 64:1414-1420, 2005. 100. Charles PJ, Smeenk RJT, De Jong J, et al: Assessment of antibodies to DsDNA induced in rheumatoid arthritis (RA) patients following treatment with infliximab, a monoclonal antibody to TNF alpha. Arthritis Rheum 43:2383-2390, 2000. 101. Mohan N, Edwards ET, Cupps TR, et al: Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 44:2862-2869, 2001. 102. van Oosten BW, Barkhof F, Truyen L, et al: Increased MRI activity and immune activation in two multiple sclerosis patients treated with monoclonal anti-tumor necrosis factor antibody cA2. Neurology 47:1531-1534, 1996. 103. The Lenercept Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group: TNF neutralization in MS: Results of a randomized, placebo-controlled multicenter trial. Neurology 53:457-465, 1999. 104. Wolfe F, Michaud K: Heart failure in rheumatoid arthritis: Rates, predictors, and the effect of anti-TNF therapy. Am J Med 116: 305-311, 2004. 105. Dinarello P: Interleukin-18 and the treatment of rheumatoid arthritis. Rheum Dis Clin North Am 30:417-434, 2004. 106. Campion GV, Lebsack ME, Lookabaugh J, et al: Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. Arthritis Rheum 39:1092-1202, 1996. 107. Bresnihan B, Alvaro-Garcia JM, Cobby M, et al: Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 41:2196-2204, 1998. 108. Jiang Y, Genant HK, Watt I, et al: A multicenter, double-blind, dose raging, randomized and placebo controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: Radiologic progression and correlation of Genant and Larsen scoring methods. Arthritis Rheum 43:1001-1009, 2000.

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109. Kavanaugh A: Anakinra (interleukin-1 receptor antagonist) has positive effects on function and quality of life in patients with rheumatoid arthritis. Adv Ther 23:208-217, 2006. 110. Metyas SK, Hoffman HM: Anakinra prevents symptoms of familial cold autoinflammatory syndrome and Raynaud’s disease. J Rheumatol 33:2085-2087, 2006. 111. Hawkins PN, Lachmann HJ, Aganna E, McDermott MF: Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum 50:607-611, 2004. 112. Fitzgerald AA, Leclerc SA, Yan A, et al: Rapid responses to anakinra in patients with refractory adult-onset Still’s disease. Arthritis Rheum 52:1794-1803, 2005. 113. Bingham C III, Genovese M, Moreland L, et al: Results of a phase II study of interleukin-1 (IL1)-Trap in moderate to severe rheumatoid arthritis [abstract]. Arthritis Rheum 50:517, 2004. 114. Fleischmann RM, Tesser J, Schiff MH, et al: Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann Rheum Dis 65:1006-1012, 2006. 115. Genovese M, Cohen S, Moreland L, et al: Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 50:1412-1419, 2004. 116. Kavanaugh A: The pharmacoeconomics of newer therapeutics for rheumatic diseases. Rheum Dis Clin North Am 32:45-56, 2006.

117. Choy EHS, Isenberg DA, Garrood T, et al: Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: A randomized, doubleblind, placebo-controlled, dose-escalation trial. Arthritis Rheum 46:3143-3150, 2002. 118. Nishimoto N, Yoshizaki K, Miyasaka N, et al: Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: A multicenter, double-blind, placebo-controlled trial. Arthritis Rheum 50:1761-1769, 2004. 119. Nishimoto N, Miyasaka N, Yamamoto K, et al: Long-term safety and efficacy of tocilizumab (an anti-IL-6 receptor monoclonal antibody) in monotherapy in patients with rheumatoid arthritis. Ann Rheum Dis 66(Suppl II):OP0227, 2007. 120. Maini RN, Taylor PC, Szechinski J, et al: Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 54: 2817-2829, 2006. 121. Nishimoto N, Hashimoto J, Miyasaka N, et al: Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): Evidence of clinical and radiographic benefit from an X-ray reader-blinded controlled trial of tocilizumab. Ann Rheum Dis (E pub ahead of print May 7, 2007).

59

Cell-Targeted Biologics and Emerging Targets: Rituximab, Abatacept, and Other Biologics Peter C. Taylor

KEY POINTS Clinical trials in active, established rheumatoid arthritis (RA) confirm that a single cycle of rituximab given as two infusions of 1 g each, together with once-weekly oral methotrexate, produces an enduring clinical response comparable to that observed with tumor necrosis factor (TNF) blockade. Current data suggest that the most appropriate interval ­between rituximab courses is 6 to 12 months. Repeat treatment produces American College of Rheumatology responses that equal or exceed those from the first course of treatment, with a comparable duration of effect. Rituximab has an acceptable safety record in RA trials, but infusion reactions of variable severity can occur; the majority are mild to moderate. Frequency and severity are reduced by the administration of intravenous methylprednisolone before rituximab infusions. Current uncertainties include how to treat rituximab failures and the lack of reliable biomarkers to inform the rational choice of a biologic agent. Clinical trials in active, established RA confirm that abatacept can result in a meaningful clinical response within 16 weeks, although additional improvement may occur for a year or beyond. Abatacept has an acceptable safety record in RA trials. It is ­administered as a 30-minute intravenous infusion that is ­usually without complications. Both rituximab and abatacept slow radiographic progression in RA. Current uncertainties include how and when abatacept should be started after rituximab is stopped and whether abatacept can be used in patients in whom anti-TNF therapy is contraindicated because of moderate to severe heart ­failure, a history of demyelination, or tuberculosis.

As appreciation of the gravity of the social and economic burden imposed by rheumatoid arthritis (RA) has grown, so has the recognition that more favorable clinical outcomes are achieved when synovitis is optimally suppressed. The evidence is particularly compelling early in the course of RA, when intervention with disease-modifying combination therapy results in improved remission rates and increased clinical and radiographic benefits.1-3 The ar­mamentarium of potential therapeutics has also grown with the identification of relevant disease molecules. Of these, biologic ­therapeutics targeting tumor necrosis factor-α (TNF-α), particularly when used in combination with oral meth­otrexate,

have enjoyed notable success in suppressing inflammation and markedly inhibiting the progression of structural damage previously thought to be an unavoidable characteristic of RA.4,5 However, despite the unprecedented clinical and commercial successes of TNF inhibitors, their availability is restricted by high costs. In addition, a substantial pro­portion of RA patients fail to demonstrate significant cl­inical responses. An entirely different treatment approach to the blockade of proinflammatory cytokines is the targeting of cells implicated in the persistence of RA. It is believed that immune responses drive the disease process in RA, and because chronicity is a hallmark of the RA phenotype, it presumably reflects the persistence of immunologic ­memory, induced and maintained by the adaptive immune system. In pa­rticular, T and B cells develop highly specific receptors and, after stimulation, expand enormously in number and then persist for long periods. If this is true of aberrant immune responses that lead to disease, then T and B cells represent rational targets for immune intervention. The focus of this chapter is on biologics with specificity for cellular targets, with a pa­rticular emphasis on two drugs that have recently been added to the pharmacologic armamentarium for RA treatment: rituximab and abatacept. Rituximab (Rituxan, Genentech Inc. and Biogen Idec Inc.; MabThera, F-­Hoffman LaRoche Ltd.) is an antibody that selectively depletes a B cell subset. Abatacept (Orencia, Bristol-Myers Squibb) is a fusion protein that selectively modulates a costim­ulatory signal necessary for T cell activation. Rituximab is approved in the United States and Europe for use in combination with methotrexate to reduce the signs and symptoms of RA in adult patients who have moderately to severely active d­isease and have failed one or more anti-TNF drugs. Abatacept is the first selective costimulation modulator to be approved in the United States for the treatment of RA patients with an inadequate response to other nonbiologic or biologic disease-modifying antirheumatic drugs.

TARGETING B CELLS The role of B cells in the pathogenesis of RA is not fully understood. Nonetheless, there are a number of known B cell functions of likely relevance, including their role in antigen presentation, secretion of proinflammatory cy­tokines, production of rheumatoid factor and thus immune complex formation, and costimulation of T cells. Of note, immune complexes are an important trigger to the production of TNF and other proinflammatory cytokines. B cells are also implicated in the process of ectopic ­lymphoid organogenesis in the rheumatoid synovium. 947

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B cells arise from stem cells in the bone marrow, where they acquire an antibody receptor bearing a unique variable region. A number of maturation and activation steps take place as the B cells migrate from the marrow compartment, through blood, and to perifollicular germinal centers and memory compartments in lymphoid tissue, before returning to the marrow as mature plasma cells.6 Successful maturation and survival of cells are tightly regulated and dependent on a number of trophic signals delivered via cell surface ligands, such as vascular cell adhesion molecule1 (VCAM-1), and soluble factors, such as B lymphocyte stimulator (BLyS).7,8 In the late 1990s, Edwards and colleagues9,10 suggested that the (assumed) underlying autoreactive response in RA might be driven by self-perpetuating B cells and that the initiation of inflammation results from ligation of the low-affinity immunoglobulin G (IgG) receptor FcRγIIIa by immune complexes. An attractive feature of this ­hypothesis, particularly in seropositive patients, is that it might account for the tissue tropisms of disease expression in the RA syndrome complex, because FcRγIIIa is expressed in high levels in synovium and other extra-articular tissues that may be involved in RA. Rheumatoid factor–­producing cells can capture antibodies bound to antigen before antigen internalization by endocytosis and subsequent presentation of peptide fragments to a T cell, with provision of T cell help to the B cell. Edwards and colleagues11 also proposed that such rheumatoid factor–producing B cells might become self-perpetuating by an amplification signal arising from coligation of the B cell receptor and small immune complexes formed by IgG rheumatoid factor bound to the complement component C3d, providing a survival signal. In contrast, co­ligation of certain other B cell surface receptors with the B cell receptor may provide a negative survival signal. In the rare event that self-perpetuating, autoreactive B cells arise, having escaped normal regulatory mechanisms, this theory predicts that a B cell depletion strategy would remove the autoreactive B cell clones and their antibody products. Because CD20 is not internalized and is highly expressed on a range of B lineage cells, including pre-B cells, immature B cells, activated cells, and memory cells, but is not found on stem, dendritic, or plasma cells (Fig. 59-1), it is an ideal target for B cell depletion by monoclonal an­tibodies. The hypothesis that B cells represent a therapeutic target in RA is also being tested in the clinic using other strategies for B cell inhibition, as discussed later. The CD20 antigen is located in the B cell membrane, with 44 amino acids exposed to the extracellular space. Its function is unknown, although it may have a role in cell signaling or in calcium mobilization.12 Interestingly, CD20 knockout mice do not have a clear-cut phenotype or ob­vious B cell defect.13 CD20+ B cells represent a prominent population in the rheumatoid synovial tissue in the majority of patients. RITUXIMAB IN RHEUMATOID ARTHRITIS Rituximab is a chimeric mouse-human monoclonal an­tibody directed against the extracellular domain of the CD20 antigen. It initiates complement-mediated B cell lysis and may permit antibody-dependent, cell-mediated cytotoxicity­

CD20 expression during the maturation of B cells

Activated Plasma Cell surface Stem Pro B Pre B Immature Memory antigens CD19 CD20 CD24 CD38 CD39 Figure 59-1  Expression of the CD20 antigen on B lineage cells.

when the Fc portion of the antibody is recognized by corresponding receptors on cytotoxic cells. Rituximab may also initiate apoptosis14 and influence the ability of B cells to respond to antigen or other stimuli.15 Rituximab initially found a role in the clinic as a single-agent treatment for relapsed or refractory low-grade or follicular CD20+ B cell non-Hodgkin’s lymphoma, for which it was approved. For this reason, there was a wide experience with rituximab in hematologic oncology before clinical trials in RA and its recent approval in the United States and Europe for the treatment of TNF inhibitor–refractory RA patients with active disease. Clinical Studies The clinical effects of B cell depletion therapy using rituximab in a number of different treatment regimens have been reported in patients with active RA, with encouraging data emerging. In 2001, Edwards and Cambridge16 reported their findings in five patients with severe, long-standing, refractory RA despite treatment with at least five previous diseasemodifying antirheumatic drugs (DMARDs); these patients received rituximab in combination with oral prednisolone and pulsed intravenous cyclophosphamide, based on the rituximab-CHOP regimen used in non-Hodgkin’s lymphoma patients. Up to four intravenous infusions of rituximab were administered: 300 mg on day 2, and 600 mg on days 8, 15, and 22. Oral prednisone at a dose of 30 to 60 mg was given on days 1 to 22, and 750 mg intravenous cyclophosphamide was given on days 4 and 17. At 6 months, all five patients achieved an American College of Rheumatology (ACR)-50 response; of these, three patients achieved the more stringent ACR-70 response and maintained that response at 1 year. The two patients with ACR-50 responses relapsed, but both achieved ACR-70 on re-treatment. In this small series, there were no major adverse events and no infusion-related events. However, the use of steroids and cyclophosphamide precludes any conclusions regarding rituximab’s co­ntribution to the observed benefit. The findings of two other small, open-label studies were published in 2002. De Vita and colleagues17 used rituximab (four weekly intravenous infusions of 375 mg/m2) to treat five patients with active RA despite combination treatment with methotrexate and cyclosporine; two of these patients were nonresponders to anti-TNF therapy. One patient had an ACR-70 response (lasting 10 months), and

PART 8 

one had an ACR-50 response (lasting 1 year). Two other patients had ACR-20 responses. Leandro and colleagues18 reported their findings following treatment with one of five different co­mbinations of rituximab, cyclophosphamide and oral prednisone in 22 patients with long-standing, active RA despite treatment with at least two DMARDs. At 6 months, 16, 13, and 8 patients achieved ACR-20, -50, and -70 responses, respectively. No major adverse events were reported, but nonserious infections occurred in five patients and mild to moderate nausea in seven patients. These encouraging findings with an acceptable safety profile pointed to a possible therapeutic role for rituximab in RA. Confirmation of benefit, however, required a randomized, double-blind, controlled study. In a phase IIa study, the efficacy of rituximab in active RA was tested in 161 patients who had failed to respond adequately to methotrexate at a dose of at least 10 mg a week for a minimum of 16 weeks.19 Patients were assigned to one of four treatment regimens: 1- g infusion of intravenous rituximab alone on days 1 and 15, methotrexate alone as a comparison arm, intravenous rituximab with cyclophosphamide infusions at a dose of 750 mg on days 3 and 17, or rituximab and methotrexate. All patients received 100 mg methylprednisolone just before each treatment, in addition to prednisolone 60 mg daily on days 2, 4, 5, 6, and 7 and 30 mg daily on days 8 to 14. The primary end point was the proportion of patients achieving an ACR-50 response at week 24, and exploratory analyses were undertaken at week 48. At week 24, a significantly greater proportion of patients achieved an ACR-50 in the rituximab and methotrexate combination group (43%; P = .005) and the rituximab and cyclophosphamide combination group (41%; P = .005) than in the group receiving methotrexate as monotherapy (13%) (Table 59-1). Thir­tythree percent of the patients receiving rituximab alone achieved an ACR-50 response, but this failed to reach statistical significance compared with methotrexate alone (P = .059). In all the rituximab groups, the mean change from baseline in disease activity score was significant compared with methotrexate alone. At 48 weeks, exploratory analyses indicated ACR-50 and -70 responses in 35% and 15%, respectively, of patients in the rituximab and methotrexate group—significantly greater than the 5% and 0% responding at the corresponding levels in the methotrexate group. In the rituximab and cyclophosphamide treatment arm, 27% of patients achieved an ACR-50 response. Rituximab treatment was associated with near-­complete peripheral blood B cell depletion, persisting throughout the 24-week period of the primary analysis. Patients in the rituximab groups had a substantial and rapid reduction in the

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concentration of rheumatoid factor in serum, but despite peripheral B cell depletion, immunoglobulin ­levels did not change substantially.19 The overall incidence of infection was similar in the control and rituximab groups at 24 and 48 weeks. By week 24, four patients in the rituximab groups had suffered a serious infection, and one in the ­ control group. Two additional serious infections were reported during the extended 48-week period in the ­ rituximab groups, one of which was fatal. Infusion reactions of any type were reported in 36% of patients receiving rituximab and 30% of patients receiving placebo, although most were characterized as mild or moderate. The reactions included hypotension, hypertension, flushing, pruritus, and rash. In the rare case of severe reactions, it has been suggested that a cytokine release syndrome ­associated with marked cell lysis following rituximab might be a ­contributing factor. In summary, the findings of the phase IIa study indicated that a single course of treatment with rituximab, particularly in combination with methotrexate, produces an enduring response in patients with severe, seropositive, active RA. Further, treatment with rituximab was well tolerated, with a favorable safety profile over 48 weeks of follow-up. To follow up the phase IIa study, a phase IIb study was undertaken to examine the efficacy and safety of rituximab at different doses, with or without glucocorticorticoids, in patients with active RA resistant to DMARDs, including biologics. The findings of this phase IIb study, known as the DANCER (Dose-ranging Assessment: International Clinical Evaluation of Rituximab in RA) trial, were recently reported.20 A total of 465 patients with active disease were recruited. They had to have failed at least one DMARD other than methotrexate, but no more than five, or failed to respond to biologic response modifiers, and they had to have been treated with methotrexate as a single DMARD for at least 12 weeks, with 4 weeks of stable therapy at a dose of at least 10 mg a week. All other DMARDs were withdrawn at least 4 weeks before randomization—8 weeks for infliximab, adalimumab, and leflunomide. Patients were randomized to receive either placebo infusions or rituximab at a dose of 500 mg or 1 g on days 1 and 15, together with one of three glucocorticoid options: glucocorticoid placebo, 100 mg of intravenous methylprednisolone before each rituximab infusion, or 100 mg of methylprednisolone before each infusion in addition to an oral corticosteroid. The results at 24 weeks confirmed the significant efficacy of a single course of rituximab in active RA when combined with methotrexate. This benefit was independent of glucocorticoids, although m­ethylprednisolone on day 1 reduced the incidence and severity of first rituximab infusion reactions by about one third (Fig. 59-2). Both rituximab doses

Table 59-1  Percentage of Patients Achieving Responses at 24 Weeks in the DANCER and REFLEX Studies Study

Drug Regimen

ACR-20

ACR-50

ACR-70

Phase IIa Edwards et al19

1 g rituximab × 2 plus methotrexate Methotrexate

73 38

43 13

23 5

Phase IIb DANCER20

1 g rituximab × 2 plus methotrexate Methotrexate

54 28

34 13

20 5

Phase III REFLEX21

1 g rituximab × 2 plus methotrexate Methotrexate

51 18

27 5

12 1

ACR, American College of Rheumatology; DANCER, Dose-ranging Assessment: International Clinical Evaluation of Rituximab in Rheumatoid Arthritis; REFLEX, Randomized Evaluation of Long-term Efficacy of Rituximab in Rheumatoid Arthritis.

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Second infusion

First infusion

50

46 39

40 Percent of patients

35 32 30

20

27

25

Placebo Rituximab 2 x 500 mg Rituximab 2 x 1000 mg

26

17

16 12

10

10

8

10

10

14

12

5 2 0

GC placebo

GC IV premedication

GC IV GC placebo GC IV GC IV premedication premedication premedication + oral + oral Figure 59-2  DANCER infusion reactions. Chart showing the occurrence of infusion reactions in the DANCER (Dose-ranging Assessment: International Clinical Evaluation of Rituximab in RA) trial, a phase IIb study undertaken to examine the efficacy and safety of rituximab at two doses, with or without glucocorticoids (GCs), in patients with active rheumatoid arthrits (RA) resistant to disease-modifying antirheumatic drugs (DMARDs), including biologics. Patients were randomized to receive either placebo infusions or rituximab at a dose of 500 mg or 1 g on days 1 and 15, together with one of three glucocorticoid options: glucocorticoid placebo, 100 mg intravenous methylprednisolone before each rituximab infusion, or 100 mg methylprednisolone before each infusion in addition to oral corticosteroid. Pretreatment with methylprednisolone before rituximab infusion reduced the incidence and severity of reactions by about one third. (Based on data in Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al [for the DANCER study group]: The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: Results of a phase IIB randomized, double-blind, placebocontrolled, dose-ranging study. Arthritis Rheum 54:1390-1400, 2006.)

0 Mean change in DAS28

were efficacious. At the lower dose, 55% of recipients achieved ACR-20 responses, as did 54% of those at the higher rituximab dose—in both cases, significantly greater than the 28% of those receiving placebo infusions. Similarly, significantly higher proportions of patients achieved ACR-50, ACR-70 (see Table 59-1), and EULAR good responses at 24 weeks at both rituximab doses compared with patients receiving placebo infusions (Fig. 59-3). At the most stringent ACR-70 response level, the difference in the percentage of responders in the placebo, lower dose rituximab, and higher dose rituximab groups was most marked at the higher rituximab dose of 1 g 2 weeks apart (5%, 13%, and 20% respectively, P < .05). Adverse events reported up to 24 weeks were largely infusion related, particularly at the time of the first infusion. Primary efficacy and safety data at 24 weeks into a phase III trial were recently published.21 Supplementary data at 12 months of follow-up have been presented at international meetings.22 This trial, known by the acronym REFLEX (Randomized Evaluation of Long-term Efficacy of Rituximab in RA), was designed to determine the efficacy and safety of rituximab when used in combination with methotrexate in patients with active RA who have an inadequate response to one or more anti-TNF therapies because of either lack of efficacy (90% of patients recruited) or toxicity (10% of patients recruited); in addition, all patients had radiographic evidence of at least one joint with definite erosion attributable to RA (Fig. 59-4). The recruited cohort comprised 520 patients with a mean disease duration of 12 years on a background regimen of methotrexate 10 to 25 mg once a week. After

Placebo (n=122)

Rituximab 2 x 500 mg (n=123)

Rituximab 2 x 1000 mg (n=122)

-0.5 -1.0

-0.67

-1.5 -2.0

-1.79 -2.05

-2.5 Figure 59-3  DANCER changes in DAS-28 at 6 months. Mean changes in disease activity score (DAS-28) from baseline in the phase IIb DANCER study were significantly greater in patients treated with two rituximab infusions 2 weeks apart at either 500 mg or 1 g each, compared with placebo infusions (P < .0001). (Based on data in Emery P, Fleischmann R, ­Filipowicz-Sosnowska A, et al [for the DANCER study group]: The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: Results of a phase IIB randomized, double-blind, placebocontrolled, dose-ranging study. Arthritis Rheum 54:1390-1400, 2006.)

a washout period during which other DMARDs and antiTNF drugs were withdrawn, patients were randomized to receive a single course of 1g rituximab or placebo infusions on days 1 and 15. All patients were given 100 mg intravenous methylprednisolone before each infusion and a brief course of oral prednisolone between the two doses: 60 mg daily from days 2 to 7, and 30 mg daily from days 8 to 14.21

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Screen: anti-TNF and/or DMARD withdrawal period

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MODALITIES OF THERAPY IN RHEUMATIC DISEASE

Treatment period

Ramdomization

951

Post-treatment period

Rituximab + MTX (group A) n=300 Methotrexate (MTX) for ≥ 3 months

Visits every 2 months Placebo + MTX (group B) n=200

Screen

Day Day Wk Wk Wk Wk Wk Wk 8 12 16 20 24 1 15 4

Rituximab or placebo infusion

Month 24

Rescue therapy

Clinic visit Group B: Rituximab + MTX

Primary efficacy timepoint

Group A: Standard of care Figure 59-4  REFLEX study design. Scheme illustrating the phase III REFLEX (Randomized Evaluation of Long-term Efficacy of Rituximab in RA) study designed to determine the efficacy and safety of rituximab when used in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who have an inadequate response to one or more anti–tumor necrosis factor (TNF) therapies. DMARD, disease-modifying antirheumatic drug.

Of the patients assigned to rituximab, 82% completed 6 months, compared with only 54% of the patients assigned to placebo. The major reason for study withdrawal was lack of response, reported in 40% of the placebo group and 12% in the rituximab group. At 6 months, significantly more patients receiving rituximab achieved ACR-20, -50, and -70 responses than did those receiving placebo: 51%, 27%, and 12%, respectively, on rituximab, versus 18%, 5%, and 1% of those on placebo (see Table 59-1). In terms of change in disease activity score (DAS-28), intention-to-treat analyses showed that in patients administered placebo infusions, the reduction from baseline was 0.34, less than the 0.6-point reduction considered to be clinically meaningful; in contrast, the reduction was 1.83 in the rituximab group.21 The ACR response evaluates RA treatment based on a 20%, 50%, or 70% improvement in five of seven core co­mponents. However, from the patient’s perspective, determining the actual benefit of an ACR-20 improvement is not straightforward. In the REFLEX study, there were significantly greater improvements in all components of the ACR core measures in the rituximab group. Rituximab demonstrated a clinically meaningful benefit for RA patients in physical function evaluated by a health assessment questionnaire (HAQ) in all nonoverlapping ACR response categories. In the active treatment arm, both clinical and subjective parameters of the ACR core components contributed to the assignment of an ACR-20 response, whereas in the placebo group, the subjective parameters dominated.21 In the REFLEX study, following a single treatment course, the maximal clinical response to rituximab plus methotrexate was observed at 24 weeks. After this time, patients were eligible to exit the study and receive further rituximab treatment based on clinical need. Of the patients in the rituximab plus methotrexate group, 37% (114 of 308) remained in the study over 48 weeks, indicating continued

clinical benefit after the single initial treatment course. The majority of patients who withdrew did so to receive further courses of rituximab between weeks 24 and 48 of the study. In contrast, 89% of the placebo plus methotrexate group (185 of 209) withdrew before week 48.22 Disease Modification The extraordinary success of TNF blockade in inhibiting structural damage to joints in patients with RA has set a new standard to which all new biologics must aspire. Preliminary analyses of REFLEX radiographic data at 1 year have been presented, with encouraging findings.23 At week 56, the mean change in Genant-modified Sharp score in the placebo plus methotrexate arm was 2.31, compared with 1.0 in the rituximab plus methotrexate group (P = .0043). Significant differences were also reported for joint space narrowing and bone erosions. The proportion of patients with no progression in erosion was 61% in the rituximab arm, versus 52% in the placebo arm. These represent the first data that B cell depletion therapy can inhibit progressive destruction to joints in a population refractory to anti-TNF treatment. Safety Issues A common concern regarding all therapies directed at B cells is the potential for toxicity related to modulation of humoral immunity. Unlike other newly introduced biologic therapies for RA, rituximab has the considerable advantage of an oncology safety database based on more than 350,000 non-Hodgkin’s lymphoma patient treatments since 1997.24 The overall safety conclusions are that serious adverse events are infrequent and often associated with well-defined risk factors such as cardiopulmonary disease or a high number of circulating cancer cells. Of note, in the lymphoma

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po­pulation, prolonged peripheral B cell depletion has not been associated with cumulative toxicity or increased occurrence of opportunist infections.25-27 However, it cannot be assumed that the toxicity profile will be identical in distinct disease phenotypes with differing pathogenic processes. In RA open-label,28 phase II,19,20 and phase III21 studies, although decreases in total serum immunoglobulin levels were observed in patients receiving rituximab, concentrations remained within normal limits. Of note, existing antibody titers against tetanus toxoid appear to be unaffected by a single course of rituximab treatment.29 However, there is some anecdotal evidence that total serum immunoglo­bulin concentrations fall below the normal range in patients receiving multiple cycles of rituximab treatment over a number of years in open-label studies.11 It is unclear whether this results in an increased risk of infection. In phase II studies, the majority of adverse events were mild to moderate and associated with infusions, including headache, nausea, and rigors. In the DANCER trial, adverse events associated with rituximab were largely associated with the first infusion; these occurred in 39% of patients treated with 500 mg (without steroid) and in 46% receiving 1 g, compared with 17% administered placebo infusions.20 The corresponding incidence with the second infusion decreased to 5%, 8%, and 10%, respectively. Two serious infusion reactions, hypersensitivity and generalized edema, occurred on day 1. Pretreatment with methylprednisolone reduced the incidence and severity of reactions by about one third (see Fig. 59-2). Infectious adverse events (largely upper respiratory tract infections) were reported in 28% of placebo and 35% of rituximab patients. There were six serious infections: two in the placebo group, four in patients receiving 1000 mg rituximab, and none in patients receiving 500 mg rituximab. No opportunistic infections or tuberculosis reactivations were reported. Duration of Benefit Among RA patients achieving clinical responses to rituximab treatment, the time to clinical relapse is heterogeneous. In some patients, relapse is closely correlated to the reappearance of peripheral blood B cells, but in others, it may be delayed by years.30 Clinical relapse is more closely associated with increases in autoantibody levels, but better biomarkers are needed to reliably inform optimal management strategies on an individual basis. All B cell populations are depleted following rituximab therapy. Of residual B lineage cells, more than 80% exhibit a memory or plasma cell precursor phenotype.31 B cell repopulation occurs at a mean of 8 months after rituximab therapy and depends on the formation of naive B cells of an immature phenotype resembling those found in umbilical cord blood. Peripheral B cell depletion is accompanied by substantial increases in blood BLyS concentrations, which tend to fall with B cell repopulation.32 BLyS is a naturally occurring protein required for the development of B lymphocytes into mature plasma cells. Elevated levels of BLyS in RA are believed to contribute to the production of autoantibodies. However, in cases of prolonged clinical responses to rituximab, more gradual reductions in BLyS concentrations have been observed, extending beyond the period of B cell depletion. Thus, BLyS may contribute to the survival or regeneration

of pathogenic, autoreactive B cells. This hypothesis predicts a potential therapeutic role for BLyS blockade in addition to B cell depletion. Current Role Recent advances in the understanding of the pathogenesis of RA emphasize the critical role of B cells in self-­sustaining chronic inflammatory processes. Rituximab is a promising addition to the therapeutic ­ armamentarium for the treatment of RA. It is not clear at this point to what extent ritux­ imab’s efficacy differs in rheumatoid factor–positive and –negative patients, although data from the REFLEX study indicate that the effect of treatment on ACR responses was not dependent on baseline rheumatoid factor status.21 How­ever, new data were recently presented from a study exploring the relationship between baseline ­autoantibodies (rheumatoid factor and anti–cyclic citrullinated peptide [anti-CCP] antibodies) and clinical response after the first cycle of rituximab treatment in RA patients with an inadequate response to one or more anti-TNF agents.33 Patients seronegative for both types of autoantibodies achieved some clinical benefit (28% ACR-20 responses at week 24 after rituximab, versus 6% after placebo), but the ACR responses were lower than in patients seropositive for one or both antibodies (50% ACR-20 responses at week 24 after rituximab, versus 18% after placebo). Higher level ACR responses were not seen in the group seronegative for rheumatoid factor and anti-CCP. These observations generate the hypothesis that other mechanisms may account for lower levels of response, such as antigen presentation, costimulation, and cytokine drive, whereas high levels of response to rituximab therapy may be mediated primarily by the suppression of pathogenic antibodies. The optimal and most cost-effective dosing regimen for rituximab remains a matter of debate. However, based on the DANCER study findings, it is recommended that rituximab be given in combination with once-weekly methotrexate, usually at doses of at least 15 mg/week, to optimize efficacy. Further, administration of 100 mg intravenous methylprednisolone is recommended before each rituximab infusion to reduce the frequency and severity of infusion reactions. The optimal dose of each of the two rituximab infusions given 2 weeks apart is 1 g, based on the slightly higher proportion of ACR-70 responses in the DANCER study; however, the proportion of ACR-20 and ACR-50 responses was essentially the same, and the lower 500-mg dose of rituximab has the advantages of lower cost and possibly a lower rate of serious adverse events. Further studies in the postlicensing phase should help clarify these issues. It is likely that in clinical practice, the major use for rituximab in the treatment of RA will be confined to the TNF inhibitor–refractory population in the short term, until there is broader experience and confidence regarding potential adverse effects. It may also have a role in those patients for whom TNF blockade is relatively contraindicated, such as those with connective tissue disease overlap syndromes. At present, there are uncertainties about the implications of long-term peripheral B cell depletion and the timing and need for redosing with rituximab in patients who respond. Current research suggests that restoration of peripheral B cell numbers takes about

PART 8 

8 months after depletion tr­eatment, although retreatment may be needed earlier. Preliminary results have been presented for an open-label study to evaluate the response to repeated courses of rituximab in patients with active RA participating in one of several phase II or III studies and to determine the optimal frequency for repeated treatment.34 In a series of 155 patients with prior exposure to TNF inhibitors, ACR-20, -50, and -70 scores were 65%, 33%, and 12%, respectively, following the first course; they were 72%, 42%, and 21%, respectively, for the second treatment course, relative to the original baseline. In 82 of these patients who received a third course of rituximab, the median interval between first and second courses was very similar to that between second and third courses: 30 to 31 weeks.34 Further studies are needed to identify the optimal regimens for maintenance therapy that will provide efficacy and limit toxicity. Although the available safety data for rituximab in RA are reassuring, they need to be interpreted with caution until larger numbers have been treated and long-term safety and retreatment data become available. Further, there is a substantial body of safety data for rituximab in the treatment of non-Hodgkin’s lymphoma, with similarly low infection rates reported. In oncology, some of the associated adverse events are related to circulating tumor loads. Overall, this is reassuring with regard to the RA population, although close monitoring of immunocompetence and for the possibility of rare opportunistic infections is advisable. Future Directions Initially, rituximab, in combination with methotrexate, will be used as a second-line biologic, after one or more anti-TNF drugs, in the treatment of active RA.35 However, as physicians become more experienced with its use, and assuming that no new safety issues come to light, it is likely that interest in its potential as a first-line biologic will increase. Evidence to support this shift will include any competitive health economic data compared with TNF inhibitors and efficacy data in early disease. A key issue will be determining the most effective strategy in early stages of RA to induce a biologic-free remission and whether this can be achieved safely and effectively with rituximab. In the much longer term, the continued success of rituximab will depend on efficacy in clinical trials and safety data for other antibodies targeting CD20, such as ocrelizumab, a humanized version of rituximab, and HuMax-CD20/ofatumumab, a fully human anti-CD20 that is also in clinical trials but still some time away from reaching the clinic. It is conceivable that the delivery of such antibodies will have a lower rate of infusion (or injection) reactions, although this is unlikely if the infusion reactions observed with rituximab are the consequence of B cell lysis. In any event, such reactions are generally mild, so any differences between these agents may not be of great clinical importance. Although many other approaches to B cell–targeted therapy are in clinical testing, it is unlikely that any of these will significantly impact the rituximab niche in the near future. Alternative strategies to target the B cell compartment include the use of antibodies to CD22 and BlyS. Belimumab, or LymphoStat-B, is a human anti-BLyS monoclonal antibody currently in clinical development

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for the treatment of RA and other rheumatic indications. An alternative approach to BLyS inhibition that is still in the early stages of clinical development is to block signaling through BLyS receptors using a soluble receptor such as transmembrane activator and calcium modulator and cyclophilin ligand interactor immunoglobulin. Preliminary results of a phase II double-blind, placebo-controlled study of belimumab in 283 active RA patients have been presented.36 Patients were randomized to receive intravenous belimumab at a dose of 1, 4, or 10 mg/kg or placebo infusions on days 0, 14, and 28, then every 28 days through 24 weeks. The ACR-20 response at week 24 in the combined belimumab groups was 29%, compared with 16% in the placebo group; no dose response was observed. The antibody was well tolerated. These preliminary findings with a functional inhibitor of B cells are surprising, given the effectiveness of rituximab; however, it may simply represent a pharmacokinetic problem indicating that the dose of belimumab was too low. RITUXIMAB IN OTHER RHEUMATIC CONDITIONS Rituximab has also been used in a number of other rheumatic diseases.11 Although all the data from controlled clinical trials are not yet available, preliminary data suggest that B cell depletion using rituximab might have efficacy for immune thrombocytopenia and systemic lupus erythematosus (SLE). Given the large body of evidence implicating abnormalities in the B cell compartment in SLE, a recent therapeutic focus has been to develop interventions that target the B cell compartment by multiple mechanisms, and rituximab has been studied most extensively. Although promising open-label data await confirmation in ongoing multicenter placebocontrolled trials, a number of preliminary conclusions can be drawn. The adequacy of peripheral B cell depletion depends on the achievement of high and sustained serum rituximab concentrations, pharmacokinetics that can be varied with treatment dose, and factors that may affect drug clearance, such as human antichimeric antibodies. In SLE patients with effective B cell depletion, the clinical response can be significant, with favorable responses observed in a diverse array of disease manifestations. Moreover, rituximab appears to be able to induce clinical remission in severe, refractory disease. B cell depletion has the potential to induce disease amelioration by inhibiting autoantibody production or by interfering with other B cell pathogenic functions. The fact that clinical improvement correlates with B cell depletion and precedes by several months any decline in serum levels of relevant autoantibodies suggests a predominant effect of autoantibody-independent functions of B cells; the subset of patients with disease remission ultimately experiences autoantibody normalization as well. Significant questions remain about rituximab therapy in SLE, including the immunologic determinants of treatment response and remission, the role of combination therapy, and the safety of repeated courses of rituximab. Rituximab has also been used in primary Sjögren’s syndrome; Wegener’s granulomatosis; hepatitis C–­associated cryoglobulinemia; antineutrophilic cytoplasmic ­ antibody– associated vasculitides other than Wegener’s, such as polyarteritis nodosa, dermatomyositis, and polymyositis37; antiphospholipid syndrome; and scleroderma.38

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TARGETING COSTIMULATORY MOLECULES Costimulation is an essential step in the induction of adaptive immune responses. Although the role of T cells in the perpetuation of RA has been debated and remains poorly understood, it has long been believed that T cell activation is a key event in the pathogenesis. Successful T cell activation requires multiple signals. One signal is provided by presentation of an antigen bound to cell surface major histocompatibility complex (MHC) molecules on antigen presenting cells to a specific T cell receptor. In the absence of further signals, T cells become unresponsive and may ultimately be eliminated through apoptosis. An important costimulatory signal is provided by an interaction between members of the B7 family (either CD80 or CD86) on antigen presenting cells and CD28 on T cells (Fig. 59-5). Other key interactions between antigen presenting cells and T cells are mediated by the binding of ICAM-1 to LFA-1, CD40 to CD40 ligand, LFA-3 to CD2, and so on. After activation, T cells express CTLA-4, which interferes with the B7-CD28 interaction and helps return the cells to the quiescent state. ABATACEPT IN RHEUMATOID ARTHRITIS Abatacept is a novel, fully human fusion protein comprising the extracellular portion of CTLA-4 and the Fc fragment of a human IgG-1 (CTLA4Ig). In December 2005, abatacept (Orencia) became the first costimulatory blocker to be approved by the U.S. Food and Drug Administration for the treatment of patients with RA who have had an inadequate response to other drugs. Abatacept binds to CD80 and CD86 on antigen presenting cells, thus preventing these molecules from binding their ligand, CD28, on T cells, with the consequent inhibition of optimal T cell activation. In

Nucleus

CD4 T cell Antigen presenting cell

MHC II

TCR Blocks activation

B7

CD28 (CD80/86) CTLA-4 (CD152)

Figure 59-5  Interactions between antigen presenting cells and T cells. Successful T cell activation requires multiple signals. One signal is provided by the presentation of an antigen bound to cell surface major histocompatibility complex (MHC) molecules on antigen presenting cells to a specific T cell receptor (TCR). In the absence of further signals, T cells become unresponsive and may ultimately be eliminated through apoptosis. An important costimulatory signal is provided by an interaction between members of the B7 family (either CD80 or CD86) on  antigen presenting cells and CD28 on T cells. After activation, T cells express CTLA4, which interferes with the B7-CD28 interaction and helps return the cells to the quiescent state.

vitro, abatacept decreases T cell proliferation and inhibits the production of TNF-α, interferon-γ, and interleukin (IL)-2. CTLA4Ig showed promising activity in rodent collagen-induced arthritis models, prompting its evaluation in several clinical trials in patients with RA.39,40 Clinical Studies Abatacept has been evaluated in five randomized, doubleblind, placebo-controlled trials in adults with active RA and an inadequate response to conventional DMARDs such as methotrexate or to TNF inhibitors. An initial 3-month, phase IIa, double-blind, randomized, placebo-controlled pilot study demonstrated the efficacy of B7 blockade in treating the signs and symptoms in patients with active RA despite treatment with at least one conventional DMARD.41 In this pilot study, the effect of one of two different biologic costimulatory modulators was compared with that of placebo infusions. The two biologic agents used were CTLA4Ig, which binds approximately fourfold less avidly to CD86 than to CD80, and LEA29Y (belatacept), a second-generation CTLA4Ig with two mutated amino acid residues conferring an increased avidity for CD86 over that of the parent molecule. Placebo or active drug was given at doses of 0.5, 2, or 10 mg/kg intravenously to 214 patients for a total of four infusions on days 1, 15, 29, and 57. Patients were evaluated on day 85. The proportion of patients achieving ACR-20 responses on day 85 was dose dependent: 23%, 44%, and 53% of abatacept-treated patients, and 34%, 45%, and 61% of LEA29Y-treated patients at 0.5, 2, and 10 mg/ kg, respectively. In contrast, 31% of placebo-treated patients achieved ACR-20 responses, suggesting clinical efficacy for both costimulatory blocking molecules, particularly at the higher doses, in the treatment of RA. The findings were confirmed in a multicenter phase IIb study of abatacept plus methotrexate in 339 patients with active RA despite methotrexate treatment.42 In this study, patients were randomized to receive infusions of placebo, abatacept 2 mg/kg, or abatacept 10 mg/kg at baseline, 2 weeks, 4 weeks, and then monthly through 6 months. ACR-20 responses were achieved in 60%, 41.9%, and 35.3% of patients receiving abatacept 10 mg/kg, abatacept 2 mg/kg, and placebo, respectively. At the more stringent ACR-50 response level, the figures were 36.5%, 22.9%, and 11.8% (Table 59-2). Improvements in the individual components of the ACR response criteria were generally greater in the 10 mg/kg group than the 2 mg/kg group. No deaths, malignancies, or opportunistic infections were reported for any patient receiving abatacept during the 6 months of therapy. Patients in the phase IIb study continued on blinded therapy for an additional 6 months, during which time response to therapy was maintained. For patients receiving abatacept 10 mg/kg, the ACR-70, -50, and -20 response rates were 21%, 42%, and 63%, respectively, compared with 8%, 20%, and 36% for patients receiving placebo infusions. Further, at the higher dose, statistically significant improvements in physical function and health-related quality of life were maintained over the 1-year period.43 In the phase IIb study, from day 90 onward, there were statistically significant and progressively rising differences in remission rates between the group receiving methotrexate plus abatacept 10 mg/kg and the group

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Table 59-2  Percentage of Patients Achieving Responses at 24 Weeks in the AIM and ATTAIN Studies Study

Drug Regimen

ACR-20

ACR-50

ACR-70

Phase IIb AIM42

Abatacept 10 mg/kg plus methotrexate Methotrexate

60

37

17

35

12

2

Phase III AIM45

Abatacept 10 mg/kg plus methotrexate Methotrexate

68

40

20

40

17

7

Phase III ATTAIN46

Abatacept 10 mg/kg plus methotrexate Methotrexate

50

20

10

20

4

1

ACR, American College of Rheumatology; AIM, Abatacept in Inadequate Responders to Methotrexate; ATTAIN, Abatacept Trial in Treatment of Anti-TNF Inadequate Responders.

assigned to methotrexate and placebo infusions. By 1 year of treatment, 34.8% of abatacept plus methotrexate patients achieved a DAS-28 remission (<2.6), in contrast to 10.1% of the methotrexate plus placebo patients (P < .001).43 Patients completing the double-blind phase over 12 months became eligible to enter a long-term extension phase in which all participants received methotrexate plus abatacept 10 mg/kg. At year 3, abatacept-treated patients experienced greater than 70% improvement in swollen and tender joint counts and approximately 50% improvement in pain and physical function.44 Patients who received placebo infusions during the double-blinded phase and then switched to abatacept during the long-term extension rapidly achieved equivalent efficacy to those treated with abatacept throughout. The findings of two large phase III studies of abatacept in different RA populations were recently reported. A population of methotrexate-refractory patients was studied in the Abatacept in Inadequate Responders to Methotrexate (AIM) trial. This study was designed to further evaluate the safety and clinical efficacy of abatacept plus methotrexate, as well as the effect on radiographic progression.45 In the other phase III study, the Abatacept Trial in Treatment of Anti-TNF Inadequate Responders (ATTAIN),46 the objective was to determine whether abatacept is a safe and effective treatment for RA patients who were unresponsive to previous anti-TNF treatment. In the AIM study, 652 RA patients with an inadequate response to methotrexate were randomly assigned to receive placebo (219 patients) or a fixed dose of abatacept approximating 10 mg/kg (433 patients) on days 1, 15, and 29 and every 4 weeks thereafter for a year; all patients remained on background methotrexate therapy.45 Both patient groups exhibited high disease activity at baseline, with a DAS-28 of 6.4. Patients receiving abatacept showed greater improvement in all ACR response criteria at 6 and 12 months than did placebo-treated patients (see Table 59-2). In findings similar to the phase IIb study, abatacept plus methotrexate induced DAS-28 remission (<2.6) in 14.8% of patients at 6 months and in 23.8% at 12 months, compared with 2.8% and 1.9% of patients receiving methotrexate plus placebo at the corresponding time points (P < .001). Physical function significantly improved in 63.7% of the abatacept plus methotrexate group, versus 39.3% of the placebo plus methotrexate group (P < .001). Further, patients on the abatacept and methotrexate combination had a slower progression of mean structural damage (1.2 total Sharp score points over 1 year) compared with methotrexate alone (2.3 Sharp score

points).45 Of interest, when assessed by conventional clinical outcome measures such as EULAR response, the data suggest that a plateau of clinical efficacy is achieved with abatacept between 4 and 6 months of treatment. However, using more stringent measures for analyses, such as time to a low DAS (DAS-28 <3.2) or time to a sustained low DAS, no plateau of efficacy was observed over the first 12 months, suggesting an ongoing recruitment of clinical benefit with abatacept plus methotrexate.47 Patients completing the double-blind phase of the AIM study over 12 months became eligible to enter a long-term extension phase in which all participants received methotrexate plus abatacept at a fixed dose approximating 10 mg/ kg every 4 weeks (Fig. 59-6). Clinically meaningful reductions in disease activity were maintained through 2 years, accompanied by an improved sense of subjective well-being assessed by patient-reported outcomes.48 Further, inhibition of structural damage to joints was sustained, as evaluated by plain radiography; the effect after 2 years of abatacept was significantly greater than that at 1 year, with minimal radiographic progression observed over the second year of treatment.49 In the ATTAIN phase III study, abatacept therapy was evaluated in 391 patients with active disease receiving conventional DMARDs or anakinra who failed to respond adequately to at least 3 months of therapy with etanercept, infliximab, or both agents at the approved doses.46 AntiTNF therapy was discontinued at the time of enrollment if it had not been stopped previously. Following a washout period, patients were randomly assigned in a 2:1 ratio to receive either the same fixed dose of abatacept (approximating 10 mg/kg) or placebo (Fig. 59-7). Patients receiving abatacept showed significantly greater improvement in all ACR response criteria through 6 months (see Table 59-2) than did placebo-treated patients (ACR-20 response 50.4% versus 19.5%, P < .001; ACR-50 response 20.3% versus 3.8%, P < .001; and ACR-70 response 10.2% versus 1.5%, P = .003) (Fig. 59-8). Further, a DAS-28 remission was achieved in 10% of patients receiving abatacept, versus only 1% of patients receiving placebo infusions plus DMARDs. ACR-20 responses were seen irrespective of whether patients had previously been exposed to etanercept, infliximab, or both anti-TNF therapies without an adequate response. Improvement in physical function was also significantly increased in the abatacept group (47% versus 23%). The incidence of infection was slightly higher in the abatacept group than in the placebo group, although no specific infection was clearly more frequent, and the

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MTX stabilization†

MTX inadequate responders with active disease* receiving MTX (n=652)

Randomization‡

Other DMARD washout period

Randomization‡ Days 0 15 29

Placebo + MTX (n=219)

Allowed to add one DMARD at 6 months§ 57

Abatacept 10 mg/kg + MTX (n=433)

85

113

141

Patients completing 12 months were eligible for LTE phase 365

169

Long-term extension phase Dosing

ACR 20

Physical function/structural damage end points

*≥swollen joints (66 joint count), ≥12 tender joints (68 count) and CRP ≥1.0 mg/dL and ≥ months on MTX ≥15 mg/week; †Stable MTX dose for >1 month before enrollment; ‡2:1 randomization to study arm; §Sulfasalazine, hydroxychloroquine, gold.

Anti-TNF failures with active disease receiving DMARDs (N=391)

d1 d15 d29

DMARD stabilization* Etanercept/infliximab† washout period

d56

d85

Randomization‡

Figure 59-6  Phase III AIM (Abatacept in Inadequate Responders to Methotrexate) study design. ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; MTX, methotrexate.

d113

Anti-TNF failures

Placebo + DMARDs (n=133)

Phase III, n=391, 24 weeks 2:1 ramdomization Refractory RA, anti-TNFs non-responder Primary end point: ACR20 at 6 months Secondary end points: HAQ, DAS28 remission

Abatacept + DMARD(s) 10 mg/kg (n=258) d141

DAS28 remission rate: 10 vs 1% 60

d169

50

50

Phase III study: Placebo Abatacept (~10mg/kg fixed)

40

Clinical end point *DMARD/anakinra regimen stable for 28 days. †Washout = 30 days for etanercept; 60 days for infliximab. ‡2:1 randomization to study arm. Figure 59-7  Phase III ATTAIN (Abatacept Trial in Treatment of Anti-TNF Inadequate Responders) study design. DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor. (From Genovese MC, Becker JC, Schiff M, et al: Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 353:1114-1123, 2005.)

intensity of infections was similar in the two groups. There were no significant differences in the number of patients discontinuing treatment as a result of infection or in the incidence of serious infection. All patients who completed the 6-month doubleblind phase of the ATTAIN study were eligible to enter a 1-year, long-term extension phase during which all patients received a once-monthly fixed dose of abatacept in addition to at least one conventional DMARD.50 Of 258 patients randomized to abatacept during the double-blind phase, 223 completed 6 months of treatment, and 218 entered the long-term extension. Of these, 168 completed 18 months’ treatment. The ACR-20 responses observed at the end of the double-blind phase were sustained throughout the 1-year extension phase, with the proportion of patients achieving the more stringent ACR-50 and ACR-70

6 months

Dosing

30 20

20

20 10

10

4

2

0

ACR20 ACR50 ACR70 Figure 59-8  Clinical responses observed in the ATTAIN study of abatacept in a TNF inhibitor–refractory population. ACR, American College of Rheumatology; DAS, disease activity score; HAQ, health assessment questionnaire; RA, rheumatoid arthritis; TNF, tumor necrosis factor.   (From Genovese MC, Becker JC, Schiff M, et al: Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 353:1114-1123, 2005.)

responses rising to 35% and 18%, respectively, at 18 months. Further, the proportion of patients meeting DAS-28 remission criteria doubled to 22.5% by the end of the extension period. Similarly, among all patients initially treated with abatacept and DMARDs who entered the long-term extension phase, the mean reduction in DAS-28 from baseline to the end of the double-blind phase was –1.99; by the end of 18 months, the mean reduction from baseline was –2.81. In the double-blind phase, patients

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assigned to placebo infusions together with DMARDs had a mean reduction in DAS-28 of –0.93; at the end of the long-term extension, after crossing over to abatacept infusions, the reduction from baseline was –2.72.51 These data again emphasize the sustained but relatively slow and incremental clinical responses observed following abatacept therapy. Safety Issues In clinical practice, it is common to use conventional DMARDs in combination regimens, based on the belief that there are additive benefits in terms of efficacy without the downside of unacceptable toxicity. Whether these same principles apply to the use of abatacept was addressed in the ASSURE trial (Abatacept Study of Safety in Use with Other RA Therapies).52 This multicenter, randomized, double-blind study investigated the safety of adding abatacept or placebo infusions to a background treatment regimen of at least one of the traditional nonbiologic or ­biologic DMARDs currently approved for RA treatment for at least 3 months. A total of 1456 patients were ­randomized 2:1 to receive abatacept at a fixed dose approximating 10 mg/kg by weight range or placebo. A number of interesting observations arose from this study. In the group as a whole, the proportion of serious adverse events occurring in each treatment arm was similar: 13% for abatacept and 12% for placebo. The discontinuations rate due to adverse events was 5% in the abatacept group and 4% in the placebo group. As expected on the basis of prior studies, serious infections occurred more frequently in the abatacept group (2.9%) than in the placebo group (1.9%). There were five deaths in the abatacept group and four in the placebo group; all but one death in each group was thought unlikely to be related to the study drug. All the deaths occurred in patients without concomitant biologic background therapy. However, a subanalysis of the data, based on whether patients were receiving biologic or nonbiologic background therapy, revealed that serious adverse events occurred almost twice as frequently in the subgroup receiving abatacept plus another biologic agent (22.3%) as in the other subgroups (12.5%). A particularly important observation in this study was the increased number of serious infections observed when abatacept was combined with other biologic therapies (5.8%, versus 1.6% for the subgroup on background biologic therapy plus placebo infusions). Further, the clinical benefits of abatacept tended to be less in the patients receiving background biologic therapy than in those with a background of nonbiologic DMARDs. There were no reported cases of lymphoma, demyelinating disorders, or tuberculosis. The ASSURE trial findings mirrored those of a smaller randomized, placebo-controlled, double-blind pilot study. This phase IIb trial investigated the efficacy and safety of the addition of abatacept infusions at 2 mg/kg over 1 year in patients with at least 8 of 66 swollen joints and 10 of 68 tender joints despite at least 3 months of treatment with twice-weekly 25 mg subcutaneous etanercept.53 The biologic combination had limited clinical benefit over etanercept and placebo infusions but was associated with an increase in the proportion of patients experiencing serious adverse events (16.5% versus 2.8%) and serious infections

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(3.5% versus 0%). On the basis of these observations, the use of abatacept is not advised in combination with other biologic therapies. Current Role Abatacept may be used as monotherapy or concomitantly with DMARDs other than TNF antagonists. It is not recommended for use concomitantly with IL-1 or TNF antagonists. The encouraging clinical trial data indicate that abatacept, like rituximab, represents a new addition to the therapeutic armentarium for patients with RA who have not responded adequately to TNF blockade. However, the comparative effects of abatacept, rituximab, and TNF blockade on structural damage are still unknown. It is clear that when clinical responses are unsatisfactory, combination therapy with methotrexate and an anti-TNF agent may confer significant joint protection compared with methotrexate alone. Thus, the merits of switching a patient from a TNF inhibitor to abatacept or rituximab on the basis of an inadequate clinical response are not yet clear-cut with respect to disease modification. Other factors likely to determine the future use and relative positioning of new biologics in the clinic include additional long-term safety data, comparative cost-effectiveness analyses, and the perceived convenience of intravenous administration. There are emerging data concerning the comparative efficacy, safety, and kinetics of response for the anti– TNF-α antibody infliximab and abatacept.54 In a 1-year ­double-blind study, RA patients with an inadequate response to methotrexate (mean baseline DAS-28 of 6.8) and no prior anti-TNF therapy were randomized to receive abatacept at a dose approximating 10 mg/kg every 4 weeks (156 patients), infliximab 3 mg/kg every 8 weeks (165 patients), or placebo every 4 weeks (110 patients). Patients randomized to placebo were switched to abatacept after 6 months but were not included in the 1-year analyses. At the end of the first 6 months, the frequency of serious adverse events was 5.1%, 11.5%, and 11.8% for abatacept, infliximab, and placebo, respectively. In the same order, the frequency of acute infusion-related adverse events was 5.1%, 18.2%, and 10%. Over the 1-year period, infections reported as serious adverse events were more frequent with infliximab (8.5%) than with abatacept (1.9%). These included two cases of tuberculosis, both in infliximab-treated patients. With respect to efficacy through 6 months, ACR response rates, changes in DAS-28, HAQ, and short form (SF)-36 were similar following treatment with either abatacept or infliximab. However, as noted in other studies, abatacept was observed to have increasing efficacy beyond 6 months in contrast to the infliximab group; in the latter, measures apparently reached a plateau or diminished over time. For example, the mean change from baseline in DAS-28 for abatacept was –2.3 at 6 months and –2.9 at 1 year; for infliximab, it was–2.3 at both 6 and 12 months. This and other studies emphasize the relatively slow time to peak clinical response with abatacept in comparison to TNF blockade, with increasing efficacy beyond 6 months. They also point to the possibility of a favorable benefit-risk profile over 1 year. It will be critical to see whether these encouraging early safety data are maintained over the longer term.

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Implications for Understanding the Pathogenesis of Rheumatoid Arthritis The clinical efficacy of abatacept in a proportion of RA patients implicates costimulatory events in disease pathogenesis. However, there are a number of different mechanisms by which abatacept might mediate immunosuppressive effects in RA. In the RA joint, blocking access of CD28 to CD80 or CD86 might be of little importance because memory T cells, which predominate in inflamed synovium, are much less dependent on this pathway.55 A more important mechanism of action in the synovium might be the induction of tolerogenic antigen presenting cells. Binding of CD80 or CD86 on antigen presenting cells by CTLA4Ig initiates a “reverse signal,” with induction of tryptophan catabolism and inhibition of antigen presentation. Naive T cells are located predominantly in lymphoid tissue, and blockade of the CD28-CD80/CD86 interaction in lymph nodes may reduce T cell priming and the production of autoreactive T cells. Interestingly, patients with RA are reported to have higher frequencies of CD28-null T cells.56 Further, the level of expression of CD28 is significantly reduced on all naive T cells and memory CD4+, CD28+ T cells, a phenomenon related to overproduction of TNF-α.57 A likely consequence of low-density cell surface expression of CD28 is that, for these T cells, abatacept can more readily block the interaction with CD80 and CD86. ABATACEPT IN OTHER RHEUMATIC CONDITIONS In addition to the use of abatacept in the established phase of RA, there are ongoing studies in early-phase disease and undifferentiated arthritis, juvenile idiopathic arthritis, and SLE.37 Abatacept was also used in a 26-week, phase I, open-label dose-escalation study of psoriasis vulgaris.58 Sustained improvements of at least 50% in clinical disease activity were reported following four infusions of abatacept in 20 of 43 patients with stable psoriasis vulgaris. Clinical improvement was associated with quantitative reduction in epidermal hyperplasia, which correlated with a quantitative reduction in skin-infiltrating T cells. However, no clear-cut increase in the rate of intralesional T cell apoptosis was identified. It may be that the observed reduction in lesional T cells numbers was due to inhibition of T cell proliferation, T cell recruitment, or apoptosis of antigen-specific T cells at extralesional sites. Altered antibody responses to T cell–dependent neoantigens were observed, but immunologic tolerance to these antigens was not demonstrated. This study illustrates the importance of the CD28-CD152 pathway in the pathogenesis of psoriasis.

TARGETING T CELLS CLINICAL STUDIES In the early years of investigating the potential of biologic therapies in RA, T cells were among the first targets to be explored. Data from several different preclinical animal models of inflammatory arthritis suggested a pathogenic role for CD4+ T cells in response to various

arthritogenic antigens presented in the context of MHC class II m­olecules.55 These observations led to a number of experimental protocols designed to investigate the effect of depleting and nondepleting antibodies directed at CD4 as well as other T cell–associated molecules. Early randomized, placebo-controlled clinical studies exploring the potential of biologic therapies targeting T cells in the treatment of RA have generally had disappointing results. Some anti–T cell agents were not efficacious; other preliminary trials demonstrating some clinical efficacy were terminated owing to adverse events, particularly prolonged and profound T cell depletion.59 However, the primatized monoclonal anti-CD4 antibody keliximab results in a dose-dependent clinical response when administered once weekly over 4 consecutive weeks, and the clinical response correlates with CD4+ T cell coating with keliximab rather than T cell depletion. In two consecutive randomized, double-blind trials with comparable populations, keliximab treatment was associated with CD4+ T cell counts below 250 cells/mm3 in 12% in one study and 47% in the other.60 Examples of biologic therapies targeting other T cell– associated molecules include Campath-1H, a monoclonal antibody directed against CD52; a monoclonal anti-CD5 antibody linked to ricin toxin; and a fusion protein comprising an IL-2 receptor–binding domain coupled to diphtheria toxin (DAB486IL-2 fusion toxin). CD52 is a polypeptide expressed on all lymphocytes. Campath-1H was tested as a treatment for refractory RA in two small trials, and although a single intravenous dose of between 1 and 100 mg resulted in significant CD4+ T cell depletion and clinical improvement in more than half of patients, there was poor correlation between biologic action and clinical response.61,62 Further, therapy was associated with significant acute toxicity, presumed to reflect a cytokine release syndrome, including headache, nausea, and hypotension. Arthritis activity returned over time despite prolonged suppression of peripheral blood CD4+ T cell numbers. CD5 is a transmembrane glycoprotein expressed on 70% of T cells. CD5-1C, a monoclonal antibody linked to ricin, a plant toxin that inhibits protein synthesis, was used to treat RA in a double-blind, placebo-controlled trial.63 At the doses tested, only modest and transient T cell depletion was observed, and there was no clinical benefit. In a strategy designed to selectively deplete activated T cells expressing IL-2 receptor, DAB486IL-2 fusion toxin was given by intravenous infusion in open-label and placebo-controlled studies.64,65 Although a small percentage of patients (18%) exhibited clinical responses in the placebo-controlled study, there was a significant incidence of adverse events, including nausea, fever, and raised plasma transaminases. Further, nearly all patients developed antibodies against diphtheria toxin. Other approaches to targeting T cells that have been tested include efforts to directly interfere with the trimolecular complex comprising HLA class II, antigenic peptide, and T cell receptor by means of a DR4-DR1 peptide vaccine, T cell receptor Vβ peptide vaccine, collagen, or cartilage glycoprotein 39.66 Despite a rationale for these approaches based on promising preclinical animal model data, all have

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been abandoned because of borderline or absent clinical benefits in human disease. FUTURE DIRECTIONS The importance of immune regulation in maintenance of the healthy state is perhaps best illustrated by the consequences of immune dysregulation, a phenomenon common to a wide range of chronic inflammatory disease phenotypes. Emerging evidence points to the importance of certain CD4+ T cell subsets in the negative regulation of the adaptive immune system. Best characterized of these subsets are the so-called naturally occurring CD4+CD25+ regulatory T cells and IL-10–producing Tr1 cells. Recent advances in the understanding of the molecular basis of CD4+CD25+ regulatory T cell generation include the observation that the X-linked forkhead–winged helix transcription factor Foxp3 is required for CD4+CD25+ T cell development and function. Although further progress in understanding the pathophysiologic role of regulatory T cells will require the identification of more specific markers for distinct regulatory T cell populations, there is already evidence of the feasibility of enhancing regulatory T cell function in vivo either by T cell receptor modulation, using antibodies to CD3, or by costimulatory signals, using a CD28 superagonist.67 Where a chronic inflammatory disease reflects an antigen-driven process, an attractive goal is to modulate T cell function in such a way as to generate antigen-specific unresponsiveness in the absence of long-term generalized immunosuppression. Some but not all studies report a relative deficiency of regulatory T cells in RA.23 Of note, antibodies to CD3 and to TNF-α appear to enhance regulatory T cell function or number in RA patients.68-71 This raises the possibility that combination treatment with anti-CD3 and anti–TNF-α might be beneficial in more completely restoring immune regulation in RA. In fact, chronic inflammation and overproduction of TNF-α perturb T cell antigen receptor–dependent signaling,72 suggesting that active inflammation may attenuate tolerogenic signals expected to be induced by a nondepleting anti-CD3 antibody. Thus, pretreatment with TNF-α blockade might restore tolerogenic signals transduced by the T cell receptor in response to drugs such as anti-CD3. Although the use of anti-CD3 in the clinic has been limited by the occurrence of druginduced cytokine release syndrome,73 the effects can be modulated by anti-TNF agents, as demonstrated in patients treated for acute allograft rejection.74 Such a combination therapy approach has yet to be tested in RA.

SUMMARY Despite recent advances in understanding the optimal use of nonbiologic DMARD therapies and the considerable success of biologic therapies targeting TNF-α, a substantial proportion of RA patients remains refractory to or intolerant of these therapeutic modalities. The data discussed in this chapter illustrate that there is a role in clinical practice for new biologics with specificity for cellular targets. In particular, depletion of B cells with the monoclonal antibody rituximab results in sustained improvement in the signs and symptoms of RA after just two doses (one treatment cycle),

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with little evidence of drug-related toxicity despite the profound and lasting depletion of B cells. Similarly, inhibition of T cell costimulation by abatacept demonstrates clear clinical efficacy within 16 weeks and, in some cases, additional improvement for 1 year or beyond, with acceptable safety. This observation is in marked contrast to the previously observed unfavorable risk-benefit ratio associated with a T cell–depleting strategy using Campath-1H. The response of RA patients to this wide spectrum of therapeutic strategies attests to the complexity and heterogeneity of the syndrome and provides further impetus for studies that use these therapies to enhance our understanding of disease pathogenesis. To date, very little is known about the comparative effects of abatacept, rituximab, and TNF blockade on symptoms and signs of disease, and the comparative effects on structural damage are unknown. It is clear, however, that when clinical responses are unsatisfactory, combination therapy with methotrexate and an anti-TNF agent may confer significant joint protection compared with methotrexate alone. Rituximab and abatacept are a welcome addition to the biologic armamentarium for RA, and both agents may also have a role in the pharmacologic management of a range of rheumatic disorders. It is anticipated that further clinical studies and experience in the use of these biologic therapies will help inform optimal treatment strategies. REFERENCES   1. Korpela M, Laasonen L, Hannonen P, et al: FIN-RACo Trial Group: Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease-modifying antirheumatic drugs: Five-year experience from the FIN-RACo study. Arthritis Rheum 50:2072-2081, 2004.   2. Grigor C, Capell H, Stirling A, et al: Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): A singleblind randomised controlled trial. Lancet 364:263-269, 2004.   3. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al: Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): A randomized, controlled trial. Arthritis Rheum 52:33813390, 2005.   4. Klareskog L, van der Heijde D, de Jager JP, et al: Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: Double-blind randomised controlled trial. Lancet 363:675-681, 2004.   5. Lipsky PE, van der Heijde DM, St Clair EW, et al: Anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study group: Infliximab and methotrexate in the treatment of rheumatoid arthritis N Engl J Med 343:1594-1602, 2000.   6. Bohnhorst JO, Bjorgan MB, Thoen JE, et al: Bm1-Bm5 classification of peripheral blood B cells reveals circulating germinal center founder cells in healthy individuals and disturbance in the B cell subpopulations in patients with primary Sjögren’s syndrome. J Immunol 167:3610-3618, 2001.   7. Koopman G, Keehnen RM, Lindhout E, et al: Adhesion through the LFA-1 (CD11a/CD18)-ICAM-1 (CD54) and the VLA-4 (CD49d)VCAM-1 (CD106) pathways prevents apoptosis of germinal center B cells. J Immunol 152:3760-3767, 1994.   8. Mackay F, Sierro F, Grey S, et al: The BAFF/APRIL system: An important player in systemic rheumatic diseases. Curr Dir Autoimmun 8:243-265, 2005.   9. Bhatia A, Blades S, Cambridge G, et al: Differential distribution of FcγRIIIa in normal human tissues and co-localisation with DAF and fibrillin-1: Implications for immunological microenvironments. Immunology 94:56-63, 1998. 10. Abrahams VM, Cambridge G, Edwards JC: Induction of tumour necrosis factor α by human monocytes: A key role for FcγRIIIa in rheumatoid arthritis. Arthritis Rheum 43:608-616, 2002.

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11. Edwards JCW, Cambridge G: B cell targeting in rheumatoid arthritis and other diseases. Nat Rev Immunol 6:394-405, 2006. 12. Riley JK, Sliwkoski MX: CD20: A gene in search of a function. Semin Oncol 27(6 Suppl 12):17-24, 2000. 13. O’Keefe TL, Williams GT, Davies SL, et al: Mice carrying a CD20 gene dist disruption. Immunogenetics 48:125-132, 1998. 14. Szodoray P, Alex P, Dandapani V, et al: Apoptotic effect of rituximab on peripheral B cells in RA. Scand J Immunol 60:209-218, 2004. 15. Tsokos GC: B cells, be gone: B-cell depletion in the treatment of rheumatoid arthritis. N Engl J Med 350:2546-2548, 2004. 16. Edwards JC, Cambridge G: Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology (Oxford) 40:205-211, 2001. 17. De Vita S, Zaja F, Sacco S, et al: Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis: Evidence for a pathogenetic role of B cells. Arthritis Rheum 46:2029-2033, 2002. 18. Leandro MJ, Edwards JC, Cambridge G: Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocyte depletion. Ann Rheum Dis 61:883-888, 2002. 19. Edwards JC, Szczepanski L, Szechinski J, et al: Efficacy of B-celltargeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350:2572-2581, 2004. 20. Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al (for the DANCER study group): The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: Results of a phase IIB randomized, double-blind, placebo-­controlled, dose-ranging study. Arthritis Rheum 54:1390-1400, 2006. 21. Cohen SB, Emery P, Greenwald MW, et al: Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebocontrolled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 54:2793-2806, 2006. 22. Cohen S, Emery P, Greenwald M, et al: Prolonged efficacy of rituximab in rheumatoid arthritis patients with inadequate response to one or more TNF inhibitors: 1-year follow-up of a subset of patients receiving a single course in a controlled trial (REFLEX study). Ann Rheum Dis 65(Suppl 2):183, 2006. 23. Keystone E, Emery P, Peterfy CG, et al: Prevention of joint structural damage at 1 year in rheumatoid arthritis patients with an inadequate response to one or more TNF inhibitors (REFLEX). Anns Rheum Dis 65(Suppl 2):58, 2006. 24. Morbacher A: B cell non-Hodgkin’s lymphoma: Rituximab safety experience. Arthritis Res Ther 7(Suppl 3):S19-S25, 2005. 25. McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four dose treatment program. J Clin Oncol 16:2825-2833, 1998. 26. McLaughlin P, Hagemeister FB, Grillo-Lopez AJ: Rituximab in indolent lymphoma: The single agent pivotal trial. Semin Oncol 26(5 Suppl 14):79-87, 1999. 27. Coffier B, Lepage E, Brier J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large B cell lymphoma. N Engl J Med 346:235-242, 2002. 28. Higashida J, Wun T, Schmidt S, et al: Safety and efficacy of rituximab in patients with rheumatoid arthritis refractory to disease modifying anti-rheumatic drugs and anti-TNFα treatment. J Rheumatol 32: 2109-2115, 2005. 29. Emery P, Fleischman RM, Filipowicz-Sosnowska A, et al: Rituximab in rheumatoid arthritis: A double-blind, placebo-controlled, dose ranging study. Arthritis Rheum 52(Suppl):S709, 2005. 30. Cambridge G, Leandro MJ, Edwards JC, et al: Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum 48:2146-2154, 2003. 31. Leandro MJ, Cambridge G, Ehrenstein MR, et al: Reconstitution of peripheral blood B cells following rituximab treatment in patients with rheumatoid arthritis. Arthritis Rheum 54:613-620, 2006. 32. Cambridge G, Stohl W, Leandro MJ, et al: Circulating levels of B lymphocyte stimulator in patients with rheumatoid arthritis following rituximab treatment: Relationships with B cell depletion, circulating antibodies, and clinical relapse. Arthritis Rheum 54:723-732, 2006. 33. Tak PP, Cohen S, Emery P, et al: Baseline autoantibody status (RF, anti-CCP) and clinical response following the first treatment course with rituximab. Arthritis Rheum 54(9 Suppl):833, 2006. 34. van Vollenhoven RF, Cohen S, Pavelka K, et al: Response to rituximab in patients with rheumatoid arthritis is maintained by repeat

therapy: Results of an open-label trial. Ann Rheum Dis 65(Suppl 2): 510, 2006. 35. Scheinberg M, Hamerschlak N, Kutner JM, et al: Rituximab in refractory autoimmune diseases: Brazilian experience with 29 patients (2002-2004). Clin Exp Rheumatol 24:65-69, 2006. 36. McKay J, Chwalinska-Sadowska H, Boling E, et al: Efficacy and safety of belimumab (BMAB), a fully human monoclonal antibody to B lymphocyte stimulator (BLyS) for the treatment of rheumatoid arthritis. Arthritis Rheum 52(Suppl):S710, 2005. 37. Furst DE, Breedveld FC, Kalden JR, et al: Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2006. Ann Rheum Dis 65(Suppl 3):iii2-iii15, 2006. 38. Looney RJ: B cells as a therapeutic target in autoimmune diseases other than rheumatoid arthritis. Rheumatology (Oxford) 44(Suppl 2): ii13-ii17, 2005. 39. Knoerzer DB, Karr RW, Schwartz BD, et al: Collagen-induced arthritis in the BB rat: Prevention of disease by treatment with CTLA-4-Ig. J Clin Invest 96:987-993, 1995. 40. Webb LM, Walmsley MJ, Feldmann M: Prevention and amelioration of collagen-induced arthritis by blockade of the CD28 co-­stimulatory pathway: Requirement for both B7-1 and B7-2. Eur J Immunol 26: 2320-2328, 1996. 41. Moreland LW, Alten R, Van den Bosch F, et al: Co-stimulatory blockade in patients with rheumatoid arthritis: A pilot, dose­finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion. Arthritis Rheum 46:1470-1479, 2002. 42. Kremer JM, Westhovens R, Leon M, et al: Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 349:1907-1915, 2003. 43. Kremer JM, Dougados M, Emery P, et al: Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: Twelve-month results of a phase IIb, double-blind, randomized, ­ placebo-controlled trial. Arthritis Rheum 52:2263-2271, 2005. 44. Westhovens R, Emery P, Aranda R, et al: Abatacept provides sustained clinical benefit through 3 years in rheumatoid arthritis patients with inadequate responses to methotrexate. Ann Rheum Dis 65(Suppl 2): 512, 2006. 45. Kremer JM, Genant HK, Moreland LW, et al: Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: A randomized trial. Ann Intern Med 144:865-876, 2006. 46. Genovese MC, Becker JC, Schiff M, et al: Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 353:1114-1123, 2005. 47. Dougados M, LeBars MA, Schmidely N: Low disease activity in rheumatoid arthritis treated with abatacept in the AIM (Abatacept in Inadequate response to Methotrexate) trial. Ann Rheum Dis 65(Suppl 2): 188, 2006. 48. Kremer JM, Emery P, Becker JC, et al: Abatacept provides significant and sustained benefits in clinical and patient-reported outcomes through 2 years in rheumatoid arthritis and an inadequate response to methotrexate: The long-term extension (LTE) of the AIM trial. Ann Rheum Dis 65(Suppl 2):327, 2006. 49. Genant HK, Peterfy C, Westhovens R, et al: Abatacept sustains inhibition of radiographic progression over 2 years in rheumatoid arthritis patients with an inadequate response to methotrexate: Results from the long-term extension (LTE) of the AIM trial. Ann Rheum Dis 65(Suppl 2):57, 2006. 50. Genovese MC, Schiff M, Luggen M, et al: Efficacy and safety of the co-stimulation modulator abatacept following two years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-TNF therapy. Ann Rheum Dis Oct 18, 2007 [Epub ahead of print]. 51. Siblia J, Schiff M, Genovese MC, et al: Sustained improvement in disease activity score 28 (DAS28) and patient reported outcomes (PRO) with abatacept in rheumatoid arthritis patients with an inadequate response to anti-TNF therapy: The long-term extension of the ATTAIN trial. Ann Rheum Dis 65(Suppl 2):501, 2006. 52. Weinblatt M, Combe B, Covucci A, et al: Safety of the selective co-stimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: A one-year randomized, placebo-controlled study. Arthritis Rheum 54:2807-2816, 2006.

PART 8  53. Weinblatt ME, Schiff MH, Goldman A, et al: Selective co-stimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: A randomized clinical trial. Ann Rheum Dis 66:228-234, 2007. 54. Schiff M, Keiserman M, Codding C, et al: The efficacy and safety of abatacept or infliximab versus placebo in ATTEST: A phase III, multicenter, randomized, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexa. Ann Rheum Dis Nov 24, 2007 [Epub ahead of print]. 55. Weyand CM, Goronzy JJ: T-cell-targeted therapies in rheumatoid arthritis. Nat Clin Pract Rheumatol 2:201-210, 2006. 56. Warrington KJ, Takemura S, Goronzy JJ, et al: CD4+, CD28– T cells in rheumatoid arthritis patients combine features of the innate and adaptive immune systems. Arthritis Rheum 44:13-20, 2001. 57. Bryl E, Vallejo AN, Matteson EL, et al: Modulation of CD28 expression with anti-tumor necrosis factor alpha therapy in rheumatoid arthritis. Arthritis Rheum 52:2996-3003, 2005. 58. Abrams JR, Lebwohl MG, Guzzo CA, et al: CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J Clin Invest 103:1243-1252, 1999. 59. Taylor PC: Antibody therapy for rheumatoid arthritis. Curr Opin Pharmacol 3:323-328, 2003. 60. Mason U, Aldrich J, Breedveld F, et al: CD4 coating, but not CD4 depletion, is a predictor of efficacy with primatized monoclonal anti-CD4 treatment of active rheumatoid arthritis. J Rheumatol 29: 220-229, 2002. 61. Weinblatt ME, Maddison PJ, Bulpitt KJ, et al: CAMPATH-1H, a humanized monoclonal antibody, in refractory rheumatoid arthritis: An intravenous dose-escalation study. Arthritis Rheum 38:1589-1594, 1995. 62. Schnitzer TJ, Yocum DE, Michalska M, et al: Subcutaneous administration of CAMPATH-1H: Clinical and biological outcomes. J Rheumatol 24:1031-1036, 1997. 63. Olsen NJ, Brooks RH, Cush JJ, et al: A double-blind, placebocontrolled study of anti-CD5 immunoconjugate in patients with rheu-

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matoid arthritis. The Xoma RA Investigator Group. Arthritis Rheum 39:1102-1108, 1996. 64. Sewell KL, Parker KC, Woodworth TG, et al: DAB486IL-2 fusion toxin in refractory rheumatoid arthritis. Arthritis Rheum 36: 1223-1233, 1993. 65. Moreland LW, Sewell KL, Trentham DE, et al: Interleukin-2 diphtheria fusion protein (DAB486IL-2) in refractory rheumatoid arthritis: A double-blind, placebo-controlled trial with open-label extension. Arthritis Rheum 38:1177-1186, 1995. 66. Keystone EC: Abandoned therapies and unpublished trials in rheumatoid arthritis. Curr Opin Rheumatol 15:253-258, 2003. 67. Thompson C, Powrie F: Regulatory T cells. Curr Opin Pharmacol 4:408-414, 2004. 68. Ehrenstein MR, Evans JG, Singh A, et al: Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNF alpha therapy. J Exp Med 200:277-285, 2004. 69. Valencia X, Stephens G, Goldbach-Mansky R, et al: TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood 108:253-261, 2006. 70. Herold KC, Burton JB, Francois F, et al: Activation of human T cells by FcR nonbinding anti-CD3 mAb, hOKT3gamma1(Ala-Ala). J Clin Invest 111:409-418, 2003. 71. Bisikirska B, Colgan J, Luban J, et al: TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+ Tregs. J Clin Invest 115:2904-2913, 2005. 72. Cope AP: Regulation of autoimmunity by proinflammatory cytokines. Curr Opin Immunol 10:669-676, 1998. 73. Chatenoud L: CD3-specific antibodies as promising tools to aim at immune tolerance in the clinic. Int Rev Immunol 25:215-233, 2006. 74. Charpentier B, Hiesse C, Lantz O, et al: Evidence that anti-human tumor necrosis factor monoclonal antibody prevents OKT3-induced acute syndrome. Transplantation 54:997-1002, 1992.

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Chronic Musculoskeletal Pain Maren Lawson Mahowald  •  Hollis E. Krug

KEY POINTS Chronic musculoskeletal pain is extremely common worldwide and is a major cause of depression, days lost from work, and overall poor quality of life. In rheumatoid arthritis, pain scores are a better predictor of functional status than either radiographic scores or disease duration. Pain can originate from a variety of peripheral and central sources, and understanding of the types and origins of pain has led to improved and more targeted treatment. Individual responses to chronic pain vary, and often are influenced by psychological factors. Occasionally, pain recurs or persists after the initial cause of the pain has been successfully treated, a condition termed psychophysiologic pain. Simple analgesics, including nonsteroidal anti-inflammatory drugs, are adequate for many patients with chronic pain, but if pain persists and interferes significantly with quality of life, experience has shown that opioids are often beneficial and safe, with minimal development of drug tolerance and a level of drug dependence no higher than is seen in the general population. Physicians who choose to use opioids for chronic pain should be aware of the potential risks for abuse and monitor for evidence that the patient may be developing dependence on the narcotic. Tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and antiepileptic drugs all are useful adjuncts in patients with chronic pain, including chronic low back pain.

Definitions Related to Pain Hypesthesia—Partial loss of tactile sensation, not loss of sensation (anesthesia) or decrease of painful sensation (hypalgesia or analgesia). Hyperalgesia—Normally painful stimuli cause an excess of pain (i.e., a heightened pain perception to a noxious stimulus resulting from abnormal processing of nociceptor inputs in the peripheral or central nervous system)7 Dysesthesia—Abnormal sensation from innocuous stimuli (i.e., light touch produces bizarre tingling) Allodynia—Normally innocuous stimulus produces pain sensation (e.g., light touch of burned skin produces pain) Paresthesias—Spontaneous sensation without stimulation, tingling, or “pins and needles” sensation

Abbreviations Related to Management of Chronic Pain AMPA—alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate ASIC—acid sensing ion channel B1/2—bradykinin receptor CCK—cholecystokinin CGRP—calcitonin gene-related peptide CNS—central nervous system DRG—dorsal root ganglia DYN—dynorphin ENK—enkephalin EP—prostaglandin E receptor FRAP—fluoride resistant acid phosphatase GABA—γ-aminobutyric acid GDNF—glial derived neutrophilic factor GRP—gastrin-releasing peptide 5-HT—5-hydroxytryptamine (serotonin) NE—norepinephrine NK1—neurokinin 1 NMDA—N-methyl-d-aspartate P2X3—purine receptor PNS—peripheral nervous system SNRI—selective serotonin-norepinephrine reuptake inhibitor SOM—somatostatin SP—substance P SSRI—selective serotonin reuptake inhibitor TCA—tricyclic antidepressant TrkA—nerve growth factor receptor VIP—vasoactive intestinal peptide TRPV1 (VR1)—transient receptor potential vanilloid 1 (also known as vanilloid receptor 1 for capsaicin) TRPV2—transient receptor potential vanilloid 2 (t­ransducer for extreme heat) TRPV3—transient receptor potential vanilloid 3 (heat capsaicin acid receptor) WDR—wide dynamic range

Pain can occur as a result of noxious stimuli, as a result of innocuous stimuli, or, in some cases, in the absence of identifiable stimuli. All physicians would agree that relief of suffering is central to patient care. Discussions about the treatment of pain, especially with opioids, reveal divergent opinions, however.1,2 Suffering is the sum of all the negative affective, sensory, and cognitive components of the pain experience, and not all individuals suffer to the same degree with similar pain symptoms.3 The amount of suffering associated with pain is determined by the intensity of the nociceptive input and the individual’s circumstances and cultural environment. This human variability permits 963

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the clinician to help relieve suffering even when the pain cannot be eliminated completely. Pain is a complex phenomenon that has been defined by the International Association for the Study of Pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Pain is always subjective and may appear in the absence of tissue damage.”4 Pain should be conceptualized as an experience that incorporates the sensory component nociception with important personality and environmental influences.5 From the clinical standpoint, it is useful to classify pain first as acute or chronic because the differential diagnosis, diagnostic evaluation, treatments, and prognosis are likely to differ. Advances in knowledge of the neurobiology of pain generation, transmission, and modulation now permit more precise definitions of pathophysiology and mechanism-based treatment approaches.6 Acute pain is temporally associated with a noxious stimulus secondary to an identifiable tissue injury, disease process, or abnormal function of a muscle or viscera, and is the normal physiologic survival response to potential harm. The function of acute pain is to protect tissue from actual or potential injury by a response of muscular reflexes, alerting processes, and autonomic responses in vascular, visceral, and endocrine tissues. The global response to pain is produced by a complex interaction of cognitive interpretation and emotional responses, which are influenced by the individual’s general physical state, past experiences, psychological state, social environment, and expectations. The source of acute pain is usually identifiable and localizable. The pain intensity is usually proportional to the severity of tissue injury and subsides as it heals. Acute pain is associated with an autonomic nervous system response, causing tachycardia; increased blood pressure; anxiety; and stereotypic behaviors of withdrawal, splinting, rubbing, grimacing, or some combination of these. In contrast, patients with sustained or chronic pain do not have autonomic overactivity, but have varying degrees of physical dysfunction, anxiety, depression, social isolation, and personality changes that result in a decrease in their quality of life. The term chronic pain is imprecise, but refers to pain lasting longer than 3 to 6 months. In some patients, the pain is chronic because the underlying pathologic condition is chronic. Examples of chronic nociceptive pain include rheumatoid arthritis, osteoarthritis, degenerative disk and joint disease, osteoporosis fractures, chronic gout, and ankylosing spondylitis. Chronic neurogenic pain may be central pain resulting from pathology in the spinal cord, brainstem, thalamus, or cortex. Neuropathic pain may be pain arising from damage to primary afferent neurons.7 Chronic pain associated with musculoskeletal disease is a combination of chronic persistent pain with intermittent acute exacerbations. The pain usually is associated with movement (incident pain), pressure (hyperalgesia or tenderness), and light touch (allodynia) if neuropathic processes are contributing. Hyperalgesia and allodynia are expressions of sensitization of peripheral nociceptors and plasticity-induced central mechanisms in the spinal cord or brain.7 The term psychogenic pain refers to pain that lasts beyond the time expected for healing, pain not alleviated by routine pain treatment, or pain that does not have an identified abnormal tissue source. Chronic pain that persists long after an injury has healed serves no beneficial physiologic

­function, but may cause physical function, mental health, and personality to deteriorate. Chronic pain related to an underlying chronic disease may become complicated by emotional distress and psychiatric disorders. Conditions in which pain seems out of proportion to the underlying disease or does not have an identifiable tissue pathology are termed pain syndromes. Such pain syndromes have standard diagnostic criteria detailed in the Diagnostic and Statistical Manual of Mental Disorders8 for somatoform disorders, malingering, factitious disorder, or personality disorders (see later). Chronic pain rarely has a pure psychogenic cause, but the psychogenic aspect must be identified to prevent unnecessary and ineffective evaluations and treatments. Similarly, most patients with chronic pain develop anxiety and depression, which require prompt detection and directed therapies.

EPIDEMIOLOGY OF PAIN A large-scale survey of 46,394 respondents from 15 European countries and Israel documented that chronic pain is common worldwide and has an impact on health care use and health-related quality of life.9 Of patients, 12% reported pain duration was less than 2 years, 60% reported pain duration was 2 to 15 years, and 21% reported pain duration was more than 20 years. An in-depth interview with 4839 patients with chronic pain (approximately 300 per country) revealed that 66% had moderate pain (5 to 7 on the numerical rating scale), and 33% had severe pain (8 to 10 on the numerical rating scale). Almost 50% had pain in the spine, more than 40% had pain in the joints, approximately 20% had head or neck pain, and 20% had hand or leg pain. Osteoarthritis and rheumatoid arthritis combined were the most common cause of pain—42% (Table 60-1). Approximately 20% had chronic pain resulting from degeneration or trauma to the disks and spine. Limitations as a result of the pain were described as being less able or unable to do specific activities, such as maintaining relationships (27%), driving (47%), having sex (43%), being independent (30%), working (61%), socializing (48%), walking (47%), doing housework (44%), lifting (72%), exercising (73%), and sleeping (65%). Depression because of pain was reported by 21%. Patients reported multiple physician visits: 70% general practitioner, 27% orthopaedist, 8% rheumatologist, 7% internist, 6% physical therapist, 10% neurologist, 3% general surgeon, and 2% osteopath. Only 69% of patients reported being treated for their pain; 69% used non­medical treatments (massage, physical therapy, and acupuncture), 36% took nonprescription medications, and 65% took one or two prescription medications (see Table 60-1). Treatment was judged to be completely or very effective by 45%, somewhat effective by 41%, and not effective by 15%. One third were worried about becoming addicted to pain medications, and two thirds were concerned about medication side effects. Only 62% were very or extremely satisfied with their physician, and 38% were not satisfied. Of respondents, 40% believed their physician would rather treat their disease than their pain, and 28% believed their physician did not know how to treat their pain. Although differences in prevalence and treatment were observed among the 16 countries, this survey documented that chronic pain is a widespread serious health care problem and negatively affects many aspects of quality of life (see Table 60-1).9

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Table 60-1  Survey of Chronic Pain in Europe: ­Prevalence, Impact on Daily Life, and Treatment Prevalence of chronic pain

19% of 46,394   respondents

Female:male

56%:44%

Duration of pain   6 mo–2 yr   2-15 yr   >15yr

12% 59% 29%

Severity   Moderate (5-7 NRS)   Severe (8-10 NRS)

In-depth interview of 4839 66% 34%

Pattern   Intermittent   Constant

46% 54%

Body location of pain   Head   Neck   Shoulder   Hand   Hip   Leg   Knee   Joints (unspecified)   Upper back   Lower back   Back (unspecified)

15% 8% 9% 6% 8% 14% 16% 10% 5% 18% 24%

Causes of chronic pain   Arthritis/osteoarthritis   Rheumatoid arthritis   Traumatic injury/whiplash   Cartilage damage   Nerve damage   Migraine headaches   Fracture/deterioration of the spine   Herniated/deteriorating disks   Surgery

34% 8% 16% 4% 4% 7% 6% 15% 3%

Impact of pain on daily life   Diagnosed with depression   because of pain   Less able or unable to work

21% 61%

Lost job Unable to do job Less able or unable to Maintain relationships Have sexual relations Drive a car Attend social activities Walk Exercise Household chores Sleep Physician visits in past 6 mo None Once 2-9 times ≥10 times Current treatment None Nonmedication treatments Nonprescription   medications NSAIDs Paracetamol Weak opioids Prescription medications NSAIDs COX-2 inhibitors Paracetamol Weak opioids Strong opioids Patient satisfaction Treatment inadequate Very or extremely satisfied with   physician Somewhat or not satisfied with   physician Felt the physician would rather   treat the illness than the pain Felt the physician did not   know how to control   the pain

19% 13% 27% 43% 47% 47% 47% 73% 54% 65% 16% 14% 60% 11% 33% 67% 50% 55% 43% 13% 67% 44% 1%-36% 18% 23% 5% 40% 52% 38% 40% 30%

COX-2, cyclooxygenase-2; NRS, numerical rating scale; NSAIDs, nonsteroidal anti-inflammatory drugs. modified from Breivik H, Collett B, Cohen R, et al: Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment. Eur J Pain 10:287-333, 2006.

Functional status and disease activity scores in rheumatoid arthritis patients are explained more by pain than radiographic scores, age, depression scores, gender, and disease duration. In 141 patients with rheumatoid arthritis, functional disability as measured by the Stanford Health Assessment Questionnaire had a higher correlation with pain severity (r  =  .652, P  <  .001) than with the Larsen score for radiographic damage (r  =  .277, P  =  .001).10 In the regression analysis, the pain score was the primary explanatory variable for functional disability (the Stanford Health Assessment Questionnaire score), accounting for 41.4% of the variability, whereas radiologic damage accounted for only 7.3%, and the Beck Depression Inventory score accounted for only 5.5% of the variability. Other variables of current disease activity, including age, duration of disease, serologic features, and gender, did not contribute significantly to physical disability. In the United States, estimates of the national prevalence of physician-diagnosed arthritis was 21.6% (46.4 million individuals), and arthritis-attributable activity limitations was 8.3% (17.4 million individuals) based on the National Health Interview Survey of approximately 31,000 households (2003 to 2005). Women, elderly individuals,

individuals with low education level, obese individuals, and individuals who are physically inactive are more likely to be affected.11 Ethnic and racial disparities have been suggested for pain severity and pain-associated disability in some reports.12 In a nationwide cross-sectional survey in the United States, approximately one third of whites, African-Americans, and Hispanics reported pain of more than 3 months’ duration, however, and one third of each group reported “disabling pain” (i.e., high severity and high functional interference). Fewer Hispanics had visited a physician for pain, and more African-Americans had used a prescription medication for pain. There were no differences in life interference according to race or ethnicity. Disabling pain (a composite variable) had a 35.8% prevalence and was associated with female gender, income less than $25,000, lower education level, and divorce. Age-adjusted prevalences were 38.3% for women and 30.9% for men. Prevalence increased with age, and there was a peak in prevalence at 55 to 64 years for men and 65 to 69 years for women. Men had a secondary peak at 40 to 44 years of age. The highest prevalences were found in manual workers, immigrants, and individuals who lived in low-income housing areas.

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Chronic pain has a substantial effect on life interference and pain-related impairments across all racial and ethnic groups. It is possible that disparities exist for undertreatment of pain or efforts to seek treatment for pain. Survey data from the American Productivity Audit, 2001 to 2002, indicated 28,902 working adults in the United States reported having had pain in a 2-week period, and 13% of the work force indicated an average of 4.6 hr/wk lost productive time during a 2-week period because of the pain condition. The pain conditions identified included headache (5.4%), back pain (3.2%), arthritis pain (2%), and other musculoskeletal pain (2%). The estimated cost of lost productive time was $61.2 billion/yr owing to reduced performance at work and lost work time.13 The prevalence of pain in elderly individuals varies, depending on how the survey questions were worded and the site setting for the survey (i.e., community-based or longterm care facility–based study populations).14 Chronic pain is reported by 25% to 50% of community-dwelling elderly individuals and 45% to 80% of nursing home residents.14 A survey of residents in a nursing home with three different skill levels found 71% had some pain, and 78% had an analgesic medication ordered.15 Residents in the board and care level had the highest prevalence of pain (84%); 66% of residents in the skilled nursing facility reported pain. Pain severity was described by 52% as severe, horrible, or excruciating. Residents who had intermittent pain related the pain to movement, weight bearing, or overexertion. Functional impairments secondary to pain included impaired enjoyable activities (54%), impaired ambulation (53%), sleep disturbance (45%), depression (32%), and anxiety (26%). Analgesics ordered included acetaminophen in 75% of the residents and codeine in 12%. Only 15% of the individuals had received any analgesic medication in the preceding 24 hours. Pain is an important problem for elderly individuals— especially in long-term care facilities, where it is usually undertreated. Some identified barriers to pain treatment included subjects not wanting to “bother the nurses,” being “tired of asking,” or not wanting to “give in to the pain.” The consequences of inadequately treated chronic pain in elderly individuals include depression, decreased socialization, sleep disturbance, impaired ambulation, and increased health care use and costs.14

PATHOPHYSIOLOGY OF PAIN GENERATION, TRANSMISSION, RECOGNITION, AND MODULATION Somatic or nociceptive pain arises from stimulation of nociceptors in body tissues and transmission of this signal via nerves in the peripheral and central nervous systems. Pain signals reach various centers in the brain via multiple neuronal pathways where pain pathways terminate and are responsible for different components of pain recognition, including discrimination and localization, arousal, and aversive reactions. Cells in the higher termination regions within the forebrain and brainstem also pro­ject back through descending pathways to the spinal cord to modulate the pain signal.16 This modulation can serve to increase or decrease pain perception. Pain also can be generated from activation of central nociceptive pathways without involving ­peripheral

A Nociceptive

Neuropathic

B

D

C

Psychogenic

Figure 60-1  Mechanisms of chronic pain. Nociceptive and neuropathic pathology, such as degenerative disk disease and radiculopathy (A). Nociceptive and psychogenic pathology, such as hypochondriasis and osteoporotic compression fracture (also known as the “crocks revenge”)  (B). Psychogenic and neuropathic pathology, substance abuse disorder, and alcoholic neuropathy (C). Nociceptive, neuropathic, and psychogenic pathology, such as rheumatoid arthritis with depression and herpes zoster (D).

nociceptors (i.e., “central pain”) owing to damage in the central nervous system.17 Inflammatory mediators released in damaged tissue and in the spinal cord stimulate cellular and biochemical changes that sensitize the structures of the ascending nociceptive pathways.16 This sensitization produces changes in function of peripheral and central neurons resulting in lower pain thresholds, secondary hyperalgesia in areas that were uninjured, and sometimes sustained pain potentiation. Chronic pain states can exist in the presence or absence of ongoing tissue damage (Fig. 60-1).16 PAIN GENERATION IN PERIPHERAL NOCICEPTORS Peripheral nociceptors are pain-sensitive neurons or primary afferent neurons whose cell bodies are in the dorsal root ganglion adjacent to the spinal cord. Nociception is the sensory process signaling a noxious stimulus that has the potential to produce trauma or tissue injury (Fig. 60-2). The noxious stimulus is transduced by the peripheral afferent nerve endings into an action potential that is transmitted to the dorsal horn of the spinal cord. Because of a high threshold for stimulation, these peripheral nerve fibers are able to distinguish between noxious and innocuous stimuli, and they can translate the intensity of the stimulus from the frequency of impulse firing. The smallest unmyelinated C fibers transmit the noxious impulse at the slowest speed, 0.5 to 2 m/sec (second pain), and the larger, thinly myelinated A-delta fibers transmit the noxious impulse at the fastest speed, 2.5 to 35 m/sec (first pain). An intense thermal stimulus (a burn) may be felt as “first” pain 0.05 second after the injury and again as “second” pain 2 seconds after the injury. Some C fibers (polymodal nociceptors) have higher thresholds and respond to intense noxious mechanical, thermal, or chemical stimuli ­ nonselectively

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MODALITIES OF THERAPY IN RHEUMATIC DISEASE Inflammatory mediators NGF

DRG cell body Dorsal Horn

ATP Nociceptor Effector Activity “Neurogenic inflammation”

967

Protein

C fiber

SP BDNF

TRPV1

Platelets

Inhibitory peptide receptors: opioids, somatostatin, NPY

SP NGF

P2X3 TRPM8

CGRP Serotonin

Neurokinin A Histamine Receptor

Mast cell

Ca

++

Na

Cold Pinch Heat,H+ Capsaicin Heat

MDEG TRPV1

Phosphorylation PKA

Histamine PKC

Injury

ATP

TRPV3 TRPV2

Heat

ASIC

H+ GDNF

Nociceptor Activation

IB-4 Phosphorylation

Vasodilatation

Edema

EP TrkA

Plasma Extravasation

Nav1.8/1.9 B1/2

Kininogen AA COX2

PGE2

NGF

BK

P2X3

Peripheral Sensitization

ATP

Figure 60-2  Pain generation in peripheral nociceptors.

(Table 60-2). In addition, there are neurons known as “silent nociceptors,” which are completely insensitive to mechanical or thermal stimuli in normal tissue. These silent nociceptors start to respond to stimuli only when tissue is inflamed, and the silent nociceptors are sensitized. These nociceptors are important in mediating neurogenic inflammation and in initiating central sensitization.16 The conscious experience of pain has a localizing component, which enables the individual to describe the location, intensity, and nature of the noxious stimulus, and an alerting and affective component, which alerts the individual to potential body danger and alters behaviors. An unconscious component of pain is an involuntary spinal motor reflex, which produces a withdrawal response for protection. Nociceptors have been described in skin, muscles, bone, joints, and viscera.18 Microneurography and microstimulation of peripheral nerves in humans have shown that the quality of pain sensation depends on the tissue innervated by the nociceptors being stimulated and the rate of stimulation (Table 60-3). Nociceptor afferents from the skin (high-threshold mechanoreceptors) are lightly myelinated, fast conducting A-delta fibers or smaller unmyelinated slow conducting C fibers. These are particularly sensitive to thermal stimuli, but nociceptors in joints are much more sensitive to mechanical stimuli.16 Afferent fibers from muscle are called group III or group IV afferents and are analogous to A-delta and C fibers.

Transduction is the process by which a noxious stimulus is converted to electrical activity in the nociceptor terminals. This process is mediated by specialized ion channels expressed only by nociceptors.17 Generally, these channels are high threshold and are gated by temperature, by shear forces, and by chemicals binding to receptors. Some C fibers express the P2X3 purine receptor, the IB4-lectin binding site, and receptors for glial derived neutrophilic factor (GDNF).17 The purinergic agonist adenosine triphosphate (ATP) can cause transient pain by binding to the purine receptors on nociceptors and increasing sodium ion permeability.7 Other C fibers synthesize substance P (SP) and calcitonin gene-related peptide (CGRP) and express the nerve growth factor receptor TrkA.16 All C fibers express the capsaicin receptor, transient receptor potential vanilloid 1 (TRPV1), which transduces noxious chemical and thermal stimuli.17 Related channels, TRPV2 and TRPV3, also transduce noxious thermal stimuli. TRPM8 responds to cold, and acid sensing ion channel (ASIC) senses hydrogen ion.17 When these channels are activated, sodium and calcium are able to flow into the peripheral nerve terminal. This ion flow produces an inward current that depolarizes the nerve membrane, allowing voltage-gated sodium channels to open, producing an action potential.16 The greater the intensity of the noxious stimulus, the higher the frequency and duration of the action potential burst. The basal threshold of the nociceptor determines the sensitivity to ­ stimulation.

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Table 60-2  Types of Afferent Nerve Fibers Normally ­ Mediators Activating Stimuli Released

Quality of Pain Sensation

Process of ­Sensitization

Innocuous touch, movement, ­pressure, ­temperature

Normally not   painful

With neuropaInjured nerve thy produces expresses SP paresthesia, and CGRP, which ­dysesthesias bind to autore(buzzing, tingling) ceptors in the periphery

Fast pain; pricking, sharp, aching   pain

Can be sensitized by exposure to noxious stimuli

Location

Nerve Fiber

Skin, tendon,   joint capsule, ­ligament, ­menisci, ­periosteum

Group II (A-beta)

Skin

A-delta fiber;   Noxious   high-threshold moderate- and mechanoreceptor; high-intensity lightly myelinated mechanical   stimuli and   intense heat

SP and CGRP

Skin

C-polymodal;   high-threshold nociceptors; unmyelinated

Poorly localized   SP, CGRP   slow pain;   terminates in superficial dorsal burning pain horn; in periphery TRPV2,3 receptor activated by heat; TRPV1 by H+, and capsaicin; ASIC by H+, P2X3 by ATP

Skin

A-delta fiber Intense noxious mechanothermal ­thermal and   nociceptors mechanical   stimuli

Muscles, fascia, tendon, vessel walls

Group III (A-delta); Mechanical stimuli, group IV (C fibers) but not stretch, thermal

Mechanical,   thermal, or   irritant chemical stimuli

A-gamma fiber

10% not pain but Bradykinin (B1/2 innocuous heat. receptors), hisA subgroup of tamine, acetylfibers has P2X3 choline, and KCl; purine recepprostaglandins tor, IB4-lectin (prostaglandin E receptor); SP binding site (neurokinin 1 reand receptor for ceptor); NGF (TrkA glial cell–derived receptor); BDNF neurotrophic (TrkB receptor); factor; termican be sensitized nates in deep by exposure to dorsal horn noxious stimuli and repetitive stimulation

Transmitter Well-localized fast glutamate and pain; pricking, aspartate; glutasharp, aching pain mate binds NMDA receptor Diffuse, aching pain

Joints, capsule Group III (A-delta); Noxious mechaniplexus, ligagroup IV (C fiber) cal and chemical ments, menisci, stimulation fat pads, vessel walls

Muscle spindle

Comment

Dull aching

Inflammation ­increases ­sensitivity, so fibers are   activated by innocuous joint movement,   pressure

Stretch reflex

ASIC, acid-sensing ion channel; ATP, adenosine triphosphate; BDNF, brain-derived neurotrophic factor; CGRP, calcitonin gene-related peptide; NGF, nerve growth factor; NMDA, N-methyl-d-aspartate; P2X3, ligand gated purinoreceptor; SP, substance P; TRP, transient receptor potential receptor.

Table 60-3  Descriptors of Various Somatogenic Pains Skin Descriptors

Localization

Muscle

Bone

Viscera

Nerve

Throbbing

Pounding

Boring

Boring

Quivering

Sharp

Stabbing

Gnawing

Stabbing

Shooting

Itchy

Cramping

Hurting

Gnawing

Pricking

Sore

Wrenching

Rasping

Cramping

Pulling

Tender

Aching

Tiring

Squeezing

Burning

Burning

Taut Tiring

Pulling Heavy Sickening

Tingling Stinging Numb

Surface

Subcutaneous

Not well localized;   often radiates

Follows distribution of neural structures

Deep

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Silent ­nociceptors have a high basal threshold and do not respond to any normal stimulus, but under conditions of tissue damage become sensitized, lowering the threshold for activation. The central terminals of most nociceptors terminate in the superficial zone of the dorsal horn of the spinal cord, whereas low-threshold, non-nociceptive sensory fibers terminate in the deep laminae. Some C fibers also terminate in the deeper parts of the substantia gelatinosa, and reorganization of the structure of the circuitry of the dorsal horn can occur. Mechanoreceptors and polymodal nociceptors contain the neurotransmitter glutamate. Polymodal nociceptors also contain neuropeptides SP, CGRP, and neurokinin A, and are sensitized by K+, H+, prostaglandin E2, bradykinin, serotonin, and ATP. Neurotransmitter release effects synaptic activation of dorsal horn neurons, but nociceptors have efferent function as well. Release of neuropeptides such as SP and CGRP from sensory endings can cause vasodilation, extravasation of plasma, chemotaxis for macrophages, and mast cell degranulation.16 The release of inflammatory mediators as a consequence of neuropeptide release produces increased inflammation (neuro­ genic inflammation) and participates in sensitization of nociceptors. Most nociceptors are normally inactive and unresponsive, but are sensitized by inflammatory mediators to develop spontaneous discharges and lower the threshold of activation to peripheral stimulation.18 A consequence of this sensitization is primary hyperalgesia, an increased painfulness of a noxious stimulus and a reduced threshold for pain (i.e., tenderness to palpation and pain with movement—mechanical stimuli that are normally not painful). SENSITIZATION OF THE PRIMARY AFFERENT NEURON In the setting of inflammation and nerve injury, sensitization of peripheral nociceptors occurs leading to chronic nociceptive pain with hyperalgesia and allodynia. The sensitivity of these receptors is increased by chemical actions on axon surface-membrane receptors that increase intracellular calcium, Na+, and K+, altering membrane potentials and lowering activation thresholds. Intracellular protein kinase C and tyrosine kinases are activated and phosphorylate sensory neuron–specific sodium channels (NaV1.8/1.9) and TRPV1 receptors (see Fig. 60-2).7 The end result is reduced activation potentials and increased sensitivity of receptors to subsequent stimuli. Nociceptors are sensitized by products of inflammation such as prostaglandins, which bind to prostaglandin E receptor (EP), and nerve growth factor, which binds to tyrosine receptor kinase A (TrkA), without directly activating the nociceptor. Bradykinin activates and sensitizes the nerve terminal through the constitutive B2 receptors. B1 receptors are expressed only after injury or inflammation. These G protein–coupled receptors activate protein kinases in the nerve terminal. Phosphorylation by these kinases can alter substantially the activity of receptors and ion channels, reducing activation thresholds and prolonging activity. This sensitization produces the burning pain of a sunburn in response to only a warm temperature stimulus. The decreased threshold produced by peripheral sensitization

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causes high-threshold and silent nociceptors to transmit pain, contributing to the sensitivity to pain at the injured or inflamed site. Because there are multiple sensitizers, the system is resistant to blocking only one of the sensitizing substances. Primary afferent nociceptors have receptors for these mediators and for opiates, γ-aminobutyric acid (GABA), and capsaicin (VR1 receptor). In addition, afferent joint fibers have excitatory amino acid receptors (glutamate). Nociceptive neurons themselves release chemical stimulants of nociception, such as SP and CGRP, which amplify the local inflammatory response by interacting with inflammatory cells and adjacent blood vessels (also known as “neurogenic” inflammation). Vasodilatation and edema resulting from neurogenic inflammation are mediated by vasoactive peptides (CGRP, SP, neurokinin A) released from perivascular C fiber afferents. Peripheral sensory impulses cause release of SP, which causes mast cells to release histamine and platelets to release serotonin, which promotes inflammation and subsequent sensitization of nearby nociceptors.7 Receptors for SP and CGRP also are present on primary afferent neurons; this would suggest that these could be autoreceptors given that SP and CGRP also are synthesized by these neurons. Tissue injury causes local release of K+, prostaglandins, and bradykinin, resulting in stimulation and additional sensitization of sensory afferents. More recent work has shown the direct sensitization of mechanical nociceptors in the rat by paw injection of tumor necrosis factor-α, interleukin-1β, and interleukin-8, which could be blocked by atenolol and indomethacin, supporting further the role of eicosanoids and sympathetic amines in hyperalgesia produced by inflammation.19 Inflammatory mediators induce increased production of nerve growth factor, which is transported from the periphery to the cell body in the dorsal root ganglion. There, nerve growth factor and interleukin-1β and tumor necrosis factor-α act directly on transduction molecules, such as p38 mitogen activated protein kinase, to induce transcriptional factors that control gene expression. This activity leads to increased production of receptors, ion channels, and other functional proteins. These changes can produce a rapid increase in sensitivity of mechanical nociceptors that is p38 dependent.17 Receptors for inhibitory peptides also are present on afferent neurons. Receptors for opioids, somatostatin, and neuropeptide Y have been identified. Opioids increase potassium currents and decrease calcium currents, reducing neuronal firing and release of SP and other transmitters. Opioids also bind to receptors in dorsal root ganglia, central terminals of primary afferent neurons in the spinal cord, and peripheral nerve fibers and terminals (nociceptors).20 At the level of transcriptional change, inflammation produces upregulation of genes and increased expression of TRPV1 and sensory nerve–specific sodium channels in response to injury and inflammatory mediators, and nerve growth factor decreases the threshold to noxious stimulation resulting in hyperalgesia.7 Nerve growth factor also stimulates an increase in the levels of synaptic neurotransmitters that modulate and amplify input to the spinal cord, such as SP and brain-derived neurotrophic factor.7 These sodium channels can be blocked by lidocaine, mexiletine, and anticonvulsants.

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DRG Cell Body

To higher brain centers Primary Afferent Neuron Central Terminal

Primary Afferent Neuron peripheral terminal

Neurotransmitters: Glutamate, Aspartate, FRAP, SP, VIP, SOM, CCK, GRP, AII, CGRP, leuenkephalin, dynorphin

C fiber

Action potential Nociceptor

Pain stimulus NMDA receptor, regulated by voltage dependent Mg blockade and phosphorylation by PKC AMPA receptor Metabotropic receptors: bind glutamate, neurokinin, GABA-A

Receptors for CCK, (+) opioids (–) and GABA-B (–) modulate neurotransmitter release

Interneuron (excitatory)

Ca++ Mg++ PKC

Interneuron (inhibitory) activated by sensory afferents (TENS acupuncture) and descending tracts from the brainstem (dorsolateral Serotonins, norepinephrine, funiculus) descending inhibition

To the Thalamus

To flexor motor neurons for spinal withdrawal reflex

Figure 60-3  Pain transmission at the spinal cord.

Damage to peripheral nerves leads to a different neurochemical signature for neuropathic pain. A-delta fibers and C fibers normally express SP and CGRP; however, expression is downregulated after nerve injury. Nonpainful sensations normally are detected by specialized corpuscle structures and free nerve endings that transduce mechanical stimuli via large myelinated A-beta afferent fibers. Injured A-beta fibers begin to express SP and CGRP; low-­threshold stimuli can lead to SP release in the dorsal horn and hyperexcitability. Regenerative sprouts “rewire” the afferent sensory system, wherein non-noxious stimuli are input as noxious stimuli (allodynia).7 Schwann cells in damaged nerves produce increased mRNA for nerve growth factors and their receptors for regenerative events. Damaged axons also express adrenoreceptors, causing discharges in response to circulating epinephrine and norepinephrine (NE). These neurotrophins also may cause aberrant regeneration, such as the ingrowth of sympathetic postganglionic axons into dorsal root ganglia, or the ingrowth of large myelinated afferents into lamina II, forming abnormal connections in the nociceptive processing circuits within the dorsal horn (which may explain allodynia).17,21 Clustering of sodium channels in the axon membrane produces foci of irritability and ectopic discharges, which are a major contributor to spontaneous neuropathic pain. The number of opioid mu receptors decreases, and the ­number

of α2γ calcium channel subunits increases, producing less effectiveness of morphine and enhanced effectiveness of gabapentin for neuropathic pain.17 PAIN TRANSMISSION TO THE SPINAL CORD The primary afferent neurons synapse onto second-order neurons or interneurons in the dorsal horn of the spinal cord (Fig. 60-3). Central terminals of primary afferent neurons contain the excitatory amino acid neurotransmitters (glutamate and aspartate); neuropeptides (fluoride resistant acid phosphatase [FRAP], SP, vasoactive intestinal peptide [VIP], somatostatin [SOM], cholecystokinin [CCK], gastrin releasing peptide [GRP], angiotensin II, CGRP, enkephalin, and dynorphin); and receptors for cholecystokinin, opioids, and GABA-B, which modulate transmitter release. The second-order neurons express receptors for N-methyld-aspartate (NMDA); alpha-amino-3-hydroxy-5-methyl-4isoxazolepropionate (AMPA); and metabotropic receptors that bind glutamate, neurokinin, and GABA-A (a ligandgated chloride channel), and have glycine binding sites, which decrease responses to stimulation. Noxious stimulation induces c-fos expression in dorsal horn neurons. Interneuronal networks in the dorsal horn are excitatory and inhibitory. The neurons are either nociceptive-specific or wide dynamic range (WDR) neurons

PART 8 

that respond to innocuous and noxious stimuli. Nociceptive neurons synapse with excitatory interneurons to stimulate flexor motor neurons for the spinal withdrawal reflex, and they stimulate nociceptive projection neurons to signal the higher centers in the brain. The interneurons that cross the anterior commissure and ascend in the contralateral spinothalamic tract transmit pain signals to the lateral thalamus, where they synapse with third-order neurons that project to the somatosensory and cingulate cortices to produce consciousness of the type and location of the tissue injury. The medial thalamocortical system is responsible for affective and motivational dimensions of pain. The central and medial thalamic neurons relay to the anterior cingulate cortex, the insula, and the prefrontal cortex. Interneurons that inhibit the nociceptive projection neurons are activated by incoming sensory afferents and descending tracts that reduce nociceptive processing at the spinal level. These pathways originate from the brainstem (periaqueductal gray, nucleus raphe magnus) and descend through the dorsolateral funiculus of the spinal cord.16,17 These inhibitory signals are consistent with the theory of “diffuse noxious inhibitory control,” have significant control over pain processing, and are a possible explanation for the analgesic effects of acupuncture and transcutaneous nerve stimulation.22 CENTRAL SENSITIZATION AT THE SPINAL CORD Development of peripheral arthritis or damage to a peripheral nerve results in changes in levels of neurotransmitters and subsequent activation of second messenger systems, which produces central sensitization with enhanced responsiveness to stimuli. Central sensitization produces allodynia (painful response to non-noxious stimuli), hyperalgesia (enhanced painful response to noxious stimuli), and spread of sensitivity to noninjured areas (secondary hyperalgesia). Most often, central sensitization resolves as the injury heals, but sometimes it fails to reverse and leads to chronic pain. This phenomenon is distinct from “wind-up,” which is progressively increased hyperalgesia produced as a result of voltage-dependent magnesium block of the NMDA receptor’s ion channel in response to repeated identical noxious stimuli. Wind-up does not lead to prolonged enhancement of neuronal sensitivity as central sensitization can, but can induce central sensitization by increasing intraneuronal calcium levels. Central sensitization is due to increased responsiveness of WDR neurons in the dorsal horn, which occurs as a result of increased intracellular calcium. Calcium enters the neuron as a result of conduction by NMDA receptors through ionophores from the extracellular space. This increased calcium enhances synaptic input from nociceptors and effectively increases the number of synapses on dorsal horn neurons and enhances neuronal excitability (see Fig. 60-3).23 The WDR neurons then respond to noxious and innocuous stimuli. Hyperexcitability in the spinal cord depends on release of excitatory amino acids, such as glutamate and neuropeptides, from afferent nerves and interneurons. Glutamate activates multiple receptors, including NMDA receptors, non-NMDA receptors, and metabotropic glutamate receptors. Glutamate reacts with postsynaptic AMPA receptors causing fast excitatory postsynaptic potentials. During

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intense noxious stimulation, SP and glutamate are coreleased causing sustained slow excitatory postsynaptic potentials (depolarization), temporal summation, and removal of the magnesium blockade of the NMDA calcium channel. Increased calcium activates protein kinase C, which phosphorylates NMDA receptors, increasing excitability of dorsal horn neurons further. In contrast to sensitization from peripheral inflammation or tissue damage, nerve damage causes downregulation of SP, somatostatin, and CGRP. Inhibitory circuits in the spinal cord release inhibitory amino acids (GABA and glycine) and the neuropeptide enkephalin. Presynaptic inhibition is mediated through opioid receptors, GABA-A, and GABA-B receptors, and postsynaptic inhibition is mediated through the glycine receptor and the two GABA receptors.17 Peripheral afferents for position sense and vibration also have cell bodies in the dorsal root ganglia and have inhibitory feedback on nociceptive processing in the dorsal horn. These large fibers can be stimulated by transcutaneous nerve stimulators to decrease pain. PROJECTION OF PAIN TO THE BRAIN Nociceptive projection neurons in the spinal cord cross the spinal cord and ascend in the spinothalamic tract, spinoreticular tract, and spinomesencephalic tract (Table 60-4). Spinothalamic cells have excitatory receptive fields sensitive to noxious stimulation and inhibitory receptive fields that can be inhibited by repetitive stimulation of peripheral nerves (i.e., transcutaneous electric nerve stimulation [TENS] unit). The lateral axons of the spinothalamic tract synapse in the ventroposterolateral thalamus with thirdorder neurons that project to the somatosensory cortex in the parietal lobe (Fig. 60-4). The medial fibers of the spinothalamic tract ascend and send fibers to the reticular formation, periaqueductal gray area, parabrachial nuclei, and medial thalamus to synapse with neurons that project to the limbic system (hypothalamus, amygdaloid nucleus, septal nucleus).17 The spinomesencephalic tract cells originate in the laminae I and IV to VI primarily and project to midbrain periaqueductal gray nuclei and synapse in the medial thalamus. These cells often have complex receptive fields on widely separated areas of the body and serve to provoke aversive behavior and activate descending analgesia. The cells of the spinoreticular tracts are in the deep laminae of the dorsal horn and ventral horn (VII and VIII), project to the caudal medulla (reticular nucleus to stimulate alertness), and send collaterals to catecholamine cell groups of the medulla and pons to signal brainstem autonomic centers, activate endogenous analgesia systems, and synapse in the medial thalamus.16,17 From the medial thalamus, neurons project to the anterior cingulate gyrus and are involved in affective responses and perception of suffering with pain. Neurons from the lateral thalamus project to the somatosensory cortex to allow precise localization and characterization of the pain stimulus. Functional brain imaging studies have shown that multiple cortical areas are activated by painful stimuli, including somatosensory cortices (for discriminative aspects of pain sensation) and cingulate cortex, insula, and prefrontal cortex (for affective motivational aspects of pain sensation).16

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Table 60-4  Pain Transmission Pathways First Synapse

Pathway

Third-Order Synapse

Destination

Dorsal horn

Contralateral

Somatosensory cortex

Dorsal horn

Contralateral

Spinoreticular tract

Dorsal horn

Ipsilateral and   contralateral

Spinomesencephalic   tract

Dorsal horn

Contralateral

Ventral, posterior lateral thalamus Reticular formation ­periaqueductal gray   and hypothalamus Midbrain reticular   formation, medial   thalamic nuclei Midbrain reticular   formation

Ascending Nociceptive Projection Pathways Lateral spinothalamic   tract Medial spinothalamic   tract

Limbic forebrain Limbic forebrain Limbic forebrain

Descending Pain-­Modulation Pathway Periaqueductal gray

Locus caeruleus

Dorsolateral funiculus; ­serotonergic and   suppresses nociception   transmission Ventrolateral funiculus,   pons pathway

Somatosensory cortex and limbic system

Thalamus and hypothalamus

Periaqueductal gray in midbrain

Reticular formation Pons and medulla Locus caeruleus Raphe nuclei

Norepinephrine and serotonin

Nucleus raphe magnus,   rostral ventromedial ­medulla, brainstem   opioid receptors

Dorsal horn, opioid receptors, serotonin, norepinephrine Dorsal horn, serotonin, norepinephrine

medulla, and to the dorsal horn of the spinal cord where the nociceptive transmission is inhibited (see Fig. 60-4).16 Analgesia produced by stimulation of periaqueductal gray matter is mediated by endogenous opioids and does not affect touch, proprioception, or thermal sensation. Binding of opiate receptors by endogenous enkephalin, β-endorphin, and dynorphin, or by exogenous opiates activates the descending analgesia tracts from the periaqueductal gray to the spinal cord. Serotonin and NE are the likely neurotransmitters in the midbrain pain modulation system. The action of these monoamines in the descending endogenous analgesic mechanism may explain the analgesic potentiating effects of tricyclic antidepressants (TCAs). Stimulation of the periaqueductal gray inhibits nociceptive dorsal horn neurons and spinothalamic tract cells. Bilateral projections descend from the locus caeruleus to innervate laminae I, II, and V of the dorsal horn. Brainstem raphe nuclei neurons contain serotonin and are the major source of serotonin in the spinal cord. Reticular formation neurons are excited by noxious stimuli and result in aversive behavior.

NEUROBIOLOGY OF ARTICULAR PAIN Spinothalamic tract Spinoreticular tract Spinomesencephalic tract Figure 60-4  Ascending and descending pain tracts.

MODULATION OF PAIN TRANSMISSION IN THE CENTRAL NERVOUS SYSTEM Transmission of a nociceptor signal to the brain initiates pain modulation via an inhibitory descending analgesia system from the cortex, limbic system, thalamus, and hypothalamus. The descending pathway projects onto the periaqueductal gray area, the nucleus raphe magnus of the pons, and rostral

Articular and periarticular nociceptors are analogous to cutaneous nociceptors (Fig. 60-5).24 C polymodal nociceptors form a diffuse lattice throughout the articular capsule. A-delta fiber free nerve endings are found in intra­articular and periarticular ligaments.25 In the synovium, SP-positive and CGRP-positive nerve fibers are associated with blood vessels or form a network of free endings up to the intima layer. Sympathetic fibers are localized to blood vessels. Nociceptive and proprioceptive signaling is the obvious function of articular nerves; however, advances in the understanding of molecular mechanisms involved in ­afferent and efferent transmissions have led to the reciprocal concept that neurogenic inflammation might play a role in the pathogenesis of joint disorders. Antidromic (reverse) stimulation of peripheral fibers proximate to blood vessels, and tissue mast cells can cause vasodilation and plasma

PART 8  Increase of Enhancement of the neuropeptide effectiveness of descending production inhibitory influences

Release of transmitters and modulators Increased synthesis of neuropeptides Gene expression

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Increased afferent inflow (group II, III, IV sensory fibers)

Release of neuropeptides from afferent fibers Hyperexcitability of spinal neurons with articular input

Ascending fibers, e.g., spinothalamic tract Sympathetic reflexes Muscles Motor reflexes

extravasation.25 Under conditions of inflammation, articular primary afferent neurons become sensitized to mechanical, thermal, and chemical stimuli, producing the characteristic inflammatory joint pain on movement and with palpation (i.e., allodynia and hyperalgesia). Sensitization of the articular primary afferent is the essential step in the generation of inflammatory joint pain. Spinal cord neurons also become sensitized by inflammation in the joint and have increased sensitivity to afferent inputs from the inflamed joint (i.e., central sensitization), amplifying nociceptive processing. Neuropeptides synthesized in dorsal root ganglion cells of C fibers and A-delta fibers are transported centrally to the dorsal horn as neurotransmitters, but also distally to interact with resident articular cells, inflammatory cells, blood vessels, and lymphatics (i.e., neurogenic inflammation). This phenomenon likely explains the more recent observation of reduced pain after intra-articular injection of botulinum toxin type A, which inhibits the release of neurotransmitters such as SP and CGRP in the periphery. These data suggest that intraarticular therapies directed against efferent nerve function may be a new approach to intra-articular therapy of refractory joint pain.26 Sympathetic efferent fibers also may be involved with neurogenic inflammation. In rat adjuvant arthritis, sectioning the nerve or applying capsaicin to the limb (which depletes SP) attenuates arthritis severity.27 Subcutaneous injection of capsaicin reduced levels of SP, CGRP, and nerve growth factor in arthritic joints and dorsal root ganglia and reduced the inflammatory response in rats.28 Later in the course of adjuvant arthritis, SP and CGRP nerve fiber density is reduced in the synovium and periarticular bone (autodenervation), followed by a regenerative phase and altered morphology.25 In the rheumatoid synovium, there are reduced free nerve endings and sympathetic fibers on blood vessels in the superficial layer. In a mouse model of antigen-induced arthritis, immunocytochemical localization studies showed the apparent reduction in SP and CGRP nerves in arthritic

Pressure

Synthesis and release of inflammatory mediators

Figure 60-5  Articular innervation. Schema of nociceptive interactions that occur during joint inflammation. (From Schaible HG, Grubb BD: Afferent and spinal mechanisms of joint pain. Pain 55:6, 1993.)

synovium was likely due to failure of reinnervation by outgrowing neural fibers because they were unable to keep up with the intense proliferation of synovial tissue during the arthritic process, rather than because of the destruction of nerve tissue.29 Sensitization of articular nociceptors by inflammation results in normally nonresponsive primary afferents becoming responsive to non-noxious movements and touch and having spontaneous activity at rest.30 SP seems to be the principal neurotransmitter of pain in arthritis and contributes to the inflammatory response by stimulating the resident cells in the joint to produce a multitude of inflammatory mediators and cytokines.31 SP can activate mast cells, synoviocytes, neutrophils, T cells, B cells, and macrophages, amplifying the inflammatory response. Neurokinin receptors that bind SP are coupled to regulatory G proteins and activate hydrolysis of inositol-containing phospholipids for the second response in cell activation.31 During inflammation, opioid receptors are upregulated on peripheral sensory nerves, and resident immune cells express endogenous opioids; intra-articular opioids reduce pain and possibly inflammation.20 More recent studies have suggested a role for nitric oxide in pain accompanying inflammation. In a rat model of polyarthritis, administration of the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) reversed thermal hyperalgesia, but not mechanical allodynia or joint inflammation. Independent of inflammation in the joint, mechanical pain in joints may be produced by nociceptors in ligaments, joint capsule, entheses, and blood vessels that are activated by increased intra-articular pressure with effusions and abnormal forces and torque with deformities. Although the description of events in the spinal cord relevant to processing nociceptive information from the joint is incomplete, it is clear the spinal cord is the integrative site for afferent sensory information and reflex functions.24 After noxious stimulation of peripheral tissues, c-fos is expressed, presumably for long-term adaptations in neurons

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such as synthesis of neuropeptides. With acute and chronic inflammation in a peripheral joint, levels of transmitters and receptors in dorsal root ganglia and the spinal cord change. Glutamate seems to be involved with NMDA receptors in transmission of nociceptive information from an inflamed joint to the spinal cord. Transmitters involved with descending inhibition of spinal neurons include serotonin and NE, which are increased under inflammatory conditions. Neuropeptide synthesis (SP, CGRP, dynorphin, enkephalin) in dorsal ganglia, the spinal cord, or both also is increased in at least some of the stages of joint inflammation.25 The functional consequences of the changes in neuropeptides, transmitters, and receptors remain to be elucidated, however. The role of the spinal cord in regulation of peripheral joint inflammation is just beginning to be defined.32 Investigators using mouse models of bone cancer pain, neuropathic pain, and inflammatory pain have helped to delineate neuromolecular signatures of the three different­ pain states. The signature for bone cancer pain was increased α 1 in a spinal cord astrocyte marker (reflecting hypertrophy of astrocytes), increased dynorphin in deep spinal laminae, no changes in SP or CGRP, increased internalization of SP receptor, and increased c-fos expression in lamina I of the dorsal horn, showing sensitization of primary afferent neurons.21 With paw inflammation pain, there was upregulation of SP and CGRP in laminae I and II of the dorsal horn and increased protein kinase C and SP receptor. In contrast, with nerve injury there was downregulation of SP and CGRP and upregulation of galanin, neuropeptide Y, and GAP-43 in primary afferent neurons and the spinal cord.16 This group of investigators also has shown that osteoprotegerin prevented cancer-induced bone destruction by osteoclasts, reduced pain, and blocked the spinal cord changes of sensitization.33 Such advances in understanding of the neuromolecular signatures for different pain states can provide a new framework for the mechanism-based development of new analgesics.

PAIN GENERATION WITH NERVOUS SYSTEM DISORDERS Rheumatologic pain conditions may have overlapping nociceptive and neuropathic components, as in intervertebral disk disease with radiculopathy or vasculitis with associated­ neuropathy. It is important to detect neuropathic pain mechanisms because the treatment of neuropathic pain differs from the treatments for immune-mediated or inflammatory musculoskeletal disorders. Assessment of neuropathic pain is complex because the varied signs and symptoms fluctu ate in number and intensity over time.34 Injured peripheral nerves produce intense and prolonged sensory information to the central nervous system and may cause a secondary increase in excitability of dorsal horn neurons and altered local or descending inhibition.16,35 Nerve injury from infection, trauma, diabetes, or other toxins causes nociceptive nerves to develop spontaneous ectopic discharges, become responsive to innocuous stimuli (allodynia), and develop expanded receptive fields. Spontaneous ectopic discharges in C fibers produce repetitive stimulation of spinal cord neurons and cause hypersensitivity mediated by glutamate interaction with NMDA, AMPA, and glutamate receptors. Glutamate can cause

excitotoxic damage to the inhibitory interneurons in the dorsal horn, resulting in central disinhibition of nociceptive input. Clinically, the symptoms are those of the neurologic deficit and abnormal sensory symptoms of dysesthesias (e.g., painful light touch), paresthesias (e.g., tingling), expanded territory of pain (expanded receptive field gives “stocking glove distribution”), steady burning pain, pins and needles pain with numbness, and spontaneous paroxysms of lancinating pain. Each of these symptoms is thought to have a different underlying mechanism. Generation of pain in the peripheral neuropathies is not due to nociception in the tissues of the painful area. The injured axons have a lowered threshold of activation and become the source of spontaneous barrages of action potentials in response to normally innocuous stimuli (allodynia) and produce exaggerated responses to noxious stimuli (hyperalgesia). This spontaneous activity is enhanced further by chemicals, ischemia, inflammation, infection, or adrenergic agonists. Pain in association with polyneuropathies can be superficial or deep. This sensitization of injured peripheral nerves also results in signs of autonomic dysfunction (changes in skin color, temperature, and edema). Transected nerves in amputees have ongoing spontaneous C fiber activity (burning, spontaneous pain) and contact-evoked stump pain that results from sensitized C nociceptors, which can be blocked by lidocaine, phenol, or botulinum toxin injections. There is an accumulation of sodium channels at the site of injury causing a lowered nociceptor depolarization threshold, and ectopic discharges. In regenerating nerve sprouts, novel receptors are expressed, including adrenergic receptors and N-type or L-type calcium channels. Central sensitization after peripheral nerve injury develops in the spinal cord.23 SP and neurokinin A released from nociceptors bind to NK1 and NK2 receptors, triggering the release of intracellular calcium. Increased calcium increases neuronal hyperexcitability and expression of NMDA receptors. Glutamate from the primary afferents is bound, leading to a further increase of intracellular calcium and sodium into the cells. The end result of increased intracellular calcium is activation of protein kinase C, phospholipase C, and nitric oxide synthetase, and induction of early gene expression (c-fos, c-jun), all processes that maintain central sensitization (see Fig. 60-4). In poststroke pain, the area of pain is within the area of abnormal sensory function, indicating that lost input causes secondary sensitization in the central neurons. PERIPHERAL NERVE DISORDERS CAUSING PAIN Generalized nerve disorders (axonal or demyelinating) and focal nerve disorders (mononeuropathy simplex and segmental neuropathies) cause neuropathic pain. Peripheral nerves have small fibers (pain and temperature sensation and autonomic fibers) and large fibers (motor function, stretch reflex, position, vibration, touch). Focal neuropathies are simple or multiple and may be due to entrapment, is­chemia, trauma, vasculitis, or infections such as herpesvirus, human immunodeficiency virus, leprosy, and Lyme disease. Acute mononeuropathies of cranial and peripheral nerves in patients with diabetes are due to ischemia or entrapment or both. In focal segmental neuropathy, groups of nerves are involved by neoplastic infiltration; radiation

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plexopathy; and ­postinfectious or immune-mediated cervical, brachial, or lumbosacral plexopathy. Mononeuropathies (either single or multiple), regardless of cause, produce burning pain and a neurologic deficit in the distribution of the involved nerve. Diabetic focal proximal neuropathy (previously known as amyotrophy or plexopathy) is an immune-mediated inflammatory process with vasculitis and demyelination. The clinical presentation is an elderly individual with type 2 diabetes who develops the gradual or abrupt onset of pain in the thighs, hips, or buttocks, followed by significant weakness that may resolve in 1 to 2 years. Entrapment syndromes occur with gradual compression of the median nerve at the wrist (carpal tunnel syndrome), ulnar nerve at the cubital tunnel, and posterior tibial nerve at the tarsal tunnel. The compression initially causes demyelination, then axonal destruction. Pain originates from nociceptors in nervi nervorum. Patients may describe tingling with numbness in the distribution of the nerve or may have a deep aching pain in the entire extremity with atrophy and weakness. Palpation or percussion of the nerve trunk produces an electric shock–like sensation. Nerve compression produces a focal nerve injury with pain in and beyond the sensory distribution of the nerve. With carpal tunnel syndrome, numbness, tingling, and burning sensations occur in the thumb, index, and middle fingers. The pain awakens the patient at night, may radiate up the forearm to the shoulder or neck, and may include thumb muscle weakness and atrophy. With ulnar nerve entrapment in the cubital tunnel, weakness and atrophy predominate over pain. Meralgia paresthetica is entrapment of the lateral femoral cutaneous nerve under the inguinal ligament, which produces numbness and burning pain over the lateral thigh. The posterior tarsal tunnel syndrome is produced by compression of the posterior tibial nerve inferior to the medial malleolus, causing pain in the sole of the foot that has a burning, unpleasant quality. The pain typically worsens with rest and at night. Severe injury to a major peripheral nerve as a result of avulsion, knife or gunshot wound, tumor invasion, or severance (as with amputation) causes post-traumatic neuralgia or causalgia. Causalgia is a devastating pain syndrome with hyperactivity of the sympathetic nervous system. There is sensory loss distal to the injury. The dysesthetic pain of a peripheral nerve injury is burning with superimposed lancinating pain thought to be due to increased firing of regenerating nerve sprouts and spontaneous firing at sites of demyelination. Nerve trunk pain is an aching pain, possibly resulting from firing of nociceptors in the nerve sheath (nervi nervorum) of the injured nerve. Causalgia is described as a burning, red-hot pain with vasomotor changes (mottled or red skin), edema, allodynia, hyperpathia, hyperalgesia, and later trophic changes. Palpation of the injured nerve produces electric shock–like pain, which travels down the nerve, and there may be a palpable nodule at the site of the nerve injury, which is a neuroma of axon sprouts at the site of axon regeneration. Causalgia is often relieved by wet applications and warming, but is aggravated by various somatosensory, visual, auditory, emotional, or psychological factors; movement; or touch. The pain gradually disappears in a few months to 2 years, but may be helped by early sympathetic blockade.

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It has been theorized that damaged nociceptor fibers become sensitive to NE after injury. Regenerating nociceptor fibers at the injury site may synapse with sympathetic fibers and give rise to spontaneous pain stimuli. Fibers in the dorsal horn may become sensitive to non-nociceptive signals produced by sympathetic activity. After amputation, most patients have persistent sensations of the limb, and the sensation is painful in some patients. The pain in the phantom limb is described as aching, cramping, burning, squeezing, crushing, or tearing, and can persist for years or be intermittent. Phantom sensations gradually disappear; sympathetic blockade may help. Stump pain after healing is due to a neuroma at the severed nerve or other complications in the stump tissues, such as ischemia, infection, osteomyelitis, or poorly fitting prosthesis. Reactivation of herpes zoster infection in the dorsal root ganglia causes a mononeuropathy, postherpetic neuralgia. This virus-induced inflammation in the dorsal root ganglion produces a sensory deficit and intractable pain in the affected dermatome. The skin is extremely tender to touch (tactile allodynia), yet firm compression relieves the pain. Cold and psychological stress adversely affect the pain. These features suggest postherpetic neuralgia is a deafferentation pain syndrome with activation of the sympathetic system, which renders nociceptors sensitive to tactile stimuli. The pain may persist for 2 years and then disappear spontaneously. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are generally ineffective in postherpetic neuralgia. Topical preparations of aspirin, lidocaine, and capsaicin (if transient increased pain can be tolerated) may be beneficial. TCAs, but not selective serotonin reuptake inhibitors, may help, and anticonvulsant drugs, such as gabapentin,36,37 can reduce the pain.38 Improvement in pain was the same for doses of either 1800 mg/day or 2400 mg/day (34% for both doses).37 TENS, but not acupuncture, reduced pain in some patients. Treatment of herpes zoster with corticosteroids and antiviral agents is recommended to prevent or reduce the severity of postherpetic neuralgia. Unilateral, recurring, sudden paroxysms of sharp, stabbing, lancinating pain in the second division, third division, or both of the fifth cranial nerve is termed tic douloureux or trigeminal neuralgia. This disorder can be caused by trauma, tumor, or demyelination, or it can be idiopathic. Possible mechanisms are an irritable focus generating nociceptive signals or an area of demyelination with spontaneous activation. The paroxysms are precipitated by touch, chewing, teeth brushing, or talking and occur in clusters lasting several hours. Between episodes, patients are asymptomatic. The finding of altered cutaneous sensation between episodes should prompt a search for a structural lesion, such as gasserian ganglion tumor, multiple sclerosis, or brainstem infarct. Treatment with carbamazepine, phenytoin, or baclofen is usually effective. Generalized peripheral neuropathies are categorized as demyelinating or axonal and may be acute or chronic. Demyelinating neuropathies are associated with toxins, viral infections, paraproteins, as a paraneoplastic proc­ess, and immune-mediated hereditary diseases. The axonal neuropathies are usually acquired and are divided into small fiber or large fiber disorders. This form is seen in diabetes, uremia, hereditary neuropathies, and immunologic and nutritional toxic neuropathies.

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The most common cause is diabetes, with a generalized distal sensory or sensorimotor neuropathy of insidious onset involving small fibers, large fibers, or both. The clinical features of large fiber neuropathy include loss of vibration, touch, and proprioception sense with loss of deep tendon reflexes and abnormal nerve conduction studies. Small fiber neuropathy is associated with burning or lancinating pain, hyperalgesia, paresthesias, and loss of pain and temperature sensation, but intact reflexes, touch, vibration, and position sense, and it is often complicated by foot skin ulcerations. Diabetic polyneuropathy causes gradual numbness, dull aching or burning pain with pins and needles sensation, and mild or no muscle weakness. There is decreased cutaneous and vibratory sense, decreased deep tendon reflexes, and a gradual decrease in pain as all sensation is lost. Large fiber neuropathies produce weakness, loss of reflexes, loss of touch sense, and various dysesthesias. CENTRAL NERVOUS SYSTEM DISORDERS CAUSING PAIN Lesions in the central nervous system can produce various pain conditions, termed central pain, including poststroke pain, thalamic pain, spinal cord injury pain, central deafferentation pain, and anesthesia dolorosa. These pain conditions originate from the central nervous system after partial, complete, or subclinical interruption of somatosensory pathways, especially the spinothalamic tracts. Causes of central pain are stroke, trauma, tumor, and multiple sclerosis. Deafferentation nerve injury can cause denervation in the next higher order neuron owing to excitotoxicity. Patients experience multiple pain symptoms: a spontaneous, unpleasant, burning pain; tingling or numbness; crawling, ripping, or tearing sensation; warm and cold allodynia; and hyperalgesia. Localization of the pain is diffuse and usually beyond the area of sensory loss. Spontaneous pain develops weeks to months after injury or thalamic infarct in the same distribution as the sensory loss, presumably from denervation hypersensitivity of sensory neurons in the midbrain reticular formation. Lesions in the spinothalamic input into the thalamus are followed by reorganization and connection of touch input to previously silent neurons with an opioid link. Central pain can be decreased with amitriptyline, lamotrigine, and intravenous lidocaine, all sodium channel blockers. Intravenous lidocaine significantly decreased spontaneous pain and evoked brush-induced allodynia and mechanical hyperalgesia, but not thermal allodynia and hyperalgesia in 16 patients with central pain owing to stroke or spinal cord injury.39 Follow-up treatment with oral mex­ iletine was disappointing because of much less pain relief and more side effects. Intravenous morphine reduced touchevoked pain (allodynia), but not other evoked pains. Overall effects of morphine on spontaneous ongoing pain were no different than placebo; however, 46% of the patients responded to morphine.40 COMPLEX REGIONAL PAIN SYNDROMES I AND II Complex regional pain syndrome, previously reflex sympathetic dystrophy, is a syndrome encompassing sensory, autonomic, and motor function changes in an extremity after an injury or operation, or it may develop spontaneously.

At a consensus meeting, the terms chronic regional pain syndrome type I for reflex sympathetic dystrophy with no definable nerve injury and chronic regional pain syndrome type II for causalgia with a definable nerve injury were defined.41 Patients experience an excruciating burning pain and functional impairment with variable occurrence of evolving symptoms beyond the area of trauma. There is a cold feeling, warm feeling, or both in the affected area; edema; increased nail and hair growth; hyperhidrosis; abnormal skin color; hypesthesia; hyperalgesia; mechanical allodynia, thermal allodynia, or both; movement disorder; and patchy demineralization of the bone (Sudek’s atrophy).42 The movement disorder with complex regional pain syndrome is complex and includes inability to initiate movement, tremor, spasms, weakness, and dystonia. Autonomic dysfunction is evident early as hyperemia of the limb with rapid capillary refill time; later, the limb becomes cool, cyanotic, and mottled with diminished blood flow and prolonged capillary refill time. More recent investigations have suggested that release of SP and CGRP from sensitized C-nociceptors causes vasodilation and increased capillary permeability to account for ongoing edema, vasodilation, and pain (i.e., neurogenic inflammation).43 Bone and periosteum are densely innervated by CGRP-positive neurons, which decrease several days after a dislocated fracture, indicating nerve damage. After fracture or surgery, surviving nerve fibers undergo sprouting and regeneration, which might be the underlying pathophysiology of some patients with complex regional pain syndrome I and patients with complex regional pain syndrome II.43 Treatment with NSAIDs, gabapentin, and narcotics; physical therapy; and TENS has been only partially effective in most patients. Treatment with sympathetic block or intravenous lidocaine followed by oral mexiletine may help refractory patients. In selected patients, spinal cord stimulation decreased pain and improved quality of life.42 Intrathecal baclofen, a GABA-receptor antagonist, reduced the dystonia in the hands and improved function with prolonged treatment.44 Complex regional pain syndrome is a devastating illness, and underlying mechanisms are becoming known. Injury to peripheral C fibers or A-delta fibers triggers neurochemical changes in the distal nociceptors, the dorsal root ganglia cells, and neurons in the dorsal horn of the spinal cord by retrograde transport of neurochemicals and nerve growth factors, with subsequent alteration in membrane channels and ectopic firing to sustain the pain and sympathetic stimulation.16

PSYCHIATRIC COMORBIDITIES IN PATIENTS WITH CHRONIC PAIN Primary or secondary psychiatric disorders, or both, are seen often in patients with chronic pain and may have a negative impact on pain severity and functional status. Psychiatrists have important expertise to elucidate a patient’s life profile and specialized skills to analyze psychodynamic mechanisms in these complex patients. They also have a specialized fund of knowledge and experience treating psychiatric disorders that medical specialists usually do not have. Axis I psychiatric disorders, such as depression, anxiety, or panic disorder, often occur at some time in patients with chronic pain, but are not thought to cause the pain. 45

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Depression is a comorbid condition that interacts with chronic pain to increase its severity and adversely affects the patient’s coping strategies and function. The role of depression must be explored in detail in patients with chronic pain so that the depression and pain can be treated appropriately. In patients with chronic pain who also are depressed, the depression may be “masked” (i.e., the patients have only vegetative symptoms of insomnia, weight loss, reduced energy or interest, loss of libido, reduced concentration, and nonproductive activity, rather than the depressed affect). Chronic pain patients also can have anxiety and panic disorder. Alcohol and drug abuse affects 16% to 20% of general medical outpatients.46 Substance abuse disorders may be more prevalent in patients with chronic pain (3.2% to 18.9%); however, the research data are discrepant, and most individuals had the substance abuse disorder before the onset of chronic pain.47 In some patients, pain emerges without an apparent physical abnormality as the source or cause. These patients have psychiatric disorders that antedated the onset of chronic pain, and the pain has become a manifestation of psychiatric disease. These disorders have specific diagnostic criteria, stereotypic life profiles, abnormal family dynamics, and social and vocational dysfunction. The diagnosis should not be made as a diagnosis of exclusion, but by positive diagnostic evidence for a somatoform disorder, depression, substance abuse disorder, personality disorder, or psychotic disorder (e.g., schizophrenia or major psychotic depression). In other patients, the chronic pain state may have become complicated by the development of a comorbid psychiatric disorder, such as depression, anxiety, or substance abuse. The in-depth history should be directed at “unlayering” the psychological components of the observed pain behaviors. The diagnosis pain disorder replaces the term somatoform pain disorder in the Diagnostic and Statistical Manual of Mental Disorders.8 Somatoform disorders, which may have pain as a symptom, include somatization disorder, hypochondriasis, conversion disorder, and pain disorder (Table 60-5). Somatization means the conversion of mental experiences or states into bodily symptoms, a psychophysiologic process wherein symptom perception varies from minimalization to amplification, yet no physical illness can be found. Somatization is a feature of numerous psychiatric disorders associated with pain. More than 50% of patients with a psychiatric disorder present with somatic complaints to a primary care ­physician. Underdiagnosis of disabling psychiatric disease occurs when the diagnosis of psychiatric disease is viewed as a diagnosis of exclusion. For patients who have pain as a manifestation of underlying psychiatric disorders, therapeutic attempts focused on symptomatic treatment of the pain are unsuccessful and delay appropriate diagnosis and treatment of the psychiatric disease. The individual attributes the symptom to some cause and reacts to the symptom. The list of unexplained somatic complaints accumulates over time and is accompanied by functional impairment, overuse of the health care system, and additional psychiatric disorders such as depression and anxiety. Somatization disorder typically begins before age 20 to 30. Symptoms are exaggerated and multifocal, involving most organ systems. The patients are preoccupied with their pain and believe they have a serious medical illness. The

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patients do not intentionally produce or magnify the pain and are unaware that the pain is linked to psychological factors or conflict. A neuropsychological basis for ­somatization disorder has been postulated, which suggests that attentional and cognitive impairments result in faulty perception and assessment of somatosensory input. Distress and interpersonal problems are common. These individuals are often anxious and depressed, and may attempt suicide. There may be a family history of marital discord, abuse, alcoholism, and sociopathy in parents and spouses. The interview is difficult because the medical history and review of systems are vague, circumstantial, and disorganized. Patients often describe their symptoms in colorful, exaggerated terms, but lack specific factual information. The patients frequently report that their prior physicians were incompetent and often have a long history of poor compliance with medical recommendations and “doctor shopping.” This disorder is much more common in women. Somatization disorder has a fluctuating course, but seldom remits completely. Treatment is directed at assisting the patient to cope and preventing unnecessary workups and surgeries. These patients need frequent clinic visits for reassurance that the pain is not due to physical illness, and supportive psychotherapy is beneficial, if they participate. Preoccupation with fears about having a serious disease based on a misinterpretation of normal body sensations or everyday aches and pains is termed hypochondriasis or hysteria. The unwarranted fears persist despite medical reassurance. Concern about the feared illness becomes the focus of the individual’s self-image. The patient relates the medical history in great detail and at length, with description of multiple unsatisfactory physician-patient relationships, and the conviction he or she is not receiving the proper care. Family history reveals illness was a prominent focus of attention. In the medical history, it becomes apparent the patient is as concerned about the meaning and diagnosis of the symptom as with its relief. Hypochondriacs are preoccupied with their bodies and physiologic functioning and are obsessed with their health. Family and social relationships deteriorate because of the self-centered focus on “the condition” and demands for special treatment and consideration.8 Physician visits become a way of life, and these patients carry out elaborate selftreatment regimens. Treatment should be by a primary care physician who conceptualizes that the symptoms are a communication, not a disease to be eradicated. Group psychotherapy also is helpful because it provides the social interaction and support these patients need. Drug therapy should be avoided because hypochondriacs tend to develop side effects or replace a cured symptom with a new one. Hypochondriasis may begin at any age and is equally common in men and women. It has a waxing and waning course with occasional complete recovery. The individual is not delusional and may become able to consider that the feared disease is not present. Conversion disorder describes symptoms and deficits affecting voluntary motor or sensory function that suggest a neurologic or medical condition. Pain may be one of the symptoms, but not the only symptom. Deficits are not feigned and do not conform to anatomic pathways or physiologic mechanisms. The individual may show surprising indifference to the deficits or be overly dramatic. ­Conversion

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Table 60-5  Features of Comorbid Psychiatric Disorders Disorders

Hallmark

Somatoform disorders

Symptoms but no physical   abnormality Preoccupied with the pain;   dramatic or exaggerated   symptoms

Additional Features

Comments

Positive evidence for link to   psychological factor or conflict Polysymptomatic, often anxious, ­depressed; common social   difficulties; onset at a young   age (<20-30 yr) Preoccupied with fear they   Often anxious, depressed,   have physical illness; unrealistic and frustrated with physicians interpretation of sensations as abnormal Preoccupation with pain in   Pain nonanatomic; antecedent   excess of physical abnormality event in adulthood with   psychological conflict Pain as a conversion reaction   Indifferent to deficit with motor or sensory deficit

No response to antidepressants, anxiolytics, or muscle relaxants Complicated history with care from multiple physicians; has no insight the pain is linked to psychological factors Symptoms but no loss of function; a “doctor shopper”; “worried well”; seeking relief from fear of illness rather than pain Pain provides secondary gain of support or avoidance

Pain-depression syndrome

Pain as a somatic manifestation   of depression, which may be   masked (only vegetative signs)

Tricyclic antidepressants improve pain and depression

Personality disorders

Pain used to carry out pathologic   DSM-IV Cluster B antisocial,  borderline, histrionic, and   relationships and get attention   (i.e., interpersonal exploitation, narcissistic personalities manipulation, theft)

The most difficult patient to   treat in an interdisciplinary ­setting—problems with ­authority and triangulate staff, impulsive and aggressive, seductive; usually oblivious to their own problems, behavior is inflexible and pervasive; they disregard and violate the rights of others and lack empathy; strong sense of entitlement, very poor treatment outcomes (i.e., “the dreaded patient”)

Substance abuse disorder

Pain used to obtain narcotics

Need rigid treatment contracts

Malingering

Symptoms intentionally   produced for a specific goal

Goal is compensation or avoidance of work

Factitious disorder

Symptoms intentionally   produced

Goal is “winning,” secondary goal not obvious

Munchausen syndrome

Psychosis (schizophrenia or psychotic depression)

Pain as a fixed somatic   delusion is uncommon

Bizarre distribution and quality

Treat underlying psychosis

Somatization disorder   (hysteria) Hypochondriasis

Pain disorder   (psychogenic pain) Conversion disorder

Depression makes pain   exaggerated and less tolerated

Self-limited but recurrent episodes of motor or sensory deficit and pain

From American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, text revision. Washington, DC, American Psychiatric ­Association, 2000.

d­ isorder usually begins before age 35 and is more common in women, and symptoms more often involve the left side of the body. Deficit symptoms usually do not last more than 2 weeks, but are often recurrent.8 Pain disorder (formerly termed somatoform pain disorder or psychogenic pain) is diagnosed in patients with a predominant focus of pain and in whom psychological factors are judged to have a significant role in the onset, severity, exacerbation, and maintenance of the pain.8 There is substantial impairment of functioning and frequent health care use, with considerable use of medications and disruption of family and social relationships. Psychodynamic theories have focused on the unconscious meaning of the pain, such as childhood means of obtaining love and affection or as a punishment for real or imagined wrongdoing. The pain does not vary and is not consistent with the innervation of the painful area. There is a long history of invalidism and frequent requests for surgery. Patients are preoccupied with the pain and claim all other areas of their lives are fine. The term psychophysiologic pain refers to a chronic pain syndrome that has recurred after a structural lesion was

treated or healed and is accompanied by various pain behaviors (sometimes also referred to as somatoform pain disorder as described previously). Examples include postoperative return of pain after herniated disk surgery or pain after a musculoskeletal injury has healed. The pain is not related to progressive structural disease and is not life-threatening, but it is associated with changes in personality and lifestyle that can be severely disabling (pain behaviors). Pain can be respondent (i.e., a response to a nociceptive stimulus) or operant (i.e., a response to the environment and the rewards for expressing pain in that environment). Moaning and grimacing increase attention or sympathy from a spouse and give the patient the ability to control his or her milieu and roles. Patients with personality disorders are vulnerable to these secondary gains. Patients often fear reinjury or jeopardizing disability payments by becoming active again or returning to work. The patients have strong but unconscious motivations to retain the pain. Emotional stress is a major factor in recurrences or exacerbations of the pain, but the patient has not made that connection. Treatment of chronic pain behaviors depends

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on controlling and changing these reinforcers (operant mechanisms). Psychotic disorders, such as schizophrenia, delusional disorder, and bipolar affective disorder, do not commonly present with pain. The finding of a fixed, intense, somatic delusion (bizarre descriptions of body sensations) in a chronic pain patient would suggest severe psychiatric disease, however, such as schizophrenia or psychotic depression. The pain descriptors in these cases are typically nonanatomic. Patients with Axis II personality disorders commonly have a comorbid chronic pain disorder. The prevalence of personality disorders in patients with chronic pain disorder has ranged from 31% to 49% in different studies.47 These patients present a great challenge to a successful physician-patient relationship and are difficult to manage in a primary care or rheumatology clinic. Personality disorders are defined by enduring maladaptive patterns of perceiving, relating to, and thinking about the environment and the self.48 Patients with personality disorders use pain to manipulate others, obtain narcotics (substance abuse disorder), avoid responsibilities, develop pathologic relationships with health care providers, and obtain nurturing attention (antisocial personality disorder). Patients who are malingering or patients with factitious disorder present particular difficulties for accurate assessment and successful treatment. Malingering refers to volitional fabrication of false symptoms or physical findings to attain some recognizable external gain (e.g., avoiding work or prosecution and obtaining drugs or financial compensation). Submaximal effort on muscle strength testing often leads to the suspicion that the patient is lying. The physician needs to be cautious when the patient was referred by an attorney for evaluation. Factitious disorder refers to presentation of false symptoms or self-inflicted abnormal findings with the poorly understood goal of “winning” or a psychological need to assume the sick role (i.e., no obvious secondary economic gain or external incentives). Examples include Munchausen syndrome, a chronic factitious disorder with self-induced physical abnormalities. The history is often dramatic, but extremely vague and inconsistent. Complaints of pain and requests for analgesics are common. Some patients with chronic pain are not categorizable. It is important to reinvestigate whether litigation is involved with the pain. Pain treatment is typically unsuccessful until litigation is settled.

PAIN-SLEEP CONNECTION Hart and colleagues49 suggested that “persistent and repeated recurrence of discomfort produces physical and mental fatigue and depression.” It is doubtful that the clinician or patient would disagree, but objective data from sleep studies are inadequate in the rheumatic diseases.50-52 Auditory perception remains active during sleep; however, responses to thermal and muscle pain stimuli during sleep seem to be attenuated.53 At least 75% of patients with chronic pain report poor sleep,54 and it is generally assumed that the complaint of poor sleep is directly attributable to the underlying pain. Rigorous systematic, objective studies of sleep in either acute or chronic pain are lacking. Chronic pain seems to play a lesser role in insomnia than might be thought.55 In one small series of patients

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c­ omplaining of low back pain and poor sleep, the objective polysomnographic sleep parameters displayed wide variability.56 Another objective study indicated that the sleep of patients complaining of pain was less disturbed than that of patients with psychiatric disease unassociated with pain.57 A more recent objective study found no differences in sleep architecture between patients with chronic low back pain with subjective reports of sleep disturbance and normal controls. Electroencephalographic power spectral analyses suggested some difference among groups, but the significance of these findings is unknown, and they remain to be replicated.58 There is some evidence that the degree of subjective sleep impairment correlates better with depressed mood than pain intensity, duration, or anxiety.59 Another study of patients with chronic pain indicated that presleep cognitive arousal, rather than pain severity, was the primary predictor of sleep quality.54 Other factors correlating with poor sleep include physical health, physical functioning, and psychosocial functioning.60 The intuitively attractive assumption that chronic pain per se causes insomnia remains to be shown. The severity of the chronic pain is not the primary predictor of the degree of subjective sleep disturbance. Identification of the precise nature of the sleep complaints associated with chronic pain has important therapeutic implications and needs further study.

STANDARDIZED APPROACH TO ASSESSMENT OF PATIENTS WITH CHRONIC PAIN A thorough investigation of a patient with chronic pain requires a comprehensive understanding of the medical, psychological, and socioeconomic complexities of chronic pain (Table 60-6). Because acute pain and chronic pain are distinct clinical entities, the duration of the pain must be identified first. With short-term acute pain, the patient can describe the onset precisely and the proximate circumstances, such as injury or other illness. Acute pain usually has an identifiable noxious stimulus of limited duration (e.g., surgical incision, burn, fracture), responds to analgesics and rest of the affected area, and diminishes as the tissue heals. When pain has been persistent for more than 6 months, it is much more difficult for the patient to describe the onset, timing, and character precisely, and psychobehavioral symptoms may have become disproportionate to the physical abnormalities evident. A multinational World Health Organization study of more than 3000 primary care patients in 14 countries61 showed that only 51% of patients with persistent pain at baseline had recovered 12 months later, and 8.8% of patients without persistent pain had developed it 12 months later. The presence of persistent pain at baseline predicted the development of anxiety or depression and vice versa. Occupational disability was the strongest predictor for pain and psychological disorder. These findings underscore the need for detailed investigation of medical, psychiatric, and functional status in the evaluation of a patient with chronic pain. Formulating a diagnostic impression of the most likely pathogenic mechanism causing the pain is essential for the initial evaluation of a patient with chronic pain (see Table 60-6). Pathogenic mechanisms causing chronic pain can be

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Table 60-6  Standardized Assessment of a Patient with Chronic Pain Pain history   Location   Onset   Intensity   Duration   Descriptors   Frequency   Aggravating factors   Alleviating factors   Past treatments   Injury/litigation   Current treatments Past medical history   Surgical history, psychiatric history, and trauma history Review of systems Psychosocial function   Mood   Depression   Sleep   Energy level   Relationships   Cognition Activity status   Walk   Sit   Stand   Lift/carry objects   Work at home   Work at job   Self-care   Recreational activities Substance use   Alcohol (CAGE questions)   Tobacco   Caffeine   Illicit drugs   Misuse prescription medications   Misuse OTC medications Family history   Chronic pain   Medical illnesses   Substance abuse   Psychiatric disease   Physical/sexual abuse   Family dysfunction

Physical examination Vital signs, weight General physical examination Detailed neurologic examination Mental state assessment Full musculoskeletal examination Health status/diagnostic screens SF-36 PRIME-MD Timed Stands  ×  10 Pain VAS Qualitative Pain Relief Laboratory tests Hematologic abnormality Immune abnormalities Hepatitis screens Indicators of inflammation Renal function Liver function Urinalysis Urine toxicology screen Radiographic imaging Take image of part that hurts Bone scan if radiographs negative CT scans MRI scans Angiograms Additional tests EMG Biopsy—rashes, masses Nerve conduction study Working diagnosis Probable cause of pain Pathophysiologic mechanism Medical comorbidity impact Psychiatric comorbidity Treatment plan Additional consultations Indicators to monitor Analgesics Adjuvant medications Exercise recommendation Benchmark of improvement Opioid rules Opioid contract

Concurrent medications CAGE, cut down, annoyed by criticism, guilty about drinking, eye-opener drinks; CT, computed tomography; EMG, electromyography; MRI, magnetic resonance imaging; OTC, over-the-counter; PRIME-MD, Primary Care Evaluation of Mental Disorders; SF-36, short form quality-of-life scale; VAS, visual analog scale.

broadly divided into mechanisms related to (1) an active or progressive underlying structural disease (somatogenic) of the musculoskeletal system or nervous system, or (2) a psychiatric disorder producing pain as a somatic delusion or as a result of chronic pain or various combinations of these mechanisms (see Fig. 60-1). The workup must include a standard medical history with focus on specific dimensions described in the following paragraphs, a thorough general physical examination, and a meticulous neurologic and musculoskeletal examination. The initial interview of a patient with chronic pain is focused on the medical history with emphasis on the character of the pain; medical, surgical, and psychiatric comorbidities; prior treatments, surgeries, and injuries; family history; current social history; education and vocational

history; functional status; current medications; and current legal or disability issues. The pain history should define the cardinal features of the pain at its onset, progression since onset, and current condition. The clinician should attempt to determine the precise location and time of onset of the pain. He or she should ask the patient to describe the tempo of onset and progression, whether abrupt and fulminant, insidious and progressive, or waxing and waning. The patient should be asked to demonstrate the position or motion when the pain started. Was the onset of the pain immediate or delayed after an injury? The patient should characterize the current pain by indicating with a single digit the precise location of the pain. Is the pain spontaneous or produced by movement (incident pain), pressure, touch, or temperature? The patient should describe the

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character of the pain (i.e., burning, lancinating, sharp, dull, aching) (see Table 60-3). If the pain radiates, the patient should describe the radiation pattern and whether the current pain is persistent or intermittent. The clinician should determine what factors worsen the pain and what tends to relieve the pain. The patient should quantify the pain severity on a 0-to-10 scale, with 0 being no pain and 10 being the worst possible pain. In addition to a detailed general medical history, the clinician should undertake a thorough review of systems to identify symptoms of systemic or localized disorders that might be associated with the pain. A detailed psychiatric history with attention to early family dynamics, history of abuse, alcoholism, and psychiatric disorders in the immediate family and spouse, and interpersonal problems with boss, friends, family, peers, and previous physicians may reveal indicators suggestive of significant psychopathology. It is often informative to ask patients if the pain has influenced how a boss, friends, or family members perceive and treat them. It is essential to have the spouse or most significant peer present for the interview. Observation of the patient in the presence of a family member and interviewing the family member help establish the accuracy of the history and self-report of functional status, medication use, substance abuse, and vocational situation. Clues for identification of patients with primary psychopathology include prior psychiatric treatment; dysfunction in family, interpersonal, or work roles or relationships, or some combination of these; polypharmacy, substance abuse, or both; and a history of multiple medical evaluations and treatments with little or no improvement. These patients have dissatisfied and hostile attitudes and are often manipulative and uncooperative. The clinician should define as concisely as possible the patient’s prepain personality, family dynamics, and functional status. A thorough assessment of the general impact of pain on current overall function should be made. The clinician should determine how much the pain is affecting self-care, family, sexual, occupational, social, and recreational functional status. The clinician should have the patient identify several activities he or she is no longer able to do because of the pain and describe the impact of this functional loss. The amount of current monthly income should be determined and how it changed because of the pain. The patient should articulate how coworkers, family, and friends treat him or her, and whether this has changed since the pain began. The clinician also should inquire about worker’s compensation or litigation issues. The patient and provider should generate a detailed inventory of all prior and current medications. It is important to include prescription and over-the-counter medications and nutriceuticals and other alternative treatments. The effects and adverse side effects of each therapy should be elicited to avoid the mistake of recommending a prior failed treatment. The patient should describe the effects of previous treatments, including benefits, costs, and side effects. The clinician should emphasize the need to know all medications being taken because drug interactions and side effects could put the patient at risk. The significant amount of time required to review prior medical records may be timesaving in the long run and permit more accurate interpretations of a patient’s account of

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a complex medical and surgical history. For patients with chronic disease, recollection of prior events may be inaccurate or distorted and cause hostility about their prior treatments. Old medical records often reveal forgotten adverse effects, substance abuse problems, and important psychosocial or legal issues. Spending sufficient time at the first interview, permitting patients to vent about their doubts and distrust, and reviewing old records, creates a stronger basis for the therapeutic relationship. IDENTIFICATION OF PSYCHIATRIC COMORBIDITIES The coexistence of a personality disorder can complicate the accuracy of a patient’s history and the clinical observations at the time of evaluation. Expression of rage toward family members, employers, insurance adjusters, and every physician seen is a “red flag” for a personality disorder diagnosis (see Table 60-5). These patients are not appropriate for multidisciplinary treatment programs and must be managed medically using rigid opioid contracts because compliance is likely to become a serious issue. Detection of malingering and deception in chronic pain patients is problematic because assessment and treatment depend on accurate patient self-reporting for the clinician to reach valid conclusions. It is crucial for the clinician to understand the factors that may affect patient self-report accuracy. It is very ­important for the clinician to consider the possibility of deliberate distortion or deception. The crucial issue is that a clinician’s ability to make an accurate diagnosis and effective treatment decisions depends totally on the completeness, honesty, and overall accuracy of the patient’s self-report. Nondeliberate and deliberate distortion by the patient can seriously jeopardize patient care and safety. Clinicians should have a strategy for deception analysis that is implemented in all patient assessments.62 There are basically five patient-response styles, which refer to how patients report symptoms: honesty, maximization, minimization, mixed, and irrelevant (when the patient is not engaged with the interview and the responses are not relevant to the question). Distortion refers to using a maximized, minimized, or mixed response style. Deception refers to intentional distortion of symptoms to achieve some desired target goal (i.e., the behavior seen in malingering). An observed lack of cooperation during the interview and examination should be viewed as a “red flag” for possible distortion or deception. A patient who reports numerous neurologic, pain, and musculoskeletal symptoms with little objective abnormality is likely exhibiting a maximizing response style. A fluctuating response style with little change in objective abnormalities suggests distortion. Nonintentional distortion is seen with a distraught patient who is fearful the physician will not understand his or her pain and magnifies the symptoms as a cry for help. Complaints of unusual, nonsensical symptoms likely represent intentional distortion. Patients who report no benefit from any treatment may be intentionally distorting the history because most patients experience at least a small benefit from some treatments. Observation that symptoms worsened while the patient was being observed and lessened when distracted suggests deliberate distortion. Most patients

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who have disability have some degree of emotional distress and depression. Cases in which patients deny emotional stress or depression yet have significant disability suggest deliberate distortion. Refusal to permit access to old medical records and a history of multiple hospitalizations and compensation claims also are “red flags” for deception. The individual clinician evaluating a chronic pain patient may use one of several health status instruments. The following are recommended because they are selfadministered or can be administered by an assistant, are easy to score, and have been validated in populations with medical illnesses. The Primary Care Evaluation of Mental Disorders (PRIME-MD)63 is an excellent screen for depression, anxiety, somatoform disorders, eating disorders, and alcohol abuse. Pain severity is best quantified on a 0-to-10 scale, with 0 being no pain and 10 being the most severe pain, and pain relief is best quantified with qualitative answers of none, some, a little, and a lot to monitor response to treatment. The short-form quality-of-life scale (SF-36) is a standardized health-related quality-of-life functional test, as is the Stanford Health Assessment Questionnaire, and both are useful in ongoing assessments (see Chapter 33). Diagnostic and therapeutic goals should be established by the clinician and patient together. The clinician should ask the patient what he or she expects from evaluation and recommendations. The patient may be seeking a second opinion to validate another physician’s evaluation and treatment recommendations, seeking a different diagnosis and treatment plan, applying for disability and needing a medical statement, or looking for a physician willing to prescribe opioids for chronic nonmalignant pain. It is important to establish at the outset that it is unlikely the pain will be eliminated completely, but some improvement can be anticipated. The process of examining the patient serves to identify objective abnormalities associated with musculoskeletal and neurologic disorders that reasonably explain the patient’s pain, find important coexistent abnormalities, and define functional status. During the examination, the decisionmaking process “rules in” and “rules out” the items in the differential diagnosis generated during the interview and review of medical records. The musculoskeletal and neurologic examination must be meticulous. For the patient, it is the opportunity to observe the examiner’s technical competence and to develop confidence in the quality of the assessment and recommendations. For the primary care physician or rheumatologist, the finding of a gross neurologic abnormality requires a prompt evaluation. The initial observation of the patient’s gait as he or she walks 20 feet away is useful to look for spine deformities, pelvic tilt, knee and hip contractures, or instability. The patient should then turn and walk back, first on the heels, then up on the toes, and then walking heel to toe. The patient should hop on one foot and then the other to assess leg strength, balance, and coordination. As a test of lower extremity function, the patient should squat and stand up from a squat or stand up and down from a seated position in a chair, without using arms, 10 times (normal time for this is 11 to 14 seconds). The clinician should observe the patient as he or she undresses, puts on an examination gown, and climbs onto the examination table, noting imbalance, weakness, and pain behaviors. The clinician should

enumerate pain behaviors such as moaning, groaning, grimacing, writhing, crying, or shouting. Unobtrusive observations of gait as the patient walks into the examination room and climbs onto the table are important to understand the effects of the patient’s pain. The neurologic and musculoskeletal examination should be focused to identify abnormalities associated with the pain and to analyze maneuvers that reproduce, worsen, or alleviate the pain. The examiner should critically consider the different possible pathogenic mechanisms and tissue sources of the pain while performing the physical examination. A mental status examination provides clues to a central nervous system lesion and reveals cognitive deficits that can influence a patient’s description of and response to painful stimuli. Cognitive abilities also influence treatment recommendations. The clinician should assess global mental status by asking the patient’s name, place, year, date, location of examination, and about a current event or the president or governor; having the patient subtract serial sevens; testing the ability to interpret a proverb; naming a pen; and identifying a coin with eyes closed. Symptoms of a thought disorder should be sought by directly asking if the patient hears or sees things that are not there, if people are after or trying to hurt him or her, if he or she has trouble controlling thoughts, and what the patient thinks is causing the pain. A detailed examination of all cranial nerves may provide evidence of unsuspected lesions in the brainstem or higher. The physician should check for facial asymmetry, pupil diameter and light responses, extraocular eye muscles, facial sensation, gag reflex, and snout and glabellar reflexes. The patient should flex the head (put chin to chest), extend the head (look at the ceiling), laterally extend right and left (put ear on shoulder), and rotate the head (put chin on each shoulder); the clinician should note increase in pain with these maneuvers, palpate for paracervical muscle tenderness, and check muscle strength of neck flexors and extensors. A comprehensive musculoskeletal examination (see Chapter 35) should assess redness, warmth, swelling, and tenderness or lack thereof at synovial reflections, joint capsule insertions, and tendon muscle insertions. Upper extremity examination of joints, bursae, and tendons should be accompanied by muscle strength testing of shoulder shrug, flexion, and abduction, with special attention to production of pain with resisted motion. Evaluation of resisted motion tests muscle strength and puts tension on tendons and ligaments, which reproduces pain if these structures are the site of pathology. Muscle strength testing may be difficult in a patient with pain because the pain may limit maximal effort. With manual muscle strength testing and coaching, it is possible to distinguish true muscle weakness from “giving way” owing to pain or lack of cooperation. The clinician should note whether the testing effort reproduces the pain or behaviors such as grimacing and moaning, and carefully distinguish whether active versus passive motion reproduces or accentuates the pain. With synovial inflammation, synovial tissue is swollen and tender to palpation, and active and passive motion increase pain. With tendinitis, the joint itself is not tender, but the area of tendon insertion is focally tender, and active, but not passive, motion reproduces the pain. The clinician should note crepitance, joint instability, and the presence of trigger points or tender points around the joints.

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Unobtrusive observation of the patient’s responses to range-of-motion testing maneuvers and palpation during the joint examination can provide insight into pain severity and the patient’s reaction to the pain. Elbow flexion and extension, wrist flexion and extension, grip strength, and finger abduction should be evaluated. The patient should make fists, flex elbows 90 degrees, and hold them at the torso. The physician should instruct the patient to resist the examiner’s attempts to bring the fists together at the midline (this checks infraspinatus, teres minor, and deltoid muscles). The physician should instruct the patient to resist the examiner’s attempts to separate the fists (this resisted external rotation checks the deltoid, pectoralis, subscapularis, teres major, and latissimus dorsi strength). Resisting attempts to extend the elbow checks biceps and brachioradialis strength, and resistance of attempts to flex the elbow checks triceps strength. The clinician should note whether changes in deep tendon reflexes correspond to changes in strength. Deep tendon reflexes at the triceps (C7 and C8), biceps, and brachioradialis (C6 and C7) tendons should be checked and cutaneous sensation to light touch, pinprick, and Hoffman’s reflex. The patient should perform rapid alternating movements of the hand and finger by touching the nose bilaterally. Sensory examination in upper and lower extremities should include testing of superficial (pinprick) and deep (tendon squeeze) pain, light touch, heat, cold, vibration, and position sense. The clinician should note whether changes conform to dermatome distribution (loss of pain, touch, and temperature sense), nerve root distribution (sensory loss, hyperesthesia, and radicular pain), or distribution of a peripheral nerve. A thorough evaluation of the spine requires an examination with the patient sitting, standing, and prone to evaluate spinal tenderness, paravertebral muscle spasm, and range of motion (flexion, extension, and rotation with pelvis fixed to eliminate hip-joint motion). The straight-leg raising test should be performed in the supine and sitting position because both positions should reproduce pain from a radiculopathy. Muscle strength testing of hip flexors, extensors, abductors, and adductors should accompany lower extremity examination of the joints, tendons, and bursae, with attention to production of pain with resisted motion in the four planes. Knee flexion and extension strength should be tested with patellar reflex testing (L3 and L4). Ankle plantar flexion, dorsiflexion, and great toe extension strength should be tested with Achilles tendon reflex testing (S1 and S2) and sensory testing to light touch, pinprick, and vibration. Heel-to-shin coordination and Babinski’s reflex should be assessed. FORMULATING THE DIAGNOSTIC IMPRESSION The initial decision point for the clinician is whether the pain is primarily somatogenic or predominantly psychological. If somatogenic, the clinician should decide whether the source of pathology is nociceptive, neuropathic, or both, and if neuropathic, whether peripheral or central. If arthritis is the most likely underlying cause, an appropriate laboratory and radiologic workup should be undertaken. If prior radiographs are more than 2 or 3 months old, they should be repeated and, if normal, bone scans, magnetic resonance

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imaging (MRI), or computed tomography scan should be obtained. If the underlying cause is most likely neuropathic, electromyography and nerve conduction studies provide immediate diagnostic information about neuromuscular disorders and prognostic indicators for traumatic injuries. If central pain is likely, MRI of the spinal cord, brain, or both should be obtained. If weakness is found, nerve or muscle biopsy should be considered. If a neurologic deficit is evident on the physical examination, a neurology consultation may be helpful. For patients with predominantly somatogenic pain, treatment strategies should be mechanism-based as described in the following paragraphs. If the pain is predominantly psychological, the clinician should determine whether there is primary or secondary psychopathology. Primary psychopathology predates the chronic pain problem (i.e., hypochondriasis, somatization and somatoform pain disorder, major depression, and substance abuse). These patients usually have had multiple medical problems, surgeries, and treatments and are dissatisfied and hostile toward physicians. They are often manipulative and uncooperative. They may appear overly depressed or surprisingly indifferent. Subjective pain report and pain behaviors are out of proportion to objective physical abnormalities, and physical signs may fluctuate from one examination to another. Secondary psychopathology occurs in patients with healthy personality and functioning before the pain but who have developed significant psychological dysfunction secondary to the pain, physical changes owing to illness, or impaired socioeconomic function and vocational losses. These patients often have a negative attitude; are anxious, depressed, and angry; and feel isolated and helpless. For patients with predominantly nonsomatogenic psychological pain, additional psychiatric evaluation is often needed, and treatment of these factors should be the initial treatment strategy. When the decision has been made confidently that there is no significant somatogenic component to the chronic pain that requires specific medical or surgical treatment, requests from the patient for more workup should be declined. Most patients are not diagnosable as having exclusively nociceptive, neuropathic, or psychogenic pain, but they have components of all three in the total clinical picture.

MECHANISM-BASED APPROACH TO TREATMENT OF CHRONIC OSTEOARTICULAR PAIN Chronic osteoarticular pain secondary to chronic inflammatory arthritis should be treated as specifically as possible to reduce inflammation and prevent further joint damage (see Chapter 67). Most patients with chronic osteoarticular pain become physically deconditioned and need a progressive rehabilitation program when pain has been decreased enough to permit such an increase in physical activity (see Chapter 64). Analgesic selection, route, dosage, and scheduling should be individualized. If pain is present for most of the day, treatment should be prescribed on a regular schedule rather than on an as-needed basis. Most patients with defined musculoskeletal disease have pain that is incident to movement and should be taught how to schedule analgesic doses to ­permit

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as high a level of physical activity as possible. Adjuvant therapies can decrease pain by modifying pain pathways, mitigating analgesic side effects, and treating concomitant problems such as depression. Alternative methods of analgesic administration, such as patient-controlled analgesia pumps, intrathecal administration of medications, or spinal cord stimulators, may be needed in a few patients. How much reduction in pain is clinically meaningful? The most widely used scale to quantify pain severity in clinical trials and now in clinical practice as the “fifth vital sign” is the pain intensity numerical rating scale from 0 to 10, with 0 being no pain and 10 being the worst possible pain. The patient’s global impression of change is a qualitative measure of pain relief with a 7-point categorical scale (1  =  very much worse; 7  =  very much improved).64 Farrar and colleagues65 examined the changes in the data from 10 different studies with more than 2700 subjects and showed that a 30% change and 2-point change in raw score on the pain intensity numerical rating scale were associated with the patient’s global impression of change of “much improved or better.” A 50% reduction in pain intensity score was associated with patient’s global impression of change of “very much improved.” It is advisable to use both scales when monitoring a patient’s pain severity and response to treatment, rather than relying only on the pain intensity scale. ANALGESICS Nonopioid analgesics are useful for mild-to-moderate pain, regardless of the underlying joint disease. Selection of acetaminophen, a salicylate, or one of the many available NSAIDs is determined by the patient’s prior treatment history, age, and comorbid conditions that affect the risk profile for side effects (see Chapter 54). Acetaminophen has no tendency to cause gastrointestinal ulceration or nephrotoxicity, and it has no antiplatelet activity. There may be an increased risk of hepatotoxicity in patients with underlying liver disease. NSAIDs inhibit cyclooxygenase (COX) production of prostaglandins, which are known to sensitize peripheral nociceptors directly, and may have some central analgesic effects. There is a ceiling effect to NSAID-induced analgesia, such that above a certain dose there is no further increase in relief. There is considerable variability in analgesic responses and the occurrence of side effects. A trial with several different NSAIDs may be needed to find the optimal medication for the individual patient. Elderly patients and patients with renal disease, hypertension, and congestive heart failure should be given NSAIDs with great caution. Increased risk of serious adverse gastrointestinal events (hemorrhage, perforation, or obstruction) is seen in patients older than 65; patients who are taking prednisone, warfarin, or both; patients who have a history of peptic ulcer disease or prior NSAID gastropathy; and patients who have poor health status. These individuals should be treated with a selective COX-2 inhibitor or opioid rather than NSAIDs. Nonopioid analgesics are much less effective for moderateto-severe pain. Until more recently, many physicians were reluctant to prescribe opioids for nonmalignant pain because of concerns about long-term opioid efficacy; side effects; tolerance requiring ever-increasing doses; and dependence, abuse, or

addiction. Evidence is accumulating that opioids are safe without major organ toxicity, and side effects are manageable when anticipated and treated expectantly.66-70 Our surveys of opioid use in a rheumatology clinic and orthopaedics spine clinic cohort found 442 of 874 patients took opioids in the preceding 3 years. Opioids were highly effective in these patients with well-defined rheumatologic and spine diseases.71,72 There was a significant decrease in pain severity in the rheumatology clinic patients (from 8.2 to 3.6 on numerical rating scale) and in the orthopaedics spine clinic patients (from 8.3 to 4.5). Figure 60-6 illustrates the important observation that opioids were just as effective in patients treated with longterm opioids as in patients treated with short-term opioids, suggesting that tolerance did not develop in these patients. Analysis of the causes for increases in daily opioid dose indicated that a progression of the underlying disease, a complication thereof, or development of a new painful problem occurred in all but four rheumatology patients and three orthopaedics patients. In the seven patients with unexplained increases in opioid dose, problems with abuse behavior, addiction, or both became evident and required the assistance of a liaison psychiatrist for management. The rheumatology clinic cohort was followed prospectively for another 5.5 years.73 Opioid efficacy was sustained, and no opioid tolerance was seen in these patients. Side effects were common but easily managed in most patients. As in the initial 3-year study period, increases in opioid dose were related to worsening or complication of the underlying rheumatic disease or development of a new disease in all but three patients. These three patients also displayed abuse or addiction behaviors and were difficult to manage. The 8.5-year surveillance of this cohort of patients treated with long-term opioids for defined rheumatic disease pain supports the concepts that opioids are effective long-term, tolerance is not inevitable, no serious organ toxicity is observed, side effects are manageable, and the incidence of

10 9 8 7 Pain severity

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6 5 4 3 2 1 0

Short-term opioid

Long-term opioid

Baseline Treated Figure 60-6  Ratings of pain severity for short-term (n  =  111) and longterm (n  =  116) opioid users before and after a dose of an opioid analgesic. Error bars show 1 SD P  <  .001. (From Ytterberg SR, Mahowald M, Woods SR: Codeine and oxycodone use in patients with chronic rheumatic disease pain. Arthritis Rheum 41:1603, 1998.)

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substance abuse behaviors is no greater than in the general population. Management of a large number of patients on opioids in a busy clinic with multiple physicians and trainees requires a controlled system for patient monitoring and prescription refills. The first step is the decision for an opioid trial. If the nonopioid analgesics are not sufficient to reduce pain below 4.5 rating, a weak opioid, such as codeine or hydrocodone with acetaminophen, should be tried next (Table 60-7). At this point, it is important to discuss with the patient a plan of 2 to 3 months for gradual titration of the opioid. Opioids do not have a ceiling effect for analgesia, but if compounded with acetaminophen, the daily dose of acetaminophen should be less than 4 g. It is important to anticipate opioid side effects and warn the patient to take a gut stimulant, rather than stool softener, to prevent constipation. When starting a new opioid medication, patients should be advised to take the first dose at home to determine whether sedation, dizziness, or confusion occurs. The physician should caution patients about taking an opioid with other sedating medications or after drinking alcohol. If the patient has a history of substance abuse, more frequent monitoring may be necessary. At the end of the 3-month opioid titration trial, a decision should be made as to whether the opioid reduced the pain, whether side effects were manageable, and whether the patient is now ready to begin an exercise program to increase function or is able to perform some activity he or she was unable to do before the opioids. If pain relief was only minimally improved, further dose titration or a trial of a stronger opioid is recommended. When the decision for long-term opioid treatment has been made, the rules for opioids must be explained clearly to the patient, preferably with an opioid contract signed by the patient and the physician (Fig. 60-7). The patient must agree to keep all scheduled appointments, have random urine toxicology screens, seek opioid prescriptions only from a single provider, and not to go to the emergency department or come into the clinic unscheduled for an early prescription refill. With rare exceptions, there should be no excuses for early refills or “lost” medications.

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When the opioid dose has been selected, a trained nurse can take over the monthly monitoring for efficacy, side effects, signs of abuse or drug diversion, and the timely refilling of prescriptions (Fig. 60-8). It is important to get all physicians in the clinic to agree to write only prescriptions prepared by the nurse managing opioid administration in the clinic. It is desirable to obtain cooperation from the local emergency department physicians not to refill opioid prescriptions at night or on the weekends. How do opioids work? Opioids block the release of neurotransmitter by preventing calcium influx into the presynaptic terminal, or they take the pain transmission neuron out of the circuit by hyperpolarizing it through opening a potassium channel. Selection of opioid preparation should begin with the weaker opioids first (codeine or hydrocodone with acetaminophen) because the prescription can be written with five refills. Codeine must be metabolized to morphine, to exert an analgesic effect. There is no analgesic effect in individuals who are poor metabolizers, or if the enzyme cytochrome P 2D6 (CYP2D6) is inhibited by concomitant medications, such as amiodarone, fluoxetine, haloperidol, paroxetine, and terbinafine. Conversion among opioid preparations is straightforward. Long-acting morphine is converted to long-acting oxycodone at an equianalgesic ratio of 2:1 (60 mg of controlled-release morphine  =  30 mg of controlled-release oxycodone every 12 hours). When converting morphine to transdermal fentanyl, a 1:2:3 rule is used that says 1 mg of parenteral morphine per day is equivalent to 2 μg/hr via fentanyl patch, which also is equivalent to 30 mg/day of oral morphine. Conversion ratios in the fentanyl package insert are recommended for opioid-naive patients and may not be high enough for patients already taking regular opioids. Although there is no ceiling dose for opioid analgesia, side effects increase with increasing opioid dose and can produce confusion, agitation, myoclonus, dry mouth, itching, and sedation. Methadone is an inexpensive opioid that has low street value. It has no active metabolites and is not eliminated via

Table 60-7  Opioids for Long-Term Treatment of Chronic Musculoskeletal Pain Oral Dose

Dosing Intervals

Comments

Codeine

30-60 mg

4 hr

For moderate pain

Hydrocodone (Lortab, Vicodin)

5-10 mg

4-6 hr

For moderate pain

Morphine (controlled release)

15-100 mg

Every 8-12 hr

Titrate slowly. For severe pain, titrate to pain relief, morphine-  6-glucuronide can accumulate in renal insufficiency

Oxycodone

5-10 mg

4-6 hr

Monitor amount of acetaminophen given per day

Oxycodone (controlled release)

10-20 mg

Every 12 hr

Titrate slowly

Hydromorphone (Dilaudid)

2-4 mg

4-6 hr

Titrate to pain relief

Methadone

2.5-10 mg

8-12 hr

Slow titration

Fentanyl

25-75 μg/hr

Every 72 hr

Titrate very slowly, variable responses

Propoxyphene napsylate

100 mg

4-6 hr

Caution in elderly

Tramadol

37.5-75 mg

Every 4-6 hr

Binds mu receptor, inhibits uptake of serotonin and norepinephrine

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Contract for Long-Term Chronic Opioid Therapy Between:

and Dr.

Patient Name

At the Minneapolis VAMC

Chronic Opioid Therapy for Intractable Pain Will Be Prescribed Under the Following Conditions: 1. If

(drug prescribed) is effective for adequate pain control with tolerable side effects

2. If Scheduled appointments are kept: if appointment is failed the prescription will not be renewed 3. If the Patient agrees to obtain pain medications only from Dr:

And NOT to go to the ER or Urgent Care for more meds

4. If the patient agrees NOT to request “early” or “partial” prescription refills from the MVAMC Pharmacy 5. If the patient agrees NOT to come to the Rheumatology clinic without an appointment to request more Pain Medications 6. There will be no acceptable excuses for “lost medications” 7. If the Patient agrees to be responsible for taking medications as directed. If the Pain medication supply is used up before the end of the prescription period, the patient has the option of admission for opioid withdrawal under supervision or will “tough it out” at home. NO additional pain medications will be prescribed. 8. Pain Severity and function will be re-evaluated after __________months of an Opioid Trial to determine whether continued use of chronic opioids is justified by clinical improvement 9. I understand that urine samples will be randomly tested for drugs PATIENT AND PHYSICIAN ARE TO SIGN BELOW: PATIENT SIGNATURE:

PHYSICIAN SIGNATURE:

DATE

NAME SSN

MEDICINE SERVICE

RHEUMATOLOGY CLINIC Figure 60-7  Patient contract for long-term opioid therapy.

the kidney. Methadone acts through mu and delta opioid receptors and inhibits NMDA receptors and serotonin and NE reuptake. When used to treat opioid addiction, the dose of methadone selected is 1:1 with the morphine dose and administered every 24 hours. When using methadone to treat pain, equianalgesic dose ratios depend on current opioid dose.74 The pharmacokinetics of methadone are complex. Slow elimination produces a long and varied half-life ranging from 12 to more than 100 hours (average 24 hours). There are important drug interactions. Buprenorphine, pentazocine, naltrexone, naloxone, and tramadol may precipitate withdrawal symptoms. The usual dosing for pain is two to three times a day, which may be lengthened after repeated administration. Agents that induce CYP3A4 (isoniazid, rifampin, phenobarbital, phenytoin, primidone, carbamazepine, ­risperidone, St. John’s Wort, nevirapine, amprenavir, ritonavir, efavirenz, clotrimazole, dexamethasone) and CYP2D6 (isoniazid and rifampin) enzyme activity increase the metabolism of methadone and reduce blood levels so that withdrawal symptoms may occur. Agents that inhibit CYP3A4 (ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazodone) and CYP2D6 (antidepressants, fluoxetine, paroxetine, fluvoxamine, sertraline, bupropion, amitriptyline, haloperidol, amiodarone, cimetidine, quinidine, hydroxychloroquine,

methadone itself, ritonavir, ketoconazole, fluconazole, and ciprofloxacin) reduce the metabolism of methadone and cause increased opioid effects. Benzodiazepines, tramadol, and alcohol increase adverse effects of methadone. Detailed methadone dosing recommendations can be found at www.atforum.com and vaww.pbm.med.va.gov. It is safer to begin with small doses, such as 2.5 to 5 mg two times a day, and adjust according to current opioid dose. If the daily morphine-equivalent dose is less than 200 mg/day, the methadone dose should be 10% of the daily morphineequivalent dose; if the daily morphine-equivalent dose is 200500 mg/day, the methadone dose should be 7% of the daily morphine-equivalent dose to begin and slowly increased by 2.5 mg at 2- to 4-week intervals, adding a short-acting opioid for breakthrough pain. While titrating the methadone dose upward, the original opioid is gradually discontinued. TROUBLESHOOTING PROBLEMS WITH LONG-TERM OPIOID THERAPY Problems arise when managing patients with long-term opioids for chronic musculoskeletal pain. Selecting appropriate candidates for long-term opioid therapy is an important first step. The DIRE score (Table 60-8) is a valid and reliable screening tool for predicting efficacy of and compliance with long-term opioid therapy for chronic noncancer pain. This

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3D Narcotic Telephone Renewal Clinic Renewal For:

Last Filled on:

How many pills are you using per day?

LEAST

Are you using any other Pain Medications? NO Does the medication help? A LOT

# Pills Dispensed

DATE STARTED

MOST YES If yes what?

SOME A LITTLE

?OTC from another MD?

NOT AT ALL

Rate your pain from 0 to 10 BEFORE you take the pain medication _________ and AFTER taking it__________ Have you had any side effects from the pain medications such as: FEEL SLEEPY OR SEDATED DIZZINESS CONSTIPATION NAUSEA How do you feel your pain control is?

CONFUSION

OTHER:

Residual Pain

Amount of Time with No Pain

How many days per week do you take the Pain Medications:

How many pills per day do you take on those days?

Do you feel the Pain Medication has lost its effectiveness? NO YES

If Yes have you increased the dose? NO

YES

COMMENTS: Do you receive pain medication from doctors not at the MVAMC

NO YES

If yes what medication

Reason it was prescribed

by whom:

Have you become addicted to the opioid NO

YES

Are you afraid of becoming addicted? NO YES

If yes describe

If yes comment:

Do you have a history of addiction to alcohol or other drugs? NO YES PRESCRIPTION WRITTEN FOR

If YES describe

# PILLS/MO

RENEWED

MD

SCHEDULE ED NARCOTIC TELEPHONE RENEWAL CLINIC ON (DATE)________________________ DATE

NAME:

ssn

MEDICINE SERVICE

3D

RHEUMATOLOGY CLINIC

Figure 60-8  Opioid monitoring form.

simple scoring system can help to predict whether a patient is a suitable candidate for long-term opioid therapy. When long-term opioid treatment has been initiated, it is important to document efficacy, increased function, side effects, and the lack of signs suggesting abuse (see Fig. 60-8). The most common problem is the patient reporting loss of analgesia. The differential diagnosis of this complaint includes (1) increased peripheral nociception from the original problem or a new problem with increased inflammation, tumor, neuropathic process, or osteoporotic fracture; (2) development of anxiety or depression; (3) cognitive change altering pain perception or reporting, such as delirium; or (4) opioid tolerance (rare). Certain aberrant behaviors raise the question of abuse or addiction behaviors. Highly suggestive behaviors include selling prescription drugs; prescription forgery; stealing drugs from others; injecting oral formulations; obtaining drugs from nonmedical sources; concurrent abuse of alcohol or illicit drugs; multiple dose escalations; multiple episodes of “lost medications”; aggressive complaining about the need for more medications; seeking medications from multiple prescribers or the emergency department; deterioration in work, family, or social functioning because of the drugs; and resistance to ­changing therapy despite adverse effects. These behaviors should prompt urine toxicology screens and request for addiction disorder evaluation.

Side effects may be troublesome in some patients. Sedation is usually transient. Nausea usually abates within 2 to 3 weeks, but can be treated with hydroxyzine or prochlorperazine suppositories. Constipation should be prevented by prophylactic gut stimulants, such as bisacodyl or senna, or an osmotic laxative, such as lactulose. Bulk-forming laxatives, such as psyllium and methylcellulose, should be avoided because they can cause obstruction in a patient being treated with opioids.74 Opioid-induced confusion, disorientation, and hallucinations can occur in patients with underlying encephalopathy or dementia and are more common with long-acting preparations. The patient should be switched to a short-acting preparation, and the dose should be reduced if necessary. Urinary retention is usually transient, but the dose should be decreased, or another opioid should be used. Pruritus may be secondary to histamine release from mast cells and may require a switch to another opioid. Multifocal myoclonus is uncommon, usually transient, and may respond to a benzodiazepine, such as lorazepam. ADJUNCTIVE MEDICATIONS FOR CHRONIC PAIN TCAs and antiepileptic drugs are useful adjuncts to analgesic therapy in patients with low back pain, radiculopathy, postherpetic neuralgia, and neuropathic pain.75 Antiepileptic drugs may decrease ectopic discharges from injured

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Table 60-8  DIRE Score Score

Factor

Explanation

1-3

Diagnosis

1  =  Benign chronic condition with minimal objective findings or no definite medical diagnosis. ­Examples—fibromyalgia, migraine headaches, nonspecific back pain 2  = Slowly progressive condition concordant with moderate pain, or fixed condition with   moderate objective findings. Examples—failed back surgery syndrome, back pain with moderate degenerative changes, neuropathic pain 3  =  Advanced condition concordant with severe pain with objective findings. Examples—­severe ischemic vascular disease, advanced neuropathy, severe spinal stenosis

1-3

Intractability

1  =  Few therapies have been tried, and the patient takes a passive role in pain management process 2  =  Most customary treatments have been tried, but the patient is not fully engaged in the pain management process, or barriers exist (insurance, transportation, medical illness) 3  =  Patient fully engaged in a spectrum of appropriate treatments, but with inadequate response (R  = Total of P  +  C  + R  + S)

Risk 1-3

Psychological

1  = Serious personality dysfunction or mental illness interfering with care. Examples—personality disorder, severe affective disorder, significant personality issues 2  =  Personality or mental health interferes moderately. Examples—depression or anxiety disorder 3  =  Good communication with clinic. No significant personality dysfunction or mental illness

1-3

Chemical health

1  =  Active or very recent use of illicit drugs, excessive alcohol, or prescription drug abuse 2  =  Chemical coper (uses medications to cope with stress) or history of chemical dependency in remission 3  = No chemical dependency history. Not drug-focused or chemically reliant

1-3

Reliability

1  =  History of numerous problems—medication misuse, missed appointments, rarely follows through 2  =  Occasional difficulties with compliance, but generally reliable 3  =  Highly reliable patient with medications, appointments, and treatment

1-3

Social support

1  =  Life in chaos. Little family support and few close relationships. Loss of most normal life roles 2  = Reduction in some relationships and life roles 3  = Supportive family/close relationships. Involved in work or school and no social isolation

1-3

Efficacy score

1  =  Poor function or minimal pain relief despite moderate-to-high doses 2  =  Moderate benefit with function improved in numerous ways (or insufficient information—has not tried opioid yet or very low doses or too short of a trial) 3  =  Good improvement in pain and function and quality of life with stable doses over time

Score 7-13: Not a suitable candidate for long-term opioid analgesia Score 14-21: Good candidate for long-term opioid analgesia From Belgrade MJ, Schamber CD, Lindgren BR: The DIRE score: Predicting outcomes of opioid prescribing for chronic pain. J Pain 7:671-681, 2006.

nerves and decrease the lancinating pains. There are three basic mechanism-based approaches to treatment of a neuropathic pain component (Table 60-9): 1. Drugs to enhance the descending inhibitory pathways by interacting with biogenic amines 2. Drugs that modulate peripheral sensitization by interacting with voltage-sensitive sodium channels 3. Drugs that modulate central sensitization by interacting with calcium channels, NK1, or NMDA receptors (NE and serotonin) There is strong evidence that TCAs decrease neuropathic pain and weaker evidence that anticonvulsants, antiarrhythmics, and topical agents are effective.76,77 Antidepressants inhibit reuptake of the biogenic amines serotonin and NE, modulate sodium channels, and inhibit excitatory neurotransmitters. Amitriptyline, imipramine, clomipramine, and doxepin block uptake of NE and serotonin, whereas nortriptyline and desipramine block only NE uptake. TCAs have adverse effects of sedation, weight gain, and orthostatic hypotension, and anticholinergic symptoms of dry mouth, urinary retention, and constipation, which are worse in elderly patients. TCAs must be used with caution in patients with heart disease, glaucoma, and prostatism. Selective serotonin-norepinephrine reuptake inhibitors, such as venlafaxine, have few anticholinergic effects, have

fewer side effects than TCAs, and are effective in diabetic neuropathic pain. Selective serotonin reuptake inhibitors are generally ineffective for neuropathic pain, but are better tolerated than the TCAs and can be useful when pain is complicated by depression. Narcotics have long been considered ineffective in neuropathic pain; however, more recent studies have shown that controlled-release oxycodone,78,79 morphine and methadone,75 and tramadol77 were effective for neuropathic pain. Drugs that inhibit sodium channel activation can modulate peripheral sensitization by decreasing action potential propagation, membrane depolarization, and neurotransmitter release. Anticonvulsants tend to inhibit repetitive firing of action potentials under conditions of sustained neuronal depolarization.34 First-generation antiepileptic drugs are carbamazepine and phenytoin. Carbamazepine is structurally similar to the TCAs and can enhance sodium channel inactivation, reduce excitatory neurotransmitter release, and modulate L-type calcium channels. It has been shown to be effective in diabetic neuropathy and postherpetic ­neuralgia pain.34 Phenytoin has had variable efficacy in neuropathic pain. The side effects of these two drugs often limit their usefulness. Newer antiepileptic drugs (gabapentin, lamotrigine, topiramate) act via multiple mechanisms and show promise

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Table 60-9  Adjuvant Therapeutic Medications Trade Name

Dose Ranges

Comments

Antidepressants

All effective in painful neuropathy independent of antidepressant properties; risk of arrhythmias in cardiac disease

Amitriptyline

Elavil

25-150 mg/day

Imipramine

Tofranil

20-100 mg/day

Serotonin and NE reuptake inhibitor

Desipramine

Norpramin

25-150 mg/day

NE reuptake inhibitor

Nortriptyline

Pamelor

25-150 mg/day

NE reuptake inhibitor

SSRIs   Paroxetine   Citalopram

Paxil Celexa

20-40 mg/day 20-40 mg/day

AEs less than TCAs; AEs asthenia, sweating, ­gastrointestinal disturbances, somnolence, ­dizziness, sexual dysfunction

Neurontin

300 mg at bedtime, slow increase   up to 3600 mg/day on a tid schedule

Variable results in clinical trials; AEs drowsiness, somnolence, fatigue (are transient); no ­interaction with warfarin or birth control pills; accumulates in renal failure

Antiepileptic Drugs Gabapentin

Enhance sodium channel inactivation

Pregabalin

Lyrica

150-600 mg/day

Dizziness, somnolence, edema

Carbamazepine

Tegretol

100 mg bid to start up to   400-1200 mg/day

Effective for trigeminal neuralgia, diabetic ­neuropathy, less effective in PHN; relative contraindication in heart disease, contraindicated with heart block; AEs dizziness, drowsiness, diplopia, rash in 7%-10%; risk of cytopenias is rare

Up to 3 patches at once for 12 hr 0.025% to 0.075% applied 3-5 times/day

Must use on intact skin; modest benefit Adjunctive treatment; depletes substance P from C fibers; transient burning may be intolerable, lasts a few weeks

200-1200 mg/day on tid schedule

Antiarrhythmic, sodium channel blocker; ­equivocal efficacy; AEs gastrointestinal symptoms, ­dizziness, tremor, palpitations, chest pain, headache

Topicals Lidocaine patch Capsaicin Miscellaneous Agents Mexiletine

AE, adverse events; bid, two times a day; CNS, central nervous system; GABA, γ-aminobutyric acid; NE, norepinephrine; NMDA, N-methyl-d-aspartate; PHN, postherpetic neuralgia; SNRI, selective serotonin-norepinephrine reuptake inhibitor; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants, tid, three times a day.

in clinical trials of painful neuropathy. Oxcarbazepine acts on sodium channels and N-type calcium channels and may modulate peripheral and central sensitization. Lamotrigine acts on sodium channels, inhibits release of excitatory neurotransmitters, and modulates N-type calcium channels. It has had variable efficacy for peripheral neuropathic pain and is associated with common side effects, including rash. In one trial, 44% of patients with central poststroke pain experienced a decrease in pain with lamotrigine.34 Potentially fatal rashes and serious hypersensitivity reactions have occurred in numerous patients taking lamotrigine, making this drug less desirable for use as an adjunct for pain. Topiramate has multiple mechanisms of action, inhibits voltagegated sodium and calcium channels, has GABAergic and glutaminergic effects, and has shown modest effects in diabetic neuropathy. Modulators of central sensitization such as gabapentin34,76 and pregabalin, which are GABA analogues, may act on calcium channels within the spinal cord, modulate GABA release, inhibit sodium channels, and alter monoamine neurotransmitter release. Levetiracetam, a novel antiepileptic drug, binds to synaptic plasma membranes in the central nervous system and inhibits burst firing. It is used primarily as adjunctive therapy with gabapentin in patients with seizures. In one small trial, levetiracetam showed some additional pain relief when added to gabapentin for painful neuropathy. Blocking NMDA (an excitatory neurotransmitter) channels to decrease central sensitization has been ­ limited by

drug side effects.80 Intravenous and subcutaneous ketamine at subanesthetic doses was effective, but caused severe dysphoria, sedation, and dissociative episodes. Dextromethorphan, an over-the-counter cough suppressant, is a low-affinity NMDA channel blocker, an isomer of the codeine analogue levorphanol, and is metabolized to dextrorphan, which also has NMDA-antagonist activity. The antitussive dose of 120 mg/day is insufficient for neuropathic analgesia. In a National Institutes of Health clinical trial, 7 of 13 patients with diabetic neuropathy reported moderate or greater relief; however, the drug was ineffective in postherpetic neuralgia.80 Side effects were substantial, including sedation, dizziness, and ataxia. In the future, NMDA antagonists will likely be combined with other agents to decrease central sensitization because neuropathic pain is the result of multiple mechanisms. Lidocaine patches may give local pain relief. Topical capsaicin, an alkaloid in hot chili peppers that binds to the vanilloid receptor on C and A-delta fibers, depletes SP from sensory nerve endings and with sustained use can reduce neuropathic and osteoarticular pain. WHEN TO REFER TO A PAIN SPECIALIST OR A MULTIDISCIPLINARY PAIN PROGRAM General internists and rheumatologists may become frustrated caring for patients with chronic pain disorders when elimination of the presumptive cause of the pain does

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not eliminate the pain. The medical, psychological, and ­socioeconomic complexity of these patients often creates an intense demand on the clinician. Patients who have predominantly psychological and socioeconomic or occupational features to their chronic pain experience are best cared for by a multidisciplinary pain team, rather than an office-based single practitioner, who would not have the breadth of skills and experience required to identify multiple layers of sensory and emotional components of the pain behaviors. These patients often have had repeated attempts to identify and eliminate the cause of the pain, yet the pain persisted, and they have become depressed, angry, and hopeless. Physicians who are unaware of the psychosocial dimensions of chronic psychophysiologic pain syndromes fail to identify such patients and become frustrated and suspicious of the lack of response to “standard” treatments. The patients behave similarly. Regardless of the underlying pathophysiology, the debility is out of proportion to the tissue injury, and these patients have atypical nonanatomic sensory abnormalities. They seem intolerant to stress, sensory stimuli, and physical activity. The patient’s response to the pain experience and coping style result in a “functional overlay” as an attempt to handle the fear and anxiety he or she is experiencing. The individual clinician usually does not possess the multiple skills and specialized knowledge to assess fully all the dimensions of the pain experience in patients with the chronic pain disorder. This chronic pain syndrome is the physical, psychological, and social degeneration of the patient with chronic pain. These patients need physical, psychological, and social rehabilitation in concert with medical management. Such a biopsychosocial model of chronic pain syndrome requires a multidisciplinary pain management program in which pain reduction has lower priority than pain acceptance and restoration of function. In specialty pain treatment programs, behavior not focused on pain is rewarded, and pain-focused behavior is ignored. This approach redirects the patient’s efforts away from seeking pain relief toward changing behavior and reducing disability. Families are taught not to be solicitous and sympathetic to grimaces and complaints of pain. The program includes intensive exercise therapy, management of depression and anxiety, supportive psychotherapy, and patient education. Cognitive and behavioral therapy includes stress management, relaxation, and biofeedback techniques to gain control over factors that exacerbate the pain. Physical modalities are used to reduce pain and permit a progressive exercise program with a timetable to attain self-care at a level consistent with objective physical abnormalities. Three to 6 weeks is required to initiate physical and emotional changes and an aftercare program to reinforce these changes. The primary criterion for selection of a patient for a multidisciplinary pain program is the definitive diagnosis of nonreversible pain (no planned surgery) and readiness to change (i.e., motivated toward rehabilitation goals). Patients must not have active substance abuse; suicidal ideation; cognitive impairment; or a personality or thought disorder that would interfere with the group milieu, learning, and communication. The patients may need additional specialized diagnostic testing (e.g., nerve blocks, electromyography, psychometric testing) or need detoxification from drugs.

Chronic pain programs vary in quality and should be carefully evaluated before referring patients. A pain specialty center should have multidisciplinary groups of medical specialists for intensive medical, neurologic, psychological, and physical therapy, not simply personnel to perform nerve blocks.

Pain Management Resources American Academy of Pain Medicine—http://www .painmed.org American Pain Foundation—http://painfoundation.org American Pain Society—http://ampainsoc.org International Association for the Study of Pain—http:// halcyon.com/iasp World Health Organization—http://www5.who.int/­ cancer/main.cfm

REFERENCES   1. American Pain Society: Guideline for the Management of Pain in Osteoarthritis, Rheumatoid Arthritis, and Juvenile Chronic Arthritis. 2nd ed. Glenview, Ill, American Pain Society, 2002.   2. Mahowald ML: Principles of opioid treatment of chronic musculoskeletal pain. In Hochberg M, Silman A, Smolen J, et al (eds): Rheumatology, 4th ed. Philadelphia, WB Saunders, 2007.   3. Cassell EJ: Diagnosing suffering: A perspective. Ann Intern Med 131:531-534, 1999.   4. Merskey HM: Classification of chronic pain syndromes: Description of chronic pain syndromes. Pain 3(Suppl):S217, 1986.   5. Russo CM, Brose WG: Chronic pain. Ann Rev Med 49:123-133, 1998.   6. Arner S: Opioids and long-lasting pain conditions: 25-year perspective on mechanisms-based treatment strategies. Pain Rev 7:81-96, 2000.   7. Bolay H, Moskowitz MA: Mechanisms of pain modulation in chronic syndromes. Neurology 59(Suppl 2):S2-S7, 2002.   8. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, text revision. Washington, DC, American Psychiatric Association, 2000.   9. Breivik H, Collett B, Cohen R, et al: Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment. Eur J Pain 10: 287-333, 2006. 10. Sokka T, Kankainen A, Hannonen P: Scores for functional disability in patients with rheumatoid arthritis are correlated at higher levels with pain scores than with radiographic scores. Arthritis Rheum 43:386-389, 2000. 11. Centers for Disease Control and Prevention: Prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation—United States, 2003-2005. MMWR Morb Mortal Wkly Rep 55:1089-1092, 2006. 12. Portenoy RK, Ugarte C, Fuller I, et al: Population-based survey of pain in the United States: Differences among white, African ­American, and Hispanic subjects. J Pain 5:317-328, 2004. 13. Stewart WF, Ricci J, Chee E, et al: Lost productive time and cost due to common pain conditions in the US workforce. JAMA 290: 2443-2454, 2003. 14. American Geriatrics Society: The management of chronic pain in older persons. J Am Geriatr Soc 46:635-651, 1998. 15. Ferrell BA, Ferrell BR, Osterweil D: Pain in the nursing home. J Am Geriatr Soc 38:409-414, 1990. 16. Schaible H-G, Schmelz M, Tegeder I: Pathophysiology and treatment of pain in joint diseae. Adv Drug Deliv Rev 58:323-342, 2006. 17. Wolfe CJ: Pain: Moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 140: 441-451, 2004. 18. Kidd BL: Osteoarthritis and joint pain. Pain 123:6-9, 2006. 19. Sachs D, Cunha FQ, Poole S, et al: Tumour necrosis factor-alpha, interleukin-1 beta and interleukin-8 induce persistent mechanical nociceptor hypersensitivity. Pain 96:89-97, 2002.

PART 8  20. Stein C: The control of pain in peripheral tissues by opioids. N Engl J Med 332:1685-1690, 1995. 21. Honore P, Rogers SD, Schwei MJ, et al: Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience 98:585-598, 2000. 22. Basbaum AI, Jessell TM: The perception of pain. In Kandell ER, Jessel TM (eds): Principles of Neural Science. New York, McGrawHill, 1999, pp 472-491. 23. Caudle RM, Perez FM, Del Valle-Pinero AY, et al: Spinal cord NR1 serine phosphorylation and NR2B subunit suppression following peripheral inflammation. Mol Pain 1:25-37, 2005. 24. Schaible HG, Grubb BD: Afferent and spinal mechanisms of joint pain. Pain 55:5-54, 1993. 25. Mapp P, Kidd BL: The role of substance P in rheumatic disease. Semin Arthritis Rheum 23:3-9, 1994. 26. Mahowald ML, Singh JA, Dykstra D: Long-term effects of intraarticular botulinum toxin A for refractory joint pain. Neurotox Res 9: 179-188, 2006. 27. Matucci-Cerinic M, Konttinen YT, Generini S, et al: Neuropeptides and steroid hormones in arthritis. Curr Opin Rheumatol 10:220-235, 1998. 28. Garrett N, Cruwys SC, Kidd BL, et al: Effect of capsaicin on substance P and nerve growth factor in adjuvant arthritic rat. Neurosci Lett 230:5-8, 1997. 29. Buma P, Elmans L, van den Berg WB, et al: Neurovascular plasticity in the knee joint of an arthritic mouse model. Anat Rec 260:51-61, 2000. 30. Konttinen YT, Sorsa T, Santavirta SS, et al: Via dolorosa: From the first to the second station. J Rheumatol 21:783-787, 1994. 31. Lotz M: Experimental models of arthritis: Identification of substance P as a therapeutic target and use of capsaicin to manage joint pain and inflammation. Semin Arthritis Rheum 23:10-17, 1994. 32. Boyle DL, Moore J, Yang L, et al: Spinal adenosine receptor activation inhibits inflammation and joint destruction in rat adjuvant arthritis. Arthritis Rheum 46:3076-3082, 2002. 33. Honore P, Luger NM, Sabino MC, et al: Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord. Nat Med 6:521-528, 2000. 34. Backonja M: Use of anticonvulsants for treatment of neuropathic pain. Neurology 59(Suppl 2):S14-S17, 2002. 35. Jensen TS, Baron R: Translation of symptoms and signs into mechanisms in neuropathic pain. Pain 102:1-8, 2003. 36. Kost RG, Straus SE: Postherpetic neuralgia—pathogenesis, treatment, prevention. N Engl J Med 335:32-42, 1996. 37. Rice ASC: Gabapentin in postherpetic neuralgia: A randomized, double blind, placebo controlled study. Pain 94:215-224, 2001. 38. Alper BS, Lewis PR: Review: Tricyclic antidepressants, capsaicin, gabapentin, and oxycodone are effective for postherpetic neuralgia. J Fam Pract 51:121-128, 2002. 39. Attal N, Brasseur L, Dupuy M, et al: Intravenous lidocaine in central pain: A double blind placebo controlled psychophysical study. Neurology 54:564-574, 2000. 40. Attal N, Guirimand F, Brasseur L, et al: Effects of IV morphine in central pain: A randomized placebo controlled study. Neurology 58: 554-563, 2002. 41. Merskey HM, Bogduk N: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. Seattle, International Association for the Study of Pain Press, 1994. 42. Kemler MA, Barendse GAM, van Kleef M, et al: Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. N Engl J Med 343:618-624, 2000. 43. Berklein F, Schmelz M, Schifter S, et al: The important role of neuropeptides in complex regional pain syndrome. Neurology 57: 2179-2184, 2001. 44. van Hilten BJ, van de Beek WJT, Hoff JI, et al: Intrathecal baclofen for the treatment of dystonia in patients with reflex sympathetic dystrophy. N Engl J Med 343:625-630, 2000. 45. Krug HE, Woods S, Mahowald ML: The importance of identifying depression in patients with rheumatoid arthritis. J Clin Rheumatol 3:248-257, 1997. 46. Staab JP, Datto CJ, Weinrieb RM, et al: Detection and diagnosis of psychiatric disorders in primary medical care settings. Med Clin North Am 85:579-596, 2001.

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47. Fishbain DA: Approaches to treatment decisions for psychiatric comorbidity in the management of the chronic pain patient. Med Clin North Am 83:737-760, 1999. 48. Miller MC: Personality disorders. Med Clin North Am 85:819-837, 2001. 49. Hart FD, Taylor RT, Huskisson EC: Pain at night. Lancet 1:881-884, 1970. 50. Mahowald MW, Mahowald ML, Bundlie S, et al: Sleep fragmentation in rheumatoid arthritis. Arthritis Rheum 32:974-983, 1989. 51. Mahowald ML, Mahowald MW: Nighttime sleep and daytime functioning (sleepiness and fatigue) in well-defined chronic rheumatic diseases. Sleep Med 1:179-193, 2000. 52. Mahowald ML, Mahowald MW: Nighttime sleep and daytime functioning (sleepiness and fatigue) in less well defined rheumatic diseases. Sleep Med 1:195-207, 2000. 53. Lavigne G, Zucconi M, Castronovo C, et al: Sleep arousal response to experimental thermal stimulation during sleep in human subjects free of pain and sleep problems. Pain 84:283-290, 2000. 54. Smith MT, Perlis ML, Smith MS, et al: Sleep quality and presleep arousal in chronic pain. Int J Behav Med 23:1-13, 2000. 55. Wooten V: Medical causes of insomnia. In Dement WC (ed): Principles and Practice of Sleep Medicine. Philadelphia, WB Saunders, 1994, pp 509-522. 56. Atkinson H, Ancoli-Israel S, Slater MA, et al: Subjective sleep disturbance in chronic back pain. Clin J Pain 4:225-232, 1988. 57. Wittig RM, Zorick FJ, Blumer D, et al: Disturbed sleep in patients complaining of chronic pain. J Nerv Ment Dis 170:429-431, 1982. 58. Harman K, Pivik RT, D’Eon JL, et al: Sleep in depressed and nondepressed participants with chronic low back pain: Electroencephalographic and behaviour findings. Sleep 25:775-783, 2002. 59. Sayar K, Arikan M, Yontem T: Sleep quality in chronic pain patients. Can J Psychiatry 47:844-848, 2002. 60. Wilcox S, Brenes GA, Levine D, et al: Factors related to sleep disturbance in older adults experiencing knee pain or knee pain with radiographic evidence of knee osteoarthritis. J Am Geriatr Soc 48:1241-1251, 2000. 61. Gureje O, Simon GE, Von Korff M: A cross national study of the course of persistent pain in primary care. Pain 92:195-200, 2001. 62. Eckman P, O’Sullivan M: Who can catch a liar? Am Psychol 46: 913-920, 1991. 63. Spitzer RL, Williams JB, Kroenke K, et al: Validity and utility of the PRIME-MD patient health questionnaire in assessment of 3000 obstetric-gynecologic patients. The PRIME-MD Patient Health Questionnaire Obstetrics Gynecology Study. Am J Obstet Gynecol 183:759-769, 2000. 64. Brena SF, Koch DF: The pain estimate model for quantification and classification of chronic pain states. Anesth Rev 2:8-13, 1975. 65. Farrar JT, Young JP, LaMoreaux L, et al: Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 94:149-158, 2001. 66. Papagallo M: Aggressive pharmacologic treatment of pain. Rheum Dis Clin N Am 25:193-212, 1999. 67. Peloso PM, Bellamy N, Bensen W, et al: Double blind randomized placebo control trial of controlled release codeine in the treatment of osteoarthritis of the hip or knee. J Rheumatol 27:764-771, 2000. 68. Portenoy RK: Opioid therapy for chronic nonmalignant pain: Current status. In Fields HL, Liebeskind JC (eds): Progress in Pain Research and Management. Seattle, International Association for the Study of Pain Press, 1994, pp 247-287. 69. Portenoy RK (ed): Opioid tolerance and responsiveness: Research findings and clinical observations. In: Proceedings of 7th World Congress on Pain. Seattle, International Association for the Study of Pain Press, 1994. 70. Portenoy RK, Dole F, Joseph H, et al: Pain management and chemical dependency: Evolving perspectives. JAMA 278:592-593, 1997. 71. Ytterberg SR, Mahowald ML, Woods SR: Codeine and oxycodone use in patients with chronic rheumatic disease pain. Arthritis Rheum 41:1603-1612, 1998. 72. Mahowald ML, Singh JL, majeski P: Opioid use by patients in an orthopedics spine clinic. Arthritis Rheum 52:312-321, 2005. 73. Lazovskis J, Mahowald ML, Singh J: Lack of evidence for opioid tolerance in patients with rheumatic disease. Arthritis Rheum 46:S102, 2003. 74. Sandoval J, Furlan A, Mailis-Gagnon A: Oral methadone for chronic noncancer pain: A systematic literature review of reasons for administration, prescription patterns, effectiveness and side effects. Clin J Pain 21:503-512, 2005.

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75. Raja SN, Haythornthwaite JA, Papagallo M, et al: Opioids versus antidepressants in postherpetic neuralgia: A randomized, placebocontrolled trial. Neurology 59:1015-1021, 2001. 76. Backonja M, Beydoun A, Edwards KR, et al: Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: A randomized controlled trial. JAMA 280:1831-1836, 1998. 77. Sindrup SH, Jensen TS: Pharmacologic treatment of pain in polyneuropathy. Neurology 55:915-920, 2000. 78. Watson CP, Babul N: Efficacy of oxycodone in neuropathic pain: A randomized trial in postherpetic neuralgia. Neurology 50:18371841, 1998.

79. Gimbel JS, Richards P, Portenoy RK: Controlled-release oxycodone for pain in diabetic neuropathy: A randomized controlled trial. Neurology 60:927-934, 2003. 80. Nelson KA, Park KM, Robinovitz E, et al: High dose oral dextrometh­ orphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology 48:1212-1218, 1997.

61

Arthritis Self-Management Kate R. Lorig

KEY POINTS Structured behavioral interventions lead to improved health status beyond that achieved by traditional medical care. Exercise, especially walking, should be a key element in the treatment of most individuals with arthritis. Coping skills training and other structured cognitive programs can lead to less pain and health-related distress. Effective behavioral programs can be delivered in a variety of formats—in small groups, via telephone, and via the Internet.

WHAT SHOULD BE TAUGHT Until more recently, the key topic of arthritis selfmanagement education was symptom management. With the advent of many new powerful medications for inflammatory arthritis, there is now a need to educate patients about compliance with medication regimens. The symptoms of ar­­ thritis—pain, fatigue, disability, and depression—are linked and feed into each other in complex patterns that are difficult to distinguish. One key to patient education is to break these patterns and lessen these symptoms by the use of selfmanagement behaviors, such as exercise, fatigue management, use of assistive devices, and cognitive coping. EXERCISE

Most arthritis treatment guidelines place patient education or patient self-management at a pivotal point in the treatment plan. For the first time, the Healthy People 2010 objectives for the United States include a developmental objective: “to … increase the proportion of persons with arthritis who have had effective, evidence-based arthritis education as an integral part of the management of their condition.”1 Despite the almost universal recognition among rheumatology professionals of the importance of patient edu­cation, it is estimated that less than 5% of all arthritis patients receive any formal or standardized education. This chapter discusses the evidence for self-management and makes some suggestions about how self-management can be included in clinical practice. The suggestions in this chapter are based on two assumptions, both of which are based on evidence. First, although there are many different types of arthritis, the problems faced by patients with different types of arthritis are more similar across conditions than they are d­ifferent. These problems include (1) medical management of the disease, including adherence to medication taking and exercise; (2) maintaining one’s important and pleasurable life roles in the face of pain, disability, and fatigue; and (3) coping with the negative emotions of anger, fear, frustration, and depression that almost always accompany the disease.2 Second, arthritis is one of the most prevalent comorbid conditions; this is especially true in elderly patients, in whom the average number of chronic conditions is 2.2. Each chronic condition has separate, although sometimes overlapping medical management, but each is distinct. Until more recently, it was believed that the same was true for self-management education. This latter assumption has now been questioned. It may be possible to create generic programs for chronic conditions and then add disease-specific content.

Probably the strongest evidence is for the effectiveness of conditioning exercise, including endurance and strengthening, in individuals with osteoarthritis and rheu­matoid arthritis.3,4 Walking, cycling, water aerobics, strength tr­aining, and low-impact exercise programs report decreased pain and improved range of motion, cardiovascular fitness, strength, endurance, function, and gait in individuals with arthritis.5 Well-controlled studies of aerobic exercise c­onsistently report that individuals with arthritis can safely ex­ercise regularly and vigorously enough to improve fitness and health without exacerbation of disease or increased joint symptoms.6 The training regimens in most aerobic exercise studies progressively increase the intensity and duration of the exercise sessions to achieve the guidelines for cardiovascular fitness set by the American College of Sports M­edicine (30 to 45 minutes of moderate-intensity, whole-body exercise, such as walking, cycling, or sw­imming, 3 to 5 days a week).7 Controlled trials of exercise interventions designed sp­ecifically for individuals with knee osteoarthritis include strengthe­ning, aerobic, and functional exercises. These studies use a short period of initial instruction followed by several months of self-directed home exercise and report improved strength, proprioception, and function, and decreased pain.8,9 Lo­­w-intensity active range-of-motion exercise, the traditional home exercise program for individuals with arthritis, can provide benefits in addition to flexibility and joint motion. Gentle exercise performed in the evening can significantly reduce morning stiffness in individuals with rheumatoid arthritis. An exercise program of active exercise and relaxation (the range of motion dance) has shown significant improvements in self-reported function and pain.5 In addition to the aforementioned benefits, exercise seems to improve depression. Although the exact mechani­ sms are not understood, it may be that depression and other 993

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n­egative mood states are mediated by self-efficacy, or the belief (confidence) that one can affect disease sy­mptoms. Several publications have documented that the combination of exercise and weight loss in individuals with osteoarthritis leads to improvement in pain, function, mobility-related performance, and other health-related quality-of-life measures.42-45 Today, the European League Against Rheumatism and the American College of Rheumatology endorse weight loss and exercise in overweight individuals with knee osteoarthritis.46 FATIGUE MANAGEMENT Fatigue has been shown to be a common symptom for pat­ i­ents with many different types of rheumatic diseases.32-38 First, the underlying cause of fatigue, if known, must be managed. Next, several self-management techniques have been shown to lessen fatigue, including the traditional strategies of balancing work with rest and assisting patients to improve their sleep patterns. Individuals with rheumatic disease who are involved in aerobic exercise of moderate intensity note improvements in pain and fatigue. Positive effects of low-impact aerobic exercise on fatigue have been found to be dose related.39 ASSISTIVE DEVICES Assistive devices frequently are recommended for individuals with arthritis to improve their functional capabilities by compensating for limitations in dexterity, joint range of motion, muscle strength, and endurance. Patients newly diagnosed with rheumatoid arthritis have associated as­sistive devices with self-care strategies for maintaining their ability to perform daily living tasks.22 Device use is related to d­isease duration independent of disease activity.23According to Kulp,24 the devices most frequently used by patients with rheumatoid arthritis were wrist splints followed by silver ring splints, raised toilet seats, bath/shower benches, and dressing sticks. Patients with severe arthritis used more devices to accommodate their physical impairments and safety needs than patients with moderate disease.25 Rogers and colleagues26-29 ascertained that most assistive device users with rheumatoid arthritis and osteoarthritis had positive impressions of assistive devices, including the ability of the devices to make task performance more independent, easier, and safer. Similarly, Nordenskiöld and colleagues30,31 found that the use of devices or altered methods reduced perceived task difficulty for 42% of the task items, and that devices decreased pain when performing tasks. Patients were generally satisfied with devices25; however, they reported a need for more adequate information about the devices that are available,25 and additional information influenced their selection of devices and increased their satisfaction.26 COGNITIVE COPING Keefe, Parker, and others10-12 have published a series of important studies indicating that (1) patients who cope with pain in an overly negative fashion (“catast­rophizing”) have much more severe pain and disability, and (2) patients who avoid catastrophizing and who report they can use more adaptive strategies (e.g., distraction, calming

se­lf-statements) to control and decrease pain have much lower levels of pain and disability. Bradley, Keefe, and others13-18 have shown that systematic training in pain coping skills can lessen pain and disability in rheumatoid arthritis and osteoarthritis patients. Involving spouses in coping skills training seems to be beneficial in managing pain and disability in osteoarthritis patients.19,20 There is evidence that early intervention with coping skills training can be effective in preventing psychological and physical disability in patients with recent-onset rheumatoid arthritis.21 Coping strategies and illness perceptions contribute to health outcomes in patients with arthritis.40 Specifically, more perceived symptoms are associated with more pain and tiredness, and more avoidant coping is associated with more tiredness. To facilitate coping with a chronic condition such as arthritis, cognitive behavioral therapy can be beneficial.41 Cognitive behavioral therapy teaches one to replace ineffective coping strategies with effective strategies.

EFFECTIVENESS OF STRUCTURED PROGRAMS Several modes of patient education have shown ef­fec­tiveness in terms of improved health status, improved co­mpliance, or decreased health care usage. These include small group education led by peers (patients) and health professionals, telephone interventions, mail-delivered interventions, c­omputer-delivered interventions, and group medical v­isits. There is substantive evidence for the effectiveness of arthritis patient education,47,48 although there also are reviews showing little or no effect.49,50 There are s­everal problems with most reviews. First, they tend to suffer from the syndrome of mixing apples and oranges, such as gro­uping early studies with later studies, and studies with many different delivery modes and interventions of varying lengths and content.51 In addition, the reviews seldom deal with the differing exclusion factors for each study. If only highly impacted patients, such as patients with high pain levels, are included in the studies, the effect sizes tend to be higher than in studies that include all individuals with the condition. Probably the most studied interventions are the ones offered in small face-to-face groups. In a professionally led, 6-week group series emphasizing behavioral change, Lindroth and colleagues52 found that participants showed improvements in knowledge, behaviors, and disability compared with randomized controls.52 Five years later, treatment subjects continued to show an increased ability to cope with their disease.53 Kovar and associates,54 in a study of individuals with osteoarthritis of the knee combining walking and educational sessions based on self-efficacy theory, showed that the program improved functional status without wo­rsening pain or other symptoms. Finally, a series of studies on the peer-led Arthritis Self-Management Program (also known as the Arthritis Self-Help Program and Challenging Arthritis) found increases in self-management behaviors, exercise, and cognitive symptom management, and decrease in pain. Decreases in pain and outpatient visits to physicians persisted for 4 years.55-57 These studies have been replicated by other authors with similar results, although sometimes with lesser results.58-61

PART 8 

Weinberger and coworkers62-64 conducted a series of t­elephone-based interventions that consisted of regular phone calls to patients by trained students. Results from randomized trials showed that patients contacted by phone compared with patients receiving the same information in the clinic had improved physical health and reduced pain.62,63 The telephone intervention also was less costly.64 Maisiak and colleagues65 followed up on the users of an arthritis hotline. They found that hotline users asked their physicians more questions and reported improved compliance with treatment. In a study that was not limited to individuals with arthritis, Wasson and associates66 showed that for older patients with a variety of chronic and morbid conditions, proactive phone calls by their health care provider between regularly scheduled visits reduced outpatient visits and hospitalizations. Goeppinger and coworkers67 used a combined telephone and mailed intervention for patients in rural areas and sho­wed increases in self-management knowledge and behaviors, and reductions in pain. Fries and colleagues68 have shown the effectiveness of a mailed intervention mediated by computer-generated personalized letters over a period of 1 year. These findings were replicated in a 3-year randomized trial.69 Computer-meditated interventions are only beginning to be used with arthritis patients. An early intervention in the 1980s with poor elderly subjects showed an increase in knowledge, improved outlook, and increase in self-management behaviors.70 More recently, a year-long e-mail discussion group for patients with back pain showed that participants experienced less disability and pain with a trend toward fewer back pain–related visits compared with randomized nonparticipants.71 The Arthritis Self-Help program has been adapted for delivery through the Internet. Results of a 1-year randomized trial indicate that the effectiveness of the program delivered in this mode is similar to when it is delivered to a small group.72 Finally, in a randomized trial, the Arthritis Self-Help Program was compared with the generic Chronic Disease Self-Management Program. This latter program was designed to include patients with different and multiple chronic conditions. There were few differences in outcomes between arthritis patients who participated in the arthritis-specific program and the generic program.73 Although the above-described interventions at first seem to have little in common, some of the components of su­ccessful interventions are beginning to be understood. Most, if not all, of these interventions are based on patient-perceived problems or symptoms or both, rather than professionally modeled activities, such as specific exercise programs. All of the successful interventions, including interventions delivered via the Internet, in one way or another allow patients to interact in a planned, structured manner. Studies have shown that self-efficacy or confidence in ability to self-manage arthritis is a key mediating variable for health outcomes. Studies of self-management interventions have shown that these interventions can improve self-efficacy, and changes in self-efficacy mediated improvements in health status.74,75 Self-efficacy, confidence, or empowerment can be accomplished by systematically using four strategies: skills mastery, modeling, reinterpretation of symptoms, and social persuasion. Skills mastery involves getting patients to try to master self-management skills; this is typically accomplished

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by having patients set a specific short-term goal or action plan.76 A typical plan might be, “This week I will walk 15 minutes before lunch on Monday, Wednesday, and Friday.” An alternative plan might be, “This week I will not eat after 7 p m. for 4 days.” In a meta-analysis of asthma studies, a Cochrane Review77 found that goal setting or action planning was a key variable that separated successful from unsuccessful interventions. It is important that an action plan be something that the patient wants to do, rather than an activity demanded by the physician. Two studies found that when physicians in primary care assisted their patients with action planning, most patients remembered the action plan and had made some behavior changes 2 weeks after the visit.78,79 The second self-efficacy strategy, modeling, involves having patients learn from other patients or patient models. The best patient education materials include patient vignettes and drawings or photos of individuals similar to the patients for whom the materials are intended. When patients meet in groups, the leader should use structure that allows patients to share experiences and to help each other with problems. Internet e-mail list serves, chatrooms, and discussion boards also provide for patient modeling. Although health professionals often fear that patients talking to patients in an unstructured manner may lead to the use of nontraditional treatments, at least one study has shown that this was not true.80 Along with social interaction and self-efficacy, there is at least one other strategy that mediates the effectiveness­ of patient education: tailoring/self-tailoring. Tailoring is accomplished by learning something about patients’ motivation, beliefs, and lifestyle and then offering patients education and suggestions tailored by this knowledge. Using this knowledge about the patient, the health professional constructs a personalized education plan. With selftailoring,­ the assumption is that the patient, when given guidance and options, would construct a self-management plan that fits his or her needs. The role of the health professional is to supply key messages (see more about this in the next section) and a structure such as action planning with which to start a program. The actual changes to be made are deter­mined by the patient. Patient education efforts that are either tailored to patient’s needs or allow patients to self-tailor are more effective than efforts that do not meet these criteria.

TIPS FOR THE BUSY CLINICIAN



1. Base one-to-one teaching on patient’s main concerns. These can be determined by asking, “When you think about arthritis, what do you think of?” or “What are you afraid might happen?” Use the answers to tailor your education. If the response to the first question is “pain,” the physician can answer that pain can be caused by several different­ things, and that there are many ways of dealing with pain. 2. Screen frequently for depression. A good single question is, “What do you do for fun?” If the patient cannot give a positive answer, further screening and possible treatment are needed. Patient education is probably not the first treatment for major depression.

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3. Have a set of consistent key messages. A key message is detailed enough to allow a patient to self-tailor, while not overwhelming the patient with details. Examples of key messages are as follows: • “You should not have more pain when you finish exercising than before you start, but exercise may not be pain-free.” • “You cannot cause yourself permanent damage by exercising.” • “Weight loss is a function of eating less and moving more.” • “Start an exercise program by doing what you can do now, do this four to five times a week, and add to it by 10% every 1 to 2 weeks.” • “Take your pills with some activity you do every day, such as brushing your teeth.” • “It is easier to control pain when it is not severe. Take your medicine when you have only mild pain. Don’t wait to see if it will get worse.” • “To lose weight, try the 200 plan. Add 100 calories of exercise a day (about a half hour) and reduce food intake by 100 calories a day (a cookie or two). This will result in a loss of 20 lb a year.” 4. Have patients set specific behavior goals or action plans for the next month or so. Ask about these during the next visit. 5. Keep a list of good books and websites to give patients. Update these at least yearly. Patients are a good source of what to put on this list. 6. Know about community resources, such as exercise classes, arthritis patient education classes, meditation classes, and support groups. If possible, visit some of these so that you really know about them. Provide patients with a specific name and telephone number for a community resource. 7. Keep a small patient education library in your waiting room. 8. Always tell patients when to expect new medications to start working. Many patients expect new medications to have effects in hours or at least in days. When this does not happen, they often stop taking medications or reduce the dose before full effectiveness is reached. 9. When asking patients about taking medications, assume that there may have been problems. Ask, “What problems have you had taking this medication?” This makes it much easier for the patients to say they forgot, the medicine was too expensive, or that they did not like the side effects. 10. Make yourself available to your patients by phone or e-mail. This is difficult given a busy schedule, legal considerations, and the present lack of reimbursement for these services. Nevertheless, most patients do not abuse this privilege, and this is an excellent way to catch problems before they grow, encourage patients, or relieve them of needless worry. The few patients who abuse this added contact could be handled by limiting them to a set number of contacts per month. 11. When a patient presents with symptoms, even if they are not medically significant, be sure to address the symptoms when giving reassurance: “The good news is that I cannot find anything seriously wrong with you, but I know that you still have pain, so I suggest ….”

12. Frame discussions to expand the patient’s perception of the problem: “Sounds like you have lots of reasons for being depressed and just like other medical problems we have treatments.” “Fatigue can be caused by lots of things—disease, deconditioning, medication, poor nutrition, poor sleep, anxiety, and depression or maybe several of these. Think about each, and try some new things, such as a little exercise when you are tired, or eating a bit better. Sometimes a little experimentation will give you helpful answers.” 13. Acknowledge that following a regimen might be difficult: “Taking these medications as directed might be a bit difficult, but I know you can do it.”

CONCLUSION Properly administered patient education can reduce symptoms and possibly health care usage above and beyond usual care. Good rheumatology care requires the systematic application of evidence-based education strategies. Acknowledgments The author acknowledges Marion Minor, PhD, PT; Francis Keefe, PhD; Joan Rogers, OTR L; Basia Belza, PhD, RN; and Bonnie Bruce, DrPH, MPH, RD, for their assistance with this chapter.

REFERENCES    1. U.S. Department of Health and Human Services: Healthy People 2010. Conference edition in two volumes. Washington, DC, US Govt Printing Office, 2000.   2. Corbin J, Strauss A: Unending Work and Care: Managing Chronic Illness at Home. San Francisco, Jossey-Bass Publishers, 1988.    3. Van den Ende CHM, Vilet Vlieland TPM, Munneke M, et al: Dynamic exercise therapy in rheumatoid arthritis. Cochrane Rev 3, 2002.   4. Van Baar ME, Assendelft WJJ, Dekker J, et al: Effectiveness of exercise therapy in patients with osteoarthritis of the hip or knee: A systematic review of randomized clinical trials. Arthritis Rheum 42:1361-1369, 1999.   5. Minor MA, Westby MD: Rest and exercise. In Robbins L, Burckhardt CS, Hannan MT (eds): Clinical Care in the Rheumatic Diseases, 2nd ed. Atlanta, Association of Rheumatology Health Professionals, 2001.   6. Westby MD: A health professional’s guide to exercise prescription for people with arthritis: A review of aerobic fitness activities. Arthritis Care Res 45:501-511, 2001.    7. Pearson TA, Blair SN, Daniels SR, et al: Consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke: 2002 update. Circulation 106:388, 2002.   8. O’Reilly S, Muir K, Doherty M: Effectiveness of a home exercise on pain and disability from osteoarthritis of the knee: A randomized controlled trial. Ann Rheum Dis 58:15-19, 1999.   9. Petrella RJ, Bartha C: Home based exercise therapy for older persons with knee osteoarthritis: A randomized clinical trial. J Rheumatol 27:2215-2221, 2000. 10. Keefe FJ, Caldwell DS, Queen KT, et al: Osteoarthritic knee pain: A behavioral analysis. Pain 28:309-321, 1987. 11. Keefe FJ, Caldwell DS, Queen KT: Pain coping strategies in osteoarthritis patients. J Consult Clin Psychol 55:208-212, 1987. 12. Parker JC, Smarr KL, Buescher KL, et al: Pain control and rational thinking: Implications for rheumatoid arthritis. Arthritis Rheum 32:984-990, 1989. 13. Bradley LA, Young LD, Anderson JO, et al: Effects of psychological therapy on pain behavior of rheumatoid arthritis patients: Treatment outcome and six-month follow-up. Arthritis Rheum 30:1105-1114, 1987.

PART 8  14. Bradley L, Young L, Anderson K, et al: Effects of cognitive-behavior therapy on rheumatoid arthritis pain behavior: One year follow-up. In Dubner R, Gebhart G, Bond M (eds): Pain Research and Clinical Management, 3 (Proceedings of the 5th World Congress on Pain). Amsterdam, Elsevier, 1988, pp 310-314. 15. Keefe FJ, Caldwell DS, Williams DA, et al: Pain coping skills training in the management of osteoarthritic knee pain, I: A comparative study. Behav Ther 21:49-62, 1990. 16. Parker J, Frank R, Beck N, et al: Pain management in rheumatoid arthritis: A cognitive-behavioral approach. Arthritis Rheum 31:593-601, 1988. 17. Parker JC, Smarr KL, Buckelew SP, et al: Effects of stress management on clinical outcomes in rheumatoid arthritis. Arthritis Rheum 38:1807-1818, 1995. 18. Astin JA, Beckner W, Soeken K, et al: Psychological interventions for rheumatoid arthritis: A meta-analysis of randomized controlled trials. Arthritis Rheum (Arthritis Care Res) 47:291-302, 2002. 19. Beaupre P, Weisberg J, Helms M: Spouse-assisted coping skills training in the management of osteoarthritis knee pain. Arthritis Care Res 9:279-291, 1996. 20. Keefe FJ, Caldwell DS, Baucom D, et al: Spouse-assisted coping skills training in the management of knee pain in osteoarthritis: Long-term follow-up results. Arthritis Care Res 12:101-111, 1999. 21. Sharpe L, Sensky T, Timberlake N, et al: A blind, randomized, controlled trial of cognitive-behavioral intervention for patients with recent onset rheumatoid arthritis: Preventing psychological and physiological morbidity. Pain 89(2-3):275-283, 2001. 22. Dubouloz CJ, Laporte D, Hall M, et al: Transformation of meaning perspectives in clients with rheumatoid arthritis. Am J Occup Ther 58:398-407, 2004. 23. van der Heaide A, Jacobs JW, van Albada-Kuipers GA, et al: Self report of functional disability scores and the use of devices: Two distinct aspects of physical function in rheumatoid arthritis. Ann Rheum Dis 52:497-502, 1993. 24. Kulp CS: The use of adaptive equipment by rheumatoid arthritis patients. Master’s thesis. Richmond, Virginia Commonwealth University, 1988. 25. Mann WC, Hurren D, Tomita M: Assistive devices used by homebased elderly persons with arthritis. Am J Occup Ther 49:810-820, 1995. 26. Haas U, Brodin H, Andersson A, et al: Assistive technology selection: A study of participation of users with rheumatoid arthritis. IEEE Trans Rehab Eng 5:263-275, 1997. 27. Rogers JC, Holm MB: Assistive technology device use in patients with rheumatic disease: A review of literature. Am J Occup Ther 46:120-127, 1992. 28. Rogers JC, Holm MB, Perkins L: Trajectory of assistive device usage and user and non-user characteristics: Long-handled bath sponge. Arthritis Care Res 47:647-650, 2002. 29. Rogers JC, Poole JL, Holm MB, et al: Assistive devices: Prescription, patient education, patient perceptions. Arthritis Rheum 32:S195, 1989. 30. Nordenskiöld U, Grimby G: Dahlin-Ivanoff S: Questionnaire to evaluate the effects of assistive devices and altered working methods in women with rheumatoid arthritis. Clin Rheum 17:6-16, 1998. 31. Nordenskiöld U: Evaluation of assistive devices after a course in joint protection. Int J Technol Assess Health Care 10:293-304, 1994. 32. Pinals RS, Masi A, Larsen R: Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum 24:1308-1315, 1981. 33. Belza B, Henke C, Yelin E, et al: Correlates of fatigue in older adults with rheumatoid arthritis. Nurs Res 42:93-99, 1993. 34. Wolfe F, Smyth HA, Yanus MD, et al: The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: Report of the multicenter criteria committee. Arthritis Rheum 33:160-172, 1990. 36. Krupp L, LaRocca N, Muir-Nash J, et al: A study of fatigue in systemic lupus erythematosus. J Rheumatol 17:1450-1452, 1990. 37. Tench CM, McCordie I, White PD, et al: The prevalence and association of fatigue in SLE. Rheumatology 39:1249-1254, 2000. 38. Calin A, Edmonds L, Kennedy L: Fatigue in ankylosing spondylitis: Why is it ignored? J Rheumatol 20:991-995, 1999. 39. Neuberger G, Press A, Lindsley H, et al: Effects of exercise on fatigue, aerobic fitness, and disease activity measures in persons with rheumatoid arthritis. Res Nurs Health 20:195-204, 1997.

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40. Scharloo M, Kaptein A, Weinman JA, et al: Predicting functional status in patients with rheumatoid arthritis. J Rheumatol 26:1686-1693, 1999. 41. Rhee SH, Parker JL, Smarr KL, et al: Stress management in rheumatoid arthritis: What is the underlying mechanism? Arthritis Care Res 13:435-442, 2000. 42. Focht BC, Rejeski WJ, Ambrosius WT, et al: Exercise, self-efficacy, and mobility performance in overweight and obese older adults with knee osteoarthritis. Arthritis Rheum 53:659-665, 2005. 43. Messier SP, Gutekunst DJ, Davis C, et al: Weight loss reduces kneejoint loads in overweight and obese older adults with knee osteoarthritis. Arthritis Rheum 52:2026-2032, 2005. 44. Rejeski WJ, Focht BC, Messier SP, et al: Obese, older adults with knee osteoarthritis: Weight loss, exercise, and quality of life. Health Psychol 21:419-426, 2002. 45. Albu J, Konorides C, Pi-Sunyer FX: Weight control in diabetes mellitus: Metabolic and cardiovascular effects. Diabetes Rev 3:335-347, 1995. 46. Pendleton A, Arden N, Dougados M, et al: EULAR recommendations for the management of knee osteoarthritis: Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis 59:936-944, 2000. 47. Riemsma RP, Kirwan JR, Taal E, et al: Patient education for adults with rheumatoid arthritis. Cochrane Rev 4, 2002. 48. Roter DL, Hall JA, Merisca R, et al: Effectiveness of interventions to improve patient compliance: A meta-analysis. Med Care 36:1138-1161, 1998. 49. Warsi A, LaValley MP, Wang P, et al: Arthritis self-management education programs: A meta-analysis of the effect on pain and disability. Arthritis Rheum 48:2207-2213, 2003. 50. Warsi A, Wang PS, LaValley MP, et al: Self-management education programs in chronic disease: A systematic review and methodological critique of the literature. Arch Intern Med 164:1641-1652, 2004. 51. Holman HR, Lorig K, Chodosh J, et al: Self-management education for osteoarthritis. Ann Intern Med 144:617-618, 2006. 52. Lindroth Y, Bauman A, Barnes C, et al: A controlled evaluation of arthritis education. Br J Rheum 28:7-12, 1989. 53. Lindroth Y, Bauman A, Brooks PM, et al: A 5-year follow-up of a controlled trial of an arthritis education programme. Br J Rheum 34:647-652, 1995. 54. Kovar PA, Allegrante JP, MacKenzie CR, et al: Supervised fitness walking in patients with osteoarthritis of the knee: A randomized, controlled trial. Ann Intern Med 116:529-534, 1992. 55. Lorig K, Lubeck D, Kraines R, et al: Outcomes of self-help education for patients with arthritis. Arthritis Rheum 28:680-685, 1985. 56. Lorig K, Mazonson P, Holman H: Evidence suggesting that health education for self-management in patients with chronic arthritis has sustained health benefits while reducing health care costs. Arthritis Rheum 36:439-446, 1993. 57. Lorig K, González V, Laurent D: The Chronic Disease Self-Management Leader’s Manual (Revised). Stanford, Calif, Stanford University, Stanford Patient Education Research Center, 1999. 58. Wong AL, Harker JO, Lau VP, et al: Spanish arthritis empowerment program: A dissemination and effectiveness study. Arthritis Rheum (Arthritis Care Res) 51:332-336, 2004. 59. Barlow J, Turner A, Wright C: A randomized controlled study of the arthritis self-management programme in the UK. Health Educ Res 15:665-680, 2000. 60. Solomon DH, Warsi A, Brown-Stevenson T, et al: Does selfmanagement education benefit all populations with arthritis? A randomized controlled trial in a primary care physician network. J Rheumatol 29:362-368, 2002. 61. Fries JF, Lorig K, Holman HR: Patient self-management in arthritis? Yes! J Rheumatol 30:1130-1132, 2003. 62. Weinberger M, Tierney WM, Boher P, et al: Can the provision of information to patients with osteoarthritis improve functional status? A randomized, controlled trial. Arthritis Rheum 32:1577-1583, 1989. 63. Rene J, Weinberger M, Mazzuca SA, et al: Reduction of joint pain in patients with knee osteoarthritis who have received monthly telephone calls from lay personnel and whose medical treatment regimens have remained stable. Arthritis Rheum 35:511-515, 1992.

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64. Weinberger M, Tierney WM, Cowper PA, et al: Cost-effectiveness of increased telephone contact for patients with osteoarthritis: A randomized, controlled trial. Arthritis Rheum 36:243-246, 1993. 65. Maisiak R, Koplon S, Heck LW: Subsequent behavior of users of an arthritis information telephone service. Arthritis Rheum 33:212-218, 1990. 66. Wasson J, Gaudette C, Whaley F, et al: Telephone care as a substitute for routine clinic follow up. JAMA 267:1788-1793, 1992. 67. Goeppinger J, Arthur MW, Baglioni AJ Jr, et al: A reexamination of the effectiveness of self-care education for persons with arthritis. Arthritis Rheum 32:706-716, 1989. 68. Fries J, Carey C, McShane D: Patient education in arthritis: Randomized controlled trial of a mail-delivered program. J Rheumatol 24:1378-1383, 1997. 69. Lorig KR, Ritter PL, Laurent DD, et al: Long-term randomized controlled trials of tailored-print and small-group arthritis selfmanagement interventions. Med Care 42:346-354, 2004. 70. Wetstone SL, Sheehan TJ, Votaw RG, et al: Evaluation of a computer based education lesson for patients with rheumatoid arthritis. J Rheumatol 12:907-912, 1985. 71. Lorig K, Laurent D, Deyo R, et al: Can a back pain e-mail discussion group improve health status and lower health care costs? Arch Intern Med 162:792-796, 2002. 72. Lorig KR, Laurent D, Plant K, et al: Arthritis self-management on-line: A 12 month randomized trial. Arthritis Rheum 54:S511, 2006.

73. Lorig K, Ritter PL, Plant K: A disease-specific self-help program compared with a generalized chronic disease self-help program for arthritis patients. Arthritis Rheum 53:950-957, 2005. 74. Lorig K, Lubeck D, Holman H: Nonassociations of new behaviors with favorable outcome in effective arthritis health education. Arthritis Rheum 25:S148, 1982. 75. Lorig K, Brown BW Jr, Ung E, et al: Development and evaluation of a scale to measure the perceived self-efficacy of people with arthritis. Arthritis Rheum 32:37-44, 1989. 76. Bandura A: Self-efficacy: The Exercise of Control. New York, WH Freeman & Company, 1997. 77. Gibson PG, Coughlan J, Wilson AJ, et al: Self-management education and regular practitioner review for adults with asthma. Cochrane Rev 4, 2002. 78. Handley M, MacGregor K, Schillinger D, et al: Using action plans to help primary care patients adopt healthy behaviors: A descriptive study. J Am Board Fam Med 19:224-231, 2006. 79. MacGregor K, Handley M, Wong S, et al: Behavior-change action plans in primary care: A feasibility study of clinicians. J Am Board Fam Med 19:215-223, 2006. 80. Bruce B, Lorig K, Laurent D, et al: The impact of a moderated e-mail discussion group on use of complementary and alternative therapies in subjects with recurrent back pain. Patient Educ Couns 58:305-311, 2005.

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Psychosocial Management of Rheumatic Diseases W. NEAL ROBERTS, JR.

KEY POINTS Treatment of unrecognized depression is probably the psychosocial intervention with the highest impact, the opportunity for which comes up frequently. Matching reading level of patient education material to that of the patient is an equally important consideration. Improvements in physician-patient communication can be made by specific actions, such as asking the patient to write down concerns in preparation for each visit or to repeat back what he or she learned. Anything that contributes to the physician’s understanding of the patient’s experience is also crucial.

The average course of RA is about 27 years. The usual psychological defenses wear out. The illness becomes integrated, an unwelcome but integrated part of the ­individual. “I used to believe that ‘my arthritis’ was separate from myself. I have come to understand, after 30 years of living with JRA [juvenile RA], that this is no less a part of me than my fingers, my voice. My appreciation for pain, especially that which goes unseen, for recognizing the reality of potential (not everyone can be whatever they want) and for the ability to work at accepting one’s limitations has guided and still guides my perspective. Everything about who I am is wrapped in and around this illness.”—woman with juvenile RA since age 6

ADDITIONAL EFFECTS OF CHRONICITY Any increment in appreciation of the experience of illness from the patient’s point of view does the most to complement the complete range of psychosocial, rehabilitation, medical, and surgical interventions. Perhaps the most important tested psychosocial intervention is recognition of, and conventional treatment of, concomitant depression. Other tested psychosocial interventions—interviewing techniques, improvement in physician-patient communication, and disease-specific patient education efforts—tend to revolve around patient education aimed at the right reading level.1,2

ILLNESS EXPERIENCE IN RHEUMATIC DISEASE PAIN What the illness means to the patient is difficult to grasp. Reading what patients have written about arthritis is not the same as having arthritis; listening and talking and teaching are not the same as the experience. Physicians who have become patients note in retrospect that the “illness experience” was much more complex than anticipated. The thing that seems to contribute most to make the experience of rheumatic diseases different from that of other medical and surgical conditions is the combination of pain with ­chronicity. “Since the pain never goes away, the emotions never go away. So it’s a matter of finding out how to escape from the emotions. That’s what gets to you; it’s like a bloodhound pursuing you. They say, ‘Most patients feel somewhat better in 6 to 8 weeks.’ Six to 8 weeks feels like an eternity, and there’s nothing left to do, no where to go.”—50-yearwoman with rheumatoid arthritis (RA) of 10 years’ duration and treatment with five different disease-modifying antirheumatic drugs

Equal to pain for many patients is loss of control and selfconfidence that comes with chronicity. “But when my symptoms are present, my self-image changes—I am aging, tentative, dependent, tinged with self-pity and regret. I am more willing to accept, rather than strive. In short, my confidence in my life and myself is reduced by how I feel physically. Despite this, a part of me rebels against this lowered self-esteem. It effectively refuses to accept the disease, to admit to not being able to do the things I once did with ease or even skill. These two conflicting personae—the hesitant reflective sick person and the unaccepting person who does what he wants despite how he feels—arise from each other in an uninterrupted, shifting pattern. The self-pity, which is the last stage of my sick person, awakens my healthy person. When he is eventually confronted with a task, however mundane, that symptoms prevent him from doing, the sick person reemerges, and the cycle begins anew.”—man with ankylosing spondylitis of 20 years’ duration

Initial events of chronic pain and loss of control and confidence give rise to reactions and adaptations analogous to stages of reactions to acute losses in general—anger, denial, anxiety, and resignation. Management of these reactions and adaptations in the chronic setting may represent new problems of their own from the patient’s point of view, depending particularly on the responses of the patients’ social support system (family, friends, coworkers). Above all, during this series of emotional events, there is the possibility of the existence of treatable depression. “Any patient with RA who tells you they haven’t ever been depressed is lying. When I see those questionnaires about depression, I just mark something in the middle of the scale. It’s embarrassing to admit how bad you feel.”— 50-year-old registered nurse with RA of 10 years’ duration 999

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FOUR LANDMARKS OF PSYCHOSOCIAL ADAPTATION IN RHEUMATIC DISEASES There are four landmark events or processes that virtually every rheumatology patient faces, and that routinely require some active management: (1) the initial ambiguity of not getting a diagnosis, (2) getting a diagnosis and the denial that comes with it, (3) repeatedly struggling to understand risks and benefits, and (4) dealing with the impact of the disease on relationships with others. Everyone either receives a diagnosis or doesn’t. If there is no immediate diagnosis, it may help to realize that such ambiguity is a good prognostic factor. If the diagnosis is clinically and serologically obvious, the prognosis may be poor. When a clear diagnosis is made, it entails the patient overcoming denial and facing the fact of having a chronic illness. Subsequently, the risk-benefit decisions about therapies are ongoing. The disease changes; decisions have to be made again. FAMILY RELATIONSHIPS Of these four landmark situations that almost every rheumatology patient encounters—facing the diagnosis of a chronic disease or the uncertainty of no diagnosis, understanding repetitive cost-benefit decisions, and threat to family relationships—the last uses the most psychological capital. There are some helpful data in this fourth landmark area, but no template approach, especially when the patient is a child. In the latter case, the re-establishment of a peer group, through school, camp, or any other setting, is a primary goal (see Chapter 97). Despite the loss of selfconfidence and the effects of pain, fatigue, and deformity, individuals with RA have the same divorce rate as the general population. RA patients have fivefold less remarriage if divorced, however.3 Rate of progression of disability in married patients is substantially less than for patients who are unmarried.4 Healthy husbands of wives with RA are affected by the realization of the vulnerability of their own health.5 Marriage increases social support and is a favorable psychosocial variable. Childhood and adolescence are particularly unfortunate times to encounter rheumatic disease.6 The physician and health care system can enable social support to some degree. From studies in systemic lupus erythematosus (SLE), it seems that such enabling effort has the greatest effect among patients who already have strong families, higher incomes, and low disease activity.7

FATIGUE Fatigue in rheumatic diseases seems to be a complex admixture of effects of circulating cytokines presumably mediated by binding to receptors within the periaqueductal gray matter (reticular activating system) of the brainstem, deconditioning, and depression. These factors appear in differing proportions in different diseases. Fatigue is the most common chief complaint of patients with SLE.8 For patients with RA, fatigue is prevalent,9 correlated with depression when that occurs,10 and the focus of elaborate coping strategies.11 The pathophysiology of chronic widespread pain, despite the lack of obvious inflammation clinically, includes a contribution from cytokine-related fatigue.

Patients with chronic widespread pain have reduced levels of anti-­inflammatory cytokines interleukin-4 and interleukin-10.12 The rapid time course of the dramatic response of RA fatigue to tumor necrosis factor blockade—less than 1 week in some patients—shows that in many RA patients fatigue must be due to circulating cytokines directly, rather than to deconditioning and psychological factors, which would not be expected to improve so rapidly. In these patients, an anti–tumor necrosis factor agent essentially turns RA fatigue into SLE fatigue, which apparently is predominantly due to deconditioning and psychological factors. Maximum oxygen consumption for patients with RA is comparable to that of patients with SLE (slightly >50%). In contrast to RA, in SLE, there is no association between fatigue and disease activity, or markers of inflammation. Unless cytokines are acting locally within the central nervous system with no concentration in serum, psychosocial factors may be a predominant cause of lupus fatigue.13 This mechanistic explanation begs the question of whether or not depression in SLE might be due to tonically elevated (or decreased) cytokines that do not vary much with disease activities. Transforming growth factor-β is an example of the latter type of cytokine elevation in SLE. Another key reason for fatigue is treatable deconditioning. When 93 patients with SLE were compared with 44 sedentary controls, the patients were about 20% worse off with regard to muscular strength, forced expiratory volume, and maximum oxygen consumption. A smaller interventional study of exercise physiology preceded this one and found the same baseline.14 The patients were selected or pretreated to suppress SLE disease activity and underwent 8 weeks of aerobic conditioning, which was successful in reducing their fatigue by about half. A stepwise regression model explaining 37% of variation in SLE fatigue featured abnormal illness-related behaviors, greater age, greater degree of helplessness, and lack of health insurance as potentially responsible psychosocial variables.8

DEPRESSION Diagnosable psychiatric disorders occur no more frequently in patients with rheumatic diseases than in patients with any other chronic disease. Two exceptions stand out statistically. First, patients with SLE have cognitive deficits, particularly as related to learning new things. Mild cognitive deficits, such as word finding difficulty,15 are prominent. Second, patients with widespread, nonarticular, axial aching have more diagnosable psychiatric illness—usually depression or anxiety—and are more likely to somaticize. Patients across the spectrum of those usually seen in office practice rheumatology were compared in an attempt to map out the relationship between pain, disability, and abnormal psychology across the diagnostic groups.16 The highest pain scores and most psychological distress were reported by patients with axial disorders—fibromyalgia, back pain, and neck pain. Patients with serious peripheral joint disease from RA had the most disability, but the least pain and most normal psychological test scores. As a rule, patients with RA psychologically adapt over time and are usually as well adjusted and productive as their anatomy allows.17

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RHEUMATOID ARTHRITIS

DISABILITY AND EMPLOYMENT

Most patients with moderately severe RA have been depressed. Patients are resilient, however, and they adapt. Even the distress accompanying chronic joint pain in RA, described earlier as the “illness experience,” fails to lead to sustained, treatable clinical depression most of the time. In RA, depression is not more common than among other rheumatology office patients, and pain causes psychological distress rather than the other way around.19

Psychosocial factors affect the course of rheumatic diseases, especially as regards employment and disability. The effect of psychological and social factors on the presentation of many important diseases has been studied. These illnesses include the most statistically and economically important of the rheumatic diseases, osteoarthritis, RA, and low back pain, and SLE and fibromyalgia, as described partially ­earlier. DISABILITY INSURANCE

KNEE OSTEOARTHRITIS Self-reported knee pain in the United States has the highest prevalence among elderly individuals and non-Hispanic black women.20 Only younger and less educated patients presenting with knee osteoarthritis are more likely to be depressed, however.21 Multiple regression analysis of a study of a mixed Asian population in Singapore revealed numerous independent variables associated with better outcome—some biologic, some fixed psychosocial, and some potentially modifiable. Among the best functioning patients with knee osteoarthritis were not only patients with less pain and less radiographic severity, but also patients with better education and less feeling of helplessness (“learned helplessness”). CHRONIC WIDESPREAD PAIN, FIBROMYALGIA, AND LOW BACK PAIN Overall, population-based studies show the chronic, ­ onarticular, axial aching rheumatic syndromes to be the n group most likely to have an underlying psychiatric diagnosis. It is usually a mood disorder, such as depression or anxiety. Somatization is an important causal factor, at least for chronic widespread pain ascertained at the community level. Arguably, fibromyalgia and chronic widespread pain are physiologically distinct. These conditions nonetheless form part of the same differential diagnostic group of ­nonarticular, axial aching and may overlap in the survey or population-based studies most generalizable to office practice. Chronic widespread pain in unselected general populations is associated with a 17% incidence of psychiatric diagnosis in Australia22; one quarter of a community sample of similar patients in Manchester, United Kingdom, had a ­ psychiatric diagnosis.23 In the Manchester group, the odds ratio for having a psychiatric illness if accompanying self-reported chronic widespread pain was 4.9 (95% confidence interval 2.6 to 9.5). In the Australian phone survey (n = 17,545), 18% of the population had widespread chronic pain, interfering with daily activity of two thirds. Psychosocial markers statistically associated with widespread chronic pain were less education, less income, lack of health ­insurance, and unemployment and disability payments. The same strong ties to psychosocial factors distinguish low back pain manifesting as part of chronic widespread pain from low back pain by itself. Finally, in prospective studies, patients initially without generalized axial aching, but who somaticize, have increased risk of developing chronic widespread pain later.

In understanding disability and communicating that understanding to patients, four different funds of knowledge are of special value: (1) a detailed knowledge of the mechanics and criteria of social security disability insurance (SSDI) in the United States,24 (2) cross-cultural comparisons, (3) an appreciation of the major criticism raised in critique of the logical assumptions underlying the current system,25 and (4) knowledge of research results showing what determines disability in specific diseases. Achieving reasonable expectations on the part of the patient and less frustration for the provider and the patient are two attainable goals of disability management. The mechanics of the SSDI system vary from state to state, but are simple and easily summarized. The patient submits a 2-page form along with medical records and waits for 18 months. The result depends on the clerk matching the medical record with an index of diseases and criteria (the “blue book”). The blue book is thin, and the criteria are strict. Two typical criteria for SLE are stroke and renal failure with dialysis. For back pain, corresponding criteria include leg paresis and bowel or bladder dysfunction. Because of backlogs, each reapplication typically takes 6 months, and the clerk has no recourse to the administrative law judge until the third application. At that stage, attorneys’ and physicians’ opinions have an effect, but not before. As an example, the court is empowered to ask and answer the question of whether a skin lesion, joint symptoms, and cognitive deficits in a patient with SLE are equivalent in severity to a stroke or renal failure. Anticipated reforms are expected to reduce the number of steps between the initial application and the administrative law judge level. These changes are expected to reduce the time needed for an application to reach the stage of final adjudication. The opportunities for the applicant to introduce new medical facts to buttress his or her case after the initial application are expected to diminish, however. The original algorithm for advocating for SSDI might have had three steps: (1) begin early because the SSDI process, including adjudication by an administrative law judge, might take 2 years; (2) accrue as much objective data as possible whether or not it is clinically necessary, as the application proceeds through levels of appeal, being especially careful to document radiographic change in patients with RA or other inflammatory arthritis; and (3) write details about how the disease limits daily activities and work activities in the office notes and correspondence. Under the ongoing reforms to U.S. SSDI, which streamline the process, early filing to avoid the 2-year period without income may become less important. The waiting period

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should be shorter. More important is completeness of data at the initial application. The appeal levels in the streamlined version of the SSDI process review the correctness of the decision, but allow little new medical data to enter the picture during the review. The patient has less opportunity to buttress medical weak points in his or her case in response to feedback from the system. The algorithm for advocacy contains similar elements, but in reverse order: (1) accrue as much objective data as possible whether or not it is clinically necessary, being especially careful to document radiographic change in patients with RA or other inflammatory arthritis; (2) write details about limits in daily and work activities in the notes before beginning correspondence about ­disability; and (3) begin late only after steps 1 and 2 are firmly in place. An algorithm for employer-provided private disability insurance in the United States might be entirely different. This difference arises from answers to the questions of who pays what when the patient is on light duty, part-time accommodation, short-term disability, or long-term disability. Some employers prefer to push ambiguous cases onto a long-term disability account, which is insured, rather than carrying a less than 100% effective employee in a current budget. Such an assignment to long-term disability ­insurance (which might eventually run out) may impede the patient’s ultimate return to full-time work at the same firm, however. Cross-cultural comparisons offer little help to individual patients experiencing economic losses, which constitute the indirect costs of rheumatic diseases. Between 1983 (Netherlands) and 1996 (Australia), many countries passed a milestone, however, at which the absolute numbers of individuals drawing disability payments surpassed the official number of unemployed for the first time. The United States and the United Kingdom passed this marker around 1993. Economists think that political incentives to record low unemployment numbers and the personal incentives of more payments for disability than for unemployment favor continuation of this trend for as long as it is fiscally sustainable. In the long-term, it may be that disability insurance will become more like unemployment insurance. Such a change would have to involve acknowledgment that disability and unemployment are related aspects of a single work problem, significantly greater incentives for employers to hire and promote disabled individuals, and new incentives to patients to avoid disability rolls in favor of remaining in the workforce. Regardless of the future, and of an individual patient’s struggle to salvage income levels in the face of illness, insight into the relationship between unemployment and disability can help maintain a perspective without which the disability issue has great potential to split the therapeutic alliance between physician and patient. The major philosophical underpinning of the current SSDI system is the assumption that amount of disease determines the amount of work disability.25 A necessary corollary is that the amount of disease is objectively quantifiable. From the rheumatologic standpoint, two things are wrong. First, pain is self-reported and, by definition, not objectively quantifiable. Second, and more important, psychosocial factors are stronger determinants of disability than disease factors in many cases. Examples of the latter situation have been studied in a range of illnesses as outlined subsequently.

In one multivariate analysis of knee osteoarthritis only, age, female sex, obesity, and severity of knee pain maintained independent effects (P < .0009). All of these factors, individually and together, had more influence on health assessment questionnaire–determined disability than did radiographic severity.26 For 180 English patients with low back pain,27 the best predictor of some pain persisting at 1 year of follow-up was concomitant widespread pain (odds ratio 6.4). Other factors, from the most clinical, such as radicular pain, to the most psychological, such as job dissatisfaction, all showed equal odds ratios of about 3. Lack of influence over work environment and poor social relations with coworkers28 are specific job-related factors influencing work disability from back pain. Whiplash injury was definitively studied29 in an experiment of nature when Saskatchewan switched from tort to no-fault auto insurance in 1995, abruptly disallowing claims for pain and suffering. Analysis of 7462 claims showed their number and the prognosis of the neck injuries improved by about 30%. Depression influenced duration of the neck pain. The relative parity of psychosocial factors with clinical disease factors seen in the spine seems to be maintained in analyses of more peripheral musculoskeletal problems, such as forearm pain.30 Patients with RA and patients with fibromyalgia report equal disability on self-report scale, but patients with RA report less pain. Labeling a patient with widespread pain or nonarticular axial aching as having fibromyalgia probably does not increase work impairment.31 Disability awards for RA are heavily influenced by objective radiographic data—erosions and narrowing. Age, pain score, and depressed mood secondary to physical disability determine overall disability in RA, however, from the patient’s point of view.32 Fatigue plays a role in RA disability in that fatigue, more disability, more anxiety, and less social support all are correlated with one another in RA.33 Odds are 2:1 to 3:1 against return to work for a patient with RA who stops working. SSDI, older age, and less education decrease the odds.34 In SLE multivariate models for patients at university centers, predictors of early disability in the first 3 years were low educational level (P = .0004), a physical job (P = .0028), plus disease activity at diagnosis (P = .0078). Cumulative organ damage and disease duration, race, and gender did not predict stopping work.35 One randomized, unblinded trial of 13,077 Madrid36 workers with temporary work disability in 1998 and 1999 showed a significant effect of an inexpensive, organized program. This program cut the incidence of long-term disability by half and saved about $5 million using more frequent visits and patient education early on.

DETERMINANTS OF USAGE AND HEALTH CARE DISPARITIES LARGE JOINT OSTEOARTHRITIS, EARLY COURSE Depression seemed to influence younger patients and less well educated patients to seek attention for osteoarthritis of the hip or knee among a community interview sample of 108 patients older than 50 years of age. In this study,37 about half of the variance in the incidence of ­depression

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was explained by the effects or interactions of age, education, and self-assessment of osteoarthritis impact. Biologic and sociologic variables were analyzed together in a second community-based, much larger (n = 1272) survey study. Pain and other factors, none of which were modifiable psychosocial features, were independent influences on disability.38 Of several psychosocial variables affecting disability and usage, only the psychological variable— depression in a younger patient—is amenable to direct intervention. LARGE JOINT OSTEOARTHRITIS, LATE COURSE, TOTAL JOINT ARTHROPLASTY Later in the course of osteoarthritis, patient education, rather than detection and treatment of depression, may play the strongest role. In countering effects of some sociologic factors important in selecting patients for total joint arthroplasty (TJA), specific defects in a patient’s fund of knowledge can be targeted. When TJA is proposed for osteoarthritis, the subsets of African-Americans and older elderly patients tend to accept fewer arthroplasties. In a study of 596 older Cleveland veterans with symptomatic hip or knee osteoarthritis, African-American men were only about half as likely (odds ratio 0.50; 95% confidence interval 0.30 to 0.84) to accept a recommendation for TJA. The underlying reasons for this racial disparity seemed to consist predominantly of expectations on the part of the African-Americans of a more prolonged and troublesome postoperative period. The African-Americans also were less familiar overall with TJA than nonblacks.39 Socioeconomic status per se has not been found to determine acceptance of TJA. In a Canadian survey of 48,218 people older than 55, 3307 had hip and knee problems verified as osteoarthritis by clinical examination and radiography.

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The individuals with the lowest socioeconomic status were equally willing to undergo TJA and needed it more than others, as might be expected from their lower educational attainment.40 In-depth interviews of elderly patients reveal three common misconceptions influencing decisions about TJA. First, older patients expect that if their physician fails to make an explicit recommendation for TJA that means they are not candidates. Patients believed that their provider was actively screening for the procedure, and that they had already been screened out. Second, elderly patients tend to believe that more pain and daily impairment are needed to make a favorable risk-benefit tradeoff than do orthopaedic surgeons.41 It has been suggested that this view is due partially to the fact that elderly patients are much more sensitive than their physicians to risk of mild postanesthesia cognitive deficits. Third is a philosophic difference: the elderly patients viewed osteoarthritis as normal aging to be tolerated, rather than as disease to be operated on.

INFLUENCE OF READING AND EDUCATIONAL LEVELS Generally, people with the lowest literacy have the worst health. Whether reading level per se carries an independent effect, or is associated with other sociodemographic features such as poverty is uncertain.42 A mechanism by which impaired literacy might have direct effects is clear enough, however. Patient information pamphlets, medication sheets, and other materials are written at reading levels too difficult for most American adults, putting a premium on non–literacy-dependent patient education. This persistent fact may be among the several reasons why face-to-face programs with groups of patients are particularly effective (Table 62-1) (see Chapter 61).

Table 62-1  Evidence-Based Psychosocial Interventions Intervention

Target

Method

Results

Arthritis self-help/courses,*   self-management programs

All arthritis diagnoses, fund of   knowledge

4-12 hr of didactic sessions, trained leader, flip charts, overheads,   handouts, discussion aimed at   problem solving; pain, stress and   depression management, medications, and communicating with providers

43% decrease in office visits over 4-yr follow-up; decreased pain satisfying criteria for clinical significance (15%-20% on visual analog scale), increased exercise, increased fund of knowledge and self-efficacy, 9% decrease in disability61; most annual cost savings by patients with RA $162; sustained effect 4 yr after the intervention

Aquatics exercise, YMCA*

All arthritis diagnoses; range of   motion, strength

12-30 hr over 6-10 wk; heated pool, lifeguard, trained instructor,   physical therapist

13%-17% improvement in range of motion, strength in lower extremities, and self-efficacy; exercise compliance declines over time

Land-based exercise programs such as Arthritis Foundation PACE or walking programs

All arthritis diagnoses; range of   motion, strength

Varies

Decreased depression and   increased self-efficacy with   respect to activities of daily   living; decreasing adherence   to exercise over time62

Phone follow-up of   osteoarthritis

Symptomatic, radiographic knee osteoarthritis

Symptom-monitoring phone call on   a scheduled basis

Pain improvement similar in   magnitude to an NSAID63

*Organized, current effort of Arthritis Foundation local chapters with certified instructor. NSAID, nonsteroidal anti-inflammatory drug; RA, rheumatoid arthritis.

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The Internet promises to multiply the effects of reading and education and research,43 but it may contribute to a digital divide effect in care of rheumatic diseases. On a theoretical basis, sociologic intervention touching on fundamental factors such as reading and education levels of the population as a whole might be expected to be the most effective psychosocial interventions for arthritis and rheumatic diseases and other diseases. It is logical that most proven psychosocial interventions are individual or small group providerpatient communication or patient education interventions that have a potential to overcome educational deficits and compensate for uncoordinated care (see Table 62-1). Reading and education are complex psychosocial factors that also may be associated with outcome through interaction with other variables, as explanatory variables that help understanding, but offer poor targets for intervention; as epiphenomena rather than causes; and as carrier variables that are markers for other factors making the real contribution to outcome. The many abilities needed to gather and act on information used to participate actively in care of a complex rheumatic disease such as SLE or RA might be seen in a study only through the carrier variable of educational attainment. For another example, there is a moderately strong doseresponse relationship between physical workload and the incidence of hip osteoarthritis. Farming and heavy lifting mediate this association with an odds ratio of 3:1.44 In that context, educational attainment is inversely related to exposure to heavy labor. Likewise, if high-salaried individuals with gratifying jobs and bonuses in their salary structures avoid disability applications for RA, whereas hourly workers do not, that tendency might be an understandable indirect effect of education on continued employment. These complex sorts of relationships of education to clinical outcome should not obscure more direct effects, however. Education and reading level also can operate directly on visit and medication compliance, having particularly noticeable effects on outcome of complex diseases such as RA and SLE.

PSYCHOSOCIAL INTERVENTIONS To be a target for intervention, a psychosocial factor should be shown to be a potential cause of a clinical outcome and be modifiable. Psychosocial factors, such as education and mood, fit these criteria and bear directly on psychosocial outcomes, such as patient satisfaction and job preservation. In addition, socioeconomic and psychosocial factors help determine biologic outcome. Effects of psychosocial factors on biologic outcome are mediated primarily by visit compliance, medication adherence and availability, and funds of knowledge about disease and the health care system. Psychosocial interventions effective in randomized clinical trials tend to revolve around the most modifiable factors (e.g., funds of knowledge). These interventions involve transfer of information or attitudes via patient education or peer support group (see Table 62-1 and Chapter 61). FIXED VERSUS MODIFIABLE DETERMINANTS There is an obvious logic to studying psychological and social factors together. Distinct features separate psychological factors and socioeconomic factors as they apply to practice, however. First, psychological characteristics of

physicians and patients are made up of fairly fixed personality traits combined with states such as mood and other modifiable factors, such as fund of knowledge about a disease or medication. In contrast to psychological states, sociologic features are almost certainly fixed. As Virchow wrote of the turbulent 1840s in Germany, “Politics is medicine written large.” His observation remains applicable.45 In addition, because sociologic variables cannot be easily changed in a hypothesis-testing experiment, inference of causality is problematic, although analysis of variance can help. Even when the biology of the disease is complex, the genetics heterogeneous, and access barriers likely—such as in U.S. urban or rural populations with SLE—detailed analysis suggests that education and counseling, coordinated with medical care, improve outcome.46 These studies found SLE disease activity and overall health status to be most strongly associated with potentially modifiable psychosocial factors, such as self-efficacy for disease management. SLE organ damage, in contrast, was best predicted by conventional clinical factors, such as duration of disease. Notably, outcomes were not associated with race. Another large study indicates that noncompliance is the largest psychosocial factor influencing outcome and confounded with race. African-American race per se had no independent effect in this large cohort in Baltimore.47 In patients with SLE, even when the sociologic factors seem overwhelming, and the biology of the disease and its therapies complex, targeted psychosocial interventions concentrating on patient education seem to have potential to change outcome.48 Psychosocial interventions fall into three main categories as follows: (1) efforts to improve physician-patient communication in usual care, (2) organized programs aimed at teaching or influencing groups of patients, or (3) psychopharmacology or psychotherapy. PHYSICIAN-PATIENT COMMUNICATION Canadian patients (n = 197) with established diagnoses representative of office practice except for the omission of widespread pain and fibromyalgia answered the following question49: What do patients want? Factor analysis condensed responses to questionnaires covering 32 possible concerns down to eight points. Patients asked for help in five areas and extra information in two. The five areas mentioned for help were psychological, coping, getting medication, social, and financial. The information deficits were in disease-specific areas of natural history and therapy, including conventional and unproven remedies. Physician sources and written material were preferred. Patients with scleroderma were particularly interested in support groups. The most common worry for patients across the diagnostic groups was probably the same as the number one worry of their physicians: progression of the disease. From contrasting studies, it seems that patients with SLE and their physicians have particularly divergent worries.50 Patients and physicians rate disease activity in SLE differently. Physicians place more emphasis on laboratory features, whereas patients place more emphasis on function,51 particularly the detrimental effect of fatigue. Data-based recommendations for improving physician-patient communications have been derived partially from taped usual care visits and post-hoc interviews with the participants (Box 62-1).52

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Box 62-1

 echniques to Improve Communication  T in Usual Care Office Visits*   1. Encourage patients to write down their concerns before each visit.   2. Address each concern specifically, however briefly.   3. Ask patients what they think has caused their problems.   4. Tailor treatments to patients’ goals and preferences as possible.   5. Explain the purpose, dosage, common side effects and inconveniences, and how to judge the efficacy of each treatment, including length of trial.   6. Assess patients’ understanding.   7. Anticipate problems in compliance with treatment plans, and discuss methods to cope with common problems.   8. Write down diagnosis and treatment plan to help patients remember.   9. Distribute written materials that are now widely available. 10. Reinforce patients’ confidence in their ability to manage their regimen. 11. Use ancillary personnel in patient education. 12. Refer patients to organized programs in the community. *From

Daltroy LH: Doctor-patient communication in rheumatological disorders. Baillieres Clin Rheumatol 7:221-239, 1993.

TIME CONSTRAINTS Time constraints in the context of usual care office visits argue for maximal use of organized programs and for the use of self-completed questionnaires and forms, such as the American College of Rheumatology new patient form. Patients sometimes see forms as an imposition if they are not referred to in the subsequent interview. If the form is part of the conversation, and even marked with a few highlights or marginal notes, it is interpreted as an element of thoroughness. Scheduled telephone contact is poorly reimbursed, but effective enough to reduce knee pain from osteoarthritis in a randomized study.53 Legal and institutional restrictions notwithstanding, a reasonable rule of thumb for clinical e-mail is to use it for nothing more sensitive than what would be said over the telephone.43 Overall, the main psychosocial impact of time pressure is to make the interview more physician directed than patient directed, putting up an obstacle to physician-patient communitation.54 ORGANIZED PROGRAMS A variety of interventional programs improve outcome measured in their own terms, when other psychosocial variables or a health status scale are the primary outcomes. These include support groups, which improve coping more than half the time,55 and stress management,56 group psychotherapy,43 and prayer.56a A smaller number (see Table 62-1) also save money, improve pain, protect anatomy, and have a durable effect. Exercise programs are effective, but patients have difficulty sustaining the effort these programs require over time.

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PSYCHOTHERAPY AND PSYCHOPHARMACOLOGIC INTERVENTIONS Depression often goes unrecognized. With psychiatric telephone interview in a survey study taken as the “gold standard,” only about 19% of depressed individuals are diagnosed and treated in the course of usual care over 1 year.57 Treatment was less likely for men, African-Americans, and individuals with lower educational level. Individuals 30 to 60 years old were more likely to get treatment. Brief psychotherapy and antidepressants are effective. Depression in rheumatic disease occurs more frequently in particular settings, including patients reporting widespread chronic pain, patients coming to grips with work disability, and patients presenting at a young age with knee osteoarthritis. More recent findings in relevant psychopharmacology include selective serotonin reuptake inhibitor equivalence for efficacy across the class.58 There also is increased recognition of large relative increases in the risk of sudden cardiac deaths on moderate doses of antipsychotics.59

SUMMARY The results of patient education and psychosocial intervention seem modest compared with very effective, biologically based interventions such as tumor necrosis factor blockade. The latter costs about $15,000 to $20,000 per year and promises to make inroads into the lifetime loss of 16 qualityadjusted life years per average 27-year course of RA, including 6.6 years of lost survival that incurred in the absence of biologics and methotrexate. In contrast, the best organized and delivered psychosocial intervention administered on a group basis, the Arthritis Foundation Self Help Course, has minimal costs and cuts outpatient visits 40%, saving each osteoarthritis patient $47 and each RA patient $162 per year. Meta-analyses and reviews indicate that organized programs aimed at specific subsets of rheumatic disease patients have effects that are favorable, but the effect sizes are small, making them hard to measure, and the effects on outcomes not purely within the psychosocial domains are hard to find. Finally, it is difficult to prove effects that are sustained over time.60,61 Specific psychosocial management techniques stand as modest adjuncts to powerful specific therapy, but must be understood as the middle part of a range of promising opportunities. Increasing health literacy and improving individual physician-patient communication are effective psychosocial interventions, along with recognition and treatment of concomitant depression. Large-scale social interventions, such as improving the reading level of the patient population where health literacy is lacking, would change disease outcome more than psychosocial interventions aimed at individual diseases. Interpreted broadly over their whole range including health literacy, psychosocial management techniques are potentially as powerful as a biologic therapy. Organized programs applied to defined patient subgroups are the most easily measured and discussed interventions in a scientific sense, however. This thought illustrates French anthropologist-philosopher Rene Dubois’ dictum that “the measurable drives out the important,” which still leaves individual patients and their physicians a fascinating set of possibilities to study and apply, and from which to benefit.

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REFERENCES   1. Weiss BD, Hart G, Pust RE: The relationship between literacy and health. J Health Care Poor Underserved 1:351-363, 1991.   2. Weiss BD, Coyne C: Communicating with patients who cannot read. N Engl J Med 337:272-274, 1997.   3. Hawley DJ, Wolfe F, Cathey MA, et al: Marital status in rheumatoid arthritis and other rheumatic disorders: A study of 7,293 patients. J Rheumatol 18:654-660, 1991.   4. Ward MM, Leigh JP: Marital status and the progression of functional disability in patients with rheumatoid arthritis. Arthritis Rheum 36:581-588, 1993.   5. Manne SL, Zautra AJ: Couples coping with chronic illness: Women with rheumatoid arthritis and their healthy husbands. J Behav Med 13:327-342, 1990.   6. Harris E, Budd R, Firestein G, et al: Kelley’s Textbook of Rheumatology, 7th ed. Philadelphia, WB Saunders, 2005.   7. Bae SC, Hashimoto H, Karlson EW, et al: Variable effects of social support by race, economic status, and disease activity in systemic lupus erythematosus. J Rheumatol 28:1245-1251, 2001.   8. Zonana-Nacach A, Roseman JM, McGwin G Jr, et al: Systemic lupus erythematosus in three ethnic groups, VI: Factors associated with fatigue within 5 years of criteria diagnosis. LUMINA Study Group. LUpus in MInority populations: NAture vs Nurture. Lupus 9:101-109, 2000.   9. Tack BB: Fatigue in rheumatoid arthritis: Conditions, strategies, and consequences. Arthritis Care Res 3:65-70, 1990. 10. Tack BB: Self-reported fatigue in rheumatoid arthritis: A pilot study. Arthritis Care Res 3:154-157, 1990. 11. Tan G, Jensen MP, Robinson-Whelen S, et al: Coping with chronic pain: A comparison of two measures. Pain 90(1-2):127-133, 2001. 12. Uceyler N, Valenza R, Stock M, et al: Reduced levels of antiinflammatory cytokines in patients with chronic widespread pain Arthritis Rheum 54:2656-2664. 2006. 13. Omdal R, Mellgren SI, Koldingsnes W, et al: Fatigue in patients with systemic lupus erythematosus: Lack of associations to serum cytokines, antiphospholipid antibodies, or other disease characteristics. J Rheumatol 29:482-486, 2002. 14. Robb-Nicholson LC, Daltroy L, Eaton H, et al: Effects of aerobic conditioning in lupus fatigue: A pilot study. Br J Rheumatol 28:500-505, 1989. 15. Bosma GP, Middelkoop HA, Rood MJ, et al: Association of global brain damage and clinical functioning in neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 46:2665-2672, 2002. 16. Hawley DJ, Wolfe F: Pain, disability, and pain/disability relationships in seven rheumatic disorders: A study of 1,522 patients. J Rheumatol 18:1552-1557, 1991. 17. Hawley DJ, Wolfe F: Depression is not more common in rheumatoid arthritis: A 10-year longitudinal study of 6,153 patients with rheumatic disease. J Rheumatol 20:2025-2031, 1993. 18. Deleted in press. 19. Smedstad LM, Vaglum P, Kvien TK, et al: The relationship between self-reported pain and sociodemographic variables, anxiety, and depressive symptoms in rheumatoid arthritis. J Rheumatol 22:514-520, 1995. 20. Andersen RE, Crespo CJ, Ling SM, et al: Prevalence of significant knee pain among older Americans: Results from the Third National Health and Nutrition Examination Survey. J Am Geriatr Soc 47: 1435-1438, 1999. 21. Dexter P, Brandt K: Distribution and predictors of depressive symptoms in osteoarthritis. J Rheumatol 21:279-286, 1994. 22. Blyth FM, March LM, Brnabic AJ, et al: Chronic pain in Australia: A prevalence study. Pain 89(2-3):127-134, 2001. 23. Macfarlane GJ, Morris S, Hunt IM, et al: Chronic widespread pain in the community: The influence of psychological symptoms and mental disorder on healthcare seeking behavior. J Rheumatol 26:413-419, 1999. 24. Hadler NM: Medical ramifications of the federal regulation of the Social Security Disability Insurance program: Social Security and medicine. Ann Intern Med 96:665-669, 1982. 25. Carey TS, Hadler NM: The role of the primary physician in disability determination for Social Security insurance and workers’ compensation. Ann Intern Med 104:706-710, 1986. 26. Jordan JM, Luta G, Renner JB, et al: Self-reported functional status in osteoarthritis of the knee in a rural southern community: The role of sociodemographic factors, obesity, and knee pain. Arthritis Care Res 9:273-278, 1996.

27. Thomas E, Silman AJ, Croft PR, et al: Predicting who develops chronic low back pain in primary care: A prospective study. BMJ 318:1662-1667, 1999. 28. Thorbjornsson CB, Alfredsson L, Fredriksson K, et al: Physical and psychosocial factors related to low back pain during a 24-year period: A nested case-control analysis. Spine 25:369-374, 2000. 29. Cassidy JD, Carroll LJ, Cote P, et al: Effect of eliminating compensation for pain and suffering on the outcome of insurance claims for whiplash injury. N Engl J Med 342:1179-1186, 2000. 30. Macfarlane GJ, Hunt IM, Silman AJ: Role of mechanical and psychosocial factors in the onset of forearm pain: Prospective population based study. BMJ 321:676-679, 2000. 31. White KP, Nielson WR, Harth M, et al: Does the label “fibromyalgia” alter health status, function, and health service utilization? A prospective, within-group comparison in a community cohort of adults with chronic widespread pain. Arthritis Rheum 47:260-265, 2002. 32. Salaffi F, Ferraccioli GF, Carotti M, et al: [Disability in rheumatoid arthritis: The predictive value of age and depression]. Recenti Prog Med 83:675-679, 1992. 33. Mancuso CA, Rincon M, Sayles W, et al: Psychosocial factors help worsen fatigue in RA. J Rheumatol 33:1496-1502, 2006. 34. Straaton KV, Maisiak R, Wrigley JM, et al: Barriers to return to work among persons unemployed due to arthritis and musculoskeletal disorders. Arthritis Rheum 39:101-109, 1996. 35. Partridge AJ, Karlson EW, Daltroy LH, et al: Risk factors for early work disability in systemic lupus erythematosus: Results from a multicenter study. Arthritis Rheum 40:2199-2206, 1997. 36. Abasolo L, Blanco M, Bachiller J, et al: A health system program to reduce work disability related to musculoskeletal disorders. Ann Intern Med 143:404-414, 2006. 37. Dexter P, Brandt K: Distribution and predictors of depressive symptoms in osteoarthritis. J Rheumatol 21:279-286, 1994. 38. Jordan JM, Luta G, Renner JB, et al: Self-reported functional status in osteoarthritis of the knee in a rural southern community: The role of sociodemographic factors, obesity, and knee pain. Arthritis Care Res 9:273-278, 1996. 39. Ibrahim SA, Siminoff LA, Burant CJ, et al: Differences in expectations of outcome mediate African American/white patient differences in “willingness” to consider joint replacement. Arthritis Rheum 46:2429-2435, 2002. 40. Hawker GA, Wright JG, Glazier RH, et al: The effect of education and income on need and willingness to undergo total joint arthroplasty. Arthritis Rheum 46:3331-3339, 2002. 41. Hudak PL, Clark JP, Hawker GA, et al: “You’re perfect for the procedure! Why don’t you want it?” Elderly arthritis patients’ unwillingness to consider total joint arthroplasty surgery: A qualitative study. Med Decis Making 22:272-278, 2002. 42. Weiss BD, Coyne C: Communicating with patients who cannot read. N Engl J Med 337:272-274, 1997. 43. Edworthy SM: World wide web: Opportunities, challenges, and threats. Lupus 8:596-605, 1999. 44. Lievense A, Bierma-Zeinstra S, Verhagen A, et al: Influence of work on the development of osteoarthritis on the hip: A systematic review. J Rheumatol 28:2520-2528, 2001. 45. Jackson RH, Davis TC: Explaining the connection between privilege and health. N Engl J Med 330:139, 1994. 46. Karlson EW, Daltroy LH, Lew RA, et al: The independence and stability of socioeconomic predictors of morbidity in systemic lupus erythematosus. Arthritis Rheum 38:267-273, 1995. 47. Petri M, Perez-Gutthann S, Longenecker JC, et al: Morbidity of systemic lupus erythematosus: Role of race and socioeconomic status. Am J Med 91:345-353, 1991. 48. Liang MH, Rogers M, Larson M, et al: The psychosocial impact of systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 27:13-19, 1984. 49. Neville C, Fortin PR, Fitzcharles MA, et al: The needs of patients with arthritis: The patient’s perspective. Arthritis Care Res 12:85-95, 1999. 50. Yen JC, Neville C, Fortin PR: Discordance between patients and their physicians in the assessment of lupus disease activity: Relevance for clinical trials. Lupus 8:660-670, 1999. 51. Alarcon GS, McGwin G Jr, Brooks K, et al: Systemic lupus erythematosus in three ethnic groups, XI: Sources of discrepancy in perception of disease activity: A comparison of physician and patient visual analog scale scores. Arthritis Rheum 47:408-413, 2002.

PART 8  52.  Daltroy LH: Doctor-patient communication in rheumatological disorders. Baillieres Clin Rheumatol 7:221-239, 1993. 53.  Maisiak R, Austin J, Heck L: Health outcomes of two telephone interventions for patients with rheumatoid arthritis or osteoarthritis. Arthritis Rheum 39:1391-1399, 1996. 54.  Waitzkin H: Doctor-patient communication: Clinical implications of social scientific research. JAMA 252:2441-2446, 1984. 55.  Baker PR, Groh JD, Kraag GR, et al: Impact of patient with patient interaction on perceived rheumatoid arthritis overall disease status. Scand J Rheumatol 25:207-212, 1996. 56.  Parker JC, Smarr KL, Buckelew SP, et al: Effects of stress management on clinical outcomes in rheumatoid arthritis. Arthritis Rheum 38:1807-1818, 1995. 56a. VandeCreek L, Paget S, Horton R, et al: Religious and nonreligious coping methods among persons with rheumatoid arthritis. Arthritis Rheum 51:44-55, 2004. 57.  Young AS, Klap R, Sherbourne CD, et al: The quality of care for depressive and anxiety disorders in the United States. Arch Gen Psychiatry 58:55-61, 2001.

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58. Kroenke K, West SL, Swindle R, et al: Similar effectiveness of paroxetine, fluoxetine, and sertraline in primary care: A randomized trial. JAMA 286:2947-2955, 2001. 59. Ray WA, Meredith S, Thapa PB, et al: Antipsychotics and the risk of sudden cardiac death. Arch Gen Psychiatry 58:1161-1167, 2001. 60. Riemsma PR, Taal ER, Kirwan JR, et al: Patient education for adults with rheumatoid arthritis. BMJ 325:558-559, 2002. 61. Warsi A, LaValley P, Wand PS, et al: Arthritis self-management education programs: A meta-analysis of the effect on pain and disability. Arthritis Rheum 48:2209-2213, 2003. 62. Sullivan T, Allegrante JP, Peterson MG, et al: One-year followup of patients with osteoarthritis of the knee who participated in a program of supervised fitness walking and supportive patient education. Arthritis Care Res 11:228-233, 1998. 63. Maisiak R, Austin J, Heck L: Health outcomes of two telephone ­interventions for patients with rheumatoid arthritis or osteoarthritis. Arthritis Rheum 39:1391-1399, 1996.

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Nutrition and Rheumatic Diseases JOEL M. KREMER

KEY POINTS The typical body weight of a patient with rheumatoid arthritis (RA) has changed in the past 2 decades. RA patients are now overweight similar to the rest of the U.S. population. Several naturally occurring enzymes inactivate reactive oxygen species. Many of these enzymes use trace elements as cofactors in these reactions. Well-designed studies of omega-3 and omega-6 fatty acids have shown clinical benefits in patients with RA. Animal studies of the addition of omega-3 fatty acids have shown marked improvements in systemic lupus erythema­ tosus mouse models. There are myriad vascular benefits of omega-3 fatty acids, which could become more relevant as clinicians consider the role of inflammation in the development of cardiovascular disease in patients with RA.

Although it has been appreciated for some time that disease processes can interfere with adequate nutrition, we are now beginning to understand how altered nutritional status may contribute to the pathogenesis of disease. As a corollary, it is now known that certain dietary manipulations can result in improvements in the inflammatory disease process. Appreciation of the possible role of nutritional manipulation in inflammatory disease has increased along with the understanding of immunity, eicosanoid metabolism, and cellular biology. Epidemiologic studies have confirmed the role of diet in other disease processes, such as vascular and gastrointestinal disease.1,2 Improvements in mortality from cardiovascular disease in some large population studies are linked not solely to favorable changes in cholesterol, hypertension, and smoking profiles, but also to alteration of other biologic processes through the intake of dietary fatty acids.3,4 Paralleling the emergence of data on the role of diet in disease states is the realization that current dietary habits are altered from those to which Homo sapiens have adapted during almost the entire span of human history (Table 63-1).5,6 Circumstantial evidence has linked an increased incidence of cancer and cardiovascular and gastrointestinal disease to high-fat, low-fiber diets.

ROLE OF PROTEIN-ENERGY MALNUTRITION AND METABOLIC RESPONSE TO INFLAMMATION The catabolic effect of inflammatory disease is multifactorial and may lead to weight loss through a variety of mechanisms. Fever is associated with increased energy expenditure

and increased calorie requirements to maintain body weight. Catecholamine-mediated increases in lipolysis and hepatic and muscular glycogenolysis occur along with hyperglycemia and hypoinsulinemia to increase energy substrates in the acute-phase response to injury.7 After a few days, hyperinsulinemia and increased protein catabolism occur in what is termed the adaptive phase of metabolic response to stress or injury.7 The increased amino acids may serve as precursors for hepatic production of acute-phase reactants and gluconeogenesis. Increased production of eicosanoids and cytokines associated with the inflammatory state leads to an enhanced catabolic effect and increased protein breakdown. Weight loss of 5% to 10% is associated with little functional impairment,8 although it should be considered to be of potential clinical significance if it occurs during a period of 1 to 6 months. Protein-calorie malnutrition is subdivided into marasmus and kwashiorkor. Marasmus is defined as a weight less than 80% of ideal weight calculated from standardized tables of height and weight with preservation of serum protein levels and immune function. Kwashiorkor may be associated with a similar degree of weight loss, but has the additional factor of lowered serum protein levels and compromised immune function. Patients with the hypoalbuminemic malnutrition of kwashiorkor have a significantly higher mortality rate as a result of infections and other metabolic stress.

ROLE OF NUTRITION RHEUMATOID ARTHRITIS Studies of dietary intake in large populations have shown no effect9 and, more recently, a diminished risk for the development of rheumatoid arthritis (RA) associated with the intake of fatty fish.10 The latter study, a large epidemiologic Danish study, found that dietary intake of 30 g of fatty fish per day was associated with a 49% reduction in the risk of developing RA. Studies of the nutritional status of patients with RA and of patients with osteoarthritis before the methotrexate and biologic treatment era typically showed that patients with osteoarthritis were 15 lb overweight on average, whereas patients with RA were an average of 10.3 lb underweight.11 A more recent study of patients with RA from a large registry in North America has shown, however, that most patients with RA are now either overweight or obese, using standard definitions of body mass index.11a This finding represents a fundamental change in the accepted body habitus as reflected by the body mass index in this disease. The reasons may be multifactorial, but have evolved at the same time as more aggressive and effective treatment regimens. More recent investigations have assessed nutrition in patients with RA by use of a 3-day food record, a reliable 1009

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Table 63-1  Comparison of the Late Paleolithic Diet, Current American Diet, and U.S. Dietary Recommendations Late Paleolithic Diet

Current American Diet

U.S. Senate Select Committee Recommendatons*

Total dietary energy (%) Protein Carbohydrate Fat

34 45 21

12 46 42

12 58 30

P:S ratio

1.41

0.44

1

Cholesterol (mg)

591

600

300

Fiber (g)

45.7

19.7

30-60 1100-3300

Sodium (mg)

690

2300-6900

Calcium (mg)

1580

740

800-1200

Ascorbic acid (mg)

392.3

87.7

45

*Select Committee on Nutrition and Human Needs, United States Senate: Dietary Goals for the United States. Washington, DC, Government Printing Office, 1977. P:S, polyunsaturated-to-saturated fats. From Eaton SB, Konner M: Paleolithic nutrition: A consideration of its nature and current implications. N Engl J Med 312:283, 1985. Reprinted with permission from The New England Journal of Medicine.

method of diet assessment. Deficient dietary intake of folic acid, zinc, magnesium, and pyridoxine has been reported by three independent groups of investigators.12-15 Intake of other nutrients, including fat, protein, and carbohydrate, was reported to be similar to that of age-matched subjects in one investigation.12

Transmembrane glycoprotein Membrane surface proteins SH HS

JUVENILE RHEUMATOID ARTHRITIS

FREE RADICALS AND NUTRITION A compound with unpaired free electrons is termed a free radical, and some of the most reactive of these compounds contain oxygen. Free radicals extract electrons from stable compounds in an attempt to stabilize themselves, and in the process, they create new free radicals (see Chapter 15).19 The rapidly proliferating cells of the immune system are uniquely prone to oxidative damage from free radicals, which also can affect the activity of thromboxane, prostaglandin (PG), and leukotriene (LT) species.20

CH3 S

Free radical damage

OOH

Protein strand Disulfide scission cross-linking Protein-protein cross-linking S S HOO

OH OH

OH

HOO

Two Swedish studies reported dietary assessments of children with juvenile RA.16,17 Biochemical measures and anthropome­tric measurements were examined in 26 11to 16-year-old girls with chronic juvenile arthritis and matched healthy control subjects. Arm muscle circumference was smaller and serum creatinine levels were lower in the children with arthritis. Significant inverse correlations were observed between disease activity and concentrations of albumin, prealbumin, and retinol-binding protein. Using standard definitions, the researchers found that five girls with chronic arthritis (19%) fit the definition of malnutrition. The intake of calories and protein did not differ from that of the control population. An analysis of nutrient intake by means of a 4-day dietary history in the same population failed to reveal any significant differences from control subjects. Children with arthritis were observed, however, to derive a larger percentage of their energy requirements from fat and a smaller percentage from carbohydrates than did control subjects. Another study observed increased spinal bone mass in children with arthritis given supplemental calcium and vitamin D.18

HO

CH3 S Amino acid oxidation

O

Lipid-lipid cross-linking

Lipid-protein cross-linking OH

HOO OH HO Fatty acid oxidation

Malondialdehyde released from oxidized fatty acids

Figure 63-1  Free radical damage to lipid membranes and proteins associated with cell membranes. (From Bendich A: Antioxidant micronutrients and immune functions. Ann N Y Acad Sci 587:168-180, 1990.)

The phospholipid bilayer of cell membranes contains polyunsaturated fatty acids, which can be common sites for free radical reactions (Fig. 63-1). Membrane damage from lipid peroxidation results in the formation of unstable lipid

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peroxyl radicals, which can damage the membrane further in a snowball-like effect.19 Potentially toxic products of lipid membrane peroxidation include malondialdehyde, volatile substances such as ethane and pentane, crosslinked membrane lipids, conjugated dienes, and proteinlipid adducts.21 Free radicals also are essential to normal immune competence.22,23 Intracellular free radical production is part of the host response necessary for the killing of invading microorganisms. Free radical reactions are associated with the release of arachidonic acid and the conversion of arachidonate to eicosanoids and subsequent eicosanoid metabolism.24 These substances are in turn essential in the functioning of a normal immune system.25 In considering the production and modulation of free radicals, therefore, the critical issue is the balance between potentially destructive reactions and naturally occurring free radical generation, which is essential for normal immunocompetence. Several naturally occurring enzymes inactivate reactive oxygen molecules. Antioxidant metalloenzymes interfere with the production of free radicals by inactivating precursor molecules. Superoxide dismutase exists in two forms, either of which can inactivate the superoxide anion. There is a manganese-containing superoxide dismutase in mitochondria and a copper-zinc–containing superoxide dismutase in the cytoplasm (Fig. 63-2). Both of these reactions produce hydrogen peroxide (H2O2). An iron-­containing catalase found in cytoplasmic peroxisomes catalyzes the decomposition of H2O2 to oxygen and water. Selenium is an essential component of two glutathione peroxidases that inactivate H2O2, lipid peroxides, and phospholipid peroxides. The nutritionally essential mineral elements copper, zinc, iron, manganese, and selenium are not antioxidants until they are incorporated into the antioxidant enzymes.19 Further addition of these elements to the system by dietary intake is not believed to enhance the activity of the antioxidative enzymes when the system is saturated. Circulating levels of these enzymes are lower than intracellular concentrations. The balance between extracellular free radical formation and release and antioxidant enzyme protection may be important in the inflammation and ­tissue

O2•- + O2•- +2H+ Superoxide radical anion H2O2 + H2O2 H2O2 + 2GSH glutathione

Cu/Zn, Mn superoxide dismutase

Fe-catalase Se-glutathione peroxidase Se-glutathione peroxidase

H2O2 + O2 Hydrogen peroxide 2H2O + O2 2H2O + GSSG Oxidized glutathione

LOH + GSSG + H2O LOOH + 2GSH Lipid aldehyde Lipid hydroperoxide Figure 63-2  Antioxidant metalloenzyme reactions. Nutritionally essential elements are not antioxidants until they are incorporated into their metalloenzyme ligand. Cu, copper; Fe, iron; Mn, manganese; Se, selenium; Zn, zinc. (From Bendich A: Antioxidant micronutrients and immune functions. Ann N Y Acad Sci 587:168-180, 1990.)

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destruction of several immune-mediated inflammatory ­diseases.

ANTIOXIDANT VITAMINS BETA CAROTENE The carotenoids are red-yellow pigments found in all photosynthesizing plants. There are more than 500 carotenoids, but only a few of these compounds can be synthesized to vitamin A. Cleavage of beta carotene results in two molecules of vitamin A, however, which makes it unique among the carotenoids. In contrast to vitamin A, beta carotene is a potent antioxidant and also can function as an immunostimulant. Enhancement of activation markers of human peripheral blood mononuclear cells was observed in vitro after exposure to carotenoids.26 In models of animal tumorigenesis, cytotoxic T lymphocyte functions and macrophage secretion of tumor necrosis factor were increased after carotenoid administration.27 These findings are part of a body of evidence suggesting that carotenoid ingestion is associated with important chemoprotective effects that are separate from their provitamin A activity. VITAMIN E Vitamin E (alpha tocopherol) is the major lipid-soluble antioxidant found in cells. Vitamin E protects the unsaturated double bonds of the fatty acids in the phospholipid bilayer from oxidation. It accomplishes this by donating electrons to lipid peroxide and other radicals and in this way can interrupt the chain reaction of free radical damage to the cell membrane. The antioxidant activity of vitamin E is regenerated by electron donation from vitamin C, glutathione, and other antioxidants. Vitamin E is crucial to maintaining the normal function of the immune system. T cells are more susceptible than B cells to membrane peroxidative damage, and peroxidative damage has been associated with the loss of certain T cell receptor activities.28 T cells are more sensitive to vitamin E status, even though the vitamin E content of T lymphocytes and B lymphocytes is more than 10 times that found in red blood cells.29 The macrophage membrane expresses decreased major histocompatibility complex (MHC) class II antigen in the vitamin E–deficient state. Phagocytic function is diminished in the presence of vitamin E deficiency in animal and human studies. A study of patients with systemic lupus erythematosus given daily dietary supplements of 800 IU of vitamin E and vitamin C showed significantly lower levels of malondialdehyde in serum after 12 weeks of this supplementation.30 VITAMIN C Vitamin C (ascorbic acid) is water soluble and is important in decreasing free radical reactions in intracellular and extracellular fluids. It also is required for the hydroxylation of proline and lysine in the production of collagen and is involved in several enzymatic reactions in the formation of neuropeptides. Neutrophils and mononuclear cells maintain concentrations of vitamin C that are approximately 150 times the serum concentration.31 Vitamin C has been

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shown to increase neutrophil and monocyte chemotaxis in vitro in experimental models.32,33 Plasma and platelet ascorbic acid levels have been shown to be low in patients with RA who take high doses of aspirin.34 The decrease was thought to be from impaired tissue uptake or increased urinary excretion. Reduced ascorbate levels may be caused by superoxide-associated oxidation at inflammatory sites. Scorbutic guinea pigs develop lesions resembling rheumatoid arthropathy, prompting a suggestion that synovial vitamin C deficiency could contribute to rheumatoid synovitis.34 An early study of vitamin C supplementation in patients with RA failed to show any effect.34 Supplements of vitamin C given to normal patients have shown a significant uricosuric effect with mean changes of 0.5 mg/dL after dietary supplements of 500 mg of vitamin C for 2 months.35 Free radicals derived from phagocytes are autotoxic to cells in their immediate environment, causing inhibition of chemotaxis, phagocytosis, and antimicrobial activity.36 Reactive oxygen species also inhibit proliferation of T lymphocytes and B lymphocytes and the cytotoxic activity of natural killer cells.37 Neutrophil-derived H2O2 and hypochlorous acid (HClO) are the most potent mediators of immunosuppression.38 At physiologically relevant concentrations, ascorbate protects neutrophil metabolic activity and function from inhibition mediated by HClO−, but not by H2O2−.39 Ascorbate is the first-line plasma antioxidant in the defense against phagocyte-derived reactive oxidants; only when it is depleted does lipid peroxidation occur.40 By neutralizing granulocyte-derived HClO, ascorbate maintains host defenses by sustaining the function of phagocytes and maintains bystander lymphocytes by protecting them from oxidative damage.39 Vitamin C also may enhance immune responses indirectly by maintaining optimal levels of vitamin E. It does this by donating an electron to the alpha tocopherol molecule to re-establish the antioxidant activity of alpha tocopherol. VITAMIN D Dietary deficiency of vitamin D may contribute to osteopenia in patients with RA and has been linked to cortical thinning and spontaneous fractures of long bones in this condition.41 Vitamin D supplementation may have some beneficial effect in the treatment of psoriasis.42 1,25-­Dihydroxyvitamin D3 has inhibitory effects in vitro on psoriatic fibroblast proliferation43 and has been shown to inhibit the effects of interleukin (IL)-1β on PG production from human fibroblasts. It has significant effects on the T lymphocyte proliferative response to mitogen stimulation44 and has demonstrated effects on cytokine production.45 1,25-Dihydroxyvitamin D3 can potentiate the inhibitory effects of cyclosporine on helper T cells from patients with RA.46 An open, uncontrolled study using increasing doses of 1,25-dihydroxyvitamin D3 for 6 months showed significant improvement in several clinical parameters of psoriatic arthritis disease activity in a few patients who completed the study.47

TRACE ELEMENTS Before the effects of certain trace elements on the immune response and inflammatory disease are considered, it is appropriate first to examine certain related areas of their

­ etabolism and processing. Copper, zinc, and iron are m bound to metalloproteinases, which are metal-binding proteins found within the intestinal mucosa.48 Because these different metals compete for binding with the same proteins, there may be a reciprocal relationship between high dietary levels of certain elements and a deficiency in others.49 Increased circulating levels of the cytokines IL-1, IL-6, and tumor necrosis factor may affect the availability of trace elements by inducing the production of increased metalloproteinases within the liver and intestine. This increased metalloproteinase production results in sequestration of these elements so that they are less readily available to peripheral tissues.49 The diets of patients with inflammatory disease may have adequate iron and zinc, but inadequate levels at metabolically important sites, with iron bound to increased cytokine-induced ferritin within the macrophages and liver and zinc bound to the excess metalloproteinases in liver and gut.50 Teleologically, the cytokine-induced decreased concentrations of iron and zinc may enhance host defenses against infection and parasitism because iron is required for bacterial replication, and zinc has a natural anti-inflammatory role.51 ZINC Zinc has been known to be an essential element for growth for more than 100 years. It is essential for a large and diverse collection of enzymes involved in multiple areas of normal metabolic functioning. Only iron exceeds zinc in total body tissue concentrations. It is considerably less reactive and less toxic than copper. Dietary sources include protein derived from meat, fish, and dairy products, and total body storage reserves are thought to be limited. Absorption of zinc is diminished by ingestion of copper or iron. As is the case with iron and copper, increased cytokine production in inflammatory disease can result in increased binding of zinc to metallothioneins and decreased serum and leukocyte zinc concentrations.51 This situation may be compounded in patients who regularly consume iron supplements because this interferes with zinc absorption. In addition, dietary surveys have documented that zinc intake is reduced in patients with RA.12-15 The unexpected incidence of autoimmune disease after treatment with penicillamine has been linked to the ability of penicillamine to chelate zinc, magnesium, and pyridoxine.52 Zinc can function as a lymphocyte mitogen when it is added in vitro to experimental systems.53 The process of activation is thought to be initiated through monocyte processing of a zinc-transferrin complex. Zinc has been shown to enhance natural killer cell activity in vitro in the presence of interferon-α or interferon-γ. The rationale for trials using zinc in inflammatory diseases has been summarized by Whitehouse.54 It is derived from a collection of evidence showing the following: • A tendency for decreased zinc concentrations at crucial tissue stores in inflammatory disease • Decreased absorption associated with iron therapy • The importance of zinc to normal immune functioning • The tendency of certain drugs, such as penicillamine and corticosteroids, to suppress zinc concentrations • Depressed oral intake of zinc in dietary surveys12,13 and serum measurements of patients with RA

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• The anti-inflammatory effect of zinc complexes in models of chronic inflammation55 The clinical studies of zinc supplementation have yielded unconvincing mixed results.56 Because zinc plays an important role as a cofactor in collagen synthesis, it has been proposed that zinc deficiency contributes to altered collagen metabolism in osteoporosis seen in patients with RA. Researchers in the field retain much interest in the potential role of zinc therapy in the rheumatic diseases. SELENIUM Selenium was recognized to be an essential nutrient in 1957. It exerts myriad effects on the immune system and functions through several different pathways that have been extensively reviewed.57 Spallholz and colleagues58 summarized its three major functions: (1) reduction of organic and inorganic peroxides; (2) metabolism of hydroperoxides, which are intermediate steps in the metabolism of PGs and LTs derived from arachidonic acid; and (3) modulation of the respiratory burst through the control of superoxide (O2−) and H2O2 generation. The effect of selenium on immune function is derived from the selenium-dependent enzymes glutathione peroxidase and phospholipid hydroperoxide. Glutathione peroxidase is responsible for antioxidant activities in reactions described earlier (see the section on free radicals and nutrition and Fig. 63-2). Both enzymes participate in the reduction of PGG2 in the arachidonic acid cascade, leading to the production of thromboxane A2, prostacyclin, and PGs.58 They also participate in the production of LTs and lipoxins through the reduction of the hydroperoxy intermediates.59 Eicosanoid synthesis is significantly diminished in the absence of selenium.60 It is likely that the anti-­inflammatory and immune-modulating effects of selenium are mediated by means of the effect of its ligand enzymes on the production of eicosanoids and the reduction of hydroperoxides. Dietary supplementation of selenium is associated with increased production of superoxide in an animal model.61 It may exert cytotoxic, protective, or modulatory effects in different biologic systems. Because selenium’s ligand enzyme glutathione peroxidase catalyzes the reduction of peroxides, and increased levels of these reactive elements are found in serum and synovial fluid of some patients with RA, there has been some interest in the selenium status of these patients and of patients with other arthritic conditions. There are conflicting reports of selenium–glutathione peroxidase status in patients with RA.62,63 Selenium has been administered to patients with RA64 and osteoarthritis65 without apparent effect. A reduction in serum selenium has been found in patients with systemic sclerosis.66 Patients with RA, but not osteoarthritis, showed an improved pain score in one study of selenium supplementation.67 COPPER Copper is an essential nutrient for biologic systems, including the immune system. Copper is the third largest trace element found in human tissues after iron and zinc. Free copper ion is rapidly complexed to specific ligands, through which it expresses its biologic activity. Most serum copper

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is bound to ceruloplasmin, which increases as part of the acute-phase response. The mechanisms of the effects of copper on the immune system are unknown, although several hypotheses are plausible. As mentioned, along with zinc and manganese, copper is a cofactor in the enzyme superoxide dismutase, which has an essential role in inhibiting free radical damage in tissues and the immune system (see Fig. 63-2). Altered glutathione levels also have been reported in copper-deficient rats.68 The circulating cuproenzyme ceruloplasmin also has antioxidant properties. Increased levels of ceruloplasmin produced as a result of the acute-phase response to inflammation may directly scavenge superoxide, although this is thought to be inefficient.51 More importantly, ceruloplasmin can oxidize Fe(II) to Fe(III), inhibiting the Fe(II)-catalyzed reactions of lipid peroxidation and the scavenging of reactive hydroxyl radicals. It also transports copper for synthesis of intracellular copper-zinc superoxide dismutase, which is crucial in the reduction of highly reactive oxygen free radical species. Two copper-dependent enzymes present within lymphocytes are important in immune function: cytochrome-c oxidase and sulfhydryl oxidase. Cytochrome-c oxidase acts in intracellular energy metabolism. Sulfhydryl oxidase is located in lymphocyte plasma membranes and is a cofactor in pentamer IgM formation and B cell differentiation.69 IRON Asymptomatic tissue iron deficiency is the most common nutritional deficiency in the world. It occurs along with the more severe iron deficiency anemia and is particularly common in infants, children, and pregnant and menstruating women. Iron-deficient populations have a high rate of infectious diseases, which paradoxically may be worsened with iron supplementation. This paradoxical situation is thought to be due to the improved replication of many microorganisms that also require iron for optimal growth.70 Iron has many well-documented effects on immune function. The iron-containing enzyme catalase is found in cytoplasmic peroxisomes and catalyzes the decomposition of H2O2 to water and oxygen, protecting the cellular environment from free radical–induced damage (see Fig. 63-2). As with zinc, serum levels of iron decrease in inflammation and infection, probably by a mechanism of cytokine-stimulated withdrawal from the circulation and enhanced synthesis of ferritin.70 The immune effects of iron may be mediated at least partially through alterations in PG synthesis. PG endoperoxide synthase is an iron-dependent enzyme that is crucial in the synthesis of PG species.70 Because PGE2 can regulate the production of IL-1, impaired PG production secondary to iron deficiency could affect the production of this important cytokine. The precise mechanism responsible for the effects of iron on the immune response has not been established and may have to do with a general role in cellular growth and protein synthesis and more specific effects on the immune system. More recent investigations of multivitamin and mineral supplements in well-conducted blinded trials have shown a reduced incidence of overall infections in a subpopulation of patients with type 2 diabetes mellitus.71 These patients are thought to be micronutrient deficient, as has already been shown in patients with RA,12-15 although these same studies have not been conducted in this population.

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FATTY ACIDS

OMEGA-6 FATTY ACIDS

BACKGROUND Because of the mammalian inability to interconvert omega-3 and omega-6 fatty acids, the composition of phospholipids in cellular membranes is determined by nutritional intake.72 The fatty acids found in the membrane bilayer are substrates for the production of PG and LT species essential for many biologic activities, including modulation of the inflammatory and immune response. It is becoming widely recognized that reproducible metabolic alterations in these pathways can be engineered by consistent modifications in dietary fatty acid content. These fatty acid–induced changes have been documented in trials in animals73 and normal humans74 and in large epidemiologic studies of populations that consume relatively homogeneous diets.75 Fatty acids are designated with a number followed by a colon, another lesser number, a lowercase n, and another number (e.g., 18:2 n-6). The first number designates the number of carbon atoms in the molecule. The number appearing after the colon represents the number of double bonds. The number after the n indicates the position of the first double bond starting from the methyl or omega end of the fatty acid chain. Linoleic acid (18:2 n-6) thus has 18 carbons and two double bonds, and the first double bond is found six carbon atoms from the terminal methyl group. It is an n-6 or omega-6 fatty acid. In discussing fatty acid dietary studies in inflammatory disease, we consider omega-6 and omega-3 intervention separately.

Classical pathway of dietary fatty acid-derived eicosanoid metabolism

corn oil, safflower oil, sunflower oil, soybean oil, margarine, baked goods

Delta-6-desaturase

Gamma-linolenic acid (GLA)

18:3 n-6 Elongase

Dihomogamma-linolenic acid 20:3 n-6 (DGLA) Delta-5-desaturase 20:4 n-6

Arachidonic acid (AA) 5-Lipoxygenase

Cyclooxygenase

5-HPETE

PGG2

5-HETE Peroxidase Epoxide hydrolase LTB4

LTA4

Synthase* LTC4

Animal Studies The subcutaneous air pouch model of inflammation was used to assess response to monosodium urate crystals or Freund’s adjuvant in Sprague-Dawley rats that consumed diets enriched with either safflower oil as a source of linoleic acid or borage seed oil as a source of GLA.78 Animals that

Dietary source

18:2 n-6

Linoleic acid (LA)

The most common fatty acid constituents in the Western diet are the omega-6 fatty acids. They are derived predominantly from terrestrial sources and are ubiquitous in plant seeds. Linoleic acid (18:2 n-6) is essential to life because it is the precursor of arachidonic acid (20:4 n-6) (Fig. 63-3). Arachidonate is present in cellular membranes, where it is esterified to phospholipids in the 2 position. It is released by phospholipase A2 to form the eicosanoid derivatives of the PG and LT families through the enzymes cyclooxygenase and 5-lipoxygenase, which catalyze the insertion of molecular oxygen into arachidonic acid. Gamma-linolenic acid (GLA) (18:3 n-6) is found in seeds from the evening primrose and borage plants. It may be converted by an elongase enzyme to dihomogammalinolenic acid (DGLA) (20:3 n-6). DGLA is oxidized by cyclooxygenase to PGE1 (Fig. 63-4), a monoenoic PG that has altered biologic activities from the dienoic PGE2. PGE1 can inhibit platelet aggregation in humans and rats in vivo and in vitro, whereas PGE2 cannot.76 PGE1 dietary supplementation can suppress inflammation and joint tissue injury in several animal models of inflammation77 and can inhibit neutrophil function. GLA dietary supplementation can suppress acute and chronic inflammation in several experimental animal models.

TXA2-D PGH2-PGI2

PGE2

LTD4 LTE4 Figure 63-3  Metabolism of linoleic acid to eicosanoids. *Synthase also is known as glutathione S-transferase. 5-HETE, 5S-hydroxy-­eicosatetraenoic acid; 5-HPETE, 5S-hydroxyperoxy-eicosatetraenoic acid; LT, leukotriene; PG, prostaglandin; TXA2, thromboxane A2.

Gamma-linolenic acid-derived alterations in eicosanoid metabolism Linolenic acid 18:2 n-6 (LA) Delta-6-desaturase

Dietary source

18:3 n-6 Gamma-linolenic acid (GLA) Elongase

Evening primrose oil, borage seed oil

Dihomogamma-linolenic acid 20:3 n-6 (DGLA) Delta-5-desaturase Arachidonic acid 20:4 n-6 (AA) Cyclooxygenase PGG2

PGG1

Peroxidase

Peroxidase

TXA2-PGH2-PGI2 PGE2

TXA1-PGH1-PGI1 PGE1

Figure 63-4  Metabolism of gamma-linolenic acid (GLA) to prostaglandin species with one double bond. Dihomogamma-linolenic acid (DGLA) cannot be converted to a leukotriene compound. Instead, it is converted by 15-lipoxygenase to 15-hydroxy DGLA (reaction not shown), which can inhibit 5-lipoxygenase activities.

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consumed GLA had a marked reduction of neutrophil exudate and lysosomal enzyme activity compared with rats fed safflower oil. PGE2 and LTB4 concentrations were significantly diminished in pouch exudates in the GLA-fed rats. The fatty acid profiles in the serum and inflammatory cells from animals that consumed primrose oil exhibited significant increases in GLA and DGLA. When DGLA is added to human synovial cells grown in tissue culture, IL-1β-stimulated growth is suppressed fivefold compared with cells grown in medium supplemented with arachidonic acid.79 Cells incubated with DGLA exhibited a 14-fold increase in PGE1 and a 70% decrease in PGE2 compared with cells in control medium. The increase in PGE1 concentrations was associated with significantly enhanced levels of cyclic adenosine monophosphate, which the researchers suggested was responsible for the antiproliferative effects. The inhibiting effect could be blocked by indomethacin, lending further support to PGE1 mediation of growth suppression. Dietary supplementation with GLA and fish oil has been shown to suppress urate crystal–induced inflammation significantly in an animal model.80

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n-3 FATTY ACID-DERIVED ALTERATIONS IN EICOSANOID METABOLISM Alpha-linolenic acid 18:3 n-3 (ALA) Delta-6-desaturase

Dietary source Flaxseed, canola oil, linseed oil, soybean oil, black currant seed, rapeseed plants, leaves

Gamma-linolenic acid 18:4 n-3 (GLA) 22:6 n-3

Elongase

Delta-4desaturase Arachidonic acid (AA)

Docosahexaenoic acid (DHA)

20:4 n-3 22:5 n-3

Delta-5-desaturase

Eicosapentaenoic acid 20:5 n-3 (EPA) 5-Lipoxygenase

Fish, shellfish marine mammals Cyclooxygenase

Human Studies Studies of dietary supplementation with GLA in humans have shown mixed results. An open study of 20 patients with RA treated with GLA in combination with various vitamins showed no significant changes of any clinical or laboratory parameters over 12 weeks.81 An investigation that compared evening primrose oil with olive oil as a source of GLA in 20 patients with RA for 13 weeks failed to show any significant difference between groups.82 In a well-designed study, investigators treated patients with RA with 1.4 g of GLA daily for 24 weeks.83 They observed a clinically important reduction in tender and swollen joint counts of 36% and 28%; the placebo group showed no improvement in these parameters. It had previously been shown that GLA can inhibit IL-2 production by peripheral blood mononuclear cells in vitro84 and may reduce the expansion of activation markers on T lymphocytes.85 The precise mechanism of the improvements observed was not studied.81 Studies of GLA in patients with RA have been reviewed.86 OMEGA-3 FATTY ACIDS The omega-3 fatty acids have their first double bond at the third carbon atom from the methyl end of the molecule. The primary dietary source of this class of fatty acids in human diets is fish and other marine sources, which derive the omega-3 fatty acids from phytoplankton and zooplankton at the base of the food chain. Eicosapentaenoic acid (EPA) (20:5 n-3) (Fig. 63-5) and docosahexaenoic acid (DHA) (22:6 n-3) are the omega-3 fatty acids derived from marine sources. The omega-3 fatty acids also may occur naturally in terrestrial sources in the form of alpha-linolenic acid (18:3 n-3) commonly found in chloroplasts of green leaves and in some plant oils, including flax, canola, and soybean oils. The ability to synthesize the longer chain omega-3 fatty acids EPA and DHA from alpha-linolenic acid is slow in humans and may diminish even further with aging or certain disease states87 as a result of a loss of the n-6 and n-5

5-HPEPE - 5-HEPE

PGG3 Peroxidase

Epoxide hydrolase LTB5

LTA5

TXA3 Synthase*

PGH3

PGI3

PGE3

LTC5 LTD5 LTE5

Figure 63-5  Metabolism of omega-3 fatty acids to eicosanoids. Alphalinolenic acid (ALA) is derived from terrestrial sources, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are derived from marine sources. Omega-3 fatty acids are converted to prostaglandin species with three double bonds, and to leukotriene species with five double bonds. They also compete with arachidonic acid as the substrate for cyclooxygenase and may selectively inhibit the epoxide hydrolase enzyme converting LTA4 to LTB4. *Also known as glutathione S-transferase. 5-HEPE, 5S-hydroxy-eicosapentaenoic acid; 5-HPEPE, 5S-hydroxyperoxy­eicosapentaenoic acid; LT, leukotriene; PG, prostaglandin; TXA3, thromboxane A3.

d­ esaturase enzyme activity. The shorter chain omega-3 fatty acids also must compete for these enzymes with the much larger amounts of omega-6 fatty acids found in the typical Western diet. The omega-6 fatty acids can competitively inhibit the formation of EPA and DHA from alpha-­linolenic acid.3 The primary source of omega-3 fatty acids in the Western diet is nonterrestrial, a reversal of the pattern of most of human prehistory, in which large sources of omega-3 fatty acids were obtained in hunter-gatherer societies through consumption of wild game.5 Fat of wild animals contains about 9% EPA and five times more polyunsaturated fat per gram than is found in domestic livestock,88 which contains almost undetectable amounts of EPA. Throughout most of human history, hunter-gatherer societies consumed a higher percentage of polyunsaturated fat, more omega-3 fatty acids, more fiber, and less total fat than are found in the present

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Western diet (see Table 63-1). The current dietary fatty acid intake must be properly viewed as a more recent alteration of long-standing dietary patterns that humans had adapted to during tens of thousands of years. Speculation has arisen about the possible influence of changing dietary patterns on the development of some major chronic diseases of industrialized society.5 EPA can be metabolized through the cyclooxygenase and 5-lipoxygenase metabolic pathways to form end products with altered biologic activity. EPA is acted on by cyclooxygenase to form thromboxane A3 and prostacyclin (see Fig. 63-5).89 Prostacyclin retains its antiaggregatory platelet activity, but thromboxane A3 is not nearly as potent as thromboxane A2 in inducing platelet aggregation; this may account partially for the diminished risk of cardiovascular morbidity and mortality that is associated with fish consumption.2,3 EPA also is metabolized to PGE3, a compound with less inflammatory activity than PGE2.90 PGE2 stimulates osteoclast activity, resulting in bone resorption, a significant process in RA. The dienoic PGs also increase vascular permeability in a synergistic effect with serotonin and bradykinin.90 The E series PGs have important functions in blood pressure regulation, fertility, and modulation of the immune response. Ingestion of omega-3 fatty acids has been documented to have significant effects in all of these areas3,90 and in cardiovascular health and well-being. The E series PGs are not localized to specific tissues, as is the case with thromboxane and prostacyclin, which are limited to platelets (thromboxane) and vascular endothelium (prostacyclin). The effect of altering PGE content in any specific site varies, depending on the tissue where the synthesis occurs.91 Of possibly greater importance than the altered end products of omega-3 fatty acid ingestion is their ability to inhibit arachidonate metabolism. They can inhibit the synthesis of arachidonic acid from its linoleic acid substrate,92 possibly through competition for the 2 position occupied by arachidonate in membrane phospholipids. EPA also directly competes with arachidonic acid as the substrate for cyclooxygenase and inhibits its metabolism into eicosanoids.93 Ingestion of omega-3 fatty acids results in the production of compounds with altered biologic activity and a decrease in the usual amounts of biologically active arachidonate derivatives. Ingestion of EPA is associated with the production of LTs with five double bonds, such as LTB5 (see Fig. 63-5), which has greatly attenuated proinflammatory activities.94 LTB5 is usually undetectable in humans who consume a Western diet. Simultaneous with the production of small amounts of LTB5 from stimulated neutrophils of normal individuals who consume fish oil, large decreases occur in the production of neutrophil LTB4.95 Neutrophil chemotaxis was significantly suppressed in these subjects after 6 weeks of fish oil ingestion and returned to normal after the supplements were discontinued. Other investigators have found evidence of a selective inhibition of the epoxide hydrolase enzyme (see Fig. 63-5) in neutrophils from normal individuals94 and patients with RA96 who consume fish oil because of unaltered quantities of 5-hydroxyeicosatetraenoic acid and 5-hydroxyeicosapentaenoic acid relative to the corresponding arachidonic acid product generated before dietary supplementation.

Chemotactic activity of neutrophils from patients with RA who had ingested fish oil was found to be enhanced compared with the pretreatment state.96 This finding seems paradoxical in view of the suppression of neutrophil chemotaxis after fish oil ingestion in normal individuals.95 The improved chemotaxis in patients with RA represents a partial correction of a reduced chemotactic activity of peripheral blood neutrophils of individuals with this disease. Platelet­activating factor acether generation of stimulated monocytes is significantly diminished95 after fish oil ingestion, suggesting an omega-3 fatty acid–induced inhibitory effect of phospholipase A2 activity on substrate alkyl ­phospholipids, which affects platelet-activating factor ­generation. This suggestion is of considerable interest in the context of inflammation in that platelet-activating factor can stimulate tumor necrosis factor and other cytokines in endothelial tissue97 and is 1000 times more potent than histamine in inducing changes in vascular permeability.98 Evidence suggests that platelet-activating factor also can modulate T cell and monocyte function.99 The omega-3 fatty acids are associated with a variety of effects on mononuclear cell function, including the production of eicosanoids, nitric oxide, and reactive oxygen species; adhesion molecule expression; chemotaxis; and cytokine production.100-103 Intake of omega-3 fatty acids also has been shown to increase apoptosis and T helper type 1–derived and T helper type 2–derived cytokine synthesis.104,105 Ingestion of omega-3 fatty acids is associated with significant changes in the fatty acid profiles of cellular lipids. Neutrophil arachidonic acid content is reduced by 33%, and EPA content is enhanced 20-fold compared with presupplement values obtained in patients with RA who ingested fish oil.96 Ingestion of omega-3 fatty acids is associated with reproducible changes in the biochemical composition of cell membranes of neutrophils and monocytes and striking alterations in the production of the metabolic end products of myriad inflammatory and immunologically active compounds that may influence the course of rheumatic disease. The lipid bilayer of cellular membranes is composed primarily of phospholipids and cholesterol (Fig. 63-6). Because cellular receptors, enzymes, and transport proteins are embedded in the phospholipid bilayer, a change in its structure could have significant implications for cellular function that extend beyond the alterations in eicosanoid and platelet-activating factor acether biosynthesis described herein. One investigation showed a significant reduction of IL-1 from monocytes of normal volunteers ingesting fish oil for 6 weeks.99 The precise mechanism of this effect is speculative, but it may be associated with membrane changes in phospholipid fatty acid content, leading to diminished amounts of eicosanoid products, such as LTB4. Animal Studies Dietary modifications containing omega-3 fatty acids reduce the severity of diffuse proliferative glomerulonephritis in several autoimmune strains of mice, including NZB × NZW F1, BXSB/Mpj, and MRL/lpr.68,106 Dietary omega-3 fatty acids reduce the severity of glomerulonephritis even when they are withheld until after the renal disease has begun to evolve.106 Not all observed effects of fish oil have been

PART 8 

Cell membrane Dietary n-6 and n-3 fatty acids

Cellular activation

Cyclooxygenase Lipoxygenase

Second messenger

Eicosanoids P1P2 PLC G

Receptor

Figure 63-6  Potential role of dietary fatty acids in the function of the membrane phospholipid bilayer of cells. Dietary fatty acids are incorporated into the phospholipid bilayer of cells, where they can be metabolized to eicosanoids. Biologically modified eicosanoids derived from ingesting omega-3 or omega-6 fatty acids may have a role in modulating receptor-ligand activity and cellular activation to various stimuli. Fatty acid changes in the lipid bilayer also may result in changes in membrane fluidity that could have potential effects on the function of other receptor-related membrane activities. The stimulated receptor transmits a signal via a G protein to phospholipase C (PLC), which splits phosphatidylinositol 4,5-biphosphate (PIP2) to products that eventually lead to second-messenger generation and cellular activation (biochemical steps not shown). (Modified from Weber PC: Membrane phospholipid modification by dietary ω-3 fatty acids: Effects on eicosanoid formation and cell function. In Karnovsky ML [ed]: Biological Membranes: Aberrations in Membrane Structure and Function. New York, Liss, 1988, pp 263-274. Copyright 1988 Wiley-Liss. Reprinted by permission of Wiley-Liss, A Division of John Wiley & Sons, Inc.)

b­ eneficial in the laboratory; an increased incidence of arthritis was observed in rats immunized with type II collagen who consumed a fish oil–enriched diet compared with animals ingesting beef tallow, although the severity of the arthritis was the same in each group.107 An increased incidence of necrotizing vasculitis was noted in renal arteries of MRL/lpr mice with systemic lupus erythematosus–like disease, even while their glomerulonephritis was alleviated on a fish oil diet.106 Studies indicate that a mixture of omega-3 fatty acids containing EPA and DHA may be more effective than either of these omega-3 fatty acids by themselves.108 Human Studies A pilot study published in 1985 suggested a possible beneficial effect of dietary supplementation with omega-3 fatty acids in patients with RA.109 In a subsequent investigation, patients received 2.8 g of EPA and 1.8 g of DHA in a blinded crossover format in which subjects received fish oil– derived omega-3 fatty acids or olive oil for 14 weeks before crossing over to receive the opposite dietary supplement.110 Patients were observed to have a highly statistically significant decrease in the number of tender joints after they took fish oil in contrast to when they consumed olive oil. Fatigue, which was quantitated as the time interval from awakening to the first feeling of tiredness, also lessened significantly in patients who consumed fish oil. All of 12 clinical parameters measured favored fish oil, although only 2 parameters

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achieved statistical significance. LTB4 from stimulated ­ eutrophils decreased by 57.8% in patients who consumed n the fish oil omega-3 supplement compared with olive oil. A significant correlation was observed between the decrease in the number of tender joints and the decrease in neutrophil LTB4 production in individual patients. LTB4 production from stimulated neutrophils was significantly reduced at week 4 in patients taking fish oil, even though significant clinical improvement did not occur until week 12.111 There is an asynchrony between omega-3 fatty acid–induced decreases in neutrophil LTB4 production, which occur after only 4 to 6 weeks,95,96,111 and the clinical benefits, which are delayed until at least week 12.109-111 This might be due partially to the delayed suppressive effects of fish oil ingestion on the production of IL-1.99 The effects of different doses of fish oil versus olive oil were studied in a 6-month randomized, double-blind, parallel investigation of 49 patients with active RA.112 Fish oil supplements were supplied according to body weight, not as a uniform dose as in previous studies. A “low-dose” group consumed 27 mg/kg/day of EPA and 18 mg/kg/day of DHA. A “high-dose” group ingested exactly twice that amount. Patients maintained their background medications and diets without change, as in the previously described studies in patients with RA. Multiple clinical parameters improved from baseline in the groups consuming fish oil; statistically significant improvements occurred in joint swelling and tenderness scores, morning stiffness, and physician evaluation of global disease activity with significantly greater frequency in the high-dose group. Significant decreases also were observed in stimulated neutrophil production of LTB4 and monocyte IL-1; the greatest decreases in IL-1 were observed in the patients consuming the higher dose of fish oil. The clinical effects of long-term dietary supplementation with omega-3 fatty acids have been summarized.113,114 A 2-week study of seal oil supplementation in patients with psoriatic arthritis did not show a significant effect, but the duration of treatment was probably suboptimal.115 The beneficial effects of omega-3 fatty acid ingestion in humans with inflammatory disease may be dose and time dependent, as in the autoimmune animal model108 and studies of the antihypertensive effects of fish oil ingestion in humans.116 Significant clinical benefits were observed more commonly after 18 and 24 weeks of fish oil ingestion. Fish oil dietary supplementation has not been effective in patients with stable lupus nephritis117 or osteoarthritis,118 but it does seem to offer a protective effect in the prevention of renal transplant rejection119 and treatment of IgA nephropathy.120 VASCULAR DISEASES The role of omega-3 fatty acids in cardiovascular disease is well established and has been reviewed elsewhere.3 Effects of omega-3 fatty acids that may improve the status of individuals with impaired circulation include the following: • Improved rheologic status secondary to increased erythrocyte deformability • Decreased plasma viscosity • More favorable vascular response to ischemia • Reduced vasospastic response to catecholamines and angiotensin

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• Increased levels of tissue plasminogen activator • Increased endothelium-dependent relaxation of arteries in response to bradykinin, serotonin, adenine diphosphate, and thrombin. Fish oil dietary intervention differs from present interventions for vascular disease because of the potential for beneficial benefits at multiple physiologic loci.121 In an investigation of the effect of fish oil ingestion in patients with Raynaud’s phenomenon, 32 patients with primary or secondary disease consumed daily dietary supplements of 3.96 g of EPA and 2.64 g of DHA or olive oil for 12 weeks.122 Digital systolic blood pressure and blood flow were evaluated by a strain gauge plethysmograph in room air and in water baths of different temperatures. Results showed significant improvements in the time to onset of symptoms and in digital systolic pressure in the cold water baths in patients with primary, but not secondary Raynaud’s phenomenon. The mechanism of these benefits was not studied.

ALLERGIC ARTHRITIS The idea that rheumatologic disease might be etiologically linked to ingestion of food is not a new one.123,124 The idea has gained some support from sporadic but convincing case reports of the reproducible onset of joint symptoms shortly after the ingestion of certain foodstuffs. Patients with Behçet’s syndrome had striking exacerbations of disease within 48 hours of ingestion of English walnuts.125 Lymphocytes from these patients also had significantly decreased reactivity to a walnut extract ex vivo within 2 days of ingestion of English walnuts, and leukocyte incorporation of tritiated thymidine after mitogen stimulation was increased.125 A hypersensitivity to certain foods has been speculated to be the cause of at least some cases of palindromic rheumatism,124 and palindromic rheumatism was documented to occur in an individual with a hypersensitivity to sodium nitrate in food preservatives.126 L-Canavanine, a nonprotein amino acid found in alfalfa, has been linked to exacerbations of systemic lupus erythematosus in monkeys127 and humans.128 For a response to food to be plausibly linked to a hypersensitivity reaction resulting in articular symptoms, it is necessary to implicate an altered intestinal permeability that would allow passage of intact food antigens into the circulation. Circumstantial evidence exists to link arthritis to damaged intestinal function in ulcerative colitis,129 Crohn’s disease,130 and the polyarthritis that follows jejunal bypass surgery for obesity.131 Immune complexes that contain intact food antigens complexed to IgE or IgG have been documented in normal and atopic subjects132 and have been observed to cause bronchospasm and pruritus in allergic individuals. A study of intestinal permeability that used oral chromium-labeled edetic acid showed that patients with RA who took nonsteroidal anti-inflammatory drugs (NSAIDs) exhibited abnormalities, whereas patients not taking NSAIDs did not have abnormal permeability.133 Indium 111–labeled leukocyte scans showed ileocecal inflammation in six of nine patients taking NSAIDs. A food antigen can be convincingly linked to arthritis if a flare of clinical symptoms occurs within 48 hours of a blinded challenge with the putative offending antigen. An elimination diet in which a patient totally discontinues ingestion

of the food in question with total clearing of articular symptoms also would provide implicative evidence, albeit weaker than a flare after a blinded challenge. Two cases have been reported involving significant flares in articular symptoms after ingestion of milk or dairy products.134,135 The challenges were open134 and blinded,135 and symptoms peaked within 24 to 48 hours. IgE antibodies to milk were shown by use of the radioallergosorbent test in one patient,134 and large amounts of IgG4 anti-milk antibodies directed to α-lactalbumin were detected in the other.135 A flare in articular disease manifestations also has been documented after blinded challenges with shrimp and nitrates.136 Interest in the possible role of food intolerance in the etiology of arthritic symptoms has been renewed137,138 as a result of these case reports. It is difficult to assess the incidence of this syndrome in that patients may be unaware of possible sensitivities to commonly ingested foods in their diet. Because of the few documented cases of food intolerance in the literature, however, the syndrome is probably rare.

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46. Gepner P, Amor B, Fournier C: 1,25-Dihydroxyvitamin D3 potentiates the in vitro inhibitory effects of cyclosporin A on T cells from rheumatoid arthritis patients. Arthritis Rheum 32:31, 1989. 47. Huckins D, Felson DT, Holick M: Treatment of psoriatic arthritis with oral 1,25-dihydroxyvitamin D3: A pilot study. Arthritis Rheum 33:1732, 1990. 48. Fukushima T, Iijima Y, Kosaka F: Endotoxin-induced zinc accumulation by liver cells is mediated by metallothionein synthesis. Biochem Biophys Res Commun 152:874, 1988. 49. Cousins RJ: Absorption, transport and hepatic metabolism of copper and zinc: Special reference to metallothionein and ceruloplasmin. Physiol Rev 65:238, 1985. 50. Kluger MJ, Rothenburg BA: Fever and reduced iron: Their interaction as a host defense response to bacterial infection. Science 203:374, 1979. 51. Svenson KLG, Hallgren R, Johansson E: Reduced zinc in peripheral blood cells from patients with inflammatory connective tissue diseases. Inflammation 9:189, 1985. 52. Seelig MS: Autoimmune complications of D-penicillamine: A possible result of zinc and magnesium depletion and of pyridoxine inactivation. J Am Coll Nutr 1:207, 1982. 53. Ruhl J, Kirshner H: Monocyte-dependent stimulation of human T cells by zinc. Clin Exp Immunol 32:484, 1978. 54. Whitehouse MW: Trace element supplements for inflammatory disease. In Dixon J, Furst D (eds): Second Line Agents in the Rheumatic Diseases. New York, Marcel Dekker, 1991, p 549. 55. Whitehouse MW, Rainsford KD, Taylor RM, et al: Zinc monoglycerolate: A slow-release source of zinc with anti-arthritic activity in rats. Agents Actions 31:47, 1990. 56. Cimmino MA, Mazzucotelli A, Rovetta G, et al: The controversy over zinc sulfate efficacy in rheumatoid and psoriatic arthritis. Scand J Rheumatol 13:191, 1984. 57. Spallholz JE: Anti-inflammatory immunologic and carcinostatic attributes of selenium in experimental animals. Adv Exp Med Biol 135:43, 1981. 58. Spallholz JE, Boyland LM, Larsen HS: Advances in understanding selenium’s role in the immune system. Ann N Y Acad Sci 587:123, 1990. 59. Ursini F, Maiorino M, Gregolin C: The selenoenzyme phospholipid hydroperoxide glutathione peroxidase. Biochem Biophys Acta 839:62, 1985. 60. Bryant RW, Bailey JM, King JC, et al: Altered platelet glutathione peroxidase activity and arachidonic acid metabolism during selenium repletion in a controlled human study. In Spallholz JE, Martin JL, Ganther HE (eds): Selenium in Biology and Medicine. Westport, Conn, AVI, 1981, p 395-399. 61. Spallholz JE, Boylan LM: Effect of dietary selenium on peritoneal macrophage chemiluminescence. Fed J 3:A778, 1989. 62. Sonne M, Helleberg L, Jenson PT: Selenium status in patients with rheumatoid arthritis. Scand J Rheumatol 14:318, 1985. 63. Borgland M, Akesson A, Adesson B: Distribution of selenium and glutathione peroxidase in plasma compared in healthy subjects and rheumatoid arthritis patients. Scand J Clin Lab Invest 48:27, 1988. 64. Tarp U, Overvad K, Thorling EB, et al: Selenium treatment in rheumatoid arthritis. Acta Pharmacol Toxicol 59(Suppl 7):382, 1986. 65. Hill J, Bird HA: Failure of selenium-ACE to improve osteoarthritis. Br J Rheumatol 29:211, 1990. 66. Herrick A, Rieley F, Schofield D, et al: Micronutrient antioxidant status in patients with primary Raynaud’s phenomenon and systemic sclerosis. J Rheumatol 21:1477, 1994. 67. Wagner E, Gruber FO: The trace element selenium in rheumatic diseases. Rio de Janeiro, XVII ILAR Congress of Rheumatology, 1989 (abstract P-682). 68. Allen KGD, Arthur JR, Morrice PC, et al: Copper deficiency and tissue glutathione concentration in the rat. Proc Soc Exp Biol Med 187:38, 1988. 69. Roth RA, Koshland ME: Identification of a lymphocyte enzyme that catalyzes pentamer immunoglobulin M assembly. J Biol Chem 256:4633, 1981. 70. Sherman AR: Influence of iron on immunity and disease resistance. Ann N Y Acad Sci 587:140, 1990. 71. Barringer TA, Kirk JK, Santaniello AC, et al: Effect of a multivitamin and mineral supplement on infection and quality of life: A randomized, double-blind, placebo-controlled trial. Ann Intern Med 138:365, 2003.

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72. Weber PC: Membrane phospholipid modification by dietary n-3 fatty acids: Effects on eicosanoid formation and cell function. In Karnovsky ML (ed): Biological Membranes: Aberrations in Membrane Structure and Function. New York, Alan R Liss, 1988, pp 263-274. 73. Prickett JD, Robinson DR, Steinberg AD: Dietary enrichment with the polyunsaturated fatty acid eicosapentaenoic acid prevents proteinuria and prolongs survival in (NZB × NZW) F1 mice. J Clin Invest 68:556, 1981. 74. Lee TH, Hoover RL, Williams JD, et al: Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil function. N Engl J Med 312:1217, 1985. 75. Shekelle RB, Missell LV, Paul O, et al: Fish consumption and mortality from coronary heart disease. N Engl J Med 313:820, 1985. 76. Willis AL, Comai K, Kuhn DC, et al: Dihomogammalinolenate suppresses platelet aggregation when administered in vitro or in vivo. Prostaglandins 7:509, 1974. 77. Zurier RB: Prostaglandins, immune responses, and murine lupus. Arthritis Rheum 25:804, 1982. 78. Tate GA, Mandell BF, Karmali RA, et al: Suppression of monosodium urate crystal-induced acute inflammation by diets enriched with gamma-linolenic acid and eicosapentaenoic acid. Arthritis Rheum 31:1543, 1988. 79. Baker DG, Krakauer KA, Tate G, et al: Suppression of human synovial cell proliferation by dihomogammalinolenic acid. Arthritis Rheum 32:1273, 1989. 80. Fam AG: Gout, diet, and the insulin resistance syndrome. J Rheumatol 29:1350, 2002. 81. Hansen TM, Lerche A, Kassis V, et al: Treatment of rheumatoid arthritis with prostaglandin E1 precursors cis-linoleic acid and gamma-linolenic acid. Scand J Rheumatol 12:85, 1983. 82. Jantti J, Nikkari T, Solakivi T, et al: Evening primrose oil in rheumatoid arthritis: Changes in serum lipids and fatty acids. Ann Rheum Dis 48:124, 1989. 83. Leventhal LJ, Boyce EG, Zurier RB: Treatment of rheumatoid arthritis with gamma-linolenic acid. Ann Intern Med 119:867, 1993. 84. Santoli D, Zurier RB: Prostaglandin E precursor fatty acids inhibit human IL-2 production by a prostaglandin E-independent mechanism. J Immunol 143:1303, 1989. 85. Santoli D, Philips PD, Zurier RB: Suppression of interleukin 2­dependent human T cell growth by prostaglandin E (PGE) and their precursor fatty acids: Evidence for a PGE-independent mechanism of inhibition by the fatty acids. J Clin Invest 85:424, 1990. 86. Zurier RB: Gammalinolenic acid treatment of rheumatoid arthritis. In Kremer JM (ed): Medicinal Fatty Acids in Inflammation. Basel, Birkhauser, 1998, pp 29-43. 87. Lands WEM: Fish and Human Health. Orlando, Fla, Academic Press, 1986, p 103. 88. Crawford MA: Fatty-acid ratios in free-living and domestic animals. Lancet 1:1329, 1968. 89. Fischer S, Weber PC: Prostaglandin I3 is formed in vivo in man after dietary eicosapentaenoic acid. Nature 307:165, 1984. 90. Robinson DR, Tateno S, Balkrishna P, et al: Lipid mediators of inflammatory and immune reactions. In Karnovsky ML (ed): Biological Membranes: Aberrations in Membrane Structure and Function. New York, Alan R Liss, 1988, pp 295-303. 91. Ferretti A, Flanagan VP: Modification of prostaglandin metabolism in vivo by long-chain omega-3 polyunsaturates. Biochim Biophys Acta 1045:299, 1990. 92. Holman RT: Nutritional and metabolic interrelationships between fatty acids. Fed Proc 23:1062, 1964. 93. Simopoulos AP, Kifer RR, Martin RE (eds): Health Effects of ­Polyunsaturated Fatty Acids in Seafoods. New York, Academic Press, 1986. 94. Lee TH, Mencia-Huerta JM, Shih C, et al: Characterization and biologic properties of 5,12-dihydroxy derivatives of eicosapentaenoic acid, including leukotriene B5 and the double lipoxygenase product. J Biol Chem 259:2383, 1984. 95. Lee TH, Hoover RL, Williams JD, et al: Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil function. N Engl J Med 312:1217, 1985. 96. Sperling RI, Weinblatt M, Robin JL, et al: Effects of dietary supplementation with marine fish oil on leukocyte lipid mediator generation and function in rheumatoid arthritis. Arthritis Rheum 30:988, 1987.

97. Dulioust A, Salem P, Vivier E, et al: Immunoregulatory functions of PAF-acether (platelet-activating factor). In: Biological Membranes: Aberrations in Membrane Structure and Function. New York, Alan R Liss, 1988, pp 87-96. 98. Humphrey DM, McManase L, Satouchi K, et al: Vasoactive properties of acetyl glyceryl ether phosphorylcholine and analogs. Lab Invest 46:422, 1982. 99. Endres S, Chorbani R, Kelley VE, et al: The effects of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med 320:265, 1989. 100. Calder PC: Effects of fatty acids and dietary lipids on cells of the immune system. Proc Nutr Soc 55:127, 1996. 101. Meydani SN: Effect of n-3 polyunsaturated fatty acids on cytokine production and their biologic function. Nutrition 12:58, 1996. 102. Endres S, von Schacky C: n-3 polyunsaturated fatty acids and human cytokine synthesis. Curr Opin Lipidol 7:48, 1996. 103. Calder PC: n-3 polyunsaturated fatty acids and mononuclear phagocyte function. In Kremer JM (ed): Medicinal Fatty Acids in Inflammation. Basel, Birkhauser, 1998, pp 1-27. 104. Fernandes G, Jolly CA: Nutrition and autoimmune disease. Nutr Rev 56:S161, 1998. 105. Fernandes G: n-3 fatty acids on autoimmune disease and apoptosis. In Kremer JM (ed): Medicinal Fatty Acids in Inflammation. Basel, Birkhauser, 1998, pp 73-89. 106. Robinson DR, Prickett JD, Makoul GT, et al: Dietary fish oil reduces progression of established renal disease in (NZB × NZW) F1 mice and delays renal disease in BXSB and MRL/1 strains. Arthritis Rheum 29:539, 1986. 107. Prickett JD, Trentham DE, Robinson DR: Dietary fish oil augments the induction of arthritis in rats immunized with type II collagen. J Immunol 132:725, 1984. 108. Robinson DR, Tateno S, Knoell C, et al: Dietary marine lipids suppress murine autoimmune disease. J Intern Med 225(Suppl 1):211, 1989. 109. Kremer JM, Bigauoette J, Michalek AU, et al: Effects of manipulating dietary fatty acids on clinical manifestations of rheumatoid arthritis. Lancet 1:184, 1985. 110. Kremer JM, Jubiz W, Michalek A, et al: Fish-oil fatty acid supplementation in active rheumatoid arthritis: A double blinded, controlled crossover study. Ann Intern Med 106:498, 1987. 111. Cleland LG, French JK, Betts WH, et al: Clinical and biochemical effects of dietary fish-oil supplements in rheumatoid arthritis. J Rheumatol 15:1471, 1988. 112. Kremer JM, Lawrence DA, Jubiz W, et al: Dietary fish oil and olive oil supplementation in patients with rheumatoid arthritis: Clinical and immunologic effects. Arthritis Rheum 33:810, 1990. 113. Geusens PP: n-3 fatty acids in the treatment of rheumatoid arthritis. In Kremer JM (ed): Medicinal Fatty Acids in Inflammation. Basel, Birkhauser, 1998, pp 111-123. 114. Cleland LG, James MJ: Marine oils for anti-inflammatory effect— time to take stock. J Rheumatol 33:207, 2006. 115. Madland TM, Bjorkkjaer T, Brunborg LA, et al: Subjective improvement in patients with psoriatic arthritis after short-term oral treatment with seal oil: A pilot study with double blind comparison to soy oil. J Rheumatol 33:307, 2006. 116. Knapp HR, FitzGerald GA: The antihypertensive effects of fish oil: A controlled study of polyunsaturated fatty acid supplements in essential hypertension. N Engl J Med 320:1037, 1989. 117. Clark WF, Parbtani A, Naylor CD, et al: Fish oil in lupus nephritis: Clinical findings and methodological implications. Kidney Int 44:75, 1993. 118. Stammers T, Sibbald B, Freeling P: Efficacy of cod liver oil as an adjunct to non-steroidal anti-inflammatory drug treatment in the management of osteoarthritis in general practice. Ann Rheum Dis 51:128, 1992. 119. Homan van der Heide JJ, Bilo HJG, Donker JM, et al: Effect of dietary fish oil on renal function and rejection in cyclosporine-treated recipients of renal transplants. N Engl J Med 329:769, 1993. 120. Donadio JV Jr, Bergstralh EJ, Offord KP, et al: A controlled trial of fish oil in IgA nephropathy. N Engl J Med 331:1194, 1994. 121. Cleland LG, James MJ, Proudman SM: Fish oil: What the prescriber needs to know. Arthritis Res Ther 8:202, 2006. 122. DiGiacomo RA, Kremer JM, Shah DM: Fish oil supplementation in patients with Raynaud’s phenomenon: A double-blind controlled prospective study. Am J Med 86:158, 1989.

PART 8  123. Lewis P, Taub SJ: Allergic synovitis due to ingestion of English walnuts. JAMA 106:214, 1936. 124. Zeller M: Rheumatoid arthritis food allergy as a factor. Ann Allergy 7:200, 1947. 125. Marquardt JC, Snyderman R, Oppenheim JJ: Depression of lymphocyte transformation and exacerbation of Behçet’s syndrome by ingestion of English walnuts. Cell Immunol 9:263, 1973. 126. Epstein S: Hypersensitivity to sodium nitrate: A major causative factor in case of palindromic rheumatism. Ann Allergy 27:343, 1969. 127. Malinow MR, Bardana EJ, Pirofsky B, et al: Systemic lupus erythematosus-like syndrome in monkeys fed alfalfa sprouts: Role of a nonprotein amino acid. Science 216:415, 1982. 128. Roberts JL, Hayashi JA: Exacerbation of SLE associated with alfalfa ingestion. N Engl J Med 308:1361, 1983 (letter). 129. Wright V, Watkinson G: The arthritis of ulcerative colitis. BMJ 2:670, 1965. 130. von Potter WN: Regional enteritis. Gastroenterology 26:347, 1954. 131. Wands JR, LaMont JT, Mann E, et al: Arthritis associated with intestinal by-pass procedure for morbid obesity: Complement activation and character of circulating cryoproteins. N Engl J Med 294:121, 1976.

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132. Paganelli R, Levinsky RJ, Brostoff J, et al: Immune complexes containing food proteins in normal and atopic subjects after oral challenge and effect of sodium cromoglycate on antigen absorption. Lancet 1:1270, 1979. 133. Bjarnason I, So A, Levi AJ, et al: Intestinal permeability and inflammation in rheumatoid arthritis: Effects of non-steroidal anti­inflammatory drugs. Lancet 2:1171, 1984. 134. Parke EL, Hughes GRV: Rheumatoid arthritis and food: A case study. BMJ 282:2027, 1981. 135. Panush RS, Stroud RM, Webster EM: Food-induced (allergic) arthritis. Arthritis Rheum 29:220, 1986. 136. Panush RS: Food induced (“allergic”) arthritis: Clinical and serologic studies. J Rheumatol 17:291, 1990. 137. Darlington LG: Does food intolerance have any role in the aetiology and management of rheumatoid disease? Ann Rheum Dis 44:801, 1985. 138. Panush RS: Possible role of food sensitivity in arthritis. Ann Allergy 19(Suppl):31, 1988.

64

Introduction to Physical Medicine and Rehabilitation Peter R. Oesch  • Stefan Bachmann

KEY POINTS The aims of rehabilitation are to maximize function and minimize activity limitation and participation restriction. The International Classification of Functioning, Disability and Health (ICF) provides the common framework for rehabilitation. Modern rehabilitation is interdisciplinary using a patient-centered approach. The main focus in the assessment and treatment of patients is on functioning. Exercise consistently has been shown to be effective in the treatment of various rheumatic diseases. Physical modalities may be used as an adjunct to active therapies. Rehabilitation includes not only the training of disabled individuals, but also intervention in the adaptation of the environment.

AIMS OF PHYSICAL MEDICINE AND REHABILITATION The aim of rehabilitation is to maximize function and minimize the limitation of activity and the restriction of participation resulting from an underlying impairment or disease. According to the definition of the World Health Organization in 1980, rehabilitation includes all measures aimed at reducing the impact of disability for an individual, enabling him or her to achieve independence, social integration, improved quality of life, and self-actualization. Rehabilitation includes not only the training of disabled individuals, but also general interventions in the social system, adaptations of the environment, and protection of human rights. Rehabilitation should begin early and is an ongoing pr­ocess throughout the course of the disease. It may be done in an outpatient or inpatient setting. The severity of a disease or the activity of an inflammatory disease defines which modality should be chosen. A rehabilitation program can be applied even in very active inflammatory diseases. The rehabilitation program consists not only of specialized therapies done by physical therapists or other health professionals, but also includes education, home exercises, and environmental interventions. Rehabilitation should be patient-centered because information about the patient can be crucial for the positive outcome of the treatment. Apart from the medical disease, the patient’s experiences with illnesses also have to be

c­ onsidered, and a common ground and rehabilitation goals have to be defined in the team together with the patient. These goals can be achieved only with the p­articipation of the patient. Ideal outcomes show a reduction of impairments and an improvement in the activation and participation level. The reduction of impairments and the improvement in the activation or participation level differ from patient to patient even in the same medical disorder.

INTERDISCIPLINARY REHABILITATION VERSUS MULTIDISCIPLINARY REHABILITATION Modern rehabilitation is interdisciplinary and based on the collaboration of health professionals and physicians. In this model, each professional evaluates the patient separately and discusses the results of these evaluations with all other team members. In team meetings, information from each team member is used to define short-term and long-term goals. In this way, the interaction of the team is used to formulate a unique patient-centered, coordinated rehabilitation plan because all team members participate in the rehabilitation program and are involved in problem solving and decision making. In contrast to this model, multidisciplinary treatments consist of input from various professionals. Each professional treats the patient separately, and the information is communicated via documentation. There is no synergistic interaction in this model. Bearing in mind these limitations of multidisciplinary treatments, it is evident that the result of interdisciplinary treatments is more than the sum of the components (i.e., the professions).

INTERNATIONAL CLASSIFICATION OF FUNCTIONING, DISABILITY AND HEALTH AIM OF THE INTERNATIONAL CLASSIFICATION OF FUNCTIONING, DISABILITY AND HEALTH The overall aim of the International Classification of Fu­nctioning, Disability and Health (ICF) classification is to provide a unified, standard language and framework for the description of health and the health-related status. It defines components of health and health-related components of well-being, such as education and work.1,2 The domains contained in the ICF can be seen as health domains and health-related domains (Fig. 64-1). These domains are described from the perspective of the body, the individual, and society in two lists: (1) body functions and structures and (2) a­ctivities and participation. 1023

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Figure 64-1  The domains of the International Classification of Functioning, Disability and Health. (From World Health Organization: International Classification of Functioning, Disability and Health: ICF. Geneva, WHO, 2001.)

As a classification, the ICF systematically organizes various aspects of an individual’s health condition. The term functioning is used to describe body functions, activities, and participation; the term disability determines impairments, activity limitations, and participation restrictions. The ICF also lists environmental factors that interact with body functions and structures and activities and participation. The ICF is part of the World Health Organization framework of international classifications to code the wide range of information about health. Health conditions (e.g., diseases, disorders, injuries) are classified in the International Statistical Classification of Diseases and Health-related Problems, 10th revision (ICD-10). Functioning and disability associated with health conditions are classified in the ICF. ICD-10 and the ICF are complementary. Together, information on diagnosis plus functioning provides a broad picture of the patient. The ICF as a tool is a multipurpose classification system. It was designed to serve various disciplines and specialties in rehabilitation and provides a scientific basis for understanding and studying health, health-related states, and outcomes. The ICF has established a common language for describing health and health-related states to improve the communication between different users and professions. Using the ICF classification and language, it is possible to compare data across countries and different disciplines and health care systems.

FRAMEWORK OF THE INTERNATIONAL CLASSIFICATION OF FUNCTIONING, DISABILITY AND HEALTH Role of the International Classification of Functioning, Disability and Health in the Rehabilitation of Patients with Rheumatic Diseases The ICF plays an important role in the rehabilitation of patients with rheumatic diseases. The diagnosis of a rheumatoid factor–positive and erosive rheumatoid arthritis (RA) according to ICD-10 (M 05) reveals nothing about the activity limitations and participation restrictions. It is even unclear if a patient with this diagnosis is impaired. Two individuals with the same disease (classified in ICD-10) do not have the same limitations that have to be treated in a rehabilitation program. Knowing this, it is important to evaluate patients according to the two components of the ICF, as phrased in the following question: “What are the problems and limitations in body function and structure of each single patient?” These are the impairments clinicians need to know about. Impairments are defined as problems in body function and structures leading to significant deviations or function loss, as phrased in the following question: “Do these impairments lead to limitations in activity and participation?” Activity limitations are defined as difficulties one may have in the execution of a task or an action.

PART 8 

Assessment Evaluation

Rehab-cycle

Assignment

Intervention Figure 64-2  The rehab-cycle. Modified from: Rehab Cycle (Document on the Internet). Available at: http:// reha. klinikum.uni-muenchen.de/  4_Fors­chung_u_Lehre/MeCum/Mecum-WS0506/Seminare/S07-08_  Rehabcycle.pdf

Participation restrictions are problems one may experience in involvement in life situations. In the ICF system, all of these domains are assessed. It is the starting point of the “rehab-cycle” (Fig. 64-2).3 The aim of a rehabilitation program is to maximize function. In the example of patients with RA, the primary goal is not to n­ormalize the erythrocyte sedimentation rate. To treat patients with a high humeral activity with medications may be an intervention to normalize function. After the essential assessment of patients in all di­mensions of the ICF, an assessment is done to choose the best way to treat the function deficits. Thereafter, the interventions are planned together with the patient and all members of the rehabilitation team with the focus on function. Goals and assessment tools are defined in this stage of the rehab-cycle to enable the evaluation of the interventions after a specified period. At the end of an intervention, the results must be reassessed using the tools defined earlier and according to the goals that were set and defined at the beginning of the intervention period. In this evaluation phase, all dimensions of the ICF have to be reassessed. After this step, a new rehab-cycle may begin with new goals. It is possible to p­ersonalize the rehabilitation process in this way for all patients with rheumatic diseases (and other diseases that affect the health and well-being of individuals). Role of Assessments in the Rehab-Cycle The identification of a patient’s problem and needs is the first step of rehabilitation. It relies on the use of sound health measurements. Health measurements also are used for the intervention management and outcome evaluation. Health professionals in rehabilitation use a wide variety of measures, including technical, clinical, and patient-oriented m­easures. Technical measures include electrophysiologic examinations, biomechanical devices, and computerized devices. Clinical measures such as range-of-motion and strength tests assess body functions and activities such as walking and lifting weights. Patient-oriented measures include patient and proxy self-reports on health status, qu­ality of life, and health preferences.4 Although most physicians who treat patients with RA are appropriately concerned about the degree of inflammation, they may not ascertain which functional activities the patient is capable of performing. Because the primary goal in rehabilitation is to restore function and to enable a return to normal life, the main focus in the rehab-cycle is on the assessment of functioning. Numerous tools have been designed to measure joint range of motion, varying from simple visual estimation to high-speed cinematography. Goniometry often is used to

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assess clinically the rehabilitation of patients with rh­eumatic diseases because of its feasibility and known psychometric properties. Considering its responsiveness of 10 degrees, it also can be used as an outcome measurement. Manual muscle testing is derived from the Medical Research Council scale and designed for patients with neurologic disorders. It is frequently employed by rheumatologists for strength assessment, although its reliability has not been proved for patients with rheumatoid disorders. Quantitative methods of maximal isometric strength measurement with hand-held dynamometers have shown good reliability in patients with RA.5,6 Hand-grip strength can be measured reliably with a hydraulic hand dynamometer.7 Gait velocity, calculated by the time to walk a specific distance, is commonly measured to assess walking functional mobility8 and serves as a test of lower extremity function. “Timed up and go” tests the basic mobility skills of frail elderly patients. It measures the time it takes a patient to rise from an arm chair of 46 cm seat height and 65 cm arm height, walk for 3 m, return to the chair, and sit down.9 To measure multiple dimensions of physical functions of older adults, a physical performance test including the following tasks was designed: writing a sentence, simulating eating, lifting a book and putting it on a shelf, putting on and removing a jacket, picking up a penny from the floor, turning 360 degrees, walking a distance of 50 feet, and climbing stairs.10 This scale is based on performance and combines assessments of lower extremity strength, gait, balance, and activities of daily living. The most often used patient-oriented measure of activities of daily living in rheumatology is the disability index of the Health Assessment Questionnaire (HAQ). The original (full) HAQ covers five dimensions of health outcomes and was developed specifically for use among adults with arthritis.11 It has since been used for a wide range of populations. The HAQ also has been modified into a version with a reduced number of items (MHAQ) and a disease-specific version (RA-HAQ). Further general activities of daily living measures are the Katz index of activities of daily living and the MacMaster Toronto Arthritis Preference Disability Questionnaire (MACTAR). The MACTAR is unique in that it allows patients to choose which activities are important to them. There is a wide range of patient-oriented, disease-specific measures of function and measures of symptoms such as pain, psychological status and well-being, fatigue and sleep, and quality of life.12 The numerous measures make it difficult for clinicians and researchers to select the most appropriate measure for their purpose. A possible solution to this problem is the adoption of the ICF as a common reference framework of functioning. It provides a clear picture of which health domains are addressed by each of the measures. This information seems far more valuable when selecting a measure with a specific purpose than using the umbrella term under which the measure was allocated because it is information on the content and clinical validity of the instrument. Linking rules have been established to link technical and clinical measures, health status measures, and interventions to the ICF.4 Assessment of Work Capacity The ultimate goal of rehabilitation is to enable patients to return to work or to achieve independence and social reintegration. Return to work requires an evaluation of permanent

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impairment, which is the responsibility of the physician. In the United States, the American Medical Association’s guide to the evaluation of permanent impairment is the most commonly used source for assessing and rating an individual’s permanent impairments. This guide has been the focus of considerable controversy, however. Critics have focused on internal deficiencies, including the lack of a comprehensive, valid, reliable, unbiased, evidence-based system for rating impairment, and on the fact that the impairment rating does not reflect the actual loss of function.13 Because of these shortcomings of the traditional medical measures, new assessment systems, called functional capacity evaluations (FCEs), have been developed. FCEs consist of a standardized battery of functional tests that purport to measure a patient’s physical ability for work-related activity. Physical capacity as found in the FCE testing is compared with the physical demands required in the patient’s occupation. Numerous FCEs are currently available and in use. Some are based on computerized devices, such as Blankenship, BTE functional testing system, or ERGOS work simulator. The Isernhagen Work System and EPIC lift capacity test use clinical observation and findings in their functional tests to evaluate physical capacity. The results of such assessments have enormous financial and social implications for the patient and for society. Consequently, these assessments and the resulting conclusions have to be reliable and valid. A comparison of four frequently used FCEs has shown good reliability only for the Isernhagen Work System.74 Because there is conflicting evidence regarding the validity of FCEs,14 further research is needed. It is unclear, however, if it is ever going to be possible to use physical factors alone to predict a safe return to work because contextual factors, such as the level of education, occupation, income, job satisfaction, state of the economy, and geographic location, greatly influence a patient’s ability to return to work.

COMPONENTS OF PHYSICAL MEDICINE AND REHABILITATION IN RHEUMATIC DISEASE IN RELATION TO INTERNATIONAL CLASSIFICATION OF FUNCTIONING, DISABILITY AND HEALTH BODY FUNCTIONS AND STRUCTURES Rest Bed rest or immobilization of joints with splints is often used to treat joint inflammation resulting from injuries or inflammatory arthropathies. Resting the affected joint may alleviate pain; however, prolonged rest also may lead to muscle atrophy and decreased joint mobility owing to arthrogenic and capsular contractures or shortening of muscles and myogenic contractures. Rest is recommended for only short periods, typically 12 to 24 hours for acute pain and inflammatory signs, after which active and passive joint motion and exercises should be resumed. Rest can be prescribed for the whole body (e.g., bed rest), for some parts of the body (e.g., immobilization of an arm with a mitella), or for joints (e.g., casts and splints). Bed rest is often used for diseases that affect the whole body (e.g., systemic inflammatory diseases to reduce

systemic inflammation). Bed rest is even more frequently used in general practice for patients with back pain because many individuals get some relief from low back pain and sciatica (pain down the back and leg) by lying down. Patients with acute low back pain who are advised to rest in bed have more pain, however, and are usually less able to perform everyday activities than patients who are advised to stay active.15,16 Nevertheless, patients with sciatica have shown similar results from staying in bed as for staying active. Manual Therapy Passive Manipulation and Mobilization. Manipulation is a sudden movement of low amplitude. It is performed at the end of the joint range at such a speed that the patient is unable to prevent it. Mobilization is a passive movement technique that is performed so that the patient can control the movements at all times. Manipulation and mobilization are performed as low-velocity, small-amplitude or large­amplitude passive movement techniques. The aim of these techniques is to restore joint function. These techniques are frequently used with patients who have spinal problems. The evidence found in meta-analyses did not favor manipulation or mobilization done alone or in combination with various other physical medicine agents in the treatment of mechanical neck disorder.17,18 There was strong evidence for the ­ benefits of multimodal care, including mobilization or manipulation or both plus exercise, regarding pain relief, functional improvement, and global perceived effect. The authors were unable to determine whether exercise was the active ingredient or not.18 There is no evidence that spinal manipulative therapy is superior to other standard treatments for patients with acute or chronic low back pain.17 Trigger Point Therapy. Acute or chronic muscle pain is a frequent problem in rehabilitation and is often diagnosed as a myofascial pain syndrome that is associated with discrete, focal, hyperirritable spots located in a taut band of skeletal muscle. Often a twitch response can be elicited in the muscle by palpation of the most tender spot of the taut band. These so-called trigger points may generate referred pain that is felt in different, usually distal sites. Chronic muscle overload, repetitive microtrauma, direct trauma to the region, and stress may lead to the activation of trigger points. Several hypotheses have been proposed to explain trigger points. The most recent theory is that trigger points are “overactive” muscle spindles. Treatment techniques consist of ischemic compression and are often accompanied by isotonic contractions of the affected muscle, local manual stretching of the affected muscle, myofascial release technique, and instruction of musclespecific self-stretches. Trigger points also can be inactivated by inserting a needle into them. A local twitch response, provocation of referred pain, and subsequent relaxation of the taut band indicate the successful application. In chronic conditions, the factors causing the twitch response must be addressed and if possible corrected. Exercises are strongly recommended to strengthen weak muscles and prevent further overload. The effectiveness of trigger point therapy in the treatment of myofascial pain syndrome is not yet supported by controlled or blinded studies.

PART 8 

Massage and Lymph Drainage. Massage is a common technique used for the rehabilitation of patients with musculo­ skeletal disorders.19,20 It can relieve muscle spasms and reduce pain and stiffness.21 Additionally, a massage decreases blood pressure, relaxes muscles, and increases the blood flow in muscles and the lymph flow. Massage can be used in a classic form with gliding movements, kneading, and percussion. Although gliding movements and kneading are helpful for muscle relaxation, improving circulation and reducing edema, percussion is mostly used for chest therapy. Lymph drainage is a special form of massage to increase lymph flow and to decrease edema.22 Massage also can be applied as deep friction massage to break up adhesions in muscles, tendons, or ligaments or as soft tissue mobilization or myofascial release techniques. The latter techniques are used as an adjunct to passive stretching for reduction of contractures. A special type of massage is the connective tissue massage (Bindegewebsmassage), which is mostly used in European countries. Connective tissue massage is applied to facilitate changes in the autonomic nervous system over cutaneovisceral reflexes. With this special technique, the therapist tries to influence organs whose innervation corresponds to cutaneous dermatomes. Massages are contraindicated over malignant tumors, open wounds, thrombophlebitis, and infected tissues. Lymph drainage should be avoided in patients with con­gestive heart failure. Exercise The rationale for advocating exercise is to overcome the consequences of prolonged rest. Exercise is part of the evidence-based recommendations for the treatment of various rheumatic diseases, such as osteoarthritis, RA, spondyloarthritis, and back pain.23-26 Despite such evidence, implementation of exercise in daily practice is often neglected, however. Pain attitudes and biomechanical beliefs of the treatment provider influence exercise prescription, and pain intensity is used as a guideline to determine exercise intensity. Such low-intensity exercise may not provide the required training stimuli to achieve an improvement in strength and joint function. In patients with back pain, it may lead to overt pain behavior. Exercise techniques can be classified into nonresistive and resistive exercises. Nonresistive exercises include rangeof-motion exercise and aerobic exercise. Resistive exercises are strengthening exercises that may be isotonic, isometric, or isokinetic. Range-of-Motion Exercise. Range-of-motion exercise can be progressed from passive to active assisted to active exercises. With passive exercises, a therapist or assistive device moves the joint without any muscle contraction exerted by the patient. In active-assisted exercises, the patient exerts some muscle contraction while attempting joint movement, but is assisted in achieving the desired range. In active exercises, the individual exerts his or her own muscle activity to achieve the desired range of motion. Aerobic Exercise. Aerobic exercise includes any type of exercise performed at moderate levels of intensity for extended periods. It includes walking, running, hiking, cycling,

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s­ wimming, inline s­kating, and stair climbing. The aim of aerobic exercise is to increase endurance so that patients can do activities longer without feeling tired. Aerobic exercises are recommended for patients with systemic lupus erythematosus.27 Aerobic exercises have been shown to have a positive effect on cardiovascular diseases and excess weight and on various rheumatic disease, such as fibromyalgia,28 RA,29 and ankylosing spondylitis.30 Strengthening Exercises. In strengthening exercises, a force from a therapist, free weights, or a machine applies resistance in opposition to the attempted movement of a specific muscle group by the subject. Resistance can be increased in strengthening exercises over time as muscle strength improves. The types of strengthening exercises are isometric or dynamic isotonic and isokinetic. Isometric (or static) exercise is performed without a change in joint range or muscle length. Isometric exercise causes the least strain on joints and places less strain on the cardiovascular system than dynamic exercise. Isotonic exercise consists of muscle shortening (concentric) and muscle lengthening (eccentric) contractions. This form of strengthening has not been recommended for patients with inflamed joints. In view of the newly emerging scientific evidence of the usefulness of high-intensity exercise, however, these recommendations must be reviewed. Isokinetic exercise involves movement through a fixed range of motion at a fixed rate of motion (velocity) against variable resistance that matches exactly the force generated by the patient at any point in the range. The stronger the force applied by the user, the greater is the resistance supplied. Equipment providing the latter type of accommodating resistance (e.g., Cybex system) is highly sophisticated and expensive. This equipment also can provide a printout of the torque developed during the exercise activity. Home-based Exercises. The term self-management emphasizes the responsibility of the individual patient in the management of the disease. Home-based self-care emphasizing exercise is part of the self-management process. It is regarded as essential for the successful management of ankylosing spondylitis. Patients receiving this advice significantly improved self-efficacy for exercise, self-reported mobility, and levels of exercise, and revealed a tendency to improve function compared with a control group.31 Consistent home-based exercise programs also can have a sustained effect on muscle strength and bone mass density for patients with early RA even at 5-year follow-up without having detrimental effects to joint structures or disease ­activity.32 Aquatic Exercise. Bathing in water (balneotherapy or spa therapy) has a long-standing tradition in the management of musculoskeletal disorders. Its effect is attributed to the physical properties of water resulting in biomechanical changes, such as joint unloading and relaxation. Further expected effects are physiologic changes, such as increased diuresis and hemodilution. A systematic review of randomized controlled trials investigating balneotherapy acknowledged the positive findings reported in most trials. Owing to insufficient scientific evidence, however, a

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conclusion about the efficacy of balneotherapy for patients with ­arthritis could not be reached.33 Aquatic therapy is a subgroup of ­balneotherapy and consists of exercises in a hot water pool. The recommended water temperature is 33°C to 34°C (92°F to 94°F). Aquatic therapy combines the benefits of balneotherapy and exercise. Exercising and independent walking are p­ossible because of the buoyancy and support of the water, even when walking aids or assistance is required on dry land. The additional benefit of the water could be an explanation for the improved muscle strength in the lower limbs of women with fibromyalgia exercising in waist-high water, while the strength of other muscles did not change. Additional benefits were improvements in pain and health-related quality of life.34 A comparison of the effects of deep water running and land-based exercises in women with fibromyalgia showed no differences in aerobic gain, but did show more advantages related to emotional aspects.35 Patients with osteoarthritis achieved more functional gains with water-based and land-based exercise programs than a control group36; pain relief was better with aquatic exercise.37 High-Intensity versus Low-Intensity Exercise. The applicability of high-intensity exercises for patients with RA and osteoarthritis has long been questioned because of concerns about accelerating joint damage. Treatment recommendations for these patients traditionally consisted of exercise restriction or exercise programs limited to non–weightbearing isometric exercises and range-of-motion exercises. There is growing evidence, ho­wever, that intensive exercise programs are more effective than conservative treatment in improving the muscle strength and functional ability of patients with RA.38,39 Patients with preexisting extensive large joint damage should be advised to refrain from ­activities that excessively strain the damaged joints because high-intensity, weight-bearing exercises seem to accelerate joint damage.40 Despite this evidence, physical therapists were the least positive about outcomes of high-intensity exercise programs as part of the treatment of RA patients, whereas rheumatologists were the most positive.41 There is insufficient evidence to draw any conclusions regarding the intensity of an exercise therapy program for individuals with osteoarthritis.42 Physical Modalities Heat and Cold.  Heat and cold modalities have been used for many years in the treatment of musculoskeletal disorders43 despite the paucity of adequate randomized controlled clinical studies. Heat can be applied by radiation (infrared light), cond­uction (hot packs, paraffin, or water) or conversion of another form of energy to heat (diathermy or ultrasound). Radiation and conduction are forms of superficial heat, whereas deep heating is achieved by conversion. These techniques must be used with caution to avoid burns. Hot water bottles should be filled with warm, but not boiling, water. Timers should be used with heating pads; application of the heating pad should not exceed 20 minutes. A s­uggested approach is to alternate between 20 m­inutes using heating pads and 20 minutes without a heating pad. Superficial heat can increase the threshold for pain, produce analgesia by acting on free nerve endings,

and decrease muscle spasm. A more recent review of the effects of superficial heat on low back pain showed moderate e­vidence for heat therapy providing a small short-term reduction in pain and disability.44 For patients with degenerative joint diseases or with soft tissue syndromes without prominent inflammation, heat is usually well tolerated and helpful. It is contro­versial, ho­wever, whether heat should be used to treat patients with inflammatory diseases. Heat therapy is contraindicated for patients with acute arthritis because it causes increased and sustained inflammation and pain. Nevertheless, heat may be helpful for patients with moderate joint infl­ammation, where it can reduce pain and muscle spasm and increase joint mobility by decreasing adhesive processes in the joint capsules. Paraffin wax baths might be a suitable treatment method for these patients.45 Besides patients with acute arthritis, heat therapy is contraindicated or precautions have to be taken in patients with acute trauma or he­morrhage, insensitivity, severe ischemia in peripheral occlusive disease and varicose veins, and for patients who cannot communicate feelings of discomfort (comatose or demented patients). Ice is useful to control pain and swelling because it induces a vasoconstriction of superficial and intra-articular tissues, reduces local metabolism and slows nerve co­nduction. It may be applied using cold packs, ice massages or ice baths and vapocoolant sprays. In knee osteoarthritis, administration of ice massages had significant effects on range of motion and the function and strength of the quadriceps muscle. Cold packs decreased knee edema.46 In RA, cryotherapy showed no significant effects on objective me­asures, including the swelling of joints, pain, range of motion, grip strength, and hand function.47 A more recent review found insufficient evidence to evaluate the effects of ice in patients with low back pain.44 Complications of cryotherapy in RA or osteoarthritis patients include frostbites, cold-induced urticaria, and nerve damage. Cryotherapy should be used with caution in patients with Raynaud’s phe­nomenon or with cryoglobulinemia. Electrotherapy.  Electrotherapy is the use of electricity as a therapeutic agent to stimulate nerves and muscles and to alleviate pain. El­ectricity is mostly applied by surface electrodes. Only electroacupuncture and dorsal horn stimulation use needle electrodes percutaneously. The types of currents used for electrotherapy include direct continuous galvanic currents and modulated direct currents. Galvanic currents slow down pain conduction in slow unmyelinated nerve fibers (C fibers) to reduce pain. Modulated middle-frequency electrotherapy is based on the gate control theory of pain. This current leads to an inhibition of pain-related potentials at the spinal and supraspinal le­vels. Basically, the electric stimulation of the fast-conducting myelinated nerve fibers can partially decrease pain through inhibition of pain impulses carried more slowly by u­nmyelinated fibers. The faster impulses arrive at the level of the dorsal horn first and “close the gate.” The gate control principle works with all classic forms of electro­therapy and with transcutaneous electrical nerve sti­mulation (TENS). The advantage of TENS devices is their small size because they can be worn by the patient and used when and where desired.

PART 8 

Common indications for TENS are musculoskeletal pain, post-traumatic or postsurgical pain, peripheral nerve injury, neuropathic pain, phantom limb pain, and sympathetically mediated pain. Electrotherapy should not be used on patients with cardiac pacemakers or implanted cardiac defibrillators. It can be used with caution on patients with atrophic skin. The effectiveness of TENS is still controversial. Concerning low back pain, the evidence is inconsistent,48 whereas in knee osteoarthritis, TENS was shown to be more effective in pain reduction than placebo. Knee stiffness also improved significantly in the active treatment group.49 Conflicting results were found using TENS for treating RA in the hand. Rest pain decreased, and muscle power scores increased, but no differences were found for grip pain or for the number of tender joints.50 Concerning patients with chronic pain, there is insufficient evidence about the effectiveness of TENS.51 Based on all of these study results, large randomized controlled trials are urgently needed in all fields of rheumatic pain. Ultrasound. Ultrasound is a special form of heating. It interacts with skin, fat, muscles, and bones during treatment. Heating occurs mostly at tissue interfaces. The most important interfaces where heating occurs are the bone–soft tissue interfaces that are well reached with ultrasound. Ultrasound may penetrate 7 to 8 cm of fat, but less than 1 mm of bone, depending on what energy level and which frequency is chosen. In practice, ultrasound with frequencies of 0.1 to 1 MHz can produce an increase of temperature of 4°C to 5°C at depths of 7 to 8 cm. Ultrasound is used for patients with localized musculoskeletal pain secondary to tendinitis or osteoarthritis of various joints.52 Ultrasound may be used in RA. A review found evidence that continuous ultrasound increases grip strength, decreases morning stiffness, and reduces the number of swollen and tender joints.53 Contraindications for a treatment with ultrasound are the same as for heat therapy. Ultrasound should not be applied over fluidfilled cavities, such as eyes and gravid uterus. The presence of metal is not a contraindication for ultrasound therapy. Several studies did not find an elevation of temperature beyond the degree that is expected if no metal is present.54-56 Orthotics.  Orthotic devices include braces, splints, corsets, collars, and shoe modifications. An orthosis may restore lost function or may help to maintain optimal function by altering b­i­o­mechanics and reducing pain. Orthotic devices decrease forces passing through painful weight-bearing joints, s­tabilize subluxating joints, improve motion patterns, and maximize functional positioning. The key to the succ­essful prescription and use of orthotics is the identification of the functional limitations (on all ICF levels) and working with the patient to adjust the orthotic. The devices can be simple and inexpensive, but also may be specially designed and consequently expensive. The occupational therapist is the specialist in these questions. Braces. Braces are external devices to support or stabilize body parts and joints. Few studies have been done to evaluate the effect of bracing of the knee joint. A randomized controlled trial showed marginal effects for patients with unicompartimental osteoarthritis with braces intended to

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reduce load. Pain severity and knee function scores were only borderline significant in the treatment group.57 Subgroup analysis showed a better effect in varus osteoarthritis, in patients with severe osteoarthritis or secondary osteoarthritis and in patients younger than 60 years. A Cochrane review in 2005 concluded that there was limited evidence for the a­rgument that braces have additional beneficial effects concerning Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and other functional tests compared with me­dical treatment alone in knee osteoarthritis.58 A major problem with braces is that patients with knee osteoarthritis do not adhere in the long-term to this special kind of conservative treatment. Splints.  Splints are often used in the treatment of patients with RA to decrease pain or swelling or to prevent ­deformity or both. Resting or dynamic hand splints, wrist supports, and finger splints (custom-made plastic splints, silver ring splints) are used. Special shoes or shoe inserts also are used to support the foot. Two randomized, controlled trials found that resting hand splints are effective for pain relief and improving grip strength. Patients with RA are more likely to prefer soft splints.59,60 In a broad Cochrane review from 2003, evidence was found that wearing working wrist splints decreased grip strength significantly and did not affect pain scores, morning stiffness, pinch grip, or quality of life for 6 months. There was no evidence found that resting hand or wrist splints changed pain, grip strength, or the number of painful or swollen joints. Patients using these splints for more than 2 months reported, however, that they preferred use to nonuse. The reviewers found some evidence that shoe insoles or special shoes decreased foot pain on weight-bearing activities. Insoles also may prevent progression of hallux valgus angle, but they did not affect pain or function.61 In osteoarthritis, splints are mostly used to treat osteoarthritis of the thumb base. These special splints may reduce pain and improve function and grip strength.62,63 As with braces, the major problem in treating patients with splints is long-term adherence to the devices. Corsets and Collars.  Subluxation of the atlantodental joint can occur in RA. If surgery is not applicable, cervical collars may be prescribed. Cervical collars include soft collars, the Philadelphia co­llar, and the sterno-occipitomandibular plaster immobilization. None of these cervical orthoses provides a high level of mechanical restriction of motion, and all are ineffective in preventing pathologic displacements.64,65 Patients with night pain resulting from a cervical disk syndrome may profit, however, from wearing a soft collar during night. Corsets and abdominal binders may give some stability to patients with back pain. They may assist weak ­abdominal muscles, but they do not replace any abdominal muscle exercises. In cases of stable fractures of the lumbar spine, three-point corsets are useful to relieve pain and to stabilize the lumbar spine. ACTIVITIES AND PARTICIPATION All necessary measures have to be taken to minimize the limitation of activity and restriction of participation that has been caused by underlying problems in body function or structure.

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Such measures include the appropriate selection of assistive and mobility devices and patient education and its implementation in comprehensive treatment programs using an interdisciplinary approach. Work hardening and vocational rehabilitation programs focus on a return to work, whereas cognitive behavioral treatment programs aim to overcome dysfunctional pain behavior and resulting disability. Assistive Devices A vast variety of assistive devices serve to reduce disability. If necessary, an experienced occupational therapist can assess which devices are appropriate for a patient. Dressing aids, such as button hooks, long-handled reachers, and sock aids, may be recommended. High toilet seats, safety bars on the bathroom wall, and bath seats or bath lifts may aid in daily hygiene. Various kitchen aids may simplify kitchen work and eating (e.g., big handles on knives, forks, and spoons; knives with vertical grip for cutting bread or meat; electric opener for bottles). Mobility Devices Mobility devices, such as canes, crutches (axillary, forearm, and platform), wheeled walkers, and wheelchairs, are used when the ability to walk is limited by lower extremity joint instability, pain, weakness, and fatigue or balance problems. These devices are easily accessible and provide immediate assistance, but they also require more physical effort than normal ambulation. The choice of a mobility device is based on the impairment and the resulting disability. Before selecting a device, the patient should be evaluated to define whether one or both upper extremities are required to achieve balance, to reduce pain, or to bear weight. Patients requiring only one upper extremity can use a cane, whereas patients requiring both upper extremities are best served by forearm crutches or walkers.66 A single-point cane can bear about 25% of the body weight, whereas axillary or forearm crutches can bear about 50%. A wheeled walker can bear weight more than 50% of the body weight.67 About 50% of patients with osteoarthritis or RA possess a walking aid.68 Possession was associated in RA patients with age, disease education, frequency of pain. and disability and in osteoarthritis patients with age and disability. About one third did not use their walking aid. Forearm crutches usually are prescribed, but for RA patients with hand or wrist problems, platform crutches are more su­itable because the hand or wrist has to bear no weight when this device is used. Because strain on the shoulder increases when crutches are used, shoulder joint stability, arm strength, and coordination are needed to use them. Less strain on the shoulder joint occurs when using a walker.69 The advantage of walkers is that they are more stable, but they are cumbersome, are difficult to maneuver, and cannot be used on stairs. Wheelchairs are necessary if patients are unable to walk with canes, crutches, or wheelers,70 such as after an operation or when patients are too frail because of the underlying disease or condition. In these cases, a wheelchair can improve the quality of life by maintaining some mobility. Individuals unable to handle a wheelchair manually can profit from electric ones. The main problems for patients with wheelchairs are accidents (falls, crashes). Accidents occur mostly while traversing ramps, sidewalks and streets,

or while transferring in or out of the wheelchair. Another big issue with wheelchair use is the need for modifications of houses and apartments. Patient Education Patient education is defined as a set of planned educational activities designed to improve patient’s health behaviors or health status or both. The classic model states that knowledge, beliefs and attitudes, coping skills, and perceived self-efficacy increase individuals’ preventive behavior (e.g., exercise, diet, joint protection). Patient education has been and is applied in various forms. It is an integral part of work hardening and cognitive behavioral programs. It also can be applied as an intervention by itself as a formal patient education program, as done in the original Swedish back school, which was intended to reduce the pain and prevent recurrences of episodes of low back pain by providing information on the anatomy of the back and biomechanics and teaching optimal posture, ergonomics, and back exercises. A meta-analysis found moderate evidence suggesting that back schools, in an occupational setting, reduce pain and improve function and the return-to work status for patients with chronic and recurrent low back pain. The most promising interventions consisted of a modification of the Swedish back school and were quite intensive.71 Patient education programs also have been developed for patients with RA. The focus of these programs is to teach patients to adjust their everyday activities according to disease symptoms. Patient education as provided in the studies reviewed in a meta-analysis had small short-term effects on disability, joint counts, patient global assessment, psychological status, and depression. There was no evidence of long-term benefits in adults with RA.72 Vocational Rehabilitation Work disability is a major consequence of rheumatic diseases and may result in loss of employment. Vocational rehabilitation contains an interdisciplinary approach aimed at the maintenance of gainful employment. The organization and content of vocational rehabilitation varies among countries. A common feature is the assessment of the problems at work and the development of individual solutions. Studies have shown that vocational support may prevent or delay work disability73,74 or improve fatigue and mental health.75 Work Hardening and Functional Restoration Programs There is growing evidence that in many musculoskeletal diseases, factors other than tissue damage and resulting pain are responsible for permanent disability. Psychosocial factors such as personal beliefs and fear avoidance and social factors such as family, work, and the wider social network especially influence the development and maintenance of symptoms and have an impact on work disability. On the basis of this evidence, work hardening programs76 and functional resto­ration programs,77 emphasizing an improvement in function and not primarily pain relief, were developed with the intention of overcoming the dysfunctional illness behavior and implementing ergonomic and social interventions to facilitate a return to work. This shift in paradigm

PART 8 

from pain-centered to function-centered treatment requires a rethinking of widespread habits and convictions. Many different professions became involved in the treatment of the injured worker. This diversity of providers and philosophies led to inconsistent definitions of programs. In an attempt to develop consistency in a wide variety of programs, the Commission on Accreditation of Rehabilitation Facilities defined and developed standards for work hardening practice.78 The Commission on Accreditation of Rehabilitation Facilities definition as defined in the 1989 Standards Manual is as follows: Work hardening is a highly structured, goal-oriented, individualized treatment program designed to maximize the individual’s ability to return to work. Work hardening programs are interdisciplinary in nature with a capability of addressing the functional, physical, behavioral, and vocational needs of the individuals served. Work hardening provides a transition between the initial injury management and return to work, while addressing issues of productivity, safety, physical tolerances, and work behavior. Work hardening programs use real or simulated work activities in a relevant environment in conjunction with the physical conditions of jobs. These activities are used to improve progressively the biomechanical, neuromuscular, cardiovascular/metabolic, behavioral, attitudinal, and vocational function of the individual served.78 Until the end of the 20th century, there was contradictory evidence whether vocational outcomes can be improved by exercises or an intensive multidisciplinary biopsychosocial intervention.79,80 Two more recently published meta-analyses found strong evidence, however, that sick days can be reduced by exercise.81,82 Cognitive Behavioral Treatment Cognitive behavioral treatment is based on the same rationale as work hardening programs. It also acknowledges that pain and its resulting disability are not only influenced by somatic pathology, but also by psychological and social factors. In general, three behavioral treatment approaches are distinguished: operant, cognitive, and respondent. The primary focus is to reduce disability. A review of 21 studies did not find any significant differences between the various types of cognitive behavioral treatments; also, the cognitive behavioral treatments did not differ from exercise. A conclusion regarding whether clinicians should refer patients with chronic low back pain to behavioral treatment programs or to active conservative treatment was not possible.83 CONTEXTUAL FACTORS Environmental and personal factors can be either barriers or facilitators to achieve independence and social integration of a patient. Health ergonomics and “barrier-free design” address these issues and must be integrated in a comprehensive rehabilitation approach. Anema and colleagues84 showed that ergonomic interventions, such as adaptation of the workplace, job tasks, and working hours, were effective on return to work of individuals who had been certified unfit for work long-term because of low back pain. Barrier-free design, a ramp that bypasses steps, may be necessary to enable a wheelchair-bound patient to return to the workplace. Because this solution may result in separate and

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stigmatizing solutions, the concept of universal design was developed. It aims to enable a wide group of individuals to use products and to give access to the built environment. In view of the increasing older population, there is a future need for the greater development and use of universal design in all aspects of the built environment.85 This is in accordance with the wider view of rehabilitation not only including the training of disabled individuals, but also intervening in the general systems of society and adaptations of the environment. REFERENCES    1. Ustun TB, Chatterji S, Bickenbach J, et al: The International Classification of Functioning, Disability and Health: A new tool for understanding disability and health. Disabil Rehabil 25:565-571, 2003.    2. World Health Organization: International Classification of Functioning, Disability and Health: ICF. Geneva, WHO, 2001.    3. Stucki G, Ewert T, Cieza A: Value and application of the ICF in rehabilitation medicine. Disabil Rehabil 25:628-634, 2003.    4. Cieza A, Geyh S, Chatterji S, et al: ICF linking rules: An update based on lessons learned. J Rehabil Med 37:212-218, 2005.    5. Stucki G, Schonbachler J, Bruhlmann P, et al: Does a muscle strength index provide complementary information to traditional disease activity variables in patients with rheumatoid arthritis? J Rheumatol 21:2200-2205, 1994.    6. Stoll T, Bruhlmann P, Stucki G, et al: Muscle strength assessment in polymyositis and dermatomyositis evaluation of the reliability and clinical use of a new, quantitative, easily applicable method. J Rheumatol 22:473-477, 1995.    7. Bohannon RW, Schaubert KL: Test-retest reliability of grip-strength measures obtained over a 12-week interval from community-dwelling elders. J Hand Ther 18:426-427; quiz 428, 2005.    8. Ward MM: Clinical measures in rheumatoid arthritis: Which are most useful in assessing patients? J Rheumatol 21:17-27, 1994.    9. Podsiadlo D, Richardson S: The timed “Up & Go”: A test of basic functional mobility for frail elderly persons. J Am Geriatr Soc 39: 142-148, 1991.  10. Reuben D, Siu A: An objective measure of physical function of elderly outpatients: The physical performance test. J Am Geriatr Soc 38:11051112, 1990.  11. Fries JF, Spitz P, Kraines RG, et al: Measurement of patient outcome in arthritis. Arthritis Rheum 23:137-145, 1980.  12. Katz P: Patient outcomes in rheumatology: A review of measures. Arthritis Care Res 495(5)[Suppl]:15-233, 2003.  13. Cocchiarella L, Turk MA, Andersson G: Improving the evaluation of permanent impairment. JAMA 2834:532-533, 2000.  14. Gouttebarge V, Wind H, Kuijer PP, et al: Reliability and validity of Functional Capacity Evaluation methods: A systematic review with reference to Blankenship system, Ergos work simulator, Ergo-Kit and Isernhagen work system. Int Arch Occup Environ Health 77: 527-537, 2004. 15. Hagen KB, Jamtvedt G, Hilde G, et al: The updated Cochrane review of bed rest for low back pain and sciatica. Spine 30: 542-546, 2005.  16. Vroomen PC, de Krom MC, Wilmink JT, et al: Lack of effectiveness of bed rest for sciatica. N Engl J Med 340:418-423, 1999. 17. Assendelft WJ, Morton SC, Yu EI, et al: Spinal manipulative therapy for low back pain. Cochrane Database Syst Rev 1:CD000447, 2004.  18. Gross AR, Hoving JL, Haines TA, et al: A Cochrane review of manipulation and mobilization for mechanical neck disorders. Spine 29:1541-1548, 2004. 19. Haraldsson BG, Gross AR, Myers CD, et al: Massage for mechanical neck disorders. Cochrane Database Syst Rev 3:CD004871, 2006.  20. Weerapong P, Hume PA, Kolt GS: The mechanisms of massage and effects on performance, muscle recovery and injury prevention. Sports Med 35:235-256, 2005.  21. Zainuddin Z, Newton M, Sacco P, et al: Effects of massage on delayedonset muscle soreness, swelling, and recovery of muscle function. J Athl Train 40:174-180, 2005.

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 22. Bernas M, Witte M, Kriederman B, et al: Massage therapy in the treatment of lymphedema: Rationale, results, and applications. IEEE Eng Med Biol Mag 24:58-68, 2005.  23. Abenhaim L, Rossignol M, Valat JP, et al: The role of activity in the therapeutic management of back pain: Report of the International Paris Task Force on Back Pain. Spine 25(Suppl):1S-33S, 2000.  24. Ottowa P: Ottawa Panel evidence-based clinical practice guidelines for therapeutic exercises in the management of rheumatoid arthritis in adults. Phys Ther 84:934-972, 2004.  25. Zhang W, Doherty M, Arden N, et al: EULAR evidence based recommendations for the management of hip osteoarthritis: Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 64: 669-681, 2005.  26. Zochling J, van der Heijde D, Burgos-Vargas R, et al: ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 65:442-452, 2006.  27. Tench C, Bentley D, Vleck V, et al: Aerobic fitness, fatigue, and physical disability in systemic lupus erythematosus. J Rheumatol 29: 474-481, 2002. 28. Sim J, Adams N: Systematic review of randomized controlled trials of nonpharmacological interventions for fibromyalgia. Clin J Pain 18:324-336, 2002. 29. Hakkinen A, Sokka T, Kotaniemi A, et al: A randomized twoyear study of the effects of dynamic strength training on muscle strength, disease activity, functional capacity, and bone mineral density in early rheumatoid arthritis. Arthritis Rheum 44:515-522, 2001. 30. Ince G, Sarpel T, Durgun B, et al: Effects of a multimodal exercise program for people with ankylosing spondylitis. Phys Ther 86:924-935, 2006. 31. Sweeney S, Taylor G, Calin A: The effect of a home based exercise intervention package on outcome in ankylosing spondylitis: A randomized controlled trial. J Rheumatol 29:763-766, 2002. 32. Hakkinen A, Sokka T, Kautiainen H, et al: Sustained maintenance of exercise induced muscle strength gains and normal bone mineral density in patients with early rheumatoid arthritis: A 5 year follow up. Ann Rheum Dis 63:910-916, 2004.  33. Verhagen AP, Bierma-Zeinstra SM, Cardoso JR, et al: Balneotherapy for rheumatoid arthritis. Cochrane Database Syst Rev 4: CD000518, 2003. 34. Gusi N, Tomas-Carus P, Hakkinen A, et al: Exercise in waist-high warm water decreases pain and improves health-related quality of life and strength in the lower extremities in women with fibromyalgia. Arthritis Rheum 55:66-73, 2006. 35. Assis MR, Silva LE, Alves AM, et al: A randomized controlled trial of deep water running: Clinical effectiveness of aquatic exercise to treat fibromyalgia. Arthritis Rheum 55:57-65, 2006. 36. Foley A, Halbert J, Hewitt T, et al: Does hydrotherapy improve strength and physical function in patients with osteoarthritis—a randomised controlled trial comparing a gym based and a hydrotherapy based strengthening programme. Ann Rheum Dis 62: 1162-1167, 2003.  37. Wyatt FB, Milam S, Manske RC, et al: The effects of aquatic and traditional exercise programs on persons with knee osteoarthritis. J Strength Cond Res 15:337-340, 2001.  38. van den Ende CH, Breedveld FC, le Cessie S, et al: Effect of intensive exercise on patients with active rheumatoid arthritis: A randomised clinical trial. Ann Rheum Dis 59:615-621, 2000.  39. de Jong Z, Munneke M, Zwinderman AH, et al: Is a long-term highintensity exercise program effective and safe in patients with rheumatoid arthritis? Results of a randomized controlled trial. Arthritis Rheum 48:2415-2424, 2003. 40. Munneke M, de Jong Z, Zwinderman AH, et al: Effect of a high-intensity weight-bearing exercise program on radiologic damage progression of the large joints in subgroups of patients with rheumatoid arthritis. Arthritis Rheum 53:410-417, 2005.  41. Munneke M, de Jong Z, Zwinderman AH, et al: High intensity exercise or conventional exercise for patients with rheumatoid arthritis? Outcome expectations of patients, rheumatologists, and physiotherapists. Ann Rheum Dis 63:804-808, 2004.  42. Brosseau L, MacLeay L, Robinson V, et al: Intensity of exercise for the treatment of osteoarthritis. Cochrane Database Syst Rev 2: CD004259, 2003.

 43. Nadler SF, Weingand K, Kruse RJ: The physiologic basis and clinical applications of cryotherapy and thermotherapy for the pain practitioner. Pain Physician 7:395-399, 2004. 44. French SD, Cameron M, Walker BF, et al: A Cochrane review of superficial heat or cold for low back pain. Spine 31:998-1006, 2006.  45. Dellhag B, Wollersjo I, Bjelle A: Effect of active hand exercise and wax bath treatment in rheumatoid arthritis patients. Arthritis Care Res 5:87-92, 1992. 46. Brosseau L, Yonge KA, Robinson V, et al: Thermotherapy for treatment of osteoarthritis. Cochrane Database Syst Rev 4:CD004522, 2003. 47. Robinson V, Brosseau L, Casimiro L, et al: Thermotherapy for treating rheumatoid arthritis. Cochrane Database Syst Rev 2: CD002826, 2002. 48. Khadilkar A, Milne S, Brosseau L, et al: Transcutaneous electrical nerve stimulation for the treatment of chronic low back pain: A systematic review. Spine 30:2657-2666, 2005. 49. Osiri M, Welch V, Brosseau L, et al: Transcutaneous electrical nerve stimulation for knee osteoarthritis. Cochrane Database Syst Rev 4:CD002823, 2000. 50. Brosseau L, Judd MG, Marchand S, et al: Transcutaneous electrical nerve stimulation (TENS) for the treatment of rheumatoid arthritis in the hand. Cochrane Database Syst Rev 3:CD004377, 2003. 51. Carroll D, Moore RA, McQuay HJ, et al: Transcutaneous electrical nerve stimulation (TENS) for chronic pain. Cochrane Database Syst Rev 3:CD003222, 2001.  52. Brosseau L, Casimiro L, Robinson V, et al: Therapeutic ultrasound for treating patellofemoral pain syndrome. Cochrane Database Syst Rev 4:CD003375, 2001. 53. Casimiro L, Brosseau L, Robinson V, et al: Therapeutic ultrasound for the treatment of rheumatoid arthritis. Cochrane Database Syst Rev 3:CD003787, 2002.  54. Brunner GD, Lehmann JF, McMillan J, et al: Can ultrasound be used in the presence of surgical metal implants: an experimental approach. Phys Ther Rev 38:823-824, 1958.  55. Skoubo-Kristensen E, Sommer J: Ultrasound influence on internal fixation with a rigid plate in dogs. Arch Phys Med Rehabil 63: 371-373, 1982.  56. Tanzer M, Kantor S, Bobyn JD: Enhancement of bone growth into porous intramedullary implants using non-invasive low intensity ultrasound. J Orthop Res 19:195-199, 2001. 57. Brouwer RW, van Raaij TM, Verhaar JA, et al: Brace treatment for osteoarthritis of the knee: A prospective randomized multi-centre trial. Osteoarthritis Cartilage 14:777-783, 2006. 58. Brouwer RW, Jakma TS, Verhagen AP, et al: Braces and ­orthoses for treating osteoarthritis of the knee. Cochrane Database Syst Rev 1:CD004020, 2005.  59. Haskett S, Backman C, Porter B, et al: A crossover trial of custommade and commercially available wrist splints in adults with inflammatory arthritis. Arthritis Rheum 51:792-799, 2004.  60. Callinan NJ, Mathiowetz V: Soft versus hard resting hand splints in rheumatoid arthritis: Pain relief, preference, and compliance. Am J Occup Ther 50:347-353, 1996. 61. Egan M, Brosseau L, Farmer M, et al: Splints/orthoses in the treatment of rheumatoid arthritis. Cochrane Database Syst Rev 1: CD004018, 2003.  62. Weiss S, Lastayo P, Mills A, et al: Splinting the degenerative basal joint: Custom-made or prefabricated neoprene?. J Hand Ther 17: 401-406, 2004. 63. Wajon A, Ada L: No difference between two splint and exercise regimens for people with osteoarthritis of the thumb: A randomised controlled trial. Aust J Physiother 51:245-249, 2005.  64. Bednar DA: Efficacy of orthotic immobilization of the unstable subaxial cervical spine of the elderly patient: Investigation in a cadaver model. Can J Surg 47:251-256, 2004.  65. Sandler AJ, Dvorak J, Humke T, et al: The effectiveness of various cervical orthoses: An in vivo comparison of the mechanical stability provided by several widely used models. Spine 21:1624-1629, 1996.  66. Van Hook FW, Demonbreun D, Weiss BD: Ambulatory devices for chronic gait disorders in the elderly. Am Fam Physician 67: 1717-1724, 2003.

PART 8   67. Youdas JW, Kotajarvi BJ, Padgett DJ, et al: Partial weight-bearing gait using conventional assistive devices. Arch Phys Med Rehabil 86: 394-398, 2005.  68. Van der Esch M, Heijmans M, Dekker J: Factors contributing to possession and use of walking aids among persons with rheumatoid arthritis and osteoarthritis. Arthritis Rheum 49:838-842, 2003.  69. Haubert LL, Gutierrez DD, Newsam CJ, et al: A comparison of shoulder joint forces during ambulation with crutches versus a walker in persons with incomplete spinal cord injury. Arch Phys Med Rehabil 87:63-70, 2006.  70. van der Woude LH, de Groot S, Janssen TW: Manual wheelchairs: Research and innovation in rehabilitation, sports, daily life and health. Med Eng Phys 28:905-915, 2006. 71. Heymans MW, van Tulder MW, Esmail R, et al: Back schools for non-specific low-back pain. Cochrane Database Syst Rev 4: CD000261, 2004. 72. Riemsma RP, Kirwan JR, Taal E, et al: Patient education for adults with rheumatoid arthritis. Cochrane Database Syst Rev 2: CD003688, 2003. 73. Allaire SH, Li W, LaValley MP: Reduction of job loss in persons with rheumatic diseases receiving vocational rehabilitation: A randomized controlled trial. Arthritis Rheum 48:3212-3218, 2003.  74. Nordmark B, Blomqvist P, Andersson B, et al: A two-year follow-up of work capacity in early rheumatoid arthritis: A study of multidisciplinary team care with emphasis on vocational support. Scand J Rheumatol 35:7-14, 2006. 75. de Buck PD, le Cessie S, van den Hout WB, et al: Randomized comparison of a multidisciplinary job-retention vocational rehabilitation program with usual outpatient care in patients with chronic arthritis at risk for job loss. Arthritis Rheum 53:682-690, 2005.

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 76. Matheson LN, Ogden LD, Violette K, et al: Work hardening: Occupational therapy in industrial rehabilitation. Am J Occup Ther 39: 314-321, 1985.  77. Mayer TG, Gatchel RJ: Functional Restoration for Spinal Disorders: The Sports Medicine Approach. Philadelphia, Lea & Febiger, 1991.  78. CARF: Standards Manual for Organizations Serving People with Disabilities. Tuscon, Ariz, Commission on Accreditation of Rehabilitation Facilities, 1989.  79. Brox JI, Hagen KB, Juel NG, et al: Is exercise therapy and manipulation effective in low back pain? Tidsskr Nor Laegeforen 119: 2042-2050, 1999.  80. Guzman J, Esmail R, Karjalainen K, et al: Multidisciplinary rehabilitation for chronic low back pain: A systematic review. BMJ 322:1511-1516, 2001. 81. Schonstein E, Kenny DT, Keating J, et al: Work conditioning, work hardening and functional restoration for workers with back and neck pain. Cochrane Database Syst Rev 1:CD001822, 2003. 82. Kool J, de Bie R, Oesch P, et al: Exercise reduces sick leave in patients with non-acute non-specific low back pain: A meta-anal­ ysis. J Rehabil Med 36:49-62, 2004. 83. Ostelo R, van Tulder M, Vlaeyen J, et al: Behavioural treatment for chronic low-back pain. Cochrane Database Syst Rev:CD002014, 2005.  84. Anema JR, Cuelenaere B, van der Beek AJ, et al: The effectiveness of ergonomic interventions on return-to-work after low back pain: A prospective two year cohort study in six countries on low back pain patients sicklisted for 3-4 months. Occup Environ Med 61:289-294, 2004.  85. Crews DE, Zavotka S: Aging, disability, and frailty: Implications for universal design. J Physiol Anthropol 25:113-118, 2006.

Part

9

RHEUMATOID ARTHRITIS

65

Etiology and Pathogenesis of Rheumatoid Arthritis GARY S. FIRESTEIN

KEY POINTS Rheumatoid arthritis (RA) is a complex disease involving numerous cell types, including macrophages, T cells, B cells, fibroblasts, chondrocytes, and dendritic cells. Several genes are implicated in susceptibility to RA and severity of disease, including class II major histocompatibility complex genes, PTPN22, and peptidylarginine transferases. Evidence of autoimmunity, including high serum levels of ­autoantibodies such as rheumatoid factors and anticitrullinated peptide antibodies, can be present for many years before the onset of clinical arthritis. Adaptive and innate immune responses in the synovium have been implicated in the pathogenesis of RA. Cytokine networks involving tumor necrosis factor, interleukin-6, and many other factors participate in disease perpetuation and can be targeted by therapeutic agents. Bone and cartilage destruction seem to be primarily mediated by osteoclasts and fibroblast-like synoviocytes.

Rheumatoid arthritis (RA) is the most common inflammatory arthritis, affecting 0.5% to 1% of the general population worldwide. Although the prevalence is constant across the globe, regardless of geographic location and race, there are some exceptions. In China, the occurrence of RA is lower (about 0.3%), whereas it is substantially higher in other populations, such as the Pima Indians in North America (about 5%). Because of its prevalence and the ready accessibility of joint samples for laboratory investigation, RA has served as a useful model for the study of many inflammatory and immune-mediated diseases. As such, the information gleaned from these studies has provided new and unique insights into the mechanisms of normal immunity. Although RA is properly considered a disease of the joints, abnormal immune responses can cause a variety of extra-articular manifestations. In some cases, production of rheumatoid factor (RF) with the formation of immune complexes that fix complement contributes to extra-articular findings. One of the mysteries of RA is why the synovium is the primary target.

Despite intensive work, the cause of RA remains unknown. Clues have been provided by detailed immunogenetic studies and the observation that underlying immunoreactivity antedates onset of arthritis by a decade. Progress in understanding the pathogenesis has been more robust. The roles of small molecule mediators of inflammation (e.g., arachidonic acid metabolites), autoantibodies, cytokines, growth factors, chemokines, adhesion molecules, and matrix metalloproteinases (MMPs) have been carefully defined. Synovial cells can exhibit behavior resembling a localized tumor, which invades and destroys articular cartilage, subchondral bone, tendons, and ligaments. Appreciation of these pathogenic mechanisms has increased awareness that irreversible loss of articular cartilage and bone begins soon after the onset of RA. Early interventions that suppress synovitis have a major impact on morbidity and mortality.

ROLES OF INNATE AND ADAPTIVE IMMUNITY IN ETIOLOGY AND PATHOGENESIS OF RHEUMATOID ARTHRITIS Many mechanisms of disease are considered in this chapter. Innate immunity, which is a primitive pattern-recognition system that can lead to rapid inflammatory responses, has been implicated through the engagement of Fc receptors by immune complexes and perhaps Toll-like receptors (TLRs) by bacterial products. Antigen-driven T cell and B cell responses also may participate as a result of either xenoantigen reactivity or, more likely, responses directed at numerous autoantigens described later in the chapter. Cytokine networks participate with paracrine and autocrine loops that maintain cellular activation in the synovial intimal lining. Finally, permanent alterations in some cell types might occur during the evolution of disease that can accelerate destruction. One potential synthesis of these data suggests that an induction phase, initiated by innate immunity, can “prepare” the joint for subsequent recruitment of inflammatory and immune cells (Fig. 65-1).1 Cigarette smoke, bacterial products, viral components, and other environmental 1035

1036

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Etiology and Pathogenesis of Rheumatoid Arthritis

Antigen presentation Cytokine production Autoantibodies

Environment (pathogens, etc) Genetics (HLA-DR, PTPN22, etc)

B

T

MΦ

PMN

Osteoclast activation Immune complexes Complement activation

DC

Innate immunity Antigen loading into DCs

MΦ

DC

FLS

Local inflammation Local antigen presentation

FLS

OC Migration to central lymphoid organs

Synovium

T

Lymph nodes Spleen T T and B cell migration to joint

DC

T

T B

Autoantibodies

Antigen presentation T and B cell activation Figure 65-1  Schematic diagram of disease mechanisms that likely occur in rheumatoid arthritis. Innate immunity activates fibroblast-like synoviocytes (FLS), dendritic cells (DC), and macrophages (MΦ) in the earliest phases in individuals with underlying immune hyperreactivity as evidenced by the production of autoantibodies. The genetic makeup of an individual, including the presence of certain polymorphisms in genes that regulate immune responses, and environmental exposures are required. DC can migrate to the central lymphoid organs to present antigen and activate T cells, which can activate B cells. These lymphocytes can migrate back to the synovium and enhance adaptive immune responses in the target organ. In ­addition, repeated activation of innate immunity can lead directly to chronic inflammation and possibly antigen presentation in the synovium. In the latter phases of disease, many cell types activate osteoclasts (OC) through the receptor activator of nuclear factor κB (NFκB)/receptor activator of NFκB ligand (RANK/ RANKL) system, although FLS and T cells likely provide the greatest stimulus. Autonomous activation of FLS also might contribute to this process.

s­ timuli can contribute to these responses. This process probably occurs often in normal individuals, but is self­limited. In some individuals, a predetermined propensity for immune hyperreactivity or autoreactivity might lead to a different outcome. The genome of these individuals encodes a variety of genes implicated in RA, including class II major histocompatibility complex (MHC) genes, protein tyrosine phosphatase-22 (PTPN22), cytokine promoter polymorphisms, population-specific genes (e.g., PADI4 in Japanese or Koreans), and other undefined genes. Abnormal T cell selection also could contribute by allowing autoreactive T cells to escape deletion. Immunoreactivity can be identified before clinical disease and can be manifested by the production of RFs and anticitrullinated peptide antibodies. When cells are recruited to the synovium, or even perhaps at extrasynovial sites, antigens can be processed by dendritic cells (DCs). They can present antigen in synovial germinal centers or, more likely, migrate to central lymphoid organs, where they can activate naive T cells through interactions with the T cell receptor (TCR) and costimulatory signals. T cells can help B cells produce pathogenic antibodies or migrate to the joint where they can influence other cells through the production of cytokines such as interleukin (IL)-17 or through nonspecific cell contact mechanisms that do not require a specific antigen.

Ultimately, a destructive phase proceeds, which can be antigen dependent and independent and supported by mesenchymal elements, such as fibroblasts and synoviocytes. Bone erosions are subsequently caused by osteoclasts,­ whereas cartilage dissolution results from proteolytic ­ en­z­ymes produced by synoviocytes in the pannus or synovial fluid neutrophils. Anti-inflammatory mechanisms, such as soluble tumor necrosis factor (TNF) receptors, suppressive cytokines, cytokine binding proteins, protease inhibitors, lipoxins (LXs), antioxidants, antiangiogenic factors, and natural cytokine antagonists, are not present in sufficient concentrations to truncate the inflammatory and destructive process. The only way to suppress this response is through therapeutic interventions that either modulate pathogenic cells or neutralize the effector molecules produced by the rheumatoid process, or restore tolerance. Although not proven, this general hypothesis takes into account many of the elements described by investigators in the field. The heterogeneity of mechanisms provides an explanation for the unpredictable response to therapeutic agents and allows clinicians to envision new therapeutic targets to prevent RA or interfere with the immunologic, inflammatory, or destructive components as separate but interrelated entities. Each of these mechanisms is discussed in detail in this chapter. Brief summaries of key points also are provided intermittently to help guide the reader through this complex maze.

PART 9 

ETIOLOGY OF RHEUMATOID ARTHRITIS Key Points • Genes play a key role in susceptibility to RA and disease severity. • Class II MHC genes, especially genes containing a specific 5-amino acid sequence in the hypervariable region of HLA-DR4, are the most prominent genetic association. • Newly defined genetic associations, including polymorphisms in PTPN22, PADI4, and many cytokines, suggest that the associations in RA are complex and involve many genes.

Although the etiology of RA is unknown, many studies ­suggest that a blend of environmental and genetic factors is responsible; both are necessary, but are insufficient alone for full expression of the disease. The most compelling evidence for a genetic component is in monozygotic twins, in whom the concordance rate is 12% to 15% when one twin is affected compared with 1% for the general population. The risk for a fraternal twin of a patient with RA also is high (about 2% to 5%), but this is not more than the rate for other first-degree relatives. Although the immunogenetics is, at best, incompletely understood, one of the best-studied and perhaps most influential genetic risk factors is the class II MHC haplotype of an individual. ROLE OF HLA-DR IN THE SUSCEPTIBILITY TO AND SEVERITY OF RHEUMATOID ARTHRITIS The structure of class II MHC molecules in antigen presenting cells is associated with increased susceptibility and severity of RA and accounts for about 40% of the genetic influence. A genetic link between HLA-DR and RA was initially described in the 1970s with the observation that HLA-DR4 occurred in 70% of RA patients compared with about 30% of controls, giving a relative risk of having RA of approximately 4 to 5 to individuals with HLA-DR4. The susceptibility to RA is associated with the third hypervariable region of DRβ-chains, from amino acids 70 through 74.2 The epitope is glutamine-leucine-arginine-alanine-alanine (QKRAA), a sequence found in DR4 and DR14 (in which RA is more prevalent), in addition to some DR1β-chains. Current nomenclature attempts to clarify these ambiguities by including information on the specific DRβ sequences. The DR4β-chains with the greatest association with RA are referred to as DRB*0401, DRB*0404, DRB*0101, and DRB*1402 (Table 65-1). When the structure of this sequence is considered, 96% of patients with RA exhibit the appropriate HLA-DR locus in some populations.3 In certain ethnic and racial groups, including Greeks, Pakistanis, Chileans, and African-Americans, the association with DR4 or QKRAA is not as prominent or is not associated.4,5 The QKRAA epitope also might predict the severity of established RA, with a greater prevalence of extra-articular disease and erosions in patients with two susceptibility alleles compared with one.6 What is special about the shared epitope? The dose effect of the QKRAA epitope argues against a role for binding of a specific “rheumatoid antigen” because DR surface density

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Table 65-1  Nomenclature for HLA-DR Alleles   and ­Associations with Rheumatoid Arthritis Old Nomenclature (HLA-DRB1* Alleles)

Current Nomenclature

Association with Rheumatoid ­Arthritis*

HLA-DR1

0101

+

HLA-DR4 Dw4

0401

+

HLA-DR4 Dw14

0404/0408

+

HLA-DRw14 Dw16

1402

+

HLA-DR4 Dw10

0402

−

HLA-DR2

1501, 1502, 1601, 1602

−

HLA-DR3

0301, 0302

− −

HLA-DR5

1101-1104, 1201, 1202

HLA-DR7

0701, 0702

−

HLA-DRw8

0801, 0803

−

HLA-DR9

0901

−

HLA-DRw10

1001

−

HLA-DRw13

1301-1304

−

HLA-DRw14 Dw9

1401

−

*+, association observed; −, no association observed From Weyand CM, Hicok KC, Conn DL, et al: The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann Intern Med 117:801, 1992.

usually does not alter T cell responses. Based on the crystal structure of HLA-DR molecules, the region associated with RA (QKRAA) primarily faces away from the antigen-binding cleft of the DR molecule that determines the specificity of peptides presented to CD4+ helper T cells. Attempts to elute peptides from the binding pocket of RA-associated alleles have not revealed a specific antigen that is either unique to or associated with RA.7 The negative findings in RA contrast with type 1 diabetes mellitus, in which fragments of a key putative autoimmune target, glutamic acid decarboxylate 65, are bound to the diabetes-associated MHC molecules. There are several additional caveats about the role of this allele in RA, as follows: 1. Other genes must be involved because many healthy individuals carry the QKRAA motif and do not develop RA. 2. The converse hypothesis also is plausible, that is, QKRAA might have limited binding to an arthro­ tropic agent, preventing an appropriate T cell– medi­ated response. 3. The association between the shared epitope and RA might have little to do with antigen recognition and might function by shaping the T cell repertoire in the thymus (or autoantibody production, as noted with anticitrullinated peptide antibodies). 4. Specific DR sequences might alter intracellular MHC trafficking and antigen loading, indirectly affecting antigen presentation in a nonspecific fashion. 5. There is some evidence that certain DR4 epitopes are protective, such as DERAA in the same region of the molecule. Various hypotheses have attempted to explain this observation, including the possibility that the protective epitope contributes to regulatory T cell function. Although more controversial, class II associations related to the DQ region of the class II MHC locus also have been described for RA.

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Etiology and Pathogenesis of Rheumatoid Arthritis

Another important discovery is that the shared epitope might not be an independent risk factor for RA, but instead is a marker for immunoreactivity and anticitrullinated peptide antibodies.8 In a large series of patients with early undifferentiated inflammatory arthritis, one third of patients met criteria for RA within 1 year. Progression to RA occurred regardless of HLA-DR genotype if patients were positive for anticitrullinated peptide. When patients were stratified according to anticitrullinated peptide antibody, the shared epitope did not make an additional contribution to progression from undifferentiated arthritis to RA. These results suggest that the shared epitope contributes to immune hyperreactivity, but that anticitrullinated peptide antibodies are more closely associated with RA. In other studies, however, the presence of the shared epitope and anticitrullinated peptide antibodies together is associated with even greater disease severity. The MHC associations can be even more complex when considering extended haplotypes in the central MHC region. The A1-B8-DR3 haplotype (also called “8.1”) is linked to RA and many other autoimmune diseases independent of the HLA-DR4.9 The locus contains more than 50 genes that could be responsible in addition to the class I and class II MHC proteins. ADDITIONAL POLYMORPHISMS: CYTOKINES, CITRULLINATING ENZYMES, PTPN22, AND OTHERS The clear genetic influences on RA have led to studies evaluating non-MHC genes. Single-nucleotide polymorphisms (SNPs) in promoter regions or coding regions have been extensively investigated in RA. SNPs in promoter regions could lead to altered gene regulation as a result of variable binding of transcription factors to promoters, whereas SNPs in coding regions directly change the amino acid sequence of the encoded protein. A second method for assessing genetic associations involves the evaluation of microsatellite sequences near key genes that are implicated in the disease. Microsatellites are tandem repeated sequences in the DNA that are primarily (but not exclusively) located in noncoding regions. Considerable heterogeneity exists in the length of each microsatellite, which can indirectly alter gene expression or be in linkage disequilibrium with other undefined genetic polymorphisms. Table 65-2 shows some of the SNPs and microsatellites that have been studied in RA. The relative contribution of each is still poorly defined, and variations in technique, stage of disease, and patient populations result in some ­disagreement among various reports. Even some HLA associations that have been exhaustively studied remain controversial. It is easy to see why the genes with relatively weak contributions to susceptibility or severity remain uncertain. Many confounding influences can interfere with data interpretation, including remarkable differences in various racial and ethnic groups. Nevertheless, some patterns emerge. Given the importance of cytokines in RA (see later), it is not surprising that many studies have focused on these genes. The most intriguing evidence relates to TNF-α. This cytokine has been implicated in the pathogenesis of RA, and the TNF gene is located in the MHC locus on chromosome 6 in humans. Several polymorphisms of the TNF-α promoter, ­ including two at positions −238

Table 65-2  Non–Class II Major Histocompatibility ­Complex Associations in Rheumatoid Arthritis Gene

Region of Gene Studied

Associated with Rheumatoid ­Arthritis*

PTPN22

Coding

+

PADI4

Coding

+

STAT4

Intron

+

TRAF1-C5

Intron

+

TNF-α

Promoter

+

IL-1

Coding region; association   with IL-1β strongest

+/−

IL-1Ra

Coding region

+

IL-3

Promoter

+

IL-4

Intron Promoter

+ −

IL-6

Promoter

−

IL-10

Promoter

−

IL-12

3′ untranslated region

−

IFN-γ

Intron microsatellite

+/−

CCR5

CCRδ32 allele

+

RANTES

Promoter

+

MIF

Promoter

+

RAGE

Ligand-binding domain

+

CTLA4

3′ untranslated region

+

TGF-β

Coding region

+

FcRγIII

Coding region

+

*+, association observed; −, no association observed; +/−, association ­observed in some studies, but not in others. CCR5, chemokine receptor 5; c-5, complement 5; FcRγIII, Fc receptor γIII; IFN-γ, interferon-γ; IL, interleukin; IL-1Ra, interleukin-1 receptor antagonist; MIF, macrophage inhibitory factor; RAGE, receptor for advanced glycosylation end products; RANTES, regulated on activation, normally T cell ­expressed and secreted; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; TRAF1, TNF-receptor associated factor 1.

and −308, can alter gene transcription. Associations among the TNF polymorphisms­ and RA susceptibility and radiographic progression have been reported, although there is not uniform agreement. In addition, certain polymorphisms in cytokines, especially TNF-α or Fc receptors, have been associated with differential responses to therapy. Substitution of a T for a C at position −857 in the TNF-α promoter might confer greater responsiveness to TNF inhibitors.10 Confirmation of such associations would require additional studies in larger patient populations and different ethnic and racial groups. Associations with other polymorphisms or microsatellites have been identified for several other cytokines, inflammatory mediators, and chemokines, including IL-1, CCR5, and RANTES (regulated on activation, normally T cell expressed and secreted). One SNP for the T cell costimulatory molecule CTLA4 also is associated with susceptibility.11 The contribution of each gene is relatively small compared with class II MHC, but combinations might provide an appropriate genetic background to influence the course of arthritis. No linkage has been noted with other cytokines that might play a role in RA, such as IL-6, osteopontin, and IL-12, and so far the data on IL-18 SNPs are variable.

PART 9 

Among the many noncytokine and non-MHC genetic linkages described for RA, the ones associated with ­peptidyl arginase deiminase (PADI) and PTPN22 are perhaps the most interesting. The PADI genes are responsible for the posttranslational modification of arginine to citrulline. Four isoforms have been identified, known as PADI1 through PADI4. In light of the striking associations of RA with anticitrullinated peptide antibodies, several groups have investigated potential associations with these genes. The most promising is an extended haplotype in the PADI4 gene that can lead to increased levels of PADI4 protein secondary to enhanced mRNA stability.12 In a Japanese cohort, a strong association was observed between PADI4 SNPs and susceptibility to RA. Confirmatory reports have been mixed because the association has been confirmed in other Asian populations, but not in Western Europe.13 These studies suggest that the contribution of PADI4 to RA might be restricted, depending on the overall genetic background of the patient population. PTPN22 associations have been discovered in largescale screening efforts to identify SNP associations in RA.14 Using 12,000 SNPs in the initial screens, a novel association was discovered at position 1858 in the PTPN22 gene. The allele containing thymidine leading to an amino acid substitution (R620W) was present in 8.5% of controls, but was found in nearly 15% in patients with seropositive RA. Subsequent studies have shown a similar association with systemic lupus erythematosus, type 1 diabetes, and several other autoimmune diseases. The precise function of PTPN22 is unknown, but it can regulate the phosphorylation status of several kinases important to T cell activation, including Lck and ZAP70. The R620W allele results in a gain of function that alters the threshold for TCR signaling. Because the PTPN22 allele is very rare in Japan, it is another gene (similar to PADI4) where ­ susceptibility is specific for particular ethnic or racial ­populations. More recently, genetic associations linking STAT4 and the TRAF1-C5 region of the genome have been described. GENDER RA is one of many autoimmune diseases that is ­predominant in women. The ratio of female-to-male patients (2:1 to 3:1) is significant, yet not nearly as high as in Hashimoto’s thyroiditis (25:1 to 50:1), systemic lupus erythematosus (9:1), or autoimmune diabetes mellitus (5:1). The gender effect also is observed in some animal models of autoimmunity, such as the NZB/NZW model of systemic lupus erythematosus in which female mice have more severe disease. The role of estrogens has been explored by various methods.15 Autoantibody-producing B cells exposed to ­ estradiol are more resistant to apoptosis, suggesting that autoreactive B cell clones might escape tolerance. The effect on T lymphocytes is more difficult to reconcile with the female preponderance in RA because estrogens tend to bias T cell differentiation toward the T helper type 2 (Th2) phenotype. The cytokines produced by this subset, such as IL-4 and IL-13, usually are considered anti-inflammatory­ in animal models of arthritis and are present in only limited­ amounts in the RA synovium. The data are still controversial, however, because estradiol also can increase interferon (IFN)-γ production (typically a Th1 cytokine) by antigen-specific clones from patients with multiple ­ sclerosis. ­ Estrogen ­ receptors are expressed on

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RHEUMATOID ARTHRITIS

1039

­fibroblast-like synoviocytes (FLS) and, when stimulated, increase production of metalloproteinases in the synovium. In macrophage cell lines, estrogen can enhance production of TNF-α. Taken together, these data suggest that the hormone milieu can have significant effects on the cells known to participate in RA. The effects are complex, however, and the specific mechanisms responsible for increased susceptibility to RA in women are uncertain. Considerable effort also has been expended on case­controlled and retrospective studies to determine the ­influence of oral contraceptives. Although some suggestive data exist for a protective effect, the effect (if it exists) is probably very small and temporary (i.e., delaying rather than preventing disease). Other endocrine influences, including corticotropin-releasing hormone or estrogen synthase, have been linked with RA. Nulliparity also has been described as a risk factor, but not all studies confirm this. Pregnancy often is associated with remission of the disease in the last trimester. More than three quarters of pregnant patients with RA improve in the first or second trimester, but 90% of these experience a flare of disease associated with an increase in RF titers in the weeks or months after delivery. The mechanism of protection is not defined, but might be due to the expression of suppressive cytokines such as IL-10 during pregnancy, production of alpha fetoprotein, or alterations in cell-mediated immunity. One intriguing finding is that fetal DNA levels in the maternal peripheral blood correlate with the propensity for improved symptoms in pregnant RA patients. It is uncertain whether the DNA itself contributes, or whether it is a marker for increased leakage of fetal cells into the maternal circulation.16 A possible relationship between the alleviation of RA symptoms during the last trimester of pregnancy and immunogenetics may be supported by the observation that during pregnancy, alloantibodies in the maternal circulation develop against paternal HLA antigens. Maternal-fetal disparity in HLA class II phenotypes can correlate with pregnancy-induced remission. More than three fourths of pregnant women with maternal-fetal disparity of HLADRB1, HLA-DQA, and HLA-DQB haplotypes have significant improvement, whereas disparity is observed in only one fourth of women whose pregnancy is characterized by continuous active arthr­itis.17 Suppression of maternal immune responses to paternal HLA haplotypes might be protective. This question remains unsettled because another study failed to find a correlation between the HLA disparity and clinical improvement during pregnancy.18 TOBACCO Numerous environmental factors certainly contribute to RA susceptibility, although no specific exposure has been identified as a pivotal agent. Smoking is the best defined environmental risk factor for seropositive RA in certain populations. The reason for its influence on the ­development of synovitis is not fully defined, but could involve the activation of innate immunity and PADI in the airway. Citrullinated peptides have been detected in bronchoalveolar lavage samples of smokers, and this could provide a stimulus for generation of anticitrullinated peptide antibodies in susceptible individuals.19 Repeated activation of innate immunity, especially in an individual with underlying genetically

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determined ­ autoreactivity, potentially could contribute to autoreactivity and the initiation of RA.

Key Points

RISE AND FALL OF RHEUMATOID ARTHRITIS Any proposed etiology for RA should incorporate one additional key element: RA might be a relatively new disease in Europe and Northern Africa. Examination of ancient skeletal remains in Europe and Northern Africa fails to reveal convincing evidence of RA, even though other rheumatic diseases, such as osteoarthritis, ­ankylosing spondylitis, and gout, are readily discernible. In ­ contrast, typical marginal erosions and rheumatoid lesions are present in the skeletons of Native Americans found in Tennessee, Alabama, and Central America from thousands of years ago. The first clear descriptions of RA in Europe appeared in the 17th century, and the disease was distinguished from gout and rheumatic fever by Garrod in the mid-19th century. Although still controversial, one line of thought suggests that the disease migrated from the New World to the Old World coincident with opening the trade and exploration routes. Because genetic ­admixture was relatively limited, an undefined environmental exposure potentially caused RA in susceptible Europeans. The most obvious explanation would be that an infectious agent is responsible. Other environmental influences, such as tobacco smoking, were introduced to the Old World at the same time, however, and could play a role. Equally intriguing, the severity and incidence of RA seem to be decreasing (Fig. 65-2).20 Lower severity could be related to the advent of new treatments, and decreasing incidence could be due to a “birth cohort” effect. In ­certain well-defined populations, including Native Americans, the incidence of RA gradually declined by 50% over the last half of the 20th century. The birth-cohort theory suggests that the earlier high incidence of disease was caused by an etiologic agent, and the exposure decreased with each ­succeeding generation. Changes in hygiene and other ­lifestyle modifications related to industrialization might contribute, and an infectious agent might be less prevalent secondary to these societal changes, as with many other infectious ­diseases. 100 Age- and sex-adjusted incidence/100,000

POSSIBLE CAUSES OF RHEUMATOID ARTHRITIS

80

• Many pathogens have been associated with RA, including viruses, retroviruses, and Mycoplasma, although a precise etiologic link has not been established. • Data suggest that a specific RA pathogen is unlikely. • Repeated inflammatory insults, especially through specialized receptors that recognize common molecules produced by pathogens, in a genetically susceptible individual might contribute to breakdown of tolerance and subsequent autoimmunity.

Although genetic factors predispose an individual to developing RA, the environment clearly also contributes. Considerable effort has been expended to assess the role of infectious agents (Table 65-3) in addition to environmental exposures such as tobacco. The pathogen potentially could initiate disease through a variety of mechanisms, including direct infection of the synovium, activation of innate immunity by pattern-recognition receptors that bind to components of the agent, or through molecular mimicry that induces an autoreactive adaptive immune response. INFECTIOUS AGENTS: DIRECT INFECTION AND INNATE IMMUNE RESPONSES Toll-like Receptors and the Inflammasome in the Joint Infectious agents could contribute to the initation or perpetuation of RA through a variety of mechanisms. Some arthrotropic microorganisms potentially could infect the synovium and cause a local inflammatory response. There is increasing awareness that the innate immune system also could directly affect the onset and course of synovitis. Pathogen-associated molecular pattern receptors, especially TLRs, are expressed by sentinel cells in the host that provide a first line of defense. These receptors recognize perserved structures in bacteria and other infectious agents and permit rapid release of inflammatory mediators, activation of antigen presenting cells, and enhancement of ­adaptive immune responses.

60

Table 65-3  Possible Infectious Causes   of Rheumatoid Arthritis

40 20 0 1960

1970

1980

1990

Year Figure 65-2  Declining incidence of rheumatoid arthritis. ­ Population studies in Minnesota have shown a gradually decreasing incidence of rheumatoid arthritis over the last 50 years. Similar results have been ­observed in Native American populations. (From Doran MF, Pond GR, Crowson CS, et al: Trends in incidence and mortality in rheumatoid ­arthritis in Rochester, Minnesota, over a forty-year period. Arthritis Rheum 46:635, 2002.)

Infectious Agent

Potential Pathogenic ­Mechanisms

Mycoplasma

Direct synovial infection; ­superantigens

Parvovirus B19

Direct synovial infection

Retroviruses

Direct synovial infection

Enteric bacteria

Molecular mimicry (QKRAA)

Mycobacterium

Molecular mimicry (proteoglycans, QKRAA), immunostimulatory DNA

Epstein-Barr virus

Molecular mimicry (QKRAA)

Bacterial cell walls

Macrophage activation

PART 9 

There are at least 11 TLRs in humans, such as TLR2 (binds peptidoglycans), TLR3 (binds double-stranded RNA), TLR4 (binds lipopolysaccharride), and TLR9 (binds bacterial DNA containing CpG motifs). When engaged, the TLRs activate signal transduction pathways such as nuclear factor κB (NFκB) and mitogen-activated protein (MAP) kinases. In some cases, such as for TLR3, additional pathways are engaged to increase expression of antiviral genes such as IFN-β. Many of these pattern-recognition receptors are expressed by rheumatoid synovial tissue and cultured FLS, including TLR2, TLR4, and TLR9.21-24 Exogenous TLR ligands, such as bacterial peptidoglycan and DNA, and endogenous ligands, such as heat shock proteins (HSPs), fibrinogen, and hyaluronan, are present in arthritic joints (see later). Engagement of these receptors participates in certain animal models of arthritis and can exacerbate synovial inflammation. TLR3, which recognizes viral double-stranded RNA and activates the antiviral response, also is expressed by cells in the intimal lining. Necrotic debris containing mRNA from RA synovial fluid cells activates TLR3 signaling and proinflammatory gene expression in synovitis. As with smoking, which activates innate immunity in the lungs and leads to citrullination of peptides, current models of RA suggest that repeated engagement of this system in the synovium could help initiate the disease. This hypothesis could explain why specific pathogens have been difficult to identify in the joint. In contrast, a genetically susceptible individual potentially could break tolerance if the TLRs are repeatedly engaged. A second mechanism that regulates innate immunity involves a novel structure called the “inflammasome.” This complex includes several proteins involved in recognition of “danger signals” and pathogens, such as muramyl dipeptides and uric acid. One central component is cryopyrin, also called NALP3, which is linked to caspase 1 (IL-1 convertase) by adapter proteins. When the inflammasome is engaged, caspase 1 is activated, and IL-1 is produced. Mutations in this pathway, especially in cryopyrin, have been associated with autoinflammatory disorders such as MuckleWells syndrome and familial cold autoinflammatory disease. Inflammation induced by uric acid crystals or adenosine triphosphate uses this pathway and can be abrogated by IL-1 inhibitors. Cryopyrin is abundant in RA synovium and is constitutively expressed by FLS and macrophages.25 Expression in cultured FLS is markedly increased by TNF-α. Although the role of the inflammasome in RA has not been fully defined, its ability to induce cytokine production by exposure to bacterial products and other danger signals suggests that it participates in IL-1 and IL-18 regulation. Bacteria, Mycobacteria, Mycoplasma, and their Components Active infection of synovial tissue by pyogenic bacteria is an unlikely cause of RA, and extensive searches for a unique or specific organism in synovial tissue or joint effusions have been negative. Antibodies to certain organisms, such as Proteus, are reportedly elevated in the blood of patients with RA, but this could represent an epiphenomenon or a nonspecific B cell activation.26 Sensitive polymerase chain reaction techniques to identify the bacterial genome in synovial ­tissue show that a high percentage of RA and ­ reactive ­ arthritis

A

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B

C Figure 65-3  Accumulation of bacterial peptidoglycan in rheumatoid synovium. A and B, Immunohistochemistry shows synovial cells containing peptidoglycan (red). C, Double staining studies show that bacterial peptidoglycan accumulates in synovial macrophages (arrow). These bacterial products can activate Toll-like receptors and stimulate cytokine production. (From Schrijver IA, Melief MJ, Tak PP, et al: Antigen-presenting cells containing bacterial peptidoglycan in synovial tissues of rheumatoid arthritis patients coexpress costimulatory molecules and cytokines. Arthritis Rheum 43:2160, 2000.)

patients contain bacterial DNA sequences.27 The bacteria identified are not unique and generally represent a cross section of skin and mucosal bacteria, including Acinetobacter and Bacillus. The synovium may function as an adjunct to the reticuloendothelial system in arthritis, allowing local macrophages to accumulate circulating bacterial products. Nucleotide sequences found in prokaryotic cells can activate TLRs and stimulate innate immune responses. In addition to prokaryotic DNA, bacterial peptidoglycans have been detected in RA synovial tissue (Fig. 65-3).28 Antigen presenting cells containing these products express TLRs and produce proinflammatory cytokines such as TNF-α. It is unknown whether the peptidoglycans activate cells in situ, or whether phagocytic cells from other sites or the blood engage the molecules and migrate to the joint. In either case, it is not difficult to imagine how they can ­contribute to synovial inflammation. The relevance to human disease has been suggested by animal models of arthritis that depend on TLR2, TLR4, and TLR9. Rodents injected with streptococcal cell walls develop severe polyarticular arthritis. The initial phase of disease resolves and is followed by a chronic T cell–­dependent phase that resembles RA. The arthritogenicity of complete

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Freund’s adjuvant in the rat adjuvant arthritis model largely depends on mycobacterial DNA that can bind to TLR9 and activate an adaptive immune repsonse. Endogenous TLR4 ligands also could play a role in disease perpetuation when the inflammatory response leads to local accumulation of HSPs and fibrinogen.29 Considerable attention has been directed toward a potential role for Mycoplasma and Chlamydia in arthritis. Mycoplasma-derived superantigens, such as from Mycoplasma arthritidis, can directly induce T cell–independent cytokine production by macrophages and can exacerbate or trigger arthritis in mice immunized with type II collagen.30 There also is a higher prevalence of anti–Mycoplasma pneumoniae IgG antibodies in RA patients than matched controls. Despite this and other circumstantial evidence, most efforts to identify Mycoplasma and Chlamydia organisms or DNA in joint samples have produced negative results, and there is no direct evidence to support these organisms as etiologic agents.31 Epstein-Barr Virus, dnaJ Proteins, and Molecular Mimicry Epstein-Barr virus (EBV) has been indirectly implicated in RA.32 It is a polyclonal B lymphocyte activator that increases the production of RF, and rheumatoid macrophages and T cells have defective suppression of EBV proliferation in human B cells. Rheumatoid patients seem to have higher levels of EBV shedding in throat washings, an increased number of virus-infected B cells in the circulating blood, higher levels of antibodies to normal and citrullinated EBV antigens, and abnormal EBV-specific cytotoxic T cell responsiveness compared with controls. Patients with RA have a defect related to the control and elimination of EBVtransformed lymphocytes; this has fueled speculation that a lymphocyte defect is a triggering event in this disease. Additional intriguing data implicating EBV in RA are derived from sequence homology between the susceptibility cassette in HLA-DR proteins and the EBV glycoprotein gp110. Similar to DRB*0401, gp110 contains the QKRAA motif, and patients with serologic evidence of a previous EBV infection have antibodies against this epitope.33 T cell recognition of EBV epitopes in some patients with HLA-DR4, HLA-DR14, or HLA-DR1 might cause an immune response directed at innocent bystander cells through “molecular mimicry.” This hypothesis could account for disease perpetuation in the absence of active infection in patients with a specific MHC genotype. Nevertheless, the data are circumstantial, and gp110 is only one of many xenoproteins that contain QKRAA. The Escherichia coli dnaJ protein, a bacterial HSP, contains the sequence and represents a potential link between gut bacteria and chronic arthritis. RA T cells, especially synovial fluid T cells, but not normal peripheral blood cells, have increased proliferative responses to this protein, perhaps supporting the molecular-mimicry link between a variety of QKRAA-containing proteins and arthritis.34 Parvovirus Antecedent infection with parvovirus B19 has been suggested in some patients with RA based on serologic evidence.35 Despite these cases, few rheumatoid patients have

evidence of such a coincident infection, and only about 5% have evidence of recently acquired parvovirus B19 infection at the time of disease onset. Using polymerase chain reaction methods to detect B19 genes in synovial tissue, however, 75% of RA synovium samples were positive compared with about 20% of non-RA controls.36 Immunohistochemical evidence of the B19 protein VP-1 was detected in patients with RA, but not other forms of arthritis.37 In other studies, no evidence of the B19 genome in joint samples was detected, or the presence of B19 DNA was not specific for RA. The mechanisms of parvovirus B19–induced synovitis, when it does occur, could be related to alterations in the function of FLS.38 In a cell culture model of synoviocyte invasion into cartilage, infection with the parvovirus significantly increased the migration of cells into the matrix. Mice that are transgenic for the B19 protein NS1 did not develop clinical arthritis, but were more susceptible to collagen-induced arthritis even though they did not have the usual arthritis-associated genetic background. Levels of anti–type II collagen antibodies and TNF-α in the serum were similar to DBA/1 mice that had been immunized with type II collagen. These data suggest that the B19 genome might not cause arthritis, but can enhance an arthritogenic response to environmental stimuli. Other Viruses Because rubella virus and the rubella vaccine can cause synovitis in humans, the virus has attracted some attention as a possible triggering agent. Live rubella virus can be isolated from synovial fluid in some patients with chronic inflammatory oligoarthritis or polyarthritis in the absence of firm clinical evidence of rubella. Rubella patients do not have the classic polyarticular involvement seen so often in RA, however. Most have an oligoarthritis involving large joints. As with parvovirus B19 infection, it is possible that a subset of patients with chronic polyarthritis have disease resulting from direct infection with wild-type or attenuated rubella virus. Studies of synovial tissue in a variety of inflammatory and noninflammatory arthropathies also have shown DNA of other viruses, such as cytomegalovirus and herpes simplex, but not adenovirus or varicella zoster.39 As with bacterial DNA, parvovirus, and EBV, the localization of viral DNA to the inflamed joint might be related to the migration of inflammatory cells containing the viral genome or other nonspecific mechanisms, rather than an active infection. Although the hypothesis that one or more of these viral infections might serve as a triggering agent in the genetically susceptible host is appealing and intellectually satisfying, the pathogenic role of these agents is uncertain. Retroviral infections have been suggested as a cause of RA. Extensive searches for potential agents have not been fruitful; this does not rule out the possibility that difficultto-detect agents might be present, or even that endogenous retroviruses might play a role. Endogenous retroviruses are abundant in inflamed and normal synovium, and certain transcripts are differentially expressed in RA cells.40 In one study, higher levels of HERV-K10 gag protein from a common endogenous retrovirus were detected by polymerase chain reaction more often in RA compared with ­ osteoarthritis

PART 9 

AUTOIMMUNITY

Key Points • Evidence of autoimmunity can be present in RA many years before the onset of clinical arthritis. • Autoantibodies, such as RFs and anticitrullinated ­protein antibodies, are commonly associated with RA. • Autoantibodies occur in RA that recognize either joint antigens, such as type II collagen, or systemic antigens, such as glucose phosphate isomerase. • The autoantibodies potentially can contribute to synovial inflammation through several mechanisms, including local activation of complement.

The idea that aberrant immune responses are directed toward self-antigens in RA was recognized with the discovery of RF in the blood of patients with the disease. Initially described by Waaler and later by Rose, it was not until the mid-1950s that Kunkel and colleagues firmly established that RF is an autoantibody. Although understanding of autoantigens has changed over the years, and the relative contributions of cellular and humoral immunity have been debated, emphasis on the role of autoantibodies in RA has re-emerged in recent years. Autoantibody titers usually do not correlate well with disease activity. Improvement can be associated with modest decreases in levels of RFs or anticitrullinated peptide antibodies, although the changes tend to be relatively modest and are not consistent. These observations suggest that autoantibodies, although they contribute to the pathogenesis of RA, are not the primary driving factor. Rheumatoid Factor: Evidence of Autoimmunity in Rheumatoid Arthritis The identification and characterization of RF as a self-antibody that binds to the Fc portion of IgG was the first direct evidence that autoimmunity might play a role in RA. For many years, immune complexes comprising RF and other immunoglobulins were thought to be solely responsible for RA. Today, the presence of RF and its resultant pathogenic consequences are still considered cardinal features of RA. Longitudinal studies show that RF ­production often precedes the onset of RA by many years (Fig. 65-4).43 Although some

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RHEUMATOID ARTHRITIS

60 Percentge of positive patients

and normal peripheral blood mononuclear cells. Some indirect studies are suggestive of retroviral infection, such as the demonstration of zinc-finger transcription factors in cultured synoviocytes. In addition, the pX domain of one human retrovirus, human T-lymphotropic virus-1, causes synovitis in transgenic mice, and synoviocytes from patients infected with human T-lymphotropic virus-1 express some features of a transformed phenotype, with increased proliferation and cytokine production.41 Other studies failed to show increased expression of human retrovirus-5 proviral DNA in rheumatoid synovium.42 The notion that retroviruses or endogenous viruses contribute to RA is appealing, although there is no direct evidence of their involvement. Some viral products potentially could interact with receptors such as TLR3 or TLR7 to enhance production of chemokines and type I interferons.

| 

50 49.4% 40

IgM or anti-CP

30 40.5% 20 10

Anti-CP 27.8%

IgM-RF 0 15 14 13 12 11 10 9 8 7 6 5 4 3 2 Years before the start of symptoms

1

0

Figure 65-4  Autoantibody production in rheumatoid arthritis. Rheumatoid factors and anticitrullinated peptide (CP) antibodies are detected in the blood long before the onset of clinical arthritis in many patients. (From Nielen MM, van Schaardenburg D, Reesink HW, et al: Specific autoantibodies precede the symptoms of rheumatoid arthritis: A study of serial measurements in blood donors. Arthritis Rheum 50:38, 2004.)

patients are initially “seronegative” for RA and subsequently convert to “seropositive,” this typically occurs during the first year of disease activity. The role of RF in the pathogenesis of RA has been suggested by circumstantial evidence. Patients with a positive test result for RF in blood have more severe clinical disease and complications than seronegative patients. RF also is able to fix and activate complement by the classic pathway, and there is clear evidence of local complement production and consumption in the rheumatoid joint. Large quantities of IgG RF are produced by rheumatoid synovial tissue and form complexes through self-association. RF-containing­ immune complexes are readily detected in RA synovial ­tissue and the surface layers of cartilage. The latter is especially relevant because immobilized complexes can facilitate complement fixation with resultant release of chemotactic peptides. In experiments performed in patients with RA, a marked inflammatory response was elicited when RF from the patient was injected into a joint, but not when normal IgG was given.44 B cell–targeted therapies, such as rituximab, can deplete peripheral B lymphocytes and modestly decrease titers of RF. Although this does not correlate with clinical responses, there is a suggestion that RF levels decrease in responders and increase again coincident with clinical relapses. Three quarters of patients with RA are seropositive using standard tests for RF, although the percentage can be 90% when assayed for IgM RF with enzyme-linked immunosorbent assays. Breaking tolerance for immunoglobulin determinants recognized by RF has a genetic influence as well because first-degree relatives of seropositive patients with RA frequently are seropositive themselves. Although IgG and IgM RFs are thought to be the most abundant and pathogenic in RA, IgE RF also has been shown in some patients, especially patients with extra-articular manifestations. IgE RF potentially can complex with aggregated IgG in synovial tissue, and the subsequent complexes could degranulate synovial mast cells through activation of Fc receptors in the synovium. IgA RFs are also produced in RA, including in

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Etiology and Pathogenesis of Rheumatoid Arthritis

patients who are seronegative as determined by standard clinical tests that primarily detect IgM RF. The RFs produced in RA patients differ from those produced in healthy individuals or from patients with paraproteins.45 The avidity of RF for the Fc portion of IgG is several orders greater in RA than in Waldenström’s macroglobulinemia or in cryoglobulins. The germlinederived RFs are produced by immature CD5-positive B cells, and many paraproteins expressed by malignant B cells (such as Waldenström’s macroglobulinemia) are derived from the germline. In addition, some normal B cells in adult human tonsil tissue express and synthesize germline-encoded RFs, although they do not secrete the protein. RFs produced by RA B cells are distinct in that these proteins often are not encoded by germline genes. Instead, their sequence seems to be derived through rearrangements and somatic mutations. RF analysis in synovial membrane cultures from patients with a variety of diseases has indicated that only cells from patients with seropositive RA synthesize RF spontaneously. IgM RF represents about 7% of the total IgM produced by cells, and IgG RF represents 3% of IgG synthesized in the synovial cultures. The expression of any particular RF idiotype is under genetic control and is related to restriction of the number of relevant or expressible variable (V) genes available in the germline.46 RFs in RA primarily use the variable heavy 3(VH3) gene and a variety of variable light (VL) genes, whereas natural antibodies use VH1 or VH4 and the Vκ3 genes. The κ light chain repertoire expressed in RF-producing cells isolated from one patient with chronic RA was enriched for two specific Vκ genes, known as Humkv325 and Humkv328, which also are frequently associated with RF paraproteins.47 The κ-variable domains contain many somatic mutations and non–germline-encoded nucleotides, however. Based on the extent of substitutions, the selection and production of these specific RFs were likely due to ­antigenic drive, rather than derived directly from the

g­ ermline, as is the case with many paraproteins. Additional RFs have been identified with characteristics similar to an antigen-driven response, although some examples of germline RFs also have been isolated from RA synovium. A crystal structure of one IgM RF bound to IgG showed a key contact residue of the RF with the Fc portion of IgG containing a somatic mutation, supporting the notion that the mutations are related to affinity maturation.48 Autoimmunity to Citullinated Peptides A striking recent observation related to autoantibodies is that immunoglobulins that bind to citrullinated peptides are produced by patients with RA and have significant prognostic implications. The discovery originated with reports in the 1970s that antibodies directed against keratin were detected in rheumatoid serum, and that the primary target antigen was filament-aggregating protein, filaggrin. These antibodies bind to epitopes on filaggrin that contain citrulline, which is derived from post-translational modification of arginine by PADI. Humans have four isoforms of PADI. PADI2 and PADI4 are especially abundant in synovium49 and certain SNPs are associated with RA in Asian populations. Induction of PADI expression and citrullination of peptides are not specific to RA and can occur in many inflamma­ tory settings.50 Not only are other inflammatory arthropathies marked by citrullinated proteins, but also other organs, such as the lungs in smokers, have significant PADI activity. Similarly, citrullinated peptides are present in most animal models of arthritis.51 The specific proteins that are modified vary widely, but include many normal constituents, such as vimentin, fibrinogen and fibronectin, and xenoproteins such as EBV-derived peptides.52 Immunohistochemistry shows citrullinated peptides in RA synovial tissue infiltrating cells (Fig. 65-5) and in extracellular deposits that often colocalize with various isoforms of PADI, especially PADI2 and PADI4.

CCP-purified Abs

Control

RA

A Figure 65-5  Citrullinated peptides in inflamed synovium. Rheumatoid arthritis (RA) synovium and nonrheumatoid synovium contain citrullinated peptides, detected with an anti–cyclic citrullinated peptide (CCP) antibody (red-brown in synovium). Control is an irrelevant antibody. Although citrullinated peptides are not specific, the production of anticitrullinated protein antibodies is more specific to RA. (From Vossenaar ER, Smeets TJ, Kraan MC, et al: The presence of citrullinated proteins is not specific for rheumatoid synovial tissue. Arthritis Rheum 50:3485, 2004.)

B

Non-RA

C

D

PART 9 

Anticitrullinated peptide antibodies have been reported in serum samples of 80% to 90% of RA patients.53 In some studies, they are more specific for RA than RF, with specificity approaching 90%. Similar to RF, anticitrullinated peptide can appear long before the onset of clinical arthritis and could be a marker for immune hyperreactivity and subclinical inflammation leading to protein citrullination in a variety of tissues. Anticitrullinated peptide antibodies also are produced by synovial tissue B cells and can be detected in synovial fluid. The antibodies are predictors of more aggressive disease marked by bone and cartilage destruction. Some data suggest that the HLA-DR associations in RA are due to an association between the susceptibility epitope and anticitrullinated peptide antibody production. Anticitrullinated peptide antibodies also might have pathogenic potential. Although anticitrullinated peptide antibodies have minimal effect when directly injected into mice, they enhance the arthritogenic potential of anti–type II collagen antibodies in the collagen-induced arthritis model.54 The autoantibodies are not simply a marker of disease, but can, similar to RF, participate in the disease process. Citrullination also can increase T cell responses to arthritogenic antigens. Citrullination of rat albumin leads to the formation of antibodies that also cross-react with the unmodified protein.55 The action of PADI on type II collagen enhances its immunogenicity, perhaps by enhancing its ability to bind to the class II MHC peptide binding groove.56 Autoimmunity to Cartilage-Specific Antigens Because synovial tissue inflammation is a hallmark of RA, it is natural to assume that certain joint-specific antigens might play an etiologic or pathogenic role. The number of potential antigens is extensive, and there is no convincing evidence to date that one specific “rheumatoid” antigen exists. In contrast, the emerging picture of autoimmunity in RA tends to implicate patterns of self-directed responses, rather than a single epitope that encompasses all patients at all times during the disease. It is possible that articular autoimmunity could vary with the stage of disease, the clinical manifestations, and treatment. Type II Collagen The discoveries that immunization with type II collagen can cause arthritis in rats and mice, and that the disease can be passively transferred by IgG fractions containing anticollagen antibodies or by transfer of lymphocytes from affected animals have spawned extensive experiments that illustrate the antigenicity of collagen, the arthrotropic nature of the disease produced, and the dependence on class II MHC genes. It is clear that functional T cells are necessary to initiate a collagen-induced arthritis, and that a major immunogenic and arthritogenic epitope on type II collagen resides in a restricted area of the type II collagen chains. Most data in humans suggest that RA is not caused by the development of antibodies to type II collagen, but that the inflammatory response is amplified by their production (Table 65-4). Serum samples from patients with RA contain antibody titers to denatured bovine type II collagen that are

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Table 65-4  Potential Autoantigens in Rheumatoid Arthritis Cartilage antigens Type II collagen gp39 Cartilage link protein Proteoglycans Aggrecan Citrullinated peptides Glucose-6-phosphoisomerase HLA-DR (QKRAA) Heat-shock proteins Heavy-chain binding protein (BiP) hnRNP-A2 Immunoglobulins (IgG)

significantly higher than the titers found in control sera57; however, there is no difference in antibody titers to native collagen, indicating that the denatured form generated after the breakdown of connective tissue might serve as the immunogen. Anticollagen antibodies purified from serum samples of patients with RA can activate complement, generating fragments derived from the fifth component of complement (C5a) when they bind to cartilage. This finding adds relevance to the observations that anticollagen antibodies can be eluted from rheumatoid articular cartilage. In addition, isolated synovial tissue B lymphocytes actively secrete anti– type II collagen antibodies in almost all patients with seropositive RA, whereas articular cells from non-RA patients do not.58 Synovial fluid T cells also recognize and respond to type II collagen, and 3% to 5% of RA synovial fluid–derived T cell clones are autoreactive to the protein. T cell responses to type II collagen, especially a dominant epitope at amino acid 263-270, are much greater if the epitope is glycosylated, or if the protein is citrullinated.59 In addition, the presence of anti–type II collagen antibodies in RA is associated with the RA-related PTPN22 polymorphism.60 gp39 and Other Cartilage-Specific Antigens Several other cartilage components besides type II collagen have been implicated as potential autoantigens in RA. Among the most provocative is cartilage glycoprotein gp39. Several gp39 peptides can bind to the HLA-DR*0401 molecule and stimulate proliferation of T cells from patients with RA.61 BALB/c mice, which are often resistant to experimental arthritis, develop polyarticular inflammatory arthritis after immunization with gp39 and complete Freund’s adjuvant. Although anti-gp39 antibodies are detected in only a small percentage of patients, it seems to be reasonably specific for RA.62 Other examples of potential cartilage autoantigens include proteoglycans, aggrecan, cartilage-link protein, and other types of collagen. T cell clones derived from RA peripheral blood can proliferate in response to aggrecan, and most of these cells have a Th1 cytokine profile, suggesting that they contribute to the Th1 bias in synovial tissue.63 Proteomic analysis of RA serum using peptide arrays to detect multiple autoantibodies also identifies anti-gp39 antibodies in patients with early RA, and this may be associated with less aggressive disease.64

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Autoimmunity to Nonarticular Antigens Increasing attention has been focused on autoimmune responses that are not specific for components unique to articular structures.65 Although their role in etiology is not always clear, at least some autoantibodies (e.g., RF and anticitrullinated peptide) can appear before the onset of clinical disease. In other cases, the antigen-antibody system might participate in patterns of autoimmune responses that can lead to synovial inflammation. Glucose-6-Phosphate Isomerase A spontaneous arthritis model in K/BxN mice shows that antigen-specific immunity against a seemingly irrelevant nonarticular antigen can lead to destructive arthritis.66 The mechanism of disease relates to the fortuitous formation of antibodies to the ubiquitous enzyme glucose-6-phosphate isomerase in the mice, and the disease can be transferred to normal mice with the serum of affected animals. The passive arthritis model is dependent on the alternate complement pathway, Fc receptors (especially FcRγIII), and mast cells, but not T cells or B cells. IL-1 seems to be more important than TNF-α, and the IL-1 knockout mice are almost completely protected from disease. This effect can be overcome by administration of a TLR ligand such as lipopolysaccharide, which shares a downstream signaling pathway with IL-1. Other cytokines, such as IL-6, and signaling pathways, such as p38 MAP kinase and upstream kinases such as MKK3, also are required for full expression of the disease. Histochemical studies indicate that glucose-6-phosphate isomerase adheres to the surface of cartilage, permitting local antibody binding and complement fixation. Initiation of synovial inflammation in this model is complex and requires mast cells. The earliest stages also require increased vascular permeability, which provides access to the synovium and cartilage.67 It is unclear whether the same mechanisms that start the synovial inflammatory response are required for continued arthritis. It is possible that the initial phases involving mast cell and vascular permeability are replaced by a more traditional mechanism of antibody-mediated complement fixation when serum proteins have access to cartilage with glucose-6-phosphate isomerase adherent to it. Although the model appears at first glance to be due to a ubiquitous antigen, articular homing of the antigen suggests that it behaves similar to other arthritis models with “jointspecific” antigens. Although initial data suggested some specificity for RA, anti–glucose-6-phosphate isomerase antibodies are detected in a small percentage of RA patients and are not specific for the disease.68 Nevertheless, glucose-6phosphate isomerase might contribute, along with several other antibody systems, to local complement fixation and inflammation. Heterogeneous Nuclear Ribonucleoprotein-A2 and Heavy-Chain Binding Protein Several other autoantigens that are expressed in synovium have been characterized in RA, although they also are produced in many other locations. Antibodies directed against the heterogeneous nuclear ribonucleoprotein-A2, sometimes called RA33, occur in about one third of RA patients and

patients with other systemic autoimmune diseases. There may be some specificity for RA, however, compared with ­osteoarthritis and seronegative spondyloarthropathies. AntiRA33 ­antibodies also are produced in the TNF-α transgenic mouse model of RA, suggesting that proinflammatory ­cytokines can ­independently lead to a breakdown of tolerance for this particular protein.69 Although not especially sensitive or specific for RA when used in isolation, an algorithm involving anti-ribonucleoprotein-A2, RF, and anticitrullinated ­peptide can be used to predict patients with early synovitis who will progress to erosive RA.70 Autoantibodies that bind to stressprotein immunoglobulin heavy-chain binding protein (BiP) also have been observed.71 About 60% of RA patients have anti-BiP antibodies, and the specificity is reportedly more than 90%. In addition to humoral responses, RA T cells can proliferate in response to this protein. Immunization of mice with BiP does not cause arthritis, but it can cross-tolerize mice and prevent collagen-induced arthritis if administered before immunization with type II collagen.72 BiP is normally expressed in many tissues, but is markedly increased in RA synovium. Heat Shock Proteins The HSPs are a family of mainly medium-sized (60 to 90 kD) proteins produced in response to stress. These proteins have conserved amino acid sequences; for example, certain HSPs of Mycobacterium tuberculosis have considerable homology with HSPs of humans. The HSPs may facilitate intracellular folding and translocation of proteins as they protect cells from insults induced by heat, bacteria, and oxygen radicals. Immunity against HSPs contributes directly to synovitis and joint destruction in the adjuvant arthritis model in rats in which T lymphocytes recognize an epitope of mycobacterial HSP65 (amino acids 180 through 188). Some of these cells also recognize cartilage proteoglycan epitopes,73 perhaps explaining the targeting of joints. Some patients with RA have elevated levels of antibodies to mycobacterial HSPs, especially in synovial fluid.74 Most T cell clones isolated from RA synovial fluid with specificity to mycobacterial components express the γδ TCR (instead of the more common αβ form) and do not display CD4 or CD8 surface antigens. Freshly isolated synovial fluid T cells from patients with RA briskly proliferate in response to the acetone-precipitable fraction of M. tuberculosis and recombinant 65-kD HSP.75 Proliferation to other recall antigens, such as tetanus toxoid, is not increased, however. Synovial fluid mononuclear cells activated by 60-kD mycobacterial HSP inhibit proteoglycan production by human cartilage explants.76 This effect depends on the generation of cytokines such as IL1 and TNF-α by the activated cells. Human 60-kD HSP is expressed in the synovium; the amount expressed per cell seems to be similar in osteoarthritis, RA, and normal tissue.

SYNOVIAL PATHOLOGY AND BIOLOGY The primary inflammatory site in RA is the synovium. Infiltration of synovial tissue with mononuclear cells, ­especially T cells and macrophages, and synovial intimal lining ­hyperplasia are hallmarks of the disease (Fig. 65-6). In this section, the various cell lineages and histologic patterns of rheumatoid synovium are discussed.

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Figure 65-6  Histopathologic appearance of rheumatoid arthritis synovium. Intimal lining hyperplasia, angiogenesis, and a prominent mononuclear cell infiltrate are present. Panels show standard histology (top) and immunostaining for macrophages (brown in the intimal lining at bottom, left) and a perivascular T cell aggregate (bottom right). (Courtesy of Dr. Paul-Peter Tak.)

Key Points • The synovium in RA is marked by intimal lining ­hyperplasia and sublining infiltration with mononuclear cells, especially CD4+ T cells, macrophages, and B cells. • Synovial pathology and function of synovial cells in RA are distinctive in that: • Intimal lining FLS display unusually aggressive ­features. • Macrophages in the intimal lining are highly ­activated. • Lymphocytes can either diffusely infiltrate the ­sublining or form lymphoid aggregates with ­germinal centers. • Sublining CD4+ T cells mainly display the memory cell phenotype. • Synovial B cells and plasma cells in RA exhibit ­evidence of antigen-driven maturation and antibody production. • DCs potentially can present antigens to T cells in synovial germinal centers. • Mast cells produce small molecule mediators of ­inflammation. • Neutrophils are rarely present in RA synovium.

SYNOVIAL INTIMAL LINING CELLS: TYPE A AND TYPE B SYNOVIOCYTES The synovial intimal lining is a loosely organized collection of cells that form an interface between the synovium and the synovial fluid space. The intimal lining cells lack tight junctions and a definite basement membrane. The increase in cell number in RA can be substantial. In the normal joint, the lining is only one to two cell layers deep, whereas

in RA, it is often 4 to 10 cells deep. Two major cell types are found in the lining: a macrophage-like cell known as a type A synoviocyte and a fibroblast-like cell known as a type B synoviocyte. The former are derived from the bone marrow and express macrophage surface markers, such as CD68, Fc receptors, and CD14, and abundant HLA-DR, whereas the latter express little if any class II MHC antigens, are devoid of macrophage markers, and have a scant endoplasmic reticulum. The type B cells, also called FLS, express certain proteins that are unusual for mesenchymal cells, including vascular cell adhesion molecule-1 (VCAM-1), CD55 (decay accelerating factor), cadherin 11, and the proteoglycan-synthesis enzyme uridine diphosphoglucose dehydrogenase. The relative numbers of type A and type B cells are usually similar in normal synovium. There is an absolute increase in both cell types in RA, although the percentage increase in macrophage-like cells is often greater. In addition, type A synoviocytes tend to accumulate in the more superficial regions of the intimal lining. Synovial macrophages are terminally differentiated cells that presumably do not divide in the joint, and the accumulation of cells in RA is likely from the ingress of new bone marrow–derived precursors. Mesenchymally derived type B synoviocytes can divide locally in response to the proliferative factors generated by the activated immune response. Platelet-derived growth factor (PDGF), transforming growth factor (TGF)-β, TNF-α, and IL-1 produced by many different cells combine with products of ­ arachidonic acid ­metabolism to induce proliferation of these cells. In addition, pluripotential mesenchymal stem cells that arise in the bone marrow and circulate through the blood can migrate into the synovium and differentiate into type B synoviocytes.77 Although local proliferation of cells in the intimal lining likely occurs, rheumatoid synovium rarely shows mitotic

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fi­ gures, and thymidine uptake occurs in only a few synovial cells. Using a monoclonal antibody that recognizes dividing cells, an even lower rate of cell division (approximately 0.05%) is apparent.78 A higher percentage of cells that express the cell cycle–specific antigen proliferating cell nuclear antigen are present in RA lining cells compared with osteoarthritis. This correlates with the lining cell expression of the proto-oncogene c-myc, a gene that is intimately linked with fibroblast proliferation. The architecture of the synovial intimal lining is distinct from other lining layers in the body. In contrast to serosal surfaces, the intimal lining does not include epithelial cells, it lacks a basement membrane, and has no tight junctions. Rather than serving as a discrete barrier, it is a loose association of cells that is discontinuous in some locations. Cadherin 11, from a class of adhesion proteins that are ubiquitous in various tissues, serves as the major mediator of homotypic aggregation by FLS.79 Immunohistochemistry shows abundant expression of this protein in the intimal lining. Its importance in the synovial architecture was confirmed in cadherin 11 knockout mice, in which the intimal lining was virtually nonexistent. Finally, cadherin 11–expressing cells self-aggregate in vitro into a structure that appears similar to a synovial lining, and this function can be blocked with a cadherin 11-Fc fusion protein. Targeting cadherin 11 with blocking antibodies suppresses arthritis in the passive K/BxN model. These data suggest that FLS, similar to T cells, B cells, and macrophages, play a crucial role in the pathogenesis of inflammatory arthritis. After rheumatoid synovium is enzymatically dispersed in vitro, two major populations of adherent cells can be readily identified.80 One type of cell is macrophage-like; these cells have DR antigens, Fc receptors, and monocyte lineagedifferentiation antigens and are capable of phagocytosis. They have a limited life span in vitro, rarely surviving more than a few weeks even in the presence of exogenous growth factors or colony-stimulating factors (CSFs). A second type is defined by the presence of antigens expressed primarily on fibroblasts and by the absence of phagocytic capability, demonstrable DR antigens, or antigens of the monocytic lineage. When the enzymatically dispersed cells are cultured for several passages, this last cell type ultimately ­ survives and proliferates, resulting in a relatively homogeneous population of fibroblast-like cells. Ultrastructural studies and cell-cloning experiments of dissociated rheumatoid synovial cells have supported this classification.81 Fibroblast-like cells grow slowly, with a doubling time of 5 to 7 days. The fibroblast-like cells grown from the dispersed cells can be passaged for several months in vitro. Their doubling rate is rapid at first, perhaps owing to the presence of cytokines produced by contaminating macrophages in the culture or a carryover effect from the synovial milieu. Over time, proliferation slows, and after 12 to 15 passages, the cells gradually become senescent and ultimately cease to grow. Although it has not been proven that these cells originate solely from the synovial intimal lining, the fact that a significant percentage of cells expresses VCAM-1 and CD55 suggests that at least some are derived from this region. Synovial fibroblasts from RA have some characteristics reminiscent of tumors or transformed cells (see following).

Experiments examining synovial tissue and FLS gene expression profiles have identified subsets of patients with specific patterns that correlated with synovial histopathology. Hierarchical clustering identified two types of FLS characterized by distinctive gene expression profiles.82 FLS from inflammatory tissues exhibited a TGF-β gene signature that also has been described in myofibroblasts and seems to be involved in wound healing. A second pattern was reminiscent of insulinlike growth factor regulated genes and was observed in relatively noninflammatory RA tissue. Whether the pathogenic processes in the synovium imprint the synoviocytes or vice versa has not been determined. Attempts to distinguish RA and osteoarthritis FLS expression profiles from each other have offered mixed results. No consistent differences have been observed, although one study suggested that IL-32 and the chemokine CCL2 are relatively overexpressed in RA cells. Aggressive Features of Rheumatoid Arthritis Fibroblast-like Synoviocytes Rheumatoid FLS show some unusual properties compared with cells obtained from other synovia. Several properties reminiscent of cell transformation have been evaluated in RA and have led to the notion that synoviocytes might be permanently altered by their environment. Adherence to plastic or extracellular matrix is generally required for normal fibroblasts to proliferate and survive in culture. Although FLS typically grow and thrive under conditions that permit adherence, RA synoviocytes also can proliferate in an anchorage-independent manner.83 In addition, cultured RA synoviocytes can exhibit defective contact inhibition and express a variety of transcription factors, such as c-Myc, which are typically abundant in tumor cells. Poorly regulated cell growth likely occurs in vivo as well; studies examining X-linked genes show oligoclonality in the synoviocyte population from RA, but not osteoarthritis, synovium.84 This oligoclonality is especially true of cells derived from the invading pannus, which is the most aggressive region of the synovium. Increased telomerase activity, another feature of transformed tissue, also is present in RA synovium and can be observed in fibroblast growth factor (FGF)–stimulated RA synoviocytes. In a severe combined immunodeficiency (SCID) mouse model, enzymatically dispersed FLS are coimplanted into the mice with cartilage explants. The rheumatoid cells invade the cartilage matrix, looking like destructive pannus.85 This phenomenon occurs even if pure populations of long-term cultured RA FLS are used (Fig. 65-7).86 Because these synoviocytes are devoid of T cells and macrophages, there is no contribution from an immune response to murine ­antigens. The invading cells express VCAM-1, which potentially could facilitate adhesion to cartilage or chondrocytes, and proteases that digest the cartilage matrix. Control ­ synoviocytes from osteoarthritis patients and ­normal dermal fibroblasts do not invade the cartilage, indicating that the activity is unique to rheumatoid FLS. These observations form the compelling evidence that rheumatoid synoviocytes have unique characteristics that can resemble partial ­transformation. Using viral vectors to introduce cytokine genes into this explanted synoviocyte, one can evaluate their respective roles in cartilage invasion. IL-1 receptor antagonist (IL-1Ra), a natural antagonist to IL-1, has no effect on

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Invading fibroblast-like synoviocytes

Cartilage matrix Figure 65-7  Invasion of rheumatoid arthritis synoviocytes into  cartilage explants in severe combined immunodeficiency syndrome (SCID) mice. Rheumatoid arthritis fibroblast-like synoviocytes were co­implanted with normal human cartilage into the renal capsule of SCID mice. The synoviocytes attached to the cartilage and invaded the matrix. Several ­chondrocytes in lacunae also are present. (Courtesy of Dr. S. Gay.)

s­ ynoviocyte invasion, but decreases perichondrocyte matrix loss.87 In contrast, IL-10 decreases invasion, but does not alter matrix loss. Finally, overexpression of soluble TNF receptors has no consistent effect in this model. These studies suggest that excessive production of IL-1 and underexpression of IL10 contribute to the invasive properties of RA synoviocytes. In another study, transfecting normal synoviocytes with the human papillomavirus gene encoding E6 induced the ­rheumatoid phenotype.88 The E6 protein leads to the inactivation and degradation of the p53 tumor-suppressor protein. Although this is not the sole explanation for the altered adhesion and invasion properties of RA synoviocytes, deficient p53 function potentially can contribute. The oncogenes Ras and c-Myc also contribute to synoviocytes’ invasiveness in this model, and transfection of cells with dominant negative constructs decreases the aggressive phenotype of the rheumatoid cells. Antisense treatment of cells to knockdown membrane type I metalloproteinase expression also reverses the abnormality.89 SYNOVIAL T LYMPHOCYTES Immunohistologic Patterns In chronic RA, the synovium contains a collection of T lymphocytes that can lead to an organizational structure that resembles a lymph node. The distribution of lymphocytes in the tissue varies from discrete lymphoid aggregates to diffuse sheets of mononuclear cells, with the most prominent location for T cells being the perivascular region. These collections consist of small, CD4+ memory T cells (CD45RO+) with scant cytoplasm. A few scattered CD8+ T cells accumulate in the aggregates; formation of ectopic germinal centers in RA synovial tissue may depend on these cells. Peripheral to these foci is a transitional zone with a heterogeneous mixture of cells, including lymphocytes, occasional undifferentiated blast cells, plasma cells, and macrophages (see Fig. 65-6). Intercellular communication by soluble mediators and direct cell-cell contact occurs here via adhesion molecules, including the lymphocyte function–associated antigens.

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Considerable heterogeneity exists in the histologic patterns within a single joint and from patient to patient. Synovial biopsy studies suggest that at least six sites must be evaluated to decrease the risk of sampling error to 10% to 20% or less.90 In situations in which the synovia of more than one joint from an individual patient is available, the same general histopathologic patterns are usually apparent in tissue from separate sites. Although the correlation between clinical disease activity is tenuous, the presence of granulomatous lesions might be associated with extra­articular disease. Regulation of Lymphoid Aggregate Formation T cells often constitute 30% to 50% of cells in RA synovia, and most are CD4+. About 5% of cells are B lymphocytes or plasma cells, although in some tissues the percentage can be considerably higher. B cells are located primarily within reactive lymphoid centers, whereas plasma cells and macrophages are often found outside these centers. This arrangement is consistent with T cell–dependent B lymphocyte activation. Plasma cells, the main immunoglobulin producers, migrate away from the germinal centers after differentiation. CD4+ cells in RA synovium are in intimate contact with B lymphocytes, macrophages, and DCs. Chemokines play a key role in the organization of tissues into lymphoid structures such as aggregates and germinal centers. CXCL13 and CCL21 seem to be especially important, and their expression in rheumatoid synovium correlates with the presence of this microarchitecture.91 CXCL13, in particular, is produced by synovial follicular DCs. Similarly, plasma cells expressing the chemokine receptor CXCR3 are present in the rheumatoid synovium. The CXCR3 ligand, Mig/CXCL9, is highly expressed in intimal lining synoviocytes and sublining cells and presumably plays a role in the recruitment and retention of plasma cells to these CD4+ T cell aggregates.92 The architecture of lymphoid structures in rheumatoid synovium also is regulated by members of the TNF superfamily. Lymphotoxin-α (LTα) and lymphotoxin-β (LTβ) form trimeric molecules in various combinations that can bind to distinct cell surfaces. LTα1β2 (one α chain and two β chains) binds exclusively to the LTβ receptor (LTβ-R), whereas LTα3 can bind to the TNF-R1 and TNF-R2. A third related member of the family, LIGHT, also can interact with the LTβ-R or to the herpesvirus entry mediator (HVEM). LTα, LTβ, and LIGHT regulate the function and organization of lymphoid tissues. Deletion of either LTα or LTβ seriously impairs lymphoid development, whereas lymph nodes develop normally in LIGHT-deficient mice. In the SCID mouse model using RA tissue explants, depletion of CD8+ T cells led to loss of follicular DCs, depletion of LTα1β2, and disintegration of the lymphoid follicles.93 IL16 production by CD8+ T cells seems to play a role in this process. Although LTα3 is difficult to detect in RA, LTα1β2 and LIGHT are present.94 In addition to regulating lymphoid aggregate and germinal center formation, LTα1β2 can dire­ctly stimulate FLS to produce chemokines such as CCL2 and CCL5 that attract T cells into the joint.95 LIGHT also enhances osteoclast differentiation and induces expression of MMP9, TNF-α, IL-6, and IL-8 by macrophages.96 When LTβ and LIGHT are inhibited in the collagen-induced

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arthritis model using a genetically engineered receptor, clinical arthritis is decreased.97 The construct is not effective, however, in the passive arthritis model, in which the pathogenic antibodies are directly administered to mice. The LIGHT axis seems to play a more important role in the early phases of disease, but not in the terminal effector stages. Synovial T Cell Phenotype RA synovial T lymphocytes display an activated surface phenotype, with high expression of HLA-DR, CD69, and CD27. CD27+CD4+ T cells provide B cell help that potentially can increase synovial antibody production.98 For maximal T cell responses, a second signal, in addition to antigen stimulation, is usually required. CD28 is one of these costimulatory molecules on T lymphocytes and is highly expressed by synovial T cells in RA. Its ligands, CD80 and CD86, also are displayed on antigen presenting cells in the joint, providing an excellent environment for T cell activation. The importance of the CD80/CD86-CD28 interaction is supported by the observation that an agent that blocks this interaction, abatacept, is effective in RA. One unusual phenotype of synovial T cells in RA is a population that expresses CD4 but lacks CD28. Oligoclonal expansion of CD4+CD28− T cells has been described in peripheral blood and joint samples of patients with RA.99 The cells can be cytotoxic and can respond to autoantigens, but are inefficient B cell stimulators. This population of T cells also occurs more frequently in patients with extra-articular manifestations of RA. CD40, another costimulatory molecule, and its ligand on T cells, CD40L, also are expressed in RA synovium.100 CD40L, a member of the TNF superfamily, can synergize with IL-1 for the production of cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), by CD40-bearing synoviocytes.101 Synovial lymphocytes also bear adhesion molecules of the very late activation antigen (VLA) and lymphocyte function–associated antigen superfamily of integrins, which may enable the inflammatory response to localize and persist within the synovium. A high level of telomerase activity also is present in synovial lymphocytes in RA, but not in osteoarthritis or trauma patients.102 Telomerase activity level in the synovial T cells correlates with the intimal lining hyperplasia, angiogenesis, and local lymphocyte accumulation. T cell activation and the induction of adhesion molecules and other “activation markers” may not occur within the joint; rather, this T cell phenotype could enter the synovium and remain within the joint under the influence of locally expressed chemotactic factors and their armamentarium of adhesion molecules. The cytokine milieu of the joint induces adhesion molecules, such as intercellular adhesion molecule1 (ICAM-1), VCAM-1, and connecting segment-1 (CS-1) fibronectin, on vascular endothelium. These, in conjunction with chemokines and other chemoattractants, call the cells to the joint based precisely on this phenotype. Synovial T cells in RA express characteristic receptors to specific chemokines. The chemokine receptor CCR5 is the ligand for macrophage inhibitory protein (MIP)-1α and MIPβ and is highly expressed in the infiltrating RA T cells.103 This particular receptor, along with CXCR3, is preferentially found on Th1 T cells, an observation that might explain accumulation of this phenotype in the ­rheumatoid synovium.

Expression of nonfunctional CCR5 alleles that protect from human immunodeficiency virus infection might diminish the risk of RA. The chemotactic factor stromal cell–derived factor-1 (SDF-1; CXCL12) also is produced by synovial tissue, and its specific receptor, CXCR4, is displayed by rheumatoid synovial T cells.104 Other T cell phenotypes are implicated in the pathogenesis of synovitis and can be detected in RA, including Th17 cells, which produce IL-17, and CD4+CD25+ regulatory T cells (Tregs), which can suppress immune responses (see subsequent section T cell subsets). Numerous groups have evaluated TCR gene rearrangements for clues related to antigen-specific expansion. In some patients, a pattern emerged suggesting an increased number of T cells expressing Vβ3, Vβ14, and Vβ17, especially in synovial tissue. These particular Vβ genes are structurally related and are unusually susceptible to activation by superantigens. Most studies either have not found evidence for the restricted clonality of T cells in RA synovial fluid, synovial tissue, and blood, or have not identified expansion of different Vβ or Vα genes.105 Overall, the data suggest that the local accumulation of T cells in the joint is not related to proliferation induced by a particular antigen. Instead, antigen-independent processes related to the expression of chemokines and adhesion molecules on vascular endothelium and circulating lymphocytes help determine the mononuclear cell infiltrate. Although local antigen-specific expansion might occur, it is probably responsible for a small component of the T cell infiltrate. The cells that encounter their appropriate antigen in the correct cytokine and antigen presenting cell environment potentially can activate other local cells through direct cellcell contact (Fig. 65-8) or the elaboration of lymphokines. An alternative explanation is that T cell activation mainly occurs in central lymphoid organs. In this scenario, DCs that encounter antigens in the synovium or other sites migrate to lymphatic tissue and present antigen to naive T cells. When activated, these T cells enter the circulation and can home to the joint where they can produce cytokines to activate resident cells.

Mp Mp

T-blast

Mp 1 Figure 65-8  T cell in rheumatoid synovial tissue surrounded by three macrophages (Mp). Arrows point to probable intercellular bridging. Contact between macrophages in T cells can lead to antigen-independent activation of macrophages with production of cytokines and proteases. (Courtesy of Dr. H. Ishikawa and Dr. M. Ziff.)

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Synovial T Cell Immune Responses The histopathologic appearance of RA, with exuberant infiltration of the synovium with T lymphocytes, is often pointed to as evidence of a T cell–mediated disease because this is also characteristic of antigen-specific responses. The synovium can respond to inflammation in only a few ways, however. The histologic appearance of chronic arthritides that are not mediated by T cells (e.g., chronic tophaceous gout) exhibits many of the same features. Progressive destruction in RA patients despite the presence of acquired immunodeficiency syndrome suggests that non–T cell mech­ anisms also are important.106 Nevertheless, efficacy of abatacept, a novel T cell–directed approach that interferes with costimulation, shows that T cell responses play a role in most patients with RA. The microheterogeneity of the rheumatoid synovial tissue, with different numbers and proportions of cell lineages in each area, suggests that antigens presented at each location also might differ, with type II collagen presented to T cells one place, proteoglycans presented elsewhere, and responses to HSPs or viral antigens in yet another region. Although synovial T cells generally are considered activated, proliferative and cytokine responses are often less than normal peripheral blood cells or even autologous peripheral blood T cells. Spontaneous and stimulated cytokine production, including Th1 factors such as IFN-γ and IL-2, is relatively low. Responses directed toward recall antigens also are deficient, although RA synovial T cells can proliferate briskly to certain HSPs. The mechanisms of decreased responsiveness in the synovial tissue compartment have not been studied as extensively as in synovial fluid or peripheral blood, but they likely include exposure to suppressive factors (e.g., TGF-β), abnormal redox potential that suppresses TCR signal transduction, or induction of anergy. Another contributor to local anergy is the relative lack of the costimulatory molecule CD80 on HLA-DR+ FLS because coculture of T cells with the synoviocytes suppresses subsequent allogeneic res­ ponses.107 Synovial T cells in RA functionally resemble resting peripheral blood T lymphocytes that have been activated by cytokines rather than antigen.108 Synovial and blood T lymphocytes are able to stimulate macrophages to produce TNF-α in a cell contact–dependent manner. This process depends on NFκB and is mechanistically distinct from T cell activation via the TCR, which is independent of NFκB. The contribution of T cells to the proinflammatory cytokine milieu may be unrelated to antigen-mediated events and could result from passive activation after exposure to the cytokine environment. Although increased immunoreactivity contributes to the etiology of RA, the search for a specific rheumatoid antigen has not been fruitful. More recent data, especially in animal models, suggest that breakdown of tolerance can be due to a combination of factors early in development. Mutations in the ZAP70 gene can lead to spontaneous T cell–dependent inflammatory arthritis in mice.109 This protein is intimately involved with transducing TCR signals and activating T lymphocytes. An abnormal ZAP70 gene leads to defective positive and negative selection in the thymus and allows autoreactive T cells to escape. As a result, mice produce

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autoantibodies (e.g., RF and anti–double-stranded DNA) and develop a severe destructive arthritis. The disease can be transferred by thymocytes or peripheral CD4+ T cells into syngeneic mice with a normal ZAP70 gene. The cytokine profile of this model is much like RA, and mice with deficient TNF-α, IL-1, or IL-6 have reduced ­synovitis. IFN-γ deficiency has no effect, whereas IL-10 deficiency exacerbates disease. These studies show that minor changes in the TCR complex can alter T cell selection and induce T cell–dependent arthritis. Despite the clear T cell dependence of the model, the cytokines implicated are remarkably similar to autoantibody-dependent models. The cytokine profile in RA (see later) in many ways represents a final common pathway for a variety of autoimmune ­mechanisms. Restoring T Cell Tolerance Assuming that synovial T cell autoreactivity plays a key role in the pathogenesis of RA, one potential therapeutic approach is to restore tolerance. This concept has been problematic because the underlying defect has not been defined and could include abnormal thymic selection, poorly defined genetic factors that lead to immune hyperreactivity, or inadequate regulatory T cell function. The lack of a specific antigen identified as pathogenic also increases the complexity of the problem. It is clear, however, that current approaches do not “cure” RA because cessation of therapy usually leads to a recurrence of disease. Two examples illustrate the potential for restoring homeostasis and immune tolerance. First, recent data suggest that aggressive treatment of early RA (within the year of clinical disease) with methotrexate and a TNF inhibitor could lead to long-lasting remissions.110 In many cases, therapy was withdrawn after 1 year of treatment, and patients did not flare for at least 1 additional year. The mechanism of prolonged remission despite discontinuing therapy in early disease is not defined, but seems to differ from clinical experience in chronic RA. Another way to induce tolerance is through mucosal immunization to enhance Th2 function. In a clinical trial, patients with RA were treated with oral administration of the dnaJP1 peptide, and T cell responses were evaluated.111 The peptide-treated patients showed immune deviation toward a Th2 phenotype. This approach has the potential for developing individualized therapy based on specific antigens that might be pathogenic for each patient, such as QKRAA, collagen epitopes, HSPs, or many others. Additional therapies that enhance regulatory T cell function, alter costimulation, or delete only pathogenic T cells may potentially be effective in RA. SYNOVIAL B CELLS Synovial B cell and plasma cell hyperreactivity are viewed increasingly as key participants in the perpetuation and initiation phases of RA. This notion has been fueled by the descriptions of novel spontaneous models of arthritis in mice, such as the K/BxN model, in which loss of tolerance leads to autoantibody production, activation of innate immunity, and chronic synovitis. B cell–directed therapies, such as anti-CD20 antibody, have shown efficacy in RA.

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Cytokine Regulation of Synovial B Cells Although many rheumatoid synovial tissues exhibit a diffuse infiltration with mononuclear cells, a significant percentage also have discrete lymphoid follicles populated by B cells in the sublining region. Follicular DCs, B cells, plasma cells, and T lymphocytes collect in these aggregates. The germinal centers are highly organized structures in which affinity maturation occurs. B cells are present in the aggregates and express the maturation marker CD20 and proliferation ­ antigens such as Ki67. The formation of these structures depends on several soluble and membrane-bound cytokines, including lymphotoxin. B cells accumulate in lymphoid aggregates in RA synovium under the influence of a variety of chemotactic factors, including CCL21 and B cell–attracting chemokine-1 (CXCL13). A member of the TNF superfamily of cytokines known as B lymphocyte stimulator (BLyS) also has been identified as a key molecule that regulates B cell differentiation. BLyS binds to transmembrane activator and CAML interactor (TACI), which is present on B cells and T cells. If this system is blocked using recombinant TACI-Ig, the number of B cells is dramatically reduced, and antibody production is decreased. The same construct is effective as a therapeutic agent in collagen-induced arthritis, a model that depends on autoantibody production.112 BLyS is produced in RA synovium, especially by macrophages. Synovial lining type B synoviocytes also can release BLyS and can be induced by TNF-α and IFN-γ in vitro.113 A related cytokine, also in the TNF superfamily, called APRIL is localized mainly to DCs in synovial germinal centers.114 TACI-Ig, which binds BLyS and APRIL, disrupts the germinal centers and decreases immunoglobulin receptors in SCID mice implanted with rheumatoid synovium.115 A clinical trial using an anti-BLyS antibody showed minimal benefit, however, in patients with RA. This result could be related to the fact that APRIL is still able to interact with cell surface TACI. Synovial B Cell Maturation B cells isolated directly from germinal centers of RA synovium show a heterogeneous pattern of V gene usage and rearrangement. Most VH genes are not mutated, suggesting that they are recent immigrants from the peripheral blood and are activated locally.116 For RF-producing cells, shared mutations containing an identical sequence throughout the variable domain of immunoglobulins have been identified in synovial tissue.117 Preferential use of a few VH and DH gene segments and marked preference for a DH reading frame encoding particular hydrophilic residues also have been observed, consistent with antigen-related selection and maturation. Analysis of expressed heavy-chain variable domains supports the notion that the B cell response in RA synovium is oligoclonal. Similarly, B cell clones isolated from either RA synovium or bone marrow with nurselike cells have limited VH usage. B cells associated with follicular DCs in the rheumatoid synovium can differentiate further and develop additional mutations, suggesting antigen-driven selection. Plasma cells in other areas of the synovium have distinct rearrangements compared with the B lymphocytes associated with DCs.

This finding raises the question of whether the plasma cells arise locally or migrate from the blood. Although plasma cell rearrangements are not similar to the B cells, groups of plasma cells used similar genes, albeit with distinct mutations. The plasma cells probably are derived from a synovial B cell clone that mutated and whose progeny proliferate and differentiate. It is uncertain whether this process represents an ectopic lymphoid organ performing normal functions, or whether it is related to autoimmunity. The presence of abundant autoantibody-producing cells in the synovium supports the latter hypothesis, although normal immune responses also might occur in the joint. Cells that produce RFs, anti–type II collagen antibody, and anticitrulline peptide antibody populate the RA synovium. Not all B cells in the joint are activated, however. A population of CD20+CD38− B cells with impaired receptor-induced signaling as previously observed in anergic cells also infiltrates the synovium.118 Some B cells also serve a more active role in synovial immune responses. In a SCID mouse model using synovial explants, T cell activation and cytokine production de­­ pended on B cells.119 In the same model, treatment with TACI-Ig, which inhibits APRIL and BLyS, decreased synovial inflammation and IFN-γ production in tissues displaying germinal centers. Maturation and survival of B cells depend on stromal cells and cells with “nurse-like cell” properties that support lymphocyte maturation in the thymus. The bone marrow and synovium of patients with RA also contain nurse-like cells, which can increase expression of CD40 and class II MHC proteins on B cells.120 B cell survival is supported by this population of cells, whereas autoreactive clones evade deletion and produce autoantibodies. A variety of cytokines, including GM-CSF, IL-6, and IL-8, are produced by RA nurse-like cells, and direct contact with B cells is crucial for maximal proliferation and antibody production.121 Cultured B cells spontaneously migrate beneath ordinary FLS, which permits them to survive in vitro for prolonged periods. The process depends on the interaction of the integrin α4β1 on B cells with synoviocytes expressing CD106 (VCAM-1).122 The chemokine SDF-1 also is constitutively expressed by synoviocytes and contributes to the process. Interference with the B cell–synoviocyte interaction decreases B cell survival and is one potential mechanism by which therapeutic interventions targeted at integrins might suppress autoreactivity and inflammation in RA. B Cell Depletion in Rheumatoid Arthritis Although the role of T cells and cytokines attracted most of the scientific interest in recent years, clinical trials with an anti-CD20 antibody (rituximab) showing efficacy in RA refocused investigators on B cells and autoantibodies. The precise function of CD20 is not well defined; it is expressed on mature B cells, but not plasma cells. Rituximab causes a rapid and profound depletion of peripheral blood B cells. In mice, anti-CD20 antibody depletes B cells in blood, spleen, lymph nodes, and bone marrow. The few remaining B cells in the spleen were of the B1, but not B2, phenotype. Peritoneal B cells are only partially depleted, suggesting that some sites are privileged and protect B cells despite adequate drug penetration.123 In RA, serial synovial biopsies show partial

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B cell depletion after rituximab therapy despite the virtual absence of peripheral B cells. The clinical responses do not always correlate closely with the extent of synovial depletion, although some patients with the most impressive responses seem to have marked declines in the number of B cells in the post-treatment specimens. The B cell depletion data raise many questions about the precise role of B cells in the rheumatoid synovium. Rituximab can modestly decrease autoantibody formation, but it is unclear that this is sufficient to account for the clinical responses. B cells also produce cytokines and can enhance T cell responses by serving as antigen presenting cells. Because plasma cells do not express CD20, a major source of autoantibodies is still present in the joint. The precise mechanism of anti-CD20 antibody might be complex and involve many B cell functions, rather than simply decreasing the autoantibody production and immune complex formation. DENDRITIC CELLS DCs are potent antigen presenting cells that populate synovial tissue and synovial effusions of patients with RA. DCs generally sample the environment, especially at mucosal and skin surfaces; process antigens; and migrate to central lymphatic sites, where they present the antigens to T cells. Rheumatoid synovium seems to function similar to lymphoid tissues in some circumstances with mature DCs expressing CD86, CD83, and DC-LAMP localized in perivascular lymphocytic infiltrates and aggregates. Ultrastructural analysis of the synovium shows the DCs in contact with lymphocytes, where they are probably presenting antigen. The presence of DCs is not unique to RA and has been identified in other inflammatory arthritides, including gout and spondyloarthropathies. The reason that DCs reside in the synovium probably relates to the chemokine milieu in the joint.124 DCs express the chemokine receptor CCR7, which usually permits them to home to lymphoid tissue and orchestrate organization into the appropriate germinal centers. Synoviocytes in RA express two CCR7 ligands (CCL19 and CCL21), which provide a signal for the DCs to remain in the peripheral tissue. Immature DCs and plasmacytoid DCs also have been observed scattered throughout the synovial sublining region. B cell–enriched lymphoid follicles, which are usually organized around follicular DCs, also are found in some RA joint tissues. The source of follicular DCs is not well defined, but cultured FLS can perform follicular DC functions in vitro and could contribute in vivo as well. Synoviocytes derived from RA patients can bind to germinal center B cells and suppress B cell apoptosis.125 Cytokines that are abundant in RA, such as GM-CSF, influence the proliferation and maturation of these antigen presenting cells. DCs can constitute 5% of synovial fluid mononuclear cells, which is almost 10-fold higher than in peripheral blood.126 RA synovial tissue DCs can respond abnormally to certain cytokines known to be present in the rheumatoid joint. IL-10 normally suppresses DC function, partly by decreasing expression of CD86 and class II MHC molecules. RA DCs isolated from the joint are resistant to this effect, however, possibly because they express smaller amounts of the IL-10 receptor.127 Aside from presenting

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antigens, DCs also can produce cytokines that can influence T cell differentiation in the joint, including IL-12 and IL-23, which can enhance the bias toward the Th1 and Th17 (see later) phenotypes, and APRIL, which enhances B cell survival. Engineered DCs have been used in animal models to suppress disease, including cells that produce excess Th2 cytokine such as IL-4.128 MAST CELLS, POLYMORPHONUCLEAR LEUKOCYTES, AND NATURAL KILLER CELLS Mast cells are present in the synovial membranes of patients with RA and, in some patients, are located at sites of cartilage erosion. Rheumatoid synovial membranes contain more than 10 times as many mast cells than do control synovial samples from patients undergoing surgery for meniscectomy. Patients with high numbers of mast cells have more intense clinical synovitis in the affected joints. Mast cells and histamine also are found in most synovial fluid specimens from inflammatory synovitis. A detailed analysis of several indicators of proliferation and the enumeration of synovial mast cells has shown strong positive correlations between the number of mast cells in synovial tissue and the degree of lymphocyte infiltration.129 Mast cells from RA synovium express significantly greater amounts of the C5a receptor compared with osteoarthritis synovium. Resident mast cells in synovium respond to cytokines that stimulate mast cell growth and chemotaxis. Extracts of mast cells can induce adherent rheumatoid synovial cells to increase production of prostaglandin (PG) E2 and collagenase, and immunostaining of RA synovial mast cells shows tryptase and TNF-α. Mast cell–derived heparin has significant effects on connective tissue. In particular, it may modulate the effects of hormones on osseous cells and alter the balance of bone synthesis toward degradation. The role of mast cells in the initiation phase of synovitis was confirmed in the passive K/BxN model, in which their absence prevented disease.130 It is uncertain if the cells are required when synovial inflammation has been established, and other cell types, such as neutrophils, supplant the mast cells in some circumstances. The production of leukotriene (LT) B4 in the same model requires neutrophils, but not mast cells in established disease. Treatment of synovial tissue explant cultures with a c-kit tyrosine kinase inhibitor induces mast cell apoptosis and decreased production of TNF-α.131 These data suggest that mast cells might contribute to synovial cytokine production in established disease. Despite the abundance of neutrophils in RA synovial effusions, only rare polymorphonuclear neutrophils (PMNs) infiltrate the synovium. Natural killer cells have been identified, however, in RA synovium.132 Cytotoxic natural killer cells contain large amounts of granzymes, which are serine proteases. One potentially important immunoregulatory role of natural killer cells is that they can stimulate B cells to produce RFs. A subset of natural killer cells that express large amounts of CD56 is unusually abundant in RA synovial tissue and fluid.133 These cells potentially can produce cytokines or enhance pro­ inflammatory cytokine production by T lymphocytes and ­macrophages.

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BONE MARROW CELLS Although most attention has been directed at the synovium, cartilage, and cortical bone in RA, the subcortical bone and bone marrow also contribute to synovial inflammatory responses. Primitive bone marrow mesenchymal cells can traverse cortical bone through pores in murine collageninduced arthritis before the onset of clinical disease, take up residence in the synovium, and produce mediators that enhance synovitis.134 This process is TNF-α dependent and is abrogated in mice that lack TNF receptors. Also, CD34+ mesenchymal cells in rheumatoid bone marrow are more highly activated as judged by their NFκB status and their ability to differentiate into fibroblast-like cells that produce MMPs and proangiogenic factors.135 The bone marrow also can contribute other relevant cells, including macrophage lineage cells that migrate to the synovium and Sertoli-like cells that support the survival of B cells. Just as the bone marrow can influence the synovium, the reverse also is true. Invasive pannus can rupture through cortical bone and invade the marrow space in some patients.136 When this occurs, B cell aggregates are especially prominent in the marrow and occur in an environment rich in B cell chemoattractants such as CCL21 and B cell survival factors such as BLyS. SYNOVIAL HISTOPATHOLOGY IN EARLY VERSUS LATE RHEUMATOID ARTHRITIS Previous observations suggested that the earliest phases of RA (i.e., during the first few weeks of symptoms) exhibit distinct histopathology with a paucity of lymphocyte infiltration in the presence of endothelial cell injury, tissue edema, and neutrophil accumulation. More recent reports suggest, however, that the histologic appearance of RA is similar regardless of the duration of clinical symptoms.137 The extent of lymphoid aggregation, T cell infiltration, and synovial lining hyperplasia can resemble chronic disease even when symptoms have been present for a short time. The cytokine patterns of these biopsy specimens as determined by immunohistochemical analysis indicated similar levels of T cell (e.g., IFN-γ) and non–T cell factors (e.g., IL-1 and TNF-α). The tumor-suppressor gene p53 also is expressed in early RA, most likely owing to intense oxidative stress in the environment. Biopsy specimens of asymptomatic joints from patients with early or late RA also have lymphocyte infiltration, cytokine production, and p53 expression.138 Although IFN-γ, IL-1, and TNF-α levels are increased compared with normal synovium, they are modestly lower than in clinically active joints. One difference might be the relative abundance of some cytokines, such as IL-8, and the number of macrophages, which are higher in the painful joints. Some aspects of synovial histology in early RA, such as macrophage and plasma cell infiltration, might predict more erosive or severe disease. Studies in animal models of arthritis also show increased expression of proinflammatory transcription factors, such as activator protein-1 (AP-1) and NFκB, before clinically evident arthritis.139 These studies suggest that patients with “early” RA, as defined by the duration of symptoms, might already have chronic disease, and that evaluation of truly early disease might require assessment of

patients long before the onset of symptoms (if this is even possible). The observation that autoantibodies are produced in RA patients years before the clinical arthritis also supports the notion that a preclinical phase may precede symptomatic synovitis.

SYNOVIAL FLUID Key Points • RA synovial effusions contain abundant neutrophils and mononuclear cells. • Immune complexes that contain autoantibodies such as RFs or anticitrullinated protein antibodies can fix complement, leading to the generation of chemoattractants. • Small molecule mediators of inflammation, such as PGs and LTs, are present in RA synovial fluid.

Synovial effusions accumulate in the joints of most patients with active RA as a result of a substantial increase in fluid influx that cannot be removed despite an increase in lymphatic flow. Components of the inflammatory and proliferative response can be evaluated in the effusions to provide clues to the proinflammatory and anti-inflammatory mechanisms that operate in RA. It has been known for many years that there is an inverse relationship between the molecular weight of proteins and their concentrations in minimally inflamed synovial fluid. High-molecular-weight serum proteins gain access more easily to synovial fluid in inflamed joints, and the relatively high concentration of IgG in RA synovial fluid is good evidence for local (synovial) synthesis of IgG. Protein traffic in human synovial effusions has been measured by determining the clearance of proteins from synovial fluid and has provided a useful measure of afferent synovial lymph flow. A markedly increased permeance of blood vessels in rheumatoid patients confirms the severity of the microvascular lesion in rheumatoid synovitis. Newer techniques evaluating the synovial fluid proteome in RA using mass spectroscopy might provide new insights into the key mediators. More than 400 proteins in RA effusions were identified as potential biomarkers of disease activity, including C-reactive protein and six members of the S100 family of calcium granule binding proteins.140 POLYMORPHONUCLEAR NEUTROPHILS The presence of PMNs remains one of the most consistent indices of inflammation within a particular joint. These cells truly amplify inflammatory responses and contribute to the perpetuation of the inflammation within joints. The articular cavity serves as a depository for PMNs; they enter the synovial fluid by direct passage from postcapillary venules in the synovium. Neutrophils adhere to activated synovial microvasculature because of the action of selectins and the β2 integrins. After adherence, chemotactic agents produced by endothelium and fibroblasts may facilitate egress through the capillaries along the chemoattractant gradients of the synovium. Considering the survival time of PMNs in synovial fluid, it has been estimated that the breakdown of an average rheumatoid effusion containing 25,000/mm3 PMNs may exceed 1 billion cells each day. The ultimate fate of

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many of these cells is apoptosis. Neutrophil survival requires expression of the forkhead transcription factor Foxo3a.141 Mice that are deficient in this gene are resistant to inflammatory arthritis because of the shortened PMN life span. Neutrophils lacking this factor increase expression of the apoptosis-inducing membrane protein Fas ligand after exposure to proinflammatory cytokines. Foxo3a inhibition potentially can limit the acute inflammatory response in certain diseases where neutrophils play a prominent role. The strong attraction of chemotactic agents within the synovial fluid in RA is responsible for the large number of cells found there. Few PMNs are seen in the pannus itself and subsynovial tissue; when in the synovium, they move rapidly to the synovial fluid, drawn by the activated component of cleavage of C5a, LTB4, platelet-activating factor, and chemokines. The CXC family of chemokines, including ENA-78 and IL-8, are especially abundant in synovial fluid and can attract neutrophils into the intra-articular space. PMNs also can release chemokines into the milieu that enhance migration of new cells into the joint space. MIP-3α mRNA is specifically produced by synovial fluid PMNs of RA patients.142 When in the joint, neutrophils engage immune complexes through Fc receptors and other activating signals. This engagement leads to cytoskeletal reorganization, release of granule content, generation of reactive oxygen and nitrogen species, and enhanced phagocytosis. Many of the cells contain immune complexes within phagosomes that include IgG and IgM along with complement proteins such as C1q, C3, and C4. PMNs from synovial fluid in RA release de novo synthesized proteins, including matrix proteins such as fibronectin, neutral proteinases, and IL-1. Neutrophils also secrete IL-1Ra as a major product. Although the amount of IL-1Ra each neutrophil produces is low compared with that produced by macrophages, the sheer number of PMNs allows them to produce large amounts in synovial effusions. Oncostatin M, a member of the IL-6 family, is released by synovial fluid neutrophils.143 These cells also release numerous proteases that can adversely effect the lubricating properties of synovial fluid and the integrity of the cartilage, including elastase, trypsin, and neutrophil collagenase. Although difficult to assess in humans, animal models show a variable role for neutrophils in the inflammatory and destructive processes. In the streptococcal cell wall model, neutrophils play a more prominent role compared with models induced by intra-articular injection with bacterial DNA. The passive K/BxN and collagen-induced arthritis models, which require systemic injection with antibodies that bind to the joint and fix complement, require neutrophils for full expression of the disease. In each case, depleting neutrophils with antibodies almost completely prevents synovial inflammation. In the K/BxN model, neutrophils initiate vascular permeability, which permits pathogenic antibodies to gain access to the joint space. SYNOVIAL FLUID LYMPHOCYTES The lymphocyte mix in synovial fluid differs from that of peripheral blood and synovial tissue, and analysis of synovial fluid cells is not an accurate reflection of the synovium. Although synovial effusions contain an abundance of T cells, the CD4+-to-CD8+ ratio is reversed compared with

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that of blood or synovial tissue, with an excess of CD8+ suppressor cells relative to CD4+ lymphocytes. In addition, synovial tissue is nearly devoid of neutrophils, which often constitute 50% to 75% of synovial fluid cells. The synovial fluid does not contain a random distribution of cells shed from synovial tissue. The percentage of regulatory T cells (CD4+CD25+) also is higher in synovial fluid compared with peripheral blood.144 Synovial fluid contains T cells that express high levels of surface HLA-DR antigens. Other activation antigens not increased on peripheral blood cells are increased on synovial fluid lymphocytes, including VLA-1. Of CD4+ cells in rheumatoid synovial fluid, most are memory cells and express CD45RO on their surface.145 Despite the phenotypic appearance of activation, synovial fluid T cell function is deficient compared with that of peripheral blood cells. Synovial fluid lymphocyte proliferation in response to mitogens or most recall antigens, such as tetanus toxoid, is significantly less than paired blood T lymphocytes. Mycobacterial antigens and the 60-kD HSP seem to be exceptions because proliferation is greater in cells isolated from rheumatoid effusions. Cytokine production by synovial fluid T cells in vitro also is low, including mitogeninduced expression of IFN-γ and IL-1.146 A possible mechanism that explains defective T cell responses by synovial fluid mononuclear cells from rheumatoid patients is the presence of local inhibitors of cell activation. IL-1Ra and TGF-β are possible T cell suppressants and have been identified as components of synovial effusions that can suppress thymocyte proliferation.147 Nonspecific components of joint effusions, such as hyaluronic acid, can be toxic to cells and can indirectly suppress T cell activation. The mechanism of diminished T cell activation could be related to abnormalities in TCR signaling. Articular T cells have diminished tyrosine phosphorylation of proteins after stimulation, especially the key signal transduction pathway p38 MAP kinase.148 Tyrosine phosphorylation of the TCR zeta chain, an early event in TCR signaling, is low compared with peripheral blood T cells. Decreased levels of the zeta protein also are observed, suggesting that the TCR apparatus is abnormal in RA. The hyporesponsiveness of synovial fluid T cells correlates with a significant decrease in the levels of the intracellular redox-regulating agent glutathione.149 Restoration of the intracellular glutathione enhances mitogenic-induced proliferative responses and IL2 production in RA synovial fluid T cells. These data suggest­ that oxidative stress in the articular environment can suppress antigen-specific T cell responses. IMMUNE COMPLEXES The significance of immunoglobulin complexes circulating in blood and in synovial fluid was appreciated several decades ago. It was not until more reliable assays for immune complexes were available, however, that broad studies correlating disease activity and immune complexes could be generated. The most relevant data relate to the production of such complexes in the joint rather than the blood except in the unusual case of systemic rheumatoid vasculitis. Nevertheless, circulating IgM immune complexes are elevated in RA. In studies designed to identify the components of immune complexes in the circulation of rheumatoid

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patients, most studies did not find a specific antigen other than IgG complexed with RF. Using more sensitive techniques, circulating immune complexes in RA were found to contain 20 polypeptides, including albumin, immunoglobulin, complement, type II collagen, fibrinogen, and acutephase reactants, and DNA. Most relevant to the pathogenesis of joint destruction in RA has been the identification of immunoglobulins and complement in articular collagenous tissues from RA patients. Almost all cartilage and meniscus samples from rheumatoid patients have evidence of these components in the avascular connective tissue. Electron microscopic morphology of immunoglobulin aggregates shows that there are pathologic changes in the matrix of cartilage in the microenvironment of the aggregates themselves. Immune complexes are absent under areas of cartilage invaded actively by synovial pannus, suggesting that phagocytic cells in the invasive synovium ingest the immune complexes. This possibility lends credence to the notion that immune complexes deposited in the avascular superficial layers of cartilage in the joint may serve as chemoattractants for the pannus. Immune complexes have been extracted from cartilage of RA and osteoarthritis patients. Rheumatoid cartilage contains more than 40-fold more IgM and more than 10-fold more IgG than healthy cartilage extracts. IgM RF is found in most RA cartilage extracts, but not in osteoarthritis or healthy control extracts. In addition, more than 60% of the RA cartilage extracts are positive for native and denatured collagen type II antibody. These observations support the hypothesis that the presence of cartilage embedded with complexes contributes to the chronicity and persistence of rheumatoid inflammation. Orthopaedic surgeons have noted for many years that joints from which all cartilage is removed do not participate in general flares of rheumatoid disease after surgery. The localization of immune complexes, as a result of either in situ formation or absorption from the synovial fluid, could be required for the full expression of RA. ARACHIDONATE METABOLITES Accompanying activation of PMNs is the increased mobilization of membrane phospholipids in these cells to arachidonic acid and its subsequent oxidation by cyclooxygenases (COX) to PGs and thromboxanes, or by lipoxygenases to LTs. Although the stable PGs, especially PGE2, produce vasodilation, cause increased vascular permeability, and are involved centrally in fever production, there is increasing evidence that they have significant anti-inflammatory activities as well. Stable PG can retard the development of adjuvant arthritis, and the drug misoprostol, a PG analogue, may have significant anti-inflammatory or immunomodulatory effects. Physiologic concentrations of PGE2 inhibit IFN-γ production by T cells, HLA-DR expression by macrophages, and T cell proliferation. Production of PGs in RA depends on two distinct COX enzymes, COX-1 and COX-2. The former is constitutively expressed and is responsible for the normal endogenous production of PGs in the joint and in other tissues. COX-2 is an inducible enzyme responsible for increased PG synthesis in inflamed tissue. Cytokines such as IL-1 and TNF-α induce

COX-2 gene expression by cultured ­synoviocytes and macrophages. COX-2 mRNA and immunoreactive protein are increased in RA synovium.150 Most nonsteroidal antiinflammatory drugs, including indomethacin and ibuprofen, inhibit COX-1 and COX-2. Much of the anti-inflammatory activity (and analgesia) results from inhibition of the latter. Clinical experience using similar compounds in patients with osteoarthritis or RA indicates that COX-2 blockade is sufficient for the therapeutic ­benefit. Although most of the emphasis has been placed on PGE, PGI2 also can contribute to synovial inflammation. Mice lacking the PGI2 receptor have significantly decreased arthritis severity in the collagen-induced arthritis model compared with wild-type mice even though they make similar amounts of anticollagen antibodies. Loss of PGE2 signaling by blocking its receptors EP2 or EP4 was much less effective. LTB is a potent proinflammatory product of neutrophil activation. It is chemotactic for neutrophils, eosinophils, and macrophages and promotes neutrophil aggregation and adherence to endothelium. Peripheral blood PMNs from rheumatoid patients have an enhanced capacity for the production of LTB4 compared with similar cells from control groups.151 In murine collagen-induced arthritis, an LTB4 antagonist significantly decreased paw swelling and joint destruction, suggesting a pivotal role for this potent chemoattractant.152 LTB4 blockade in RA has been less impressive, however. Certain arachidonic acid metabolites, such as 15deoxy-delta(12,14)-PGJ(2), can bind to peroxisome proliferator activated receptors and inhibit cytokine production and adjuvant arthritis.152 Cyclopentenone PGs also can inhibit NFκB by blocking IκB kinase (IKK), suppressing the NFκB-driven array of proinflammatory genes.153 Lipoxins (LXs) represent a unique class of lipid mediators that help resolve inflammatory diseases. LXs have a trihydroxytetraene structure and are produced from arachidonic acid via the lipoxygenase pathway during cell-cell interactions. LXA4 binds with high affinity to a G protein–coupled receptor denoted LXA4 receptor. Activation of LXA4 receptor inhibits recruitment of neutrophils by attenuating chemotaxis, adhesion, and transmigration into tissues, and by diminishing chemokine and cytokine production. LXA4 significantly decreased cytokine and MMP expression in FLS through an NFκB-dependent mechanism.154 COMPLEMENT The liver is the major source of complement synthesis in humans, and passive transfer of serum proteins into effusions accounts for many of the complement proteins found there. Synovial tissue also actively produces complement proteins, however.155 Macrophages and fibroblasts produce complement proteins under the influence of cytokines such as IFNγ, IL-1, and TNF-α. In situ hybridization shows that C2 is expressed in the synovial intimal lining, whereas C3 seems to be produced by synovial sublining macrophages. Analysis of synovial tissue shows that all complement genes from the classic pathway are expressed in RA and in healthy synovium. Despite the local production of complement components, the activities of C4, C2, and C3 and total hemolytic complement in rheumatoid synovial effusions are

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lower than in synovial fluids from patients with other joint diseases.156 Although the most prominent evidence of activation implicates the classic pathway, cleavage products of the alternate pathway, including factor B and properdin, also have been documented in RA. Using a sensitive solid-phase radioimmunoassay to quantify the activation of the classic pathway of complement by RF, IgM RF is a much more important determinant of complement activation than IgG RF in serum and synovial fluid. Combined with other data showing accelerated catabolism of C4 in RA and that the presence of C4 fragments in the plasma of rheumatoid patients correlates with titers of IgM RF, the weight of evidence indicates a role in vivo for IgM RF in complement activation. The biologically active products of complement activation are probably the most important consequence of intraarticular complement consumption. Similar to proteases from PMNs, these inflammatory components accumulate in synovial fluid during acute inflammation. The potential for interaction between PMNs and the complement system is substantial. Neutrophil lysosomal lysates contain enzymatic activity capable of generating chemotactic activity (probably C5a) from fresh serum. C5a, in addition to being a principal chemotactic factor in inflammatory effusions, mediates lysosomal release from human PMNs; this sets up one of many amplification loops in inflammatory synovial fluid. The chemotactic anaphylatoxins C3a and C5a are often present in rheumatoid effusions, as are C5a complement components that comprise the C5b-C9 membrane attack complex. Low levels of the C5b-C9 membrane attack complex can activate synoviocytes in vitro. Complement activation as a potential therapeutic target has received increasing attention. In rat antigeninduced arthritis, intra-articular treatment with soluble complement receptor 1 inhibits joint swelling.157 Knockout mice lacking various complement components also provide evidence for the utility of this approach. C5-deficient mice have decreased joint inflammation in collageninduced arthritis and the passive K/BxN model.158 Absence of C3 or factor B also inhibits collagen-induced arthritis. In contrast to the C5 knockout mice, which had normal antibody responses, the C3-null and factor B–null animals had lower levels of anti–type II collagen antibodies.159 The role of C3 convertase was explored in more detail using mice that were transgenic for the rodent complement regulatory protein complement receptor 1-related gene/protein y.160 These mice have no obvious phenotype and are not more susceptible to infection. Clinical arthritis and histologic damage in collagen-induced arthritis were significantly decreased in complement receptor 1related gene/protein y transgenic mice compared with wild-type mice. These data suggest that classic and alternative complement pathways are implicated in inflammatory arthritis. The role of complement can be through activation of innate immune responses or classic adaptive immunity, depending on the specific model and complement components targeted. A humanized anti-C5 antibody has been evaluated in a placebo-controlled study. The antibody inhibits C5 activation and function of the C5b-C9 attack complex. Although the monoclonal antibody was well tolerated, there was only modest evidence of clinical efficacy.

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PERIPHERAL BLOOD LYMPHOCYTE IMMUNE RESPONSES Although peripheral lymphocytes are the most accessible, many investigators believe there is greater value studying cells isolated from the site of disease. Nevertheless, numerous studies show functional and phenotypic differences between RA and normal peripheral blood cells. The number of CD4+ helper T cells is mildly increased in the circulation of patients with RA, with a concomitant decrease in CD8+ lymphocytes (and an increased CD4+-to-CD8+ ratio). The surface phenotype of circulating T cells in RA suggests activation in some studies, but not in others. An increased percentage of αβ and γδ TCR-bearing cells might express HLA-DR and the adhesion protein VLA-4 (α4β1-integrin). VLA-4 plays an important role in the recruitment of cells to the synovium through interactions with VCAM-1 on endothelial cells. Other markers of activation are not elevated on RA T cells in the circulation. Peripheral blood T cells express some phenotypic characteristics of incomplete activation. It is unclear whether this process occurs in the peripheral or central lymphoid organs, or whether cells are activated in the synovium and re-enter the circulation via the synovial lymphatics. Immunoregulatory dysfunction in RA has been described in the blood cells of some patients. An early observation was the inadequate control of EBV-infected B lymphocyte growth owing to a defect in T cell function in RA. The abnormal T cell response could be correlated with disease activity, but it also was noted that the abnormality was present in T cells of some patients with inflammatory arthropathies other than RA.161 IFN-γ and IL-2 production can be significantly suppressed in these RA lymphocyte cultures under certain conditions. T cell diversity and maturation are abnormal in RA. Thymic output normally decreases with age, whereas this process seems to be accelerated in RA.162 The presence of TCR rearrangement excision circles is a measure of thymic release of mature T cells. Using this parameter, the thymic output in RA may decline prematurely. Similarly, telomere attrition suggests inappropriate “aging” of the T cells. This aging could be due to a primary defect in peripheral T cell homeostasis or due to impaired thymic function with increased T cell turnover secondary to chronic immune stimulation. This concept is supported by the observation that telomere length in RA T cells is shorter than in normal controls and more closely resembles older populations. Increased numbers of CD4+CD28− T lymphocytes have been reported in the peripheral blood of RA patients. Activated B lymphocytes also are present in the peripheral blood of patients with RA. The number of circulating B cells that spontaneously produce RF levels are significantly higher in RA patients compared with normal indi­ viduals. B cells that are enriched in autoantibody production are characterized by a surface determinant CD5.163 This antigen is normally expressed by T cells, but it also is displayed by fetal B cells and a few immature B cells in adults. RA patients with normal circulating numbers of lymphocytes show an abnormal kappa-to-lambda-chain analysis ­compared with controls, implying oligoclonal B cell proliferation164; it is unknown whether this reflects expansion of the restricted number of clones capable of

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producing RF, or whether an inciting antigen is something other than IgG and related specifically to RA. Normal and RA peripheral blood B cells have equal numbers of B cells that produce IgM anti–type II collagen antibodies. The B cells that accumulate in the synovial fluid produce IgG antibodies that are more likely to be pathogenic, however.165 Attempts to characterize the unique gene expression profiles in the peripheral blood cells of patients with RA have met with mixed results. In some cases, RNA transcripts potentially can distinguish between RA and psoriatic arthritis and include differential expression of tumor suppressors, MAP kinases, and other proinflammatory proteins. Similar studies have been performed in animals, such as rat collagen-induced arthritis, although the ability to classify patients, stage disease, assign a diagnosis, or assess response to therapy has still eluded investigators.

ROLE OF T CELL CYTOKINES Key Points • Multiple subsets of T cells have been implicated in the pathogenesis of RA. • Relatively low levels of T cell cytokines are present in RA ­synovium. • The T cell cytokines that are present, such as IFN-γ and IL-17, are produced by Th1 cells or Th17 cells. • Regulatory T cell function, which suppresses activation of other T cells, might be reduced in RA syn­ ovium. • The contribution of T cells to synovial inflammation can be through antigen-independent mechanisms, such as direct cell-cell contact with macrophages.

Cytokines are hormone-like proteins that enable immune cells to communicate. Cytokines either can interact with cells after being released in a soluble form or can be involved with direct cell-cell communication through membrane-bound factors such as TNF-α. In addition to participating in normal immune responses, they play an integral role in the initiation and perpetuation of synovitis. The cytokine milieu in RA is not ­random, although early studies suggested an unrestricted abundance of cytokines. Factors produced by T lymphocytes are low in RA, whereas factors generated by macrophages and by synovial fibroblasts are markedly increased (Table 65-5).166 Helper T cells have been divided into cytokine-specific subsets. Th1 cells, which develop under the influence of IL12 and perhaps IL-23, produce IFN-γ, IL-2, and IL-6, but not IL-4, IL-5, or IL-10. The cells are characterized by T-bet gene expression and use the signal transducers and activators of transcription 4 (STAT4) signaling pathway. In contrast, Th2 cells express GATA-3, use STAT6, and produce the opposite profile (IL-4+, IL-5+, IL-10+, IL-2−, IFN-γ−). Some cytokines are produced by both subsets, including TNF-α, IL-3, and GM-CSF, whereas Th0 cells have an unrestricted cytokine profile. Th1 cells primarily mediate delayed-type hypersensitivity in vivo, whereas Th2 cells are more prominent regulators of isotype switching and ­ antibody production. Some cytokines produced by Th2 cells are immunosuppressive because IL-4 and IL-10 downregulate Th1 cell differentiation and activation and delayed-type hypersensitivity.

Table 65-5  Level of Production of Synovial Cytokines   in Rheumatoid Arthritis According to Cellular Source Cellular Source

Level of Production in Rheumatoid Arthritis Synovium*

T cells IL-2 IL-3 IL-4 IL-6 IL-13 IL-17 IFN-γ TNF-α TNF-β (LTα 3) RANKL GM-CSF

− − − ± ± + ± − − + −

Macrophages†/Fibroblasts‡ IL-1 IL-1Ra IL-6 IL-10 IL-12 IL-15 IL-16 IL-18 IL-32 TNF-α M- CSF GM-CSF BLyS LIGHT RANKL TGF-β Chemokines (IL-8, MCP-1) Fibroblast growth factor

+++ + +++ + + ++ + ++ + ++ + ++ ++ ++ + ++ +++ ++

*−, absent or very low concentrations; +, present. †Tissue macrophages or type A synoviocytes. ‡Tissue fibroblasts or type B synoviocytes. BLyS, B lymphocyte stimulator; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN-γ, interferon-γ; IL, interleukin; MCP-1, monocyte chemoattractant; M-CSF, macrophage colony-stimulating factor; RANKL, receptor activator of nuclear factor κB ligand; TGF-β, transforming growth factor-β; TNF, tumor necrosis factor.

This simple system has become more complicated as new subsets have been defined. The Th3 subset that mainly produces TGF-β has been identified. The Th17 subset, which produces IL-17 but not IFN-γ and uses STAT3, seems to be especially relevant to autoimmunity and inflammatory arthritis. This phenotype can be induced when T cells are exposed to TGF-β plus IL-6 or by IL-23, all of which are present in the rheumatoid joint. Finally, a suppressive subset, Tregs, can be identified by virtue of coexpression of CD4 and CD25 on their surface. These cells are marked by Foxp3 expression and suppress the responses of other T cells through poorly defined cell contact mechanisms that involve costimulatory blockade and release of cytokines such as IL-10 and TGF-β. Defective Tregs populations have been associated with inflammatory diseases in mice, and autoimmunity can be suppressed by enhancing Tregs function. T HELPER TYPE 1 CELL CYTOKINES Extensive investigations into the cytokine profile of RA suggest a Th1 bias in the synovium based on cell phenotype (CXCR3 and CCR5 expression), cytokine levels in the

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joint (especially IFN-γ), the presence of cytokines that bias T cell differentiation toward Th1 (e.g., IL-12), and a Th1 phenotype of many T cell clones derived from RA synovial tissue. Considerable data have accumulated on the relative abundance and function of the prototypic Th1 cytokine, IFN-γ, which is the most potent inducer of MHC class II antigen on many cell types. IFN-γ also induces adhesion molecules, such as VCAM-1 and ICAM-1, on the surface of endothelial cells and can help recruit inflammatory cell accumulation at sites of injury. One of the most important functions of IFN-γ is its capacity to alter the balance of extracellular matrix synthesis and degradation by decreasing collagen synthesis and inhibiting MMP production by cytokine-stimulated cultured FLS.167 IFN-γ knockout mice or IFN-γ receptor deficiency can exacerbate collagen-induced arthritis in mice, and this serves as a reminder that the effects of cytokines can vary depending on the model and timing of expression. Despite the evidence for T cell activation in the rheumatoid synovium, only relatively low concentrations of IFN-γ have been detected,168 much less than the amounts needed to induce HLA-DR expression on monocytes. The relative lack of IFN-γ in rheumatoid joints has been observed at the level of mRNA using a variety of techniques, including reverse-transcriptase polymerase chain reaction.169 Immunohistochemical analysis shows IFN-γ in a few RA synovial T cells, although the percentage is far less than in chronically inflamed tonsils.170 Another Th1 cytokine, IL-2, is a T cell–derived cytokine that serves as an autocrine or paracrine T cell growth factor. Although it originally was reported to be present in synovial fluid using biologic assay, more ­ specific immunoassays showed that IL-2 is detected in only a small percentage of RA synovial effusions and synovial tissues and, when present, is found only in low concentrations.171 TNF-α, GMCSF, and IL-6 can be expressed by Th1 and Th2 cells. All three are abundant in synovial fluid and ­ produced by RA synovial tissue. The primary sources of these cytokines in the rheumatoid joint are macrophages and fibroblasts, however, rather than T cells (see later). IL-17 originally was considered a Th1 cytokine, although more recent data suggest that it is mainly produced by another distinct subset known as Th17 (see later). T HELPER TYPE 2 CELL CYTOKINES Although Th1 cytokines have been detected (albeit in low concentrations), Th2 cytokine levels are exceedingly low in RA. Using immunoassays, IL-4 and TNF-β generally are not detected in RA synovial fluid. In situ hybridization also shows little or no IL-4 in RA synovial tissue, although a small amount of IFN-γ is detected using the same method. When extremely sensitive nested reverse-transcriptase pol­ ymerase chain reaction techniques are used on synovial biopsy specimens, Th2 cytokines IL-4 and IL-13 are absent in RA, whereas IFN-γ and IL-12 (a cytokine that induces T cell maturation toward the Th1 phenotype) are present. In one study, IL-13 protein was detected in RA synovial effusions. IL-10, which has potent anti-inflammatory activities, is expressed in RA synovium. Macrophages rather than T cells are the major producers of IL-10 in RA, however.

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T HELPER TYPE 17 CYTOKINES The proinflammatory cytokine IL-17 exists as six isoforms (IL-17A through IL-17F). It originally was described as a Th1 cytokine, but now seems to be produced mainly by a distinct subset known as Th-17. IL-17A mimics many of the activities of IL-1 and TNF-α with respect to FLS function, including induction of collagenase and cytokine production.172 IL-17 is present in modest, but functionally relevant, concentrations in RA synovial effusions.173 More important, T cell–derived IL-17 in synovial tissue can synergize with IL-1 and TNF-α by activating synoviocytes to produce MMPs and other proinflammatory cytokines. Specific IL-17 receptors are expressed by synoviocytes and, when engaged, can activate the transcription factor NFκB and initiate an inflammatory cascade. In addition to its effect on mesenchymal cells, IL-17 can participate in bone erosion by enhancing osteoclast activation.174 Bone resorption in an in vitro model using synovial explants and bone shows that blockade of IL-17, IL-1, and TNF-α is more effective than blocking the individual factors.175 Immunohistochemistry shows that IL-17 is mainly present in synovial sublining T cells. Because immunoreactive IL-17 can be detected near the erosive front of pannus, it also could participate in extracellular matrix destruction.176 Animal models of arthritis show that IL-17 inhibition is anti-inflammatory and protects animals from bone and cartilage destruction.177 It is uncertain whether Th17 cells, per se, are responsible for all IL-17 isoforms production in the joint. Either IL-23 or the combination of IL-6 and TGF-β in the joint can enhance Th17 cell differentiation. All three of these cytokines are present in RA synovium, providing an excellent milieu to encourage the generation of these cells. REGULATORY T CELLS The function of Tregs, defined by the CD4+CD25+ phenotype, in RA is poorly defined. Deficiency of this subset, which produces TGF-β and regulates other T cells through cell contact, might contribute to autoimmunity. Studies of RA peripheral blood show normal numbers of Tregs, although the CD4+CD25+ subset seems to accumulate in rheumatoid synovial effusions. Peripheral blood Treg responses in vitro to stimuli such as anti-CD3 and anti-CD28 antibody displayed an anergic phenotype, however, and were unable to suppress T cell or monocyte cytokine production. This abnormality might be reversed when patients are treated with TNF inhibitors.178 These data suggest that abnormal Treg function could be secondary to cytokine imbalance in RA, rather than a primary event. Nevertheless, enhancing or restoring Treg activity as a therapeutic intervention potentially could downregulate other T cells and cytokine production. More recently, a novel phenotype defined by CD4+CD25+CD27+ has been identified in synovial effusions of patients with juvenile inflammatory arthritis.179 This population expresses FoxP3 and does not produce Th1 cytokines. The suppressor function of these cells was decreased in vitro by cytokines such as IL-7 and IL-15, both of which have been identified in inflammatory synovitis. Enhancing Treg function has been used to treat animal models of arthritis. Antigen-induced arthritis is exacerbated

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when CD4+CD25+ cells are depleted, and suppressed when the cells are passively transferred to affected animals. Treg function is reduced in some inflammation models.180 Administration of neuropeptides, such as vasoactive intestinal peptide, seems to suppress collagen-induced arthritis by enhancing the Treg function in synovium and lymph nodes.181 T HELPER CELL CYTOKINE IMBALANCE IN RHEUMATOID ARTHRITIS The relative abundance of Th1 cells and cytokines suggests that the synovium resembles a Th1-like delayed-type hypersensitivity reaction. Th2 cytokines and cellular responses that normally suppress Th1 activation are nearly absent, raising the possibility that the lack of T cell activation along the Th2 pathway in RA contributes to disease perpetuation. Addition of exogenous IL-10 or IL-4 to cultures of synovial tissue cells or synovial tissue explants suppresses synthesis of proinflammatory cytokines, such as IL-6, IL-1, TNF-α, and GM-CSF, and MMPs by cultured RA synovial tissue explants.182 The inhibitory action of IL-4 might be mediated by decreased c-jun and c-fos expression, which is required for efficient production of MMPs and cytokines. In addition, IL-10 and IL-4 increase the release of other antiinflammatory cytokines, such as IL-1Ra, by synovial cells. Although IL-10 protein is present in RA synovial fluid, and the gene is expressed by synovial tissue cells,183 in vitro studies of cultured synovial cells suggest that not enough IL-10 is produced to suppress IFN-γ production. The notion that Th1 and Th17 cytokines initiate and perpetuate arthritis, whereas Th2 cytokines are suppressive is supported by studies in animal models. IL-4 and IL-10 were administered individually or in combination in collagen-induced arthritis.184 The cytokines had modest or no benefit when used separately, but together the effect was impressive. Clinical improvement correlated with decreased synovial IL-1, TNF-α, and cartilage destruction. Anti-IL-10 antibody therapy in collagen-induced arthritis accelerates disease. The complexity of cytokine networks in inflammatory arthritis is underscored by studies on the role of IL-12 in collagen-induced arthritis. In early arthritis, IL-12 administration increases the incidence of collagen-induced arthritis, whereas anti-IL-12 is beneficial.185 In late disease, IL-12 administration suppresses arthritis, however, and anti-IL-12 causes an exacerbation. Although the notion that enhancing Th2 cytokines is attractive, a clinical trial using IL-10 in RA did not show significant clinical benefit or improvement in histologic evidence of synovial inflammation.186 Combinations of Th2 cytokines might be required to coordinate a maximal effect. ACTIVATION OF SYNOVIAL CELLS BY CELL-CELL CONTACT WITH T LYMPHOCYTES Although T cell activation is unexpectedly modest in rheumatoid synovium, alternative mechanisms permit these cells to participate in synovial cytokine networks and matrix destruction. A second process by which T cells can activate macrophages and fibroblasts in RA is through direct cell-cell contact. Membranes prepared from activated T cells can stimulate macrophages and FLS directly to produce cytokines and MMPs.187 The membrane constituents that ­regulate this

process vary, depending on the particular culture conditions, but include adhesion molecules such as lymphocyte function–associated antigen-1 and membrane-bound TNF-α. A T cell displaying these proteins, even if the cell is no longer functional, potentially can contribute to macrophage and fibroblast activation in an antigen-independent fashion. One of the best-characterized consequences of this pathway is the ability of T cells to enhance synovial macrophage TNF-α production in a contact-dependent manner after exposure to macrophage-derived IL-15.188 Cell contact–dependent activation of macrophages can be enhanced by other cytokines present in rheumatoid synovium, such as IL-7.189 The concept that lymphocytes can activate cells in the environment through direct contact suggests an unanticipated role for T cells in RA. The traditional paradigm assumes that T cells in the joint respond to a pathogenic stimulus and subsequently drive an antigen-specific response. Cell-cell contact influences can be antigen-independent, however, and require only colocalization of memory T cells with synoviocytes or macrophages. Because T cells with a memory phenotype accumulate in the joint owing to the release of chemoattractants, there is no requirement for a specific arthritogenic antigen to initiate the process. Instead, activation of innate immunity by nonspecific stimuli permits subsequent ingress of the correct T cell phenotype to engage resident synovial lining cells.

ROLE OF MACROPHAGE AND FIBROBLAST CYTOKINES Key Points • Macrophage and fibroblast cytokines are abundant in RA synovium. • Cytokine networks that involve proinflammatory ­cytokines, such as IL-1, TNF-α, IL-6, IL-15, IL-18, GM-CSF, and many others, can help perpetuate synovial inflammation. • Chemokines that recruit inflammatory cells into the joint generally are produced by macrophages and ­fibroblasts. • Anti-inflammatory cytokines, such as IL-1Ra and IL-10, are produced in rheumatoid synovium, albeit in amounts insufficient to offset proinflammatory ­cytokines.

Although the production of T cell cytokines is relatively low in RA, the same is not true for products of macrophages and fibroblasts. Virtually every macrophage and fibroblast proinflammatory mediator investigated in the RA synovium is abundant. This section enumerates some major cytokines and effectors produced in the joint, with an emphasis on the prevalence of macrophage and fibroblast products as driving forces during the perpetuation phase of RA. Macrophages, in particular, are the most vigorous producers of cytokines. These cells, which are present in small numbers in normal synovium, increase in number by migration from extrasynovial sites (e.g., bone marrow) after inflammation begins. Their responses include secretion of more than 100 substances and regulation of a biologic array of activity from the induction of cell growth to cell death. The role of macrophage and fibroblast cytokines in the pathogenesis of RA

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Table 65-6  Effect of Cytokine Blockade in Animal Models of Arthritis and Rheumatoid Arthritis Model

T Cell Dependence

SKG

Yes

Active CIA

Yes then no

Passive CIA K/BxN

TNF-α ↓↓↓

IL-1 ↓↓

↓↓

No

↓↓↓

↓↓

Yes then no

0

Passive K/BxN

No

↓

↓↓↓

SCW arthritis

No then yes

Rheumatoid arthritis

Yes

↓

↓↓

↓↓↓

IL-6 ↓↓↓

↓↓↓

0

0

↓

↓↓

IL-10 ↑

IFN-γ 0

↑

↑

↑↑

↑

↑

↑B

0A

0A

0

↓↓↓

↓

IL-4

↓

�, cytokine blockade suppresses arthritis; �, cytokine blockade increases arthritis; 0, minimal or no role; Aadministration of exogenous cytokine is ineffective; Badministration of exogenous IFN-γ suppresses disease. IFN, interferon; IL, interleukin; SCW, streptococcal cell wall; TNF, tumor necrosis factor. From Firestein GS: The T cell cometh: Interplay between adaptive immunity and cytokine networks in rheumatoid arthritis. J Clin Invest 114:471, 2004.

initially was suggested by studies involving patient samples and preclinical experiments in animal models. No animal model truly replicates RA. Table 65-6 shows the relative contribution of various cytokines to murine and rat models compared with human disease.190 Despite dramatic differences in pathogenesis, there are remarkable similarities related to cytokine function in the various models. PROINFLAMMATORY MACROPHAGE AND FIBROBLAST CYTOKINES Interleukin-1 Family The IL-1 family is a ubiquitous group of polypeptides with a wide range of biologic activity; they include IL-1α, IL-1β, IL-18, and IL-1Ra, which is a natural inhibitor of IL-1 (see the following section on suppressive cytokines and cytokine antagonists for a description of IL-1Ra). Abundant animal data indicate that IL-1 can serve as a key regulatory factor in inflammatory arthritis. Recombinant IL-1β induces the accumulation of PMNs and mononuclear leukocytes in the joint space and the loss of proteoglycan from articular cartilage when injected directly into rabbit knee joints. Transgenic mice that overexpress IL-1 also develop inflammatory arthritis, whereas mice that lack the natural IL-1 antagonist IL-1Ra have increased susceptibility to collagen-induced arthritis. In most cases, IL-1 blockade in animal models modestly decreases synovial inflammation, while markedly diminishing bone and cartilage­destruction. Interleukin 1. Synovial macrophages are the most prolific source of IL-1 in the joint, and nearly half of all macrophages in the RA synovium express IL-1β.191 Immunohistologic studies confirm this, with especially abundant IL-1 protein in synovial lining macrophages adjacent to type B synoviocytes and in sublining macrophages near blood vessels. The IL-1 in the lining subsequently can activate type B synoviocytes to proliferate and secrete a variety of mediators. A broad range of stimuli are capable of inducing IL-1 production by macrophages; immunoglobulin Fc fragments and, to a lesser extent, immune complexes can generate IL-1 production by rheumatoid synovial macrophages. Collagen fragments can induce IL-1 production, and type IX collagen, which has been found only in articular cartilage and localized into intersections of collagen fibrils, is a potent inducer of IL-1 by human monocytes.

Within the rheumatoid joint, IL-1 induces fibroblast proliferation; stimulates the biosynthesis of IL-6, IL-8, and GM-CSF by synovial cells; and enhances collagenase and PG production.192 It increases glycosaminoglycan release in human synovial fibroblast cultures, although the effect of IL-1 on the production of intact proteoglycan molecules by intact articular cartilage explants can be the opposite. IL-1 induces numerous adhesion molecules on FLS and endothelial cells, including VCAM-1 and ICAM-1, and enhances bone resorption. IL-1 has been implicated in RA, and inhibition of this mediator using IL-1Ra (anakinra) has modest anti­inflammatory activities in humans. Improvement generally has been observed in 40% to 45% of patients. IL-1Ra also has been used in combination with TNF inhibitors and provided no additional benefit even though biologic activity was shown by virtue of a decreased C-reactive protein and an increased incidence of infections.193 The limited activity of IL-1Ra in RA was presumed to be related to its short halflife and the need for very high concentrations. The same protein is extremely effective, however, in diseases with a well-defined role for IL-1, such as Still’s disease, familial cold autoinflammatory syndrome, and Muckle-Wells syndrome. Another biologic IL-1 inhibitor with high avidity for IL-1 and improved pharmacokinetics and an IL-1 convertase inhibitor had clinical responses in RA that were similar to anakinra. These data suggest that IL-1 plays a less important role in the clinical manifestations of RA than initially considered. Its contributions to cartilage and bone destruction are still uncertain. An alternative explanation for the relatively modest benefit of IL-1 in RA relates to its signaling mechanisms. Similar to many TLRs, IL-1 activates NFκB through the kinase MyD88. Both pathways (IL-1 and TLR) converge and share a common mechanism for activating transcription of proinflammatory cytokines. When IL-1 signaling is blocked, it is possible that TLR ligands in the synovium, including exogenous ones such as peptidoglycan or endogenous ones such as HSPs, can provide the stimulus required to overcome IL-1 blockade. This concept was tested in the passive K/BxN model where mice lacking the IL-1 receptor had markedly decreased arthritis severity. When small amounts of the TLR4 ligand lipopolysaccharide were administered, robust synovitis ensued. If a similar system occurs in RA, IL-1 blockade would be unable to control synovitis as long as TLR signaling remains intact.

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Interleukin-18. In addition to IL-1α and IL-1β, a homologous protein in the IL-1 family known as IL-18 has been implicated in RA. This cytokine originally was defined by its ability to bias the immune response toward the Th1 phenotype, especially in the presence of IL-12. In collageninduced arthritis, IL-18 inhibition significantly attenuates disease.194 The same effect was observed in IFN-γ knockout mice, indicating that other non–Th1-related activities of IL-18 might be important. Subsequent studies showed that IL-18 induces GM-CSF, nitric oxide production, and TNFα expression by synovial macrophages.195 Although IL-18, along with IL-12 or IL-15, can increase IFN-γ production by synovial tissue in vitro, the relative importance of this activity is uncertain compared with the IL-1-like activities of the cytokine. IL-18 is expressed by RA synovial tissue, especially by synovial fibroblasts and macrophages, and its production is markedly increased by TNF-α and IL-1β. A natural inhibitor, the IL-18 binding protein, potentially can be used as a therapeutic agent to block the proinflammatory effects and pro-Th1 effects of IL-18. One potential concern for IL-18 as a target for RA is the fact that the IL-1 convertase inhibitor had only modest benefit. IL-18, similar to IL-1β, is processed by this enzyme to produce biologically active cytokine. An effective IL-1 convertase inhibitor theoretically should block IL-1β and IL-18 release by macrophages. Tumor Necrosis Factor Superfamily The TNF superfamily is an extended group of related genes that play a major role in inflammation, immune responses, cell survival, and apoptosis. At least 19 members of the family have been identified, with TNF-α identified as the eponymous member. Each cytokine has its own preference for cell surface receptor, although there is some promiscuity of receptor binding and functional overlap. The TNF superfamily members exhibit conserved amino acid sequences suggesting a single ancestral gene. Many sequences include type II membrane protein characteristics and can be released from cell surfaces after proteolytic cleavage. A C-terminal conserved domain called the TNF-homology domain also is shared by several superfamily members. The active forms of the proteins are homotrimers except for LTα and LTβ, which can form either heterotrimers or homotrimers. Several members already have been discussed in the relevant sections (lymphotoxin, LIGHT, BLyS, and APRIL in Synovial Pathology and Biology; Fas ligand and TWEAK in Life and Death in the Rheumatoid Synovium; and receptor activator of NFκB ligand (RANKL) in Bone and Cartilage Destruction). In this section, one of the “founding” members of the superfamily is discussed because of its crucial role in synovial ­inflammation. TNF-α is a pleiotropic cytokine that has been implicated as a key proinflammatory cytokine in RA and detected in rheumatoid synovial fluid and serum. It is produced as a membrane-bound protein that is released from the cell surface after proteolytic cleavage by TNF convertase, a membrane MMP. IL-1 and TNF-α have many similar activities, including the ability to enhance cytokine production, adhesion molecule expression, proliferation, and MMP production by cultured synoviocytes. In some systems, the effects of these two agents are synergistic. Although they share many

functions and signal transduction pathways, IL-1 and TNF use distinct surface receptors and intracellular signaling pathways. The clearly defined efficacy of TNF inhibitors in RA shows its crucial role in the disease; heterogeneity of the rheumatoid process also is apparent because only about one third of patients have a dramatic response to TNF inhibitors. Efficacy requires continuous therapy because cessation typically leads to a flare of disease. Evidence is beginning to accumulate suggesting that early aggressive therapy with anti-TNF agents can induce long-term remissions even after therapy is withdrawn. This exciting notion suggests that interventions in the earliest stages of disease could prevent the establishment of chronic synovitis. TNF-α, similar to IL-1, stimulates collagenase and PGE2 production by human synovial cells, induces bone resorption, inhibits bone formation in vitro, and stimulates resorption of proteoglycan and inhibits its biosynthesis in explants of cartilage.196 In situ hybridization and immunohistochemical studies show that TNF-α is primarily produced by synovial macrophages in RA. Animal models also have supported the general role played by TNF-α in inflammatory arthritis. Overexpression of TNF-α in transgenic mice leads to an aggressive and destructive synovitis. The arthritis also spontaneously occurs in transgenic mice that express only a membrane-bound form of TNF-α on T cells.197 TNF blockade is an effective anti-inflammatory agent in many animal models of arthritis,198 although the effects on bone and cartilage destruction are less prominent than with IL-1 inhibitors. TNF inhibition in RA significantly decreases extracellular matrix destruction as measured by radiographic progression.199 It is unclear why the bone-protective effects are more prominent in humans than in animal models. TNF blockade also is more effective in animal models when combined with an IL-1 inhibitor, supporting the additive or synergistic relationship between the two cytokines in animal models; this has not been observed in RA, however. The mechanisms by which anti-TNF-α influences synovitis are distinct from the mechanisms of other biologic therapies. Individuals with an inadequate response to a TNF inhibitor are still likely to respond to either rituximab or abatacept. This likelihood supports the notion that multiple independent pathways can contribute to the pathogenesis of RA and the heterogeneous nature of the disease. Another complexity related to the role of TNF-α is that clinical responses do not always correlate with protection of the extracellular matrix. Patients with little or no clinical improvement in signs and symptoms of RA still have significant delay or arrest of joint damage. This observation supports the contention that inflammation and destruction have distinct pathogenic mechanisms. Interleukin-6 Family IL-6 is a protein produced by many cells including T cells, monocytes, and cultured FLS.200 Originally defined by its B cell–stimulating properties, it induces immunoglobulin synthesis in B cell lines, is involved in the differentiation of cytotoxic T lymphocytes, and is a major factor in the regulation of acute-phase response proteins by the liver. The IL-6 receptor includes a common chain (gp130) that is shared with other cytokines and an IL-6-specific chain (IL6R). IL-6R can be shed from cell surfaces, bind to IL-6, and

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deliver it to cells that lack IL-6 receptors by combining with gp130. A striking correlation between serum IL-6 activity and serum levels of acute-phase reactants such as C-reactive protein, α1-antitrypsin, fibrinogen, and haptoglobin occurs in patients with RA. Very high levels of IL-6 are present in RA synovial fluid, and synovial cells in culture from diverse inflammatory arthropathies produce IL-6.200 In situ hybridization of synovial tissue also shows IL-6 mRNA in the intimal lining, and immunohistochemistry studies show IL-6 protein in the lining and sublining regions.201 Although many synovial macrophages express the IL-6 gene, most ­ IL-6 seems to be produced by type B synoviocytes. The pivotal role of IL-6 in RA has been shown by clinical trials using a monoclonal antibody that binds to IL-6R. The clinical responses are similar to TNF inhibitors.202 Cytokines with structural similarity to IL-6 and that share surface receptor subunits also have been implicated in RA. Several of these—IL-11, leukemia inhibitory factor, and oncostatin M—are expressed by rheumatoid synovium and can be detected in synovial effusions. The biologic effects of these factors are complex and can be either protective (e.g., by increasing expression of protease inhibitors, such as tissue inhibitors of metalloproteinase [TIMP]) or proinflammatory (e.g., by increasing expression of chemokines or MMPs) depending on the culture conditions or the specific model evaluated. This dichotomy among the family members is shown by the fact that IL-11 administration ameliorates collagen-induced arthritis,203 whereas antibodies to oncostatin M are protective.204 Interleukin-12 Family The IL-12 family includes a group of cytokines that play a key role in the differentiation of T cells and inflammation. IL-12 is a heterodimeric cytokine with two subunits (e.g., p35 and p40) encoded on separate genes. It is produced by antigen presenting cells and phagocytic cells. IL-23 and IL27 have similar heterodimeric structures to IL-12, with p29/ p40 and p28/EB13 components. In the context of antigen presentation, IL-12, IL-23, and IL-27 can bias T cell responses toward the Th1 phenotype. IL-23 also can play a pivotal role in the production of Th17 cells, along with IL-6 and TGF-β. The members of the IL-12 family of cytokines generally are produced by macrophages in the rheumatoid joint, but also are produced by other antigen presenting cells such as DCs. Although clinical data defining the role of these cytokines are still lacking, there are anecdotal case reports of RA patients with malignancy treated with recombinant IL-12 developing a flare of disease. Animal models, ­including adjuvant arthritis in rats and collagen-induced arthritis in mice, are partially ameliorated by neutralization of IL-12, IL-23, or IL-27 depending on the timing of treatment. In some situations, however, IL-27 has anti-inflam­ matory effects.205,206 Interleukin-15 IL-15 is an IL-2-like cytokine that regulates numerous immunologic functions relevant to RA, including T cell chemotaxis and proliferation, production of immunoglobulins by B cells, and the generation of natural killer cells.

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The IL-15 receptor is a complex heterotrimer that includes a common chain shared with the IL-2 receptor, a common chain shared with many other cytokines, and a high-affinity specific IL-15 chain. Because it can transduce a signal directly to IL-15R-expressing cells or present the bound cytokine to stimulate neighboring cells, IL-15 can serve as an IL-2-independent mechanism for activating T cells, although its role in RA may be related to its key role in TNF-α regulation. Macrophages are the primary source of IL-15 in RA, and the cytokine is able to induce a cell-contact mechanism of macrophage TNF-α production that requires T cells. Although T lymphocytes, or at least their membranes, are required for this process, the macrophages produce the TNF-α. This network provides a potential mechanism whereby local IL-15 production in the synovium can lead to autocrine production of TNF-α in a T cell– dependent, but antigen-independent, fashion. IL-15 has been shown in RA synovial macrophages using immunohistochemical techniques.207 Soluble IL-15 receptors can function as an IL-15 inhibitor, and when used in vivo can decrease joint inflammation in collagen-induced arthritis.208 The mechanism of action probably includes TNF-α inhibition, although decreased IFN-γ production and immune responses to type II collagen indicate that IL-15 also regulates antigen-dependent responses. Interleukin-32 IL-32 is a novel cytokine that activates NFκB and induces the production of several proinflammatory cytokines and chemokines, including TNF-α, IL-1, IL-6, and IL-8. It has been implicated in Crohn’s disease because of its ability to enhance markedly caspase 1 activation and IL-1 production in cells that have been exposed to muramyl dipeptides. More recently, IL-32 was shown by immunohistochemistry in synovial tissues of patients with RA, especially in synovial lining macrophage-like cells.209 The level of IL-32 expression correlated with the presence of other cytokines implicated in RA, including TNF-α, IL-1, and IL-18. Injection of IL-32 into the joints of naive mice causes a robust transient synovitis. The synovial response could be partially abrogated by anti-TNF-α antibodies, suggesting that IL-32 induces this cytokine in vivo. These data suggest that IL-32 might be upstream from several proinflammatory mediators in RA and could represent a therapeutic target. Colony-Stimulating Factors GM-CSF supports the differentiation of bone marrow precursor cells to mature granulocytes and macrophages. As with other major CSFs, GM-CSF also participates in normal immune responses. It is a potent macrophage activator, including the induction of HLA-DR expression, tumoricidal activity, IL-1 secretion, intracellular parasite killing, and priming for enhanced release of TNF-α and PGE2. Neutrophil function also is regulated by GM-CSF, which enhances antibody-dependent cytotoxicity, phagocytosis, chemotaxis, and the production of oxygen radicals. RA synovial fluid contains GM-CSF, which is produced by RA synovial tissue cells.210 The major source in the synovium is macrophages, although IL-1-stimulated or TNF-α-stimulated FLS also express the GM-CSF gene.211

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In situ hybridization studies show little or no GM-CSF mRNA in synovial T cells. The ability of GM-CSF to induce HLA-DR gene expression on macrophages might be of particular importance in RA. GM-CSF, not IFN-γ, is the major DR-inducing cytokine in RA synovial fluid and in supernatants of cultured synovial tissue cells. Collagen-induced arthritis in mice is less severe in animals that lack a functional GM-CSF gene or are treated with anti-GM-CSF antibody, which supports the hypothesis that GM-CSF is an important proinflammatory mediator.212 Macrophage colony-stimulating factor (M-CSF) also is expressed by RA synovium and is present in synovial effusions. Its primary pathogenic role in RA probably relates to its osteoclast-differentiating capacity. As is described later, this factor cooperates with RANKL to facilitate bone ­erosions. Chemokine Families Chemokines are a family of related chemoattractant peptides that, with the assistance of adhesion molecules, summon cells into inflammatory sites. They generally are divided into families, including C-C, C-X-C, and C-X3-C, based on the position of characteristic cysteine residues. In the C-C family, two conserved cysteines are adjacent to one another, whereas in the C-X-C family, the cysteines are separated by a nonconserved amino acid. Each individual factor has the ability to attract specific lineages of cells after interacting with specific surface receptors. Many chemokines have been identified in the rheumatoid joint. IL-8, a C-X-C chemokine that was originally characterized as a potent chemoattractant for neutrophils, along with immune complexes and other chemotactic peptides such as C5a, contributes to the large influx of PMNs into the joint. Immunohistochemical analysis of synovial tissue shows IL8 protein in sublining perivascular macrophages and in scattered lining cells.213 Cultured synovial tissue macrophages constitutively produce IL-8, and FLS express the gene if they are stimulated with IL-1 or TNF-α. IL-8 accounts for about 40% of the neutrophil chemoattractant activity in synovial fluid. In addition, IL-8 activates neutrophils through G protein–coupled receptors and is a potent angiogenesis factor. Many other chemoattractant proteins are implicated in RA. MIP-1α, MIP-1β, macrophage chemoattractant protein (MCP)-1, and RANTES—members of the C-C subfamily—are produced by RA synovium.214 CXCL16 and epithelial neutrophil-activating peptide-78 (ENA-78) are C-X-C chemokines and are abundant along with many others in that family.215 The former, which binds to CXCR6 on T cells, can contribute to the recruitment of lymphocytes into the synovium. ENA-78 accounts for about 40% of the chemotactic activity for neutrophils in RA synovial fluid. In each case, the source of the chemokine seems to be synovial macrophages or cytokine-stimulated type B synoviocytes. The regulation of each chemokine seems to be distinct in FLS. The concentrations of chemokines are higher in RA synovial effusions compared with samples from noninflammatory arthritides, such as osteoarthritis. Although the chemokines also can be detected in the blood, the levels are considerably lower than in the joint, providing a gradient that signals cells to migrate into the synovium.

As noted earlier, lymphocyte-specific factors might c­ ontribute to the germinal center architecture of RA. The C-X-C factor B cell–activating chemokine-1 (BCA-1; CXCL13) binds to specific CXCR5 receptors on B cells. BCA-1 is expressed in the RA synovial tissues, especially by follicular DCs in germinal centers, and likely accounts for B cell migration to these regions.216 CCL21 and several other factors participate in the anatomic organization of germinal centers, marginal zones, and other regions of lymphoid follicles. Another chemokine, SDF-1, is expressed by synoviocytes and endothelial cells and can play a major role as a chemoattractant for T cells in synovium via its receptor CXCR4.217 In contrast to other chemokine receptors that can bind multiple members of the family, CXCR4 is highly specific for SDF-1 and is expressed by memory CD4+ lymphocytes. Chemokine-directed approaches have garnered considerable attention as potential therapeutic targets to prevent recruitment of cells into the synovium. Numerous preclinical models support the use of chemokine blockers. Antibodies to fractalkine (CXC3L1) suppressed murine collagen-induced arthritis even though anti–type II collagen antibody production was not affected.218 Anti-CXCL16 antibody decreased clinical arthritis in the same model. One problem is that the system is highly redundant, and several different chemotactic proteins can bind to the same receptor. No clinical improvement was observed in a study using anti-MCP-1 antibody, perhaps because the antibody also altered the kinetics of MCP-1 metabolism. Anti-IL-8 antibodies have met with limited success in psoriasis. Alternatively, chemokines bind to G protein–coupled receptors and can be targeted to block multiple factors. A CCR1 antagonist, which blocks RANTES and MIP-1α, has been evaluated in a synovial biopsy clinical trial.219 The compound significantly decreased synovial infiltration by CCR1expressing cells, including macrophages and T cells. There was a trend toward clinical improvement. Chemokine receptor blockade has other levels of complexity, such as CCR2-deficient mice that develop more severe arthritis in some models. CCR2 antagonists, which block MCP-1, have not shown significant efficacy in RA clinical trials. These data suggest that the chemokine system, including the receptors, is redundant, complex, and, in some cases, perhaps protective in arthritis. Chemokines and other chemotactic factors (e.g., C5a and LTB4) can signal through a variety of mechanisms, although many pathways converge on phosphatidylinositol-3′-kinase (PI3K). Of the several PI3K isoforms, PI3Kγ is specific for chemokine signal transduction. This specificity provides an opportunity to block multiple chemokine receptors simultaneously. Proof of concept for this approach was provided by studies in PI3Kγ knockout mice, which have less synovial inflammation in passive and active collagen-induced arthritis than wild-type mice.220 A small molecule PI3Kγ inhibitor provided similar benefit. Targeting shared intracellular pathways potentially can overcome some of the limitations presented by the complex chemoattractant system. Platelet-Derived Growth Factor and Fibroblast Growth Factor PDGF is a potent growth factor that is chemoattractant and mitogenic for fibroblasts and induces collagenase expression. It is the most potent stimulator of long-term growth

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of synovial cells in culture.221 PDGF is expressed in vascular endothelial cells and other synovial sublining cells in rheumatoid synovium compared with healthy tissue.222 Multiple isoforms of this molecule have been identified (PDGF A through D), all of which have been detected in RA synovial membranes. Most recently, PDGF D has been identified as an especially potent stimulator of MMP-1 expression in cultured synoviocytes. The PDGF receptor also is expressed in the same regions of RA synovium, suggesting the presence of an autocrine or paracrine system. FGFs are a family of peptide growth factors with pleiotropic activities. In rheumatoid patients, it is likely that heparin-binding growth factor, the precursor of acidic FGF, is a major mitogen for many cell types and stimulates angiogenesis. An interaction between FGF and proteoglycans is required for biologic activity.223 It induces capillary endothelial cells to invade a three-dimensional collagen matrix, organizing themselves to form characteristic tubules that resemble blood capillaries. Synoviocytes also can be induced to increase expression of RANKL by FGF, enhancing osteoclast activation and bone resorption. FGF is present in RA synovial fluid, and the genes are expressed by synovial cells. Synovial fibroblasts express FGF receptors and proliferate after exposure to the growth factor. SUPPRESSIVE CYTOKINES AND CYTOKINE ANTAGONISTS The proinflammatory cytokine network in RA is offset by a variety of suppressive and anti-inflammatory factors that attempt to re-establish homeostasis. Underproduction of these suppressive cytokines potentially can contribute to the perpetuation of the synovitis. There are many cytokine antagonists or natural immunosuppressives that represent potential therapeutic targets for the treatment of inflammatory diseases. Interleukin-1 Receptor Antagonist IL-1Ra is a naturally occurring IL-1 inhibitor that binds directly to type I and type II IL-1 receptors and competes with IL-1 for the ligand-binding site. Interaction of IL-1Ra with the IL-1 receptors does not result in signal transduction, and, in contrast to IL-1α or IL-1β, the receptor-ligand complex is not internalized after it binds to the IL-1 receptor. Although IL-1Ra has high affinity for the IL-1 receptor, it is a relatively weak inhibitor because IL-1 can activate cells even if only a small percentage of IL-1 receptors are occupied. Because of this, a substantial excess of the inhibitor is required to saturate the receptor and block IL-1-mediated stimulation (usually 10-fold to 100-fold excess of IL-1Ra). Recombinant IL-1Ra inhibits a variety of IL-1-mediated events in cultured cells derived from the joint, including the induction of MMP and PG production by chondrocytes and synoviocytes. It can block synovitis in rabbits induced by direct intra-articular injection of recombinant IL-1.224 IL-1Ra is present in rheumatoid synovial effusions; much of it is produced by neutrophils and macrophages.225 Immunohistochemical studies of rheumatoid synovium reveal IL1Ra protein, especially in perivascular mononuclear cells and the synovial intimal lining. The IL-1Ra protein and mRNA can be detected in synovial macrophages and, to a

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A

B Figure 65-9  Localization of interleukin-1 receptor antagonist (IL-1Ra) messenger RNA in rheumatoid arthritis synovial tissue by in situ hybridization. The specific RNA transcript was detected in perivascular cells, especially macrophages. A, Bright field view. B, Same area using a dark field filter. Silver grains in the dark field view show the location of IL-1  Ra-positive cells.

lesser extent, in type B synoviocytes (Fig. 65-9). The ­presence of IL-1Ra in synovium is not specific to RA because osteoarthritis synovial tissue also contains IL-1Ra, albeit in lesser amounts; normal synovium contains little, if any, IL1Ra protein. Despite the presence of significant amounts of IL-1Ra in synovial tissue, its importance as an IL-1 antagonist can be evaluated only in the context of the IL-1-to-IL1Ra ratio. Studies of synovial cell culture supernatants show that the amount of IL-1Ra is insufficient to antagonize synovial IL-1.226 Interleukin-10 IL-10 is an immunosuppressive cytokine that was originally characterized as an inhibitor of T cell cytokine ­production. Its immunosuppressive actions might be important in pregnancy to suppress an immune response directed against paternal MHC antigens, and it might regulate susceptibility to some parasitic infections. As noted previously, IL-10 ­protein is present in RA synovial fluid, and the gene is expressed by synovial tissue macrophages. Serial synovial biopsy specimens in RA patients who were treated with recombinant IL-10 did not show any significant histologic improvement, and clinical responses were not impressive in a limited study. Transforming Growth Factor-β TGF-β is a key member of the TGF superfamily, which includes the bone morphogenetic proteins (BMPs) that signal through intracellular signaling molecules known as

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Smads. It is widely distributed in different tissues and produced by many cells, including T cells, monocytes, and platelets. TGF-β suppresses the production of collagenase and induces the expression of TIMP. TGF-β accelerates the healing of incisional wounds and induces fibrosis and angiogenesis in experimental animal models. Substantial amounts of TGF-β are present in synovial fluid (although it is mainly present in an inactive, latent form), and mRNA can be detected in RA synovial tissue.227 Although typically considered an immunosuppressive cytokine with wound-healing properties, the role of TGF-β in RA is complex as shown by the conflicting results of its administration in various animal models. In RA, TGF-β is one of the factors responsible for blunted responses of T cells that have been exposed to synovial fluid. TGF-β also downregulates IL-1 receptor expression on some cell types, including chondrocytes. When TGF-β is injected directly into the knees of animals, fibrosis and synovial lining hyperplasia develop.228 In streptococcal cell wall arthritis, parenteral administration or systemic gene therapy with the TGF-β gene ameliorates the disease.229 Intra-articular administration of anti-TGF-β antibody decreases arthritis in the injected joint, but not in the contralateral joint in the same model. Although mainly considered anti-inflammatory, TGF-β also can support the differentiation of T cells into the Th17 phenotype. Soluble Cytokine Receptors and Binding Proteins Soluble cytokine receptors and binding proteins can absorb free cytokines and prevent them from engaging functional receptors on cells. Although these could inhibit cytokine action, they also could act as carrier proteins that protect cytokines from proteolytic degradation or deliver them directly to cells, such as the IL-6 receptor. TNF receptors are normally expressed as membranebound proteins and can be released from the cell surface after proteolytic cleavage. Soluble p55 and p75 TNF receptors have been detected in RA synovial fluid, sometimes in very high concentrations.230 Soluble TNF receptor levels can be considerably higher than the concentration of TNF-α in blood or synovial fluid and probably explains why biologically active TNF is difficult to detect in RA synovial fluid despite the presence of immunoreactive protein. Synovial membrane mononuclear cells have increased surface expression and mRNA levels of both TNF receptors compared with osteoarthritis synovial tissue cells or peripheral blood cells.231 Cultured FLS express TNF receptors and shed them into culture supernatants. Many other soluble receptors and binding proteins are produced in RA, albeit in concentrations too low to suppress the exuberant proinflammatory cytokine milieu of the joint effectively. The IL-1 type II receptor is present in RA synovial fluid, along with lesser amounts of the type I receptor.232 These soluble receptors can bind to IL1 or IL-1Ra in synovial effusions. Soluble receptors to IL15 and IL-17 have been characterized, and an IL-18 binding protein can inhibit cytokine activity. In some cases, a soluble receptor can protect a cytokine from degradation or transport it to the cells, as with the IL-6 receptor.

Th1/ Th17 cytokines IL-17 + Macrophage

IL-1 TNF-α + IL-15 GM-CSF M-CSF

IL-10 IL-1Ra

TGF-β

IL-1 TNF-α + IL-18 IL-8 IL-6 + GM-CSF

Th2 cytokines IL-4, IL-10, IL-13

Fibroblast

TGF-β + FGF Metalloproteinases Prostaglandins Complement

Figure 65-10  Cytokine networks in rheumatoid arthritis. Paracrine and autocrine pathways can lead to activation of fibroblast-like and macrophage-like synoviocytes in the synovial intimal lining. Positive (+) and negative (−) feedback loops are present, although in rheumatoid arthritis the former predominate. T helper type 1 (Th1) cytokines potentially can enhance the network, whereas Th2 cytokines are suppressive. FGF, fibroblast growth factor; GM-CSF, granulocyte-macrophage colony­stimulating factor; IL, interleukin; M-CSF, macrophage colony-stimulating­ factor; TGF, transforming growth factor; TNF, tumor necrosis factor.

PERPETUATION OF SYNOVITIS BY MACROPHAGE-FIBROBLAST CYTOKINE NETWORKS Studies to map the cytokine profile and advances in therapy using biologic reagents to inhibit cytokines support the concept that cytokine networks play a key role in the pathogenesis of RA. Initially proposed as a potential mechanism to explain T cell–independent disease perpetuation, it is now clear that these pathways are not autonomous, and except for certain patients with early disease, discontinuation of the therapy leads to a flare. Nevertheless, paracrine and autocrine cytokine networks in the synovial intimal lining contribute largely to inflammatory arthritis in RA (Fig. 65-10). Many cytokines that have been identified in the synovium or synovial fluid can participate in this system and might explain lining cell hyperplasia, HLA-DR and adhesion molecule induction, and synovial angiogenesis. The list of potential candidates in this highly redundant system is extensive. Several of these, including IL-1, TNF-α, and IL6, now have well-defined roles. The first two, along with numerous other factors (e.g., IL-15, IL-18, and IL-32) are produced by synovial macrophages and stimulate synovial fibroblast proliferation and secretion of IL-6, GM-CSF, and chemokines and effector molecules such as MMPs and PGs. GM-CSF, which is produced by synovial macrophages and IL-1β-stimulated or TNF-α-stimulated synovial fibroblasts, can induce IL-1 secretion to form a positive feedback loop. GM-CSF, especially in combination with TNF-α, also increases HLA-DR expression on macrophages. Macrophage and fibroblast cytokines also can indirectly contribute to the evidence for local T cell and B cell activation, including RF production. Cytokines also help recruit other cells into the synovium through the production of chemokines that select specific cell lineages for admission into the synovium. Many of these chemokines, including the C-X-C and C-C families, are produced by macrophages and fibroblasts and attract neutrophils, macrophages, and certain subpopulations of

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T and B cells. The sublining chemokine profile helps organize these newly infiltrated cells into germinal centers in some patients. Other factors, such as IL-12 and IL-23, differentiate CD4+ T cells into the Th1 phenotype to produce relatively small amounts of IFN-γ and other relevant cytokines. IL-6 and TGF-β produced mainly by the lining, along with IL-23, can support the production of Th17 cells that release the potent proinflammatory cytokine IL-17 into the local milieu. All of this occurs in the presence of inhibitor factors, soluble receptors, and binding proteins that are overwhelmed by the inflammatory drive. Other cytokines, such as RANKL and M-CSF, activate osteoclasts that remodel bone. Although they do not cause RA per se, cytokines orchestrate the rheumatoid process. For individual patients, the pivotal cytokine or cytokines that must be blocked can be different, and even this can vary with the stage of disease. Ultimately, understanding the genetic predisposition to disease and the specific patterns of cytokine production could help determine the correct combination of cytokine inhibitors that would be effective.

SIGNAL TRANSDUCTION AND TRANSCRIPTION FACTORS Key Points • Complex intracellular signaling mechanisms regulate cytokine production and actions in RA synovium. • NFκB, MAP kinases, AP-1, and several other pathways are potential therapeutic targets in RA.

Intracellular signal transduction systems transmit environmental stimuli from the cell surface to the cytoplasm or nucleus, where they subsequently are integrated at the level of transcription factor activity. The transcription factors bind to specific DNA sites in promoter regions and regulate the expression of the appropriate genes. The remarkable diversity of signaling pathways and transcription factors provides a selective mechanism for orchestrating activation and repression for appropriate arrays of genes in response to an extracellular stress. Many of the inflammatory responses observed in RA synovium, including the activation of cytokine and adhesion molecule genes, can be traced to specific transcription factors and signal transduction pathways. An extensive description of these mechanisms is beyond the scope of this chapter, and they are reviewed in Chapter 20. Considerable enthusiasm abounds for targeting signal transduction pathways. One recurrent theme is that these pathways play a role in normal cells and host defense, which raise the issues of balancing efficacy with toxicity. NUCLEAR FACTOR κB NFκB is a ubiquitous transcription factor that plays a key role in the expression of many genes central to RA, including IL-1β in monocytes and ICAM-1, TNF-α, IL-6, and IL8 in rheumatoid synoviocytes. NFκB normally resides as an inactive heterodimer or homodimer in the cell cytoplasm associated with an inhibitory protein called IκB that regulates the DNA binding and subcellular localization of NFκB

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proteins by masking a nuclear localization signal. Extracellular stimuli such as cytokines or TLR agonists initiate a signaling cascade leading to activation of two IKKs (IKKα and IKKβ), which phosphorylate IκB at two NH2-terminal serine residues. Phosphorylated IκB is selectively ubiquitinated and degraded by the 26S proteasome. This process permits NFκB to migrate to the cell nucleus, where it binds its target genes to initiate transcription. NFκB is abundant in rheumatoid synovium, and immunohistochemical analysis shows p50 and p65 NFκB proteins in the nuclei of cells in the synovial intimal lining.233 Although the proteins also can be detected in osteoarthritis synovium, NFκB activation is much greater in RA because of phosphorylation and degradation of IκB in RA intimal lining cells (Fig. 65-11). Nuclear translocation of NFκB in cultured FLS occurs rapidly after stimulation by IL-1 or TNF-α through the activation of the IKK signaling complex. The relevance of NFκB to inflammatory arthritis has been tested in several animal models. Synovial NFκB is rapidly activated, often long before clinical arthritis is evident. Adjuvant arthritis in rats is ameliorated by intra-articular gene therapy with the dominant negative IKKβ construct that blocks the IKK pathway,234 and streptococcal cell wall arthritis is blocked by decoy oligonucleotides or a dominant negative IκB adenovirus. NFκB inhibition is associated with decreased synovial cellular infiltration and increased apoptosis. The role of this transcription factor in murine collagen-induced arthritis has been shown using selective IKKβ inhibitors, which suppress arthritis and joint destruction. The role of IKKα is less well defined in RA. It is not required for the classic IKK pathway, but an alternative signaling method through lymphotoxin specifically uses IKKα to engage NFκB. This mechanism might contribute to NFκB activation in sublining cells, especially those in lymphoid ­aggregates. MITOGEN-ACTIVATED PROTEIN KINASES MAP kinases, which are signal transduction enzymes activated in response to cellular stress, are composed of parallel protein kinase cascades that regulate cytokine and MMP gene expression. There are three different families of MAP kinases known as c-Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK). MAP kinases phosphorylate selected intracellular proteins, including­ transcription factors, which subsequently regulate the expression of various genes by transcriptional and post-transcriptional mechanisms. MAP kinases are activated by phosphorylation at conserved threonine and tyrosine residues by a cascade of dual-specificity kinases. These are activated by MAP kinase kinase kinases. The relative hierarchy of the individual MAP kinases depends on the cell type and inflammatory stimulus. The MAP kinases are widely expressed in synovial tissue and are activated in rheumatoid synovium. Phosphorylated ERK, p38, and JNK can be detected by immunohistochemistry or Western blot analysis.235 All three kinases are constitutively expressed by cultured FLS and can be activated within minutes after exposure to ­cytokines and regulate production of proinflammatory cytokines and MMPs.

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RA 1

2

3

4

OA NF-kB

mutant NF-kB c

1

2

3

mutant NF-kB 4

1

2

3

4

NF-kB 1

2

3

4

NFκB Figure 65-11  Nuclear factor κB (NFκB) activation in rheumatoid arthritis (RA) synovium. Electromobility shift assays have been performed on extracts of RA and osteoarthritis (OA) synovium. NFκB activity is significantly higher in RA synovial tissue extracts compared with extracts of OA. This is consistent with increased expression of NFκB-driven genes in RA synovium, such as proinflammatory cytokines and vascular adhesion molecules. Mutant probe is shown on the left as a negative control, and C is a positive control. (From Han Z, Boyle DL, Manning AM, et al: AP-1 and NF-κB regulation in rheumatoid arthritis and murine collagen-induced arthritis. Autoimmunity 28:197, 1998.)

Figure 65-12  p38 mitogen-activated protein (MAP) kinase blockade suppresses murine collagen-induced arthritis. MAP kinases play a key role in cytokine regulation. Inhibitors of p38 MAP kinase suppress synovial inflammation and joint destruction in ­several models of arthritis. Left panels show near-normal joint in animal treated with p38 inhibitor. Right panels show control animals with arthritis. (From Medicherla S, Ma JY, Mangadu R, et al: A selective p38α mitogen-activated ­pr­otein kinase inhibitor reverses cartilage and bone destruction in mice with collagen-induced arthritis. J Pharmacol Exp Ther 318:132, 2006.)

A

B1

C

B2

p38 inhibitors are effective anti-inflammatory agents in murine collagen-induced arthritis and rat adjuvant arthritis, possibly by decreasing the production of proinflammatory cytokines (Fig. 65-12).236 Treated animals also have improved bone mineral density and decreased histologic evidence of joint inflammation. Spinal p38 also plays a major role in pain processing, and inhibitors have potential for analgesic and anti-inflammatory action. Recent studies suggest that p38 in the central nervous system can regulate peripheral inflammation because intrathecal ­administration

p38 ­blockade suppresses inflammation and joint destruction in rat adjuvant arthritis.237 Although p38 is an attractive therapeutic target, the response rates of p38 inhibitors have been modest in RA and Crohn’s disease. JNK inhibition blocks collagenase gene expression in the cultured synoviocytes. Using a selective JNK inhibitor, marked protection of bone destruction was observed in the adjuvant arthritis model, along with decreased synovial AP-1 activation and collagenase-3 gene expression.238 Because JNK has multiple isoforms and splice variants, some

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s­ pecificity possibly can be achieved by inhibiting certain forms of the enzyme to minimize potential for toxicity. This question was partially addressed in passive collagen-induced arthritis using JNK2 knockout mice and the TNF-α transgenic mice that lack JNK1. No benefit was observed in the JNK1−/− mice, and only modest cartilage protection was seen in the JNK2−/− animals.239 However, additional studies are needed to assess the potential benefit of a selective JNK isoform inhibitor. As an alternative to blocking MAP kinases themselves, kinases that regulate p38, JNK, and ERK also can be targeted. MKK3 and MKK6, which are upstream of p38, are activated in the rheumatoid synovial intimal lining. MKK3 knockout mice have markedly decreased joint inflammation in the passive K/BxN model.240 These mice have nearly normal responses to lipopolysaccharide. MKK4 and MKK7 are the main kinases that modulate JNK function and are activated in the rheumatoid synovium. Small interfering RNA (siRNA) knockdown shows that only MKK7 is required for cytokine-stimulated JNK activation and MMP expression in cultured synoviocytes.241 These studies suggest that targeting upstream kinases in RA might suppress inflammatory joint disease, while leaving other aspects of host defense or innate immunity intact. ACTIVATOR PROTEIN-1 Similar to NFκB, AP-1 regulates many genes implicated in RA, including TNF-α and the MMPs. AP-1 activity can be induced by extracellular signals, including cytokines, growth factors, tumor promoters, and the Ras oncoprotein. AP-1 includes members of the Jun and Fos families of transcription factors, which are characterized by leucine zipper DNA­binding domains. AP-1 proteins bind to DNA and activate transcription as Jun homodimers, Jun-Jun heterodimers, or Jun-Fos heterodimers. Multiple Jun and Fos family members (c-Jun, JunB, JunD, c-Fos, FosB, Fra-1, Fra-2) are expressed in different cell types that mediate the transcription of unique and overlapping genes. AP-1-driven gene expression is greatly enhanced when one of its components, especially c-Jun, is phosphorylated. Several kinases, including JNK, ERK, p38, caseine II, and IKKε, can activate this protein complex. AP-1 proteins and mRNA, including c-jun and c-fos, are expressed in RA synovium, especially in the nuclei of cells in the intimal lining layer.242 c-Jun and c-Fos proteins also are expressed in the sublining inflammatory infiltrate, albeit to a lesser degree. Localization of AP-1 to the intimal lining correlates with the site where most protease and cytokine genes are overexpressed in RA. AP-1 proteins usually are not detected in normal synovium, although modest amounts also have been detected in osteoarthritis. Electromobility shift assays show high levels of AP-1-binding activity in nuclear extracts from RA synovium compared with osteoarthritis tissue.243 Cytokines such as IL-1 and TNF-α probably contribute to the activation of AP-1 in RA synovium. These factors are potent inducers of AP-1 nuclear binding in cultured FLS; this is accompanied by increased c-jun and c-fos mRNA and enhanced collagenase gene transcription. The specific Jun family genes that constitute AP-1 in synoviocytes have a clear effect on function. c-Jun increases the production of proinflammatory mediators, whereas JunD suppresses cytokine and

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MMP production.244 AP-1 decoy oligonucleotides suppress collagen-induced arthritis and inhibit IL-1, IL-6, TNF-α, MMP-3, and MMP-9 production by synovial tissue.245 SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION The STATs are a family of latent cytoplasmic transcription factors that are activated in response to cytokine stimulation of cells. STAT proteins contain domains that promote docking to the appropriate tyrosine-phosphorylated cytokine receptor after activation by the Janus kinases (Jak). STATs have been implicated in the expression of many proinflammatory genes. IL-4 and IFN-α signal through STAT1, whereas IL-12 signals through STAT4. The Th2 cytokine IL-4 uses STAT6. Active STATs have been identified in patients with RA. Using immunohistochemistry, STAT1, STAT4, and STAT6 expression was observed in rheumatoid synovium, as was a downstream target of STAT4, Jak3.246 STAT1 expression and activation has been identified in the synovium of patients with active disease, and a STAT1 decoy oligonucleotide suppresses antigen-induced arthritis in mice.247 STAT3 also has been detected in cells from inflamed joints and can ­promote survival of cultured FLS.248 Synovial fluid from RA patients can activate STAT3, but not STAT1, in monocytes.249 This action is independent of IFN-γ and seems to be regulated primarily by IL-6. STAT3 also is strongly phosphorylated in RA synovium and supports the hypothesis that IL-6 plays a pathogenic role in the disease. Activation of the IL-4 pathway (STAT6) also has been shown in RA tissues even though IL-4 expression is very low.250 Gene signature patterns using microarray technology have been evaluated in RA and correlated to histopathology. These studies can be difficult to interpret because of wide variations in the synovial cell populations, sampling error, and the statistical vagaries of managing large volumes of data. One study suggested that RA patients could be divided into two groups.251 The first is marked by expression of proinflammatory genes, with a pattern reminiscent of regulation by the STAT1 pathway. A second pattern is dominated by genes that participate in tissue repair and remodeling, and this signature is similar to osteoarthritis tissues. With sufficient refinement, one potentially could identify subpopulations of patients that could respond to targeted therapies. In an animal model of arthritis, treatment with the ­suppressor of cytokine signaling repressor (SOCS3), which blocks the activation of certain STATs, suppresses ­arthritis.252 This inhibitor also is expressed in the synovium of patients with RA, although it seems to be insufficient to block STAT3 phosphorylation. These data suggest that STATs play a crucial role in cytokine signal transduction in the synovium and can be manipulated to suppress disease. ANTIVIRAL PROTEIN REGULATION: IκB KINASE–RELATED KINASES AND INTERFERON REGULATORY FACTOR-3 The rheumatoid joint displays some characteristics that resemble an antiviral response, such as IFN-β, RANTES, IP-10, and MCP-1 expression. This group of genes can be

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induced by ligation of TLR3 by viruses and other TLR ligands that are present in the rheumatoid joint. The relevance of this observation to inflammatory synovitis is supported by the fact that intra-articular injection of viral double-stranded RNA induces inflammatory arthritis in mice. Synoviocytes can be activated by poly I-C (which binds to TLR3) or RNA from necrotic cells. This does not imply that RA is caused by viruses; rather, it implies that factors within the joint can activate pathways that traditionally are viewed as crucial to host defense, but also can have pathogenic results. The antiviral response is regulated by two IKK-related kinases, known as IKKε and TANK binding kinase 1 (TBK1), which have about 30% homology to the classic IKKs. Triggered by TLR3 ligation by viral double-stranded RNA, IKKε and TBK1 phosphorylate the transcription factor interferon regulatory factor 3 (IRF3) and induce production of an array of genes that orchestrate this response, including RANTES and IFN-β. IKKε and its substrate IRF3 are expressed and highly activated in RA synovium. Using a combination of IKKε knockout mice and genetic constructs that block endogenous IKKε activity, this kinase was shown to be a key regulator of IFN-β, RANTES, and MMP expression in cultured FLS.253 Induction of the antiviral genes has positive and negative potential in RA. Overexpression of some IRF3-driven genes, most notably IFN-β, could have a beneficial impact on the course of inflammatory arthritis. Mice with collageninduced arthritis injected with transduced fibroblasts expressing IFN-β have less severe disease compared with controls, including decreased bone and cartilage destruction. Despite minimal efficacy in a clinical trial of IFN-β in RA, synovial biopsy specimens in treated patients contain smaller amounts of IL-1, IL-6, MMP1, and TIMP compared with placebo controls. Ultimately, clinical interventions will be required to determine if the beneficial effects of MMP and chemokine suppression regulated by IKK-related kinases outweigh modulation of IFN-β.

LIFE AND DEATH IN THE RHEUMATOID SYNOVIUM Key Points • Reactive oxygen and nitrogen in RA joints contributes to a toxic environment that can damage cells and increase inflammation. • Deficient apoptosis, or cell death, can contribute to the accumulation of cells in rheumatoid synovium. • Abnormalities of key regulatory genes, such as the p53 tumor-suppressor gene, can enhance accumulation of cells in the joint. • Inducing apoptosis potentially can suppress synovial inflammation and joint destruction.

Studies defining the life cycle of cells have opened a new door to understanding the pathogenesis of neoplastic and inflammatory diseases. Although most investigators previously focused on cell proliferation as a mechanism of synovial hyperplasia, increasing attention has been paid to the role of insufficient cell death in this process. In this section,

the roles of oxidative damage, programmed cell death, and permanent changes in the genome are discussed, as they can alter the natural history of RA. REACTIVE OXYGEN AND NITROGEN Oxidative stress in the joints of RA patients results from a confluence of several stimuli, including increased pressure in the synovial cavity, reduced capillary density, vascular changes, an increased metabolic rate of synovial tissue, and locally activated leukocytes. The generation of reactive oxygen species also can be facilitated by repetitive ischemia-reperfusion injury in the joint. Tissue injury releases iron and copper ions and heme proteins that are catalytic for free-radical reactions. Electron transport chains also are disrupted in the mitochondria and endoplasmic reticulum, leading to leakage of electrons to form superoxide. Evidence for increased production of reactive oxygen species in RA patients includes elevated levels of lipid peroxidation products, degradation of hyaluronic acid by free radicals, decreased levels of ascorbic acid in serum and synovial fluid, and increased breath pentane excretion. The levels of thioredoxin, a marker of oxidative stress, are significantly higher in synovial fluid from RA patients compared with synovial fluid from patients with other forms of arthritis.254 Peripheral blood lymphocyte DNA from RA patients contains significantly increased levels of the mutagenic 8-oxohydrodeoxyguanosine,255 which is a product of oxidative damage to DNA, pointing to the genotoxic effects of oxidative stress. Nitric oxide production also is high in rheumatoid synovial tissue.256 Low levels of nitric oxide are constitutively produced by endothelial or neuronal synthases, and this is substantially increased by inducible nitric oxide synthase after stimulation by cytokines or bacterial products. The nitrite levels in synovial fluid are elevated in RA patients, indicating local nitric oxide production.257 In addition, the urinary nitrate-to-creatinine ratio is increased, and inducible nitric oxide synthase is present in the synovium. APOPTOSIS Programmed cell death, or apoptosis, is a process by which cells can be safely eliminated in the midst of living tissue. This stereotypic response provides a mechanism for tissue development, remodeling, or cell deletion without instigating an inflammatory response. Apoptosis is a normal process that is tightly regulated and can be initiated by withdrawal of hormones and growth factors. It is evident in the elimination of autoreactive cells such as thymocytes in the thymus gland and the loss of cells after DNA damage. It also plays a crucial role in immune response by deleting activated T cells and terminating an inflammatory response by rapidly removing neutrophils. Genes Regulating Apoptosis The accumulation of cells in RA is typically considered as a process involving in situ cell proliferation or recruitment of cells from the bloodstream. It is equally tenable, however, that increased cell numbers could accumulate in

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the synovium as a result of insufficient cell deletion. T cell apoptosis in RA synovial effusions is significantly less than apoptosis of lymphocytes from crystal-induced arthropathy.258 The RA T cells show high Fas (CD95) expression, high Bax, and low Bcl-2, which is a phenotype typically associated with increased susceptibility to apoptosis. This finding contrasts with synovial tissue cells, in which high Bcl-2 expression is found in lymphoid aggregates and protects synovial T cells from programmed cell death. Resistance to apoptosis in vitro is prolonged if the RA T cells are cocultured with FLS or IL-15. The specific adhesion molecules involved are ­undefined, although the integrin-binding RGD motif (arginine-glycine-asparagine) could block the protective effects of synoviocytes. Fas and its TNF superfamily counterreceptor Fas ligand (FasL) are potent regulators of cell death for many cell types, including synovial T cells and synoviocytes. Fas is expressed by rheumatoid synovial fluid T cells, and the number of Fas+ cells in the peripheral blood of RA patients is greater than in healthy controls.259 Anti-Fas antibody, which cross-links Fas on cell surfaces, rapidly causes apoptosis in synovial fluid B and T lymphocytes in RA, although peripheral blood T cells are more resistant. Another member of the TNF superfamily, TRAIL (TNF-related apoptosis-inducing ligand) binds to two receptors (DR4 or DR5) to induce caspasedependent apoptosis. DR5 is expressed in RA FLS, but not osteoarthritis cells, and apoptosis can be induced by either TRAIL or agonistic anti-DR5 antibody.260 Studies of apoptosis in RA synovial tissue have relied on many techniques that label damaged DNA. Using the most stringent methods, only a few apoptotic nuclei have been detected in the intimal lining and the sublining.261 Electron microscopic studies show rare cells that exhibit the typical findings of programmed cell death. Less specific techniques that detect any DNA damage show abundant cells in the intimal lining with nuclear fragmentation.262 There is an unexpected discrepancy between the cytologic evidence of DNA damage and the rarity of typical morphologic changes of apoptosis, even using ultrastructural criteria.263 One explanation for synovial macrophages is that they express high levels of the caspase 8 inhibitor FLICE-like inhibitory protein, which can inhibit Fas-mediated apoptosis.264 Despite the dearth of apoptotic cells in the lining, Bcl2 expression (which inhibits apoptosis) is reduced in this region. The mechanisms for inducing apoptosis in FLS can involve several pathways, including induction of JNK and AP-1 activation, inhibition of the kinase Akt, or suppression of NFκB.265 p53, which typically induces cell cycle arrest and either DNA repair or apoptosis, also is expressed in the synovial lining and sublining. One of the main effectors of p53mediated apoptosis, PUMA (p53 upregulated modulator of apoptosis), is present in only very low concentrations, however, in the synovium and cultured synoviocytes. Because of these unexpected findings, the regulation of apoptosis has been evaluated in cultured FLS in RA. Fas is constitutively expressed by cultured synoviocytes, and programmed cell death is initiated in a few cells (generally ≤20%) when it is cross-linked by anti-Fas antibody. Most investigators find that RA and osteoarthritis synoviocytes are equally susceptible to anti-Fas-mediated death. PUMA can induce cell death in FLS when overexpressed using genetic methods.266 Gene transfection experiments showed,

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however, that p53 directs synoviocytes to cell cycle arrest through expression of p21 instead of inducing apoptosis through PUMA. Synoviocyte apoptosis also can be initiated by oxidative stress, such as hydrogen peroxide, or by exposure to nitric oxide. The relative paucity of apoptosis in RA also can be explained by patterns of gene expression that favor cell survival. As noted earlier, p53 preferentially induces p21 and favors survival. Sentrin-1, a ubiquitin-like protein, regulates the cell survival by modifying proteins involved in apoptosis (including p53). Sentrin-1 is expressed in RA synovium, especially at sites of cartilage invasion, and protects cells from Fas-mediated apoptosis.267 A second protein, PTEN (phosphatase and tensine homolog on chromosome ten) originally was defined as a key factor that protects from tumorigenesis through antagonism of PI3K, Akt, and many other proliferative pathways. Underexpression of PTEN in RA has been described in rheumatoid synovial intimal lining and cultured FLS.268 Therapeutic Interventions That Increase Apoptosis The potential relevance of Fas-induced death as a therapeutic modality has been shown in murine collageninduced arthritis, in which high levels of Fas and low levels of FasL are expressed by synovial cells.269 Mice treated with an intra-articular injection of an adenoviral vector encoding Fas ligand had decreased synovial inflammation. DNAlabeling studies showed that the construct increased synovial apoptosis. Anti-Fas antibody also induces synovial cell death in RA synovial tissue explanted in SCID mice. In the SCID mouse model using RA synovial explants, anti-DR5 antibody decreased cartilage erosion. Similarly, adenoviral transfer of TRAIL in a rabbit model of arthritis decreases synovial inflammation.270 The importance of apoptosis as a regulator of inflammation was confirmed in murine collagen-induced arthritis, where anti-DR5 antibody or genetic DR5 deficiency exacerbated the disease. Other targets that regulate apoptosis also have shown potential utility in animal models. NFκB blockade in streptococcal cell wall arthritis induces synovial apoptosis and suppresses arthritis. p53 gene therapy in rabbit antigen– induced arthritis induces synovial apoptosis and decreases inflammation.271 The pleiotropic activities of p53 were shown in collagen-induced arthritis because p53 knockout mice with the disease developed increased inflammation and greater joint destruction in association with decreased apoptosis. Joint damage was mediated by increased expression of collagenase genes in the knockout mice, most likely because p53 directly suppresses MMP gene transcription.272 p53 knockout mice with either passive collagen-induced arthritis or passive K/BxN arthritis do not manifest increased disease activity, however.273 These data suggest that p53 mediates its protective effects through modulation of the adaptive immune response. TUMOR-SUPPRESSOR GENES The p53 tumor-suppressor gene is a key regulator of DNA repair and cell replication. p53 protein expression is significantly greater in the rheumatoid synovium compared

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with osteoarthritis and normal tissue. In long-standing disease marked by joint destruction, immunostaining localizes the protein to sublining mononuclear cells and the intimal lining.274 p53 protein also can be detected in RA synovium from patients with very early RA and asymptomatic rheumatoid joints.275 Its expression is much lower in other inflammatory arthropathies, however, such as reactive arthritis, which might reflect the generally greater amount of DNA damage and oxidative stress in RA. The possibility that somatic mutations in the p53 gene might contribute to the unusual phenotype of RA synoviocytes and inadequate apoptosis in rheumatoid synovial tissue has been investigated.276 p53 mutations have been identified in RA synovial tissue and synoviocytes, although their presence is controversial. Transition mutations, which are characteristic of damage induced by reactive oxygen or nitric oxide, account for more than 80% of the base changes. Some mutant p53 genes exhibit dominant negative characteristics and suppress the function of the wild-type allele.277 Microdissection studies confirmed the presence of mutant islands, and the loss of p53 function in a region of RA synovium was associated with increased IL-6 gene expression in the same location.278 The data suggest that mutations do not cause RA, but, instead, are the result of the long-standing oxidative stress. The gene alterations potentially can increase the aggressive nature of the synovium and alter the natural history of RA. Abnormalities in other genes also have been reported in RA. Synovial T cells in RA have an increased incidence of mutations in the hprt gene.279 Although not functionally important, these mutations act as a marker for oxidative damage that occurs in the synovial milieu. Some of these abnormal lymphocytes also can be detected in the peripheral blood, suggesting that articular T cells can migrate out of the joint to other parts of the body. Abnormalities of the ras gene, which is involved in many signal transduction pathways, also have been noted in some patients. The H-ras oncogene is expressed in the synovium of patients with a variety of arthritides, and mutations have been identified in RA and osteoarthritis synovium.280 Recently, mutations in synovial vimentin have been identified that could enhance its immunogenicity.280a Microsatellite instability, which is marked by mutations in mononucleotide and dinucleotide repeat sequences in noncoding DNA, also is significantly greater in RA than osteoarthritis synovial tissue. Occasional mutations in a coding region microsatellite in the WISP-3 gene, which can regulate type II collagen and aggrecan expression, have been identified in RA synovium. Similar mutations were observed in osteoarthritis, suggesting that these are not specific. Mutations in mitochondrial genes also have been described in RA, most likely owing to oxidative damage.281 Evaluation of DNA mismatch repair genes in rheumatoid synovium suggests that the balance of two genes that protect against mutations might contribute to the pattern of DNA damage in RA, with relatively high levels of mutS homolog 3(MSH3) and low levels of MSH6 after reactive nitrogen stress.282 The former repairs large insertions and deletions, whereas the latter repairs single base abnormalities. Because most mutations detected in RA involve single bases, the balance of mismatch repair enzymes seems to favor these limited mutations rather than more ­substantial ones.

BLOOD VESSELS IN ARTHRITIS Key Points • Angiogenesis is a dynamic process in RA that provides nutrients to expanding synovium. • Angiogenic factors, such as IL-8 and vascular endothelial growth factor, can enhance blood vessel proliferation in the synovium. • Microvascular endothelia in the synovium express adhesion molecules that guide circulating cells into the joint under the influence of chemoattractants.

Blood vessels previously were thought of as passive conduits through which red blood cells and leukocytes circulated while en route to an inflammatory site. This is now known to be far from the truth: The microvasculature plays an active role in such processes, not only as the means of selecting which cells should enter the tissue, but also as a determinant of tissue growth and nutrition through the proliferation of new capillaries.

ANGIOGENESIS IN RHEUMATOID ARTHRITIS: FEEDING THE STARVED SYNOVIUM The importance of luxurious new capillary growth early in the development of synovitis has been recognized for many years. The absolute number of blood vessels is increased in RA synovium (Fig. 65-13), with a rich network of sublining capillaries and postcapillary venules in histologic sections stained with endothelium-specific antibodies. The mass of tissue outstrips angiogenesis in RA, however, as determined by the number of blood vessels per unit area and causes local tissue ischemia.283 Synovial fluid oxygen tensions are remarkably low, lactate measurements are frequently high, and the pH can be as low as 6.8. The mean rheumatoid synovial fluid partial pressure of oxygen in samples from rheumatoid knees is approximately 30 mm Hg and ­ occasionally less than 15 mm Hg. Another cause of ­diminished blood flow is increased

Figure 65-13  Human rheumatoid synovial membrane stained with a­ ntibody to von Willebrand factor to delineate blood vessels. Most of these blood vessels formed in response to angiogenic stimuli after the rheumatoid process had been initiated. (Courtesy of Dr. Paul-Peter Tak.)

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positive pressure exerted by synovial effusions within the joint, a process that obliterates capillary flow, while producing ischemia-reperfusion injury in the joint. Altered vascular flow may not be the only cause of hypoxia in joints; oxygen consumption of the rheumatoid synovium (per gram of tissue) is 20 times normal. Hypoxia is a potent stimulus for angiogenesis. One of the mechanisms by which this occurs is through the production of angiogenic factors regulated by hypoxia-inducible factor 1α (HIF-1α), such as vascular endothelial growth factor (VEGF).284 This oxygen-sensing transcription factor regulates numerous responses to hypoxia. HIF-1α deficiency in the myeloid lineage suppresses inflammation in numerous models, including the passive K/BxN model of arthritis.285 Low oxygen tension also leads to HIF-1α-induced transcription of VEGF, a specific endothelial cell mitogen that is present in high concentrations in rheumatoid synovial fluid and tissue. Elevated serum concentrations in early disease correlate with subsequent radiographic progress, although it is unclear if there is a causal relationship. VEGF also is able to stimulate the expression of collagenase, which can degrade the extracellular matrix to make room for the advancing vasculature and pannus.286 VEGF expression is especially high in the synovial intimal lining, and the angiogenesis factor also is produced by cultured FLS that have been exposed to hypoxia and IL-1.287 VEGF can bind to two receptors with tyrosine kinase domains, VEGF-R1/Flt-1 and VEGF-R2. Genetic deletion of VEGF-R1 decreases VEGF-driven expression of IL-6 and suppresses macrophage phagocytosis. VEGF-R1−/− mice also are resistant to arthritis in the human T lymphotropic virus1 pX model, which is marked by unregulated proliferation of synovial cells. Small molecule VEGF-R inhibitors also suppress acute models of inflammation, such as carrageenan paw edema, and mouse collagen-induced arthritis. Targeting this receptor with a small molecule might suppress the angiogenic and proinflammatory actions of VEGF. In addition to the hypoxia-driven stimulus for blood vessel growth, the inflammatory cytokine milieu of the joint encourages angiogenesis. Several proinflammatory factors expressed by the rheumatoid joint, including IL-8, FGF, and TNF-α, are angiogenic. Many of these cytokines, including TNF-α, enhance angiogenesis further by increasing expression of angiopoietins (Ang-1 and Ang-2) by synoviocytes, which can then bind to their tyrosine kinase receptor, Tie-1, on RA capillary endothelial cells.288 Additional angiogenesis factors, such as soluble E-selectin and soluble VCAM, are released by activated endothelium in RA synovium and contribute to vascular proliferation.289 Limited quantities of some antiangiogenic mediators that inhibit capillary proliferation, such as platelet factor-4 and thrombospondin, also are produced by the joint.290,291 Vascular remodeling is an active process that involves the continuous creation and resorption of blood vessels. In RA, new capillaries that form under the influence of proangiogenic factors can be identified by the expression of integrins such as αvβ3. Endothelial proliferation is especially prominent in synovial tissue regions containing VEGF. Synovial blood vessel involution also can be detected as evidenced by apoptosis of the endothelium in other synovial locations. An index comparing proliferation and death of blood vessels is significantly higher in RA compared with osteoarthritis or normal synovium.

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The importance of new blood vessel formation in inflammatory arthritis was elegantly shown in the collagen-induced arthritis model. The disease was markedly attenuated in ani­ mals pretreated with an angiostatic compound similar to fumagillin, which is derived from Aspergillus.292 This compound is cytotoxic to proliferating, but not resting, endothelial cells. In addition, there was regression of established arthritis if treatment was initiated well into the course of the disease. Angiogenesis is essential for the establishment and progression of inflammatory arthritis because of the need for blood vessels either to recruit leukocytes or to provide nutrients and oxygen to starved tissue. Several other antiangiogenesis approaches are effective in animal models of arthritis. Thrombospondin 1 overexpression significantly decreases blood vessel density, inflammation, and joint destruction in rat collagen-induced arthritis. Direct intra-articular administration of a cyclic RGD peptide was used in a rabbit model to block αvβ3 integrin.293 As with RA synovium, αvβ3 is expressed by proliferating blood vessels in inflamed rabbit synovial tissue. The cyclic peptide decreased joint inflammation, increased endothelial cell apoptosis, and suppressed bone and cartilage destruction. The ability of RGD to bind selectively to proliferating blood vessels also was used to home a proapoptotic agent to synovial neovasculature in murine collagen-induced arthritis.294 The cyclic RGD peptide was administered systemically and accumulated in inflamed synovium, but not normal joints or other organs. Apoptosis was induced in synovial blood vessels, and arthritis regressed. The potent angiogenesis inhibitor endostatin has been tested in the SCID mouse model, and it decreased synovial explant inflammatory cell infiltration and capillary density.295 Despite the compelling rationale for antiangiogenic therapy, an anti-αv antibody showed minimal efficacy in clinical trials, perhaps because other pathways are more important in the synovium.

ADHESION MOLECULE REGULATION The formation of new capillaries is only one aspect of blood vessel involvement in the rheumatoid process. Endothelial cells also are activated by cytokines to express adhesion molecules that bind to counterreceptors on mononuclear cells and neutrophils from the circulation and facilitate their transfer from the blood into the subsynovial tissue. There are several categories of vascular adhesion molecules. The selectins (E-selectin, L-selectin, and P-selectin) are a family of adhesion molecules whose primary ligands are carbohydrates, especially sialyl Lewisx, and related oligosaccharides. A second family comprises integrins, which are heterodimers that include an α chain and a β chain. The counterreceptors depend on the specific combination of these chains and are frequently proteins in the immunoglobulin supergene family (e.g., the combination of ICAM-1 and αMβ2) or extracellular matrix proteins (e.g., the ­combination of fibronectin and α5β1 or vitronectin and αvβ3). Several novel peptides have been described that selectively bind to the blood vessels of human synovial explants in SCID mice.296 Adhesion molecule expression is increased in the RA synovium. This increased expression is almost certainly due to exposure of the vasculature to the rich cytokine milieu. Immunohistochemical techniques localize high levels of

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ICAM-1 to sublining macrophages, macrophage-like synovial lining cells, and fibroblasts compared with normal tissue.297 Significant amounts also are present on most vascular endothelial cells, although the ICAM-1 levels are quantitatively similar to those of vessels in normal endothelium. Cultured FLS also constitutively express ICAM-1, which can be markedly increased by TNF-α, IL-1, and IFN-γ. Adhesion of α4β1-expressing mononuclear cells, such as memory T cells or monocytes, to cytokine-activated endothelial cells can be mediated by VCAM-1. VLA-4, which is predominantly expressed on lymphocytes, monocytes, and eosinophils, but not on neutrophils, serves as a receptor for VCAM-1 and an alternatively spliced region of fibronectin known as CS-1. A role for VLA-4 in arthritis has been suggested by numerous experimental observations. In adjuvant arthritis in rats, anti-α4 antibody decreases lymphocyte accumulation in the joint, but not lymph nodes, suggesting that VLA-4 is more important in recruitment to inflamed sites than to noninflamed sites.298 In streptococcal cell wall arthritis, intravenous injection of CS-1 peptide decreases the severity of acute and chronic arthritis.44,299 T lymphocytes isolated from the synovial fluid and synovial membrane of RA patients exhibit increased VLA-4-mediated adherence to CS-1 and VCAM-1, relative to autologous peripheral blood lymphocytes.300 These studies also suggest that leukocytes expressing functionally activated VLA-4 are selectively recruited to inflammatory sites in RA. Moderate amounts of VCAM-1 are expressed in RA synovial blood vessels. The intimal lining is the location of the most intense staining with anti-VCAM-1 antibodies on histologic sections. Even normal synovial tissue expresses VCAM-1 in the lining, albeit less than in RA. Cultured FLS constitutively express small amounts of VCAM-1, and the level is increased by a variety of macrophage-derived and T cell–derived cytokines. VCAM-1 also contributes to T cell adhesion to high endothelial venules in frozen sections of RA synovium.301 The other VLA-4 counterreceptor, CS-1-containing forms of fibronectin, is restricted to inflamed RA vascular endothelium and the synovial intimal lining.302 Normal synovial tissue contains little, if any, CS-1 fibronectin. The integrin α4β7, which also can bind to VCAM-1, is a specific adhesion molecule involved in lymphocyte homing to Peyer’s patches. Most intraepithelial and lamina propria lymphocytes express α4β7; this molecule is rarely identified in other lymphoid tissues. The expression of α4β7 on peripheral blood lymphocytes from patients with RA is low (similar to normal individuals), but a quarter of synovial fluid lymphocytes, mostly CD8+ T lymphocytes, express this adhesion molecule, which provides an interesting link between arthritis and the gut.303 E-selectin expression also is elevated in rheumatoid synovium, although the increase is less dramatic than for the integrins and their counterreceptors. This might be due partly to the kinetics of E-selectin expression on endothelial cells. The protein is not found on resting endothelial cells and peaks after about 3 hours of cytokine stimulation. Even in the continued presence of cytokines, however, E-selectin expression declines to near-basal levels after about 6 hours. In one study, E-selectin expression was decreased in synovial biopsy specimens after patients were treated with injectable gold and corticosteroids.304

The therapeutic potential for antiadhesion therapy has been studied in the SCID mouse model. Labeled human peripheral mononuclear cells were injected into engrafted mice, and migration into the tissue was examined.305 If the mice were treated with TNF-α, ICAM-1 expression and trafficking into synovium was significantly increased. AntiICAM-1 antibody blocked leukocyte migration into the explant under these conditions. In another study, tonsil mononuclear cells also migrated into the RA synovial grafts in SCID mice.306 RA clinical trials using ICAM-1 targeted therapy have been reported using anti-ICAM-1 antibody or antisense ICAM-1 oligonucleotides, although no significant clinical benefit was observed.307 In addition, mice lacking E-selectin and P-selectin had accelerated disease in the collagen-induced arthritis model. This paradoxical result serves as a reminder of the complexity of the inflammatory process.308

CARTILAGE AND BONE DESTRUCTION Key Points • Distinct mechanisms and cell types regulate cartilage degradation and bone destruction in RA. • Several classes of proteases, including metalloproteinases, serine proteases, cathepsins, and aggrecanases, are produced by intimal lining cells in RA, especially FLS. • Synovial lining cells, especially FLS, can attach to and invade cartilage in RA. • Bone destruction is mediated by osteoclasts that are activated under the influence of RANKL and other cytokines produced by RA synovium.

CARTILAGE DESTRUCTION AND THE PANNUS-CARTILAGE JUNCTION In RA, the cartilage is often covered by a layer of tissue composed of mesenchymal cells, which might represent the progenitor of the aggressive, mature pannus. In the established lesion, numerous areas are seen in which macrophagelike and fibroblast-like cells penetrate into cartilage matrix far from lymphocytes (Fig. 65-14).309 Some regions show relatively acellular pannus tissue, however, suggesting that there is little, if any, enzyme-mediated tissue destruction in these areas. Invasive pannus is more commonly found in metatarsophalangeal joints compared with hip and knee joints in which a layer of resting fibroblasts seems to separate pannus from cartilage, perhaps explaining why erosions occur more often around small joints. FLS from the intimal lining usually are considered major effectors of cartilage destruction in RA based on the prodigious amount of proteases that they produce. Rheumatoid FLS can bind to cartilage and invade into the extracellular matrix in the SCID mouse model, showing their propensity for eroding the extracellular matrix. Other cells in the joint, especially neutrophils and cells from the pannus that burrow directly into cartilage, also could be responsible for cartilage-mediated and osteoclast-mediated bone erosions. More primitive mesenchymal cells isolated directly from the cartilage-pannus junction express phenotypic and ­ functional features of synoviocytes and chondrocytes that also have been described in the synovium.

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Figure 65-14  Pannus-cartilage junction. The invasive front of pannus burrows into cartilage matrix in rheumatoid arthritis joints. The pannus is primarily composed of macrophages and mesenchymal cells. Immuno­ staining with anti-CD68 antibody shows the distribution of macrophages in the invasive tissue. (Courtesy of Dr. Paul-Peter Tak.)

Cartilage is destroyed in RA by enzymatic and mechanical processes. The enzymes induced by factors such as IL-1, IL-17, TNF-α, phagocytosis of debris by synovial cells, and mechanical trauma cause the joint destruction. Early in synovitis, proteoglycans are depleted from the tissue, most likely owing to the catabolic effect of cytokines such as IL-1 on chondrocytes with the production of MMPs and aggrecanases, and this leads to mechanical weakening of cartilage. As proteoglycans are depleted, cartilage loses the ability to rebound from a deforming load and becomes susceptible to mechanical fragmentation and fibrillation. Eventually, the tissue loses functional integrity concurrent with its complete dissolution by collagenase and stromelysin. Some of the MMPs responsible for this process also are derived from the chondrocytes themselves. Multiple MMPs, especially stromelysins and collagenases, are expressed in RA cartilage, and in situ hybridization studies confirm the presence of the specific RNA transcripts within chondrocytes.310 The cartilage is under attack from a multitude of sources: It is being bathed in protease-rich synovial fluid, it is under extrinsic attack from the invasive pannus, and the chondrocytes themselves contribute to destruction from within. Enzymes released by PMNs in synovial fluid, including neutrophil collagenase and multiple serine proteases, also contribute to cartilage loss. Immune complexes containing RFs are embedded in the superficial layers of cartilage and can attract and activate neutrophils. Electron microscopic examinations of articular cartilage in RA reveal amorphous-appearing material and evidence of breakdown of collagen and proteoglycan consistent with superficial diffuse activity of joint fluid enzymes.311 In a rabbit model of arthritis in which IL-1 was injected directly into the joint, the degree of cartilage damage as measured by proteoglycan levels in synovial fluid correlated best, however, with the stromelysin concentrations in synovial effusions (presumably derived from synoviocytes). Neutrophil depletion of animals did not interfere with subsequent destruction of extracellular matrix, suggesting that MMPs derived from the synovium are more important.

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Most animal studies indicate that IL-1 is a key regulator of matrix degradation in arthritis312; this has been true across a broad range of arthritis models, including zymosan-induced arthritis, collagen-induced arthritis, antigen-induced arthritis, and streptococcal cell wall–induced arthritis. Although TNF-α blockade has clear anti-­inflammatory effects, chondroprotection is less prominent. Bone and cartilage protection observed in patients receiving TNF inhibitors reminds us that animal models are imperfect predictors of RA responses. More recent data suggest that IL-17 also can contribute to joint destruction directly or by synergizing with IL-1 and TNF-α. The rate-limiting step in cartilage loss is the cleavage of collagen because proteoglycans are degraded soon after inflammation begins. MMPs, released into the extracellular space and active at neutral pH, are probably responsible for most of the effective proteolysis of articular-cartilage proteins, but other classes of enzymes may contribute to joint destruction. Enzymes such as cathepsins B, D, G, K, L, and H may play a role within and outside cells in degrading noncollagenous matrix proteins. Serine proteinases (e.g., elastase and plasmin) and aggrecanases are doubtless involved as well. PROTEASES—KEY MEDIATORS OF JOINT DESTRUCTION Matrix Metalloproteinases The MMPs are a family of enzymes that participate in extracellular matrix degradation and remodeling. MMPs usually are secreted as inactive proenzymes, and their proteolytic activity requires limited cleavage or denaturation to reveal a zinc cation at the core. Their activation can be mediated by other proteases, including trypsin, plasmin, or tryptase. The substrates for MMPs vary, but are quite specific for individual members of the family. Collagenases degrade native collagen types I, II, III, VII, and X, whereas gelatinases are able to degrade denatured or cleaved collagen. Stromelysins have broader specificity and can digest proteoglycans in addition to proteins. They also process procollagenase to the active form, serving as a positive feedback signal for matrix destruction. Some MMPs such as TNF convertase are responsible for the processing and release of cytokines from the cell surface. Many different families of proteinases are found in the joint (Table 65-7), but the MMPs are thought to play a pivotal role in joint destruction. Regulation of Matrix Metalloproteinase Production The cytokine milieu has the capacity to induce the biosynthesis of MMPs by synovial cells and alter the balance between extracellular matrix production and degradation. IL-1 and TNF-α, in particular, directly induce MMP gene expression by many cells, including FLS and chondrocytes. These two cytokines are additive or synergistic when used in combination. Many other cytokines implicated in rheumatoid synovitis also can induce MMP expression, including IL-17 and leukemia inhibitory factor. MMP induction is mediated by a change in gene transcription and mRNA stabilization. Culture medium from rheumatoid synovium stimulates cartilage degradation in vitro, and this can be inhibited by an antibody against IL-1;

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Table 65-7  Key Proteases and Inhibitors   in Rheumatoid Arthritis Synovium Protease

Inhibitor

Metalloproteinases Collagenase-1 Collagenase-3 Stromelysin-1 92-kD gelatinase

TIMP family; α2-macroglobulin

Serine proteases Trypsin Chymotrypsin Tryptase

SERPINs; α2-macroglobulin

Cathepsins Cathepsin B Cathepsin L Cathepsin K

α2-macroglobulin

SERPIN, serine protease inhibitors; TIMP, tissue inhibitor of metalloproteinases.

these data implicate rheumatoid synovium as a source of IL1 that activates chondrocytes to produce proteases. IL-6 does not induce MMP production by synovial cells, but instead increases the production of TIMP-1, a naturally occurring inhibitor of MMPs.313 TGF-β inhibits collagenase synthesis in vitro and enhances the production of TIMP by fibroblasts and chondrocytes.314 It also increases collagen production, shifting the balance to matrix repair. Although multiple upstream regulatory sequences are involved in the regulation of MMP gene transcription, the dominant element in the promoter is AP-1. Other regulatory sites, such as an NFκB-like region, also can contribute to collagenase expression. AP-1 activity is markedly increased in FLS by proinflammatory cytokines, and its transcriptional activity is mediated by increased expression of components such as c-Jun and post-translational modification by phosphorylation. The MAP kinases are especially important for this activity, and JNK is the most efficient upstream activator. Glucocorticoid-mediated inhibition of collagenase gene expression is due to interference with the Fos-Jun complex by the glucocorticoid receptor. Collagenases and stromelysins have the capacity to degrade virtually all of the important structural proteins in the extracellular tissues within joints. Collagenase-1 (MMP-1) cleaves through the triple-helical collagen molecule at a single glycine-isoleucine bond approximately three quarters of the distance from the NH2 terminus. This enzyme has the capability to degrade only the interstitial helical collagens (e.g., types I, II, III, and X). It has little or no activity against types IV, V, and IX and other nonhelical collagens or denatured collagen; the degradation of the latter is primarily accomplished by the gelatinases. MMP-1 is a relatively inefficient enzyme, however, and the more recently characterized collagenase-3 (MMP-13) has more favorable kinetics. Similar to collagenase-1, collagenase-3 has an AP-1-binding site in the promoter that is an important regulator of MMP-13 gene transcription. Neutrophil collagenase, or MMP-8, is constitutively stored in neutrophil granules and is released into the milieu after degranulation. The relative importance of this enzyme in inflammatory arthritis is uncertain, and neutrophil depletion does not prevent cartilage damage in animal models. Rodents lack the collagenase-1 gene, whereas the collagenase-3 gene is preserved; this is especially important to note when evaluating effects of MMP inhibitors in animal models.

Matrix Metalloproteinase Expression in Synovium The collagenase-1 and collagenase-3 genes are produced by RA synovial tissue, and the collagenase-3 gene is highly expressed by chondrocytes in cartilage. In situ hybridization studies show that the primary location of collagenase-1 gene expression in the synovium, similar to many other MMPs, is the intimal lining, especially in fibroblast-like cells.315 Subchondral bone is another region in which proteinase expression occurs in RA and could participate in bone resorption. Increased MMP gene expression is an early feature of RA and occurs during the first few weeks or months of disease316; this underscores the need for early therapy to prevent joint destruction. High expression of collagenase-1 and gelatinases such as MMP-2 early in disease correlates with rapidly progressive erosions. Similarly, increased blood levels of the proenzymes are associated with more severe disease. Stromelysin-1 (MMP-3) and the other members of the stromelysin family have no activity against interstitial collagen, but effectively degrade type IV collagen, fibronectin, laminin, proteoglycan core protein, and type IX collagen. Stromelysin removes the NH2-terminal propeptides from type I procollagen and is integrally involved in the activation of procollagenase. Similar to collagenase, stromelysin gene expression is almost exclusively in the synovial intimal lining (Fig. 65-15). Prostromelysin from human synovial cells can be activated by other proteases, including cysteine proteases (the cathepsins), trypsin, chymotrypsin, plasma kallikrein, plasmin, and mast cell tryptase. Despite the putative importance of this enzyme in matrix destruction, stromelysin knockout mice are susceptible to collageninduced arthritis and develop as much joint destruction as mice with functional stromelysin.317 MMP inhibitors are effective in animal models of RA and can suppress bone destruction and the inflammatory synovitis.318 In models of osteoarthritis, deletion of MMP genes such as stromelysin does not improve outcomes. Clinical trials in RA using nonselective inhibitors have had minimal success and significant side effects, possibly related to decreased matrix turnover. Inhibitors of TNF convertase (which also can block other MMPs) appear to increase disease activity in RA for uncertain reasons. One of the most consistent side effects of MMP inhibitors is stiffness thought to result from deposition of fibrous tissue without sufficient protease activity to permit removal of matrix proteins during remodeling. This observation has been replicated in rats, which provides an opportunity to determine if highly selective MMP inhibitors would have a better risk-to-benefit ratio.319 Cysteine Proteases—the Cathepsins Cathepsins are an extensive family of cysteine proteases that have broad proteolytic activity, including activity on types II, IX, and XI collagen and proteoglycans.320 Similar to MMPs, the cathepsins are regulated by cytokines and by proto-oncogenes such as ras. IL-1 and TNF-α induce cathepsin L expression in cultured FLS.321 In situ hybridization studies show expression of cathepsin B and L in RA synovium, especially at sites of erosion. A ribozyme that cleaves cathepsin L decreases FLS invasion and cartilage destruction in the SCID mouse model with implanted ­cultured synoviocytes. A novel cysteine protease called

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Stromelysin

Figure 65-15  Localization of stromelysin, tissue inhibitor of metalloproteinase-1 (TIMP-1), and actin mRNA in rheumatoid arthritis (RA) synovial tissue by in situ  hybridization. Stromelysin is mainly expressed in the synovial intimal lining, presumably by cytokine-  stimulated type B synoviocytes. Bright field and dark field views are shown. (Courtesy of D. Boyle.) TIMP-1

Actin

cathepsin K has been implicated in bone resorption by osteoclasts. It is unique among the cathepsins in its ability to degrade native type I collagen.322 Cathepsin K is expressed in RA synovial tissue by macrophages and fibroblasts and is present in significantly higher concentrations in RA than in osteoarthritis.323 Serum levels of cathepsin K correlate with the extent of radiographic damage. A potential role of cathepsins as mediators of bone destruction in arthritis was confirmed in studies in which a cysteine protease inhibitor significantly decreased joint damage in the rat adjuvant arthritis model.324

­constitutively expressed by RA and osteoarthritis FLS and synovial tissues.327 Aggrecanase-1 can be induced in synoviocytes by cytokines, especially TGF-β, whereas aggrecanase-2 expression remains constant. Genetic deletion of aggrecanase-1 has no effect on a murine osteoarthritis model. Loss of aggrecanase-2 essentially prevents degenerative changes, however.328 ­Alth­ough data in RA are unavailable, these studies suggest that aggrecanase-2 might be largely responsible for proteoglycan depletion from cartilage in either inflammatory or noninflammatory arthritis. INHIBITORS OF PROTEASE ACTIVITY

Aggrecanases In addition to type II collagen, aggrecan is a crucial component of cartilage as one of the major proteoglycan components. Because of its large size and negative charge, aggrecan contains a considerable amount of water, which increases compressibility. Two proteolytic sites are available on aggrecan in its globular domain. One site is susceptible to MMP cleavage, whereas the other, located 32 amino acids toward the carboxy terminus, is the site for cleavage by a family of enzymes known as aggrecanases. The two sites can be identified in tissues using monoclonal antibodies after cleavage when specific neoepitopes are revealed. Normal cartilage contains a surprising amount of aggrecanase neoepitope, suggesting continuous matrix turnover. The level of aggrecanase cleavage product increases with age. Two aggrecanase genes, aggrecanase-1 and aggrecanase2, have been cloned and are members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) family of proteins (ADAMTS-4 and ADAMTS5).325 These genes are expressed in osteoarthritis and RA cartilage, and their proteolytic activity can be detected in synovial fluid using bioassays. Especially high levels of the neoepitope are present in arthritic cartilage.326 IL-1 increases aggrecanase expression in cartilage explants and cultures of chondrocytes. Aggrecanase-1 and aggrecanase-2 are

α2-Macroglobulin accounts for more than 95% of collagenase inhibitory capacity in serum. The mechanism of inhibition by α2-macroglobulin involves hydrolysis by the proteinase of a susceptible region in one of the four polypeptide chains of α2-macroglobulin (sometimes called the “bait”), with ­subsequent trapping of the proteins within the interstices of the α2-macroglobulin. Ultimately, the protease is covalently linked to a portion of the α2-macroglobulin molecule. The serine protease inhibitors also are abundant in synovial effusions and plasma and can serve a dual ­purpose of directly blocking serine protease function and indirectly decreasing MMP activity by preventing serine proteases from activating MMP proenzymes. One serine protease inhibitor, α1-antitrypsin, has been well characterized in synovial fluid and is frequently inactivated after oxidation by reactive oxygen species.329 A family of proteins that specifically block MMP activity, called TIMPs, has been cloned and characterized. The TIMP proteins block proteinase activity by binding directly to MMPs in a 1:1 molar ratio. TIMP generally binds only to the active enzyme, although there are some exceptions, such as TIMP-2, which can interact with a progelatinase (MMP2). The inhibitors bind to MMPs with extremely high avidity. Although the interaction does not result in new covalent bonds, it is essentially irreversible.

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TIMP proteins are present in RA synovial fluid in excess. It is difficult to detect free active collagenase or stromelysin because these are usually complexed with the inhibitors. Most MMP is in the proenzyme form, however. Immunohistochemical and in situ hybridization studies have localized the TIMPs in hyperplastic synovial lining cells in rheumatoid synovium, but not in the cells of normal synovium. TIMP gene expression is not altered significantly by IL-1 or TNF-α, but it is increased by IL-6, oncostatin M, and TGFβ. TIMP-3 knockout mice have significantly more synovial inflammation and TNF-α production in antigen-induced arthritis, perhaps because it is unavailable to inhibit TNF convertase.330 Similarly, TIMP-1 or TIMP-3 gene transfer limits rheumatoid FLS invasion into cartilage in a SCID mouse model. The function of these genes can extend beyond protease inhibition and can include many paracrine functions and induction of apoptosis when expressed intracellularly in cultured synoviocytes. Given the important role of MMPs in tissue destruction, the relative balance between MMPs and TIMPs ultimately determines the fate of the extracellular matrix. The ratio in RA, with its more destructive potential, favors degradation, whereas osteoarthritis has a lower MMP-to-TIMP ratio. The levels of TIMP gene expression are similar in the two diseases and may be maximal. The higher ratio in RA results from increased MMP production. This balance between protease and inhibitor can be modified in vivo with drug therapy. Intraarticular corticosteroid injections markedly decrease synovial collagenase, stromelysin, and TIMP gene expression. In contrast, low-dose methotrexate therapy specifically decreases collagenase, but not TIMP-1 mRNA.331 Suppressed collagenase gene expression suggests that a low collagenase-to-TIMP ratio is one mechanism of decreased tissue destruction observed in patients treated with methotrexate. REGULATION OF BONE DESTRUCTION BY THE RECEPTOR ACTIVATOR OF NUCLEAR FACTOR κB LIGAND SYSTEM Osteoclasts are the major cells responsible for bone degradation. RANKL, which was originally described for its role in T cell–DC interactions and lymphocyte and lymph node development, is perhaps the most important factor that modulates bone resorption.332 Osteoclast development is complex and involves the differentiation of monocytes under the influence of cytokines such as M-CSF in combination with RANKL. Subsequent osteoclast activation can involve several pathways, most of which also depend on the presence of RANKL. Its receptor, known as RANK, is expressed by the osteoclast precursors. RANKL is produced by many cell types, including activated T cells and FLS. RANKL knockout mice have abnormally dense bones owing to a nearly complete lack of osteoclasts. When osteoclasts or their precursors are activated by soluble RANKL or by direct contact with cells displaying RANKL on their surface, bone resorption can occur through the elaboration of MMPs and cathepsin K. The RANKL-RANK system is antagonized by a soluble decoy receptor, osteoprotegerin, which binds to RANK and competes with RANKL. Abundant evidence implicates this powerful mechanism in inflammatory arthritis. Administration of osteoprotegerin to rats with adjuvant arthritis inhibits bone destruction, but

Bone

Pannus

Osteoclasts

Figure 65-16  Tartrate-resistant acid phosphatase–positive osteoclasts are shown invading bone in rheumatoid arthritis (see arrows for examples). This process is regulated by receptor activator of nuclear factor κB ligand (RANKL) in the presence of other cytokines, such as macrophage colony-stimulating factor and tumor necrosis factor-α. (Courtesy of Dr. Steven Goldring, Dr. Ellen Gravallese, and Dr. Allison Pettit.)

has almost no effect on inflammation or clinical signs of arthritis.333 RANKL knockout mice also are protected from bone erosions in the passive K/BxN model of arthritis, although cartilage destruction still occurs.334 Animal models of arthritis point to IL-17 as a mediator of osteoclast generation. Genetic deficiency of IL-17 or anti-IL-17 antibodies has remarkable bone-sparing effects in these experiments. RANK, RANKL, and osteoprotegerin (and M-CSF and IL-17) have been detected in the synovium and synovial fluid of patients with RA. The ratio of RANKL to osteoprotegerin is significantly higher in RA synovial effusions than in either osteoarthritis or gout, which is consistent with the more destructive nature of RA.335 Osteoclasts expressing tartrate-resistant acid phosphatase, capable of forming resorption lacunae, can be generated from cultured RA synovial cells (Fig. 65-16).336 This activity is blocked by the addition of exogenous osteoprotegerin. RA synoviocytes and synovial membrane T cells that display RANKL also can induce differentiation of osteoclasts from peripheral blood cells.337 TISSUE REPAIR Extracellular matrix turnover in RA has been likened to wound healing owing to the crucial role of collagen production, proteases, and protease inhibitors. Remodeling the matrix by removing damaged proteins is a key element in early repair. Subsequently, the balance shifts to protease inhibition, production of cytokine inhibitors, removal of inflammatory cells through apoptosis, and release of antiinflammatory eicosanoids such as LXs to suppress inflammation. Neutralization of oxidants via glutathione reductase or superoxide dismutase further limits tissue damage. This process permits either a return to normal architecture or scar formation. TGF-β, in particular, seems to play a key role in that it increases collagen deposition, suppresses MMP expression, and enhances production of the TIMPs. Although TGF-β levels in the joint are substantial, they are

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insufficient to overcome the impressive array of MMPs expressed in synovitis. The repair process seems to be inadequate in RA, perhaps because of persistent T cell activation or autonomous activation of other cell lineages. Strategies to shift from tissue damage by enhancing endogenous mechanisms not only might suppress symptoms, but also enhance appropriate remodeling of the matrix to restore homeostasis. Because the rheumatoid synovium exhibits some properties similar to neoplastic diseases, the possibility that the tissue contains immature cells or embryonic genes that regulate repair has been explored. The embryonic growth factors from the wingless (wnt) and frizzled (fz) gene families are expressed in RA synovium.338 Normally, these proteins participate in bone marrow progenitor differentiation and limb bud mesenchyme. Wnt5a and Fz5, in particular, are markedly elevated in RA tissues and cultured synoviocytes. When normal fibroblasts are transfected with the wnt5a gene, cytokine expression, such as IL-6, increases significantly. Antisense wnt-5A and dominant negative wnt-5A vectors diminish IL-6 and IL-15 expression by synoviocytes.339 These data raise the possibility that immature mesenchymal cells populate the synovium in RA, either as a primary event or as a repair mechanism. Similar primitive mesenchymal cells circulate in the peripheral blood of RA and normal individuals, and in collagen-induced arthritis they infiltrate the synovium before clinically apparent synovial inflammation. Restoring homeostasis and tissue repair in RA is a complex process that involves the ingress or dedifferentiation of mesenchymal cells that can remodel the matrix. In addition to TGF-β, the function of these cells is modulated by the BMPs. The BMPs are members of the TGF-β superfamily and, similar to TGF-β, signal through the Smad pathway. Several members, especially BMP-2 and BMP-7, are expressed in the joint and facilitate repair, although inappropriate release also can enhance joint damage or lead to ankylosis or enthesophyte formation.340 BMP function also is regulated by a family of inhibitors such as Noggin, which can limit cartilage damage when overexpressed in murine antigen-induced arthritis.341 Modulating the relative balance and timing of BMP expression ultimately could be used either to modify the destructive influence of synovitis or to regenerate damaged tissues.

SUMMARY Understanding the etiology and pathogenesis of RA remains a complex problem, although the level of understanding has progressed considerably in recent years. T cell–dependent and T cell–independent processes contribute to disease initiation and perpetuation. It might be important to appreciate differences in disease pathogenesis at various stages of the process. These hypotheses have revealed many novel therapeutic targets and interventions that might lead to significant clinical benefit. Such was the case with the TNF inhibitors that have joined the pharmacopeia for the treatment of RA; initial observations that defined the cytokine profile in arthritis and that delineated the biology of ­macrophage cytokines led to this breakthrough. Similarly, understanding of apoptotic pathways, abnormalities in tumor-suppressor genes, the function of the susceptibility cassette, B cell function, or T cell differentiation might have abundant rewards.

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PART 9  250. Muller-Ladner U, Judex M, Ballhorn W, et al: Activation of the IL-4 STAT pathway in rheumatoid synovium. J Immunol 164: 3894, 2000. 251. van der Pouw Kraan TC, van Gaalen FA, Kasperkovitz PV, et al: Rheumatoid arthritis is a heterogeneous disease: Evidence for differences in the activation of the STAT-1 pathway between rheumatoid tissues. Arthritis Rheum 48:2132, 2003. 252. Shouda T, Yoshida T, Hanada T, et al: Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J Clin Invest 108:1781, 2001. 253. Sweeney SE, Hammaker D, Boyle DL, et al: Regulation of c-Jun phosphorylation by the I kappa B kinase-epsilon complex in fibroblast-like synoviocytes. J Immunol 174:6424, 2005. 254. Maurice MM, Nakamura H, van der Voort EAM, et al: Increased expression of thioredoxin in rheumatoid arthritis. Arthritis Rheum 41:S319, 1998. 255. Bashir S, Harris G, Denman MA, et al: Oxidative DNA damage and cellular sensitivity to oxidative stress in human autoimmune diseases. Ann Rheum Dis 52:659, 1993. 256. Sakurai H, Kohsaka H, Liu MF, et al: Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides. J Clin Invest 96:2357, 1995. 257. Farrell AJ, Blake DR, Palmer RM, et al: Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic diseases. Ann Rheum Dis 51: 1219, 1992. 258. Salmon M, Scheel-Toellner D, Huissoon AP, et al: Inhibition of T cell apoptosis in the rheumatoid synovium. J Clin Invest 99:439, 1997. 259. Chou CT, Yang JS, Lee MR: Apoptosis in rheumatoid arthritis: Expression of Fas, Fas-L, p53, and Bcl-2 in rheumatoid synovial tissues. J Pathol 193:110, 2001. 260. Morel J, Audo R, Hahne M, et al: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rheumatoid arthritis synovial fibroblast proliferation through mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt. J Biol Chem 280: 15709, 2005. 261. Catrina AI, Ulfgren AK, Lindblad S, et al: Low levels of apoptosis and high FLIP expression in early rheumatoid arthritis synovium. Ann Rheum Dis 61:934, 2002. 262. Firestein GS, Yeo M, Zvaifler NJ: Apoptosis in rheumatoid arthritis synovium. J Clin Invest 96:1631, 1995. 263. Matsumoto S, Muller-Ladner U, Gay RE, et al: Ultrastructural demonstration of apoptosis, Fas and Bcl-2 expression of rheumatoid synovial fibroblasts. Rheumatology 23:1345, 1996. 264. Perlman H, Pagliari LJ, Liu H, et al: Rheumatoid arthritis synovial macrophages express the Fas-associated death domain-like interleukin 1beta-converting enzyme-inhibitory protein and are refractory to Fas-mediated apoptosis. Arthritis Rheum 44:21, 2001. 265. Zhang HG, Wang Y, Xie JF, et al: Regulation of tumor necrosis factor alpha-mediated apoptosis of rheumatoid arthritis synovial fibroblasts by the protein kinase Akt. Arthritis Rheum 44:1555, 2001. 266. Cha HS, Rosengren S, Boyle DL, et al: PUMA regulation and proapoptotic effects in fibroblast-like synoviocytes. Arthritis Rheum 254:587, 2006. 267. Franz JK, Pap T, Hummel KM, et al: Expression of sentrin, a novel antiapoptotic molecule, at sites of synovial invasion in rheumatoid arthritis. Arthritis Rheum 43:599, 2000. 268. Pap T, Franz JK, Hummel KM, et al: Activation of synovial fibroblasts in rheumatoid arthritis: Lack of expression of the tumour suppressor PTEN at sites of invasive growth and destruction. Arthritis Res 2:59, 2000. 269. Zhang H, Yang Y, Horton JL, et al: Amelioration of collagen-induced arthritis by CD95 (Apo-1/Fas)-ligand gene transfer. J Clin Invest 100:1951, 1997. 270. Yao Q, Seol DW, Mi Z, et al: Intra-articular injection of recombinant TRAIL induces synovial apoptosis and reduces inflammation in a rabbit knee model of arthritis. Arthritis Res Ther 8:R16, 2005. 271. Yao Q, Wang S, Glorioso JC, et al: Gene transfer of p53 to arthritic joints stimulates synovial apoptosis and inhibits inflammation. Mol Ther 3:901, 2001. 272. Yamanishi Y, Boyle DL, Pinkoski MJ, et al: Regulation of joint destruction and inflammation by p53 in collagen-induced arthritis. Am J Pathol 160:123, 2002.

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298. Issekutz TB, Issekutz AC: T lymphocyte migration to arthritic joints and dermal inflammation in the rat: Differing migration patterns and the involvement of VLA-4. Clin Immunol Immunopathol 61: 436, 1991. 299. Wahl SM, Allen JB, Hines KL, et al: Synthetic fibronectin peptides suppress arthritis in rats by interrupting leukocyte adhesion and recruitment. J Clin Invest 94:655, 1994. 300. Laffon A, Garcia-Vicuna R, Humbria A, et al: Upregulated expression and function of VLA-4 fibronectin receptors on human activated T cells in rheumatoid arthritis. J Clin Invest 88:546, 1992. 301. Van Dinther-Janssen AC, Pals ST, Scheper RJ, et al: Role of the CS1 adhesion motif of fibronectin in T cell adhesion to synovial membrane and peripheral lymph node endothelium. Ann Rheum Dis 52:672, 1993. 302. Elices MJ, Tsai V, Strahl D, et al: Expression and functional significance of alternatively spliced CS1 fibronectin in rheumatoid arthritis microvasculature. J Clin Invest 93:405, 1994. 303. Jorgensen C, Travaglio-Encinoza A, Bologna C: Human mucosal lymphocyte marker expression in synovial fluid lymphocytes of patients with rheumatoid arthritis. J Rheumatol 21:1602, 1994. 304. Corkill MM, Kirkham BW, Haskard DO, et al: Gold treatment of rheumatoid arthritis decreases synovial expression of the endothelial leukocyte adhesion receptor ELAM-1. J Rheumatol 18:1453, 1991. 305. Jorgensen C, Couret I, Canovas F, et al: Mononuclear cell retention in rheumatoid synovial tissue engrafted in severe combined immunodeficient (SCID) mice is up-regulated by tumour necrosis factoralpha (TNF-alpha) and mediated through intercellular adhesion molecule-1 (ICAM-1). Clin Exp Immunol 106:20, 1996. 306. Jorgensen C, Couret I, Canovas F, et al: In vivo migration of tonsil lymphocytes in rheumatoid synovial tissue engrafted in SCID mice: Involvement of LFA-1. Autoimmunology 24:179, 1996. 307. Haraoui B, Strand V, Keystone E: Biologic agents in the treatment of rheumatoid arthritis. Curr Pharm Biotechnol 1:217, 2000. 308. Ruth JH, Amin MA, Woods JM, et al: Accelerated development of arthritis in mice lacking endothelial selectins. Arthritis Res Ther 7:R959, 2005. 309. Annefeld M: The potential aggressiveness of synovial tissue in rheumatoid arthritis. J Pathol 139:399, 1983. 310. Wolfe GC, MacNaul KL, Buechel FF, et al: Differential in vivo expression of collagenase messenger RNA in synovium and cartilage: Quantitative comparison with stromelysin messenger RNA levels in human rheumatoid arthritis and osteoarthritis patients and in two animal models of acute inflammatory arthritis. Arthritis Rheum 36:1540, 1993. 311. Cooke TD, Hurd ER, Jasin HE, et al: Identification of immunoglobulins and complement in rheumatoid articular collagenous tissues. Arthritis Rheum 18:541, 1975. 312. Kuiper S, Joosten LA, Bendele AM, et al: Different roles of tumour necrosis factor alpha and interleukin 1 in murine streptococcal cell wall arthritis. Cytokine 10:690, 1998. 313. Lotz M, Guerne PA: Interleukin-6 induces the synthesis of tissue inhibitor of metalloproteinases-1/erythroid potentiating activity (TIMP-1/EPA). J Biol Chem 266:2017, 1991. 314. Gunther M, Haubeck HD, van de Leur E, et al: Transforming growth factor beta 1 regulates tissue inhibitor of metalloproteinases-1 expression in differentiated human articular chondrocytes. Arthritis Rheum 37:395, 1994. 315. Firestein GS, Paine MM, Littman BH: Gene expression (collagenase, tissue inhibitor of metalloproteinases, complement, and HLA-DR) in rheumatoid arthritis and osteoarthritis synovium: Quantitative analysis and effect of intraarticular corticosteroids. Arthritis Rheum 34:1094, 1991. 316. Zvaifler NJ, Boyle D, Firestein GS: Early synovitis: Synoviocytes and mononuclear cells. Semin Arthritis Rheum 23(Suppl 2):11, 1994. 317. Mudgett JS, Hutchinson NI, Chartrain NA, et al: Susceptibility of stromelysin 1-deficient mice to collagen-induced arthritis and cartilage destruction. Arthritis Rheum 41:110, 1998. 318. Hamada T, Arima N, Shindo M, et al: Suppression of adjuvant arthritis of rats by a novel matrix metalloproteinase-inhibitor. Br J Pharmacol 131:1513, 2000. 319. Peterson JT: The importance of estimating the therapeutic index in the development of matrix metalloproteinase inhibitors. Cardiovasc Res 69:677, 2006.

320. Muller-Ladner U, Gay RE, Gay S: Cysteine proteinases in arthritis and inflammation. Perspect Drug Discovery Design 6:87, 1996. 321. Lemaire R, Huet G, Zerimech F, et al: Selective induction of the secretion of cathepsins B and L by cytokines in synovial fibroblastlike cells. Br J Rheumatol 36:735, 1997. 322. Garnero P, Borel O, Byrjalsen I, et al: The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J Biol Chem 273:32347, 1998. 323. Hou WS, Li W, Keyszer G, et al: Comparison of cathepsins K and S expression within the rheumatoid and osteoarthritic synovium. Arthritis Rheum 46:663, 2002. 324. Esser RE, Angelo RA, Murphey MD, et al: Cysteine proteinase inhibitors decrease articular cartilage and bone destruction in chronic inflammatory arthritis. Arthritis Rheum 37:236, 1994. 325. Tortorella MD, Burn TC, Pratta MA, et al: Purification and cloning of aggrecanase-1: A member of the ADAMTS family of proteins. ­Science 284:1664, 1999. 326. Lark MW, Bayne EK, Flanagan J, et al: Aggrecan degradation in human cartilage: Evidence for both matrix metalloproteinase and aggrecanase activity in normal, osteoarthritic, and rheumatoid joints. J Clin Invest 100:93, 1997. 327. Yamanishi Y, Boyle DL, Clark M, et al: Expression and regulation of aggrecanase in arthritis: The role of TGF-beta. J Immunol 168: 1405, 2002. 328. Stanton H, Rogerson FM, East CJ, et al: ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434: 648, 2005. 329. Abbink JJ, Kamp AM, Nuijens JH, et al: Proteolytic inactivation of alpha 1-antitrypsin and alpha 1-antichymotrypsin by neutrophils in arthritic joints. Arthritis Rheum 36:168, 1993. 330. Mahmoodi M, Sahebjam S, Smookler D, et al: Lack of tissue inhibitor of metalloproteinases-3 results in an enhanced inflammatory response in antigen-induced arthritis. Am J Pathol 166: 1733, 2005. 331. Firestein GS, Paine MM, Boyle DL: Mechanisms of methotrexate action in rheumatoid arthritis: Selective decrease in synovial collagenase gene expression. Arthritis Rheum 37:193, 1994. 332. Goldring SR, Gravallese EM: Mechanisms of bone loss in inflammatory arthritis: Diagnosis and therapeutic implications. Arthritis Res 2:33, 2000. 333. Kong YY, Feige U, Sarosi I, et al: Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402:304, 1999. 334. Pettit AR, Ji H, von Stechow D, et al: TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol 159:1689, 2001. 335. Feuerherm AJ, Borset M, Seidel C, et al: Elevated levels of osteoprotegerin (OPG) and hepatocyte growth factor (HGF) in rheumatoid arthritis. Scand J Rheumatol 30:229, 2001. 336. Haynes DR, Crotti TN, Loric M, et al: Osteoprotegerin and receptor activator of nuclear factor kappaB ligand (RANKL) regulate osteoclast formation by cells in the human rheumatoid arthritis joint. Rheumatology (Oxf) 40:623, 2001. 337. Kotake S, Udagawa N, Hakoda M, et al: Activated human T cells directly induce osteoclastogenesis from human monocytes: Possible role of T cells in bone destruction in rheumatoid arthritis patients. Arthritis Rheum 44:1003, 2001. 338. Sen M, Lauterbach K, ElGabalawy H, et al: Expression and function of wingless and frizzled homologs in rheumatoid arthritis. Proc Natl Acad Sci U S A 97:2791, 2000. 339. Sen M, Chamorro M, Reifert J, et al: Blockade of Wnt-5A/frizzled 5 signaling inhibits rheumatoid synoviocyte activation. Arthritis Rheum 44:772, 2001. 340. Lories RJ, Luyten FP: Bone morphogenetic protein signaling in joint homeostasis and disease. Cytokine Growth Factor Rev 16:287, 2005. 341. Lories RJ, Daans M, Derese I, et al: Noggin haploinsufficiency differentially affects tissue responses in destructive and remodeling arthritis. Arthritis Rheum 54:1736, 2006.

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Clinical Features of Rheumatoid Arthritis EDWARD D. HARRIS, JR.  •  GARY S. FIRESTEIN

KEY POINTS Rheumatoid arthritis is a symmetric inflammatory arthritis that mainly affects the small joints of the hands and feet. Larger joints can be involved, usually in a symmetric fashion. Cartilage destruction and bone erosions are common, especially in rheumatoid factor–positive or anticitrullinated protein antibody–positive patients. Uncontrolled synovitis can lead to severe deformities, loss of function, and increased mortality. Early aggressive therapy seems to improve long-term ­outcomes in rheumatoid arthritis. Systemic manifestations include pulmonary disease, ­vasculitis, nodules, and eye disease.

EPIDEMIOLOGY AND THE BURDEN OF DISEASE In past years, most investigators accepted a prevalence of rheumatoid arthritis (RA) in most populations of around 1%, with an incidence in women twice that in men. This number was based on many studies of population samples1-3 that varied among the surveys from 0.3% to 1.5%. This figure of 1% prevalence of RA in most populations may be changing, however, as incidence rates in different decades are studied. The incidence of RA in Rochester, Minnesota, declined 50% between 1950 and 1974.4 The differences between incidence and prevalence are enhanced by realizing that as the population ages, the prevalence of RA may increase or stay the same, even though the incidence stays the same or is decreasing, simply because individuals with RA are living longer. The incidence of RA increases dramatically during adulthood; the exception is men in their 40s through 60s. In Olmstead County, Minnesota, this increased incidence with increasing age continues until age 85, after which the incidence declines.5 In a 10-year extension of this study, making it a 40-year, population-based history of RA, the age-adjusted and sex-adjusted incidence per 100,000 population decreased from 62 in the decade 1955 to 1964 to 32.7 in the decade 1985 to 1994.6 The decrease was more prominent in women than in men, and the average age at onset of the disease shifted upward. Most intriguing were the cyclic patterns of incidence within decades, suggesting the influence of environmental factors. One explanation for the decline in incidence and shift toward an older age at onset is a birth cohort effect, the greatest impact of which is early in life.7

Throughout the world, there are pockets of ethnic groups that have a much higher incidence of RA. Native Americans are one of these groups. In one geographic area, non–Native American populations had an RA prevalence of 1.1% to 0.9% between 1986 and 1994, whereas the prevalence in Algonquian Indians in the same region ranged from 2% to 2.1%, and the disease onset was 12 years earlier in the Native American population.8 In Pima Indians, who bear a very high incidence of RA, a decline in incidence has been correlated with a decrease in seropositivity for rheumatoid factor (RF). The highest likelihood of seropositivity was in Pima Indians born at the turn of the 20th century, and it has decreased ever since. This is additional supportive evidence for a birth cohort effect.9 Although newer, more effective therapy for rheumatoid patients has reduced morbidity and disability from the disease, there are still substantial dollar costs for RA. In a panel of 1156 individuals with RA in San Francisco followed for 15 years, medical care costs for RA averaged $5919 per year with an additional $2582 incurred for medical but non-RA reasons.10 More than half of the costs were for hospitalizations, with some patients bearing costs of more than $85,000/yr, as their function declined. In another cohort of 4258 patients with RA followed for 17,085 patient-years, lifetime direct medical care costs were estimated to be $93,296.11

RISK FACTORS A predisposition to RA seems to be multifactorial when one considers the following: (1) Relatively few identical twins have RA (about 15%), even though it is much more likely that there is concordance for the disease in twins than in the normal population; (2) despite the powerful influence of the “shared epitope” on HLA-DRB chains in predisposing to the severity of disease, this susceptibility cassette is not a risk factor in certain population studies; and (3) the combination of many gene polymorphisms confers a modestly increased risk of disease. A reasonable hypothesis is that the genetic predisposition to RA involves a propensity to autoimmune responses, but that repeated exposure to environmental agents is ultimately responsible for ­ tipping the balance from subclinical autoimmunity to diseases such as RA. Many of the risk factors for RA are discussed in Chapter 65, especially genetic associations, environmental exposures, and the role of autoantibodies.

CLINICAL SYNDROMES OF EARLY RHEUMATOID ARTHRITIS In the Northern Hemisphere, the onset of RA is more frequent in winter than in summer. In several series, the onset of RA from October to March in the Northern

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Hemisphere was found to be twice as frequent as in the other 6 months.12 Data suggest that the appearance of RF may be more likely to precede symptoms of arthritis in patients than was previously recognized. In 30 patients whose frozen serum samples were available from a time before symptoms of RA began, half had a positive latex fixation test,13 and many more of these were men than women.

onset. Diagnosis of acute-onset RA is difficult to make, and sepsis or vasculitis must be ruled out. Fever, suggesting an infectious process, can be a prominent sign. An intermediate type of onset, in which symptoms develop over days or weeks, occurs in 15% to 20% of patients. Systemic complaints are more noticeable than in the insidious type of onset. Joint Involvement

PATTERNS OF ONSET Insidious Onset RA has an insidious, slow onset over weeks to months in 55% to 65% of cases.14 The initial symptoms may be systemic or articular. In some individuals, fatigue, malaise, swollen hands, and diffuse musculoskeletal pain may be the first nonspecific complaints, with joints becoming involved later. Involvement of tendon sheaths early in the process can focus attention on periarticular structures. In retrospect, the patient often can identify one joint that was involved first, quickly followed by others. Asymmetric initial presentations (often with more symmetry developing later in the course of disease) are common. The reason for the symmetry of joint involvement compared with other forms of arthritis, such as the seronegative spondyloarthropathies, is unknown. Morning stiffness is a cardinal sign of inflammatory arthritis that can appear even before pain and may be related to the accumulation of edema fluid within inflamed tissues during sleep. The morning stiffness dissipates as edema and products of inflammation are absorbed by lymphatics and venules and returned to the circulation by motion accompanying the use of muscles and joints. To be specific for joint inflammation, morning stiffness (e.g., “difficulty moving around”) should persist for at least 30 to 45 minutes before disappearing. A similar “gel” ­phenomenon can occur if a patient is inactive for a period during the day. It is rare for symptoms to remit completely in one set of joints while developing in another. This quality of arthritis sets RA apart from rheumatic fever or palindromic rheumatism, in which a true migratory pattern of arthritis is common. A subtle, early change in RA is the development of muscle atrophy around affected joints. Muscle efficiency and strength become diminished. As a result, weakness develops that can be out of proportion to pain. Opening doors, climbing stairs, and doing repetitive work rapidly become more demanding. A low-grade fever without chills is rarely present. Depression and focused and nonspecific anxiety accentuate symptoms. A small but significant weight loss is common and reflects the catabolic effects of cytokines and an associated anorexia. Acute or Intermediate Onset Of patients, 8% to 15% have an acute onset of symptoms that peak within a few days. Rarely, a patient can pinpoint the onset of symptoms to a specific time or activity, such as opening a door or driving a golf ball. Symptoms mount, with pain developing in other joints, often in a less symmetric pattern than in patients who have an insidious

The joints most commonly involved first in RA are the metacarpophalangeal (MCP) joints, proximal interphalangeal (PIP) joints, metatarsophalangeal joints, and wrists (Table 66-1).15 Larger joints generally become symptomatic after small joints. Synovitis in large joints is likely to remain asymptomatic for a longer time than in smaller ones, and a biopsy specimen of an asymptomatic knee often shows histologic evidence of synovitis. One anatomic study correlated the area, in square centimeters, of synovial membrane with that of hyaline cartilage in each joint. The joints with the highest ratio of synovium to articular cartilage correlated positively with the joints most frequently involved in the disease (see Table 66-1).16 EARLY SYNOVITIS: WHICH PATIENTS DEVELOP RHEUMATOID ARTHRITIS? Distinguishing early RA from other inflammatory arthropathies can be challenging. In its earliest stages, RA might involve only a few joints and without the typical symmetric distribution. What are the diagnostic clues that can be used to determine who will progress to classic RA and who will develop an alternative inflammatory arthritis such as seronegative spondyloarthropathies or have spontaneous remission? The implications for disease management are obvious because early treatment potentially could limit or prevent joint damage and possibly permit long-term remissions or even cures. Because 30% to 40% of patients with Table 66-1  Distribution of Joints Involved in Attacks Based on a Cumulative Experience with 227 Patients Joint Involvement

% Patients (Mean)

% Patients (Range)

MCP, PIP

91

74-100

Wrists

78

54-82

Knees

64

41-94

Shoulders

65

33-75

Ankles

50

10-67

Feet

43

15-73

Elbows

38

13-60

Hips

17

  0-40

Temporomandibular

 8

  0-28

Spine

 4

  0-11

Sternoclavicular

 2

  0-6

Para-articular sites

27

20-29

MCP, metacarpophalangeal; PIP, proximal interphalangeal. Modified from Guerne P-A, Weisman MH: Palindromic rheumatism: Part of or apart from the spectrum of rheumatoid arthritis. Am J Med 16:451-460, 1992. Copyright 1992, with permission from Excerpta Medica, Inc.

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Table 66-2  Evolution of Patients with Palindromic Rheumatism in Nine Series Totaling 653 Patients* No. Cases

Remission or Cure (%)

Persistent PR (%)

PR-RA (%)

Other Diseases (%)

1

Series of Patients

  34

15

85

 0

 0

2

140

 8

52

36

 4

3

179

10

47

38

 5

4

  39

 0

56

44

 0

5

  70

24

34

30

12

6

  38

 8

66

15

11

7

  43

23

23

49

 5

8

  50

 0

46

54

 0

9

  60

43

21

35

 2

Total or average

653

15

48

33

 4

*In each series, the number of patients undergoing a remission or a cure, remaining palindromic, evolving toward rheumatoid arthritis (PR-RA), or developing another disease is expressed as a percentage PR, palindromic rheumatism; RA, rheumatoid arthritis. Modified from Guerne P-A, Weisman MH: Palindromic rheumatism: Part of or apart from the spectrum of rheumatoid arthritis. Am J Med 16:451-460, 1992. Copyright 1992, with permission from Excerpta Medica, Inc.

early inflammatory synovitis have spontaneous remission, accurate identification of patients with RA is essential to avoid undertreatment and overtreatment. Some of these questions have been addressed by the Leiden Early Arthritis Clinic, which evaluates patients with less than 2 years of symptoms (most patients evaluated have symptoms for <6 months). In this cohort, only about 20% of patients met criteria for RA when initially evaluated by a rheumatologist.17 One third of patients defied categorization and were considered to have “undifferentiated arthritis.” When this group of patients was followed for 1 year, 27% ultimately developed RA, and 40% remained undifferentiated. Clinical features that were more commonly seen in the patients who developed RA included greater number of joints involved (mean of seven joints versus four joints), duration of morning stiffness (90 minutes versus 60 minutes), and the presence of autoantibodies. These features were insufficient individually to permit early diagnosis of RA, although a composite scoring system has been proposed.18 The predictive value of this system might approach 90%. Of the predictive features most likely to be useful in patients, serum autoantibody production might be the most powerful. Anticitrullinated protein antibodies, in ­particular, are strongly associated with evolution of undifferentiated arthritis into RA and progression to erosive disease. Other autoantibodies also have been used in a diagnostic algorithm for patients with very early synovitis (<3 months of symptoms), including RFs, anticitrullinated protein, and anti-RA33.19 Using stepwise analysis of each antibody, RA could be diagnosed in 72% of patients and confirmed by subsequent clinical course. UNUSUAL PATTERNS OR VARIANTS OF DISEASE Palindromic Pattern of Onset Palindromic rheumatism was described by Hench and Rosenberg in 1942.20 Pain usually begins in one joint or in periarticular tissues; symptoms worsen for several hours to a few days and are associated with swelling and erythema. Then, in reverse sequence, symptoms resolve, leaving

no residua. Table 66-2 lists joints involved in a series of 227 patients. An intercritical period, similar to that of gout, is asymptomatic. Half of patients with palindromic rheumatism go on to develop RA, particularly patients with HLA-DR4. In a compilation of 653 patients from nine series, only 15% became asymptomatic after at least 5 years with a palindromic syndrome (see Table 66-2).21 In the remainder, multiple joints became involved, swelling did not subside completely between attacks, and tests for RF became positive. Neither the characteristics of joint fluid nor the pathologic findings of synovial biopsy specimens allow the prediction that RA will evolve from palindromic rheumatism,22 although in the future, it may be worthwhile to measure anti–cyclic citrullinated peptide antibodies in these individuals. Individuals who do not develop RA rarely have constitutional symptoms, and the involved joints have no erosions because the synovitis does not become chronic. Of 51 patients with palindromic rheumatism, 41 experienced marked improvement in frequency and duration of attacks during treatment with antimalarials.23 Effect of Age on Onset Older individuals (≥65 years old) developing RA often present with stiffness, limb girdle pain, and diffuse boggy swelling of the hands, wrists, and forearms. A clinical onset that mimics polymyalgia rheumatica or remitting seronegative synovitis with pitting edema also can occur in the elderly. Individuals with onset at age 60 years or older are less likely to have subcutaneous nodules or RF at the onset of disease, despite the high prevalence of RF in the general population in this age group. Generally, elderly individuals who develop RA tend to have a more benign course than younger patients; there is a lower frequency of positive tests for RF, but there is a strong association with HLA-DR4. The onset is slow, but the stiffness is often incapacitating. In one study of 186 patients with RA of less than 15 months’ duration, older patients had higher scores for joint space narrowing and osteophytes at baseline than

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patients younger than 55 years. There was no evidence, however, that the older patients had more rapid progression of damage, indicating that the osteoarthritis was responsible for a significant portion of the damage noted at the onset of disease.24 Rheumatoid Arthritis and Paralysis: Asymmetric Disease Being relatively common, RA is likely to occur with many other types of chronic disease. A striking asymmetry or even unilateral involvement has been described in patients with poliomyelitis, meningioma, encephalitis, neurovascular syphilis, strokes, and cerebral palsy.25 Joints are typically spared on the paralyzed side, and the degree of protection shows a rough correlation with the extent of paralysis. The protective effect on the affected side is less if a neurologic deficit develops in a patient who already has RA. Arthritis Robustus Arthritis robustus is not so much an unusual presentation of disease as an unusual reaction of patients to the disease.26 Most patients are men; their disease is characterized by proliferative synovitis, often with deformity, that seems to cause little pain and even less disability. Patients are athletic and invariably keep working (often at physical labor). Periarticular osteopenia is unusual, whereas new bone proliferation at joint margins near significant erosions of bone and cartilage are common. Bulky subcutaneous nodules develop. Subchondral cysts also develop, presumably from the excessive pressure developed from synovial fluid within a thick joint capsule during muscular effort. Rheumatoid Nodulosis Whether rheumatoid nodulosis is a variant subset of RA or a different entity has not been clarified. The clinical picture is of a palindromic set of recurrent pain and swelling in different joints, radiologic subchondral bone cysts, and subcutaneous rheumatoid nodules. In one series of 16 patients followed 12 years, 6 had an aggressive course indistinguishable from classic erosive polyarticular RA. In seven patients, cholesterol crystals were found in fluid from olecranon bursae. Second-line drugs helped articular disease, but not other components of the process.27

COURSE AND COMPLICATIONS OF ESTABLISHED RHEUMATOID ARTHRITIS INVOLVEMENT OF SPECIFIC JOINTS: EFFECTS OF DISEASE ON FORM AND FUNCTION The effects of rheumatoid synovitis on joints are a complex function of the intensity of the underlying disease, its chronicity, and the stress put on individual joints by the patient. Most well-documented observations of specific joint involvement and of complications of the disease were reported in the decades before 1980. Since then, there have been refinements on these observations, but few new data.

Despite advances in understanding the pathophysiology of RA, including delineations of the cellular and enzymatic pathways that destroy joints, guidelines for the practicing physician—so that in an individual patient the probability that he or she would go on to develop erosive disease and needs aggressive treatment can be determined—are only in early stages of development. The spectrum of the clinical course of RA can range from patients who have mild pauciarticular synovitis, negative serum RF, with few radiographic changes, to patients who have unrelenting pain, synovitis, joint damage, and extra-articular manifestations. Cervical Spine In contrast to other nonsynovial joints, such as the manubriosternal joint or symphysis pubis, the diskovertebral joints in the cervical spine often manifest osteochondral destruction in RA and on lateral radiographs may be found to be narrowed (Fig. 66-1). There is significant pain, but passive range of motion in the absence of muscle spasm may be normal. There are at least two possible mechanisms for this process: (1) extension of the inflammatory process from adjacent neurocentral joints (the joints of Luschka), which are lined by synovium, into the diskovertebral area, and (2) chronic cervical instability initiated by apophyseal joint destruction leading to vertebral malalignment or subluxation. This process may produce microfractures of the vertebral end plates, disk herniation, and degeneration of disk cartilage. The atlantoaxial joint is prone to subluxation in several directions, as follows: 1. The atlas can move anteriorly on the axis (most common). This results from laxity of the ligaments induced by proliferative synovial tissue developing in adjacent synovial bursae or from fracture or erosion of the odontoid process. 2. The atlas can move posteriorly on the axis. This can occur only if the odontoid peg has been fractured from the axis or destroyed. 3. The atlas can sublux vertically in relation to the axis (least common). This results from destruction of the lateral atlantoaxial joints or of bone around the foramen magnum. It is apparent now that vertical (superior) migration of the odontoid can develop from unattended anterior or posterior subluxation. The earliest and most common symptom of cervical subluxation is pain radiating up into the occiput. Two other serious, but less common, clinical patterns are as follows: 1. Slowly progressive spastic quadriparesis, frequently with painless sensory loss in the hands 2. Transient episodes of medullary dysfunction associated with vertical penetration of the dens and probable vertebral artery compression; paresthesias in the shoulders or arms may occur during movement of the head Physical findings suggestive of atlantoaxial subluxation include a loss of occipitocervical lordosis, resistance to passive spine motion, and abnormal protrusion of the axial arch felt by the examining finger on the posterior pharyngeal wall. Radiographic views (lateral, with the neck in flexion) reveal more than 3 mm of separation between the odontoid peg and the axial arch. In symptomatic patients, the films in flexion should be taken only after radiographs (including an

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** * *

A

B

Figure 66-1  Rheumatoid arthritis of the cervical spine. A, Lateral radiograph in flexion shows severe anterior atlantoaxial subluxation with a wide anterior atlantodental interval (asterisks) and decreased posterior atlantodental interval (arrow). B, Almost complete reduction of subluxation is noted on the lateral view in extension. There also is subaxial subluxation at the level of C4-C5 (arrowheads) with erosive changes in various facet joints.  O, odontoid. (Courtesy of Dr. Barbara Weissman.)

open-mouth posteroanterior view) have ruled out an odontoid fracture or severe atlantoaxial subluxation. Studies have indicated that computed tomography (CT) is useful for showing spinal cord compression by a loss of posterior subarachnoid space in patients with C1 to C2 subluxation. Magnetic resonance imaging (MRI) has proved particularly valuable in determining pathologic anatomy in this syndrome (Fig. 66-2). Neurologic symptoms often have little relationship to the degree of subluxation and may be related to individual variations in the diameter of the spinal canal. Symptoms of spinal cord compression that demand intervention include the following: • A sensation of the head falling forward on flexion of the cervical spine • Altered consciousness • Syncope • A loss of sphincter control • Dysphagia, vertigo, convulsions, hemiplegia, dysarthria, or nystagmus • Peripheral paresthesias without evidence of peripheral nerve disease or compression Some of these symptoms may be related to compression of the vertebral arteries, which must wind through foramina in the transverse processes of C1 and C2, rather than to compression of the spinal cord. The progression of peripheral joint erosions parallels cervical spine disease in RA. The two coincide in severity and timing; the development of cervical subluxation is more likely in patients with erosion of the hands and feet. In a series of 113 patients with RA referred for hip or knee arthroplasty, 61% had radiographic evidence of cervical spine instability.28

Is mortality increased in patients with atlantoaxial subluxation? Neurologic signs do not inevitably develop in patients with large subluxations. When signs of cervical cord compression do appear, however, myelopathy progresses rapidly, and 50% of these patients die within 1 year.29 These patients are at risk from small falls, whiplash injuries, and general anesthesia with intubation. Cervical collars should be prescribed for stability. Operative stabilization may be considered if symptoms are progressive. Some data support the hypothesis that early C1-to-C2 fusion for atlantoaxial subluxation before the development of superior migration of the odontoid decreases the risk of further progression of cervical spine instability.30 The incidence of sustained neurologic deterioration related to surgery may be 6%, however, and this emphasizes the importance of a skilled surgical team and the careful assessment of each patient. In many cases, surgical intervention in asymptomatic patients is riskier than conservative management despite the dire appearance of imaging studies. Vertical atlantoaxial subluxation is important and may follow anterior or posterior subluxation. Symptoms associated with this collapse of the lateral support system of the atlas occur in patients with severe erosive disease. Neurologic findings include decreased sensation in the distribution of cranial nerve V, sensory loss in the C2 area, nystagmus, and pyramidal lesions. Thoracic, Lumbar, and Sacral Spine The thoracic, lumbar, and sacral portions of the spine are usually spared in RA. The exceptions are the apophyseal joints; rarely, synovial cysts at the apophyseal joint can

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P

in 30% of rheumatoid patients. This hoarseness is not disabling in itself, but there is a danger that the cricoarytenoid joints may become inflamed and immobilized, with the vocal cords adducted to the midline, causing inspiratory stridor. Autopsy examinations have shown cricoarytenoid arthritis in almost half of the patients with RA, suggesting that much significant disease of the larynx may be asymptomatic. This suggestion is borne out by the finding that although CT scans detected laryngeal abnormalities in 54% of patients with moderately severe RA, no symptoms suggested that these abnormalities would be found.32 In contrast, findings with indirect laryngoscopy, which detected mucosal and gross functional abnormalities (including rheumatoid nodules), were abnormal in 32% of the same patients and correlated with symptoms of sore throat and difficult inspiration. It follows that the latter examination should be obtained in symptomatic rheumatoid patients. Asymptomatic cricoarytenoid synovitis occasionally may lead to aspiration of pharyngeal contents, particularly at night.

v

v

Ossicles of the Ear

impinge as an epidural mass on the spinal cord, causing pain, neurologic deficits, or both.

Many rheumatoid patients experience a decrease in hearing as a result of conductive hearing loss. Studies using otoadmittance measurements have been done in patients with RA in an attempt to determine whether the interossicle joints were involved.33 The data showed that 38% of “rheumatoid ears” and only 8% of controls had a pattern characteristic of increased flaccidity of a clinically normal tympanic membrane. This finding is consistent with erosions and shortening of the ossicles produced by the erosive synovitis, not with ankylosis.

Temporomandibular Joint

Sternoclavicular and Manubriosternal Joints

The temporomandibular joint is commonly involved in RA. Histories reveal that 55% of patients have jaw symptoms at some time during the course of their disease. ­Radiographic examination reveals structural alterations in 78% of the joints examined. An overbite may develop as the mandibular condyle and the corresponding surface of the temporal bone, the eminentia articularis, are eroded. Physical examination of the rheumatoid patient should include palpation of the temporomandibular joint for tenderness and auscultation for crepitus. Occasionally, patients have acute pain and an inability to close the mouth, necessitating intra-articular glucocorticoid therapy to suppress the acute process. Temporomandibular joint abnormalities are common in nonrheumatoid populations. The only specific findings for RA in the temporomandibular joint are erosions and cysts of the mandibular condyle detected by CT or MRI. There is no correlation between clinical and CT findings of the temporomandibular joint in RA.31

Sternoclavicular and manubriosternal joints, both possessing synovium and a large cartilaginous disk, are often involved in RA. Because of their relative immobility, there are few symptoms. Patients occasionally complain of experiencing pain in sternoclavicular joints, however, while lying on their sides in bed. When symptoms do occur, the physician must be concerned about superimposed sepsis. CT or MRI is useful for careful delineation of the sternoclavicular joint. Manubriosternal involvement is almost never clinically important, although by tomographic criteria it is common in RA.

Figure 66-2  Rheumatoid arthritis of the cervical spine. T2-weighted sagittal image shows low signal periodontoid pannus (P). Odontoid ­process appears irregular secondary to erosions (arrow). The atlantodental ­distance shows mild widening (solid line). There also is vertical subluxation without signs of cord compression. Anterior subarachnoid space is compromised by disk protrusions at multiple levels. Erosions (arrowheads) are seen at the vertebral end plates at the C6-C7 level. (Courtesy of Dr. Barbara Weissman.)

Cricoarytenoid Joints The cricoarytenoid joints are small diarthrodial joints with an important function: They rotate with the vocal cords as the vocal cords abduct and adduct to vary the pitch and tone of the voice. Careful histories may reveal hoarseness

Shoulder RA of the shoulder not only affects synovium within the glenohumeral joint, but also involves the distal third of the clavicle, various bursae and the rotator cuff, and multiple muscles around the neck and chest wall. Severe shoulder pain is often bilateral and can lead to sleep disorders because of difficulty finding a comfortable position. Involvement of the rotator cuff in RA also has been recognized as a principal cause of morbidity. The function of the rotator cuff is to stabilize the humeral head in the glenoid. Weakness of the cuff results in superior subluxation. Rotator cuff tears or insufficiency from other causes can be shown by shoulder arthrography or MRI. In a series of 200 consecutive patients

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A

Figure 66-3  Abnormalities of the shoulder in rheumatoid arthritis. The Grashey posterior oblique view of a shoulder shows severe glenohumeral joint space narrowing with a marginal erosion and cystic change of the humeral head adjacent to the greater tuberosity (lower arrow). Elevation of the humeral head with respect to the glenoid indicates chronic rotator cuff tear. There also is tapering of the distal end of the clavicle and widening of the acromioclavicular joint (upper arrow). (Courtesy of Dr. Barbara Weissman.)

with RA studied by arthrography, 21% had rotator cuff tears, and an additional 24% had evidence of frayed tendons.34 One likely mechanism behind tears is that the rotator cuff tendon insertion into the greater tuberosity is vulnerable to erosion by the proliferative synovitis that develops there. Previous injury and aging may predispose to the development of tears. Sudden tears may be accompanied by pain and inflammation so great as to suggest sepsis. Standard radiographic examinations of the shoulder in RA reveal erosions and superior subluxation (Fig. 66-3). Arthrograms, in addition to showing tears of the rotator cuff, can show diffuse nodular filling defects, irregular capsular attachment, bursal filling defects, adhesive capsulitis, and dilation of the biceps tendon sheath (perhaps unique to RA).35 High-resolution CT or MRI may provide much of this information without invasive techniques. Marked soft tissue swelling of the anterolateral aspect of the shoulders in RA may be caused by chronic subacromial bursitis rather than by glenohumeral joint effusions. In contrast to rotator cuff tears, bursal swelling is not associated with a decreased range of motion or pain. Synovial proliferation within the subdeltoid bursa may explain the resorption of the undersurface of the distal clavicle seen in this disease. Rarely, the shoulder joint may rupture, with symptoms resembling those of obstruction of venous return from the arm. Elbow RA rarely manifests with severe pain in the elbow, perhaps because the elbow is a stable hinge joint. Nevertheless, involvement of the elbow is common, and if lateral stability

B Figure 66-4  A, Polyarticular arthritis, especially with fusiform swelling of the proximal interphalangeal joints. Note deformity of wrists with  radial deviation. B, Complete subluxation with marked ulnar deviation at the metacarpophalangeal joints in a patient with rheumatoid arthritis. The heads of the metacarpals are now in direct contact with the joint ­capsule instead of the proximal phalanges. (Courtesy of Iain McInnes, MD.)

at the elbow is lost as the disease progresses, disability can be severe. The frequency of elbow involvement varies from 20% to 65%, depending on the severity of disease in the patient populations studied. One of the earliest findings, often unnoticed by the patient, is a loss of full extension. Because the elbow is principally a connecting joint between the hand and the trunk, the shoulder and wrists can compensate partially for the loss of elbow motion. Hand and Wrist The hand and wrist should be considered together because they form a functional unit. There are data linking disease of the wrist to ulnar deviation of the MCP joints.36 The hypothesis is that weakening of the extensor carpi ulnaris muscle leads to radial deviation of the wrist as the carpal bones rotate (the proximal row in an ulnar direction and the distal ones in a radial direction). In response to this, ulnar deviation of the fingers (a “zigzag” deformity) occurs to keep the tendons to the phalanges in a normal line with the radius. Other factors, including the tendency for a power grasp to pull the fingers into an ulnar attitude and inappropriate intrinsic muscle action, are involved (Fig. 66-4). Erosion of bone or articular cartilage is

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Figure 66-5  Ulnar deviation and subluxation. The hands show typical manifestations of end-stage erosive changes around the metacarpophalangeal joints, with volar dislocation and ulnar drift of the fingers.  (Copyright A.L. Ladd.)

not essential for the development of ulnar deviation (Fig. 66-5). Significant, although reducible, ulnar deviation can result from repeated synovitis or muscle weakness in the hands (e.g., in systemic lupus erythematosus [SLE] and Parkinson’s ­disease). Dorsal swelling on the wrist within the tendon sheaths of the extensor muscles is one of the earliest signs of disease. Typically, the extensor carpi ulnaris and extensor digitorum communis sheaths are involved. Rarely, cystic structures resembling ganglia are early findings of RA. As the synovial proliferation develops within the wrist, pressure increases within the relatively nondistensible joint spaces. Proliferative synovium develops enzymatic machinery sufficient to destroy ligaments, tendons, and the articular disk distal to the ulnar head. Pressure and enzymes combine to produce communications among radiocarpal, radioulnar, and midcarpal joints. Integrity of the distal radioulnar joint is lost. The ulnar collateral ligament, stretched by the proliferative synovium of the radioulnar joint, finally either ruptures or is destroyed, and the ulnar head springs up into dorsal prominence, where it “floats” and is easily depressed by the examiner’s fingers. On the volar side of the wrist, synovial protrusion cysts develop; they can be palpated, and their origins can be confirmed by arthrography. The thick transverse carpal ligament provides significant resistance to decompression, however, and the hyperplastic synovium can compress the median nerve and cause carpal tunnel syndrome, often bilaterally. Progression of disease in the wrist is characterized either by loss of joint space and bone or by ankylosis (Fig. 66-6). Disintegration of the carpus has been quantified in terms of a carpal-to-metacarpal ratio (the length of the carpus divided by the length of the third metacarpal). There is a linear decrease in the carpal-to-metacarpal ratio with progressive disease.37 This decrease is caused by compaction of bone at the radiolunate, lunate-capitate, and capitate–

Figure 66-6  Typical sites of osseous erosion of a rheumatoid wrist shown here include triquetrum, pisiform, scaphoid, and radius. There also are erosions at the ulnar aspect of the distal radius and the distal ulnar styloid process secondary to involvement of the inferior radioulnar compartment. Diffuse cartilage loss also is evident in the radiocarpal compartment. (Courtesy of Dr. Barbara Weissman.)

third metacarpal joints, which usually accompanies severe ­disease. Early detection of carpal bone involvement by RA is possible using MRI, which reveals early synovial proliferation and carpal bone erosions. Bony ankylosis is associated with the duration and the severity of disease and is found in joints that have been immobilized by pain, inflammation, treatment, or all of these. The hand may have many joints involved in RA. A sensitive index of hand involvement is grip strength. The act of squeezing puts stress on all hand joints. Muscular contraction causes ligamentous tightening around joints, compressing inflamed synovium. The immediate result is weakness, with or without pain; the reflex inhibition of muscular contraction owing to pain may be a primary factor in this weakness. Quantitative radiographic scores for joint space narrowing, erosion, and malalignment correlate well with loss of motion, but do not correlate with joint count tenderness scores38; these data support the concept that inflammatory synovitis and the erosive-destructive potential of proliferative synovitis in RA are not one and the same, but rather reflect different aspects of the same disease. The swan neck deformity is one of flexion of the distal interphalangeal (DIP) and MCP joints with hyperextension of the PIP joint. The lesion probably begins with shortening of the interosseous muscles and tendons. Shortening of the intrinsic muscles exerts tension on the dorsal tendon sheath, leading to hyperextension of the PIP joint (Fig. 66-7A).39 Deep tendon contracture or, rarely, DIP joint involvement with RA leads to the DIP joint flexion. Marginal erosive changes in the DIP joints occur more often in patients with RA who have coexisting osteoarthritis.40 If, during chronic inflammation of a PIP joint, the extensor hood stretches or is avulsed, the joint may pop up in flexion, producing a boutonnière deformity (Fig. 66-7B). The DIP joint remains in hyperextension.

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A

Figure 66-8  Bilateral protrusio acetabuli in rheumatoid arthritis. The medial acetabular margins protrude into the pelvis. There is severe ­accompanying cartilage loss. (Courtesy of Dr. Barbara Weissman.)

B Figure 66-7  A, Swan neck deformity. This common deformity leads to hyperextension of the proximal interphalangeal joints and flexion of the distal interphalangeal joints. B, Boutonnière deformity. This deformity, which is the opposite of swan neck deformity, is marked by flexion of the proximal interphalangeal joints and extension of the distal interphalangeal joints. (Courtesy of Iain McInnes, MD.)

The most serious result of rheumatoid involvement of the hand is resorptive arthropathy owing to severe resorption of bone that begins at the articular cartilage and spreads along the diaphysis of the involved phalanges. Digits appear shortened, excess skin folds are present, and phalanges can be retracted (telescoped) into one another and then pulled out into abnormally long extension, often without pain. With the availability of more effective therapy for RA, resorptive arthropathy has become rare. Three types of deformity have been described for the thumb, as follows: Type I: MCP inflammation leads to stretching of the joint capsule and a boutonnière-like deformity. Type II:Inflammation of the carpometacarpal joint leads to volar subluxation during contracture of the adductor hallucis. Type III:After prolonged disease of both MCP joints, exaggerated adduction of the first metacarpus, flexion of the MCP joint, and hyperextension of the DIP joint result from the patient’s need to provide a means to pinch. One of the most common manifestations of RA in the hands is tenosynovitis in flexor tendon sheaths, and this can be a major cause of hand weakness.41 Tenosynovitis manifests on the volar surfaces of the phalanges as diffuse swelling between joints or a palpable grating within flexor tendon sheaths in the palm and may occur in half of RA patients. It is particularly important to diagnose de Quervain’s tenosynovitis because it causes severe discomfort and yet is easily treated. de Quervain’s tenosynovitis is tenosynovitis

in the extensors of the thumb. Pain originating from these sheaths can be shown by Finkelstein’s test—ulnar flexion at the wrist after the thumb is maximally flexed and adducted. Frequently, rheumatoid nodules or less well-­differentiated fibrin deposits develop within tendon sheaths and may “lock” the finger painfully into fixed flexion. When they are chronic and recurrent, it may be necessary to inject the tendon sheath or, if that fails, remove it surgically. Hip The hip is less frequently involved early in RA than in juvenile RA. Hip joint involvement must be ascertained by a careful clinical examination; symptoms of hip synovitis are pain in the lower buttock or groin. Pain on the lateral aspect of the hip is often a manifestation of trochanteric bursitis rather than synovitis. About half of patients with well-established RA have radiographic evidence of hip disease. In contrast to osteoarthritis, in which the femoral head usually migrates superiorly, symmetric thinning of the cartilage in RA leads to axial migration. The femoral head may collapse and be resorbed, and the acetabulum is remodeled and pushed medially, leading to protrusio acetabuli (Fig. 66-8). Significant protrusion occurs in about 5% of all patients with RA.42 Loss of internal rotation on physical examination correlates best with radiographic findings. Similar to the situation in other weight-bearing joints, the femoral head may develop cystic lesions that communicate with the joint space. Knees In contrast to the hips, synovial inflammation and proliferation in the knees are readily shown on physical examination. Early in knee disease, often within 1 week after the onset of symptoms, quadriceps atrophy is noticeable and leads to the application of more force than usual through the patella to the femoral surface. Another early

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Figure 66-9  MRI of the knee in rheumatoid arthritis. Sagittal fast spin echo T2-weighted (TR 3625/TE 133) fat suppressed image allows excellent contrast. Synovial fluid is shown in white and shows a posterior fluid collection. (Courtesy of Dr. Barbara Weissman.)

­ anifestation of knee disease in RA is a loss of full extension, m a functional loss that can become a fixed flexion contracture unless corrective measures are undertaken. Some patients have a genu varum or valgus that precedes the onset of RA owing to preexisting osteoarthritis. In these individuals, the medial or lateral compartment bears the most stress from the malalignment that is first symptomatic and is likely to have radiographic evidence of erosion of bone and thinning of cartilage. Flexion of the knee that has a moderate to large effusion markedly increases the intra-articular pressure. This increased intra-articular pressure may cause an outpouching of posterior components of the joint, producing a popliteal or Baker’s cyst. Jayson and Dixon43 have shown that fluid from the anterior compartments of the knee may enter a pop­liteal cyst, but does not readily return. This one-way valve may generate pressures so high in the popliteal space that it may rupture down into the calf or, less often, superiorly into the posterior thigh. Rupture occurs posteriorly between the medial head of the gastrocnemius and the tendinous insertion of the biceps. Clinically, popliteal cysts and their complications have several manifestations. An intact popliteal cyst may compress superficial venous flow to the upper part of the leg, producing dilation of superficial veins, edema, or both.44 Rupture of the joint posteriorly with dissection of joint fluid into the calf may resemble acute thrombophlebitis with swelling and tenderness and produce systemic signs of fever with leukocytosis. One helpful sign in identifying joint rupture may be the appearance of a crescentic hematoma beneath one of the malleoli of the ankle.45 Although arthrography clearly defines the abnormal anatomy of a Baker’s cyst, this invasive procedure has been replaced by ultrasonography and, when necessary, MRI (Fig. 66-9).

Figure 66-10  Rheumatoid arthritis of the ankle. There is diffuse loss of cartilage space with erosions of the fibula (arrows). The scalloping along the medial border of the distal fibula is designated the fibular notch sign and is a characteristic finding in rheumatoid arthritis. The hindfoot is in valgus alignment.

Ankle and Foot The ankle involvement is usually mild in RA, but damage can occur in severe progressive forms of the disease. Clinical evidence for ankle involvement is a cystic swelling anterior and posterior to the malleoli. Much of the stability of the ankle depends on the integrity of the ligaments holding the fibula to the tibia and these two bones to the talus. In RA, inflammatory and proliferative disease may loosen these connections by stretching and eroding the collagenous ligaments and cause erosions (Fig. 66-10). The result is incongruity, which progresses to pronation deformities and eversion of the foot. The Achilles tendon is a major structural component and kinetic force in the foot and ankle. Rheumatoid nodules develop in this collagenous structure, and spontaneous rupture of the tendon has been reported when diffuse granulomatous inflammation is present.46 The subtalar joint controls eversion and inversion of the foot on the talus; patients with RA invariably have more pain while walking on uneven ground, and this is related to the relatively common subtalar joint involvement in RA. Progressive eversion at the subtalar joint, combined with foot pain, leads also to a lateral subluxation beginning in the midfoot and the development of a rocker-bottom deformity. Midfoot disease leads to collapse of the arch, which contributes to difficulty walking because of pain. More than one third of patients with RA have significant disease in the feet (Fig. 66-11). Metatarsophalangeal (MTP) joints are often involved, and gait is altered as pain develops during push-off in striding. Downward subluxation of the metatarsal heads occurs soon after the MTP joints become involved, producing “cock-up” toe deformities of

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These patients with systemic immune responses have true ­rheumatoid disease, not just RA. Other unusual proteins and protein complexes in the circulation of patients with active rheumatoid disease include antiphospholipid antibodies, circulating immune complexes, and cryoglobulins. Extra-articular manifestations of RA are associated with excess mortality.50 SKELETON

Figure 66-11  Valgus of ankle, pes planus, and forefoot varus ­deformity of the left foot related to painful synovitis of the ankle, forefoot, and metatarsophalangeal joint in a 24-year-old man with severe rheumatoid arthritis.

the PIP joints. Hallux valgus and bunion or callus formation occur if disease continues. Cystic collections representing outpouchings of flexor tendon sheaths often develop under the MTP joints.47 Patients with subluxation of metatarsal heads can develop pressure necrosis of the plantar surfaces. Alternatively, patients who have subluxation of MTP joints often develop ulceration over the PIP joints that protrude dorsally (hammer toes). The net result is increased pressure on the MTPs with a sensation described as “walking on marbles” by many patients. The sequence of changes as disease progresses in the foot is as follows:48 1. Intermetatarsal joint ligaments stretch in response to inflammation. 2. Spread of the forefoot occurs. 3. The fibrofatty cushion on the plantar surface migrates anteriorly. 4. Subluxation of toes occurs dorsally, and extensor tendons shorten. 5. Subluxation of metatarsal heads to a subcutaneous site on the plantar surface develops. 6. Concurrently, a hallux valgus results in “stacking” of the second and third toes on top of the great toe. DIP joints of the foot are rarely affected in RA, but a functional rigid hallux caused by muscle spasm of the great toe intrinsic muscles in an effort to relieve pressure on the lesser metatarsal heads can be extremely painful and require surgical intervention. Another cause of foot pain in rheumatoid patients is the tarsal tunnel syndrome. In a group of 30 patients with RA, erosions in the feet shown on radiographs, and foot pain, 4 (13%) were shown by electrodiagnostic techniques to have slowing of medial or lateral plantar nerve latency, or both. Extra-articular Complications of Rheumatoid Arthritis Generally, the number and severity of extra-articular features vary with the duration and severity of the disease. Several of these features may be related to extra-articular foci of an immune response,49 based on evidence of independent and qualitatively different production of RF in the pleural space, pericardium, muscle, and even meninges.

The skeleton has two anatomically and functionally separate components, cortical and trabecular bone, which respond differently to systemic and local diseases and to drugs. RA can be associated with generalized osteopenia and osteoporosis owing to the effects of drugs (especially corticosteroids); cytokine-induced and RANKL-induced activation of osteoclasts; and the fact that certain groups of patients with the disease, especially postmenopausal women, have other risk factors that enhance the potential for bone loss. The risk of hip fracture and vertebral compression fracture can be quite high. Bone densitometry should be performed routinely in patients with RA, and treatment with bisphosphonates should be considered as an adjunct to therapy. Because postmenopausal women are more at risk for RA and for osteoporosis, this group should be treated aggressively. At least one study indicates that adequate management of patients with RA that addresses RA and osteoporosis can protect against bone loss.51 Minimizing steroid use is one method to decrease the risk of osteoporosis in this group and other patients with RA. There seems to be a two-phase loss of bone induced by glucocorticoids: a rapid first phase when 12% of bone mass disappears in the first 6 to 12 months of therapy, followed by a subsequent chronic phase that has a slower rate of bone loss.52 It is encouraging, however, that the axial bone loss in patients with RA induced early by glucocorticoids can be reversed.53 The evaluation, biology, and management of osteoporosis is discussed in Chapter 92. Although the focus on the relationship between RA and bone is, appropriately, on osteoporosis, the diffuse loss of bone in RA, whether or not it is related to glucocorticoid therapy, leads to the high incidence of stress fractures of long bones in RA.54 The fibula is the most common fracture site. Acute leg pain in a thin, elderly rheumatoid patient, even without a history of trauma, should generate suspicion of a stress fracture. Geodes (i.e., subchondral cysts developed by synovial penetration of the cortex or subchondral plate and subsequent proliferation) weaken bone and can predispose bone to fracture. MUSCLE Clinical weakness is common in RA, but is it caused by muscle involvement in the rheumatoid inflammation, or is it a reflex weakness response to pain? Most rheumatoid patients have muscle weakness, but few have muscle tenderness or elevated muscle enzymes in the blood. In an early autopsy series, focal accumulations of lymphocytes and plasma cells with some contiguous degeneration of muscle fibers were found in all rheumatoid patients, a condition termed nodular myositis. More recent studies have pointed to at least five different types of muscle disease in RA, although clinically relevant active myositis is uncommon55:

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1. Diminution of muscle bulk with atrophy of type II fibers 2. Peripheral neuromyopathy, usually due to a mononeuritis multiplex 3. Steroid myopathy 4. Active myositis and muscle necrosis with foci of endomysial mononuclear cell infiltration 5. Chronic myopathy resembling a dystrophic process, probably the end stage of inflammatory myositis In biopsy specimens, atrophy of type II fibers is most common. Evidence of myositis and focal necrosis is found occasionally on biopsy specimens of patients with active disease, particularly in a subset with mild synovitis and a disproportionately high erythrocyte sedimentation rate (ESR). In some patients, the lymphocytes in muscle synthesize IgM RF, emphasizing the systemic nature of RA. The patchy “nodules of myositis” contain plasma cells and lymphocytes. SKIN The most frequently recognized skin lesion in RA is the rheumatoid nodule (discussed subsequently in a separate section), but there are several other manifestations as well. “Senile” purpura resulting from skin atrophy and capillary fragility is especially common in patients treated with glucocorticoids. Palmar erythema is common, but Raynaud’s syndrome is rare. Manifestations of vasculitis range from occasional nail fold infarcts to a deep, erosive, scarring pyoderma gangrenosum. Palpable purpura in rheumatoid patients is often related to a reaction to a drug that the patient is taking, but can be primary and a direct function of the severity of articular disease. Livedo reticularis, the lacy, dusky purple, asymptomatic discoloration seen on the extremities, is believed to signify a deep dermal vasculopathy. It can be present in any or all diffuse connective tissue diseases and is associated often with antiphospholipid antibodies in the circulation.56 EYE Virtually all ocular manifestations of RA can be considered complications of the disease (see Chapter 46). Keratoconjunctivitis sicca is a component of Sjögren’s syndrome and is discussed in Chapter 69. More directly related to the rheumatoid process and seen in the synovium and within rheumatoid nodules are scleritis and episcleritis. The highly differentiated connective tissues in the eye make rheumatoid manifestations particularly interesting and, when they occur in aggressive form, very serious. The episclera of the eye is highly vascular compared with the dense sclera. Scleritis, episcleritis, or both occur in less than 1% of rheumatoid patients. In episcleritis, the eye becomes red and, in contrast to conjunctivitis, results in no discharge other than tearing in response to the gritty discomfort. Loss of vision does not occur as a direct result of the episcleritis, but a keratitis or cataract developing secondarily can cause visual loss. Scleritis causes severe ocular pain and a dark red discoloration (Fig. 66-12C). No discharge is present. Depending on the intensity of the process, scleritis can be localized and superficial or generalized, with or without granulomatous resorption of the sclera down to the uveal layer; when this complication occurs, it is termed

scleromalacia perforans. In contrast to superficial eye disease, which usually can be treated conservatively with topical steroids, scleritis usually requires systemic or intraocular corticosteroid treatment. In some cases, the sclera can become thin even in the absence of overt inflammation and lead to scleromalacia (Fig. 66-12D). Rarely, perilimbic ischemic ulcers can be caused by cryoproteins (RF-IgG complexes) and if untreated can result in perforation of the anterior chamber. Patients with RA who have an associated keratoconjunctivitis sicca secondary to Sjögren’s syndrome have pruritic and painful eyes, sometimes leading to chronic blepharitis. RHEUMATOID NODULES The mature rheumatoid nodule has a central area of necrosis rimmed by a corona of palisading fibroblasts that is surrounded in turn by a collagenous capsule with perivascular collections of chronic inflammatory cells. The earliest nodules, nests of granulation tissue, have been identified at a size of less than 4 mm. The nodules grow by accumulating cells that expand centrifugally, leaving behind central necrosis initiated by vasculopathy and compounded by protease destruction of the connective tissue matrix. Occurring in 15% to 20% of patients with definite or classic RA, nodules are found most often on extensor surfaces or pressure points, such as the olecranon process and the proximal ulna (Fig. 66-12A). They are subcutaneous and vary in consistency from a soft, amorphous, entirely mobile mass to a hard, rubbery mass attached firmly to the periosteum. The appearance of nodules in unusual sites may lead to confusion in diagnosis, and they can sometimes appear identical to other types of nodules such as tophi. Sacral nodules may be mistaken for bedsores if the overlying skin breaks down. Occipital nodules also occur in bedridden patients. In the larynx, rheumatoid nodules on the vocal cords may cause progressive hoarseness. Nodules found in the heart and lungs are discussed later. Nodules on the sclera can produce perforation of this collagenous tissue. There have been multiple reports of rheumatoid nodule formation within the central nervous system, involving leptomeninges more than parenchyma.57 Some patients develop rheumatoid nodules within vertebral bodies, resulting in bone destruction and signs of myelopathy. Careful histologic study of early lesions58 suggests that development of the nodule is mediated through affected small arterioles and resulting complement activation and terminal vasculitis. This immunologic response is linked to proliferation of resident histiocytes and fibroblasts and to an influx of macrophages from the circulation. The proliferation of cells and the supporting scaffold of connective tissue is mediated by cytokines expressed in patterns similar to those found in rheumatoid synovium. Data from studies using monoclonal antibodies against receptors for complement C3b and C3bi, monocytes, activated macrophages, and HLA-DR molecules suggest that mononuclear phagocytes are constantly being recruited into the peripheral layers and subsequently migrate into the palisade to constitute most of the cell population in this area.59 Other studies, using cytochemical markers (nonspecific esterase and CD68—a protein associated with lysosomes—for macrophages, and prolyl hydroxylase for fibroblasts), indicate that a mixture of macrophages and nonsynoviocyte fibroblasts make up the cellular content of nodules.60 This evidence fits with data

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Figure 66-12  A-D, Manifestations of increased reactivity of mesenchymal tissue in rheumatoid arthritis include nodules on the elbow (A) and on the Achilles tendon (B), episcleritis (C), and scleromalacia (D). (Courtesy of Iain McInnes, MD.)

from nodule tissue in organ culture; similar to synovial tissue, the cells in the palisading region have the capacity to produce collagenase and proteases in large quantity.61 RF is almost always found in the serum of patients with rheumatoid nodules. Rarely, such nodules are present in the absence of obvious arthritis. A condition called rheumatoid nodulosis is characterized by the presence of multiple nodules on the hands, a positive test for RF, episodes of acute intermittent synovitis, and subchondral cystic lesions of small bones of the hands and feet.62 Many clinicians have noted that during methotrexate therapy that is successful in downregulating synovitis, existing nodules may enlarge, and new ones may develop; the pathophysiology underlying this phenomenon is unknown, although it may relate to the effects of methotrexate or adenosine (see Chapter 56). Discontinuing methotrexate in these patients usually leads to regression of some nodules. Some case reports suggest that tumor necrosis factor (TNF) inhibitors also can be associated with accelerated rheumatoid nodulosis. The differential diagnosis of rheumatoid nodules includes the following: 1. “Benign” nodules: These usually are found in healthy children without RF or arthritis. They are nontender; appear often on the pretibial regions, feet, and scalp;









increase rapidly in size; and are histologically identical to rheumatoid nodules. 2. Granuloma annulare: These nodules are intracutaneous, but histologically identical to rheumatoid nodules. They resolve slowly and are not associated with other disease. 3. Xanthomatosis: These nodules usually have a yellow tinge, and patients have abnormally high plasma lipoprotein and cholesterol levels. There is no underlying bone involvement. 4. Tophi: These collections of monosodium urate crystals in patients with gout are associated with small, punchedout bone lesions and are found rarely in patients with a normal serum urate concentration. A search for crystals with a polarizing microscope reveals the classic needleshaped, negatively birefringent crystals. 5. Miscellaneous nodules: The nodules of multicentric reticulohistiocytosis contain large, lipid-filled macrophages. Numerous proliferative disorders that affect cutaneous tissue, including erythema elevatum diutinum, acrodermatitis chronica atrophicans, bejel, yaws, pinta, and leprosy, can resemble rheumatoid nodules. A rheumatoid nodule, particularly when it occurs on the face, may simulate basal cell carcinoma.

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FISTULA DEVELOPMENT Cutaneous sinuses near joints develop rarely in seropositive patients with long-standing disease and positive tests for RF. These fistulas can be either sterile or septic and connect the skin surface with a joint, with a para-articular cyst in bone or soft tissues, or with a bursa. The pathogenesis of fistulas without a septic origin is particularly difficult to understand because the rheumatoid process usually is so clearly centripetal (i.e., progressing toward the center of the joint), rather than centrifugal. INFECTION The incidence of infections as a complication of RA has paralleled the use of glucocorticoids, biologics, and immunosuppressive agents. TNF blockers are especially noteworthy because they have been associated with reactivation of tuberculosis and other opportunistic infections such as histoplasmosis. Pulmonary infections, skin sepsis, and pyarthrosis are the most common infection in RA.63,64 Difficulty in diagnosis is accentuated by the similarity of aggressive RA to infection, particularly in joints; a “pseudoseptic” arthritis in rheumatoid patients, associated with fever, chills, and grossly purulent synovial fluid, can be part of a severe exacerbation of RA and must be distinguished from infection.65 A retrospective longitudinal cohort study compared the frequency of infections in a population-based incidence cohort of RA patients with that in a group of individuals without RA from the same population; this study looked at more than 7900 to 9100 person-years.66 There were 609 RA patients and 609 non-RA patients; 73% were women, and the mean age was 58 years. Hazard ratios for RA patients versus controls after adjustment for age, sex, smoking status, leukopenia, corticosteroid use, and diabetes mellitus were as follows: • Objectively confirmed infections = 1.7:1 • Infections requiring hospitalization = 1.83:1 Bone, joints, skin, respiratory tract, and soft tissues were the organs with highest hazard ratios. In a subsequent study in this cohort, the predictors of infection were shown to be the following: • Increasing age • Extra-articular manifestations of RA • Leukopenia • Comorbidities, such as chronic lung disease, alcoholism, diabetes mellitus, and the use of glucocorticoids Traditional disease-modifying antirheumatic drug use generally is not associated with a major increased incidence with infection, although vigilance when using these agents, such as biologics, is essential.67 Physicians must have a low threshold of concern for infection in rheumatoid patients. CANCER There is an increased risk for malignancy in RA patients, with an increased risk for lymphoma in certain patient subsets. Interstitial fibrosis may be a risk factor for lung carcinoma, particularly of the bronchoalveolar variety.68 One exception is cancer of the gastrointestinal tract, for which there seems to be a reduced risk for RA patients.69 It is possible that nonsteroidal anti-inflammatory drugs

(NSAIDs) lower the risk of this form of cancer, as supported by evidence that these drugs can diminish the occurrence and numbers of colonic polyps. RA patients are at a two to three times higher risk of Hodgkin’s disease, non-Hodgkin’s lymphoma, and leukemia than the normal population; this is independent of immunosuppressive therapy. Of lymphomas arising in RA, about half are low grade, and half are high grade; most of these are B cell lymphomas, although there is no evidence that these originate from clonally proliferated lymphocytes associated with RA. In contrast, although the relative risk for total cancer in patients with Felty’s syndrome is only 2, the relative risk for non-Hodgkin’s lymphoma in this complication of RA is near 13,70 similar to that associated with Sjögren’s syndrome. More recent data have raised the possibility that solid tumors also can be increased in patients with RA who have been treated with TNF blockers.71 Similar data in patients with Wegener’s granulomatosis suggest that the combination of etanercept and cyclophosphamide can increase the risk of cancer.72 Several cohorts evaluating the effect of TNF inhibitors on cancer rates in RA patients suggest, however, that the oncogenic effect, if it exists, is small. HEMATOLOGIC ABNORMALITIES Most patients with RA have a mild normocytic normochromic anemia that correlates with ESR elevation and the activity of the disease. Anemia has mixed causes in RA. One deficiency may mask evidence of others. A useful guide is that three quarters of rheumatoid patients with anemia have the anemia of chronic disease, whereas one quarter respond to iron therapy. Patients in both groups may have superimposed vitamin B12 or folate deficiencies.73 The following guidelines may be helpful in diagnosing the cause of anemia in rheumatoid patients: 1. Anemia of chronic disease is associated with significantly higher serum ferritin concentration than is found in isolated iron deficiency. 2. Folate or vitamin B12 deficiency or the use of methotrexate can mask iron deficiency, especially in patients taking NSAIDs with chronic gastrointestinal blood loss, by increasing the mean cell volume and mean cell hemoglobin level of erythrocytes. 3. The ESR correlates inversely with hemoglobin levels in RA, as expected in anemia of chronic disease. 4. Erythropoietin levels are higher in patients with iron deficiency anemia compared with patients with anemia of chronic disease; rheumatoid patients also have a diminished response to erythropoietin.74 In patients with the anemia of chronic disease, the total erythroid heme turnover is slightly reduced, and ineffective erythropoiesis accounts for a much higher than normal percentage of total heme turnover. In contrast to anemia associated with blood loss, the ineffective erythropoiesis returns to normal in RA if remission can be induced.75 Red blood cell aplasia, immunologically mediated, is a rare finding in RA. Because erythropoiesis in animals has been shown to be dependent on T lymphocytes, however, it is logical to search for immunologic factors that can induce anemia in RA. Serum from RA patients can profoundly suppress erythroid colony formation,76 but T lymphocytes from bone

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Figure 66-13  A, Digital vasculitis in a 65-year-old man with seropositive rheumatoid arthritis. B, Nail fold infarcts can occur in patients with rheumatoid arthritis, typically associated with rheumatoid factor positivity and active joint disease. (A courtesy of Eileen Moynihan, MD.)

marrow of rheumatoid patients have not been shown to inhibit erythroid development in vitro. Thrombocytosis is often associated with RA. There is a significant relationship between thrombocytosis and extraarticular manifestations of rheumatoid disease and disease activity.77 Eosinophilia (5% of total white blood cell count) also was observed in some patients. A subset of patients with RA has increased numbers of large granular lymphocytes in the peripheral blood, bone marrow, and liver. The lymphocytes contain many azurophilic granules in the cytoplasm and may account for more than 90% of mononuclear cells in blood. They are increased in certain viral infections. The cells are Fc receptor positive, do not produce interleukin (IL)-2, respond poorly to mitogens, and have either antibody-dependent cell-mediated cytotoxicity activity (expressing CD3, CD8, and CD57) or natural killer cells (expressing CD16 and CD56).78,79 Of previously described patients with large granular lymphocyte proliferation, almost one third have had RA.80 Because the large granular lymphocyte syndrome in patients with RA has the same HLA-DR4 association seen in Felty’s syndrome, the proposal has been made that Felty’s syndrome and large granular lymphocyte syndrome represent different variants of a broader syndrome comprising RA, neutropenia, large granular lymphocyte expansions, HLA-DR4 positivity, and variable splenomegaly.81 Paraproteinemia, typified by monoclonal gammopathies, has a poor prognostic significance when it appears in rheumatoid patients. This evidence for monoclonal B cell proliferation carries with it a high frequency of malignant transformation to lymphoma or myeloma.82 VASCULITIS The initial pathologic change in RA often includes inflammatory changes in medium and small blood vessels. It is useful, however, to use the term vasculitis to group extra-articular complications related not to proliferative granulomas, but rather to inflammatory vascular disease. Systemic rheumatoid vasculitis, one of the most feared complications of RA, has become increasingly uncommon in recent years. This

decline in rheumatoid vasculitis likely relates to the marked improvement in therapy resulting from widespread use of methotrexate and the new biologic agents. Variables associated with the development of rheumatoid vasculitis include the following83: • Male gender • High titers of RF in serum • Hypocomplementemia • Joint erosions • Subcutaneous nodules and other extra-articular features • Long-standing disease • Circulating cryoglobulins Rheumatoid vasculitis affects a subset of patients with established, often severe, RA with a prevalence of less than 5% of all cases. Clinical vasculitis usually takes one of the following forms: • Distal arteritis (including from splinter hemorrhage, nail fold infarcts, and gangrene) (Fig. 66-13) • Cutaneous ulceration (including pyoderma gangrenosum) • Peripheral neuropathy (mononeuritis multiplex) • Arteritis of viscera, including heart, lungs, bowel, kidney, liver, spleen, pancreas, lymph nodes, and testis • Palpable purpura The pathologic finding in rheumatoid vasculitis is a panarteritis. All layers of the vessel wall are infiltrated with mononuclear cells. Fibrinoid necrosis is seen in active lesions. Intimal proliferation may predispose to thrombosis. Obliterative endarteritis of the finger is a common manifestation of vasculitis, and immune complex deposits have been shown in the affected vessels.84 When larger vessels are involved, the pathologic changes resemble those of polyarteritis nodosa. In addition, a venulitis associated with RA has been described.85 In patients with hypocomplemente­ mia, the cellular infiltrate around the vessels contains neutrophils. In normocomplementemic patients, lymphocytes predominate. It is unusual for vasculitis to be active in any but the sickest patients, including patients with severe deforming

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arthritis, extra-articular manifestations, and high RF titers86; this subgroup represents less than 1% of patients with RA. Although RA is more common in women than in men, vasculitis is seen more often in men than in women with RA. Supporting the hypothesis that vascular injury is mediated by deposition of circulating immune complexes are (1) depressed levels of C2 and C4; (2) hypercatabolism of C387; (3) deposition of IgG, IgM, and C3 in involved arteries; and (4) the presence of large amounts of cryoimmunoglobulin in the serum of occasional patients with vasculitis. Neurovascular disease may be the only manifestation of vasculitis. The two common clinical patterns are a mild distal sensory neuropathy and a severe sensorimotor neuropathy (mononeuritis multiplex).88 The latter form is characterized by severe arterial damage on nerve biopsy specimens. Symptoms of the milder form may be paresthesias or “burning feet” in association with decreased touch and pin sensation distally. Patients with mononeuritis multiplex have weakness (e.g., footdrop) in addition to sensory abnormalities. Symptoms and signs are identical to those found in polyarteritis. Rheumatoid pachymeningitis is a rare complication of RA; confined to the dura and pia mater, this process may be limited to certain areas (e.g., lumbar cord or cisternae).89 Elevated levels of IgG (including IgM and IgG RFs and lowmolecular-weight IgM) and immune complexes are found in the cerebrospinal fluid. Visceral lesions occur generally as claudication or infarction of the organ supplied by the involved arteries. Intestinal involvement with vasculitis manifests as abdominal pain, at first intermittent and progressing often to continuous pain and a tender, quiet abdomen on examination. If infarction develops, resection must be accomplished promptly. The presence of gangrene of digits and extremities, the development of intestinal lesions with bleeding or perforation, cardiac or renal involvement, and mononeuritis multiplex indicate extensive vasculitis and are associated with a poor prognosis.90 Other entities in the differential diagnosis for rheumatoid vasculitis include diabetes mellitus, infection, atherosclerosis, and drug reactions. Current practice is to treat organ-specific vasculitis aggressively when it occurs in rheumatoid patients, similar to the treatment for patients with polyarteritis. This therapeutic approach may be responsible for the small excess mortality in rheumatoid vasculitis patients compared with “controls” with RA alone. In 61 patients with rheumatoid vasculitis, after allowance for general risk factors such as age and sex, the mortality risk was only 1.26 times that of rheumatoid patients without vasculitis.91 RENAL DISEASE The kidney is rarely involved directly in RA, but often is compromised indirectly by therapy. Amyloidosis is an unusual complication of chronic RA. AA amyloidosis, along with vasculitis and sepsis, is one of the most important lifethreatening complications of RA. Phenacetin abuse causes renal papillary necrosis, and salicylates and other NSAIDs may cause abnormalities as well. Membranous nephropathy is related to therapy with gold salts and penicillamine and was seen when these agents were commonly used to treat RA. Rarely, a focal necrotizing glomerulitis is seen in patients dying with RA and disseminated vasculitis.

PULMONARY DISEASE There are at least six forms of lung disease in RA, as ­follows: • Pleural disease • Interstitial fibrosis • Nodular lung disease • Bronchiolitis obliterans with organizing pneumonia • Arteritis, with pulmonary hypertension • Small airways disease It is not surprising that lung disease is associated with RA, considering that the drugs used to treat the disease, such as methotrexate, can cause pulmonary problems. In some cases, it may be difficult to distinguish pulmonary fibrosis related to RA from methotrexate pulmonary toxicity, although the latter is often associated with fever and eosinophilia secondary to an idiosyncratic reaction. Treatment with TNF inhibitors can lead to reactivation of pulmonary or extrapulmonary tuberculosis. Pleural Disease Pleuritis is commonly found on autopsy of patients with RA, but clinical disease during life is seen less frequently. In about 20% of patients, pleuritis develops concurrently with the onset of the arthritis. Pleuritic pain is not usually a major complaint. Effusions can be large enough to cause dyspnea. Characteristics of exudative rheumatoid effusions are as follows: Glucose, 10 to 50 mg/dL Protein, greater than 4 g/dL Cells (mononuclear), 100 to 3500/mm3 Lactate dehydrogenase, elevated CH50, depressed The low glucose concentrations are of interest. Sepsis (particularly tuberculosis) is the only other condition that commonly has such a low pleural fluid glucose level. An impaired transport of glucose into the pleural space seems to be the cause of this.92 Interstitial Pneumonitis and Fibrosis Pulmonary fibrosis, either slowly progressive or as a result of pulmonary inflammatory disease, can occur in RA. Similar to the findings in scleroderma, physical findings are of fine, diffuse, dry rales. Radiographs show a diffuse reticular (interstitial) or reticulonodular pattern in both lung fields; these can progress to a honeycomb appearance on plain radiographs and a characteristic lattice network seen on highresolution CT scans. The pathologic findings are those of diffuse fibrosis in the midst of a mononuclear cell infiltrate. The principal functional defect is impairment of alveolocapillary gas exchange with decreased diffusion capacity, best measured using single-breath carbon monoxide diffusion capacities.93 RA patients who smoke are likely to be at a higher risk for fibrotic complications in the lungs than are patients in the general population. Bronchoalveolar lavage may reveal increased numbers of lymphocytes, even in patients with only mildly abnormal chest radiographs and normal pulmonary function test results.94 In more aggressive disease, a higher proportion of neutrophils can be found in bronchoalveolar lavage. Lymphoid interstitial pneumonitis

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has been described in patients with RA and Sjögren’s syndrome. This is a relatively indolent disorder and is associated with elevated serum globulin levels. Bronchoalveolar lavage shows a primarily lymphocytic response.95 Nodular Lung Disease Pulmonary nodules may appear singly or in clusters that coalesce. Single nodules appear as coin lesions and, when significant peripheral arthritis and nodules are present, can be diagnosed by needle biopsy without thoracotomy. Caplan’s syndrome,96 in which pneumoconiosis and RA are synergistic, producing a violent fibroblastic reaction with obliterative granulomatous fibrosis, has become a rare occurrence as the respiratory environment in mining operations has improved. Nodules may cavitate, creating a bronchopleural fistula. In several cases, solitary pulmonary nodules in RA patients have proved to be a rheumatoid nodule and a coexistent bronchogenic carcinoma,97 a finding that suggests caution in interpreting “benign” results from fine-needle aspiration biopsy in such patients. Bronchiolitis An uncommon finding is an interstitial pneumonitis that progresses to alveolar involvement and bronchiolitis, respiratory insufficiency, and death. Pathologic studies show a cellular loose fibrosis and proteinaceous exudate in bronchioles and alveoli; interstitial infiltrations of lymphocytes attest to the immunogenic aspects of the disease. The course and prognosis are similar to idiopathic bronchiolitis obliterans with organizing pneumonia. Pulmonary Hypertension Pulmonary hypertension is more common than previously appreciated in RA. Noninvasive echocardiograms have suggested that mild pulmonary hypertension can be detected in more than 30% of patients with RA.98 Most of these patients are asymptomatic. Small Airways Disease Defined by a reduced maximal midexpiratory flow rate and maximal expiratory flow rate at 50% of functional vital capacity, small airways disease was observed in 50% of 30 RA patients compared with 22% of a control population.99 The study was adjusted for pulmonary infections, α1-­antitrypsin deficiency, penicillamine treatment, environmental pollution, and smoking. Other investigations have not found small airways dysfunction in RA and have suggested that, if present, it probably is related to factors other than RA.100 If real, this phenomenon may be part of a generalized exocrinopathic process in the disease, expressed most flagrantly in Sjögren’s syndrome.

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heart failure. Advances in echocardiography have made the ­diagnosis of pericarditis and endocardial inflammation easier and more specific. Myocardial biopsy through vascular catheters has facilitated diagnosis and classification of myocarditis. In a detailed study of rheumatoid patients using echocardiography, Holter monitors, and electrocardiogram, it was reported that 70% of patients with nodular disease and 40% of patients with non-nodular RA have some cardiac involvement, including valve thickening or incompetence.101 Atherosclerosis There are multiple risk factors for coronary artery disease in RA patients in addition to the risk factors that are relevant in the general population. Patients with prolonged RA have more atherosclerosis than patients of the same age with more recent disease onset.102 Many of the same risk factors present in RA patients have been implicated in patients without rheumatic diseases, including molecules involved in the immune response, markers of inflammation, and therapeutic agents. It also is apparent that, all else being equal, tobacco smoking is an important factor in augmenting early atherosclerosis in RA patients.103 In the large and well-studied population of rheumatoid patients at the Mayo Clinic, patients were followed until death, migration from Olmstead County, or 2001. The data showed that congestive heart failure was more important than ischemic heart disease as cause of death.104 Even in RA patients without clinically evident cardiovascular disease, the left ventricular diastolic function and the right ventricular diastolic function are reduced.105 Pericarditis Infrequently diagnosed on the basis of history and physical examination in RA, pericarditis is present in 50% of patients at autopsy. In one study, 31% of patients with RA had echocardiographic evidence of pericardial effusion. The same study revealed only rare evidence of impaired left ventricular function in prospectively studied outpatients with RA.106 Although unusual, cardiac tamponade with constrictive pericarditis can develop in RA and may require pericardiectomy. Almost all patients have a positive test for RF, and half have nodules. The preservation of good ventricular function on echocardiography in the face of deteriorating clinical myocardial function should raise a high index of suspicion of constrictive pericarditis. Myocarditis Myocarditis can take the form of either granulomatous disease or interstitial myocarditis. The granulomatous process resembles subcutaneous nodules and could be considered specific for the disease. Diffuse infiltration of the myocardium by mononuclear cells may involve the entire myocardium and yet have no clinical manifestations, but it could possibly be suggested by echocardiography.

CARDIAC COMPLICATIONS Cardiac disease in RA can take many forms. It has become apparent that the increased risk of premature death in RA is due largely to an increased incidence of cardiovascular disease, primarily myocardial infarction and congestive

Endocardial Inflammation Echocardiographic studies have reported evidence of previously unrecognized mitral valve disease of the anterior leaflet of the mitral valve. Although aortic valve disease and

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arthritis are generally associated through ankylosing spondylitis, numerous patients with granulomatous nodules on the valve have been reported.107 Conduction Defects Atrioventricular block is unusual in RA, but is probably related to direct granulomatous involvement. Pathologic examination may reveal proliferative lesions or healed scars. Complete heart block has been described in more than 30 patients with RA. It generally occurs in patients with established erosive nodular disease.108 It usually is permanent and is caused by rheumatoid granulomas in or near the atrioventricular node or bundle of His. Rarely, amyloidosis is responsible for heart block. Coronary Arteritis Patients with severe RA and active vasculitis who develop a myocardial infarction are likely to have coronary arteritis as a basis for the process along with accelerated atherosclerosis. Granulomatous Aortitis or Valvular Disease In severe rheumatoid heart disease, granulomatous disease can spread to involve even the base of the aorta. Occasionally, granulomatous disease associated with RA necessitates urgent valve replacement for aortic regurgitation.109

DIAGNOSIS Criteria to establish the diagnosis of RA are based on an effective clinical history and physical examination, laboratory tests, and exclusion of other diagnoses. No single feature or laboratory test is sufficient for a definite diagnosis. The 1988 American College of Rheumatology criteria for classification usually are not used in individual cases for diagnosis; however, the requirement that objective evidence for synovitis must be present for at least 6 weeks is an important one especially because many transient forms of synovitis are observed in primary care settings (Table 66-3). A physician should not make a premature diagnosis of RA in a patient who might have a self-limited synovitis. To attempt preventing irreversible damage to joints, the diagnosis of RA should be confirmed or ruled out within 2 months after the onset of synovitis. The characteristic patient with RA complains of pain and stiffness in multiple joints, with morning stiffness being prominent and prolonged. The joint swelling is boggy and includes soft tissue and synovial fluid. Joints are tender, especially the small joints of the hands and feet, but usually are not painful when the patient is at rest. Palmar erythema and prominent veins on the dorsum of the hand and wrist indicate increased blood flow. DIP joints are rarely involved. The temperature over the involved joints (except the hip) can be elevated, but the joints are not usually red. The range of motion is limited, and muscle strength and function around inflamed joints are diminished. Soft, poorly delineated subcutaneous nodules are often found in the extensor surface of the forearm. Findings on general physical examination are normal except for a possible low-grade fever in occasional patients (38°C) and a pulse more rapid than normal for that individual. Soft, small lymph nodes are found occasionally

in epitrochlear, axillary, and cervical areas. The history and physical examination are the most sensitive and specific tools for diagnosis of RA. Initial laboratory tests often show the results in the following list (essential tests are indicated with an asterisk (*). The other tests listed are largely of academic interest and should not be ordered routinely. • Normal white blood cell count and differential* • Thrombocytosis* • Mild anemia (hemoglobin 10 g/dL), normochromic and either normocytic or microcytic* • Normal urinalysis* • ESR 30 mm/hr or greater and C-reactive protein level greater than 0.7 pg/mL* • Normal renal, hepatic, and metabolic tests* • Normal serum uric acid level • Positive RF test (about 70% to 80% of patients; present in many normal individuals, patients with other rheumatic diseases, and individuals with chronic infections)* • Anticitrullinated protein antibody (about 80% to 90% of patients; can be seen in other diseases, including active tuberculosis) (especially useful in early synovitis)* Some investigators are convinced that anticitrullinated protein antibody will replace RF in the future as the autoantibody most useful in diagnosis. At this time, until it is costeffective, it can be used to supplement RF in the presence of a strong clinical suspicion. • Other autoantibodies (commonly found but with limited differential diagnosis utility, including antinuclear antibody, SS-A, SS-B) • Polyclonal gammopathy as determined by serum protein electrophoresis • Normal or elevated serum complement level • Negative antineutrophil cytoplasmic antibody and anti–double-stranded DNA antibody tests • “Typical” arthrocentesis, when obvious fluid is present, in RA reveals the following: Joint fluid is straw-colored, is slightly cloudy, and contains many flecks of fibrin 5000 to 25,000 white blood cells/mm3, and at least 50% of these are polymorphonuclear leukocytes No crystals Complement C4 and C2 levels are depressed, but C3 level can be normal Normal synovial fluid glucose level Cultures are negative DIFFERENTIAL DIAGNOSIS Other diseases must be excluded before the diagnosis of RA is established.110 One of the most difficult challenges is an adult presenting with polyarthritis and fever; for this patient, a full workup may be required to define the underlying cause (Table 66-4).111 The following sections on various diseases are listed in alphabetic order, and the illness’ relative frequency is specified as common, uncommon, or rare. Adult-Onset Still’s Disease (Uncommon) Significant fever at the onset of definite RA in adults is unusual. Later in the course, if vasculitis or serositis is present, or if there are intense exacerbations of disease, fever

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Table 66-3  1988 Revised American Rheumatism Association Criteria for Classification of Rheumatoid Arthritis* Criterion

Definition

1. Morning stiffness

Morning stiffness in and around the joints lasting at least 1 hr before maximal improvement

2.  Arthritis of ≥3 joint areas

At least 3 joint areas simultaneously having soft tissue swelling or fluid (not bony overgrowth alone) observed by a physician (the 14 possible joint areas are [right or left] PIP, MCP, wrist, elbow, knee, ankle, and MTP joints)

3.  Arthritis of hand joints

At least 1 joint area swollen as above in wrist, MCP, or PIP joint

4.  Symmetric arthritis

Simultaneous involvement of the same joint areas (as in criterion 2) on both sides of the body (bilateral involvement of PIP, MCP, or MTP joints is acceptable without absolute symmetry)

5.  Rheumatoid nodules

Subcutaneous nodules over bony prominences or extensor surfaces, or in juxta-articular regions,   observed by a physician

6.  Serum rheumatoid factor

Demonstration of abnormal amounts of serum rheumatoid factor by any method that has been positive

7.  Radiographic changes

Changes typical of RA on posteroanterior hand and wrist radiographs, which must include erosions or unequivocal bony decalcification localized to or most marked adjacent to the involved joints   (osteoarthritis changes alone do not qualify)

American College of Rheumatology Criteria

Sensitivity (%)

 Specificity (%)

Morning stiffness

68

  65

Arthritis of >3 areas

80

  43

Arthritis of the hand joints

81

  46

Symmetric arthritis

77

  37

Rheumatoid nodules

 3

100

Rheumatoid factor

59

  93

Radiographic change

22

  98

Clinical or Laboratory Variable

Persistent Nonerosive versus Self-limiting Odds Ratio Score

Persistent Erosive versus Persistent Nonerosive Odds Ratio Score

Symptom duration at first visit >6 wk, <6 mo >6 mo

2.49 5.49

2 3

0.96 1.44

0 0

Morning stiffness >1 hr

1.96

1

1.96

1

Arthritis in ≥3 joints

1.73

1

1.73

1

Bilateral MTP compression pain

1.65

1

3.78

2

Rheumatoid factor positivity

2.99

2

2.99

2

Anticitrullinated peptide antibody positivity

4.58

3

4.58

3

Radiographic erosions (hands or feet)

2.75

2

Infinite

Infinite

*For classification purposes, a patient is said to have RA if he or she has satisfied at least four of the seven criteria. Criteria 1 through 4 must be present for at least 6 weeks. Patients with two clinical diagnoses are not excluded. Designation as classic, definite, or probable RA is not to be made. MCP, metacarpophalangeal; MTP, metatarsophalangeal; PIP, proximal interphalangeal; RA, rheumatoid arthritis.

is more common. Adult Still’s disease, in contrast, usually manifests with spiking fevers. Adult Still’s disease was first described in 14 patients by Bywaters.112 Women and men are affected equally. It usually appears during the third or fourth decade of life. Serologic studies (RF and antinuclear antibody) are negative, and patients do not have subcutaneous nodules. Most patients are febrile, and fevers can develop before arthritis. Fever patterns in these patients are often quotidian (i.e., reaching normal levels at least once each day). Occasionally, evanescent salmon-colored or pink macules appear on the trunk and extremities that become more prominent when patients are febrile. The cervical spine is involved, and loss of neck motion may be striking. Abnormal liver function tests consistent with hepatitis and severe abdominal pain can be present and may confound attempts at diagnosis. Liver involvement is observed in most cases and was noted in more than two thirds of patients in one series113; hypergammaglobulinemia is present in more than 60%. Pericarditis and pleural effusions are found in less

than 25% of cases. In contrast to active SLE with nephritis, the serum complement level is normal or high. Serum ferritin levels can be enormously elevated, well beyond levels expected compared with other acute-phase reactants in the same individual.114 Levels in serum of 30,000 ng/mL have been reported in some patients with highly active disease; when levels are greater than 10,000 ng/mL, physicians should strongly consider adult Still’s disease as the diagnosis. The glycosylated form of serum ferritin, usually greater than 50% of the total, is reportedly low (mean 16%) during active phases and in remission.115 The diagnosis of adult-onset Still’s disease still remains one of exclusion, despite the unusually elevated ferritin levels in serum. Systemic infection, malignancy (e.g., lymphoma), and diffuse vasculitis usually are entertained as diagnoses, searched for, and then discarded before a diagnosis of adult-onset Still’s disease is made. Yamaguchi and associates116 developed criteria for establishing the diagnosis of adult Still’s disease that, in

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Table 66-4  Discriminating Features in Patients   Presenting with Polyarthritis and Fever

Table 66-5  Criteria for Diagnosis of Still’s Disease Major Criteria

Minor Criteria

Symptom or Sign

Possible Diagnoses

Temperature >39°C for >1 wk

Sore throat

Temperature >40°C

Still’s disease Bacterial arthritis SLE

Leukocytosis >10,000/mm3   with >80% PMNs

Lymph node enlargement

Fever preceding arthritis

Viral arthritis Lyme disease Reactive arthritis Still’s disease Bacterial endocarditis

Typical rash

Splenomegaly

Arthralgias >2 wk

Liver dysfunction (high AST/ALT) Negative ANA, RF

Migratory arthritis

Rheumatic fever Gonococcemia Meningococcemia Viral arthritis SLE Acute leukemia Whipple’s disease

Effusion disproportionately   greater than pain

Tuberculous arthritis Bacterial endocarditis Inflammatory bowel disease Giant cell arteritis Lyme disease

Pain disproportionately   greater than effusion

Rheumatic fever Familial Mediterranean fever Acute leukemia Acquired immunodeficiency   syndrome

Positive test for rheumatoid   factor

Rheumatoid arthritis Viral arthritis Tuberculous arthritis Bacterial endocarditis SLE Sarcoidosis Systemic vasculitis

Morning stiffness

Rheumatoid arthritis Polymyalgia rheumatica Still’s disease Some viral and reactive   arthritides Rheumatoid arthritis SLE Viral arthritis

Symmetric small joint synovitis

Leukocytosis (>15,000/mm3)

Bacterial arthritis Bacterial endocarditis Still’s disease Systemic vasculitis Acute leukemia

Leukopenia

SLE Viral arthritis

Episodic recurrences

Lyme disease Crystal-induced arthritis Inflammatory bowel disease Whipple’s disease Mediterranean fever Still’s disease SLE

SLE, systemic lupus erythematosus From Pinals RS: Polyarthritis and fever. N Engl J Med 330:769, 1999. Copyright 1999 Massachusetts Medical Society. All rights reserved.

numerous series, have greater than 90% sensitivity (Table 66-5). After excluding other diseases, adult Still’s disease should be considered if five criteria (more than two being major ones) are met. It is unknown yet whether adding hyperferritinemia would increase the specificity of diagnosis.

ALT, alanine transaminase; ANA, antinuclear antibody; AST, aspartate transaminase; PMNs, polymorphonuclear neutrophils; RF, rheumatoid factor.

In one series of adult-onset Still’s disease, 11 patients (all of whom were white women), followed for a mean of 20.2 years after disease onset, had the following characteristics117: • Ten patients had a polycyclic pattern (characterized by remissions and exacerbations). • Patterns of exacerbations were similar to, but less severe than, the original presentations. • Loss of wrist extension was the most common clinical abnormality, and carpal ankylosis was present in 10 patients. In another group, 20% showed significant functional deterioration from erosive joint disease.118 Functional class III/IV (Steinbrocker’s classification) was usually related to hip disease. The overall long-term prognosis of adult-onset Still’s disease is good for systemic manifestations, but less so for articular disease. The incidence of amyloidosis may be 30% within 10 years of onset of the illness, perhaps reflecting the sustained high titers of acute-phase reactants found in this disease. Therapy must be aggressive. Full doses of NSAIDs should be prescribed soon after diagnosis. Oral glucocorticoids are often needed to control systemic symptoms. It is reasonable to prescribe weekly methotrexate to help control the inflammation and serve as a steroid-sparing drug. Because of the high likelihood that this is an example of a cytokine-driven disease, use of TNF or IL-6 blockers might be effective. Still’s disease also is more likely to respond to IL-1 antagonists than is RA.119 Amyloidosis (Rare) Deposits of amyloid can be found in synovial and periarticular tissues and are presumably responsible for the joint complaints of some patients. The synovial fluid in amyloid arthropathy is noninflammatory, and particulate material with apple-green fluorescence after Congo red staining may be found in the fluid. Amyloid formed of β2-microglobulin is found in joints of patients with chronic renal failure, usually patients who are on dialysis (see Chapter 106). Angioimmunoblastic Lymphadenopathy (Rare) Nonerosive symmetric seronegative polyarthritis involving large joints can be an initial complaint in angioimmunoblastic lymphadenopathy.120 Typical clinical features are lymphadenopathy, hepatosplenomegaly, rash, and hypergammaglobulinemia. It can resemble Still’s disease in adults if the arthritis precedes other manifestations. Diagnosis is based on the characteristic appearance of a lymph node or skin biopsy specimen, which includes effacement of lymph

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node architecture, proliferation of small vessels, and a cellular infiltrate (immunoblasts, plasma cells, T lymphocytes, and histiocytes) within amorphous acidophilic interstitial material. Symptoms may be related to excessive production of IL-2 by helper T cells in this process. Ankylosing Spondylitis, Seronegative Spondyloarthropathy, and Reactive Arthritis (Common) Ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease–associated arthritis, and reactive arthritis are often referred to as seronegative spondyloarthropathies. These diseases are generally marked by their respective nonarticular features and the following pattern of joint disease: asymmetric, oligoarticular, lower extremities more than upper extremities, and large joints more than small joints (there are many exceptions to these general guidelines). The problem in differentiating these diseases from RA arises with a patient (particularly a woman) who has minimal back pain and definite peripheral joint involvement. The presence of low back pain and lumbar involvement also distinguish these diseases from RA. In some unusual cases, RA and ankylosing spondylitis are present in the same patient. In one series, nine patients with RF in serum had spinal ankylosis and symmetric ­ erosive polyarthritis; eight of the nine carried HLA-B27.121 If these two diseases occur completely independently of each other, simultaneous appearance in the same patient should occur in 1 in 50,000 to 200,000 adults. In distinguishing patients with Reiter’s syndrome from patients with RA, a careful search for heel pain or tenderness and ocular or urethral symptoms is of great importance. Polyarthritis persists chronically in more than 80% of patients with Reiter’s syndrome. The characteristics of enthesopathy in patients with Reiter’s syndrome (i.e., “sausage” digits indicating periarticular soft tissue inflammation, insertional tendinitis, periostitis, and peri-insertional osteoporosis or erosions) may point to the diagnosis. The differential diagnosis between RA with psoriasis and some forms of psoriatic arthritis may be artificial (see Chapter 47). Some patients with DIP joint involvement and severe skin involvement have a disease that is not RA. Others have a seropositive symmetric polyarthritis that appears to be RA, yet they also have psoriasis. These patients can be treated with the same disease-modifying drugs as patients with progressive RA, including TNF-α inhibitors. A syndrome described extensively in the French literature, acne pustulosis hyperostosis osteitis,122 may resemble psoriatic arthritis and, occasionally, when peripheral arthritis is present, RA. As the name implies, these patients variably have severe acne, palmar and plantar pustules, hyperostotic reactions (particularly in the clavicles and sternum), sacro­ iliitis, and peripheral inflammatory arthritis. Inflammatory bowel disease (ulcerative colitis and Crohn’s disease) is associated with arthritis in 20% of cases (see Chapter 73). Peripheral arthritis occurs more commonly than spondylitis in many series.123 Ankles, knees, and elbows are the most typically involved peripheral joints, with PIP joints and wrists next in frequency. Simultaneous attacks of arthritis and the development of erythema nodosum are common. Only two or three joints are

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affected at once. Involvement is usually asymmetric, and erosions are uncommon. The occurrence of peripheral arthritis in inflammatory bowel disease is not related to HLA-B27. Behçet’s syndrome is marked by asymmetric polyarthritis in 50% to 60% of cases (see Chapter 86).124 It is rare, with a prevalence of less than 1 in 25,000 in the United States. In more than half of cases, the attacks of arthritis are monarticular. Knees, ankles, and wrists are affected most often; synovial fluid usually contains more than 5000, but less than 30,000 white blood cells/mm3. Joint deformity is unusual. Painful oral and genital ulcers and central nervous system involvement are characteristic. Uveal tract involvement in Behçet’s syndrome must be differentiated from the scleritis characteristic of RA in patients with ocular and joint disease. Enteric infections are complicated occasionally by inflammatory joint disease resembling RA. The joint disease associated with Yersinia enterocolitica infections occurs several weeks after the gastrointestinal illness. Knees and ankles are the joints most commonly involved, and most patients (even patients with peripheral arthritis and no spondylitis) have HLA-B27. Reactive arthritis also has been reported after Salmonella, Shigella, and Campylobacter (Helicobacter) jejuni infection. Arthritis Associated with Oral Contraceptives (Uncommon) A syndrome of persistent arthralgias, myalgias, and morning stiffness with occasional development of polyarticular synovitis has been described in women, usually in their 20s, who have been taking oral contraceptives (estrogens and progestins). Positive tests for antinuclear antibody are common, and patients may have circulating RF. Symptoms resolve after the oral contraceptive is discontinued. Arthritis of Thyroid Disease (Uncommon) In hypothyroidism (see Chapter 111), synovial effusions and synovial thickening that simulate RA have been described.125 The ESR may be elevated because of hypergammaglobulinemia, but C-reactive protein is normal. The joint fluid is noninflammatory and may have increased viscosity. Knees, wrists, hands, and feet are involved most often, and coexisting calcium pyrophosphate dihydrate deposition disease is frequently found. This syndrome should be distinguished from arthralgias and other nonspecific musculoskeletal complaints that often accompany hyperthyroidism and hypothyroidism. The syndrome of thyroid acropachy complicates less than 1% of cases of hyperthyroidism. This syndrome comprises periosteal new bone formation, which may be associated with a low-grade synovitis similar to hypertrophic osteoarthropathy. Patients with coexisting RA and hyperthyroidism have pain from the arthritis that, although impossible to quantify, seems to exceed the pain expected from the degree of inflammation. Bacterial Endocarditis (Uncommon) Arthralgias, arthritis, back pain, and myalgias occur in approximately 30% of patients with subacute bacterial endocarditis.126 Symptoms typically occur in one or

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several joints, usually large, proximal ones. This synovitis is probably caused by the deposition of circulating immune complexes. Confusion with RA may arise because more than half of patients with endocarditis are seropositive for RF. Fever out of proportion to joint findings in the setting of leukocytosis should lead to a consideration of infective endocarditis as a diagnostic possibility, even in the absence of a significant heart murmur. Peripheral emboli with digital infarctions may be found, simulating palpable purpura when they occur on the lower legs. Blood cultures should be obtained in all patients with polyarthritis and significant fever. Embolic phenomena with constitutional symptoms, including arthralgias, can be presenting symptoms of atrial myxoma, but this process usually mimics systemic vasculitis or subacute bacterial endocarditis more than it does RA.

hood or adolescence, mimicking oligoarthritic forms of juvenile RA. The disease is caused by a genetic abnormality owing to a mutation in the pyrin gene, and 60% of reported cases have been in Sephardic Jews. Episodes of arthritis begin acutely with fever and other signs of inflammation (e.g., peritonitis or pleuritis) and can precede other manifestations of the disease. Although usually limited to days or weeks, attacks occasionally last for months and are associated with radiographic changes of periarticular osteopenia without erosions. The abdominal pain that these patients experience can be a key to diagnosis. Amyloidosis (type AA) is a late complication of this syndrome in numerous patients. Familial Mediterranean fever and related forms of periodic inflammatory syndromes are discussed fully in Chapter 113.

Calcium Pyrophosphate Dihydrate Deposition Disease (Common)

Fibromyalgia (Common)

Calcium pyrophosphate dihydrate deposition disease is a crystal-induced synovitis that takes many forms, ranging from a syndrome of indolent osteoarthrosis to that of an acute, hot joint. About 5% of patients have a chronic polyarthritis (sometimes referred to as pseudo-RA) associated with proliferative erosions of subchondral bone. Although radiographs are helpful when chondrocalcinosis is present, calcium pyrophosphate dihydrate deposition disease may be present in the absence of calcification on radiographs.127 Diagnosis then can be made only by arthrocentesis. A radiographic sign of calcium pyrophosphate dihydrate deposition disease that helps to differentiate it from RA is the presence of unicompartmental disease in the wrists (see Chapter 44). On physical examination, the MCPs in calcium pyrophosphate dihydrate deposition disease generally have bony enlargement rather than soft tissue swelling owing to synovial hyperplasia.

In fibromyalgia, there is no evidence of synovitis. Although no specific diagnostic tests define this entity, certain nonarticular locations of pain are common to different patients. In an analysis contrasting the pain properties with those of RA,129 the fibromyalgia patients used diverse adjectives to describe their pain, the most common being “pricking,” “pressing,” “shooting,” “gnawing,” “cramping,” “splitting,” and “crushing.” Most patients in both groups defined the pain as aching and exhausting. Evidence is accumulating that patients with diffuse connective tissue diseases, including RA, may develop a superimposed fibromyalgia, adding to the difficulty of treating the arthritis. Rheumatoid patients have fewer psychological disturbances than patients with fibromyalgia, and RA patients who develop fibromyalgia score higher on testing scales for hypochondriasis, depression, and hysteria than patients with RA who do not have fibromyalgia (see Chapter 38).

Calcific Periarthritis (Uncommon)

Glucocorticoid Withdrawal Syndrome (Common)

Although usually involving single joints, calcific periarthritis secondary to hydroxyapatite deposition can be confused with polyarthritis. The skin is red over and around the affected joints; the tissues are boggy and tender, but no joint effusion is present. Passive motion is easier than active motion. Periarticular calcification is visible on radiographs. Unless the periarthritis can be differentiated from true arthritis, the findings may mimic those of palindromic rheumatism or early monarticular RA.

The symptoms of glucocorticoid withdrawal are often confused with RA. Patients on glucocorticoid therapy who are being treated for nonrheumatic diseases may have diffuse polyarticular pain, particularly in the hands, if the glucocorticoid dose is tapered too rapidly.

Congenital Camptodactyly and Arthropathy (Rare) Congenital camptodactyly and arthropathy is a deformity that begins in utero and produces synovial cell hypertrophy and hyperplasia without inflammatory cells.128 Clinical manifestations include contractures of the fingers; flattening of the metacarpal heads; and short, thick femoral necks. This condition can manifest as oligoarticular seronegative RA. Familial Mediterranean Fever (Uncommon) The articular syndrome in familial Mediterranean fever and many other periodic fevers is an episodic monarthritis or oligoarthritis of the large joints that appears in child-

Gout (Common) Before a diagnosis of chronic erosive RA is made, chronic tophaceous gout must be ruled out. The reverse applies as well. Features of gouty arthritis that can mimic the features of RA include polyarthritis, symmetric involvement, fusiform swelling of joints, subcutaneous nodules, and a subacute presentation of attacks. Conversely, certain aspects of RA that suggest gouty arthritis include hyperuricemia after treatment with low doses of aspirin, periarticular nodules, and seronegative disease (particularly in men). Radiographic findings may be similar, with the appearance of the subcortical erosions of RA resembling small osseous tophi in gout. Although large asymmetric erosions with ballooning of the cortex and overhanging edges are more likely to be caused by gout than by RA, this is not always the case. Serologic test results may be misleading as well; RF has been found in 30% of patients with chronic tophaceous gout who have

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no clinical or radiographic signs of RA.130 Gout occurring concomitantly with RA is extremely rare. Hemochromatosis (Uncommon) The characteristic articular feature of hemochromatosis that is almost diagnostic is firm bony enlargement of the MCP joints, particularly the second and third joints, with associated cystic degenerative disease and large hooklike osteophytes on radiographs and, frequently, chondrocalcinosis. Marginal erosions, juxta-articular osteoporosis, synovial proliferation, and ulnar deviation are not seen in the arthropathy of hemochromatosis, but are common in RA. Wrists, shoulders, elbows, hips, and knees are involved less often than the MCP joints. Arthritis leads the list of diagnoses provided to patients to explain their symptoms before the diagnosis of hemochromatosis.131 In the series by McDonnell and colleagues,131 individuals with symptoms received a diagnosis of hemochromatosis only after the symptoms had been present, on average, for an extended period (10 years) and after visiting an average of 3.5 physicians (see Chapter 108). Hemoglobinopathies (Uncommon) In homozygous (SS) sickle cell disease, the most common arthropathy is associated with crisis and is believed to be a result of microvascular occlusion in articular tissues. A destructive arthritis with a loss of articular cartilage that resembles severe RA has been reported in some cases, however.132 In most patients with sickle cell disease and joint complaints, periosteal elevation, bone infarcts, fish-mouth vertebrae, and avascular necrosis can be found on radiographs. In a series of 37 patients with SS disease, from which patients with gout or avascular necrosis of the femoral head were excluded, 12 complained of a monarthritis or oligoarthritis associated with painful crises; tenderness was most marked over the epiphyses rather than the joint space, and synovial fluid was noninflammatory. Another 12 patients had arthritis of the ankle associated with a malleolar ulcer; this arthritis was chronic and resolved with improvement of the leg ulcer.133 Episodic polyarthritis and noninflammatory synovial effusions also are found in sickle cell–β-thalassemia (see Chapter 110). Hemophilic Arthropathy (Uncommon) A deficiency of factor VIII or, less frequently, factor IX, sufficient to produce clinical bleeding frequently results in hemarthroses. The iron overload in the joint generates a proliferative synovitis that often leads to joint destruction. Because iron stimulates metalloproteinase production by synovial cells, when feasible, large hemarthroses should be aspirated, and the joint should be immobilized and wrapped well. The clotting abnormality is rarely overlooked, however, and it is unlikely that a diagnosis of RA would be made in the setting of hemophilia A or B (see Chapter 109). Human Immunodeficiency Virus Infection (Common) Several types of arthropathy have been described in association with human immunodeficiency virus (HIV) infection, including the following134:

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1. Brief, acute arthralgias concurrent with initial HIV viremia 2. HIV-associated arthritis, lower extremity noninflammatory oligoarthritis, or a persistent polyarthritis 3. Seronegative spondyloarthropathy, resembling Reiter’s syndrome, psoriatic arthritis, or reactive arthritis, often more severe than in patients without HIV infection135 It is crucial to rule out HIV in any patient with an acute polyarthritis and fever: HIV-positive patients have a greater risk for toxicity or opportunistic infections when using immunosuppressive drugs (see Chapter 104). HIV-positive patients also can present with syndromes of vasculitis. Hyperlipoproteinemia (Uncommon) Achilles tendinitis and tenosynovitis can be presenting symptoms in familial type II hyperlipoproteinemia and may be accompanied by arthritis. Synovial fluid findings may resemble the findings of mild RA, and the tendon xanthomas may be mistaken for rheumatoid nodules or gouty tophi. Conversely, bilateral pseudoxanthomatous ­ rheumatoid nodules have been described. The treatment of hyperlipoproteinemia with statins may cause an acute or subacute muscular syndrome that resembles myositis or polymyalgia rheumatica more than RA (see Chapter 78). Hypertrophic Osteoarthropathy (Uncommon) Hypertrophic osteoarthropathy may present as oligoarthritis involving the knees, ankles, or wrists. The synovial inflammation accompanies periosteal new bone formation that can be seen on radiographs. Correction of the inciting factor (e.g., cure of pneumonia in a child with cystic fibrosis) is likely to alleviate the synovitis. The synovium is characterized primarily by an increased blood supply and synovial cell proliferation. Little infiltration by mononuclear cells is seen. Pain in the bones that increases when extremities are dependent is characteristic, although it is not always present. If clubbing is not present or is not noticed, this entity is easily confused with RA (see Chapter 90). Hypercytokine Syndrome (Uncommon) Unusual patients present to clinics and hospitals with acute or subacute wasting, often febrile diseases that have manifestations in multiple organs, but without histopathologic or clinical clues that would enable specific classification. With very high acute-phase reactants and serum ferritin levels exceedingly high, adult-onset Still’s disease (without arthritis) and infection or various forms of vasculitis must be considered. These patients are inevitably given glucocorticoid therapy, and anecdotal reports have indicated successful or partially effective therapy with anti-TNF agents. Idiopathic Hypereosinophilic Syndrome with Arthritis (Rare) The poorly defined idiopathic hypereosinophilic syndrome often includes myalgias and arthralgias and evolves into a clinical picture of hepatomegaly with or without pericarditis, pulmonary hypertension, subcutaneous nodules, and cardiomyopathy. Synovitis, characterized by inflammatory

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joint fluid, is rarely erosive or deforming. The similarities between this and toxic oil syndrome and eosinophilia-myalgia syndrome, both of which are caused by the ingestion of toxic substances, suggest a basic hypersensitivity reaction. Infectious Diseases (Including Viral Causes Such as Hepatitis C) (Common) Bacterial sepsis may be superimposed on RA. Viral infections may manifest as arthritis, however, with many characteristics of RA. Arthritis complicates rubella more often in adults than in children and may affect the small joints of the hands. Lymphocytes predominate in synovial effusions. Arthritis often precedes jaundice in viral hepatitis and is associated with the presence of circulating hepatitis B surface antigen and hypocomplementemia. The surface antigen has been found in synovial tissues with the use of direct immunofluorescence, and this supports the concept that this synovitis is mediated by immune complexes.136 An acute onset of diffuse polyarthritis with small joint effusions and minimal synovial swelling, often accompanied by urticaria, should prompt the physician to obtain liver function tests in the patient with a history of exposure to hepatitis. With the onset of icterus, the arthritis usually resolves without a trace. The increasing recognition of the RNA virus hepatitis C as a cause of joint complaints is related to the availability of specific serologic tests for this virus. About one third of individuals infected with hepatitis C virus have arthralgias or arthritis, and in a Korean series, the prevalence of cryoglobulins (mean concentration of 9.8 g/L) was 59%.137 These individuals can present with palmar tenosynovitis, small joint synovitis, carpal tunnel syndrome, and positive tests for RF. The presence of anticitrullinated protein antibodies can be a useful feature to distinguish RA from hepatitis C–associated arthritis.138 Other findings, including mixed cryoglobulinemia syndrome, glomerulonephritis, and cutaneous vasculitis, round out the clinical spectrum of rheumatic complaints associated with this viral ­ infection. Because exacerbation of hepatitis can be associated with the use and the cessation of methotrexate therapy, a good case has been made for testing for hepatitis C in every patient with RA scheduled to be started on therapy with this drug.139 Fever, sore throat, and cervical adenopathy followed by symmetric polyarthritis are compatible with infection resulting from hepatitis B, rubella, adenovirus type 7, echovirus type 9, Mycoplasma pneumoniae, or Epstein-Barr virus and acute rheumatic fever or adult-onset Still’s disease. In Japan, many more patients with RA have circulating antibodies against human T-lymphotropic virus 1 (HTLV-1). Multiple nodules within tendon sheaths associated with inflammation resembling rheumatoid tenosynovitis have been described in a patient with HTLV-1 arthropathy.140 A chronic polyarthritis resembling RA has been described after serologic proof of parvovirus infection. Usually the process is self-limited and does not progress to a destructive synovitis (see Chapter 104). Adults, often those involved in child care, present with a history of a viral-like illness, sometimes with desquamating finger involvement and a diffuse, red facial rash (“slapped cheeks”) that is followed by arthralgias and synovitis.

Poststreptococcal arthritis also can resemble RA. Typically, patients have an antecedent skin or oropharynx group A streptococcal infection in the weeks preceding symptoms. Antistreptolysin O antibody titers are usually elevated. Although the same bacteria can cause glomerulonephritis, it is uncommon to see concomitant arthritis and renal ­disease. Intermittent Hydrarthrosis (Common) Intermittent hydrarthrosis is a syndrome of periodic attacks of benign synovitis in one or a few joints, usually the knee, beginning in adolescence. The difference between this and oligoarticular juvenile RA or RA is one of degree, not kind. In contrast to palindromic rheumatism, in which acute synovitis may occur in different joints during successive attacks, the same joint or joints are affected during each attack in intermittent hydrarthrosis. Joint destruction does not occur because there is no chronic, persistent, proliferative synovitis. Lyme Disease (Common in Some Areas) Lyme disease can closely simulate RA in adults or children because of its intermittent course with the development of chronic synovitis. A proliferative, erosive synovitis necessitating synovectomy has evolved in several cases. The histopathologic appearance of the proliferative synovium is not different from that of RA (see Chapter 100) and the Lyme synovial cells produce a similar excess of metalloproteinases. Lyme serologic tests can help distinguish this disease from RA, along with history of tick bites, characteristic skin rash, or neurologic involvement. Malignancy (Rare) Direct involvement by cancer of synovium usually manifests as a monarthritis. Non-Hodgkin’s lymphoma can manifest as seronegative polyarthritis, however, without ­hepatomegaly or lymphadenopathy. Intravascular lymphoma can manifest as a symmetric polyarthritis.141 In children, acute lymphocytic leukemia can manifest as a polyarticular arthritis. Paraneoplastic syndromes and others related to direct involvement with cancer are described in detail later. Multicentric Reticulohistiocytosis (Rare) Multicentric reticulohistiocytosis causes severe arthritis mutilans with an opera-glass hand (main en lorgnette).142 Other causes of arthritis mutilans are RA, psoriatic arthritis, erosive osteoarthritis treated with glucocorticoids, and gout (after tophi are resorbed by treatment with allopurinol). The cell that causes damage to tissues is the multinucleate lipid-laden histiocyte, which apparently releases degradative enzymes sufficient to destroy connective tissue. These cells in aggregates produce multiple small nodules around joints of the hands. Osteoarthritis (Common) Although osteoarthritis can begin as a degenerative cartilage disease, and RA begins as synovial inflammation, the diseases can overlap as they progress (Table 66-6). In osteoarthritis, as cartilage deteriorates and joint congruence is altered and stressed, a reactive synovitis often develops.

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Table 66-6  Factors Useful for Differentiating Early Rheumatoid Arthritis from Osteoarthritis Rheumatoid Arthritis

Osteoarthritis

Age at onset

Childhood and adults, peak incidence in 50s

Increases with age

Predisposing factors

Susceptibility epitopes (HLA-DR4, HLA-DR1) PTPN22, PADI4 polymorphisms and others Smoking

Trauma Congenital abnormalities (e.g., shallow ­acetabulum)

Early symptoms

Morning stiffness

Pain increases through the day and with use

Joints involved

Metacarpophalangeal joints, wrists, proximal   interphalangeal joints most often; distal ­  interphalangeal joints almost never

Distal interphalangeal joints (Heberden’s nodes),   weight-bearing joints (hips, knees)

Physical findings

Soft tissue swelling, warmth

Bony osteophytes, minimal soft tissue swelling early

Radiologic findings

Periarticular osteopenia, marginal erosions

Subchondral sclerosis, osteophytes

Laboratory findings

Increased C-reactive protein, rheumatoid factor,   anticitrullinated peptide antibody, anemia,   leukocytosis

Normal

Conversely, as the rheumatoid pannus erodes cartilage, secondary osteoarthritic changes in bone and cartilage develop. In end stages of degenerative joint disease and RA, the involved joints appear the same. To differentiate clearly between the two, the physician must delve into the early history and functional abnormalities of the disease. Erosive osteoarthritis occurs frequently in middle-aged women (more frequently than in men) and is characterized by inflammatory changes in PIP joints with destruction and functional ankylosis of the joints. The PIP joints can be red and hot, yet there is almost no synovial proliferation or effusion; joint swelling involves hard, bony tissue and not synovium. The ESR may be slightly elevated, but RF is not found (see Chapter 90).143 Parkinson’s Disease (Common) Although the tremor or rigidity of Parkinson’s disease is rarely confused with symptoms of RA, Parkinson’s patients have a predilection for developing swan neck deformities of the hands, a phenomenon generally unappreciated by rheumatologists. This abnormality was first described in 1864,144 and its pathogenesis is still unknown (Fig. 66-14). Pigmented Villonodular Synovitis (Rare) Pigmented villonodular synovitis is a nonmalignant but proliferative disease of synovial tissue that has many functional characteristics similar to those of RA and usually involves only one joint. The histopathologic appearance is characterized by proliferation of histiocytes, multinucleate giant cells, and hemosiderin and lipid-laden macrophages. Clinically, this is a painless chronic synovitis (most often of the knee) with joint effusions and greatly thickened synovium. Subchondral bone cysts and cartilage erosion may be associated with the bulky tissue. It is unclear whether this condition should be classified as an inflammation or a neoplasm of synovium (see Chapter 114). Polychondritis (Uncommon) Polychondritis can mimic infectious processes, vasculitis, granulomatous disease, or RA. Patients with RA and ­ocular inflammation (e.g., scleritis) usually have active joint

Figure 66-14  These swan neck deformities are a result of Parkinson’s disease, not rheumatoid arthritis. (From Ordenstein L: Sur la Paralysie Agitante et la Sclérose en Plaques Generalisée. Paris, Imprimerie de E Martinet, 1864.)

d­ isease before ocular problems develop; the reverse is true in polychondritis. In addition, polychondritis is not associated with RF. The joint disease is usually episodic. Nevertheless, erosions can develop that are similar to erosions of RA. In affected tissues of the external ears, nose, larynx, trachea, and costochondral areas, this disease may represent a true immune response against cartilage (see Chapter 95). Polymyalgia Rheumatica and Giant Cell Arteritis (Common) Although joint radionuclide imaging studies have indicated increased vascular flow in the synovium of patients with classic polymyalgia rheumatica, it is appropriate to exclude polymyalgia rheumatica as a diagnosis if significant synovitis (soft tissue proliferation or effusions) is detected. Otherwise,

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many patients who actually have RA would be diagnosed as having polymyalgia rheumatica and treated inappropriately with glucocorticoids. A careful history usually can differentiate shoulder or hip-girdle muscle pain from shoulder or hip joint pain. Examination of synovial biopsy specimens from patients with polymyalgia rheumatica indicates that the synovitis is usually milder than that found in RA. RA and polymyalgia rheumatica might coexist in some patients, but careful descriptions of such patients are rare. Several patients have been described whose initial symptom of giant cell arteritis was a peripheral polyarthritis clinically indistinguishable from RA.145 In 19 such patients in a group of 522 with biopsy-proven giant cell arteritis, however, only 3 were RF positive. The interval between the onsets of each set of symptoms was 3 years or less in 15 of the 19 patients, which also suggests a relationship between the two (see Chapter 81), and it is known that patients with giant cell arteritis often have HLA-DR4 alleles. Relapsing Seronegative Symmetric Synovitis with Pitting Edema (Uncommon) Relapsing seronegative symmetric synovitis with pitting edema is an uncommon syndrome marked by significant pitting edema of the hands with synovial thickening and joint tenderness. The symptoms rapidly respond to short courses of corticosteroids and can lead to residual abnormalities, including flexion contractures of the wrists and fingers. These patients are RF negative, and there has been a suggestion of increased risk of neoplastic disease. The syndrome might represent a variant of another disease, such as polymyalgia rheumatica or reflex sympathetic dystrophy, rather than a distinct entity.146 Rheumatic Fever (Uncommon) Rheumatic fever is much less common than it once was, but still must be considered in adults with polyarthritis. In adults, arthritis is the most prominent clinical finding of rheumatic fever; carditis is less common than in children; and erythema marginatum, subcutaneous nodules, and chorea are rare. The presentation is often that of an additive, symmetric, large joint polyarthritis (involving lower extremities in 85% of patients), developing within 1 week and associated with a severe tenosynovitis. This extremely painful process is often dramatically responsive to salicylates. In contrast to Still’s disease in adults, rheumatic fever generally has no remittent or quotidian fevers and shows evidence of antecedent streptococcal infection. It also has a less protracted course than Still’s disease. There are many similarities between rheumatic fever in adults and “reactive” postinfectious synovitis developing from Shigella, Salmonella, Brucella, Neisseria, or Yersinia infections. As rheumatic fever becomes less common, and as penicillin prophylaxis effectively prevents recurrence of the disease, Jaccoud’s arthritis (chronic post–rheumatic fever arthritis) is now quite rare. This entity, described by Bywaters in 1950,147 results from severe and repeated bouts of rheumatic fever and synovitis, which stretches joint capsules and produces ulnar deformity of the hands without erosions. The same deformity can develop in SLE characterized by recurrent synovitis and soft tissue inflammation and in Parkinson’s disease. ­Differentiating rheumatic fever from RA is particularly difficult when subcutaneous nodules are present with rheumatic fever.

Sarcoidosis (Uncommon) The two most common forms of sarcoid arthritis often can be easily distinguished from RA. In the acute form with erythema nodosum and hilar adenopathy (Löfgren’s syndrome), the articular complaints usually are related to periarthritis affecting large joints of the lower extremities. Differential diagnosis may be complicated because many of these patients have RF in serum. Joint erosions and proliferative synovitis do not occur in this form of sarcoidosis. In chronic granulomatous sarcoidosis, cystlike areas of bone destruction, mottled rarefaction of bone, and a reticular pattern of bone destruction with a lacelike appearance on radiographs may simulate destructive RA. This form of sarcoidosis is often polyarticular, and biopsy of bone or synovium for diagnosis may be essential because there is often no correlation between joint disease and clinical evidence for sarcoid involvement of other organ systems. Poncet disease (tuberculous rheumatism) might actually represent granulomatous “idiopathic” arthritis (i.e., sarcoidosis) (see Chapter 105).148 Systemic Lupus Erythematosus (Common) The distribution of involved joints and the deformities in SLE can be identical to RA. In contrast to RA, SLE arthritis does not usually cause cartilage destruction or bone erosions. The deformities are often reducible, sometimes leading to normal hand radiographs owing to the effect of placing the hand firmly on the film cassette. Serologies (antinuclear antibody, anti–double-stranded DNA) and major organ system involvement usually can distinguish RA from SLE. Thiemann’s Disease (Rare) Thiemann’s disease is a rare form of idiopathic vascular necrosis of the PIP joints of the hands with occasional involvement of other joints. Bony enlargement begins painlessly, and the digits (one or more may be involved) become fixed in flexion. The primary lesion is in the region of the epiphysis and generally begins before puberty, distinguishing it from erosive osteoarthritis, which it resembles radiographically. It is a heritable disease, but the genetic factors have not been defined. Vasculitis (Common) Patients with a variety of vasculitic syndromes can present with inflammatory arthritis, and these syndromes are readily distinguished from RA. Many small vessel vasculitides show palpable purpura and are associated with hepatitis C and cryoglobulinemia. Medium vessel forms of vasculitis, such as Wegener’s granulomatosis, Churg-Strauss syndrome, or microscopic polyangiitis, include major organ system involvement (e.g., reactive airways disease, glomerulonephritis), and are usually antineutrophil cytoplasmic antibody positive. Polyarteritis nodosa usually is distinguished by renovascular hypertension and other systemic complaints. Systemic rheumatoid vasculitis can be indistinguishable from polyarteritis, necessitating a high index of suspicion.

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Whipple’s Disease (Common) Since the identification of the uncultured bacillus of Whipple’s disease in 1992,149 numerous proven cases of this ­process that resemble adult Still’s disease, in particular, have been described. Eight times as many men as women develop Whipple’s disease. Many have a low-grade, intermittent fever; 80% or more have arthralgias in large joints. Diarrhea, abdominal pain, and weight loss are more common than in Still’s disease, but patients with Whipple’s disease do not have a characteristic skin rash.200

COURSE OF DISEASE Epidemiologists have pointed out the many difficulties in attempting to establish a change in patterns of RA in different time periods or different communities. The best data suggest that the clinical manifestations of disease and the extent of disability are declining. Epidemiologic studies suggest that the disease is not changing, but that earlier, more effective treatment has diminished morbidity. There are now well-tested criteria for clinical remission.150 Definitions vary widely and can mean either absence of clinical and radiologic signs of disease while on treatment or a disease state with minimal or no activity after therapy is withdrawn. One composite system using the Disease Activity Score is a mathematical method that includes swollen and tender joints, ESR, and patient assessments of global health.151 Notably, this criterion does not mean that the patient truly has complete remission without any evidence of synovitis. The American College of Rheumatology criteria require absence of joint tenderness, fatigue, joint pain, joint swelling, and morning stiffness, along with a normal ESR. With an increased number of effective therapies available, it becomes increasingly important for physicians to be able to determine which patients would be most at risk for progressive destructive disease, and which patients would have a more benign illness that is not erosive and responsive to moderate intervention. In addition to predicting which patients may or may not develop erosions, it is equally important to identify which patients who already have erosions are more likely to progress rapidly to joint destruction. One study of an inception cohort of patients newly presenting with inflammatory polyarthritis confirmed the fact that although the initial radiographic score is, as expected, a powerful predictor of subsequent radiographic damage, a high titer of RF and anticitrullinated protein antibodies continue to be powerful predictors of deteriorating radiographic damage in subjects receiving conventional therapy.152 Joint erosions and deformity may not be the most important aspects of disease to the patients. It has been shown in several studies that the Health Assessment Questionnaire is an excellent predictor of work disability and mortality153 and can be discrepant from damage measured by radiographs. MORTALITY In well-established RA, the median life expectancy is less than in control populations.154,155 In one study, a 25-year prospective follow-up of 208 patients, the median life

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expectancy was shortened by 7 years in men and 3 years in women. Infection, renal disease, and respiratory failure traditionally have been the primary factors contributing to excess mortality in RA patients, although it has been belatedly recognized that congestive heart failure, is­chemic heart disease, and peripheral atherosclerosis deserve the appellation as the prime killers of rheumatoid patients. One study published in 1990 revealed that of 100 patients with RA followed for 25 years, 63 had died—an excess mortality of approximately 40%.156 Although it is apparent that disability develops most rapidly during the first 2 years of RA,157 the current focus of interest is on this increased mortality. Careful epidemiologic studies have indicated that, in addition to infection and gastrointestinal hemorrhage secondary to NSAIDs, cardiovascular mortality is increased in RA. In the Norfolk Arthritis Register, a primary care–based inception cohort, patients who were seropositive for RF died within the first 7 years of disease at an excess rate from cardiovascular causes (men 1.34, women 2.02) compared with controls.158 This increased incidence of cardiovascular events in RA patients is independent of traditional risk factors, such as age, sex, smoking status, diabetes mellitus, hypercholesterolemia, systolic blood pressure, and body mass index.159 The generally accepted explanation is that inflammatory cytokines that are produced in excess in RA (e.g., TNF-α, platelet-derived growth factor) have the capacity to activate endothelial and subendothelial myofibroblasts, and numerous inflammatory cells are found in atheromatous plaques. Considering that nonrheumatoid patients who have higher levels of C-reactive protein than control groups have higher incidences of coronary disease, these data are consistent with hypotheses. Ultrasonography has shown that RA patients have greater thickness of the common carotid and femoral arteries than do healthy controls, a finding that was independent of glucocorticoid therapy, but related to the duration and severity of RA.160 Platelet-derived microparticles, the small vesicles that are released from the plasma membrane when these cells are activated, are elevated in RA in proportion to disease activity.161 As noted earlier, the following factors and pathobiologic mechanisms could contribute to atherosclerosis in RA162: • Immune complex–mediated endothelial damage • Acute-phase reactants (C-reactive protein and serum amyloid A, both of which have proinflammatory activity) • Inflammatory cytokines • High expression of endothelial cell leukocyte adhesion molecules • Medications (e.g., steroids) • Prothrombotic factors (e.g., increased platelets, fibrinogen, and thromboxane) • Endothelial cell dysfunction induced by inflammation Considerations of therapy in rheumatoid patients must factor in the effects on atherogenesis. These considerations might include, in patients with an unfavorable vascular profile, supplementation with omega-3 fatty acids in the diet, early use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins that, in addition to lipid-­lowering effects, reduce C-reactive protein), attempts to reduce elevated levels of homocysteine induced by ­ methotrexate,

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avoidance of cyclosporine, and aggressive weight-loss disciplines and smoking cessation. The IL-6 receptor antibody tocilizumab suppresses several risk factors for mortality, including inflammation, elevated ESR, and elevated Creactive protein. It also alters the lipid profile by ­increasing low-density lipoproteins, albeit with a concomitant increase in high density lipoproteins to maintain a similar ratio. The ultimate effects on cardiovascular risk factors and mortality are still uncertain under these circumstances. In addition to cardiovascular causes of death associated with RA are causes of death due to the complications (articular and extra-articular) of RA and to side effects of therapy. The probability of death varies directly with the severity of complications. Potentially morbid articular complications include the various forms of atlantoaxial subluxation, cricoarytenoid synovitis, and sepsis of involved joints. Extraarticular complications directly causing a higher mortality include Felty’s syndrome, Sjögren’s syndrome, pulmonary complications, and diffuse vasculitis. One of the largest and best-documented studies of survival, prognosis, and causes of death in RA was published by Mitchell and associates.163 In this prospective study of 805 patients including 12 years of observation, 233 died during the course of the study; survivorship was only 50% of that in population controls. The increased mortality associated with RA is impressive and equals that of all patients with Hodgkin’s disease, diabetes mellitus, or stroke (age adjusted). In another group of 107 patients followed for 8 years, each of whom had extra-articular disease or needed hospitalization for some aspect of the disease,164 patients with cutaneous ulcers, vasculitic rash, neuropathy, and scleritis had a higher mortality than patients whose disease was confined to joints. Of great concern to all health care workers is the correlation of a lack of formal education with increased mortality in RA.165 One prediction is that tight control of inflammation might decrease the cardiovascular and cerebrovascular events and improve survival. Although the data remain preliminary, it seems that aggressive use of methotrexate can decrease mortality in patients.166 Biologic agents such as TNF inhibitors also seem to improve survival, especially in women.167 TNF blockade exacerbates heart disease, however, and increases mortality in individuals with preexisting congestive heart failure. Longer term studies are required to assess the impact of new agents such as rituximab and abatacept on mortality (see Chapter 59). VARIABLES RELATED TO PROGNOSIS In attempting to sort out the relative roles of disease manifestations, compared with nondisease factors, in generating disability in RA, investigators have generated hypothetical models of the disablement process in RA using the demographic, sociocultural, and clinical characteristics of a consecutive cohort of RA patients.168 Although their methods were unable to explain the dynamics of disability in 41% of cases, disease-related factors explained 33%, and ­nondisease factors (e.g., depression and psychological status, education) accounted for 26% of the disability. Other studies have emphasized the following disease factors that correlate with a poorer prognosis and greater likelihood of joint ­destruction:

• Positive RF in serum169 • Positive anticitrullinated protein in serum • Rheumatoid nodules170 • Elevated Health Assessment Questionnaire level of disability171 • Depression172 • Persistent ESR elevation (serving as a surrogate for disease control) • Presence of the shared epitope (QKRAA) on class II major histocompatibility genes

ASSESSMENT OF THE INDIVIDUAL PATIENT Assessment of disease activity and its progression is different from prognosis. Prognosis extrapolates from a known set of indices (as noted earlier) and the degree of measured activity of disease to a prediction of the outcome. Assessment is the accurate evaluation of disease progression over time. Although the indices listed in the previous section are useful as a way to predict the outcome from one-time measurements, having three or more assessment measures provides the physician with a graph of progression in an individual patient that he or she can try to flatten out by therapy.173 Whatever assessment index is used, it should be used for the first time early in the patient’s disease so that values before a significant loss of function are recorded. For most patients, a self-report questionnaire based on degrees of difficulty in performing activities of daily living correlates well with the joint count, radiographic score, acute-phase reactants, grip strength, walking time, ­functional class estimates, and global self-assessment. One useful selfreport includes only eight items from the much longer Stanford Health Assessment Questionnaire (Table 66-7).174 The limitation of this form—failure to detect clinical improvement in patients with few impairments in activities of daily living—may be offset by its acceptability to patients within busy office practices. In some situations, more comprehensive joint counts are needed. These include points when large changes in drug therapy are about to be instituted, and when patients are to undergo joint reconstruction by orthopaedic or hand surgeons. The Thompson index175 uses a few joints and weights data from each joint to reflect the joint surface area, giving a better measure of the “burden of synovitis.” The choice of imaging techniques and measures is important in the assessment of the destructive lesions of RA. The inflammatory lesion in RA is reflected reasonably well by heat, pain, swelling, and tenderness. Joint destruction can occur with minimal inflammation, however. MRI and ultrasound provide ways to visualize pannus development and the loss of cartilage (see Chapter 53). It is paramount that rheumatologists and radiologists come to a consensus on cost-benefit analyses for MRI. For which patients is it appropriate to order this procedure? In each patient, when the diagnosis of RA is reasonably certain, these measures of assessment and estimates of prognosis should be recorded. They should be major determinants of what therapies are instituted. Therapy is discussed in the following chapter.

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Table 66-7  Activities of Daily Living and Visual Analog Questionnaire A. How often is it PAINFUL for you to: Dress yourself? Get in and out of bed? Lift a cup or glass to your lips? Walk outdoors on flat ground? Wash and dry your entire body? Bend down to pick up clothing   from the floor? Turn faucets on or off? Get in and out of a car?

Never

Sometimes

Most of the Time

Always

_________ _________ _________ _________ _________ _________

__________ __________ __________ __________ __________ __________

____________ ____________ ____________ ____________ ____________ ____________

________ ________ ________ ________ ________ ________

_________ _________

__________ __________

____________ ____________

________ ________

B. How much pain have you had in the PAST WEEK (mark the scale) No pain_____________________________________________________________________________Pain as bad as it could be 0 100 From Callahan LF, Brooks RH, Summey JA, et al: Quantitative pain assessment for routine care of rheumatoid arthritis patients, using a pain scale based on activities of daily living and a visual analog pain scale. Arthritis Rheum 30:630, 1987.

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36. Hastings DE, Evans JA: Rheumatoid wrist deformities and their relation to ulnar drift. J Bone Joint Surg Am 57:930-934, 1975. 37. Trentham DE, Masi AT: Carpometacarpal ratio: A new quantitative measure of radiologic progression of wrist involvement in rheumatoid arthritis. Arthritis Rheum 19:939-944, 1976. 38. Fuchs HA, Callahan LF, Kaye JJ, et al: Radiographic and joint count findings of the hand in rheumatoid arthritis: Related and unrelated findings. Arthritis Rheum 31:44-51, 1988. 39. Brewerton DA: Hand deformities in rheumatoid disease. Ann Rheum Dis 16:183-197, 1957. 40. Abbott GT, Bucknall RC, Whitehouse GH: Osteoarthritis associated with distal interphalangeal joint involvement in rheumatoid arthritis. Skeletal Radiol 20:495-497, 1991. 41. Gray RG, Gottlieb NL: Hand flexor tenosynovitis in rheumatoid arthritis: Prevalence, distribution, and associated rheumatic features. Arthritis Rheum 20:1003-1008, 1977. 42. Hastings DE, Parker SM: Protrusio acetabuli in rheumatoid arthritis. Clin Orthop 108:76-83, 1975. 43. Jayson MIV, Dixon A: Valvular mechanisms in juxta-articular cysts. Ann Rheum Dis 29:415-420, 1970. 44. Hench PK, Reid RT, Reames PM: Dissecting popliteal cyst stimulating thrombophlebitis. Ann Intern Med 64:1259-1264, 1966. 45. Kraag G, Thevathasan EM, Gordon DA, et al: The hemorrhagic crescent sign of acute synovial rupture. Ann Intern Med 85:477-478, 1976 (letter). 46. Rask MR: Achilles tendon rupture owing to rheumatoid disease: Case report with a nine-year follow-up. JAMA 239:435-436, 1978. 47. Bienenstock H: Rheumatoid plantar synovial cysts. Ann Rheum Dis 34:98-99, 1975. 48. Calabro JJ: A critical evaluation of the diagnostic features of the feet in rheumatoid arthritis. Arthritis Rheum 5:19-29, 1962. 49. Halla JT, Schrohenloher RE, Koopman WJ: Local immune responses in certain extra-articular manifestations of rheumatoid arthritis. Ann Rheum Dis 51:698-701, 1992. 50. Turesson C, O’Fallon WM, Crowson CS, et al: Occurrence of extra­ articular disease manifestations is associated with excess mortality in a community based cohort of patients with rheumatoid arthritis. J Rheumatol 29:62-67, 2002. 51. Haugeberg G, Ørstavik RE, Uhlig T: Bone loss in patients with rheumatoid arthritis: Results from a population-based cohort of 366 patients followed up for two years. Arthritis Rheum 46:1720-1728, 2002. 52. Manolagas SC, Weinstein RS: Perspective: New developments in the pathogenesis and treatment of steroid-induced osteoporosis. J Bone Mineral Res 14:1061-1066, 1999. 53. Laan RF, van Riel PL, van de Putte LB, et al: Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid arthritis: A randomized, controlled study. Ann Intern Med 119: 963-968, 1993. 54. Maddison PJ, Bacon PA: Vitamin D deficiency, spontaneous fractures and osteopenia in rheumatoid arthritis. BMJ 4:433-435, 1974. 55. Halla JT, Koopman WJ, Fallahi S, et al: Rheumatoid myositis: Clinical and histologic features and possible pathogenesis. Arthritis Rheum 27:737-743, 1984. 56. Wolf P, Gretler J, Aglas F, et al: Anticardiolipin antibodies in rheumatoid arthritis: Their relation to rheumatoid nodules and cutaneous vascular manifestations. Br J Dermatol 131:48-51, 1994. 57. Jackson CG, Chess RL, Ward JR: A case of rheumatoid nodule formation within the central nervous system and review of the literature. J Rheumatol 11:237-240, 1984. 58. Sokoloff L: The pathophysiology of peripheral blood vessels in collagen diseases. In Orbison JL, Smith DE (eds): The Peripheral Blood Vessels. Baltimore, Williams & Wilkins, 1963, p 297. 59. Palmer DG, Hogg N, Highton J, et al: Macrophage migration and maturation within rheumatoid nodules. Arthritis Rheum 30:728-736, 1987. 60. Edwards JCW, Wilkinson LS, Pitsillides AA: Palisading cells of rheumatoid nodules: Comparison with synovial intimal cells. Ann Rheum Dis 52:801-805, 1993. 61. Harris ED Jr: A collagenolytic system produced by primary cultures of rheumatoid nodule tissue. J Clin Invest 51:2973-2976, 1972. 62. Ginsberg MH, Genant HK, Yu TF, et al: Rheumatoid nodulosis: An unusual variant of rheumatoid disease. Arthritis Rheum 18:49-58, 1975. 63. Baum J: Infection in rheumatoid arthritis. Arthritis Rheum 14: 135-137, 1971.

64. Huskisson EC, Hart FD: Severe, unusual and recurrent infections in rheumatoid arthritis. Ann Rheum Dis 31:118-121, 1972. 65. Singleton JD, West SG, Nordstrom DM: “Pseudoseptic” arthritis complicating rheumatoid arthritis: A report of six cases. J Rheumatol 18:1319-1322, 1991. 66. Doran MF, Crowson CS, Pond GR, et al: Frequency of infection in patients with rheumatoid arthritis compared with controls. Arthritis Rheum 46:2287-2293, 2002. 67. Doran MF, Crowson CS, Pond GR: Predictors of infection in rheumatoid arthritis. Arthritis Rheum 46:2294-2300, 2002. 68. Samet JM: Does idiopathic pulmonary fibrosis increase lung cancer risk? Am J Respir Crit Care Med 161:1-2, 2000. 69. Gridley G, McLaughlin JK, Ekbom A, et al: Incidence of cancer among patients with rheumatoid arthritis. J Natl Cancer Inst 85: 307-311, 1993. 70. Gridley G, Klippel JH, Hoover RN, et al: Incidence of cancer among men with the Felty syndrome. Ann Intern Med 120:35-39, 1994. 71. Ongartz T, Sutton AJ, Sweeting MJ, et al: Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: Systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295:2275-2285, 2006. 72. Stone JH, Holbrook JT, Marriott MA, et al: Wegener’s Granulomatosis Etanercept Trial Research Group. Solid malignancies among patients in the Wegener’s Granulomatosis Etanercept Trial. Arthritis Rheum 54:1608-1618, 2006. 73. Peeters HRM, Jongen-Lavrencic M, Raja AN, et al: Course and characteristics of anaemia in patients with rheumatoid arthritis of recent onset. Ann Rheum Dis 55:162-168, 1996. 74. Vreugdenhil G, Wognum AW, van Eijk HG, et al: Anaemia in rheumatoid arthritis: The role of iron, vitamin B12, and folic acid deficiency, and erythropoietin responsiveness. Ann Rheum Dis 49:93-98, 1990. 75. Williams RA, Samson D, Tikerpae J, et al: In-vitro studies of ineffective erythropoiesis in rheumatoid arthritis. Am J Rheum Dis 41: 502-507, 1982. 76. Reid CD, Prouse PJ, Baptista LC, et al: The mechanism of anaemia in rheumatoid arthritis: Effects of bone marrow adherent cells and of serum on in vivo erythropoiesis. Br J Haematol 58:607-615, 1984. 77. Farr M, Scott DL, Constable TJ, et al: Thrombocytosis of active rheumatoid disease. Ann Rheum Dis 42:545-549, 1983. 78. Bowman SJ, Sivakumaran M, Snowden N, et al: The large granular lymphocyte syndrome with rheumatoid arthritis: Immuno-genetic evidence for a broader definition of Felty’s syndrome. Arthritis Rheum 37:1326-1330, 1994. 79. Combe B, Andary M, Caraux J, et al: Characterization of an expanded subpopulation of large granular lymphocytes in a patient with rheumatoid arthritis. Arthritis Rheum 29:672-679, 1986. 80. McEwen C, Lingg C, Kirsner JB: Arthritis accompanying ulcerative colitis. Am J Med 33:923, 1962. 81. Loughran TP Jr: Clonal diseases of large granular lymphocytes. Blood 82:1-14, 1993. 82. Kelly C, Baird G, Foster H, et al: Prognostic significance of paraproteinaemia in rheumatoid arthritis. Ann Rheum Dis 50:290-294, 1991. 83. Voskuyl AE, Zwinderman AH, Westedt ML, et al: Factors associated with the development of vasculitis in rheumatoid arthritis: Results of a case-control study. Ann Rheum Dis 55:190-192, 1996. 84. Fischer M, Mielke H, Glaefke S, et al: Generalized vasculopathy and finger blood flow abnormalities in rheumatoid arthritis. J Rheumatol 11:33-37, 1984. 85. Soter NA, Mihm MC Jr, Gigli I, et al: Two distinct cellular patterns in cutaneous necrotizing angiitis. J Invest Dermatol 66:344-350, 1976. 86. Mongan ES, Cass RM, Jacox RF, et al: A study of the relation of seronegative and seropositive rheumatoid arthritis to each other and to necrotizing vasculitis. Am J Med 47:23-25, 1969. 87. Weinstein A, Peters K, Brown D, et al: Metabolism of the third component of complement (C3) in patients with rheumatoid arthritis. Arthritis Rheum 15:49-56, 1972. 88. Conn DL, McDuffie FC, Dyck PJ: Immunopathologic study of sural nerves in rheumatoid arthritis. Arthritis Rheum 15:135-143, 1972. 89. Schmid FR, Cooper NS, Ziff M, et al: Arteritis in rheumatoid arthritis. Am J Med 30:56-83, 1961. 90. Geirsson AJ, Sturfelt G, Truedsson L: Clinical and serological features of severe vasculitis in rheumatoid arthritis: Prognostic implications. Ann Rheum Dis 46:727-733, 1987. 91. Voskkuyl AE, Zwinderman AH, Westedt ML, et al: The mortality of rheumatoid vasculitis compared with rheumatoid arthritis. Arthritis Rheum 39:266-271, 1996.

PART 9  92. Dodson WH, Hollingsworth JW: Pleural effusion in rheumatoid arthritis: Impaired transport of glucose. N Engl J Med 275:1337-1342, 1966. 93. Frank ST, Weg JG, Harkleroad LE, et al: Pulmonary dysfunction in rheumatoid disease. Chest 63:27-34, 1973. 94. Tishler M, Grief J, Fireman E, et al: Bronchoalveolar lavage: A sensitive tool for early diagnosis of pulmonary involvement in rheumatoid arthritis. J Rheumatol 13:547-550, 1986. 95. Constantopoulos SH, Tsianos EV, Moutsopoulos HM: Pulmonary and gastrointestinal manifestations of Sjögren’s syndrome. Rheum Dis Clin N Am 18:617-635, 1992. 96. Caplan A: Certain unusual radiographic appearances in the chest of coal miners suffering from RA. Thorax 8:29, 1953. 97. Shenberger KN, Schned AR, Taylor TH: Rheumatoid disease and bronchogenic carcinoma: case report and review of the literature. J Rheumatol 11:226-228, 1984. 98. Dawson JK, Goodson NG, Graham DR, et al: Raised pulmonary artery pressures measured with Doppler echocardiography in rheumatoid arthritis patients. Rheumatology 39:1320-1325, 2000. 99. Radoux V, Menard HA, Begin R, et al: Airways disease in rheumatoid arthritis patients: One element of a general exocrine dysfunction. Arthritis Rheum 30:249-259, 1987. 100. Sassoon CS, McAlpine SW, Tashkin DP, et al: Small airways function in non-smokers with rheumatoid arthritis. Arthritis Rheum 27:1218-1226, 1984. 101. Wislowska M, Sypula S, Kowalik I: Echocardiographic findings and 24-hour electrocardiographic Holter monitoring in patients with nodular and non-nodular rheumatoid arthritis. Rheumatol Int 18:163-169, 1999. 102. Del Rincon I, O’Leary DH, Freeman GL, et al: Acceleration of atherosclerosis during the course of rheumatoid arthritis. Atherosclerosis 195:354-360, 2006. 103. Gerli R, Sherer Y Vaudo G, et al: Early atherosclerosis in rheumatoid arthritis: Effects of smoking on thickness of the carotid artery intima media. Ann N Y Acad Sci 1051:281-290, 2005. 104. Nicola PJ, Crowson CS, Maradit-Kremers H, et al: Contribution of congestive heart failure and ischemic heart disease to excess mortality in rheumatoid arthritis. Arthritis Rheum 54:60-67, 2006. 105. Rexhepaj N, Bajraktari G, Berisha I, et al: Left and right ventricular diastolic functions in patients with rheumatoid arthritis without clinically evident cardiovascular disease. Int J Clin Pract 60:683-688, 2006. 106. MacDonald WJ Jr, Crawford MH, Klippel JH, et al: Echocardiographic assessment of cardiac structure and function in patients with rheumatoid arthritis. Am J Med 63:890-896, 1977. 107. Iveson JM, Thadani U, Ionescu M, et al: Aortic valve incompetence and replacement in rheumatoid arthritis. Ann Rheum Dis 34: 312-320, 1975. 108. Ahern M, Lever JV, Cosh J: Complete heart block in rheumatoid arthritis. Ann Rheum Dis 42:389-397, 1983. 109. Camilleri JP, Douglas-Jones AG, Pritchard MH: Rapidly progressive aortic valve incompetence in a patient with rheumatoid arthritis. Br J Rheumatol 30:379-381, 1991. 110. Hoffman GS: Polyarthritis: The differential diagnosis of rheumatoid arthritis. Semin Arthritis Rheum 8:115-141, 1978. 111. Pinals RS: Polyarthritis and fever. N Engl J Med 330:769-774, 1994. 112. Bywaters EGL: Still’s disease in the adult. Ann Rheum Dis 30: 121-133, 1971. 113. Appenzeller S, Castro GR, Costallat LT: Adult-onset Still disease in southeast Brazil. J Clin Rheumatol 11:76-80, 2005. 114. Van Reeth C, Le Moel G, Lasne Y: Serum ferritin and isoferritins are tools for diagnosis of active adult Still’s disease. J Rheumatol 21: 890-895, 1994. 115. Vignes S, le Moel G, Fautrel B, et al: Percentage of glycosylated serum ferritin remains low throughout the course of adult onset Still’s disease. Ann Rheum Dis 59:347-350, 2000. 116. Yamaguchi M, Ohta A, Tsunematsu T, et al: Preliminary criteria for classification of adult Still’s disease. J Rheumatol 19:424-430, 1992. 117. Elkon KB, Hughes GR, Bywaters EG, et al: Adult-onset Still’s disease: Twenty-year followup and further studies of patients with active disease. Arthritis Rheum 25:647-654, 1982. 118. Cush JJ, Medsger TA Jr, Christy WC, et al: Adult-onset Still’s disease: Clinical course and outcome. Arthritis Rheum 30:186-194, 1987. 119. Pascual V, Allantaz F, Arce E, et al: Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med 201:1479-1486, 2005.

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163. Mitchell DM, Spitz PW, Young DY, et al: Survival, prognosis, and causes of death in rheumatoid arthritis. Arthritis Rheum 29:706-714, 1986. 164. Erhardt CC, Mumford PA, Venables PJ, et al: Factors predicting a poor life prognosis in rheumatoid arthritis: An eight-year prospective study. Ann Rheum Dis 48:7-13, 1989. 165. Pincus T, Callahan LF, Sale WG, et al: Severe functional declines, work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine years. Arthritis Rheum 27: 864-872, 1984. 166. Choi HK, Hernan MA, Seeger JD, et al: Methotrexate and mortality in patients with rheumatoid arthritis: A prospective study. Lancet 359:1173-1177, 2002. 167. Jacobsson LT, Turesson C, Nilsson JA, et al: Treatment with TNFblockers and mortality risk in patients with rheumatoid arthritis. Ann Rheum Dis 66:670-675, 2007. 168. Escalante A, del Rincon I: How much disability in rheumatoid arthritis is explained by rheumatoid arthritis? Arthritis Rheum 42: 1712-1721, 1999. 169. Masi AT, Maldonado-Cocco JA, Kaplan SB, et al: Prospective study of the early course of rheumatoid arthritis in young adults: Comparison of patients with and without rheumatoid factor positivity at entry and identification of variables correlating with outcome. Semin Arthritis Rheum 4:299-326, 1976. 170. Sharp JT, Calkins E, Cohen AS, et al: Observations on the clinical, chemical, and serological manifestations of rheumatoid arthritis, based on the course of 154 cases. Medicine 43:41-58, 1964. 171. Wolfe F, Michaud K, Gefeller O, Choi HK: Predicting mortality in patients with rheumatoid arthritis. Arthritis Rheum. 48:15301542, 2003. 172. Ang DC, Choi H, Kroenke K, et al: Comorbid depression is an independent risk factor for mortality in patients with rheumatoid arthritis. J Rheumatol 32:1013-1019, 2005. 173. Edworthy SM, Bloch DA, Brant RF, et al: Detecting treatment effects in patients with rheumatoid arthritis: The advantage of longitudinal data. J Rheumatol 20:40-44, 1993. 174. Pincus T, Callahan LF, Brooks RH, et al: Self-report questionnaire scores in rheumatoid arthritis compared with traditional physical, radiographic, and laboratory measures. Ann Intern Med 110: 259-266, 1989. 175. Thompson PW, Silman A, Kirwan JR, et al: Articular indices of joint inflammation in rheumatoid arthritis. Arthritis Rheum 30:618-625, 1987.

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Treatment of Rheumatoid Arthritis MARK C. GENOVESE

Key Points The initial approach to treatment of rheumatoid arthritis begins with a diagnosis, estimation of the patient’s prognosis, and the implementation of a therapeutic plan. The physician should employ aggressive treatment with disease-modifying antirheumatic drugs. Combination therapies, particularly using methotrexate as the cornerstone, seem to be the most effective. Biologic agents, particularly when used in combination with methotrexate, offer the greatest ability to slow structural damage. Useful adjuncts to reduce pain and improve function include glucocorticoids, nonsteroidal anti-inflammatory drugs, and physical and occupational therapy. The treatment plan should include patient education. The patient needs to be monitored carefully for the side ­effects of treatment. The ultimate goal is to induce remission; however, practical goals are to prevent structural damage, reduce the signs and symptoms of disease, and improve function.

Since the mid-1990s, there have been major changes in the treatment and management of rheumatoid arthritis (RA). Generally, approaches have been aimed at earlier identification of the disease, earlier intervention with disease-­modifying antirheumatic drugs (DMARDs), aggressive dosing of existing medications, combination therapy, and the introduction of new classes of therapeutic agents such as protein-based biologic therapies. These changes have resulted in significant improvements for patients with RA, including a reduction in the symptoms and signs of disease, joint preservation and a reduction of structural progression, and an improvement in function and quality of life. The evolution of the changes in the approach to treatment is based on the great progress investigators in many laboratories have made in understanding basic mechanisms that underlie the development of RA and its perpetuation within joints and throughout the body. In addition, sound epidemiologic studies have provided useful information on the factors that amplify disease in individuals who have it, and well-planned, double-blind, placebo-controlled clinical trials have provided the evidence-based therapy to help guide physicians. The initial approach to treatment of RA begins with a diagnosis, estimation of the patient’s prognosis, and the implementation of a therapeutic plan. It is never too early

or too late to initiate treatment. This philosophy epitomizes the importance of initiating therapy at any stage of this disease. When a patient has been diagnosed with RA, or at the very least has features of inflammatory arthritis unattributed to other causes, such as infection, malignancy, or metabolic disease, therapy with DMARDs should be initiated with the goals of preventing or controlling joint damage, preventing loss of function, and decreasing pain.1 DMARDs are the fundamental treatment for inflammatory arthritis, and all other therapeutic approaches should be considered adjuncts. Optimal therapeutic plans include more than just DMARD therapy, however. The treatment plan also should include patient education; possible consultation with physical therapists, social workers, and occupational therapists1; and adjunctive therapies, such as nonsteroidal anti­inflammatory drugs (NSAIDs) and glucocorticoids orally (in low dosages), intramuscularly, or intra-articularly.

DISEASE MODIFICATION THERAPY Initiating DMARD therapy is paramount in the treatment of RA. The decision of which DMARD or DMARDs to start is less clear, however. In any given patient, any of the DMARDs can be efficacious and well tolerated, but no one DMARD is efficacious and safe in every patient. Few patients experience remission on any DMARDs, and most experience some sort of side effect from the medications prescribed to treat the disease if treated long enough. The American College of Rheumatology (ACR) treatment guidelines for the management of RA provide an important frame of reference from which to guide therapeutic decision making.1 The ACR treatment guidelines call for a comprehensive approach to the patient with involvement of the primary care provider and the rheumatologist, and provide a general guideline for starting, changing, or adding DMARDs to the treatment of a patient with active disease (Fig. 67-1). DMARD therapy generally begins with the initiation of therapy with the traditional small molecules, such as methotrexate (MTX), hydroxychloroquine (HCQ), or sulfasalazine (SSZ) (see Chapter 56). These agents are of proven benefit, are generally well tolerated with well-known sideeffect profiles, and can be prescribed at a reasonable cost (Table 67-1). Of the three agents, MTX is the most commonly prescribed DMARD. After initiating a DMARD, patients need to be re-evaluated periodically with a goal of strict control of disease activity and monitored for potential side effects from the medications being used. Although other small molecule treatments exist (e.g., azathioprine, gold salts, penicillamine, cyclosporine) (see Chapter 57), these agents are used infrequently and usually 1119

1120

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Treatment of Rheumatoid Arthritis ACR TREATMENT ALGORITHM

Primary care physician

Rheumatologist

* Establish diagnosis of rheumatoid arthritis early * Document baseline disease activity and damage * Estimate prognosis Initiate therapy * Patient education * Start DMARD(s) within 3 months * Consider NSAID * Consider local or low-dose systemic steroids * Physical therapy/occupational therapy Periodically assess disease activity

Inadequate response (i.e., ongoing active disease after 3 months of maximum therapy)

Adequate response with decreased disease activity

Change/add DMARDs Suboptimal MTX response

MTX naive MTX

Other Combination mono rx rx

Combination rx

Other Biologics mono rx Mono rx

Combination rx

Multiple DMARD failure Symptomatic and/or structural joint damage Surgery Figure 67-1  A general guide from the American College of Rheumatology (ACR) for the physician after making a diagnosis of rheumatoid arthritis.  The general theme of this guideline is adding multiple drugs to basic general care until the disease has been brought under control. Although methotrexate (MTX) has become the mainstay of therapy in rheumatoid arthritis, numerous drugs can be used individually (mono rx) or more commonly added in combination (combination rx) to result in significant improvement. DMARD, disease-modifying antirheumatic drug; NSAID, nonsteroidal antiinflammatory drug. (From ACR: Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum 46:328-346, 2002.)

reserved for patients refractory to other therapy or with idiosyncratic side effects with the other agents. After consideration has been given to the use of these traditional small molecule therapies, the practitioner must take stock of the growing efficacy and safety data in the support of the newer generation DMARDs such as leflunomide (see Chapter 56); the tumor necrosis factor (TNF) inhibitors adalimumab, etanercept, and infliximab (see Chapter 58); the interleukin (IL)-1 receptor antagonist anakinra (see Chapter 58); the selective costimulation modulator abatacept (see Chapter 59); and the B cell–targeted approach using rituximab (RTX) (see Chapter 59). These agents have been well studied in clinical trials showing efficacy alone or in combination with traditional therapies. The ability of these agents to slow radiographic progression of disease and restore function seems to be at least equal to, and in some cases greater than, that seen with traditional therapies.

INDIVIDUAL DISEASE-MODIFYING ANTIRHEUMATIC DRUGS HYDROXYCHLOROQUINE HCQ is a logical consideration as an agent in patients with mild disease, or as an adjunct to other DMARDs as part of a combination approach in patients with more aggressive disease. There are few side effects, and approximately 40% of patients receive measurable benefit. In the United States, HCQ is used more often than its cousin, chloroquine. When employing dosing schedules not exceeding 400 mg of HCQ each day, few cases of true retinopathy causing visual loss have been reported in the past,2 providing a measure of reassurance to clinicians about its safety. It has been hypothesized that these antimalarial agents inhibit antigen processing and presentation, leading to downregulation of the CD4+ response in sites of immune damage.3

PART 9 

Table 67-1  Average Wholesale Prices of Therapy* Medication

Cost Per Unit

Disease-Modifying Antirheumatic Drugs Methotrexate 2.5-mg tab Hydroxychloroquine 200-mg tab Leflunomide   10-mg tab   20-mg tab Sulfasalazine   500-mg tablet   500 mg EC tablet

$0.30 $1.10 $17.52 $17.52 $0.13 $0.38

Biologic Agents Etanercept   25-mg vial   50-mg vial Adalimumab 40-mg syringe Infliximab 100-mg vial Abatacept 250-mg vial Rituximab   100-mg vial   500-mg vial Anakinra 100-mg syringe

$179.96 $359.93 $719.86 $662.68 $562.50 $567.99 $2839.85 $48.16

*Based on the average wholesale price in 2006 Redbook.

It also has been shown that HCQ increases apoptosis of rheumatoid synoviocytes.4 HCQ has been found to have equal efficacy to SSZ,5 and as a single agent it was no less effective than the combination of SSZ and HCQ. Strong evidence supporting its utility in early and in mild disease comes from the Hydroxychloroquine in Early Rheumatoid Arthritis (HERA) trial,6 in which patients with RA were randomly assigned to receive either HCQ or placebo over 36 weeks. At the conclusion of the study, patients who had received HCQ had improvements in joint findings, pain, and physical function superior to what was seen in the placebo group. After 3 years of follow-up of the original cohorts, the patients who had previously been treated in the HCQ arm of the study continued to have significantly less pain and disability compared with patients who had DMARD therapy delayed for 9 months (the placebo arm). These results could not be explained based on differences in glucocorticoid, DMARD, or nonsteroidal anti-inflammatory drug (NSAID) use after the trial and were attributed to a delay in the introduction of therapy.7 To date, there are no convincing data on the ability of HCQ to slow radiographic progression, and for patients with active, progressing disease, HCQ would be inadequate as monotherapy. Generally, the mild benefits and the lack of toxicity make HCQ a reasonable agent in early or mild disease, or as an adjunct to other DMARDs in combination therapy. SULFASALAZINE SSZ is another DMARD alternative in the treatment of RA (see Chapter 56). In 1942, Svartz8 reported, in uncontrolled studies, the benefits of SSZ, which she synthesized from salicylic acid and a sulfonamide.8 The drug was first used by gastroenterologists for treatment of inflammatory bowel disease. The drug is generally thought to be efficacious for the treatment of RA in doses of 2000 to 3000 mg/day. Although allergic reactions and rashes can occur, gastrointestinal

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complaints tend to be more common; these potentially can be lessened through the use of enteric-coated preparations. Several studies have established the efficacy of SSZ in RA.9-11 In early RA, investigators showed that SSZ was superior to placebo in reducing inflammation and clinical disease activity.9 In a double-blind, randomized trial of 60 patients with RA who had not previously been treated with DMARDs, investigators showed that patients randomly assigned to receive SSZ had significantly less evidence of radiographic progression than did patients treated with HCQ. This difference became apparent at 24 weeks in even this small study, which suggested the possible superiority of SSZ to HCQ as a DMARD.10 A study comparing SSZ with leflunomide showed further the utility of SSZ in the treatment of RA.11 In this doubleblind, placebo-controlled study, patients were treated with leflunomide, SSZ, or placebo, and ACR-20 response rates were seen at 24 weeks in 49% (leflunomide), 45% (SSZ), and 29% (placebo) of patients. Leflunomide and SSZ were statistically better than placebo in reducing symptoms and signs of disease. Leflunomide and SSZ were significantly better than placebo at slowing radiographic progression of disease. Beyond its role early in disease, or in the treatment of mildto-moderate disease, is the potential role of SSZ in combination therapy. This therapy seems to be efficacious and well tolerated in combination with MTX and HCQ.12-14 METHOTREXATE The question for rheumatologists generally is not whether to use MTX, but rather, in a given patient, whether there are any reasons not to use it. Beginning with uncontrolled trials in the 1970s, and borrowed by rheumatologists from the dermatologists, there has been a gradual increase in acceptance of MTX as the preferred DMARD in the treatment of RA (see Chapter 56). Many factors, now well documented, support this strategy, as follows: • MTX acts quickly after being started, often within several weeks of the once-weekly dosing schedule. • Doses can be escalated over time, from the initial levels of approximately 7.5 mg once weekly to more than 25 mg weekly (often given subcutaneously), to achieve efficacy without parallel increases in toxicity. • MTX is inexpensive (see Table 67-1), and the monitoring necessary for toxicity is less expensive than for gold, penicillamine, other immunosuppressive agents, or cytotoxic drugs. • MTX can suppress disease activity in a significant proportion of patients with long-standing RA in whom other traditional therapies have failed.15 • MTX is well tolerated with more patients likely to be taking MTX than any other nonbiologic DMARD therapy 2 to 5 years after it is first prescribed.16 • In addition to providing efficacy in clinical parameters, MTX slows structural damage.17-20 • Using MTX as a building block or the cornerstone of combination therapy has resulted in enhanced efficacy over MTX alone, without added increases in side ­effects.13,14,21-26 • There have been minimal unexpected side effects ­after more than 20 years of surveillance.

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In early RA, after 24 months of continued use, MTX is almost as effective as etanercept.19,20 In other studies versus biologic agents in early disease, MTX is almost as effective as adalimumab or the combination of MTX and infliximab.25,26 For patients with disease of longer duration, MTX seemed to be equally as effective as leflunomide in headto-head studies.27,28 As a practical matter, it seems that the dose of MTX can be rapidly escalated. Rapid dose escalation from 7.5 mg/wk to 20 mg/wk orally over 8 weeks has become the standard regimen for initiating therapy in early RA trials.19,20,25,26 This rapid dose escalation is generally well tolerated and has been shown to lead to rapid and sustained benefits in patients receiving MTX.19,20,25,26 Patients on MTX with persistent disease should have their dose titrated higher (either rapidly or in the more traditional 2.5-mg increments) until they improve, develop side effects, or reach the 20-mg to 25-mg threshold. For patients unable to tolerate oral MTX, it is reasonable to consider changing to a subcutaneous or intramuscular injection once per week to limit some of the gastrointestinal side effects. Another alternative would be to use folic acid daily or folinic acid weekly as a means to reduce some of the side effects of the medication. Many studies, including one meta-analysis,29 have reinforced the evidence that folic acid and folinic acid reduce the nausea and mucous membrane ulcerations that are bothersome side effects of the drug; administration of 5 mg of folic acid once weekly seems to be sufficient, although many physicians prescribe 1 mg daily. Another reason to use folic acid in MTX-treated patients is for its effectiveness in reducing plasma homocysteine levels30; hyperhomocysteinemia is an independent risk factor for coronary artery disease, presumably mediated by a toxic effect on the endothelium. Concerns by rheumatologists about liver toxicity of longterm MTX therapy have gradually diminished. Although the ACR guidelines for MTX use31 are appropriate to follow, it is generally accepted that in patients with normal liver function, minimal use of alcohol, and negative serologies for hepatitis B and C, liver function tests are necessary only once every 4 to 8 weeks. Routine biopsies of the liver, even after many years of continuous therapy, are not required as long as patients are appropriately monitored. If liver function tests suggest hepatocellular inflammation and a decreasing serum albumin despite improvement in the clinical activity of disease, biopsies should be considered if the drug is to be continued. The other organ threatened by MTX, more in an idiosyncratic or hypersensitivity pattern than liver toxicity, has been the lungs.32 Reasonable criteria for the diagnosis of MTX-associated pneumonitis are summarized in Chapter 56. The pathology shows interstitial pneumonitis and bronchiolitis. Initial symptoms are often vague and nonspecific—a cough, sometimes with fever and dyspnea. While anticipating such a complication, the physician also must be concerned about and rule out infection with opportunistic organisms. Patients started on MTX must be given guidance and reminded to report any upper respiratory symptoms to the physician. It also is important to acknowledge that patients with RA are at increased risk for the development of malignancy. Although rare, lymphomas have been associated with the use

of MTX, particularly in association with Epstein-Barr virus infection. This topic is discussed further in Chapter 112. LEFLUNOMIDE The role of leflunomide in the treatment of RA continues to evolve. It seems to be effective as a monotherapy and safe and effective as an addition to MTX in combination therapy. Leflunomide suppresses the de novo synthesis of pyrimidine (uridine and cytidine) nucleotides by inhibiting dihydroorotate dehydrogenase. T lymphocytes and B lymphocytes have low amounts of this enzyme and no salvage pathways for pyrimidine nucleotide synthesis. The action of leflunomide is specific for lymphocytes (see ­Chapter 56).33 In a trial of leflunomide versus MTX versus placebo, the number of patients achieving an ACR-20 response over the 52-week study was 52% with leflunomide, 46% with MTX, and 26% with placebo.27 Progression of joint erosions was at a rate significantly slower for leflunomide and MTX than in the placebo group. Assays of quality of life using several instruments, such as the Health Assessment Questionnaire (HAQ),34 were slightly better for leflunomide than MTX, and both were substantially better than placebo. Regarding adverse events, diarrhea was more common in leflunomide-treated patients, but others were the same as for MTX, including sporadic elevations of parenchymal liver enzymes. A second multicenter phase III study compared leflunomide head to head with MTX.28 In this study of 999 patients with RA, both agents showed substantial abilities to improve the symptoms and signs of disease. The improvements seen with MTX at 52 weeks were greater, however, than the improvements with leflunomide. Both drugs were well tolerated, and both led to inhibition of radiographic progression as assessed by radiographs. A third phase III, double-blind, randomized, multicenter trial of leflunomide, placebo, and SSZ in active RA (358 patients) showed that leflunomide was more effective than placebo in treatment, but no more effective than SSZ.11 Leflunomide is effective as monotherapy and has the ability to slow the radiographic progression of RA.35 It is reasonable, however, to consider using leflunomide as an add-on to MTX for patients who have only a partial response to MTX. Starting with 10 mg of leflunomide daily after a loading dose smaller than usual (e.g., 100 mg for the first 2 days) is a reasonable strategy.23 Based on the results of a 24-week, 263-patient multicenter study, the addition of leflunomide to MTX resulted in 46% of patients achieving an ACR-20 compared with only 24% who had placebo added to background MTX.23 The rates of liver function test abnormalities, diarrhea, rash, and alopecia all were similar to what had been seen in the prior phase III studies. Leflunomide has an extended plasma half-life of 15 to 18 days because it binds to plasma proteins; this has led to the recommendation that it be given as a loading dose (100 mg/day for 3 days), followed by doses of 20 mg/day. The extended plasma half-life also means, however, that if a patient has an adverse gastrointestinal event (e.g., nausea, diarrhea) during or after the loading schedule, it may take some time for the symptoms to subside. Alternative dosage schedules have evolved with time and experience with the

PART 9 

drug, including the attenuated loading regimen and daily therapy used in the combination trial (100 mg/day for 2 days, then 10 mg/day).23 Completely avoiding the loading dose also may decrease the likelihood of side effects in some patients, but not negatively affect the efficacy of the drug in the long-term. In one of the first randomized, placebo-controlled (phase II) studies, leflunomide was more effective than placebo, and it was almost as effective as a 10-mg daily dose as it was as a 20-mg daily dose.36 The higher dose had disproportionately more skin rash/allergic reactions, gastrointestinal symptoms, weight loss, and reversible alopecia than the 10-mg daily dose. It is reasonable to try the 10-mg daily dose initially, with subsequent escalation to a 20-mg daily dose after safety has been established, or after the patient has failed to achieve adequate response. Maintenance therapy of 10 mg rather than 20 mg daily, or 20 mg every other day because of the long biologic half-life, can be beneficial for some patients. It has been recommended that if serum aspartate transaminase or alanine transaminase increases to twice the upper limits of normal, or if these values are repeatedly mildly abnormal, the leflunomide dose should be reduced and discontinued if these abnormalities persist. Generally, it is prudent to consider following the same guidelines for monitoring leflunomide that are applied to MTX,31 including warnings for patients regarding alcohol intake and screening for preexisting hepatitis B and C. Leflunomide can be used anywhere in the treatment algorithm, but generally has been given most commonly to patients instead of MTX when the latter drug is poorly tolerated or contraindicated. It also can be used in combination with MTX in resistant active arthritis. MINOCYCLINE AND DOXYCYCLINE Tetracycline derivatives have a capacity to inhibit biosynthesis and activity of matrix metalloproteinases that have a principal role in degrading articular cartilage in RA. The presumed mechanism is through chelation of calcium and zinc molecules, which subsequently leads to altered molecular conformations of proenzymes sufficiently to inactive them.37,38 Minocycline has mild but definite inhibitory effects on synovial T cell proliferation and cytokine production. Given in a dose of 100 mg daily, moderate improvement in clinical parameters of disease activity was found in patients treated with minocycline more often than in patients given placebo.39,40 A study of 46 patients with early RA who had not received systemic glucocorticoids or second-line drugs reported 65% of patients meeting 50% improvement in tender and swollen joints, duration of morning stiffness, and erythrocyte sedimentation rate (ESR),41 whereas only 13% of the placebo recipients improved similarly over a 6-month period. In 2001, the results of a 2-year trial comparing minocycline with HCQ were published.42 In this small study of patients with early RA, the patients treated with minocycline were more likely to achieve a 50% improvement than the patients treated with HCQ (60% versus 33%). This study reconfirms the potential utility of minocycline, particularly in early disease. Although the doses used in the previously described studies do not differ from the doses for patients given

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t­ etracyclines for acne, some bothersome side effects have been noted, including light-headed feelings, vertigo, and, rarely, liver toxicity. More worrisome have been reports of patients who are taking tetracycline derivatives who develop lupus-like syndromes, complete with autoantibodies. Mino­ cycline-induced autoimmune syndrome is characterized by reversible polyarthralgia or arthritis, morning stiffness, fever, frequent skin involvement, occasional chronic active hepatitis, positive tests for antinuclear antibodies, and increased titers of perinuclear antineutrophil cytoplasmic antigen.43 With proper warning to patients and careful monitoring, however, minocycline seems to be an appropriate drug for use in patients with early synovitis. Although less studied, there is evidence supporting the use of doxycycline in the treatment of RA. In a trial of patients with early RA, doxycycline plus MTX was compared with the use of MTX alone. Investigators studied low-dose doxycycline (20 mg twice a day) and high-dose doxycycline (100 mg twice a day) in combination with MTX and found that both approaches were superior to MTX alone.44 Despite the positive results of this study, it was small in number, and the MTX dose was escalated very slowly. It would be important to see these results replicated over time. GOLD SALTS, PENICILLAMINE, AND AZATHIOPRINE Three other secondary choices, some of which can be used in combinations with primary choices in active synovitis, are gold salts, penicillamine, and azathioprine. These agents generally would not be favored in early disease and have now been relegated to a role as agents used when other therapies have failed for either lack of efficacy or side effects. There is ample published evidence that intramuscular gold therapy is beneficial for RA. Early use of gold salt injections may retard progression of joint erosions.45 In a 48-week, placebo-controlled trial, the addition of intramuscular gold salts to patients with active disease despite the use of MTX resulted in 61% of patients achieving an ACR-20 compared with 30% of patients randomly assigned to placebo, suggesting the effectiveness of the combination of MTX and gold salts.46 Despite the known benefits, there also is ample evidence that the two intramuscular compounds, gold sodium thiomalate and gold sodium thioglucose, are being used less by rheumatologists because of the need for meticulous monitoring for serious toxicity (e.g., cytopenias, proteinuria) and the costs of administration and monitoring. HLA-DR3 is found in more patients who develop either thrombocytopenia or nephropathy while taking gold injections.47 These data must be balanced against the evidence that HLA-DR3 may be associated with a better response to gold therapy. Auranofin, the triethylphosphine gold compound taken by mouth, has been available since the mid-1980s and continues to search for its niche in treatment strategies. Several issues are clear. Auranofin has different and less severe toxicity than the intramuscular preparations. Cytopenia and proteinuria do not occur, but a bothersome mild enterocolitis that generates diarrhea leads to treatment failure in many cases. Auranofin is less efficacious than MTX, injectable gold, penicillamine, or SSZ.48 The efficacy of auranofin, although less than the more potent drugs, has been shown,49

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Treatment of Rheumatoid Arthritis

and there is justification for combining it with HCQ, SSZ, or MTX in treating early stages of active synovitis. Azathioprine, in doses of 1 to 2.5 mg/kg/day, has been used alone and in combination in RA, often as a “steroidsparing agent.” Neutropenia is the most common complication. One factor that leads to early toxicity from azathioprine is heterozygosity for mutant thiopurine methyltransferase alleles. Patients who have this defect (perhaps 10% of the population is at risk) metabolize the drug poorly and are forced to discontinue azathioprine therapy within 1 month because of hematologic side effects.50 Although unproved, this subset of patients could be the patients who, when azathioprine was added to a stable MTX regimen, developed an acute febrile toxic reaction characterized by fever, leukocytosis, and a cutaneous leukocytoclastic vasculitis.51 Initially used with apparent success, penicillamine was found to cause a selective decrease in CD4+ helper T cells. Although the “go low, go slow” sequence of starting with 125 or 250 mg/day and keeping doses no higher than 750 mg/day resulted in diminished toxicity, there have been sufficient side effects in many patients to discourage the routine use of penicillamine. Perhaps because of genetic differences among patients, the drug has been used with more apparent success and definite enthusiasm in the United Kingdom and Europe. In one study, 5 years in duration, 53% of patients remained on penicillamine, whereas only 34% remained on gold salts, 31% remained on auranofin, and 30% remained on HCQ.52 CYCLOSPORINE Cyclosporine, used by transplantation immunologists for many years to reduce solid organ allograft rejection, inhibits the activation of CD4+ helper-inducer T lymphocytes by blocking IL-2 and other T helper type 1 cytokine production,53 and by inhibiting CD40 ligand expression in T lymphocytes.54 The latter effect prevents T cells from delivering CD40 ligand–dependent signals to B cells. Newer microemulsion forms of cyclosporine are absorbed better and more consistently than older oil-based formulations. Cyclosporine was first used in Europe in doses (e.g., 10 mg/kg/day) that caused unacceptable declines in renal function. Adding lower doses (2.5 to 5 mg/kg/day) to a stable dose of MTX and decreasing the cyclosporine if the patient’s creatinine level increases to more than 30% of initial values have been shown to provide substantial additive benefit over MTX alone.55 Thirty-six patients (48%) of the cyclosporine/MTX group and 12 patients (16%) of the MTX-alone group achieved 20% improvement according to the ACR criteria. No unacceptable toxicity was observed during an open label extension of the study for 1 year,56 and similar to several of the other recommended regimens, this therapy seemed to slow radiographic progression of erosions.57 There is little to be gained by using cyclosporine as monotherapy early in disease, but in patients with RA who have an insufficient response to MTX, cyclosporine is a reasonable alternative to be added. TACROLIMUS Similar to cyclosporine, tacrolimus (FK506) has specific effects limited to inhibiting CD4+ T cell function. The adverse effects of tacrolimus are dose related and similar to

cyclosporine. Tacrolimus is not absorbed as readily or consistently as is the microemulsion formulation of cyclosporine. It can be useful in patients for whom cyclosporine is inappropriate, but for whom T cell suppression is desired. It has been shown that some patients who have failed MTX treatment can respond to carefully dose-adjusted tacrolimus.58 In a large phase III study, 464 patients with active RA were randomly assigned to receive placebo, 2 mg/day of tacrolimus, or 3 mg/day of tacrolimus. At 6 months, the results were disappointing with ACR-20 responses of 10.2%, 18.8%, and 26.8% for each of the treatment groups. Greater than 20% of patients in the tacrolimus arms experienced an increase in serum creatinine of 40% or more at some point in the trial, suggesting that careful monitoring is necessary, and that the risks may not be worth the modest benefits.59

TREATMENT STRATEGIES The question of when to change or to add DMARD therapies in the treatment regimen is a difficult one, and in many cases it can be a matter of individual style. In some cases, it can be a socioeconomic decision, however, based on the costs of therapies (see Table 67-1). In some situations, use of newer DMARDs or biologic agents may be limited by thirdparty payers, and in most circumstances, they are allowed only after failure of one or more of the standard agents. When initiating DMARD therapy, most patients are started on traditional small molecules, as outlined earlier, initially as monotherapy or used together in combinations. Data suggest that when given as monotherapy, these agents can be safe and effective. When an approach of careful monitoring and tight control is used, significant results can be obtained even with traditional compounds. Investigators in the United Kingdom randomly assigned patients with RA of less than 5 years’ duration to receive intensive outpatient monitoring with a goal of sustained tight control of disease.60 Patients randomly assigned to intensive control were seen monthly; their disease activity was carefully measured; and if their disease was active, they were offered joint injection with glucocorticoids, and their DMARDs were algorithmically escalated from monotherapy to combination therapy (step-up therapy). The patients in the intensive treatment group had greater improvement in most disease activity variables, including radiographic disease progression, showing that intensive outpatient monitoring with a goal of sustained tight control resulted in better outcomes than when patients are treated with routine care (Fig. 67-2).60 Over time, numerous different approaches to DMARD use have materialized, including sequential monotherapy, step-up combination approaches, initial combination therapy, and step-down combination approaches. Each approach has its own merits and is examined more fully subsequently. The ACR guidelines for the management of RA call for a comprehensive approach to the patient, but rely on DMARDs to result in disease modification. The traditional approach has called for sequential monotherapy, reassessment of disease, and change to an alternative DMARD if the patient has inadequate benefit or has adverse side effects. This type of approach was modified further into the “sawtooth” strategy. This approach advocated early DMARD initiation with continual serial use and careful quantitative monitoring of disability. When a patient’s

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RHEUMATOID ARTHRITIS

1125

100

6 Patients with good responses (%)

Intensive Routine

5 Disease activity score

| 

4

3 2

All three drugs

90 80 70

Sulfasalazine and hydroxychloroquine

60 50 40 30

Methotrexate

20 P = 0.003 by log-rank test

10

1

0 0 0

3

6

9 Month

12

15

18

Figure 67-2  The difference in disease activity between patients ­treated with intensive tight control of rheumatoid arthritis versus patients ­treated with routine care. (Adapted with permission from Grigor C, Capell H, Stirling A, et al: Effect of a treatment strategy of tight control for ­rheumatoid arthritis (the TICORA study): A single-blind randomised controlled trial. Lancet 364:263-269, 2004.)

disability worsens, there is a sequential change in DMARD therapy in an attempt to decrease disability to prior levels if possible.61 This strategy has merit because it offers the potential for long-term disease modification, careful monitoring, and a reliance on DMARD approaches over that of analgesics and NSAIDs. This approach has been modified further to include combination approaches as increasing data continue to support the superiority of combinations over sequential monotherapy.

STEPPING AWAY FROM SEQUENTIAL MONOTHERAPY Another element in the evolving optimism about treatment of RA has been the use of multiple agents in combination therapy, many of which are aimed at a different segment of the pathophysiologic processes within the synovium. Beginning with uncontrolled, but encouraging, results using combination therapy in the early 1980s,62 it has been shown that a combination of disease-modifying drugs provides additive, perhaps synergistic, benefit to patients without increasing toxicity. Considerable data suggest that many therapies can be used in combination safely and efficaciously. In most cases, MTX has served as the building block on which combination therapy is based.63,64 Drugs that have shown benefit when combined with MTX include HCQ, SSZ, cyclosporine, leflunomide, anakinra, adalimumab, etanercept, infliximab, abatacept, and rituximab (RTX). As illustrated earlier, the traditional approach to the management of RA has evolved from a step-up treatment with sequential monotherapy to a step-up combination approach, where initial treatment with MTX is supplemented with a combination of DMARD interventions in patients with an inadequate response. This has become a favored approach among many rheumatologists. Other combination strategies have proved efficacious as well.

0

6

Number of patients Methotrexate Sulfasalazine and hydroxychloroquine All three drugs

12 Month

18

24

36 35

34 31

20 19

14 15

12 14

31

29

27

25

24

Figure 67-3  The benefits of triple therapy over individual therapy  with methotrexate or the combination of sulfasalazine and hydroxychloroquine. (Adapted from O’Dell JR, Haire CE, Erikson N, et al: ­Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxy­ chloroquine, or a combination of all three medications. N Engl J Med 334:

The initial use of combinations of DMARDs has significant merit and differs from the step-up approach in that combinations are used initially, rather than waiting for an inadequate response to one or more agents before adding additional agents to the regimen. Supporting this approach to combination therapy are data that “triple therapy”— MTX, SSZ, and HCQ—has been found to be more effective than MTX alone.13 In a well-done trial, 77% of patients with active RA had a significant improvement on triple therapy compared with 33% of patients started on MTX alone over a 2-year period (Fig. 67-3).13 A follow-up study to this one showed that the combination of all three agents was superior to MTX plus SSZ or MTX plus HCQ.65 The FIN-RACo trial looked further at monotherapy versus combination therapy and showed the utility, if not superiority, of the combination approach over that of monotherapy with traditional DMARD therapy.14,66 Investigators sought to show that the combination approach with MTX, SSZ, HCQ, and prednisolone would have greater efficacy and tolerability than a single DMARD with or without prednisolone in the treatment of early RA. Ninetyseven patients were treated with combination therapy, and 98 patients were treated with a single DMARD. The primary outcome of the study was the induction of remission. At the end of 1 year, 24 of 97 patients in the combination arm met the definition of remission compared with 11 of 98 in the single DMARD arm. At 2 years, the remission rate was twice as high in the combination approach with a similar frequency of adverse events seen in both arms. A further approach to combination therapy was first proposed by Wilske and Healey in 1989.67 These authors proposed the “step-down bridge” approach, which advocated

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initial use of prednisone for the first month, a combination of DMARDs, and then an attempt to taper the multiple DMARDs to a single agent. This approach did not become more mainstream, however, until 1997 and the publication of the COBRA trial.12 In the COBRA trial, patients were randomly assigned to receive monotherapy with SSZ or combination therapy in a step-down approach with SSZ, MTX, and high-dose glucocorticoids (Fig. 67-4). At the end of 28 weeks, there seemed to be a significant advantage for the use of the step-down combination therapy based on clinical response, and at 1 year, there also was less radiographic progression in the combination group than seen in the monotherapy group.12 Perhaps of even greater interest is the 4-year follow-up data from this cohort. The patients who had been treated with the initial 6-month cycle of intensive combination treatment had a sustained suppression of the rate of radiographic progression independent of subsequent antirheumatic therapy. The patients initially treated with monotherapy had a change in Sharp score of 8.6 units/yr, whereas the patients on the combination regimen progressed at only 5.6 units/yr.68 Initial combination therapy may offer longer term benefits regardless of what type of therapy or intervention is used in the future. Perhaps the best attempt to establish the ideal algorithmic approach to the treatment of RA was done in the BeST trial.69 In this study, patients were randomly assigned to one

Pooled index

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Figure 67-4  The benefits of step-down combination therapy over individual therapy with sulfasalazine. (Adapted from Boers M, Verhoeven AC, Markusse HM, et al: Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 350:309-318, 1997.)

of four treatment strategies: monotherapy, step-up combination with traditional DMARD therapy, step-down therapy with initial combination therapy with tapered high-dose prednisone, or initial combination therapy with MTX and a TNF inhibitor (infliximab). These patients were monitored carefully with therapeutic adjustments made every 3 months. Ultimately, all the treatment approaches proved effective. Early functional benefit at 3 months was greater in the stepdown (group 3) and the MTX-infliximab (group 4) arms. This finding should not be surprising given the high doses of steroids used in group 3, and this should not be a surprising result for group 4 because this group received intensive initial therapy with MTX (25 to 30 mg/wk) in addition to infliximab, which is known to have a rapid onset of action. At 1 year, there were still functional advantages seen in groups 3 and 4, but less impressive differences seen between groups based on the ACR-20 response and the Disease Activity Score (DAS) (Fig. 67-5). Most notable were the differences seen in radiographic progression at 1 year, with median increases in radiographic scores being 2, 2.5, 1, and 0.5 in groups 1, 2, 3, and 4 (Fig. 67-6).69 No significant differences were seen in adverse events or attrition in the different groups. Although some of the approaches may be more or less favored in different regions of the world, any of these approaches can be effective in a given patient. This study does support the conclusion, however, that initial combination therapy resulted in earlier functional improvements and less structural damage than did sequential monotherapy or step-up combination therapy. It also suggests potential advantages with the use of biologic therapy, especially combined with MTX.

BIOLOGIC DISEASE-MODIFYING ANTIRHEUMATIC DRUGS Since the late 1990s, increasing emphasis has been placed on the use of biologic agents combined with small ­molecule agents such as MTX. These combinations have proved effective in the treatment of patients with severe or long-standing disease and have proved their ability to slow or prevent radiographic progression of disease.21,22,70,71 As a class, the most effective of biologic approaches to date has been the combination of TNF antagonists (e.g., adalimumab, etanercept, and infliximab) with MTX. In refractory disease, the addition of adalimumab, etanercept, or infliximab to MTX treatment provides additional benefit to patients with persistent active disease.21,22,24 With all three of the available TNF inhibitors, trials have shown that more than 50% to 70% of the patients had at least a 20% response, and more than 40% of patients had a 50% improvement, as measured by the ACR criteria.72,73 Although each of the cohorts studied in these trials was slightly different, no significant side effects were apparent in the combination arms above and beyond what was seen in the MTX-only arms of the studies, suggesting a good safety profile and strong benefit-to-risk ratio when put into perspective with the relative severity of the disease. Beyond the TNF inhibitors, there are increasing data that biologic agents such as abatacept and RTX can work effectively even in patients who have failed TNF inhibitors, continuing to provide disease control in patients with the most refractory disease.

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Sequential monotherapy Step-up combination therapy Initial combination with prednisone Initial combination with infliximab Figure 67-5  The changes in various outcome assessment tools for the four treatment strategies in rheumatoid arthritis patients over the first  12 months of treatment. (Adapted from Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al: Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): A randomized, controlled trial. Arthritis Rheum 52:3381-3390, 2005.)

INHIBITION BY TUMOR NECROSIS FACTORS The pivotal roles for TNF-α in initiation and perpetuation of the inflammatory and proliferative processes of rheumatoid synovitis are outlined in Chapter 65. As a class, the TNF inhibitors (adalimumab, etanercept, and infliximab) seem to be one of the most effective means of improving symptoms and signs of disease, increasing function, and reducing structural progression of RA. Etanercept Etanercept was the first TNF-α inhibitor to be approved by the U.S. Food and Drug Administration (FDA) for use in RA. It is a fusion protein of the soluble portion of the

human TNF p75 chain of the receptor and the fragment crystallizable (Fc) portion of human IgG1. The receptor portion binds extracellular TNF-α, effectively neutralizing it, and the Fc moiety prolongs its circulating half-life. This drug is administered as a subcutaneous injection of 25 mg twice weekly or a single 50-mg injection once a week. Similar to other trials of newer agents, etanercept was tested in combination with MTX (stable dose of 15 to 25 mg/wk) against MTX alone.22 At 24 weeks, 71% of the patients receiving etanercept plus MTX and 27% of patients receiving placebo plus MTX met the ACR-20 criteria (P < .001). Particularly important were the data that 39% of the patients receiving the combination and only 3% of the patients receiving MTX alone met the ACR-50

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No progression SHS >0.5 No progression SHS>SDD 100

† *

Percentage of patients

80

60

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Treatment groups Figure 67-6  The percentage of patients without radiographic evidence of progression based on various treatment strategies in rheumatoid arthritis patients over the first 12 months of treatment. SDD, smallest detectable difference; SHS, modified Sharp–Van der Heijde score. (Adapted from Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al: Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): A randomized, controlled trial. Arthritis Rheum 52:3381-3390, 2005.)

i­mprovement criteria (P < .001), and 15% of the combination group met the ACR-70 criteria.22 A second important study evaluated etanercept as monotherapy and involved patients who had failed traditional DMARDs.74 They were randomly assigned to etanercept or placebo, and at 6 months 59% of patients receiving 25 mg of etanercept twice weekly and 11% of the placebo group had achieved an ACR-20 criteria response. A third important study looked at patients with early RA and compared the effects of MTX or etanercept on symptoms and signs, joint destruction, and function.19,20 In this study, 632 patients with disease of less than 3 years’ duration and who were naive to MTX and biologic agents were randomly assigned to receive either aggressively dosed MTX (20 mg/wk) or one of two different doses of etanercept (10 mg subcutaneously twice a week or 25 mg subcutaneously twice a week). Patients treated with etanercept had a more rapid response than was seen with MTX. This more rapid response led to significantly greater improvements at the ACR-20, ACR-50, and ACR-70 levels with etanercept compared with MTX for the first 4 months of the study. Although there was still a numerical trend favoring the 25-mg dose of etanercept over MTX at 1 year, the statistical significance was lost. As part of this study, radiographs also were obtained, and there was a statistically significant advantage for etanercept at 6 months, but, as with the clinical improvement, the radiographic assessments showed a trend, but no statistical significance at 1 year.19 At 2 years, the ACR-20 response rate was 72% in the 25-mg etanercept arm versus 59% in the MTX arm. Etanercept seemed to be better tolerated with fewer side effects than seen in the MTX cohort.20 The most interesting result of this study was the ability of etanercept to slow ­radiographic

progression more than MTX. The mean change in the total Sharp score at 2 years was 1.3 in the 25-mg etanercept arm versus 3.2 in the MTX group, showing statistically meaningful differences in radiographic progression between the two arms. Patients also showed a significant improvement in function and a reduction in disability. A fourth study, the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) trial, examined the effect of monotherapy with either MTX or etanercept versus the combination of the two agents in a double-blind controlled trial. The trial randomly assigned 686 patients between the three arms. At 1 year, the results in the combination arm suggested substantially better reduction of disease activity, improvement in function, and slowing of structural damage compared with either approach as monotherapy. Similar side effects were reported in each of the three treatment arms. Possibly the most impressive finding was that the mean radiographic progression in the combination approach was a negative score.75,76 The 2-year follow-up continued to reaffirm the superiority of the combination approach of etanercept plus MTX over either monotherapy for reducing disease activity, slowing radiographic progression, and improving function.77 Infliximab Infliximab is a chimeric monoclonal antibody against TNF. It was the second anti-TNF agent approved for use by the FDA in treatment of RA and had previously been approved for use in Crohn’s disease. Most of the antibody is human; however, a small portion of the Fab region is murine in origin. The antibody is given via intravenous infusions of 3 to 10 mg/kg. The recommended dosing regimen is 3 mg/kg with infusions at weeks 0, 2, and 6, and every 8 weeks thereafter. If patients fail to achieve a significant benefit, the dose can be increased, or the dosing interval can be shortened. For pharmacokinetic and pharmacoeconomic reasons, it may be more desirable to shorten the dosing interval rather than to increase the dose.78 Concomitant administration of MTX gives more sustained benefit, may reduce the clearance of the drug, and possibly may lead to less immunogenicity, reflected by a reduction in human antichimeric antibody formation.79,80 Whether concomitant use of other small molecules affords the same advantage is unknown, but plausible. In the ATTRACT trial, a phase III study involving 428 patients, infliximab exhibited significant benefit in patients with long-standing and refractory RA. Patients failing to respond to MTX were randomly assigned to receive placebo, infliximab (3 mg/kg every 4 weeks or every 8 weeks), or in­­ fliximab (10 mg/kg every 4 weeks or every 8 weeks). After 54 weeks, there was a statistically significant advantage favoring all the infliximab/MTX arms compared with the placebo/MTX arm. The ACR-20 response rate seen with placebo/MTX was 17% compared with 42%, 48%, 59%, and 59% in the infliximab 3 mg/kg every 4 weeks (42%), 3 mg/kg every 8 weeks (48%), 10 mg/kg every 4 weeks (59%), and 10 mg/kg every 8 weeks (59%) groups. ACR-50 responses also were significant and exceeded 34% in the three highest dosed cohorts.21 Although infliximab showed marked improvement in the symptoms and signs of disease, the most impressive

PART 9 

result of this study was the ability of infliximab to slow the radiographic progression of RA. Each of the infliximab/ MTX arms showed a dramatic decrease in what would have been their predicted rate of radiographic progression and statistical superiority to the placebo/MTX arm. Commensurate with the improvement in clinical manifestations was an improvement in function and a reduction in disability measured by the HAQ and the short-form health survey (SF-36).21 A second large trial, the Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) study, looked at infliximab and MTX in patients with early RA. The study randomly assigned 1049 patients to receive MTX, MTX plus 3 mg/kg of infliximab, or MTX plus 6 mg/kg of infliximab. Significantly better responses were seen at 1 year in the combination MTX/infliximab arms than were seen in the MTXonly arm. This study reaffirmed that in early disease the combination of a TNF inhibitor (infliximab) plus MTX provided better clinical, radiographic, and functional improvement than seen with monotherapy with MTX alone.26 Adalimumab Adalimumab is the third biologic agent directed against TNF to be approved by the FDA for the treatment of RA. Adalimumab is a fully human monoclonal antibody directed against TNF and is delivered as a subcutaneous injection once every other week, or, in patients with insufficient response, it can be given once a week. Use of background MTX with this agent also seems to increase the duration of response, possibly by slowing the clearance of the drug. As was shown with etanercept and infliximab, adalimumab showed significant benefits when combined with MTX.24,25,70 In the Anti-TNF Research Study Program of the Monoclonal Antibody D2E7 in Patients with Rheumatoid Arthritis (ARMADA) with adalimumab, patients with severe refractory RA were randomly assigned to receive placebo or subcutaneous adalimumab, at doses of 20 mg, 40 mg, or 80 mg every other week, in combination with MTX.24 The efficacy of adalimumab given subcutaneously every other week in combination with MTX was significantly better than MTX plus placebo, with ACR-20, ACR-50, and ACR-70 scores of 65%, 53%, and 26% at the 40-mg every-other-week dose. In a second large study,81 patients with active RA, after a 4-week DMARD washout period, were randomly assigned to one of five groups: 20 mg of adalimumab every other week or weekly, 40 mg of adalimumab every other week or weekly, or placebo. Patients who received 40-mg of adalimumab every other week showed substantial benefit, with an ACR-20 response of 46% compared with placebo response of 19%. The patients in the 40-mg group with weekly treatment did even better, with an ACR-20 response of 53.4%. A 52-week, double-blind, placebo-controlled study70 was carried out on patients with active RA who were receiving stable doses of MTX. Patients were randomly assigned to receive adalimumab, 20 mg subcutaneously once a week; adalimumab, 40 mg every other week with placebo on the alternate weeks; or placebo once a week. Substantial inhibition of radiographic progression was observed for joint space narrowing and erosions, particularly for the 40-mg everyother-week group. The authors concluded that 20 mg of

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adalimumab given subcutaneously weekly or 40 mg given every other week, both with concomitant MTX, significantly inhibited progression of structural joint damage and improved signs and symptoms of RA in patients who previously were incomplete responders to MTX. Similar to the other TNF inhibitors, adalimumab also has been studied in early disease. The PREMIER study evaluated the effect of combination therapy with adalimumab and MTX versus monotherapy with either agent alone.25 Substantial benefits were seen at 1 and 2 years in the combination arm over either of the monotherapy arms with significant advantages for the combination approach to slow structural damage, reduce disease activity, and improve function. SAFETY OF TUMOR NECROSIS FACTOR INHIBITION Tempering enthusiasm about the anti-TNF approaches to treatment is the reality that the beneficial effects are not permanent. Cessation of therapy is followed by a recrudescence of disease. The cytokine “rheostat” is not reset, and the as-yet-unknown forces initiating the inflammatory and proliferative process are still at work.82 TNF inhibition does not work in all patients, and some safety concerns remain. Serious Infections (Excluding Tuberculosis) When TNF inhibitors were first introduced in the late 1990s, there was concern that blocking TNF might impair the host defense system. Clinicians have since been reassured that, in general, there have not been significant problems with serious bacterial infections for most patients treated with TNF inhibitors. Occasional patients taking etanercept, in­­ fliximab, or adalimumab have developed serious bacterial infections or opportunistic infection, however. Predicting which patients will develop an infection is almost impossible. A degree of vigilance and the recognition that infections can occur should be part of all treatment initiation and monitoring efforts. In addition, it is apparent that in debilitated patients (e.g., patients with infections such as skin ulcers or pneumonia or patients with other illnesses that would increase the risk of infection or diminished immune surveillance) TNF inhibition should be used with caution. Tuberculosis Reactivation of tuberculosis has been reported with all the TNF inhibitors. There seem to be more reports with infliximab than with etanercept or adalimumab. Researchers are unclear as to whether these differences are related to differing mechanism of action, structure, pharmacokinetics, route of administration, or the patient populations studied. Given the potential for reactivation of tuberculosis, appropriate screening should be done before the initiation of treatment with a TNF inhibitor. Malignancies RA conveys an increased risk for the development of lymphoproliferative disease. The development of lymphoma has been reported with each of the TNF inhibitors. It is unclear,

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however, whether this development is related to the medication itself or the underlying disease (see Chapter 113). Demyelination Rare cases of multiple sclerosis, optic neuritis, and demyelination have been reported in patients taking TNF inhibitors.83-86 These cases have been sporadic and seem mostly to resolve when the TNF inhibitor is withdrawn. Because demyelination is a rare occurrence in the population at large, it is unclear whether these events are occurring more often than expected. It is recommended that TNF inhibition be avoided in patients with a history of demyelinating illness or who have features of unique neurologic ­problems. Congestive Heart Failure In patients with known congestive heart failure, TNF inhibitors should be used with caution because they may worsen cardiac function. ROLE OF TUMOR NECROSIS FACTOR INHIBITION IN THE TREATMENT OF RHEUMATOID ARTHRITIS The TNF inhibitors have exhibited a superior ability to reduce the signs and symptoms of RA, inhibit the progression of structural damage, and improve physical function in patients with this disease. Despite this, their role in the armamentarium is debated. The debate focuses on several factors, including the ability of traditional approaches to treat numerous patients effectively, particularly when used in combination; the lack of long-term safety data beyond 10 years; and the high costs of these agents (see Table 67-1). In all of the previously mentioned studies, the combination of a TNF inhibitor plus MTX showed statistically significant benefits over MTX alone. Questions are raised, however, as to whether this numerical/statistical advantage is clinically meaningful enough to warrant the difference in cost, particularly when numerous patients on MTX alone or in combination approaches achieved substantial benefits in those studies. In the absence of truly useful biomarkers or surrogates to distinguish patients likely to respond to therapy from patients who would not respond, it is reasonable to suggest that most patients should be treated with MTX before advancing to a TNF inhibitor. Should a patient fail to achieve a significant response to MTX over a few months, however, switching the patient to a TNF inhibitor as monotherapy or adding a TNF inhibitor and treating in combination with background DMARDs should be ­considered. Without head-to-head studies, the question as to which of the TNF inhibitors affords the greatest efficacy cannot be answered. There is evidence, however, that some patients may respond better to one TNF inhibitor than another. Deciding which agent to use for which patient is a difficult decision and is often influenced by a host of issues, including patient preference of injection or infusion, monotherapy or combination therapy, and, most frequently, what agent third-party payers would reimburse. Despite these factors, there continues to be an earlier adoption of TNF inhibitors in the treatment of RA.

INTERLEUKIN-1 RECEPTOR ANTAGONIST AND INTERLEUKIN-1 RECEPTOR IL-1, similar to TNF-α, has been implicated in the pathogenesis of RA. It is produced by rheumatoid synovium and other tissues, predominantly by macrophages. There is, however, a circulating protein found in extracellular tissues, IL-1 receptor antagonist, which is a biologically important protein that functions as a naturally occurring antagonist to IL-1. A recombinant human form, anakinra, has been developed. In 2002, anakinra was approved by the FDA for the treatment of RA. It is given as a daily subcutaneous injection of 100 mg. A 24-week, double-blind, randomized, placebo-controlled, multicenter study of 472 patients reported that of the patients who received 150 mg/day of anakinra as monotherapy, 43% met the ACR-20 criteria for improvement, although 27% of the placebo group did as well.87 A study of combination anakinra/MTX was done in 419 patients who had failed to achieve an adequate response to MTX alone.88 At 24 weeks, the ACR-20 response rate in the 1 mg/kg anakinra (46%) and 2 mg/kg anakinra (38%) dose groups was significantly greater than in the placebo group (19%). Anakinra also has been shown to be safe and effective with many other DMARDs, including HCQ, SSZ, and leflunomide.89 Two separate trials looking at combination use of anakinra with etanercept showed higher rates of infections, however, and failed to show clinical benefits of the combination of these two anticytokine therapies.90,91 In addition to the clinical benefits in signs and symptoms of disease, two studies have shown that use of anakinra can reduce radiologic progression of RA.92,93 Generally, anakinra has been shown to be safe and well tolerated. The most frequent side effect has been injection site reactions, which occur in more than 50% of the patients who take this medication. Although mild and self-limited, this side effect can be very uncomfortable. Anakinra is an infrequently used agent for the treatment of RA and is often reserved for patients who have failed other agents or may be inappropriate candidates for TNF inhibition. This restriction of use is partially related to its cost (see Table 67-1), the need for daily subcutaneous injections, and the perception of being less effective as a therapeutic biologic compound than are the TNF inhibitors. PROTEIN A IMMUNOABSORPTION COLUMN The FDA has approved a device containing staphylococcal protein A that binds IgG and IgG-antigen complexes, removing them from the circulation of patients with severe RA who are not responsive to DMARD therapy. The device has been effective in immune thrombocytopenic purpura and has been moderately more effective in RA than a “­placebo” that provided sham immunoabsorption.94 Use of this device is expensive, time-consuming for expert staff, and accompanied by side effects. The trials in RA necessitated a column treatment once a week for 12 weeks; further trials are essential to determine whether the treatment is effective in patients resistant to combinations of small molecules and biologic DMARDs. This device should be reserved as an option only for patients who have failed treatment with traditional DMARDs and the newer biologic agents.

PART 9 

NEW THERAPEUTIC CLASSES New therapeutic classes also have become available with the introduction of abatacept (a selective costimulatory modulator) and RTX (a peripheral B cell–depleting agent). The addition of newer therapeutic agents generated by recombinant or monoclonal antibody biotechnology has enhanced the concept and practice of combination therapy and has effectively exploited the promise of treatments that target certain inflammatory mediators believed to play an important role in initiation and amplification of the disease process. Generally, these agents, although quite effective at various stages of disease, are most frequently reserved for patients who have developed an inadequate response to MTX and frequently have failed TNF inhibition. Abatacept Abatacept is a soluble, recombinant fusion protein that is composed of the extracellular domain of cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) and the modified Fc portion of IgG1.95 It seems to be effective in the treatment of RA by selectively modulating the CD80 or CD86/CD28 costimulatory signal required for full T cell activation.96 T cells normally require two signals for full activation. The first signal is the antigen expressed in the context of the major histocompatibility complex (MHC) binding to the T cell receptor. The second signal is a costimulatory signal. One important costimulatory pathway is the engagement of CD80/CD86 on the surface of an antigen-presenting cell with CD28 on the T cell, facilitating T cell activation. In the normal sequence of events, the naturally occurring inhibitory molecule CTLA-4 is induced on the surface of the T cell downregulating the CD28-mediated T cell activation. CTLA-4 has a markedly greater affinity for CD80 or CD86 than does CD28, out-competing CD28 for CD80 or CD86 binding.97 Abatacept, similar to CTLA-4, competes with CD28 for CD80 and CD86 binding and can be used to modulate T cell activation selectively. Clinical trials have shown the efficacy of abatacept in the treatment of RA. In an early phase IIB trial, patients with active RA and an inadequate response to MTX were randomly assigned to MTX plus placebo, MTX plus 2 mg/kg of abatacept, or MTX plus 10 mg/kg of abatacept. Abatacept was administered as a 30-minute infusion days 1, 15, and 30, and monthly thereafter. At the 6-month end point, significantly more patients treated with 10 mg/kg of abatacept had obtained an ACR-20 response (60%) than patients on MTX alone (35%). Significantly greater ACR-50 and ACR-70 responses also were seen in the abatacept groups compared with placebo.98 The safety profile was similar to placebo. These results were corroborated further in a much larger phase III study looking at a similar population of patients with active RA and an inadequate response to MTX. In the AIM trial,71 652 patients with active RA and an inadequate response to MTX were randomly assigned to either 10 mg/kg of abatacept plus MTX or MTX alone. ACR responses (ACR-20, ACR-50, and ACR-70) at 6 and 12 months were all significantly better for the abatacept plus MTX group compared with the MTX-alone group with scores of 67% versus 39% (ACR-20), 39% versus 16% (ACR-50), and 19% versus 6% (ACR-70). At 1 year, the ACR responses

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had increased in the abatacept arm. Slightly higher incidences of adverse events and serious adverse events were seen with abatacept plus MTX compared with MTX alone. An important end point of this study was structural damage assessed through radiographs taken at baseline and 12 months. Abatacept significantly slowed structural progression with an approximate 50% reduction in radiographic progression in the abatacept-treated patients.71 Perhaps the most important of the studies with this agent to date has been the ATTAIN trial, which was designed to assess the safety and efficacy of abatacept in anti-TNF inadequate responders with active RA who continued to receive DMARDs or anakinra.99 In the trial, 258 patients received abatacept plus DMARD or anakinra, and 133 received placebo plus DMARD alone. Abatacept was administered as a 30-minute infusion on days 1, 15, and 29, and monthly thereafter, with a clinical end point at 6 months. At 6 months, the ACR-20, ACR-50, and ACR-70 on abatacept compared with placebo were 50% versus 19%, 20% versus 3%, and 10% versus 1%. As was true in the other studies, the abatacept arm had a significant improvement in function and reduction in pain.99 The largest of the phase III studies was the Assure trial. This randomized, double-blind, placebo-controlled trial primarily evaluated the safety of abatacept in 1441 active RA patients on traditional DMARDs and biologic DMARDs. Four groups of patients were treated for 1 year as follows: abatacept plus nonbiologic DMARD, placebo plus nonbiologic DMARD, abatacept plus biologic DMARD, or placebo plus biologic DMARD. At 1 year, there were higher rates of adverse events and serious adverse events (including serious infections) in the abatacept plus biologic DMARD group. This higher incidence led to a warning against concomitant use of abatacept with other biologic DMARDs.100 Rituximab RTX is a chimeric monoclonal antibody targeting CD20+ B cells.101 Clinical trials using RTX have shown efficacy and safety in treating RA and have provided further evidence for the role of B cells in the pathogenesis of the disease.102,103 CD20 is a target for B cell–depleting therapy because it is uniformly expressed on B cells, but not on stem cells or plasma cells.104 By binding CD20, RTX depletes peripheral B cells through several postulated mechanisms, including cell-mediated and complement-dependent cytotoxicity and promotion of apoptosis.101,105,106 In an early phase II study, 161 patients with inadequate response to MTX were treated with MTX only (n = 40), RTX only (n = 40), RTX plus cyclophosphamide (cyclophosphamide, 750 mg days 3 and 17) (n = 41), or RTX plus MTX (n = 40). All patients were treated with intravenous and oral steroids during the first 2 weeks of treatment. All RTX patients received two doses of 1000 mg, one each on days 1 and 15. At 24 weeks, all RTX treatment groups showed statistically significantly higher ACR-20 scores than MTX alone with the ACR-20 response rate of 73% in patients treated with RTX plus MTX and 38% in patients treated with MTX alone. Similarly, patients receiving RTX plus cyclophosphamide and RTX plus MTX had statistically significant ACR-50 responses over patients receiving MTX alone. A 6-month exploratory extension of treatment found

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33% of patients with an ACR-20 in the RTX plus MTX group compared with 13% for RTX plus cyclophosphamide and MTX alone and 8% for RTX alone. The duration of this response, although not quite statistically significant, is impressive for a single-infusion response.103 A second phase II study, the DANCER trial, was designed to determine the appropriate regimen of RTX combined with MTX, with or without corticosteroids. The trial assigned 465 patients with active RA despite the use of MTX to one of nine dosing groups: placebo with no steroid, placebo with only intravenous steroids, placebo with intravenous and oral steroids, 500 mg of RTX × 2 with no steroid, 500 mg of RTX × 2 with intravenous steroids, 500 mg of RTX × 2 with intravenous and oral steroids, 1000 mg of RTX × 2 with no steroid, 1000 mg of RTX × 2 with intravenous steroids, or 1000 mg of RTX × 2 with intravenous and oral steroids. All patients were on background MTX. The RTX was given intravenously 2 weeks apart. The intravenous steroid regimen was 100 mg of methylprednisolone given on days 1 and 15. The oral steroid regimen consisted of prednisone, 60 mg/day on days 2 to 7, and prednisone, 30 mg/day on days 8 to 14.107 The primary end point looked at only rheumatoid factor–positive patients at 24 weeks. There was a statistically significant benefit in the RTX arms compared with the placebo arm with ACR-20 of 54%, 55%, and 28% in the 1000-mg, 500-mg, and placebo RTX regimens, respectively. The steroid regimens did not seem to affect the efficacy results at 24 weeks, but the use of intravenous steroids did reduce significantly the number of infusion reactions associated with RTX. The use of intravenous steroids before administration of RTX has become routine in an effort to limit infusion reactions. The ideal dose of RTX has become less certain given the similar results seen with the 500-mg and the 1000-mg regimens. A more recent, and perhaps more important than the earlier trials, phase III trial studied the efficacy and safety of RTX when administered in combination with MTX in 500 patients with active RA who had an inadequate response to one or more anti-TNF-α therapies. RTX 1000 mg plus MTX or placebo plus MTX was administered by infusion on days 1 and 15. Pretreatment with intravenous methylprednisolone was followed by oral prednisone for 2 weeks after the initial RTX dosing. The primary efficacy parameter, ACR20, was statistically significantly higher for RTX patients than for placebo patients, with 51% of patients achieving an ACR-20 compared with 18% in the placebo arm. Radiographs were obtained as part of this study, and although not achieving statistical significance at 6 months, they did show a trend toward slowing of structural progression in the RTX plus MTX arm.72 As with the first two studies, RTX treatment produced a rapid and sustained peripheral depletion of B cells. Additionally, immunoglobulin levels were modestly decreased, with IgM in a few patients decreasing below the lower limits of normal, but with no signs of increased infectious episodes seen during this study. Overall adverse events were reported almost equally by both treatment groups. Twenty-three percent of RTX patients developed an acute infusion reaction during or after the first infusion compared with 18% of placebo patients. Infusion-related reactions are thought to be related to cytokine release and include pruritus, fever, rash, pyrexia, rigors, sneezing, throat irritation, cough,

bronchospasm, hypotension, and hypertension. There also was a slightly higher incidence of infections and serious infections in the RTX-treated group compared with the placebo group.72 Overall, abatacept and RTX seem to offer significant benefits and reasonable safety profiles to date, particularly for patients who have tried and failed anti-TNF agents. Both agents improve the symptoms and signs of disease, improve function, and slow radiographic progression of disease. These agents represent a particularly noteworthy advance in the treatment of RA because they work in patients who have failed TNF inhibition, and this group represents the most refractory of RA patients. Although unique questions remain as to where each of these agents will ultimately be placed in the therapeutic armamentarium, studies with these agents have confirmed the rationale of using recombinant engineering to target crucial steps that have been identified by laboratory research in the pathogenesis of disease.

ADJUNCTIVE DRUG THERAPY Patients with inflammatory polyarthritis have pain generated by the inflammation in their joints. The classes of compounds that treat this pain effectively are analgesics, NSAIDs, and glucocorticoids. For RA, these therapies must be considered adjuncts rather than primary therapy (disease-modifying drugs). Adjunctive therapy may be useful in the short-term, and in some cases it is sufficient for management, particularly in cases of polyarthritis that do not become chronically embedded in joints and defined as RA. The goal of RA therapy should be to make these adjunctive drugs unnecessary and redundant through control of the disease. The NSAIDs are discussed in detail in Chapter 54, and glucocorticoids are discussed in Chapter 55. GLUCOCORTICOID THERAPY Steroids in short courses and at low doses can result in a reduction of symptoms and signs of disease and improve patient function. Glucocorticoids are the fastest and most effective approach to immediate symptomatic improvement. It is hoped, however, that in future years their use can be minimized. Perhaps the most common use of glucocorticoids in RA is as an adjunct in low doses as a daily therapy. Although the benefits of low-dose therapy (�7.5 mg/day given as one dose in the morning) have been shown, data suggest that the cumulative effects on bone produce osteoporosis and other deleterious effects associated with significant morbidity. There are multiple actions of glucocorticoids on bone, including a recognized decreased production of osteoclasts and decreased production and apoptosis of osteoblasts resulting in decreased bone formation and trabecular width.108 The arguments supporting use of low-dose, daily prednisone are as follows. First, the rheumatoid process diminishes bone formation in patients compared with control populations.109 Physical impairment is the major determinant of spinal and femoral bone mass deficiency in RA patients, and if the clinical activity of arthritis is factored into equations, the effect of low-dose glucocorticoid therapy on bone loss in these patients is minimal,110 particularly if the glucocorticoid encourages more physical activity by relieving

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inflammation. Metabolic marker studies have indicated that generalized bone turnover is increased in RA.111 Second, evidence also has been presented that low-dose daily glucocorticoids reduce the rate of radiographically detected progression of disease.112-115 This work was initially done with 128 adults with active RA of less than 2 years’ duration. Patients were randomly assigned to receive 7.5 mg of prednisone per day in addition to other medications, and others received placebo. Most patients in both groups did not develop worsening radiologic scores, but the patients who did were primarily in the placebo group, and the erosions progressed more rapidly over the next 2 years. In a more recent 2-year, double-blind, placebo-controlled trial, the benefits and risks of 10 mg of prednisone per day were evaluated. Investigators found that, particularly in the first 6 months, patients receiving prednisone had more clinical improvement, and there was significantly less radiographic progression than seen in the placebo group.113 This finding was corroborated further in another 2-year study of patients with disease of less than 1 year’s duration. Patients were randomly assigned to receive either 7.5 mg of prednisolone per day or not when they were initially started on DMARDs for the treatment of RA. After 2 years, the patients given glucocorticoids in addition to DMARDs had higher remission rates and significantly less radiographic progression than the patients treated with DMARDs alone. There was no significant difference seen in adverse events or in loss of bone between the two groups.114 Even lower doses (5 mg of prednisolone per day) also have proved effective in substantially decreasing radiographic progression in patients with early RA with only mild increases in adverse events at 2 years.115 Some rheumatologists have used intramuscular injections of depot preparations of methylprednisolone intermittently in patients with active polyarthritis, although this is not a universal practice. The rationale is that this route and quantity of glucocorticoids give a sustained, gradually declining therapeutic effect that would not induce “dependence” on the drug, which often happens when even low doses are prescribed in pill form. In a 2-year randomized trial of intramuscular depot steroids in patients with RA and an incomplete response to DMARDs, the short-term and longterm (2-year) effects were assessed. In the short-term, disease activity improved faster than with placebo, but little difference remained at 6 months between the two groups. There also was a small reduction in radiographic progression in the intramuscular steroid group with fewer erosions seen. There were consequences of this approach, however, including more adverse events in the steroid arm and significant loss of bone density in the hip.116 Counter to efficacy data supporting glucocorticoid use are side-effect data showing that prednisone has higher cumulative toxicity over many years than nearly all other agents used to treat RA117 and a twofold increase in standardized mortality rates.118 Although most emphasis has been placed on osteoporosis, there is a definite association of low-dose glucocorticoid use on a daily basis with cataracts, glaucoma, impaired glucose tolerance, hirsutism, skin atrophy, and atherogenesis. Although side effects may be limited by alternate-day regimens, alternate-day administration of glucocorticoids in asthmatic patients did not produce less bone loss than daily regimens.119

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When glucocorticoids are being used, attempts should be made to guard patients against the known side effects. The ACR task force on osteoporosis guidelines120 has published recommendations for the following subsets of patients: • Patients receiving long-term glucocorticoid treatment who develop a nontraumatic osteoporotic fracture • Patients receiving long-term glucocorticoid treatment who do not have fractures • Patients beginning long-term glucocorticoid treatment Patients in the first group, who have developed a fracture (usually a compression fracture of the spine), are often at great risk for a higher mortality rate not only from the fracture, but also from other side effects of the glucocorticoids. These individuals not only need pharmacologic intervention, but also lifestyle changes. Patients in the second group, who are receiving longterm glucocorticoid treatment and do not have fractures, should have baseline laboratory tests and a dual-energy x-ray absorptiometry determination of bone mineral density. Physical therapy and exercise should be started, along with calcium and vitamin D supplementation. If appropriate, additional pharmacologic therapy should be considered to prevent glucocorticoid-induced osteoporosis. Yearly measurements of bone mineral density using the same equipment in these patients would enable the physician to determine the rate of bone loss and to institute therapy appropriately. Patients in the third group, who have RA and are beginning glucocorticoid therapy, should be evaluated carefully for associated diseases other than RA that affect bone metabolism. Women who are postmenopausal should be evaluated for the consideration of hormone replacement therapy or other antiresorptive agents. Other risk factors should be removed, when possible, and exercise, supplemental calcium, and vitamin D should be prescribed. A baseline bone mineral density determination is appropriate. Most importantly, the potential toxicity of the glucocorticoids, if taken for long periods, must be communicated to the patient, and the patient and the physician must have as their goal to control the disease within 6 months to the point that glucocorticoids are no longer deemed necessary and can be slowly tapered. Chapter 92 contains additional discussion and therapeutic options for the treatment of osteoporosis. Overall, the use of low-dose oral glucocorticoids for short periods as an adjunct to DMARD therapy can be justified, particularly in early disease, in a patient with refractory disease and in patients during pregnancy. Intramuscular glucocorticoid use should be considered as a short-term approach, whereas intra-articular steroids provide localized benefits particularly for patients with one or only a few active joints. Careful attention should be directed toward minimizing the potential side effects of any of these regimens. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS More than 70 million prescriptions for NSAIDs are written each year in the United States, and more than 30 billion over-the-counter tablets are sold annually. As a class, NSAIDs are the most often used and are a very effective adjunctive therapy in RA, providing analgesic and antiinflammatory benefits. Chapter 54 provides a comprehensive

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review of these compounds, with details of their molecular activity and toxicity. The introduction of the cyclooxygenase-2 (COX-2) selective agents has fueled debate further regarding safety, toxicity, and costs of NSAID therapy. Given that most patients with RA are treated with NSAID therapy, physicians must evaluate the individual patient carefully to assess chronicity of use, risk factors for NSAID toxicity, risk factors for heart disease, and the ability of the patient or the insurance plan to cover the costs of the agent prescribed. Risk factors for use of NSAIDs (including aspirin) have been identified and include the following121: • Advanced age • History of peptic ulcer (with or without a known infection with Helicobacter pylori) • Concomitant use of glucocorticoids or anticoagulants • Thrombocytopenia or platelet dysfunction • Pregnancy • Moderate or severe congestive heart failure, cirrhosis, or renal insufficiency • Aspirin intolerance, asthma, and nasal polyposis Which NSAID should be prescribed first is perhaps the most frequently encountered and possibly the most difficult question. In a young patient without any of the aforementioned risk factors, salicylates should not be excluded automatically from use. Aspirin has the advantages of being inexpensive (even in enteric-coated preparations), having an inexpensive test for blood levels, having toxicity directly related to dose, and often having a biologic manifestation of excessive blood levels (i.e., tinnitus). Nonacetylated salicylates (e.g., salsalate, choline salicylate) also merit consideration. They are moderately effective, have a good safety profile, and are inexpensive. They have only a weak and reversible effect on COX. This finding has led to studies showing that, at concentrations below those needed to inhibit either COX-1 or COX-2, salicylates interrupt signal transduction across cell membranes in such a way that activation of inflammatory pathways in cells such as the neutrophil is inhibited.122 If a clinician chooses to use an NSAID other than a salicylate, the only major differences, other than those afforded by the selective COX-2 inhibitors, are in frequency of dosing and in subtle differences in side-effect profiles. The selective COX-2 inhibitors have been described in detail in Chapter 54. The fundamental difference between COX-1 and COX-2 is that COX-1 is a constitutively expressed enzyme synthesized at a constant rate by the tissues that produce it, whereas COX-2 is induced in monocytes or macrophages, endothelial cells, chondrocytes, synovial cells, and osteoblasts by cytokines and other products generated during inflammation. The selective COX-2 inhibitors seem to be more effective than placebo in the treatment of arthritis and as effective as moderate doses of standard nonselective NSAIDs. The utility of the selective agents comes from potential safety advantages, including a lower risk of the development of gastrointestinal bleeding.123,124 The selective agents also have no significant effects on platelets. They do not confer any advantage to the kidney, however, and risks of increasing hypertension or renal insufficiency because of their use must be recognized. Also, evidence suggests that selective COX-2 inhibition may increase risks for cardiovascular events. This controversy is discussed further in Chapter 54.

ANALGESICS Acetaminophen is a very useful drug and can prove a useful adjunct in the treatment of arthritis. In patients without evidence of liver disease, acetaminophen can be taken in doses of 3 g or more per day without generating significant side effects. Combinations of acetaminophen with codeine or other narcotic derivatives produce a powerful but potentially addictive combination. Their use alone in polyarthritis for more than 6 weeks (i.e., the minimum period for acceptably classifying a polyarthritis as RA) should be discouraged and reserved only for patients who have severe and persistent disease despite all attempts to bring the disease under better control through the use of DMARDs and other adjuncts.

ASSESSING RESPONSE TO THERAPY Assessing the effectiveness of a therapeutic approach is crucial to the appropriate management of an individual patient. The ACR guidelines for the management of RA call for periodic assessment of disease activity, and patients with inadequate response should have DMARDs changed or added.1 In most clinical practices, this assessment is done by physician gestalt or global assessment after a careful history, examination, laboratory studies, and radiographs. In most situations, this approach leads to quality care; however, when intensive monitoring is applied with a goal of tighter control, better outcomes can be achieved.60 More quantitative (but more time-consuming) approaches exist, such as the ACR response criteria, the DAS/DAS28, the HAQ, the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI). The ACR responder criteria were designed to measure improvement in disease and have been used extensively as an outcome in clinical trials.73 The core criteria include swollen joint count, tender joint count, physician assessment of global status, patient assessment of global status, measurement of functional status (HAQ), patient assessment of pain, and a measure of inflammation such as the ESR or C-reactive protein (CRP). Although quite effective at assessing percentage improvement, such as the ACR-20, ACR-50, ACR-70, ACR responder criteria are considered a research tool and are not generally used in clinical practice. The DAS is an effective tool to assess disease activity and measure change in activity.125,126 It is a composite score making use of tender joint count (53 or 28), swollen joint count (44 or 28), general health assessment, and a marker of inflammation (ESR or CRP). It is a continuous measure allowing for measurement of absolute change in disease burden and percentage improvement. The DAS also has thresholds or cutoffs for low disease activity and for remission. Although a useful tool in clinical studies and in registries, the DAS is not used frequently in clinical practice; this is related partly to the need for careful joint counts, partly to the need for laboratory measures, and partly to the specific formula needed to calculate the score. DAS calculators can be found online to simplify this process for clinicians wishing to use this tool.127 The HAQ is a widely accepted and validated instrument for the assessment of function and disability. It is a patient self-reported questionnaire, and the HAQ disability index

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is frequently used in trials, registries, and many practice settings.34 The HAQ measures eight subscales relating to physical disability and is scored between 0 and 3 (0 = no disability and 3 = completely disabled). Many variations have been made to the HAQ by other investigators, but in general they measure similar features of function and disability. Chapter 31 contains a broader discussion of health outcomes tools. The SDAI and the CDAI are two relatively new composite scoring systems.128,129 The SDAI is calculated using the numerical sum of the tender joint count (28 joints), the swollen joint count (28 joints), the patient’s global assessment, the physician’s global assessment, and the CRP (mg/ dL).128 The CDAI is similar to the SDAI, but does not use an acute-phase marker.129 The removal of the laboratory measure makes it feasible to perform this measure directly in the office with the patient and base decisions on it without having to wait. Regardless of which tool is used, it is increasingly important to incorporate validated outcomes tools into clinical practice to assess disease activity, and to guide decision making regarding change and addition of DMARDs and expensive biologic agents.

EARLY RHEUMATOID ARTHRITIS— WINDOW OF OPPORTUNITY For patients with a symmetric polyarthritis in three or more joint areas involving the hands, feet, or both for at least 6 weeks, and a presumptive diagnosis of RA, aggressive treatment is warranted. Patients generally are apprehensive and concerned about developing a chronic, debilitating disease. Anxiety, depression, loss of self-esteem, inability to work, and an inability to develop new coping behaviors may evolve. This “learned helplessness” must be combated by education, reassurance, counseling, and the confident attitude of the physician. Most important is the initiation of a program to downregulate activity of the synovitis with the goal of inducing a remission, or at least marked improvement, in the disease. Disease-modifying therapy is indicated at this point (see earlier), as are some adjunctive therapies. Early intervention may offer the greatest likelihood of preventing disability, and there may be a window of opportunity to have a significant impact on the trajectory of the disease over a lifetime. The case for early intervention and for a window of opportunity has been made using several lines of evidence, as follows: 1. Functional health status declines early, with mild functional loss by 1 year and moderate-to-severe functional losses by 6 years.130 Subsequently, work disability also occurs, especially early in disease, with work disability estimated to occur in 25% of RA patients at 6.4 years and 50% at 20.9 years after disease onset.131 2. Mortality rates are increased in patients with RA. Mortality rate has been shown to increase over 5 to 20 years, with 35% mortality by 20 years.132 Morbidity and mortality rates in RA are predicted by, and are directly proportional to, clinical status. More severe and active disease has a poorer outcome.133 3. Radiographic changes develop early in disease.134-136 Erosions of bone and narrowing of joint spaces develop within the first 2 years of disease in most patients and

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are progressive afterward over several decades.137 The rate of progression of radiographic scores is rapid early in disease and apparently continues along a similar trajectory for the duration of the disease if left untreated. When the proliferative synovium has begun to invade and destroy articular cartilage, joints are at risk for irreversible destruction, even when disease activity decreases. 4. In terms of economic impact, early disease activity predicts long-term costs. Data suggest that long-term medical costs and outcomes are significantly associated with early changes in disability.138 Further data would support the fact that patients with very poor function may experience direct medical costs 2.55 to 6.97 times as high as patients with good function, with most of those costs coming from hospitalization.139 5. An interval of time may exist in which the introduction of DMARD therapy can result in a change in the natural course of disease—not just for a transient to short-lived time frame, but more fundamentally in the scope of the progression of the disease for a lifetime.140 Data supporting this view have come from numerous trials looking at intervention in early RA. In the HERA trial,6 patients with RA were randomly assigned to receive either HCQ or placebo over 36 weeks. At the conclusion of the study, the patients who had received HCQ had improvements in joint findings, pain, and physical function superior to what was seen in the placebo group. Of more interest were the results seen after 3 years of follow-up of the original cohorts. The patients who had therapy instituted early in the disease (the HCQ arm) versus the patients who had DMARD therapy delayed for 9 months (the placebo arm) continued to have significantly less pain and disability. These results could not be explained based on differences in glucocorticoid, DMARD, or NSAID use subsequent to the trial and were attributed to the delay in the introduction of therapy.7 Stronger support for this line of thinking stems from data from many other trials. In the COBRA trial, patients were initially randomly assigned to receive monotherapy with SSZ or combination therapy in a step-down approach with SSZ, MTX, and high-dose glucocorticoids. At the end of 28 weeks, there seemed to be a significant advantage for the use of combination therapy based on clinical response, and at 1 year, there also was less radiographic progression in the combination group.12 Of greatest interest is the 4-year follow-up data from this cohort. The patients who had been treated with the initial 6-month cycle of intensive combination treatment had a sustained suppression of the rate of radiographic progression independent of subsequent antirheumatic therapy. The patients initially treated with monotherapy had a change in Sharp score of 8.6 units/yr, whereas the patients on the combination regimen progressed at only 5.6 units/yr.68 In the FIN-RACo trial, investigators showed that combination therapy was superior to monotherapy with higher remission rates seen at 1 year and 2 years in the combination arm compared with the single DMARD arm.14,66 Perhaps more interesting were the radiographic results at 5 years suggesting significant slowing of radiographic progression at 5 years in the patients treated with combination therapy within the first 2 years of their disease compared with the

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single DMARD approach.141 Also, prompt induction of remission translated into better maintenance of work capacity at 5 years.142 In another study, the early introduction of infliximab in addition to background MTX in patients with early RA and a poor prognosis resulted in not only a significantly better improvement in symptoms, function, and structural progression, but also an apparent ability to withdraw the infliximab and maintain the sustained benefits compared with placebo.143 Given the growing body of evidence, it seems that the introduction of effective therapy (particularly combination therapies) early in the course of disease can result in a profound impact on the nature of the disease years later. An interval of time may exist for intervention whereupon the outcome is a long-term change in the nature of the disease, regardless of what type of therapy or intervention is used in the future. Estimation of a patient’s prognosis may assist further in choosing which patients may need the most aggressive approaches.

ESTIMATING PROGNOSIS The challenge for the physician is to form an appreciation for the severity of a patient’s disease and formulate a treatment plan accordingly. As a general guideline, the rate of progression toward joint destruction and disability in RA is proportional to the intensity of inflammatory and proliferative reactions within the joints, the degree of disability, and the persistence of this disease over time. In other words, a patient who has low-grade attacks of synovitis that are separated in time from each other would be much less likely to advance to joint deformity than a patient who has continuous, highly active synovitis. Markers that have been identified have varied widely with individual studies, end points used, and the types of therapy implemented. An instructive study was done on 142 consecutive patients with early RA (median duration of disease was 7 months) treated actively with disease-modifying drugs and followed prospectively for an average of 6.2 years. Functional outcome and radiographic damage were the end points. The significant prognostic factors were high clinical disease activity at baseline, including morning stiffness, pain, grip strength, joint count, hemoglobin, and ESR, and a positive test for rheumatoid factor.144 The function/disability, age, and comorbid conditions predicted 5-year mortality rate more effectively than radiographic or laboratory data.145 The implication of this study is that functional measures may be superior to radiographs or markers of inflammatory activity in predicting outcome in RA. In a similar cohort of 191 patients with early disease, multivariate analysis revealed that progression of joint damage was best predicted by ESR, IgM rheumatoid factor positivity, erosions at baseline, and the presence of HLA-DRB1*04 alleles.146 Multivariate analysis of the same cohort suggested that disability at 5 years was associated with baseline HAQ scores, swollen and tender joint counts, elevated acutephase proteins, and the presence of erosions on radiographs. Sex, age, rheumatoid factor, and the presence of HLA-DR1 alleles did not contribute to the prediction of disability at 5 years.147 Another study of a similar cohort found that the HAQ score during the first 3 months predicted disability at 10 years with a very high odds ratio.148

Post-hoc analysis of clinical trials also has provided insight into factors predicting lack of clinical response to given therapies. In the ASPIRE trial,26 patients with early disease were randomly assigned to receive MTX or MTX plus infliximab. On average, patients treated with the combination did better than patients treated with MTX alone. Certain factors predicted which of the patients treated with MTX alone might have a less than satisfactory result. Elevated acute-phase proteins, CRP or ESR, and swollen joint count were associated with greater structural damage in the MTX group, but not in the combination group, suggesting that this might be a subpopulation more likely to benefit from the combination approach early in disease.149 In an even larger cohort of 3500 patients, rheumatoid factor, elevated CRP, and high baseline HAQ scores all were predictors of poor outcome, and there was a strong association between the presence of HLA-DR1 alleles and the development of erosions.150 Another indication of how function may predict outcome comes from an extensive study of the predictors for total joint replacement in 1600 patients seen during a period of observation that extended 23 years. Patients with highly abnormal values on the HAQ, global severity of disease, and ESR had a threefold to sixfold increased risk of undergoing a joint replacement.151 As alluded to earlier, additional markers of prognosis include genetic predispositions, such as the presence of certain genetic loci (e.g., HLA-DR alleles that are associated with RA). Although some studies have yielded conflicting results, it is generally believed that the HLA-DRB1 locus can increase the likelihood of developing RA and the severity of disease. There have already been attempts to use HLA-DRB1 typing in RA to predict responses to specific treatments.152 In one study, the patients previously had been followed carefully in a study of combination therapy (HCQ/SSZ/MTX, HCQ/SSZ, or MTX alone).13 Patients were classified, in simplest terms, as “successes” or “failures” in achieving 50% improvement. DR4 subtyping was detected by hybridization of the patients’ DNA with allelespecific oligonucleotide probes specific for the shared epi­ tope region. Of the patients, 74% were positive for at least one shared epitope allele, and 29% were positive for two. Although simplified, it can be concluded that patients who had one or two of the shared epitopes in their DRB1 chains were less likely to respond to MTX alone than to all three drugs, whereas the patients who had no shared epitopes in DRB1 chains did equally well on MTX alone as with all three drugs. Among patients positive for the shared epitope, 94% were “successes” if treated with triple therapy, but only 32% were “successes” if treated with MTX alone. These data are consistent with observations that patients positive for the shared epitope are at greatest risk for progressively active erosive disease and need more aggressive therapy earlier. Further studies have suggested that the HLA-DRB1 shared epitope alleles may not be independent risk factors for the development of RA, but rather a risk factor for the development of anti–cyclic citrullinated peptide (antiCCP) antibodies. Anti-CCP antibodies are believed to be sensitive and specific for the diagnosis of RA and may predate the development of the disease.153 Research has continued to suggest that the presence of anti-CCP antibodies is highly specific for RA, and that anti-CCP-positive patients have more active disease and more severe radiographic

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evidence of destruction,154 and that the presence of antiCCP antibodies early in disease is a prognostic marker of erosive disease.155,156 Data also suggest that the presence of anti-CCP is strongly associated with severe extra-articular features of RA.157 In the future, genetic analyses could lead to the choice of early effective therapy custom-designed for each patient. It may be possible—using relatively inexpensive microchip technology—to obtain a detailed printout that records the genetic predisposition to develop RA of each patient and the genes governing autoantibody formation and the B cell repertoire, T cell receptor sequences, cytokine and adhesion molecule production, receptor density for inflammatory ligands, and susceptibility to good and toxic effects of drugs.158 Refined imaging techniques can help in the staging of disease and in following effects of therapy. Magnetic resonance imaging (MRI) (see Chapter 53), although not yet justified as a cost-effective measure of synovitis, nevertheless can provide a good estimate of synovial volume within joints. In a study using gadopentetate dimeglumine– enhanced MRI,159 it was found that the rate of erosive progression on MRI was highly correlated with the values of synovial membrane volume, but not with local or global clinical or laboratory parameters. Erosions of bone seen on MRI grew into radiographically visible erosions, but with a delay of 1 year. Ultrasound also is proving potentially useful for diagnosing active disease at an early stage. Compared with clinical examination, MRI, three-phase bone scan, and conventional radiology in a study of 60 patients with various types of arthritis, ultrasound proved to be a sensitive tool. When looking specifically at 32 of the 60 patients without radiographic erosions, bone scan identified 58% of the joints as abnormal, ultrasound identified 54% as abnormal, and MRI showed erosions in 20% of the joints and enhancement in 41%.160 Further radiographic studies have shown that MRI and ultrasound exhibit very high specificity and a sensitivity much higher than traditional radiographs.161 As imaging modalities (it is hoped) decrease in cost, increase in availability, and grow in sophistication, it is possible they will have increased utility in the future for diagnostic and prognostic purposes in patients with inflammatory arthritis. Generally, the markers discussed previously, including severe or aggressive baseline disease, poor function, the presence of rheumatoid factor and anti-CCP antibodies, and elevation of acute-phase markers, all suggest a worse prognosis. Beyond this, the presence of erosions and joint space narrowing on imaging studies early in the disease also are predictive of more destructive disease.

IMPORTANT ADJUNCTS EDUCATION The point has been made that a “low formal educational level is a composite/surrogate variable [that] identifies behavioral risk factors predisposing to the etiology and poor outcomes in most chronic diseases.”162 In studies of RA, morbidity and mortality rates over a 9-year period in one series were inversely proportional to the formal educational level and could not be explained by age, duration of disease,

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joint count, functional measures, or medications.163 Although the reasons behind this link of formal education to outcome are obscure, the corollary is that teaching patients about how arthritis affects people, how they can be involved in helping themselves, and what physicians use to treat arthritis leads to better outcomes.164 Use of the Arthritis Self-Management Program has been rigorously shown to enable pain reduction, decrease visits to physicians, and save money.165,166 Participation of spouses in educational group sessions for patients leads to additional beneficial effects.167 Psychological counseling, a form of education, also is useful for patients with arthritis. Stress management training can be particularly effective, leading to statistically significant improvements in measures of helplessness, self-efficacy, coping, pain, and health status.168 Chapter 61 provides a more in-depth discussion of education and its role in arthritis; however, in general, patients need to feel they have some control over their illnesses—a capacity to do something for themselves that has a positive effect. They do not want to be bystanders, watching a contest between a disease they did nothing to bring on and physicians whose words and strategies they insufficiently understand. Education can make a big difference, enabling patients to form a therapeutic contract with their physicians and making it more likely that they will not turn, out of frustration, to alternative therapies that may do more harm than good. PAIN CONTROL Pain can be the factor that limits effectiveness of physical and occupational therapy, and as pointed out during a special workshop sponsored by the National Advisory Board for Arthritis and Musculoskeletal and Skin Diseases, it is frequently undertreated in patients with arthritis.169 In addition to inhibiting function, pain is a major cause of depression in patients with polyarthritis. To maximize therapy in patients with early RA or undifferentiated polyarthritis, pain must be controlled without altering consciousness or generating addiction. Treatment strategies favoring education, rest, exercise, and disease-modifying therapies generally are favored as an approach to pain control in arthritis, and strategies that rely on narcotic derivatives alone are discouraged. In most medical centers, experts in pain management are available for consultation by rheumatologists and primary care physicians. REST, EXERCISE, AND ACTIVITIES OF DAILY LIVING Education and supervision of a patient by trained professionals on the importance of finding the best balance of rest and exercise for inflamed joints is essential. This component of therapy can be started well before a definitive diagnosis is made. No matter what the cause, finding this balance should ensure that a patient develops, or retains, sufficient strength to support joint function without exacerbating inflammation. Details of physical and occupational therapy are outlined in Chapter 64. A patient with acutely and severely inflamed joints may need application of resting splints to immobilize the joint until anti-inflammatory medication takes effect. Even the most painful joints, when splinted, must be moved

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passively through a full range of motion each day to prevent flexion contractures, particularly in children. For moderately inflamed joints, isometric exercise with muscles contracted in a fixed position (the resting length of the muscle) provides adequate muscle tone without exacerbating joint inflammation and pain. Maximal contractions, held for 6 seconds and repeated 5 to 10 times, performed several times each day, can prevent further loss of muscle mass around arthritic joints. Patients with inactive or well-controlled arthritis can profit from variable-resistance programs or even highintensity strength training, which has been shown to provide significant improvements in strength, pain, and fatigue. Elderly patients with RA can benefit from progressive resistance exercises, similar to younger patients. In a study of older patients given closely regulated workouts on pneumatic resistance equipment, maximal strength of all major exercised muscle groups was increased 75% without exacerbation of clinical disease activity.170 Not only does prescribed sustained exercise increase muscle strength, but also it helps the ability of patients to perform daily routines, improves global assessments and moods, and can decrease pain.171 Every patient with RA should have one or more sessions with a licensed occupational therapist to learn how to preserve joint function and alignment, while carrying out the necessary and enjoyable activities of daily living. The basic concept is to avoid excessive force applied across non– weight-bearing joints and to avoid unnecessary impact loading on weight-bearing joints. The Arthritis Society Home Service in Toronto, Canada, participated in a prospective and controlled trial showing that home therapy by occupational therapists produced a statistically significant and clinically important improvement in function in rheumatoid patients.172 ROLE OF THE RHEUMATOLOGIST IN MANAGEMENT The increasing complexity of management options, combination therapies, and possible toxicities of therapy have all but necessitated that the rheumatologist be involved in the management decisions of patients with RA. Data indicate that continuing care by a rheumatologist (mean of 8.6 visits per year) results in a crude rate of progression of functional disability that is significantly less (P = .001) than for patients who receive only intermittent, sporadic care by a rheumatologist.173 Analysis of the data has supported the interpretation that worsening disability was not the reason for intermittent care, but rather a consequence of it. In another series of 561 patients with definite RA followed over 20 years, the patients seen by a rheumatologist during the first 2 years of disease improved significantly compared with others.174 The favorable outcome could be related to an early start with aggressive therapy. It is probable that the best care is given by a team of a rheumatologist and a primary care physician working closely with each patient, plus adequate consultation from physical and occupational therapists and orthopaedic surgeons. Additional evidence

supporting this approach showed that patients who had access to a specialist (rheumatologist) had higher performance scores than patients who saw only a general practitioner. Access to primary care and specialist care resulted in significant improvements in arthritis care, comorbid illness, and health care maintenance overall beyond seeing a primary care physician alone.175 Among rheumatologists, there is a wide variation of frequency with which follow-up visits are scheduled, even though clinical outcome for patients varies little.176 With the increasing restraints of managed care on medical care, all physicians must struggle to give adequate time to each patient. COMPLEMENTARY THERAPY AND DIET Patients with RA often want to be personally involved in attempts to control the disease. Along with direct advertising about pharmaceutical medications, patients are saturated with information about complementary therapy and diets for RA. It is important to inform patients of the risk of taking herbal medicines that can be toxic and to let them know that there are no data to support the claims that copper bracelets, glucosamine and chondroitin sulfate, wheat germ, or tomato-free diets benefit RA. Patients interested in trying dietary modification should be informed about addition of omega-3 or omega-6 fatty acids to the diet. Eicosapentaenoic acid, in doses of 54 mg/kg/day, and docosahexaenoic acid, in doses of 36 mg/kg/day, added to the diet have been shown in double-blind, randomized, placebo-controlled studies to improve joint counts in a 30-week trial.177 Another study proved the benefit of these fish oils over 12 months when compared with olive oil supplementation.178 Manipulation of the omega-6 pathway of metabolism of fatty acids has been achieved by giving 1.4 g/day of gammalinolenic acid to RA patients in a double-blind, placebocontrolled study of 24 weeks’ duration.179 Joint tenderness improved significantly in the treated group. Giving omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) diminishes prostaglandin E2 and leukotriene B4 biosynthesis and increases production of prostaglandin E3 and leukotriene B5, both of which are less inflammatory than the usual products. Addition of gammalinolenic acid to diets increases prostaglandin E1 (an antiinflammatory prostaglandin) production, and prostaglandin E2 and leukotriene B4 levels do not change. Data also suggest that long-term fish oil treatment may reduce cardiovascular risk factors in patients with early RA.180 These added oils in the diet can leave a fishy taste in the mouth and generate oily, foul-smelling stools. Some patients cannot tolerate these effects, but most can. Most important, the fish oil supplements do no apparent harm. No other diets have been useful besides diets associated with enhancing weight loss. Excess weight is a liability for RA patients, and weight control is an important component of a good therapeutic plan. “Starvation diets,” despite the fact that they may suppress the immune response, should be discouraged.

PART 9 

Future Directions The growing body of data lends credence to the belief that early diagnosis and initiation of therapy in RA is appropriate and necessary to maximize the short-term and long-term benefits to the patient. It may afford a window of opportunity for substantive disease modification, which may lead to long-term protective benefits. In addition to the growing emphasis on early intervention, the rheumatology community is continually striving to improve overall response rates among current patients and to expand intervention into untreated populations. There also is a strong desire to develop therapies that work in 90% to 100% of patients, not the 60% seen today. The long-term goal of treatment intervention should be to achieve remission. Although a unique opportunity for intervention may exist early in the course of disease, it is believed that DMARDs should be introduced at all stages of disease for long-term disease modification. What also has become fundamentally clear is that even in later stages of disease, the use of DMARDs can reduce symptoms and signs, improve function, and slow structural progression. The remarkable efficacy and safety of biologic agents has been reassuring. Monitoring for adverse events and for unforeseen occurrences must continue, however. Differences between agents also warrant considerable research. It may be that different populations and disease states would be better suited to one or another agent as monotherapy or particularly in combination with other agents. In the future, we may see improvements in combination approaches including combination biologic agents. To date, combination biologic approaches have led to increased risks of infection, however.91,100 With the right targets or the appropriate modulations of dosages, we may be able to overcome this increased risk. The future may see additional agents being used as adjuncts. An example would be the use of statin agents. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have significant benefits toward lowering cholesterol and reducing risks of cardiovascular events. The fact that patients with RA are at increased risk of cardiovascular mortality itself might be reason to consider statin use. Statins may influence other inflammatory factors, however, effecting the symptoms and signs of disease. In one study, 116 patients with RA were randomly assigned to receive placebo or 40 mg of atorvastatin in addition to their existing DMARD regimen. After 6 months, significant improvements were seen in disease activity scores and reductions in C-reactive protein and erythrocyte sedimentation rates, suggesting modest anti-inflammatory effects.181 In the years ahead, it will be increasingly important for rheumatologists and primary care physicians treating patients with RA to expect rigorous confirmation of efficacy and safety by double-blind, placebo-controlled studies of all new products and long-term registries to ensure the safety of these agents in the long run. Physicians must be armed with data because their patients will be armed with testimonies from the Internet and convincing ads from television, newspapers, and magazines for many diverse therapies. Another issue will be finding suitable patients to enroll in studies of the most promising medications that are ready to move into advanced phase trials. Rheumatologists must take a leading role in ensuring their patients have the chance to participate in studies of the most promising drugs and devices.

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45. Buckland-Wright JC, Clarke GS, Chikanza IC, et al: Quantitative microfocal radiography detects changes in erosion area in patients with early rheumatoid arthritis treated with Myochrysine. J Rheumatol 20:243, 1993. 46. Lehman AJ, Esdaile JM, Klinkhoff AV, et al; METGO Study Group: A 48-week, randomized double-blind, double-observer, placebocontrolled multicenter trial of combination methotrexate and intramuscular gold therapy in rheumatoid arthritis: Results of the METGO study. Arthritis Rheum 52:1360-1370, 2005. 47. Sakkas LI, Chikanza IC, Vaughn RW, et al: Gold induced nephropathy in rheumatoid arthritis and HLA class II genes. Ann Rheum Dis 52:300, 1993. 48. Felson DT, Anderson JJ, Meenan RF: The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis: Results of second-line drugs in rheumatoid arthritis. Arthritis Rheum 33:1449, 1990. 49. Borg G, Allander E, Berg E: Auranofin treatment in early rheumatoid arthritis may postpone early retirement: Results from a 2-year double blind trial. J Rheumatol 18:1015, 1991. 50. Black AJ, McLeod HL, Capell HA: Thiopurine methyltransferase genotype predicts therapy limiting severe toxicity from azathioprine. Ann Intern Med 129:716, 1998. 51. Blanco R, Martinez-Taboada VM, Gonzalez-Gay MA: Acute febrile toxic reaction in patients with refractory rheumatoid arthritis who are receiving combined therapy with methotrexate and azathioprine. Arthritis Rheum 39:1016, 1996. 52. Jessop JD, O’Sullivan MM, Lewis PA, et al: A long term five-year randomized trial of hydroxychloroquine, sodium aurothiomalate, auranofin and penicillamine in the treatment of patients with rheumatoid arthritis. Br J Rheumatol 37:992, 1998. 53. Dronke M, Leonard WJ, Depper JM, et al: Cyclosporin A inhibits T-cell growth factor gene expression at the level of mRNA transcription. Proc Natl Acad Sci U S A 81:5214, 1984. 54. Fuleihan R, Ramesh N, Horner A, et al: Cyclosporin A inhibits CD40 ligand expression in T lymphocytes. J Clin Invest 93:1315, 1994. 55. Tugwell P, Pincus T, Yocum D, et al: Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. N Engl J Med 333:137, 1995. 56. Stein CM, Pincus T, Yocum D, et al: Combination treatment of severe rheumatoid arthritis with cyclosporine and methotrexate for fortyeight weeks: An open-label extension study. The Methotrexate-Cyclosporine Combination Study Group. Arthritis Rheum 40:1843, 1997. 57. Tugwell P, Bombardier C, Gent M, et al: Low-dose cyclosporin versus placebo in patients with rheumatoid arthritis. Lancet 335:1051, 1990. 58. Furst DE, Saag K, Fleischmann MR, et al: Efficacy of tacrolimus in rheumatoid arthritis patients who have been treated unsuccessfully with methotrexate: A six-month, double-blind, randomized, doseranging study. Arthritis Rheum 46:2020-2028, 2002. 59. Yocum DE, Furst DE, Kaine JL, et al: Tacrolimus Rheumatoid Arthritis Study Group: Efficacy and safety of tacrolimus in patients with rheumatoid arthritis: A double-blind trial. Arthritis Rheum 48: 3328-3337, 2003. 60. Grigor C, Capell H, Stirling A, et al: Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): A single-blind randomised controlled trial. Lancet 364:263-269, 2004. 61. Fries JF: Re-evaluating the therapeutic approach to rheumatoid arthritis: The “sawtooth” strategy. J Rheumatol 22(Suppl):12-15, 1990. 62. McCarty DJ, Carrera GF: Treatment of intractable rheumatoid arthritis with combined cyclophosphamide, azathioprine and hydroxychloroquine. JAMA 255:2215, 1982. 63. Pincus T, O’Dell JR, Kremer JM: Combination therapy with multiple disease-modifying antirheumatic drugs in rheumatoid arthritis: A preventive strategy. Ann Intern Med 131:768-774, 1999. 64. Kremer JM: Rational use of new and existing disease-modifying agents in rheumatoid arthritis. Ann Intern Med 134:695-706, 2001. 65. O’Dell JR, Leff R, Paulsen G, et al: Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: Results of a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 46:1164-1170, 2002. 66. Mottonen T, Hannonen P, Korpela M, et al: Delay to institution of therapy and induction of remission using single-drug or combinationdisease-modifying antirheumatic drug therapy in early rheumatoid arthritis. Arthritis Rheum 46:894-898, 2002.

PART 9  67. Wilske KR, Healey LA: Remodeling the pyramid—a concept whose time has come. J Rheumatol 16:565-567, 1989. 68. Landewe RB, Boers M, Verhoeven AC, et al: COBRA combination therapy in patients with early rheumatoid arthritis: Long-term structural benefits of a brief intervention. Arthritis Rheum 46:347-356, 2002. 69. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al: Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): A randomized, controlled trial. Arthritis Rheum 52:33813390, 2005. 70. Keystone EC, Kavanaugh AF, Sharp JT, et al: Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: A randomized, placebo-controlled, 52-week trial. Arthritis Rheum 50:1400-1411, 2004. 71. Kremer JM, Genant HK, Moreland LW, et al: Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: A randomized trial. Ann Intern Med 144:865-876, 2006. 72. Cohen SB, Emery P, Greenwald MW, et al: Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 54:2793-2806, 2006. 73. Felson DT, Anderson JJ, Boers M, et al: American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 38:727, 1995. 74. Moreland LW, Schiff MH, Baumgartner SW, et al: Etanercept therapy in rheumatoid arthritis. Ann Intern Med 130:478, 1999. 75. Klareskog L, van der Heijde D, de Jager JP, et al: TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) Study Investigators: Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: Double-blind randomised controlled trial. Lancet 363:675-681, 2004. 76. van der Heijde D, Landewe R, Klareskog L, et al: Presentation and analysis of data on radiographic outcome in clinical trials: Experience from the TEMPO study. Arthritis Rheum 52:49-60, 2005. 77. van der Heijde D, Klareskog L, Rodriguez-Valverde V, et al; TEMPO Study Investigators: Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: Twoyear clinical and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum 54:1063-1074, 2006. 78. St Clair EW, Wagner CL, Fasanmade AA, et al: The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: Results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 46: 1451-1459, 2002. 79. Maini RN, Breedveld FC, Kalden JR, et al: Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 41:1552-1563, 1998. 80. Infliximab package insert. Malvern, Penn, Centocor, 2006. 81. van de Putte LB, Atkins C, Malaise M, et al: Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann Rheum Dis 63:508-516, 2004. 82. Firestein GS, Zvaifler NJ: Anticytokine therapy in rheumatoid arthritis. N Engl J Med 337:195, 1997. 83. Robinson WH, Genovese MC, Moreland LW: Demyelinating and neurologic events reported in association with tumor necrosis factor alpha antagonism: By what mechanisms could tumor necrosis factor alpha antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis? Arthritis Rheum 44:1977-1983, 2001. 84. Sicotte NL, Voskuhl RR: Onset of multiple sclerosis associated with anti-TNF therapy. Neurology 57:1885-1888, 2001. 85. van Oosten BW, Barkhof F, Truyen L, et al: Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology 47:1531-1534, 1996. 86. Mohan N, Edwards ET, Cupps TR, et al: Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 44:2862-2869, 2001.

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87. Bresnihan B, Alvaro-Gracia JM, Cobby M, et al: Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 41:196, 1998. 88. Cohen S, Hurd E, Cush J, et al: Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: Results of a twenty-fourweek, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 46:614-624, 2002. 89. Tesser J, Fleischmann R, Dore R, et al; 990757 Study Group: Concomitant medication use in a large, international, multicenter, placebo controlled trial of anakinra, a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis. J Rheumatol 31:649-654, 2004. 90. Schiff MH, Bulpitt K, Weaver AA, et al: Safety of combination therapy with anakinra and etanercept in patients with rheumatoid arthritis. Arthritis Rheum 45:157, 2001 (abstract). 91. Genovese MC, Cohen S, Moreland L, et al: Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 50:1412-1419, 2004. 92. Jiang Y, Genant HK, Watt I, et al: A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: Radiologic progression and correlation of Genant and Larsen scores. Arthritis Rheum 43:1001-1009, 2000. 93. Shergy WJ, Cohen S, Greenwald M, et al: Anakinra inhibits the progression of radiographically measured joint destruction in rheumatoid arthritis. Arthritis Rheum 46:3420, 2002. 94. Wiesenhutter CW, Irish BL, Bertram JR: Treatment of patients with refractory rheumatoid arthritis with extracorporeal protein A immunoadsorption columns: A pilot trial. J Rheumatol 21:5, 1994. 95. Linsley PS, Brady W, Urnes M, et al: CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 174:561-569, 1991. 96. Moreland LW, Alten R, Van den Bosch F, et al: Costimulatory blockade in patients with rheumatoid arthritis: A pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion. Arthritis Rheum 46:1470-1479, 2002. 97. Collins AV, Brodie DW, Gilbert RJ, et al: The interaction properties of costimulatory molecules revisited. Immunity 17:201-210, 2002. 98. Kremer JM, Westhovens R, Leon M, et al: Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 349:1907-1915, 2003. 99. Genovese MC, Becker JC, Schiff M, et al: Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 353:1114-1123, 2005. 100. Weinblatt M, Combe B, Covucci A, et al: Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: A one-year randomized, placebo-controlled study. Arthritis Rheum 54:2807-2816, 2006. 101. Reff ME, Carner K, Chambers KS, et al: Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83:435-445, 1994. 102. Edwards JCW, Cambridge G: Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology (Oxf) 40:205, 2001. 103. Edwards JCW, Szczepanski L, Szechinski J, et al: Efficacy of B-celltargeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350:2572-2581, 2004. 104. Sell S, Max EE: All about B cells. In: Immunology, Immunopathology, and Immunity. Washington DC, ASM Press, 2001, p 101. 105. Anderson DR, Grillo-Lopez A, Varns C, et al: Targeted anti-cancer therapy using rituximab, a chimaeric anti-CD20 antibody (IDECC2B8) in the treatment of non-Hodgkin’s B-cell lymphoma. Biochem Soc Trans 25:705-708, 1997. 106. Clynes RA, Towers TL, Presta LG, et al: Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 6:443-446, 2000. 107. Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al; DANCER Study Group: The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: Results of a phase IIB randomized, double-blind, placebo-controlled, doseranging trial. Arthritis Rheum 54:1390-1400, 2006.

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108. Weinstein RS, Jilka RL, Parfitt AM, et al: Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. J Clin Invest 102:274, 1998. 109. Compton JE, Vedi S, Croucher PL, et al: Bone turnover in non-steroid treated rheumatoid arthritis. Ann Rheum Dis 53:163, 1994. 110. Kröger H, Honkanen R, Saarikoski S, et al: Decreased axial bone mineral density in perimenopausal women with rheumatoid arthritis: A population based study. Ann Rheum Dis 53:18, 1994. 111. Dequeker J, Geisems P: Osteoporosis and arthritis. Ann Rheum Dis 49:276, 1990. 112. Kirwan JR: The effect of glucocorticoids on joint destruction in rheumatoid arthritis. N Engl J Med 333:142, 1995. 113. van Everdingen AA, Jacobs JW, Siewertsz Van Reesema DR, et al: Low-dose prednisone therapy for patients with early active rheumatoid arthritis: Clinical efficacy, disease-modifying properties, and side effects: A randomized, double-blind, placebo-controlled clinical trial. Ann Intern Med 136:1-12, 2002. 114. Svensson B, Boonen A, Albertsson K, et al: Low-dose prednisolone in addition to the initial disease-modifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: A two-year randomized trial. Arthritis Rheum 52:3360-3370, 2005. 115. Wassenberg S, Rau R, Steinfeld P, et al: Very low-dose prednisolone in early rheumatoid arthritis retards radiographic progression over two years: A multicenter, double-blind, placebo-controlled trial. Arthritis Rheum 52:3371-3380, 2005. 116. Choy EH, Kingsley GH, Khoshaba B, et al; Intramuscular Methylprednisolone Study Group: A two year randomized controlled trial of intramuscular depot steroids in patients with established rheumatoid arthritis who have shown an incomplete response to disease modifying antirheumatic drugs. Ann Rheum Dis 64:1288-1293, 2005. 117. Fries JF, Williams CA, Ramsey DR, et al: The relative toxicity of disease-modifying antirheumatic drugs. Arthritis Rheum 36:297, 1993. 118. Wolfe F, Mitchell DM, Sibley JT, et al: The mortality of rheumatoid arthritis. Arthritis Rheum 37:481, 1994. 119. Ruegsegger P, Medici TC, Anliker M: Corticosteroid-induced bone loss: A longitudinal study of alternate day therapy in patients with bronchial asthma using quantitative computed tomography. Eur J Clin Pharmacol 25:615, 1994. 120. Hochberg MC, Prashker MJ, Greenwald M, et al: Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Am Coll Rheum 39:1791, 1996. 121. Wolfe MM, Lichtenstein DR, Singh G: Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 340:1888, 1999. 122. Abramson S, Weissmann G: The mechanisms of action of nonsteroidal anti-inflammatory drugs. Arthritis Rheum 32:1, 1989. 123. Silverstein FE, Faich G, Goldstein JL, et al: Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS (Celecoxib Long-Term Arthritis Safety Study) study: A randomized controlled trial. JAMA 284:1247-1255, 2000. 124. Bombardier C, Laine L, Reicin A, et al: Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 343: 1520-1528, 2000. 125. van der Heijde DMFM, van’t Hof MA, van Riel PLCM, et al: Judging disease activity in clinical practice in rheumatoid arthritis: First step in the development of a ‘disease activity score.’ Ann Rheum Dis 49:916-920, 1990. 126. van der Heijde DMFM, van’t Hof MA, van Riel PLCM, et al: Validity of single variables and composite indices for measuring disease activity in rheumatoid arthritis. Ann Rheum Dis 51:177-181, 1992. 127. www.das-score.nl/www.das-score.nl/home.html. Accessed May 13, 2008. 128. Smolen JS, Breedveld FC, Schiff MH, et al: A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology 42:244-257, 2003. 129. Aletaha D, Smolen J: The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): A review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol 23:S100-S108, 2005. 130. Wolfe F, Cathey MA: The assessment and prediction of functional disability in rheumatoid arthritis. J Rheumatol 18:1298-1306, 1999. 131. Wolfe F, Hawley DJ: The longterm outcomes of rheumatoid arthritis: Work disability: a prospective 18 year study of 823 patients. J Rheumatol 25:2108-2117, 1998.

132. Scott DL, Symmons DPM, Coulton BL, et al: Long-term outcome of treating rheumatoid arthritis: Results after 20 years. Lancet 1:1108, 1987. 133. Pincus T, Callahan LF, Sale WG, et al: Severe functional declines, work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over nine years. Arthritis Rheum 27:864, 1984. 134. Wolfe F, Sharp JT: Radiographic outcome of recent-onset rheumatoid arthritis: A 19-year study of radiographic progression. Arthritis Rheum 41:1571-1582, 1998. 135. Pincus T, Callahan LF, Fuchs HA, et al: Quantitative analysis of hand radiographs in rheumatoid arthritis: Time course of radiographic changes, relation to joint examination measures, and comparison of different scoring methods. J Rheumatol 22:1983-1989, 1995. 136. Pincus T, Fuchs HA, Callahan LF, et al: Early radiographic joint space narrowing and erosion and later malalignment in rheumatoid arthritis: A longitudinal analysis. J Rheumatol 25:636-640, 1998. 137. Fuchs HA, Kaye JJ, Callahan LF, et al: Evidence of significant radiographic damage in rheumatoid arthritis within the first two years of disease. J Rheumatol 16:585, 1989. 138. Singh G, Terry R, Ramey D, et al: Long-term medical costs and outcomes are significantly associated with early changes in disability in rheumatoid arthritis. Arthritis Rheum 39:S318, 1996. 139. Yelin E, Wanke LA: An assessment of the annual and long-term direct costs of rheumatoid arthritis: The impact of poor function and functional decline. Arthritis Rheum 42:1209-1218, 1999. 140. O’Dell JR: Treating rheumatoid arthritis early: A window of opportunity? Arthritis Rheum 46:283-285, 2002. 141. Korpela M, Laasonen L, Hannonen P, et al; FIN-RACo Trial Group: Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease-modifying antirheumatic drugs: Five-year experience from the FIN-RACo study. Arthritis Rheum 50:2072-2081, 2004. 142. Puolakka K, Kautiainen H, Mottonen T, et al; FIN-RACo Trial Group: Early suppression of disease activity is essential for maintenance of work capacity in patients with recent-onset rheumatoid arthritis: Five-year experiencee from the FIN-FACo trial. Arthritis Rheum 52:36-41, 2005. 143. Quinn MA, Conaghan PG, O’Connor PJ, et al: Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: Results from a twelve-month randomized double-blind, placebo-controlled trial. Arthritis Rheum 52:27-35, 2005. 144. Mottonen T, Paimela L, Leirisalo-Repo M, et al: Only high disease activity and positive rheumatoid factor indicate poor prognosis in patients with early rheumatoid arthritis treated with “sawtooth” strategy. Ann Rheum Dis 57:533, 1998. 145. Callahan LF, Pincus T, Huston JW III, et al: Measures of activity and damage in rheumatoid arthritis: Depiction of changes and prediction of mortality over five years. Arthritis Care Res 10:381, 1997. 146. Combe B, Dougados M, Goupille P, et al: Prognostic factors for radiographic damage in early rheumatoid arthritis: A multiparameter prospective study. Arthritis Rheum 44:1736-1743, 2001. 147. Combe B, Cantagrel A, Goupille P, et al: Predictive factors of 5-year health assessment questionaire disability in early rheumatoid arthritis. J Rheumatol 30:2344-2349, 2003. 148. Lindqvist E, Saxne T, Geborek P, et al: Ten year outcome in a cohort of patients with early rheumatoid arthritis: Health status, disease process, and damage. Ann Rheum Dis 61:1055-1059, 2002. 149. Smolen JS, Van Der Heijde DM, St Clair EW, et al; Active­Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) Study Group: ­Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: Results from the ASPIRE trial. Arthritis Rheum 54: 702-710, 2006. 150. Symmons DPM, Silman AJ: Aspects of early arthritis: What determines the evolution of early undifferentiated arthritis and rheumatoid arthritis? An update from the Norfolk Arthritis Register. Arthritis Res Ther 8:214, 2006. 151. Wolfe F, Zwillich SH: The long-term outcomes of rheumatoid arthritis: A 23-year prospective, longitudinal study of total joint replacement and its predictors in 1,600 patients with rheumatoid arthritis. Arthritis Rheum 41:1072, 1998.

PART 9  152. O’Dell JR, Nepom BS, Haire C, et al: HLA-DRB1 typing in rheumatoid arthritis: Predicting response to specific treatments. Ann Rheum Dis 57:209, 1998. 153. van der Helm-van Mil AH, Verpoort KN, Breedveld FC, et al: The HLA-DRB1 shared epitope alleles are primarily a risk factor for anticyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis. Arthritis Rheum 54:1117-1121, 2004. 154. van der Helm-van Mil AH, Verpoort KN, Breedveld FC, et al: Antibodies to citrullinated proteins and differences in clinical ­progression of rheumatoid arthritis. Arthritis Res Ther 7:R949-R958, 2005. 155. Vencovshy J, Machacek S, Sedova L, et al: Autoantibodies can be prognostic markers of an erosive disease in early rheumatoid arthritis. Ann Rheum Dis 62:427-430, 2003. 156. Berglin E, Johansson T, Sundin U, et al: Radiological outcome in rheumatoid arthritis is predicted by presence of antibodies against cyclic citrullinated peptide before and at disease onset, and by IgARF at disease onset. Ann Rheum Dis 65:453-458, 2006. 157. Turesson C, Jacobsson LT, Sturfelt G, et al: Rheumatoid factor and antibodies to cyclic citrullinated peptides are associated with severe extra-articular manifestations in rheumatoid arthritis. Ann Rheum Dis 66:59-64, 2007. 158. Weyand C, Goronzy J: Prognosis in rheumatoid arthritis: Applying new technologies to old questions. J Rheumatol 20:11, 1993. 159. Ostergaard M, Hansen M, Stoltenberg M, et al: Magnetic resonance imaging-determined synovial membrane volume as a marker of disease activity and a predictor of progressive joint destruction in the wrists of patients with rheumatoid arthritis. Arthritis Rheum 42:918, 1999. 160. Backhaus M, Kamradt T, Sandrock D, et al: Arthritis of the finger joints: A comprehensive approach comparing conventional radiography, scintigraphy, ultrasound, and contrast-enhanced magnetic resonance imaging. Arthritis Rheum 42:1232-1245, 1999. 161. Dohn UM, Ejbjerg BJ, Court-Payen M, et al: Are bone erosions detected by magnetic resonance imaging and ultrasonography true erosions? A comparison with computed tomography in rheumatoid arhritis. Arthritis Res Ther 8:R110, 2006. 162. Pincus T: Formal educational level: A marker for the importance of behavioral variables in the pathogenesis, morbidity, and mortality of most diseases? J Rheumatol 15:10, 1988. 163. Pincus T, Callahan LF: Formal education as a marker for increased mortality and morbidity in rheumatoid arthritis. J Chron Dis 311:552, 1984. 164. Lorig K, Seleznick M, Lubeck D, et al: The beneficial outcomes of the arthritis self-management course are not adequately explained by behavioral change. Arthritis Rheum 32:91, 1989. 165. Lorig KR, Mazonson PD, Holman HR: Evidence suggesting that health education for self-management in patients with chronic

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arthritis has sustained health benefits while reducing health care costs. Arthritis Rheum 36:439, 1993. 166. Lorig K, Ritter PL, Plant K: A disease-specific self-help program compared with a generalized chronic disease self-help program for arthritis patients. Arthritis Rheum 53:950-957, 2005. 167. Taal E, Rasker JJ, Wiegman O: Patient education and self-management in the rheumatic diseases: A self-efficacy approach. Arthritis Care Res 9:229, 1996. 168. Parker JC, Smarr KL, Buckelew SP, et al: Effects of stress management on clinical outcomes in rheumatoid arthritis. Arthritis Rheum 38:1807, 1995. 169. Bellamy N, Bradley L: Workshop on chronic pain, pain control, and patient outcomes in rheumatoid arthritis and osteoarthritis. Arthritis Rheum 39:357, 1996. 170. Rall LC, Meydani SN, Kehayias JJ, et al: The effect of progressive resistance training in rheumatoid arthritis. Arthritis Rheum 39:415, 1996. 171. Harcom TM, Lampan RM, Banwell BF, et al: Therapeutic value of graded aerobic exercise training in rheumatoid arthritis. Arthritis Rheum 28:32, 1985. 172. Helewa A, Goldsmith CH, Lee P, et al: Effects of occupational therapy home service on patients with rheumatoid arthritis. Lancet 337:1453, 1991. 173. Ward MM, Leigh JP, Fries JF: Progression of functional disability in patients with rheumatoid arthritis. Arch Intern Med 153:2229, 1993. 174. Wolfe F, Hawley DJ, Cathey MA: Clinical and health status measures over time: Prognosis and outcome assessment in rheumatoid arthritis. J Rheumatol 18:1290, 1991. 175. MacLean CH, Louie R, Leake B, et al: Quality of care for patients with rheumatoid arthritis. JAMA 284:984-992, 2000. 176. Criswell LA, Such CL, Neuhaus JM, et al: Variation among rheumatologists in clinical outcomes and frequency of office visits for rheumatoid arthritis. J Rheumatol 24:7, 1997. 177. Kremer JM, Jubiz W, Michalek A, et al: Fish-oil fatty acid supplementation in active rheumatoid arthritis: A double-blinded, controlled, crossover study. Ann Intern Med 106:497, 1987. 178. Geusens P, Wouters C, Nijs J, et al: Long-term effect of omega-3 fatty acids of active rheumatoid arthritis. Arthritis Rheum 37:824, 1994. 179. Leventhal LJ, Boyce EG, Zurier RB: Treatment of rheumatoid arthritis with gamma-linolenic acid. Ann Intern Med 119:867, 1993. 180. Cleland LG, Caughey GE, James MJ, et al: Reduction of cardiovascular risk factors with longterm fish oil treatment in early rheumatoid arthritis. J Rheumatol 33:1931-1933, 2006. 181. McCarey DW, McInnes IB, Madhok R, et al: Trial of Atorvastatin in Rheumatoid Arthritis (TARA): Double-blind, randomized placebocontrolled trial. Lancet 363:2015-2021, 2004.

68

Felty’s Syndrome ROBERT S. PINALS

KEY POINTS Diagnosis of Felty’s syndrome requires granulocytopenia, but splenomegaly is not always present. Felty’s syndrome must be distinguished from large granular lymphocytosis. There is a high frequency of vasculitis and other extraarticular complications. Decreased granulocyte numbers and function lead to bacterial infections. Treatment includes disease-modifying antirheumatic drugs and granulocyte growth factors. Splenectomy is rarely indicated.

In 1924, Felty described the triad of chronic arthritis, splenomegaly, and granulocytopenia. Felty’s syndrome represents one of many systemic complications of seropositive rheumatoid arthritis (RA) occurring in patients with unusually severe extra-articular disease and immunologic abnormalities.1 Persistent granulocytopenia (<2000/mm3) must be present, but the complete triad is not required for a diagnosis of Felty’s syndrome because patients without splenomegaly resemble patients with full-blown Felty’s syndrome in terms of most clinical, serologic, and immunogenetic features.1

EPIDEMIOLOGY The true prevalence of Felty’s syndrome is unknown, but it may be 3% in RA patients.2 About two thirds of patients are women. HLA-DR4 is found in 95% of patients with Felty’s syndrome.1 This fact may account for the rarity of Felty’s syndrome in blacks, who are known to have a low frequency of HLA-DR4. The condition usually is recognized in the fifth through seventh decades of life in patients who have had RA for 10 years or more.2 Splenomegaly and granulocytopenia may be present before symptoms or signs of arthritis in rare instances.

GENETICS The familial occurrence of Felty’s syndrome suggests that immunogenetic factors are operative.3 The presence of two HLA-DRB1*04 alleles encoding the shared epitope is associated with increased risk of extra-articular manifestations in RA, but only Felty’s syndrome is also associated with HLA-DRB1*0401.4 About one third of patients with Felty’s syndrome have significant clonal expansions of CD3+/CD8+ large granular

lymphocytes in their peripheral blood (Fig. 68-1). When originally described, this group of patients with RA and large granular lymphocytosis (LGL), an indolent lymphocytic leukemia, was considered to represent a separate syndrome. Immunogenetic studies have shown, however, the same HLA-DR4 associations in LGL as in other patients with Felty’s syndrome.5 Additionally, there is an absence of distinguishing clinical or serologic features, suggesting that separation on the basis of peripheral blood lymphocyte morphology may be unjustified.5,6 Large granular lymphocytes compose about 5% of the mononuclear cells in normal human blood. Cells with natural killer and antibody-dependent cell-mediated cytotoxic activity are found in this population. The cells usually lack surface immunoglobulin, but frequently express certain surface phenotypes, such as CD3, CD8, CD16, and CD57. Among patients with a clonal proliferation of these cells, neutropenia, splenomegaly, and susceptibility to infections are common. In some cases, there is a progressive course of malignant proliferation, but most cases are benign and require no specific therapy. About 25% of patients with LGL have inflammatory arthritis, and these patients have an immunogenetic pattern typical of Felty’s syndrome. In contrast, the frequency of HLA-DR4 in patients without arthritis is not different from that in control subjects.

PATHOGENESIS Mechanisms for the development of granulocytopenia include accelerated removal of granulocytes from the circulating pool and suppression of granulopoiesis. Ingestion and surface coating of immune complexes leads to impaired granulocyte function and facilitates their removal by the reticuloendothelial system. Specific antibodies directed against granulocyte cell surface antigens and complement activation also may be involved. Sequestration or margination of granulocytes in the spleen and venules in the lungs and elsewhere results in a diminished circulating pool. In some patients, the marrow does not respond appropriately to granulocytopenia because of humoral or T cell suppression of myelopoiesis.7-9 There may be different subsets of Felty’s syndrome, based on humoral and cell-mediated mechanisms, and more than one mechanism may account for neutropenia in an individual patient. Autoantibodies against granulocyte colony-stimulating factor (G-CSF) may play a role in some cases.9 Elevated levels of serum G-CSF are usually present, regardless of the presence or absence of autoantibodies, suggesting that the myeloid cells in Felty’s syndrome are hyposensitive to G-CSF. In LGL, an additional factor in the pathogenesis of neutropenia is the Fas ligand, a member of the tumor necrosis 1145

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Felty’s Syndrome

Table 68-1  Frequency of Extra-articular   Manifestations in Felty’s Syndrome* Manifestation

76

Weight loss

68

Sjögren’s

Figure 68-1  Peripheral blood smear with large granular lymphocytes.

factor family.7,10 Fas ligand is expressed on the surface of activated cytotoxic T cells, and elevated levels of soluble Fas ligand are found in sera of most patients.11 Sera from patients with LGL have been shown to facilitate apoptosis of normal neutrophils in vitro. The increased susceptibility to infection is probably related to several factors in addition to granulocytopenia. Granulocyte reserves are diminished, and defective function of granulocytes in phagocytosis, chemotaxis, and superoxide production has been shown.

CLINICAL FEATURES The articular disease is usually severe, but not more so than in seropositive RA of comparable duration.2 About one third of patients have inactive synovitis as judged by signs and symptoms, but even these patients continue to have an elevated erythrocyte sedimentation rate. In one large series, the mean erythrocyte sedimentation rate was 85 mm/hr.12 The spleen size varies. In 5% to 10% of patients, the spleen is not large enough to be palpable, but occasionally there is massive splenomegaly.12 The median splenic weight in Felty’s syndrome is about four times normal. There is no correlation between spleen size and the degree of granulocytopenia.12 Patients with Felty’s syndrome tend to have more extraarticular manifestations than other patients with RA (Table 68-1). Weight loss may be striking and unexplained, often occurring for several months before the diagnosis of Felty’s syndrome is made. Brown pigmentation over exposed surfaces of the extremities, especially over the tibia, may be related to stasis and to extravasation of red blood cells secondary to disease of small vessels.12 Leg ulcers are seen frequently, but do not seem to differ from ulcers in other RA patients in terms of chronicity, recurrence, and presumed relationship to vasculitis.

COMPLICATIONS Felty’s syndrome patients have an increase in frequency of infections compared with matched RA control subjects.1,13 The degree of granulocytopenia correlates poorly with the number and severity of infections until the granulocyte count is less than 1000/mm3. Other risk factors for ­infection

Frequency (%)

Rheumatoid nodules syndrome†

56

Lymphadenopathy

34

Leg ulcers

25

Pleuritis

19

Skin pigmentation

17

Neuropathy

17

Episcleritis 8 *From a review of 10 reports since 1962. †Determined by positive Schirmer’s test. Data from Goldberg J, Pinals RS: Felty syndrome. Semin Arthritis Rheum 10:52, 1980.

include skin ulcers, corticosteroids, comorbid medical conditions, severity of the underlying rheumatoid process, and resulting disability.13,14 Most infections are caused by common bacteria, such as staphylococci, streptococci, and gramnegative bacilli,1,14 and involve common sites, particularly the skin and respiratory tract. Despite the granulocytopenia, pus may accumulate in an appropriate fashion, suggesting that the site of infection is capable of competing successfully with the spleen for available granulocytes. The response to antibiotic therapy is usually adequate.12,14 Mild hepatomegaly is common in Felty’s syndrome, and elevations of alkaline phosphatase and the transaminases are described in about a quarter of the patients.1,12 An unusual type of liver involvement may be associated with Felty’s syndrome, but occurs rarely in other RA patients.15 Histologically, the picture is described as nodular regenerative hyperplasia. Although there is mild portal fibrosis or infiltration with lymphocytes and plasma cells, the appearance is not characteristic of cirrhosis. Obliteration of portal venules may compromise portal blood flow, leading to atrophy and regenerative nodule formation, portal hypertension, and gastrointestinal hemorrhage. Patients with Felty’s syndrome are at increased risk for the development of malignancies, particularly non-Hodgkin’s lymphoma.16

HEMATOLOGIC AND SEROLOGIC FEATURES The leukopenia in Felty’s syndrome is relative with absolute granulocytopenia, in contrast to systemic lupus erythematosus, in which lymphopenia is a more prominent feature. There is often considerable spontaneous variation in the granulocyte count. Patients with mild lowering may return to the normal range, but this is rarely seen when depression is severe. Spontaneous remissions have been observed,1 but are uncommon.12 During infections or other stressful episodes, the granulocyte count often returns to the normal range, but is seldom elevated. This situation may conceal the diagnosis temporarily because blood counts may be ordered mainly in the setting of an infection or other acute illness. The bone marrow may show no abnormality, but in most cases, there is a myeloid hyperplasia, with an excess

PART 9 

of immature forms, often described as “maturation arrest.” Although this condition might reflect an impaired myelopoietic response, early release of mature forms would result in the same appearance.12 Rarely, in Felty’s syndrome but more commonly in LGL, the marrow shows a depression in myeloid activity and increased lymphocytic infiltration. A mild-to-moderate anemia is found in most patients, representing the anemia of chronic disease with an additional component of shortened red blood cell survival, which is corrected by splenectomy. Thrombocytopenia is seldom severe enough to cause purpura. The alterations in immune response commonly found in RA are amplified in patients with Felty’s syndrome. Rheumatoid factor is present in 98% of patients, generally in high titer1,12; antinuclear antibodies are found in 62% to 80%1; and antineutrophil cytoplasmic antibodies are found in 77%. Most of the last-mentioned are reactive against lactoferrin.17 Immunoglobulin levels are higher than in other RA patients, and complement levels are occasionally low, although most patients have levels within the normal range.1,12 Immune complexes have been detected by various techniques in most patients with Felty’s syndrome, always in much higher frequency than in RA control subjects.1,12

DIFFERENTIAL DIAGNOSIS Patients with RA also may develop superimposed illnesses that result in splenomegaly or granulocytopenia. Drug reactions, myeloproliferative disorders, reticuloendothelial malignancies, hepatic cirrhosis, amyloidosis, sarcoidosis, tuberculosis, and other chronic infections must be considered and excluded with reasonable clinical certainty before the diagnosis of Felty’s syndrome is accepted.

MANAGEMENT There have been no controlled trials of any treatment for Felty’s syndrome. Specific treatment for granulocytopenia is unnecessary except in patients who have experienced bacterial infections or patients who are at high risk (granulocyte count <1000/mm3). Frequently, granulocytopenia may improve during treatment with disease-modifying antirheumatic drugs.12 Gold salt injections resulted in a complete hematologic response in 60% of patients and partial response in 20% in the largest reported series, but gold salts and other older diseasemodifying antirheumatic drugs have been displaced by newer drugs. Methotrexate is currently the most commonly used agent.3,7,18 No controlled or comparative studies are available, but granulocytopenia usually improves with this treatment more rapidly than with gold salts, often within 2 months. Some patients have been followed for more than 1 year, without relapse or infection.18 Low doses of corticosteroids do not produce consistent improvement in granulocytopenia and predispose to infection. There is limited experience with other drugs, including leflunomide and cyclosporine.3,7 A few case reports on the use of new biologic agents have shown mixed results.19 The mechanisms whereby second-line agents increase granulocyte counts are undetermined, as are their response rates and efficacy. Treatment may be directed specifically at the granulocytopenia, using the granulopoietic growth factors. Several

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years of experience with the granulopoietic growth factors have confirmed their usefulness in increasing granulocyte counts within a short time and aiding in the resolution of infection.20-23 Continued therapy is necessary to maintain these benefits, however, and high costs may become an issue. Prolonged use has been reported in some patients,21-23 but it may be more reasonable to use granulopoietic growth factors for a limited period, during which disease-modifying antirheumatic drug therapy is undertaken. G-CSF seems to have fewer adverse effects than granulocyte-macrophage colony-stimulating factor. Significant adverse effects of these agents include exacerbation of arthritis, new onset of leukocytoclastic vasculitis, anemia, thrombocytopenia, and bone pain. To avoid or minimize these adverse effects, the initial use of low doses of G-CSF (3 μg/kg/day) and a short course of prednisone (20 to 30 mg/day) has been suggested.7 A few patients are partially or completely unresponsive to G-CSF. Because splenectomy usually reverses the hematologic abnormalities in Felty’s syndrome, it has been advocated in the past as the treatment of choice.12 The frequency of splenectomy has declined over the last 20 years, however, and currently it is reserved for patients who have not responded adequately to drug therapy. A prompt hematologic response is observed within minutes or hours after splenectomy, but granulocytopenia recurs and persists in about one quarter of these patients.12 Continuing immune-mediated granulocyte sequestration may be responsible for these secondary failures. Recurrent or persistent infection was noted in only 26% of patients in one large series, but in 60% in four others.12 Patients who did not experience infection before splenectomy usually continued to be free of infection afterward, whereas the patients with the most severe infections had variable and inconsistent responses to splenectomy, suggesting that functional defects in granulocytes and disease severity variables may be as important as granulocytopenia in determining susceptibility to infection.14 Thrombocytopenia usually improves after splenectomy, and anemia improves, to the extent that it is due to a hemolytic component. Although dramatic improvement in synovitis has been observed, it is often temporary and does not occur in most cases. Leg ulcers also may respond, even ulcers that are not significantly infected, but the variability in etiology and natural course makes these reports difficult to interpret.12 Remission was induced in two patients with refractory Felty’s syndrome by immunoablative high-dose cyclophosphamide without stem cell rescue.24 This approach is experimental, and long-term results are unknown. The treatment of granulocytopenia in patients with LGL is generally similar to that in Felty’s syndrome. Methotrexate3,7,25 and G-CSF3,20,21 have been used successfully. Cyclosporine may be indicated in refractory cases because it inhibits secretion of Fas ligand.7 Splenectomy is less likely to be effective.3

PROGNOSIS Patients with Felty’s syndrome had a death rate similar to matched RA control subjects in a prospective study initiated in 1966. Despite a higher rate of infection, death as a result of sepsis (10%) was not more frequent in patients with

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Felty’s Syndrome

Felty’s syndrome than in control subjects.2 In another large series, 25% of deaths in patients with Felty’s syndrome were due to sepsis.1 There is little information on survival and prognosis in LGL, but no marked differences from Felty’s syndrome have been reported.6 REFERENCES   1. Campion G, Maddison PJ, Goulding N, et al: The Felty syndrome: A case-matched study of clinical manifestations and outcome, serologic features, and immunogenetic association. Medicine 69:69, 1990.   2. Sibley JT, Haga M, Visram DA, et al: The clinical course of Felty’s syndrome compared to matched controls. J Rheumatol 18:1163, 1991.   3. Burks EJ, Loughran TP Jr: Pathogenesis of neutropenia in large granular lymphyocyte leukemia and Felty’s syndrome. Blood Rev 20:245, 2006.   4. Turesson C, Schaid DJ, Weyand CM, et al: The impact of HLADRB1 genes on extra-articular disease manifestations in rheumatoid arthritis. Arthritis Res Ther 7:1386, 2005.   5. Bowman SJ, Corrigall V, Panayi GS, et al: Hematologic and cytofluorographic analysis of patients with Felty’s syndrome: A hypothesis that a discrete event leads to large granular lymphocyte expansions in this condition. Arthritis Rheum 38:1252, 1995.   6. Starkebaum G, Loughran TP Jr, Gaur LK, et al: Immunogenetic similarities between patients with Felty’s syndrome and those with clonal expansions of large granular lymphocytes in rheumatoid arthritis. Arthritis Rheum 40:62, 1997.   7. Starkebaum G: Chronic neutropenia associated with autoimmune disease. Semin Hematol 39:121, 2002.   8. Ditzel HJ, Masaki Y, Nielsen H, et al: Cloning and expression of a novel human antibody-antigen pair associated with Felty’s syndrome. Proc Natl Acad Sci U S A 97:9234, 2000.   9. Hellmich B, Csernok E, Schatz H, et al: Autoantibodies against granulocyte colony-stimulating factor in Felty’s syndrome and neutropenic systemic lupus erythematosus. Arthritis Rheum 46:2384, 2002.

10. Perzova R, Loughran TP: Constitutive expression of Fas ligand in large granular lymphocyte leukemia. Br J Haematol 97:123, 1997. 11. Liu JH, Wei S, Lamy T, et al: Chronic neutropenia mediated by fas ligand. Blood 95:3219, 2000. 12. Goldberg J, Pinals RS: Felty syndrome. Semin Arthritis Rheum 10:52, 1980. 13. Doran MF, Crowson CS, Pond GR, et al: Predictors of infection in rheumatoid arthritis. Arthritis Rheum 46:2294, 2002. 14. Breedveld FC, Fibbe WE, Hermans J, et al: Factors influencing the incidence of infections in Felty’s syndrome. Arch Intern Med 147:915, 1987. 15. Thorne C, Urowitz MB, Wanless IR, et al: Liver disease in Felty’s syndrome. Am J Med 73:35, 1982. 16. Gridley G, Klippel JH, Hoover RN, et al: Incidence of cancer among men with the Felty syndrome. Ann Intern Med 120:35, 1994. 17. Coremans IEM, Hagen EC, van der Voort EAM, et al: Autoantibodies to neutrophil cytoplasmic enzymes in Felty’s syndrome. Clin Exp Rheumatol 11:255, 1993. 18. Wassenberg S, Herborn G, Rau R: Methotrexate treatment in Felty’s syndrome. Br J Rheumatol 37:908, 1998. 19. Ghavami A, Genevay S, Fulpius T, et al: Etanercept in treatment of Felty’s syndrome. Ann Rheum Dis 64:1090, 2005. 20. Hellmich B, Schnabel A, Gross WL: Treatment of severe neutropenia due to Felty’s syndrome or systemic lupus erythematosus with granulocyte colony-stimulating factor. Semin Arthritis Rheum 29:82, 1999. 21. Stanworth SJ, Bhavnani M, Chattopadhya C, et al: Treatment of Felty’s syndrome with the haemopoietic growth factor granulocyte colony-stimulating factor (G-CSF). QJM 91:49, 1998. 22. Starkebaum G: Use of colony-stimulating factors in the treatment of neutropenia associated with collagen vascular disease. Curr Opin Hematol 4:196, 1997. 23. Graham KE, Coodley GO: A prolonged use of granulocyte colony stimulating factor in Felty’s syndrome. J Rheumatol 22:174, 1995. 24. Brodsky RA, Petri M, Smith BD, et al: Immunoablative high-dose cyclophosphamide without stem-cell rescue for refractory, severe autoimmune disease. Ann Intern Med 129:1031, 1998. 25. Hamidou MA, Sadr FB, Lamy T, et al: Low-dose methotrexate for the treatment of patients with large granular lymphocyte leukemia associated with rheumatoid arthritis. Am J Med 108:730, 2000.

69

Sjögren’s Syndrome STEVEN CARSONS

KEY POINTS Sicca complex consists of xerostomia, xerophthalmia, and salivary gland swelling. Extracranial xeroses include xerotrachea, bronchitis sicca, dry skin, and vaginal dryness. Extraglandular manifestations include neuropathy, pulmonary involvement, interstitial nephritis, cutaneous vasculitis, and lymphoproliferation.

In 1933, Sjögren1 described the association of filamentary ­ keratitis with arthritis. Previously, in 1882, Leber2 had described filamentary keratitis, and in 1888, Mikulicz3 had described a patient with bilateral lacrimal and parotid gland enlargement. Biopsy of these glands revealed extensive round cell infiltration. In 1953, Morgan and Castleman4 noted the similarity between the glandular enlargement described by Mikulicz and the keratitis described by Sjögren. Subsequently, these disorders were considered to be variants of the same process, and the term Sjögren’s syndrome (SS) became more widely used.5 In 1980, Talal6 introduced the term autoimmune exocrinopathy; subsequently, Skopouli and Moutsopoulos7 introduced the term autoimmune epitheliitis. Both these terms emphasize the cause and systemic nature of the disease.

DEFINITIONS The use of multiple terms to describe this condition, along with (until recently) the lack of consensus regarding classification criteria, has led to confusion. Primary SS is best defined as dry eyes and dry mouth secondary to autoimmune dysfunction of the exocrine glands. Secondary SS is the same disease in the presence of another autoimmune connective tissue disorder. Until relatively recently (1980), the terms sicca syndrome and sicca complex were used interchangeably with SS in the literature, and their routine use in clinical settings persists today. Sicca is probably best used in its most literal sense, which is “dry” (Latin). Some clinicians use the term sicca to describe patients with dry eyes, dry mouth, or both who do not fulfill the accepted criteria for complete SS. The term Sjögren’s syndrome is preferred for all patients who meet the classification criteria for the disorder or who are definitively diagnosed with it.

EPIDEMIOLOGY SS is a common autoimmune disorder. Prevalence estimates range from approximately 0.5% to 5%. The incidence rate in Olmstead County, Minnesota, was estimated to be 3.9 cases

per 100,000 population.8 Approximately half of all cases of SS are primary. Similar to most autoimmune disorders, the vast majority of cases (approximately 90%) occur in women.8 Although the majority of cases occur in midlife, the disorder is also seen in children9 and the elderly.10 Remarkably little difference in clinical presentation is noted among populations that differ on the basis of age, gender, and geographic origin.9,11-13 Prevalence rates stated in the literature vary, depending on the identifying variable chosen for study. For instance, a postmortem survey of lacrimal pathology found that 7.8% of individuals lacking a premortem diagnosis of an autoimmune disorder had moderate to severe (grade III or IV) lymphocytic infiltration.14 Of 2500 serum samples obtained from female blood donors between the ages of 20 and 50 years, 0.44% had antibodies to SS-A.15 Schein and colleagues16 assessed 2481 elderly individuals residing in Salisbury, Maryland, and found the prevalence of dry eye or mouth to be 27%. In populations in which the prevalence of keratoconjunctivitis sicca (KCS) and primary SS is measured simultaneously, the prevalence of KCS always exceeds that of complete primary SS.10,17-26 Table 69-1 describes the prevalence of primary SS in several diverse populations.

CAUSE AND PATHOGENESIS Animal models of SS have provided some important insights regarding the immunopathogenesis of this disease: (1) SS has a strong immunogenetic component, (2) the inflammatory infiltrate is largely T cell driven, (3) autoimmune sialadenitis can be triggered by viral infection, (4) relatively specific autoantibodies are produced, and (5) genes regulating apoptosis influence the chronicity of lymphocytic infiltration and are candidates for therapeutic manipulation. IMMUNOGENETICS Direct clinical observation suggests a genetic component to SS, such as the presence of primary SS and autoimmune hemolytic anemia in sisters27 and the identification of primary SS in Caucasian monozygotic twins and their mother.28 Like many other autoimmune disorders, early human lymphocyte antigen (HLA) studies identified an association with serologically defined HLA-B829 and HLADR3.30 Later studies demonstrated that the HLA-DR2 and -DR3 associations were secondary to linkage disequilibrium with HLA-DQ alleles.31 Genetically defined allelic markers subsequently identified a large number of polymorphisms involving the HLA-DRB1/DQA1/DQB1 haplotype, which adds to the complexity of the genetic background of SS. These polymorphisms vary with ethnicity, clinical manifestations, and, importantly, the autoantibody response. 1149

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Table 69-1  Prevalence of Primary Sjögren’s Syndrome Reported from Different Populations Author of Study

Year of Study

Population Studied

Criteria Used

Findings

Reference

Strickland

1987

103 Caucasian females

European

PSS: 2%  Probable PSS: 12%

10

Drosos

1988

62 Greek nursing home residents

Greek

PSS: 6%  Probable PSS: 12%

17

Jacobsson

1989

705 Swedish adults

Copenhagen

KCS: 14.9%  PSS: 2.7%

18

Zhang

1995

2166 Chinese adults

Copenhagen

PSS: 0.77%

19

Bjerrum

1997

504 Danish adults   (aged 30-60 yr)

Preliminary European

KCS: 8%  PSS: 0.6-2.1%

20

Dafni

1997

837 rural Greek females

Preliminary European

PSS: 0.6%  Probable PSS: 2.99%

21

Thomas

1998

1000 British adults

Preliminary European

PSS: 3.3%

22

Tomsic

1999

332 Slovenian adults

Preliminary European

PSS: 0.6%

23

Bowman

2004

864 Caucasian females

AEC

PSS: <0.1-0.4%

24

Alamanos

2006

422 Greek cases

AEC

PSS: 0.92%

25

Kabasakal

2006

Turkish females

AEC

PSS: 1.56%

26

AEC, American-European consensus; KCS, keratoconjunctivitis sicca; PSS, primary Sjögren’s syndrome.

In Caucasian individuals, the HLA-DRB1*0301/DQA1* 0501/DQB1*0201 haplotype has the strongest association with the production of SS-A and SS-B. Additional genes located in the major histocompatibility complex (MHC) region on chromosome 6, but not classically associated with class I or II alleles, have been linked to SS. These include transporters associated with antigen processing, genes situated between the DP and DQ regions,32,33 and the tumor necrosis factor (TNF) alleles (particularly TNF-α)34 located in the central MHC, telomeric to the complement synthesis genes.31 Recently, two genes located on chromosome 1—the interleukin (IL)-10 promoter region35 and glutathione S-transferase M136—have been linked to susceptibility to SS. IMMUNOLOGIC ALTERATIONS IN PERIPHERAL BLOOD Similar to other autoimmune disorders, the peripheral blood of patients with SS demonstrates a relative T cell lymphopenia, normal ratios of CD4+ and CD8+ T cells, and increases in activated T cells as determined by coexpression of CD3, CD4, and CD8 antigens with HLA-DR, CD25 (IL-2R), and very late antigen-1 (CD49a).37-39 Expression of natural killer antigens (CD16) is variable, ranging from normal to diminished.37,40 However, killing of K562 cells by SS peripheral blood mononuclear cells is reduced compared with normal controls.41 In contrast to T cells, circulating B cells are increased in SS.42 B cells from the majority of SS patients express enhanced levels of CD5 (also known as Ly-1 or B1),43 an interesting finding in light of the role played by CD5 B cells in B cell malignancies such as chronic lymphocytic leukemia. In addition to the presence of antibody to SS-A and SS-B in 75% and 40% of patients, respectively,44 approximately two thirds of SS patients have serum antinuclear antibody (ANA) and rheumatoid factor (RF) activity. Many SS patients have striking polyclonal hypergammaglobulinemia. In fact, immunoglobulin (Ig) levels in SS are often higher than those seen in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and other connective tissue disorders. Several studies point to a role for IgA in the

Figure 69-1  Histopathologic section of a salivary gland from a patient with Sjögren’s syndrome. Normal glandular architecture is replaced by a sea of mononuclear cells. Remnants of acinar and ductal structures can be seen. Note the formation of a germinal center–like cluster. (Courtesy of Dr. John Fantasia, Long Island Jewish Medical Center.)

­immunopathogenesis of this disorder, especially because it appears to be synthesized locally in inflamed glands. IgA is frequently elevated in the serum of SS patients,45 particularly as IgA-containing RF.46 AUTOIMMUNE SIALADENITIS: THE IMMUNOPATHOLOGIC LESION The hallmark of autoimmune exocrinopathy is infiltration of tissue by mononuclear cells that form distinct aggregates termed foci.47 Aggregates tend to occur in periductal and periacinar locations and may become confluent, resulting in the replacement of epithelial structure (Fig. 69-1). Remnants of glands surrounded by large numbers of infiltrating mononuclear cells are known as epimyoepithelial islands. Plasma cells are noted within foci and at the periphery of periductal and periacinar foci. Glands with significant mononuclear infiltration may also display germinal center formation.

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PHENOTYPE OF THE INFILTRATING LYMPHOCYTES T Cell Compartment In 1982, Fox and coworkers48 described the classic finding of the predominance of CD4+ T cells among lymphocytes infiltrating the minor salivary gland (MSG). In this study, the CD4/CD8 ratio was 3:1. CD4+ predominance was also noted in peripheral blood. Although CD8+ T cells constitute a minority, they tend to localize around acinar epithelial cells.49 B cells make up a minority of the lymphocyte population in tissue, and a subset of B cells present in tissue is absent in peripheral blood.50 Infiltrating lymphocytes are activated, expressing DR, DQ, CD25, CD9, and CD10, but they are specifically distributed in the peripheral portion of the periductal foci. Bias in T cell receptor gene use has been examined as a measure of response to putative autoantigen. Most studies do not support clonal T cell restriction but rather relative expansion of certain T cell receptor genes. Studies from Japan and Europe have identified expansion of Vβ2, Vβ8, and Vβ13 T cells.51-53 B Cell Compartment Plasma cells expressing IgG, IgA, and IgM are found in SS salivary glands. IgA is the predominant isotype; however, enrichment of IgM-positive cells to a level exceeding 10% appears to be specific for SS.54 Clusters of IgA-­positive cells have been localized adjacent to DR-expressing epithelium,55 suggesting that the microenvironment of the activated glandular epithelium contributes to plasma cell differentiation and local IgA synthesis. Enhanced local synthesis of immunoglobulin is suggested by the finding of enrichment of anti–SS-B IgA in the saliva of SS patients.56 CD20+ B cells constitute a significant and early component of periductal foci, where they eventually colocalize with distinct CD27+/CD38+ cells.57 Germinal centers have been identified in SS glands; serum levels of membrane cofactor protein-1, interferon-γ, and B cell activating factor (BAFF) best ­ correlate with the presence of germinal centers.58 There is evidence that BAFF is antiapoptotic in SS, and BAFF levels are highest in SS patients with hypergammaglobulinemia.59 Thus, BAFF may represent a new therapeutic target. TRAFFICKING AND ADHESION OF INFLAMMATORY CELLS The first step in inflammatory cell infiltration occurs at the glandular endothelium. Vessels in the inflamed gland express vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecules (ICAMs), and P- and E-selectins. Mononuclear cells surrounding blood vessels express lymphocyte function-associated antigen-1 (LFA-1), α4 and α5 integrins, and CD44.60 Marked expression of ICAM and VCAM-1 can be observed in venules surrounded by CD4+CD45RO+ T cells.61 High levels of the chemokine CXCL-13 has been found on endothelial cells; its counterreceptor, CXCR5, is observed on B cells organizing into germinal center–like structures.62 Treatment of nonobese diabetic mice with antibody to VCAM-1, α4 integrin, L-selectin, or LFA-1 almost completely inhibits lymphocyte ingress into inflamed glands.63

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Mononuclear cells use adhesion mechanisms to migrate to epithelial structures. Enhanced laminin expression is often found in the ductal epithelium of involved glands and is observed in areas not yet affected by lymphocytic infiltrate,64 leading to speculation that laminin expression is an early event in the disease process. ICAM-1 is expressed on ductal and acinar epithelial cells together with LFA-1, which is expressed on surrounding mononuclear cells.60 In contrast to the marked expression of CXCL-13 seen on endothelium, CXCL-12 (SDF-1) is strongly expressed on ductal epithelium, accompanied by only weak expression of CXCL-13. CXCR4, the counterreceptor for CXCL-12, localizes to periductal T cells.62 CD8+ T cells surrounding acinar epithelium display the integrin αEβ7 and thus may use cadherin E to bind epithelial cells.49 Importantly, acinar epithelial cells adjacent to αEβ7+ CD8+ T cells display apoptotic changes consistent with cytotoxic acinar cell destruction. CYTOKINE PROFILE Studies using immunohistochemical and in situ hybridization methods demonstrate the uniform presence of the proinflammatory cytokines IL-1β, TNF-α, IL-2, and IL-6 in MSG biopsies of SS patients.65-69 These cytokines localize to mononuclear cell infiltrates and epithelium. TNF-α and TNF receptor (TNF-R) are present in the inflammatory infiltrate, vascular endothelium, and ductal epithelium, where they appear to be tightly coexpressed.70 Acinar cells, however, do not express TNF-α or TNF-R-p75, but they do express TNF-R-p55, suggesting regional differences in susceptibility to apoptosis. Enhanced expression of STAT-1α mRNA and STAT-1α phosphorylation in SS labial salivary glands suggests a proinflammatory role for interferon-γ.71 Interestingly, CD4+ T cell clones originating from the MSG in organ culture produce levels of IL-10 that are 15-fold higher than those produced by similar clones derived from peripheral blood. In peripheral blood, B cells and monocytes produce approximately 90% of mononuclear-derived IL-10.72 Perhaps factors present in MSG tissue in vivo inhibit IL-10 production. BAFF levels are elevated in primary SS. MECHANISMS OF GLANDULAR DESTRUCTION Role of Apoptosis Mononuclear cells infiltrating affected tissue display ­elevated levels of the apoptosis-related molecules Fas, FasL, and Bcl273,74 and undergo apoptosis rarely (approximately 1%),75 a phenomenon referred to as blocked apoptosis. Approximately 50% of infiltrating mononuclear cells express CD40 and CD40L. Bcl-2 expression colocalizes with that of CD40, suggesting that signaling through CD40 increases the expression of Bcl-2.76 Interestingly, lymphocytes from patients with enlarged exocrine glands display reduced levels of Fas but enhanced sensitivity to steroids.77 Despite a paucity of apoptosis in infiltrating mononuclear cells, apoptosis appears to play a role in glandular epithelial cell dysfunction. Enhanced expression of Fas and DNA strand breaks have been demonstrated on acinar epithelial cells.73 DNA strand breaks occur even more frequently in ductal epithelium (68%) in SS, far exceeding the rate in controls (3%). This is accompanied by a significant reduction in Bcl-2 expression and ­enhancement

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of Bax expression in SS ductal epithelium.74,78 Acinar epithelial cells adjacent to CD8+ T cells are apoptotic.49

intrinsic epithelial cell apoptosis and cytotoxic lymphocyte granule release,

Role of Metalloproteinases

Antimuscarinic M3 Receptor

In addition to epithelial cell death, degradation of extracellular matrix contributes to the destruction of glandular architecture. Metalloproteinase (MMP)-2, -3, and -9 are present in SS salivary glands, where they may degrade basement membrane collagen IV. Immunohistochemical studies reveal localization of MMPs to glandular cells, particularly acinar end-piece cells79 and acinar cells adjacent to lymphocytic infiltrates.80

Forty years ago, antibodies directed against salivary duct epithelium were reported90 and were assumed to be a consequence of organ-specific autoimmunity in SS. Identification of specific glandular autoantigens was hampered by methodologic issues and perhaps by the intense interest in SS-A and SS-B, which were discovered shortly thereafter. Thirty years later, IgG present in the sera of SS patients was found to bind to and activate cholinergic receptors present on rat parotid glands.91 Pharmacologic stimulation and inhibition studies pointed to a type M3 muscarinic receptor (M3R). Subsequently, it was demonstrated that serum and purified IgG from 11 of 15 patients with primary and secondary SS inhibited carbachol-induced contraction of isolated bladder strips, indicative of an inhibitory effect on parasympathetic neurotransmission.92 Peptides derived from the second extracellular loop of M3R generated antibodies in rabbits that were capable of inhibiting experimental carbachol-induced colon contractions.93 Interestingly, M3R can be cleaved in vitro by granzyme B derived from cytotoxic granules,89 consistent with the model of autoantigen production described previously.

AUTOANTIGENS The existence of a strong autoantibody response and the presence of germinal center–like structures in the salivary glands of SS patients imply that the aberrant immune response is directed against one or multiple autoantigens. Molecular characterization of B cell Ig genes has provided considerable evidence for an antigen-driven response in SS. Analysis of heavy-chain Ig rearrangements using reverse transcriptase polymerase chain reaction on tissue obtained by labial salivary gland and lymph node biopsy in SS patients revealed that 92 of 94 V(H)-D-J(H) transcripts were modified by somatic mutation.81 Analysis of rearranged V genes from B cells obtained by microdissection of germinal center–like clusters in SS labial salivary glands revealed a mixture of polyclonality containing some somatic mutation, along with dominant B cell clones expressing hypermutated V genes.82 Epstein-Barr Virus Case reports detailing the development of SS following acute mononucleosis83,84 and the identification of salivary glands as sites of latent Epstein-Barr virus (EBV) infection have given credence to EBV’s role in the pathogenesis of SS. Some studies have demonstrated elevated antibody titers to EBV antigens in SS patients,85 whereas others have not. EBV DNA has been detected by in situ hybridization and polymerase chain reaction in SS glandular tissue, saliva, and tears.86 These studies suggest that in certain patients, persistent glandular EBV infection may be associated with or result in immunoregulatory abnormalities, which lead to persistent inflammation and possibly lymphoma (see later). α-Fodrin is a 120-kD constituent of the epithelial cytoskeleton that was first observed to be a target of the autoimmune response in the NFS/sld mouse model of SS.87 Serum IgG from affected mice recognized α-fodrin in immuno­blots of salivary gland homogenates. Mouse IgG and human IgG isolated from SS patients also bind to a recombinant α-fodrin fusion protein. EBV activation of lymphoid cells results in the cleavage of α-fodrin to 120-kD fragments, which occurs concomitantly with cellular apoptosis and expression of ZEBRA protein, which is a marker for ­activation of the lytic cycle of EBV.88 This cleavage can be blocked by caspase inhibitors. α-Fodrin is also cleaved into a unique 155-kD fragment by enzymes present in the granules of cytotoxic lymphocytes.89 As demonstrated by these animal and in vitro experimental models, viruses such as EBV may induce the formation of autoantigens linked to SS via

SS-A and SS-B SS-A and SS-B (Ro and La) represent the dominant humoral immune target to nuclear antigen in SS. Thus, these antigens have long been speculated to be of prime diagnostic and etiologic importance, especially because the antibody response to SS-A and SS-B has characteristics of an antigen-driven response.94 A more detailed description of these antigens is found in Chapter 20. Evidence of a local response to autoantigen is derived from studies demonstrating local antibody synthesis in salivary glands. In one study, all eight submucosal salivary gland biopsies from SS patients with circulating anti–SS-A demonstrated local production of anti–52-kD Ro.95 In addition, the expression pattern of SS-B in acinar epithelial cells was aberrant in SS patients, demonstrating cytoplasmic and nucleoplasmic staining; in normal individuals, in contrast, staining was restricted to the nucleolus.96

CLINICAL MANIFESTATIONS OCULAR Although the most prominent ocular manifestation of SS is dry eye, patients are often unaware of dryness as a presenting symptom. Instead, they may complain of a foreign body–type sensation manifested by scratchiness, grittiness, or irritation from a “grain of sand.” These symptoms may be interpreted by both the patient and the physician as atopic in nature. An early manifestation of dry eye is the inability to tolerate contact lenses. Other common symptoms of dry eye include photophobia, redness, and ocular fatigue. Thick mucous strands may cause blurring of vision, and the eyelids may be encrusted, especially on awakening. If the condition persists and is untreated, symptoms may reflect

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A

Figure 69-3  Patient with Sjögren’s syndrome and moderate parotid swelling. In this patient, parotid enlargement fluctuates with time and is bilateral.

B Figure 69-2  Ocular manifestations of Sjögren’s syndrome. A, A patient with moderate dry eye, in addition to surface staining, may develop filamentary keratitis, in which the epithelium of the cornea sloughs off and becomes attached to the ocular surface, along with mucin and debris. This causes a significant foreign body sensation and discomfort.  B, This patient with severe dry eye did not receive adequate treatment and has developed corneal scarring. (Courtesy of Dr. Reza Dana, Harvard Medical School.)

c­ omplications of xerophthalmia, including pain, intense photophobia indicative of corneal abrasion, and discharge, possibly indicative of infection (Fig. 69-2). Infections threaten sight and are most often caused by gram-positive bacteria. Previous corneal surgery, topical corticosteroid therapy, and the use of contact lenses are predisposing factors for infection.97 Rarely, patients may present with an orbital mass, representing a swollen lacrimal gland. Examination may reveal a paucity of tears in the conjunctival sac. The conjunctivae may appear injected. Specific maneuvers such as the Schirmer test and slit-lamp examination may be able to quantitate dryness and corneal disease, respectively. Corneal examination is aided by the instillation of dye. Fluorescein stains epithelial defects, whereas rose bengal binds devitalized cells and is thus more sensitive. Small punctate defects are often first observed at the inferior corneal margin.98 Lissamine green is thought to be equally sensitive to rose bengal but less irritating. ORAL In contrast to dry eye, patients often complain of a dry mouth. Physicians caring for SS patients are accustomed to seeing them carry plastic water bottles because they require a constant supply of moisture to be comfortable. The

dry-mouth patient describes a parched feeling in the mouth, often extending to the throat. Eating is often difficult without supplemental liquids. Talal has popularized the “cracker sign,” in which patients are asked whether they can chew and swallow a saltine cracker without any exogenous liquid. Dry-mouth patients often respond with visible disgust or by demonstrating a choking sign, bringing their hands up to the neck. Patients also may describe thickened saliva and may experience dysgeusia. Many of the more severe symptoms associated with dry mouth are secondary to complications of chronic dryness. Owing to a reduction in salivary volume and the subsequent loss of the antibacterial properties of saliva, tooth decay is accelerated. In fact, unexplained rampant dental caries may be the first sign of dry mouth. Caries occurring in unusual places, such as on the incisal surfaces and at the gingival line, are common in patients with dry mouth. Enamel at the junction of fillings and crowns is particularly susceptible to decay. Fillings that fall out may also be an early sign of dry mouth. In a European Community study, 40% of SS patients experienced early dental loss. In partially or completely edentulous patients, dental loss occurred an average of 9 years before the first symptom of xerostomia.99 For the reasons stated previously, a dry mouth is also extremely susceptible to the development of intraoral candidiasis. In one study, more than 80% of all SS subjects were culture positive for Candida albicans, versus none of the controls.100 Patients report a burning mouth and tongue. During the course of their illness, the majority of SS patients will experience swelling of the salivary glands. The parotids are most commonly involved; however, the sublingual and ­ submandibular glands may also be affected. Swelling may be bilateral or unilateral and may fluctuate with time (Fig. 69-3). In a series of patients with adult recurrent sialadenitis of the parotid glands followed prospectively, more than 50% developed SS.101 These patients experienced parotid swelling a mean of 5 years before xerostomia. Patients may experience “glandular flares” manifested by periods of increased

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swelling accompanied by pain and tenderness. Thickened, inspissated saliva places SS patients at increased risk for the formation of calculi, which may be found incidentally on imaging studies. Infectious parotitis or abscess presents as erythematous, painful swelling of the gland, often accompanied by fever, chills, and malaise. The presence of a dominant hard mass should raise suspicion of lymphoma. Examination of the oral cavity of SS patients often reveals multiple caries in the distribution noted previously. Patients with more advanced disease may be edentulous or have complete dentures. The mouth appears dry, the mucosa is thin and parchment like, and a tongue blade adheres to the tongue and buccal surfaces in a “sticky” fashion. Centers specializing in SS or dry mouth can measure the salivary flow rate quantitatively; however, by having the patient open the mouth and elevate the tongue for 1 minute, the clinician can estimate the flow rate by observing infralingual salivary pooling. Massaging the parotid yields little or no saliva from Stensen’s duct. In a dry mouth, candidiasis is not manifested by thrush; rather, there is extensive erythema of the oral mucosa and loss of filiform papillae from the dorsal surface of the tongue. Small amounts of thin, whitish exudate may be found on the tongue and buccal mucosa. Bilateral angular chelitis is often observed. Examination of the parotid glands often reveals some degree of swelling, appreciated as a subtle, “grainy” enlargement. In severe cases, “chipmunk-like facies,” indicative of massive bilateral glandular involvement, is seen.

Table 69-2  Systemic Manifestations Associated   with Sjögren’s Syndrome

OTHER XEROSES

evidence of ­ polymyositis.107,108 Muscle biopsy findings did not correlate with muscle pain; 27% of patients in one series met American College of Rheumatology criteria for fibromyalgia.107

Dry nose is common and may lead to inflammation with subsequent congestion, crusting, and epistaxis. Xerotrachea may result in a chronic dry cough. Dry skin may lead to pruritus and excoriation. Rarely, secondary infection may occur. Vaginal dryness may lead to pruritus, irritation, and dyspareunia. Although the most common cutaneous manifestation of SS is dryness, little is known about the precise cause or whether cutaneous dryness is truly part of the autoimmune exocrinopathy of SS. Sweat volume is reduced in SS patients,102 and a skin biopsy revealed lymphocytic infiltrates surrounding eccrine glands and ducts in one patient suffering from severe anhidrosis.103

SYSTEMIC MANIFESTATIONS MUSCULOSKELETAL Patients with primary SS often experience musculoskelatal symptoms, including arthralgias and transient ­synovitis (Table 69-2). Prevalence estimates range from 54% to 84%.104,105 Joint erosion is rare, but mild joint-space ­narrowing appears to be common.105,106 Muscle pain is also common in SS; however, persistent and significant elevation in creatine phosphokinase is extremely uncommon.107 Nonetheless, two studies demonstrated abnormal muscle biopsy findings in a relatively high number (72% and 73%, respectively) of primary SS patients. These abnormalities ­consisted of inflammatory myositis, perivascular lymphocytic infiltrates, and inclusion bodies. Despite these findings, only 11% of the combined series had clinical

Musculoskeletal Arthralgias Myalgias Cutaneous Dry skin Hyperglobulinemic purpura Vasculitis Pulmonary Xerotrachea Pulmonary infiltrate Micronodules Gastrointestinal Esophageal dysmotility Pancreatitis Hepatitis Renal Renal tubular acidosis Interstitial nephritis Neurologic Peripheral neuropathy Cranial neuropathy (especially fifth cranial nerve) Central nervous system disease Hematologic Leukopenia Anemia Lymphoma

PULMONARY Clinical pulmonary involvement is relatively common in primary SS. Cough reportedly occurs in 40% to 50% of patients.109,110 It is usually a symptom of xerotrachea, which, in turn, is strongly associated with impaired mucociliary clearance.111,112 Postmortem morphometric analysis of SS patients’ lungs revealed an increase in the size of bronchial glands and goblet cells in central airways and in the mucus-occupying ratio in small airways; these changes are not dissimilar to those seen in chronic bronchitis.113 Cough may also be secondary to bronchial hyperresponsiveness, which is found in 50% to 60% of primary SS patients studied by methacholine challenge.114 Other pulmonary sympotms, including dyspnea and chest pain (referable to pleural and parenchymal disease, respectively), occur in 9% to 43% of patients.115,116 When abnormalities found on pulmonary function testing are included, approximately 75% of SS patients display evidence of pulmonary involvement.117 Abnormal findings on high-resolution computed tomography occur in 65% to 92% of SS patients and include ­primarily ground-glass attenuation, bronchiectasis, septal thicking, micronodules, and parenchymal cysts.118,119 These abnormalities do not necessarily correlate with abnormal pulmonary function tests.

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Despite normal chest radiographs and the absence of clinical symptoms, primary SS patients may show evidence of subclinical lung inflammation on bronchoalveolar lavage.120 A wide range of pulmonary function test abnormalities has been reported in primary SS; however, the most common are a reduction in maximal expiratory flow, indicative of small airway disease, and reduced Dlco secondary to interstitial involvement.109,110,116 Lung biopsy reveals a spectrum of inflammatory changes, including bronchiolitis, lymphoid interstitial pneumonia, and fibrosis.121 Recent studies have identified nonspecific interstitial pneumonitis as a common histologic subtype.122,123 Immunohistochemical analysis demonstrates an increase in CD4+ T cells in the bronchial submucosa.124 Taken together, the predominance of small airway disease, the correlation with indicators of systemic inflammation, and CD4+ T cell infiltration of bronchial submucosa imply a significant role for autoimmune exocrinopathy in SS lung disease. RENAL The predominant form of renal disease in primary SS is a distal renal tubular acidosis syndrome resulting from tubulointerstitial lymphocytic infiltration. On rare occasions, the first presenting symptom of SS is hypokalemic paralysis. In these cases, the sicca component was mild and previously unrecognized.125 Overt renal disease of any form was seen in 4% of 471 patients followed for 10 years by Goules and colleagues.126 More commonly, renal metabolic studies reveal mild disturbances in tubular function in the absence of clinical disease.127 Proteinuria is sometimes detected in primary SS (in approximately 20% of cases) and is mainly of tubular origin (β2-microglobulin and α1-microglobulin), suggesting proximal tubular dysfunction. Filtration of increased amounts of proteins, such as Ig light chain and β2-microglobulin (MHC class I–associated light chain), and local synthesis of these proteins by tubular lymphocytes may result in tubular damage. On renal biopsy, Talal and coworkers128 noted lymphocytic infiltrates in all patients with tubular acidification defects. Similar to findings in exocrine glands, most infiltrating lymphocytes were CD4+ (CD4/CD8 ratio approximately 2:1); however, lymphocytes invading tubular epithelial cells were CD8+, suggesting a cytotoxic role.129 Glomerular disease is rare but has been found in 1% to 2% of cases by clinical and biopsy studies.126 Patients with glomerulonephritis have type II mixed cryoglobulins and low C4.126 GASTROINTESTINAL Xerostomia is the most common upper alimentary abnormality in SS, and hyposalivation undoubtedly contributes to digestive abnormalities. Dysphagia has been reported in approximately 75% of patients,130 and manometric evidence of esophageal dysmotility has been reported in at least 33%.131 More significant dysphagia may indicate the presence of esophageal webs, which have been noted in 10% of patients.130 Gastric symptoms have been recorded in approximately half of patients with primary SS.132 Endoscopic examination with biopsy reveals evidence of ­ atrophic (usually antral) gastritis in 10% to 25% and

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superficial ­ gastritis in approximately 80%.132,133 Hypopepsinogenemia has been reported in up to 67% of patients134; however, parietal cell antibodies have been detected in only 10%.132 Endoscopic surveillance may be required for persisent symptoms of epigastric discomfort, fullness, and early satiety, which might indicate the presence of severe atrophic gastritis or a mucosa-associated lympoid tissue (MALT) lymphoma (see later). HEPATIC Evidence of mild autoimmune hepatitis has been identified in approximaely 25% of primary SS patients,135 with smooth muscle antibodies seen in 7% to 33%.135,136 Antimitochondrial antibodies (AMA) have been reported in 7% to 13% of patients,135-137 suggesting a close association between primary SS and primary biliary cirrhosis. In one series, more than 90% of AMA-positive SS patients had stage I primary biliary cirrhosis on liver biopsy.137 Although 93% of patients with primary biliary cirrhosis display focal sialadenitis on salivary gland biopsy,138 significant clinical evidence of SS has been reported in only 33% to 47%.138 Some features of SS may be observed in up to 75% of patients, however.139 An interesting relationship has emerged between hepatitis C virus (HCV) infection and SS. As many as 57% to 77% of patients diagnosed with HCV infection exhibit clinical and histologic abnormalities suggestive of SS.140-142 Similarly, HCV was detected in 6% to 19% of patients with SS.143-145 Not surprisingly, patients diagnosed with SS who are HCV positive have a much higher incidence of hepatic involvement (approximately 90% versus 10%).143,146 HCV-positive SS patients also have a higher prevalence of cryoglobulinemia, hypocomplementemia, and neurologic involvement, but they are less often SS-A or SS-B positive (10% versus 38%). Primary SS patients with cryoglobulinemia are six times more likely to have antibodies to HCV than are those without cryoglobulins.147 Histologically, the salivary lesion in HCV-positive SS patients is similar to that in HCV-negative SS patients, except for the severity of the infiltrate. HCV-positive patients have milder lesions and lower focus scores.141 Immunohistochemically, the lesions are also similar, displaying a preponderance of T cells with a CD4/CD8 ratio of 2:1.148 Of interest is a report describing the onset of SS after interferon-α treatment for HCV.149 HCV may be another viral agent that triggers autoimmune exocrinopathy given the appropriate genetic and immunologic background. PANCREATIC Laboratory evidence of exocrine pancreatic abnormality is not infrequent in SS. Some abnormality in pancreatic function testing has been reported in 50% to 75% of patients.150,151 The most frequent abnormality is elevation of immunoreactive trypsin, occurring in 30% to 40%.150 Episodes of abdominal pain and steatorrhea occur in SS but cannot always be attributed to pancreatitis, owing in part to the difficulty of interpreting serum amylase elevations. Approximately 30% of primary SS patients have elevations of P and S amylase.152

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VASCULAR Vasculitis has been reported in approximately 15% of SS patients. Subtypes range from hypersensitivity vasculitis to a necrotizing vasculitis resembling polyarteritis nodosa.153 By far, the majority of cases involve the skin and manifest as recurrent crops of purpura. The lesions range from micro­ petechiae to large purpura and may be noninflammatory, demonstrating only extravasated red blood cells, or vascu­ litis. Urticarial lesions may occur. Immunopathologically, the purpura are caused by a combination of blood hyperviscosity and immune complex–mediated cutaneous vasculitis. Most biopsy specimens display immunofluorescent staining for immunoglobulin in the vessel wall.154 Exacerbations of purpura occur secondary to increased hydrostatic pressure, such as that caused by prolonged standing and the wearing of elastic stockings. Patients with long-standing purpura often display chronic, older brawny lesions with superimposed showers of new petechiae or purpura (Fig. 69-4). In the 1980s, Alexander and colleagues155 described the association of SS with cutaneous vasculitis, purpura, and adenopathy; 84% of their patients had antibodies to SS-A. It is important to rule out the presence of HCV in individuals presenting with cutaneous vasculitis, cryoglobulinemia, and sicca complaints. The constellation of purpura, mixed cryoglobulinemia, and hypocomplementemia (C4) has been identified as a risk for lymphoproliferation in SS patients (see later). Raynaud’s phenomenon affects 13% to 66% of SS patients.156-159 It is often associated with nonerosive arthritis, frequently precedes the onset of xerostomia, and rarely results in digital ulceration. Nail-fold capillary microscopic changes include increased loop dilation and tortuosity and may resemble the changes seen in SLE.160 AUTOIMMUNE THYROID DISEASE A strong association between SS and thyroid disease has been documented. In patients with primary SS who are examined for thyroid disease, the prevalence of thyroid abnormality ranges from 35% to 45%, and the prevalence of autoimmune thyroiditis is 18% to 24%.161,162 Autoimune thyroid disease occurs much more frequently in patients with SS than in those with RA.163 NEUROLOGIC Neurologic disease is perhaps the most common significant extraglandular manifestation of SS. It can involve the cranial nerves, peripheral nerves, and, rarely, the central nervous system (CNS). Clinical reports suggest that half of SS patients have some form of neurologic involvement, with estimates ranging from 22% to 76%.164-170 Peripheral neuropathy has been found in approximately 20% of SS patients171,172; in one study, it was symmetric in 33% of patients and was the presenting symptom in approximately 10%.171 A predominantly sensory neuropathy may present with ataxia.173 Sural nerve biopsy in SS patients with sensorimotor polyneuropathy reveals perivascular inflammatory infiltrates and changes suggestive or diagnostic of vasculitis in the majority.174,175 Progressive neuropathy, especially with motor involvement (e.g., footdrop), may indicate the presence of necrotizing vasculitis, particularly in the context of palpable purpura or

Figure 69-4  Vascular manifestations of Sjögren’s syndrome. This patient with Sjögren’s syndrome exhibits dermopathy involving the lower extremities secondary to hyperglobulinemic purpura. Recurrent showers of micropetechiae become chronic, resulting in brawny hyperpigmentation.

cutaneous ulceration. Biopsies of SS patients with pure sensory neuropathy demonstrate dorsal root ganglionitis in addition to perivascular mononuclear cell infiltrates involving cutaneous nerves.173 Approximately one quarter of patients with peripheral neuropathy have a superimposed autonomic or cranial neuropathy.175 Low intraepidermal nerve fiber densities indicative of small fiber neuropathy are rare.176 Cranial neuropathy, particularly trigeminal neuropathy, is the most distinctive type of neuropathy associated with primary SS.166,167,177 Sensorineural hearing loss, especially involving high frequencies, is noted in approximately half of SS patients undergoing audiometric testing.178 Disturbances in autonomic nervous system function can be demonstrated by objective testing (e.g., tilt table, digital blood flow, deep breathing) in a significant number of SS patients179,180; however, clinical symptoms are uncommon. Rarely, patients may develop significant postural hypotension. Adie’s pupil has been described in several reports.181,182 The incidence of CNS disease in primary SS ranges from 0 to 30%. Interpretation of these figures is controversial owing to several issues, including lack of a uniform description of the clinical syndrome, especially when symptoms are restricted to mild cognitive or depressive features; inclusion of cases defined solely by electrophysiologic or imaging abnormalities; and the strict exclusion of SLE, primary angiitis of the CNS, antiphospholipid syndrome, or other causes, including hepatitis C. In rheumatologic practice, significant CNS disease is rare, whereas peripheral and cranial neuropathies are common. In the largest series of CNS cases reporting clinical, serologic, and pathologic characteristics, patients had an increased frequency of SS-A positivity and a strong association with peripheral inflammatory vascular disease, most commonly expressed as cutaneous vasculitis (see previous discussion); there was also an association with peripheral neuropathy and inflammatory myopathy.183,184 Postmortem examination of primary SS patients from

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Table 69-3  Risk of Lymphoproliferation in Sjögren’s Syndrome Number in Study

Region

Method

110

Finland

SIR

676

Finland

SIR

136

USA

RR

62

France

PP

331

Italy

RR

55

France

30

Netherlands

261

Risk (%) 13 8.7 44 6.4

Reference 202 203 201 204

33

205

PP

9

206

PP

10

207

Greece

IR

12.2

208

723

Greece

PP

3.9

210

138

USA

Meta-analysis

PP

6.0

211

SIR

18.8

209

IR, incidence ratio per 1000 person-years; PP, point prevalence (%); RR, relative risk; SIR, standardized incidence ratio.

another center revealed mixed inflammatory infiltrates in the leptomeninges and choroid plexus; only 5 of 11 patients had neurologic symptoms.185 In a study by Alexander and colleagues,186 75% of SS patients with active neuropsychiatric disease had abnormalities on magnetic resonance imaging (MRI), particularly in the subcortical and periventricular white matter. Twenty patients from this cohort had neurologic disease mimicking multiple sclerosis (MS).187 Over the past several years, evidence of SS has been sought among MS outpatient populations.188-195 Of 486 patients reported collectively, 3.3% met the criteria for SS, and 8.4% had at least one feature of SS. Of 100 consecutive patients admitted to an inpatient neurology service, 3 had SS.196 Thus, it is likely that only a very small percentage of MS patients has undetected SS. Additionally, the existence of an SS-MS overlap syndrome cannot be excluded. Myelopathy was a prominent component of the MS-like disease reported in Alexander’s series and was subsequently reported on multiple occasions, as summarized by Williams and coworkers.197 The majority of patients demonstrate an acute or progressive transverse myelopathy. Good therapeutic outcomes have been reported with a combination of corticosteroid and cyclophosphamide. Several instances of optic neuropathy in patients with primary SS have been reported in the absence of MS.198 SS patients lacking clinical CNS disease may also have MRI abnormalities.199 SS patients who displayed no evidence of neurologic abnormality except for cognitive dysfunction had abnormal single photon emission computed tomography scans but normal MRI studies.200 Extreme caution must be used when the diagnosis of neurologic SS is entertained in patients demonstrating mild cognitive or psychiatric symptoms and minor abnormalities on sensitive imaging techniques, particularly in the absence of objective focal and serologic findings. LYMPHOPROLIFERATIVE DISEASE One of the major concerns of internists and rheumatologists caring for SS patients is the potential for the development of lymphoma. The original study by Kassan and colleagues201 estimated that a primary SS patient has an approximately 40fold enhanced risk of developing non-Hodgkin’s ­lymphoma

(NHL) compared with age-matched controls. Subsequent studies confirmed this risk, but at a somewhat lower magnitude, which may be due in part to population differences. Table 69-3 summarizes studies examining the risk of lymphoma in primary SS.202-212 Younger SS patients may be at somewhat higher risk than older patients.213 A survey of 113 patients with NHL revealed that 12% had SS.214 SS-associated NHLs are largely B cell in origin215 and may display a monocytoid phenotype.216 They frequently involve MALT near the marginal zone.217 Extranodal sites are often involved and include the salivary glands themselves (50%),217 gastrointestinal tract (see previous ­ discussion), lung, skin, thymus, and thyroid gland.218-220 These NHLs are often indolent but may transform into large cell NHL.221 Waldenström’s macroglobulinemia may be heralded by the hyperviscosity syndrome, accompanied by lower extremity purpura. The clinician should be aware of signs suggestive of lymphoproliferation, including a significant increase in the size of the salivary glands, especially when accompanied by dominant masses, lymphadenopathy, splenomegaly, and pulmonary infiltrates. Longitudinal monitoring of laboratory parameters is appropriate. Development of a monoclonal protein, appearance of new-onset leukopenia and anemia, and loss of previously present specific autoantibodies (i.e., ANA, SS-A, SS-B) have all been associated with the development of lymphoma. The presence of low C3, C4, cryoglobulins, and lymphocytopenia conferred an approximate 6- to 10-fold increased risk for the development of lymphoma.208,212 On occasion, a patient presents with significant increases in glandular swelling and lymphadenopathy suggestive of lymphoma. Tissue biopsy, however, is inconclusive, revealing lymphoid architecture that is atypical but not diagnostic of malignancy. This condition is referred to as pseudolymphoma and may represent an intermediate step in lymphomagenesis.222 Molecular immunoglobulin rearrangement and immunophenotyping studies are often helpful in resolving this diagonstic issue.

SECONDARY SJÖGREN’S SYNDROME Although secondary SS is defined as xerostomia and xerophthalmia in the presence of an autoimmune connective tissue disease, it is important to note that secondary SS is not

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monolithic. In other words, the characteristics of SS may vary among the different connective tissue disorders. Additionally, SS is a common accompaniment of autoimmune disorders not generally considered to be connective tissue diseases, such as thyroiditis, primary biliary cirrhosis, and MS. Thus, signs of SS should not be overlooked in these contexts. Because of clinical, immunogenetic, and serologic overlap, many investigators and clinicians consider SS and SLE to be more intimately related than SS and other connective tissue diseases. Patients with SS-SLE overlap meet three or more criteria for both conditions and demonstrate a higher prevalence of inflammatory arthritis and renal, pulmonary, and CNS disease than those with primary SS alone.223-225 Clinical signs suggestive of SS have been noted in 8% to 31% of patients with SLE,226,227 whereas lymphocytic infiltration of MSGs has been reported in 50% of unselected SLE patients.228 SLE patients who have more severe grades of lymphocytic infiltration appear to have less renal disease but more adenopathy, circulating RF, positivity to SS-A and SS-B, and erosive arthritis,226-228 in addition to overt xerophthalmia and parotid enlargement. SLE patients with renal tubular acidosis and interstitial nephritis have been described as having concomitant primary SS.229 In several reported series, primary SS transformed into SLE at intervals ranging from 1 to 10 years after the diagnosis of SS.230-234 Clinical SS affects approximately 20% of patients with RA. Thirty-one percent have positive MSG biopsies.235 SS-A antibodies have been found in 4% to 23% of RA patients.235-237 These patients are more likely to have severe sicca complaints and positive MSG biopsies; they are less likely to display HLA-DR4–related antigens. Interestingly, focal sialadenitis was common among an early synovitis cohort, 70% of whom were diagnosed with RA 1 year later.238 Between 14% and 20% of scleroderma patients have been diagnosed with SS.239,240 On histopathologic examination, salivary glands from some patients with scleroderma display fibrosis alone, whereas others demonstrate typical lymphocytic sialadenitis and fibrosis. Despite similarities in the prevalence of SS in scleroderma and RA, individuals with scleroderma are more frequently symptomatic, perhaps due to the high prevalence of fibrosis.239 SS is well known to complicate limited scleroderma.241 An overlap among SS, CREST syndrome, and primary biliary cirrhosis is known to occur. Scleroderma patients meeting the criteria for SS are more likely to have limited disease.242 Among a cohort of patients with mixed connective tissue disease, 33% had antibodies to SS-A, and 42% had sicca symptoms.243 Approximately 15% of primary SS patients had cardiolipin antibodies.244 When sought, β2-glycoprotein I antibodies were not detected, and clinical evidence of antiphospholipid syndrome was absent.

CLINICAL OUTCOMES When followed over a 10-year period, approximately one third of patients with sicca complaints eventually fulfilled the criteria for SS.245,246 Development of disease and severity of sicca symptoms correlate with the presence of autoantibodies, particularly ANA and SS-A, and the serum IgG level.245,247 More advanced sialographic findings are seen in patients who are SS-A positive.248 Glandular SS appears to progress very slowly. Once established,

diminished salivary flow remains relatively constant for several years, despite increases in focus score on repeat biopsy.245,246,249 The most prevalent extraglandular manifestations developing during 9 years of follow-up were arthralgias, arthritis, Raynaud’s phenomenon, dry skin, skin rash, and leukopenia.250 The severity of extraglandular disease has been correlated to the severity of exocrine surface disease and to the presence of SS-A.251,252 SS-A positivity has also been linked to the development of other rheumatologic diagnoses, including SLE, RA, and scleroderma.253 Overall, there is apparently no excess mortality in patients with primary SS.254 Recent studies from Sweden demonstrated 5- and 10-year survival rates of 96.6% and 92.8%, respectively.255 Standardized mortality rates for the SS groups were 1.07 and 1.17 compared with the general population.255 Excess mortality was associated only with lymphoma. Using short-form 36 (SF-36), it was found that women with primary SS had a diminished quality of life on all SF-36 scales. Although the psychological subdimension scales were similar to those of women with RA and fibromyalgia, the physical function quality of life was better in women with SS.256 A study from the United Kingdom demonstrated that health care costs for primary SS patients were twice that of controls and approximated those for RA.257

DIFFERENTIAL DIAGNOSIS Many common conditions cause dryness. Human immunodeficiency virus (HIV) causes a syndrome known as diffuse infiltrative lymphocytosis syndrome (DILS) in approximately 3% to 8% of patients.258,259 These patients display nearly an exact replica of SS symptoms, including dry eyes, dry mouth, salivary swelling, and a propensity to develop lymphoma.260 They are more commonly male, however, and lack specific SS-A and SS-B antibodies, although approximately 10% may exhibit ANA and RF. When it is difficult to distinguish SS from DILS, immunohistochemical study of MSGs may be useful, revealing a CD4+/CD8+ ratio of approximately 0.66 in DILS, in contrast to a ratio of more than 3.0 in SS.258,259 In Japan, where human T-lymphotropic virus 1 (HTLV-1) infection is endemic, a relationship between a Sjögren-like syndrome and HTLV-1 disease has been described. Clinical and serologic findings differ little between HTLV-1–positive and –negative SS patients,261 although the former may not possess characteristic sialographic findings.262 Lymphocytic infiltration of salivary glands in graft­versus-host disease results in a syndrome that mimics SS263 and appears within 12 weeks of bone marrow transplantation; infiltration peaks between 26 and 52 weeks after transplantation. Dry eye and dry mouth occur between 12 and 24 months. Symptoms may abate after 2 years.264,265 ANA and smooth muscle antibodies are frequently positive; however, SS-A and SS-B are not.266 Infiltrate T cell CD4/CD8 is either lower than that found in SS or inverse.267 In these individuals, skin changes may mimic scleroderma. Patients with sarcoidosis may present with lacrimal and salivary swelling, hypergammaglobulinemia; bone, muscle, and joint pain; and pulmonary infiltrates. In most cases, the characteristic features of sarcoidosis should pose little diagnostic difficulty. MSG biopsy reveals noncaseating

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­granulomas.268 Amyloid infiltration may also result in salivary gland enlargement, tongue swelling, and dry mouth, in addition to joint pain and renal insufficiency.269 Lymphoma may arise spontaneously in a salivary gland. The majority of tumors occur in the parotid gland and pre­ sent as firm masses that are usually painless. Sicca symptoms are present in a minority (approximately 15%) of cases.270 Other conditions causing sicca complaints are listed in Table 69-4.271-279 Table 69-4  Systemic Conditions Associated   with Sicca Symptoms Viral: mumps, EBV, HIV, HTLV-1 Graft-versus-host disease Sarcoidosis Amyloidosis Lymphoma Radioiodine therapy271 Fibromyalgia-like syndromes: chronic fatigue syndrome, dry eye   and mouth syndrome272,273 Aging274 Dyslipoproteinemia275 Hemochromatosis276 Lipodystrophy277,278 Bulimia279 EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; HTLV-1, human T-lymphotropic virus 1.

Yes- 1 criteria consider SS

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WORKUP The modalities used for the workup of SS are the basis for most of the criteria proposed for the classification of SS. Thus, the evaluation of a patient with suspected SS often requires cooperation among the rheumatologist, ophthalmologist, and dental specialist. Figure 69-5 is a stepwise approach to the workup of SS based on the American-European Consensus Group modification of the European Community criteria shown in Table 69-5.280 It is critical to ensure that the clinical conditions listed as exclusions, including medications that cause dryness, are absent. It is also important to understand the performance characteristics of the testing components used. No individual test is absolutely specific for SS, including MSG biopsy. Among ophthalmologic tests, the Schirmer test, tear breakup time, and rose bengal dye test are all sensitive; however, only the rose bengal test is specific (approximately 95%).281,282 The Schirmer test is not very reproducible either in controls283 or in SS patients.284 The salivary scintigraphic time-activity pattern correlates well with salivary flow rate285 but is diagnostically nonspecific; abnormalities could be caused by any infiltrative disorder. Sialography has the capacity to visualize the salivary ductal pattern, demonstrating abnormal arborization and ductal ectasia. Sialography appears to be as sensitive as biopsy and only slightly less specific,286,287 but it is invasive, potentially causing flares of glandular pain and swelling. At focus scores greater than 3, scintigraphy, sialography, and biopsy display fairly good agreement.288 Recently, parenchymal heterogeneity on ultrasonography and alterations in signal strength on

Oral symptoms dry mouth > 3 mo or swollen glands as adult or drink liquids to aid swallowing food

Dry eye symptoms daily dry eye > 3x mo or recurrent foreign body sensation or artificial tears > 3x/day

Screening questionnaire

| 

Yes - criteria consider SS

No

Autoantibodies SS-A/SS-B

No

Schirmer test <5mm/5 min

Office testing Positive 1 criterion

Positive 1 criterion

Negative

Negative

Advanced testing Rose bengal dye test

Negative

Positive 1 criterion

Salivary scintigram

Negative

Positive 1 criterion

MSG biopsy

Negative

Positive 1 criterion

Salivary flow rate

Normal

<1.5 mL min 1 criterion

Figure 69-5  Approach to using the American-European consensus criteria for the diagnosis of Sjögren’s syndrome (SS).280 The six criteria are (1) symptoms of dry eye, (2) symptoms of dry mouth or salivary swelling, (3) evidence of dry eye by the Schirmer test or abnormal corneal staining, (4) evidence of salivary dysfunction (abnormal salivary flow, scintigram, sialogram), (5) presence of SS-A or SS-B, and (6) positive minor salivary gland (MSG) biopsy. Patients must have at least four of the six criteria, including either autoantibodies or a positive biopsy. Major exclusions include other major connective tissue disorders (for primary SS), lymphoma, sarcoidosis, amyloidosis, human immunodeficiency virus (HIV), and treatment with anticholinergic medication. The requisite four criteria may be verified by a simple office history, physical examination, and laboratory testing. If required, patients should be referred to an ophthalmologist, oral surgeon, otolaryngologist, or nuclear medicine physician to complete the workup.

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Table 69-5  AEC Criteria for Sjögren’s Syndrome      I.  Symptoms of dry eye Patients must have a positive response to at least one of the ­following: Have you had daily, persistent, troublesome dry eyes for more than 3 months? Do you have a recurrent sensation of sand or gravel in the eyes? Do you use tear substitutes more than three times a day?     II.  Oral symptoms Patients must have a positive response to at least one of the ­following: Have you had a daily feeling of dry mouth for more than 3 months? Have you had recurrently or persistently swollen salivary glands as an adult? Do you frequently drink liquids to aid in swallowing dry food?   III.  Ocular signs Patients must have objective evidence of ocular involvement, defined as a positive result from at least one of the following two tests: Schirmer test performed without anesthesia (5 mm in 5 min) Rose bengal score or other ocular dye score (4 according to van Bijsterveld’s scoring system) IV.  Histopathology This criterion is met if an expert histopathologist evaluates focal lymphocytic sialadenitis with a focus score of 1 in the patient’s ­minor salivary glands (obtained through normal-­appearing mucosa). The focus score is defined as the number of   lymphocytic foci adjacent to normal-appearing mucous   acini and containing more than 50 lymphocytes/4 mm2   of glandular tissue.   V.  Salivary gland involvement Patient must have objective evidence of salivary gland ­involvement, defined by a positive result for at least one of the following ­diagnostic tests: Unstimulated whole salivary flow (1.5 mL in 15 min) Parotid sialography showing the presence of diffuse sialectasis (punctate, cavitary, or destructive pattern) without evidence of obstruction in the major ducts Salivary scintigraphy showing delayed uptake, reduced ­concentration, delayed excretion of tracer, or some ­combination of these VI.  Autoantibodies Patient must have the following autoantibodies present in serum: antibodies to Ro (SS-A) or La (SS-B) Definite Sjögren’s syndrome requires the presence of four criteria, one of which must be either a positive biopsy or ­autoantibodies Exclusions: prior head and neck radiation, hepatitis C infection, ­human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), preexisting lymphoma, sarcoidosis, graft-versus-host disease, use of anticholinergic drugs From Vitali C, Bombardiere S, Jonsson R, et al: Classification criteria for Sjögren’s syndrome: A revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61:554, 2002.

MRI have been shown to be relatively sensitive and specific for glandular involvement with SS.289-291 The MSG biopsy is often used to confirm a diagnosis of SS. It is important to verify that the biopsy is read by a ­patho­logist experienced in interpreting salivary gland pathology. Vivino and colleagues292 documented that the diagnosis was revised in 53% of biopsy samples reexamined at a university center. Only samples demonstrating periductal lymphocytic infiltrates in the form of foci should be regarded as being consistent with SS; biopsies revealing nonspecific scattered lymphocytic infiltrates, fibrosis, or fatty changes should not. In patients assessed ­specifically for

the ocular and oral components of SS, only focal ­sialadenitis correlates with KCS293; however, even biopsies with focus scores greater than 1 are not always specific for SS. Approximately 15% to 20% of specimens obtained from random postmortem samples and from healthy individuals have focus scores greater than 1.294,295 Approximately 10% of samples from healthy elderly individuals can be interpreted as positive.274 Focal lymphocytic sialadenitis has been found on submandibular gland biopsy, despite repeatedly negative MSG (lip) biopsies.296 Cigarette smoking appears to lower the focus score of MSG biopsies.297 An MSG biopsy should always be performed if the clinician cannot rule out or suspects an alternative cause of salivary swelling (e.g., lymphoma, sarcoidosis). In cases in which SS is not reasonably suspected or in which the diagnosis is readily apparent from noninvasive testing, the biopsy adds little.298 Serologies, particularly ANA and SS-A and SS-B, correlate with focus score on biopsy.299 Serum IgG is the most specific predictor of a positive biopsy but has relatively low sensitivity.300 A recent report of 41 patients tested for the presence of anti–SS-A and anti–SS-B and undergoing MSG biopsy showed a fairly high negative predictive value of anti–SS-A for MSG biopsy.301 Anti–SS-B may be useful in identifying primary SS among patients ­ presenting with xerostomia, xerophthalmia, and undifferentiated features of connective tissue disorder.287 Adult classification criteria may not be applicable to children with suspected SS.302

TREATMENT Therapy for SS has three phases. The first phase consists of external moisture replacement or capture. This approach can be applied to the oral cavity, eyes, nose, skin, and genital tract. The second phase consists of stimulation of endogenous secretions, which has proved effective mainly for xerostomia. This approach is currently under investigation for other xeroses, including the eyes and skin. Finally, patients with systemic manifestations, such as pulmonary disease, vasculitis, and pseudolymphoma, may require corticosteriods, cytotoxic agents, or both. OCULAR DISEASE Therapy of xerophthalmia begins with moisture replacement. Patients should be encouraged to use tear substitutes often. Myriad over-the-counter preparations exist. The rheumatologist should become familiar with one or two preparations from each of the following categories: (1) Standard artificial tears consist of polyvinyl alcohol or methylcellulose. (2) Preservative-free artificial tears should be used if irritation occurs with frequent use. These preparations are available as sealed, sterile, individual units that must be refrigerated or discarded after one use. (3) A subset of tear preparations has a higher viscosity by virtue of the inclusion of 0.1% dextran or 1% carboxymethylcellulose. These are useful for periods of increased symptoms but may cause some blurring. (4) Lubricating ointments and hydroxypropyl cellulose inserts are ­generally longer lived; however, they leave residue, may cause significant blurring, and are often reserved for nocturnal use. Vivino and Orlin303 published an excellent compendium of these agents.

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Existing tears may be retained in the eye by blocking their drainage or inhibiting their evaporation. The former can be accomplished by occluding the puncta by inserting collagen or silicone plugs (temporary) or by electrocautery (permanent). The latter can be accomplished by wearing goggles or glasses with specially constructed side chambers. These devices are not well accepted by patients but are valuable in certain environmental conditions (i.e., wind). Inflammation of the meibomian glands (blepharitis) may complicate dry eye and can be treated with warm compresses, cleansing of the lids, and a topical antibiotic when needed. Recently, data have demonstrated the efficacy of the secretagogues pilocarpine and cevimeline for xerophthalmia,304,305 although the maximal effect may require 12 weeks of therapy.

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Table 69-6  Comparison of Muscarinic Stimulants   for Sjögren’s Syndrome Pilocarpine

Cevimeline

Brand name

Salagen

Evoxac

Dose form

Tablet

Capsule

Dose strength

5 mg

30 mg

Half-life

Approximately 1 hr

Approximately 5 hr

Peak onset   of reaction

1 hr

1.5-2 hr

Major muscarinic side effects (%) Diaphoresis 40 Nausea 10 Rhinitis 9 Diarrhea 9

19 14 11 10

ORAL DISEASE Surprisingly, replacement of saliva is not as easily accomplished as tear supplementation. Artificial salivas are available,303 but they are generally short-lived and unappetizing. A moisturizing gel (e.g., Oral Balance) is longer lived but must be applied intraorally. Patients generally find it most suitable for nighttime application. Patients should be counseled with regard to general environmental measures designed to enhance moisture, such as the use of a humidifier and the avoidance of forced hot-air heating systems and excessive air-conditioning. Emphasis should be given to fastidious dental care, including frequent examinations and office and home fluoride application. Patients should be advised not to retain sugar-containing foods in the mouth for long periods. SS patients often chew gum or candy to stimulate salivation, but only sugar-free products should be used. Some of the more severe symptoms encountered by dry-mouth patients are secondary to intraoral candidiasis.306 Treatment should be initiated with nystatin (Mycostatin). The oral suspension (100,000 U/5 mL four times a day for 10 days) is commonly used; however, it contains significant amounts of sucrose and could, therefore, be cariogenic. Mycostatin vaginal tablets dissolved orally offer an alternative. Clotrimazole troches (10-mg troche dissolved in the mouth five times a day for 14 days) also may be used. Dentures must be removed and immersed in antifungal solutions to avoid recontamination. Oral candidiasis is recurrent and often requires retreatment. Systemic antifungals may be used, but they become ineffective as salivary flow diminishes. Interferon-α lozenges appear to increase salivary flow and reduce symptoms.307 SECRETORY STIMULATION Patients whose symptoms of dryness are not optimally controlled by moisture replacement should be considered for treatment with secretory stimulants (secretagogues). Secretagogues stimulate muscarinic receptors in salivary glands and other organs, leading to enhanced secretion. Because there is a poor correlation among length of disease, biopsy findings, and response to these agents, and because M3R is upregulated in SS labial salivary gland acini,308 a trial of secretagogue therapy should be offered. Secretagogues stimulate muscarinic activity in multiple organ systems, requiring caution in patients with asthma, narrow-angle glaucoma, acute iritis, severe cardiovascular disease, ­biliary

disease, nephrolithiasis, diarrhea, and ulcer disease. Two approved agents are available for use as secretagogues in SS: pilocarpine (Salagen) and cevimeline (Evoxac). Controlled clinical trials indicate that both drugs significantly increase the salivary flow rate in SS.309-311 Preliminary data suggest that other xeroses may be improved as well. Pilocarpine is administered as 5-mg tablets four times a day. Cevimeline is administered as 30-mg capsules three times a day. Table 69-6 compares the properties of these agents. Oral corticosteroids do not improve salivary flow.312 Methotrexate and oral cyclosporine A improve subjective symptoms of dryness but not exocrine function.313,314 Although a 14-week pilot study315 with a subsequent 1-year follow-up316 demonstrated a potential use for infliximab in treating the ocular, oral, and systemic inflammatory manifestations of SS, a subsequent 22-week double-blind, placebo-controlled trial revealed no advantage for infliximab-treated patients.317 Similarly, a 12-week randomized, placebo-controlled trial revealed no benefit to etanercept treatment.318 Additional placebo-controlled studies are required to demonstrate efficacy and safety with regard to lymphoproliferation. Recent retrospective and open-label trials suggest that anti–B cell therapy with rituximab may be useful.319,320 B cell–directed therapies offer the potential advantages of reducing autoantibody production and interrupting B cell lymphomagenesis; however, controlled trials are required. SYSTEMIC DISEASE Minor musculoskeletal symptoms usually respond to nonsteroidal anti-inflammatory drug therapy. Because erosive joint disease is rare, therapy with disease-modifying antirheumatic drugs is usually unnecessary; however, hydroxychloroquine at doses of 6 to 7 mg/kg per day has been used to treat fatigue, arthralgia, and myalgia in primary SS. Hydroxychloroquine does not improve dryness; however, it does reduce acute-phase proteins and elevated immunoglobulin levels in primary SS.321 Rarely, short courses of low-dose corticosteroid (e.g., prednisolone 5 to 10 mg/ day) may be necessary for very painful or disabling joint symptoms. To combat cutaneous dryness, patients should be instructed not to dry completely after bathing; instead, they should gently blot the skin dry, leaving a slight amount of

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moisture, followed by application of a moisturizer. Some data suggest that secretagogues (e.g., pilocarpine) at doses of 20 to 30 mg/day ameliorate the symptoms of dry skin. Tight or constricting elastic clothing on the lower extremities may exacerbate hypergammaglobulinemic purpura; however, support hosiery may be helpful. Intermittent use of a mild corticosteroid cream may be useful to control pruritus. Mild cases of leukocytoclastic vasculitis can be treated expectantly. Severe cases manifested by necrotic or ulcerating lesions require more aggressive therapy. Xerotrachea can be managed with humidification, secretagogues, and guaifenesin (1200 mg twice a day). Cough and dyspnea associated with pulmonary lymphocytic infiltration can be treated with a moderate-dose corticosteroid but may also require low to moderate doses of oral cyclophosphamide (50 to 150 mg/day). Frank lymphoma, when demonstrated by biopsy, requires standard chemotherapeutic intervention. Localized MALT lesions can be treated by external beam radiation or anti-CD20 monoclonal antibodies. Treatment of mild to moderate renal tubular acidosis consists of supplementation with potassium chloride and alkalinization with potassium citrate. For cases resistant to replacement therapy or demonstrating evidence of renal insufficiency, corticosteroid therapy (0.5 to 1.0 mg/kg) should be considered. Manifestations of gastroesophageal reflux disease are usually managed with antacids, H2 blockers, and proton pump inhibitors. Intermittent endoscopic evaluation and intervention may be required. Sjögren’s-associated hepatitis is often mild and may not require specific therapy. Persistent and progressive liver function test elevation may require therapy with prednisone and azathioprine. Standard measures for the management of acute pancreatitis or pancreatic enzyme deficiency should be used. Corticosteroid therapy has not proved useful and may itself be associated with pancreatitis; it should be avoided unless abdominal vasculitis is suspected. Cranial and peripheral neuropathy can be treated with low-dose tricyclic antidepressants or gabapentin (300 to 1800 mg/day). Symptomatic cases resistant to the previously mentioned therapies can be treated with intravenous gammaglobulin (0.4 g/kg per day for 5 days). When demonstrated by muscle and nerve biopsy, vasculitis should be treated with moderate-dose corticosteroid (approximately 1 mg/kg per day, with subsequent tapering) and oral cyclophosphamide (50 to 150 mg/day). CNS manifestations thought to be caused by primary SS should be treated aggressively with high-dose corticosteroid orally (1 to 2 mg/kg) or by intravenous pulse (1 g/day for 3 days) and cyclophosphamide daily (50 to 150 mg/day) or monthly by intravenous pulse (0.5 to 1 g/m2). REFERENCES   1. Sjögren H: Zur Kenntnis der keratoconjunctivitis sicca (keratitis filiformis bei hypofunktion der tranendrusen). Acta Ophthalmol (Kbh) 11(Suppl 2):1, 1933.   2. Leber: Uber die entstenhung der netzhautablosung. Klin Monatsbl Augenheilkd 20:165, 1882.   3. Mikulicz J: In discussion at Verein fur wissenschaftliche Heilkunde zu Konigsberg. Berl Klin Wochenschr 25:759, 1888.   4. Morgan WS, Castleman B: A clinicopathologic study of Mikulicz’s disease. Am J Pathol 29:471, 1953.   5. Mason AM, Gumpel JM, Golding PL: Sjögren’s syndrome: A clinical review. Semin Arthritis Rheum 2:301, 1973.

  6. Talal N: Recent developments in the immunology of Sjögren’s syndrome (autoimmune exocrinopathy). Scand J Rheumatol Suppl 61:76, 1986.   7. Skopouli FN, Moutsopoulos HM: Autoimmune epitheliitis: Sjögren’s syndrome. Clin Exp Rheumatol 12(Suppl 11):S9, 1994.   8. Pillemer SR, Matteson EL, Jacobsson LT, et al: Incidence of physician-diagnosed primary Sjögren’s syndrome in residents of Olmsted County, Minnesota. Mayo Clin Proc 76:593, 2001.   9. Chudwin DS, Daniels TE, Wara DW, et al: Spectrum of Sjögren’s syndrome in children. J Pediatr 98:213, 1981. 10. Strickland RW, Tesar JT, Berne BH, et al: The frequency of sicca syndrome in an elderly female population. J Rheumatol 14:766, 1987. 11. Molina R, Provost TT, Arnett FC, et al: Primary Sjögren’s syndrome in men: Clinical, serologic and immunogenetic features. Am J Med 80:23, 1986. 12. Brennan MT, Fox PC: Sex differences in primary Sjögren’s syndrome. J Rheumatol 26:2373, 1999. 13. Cervera R, Font J, Ramos-Casals M, et al: Primary Sjögren’s syndrome in men: Clinical and immunological characteristics. Lupus 9:61, 2000. 14. Nasu M, Matsubara O, Yamamoto H: Postmortem prevalence of lymphocytic infiltration of the lacrimal gland: A comparative study in autoimmune and non-autoimmune diseases. J Pathol 143:11, 1984. 15. Fritzler MJ, Pauls JD, Kinsella TD, et al: Antinuclear, anticytoplasmic, and anti-Sjögren’s syndrome antigen A (SS-A/Ro) antibodies in female blood donors. Clin Immunol Immunopathol 36:120, 1985. 16. Schein OD, Hochberg MC, Munoz B, et al: Dry eye and dry mouth in the elderly: A population-based assessment. Arch Intern Med 159:1359, 1999. 17. Drosos AA, Andonopoulos AP, Costopoulos JS, et al: Prevalence of primary Sjögren’s syndrome in an elderly population. Br J Rheumatol 27:123, 1988. 18. Jacobsson LT, Axell TE, Hansen BU, et al: Dry eyes or mouth: An epidemiological study in Swedish adults, with special reference to primary Sjögren’s syndrome. J Autoimmun 2:521, 1989. 19. Zhang NZ, Shi CS, Yao QP, et al: Prevalence of primary Sjögren’s syndrome in China. J Rheumatol 22:659, 1995. 20. Bjerrum KB: Keratoconjunctivitis sicca and primary Sjögren’s syndrome in a Danish population aged 30-60 years. Acta Ophthalmol Scand 75:281, 1997. 21. Dafni UG, Tzioufas AG, Staikos P, et al: Prevalence of Sjögren’s syndrome in a closed rural community. Ann Rheum Dis 56:521, 1997. 22. Thomas E, Hay EM, Hajeer A, et al: Sjögren’s syndrome: A community-based study of prevalence and impact. Br J Rheumatol 37:1069, 1998. 23. Tomsic M, Logar D, Grmek M, et al: Prevalence of Sjögren’s syndrome in Slovenia. Rheumatology (Oxford) 38:164, 1999. 24. Bowman SJ, Ibrahim GH, Holmes G, et al: Estimating the prevalence among Caucasian women of primary Sjögren’s syndrome in two general practices in Birmingham, UK. Scand J Rheumatol 33:39, 2004. 25. Alamanos Y, Tsifetaki N, Voulgari PV, et al: Epidemiology of primary Sjögren’s syndrome in north-west Greece. Rheumatology (Oxford) 45:187, 2006. 26. Kabasakal Y, Kitapcioglu G, Turk T, et al: The prevalence of Sjögren’s syndrome in adult women. Scand J Rheumatol 35:379, 2006. 27. Boling EP, Wen J, Reveille JD, et al: Primary Sjögren’s syndrome and autoimmune hemolytic anemia in sisters: A family study. Am J Med 74:1066, 1983. 28. Bolstad AI, Haga HJ, Wassmuth R, et al. Monozygotic twins with primary Sjögren’s syndrome. J Rheumatol 27:2264, 2000. 29. Fye KH, Terasaki PI, Moutsopoulos H, et al: Association of Sjögren’s syndrome with HLA-B8. Arthritis Rheum 19:883, 1976. 30. Chused TM, Kassan SS, Opelz G, et al: Sjögren’s syndrome association with HLA-Dw3. N Engl J Med 296:895, 1977. 31. Arnett FC, Bias WB, Reveille JD: Genetic studies in Sjögren’s syndrome and systemic lupus erythematosus. J Autoimmun 2:403, 1989. 32. Kumagai S, Kanagawa S, Morinobu A, et al: Association of a new allele of the TAP2 gene, TAP2*Bky2 (Val577), with susceptibility to Sjögren’s syndrome. Arthritis Rheum 40:1685, 1997. 33. Jean S, Quelvenec E, Alizadeh M, et al: DRB1*15 and DRB1*03 extended haplotype interaction in primary Sjögren’s syndrome genetic susceptibility. Clin Exp Rheumatol 16:725, 1998. 34. Guggenbuhl P, Veillard E, Quelvenec E, et al: Analysis of TNF alpha microsatellites in 35 patients with primary Sjögren’s syndrome. Joint Bone Spine 67:290, 2000.

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80. Azuma M, Motegi K, Aota K, et al: Role of cytokines in the destruction of acinar structure in Sjögren’s syndrome salivary glands. Lab Invest 77:269, 1997. 81. Gellrich S, Rutz S, Borkowski A, et al: Analysis of V(H)-D-J(H) gene transcripts in B cells infiltrating the salivary glands and lymph node tissues of patients with Sjögren’s syndrome. Arthritis Rheum 42: 240, 1999. 82. Stott DI, Hiepe F, Hummel M, et al: Antigen-driven proliferation of B cells within the target tissue of an autoimmune disease: The salivary glands of patients with Sjögren’s syndrome. J Clin Invest 102:938, 1998. 83. Whittingham S, McNeilage J, Mackay IR: Primary Sjögren’s syndrome after infectious mononucleosis. Ann Intern Med 102: 490, 1985. 84. Gaston JS, Rowe M, Bacon P: Sjögren’s syndrome after infection by Epstein-Barr virus. J Rheumatol 17:558, 1990. 85. Inoue N, Harada S, Miyasaka N, et al: Analysis of antibody titers to Epstein-Barr virus nuclear antigen in sera of patients with Sjögren’s syndrome and with rheumatoid arthritis. J Infect Dis 164:22, 1991. 86. Fox RI, Pearson G, Vaughan JH: Detection of Epstein-Barr virusassociated antigens and DNA in salivary gland biopsies from patients with Sjögren’s syndrome. J Immunol 137:3162, 1986. 87. Haneji N, Nakamura T, Takio K, et al: Identification of alpha-fodrin as a candidate autoantigen in primary Sjögren’s syndrome. Science 276:604, 1997. 88. Inoue H, Tsubota K, Ono M, et al: Possible involvement of EBVmediated alpha fodrin cleavage for organ-specific autoantigen in Sjögren’s syndrome. J Immunol 166:5801, 2001. 89. Nagaraju K, Cox A, Casciola-Rosen L, et al: Novel fragments of the Sjögren’s syndrome autoantigens alpha-fodrin and type 3 muscarinic acetylcholine receptor generated during cytotoxic lymphocyte granule-induced cell death. Arthritis Rheum 44:2376, 2001. 90. MacSween RN, Goudie RB, Anderson JR, et al: Occurrence of antibody to salivary duct epithelium in Sjögren’s disease, rheumatoid arthritis, and other arthritides: A clinical and laboratory study. Ann Rheum Dis 26:402, 1967. 91. Bacman S, Sterin-Borda L, Camusso JJ, et al: Circulating antibodies against rat parotid gland M3 muscarinic receptors in primary Sjögren’s syndrome. Clin Exp Immunol 104:454, 1996. 92. Waterman SA, Gordon TP, Rischmueller M: Inhibitory effects of muscarinic receptor autoantibodies on parasympathetic neurotransmission in Sjögren’s syndrome. Arthritis Rheum 43:1647, 2000. 93. Cavill D, Waterman SA, Gordon TP: Antibodies raised against the second extracellular loop of the human muscarinic M3 receptor mimic functional autoantibodies in Sjögren’s syndrome. Scand J Immunol 59:261, 2004. 94. Lindstrom FD, Eriksson P, Tejle K, et al: IgG subclasses of anti-SSA/Ro in patients with primary Sjögren’s syndrome. Clin Immunol Immunopathol 73:358, 1994. 95. Tengner P, Halse AK, Haga HJ, et al: Detection of anti-Ro/SSA and anti-La/SSB autoantibody-producing cells in salivary glands from patients with Sjögren’s syndrome. Arthritis Rheum 41:2238, 1998. 96. de Wilde PC, Kater L, Bodeutsch C, et al: Aberrant expression pattern of the SS-B/La antigen in the labial salivary glands of patients with Sjögren’s syndrome. Arthritis Rheum 39:783, 1996. 97. Ormerod LD, Fong LP, Foster CS: Corneal infection in mucosal scarring disorders and Sjögren’s syndrome. Am J Ophthalmol 105: 512, 1988. 98. Friedlaender MH: Ocular manifestations of Sjögren’s syndrome: Keratoconjunctivitis sicca. Rheum Dis Clin North Am 18:591, 1992. 99. Baudet-Pommel M, Albuisson E, Kemeny JL, et al: Early dental loss in Sjögren’s syndrome: Histologic correlates. European Community Study Group on Diagnostic Criteria for Sjögren’s Syndrome (EEC COMAC). Oral Surg Oral Med Oral Pathol 78:181, 1994. 100. Rhodus NL, Bloomquist C, Liljemark W, et al: Prevalence, density and manifestations of oral Candida albicans in patients with Sjögren’s syndrome. J Otolaryngol 26:300, 1997. 101. Wang SL, Zou ZJ, Yu SF, et al: Recurrent swelling of parotid glands and Sjögren’s syndrome. Int J Oral Maxillofac Surg 22:362, 1993. 102. Katayama I, Yokozeki H, Nishioka K: Impaired sweating as an exocrine manifestation in Sjögren’s syndrome. Br J Dermatol 133: 716, 1995. 103. Mitchell J, Greenspan J, Daniels T, et al: Anhidrosis (hypohidrosis) in Sjögren’s syndrome. J Am Acad Dermatol 16:233, 1987.

104. Castro-Poltronieri A, Alarcon-Segovia D: Articular manifestations of primary Sjögren’s syndrome. J Rheumatol 10:485, 1983. 105. Pease CT, Shattles W, Barrett NK, et al: The arthopathy of Sjögren’s syndrome. Br J Rheumatol 32:609, 1993. 106. Tsampoulas CG, Skopouli FN, Sartoris DJ, et al: Hand radiographic changes in patients with primary and secondary Sjögren’s syndrome. Scand J Rheumatol 15:333, 1986. 107. Lindvall B, Bengtsson A, Ernerudh J, et al: Subclinical myositis is common in primary Sjögren’s syndrome and is not related to muscle pain. J Rheumatol 29:717, 2002. 108. Vrethem M, Lindvall B, Holmgren H, et al: Neuropathy and myopathy in primary Sjögren’s syndrome: Neurophysiological, immunological and muscle biopsy results. Acta Neurol Scand 82:126, 1990. 109. Papiris SA, Maniata M, Constantopoulos SH, et al: Lung involvement in primary Sjögren’s syndrome is mainly related to the small airway disease. Ann Rheum Dis 58:61, 1999. 110. Mialon P, Barthelemy L, Sebert P, et al: A longitudinal study of lung impairment in patients with primary Sjögren’s syndrome. Clin Exp Rheumatol 15:349, 1997. 111. Fairfax AJ, Haslam PL, Pavia D, et al: Pulmonary disorders associated with Sjögren’s syndrome. Q J Med 50:279, 1981. 112. Mathieu A, Cauli A, Pala R, et al: Tracheobronchial mucociliary clearance in patients with primary and secondary Sjögren’s syndrome. Scand J Rheumatol 24:300, 1995. 113. Andoh Y, Shimura S, Sawai T, et al: Morphometric analysis of airways in Sjögren’s syndrome. Am Rev Respir Dis 148:1358, 1993. 114. La Corte R, Potena A, Bajocchi G, et al: Increased bronchial responsiveness in primary Sjögren’s syndrome: A sign of tracheobronchial involvement. Clin Exp Rheumatol 9:125, 1991. 115. Strimlan CV, Rosenow EC III, Divertie MB, et al: Pulmonary manifestations of Sjögren’s syndrome. Chest 70:354, 1976. 116. Kelly C, Gardiner P, Pal B, et al: Lung function in primary Sjögren’s syndrome: A cross sectional and longitudinal study. Thorax 46: 180, 1991. 117. Constantopoulos SH, Papadimitriou CS, Moutsopoulos HM: Respiratory manifestations in primary Sjögren’s syndrome: A clinical, functional, and histologic study. Chest 88:226, 1985. 118. Uffmann M, Kiener HP, Bankier AA, et al: Lung manifestation in asymptomatic patients with primary Sjögren’s syndrome: Assessment with high resolution CT and pulmonary function tests. J Thorac Imaging 16:282, 2001. 119. Koyama M, Johkoh T, Honda O, et al: Pulmonary involvement in primary Sjögren’s syndrome: Spectrum of pulmonary abnormalities and computed tomography findings in 60 patients. J Thorac Imaging 16:290, 2001. 120. Hatron PY, Wallaert B, Gosset D, et al: Subclinical lung inflammation in primary Sjögren’s syndrome: Relationship between bronchoalveolar lavage cellular analysis findings and characteristics of the disease. Arthritis Rheum 30:1226, 1987. 121. Deheinzelin D, Capelozzi VL, Kairalla RA, et al: Interstitial lung disease in primary Sjögren’s syndrome: Clinical pathological evaluation and response to treatment. Am J Respir Crit Care Med 154: 794, 1996. 122. Ito I, Nagai S, Kitaichi M, et al: Pulmonary manifestations of primary Sjögren’s syndrome: A clinical, radiologic and pathological study. Am J Respir Crit Care Med 171:632, 2005. 123. Parambil JG, Myers JL, Lindell RM, et al: Interstitial lung disease in primary Sjögren’s syndrome. Chest 130:1489, 2006. 124. Papiris SA, Saetta M, Turato G, et al: CD-4 positive T-lymphocytes infiltrate the bronchial mucosa of patients with Sjögren’s syndrome. Am J Respir Crit Care Med 156:637, 1997. 125. Raskin RJ, Tesar JT, Lawless OJ: Hypokalemic periodic paralysis in Sjögren’s syndrome. Arch Intern Med 141:1671, 1981. 126. Goules A, Masouridi S, Tzioufas AG, et al: Clinically significant and biopsy-documented renal involvement in primary Sjögren’s syndrome. Medicine 79:241, 2000. 127. Shiozawa S, Shiozawa K, Shimizu S, et al: Clinical studies of renal disease in Sjögren’s syndrome. Ann Rheum Dis 46:768, 1987. 128. Talal N, Zisman E, Schur PH: Renal tubular acidosis, glomerulonephritis and immunologic factors in Sjögren’s syndrome. Arthritis Rheum 11:774, 1968. 129. Matsumura R, Kondo Y, Sugiyama T, et al: Immunohistochemical identification of infiltrating mononuclear cells in tubulointerstitial nephritis associated with Sjögren’s syndrome. Clin Nephrol 30: 335, 1988.

PART 9  130. Kjellen G, Fransson SG, Lindstrom F, et al: Esophageal function, radiography, and dysphagia in Sjögren’s syndrome. Dig Dis Sci 31:225, 1986. 131. Tsianos EB, Chiras CD, Drosos AA, et al: Oesophageal dysfunction in patients with primary Sjögren’s syndrome. Ann Rheum Dis 44:610, 1985. 132. Ostuni PA, Germana B, DiMario F, et al: Gastric involvement in primary Sjögren’s syndrome. Clin Exp Rheumatol 11:21, 1993. 133. Pokorny G, Karacsony G, Lonovics J, et al: Types of atrophic gastritis in patients with primary Sjögren’s syndrome. Ann Rheum Dis 50:97, 1991. 134. Maury CP, Tornroth T, Teppo AM: Atrophic gastritis in Sjögren’s syndrome: Morphologic, biochemical and immunologic findings. Arthritis Rheum 28:388, 1985. 135. Lindgren S, Manthorpe R, Eriksson S: Autoimmune liver disease in patients with primary Sjögren’s syndrome. J Hepatol 20:354, 1994. 136. Manthorpe R, Permin H, Tage-Jensen U: Autoantibodies in Sjögren’s syndrome, with special reference to liver-cell membrane antibody (LMA). Scand J Rheumatol 8:168, 1979. 137. Skopouli FN, Barbatis C, Moutsopoulos HM: Liver involvement in primary Sjögren’s syndrome. Br J Rheumatol 33:745, 1994. 138. Hansen BU, Lindgren S, Eriksson S, et al: Clinical and immunological features of Sjögren’s syndrome in patients with primary biliary cirrhosis with emphasis on focal sialadenitis. Acta Med Scand 224:611, 1988. 139. Uddenfeldt P, Danielsson A, Forssell A, et al: Features of Sjögren’s syndrome in patients with primary biliary cirrhosis. J Intern Med 230:443, 1991. 140. Haddad J, Deny P, Munz-Gotheil C, et al: Lymphocyte sialadenitis of Sjögren’s syndrome associated with chronic hepatitis C virus liver disease. Lancet 339:321, 1992. 141. Pirisi M, Scott C, Fabris C, et al: Mild sialoadenitis: A common finding in patients with hepatitis C virus infection. Scand J Gastroenterol 29:940, 1994. 142. Verbaan H, Carlson J, Eriksson S, et al: Extrahepatic manifestations of chronic hepatitis C infection and the interrelationship between primary Sjögren’s syndrome and hepatitis C in Swedish patients. J Intern Med 245:127, 1999. 143. Jorgensen C, Legouffe MC, Perney P, et al: Sicca syndrome associated with hepatitis C virus infection. Arthritis Rheum 39:1166, 1996. 144. Garcia-Carrasco M, Ramos M, Cervera R, et al: Hepatitis C virus infection in primary Sjögren’s syndrome: Prevalence and clinical significance in a series of 90 patients. Ann Rheum Dis 56:173, 1997. 145. Szodoray P, Csepregi A, Hejjas M, et al: Study of hepatitis C virus infection in 213 Hungarian patients with Sjögren’s syndrome. Rheumatol Int 21:6, 2001. 146. Ramos-Casals M, Garcia-Carrasco M, Cervera R, et al: Hepatitis C virus infection mimicking primary Sjögren’s syndrome: A clinical and immunologic description of 35 cases. Medicine 80:1, 2001. 147. Ramos-Casals M, Cervera R, Yague J, et al: Cryoglobulinemia in primary Sjögren’s syndrome: Prevalence and clinical characteristics in a series of 115 patients. Semin Arthritis Rheum 28:200, 1998. 148. Coll J, Gambus G, Corominas J, et al: Immunohistochemistry of minor salivary gland biopsy specimen from patients with Sjögren’s syndrome with and without hepatitis C virus infection. Ann Rheum Dis 56:390, 1997. 149. Unoki H, Moriyama A, Tabaru A, et al: Development of Sjögren’s syndrome during treatment with recombinant human interferon-alpha2b for chronic hepatitis C. J Gastroenterol 31:723, 1996. 150. Coll J, Navarro S, Tomas R, et al: Exocrine pancreatic function in Sjögren’s syndrome. Arch Intern Med 149:848, 1989. 151. Nishimori I, Morita M, Kino J, et al: Pancreatic involvement in patients with Sjögren’s syndrome and primary biliary cirrhosis. Int J Pancreatol 17:47, 1995. 152. Tsianos EB, Tzioufas AG, Kita MD, et al: Serum isoamylases in patients with autoimmune rheumatic diseases. Clin Exp Rheumatol 2:235, 1984. 153. Tsokos M, Lazarou SA, Moutsopoulos HM: Vasculitis in primary Sjögren’s syndrome: Histologic classification and clinical presentation. Am J Clin Pathol 88:26, 1987. 154. Sugai S, Shimizu S, Tachibana J, et al: Hypergammaglobulinemic purpura in patients with Sjögren’s syndrome: A report of nine cases and a review of the Japanese literature. Jpn J Med 28:148, 1989. 155. Alexander EL, Arnett FC, Provost TT, et al: Sjögren’s syndrome: Association of anti-Ro(SS-A) antibodies with vasculitis, ­hematologic abnormalities, and serologic hyperreactivity. Ann Intern Med 98:155, 1983.

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183. Molina R, Provost TT, Alexander EL: Peripheral inflammatory vascular disease in Sjögren’s syndrome: Association with nervous system complications. Arthritis Rheum 28:1341, 1985. 184. Alexander EL, Ranzenbach MR, Kumar AJ, et al: Anti-Ro(SS-A) autoantibodies in central nervous system disease associated with Sjögren’s syndrome (CNS-SS): Clinical, neuroimaging, and angiographic correlates. Neurology 44:899, 1994. 185. de la Monte SM, Hutchins GM, Gupta PK: Polymorphous meningitis with atypical mononuclear cells in Sjögren’s syndrome. Ann Neurol 14:455, 1983. 186. Alexander EL, Beall SS, Gordon B, et al: Magnetic resonance imaging of cerebral lesions in patients with Sjögren’s syndrome. Ann Intern Med 108:815, 1988. 187. Alexander EL, Malinow K, Lejewski JE, et al: Primary Sjögren’s syndrome with central nervous system disease mimicking multiple sclerosis. Ann Intern Med 104:323, 1986. 188. Noseworthy JH, Bass BH, Vandervoort MK, et al: The prevalence of primary Sjögren’s syndrome in a multiple sclerosis population. Ann Neurol 25:95, 1989. 189. Montecucco C, Franciotta DM, Caporali R, et al: Sicca syndrome and anti-SSA/Ro antibodies in patients with suspected or definite multiple sclerosis. Scand J Rheumatol 18:407, 1989. 190. Metz LM, Seland TP, Fritzler MJ: An analysis of the frequency of Sjögren’s syndrome in a population of multiple sclerosis patients. J Clin Lab Immunol 30:121, 1989. 191. Miro J, Pena-Sagredo JL, Berciano J, et al: Prevalence of primary Sjögren’s syndrome in patients with multiple sclerosis. Ann Neurol 27:582, 1990. 192. Ellemann K, Krogh E, Arlien-Soeborg P, et al: Sjögren’s syndrome in patients with multiple sclerosis. Acta Neurol Scand 84:68, 1991. 193. Sandberg-Wollheim M, Axell T, Hansen BU, et al: Primary Sjögren’s syndrome in patients with multiple sclerosis. Neurology 42:845, 1992. 194. de Andres C, Guillem A, Rodriguez-Mahou M, et al: Frequency and significance of anti-Ro(SS-A) antibodies in multiple sclerosis patients. Acta Neurol Scand 104:83, 2001. 195. de Seze J, Devos D, Castelnovo G, et al: The prevalence of Sjögren’s syndrome in patients with primary progressive multiple sclerosis. Neurology 57:1359, 2001. 196. Olsen ML, O’Connor S, Arnett FC, et al: Autoantibodies and rheumatic disorders in a neurology inpatient population: A prospective study. Am J Med 90:479, 1991. 197. Williams CS, Butler E, Roman GC: Treatment of myelopathy in Sjögren’s syndrome with a combination of prednisone and cyclophosphamide. Arch Neurol 58:815, 2001. 198. Wise CM, Agudelo CA: Optic neuropathy as an initial manifestation of Sjögren’s syndrome. J Rheumatol 15:799, 1988. 199. Pierot L, Suave C, Leger JM, et al: Asymptomatic cerebral involvement in Sjögren’s syndrome: MRI findings of 15 cases. Neuroradiology 35:378, 1993. 200. Belin C, Moroni C, Caillat-Vigneron N, et al: Central nervous system involvement in Sjögren’s syndrome: Evidence from neuropsychological testing and HMPAO-SPECT. Ann Med Interne (Paris) 150:598, 1999. 201. Kassan SS, Thomas TL, Moutsopoulos HM, et al: Increased risk of lymphoma in sicca syndrome. Ann Intern Med 89:888, 1978. 202. Pertovaara M, Pukkala E, Laippala P, et al: A longitudinal cohort study of Finnish patients with primary Sjögren’s syndrome: Clinical, immunological, and epidemiologic aspects. Ann Rheum Dis 60:467, 2001. 203. Kauppi M, Pukkala E, Isomaki H: Elevated incidence of hematologic malignancies in patients with Sjögren’s syndrome compared with patients with rheumatoid arthritis (Finland). Cancer Causes Control 8:201, 1997. 204. Pariente D, Anaya JM, Combe B, et al: Non Hodgkin’s lymphoma associated with primary Sjögren’s syndrome. Eur J Med 1:337, 1992. 205. Valesini G, Priori R, Bavoillot D, et al: Differential risk of non-Hodgkin’s lymphoma in Italian patients with primary Sjögren’s syndrome. J Rheumatol 24:2376, 1997. 206. Zufferey P, Meyer OC, Grossin M, et al: Primary Sjögren’s syndrome (SS) and malignant lymphoma: A retrospective cohort study of 55 patients with SS. Scand J Rheumatol 24:342, 1995. 207. Kruize AA, Hene RJ, van der Heide A, et al: Long-term follow-up of patients with Sjögren’s symdrome. Arthritis Rheum 39:297, 1996.

208. Skopouli FN, Dafni U, Ioannidis JP, et al: Clinical evolution, and morbidity and mortality of primary Sjögren’s syndrome. Semin Arthritis Rheum 29:296, 2000. 209. Zintzaras E, Voulgarelis M, Moutsopoulos HM: The risk of lymphoma development in autoimmune diseases: A meta-analysis. Arch Intern Med 165:2337, 2005. 210. Ioannidis JP, Vassikiou VA, Moutsopoulos HM: Long-term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjögren’s syndrome. Arthritis Rheum 46:741, 2002. 211. McCurley T, Collins RD, Ball E, et al: Nodal and extranodal lymphoproliferative disorders in Sjögren’s syndrome: A clinical and immunopathologic study. Hum Pathol 21:482, 1990. 212. Theander E, Henriksson G, Ljungberg O, et al: Lymphoma and other malignancies in primary Sjögren’s syndrome: A cohort study on cancer incidence and lymphoma predictors. Ann Rheum Dis 65:796, 2006. 213. Ramos-Casals M, Cervera R, Font J, et al: Young onset of primary Sjögren’s syndrome: Clinical and immunological characteristics. Lupus 7:202, 1998. 214. Janin A, Morel P, Quiquandon I, et al: Non-Hodgkin’s lymphoma and Sjögren’s syndrome: An immunopathological study of 113 patients. Clin Exp Rheumatol 10:565, 1992. 215. Zulman J, Jaffe R, Talal N: Evidence that the malignant lymphoma of Sjögren’s syndrome is a monoclonal B-cell neoplasm. N Engl J Med 299:1215, 1978. 216. Sheibani K, Burke JS, Swartz WG, et al: Monocytoid B-cell lymphoma: Clinicopathological study of 21 cases of a unique type of lowgrade lymphoma. Cancer 62:1531, 1988. 217. Voulgarelis M, Dafni UG, Isenberg DA, et al: Malignant lymphoma in primary Sjögren’s syndrome: A multicenter, retrospective, clinical study by the European Concerted Action on Sjögren’s Syndrome. Arthritis Rheum 42:1765, 1999. 218. Isaacson P, Wright DH: Extranodal malignant lymphoma arising from mucosa-associated lymphoid tissue. Cancer 53:2515, 1984. 219. Hansen LA, Prakash UB, Colby TV: Pulmonary lymphoma in Sjögren’s syndrome. Mayo Clin Proc 64:920, 1989. 220. Royer B, Cazals-Hatem D, Sibilia J, et al: Lymphomas in patients with Sjögren’s syndrome are marginal zone B cell neoplasms, arise in diverse extranodal and nodal sites and are not associated with viruses. Blood 90:766, 1997. 221. Biasi D, Caramaschi P, Ambrosetti A, et al: Mucosa-associated lymphoid tissue lymphoma of the salivary glands occurring in patients affected by Sjögren’s syndrome: Report of 6 cases. Acta Haematol 105:83, 2001. 222. Talal N, Aufdemorte TB, Kincaid WL, et al: Two patients illustrating lymphoma transition and response to therapy in Sjögren’s syndrome. J Autoimmun 1:171, 1988. 223. Ramos-Casals M, Brito-Zeron P, Font J: The overlap of Sjögren’s syndrome with other systemic autoimmune diseases. Semin Arthritis Rheum 36:246, 2007. 224. Szanto A, Szodoray P, Kiss E, et al: Clinical, serologic and genetic profiles of patients with associated Sjögren’s syndrome and systemic lupus erythematosus. Hum Immunol 67:924, 2006. 225. Manoussakis MN, Georgopoulou C, Zintzaras E, et al: Sjögren’s syndrome associated with systemic lupus erythematosus: Clinical and laboratory profiles and comparison with primary Sjögren’s syndrome. Arthritis Rheum 50:882, 2004. 226. Andonopoulos AP, Skopouli FN, Dimou GS, et al: Sjögren’s syndrome in systemic lupus erythematosus. J Rheumatol 17:201, 1990. 227. Grennan DM, Ferguson M, Williamson J, et al: Sjögren’s syndrome in SLE. Part 1. The frequency of the clinical and subclinical features of Sjögren’s syndrome in patients with SLE. N Z Med J 86:374, 1977. 228. Skopouli F, Siouna-Fatourou H, Dimou GS, et al: Histologic lesion in labial salivary glands of patients with systemic lupus erythematosus. Oral Surg Oral Med Oral Pathol 72:208, 1991. 229. Graninger WB, Steinberg AD, Meron G, et al: Interstitial nephritis in patients with systemic lupus erythematosus: A manifestation of concomitant Sjögren’s syndrome? Clin Exp Rheumatol 9:41, 1991. 230. Romero RW, Nesbitt LT Jr, Ichinose H: Mikulicz disease and subsequent lupus erythematosus development. JAMA 237:2507, 1977. 231. Provost TT, Talal N, Harley JB, et al: The relationship between anti-Ro(SS-A) antibody-positive Sjögren’s syndrome and anti-Ro (SS-A) antibody-positive lupus erythematosus. Arch Dermatol 124:63, 1988.

PART 9  232. Chevalier X, de Bandt M, Bourgeois P, et al: Primary Sjögren’s syndrome preceding the presentation of systemic lupus erythematosus as a benign intracranial hypertension syndrome. Ann Rheum Dis 51:808, 1992. 233. Zufferey P, Meyer OC, Bourgeois P, et al: Primary systemic Sjögren’s syndrome (SS) preceding systemic lupus erythematosus: A retrospective study of 4 cases in a cohort of 55 SS patients. Lupus 4:23, 1995. 234. Satoh M, Yamagata H, Watanabe F, et al: Development of anti-Sm and anti-DNA antibodies followed by clinical manifestation of systemic lupus erythematosus in an elderly woman with long-standing Sjögren’s syndrome. Lupus 4:63, 1995. 235. Andonopoulos AP, Drosos AA, Skopouli FN, et al: Secondary Sjögren’s syndrome in rheumatoid arthritis. J Rheumatol 14:1098, 1987. 236. Skopouli FN, Andonopoulos AP, Moutsopoulos HM: Clinical implications of the presence of anti-Ro(SSA) antibodies in patients with rheumatoid arthritis. J Autoimmun 1:381, 1988. 237. Boire G, Menard HA, Gendron M, et al: Rheumatoid arthritis: Anti-Ro antibodies define a non-HLA-DR associated clinicoserological cluster. J Rheumatol 20:1654, 1993. 238. Brennan MT, Pillemer SR, Goldbach-Mansky R, et al: Focal sialadenitis in patients with early synovitis. Clin Exp Rheumatol 19:444, 2001. 239. Cipoletti JF, Buckingham RB, Barnes EL, et al: Sjögren’s syndrome in progressive systemic sclerosis. Ann Intern Med 87:535, 1977. 240. Andonopoulos AP, Drosos AA, Skopouli FN, et al: Sjögren’s syndrome in rheumatoid arthritis and progressive systemic sclerosis: A comparative study. Clin Exp Rheumatol 7:203, 1989. 241. Frayha RA, Tabbara KF, Geha RS: Familial CREST syndrome with sicca complex. J Rheumatol 4:53, 1977. 242. Avouac J, Sordet C, Depinay C, et al: Systemic sclerosis-associated Sjögren’s syndrome and relationship to the limited cutaneous subtype: Results of a prospective study of sicca syndrome in 133 consecutive patients. Arthritis Rheum 54:2243, 2006. 243. Setty YN, Pittman CB, Mahale AS, et al: Sicca symptoms and antiSSA/Ro antibodies are common in mixed connective tissue disease. J Rheumatol 29:487, 2002. 244. Jedryka-Goral A, Jagiello P, D’Cruz DP, et al: Isotype profile and clinical relevance of anticardiolipin antibodies in Sjögren’s syndrome. Ann Rheum Dis 51:889, 1992. 245. Pertovaara M, Korpela M, Uusitalo H, et al: Clinical follow-up study of 87 patients with sicca symptoms (dryness of eyes or mouth, or both). Ann Rheum Dis 58:423, 1999. 246. Kruize AA, van Bijsterveld OP, Hene RJ, et al: Long-term course of tear gland function in patients with keratoconjunctivitis sicca and Sjögren’s syndrome. Br J Ophthalmol 81:435, 1997. 247. Haga HJ: Clinical and immunological factors associated with low lacrimal and salivary flow rate in patients with primary Sjögren’s syndrome. J Rheumatol 29:305, 2002. 248. Miyachi K, Naito M, Maeno Y, et al: Sialographic study in patients with and without antibodies to Sjögren’s syndrome A (Ro). J Rheumatol 10:387, 1983. 249. Jonsson R, Kroneld U, Backman K, et al: Progression of sialadenitis in Sjögren’s syndrome. Br J Rheumatol 32:578, 1993. 250. Markusse HM, Oudkerk M, Vroom TM, et al: Primary Sjögren’s syndrome: Clinical spectrum and mode of presentation based on an analysis of 50 patients selected from a department of rheumatology. Neth J Med 40:125, 1992. 251. Asmussen K, Andersen V, Bendixen G, et al: Quantitative assessment of clinical disease status in primary Sjögren’s syndrome: A cross-sectional study using a new classification model. Scand J Rheumatol 26:197, 1997. 252. Kelly CA, Foster H, Pal B, et al: Primary Sjögren’s syndrome in northeast England: A longitudinal study. Br J Rheumatol 30:437, 1991. 253. Davidson BK, Kelly CA, Griffiths ID: Primary Sjögren’s syndrome in the northeast of England: A long-term follow-up study. Rheumatology (Oxford) 38:245, 1999. 254. Martins PB, Pillemer SR, Jacobsson LT, et al: Survivorship in a population based cohort of patients with Sjögren’s syndrome, 1976-1992. J Rheumatol 26:1296, 1999. 255. Theander E, Manthorpe R, Jacobsson LT: Mortality and causes of death in primary Sjögren’s syndrome: A prospective cohort study. Arthritis Rheum 50:1262, 2004. 256. Strombeck B, Ekdahl C, Manthorpe R, et al: Health-related quality of life in primary Sjögren’s syndrome, rheumatoid arthritis and fibromyalgia compared to normal population data using SF-36. Scand J Rheumatol 29:20, 2000.

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257. Callaghan R, Prabu A, Allan RB, et al: Direct healthcare costs and predictors of costs in patients with primary Sjögren’s syndrome. Rheumatology (Oxford) 46:105, 2007. 258. Williams FM, Cohen PR, Jumshyd J, et al: Prevalence of the diffuse infiltrative lymphocytosis syndrome among human immunodeficiency virus-type 1-positive outpatients. Arthritis Rheum 41:863, 1998. 259. Kordossis T, Paikos S, Aroni K, et al: Prevalence of Sjögren’s-like syndrome in a cohort of HIV-1-positive patients: Descriptive pathology and immunopathology. Br J Rheumatol 37:691, 1998. 260. Ulirsch RC, Jaffe ES: Sjögren’s syndrome-like illness associated with the acquired immunodeficiency syndrome-related complex. Hum Pathol 18:1063, 1987. 261. Nakamura H, Kawakami A, Tominaga M, et al: Relationship between Sjögren’s syndrome and human T-lymphotropic virus type 1 infection: Follow-up study of 83 patients. J Lab Clin Med 135:139, 2000. 262. Izumi M, Nakamura H, Nakamura T, et al: Sjögren’s syndrome (SS) in patients with human T cell leukemia virus 1 associated myelopathy: Paradoxical features of the major salivary glands compared to classical SS. J Rheumatol 26:2609, 1999. 263. Gratwhol AA, Moutsopoulos HM, Chused TM, et al: Sjögren-type syndrome after allogeneic bone marrow transplantation. Ann Intern Med 87:703, 1977. 264. Lindahl G, Lonnquist B, Hedfors E: Lymphocytic infiltration of lip salivary glands in bone marrow recipients: A model for the development of the histopathological changes in Sjögren’s syndrome?. J Autoimmun 2:579, 1989. 265. Janin-Mercier A, Devergie A, Arrago JP, et al: Systemic evaluation of Sjögren-like syndrome after bone marrow transplantation in man. Transplantation 43:677, 1987. 266. Rouquette-Gally AM, Boyeldieu D, Gluckman E, et al: Auto-immunity in 28 patients after allogeneic bone marrow transplantation: Comparison with Sjögren’s syndrome and scleroderma. Br J Haematol 66:45, 1987. 267. Hiroki A, Nakamura S, Shinohara M, et al: A comparison of glandular involvement between chronic graft-versus-host disease and Sjögren’s syndrome. Int J Oral Maxillofac Surg 25:298, 1996. 268. Drosos AA, Constantopoulos SH, Psychos D, et al: The forgotten cause of sicca complex: Sarcoidosis. J Rheumatol 16:1548, 1989. 269. Gogel HK, Searles RP, Volpicelli NA, et al: Primary amyloidosis presenting as Sjögren’s syndrome. Arch Intern Med 143:2325, 1983. 270. Nime FA, Cooper HS, Eggleston JC: Primary malignant lymphomas of the salivary glands. Cancer 37:906, 1976. 271. Solans R, Bosch JA, Galofre P, et al: Salivary and lacrimal gland dysfunciton (sicca syndrome) after radioiodine therapy. J Nucl Med 42:738, 2001. 272. Sirois DA, Natelson B: Clinicopathological findings consistent with primary Sjögren’s syndrome in a subset of patients diagnosed with chronic fatigue syndrome: Preliminary observations. J Rheumatol 28:126, 2001. 273. Price EJ, Venables PJ: Dry eyes and mouth syndrome: A subgroup of patients presenting with sicca symptoms. Rheumatology (Oxford) 41:416, 2002. 274. De Wilde PC, Baak JP, van Houwelingen JC, et al: Morphometric study of histological changes in sublabial salivary glands due to aging process. J Clin Pathol 39:406, 1986. 275. Goldman JA, Julian EH: Pseudo-Sjögren’s syndrome with hyperlipoproteinemia. JAMA 237:1582, 1977. 276. Takeda Y, Ohya T: Sicca symptom in a patient with hemochromatosis: Minor salivary gland biopsy for differential diagnosis. Int J Oral Maxillofac Surg 16:745, 1987. 277. Alarcon-Segovia D: Ramos-Niembro F: Association of partial lipodystrophy and Sjögren’s syndrome. Lett Ann Intern Med 85:474, 1976. 278. Ipp MM, Howard NJ, Tervo RC, et al: Sicca syndrome and total lipodystrophy. Ann Intern Med 85:443, 1976. 279. Levin PA, Falko JM, Dixon K, et al: Benign parotid enlargement in bulimia. Ann Intern Med 93:827, 1980. 280. Vitali C, Bombardiere S, Jonsson R, et al: Classification criteria for Sjögren’s syndrome: A revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61:554, 2002. 281. Paschides CA, Kitsios G, Karakostas KX, et al: Evaluation of tear break-up time, Schirmer’s-1 test and rose bengal staining as confirmatory tests for keratoconjunctivitis sicca. Clin Exp Rheumatol 7:155, 1989.

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Sjögren’s Syndrome

282. Kalk WW, Mansour K, Vissink A, et al: Oral and ocular manifestations in Sjögren’s syndrome. J Rheumatol 29:924, 2002. 283. Clinch TE, Benedetto DA, Felberg NT, et al: Schirmer’s test. Arch Ophthalmol 101:1383, 1983. 284. Haga HJ, Hulten B, Bolstad AI, et al: Reliability and sensitivity of the diagnostic tests for primary Sjögren’s syndrome. J Rheumatol 26:604, 1999. 285. Saito T, Fukuda H, Horikawa M, et al: Salivary gland scintigraphy with 99mTc-pertechnetate in Sjögren’s syndrome: Relationship to clinicopathologic features of salivary and lacrimal glands. J Oral Pathol Med 26:46, 1997. 286. Vitali C, Tavoni A, Simi U, et al: Parotid sialography and minor salivary gland biopsy in the diagnosis of Sjögren’s syndrome: A comparative study of 84 patients. J Rheumatol 15:262, 1988. 287. Vitali C, Monti P, Giuiggioli C, et al: Parotid sialography and lip biopsy in the evaluation of oral component in Sjögren’s syndrome. Clin Exp Rheumatol 7:131, 1989. 288. Lindvall AM, Jonsson R: The salivary gland component of Sjögren’s syndrome: An evaluation of diagnostic methods. Oral Surg Oral Med Oral Pathol 62:32, 1986. 289. Niemela RK, Paakko E, Suramo I, et al: Magnetic resonance imaging and magnetic resonance sialography of parotid glands in primary Sjögren’s syndrome. Arthritis Rheum 45:512, 2001. 290. Izumi M, Eguchi K, Ohki M, et al: MR imaging of the parotid gland in Sjögren’s syndrome: A proposal for new diagnostic criteria. AJR Am J Roentgenol 166:1483, 1996. 291. Niemela RK, Takalo R, Paakko E, et al: Ultrasonography of salivary glands in primary Sjögren’s syndrome: A comparison with magnetic resonance imaging and magnetic resonance sialography of parotid glands. Rheumatology (Oxford) 43:875, 2004. 292. Vivino FB, Gala I, Hermann GA: Change in final diagnosis on second evaluation of labial minor salivary gland biopsies. J Rheumatol 29:938, 2002. 293. Daniels TE, Whitcher JP: Association of patterns of labial salivary gland inflammation with keratoconjunctivitis sicca: Analysis of 618 patients with suspected Sjögren’s syndrome. Arthritis Rheum 37:869, 1994. 294. Segerberg-Konttinen M: A postmortem study of focal adenitis in salivary and lacrimal glands. J Autoimmun 2:553, 1989. 295. Radfar L, Kleiner DE, Fox PC, et al: Prevalence and clinical significance of lymphocytic foci in minor salivary glands of healthy volunteers. Arthritis Rheum 47:520, 2002. 296. Katz J, Yamase H, Parke A: A case of Sjögren’s syndrome with repeatedly negative findings on lip biopsy. Arthritis Rheum 34:1325, 1991. 297. Manthorpe R, Benoni C, Jacobsson L, et al: Lower frequency of focal lip sialadenitis (focus score) in smoking patients: Can tobacco diminish the salivary gland involvement as judged by histological examination and anti-SSA/Ro and anti-SSB/La antibodies in Sjögren’s syndrome? Ann Rheum Dis 59:54, 2000. 298. Lee M, Rutka JA, Slomovic AR, et al: Establishing guidelines for the role of minor salivary gland biopsy in clinical practice for Sjögren’s syndrome. J Rheumatol 25:247, 1998. 299. Shah F, Rapini RP, Arnett FC, et al: Association of labial salivary gland histopathology with clinical and serologic features of connective tissue diseases. Arthritis Rheum 33:1682, 1990. 300. Brennan MT, Sankar V, Leakan RA, et al: Risk factors for positive minor salivary gland biopsy findings in Sjögren’s syndrome and dry mouth patients. Arthritis Rheum 47:189, 2002. 301. Kessel A, Toubi E, Rozenbaum M, et al: Sjögren’s syndrome in the community: Can serology replace salivary gland biopsy? Rheumatol Int 26:337, 2006.

302. Houghton K, Malleson P, Cabral D, et al: Primary Sjögren’s syndrome in children and adolescents: Are proposed diagnostic criteria applicable? J Rheumatol 32:2225, 2005. 303. Vivino FB, Orlin SE: Sjögren’s syndrome: Giving dry mouth and dry eye the full treatment. J Musculoskel Med 17:350, 2000. 304. Papas AS, Sherrer YS, Charney M, et al: Successful treatment of dry mouth and dry eye symptoms in Sjögren’s syndrome patients with oral pilocarpine: A randomized, placebo-controlled, dose-adjustment study. J Clin Rheumatol 10:169, 2004. 305. Ono M, Takamura E, Shinozaki K, et al: Therapeutic effect of cevimeline on dry eye in patients with Sjögren’s syndrome: A randomized, double-blind clinical study. Am J Ophthalmol 138:6, 2004. 306. Hernandez YL, Daniels TE: Oral candidiasis in Sjögren’s syndrome: Prevalence, clinical correlations, and treatment. Oral Surg Oral Med Oral Pathol 68:324, 1989. 307. Shiozawa S, Tanaka Y, Shiozawa K: Single-blinded controlled trial of low-dose oral IFN-alpha for the treatment of xerostomia in patients with Sjögren’s syndrome. J Interferon Cytokine Res 18:255, 1998. 308. Beroukas D, Goodfellow R, Hiscock J, et al: Up-regulation of M3-muscarinic receptors in labial salivary gland acini in primary Sjögren’s syndrome. Lab Invest 82:203, 2002. 309. Fox PC, Atkinson JC, Macynski AA, et al: Pilocarpine treatment of salivary gland hypofunction and dry mouth (xerostomia). Arch Intern Med 151:1149, 1991. 310. Vivino FB, Al-Hashimi I, Khan Z, et al: Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjögren’s syndrome: A randomized, placebo-controlled, fixeddose, multicenter trial: P92-01 Study Group. Arch Intern Med 159:174, 1999. 311. Fife RS, Chase WF, Dore RK, et al: Cevimeline for the treatment of xerostomia in patients with Sjögren’s syndrome: A randomized trial. Arch Intern Med 162:1293, 2002. 312. Fox PC, Datiles M, Atkinson JC, et al: Prednisone and piroxicam for treatment of primary Sjögren’s syndrome. Clin Exp Rheumatol 11:149, 1993. 313. Skopouli FN, Jagiello P, Tsifetaki N, et al: Methotrexate in primary Sjögren’s syndrome. Clin Exp Rheumatol 14:555, 1996. 314. Drosos AA, Skopouli FN, Costopoulos JS, et al: Cyclosporin A (CyA) in primary Sjögren’s syndrome: A double-blind study. Ann Rheum Dis 45:732, 1986. 315. Steinfeld SD, Demols P, Salmon I, et al: Infliximab in patients with primary Sjögren’s syndrome: A pilot study. Arthritis Rheum 44:2371, 2001. 316. Steinfeld SD, Demols P, Appelboom T: Infliximab in primary Sjögren’s syndrome: One year follow-up. Arthritis Rheum 46:3301, 2002. 317. Mariette X, Ravaud P, Steinfeld S, et al: Inefficacy of infliximab in primary Sjögren’s syndrome: Results of the randomized, controlled trial of Remicade in primary Sjögren’s syndrome. Arthritis Rheum 50:1270, 2004. 318. Sankar V, Brennan MT, Kok MR, et al: Etanercept in Sjögren’s syndrome: A twelve-week randomized, double-blind, placebo-controlled pilot clinical trial. Arthritis Rheum 50:2240, 2004. 319. Pijpe J, van Imhoff GW, Spijkervet FK, et al: Rituximab treatment in patients with primary Sjögren’s syndrome: An open-label phase II study. Arthritis Rheum 52:2740, 2005. 320. Seror R, Sordet C, Guillevin L, et al: Tolerance and efficacy of rituximab and changes in serum B cell biomarkers in patients with systemic complications of primary Sjögren’s syndrome. Ann Rheum Dis 66:351, 2007. 321. Fox RI, Chan E, Benton L, et al: Treatment of primary Sjögren’s syndrome with hydroxychloroquine. Am J Med 85:62, 1988.

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10

SPONDYLOARTHROPATHIES

70

Ankylosing Spondylitis Sjef M. van der Linden  • Désirée van der Heijde  • Walter P. Maksymowych

KEY POINTS In early stages of ankylosing spondylitis (AS), radiographic evidence of sacroiliitis may be absent. Magnetic resonance imaging may be helpful in cases of suspected AS. The modified New York criteria are useful primarily to classify groups of patients (e.g., for clinical or epidemiologic studies). They are not well suited to establish the diagnosis of AS in individual patients. Radiographic sacroiliitis is a usual but by no means obligatory sign of AS. Observer variation in reading pelvic radiographs for the presence or absence of sacroiliitis is considerable. Inflammatory back pain is the usual clue to the early diagnosis of AS. A positive family history of AS or other manifestations of spondyloarthritis increases the likelihood of AS if an individual’s symptoms suggest that disease. Among patients with chronic inflammatory back pain, HLAB27 typing may aid in establishing the diagnosis AS. Physiotherapy and spa exercise therapy are important components of disease management. Group physiotherapy is more effective than exercises performed at home by the patient. If treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) fails, biologics should be considered. For AS patients with active disease, the response to treatment with tumor necrosis factor (TNF) blockers is usually quick, impressive, and sustained. Most AS patients have a normal or marginally elevated erythrocyte sedimentation rate and C-reactive protein level. Patients with normal levels of acute-phase reactants tend to have a somewhat lower response to anti-TNF agents. AS patients who have full ankylosis of the spine may still respond to TNF blockers if they have inflammatory back pain. The Bath ankylosing spondylitis disease activity index (BASDAI) is the most frequently used instrument to assess patientreported disease activity.   Video available on the Expert Consult Premium Edition website.

Expert’s opinion and BASDAI greater than 4 (scale 0 to 10) are important in considering TNF blocking agents if conservative treatment with NSAIDs and physiotherapy fails. In many populations, AS occurs in 1% to 3% of HLA-B27–positive individuals. The disease is more common (about 10%) among first-degree relatives of HLA-B27–positive AS patients.

Ankylosing spondylitis (AS) is a chronic inflammatory ­disease of unknown cause associated with human leukocyte antigen (HLA)-B27. It usually affects the sacroiliac joints at early stages and may involve the axial skeleton at later stages of the disease. Peripheral joint involvement may also be an important feature. The disease can be accompanied by extraskeletal manifestations such as acute anterior uveitis, aortic incompetence, cardiac conduction defects, fibrosis of the upper lobes of the lungs, neurologic involvement, or renal (secondary) amyloidosis. AS causes significant pain, disability, and social burden around the world. Favorable results of treating AS with anti–tumor necrosis factor (TNF) agents have largely redefined the entire therapeutic approach to this disease. AS belongs to the group of diseases known as the spondyloarthropathies or spondyloarthritides. This group of disorders constitutes a family of related but heterogeneous conditions rather than a single disease with different clinical manifestations1 (Tables 70-1 and 70-2).

HISTORICAL ASPECTS It is controversial whether the skeletal abnormalities described in many Egyptian pharaohs, including Rameses II, were due to AS, diffuse skeletal hyperostosis, or spondylosis deformans.2 In 1850, Brodie described the clinical features of a 31-yearold man with an ankylosed spine who “occasionally suffer[ed] severe inflammation of the eye.” In 1884, Struempell from Leipzig, Germany, described two patients with complete ankylosis of the spine and hip joints.3 This report was soon followed by descriptions of the disease by von Bechterew from St. Petersburg, Russia, and Marie from Paris, France.4,5 Although Roentgen had developed his radiographic technique by 1896, 1169

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Table 70-1 Spondyloarthropathies Ankylosing spondylitis Reiter’s syndrome or reactive arthritis Arthropathy of inflammatory bowel disease (Crohn’s disease, ulcerative colitis) Psoriatic arthritis Undifferentiated spondyloarthropathies Juvenile chronic arthritis and juvenile-onset ankylosing spondylitis

Table 70-2  Clinical Characteristics of Spondyloar­thropathies

Table 70-3  European Spondyloarthropathy Study Group Classification Criteria Inflammatory spinal pain or Synovitis (asymmetric, predominantly in lower limbs) and Any one of the following (sensitivity, 77%; specificity, 89%): Positive family history Psoriasis Inflammatory bowel disease Alternate buttock pain Enthesopathy Adding sacroiliitis (sensitivity, 86%; specificity, 87%) From Dougados M, van der Linden S, Juhlin R, et al: The European Spondyloarthropathy Study Group preliminary criteria for the classification of ­spondyloarthropathy. Arthritis Rheum 34:1218-1227, 1991.

Typical pattern of peripheral arthritis—predominantly of lower limb, asymmetric Tendency toward radiographic sacroiliitis Absence of rheumatoid factor Absence of subcutaneous nodules and other extra-articular features of rheumatoid arthritis Overlapping extra-articular features characteristic of the group (e.g., anterior uveitis) Significant familial aggregation Association with HLA-B27

it was not until 1930 that sacroiliac disease, now considered the radiographic hallmark of AS, was fully recognized.

NOMENCLATURE The term ankylosing spondylitis is derived from the Greek roots ankylos, or “bent” (although it now usually implies fusion or adhesions), and spondylos, or “vertebral disk.” Because ankylosis of the spine tends to appear in late stages of the disease and does not occur in many patients with mild disease, it has been suggested that it would be better to rename the disease spondylitis or spondylitic disease.6

CLASSIFICATION CLASSIFICATION CRITERIA FOR SPONDYLOARTHROPATHIES The spectrum of spondyloarthropathies is wider than the disorders listed in Table 70-1. To encompass patients with seronegative oligoarthritis, dactylitis, or polyarthritis of the lower extremities; heel pain due to enthesitis; and other undifferentiated spondyloarthropathies, classification criteria for the whole group of spondyloarthropathies were developed1 (Table 70-3). The European Spondyloarthropathy Study Group (ESSG) criteria resulted in a sensitivity of 86% and a specificity of 87%. In the subgroup of early cases (i.e., those in whom signs and symptoms had developed within the last year), the sensitivity declined to 68%, although the specificity increased to 93%. These criteria, though clearly not intended for diagnostic purposes, might be useful to identify atypical and undifferentiated forms of spondyloarthropathies. This set of criteria performed quite well in patients with different sociocultural and geographic characteristics.7

CLASSIFICATION CRITERIA FOR ANKYLOSING SPONDYLITIS The diagnosis of AS is based on clinical features. The disease is “primary” or “idiopathic” if no associated disorder is present; it is “secondary” if the disease is associated with psoriasis or chronic inflammatory bowel disease. In daily practice, a presumptive clinical diagnosis of AS is usually supported by radiographic evidence of sacroiliitis; indeed, many think of AS as symptomatic sacroiliitis. The presence of sacroiliitis does not necessarily indicate the presence of AS, however. Moreover, although radiographic sacroiliitis is frequent in AS, it is by no means an early or obligate manifestation of the disease.8 Lack of either sensitivity or specificity in previous classifications led to a modification of the New York criteria for AS9 (Table 70-4). Two criteria—limitation of lumbar spine motion and limitation of chest expansion—appear to reflect disease duration; they are usually not present in early disease.10 It should be stressed that classification criteria are usually not useful for early diagnosis owing to a lack of sensitivity. In particular, in the early phase of AS, conventional sacroiliac radiographs may be normal. An approach based on pretest probabilities and likelihood ratios has been proposed to diagnose the disease with predominantly axial manifestations before the presence of radiographic sacroiliitis.11

EPIDEMIOLOGY PREVALENCE The prevalence of AS closely parallels the frequency of HLAB27. This holds true for those B27 subtypes that are associated with the disease, but it is not true for populations in which certain subtypes that lack an association with AS occur rather frequently, such as the Indonesian population.12-14 Among whites, the estimated prevalence rate of AS as defined by the modified New York criteria ranges from 68 per 100,000 population older than 20 years in the Netherlands to 197 per 100,000 in the United States.15,16 The prevalence of clinical AS in France is 150 per 100,000 adults, whereas in Norway it is 210 per 100,000 adults.17,18 The prevalence of the disease in Finland is similar, with a figure of 150 per 100,000 people.19 Higher prevalence rates have been reported in central Europe. An epidemiologic study from Berlin reported a prevalence figure of 0.86%.20 In the general population, AS

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Table 70-4  Criteria for Ankylosing Spondylitis Rome, 1961 Clinical Criteria 1. Low back pain and stiffness for more than 3 months, not relieved by rest 2. Pain and stiffness in thoracic region 3. Limited motion in lumbar spine 4. Limited chest expansion 5. History or evidence of iritis or its sequelae

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Table 70-5  HLA-B27 Prevalence in White Populations Population Subgroup

HLA-B27 Phenotype ­Frequency (%)

Urgo Finnish

12-18

Northern Scandinavian

10-16

Slavic

  7-14

Western European

  6-9

Southern European

  2-6

Radiographic Criterion

Basque

  9-14

6. Radiograph showing bilateral sacroiliac changes characteristic of ankylosing spondylitis (this excludes bilateral osteoarthritis of sacroiliac joints)

Gypsy (Spain)

16-18

Arab, Jew, Armenian, Iranian

  3-5

Definite Ankylosing Spondylitis

Pakistani

  6-8

Grade 3 or 4 bilateral sacroiliitis with at least one clinical criterion or At least four clinical criteria

Indian

  2-6

New York, 1966 Diagnostic Criteria 1. Limitation of lumbar spine motion in all three planes: anterior flexion, lateral flexion, extension 2. Pain at dorsolumbar junction or in lumbar spine 3. Limitation of chest expansion to 2.5 cm or less measured at level of fourth intercostal space Grading of Radiographs Normal, 0; suspicious, 1; minimal sacroiliitis, 2; moderate sacroiliitis, 3; ankylosis, 4

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INCIDENCE There is no adequate evidence that the incidence of AS has changed in the last few decades. Clinical features, age of onset, and survival time have remained stable.22 One study revealed an overall age and gender-adjusted incidence of 7.3 per 100,000 person-years. This U.S. figure compares quite well with the Finnish study, which revealed a stable incidence of 8.7 (95% confidence interval [CI] 6.4 to 11.0) per 100,000 people aged 16 or older.17

Definite Ankylosing Spondylitis Grade 3 or 4 bilateral sacroiliitis with at least one diagnostic criterion or Grade 3 or 4 unilateral or grade 2 bilateral sacroiliitis with diagnostic criterion 1 or with criteria 2 and 3 Probable Ankylosing Spondylitis Grade 3 or 4 bilateral sacroiliitis with no diagnostic criteria Modified New York, 1984 Criteria 1. Low back pain of at least 3 months’ duration improved by exercise and not relieved by rest 2. Limitation of lumbar spine in sagittal and frontal planes 3. Chest expansion decreased relative to normal values for age and sex 4. Bilateral sacroiliitis grade 2 to 4 5. Unilateral sacroiliitis grade 3 or 4 Definite Ankylosing Spondylitis Unilateral grade 3 or 4, or bilateral grade 2 to 4 sacroiliitis and any clinical criterion Data from van der Linden SM, Valkenburg HA, Cats A: Evaluation of diagnostic criteria for ankylosing spondylitis: A proposal for modification of the New York criteria. Arthritis Rheum 27:361-368, 1984.

is likely to develop in about 1% to 2% of HLA-B27–positive adults who have a disease-associated B27 subtype, although there may be regional or geographic differences. For example, in northern Norway, AS may develop in 6.7% of HLAB27–positive people.21 The disease is much more common among HLA-B27– positive first-degree relatives of HLA-B27–positive AS patients; roughly 10% to 30% of them have signs or symptoms of AS.15 In fact, a positive family history of AS is a strong risk factor for the disease.

RACIAL DISTRIBUTION AS occurs in all parts of the world, but there are race-related differences in prevalence. This might reflect differences in the distribution of HLA-B27 among races (Table 70-5). Approximately 90% of white patients with AS possess HLA-B27, whereas AS and HLA-B27 are nearly absent (prevalence of B27  <  1%) in African blacks and Japanese. In African Americans, owing to racial admixture with whites, 2% possess B27, but only about 50% of black patients with AS possess B27. Correspondingly, African Americans are affected far less frequently than American whites. BURDEN OF DISEASE AS is associated with a considerable burden to the patient and society. Apart from the axial and articular manifestations, extra-articular manifestations, such as enthesitis and acute anterior uveitis, and comorbidities, such as inflammatory bowel disease and psoriasis, contribute to the burden of disease. In addition, a large proportion of patients has spinal osteoporosis, leading to vertebral fractures and thoracic kyphosis. All these features result in a decreased quality of life. Disease status scores for physical functioning and disease activity correlate clearly with psychological scores for anxiety and depression.23 The impact of AS also can be seen in various aspects of employment, ranging from requiring assistance at work to withdrawal from the workforce.24 Apart from the impact on labor force participation, AS patients have an important impact on health care and non–health care resource utilization, resulting in mean total costs (direct and productivity) of about $6700 to $9500 per year per patient when applying the human capital approach to calculate productivity costs.25-27

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Table 70-6  Components of Disease Duration Onset of axial AS manifestations (inflammatory back pain) Onset of extra-axial AS manifestations (peripheral arthritis, ­enthesitis) Onset of associated spondyloarthropathic diseases (acute anterior uveitis, inflammatory bowel disease, psoriasis) Time since diagnosis of AS by health care provider AS, ankylosing spondylitis. From Davis, JC, Dougados M, Braun J, et al: Definition of disease duration in ankylosing spondylitis: Reassessing the concept. Ann Rheum Dis 65: 1518-1520, 2006.

The burden of illness increases with duration of disease. Important components of the definition of disease duration are provided in Table 70-6.28 Because the burden reduces quality of life, and because all types of costs associated with AS result from loss of function and disease activity, early diagnosis and treatment are necessary to prevent or reduce functional decline and improve patient outcome.29

CAUSE AND GENETICS The precise cause of AS is still unclear, although several dominant themes have emerged. First, there is a major genetic contribution. Although it is now well established that HLA-B27 is directly involved in the pathogenesis of disease, its precise pathophysiologic role is unclear, and additional non–major histocompatibility complex (MHC) genes contribute to the risk for disease. Second, cartilage appears to be the primary target tissue for the abnormal immune response. Third, cytokine dysregulation, with overexpression of TNF-α, and intestinal inflammation are prominent features of disease. Fourth, emerging evidence implicates bone morphogenetic proteins in the pathogenesis of ankylosis. The dominant role of genetic factors is highlighted by data demonstrating disease concordance in 75% of monozygotic twins compared with 13% of nonidentical twins,30 familial aggregation,31 and population data demonstrating associations with B27.32 Genetic data also suggest that 97% of the population variance can be explained by additive genetic effects, the environmental trigger is ubiquitous, three to nine genes are involved in addition to B27, and genes influence disease severity and phenotype.33 HLA-B27 Despite the near-pervasive nature of this association, it has been estimated that B27 contributes only 16% of the total genetic risk. The association with B27 is also less evident in other populations, such as native Indonesians, Lebanese, Thais, and West African blacks. It is present in only 60% to 80% of those with concomitant psoriasis and inflammatory bowel disease. Forty-five subtypes have been assigned on the basis of nucleotide sequence homology that encodes more than 20 different products. The most common subtype in Caucasians is B*2705, followed by B*2702; both are associated with disease. The most common subtype in Chinese and Japanese is B*2704, which is associated with disease. B*2706 is the most common subtype in other Asians, but it is neutral or only weakly associated with disease.13 B*2709 is observed primarily in southern Italy and is not associated with axial disease, although peripheral arthritis has been

reported.34 There are insufficient epidemiologic data on other subtypes to evaluate disease associations. The main function of HLA class I molecules such as B27 is to present peptides to CD8+ T cells. Crystallographic analysis of B*2705 shows a peptide-binding groove with pockets (A to F) that accommodate the side chains and amino and carboxyl termini of the bound peptide.35 The B pocket is conserved among B27 subtypes but differs from most other B molecules. It has a glutamine amino acid at its apex at amino acid position 45 that interacts with arginine at position 2 of B27-bound peptides; this pocket conveys specificity for the type of peptide bound to B27. In addition, both B*2706 and B*2709 differ from B*2705 at a single amino acid position in the F pocket that binds the peptide C terminal amino acid. This influences the type of peptide bound to disease-associated and nonassociated B27 subtypes and thereby recognition by CD8+ T cells. NON-B27 GENES It has been estimated that the entire HLA region contributes about half the total genetic risk for disease, implicating additional HLA genes beyond B27. Population and family studies have implicated HLA-B60 in B27-positive Caucasians but not in non-Caucasians.36 Several B alleles (B60, B61, B7, B13, B22, B39, B40, B41, B42) have been implicated in B27-negative AS. Some alleles, such as B39, have a peptide-binding groove that shares similarities with B27. Several case-control studies have now reported associations with HLA-DRB1*01, 07, and 08 that are independent of B27.37 Two observations clearly suggest a role for non-HLA genes. First, there is an increased risk for disease in B27positive first-degree relatives of AS probands (10% to 20%) compared with B27-positive individuals in the general population (2% to 5%).15 Second, disease concordance is 75% in identical twins versus 27% in HLA-B27 concordant dizygotic twins.30 The contribution of non-HLA genes is comparable to the entire genetic contribution to insulin-dependent diabetes. Case-control studies in Caucasian and Taiwanese populations support an association with the cytochrome P-450 CYP2D6 gene on chromosome 22, which is involved in the metabolism of drugs.38 An association has also been described with the CARD15 gene in AS patients with concomitant intestinal inflammation.39 CARD15 binds bacterial cell wall components and is a regulator of the proinflammatory transcriptional factor nuclear factor κB (NFκB). Several gene consortia have used linkage approaches and microsatellite markers to identify regions of the genome demonstrating nonrandom inheritance in AS families. Relatively weak linkage has been demonstrated with regions on chromosomes 1p, 6q, 9q, 10q, 11q, 16q, and 19q; there has been little agreement among studies, however, likely reflecting the weak contributions of individual loci and the small sample size of each study.40-42 Several case-control and familybased association studies have now reported associations with the interleukin (IL)-1 gene cluster on chromosome 2.43-45 This cluster includes genes for IL-1A, IL-1B, IL-1RN, and six genes demonstrating structural homology to these genes, namely, IL-1F5 to F10. A meta-analysis of these studies ­ suggests that the primary association is with a locus at

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or close to IL-1A.46 Additional reports show that despite a male ­predominance, there is no association with loci on the X chromosome, and non-HLA genes may influence disease severity.47 Recently, genome-wide association studies have identified two new genes definitely involved in the pathogenesis of the disease, IL23R and ARTS1.47a HYPOTHESES The primary hypotheses address the pathophysiologic role of B27 and focus either on some aspect of its principal function, which is to present peptides to CD8+ T cells, or on less conventional properties of B27, such as its propensity to misfold and its expression as heavy-chain dimers on the cell surface. The former hypothesis proposes that CD8+ T cell autoreactivity to self-peptide from joint tissue is induced by cross-reactivity with bacterial peptide that demonstrates molecular mimicry with this self peptide; both peptides are therefore presented by B27 in the course of T cell–mediated defense to bacterial infection. This arthritogenic peptide hypothesis is supported by epidemiologic data demonstrating differential disease associations with B27 subtypes that vary in their ability to bind and present peptides. The relevance to human disease has been reinforced in crystallographic studies showing that although B*2709 binds a self-peptide—vasoactive intestinal peptide receptor 1—in a single conformation that does not elicit CD8 T cell reactivity, B*2705 binds the same peptide in a dual conformation that does elicit CD8 T cell reactivity.48 There are, however, no in vivo studies of patients showing CD8 T cell cross-reactivity to bacterial peptides demonstrating molecular mimicry with joint tissue–derived self-peptides presented by B27. An alternative hypothesis is based on the finding that B27 is more likely to misfold than are other class I HLA molecules, which may be due to its weaker binding of peptides in the endoplasmic reticulum. This property appears to be dependent on the unique structural properties of the B27 peptidebinding pocket.49 The accumulation of misfolded B27 within the cell activates the unfolded protein response, which includes activation of a variety of proinflammatory transcriptional factors (e.g., NFκB) and cytokines (e.g., IL-1, TNF-α). Evidence of this unfolded protein response has been obtained from synovial fluid cells from AS patients. This hypothesis does not address the differential B27 subtype associations with disease, but this property of B27 may be important in expanding and perpetuating the inflammatory response. A third hypothesis proposes that B27 forms heavy-chain homodimers on the cell surface through the formation of a disulfide bond linking the cysteine residues at position 67.50 The likelihood of dimer formation appears to be linked to B27’s propensity to misfold. These structures have been detected in patients with AS, and their formation has been shown to stimulate the release of TNF-α, but B27 is not the only class I molecule that can form such dimers. ANIMAL MODELS Our understanding of the direct role of B27 in the pathogenesis of disease was advanced with the first report of a B27 transgenic rat model of arthritis. HLA-B27 is overexpressed in these animals, which develop chronic intestinal inflammation similar to Crohn’s disease at 16 weeks of age, followed by

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peripheral arthritis in 70% of animals by 20 weeks and occasional spondylitis of tail vertebrae.51 Disease is more ­common in males and is related to the degree of ­ overexpression of B27. The presence of T cells and B27 expression on a bone marrow–derived cell are required. Moreover, animals maintained in a germ-free environment do not develop either colitis or arthritis until they are introduced into the normal laboratory environment.52 The lack of spondylitis in this model, however, raises questions about its relevance to human disease. In a more recent B27 transgenic rat model, B27 is overexpressed together with human β2-microglobulin. These animals show a much higher incidence of spondylitis, despite the absence of concomitant colitis.53 This model more closely resembles human disease. Several animal models of AS have also been developed, based on the induction of autoimmunity to antigens present in cartilage and fibrous tissue, such as aggrecan and versican.54,55 The importance of TNF-α to the pathogenesis of AS is highlighted in the phenotype of a transgenic mouse model that overexpresses TNF-α. These animals develop sacroiliitis characterized by the formation of osteoclasts and granulation tissue.56 HUMAN STUDIES Pathologic studies show a disease predilection for sites rich in cartilage, particularly fibrocartilage. These include articular sites such as the sacroiliac joints, intervertebral disks, and facet joints, but also certain entheses, such as the Achilles tendon, where the presence of fibrocartilage allows ­dissipation of compressive forces against bone. Immunohistochemical studies have shown an abundance of aggrecan and type II collagen at the fibrocartilaginous insertions of entheses.57 The presence of fibrocartilage extends to extraskeletal sites such as the anterior uvea and the root and wall of the aorta. This strongly implies that cartilage may be the primary target for an immune response as the initiating event in this disease. Cellular immunity to the G1 domain of aggrecan has been observed in AS as well as in other inflammatory joint disorders, implying a nonspecific response to joint damage.58 However, a specific HLA-B27–restricted CD8+ T cell response to a cartilage antigen derived from type VI collagen has now been identified in the peripheral blood and synovial fluid of AS patients.59 The pathogenetic significance of these T cells requires further study. ROLE OF BACTERIA B27 transgenic rats do not develop arthritis if maintained in a germ-free environment. Exposure of these animals to bacteria, especially Bacteroides species, triggers the onset of both intestinal and joint inflammation. In humans, evidence of intestinal inflammation is present in up to 60% of AS patients; its presence in juvenile patients with only peripheral joint inflammation increases the likelihood of the development axial disease.60 Oligoclonal T cell expansions have been reported in both the colonic mucosa and synovial fluid of patients with enterogenic AS, suggesting a common antigenic stimulus.61 Examination of peripheral blood and colonic lamina propria T cells from patients with AS demonstrated impaired production of interferon-γ, TNF-α, and IL-2 compared with healthy B27-positive controls.62 This, together

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with evidence of increased intestinal permeability, might account for impaired immune responses to bacteria. Elevated immunoglobulin (Ig) A antibodies to several ­bacteria have been observed, such as Klebsiella pneumoniae and Escherichia coli, but bacterial products have not been detected in sacroiliac joint biopsies.63 Another mechanism that implicates intestinal bacteria focuses on the finding of antigen presenting cells in both intestinal mucosa and synovium that express the CD163 scavenger receptor and possess the capacity to secrete TNF-α and IL-1 in response to bacterial lipopolysaccharide.64 This subset of macrophages is increased in AS compared with rheumatoid arthritis (RA) synovium. ANKYLOSIS The development of ankylosis may be a sequela of prior inflammation, but this remains to be proved. An animal model of ankylosing enthesitis showed evidence of the uncoupling of inflammation and ankylosis, the latter being regulated by bone morphogenetic proteins; these members of the transforming growth factor-ß superfamily control a wide array of cellular processes, such as proliferation, differentiation, and motility.65 Expression of bone morphogenetic protein has also been documented in the entheses of AS patients.

PATHOLOGY Characteristic pathologic features of AS include inflammation in axial joints, large peripheral joints, and entheses associated with inflammation in subchondral bone marrow. Reparation is also characteristic in terms of the development of chondroid metaplasia, followed by calcification of cartilage and formation of bone, particularly in the axial joints. SACROILIAC JOINT Disease typically originates in the sacroiliac joints, where magnetic resonance imaging (MRI) reveals inflammation in the posteroinferior capsular region and subchondral bone of the synovial portion of the joint.66 Detailed histopathologic studies in early disease are limited owing to the inaccessibility of biopsy material. A controlled study of sacroiliac biopsies from AS patients at various stages of disease and controls showed cellular infiltration with lymphocytes, macrophages, and plasma cells in the synovium and subchondral marrow as the earliest features of disease.67 Later features include the development of pannus extending from both synovium and subchondral bone marrow, with erosion of articular cartilage and its replacement by granulation tissue. Osteoclast formation and erosion of subchondral bone account for the typical widening of the joint space seen on plain radiography. Enthesitis is also evident in later stages of disease at the insertion of the posterior capsule. Reparative changes include cartilage metaplasia at sites of active inflammation, followed by its calcification and then replacement by ­endochondral bone, leading to obliteration of the joint space by ankylosis. Para-articular changes include bone sclerosis and fat replacement of bone marrow. Immunohistologic studies show the presence of dense cellular infiltrates of T lymphocytes and macrophages expressing TNF-α.68 Transforming growth factor is evident at sites of new bone formation.

SPINE Several regions of the spine are affected, although histopathologic reports that clearly document the findings in early disease are confined to single case studies. Inflammation typically ascends the spine but may involve the cervical region first and may skip vertebral segments. Chronic ­inflammation with lymphocytes, plasma cells, and macrophages is first observed in the outer annulus fibrosus, particularly at its insertion into the rim of the vertebral end plate. This leads to resorption of bone, followed by reparative changes in adjacent trabecular bone and bone apposition on the waist of the vertebral body during postinflammatory remodeling, accounting for the squaring and shining corner appearance on plain radiography. Cartilage metaplasia of granulation tissue is followed by its calcification and then replacement by bone at the vertebral margin and in the outer annulus. This extends across the vertical length of the disk, eventually leading to complete bony fusion of adjacent vertebrae and the appearance of a syndesmophyte on plain radiography. Extensive involvement of the entire spine results in the “bamboo spine” appearance on plain radiography. The proc­ ess of inflammation may also involve the central portion of the disk, which is best seen on MRI as spondylodiscitis. Involvement of the atlantoaxial structures, particularly the insertion of the transverse ligament into the arch of the atlas and the capsular insertion of the lateral atlantoaxial joint, may lead to atlantoaxial dislocation and cord compression. Chronic inflammation is also seen at the capsular insertion of apophyseal joints. The characteristic sequence of pannus formation, subchondral inflammation, erosion of articular cartilage and bone at the capsular insertion, cartilage metaplasia, and ossification of subsynovium and fibrous capsule at its insertion is observed. This leads first to marginal and then complete bony ankylosis of the joint. There is evidence that ankylosis of the apophyseal joint precedes and is a factor in the development of ankylosis in the adjacent intervertebral disk.69 Immunohistologic analysis shows subchondral lymphocyte infiltrates with CD4+ and CD8+ T cells, together with hypervascularization and foci of CD68+ osteoclastic cells.70 Pathologic involvement of costotransverse and costovertebral joints follows the same pattern described earlier, and MRI indicates that involvement of these joints is common.71 Enthesitis with bone erosion and then ossification may affect the insertions of the supraspinous and intraspinous ligaments. Osteoporosis with kyphosis is a typical feature of late stages of disease. EXTRASPINAL LESIONS Extraspinal lesions can be broadly divided into articular and nonarticular inflammatory lesions. The former include synchondrotic joints such as the manubriosternal joint and symphysis pubis, large synovial joints such as the hips and knees, and entheses. The pathologic sequence of changes in synchondrotic joints is typical of those observed in the spine. Involvement of the hips is characterized by subchondral granulation tissue and osteoclast formation in the femoral heads and acetabulum that is associated with degradation of overlying articular cartilage.72 Knee assessment has been conducted in patients representing a broad category of

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s­ pondyloarthritis, with limited information specific to AS. The appearance of synovitis appears to be similar to that observed in RA, although with more pronounced vascularity and differential expression of integrins.73 Entheseal involvement most frequently occurs at sites rich in fibrocartilage, such as the Achilles tendon. Inflammation and chronic cellular infiltration of soft tissues are relatively sparse but may be extensive within the adjacent subchondral bone, particularly in B27-positive individuals.74 A comparative study of the subchondral marrow from knee and hip joint entheses showed that AS patients clearly differ from those with RA and osteoarthritis with respect to the frequency of marrow inflammation, infiltration with CD8+ T cells, and presence of hyperosteoclastic erosive lesions. Inflammation in nonarticular sites may involve the anterior uvea and ciliary body. Elsewhere, granulation tissue forms, with an accumulation of lymphocytes and plasma cells around the small blood vessels in the adventitia of the ascending aorta, followed by fibrosis extending below the base of the aortic valve to form a characteristic subvalvular ridge. Apical fibrosis of the lungs also occurs.

CLINICAL MANIFESTATIONS SKELETAL MANIFESTATIONS Low Back Pain and Stiffness Back pain is an extremely common symptom, occurring in up to 80% of the general population. Therefore, it is ­important to note that back pain in AS has special features that differentiate it from mechanical back pain75,76 (Table 70-7). The pain is initially felt primarily deep in the gluteal region, is dull in character, is difficult to localize, and is insidious in onset. The pain can be severe at this early phase of the disease; it localizes in the sacroiliac joints but is occasionally referred toward the iliac crest or greater trochanteric region or down the dorsal thigh. Radiation of buttock pain may suggest root compression of the ischiadic nerve. The buttock pain typically alternates from side to side. Coughing, sneezing, or other maneuvers that cause a sudden twist of the back may accentuate pain. Although the pain is often unilateral or intermittent at first, within a few months it usually becomes persistent and bilateral, and the lower lumbar area becomes stiff and painful. The pain is associated with a feeling of low back stiffness that is worse in the morning and may awaken the patient from sleep, particularly during the second half of the night. Many patients do not differentiate between low back pain and stiffness. The morning stiffness may last up to 3 hours. Both the stiffness and the pain tend to be eased by a hot shower, an exercise program, or physical activity; they do not improve with rest. Fatigue as a result of chronic back pain and stiffness may be an important problem and can be accentuated by sleep disturbances due to these symptoms. Chest Pain With subsequent involvement of the thoracic spine (including costovertebral and costotransverse joints) and the occurrence of enthesopathy at the costosternal and manubriosternal joints, patients may experience chest pain

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Table 70-7  Diagnostic Features of Ankylosing ­Spondylitis Inflammatory spinal pain Onset before age 40 yr Insidious onset Persistence for at least 3 mo Morning stiffness of at least 30 min duration Improvement with exercise but not with rest Awakening because of back pain during second half of night Chest pain Alternate buttock pain Acute anterior uveitis Synovitis (predominantly of lower limbs, asymmetric) Enthesitis (heel, plantar) Radiographic sacroiliitis Positive family history of Ankylosing spondylitis Chronic inflammatory bowel disease Psoriasis

accentuated by coughing or sneezing, which is sometimes characterized as “pleuritic.” The chest pain is often associated with tenderness over the sternocostal or costosternal junctions. Mild to moderate reduction of chest expansion is often detectable in an early stage of AS. Chest pain occurs relatively often in HLA-B27–positive relatives, even in the absence of radiographic evidence of sacroiliitis.77 Tenderness Extra-articular tenderness at certain loci is a prominent complaint in some patients. These lesions are due to enthesitis. Common tender sites are the costosternal junctions, spinous processes, iliac crests, greater trochanters, ischial tuberosities, tibial tubercles, and heels (Achilles tendinitis or plantar fasciitis). Radiographically, bone spurs may develop at these sites. Joints The girdle or “root” joints (hips and shoulders) are the most frequently involved extra-axial joints in AS, and pain in these areas is the presenting symptom in up to 15% of patients. Shoulder involvement, but especially hip involvement, may cause considerable physical disability. Coexisting disease in the lumbar spine often contributes significantly to disability of the lower extremities. Hips and shoulders are involved at some stage of disease in up to 35% of patients. Hip disease is more common in Algeria, India, and Mexico. It is relatively more common as a presenting manifestation if the disease starts in childhood (juvenile AS). In boys 8 to 10 years of age, hip disease as a manifestation of juvenile AS is the most frequent type of chronic arthritis. These children with hip disease are mostly HLA-B27 positive, and they are serologically negative for antinuclear antibodies. The knee joint may also be affected in AS, often as an intermittent effusion. The temporomandibular joint is involved in about 10% of patients.

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EXTRASKELETAL MANIFESTATIONS Constitutional symptoms, such as fatigue, weight loss, and low-grade fever, occur frequently. Other extraskeletal manifestations are more localized. Eye Disease Acute anterior uveitis or iridocyclitis is the most ­ common extra-articular manifestation of AS, occurring in 25% to 30% of patients at some time during the course of the ­disease. There is no clear relationship between activity of the articular disease and this extra-articular manifestation. The onset of eye inflammation is usually acute and typically unilateral, but the attacks may alternate. The eye is red and painful, with visual impairment. Photophobia and increased lacrimation may be present. If the eye remains untreated or if treatment is delayed, posterior synechiae and glaucoma may develop. Most attacks subside in 4 to 8 weeks without sequelae if early treatment is provided. Acute anterior uveitis is more common in B27-positive than B27-negative patients with AS.78 Relatives who have acute anterior uveitis seem to be at higher risk for AS themselves. The calculated incidence of acute anterior uveitis in a Swiss family study was 89 attacks per 1000 patient-years for AS patients, but only 8 per 1000 person-years among healthy B27-positive relatives.79 Cardiovascular Disease Cardiac involvement may be clinically silent or may cause considerable problems. Manifestations of cardiac involvement include ascending aortitis, aortic valve incompetence, conduction abnormalities, cardiomegaly, and pericarditis. In rare situations, aortitis may precede other features of AS. Aortic incompetence was noted in 3.5% of patients who had the disease for 15 years and in 10% after 30 years.80 Inflammation and dilation of the aorta are the main cause of aortic valve incompetence. Cardiac conduction disturbances are seen with increasing frequency with the passage of time, occurring in 2.7% of those with disease of 15 years’ duration and in 8.5% after 30 years.80 Both aortic incompetence and cardiac conduction defects occur twice as often in patients with peripheral joint involvement. Pulmonary Disease Lung involvement is a rare and late manifestation of AS. It is characterized by slowly progressive fibrosis of the upper lobes of the lungs, appearing, on average, 2 decades after the onset of AS. Patients may complain of cough, dyspnea, and sometimes hemoptysis.81 High-resolution computed tomography (CT) may be helpful in detecting interstitial lung disease in patients with respiratory symptoms whose chest radiographs are normal.82 This imaging technique reveals a high prevalence of lung changes even among AS patients with early disease and without respiratory symptoms. The clinical significance of these findings is unknown. Long-term prospective studies need to be performed.83 Pulmonary ventilation is usually well maintained; an increased diaphragmatic contribution helps compensate for chest wall rigidity, which is due to involvement of the thoracic

joints in the inflammatory process. Vital capacity and total lung capacity may be moderately reduced as a consequence of the restricted chest wall movement, whereas residual volume and functional residual capacity are usually increased. Neurologic Involvement Neurologic complications of AS can be caused by fracture, instability, compression, or inflammation. Traffic accidents or minor trauma can cause spinal fractures. The C5-C6 or C6-C7 level is the most commonly involved site. As in RA, atlantoaxial joint subluxation, atlanto-occipital subluxation, and upward subluxation of the axis may occur in AS as a consequence of instability resulting from the inflammatory process. Spontaneous anterior atlantoaxial subluxation is a well-recognized complication in about 2% of patients and manifests with or without signs of spinal cord compression. It is observed more commonly in patients with spondylitis and peripheral arthritis than in those with exclusively axial involvement.84 Causes of neurologic complications due to compr­ession include ossification of the posterior longitudinal ligament (which may lead to compressive myelopathy), destructive intervertebral disk lesions, and spinal stenosis. The cauda equina syndrome is a rare but serious complication of long-standing AS. The syndrome affects lumbosacral nerve roots. This gives rise to pain and sensory loss, but frequently there are also urinary and bowel symptoms. There is a gradual onset of urinary and fecal incontinence, impotence, saddle anesthesia, and occasionally loss of ankle jerks. Motor symptoms, if present, are usually mild. Newer imaging techniques, such as CT and MRI, allow the accurate noninvasive diagnosis of this complication of AS.85 There are no compressive lesions. ­Arachnoiditis and arachnoid adhesions may be important in the pathogenesis. Renal Involvement IgA nephropathy has been reported in many patients with AS. These patients often have an elevated IgA level (93%) and renal impairment (27%) at presentation.86 Microscopic hematuria and proteinuria may occur in up to 35% of patients. The significance of these findings in terms of subsequent deterioration of renal function is unclear.87 Amyloidosis (secondary type) is a rare complication. Amyloid deposits detected through abdominal subcutaneous fat aspiration are not invariably associated with a poor renal prognosis.88 Osteoporosis Osteopenia is seen in the early stages of AS.89 In patients with this disease, osteoporotic deformities of the thoracic spine contribute significantly to abnormal posture, particularly fixed hyperkyphosis.90 Radiographic damage to the cervical and lumbar spine, thoracic wedging, and disease activity are determinants of hyperkyphosis in AS. 91 An increased occiput-to-wall distance is associated with vertebral fractures. The prevalence of symptomatic osteoporotic spinal fractures is increased in AS.92 Neurologic complications occur rather frequently, even after minor trauma.93 Proper assessment of bone density in the spine is difficult

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in the presence of syndesmophytes, because they may give rise to falsely high values. This measurement error can be avoided by using quantitative CT. Further research is needed to determine the true fracture risk and complication rate in early and late disease and the relation to disease activity. Currently, it is unclear whether any specific therapy to prevent osteoporotic spinal fractures is effective.

PHYSICAL FINDINGS SPINAL MOBILITY To arrive at an early diagnosis, the physician must perform a thorough physical examination. On examination of the spine, there may be some limitation of motion of the lumbar spine as elicited by forward flexion, hyperextension, or lateral flexion. Early loss of the normal lumbar lordosis is often the first sign and is easily assessed on inspection. The Schober test (or its modifications) is useful to detect any limitation of forward flexion of the lumbar spine, although it is typically normal in early disease. As the patient stands erect, one mark is placed with a pen on the skin overlying the fifth lumbar spinous process (usually at the level of the posterosuperior iliac spine or the “dimple of Venus”), and another mark is placed 10 cm above in the midline. The patient is then asked to bend forward maximally without bending the knees. In healthy people, the distance between the two marks on the skin should increase as the skin stretches. If the distance between both marks does not reach 15 cm, this indicates reduced lumbar spine mobility. Lateral flexion may also be diminished, and spinal rotation may cause pain. CHEST EXPANSION Mild to moderate reduction of chest expansion is often detectable in early stages of AS. Normal values are age and sex dependent, and there is considerable overlap between normal values and those obtained from AS patients. Reduction below 5 cm in young persons with an insidious onset of chronic, inflammatory low back pain strongly suggests AS. Chest expansion should be measured on maximal inspiration after forced maximal expiration at the level of the fourth intercostal space in males and just below the breasts at the xiphisternal level in females. ENTHESITIS Examination of the ischial tuberosities, greater trochanters, spinous processes, costochondral and manubriosternal junctions, supraspinatus insertion, and iliac crests can determine the presence of enthesitis. Heel pain, especially when getting out of bed, is a characteristic manifestation of Achilles and plantar fasciitis enthesitis. SACROILIITIS Direct pressure over the sacroiliac joints may elicit pain, as may special testing maneuvers, although the latter lack specificity and sensitivity. These signs may also be

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negative in early disease or may become negative in late stages as inflammation is replaced by fibrosis or bony ankylosis. POSTURE Over the course of the disease, the patient may lose normal posture. Involvement of the cervical spine is manifested by pain and limitation of neck movement. A forward slope of the neck can be detected by having the patient stand against a wall and try to position his or her occiput against it. After many years of progression in patients with severe disease, the entire spine may become increasingly stiff, with loss of normal posture from gradual loss of lumbar lordosis and the development of thoracic kyphosis. The abdomen becomes protuberant; breathing is primarily by diaphragmatic action. These typical deformities usually evolve after a disease duration of 10 years or more.

LABORATORY TESTS Generally, routine blood tests are not helpful. A normal erythrocyte sedimentation rate (ESR) or normal C-reactive protein (CRP) level does not exclude active disease. An elevated ESR or CRP is reported in up to 75% of patients, but it may not correlate with clinical disease activity.94 In an unselected patient population, an elevated ESR and CRP was present in 45% and 38%, respectively, of patients with ­ spinal disease only, compared with 62% and 61%, ­respectively, of patients with peripheral arthritis with or without inflammatory bowel disease. Neither ESR nor CRP is superior in assessing disease activity.95 A mild normochromic anemia may be present in 15% of patients. Elevation of serum ­ alkaline phosphatase (derived primarily from bone) is seen in some patients but is unrelated to disease activity or duration. Some elevation of serum IgA is frequent in AS. Its level correlates with acute-phase reactants. Active disease is ­associated with decreased lipid levels, particularly high-­density lipoprotein cholesterol, resulting in a more ­atherogenic lipid profile.96

IMAGING STUDIES CONVENTIONAL RADIOGRAPHY The typical radiographic changes of AS are seen primarily in the axial skeleton, especially in the sacroiliac, discovertebral, apophyseal, costovertebral, and costotransverse joints. They evolve over many years, with the earliest, most consistent, and most characteristic findings seen in the sacroiliac joints. However, otherwise typical AS has been described in the absence of radiographic evidence of sacroiliitis.15 The radiographic findings of sacroiliitis are usually symmetric and consist of blurring of the subchondral bone plate, followed by erosions and sclerosis of the adjacent bone. The changes in the synovial portion of the joint (i.e., the lower two thirds of the joint) result from inflammatory synovitis and osteitis of the adjacent subchondral bone.97 The cartilage covering the iliac side of the joint is much thinner than that covering the sacral side. Therefore, the erosions and subchondral sclerosis are typically seen first and tend to be more prominent on the iliac side.

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Table 70-8 Grading of Sacroiliitis: New York Criteria Grade 0, normal Grade 1, suspicious Grade 2, minimal sacroiliitis Grade 3, moderate sacroiliitis Grade 4, ankylosis

In the upper one third of the sacroiliac joint, where strong intra-articular ligaments hold the bones together, the inflammatory process may lead to similar radiographic abnormalities. Progression of the subchondral bone erosions can lead to pseudowidening of the sacroiliac joint space. Over time, gradual fibrosis, calcification, interosseous bridging, and ossification occur. Erosions become less obvious, but the subchondral sclerosis persists, becoming the most prominent radiographic ­feature. Ultimately, usually after several years, there may be complete bony ankylosis of the sacroiliac joints, with resolution of bony sclerosis. It is practical to grade radiographic sacro­ iliitis according to the New York criteria (Table 70-8). Bony erosions and osteitis (“whiskering”) at sites of osseous attachment of tendons and ligaments are frequently seen, particularly at the calcaneus, ischial tuberosities, iliac crest, femoral trochanters, supraspinatus insertion, and spinous processes of the vertebrae. In the early stages of the evolution of syndesmophytes, there is inflammation of the superficial layers of the annulus fibrosus, with subsequent reactive sclerosis and erosions of the adjacent corners of the vertebral bodies. This combination of destructive osteitis and repair leads to “squaring” of the vertebral bodies. This squaring is associated with gradual ossification of the annulus fibrosus and eventual “bridging” between vertebrae by syndesmophytes.98 There are often concomitant inflammatory changes, ankylosis in the apophyseal joints, and ossification of the adjacent ligaments. In a number of patients, this may ultimately result in a virtually complete fusion of the vertebral column (“bamboo spine”). Hip involvement may lead to symmetric, concentric joint space narrowing, irregularity of the subchondral bone with subchondral sclerosis, osteophyte formation at the outer margin of the articular surface, and, ultimately, bony ankylosis of these joints. There are several validated scoring methods available to quantify structural damage in AS: the Bath AS radiology index (BASRI), the stoke AS spondylitis score (SASSS), and the modified SASSS.99-101The BASRI includes scores for the cervical and lumbar spine as well as the sacroiliac joints. A similar score for the hips is also available. The SASSS evaluates the lumbar spine only; the modified SASSS assesses the cervical and lumbar spine. These scoring methods are most suited for use in clinical trials and observational studies. COMPUTED TOMOGRAPHY AND MAGNETIC RESONANCE IMAGING The conventional plain pelvic radiograph is still the initial tool for the evaluation of sacroiliac joints in patients with inflammatory low back pain. This technique, however, lacks

Figure 70-1  T1-weighted, opposed-phase, gradient echo magnetic resonance image 3 minutes after the intravenous injection of ­gadolinium-DTPA in a 23-year-old man with ankylosing spondylitis and severe inflammatory back pain localized mainly to the right side, of 3 years’ duration. Acute sacroiliitis is demonstrated by the strong contrast enhancement of the right sacroiliac joint (arrowheads), with impressive bone marrow edema (white arrow) and erosions (black arrow). (Enhancement factor 150%, graded 3B right, 1× left.)

sensitivity in the early stages of sacroiliac inflammation. In such cases, dynamic MRI with a T1-weighted sequence after the intravenous injection of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) is able to demonstrate early stages of sacroiliitis102,103(Fig. 70-1). Fat-saturating techniques such as short tau inversion recovery (STIR) sequences are very sensitive in the detection of bone marrow edema, which is a frequent finding in AS-related inflammation of the musculoskeletal system.104 STIR imaging is cheaper than Gd-DTPA sequences and almost as good. Thus, active, early sacroiliitis can best be searched for by STIR or contrast-based sequences. Similarly, spinal involvement is first assessed by conventional radiography. Square vertebrae, shiny corners (the Romanus lesion), spondylodiscitis (the Anderson lesion), and syndesmophytes with partial and complete fusion are typical radiographic features of AS. Spinal inflammation cannot be assessed by conventional radiography but can be visualized by MRI,20 where it is typically seen in the vertebrae, at both anterior and posterior sites as well as around the intervertebral disk. Posterior elements such as the facet joints, pedicles, and transverse processes can show inflammatory lesions as well. MRI and ultrasonography can be very useful to assess enthesitic problems such as Achilles tendinitis and heel pain. To quantify spinal inflammation, mainly for use in clinical trials, several scoring methods exist. Currently, one cannot prioritize among these methods. The relation between ­clinical symptoms and structural damage needs to be explored further.105 For the detection of bone changes, such as erosions and ankylosis, CT is usually considered superior to MRI, but MRI is better in the imaging of cartilage and provides the possibility of dynamic measurements.102,106,107 CT is definitely

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not indicated in the routine evaluation of the sacroiliac joint. CT scanning may be useful in the diagnosis of spinal fractures, spinal stenosis, or thecal diverticula. A major difference between CT and MRI is the radiation exposure associated with the former but not with the latter.

DIAGNOSIS Clinical manifestations of AS usually begin in late adolescence or early adulthood; only rarely do they begin after age 40 years.15 The diagnosis of AS at an early stage of disease depends primarily on a careful history and physical examination. Two features of the history are critical: the presence of inflammatory low back pain and stiffness, and a positive family history for AS. Low back pain is very common in the general population and is frequently due to noninflammatory, nonspecific mechanical causes. However, the low back pain in AS has typical “inflammatory” features (see Table 70-7). A history of inflammatory low back pain can be used as a diagnostic tool. A reassessment of the clinical history for diagnostic purposes among young to middle-aged adults (younger than 50 years) with chronic back pain and an established diagnosis of either AS or mechanical back pain revealed a sensitivity of 37% (95% CI 28 to 46), a specificity of 84% (95% CI 76 to 90), a positive likelihood ratio of 2.3 (95% CI 1.4 to 3.7), and a post-test probability of AS of 11% (given a pretest probability of 5%) if two of the four parameters listed in Table 70-9 were present. If three or four of these items were present, the sensitivity was 34% (95% CI 25 to 43), the specificity was 97% (95% CI 92 to 99), the positive likelihood ratio was 12.4 (95% CI 4.0 to 40), and the post-test probability of AS was 39%.76 Because the prevalence of AS in many white populations is as low as approximately 0.1% to 0.3%, applying the clinical history as a test for the disease in such low-probability settings provides rather low posttest probability values. However, a positive family history increases the pretest probability of AS from 0.1% for a person belonging to the general population to about 10% for any first-degree relative of an AS proband.15 The probability of having AS for a first-degree relative with a positive family history of AS increases from 10% to nearly 50% if this relative has inflammatory low back pain. In contrast, the likelihood of having AS increases from 0.1% to only 1% for a person who has inflammatory back pain (without any other inflammatory indications listed in Table 70-9) but has a negative family history for AS. A definite diagnosis of AS is usually established by radiographic evidence of bilateral sacroiliitis. The plain anteroposterior view of the pelvis is usually adequate for diagnostic purposes. There is, however, considerable intra- and interobserver variation in the radiographic diagnosis of sacroiliitis for both conventional pelvic films and CT of the sacroiliac joints. Training in reading these films has limited value. Improvement in sensitivity tends to be associated with a decrease in specificity.108 In most adult patients, AS can be diagnosed clinically without the HLA-B27 test. This assessment has no additional value in established disease or as a pure screening tool.109 However, in young patients with inflammatory chronic back pain, a positive HLA-B27 test increases the likelihood of having AS, particularly if imaging of the

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Table 70-9 Proposed Criteria for Inflammatory Back Pain in Young to Middle-aged Adults* with Chronic Back Pain Morning stiffness of at least 30 min duration Improvement of back pain with exercise but not with rest Awakening because of back pain during second half of night only Alternating buttock pain *Younger than 50 yr. From Rudwaleit M, Metter A, Listing J, et al: Inflammatory back pain in ankylosing spondylitis: A reassessment of the clinical history for application as classification and diagnostic criteria. Arthritis Rheum 65:569-578, 2006.

­sacr­oiliac joints does not provide conclusive results. Usually, however, the contribution of MRI and HLA-B27 typing to purely clinical factors in diagnosing axial manifestations of AS among patients with inflammatory back pain of short duration is rather limited.110 Physicians are reluctant to make the diagnosis of AS when radiographic evidence of sacroiliitis is not present. In particular, relatives of AS patients may have signs and symptoms of AS, including inflammatory back pain, but sometimes do not show radiographic sacroiliitis even after lengthy follow-up. Radiographic sacroiliitis is frequent in AS but is by no means an early or obligate manifestation of the disease. In patients with a clinical diagnosis of possible AS, radiographic sacroiliitis may become manifest only after appropriate follow-up. Therefore, diagnosing the disease early, before (conventional) radiographic evidence of sacroiliitis is manifest, constitutes a challenge to the clinician. This is especially true as more effective treatments become increasingly available. In this context, the term preaxial AS is often used. An approach based on pretest probabilities and likelihood ratios has been proposed to diagnose early disease with predominantly axial manifestations before convincing evidence of radiographic sacroiliitis is present.76 AS rarely develops after age 40; however, late-onset AS does occur. In this case, there may be little or no clinical involvement of the axial skeleton initially, but patients may show moderate oligoarthritis with low cell counts in the synovial fluid and pitting edema of the lower limbs.111 At the other end of the age scale, juvenile-onset AS is not uncommon among patients with spondyloarthropathies. Such patients tend to have enthesopathy and peripheral arthritis that may be severe and disabling.

GENDER ISSUES Clinically, AS is more common in males, with a reported male-female ratio of about 2:1 to 3:1. However, extrapolation of studies employing the genetic marker HLA-B27 suggests that, based on radiographs of the sacroiliac joints, prevalence rates are about equal in both sexes.15 Disease expression is thought to be different in males and females. A case-control study comparing 35 female patients to 70 male patients as controls showed no differences in spinal symptoms, chest expansion, peripheral arthritis, extraarticular manifestations, or functional outcome. The males with AS more often had radiographic spinal changes and

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hip joint involvement than their female counterparts. There is still some controversy, but overall, there are no significant clinical or radiographic differences between women and men with AS. However, on average, the disease seems to be more severe in men.112,113 Fertility among female patients with AS is normal.114 Most patients (50% to 60%) do not experience major changes in disease activity during pregnancy, but an increase in morning stiffness and low back pain, particularly at night, may occur at about the 20th week of gestation and last for a few days to weeks.115 In about 50% of patients, an exacerbation of symptoms is seen within the first half year after delivery. Sacroiliitis, including complete ankylosis of the sacroiliac joints, does not constitute a contraindication for vaginal delivery. Epidural anesthesia is usually possible, because most patients have a rather short duration of disease and do not have extensive spinal syndesmophytes. The fetal ­outcome is not impaired in patients with AS. Every pregnancy in patients with this disease should be considered high risk, however, and such pregnancies require close collaboration between rheumatologists and obstetricians.

PROGNOSIS The course of AS is highly variable, characterized by spontaneous remissions and exacerbations. Its prognosis has generally been considered rather favorable. The disease may run a relatively mild or self-limited course. However, the disease may also remain active over many years. Life expectancy is somewhat reduced, particularly after 10 years of disease.116 A study from Finland indicates that the risk of dying for patients with AS is increased by 50% compared with controls matched for age and gender. Causes of death include complications of the disease such as amyloidosis and spinal fractures, as well as cardiovascular, gastrointestinal, and renal disease.117 There is no convincing evidence that the natural history of the disease has essentially changed over the last few decades.118,119 No differences exist between familial and sporadic AS in terms of age at onset, age at diagnosis, or prevalence of peripheral arthritis and acute anterior uveitis.120 Functional limitations increase with disease duration. Although structural damage seen on radiographs is clearly associated with physical function and spinal mobility at the group level, individual patients with normal radiographs might exhibit a major reduction in spinal mobility, whereas those with severe radiographic abnormalities might function quite well in everyday tasks.121 Recent data show that the functional prognosis of AS is less favorable than was previously thought. Withdrawal from work in those with paid jobs varies from 10% after 20 years of disease duration to 30% after 10 years, depending on the characteristics of the patients included and the social security system considered122-125 (Table 70-10). The age- and sex-adjusted withdrawal rate from labor-force participation was 3.1 times higher among Dutch patients compared with the general population.125 Older age at disease onset, manual work, lower educational level, and coping strategies characterized by the limitation and pacing of activities were associated with a higher risk for work disability.123-125 Vocational counseling, job training, easy access to the workplace, and support of colleagues and management may reduce the probability of withdrawal from work.122,126 Sick leave in those

Table 70-10  Withdrawal from Workforce Due to Disability among Patients with Ankylosing Spondylitis Country

Withdrawal Rate Comments

Mexico (103 patients)

3%/yr

France (182 patients)

36% after 20 yr

Netherlands (529 patients)

30% after 20 yr

RR compared to general population: 3.1 (95% CI: 2.5 to 3.7)

USA (234 patients)

10% after 20 and 30 yr

Highly educated ­patients; IBD excluded

CI, confidence interval; IBD, inflammatory bowel disease; RR, relative risk.

with paid jobs was linked to disease activity and presence of extraspinal disease manifestations.122,125,127 Patients with peripheral joint involvement are more likely to take sick leave than are AS patients with axial manifestations only. Overall, the first 10 years of disease are particularly important with respect to subsequent outcome. Most of the loss of function among patients with AS occurs within this period and is associated with the presence of peripheral arthritis, spinal radiographic changes, and development of a so-called bamboo spine.128 In a retrospective study of patients with spondyloarthropathies, including AS, of at least 10 years’ duration, seven variables were associated with disease severity if these factors occurred within the first 2 years of follow-up. These factors, expressed as an odds ratio together with its 95% CI, are as follows: arthritis of hip joints (22.9; 4.4 to 118), ESR more than 30 mm/hr (7; 4.8 to 9.5), poor efficacy of nonsteroidal antiinflammatory drugs (NSAIDs) (8.3; 2.6 to 27.1), limitation of lumbar spine (7; 2 to 25), sausage-like digits (8.5; 1.5 to 9.0), oligoarthritis (4.3; 1.4 to 13.1), and onset before age 16 years (3.5; 1.1 to 12.8).129 However, the only factor consistently associated with a severe course is involvement of the hip. The long-term results of total hip replacement in AS are satisfactory. The outcome of 138 total hip replacements and 12 revisions was good or very good in 86%, and 63% of patients had no pain. Mobility was good or very good in 44%. The mean follow-up was 7.5 years (range, 1 to 34 years). Altogether, 69% of the male hip recipients younger than 60 years were at work at the time of the survey.130

ASSESSMENT AND MONITORING Signs and symptoms such as spinal pain and limitation of motion might be due to current disease activity or to damage. A plethora of tools is available to assess these dimensions. For example, there are many ways to measure limitation of motion of the lumbar spine. New instruments have been developed to assess various aspects of the disease, including the Bath and Edmonton AS metrology indexes, Bath AS global index, BASRI, Bath AS disease activity index, and Dougados functional index.131-134 However, standardization and validation of many of these instruments are lacking or incomplete. An international Assessment in Ankylosing Spondylitis (ASAS) working group was formed with the aim of selecting, proposing, and testing core sets of measures for different settings.135 It was thought that a certain set of variables should be targeted to a specific task. For example, when assessing the efficacy of

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Table 70-11  World Health Organization–International League of Associations for Rheumatology Core Sets for Ankylosing Spondylitis

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Table 70-12  Assessment in Ankylosing Spondylitis (ASAS) International Working Group ­Improvement Criteria and Partial ­Remission Criteria

Domain

Instrument

ASAS-20 Improvement Criteria

  1.  Function

BASFI or Functional Index Dougados

  2. Pain

VAS: last week, spine pain at night due to AS VAS: last week, spine pain due to AS

  3. Spinal mobility

Chest expansion and modified Sc­hober and occiput to wall distance (lateral spinal flexion or BASMI)

At least 20% improvement and 10 units improvement in three of the four following domains, without 20% or more worsening and 10 units worsening in the remaining domain: BASFI Morning stiffness Patient global assessment Pain

  4. Patient global assessment

VAS: last week

  5. Stiffness

Duration of morning spine stiffness, last week

  6. Peripheral joints and entheses

Number of swollen joints (44 joint count); validated enthesis index

  7.  Acute-phase reactants

Erythrocyte sedimentation rate

  8. Spine radiographs

Lateral view of lumbar spine and lateral view of cervical spine

  9.  Hip radiographs

Pelvic radiograph including sacroiliac joints and hips

10.  Fatigue

VAS on fatigue from BASDAI

Disease-controlling antirheumatic therapy domains: 1-10; symptommodifying antirheumatic drug domains: 1-5, 10; physical therapy domains: 1-5, 10; clinical record-keeping domains: 1-7. AS, ankylosing spondylitis; BASDAI, Bath ankylosing spondylitis disease activity index; BASFI, Bath ankylosing spondylitis functional index; BASMI, Bath ankylosing spondylitis metrology index; VAS, visual analog scale. From van der Heijde D, Calin A, Dougados M, et al: Selection of instruments in the core set for DC-ART, SMARD, physical therapy, and clinical record keeping in ankylosing spondylitis: Progress report of ASAS Working Group—assessments in ankylosing spondylitis. J Rheumatol 26:951-954, 1999.

p­ hysical therapy, it would not be realistic to include measures of radiographic changes of the spine. Clearly, the set of measures for a drug’s disease-modifying capabilities will differ from a set that measures analgesic effectiveness only. Four settings have been defined: disease-controlling antirheumatic therapy; symptom-modifying antirheumatic drugs, such as NSAIDs; physical therapy; and clinical record keeping in daily practice (Table 70-11).135 Also, criteria to assess the response of individual patients have been developed and validated. These ASAS-20 improvement criteria are frequently used in clinical trials.136 In addition, more stringent improvement criteria— ASAS-40 and ASAS-5/6—have been proposed, 137 as well as criteria to define partial remission. The three sets of improvement criteria and the partial remission criteria are presented in Table 70-12.136,137 A needs-based quality of life instrument specific for AS has been developed. It is well accepted and easy to perform and, in terms of assessing the impact of interventions, has shown good scaling and psychometric properties and sensitivity to change.138,139

MANAGEMENT A recent systematic review of the literature on the management of AS culminated in a series of treatment proposi­tions developed by ASAS/European League Against Rheumatism (EULAR) that emphasize the key evidence-based

ASAS-40 Improvement Criteria At least 40% improvement and 20 units improvement in three of the four following domains, without any worsening in the remaining domain: BASFI Morning stiffness Patient global assessment Pain ASAS-5/6 Improvement Criteria At least 20% improvement in five of the six following domains: BASFI Morning stiffness Patient global assessment Pain Acute-phase reactants Spinal mobility ASAS Partial Remission Criteria A value below 20 units in all four domains of the ASAS-20 improvement criteria Data from Anderson et al136 and Brandt et al137 BASFI, Bath ankylosing spondylitis functional index.

components of disease management (Table 70-13; Fig. 70-2).140,141 For most patients, AS is a relatively mild disease with a good functional prognosis. Most do not experience significant extraskeletal manifestations except for acute anterior uveitis, which occurs in about 30% of patients. Usually, this eye disease can be well managed with eye drops containing corticosteroids to reduce inflammation and with pupil-dilating, atropine-like agents to prevent or diminish synechiae. At the outset, patients should be warned that acute anterior uveitis may occur at any time during the course of the disease. The treatment objectives in AS are to relieve pain, stiffness, and fatigue and to maintain good posture and good physical and psychosocial functioning.142 No drug is currently available that significantly influences the course of spinal disease and retards the process of ossification in ­ particular. Similarly, evidence is lacking that any of the conventional disease-modifying antirheumatic drugs, including sulfasalazine and methotrexate, alter or inhibit the inflammation seen in the spine and entheses in AS. A full explanation of the disease, its course, possible complications (e.g., acute anterior uveitis), and its prognosis is essential to achieve compliance by the patient. Selfhelp groups provide important information and social support. In addition, patient organizations often provide access to hydrotherapy and group physiotherapy. Exercises are the mainstay of treatment. Preferably, they should be started after a hot shower or a hot bath. Swimming and extension-promoting exercises or sporting activities such as volleyball or cross-country skiing are appropriate. These

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Table 70-13 Treatment Recommendations   1. Treatment of AS should be tailored according to: Current manifestations of disease (axial, peripheral, entheseal, extra-articular symptoms and signs) Level of current symptoms, clinical findings, and prognostic indicators Disease activity, inflammation Pain Function, disability, handicap Structural damage, hip involvement, spinal deformities General clinical status (age, sex, comorbidity, concomitant drugs) Patient’s wishes and expectations   2. Disease monitoring of patients with AS should include patient history (e.g., questionnaires), clinical parameters, laboratory tests, and imaging, all based on clinical presentation and ASAS core set. Monitoring frequency is individualized, based on symptoms, severity, and drug treatment.   3.  Optimal management of AS requires a combination of nonpharmacologic and pharmacologic treatments.   4.  N  onpharmacologic treatment of AS should include patient education and regular exercise. Individual and group physical therapy should be considered. Patient associations and selfhelp groups may be useful  SAIDs are recommended as first-line drug treatment for   5.  N patients with pain and stiffness. In those with increased GI risk, nonselective NSAIDs plus a gastroprotective agent or a selective COX-2 inhibitor could be used.   6. Analgesics, such as paracetamol and opioids, might be considered for pain control in patients in whom NSAIDs are insufficient, contraindicated, or poorly tolerated.   7. Corticosteroid injections directed to the local site of musculoskeletal inflammation may be considered. The use of systemic corticosteroids for axial disease is not supported by evidence.   8. There is no evidence of the efficacy of DMARDs, including sulfasalazine and methotrexate, for the treatment of axial disease. Sulfasalazine may be considered in patients with peripheral arthritis.   9. Anti-TNF treatment should be given to patients with persistently high disease activity despite conventional treatments, according to ASAS recommendations. There is no evidence to support the obligatory use of DMARDs before or concomitant with anti-TNF treatment in patients with axial disease. 10. Total hip arthroplasty should be considered in patients with refractory pain or disability and radiographic evidence of structural damage, independent of age. Spinal surgery for example, corrective osteotomy and stabilization procedures—may be of value in selected patients. AS, ankylosing spondylitis; ASAS, Assessment in Ankylosing Spondylitis; COX, cyclooxygenase; DMARDs, disease-modifying antirheumatic drugs; GI, gastrointestinal; NSAIDs, nonsteroidal anti-inflammatory drugs; TNF, tumor necrosis factor. From Zochling J, van der Heijde D, Burgos-Vargas R, et al: ASAS/EULAR ­recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 65:444-452, 2006.

activities counteract the kyphotic effects of pain and fatigue on posture and reduce stiffness. Patients should avoid vigorous or contact sports if the spine has become fused or osteoporotic, because such a spine is susceptible to fracture. Appliances such as driving mirrors may improve comfort and safety, especially if there is considerable involvement of the cervical spine. In that case, appropriate neck support is also required to reduce the risk of fracturing the vulnerable osteoporotic cervical spine as a consequence of traffic accidents. For the same reason, automobile air bags are strongly recommended.

ASAS/EULAR recommendations for the management of AS NSAIDs Education, exercise, physical therapy, rehabilitation, patient associations, self help groups

Axial disease

Peripheral disease Sulfasalazine

Local corticosteroids

Surgery

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TNF blockers Figure 70-2  Recommended management of ankylosing spondylitis (AS), based on clinical expertise and research evidence. The disease ­progression with time moves vertically from top to bottom. ASAS/EULAR, Assessment in Ankylosing Spondylitis European League Against Rheumatism; NSAIDs, nonsteroidal anti-inflammatory drugs; TNF, tumor necrosis factor.

PHYSIOTHERAPY There is now ample evidence that physiotherapy in the form of exercises is effective, at least in the short term (up to 1 year), and particularly in groups of patients with AS (level A evidence). Scientific evidence of long-term effectiveness is not yet available.143-145 In a randomized, controlled trial, a program of supervised physiotherapy in groups was found to be superior to individualized programs in improving thoracolumbar mobility and fitness. The program, which consisted of hydrotherapy, exercises, and sporting activities twice weekly for 3 hours per session, resulted in improved overall health and less stiffness, as reported by the patient.144 An intensive 3-week spa exercise therapy program resulted in marked improvement in both subjective and objective assessments that lasted for up to 9 months. Health resource utilization, in particular NSAID use and sick leave, was significantly reduced during this 9-month follow-up period. The clinical benefits of such treatments can be achieved at acceptable costs.146,147 Level A evidence from a recent Cochrane review on the efficacy of physiotherapeutic interventions, including exercises, is summarized in Table 70-14.148 Lying prone for 15 to 30 minutes once or several times a day is useful to reverse the tendency toward kyphosis, which is aggravated by pain and fatigue, and flexion contractures of the hip joints. Patients should sleep fully supine on a firm mattress with only a small neck-support pillow. MEDICATION Nonsteroidal Anti-inflammatory Drugs The efficacy and effectiveness of NSAID therapy for the alleviation of symptoms have been well established (level A evidence). When given for prolonged periods of up to a year, there may be improvement in spinal mobility and acutephase reactants.149 Many NSAIDs are effective in patients with AS, and no NSAID has documented superiority in terms of efficacy. Selective cyclooxygenase-2 (COX-2) inhibitors have similar efficacy to conventional NSAIDs (level A evidence).150 A nonselective NSAID is appropriate for most patients with AS, who tend to be relatively young

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Table 70-14  Cochrane Review of Physiotherapeutic Interventions and Spa Therapy for Patients with Ankylosing Spondylitis: Conclusions Home exercise programs are better than no intervention Supervised group physiotherapy is better than home exercise Combined inpatient spa and exercise therapy followed by supervised outpatient weekly group physiotherapy is better than weekly group physiotherapy alone From Dagfinrud H, Kvien TK, Hagen KB: Physiotherapy interventions for ankylosing spondylitis. Cochrane Database of Systematic Reviews 4, art. no.CD002822.pub2.DOI, 2004.

and without comorbidity. A COX-2 ­selective agent may be used in the presence of risk factors for peptic ulceration, although both categories of NSAIDs may exacerbate inflammatory bowel disease. Once-daily drug regimens may improve patient compliance. Up to 2 weeks may be required to demonstrate maximal symptomatic benefit from an NSAID. If symptomatic relief is inadequate, a switch to another NSAID may be worthwhile; failure of two NSAIDs should prompt an exploration of other management strategies. Given the gastrointestinal and cardiovascular risks of taking NSAIDs or coxibs, one must address whether this treatment should be on a daily or an “on-demand” basis. A 2-year randomized, prospective, controlled trial in AS patients compared the efficacy of continuous NSAID therapy to that of intermittent on-demand use. The results suggest that continuous therapy retards radiographic disease progression.151 This study is in line with an older study that also suggested a possible disease-controlling effect of continuous therapy.152 However, these findings are controversial.153 Second-Line Drugs Borrowing well-established concepts in the treatment of RA, disease-controlling therapy for AS has been defined as an agent that decreases inflammatory manifestations of disease, sustains or improves function, and prevents or decreases the rate of progression of structural damage. Although most of the second-line agents developed primarily for RA have been studied in AS, none can be considered disease controlling in AS. The greatest amount of data is available for sulfasalazine, which was first proposed as a therapy for AS in 1984, based on the common association between inflammatory bowel disease and spondyloarthropathies, the description of inflammatory lesions in the ileum of patients with spondyloarthropathies, and its success in the treatment of intestinal inflammation.154 A total of 11 double-blind, placebo-controlled trials have been published, as well as two meta-analyses. The results of the two largest trials were consistent, demonstrating no significant benefit for sulfasalazine in AS, although subgroup analysis showed that patients with (peripheral) polyarthritis—mostly those with psoriatic arthritis, but also AS patients with peripheral joint involvement—had a significant but modest response.155,156 An important limitation in most of these studies was the long disease duration (  >  10 years) of recruited patients, and it has been suggested that early disease may be more responsive to therapy. However, a 24-week placebo-controlled trial that recruited 230 patients meeting ESSG criteria for ­spondyloarthropathies and with symptom duration of less

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than 5 years confirmed that sulfasalazine was ineffective.157 The most recent meta-analysis, based on 11 trials, concluded that this agent has a significant impact only on the ESR and the severity of spinal stiffness (level A evidence).158 The primary indication for the use of sulfasalazine in routine practice is a patient who has concomitant peripheral arthritis and has had an inadequate response to NSAIDs and physical modalities. The evaluation of methotrexate in AS has been limited to case reports and open analyses, mostly reported in abstract form. These studies have included limited numbers of patients for periods of 6 months to 3 years, at doses from 7.5 to 15 mg weekly. The results have been mixed, with some benefit noted in patients with concomitant peripheral arthritis. Two small placebo-controlled trials assessed methotrexate in doses of 10 and 7.5 mg weekly for 24 weeks, with contradictory findings.159,160 A meta-analysis concluded that there was no evidence of efficacy and that higher-quality trials, larger sample sizes, longer durations of treatment, and higher dosages of methotrexate were necessary before any definitive conclusions could be drawn (level B evidence).161 Corticosteroids may be effective for local intra-articular treatment in AS, including the sacroiliac joints, if given under fluoroscopic guidance (level B evidence). Systemic steroids are of unproven benefit and are thought to be less effective than in RA (level C evidence). Leflunomide has been studied in AS, and although an open-label study suggested a benefit in patients with peripheral arthritis, a small placebocontrolled study reported no benefit (level B evidence).162,163 A controlled dose-response (60 mg versus 10 mg) evaluation of a bisphosphonate, pamidronate, given intravenously on a monthly basis for 6 months showed evidence of symptomatic efficacy, primarily in patients with only axial disease (level B evidence).164 However, this finding needs to be confirmed. Thalidomide has been used in two open-label studies in AS because it enhances the degradation of TNF-α messenger RNA. In a Chinese study, improvement was reported in 80% of patients, with deterioration 3 months after treatment discontinuation. Frequent side effects are drowsiness, constipation, and dizziness (level B evidence).165 BIOLOGIC THERAPIES A milestone in the treatment of AS is the development of anti–TNF-α therapies. The rationale is based on the finding of TNF-α expression in sacroiliac joint biopsies of AS patients, the observation that overexpression of TNF-α leads to sacroiliitis in animal models, and earlier clinical trial data demonstrating the efficacy of one anti–TNF-α agent, infliximab, in Crohn’s disease. Three anti–TNF-α agents are of proven benefit in AS according to pivotal phase III trials (level A evidence): infliximab, etanercept, and ­adalimumab. Infliximab is an IgG1 chimeric monoclonal antibody with the Fab portion derived from the mouse. It is given in a dose of 3 to 5 mg/kg every 6 to 8 weeks after loading at 0, 2, and 6 weeks. Etanercept is a recombinant 75-kD TNF receptor IgG1 fusion protein that is self-administered by subcutaneous injection either once (50 mg) or twice (25 mg) weekly. Adalimumab is a human monoclonal antibody that is self-administered by ­ subcutaneous injection on alternate weeks (40 mg). None requires concomitant therapy with methotrexate.

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Table 70-15  Assessment in Ankylosing Spondylitis (ASAS) Recommendations for the Initiation of Treatment with ­Biologics Patient Selection Diagnosis Patients normally fulfilling modified New York criteria for definitive AS Modified New York criteria 1984: Radiological criterion: sacroiliitis, grade  ≥  II bilaterally or grade III to IV unilaterally Clinical criteria (two of three): low back pain and stiffness for  >3  mo that improves with exercise but is not relieved by rest; limitation of motion of lumbar spine in both sagittal and frontal planes; limitation of chest expansion relative to normal values correlated for age and sex Active Disease Active disease for  ≥  4 wk BASDAI  ≥  4 (scale, 0–10) and an expert* opinion† Treatment Failure All patients should have had adequate therapeutic trials of at least two NSAIDs. An adequate therapeutic trial is defined as: Treatment for at least 3 mo at maximum recommended or tolerated anti-inflammatory dose unless contraindicated Treatment for  <3 mo if treatment was withdrawn because of intolerance, toxicity, or contraindications Patients with pure axial manifestations do not have to take DMARDs before anti-TNF treatment can be started Patients with symptomatic peripheral arthritis should have an insufficient response to at least one local corticosteroid injection, if appropriate Patients with persistent peripheral arthritis must have had a therapeutic trial of sulfasalazine‡ Patients with symptomatic enthesitis must have failed appropriate local treatment Contraindications Women who are pregnant or breastfeeding; effective contraception must be practiced Active infection Patients at high risk of infection, including those with: Chronic leg ulcer Previous tuberculosis (follow local recommendations for prevention or treatment) Septic arthritis of a native joint within the past 12 mo Sepsis of a prosthetic joint within the past 12 mo, or indefinitely if the joint remains in situ Persistent or recurrent chest infections Indwelling urinary catheter History of lupus or multiple sclerosis Malignancy or premalignancy states, excluding: Basal cell carcinoma Malignancies diagnosed and treated more than 10 yr previously (and the probability of total cure is very high) Assessment of Disease ASAS Core Set for Daily Practice Physical function (BASFI or Dougados functional index) Pain (VAS for spine at night from AS in the past week and VAS for spine from AS in the past week) Spinal mobility (chest expansion, modified Schober and occiput to wall distance, and lateral lumbar flexion) Patient’s global assessment (VAS for the past week) Stiffness (duration of morning spine stiffness in the past week) Peripheral joints and entheses (number of swollen joints [44 total], enthesitis score such as developed in Maastricht, Berlin, or San Francisco) Acute-phase reactants (ESR or CRP) Fatigue (VAS) BASDAI VAS for overall level of fatigue or tiredness in the past week VAS for overall level of AS neck, back, or hip pain in the past week VAS for overall level of pain or swelling in joints other than neck, back, or hips in the past week VAS for overall discomfort from any areas tender to touch or pressure in the past week VAS for overall level of morning stiffness from time of awakening in the past week Duration and intensity (VAS) of morning stiffness from time of awakening (up to 120 min) Assessment of Response Responder criteria: BASDAI—50% relative change or absolute change of 20 mm (scale between 0 and 100) and expert opinion in favor of continuation Time of evaluation: 6 to 12 wk *The expert is a physician, usually a rheumatologist, with expertise in inflammatory back pain and the use of biologic agents. Expert should be locally defined. † The expert should consider clinical features (history and examination), serum acute-phase reactant levels, or imaging results, such as radiographs demonstrating rapid progression or magnetic resonance images indicating ongoing inflammation. ‡ Sulfasalazine treatment for at least 4 mo at standard target dose or maximally tolerated dose unless contraindicated or not tolerated. Treatment for less than 4 mo if treatment was withdrawn because of intolerance or toxicity or contraindicated. AS, ankylosing spondylitis; BASDAI, Bath ankylosing spondylitis disease activity index; BASFI, Bath ankylosing spondylitis functional index; CRP, C-reactive protein; DMARD, disease-modifying antirheumatic drug; ESR, erythrocyte sedimentation rate; NSAID, nonsteroidal anti-inflammatory drug; TNF, tumor necrosis factor; VAS, visual analog scale (all VASs can be replaced by a numerical rating scale). From Braun J, Davis J, Dougados M, et al: ASAS Working Group: First update of the international ASAS consensus statement for the use of anti-TNF agents in patients with ankylosing spondylitis. Ann Rheum Dis 65:316-320, 2006. See also http://www.ASAS-group.org.

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All three agents demonstrate ASAS-20 response rates of 55% to 60% and ASAS-40 response rates of 45% to 50% in phase III trials.166-168 Improvement is evident by 2 to 4 weeks and is sustained as long as the patient remains on treatment; virtually all patients relapse by 4 months after discontinuation of treatment.169 Significant improvement is also observed in function, spinal mobility, peripheral synovitis, enthesitis score, and quality of life. Sick leave and work disability are reduced. The number of patients who must be treated to achieve one patient who experiences at least 50% improvement in disease activity is just two (95% CI 1 to 6). Objective parameters of disease activity that show improvement include acute-phase reactants, synovial histopathology, and MRI features of inflammation in the spine and sacroiliac joints.170 There is as yet no evidence that these agents are disease controlling with respect to the prevention of structural damage on plain radiography. Response to treatment appears to be increased in those with high disease activity and worse in those with a long disease duration, impaired function, and no discernible evidence of inflammation on MRI.171 However, patients with complete spinal ankylosis may benefit from these treatments.168 Adverse events in AS patients are no different from those reported in RA, and infusion reactions in patients receiving infliximab have been no more frequent than in RA patients on concomitant methotrexate. Recommendations for the use of anti–TNF-α therapies have been developed (Table 70-15).172-174 These new therapeutic modalities identify important clinical questions to be answered by further research. All the anti–TNF-α agents examined to date have disease-modifying properties, but their long-term safety and disease-controlling effects in terms of preventing structural damage have yet to be demonstrated. SURGERY Involvement of the hip joint may cause serious disability. Ectopic bone formation may occur, but the outcome of total hip replacement is generally favorable.130 Vertebral osteotomy may be required in selected cases to correct marked flexion deformity when forward vision is severely impaired. Diaphragmatic herniation may result from the procedure.

SUMMARY Although our understanding of the genetics of AS has improved greatly, our knowledge about its cause and pathogenesis is far from complete. A lot has been accomplished in terms of classification and assessment of the disease. Treatment with biologics such as anti–TNF-α is very effective and may be the first therapy that actually controls the disease. The challenge now is to determine how to predict and improve outcomes at the level of individual patients.

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Future Directions Diagnostic criteria must be defined for individual patients with AS at an early stage of the disease. The long interval (on average) between the first symptoms of AS and the clinical diagnosis must be shortened. Research into factors that accurately predict final outcome at the time of diagnosis is essential. Study of which factors predict response to biologic therapy for individual AS patients is highly desirable. In addition, the long-term effects of treatment with biologics are not yet known. Evidence of the effectiveness of preventing damage in terms of the development of syndesmophytes is contradictory. It is largely unknown what triggers the process of ankylosing. A few studies suggest that continuous (versus intermittent) use of NSAIDs or coxibs may slow the progression of axial radiographic manifestations of AS. These findings, however, are controversial.

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110. Heuft-Dorenbosch L, Landewe R, Weijers R, et al: Performance of various criteria sets in patients with inflammatory back pain of short duration: The Maastricht Early Spondyloarthritis Clinic. Ann Rheum Dis 66:92-98, 2007. 111. Dubost JJ, Sauvezie B: Late onset peripheral spondyloarthropathy. J Rheumatol 16:1214-1217, 1989. 112. Kidd B, Mullee M, Frank A, et al: Disease expression of ankylosing spondylitis in males and females. J Rheumatol 15:1407-1409, 1988. 113. Jimenez-Balderas FJ, Mintz G: AS: Clinical course in women and men. J Rheumatol 20:2069-2072, 1993. 114. Østensen M, Østensen H: Ankylosing spondylitis—the female aspect. J Rheumatol 25:120-124, 1998. 115. Østensen M, Fuhrer L, Mathieu R, et al: A prospective study of pregnant patients with rheumatoid arthritis and ankylosing spondylitis using validated clinical instruments. Ann Rheum Dis 63:1212-1217, 2004. 116. Khan MA, Khan MK, Kushner I: Survival among patients with ankylosing spondylitis: A lifetable analysis. J Rheumatol 8:86-90, 1981. 117. Lehtinen K: Mortality and causes of death in 398 patients admitted to hospital with ankylosing spondylitis. Ann Rheum Dis 52:174-176, 1993. 118. Calin A, Elswood J, Rigg S, et al: Ankylosing spondylitis: An analytical review of 1500 patients—the changing pattern of disease. J Rheumatol 15:1234-1238, 1988. 119. Fries JF, Singh G, Bloch DA, et al: The natural history of ankylosing spondylitis: Is the disease really changing? J Rheumatol 16:860-863, 1989. 120. Van der Paardt M, Dijkmans B, Giltay E, van de Horst-Bruinsma I: Dutch patients with familial and sporadic ankylosing ­spondylitis do not differ in disease phenotype. J Rheumatol 29:2583-2584, 2002. 121. Wanders A, Landewe R, Dougados M, et al: Association between radiographic damage of the spine and spinal mobility for individual patients with ankylosing spondylitis: Can assessment of spinal mobility be a proxy for radiographic evaluation? Ann Rheum Dis 64: 988-994, 2005. 122. Guillemin F, Briancon S, Pourel J, Gaucher A: Long-term disability and prolonged sick leaves as outcome measurements in ankylosing spondylitis: Possible predictive factors. Arthritis Rheum 33: 1001-1006, 1990. 123. Ramos-Remus C, Prieto-Parra RE, Michel-Diaz J, et al: A five-year cumulative analysis of labor-status and lost working days in patients with ankylosing spondylitis (AS). Arthritis Rheum 41(Suppl):1136, 1998. 124. Ward M, Kuzis S: Risk factors for work disability in patients with ankylosing spondylitis. J Rheumatol 28:315-321, 2001. 125. Boonen A, Chorus A, Miedema H, et al: Withdrawal from labour force due to work disability in patients with ankylosing spondylitis. Ann Rheum Dis 60:1033-1039, 2001. 126. Chorus AMJ, Boonen A, Miedema HS, van der Linden S: Employment perspectives of patients with ankylosing spondylitis. Ann Rheum Dis 61:693-699, 2002. 127. Boonen A, Chorus A, Miedema H, et al: Employment, work disability, and work days lost in patients with ankylosing spondylitis: A cross sectional study of Dutch patients. Ann Rheum Dis 60:353-358, 2001. 128. Gran JT, Skomsvolly JF: The outcome of ankylosing spondylitis: A study of 100 patients. Br J Rheumatol 36:766-771, 1997. 129. Amor B, Silva-Santos R, Nahal R, et al: Predictive factors for the long-term outcome of spondyloarthropathies. J Rheumatol 21: 1883-1887, 1994. 130. Calin A, Elswood J: The outcome of 138 total hip replacements and 12 revisions in ankylosing spondylitis: High success rate after a mean followup of 7.5 years. J Rheumatol 16:955-958, 1989. 131. Calin A, Garrett S, Whitelock H, et al: A new approach to defining functional ability in ankylosing spondylitis: The development of the Bath ankylosing spondylitis functional index (BASFI). J Rheumatol 21:2281-2285, 1994. 132. Dougados M, Gueguen A, Nakache JP, et al: Evaluation of a functional index and an articular index in ankylosing spondylitis. J Rheumatol 15:302-307, 1988. 133. Garrett S, Jenkinson T, Whitelock H, et al: A new approach to ­defining disease status in AS: The Bath ankylosing spondylitis ­ disease activity index (BASDAI). J Rheumatol 21:2286-2291, 1994.

134. Jenkinson TR, Mallorie PA, Whitelock H, et al: Defining spinal mobility in ankylosing spondylitis (AS): The Bath AS metrology index (BASMI). J Rheumatol 21:1694-1698, 1994. 135. Van der Heijde D, Calin A, Dougados M, et al: Selection of specific instruments for each domain in core set for DC-ART, SM-ARD, physical therapy and clinical record keeping in ankylosing spondylitis: Progress report of ASAS working group. J Rheumatol 26: 951-954, 1999. 136. Anderson JJ, Baron G, van der Heijde D, et al: Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis. Arthritis Rheum 44:1876-1886, 2001. 137. Brandt J, Listing J, Sieper J, et al: Development and preselection of criteria for short term improvement after anti-TNFα treatment in ankylosing spondylitis. Ann Rheum Dis 63:1438-1444, 2004. 138. Doward LC, Spoorenberg A, Cook SA, et al: Development of the ASQoL: A quality of life instrument specific to ankylosing spondylitis. Ann Rheum Dis 62:20-26, 2003. 139. Davis J, Revicki D, van der Heijde D, et al: Health-related quality of life outcomes in patients with active ankylosing spondylitis treated with adalimumab: Results from a randomized controlled study. Arthritis Rheum (in press). 140. Zochling J, van der Heijde D, Dougados M, et al: Current evidence for the management of ankylosing spondylitis: A systematic literature review for the ASAS/EULAR management recommendations in ankylosing spondylitis. Ann Rheum Dis 65:423-432, 2006. 141. Zochling J, van der Heijde D, Burgos-Vargas R, et al: ASAS/ EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 65:444-452, 2006. 142. Khan MA, Skosey JL: Ankylosing spondylitis and related spondyloarthropathies. In Samter M (ed): Immunological Diseases. Boston, Little, Brown, 1988, pp 1509-1538. 143. Band DA, Jones SD, Kennedy LG, et al: Which patients with ankylosing spondylitis derive most benefit from inpatient management program? J Rheumatol 24:2381-2384, 1997. 144. Hidding A, van der Linden S, Boers M, et al: Is group physical therapy superior to individualized therapy in ankylosing spondylitis? A randomized controlled trial. Arthritis Care Res 6:117-125, 1993. 145. Dagfinder H, Hagen K: Physiotherapy interventions for ankylosing spondylitis (Cochrane review). Oxford, Cochrane Library, 2001. 146. van Tubergen A, Landewé R, van der Heijde D, et al: Combined spaexercise therapy is effective in patients with ankylosing spondylitis: A randomized controlled trial. Arthritis Rheum 45:430-438, 2001. 147. van Tubergen A, Boonen A, Landewé R, et al: Cost-effectiveness of combined spa-exercise therapy in ankylosing spondylitis: A randomized controlled trial. Arthritis Rheum 47:459-467, 2002. 148. Dagfinrud H, Kvien TK, Hagen KB: Physiotherapy interventions for ankylosing spondylitis. Cochrane Database of Systematic Reviews 4, art. no.CD002822.pub2.DOI, 2004. 149. Dougados M, Gueguen A, Nakache JP, et al: Ankylosing spondylitis: What is the optimum duration of a clinical study? A one year versus 6 weeks non-steroidal anti-inflammatory drug trial. Rheumatology 38:235-244, 1999. 150. Dougados M, Behier JM, Jolchine I, et al: Efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis: A six week controlled study with comparison against placebo and against a conventional nonsteroidal anti-inflammatory drug. Arthritis Rheum 44:180-185, 2001. 151. Wanders A, van der Heijde D, Landewe R, et al: Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: A randomized controlled trial. Arthritis Rheum 52:1756-1765, 2005. 152. Boersma JW: Retardation of ossification of the lumbar vertebral column in ankylosing spondylitis by means of phenylbutazone. Scand J Rheumatol 5:60-64, 1976. 153. Akkoc N, van der Linden S, Khan MA: Ankylosing spondylitis and symptom-modifying vs disease-modifying therapy. Clin Rheumatol 20:539-557, 2006. 154. Amor B, Kahan A, Dougados M, Delrieu F: Sulphasalazine in ankylosing spondylitis. Ann Intern Med 101:878, 1984. 155. Dougados M, van der Linden S, Leirisalo-Repo M, et al: Sulfasalazine in the treatment of spondyloarthropathy. Arthritis Rheum 38: 618-627, 1995. 156. Clegg DO, Reda DJ, Weisman MH, et al: Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis. Arthritis Rheum 39:2004-2012, 1996.

PART 10  157. Braun J, Zochling J, Baraliakos X, et al: Efficacy of sulfasalazine in patients with inflammatory back pain due to undifferentiated spondyloarthritis and early ankylosing spondylitis: A multicentre randomised controlled trial. Ann Rheum Dis 65:1147-1153, 2006. 158. Chen J, Liu C: Is sulfasalazine effective in ankylosing spondylitis? A systematic review of randomized controlled trials. J Rheumatol 33:722-731, 2006. 159. Roychowdhury B, Bintley-Bagot S, Hunt J, Tunn EJ: Methotrexate in severe ankylosing spondylitis: A randomised placebo controlled, double-blind observer study. Rheumatology 40(Suppl 1):43, 2001. 160. Gonzalez-Lopez L, Garcia-Gonzalez A, Vazquez-del-Mercado M, et al: Efficacy of methotrexate in ankylosing spondylitis: A randomized, double-blind, placebo-controlled trial. J Rheumatol 31:15681574, 2004. 161. Chen J, Liu C: Methotrexate for ankylosing spondylitis. Cochrane Database of Systematic Reviews 3, art. no. CD004524.pub2, 2003. 162. Haibel H, Rudwaleit M, Braun J, et al: Six month open label trial of leflunomide in ankylosing spondylitis. Ann Rheum Dis 64:124-126, 2005. 163. Van Denderen JC, Van der Paardt M, Nurmohamed MT, et al: Double-blind study of leflunomide in the treatment of active ankylosing spondylitis. Ann Rheum Dis 63(Suppl 1):SAT0033, 2004. 164. Maksymowych WP, Jhangri GS, Fitzgerald AA, et al: A six-month randomized, controlled, double-blind, dose response comparison of intravenous pamidronate (60 mg versus 10 mg) in the treatment of nonsteroidal antiinflammatory drug-refractory ankylosing spondylitis. Arthritis Rheum 46:766-773, 2002. 165. Huang F, Gu J, Zhao W, et al: One-year open-label trial of thalidomide in ankylosing spondylitis. Arthritis Rheum 47:249-254, 2002. 166. Van der Heijde D, Dijkmans B, Geusens P, et al: Efficacy and safety of infliximab in patients with ankylosing spondylitis: Results of a randomized placebo-controlled trial (ASSERT). Arthritis Rheum 52:582-591, 2005.

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167. Davis JC Jr, van der Heijde D, Braun J, et al: Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis. Arthritis Rheum 48:3230-3236, 2003. 168. Van der Heijde D, Kivitz A, Schiff MH, et al: Efficacy and safety of adalimumab in patients with ankylosing spondylitis: Results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 54:2136-2146, 2006. 169. Baraliakos X, Listing J, Brandt J, et al: Clinical response to discontinuation of anti-TNF therapy in patients with ankylosing spondylitis after 3 years of continuous treatment with infliximab. Arthritis Res Ther 7:439-444, 2005. 170. Braun J, Landewe R, Hermann KG, et al: Major reduction in spinal inflammation in patients with ankylosing spondylitis after treatment with infliximab: Results of a multicenter, randomized, double-blind, placebo-controlled magnetic resonance imaging study. Arthritis Rheum 54:1646-1652, 2006. 171. Rudwaleit M, Listing J, Brandt J, et al: Prediction of a major clinical response (BASDAI 50) to tumour necrosis factor α blockers in ankylosing spondylitis. Ann Rheum Dis 63:665-670, 2004. 172. Maksymowych WP, Inman RD, Gladman D, et al: Canadian Rheumatology Association consensus on the use of anti-TNFα-directed therapies in the treatment of spondyloarthritis. J Rheumatol 30: 1356-1363, 2003. 173. Braun J, Pham T, Sieper J, et al: International ASAS consensus statement for the use of anti-tumour necrosis factor agents in patients with ankylosing spondylitis. Ann Rheum Dis 62:817824, 2003. 174. Braun J, Davis J, Dougados M, et al: ASAS Working Group: First update of the international ASAS consensus statement for the use of anti-TNF agents in patients with ankylosing spondylitis. Ann Rheum Dis 65:316-320, 2006.

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KEY POINTS Undifferentiated spondyloarthritis and reactive arthritis are members of the spondyloarthritis family. Spondyloarthritis is characterized by inflammatory spinal pain or asymmetric oligoarthritis predominantly of the lower extremities. Undifferentiated spondyloarthritis is distinguished by an ­absence of ankylosing spondylitis, preceding infection, ­psoriasis, ulcerative colitis, or Crohn’s disease. Reactive arthritis is characterized by the presence of a ­triggering infection. No prospectively validated diagnostic criteria or algorithms exist for undifferentiated spondyloarthritis or reactive ­arthritis. Enthesitis is an underlying feature unifying the spondyloarthritis family. The course of undifferentiaed spondyloarthritis and reactive arthritis varies from individual to individual. Nonsteroidal anti-inflammatory drugs are the first line of treatment. The only effective disease-modifying antirheumatic drug is sulfasalazine. There is a high probability that biologics that block tumor necrosis factor-α are very effective.

The spondyloarthritis family consists of ankylosing spondylitis (AS), undifferentiated spondyloarthritis, some forms of psoriatic arthritis, reactive arthritis, Reiter’s syndrome, and arthritis associated with inflammatory bowel disease. The first two are the most common. AS is the best defined, using a series of classification criteria; the most recent are the 1984 modified New York criteria (see Chapter 70). Until recently, this family was known as the spondyloarthropathies. In 2002, however, the Assessment in Ankylosing Spondylitis (ASAS) international working group replaced spondyloarthropathy with spondyloarthritis to stress that these are inflammatory diseases.1 There has also been some confusion over the definition of Reiter’s syndrome. Initially, based on a 1916 report of a single patient, the syndrome consisted of the triad of arthritis, urethritis, and conjunctivitis. Eventually, by convention, the term was applied to patients who did not have all three features, as well as being used interchangeably with the term reactive arthritis. At this time, the term Reiter’s syndrome is probably of historical value only.

Undifferentiated Spondyloarthritis and Reactive Arthritis David Tak Yan Yu  •  Dennis McGonagle  •  Helena Marzo-Ortega  •  Filip van den Bosch  •  Marjatta Leirisalo-Repo

UNDIFFERENTIATED SPONDYLOARTHRITIS Because undifferentiated spondyloarthritis is a member of the spondyloarthritis family, strictly speaking, one must define spondyloarthritis before one can define undifferentiated spondyloarthritis. Spondyloarthritis is caused by multiple genetic and environmental factors, each contributing to various degrees in individual patients. Thus, as in most rheumatic diseases caused by multiple factors, diagnosis ultimately relies on what is termed expert opinion. In other words, when an expert in the field, after weighing all the available clinical, laboratory, and imaging information, diagnoses a particular patient as having spondyloarthritis, that patient is regarded as having spondyloarthritis. Although this approach can be effective in clinical practice, if used in research, it would lead to chaos. For purposes of comparing data among different studies, a unified classification definition of spondyloarthritis is needed. CLASSIFICATION CRITERIA FOR SPONDYLOARTHRITIS To generate classification criteria for spondyloarthritis, investigators first use the expert-opinion approach to generate two groups of patients: one with spondyloarthritis, and one with other rheumatic diseases. A predetermined set of clinical, laboratory, and radiographic data is collected from these two groups of patients and then submitted to statistical analysis to arrive at a distinguishing set of parameters. Unfortunately, in the case of spondyloarthritis, no single parameter has sufficient discriminating power. To distinguish between the spondyloarthritis group and the control group, investigators must resort to either an algorithm or a combination of parameters. Using these strategies, two sets of classification criteria have been generated by two groups of investigators. In 1990, a group of French investigators devised a point system, assigning values of 1 to 3 points to each of 12 parameters.2 A patient is regarded as having spondyloarthritis if the sum of the points is greater than 6. This set is known as the Amor criteria (Table 71-1). Independent of this French study, in 1991, a task force of 11 spondyloarthritis specialists from five different European countries (the European Spondyloarthropathy Study Group [ESSG]) also compared a group of spondyloarthritis patients with a control group of patients with other rheumatic diseases.3 Again, no single parameter had the power to discriminate between the two groups. This study group selected two parameters as “entry criteria” with moderate discriminative power

Supplemental images available on the Expert Consult Premium Edition website.

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Table 71-1  Amor Multiple Entry Criteria for Diagnosing Spondyloarthropathies   A. Clinical Symptoms or Past History

  1. Lumbar or dorsal pain at night, or morning stiffness of lumbar or dorsal spine…………………………1   2.  Asymmetric oligoarthritis…………………………………………………………………………………………...……2   3. Buttock pain………………………………………………………………………………………………………………1 If affecting the right and left buttock alternately……………………………………………………………………..…2   4.  Sausage-like toe or digit…………………………………………………………………………………….……………2   5. Heel pain……………………………………………………………………………………………………………..……2   6. Iritis…………………………………………………………………………………………………………………………2   7.  Nongonococcal urethritis or cervicitis accompanying, or within 1 mo before, the onset of ­arthritis.……….……..…1   8.  Acute diarrhea accompanying, or within 1 mo before, the onset of arthritis………………………………………….1   9. Presence or history of psoriasis, balanitis, or inflammatory bowel disease (ulcerative colitis or Crohn’s disease).­.. …2 B. Radiographic Finding 10.  Sacroiliitis (grade �2 if bilateral; grade �3 if unilateral)……………………..........……………………………………3 C. Genetic Background 11. Presence of HLA-B27 or family history of ankylosing spondylitis, Reiter’s syndrome, uveitis, psoriasis, or chronic enterocolopathies………………………………………………………………………………...………………………2 D. Response to Treatment 12. Clear-cut improvement of rheumatic complaints with nonsteroidal anti-inflammatory drugs (NSAIDs) in less than 48 hr or relapse of pain in less than 48 hr if NSAIDs discontinued…….......................………....………………………2 A patient is considered to be suffering from a spondyloarthropathy if the sum of the applicable criteria is at least 6.

and ­ minimum overlap: inflammatory low back pain or ­asymmetric ­oligoarthritis, preferably of the lower extremities (Table 71-2). Any patient with one of these entry criteria is ­classified as having spondyloarthritis if he or she satisfies one additional ESSG parameter. This classification system also divides spondyloarthritis patients into two overlapping groups—one with predominantly axial involvement and the other with peripheral involvement. The axial type is mostly likely forme fruste or early AS (see Chapter 70). Using the ESSG criteria, about half of spondyloarthritis patients can be classified as having AS, reactive arthritis, or arthritis associated with psoriasis or with Crohn’s disease or ulcerative colitis. For those patients who cannot be classified into these categories, the term undifferentiated spondyloarthritis is used. DIAGNOSTIC ALGORITHMS The ESSG classification criteria are not very useful in clinical practice because they do not assign to individual patients a degree of probability of having spondyloarthritis. In clinical practice, a considerable number of patients are diagnosed as having “probable” spondyloarthritis, based on expert opinion, but they might not satisfy the classification criteria. For example, data from the ESSG indicate that inflammatory spinal pain is pivotal in axial spondyloarthritis, but it is not sufficient for a diagnosis. Rudwaleit and colleagues4 extracted data from more than 25 publications on patients with axial ­ spondyloarthritis and arrived at a diagnostic algorithm. The probability, expressed as likelihood ratio, of an individual patient having spondyloarthritis can be calculated according to the number of positive parameters. A patient has a greater than 90% probability of having spondyloarthritis if he of she has inflammatory spinal pain plus three to four other features of the disease. This algorithm is called the Berlin criteria for spondyloarthritis.

Table 71-2  European Spondyloarthropathy Study Group Criteria for Spondyloarthropathy A patient might have a spondyloarthropathy if he or she has at least one of the two following entry criteria: 1. Inflammatory spinal pain: This is defined as a history or present symptoms of spinal pain in the back, dorsal, or cervical region, with at least 4 of the following: (a) onset before age 45 yr, (b) insidious onset, (c) improved by exercise, (d) associated with morning stiffness, (e) at least 3 mo duration. 2. Synovitis: This is defined as past or present asymmetric arthritis or arthritis predominantly in the lower limbs. A patient who satisfies at least one of the entry criteria is classified as having a spondyloarthropathy if he or she also has one or more of the following parameters: Positive family history—presence in first-degree or second-degree relatives of any of the following: (a) ankylosing spondylitis, (b) psoriasis, (c) acute uveitis, (d) reactive arthritis, (e) ­inflammatory bowel disease Psoriasis—past or present, diagnosed by a physician Inflammatory bowel disease—past or present Crohn’s disease or ulcerative colitis diagnosed by a physician and confirmed by radiographic examination or endoscopy Urethritis, cervicitis, or acute diarrhea within 1 mo before ­ arthritis—nongonococcal Buttock pain alternating between right and left gluteal areas—past or present Enthesopathy—past or present spontaneous pain or tenderness at sites of insertion of the Achilles tendon or plantar fascia Sacroiliitis—bilateral grade 2 to 4 or unilateral grade 3 or 4, according to the following radiographic grading system: 0  =   normal, 1  =  possible, 2  =  minimal, 3  =  moderate, 4  =  ankylosis

Most of the studies that have generated the various s­ pondyloarthritis criteria have been based on patients with a ­disease duration of several years. To address early diagnosis, and to compare the various sets of criteria, a Dutch group examined 68 patients with inflammatory back pain of less than 2 years’ duration.5 Their analysis showed that only 6% of these patients did not fulfill any of the sets of criteria. As many as 53% of patients fulfilled all three sets of criteria for spondyloarthritis. The most sensitive set was the ESSG criteria.

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Thus, at this point, we have a plethora of clinical criteria and algorithms for the classification and diagnosis of spondyloarthritis. It is clear that large-scale prospective studies are necessary to arrive at even more useful diagnostic criteria. It is also clear that additional parameters are required to provide a higher degree of predictive power. The most promising involves magnetic resonance imaging (MRI). SIGNS, SYMPTOMS, AND COURSE OF SPONDYLOARTHRITIS No large-scale multinational studies have reported on the signs and symptoms of undifferentiated spondyloarthritis. Because it is defined by the exclusion of traditionally well-recognized arthritides, patients determined to have ­undifferentiated spondyloarthritis probably exhibit a mixture of diverse signs and symptoms, one of which is either inflammatory low back pain or asymmetric oligoarthritis. No large-scale longitudinal studies are available ­concerning the course and prognosis of undifferentiated spondyloarthritis. Some studies show that after several years of follow-up, some patients go into remission, some develop AS, and others continue to have undifferentiated ­ spondyloarthritis.1 A considerable number of patients were initially misdiagnosed with spondyloarthritis, and their actual diagnoses, such as rheumatoid arthritis (RA) or gout, did not become clear until several years later. Clearly, a ­diagnostic method based on something other than expert opinion or classification criteria is needed. Most useful would be parameters that can predict whether a patient will progress rapidly into AS, because these patients might benefit from early, aggressive therapy. In addition, a unifying hypothesis regarding the basic underlying concept of spondyloarthritis would be helpful. ENTHESITIS Both spondyloarthritis and rheumatoid arthritis (RA) are inflammatory rheumatic diseases that attack multiple joints. At one time, spondyloarthritis was considered a form of RA. It was Ball6 who first reported that ­inflammation at insertions is the important anatomic ­difference between RA and spondyloarthritis. ­Inflammation at these areas is termed enthesitis. ­Currently, enthesitis is recognized as one of the three cardinal anatomic lesions in spondyloarthritis; the other two are osteitis and synovitis. Enthesitis has been ­ proposed as the unifying lesion among the diverse inflammatory abnormalities seen in spondyloarthritis.7 Anatomy The enthesis is the site of insertion of a ligament, tendon, fascia, or joint capsule to bone. There are two types of entheses: fibrocartilaginous and fibrous. Fibrocartilaginous entheses are much more numerous than fibrous entheses, and they are usually situated close to the articular margin of the joints. Fibrous entheses are situated at a considerable distance from the joint; the most typical example is the deltoid insertion. Fibrocartilaginous entheses are composed of four regions: tendon, ligament, or joint capsule; fibrocartilage; calcified fibrocartilage; and underlying bone. Hence, the enthesis is

Figure 71-1  Swelling of the right Achilles tendon in a 26-year-old man with spondyloarthritis.

an organ, defined as a group of tissues working collectively to carry out a shared function.8 The enthesis organ functions to aid movement and to limit damage from joint locomotion. The function of fibrocartilage is to dissipate stress and prevent the breakdown of protective mechanisms. Because of the complexity of the entheses and the weight bearing that takes place, there are myriad forces acting at these sites. Insertions are in fact highly prone to microdamage, which includes disruption of the bone cortex, altered vascularity, and tissue repair responses. Therefore, it appears that even healthy, normal insertions have constant tissue turnover and repair and probably microinflammation.9 These factors are likely important for the localization of inflammatory responses in spondyloarthritis patients. From the clinical perspective, enthesitis is recognized at characteristic sites, including the Achilles tendon, plantar fascia, patellar tendon, and others (Fig. 71-1). Because of clinical inaccessibility, it has not been well understood until recently that enthesitis is very common at virtually all sites of disease in spondyloarthritis, including the spine and synovial joints. Histology Because of the inaccessibility of the enthesis in ­comparison to the synovium, there is a paucity of data on acute ­entheseal lesions. However, studies from the sacroiliac joint and peripheral sites confirm the presence of an inflammatory cell infiltrate as well as cytokines, such as tumor necrosis factor-α (TNF-α), at these sites.10-12 Historically, enthesitis and osteitis were viewed as separate processes. However, it is now clear that the underlying trabecular bone network plays an integral role in enthesitis. Indeed, the bone cortex and insertions may be focally absent, and the enthesis insertions appear to be linked directly to trabecular bone. This allows for a smooth transition between the soft tissue and the enthesis component and the hard tissue from the adjacent bone component. This close relationship between the entheses and the underlying bone is clinically relevant and is often the basis for recognizing enthesis-related pathology on MRI, where it translates into bone marrow edema or osteitis.13

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ATL X

X

X

X Figure 71-2  Ultrasound (US) images for the patient in Figure 71-1. Images were taken with an HDI 5000 using a linear 12.5-MHz transducer. Both images are longitudinal sections. A, Left Achilles tendon (AT), which was normal on both clinical and US examination. The short white arrows point to the edges of the tendon, and the white dotted line (with arrows) indicates the depth of the tendon. B, Abnormal right side, with thickening and hypoechogenicity of the Achilles tendon extending to the insertion. There is also a ­ distended retrocalcaneal bursa. KFP, Kager’s fat pad; *, fluid; **, fat pad or synovium.

–1

–1

KFP

**

–2

*

Calcaneum

–3

A

Imaging

–2

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Calcaneum

Abnormal: LS

H

Conventional plain radiography shows enthesitis only at skeletal sites, such as the Achilles tendon or the plantar fascia. However, on MRI or ultrasonography, ­ enthesitis is commonly found at all sites of disease, including the spine and synovial joints.14 The ultrasound ­appearance of enthesitis is that of hypoechoic thickening and edema, with erosion, new bone formation, or changes in ­entheseal vascularity on power Doppler ultrasonography (Fig. 712). On MRI, enthesitis can be visualized as perientheseal inflammation with adjacent bone edema in fat-suppressed T2-weighted sequences (Fig. 71-3). Although both MRI and ultrasonography are useful, they are not perfect. Many entheseal sites are inaccessible to the ultrasound probe. In the case of MRI, the intrinsic low water content of insertions makes it difficult to appreciate changes at attachments, especially in small joints. Clinical Assessment Only a few entheses are accessible enough for accurate physical examination. The majority of spinal entheses, a common target for spondyloarthritis, are inaccessible. The same is true for entheses around peripheral joints such as the knee, where only 5 or 6 of the more than 30 insertions are accessible to clinical examination. Further, when synovial joints are inflamed and distended, it may be clinically impossible to differentiate among bursitis, synovitis, and enthesitis. For plantar fasciitis, physical examination cannot distinguish between inflammatory and degenerative enthesitis, so the clinician must rely on other features. Also, conditions such as fibromyalgia must be considered, because entheseal sites are commonly affected in this disease. Notwithstanding these limitations, investigators have developed clinical schemes for scoring enthesitis. These have proved to be of some benefit as disease outcome measures during drug trials.15

–3

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5 cm

LT RL 58 left Figure 71-3  Fat-suppressed magnetic resonance image of the foot of a young patient with ankylosing spondylitis. The high signal is consistent with marrow edema, reflecting acute plantar fasciitis (white arrow). In ­addition, there is retrocalcaneal bursitis (asterisk).

Therapy and Future Directions There is a misconception that treatment for enthesitis in spondyloarthritis is restricted to isolated lesions, such as those at the Achilles tendon or the plantar fascia. It must be recognized that spondyloarthritis is an inflammatory disease of multiple entheses and associated osteitis. Global treatment of spondyloarthritis is discussed in the next section; however, we have noted that up to 60% of enthesitis or osteitis inflammatory lesions regress almost completely after treatment with a TNF-α blocker.16 The concept of a functional enthesis as a joint-specific factor, perhaps playing as great a role as the HLA-B27 gene in spondyloarthritis, opens up novel avenues for research into the pathogenesis of spondyloarthritis.

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TREATMENT There are no studies focusing specifically on the pharmacologic approach to undifferentiated spondyloarthritis. Consequently, undifferentiated spondyloarthritis is treated with drugs that are effective for AS: nonsteroidal anti-inflammatory drugs (NSAIDs), conventional diseasemodifying antirheumatic drugs (DMARDs), and drugs that block TNF-α. Nonsteroidal Anti-inflammatory Drugs The efficacy of NSAIDs in AS and, more generally, in spondyloarthritis is so well accepted that a clear-cut improvement in pain and morning stiffness within 48 hours after starting NSAID therapy, or a rapid relapse of pain after discontinuation of the agent, is one of the Amor spondyloarthritis classification criteria (see Table 71-1). In a multicenter study specifically addressing the effect of NSAIDs in spondyloarthritis,17 741 of the 2228 patients suffered from back pain, with spondyloarthritis in 69 and mechanical disorders in 672. Treatment with NSAIDs was considered effective by 53 spondyloarthritis patients (77%), in contrast to only 102 mechanical disorder patients (15%). No data exist on the superiority of one particular NSAID over another, whether NSAIDs should be used continually or on demand, or whether NSAIDs by themselves modify the course of undifferentiated spondyloarthritis. The dosage should be individualized to obtain a good clinical response with minimal side effects. In a substantial number of cases, NSAIDs have to be given at the maximal tolerable dosage. Disease-Modifying Antirheumatic Drugs Sulfasalazine at a dose of 2 g/day is the only DMARD that has been tested specifically in undifferentiated spondyloarthritis in a placebo-controlled study.18 The entry criteria for that 230-patient study were inflammatory low back pain for less than 5 years and classification of spondyloarthritis according to the ESSG criteria (see Table 71-2). None of the patients had radiographic spinal ankylosis, but more than half of them also had peripheral arthritis or enthesitis. After 6 months of therapy, there was no difference between the sulfasalazine group and the placebo group in the primary outcome, which was the Bath ankylosing spondylitis disease activity index (BASDAI). In the subgroup of patients with back pain but no peripheral arthritis, there was significant improvement with sulfasalazine in BASDAI, spinal pain, and morning stiffness. Efficacy in the subgroup without peripheral arthritis contradicted the findings of an earlier study of 619 patients with AS, psoriatic arthritis, and reactive arthritis.19 There, sulfasalazine was effective only in the subgroup of patients with peripheral arthritis and not the subgroup with ­ predominantly axial disease. Because the entry criteria and primary outcome measures in the two studies were different, it is difficult to determine why the outcomes were different. At this time, it is reasonable for practicing physicians to provide undifferentiated spondyloarthritis patients a limited trial of sulfasalazine. There are no data that

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use of sulfasalazine beyond 6 months is useful even in those with a positive response. Although other conventional DMARDs, such as methotrexate, leflunomide, or ­ cyclosporine, are regularly used in psoriatic arthritis, there is no evidence of a beneficial effect in undifferentiated spondyloarthritis. Antibiotics Three studies have addressed the usefulness of antimicrobial drugs in patients with undifferentiated spondyloarthritis. In two of the studies, a 3-month course of ciprofloxacin or doxycycline did not produce favorable results in comparison to placebo.20,21 The third study compared doxycycline alone with a combination of doxycycline and rifampin in 30 undifferentiated spondyloarthritis subjects over a 9-month period.22 The combination was more effective in treating pain and morning stiffness and in reducing the swollen and tender joint count; however, there was no placebo control. Tumor Necrosis Factor-α Blockers As a consequence of the dramatic improvements observed with TNF-α blocking agents in AS and psoriatic arthritis, this cytokine has also been regarded as a prime therapy in other spondyloarthritides. However, it must be stressed that the only evidence in undifferentiated spondyloarthritis comes from case reports or small open-label ­ studies. Brandt and coworkers23 published their experience in six patients with severe undifferentiated spondyloarthritis treated with 3 or 5 mg/kg infliximab at weeks 0, 2, and 6. The authors reported a significant improvement on day 1 after the first infusion, which lasted until week 12 in five of six patients. Improvement of 50% or greater in disease activity, function, pain, and swollen joint scores was observed in the patients taking 5 mg/kg. The same investigators treated 10 undifferentiated spondyloarthritis patients with etanercept 25 mg twice weekly for 12 weeks and reported a similar 50% or greater regression of disease activity in 60% of patients.24 After cessation of anti–TNF-α therapy, four of eight patients relapsed after 3 to 6 weeks; two patients went into long-standing ­remission.

Future Directions in Spondyloarthritis Even though the prevalence of undifferentiated spondyloarthritis is comparable to that of AS, there is no category I evidence-based recommendation for treatment, with the exception of sulfasalazine; even with that drug, the results of studies are conflicting. There is a high likelihood that TNF-α blockers can be highly effective in many patients. Given the fact that undifferentiated spondyloarthritis is the second most frequent spondyloarthritis subset and that almost 60% of these patients go on to develop AS within 10 years, it is imperative to identify those patients at high risk for functional disability or evolution to more specified diseases. Whether TNF-α therapies can arrest disease progression in this subgroup of patients needs to be studied.

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Undifferentiated Spondyloarthritis and Reactive Arthritis

REACTIVE ARTHRITIS DEFINITION AND CAUSE The term reactive arthritis was defined in 1969 as an arthritis that develops soon after or during an extra-articular infection but in which the microorganism does not enter the joint.25 Since then, there have been several attempts to generate a validated set of classification and diagnostic criteria; however, at this time, universal agreement has not been reached.26,27 In 1999, during the Fourth International Workshop on Reactive Arthritis in Berlin, a consensus was reached to use the term reactive arthritis only if the clinical picture and the triggering pathogens are “typical.”26 The typical pathogen and most common cause of genital infections is Chlamydia trachomatis; 4% of infected patients develop reactive arthritis.28 The typical microbes in the gastrointestinal tract include Yersinia, Salmonella, Shigella, Campylobacter, and, less frequently, Clostridium difficile. Besides these classic pathogens, there is a growing list of other alleged candidates (Table 71-3). GENETICS AND PATHOGENESIS In hospital-based series, about 60% to 80% of patients are human leukocyte antigen (HLA)-B27 positive. The presence of HLA-B27 is associated with more severe arthritis and extra-articular features and predicts a prolonged disease. In studies of individual outbreaks or in epidemiologic surveys at the population level, there is only a slight or no increased frequency of HLA-B27.29,30 The classic reactive arthritis–triggering pathogens are gram-negative obligate or facultative intracellular aerobic bacteria with a lipopolysaccharide-containing outer ­membrane. They are invasive, and in reactive arthritis, bacterial antigens seem to disseminate from the mucosa to the joints. Chlamydia, Yersinia, Salmonella, and Shigella antigens as well as nucleotides have been detected

in the synovial compartment. The significance of these findings is not clear because bacterial macromolecules and nucleotides have also been found in other types of arthritis and, in the case of Chlamydia, in some asymptomatic controls.31-33 A recent and more comprehensive hypothesis is one proposed by Gaston and Lillicrap.34 After invasion via a mucosal route, the microbes persist either in the epithelium or within associated lymphoid tissues, liver, and spleen. The viable organisms or bacterial antigens are disseminated to the joint, causing a local inflammatory response there. A CD4+ T cell response to the invading microorganism drives the arthritic process, most likely supported by a CD8+ T cell response. A deviating or poor T helper type 2 cytokine response may favor the persistence of the microbes or the microbial antigens and contribute to poor elimination of the antigens in the host. Although HLA-B27 is not required for the development of reactive arthritis, its presence contributes to the chronicity of the disease. The favorite hypothesis involves a cross-reaction between microbial structures and HLAB27 or that HLA-B27 itself might be a target of the immune response. EPIDEMIOLOGY There are a few population-based studies on the annual incidence of reactive arthritis, most from Scandinavia. The total incidence has been estimated at 10 to 30 per 100,000.35-38 Two community-based epidemiologic studies found that C. trachomatis and Enterobacteriae play an equal causative role.38 Single-source epidemics have been observed in association with Yersinia enterocolitica, Yersinia pseudotuberculosis, Campylobacter jejuni, Shigella flexneri, and Salmonella enterica. The results show that the frequency of reactive arthritis varies greatly among outbreaks, from 0% to 21%. CLINICAL FEATURES

Table 71-3  Microbial Infections Associated with Reactive Arthritis Enteric Bacteria Salmonella: various serovars Shigella   S. flexneri   S. dysenteriae   S. sonnei Yersinia   Y. enterocolitica (especially O:3 and O:9)   Y. pseudotuberculosis Campylobacter   C. jejuni   C. coli Clostridium difficile Bacteria Causing Urethritis Chlamydia trachomatis Mycoplasma genitalium* Ureaplasma urealyticum* Bacteria Causing Upper Respiratory Infection Beta-hemolytic streptococcus* Chlamydia pneumoniae *Not well accepted as triggers for reactive arthritis.

There is usually a lag of 1 to 4 weeks from the start of infection to the onset of musculoskeletal symptoms. The triggering infection can also be asymptomatic. The patients are usually young adults; reactive arthritis is uncommon in children.39 Male and female patients have a similar risk of developing reactive arthritis induced by gastrointestinal infection, whereas reactive arthritis triggered by C. trachomatis is more frequent in males. The clinical features of reactive arthritis are summarized in Table 71-4. The typical clinical picture is asymmetric oligoarthritis, often in the large joints of the lower extremities; however, about 50% of patients have arthritis in the upper limbs as well. A mild polyarticular form of arthritis in the small joints has been observed when reactive arthritis is being studied at the population level. Patients can also have dactylitis (Fig. 71-4). About 30% of patients have acute low back pain, typically worse at night, that radiates to the buttocks. Extra-articular inflammatory symptoms and signs are frequent (see Table 71-4). Enthesitis or bursitis can occur, either in association with arthritis or as the only reactive complication. Other extra-articular features ­ (common

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Table 71-4  Clinical Features of Reactive Arthritis in Hospital-Based Studies Triggering infection

Number of joints, mean (range)

Clostridium difficile

Chlamydia/­ Urethritis

Yersinia

Salmonella

Shigella

Campylobacter

6 (1-22)

6 (0-22)

4 (2-11)

3 (1-10)

NA

7 (1-24) 47

Low back pain (%), mean (range)

30 (16-45)

37 (18-67)

3 (2-50)

24

NA

Radiographic sacroiliitis (%), mean (range)

19 (11-20)

11

NA

NA

NA

Urethritis (%), mean (range)

15 (4-23)

14

69 (50-69)

NA

NA

93

Conjunctivitis (%), mean (range)

6 (6-7)

13 (6-18)

72 (17-78)

NA

NA

41

Iritis (%), mean (range)

7 (6-17)

3

4 (3-17)

NA

NA

Skin lesions (%), mean (range)

5 (4-7)

2 (2-6)

17

NA

NA

14

Duration of arthritis (mo), mean (range)

3 (1-13)

5 (0-30)

1

0

NA

5 (1-16)

Chronic (>12 mo) course (%), mean (range)

4 (1-24)

19 (0-30)

1

0

NA

14

HLA-B27 positive (%), mean (range)

71 (56-72)

77 (0-94)

83 (83-85)

59

NA

81

NA, not available.

Figure 71-4  Dactylitis (sausage digit) of the right third finger. (Courtesy of Filip De Keyser.)

to the other spondyloarthritides as well) include eye ­symptoms such as conjunctivitis (usual) or acute anterior uveitis (less frequent), various skin rashes, and, in ­prolonged or chronic cases, nail changes resembling those seen in psoriasis. LABORATORY TESTS The only reactive arthritis–specific laboratory tests are those aimed at identifying the triggering pathogens. The most specific tests involve the isolation of microbes from patient samples. Most chlamydial infections are asympto­ matic, but for diagnosis, a search for Chlamydia in the first portion of the morning urine by ligase reaction is the test of choice. During the acute phase of enteric infections, isolation is usually possible from the stools. However, by the time arthritic complications appear, patients may have recovered from the gastroenteritis, and the microbes may not be detectable in the feces. Salmonella and Yersinia infections are usually associated with a strong antibody response; consequently, the laboratory diagnosis of reactive arthritis is often dependent on the detection of specific antibodies in the serum.40 The problem is that there are no international

standards for the constellation of serologic tests. Therefore, the usefulness of a test must be validated in each community before it can be applicable to the diagnosis of reactive arthritis. In only about 60% of clinically diagnosed cases of reactive arthritis is evidence of previous infection detected either by serology or by cultures from urogenital or stool samples. If the clinical picture is typical of reactive arthritis, a positive serologic finding of Chlamydia, Yersinia, or Salmonella has a sensitivity of 73% to 90% and a specificity of 78% to 90%; if Chlamydia is detected in the urogenital tract, the sensitivity is 50% and the specificity is 96%. If the clinical picture is not compatible with reactive arthritis, the post-test probability of diagnosing reactive arthritis is much lower.41 Hence, the clinical picture is pivotal in the diagnosis. Routine laboratory tests such as acute-phase reactants and synovial fluid analysis are not specific for reactive arthritis. HLA-B27 is not a useful diagnostic tool. NATURAL HISTORY Following the acute episode, residual episodic or continuous mild joint or enthesopathy pain is common. Also, one third of patients have occasional attacks of low back pain. Among patients with previous postenteric reactive arthritis, signs and symptoms of chronic spondyloarthritis may occur in 14%. Duration of arthritis for longer than 6 months is arbitrarily regarded as a sign of chronicity. A prolonged (>1 year) extension of acute arthritis has been described in about 4% of Yersinia, 19% of Salmonella, 19% of Shigella, and 17% of Chlamydia arthritis patients.29,30,42 Depending on the triggering infection and the duration of follow-up, chronic arthritis is observed in 2% to 18%, sacroiliitis in 14% to 49%, and AS in 12% to 26% (Table 71-5). Factors determining the progression of acute reactive arthritis to chronic spondyloarthritis are not clear, but they include the species of the triggering pathogen, the presence of HLA-B27, a positive family history for spondyloarthritis, and the presence of chronic gut inflammation. Patients with Reiter’s syndrome triggered by urogenital infection seem to

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Table 71-5  Long-Term Prognosis of Enteric Reactive Arthritis Salmonella

Yersinia enterocolitica

Shigella

Follow-up time (yr)

5

11

4-5

10

20

No. of patients

27

50

58

107

100

Males (%)

NA

57

39

49

93

HLA-B27 positive (%)

22

88

NA

78

NA

Recovered (%)

33

40

19

49

20

Arthralgia (%)

NA

20

32

19

NA

Low back pain (%)

30

44

NA

37

NA

Recurrent arthritis (%)

37

22

NA

5

18

Iritis during follow-up (%)

NA

NA

NA

14

7

Chronic arthritis (%)

52

16

16

2

18

Ankylosing spondylitis (%)

NA

12

9

16

14

Radiographic sacroiliitis (%)

NA

12

9

30

32

Patients with radiographic erosions in peripheral joints (%)

15

NA

3

0

12

Each column represents results from a single study. NA, not available.

Table 71-6  Randomized, Double-Blind, Placebo-Controlled Studies of Antimicrobial Chemotherapy for Reactive Arthritis Number of Patients

Duration of Therapy (mo)

Treatment

Result Compared with Placebo

Chlamydia Enteric infections

21 19

3 3

Lymecycline Lymecycline

Lymecycline effective No difference

Reference

Cause

45 46

Yersinia

36

3

Ciprofloxacin

No difference

20

Various triggers

55

3

Ciprofloxacin

No difference

47

Various triggers

71

3

Ciprofloxacin

No difference

44

Clinical suspicion of reactive arthritis

152

3

Azithromycin

No difference

be more vulnerable to recurrent urethritides and recurrent episodes of arthritides. In a genetically predisposed subject, it is still uncertain to what extent reactive arthritis contributes to the cause of sacroiliitis or AS. It is possible that sacroiliac changes would have occurred anyway, even in the absence of preceding reactive arthritis.

patient is bedridden due to severe polyarthritis, is febrile, or has carditis or an atrioventricular conduction disturbance. Reactive arthritis patients seem to need higher doses of systemic prednisone or prednisolone, such as 20 to 40 mg/day, compared with RA patients. Antibiotics

TREATMENT Treatment of the Triggering Infection All patients with acute C. trachomatis infection, as well as their partners, should receive the standard treatment for chlamydial infections. At this time, uncomplicated enteritis preceding reactive arthritis is not an indication for treatment with antimicrobials.

The effect of short-term and long-term antibiotic therapy to treat reactive arthritis has been a focus of research during the last 20 years. Although no controlled studies exist, some ­evidence speaks in favor of antibiotics during the infectious phase, even before the arthritis has had time to develop.43 Once arthritis has developed, however, the introduction of antibiotics does not modify the course of the disease20, 44-47 (Table 71-6). Disease-Modifying Antirheumatic Drugs

Treatment of Arthritis The use of NSAIDs, often at the full dose, is usually of major benefit for acute arthritis and spinal pain. Local glucocorticoid injections are also beneficial in patients with mon- or oligoarthritis. Enthesitis responds to local corticosteroid injections as well. Systemic corticosteroids are used if the

Because about 50% of patients recover from reactive arthritis within the first 6 months, use of DMARDs is often not considered. There is only limited information on the efficacy of such drugs. Patients with acute reactive arthritis who started sulfasalazine treatment during the first 3 months reached clinical remission more rapidly compared with those in the

PART 10 

placebo arm.48 Sulfasalazine is also effective in chronic reactive arthritis.49 However, if the drug is ineffective, it should not be continued for more than 6 months. TNF-α blockers are effective in chronic HLA-B27–associated AS, but their use has been reported in only a few cases of reactive arthritis. There appears to be a benefit, and these agents do not cause a relapse of the triggering infection.50 REFERENCES   1. Zochling J, Brandt J, Braun J: The current concept of spondyloarthritis with special emphasis on undifferentiated spondyloarthritis. Rheumatology (Oxford) 44:1483-1491, 2005.   2. Amor B, Dougados M, Mijiyawa M: Criteria of the classification of spondylarthropathies. Rev Rhum Mal Osteoartic 57:85-89, 1990.   3. Dougados M, van der Linden S, Juhlin R, et al: The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 34:1218-1227, 1991.   4. Rudwaleit M, van der Heijde D, Khan MA, et al: How to diagnose axial spondyloarthritis early. Ann Rheum Dis 63:535-543, 2004.   5. Heuft-Dorenbosch L, Landewe R, Weijers R, et al: Performance of various criteria sets in patients with inflammatory back pain of short duration: The Maastricht early spondyloarthritis clinic. Ann Rheum Dis 2006. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi ?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16868021 (accessed July 25, 2006).   6. Ball J: Enthesopathy of rheumatoid and ankylosing spondylitis. Ann Rheum Dis 30:213-223, 1971.   7. McGonagle D, Gibbon W, Emery P: Classification of inflammatory arthritis by enthesitis. Lancet 352:1137-1140, 1998.   8. Benjamin M, Moriggl B, Brenner E, et al: The “enthesis organ” concept: Why enthesopathies may not present as focal insertional disorders. Arthritis Rheum 50:3306-3313, 2004.   9. Benjamin M, Toumi H, Suzuki D, et al: Microdamage and altered vascularity at the enthesis bone interface provides an anatomical explanation for bone involvement in the HLA-B27 associated spondyloarthropathies and allied disorders. Arthritis Rheum.56:224-233, 2007.  10. Braun J, Bollow M, Neure L, et al: Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum 38:499-505, 1995.  11. Laloux L, Voisin MC, Allain J, et al: Immunohistological study of entheses in spondyloarthropathies: Comparison in rheumatoid arthritis and osteoarthritis. Ann Rheum Dis 60:316-321, 2001.  12. McGonagle D, Marzo-Ortega H, O’Connor P, et al: Histological assessment of the early enthesitis lesion in spondyloarthropathy. Ann Rheum Dis 61:534-537, 2002.  13. McGonagle D, Marzo-Ortega H, Benjamin M, et al: Report on the Second International Enthesitis Workshop. Arthritis Rheum 48: 896-905, 2003.  14. Balint PV, Kane D, Wilson H, et al: Ultrasonography of entheseal insertions in the lower limb in spondyloarthropathy. Ann Rheum Dis 61:905-910, 2002.  15. Mander M, Simpson JM, McLellan A, et al: Studies with an enthesis index as a method of clinical assessment in ankylosing spondylitis. Ann Rheum Dis 46:197-202, 1987.  16. Marzo-Ortega H, McGonagle D, O’Connor P, et al: Efficacy of etanercept in the treatment of the entheseal pathology in resistant spondylarthropathy: A clinical and magnetic resonance imaging study. Arthritis Rheum 44:2112-2117, 2001.  17. Amor B, Dougados M, Listrat V, et al: Evaluation of the Amor criteria for spondylarthropathies and European Spondylarthropathy Study Group (ESSG): A cross-sectional analysis of 2228 patients. Ann Med Interne (Paris) 142:85-89, 1991. 18. Braun J, Zochling J, Baraliakos X, et al: Efficacy of sulfasalazine in patients with inflammatory back pain due to undifferentiated spondyloarthritis and early ankylosing spondylitis: A multicentre randomised controlled trial. Ann Rheum Dis 65:1147-1153, 2006. 19. Clegg DO, Reda DJ, Abdellatif M: Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies: A Department of Veterans Affairs cooperative study. Arthritis Rheum 42:23252329, 1999.

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20. Sieper J, Fendler C, Laitko S, et al: No benefit of long-term ­ciprofloxacin treatment in patients with reactive arthritis and undifferentiated oligoarthritis: A three-month, multicenter, double-blind, randomized, placebo-controlled study. Arthritis Rheum 42:13861396, 1999. 21. Smieja M, MacPherson DW, Kean W, et al: Randomised, blinded, placebo controlled trial of doxycycline for chronic seronegative arthritis. Ann Rheum Dis 60:1088-1094, 2001.  22. Carter JD, Valeriano J, Vasey FB: Doxycycline versus doxycycline and rifampin in undifferentiated spondyloarthropathy, with special reference to chlamydia-induced arthritis: A prospective, randomized 9-month comparison. J Rheumatol 31:1973-1980, 2004.  23. Brandt J, Haibel H, Reddig J, et al: Successful short term treatment of severe undifferentiated spondyloarthropathy with the anti-tumor necrosis factor-alpha monoclonal antibody infliximab. J Rheumatol 29:118-122, 2002.  24. Brandt J, Khariouzov A, Listing J, et al: Successful short term treatment of patients with severe undifferentiated spondyloarthritis with the anti-tumor necrosis factor-alpha fusion receptor protein etanercept. J Rheumatol 31:531-538, 2004.  25. Ahvonen P, Sievers K, Aho K: Arthritis associated with Yersinia enterocolitica infection. Acta Rheumatol Scand 15:232-253, 1969.  26. Kingsley G, Sieper J: Third International Workshop on Reactive Arthritis. 23-26 September 1995, Berlin, Germany: Report and abstracts. Ann Rheum Dis 55:564-584, 1996.  27. Pacheco-Tena C, Burgos-Vargas R, Vazquez-Mellado J, et al: A proposal for the classification of patients for clinical and experimental studies on reactive arthritis. J Rheumatol 26:1338-1346, 1999.  28. Rich E, Hook EW 3rd, Alarcon GS, et al: Reactive arthritis in patients attending an urban sexually transmitted diseases clinic. Arthritis Rheum 39:1172-1177, 1996.  29. Leirisalo-Repo M, Helenius P, Hannu T, et al: Long-term prognosis of reactive salmonella arthritis. Ann Rheum Dis 56:516-520, 1997.  30. Leirisalo-Repo M, Suoranta H: Ten-year follow-up study of patients with Yersinia arthritis. Arthritis Rheum 31:533-537, 1988.  31. Cox CJ, Kempsell KE, Gaston JS: Investigation of infectious agents associated with arthritis by reverse transcription PCR of bacterial rRNA. Arthritis Res Ther 5:R1-8, 2003.  32. Schumacher HR Jr, Arayssi T, Crane M, et al: Chlamydia trachomatis nucleic acids can be found in the synovium of some asymptomatic subjects. Arthritis Rheum 42:1281-1284, 1999.  33. Wilkinson NZ, Kingsley GH, Jones HW, et al: The detection of DNA from a range of bacterial species in the joints of patients with a variety of arthritides using a nested, broad-range polymerase chain reaction. Rheumatology (Oxford) 38:260-266, 1999.  34. Hill Gaston JS, Lillicrap MS: Arthritis associated with enteric infection. Best Pract Res Clin Rheumatol 17:219-239, 2003.  35. Isomaki H, Raunio J, von Essen R, et al: Incidence of inflammatory rheumatic diseases in Finland. Scand J Rheumatol 7:188-192, 1978.  36. Kvien TK, Glennas A, Melby K, et al: Reactive arthritis: Incidence, triggering agents and clinical presentation. J Rheumatol 21:115-122, 1994.  37. Savolainen E, Kaipiainen-Seppanen O, Kroger L, et al: Total incidence and distribution of inflammatory joint diseases in a defined ­population: Results from the Kuopio 2000 arthritis survey. J Rheumatol 30: 2460-2468, 2003.  38. Soderlin MK, Kautiainen H, Puolakkainen M, et al: Infections preceding early arthritis in southern Sweden: A prospective populationbased study. J Rheumatol 30:459-464, 2003.  39. Rudwaleit M, Richter S, Braun J, et al: Low incidence of reactive arthritis in children following a salmonella outbreak. Ann Rheum Dis 60:1055-1057, 2001.  40. Granfors K, Viljanen M, Tiilikainen A, et al: Persistence of IgM, IgG, and IgA antibodies to Yersinia in Yersinia arthritis. J Infect Dis 141: 424-429, 1980.  41. Sieper J, Rudwaleit M, Braun J, et al: Diagnosing reactive arthritis: Role of clinical setting in the value of serologic and microbiologic assays. Arthritis Rheum 46:319-327, 2002.  42. Sairanen E, Paronen I, Mahonen H: Reiter’s syndrome: A follow-up study. Acta Med Scand 185:57-63, 1969.  43. Bardin T, Enel C, Cornelis F, et al: Antibiotic treatment of venereal disease and Reiter’s syndrome in a Greenland population. Arthritis Rheum 35:190-194, 1992. 44. Kvien TK, Gaston JS, Bardin T, et al: Three month treatment of ­reactive arthritis with azithromycin: A EULAR double blind, placebo controlled study. Ann Rheum Dis 63:1113-1119, 2004.

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45. Lauhio A, Leirisalo-Repo M, Lahdevirta J, et al: Double-blind, placebo-controlled study of three-month treatment with lymecycline in reactive arthritis, with special reference to Chlamydia arthritis. Arthritis Rheum 34:6-14, 1991.  46. Toivanen A, Yli-Kerttula T, Luukkainen R, et al: Effect of antimicrobial treatment on chronic reactive arthritis. Clin Exp Rheumatol 11:301-307, 1993.  47. Yli-Kerttula T, Luukkainen R, Yli-Kerttula U, et al: Effect of a three month course of ciprofloxacin on the outcome of reactive arthritis. Ann Rheum Dis 59:565-570, 2000.

48. Egsmose C, Hansen TM, Andersen LS, et al: Limited effect of sulphasalazine treatment in reactive arthritis: A randomised double blind placebo controlled trial. Ann Rheum Dis 56:32-36, 1997. 49. Clegg DO, Reda DJ, Weisman MH, et al: Comparison of sulfasalazine and placebo in the treatment of reactive arthritis (Reiter’s syndrome): A Department of Veterans Affairs cooperative study. Arthritis Rheum 39:2021-2027, 1996.  50. Flagg SD, Meador R, Hsia E, et al: Decreased pain and synovial inflammation after etanercept therapy in patients with reactive and undifferentiated arthritis: An open-label trial. Arthritis Rheum 53:613-617, 2005.

72

Psoriatic Arthritis Oliver Fitzgerald

Key Points Psoriatic arthritis should be suspected in a patient with an asymmetric joint distribution pattern who may have additional clinical features, such as dactylitis, enthesitis, or inflammatory-type back pain, and who is negative for rheumatoid factor. In such patients, a careful search for psoriasis is warranted. New classification criteria, the Classification of Psoriatic Arthritis (CASPAR) criteria, have been published more recently. Psoriatic arthritis is a progressive disease, with 47% of patients developing erosions within 2 years of diagnosis. Polyarticular disease and an elevated erythrocyte sedimentation rate are markers of poor outcome. An essential core set of domains and instruments is now agreed as being necessary for inclusion in clinical trials. Studies of synovial tissue have highlighted an increase in vascularity and the presence of neutrophils as helping to distinguish spondyloarthropathy from rheumatoid arthritis. Prominent entheseal involvement with bone marrow edema at entheseal insertions on magnetic resonance imaging has prompted the hypothesis that psoriatic arthritis may originate at the enthesis. A role for CD8+ T cells and the innate immune response has been proposed. Although there is a paucity of evidence for efficacy of disease-modifying antirheumatic drugs in psoriatic arthritis, tumor necrosis factor inhibitors have proved effective for skin and joint disease.

Psoriatic arthritis is a member of the spondyloarthropathy family and may be defined as an inflammatory arthropathy associated with psoriasis and usually negative for rheumatoid factor. Until the 1950s, an inflammatory arthritis occurring in the presence of psoriasis was thought to represent rheumatoid arthritis (RA) occurring coincidentally with psoriasis. Based primarily on clinical and radiologic grounds and using the rheumatoid factor, the distinction between RA and psoriatic arthritis became gradually accepted. Wright described the classic clinical features in 1959 and together with his colleague Moll, he published his classification criteria in 1973.1,2 These criteria have remained until more recently the simplest and the most frequently used in clinical studies. The American Association of Rheumatism included psoriatic arthritis as a distinct clinical entity in the classification of rheumatic diseases for the first time in 1964.3

EPIDEMIOLOGY Epidemiologic studies have supported the concept that psoriatic arthritis is a unique disease entity separate from RA. The prevalence of inflammatory arthritis is increased among patients with psoriasis, ranging from 7% to 25% compared with a general population estimate of 2% to 3%. The prevalence of psoriasis subjects with arthritis also is increased at 2.6% to 7% compared with a general population estimate of 0.1% to 2.8%.4 Psoriasis affects about 2% of the population. The prevalence varies, with 5% to 10% of Russians and Norwegians affected and only 0% to 0.3% of West Africans or Native Americans affected.5 Onset of psoriasis may be at any age, but most frequently peaks in the 20s. Although there is no gender predilection, there is a genetic predisposition. Of patients with psoriasis, 7% to 42% develop arthritis. This figure varies so widely partly because of a lack of widely accepted diagnostic criteria, but also depending on what population is being studied. The exact prevalence and incidence of psoriatic arthritis are unknown. The reported prevalence of psoriatic arthritis varied from 0.056% to 0.28% in a large population-based study in the United States.6 Cases were defined as patients who reported a “physician diagnosis” of psoriasis and psoriatic arthritis. The prevalence was calculated at 0.25% (95% confidence interval, 0.18% to 0.31%). Kay and colleagues7 did a prevalence study in ­northeast England evaluating records from six general practices; 81 of 772 psoriasis subjects had an inflammatory arthritis with a prevalence of 0.28%. The reported incidence of psoriatic arthritis has varied from 3 to 23 per 100,000. Data from Rochester, New York, have shown an incidence rate of 6.59 per 100,000, whereas in Finland, 16 new cases of psoriatic arthritis were identified in a population of 87,000, giving a mean incidence rate of 23 per 100,000.8,9

CLINICAL FEATURES Plaque psoriasis or psoriasis vulgaris is the most common skin phenotype in patients with psoriatic arthritis. Other patterns of skin involvement may be seen (Fig. 72-1). Although the arthritis usually develops in a setting of an established diagnosis of psoriasis, some patients may be unaware that they have psoriasis, or psoriasis may develop after the onset of arthritis in approximately 15% of cases.10 If a patient presents with the classic articular manifestations of psoriatic arthritis, but does not volunteer psoriasis or the presence of a rash, it is incumbent on the physician to examine the patient’s skin carefully, including the scalp and nails because psoriasis frequently lurks in such areas. Examples of nail dystrophic changes are shown in Figure 72-2.

  Supplemental images available on the Expert Consult Premium Edition website.   Video available on the Expert Consult Premium Edition website.

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A

B

C

D

E

F

Figure 72-1  Clinical phenotypes in psoriasis; A to H, Plaque psoriasis (psoriasis vulgaris). A, At extensor surface of elbow and on scalp (B); genital psoriasis  (C); inframammary and umbilical flexural psoriasis (D); guttate psoriasis in a father and child (E); erythrodermic psoriasis on the trunk and upper limbs (F). Continued

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G

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H Figure 72-1, cont’d  G, Pustular psoriasis on the foot; and the Koebner phenomenon on a surgical abdominal wound (H).

A

B

C Figure 72-2  Nail dystrophic changes. Nail pitting (A); onycholysis (B), and severe destructive change with nail loss and pustule formation (C).

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Tender

Swollen

3

2

11

11 9

12

4

8

23

19

21

14

41

33

38

35

38

29

36

33

20

19

4

4 Left

Right

29

36

0

0 Right

Left

23

38

26

19

Ankle

14

16

Ankle

12

0

Subtalar

0

0

Subtalar

0

3

Midtarsal

2

2

Midtarsal

2

35

22

20

19

14

16

12

Figure 72-3  Frequency (%) of peripheral limb joint involvement in 129 patients with early psoriatic arthritis as assessed by joint tenderness and s­ welling (distal interphalangeal joints of hand and proximal and distal interphalangeal joints of feet not assessed for tenderness as part of Ritchie ­Articular Index).

Although a more recent U.S. study suggests that the prevalence of psoriatic arthritis among psoriasis patients increases with psoriasis severity,6 in clinical practice, there seems to be little relationship between severity of skin involvement and severity of arthritis. In one prospective study, only 35% of patients reported that their skin and joint components flared at the same time.10 Patients with psoriatic arthritis present with symptoms and signs of joint, entheseal, or spinal inflammation. The joints involved at presentation in 129 early psoriatic arthritis patients are shown in Figure 72-3. In one of their seminal papers on psoriatic arthritis, Wright and Moll11 described five clinical patterns of psoriatic arthritis (Fig. 72-4): 1. Asymmetric oligoarthritis 2. Symmetric polyarthritis 3. Predominant distal interphalangeal (DIP) joint involvement 4. Predominant spondyloarthritis 5. Destructive (mutilans) arthritis These classification criteria are the most commonly quoted, although many alternative criteria have been proposed. Variability in the definition of terms has led to

differences in the reported frequency of psoriatic arthritis subsets among the different studies. The pattern of joint involvement is not fixed; the patient’s disease may fluctuate and may be influenced by treatment. In a study of 129 patients with early psoriatic arthritis, 53 of 77 initially classified as polyarticular were reassessed at 2 years; 26 of 53 (49%) patients were subsequently classified as oligoarticular, 19 of 53 (36%) remained classified as polyarticular, and 12 of 53 (23%) were in remission.12 The Classification of Psoriatic Arthritis (CASPAR) study has included in the analysis a breakdown of disease pattern subtypes.13 This multicenter study included data on 588 psoriatic arthritis cases and 536 controls. In contrast to the original Moll and Wright paper, but similar to many subsequent publications, approximately 63% of patients had polyarticular joint involvement compared with 13% with oligoarticular disease. The other patterns of joint involvement described by Moll and Wright occurred much less commonly. Predominant DIP disease was found in less than 5%, but DIP involvement can occur in any of the subtypes. Predominant spondyloarthritis also is uncommon, although spinal involvement may be found in 40% to 70% of psoriatic

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A

C

B

D Figure 72-4  Patterns of peripheral joint disease. A-D, Asymmetric polyarticular disease. A, Distal interphalangeal joint involvement and f­ orearm lymphedema; toe dactylitis with skin and nail change (B); predominant distal interphalangeal joint involvement (C); and arthritis  mutilans (D).

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arthritis cases depending on whether or not radiographs are taken.14 Finally, arthritis mutilans, a destructive form of arthritis associated with flail joints, is rare, although more patients may develop this form of joint involvement with time if their disease is not properly controlled. Features that are typical of psoriatic arthritis are helpful in diagnosis, including dactylitis and enthesitis. Dactylitis, in which there is a sausage-shaped swelling of the fingers or toes (see Fig. 72-4B), may be found in 29% to 33.5% of psoriatic arthritis patients at first presentation, and 48% may have an episode of dactylitis during follow-up.12,15 Ultrasound and magnetic resonance imaging (MRI) studies have shown that joint and tenosynovial inflammation are prominent in involved digits.16,17 Enthesitis, inflammation at tendon or ligament insertion into bone, is a feature of all of the spondyloarthropathies and may be a presenting ­feature in psoriatic arthritis. Overall, enthesitis is found in 38% of patients at presentation.12 The most common entheseal sites involved are the Achilles and plantar fascia insertions. Other sites include the insertions of the quadriceps and patellar tendons, the iliac crest, the rotator cuff, and the epicondyles at the elbow. Patients complain of pain at these sites with tenderness and sometimes swelling found on examination. Entheseal involvement may be asymptomatic, with ultrasound being more sensitive than clinical palpation. Often spurs are detected on x-ray, although spurs are not always associated with symptoms. With the obvious exception of psoriasis and nail dystrophic change, extra-articular disease is less common in psoriatic arthritis compared with RA. Iritis or uveitis occurs in 7% to 18%, more bilateral than in ankylosing spondylitis, but usually found in patients with spinal involvement.10,18 Numerous studies have suggested that psoriatic arthritis patients have a higher prevalence of inflammatory bowel disease, sometimes asymptomatic and detected only on biopsy specimen.19,20 Whether this inflammatory bowel disease is coincidental or possibly related to medication effects remains to be clarified. Distal limb edema or lymphedema may occur more commonly in psoriatic arthritis; one case-control study found it in 21% of psoriatic arthritis patients compared with 4.9% of controls (see Fig. 72-4A).21 Finally, amyloid is rare, but is described in psoriatic arthritis.

DIFFERENTIAL DIAGNOSIS Certain articular features if present are useful in distinguishing psoriatic arthritis from RA, including dactylitis, DIP involvement, and inflammation at entheseal sites (Table 72-1; see Fig. 72-4). In addition, inflammatory-type back pain or sacroiliitis on plain-x-ray or MRI should raise the suspicion of psoriatic arthritis because spinal involvement is uncommon in RA. The absence of rheumatoid nodules or other systemic features common to RA can be another useful differentiating feature. Distinguishing psoriatic arthritis from other spondyloarthropathies also is important. Dactylitis may be a feature in reactive arthritis where a palmoplantar pustular rash (keratoderma blennorrhagicum) may be clinically and ­histologically indistinguishable from pustular psoriasis (see Fig. 72-1G). In relation to spinal involvement, sacroiliitis may be unilateral more frequently, and the spinal changes

Table 72-1  Clinical Features That Best Distinguish ­Psoriatic Arthritis from Rheumatoid Arthritis Psoriatic Arthritis

Rheumatoid Arthritis

Psoriasis

+

−

Symmetric

+

++

Asymmetric

++

+

Enthesopathy

+

−

Dactylitis

+

−

Nail dystrophy

+

−

HIV association

+

−

HIV, human immunodeficiency virus.

on plain radiography may be more asymmetric in psoriatic arthritis compared with classic ankylosing spondylitis. Finally, crystal-associated arthropathies occasionally can confuse, especially with monarticular disease, and are best distinguished by synovial fluid crystal analysis. Serum urate levels may be increased in patients with psoriatic arthritis adding to the confusion.

LABORATORY FEATURES There is no diagnostic laboratory test for psoriatic arthritis. Although the absence of rheumatoid factor is considered an important distinguishing feature from RA, low levels of rheumatoid factor may be found in patients (5% to 16%) with typical psoriatic arthritis features. Until there is a more definitive diagnostic test, it is difficult to be categorical about diagnosis in these patients. Cyclic citrullinated peptide antibodies were initially thought to be specific to RA, but it is now recognized that cyclic citrullinated peptide antibodies are found in approximately 5% of psoriatic arthritis patients as well.22 Acute-phase markers, such as erythrocyte sedimentation rate, C-reactive protein, or serum amyloid A, all may be elevated in psoriatic arthritis patients, but less commonly and to a lesser degree than in RA patients. These markers are elevated in particular in patients with polyarticular disease and act as a marker of poor prognosis.23 Finally, as mentioned previously, hyperuricemia may be found in association with metabolic abnormalities in psoriatic arthritis patients and not reflecting the extent of skin involvement.

RADIOGRAPHIC FEATURES Although there have been substantial advances in the application, in particular, of musculoskeletal ultrasound (MSUS) and of MRI in patients with arthritis, including psoriatic arthritis, plain radiographic imaging remains the “gold standard” for assessing bony changes in peripheral joints in psoriatic arthritis. PLAIN RADIOGRAPHY Sixty-seven percent of patients with established psoriatic arthritis have radiographic abnormalities,10 and 47% of patients with recent-onset psoriatic arthritis will have ­developed erosions within 2 years of disease onset.12 Distinctive radiographic features reflect in some cases the clinical

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RT

A

C

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LT

B

D

Figure 72-5  Radiologic features in psoriatic arthritis. A, Third left distal interphalangeal joint monarthritis with prominent new bone formation.  B, Bone scan from same patient as in A. C, Asymmetric right-sided sacroiliitis. D, Severe destructive changes (arthritis mutilans) with multiple erosions and “pencil-in-cup” deformities. (Courtesy of Dr. Robin Gibney.)

phenotype (Fig. 72-5). These features include asymmetric joint involvement; involvement of the interphalangeal joints of the fingers and toes, with features of bony erosion and resorption sometimes seen together and resulting in the classic “pencil-in-cup” deformity; joint space narrowing or involvement of entheseal sites, often with bony spurs developing or periostitis; and spinal involvement, frequently less severe and asymmetric compared with classic ankylosing spondylitis. Radiographic progression in psoriatic arthritis is slow in early psoriatic arthritis with the mean modified Sharp (to include DIP joints in the hands) erosion score at presentation increasing from 1.2 to 3 at 2 years.12 The Larson and the Sharp scoring systems have been used in psoriatic arthritis, but neither the Larson nor the Sharp score has been developed

specifically for psoriatic arthritis or has been extensively validated. MUSCULOSKELETAL ULTRASOUND There are many MSUS applications in psoriatic arthritis, and the applications are likely to develop further as the technology, in particular power Doppler to allow identification of blood flow, develops further (Fig. 72-6). Already it has been shown that MSUS is more sensitive than clinical examination in detecting knee synovitis in patients with various arthritides, including psoriatic arthritis.24 One study has suggested further that this increased sensitivity may result in reclassification of some patients as polyarticular when they were previously diagnosed as oligoarticular on clinical grounds.25 This

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Left PL fascia long

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Psoriatic Arthritis

Left 3F trans MCP

Right

A

Left long 3rd F dorsum MCP

B

Right

CPA

C

Right achilles tend long

D

Figure 72-6  Musculoskeletal ultrasound features in psoriatic arthritis. A, Right plantar fascia thickening compared with the left. B, Transverse section through left third finger at the metacarpophalangeal joint showing right tenosynovitis. C, Power Doppler ultrasound through left third finger at the metacarpophalangeal joint confirming increased vascularity (synovitis). D, Right Achilles tendinitis with calcaneal erosion. (Courtesy of Dr. Robin Gibney.)

reclassification may result in significant changes in prognosis and therapy. Finally, MSUS has been used in the objective monitoring of response of synovitis to therapy.26 The MSUS features at the enthesis include entheseal thickening, hypoechoic change, increased vascularity as shown on power Doppler, tenosynovitis, and bony erosions or enthesophyte formation.27,28 MSUS has been shown to be more sensitive than clinical examination in detecting lower limb enthesopathy.28,29 MSUS has been used in studies of dactylitic digits. Together with MRI, MSUS has shown dactylitis to be due to a combination of synovial and tenosynovial inflammation.16,17 Finally, MSUS guidance for small joint or entheseal aspiration or injection may have particular application in patients with psoriatic arthritis. MAGNETIC RESONANCE IMAGING MRI studies have been particularly useful in offering new insights into disease pathogenesis in psoriatic arthritis. Based on the prominent entheseal-related bone marrow edema seen on MRI, McGonagle and colleagues30 have proposed that psoriatic arthritis, in contrast to RA, is an entheseal-based disease. MRI can be used to study all aspects of joint involvement including the enthesis, but the use of MRI as a routine clinical tool in psoriatic arthritis is not yet clarified. The application of MRI to the spine or sacroiliac joints in psoriatic arthritis may prove especially helpful as has been shown in ankylosing spondylitis, but studies in psoriatic arthritis patients are awaited. Preliminary studies have suggested that MRI can be useful as an outcome measure in the detection of synovitis or of

vascularity in patients with psoriatic arthritis undergoing biologic therapies (Fig. 72-7). More detailed studies are required. OTHER IMAGING MODALITIES The use of other imaging modalities, such as computed tomography (CT) or scintigraphy, has largely been superseded by MRI. CT is now mainly reserved for patients in whom MRI is contraindicated or for whom MRI is unavailable. Positron emission tomography has been found to be comparable to MSUS and MRI in RA knees; this work needs to be extended to psoriatic arthritis.

DIAGNOSIS A diagnostic test for psoriatic arthritis is currently unavailable. Nevertheless, in its simplest form, psoriatic arthritis can be considered as an arthritis occurring in the presence of psoriasis, but in the absence of rheumatoid factor. Most psoriatic arthritis patients meet this simple definition. The arthritis can be predominantly spinal, it may involve only entheseal sites, psoriasis may present after the arthritis in 15%, and low-titer positive rheumatoid factor may be found. Recognizing these difficulties, the CASPAR group have published new classification criteria based on an analysis of 588 psoriatic arthritis cases and 536 controls (Table 72-2).31 These criteria have yet to be validated in other large patient cohorts, and they should not be used in individual patient diagnosis. In the setting of clinical research, the CASPAR criteria have a specificity of 0.987 and a sensitivity of 0.914. For the individual patient, an algorithm for diagnosis is suggested in Figure 72-8.

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Figure 72-7  A, T1-weighted MR image of left foot confirming severe talonavicular disease with bone edema. B, Contrast-enhanced MR image of an inflamed knee joint in psoriatic arthritis showing synovial enhancement and large suprapatellar effusion. C, CT scan of sacroiliac joint showing sclerosis, erosion, and needle in place just before corticosteroid injection. (Courtesy of Dr. Robin Gibney.)

CLINICAL COURSE AND OUTCOME Five early psoriatic arthritis cohorts have been studied.12,32-35 The mean disease duration in these cohorts was 6 to 12 months, the median age at onset of psoriasis was 27 to 31 years, and the median age at onset of arthritis was 38 to 52 years. Overall, there was little relationship between skin disease severity and psoriatic arthritis onset; the small joints of hands and feet were the most common joints involved; the DIP joints were involved in one third of patients, usually associated with nail disease, which was present in two thirds; dactylitis and enthesitis were present in one third; and spinal involvement only was found in 2% to 4%, but was present in 20% overall. In follow-up, disease continued to progress in most patients with 47% developing erosive disease within 2 years.12 Markers for progression included polyarticular disease and an elevated erythrocyte sedimentation rate. Long-term follow-up studies have shown significant morbidity and increased mortality in psoriatic arthritis: 17% have five or more deformed joints, 40% to 57% have a deforming arthritis, 20% to 40% have spinal involvement, 11% to 19% are disabled, and mortality is increased compared with the general population.10,36,37 In a more recent study, carotid intimal medial thickness was increased in psoriatic arthritis patients compared with controls,

but significantly reduced compared with an RA cohort of similar disease duration (unpublished observations).

OUTCOME DOMAINS AND INSTRUMENTS Measuring response to treatment of psoriatic arthritis in clinical trials has been the subject of much interest for members of the Group for Research and Assessment of Psoriasis and ­Psoriatic Arthritis (GRAPPA) and Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT). Much of the data that have been used to date in clinical trials have been adapted from RA and have not been validated. Controversial issues have included the number of joints to count, the usefulness of the acute-phase response in psoriatic arthritis, and how important is it to include a measure of function or quality of life. An essential core set of domains that must be included in clinical trials has now been agreed on with other domains necessary but not mandatory, and yet others requiring considerably more research (Fig. 72-9). Instruments for many of these domains have yet to be developed and validated, and some instruments, such as the Psoriasis Assessment Severity Index (PASI), have acknowledged limitations. Table 72-3 lists the currently available instruments for the core domains.

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Table 72-2  CASPAR Classification Criteria for Psoriatic Arthritis Inflammatory articular disease (joint, spine, or entheseal) with   ≥3 points from the following:

Rad iolo gy

ion

Peripheral joint activity Skin activity Patient global pain Physical function HRQoL

t ipa tic

Tiss ue an aly sis G l o bal ician s E y nth Ph es

tylitis Dac

r Pa

4. Dactylitis (one of a, b) a. Current swelling of an entire digit b. History—history of dactylitis recorded by a rheumatologist

CT

Spi na l

3. Negative test for rheumatoid factor—by any method except latex, but preferably by ELISA or nephelometry, according to the local laboratory reference range

itis

Ultrasound

I

Nails

2. Psoriatic nail dystrophy—typical psoriatic nail dystrophy, ­including onycholysis, pitting, and hyperkeratosis observed on current physical examination

MR

e tigu Fa

1. Evidence of psoriasis (one of a, b, c) a. Current psoriasis*—psoriatic skin or scalp disease present today as judged by a rheumatologist or dermatologist b. Personal history of psoriasis—history of psoriasis that may be obtained from patient, family physician, dermatologist, ­rheumatologist, or other qualified health care provider c. Family history of psoriasis—history of psoriasis in a first-degree or second-degree relative according to patient report

Ac ts utephase reactan

5. Radiologic evidence of juxta-articular new bone formation—  ill-defined ossification near joint margins (but excluding osteophyte formation) on plain x-rays of hand or foot Specificity 0.987, sensitivity 0.914. *Current psoriasis scores 2, whereas all other items score 1. CASPAR, Classification of Psoriatic Arthritis; ELISA, enzyme-linked immunosorbent assay.

Inflammatory arthritis Enthesitis Inflammatory back pain Yes Psoriasis Nail dystrophy

RF neg

Psoriatic arthritis

RF pos (high titer)

Rheumatoid arthritis and psoriasis

Figure 72-9  Outcome domains in psoriatic arthritis. The central core domains are considered essential for inclusion in clinical trials. The middle circle contains domains that are considered important, but not essential. The outer circle contains domains that all require further research and validation. HRQoL, health-related quality of life.

Table 72-3  Core Set Instruments Proposed for Use   in Clinical Trials

No Psoriaasis Nail dystrophy

RF neg

RF pos

Psoriatic arthritis?

Rheumatoid arthritis or SpA

Figure 72-8  Algorithm to be used in diagnosis of individual patients presenting with possible psoriatic arthritis. Some patients may pre­sent with typical articular manifestations of psoriatic arthritis, but in the ­absence of skin or nail disease. They can be diagnosed as definite psoriatic arthritis only when psoriasis subsequently develops. RF, rheumatoid factor; SpA, spondyloarthropathy.

In the setting of clinical trials, numerous composite scores (e.g., American College of Rheumatology [ACR]20, ACR-50, ACR-70; European League Against Rheumatism (EULAR) Disease Activity Score [DAS] response criteria) have been used in psoriatic arthritis, most again adapted from RA and not extensively validated in psoriatic arthritis. One scoring system was developed for psoriatic arthritis, the PsARC, and although it has been used in numerous studies, it too has not been extensively validated

Domain

Instrument

Peripheral joint inflammation

Tender/swollen joint count 68/66

Patient global assessment

Instrument under study

Skin assessment

PASI (if BSA ≥3%) Lesion score (erythema, ­induration, scale) BSA

Pain

Visual analogue scale or ­numerical rating scale

Physical function

HAQ/SF-36 physical function composite

Health-related quality of life

Generic Disease specific (e.g., DLQI or PsAQoL)

BSA, body surface area; DLQI, Dermatology Life Quality Index; HAQ, health assessment questionnaire; PASI, Psoriasis Assessment Severity Index; PsAQoL psoriatic arthritis quality of life; SF-36, short-form health survey.

and is considered perhaps less responsive and discriminant.38 Much work is required to develop a validated and responsive composite instrument in psoriatic arthritis.

PATHOGENESIS Many more recent studies have explored key components of disease pathogenesis, including the contribution of genetic factors, the role of infection or trauma, ­ studies

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of animal models or involved sites of disease, and the importance of components of the immune system such as ­cytokines. GENETIC FACTORS Familial clustering of psoriasis and psoriatic arthritis is well described. Twin studies in psoriasis also have shown a high rate of concordance in monozygotic twins.39 The genetic basis for this clustering has been the subject of extensive investigations in psoriasis, but has been much less well studied in psoriatic arthritis. Studies of psoriatic arthritis have often included patients as a subset of larger psoriasis cohorts, and there has been little recognition of the diversity of ­clinical phenotypes. It has long been recognized that there is a strong association between psoriasis and the HLA-C region of the major histocompatibility complex (MHC). Whether this was HLA-Cw6 itself, found in approximately 60% of psoriasis cohorts, or a region telomeric to this has been the subject of much controversy. More recently, Elder40 has definitively shown that the HLA susceptibility region for psoriasis is HLA-Cw6, often in linkage disequilibrium with other HLA-B alleles—HLA-B57, HLA-B37, and HLA-B13. The presence of HLA-Cw6 is associated with an earlier age of onset of psoriasis (type 1 disease, <40 years old) and with more extensive and severe disease. In individuals with psoriatic arthritis, the association with HLA-Cw6 is slightly weaker, whereas additional associations have been found with HLA-B27, chiefly in patients with predominant spinal disease, and with HLA-B38 and HLA-B39.41 These findings have been interpreted to suggest that the MHC association with psoriasis lies close to the HLA-C region, whereas the association with the articular manifestations more likely lies in or close to the HLA-B region. A study of a large cohort of psoriatic arthritis patients in the United Kingdom has found HLA-Cw6 to be in linkage disequilibrium with HLA-DRBI*07, and that possession of both alleles were associated with fewer involved or damaged joints (Pauline Ho, et al: personal communication, 2007). Other genes within the MHC region have been explored in psoriasis and psoriatic arthritis. Tumor necrosis factor (TNF)-α promoter polymorphisms or a gene in linkage disequilibrium with TNF-α may predispose the patient to or increase susceptibility to psoriasis and to psoriatic arthritis. One study has found further an association between the TNF-308A allele and disease progression in early psoriatic arthritis.42 Whole-genome scans in psoriasis also have identified additional non-MHC susceptibility regions, known as the PSORS regions on chromosomes 4, 6, and 17. To date, no candidate genes have been identified. Increasing evidence suggests that an additional or distinct genetic contribution is responsible for the development of psoriatic arthritis. More recent work has pointed to an MHC class I chain-related A (MICA)-A9 polymorphism, which confers additional relative risk in particular for polyarticular disease in psoriasis patients who carry Cw*0602.43 MICA-A9 polymorphism was found in linkage disequilibrium with HLA-B alleles (B*5701, B*3801). These results suggest that the MICA gene or other nearby genes may be involved in the development of psoriatic arthritis. ­Additionally, a genome scan identified a paternally

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influenced locus on chromosome 16, a region not known to be implicated in psoriasis susceptibility.44 ENVIRONMENTAL FACTORS The role of environmental factors in triggering either skin or joint disease in patients with psoriasis or psoriatic arthritis has been supported largely by clinical observations, although the mechanism is poorly understood. It has long been recognized that there is a strong association between guttate psoriasis and preceding streptococcal infections in children.45 That this association might be related to a streptococcal superantigen has been proposed. Some authors also have found bacterial antigens in synovial tissue samples from psoriatic arthritis patients, but this may be no different from noninflammatory control subjects.46 The Koebner phenomenon (see Fig. 72-1H) has been reported to occur in 52% of patients with psoriasis. The Koebner phenomenon is the development of psoriasis along the site of skin trauma. It has been proposed that trauma also may play a role in triggering episodes of joint inflammation, and the term deep Koebner phenomenon has been coined. Although the role of trauma has not been proved, in one study, 24.6% of patients reported a traumatic event before the onset of arthritis.47 Finally, a link between stress and exacerbation of psoriasis has been proposed, supported largely by clinical observational studies. A similar association may exist in psoriatic arthritis, but this has not been systematically examined. ANIMAL MODELS Although spondyloarthropathy has been detected in a variety of primates, more recent rodent models have proved helpful in deciphering pathogenic pathways. In rodents transgenic for HLA-B27 class I molecules, skin, nail, and joint features have been described that mimic some of the features of the human phenotype.48 When HLA-B27 transgenic rats were raised in a germ-free environment, they seemed to be protected from joint disease. Mice genetically lacking MHC class II also have developed skin and joint disease, but confined to the distal phalanges with skin and nail disease also on the affected digits.49 Involvement of the distal phalanges and nails also was reported in aging male DBA/1 mice from different litters that were caged together from 12 weeks.50 In these animals, dactylitis, periostitis, and ankylosing enthesitis were observed. Finally, in a more recent study, JunB protein was shown to be expressed in normal and in clinically uninvolved psoriatic skin, but expression was considerably reduced in involved psoriatic lesions.51 Epidermal deletion of JunB and c-Jun in a mouse model resulted in skin and joint disease with 100% penetrance and a clinical and histologic phenotype highly consistent with human psoriasis and psoriatic arthritis. In further experiments, the same authors showed that the joint disease, but not the skin disease, required T and B cells and intact TNF receptor 1 signaling. IMMUNOPATHOLOGY The key pathologic events in psoriatic arthritis occur in the skin, synovium, entheseal sites, and cartilage and bone. The pathobiologic features in the skin and synovium have

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been well described, but only a few studies have focused on the enthesis. In relation to cartilage and bone, more recent studies have shown the presence of osteoclasts at the cartilage-pannus junction and high numbers of circulating osteoclast precursors in the circulation of psoriatic arthritis patients. Detailed studies similar to those done in RA on the synovial-cartilage-bone interface possibly could yield valuable information regarding joint destruction in psoriatic arthritis.

factors, including TNF-α, transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF), angiopoietins (ANG-1, ANG-2), and vascular endothelial growth factor (VEGF), have been described in skin and synovial tissue.57,58 Because this expression is found at an early stage of inflammation, it may represent a primary event in psoriatic arthritis as opposed to a reaction or response to hypoxia. One possibility is that there is a genetic predisposition to endothelial activation, which results in new vessel formation and increased cellular trafficking.

Psoriasis Skin Involved psoriasis skin is characterized by epidermal hyperplasia, mononuclear leukocytes in the papillary dermis, neutrophils in the stratum corneum, and an increase in various subsets of dendritic cells.52 CD8+ T cells are the predominant T cell subset chiefly found in the epidermis, whereas dermal T cells contain a mixture of CD4+ and CD8+. Most T cells in skin lesions express the addressin, cutaneous lymphocyte antigen, in contrast to circulating T cells and T cells found in the inflamed synovium in psoriatic arthritis.53 Finally, vascular changes also are prominent in psoriasis with an impressive growth and dilation of superficial blood vessels. Psoriatic Synovium Many early studies of synovial pathology in psoriatic arthritis highlighted the presence of prominent and striking vascular changes. In the first study that compared psoriatic arthritis and RA synovial tissue, quantitative immunopathologic analysis confirmed these prominent vascular changes and found that vessel number was significantly increased in ­ psoriatic arthritis.54 Lining layer hyperplasia was less marked in psoriatic arthritis, and fewer macrophages were seen trafficking into the synovium and out to the lining layer. The number of T lymphocytes and their subsets and the number of B cells were similar to the frequency found in RA. Although neutrophil infiltration was not assessed, this study examined adhesion molecule expression further in the two patient subgroups and found E-selectin expression to be considerably reduced in psoriatic arthritis. Many of these observations have been confirmed by other authors. In a more recent study by Kruithof and coworkers,55 the synovial immunopathologic features in patients with spondyloarthropathy, including psoriatic arthritis, were compared with the features seen in RA.55 Using a semiquantitative scoring system, the authors identified many features characteristic of the spondyloarthropathy group as a whole and in the psoriatic arthritis subgroup alone. Increased vascularity, higher neutrophil numbers (also seen in involved psoriasis skin), and a higher number of infiltrating CD163+ macrophages, a marker of mature tissue macrophages, reliably distinguished spondyloarthropathy from RA. No significant differences were seen between oligoarticular versus polyarticular psoriatic arthritis. The important role of the vasculature in psoriatic arthritis pathogenesis is perhaps most elegantly shown by the large numbers of tortuous and dilated blood vessels observed through an arthroscopic view of psoriatic joints.56 An interaction of key growth factors is thought to regulate closely the new vessel formation or angiogenic process. Growth

Entheseal Sites Laloux and associates59 described the immunopathologic features of the enthesis in patients undergoing joint replacement surgery with spondyloarthropathy, including psoriatic arthritis, and compared with RA. Numbers of patients were small in this study, but there was a consistent increase in CD8+ T cell expression at the enthesis in patients with psoriatic arthritis compared with RA patients. Ultrasoundguided biopsy of five sites of acute enthesitis in early spondyloarthropathy also confirmed an inflammatory response with increased vascularity and cellular, predominantly macrophage, infiltration.60 These findings are consistent with the well-described association of psoriatic arthritis with HLA class I antigens. They also are consistent with the previously described dominance of activated and mature CD8+ T cells in psoriatic arthritis synovial fluid samples compared with RA.61 It is attractive to suggest that entheseal-derived antigens might trigger an immune response in the adjacent synovial tissue. To date, evidence for this hypothesis has not been found, although it is clearly an area for future study. A search for candidate antigens common to the enthesis and the skin might be informative. CYTOKINES Synovial explant tissues obtained from psoriatic arthritis joints have been shown to produce higher levels of the T helper type 1 cytokines interleukin (IL)-2 and interferon-γ protein than explants similarly cultured from osteoarthritis and RA patients.62 This T helper type 1 lymphocyte profile also has been observed in psoriasis plaques.63 The cytokines IL-1β and TNF-α also were released by psoriasis synovial explants in high concentrations. In contrast, IL-4 and IL-5 were not identified, but IL-10 was highly expressed in psoriatic synovium, although not in skin. A similar pattern of cytokine production in psoriatic arthritis synovium was shown using immunohistochemical and gene expression techniques.64,65 Other innate cytokines, such as IL-18 and IL-15, also are present in psoriatic arthritis synovial tissue and are downregulated by methotrexate therapy. TNF-α levels are elevated in psoriatic skin, synovium, and joint fluid of patients with psoriatic arthritis.62,66 Several lines of evidence support the concept that TNF-α is an important cytokine in the psoriatic joint. TNF-α transgenic mice exhibit extensive bone destruction similar to that observed in some psoriatic arthritis patients. In a study of 129 patients with early psoriatic arthritis, patients with erosions were significantly more likely to have the TNF-α-308 A allele, an allele associated with high TNF-α production.42 As mentioned earlier, immunohistochemical and gene expression

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studies have shown marked upregulation of ­ TNF-α in the psoriatic synovial membrane. Histopathologic analysis of synovial specimens from eight spondyloarthropathy patients, four of whom had psoriatic arthritis, treated with the antiTNF-α monoclonal antibody infliximab revealed decreased vascularity, synovial lining thickness, and mononuclear cell infiltration after therapy.67,68 In another study, a significant reduction in the quantity of infiltrating macrophages, the CD31+ vascular area, αvβ3-positive neovessels/Ulex europaeus agglutinin–positive vessels, VEGF and its receptor KDR/flk-1 (VEGFR-2), and SDF-1-positive vessels in psoriatic arthritis synovium was noted after 8 weeks (three infusions) of infliximab treatment.69 MATRIX METALLOPROTEINASES AND CARTILAGE DESTRUCTION Radiographs of psoriatic joints often reveal cartilage loss manifested as joint space narrowing. Similar to RA, matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) were identified in psoriatic arthritis synovial lining and sublining layers.70,71 In particular, immunohistochemical studies revealed that MMP-9 localized to blood vessel walls, whereas MMP-1, MMP-2, MMP-3, TIMP-1, and TIMP-2 showed a cellular and interstitial staining pattern in the synovial lining. Serum levels of MMP-3 exhibited a marked and rapid decrease after successful anti-TNF-α therapy raising the possibility that this molecule may serve as a biomarker. In another study, similar levels of MMP-1 and MMP-3 mRNA were detected in RA and psoriatic arthritis synovial tissue despite the fact that the RA patients exhibited more erosions on plain radiographs.72 The elevated ratio of MMPs to TIMP-1 in the synovial tissue favored cartilage degradation, although the expression of MMPs was not significantly elevated at the cartilage-pannus junction compared with other sites. These reports indicate that MMPs are upregulated in psoriatic arthritis synovium, but their precise functions remain to be defined. BONE REMODELING Radiographs of psoriatic arthritis joints also can reveal markedly altered bone remodeling in the form of bone resorption (tuft resorption or osteolysis, large eccentric erosions, and pencil-in-cup deformities) and new bone formation (periostitis, spur or enthesophyte formation, bony ankylosis). Important in bone resorption, psoriatic joint biopsy specimens show large multinucleated osteoclasts in deep resorption pits at the bone-pannus junction.73 Osteoclastogenesis (differentiation of monocytes into osteoclasts) is a contactdependent process directed by osteoblasts and stromal cells in the bone marrow. These cells release signals necessary for differentiation of an osteoclast precursor derived from the CD14+ monocyte population into an osteoclast. One of these signals is the receptor activator of nuclear factor κB ligand (RANKL), a member of the TNF superfamily that binds to RANK on the surface of osteoclast precursors and osteoclasts. This ligand-receptor interaction stimulates proliferation and differentiation of osteoclast precursors and activation of osteoclasts. It has been proposed that the relative expression of RANKL and of its natural antagonist osteoprotegerin ultimately controls osteoclastogenesis.

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In psoriatic arthritis synovial tissues, marked upregulation of RANKL protein and low expression of osteoprotegerin were detected in the adjacent synovial lining.73 Osteoclasts also were noted in cutting cones traversing the subchondral bone supporting a bidirectional attack on the bone in psoriatic joints. In addition, osteoclast precursors, derived from circulating CD14+ monocytes, were markedly elevated in the peripheral blood of patients with psoriatic arthritis compared with healthy controls. Treatment of patients with psoriatic arthritis with anti-TNF-α agents significantly decreased the level of circulating osteoclast precursor, supporting a central role for TNF-α in the generation of this precursor population. The mechanisms responsible for new bone formation in the psoriatic joint are poorly understood. TGF-β and VEGF may be pivotal in this process given that TGF-β is strongly expressed in synovial tissues isolated from patients with ankylosing spondylitis and synergizes with VEGF to induce bone formation in animal models.74 De Klerck and colleagues75 showed that the bone morphogenetic proteins (BMPs) BMP-2 and BMP-7 are upregulated in regions of pathologic new bone formation. The same investigators showed that the expression of phosphorylated Smad-1 and Smad-5, important signaling molecules downstream of BMP, was markedly increased in regions of new bone formation taken from the calcaneus in a patient with Achilles tendinitis and periostitis. These studies provide evidence that potential mediators of ankylosis and periostitis in the psoriatic enthesis and joint include BMP molecules and possibly VEGF and TGF-β. SUMMARY In considering a model for disease pathogenesis in psoriatic arthritis, we have to try to take into account the genetic susceptibility; the role of the environment; cellular immunologic mechanisms; and secreted cytokines, chemokines, and other proteins. For some time, the primary hypothesis has been that psoriatic arthritis is an HLA class I–restricted, antigen-driven immune process (Fig. 72-10). Considerable evidence has been presented to support this hypothesis; however, despite careful analysis of T cell receptor phenotype, no antigen-driven process other than that driven by Epstein-Barr virus has been identified.75a The potential role of components of the innate immune response, such as Toll-like receptors or cells bearing natural killer receptors, is currently under active investigation. It is possible that the interaction of environmental factors, such as those derived from pathogens or expressed after trauma, with Tolllike receptors in a genetically susceptible individual may set in train intracellular signaling events leading to cytokine release, immune activation, and release of destructive enzymes such as MMPs (Fig. 72-11).

TREATMENT In considering treatment strategies for psoriatic arthritis, the diverse nature of the clinical phenotype (peripheral arthritis, skin and nail disease, axial disease, dactylitis and enthesitis) may complicate therapeutic decisions because not all treatments are effective for all of the features, and patients often display a mixture of all of the features

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MHC Class II CD4 T cell

MHC Class I

CD4 TCR

Ag

APC

CD8 CD8 T cell

Ag TCR

IL-1 TNF-α IL-8 IL-10 IL-15 IFN-γ

Pathogenesis of Psoriatic Arthritis

IL-5 IL-10 IL-18

Angiogenesis Cellular trafficking

CD4+ T cells

Lymphocytes, PMNs Macrophages,

FVIII+ vessels

Clinical joint disease Figure 72-10  Traditional disease pathogenesis model in psoriatic arthritis. APC, antigen-presenting cell; IFN, interferon; IL, interleukin; PMNs, polymorphonuclear neutrophils; TCR, T cell receptor; TNF, tumor necrosis factor. Exo/endogenous ligand, e.g., bacterial peptide, stress related

TLR activation

Figure 72-11  Alternative model incorporating new disease pathogenesis concepts. TLR, Toll-like receptor.

Modulation of transcription factors, e.g., AP-1 and chemokine/ cytokine release

Genetically primed

s­ imultaneously. GRAPPA published a systematic review of the evidence for treatment strategies in psoriatic arthritis, and this review provides treatment guidelines that are currently being devised. The reader is referred to this GRAPPA publication for a detailed review of the evidence; Figure 72-12 is a proposed preliminary algorithm for treatment choices.76 Treatment choices may be driven by the disease feature considered most severe at the time of the evaluation. Finally, in reviewing the evidence for therapeutic effect presented next, the recommendations from the Agency for

Health Care Policy Research were used where interventions are scored by categories of evidence (level 1 through 4) and strength of recommendation (grade A through D).77 TRADITIONAL AGENTS Although there is little published evidence of a favorable therapeutic effect in psoriatic arthritis, nonsteroidal antiinflammatory drugs are most often the agents first used in psoriatic arthritis whatever the clinical phenotype (level 1b,

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Peripheral Arthritis

Initiate therapy NSAIDs, IA Steroids DMARDs (MTX, CsA, SSZ, LEF), Biologics (anti-TNF)

Skin and Nail Disease

Initiate therapy Topicals PUVA/UVB DMARDs (MTX, CsA, etc) Biologics (anti-TNF, etc)

Axial Disease

Initiate therapy NSAID PT Biologics (anti-TNF)

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Dactylitis

Initiate therapy NSAID Injection Biologics (anti-TNF)

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Enthesitis

Initiate therapy NSAID Injection Biologics (anti-TNF)

Reassess Response to Therapy and Toxicity Figure 72-12  Preliminary treatment algorithm for the various clinical manifestations in psoriatic arthritis. (From Kavanaugh AF, Ritchlin CT: Systematic review of treatments for psoriatic arthritis: An evidence based approach and basis for treatment guidelines. J Rheumatol 33:1417-1421, 2006.)

grade A).78 Expert opinion supports use of nonsteroidal anti-inflammatory drugs, although occasional exacerbations of psoriasis have been reported. The use of systemic corticosteroids is not evidence-based (level 4, grade D), although 24% of patients in one study were taking prednisolone.79 There are concerns that exacerbations of psoriasis may follow corticosteroid withdrawal. There have been no randomized controlled trials of intra-articular steroids in psoriatic arthritis or of local entheseal or dactylitis injections. Expert opinion indicates that intra-articular steroids can be quite effective, especially in oligoarticular disease or where there is localized entheseal involvement, such as in plantar fasciitis (level 4, grade D). Mild skin disease (PASI <10) is usually controlled with topical steroids or vitamin D derivatives, with the latter best used for maintenance therapy.80 Systemic therapy is considered in patients with three or more inflamed joints despite conventional therapy as described previously; persistent or treatment-resistant axial, entheseal, or dactylitic disease especially where multiple sites are involved; or moderate or severe psoriasis (PASI >10). Randomized controlled trials of disease-modifying antirheumatic drugs (DMARDs) are few and limited by size. Based on evidence and expert opinion, nearly all DMARDs may have small-to-moderate beneficial effects on peripheral joints, enthesitis, and dactylitis.78,81,82 Axial features and nail disease do not seem to respond.83 Good or moderate improvements in skin disease have been reported with some of the older systemic agents, such as methotrexate, cyclosporine, sulfasalazine, leflunomide, and acetretin (all level 1b, grade A).80 The best evidence for DMARD use comes from studies of peripheral joint disease and of psoriasis. There have been six randomized controlled trials of sulfasalazine in psoriatic arthritis (level 1a, grade A), the largest including 221 patients. Fifty-nine percent of patients achieved a therapeutic response (PsARC), but in keeping with other studies a high therapeutic response (42.7%) also was noted in placebo-treated patients.38 Methotrexate remains for many rheumatologists the DMARD of first choice for patients with psoriatic arthritis, but evidence for its use is limited (level 3, grade B). A small,

prospective randomized controlled trial concluded that methotrexate was as effective as cyclosporine, and a more recent study of 72 patients with active psoriatic arthritis and an incomplete response to methotrexate, in which cyclosporine was added in, showed significant differences only in synovitis as detected by MSUS and PASI score in favor of the combination therapy.26,84 Although evidence for methotrexate is lacking, an open study reported significant reductions in synovial cellular infiltration and in cytokine gene expression after 3 months of therapy.65 Although there is evidence that cyclosporine may be as effective as methotrexate, its use is limited because its toxicity profile is considered to be high (level 1b, grade B).85 Perhaps the best randomized controlled trial in psoriatic arthritis of a DMARD is with leflunomide (level 1b, grade A).86 This trial included 190 patients who received either leflunomide or placebo for 24 weeks. Fifty-nine percent of patients treated with leflunomide compared with 30% of patients given placebo met the primary response criteria (PsARC) with significant, although small improvements in other individual parameters, including joint scores, health assessment questionnaire, PASI, and Dermatology Life Quality Index. Regarding some older DMARDs, such as gold salts and antimalarials, there is no evidence of treatment benefit; exacerbation of psoriasis is reported, and they cannot be recommended. One small randomized controlled trial with azathioprine suggested benefit with a reduction in Ritchie score (level 2b, grade B). Finally, apart from the cyclosporine/methotrexate study referred to earlier, there is little or no evidence that DMARD combination therapy is either beneficial or safe in psoriatic arthritis. With the exception of psoriasis, there is a paucity of evidence that DMARDs are beneficial for the other features of psoriatic arthritis, including dactylitis, axial disease, or enthesitis. The absence of evidence does not mean the absence of an effect, however. Further randomized controlled trials specifically examining these features in psoriatic arthritis are required. In psoriasis, methotrexate and cyclosporine have been shown to be highly and probably equally effective (level 1b, grade A).80 Adverse effects, in particular with cyclosporine, may limit usage in some patients.

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BIOLOGICS The approach to treatment in psoriatic arthritis has changed considerably with the introduction of biologic therapies. As a result of numerous large, well-conducted, randomized controlled trials, there is now accumulating evidence that anti-TNF treatments are effective in controlling peripheral arthritis symptoms and signs, improving quality of life, and preventing radiologic progression (overall level 1b, grade A).78 Patients receiving 25 mg subcutaneously twice weekly of etanercept had significant improvements in ACR-20 responses (59% versus 15%) at 12 weeks compared with placebo.87 At 12 months, radiographic disease progression (modified total Sharp score) was inhibited in the etanercept group (−0.03 unit) compared with worsening of +1.00 unit in the placebo group. Although the anti-TNF therapies have not been compared in any study, the effect on peripheral arthritis seems to be similar. There also is evidence that anti-TNF therapies are effective for other disease features, such as nail disease, enthesitis, and dactylitis.81,82,88 These studies are limited by the absence of a validated instrument to measure these features. With psoriasis, the effects of anti-TNF therapies can be quite dramatic.89 In particular with the antibody therapy, highly significant improvements in PASI scores were achieved (e.g., PASI = 75 in 59% of adalimumab-treated patients versus 1% of placebo-treated patients after 24 weeks, and PASI = 90 in 50%).90 Alefacept is a fusion protein of soluble lymphocyte function antigen 3 with Fc fragments of IgG1. Alefacept was the first biologic agent approved for moderate-to-severe psoriasis (level 1b, grade A). Efficacy was dose dependent and slow, but PASI = 75 was achieved in 33% of patients at some point.91 More recently, alefacept in combination with methotrexate was evaluated in 185 patients with active psoriatic arthritis.92 At 6 months, 54% of alefacept-treated patients versus 23% of placebo-treated patients achieved an ACR-20 response. Finally, efalizumab, a humanized monoclonal antibody targeting the CD11a component of lymphocyte function antigen 1, also has been approved for

Future Directions The surge of interest in new therapies for psoriatic ­arthritis is most welcome, in particular for patients with poor prognostic features (polyarticular disease, elevated erythrocyte sedimentation rate, dactylitis, and progressive change on radiograph) who fail to respond to standard treatment approaches. Much additional research on ­ currently available agents and on new treatments is ­ required. New instruments to measure key outcome ­domains, such as enthesitis, need to be developed and validated, and comparisons of newer agents with standard DMARDs, such as methotrexate, are required to inform treatment decisions. GRAPPA is currently developing treatment guidelines based on current evidence, but there are many gaps in our knowledge, and expert opinion is the best available guide in many situations. It is hoped, however, that guidelines or recommendations can be agreed on that would help inform the physician when treating ­psoriatic arthritis and its diverse clinical manifestations.

psoriasis with PASI = 75 achieved in 22% to 39% in randomized controlled trials.89 To date, there is no evidence for beneficial effect of efalizumab in other psoriatic arthritis disease manifestations. REFERENCES   1. Wright V: Rheumatism and psoriasis: A re-evaluation. Am J Med 27:454-462, 1959.   2. Moll JMH, Wright V: Psoriatic arthritis. Semin Arthritis Rheum 3: 55-78, 1973.   3. Blumberg BS, Bunim JJ, Calkins E, et al: ARA nomenclature and classification of arthritis and rheumatism (tentative). Arthritis Rheum 7:93-97, 1964.   4. Gladman DD, Antoni C, Mease P, et al: Psoriatic arthritis: Epidemiology, clinical features, course, and outcome. Ann Rheum Dis 64(Suppl 2):ii-14-ii-17, 2005.   5. Krueger G, Ellis CN: Psoriasis—recent advances in understanding its pathogenesis and treatment. J Am Acad Dermatol 53(Suppl 1): S94-S100, 2005.   6. Gelfand JM, Gladman DD, Mease PJ, et al: Epidemiology of psoriatic arthritis in the population of the United States. J Am Acad Dermatol 53:573, 2005.   7. Kay L, Perry-James J, Walker D: The prevalence and impact of psoriasis in the primary care population in northeast England. Arthritis Rheum 42:S299, 1999.   8. Shbeeb M, Uramoto KM, Gibson LE, et al: The epidemiology of psoriatic arthritis in Olmsted County, Minnesota, USA, 1982-1991. J Rheumatol 27:1247-1250, 2000.   9. Savolainen E, Kaipiainen-Seppanen O, Kroger L, et al: Total incidence and distribution of inflammatory joint diseases in a defined population: Results from the Kuopio 2000 arthritis survey. J Rheumatol 30: 2460-2468, 2003. 10. Gladman DD, Shuckett R, Russell ML, et al: Psoriatic arthritis (PSA)—an analysis of 220 patients. QJM 62:127-141, 1987. 11. Moll JMH, Wright V: Familial occurrence of psoriatic arthritis. Ann Rheum Dis 22:181-195, 1973. 12. Kane D, Stafford L, Bresnihan B, et al: A prospective, clinical and radiological study of early psoriatic arthritis: An early synovitis clinic experience. Rheumatology (Oxf) 42:1460-1468, 2003. 13. Helliwell PS, Porter G, Taylor WJ: Polyarticular psoriatic arthritis is more like oligoarticular psoriatic arthritis, than rheumatoid arthritis. Ann Rheum Dis 66:113-117, 2007. 14. Battistone MJ, Manaster BJ, Reda DJ, et al: The prevalence of sacroilitis in psoriatic arthritis: New perspectives from a large, multicenter cohort. A Department of Veterans Affairs Cooperative Study. Skeletal Radiol 28:196-201, 1999. 15. Brockbank JE, Stein M, Schentag CT, et al: Dactylitis in psoriatic arthritis: A marker for disease severity? Ann Rheum Dis 64:188-190, 2005. 16. Kane D, Greaney T, Bresnihan B, et al: Ultrasonography in the diagnosis and management of psoriatic dactylitis. J Rheumatol 26: 1746-1751, 1999. 17. Olivieri I, Barozzi L, Pierro A, et al: Toe dactylitis in patients with spondyloarthropathy: Assessment by magnetic resonance imaging. J Rheumatol 24:926-930, 1997. 18. Queiro R, Torre JC, Belzunegui J, et al: Clinical features and predictive factors in psoriatic arthritis-related uveitis. Semin Arthritis Rheum 31:264-270, 2002. 19. Schatteman L, Mielants H, Veys EM, et al: Gut inflammation in psoriatic arthritis: A prospective ileocolonoscopic study. J Rheumatol 22:680-683, 1995. 20. Williamson L, Dockerty JL, Dalbeth N, et al: Gastrointestinal disease and psoriatic arthritis. J Rheumatol 31:1469-1470, 2004. 21. Cantini F, Salvarani C, Olivieri I, et al: Distal extremity swelling with pitting edema in psoriatic arthritis: A case-control study. Clin Exp Rheumatol 19:291-296, 2001. 22. Korendowych E, Owen P, Ravindran J, et al: The clinical and genetic associations of anti-cyclic citrullinated peptide antibodies in psoriatic arthritis. Rheumatology (Oxf) 44:1056-1060, 2005. 23. Gladman DD, Farewell VT, Nadeau C: Clinical indicators of progression in psoriatic arthritis: Multivariate relative risk model. J Rheumatol 22:675-679, 1995.

PART 10  24. Karim Z, Wakefield RJ, Quinn M, et al: Validation and reproducibility of ultrasonography in the detection of synovitis in the knee: A comparison with arthroscopy and clinical examination. Arthritis Rheum 50:387-394, 2004. 25. Wakefield RJ, Green MJ, Marzo-Ortega H, et al: Should ­oligoarthritis be reclassified? Ultrasound reveals a high prevalence of subclinical ­disease. Ann Rheum Dis 63:382-385, 2004. 26. Fraser AD, van Kuijk AW, Westhovens R, et al: A randomised, double blind, placebo controlled, multicentre trial of combination therapy with methotrexate plus cyclosporine in patients with active psoriatic arthritis. Ann Rheum Dis 64:859-864, 2005. 27. Balint PV, Sturrock RD: Inflamed retrocalcaneal bursa and Achilles tendonitis in psoriatic arthritis demonstrated by ultrasonography. Ann Rheum Dis 59:931-933, 2000. 28. D’Agostino MA, Said-Nahal R, Hacquard-Bouder C, et al: Assessment of peripheral enthesitis in the spondylarthropathies by ultrasonography combined with power Doppler: A cross-sectional study. Arthritis Rheum 48:523-533, 2003. 29. Balint PV, Kane D, Wilson H, et al: Ultrasonography of entheseal insertions in the lower limb in spondyloarthropathy. Ann Rheum Dis 61:905-910, 2002. 30. McGonagle D, Conaghan PG, Emery P: Psoriatic arthritis: A unified concept twenty years on. Arthritis Rheum 42:1080-1086, 1999. 31. Taylor W, Gladman D, Helliwell P, et al: Classification criteria for psoriatic arthritis: Development of new criteria from a large international study. Arthritis Rheum 54:2665-2673, 2006. 32. Harrison BJ, Silman AJ, Barrett EM, et al: Presence of psoriasis does not influence the presentation or short-term outcome of patients with early inflammatory polyarthritis. J Rheumatol 24:1744-1749, 1997. 33. Jones SM, Armas JB, Cohen MG, et al: Psoriatic arthritis: Outcome of disease subsets and relationship of joint disease to nail and skin disease. Br J Rheumatol 33:834-839, 1994. 34. Punzi L, Pianon M, Rossini P, et al: Clinical and laboratory manifestations of elderly onset psoriatic arthritis: A comparison with younger onset disease. Ann Rheum Dis 58:226-229, 1999. 35. Khan M, Schentag C, Gladman DD: Clinical and radiological changes during psoriatic arthritis disease progression. J Rheumatol 30: 1022-1026, 2003. 36. Torre Alonso JC, Rodriguez Perez A, Arribas Castrillo JM, et al: Psoriatic arthritis (PA): A clinical, immunological and radiological study of 180 patients. Br J Rheumatol 30:245-250, 1991. 37. Hanly JG, Russell ML, Gladman DD: Psoriatic spondyloarthropathy: A long term prospective study. Ann Rheum Dis 47:386-393, 1988. 38. Clegg DO, Reda DJ, Mejias E, et al: Comparison of sulfasalazine and placebo in the treatment of psoriatic arthritis. A Department of Veterans Affairs Cooperative Study. Arthritis Rheum 39:2013-2020, 1996. 39. Eastmond CJ: Psoriatic arthritis: Genetics and HLA antigens. Baillieres Clin Rheumatol 8:263-276, 1994. 40. Elder JT: PSORS1: Linking genetics and immunology. J Invest Dermatol 126:1205-1206, 2006. 41. Gladman DD, Farewell VT: The role of HLA antigens as indicators of disease progression in psoriatic arthritis: Multivariate relative risk model. Arthritis Rheum 38:845-850, 1995. 42. Balding J, Kane D, Livingstone W, et al: Cytokine gene polymorphisms: Association with psoriatic arthritis susceptibility and severity. Arthritis Rheum 48:1408-1413, 2003. 43. Gonzalez S, Martinez-Borra J, Lopez-Vazquez A, et al: MICA rather than MICB, TNFA, or HLA-DRB1 is associated with susceptibility to psoriatic arthritis. J Rheumatol 29:973-978, 2002. 44. Karason A, Gudjonsson JE, Upmanyu R, et al: A susceptibility gene for psoriatic arthritis maps to chromosome 16q: Evidence for imprinting. Am J Hum Genet 72:125-131, 2003. 45. Rasmussen JE: The relationship between infection with group A beta hemolytic streptococci and the development of psoriasis. Pediatr Infect Dis J 19:153-154, 2000. 46. Wilbrink B, van der Heijden IM, Schouls LM, et al: Detection of bacterial DNA in joint samples from patients with undifferentiated arthritis and reactive arthritis, using polymerase chain reaction with universal 16S ribosomal RNA primers. Arthritis Rheum 41:535-543, 1998. 47. Langevitz P, Buskila D, Gladman DD: Psoriatic arthritis precipitated by physical trauma. J Rheumatol 17:695-697, 1990. 48. Yanagisawa H, Richardson JA, Taurog JD, et al: Characterization of psoriasiform and alopecic skin lesions in HLA-B27 transgenic rats. Am J Pathol 147:955-964, 1995.

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49. Bardos T, Zhang J, Mikecz K, et al: Mice lacking endogenous major histocompatibility complex class II develop arthritis resembling psoriatic arthritis at an advanced age. Arthritis Rheum 46:2465-2475, 2002. 50. Lories RJ, Matthys P, de Vlam K, et al: Ankylosing enthesitis, dactylitis, and onychoperiostitis in male DBA/1 mice: A model of psoriatic arthritis. Ann Rheum Dis 63:595-598, 2004. 51. Zenz R, Eferl R, Kenner L, et al: Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature 437:369-375, 2005. 52. Bos JD, de Rie MA, Teunissen MB, et al: Psoriasis: Dysregulation of innate immunity. Br J Dermatol 152:1098-1107, 2005. 53. Pitzalis C, Cauli A, Pipitone N, et al: Cutaneous lymphocyte antigenpositive T lymphocytes preferentially migrate to the skin but not to the joint in psoriatic arthritis. Arthritis Rheum 39:137-145, 1996. 54. Veale D, Yanni G, Rogers S, et al: Reduced synovial membrane macrophage numbers, ELAM-1 expression, and lining layer hyperplasia in psoriatic arthritis as compared with rheumatoid arthritis. Arthritis Rheum 36:893-900, 1993. 55. Kruithof E, Baeten D, De Rycke L, et al: Synovial histopathology of psoriatic arthritis, both oligo- and polyarticular, resembles spondyloarthropathy more than it does rheumatoid arthritis. Arthritis Res Ther 7:R569-R580, 2005. 56. Reece RJ, Canete JD, Parsons WJ, et al: Distinct vascular patterns of early synovitis in psoriatic, reactive, and rheumatoid arthritis. Arthritis Rheum 42:1481-1484, 1999. 57. Fearon U, Griosios K, Fraser A, et al: Angiopoietins, growth factors, and vascular morphology in early arthritis. J Rheumatol 30:260-268, 2003. 58. Leong TT, Fearon U, Veale DJ: Angiogenesis in psoriasis and psoriatic arthritis: Clues to disease pathogenesis. Curr Rheumatol Rep 7: 325-329, 2005. 59. Laloux L, Voisin MC, Allain J, et al: Immunohistological study of entheses in spondyloarthropathies: Comparison in rheumatoid arthritis and osteoarthritis. Ann Rheum Dis 60:316-321, 2001. 60. McGonagle D, Marzo-Ortega H, O’Connor P, et al: Histological assessment of the early enthesitis lesion in spondyloarthropathy. Ann Rheum Dis 61:534-537, 2002. 61. Costello P, Bresnihan B, O’Farrelly C, et al: Predominance of CD8+ T lymphocytes in psoriatic arthritis. J Rheumatol 26:1117-1124, 1999. 62. Ritchlin C, Haas-Smith SA, Hicks D, et al: Patterns of cytokine production in psoriatic synovium. J Rheumatol 25:1544-1552, 1998. 63. Austin LM, Ozawa M, Kikuchi T, et al: The majority of epidermal T cells in psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: A type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol 113:752-759, 1999. 64. Danning CL, Illei GG, Hitchon C, et al: Macrophage-derived cytokine and nuclear factor kappaB p65 expression in synovial membrane and skin of patients with psoriatic arthritis. Arthritis Rheum 43: 1244-1256, 2000. 65. Kane D, Gogarty M, O’Leary J, et al: Reduction of synovial sublining layer inflammation and proinflammatory cytokine expression in psoriatic arthritis treated with methotrexate. Arthritis Rheum 50: 3286-3295, 2004. 66. Partsch G, Steiner G, Leeb BF, et al: Highly increased levels of tumor necrosis factor-alpha and other proinflammatory cytokines in psoriatic arthritis synovial fluid. J Rheumatol 24:518-523, 1997. 67. Baeten D, Kruithof E, Van den Bosch F, et al: Immunomodulatory effects of anti-tumor necrosis factor alpha therapy on synovium in spondylarthropathy: Histologic findings in eight patients from an open-label pilot study. Arthritis Rheum 44:186-195, 2001. 68. Kruithof E, De Rycke L, Roth J, et al: Immunomodulatory effects of etanercept on peripheral joint synovitis in the spondylarthropathies. Arthritis Rheum 52:3898-3909, 2005. 69. Canete JD, Pablos JL, Sanmarti R, et al: Antiangiogenic effects of anti-tumor necrosis factor alpha therapy with infliximab in psoriatic arthritis. Arthritis Rheum 50:1636-1641, 2004. 70. Ribbens C, Martin y Porras M, et al: Increased matrix metalloproteinase-3 serum levels in rheumatic diseases: Relationship with synovitis and steroid treatment. Ann Rheum Dis 61:161-166, 2002. 71. Vandooren B, Kruithof E, Yu DT, et al: Involvement of matrix metalloproteinases and their inhibitors in peripheral synovitis and down-regulation by tumor necrosis factor alpha blockade in spondylarthropathy. Arthritis Rheum 50:2942-2953, 2004.

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72.  Kane D, Jensen LE, Grehan S, et al: Quantitation of metalloproteinase gene expression in rheumatoid and psoriatic arthritis synovial tissue distal and proximal to the cartilage-pannus junction. J Rheumatol 31:1274-1280, 2004. 73.  Ritchlin CT, Haas-Smith SA, Li P, et al: Mechanisms of TNF­alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Invest 111:821-831, 2003. 74.  Peng H, Wright V, Usas A, et al: Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. J Clin Invest 110:751-759, 2002. 75.  De Klerck B, Carpentier I, Lories RJ, et al: Enhanced osteoclast development in collagen-induced arthritis in interferon-gamma receptor knock-out mice as related to increased splenic CD11b+ myelopoiesis. Arthritis Res Ther 6:R220-R231, 2004. 75a. Curran SA, Fitzgerald OM, Costello PJ, et al: Nucleotide sequencing of psoriatic arthritis tissue before and during methotrexate administration reveals a complex inflammatory T cell infiltrate with very few clones exhibiting features that suggest they drive the inflammatory process by recognizing autoantigens. J Immunol 172:1935-1944, 2004. 76.  Kavanaugh AF, Ritchlin CT: Systematic review of treatments for psoriatic arthritis: An evidence based approach and basis for treatment guidelines. J Rheumatol 33:1417-1421, 2006. 77.  Shiffman RN, Shekelle P, Overhage JM, et al: Standardized reporting of clinical practice guidelines: A proposal from the Conference on Guideline Standardization. Ann Intern Med 139:493-498, 2003. 78.  Soriano ER, McHugh NJ: Therapies for peripheral joint disease in psoriatic arthritis: A systematic review. J Rheumatol 33:1422-1430, 2006. 79.  Grassi W, De Angelis R, Cervini C: Corticosteroid prescribing in rheumatoid arthritis and psoriatic arthritis. Clin Rheumatol 17: 223-226, 1998. 80.  Strober BE, Siu K, Menon K: Conventional systemic agents for psoriasis: A systematic review. J Rheumatol 33:1442-1446, 2006.

81. Ritchlin CT: Therapies for psoriatic enthesopathy: A systematic review. J Rheumatol 33:1435-1438, 2006. 82. Helliwell PS: Therapies for dactylitis in psoriatic arthritis: A systematic review. J Rheumatol 33:1439-1441, 2006. 83. Nash P: Therapies for axial disease in psoriatic arthritis: A systematic review. J Rheumatol 33:1431-1434, 2006. 84. Spadaro A, Riccieri V, Sili-Scavalli A, et al: Comparison of cyclosporin A and methotrexate in the treatment of psoriatic arthritis: A one-year prospective study. Clin Exp Rheumatol 13:589-593, 1995. 85. Mihatsch MJ, Wolff K: Consensus conference on cyclosporin A for psoriasis, February 1992. Br J Dermatol 126:621-623, 1992. 86. Kaltwasser JP, Nash P, Gladman D, et al: Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: A multinational, double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum 50:1939-1950, 2004. 87. Mease P.J., Kivitz A.J., Burch F.X., et al: Etanercept treatment of psoriatic arthritis: Safety, efficacy, and effect on disease progression. Arthritis Rheum 50:2264-2272, 2004. 88. Cassell S, Kavanaugh AF: Therapies for psoriatic nail disease: A systematic review. J Rheumatol 33:1452-1456, 2006. 89. Boehncke WH, Prinz J, Gottlieb AB: Biologic therapies for psoriasis: A systematic review. J Rheumatol 33:1447-1451, 2006. 90. Mease PJ, Gladman DD, Ritchlin CT, et al: Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: Results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum 52:3279-3289, 2005. 91. Lebwohl M, Christophers E, Langley R, et al: An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol 139:719-727, 2003. 92. Mease PJ, Gladman DD, Keystone EC: Alefacept in combination with methotrexate for the treatment of psoriatic arthritis: Results of a randomized, double-blind, placebo-controlled study. Arthritis Rheum 54:1638-1645, 2006.

73

Enteropathic Arthritis Frank A. Wollheim

KEY POINTS The gut microflora (biota) is essential for early childhood development and maintenance of adult health. Loss of normal tolerance causes diseases such as asthma and inflammatory bowel disease (IBD). The gut-associated lymphoid tissue is the largest immune organ in the body, disseminating cells to other organs, including the joints. These lymphocytes produce protective secretory immunoglobulin (Ig) A and IgM but also leak complement-binding IgG, mediating both local protection and inflammation. Genetic polymorphism causes impaired defense to microbes in Crohn’s disease. Peripheral and central joint disease in IBD is determined by different genes on several chromosomes. HLA-B27 contributes to the pathogenesis of enteric reactive arthritis by molecular mechanisms that involve misfolding and are unrelated to antigen recognition. Aggressive antibiotic therapy is of no benefit. Celiac disease has been underdiagnosed in adults and is associated with arthritis in 25% of patients. Whipple’s disease induces a reduced T helper type 1 response against the agent. Joint complaints are the presenting symptom in two thirds of patients. Microscopic colitis is an underdiagnosed entity in elderly women, and chronic arthritides are overrepresented in collagenous colitis.

Enteropathic arthritis is the name given to several different conditions in which pathology in the gut and the musculoskeletal system dominates. It was realized centuries ago that dysentery was sometimes followed by arthritis, a condition now known as reactive arthritis. Inflammatory bowel disease (IBD) and reactive arthritis are the dominant entities discussed in this chapter. The gut has three major biologic functions: it is a barrier against hostile factors in the environment, it has an obvious role in nutrition and in the excretion of waste, and it has major trophic functions in the host. The gut is constantly exposed to living and dead antigenic material, and 25% of it consists of lymphoid tissue. The gut is a privileged tissue, in that it is tolerant of food constituents and most microbes. Tolerance, however, is not a passive process; it involves active host immune responses.1 Disturbances in these responses result in signs and symptoms, such as food allergy or IBD (Fig. 73-1). The generation of arthritis is at

the core of this chapter, and different mechanisms are operative, many of which are still elusive.

GUT BIOLOGY PHYSIOLOGY The gut has an estimated surface area of 300 to 400 m2, which is 200 times the body’s skin surface area. Molecules smaller than 5000 daltons can pass through the epithelial membranes of the microvilli, whereas larger molecules can enter Peyer’s patches by endocytosis. Altered gut permeability can be observed in several diseases; the causes are genetic in part but are triggered by exogenous factors such as drugs and microorganisms.3 Oral feeding of lactalbumin, lactoglobulin, polyethylene glycol particles, 51Cr-labeled EDTA, and sugars such as lactulose and mannitol, followed by urinalysis, is used to quantify pathologic changes, including changes in permeability and absorptive mechanisms. In addition, intestinal permeability and function can be studied by regional perfusion with the help of endoscopic techniques that close off segments of the gut with inflatable balloons.4 A recent study applying enzyme-linked ­immunosorbent assays to fluid collected by this technique showed marked local immunity to a number of food-related antigens in patients with rheumatoid arthritis.5 Ethnic differences in gut permeability have also been described.6 The healthy gut harbors a mixture of native bacteria acquired at birth or shortly thereafter that retains a relatively constant composition; it also has a smaller population of transient bacteria of varying composition. The former are essential for health and live in symbiosis; the latter contain potential pathogens. Whereas the stomach and duodenum normally contain less than 103 mucosa-adhering bacteria, the number of bacteria increases to 104 in the jejunum and 107 in the ileum. Most of this last group are gram-negative aerobic species. In the colon, the bacterial density is 1012 or more, consisting mostly of anaerobic bacteria. Transit time is fast in the upper gut and slow in the distal gut, but the immunologic impact of the microflora is higher in the proximal parts of the gut.7 The trophic functions of the gut require this microflora, as demonstrated by host defects in germ-free animals. Bacteria digest food carbohydrates into short-chain fatty acids, which facilitates the absorption of Ca2+, Mg2+, and Fe2+ ions, and they synthesize amino acids and vitamins and secrete antibacterial protective substances. Commensal bacteria also produce immunomodulatory saccharides that regulate the T helper type 1 (Th1)–T helper type 2 (Th2) balance. Some 300 to 500 different species are represented, and the composition is unique for each individual. Some of the common colonic species and their functions are shown in Figure 73-2.7

  Supplemental images available on the Expert Consult Premium Edition website.

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Commensal microbes

Food

Harmful pathogenic effects

1011cfu/g

Gut immune privilege

Bacteroides

Intestinal epithelial barrier Phagocytic innate immune cells Tolerogenic antigen-presenting cells Regulatory adaptive immune cells

Eubacteria

Tolerance to dietary antigen (oral tolerance)

Tolerance to microbiome (maintaining gut homeostasis)

Potential for: Translocation Putrefaction Production of toxins Production of carcinogens

Health-promoting effects

Bifidobacteria Potential for: Lower intestinal gas production Peptostreptococci Short chain fatty and ruminococci acids Immunostimulation Clostridia Antitumor activity Lactobacilli

Dysregulation of mucosal homeostasis Inflammatory bowel disease

Food allergy

Th2

Th2

B

Enterobacteria

UC NK-T

CD Th1

IgE

IL-4, IL-13

Sulfate reducers and fusobacteria Veillonellae Staphylococci

IL-4, IL-13

IFN-γ, TNF-α

Figure 73-1  Immune privilege in the gut. CD, Crohn’s disease; IFN, in­ terferon; IL, interleukin; UC, ulcerative colitis. (From Iweala OI, Nagler CR: ­Immune privilege in the gut: The establishment and maintenance of non­responsiveness to dietary antigens and commensal flora. Immunol Rev 213:82-100, 2006.)

GUT-ASSOCIATED LYMPHOID TISSUE Gut-associated lymphoid tissue (GALT) is the largest lymphoid organ of the body, constituting 25% of the mucosal mass. GALT components are found in Peyer’s plaques, gut lymphoid follicles, lamina propria, and intraepithelial T cells. The epithelial glycoprotein called secretory component or polymeric immunoglobulin receptor is a 100-kD transmembrane receptor for polymeric immunoglobulin, that is, J chain–containing immunoglobulin (Ig) A and IgM. It is abundantly present in Peyer’s patches in the distal ileum. It forms complexes—secretory IgA and, to some extent, secretory IgM—that are secreted into the lumen and constitute a noninflammatory, non–complement-­binding first line of defense. It is estimated that a healthy adult secretes 3 to 5 g of secretory IgA into the gut daily (Fig. 73-3). Breastfeeding provides the newborn with secretory IgA and IgM, which confers passive protection and also regulates much of the child’s immune system (Fig. 73-4). From the Peyer’s patches, primed B lymphocytes disseminate throughout the body’s mucous membranes, notably to other parts of the alimentary tract. Primed T lymphocytes also disseminate into the circulation and lymph nodes and home into target organs, such as salivary glands (in Sjögren’s disease), lungs, and synovium.8 Vascular adhesion protein-1 (VAP-1) expressed on synovial epithelial cells is involved in lymphocyte homing, and P-selectin is a part of macrophage recruitment. VAP-1 is a bifunctional glycoprotein with both adhesive and oxidative properties.9 The inhibition of this molecule may become a target in the treatment of enteropathic arthritis. Most T lymphocytes in the ­mucosal lamina

104cfu/g Figure 73-2  Physiologic roles of the intestinal microflora. (From Guarner F: Enteric flora in health and disease. Digestion 73(Suppl 1):5-12, 2006.)

propria are CD4+, whereas intraepithelial T cells are mostly CD8+. Gut-associated lymphocytes preferentially express the integrins α4β7 and αEβ7 and the integrin receptor CCR9 upon stimulation by intestinal dendritic cells.9 A chain of events in the pathogenesis of enteropathic arth­ritis can begin with ­ gastrointestinal infection with the appropriate ­microorganism in a genetically predisposed patient. This causes local inflammation in the gut mucosa, formation of secretory IgA, increased permeability, absorption of foreign material, and triggering of T lymphocytes. Circulating immune complexes and memory T cells localize to joints and cause synovitis (Fig. 73-5).

SPONDYLOARTHROPATHIES Seronegative spondyloarthropathy is the designation for a group of diseases exhibiting some common characteristics and with overlapping genetic and clinical features. Included in this group, among other conditions, are arthritis with IBD, reactive arthritis, and a syndrome termed undifferentiated spondyloarthritis. The gut is a putative or proven port of entry for microbial agents, and the joint disease is characterized by sacroiliitis, spinal involvement, enthesopathy, or peripheral oligoarthritis with dominant localization to the lower extremities. Systemic manifestations involving the eyes, skin, heart, and urogenital tract are also common.

INFLAMMATORY BOWEL DISEASE EPIDEMIOLOGY The prevalence of Crohn’s disease and ulcerative colitis is about equal, and in the United States, there are between 50 and 100 cases per 100,000 population.3 In recent years,

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IgA-coated bacteria

Lumen

Free SC: Membrane SC (plgR) Dimeric IgA

IgA+J

SPONDYLOARTHROPATHIES

SlgA

IgA+J J chain

Gland

SlgM

IgM+J

Pentameric IgM IgG Mucus IgG (±J)

A

B

Figure 73-3  Mucosal immunoglobulin defense system. IgA and IgM are coupled to secretory component (SC), whereas IgG passes into the lumen unattached and is still complement binding. (From Brandtzaeg P, Johansen FE: Mucosal B cells: Phenotypic characteristics, transcriptional regulation, and homing properties. Immunol Rev 206:32-63, 2005.)

Mother

Microorganisms Food antigens Child Protection of upper airways and gut

Mammary gland

Breast milk SIgA, SIgM

Gut Mucosa

Innate defense factors

Peripheral blood

Immune cells GALT B Immune mediators T

Lymphatic vessel Mesenteric lymph node

Thoracic duct

Figure 73-4  Integration of mucosal immunity between mother and newborn. Primed B (and probably T) cells from Peyer’s patch migrate via lymph and peripheral blood to the lactating mammary gland, resulting in the presence in breast milk of secretory antibodies (SIgA and SIgM) specific for  enteric antigens. (From Brandtzaeg P: Mucosal immunity: Integration between mother and the breast-fed infant. Vaccine 21:3382-3388, 2003.)

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ion

osit

disp pre ? c i t e + B27 Gen

Microbial agents

Other noxae?

ut

The g

mation

Inflam

Permeability SIgA B and T lymphocytes

Deposition Circulating immune complexes

The joint

Synovitis

Microbial material

Macrophages Figure 73-5  Immune pathogenesis of enteropa­ thic arthritis.

Table 73-1  Extraintestinal Manifestations   of ­Inflammatory Bowel Disease Feature or Disease

Crohn’s

Ulcerative Colitis

Peripheral arthritis

≈15%

≈15%-20%

≈10%

Axial or sacroiliac arthritis Septic arthritis

Rare

Not reported

Skin Erythema nodosum Erythema multiforme Pyoderma gangrenosum

Up to 15% Rare 0.5%-2%

<15% ? 0.3%-0.4% in severe disease 1%-8%

Aphthous ulcers

Rare

≈10%-15%

Nephrolithiasis (oxalate)

<15%

?

Amyloidosis

Very rare

Not reported

Liver disease

3%-5%

7%

Uveitis

13%

4%

Vasculitis

Takayasu’s

<5%

Clubbing of fingers

Yes

1%-5%

Increased prevalence of asthma

Yes

Yes

Increased prevalence of multiple sclerosis

No

Yes

the incidence of ulcerative colitis has decreased in ­Western countries, whereas the previously low incidence of IBD in eastern Europe, South America, and the Pacific have increased.10 This may be due in part to better reporting. The overall concordance in monozygotic twins is 36%, but it is only 16% in ulcerative colitis.11 Joint involvement has been reported in up to 25% of patients.4 Lower figures were reported from a large population-based Canadian study,12 but it excluded peripheral arthritis, which may explain why less than 10% of patients had “arthritis.” Interestingly, asthma and multiple sclerosis were overrepresented in two recent studies of extraintestinal autoimmune manifestations of IBD (Table 73-1).13

Homing

CAUSE Intestinal microflora remain a major suspect in the cause of IBD, but final proof is lacking. Experimental models require gut bacteria. Postoperative therapy with metronidazole has prolonged the time to relapse.14 Genome-wide screening has identified a region on chromosome 16 with polymorphisms that in 2001 were linked to CARD15 (caspase-activating recruitment domain 15), also known as NOD2 (nuclear oligomerization domain 2). This region, named IBD1, shows mutations in up to 80% of patients with Crohn’s disease. A number of putative susceptibility loci (IBD1 to 9), seven of which have been confirmed in independent studies, are present on different genes15 (Fig. 73-6). CARD15 and CARD4 are cytosolic sensors for the bacterial peptidoglycan muramide dipeptide and trigger the synthesis of antibacterial α-defensins.16,17 Reduced mucosal expression of these defensins is found in patients with Crohn’s disease.18 Whereas CARD15 mutations were present in 43% of pat­ ients in the initial French study,19 later population studies found a much lower prevalence in northern European populations and no correlation in Asians. CARD15 mutations are not related to susceptibility in the United States. High expression of CARD15 messenger RNA has been found in the small intestine, and it is believed to be a regulator of nuclear factor κB (NFκB) signaling after the engagement of Toll-like receptors (TLRs). IBD3 on chromosome 6 has shown the most constant association with IBD, and HLADRB1*0103 has been linked to severe ulcerative colitis in several studies.9 Further, a tumor necrosis factor-α (TNF-α) microsatellite gene factor was associated with Crohn’s disease but not with ulcerative colitis. Human leukocyte antigen (HLA)-DR2 and DR3 associations have been linked to ulcerative colitis but not to Crohn’s disease. Mutations of the detoxifying ATP-binding cassette, ­subfamily B, member 1 gene (ABCB1), also known as multidrug resistance 1 gene (MDR1), are strongly downregulated in unaffected colonic tissue of both Crohn’s disease and ulcerative colitis patients. TLR4 and TLR5 associations

PART 10 

1

3

4

5

6

IBD9 CCR5 CCR9 hMLH1

IBD7 TNF-R family HSPG2 UBE1L

IL-2 gene IL-12A

TGF-β2 TGF-β4 E2G

SPONDYLOARTHROPATHIES

7

IBD3 HLA class I-III TNF

IBD5 IL-4, -6 CD14 OCTN

| 

1223

10

MUC 3 EGFR HGF

B1-integrin

Linkage significance

12

IBD2 VDR NRAMP2 STAT6 MMP 18 AVIL Interferon-γ B7-integrin

Confirmed and replicated Other

14

IBD4 TCR α and δ Proteasome cluster Leukotriene B4 receptor

IBD8 IBD1 NOD2

16

IBD6 ICAM-1 C3 TBXA2 LTB4H 19

X

Figure 73-6  Susceptibility loci for inflammatory bowel disease as identified by genome-wide scanning. (From Ahmad T, Tamboli CP, Jewell D, Colombel JF: Clinical relevance of advances in genetics and pharmacogenetics of IBD. Gastroenterology 126:1533-1549, 2004.)

have been identified in several populations; this may be of special interest, because they act in synergy with CARD15 and CARD4 in the induction of proinflammatory cytokines. TLR inhibitors are being investigated for therapeutic efficacy. The relation of these new genetic factors to the occurrence of joint or other extraintestinal manifestations has not been studied in detail. Recently, several new susceptibility loci for IBD have been confirmed using genome-wide screening. These involve IL23R and other factors influencing the barrier function of the gut and innate immunity.19a IL23 and its receptor deserve special attention since gene-manipulated mice are resistant to colitis and since IL23 is upregulated in patients with CD.19b PATHOGENESIS Crohn’s disease and ulcerative colitis are clinically distinct entities with a different pathogenesis, but new genetic evidence also shows some common features. Both are familial, but hereditary factors are more important in Crohn’s disease, according to twin studies. Whereas the entire gut wall is involved in a patchy way in Crohn’s disease, diffuse mucosal pathology is typical of ulcerative colitis. T lymphocyte proliferation and cytokine generation are also different. In Crohn’s disease, a Th1 response dominates,20 but no such dominance has been documented for ulcerative colitis. Increased amounts of proinflammatory cytokines, TNF-α, interleukin (IL)-1β, IL-6, and IL-8, are released locally in both diseases (see Fig. 73-1).21 The interplay between the intestinal microflora and gen­ etic host factors is disturbed in IBD. The microbial contribution is still largely unclear, and animal work indicates that parts of the normal gut flora may be involved. In addition, pathogenic organisms, such as Clostridium difficile, have been linked to exacerbations of IBD.22 As discussed earlier, genetic factors related to innate immunity are involved in susceptibility to IBD. Experimental work with transgenic animals

transfected with human HLA-B27 and β2-­microglobulin has shown that certain strains of conventional mice and rats develop spondyloarthropathies, whereas identical animals in a germ-free environment are protected.23,24 In human disease, HLA-B27 is clearly one predisposing factor, but only in the minority of cases with spinal joint involvement. Jejunal fluid from patients with ankylosing spondylitis (AS) and rheumatoid arthritis collected with the closed-segment endoscopic technique contained antibodies against Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis.3 A disturbed and augmented local immune response in parts of the gut against a variety of microorganisms is emerging as a prevalent feature of several chronic joint diseases, but it has not been examined in IBD with this endoscopic technique. Gene manipulation in mice indicates that IL-2, IL-10, and transforming growth factor-β may be protective factors and that HLA-B27 may influence cytokine expression.25 Altered cytokine balance in the gut mucosa may be an important contributing pathogenic factor. Increased gut permeability has already been alluded to as an important factor in pathogenesis.4 Bacteria recovered from the gut lumen in IBD are covered by immunoglobulin, part of which is circulatory IgG.26 Increased leakage of tissue fluid from the inflamed mucosa allows the egress of complementbinding IgG, which may contribute to inflammation and further augment permeability. The altered immune response to bacteria differs between Crohn’s disease and ulcerative colitis.27 Increased gut permeability in IBD is under genetic influence. Basal permeability was normal in a study of relatives of patients with Crohn’s disease, but it became abnormally increased after the ingestion of acetylsalicylic acid.28 Environmental influences on permeability may be partly mediated by bacterial endotoxin. An in vitro perfusion study on rat gut showed that serosal rather than mucosal application of endotoxin impairs the ­barrier.29 Absorbed bacterial material could therefore add to an already damaged barrier.

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Table 73-2  Distinct Features of Inflammatory   Bowel Disease

Table 73-3  Peripheral Joint Disease in Inflammatory Bowel Disease

Feature

Crohn’s

Ulcerative Colitis

Feature

Type 2 (>5 Joints)

Type 1 (< 5 Joints)

Genetic base

Strong, recessive

Weaker, dominant

Ulcerative colitis

3; 3%

2; 5%

Concordance in   monozygotic twins

36%

19%

Crohn’s disease

6; 0%

4; 6%

Clinical course

Self-limited arthritis

Persistent arthritis

Non-HLA genes

Yes

Yes

Course of IBD

Relapsing in <85%

Relapsing in 30%-40%

Gut permeability sensitive   to ASA on genetic base

Yes

?

MHC association

HLA-B27, B35, DRB1*0103

HLA-B44

T lymphocyte   response in gut

Th1 (IFN-γ↑)

No Th1-Th2   imbalance

Fas ligand expression

No

Yes

Effect of smoking

None (?)

Protective

Correlation of gut activity   to arthritis symptoms

No

Yes

ICAM-1 antisense therapy

Beneficial

No response (?)

Response to   anti-TNF therapy

Well established

Probably effective

ASA, acetylsalicylic acid; HLA, human leukocyte antigen; ICAM, intercellular adhesion molecule; IFN, interferon; Th1, T helper type 1; Th2, T helper type 2; TNF, tumor necrosis factor.

CLINICAL FEATURES Although Crohn’s disease and ulcerative colitis are clinically distinct entities, they share many features (Table 73-2). ­Spinal involvement occurs in 10% to 20% of cases. The back symptoms are often silent, so their prevalence is underestimated; they may precede the onset of IBD or appear later.4 In contrast to AS, there is an equal sex distribution. In general, the involvement is similar to or identical with that in classic AS, although small differences have been found.30 Changes in enteropathic disease tended to be milder, squaring was more prevalent, and Romanus lesions were not found. The majority of radiographic features were similar. As noted, spinal involvement is often asymptomatic, but when symptoms are present, they do not correlate with intestinal symptoms. The issue is complicated by the association of AS with silent Crohn’s disease, as diagnosed by biopsy.31 Isolated sacroiliitis is not strongly associated with HLA-B27. In full-blown IBD-related AS, the prevalence of B27 is between 50% and 70%.4 Between 5% and 15% of patients in most studies develop peripheral arthritis, slightly more often in Crohn’s disease than in ulcerative colitis (Table 73-3). It is often nondestructive and reversible, but erosive changes may also occur. Limited histopathologic evidence indicates the presence of granulomas in Crohn’s disease and nonspecific synovitis in ulcerative colitis.4 In Crohn’s patients, rapidly destructive septic arthritis has been reported in the hip. Joint symptoms tend to coincide with gut activity in ulcerative colitis but not in Crohn’s disease. Total colectomy is associated with remission of arthritis in half the patients with ulcerative colitis, but paradoxically, arthritis may also begin after surgery.32 This may represent a form of bypass arthritis related to altered gut microbiology. Based on the examination of about 1500 patients with IBD, a distinction was made between two forms of peripheral arthritis33 (Fig. 73-7). Oligoarthritis, or type 1, affects less than five joints, while polyarthritis, or type 2, involves more than five joints. The highest prevalence was found in metacarpophalangeal, proximal interphalangeal, knee, and

HLA, human leukocyte antigen; IBD, inflammatory bowel disease; MHC, major histocompatibility complex.

ankle joints. Shoulder involvement was more common in ulcerative colitis, but joint involvement was otherwise strikingly similar. It is important that the majority of type 1 cases were acute and resolved within 6 weeks, whereas the type 2 cases persisted.34 Type 1 arthritis was 12 times more prevalent in carriers of the rare HLA-DRB1*0103 allele. This is an example of genetic influence on disease phenotype and may be a clue to pathogenesis. Clubbing of fingers, uveitis, and skin manifestations are other extraintestinal manifestations of IBD, with a higher frequency in Crohn’s disease. Erythema nodosum, which is usually self-limited, is most frequent in young female patients with ulcerative colitis. Pyoderma gangrenosum is a more severe, painful, ulcerating skin reaction that is frequently associated with systemic disease35 (Fig. 73-8). In a series of 86 patients with pyoderma gangrenosum seen at the Mayo Clinic between 1970 and 1983, 31 had IBD.4 Erythema nodosum, uveitis, and peripheral arthritis commonly occur together in IBD and have been linked to HLADRB1*0103 and TNF-α gene polymorphism.36 Uveitis is also a feature of other spondyloarthropathies, such as AS and reactive arthritis. In IBD, however, uveitis is more often bilateral, and the tendency toward chronicity is more pronounced.37,38 DIAGNOSIS A careful history and clinical examination, supplemented by imaging, are the principal diagnostic tools. As mentioned, genetic mapping has shown interesting clinical correlates, but genotyping is not part of the routine clinical workup at present, except perhaps for HLA-B27. Stool cultures should be performed when infection with special pathogens is suspected. TREATMENT Joint manifestations are considered secondary to active IBD. Current dogma states that treating the latter will benefit the former, but there is no rigorous proof that this is so. Placebo effects account for perhaps 20% of the treatment response in IBD; therefore, only placebo-controlled evidence can be trusted. Sulfasalazine and its derivative 5-ASA inhibit the function of NFκB, and several studies have shown the efficacy of these drugs compared with placebo in ulcerative colitis but not in Crohn’s disease.3 Glucocorticoids are effective in both forms of IBD, although the response of uveitis to topical therapy with glucocorticoids may be less prompt than in uveitis of other causes.4

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80 Type 1 Type 2

70 60 50 40 30 20

MTP CD

MTP UC

Ankle CD

Ankle UC

Knee CD

Knee UC

Hip CD

Hip UC

DIP CD

DIP UC

PIP CD

PIP UC

MCP CD

MCP UC

Wrist CD

Wrist UC

Elbow CD

Elbow UC

0

Shoulder CD

10 Shoulder UC

Percentage with joints involved (%)

PART 10 

Joints

Figure 73-7  Articular distribution of peri­ pheral arthropathies in inflammatory bowel disease. See also Table 73-3. CD, Crohn’s dis­ ease; DIP, distal interphalangeal joint; MCP, metacarpophalangeal joint; MTP, metatarso­ phalangeal joint; PIP, proximal interphalange­ al joint.; UC, ulcerative colitis. (From ­Orchard TR, Wordsworth BP, Jewell DP: ­Peripheral arthro­ pathies in inflammatory bowel disease: Their articular distribution and natural history. Gut 42:387, 1998.)

tested in controlled studies, but there is no convincing evidence that they are better than placebo, and they are usually inferior to glucocorticoids.45 OUTCOME There are no prospective studies addressing the outcome of arthritis complicating IBD.

ENTERIC REACTIVE ARTHRITIS

Figure 73-8  Pyoderma gangrenosum in a case of Crohn’s disease. (From Rothfuss KS, Stange EF, Herrlinger KR: Extraintestinal manifestations and complications in inflammatory bowel diseases. World J Gastroenterol 12:4819-4831, 2006.)

Azathioprine has been widely used to maintain remission in IBD. It has proven long-term efficacy in both ulcerative colitis and Crohn’s disease, according to a large European study.39 It should not be combined with 5-ASA owing to a pharmacokinetic interaction.40 TNF inhibition with infliximab (but not with etanercept) results in remission of gastrointestinal manifestations in close to 60% of patients with Crohn’s disease, as confirmed in several placebo-controlled studies.41 More recently, in­ fliximab was found to be superior to placebo in ulcerative colitis patients resistant to conventional drug therapy, although the evidence is less robust if compared to glucocorticoid therapy.42 Anecdotal evidence supports the efficacy of infliximab in the treatment of pyoderma gangrenosum. Natalizumab, an antibody against α4 integrin, has shown promising effects in both multiple sclerosis and Crohn’s disease. However, enthusiasm was reduced after the occurrence of three cases of the severe form of leukoencephalitis; two of the patients died.43 The drug is still in limited use. Pain control with nonsteroidal anti-inflammatory drugs is a potential problem owing to their potential induction of flares. However, they are widely used and often well tolerated. Probiotics, though widely promoted, have not been effective in IBD.44 Metronidazole, ciprofloxacin, and other poorly absorbed broad-spectrum antibiotics have been widely

Enteric reactive arthritis is a common postinfectious condition related to uroarthritis but triggered from the gut. The French physician Broussais founded the so-called physiologic medicine, claiming that all human disease was caused by gastrointestinal infections; he was familiar with postdysenteric arthritis. Various eponyms have been attached to reactive arthritis, perhaps the best being Fiessinger-Leroy syndrome.46 Yersinia was identified by Winblad and co workers47 in Sweden as a human pathogen causing enteritis. Ahvonen and colleagues48 in Finland confirmed it as a trigger for reactive arthritis in 1969. EPIDEMIOLOGY The occurrence of enteric reactive arthritis is determined by the prevalence of exposure to triggering agents and the susceptibility of infected individuals. Therefore, incidence and prevalence figures vary among populations and over time. A population-based study from Oslo over 2 years estimated that the minimum annual incidence of enteric reactive arthritis among individuals aged 18 to 60 years was 5 per 100,000.49 The risk of developing enteric reactive arthritis in exposed individuals varies from very low to 20% in different outbreaks3; it may be lower in children.50 The prevalence of Yersinia infections has diminished in recent years, probably as a consequence of improved slaughterhouse hygiene. Salmonella and Campylobacter are presently the two dominant causes of enteric reactive arthritis in most countries.50 CAUSE The triggering agents are usually gram-negative obligate or facultative intracellular organisms. Table 73-4 shows the agents most commonly implicated as triggers. In most series,

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Table 73-4  Causative Agents in Postenteric   Reactive Arthritis Common

Less Common

Shigella flexneri

Shigella sonnei

Salmonella typhimurium

Shigella dysenteriae

Salmonella enteritidis

Salmonella paratyphi B

Yersinia enterocolitica O3

Salmonella paratyphi C

Yersinia enterocolitica O9

Yersinia enterocolitica O8

Yersinia pseudotuberculosis

Giardia lamblia (septic?)

Campylobacter jejuni

Group A streptococci

no organism can be identified in one quarter of patients.4,49,50 The list of confirmed triggering organisms remains remarkably short. Group A streptococcus is a relatively new trigger of reactive arthritis. In one pediatric center in Florida, 25 children with this trigger were identified,4 but the majority of cases have been published by one group in Canada.51 These reports have not been followed up by more recent studies. Giardia lamblia has been implicated in occasional cases.1 Although other triggers may still be identified, clearly only a small number of microorganisms have the potency to trigger reactive arthritis. It is not clear which features determine arthritogenicity.4 Brucella infection is also frequently associated with arthritis, which is an important differential diagnosis in endemic areas (see later). PATHOGENESIS In enteric reactive arthritis, a triggering gut pathogen starts an inflammatory reaction in the gut; immune cells and antigenic material then disseminate into the joint. By definition, no living organisms are present in the joint after the outbreak of arthritis. Several steps in the pathogenesis remain elusive. The humoral immune response to the trigger involves secretory IgA and IgM and also IgG, and it is prolonged in comparison to patients who do not develop enteric reactive arthritis. This indicates a surviving reservoir of the trigger, perhaps only in the form of antigenic material, somewhere in the body.52,53 Living pathogens are not considered instrumental in enteric reactive arthritis. The role of HLA-B27 has been studied intensely for decades. Some evidence indicates that it enhances the activation of NFκB and the expression of proinflammatory signals, resulting in a glutamic acid located in the B pocket.54 In vitro experiments have shown normal cellular uptake of bacteria but delayed elimination.53 Ex vivo studies have identified antigenic material, in part in the form of processed lipopolysaccharid, and DNA in the joints.52,53 It is not known how this material gets into the joints. Bacterial lipopolysaccharide and heat shock protein can be found in joint tissue up to 4 years after the acute episode.48 Carriage of HLA-B27 does not influence the duration of bacterial presence in feces in salmonellosis, and joint involvement does not correlate with carriage. However, transfection of human HLA-B27 into monocytes and macrophages did prolong the intracellular persistence of Salmonella in comparison to untransfected cells and cells transfected with HLA-A2.53 For many years, molecular mimicry was suspected to play a part, but this has never been confirmed.4 New insights implicate mechanisms unrelated to antigen presentation. The discovery of a propensity toward misfolding

Figure 73-9  Ankle arthritis in a man with Yersinia arthritis.

of the HLA-B27 B pocket, leading to impaired elimination, opens new vistas to explain the enhanced lipopolysaccharidestimulated formation of TNF-α.55 CLINICAL FEATURES Reactive arthritis is characterized by the acute onset of asymmetric oligoarthritis, with dominant localization to the lower extremities and often affecting the large joints (Fig. 73-9). Aseptic urethritis is a common feature, and the presence of circinate balanitis is almost pathognomonic. Enthesopathy, manifested by heel pain, is very common. Erythema nodosum is rather unusual. Unequivocal signs of synovitis are often accompanied by less distinct arthralgias, which may outlast synovitis by several months. The enteritis is typically mild and may escape recognition, suggesting that a vigorous inflammatory response in the gut may provide protection against arthritis. Fever and acute-phase reactants may be low grade or intense. Self-limited glomerulonephritis, myocarditis, and conjunctivitis are other clinical features. Streptococcus-triggered enteric reactive arthritis develops, on average, 3 weeks after throat infection, at which time high-titer antistreptococcal antibodies are found, most often against nonhemolytic atypical streptococci. The arthritis is not migratory, in contrast to that seen in rheumatic fever. Symptoms last an average of 60 days, and there is an equal sex distribution . HLA-B27 is not prevalent.47 DIAGNOSIS Asymmetric, nondestructive oligoarthritis starting some weeks after mild gastroenteritis in a previously healthy individual should raise the suspicion of enteric reactive arthritis. The presence of balanitis blennorrhagica in males is almost pathognomonic. Rheumatoid factor and anticyclic citrullinated peptide antibody (anti-CCP) should be negative. A triggering agent may be cultured from the stools or traced serologically in the blood. However, even a systematic search reveals a trigger in only 60% of cases. Conversely, it is not unusual to find triggers in patients without previous symptomatic disease.49 TREATMENT Importantly, enteric reactive arthritis cannot be prevented with aggressive antibiotic therapy, even when started early.4,56 Symptomatic analgesic treatment is usually sufficient but

PART 10 

may be supplemented by short periods of systemic glucocorticoids or antimalarials. Short-term antibiotic therapy is usually administered if a triggering agent can be identified. The rationale for the use of antibiotics is to eradicate remaining microorganisms (e.g., Salmonella) in carriers and to prevent recurrence. However, there is no evidence that antibiotics influence the outcome. One small, controlled Finnish study showed no effect after 12 months but claimed that after 5 years, chronic symptoms were more common in patients who had not received antibiotics during the initial episode of enteric reactive arthritis. This study may not be valid owing to incomplete data and unbalanced patient groups.57 OUTCOME Full recovery from the acute joint episode is the rule, but this may take 3 to 18 months or longer. When Salmonella is the trigger, the duration is often long. Enteric reactive arthritis was once considered less likely to result in chronic or recurrent disease than uroarthritis.3 However, several follow-up studies have documented arthralgias, tendinitis, or even frank spondyloarthropathy in two thirds of patients.4,52,57,58 Spinal disease eventually develops in approximately 20% of patients.3

BRUCELLA ARTHRITIS EPIDEMIOLOGY Brucellosis has been eradicated in western Europe and North America but is still a major zoonosis in areas of South America, the Middle East, India, and other places where goat and sheep farming is practiced and poverty is prevalent. With increased global travel, sporadic cases can be expected in Europe and the United States. In endemic areas, the reported incidence is between 1 and 200 cases per 100,000.58

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The arthritis can become destructive unless treated early. Spinal stenosis may be a complication.

BYPASS ARTHRITIS-DERMATITIS SYNDROME EPIDEMIOLOGY Improved surgical techniques for overweight treatment have eliminated a major cause of bypass arthritis-dermatitis syndrome. It may occur as a rare complication in gastrointestinal diseases with defective peristalsis, systemic sclerosis, and IBD, particularly after colorectal surgery.4 CAUSE AND PATHOGENESIS Bacterial overgrowth in a blind loop is the likely cause. The formation and absorption of complement-binding immune complexes with increased gut permeability are contributing factors in pathogenesis. CLINICAL FEATURES AND DIAGNOSIS The main features seen in patients in the 1970s were an intensely painful oligoarthritis of the large and small joints and the spine, without structural changes, and a recurrent papulopustular rash (Fig. 73-10). Today, gastrointestinal dysfunction in combination with painful, nondestructive oligoarthritis and intermittent papular skin rash is seen. TREATMENT AND OUTCOME Correction of gastrointestinal function, nonresorbed antibiotics such as neomycin, and symptomatic pain relief are the principal therapeutic options. Prolonged complaints have been reported, but cure is the rule.

CAUSE AND PATHOGENESIS Brucella are small gram-negative bacteria that infect macrophages and are harbored in the liver, spleen, and bone marrow; from there, they can spread to joints. The four species causing human disease are Brucella melitensis, Brucella abortus, Brucella suis, and Brucella canis. Brucella arthritis is thought to be reactive, based on the failure to grow microorganisms from joint fluid and the poor response to antibiotic therapy, but this has never been proved.4 CLINICAL FEATURES AND DIAGNOSIS Brucellosis causes arthritis in about one third of cases. The main locations are the spine in adults and the peripheral joints in children and adolescents. Knees, hips, and ankles are the dominant peripheral locations. Sacroiliitis can be extremely acute and painful. Rising titers of serum antibodies and a confirmatory culture solidify the diagnosis. TREATMENT AND OUTCOME Rifampicin 600 to 900 mg and doxycycline 200 mg daily for at least 6 weeks are recommended by the World Health Organization, but other combinations have been tried.58

CELIAC DISEASE EPIDEMIOLOGY Celiac disease is a common condition with a global distribution. It used to be considered most prevalent in children, but new evidence shows that it is even more common in adults. Intestinal symptoms are often minimal or absent; consequently, published prevalence figures of 1% may be too low.4,59 CAUSE AND PATHOGENESIS Celiac disease is caused by an immune reaction to partly dig­ ested wheat gluten by T lymphocytes in the gut of genetically HLA-DQ2–positive or HLA-DQ8–positive individuals. It was shown in 2002 that dietary gluten is partly digested by gastric enzymes to generate a stable 33–amino acid peptide that is deamidated by tissue transglutaminase.60 The peptide is then presented in the context of HLA-DQ2 or HLA-DQ8 to CD4+ T cells, resulting in interferon-γ release and inflammation, altered gut permeability, and eventually villus atrophy. Autoantibodies against tissue transglutaminase are also formed.59

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found in ­ sewage, but the source of infection in humans is not known. Six different genotypes have been confirmed in culture from diseased tissue.63 The organism lives in macrophages, and these elicit a skewed lymphocyte response, with suppressed Th1 dominating Th2 cells. Expression of the cytokine IL-16 stimulates growth of the pathogen.64 Altered gut permeability may be implicated in joint involvement. CLINICAL FEATURES

Figure 73-10  Relapsing pustulosis in a woman with bypass arthritisdermatitis syndrome.

CLINICAL FEATURES AND DIAGNOSIS Only two thirds of patients present with diarrhea or irritated bowel symptoms. Celiac disease is a systemic disease that can involve type 1 diabetes, anemia, osteoporosis, neuropathies, and joint symptoms in up to 25% of patients.61 This can be an asymmetric oligoarthritis or polyarthritis, and axial involvement is common. Arthritis may be the presenting symptom of the disease.62 In addition to small-bowel biopsy, the diagnosis can be established by assay of anti–tissue glutaminase antibodies of the IgA type.59 TREATMENT AND OUTCOME Elimination of gluten from the diet is the rational therapy and is often the only one required. In addition, various experimental approaches have been discussed but are not yet supported by data. These include the administration of IL-10 to boost regulatory T cells, the induction of tolerance by nasal application of gluten peptides, and gene therapy. No specific therapy has been established for the joint problems. Children with verified celiac disease still have abnormal mucosa in adulthood and must continue the dietary restriction. There are no outcome reports dealing with joint involvement.

WHIPPLE’S DISEASE EPIDEMIOLOGY Whipple’s disease is a rare condition. Incidence and prevalence figures are unknown. A retrospective French study identified 52 patients, 73% of whom were men.4 CAUSE AND PATHOGENESIS Whipple’s disease, or intestinal lipodystrophy, as it was initially called in 1907,4 is an intestinal infection with a unique microorganism called Tropheryma whippelii, belonging to the Actinomycetes family. The organism has been

The disease can have many faces and may remain undiagnosed for many years. Recurrent fever; malaise; hem­atologic, pulmonary, and cardiac disturbances; and neurologic and ophthalmic symptoms are sometimes present and misinterpreted. Articular symptoms, however, are the presenting feature in 67% of cases, compared with intestinal symptoms in only 15%. Eventually, 83% of patients develop diarrhea, abdominal pain, and malnutrition. Arthralgias and arthritis are most commonly seen in knee joints but can localize in any peripheral joint, as well as in spinal joints and disks. Sacroiliitis has been described. DIAGNOSIS The diagnosis rests on immune histology, with the occurrence of periodic acid–Schiff–positive material, an abundance of CD68+ macrophages, and staining with antisera specific for T. whippelii. It is now also possible to grow the organism in culture, which takes an average of 30 days. In one study, only 2 of 10 small-bowel specimens were growth positive; the yield is higher using sterile cardiac or nerve tissue.63 Culture therefore remains a research tool. TREATMENT There are no randomized, controlled studies available. Initial treatment should be ceftriaxone for 2 weeks to ensure entrance into the central nervous system. Then oral trimethoprim-sulfamethoxazole is administered for a prolonged or indefinite period. In case of intolerance or lack of efficacy, tetracycline can be used. Use of penicillin, streptomycin, and chloramphenicol has been abandoned.65 OUTCOME Without treatment, Whipple’s disease is chronic or relapsing, usually progressive, and ultimately fatal. With adequate antibiotic therapy, clinical remission is usually complete or near complete. However, immune histology still shows some evidence of remaining pathology, indicating that therapy should not be interrupted.65

MICROSCOPIC COLITIS Chronic diarrhea is common, and its prevalence increases in the elderly.66 Microscopic colitis includes two diseases presenting with diarrhea—collagenous colitis and lymphocytic colitis, described in 1976 and 1989, respectively—and associated with rheumatologic conditions.67

PART 10 

Figure 73-11  Collagenous colitis. Note the intact epithelium and mas­ sive subepithelial collagen layer. (Courtesy of Dr. Claes Lindström.)

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Figure 73-12  Lymphocytic colitis. Note the epithelial lesions with intraepithelial lymphocytosis and inflammation of the lamina propria. (From Wollheim FA: Collagenous colitis and rheumatology. Curr Rheumatol Rep 2:183-184, 2000.)

EPIDEMIOLOGY Microscopic colitis is the recognized cause in 10% to 20% of patients investigated for nonbloody diarrhea in Europe and North America. The annual incidence for collagenous and lymphocytic colitis is 4 to 12 per 100,000 each in population-based studies from Sweden and Minnesota, and the figures are rising. 67 The female-male ratio is 7:1 in collagenous colitis and 2:1 in lymphocytic colitis. The peak incidence is among those 60 to 80 years old. CAUSE The cause is unknown. No genetic factors have been identified. Exposure to antirheumatic therapy has been suspected in patients with rheumatoid arthritis, based on the observation that arthritis usually precedes the onset of collagenous colitis. Reaction against some luminal factor is deduced from the observation that histology is normalized when ileostomy is performed but recurs after closure. Drugs that are prime suspects include NSAIDs and acetylsalicylic acid, lansoprazole, ranitidine, sertraline, and ticlopidine.67 PATHOGENESIS Infection is suspected, but no agent has been identified. Luminal factors are strongly suggested by almost complete histologic normalization after performing ileostomy and recurrence of pathology and symptoms after its closure. CLINICAL FEATURES The intestinal symptoms consist of chronic, intermittent (or sometimes chronic, persistent) painful watery stools; weight loss; and fatigue. There is no difference between collagenous and lymphocytic colitis. The course is acute or chronic but usually benign. Collagenous colitis is associated with a variety of joint syndromes in at least 20% of cases. These include Sjögren’s syndrome, nondestructive oligoarthritis, migratory arthralgias, sacroiliitis, and rheumatoid arthritis. A survey of 63 consecutive cases in one Swedish center identified 8 cases of rheumatoid arthritis and 3 cases of AS, clearly suggesting

a correlation between colitis and chronic joint disease.66 The prevalence of rheumatologic conditions in lymphocytic colitis is probably lower, but no study has been published. DIAGNOSIS The diagnosis can be made only by histology obtained at co­­ lonoscopy. The barium radiograph is essentially normal, and ­laboratory tests are unhelpful. Lindström found a characteris­ tic thickening of the collagen layer under the gut epithelium. This layer is normally 3 μm, but in collagenous colitis, it is more than 10 μm and may reach 50 to 100 μm (Fig. 73-11). In addition, one can see inflammation and an increased number of lymphocytes. The histology of lymphocytic colitis shows an abundance of epithelial lymphocytes (Fig. 73-12). In both conditions, the gut epithelium remains intact, although colonic mucosal tears are occasionally present. TREATMENT AND OUTCOME Seven randomized, placebo-controlled studies of collagenous colitis have been published, but none on lymphocytic colitis. Budesonide resulted in clinical and histologic improvement in three studies. Bismuth subsalicylate, probiotics, Boswellia serrata extract, and various antibiotics have been tried in a few patients but did not prove effective and cannot be recommended.67 Most patients recover after an illness of variable length.

PONCET’S DISEASE AND BACILLE CALMETTE-GUÉRIN–INDUCED ARTHRITIS Tuberculous arthritis, or Poncet’s disease, is a rare aseptic form of insidious fever, weakness, and arthritis described mostly in young adults suffering from extrapulmonary tuberculosis.14 It responds slowly to antituberculous therapy, and in the absence of pulmonary changes, the intestine is assumed to be the port of entry. The attenuated Mycobacterium strain bacille Calmette-Guérin (BCG) is used intradermally as an adjuvant in cancer therapy to stimulate T cell–mediated immunity; it is also instilled into the urinary bladder to treat superficial cancer.

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EPIDEMIOLOGY No epidemiologic data are available. A recent review identified 50 bona fide cases of Poncet’s disease.68 Aseptic arthritis occurs in 0.4% to 0.8% of patients treated with the instillation of BCG for bladder malignancy,4 and anecdotal evidence indicates an increased prevalence of HLA-B27 among them.51 This finding was associated with sacroiliitis in 20% and oligoarthritis with predominant localization to the lower limbs; it occurred more often in men. In cases of reactive arthritis occurring after the intradermal administration of BCG, 6 of 10 patients were women, and symmetric hand arthritis dominated. CAUSE AND PATHOGENESIS An aseptic complication of active tuberculosis or the administration of BCG precipitates the process. By definition, it is a reactive arthritis, which means that the infectious agent triggers an immune reaction; however, the enteropathic nature is not firmly established. HLA-B27 may be a susceptibility factor in post-BCG arthritis.4 Mycobacterium heat shock protein 65 has been incriminated in both these sterile forms of arthritis, as well as in others.52 Mycobacterial and human heat shock proteins are 50% homologous, and one hypothesis is that both the therapeutic efficacy and the arthritis are caused by cross-reactive T lymphocytes. Heat shock protein also has homologies with proteoglycan and HLA-DR. The pathogenesis of arthritis after intravesical instillation of BCG might be different and related to antigen persistence, setting the stage for a kind of reactive arthritis. CLINICAL FEATURES AND DIAGNOSIS Insidious fever, weakness, and arthritis are described mostly in young adults suffering from extrapulmonary tuberculosis.4 The arthritis consists of oligo- or polyarthritis of large or small joints, or both. The onset is not as acute as in regular enteric reactive arthritis. Most peripheral joints can be affected.4 Arthritis developing in the presence of active tuberculosis or after recent exposure to BCG and proven to be aseptic is sufficient for diagnosis. TREATMENT AND OUTCOME There is no established treatment. Post-BCG cases usually heal within 3 months. REFERENCES   1. Iweala OI, Nagler CR: Immune privilege in the gut: The establishment and maintenance of non-responsiveness to dietary antigens and commensal flora. Immunol Rev 213:82-100, 2006.   2. Wollheim FA: Enteropathic arthritis: How do the joints talk with the gut? Curr Opin Rheumatol 13:305-309, 2001.   3. Wollheim FA: Enteropathic arthritis. In Kelley WN, Harris ED Jr, Ruddy S, Sledge CB (eds): Textbook of Rheumatology, 5th ed. Philadelphia, WB Saunders, 1997, p 1006.   4. Wollheim FA: Enteropathic arthritis. In Kelley WN, Harris ED Jr, Ruddy S, Sledge CB (eds): Textbook of Rheumatology, 7th ed. Philadelphia, WB Saunders, 2005, p 1165.   5. Hvatum M, Kanerud L, Hallgren R, Brandtzaeg P: The gut-joint axis: Cross reactive food antibodies in rheumatoid arthritis. Gut 55:12401247, 2006.

  6. Iqbal TH, Lewis KO, Gearty JC, Cooper BT: Small intestinal permeability to mannitol and lactulose in the three ethnic groups resident in west Birmingham. Gut 39:199, 1996.   7. Guarner F: Enteric flora in health and disease. Digestion 73(Suppl 1): 5-12, 2006.   8. Brandtzaeg P: Mucosal immunity: Integration between mother and the breast-fed infant. Vaccine 21:3382-3388, 2003.   9. Marttila-Ichihara F, Smith DJ, Stolen C, et al: Vascular amine oxidases are needed for leukocyte extravasation into inflamed joints in vivo. Arthritis Rheum 54:2852-2862, 2006. 10. Lakatos PL: Recent trends in the epidemiology of inflammatory bowel diseases: Up or down? World J Gastroenterol 12:6102-6108, 2006. 11. Tysk C, Lindberg E, Jarnerot G, Floderus-Myrhed B: Ulcerative colitis and Crohn’s disease in an unselected population of monozygotic and dizygotic twins: A study of heritability and the influence of smoking. Gut 29:990, 1988. 12. Bernstein CN, Wajda A, Blanchard JF: The clustering of other chronic inflammatory diseases in inflammatory bowel disease: A population-based study. Gastroenterology 129:827-836, 2005. 13. Loftus EV Jr: Inflammatory bowel disease extending its reach. Gastroenterology 129:1117-1120, 2005. 14. Perencevich M, Burakoff R: Use of antibiotics in the treatment of inflammatory bowel disease. Inflamm Bowel Dis 12:651-664, 2006. 15. Gaya DR, Russell RK, Nimmo ER, Satsangi J: New genes in inflammatory bowel disease: Lessons for complex diseases? Lancet 367: 1271-1284, 2006. 16. Vermeire S: Review article: Genetic susceptibility and application of genetic testing in clinical management of inflammatory bowel disease. Aliment Pharmacol Ther 24(Suppl 3):2-10, 2006. 17. Voss E, Wehkamp J, Wehkamp K, et al: NOD2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2. J Biol Chem 281:2005-2011, 2006. 18. Hugot JP, Laurent-Puig P, Gower-Rousseau C, et al: Mapping of a susceptibility locus for Crohn’s disease on chromosome 16. Nature 379:821-823, 1996. 19. Fuss IJ, Neurath M, Boirivant M, et al: Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease: Crohn’s disease LP cells manifest increased secretion of IFN-γ, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol 157:1261, 1996. 19a. Xavier RJ, Podolsky DK: Unravelling the pathogenesis of inflammatory bowel disease. Nature 448:427-434, 2007. 19b. Neurath M: IL-23: A master regulator in Crohn disease. Nature Med 13:26-28, 2007. 20. Camoglio L, Te Velde AA, Tigges AJ, et al: Altered expression of interferon-γ and interleukin-4 in inflammatory bowel disease. Inflamm Bowel Dis 4:285, 1998. 21. Guimbaud R, Bertrand V, Chauvelot-Moachon L, et al: Network of inflammatory cytokines and correlation with disease activity in ulcerative colitis. Am J Gastroenterol 93:2397, 1998. 22. Mylonaki M, Langmead L, Pantes A, et al: Enteric infection in relapse of inflammatory bowel disease: Importance of microbiological examination of stool. Eur J Gastroenterol Hepatol 16:775-778, 2004. 23. Hammer RE, Maika SD, Richardson JA, et al: Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human β2m: An animal model of HLA-B27-associated human disorders. Cell 63:1099, 1990. 24. Taurog JD, Richardson JA, Croft JT, et al: The germfree state prevents development of gut and joint inflammatory disease in HLAB27 transgenic rats. J Exp Med 180:2359, 1994. 25. Rath HC, Herfarth HH, Ikeda JS, et al: Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human β2-microglobulin transgenic rats. J Clin Invest 98:945, 1996. 26. van der Waaij LA, Kroese FG, Visser A, et al: Immunoglobulin coating of faecal bacteria in inflammatory bowel disease. Eur J Gastroenterol Hepatol 16:669-674, 2004. 27. Macpherson A, Khoo UY, Forgacs I, et al: Mucosal antibodies in inflammatory bowel disease are directed against intestinal bacteria. Gut 38:365, 1996. 28. Söderholm JD, Olaison G, Lindberg E, et al: Different intestinal permeability patterns in relatives and spouses of patients with Crohn’s disease: An inherited defect in mucosal defence? Gut 44:96, 1999. 29. Osman NE, Waström B, Karlsson B: Serosal but not mucosal endotoxin exposure increases intestinal permeability in vitro in the rat. Scand J Gastroenterol 33:1170, 1998.

PART 10  30. Helliwell PS, Hickling P, Wright V: Do the radiological changes of classical ankylosing spondylitis differ from the changes found in the spondylitis associated with inflammatory bowel disease, psoriasis, and reactive arthritis? Ann Rheum Dis 57:135, 1998. 31. Mielants H, Veys EM, Goemaere S, et al: A prospective study of patients with spondylarthropathy with special reference to HLA-B27 and to gut histology. J Rheumatol 20:1353, 1993. 32. Andreyev HJ, Kamm MA, Forbes A, Nicholls RJ: Joint symptoms after restorative proctocolectomy in ulcerative colitis and familial polyposis coli. J Clin Gastroenterol 23:35, 1996. 33. Orchard TR, Wordsworth BP, Jewell DP: Peripheral arthropathies in inflammatory bowel disease: Their articular distribution and natural history. Gut 42:387, 1998. 34. Orchard TR, Thiyagaraja S, Welsh KI, et al: Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease. Gastroenterology 118:274, 2000. 35. Rothfuss KS, Stange EF, Herrlinger KR: Extraintestinal manifestations and complications in inflammatory bowel diseases. World J Gastroenterol 12:4819-4831, 2006. 36. von den Driesch P: Pyoderma gangrenosum: A report of 44 cases with follow-up. Br J Dermatol 137:1000, 1997. 37. Orchard TR, Chua CN, Ahmad T, et al: Uveitis and erythema nodosum in inflammatory bowel disease: Clinical features and the role of HLA genes. Gastroenterology 123:714, 2002. 38. Banares A, Hernandez-Garcia C, Fernandez-Guitierrez B, Jover JA: Eye involvement in the spondyloarthropathies. Rheum Dis Clin North Am 24:771, 1998. 39. Holtmann MH, Krummenauer F, Claas C, et al: Long-term effectiveness of azathioprine in IBD beyond 4 years: A European multicenter study in 1176 patients. Dig Dis Sci 51:1516-1524, 2006. 40. Hande S, Wilson-Rich N, Bousvaros A, et al: 5-Aminosalicylate ­therapy is associated with higher 6-thioguanine levels in adults and children with inflammatory bowel disease in remission on 6-­mercaptopurine or azathioprine. Inflamm Bowel Dis 12:251-257, 2006. 41. Akobeng AK, Zachos M: Tumor necrosis factor-alpha antibody for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 1:CD003574, 2004. 42. Lawson MM, Thomas AG, Akobeng AK: Tumour necrosis factor alpha blocking agents for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 3:CD005112, 2006. 43. Berger JR: Natalizumab and progressive multifocal leucoencephalopathy. Ann Rheum Dis 65(Suppl 3):iii48-iii53, 2006. 44. Rolfe V, Fortun P, Hawkey C, Bath-Hextall F: Probiotics for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev 4: CD004826, 2006. 45. Perencevich M, Burakoff R: Use of antibiotics in the treatment of inflammatory bowel disease. Inflamm Bowel Dis 12:651-664, 2006. 46. Wallace DJ, Weisman M: Should a war criminal be rewarded with eponymous distinction? The double life of Hans Reiter (1881-1969). J Clin Rheumatol 6:49, 2000. 47. Winblad S, Nilehn B, Jonsson M: Two further cases, bacteriologically verified, of human infection with “Pasteurella X” (syn. Yersinia enterocolitica). Acta Pathol Microbiol Scand 67:537-541, 1966. 48. Ahvonen P, Sievers K, Aho K: Arthritis associated with Yersinia enterocolitica infection. Acta Rheumatol Scand 15:232-253, 1969. 49. Kvien TK, Glennas A, Melby K, et al: Reactive arthritis: Incidence, trigger­­ing agents and clinical presentation. J Rheumatol 21:115-122, 1994.

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50. Rudwaleit M, Richter S, Braun J, Sieper J: Low incidence of reactive arthritis in children following a salmonella outbreak. Ann Rheum Dis 60:1055-1057, 2001. 51. Jansen TL, Janssen M, Traksel R, de Jong AJ: A clinical and serological comparison of group A versus non-group A streptococcal reactive arthritis and throat culture negative cases of post-streptococcal reactive arthritis. Ann Rheum Dis 58:410-414, 1999. 52. Gaston JS, Lillicrap MS: Arthritis associated with enteric infection. Best Pract Res Clin Rheumatol 17:219-239, 2003. 53. Hannu T, Inman R, Granfors K, Leirisalo-Repo M: Reactive arthritis or post-infectious arthritis? Best Pract Res Clin Rheumatol 20: 419-433, 2006. 54. Penttinen MA, Heiskanen KM, Mohapatra R, et al: Enhanced intracellular replication of Salmonella enteritidis in HLA-B27-expressing human monocytic cells: Dependency on glutamic acid at position 45 in the B pocket of HLA-B27. Arthritis Rheum 50:2255-2263, 2004. 55. Turner MJ, Sowders DP, DeLay ML, et al: HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response. J Immunol 175:2438-2448, 2005. 56. Kvien TK, Gaston JS, Bardin T, et al: Three month treatment of reactive arthritis with azithromycin: A EULAR double blind, placebo controlled study. Ann Rheum Dis 63:1113-1119, 2004. 57. Yli-Kerttula T, Luukkainen R, Yli-Kerttula U, et al: Effect of a three month course of ciprofloxacin on the late prognosis of reactive arthritis. Ann Rheum Dis 62:880-884, 2003. 58. McGill PE: Geographically specific infections and arthritis, including rheumatic syndromes associated with certain fungi and parasites, Brucella species and Mycobacterium leprae. Best Pract Res Clin Rheumatol 17:289-307, 2003. 59. Lee SK, Green PH: Celiac sprue (the great modern-day imposter). Curr Opin Rheumatol 18:101-107, 2006. 60. Shan L, Molberg O, Parrot I, et al: Structural basis for gluten intolerance in celiac sprue. Science 297:2275-2279, 2002. 61. Lubrano E, Ciacci C, Ames PR, et al: The arthritis of coeliac disease: Prevalence and pattern in 200 adult patients. Br J Rheumatol 35:1314, 1996. 62. Slot O, Locht H: Arthritis as presenting symptom in adult coeliac disease: Two cases and review of the literature. Scand J Rheumatol 29:260, 2000. 63. Fenollar F, Birg ML, Gauduchon V, Raoult D: Culture of Tropheryma whippelii from human samples: A 3-year experience (1999 to 2002). J Clin Microbiol 41:3816-3822, 2003. 64. Moos V, Kunkel D, Marth T, et al: Reduced peripheral and mucosal Tropheryma whippelii-specific Th1 response in patients with Whipple’s disease. J Immunol 177:2015-2022, 2006. 65. Mahnel R, Marth T: Progress, problems, and perspectives in diagnosis and treatment of Whipple’s disease. Clin Exp Med 4:39-43, 2004. 66. Nyhlin N, Bohr J, Eriksson S, Tysk C: Systematic review: Microscopic colitis. Aliment Pharmacol Ther 23:1525-1534, 2006. 67. Wollheim FA: Collagenous colitis and rheumatology. Curr Rheumatol Rep 2:183-184, 2000. 68. Kroot EJ, Hazes JM, Colin EM, Dolhain RJ: Poncet’s disease: Reactive arthritis accompanying tuberculosis. Two case reports and a review of the literature. Rheumatology (Oxford) 46:484-489, 2007.

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systemic lupus erythematosus and related syndromes

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Pathogenesis of Systemic Lupus Erythematosus Bevra Hannahs Hahn  •  Betty P. Tsao

KEY POINTS Systemic lupus erythematosus (SLE) results from failure to regulate production of pathogenic autoantibodies, which appear years before the first clinical symptom of disease. Pathogenic autoantibodies are subsets of antibodies to various antigens, including nucleosome, double-stranded DNA, Ro, NR2, band 3 on erythrocytes, and phospholipids—usually IgG and complement-fixing. Antigens that stimulate production of antibodies are derived from blebs on apoptotic cells (nucleosomes, Ro, La, ribonucleoprotein [RNP], phospholipids), bacterial CpG DNA and viral RNA (both of which stimulate the innate immune system), and membranes of activated cells. Abnormalities of regulation of the immune responses include decreased ability to clear immune complexes and apoptotic cells, intrinsic hyperactivation of B lymphocytes and T lymphocytes, skewed cytokine production favoring immunity and inflammation (including increases in interferon [IFN]-α, IFN-γ, interleukin [IL]-6, and IL-10, and decreases in IL-2 and transforming growth factor [TGF]-β), and defective numbers/function of regulatory CD4+CD25+Foxp3+ and CD8+ inhibitory T cells. Genetic predisposition to SLE involves multiple genes, with homozygous deficiencies of complement components (which are uncommon) accounting for the highest risk. HLA-D (especially DR2 and DR3) and HLA class III haplotypes increase risk, as do genes in several non-HLA regions on other chromosomes. Gene variants predisposing to SLE may influence clearance of immune complexes or apoptotic bodies (FCGR2A, C1q), activation of B cells or T cells (IL-10 promoter, protein tyrosine phosphatase 22 (PTPN22), programmed cell death 1 [PDCD1]), and inflammation related to dendritic cell activation (interferon regulatory factor 5 [IRF5]). Studies of pedigrees stratified by clinical manifestations of SLE have identified linkages with “SLE loci” for hemolytic anemia, neuropsychiatric disease, and renal disease. Environmental/microenvironmental factors that predispose to or activate SLE include ultraviolet B light, infection with Epstein-Barr virus, female gender, and exposure to estrogen-containing medications or “lupus-inducing” medications.

The pathogenesis of systemic lupus erythematosus (SLE) is complex, as shown in Figure 74-1.1 Target tissue damage is caused primarily by pathogenic autoantibodies and immune complexes. The abnormal immune response that permits persistence of pathogenic B cells and T cells has multiple components, including activation of the innate immune system by DNA-containing and RNA-containing antigens (probably from infectious agents), processing of increased quantities of self-antigens by antigen presenting cells (APCs), hyperactivation of T cells and B cells, and failure of multiple regulatory networks to interrupt this process. The immunologic abnormalities occur in a framework of interactions between multiple susceptibility genes (and insufficient protective genes)2,3; gender influences; and environmental stimuli, at least one of which (ultraviolet [UV] light) can induce apoptosis in dermal cells that results in presentation of RNA protein, DNA protein, and phospholipid self­antigens to the immune system.4

EFFECTORS OF SYSTEMIC LUPUS ERYTHEMATOSUS PATHOGENIC AUTOANTIBODIES All individuals produce numerous antibodies that react with self-molecules. Characteristics of the normal background antiself repertoire include the following: most of the antibodies are IgM, they have weak avidity for self-antigens, and they are widely cross-reactive with multiple antigens. Pathogenic autoantibodies are different (Table 74-1). They are usually IgG, have high avidity for self-antigens, and have restricted specificity.5,6 High-avidity antiself antibodies can be constructed from many different immunoglobulin genes, but they tend to derive from a few “preferred” families of genes, suggesting derivation from initial, antigen-activated “mother” B cells.7,8 Pathogenic immunoglobulin molecules are often highly mutated, particularly in the hypervariable (complementarity determining) regions of their heavy and light chains.5-10 Several features of autoantibodies influence their pathogenic potential, including what antigens they bind, avidity for those antigens, the net charge of the immunoglobulin 1233

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1. Susceptibility A. Genes Deficiency of C1q, C2, C4 HLA-D2, 3, 8

2. Abnormal innate and adaptive immune responses CpG DNA RNA/prot

4. Inflammation

TLR DC

5. Damage

T cell

Fcr 2A, 3A, 2B MBL, IL-10, MCP-1, IRF5, TLR5, PTPN22 B. Female gender

APC

Ag TLR B cell

Suppressive networks

Chronic inflammation C3 C3a

Chronic oxidative damage

C. Environment

Rash Nephritis Renal failure Arthritis Atherosclerosis Leukopenia Pulmonary fibrosis 3. Autoantibodies, CNS disease Stroke immune complexes Carditis Damage from Rx Clotting Etc. Etc. Figure 74-1  Overview of the stages and pathogenesis of systemic lupus erythematosus (SLE). The immune abnormalities that characterize SLE are pictured in five phases. In phase 1, an individual is susceptible to SLE because of genetics, gender, and the external environment that influences antigen presentation and other immune responses. In an individual with adequate numbers of predisposing factors, stage 2 develops, consisting of abnormal  persistence of antigens, including hypomethylated DNA (CpG DNA) in DNA/anti-DNA complexes, and other DNA/protein and RNA/protein self-  antigens. These antigens activate cells of innate (dendritic cells [DC]) and adaptive (B cells) immune systems via Toll-like receptors (TLR); the activated cells then activate T lymphocytes. The adaptive system is working at the same time, where antigen presenting cells (APC) present self-antigens to  T lymphocytes and B lymphocytes; the B cells mature to plasma cells and secrete autoantibodies. At the same time, suppressive networks (regulatory and inhibitory T cells, phagocytic cells, idiotypic networks) are in place to dampen the harmful immune responses. Phase 3 begins with a clinically healthy individual having positive tests for autoantibodies in the serum. Immune complexes form. Phase 4, following phase 3 by a mean of 3 years, is clinical disease. The result of complement activation and other proinflammatory responses from tissue attacked by autoantibodies and immune complexes causes symptoms and signs of disease, which can include the features listed in the figure. Phase 5 occurs after months and years of chronic inflammation and chronic oxidative damage, which promote scarring of tissue such as kidney and lung, plaque deposition in arteries, and clotting. ­Irreversible tissue damage occurs. It is likely that at each of these phases, some individuals progress to the next phase, and others do not. CNS, central nervous system; EBV, Epstein-Barr virus; UV, ultraviolet. UV light EBV ? Other

molecule and the immune complex it forms with antigen, the presence in the immunoglobulin molecule of charged amino acids that interact with opposite charges on cell membranes or DNA, presence in the immunoglobulin molecules of sequences recognized by helper T cells, and ability to fix and activate complement.9 Although we understand many of these principles, it is difficult to predict that a given monoclonal antiself antibody will be a pathogen. Two highavidity, IgG2a, complement-fixing murine monoclonal anti-DNA antibodies were transferred to normal mice— one caused nephritis, whereas the other did not.11 Among monoclonal human antibodies to DNA, some caused proteinuria on transfer to severe combined immunodeficiency mice, whereas others did not.12 In terms of antigens bound, it is convenient to think of the autoantibodies of SLE as belonging to one of several groups directed against DNA/protein complexes, RNA/protein complexes, cell membrane structures, and intracellular molecules that reach cell surfaces during cell activation. The antibodies considered to be the hallmark of SLE are IgG antibodies to double-stranded (ds) DNA. These antibodies probably develop from antibodies to histone proteins on nucleosomes (antinucleosomal antibodies). Nucleosomes are presented to the immune system in surface membrane blebs of cells undergoing apoptosis and are released from cells undergoing programmed cell death.4,13

Studies in mice suggest that the initial antibodies to DNA/protein are directed against nucleosomes.13 As the antibodies mature and gain somatic mutations, some daughter cells bind single-stranded (ss) DNA, and then ultimately anti-ssDNA and anti-dsDNA. In support of this “antinucleosome-to-anti-dsDNA” hypothesis are observations that mice and humans with SLE have T cells activated by nucleosomes and nucleosomal peptides; such cells can help B cell synthesis of IgG anti-dsDNA.14-16 In addition, CpG regions of DNA from bacteria, viruses, or mammalian self (rare in human DNA, but increased in SLE patients) can activate B cells and dendritic cells directly via Toll-like receptor 9 (TLR9), using the innate immune system that protects against pathogens to initiate an immune response to self.17-19 Similarly, dsRNA and ssRNA from viruses and selfantigens can activate innate immunity via TLR7 (dsRNA) and TLR3 (ssRNA).20,21 It is likely that at least some pathogenic anti-DNA antibodies bind directly or in complexes to DNA deposited in basement membranes and to other renal structures, including heparan sulfate, histone, laminin, α-actinin, and collagen in glomerular basement membranes.22-24 Sera from patients with lupus nephritis contain antibodies that bind to glomeruli; some bind DNA, and others do not. More recent data suggest that most antibodies binding to human glomeruli recognize nucleosomes,24

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Table 74-1  Characteristics of Pathogenic   Autoantibodies Most are immunoglobulin isotypes that fix complement—primarily IgG (and some IgM) Most are T cell–dependent antibodies derived from B cells reacting to specific autoantigens High quantities are more likely to be associated with clinical disease and active disease than low quantities Many different V-region, D-region, and J-region genes of the ­immunoglobulin heavy chain and V-region and J-region genes of the light chain used to assemble protective antibodies against external antigens also can be used to assemble pathogenic autoantibodies There is probably some restriction in the immunoglobulin genes used to assemble autoantibodies because they tend to be derived from a few families, suggesting that many cells are daughters of cells initially activated by antigen Many pathogenic autoantibodies are mutated in variable regions (and often in framework regions), suggesting modification by specific antigenic stimulation General characteristics that favor ability of an autoantibody to be pathogenic:   Ability to bind directly to target tissues, such as erythrocyte, ­lymphocyte, and platelet membranes, or to glomerular antigens   Ability to activate complement   Cationic charge favoring adherence to polyanionic regions of membranes   High avidity for the autoantigens present in target tissue* *Presence of amino acids in antigen-contacting region of the ­ immuno globulin molecule that favor charge-charge or hydrogen-bonding interactions with molecules in the antigen; this contributes to high avidity for antigen.

confirming a major role of antinucleosome/DNA in lupus nephritis. Non–DNA-binding autoantibodies that probably can cause nephritis include antibodies to C1q25,26 and Ro/ SS-A.27 A subset of autoantibodies has been discovered within the anti-DNA repertoire that bind the glutamate receptor on neurons (N-methyl-d-aspartate receptor subunits NR2a and NR2b).28 These antiglutamate receptors have been found in cerebrospinal fluid of a patient with SLE central nervous system disease. In vitro, they cause apoptosis of neurons; transferred to mice, they fix primarily to the hippocampus or lateral amygdala, depending on the method used to open the blood-brain barrier.29 In patients with SLE, antibodies to NR2 are associated with depression, rather than with cognitive defects.30 Another autoantibody highly specific for SLE is antiSmith (anti-Sm). High-affinity anti-Sm antibodies have a prevalence of 5% to 25% in SLE patients. They are usually of IgG subclass, suggesting T cell dependence. T cell immunity against Sm peptides has been described in peripheral blood mononuclear cells and lymphoid tissues of SLE patients and mice.31 Sm-reactive T cells show highly restricted T cell receptor (TCR) usage, which is characteristic of an antigendriven response. SmD1 seems to be the most frequently recognized peptide in the molecule. It is remarkably conserved and bears a 99% homology with the mouse D1 protein. The epitope SmD183-119 seems to be recognized with remarkable sensitivity and specificity by human SLE sera (70% in SLE patients versus 8.3% in healthy controls and patients with other autoimmune diseases), possibly owing to its highly

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positive charge and its conformation.32,33 In murine systems, SmD183-119 is effective as an immunogen (accelerating disease) and as a tolerogen (preventing or delaying disease) in lupus-prone mice.31,33 Other autoantibodies that directly cause disease in­­ clude autoantibodies that coat platelets or erythrocytes. Antibodies that cause hemolysis in SLE are primarily warm-reactive IgG non-Rhesus, often reactive with oligomerized band 3, an anion transporter protein on erythrocyte membranes. Such erythrocytes usually have deficient surface expression of CD55 or CD59 or both, which are glycoprotein-anchored molecules that control complement activation. Hemolysis probably requires antibody plus C3b deposition on membranes, with subsequent phagocytosis after interaction with CR1 (complement) receptors or fragment crystallizable (Fc) receptors or both on phagocytes.34 Antibodies against platelets in SLE patients with thrombocytopenia recognize a wider variety of antigens than do antibodies in patients with idiopathic thrombocytopenic purpura. In both diseases, antibodies are directed against surface glycoprotein II and glycoprotein III antigens on intact platelets, but in SLE there are additional antibodies against cytoplasmic antigens, which come to the surface of activated platelets, and against phospholipids, suggesting that activated, damaged cells and cells undergoing apoptosis (in which antigenic portions of phospholipids in cell membranes are directed outward rather than inward) are important in stimulating pathogenic responses in SLE.35 Antibodies against proteins associated with the Ro/La particle are probably also direct pathogens, particularly in congenital heart block.36-40 IgG anti-Ro crosses the placenta, can bind to certain areas of the fetal heart conduction system tissue, can alter myosin-actin function, and probably can cause heart block. The syndrome has been essentially reproduced in fetal mice; infusion of IgG anti-Ro from mothers with fetuses with congenital heart block induces electrocardiographic abnormalities in the fetal mouse heart compatible with heart block.37 When a woman has produced a fetus with congenital heart block, the chances of subsequent fetuses having the same problem are greatly increased. Most infants with congenital heart block have mothers with anti-Ro (or rarely anti-ribonucleoprotein [RNP] or anti-La). Many of these mothers are healthy at the time of this occurrence, but some develop SLE or lupus-like syndromes later.36 Antibodies against phospholipids (either anticardiolipin or the lupus anticoagulant) increase the risk for venous or arterial thrombosis, for fetal loss, and for thrombocytopenia. They are likely to be involved directly in induction or maintenance of blood clots.41 Their ability to cause fetal loss has been confirmed by transfer of human antiphospholipid to pregnant mice. Fetal death was increased and depended on activation of complement by the antibodies.42,43 Antibodies to ribosomal P have been associated with depression and psychosis in SLE patients in some studies and with hepatitis and nephritis in others.44-46 The mechanism by which they cause disease is unclear, but may be related to the fact that they, similar to some antibodies to DNA and RNP, can penetrate membranes of living cells, bind cytoplasmic or nuclear structures, and alter cell function.47

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Table 74-2  Factors Favoring Tissue Deposition   and Pathogenicity of Immune Complexes Excessive quantities of immune complexes, which overwhelm ­clearance mechanisms “Correct” size (large complexes are bound by the mononuclear phagocytic system and cleared rapidly; small complexes are excreted in urine; intermediate-size complexes are most likely to escape these mechanisms and to be tissue bound) Tissue tropism of immune complexes (cationic charge of complexes allows binding to anions in tissue; antibody in complex may ­recognize components of tissues such as actinin in glomeruli) Decreased immune complex and apoptotic bodies clearance and ­catabolism (relates to acquired and genetically ­determined   low levels of surface complement receptors, genetic acquisition of fragment crystallizable [Fcγ] receptors that are inefficient binders of immunoglobulin in immune complexes, decreased ­solubilization of immune complexes by complement as ­complement levels fall or are genetically low, delayed ­phagocytosis of apoptotic bodies) CpG regions in DNA of DNA/anti-DNA complexes (binds TLR9 in dendritic cells and B cells)

PATHOGENIC IMMUNE COMPLEXES Similar to autoreactive antibodies, some immune complexes are pathogenic, and others are not. The characteristics of pathogenic immune complexes are summarized in Table 74-2 and reviewed elsewhere.48 The size of the immune complex is important. Large immune complexes are cleared by the mononuclear phagocytic cell system on their first pass through the circulation, whereas small immune complexes are more likely to deposit in tissue. Excessive quantities of immune complexes overwhelm the mechanisms used to clear them, as discussed earlier. Finally, some immune complexes are “tissue tropic” and prone to bind to tissues because they have a net cationic charge or because the antibodies they contain are directed against tissue components. It is well accepted that immune complexes that fix complement are responsible for much of the tissue damage that characterizes SLE. In mammals, immune complexes are transported bound to complement receptor 1 (CR1), predominantly on erythrocytes. If surface CR1 molecule numbers are low, either because of genetic factors or because they have been stripped from the cell surfaces by an overload of activated complement, pathogenic immune complexes may persist long enough to cause tissue damage.49,50

GENETICS OF SYSTEMIC LUPUS ERYTHEMATOSUS As with other autoimmune diseases, susceptibility to SLE depends on multiple genes.3,51,52 Susceptibility genes are defined as genes that increase the relative risk for a disease, even though most individuals with that gene are healthy. The number of genes an individual must inherit to develop clinical SLE is unknown. It is likely to be several, with full gene effect depending partly on other modifying or protective genes in the same individual, gender, and the strength of environmental stimuli that can trigger disease (e.g., a severe sunburn in an individual with susceptibility genes).

Evidence for genetic predisposition in humans includes the following: 1. An approximately 10-fold increase in clinical disease in monozygotic compared with dizygotic twins53-55 2. A 5-fold to 29-fold relative risk for SLE in first-degree relatives, with approximately 10% of patients with SLE having an affected first-degree, second-degree, or third-degree relative56 3. Eight established and confirmed chromosomal regions linked to SLE, and five such genomic segments linked to disease subsets3,52 4. Many established and confirmed associations of SLE with particular gene variants and haplotypes1,3,52 5. Functional demonstration of a few SLE-associated gene polymorphisms1,3,52 Because the highest reported concordance rate in monozygotic twins is 57%,53 it is likely that environmental factors and epigenetic factors also are required. The evidence for genetic control of disease is even more compelling in mice. Several strains are predisposed to SLE, with almost all individuals (gender dependent in some strains) developing the disease as they age. Major histocompatibility complex (MHC) class II genes on chromosome 17 (similar to HLA-D on chromosome 6) and regions on several other chromosomes contribute to susceptibility in these strains.57,58 Some locations on mouse chromosomes have potential ­homologues in the human genome. Mice predisposed to SLE that also inherit the lpr or gld genes have accelerated disease based on mutations in the genes encoding Fas (in lpr) and Fas ligand (in gld) that impair apoptosis and permit autoreactive T cells and B cells to persist for abnormally long periods.59 Abnormalities of the human Fas or Fas ligand genes are responsible for the hereditary autoimmune lymphoproliferative syndrome, a disease characterized by lymphoid hyperplasia and hematologic autoimmunity (Online Mendelian Inheritance in Man #601859). B6 × satin beige (BXSB) male mice spontaneously develop severe systemic autoimmunity owing to the presence of the yaa gene in the Y chromosome, which is the duplicated Tlr7 gene usually located on the X chromosome, but in the BXSB strain it is translocated to the Y chromosome.60 Compared with normal mice, male mice carrying the yaa gene have increased expression levels of TLR7 in B cells, which activates B cells to produce autoantibodies to RNA-containing nucleolar antigens and accelerates a lupus-like disease mediated by interactions with several genes in the BXSB genome.60,61 HUMAN GENETIC STUDIES Multiple ethnic populations have been analyzed for susceptibility genes. The following four principles have emerged: 1. Some of the susceptibility gene variants differ between ethnic/racial populations. 2. There are individual gene variants that predispose to disease across multiple ethnic groups. 3. There are individual gene variants that predispose to multiple autoimmune diseases. 4. Genetic predisposition may be linked to autoantibody repertoires and to clinical subsets of disease. The currently known genes and gene regions associated with murine and human SLE are shown in Table 74-3. ­

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Table 74-3  Genetic Basis of Systemic Lupus ­Erythematosus (SLE) Genes Involved in Murine Lupus MHC (chromosome 17)—H2z of NZW mouse permits production of pathogenic IgG antibodies to DNA lpr (chromosome 19)—contains mutation in Fas that accelerates SLE on permissive genetic backgrounds, such as MRL/lpr gld (chromosome 1)—contains mutation in Fas ligand that ­accelerates SLE on permissive genetic backgrounds yaa (chromosome Y)—accelerates SLE in males of genetically ­predisposed strains (BXSB) Multiple regions on different chromosomes protect NZW mice from developing SLE, although they possess several predisposing genes In mice with combined New Zealand Black (NZB) and New ­Zealand White (NZW) backgrounds Chromosome 1—contains at least two regions that predispose to SLE Nba2—associated with break in tolerance to DNA-containing molecules; a candidate susceptibility gene for the Nba2 locus has been identified—Ifi202 (chromosome 1)—a NZB-derived interferon-inducible gene Sle1—promotes loss of tolerance to nucleosomes and permits development of histone-specific T cells; ANA develops along with minimal nephritis; this chromosomal region contains four separate susceptibility loci—Sle1a, Sle1b, Sle1c, and Sle1d—the NZM2410/ NZW-derived complement receptor 2 gene, Cr2, has been implicated as a candidate susceptibility gene for the Sle1c locus Chromosome 4—Sle2 permits hyperactivation of B cells with high levels of IgM, no nephritis Chromosome 7—Sle3 permits hyperactivation of T cells, increased numbers of CD4+ T cells with delayed apoptosis, increased IgG antibodies to nucleosomal antigens, moderate nephritis Combination of Sle1 and Sle3 permits severe SLE with IgG ­antibodies to DNA and lethal, early nephritis Sle1 suppressor in MHC regimen reduces percentage of mice with lethal nephritis in Sle1 + Sle2 + Sle1s Genes Involved in Human Lupus Histocompatibilty (HLA) Genes Extended haplotypes predispose to lupus in some ethnic groups: HLA-B8/DRB1*0301/DQB1*0201/C4AQO (anti-Ro) HLA-DRB1*1501/DQB1*0602 (nephritis, low levels of tumor necrosis factor-α) HLA-DRB1*0801/DQB1*0402 HLA-A10/B18/C4A4/C4B2/BFS (associated with C2 deficiency) DR2 (increases relative risk twofold to threefold) DR3 (increases relative risk twofold to threefold) DR2/DQw1 (anti-Ro) DR3/DQw2 (anti-Ro plus anti-La) DR2 or DR3 with DQB1*0201, DQB1*0602, DQB1*0302 (anti-DNA) DR4 with DQw5, DQw8, and others (anti-U1 RNP) DR2 with DQw6 or DQw7 and others (anti-Sm) DR4, DR7 with DQw7, DQw8, DQw6, and others (lupus ­anticoagulant) Homozygous deficiencies of early complement components (C2, C4) Nonhistocompatibility Genes Protein tyrosine phosphatase 22 (PTPN22) polymorphism c chromosome 1 C1q (chromosome 1) FcγRIIA receptor allele (chromosome 1) FcγRIIIA receptor allele (chromosome 1) Promoter polymorphisms of interleukin-10 (chromosome 1) PDCD1 polymorphisms (chromosome 2) Interferon regulating factor 5 polymorphisms

Table 74-4 shows the putative susceptibility loci significantly linked to SLE by genome scanning. Some genes associated with SLE in humans are located on chromosome 6, in the region that encodes HLA genes, especially class II (DR, DQ, DP) and class III (C2, C4).2,3,62 Other

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Table 74-4  Putative Susceptibility Loci Significantly Linked to Systemic Lupus Erythematosus by Genome Scanning Locus

LOD Scores

Candidate Genes

Syntenic Murine Susceptibility Loci

1q22-24

3.4

FCGR2A, FCGR3A

Sle1a, Sle1b

1q31

3.79

1q41-43

3.3, 3.5

2q35-37

4.2

4p16-15

3.8

6p11-22

4.2

12q24

4.0

16q12-13

3.8

Sle1d, Bxs3 PDCD1 DR, DQ

Lbw1, Sle1s

LOD scores, logarithm of the odds that the two loci are linked; PDCD1, ­programmed cell death 1 gene.

chromosomes contain susceptibility genes, with general agreement that those linked to SLE include two regions on chromosome 1, and chromosomes 2, 4, and 16.62-66 Extended haplotypes predispose to disease in certain ethnic groups. As shown in Table 74-3, several investigators have reported an association between HLA class I-B8 and SLE in whites of Western and Northern European ancestry.3,67-71 There is linkage disequilibrium between class I-B8 and class II-DR3. DR3 and DR2 are linked to SLE in different haplotypes and predispose to different clinical subsets of disease.67,69,70,72-85 HLA-B8/DR3/DQw2/C4AQO is a haplotype associated with a deletion of class III genes—C4A and a neighboring CYP21A gene72,76,78,80,81—and predisposes to SLE in whites. Abnormalities in C4, particularly C4A gene expression, are common in SLE patients from multiple ethnic/race groups (including northern and central Europeans, AngloSaxons, U.S. whites, African-Americans, Asian Chinese, Koreans, and Japanese), and various molecular mechanisms result in C4AQ0 (the null allele of C4).86 The significant association between C4AQ0 and SLE in the context of ­multiple MHC haplotypes, ethnic/racial groups, and molecular mechanisms strongly supports the notion that no or low expression level of C4A protein predisposes to SLE susceptibility. The extended haplotype HLA-A10/B18/C4A4/ C4B2/BFS is in disequilibrium with class III complement C2 deficiency2; homozygous deficiency for C2 occurs in 1 in 10,000 individuals,87-90 many of whom have SLE or similar disease. The SLE is clinically distinct; patients have primarily joint and skin disease and are often antinuclear antibody (ANA) negative. A more recent study using a large cohort (334 families containing 576 SLE patients) identified three distinct SLEassociated haplotypes containing DRB1*1501/DQB1*0602, DRB1*0801/DQB1*0402, and DRB1*0301/DQB1*0201 alleles.91 By defining ancestral recombinants, the DRB1*1501 (formerly known as DR2) risk haplotype contains the DRB1 and DQB1 genes, but excludes the class I and class III regions including tumor necrosis factor (TNF)-α. The DRB1*0301 haplotype corresponds to the HLA A1-B8-DR3 haplotype of the Northern European origin that has been associated with several other autoimmune diseases, including type 1 diabetes, Graves’ disease, and myasthenia gravis.92 The extensive linkage disequilibrium of the DRB1*0301 haplotype makes

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ancestral recombinants within this region rare and difficult to narrow the SLE-associated region beyond the 1-Mb interval containing most class III and class II genes.91 The DRB1*0801 (DR8) haplotype is less common in this cohort, and ancestral recombinants narrow the risk region to approximately 500 kb containing the DRB1 and DQB1 genes.91 These three SLE class II risk haplotypes are highly enriched in white families; among the 254 families carrying at least one risk haplotype, 229 (90%) were white or had known white admixture. Analysis of haplotype frequencies in 280 female SLE cases from the family collection and 174 female white controls revealed an approximately twofold increase in frequencies of risk haplotypes of SLE patients compared with controls and a doubling of risk for homozygotes compared with heterozygotes.91 The disease-­associated HLA genotypes seem to be not-as-strong contributors for risks to develop SLE compared with other autoimmune ­diseases, such as ankylosing spondilitis, type 1 diabetes, or rheumatoid arthritis. INDIVIDUAL HUMAN LEUKOCYTE ANTIGEN GENES PREDISPOSING TO SYSTEMIC LUPUS ERYTHEMATOSUS High risk for SLE is conferred by homozygous deficiencies of early complement components or their inhibitors, including C2 and C4 within the HLA gene complex and non-HLA C1q, C1r, and C1-INH.87-90 Individuals with nearly total absence of these proteins are rare and account for less than 5% of patients with SLE. Most individuals with homozygous deficiencies have SLE or SLE-like diseases, however. Although null alleles for C4 are genes predisposing to SLE in multiple ethnic groups (see Table 74-3), complete deficiency of C4 is rare because four alleles (two at C4A and two at C4B) contribute to synthesis of the protein. In affected populations, about 50% of SLE patients have a C4 gene abnormality compared with 15% or less in healthy, ethnically matched control subjects. DR3 and DR2 are individual genes that predispose to SLE in multiple ethnic groups, but the relative risk conferred by those genes alone is 2 to 3.2,67,69,79,84-93 As described previously, DR3 is a part of an extended HLA haplotype in linkage disequilibrium with the promoter polymorphism of the TNF-α gene (−308A TNFA).94 The −308A TNFA allele has been shown to confer higher transcriptional activity than the −308G TNFA allele.95 The high-activity allele has been associated with SLE in multiple studies and may be an independent risk factor or a part of the HLA risk haplotype.96-100 Neither the disease association nor the elevated activity has been consistently shown in similar studies, however.101 GENES ASSOCIATED WITH AUTOANTIBODY PRODUCTION Familial aggregation of autoantibody profiles (including ANA; rheumatoid factor; IgM antiphospholipid antibodies; and antibodies to dsDNA, Sm, Ro/SSA, La/SSB, or RNP) has been established in 1506 individuals from 229 SLE multiplex families.102 In this study, genome-wide linkage analyses have identified several non-HLA chromosomal regions that may contain gene variants that predispose to the generation of specific autoantibody. Major autoantigens in SLE

are nuclear complexes containing either RNA or DNA, which may serve as ligands to particular TLRs on B cells or dendritic cells, or both, leading to the initiation and perpetuation of autoantibody production (also known as Toll hypothesis).103 In murine lupus, TLR7 (a receptor for ssRNA) and TLR9 (a receptor for CpG-containing dsDNA) control the generation of autoantibodies to RNA-containing antigens (including Sm antigen) and DNA-containing antigens (such as anti-dsDNA and antinucleosome antibodies).104 TLR8 also may be important in the recognition of autoantigens containing RNA in humans.105 Members in the TLR7/TLR8/ TLR9 activation pathways are candidate genes for increased risk of the generation of autoantibodies to nuclear complexes that are frequently found in SLE patients. TLR9 gene variants have not been associated, however, with the production of autoantibodies (Sm, RNP, Ro, and La) and SLE susceptibility in Asians,106 or with SLE/lupus nephritis in whites.107 Other TLRs may play a role in the pathogenesis of SLE. TLR4 (innate receptor for bacterial liposaccharide) and commensal flora are required for the production of antidsDNA and the development of immune complex–mediated glomerulonephritis in a mouse model.58 A TLR5 stop codon has been associated with protection from the development of SLE susceptibility in whites, particularly in anti-dsDNA seronegative subsets, suggesting a role for flagellated bacteria triggering TLR5 activation in the pathogenesis of SLE.108 Associations between HLA genes and autoantibodies have been reported for anti-DNA,109 anti-U1 RNP,110 the 70-kD polypeptide of U1 RNP,110,111 the lupus anticoagulant,112 and autoantibodies to nucleosomes.65 A strong association exists between certain HLA genes, particularly amino acid sequences in the DR and DQα and DQβ regions, and the ability to make certain autoantibodies.3,109-114 AntiRo/SS-A and La/SS-B are examples.113,114 They are genetically linked antibodies specific for proteins associated with small nuclear RNP; they are associated clinically with sicca complex, neonatal lupus, and subacute cutaneous lupus. Anti-Ro without anti-La is associated with DR2/DQw1; anti-Ro plus anti-La is associated with DR3/DQw2 and exhibits a gene-dose effect. That is, patients heterozygous for DQw1/DQw2 have high quantities of anti-Ro,113 which strengthens the evidence linking the genes and the autoantibodies. Most patients who have anti-Ro plus anti-La have three or four of the relevant DR/DQ alleles, and none has less than two.3 All of the DQα alleles associated with anti-Ro share a Glu in position 34; all the DQβ alleles have Leu in position 26. These amino acids are found in those positions in the I-A molecules of MRL/lpr mice, the only murine lupus model that makes large quantities of anti-Ro and antiLa.3,114 Many of these autoantibodies are associated with certain clinical manifestations of SLE. The genetic background may control the autoantibody pattern, which helps determine the clinical subset. NONLEUKOCYTE ANTIGEN GENES PREDISPOSING TO SYSTEMIC LUPUS ERYTHEMATOSUS IN HUMANS Non-HLA gene/genomic regions linked to or associated with SLE are listed in Table 74-3. A strong association between the rare disorder of complement C1q deficiency

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and SLE reveals the importance of C1q in preventing the development of SLE. Of approximately 40 individuals of European or Asian ethnic origin identified to have homozygous deficiency of C1q, more than 90% (30 individuals) developed SLE.115,116 Mice lacking C1q are defective in removal of apoptotic bodies, and many develop lupuslike glomerulonephritis on a permissive genetic background.117 Structurally similar to C1q, mannose-binding ligand (MBL) activates classic and alternative pathways of the complement cascade and opsonizes bacteria. Polymorphisms in the MBL promoter and exon 1, which result in lower levels of MBL, are more prevalent in SLE patients than in ethnically matched white, Asian, and AfricanAmerican controls.118-121 C-reactive protein (CRP), a pendraxin similar to C1q and MBL, assists in complement binding to foreign and damaged cells and is involved in clearance of immune complexes and apoptotic cells. The CRP gene is located on chromosome 1q23 within an interval linked to SLE in multiple populations. CRP variants that result in defective clearance of apoptotic products may provide autoantigens in SLE. Two CRP single-nucleotide polymorphisms (SNPs) have been associated with decreased levels (rs1800947, rs1205), ANA production (rs1800947), and risk for SLE (rs1800947) in a British family-based association study.122 An intronic GT repeat of CRP has been associated with plasma levels of CRP, and the GT20 allele is associated with high basal CRP in normal populations. The CRP GT20 allele occurs more frequently in AfricanAmerican and Hispanic SLE patients than in white SLE patients, and SLE patients carrying this allele are at risk for vascular arterial events.123 Administration of a single dose of CRP reverses lupus nephritis and nephrotoxic nephritis in mice, which suggests that CRP may reduce tissue inflammation and damage as the acute-phase reactant.124 Genetic effects of CRP may be modulated by FCGR2A variants. FcγRIIa receptor is the major receptor for CRP, and the R131 FCGR2a allele confers higher binding than the H131 allele.125 Current results of genetic studies are promising, and future investigation of this gene not only would allow better understanding of the genetic influence of CRP, but also its role in the pathogenesis of SLE manifestations. The Fc gene cluster located on chromosome 1q23 contains a set of structurally similar genes derived from gene duplications evolutionally. Human leukocytes express surface receptors that bind the Fc portions of IgG in immune complexes, which mediate immune clearance. Missense polymorphisms in the genes encoding FcγIIA or FcγIIIA receptors (H131R FCGR2A or V176F FCGR3A) result in differential affinity to IgG-containing immune complexes. The low binding alleles (the R131 allele of FCGR2A for IgG2 and the 176F allele of FCGR3A for IgG1/IgG3) are risk factors for susceptibility to SLE in multiple ethnic populations125-127 probably by virtue of decreased capacity in clearance of circulating immune complexes, which may result in tissue deposition and inflammation. In contrast, the V176 FCGR3A high binding allele may be a risk factor for progression of renal disease to end-stage renal disease among SLE patients.128 It is possible that when renal disease is initiated, the high binding allele may cause more tissue deposition of immune complexes and severe local damage. The risk allele of these two activating ­receptor

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genes are often coinherited as a risk haplotype for SLE.129 Of the two gene effects, V176 FCGR3A is associated with SLE more consistently and is associated with other autoimmune diseases, such as rheumatoid arthritis.130,131 Another member of Fc receptor genes, FCGR3B, has copy number variations that are associated with susceptibility to lupus nephritis.132 The gene copy number varies from zero to four, causing a dose effect of expression levels of FcγRIIIb.132 SLE patients with low FCGR3B copy number have reduced expression on surfaces of neutrophils, which may reduce glomerular clearance of immune complexes and increase risk for glomerulonephritis. FCRL3 encodes Fc receptor–like 3, which is structurally similar to FcγRs. A Japanese case-control study revealed the association of a functional SNP −C169T in the promoter region of FCRL3 with multiple autoimmune diseases, including SLE.133 This association with SLE was not confirmed in a Spanish study, however.134 FCGR2B is an inhibitory receptor that can downmodulate B cell receptor (BCR) signaling and decrease antibody-mediated phagocytosis in macrophages.135 The I232T allele affects the inclusion of the FcγIIb in membrane lipid rafts, in resting stage and in coligation with BCR, and the SLE-associated T232 allele is less potent in inhibition of B cell activation.136 The T232 FCGR2B is associated with SLE in multiple Asian populations, but this allele is rare in whites. Promoter polymorphisms of FCGR2B associated with SLE identified in two white cohorts are not found in Asians, supporting the notion of ethnic variations in FCGR2B variants predisposing to SLE.136 Interleukin (IL)-10, an immunoregulatory cytokine, can inhibit monocyte and dendritic cell function, but it stimulates B cell activation, proliferation, differentiation, and immunoglobulin secretion.137 Increased serum levels of IL-10 in SLE patients compared with normals have been shown consistently.137 The molecular basis of high IL-10 levels in SLE has been associated with several promoter polymorphisms (including two CA-repeat microsatellites and 10 SNPs). One microsatellite, IL-10.G, has been associated with susceptibility to SLE in Scottish, Mexican-American, and Italian populations, but not in Mexican, Swedish, or Taiwanese populations.138-143 Although no association between the three SNP haplotypes (−1082 G/A, −819 C/T, and −592 C/A) and SLE has been established in five studies, significant association with various SLE manifestations has been reported.144-148 The remaining seven promoter SNPs were identified more recently and led to the definition of eight SNP haplotypes.149 These haplotypes correlated with IL-10 production in normals and were significantly associated with SLE in African-Americans.149 These genetic studies suggested a molecular basis for elevated levels of IL-10 contributing to the pathogenesis of SLE. Polymorphisms of cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PDCD1), and protein tyrosine phosphatase PTPN22 may be a shared genetic factor for multiple autoimmune diseases in humans. CTLA4, a structural homologue of CD28 that competes with CD28 for the binding of B7 on APCs, can transduce inhibitory signals by activation of serine/threonine phosphatases, downregulate T cell function, and prevent autoimmune diseases by promoting anergy. The CT60A/G in the 3′UTR of CTLA4 decreased the production of a spliced variant with

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inhibitory activity and has been associated with multiple autoimmune diseases, including type 1 diabetes, autoimmune hypothyroidism, and Graves’ disease.150 Association between CTLA4 and SLE has yielded inconsistent results. Polymorphisms within the CTLA4 promoter (−1722T/C, −1661A/G, −319C/T) and exon 1 (+49G/A) have been associated with SLE in multiple ethnic groups.151 PDCD1 (also known as PD-1), a member of the CD28/ CTLA4/ICOS costimulatory receptor family containing an inhibitory immunoreceptor tyrosine-based motif, is expressed on activated T cell and B cell surfaces to regulate their peripheral tolerance.152 An intronic PDCD1 SNP (PD1.3A; the minor A allele of 7146 G/A) was associated with SLE in Europeans and Mexicans,153 with type 1 diabetes,154 and with rheumatoid arthritis subsets.155 This allele subsequently was associated with renal manifestations in SLE patients from Northern Sweden, but not with overall SLE susceptibility.156 Functionally, this SNP affects the binding of runt-related transcription factor 1 (RUNX1) in the intronic enhancer, which may influence hyperactivity of lymphocytes in SLE. The R620W polymorphism of PTPN22 disrupts the interaction of its protein product and Src tyrosine kinase (Csk), and alters negative regulation of T cell signaling.157 The 620W PTPN22 polymorphism was first identified as a candidate gene for type 1 diabetes158 and was subsequently associated with rheumatoid arthritis, SLE, autoimmune thyroid disease, and other autoimmune disorders in whites.159 Association of 620W PTPN22 with SLE has been variable—not consistently shown in sporadic SLE, but more likely to be found in SLE patients who have another overlapping autoimmune disease, family history of SLE, or other autoimmune diseases.160-163 The 620W is twice as active as R620 in suppressing TCR signaling, which presumably permits autoreactive T cells to escape from deletion during thymic development.159 Variants of CTLA4, PDCD1, and PTPN22 that affect either expression levels or functions have been associated with multiple autoimmune diseases, but their cellular pathways leading to disease onset await further investigation. A link between type 1 interferon (IFN) and the pathogenesis of SLE in humans and mice has been established by a series of studies.164 Genetic factors that cause increased production of type 1 IFN or stimulation of the IFN pathway or both may predispose to SLE. An initial screen of 13 genes in the type 1 IFN pathway identified association between SLE and variants in tyrosine kinase 2 (TYK2) and interferon regulatory factor 5 (IRF5) in a Scandinavian population.165 Tyk2 binds to type 1 IFN receptor α subunit, and its catalytic activity promotes ligand-induced downmodulation of receptor expression and negatively regulates cellular signaling.166 IRF5 is important for transactivation of type 1 IFN and IFN-responsive genes and for the production of proinflammatory cytokines (IL-6, IL-12, and TNF-α) after TLR signaling.167 Functions of these two gene products provide potential mechanisms to predispose to the development of SLE. Allelic association of IRF5 SNP (the T allele of rs2004640, 2 bp downstream from exon 1B) with SLE has been convincingly replicated using case-control and family-based cohorts in which the SLE-associated allele introduces an alternative splice site and expression of several unique IRF5 isoforms

with different coding and noncoding sequences.168 This allele together with an independent variant (rs2280714 T allele, approximately 5 kb downstream of IRF5, previously associated with elevated expression of IRF5 transcripts) forms a common haplotype that is strongly associated with increased risk for SLE.168 This IRF5 haplotype may cause increased production of various IRF5 isoforms with different activation properties, affinity to transcription cofactors, or stability, predisposing to the development of SLE. Linkage analysis in complex diseases (e.g., SLE) usually leads to the identification of large genomic intervals of approximately 20 centimorgans (approximately 20 million bp) that are likely to contain disease-susceptibility genes. This method uses DNA samples from families with multiple affected members to assess cosegregation of the test genetic marker allele with a phenotype of interest (e.g., SLE). As shown in Table 74-4, genome scanning of genetic markers from several groups using different collections of multiplex pedigree materials shows significant linkage of the 1q22-24,63 1q31,169 1q41-42,63,66,170 2q37,171 4p1615,172 6p21-11,62,173 12q24,174 and 16q12-1362,173 chromosomal regions to SLE (the threshold for significant linkage is defined as a logarithm of odds [LOD] scores = 3.3 or 3.6 depending on linkage methods).175 Confirmation of significant linkage in an independent cohort has been established for all eight loci, providing strong evidence for the presence of SLE susceptibility genes in each putative locus.64,170,172-174,176-178 Because linkage analysis identifies large genomic intervals that are likely to harbor disease-susceptibility genes, efforts to fine-map and assess positional candidate genes (candidate genes mapped within the linked region) are in progress. To this end, a positional candidate gene for the 2q37 locus,171,179 PDCD1, has been associated with SLE.153 PDCD1 is a strong candidate because mice deficient in PDCD1 are defective in peripheral tolerance of T cells and B cells and develop lupus-like arthritis and glomerulonephritis.150,180,181 An intronic SNP in PDCD1 is associated with susceptibility to SLE in Europeans and Mexicans with relative risks of 2.6 and 3.5.153 This SLE-associated SNP located in an intronic enhancer abolishes binding to the RUNX1 transcription factor, which could lead to aberrant regulation of PDCD1 contributing to breakdown of immune tolerance and development of SLE. The 1q41-42 linked region contains poly(adenosine diphosphate–ribose) polymerase, an enzyme that participates in DNA repair triggered by apoptosis, and that has been associated with SLE by one group of investigators,66 but not confirmed by others.182-184 The 1q22-24-linked region contains FCGR2A and FCGR3A, which have been associated with SLE susceptibility in many studies as described previously. These two genes may be in linkage disequilibrium because of their physical proximity, which complicates the assessment of the relative role of each gene in susceptibility to SLE. A more recent study provides strong genetic evidence (linkage and family-based and population-based association) to support a role of FCGR3A in susceptibility to SLE.185 No positional candidate genes within the 4p16-15 region have been associated so far with SLE. The 6p21-11-linked region contains the approximately 3.6-Mb HLA region that contains several class II risk haplotypes of SLE. CARD15/ NOD2, encoding a protein involved in bacterial recognition

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by monocytes, is the positional candidate gene within the 16q12-13 region linked to SLE. The functional role of CARD15 in innate immunity makes its genetic variants candidates for predisposition to autoimmune diseases. Multiple polymorphisms of CARD15 have been shown to contribute to susceptibility to Crohn’s disease.186-188 The three most common polymorphisms associated with Crohn’s disease are not associated with SLE in a Spanish population,189 but the 908R CARD15 allele is associated with SLE in a larger study of European whites.190 Interaction between genetic risk factors may affect susceptibility; data supporting linkage and genetic interaction of 1q23 and 16q12 have been observed in a multiethnic cohort containing 145 SLEaffected sibling pairs.176 The highly heterogeneous nature of manifestations among SLE patients may represent genetic heterogeneity that confounds the identification of lupus-susceptibility genes. One approach to reduce heterogeneity is to stratify pedigrees for the presence of a single manifestation and to re-evaluate the genome-wide scanning data for linkage evidence for the particular manifestation-associated SLE locus. This strategy has led to the identification of (1) a vitiligorelated SLE locus, SLEV1, at chromosome 17p13,191 which has been confirmed by an independent study192; (2) an SLE susceptibility locus, SLEH1, at 11q14 in African-American SLE pedigrees stratified by hemolytic anemia (maximum LOD = 4.5 at D11S2002)193 and a nucleolar antibody pattern (maximum LOD = 5.62 at D11S2002)194; (3) an SLEB3 locus at 4p16 in 23 European-American SLE pedigrees stratified by neuropsychiatric manifestations (maximum LOD = 5.19 at D4S2366)195; (4) an SLED1 locus at 19p13.2 (maximum LOD = 4.93 at D19S714) and another SLED2 at 18q21.1 (maximum LOD = 3.40 at D18S858) in 37 European-American and 29 African-American pedigrees, containing at least one affected case with a positive antidsDNA196; and (5) SLEN1 at 10q22.3 (maximum LOD = 3.16 at D10S2470) and SLEN2 at 2q34-35 (maximum LOD = 2.15 at D2S2972) in 31 European-American pedigrees and SLEN3 at 11p15.6 (maximum LOD = 3.34 at D11S1984) stratified by renal disease in 20 African-American pedigrees with two or more patients with SLE and renal disease,197 in which SLEN1 and SLEN2 have been confirmed.198 The advantage of this approach is the improved evidence for linkage revealed by pedigree stratification based on select clinical manifestations compared with the disease status of SLE. These results from testing each manifestation separately increase the possibility of false-positive results using a smaller subset of family materials, however, which highlights the importance of replications in independent samples. MURINE LUPUS GENETIC STUDIES Several inbred mouse strains are genetically “programmed” to develop SLE.199,200 New Zealand Bielchowsky/Black (NZB/Bl) mice develop IgG1 antibodies to erythrocytes, IgM antibodies to ssDNA, and mild lymphoproliferation; most die of hemolytic anemia, with disease earlier in females than in males. NZB/NZW and NZB/SWR F1 hybrids develop IgG2a and IgG2b anti-dsDNA; females die of glomerulonephritis mediated primarily by anti-DNA, and males develop slowly progressive disease at a later age.

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NZB/NZW F1 hybrid brother-sister matings have generated substrains of mice designated NZM mice that vary widely in prevalence and severity of nephritis, serum levels of IgG and IgM, and antibodies to nucleosomes and DNA. Linkage studies of the entire mouse genome of the New Zealand genetic background have identified specific chromosomal regions that harbor lupus susceptibility genes, including genes located on chromosomes 1, 4, 7, and 17 (containing the MHC region). The importance of these chromosomal regions has been elucidated by detailed phenotypic characterization and successive backcrosses into another normal mouse strain (C57BL/6 or B6) to analyze the locations and component phenotypes of individual susceptibility genes. Heterozygosity at the H2 locus on chromosome 17 (particularly containing H2z from NZW) has been identified as important in conferring certain autoantibodies and nephritis.201-204 The regions of interest on chromosomes 1 and 4 contain DNA contributed by NZB and NZW parents. One NZB-derived locus on chromosome 1, Nba2, may contribute to loss of tolerance to DNA-containing self-antigens.200,202,203 The Nba2 lupus susceptibility locus was characterized further by developing congenic mice via repeatedly backcrossing mice containing the NZB chromosome 1 interval into the normal B6 genetic background and then intercrossing siblings to generate B6.Nba2 congenic mice homozygous for the Nba2 locus. Comparisons of 11,000 gene microarrays revealed only two differentially expressed genes of spleen cells from B6.Nba2 and B6 mice: IFN-inducible Ifi202 and Ifi203.205 Ifi202 has been implicated as a candidate susceptibility gene supported by studies of strain distribution of expression, promoter polymorphisms, and effects on cell proliferation and apoptosis. A similar approach has produced multiple congenic strains of mice, each carrying a single susceptibility locus from the NZM2410 genome.206 The region designated Sle1 on chromosome 1 (close to Nba2), when expressed in B cells and T cells of a normal B6 background (B6.NZMc1), promotes development of IgG antibodies to nucleosome and generates histone-specific T cells.207-210 Although the mice lose tolerance to nucleosome and develop ANAs induced by the exposed portion of chromatin (H2A/H2B/DNA)— antibodies thought to precede pathogenic anti-DNA—these antibodies do not evolve, and animals develop minimal nephritis. Subsequent studies reveal that the potent autoimmunity conferred by the genomic interval of Sle1 reflects the combined effects of a cluster of four independent, but functionally related, susceptibility genes: Sle1a, Sle1b, Sle1c, and Sle1d.211 Congenic strains for each of these four subintervals have been generated, in which Sle1b is the strongest contributor of the observed Sle1 phenotype and has been isolated to a small genomic segment containing the SLAM family of lymphocyte adhesion receptors. The lupus-susceptible allele results in alternative splicing of messenger RNA of one SLAM family member, Ly108, which reduces the ability of self-reactive BCR to signal clonal anergy and receptor editing, resulting in accumulation of self-reactive B cells in the spleen and lymph nodes.212 The congenic interval of Sle1c results in the production of autoreactive B cells and T cells mediated through three genes.213 One of these genes, Cr2, which encodes complement receptors 1 and 2 by alternative splicing of a common transcript, has been implicated

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as a lupus susceptibility gene.214 An SNP of the NZM2410/ NZW Cr2, creating a novel glycosylation site within the C3d binding domain, may interfere with receptor dimerization, reduce receptor-mediated signaling, and consequently lower the threshold for negative selection of autoreactive B cells.214 Mice congenic for the region on chromosome 4 (B6. NZMc4 expressing the Sle2 region) show hyperactivation of B cells with hypersecretion of IgM, but develop no nephritis.210 Mice congenic for the chromosome 7 region (B6.NZMc7 containing the Sle3 region) have hyperactivation of T cells, increased numbers of CD4+ helper T cells, reduced apoptosis, and increased levels of IgG antibodies to multiple nucleosomal antigens; they develop moderate nephritis.210 When mice are bred to express Sle1 and Sle3, they develop severe disease, with IgG antibodies to DNA and other self-antigens, and lethal, early glomerulonephritis—confirming the hypothesis that multiple genes conferring multiple abnormalities in immune tolerance and B cell and T cell function are required for an individual to develop severe SLE.210 Finally, studies of this type have shown that several chromosome regions in NZW mice (a strain that inherits multiple susceptibility genes, including H2z, Sle1, and Sle3) are linked to protection from disease.210 One of these, Sle1 suppressor (Sle1s), when bred into mice with Sle1 plus Sle3, reduces the incidence of severe nephritis by half.215 Sle1s has been narrowed to a 956-kb genomic interval that definitely excludes TNFA, but includes many functionally important candidates, including MHC class II genes, the complement genes proximal to TNF-α, and others.215 Modifying and protective genes are crucial in determining exactly how “predisposed” an individual is to this autoimmune disease.

ENVIRONMENTAL FACTORS, GENDER, AND APOPTOSIS AS SOURCES OF AUTOANTIGENS As mentioned in the discussion of genetics, the fact that most monozygotic twins are discordant for clinical SLE suggests that environmental factors play a role in disease pathogenesis (Table 74-5).53-55,216 Two environmental factors are clearly important: UV light and gender. There also is increasing evidence for a role for Epstein-Barr virus (EBV) infection. Seventy percent of SLE patients experience disease flares after exposure to UV light217; the B spectrum may be more important than the A spectrum in activating disease in humans. Although patients might be wise to avoid intense exposure to UVA and UVB spectra, some data suggest that exposure to UVA might benefit SLE.218 Several experiments have suggested mechanisms by which exposure to UV light might accelerate disease. Exposure of DNA to UV light increases thymine dimers, which renders the DNA more immunogenic.219 It has been observed that exposure of keratinocytes to UV light induces apoptosis.4,220 During apoptosis, three events occur that probably expose self-molecules to the immune system or render them immunogenic, or both: (1) movement of nuclear and cytoplasmic DNA-protein and RNA-protein antigens to the surface of cells in membrane-encased blebs (e.g., nucleosomes, Ro/SS-A, and U1 RNP antigens),4,220

(2) flipping of the membrane inside-out so that antigenic portions of membrane ­ phospholipids are exposed on the cell surface, and (3) modification of intracellular proteins that might render them antigenic.221 Each of these changes presents nucleoprotein and cytoplasmic and phospholipid self-antigens to the immune system; this might be the major stimulus that allows the few lymphocytes that escape selftolerance mechanisms to become self-reactive. More recent evidence indicates that apoptotic lymphocytes also release lipid microparticles, which have proinflammatory and antiinflammatory effects and can induce apoptosis in monocytes/macrophages, contributing to the defective clearance of apoptotic cells and immune complexes characteristic of SLE.222 The potential role of EBV in inducing or flaring SLE, originally suggested by James and colleagues in 1997,223 has been confirmed in more recent work. Because EBV lives chronically in B cells, and B cell activation is a feature of SLE, it is difficult to say whether EBV infection initiates B cell hyperactivity, autoantibody formation, and disease, or whether the upregulation of EBV in B cells results from other activating stimuli. It may not matter which is true because the appearance of the response is likely to initiate much broader autoimmunity in susceptible individuals. Patients with SLE have abnormally high frequencies of EBV-infected cells in their blood, and in one study high copy numbers were associated with disease flares.224 EBV latency membrane proteins also are expressed, and these Table 74-5  Environmental Factors That May Play   a Role in the Pathogenesis of Systemic Lupus   Erythematosus (SLE) Definite UVB light EBV Probable Estrogen and prolactin—in humans, female-to-male ratio is 9:1 between menarche and menopause, 3:1 in young and old Lupus-inducing medications*   Hydralazine   Procainamide   Isoniazid   Hydantoins   Chlorpromazine   Methyldopa   Penicillamine   Minocycline   Tumor necrosis factor-α inhibitors   Interferon-α Possible Dietary factors   Alfalfa sprouts and related sprouting foods containing     Canavanine     Pristane and similar substances Infectious agents other than EBV Bacterial DNA Human retroviruses Endotoxins, bacterial lipopolysaccharides *Although each of the drugs listed, and many others, can induce lupus-like symptoms in predisposed individuals, there is little evidence that they can induce true SLE or even activate disease in individuals with spontaneous, established SLE. If the clinical care of a patient with SLE would benefit from use of one of these drugs, the drug should not be withheld. EBV, Epstein-Barr virus; UVB, ultraviolet B.

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proteins can heighten activation of TLR, a mechanism that could allow autoreactive B cells to avoid tolerance.225 In another study,226 EBV viral loads measured by multiple methods showed a 40-fold increase in SLE patients compared with controls and a greater frequency of EBV-specific CD69+CD4+ T cells producing IFN-γ. EBV viral loads were inversely correlated, however, with the frequency of EBVspecific CD69+CD4+ IFN-γ-producing cells, and with lower levels of HLA-A2 tetramer-positive CD8+ T cells. Whether EBV infection triggers SLE or is stimulated by it, T cell control of the viral production is inadequate, and the response persists too long; this fits with the general principle that immunoregulation of autoantibody production is defective. Children with SLE are 50 times more likely to have been infected with EBV than children from the same clinics who do not have SLE (discussed subsequently).223 Even in adults with SLE, the odds ratio for infection with EBV is 8.227 Infection with EBV results in production of the viral protein EBV nuclear antigen-1 (EBNA-1). Antibodies against EBNA-1 are found in all infected individuals, but in SLE the antibodies diversify more than in normals, developing cross-reactivity with Ro, Sm B/B′, and SmD1—all antibodies characteristic of SLE. In the permissive genetic background, the single common infection with EBV can lead to unusually extensive epi­ topic spreading, generating multiple autoantibodies.228,229 IgA and IgG antibodies to EBV were associated with SLE in African-Americans and in older whites with the disease. There was an additional association between an allelic variant of the CTLA4 gene promoter and the anti-EBV response.230 It is likely that EBV (but not other herpesviruses tested or cytomegalovirus) can push a predisposed individual from nonautoimmunity to autoantibody production, starting the cycle that may lead to disease. In addition, cycles of disease worsening could relate to B cell activation with increased EBV antigens stimulating production of other autoantibodies. Breakthroughs in understanding of the role of the innate immune system in predisposing to SLE are likely to lead to discovery of other inciting infectious agents. Administration of bacterial lipopolysaccharides to mice with SLE accelerates disease.231 One study232 detected antibodies to the retroviral gag protein p24 from human immunodeficiency virus type 1 in one third of SLE patients compared with 1 of 120 control subjects. Type C coronavirus has been implicated in the nephritis of NZB/Bl mice and related strains.233 One group found persistent BK polyomavirus more frequently in patients with SLE than in control subjects.234 To date, only the EBV explanation has consistent support from multiple laboratories. Gender is of great importance in susceptibility to SLE, which is predominantly a disease of women, particularly during the reproductive years.216,235 The basis of this sex predisposition is not fully understood. It seems unlikely that gene polymorphisms on the X chromosome are involved because the disease does not follow a sex-linked genetic pattern. More recent work shows, however, that regulatory regions controlling expression of CD40L on T cells, located on the inactive X chromosome in women with SLE. are demethylated (compared with healthy women), resulting in increased CD40L expression, which should provide increased activation signals between T and B cells.236

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Epigenetic changes in methylation of DNA also can be induced by environmental exposure to drugs237 and may play a role in drug-induced lupus. In lupus-prone mice (BXSB) strain, a lupus-accelerating gene (Yaa) has been mapped to the Y chromosome; Yaa results from increased copy numbers of TLR7 after translocation of the TLR7 gene from X to Y. This translocation probably leads to increased immunoreactivity to RNA-containing antigens.61 It is unknown whether increased copy numbers of TLR7 predispose to SLE in humans. Another idea is that women who have been pregnant have fetal cells that persist for decades in their circulation or tissues; the fetal cells induce chronic graft-versus-host disease, which resembles SLE.238 Similarly, maternal cells persist in offspring for many years. Abnormalities in sex hormone metabolism might contribute to gender differences in susceptibility to SLE. Men and women with SLE have accelerated metabolism of testosterone.235,239,240 Estrone is preferentially hydroxylated at the C-16 position in men and women with SLE and in their first-degree relatives, resulting in the accumulation of 16-hydroxylated metabolites, which have sustained high estrogenic activity. Men and women with SLE might have too much estrogenic and too little androgenic hormone, shifting their immune system toward increased responses. Among menopausal nurses (N = approximately 70,000), those treated with hormone replacement therapy had an increased risk for development of SLE compared with nurses who did not receive hormone replacement therapy (age-adjusted relative risk 2.1 to 2.5),241 and women in this cohort exposed to estrogen-containing oral contraceptives also had slightly increased risk for SLE (relative risk 1.4 to 1.9).242 The increased risk conferred by prior use of oral contraceptives was not confirmed in a subsequent study of a smaller population (N = 240) of women who already had SLE.243 A lupus-enhancing effect of estrogen was confirmed in a study in which treatment of women with 1 year of hormone replacement therapy containing estradiol and progesterone significantly increased the rate of mild and moderate disease flares, although not severe flares.244 In contrast, treatment with oral contraceptives for 1 year was not associated with increased flare rates.245,246 Prolactin levels are elevated in some individuals with SLE and may increase disease activity.247 Finally, there is evidence that T cells (from humans) and B cells (from mice), when exposed to estradiol, develop resistance to tolerance. In a transgenic mouse model of antiDNA expression, B cells that bind DNA with high avidity are deleted in the bone marrow and do not reach peripheral tissues. Treatment of the mice with estradiol (or prolactin) rescues those cells, however; they survive to enter either marginal zones (T cell–independent responses) or follicular regions (T cell–dependent antibody responses) of peripheral lymphoid tissues.248 In the estradiol group, Bcl-2 is upregulated (probably protecting from apoptosis),249 and calcium signaling and tyrosine protein kinase phosphorylation are diminished. The presence of female sex hormones is a factor that allows autoreactive B cells to survive tolerance and persist in peripheral tissues, where they can increase autoantibody production if the correct activating signals are provided.

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In SLE, some B cells fail to be appropriately deleted when exposed to self-antigen. There is substantial evidence in mice and humans that lymphocytes resistant to apoptosis lead to lymphoid compartment expansion and autoimmunity (e.g., the lpr and gld mutations that permit mice with susceptible genetic backgrounds to develop full-blown SLE). With regard to T cells, in vitro exposure of human SLE T cells to estradiol upregulates surface CD40L expression and production of calcineurin, along with reducing apoptosis in those cells.250,251 The general theme here is that estradiol is likely to prolong the life of autoreactive B cells and T cells, providing another permissive factor for development of disease. An additional factor that may promote development of disease in genetically predisposed individuals is diet. Some macaque monkeys fed alfalfa sprouts developed SLE; sprouting vegetables contain an aromatic amino acid, canavanine, that is immunostimulatory.252 Mice with SLE are protected from disease if they have severely restricted calorie intake, restricted fat intake, or high intake of omega-3 unsaturated fat such as eicosapentaenoic acid (fish oil).253-255 A study in human SLE suggested that 20 g of fish oil daily may be steroid sparing.256 The role of these dietary observations in human disease is uncertain, but we recommend that patients with SLE minimize their dietary intake of sprouts, excessive calories, and saturated fat. Reports suggesting that exposure of women to hair dye, permanent-wave solutions, and lipstick increased their risk for SLE were not confirmed in subsequent studies.257,258 Drugs appear on the list of environmental exposures that might induce SLE-like disease. The drugs listed in Table 74-5 are frequently implicated in drug-induced SLE.259 This disease is probably different from spontaneous SLE. The clinical manifestations of drug-induced SLE are predominantly arthritis, serositis, fatigue, malaise, and low-grade fever; nephritis and central nervous system disease are rare. These manifestations disappear in most patients within a few weeks of discontinuation of the offending drug, never to reappear unless re-exposure occurs. Although ANAs appear in all patients, it is unusual for high titers of anti-dsDNA or profound hypocomplementemia to develop. Antibodies to histones are common with some of the inducing drugs; these antibodies also are found in SLE. In drug-induced SLE and spontaneous SLE, the response is probably directed primarily against chromatin nucleosomes, with different histones dominating the response in the two diseases.259 Antibodies to lymphocytes, platelets, erythrocytes, and phospholipids occur in drug-induced SLE and spontaneous SLE. It is possible that an individual predisposed to SLE might have the disease triggered by exposure to one of these drugs. Experience has suggested that such an event is rare, however. If a patient with spontaneous SLE needs one of these drugs (e.g., hydantoin or isoniazid), the drug should not be withheld. If one drug has probably induced SLE, the patient should not be rechallenged with that agent. Specificity of autoantibodies to DNA-protein or RNA-protein complexes may spread over time to involve other self-antigens in individuals with the correct permissive genes. Of note to rheumatologists is the more recent implication of therapies with minocycline,260 statins, and TNF inhibitors261,262 as potential inducers of SLE-like reactions.

What are the antigens that induce SLE? Are the stimulating antigens foreign (cross-reacting or mimicking “self,” such as EBV, which contains a sequence found in proteins associated with Ro), or are they normal or altered self-molecules (e.g., apoptotic bodies) that induce responses that overwhelm tolerance? The role of DNA has been a particular mystery because mammalian DNA (in contrast to bacterial DNA) is weakly immunogenic,263,264 and yet the IgG anti-dsDNA response correlates with disease activity and nephritis in some patients with SLE, and antibodies to DNA cause nephritis in mice.11 Immunogenic DNA could originate from certain bacteria after infection,265 but it is likely that mammalian DNA-protein complexes, particularly those in nucleosomes, are the initial stimulators of this response.266,267 Early responses in mice are directed against nucleosomes and “spread” to involve ssDNA and dsDNA over time.267 Helper T cells that support anti-DNA production are activated by nucleosomes,266 and some nephritogenic monoclonal antibodies to DNA bind DNA-histone complexes; the anti-DNA/DNA-histone complex can bind to heparan sulfate in glomerular basement membranes.11 Some antibodies of this type can penetrate cells and bind to cytoplasmic and nuclear structures, probably altering cell function and contributing to disease by mechanisms other than classic complement-mediated tissue injury.47,268 The stimulatory role of the Ro molecules is probably similar in that RNA-protein globular complexes induce an immune response in B cells that spreads to include reactivity to other antigens.269 Cells undergoing apoptosis are capable of presenting nucleosomes, Ro, U1 RNP, and antigenic portions of membrane phospholipids to immune systems and may be crucial in inducing autoreactivity or permitting it to persist.270,271 It is likely that apoptosis must be precisely balanced to avoid autoimmunity. In humans, defects in Fas (Fas is required for normal apoptosis) are associated with lymphoproliferative disease and autoimmunity, particularly hemolytic anemia and thrombocytopenia—the CanaleSmith syndrome.270 Apoptosis that is too rapid might allow quantitative increases in presentation of self-antigens. Apoptosis in some patients with SLE is defective; levels of the Bcl-2 protein that protects from apoptosis are high in human SLE T cells,271 but levels of Fas ligand (which promotes apoptosis) also are high, and in vitro apoptosis of lymphocytes is increased.270,272 Another potential mechanism promoting SLE through altered apoptosis involves deficiencies of C1q. It is likely that C1q is involved in clearance of cells undergoing apoptosis273; perhaps failure to clear such cells is important in individuals with homozygous deficiencies of C1q, almost all of whom develop SLE.88,89 Mice homozygous for C1q deficiency also are predisposed to lupus nephritis.274 There are likely to be four major sources of nucleosomelike antigens that stimulate antinucleosomal immunity so central to SLE: (1) CpG DNA in bacteria and in DNA/ anti-DNA complexes that bind to TLR in dendritic cells and B cells, (2) viral RNA that binds TLR and other receptors in dendritic cells and B cells, (3) apoptotic bodies, and (4) debris from dying cells. In addition to the available sources, normal clearance mechanisms for immune complexes (e.g., nucleosome/antinucleosome) and for apoptotic cells are defective.

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ABNORMAL IMMUNE RESPONSES CHARACTERISTIC OF SYSTEMIC LUPUS ERYTHEMATOSUS The result of interactions between susceptibility genes and triggering environmental factors is development of the pathogenic autoantibodies and immune complexes that characterize SLE. This development requires hyperactivity of B cells and T cells and failure of multiple immunoregulatory circuits to downregulate those responses. The most prominent of these abnormalities are listed in Tables 74-6, 74-7, and 74-8. CHARACTERISTICS OF LUPUS B CELLS Abnormalities of B cells are summarized in Table 74-6. B cells play a central role in SLE. Along with their traditional functions as precursors of antibody-producing plasma cells, B cells are efficient APCs and regulate T cell functions, produce cytokines, and express receptor-ligand pairs (i.e., CD154-CD40) previously thought to be restricted to other cell types.275 B cells develop in bone marrow from stem cells to progenitor B cells to pro-B cells to pre-B cells (pre-B cells are the earliest cells that express surface CD20), then to immature B cells that circulate in the peripheral blood and populate lymphoid tissues. In the periphery, B cells become

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mature. There are several transitional stages between immaturity and maturity, and at each of these points are mechanisms designed to eliminate highly autoreactive cells. In the presence of a new antigen, mature B cells recognizing it become activated, then die from activation-induced death; form blast cells, which become antibody-secreting plasma cells; or become memory B cells stored in peripheral compartments. During periods of clinically active SLE in humans, numbers of plasma cells increase, numbers of naive mature B cells decline, and the proportion of memory B cells increases.276 Long-lived plasma cells (which express little, if any, CD20) are resistant to most of the treatments currently used in SLE, and their persistence might account for flares.276,277 In the periphery, at least three types of B cells participate in autoimmunity: (1) the B-1 B cell (about 20% of circulating B cells in adults), which has limited antigen reactivity, secretes IgM, and is primarily self-renewing; (2) the marginal zone B cell in peripheral lymphoid tissue, which is largely responsible for T cell–independent antibody production; and (3) the follicular B cell, which exists in peripheral lymphoid tissue in close approximation to T cells and matures into cells that make T cell–dependent antibodies. All of these B cells can make anti-DNA, but the large quantities of IgG subsets that are major pathogens probably derive primarily from follicular B cells.

Table 74-6  Characteristics of B Cells in the Abnormal ­Immune Response in Patients with Systemic Lupus ­Erythematosus (SLE) Numbers

Surface/Cytoplasm Markers

Functions

Increased immunoglobulin-synthesizing   plasma cells

Increased surface CD40L (enhances activation)

Activation via BCR produces increased ­intracellular Ca2+

Increased mature B cells

Increased surface CD80 and CD86 (enhances ­activation)

Decreased naive B cells

Decreased surface CR2 (decreased binding C′, interferon-α)

Increased memory B cells

Increased BlyS in serum drives maturation, ­immunoglobulin secretion Mature B express RAG1 and RAG2 (ready for ­immunoglobulin secretion)

Expression of VH4.34 H chain

Increased germinal center phenotype (exposed   to T cells)

Genetic variants that reduce activity of inhibitory pathways (lyn, FcγRIIB1) predispose to SLE Increased production of IL-6 and IL-10 supports   B cell maturation and proliferation

BCR, B cell receptor; IL, interleukin.

Table 74-7  Abnormalities in T Cells in Systemic Lupus Erythematosus Numbers

Functions

Responses to T Cell Receptor Stimulation

Decreased CD4+ T cells

Abnormal rates of apoptosis lead to imbalance

Autoantigens stimulate T cell help

Decreased CD8+ T cells

Hyperreaction to signaling through TCR

TCR recognizes peptides from immunoglobulin VH, histone in nucleosomes, Sm, RNP, Ro

Increased double negative T cells

Activation results in reduced IL-2 production with   increased intracellular Ca2+, increased phosphorylation   of tyrosine kinases, increased CREM

T cells of many phenotypes provide help

Decreased iNK T cells

Respond to interferon-α from dendritic cells

Defective regulation of T cell help by CD4+CD25+ regulatory T cells and CD8+ T cells Increased release of sIL-2R, TNFR, sCD40L Increased secretion of IL-10, interferon-γ

Mitochondrial abnormalities IL, interleukin; TCR, T cell receptor.

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Table 74-8  Abnormalities in Immunoregulation in Systemic Lupus Erythematosus B Cells

T Cells

Dendritic Cells (and Monocytes)

Deletion of cells with high affinity for self is defective

Deletion of cells with high affinity for self is defective, delayed, or accelerated

Helper dendritic cells are activated and express surface MHC class II, CD80, CD40, FasL (poised to activate B and T)

Inadequate generation of regulatory T cells   and inhibitory/cytotoxic T cells

Defects in maturity arrest necessary for tolerizing T cells, or in IL-10 production

Resistant to apoptosis BCR receptor editing may be defective

Antibody idiotypic networks fail to suppress   T cell–activating determinants fail to activate B cells CD4+CD25+ regulatory T cells and CD8+CD28− suppressive T cells Cytokine shift favors activation of T cell help,   rather than regulation

Phagocytic cells fail to remove immune complexes and apoptotic cells adequately

BCR, B cell receptor; IL, interleukin.

The following abnormalities of SLE B cells have been described in human and murine lupus: 1. Aberrant survival of autoreactive autoantibodyproducing cells in the periphery 2. Enhanced B cell activation resulting from increased signaling responses after ligation of surface receptors, and diminished activity of inhibitory signaling pathways278 3. Enhanced production of and response to several cytokines and other growth factors 4. Secretion of high-affinity IgG antibodies to selfantigens The descriptions that follow apply to B cells identified after the diagnosis of SLE, and by that time, many factors have influenced the B cells. B cell–B cell interactions mediated by CD154-CD40 are essential for differentiation of germinal center B cells into memory cells and for the formation of secondary germinal center structures that allow reactivated memory B cells to differentiate into plasma cells secreting high-affinity antibodies.275,279 IL-21 also drives naive and memory B cells to mature into plasma cells, particularly cells activated by the costimulatory CD154-CD40 interaction.280 Autoantibody-producing B cells may be redirected into T cell–dependent germinal center regions, leading to differentiation into plasma cells secreting pathogenic autoantibodies.275 Evidence from studies in MRL/lpr and (NZB/NZW) F1 mice suggests that autoreactive B cells are able to form or enter splenic follicles where they contact T cells, whereas in normal mice, autoreactive B cells are retained outside follicles.281,282 Freshly isolated B cells from the periphery of patients with active SLE are poised to be easily activated and to escape regulation. Their surfaces constitutively express CD154; they are enriched in cells that express a germinal center phenotype or TLR9 or both,275,276,283 and they have downregulated the complement-inhibitory proteins CD55 and CD59.284 In addition, they are pushed to activation and survival by a microenvironment rich in B cell growth factors, such as B cell activating factor (BAFF), or BlyS, and IL-10.285 In addition, SLE memory B cells have decreased expression of the downregulating Fc receptor, FcIIB, in contrast to cells from normal healthy controls.286 When B cells from SLE patients are activated, aberrant cell signaling occurs.278,287-290 This occurrence is characterized by recruitment of a low-molecular-weight isoform

of CD45 to lipid rafts on cell membranes, with resultant reduced recruitment of Lyn, a protein tyrosine kinase, which alters signal transduction. There is increased intracellular calcium flux and abnormal phosphorylation of multiple proteins; these changes are independent of disease activity287 and are indicative of intrinsic abnormalities in SLE B cells. As further evidence of intrinsic B cell defects, in the MRL/lpr mouse model of SLE, mice unable to generate T cell help because they are TCR−/− still develop anti-DNA and nephritis,291 and mice with B cells expressing surface BCR, but unable to secrete immunoglobulin, still develop nephritis, although in lower frequency than the wild-type MRL/lpr mice.292 Although these abnormal B cells might be accounted for by delayed apoptosis with the lpr (mutated Fas) background, there also is evidence for intrinsic B cell abnormalities in the Fas-intact (NZB×NZW)F1 mice, where adoptive transfer of pre-B cells from embryonic liver into severe combined immunodeficiency mice resulted in production of anti-DNA and nephritis.293 Finally, expression of the antiapoptotic molecule, Bcl-2, is increased in SLE B cells of some mouse models and of some patients, probably contributing to prolonged survival.271,294 Defects in the induction or regulation of B cell apoptosis have been well characterized in human and murine systems of SLE and can be summarized as follows: 1. Autoantigens that drive B cells are readily available. 2. Altered homeostasis of apoptosis favors either antigen presentation (acclerated apoptosis) or persistence of autoreactive B cells (delayed apoptosis). a. Mutations of Fas or Fas ligand genes are associated with delayed apoptosis in lymphocytes, including B cells, of lpr and gld mice, resulting in lymphoproliferation and systemic autoimmunity. Sporadic cases of humans with Fas and Fas ligand mutations have been reported who also develop lymphoproliferative diseases with some lupus-like features.295 Increased expression of Fas ligand on anti-DNA–secreting B cells in patients with SLE may increase killing of Fas-expressing immunoregulatory T cells, facilitating escape of autoreactive B cells from the immune tolerance system.296 b. Mice congenitally deficient for the proapoptotic protein Bim297 or transgenic for the antiapoptotic protein Bcl-2294 develop a lupus-like disorder.

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c. Bcl-2 expression is increased in peripheral lymphocytes and sera of some SLE patients, but not all.298-300 3. B cell growth factors play a role in promoting B cell maturation and immunoglobulin secretion in individuals with predisposing genetic or environmental factors. Mice transgenic for BlyS (a member of the TNF superfamily, also called BAFF or TALL-1) develop lymphoproliferation and a lupus-like disorder associated with inhibition of B cell apoptosis mediated by Bcl-2 upregulation.301,302 BlyS is important for driving immature B cells to mature B cells.303 Some SLE patients exhibit elevated serum levels, lymphocyte levels, and target tissue levels of this protein.304 4. Estradiol and prolactin sex hormones influence the location and activation of B cells. Altered selection of naive B cells and their rescue from tolerance induction, with subsequent persistence in the periphery, as a result of hormonal treatment with estradiol or prolactin,247-249,300 is associated with an upregulation of Bcl-2 expression and impaired apoptosis in these cells. The antigens recognized by B cells are important in stimulating pathogenic autoantibody production by the hyperactivatable cells. In lupus mice, polyclonal activation of B cells precedes the high-avidity, single autoantigen–specific B cell activation that characterizes well-developed disease. This fact suggests that B cells in SLE are subject to increased polyclonal activation and antigen-specific activation before disease appears.305,306 Either type of stimulation induces altered intracellular events that result in increased B cell function and delayed apoptosis. Because patients have autoantibody repertoires that differ among individuals (e.g., almost all have ANAs, but only some have anti-dsDNA, anti-Ro, anti-RNP, or antiplatelet antibodies), it is likely that many B cells are activated by specific antigens. After autoantibody responses are initiated, B cells and helper T cells develop that recognize additional antigens—a process known as epitope spreading. A lupus-predisposed individual may make an antibody to immunogenic portions of nucleosome, Sm peptides, or immunoglobulin-derived peptides, and a few months later, B cells can be detected that make antinucleosome or anti-Sm, anti-dsDNA, and ANAs.306-308 Whether spreading is more common in SLE than in normal individuals may depend on intrinsic abnormalities of B cells and T cells, failure to regulate the initial response, the presence of an antigen that mimics these DNA-protein or RNA-protein complexes (especially on their surface), or engagement of dendritic cells via DNAprotein and RNA-protein complexes, or all four.307-309 Another possible reason for hyperactivity of B cells in SLE is abnormalities in the CR2 pathway.310 CR2 is a polymeric surface complex containing CD21, CD19, and CD81; it binds EBV, C3b, C3dg, C3d, and IFN-α, and possibly DNA in immune complexes. When BCR and CR2 are cross-linked, the activating signal for B cells is greatly magnified. In SLE patients, CR2 expression is decreased during active disease. Although one might predict that low CR2 would result in less B cell activity, full expression of CR2 may be required for enough activation to induce apoptosis. Low CR2 might result in defective B cell tolerance. In addition, inhibitory signaling pathways may be impaired in SLE B cells. The coreceptors that negatively regulate surface immunoglobulin signaling, CD22 and CD45, and a

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downstream signal transduction molecule (SH2-containing phosphatase 1) all have been shown to be downregulated in SLE B cells.311-313 An additional abnormality of SLE B cells is enhanced production and response to cytokines, such as IL-6 and IL10. SLE B cells are more easily driven to differentiate by IL-6 than are normal B cells.314 SLE patients have increased numbers of IL-6-secreting cells, and SLE B cells constitutively express surface receptors for IL-6, in contrast to B cells from normal controls.314,315 IL-6 increases in vitro production by B cells of IgG and anti-DNA-IgG, whereas addition of anti-IL-6 inhibits those effects.315 Administration of IL-6 to mice accelerates lupus.316 IL-10 has immunostimulatory and immunosuppressive effects. SLE patients display increased serum concentrations of IL-10 and increased numbers of IL10-secreting cells during active disease.317,318 Administration of anti-IL-10 to SLE-predisposed mice is effective in preventing disease, probably by permitting transforming growth factor (TGF)-β–mediated suppression of T cell and B cell functions.319 In patients with SLE, anti-IL-10 monoclonal antibody suppressed the in vitro production of autoantibody from B cells, whereas recombinant IL-10 promoted it.317 An immunoprotective role of IL-10 was found in lupus-prone MRL/lpr mice; mice made deficient in IL-10 developed severe lupus with earlier skin lesions, increased lymphadenopathy, and more severe glomerulonephritis than IL-10-sufficient mice. The protective effect of IL-10 was mediated through downregulation of pathogenic T helper type 1 (Th1) responses.320 A hypothesis reconciling the previous contrasting observations is that during the initial phase of SLE, in which IFN-γ (which stimulates helper T cells) and its induced IgG2a autoantibody ­ production promote disease, IL-10 is needed to suppress the pathogenic Th1 responses. By contrast, at later phases of disease, excessive IL-10 production may lead to enhanced autoantibody production and subsequent formation of pathogenic immune complexes. CHARACTERISTICS OF LUPUS T CELLS Abnormalities in T cell function are reviewed in Table 74-7. These abnormalities play a major role in murine and human SLE. In all the strains of lupus mice that have been tested, elimination or inactivation of CD4+ helper T cells protects from disease,321,322 and athymic mice do not develop SLE.323 Quantitative variations in T cells and their subsets may be important. In human SLE, the total number of T cells is usually reduced, probably as a result of the effects of antilymphocyte antibodies.324,325 Decreased CD4+ T cell numbers correlate well with antilymphocyte antibodies specifically reactive against CD4+, and there is strong correlation among high antilymphocyte antibody titers, lymphopenia, and disease activity.326,327 Data vary as to which T cell subset is most frequently reduced, and the characteristics of cells in peripheral blood may not be as important as cells in target organs. Although CD4+ and CD8+ T cells are often decreased in blood of SLE patients, numbers of double-negative T cells are increased.328,329 Double-negative natural killer T cells respond to glycolipid antigens presented by nonpolymorphic MHC molecules such as CD1 and can provide help for autoantibody production in SLE.329-331 In addition, ­certain

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subsets of double-negative cells possess potent suppressive activity. Such a subset (bearing the invariant Va24JaQ TCR) was decreased in peripheral blood of Japanese SLE patients.332 Generally, many T cell subsets of human SLE peripheral blood T cells (CD4+CD8−, CD4−CD8+, and CD4−CD8−) can provide help for autoantibody production, whereas only CD4+CD8− cells have this capacity in healthy individuals. Several functional abnormalities have been reported in SLE T cells in terms of proliferation, activation, expression of costimulatory or effector surface molecules, intracellular signaling pathways, helper or cytolytic activity, and ability to synthesize IL-2 after TCR activation. Accessory cell–dependent TCR/CD3-mediated proliferation in unfractionated peripheral blood mononuclear cell cultures from SLE patients is significantly decreased compared with normal controls,333 whereas CD3/TCR-mediated proliferation of purified SLE T cells ranges from low to normal to enhanced.334 Decreased proliferative responses have been reported in some patients in response to mitogenic lectins (PHA, ConA, PWM), anti-CD2, and allogeneic and autologous mixed lymphocyte reactions.324,335 There is considerable evidence for the presence of in vivo polyclonal T cell activation in SLE. Increased numbers of circulating T cells show spontaneous proliferation336 and express proliferating cell nuclear antigen.337 There is increased expression of MHC class II molecules336 on T cell surfaces and increased release of soluble IL-2 receptors,338 TNF receptors,339 and soluble CD40L into the serum.340 A pan–T cell dysfunction seems to exist in SLE, which is characterized by exaggerated helper and diminished regulatory/suppressor CD4+CD25+ and CD8+ T cell activities.341 Natural killer cell functions are defective.342 Partly as a result of loss of effective CD8+ T and natural killer cell negative feedback on B cells,343 autoreactive B cell clones produce autoantibodies against an array of intracellular and extracellular autoantigens (see the preceding section for discussion of intrinsic abnormalities in SLE B cells). The ability of T cells to help antibody production and their inability to suppress it are probably the T cell functions most pertinent to clinical SLE. Because many of the pathogenic autoantibodies in patients with SLE are IgG, T cell help plays a major role in their production and maintenance. As mentioned previously, in human SLE, T cells with many different surface phenotypes give help for autoantibody production,331,344 including classic helper cells (CD4+CD8− α/β TCR), CD4+CD8− γ/δ TCR cells, CD4−CD8+ α/β TCR cells, and CD1-restricted double-negative natural killer T cells.345 This unusual situation of cells of many phenotypes providing help to B cells may represent intrinsic defects in the T cells and B cells, failure of regulatory CD4+CD25+ or suppressive CD8+ T cells to mature or function to regulate their targets, or absence of other downregulating networks. CD8 T cell function is impaired in peripheral blood T cells from patients with SLE.346,347 Impaired generation of CD8 cytolytic T cells against allogeneic targets348 and cytolytic activity induced by anti-CD3 stimulation have been reported.347,349 CD8 cells from some SLE patients sustain, rather than suppress, spontaneous polyclonal IgG production; they synergize with CD4 T cells to support autoantibody synthesis.344,350 CD8 suppressive activity for autoantibody production also is defective in several murine

models of SLE, and becomes increasingly apparent as the mice age.351 Inquiries into the mechanisms causing T cell dysfunctions have led to identification of several defects of signal transduction. In contrast to T cells from the peripheral blood of normal individuals or patients with nonlupus rheumatic diseases, peripheral blood T cells from SLE patients show diminished TCR ζ chain expression.352,353 An enhanced and prolonged increase in intracellular Ca2 concentration ([Ca2]) following TCR-mediated cell activation has been identified in human primary SLE T cells, T cell lines, and antigen-specific T cell clones,278 which is unrelated to disease activity. Ca2 as a second messenger mediates calcineurin-catalyzed dephosphorylation of nuclear factor of activated T cell and its nuclear translocation, and overexpression of CD154, Fas ligand, and c-myc in SLE T cells.352-354 There are reports of defective cyclic adenosine monophosphate (cAMP)–dependent protein phosphorylation in peripheral blood T cells from SLE patients. This defect may be attributed to deficient activities of type I and type II isoenzymes of protein kinase A.355-357 Among SLE patients, the prevalences of deficient type I and type II protein kinase A activities are approximately 80% and 40%. These deficiencies are persistent over time and are independent of clinical disease activity. Regulation of apoptosis in human and murine lupus T cells is impaired. Although mutations in the apoptosismediating Fas receptor or the Fas ligand in the lpr and gld mouse backgrounds are associated with impaired lymphocyte apoptosis or lupus-like disease, the Fas-mediated signaling pathway seems to be normal in human SLE.358 SLE T cells in many patients show defective activation-induced cell death, however; this could be due to abnormalities in a second major pathway leading to activation-induced cell death, which involves signaling between members of the TNF-α surface receptor family and their ligands. T cells from peripheral blood of some SLE patients show decreased intracellular synthesis of TNF-α, which could result in undesirable survival of autoreactive cells.359 In contrast, increased spontaneous apoptosis also has been observed in SLE.360 This accelerated apoptosis is likely to provide more autoantigens to stimulate the immune system. Apoptosis must be in perfect balance for avoidance of autoreactivity—if autoreactive lymphocytes persist too long, as in MRL/lpr mice, or are increased in quantity with cell survival too brief, as in some patients with active SLE, autoimmunity results. Disruption of the mitochondrial transmembrane potential with mitochondrial hyperpolarization has been proposed as the point of no return in apoptotic signaling. This phenomenon precedes caspase activation and phosphatidylserine externalization in the early phase of Fas-induced, p53-induced, and hydrogen peroxide–induced apoptosis.361-363 Deviations in key mitochondrial checkpoints associated with abnormal T cell apoptosis in SLE have been identified:363 (1) deficient elevation of transmembrane potential, (2) diminished CD3/CD28-induced reactive oxygen intermediates and hydrogen peroxide production, and (3) reduced hydrogen peroxide–induced apoptosis. One of the cardinal biochemical abnormalities in SLE T cells is a global decrease in genomic deoxymethylcytosine content.364 Because methylation of deoxycytosine in regulatory sequences can suppress transcription of the associated gene,365 abnormal hypomethylation could contribute to

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overexpression of some genes in SLE T cells. More importantly, T cells treated with methylation inhibitors, including procainamide and hydralazine, become autoreactive as a result of surface lymphocyte function antigen-1 (CD11a) overexpression, leading to a lupus-like disease in murine models.366 Lymphocyte function antigen-1 overexpression lowers the threshold for T cell activation, allowing the cells to respond to self-class II MHC molecules presenting inappropriate antigens.367 In particular, lymphocyte function antigen-1 overexpression seems to overstabilize the normally low-affinity interaction between the TCR and class II MHC molecules lacking the relevant antigenic peptide, allowing the signaling apparatus to assemble and transmit its signal.368 Defective signaling via the extracellular regulating kinase pathway in active SLE T cells has been associated with DNA hypomethylation. More recently, hypomethylation of the “silenced” X chromosome in women with SLE has been shown and associated with increased expression of CD40L on T cell surfaces, another example of hypomethylation in regulatory sequences permitting upregulation of the protein-encoding gene.57 More recent work has shown that peripheral blood T cells from SLE patients on TCR stimulation with anti-CD8 and anti-CD28 produce abnormally low levels of IL-2.357,369 Such a deficiency could lead to failure of autoreactive T cells to undergo apoptosis after strong activation signals and to defective generation of regulatory and suppressor T cells. The basis of this defect is multifactorial, with (1) reduced generation of p65 (required for activation of NF-κB on the IL-2 promoter), (2) elevation of CREM/CREB ratios (CREM is cAMP-responsive element modulator—a transcriptional repressor that binds to cAMP response elements and downregulates the expression of genes having this binding site), and (3) increased CREM binding of the c-fos promoter (which decreases transcription of c-fos, reducing AP-1 binding of the IL-2 promoter), all of which lead to (4) inadequate IL-2 production. Increased expression of Ca2+/calmodulin-dependent kinase IV and of protein phosphatase 2A may contribute to increased production of CREM. To summarize this work, several molecules required for full activation of the IL-2 promoter are altered in SLE T cells, possibly centering on increased expression of CREM, with the end result being reduced production of IL-2, an essential growth cytokine for T cells.357,370-372 Altered cytokine homeostasis characterizes T cells, B cells, and dendritic cells in active SLE. Increased levels of IL-10 in the serum and increased numbers of IL-10-secreting cells are observed. IL-10 inhibits some T cell functions and can lead to downregulation of IL-2, TNF-α, and IFNγ,373 each of which plays a cardinal role in the generation of cytotoxic and suppressive T cells. Secretion of IL-2 by SLE T cells is often low as discussed in the preceding paragraphs, whereas secretion of IFN-γ may be high.374 Murine lupus seems to depend strongly on increased levels of IFN-γ, however, because mice that are congenitally deficient for the IFN-γ receptor are partially protected from developing SLE,375 and treatment with soluble IFN-γ receptor prevents disease.376 Perhaps the cells isolated from patients with active disease are exhausted, and the cytokine profile they produce does not reflect the initiation of disease or flares.

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Several investigators have found dramatic elevations in expression of genes that are IFN-inducible (particularly by IFN-α) during periods of SLE activity.377-382 A major source of this cytokine is plasmacytoid dendritic cells, rather than lymphocytes, but many cells can secrete IFN-α. IFN-α activates immature dendritic cells, providing APCs that drive innate and adaptive autoimmunity. The upregulation of IFN-inducible genes is associated with disease activity, but is much more common in SLE than in other chronic inflammatory diseases. The presence of a granulopoiesis signature in gene expression by peripheral blood cells from SLE patients also is notable, and we expect to understand the importance of these cells in SLE over the next few years. Autoantigens that activate T cells are crucial in SLE. These are derived from nucleosomes, RNA/protein antigens such as RNP and Sm, and the autoantibodies themselves. Autoantibodies can activate their own T cell help; B cells process their surface immunoglobulin and present immunoglobulin-derived peptides in their surface MHC class II molecules to nearby helper T cells, which are activated to help the synthesis of additional autoantibody.383-387 This may be an important mechanism for sustaining the production of pathogenic autoantibodies in SLE. In human and murine lupus, the V regions of anti-DNA antibodies contain peptide determinants that activate T cells and can accelerate the disease process.374,383 Peripheral blood T cells from many patients with SLE recognize VH determinants of human anti-DNA.374 Used as a tolerogen, an artificial VH peptide (pCONSENSUS), based on VH peptides, inhibits responses to nucleosomes and other autoantigens, but it leaves the murine immune system intact and able to generate responses to external antigens.384 Similar observations have been made with a peptide from the VH region of another monoclonal antibody anti-DNA; that product (Edratide) is in clinical trials in patients with SLE.388,389 Similarly, patients with SLE have circulating T cells that recognize peptides from nucleosomes, and it is likely that these cells also upregulate anti-DNA antibody production.390,391 These peptides also can be used as tolerogens.385-389 It is the authors’ opinion that the main mechanism by which these tolerizing peptides suppress SLE-like autoimmunity is by induction of regulatory CD4+CD25+ cells and of suppressive CD8+ T cells.386,387,389,391 The role of T cells in directly causing tissue damage in SLE has not been emphasized, but it is probably important. Because 50% of individuals with subacute cutaneous lupus and anti-Ro/SS-A do not have immunoglobulin and complement deposited at the dermal-epidermal junction, dermatitis in those individuals may be caused by T cells sensitized to Ro.392 Finally, although the classic explanation for vasculitis is deposition of immune complexes in vessel walls, some T cells, probably sensitized to endothelial cell antigens, can cause vasculitis.393 Kidney-infiltrating T cells in SLE patients show a relatively restricted TCR Vβ repertoire. TCR Vβ8 and Vβ20 were preferentially expressed in 50% and 40% of kidney biopsy specimens in one study,394 and junctional sequences of complementary DNA encoding the TCR Vβ8 and Vβ20 genes in intrarenal T cells showed oligoclonal expansion, indicating antigen-driven stimulation. Where are the suppressor/regulatory T cells that should eliminate these pathogenic, hyperactive T cells and B cells?

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More recent work has suggested abnormalities in interactions between CD4 T cells that are required for maturation of CD4+CD25+ regulatory T cells and cytotoxic CD8 cells. These abnormalities might result from the inability of natural killer cells from SLE patients to secrete adequate quantities of activated TGF-β.395 It is likely that CD4 T cells stimulate natural killer cells to secrete active TGF-β under normal circumstances, but not when SLE is active. In the chronic graft-versus-host mouse model of lupus-like disease, autoantibody formation and nephritis are delayed by administration of T cells preincubated with TGF-β, suggesting that this cytokine may partially restore suppression/regulation in individuals with autoimmunity.395 T lymphocytes are quantitatively and qualitatively abnormal in human lupus and in murine models of the disease. Qualitative abnormalities include increased responsiveness to surface activating signals, which results in increased calcium flux that may depend on defects in protein kinase A type I and II isoenzymes. The end result is decreased synthesis of IL-2. Hypomethylation of DNA may be another outcome. For unknown reasons, T cells with many different surface phenotypes promote help of autoantibody production without appropriate suppression. Quantitative abnormalities in several cytokines, such as IL-2 (low), IFN-γ (high), IL-10 (high), and TGF-β (low), are important in aberrant cell function. There are several adverse outcomes of all these abnormalities, including resistance to apoptosis in some autoreactive T cells, accelerated apoptosis in other T lymphocytes that release autoantigens, and defective regulation of the skewing of many different subsets to provide help. Finally, defects in regulatory, cytotoxic, and suppressive T cells are important in allowing autoantibody production.

ABNORMALITIES IN IMMUNOREGULATION The ability to make pathogenic subsets of autoantibodies and immune complexes must be accompanied by inability to downregulate them if disease is to be sustained. In murine lupus, when autoantibodies appear, they increase steadily until organ damage occurs, and death follows. In humans, autoantibodies of SLE appear years before the first clinical manifestation of disease, and after disease onset the levels of many autoantibodies fluctuate, sometimes increasing with clinical exacerbations and decreasing during periods of improvement (e.g., ANA, anti-DNA, anti-SmD peptide). Autoantibodies including ANA, anti-DNA, antiphospholipids, anti-Sm, and anti-RNP appear years before the first symptom of disease in most patients, suggesting that for many months regulatory mechanisms are effective in preventing disease. Nevertheless, when the diagnosis of SLE has been made, virtually every mechanism of regulating antibodies that has been studied is abnormal. IMMUNE TOLERANCE Highly autoreactive B lymphocytes and T lymphocytes are deleted, inactivated, or suppressed in healthy individuals by immune tolerance. Mechanisms of tolerance include deletion (B cells and T cells), anergy (B cells and T cells), BCR editing (B cells), cytokine shifts (T cells), and induction of

regulatory cells (suppressing B cells and T cells). Tolerance steps occur at several points along cell development, beginning with immature or naive cells in the thymus (T cells) or bone marrow (B cells) and extending to peripheral lymphoid organs (B cells and T cells).396-402 For T cells, strong interaction between autoantigenrecognizing TCRs and MHC class I and class II molecules on thymic epithelial cells (containing autoantigens) may deliver one or two signals to the cells: (1) cross-linking of antigen receptors, followed by (2) engagement of second surface receptors after activation of T cell help (especially CD28 and its B7 ligands, CD80 and CD86). If two signals are received, apoptosis results; the cells are deleted. A few that “leak” into the periphery can be deleted there. Cells that receive only one activation signal are anergized; they are difficult to activate when they reach the periphery, and they may eventually undergo apoptosis. B cells undergo the same processes, with the bone marrow and peripheral lymphoid organs as sites of deleting and anergizing signals. In addition, B cells can undergo receptor editing—a process in which an autoreactive surface immunoglobulin molecule is changed by different combinations of heavy and light chains within each cell. The resultant surface immunoglobulin molecule (BCR) is no longer highly autoreactive; the edited “safe” B cells are selected for expansion.396-399 Dendritic cells also influence tolerance, particularly in T cells. One paradigm is that immature dendritic cells educate T cells to be tolerant (i.e., anergic or regulatory), whereas mature dendritic cells activate T cells. More recent data suggest that dendritic cells are tolerogenic or activating not because of their maturity, but because of the cytokines they secrete, with IL-10, TGF-β, granulocyte colony-stimulating factor, and hepatic growth factor all playing roles in induction of tolerance.402 In murine and human B cells, there are several points in cell development during which deletion of autoreactive cells can occur.398,399 The first is the step between an immature cell in the bone marrow and the transitional T1 cell in peripheral lymphoid tissue, the second is between the T1 and more mature T2/3 stage, and the third is between the Tr/3 and mature B cell. The mature B cells that can make pathogenic autoantibodies include marginal zone B2 cells, B1 self-renewing B cells, and follicular, germinal center B2 cells (which are the cells best poised to receive T cell help and to generate long-lived memory B cells and plasma cells). Autoreactive B cells from SLE patients can enter germinal centers in greater numbers than cells from healthy individuals, suggesting increased exposure to T cell stimulation.403 These intrinsic checkpoints in B cell development are influenced by sex hormones; second signals (especially CD40/CD40L, both of which are overexpressed in SLE B cells and T cells); BAFF, which is elevated in some SLE patients; and cytokines that are B cell growth factors, such as IL-6 and IL-10 (both increased in some SLE patients). Ability of this intrinsic B cell tolerance to proceed in an orderly fashion is altered by the external factors listed, and by genetic background and the tolerogenic or activated states of APCs, including dendritic cells.212,404 In addition, B cells can be activated independent of BCR via TLR9 receptors.21

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T cell functions can be altered by shifts in the cytokines they release; deviation from Th1 to Th2 patterns protects from some T cell–induced autoimmune diseases in animals, such as experimental allergic encephalitis and diabetes.347 Finally,T cells and dendritic cells can be generated that suppress effector T cells or B cells or both; most authorities consider this a form of tolerance.402,405 In patients with SLE, immune tolerance is presumably defective with enhanced numbers and survival of autoreactive T cells and B cells. Many of the abnormalities that could account for this finding are discussed under the previous B lymphocyte and T lymphocyte sections and listed in Table 74-8. INADEQUATE CLEARING OF IMMUNE COMPLEXES Several defects contribute to inadequate clearing of soluble and insoluble immune complexes.48 Immune complexes are transported by complement receptors, primarily on erythrocytes in humans. The numbers of complement receptors (CR1 and CR2) on cell surfaces are reduced in patients with active SLE90,406 so that immune complexes are not transported adequately to the mononuclear phagocytic cell system that clears them, leaving the immune complexes to deposit in tissues. In some individuals, the low numbers of complement receptors may be genetically determined; in most, they are probably low because they have been stripped away by large quantities of immune complex.90,406 CR2 is of additional importance because it is a receptor for EBV and IFN-α, each of which has been implicated in the pathogenesis of SLE.310 Phagocytosis of immune complexes occurs after binding to Fcγ receptors of several types on monocytes, macrophages, and neutrophils. Binding and internalization of immunoglobulin in immune complexes may be less than normal in some SLE patients with certain alleles of Fcγ RIIA and FcγRIIIA.125-129,134,135,407 In many SLE patients, immune complexes are not phagocytosed properly, and this permits persistence of harmful immune complexes in the circulation.48,207 In an earlier section, we discussed impaired clearing of apoptotic bodies in patients with SLE59,270,271; persistence of these bodies probably permits sustained exposure of the immune system to autoantigens contained in them and contributes to autoantibody production. INADEQUATE DOWNREGULATION BY T CELLS Autoimmune disease is prevented by mechanisms of central and peripheral immune tolerance, among which a cardinal role is played by regulatory/inhibitory cells.386,387,408-410 These cells belong to the CD4, CD8, or natural killer T cell compartments and exert an array of complex functions on diverse cell subsets. Several functional abnormalities have been described for each of these T cell subsets in human and murine lupus. In the CD8+ compartment, at least two distinct subsets of suppressor cells have been identified in mice and humans that share the CD8+CD28− surface phenotype, are not cytotoxic, and do not induce apoptosis. The first CD8+ suppressor subset induces antigen-specific immunosuppression through cell-to-cell contact with APC presenting antigen.411 The second subset mediates an antigen-nonspecific suppression of T cell proliferation via soluble factors, such as IFN-α, IL-10,

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and TGF-β.386,412 This subset is functionally impaired in SLE,346,347 suggesting involvement in disease pathogenesis. In human SLE, there is impaired generation of CD8 cytolytic T cells against allogeneic targets348 and depressed antiCD3–dependent cytolytic activity.349 CD8 lymphocytes from lupus patients sustain, rather than suppress, spontaneous polyclonal IgG production; they synergize with CD4 T cells to support autoantibody synthesis.350 In addition to loss of function, numbers of CD8+ T cells also may decline as autoimmune disease appears. Studies in mice and dogs have shown that CD8 cells decline in number or do not expand at the rapid rate occurring in CD4+ T cells and B cells as the animals develop SLE.351 In patients with SLE, there is considerable variation in numbers of CD8+ cells413; in some individuals, they are lower than normal.414,415 How do suppressor T cells evolve? In mice and humans, interactions between CD4 and CD8 cell subsets are required to induce suppression of immunoglobulin production in antigen, PWM, or autologous mixed lymphocyte response systems.416,417 Similarly, differentiation of cytotoxic CD8 precursors into cytotoxic CD8+ effectors requires the presence of CD4 cells, possibly as a source of IL-2. In some systems, TGF-β may be an additional requirement; its major source in humans is the natural killer cell.343,348,351,417 In combination with IL-2, TGF-β can induce peripheral CD8+ T cells to become inhibitory and naive CD4+ T cells to become CD4+CD25+ regulatory T cells.343 Such cells, either CD4+ or CD8+, suppress antibody production.345,387,418,419 Unmanipulated adult BWF1 mice and SLE patients cannot generate CD8+ inhibitory/cytotoxic T cells capable of ­ suppressing autoantibody production.346,351 That could result from defects in generation of inhibitory/cytotoxic T cells, inadequate functional capacities of inhibitory/cytotoxic T cells, antibodies to inhibitory/cytotoxic T cells or to their CD4+ precursor cells, or defective CD4+ precursor cells (e.g., making inadequate quantities of IL-2). There is evidence for all of these hypotheses.347-349,357,363,368,420 CD4+ T cells, dendritic cells, and possibly other APCs participate in generation of inhibitory/cytotoxic T cells. Generation of cytotoxic CD8+ cells requires help from a CD4 helper cell through CD40-CD40L interactions, usually with the surface of a dendritic cell.421-423 Other studies have reported, however, that if CD8 cytotoxic precursor frequencies are high, priming of CD8 T cell responses may not require CD4 T cell help.424 When generated, the CD8 suppressor/effector can subsequently act directly on the CD4 T helper cell and abrogate its ability to provide help. Alternatively, it can act on an APC via cell-to-cell contact and render it tolerogenic through induction of surface expression of inhibitory receptors, such as ILT-3 and ILT-4, and downregulation of surface expression of CD80 and CD86.425 Such a “tolerogenic” APC, on subsequent contact with a CD4 T helper or CD8+CD28− suppressor, would render it anergic. Based on this model, failure to generate CD8 inhibitory/cytotoxic T cells in patients with SLE or lupus-prone mice could result from abnormalities in dendritic cells or in CD4 T cell suppressor/inducers. It also is possible that the inhibitory/cytotoxic T cells are generated, but cannot function well enough to oppose activated T helper cells and B cells. The multiple defects described in the CD8 T cells can be overcome. More recent evidence suggests that, in the BWF1

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model of lupus, CD8 inhibitory cells still may be present and may be induced to protect against the development of systemic autoimmunity in young BWF1 mice. Vaccination of BWF1 mice with plasmid DNA vectors encoding immunoglobulin VH-derived MHC class I–binding epitopes activates cytotoxic T cells that ablate autoantibody-producing B cells and inhibit the development of lupus nephritis.419 Similarly, injection of tolerogenic doses of peptides from anti-DNA or from the histone of nucleosomes can activate CD4+ regulatory T cells and CD8+ inhibitory T cells.387,391 In human SLE, functional CD8+ inhibitory/cytotoxic T cells seem to be restored during periods of clinical improvement.346 Novel therapies that aim to restore suppressive capacity to CD8+ inhibitory/cytotoxic T cells are an attractive option. Natural killer T cells, which are double negative (which is CD4−CD8−TCR+CD56+), possess potent suppressive activity. Such a subset (bearing the invariant Va24JaQ TCR; iNKT) was reported to be decreased in peripheral blood of two groups of SLE patients.332,426 The role of natural killer and iNKT cells in various models of lupus has varied, and the authors are reluctant to state a general principle about the role of these cells in pathogenesis. Studies of these cells are in progress. Another important subset of regulatory cells is a thymus-derived CD4 subset constitutively expressing the IL-2 receptor β chain (CD25); these cells protect the host from spontaneous organ-specific autoimmune disease. CD4+CD25+ T cells have been called “professional” suppressor cells and have a contact-dependent mechanism of action in vitro.427 In mice, CD4+CD25+ T cells appear in the peripheral immune system on day 3 of life. CD4+CD25− T cells in the absence of CD4+CD25+ T cells cause severe and progressive organ-specific autoimmune disease. In human SLE, some groups have reported reduced numbers of presumptive regulatory T cells (CD4+CD25High cells) in adults or children with active SLE, and that the numbers of those cells correlated inversely with clinical disease activity.428,429 Induction of CD4+CD25+ regulatory T cells by tolerization with selected peptides protects lupus mice from developing disease.387,389,391 Several sets of regulatory/suppressor T cells, including CD8+CD28− inhibitory/cytotoxic T cells, CD4+CD25+ regulatory T cells, and natural killer T cells, protect from autoimmunity in normal mice, and probably in healthy humans. It is likely that abnormalities affecting any of these subsets contribute to the imbalance between autoantibody synthesis and regulation that is characteristic of SLE. INADEQUATE IDIOTYPIC CIRCUITS CONTROLLING PATHOGENIC B CELLS AND T CELLS In human and murine SLE, a substantial proportion of autoantibodies express a restricted number of public idiotypes (Ids).430-432 Ids are sequences within the heavy and light chains of immunoglobulin molecules that are themselves antigenic; they induce anti-Id responses. Normally, anti-Ids can suppress Ids and downregulate production of Id+ antibodies. Some Ids (e.g., 16/6, O-81, and IdGN2) dominate tissue lesions in human SLE.430 In murine lupus, treating mice with anti-Ids directed against the public Ids dominating their anti-dsDNA antibodies can prevent or

suppress disease, at least temporarily.430 T cells have a similar idiotypic regulatory system; the Ids reside in the TCR molecules, and the anti-Ids reside on TCRs of regulatory T cells that are expected to suppress the Id+ T cells. It is unclear why this idiotypic B cell and T cell process is not operating normally to suppress disease in either human or murine lupus.

SUMMARY As shown in Table 74-9, many of the clinical manifestations of SLE are probably caused by or are associated with the pathogenic autoantibodies, immune complexes, and B cell and T cell abnormalities that have been described. Certain immune complexes, selected antibodies to DNA or Ro/ SS-A, and antibodies that bind glomerular structures can cause nephritis. Antibodies that bind to the fetal conduction system or cell membranes (lymphocytes, erythrocytes, platelets, neurons) or enter cells and alter cell functions also have the potential to cause disease. Immune complexes, antibodies to endothelial cells, antineutrophil cytoplasmic antibodies, and T cells may participate in vasculitis and in endothelial cell damage that promotes accelerated atherosclerosis—onto which may be added the prothrombotic effects of antibodies to phospholipids. An individual’s ability to manufacture pathogenic immunoglobulin and sustain its production depends on intrinsic abnormalities of immune complex and apoptotic cell clearance and of B lymphocytes and T lymphocytes, and these abnormalities depend on inheriting an appropriate

Table 74-9  Correlation among Clinical Manifestations of Systemic Lupus Erythematosus and Autoantibodies, Immune Complexes, and T Cells Immune T Complexes Cells

Manifestation

Autoantibodies

Nephritis

Anti-dsDNA Anti-Ro Anti-C1q Ids 16/6, 3I and GN2

+

Arthritis

?

+

Dermatitis

Anti-Ro Anti-dsDNA Id 16/6

Vasculitis

Anti-Ro

+

Central nervous   system

Anti-ribosomal P Antineuronal Anti-NR2

+

Hematologic Lymphopenia Hemolysis Thrombocytopenia Clotting

Antilymphocyte Antierythrocyte Antiplatelet Antiphospholipid

Fetal loss

Antiphospholipid

Neonatal lupus

Anti-Ro

Sicca syndrome

Anti-Ro

Mild disease

Anti-RNP without   other autoantibody except ANA

+

+ +

+

+

ANA, antinuclear antibody; anti-dsDNA, anti–double-stranded DNA.

+

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number of susceptibility genes, lacking protective genes, and encountering an environmental stimulus such as EBV infection that sets the whole process into action. Even after an individual has detectable autoantibodies, years pass before the first clinical symptom of disease appears, suggesting that immunoregulation is effective for a while in most individuals, and then becomes exhausted. Understanding this complex process is evolving rapidly, making the study of the pathogenesis of SLE a fascinating area in modern medicine. REFERENCES   1. Croker JA, Kimberly RP: SLE: Challenges and candidates in human disease. Trends Immunol 26:580-586, 2005.   2. Forabosco P, Gorman JD, Cleveland C, et al: Meta-analysis of genome-wide linkage studies of systemic lupus erythematosus. Genes Immun 7:609-614, 2006.   3. Harley JB, Kelly JA, Kaufman KM: Unraveling the genetics of systemic lupus erythematosus. Springer Semin Immunopathol 28: 119-130, 2006.   4. Casciola-Rosen L, Rosen A: Ultraviolet light-induced keratinocyte apoptosis: A potential mechanism for the induction of skin lesions and autoantibody production in LE. Lupus 6:175-180, 1997.   5. Katz JB, Limpanasithikul W, Diamond B: Mutational analysis of an autoantibody: Differential binding and pathogenicity. J Exp Med 180:925-932, 1994.   6. Frenchi G, Putterman C, Diamond B: The structure and derivation of antibodies and autoantibodies. In Wallace DR, Hahn BH (eds): Dubois’ Lupus Erythematosus, 7th ed. Philadelphia, Lippincott Williams & Wilkins, 2007, pp 408-431.   7. Shlomchik M, Mascelli M, Shan H, et al: Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation. J Exp Med 171:265-292, 1990.   8. Tillman DM, Jou NT, Hill RJ, et al: Both IgM and IgG anti-DNA antibodies are the products of clonally selective B cell stimulation in (NZB x NZW)F1 mice. J Exp Med 176:761-779, 1992.   9. Hahn BH: Antibodies to DNA. N Engl J Med 338:1359-1368, 1998. 10. van Es JH, Gmelig Meyling FH, van de Akker WR, et al: Somatic mutations in the variable regions of a human IgG anti-double-stranded DNA autoantibody suggest a role for antigen in the induction of systemic lupus erythematosus. J Exp Med 173:461-470, 1991. 11. Ohnishi K, Ebling FM, Mitchell B, et al: Comparison of pathogenic and non-pathogenic murine antibodies to DNA: Antigen binding and structural characteristics. Int Immunol 6:817-830, 1994. 12. Ehrenstein MR, Katz DR, Griffiths MH, et al: Human IgG anti-DNA antibodies deposit in kidneys and induce proteinuria in SCID mice. Kidney Int 48:705-711, 1995. 13. Burlingame RW, Rubin RL: Autoantibody to the nucleosome subunit (H2A-H2B)-DNA is an early and ubiquitous feature of lupuslike conditions. Mol Biol Rep 23(3-4):159-166, 1996. 14. Bruns A, Blass S, Hausdorf G, et al: Nucleosomes are major T and B cell autoantigens in systemic lupus erythematosus. Arthritis Rheum 43:2307-2315, 2000. 15. Kaliyaperumal A, Michaels MA, Datta SK: Naturally processed chromatin peptides reveal a major autoepitope that primes pathogenic T and B cells of lupus. J Immunol 168:2530-2537, 2002. 16. Lu L, Kaliyaperumal A, Boumpas DT, et al: Major peptide autoepitopes for nucleosome-specific T cells of human lupus. J Clin Invest 104:345-355, 1999. 17. Viglianti GA, Lau CM, Hanley TM, et al: Activation of autoreactive B cells by CpG dsDNA. Immunity 19:837-847, 2003. 18. Christensen SR, Kashgarian M, Alexopoulou L, et al: Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J Exp Med 202:321-331, 2005. 19. Boule MW, Broughton C, Mackay F, et al: Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin-immunoglobulin G complexes. J Exp Med 199:1631-1640, 2004. 20. Lau CM, Broughton C, Tabor AS, et al: RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J Exp Med 202:1171-1177, 2005.

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45. Hulsey M, Goldstein R, Scully L, et al: Anti-ribosomal P antibodies in systemic lupus erythematosus: A case-control study correlating hepatic and renal disease. Clin Immunol Immunopathol 74:252-256, 1995. 46. Schneebaum AB, Singleton JD, West SG, et al: Association of psychiatric manifestations with antibodies to ribosomal P proteins in systemic lupus erythematosus. Am J Med 90:54-62, 1991. 47. Reichlin MN: Autoantibodies to intracellular antigens in SLE that bind and penetrate cells. In Kammer GM, Tsokos GC (eds): Molecular and Cellular Pathogenesis. Totowa, NJ, Humana Press, 1999. 48. Salmon JE: Abnormalities in immune complex clearance and Fcgamma receptor function. In Wallace DJ, Hahn BH (eds): Dubois’ Lupus Erythematosus, 7th ed. Philadelphia, Lippincott Williams & Wilkins, 2007, pp 191-213. 49. Carroll MC: The role of complement in B cell activation and tolerance. Adv Immunol 74:61-88, 2000. 50. Cook HT, Botto M: Mechanisms of disease: The complement system and the pathogenesis of systemic lupus erythematosus. Nat Clin Pract Rheumatol 2:330-337, 2006. 51. Croker BP, Gilkeson G, Morel L: Genetic interactions between susceptibility loci reveal epistatic pathogenic networks in murine lupus. Genes Immun 4:575-585, 2003. 52. Wong M, Tsao BP: Current topics in human SLE genetics. Springer Semin Immunopathol 28:97-107, 2006. 53. Block SR, Winfield JB, Lockshin MD, et al: Studies of twins with SLE: A review of the literature and presentation of 12 additional sets. Am J Med 59:533-552, 1979. 54. Deapen D, Escalante A, Weinrib L, et al: A revised estimate of twin concordance in SLE. Arthritis Rheum 35:311, 1992. 55. Jarvinen P, Kaprio J, Makitalo R, et al: Systemic lupus erythematosus and related systemic diseases in a nationwide twin cohort: An increased prevalence of disease in MZ twins and concordance of disease features. J Intern Med 231:67-72, 1992. 56. Alarcon-Segovia D, Alarcon-Riquelme ME, Cardiel MH, et al: Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis Rheum 52:1138-1147, 2005. 57. Kono DH, Theofilopoulos AN: Genetics of SLE in mice. Springer Semin Immunopathol 28:83-96, 2006. 58. Liu K, Mohan C: What do mouse models teach us about human SLE? Clin Immunol 119:123-130, 2006. 59. Cohen PL: Apoptotic cell death and lupus. Springer Semin Immunopathol 28:145-152, 2006. 60. Pisitkun P, Deane JA, Difilippantonio MJ, et al: Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312:1669-1672, 2006. 61. Subramanian S, Tus K, Li QZ, et al: A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. Proc Natl Acad Sci U S A 103:9970-9975, 2006. 62. Gaffney PM, Kearns GM, Shark KB, et al: A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families. Proc Natl Acad Sci U S A 95:14875-14879, 1998. 63. Moser KL, Neas BR, Salmon JE, et al: Genome scan of human systemic lupus erythematosus: Evidence for linkage on chromosome 1q in African-American pedigrees. Proc Natl Acad Sci U S A 95: 14869-14874, 1998. 64. Shai R, Quismorio FP Jr, Li L, et al: Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families. Hum Mol Genet 8:639-644, 1999. 65. Tsao BP, Cantor RM, Kalunian KC, et al: Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus. J Clin Invest 99:725-731, 1997. 66. Tsao BP, Cantor RM, Grossman JM, et al: PARP alleles within the linked chromosomal region are associated with systemic lupus erythematosus. J Clin Invest 103:1135-1140, 1999. 67. Bell DA, Rigby R, Stiller CR, et al: HLA antigens in systemic lupus erythematosus: Relationship to disease severity, age at onset, and sex. J Rheumatol 11:475-479, 1984. 68. Gibofsky A, Winchester RJ, Patarroyo M, et al: Disease associations of the Ia-like human alloantigens: Contrasting patterns in rheumatoid arthritis and systemic lupus erythematosus. J Exp Med 148: 1728-1732, 1978. 69. Schur PH, Marcus-Bagley D, Awdeh Z, et al: The effect of ethnicity on major histocompatibility complex complement allotypes and extended haplotypes in patients with systemic lupus erythematosus. Arthritis Rheum 33:985-992, 1990.

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425. Chang CC, Ciubotariu R, Manavalan JS, et al: Tolerization of dendritic cells by T(S) cells: The crucial role of inhibitory receptors ILT3 and ILT4. Nat Immunol 3:237-243, 2002. 426. Green MR, Kennell AS, Larche MJ, et al: Natural killer cell activity in families of patients with systemic lupus erythematosus: Demonstration of a killing defect in patients. Clin Exp Immunol 141:165-173, 2005. 427. Shevach EM: Certified professionals: CD4(+)CD25(+) suppressor T cells. J Exp Med 193:F41-F46, 2001. 428. Lee JH, Wang LC, Lin YT, et al: Inverse correlation between CD4+ regulatory T-cell population and autoantibody levels in paediatric patients with systemic lupus erythematosus. Immunology 117: 280-286, 2006. 429. Liu MF, Wang CR, Fung LL, et al: Decreased CD4+CD25+ T cells in peripheral blood of patients with systemic lupus erythematosus. Scand J Immunol 59:198-202, 2004. 430. Hahn BH: Idiotypes and idiotype networks. In Wallace DJ, Hahn BH (eds): Dubois’ Lupus Erythematosus, 7th ed. Philadelphia, Lippincott Williams & Wilkins, 2007, pp 255-272. 431. Shoenfeld Y, Mozes E: Pathogenic idiotypes of autoantiodies in autoimmunity: Lessons from new experimental models of SLE. FASEB J 4:2646-2651, 1990. 432. Kalunian KC, Panosian-Sahakian N, Ebling FM, et al: Idiotypic characteristics of immunoglobulins associated with systemic lupus erythematosus: Studies of antibodies deposited in glomeruli of humans. Arthritis Rheum 32:513-522, 1989.

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Clinical Features and Treatment of Systemic Lupus Erythematosus IOANNIS O. TASSIULAS  •  DIMITRIOS T. BOUMPAS

KEY POINTS The diagnosis of systemic lupus erythematosus (SLE) remains largely clinical. Undifferentiated connective tissue disease and incomplete lupus represent 10% to 20% of patients referred to rheumatologists. Antiphospholipid antibody–mediated morbidity is an important part of the natural history of SLE. SLE patients are at increased risk for certain comorbidities secondary to the disease or its treatment or both. Evidence-based recommendations for the management of SLE have been developed.

Systemic lupus erythematosus (SLE) is the prototypic autoimmune disease characterized by the production of autoantibodies to components of the cell nucleus in association with diverse clinical manifestations encompassing almost all organ systems. SLE is a complex disease with variable presentations, course, and prognosis characterized by remissions and flares. The extreme heterogeneity of the disease has led some investigators to propose that SLE represents a syndrome rather than a single disease. This chapter discusses clinical aspects of SLE, including diagnosis and treatment. Important aspects of the disease are highlighted, and practical information that could be used by readers with various backgrounds and expertise is presented. SLE is an intensively studied disease with abundant data. Where possible, evidence-based recommendations are presented based on a systematic review of the literature.1 Where data are scarce, a critical overview of expert-based opinions is presented.

HISTORICAL BACKGROUND The term lupus (Latin for “wolf”) was first used during the Middle Ages to describe erosive skin lesions that were evocative of a wolf’s bite. The “classical” period of lupus starts in 1846 with the Viennese physician von Hebra (1816-1880), who introduced the butterfly metaphor to describe the malar rash. Von Hebra also used the term lupus erythematosus and published the first illustrations in his Atlas of Skin Diseases in 1856. The “neoclassical” period of lupus starts with the recognition of lupus as a systemic disease with visceral manifestations. Kaposi (1837-1902) first recognized the systemic nature of the disease. The existence of a systemic form was

firmly established by Osler in Baltimore and Jadassohn in Vienna. Other important milestones in this period include the description of the false-positive test for syphilis in SLE by Reinhart and Hauck from Germany (1909); the description of the typical endocarditis lesions in SLE by Libman and Sacks in New York (1923); the description of the typical glomerular changes by Baehr (1935); and finally the use of the term diffuse connective tissue disease by Klemperer, Pollack, and Baehr (1941). The major serologic breakthrough in the diagnosis of SLE was the discovery of the LE cell by Hargraves, Richmond, and Morton at the Mayo Clinic in 1948; this marks the beginning of the modern era in SLE. Major advances in understanding of the pathology and immunology of SLE include the identification of antibodies to DNA and other extractable nuclear antigens; the development of animal models of SLE and the recognition of the role of genetic predisposition to the development of SLE; and the contribution of the major histocompatibility complex loci, various cytokines, cellular components of the innate and adaptive im­mune system, mechanisms of central and peripheral immune tolerance, and apoptotic cell death. Intensive study of the immune system abnormalities and the genetics in SLE has identified new therapeutic targets for this complex ­disease.

EPIDEMIOLOGY AND CLASSIFICATION EPIDEMIOLOGY Prevalence rates in SLE are estimated to be 51 per 100,000 in the United States.2 The incidence of SLE has nearly tripled in the last 40 years, mainly as a result of improved diagnosis of mild disease.3 Estimated incidence rates in North America, South America, and Europe range from 2 to 8 per 100,000 per year.4,5 Women are affected nine times more frequently than men, and African-Americans and Hispanics are affected much more frequently than whites and have a higher disease morbidity.6-9 The disease seems to be more common in urban than rural areas. Of patients with SLE, 65% have disease onset between ages 16 and 55, 20% ­present before age 16, and 15% present after the age of 55.10 Men with SLE tend to have less photosensitivity, more serositis, an older age at diagnosis, and a higher 1-year mortality compared with women.11,12 SLE tends to be milder in the elderly with a lower incidence of malar rash, photosensitivity, purpura, alopecia, Raynaud’s phenomenon, renal system involvement, and central nervous system (CNS) involvement, but a greater prevalence of serositis, pulmonary involvement, sicca symptoms, and musculoskeletal manifestations.13 1263

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CLASSIFICATION CRITERIA Many autoimmune rheumatic diseases are characterized by overlapping organ system involvement and lack a pathognomonic test. Criteria for disease classification were developed in 1971, revised in 1982, and revised again in 1997 (Table 75-1).14 Classification criteria help to distinguish patients with the disease in question from individuals without the disease. The American College of Rheumatology (ACR) classification criteria for SLE were developed for clinical studies to ensure that SLE patients reported in the literature actually have the disease. In addition to the wide variety of manifestations, SLE runs an unpredictable course. The dynamic nature of the disease makes its diagnosis challenging in some cases. Often a prolonged period of observation is required before making a definitive diagnosis. USE OF CLASSIFICATION CRITERIA FOR DIAGNOSTIC PURPOSES Although the classification criteria also may be used as diagnostic aids, there are several caveats for their use for ­diagn­ostic purposes. These criteria were developed and validated for the classification of patients with long-standing established disease and may exclude patients with early disease or disease limited to a few organs. Despite excellent sensitivity (>85%) and specificity (>95%) for patients with established disease, the sensitivity of the criteria for patients early in the disease may be significantly lower. Some systems are overrepresented; the mucocutaneous manifestations of

lupus are represented with four criteria (photosensitivity, malar rash, discoid lesions, and oral ulcers). At the same time, all features included in the classification criteria ­contribute equally without any weight based on sensitivity and specificity for each individual criterion. Studies have shown and experience supports that criteria such as objective evidence of renal disease (significant proteinuria, active urine sediment, or renal biopsy specimen with evidence of lupus nephritis), discoid rash, and cytopenias are more useful in establishing the diagnosis of SLE than the other criteria. Because SLE is a disease whose course is typified by periodic involvement of one organ system after another, it is apparent that patients must have the disease for years before they fulfill the classification criteria; medical literature may overestimate the diagnostic utility of some tests or features of the disease because they are usually analyzed among patients with an uncertain cause of symptoms, as is common in practice. Data from tertiary care centers among patients referred for SLE suggest that two thirds of patients fulfill ACR criteria for SLE; approximately 10% have clinical SLE, but do not fulfill criteria; and 25% have fibromyalgia-like symptoms and positive antinuclear antibody (ANA), but never develop SLE.15 ACTIVITY AND DAMAGE INDICES SLE has a chronic course that is often complicated by ­exa­cerbations and flares of varying severity. Assessing disease activity in a patient with SLE is crucial to the physician because it forms the basis of most treatment decisions. ­Disease activity in chronic diseases such as SLE needs to be

Table 75-1  American College of Rheumatology Revised Classification Criteria for Systemic Lupus Erythematosus Criteria

Definition

Malar rash

Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds

Discoid rash

Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring occurs in older lesions

Photosensitivity

Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation

Oral ulcers

Oral or nasopharyngeal ulceration, usually painless, observed by a physician

Arthritis

Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion

Serositis

a. Pleuritis—convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion or b. Pericarditis—documented by ECG or rub or evidence of pericardial effusion

Renal disorder

a. Persistent proteinuria >0.5 g/day >3+ if quantitation is not performed or b. Cellular casts—may be red blood cell, hemoglobin, granular tubular, or mixed

Neurologic disorder

a. Seizures—in the absence of offending drugs or known metabolic derangements (e.g., uremia, acidosis, or electrolyte imbalance) or b. Psychosis—in the absence of offending drugs or known metabolic derangements (e.g., uremia, acidosis, or electrolyte imbalance)

Hematologic disorder

a. Hemolytic anemia with reticulocytosis, or b. Leukopenia—<4000/mm3, or c. Lymphopenia—<1500/mm3, or d. Thrombocytopenia—<100,000/mm3 in the absence of offending drugs

Immunologic disorder

a. Anti-DNA—antibody to native DNA in abnormal titer, or b. Anti-Sm—presence of antibody to Sm nuclear antigen, or c. Positive finding of antiphospholipid antibodies based on (1) abnormal serum concentration of IgG or IgM anticardiolipin antibodies, (2) positive test result for lupus anticoagulant using a standard method, or (3) false-positive serologic test for syphilis known to be positive for at least 6 mo and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test

ANA

Abnormal titer of ANA by immunofluorescence or equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus syndrome

ANA, antinuclear antibody; ECG, electrocardiogram. Adapted from Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. ­Arthritis Rheum 40:1725, 1997.

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Table 75-2  Systemic Lupus Erythematosus Disease Activity Index Descriptor

Definition

Weighted Score

Seizure

Recent onset; exclude metabolic, infectious, or drug-related causes

8

Psychosis

Altered ability to function in normal activity owing to severe disturbance in the perception of reality; includes hallucinations, incoherence marked by loose associations, impoverished thought content, marked illogical thinking, and bizarre disorganized or catatonic behavior; exclude the presence of uremia and offending drugs

8

Organic brain syndrome

Altered mental function with impaired orientation or impaired memory or other intellectual function, with rapid onset and fluctuating clinical features; includes clouding of consciousness with reduced capacity to focus and inability to sustain attention on environment, and at least two of the following—perceptual disturbance, incoherent speech, insomnia or daytime drowsiness, and increased or decreased psychomotor activity; exclude metabolic infectious and drug-related causes

8

Visual

Retinal changes from systemic lupus erythematosus cytoid bodies, retinal hemorrhages,   serous exudate or hemorrhage in choroid, optic neuritis (not due to hypertension, drugs,   or infection)

8

Cranial nerve

New onset of sensory or motor neuropathy involving a cranial nerve

8

Lupus headache

Severe, persistent headache; may be migrainous, unresponsive to narcotic analgesia

8

Cerebrovascular   accident

New syndrome; exclude arteriosclerosis

8

Vasculitis

Ulceration, gangrene, tender finger nodules, periungual infarction, splinter hemorrhages; vasculitis confirmed by biopsy or angiogram

8

Arthritis

More than two joints with pain and signs of inflammation (tenderness, swelling, or effusions)

4

Myositis

Proximal muscle aching or weakness associated with elevated creatine phosphokinase/aldo­ lase levels, electromyographic changes, or biopsy specimen showing myositis

4

Casts

Heme, granular, or erythrocyte

4

Hematuria

>5 erythrocytes per high-power field; exclude other causes (stone, infection)

4

Proteinuria

>0.5 g of urinary protein excreted per 24 hr; new onset or recent increase of >0.5 g/24 hr

4

Pyuria

>5 leukocytes per high-power field; exclude infection

4

New malar rash

New onset or recurrence of inflammatory type of rash

4

Alopecia

New or recurrent; patch of abnormal, diffuse hair loss

4

Mucous membrane

New onset or recurrence of oral or nasal ulceration

4

Pleurisy

Pleuritic chest pain with pleural rub or effusion, or pleural thickening

4

Pericarditis

Pericardial pain with at least one rub or effusion; confirmation by ECG or echocardiography

4

Low complement

Decrease in CH50, C3, or C4 levels (to less than the lower limit of the laboratory-determined normal range)

2

Increased DNA binding

>25% binding by Farr assay (to more than the upper limit of the laboratory-determined   normal range, e.g., 25%)

2

Fever

>38°C after exclusion of infection

1

Thrombocytopenia

<100,000 platelets

1

Leukopenia

Leukocyte count <3000/mm3 (not due to drugs)

1

ECG, electrocardiogram.

distinguished from damage. This distinction has important implications for the long-term prognosis and the appropriate treatment in individual patients. A detailed history and physical examination should be done in every SLE patient. Appropriate laboratory evaluation, including pulmonary function tests, magnetic resonance imaging (MRI), high-resolution computed tomography (CT), magnetic resonance arteriography, and conventional arteriography, should be used to help differentiate active from chronic lesions where applicable. Several validated global and organ-specific activity indices are widely used in the evaluation of SLE patients.16,17 These include British Isles Lupus Assessement Group Scale, European Consensus Lupus Activity Measure (ECLAM), Lupus Activity Index, National Institutes of Health SLE Index Score, Systemic Lupus Activity Measure, and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).

These indices have been developed in the context of longterm observational studies and have been shown to be strong predictors of damage and mortality, and to reflect change in disease activity. They have been validated against each other. We recommend the use of at least one of these indices for monitoring of disease activity. In our experience, the ECLAM and the SLEDAI (Table 75-2) are more convenient for use in daily practice. Computerized clinical charts that compute several disease activity indices simultaneously have been developed.18 The Systemic Lupus International Collaborating Clinics/ACR damage index is a validated instrument specifically designed to ascertain damage in SLE.19 The damage in SLE may be due to SLE itself or to drug therapy. The index records damage in 12 organs or systems (Table 75-3). There is no index to measure damage caused by drugs in SLE at present. The change must have been present for at least

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Table 75-3  Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index   for Systemic Lupus Erythematosus Item

Score

Ocular (either eye by clinical assessment)   Any cataract ever   Retinal change or optic atrophy

0, 1 0, 1

Neuropsychiatric   Cognitive impairment (e.g., memory deficit, difficulty with calculation, poor concentration,   difficulty in spoken or written language, impaired performance level) or major psychosis   Seizures requiring therapy for 6 mo   Cerebrovascular accident ever (score 2 if >1)   Cranial or peripheral neuropathy (excluding optic)   Transverse myelitis

0, 1 0, 1 0, 1, 2 0, 1 0, 1

Renal Estimated or measured glomerular filtration rate <50% Proteinuria >3.5 g/24 hr or End-stage renal disease (regardless of dialysis or transplantation)

0, 1 0, 1 or 3

Pulmonary   Pulmonary hypertension (right ventricular prominence, or loud P2)   Pulmonary fibrosis (physical and radiographic)   Shrinking lung (radiograph)   Pleural fibrosis (radiograph)   Pulmonary infarction (radiograph)

0, 1 0, 1 0, 1 0, 1 0, 1

Cardiovascular   Angina or coronary artery bypass   Myocardial infarction ever (score 2 if >1)   Cardiomyopathy (ventricular dysfunction)   Valvular disease (diastolic murmur, or systolic murmur >3/6)   Pericarditis for 6 mo or pericardiectomy

0, 1 0, 1, 2 0, 1 0, 1 0, 1

Peripheral vascular   Claudication for 6 mo   Minor tissue loss (pulp space)   Significant tissue loss ever (e.g., loss of digit or limb) (score 2 if >1 site)   Venous thrombosis with swelling, ulceration, or venous stasis

0, 1 0, 1 0, 1, 2 0, 1

Gastrointestinal   Infarction or resection of bowel below duodenum, spleen, liver or gallbladder ever,   for any cause (score 2 if >1 site)   Mesenteric insufficiency   Chronic peritonitis   Stricture or upper gastrointestinal tract surgery ever   Chronic pancreatitis

0, 1, 2 0, 1 0, 1 0, 1 0, 1

Musculoskeletal   Muscle atrophy or weakness   Deforming or erosive arthritis (including reversible deformities, excluding avascular necrosis)   Osteoporosis with fracture or vertebral collapse (excluding avascular necrosis)   Avascular necrosis (score 2 if >1)   Osteomyelitis   Tendon rupture

0, 1 0, 1 0, 1 0, 1, 2 0, 1 0, 1

Skin   Scarring chronic alopecia   Extensive scarring of panniculus other than sculp and pulp space   Skin ulceration (excluding thrombosis for >6 mo) Premature gonadal failure Diabetes (regardless of treatment) Malignancy (exclude dysplasia) (score 2 if >1 site)

0, 1 0, 1 0, 1 0, 1 0, 1 0, 1

6 months and is ascertained clinically or by simple investigations. Several independent studies have shown that the early acquisition of damage is a poor prognostic sign.20,21

can be subclassified further as acute, subacute, and chronic lesions.22,23 Acute Rashes—Malar Rash

CLINICAL FEATURES MUCOCUTANEOUS INVOLVEMENT Mucocutaneous involvement is almost universal in SLE. Cutaneous lesions in SLE can be classified as lupus specific and nonspecific (Table 75-4). The lupus-specific lesions

The classic lupus butterfly rash manifests acutely as an erythematous, elevated lesion, pruritic or painful, in a malar distribution, commonly precipitated by exposure to sunlight (Fig. 75-1). The rash may last days to weeks and is commonly accompanied by other inflammatory manifestations of the disease. The acute butterfly rash should be

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Table 75-4  Classification of Lupus Erythematosus–  Associated Skin Lesions LE-Specific Skin Lesions Acute cutaneous LE Localized Generalized Subacute cutaneous LE Annular Papulosquamous (psoriasiform) Chronic cutaneous LE “Classic” DLE Localized Generalized Hypertrophic (verrucous) DLE Lupus panniculitis (profundus) Mucosal LE Tumid lupus Chilblain lupus LE-Nonspecific Skin Lesions Cutaneous vascular disease Vasculitis Leukocytoclastic Palpable purpura Urticarial vasculitis Polyarteritis nodosa–like Papulonodular mucinosis Degos disease–like Atrophie blanche–like Livedo reticularis Thrombophlebitis Raynaud’s phenomenon Erythromelalgia LE-nonspecific bullous lesions Acquired epidermolysis bullosa Dermatitis herpetiformis–like bullous LE Pemphigus erythematosus Porphyria cutanea tarda Urticaria Vasculopathy Anetoderma/cutis laxa Acanthosis nigricans (type B insulin resistance) Periungal telangiectasia Erythema multiforme Leg ulcers Lichen planus Alopecia (nonscarring) “Lupus hair” Telogen effluvium Alopecia areata Sclerodactyly Rheumatoid nodules Calcinosis cutis DLE, discoid lupus erythematosus; LE, lupus erythematosus. Modified from Sontheimer RD, Provost TT: Cutaneous Manifestations of Rheumatic Diseases. Baltimore, Williams & Wilkins, 1996.

d­ ifferentiated from other causes of facial erythema, such as rosacea; seborrheic, atopic, and contact dermatitis; glucocorticoid-induced dermal atrophy; and flushing. Other acute cutaneous lesions include generalized erythema and bullous lesions. The rash of acute cutaneous lupus erythematosus can be transient and heal without scarring.22,23 Subacute Rashes Subacute cutaneous lupus erythematosus (SCLE) is not uniformly associated with SLE.24 Approximately 50% of ­aff­ected patients have SLE, and about 10% of patients with SLE have this type of skin lesion.25 Patients with SCLE may

Figure 75-1  Localized acute cutaneous lupus erythematosus (malar rash). These lesions are abrupt in onset, frequently appear after exposure to the sun, and are characterized by erythema and edema. The sparing of the nasolabial folds and the absence of discrete papules and pustules help to differentiate this condition from acne rosacea (including glucocorticoid-induced rosacea).

present with annular or psoriasiform skin lesions, and this is strongly associated with anti-Ro (SS-A) and anti-La (SSB) antibodies. Patients with SCLE have a high incidence of photosensitivity and rarely can present with erythema ­multiforme–like lesions (Rowell’s syndrome).26 SCLE lesions begin as small, erythematous, slightly scaly papules that evolve into either a psoriasiform (papulosquamous) or annular form. The latter lesions often coalesce to form polycyclic or figurative patterns (Fig. 75-2). The lesions typically have erythematous, and sometimes crusted, margins. The most frequently affected areas in SCLE are the shoulders, forearms, neck, and upper torso. The face is usually spared. Chronic Rashes Discoid lupus erythematosus (DLE) lesions develop in 25% of patients with SLE, but also may occur in the absence of any other clinical features of SLE.27 Patients with DLE have approximately a 5% to 10% risk of developing SLE, which tends to be mild. Patients with numerous and widespread lesions seem to be more likely to develop SLE. Discoid lesions are characterized by discrete, erythematous, slightly infiltrated plaques covered by a well-formed adherent scale that extends into dilated hair follicles (follicular plugging) (Fig. 75-3). Discoid lesions are most often seen on the face, neck, and scalp, but also occur on the ears and infrequently on the upper torso. They tend to expand slowly with active inflammation at the periphery, and then to heal, leaving depressed central scars, atrophy, telangiectasias, and dyspigmentation (hyperpigmentation or hypopigmentation). The differential diagnosis of discoid lesions includes hypertrophic lichen planus, eczema, and actinic keratosis; some early and scaly discoid lesions also must be differentiated from psoriasis. Other Rashes Additional SLE-specific skin lesions include lupus profundus, presenting as a firm nodular lesion with or without an overlying cutaneous lesion. The nodules are often painful and consist of

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Figure 75-2  Subacute cutaneous lupus lesions. Typical features include symmetric, widespread, superficial, and nonscarring lesions. Involvement of the neck, shoulders, upper chest, upper back, and extensor surface of the hand is common. These lesions begin as small photosensitive, erythematous, scaly papules or plaques that evolve into a papulosquamous (psoriasiform) or annular polycyclic form as in this patient. Subacute  cutaneous lupus erythematosus has been associated with the presence of anti-Ro/SS-A antibodies, genetic deficiencies of complement C2 and C4,  and certain medications, such as hydrochlorothiazide.

Figure 75-3  Discoid lupus erythematosus. Refractory to treatment, facial discoid lupus erythematosus lesions produce large areas of disfigurement on confluence. Note the erythema (indicating disease activity), keratin-plugged follicles, and dermal atrophy. The characteristic pattern of hyperpigmentation at the active border and hypopigmentation at the inactive center is especially evident in black patients. Discoid lesions are usually found on the face, scalp, ears, or neck. Facial involvement of this sort can produce extreme psychosocial disability.

perivascular infiltrates of mononuclear cells plus panniculitis, manifested as hyaline fat necrosis with mononuclear cell infiltration and lymphocytic vasculitis. The nodules usually appear on the scalp, face, arms, chest, back, thighs, and buttocks; ulcerations are uncommon, and they usually resolve leaving a depressed area. Some patients with lupus profundus exhibit no other manifestations of SLE. Tumid lupus, a rare variant, is characterized by photodistributed lesions with chronic pinkto-violaceous papules, nonscarring plaques, and nodules.

the enhanced apoptosis of keratinocytes that leads to the exposure of autoantigens and the production of proinflammatory cytokines and other immune mediators by keratinocytes and Langerhans cells.29,30

Alopecia Hair loss occurs in most patients with lupus and in some cases can precede other manifestations of SLE.28 Lupus alopecia may involve the scalp, eyebrows, eyelashes, beard, and body hair. Scarring alopecia is a complication of DLE that typically affects the scalp. Lupus hair is characterized by thin hair that easily fractures, usually occurs along the frontal hairline, is associated with disease activity, and grows back normally as the disease subsides. Photosensitivity Photosensitivity refers to the development of a rash after exposure to ultraviolet B (UVB) radiation found in sunlight or fluorescent lights. It occurs in 60% to 100% of patients with SLE. Some patients also are sensitive to UVA radiation (emitted from photocopiers) and rarely may even be sensitive to the visible light spectrum. Not all photosensitive individuals have SLE, and the two disorders are not causally linked in every patient with SLE. Acute, subacute, and DLE lesions and some bullous and urticarial lesions are photosensitive. The severity of cutaneous reaction depends on the intensity of the UV source and the duration of exposure. Although the exact mechanism by which UV radiation causes skin lesions is unknown, it may be related to

Differential Diagnosis Several dermatologic entities can simulate the appearance of lupus-specific lesions and should be considered in patients with atypical features or refractoriness to standard therapy or both. Acne rosasea can result in a red face and is often confused with acute cutaneous lupus erythematosus. Photosensitive psoriasis can simulate papulosquamous SCLE, whereas occasionally erythema multiforme may be confused with annular SCLE. Finally, other common dermatoses that are not related to SLE may be found in SLE patients, such as contact dermatitis, eczema, and seborrheic dermatitis. Mucous Membranes Involvement of the mucous membranes occurs in 25% to 45% of patients with SLE.31 The most common manifestations include irregularly shaped, raised, white plaques; areas of erythema; silvery white scarred lesions; and ulcers with surrounding erythema on the soft or hard palate or buccal mucosa.32 These lesions should be distinguished clinically from lichen planus, candidiasis, aphthous stomatitis, intraoral herpes, Behçet syndrome (also known as Adaman­tiadesBehçet syndrome), bite marks, leukoplakia, and malignancy. The oral ulcers in SLE are usually painless, and sometimes there is no apparent association between their presence and systemic disease activity. Oral lesions may be the first signs of SLE. Characteristic discoid lesions with erythema, atrophy, and depigmentation can occur on the lips. Nasal ulcers have been noted in patients with SLE. They usually are found in the lower nasal septum, tend to be bilateral, and

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are associated with active disease. Nasal septum perforation has been reported in 4% of SLE patients and is secondary to vasculitis.33 Involvement of the upper airway mucosa also can occur and cause hoarseness. Pathology Biopsy specimens of skin lesions from patients with DLE and SLE contain the membrane attack complex, which comprises C5b through C9, and immune complexes at the dermal-epidermal junction.34 The basilar epithelium in these areas is vacuolated and edematous, and the dermis contains an inflammatory infiltrate. In contrast, 19 of 29 specimens of normal-appearing skin from patients with DLE or SLE showed only immune complexes at the dermal-epidermal junction, without the membrane attack complex. The other 10 specimens, all from patients without cutaneous involvement, showed neither immune complexes nor membrane attack complexes. These data suggest that immune ­com­plexes within skin lesions selectively generate the assembly of the membrane attack complex, which mediates membrane injury. A synergistic interaction of immune complexes and cofactors may be required to activate complement in areas of skin that are predisposed to tissue injury.34 The search for immunoreactant deposition in nonlesional skin of SLE patients has been referred to as the “lupus band test.” The diagnostic and prognostic significance of the nonlesional lupus band test is controversial. The following issues should be taken into account when interpreting a nonlesional lupus band test: The biopsy specimen should be taken from a non–sun-exposed area because a lupus band test is positive in 20% of sun-exposed areas of normal individuals35; the diagnostic specificity for SLE is very high when three or more immunoglobulin or complement components are identified.36 Under these conditions, a positive nonlesional LBT can serve as a useful piece of information in cases with atypical clinical and laboratory manifestations of SLE. MUSCULOSKELETAL INVOLVEMENT The musculoskeletal system is the most commonly involved system in SLE, affecting 53% to 95% of patients. Arthritis and Arthropathy Joint involvement in SLE is classically described as nonerosive, nondeforming arthralgias and arthritis in a distribution similar to that of rheumatoid arthritis, primarily affecting the small joints of the hands, wrists, and knees (Fig. 75-4). It may be the presenting symptom of SLE or accompany other manifestations during a flare of the disease. A study of hand arthritis in SLE found deforming arthritis in only 17 of 176 patients. The authors described three patterns of deforming arthritis in SLE: a deforming and typically nonerosive arthropathy known as Jaccoud’s arthritis (8 of 17), an erosive arthropathy (3 of 17), and a mild deforming arthropathy (6 of 17).37 Patients’ symptoms (pain and stiffness) are usually out of proportion to the degree of synovitis present on physical examination, and synovitis may be transient (resolving within a few days in some patients), migratory, and reversible.38 At the other extreme are a few patients with an impressive synovitis indistinguishable from rheumatoid

Figure 75-4  Jacoud-type arthropathy. Deformities in the hands, such as ulnar drift at the metacarpophalangeal joints, swan-neck and boutonnière deformities, and hyperextension at the interphalangeal joint of the thumb, closely resemble the deformities seen in rheumatoid arthritis. The absence of erosions on radiographs and their reducibility distinguish this condition from the deforming arthritis of rheumatoid arthritis. (Courtesy of Dr. D. Vassilopoulos.)

arthritis, for whom the term “rhupus” has been coined.39 Radiologic features in lupus hand arthritis include scapholunate dissociation, joint space narrowing, cystic change, and palmar/ulnar subluxation in the wrist. In the fingers, metacarpophalangeal hook erosions, metacarpophalangeal subluxation, and cystic changes are the most common features, but marginal erosions are rare. With the use of more sensitive imaging techniques, such as high-resolution ultrasound combined with power Doppler, wrist synovial hypertrophy and effusion were detected in 16 (94%) of 17 patients with SLE hand arthritis. Eight patients (47%) had erosions at the second and third metacarpophalangeal joints, which were not detectable by simple x-rays in three of them. Eleven patients (65%) had evidence of tenosynovitis, with detectable power Doppler signal in half of them.40 Tenosynovitis is an early manifestation of SLE, and tendon rupture syndromes have been reported in many different sites in the body, including the patellar tendons, the Achilles tendon, the long head of the biceps, the triceps, and the extensor tendons of the hands.41,42 Tendon rupture has been associated with male gender, trauma, oral and intra-articular steroid use, and long disease duration.43 Flexure tendon contractures of the elbow also have been reported.44 Synovitis can induce the carpal tunnel syndrome, which may be the initial manifestation of SLE or drug-induced lupus (DIL).45 Although septic arthritis is uncommon in SLE, it should be suspected when one joint is inflamed out of proportion to all others. Aspiration and culture of the synovial fluid are essential to rule out infection in this case. Subcutaneous nodules along the flexor tendons of the hand can be found in SLE. The histologic appearance is similar to that of rheumatoid nodules.46 Periarticular calcification has been reported in the small joints of the hand, whereas soft tissue calcification is rarely seen in SLE.47,48 Myositis Generalized myalgia and muscle tenderness are common, especially during disease exacerbations. Inflammatory myositis involving the proximal muscles has been reported to occur in 5% to 11% of patients and may develop at any

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time during the course of the disease.49,50 The differential diagnosis of proximal muscle weakness in SLE includes a drug-related myopathy secondary to corticosteroid, antimalarial, or statin medications use. Concurrent hypothyroidsm also can cause an increase in creatine phosphokinase and proximal myopathy. Muscle biopsy, electromyographic studies, and elevation of the serum creatine phosphokinase or aldolase levels help to differentiate between inflammatory and drug-related myopathy. The histologic features of myositis in SLE may be less striking than in idiopathic polymyositis. Histologic fea­ tures include muscle atrophy, microtubular inclusions, and a mononuclear cell infiltrate. Fiber necrosis is an uncommon finding, but immunoglobulin deposition is almost always present despite the rarity of concurrent inflammation.51-53 A low serum creatine phosphokinase value can be found in patients with connective tissue disease including SLE; a normal creatine phosphokinase value in the presence of symptoms and signs of myositis should not dissuade the physician from a diagnosis of myopathy. The skin lesions of dermatomyositis also can appear in patients with SLE. Chest pain or discomfort secondary to costochondritis has been reported in SLE, and other conditions, such as angina pectoris, pericarditis, and esophageal spasm, must be ruled out first. Relapsing polychondritis also has been described in patients with SLE and in most cases responds to low-dose corticosteroid treatment.54,55 Avascular Bone Necrosis Avascular necrosis of bone is a major cause of significant morbidity and disability in patients with SLE. Symptomatic avascular necrosis occurs in 5% to 12% of SLE patients. Higher prevalences have been reported in series that used MRI for its detection.56 Acute joint pain manifesting late in the course of SLE and localized to a very few areas, especially shoulders, hips, and knees, may indicate the development of avascular necrosis. The initial pathologic lesion that leads to osteonecrosis begins by interruption of the blood supply to the bone followed by reactive hyperemia of the adjacent bone resulting in demineralization, trabecular thinning, and finally collapse if stressed. In SLE, factors that can induce ischemia leading to bone necrosis include Raynaud’s phenomenon, vasculitis, fat emboli, corticosteroids, and anti­ phospholipid antibody syndrome (APS). A large study of 744 patients followed for an average of 25 years found that only the presence of arthritis and the use of corticosteroids or cytotoxic medications or both are independent risk factors for development of avascular necrosis in patients with SLE.57 Osteonecrosis often develops a short time after the onset of corticosteroid therapy, within 1 month in some patients who receive high doses.58-61 RENAL INVOLVEMENT Renal involvement is a major cause of morbidity and hospital admissions in SLE patients and occurs in 40% to 70% of all patients. Generally, renal involvement tends to occur within the first 2 years of SLE with its frequency decreasing significantly after the first 5 years of disease. The disease displays a remarkable clinical and histologic heterogeneity (see later). Almost half of patients present with asymptomatic

urine abnormalities, such as hematuria and proteinuria. Nephrotic or nephritic syndrome or both also may be observed in 30% of patients. Rarely (<5%), patients may present with chronic renal insufficiency, rapidly progressive glomerulonephritis, or a pulmonary-renal vasculitis syndrome. Immunopathology Immune complex formation and deposition in the kidney results in intraglomerular inflammation with recruitment of leukocytes and activation and proliferation of resident renal cells.62 A plethora of humoral and cellular elements contributes to glomerular injury. Intense inflammation may destroy resident renal cells by necrosis or apoptosis, resulting in fibrinoid necrosis. In a few patients, intense capillary inflammation results in rupture of the capillary wall and the capsule itself with epithelial cells, mononuclear cells, fibrin basement membrane material, and collagen accumulating in the urinary space of the glomerulus (crescentic glomerulonephritis). When injury is less intense, endocapillary cells respond by proliferating and producing extracellular matrix (proliferative lesions). Extreme injury or protracted inflammation activates a final common pathway of all types of glomerular injury, resulting in atrophy and scarring. In lupus nephritis, the location of immune complex depo­ sition and formation is closely linked to histopathology and the intensity of the inflammatory response. Deposition of immune complexes in the mesangium is characteristic of mesangial lupus nephritis. Immune complex deposition in the subendothelial area of the capillary loops results in proliferative lupus nephritis (focal or diffuse) with exuberant glomerular hypercellularity. This hypercellularity is due to proliferation of mesangial and endothelial cells and leukocytic infiltrates, resulting in compromised capillary flow and renal function. Epimembranous (subepithelial) deposits along peripheral glomerular capillary loops that are diffusely thickened and the lack of inflammatory infiltrate are characteristic of membranous nephropathy. The standard 1982 World Health Organization classification has been revised to provide a clearer and unequivocal description of various lesions and classes of lupus nephritis (Table 75-5).63 In several studies of lupus nephritis, type IV nephritis is the most common (approximately 40%), whereas type III and type V follow with an approximate frequency of 25% and 15%. Transformation from one class to another can occur, spontaneously and as a result of treatment. Prognosis is worse when membranous and proliferative changes coexist.62 Laboratory Findings Proteinuria of various levels is the dominant feature of lupus nephritis and is usually accompanied by glomerular hematuria.64 Nephritic syndrome accounts for an additional 30% to 40% of patients; rapidly progressive glomerulonephritis is rare and accounts for less than 10% of the initial presentations. Generally, untreated patients with mesangial nephritis have small amounts of proteinuria (<1 g/day) with hematuria, but typically no cellular casts. Patients with membranous glomerulopathy have proteinuria often at ne­­ ph­rotic range, but otherwise unremarkable urine sediments.

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Table 75-5  Histologic Classification of Lupus Nephritis According to the International Society of Nephrology/Renal Pathology Society, 2003 WHO Type Class I

Minimal mesangial lupus nephritis Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence

Class II

Mesangial proliferative nephritis Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light microscopy, with   mesangial immune deposits Few isolated subepithelial or subendothelial deposits may be visible by immunofluorescence or electron   microscopy, but not by light microscopy

Class III

Focal lupus nephritis Active or inactive focal, segmental, or global endocapillary or extracapillary glomerulonephritis involving <50% of all glomeruli, typically with focal subendothelial immune deposits, with or without mesangial alterations

Class IV

Diffuse lupus nephritis Active or inactive diffuse, segmental, or global endocapillary or extracapillary glomerulonephritis involving ≥50% of all glomeruli, typically with diffuse subendothelial immune deposits, with or without mesangial alterations. This class is subdivided into diffuse segmental (IV-S) lupus nephritis when ≥50% of the involved glo­ meruli have segmental lesions, and diffuse global (IV-G) lupus nephritis when ≥50% of the involved glomeruli have global lesions. Segmental is defined as a glomerular lesion that involves less than half of the glomerular tuft. This class includes cases with diffuse wire loop deposits, but with little or no glomerular proliferation

Class V

Membranous lupus nephritis Global or segmental subepithelial immune deposits or their morphologic sequelae by light microscopy and by immunofluorescence or electron microscopy, with or without mesangial alterations Class V nephritis may occur in combination with class III or class IV, in which case both are diagnosed Class V nephritis may show advanced sclerotic lesions

Class VI

Advanced sclerotic lupus nephritis ≥90% of glomeruli globally sclerosed without residual activity

WHO, World Health Organization. Adapted from Weening JJ, et al: The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol 15:241, 2004.

C3 tends to be normal, and anti-DNA antibodies when present are usually found in low titers. In contrast, patients with proliferative nephritis have hypertension, a nephritic urine sediment with various degrees of proteinuria (often at nephrotic range), low C3, and typically high titers of anti-DNA antibodies. The clinical presentation does not always predict the underlying histologic class of nephritis. In patients who have been previously treated with steroids, the findings in the urinalysis may be more subtle than previously, creating a sense of false security. In these cases, a high index of suspicion is crucial. Urinalysis Urinalysis is the most important and effective method to detect and monitor disease activity in lupus nephritis.64 To ensure quality, several steps have to be taken, including expeditious examination of a fresh, early morning, midstream, clean-catch, nonrefrigerated specimen and flagging of specimens from patients at substantial risk to develop nephritis to ensure careful examination at central laboratories. Hematuria (usually microscopic, rarely macroscopic) indicates inflammatory glomerular or tubulointerstitial disease. Erythrocytes are fragmented or misshapen (dysmorphic). Granular and fatty casts reflect proteinuric states, whereas red blood cell, white blood cell, and mixed cellular casts reflect nephritic states (Fig. 75-5). Broad and waxy casts reflect chronic renal failure. In severe proliferative disease, urine sediment containing the full range of cells and casts can be found (“telescopic urine sediment”) as a result of severe glomerular and tubular ongoing disease superimposed on chronic renal damage.

Figure 75-5  Urinary specimen in active lupus nephritis. Urinalysis is the most useful test to monitor for renal involvement and relapses after remission in lupus patients. Dysmorphic urinary red blood cells (RBCs) are seen in the urine of a patient with active glomerulonephritis and an active urine sediment. Note the fragmented RBCs and the abnormal sizes and shapes of most of them. The proteinacious matrix of this cellular cast in the middle of the figure contains RBCs. (Courtesy of Dr. D. ­Vassilopoulos.)

Renal Biopsy Indications. Renal biopsy rarely helps in the diagnosis of SLE, but is the best way of documenting the renal pathology. In the absence of renal abnormalities, renal biopsy has nothing to offer and should not be done. Standard indications for renal biopsy before treatment include (1) nephritic

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urine sediment (glomerular hematuria and cellular casts); (2) glomerular hematuria with proteinuria greater than 0.5 to 1 g/day; (3) glomerular hematuria with proteinuria less than 0.3 to 0.5 g/day, and low C3 or positive anti–doublestranded DNA (dsDNA); and (4) proteinuria greater than 1 to 2 g/day (especially if C3 is low or anti-dsDNA antibodies are present or both). Selected patients with clinical and laboratory evidence of severe lupus nephritis, nephritic or nephrotic syndrome, azotemia, and hypertension may not require a renal biopsy before treatment with cytotoxic drugs. Patients with concomitant serologic abnormalities (i.e., low C3, positive anti-dsDNA) or patients who had previous immunosuppressive treatment may be candidates for renal biopsy even with more subtle findings. Studies have suggested (and experience supports) that patients and physicians are more willing to decide on aggressive therapies when faced with a renal biopsy specimen indicating severe renal involvement; this translates into earlier institution of cytotoxic therapy and better renal outcomes.65 The decision for repeat biopsy is more complex and should be considered in cases of (1) unexplained worsening proteinuria (e.g., >2 g/day increase if non-nephrotic at baseline or >50% increase if nephrotic), (2) unexplained worsening of renal function (e.g., reproducible 30% increase in serum creatinine), (3) persistent glomerular hematuria with proteinuria greater than 2 g/ day or proteinuria greater than 3 g/day (especially if C3 is decreased), and (4) nephritic or nephrotic flare. Evaluation and Interpretation of Renal Biopsy Specimen. Evaluation of the renal biopsy specimen is of paramount importance and typically includes light microscopy, immunofluorescence, and electron microscopy (Figs. 75-6 and ­ 75-7).62 Evaluation of specimens with less than 10 glomeruli is suboptimal. Light microscopy stains commonly used include hematoxylin and eosin (best to identify inflammatory cells), Masson trichrome (best for interstitial fibrosis and glomerulosclerosis), and periodic acid–Schiff (best

Figure 75-6  World Health Organization types of lupus nephritis (see Table 75-5 for a detailed description of histologic findings). A, Normal glomerulus (type I). B, Mesangial disease (type II). Note mesangial hypercellularity and expansion of the mesangial matrix, which does not compromise the capillary loops. C, Proliferative nephritis. Dramatic increase in mesangial and endocapillary cellularity produce a lobular appearance of the glomerular tufts and compromise the patency of most capillary loops. When less than 50% of glomeruli are involved, nephritis is denoted as focal (type III). When more than 50% of glo­meruli are involved, nephritis is denoted as diffuse (type IV). D, Membranous nephropathy (type V). In membranous lupus nephropathy, the capillary walls of the glomerular tuft are prominent and widely patent, resembling “stiff” structures with decreased compliance.

for ­ basement membrane abnormalities). Immunofluoresence studies do not help if the diagnosis of SLE is established. In SLE, the “pan-house” staining is usually observed with numerous deposits of immunoglobulins and complement. Electron microscopy helps to define distribution (i.e., ­ subendothelial, epithelial, membranous deposits) of immune complexes and may be useful in the recognition of early proliferative changes when the light microscopy findings may be more subtle. In such cases, the presence of subendothelial deposits—even if scarce—may help guide treatment, especially in the presence of other features of proliferative nephritis (nephritic sediment, low C3, antiDNA antibodies). Activity and chronicity indices are useful in the renal biopsy report as a complement to the World Health Organization classification. In the activity index, a variety of lesions are scored 0 to 3+ with a maximum score of 24 points. This index includes features suggesting active inflammation such as proliferative changes, necrosis/karyorrhexis, cellular crescents, leukocyte infiltration, hyaline thrombi, and interstitial inflammation. In the chronicity index, lesions are scored 0 to 3+ with a maximum score of 12 points. This index includes chronic, irreversible features such as sclerotic glomeruli, fibrous crescents, tubular atrophy, and interstitial fibrosis. In our experience, the most important elements to recognize and consider in a renal biopsy specimen are (1) the presence of crescents, fibrinoid necrosis, or a high activity index (e.g., >9) and (2) interstitial fibrosis, tubular atrophy, glomerular sclerosis, or moderate-to-high chronicity scores (e.g., >3). Their presence denotes severe disease with an ominous prognosis unless treated aggressively (Fig. 75-7). Monitoring of Lupus Nephritis Renal Function. Serum creatinine is a practical, but insensitive, early indicator of abnormalities in glomerular filtration rate. Its absolute level is affected by muscle mass and age in addition to glomerular filtration rate. In clinical ­ practice,

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detecting changes in renal function is more important than the absolute level. Creatinine clearance has several shortcomings in estimating changes in function, the most important of which is overestimation of true glomerular filtration rate with declining renal function. Serum creatinine is a more practical approach for detecting changes in the glomerular filtration rate and is the examination of choice. Significant reproducible changes in serum creatinine (e.g., 20% to 30% increase) are of concern—even if they fall within the normal range—because they indicate significant loss of renal function.64 Serum cystatin C may be a more sensitive and specific biomarker for renal function and glomerular filtration rate, but its role in monitoring patients with lupus nephritis has not been studied. Urine Collection. Two or three timed collections of urine to determine 24-hour protein excretion and baseline creatinine clearance is the “gold standard.” We obtain urine samples before therapy and periodically thereafter before decisions regarding assessing response and changes in therapy. Urine samples containing creatinine concentrations that deviate significantly from population averages for men (20 mg/kg/day) or women (15 mg/kg/day) should raise suspicions about the adequacy of the urine collection. Spot urine protein/creatinine is a simpler method to estimate the severity of proteinuria and could be used in between 24-hour collections to provide (together with serum albumin and cholesterol levels) rough estimates of the response of proteinuria to therapy. The numeric ratio generally approaches the number of grams per day of proteinuria. If the ratio is 3.4, the 24-hour protein excretion is approximately 3.4 g/day.64 Urinalysis. Resolution of active urine sediment is a feature of renal remission, but to be clinically meaningful, it has to be sustained for several months. Reappearance of ­ cellular casts with significant proteinuria is an early and ­ reliable

Figure 75-7  High-risk histologic features suggesting severe nephritis. A, Fibrinoid necrosis with karyorrhexis in a patient with focal proliferative glomerulonephritis. B and C, Cellular crescents with layers of proliferative endothelial cells and monocytes lining Bowman’s capsule along with a predominantly mononuclear interstitial infiltrate. D, Severe interstitial fibrosis and tubular atrophy. Note the thickening of the tubular basement membranes and tubular epithelial degeneration with separation of residual tubules owing to deposition of collagenous connective tissue among tubules.

p­ redictor of renal relapse and in most patients usually precedes increases in anti-DNA titers or decreases in C3 by several weeks.66 Serology. Anti-DNA antibodies and C3 and C4 complement components are useful in monitoring activity of lupus nephritis and in guiding treatment. Generally, changes in anti-DNA titers are more valuable than their absolute values. Patients with rising titers of anti-DNA antibodies warrant close monitoring for evidence of lupus activity. Because C4 deficiency is common in patients with lupus nephritis and C3 levels correlate best with renal histology on repeat renal biopsy specimens, C3 is the preferred choice for monitoring disease activity. Assessment of Prognosis and Risk Stratification Prognosis varies greatly among the many clinical and pathologic forms of lupus nephritis and has important implications for treatment decisions. Numerous demographic and clinical variables can affect prognosis, and individual patients have unique combinations of such risk factors. Although individual risk factors are extremely heterogeneous and vary in their overall impact, patients with the largest number of risk factors carry a worse prognosis, are less likely to respond to therapy, tend to respond more slowly, and need more aggressive treatment. Patient characteristics associated with bad outcomes include African-American race, azotemia, anemia, APS, failure to respond to initial immunosuppressive therapy, and flares with worsening in renal function.67-70 Combinations of severe active (crescents and fibrinoid necrosis) with marked chronic changes (moderate-to-severe tubulointerstitial fibrosis and tubular atrophy, e.g., chronicity index >3) are particularly ominous. The impact of race in determining severity of disease, response to treatment, and final outcome is becoming increasingly apparent. Significant differences in

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Figure 75-8  Severe neuropsychiatric systemic lupus erythematosus. A-D, MRI showing cerebrovascular disease (A and B), thrombosis in the sagittal sinus in a patient with antiphospholipid antibodies (C), and acute transverse myelitis (D).

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D

these risk factors may explain the marked heterogeneity in course, prognosis, and treatment responses in randomized controlled studies around the world. NERVOUS SYSTEM INVOLVEMENT SLE affects the CNS and the peripheral nervous system. Nervous system involvement in SLE is a major cause of morbidity and mortality. Nervous system involvement in SLE is the least understood manifestation of the disease and remains a complex diagnostic entity as a result of its multiple clinical presentations (Fig. 75-8). The ACR described case definitions and classification criteria for 19 CNS and peripheral nervous system syndromes that have been observed in patients with SLE, which collectively are referred to as neuropsychiatric systemic lupus erythematosus (NPSLE) syndromes (Table 75-6).71 Approximately 40% of the NPSLE manifestations develop before the onset of SLE or at the time of diagnosis, and 63% develop within the first year after the diagnosis.72 Table 75-7 shows an approach to the management of neuropsychiatric symptoms and findings in SLE. The prevalence of specific NPSLE syndromes varied wid­ ely in the literature before the introduction of the ACR criteria for NPSLE, with estimates of the overall prevalence ranging from 14% to 75%.73 The plethora of neuropsychiatric manifestations reported in SLE points to multiple pathogenic mechanisms. Neuropsychiatric events in SLE may be caused by a primary manifestation of the disease; secondary complications of the disease or therapy, such as hypertension, infection, or drug-induced aseptic meningitis, especially with nonsteroidal anti-inflammatory drugs (NSAIDs); or a coincidental problem unrelated to SLE. Vascular abnormalities, autoantibodies, and inflammatory mediators have been reported to play significant pathogenic roles in the development of NPSLE. A bland noninflammatory vasculopathy involving small vessels was the

Table 75-6  Neuropsychiatric Syndromes in Systemic Lupus Erythematosus Central Nervous System Aseptic meningitis Cerebrovascular disease Demyelinating syndrome Headache (including migraine and benign intracranial hypertension) Movement disorder (chorea) Myelopathy Seizure disorder Acute confusional state Anxiety disorder Cognitive dysfunction Mood disorder Psychosis Peripheral Nervous System Acute inflammatory demyelinating polyradiculoneuropathy   (Guillain-Barré syndrome) Autonomic disorder Mononeuropathy, single/multiplex Myasthenia gravis Neuropathy, cranial Plexopathy Polyneuropathy Adapted from The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndrome. Arthritis Rheum 42:599, 1999.

p­ redominant finding in neuropathologic autopsy studies.74 In the same study, vasculitis of small and large vessels was rare, and brain microinfarcts occurred in association with microangiopathy. A variety of autoantibodies has been associated with the pathogenesis of different manifestations of NPSLE. Autoanti­ bodies include, among others, antineuronal antibodies,75 antiganglioside antibodies,76,77 anti-NR2 glutamate receptor antibodies,78 anti-DNA antibodies,79 antiribosomal (P) anti­bo­ dies,80,81 anti-β2-glycoprotein I antibodies, antiprothrombin

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antibodies,82 and lupus anticoagulants.83 Increased intracranial and intrathecal levels of cytokines, such as interleukin6, interferon-α, interleukin-10, interleukin-8, and tumor necrosis factor-α, have been associated with seizures and psychosis.84-87 Cognitive dysfunction has been reported in 80% of SLE patients.88 The association between SLE and headache is controversial. Psychosis is reported in 8% of SLE patients and is characterized by the presence of either delusions or hallucinations.88-92 The latter are most frequently auditory. Table 75-7  Approach to the Management   of ­Neuropsychiatric Symptoms in Systemic Lupus ­Erythematosus Diffuse or focal process? Classify symptoms (see Table 75-6) Primary or secondary?   Evidence for generalized lupus activity? If yes, probably related to lupus   Exclude nonlupus-related causes (e.g., infections, drugs, electrolyte abnormalities, hypoxia) Recent evolving or old, inactive process? Thrombotic or inflammatory process?   Inflammatory   Generalized lupus activity (clinical or serologic)   High-grade abnormalities in lumbar puncture (i.e., protein, cells)   MRI findings suggestive of cerebritis or myelitis Thrombotic   Antiphospholipid antibodies or stigmata for APS   MRI findings suggestive of thrombosis Severe inflammatory disease?   Myelitis, cerebritis, coma, status epilepticus, large (or multiple) cerebrovascular accident, mononeuritis multiplex, severe psychosis, catatonia   Consider cytotoxic therapy APS, antiphospholipid antibody syndrome; MRI, magnetic resonance imaging.

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When psychosis is present, it must be distinguished from other causes, including drug abuse, schizophrenia, and de­ p­ression. Generalized and focal seizures are reported in 6% to 51% of patients and may occur either in the setting of active generalized multisystem SLE or as isolated neurologic events. Seizures frequently are associated with the presence of antiphospholipid antibodies, which are associated with microangiopathy, arterial thrombosis, and subsequent cerebral infarction. Demyelination, transverse myelopathy, and chorea are rare manifestations of NPSLE and occur in 1% to 3% of patients. Clinical and neuroimaging evidence of demyelination may be indistinguishable from multiple sclerosis.93 Transverse myelopathy and chorea manifest acutely and often are associated with the presence of antiphospholipid antibodies (see Fig. 75-8).94,95 A peripheral sensorimotor neuropathy has been reported in 28% of SLE patients and may occur independently of other disease characteristics.96 CARDIOVASCULAR INVOLVEMENT A variety of cardiac manifestations can be seen in SLE, with pericarditis being the most common and found in approximately one quarter of the patients. Pericardial effusions may be asymptomatic and are usually mild to moderate. Tamponade is rare, but can occur. Myocardial involvement is rare (<5% of patients) and typically occurs in the presence of generalized SLE activity. Clinical features of left ventricular dysfunction, nonspecific ST/T wave changes, segmental wall motion abnormalities, and decreased ejection fraction are found in greater than 80% of patients. MRI has been used to detect clinical and subclinical myocardial involvement in SLE (Fig. 75-9). Patients may present with fever, dyspnea, tachycardia, and congestive heart failure. Patients with SLE have substantially increased morbidity

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Figure 75-9  Lupus myocarditis. MRI shows enhancement of the myocardium, which spares the endocardium. A-C, Contrast-enhanced inversion recovery technique with late imaging after contrast administration in horizontal long-axis plane (A), vertical long-axis plane (B), and short-axis plane (C). Strong enhancement is found in the midwall of the ventricular septum (A and C), in the apex (A), and in the midanterior and posterior wall (B).

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and ­ mortality from cardiovascular disease.97-99 Morbidity includes accelerated, premature atherosclerosis and valvular heart disease. Cardiovascular disease and atherosclerosis are a common cause of morbidity and mortality in various SLE cohorts. Autopsy studies from the early 1980s showed severe atherosclerosis in 40% of SLE patients compared with 2% of control subjects, matched for age at the time of death.100 Analysis of the Swedish Hospital Discharge Register followed by linkage to the Cause of Death Register during the period 1964 to 1995 showed that SLE patients were at increased risk for death as a result of coronary heart disease or stroke (standardized mortality ratio 2.97, 95% confidence interval 2.78 to 3.16).101 The risk was substantially higher in the younger group of patients (20 to 39 years old; standardized mortality ratio 16, 95% confidence interval 10.4 to 23.6). Other studies have shown that SLE patients carry an increased risk for myocardial infarction or stroke compared with the healthy population. This risk cannot be fully explained by the traditional cardiovascular disease risk factors.98,102-104 Atherosclerosis—defined by coronary artery calcification or carotid plaque size—also is more common in SLE patients than in healthy controls (e.g., 31% versus 9%, in subjects with an average age of 40; relative risk 9.8, 95% confidence interval 2.5 to 39), even after adjustment for possible confounding factors, and it correlates with disease activity and damage scores.105,106 Valvular Heart Disease Valvular heart disease is common in patients with SLE. In a prospective study evaluating 69 SLE patients and 56 healthy controls with transesophageal echocardiograms over 2 years, the prevalence of valvular heart disease was 61% in SLE patients compared with 9% of the controls.107 The most common abnormality was diffuse thickening of the mitral and aortic valves followed by vegetations, valvular regurgitation, and stenosis in decreasing order of frequency. Valvular abnormalities frequently resolved, appeared for the first time, or persisted but changed in appearance or size between the two studies. Mild or moderate valvular regurgitation did not progress to become severe, and new stenoses did not develop. Neither the presence of valvular disease nor changes in the echocardiographic findings were temporally related to the duration, activity, or severity of SLE or to its treatment. The combined incidence of stroke, peripheral embolism, heart failure, infective endocarditis, and the need for valve replacement was 22% in patients with valvular disease and 8% in patients without valvular disease. Several pathologic studies of SLE patients have shown active and healed valvulitis and active Libman-Sacks vegetations with acute thrombus, healed vegetations with or without hyalinized thrombus, or active and healed vegetations, in the same or different valves. Thrombotic vegetations secondary to a hypercoagula­ble state also have been shown in patients with lupus.108-111 These vegetations cannot be clearly differentiated from Libman-Sacks vegetations on echocardiography.112,113 Valvular vegetations can embolize, which may result in a change in their appearance or resolution.109,110,114,115 Acute and subacute bacterial endocarditis may occur on previously involved valves (see later).

Pleura and Lungs The most common pleuropulmonary manifestation of SLE is pleuritis (Table 75-8). Pleuritic pain is present in 45% to 60% of patients and may occur with or without a pleural effusion.116,117 Clinically apparent pleural effusions have been reported in 50% of patients with SLE and may be found in 93% of cases at autopsy. Effusions are usually bilateral, but may be unilateral, equally distributed between the left and the right hemithoraces. Pleural effusions in SLE are invariably exudative, but with higher glucose and lower lactate dehydrogenase levels than those found in rheumatoid arthritis.118 Pleural biopsy findings are nonspecific and include lymphocytic and plasma cell infiltration, fibrosis, and fibrinous pleuritis. Thoracoscopy has revealed nodules on the visceral pleura, and immunofluorescence of biopsy samples of these nodules revealed immunoglobulin deposits.119 Clinically significant interstitial lung disease complicates SLE in 3% to 13% of patients, but is rarely severe.116,120 Asymptomatic involvement is more common, and abnormalities in pulmonary function tests have been reported in two Table 75-8  Pleuropulmonary Manifestations   of Systemic Lupus Erythematosus Pleuropulmonary Manifestation

Common

Pleuritic chest pain or pleurisy

Common, with or without   effusion or friction rub

Pleural effusion

Exudate; unilateral or bilateral

Acute pneumonitis

Not common; presentation includes fever, nonproductive cough, infiltrates, hypoxia; high mortality rates

Interstitial lung disease

Insidious onset of dyspnea on exertion, nonproductive cough, pleuritic chest pain

Bronchiolitis obliterans with organizing pneumonia

Can be difficult to diagnose; requires biopsy; responds to corticosteroids

Pulmonary capillaritis or   diffuse alveolar hemorrhage

Rare, associated with antiphospholipid antibodies; poor prognosis

Shrinking-lung syndrome

Occurs in patients with longstanding SLE; diaphragmatic weakness possible cause

Pulmonary embolism or   infarction

Common in patients with   antiphospholipid antibodies

Pulmonary hypertension

Insidious onset of dyspnea on exertion, chronic fatigue, weakness, palpitations, edema

Lymphadenopathy

Massive mediastinal lymphadenopathy uncommon in patients with SLE alone; cervical and auxillary lymphadenopathy common, correlates with disease activity

Infection

Typical and atypical pathogens; caused by immune dysfunction and immunosuppressive medications

Malignant tumor

Lung cancer; lymphoma more common in SLE

SLE, systemic lupus erythematosus.

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thirds of patients with SLE in some studies.116 ­Abnormalities in high-resolution CT have been reported in 70% of patients with SLE.121 Symptomatic interstitial lung disease is rarely an early or dominant feature of SLE, and severe pulmonary fibrosis is extremely rare. Histologic features of interstitial lung disease complicating SLE are nonspecific and include varying degrees of chronic inflammatory cell infiltrates, peribronchial lymphoid hyperplasia, interstitial fibrosis, and hyperplasia of type II pneumocytes.116 The presence of Raynaud’s phenomenon, swollen fingers, sclerodactyly, telangiectasia, and nail-fold capillary ­ abnormalities among patients with SLE was associated with a higher ­prevalence of restrictive defects and decreased diffusing capacity.122 Acute lupus pneumonitis manifesting as cough, dyspnea, pleuritic pain, hypoxemia, and fever occurs in 1% to 4% of patients with SLE. Chest radiographs reveal infiltrates, which may be unilateral or bilateral. Histologic features are nonspecific and include alveolar wall damage and necrosis, inflammatory cell infiltration, edema, hemorrhage, and hyaline membranes. A microangiitis involving capillaries, with fibrin thrombi and infiltration with necrotic neutrophils, may be present.123 Pulmonary hemorrhage is a rare but potentially catastrophic complication of SLE. Mortality has been reported to be 50% to 90%.124 Clinical features are nonspecific, but diffuse alveolar infiltrates, hypoxemia, dyspnea, and anemia are characteristic. Alveolar hemorrhage usually occurs in patients with a known history of SLE, high titers of anti-DNA antibodies, and active extrapulmonary disease. Fiberoptic bronchoscopy with bronchoalveolar lavage and transbronchial lung biopsy is usually adequate to substantiate the diagnosis in patients with suspected alveolar hemorrhage. Lung biopsy specimens show extensive hemorrhage within alveolar spaces and capillaritis. Deposits of IgG, C3, or immune complexes have been found in 50% of patients with alveolar hemorrhage complicating SLE.123 The “shrinking lung syndrome” is characterized by progressive dyspnea and small lung volumes on chest radiographs and is thought to be secondary to diaphragmatic dysfunction.125 It can be difficult to differentiate from respiratory muscle weakness, primary parenchymal disease, or pleural causes of low lung volumes without the use of invasive studies. LYMPH NODE AND SPLEEN INVOLVEMENT Lymphadenopathy occurs in approximately 40% of patients usually at the onset of disease or during disease flares. The nodes are typically soft, nontender, and discrete, and usually are detected in the cervical, axillary, and inguinal area. Biopsy specimens reveal areas of follicular hyperplasia and necrosis.126 The appearance of hematoxylin bodies is highly suggestive of SLE, but is uncommon. Clinically significant lymphadenopathy that raises diagnostic issues is less common. Generally, patients with lymphadenopathy are more likely to have nonspecific symptoms, such as fever and malaise. A lymph node biopsy may be warranted when the degree of lymphadenopathy is out of proportion to the activity of the lupus. Splenomegaly occurs in 10% to 45% of patients, particularly during active disease, and is not associated with cytopenias. Periarterial fibrosis, or “onionskin” lesions, in the

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spleen has been considered pathognomonic of SLE and is thought to represent healed vasculitis. Splenic atrophy and functional hyposplenism also have been reported in SLE and may predispose to severe septic complications.127,128 HEMATOLOGIC INVOLVEMENT Hematologic abnormalities are common and can be the presenting symptom in SLE. Major clinical manifestations include anemia, leukopenia, thrombocytopenia, and APS. Anemia Anemia is common and affects most SLE patients at some time during the course of their disease. The mechanisms of anemia in SLE vary and include anemia of chronic disease, hemolysis (immune or microangiopathic), blood loss, renal insufficiency, medications, infection, hypersplenism, myelodysplasia, myelofibrosis, and aplastic anemia.129-133 A frequent cause of anemia in SLE is suppressed erythropoiesis from chronic inflammation. The mechanism is multifactorial and includes suppression of hematopoiesis by inflammatory cytokines via apoptosis of progenitor cells or other mechanisms and antibodies against red blood cell growth factors or progenitor cells.129 Overt autoimmune hemolytic anemia has been reported in 10% of patients with SLE.133 SLE patients may have a positive Coombs test without overt hemolysis. Blood loss, either from the gastrointestinal tract, usually secondary to medications (NSAIDs), or as a result of excessive menstrual bleeding may cause iron deficiency anemia. A rare cause of iron deficiency anemia in SLE may be low-grade pulmonary hemorrhage without actual hemoptysis. A microangiopathic hemolytic anemia with or without the other features (e.g., fever, thrombocytopenia, kidney involvement, and neurologic symptoms) of thrombotic ­thro­mbocytopenic purpura has been rarely described in SLE.134 The presence of schistocytes in the peripheral blood smear and increased lactate dehydrogenase levels are the hallmarks of this disorder. When this disorder occurs in the setting of generalized lupus activity, we prefer to call it thrombotic thrombocytopenic purpura–like syndrome and use immunosuppressive therapy when it is severe. In the absence of generalized lupus activity, we view this disorder as bona fide thrombotic thrombocytopenic purpura. Autoantibodies against a metalloprotease that is responsible for cleaving the high-molecular-weight von Willebrand factor have been implicated in the pathogenesis of this disorder.135 A similar syndrome can occur in the presence of antiphospholipid antibodies.136 Red blood cell aplasia resulting from antibodies against erythrocyte progenitors has been rarely reported in SLE patients.131,132 Bone marrow suppression also can be induced by medications, including immunosuppressive drugs and antimalarials. Leukopenia Leukopenia is common in SLE; it can be the presenting symptom and usually is associated with disease activity. A white blood cell count of less than 4500/μL has been reported in approximately 50% of patients, especially patients with active disease.133 Severe leukopenia (neutrophil count <500/μL) is rare, however. Lymphocytopenia (lymphocyte

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count <1500/μL) occurs in approximately 20% of SLE patients.137 Cytotoxic lymphocyte antibodies have been detected in the serum of SLE patients, and their titers have been correlated with the degree of lymphocytopenia.138 Another potential mechanism of lymphopenia is increased apoptosis secondary to increased Fas antigen expression on the peripheral T cells in patients with SLE.139 Neutropenia in SLE patients can result from immune mechanisms, medications, bone marrow suppression, or hypersplenism.140 Decreased eosinophil and basophil counts are usually secondary to corticosteroid use in lupus. Leukocytosis in lupus can occur and usually reflects an infection or the use of high-dose corticosteroids.141

Table 75-9  Management of Thrombocytopenia   in Systemic Lupus Erythematosus Lupus related? Rule out drug effects. Ask about over-the-counter drugs such as quinine for leg cramps, vitamins, supplements, or herbal medicines Discontinue all but absolutely essential drugs Discontinue agents that may interfere with platelet function (e.g., aspirin, NSAIDs) Confirm autoimmune etiology by examining peripheral smear. Rule out platelet clumping that can cause false thrombocytopenia and abnormalities of the white or red blood cells Consider bone marrow examination, especially in older patients, to rule out occult myelodysplasia Tests for antiplatelet antibodies are not helpful

Thrombocytopenia Mild thrombocytopenia (platelet counts 100,000 to 150,000/μL) has been reported in 25% to 50% of patients; counts less than 50,000/μL occur in only 10%.133,140 The most common cause of thrombocytopenia in SLE is immune-mediated platelet destruction, but increased platelet consumption also may occur as a result of microangiopathic hemolytic anemia or hypersplenism. Impaired platelet production as a result of bone marrow suppression secondary to medications is another potential contributing factor (Table 75-9). The major mechanism is immunoglobulin binding to platelets followed by destruction in the spleen, as in idiopathic thrombocytopenic purpura.142 Antibodies against thrombopoietin have been reported in the serum of SLE patients and correlated with thrombocytopenia.143 Idiopathic thrombocytopenic purpura may be the first sign of SLE, followed by other symptoms even many years later. In such cases, the presence of high-titer ANAs or the presence of extractable nuclear antigens raises the possibility of underlying SLE. A careful history and physical examination in many of these cases may reveal additional features of SLE. LIVER AND GASTROINTESTINAL TRACT INVOLVEMENT Gastrointestinal manifestations have been reported in 25% to 40% of patients with SLE and reflect either lupus of the gastrointestinal tract or the effects of medications.144,145 Esophageal involvement has been reported in less than 5% of SLE patients. Dysphagia caused by esophageal dysmotility and aperistalsis is the most usual symptom, tends to be episodic, and is associated with Raynaud’s phenomenon and the presence of antiribonucleoprotein antibodies.146 The esophageal dysmotility may be caused by an inflammatory reaction in the esophageal muscles, by ischemia, or by vasculitic changes in Auerbach’s plexus. Other causes of dysphagia in lupus include gastroesophageal reflux disease resulting in esophagitis, esophageal spasm, and esophageal strictures; esophageal candidiasis, especially in patients ­tre­ated with corticosteroids or immunosuppressive agents or both; and esophageal ulcers. Dyspepsia has been reported in 11% to 50% of patients with SLE, and peptic ulcers (usually gastric) have been re­ ported in 4% to 21%. These complications are more common in patients treated with NSAIDs. It also has been suggested that SLE itself predisposes to ulcer formation.147 Bleeding

Rule out thrombotic thrombocytopenic purpura or antiphospholipid-related microangiopathic hemolytic anemia (anemia with pronounced reticulocytosis and fragmented erythrocytes in the peripheral smear), antiphospholipid antibodies, or antiphospholipid antibody syndrome Look for evidence of lupus activity in other organs (especially major organs) Determine severity Severe: platelets <20 × 103/μL Moderate-to-severe: platelets 20-50 × 103/μL Treat. Goal is not a normal platelet count, but a safe platelet count (30-50 × 103/μL) NSAIDs, nonsteroidal anti-inflammatory drugs.

from peptic ulcer disease in SLE is uncommon, and perforation is rare. Abdominal pain accompanied by nausea and vomiting occurs in 30% of patients with SLE.144,148 Special consideration should be given to conditions associated with SLE, such as peritonitis, mesenteric vasculitis with intestinal infarction, pancreatitis, and inflammatory bowel disease. Mesenteric vasculitis with infarction is a serious and potentially life-threatening manifestation. Risk factors for the development of mesenteric vasculitis include peripheral vasculitis and CNS lupus.149 The clinical presentation is usually with insidious symptoms that may be intermittent for months before the development of an acute abdomen with nausea, vomiting, diarrhea, gastrointestinal bleeding, and fever.144,149 Patients with mesenteric vasculitis occasionally have an acute presentation with mesenteric thrombosis and infarction, often in association with antiphospholipid antibodies. The diagnosis of mesenteric vasculitis may be difficult to establish. Plain radiographic studies may reveal segmental bowel dilation, air-fluid levels, “thumbprinting” or narrowing of the lumen, and pseudo-obstruction. Abdominal CT scan findings compatible with mesenteric vasculitis include prominence of mesenteric vessels with a comblike appearance supplying dilated bowel loops, small bowel thickening, and ascites.150 Arteriography may reveal evidence of vasculitis or ischemia of the small intestine or colon. Vasculitis generally involves small arteries, which can lead to a negative arteriogram. Pancreatitis associated with SLE may result from vasculitis or thrombosis and occurs in 2% to 8% of patients.151 Elevated levels of serum amylase have been described in patients with SLE without pancreatitis and should be interpreted in light of the overall clinical examination. The role of azathioprine and corticosteroids as a cause of acute pancreatitis in patients with SLE is controversial.152

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Hepatic disease may be more common in SLE than previously thought. Clinically significant hepatic disease is generally unusual in SLE. The incidence of hepatomegaly is 12% to 55% depending on the series.153,154 Pathologically, a wide variety of lesions may be seen. Excessive fatty infiltration (steatosis) is a common finding and may occur as part of the disease process or may be secondary to corticosteroid treatment.155 Liver chemistries (e.g., aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase) may be abnormal in patients with active SLE or in patients receiving NSAIDs. The term lupoid hepatitis was formerly used to describe autoimmune hepatitis because of clinical and serologic similarities to SLE. Autoantibodies may help to distinguish between autoimmune hepatitis and liver disease associated with SLE. ANAs can be seen in both disorders, but anti–smooth muscle and antimitochondrial antibodies are uncommon in SLE (<30%) and usually when found are in low titers. Histology in lupus-associated hepatitis rarely shows the periportal (interface) hepatitis with piecemeal necrosis characteristic of autoimmune hepatitis, and liver-associated chemistries tend to be lower in SLE with only mild (usually three to four times normal) elevations. The absence of these antibodies and the presence of anti–ribosomal P protein antibodies suggest lupus hepatitis.153 Ascites is uncommon in SLE, and when detected, infectious causes or perforation or both must be excluded by paracentesis. Congestive heart failure and hypoalbuminemia secondary to nephrotic syndrome or protein-losing enteropathy represent other possible causes of ascites in patients with SLE. Protein-losing enteropathy has been described in some patients with SLE and can be the first manifestation of the disease. It usually occurs in young women and is characterized by the onset of profound edema and hypoalbuminemia.145 OPHTHALMIC INVOLVEMENT Eight percent of patients with SLE develop inflammation of the retinal artery during the course of their disease. An equal number of patients have infarction of the retinal vasculature secondary to the presence of antiphospholipid antibodies. Both conditions can lead to the presence of cotton-wool spots in the retina visible on ophthalmoscopy or fluorescein angiography (where perivascular exudates and patches of dye leakage along the vessels are seen). Cottonwool spots result from focal ischemia and are not pathognomonic for SLE. The presence of retinal vasculitis is usually associated with generalized active systemic disease, and retinal vasculitis occurs early in the disease process.156 Corneal and conjunctival involvement is usually part of secondary Sjögren’s syndrome; uveitis and scleritis are extremely rare manifestations in SLE.

DIAGNOSIS DIAGNOSTIC TESTS Antinuclear Antibodies ANA testing is usually the first step in the immunologic diagnosis of SLE and other systemic autoimmune diseases. A retrospective study has shown that autoantibodies are typically present and accumulate progressively many years

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before the clinical diagnosis of SLE.157 Immunofluorescence is the standard approach for detecting ANAs, and the staining patterns (i.e., homogeneous or diffuse, speckled, rim, nucleolar, or centromere) depend on the location of the target antigen. These patterns correspond to the presence of autoantibodies against different nuclear antigens. The ANA assay is an ideal screening test because of its sensitivity (95% when using human cultured cells as the substrate) and simplicity.158 The entity of “ANA-negative lupus” described in previous years is usually associated with the presence of other cytoplasmic autoantibodies, such as anti-Ro (SS-A) and anti-ribosomal P protein. The specificity of ANAs for SLE is low because multiple other conditions are associated with a positive ANA (i.e., scleroderma, polymyositis, dermatomyositis, rheumatoid arthritis, autoimmune thyroiditis, autoimmune hepatitis, infections, neoplasms, and many drugs). Also, some healthy individuals test positive for ANAs.159 The formation of ANAs is age-dependent; it is estimated that 10% to 35% of individuals older than 65 years have ANAs. The titers are generally lower (<1:40), however, than the titers in systemic autoimmune diseases. In contrast to the low positive predictive value of ANA testing, a patient with a negative test has less than a 3% chance of having SLE; a negative ANA test is useful for excluding the diagnosis of SLE. In the presence of typical features of SLE, a negative ANA test does not exclude the diagnosis. Antibodies to Extractable Nuclear Antigens The nucleosome, a complex of DNA and histones, was the first lupus autoantigen to be identified. Autoantibodies to single-stranded DNA (ssDNA) and individual histones are commonly detected in SLE and in DIL and are nonspecific. Antibodies to dsDNA are found in 70% of SLE patients at some point during the course of their disease and are 95% specific for SLE, making them a valuable disease marker. A subset of anti-dsDNA antibodies has been shown to be nephritogenic, and their titer usually correlates with the activity of kidney disease.160 Anti-Sm (Smith) antibodies are detected in 10% to 30% of SLE patients, and their presence is pathognomonic for SLE. Anti–nuclear ribonucleoprotein antibodies are associated with anti-Sm, but are not disease specific. Their role in diagnosis or prognosis of the disease is limited. Anti-Ro (SS-A) and anti-La (SS-B) antibodies are detected in 10% to 50% and 10% to 20% of SLE patients, but are not disease specific. Their presence has been associated with the development of secondary Sjögren’s syndrome, photosensitivity, CNS disease, neonatal lupus, and development of congenital heart block in the children of mothers who carry these antibodies. Antiribosomal antibodies are highly specific for the diagnosis of SLE, but less sensitive than anti-dsDNA or anti-Sm antibodies. Anti–ribosomal P antibodies have been linked retrospectively with neuropsychiatric manifestations of SLE, especially lupus psychosis. It is unclear why some autoantibodies are specific for SLE and some are not. There is experimental and clinical evidence that some of these autoantibodies may play a role in the pathogenesis of the disease (e.g., anti-dsDNA and renal disease). Alternatively, autoantibodies may reflect disease-specific immune mechanisms, but not be pathogenetic by themselves.

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TYPICAL AND ATYPICAL PRESENTATIONS As in other systemic rheumatic diseases, the diagnosis of SLE requires an integration of the patient’s symptoms, physical examination findings, and results of diagnostic tests. Table 75-10 shows the frequency of various manifestations of SLE at disease onset and during the disease course. The presence of one or more of these features or the involvement of at least two different organs in young women should always raise the possibility of SLE. Many of these features are not unique to SLE, however, and could be seen in other infectious, metabolic, and malignant diseases and in other systemic rheumatic diseases. The recognition that systemic rheumatic diseases have several common features, which makes a specific diagnosis difficult, has led to the concept of the undifferentiated connective tissue syndrome. These patients account for 10% to 20% of patients referred to tertiary care centers. Among patients presenting with symptoms suggestive of a connective tissue disease, only 10% to 15% fulfill classification criteria for SLE 5 years later. Prognostic factors for SLE were young age, alopecia, serositis, DLE, positive Coombs test, and positive anti-Sm and anti-DNA antibodies.161 Latent or incomplete lupus describes patients who present with a constellation of symptoms suggestive of SLE, but do not qualify by clinical intuition or classification criteria as having classic SLE.162,163 These patients usually present with one or two of the ACR criteria and other features not incl­uded in the classification criteria. Most of these patients do not develop SLE, or if they do, it is usually mild and rarely involves major organs. Table 75-10  Frequency of Various Manifestations   of Systemic Lupus Erythematosus at Disease Onset   and during the Disease Manifestation

Onset (%)

During (%)

Arthralgia

77

85

Constitutional

53

77

Skin

53

78

Arthritis

44

63

Renal

38

74

Raynaud’s phenomenon

33

60

Central nervous system

24

54

Vasculitis

23

56

Mucous membranes

21

52

Gastrointestinal

18

45

Lymphadenopathy

16

32

Pleurisy

16

30

Pericarditis

13

23

Lung

 7

14

Nephrotic syndrome

 5

11

Azotemia

 3

 8

Myositis

 3

 3

Thrombophlebitis

 2

 6

Myocarditis

 1

 3

Pancreatitis

 1

 2

Modified from Gladman DD, Urowitz MB: Systemic lupus erythematosus. In Klippel JH, Weyend CM, Wortmann RL: Primer on the Rheumatic Diseases, 11th ed. Atlanta, Arthritis Foundation, 1997.

Patients presenting with unusual manifestations of SLE without accompanying features that help establish the diagnosis constitute a small but challenging group of patients. Case reports and case series suggest that SLE may manifest with high fever and lymphadenopathy simulating lymphoid or hematologic malignancy, neurologic events (e.g., chorea, cerebrovascular accident, myelitis), unusual skin rashes such as chronic urticaria or panniculitis, abdominal vasculitis, pneumonitis and pulmonary hemorrhage, pulmonary hypertension, isolated serositis, myocarditis, aplastic anemia, and isolated cytopenias. In such cases, a careful history for manifestations of SLE in the past and a careful physical examination together with serology may help to recognize the disease early. In our experience with such cases, nonrheumatologists may fail to recognize subtle evidence for the disease, such as a faint or transient malar rash, transient arthritis, or oral and nasal ulcers. Nonrheumatologists also may fail to elicit a history of photosensitivity or Raynaud’s phenomenon or other features of SLE that are not present at the time of the evaluation. The latter are typically not volunteered by the patient unless specifically asked for. In some cases, this information may have been retrieved but not integrated into the diagnostic thinking. SLE remains largely a clinical diagnosis. The diagnosis of mild SLE at the early stages of the disease may present considerable challenges. Strict adherence to the classification criteria may miss many patients. In cases of patients with typical features of SLE with low-titer or, rarely, a negative ANA, the diligent clinician should not hesitate to establish the diagnosis after excluding other diseases. At the same time, knowledge of the epidemiology of the disease in the age or sex group of the patient helps; autoimmune thyroid disease is more common in young women than SLE, and young girls with positive ANA and arthralgias are more likely to have autoimmune thyroid disease. Patients may manifest numerous features suggestive of SLE, yet never develop the disease. In such cases, use of the term “possible or probable lupus” with longer follow-up is recommended. These patients should be reassured that their prognosis is excellent. DIFFERENTIAL DIAGNOSIS Because of the pleiotropic manifestations of SLE, the differential diagnosis is large depending on the specific manifestations in each patient. Differential diagnosis from other polyarticular diseases affecting young women, such as rheumatoid arthritis or Still disease, may not be easy in the initial stages. Many other diseases also may be confused with early SLE, including undifferentiated connective tissue disease, primary Sjögren’s syndrome, primary APS, fibromyalgia with positive ANA, idiopathic thrombocytopenic purpura, DIL, and autoimmune thyroid disease. The differential in patients presenting with fever or splenomegaly and lymphadenopathy must include infectious diseases or lymphoma. In febrile patients with known SLE, leukocytosis, neutrophilia, shaking chills, and normal levels of anti-DNA antibodies favor infection.164 SLE may manifest with localized or generalized lymphadenopathy or splenomegaly, but the size of lymph nodes is rarely more than 2 cm, and splenomegaly is mild to moderate. Patients with

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known or suspected SLE with prominent lymphadenopathy, massive splenomegaly, or expansion of a monoclonal CD19+/CD22+ B cell population should raise the suspicion of non-Hodgkin’s lymphoma.165 In patients presenting with neurologic symptoms, infections, cerebrovascular accidents, or immune-mediated neurologic diseases (e.g., multiple sclerosis, Guillain-Barré disease) must be considered. Finally, in patients presenting with a pulmonary renal syndrome, the disease must be differentiated from Goodpasture syndrome and antineutrophilic cytoplasmic antibody–associated vasculitis. In patients presenting with glomerulonephritis, the differential diagnosis includes postinfectious glomerulonephritis (streptococcal, staphylococcal, subacute bacterial endocarditis, or hepatitis C virus), membranoproliferative glomerulonephritis, or renal vasculitis (antineutrophilic cytoplasmic antibody or anti–glomerular basement membrane associated).

Antimalarials—mainly hydroxychloroquine—are widely used for musculoskeletal and cutaneous manifestations of lupus. The drug has a long-term effect in preventing major flares in SLE.166,167 Additional nonrandomized studies have shown favorable effects of hydroxychloroquine on disease activity, damage accrual, and serum total cholesterol. Several studies indicate beneficial effects of methotrexate on disease activity and articular and cutaneous manifestations in SLE. In SLE patients without CNS or renal involvement, azathioprine therapy has been associated with fewer hospitalizations (0.02/patient-year versus 0.17/patientyear; P < .05), but no decrease in prednisone maintenance requirement. Mycophenolate mofetil also has been used in the treatment of SLE without major organ involvement in a few uncontrolled case studies.

TREATMENT

Table 75-11 presents a working, albeit arbitrary, definition of moderate-to-severe SLE. To date, most experts agree that the treatment of moderate-to-severe SLE consists of a period of intensive immunosuppressive therapy (induction therapy) followed by a longer period of less intensive maintenance therapy.70 The primary objective of the induction therapy is to halt injury, recover function, and induce remission by controlling immunologic activity. Maintenance therapy is used to consolidate remission and prevent flares with agents (or schedules) that are associated with a lower risk for complications and are more convenient to the patient. Table 75-12 summarizes randomized controlled trials for the treatment of moderate-to-severe SLE.

GENERAL PRINCIPLES OF MANAGEMENT The management of SLE requires a comprehensive assessment of disease activity and damage from the disease and careful tailoring of the treatment according to the organ involved and its severity. Patient education and multidisciplinary interventions, particularly in newly diagnosed patients, are an important aspect of the management of SLE. Generally, the management of the disease is divided between the management of disease with nonmajor organ (or nonvisceral) involvement and disease with major organ (or visceral) involvement. In the first case, the agents that are used have fewer side effects, whereas the management in the second case involves agents that suppress the immune system (immunosuppressive/cytotoxic agents). Because of their significant side effects, cytotoxic agents in SLE are reserved only for patients with moderate-to-severe disease. MANAGEMENT OF MILD SYSTEMIC LUPUS ERYTHEMATOSUS WITHOUT MAJOR ORGAN INVOLVEMENT NSAIDs, antimalarials, glucocorticoids, and, in severe, refractory cases, immunosuppressive agents (azathioprine, mycophenolate mofetil, methotrexate) are used in the treatment of SLE patients without major organ involvement. Despite their widespread use, there are few randomized controlled trials showing their efficacy in uncomplicated SLE. Although most studies have shown improvement, it is not apparent whether patients were left with residual disease activity or its extent. NSAIDs are believed to be effective in the treatment of musculoskeletal disorders and complaints in SLE patients, based mostly on experience with musculoskeletal complaints in other conditions. In view of their gastrointestinal toxicity together with concerns about the cardiovascular safety of NSAIDs, we recommend judicious use of NSAIDs for limited periods for patients at low risk for gastrointestinal, renal, and cardiovascular toxicity. Dehydroepiandrosterone, an adrenal hormone with androgenic properties, has shown efficacy in mild lupus in several controlled trials, but its use is limited in SLE.

TREATMENT OF MODERATE-TO-SEVERE SYSTEMIC LUPUS ERYTHEMATOSUS

Immunosuppressive, Cytotoxic, and Biologic Agents Corticosteroids. For patients with moderate-to-severe disease, corticosteroids are used either as single or as background Table 75-11  Indications for Cytotoxic Drug Use   in Systemic Lupus Erythematosus General Involvement of major organs or extensive involvement of nonmajor organs (i.e., skin) refractory to first-line agents Failure to respond to or inability to taper corticosteroids to acceptable doses for long-term use Specific Organ Involvement Renal Proliferative or membranous nephritis (nephritic or nephritic syndrome) Hematologic Severe thrombocytopenia (platelets <20 × 103/μL) Thrombotic thrombocytopenic purpura–like syndrome Severe hemolytic or aplastic anemia, or immune neutropenia not responding to corticosteroids Pulmonary Lupus pneumonitis or alveolar hemorrhage Cardiac Myocarditis with depressed left ventricular function, pericarditis with impending tamponade Gastrointestinal Abdominal vasculitis Nervous system Transverse myelitis, cerebritis, psychosis refractory to corticosteroids, mononeuritis multiplex, severe peripheral neuropathy

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Table 75-12  Randomized Controlled Trials for Moderate-to-Severe Systemic Lupus Erythematosus Author, Year

Main Findings and Comments

Austin et al, 1986

Renal function was better preserved in patients who received IV-CY plus low-dose prednisone compared with high-dose prednisone alone; long-term study with approximately 10 yr of follow-up; significant differences among groups emerged only after the first 5 yr

Lewis et al, 1992

Treatment with plasmapheresis plus a standard regimen of prednisone and cyclophosphamide therapy does not improve the clinical outcome in patients with lupus nephritis

Boumpas et al, 1992

Extended course of pulse cyclophosphamide (15 pulses) is more effective than 6 mo of pulse methylprednisolone in preserving renal function in patients with severe lupus nephritis; addition of a quarterly maintenance regimen to monthly pulse cyclophosphamide reduces the rate of exacerbations

Gourley et al, 1996

In patients with lupus nephritis, monthly bolus therapy with methylprednisolone was less effective than monthly bolus therapy with cyclophosphamide; a trend toward greater efficacy with combination therapy also was noted; cyclophosphamide therapy was accompanied by increased risk for adverse effects (amenorrhea, cervical dysplasia, infections)

Illei et al, 2001

With extended follow-up (median 11 yr), pulse cyclophosphamide continued to show superior efficacy over pulse methylprednisolone alone for treatment of lupus nephritis; the combination of pulse cyclophosphamide and methylprednisolone provided additional benefit over pulse cyclophosphamide alone without conferring additional risk for adverse events

Illei et al, 2002

Nephritic flares are common (observed in approximately one third of patients) in subjects with proliferative lupus nephritis, even in those with a complete response to therapy, but flares do not result in loss of renal function if treated with additional immunosuppressive agents; renal flares are an important feature of the natural history of lupus nephritis

Chan et al, 2000

For treatment of diffuse proliferative lupus nephritis, the combination of MMF and prednisolone is as effective as a regimen of daily oral cyclophosphamide (≤6 mo) and prednisolone followed by azathioprine and prednisolone; short-term study (2-yr follow-up) involving Chinese patients with most patients with nephritis of <6 mo duration

Chan et al, 2005

With longer follow-up, flares in the MMF group were twice as many compared with the cyclophosphamide group and were observed on discontinuation of MMF; for this reason, during the extension period of this study, MMF was continued as a maintenance therapy at lower doses (from 2 g/day initially, reduced to 1.5 g/ day and then 1 g/day in 6-mo intervals); rates of doubling of baseline creatinine and relapse-free survival were similar in the MMF group (MMF as induction and maintenance) compared with those of cyclophosphamide as induction with azathioprine as maintenance; MMF treatment was associated with fewer infections and fewer infections that required hospitalization; azathioprine is a reasonable option for maintenance therapy in lupus nephritis after induction with IV-CY; medium-term study with 5 yr of follow-up

Houssiau et al, 2002

In European SLE patients with proliferative lupus nephritis, a remission-inducing regimen of low-dose intravenous cyclophosphamide (cumulative dose 3 g) followed by azathioprine achieves clinical results comparable to those obtained with a high-dose intravenous cyclophosphamide regimen (a course of 8 pulses of IV-CY); patients had milder nephritis compared with NIH studies (Austin, Boumpas, Gourley, Illei)

Houssiau et al, 2004

Extended follow-up (median 73 mo) of previous trial with similar results; early response (6 mo) to therapy (defined as a decrease in serum creatinine level and proteinuria <1 g/24 hr) is predictive of good long-term renal outcome

Contreras et al, 2004

After induction therapy with monthly and maintenance with quarterly IV-CY, MMF (0.5-3 g/day), or azathioprine, rates of event-free survival (composite end point including death or renal failure) and relapse-free survival better with MMF; no significant differences between MMF and azathioprine; efficacy and dose of IV-CY significantly lower than in other randomized controlled studies; 95% of patients were Hispanic or African-American

Ginzler et al, 2005

Short-term induction therapy with evaluation at 24 mo and approximately 2 yr follow-up; more remissions with MMF compared with monthly pulses of IV-CY; most patients in both groups did not achieve remission; patients with no improvement at 12 wk were crossed to the other group; this was more common with IV-CY, resulting in a smaller number of patients in the IV-CY available for comparison; 56% of patients were AfricanAmerican (approximately 20% in the NIH studies)

Barile-Fabris et al, 2005

32 Mexican SLE patients presenting with severe neuropsychiatric SLE manifestations (peripheral/cranial neuropathy, optic neuritis, transverse myelitis, brainstem disease, or coma) were treated with induction therapy with 3 pulses of IV-MP, followed by monthly cyclophosphamide (IV-CY) versus IV-MP bimonthly every 4 mo for 1 year, and then by IV-CY or IV-MP every 3 mo for another year; IV-CY was more effective than IV-MP, resulting in significant improvement in clinical, laboratory, or specific neurologic testing variables

IV-CY, intravenous pulse cyclophosphamide; IV-MP, intravenous methylprednisolone; MMF, mycophenolate mofetil; NIH, National Institutes of Health; SLE, systemic lupus erythematosus.

therapy in combination with immunosuppressive agents at prednisone doses ranging from 0.5 to 1 mg/kg/day in a single dose, usually in the morning. When corticosteroids are combined with immunosuppressive agents, we rarely use more than 0.5 to 0.6 mg/kg of prednisone because of concerns for infections, including opportunistic infections (see later). Corticosteroid toxicity is a major problem in SLE, and ta­ pering of the dosage is a primary concern. Generally, ­tapering

starts after the first 4 to 6 weeks of therapy. The goal is a dose of 0.25 mg/kg every other day at 2 to 3 months, which is an acceptable dosage for long-term use. The concomitant use of other immunosuppressive agents facilitates tapering and decreases toxicity. In cases of doses greater than 0.6 mg/kg/day or in rapidly progressing severe disease, we use bolus therapy (1 to 3 daily pulses of methylprednisolone at a dose of 1000 mg/day followed by 0.5 mg/kg/day of prednisone).

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Protection from osteoporosis is of paramount importance and should be initiated as soon as use of these agents is anticipated. In patients with severe or life-threatening disease, the use of a low dose of prednisone for several years after remission is widely accepted. Azathioprine. The starting dose of azathioprine is 1 mg/kg/ day with the usual maintenance dose being 2 to 3 mg/kg/day in one to three doses taken with food. The role of screening patients in advance for thiopurine methyltransferase activity is controversial, but is recommended by many authors to detect the roughly 1 in 300 individuals with very low levels. These patients are susceptible to abrupt and prolonged marrow aplasia at the usual doses of azathioprine. When the drug is instituted, monitoring includes complete blood count with platelets, creatinine, and aspartate aminotransferase or alanine aminotransferase. Liver enzyme activity should be measured every 3 to 4 months (see Table 75-2). Azathioprine should be used cautiously in patients with renal or liver disease and in patients who use allopurinol. Randomized controlled trials in lupus nephritis have not shown superiority for azathioprine compared with high-dose corticosteroids, and the drug is used as a corticosteroid-sparing agent in various manifestations of SLE (see later). In moderate-to-severe SLE, azathioprine has been used as a maintenance therapy at doses ranging from 1 to 3 mg/ kg/day, especially in women of reproductive age because of its acceptable safety profile during pregnancy (see later). Although discontinuation of the drug because of side effects is common, in SLE, more often the drug is discontinued for lack of efficacy. Mycophenolate Mofetil. After its introduction in transplantation, mycophenolate mofetil was used to treat SLE patients refractory to corticosteroids or cytotoxic agents in small case series. It subsequently was studied in randomized controlled trials in lupus nephritis where it was compared (in doses of 1 to 3 g/day for 6 to 24 months) with either oral or pulse cyclophosphamide for the induction and maintenance of remission.168-171 In these studies, mycophenolate mofetil showed comparable efficacy and fewer side effects than cyclophosphamide. In the absence of long-term data and harder outcomes (e.g., doubling of serum creatinine or end-stage renal disease), claims of superiority in terms of efficacy to cyclophosphamide cannot be adequately substantiated at present. This is especially true for the most severe cases, where cyclophosphamide has a track record of efficacy, something that it is hoped will also be shown for mycophenolate mofetil. In these patients, the combination of pulse intravenous cyclophosphamide with intravenous methylprednisolone is the treatment of choice (see later). Mycophenolate mofetil has been used for the treatment of a variety of other manifestations of SLE in addition to proliferative nephritis, including membranous nephropathy, skin disease, refractory thrombocytopenia, and pulmonary hemorrhage.52-56 Further controlled trials are needed, however, to establish the role of this agent for other disease manifestations. Cyclophosphamide. Although some centers still employ daily oral cyclophosphamide regimens for short periods (2 mg/kg/day every morning in a single dose for 3 to 12 months

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until remission), the National Institutes of Health protocol has become the protocol of choice for most physicians (Table 75-13). With the notable exception of NPSLE, randomized controlled trials are available only for lupus nephritis; recommendations for other indications are based on extrapolation from those data. Randomized controlled trials with long-term follow-up have shown that intermittent pulse cyclophosphamide therapy (intravenous cyclophosphamide) is effective for moderate-to-severe proliferative lupus nephritis with a better toxicity profile than daily oral cyclophosphamide.172 After induction therapy, a maintenance regimen is essential to decrease the risk of flares.173 Subsequent studies from the National Institutes of Health have shown that ­combination pulse therapy with cyclophosphamide and methylprednisolone (intravenous methylprednisolone) improves renal outcomes without increasing toxicity.174,175 Based on these studies, we propose 7 monthly pulses of intravenous cyclophosphamide (0.5 to 1 g/m2) followed by quarterly pulses for at least 1 year beyond remission (Table 75-14). For patients with moderate-to-severe disease, monthly pulses of intravenous methylprednisolone are added during the induction period.174,175 Ovarian toxicity (found to be age-related and dose-related),176 infections (especially herpes zoster), flares (observed in approximately one third of patients), incomplete response, and, in rare cases, refractoriness to treatment have emerged from these studies as significant limitations of current cytotoxic therapy. Because of concerns about the toxicity, together with the appreciation that lupus nephritis may be less severe in whites, European investigators sought alternative protocols to administer cyclophosphamide (Euro-Lupus Nephritis Trial). In studies involving mostly patients with milder forms of disease, less intensive regimens of cyclophosphamide (6 semiweekly pulses at a fixed dose of 500 mg each in combination with three daily doses of 750 mg of intravenous methylprednisolone) followed with azathioprine as maintenance had comparable efficacy—but less toxicity—than a short course of high-dose intravenous cyclophosphamide (8 pulses).177 By multivariate analysis, early response to therapy at 6 months (defined as a decrease in serum creatinine level and proteinuria <1 g/24 hr) was the best predictor of good long-term renal outcome.178 In addition to showing that in patients with milder forms of lupus nephritis less intensive regimens of intravenous cyclophosphamide may be used, this study showed that sequential therapy with a short course of intravenous cyclophosphamide followed by azathioprine is a valid approach in lupus. In addition to proliferative and membranous lupus nephritis, case reports, case series, and uncontrolled clinical studies support the efficacy of intravenous cyclophosphamide in severe thrombocytopenia, neurologic disease (myelitis, encephalitis, psychosis, mononeuritis multiplex, and polyneuropathy), abdominal vasculitis, acute pneumonitis and alveolar hemorrhage, dermatologic disease, and other severe manifestations of SLE. A randomized controlled trial in NPSLE has confirmed its efficacy in severe NPSLE.179 Reversible alopecia and nausea are the most commonly observed side effects of cyclophosphamide; myelotoxicity, gonadal toxicity, and malignancy are less frequent, although much more serious adverse effects. A variety of different infections can occur, including bacterial infections

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Table 75-13  Recommended Monitoring of Cytotoxic Drug Therapy in Systemic Lupus Erythematosus Drug

Dosage

Toxicities Requiring Monitoring

Baseline Evaluation

Laboratory Monitoring

Azathioprine (FDA   50-100 mg/day in   pregnancy category D*) 1-3 doses with food

Myelosuppression, hepato- CBC, platelets, creatinine,   toxicity, lymphoproliferaAST or ALT tive diseases

CBC and platelets every   2 wk, with changes in dosage; baseline tests every 1-3 mo

Mycophenolate mofetil (FDA pregnancy   category C)

1-3 g/day in 2 divided   doses with food

Myelosuppression, hepato- CBC, platelet, creatinine,   toxicity, infection AST or ALT

CBCs and platelets every 1-2 wk with changes in dosage; baseline tests every 1-3 mo

Cyclophosphamide (FDA pregnancy category D)

50-150 mg/day in a single dose with breakfast; lots of fluids, empty bladder before bedtime

Myelosuppression, hemorrhagic cystitis, myelo­ proliferative disease,   malignancies

CBC with differential every 1-2 wk, with changes in dosage and then every 1-3 mo; keep WBC >4000/mm3 with dosage adjustment; urinalysis and AST or ALT every   3 mo; urinalysis every   6-12 mo after cessation

Methotrexate (FDA pregnancy category X)

7.5-15 mg/wk in 1-3 doses with food or milk/water

Myelosuppression, hepatic Chest x-ray, hepatitis B and   CBC with platelet, AST, fibrosis, pneumonitis C serology in high-risk   albumin, creatinine every patients, AST or ALT,   1-3 mo albumin, alkaline phos­ phatase and creatinine

Cyclosporine (FDA pregnancy category C)

100-400 mg/day in 2 doses   Renal insufficiency,   at the same time every   anemia, hypertension day with meal or   between meals

CBC, platelet, creatinine,   AST or ALT, urinalysis

CBC, creatinine, uric acid, LFTs, blood pressure

Creatinine every 2 wk until dose is stable, then monthly; CBC, potassium, and LFTs every 1-3 mo; cyclosporine levels only with high doses

*Azathioprine may be used during pregnancy if needed. ALT, alanine transaminase; AST, aspartate transaminase; CBC, complete blood count; FDA, Food and Drug Administration; LFTs, liver function tests; WBC, white blood cell count. Modified from ACR Ad Hoc committee on clinical guidelines for monitoring drug therapy in rheumatoid arthritis. Arthritis Rheum 39:723-731, 1996.

and opportunistic infections, such as Pneumocystitis jiroveci (carinii), fungal infections, and Nocardia, and reactivation of latent infections, including herpes zoster, tuberculosis, and human papillomavirus. More recent studies have shown by multivariate analysis that the dosage of corticosteroids is the overriding independent determinant of the risk of infection among patients with SLE receiving cyclophosphamide with concomitant high doses of corticosteroids. The risk of developing premature ovarian failure depends on the age of the patient at the initiation of treatment and the cumulative dose of the drug, as we first reported in 1993. In our study, the rates of sustained amenorrhea after a short course (≤7 pulses) of cyclophosphamide were 0% for patients younger than 25 years old, 12% for patients 26 to 30 years old, and 25% for patients older than 30 years. A long course (≥15 pulses) of cyclophosphamide induced sustained amenorrhea in 17% of patients younger than 25 years old, 43% of patients of 26 to 30 years old, and 100% of patients older than 30 years. In men, gonadal toxicity may be observed with 7 g cumulative dose, corresponding to approximately 2 months of daily oral therapy. To reduce morbidity from cyclophosphamide treatment, gonadal protection and less intensive regimens of cyclophosphamide have been advocated. Preliminary data suggest that gonadal protection from cyclophosphamide may be feasible, a finding requiring further confirmation. In a nonrandomized trial, the use of depot leuprolide acetate, a synthetic gonadotropin-releasing hormone analogue, significantly decreased rates of gonadal failure (30% versus 5%)

in young women with severe SLE treated with cyclophosphamide (n = 20 in both groups).180 For white patients with proliferative disease, sequential therapy with a short course of intravenous cyclophosphamide followed by azathioprine has been found to be effective and to decrease the cumulative dose of cyclophosphamide. Other strategies for preserving fertility, such as cryopreservation of unfertilized ova and ovarian tissue germ cell transplantation, are currently under investigation and should be considered experimental at present. In male patients receiving cyclophosphamide for malignancies, the frequency of azoospermia ranges from 50% to 90%. The administration of testosterone 100 mg intramuscularly and sperm banking represent valid strategies for testicular function preservation.181 The use of intermittent pulse cyclophosphamide, together with adequate hydration, has practically eliminated the cases of bladder carcinoma, although hemorrhagic cystitis may be seen in patients who are unable to empty the bladder (e.g., neurogenic bladder) or in cases where the practice of adequate hydration and frequent emptying of the bladder are not followed meticulously. We routinely give mesna—an agent that has been advocated to reduce the concentration of acrolein and probably other toxic metabolites in the bladder—although controlled studies showing its efficacy in SLE are unavailable. Rituximab. Rituximab is an anti-CD20 chimeric murine/ human monoclonal antibody that depletes B cells—but not plasma cells—resulting in a dramatic and predictable

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Table 75-14  National Institutes of Health Protocol   for Administration and Monitoring of Pulse   Cyclophosphamide Therapy Estimate creatinine clearance by standard methods Calculate body surface area (m2): BSA = √height (cm) × weight (kg)/3600 CY dosing and administration Initial dose CY 0.75g/m2 (0.5g/m2 of CY if creatinine clearance rate is less than one third of expected normal) Administer CY in 150 mL normal saline intravenously over 30-60 min (alternative: equivalent dose of pulse CY may be taken orally in highly motivated and compliant patients) WBC at days 10 and 14 after each CY treatment (patient should delay prednisone until after blood tests are drawn to avoid transient corticosteroid-induced leukocytosis) Adjust subsequent doses of CY to maximum dose of 1 g/m2 to keep nadir WBC >1500/μL. If WBC nadir becomes <1500/μL, decrease next dose by 25% Repeat CY doses monthly (every 3 wk in patients with extremely aggressive disease) for 6 mo (7 pulses), then quarterly for 1 yr after remission is achieved (inactive urine sediment, proteinuria <1 g/day, normalization of complement [and ideally anti-DNA], and minimal or no extrarenal lupus activity). Alternative maintenance therapy: azathioprine or MMF for 1-2 yr Protect bladder against CY-induced hemorrhagic cystitis Diuresis with 5% dextrose and 0.45% saline (e.g., 2 L at 250 mL/hr). With frequent voiding, continue high-dose oral fluids for 24 hr. Patients should return to clinic if they cannot sustain inadequate fluid intake Consider mesna (each dose 20% of total CY dose) intravenously or orally at 0, 2, 4, and 6 hr after CY dosing. Mesna is especially important to use when sustained diuresis may be difficult to achieve, or if pulse CY is administered in outpatient setting If anticipated difficulty with sustaining diuresis (e.g., severe nephrotic syndrome) or with voiding (e.g., neurogenic bladder), insert a three-way urinary catheter with continuous bladder flushing with standard antibiotic irrigating solution (e.g., 3 L) or normal saline for 24 hr to minimize risk of hemorrhagic cystitis Antiemetics (usually administered orally) Dexamethasone 10 mg single dose plus Serotonin receptor antagonists: granisetron (Kytril) 1 mg with CY dose (usually repeat dose in 12 hr); ondansetron (Zofran) 8 mg 3 times a day for 1-2 days Monitor fluid balance during hydration. Use diuresis if patient develops progressive fluid accumulation Complications of pulse CY Expected: nausea and vomiting (central effect of CY) mostly controlled by serotonin receptor antagonists; transient hair thinning (rarely severe at CY doses ≤1 g/m2) Common: significant infection diathesis only if leukopenia not carefully controlled; modest increase in herpes zoster (very low risk of dissemination); infertility (male and female); amenorrhea proportional to age of patient during treatment and to the cumulative dose of CY. In women at high risk for persistent amenorrhea, consider using leuprolide 3.75 mg subcutaneously 2 wk before each dose of CY. In men, use testosterone 100 mg intramuscularly every 2 wk CY, Cyclophosphamide (Cytoxan); MMF, mycophenolate mofetil; WBC, white blood cell count.

peripheral blood B cell lymphopenia in most patients that lasts for at least 4 to 12 months after therapy. Response to therapy does not consistently correlate with B cell depletion. To date, experience comes from uncontrolled trials in various manifestations of SLE refractory to conventional therapy (renal, CNS, cytopenias, serositis, APS). Treatment protocols range from the usual regimen of 375 mg/m2 × 4

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weeks to shorter schemes (500 to 1000 mg × 2 weeks). In a case series involving severe refractory pemphigus vulgaris, a different scheme using rituximab as induction (3 weekly pulses) and maintenance (4 monthly pulses of 375 mg/m2) was used.182 Most, but not all, patients were on concurrent intravenous cyclophosphamide, corticosteroids, or mycophenolate mofetil. No opportunistic infections have been reported so far, but allergic reactions, usually mild to moderate, may occur. Response (partial or complete) has been seen in half of the patients, but follow-up is short. In some patients, the disease relapses after 6 to 12 months, and they have been successfully retreated.183 Open questions with rituximab concern (1) optimal treatment regimen (i.e., frequency, use of concomitant immunosuppressive agents), (2) better documentation of potential for retreatment after relapse without developing neutralizing antibodies, and (3) randomized controlled trials versus intravenous cyclophosphamide. Although the drug potentially could be used for induction and maintenance, at present we view it more as a remissioninducing agent in patients with severe SLE who have failed intravenous cyclophosphamide combined with intravenous methylprednisolone. Immunosuppressive Therapy in Systemic Lupus Erythematosus: Which Agent and for Whom? Table 75-15 provides cytotoxic therapy recommendations for SLE patients based on severity of disease. Although azathioprine is considered by many authors to be superior to corticosteroids, in randomized controlled trials, the superiority of azathioprine is marginal at best, and its primary use is as induction therapy in mild cases of SLE or as maintenance therapy in patients with various degrees of severity. Although azathioprine and mycophenolate mofetil have not been formally tested “head-to-head” as induction therapy, published and anecdotal experience suggests that some patients with disease refractory to intravenous cyclophosphamide (which usually does not respond to azathioprine) may respond to mycophenolate mofetil, an observation that underscores the potential superiority of mycophenolate mofetil to azathioprine as induction treatment. The initial data so far in the Contreras study169 have failed to show superiority of mycophenolate mofetil as maintenance treatment, however. Because of the significant difference in the cost between the two drugs, comparison studies are needed. Mycophenolate mofetil is less toxic than cyclophosphamide, does not cause ovarian failure, and is more acceptable to patients than cyclophosphamide. Taking all these facts together, at present we view mycophenolate mofetil as an agent for moderate cases of SLE where in the past intravenous cyclophosphamide may have been used. This is especially the case in patients for whom ovarian toxicity is an important consideration (see Table 75-5). Although there are uncertainties regarding the optimal administration and its long-term safety and efficacy, the more recent followup study by Chan and coworkers170 has resolved several of these issues. For severe cases or cases where the disease does not remit after the first 4 to 6 months of therapy with mycophenolate mofetil (or does not improve substantially after the first 3 months of therapy), the combination of pulses of

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Table 75-15  Recommended Cytotoxic Therapy   for Major Organ Involvement in Systemic Lupus   Erythematosus Disease Severity Mild

Moderate

Induction Therapy High-dose cortico­ steroids (i.e., 0.5-1 mg/kg/day prednisone for 4-6 wk with gradual tapering to 0.125 mg/kg every other day within 3 mo) alone or in combination with azathioprine (1-2 mg/kg/day) If no remission within   3 mo, treat as ­moderately severe MMF (2 g/day) (or ­azathioprine) with corticosteroids as above; if no remission after the first 6-12 mo, advance to next therapy or

Pulse cyclophosphamide alone or in combination with pulse corticosteroids for the first   6 mo (background corticosteroids 0.5 mg/kg/day for 4 wk, then taper) for   7 pulses

Maintenance Therapy Low-dose corticosteroids (i.e., prednisone ≤0.125 mg/kg on alternate days) alone or with azathioprine (1-2 mg/kg/day)

Consider further gradual tapering at the end of each year of remission If remission after first 6-12 mo, MMF may be tapered to 1.5 g/day twice a day for 6-12 mo and then to 1 g/day; consider further tapering at the end of each year in remission or Quarterly pulses of   cyclophosphamide or

Monthly pulses of cyclophosphamide combined with pulse corticosteroids for 6-12 mo If no response, consider adding rituximab or switch to MMF

OTHER AGENTS Methotrexate Although there has been substantial evidence supporting the effectiveness of methotrexate in rheumatoid arthritis, there are scarce data on its use in SLE. Current recommendations suggest its use as a steroid-sparing agent for articular and cutaneous manifestations of the disease. A randomized double-blind, placebo-controlled trial of methotrexate in SLE patients showed that a weekly dose of 15 to 20 mg for 6 months effectively controlled disease activity and allowed for corticosteroid reduction.185 Cyclosporine Cyclosporine is most commonly used for membranous lupus nephropathy at doses of 1 to 2 mg/kg. Small case series also suggest a clinical benefit in other manifestations of SLE, such as skin rashes, thrombocytopenia, and aplastic anemia. More recently, cyclosporine has shown comparable efficacy to azathioprine in preventing flares in patients with proliferative lupus nephritis after induction of remission with oral cyclophosphamide. Despite this evidence, and with the notable exception of membranous nephropathy, use of cyclosporine in SLE is limited. Intravenous Gamma Gobulin

Azathioprine   (1-2 mg/kg/day) Severe

lupus nephritis by Esdaile and colleagues.184 Whether physicians, in view of the better toxicity profile of mycophenolate mofetil, would be more likely to use this drug earlier in the course of the disease remains to be seen.

Quarterly pulses of cyclophosphamide for at least 1 yr beyond remission Azathioprine   (1-2 mg/kg/day) MMF (1-2 g/day)

MMF, mycophenolate mofetil.

intravenous cyclophosphamide and intravenous methyl­ prednisolone until remission remains the treatment of ­choice (see Table 75-5). Initial data and anecdotal experience ­suggest that individual patients may respond unpredictably to one treatment or the other, and that it may be necessary to switch therapy if response is inadequate within the first few months of disease. For patients who enter into remission within 6 months, maintenance therapy with mycophenolate mofetil for the initial 1 to 2 years of remission may be preferable to azathioprine, although the efficacy of this approach has not been tested in patients with severe disease, in contrast to the quarterly pulses of intravenous cyclophosphamide. Figure 75-10 is an algorithm for the treatment of lupus nephritis. Regardless of the agent used, early effective cytotoxic therapy is of paramount importance as first show in

Intravenous gamma globulin has been used for the treatment of a variety of severe SLE manifestations. Proposed mechanisms of action include Fcγ receptor blockade, ­downregulation of the immune response by anti-idiotype antibodies, a decrease in T suppressor cells, accelerated immunoglobulin catabolism, and neutralization of C3a and C5a, all of which have been advocated to contribute to its therapeutic effect in SLE. Intravenous gamma globulin is administered in doses of 400 mg/kg/day for 5 consecutive days and is most commonly used for the treatment of severe, refractory thrombocytopenia, usually achieving a rapid increase in the number of platelets within hours of administration. Nephritis, arthritis, fever, rashes, and immunologic parameters improve with intravenous gamma globulin.186 Side effects of intravenous gamma globulin include fever, myalgia, headache, arthralgia, and, rarely, aseptic meningitis. The drug is contraindicated in cases of known IgA ­deficiency.

GENERAL ISSUES CYTOTOXIC DRUGS IN SEVERE, LIFE-THREATENING DISEASE Controlled trials and clinical experience suggest that intravenous cyclophosphamide in combination with intravenous methylprednisolone is the treatment of choice for most patients. For refractory patients, based on initial ­experience,

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Suspected nephritis Renal biopsy Proliferative

Membranous

Risk stratification

Risk stratification

Severe

Mild-moderate

Severe

Mild-moderate

Induction Monthly pulses MP + CY (p.o. CY)

Induction AZA (if mild) MMF (mild-to-moderate)

Induction i.v. MP + i.v. CY MMF CsA AZA

Induction GC CsA AZA MMF

Maintenance i.v. CY AZA CsA MMF

Maintenance

No

Response

Response

Maintenance AZA MMF (i.v. CY)

Maintenance AZA MMF

AZA CsA MMF

Figure 75-10  Algorithm for the treatment of lupus nephritis. All regimens include a background of glucocorticosteroids (0.5 to 0.8 mg/kg for the first 4 weeks of induction, 0.25 mg/kg every other day for maintenance). AZA, azathioprine; CsA, cyclosporine; CY, cyclophosphamide; GC, glucocorticosteroids; MMF, mycophenolate mofetil; MP, methylprednisolone.

availability, and potential side effects, combinations of intravenous cyclophosphamide with rituximab may be an acceptable strategy. Mycophenolate mofetil may rescue a few refractory patients, but its efficacy in critically ill patients requires further documentation. For selected patients (e.g., patients with neurologic disease, antiphospholipid antibody syndrome, thrombocytopenia), intravenous gamma globulin may be considered as an adjunctive therapy. In critically ill patients, plasmapheresis may offer some benefit to selected patients. Cyclophosphamide may be administered either orally or as pulse therapy in the intensive care unit. The major concern is bladder protection and respiratory and intravenous line infections. Bladder irrigation through a threeway catheter in case of urine output less than 100 mL/hr is essential along with diligent care of the lines and tapering of corticosteroids. An aggressive search for infection is essential before and after therapy. Until infection is ruled out, we usually use high-dose corticosteroids. An aggressive tapering of corticosteroids when the patient improves is essential to minimize the risk of infectious and other complications. The importance of a multidisciplinary approach involving several medical subspecialties cannot be overemphasized. PREVENTION AND MANAGEMENT OF INFECTION AND IMMUNIZATIONS Infections attributed predominantly to corticosteroids and cytotoxic drugs are an important cause of hospital admissions and account for approximately one quarter of all deaths. In one of the earliest studies from the National Institutes of Health, 60% of the febrile episodes were ascribed to active SLE alone and 23% to infections. Leukocytosis, neutrophilia, shaking chills, and normal levels of anti-DNA

antibodies were associated with infection in febrile patients with SLE.164 Judicious use of corticosteroids and immunizations may decrease the frequency of infections. Strategies to decrease the impact of infections include (1) simple hygienic measures and education aimed at patients and physicians; (2) antimicrobial prophylaxis in cohorts of patients with increased prevalence of certain infections, patients who receive heavy doses of immunosuppressive agents, or patients who undergo procedures associated with temporary bacteremia; and (3) immunizations similar to those available to the general population. Bacterial Endocarditis Clinical or subclinical valvular abnormalities are common in patients with moderate-to-severe SLE and may predispose to bacterial endocarditis. Patients with known valvular abnormalities should receive endocarditis prophylaxis before invasive dental, intestinal, or genitourinary procedures according to the standard regimens of the American Heart Association. For patients without known valvular abnormalities, some investigators also have advocated the use of prophylactic antibiotic prophylaxis. In our opinion, this is a reasonable suggestion, especially when patients receive high-intensity immunosuppressive therapy, but firm data to support this suggestion are lacking at present. Tuberculosis and Pneumocystis jiroveci Widely applicable guidelines for tuberculosis prophylaxis in SLE do not exist. Purified protein derivative testing may be considered in areas with a high prevalence of tuberculosis for patients who may receive long-term prednisone equal to or greater than the equivalent of 15 mg/day of prednisone. In such cases, a 5-mm tuberculin reaction represents a

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realistic cutoff. For patients living in low-prevalence countries, current data do not support the routine use of purified ­protein derivative testing before cytotoxic therapy. In contrast to patients with systemic vasculitis, we do not routinely employ prophylaxis for Pneumocystis jiroveci in patients with SLE. Some authors recommend prophylaxis, however, for patients on high-dose corticosteroids alone or in combination with cytotoxic drugs if the CD4 count is less than 300 cells/μL (1 double-strength tablet of trimethoprim­sulfamethoxazole three times a week or dapsone 100 mg/day if allergic to sulfamethoxazole). Immunizations Although vaccination theoretically may induce polyclonal activation in SLE and induce a flare, it is believed to be safe. More specifically, the influenza vaccine has been shown to be safe and effective; the pneumococcal vaccine also is safe, but the resultant antibody titers may be decreased in patients with SLE compared with controls. The use of corticosteroids may contribute to the blunted antibody response. A protective immune response can be achieved safely in patients with SLE with tetanus toxoid and Haemophilus influenzae type B in addition to pneumococcus. Immunization with live vaccines (e.g., measles, mumps, rubella, polio, varicella, varicella-zoster virus) is contraindicated in patients on corticosteroids at doses equivalent to 20 mg/day of prednisone for more than 2 weeks and in patients on cytotoxic drugs. The efficacy and safety of hepatitis B vaccination in SLE patients requires further documentation. Rheumatic syndromes temporally related to vaccination have been described, but a causal relationship has not been established. PULMONARY INFILTRATES Pulmonary complications are a major cause of morbidity and mortality in SLE patients receiving cytotoxic drugs. The differential diagnosis in this setting is broad and includes infectious and noninfectious processes. The radiographic findings are rarely specific for one disease, and most potential etiologies have overlapping clinical and radiographic appearances. An aggressive approach to identifying a specific etiology is of paramount importance; this includes bronchoscopy and early use of CT. SCREENING FOR MALIGNANCY Certain cancers occur more frequently in SLE compared with the general population, as more recent data substantiate, and may be due partly to cytotoxic/immunosuppressive drugs. The risk seems to be most heightened for lymphoma.187 Cooperative efforts to evaluate this risk have been undertaken by several groups. An increased frequency of abnormal cervical Papanicolaou (Pap) smears in women with SLE has been reported by several groups.188,189 In one study, the risk factors for the development of an abnormal Pap smear include a history of sexually transmitted diseases, the use of oral contraceptives, and the use of immunosuppressive drugs, especially cyclophosphamide.189 Vigilance in cancer preventive strategies similar to that of the general population is essential. This vigilance is particularly important in view of more recent data suggesting that

a­ ppropriate cancer screening may be overlooked in patients with SLE.190 USE OF CYTOTOXIC DRUGS IN PREGNANCY Pregnant patients with active SLE and mild disease generally are managed with corticosteroids. In moderateto-severe disease, corticosteroids, azathioprine, ­cyclosporine, and intravenous gamma globulin may be acceptable for the fetus. In life-threatening disease, cyclophosphamide may be used only if there are no alternative therapies. ­Cyclophosphamide and methotrexate are contraindicated (U.S. Food and Drug Administration category D—positive evidence for risk), whereas adequate information is lacking for mycophenolate mofetil (category C—risk cannot be ruled out). Because azathioprine may be excreted in breast milk, breastfeeding is not recommended. The American Academy of Pediatrics recommends that nursing is permissible for women receiving corticosteroids, but the interval between dose and nursing should be at least 4 hours if the prednisone dose is more than 20 mg/day. The American Academy of Pediatrics recommendations also indicate that hydroxychloroquine is compatible with breastfeeding. Although low concentrations of this drug are found in breast milk, because of the slow elimination rate and potential for accumulation of toxic amounts in the infant, breastfeeding during daily therapy should be undertaken cautiously. ADJUNCT THERAPY Photoprotection may be beneficial in patients with skin manifestations and is commonly used throughout the year. Lifestyle modifications (e.g., smoking cessation, weight control, exercise) are likely to be beneficial for outcomes in SLE and should be encouraged. Depending on the individual medication and the clinical situation, other agents (e.g., low-dose aspirin, calcium/vitamin D, bisphosphonates, statins, antihypertensives including angiotensin-converting enzyme inhibitors) are commonly used. The efficacy and safety of oral estrogen contraceptives in SLE patients has been assessed in two randomized controlled trials, which concluded that they do not increase the risk for flare in stable disease.191,192 These results may not be generalized to patients with increased risk for thombo-occlusive events, and accompanying risks should be assessed before estrogen therapy is prescribed.

SPECIAL CONSIDERATIONS PREGNANCY: THE MOTHER AND FETUS IN SYSTEMIC LUPUS ERYTHEMATOSUS SLE affects predominantly women of childbearing age. Sterility and fertility rates for women with SLE are comparable to healthy control groups. Secondary amenorrhea is associated with increased disease activity. Menstrual irregularities have been reported in women taking high doses of corticosteroids, and premature ovarian failure occurs in women receiving cyclophosphamide. SLE patients also are at risk for various adverse pregnancy outcomes, including miscarriage, stillbirth, and premature delivery (relative risk 2.2 to 5.8).193 This risk is even higher for patients with ­antiphospholipid

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antibodies, as suggested by several prospective and retrospective studies, with relative risks ranging from 1.4 to 12.3 depending on the adverse outcome studied.194-199 The management of a pregnant SLE patient has always been a challenge for the practicing physician because SLE may affect pregnancy and vice versa (Table 75-16). There is not enough evidence to support a deleterious effect of SLE on fertility.200-202 An increased frequency of SLE has been re­ported in endometriosis patients, which may have an im­pact on fertility.203 A meta-analysis of epidemiologic studies that were published during 1980 to 1992204 and subsequent controlled196,205-211 and uncontrolled ­ studies193,197,198,212,213 have indicated that pregnancy may increase SLE disease activity and cause flares (reported frequency of flares 13% to 74%), but these flares are usually (33% to 88%) mild to moderate, involving mostly skin, joints, and blood. SLE may affect the outcome of pregnancy. Lupus nephritis has been identified as risk factor for hypertensive complications and preeclampsia.206,210,214-216 In a prospective study of SLE pregnancies, patients with preexisting lupus nephritis developed hypertension more frequently (50% versus 12%) than patients without nephritis.206 The presence of antiphospholipid antibodies also is associated with increased risk for preeclampsia during pregnancy,217,218 and the relative risk was estimated to be 16.8 (95% confi­ dence interval 1.3 to 2.58) in a study of Chinese patients.219 Patients with active nephritis also carry increased risk for adverse pregnancy outcomes, although the evidence comes from fewer studies.211,220 In a retrospective analysis of 70 pregnancies in 48 women with lupus nephritis, the prevalence of fetal loss was 52% in active nephritis compared with 11% in cases of complete remission.221 A single retrospective study in African-American women with SLE showed that anti-Ro positivity is associated with fetal wastage (71% versus 18%).222 SLE pregnancies are accompanied by increased rates (12% to 35%) of intrauterine growth restriction, with a relative risk of 8.6 (95% confidence interval 3 to 24.3) determined in a retrospective case-control study.223 Antiphospholipid antibodies and nephritis also are associated with low birth weight and intrauterine growth restriction.224-226 Women with SLE have higher rates of spontaneous abortion, intrauterine fetal death, and premature birth compared with healthy women. Pregnancy outcome is optimal when the disease is in clinical remission for 6 to 12 months, and the patient’s renal function is stable and normal or near-normal. Contraception and family planning are important.193 Proteinuria may increase during pregnancy in women with underlying kidney disease. Differentiation of ­ preeclampsia from lupus activity in the kidneys is not difficult in most cases. Very low serum complement, active urine sediment, and evidence of generalized lupus activity favor lupus nephritis. Other features, such as hypertension, thrombocytopenia, an increase in serum uric acid levels, and proteinuria, may be observed in both conditions. Low-grade activation of the classic complement pathway may be attributable to pregnancy alone. Lupus placentae are small in size, and they exhibit ischemic-hypoxic changes, decidual vasculopathy and thrombi, chronic villitis, and perivillous fibrin. Fetal growth and development in SLE may be affected by disease activity, by abnormality of maternal kidney function,

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Table 75-16  Approach to the Management   of Pregnancy in Systemic Lupus Erythematosus Planning of pregnancy Ensure that lupus is inactive for at least 6 mo. Reassure patient   (small risk for major flare) Discourage pregnancy if creatinine is >2 mg/dL Check for antiphospholipid antibodies and other antibodies that may be relevant during pregnancy (e.g., anti-SSA, anti-SSB) Check baseline laboratory tests (serology, serum chemistry including creatinine, albumin, uric acid, anti-dsDNA, C3, C4) Be aware of the small risk for CHB, especially in women with anti-SSA and anti-SSB antibodies or with a prior episode of CHB. In such cases, monitor for CHB between 16 and 24 wk of gestation Monitor blood pressure and proteinuria closely. Should this develop, differentiate between active nephritis and preeclampsia. The presence of generalized lupus activity and active urine sediment, and significantly low serum complement suggests lupus nephritis For patients with APS, consider combined heparin and aspirin to reduce risk for pregnancy loss and thrombosis. For patients with antiphospholipid antibodies, consider aspirin, although there are no adequate data to support its use APS, antiphospholipid antibody syndrome; CHB, congenital heart block.

by antiphospholipid antibody, and by SS-A/Ro and SS-B/La antibodies. Elevation of maternal alpha fetoprotein levels occurs in patients with SLE and is associated with ­preterm delivery, high corticosteroid dosage, and the presence of antiphospholipid antibody.227 False elevation in human chorionic gonadotropin also has been reported.228 Maternal IgG-mediated thrombocytopenia may be transmitted to the fetus; however, most infants born of thrombocytopenic mothers with SLE have normal platelet counts. IgG Coombs hemolytic antibody may be transmitted and cause hemolysis in the fetus and newborn. Anti-DNA antibodies have no pathologic effect on the fetus. Antiphospholipid antibodies cause placental insufficiency, intrauterine growth restriction, and fetal death. They do not usually cause abnormalities in the infant. Neonatal lupus is a passively transferred autoimmune disease that occurs in some infants born to mothers with anti-SS-A/Ro or anti-SS-B/La antibodies or both. The most serious complication in the neonate is complete heart block, which occurs in 2% of such pregnancies.229,230 Isolated skin rash occurs in a similar percentage. When a woman has given birth to an infant with congenital heart block, the risk in future pregnancies is about 15%. Ovarian induction and fertilization can be successful in SLE patients, but rates of fetal and maternal complications may be higher. There is only a little evidence regarding therapy of SLE during pregnancy. Prednisolone, other nonfluorinated glucocorticoids, and azathioprine may be used in SLE pregnancy, but their efficacy and safety have not been shown in randomized trials.198,211,215,231,232 Low-dose aspirin has been used in SLE pregnancy.233 Evidence is stronger for hydroxychloroquine, and its efficacy and safety have been evaluated in one randomized controlled trial,234 three nonrandomized studies (one prospective, two retrospective),220,235,236 and several case series.215,237,238 These recommendations differ from those of the Food and Drug Administration (see Table 75-12). There is no evidence to support the use of mycophenolate mofetil, cyclophosphamide, or ­ methotrexate,

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and these agents must be avoided during pregnancy.239-241 Although cyclosporine has been used in pregnancy, its safety has not been established.242,243 ANTIPHOSPHOLIPID ANTIBODY SYNDROME Antiphospholipid antibodies (see Chapter 76) are commonly encountered in SLE patients and are associated with increased risk for thrombo-occlusive incidents. In such patients, ­primary or secondary prevention of thrombosis is warranted, but the clinical decision is often hampered by accompanying risks for treatment-related adverse effects (i.e., major bleeding). Despite the lack of evidence for primary prevention of thrombosis and pregnancy loss, some experts recommend the use of low-dose aspirin in SLE patients with antiphospholipid antibodies, especially when other risk factors for thrombosis coexist. The effectiveness of oral anticoagulation over ­ aspirin alone in secondary prevention of thrombosis in (nonpregnant) SLE patients with a history of antiphospholipid antibodies and thrombosis has been established in several retrospective controlled studies244-248 and randomized controlled trials with mixed APS populations (i.e., primary and SLE-related).249,250 The intensity of anticoagulation has been a matter of debate, however. The two randomized controlled trials of 114 and 109 patients have shown no superiority of high-intensity warfarin (target international normalized ratio [INR] 3.1 to 4.0) over moderate-intensity warfarin (target INR 2.0 to 3.0) for secondary prevention, and there was an increased risk for minor bleeding incidents in the high-intensity arm (hazard ratio 2.92, 95% confidence interval 1.13 to 7.52). In these studies, most patients (>70%) had a history of venous, rather than arterial, thrombosis, and patients who had already had recurrent events on oral anticoagulation were excluded. Retrospective studies including more patients with previous arterial thrombosis or stroke have concluded that high-intensity warfarin is more efficacious in secondary prevention of thrombosis, and it carries a risk for major bleeding that is similar to that of lower intensity anticoagulation. Based on these findings, it is recommended that in patients with APS and a first event of venous thrombosis, oral anticoagulation should target INR 2.0 to 3.0. In the case of arterial or recurrent thrombosis, high-intensity anticoagulation (target INR 3.0 to 4.0) is warranted. As for pregnant SLE patients with APS, a Cochrane Database Review concluded that combined unfractionated heparin and aspirin may reduce the risk for pregnancy loss (relative risk 0.46, 95% confidence interval 0.29 to 0.71).251 The combination of low-molecular-weight heparin and aspirin also seems to be effective, although the results did not reach statistical significance (relative risk 0.78, 95% confidence interval 0.39 to 1.57). These results are based on findings from randomized controlled trials252-254 and prospective232,255,256 and retrospective controlled studies247,257-259 in SLE pregnancies complicated by antiphospholipid antibodies or APS and previous history of pregnancy loss or thrombosis. No randomized trials have assessed the usefulness of anticoagulation in prevention of recurrent thrombosis during pregnancy. We recommend the use of aspirin and anticoagulation for the prevention of APS-related thrombosis during pregancy.

SYSTEMIC LUPUS ERYTHEMATOSUS IN CHILDHOOD AND ADOLESCENCE Approximately 15% to 20% of all cases of SLE are diagnosed in childhood. Pediatric SLE may differ from adult SLE in regard to disease expression and physiologic, developmental, and psychosocial issues. Because of a paucity of data in pediatric SLE, little is known about its epidemiology, long-term outcome, and optimal management. Generally, the same principles are applied in the management of pediatric SLE; however, the special needs of this population have to be taken into consideration. DRUG-INDUCED LUPUS DIL represents a paradigm of an environmental agent triggering lupus in a genetically predisposed individual. It is well established that certain drugs induce autoantibodies in numerous patients, most of whom do not develop signs of an autoantibody-associated disease.260 More than 100 drugs have been reported to cause DIL, including many of the newer biologics and antiviral therapeutics. The incidence of DIL in the United States has been estimated to be 15,000 to 20,000 new cases per year. The frequency of DIL is probably underreported; many cases are mild and self-limited when the offending drug is removed. DIL should be suspected in patients who do not have a diagnosis or history of SLE, who develop a positive ANA and at least one clinical feature of SLE after an appropriate duration of drug exposure, and whose symptoms resolve after discontinuation of the drug. The clinical features of DIL include fever, myalgias, rash, arthritis, and serositis. Hematologic abnormalities, kidney disease, and CNS lupus are rare, although they have been reported. Antihistone antibodies are present in more than 95% of cases, whereas hypocomplementemia and anti-DNA antibodies are rare (with the exception of disease associated with use of interferon-α and anti–tumor necrosis factor therapies). A variety of drugs have been identified as being definite, probable, or possible causes of lupus (Table 75-17). Although the pathogenesis of DIL is not well understood, a genetic predisposition may play a role in the case of ­ certain drugs, particularly agents that are metabolized by acetylation, such as procainamide and hydralazine. The ­disease is more likely to develop in patients who are slow acetylators.261 Data also suggest that these drugs may alter gene expression by inhibiting T cell DNA methylation.262 Pharmacologic levels of these drugs induce overexpression of leukocyte function–associated 1 antigen by this ­mechanism, causing autoreactivity in CD4+ T cells. DIALYSIS AND RENAL TRANSPLANTATION End-Stage Renal Disease and Dialysis Approximately 10% to 20% of patients with SLE develop end-stage renal disease. Progression of lupus nephritis to the point of dialysis does not indicate end-stage renal disease. Approximately 5% to 10% of SLE patients requiring dialysis recover sufficient function to interrupt dialysis temporarily or for long periods. Patients with rapid deterioration of renal function are more likely to have a reversible physiologic

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Table 75-17  Drugs Reported to Induce Lupus-like   Disease and Associated Autoantibodies Agent

Risk

Antiarrhythmics Procainamide Quinidine Disopyramide Propafenone

High Moderate Very low Very low

Antihypertensives Hydralazine Methyldopa Captopril Enalapril Acebutolol Labetalol Pindolol Clonidine Minoxidil Prazosin

High Low Low Low Low Very low Very low Very low Very low Very low

Antipsychotics Chlorpromazine Perphenazine Phenelzine Lithium carbonate

Low Very low Very low Very low

Anticonvulsants Carbamazepine Phenytoin Trimethadione Primidone Ethosuximide

Low Very low Very low Very low Very low

Antibiotics Isoniazid Minocycline Nitrofurantoin

Low Very low Very low

Anti-inflammatories Penicillamine Sulfasalazine Phenylbutazone Zafirlukast Mesalamine

Low Low Very low Very low Low

Diuretics Chlorthalidone Hydrochlorothiazide

Very low Very low

Antihyperlipidemics Lovastatin Simvastatin

Very low Very low

Miscellaneous Propylthiouracil Levodopa Aminoglutethimide Timolol eye drops

Low Very low Very low Very low

Biologic Agents Tumor necrosis factor-α blockers Interferon-α

High Low

(e.g., acute tubular necrosis) or pathologic (e.g., crescentic glomerulonephritis) component accounting for their renal failure. In these patients, immunosuppressive therapy (pulse of methylprednisolone with pulses of cyclophosphamide, 0.4 to 0.5 g/m2, administered 8 to 10 hours before dialysis) may continue during dialysis.

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Discontinuation of immunosuppressive therapy is an emotional issue for patients and physicians. We generally consider discontinuing therapy in patients with steadily increasing creatinine to 3.5 mg/dL with inactive urine sediment, renal biopsy specimen showing exclusively scarring and atrophy, or contracted renal size. Peritoneal dialysis is a reasonable option for SLE patients and offers greater independence. Most SLE patients with advancing renal disease experience a significant decline in lupus activity. Half of patients on maintenance hemodialysis continue to experience lupus activity, however, which often is difficult to distinguish from the complication of uremia.263 Lupus activity is more likely to persist on dialysis when renal failure develops rapidly. Uremia is a major predisposing factor for infections, and judicious use of corticosteroids and immunosuppressive drug therapy is essential to minimize the high risk of septic death in SLE patients with end-stage renal disease. Cardiovascular and cerebrovascular mortality and morbidity are increased in SLE patients with end-stage renal disease compared with SLE patients without end-stage renal disease.264 Data from the United States Renal Data System (USRDS) suggest that, similar to other primary renal diseases, the incidence of end-stage renal disease secondary to lupus nephritis increased steadily over the period 1982 to 1995, despite the introduction of efficacious new treatment regimens; this may be related to the limited or delayed use of these ­modalities.265 Renal Transplantation There are no firm rules for the optimal timing of renal transplantation in lupus nephritis patients. Although some patients with living related donors proceed directly to transplantation without prior dialysis, a period of at least 3 months on dialysis may allow some patients to recover adequate function for significant periods. A study in 8481 patients with a variety of renal diseases has suggested that avoiding long-term dialysis improves allograft survival of renal transplants from living donors. Improved immune function after dialysis may have contributed to this effect.266 Kidney transplantation is a viable alternative for SLE patients. Data from the USRDS and a European center suggest that graft and patient survival are similar between patients with end-stage renal disease caused by SLE and controls.267,268 Recurrence of lupus nephritis in the renal allograft is a rare event (approximately 2% of transplants) and not an important cause of graft loss. The importance of antiphospholipid antibodies in vascular thrombosis in transplant recipients that was suggested by previous studies263 was confirmed in a retrospective multicenter study.269 In this study, all seven of the patients with APS not treated with anticoagulation therapy lost their allografts within 1 week as a result of renal thrombosis. In contrast, three out of four transplant patients with APS treated with anticoagulation therapy maintained their allografts for more than 2 years. The authors concluded that patients with APS are at high risk of post-transplant renal thrombosis and recommended anticoagulation therapy. The risk for thrombotic complications in antiphospholipid-positive SLE patients was confirmed more recently from a single-center European study.267 In a subsequent pediatric study involving 100 renal transplants performed in 94 young SLE patients, comparable

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outcomes to those seen in the control group were reported, but an unexplained increase in the incidence of recurrent rejections (four or more) was seen in SLE patients.270 CRITICAL ILLNESS Life-threatening illness can develop in patients with SLE from any of the following causes: (1) exacerbation of preexisting manifestations of SLE; (2) development of new lifethreatening manifestations of SLE; (3) infections resulting from immunosuppression; (4) adverse effects of drugs used to treat SLE; (5) malignancy resulting from prolonged use of cytotoxic drugs; and (6) acute serious illnesses that are unrelated to SLE, but whose manifestations are altered or exaggerated by it. Infection is the most common form of pulmonary involvement in patients with SLE.271 Infections in patients with SLE can be confused with exacerbation of the underlying disease process, and empiric therapy with broad-spectrum antibiotics is warranted until infection is conclusively ruled out. Bronchoscopy or open lung biopsy may be needed in addition to routine cultures to exclude an infectious origin. A diagnosis of acute lupus pneumonitis can be made after rigorously excluding ­infections in patients presenting with features resembling infectious pneumonia. Unilateral or bilateral alveolar infiltrates are seen on the chest radiograph, hypoxemia and respiratory alkalosis may be seen on arterial blood gases, and ventilatory assistance may be required in severe cases.272,273 Mortality in patients with lupus pneumonitis may be 50%. A high index of suspicion should be maintained for a young female patient presenting with unexplained pulmonary infiltrates. Alveolar hemorrhage is a serious but rare complication of SLE with high morbidity and mortality. The severity of alveolar hemorrhage in SLE may range from an uncommon mild and chronic form to massive bleeding resulting in death. The classic triad of hemoptysis, falling hematocrit, and pulmonary infiltrates is not uniformly present in all patients.124,274 Bilateral diffuse alveolar infiltrates are seen on chest radiograph, but may be patchy, with lower lobe predominance. Respiratory failure may occur, and more than half of affected patients in most series required mechanical ventilation. Patients with alveolar hemorrhage usually have lupus nephritis as a preexisting condition.275,276 Early bronchoscopy with bronchoalveolar lavage is recommended to show alveolar hemorrhage and to collect specimens for culture. Mortality in patients with alveolar hemorrhage is 40% to 90%.124,273,277-279 Cardiovascular disease secondary to premature accelerated atherosclerosis is increasingly recognized among SLE patients.105,106,280 Although patients with SLE are often concerned about vasculitis, most coronary occlusive disease in SLE results from atherosclerosis or thrombosis.281 Cases of left ventricular free wall rupture, acute mitral regurgitation after rupture of chordae tendinae, and aortic dissection have been described in patients with SLE. Cerebrovascular accidents manifesting acutely with hemiplegia, aphasia, cerebral dysfunction, cortical blindness, or other deficits of cerebral function can be caused by intracranial hemorrhage from ruptured aneurysms, thrombotic strokes from vasculitis or vasculopathy secondary to antiphospholipid antibodies, or embolic strokes from cardiac emboli.114,282

Spinal cord myelopathy is a devastating manifestation of SLE. Patients present with weakness or paralysis, bilateral sensory deficits, and impaired sphincter control. Symptoms usually evolve in a matter of hours or days. MRI of the spinal cord may show characteristic abnormalities of cord edema if obtained early. Because of the poor prognosis, early diagnosis and aggressive therapy are important.94,283 Patients with SLE presenting with an acute abdomen are challenging. The clinical syndrome may be secondary to mesenteric arterial thrombosis; ischemic bowel; ruptured hepatic aneurysms; cholecystitis; pancreatitis; or perforation of a viscus including a peptic ulcer, the appendix, the cecum, or the colon.284,285 Patients with active SLE presenting with an acute abdomen and a high SLEDAI score are more likely to have active intra-abdominal vasculitis than patients with active lupus, but low SLEDAI scores. The former group, in view of the high mortality, should be considered for early laparotomy.286 Recommended Assessment and Monitoring and Referral Guidelines Because of the low prevalence of moderate-to-severe SLE, most general internists do not have experience in its management. The role of the general internist in the early diagnosis, monitoring of patients with mild, stable diseases, and referral of patients with unstable or moderate-to-severe disease is essential, however.287 Table 75-18 presents guidelines for the initial assessment and frequency of monitoring for general use.

Table 75-18  Recommended Initial Assessment   and Monitoring of Systemic Lupus Erythematosus History and review of systems Joint pain and swelling, Raynaud’s phenomenon Photosensitivity, rash, hair loss Shortness of breath, pleuritic chest pain General symptoms (depression, fatigue, fever, weight change) Physical examination Rashes (acute, subacute, chronic, nonspecific, others), alopecia, oral or nasal ulcers Lymphadenopathy, splenomegaly, pericardial or pleural effusions Funduscopic examination, edema Other features as suggested by history and symptoms Imaging and laboratory tests Hematology* Chemistry* PT/PTT, antiphospholipid antibodies Urinalysis* Serology (ANA, ENA including anti-dsDNA,† complement†) Chest x-ray ECG Other tests as suggested by history and symptoms Disease activity index (at each visit or at major changes in therapy) Side effects of therapy Damage index (SLICC) (every 1-2 yr) *Every 3-6 months, if stable. †Every 3-6 months in patients with active renal disease. ANA, antinuclear antibody; ECG, electrocardiogram; ENA, extractable ­nuclear antigen; PT/PTT, prothrombin time/partial thromboplastin time; SLICC, Systemic Lupus International Collaborating Clinics.

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Prognosis, Morbidity, and Mortality A bimodal mortality pattern in SLE was first described in 1974 showing that early mortality in SLE is associated with SLE disease activity and infection, whereas late mortality is associated with atherosclerotic complications.288 Although current treatment of SLE has improved survival, prolonged and complete remission—defined as 5 years without clinical and laboratory evidence of active disease and on no treatment—has remained elusive, occurring in 1.7% of patients.289,290 In the Hopkins Lupus Cohort, hemolytic anemia was significantly associated with mortality risk in adjusted analyses, regardless of whether it was present at diagnosis or at a later time.291 Other factors associated with decreased survival in the same cohort were lower socioeconomic status, age older than 50 years at the time of diagnosis, male gender, and low complement level at diagnosis. Renal disease was less strongly associated with survival, as had been reported in previous studies.97,292 Many patients (20% to 40% in various studies) do not respond adequately to current immunosuppressive therapies. Half (50%) of these patients reach end-stage renal disease. A relapsing remitting, or “flare,” pattern is the classic pattern of SLE activity. Flares are common in SLE patients. The incidence of flare has been estimated to be 0.65 per patient-year of follow-up.209 In patients with moderateto-severe lupus nephritis participating in a randomized controlled trial, renal flares were seen in 20% to 40% of patients. The mean time for flare is 3 years—hence long follow-up is

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important. Of patients who flare, one third reach end-stage renal disease despite therapy.293 In SLE, treatment-related morbidity may not be easily separable from disease-related morbidity. The incidence of hospital admissions for patients with SLE is 0.69 admissions per patient-year. Infections, coronary artery disease, and orthopaedic management of osteonecrosis were prominent reasons for hospitalization.294 EVIDENCE-BASED RECOMMENDATIONS FOR THE MANAGEMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS SLE is a complex disease with variable presentations, course, and prognosis. Because of the systemic nature of the disease, multiple medical subspecialties are involved in the care of patients dictating an integrated approach to its care. To this end, the European League Against Rheumatism task force on SLE has developed recommendations covering the most important aspects in the management.1 These recommendations, developed not only for specialists, but for all internists, were based on a combined research-based evidence approach and expert opinion consensus. The ­ recommendations for the management of SLE are shown in Table 75-19. Acknowledgments The authors thank Drs. P. Sidiropoulos, G. Bertsias, and Eva Padimitraki for critical review of the manuscript; Dr. D. Vassilopoulos for sharing of patient and laboratory pictures; and Dr. K. Pagonidis for his help with the imaging studies.

Table 75-19  Summary of Statements and Recommendations on the Management of Systemic Lupus   Erythematosus Based on Evidence and Expert Opinion* General Management Prognosis In patients with SLE, new clinical signs (rashes (B), arthritis (B), serositis (B), neurologic manifestations [seizures/psychosis] (B)), routine laboratory (CBC (B), serum creatinine (B), proteinuria (B), and urinary sediment (B)), and immunologic tests (serum C3 (B), anti-dsDNA (B), anti-Ro/SSA   (B), anti-La/SSB (C), antiphospholipid antibody (B), anti-RNP (B)) may provide prognostic information for the outcome in general and involvement of major organs, and should be considered in the evaluation of patients. Confirmation by imaging (brain MRI (B)) and pathology (renal biopsy (B)) may add prognostic information and should be considered in selected patients Monitoring New clinical manifestations, such as number and type of skin lesions (C) or arthritis (D), serositis (D), and neurologic manifestations (seizures/psychosis) (D); laboratory tests (CBC) (B); immunologic tests (serum C3/C4 (B), anti-C1q (B), anti-dsDNA (B)); and validated global activity indices   (D) have diagnostic ability for monitoring for lupus activity and flares, and may be used in the monitoring of lupus patients Comorbidities SLE patients are at increased risk for certain comorbidities secondary to the disease or its treatment or both. These comorbidities include infections (urinary tract infections (B), other infections (C)), atherosclerosis (B), hypertension (B), dyslipidemias (B), diabetes (C), osteoporosis (C), avascular necrosis (C), and malignancies (especially non-Hodgkin’s lymphoma) (B). Minimization of risk factors together with a high index of suspicion, prompt evaluation, and diligent follow-up of these patients is recommended Treatment In the treatment of SLE without major organ manifestations, antimalarials (A) or glucocorticoids (A) or both are beneficial and may be used. NSAIDs may be used judiciously for limited periods in patients at low risk for their complications (D). In nonresponsive patients or patients in whom steroids cannot be reduced below doses acceptable for long-term use, immunosuppressive agents such as azathioprine (B), mycophenolate mofetil (D), and methotrexate (A) also should be considered *The strength of each statement (A-D) is given in parentheses, in bold. A = Evidence from randomized controlled trials or meta-analyses of randomized controlled trials without concerns for the validity. B = As in A, but with concerns about the validity of the evidence, or evidence from meta-analyses of epidemiologic studies or prospective controlled studies without concerns about the validity of the evidence. C = Evidence from nonprospective controlled (retrospective cohort, case-control, or cross-sectional) or uncontrolled studies without concerns about the validity. D = Based on evidence from meta-analyses from epidemiologic studies, nonrandomized controlled studies (prospective or nonprospective), or uncontrolled studies with major concerns about the validity of the evidence; or no data (expert opinion). APS, antiphospholipid antibody syndrome; CBC, complete blood count; MRI, magnetic resonance imaging; NSAIDs, nonsteroidal anti-inflammatory drugs; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus. Continued

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Table 75-19  Summary of Statements and Recommendations on the Management of Systemic Lupus   Erythematosus Based on Evidence and Expert Opinion—cont’d Adjunct Therapy Photoprotection may be beneficial in patients with skin manifestations and should be considered (B). Lifestyle modifications (smoking cessation, weight control, exercise) (D) are likely to be beneficial for lupus outcomes and should be encouraged. Depending on the individual medication and the clinical situation, other agents (low-dose aspirin (D), calcium/vitamin D (D), bisphosphonates (A), statins (D), antihypertensives [including angiotensin-converting enzyme inhibitors] (D)) should be considered. Estrogens (oral contraceptives (A), hormonal replacement therapy (A)) may be used, but accompanying risks should be assessed Neuropsychiatric Lupus Diagnosis In SLE patients, the diagnostic workup (clinical (A-C), laboratory (B), neuropsychologic (C), and imaging tests (B-C)) of neuropsychiatric manifestations should be similar to that in the general population presenting with the same neuropsychiatric manifestations Treatment SLE patients with major neuropsychiatric manifestations considered to be of inflammatory origin (optic neuritis, acute confusional state/coma, cranial or peripheral neuropathy, psychosis, and transverse myelitis/myelopathy) may benefit from immunosuppressive therapy (A) Pregnancy in Lupus Pregnancy affects mothers with SLE and their offspring in several ways Mother: There is no significant difference in fertility in lupus patients (C). Pregnancy may increase lupus disease activity, but these flares are usually mild (B). Patients with lupus nephritis and antiphospholipid antibodies are more at risk of developing preeclampsia and should be monitored more closely (B) Fetus: SLE may affect the fetus in several ways, especially if the mother has a history of lupus nephritis or antiphospholipid, anti-Ro, or anti-La antibodies. These conditions are associated with an increase of the risk of miscarriage (B), stillbirth (B), premature delivery (B), intrauterine growth restriction (C), and fetal heart block (B). Prednisolone (D), azathioprine (D), hydroxychloroquine (A), and low-dose aspirin (D) may be used in lupus pregnancies. Current evidence suggests that mycophenolate mofetil, cyclophosphamide, and methotrexate must be avoided (D) APS In patients with SLE and antiphospholipid antibodies, low-dose aspirin may be considered for primary prevention of thrombosis and pregnancy loss (D). Other risk factors for thrombosis also should be assessed. Estrogen-containing drugs increase the risk for thrombosis (D). In nonpregnant patients with SLE and APS-associated thrombosis, long-term anticoagulation with oral anticoagulants is effective for secondary prevention of thrombosis (A). In pregnant patients with SLE and APS combined, unfractionated or low-molecular-weight heparin and aspirin reduce pregnancy loss and thrombosis and should be considered (A) Lupus Nephritis Monitoring Renal biopsy (B), urine sediment analysis (B), proteinuria (B), and kidney function (B) may have independent predictive ability for clinical outcome in therapy of lupus nephritis, but need to be interpreted in conjunction. Changes in immunologic tests (anti-dsDNA, serum C3) (B) have limited ability to predict the response to treatment and may be used only as supplemental information Treatment In patients with proliferative lupus nephritis, glucocorticoids combined with immunosuppressive agents are effective against progression to endstage renal disease (A). In short-term and medium-term trials, mycophenolate mofetil has shown at least similar efficacy compared with pulse cyclophosphamide and a more favorable toxicity profile (A); failure to respond by 6 mo should lead to discussions for intensification of therapy. Long-term efficacy has been shown only for cyclophosphamide-based regimens, which are associated with considerable adverse effects (A). Flares after remission are common and require diligent follow-up End-Stage Renal Disease Dialysis (B) and transplantation (B) in SLE have comparable rates for long-term patient and graft survivals as those observed in nondiabetic, nonSLE patients, with transplantation being the method of choice (C) APS, antiphospholipid antibody syndrome; CBC, complete blood count; MRI, magnetic resonance imaging; NSAIDs, nonsteroidal anti-inflammatory drugs; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus.

REFERENCES 1. Bertsias G, et al: EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 65(Suppl II):194, 2006. 2. Lawrence RC, Helmick CG, Arnett FC, et al: Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 41:778-799, 1998. 3. Uramoto KM, Michet CJ Jr, Thumboo J, et al: Trends in the incidence and mortality of systemic lupus erythematosus, 1950-1992. Arthritis Rheum 42:46-50, 1999. 4. Vilar MJ, Sato EI: Estimating the incidence of systemic lupus erythematosus in a tropical region (Natal, Brazil). Lupus 11:528-532, 2002. 5. Jimenez S, Cervera R, Font J, et al: The epidemiology of systemic lupus erythematosus. Clin Rev Allergy Immunol 25:3-12, 2003.

6. Bresnihan B: Outcome and survival in systemic lupus erythematosus. Ann Rheum Dis 48:443-445, 1989. 7. Rivest C, Lew RA, Welsing PM, et al: Association between clinical factors, socioeconomic status, and organ damage in recent onset systemic lupus erythematosus. J Rheumatol 27:680-684, 2000. 8. Alarcon GS, Friedman AW, Straaton KV, et al: Systemic lupus erythematosus in three ethnic groups, III: A comparison of characteristics early in the natural history of the LUMINA cohort. LUpus in MInority populations: NAture vs. Nurture. Lupus 8:197-209, 1999. 9. Alarcon GS, Roseman J, Bartolucci AA, et al: Systemic lupus erythematosus in three ethnic groups, II: Features predictive of disease activity early in its course. LUMINA Study Group. LUpus in MInority populations: NAture vs. Nurture. Arthritis Rheum 41:1173-1180, 1998.

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164. Stahl NI, Klippel JH, Decker JL: Fever in systemic lupus erythematosus. Am J Med 67:935-940, 1979. 165. Papadaki HA, Xylouri I, Katrinakis G, et al: Non-Hodgkin’s lymphoma in patients with systemic lupus erythematosus. Leuk Lymphoma 44:275-279, 2003. 166. Tsakonas E, Joseph L, Esdaile JM, et al: A long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group. Lupus 7:80-85, 1998. 167. A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group. N Engl J Med 324:150-154, 1991. 168. Ginzler EM, Dooley MA, Aranow C, et al: Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 353:2219-2228, 2005. 169. Contreras G, Pardo V, Leclercq B, et al: Sequential therapies for proliferative lupus nephritis. N Engl J Med 350:971-980, 2004. 170. Chan TM, Tse KC, Tang CS, et al: Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol 16: 1076-1084, 2005. 171. Chan TM, Li FK, Tang CS, et al: Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong KongGuangzhou Nephrology Study Group. N Engl J Med 343:1156-1162, 2000. 172. Austin HA 3rd, Klippel JH, Balow JE, et al: Therapy of lupus nephritis: Controlled trial of prednisone and cytotoxic drugs. N Engl J Med 314:614-619, 1986. 173. Boumpas DT, Austin HA 3rd, Vaughn EM, et al: Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 340:741-745, 1992. 174. Illei GG, Austin HA, Crane M, et al: Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis. Ann Intern Med 135:248-257, 2001. 175. Gourley MF, Austin HA 3rd, Scott D, et al: Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis: A randomized, controlled trial. Ann Intern Med 125: 549-557, 1996. 176. Boumpas DT, Austin HA 3rd, Vaughan EM, et al: Risk for sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy. Ann Intern Med 119:366-369, 1993. 177. Houssiau FA, Vasconcelos C, D’Cruz D, et al: Immunosuppressive therapy in lupus nephritis: The Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis Rheum 46:2121-2131, 2002. 178. Houssiau FA, Vasconcelos C, D’Cruz D, et al: Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: Lessons from long-term followup of patients in the EuroLupus Nephritis Trial. Arthritis Rheum 50:3934-3940, 2004. 179. Barile-Fabris L, Ariza-Andraca R, Olguin-Ortega L, et al: Controlled clinical trial of IV cyclophosphamide versus IV methylprednisolone in severe neurological manifestations in systemic lupus erythematosus. Ann Rheum Dis 64:620-625, 2005. 180. Somers EC, Marder W, Christman GM, et al: Use of a gonadotropin-releasing hormone analog for protection against premature ovarian failure during cyclophosphamide therapy in women with severe lupus. Arthritis Rheum 52:2761-2767, 2005. 181. Masala A, Faedda R, Alagna S, et al: Use of testosterone to prevent cyclophosphamide-induced azoospermia. Ann Intern Med 126: 292-295, 1997. 182. Ahmed AR, Spigelman Z, Cavacini LA, et al: Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med 355:1772-1779, 2006. 183. Smith KG, Jones RB, Burns SM, et al: Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: Remission, relapse, and re-treatment. Arthritis Rheum 54:2970-2982, 2006. 184. Esdaile JM, Joseph L, MacKenzie T, et al: The benefit of early treatment with immunosuppressive agents in lupus nephritis. J Rheumatol 21:2046-2051, 1994. 185. Carneiro JR, Sato EI: Double blind, randomized, placebo controlled clinical trial of methotrexate in systemic lupus erythematosus. J Rheumatol 26:1275-1279, 1999.

186. Boletis JN, Ioannidis JP, Boki KA, et al: Intravenous immunoglobulin compared with cyclophosphamide for proliferative lupus nephritis. Lancet 354:569-570, 1999. 187. Bernatsky S, Boivin JF, Joseph L, et al: An international cohort study of cancer in systemic lupus erythematosus. Arthritis Rheum 52: 1481-1490, 2005. 188. Ognenovski VM, Marder W, Somers EC, et al: Increased incidence of cervical intraepithelial neoplasia in women with systemic lupus erythematosus treated with intravenous cyclophosphamide. J Rheumatol 31:1763-1767, 2004. 189. Bernatsky S, Ramsey-Goldman R, Gordon C, et al: Factors associated with abnormal Pap results in systemic lupus erythematosus. Rheumatology (Oxf) 43:1386-1389, 2004. 190. Bernatsky SR, Cooper GS, Mill C, et al: Cancer screening in patients with systemic lupus erythematosus. J Rheumatol 33:45-49, 2006. 191. Sanchez-Guerrero J, Uribe AG, Jimenez-Santana L, et al: A trial of contraceptive methods in women with systemic lupus erythematosus. N Engl J Med 353:2539-2549, 2005. 192. Petri M, Kim MY, Kalunian KC, et al: Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J Med 353:2550-2558, 2005. 193. Mintz G, Niz J, Gutierrez G, et al: Prospective study of pregnancy in systemic lupus erythematosus: Results of a multidisciplinary approach. J Rheumatol 13:732-739, 1986. 194. Derksen RH, Bouma BN, Kater L: The prevalence and clinical associations of the lupus anticoagulant in systemic lupus erythematosus. Scand J Rheumatol 16:185-192, 1987. 195. Ishii Y, Nagasawa K, Mayumi T, et al: Clinical importance of persistence of anticardiolipin antibodies in systemic lupus erythematosus. Ann Rheum Dis 49:387-390, 1990. 196. Cortes-Hernandez J, Ordi-Ros J, Paredes F, et al: Clinical predictors of fetal and maternal outcome in systemic lupus erythematosus: A prospective study of 103 pregnancies. Rheumatology (Oxf) 41: 643-650, 2002. 197. Kiss E, Bhattoa HP, Bettembuk P, et al: Pregnancy in women with systemic lupus erythematosus. Eur J Obstet Gynecol Reprod Biol 101:129-134, 2002. 198. Lima F, Buchanan NM, Khamashta MA, et al: Obstetric outcome in systemic lupus erythematosus. Semin Arthritis Rheum 25:184-192, 1995. 199. Lynch A, Marlar R, Murphy J, et al: Antiphospholipid antibodies in predicting adverse pregnancy outcome: A prospective study. Ann Intern Med 120:470-475, 1994. 200. Silva CA, Leal MM, Leone C, et al: Gonadal function in adolescents and young women with juvenile systemic lupus erythematosus. Lupus 11:419-425, 2002. 201. Geva E, Lerner-Geva L, Burke M, et al: Undiagnosed systemic lupus erythematosus in a cohort of infertile women. Am J Reprod Immunol 51:336-340, 2004. 202. Balasch J, Creus M, Fabregues F, et al: Antiphospholipid antibodies and human reproductive failure. Hum Reprod 11:2310-2315, 1996. 203. Sinaii N, Cleary SD, Ballweg ML, et al: High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: A survey analysis. Hum Reprod 17:2715-2724, 2002. 204. Hayslett JP: The effect of systemic lupus erythematosus on pregnancy and pregnancy outcome. Am J Reprod Immunol 28:199-204, 1992. 205. Tandon A, Ibanez D, Gladman DD, et al: The effect of pregnancy on lupus nephritis. Arthritis Rheum 50:3941-3946, 2004. 206. Carmona F, Font J, Cervera R, et al: Obstetrical outcome of pregnancy in patients with systemic lupus erythematosus: A study of 60 cases. Eur J Obstet Gynecol Reprod Biol 83:137-142, 1999. 207. Ruiz-Irastorza G, Lima F, Alves J, et al: Increased rate of lupus flare during pregnancy and the puerperium: A prospective study of 78 pregnancies. Br J Rheumatol 35:133-138, 1996. 208. Petri M, Howard D, Repke J: Frequency of lupus flare in pregnancy. The Hopkins Lupus Pregnancy Center experience. Arthritis Rheum 34:1538-1545, 1991. 209. Petri M, Genovese M, Engle E, et al: Definition, incidence, and clinical description of flare in systemic lupus erythematosus: A prospective cohort study. Arthritis Rheum 34:937-944, 1991. 210. Nossent HC, Swaak TJ: Systemic lupus erythematosus, VI: Analysis of the interrelationship with pregnancy. J Rheumatol 17:771-776, 1990. 211. Georgiou PE, Politi EN, Katsimbri PV, et al: Outcome of lupus pregnancy: A controlled study. Rheumatology (Oxf) 39:1014-1019, 2000.

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212. Lockshin MD: Pregnancy does not cause systemic lupus erythematosus to worsen. Arthritis Rheum 32:665-670, 1989. 213. Le Thi Huong D, Wechsler B, Piette JC, et al: Pregnancy and its outcome in systemic lupus erythematosus. QJM 87:721-729, 1994. 214. Soubassi L, Haidopoulos D, Sindos M, et al: Pregnancy outcome in women with pre-existing lupus nephritis. J Obstet Gynaecol 24: 630-634, 2004. 215. Huong DL, Wechsler B, Vauthier-Brouzes D, et al: Pregnancy in past or present lupus nephritis: A study of 32 pregnancies from a single centre. Ann Rheum Dis 60:599-604, 2001. 216. Julkunen H, Kaaja R, Palosuo T, et al: Pregnancy in lupus nephropathy. Acta Obstet Gynecol Scand 72:258-263, 1993. 217. Faden D, Tincani A, Tanzi P, et al: Anti-beta 2 glycoprotein I antibodies in a general obstetric population: Preliminary results on the prevalence and correlation with pregnancy outcome: Anti-beta2 glycoprotein I antibodies are associated with some obstetrical complications, mainly preeclampsia-eclampsia. Eur J Obstet Gynecol Reprod Biol 73:37-42, 1997. 218. Branch DW, Andres R, Digre KB, et al: The association of antiphospholipid antibodies with severe preeclampsia. Obstet Gynecol 73:541-545, 1989. 219. Mok MY, Chan EY, Fong DY, et al: Antiphospholipid antibody profiles and their clinical associations in Chinese patients with systemic lupus erythematosus. J Rheumatol 32:622-628, 2005. 220. Moroni G, Quaglini S, Banfi G, et al: Pregnancy in lupus nephritis. Am J Kidney Dis 40:713-720, 2002. 221. Moroni G, Ponticelli C: The risk of pregnancy in patients with lupus nephritis. J Nephrol 16:161-167, 2003. 222. Watson RM, Braunstein BL, Watson AJ, et al: Fetal wastage in women with anti-Ro(SSA) antibody. J Rheumatol 13:90-94, 1986. 223. Julkunen H, Jouhikainen T, Kaaja R, et al: Fetal outcome in lupus pregnancy: A retrospective case-control study of 242 pregnancies in 112 patients. Lupus 2:125-131, 1993. 224. Lockwood CJ, Romero R, Feinberg RF, Clyne LP, et al: The prevalence and biologic significance of lupus anticoagulant and anticardiolipin antibodies in a general obstetric population. Am J Obstet Gynecol 161:369-373, 1989. 225. Polzin WJ, Kopelman JN, Robinson RD, et al: The association of antiphospholipid antibodies with pregnancies complicated by fetal growth restriction. Obstet Gynecol 78:1108-1111, 1991. 226. Rubbert A, Pirner K, Wildt L, et al: Pregnancy course and complications in patients with systemic lupus erythematosus. Am J Reprod Immunol 28:205-207, 1992. 227. Petri M, Ho AC, Patel J, et al: Elevation of maternal alpha-­fetoprotein in systemic lupus erythematosus: A controlled study. J Rheumatol 22:1365-1368, 1995. 228. Clark F, Dickinson JE, Walters BN, et al: Elevated mid-trimester hCG and maternal lupus anticoagulant. Prenat Diagn 15:1035-1039, 1995. 229. Buyon JP, Hiebert R, Copel J, et al: Autoimmune-associated congenital heart block: Demographics, mortality, morbidity and recurrence rates obtained from a national neonatal lupus registry. J Am Coll Cardiol 31:1658-1666, 1998. 230. Lockshin MD, Bonfa E, Elkon K, et al: Neonatal lupus risk to newborns of mothers with systemic lupus erythematosus. Arthritis Rheum 31:697-701, 1988. 231. Clowse ME, Magder LS, Witter F, et al: The impact of increased lupus activity on obstetric outcomes. Arthritis Rheum 52:514-521, 2005. 232. Buchanan NM, Khamashta MA, Morton KE, et al: A study of 100 high risk lupus pregnancies. Am J Reprod Immunol 28:192-194, 1992. 233. Tincani A, Faden D, Tarantini M, et al: Systemic lupus erythematosus and pregnancy: A prospective study. Clin Exp Rheumatol 10: 439-446, 1992. 234. Levy RA, Vilela VS, Cataldo MJ, et al: Hydroxychloroquine (HCQ) in lupus pregnancy: Double-blind and placebo-controlled study. Lupus 10:401-404, 2001. 235. Costedoat-Chalumeau N, Amoura Z, Duhaut P, et al: Safety of hydroxychloroquine in pregnant patients with connective tissue diseases: A study of one hundred thirty-three cases compared with a control group. Arthritis Rheum 48:3207-3211, 2003. 236. Buchanan NM, Toubi E, Khamashta MA, et al: Hydroxychloroquine and lupus pregnancy: Review of a series of 36 cases. Ann Rheum Dis 55:486-488, 1996.

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237. Parke A, West B: Hydroxychloroquine in pregnant patients with systemic lupus erythematosus. J Rheumatol 23:1715-1718, 1996. 238. Al-Herz A, Schulzer M, Esdaile JM: Survey of antimalarial use in lupus pregnancy and lactation. J Rheumatol 29:700-706, 2002. 239. Armenti VT, Radomski JS, Moritz MJ, et al: Report from the National Transplantation Pregnancy Registry (NTPR): Outcomes of pregnancy after transplantation. Clin Transpl 121-130, 2002. 240. Ramsey-Goldman R, Schilling E: Immunosuppressive drug use during pregnancy. Rheum Dis Clin N Am 23:149-167, 1997. 241. Ramsey-Goldman R, Mientus JM, Kutzer JE, et al: Pregnancy outcome in women with systemic lupus erythematosus treated with immunosuppressive drugs. J Rheumatol 20:1152-1157, 1993. 242. Doria A, Di Lenardo L, Vario S, et al: Cyclosporin A in a pregnant patient affected with systemic lupus erythematosus. Rheumatol Int 12:77-78, 1992. 243. Hussein MM, Mooij JM, Roujouleh H: Cyclosporine in the treatment of lupus nephritis including two patients treated during pregnancy. Clin Nephrol 40:160-163, 1993. 244. Ruiz-Irastorza G, Khamashta MA, Hunt BJ, et al: Bleeding and recurrent thrombosis in definite antiphospholipid syndrome: Analysis of a series of 66 patients treated with oral anticoagulation to a target international normalized ratio of 3.5. Arch Intern Med 162: 1164-1169, 2002. 245. Rosove MH, Brewer PM: Antiphospholipid thrombosis: Clinical course after the first thrombotic event in 70 patients. Ann Intern Med 117:303-308, 1992. 246. Rivier G, Herranz MT, Khamashta MA, et al: Thrombosis and antiphospholipid syndrome: A preliminary assessment of three antithrombotic treatments. Lupus 3:85-90, 1994. 247. Munoz-Rodriguez FJ, Font J, Cervera R, et al: Clinical study and follow-up of 100 patients with the antiphospholipid syndrome. Semin Arthritis Rheum 29:182-190, 1999. 248. Khamashta MA, Cuadrado MJ, Mujic F, et al: The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 332:993-997, 1995. 249. Finazzi G, Marchioli R, Brancaccio V, et al: A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost 3:848-853, 2005. 250. Crowther MA, Ginsberg JS, Julian J, et al: A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 349:1133-1138, 2003. 251. Empson M, Lassere M, Craig J, et al: Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev CD002859, 2005. 252. Triolo G, Ferrante A, Ciccia F, et al: Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies. Arthritis Rheum 48:728-731, 2003. 253. Farquharson RG, Quenby S, Greaves M: Antiphospholipid syndrome in pregnancy: A randomized, controlled trial of treatment. Obstet Gynecol 100:408-413, 2002. 254. Rai R, Cohen H, Dave M, et al: Randomised controlled trial of ­aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 314:253-257, 1997. 255. Franklin RD, Kutteh WH: Antiphospholipid antibodies (APA) and recurrent pregnancy loss: Treating a unique APA positive population. Hum Reprod 17:2981-2985, 2002. 256. Balasch J, Carmona F, Lopez-Soto A, et al: Low-dose aspirin for prevention of pregnancy losses in women with primary antiphospholipid syndrome. Hum Reprod 8:2234-2239, 1993. 257. Pauzner R, Dulitzki M, Langevitz P, et al: Low molecular weight heparin and warfarin in the treatment of patients with antiphospholipid syndrome during pregnancy. Thromb Haemost 86:1379-1384, 2001. 258. Many A, Pauzner R, Carp H, et al: Treatment of patients with antiphospholipid antibodies during pregnancy. Am J Reprod Immunol 28:216-218, 1992. 259. Carmona F, Font J, Azulay M, et al: Risk factors associated with fetal losses in treated antiphospholipid syndrome pregnancies: A multivariate analysis. Am J Reprod Immunol 46:274-279, 2001.

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260. Olsen NJ: Drug-induced autoimmunity. Best Pract Res Clin Rheumatol 18:677-688, 2004. 261. Reidenberg MM, Drayer DE, Lorenzo B, et al: Acetylation phenotypes and environmental chemical exposure of people with ­idiopathic systemic lupus erythematosus. Arthritis Rheum 36:971-973, 1993. 262. Kretz-Rommel A, Rubin RL: Disruption of positive selection of thymocytes causes autoimmunity. Nat Med 6:298-305, 2000. 263. Stone JH: End-stage renal disease in lupus: Disease activity, dialysis, and the outcome of transplantation. Lupus 7:654-659, 1998. 264. Ward MM: Cardiovascular and cerebrovascular morbidity and mortality among women with end-stage renal disease attributable to lupus nephritis. Am J Kidney Dis 36:516-525, 2000. 265. Ward MM: Changes in the incidence of end-stage renal disease due to lupus nephritis, 1982-1995. Arch Intern Med 160:3136-3140, 2000. 266. Mange KC, Joffe MM, Feldman HI: Effect of the use or nonuse of long-term dialysis on the subsequent survival of renal transplants from living donors. N Engl J Med 344:726-731, 2001. 267. Moroni G, Tantardini F, Gallelli B, et al: The long-term prognosis of renal transplantation in patients with lupus nephritis. Am J Kidney Dis 45:903-911, 2005. 268. Ward MM: Outcomes of renal transplantation among patients with end-stage renal disease caused by lupus nephritis. Kidney Int 57: 2136-2143, 2000. 269. Vaidya S, Sellers R, Kimball P, et al: Frequency, potential risk and therapeutic intervention in end-stage renal disease patients with antiphospholipid antibody syndrome: A multicenter study. Transplantation 69:1348-1352, 2000. 270. Bartosh SM, Fine RN, Sullivan EK: Outcome after transplantation of young patients with systemic lupus erythematosus: A report of the North American pediatric renal transplant cooperative study. Transplantation 72:973-978, 2001. 271. Murin S, Wiedemann HP, Matthay RA: Pulmonary manifestations of systemic lupus erythematosus. Clin Chest Med 19:641-665, viii, 1998. 272. Matthay RA, Schwarz MI, Petty TL, et al: Pulmonary manifestations of systemic lupus erythematosus: Review of twelve cases of acute lupus pneumonitis. Medicine (Balt) 54:397-409, 1975. 273. Carette S, Macher AM, Nussbaum A, et al: Severe, acute pulmonary disease in patients with systemic lupus erythematosus: Ten years of experience at the National Institutes of Health. Semin Arthritis Rheum 14:52-59, 1984. 274. Santos-Ocampo AS, Mandell BF, Fessler BJ: Alveolar hemorrhage in systemic lupus erythematosus: Presentation and management. Chest 118:1083-1090, 2000. 275. Liu MF, Lee JH, Weng TH, et al: Clinical experience of 13 cases with severe pulmonary hemorrhage in systemic lupus erythematosus with active nephritis. Scand J Rheumatol 27:291-295, 1998. 276. Lee JG, Joo KW, Chung WK, et al: Diffuse alveolar hemorrhage in lupus nephritis. Clin Nephrol 55:282-288, 2001. 277. Mintz G, Galindo LF, Fernandez-Diez J, et al: Acute massive pulmonary hemorrhage in systemic lupus erythematosus. J Rheumatol 5:39-50, 1978.

278. Eagen JW, Memoli VA, Roberts JL, et al: Pulmonary hemorrhage in systemic lupus erythematosus. Medicine (Balt) 57:545-560, 1978. 279. Marino CT, Pertschuk LP: Pulmonary hemorrhage in systemic lupus erythematosus. Arch Intern Med 141:201-203, 1981. 280. Bruce IN, Gladman DD, Urowitz MB: Premature atherosclerosis in systemic lupus erythematosus. Rheum Dis Clin N Am 26:257-278, 2000. 281. Karrar A, Sequeira W, Block JA: Coronary artery disease in systemic lupus erythematosus: A review of the literature. Semin Arthritis Rheum 30:436-443, 2001. 282. Kitagawa Y, Gotoh F, Koto A, et al: Stroke in systemic lupus erythematosus. Stroke 21:1533-1539, 1990. 283. Boumpas DT, Patronas NJ, Dalakas MC, et al: Acute transverse myelitis in systemic lupus erythematosus: Magnetic resonance imaging and review of the literature. J Rheumatol 17:89-92, 1990. 284. Kojima E, Naito K, Iwai M, et al: Antiphospholipid syndrome complicated by thrombosis of the superior mesenteric artery, co-existence of smooth muscle hyperplasia. Intern Med 36:528-531, 1997. 285. McCollum CN, Sloan ME, Davison AM, et al: Ruptured hepatic aneurysm in systemic lupus erythematosus. Ann Rheum Dis 38: 396-398, 1979. 286. Medina F, Ayala A, Jara LJ, et al: Acute abdomen in systemic lupus erythematosus: The importance of early laparotomy. Am J Med 103:100-105, 1997. 287. Guidelines for referral and management of systemic lupus erythematosus in adults. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Arthritis Rheum 42:1785-1796, 1999. 288. Urowitz MB, Bookman AA, Koehler BE, et al: The bimodal mortality pattern of systemic lupus erythematosus. Am J Med 60:221-225, 1976. 289. Tozman EC, Urowitz MB, Gladman DD: Prolonged complete remission in previously severe SLE. Ann Rheum Dis 41:39-40, 1982. 290. Urowitz MB, Feletar M, Bruce IN, et al: Prolonged remission in systemic lupus erythematosus. J Rheumatol 32:1467-1472, 2005. 291. Kasitanon N, Magder LS, Petri M: Predictors of survival in systemic lupus erythematosus. Medicine (Balt) 85:147-156, 2006. 292. Mok CC, Lee KW, Ho CT, et al: A prospective study of survival and prognostic indicators of systemic lupus erythematosus in a southern Chinese population. Rheumatology (Oxf) 39:399-406, 2000. 293. Illei GG, Takada K, Parkin D, et al: Renal flares are common in patients with severe proliferative lupus nephritis treated with pulse immunosuppressive therapy: Long-term followup of a cohort of 145 patients participating in randomized controlled studies. Arthritis Rheum 46:995-1002, 2002. 294. Petri M, Genovese M: Incidence of and risk factors for hospitalizations in systemic lupus erythematosus: A prospective study of the Hopkins Lupus Cohort. J Rheumatol 19:1559-1565, 1992.

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Antiphospholipid Syndrome Doruk Erkan  •  Jane E. Salmon  •  Michael D. Lockshin

KEY POINTS Antiphospholipid antibodies (aPLs) are a family of autoantibodies directed against phospholipid-binding plasma proteins, most commonly ß2-glycoprotein I. The origin of aPLs is unknown but is hypothesized to be an incidental exposure to infectious agents that induce autoantibodies in susceptible individuals. The clinical manifestations of aPLs range from asymptomatic to catastrophic antiphospholipid syndrome (APS); thus, patients should not be evaluated and managed as if they had a single disease. Stroke is the most common presentation of arterial thrombosis; deep vein thrombosis is the most common venous manifestation of APS. Pregnancy losses in patients with aPLs typically occur after 10 weeks’ gestation (fetal loss), but earlier losses also occur. Catastrophic APS is a rare, abrupt, life-threatening complication that consists of multiple thromboses of medium and small arteries occurring over days. The diagnosis of APS should be made in the presence of characteristic clinical manifestations and persistently positive aPLs (measured at least 12 weeks apart). The prevention of secondary thrombosis in persistently aPL-positive individuals lacks a risk-stratified approach; the effectiveness of high-intensity anticoagulation in APS patients with vascular events is not supported by prospective controlled studies. A common strategy to prevent fetal loss in aPL-positive patients with a history of pregnancy morbidities is low-dose aspirin and heparin; if patients fail this regimen, the next step is to add intravenous immunoglobulin (IVIG), although this approach is not supported by controlled studies. Prevention of primary thrombosis in persistently aPL-positive individuals lacks an evidence-based approach; elimination of reversible thrombosis risk factors and prophylaxis during high-risk periods (e.g., surgical procedures) are crucial. Currently, there is no evidence that anticoagulation is effective for nonthrombotic manifestations of aPLs, such as livedo reticularis, thrombocytopenia, hemolytic anemia, or heart valve disease. Catastrophic APS patients usually receive a combination of anticoagulation, corticosteroids, IVIG, and plasma exchange.

DEFINITION Diagnosis of the antiphospholipid syndrome (APS) requires that a patient have both a clinical event (thrombosis or pregnancy morbidity) and the persistent presence of antiphospholipid antibody (aPL), documented by a solid-phase serum assay (anticardiolipin or anti–ß2-glycoprotein I [anti-ß2GPI] immunoglobulin [Ig] G or M), a coagulation assay (inhibitor of phospholipid-dependent clotting—the lupus anticoagulant test), or both. Preliminary (Sapporo) classification criteria for APS,1 revised in 2004,2 are listed in Table 76-1. Certain factors are not included as criteria but may be helpful in the diagnosis of individual patients. These include IgA anticardiolipin or anti-ß2GPI, valvular heart disease, thrombocytopenia, early preeclampsia, and livedo reticularis (Table 76-2). These factors are rare, nonstandardized, or nonspecific phenomena that are too unreliable for use in clinical studies but occur in a sufficient number of patients to support a suspected diagnosis. A false-positive test for syphilis does not fulfill the laboratory criterion. APS can occur as an isolated diagnosis, or it can be associated with systemic lupus erythematosus (SLE) or another rheumatic disease. Antiphospholipid antibodies, but probably not the syndrome, can be induced by drugs and infections.3

EPIDEMIOLOGY Low-titer, usually transient, anticardiolipin occurs in up to 10% of normal blood donors,4,5 and moderate- to high-titer anticardiolipin or a positive lupus anticoagulant test occurs in less than 1%. The prevalence of positive aPL tests increases with age. Ten percent to 40% of SLE patients5 and approximately 20% of rheumatoid arthritis patients6 have positive aPL tests. Based on a limited number of uncontrolled and non–riskstratified studies, asymptomatic (no history of vascular or pregnancy events) aPL-positive patients have a 0% to 4% annual risk of thrombosis; patients with other autoimmune diseases such as SLE are at the higher end of the range.7,8 The aPL profile (low versus high risk for thrombosis) and patients’ clinical characteristics (presence or absence of other acquired or genetic thrombosis risk factors) influence the individual risk of thrombosis.9 Ten percent of first-stroke victims have aPLs,10 especially those who are young (up to 29%),5,11 as do up to 20% of women who have suffered three or more consecutive fetal losses.12 Fourteen percent of patients with recurrent venous thromboembolic disease have aPLs.13

CAUSE The main antigen to which aPLs bind is not a phospholipid but rather a phospholipid-binding plasma protein—namely, ß2GPI (apolipoprotein H). ß2GPI is normally present at a   Supplemental images available on the Expert Consult Premium Edition website.

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Table 76-1 Revised Sapporo Classification Criteria for Antiphospholipid Syndrome

Table 76-2 Other Features Suggesting the Presence of Antiphospholipid Antibodies

Clinical Criteria

Clinical

1.  Vascular thrombosis* One or more clinical episodes† of arterial, venous, or small vessel thrombosis‡ in any tissue or organ. 2. Pregnancy morbidity   (a) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, or   (b) One or more premature births of a morphologically normal neonate before the 34th week of gestation because of eclampsia, severe preeclampsia, or recognized features of placental insufficiency§, or   (c) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded.

Livedo reticularis Thrombocytopenia (usually 50,000-100,000 platelets/mm3) Autoimmune hemolytic anemia Cardiac valve disease (vegetations or thickening) Multiple sclerosis–like syndrome, chorea, or other myelopathy

Laboratory Criteria� 1. Lupus anticoagulant present in plasma on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Hemostasis 2. Anticardiolipin antibody of immunoglobulin (Ig) G or IgM isotype in serum or plasma, present in medium or high titer (>40 GPL or MPL, or >99th percentile), on two or more occasions at least 12 weeks apart, measured by a standardized enzyme-linked immunosorbent assay (ELISA). 3. Anti–ß2-glycoprotein I antibody of IgG or IgM isotype in serum or plasma (in titer >99th percentile) present on two or more occasions at least 12 weeks apart, measured by a standardized ELISA. Definite antiphospholipid syndrome (APS) is present if at least one of the clinical criteria and one of the laboratory criteria are met. Classification of APS should be avoided if less than 12 weeks or more than 5 years separate the positive antiphospholipid antibody test and the clinical manifestation. In studies of populations of patients who have more than one type of pregnancy morbidity, investigators are strongly encouraged to stratify groups of subjects according to a, b, or c above. *Coexisting inherited or acquired factors for thrombosis are not reasons to exclude patients from APS trials. However, two subgroups of APS patients should be recognized, based on the presence and absence of additional risk factors for thrombosis. Indicative (but not exhaustive) cases include age (>55 yr in men and >65 yr in women) and the presence of any of the established risk factors for cardiovascular disease (hypertension, diabetes mellitus, elevated low-density lipoprotein or low high-density lipoprotein cholesterol, cigarette smoking, family history of premature cardiovascular disease, body mass index >30 kg/m2, microalbuminuria, estimated glomerular filtration rate <60 mL/min), inherited thrombophilias, oral contraceptive use, nephritic syndrome, malignancy, immobilization, and surgery. Thus, patients who fulfill criteria should be stratified according to contributing causes of thrombosis. †A thrombotic episode in the past can be considered a clinical criterion, provided that thrombosis is proved by appropriate diagnostic means and that no alternative diagnosis or cause of thrombosis is found. ‡ Superficial venous thrombosis is not included in the clinical criteria. §Generally accepted features of placental insufficiency include an abnormal or nonreassuring fetal surveillance test (e.g., nonreactive nonstress test) suggestive of fetal hypoxemia, an abnormal Doppler flow velocimetry waveform analysis suggestive of fetal hypoxemia (e.g., absent end-diastolic flow in the umbilical artery), oligohydramnios (e.g., amniotic fluid index ≤5 cm), or a postnatal birth weight less than the 10th percentile for gestational age. �Investigators are strongly advised to classify APS patients participating in studies into one of the following categories: I, more than one laboratory criteria present (any combination); IIa, only lupus anticoagulant present; IIb, only anticardiolipin antibody present; IIc, only anti-β2-glycoprotein I antibody present. From Miyakis S, Lockshin MD, Atsumi T, et al: International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome. J Thromb Haemost 4:295-306, 2006.

Laboratory Immunoglobulin A anticardiolipin antibody Immunoglobulin A anti–ß2-glycoprotein I

concentration of 200 mg/mL, is a member of the complement control protein family, and has five repeating domains and several alleles. An octapeptide in the fifth domain and critical cysteine bonds are necessary for both phospholipid binding and antigenicity14; a first-domain site activates platelets.15,16 In vivo, ß2GPI binds to phosphatidylserine on activated or apoptotic cell membranes, including those of trophoblasts, platelets, and endothelial cells. Under physiologic conditions, ß2GPI may function in the elimination of apoptotic cells17 and as a natural anticoagulant.18 Other, less relevant antigens targeted by aPLs are prothrombin, annexin V, protein C, protein S, high- and lowmolecular-weight kininogens, tissue plasminogen activator, factor VII, factor XI, factor XII, complement component C4, and complement factor H.19 In experimental animal models, passive or active immunization with viral peptides,20 bacterial peptides,21 and heterologous ß2GPI22 induces polyclonal aPLs and clinical events associated with APS. These data suggest that pathologic autoimmune aPL is induced in susceptible humans by infections via molecular mimicry. However, infection-induced aPLs (syphilitic and nonsyphilitic Treponema, Borrelia burgdorferi, human immunodeficiency virus, Leptospira, or parasites) are usually ß2GPI independent and bind phospholipids directly.23 Drugs (chlorpromazine, procainamide, quinidine, and phenytoin) and malignancies (lymphoproliferative disorders) can also induce ß2GPI-independent aPLs. Conversely, autoimmune aPLs bind ß2GPI or other phospholipid-binding plasma proteins, which in turn bind negatively charged phospholipids such as cardiolipin (ß2GPI-dependent aPLs). Low levels of aPLs may be present normally; one of the functions of normal aPLs may be to participate in the physiologic removal of oxidized lipids.

PATHOGENESIS Antiphospholipid antibody is most likely related to thrombosis through multiple mechanisms; a proposed pathogenesis is illustrated in Figure 76-1. The process begins with activation or apoptosis of platelets, endothelial cells, or trophoblasts, during which phosphatidylserine (a negatively charged phospholipid) migrates from the inner to the normally electrically neutral outer cell membrane. Circulating ß2GPI binds to phosphatidylserine, and then aPL binds to a ß2GPI dimer.24 Antiphospholipid antibody–ß2GPI dimer binding activates the complement cascade extracellularly; initiates an

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C5aR C5a C5aR Platelet Monocyte aPL

C5aR

PMN β2-GPI surface receptor?

β2-GPI

TNF-α Adhesion molecules

Outer layer

TF

PS PC Inner layer

IGFBP-1 PRL STAT-5

p38MAPK NFκB

Inflammation Tissue damage Fetal death Thrombus

Cell activation Nucleus

Figure 76-1  Proposed mechanism of antiphospholipid antibody (aPL)–related thrombosis and placental injury. The negatively charged phospholipid phosphatidylserine (PS, yellow circles) migrates from the inner to the outer cell membrane during activation or apoptosis of platelets and endothelial cells, and it is normally present on trophoblasts. The neutral phospholipid phosphatidylcholine (PC, red circles) is the major constituent of the outer layer of unactivated cells. Dimeric ß2-glycoprotein I (ß2GPI) then binds to PS (probably via ß2GPI surface receptors such as apoER2’, annexin A2, or a Toll-like receptor), and aPL binds to ß2GPI, activating the classic complement pathway and leading to the generation of C5a, which induces (a) expression of adhesion molecules (e.g., intracellular adhesion molecule [ICAM]-1) and tissue factor [TF]) and (b) activation of monocytes, polymorphonuclear (PMN) cells, and platelets, resulting in the release of proinflammatory mediators (e.g., tumor necrosis factor [TNF]-α, vascular endothelial growth factor receptor-1 [VEGFR1]) and the prothrombotic stage. Both nuclear factor кB (NFкB) and p38 mitogen-activated protein kinase (p38MAPK) may play a role in the intracellular signaling cascade. Antiphospholipid antibodies also downregulate the expression of trophoblast signal transducer and activator of transcription 5 (STAT-5), reducing the endometrial stromal cell production of prolactin (PRL) and insulin growth factor binding protein-1 (IGFBP-1).

intracellular signaling cascade, probably through the C5a and ß2GPI surface receptors; and recruits and activates inflammatory effector cells, including monocytes, neutrophils, and platelets, leading to the release of proinflammatory products (e.g., tumor necrosis factor [TNF]-α, oxidants, proteases) and the induction of a prothrombotic phenotype.25-27 The putative receptor of ß2GPI binding protein that transduces signals from the cell membrane to the nucleus is not yet identified and may vary among cells. The following candidates have been suggested: apoER2� (a member of the low-density lipoprotein receptor superfamily), annexin A2, and a Toll-like receptor.28,29 Both nuclear factor кB and p38 mitogen-activated protein kinase may play a role in the intracellular signaling cascade30,31 In addition, through downregulation of the signal transducer and activator of transcription 5 (Stat5), aPLs inhibit the production of placental prolactin and insulin growth factor binding protein-1,32 and they adversely affect the formation of a trophoblast syncytium, placental apoptosis, and trophoblast invasion—all processes that are required for the normal establishment of placental function.

Other possible contributory mechanisms of aPL-­mediated thrombosis include inhibition of coagulation cascade reactions catalyzed by phospholipids (e.g., activation of circulating procoagulant proteins or inhibition of protein C and S activation), induction of tissue factor (a physiologic initiator of coagulation) expression on monocytes, reduction of fibrinolysis, and interaction with the annexin V anticoagulant shield in the placenta.29 In experimental animal models, aPLs cause fetal resorption and increase the size and duration of trauma-induced venous and arterial thrombi.33,34 Inhibiting complement activation prevents experimental aPL-induced fetal death, and C5 knockout mice carry pregnancies normally despite aPL,35 implying that a complement-mediated effector mechanism is an absolute requirement for fetal death to occur. Complement activation is also required for experimental thrombosis.36 Because high-level aPLs may persist for years in asymptomatic persons, it is likely that vascular injury, endothelial cell activation, or both immediately precede the occurrence of thrombosis in those bearing the antibody (second-hit

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hypothesis). Of note, at least 50% of APS patients with vascular factors possess other acquired thrombosis risk factors at the time of their events.37,38 Both persons congenitally lacking ß2GPI39 and ß2GPI knockout mice appear normal.40 ß2GPI polymorphisms influence the generation of aPLs in individuals, but they have only a weak relationship to the occurrence of APS.41 A cluster of 50 upregulated genes may have an effect on the occurrence of thrombosis in aPL-positive individuals.42

CLINICAL FEATURES The clinical manifestations range from asymptomatic aPL positivity (no history of vascular or pregnancy events) to catastrophic APS (multiple thromboses occurring over days). Thus, patients should not be evaluated and managed as if they have a single disease. VASCULAR OCCLUSION APS affects all organ systems. Its principal manifestations are venous or arterial thromboses and pregnancy loss (see Table 76-1). Except for their severity, the youth of affected patients, and the unusual anatomic locations (Budd-Chiari syndrome; sagittal sinus and upper extremity thromboses), venous thromboses in APS do not differ clinically from thromboses attributable to other causes. Similarly, arterial thromboses differ from non–aPL-associated thromboses only by their recurrent nature, unusual locations, and occurrence in young patients. Deep vein thrombosis and stroke are the most common clinical manifestations of APS. Renal thrombotic microangiopathy, glomerular capillary endothelial cell injury, and thrombosis of renal vessels cause proteinuria without celluria or hypocomplementemia and may lead to severe hypertension, renal failure, or both.43 PREGNANCY MORBIDITY Pregnancy losses in patients with aPLs typically occur after 10 weeks’ gestation (fetal loss), although earlier losses also occur. However, these pre-embryonic or embryonic pregnancy losses (<10 weeks’ gestation) are more commonly due to chromosomal and other genetic defects. Pregnancy in those with APS is often normal until the second trimester, when fetal growth slows and amniotic fluid volume decreases. APS patients may develop severe, early preeclampsia or HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. Placental infarction is a cause of fetal growth restriction or death; nonthrombotic mechanisms of placental dysfunction also occur.44 Prior late pregnancy losses predict future losses, independent of the aPL profile. MISCELLANEOUS MANIFESTATIONS Many patients have livedo reticularis (Fig. 76-2), although this is not specific for APS. Cardiac valve disease (vegetations, thickening, or both), a late manifestation, may necessitate valve replacement. Its pathogenesis in APS is unknown. Recent studies suggest that APS does not add to the risk of atherosclerosis imparted by SLE.45 Pulmonary hypertension may develop due to recurrent pulmonary

Figure 76-2  Livedo reticularis in antiphospholipid syndrome.

embolism or small vessel thrombosis; rarely, aPL-positive patients may present with diffuse pulmonary hemorrhage. Some patients develop nonfocal neurologic symptoms such as lack of concentration, forgetfulness, and dizzy spells. Multiple small, hyperintense lesions seen on magnetic resonance imaging (MRI), primarily in the periventricular white matter, do not correlate well with clinical symptoms. Rarely, high-affinity antiprothrombin antibodies may cause hemorrhage by depleting prothrombin (lupus anticoagulant hypoprothrombinemia syndrome).46 CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME Catastrophic APS is a rare, abrupt, life-threatening complication. It consists of multiple thromboses of medium and small arteries occurring (despite apparently adequate anticoagulation) over a period of days and causing stroke; cardiac, hepatic, adrenal, renal, and intestinal infarction; and peripheral gangrene.4,47 In a review of 220 patients with catastrophic APS, the main clinical manifestations included renal involvement in 154 patients (70%), pulmonary in 146 (66%), cerebral in 133 (60%), cardiac in 115 (52%), and cutaneous in 104 (47%).48 Acute adrenal failure may be the initial clinical event. Proposed formal criteria for this syndrome are shown in Table 76-3.49 Patients often have moderate thrombocytopenia; erythrocytes are less fragmented than in the hemolytic uremic syndrome or thrombotic thrombocytopenic purpura, and fibrin split products are not strikingly elevated. Renal failure and pulmonary hemorrhage may occur. Tissue biopsies show noninflammatory vascular occlusion.

DIAGNOSIS AND DIAGNOSTIC TESTS LABORATORY STUDIES The diagnosis of APS requires a positive lupus anticoagulant test or a moderate- to high-titer anticardiolipin IgG or IgM test in patients with characteristic clinical manifestations. Patients with negative lupus anticoagulant and anticardiolipin tests should be tested for IgA anticardiolipin and IgG, IgM, or IgA anti-ß2GPI when there is a high suspicion for APS. Positive aPL results require a repeat test after 12 or more weeks to exclude a transient, clinically unimportant

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Table 76-3 Preliminary Criteria for the Classification of Catastrophic Antiphospholipid Syndrome (APS) 1. Evidence of involvement of three or more organs, systems, or tissues* 2. Development of manifestations simultaneously or in less than 1 wk 3. Confirmation by histopathology of small vessel occlusion in at least one organ or tissue† 4. Laboratory confirmation of the presence of antiphospholipid antibody (lupus anticoagulant or anticardiolipin or anti–β2glycoprotein I antibodies)‡ Definite Catastrophic APS All 4 criteria Probable Catastrophic APS Criteria 2 through 4 and two organs, systems, or tissues involved Criteria 1 through 3, except no confirmation 6 wk apart due to early death of patient not tested before catastrophic episode Criteria 1, 2, and 4 Criteria 1, 3, and 4 and development of a third event more than 1 wk but less than 1 mo after the first, despite anticoagulation *Usually, clinical evidence of vessel occlusions, confirmed by imaging techniques when appropriate. Renal involvement is defined by a 50% rise in serum creatinine, severe systemic hypertension, proteinuria, or some combination of these. †For histopathologic confirmation, significant evidence of thrombosis must be present, although vasculitis may coexist occasionally. ‡If the patient had not previously been diagnosed with APS, laboratory confirmation requires that the presence of antiphospholipid antibody be detected on two or more occasions at least 6 weeks apart (not necessarily at the time of the event), according to the proposed preliminary criteria for the classification of APS. From Asherson RA, Cervera R, de Groot PG, et al: Catastrophic antiphospholipid syndrome: International consensus statement on classification criteria and treatment guidelines. Lupus 12:530-534, 2003.

antibody. The diagnosis of APS should be questioned if less than 12 weeks or more than 5 years separate the positive aPL test from the clinical manifestation.2 The lupus anticoagulant test is a more specific but less sensitive predictor of thromboses than is anticardiolipin; it correlates better with aPL-related clinical events.50 Documentation of a lupus anticoagulant requires a fourstep process: (1) demonstration of a prolonged phospholipid-dependent coagulation screening test, such as activated partial thromboplastin time or dilute Russell viper venom time (however, low-level abnormalities are not clearly linked to APS); (2) failure to correct the prolonged screening test by mixing the patient’s plasma with normal platelet-poor plasma, demonstrating the presence of an inhibitor; (3) shortening or correction of the prolonged screening test by the addition of excess phospholipid, demonstrating phospholipid dependency; and (4) exclusion of other inhibitors.51 Approximately 80% of patients with lupus anticoagulant have anticardiolipin, and 20% of patients positive for anticardiolipin have lupus anticoagulant.52 The anticardiolipin enzyme-linked immunosorbent assay (ELISA) is sensitive but not specific for the diagnosis of APS.53 Although the widely available ELISA test for IgG and IgM anticardiolipin is standardized, considerable variability exists among commercial laboratories that perform the test, especially for the IgA isotype.54 Low-titer anticardiolipin or anti-ß2GPI, transient aPLs, and antibody to

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noncardiolipin phospholipids (phosphatidylserine, phosphatidylethanolamine) have no proven relationship to APS. The ELISA tests other than anticardiolipin and anti-ß2GPI are neither standardized nor widely accepted as predictors of clinical illness. Whether to test persons with venous occlusive disease or recurrent fetal loss simultaneously for protein C, protein S, and antithrombin III deficiency or for the factor V Leiden and prothrombin mutations is a matter of economics and clinical likelihood; such testing is advisable when feasible. It is useful to test persons with arterial occlusive disease for hyperhomocysteinemia. Antinuclear and anti-DNA antibodies occur in approximately 45% of patients clinically diagnosed as having primary APS without an accompanying illness55; these antibodies do not mandate the additional diagnosis of SLE if the patient has no clinical indicators of SLE. Thrombocytopenia in APS is usually modest (>50,000/mm3); proteinuria and renal insufficiency occur in patients with thrombotic microangiopathy. Pathologic examination demonstrates small artery and glomerular thrombi and recanalization (Fig. 76-3). Hypocomplementemia, erythrocyte casts, and pyuria are not characteristic of thrombotic microangiopathy and, when present, imply lupus glomerulonephritis. Erythrocyte sedimentation rate, hemoglobin, and leukocyte count are usually normal in patients with uncomplicated primary APS, except during acute thrombosis. Prothrombin fragment 1 + 2 and other markers of coagulation activation do not predict impending thrombosis. IMAGING STUDIES MRI shows vascular occlusion and infarction consistent with clinical symptoms, with no special characteristics (other than multiple, otherwise unexplained cerebral infarctions in a young person). Multiple small, hyperintense white-matter lesions are common and do not unequivocally imply brain infarction. Occlusions usually occur in vessels below the resolution limits of angiography; hence, angiography or magnetic resonance angiography is not indicated unless clinical findings suggest medium- or large-vessel disease. Echocardiography or cardiac MRI may show severe Libman-Sacks endocarditis and intracardiac thrombi.56 PATHOLOGY Skin, renal, and other tissues show noninflammatory occlusion of all caliber arteries and veins, acute and chronic endothelial injury and its sequelae, and recanalization in late lesions. Uteroplacental insufficiency was once thought to be due to thrombosis or spiral artery vasculopathy (atherosis, intimal thickening, fibrinoid necrosis, and absence of physiologic changes in the spiral arteries).57 Consistent with the importance of inflammation in murine models of APS, recent findings demonstrate inflammatory infiltrates, particularly macrophages, and suggest that inflammation contributes to placental injury in patients.58 The finding of necrotizing vasculitis suggests concomitant lupus or other connective tissue disease. There are no other diagnostic immunofluorescence or electron microscopic findings.

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A

B

C

D

Figure 76-3  Renal thrombotic microangiopathy in antiphospholipid syndrome (APS). A, Kidney biopsy from a 35-year-old woman with primary APS, microhematuria, and non-nephrotic proteinuria. The glomerulus contains microthrombi, occluding capillary lumina, and there is endothelial swelling. B, The same patient’s small renal artery contains organized thrombus, with recanalization and arteriosclerosis (periodic acid–Schiff, ×100). C, Autopsy specimen from a 45-year-old man with primary APS. Note the thrombus in various stages of organization, intact elastic lamina with focal reduplication, and medial thickening (elastic Verhoeff stain, ×100). D, The same patient’s medium-sized peripheral artery. Note the organized thrombus with recanalization, severe fibrointimal thickening, medial hypertrophy, and extreme stenosis of lumen (hematoxylin and eosin, ×75). (Courtesy of Dr. Surya V. Seshan.)

DIFFERENTIAL DIAGNOSIS Infection-induced anticardiolipin is usually transient and is more commonly IgM than IgG.59 Transient aPLs or lowtiter anticardiolipin is inconclusive for diagnosis. Research laboratories can distinguish autoimmune from infectioninduced aPLs by determining the antibody’s ß2GPI dependence. In a patient who has lupus or lupus-like disease, livedo reticularis, or long-standing thrombocytopenia and who has a persistently positive aPL test, it is usually unnecessary to exclude other diagnoses. Because the prevalence of aPL-positive ELISA tests increases with age, and because the differential diagnosis of vascular occlusion is broader than it is in young adults, particular care is necessary in diagnosing APS in patients older than 60 years. Sustained high-titer anticardiolipin IgG, livedo reticularis, thrombocytopenia, coexisting rheumatic disease, and absence of other causes support a diagnosis of APS. Five percent to 21% of women with recurrent pregnancy losses, and 0.5% to 2% of normal pregnant women, have aPLs. Heritable deficiency of protein C, protein S, and antithrombin III and the presence of the factor V Leiden (A506G), prothrombin (G20210A), and methylene tetrahydrofolate reductase (MTHFR, C677T) mutations are less

common causes of fetal loss.60 Attribution of pregnancy loss to APS is most certain when there is no coexisting plausible explanation, when the loss occurs after the demonstration of a fetal heartbeat (10 weeks), when a significant aPL profile is repeatedly positive before and after pregnancy, and when the placenta shows vasculopathy and infarction. A single pregnancy loss before 10 weeks’ gestation in a patient with a lowpositive anticardiolipin test is more likely to be attributable to fetal chromosomal abnormalities, infection, or maternal hormonal or anatomic abnormalities. Independent coagulopathies may further increase the thrombotic risk in patients with aPLs. These and other acquired thrombotic risk factors (hypertension, diabetes, nephrotic syndrome, venous insufficiency, immobility) are alternative causes of thromboembolic disease. Arterial occlusion occurs in patients with thrombotic thrombocytopenic purpura, infected or sterile emboli of cardiac or vascular origin, septicemia, hyperhomocysteinemia, myxoma, Takayasu’s arteritis, polyarteritis nodosa, and severe Ray­ naud’s disease. The relationship of Sneddon’s syndrome (stroke and livedo reticularis, with or without aPLs) to APS is uncertain. Catastrophic APS has few mimics. Among them are sepsis, disseminated intravascular coagulation, thrombotic

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thrombocytopenic purpura, hemolytic uremic syndrome, polyarteritis nodosa, and disseminated embolization from myxoma, atrial thrombus, or atherosclerotic plaque. Small vessel occlusions occurring in rapid succession suggest disseminated intravascular coagulation. Severe cerebral and renal disease suggests thrombotic thrombocytopenic purpura; renal failure and hemolysis suggest hemolytic uremic syndrome. Antiphospholipid antibodies are rarely present in patients with the alternative diagnoses. Acute adrenal insufficiency is characteristic of APS and WaterhouseFriderichsen syndrome.

TREATMENT THROMBOSIS Treatment recommendations are summarized in Table 76-4. Anticoagulation with heparin is the treatment for acute thrombosis in APS patients. Warfarin, occasionally in association with low-dose aspirin, is used for secondary thrombosis prophylaxis. Two randomized, controlled trials demonstrated that moderate warfarin (international normalized ratio [INR] 2 to 3) and high-intensity warfarin (INR 3 to 4) are equally protective against recurrence in APS patients after the first thrombosis.61,62 The intensity of anticoagulation for aPL-related arterial thrombosis is still a matter for debate, because in both studies, patients with arterial events constituted less than half the study population. Although APS patients with arterial thrombosis who are at high risk for recurrence may require high-intensity anticoagulation, in the absence of risk-stratified studies, high risk has no consensus definition and is currently based solely on clinical judgment. Aspirin is the standard of care after an ischemic stroke or transient ischemic attack to prevent a recurrence in aPLnegative patients. Although most aPL-positive patients with ischemic strokes receive warfarin, the Antiphospholipid Antibody in Stroke Study (APASS) concluded that for selected aPL-positive patients who do not have atrial fibrillation or high-grade stenosis, aspirin and warfarin (target INR 2.2) are equivalent in terms of both efficacy and major bleeding complications.63 The APASS results probably do not apply to conventionally defined APS, because the average age of study participants was much higher than that of the average APS population; in addition, the aPL determination was performed only once at study entry, and the titer cutoff for assigning a patient to the positive anticardiolipin group was very low. However, aspirin is an option for older aPL-positive patients who have a single low-titer anticardiolipin test and whose presentation is one stroke. Some patients require larger than expected doses of both heparin and warfarin to achieve therapeutic anticoagulation. Uncommonly, positive lupus anticoagulant tests cause the INR to be unreliable.64 Such patients may be treated with high-dose warfarin or unfractionated or lowmolecular-weight heparin, monitored by the measurement of anti–factor Xa activity or other appropriate assay. For well-anticoagulated patients who continue to have thromboses, aspirin (81 to 325 mg/day), hydroxychloroquine, a statin drug, intravenous immunoglobulin (IVIG), and plasmapheresis have theoretical bases for efficacy, and all have been used.65 Corticosteroids have no established role in the treatment of APS but are used for rheumatic

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Table 76-4 Treatment Recommendations for Persistently Antiphospholipid Antibody–Positive Individuals Clinical Circumstance

Recommendation

Asymptomatic

No treatment*

Venous thrombosis

Warfarin INR 2.5 indefinitely

Arterial thrombosis

Warfarin INR 2.5 indefinitely

Recurrent thrombosis

Warfarin INR 3 to 4 + low-dose aspirin

Pregnancy First pregnancy No treatment* Single pregnancy loss at No treatment* <10 wk ≥1 Fetal or ≥3 (pre) embryonic Prophylactic heparin† + low-dose loss, no thrombosis aspirin throughout pregnancy, discontinue 6-12 wk post partum Thrombosis regardless of Therapeutic heparin‡ or low-dose pregnancy history aspirin throughout pregnancy, warfarin post partum Valve nodules or deformity

No known effective treatment; full anticoagulation if emboli or intracardiac thrombi demonstrated

Thrombocytopenia >50,000/mm3 No treatment Thrombocytopenia <50,000/mm3 Prednisone, IVIG Catastrophic APS

Anticoagulation + corticosteroids + IVIG or plasmapheresis

*Aspirin (81 mg/day) may be given. †Enoxaparin 0.5 mg/kg subcutaneously once daily. ‡Enoxaparin 1 mg/kg subcutaneously twice daily or 1.5 mg/kg subcutaneously once daily. APS, antiphospholipid syndrome; INR, international normalized ratio; IVIG, intravenous immunoglobulin.

symptoms in patients with accompanying systemic autoimmune illness. However, high doses of corticosteroids are usually given empirically to patients with severe thrombocytopenia, hemolytic anemia, and catastrophic APS. No controlled studies in APS patients have been published for clopidogrel, pentoxifylline, aspirin-dipyridamole, argatroban, hirudin, and other new anticoagulant agents. Neither hirudin nor fondaparinux inactivates complement, and neither drug protects mice with experimental APS against pregnancy loss, so they may be ineffective in human disease. Clinical experience suggests that thrombolytic agents for acute thrombosis are unhelpful, because reocclusion occurs rapidly. Currently available data, although retrospective and not risk-stratified, indicate that lifelong anticoagulation of APS patients with vascular events is appropriate.66 However, the recent recognition that some patients have full remission of antibody and that most thrombotic events have recognizable triggers raises the possibility of discontinuing anticoagulation in highly selected patients when the triggers are eliminated. PREGNANCY MORBIDITY Heparin anticoagulation is indicated at the diagnosis of pregnancy in an aPL-positive woman who has had prior pregnancy losses attributable to APS. Because warfarin is teratogenic, only unfractionated or low-molecular-weight

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heparin is used for the treatment of affected pregnancies in the United States; in other countries, converting to warfarin after the first trimester may be considered acceptable.67 Most physicians with a special interest in this field now use low-molecular-weight heparin owing to the decreased risk of thrombocytopenia and osteoporosis. Patients with prior fetal losses later than 10 gestational weeks should be treated with prophylactic heparin (enoxaparin 30 to 40 mg subcutaneously once daily), together with low-dose aspirin; this regimen increases the fetal survival rate from 50% (untreated) to 80%.68,69 Women who have had prior thromboses must be fully anticoagulated (enoxaparin 1 mg/kg subcutaneously twice daily or 1.5 mg/kg subcutaneously once daily) throughout pregnancy, because the risk of new thrombosis markedly increases both during pregnancy and post partum. Even with treatment, prematurity and fetal growth restriction still occur. Clopidogrel and newer antithrombotic agents are not cleared for use in pregnancy, but together with IVIG and hydroxychloroquine, they may be considered in patients who are unable to use heparin or who fail heparin treatment. In aPL-positive women with prior thrombosis, warfarin is changed to heparin or low-molecular-weight heparin before conception, if possible, or at the first missed menstrual period. In aPL-positive women without prior thrombosis, heparin treatment begins after confirmation of pregnancy, continues until 48 hours before anticipated delivery (to allow epidural anesthesia), and resumes for 8 to 12 weeks post partum. Some physicians recommend the initiation of heparin before conception; no clinical trial supports this recommendation, however, and the risk of longer-duration heparin therapy is considerable. Patients in most published series received low-dose aspirin as well as heparin, but the benefit of adding aspirin is unknown. Because of the risk of postpartum thrombosis, it is prudent to continue anticoagulation for 8 to 12 weeks post partum and then discontinue it by tapering the doses. If desired, conversion from heparin to warfarin may be accomplished after the first or second postpartum week. Breastfeeding is permissible with both heparin and warfarin. No studies unequivocally justify the treatment of women with aPLs during a first pregnancy, women with only very early losses, or women whose aPL titers are low or transient. Nonetheless, it is common to offer such patients low-dose aspirin. ASYMPTOMATIC ANTIPHOSPHOLIPID ANTIBODY–POSITIVE INDIVIDUALS Persistence of aPLs for decades without clinical events is well documented. The probability that an asymptomatic person incidentally found to have aPLs will eventually develop the syndrome is likely low.7 Anticoagulation is not indicated for the prophylactic treatment of asymptomatic aPL-positive individuals. For those with moderate- to hightiter anticardiolipin and persistent aPLs, education about the meaning of abnormal tests is appropriate, as is a discussion of warning signs to report. Elimination of reversible thrombosis risk factors and prophylaxis during high-risk periods, such as surgical procedures, are crucial. Ongoing prospective clinical trials will determine whether asymptomatic persons with high-titer aPLs should be treated prophylactically.

Although drugs that induce lupus (hydralazine, pheny­ toin) may also induce aPLs, if no alternatives are available, they may be prescribed for patients with aPLs. Drugs that promote thrombosis (estrogen and estrogen-containing oral contraceptives) are not currently deemed safe, even for asymptomatic women serendipitously known to have hightiter antibodies. This advice does not translate to a recommendation to test all normal women before the prescription of such medications, but it does suggest that special attention and further evaluation be provided to those with family histories or clinical suggestions of rheumatic disease, livedo reticularis, biologic false-positive tests for syphilis, or borderline thrombocytopenia. There is no reliable information regarding the safety of progestin-only contraception, “morning after” contraception, or the use of raloxifene, bromocriptine, or leuprolide in APS patients. A small retrospective review of women undergoing artificial reproductive technology (in vitro fertilization) procedures demonstrated no thrombotic events.70 ANTIPHOSPHOLIPID ANTIBODY–POSITIVE INDIVIDUALS WITH AMBIGUOUS EVENTS Some patients with positive aPL tests have clinical events of ambiguous meaning (dizzy or confusional episodes, nonspecific visual disturbance, very early pregnancy loss). There is no consensus for the treatment of such persons. Because full anticoagulation carries high risk, many physicians prescribe lowdose (81 mg) aspirin, hydroxychloroquine, or both daily. No published data support or repudiate this recommendation. Based on the presumed pathogenesis, some physicians prescribe anticoagulation for patients with livedo reticularis, thrombocytopenia, leg ulcers, thrombotic microangiopathy, or valvulopathy. The efficacy of anticoagulation is unknown in these conditions. One small, descriptive, cross-sectional study provides evidence that B cell depletion with rituximab is well tolerated and can be effective for refractory thrombocytopenia and skin ulcers in aPL-positive patients.71 CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME The onset of catastrophic APS is usually sudden and immediately life threatening. Early diagnosis can be a challenge, but it is critical because, in contrast to other causes of multiple organ dysfunction syndrome, appropriate therapy includes anticoagulation and corticosteroids in combination with repeated plasma exchange, IVIG, and, in desperate situations, other modalities such as cyclophosphamide or rituximab. However, mortality remains as high as 48% despite all attempts at effective therapy.72 There are no systematic studies of the treatment of catastrophic APS owing to the rarity of the condition. ANTIPHOSPHOLIPID ANTIBODY–NEGATIVE INDIVIDUALS WITH A CLINICAL EVENT In patients clinically suspected of having APS but with normal anticardiolipin, lupus anticoagulant, and anti-ß2GPI tests, alternative causes of clotting must be sought. Even among patients with concomitant rheumatic disease, APS may not be the cause of recurrent thromboembolism or pregnancy loss. Patients with SLE develop emboli from

PART 11 

| SYSTEMIC LUPUS ERYTHEMATOSUS AND RELATED SYNDROMES

SLE-related cardiac valvular disease, vasculitis, or atheroma. Other patients have factor V Leiden or some other procoagulant mutation. Recurrent pregnancy losses may be caused by chromosomal abnormalities, uterine infection, diabetes, hypertension, or non-aPL coagulopathy. The concept of “seronegative” APS is not recognized.

PROGNOSIS Pulmonary hypertension, neurologic involvement, myocardial ischemia, nephropathy, gangrene of extremities, and catastrophic APS are associated with a worse prognosis. During long-term follow-up, serious morbidity and disability occur in an unpredictable proportion of primary APS patients who experience major vascular events and in those who have delays in diagnosis and treatment. Thus, the long-term functional outcome of primary APS patients is poor; at 10 years, one third of patients develop permanent organ damage, and one fifth are unable to perform everyday activities.73 In a retrospective study of obstetric APS patients without thrombosis, 35% developed aPL-related clinical events during 8 years of follow-up. The studied populations were highly selected referral populations that may have been biased toward severe disease, but follow-up studies of obstetric patients with autoantibodies show similar results.74 Long-term outcomes of children born of APS pregnancies are not known. In many patients with long-standing APS, the development of severe cardiac valvular disease necessitates valve replacement, and rare patients develop renal failure due to thrombotic microangiopathy. Immediate thrombosis may cause loss of a transplanted kidney or other organ; aPL positivity correlates with poor graft survival after renal transplantation in SLE patients.75 Serious perioperative complications may occur despite prophylaxis in aPL-positive patients, because they are at additional risk for thrombosis when undergoing surgical procedures. Thus, perioperative strategies should be clearly identified before any surgical procedure, pharmacologic and physical antithrombosis interventions should be vigorously employed, periods without anticoagulation should be kept to an absolute minimum, intravascular manipulation for access and monitoring should be minimized, and any deviation from a normal course should be considered a potential disease-related event.76 REFERENCES   1. Wilson WA, Gharavi AE, Koike T, et al: International consensus statement on preliminary classification criteria for antiphospholipid syndrome: Report of an international workshop. Arthritis Rheum 42:1309-1311, 1999.   2. Miyakis S, Lockshin MD, Atsumi T, et al: International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome. J Thromb Haemost 4:295-306, 2006.   3. Gharavi AE, Sammaritano LR, Wen J, et al: Characteristics of human immunodeficiency virus and chlorpromazine-induced antiphospholipid antibodies: Effect of beta 2 glycoprotein I on binding to phospholipid. J Rheumatol 21:94-99, 1994.   4. Vila P, Hernandez MC, Lopez-Fernandez MF, et al: Prevalence, follow-up and clinical significance of the aCL in normal subjects. Thromb Haemost 72:209-213, 1994.   5. Petri M: Epidemiology of the antiphospholipid antibody syndrome. J Autoimmun 15:145-151, 2000.   6. Olech E, Merrill JT: The prevalence and clinical significance of antiphospholipid antibodies in rheumatoid arthritis. Curr Rheumatol Rep 8:100-108, 2006.

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  7. Giron-Gonzalez JA, Garcia del Rio E, Rodriguez C, et al: Antiphospholipid syndrome and asymptomatic carriers of antiphospholipid antibody: Prospective analysis of 404 individuals. J Rheumatol 31:1560-1567, 2004.   8. Somers E, Magder LS, Petri ML: Antiphospholipid antibodies and incidence of venous thrombosis in a cohort of patients with systemic lupus erythematosus. J Rheumatol 29:2531-2536, 2002.   9. Erkan D, Harrison MJ, Levy R, et al: APLASA—a randomized double-blind placebo-controlled primary thrombosis prevention trial in asymptomatic persistently antiphospholipid antibody (APL)-positive individuals with aspirin (ASA) [abstract]. Clin Exp Rheumatol 25:14, 2007. 10. The Antiphospholipid Antibody Stroke Study (APASS) Group: Anticardiolipin antibodies are an independent risk factor for first ischemic stroke. Neurology 43:2069-2073, 1993. 11. Levine SR, Brey RL, Sawaya KL, et al: Recurrent stroke and thromboocclusive events in the antiphospholipid syndrome. Ann Neurol 38:119-124, 1995. 12. Stephenson MD: Frequency of factors associated with habitual abortion in 197 couples. Fertil Steril 66:24-29, 1996. 13. Ginsberg JS, Wells PS, Brill-Edwards P, et al: Antiphospholipid antibodies and venous thromboembolism. Blood 86:3685-3691, 1995. 14. Koike T, Ichikawa K, Kasahara H: Epitopes on beta2-GPI recognized by anticardiolipin antibodies. Lupus 7(Suppl 2):S14, 1998. 15. Shi T, Giannakopoulos B, Yan X, et al: Anti-beta2-glycoprotein I antibodies in complex with beta2-glycoprotein I can activate platelets in a dysregulated manner via glycoprotein Ib-IX-V. Arthritis Rheum 54:2558-2567, 2006. 16. Reddel SW, Wang YX, Sheng YH, et al: Epitope studies with anti-beta 2-glycoprotein I antibodies from autoantibody and immunized sources. J Autoimmun 15:91-96, 2000. 17. Casciola-Rosen L, Rosen A, Petri M, et al: Surface blebs on apoptotic cells are sites of enhanced procoagulant activity: Implications for coagulation events and antigenic spread in systemic lupus erythematosus. Proc Natl Acad Sci U S A 93:1624-1629, 1996. 18. Mori T, Takeya H, Nishioka J, et al: Beta 2-glycoprotein I modulates the anticoagulant activity of activated protein C on the phospholipid surface. Thromb Haemost 75:49-55, 1996. 19. Bertolaccini ML, Hughes GR: Antiphospholipid antibody testing: Which are most useful for diagnosis? Rheum Dis Clin North Am 32:455-463, 2006. 20. Gharavi AE, Pierangeli SS, Harris EN: Origin of antiphospholipid antibodies. Rheum Dis Clin North Am 27:551-563, 2001. 21. Blank M, Krause I, Fridkin M, et al: Bacterial induction of autoanti­ bodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome. J Clin Invest 109:797-804, 2002. 22. Gharavi AE, Sammaritano LR, Wen J, et al: Induction of antiphospholipid antibodies by immunization with beta 2 glycoprotein I (apolipoprotein H). J Clin Invest 90:1105-1109, 1992. 23. Arvieux J, Renaudineau Y, Mane I, et al: Distinguishing features of anti-beta2 glycoprotein I antibodies between patients with leprosy and the antiphospholipid syndrome. Thromb Haemost 87:599-605, 2002. 24. Lutters BC, Derksen RH, Tekelenburg WL, et al: Dimers of beta 2-glycoprotein 1 increase platelet deposition to collagen via interaction with phospholipids and the apolipoprotein E receptor 2′. J Biol Chem 278:33831-33838, 2003. 25. Bordron A, Dueymes MY, Levy Y, et al: Anti-endothelial cell antibody binding makes negatively charged phospholipids accessible to antiphospholipid antibodies. Arthritis Rheum 41:1738-1747, 1998. 26. Simantov R, LaSala J, Lo SK, et al: Activation of cultured vascular endothelial cells by antiphospholipid antibodies. J Clin Invest 96:2211-2219, 1996. 27. Font J, Espinosa G, Tassies D, et al: Effects of β2-glycoprotein I and monoclonal anticardiolipin antibodies in platelet interaction with subendothelium under flow conditions. Arthritis Rheum 46: 3283-3289, 2002. 28. van Lummel M, Pennings MT, Derksen RH, et al: The binding site in β2-glycoprotein I for ApoER2� on platelets is located in domain V. J Biol Chem 280:36729-36736, 2005. 29. Erkan D, Lockshin MD: What is antiphospholipid syndrome? Curr Rheumatol Rep 6:451-457, 2004. 30. Dunoyer-Geindre S, de Moerloose P, Galve-de Rochemonteix B, et al: NFkappaB is an essential intermediate in the activation of endothelial cells by anti-beta2-glycoprotein 1 antibodies. Thromb Haemost 88:851-857, 2002.

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| Antiphospholipid Syndrome

31. Pierangeli SS, Vega-Ostertag M, Harris EN: Intracellular signaling triggered by antiphospholipid antibodies in platelets and endothelial cells: A pathway to targeted therapies. Thromb Res 114:467-476, 2004. 32. Mak IYH, Brosens JJ, Christian M, et al: Regulated expression of signal transducer and activator of transcription, Stat5, and its enhancement of PRL expression in human endometrial stromal cells in vitro. J Clin Endocrinol Metab 87:2581-2587, 2002. 33. Pierangeli SS, Liu XW, Barker JH, et al: Induction of thrombosis in a mouse model by IgG, IgM, and IgA immunoglobulins from patients with the antiphospholipid syndrome. Thromb Haemost 74:1361-1367, 1995. 34. Jankowski M, Vreys I, Wittevrongel C, et al: Thrombogenicity of β2-glycoprotein I-dependent antiphospholipid antibodies in a photochemically-induced thrombosis model in the hamster. Blood 101: 157-162, 2003. 35. Girardi G, Bulla R, Salmon JE, et al: The complement system in the pathophysiology of pregnancy. Mol Immunol 43:68-77, 2006. 36. Fleming SD, Egan RP, Chai C, et al: Anti-phospholipid antibodies restore mesenteric ischemia/reperfusion-induced injury in complement receptor 2/complement receptor 1-deficient mice. J Immunol 173:7055-7061, 2004. 37. Kaul M, Erkan D, Sammaritano L, et al: Assessment of the 2006 revised antiphospholipid syndrome (APS) classification criteria [abstract]. Arthritis Rheum 54:S796, 2006. 38. Erkan D, Yazici Y, Peterson MG, et al: A cross-sectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome. Rheumatology (Oxford) 41:924-929, 2002. 39. Bancsi LF, van der Linden IK, Bertina RM: Beta 2-glycoprotein I deficiency and the risk of thrombosis. Thromb Haemost 67:649-653, 1992. 40. Sheng Y, Reddel SW, Herzog H, et al: Impaired thrombin generation in beta 2-glycoprotein I null mice. J Biol Chem 276:13817-13821, 2001. 41. Kamboh MI, Manzi S, Mehdi H, et al: Genetic variation in apolipoprotein H (beta2-glycoprotein I) affects the occurrence of antiphospholipid antibodies and apolipoprotein H concentrations in systemic lupus erythematosus. Lupus 8:742-750, 1999. 42. Potti A, Bild A, Dressman HK, et al: Gene-expression patterns predict phenotypes of immune-mediated thrombosis. Blood 107:1391-1396, 2006. 43. Bhandari S, Harnden P, Brownjohn AM, et al: Association of anticardiolipin antibodies with intraglomerular thrombi and renal dysfunction in lupus nephritis. QJM 91:401-409, 1998. 44. Rand JH, Wu X, Andree HAM, et al: Pregnancy loss in the antiphospholipid-antibody syndrome: A possible thrombogenic mechanism. N Engl J Med 337:154-160, 1997. 45. Roman MJ, Shanker BA, Davis A, et al: Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 349:2399-2406, 2003. 46. Erkan D, Bateman H, Lockshin MD: Lupus-anticoagulant-hypoprothrombinemia syndrome associated with systemic lupus erythematosus: Report of 2 cases and review of literature. Lupus 8:560-564, 1999. 47. Erkan D, Cervera R, Asherson RA: Catastrophic antiphospholipid syndrome: Where do we stand? Arthritis Rheum 48:3320-3327, 2003. 48. Cervera R, Font J, Gomez-Puerta JA, et al: Validation of the preliminary criteria for the classification of catastrophic antiphospholipid syndrome. Ann Rheum Dis 64:1205-1209, 2005. 49. Asherson RA, Cervera R, de Groot PG, et al: Catastrophic antiphospholipid syndrome: International consensus statement on classification criteria and treatment guidelines. Lupus 12:530-534, 2003. 50. Galli M, Luciani D, Bertolini G, et al: Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: A systematic review of the literature. Blood 101:1827-1832, 2003. 51. Brandt JT, Triplett DA, Alving B, et al: Criteria for the diagnosis of lupus anticoagulants: An update. Thromb Haemost 74:1185-1190, 1995. 52. Cervera R, Piette JC, Font J, et al: Antiphospholipid syndrome: Clinical and immunologic manifestations and patterns of disease expression in a cohort of 1000 patients. Arthritis Rheum 46:1019-1027, 2002. 53. Day HM, Thiagarajan P, Ahn C, et al: Autoantibodies to β2­glycoprotein I in systemic lupus erythematosus and primary antiphospholipid syndrome: Clinical correlations in comparison with other antiphospholipid antibody tests. J Rheumatol 25:667-674, 1998.

54. Erkan D, Derksen WJ, Kaplan V, et al: Real world experience with antiphospholipid antibody tests: How stable are results over time? Ann Rheum Dis 64:1321-1325, 2005. 55. Lockshin MD, Sammaritano LR, Schwartzman S: Brief report: Validation of the Sapporo criteria for antiphospholipid antibody syndrome. Arthritis Rheum 43:440-443, 2000. 56. Erel H, Erkan D, Lehman TJ, et al: Diagnostic usefulness of 3 dimensional gadolinium enhanced magnetic resonance venography in antiphospholipid syndrome. J Rheumatol 29:1338-1339, 2002. 57. Khong TY, De Wolf F, Robertson WB, et al: Inadequate maternal vascular response to placentation in pregnancies complicated by preeclampsia and by small-for-gestational-age infants. Br J Obstet Gynaecol 93:1049-1059, 1986. 58. Stone S, Pijnenborg R, Vercruysse L, et al: The placental bed in pregnancies complicated by primary antiphospholipid syndrome. Placenta 27:457-467, 2006. 59. Levy RA, Gharavi AE, Sammaritano LR, et al: Characteristics of IgG antiphospholipid antibodies in patients with systemic lupus erythematosus and syphilis. J Rheumatol 17:1036-1041, 1990. 60. Kupferminc MJ, Eldo A, Steinman N, et al: Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 340:9-13, 1999. 61. Crowther MA, Ginsberg JS, Julian J, et al: Comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 349:1133-1138, 2003. 62. Finazzi G, Marchioli R, Brancaccio V, et al: A randomized clinical trial of high-intensity warfarin vs conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost 3:848853, 2005. 63. Levine SR, Brey RL, Tilley BC, et al: Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. JAMA 291:576-584, 2004. 64. Ortel TL, Moll S: Monitoring warfarin therapy in patients with lupus anticoagulants. Ann Intern Med 127:177-185, 1997. 65. Erkan D, Lockshin MD: New treatments for antiphospholipid syndrome. Rheum Dis Clin North Am 32:129-148, 2006. 66. Brunner HI, Chan WS, Ginsberg JS, et al: Long term anticoagulation is preferable for patients with antiphospholipid antibody syndrome: Result of a decision analysis. J Rheumatol 29:490-501, 2002. 67. Vilela VS, de Jesus NR, Levy RA: Prevention of thrombosis during pregnancy. Isr Med Assoc J 4:794-797, 2002. 68. Kutteh WH: Antiphospholipid antibody-associated recurrent pregnancy loss: Treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 174:1584-1589, 1996. 69. Rai R, Cohen H, Dave M, et al: Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 314:253-257, 1997. 70. Guballa N, Sammaritano L, Schwartzman S, et al: Ovulation induction and in vitro fertilization in systemic lupus erythematosus and antiphospholipid syndrome. Arthritis Rheum 43:550-556, 2000. 71. Tenedios F, Erkan D, Lockshin MD: Rituximab in the primary antiphospholipid syndrome (PAPS) [abstract]. Arthritis Rheum 52:4078, 2005. 72. Vero S, Asherson RA, Erkan D: Critical care review: Catastrophic antiphospholipid syndrome. J Intensive Care Med 21:144-159, 2006. 73. Erkan D, Yazici Y, Sobel R, et al: Primary antiphospholipid syndrome: Functional outcome after 10 years. J Rheumatol 27:2817-2821, 2000. 74. Erkan D, Merrill JT, Yazici Y, et al: High thrombosis rate after fetal loss in antiphospholipid syndrome: Effective prophylaxis with aspirin. Arthritis Rheum 44:1466-1467, 2001. 75. Raklyar I, DeMarco PJ, Wu J, et al: Anticardiolipin antibody correlates with poor graft survival in renal transplantation for systemic lupus erythematosus. Arthritis Rheum 52:S384, 2005. 76. Erkan D, Leibowitz E, Berman J, Lockshin MD: Perioperative medical management of antiphospholipid syndrome: Hospital for Special Surgery experience, review of the literature and recommendations. J Rheumatol 29:843-849, 2002.

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12

scleroderma, inflammatory myopathies, and overlap syndromes

77

Systemic Sclerosis and the SclerodermaSpectrum Disorders JOHN VARGA  •  CHRISTOPHER P. DENTON

Key Points Systemic sclerosis (SSc) is a multisystem connective tissue disease of unknown etiology that occurs more commonly in women, follows a chronic course, and is associated with substantial morbidity and mortality. SSc has a complex pathogenesis and protean clinical ­manifestations that reflect the underlying autoimmunity, vasculopathy, and fibrosis. The hallmark of SSc is induration of the skin (scleroderma), whereas leading causes of death are pulmonary arterial ­hypertension; pulmonary fibrosis; and complications of ­cardiac, renal, and gastrointestinal tract involvement. Scleroderma may occur in localized forms and in a distinct group of scleroderma-spectrum disorders

Systemic sclerosis (SSc) is a multisystem connective tissue disease of unknown etiology. Similar to other connective tissue diseases, SSc follows a chronic course, occurs more commonly in women, and is highly heterogeneous in its protean clinical manifestations. The hallmarks of SSc are autoimmunity and inflammation, functional and structural abnormalities in small blood vessels in multiple vascular beds, and progressive interstitial and vascular fibrosis in the skin and internal organs. This constellation of seemingly disparate pathophysiologic and clinical features occurs in most patients, and helps to differentiate SSc from other connective tissue diseases. Although the outcome of SSc has improved considerably during the past 2 decades, the disease carries the highest case fatality among the connective tissue diseases and is still considered incurable.

CLASSIFICATION OF SCLERODERMA-SPECTRUM DISORDERS The hallmark of SSc is induration and thickening of the skin (scleroderma). The scleroderma spectrum of disorders encompasses, in addition to SSc, numerous disparate conditions that exhibit common clinical and pathologic features (Table 77-1). In SSc, the skin involvement ranges from

widespread thickening (diffuse cutaneous SSc) to thickening limited to the face and distal extremities (limited cutaneous SSc), and may be altogether absent in some cases (SSc sine scleroderma). Localized scleroderma is a family of disorders that includes morphea, linear scleroderma, and coup de sabre. These disorders are more common in childhood, and in marked contrast to SSc are almost never associated with significant systemic involvement. Related disorders include hemifacial atrophy and inflammatory fibrosing conditions affecting the subcutaneous tissue, such as eosinophilic fasciitis and eosinophilia-myalgia syndrome, which are associated with chronic scleroderma-like skin changes. Differentiation of the major subset of SSc into limited or diffuse cutaneous forms is based on the maximum extent of skin involvement.1 In diffuse cutaneous SSc, there is widespread involvement of the skin with thickening proximal to the elbows or knees and often involving the chest or abdominal wall (Fig. 77-1). In limited cutaneous SSc, skin involvement is limited to the distal extremities or face, or may involve only the fingers (sclerodactyly) (Fig. 77-2). Another subgroup of SSc includes patients who manifest features of another autoimmune rheumatic disease (overlap syndrome). Some patients with characteristic vascular and internal organ manifestations and serologic findings of SSc lack typical skin sclerosis. This subset, called SSc sine scleroderma, comprises only approximately 1% of cases, but presents a particular diagnostic challenge.2 Some patients with unexplained pulmonary fibrosis or pulmonary arterial hypertension (PAH) likely fall into this category. Clues to this diagnosis include the presence of Raynaud’s phenomenon, nail-fold capillary changes of SSc, and hallmark SSc-associated autoantibodies. Some patients with isolated Raynaud’s phenomenon eventually develop SSc or another full-blown connective tissue disease. There is no single test that is diagnostic for SSc. For the purposes of distinguishing SSc from other autoimmune connective tissue diseases, preliminary criteria were developed.3,4 These criteria had a high sensitivity and specificity for the diffuse cutaneous form, but not the limited cutaneous form, of SSc. In addition, the criteria do not take into account the hallmark autoantibodies now recognized in SSc. Key clinical features of the major subsets of SSc are summarized 1311

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Systemic Sclerosis and the Scleroderma-Spectrum Disorders

Table 77-1  Scleroderma-Spectrum Disorders Skin Sclerosis Systemic sclerosis Limited cutaneous Diffuse cutaneous Localized scleroderma Infiltrative disorders   Amyloidosis   Scleromyxedema   Sclerodema of Buschke   Lichen sclerosis et atrophicus Inflammatory   Overlap connective tissue diseases   Eosinophilic fasciitis   Chronic graft-versus-host disease   Sarcoidosis Metabolic disorders   Myxedema   Porphyria cutanea tarda   Congenital porphyrias   Acromegaly Digital Vascular Insufficiency Raynaud’s phenomenon   Primary Raynaud’s phenomenon   Associated Raynaud’s phenomenon   Other autoimmune rheumatic disorders (e.g., SLE, polymyositis, undifferentiataed connective tissue disease, overlap [mixed] connective tissue disease) Other vascular disease   Hematologic     Cryoglobulinaemia     Cold agglutinin disease Hyperviscosity syndrome Systemic vasculitis Buerger disease (thromboangiitis obliterans) Macrovascular disease (e.g., thrombotic, embolic, atherosclerotic) SLE, systemic lupus erythematosus.

in Table 77-2. Beyond classification of SSc by subset, it is important to consider the stage of disease. Diffuse cutaneous SSc tends to have a more abrupt onset and progressive course, with organ failure often developing within 5 years of the first symptoms. In limited cutaneous SSc, major visceral complications generally occur later. Placing SSc patients into subsets of diffuse and limited cutaneous forms represents a clinically useful approach to risk stratification. In the early stage of diffuse cutaneous SSc, there is progressive extension of skin sclerosis and new onset of internal organ complications. In many cases, skin involvement peaks within 12 to 18 months of onset, often followed by declining extent and severity.5 In contrast, patients with limited cutaneous SSc generally have insidious progression of skin involvement. Localized forms of scleroderma generally do not affect the internal organs and are not associated with Raynaud’s phenomenon. Plaque morphea is the most common form of localized scleroderma in adults (Fig. 77-3), whereas linear scleroderma predominates in childhood.

EPIDEMIOLOGY SSc is a sporadic disease that has a worldwide distribution and occurs in every ethnic group. No seasonal or geographic clustering of cases has been convincingly documented. The epidemiology of SSc has proven difficult to establish, reflecting the clinical diversity of the disease, the absence of

widely accepted criteria for diagnosis or classification, and the methodologic challenges associated with populationbased case ascertainment. Incidence estimates range from 9 to 19 cases/1 million/yr, with prevalence rates ranging from 28 to 253 cases/1 million/yr in the United States,6,7 and 120 cases/1 million/yr in the United Kingdom.8,9 Based on incidence and survival rates, it is estimated that there are 75,000 to 100,000 cases of SSc in the United States. The only community-based survey of SSc yielded a prevalence of 286 cases/1 million population.10 This study also suggested that SSc is frequently misdiagnosed, implying that its true prevalence may be higher than previously estimated. Similar to other connective tissue diseases, SSc is more frequent in women than men, with the most common age of disease onset in the 30 to 50 years range. The incidence of SSc is higher and disease onset occurs at an earlier age among African-Americans compared with whites. AfricanAmericans with SSc are more likely to have diffuse skin involvement and pulmonary fibrosis and to have a worse prognosis.11

ETIOLOGY GENETIC FACTORS The genetics of SSc are complex, and the disease is not inherited in a straightforward mendelian fashion. Twins show a low rate of disease concordance (<5%).12 This rate is similar between monozygotic and dizygotic twin pairs. Other studies have shown that SSc occurs significantly more frequently in families with SSc (1.6%) than in the general population (0.026%).13 Although the absolute risk of SSc for each family member is low, a positive family history represents the strongest risk factor yet identified for SSc, indicating an important role for heredity in disease susceptibility. Firstdegree relatives of SSc patients also are more likely to have a positive antinuclear antibody than controls.14 In contrast to other connective tissue diseases, HLA linkages are generally weak in SSc. Particular HLA haplotypes do show associations with distinct serologically defined SSc subsets, however. A cluster of SSc cases had been described among Choctaw Native Americans living in Oklahoma, with affected individuals sharing a unique American Indian HLA haplotype.15 Current investigations in SSc genetics focus primarily on polymorphisms in candidate genes. Associations of specific single nucleotide polymorphisms have been reported in genes involved in immunity and inflammation, vascular function, and connective tissue homeostasis.16 VIRUSES The etiology of SSc is unknown. Along with exposure to certain environmental and occupational agents and drugs, infection with human cytomegalovirus (CMV) and other viruses has been implicated as a potential trigger.17 Several reports have described the presence of antibodies directed against human CMV in the serum of patients with SSc. These antibodies recognized the UL83 and UL94 protein epitopes on human CMV.18-20 Anti–topoisomerase I ­antibodies in some SSc patients show cross-reactivity with human CMV–derived proteins, providing evidence for molecular mimicry as a potential mechanistic link between

PART 12 

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SCLERODERMA, INFLAMMATORY MYOPATHIES, AND OVERLAP SYNDROMES

B

A

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C

D

Figure 77-1  Diffuse cutaneous systemic sclerosis. Characteristic features of diffuse cutaneous systemic sclerosis are illustrated. A, Skin over the face is tightened; there is reduced opening of the mouth, owing in part to diminished oral aperture, but also to contractural changes in the soft tissues around the face and jaw. B-D, Hands exhibit reduced flexion and extension and fixed contractures at the interphalangeal joints. Ulceration occurs at sites of pressure or trauma, distinct from the ischemic digital lesions of limited cutaneous systemic sclerosis. Skin changes proximal to the knees or elbows on the limb, or involving the chest or abdominal wall, define the diffuse cutaneous subset.

human CMV infection and SSc.21 Antibodies to UL94 can induce endothelial cell apoptosis and fibroblast activation in cell culture assays, suggesting a direct role for antiviral antibodies in tissue damage.22,23 CMV infection is implicated in allograft vasculopathy, a complication of organ transplantation characterized by vascular neointima formation and smooth muscle cell proliferation reminiscent of the obliterative proliferative vasculopathy seen in SSc. In human dermal fibroblasts, CMV can directly induce the synthesis of the profibrotic growth factor connective tissue growth factor (CTGF), or CCN2, in vitro.24 Evidence of infection with human parvovirus B19 also has been described in patients with SSc.25,26 ENVIRONMENTAL EXPOSURES, DRUGS, AND RADIATION Although reports of putative geographic clustering of SSc cases suggest shared environmental exposures, careful investigations have generally failed to substantiate apparent clusters. Well-documented epidemic outbreaks of SSclike multisystemic illnesses with acute onset and chronic persistence have been reported. One such illness, called the toxic oil syndrome, was linked to the ingestion of contaminated rapeseed cooking oils in Spain.27 In the United

States, dietary supplements of tryptophan were implicated in an outbreak of the eosinophilia-myalgia syndrome epidemic in 1989.28-30 Although scleroderma-like chronic skin lesions, multisystem involvement, and evidence of autoimmunity were prominent features of these apparently novel toxicoepidemic syndromes, associated clinical, histopathologic, and laboratory features clearly distinguished them from SSc.31,28 The frequency of SSc seems to be increased among men with occupational exposure to silica dust. Other occupational exposures linked with SSc include polyvinyl chloride, trichloroethylene, and organic solvents.32,33 Anecdotal reports also have alleged an association between SSc and environmental exposures to pesticides, hair dyes, and industrial fumes.32,34-36 No well-controlled studies have shown a causative association between cigarette smoking and SSc, in contrast to rheumatoid arthritis, in which smoking is the most definitive environmental risk factor. Drugs implicated as potentially causative for SSc-like illnesses include bleomycin, pentazocine, and cocaine. The use of fenfluramine appetite suppressants has been linked to the development of PAH. The occurrence of SSc in women who had ­undergone cosmetic breast augmentation with silicone implants raised concern regarding a possible association.28 Subsequent large-scale epidemiologic surveys

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B

A

C

D

Figure 77-2  Limited cutaneous systemic sclerosis. A, The facial appearance of limited cutaneous systemic sclerosis contrasts markedly with diffuse cutaneous systemic sclerosis. There is marked perioral furrowing and much less skin induration. Telangiectasias are common and often widespread. B-D, Raynaud’s phenomenon and digital ischemia may be severe and may lead to autoamputation. Subcutaneous calcinosis occurs. Esophageal ­involvement is common.

did not indicate an increased risk of SSc, however, or of other well-defined connective tissue diseases among women with silicone breast implants.37-39 Radiation treatment for malignant neoplasms has been linked with the onset of de novo SSc and exacerbation of tissue fibrosis in patients with preexisting SSc.40,41 Table 77-3 lists some environmental agents and drugs that have been linked with the development of SSc.

PATHOLOGY

Table 77-2  Classification of Systemic Sclerosis (SSc)* Limited cutaneous SSc

Skin thickening restricted to sites distal to elbows and knees, but may involve face and neck

CREST syndrome

Subset of limited cutaneous SSc with prominent calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia

Diffuse cutaneous SSc

Skin thickening on the trunk and ­proximal extremities in addition to distal extremities and face

Overlap SSc

Skin changes and other ­characteristic features of SSc coexisting with ­features of another connective ­tissue disease, including SLE, ­myositis, or rheumatoid arthritis

SSc sine scleroderma

Raynaud’s phenomenon, characteristic internal organ complications, and serologic abnormalities of SSc, but no apparent skin involvement

GENERAL FEATURES The characteristic pathologic findings in SSc are a noninflammatory proliferative/obliterative vasculopathy affecting small arteries and arterioles in multiple vascular beds, in combination with interstitial and vascular fibrosis in the skin, lungs, and multiple other internal organs.42 Although in long-standing SSc these lesions generally occur in the absence of inflammation, in early-stage disease, inflammatory cell infiltrates are prominent in many organs. In the skin, the infiltrates are located predominantly around

*Limited SSc has been suggested as a classification to define patients with Raynaud’s phenomenon and capillaroscopic changes and serologies characteristic of SSc. SLE, systemic lupus erythematosus.

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C

Figure 77-3  Localized scleroderma. A-C, Localized forms of scleroderma include morphea and linear scleroderma. When extensive, morphea can be a substantial problem. Clinical activity is suggested by pain, aching, or itching of affected areas of skin; enlargement of an existing plaque; or development of new lesions. Although localized scleroderma may occur in patients with systemic sclerosis, evolution to systemic disease has not been described.

Table 77-3  Environmental Agents and Drugs   Implicated in Scleroderma-like Syndromes Chemicals Silica Heavy metals Mercury Organic chemicals   Vinyl chloride   Benzene   Toluene   Trichloroethylene Drugs Bleomycin Pentazocine Paclitaxel Cocaine Dietary supplement/appetite suppressants Tryptophan (contamination) Mazindol Fenfluramine Diethylpropion

blood vessels and in the reticular dermis and are composed ­primarily of CD4+ T lymphocytes and monocytes, whereas in the lungs, cellular infiltrates consist predominantly of CD8+ T lymphocytes (Fig. 77-4). VASCULAR PATHOLOGY Vascular injury and activation are the earliest and possibly primary events in the pathogenesis of SSc. Histopathologic evidence of vascular damage is present before fibrosis and can be detected in involved and uninvolved skin, indicating a generalized process.43 Manifestations of vascular ­involvement, such as Raynaud’s phenomenon, generally precede other disease manifestations. Additional clinical signs of SSc vasculopathy include cutaneous telangiectasia, nail-fold capillary alterations, PAH, digital pit formation,

gastric antral vascular ectasia (also called watermelon stomach), and scleroderma renal crisis. In patients with established SSc, the most characteristic vascular finding is bland intimal proliferation in the small and medium-sized arteries (Fig. 77-5). Expansion of the intimal layer, a striking finding that SSc shares with chronic allograft arteriopathy, is thought to be due to increased proliferation and migration of myointimal cells and local accumulation of collagen.44 The vascular basement membranes are thickened and reduplicated. The blood vessels of the heart, lungs, kidneys, and intestinal tract are prominently affected. Impaired fibrinolysis, increased levels of von Willebrand factor, and ongoing platelet aggregation are noted.45 Endothelial cell injury results in further platelet aggregation, release of platelet-derived growth factor (PDGF) and endothelin-1 (ET-1), and endothelial cell apoptosis.45,46 Vasculitic lesions and immune complex deposition in the vessel walls are uncommon. In late stages of the disease, extensive fibrin deposition and perivascular fibrosis cause progressive luminal ­occlusion, and there is striking paucity of small blood vessels in lesional tissue.47 Loss of vascular supply leads to chronic tissue hypoxia. Widespread proliferative/obliterative vasculopathy of small and medium-sized arteries in multiple vascular beds is the pathologic hallmark of all forms of SSc. TISSUE FIBROSIS Fibrosis is characterized by accumulation of excessive amounts of type I collagen and other fibrillar collagens, fibronectin, elastin, proteoglycans, and other connective tissue molecules in the extracellular matrix (ECM). The process causes ­disruption of tissue architecture. In SSc, interstitial and vascular fibrosis in the skin and parenchymal organs contributes directly to their progressive dysfunction and eventual failure. Most prominently affected are the lungs, gastrointestinal tract, heart, tendon sheath, and perifascicular tissue surrounding skeletal muscle. ­Histopathologic

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Figure 77-4  Histology of skin in diffuse cutaneous systemic sclerosis. A, There is perivascular infiltration in the dermis with inflammatory cells of multiple lineages. Microvascular endothelial cell activation and increased extracellular matrix deposition also are seen. B, Later, there is regression of the inflammatory features. Secondary structures within the skin, such as hair follicles and sweat glands, are reduced, and rete pegs are flattened. (Hematoxylin and eosin stain, original magnification ×40.)

A

Figure 77-5  Histologic appearance of scleroderma vasculopathy. In the finger, changes in the digital artery may narrow the lumen and reduce response to vasodilators. Pulmonary arterial changes may lead to pulmonary arterial hypertension. The histologic appearance is reminiscent of idiopathic pulmonary arterial hypertension (previously termed primary pulmonary hypertension).

examination of these organs indicates accumulation of homogeneous and acellular connective tissue with thick hyalinized collagen bundles. ORGAN-SPECIFIC PATHOLOGIC FINDINGS Skin Fibrosis of the skin, the hallmark of SSc, causes marked expansion of the dermis. The process obliterates the hair follicles, sweat glands, and other skin appendages. ­Collagen

B

fiber accumulation is most prominent in the reticular (deep) dermis, and gradually invades the subjacent adipose layer with entrapment of fat cells. Skin biopsy in early stages of SSc may reveal deep dermal perivascular infiltrates ­composed of T lymphocytes and monocytes. Less commonly, mast cells48 and eosinophils46,49,50 may be detected. The proportion of alpha smooth muscle actin–positive myofibroblasts, a mesenchymal cell that is intermediate between fibroblasts and contractile smooth muscle cells and plays a major role in fibrogenesis, is increased in the lesional skin.51 With disease progression, the skin undergoes atrophy with thinning of the epidermis and effacement of the rete pegs (see Fig. 77-4). The fibrotic dermis is largely acellular and contains dense accumulation of compact hyalinized ­collagen bundles, fibronectin, and other structural matrix proteins. Paucity of dermal capillaries is associated with chronic tissue hypoxia that induces vascular endothelial growth factor (VEGF) and other angiogenic factors. Evidence of tissue hypoxia can be found in clinically uninvolved, apparently “normal” skin.52 Biochemically, the collagens in the fibrotic dermis are normal, and relative proportions of the main fibrillar collagens (type I and type III) are comparable to those of normal skin. In contrast, the minor nonfibrillar type VII collagen, normally restricted to the dermal-epidermal basement ­membrane zone, is abundant throughout the lesional dermis.53 The levels of enzymes mediating post-translational collagen modification, such as lysyl hydroxylase (PLOD2), are elevated, resulting in an increase in aldehyde-derived collagen cross-links, which may account for the dense sclerotic nature of the fibrotic dermis.54 Studies using DNA microarray technology have defined better the sequence of activation events that underlie the development of irreversible fibrosis. The results reveal strikingly altered patterns of gene expression in skin from SSc patients compared with healthy controls. Clinically involved skin and uninvolved skin seem to be indistinguishable in terms of their gene expression profiles. The expression of many genes involved in ECM homeostasis, and in transforming growth factor (TGF)-β, CCN2, and Wnt signaling pathways, is elevated.55,56

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Lungs In early SSc, patchy infiltration of the alveolar walls with lymphocytes, plasma cells, macrophages, and eosinophils is seen (Fig. 77-6). At this stage, elevated proportions of inflammatory leukocytes can be found in alveolar lavage fluid. With progression, interstitial lung fibrosis and vascular damage predominate, often coexisting within the same lesions. Intimal thickening of the pulmonary arteries, best seen with elastin stain, underlies PAH, and at autopsy is often associated with multiple pulmonary emboli and myocardial fibrosis. Fibrosis in the lungs is characterized by expansion of the alveolar interstitium, owing to accumulation of ­collagens and other connective tissue proteins. The typical histologic pattern seen on lung biopsy specimen is nonspecific interstitial pneumonitis, a form of interstitial lung disease characterized by mild-to-moderate interstitial inflammation, type II pneumocyte hyperplasia, and ­ uniform distribution of fibrosis. Less commonly, SSc is associated with the usual interstitial pneumonia pattern, which is ­characterized by scattered fibroblastic foci and patchy distribution of fibrosis and has a worse prognosis.57,58 Progressive thickening of the alveolar septa ultimately results in obliteration of the airspaces and honeycombing, and consequent loss of pulmonary blood vessels. This process impairs gas exchange and contributes to worsening of PAH. Extensive pulmonary fibrosis may predispose to primary lung carcinoma.47 Gastrointestinal Tract Prominent pathologic changes can occur at any level from the mouth to the rectum. The esophagus is virtually always affected, with fibrosis in the lamina propria, submucosa, and muscular layers, and characteristic vascular lesions.42,59 Replacement of the normal intestinal architecture results in disordered peristaltic activity, gastroesophageal reflux and small bowel dysmotility, pseudo-obstruction, and bacterial overgrowth. Chronic gastroesophageal reflux is complicated by esophageal inflammation, ulcerations, and stricture formation. One third of SSc patients with severe gastroesophageal reflux develop Barrett’s esophagus, characterized by metaplasia of the normal squamous lining of the esophagus into columnar epithelium.60,61 Because it is a premalignant lesion associated with a greater than 30-fold increased risk of adenocarcinoma, patients with Barrett’s metaplasia need monitoring for the development of dysplasia and adenocarcinoma. Kidneys In the kidneys, vascular lesions predominate, and glomerulonephritis is rare except in overlap syndromes. Chronic renal ischemia is associated with shrunken glomeruli and other ischemic changes. Patients with acute scleroderma renal crisis show dramatic histopathologic changes that are indistinguishable from the changes observed in other forms of malignant hypertension.62 Vascular changes in SSc kidneys are most prominent in the small interlobular and arcuate renal arteries, which show reduplication of elastic lamina, marked intimal proliferation, and accumulation of

Figure 77-6  Histologic appearance of the lung. Evidence of interstitial lung disease is common in systemic sclerosis. Although there is substantial variation in the appearance of lung histology, consistent features include reduction in airspaces and thickening of alveolar walls with increased extracellular matrix deposition. Inflammatory cell infiltrates may be prominent. Lung biopsy is rarely required for diagnosis of interstitial lung disease in SSc.

ground substance.63 These changes also can be found in SSc patients who do not have renal crisis.64 Fibrinoid necrosis of the arteriolar walls may be seen. Intimal thickening leads to severe narrowing and total obliteration of the lumen, often with microangiopathic hemolysis. Tubular changes occur secondary to vascular insufficiency and include flattening and degeneration of tubular cells. The clinical picture may resemble thrombotic thrombocytopenic purpura, especially in severe cases of scleroderma renal crisis. The reported association of thrombotic thrombocytopenic purpura with low levels of activity of the enzyme plasma von Willebrand factor cleaving protease (ADAMTS13) has not been reported in SSc renal crisis, however. Nonspecific immunoglobulin and complement C3 deposition may be found, but inflammatory infiltrates are uncommon. Histologic features of scleroderma renal crisis are shown in Figure 77-7. Heart At autopsy, evidence of cardiac involvement is found in 80% of patients with SSc.42,65 Modest pericardial effusions are common; occasionally, fibrosis and constrictive pericarditis may occur. A characteristic pathologic finding is myocardial contraction band necrosis, which is thought to reflect repeated ischemia-reperfusion injury and may be a manifestation of “myocardial Raynaud’s phenomenon.”65 Significant interstitial and perivascular fibrosis may occur in the absence of clinically evident heart involvement.66,67 Skeletal muscle myositis in SSc may be accompanied by acute myocarditis.65,68,69 PATHOLOGIC FINDINGS IN OTHER ORGANS The major patterns of organ-based disease in SSc are summarized in Table 77-4. Many other systems can be affected by the disease, however. Fibrosis of the thyroid glands is

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B

A

Figure 77-7  Histologic appearance of scleroderma renal crisis. A and  B, Typical histologic features are present, including interstitial fibrosis  (A), occlusion of intrarenal arteries with neointima formation, fibrinoid necrosis of the vessel wall, and reduplication of the internal elastic lamina (B). C, The glomeruli are shrunken and lack inflammatory cells or proliferative changes. D, In severe cases, there is evidence of intravascular thrombosis resembling the changes of ­thrombotic thrombocytopenic purpura.

D

C

Table 77-4  Prevalence of Major Internal Organ–Based Complications in Systemic Sclerosis (SSc) Approximate Frequency (%) Limited Cutaneous SSc

Diffuse ­ Cutaneous SSc

Raynaud’s phenomenon

99

98

Gastrointestinal tract

74

60

Kidney (scleroderma   renal crisis)

 1

15

Heart

 9

12

Lungs Pulmonary hypertension Interstitial lung disease

50 25 25

65 20 40

Organ Involved

Skeletal myopathy

10

25

Thyroid

15

10

common.70,71 Broad bands of fibrous tissue are seen in the ­thyroid gland, with atrophy and obliteration of the follicles, in the absence of inflammation.72 Patients with SSc frequently have abnormal thyroid function tests and antithyroid ­antibodies.73,74 Erectile dysfunction is common in men with SSc and may be a presenting manifestation of the disease. Pathologic examination shows extensive proliferative/obliterative changes in the penile blood vessels.75 Fibrosis of the salivary and lacrimal glands in the absence of inflammation can occur and may be associated with Sjögren’s syndrome. Synovial biopsy specimens show fibrosis and characteristic vascular changes in the small arterioles.76

ANIMAL MODELS OF SCLERODERMA Animal models of human disease can be valuable for investigating complex pathogenesis, for identifying the genetic underpinnings and cellular and molecular components of the process and their interactions, and for developing novel treatment strategies and evaluating their efficacy. A variety of animal models have been investigated as potential models for SSc. Although none reproduce all three cardinal features of the disease (obliterative/proliferative vasculopathy, autoimmunity, and fibrosis), some models do recapitulate selected characteristics.77 Mouse models of scleroderma can be divided into three types: (1) naturally occurring, where spontaneous mutations are associated with a genetically transmitted scleroderma-like phenotype, such as tight skin (Tsk1/+ mouse); (2) induced models, where the scleroderma phenotype is elicited by chemical exposures or manipulation of the immune system (bleomycin-induced skin and lung fibrosis); and (3) transplantation of HLA-mismatched bone marrow cells resulting in chronic sclerodermatous graft-versus-host disease and genetic manipulations giving rise to mouse strains with heritable scleroderma-like traits (Table 77-5). HERITABLE ANIMAL MODELS OF SCLERODERMA The tight skin mouse (Tsk1/+) is characterized by diffuse thickening and tethering of the skin. Although mice ­homozygous for the Tsk1 mutation die in utero at 8 to 10 days of gestation, heterozygous mice (Tsk1/+) survive and develop tight skin that is firmly bound to the underlying

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Table 77-5  Mouse Models of Scleroderma Aspects of Pathogenesis Vasculopathy, Vascular Activation

Inflammation

Autoimmunity

Fibrosis

Tsk-1

−

−

+

+

Tsk-2

−

+

+

+

Bleomycin (subcutaneous   injection)

−

+

−

+

GVHD (B10.D2 versus Balb/C)

+

+

−

+

GVHD (B10.D2 versus Rag-2−/−)

+

+

+

+

TGFβRII DN

−

+

−

+

MRL/lpr/IFNγR−/−

−

+

+

+

Conditional TGFβRI

+

+

−

+

Model

Key Features

Naturally Occurring Duplication mutation in fibrillin-1 gene Unknown genetic defect; early cutaneous inflammatory cell infiltrate

Induced Production of reactive oxygen species, monocytic inflammation, skin and lung fibrosis Transfer of spleen cells from B10.D2 mice into irradiated Balb/C mice results in chronic GVHD and fibrosis Transfer of spleen cells into RAG-2 null mice results in systemic fibrosis, inflammation, and autoantibodies

Transgenic Mice expressing a dominant negative TFGβRII develop systemic tissue fibrosis MRL/lpr mouse strain lacking IFN-γ receptors spontaneously develop systemic fibrosis Conditional expression of constitutively active TGF-β receptor in fibroblasts causes tissue fibrosis and inflammation

GVHD, graft-versus-host disease; IFN, interferon; TGF, transforming growth factor.

subcutaneous tissue. In contrast to human SSc, Tsk1/+ mice have subcutaneous hyperplasia, with unremarkable ­dermis.78 Tsk1/+ mice develop emphysematous changes in the lungs rather than fibrosis, and vasculopathy does not occur. Although skin inflammation is uncommon, Tsk1/+ mice do mount an autoimmune response with serum antibodies directed against topoisomerase I. The Tsk1 mutation has been localized to mouse chromosome 2, and subsequently identified as an intragenic tandem duplication in the gene encoding fibrillin-1.79 Fibrillin-1 is a large structural protein that is widely distributed in connective tissue microfibrils and is involved in the regulation of the latency and activation of TGF-β.80 Mutations in the fibrillin-1 gene are responsible for Marfan syndrome, characterized by activation of TGF-β in multiple tissues. The Tsk1/+ fibrillin-1 duplication mutation gives rise to an abnormally large 450-kD protein.79 No corresponding mutations in the fibrillin-1 gene have been shown in patients with SSc. As mentioned previously, the skin lesions in Tsk1/+ are due to tethering and thickening of the hypodermal tissue, rather than the dermal fibrosis characteristic of SSc, raising some doubt regarding the relevance of the Tsk1/+ mouse as a bona fide model for the human disease.78,81 Although it has been hypothesized that accumulation of abnormally

large mutant fibrillin-1 in Tsk1/+ mice destabilizes the ECM,82,81 or perturbs the homeostatic control of TGF-β latency, the precise mechanisms linking the Tsk1/+ mutation in fibrillin-1 to the development of cutaneous hyperplasia are unknown.77 Another potential animal model of scleroderma is the Tsk2 mouse. Heterozygous Tsk2 mice spontaneously develop scleroderma-like skin changes by age 3 to 4 weeks.83 The dermis is fibrotic and, in contrast to Tsk1/+ mice, shows extensive infiltration with mononuclear inflammatory cells. Tsk2/+ mice have evidence of autoimmunity.84 The Tsk2 mutation, originally induced by exposure of normal mice to ethyl nitrosurea, is located on mouse chromosome 1 and is inherited as an autosomal dominant trait, although the underlying molecular defect has not yet been ­identified.77 INDUCIBLE ANIMAL MODELS OF SCLERODERMA Chronic skin and lung fibrosis can be induced in normal BALB/c or C57 mice by subcutaneous bleomycin injections.85 The sequence of histopathologic changes in the lesional skin closely resembles that seen in SSc: early and self-limited mononuclear cell infiltration and upregulation of cytokines such as TGF-β and monocyte chemotactic protein (MCP)-1, followed by development of dermal fibrosis

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with excessive collagen deposition and accumulation of alpha smooth muscle actin–positive myofibroblasts.86,87 In contrast to SSc, bleomycin-induced scleroderma in the mouse is not associated with either vascular changes or autoantibodies, and skin fibrosis is limited in its extent and duration. Nevertheless, in light of its reproducibility, relative strain independence, and ease of induction, this mouse model of scleroderma is now widely used for investigating the pathogenic roles of specific gene products in fibrosis.87,88 Subcutaneous injection of TGF-β in newborn mice causes granulation tissue formation and transient fibrosis. Simultaneous injection of CTGF with TGF-β causes persistent fibrosis, suggesting that CTGF is required for sustaining the fibrotic response.89 Transplantation of HLAmismatched bone marrow or spleen cells into sublethally irradiated recipient mice results in sclerodermatous graftversus-host disease, characterized by chronic fibrosis of the skin and lung, perivascular fibrosis, and autoimmunity.90,91 In this model, skin fibrosis is preceded by mononuclear cell infiltration and elevation of TGF-β and chemokines. GENETIC MANIPULATIONS IN MICE GIVING RISE TO SYSTEMIC SCLEROSIS PHENOTYPES Various mouse strains with genetic modifications resulting in spontaneous development of scleroderma-like phenotypes have been created (see Table 77-5). These transgenic and knockout mice are currently undergoing intensive study and provide robust novel experimental tools in scleroderma research.92,93,88 Mouse strains with constitutive or inducible upregulation of TGF-β signaling in fibroblasts recapitulate key clinical, histologic, and biochemical features of SSc and provide support for the likely role of perturbed TGF-β signaling in pathogenesis.94,92

PATHOGENESIS INTEGRATED OVERVIEW The pathogenesis of SSc is complex and incompletely understood. Animal models reproduce only some of the diverse pathologic and clinical attributes of the disease. A holistic view of pathogenesis must integrate the three ­ cardinal features of SSc: vascular injury and damage, activation of the innate and adaptive arms of the immune system autoimmunity, and generalized interstitial and vascular fibrosis.71,95 Although each of these processes occurs in each patient, their relative contribution to the disease varies from one patient to another. The clinical heterogeneity of SSc is likely to be a reflection of the variable contributions of these pathogenetic processes. As illustrated in Figure 77-8, complex and dynamic interplay between these distinct processes is thought to be responsible for initiating, amplifying, and sustaining tissue damage in SSc.70 VASCULOPATHY Vascular Injury and Activation Vascular injury and activation are likely to be the initiating events in SSc. Evidence of vascular involvement is early and widespread, and is associated with significant

Inflammation Autoimmunity

Vascular injury

Fibrosis

Figure 77-8  Pathogenetic triad of systemic sclerosis. Patients with systemic sclerosis display evidence of autoimmunity and inflammation, vasculopathy, and fibrosis. Autoimmunity and vasculopathy apparently precede the onset, and contribute to the development and progression, of fibrosis. Vascular injury and fibrosis may contribute to chronic autoimmunity and inflammation.

clinical sequelae. The initial vascular insult apparently is endothelial cell injury, possibly triggered by unidentified serum cytotoxic factors or T cell–derived proteolytic granzymes.96 Other potential causes include endothelial cell–directed autoantibodies, vasculotropic viruses, inflammatory cytokines, and environmental stress. Vascular injury causes endothelial cell activation and dysfunction, with increased expression of vascular endothelial cell adhesion molecule-1 and endothelial leukocyte adhesion molecule-1, altered secretion of vasoactive mediators, and activation of platelets and fibrinolytic pathways.97,98 Activated platelets release thromboxane A2, PDGF, and TGF-β, which potentiate vasoconstriction, and contribute to fibroblast activation and myofibroblast transdifferentiation. Pericytes, which are smooth muscle–like structural cells normally found in the walls of small blood vessels, show marked hyperplasia in lesional skin from patients with early-stage SSc, and express the surface marker Thy-1 (CD90) and receptors for PDGF.99-101 Production of and responsiveness to endothelium-derived vasodilatory factors (nitric oxide, calcitonin gene–related peptide, and prostacyclin) are defective in SSc endothelium, and the altered vasodilator/vasoconstrictor balance results in impaired blood flow responses and episodes of ischemia-reperfusion with oxidative stress that amplifies vascular injury. Microvessels show increased permeability and enhanced transendothelial leukocyte migration. Fibrinolytic cascades are activated, and platelets are exposed to subendothelial structures, with resultant platelet activation and aggregation culminating in thrombosis. Activated endothelial cells release ET-1, the most potent potent vasoconstrictor known (Fig. 77-9). In addition, ET-1 promotes leukocyte adhesion and vascular smooth muscle cell proliferation, and induces fibroblast activation. The levels of ET-1 are elevated in the blood and in bronchoalveolar lavage fluids from patients with SSc.102-104 Expression of allograft inflammatory protein (AIF)-1, a macrophagederived protein important in the immune response and proliferative vasculopathy that occur during chronic allograft rejection (allograft vasculopathy), is elevated in blood

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Insult (virus, ROS, autoantibody)

Endothelial Cell Injury

Endothelial dysfunction Reduced NO, PGI, increased ET-I Vasoconstriction, impaired relaxation Ischemic-reperfusion, ROS generation

Vascular wall remodeling Neointimal formation SMC proliferation Adventitial fibrosis

Defective ECP mobilization from bone marrow

Impaired Vasculogenesis

1321

An apparent paradox is why, in the face of tissue hypoxia and ongoing angiogenic drive, is SSc associated with progressive loss of blood vessels. More recent studies implicate failure of vasculogenesis, owing to a reduction in the number of circulating endothelial progenitor cells and their impaired differentiation into mature endothelial cells.108-110 Because bone marrow–derived CD34+ circulating endothelial progenitor cells are essential for physiologic vasculogenesis in ischemic tissues, their defective mobilization or function compromises the vascular repair process. Whether the reduction in circulating endothelial progenitor cells noted in SSc patients is due to “exhaustion” of the bone marrow, or destruction in the peripheral circulation, remains unresolved. INFLAMMATION AND AUTOIMMUNITY T Cell Activation in Systemic Sclerosis

Luminal narrowing Shear stress Platelet aggregation Thrombosis

Vascular obliteration Tissue hypoxia Figure 77-9  Pathogenesis of vasculopathy. Initial endothelial insult results in endothelial cell activation, with reversible functional changes, increased expression of adhesion molecules, and enhanced leukocyte diapedesis resulting in perivascular inflammation. Damaged endothelial cells have impaired production of vasodilators, such as nitric oxide, and increased production of vasoconstrictors, such as endothelin-1. Consequent vasoconstriction and defective vasodilation aggravate vascular damage, leading to irreversible and progressive vascular wall remodeling, luminal occlusion, platelet aggregation, in situ thrombosis, and tissue ischemia. Loss of blood vessels may be compounded further by insufficient vasculogenesis.

and in affected vessels in lesional skin and lungs of patients with SSc.104a Because AIF-1 stimulates vascular smooth muscle cell proliferation, its increased expression and ­induction by TGF-β are likely to contribute to the vasculopathy of SSc. Vascular Damage and Defective Vasculogenesis in Systemic Sclerosis Hypertrophy of the intimal and medial layers of small blood vessels in combination with adventitial fibrosis causes progressive luminal narrowing. Together with endothelial cell apoptosis, the process culminates in obliterative vasculopathy and vascular rarefaction, with the characteristic striking decrease of blood vessels seen on angiograms of SSc patients with late-stage disease.104b Loss of microvasculature leads to chronic tissue hypoxia, which induces hypoxia-inducible factor-1–dependent genes such as VEGF and its receptors. Plasma levels of the angiogenesis inhibitor endostatin, a degradation product of type XVIII collagen, were reported to be increased in SSc (Fig. 77-10).105 Other studies found elevated levels of angiogenic factors VEGF, fibroblast growth factor, and PDGF. The expression of VEGF and its receptors were elevated in lesional tissue.52,106,107

The innate and the adaptive arms of the immune system seem to be activated in early SSc, and autoimmunity is prominent; however, the role of cellular and humoral autoimmune effector pathways in the pathogenesis is uncertain. Activation of T cells is evident in lesional tissues and in peripheral blood, and seems to play a direct role in tissue injury. In early stages of the disease, activated CD4 and CD8 T lymphocytes and monocytes/macrophages, and less commonly B cells, eosinophils, mast cells, and natural killer cells, are observed in perivascular regions in the lesional skin, lungs, and other affected organs; these inflammatory cell infiltrates are detectable before the appearance of fibrosis.43,111,112 Studies using in situ hybridization of skin biopsy specimens from patients with early SSc show that procollagen gene expression is higher in fibroblasts that are adjacent to inflammatory cells, suggesting a role for the inflammatory cells or their soluble products in inducing fibroblast activation.113 The extent of lymphocytic tissue infiltration correlates with the severity and progression of skin fibrosis.111 Tissue-infiltrating mononuclear cells are predominantly CD3+ and CD4+; express activation markers CD45, HLA-DR, and the interleukin (IL)-2 receptor; and display restricted T cell receptor signatures indicative of oligoclonal T cell expansion in specific response to antigen.114,115 In the lungs, a predominance of CD8+ cells and γ/δ T cells is observed.115 It is unknown whether T cells in lesional tissue are activated nonspecifically (by cytokines or chemokines) or specifically in response to an (unknown) antigen.116 Evidence of T cell activation in SSc also is detected in the peripheral blood. Serum levels of IL-2 are elevated, and circulating T cells show spontaneous cytokine secretion and increased expression of the IL-2 receptor. The mechanisms responsible for the migration and homing of activated mononuclear cells from the peripheral blood to target tissues, and their retention and accumulation there, are not well understood. Increased expression of lymphocyte function–associated antigen-1 and other adhesion molecules on SSc T lymphocytes may enable them to adhere directly to fibroblasts.117 Circulating CD4+ T cells in SSc cells also express elevated chemokine receptors and α1 integrin adhesion molecules, accounting for their enhanced binding ability to endothelium and to fibroblasts.118 Vascular endothelial cells express intracellular adhesion ­molecule-1,

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Injury

Endothelial cell activation

Inflammation Macrophages TGF-β production Chemokine production

Adaptive autoimmune responses T cell activation Th2 cytokine production B cell activation IL-6 production Autoantibody production

Endothelial dysfunction Adhesion molecules Endothelin-I production Impaired vasodilatation Enhanced vasoconstriction Vascular wall remodeling

Vascular obliteration Resident fibroblast activation Collagen production, deposition Matrix contracture, remodeling Myofibroblast transdifferentiation

Tissue hypoxia

Defective vasculogenesis

Bone-marrow-derived progenitor cells, fibrocytes

Tissue fibrosis Organ dysfunction Figure 77-10  Pathogenesis of fibrosis in systemic sclerosis. Fibrosis is the end result of chronic inflammation and autoimmunity and vascular damage and hypoxia. Injury results in vascular damage and perivascular inflammation, with local secretion and activation of fibrogenic cytokines and chemokines, inducing fibroblast activation and myofibroblast accumulation. Circulating mesenchymal progenitor cells traffic to and accumulate within the lesional tissue and transdifferentiate into fibrotic fibroblasts, accelerating matrix accumulation. Tissue hypoxia, matrix remodeling, and contraction contribute further to the fibrotic process, which disrupts tissue architecture and interferes with organ function.

E-selectin, and other adhesion molecules that facilitate leukocyte diapedesis. Studies employing DNA microarray analysis indicate that peripheral blood leukocytes from patients with SSc show increased expression of interferon (IFN)-regulated genes119 and genes encoding AIF-1, and selectins and integrins mediating leukocyte adhesion to the endothelium.120 T Helper Type 1/T Helper Type 2 Cytokine Balance and T Helper Type 2 Polarized Immune Responses in Systemic Sclerosis An emerging hypothesis for the pathogenesis of fibrotic disorders implicates an altered balance between T helper type 1 (Th1) and T helper type 2 (Th2) cytokines in aberrant response to tissue injury. T cells polarized to a Th2 pattern secrete abundant IL-4, IL-5, and IL-13, with a paucity of the hallmark Th1 cytokine IFN-γ. The Th2 cytokines are profibrogenic because they can directly stimulate collagen synthesis and myofibroblast transdifferentiation, and induce TGF-β, a powerful modulator of immunoregulation and ECM accumulation. In contrast, the Th1 cytokine IFN-γ blocks these responses and exerts antifibrotic effects. Skewing of the immune response toward a Th2 pattern contributes to a more profibrotic environment.

Animal studies have provided support for the significance of a Th2-polarized immune response in the pathogenesis of fibrosis. Cells that have been polarized in vitro to a Th2 pattern induce fibrosis when passively transferred in vivo.121 Mice lacking the transcription factor T-bet, which directs differentiation of T cells toward a Th1-predominant phenotype, spontaneously show a Th2-polarized immune response and develop exaggerated skin fibrosis in response to injection of bleomycin.122,123 Patients with SSc display a relative shift in the Th1/Th2 cytokine balance toward a Th2 predominance. The serum levels of IFN-γ, and its in vitro production by peripheral blood monocytes, are reduced.124,125 Peripheral blood leukocytes from SSc patients show elevated expression of the gene for the transcription factor GATA3, which drives Th2 polarization.126 Clones of CD4+ T cells generated from SSc skin biopsy specimens show a Th2 cytokine profile, with in vitro secretion of IL-4, but not IFN-γ.127 Alveolar CD8+ T cells from SSc patients show elevated Th2 cytokine production, and the Th2 predominance predicts accelerated decline in lung function.128,129 Proteomic analysis also showed a predominance of Th2 cytokines in SSc bronchoalveolar lavage fluids.130 Using DNA microarray technology, bronchoalveolar lavage fluid CD8+ cells from patients with SSc were shown to have an activated Th2 pattern of gene

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expression with increased levels of IL-4 and IL-13, and reduced production of IFN-γ.129 A longitudinal study of 26 patients with diffuse cutaneous SSc showed that improvement in skin involvement over time was associated with a decline in serum Th2 cytokines and a concomitant increase in IL-12, a Th1-inducing cytokine.131 The specific roles of the regulatory T cell and T helper type 3 T cell subsets in SSc have not yet been characterized.

Table 77-6  Autoantibody Associations in Systemic Sclerosis Antibody

Prevalence (%)* Clinical Association

Antinuclear antibody

>95

Limited and diffuse skin subsets

Anti–topoisomerase 1 (Scl-70)

15-20

Diffuse skin, tendon rubs, pulmonary fibrosis, increased mortality

Anticentromere

15-20

Limited skin (CREST), severe Raynaud’s phenomenon, digital ischemia, pulmonary hypertension

Nucleolar antibodies RNA polymerases

4-20

Diffuse skin, tendon friction rubs, scleroderma renal crisis, increased mortality Diffuse skin, AfricanAmerican, male Limited skin, isolated pulmonary hypertension Limited skin, myositis

Monocytes and Macrophages Phagocytic monocytes and macrophages have central roles in host defense, innate immunity, and tissue repair. Monocytes are a major source of regulatory cytokines and chemokines, including IL-1, tumor necrosis factor (TNF)-α, MCP-1, PDGF, and TGF-β, all of which are important in regulating immune, inflammatory, and fibroproliferative responses. In addition, monocytes produce collagenases and other matrix metalloproteinase enzymes that mediate tissue remodeling. Macrophages are prominent among the mononuclear cells infiltrating the lesional skin in early SSc.132 In addition, evidence of local mast cell and eosinophil activation and degranulation are seen in lesional skin. In SSc patients with active lung disease, alveolar macrophages obtained by bronchoalveolar lavage have an alternatively activated phenotype, characterized by secretion of the profibrotic mediators TGF-β, PDGF, and IL-13.133 Autoantibodies and Humoral Autoimmunity in Systemic Sclerosis Circulating autoantibodies with multiple antigenic specificities can be detected in virtually all patients with SSc, but a direct role of humoral autoimmunity in the pathogenesis of tissue damage has not been conclusively established. Autoantibodies in SSc tend to be highly specific and mutually exclusive (see later), and show strong associations with individual disease phenotypes. Serum levels of autoantibodies, in particular anti–topoisomerase I, may correlate with the extent of skin and lung fibrosis and show fluctuations with disease activity.134 Various hypotheses have been proposed to explain the generation of autoantibodies in SSc. According to one hypothesis involving the altered processing of self-antigens, patients with SSc-specific self-antigens, such as topoisomerase I, undergo fragmentation owing to proteolytic cleavage by reactive oxygen species. This fragmentation results in exposure of normally cryptic epitopes, and a break in immune tolerance with recognition of the peptide as immunogenic.135 Other mechanisms invoked to explain the generation of specific autoantibodies in SSc include molecular mimicry as a consequence of viral infection, chronic B cell hyperreactivity resulting from intrinsic abnormalities in B cell signaling, and increased expression or altered subcellular localization of potential autoantigenic peptides.136 Although SSc-associated autoantibodies have validated clinical utility as diagnostic markers, their contribution to disease manifestations is uncertain. More recent studies highlight the occurrence and potential biologic activities of autoantibodies directed against ECM components, ­fibroblasts, and endothelial cells or the PDGF receptor in some patients with SSc. The antibodies can induce target

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Fibrillarin (U3-RNP)

8

Th

5

PM/Scl

1

*Estimated prevalence in North American patients. CREST, calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia.

cell activation or apoptosis in vitro.15,137-139 It is unknown whether these autoantibodies precede, or are a consequence of, fibrosis, and their direct pathogenetic role in SSc remains to be established. Target specificities and clinical ­associations of key autoantibodies in SSc are summarized in Table 77-6. B Cell Activation and Function in Systemic Sclerosis More recent studies provide evidence for a potential direct role for B lymphocytes in the pathogenesis of SSc. B cells have multiple immunoregulatory functions in addition to the generation of antibodies, including antigen presentation, cytokine production, lymphoid organogenesis, and T cell differentiation. Although B cells are not generally prominent in lesional tissue, an activated B cell “signature” with increased expression of immunoglobulin genes was shown by DNA microarray analysis in SSc skin.55 Patients with SSc display intrinsic abnormalities of B cells.140 The number of naive B cells is elevated in the circulation, whereas plasma cells are markedly decreased. Memory B cells are chronically activated and display increased CD95, CD86, and CD19, a cell surface signaling receptor that regulates intrinsic and antigen receptor–induced B cell responses.140 Upregulation of CD19 seems to be specific for SSc and was not seen in other autoimmune diseases. Mice transgenic for CD19 develop spontaneous autoimmunity with production of high titers of anti–topoisomerase I antibodies.141 Altered B cell function and chronic activation in SSc may account not only for autoantibody production, but also fibrosis because activated B cells secrete IL-6, which directly stimulates fibroblast activation and the synthesis of collagen. Patients with SSc also have elevated levels of the potent

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B cell survival factor B cell activating factor belonging to the TNF family (BAFF) in the serum and in lesional skin, and B cells express increased levels of the BAFF receptor.131 FIBROSIS Overview: Molecular and Cellular Determinants of the Extracellular Matrix Interstitial and vascular fibrosis, the most characteristic and prominent pathologic manifestation of SSc, is characterized by replacement of normal tissue architecture with dense connective tissue. The ECM consists of a cellular compartment of resident and infiltrating cells, and connective tissue composed of collagens, proteoglycans, fibrillins, and adhesion molecules. The ECM also serves as a reservoir for growth factors and matricellular proteins that, together with the connective tissue compartment, control the differentiation, function, and survival of fibroblasts. Excessive connective tissue accumulation results from overproduction by fibroblasts and related mesenchymal cells that are activated by soluble factors in an autocrine/paracrine manner, by the surrounding ECM, or via cell-cell interactions. Impaired matrix degradation and turnover, and expansion of the pool of mesenchymal cells contributing to ECM synthesis also play a role. Regulation of Collagen Synthesis The collagens, the most abundant proteins of the ECM, constitute a family of more than two dozen structural proteins with critical roles in organ development, growth, and differentiation. Collagens can be classified as fibrillar and nonfibrillar. The ECM of the skin, bones, and tendons is composed largely of type I collagen, with smaller amounts of associated type III collagen. Type II collagen is found mainly in articular cartilage. The fibrillar collagens consist of three α chains wound into a characteristic triple helix, a structure made possible by the presence of a glycine at every third residue of repeating Gly-X-Y sequence, where X is frequently a proline, and Y is frequently a hydroxyproline. During their biosynthesis, fibrillar collagens undergo extensive enzymatic modifications inside the cell, and additional processing after their secretion. Covalent cross-linking stabilizes the collagen fiber network in the extracellular space. In normal fibroblasts, type I collagen synthesis can be regulated by cytokines and other soluble extracellular factors, and cell-cell and cell-matrix contact and tissue hypoxia (Table 77-7). These environmental cues allow fibroblast to respond to dynamic tissue requirements during development and tissue repair.71 The genes encoding the various collagens harbor cis-acting regulatory elements with conserved nucleotide sequences that are specifically recognized by DNA-binding transcription factors, including Sp1, Ets1, Smad2 and Smad3, Egr-1, and CCAAT-binding factor, which stimulate transcription, and Sp3, C/EBP, YB1, c-Krox, and Fli1, which suppress transcription.141 These transcription factors interact with one another and with non–DNA-binding cofactors, scaffold proteins, and chromatin-modifying enzymes such as p300/CREB binding protein (p300/CBP), PCAF, and histone deacetylases.

Table 77-7  Signaling Molecules Implicated   in the Pathogenesis of Fibrosis in Systemic Sclerosis Elevated in Systemic Sclerosis

Molecule

Cellular Source

Transforming   growth factor-β

Inflammatory cells, platelets, fibroblasts, macrophages

+

Platelet-derived growth factor

Platelets, macrophages, fibroblasts, endothelial cells

+

CTGF/CCN2

Fibroblasts

+

Insulin-like   growth factor-I

Fibroblasts

+

IL-4, IL-13

T helper type 2 lymphocytes, mast cells

+

IL-6

Macrophages, B cells,   T cells, fibroblasts

+

Chemokines   (MCP-1, MCP-3)

Neutrophils, epithelial cells, endothelial   cells, fibroblasts

+

Fibroblast growth factor

Fibroblasts

+

Endothelin-1

Endothelial cells

+

Serotonin

Platelets

+

The activities and interactions of transcription factors and cofactors are controlled by extracellular cues. Because enzymes that modify chromatin structure at target gene promoters enhance the availability of DNA-binding factors to their corresponding cis-acting regulatory sequences and induce transcription, the histone acetyltransferase p300/CBP and related chromatin-modifying enzymes are important components of the transcriptional regulatory network.142,157 Alterations in the expression levels, activities, or interactions among the various transcription factors and cofactors contribute to persistent fibroblast activation in SSc.143 Cellular Determinants of Fibrosis Fibroblasts.  Fibroblasts are capable of synthesis and degradation of ECM and are key effectors of the process of fibrosis. Under the influence of appropriate extracellular signals, these cells or their progenitors synthesize collagens and other ECM macromolecules; adhere to and contract connective tissue; secrete growth factors, cytokines, and chemokines or express surface receptors for them; and undergo transdifferentiation into myofibroblasts. Together, these biosynthetic, proinflammatory, contractile, and adhesive functions enable fibroblasts to mediate effective wound healing. Although under physiologic conditions the fibroblast repair program is self-limited, pathologic fibrosis is characterized by sustained and amplified fibroblast activation, resulting in exaggerated ECM accumulation and remodeling. Inappropriate fibroblast activation is the fundamental pathogenetic alteration underlying fibrosis in SSc.70 Fibroblasts are spindle-shaped cells that are responsible for connective tissue synthesis and turnover, and they play essential roles in organ development, tissue repair, and ECM homeostasis. Studies with DNA microarrays revealed that fibroblasts from different anatomic locations differ ­markedly in their pattern of gene expression, suggesting that ­fibroblasts

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in different sites in the body could be considered distinct differentiated cell types.144,145 The apparent “positional memory” of fibroblasts is governed by genetic imprinting by the HOX family transcription factors. Myofibroblasts, Pericytes, and Mesenchymal Cell ­Plasticity.  In fibrosis, the pool of activated mesenchymal cells contributing to ECM accumulation and remodeling in a tissue is expanded not only by proliferation of resident fibroblasts, but also by local transdifferentiation of other cell types, and the influx of mesenchymal progenitor cells from the circulation. Myofibroblasts are specialized cells that develop from fibroblasts in response to mechanical tension and TGF-β and express the cytoskeletal protein alpha–smooth muscle actin.146 Myofibroblasts synthesize collagens, tissue inhibitors of metalloproteinase (TIMP), and other ECM components, and are a major source of activated TGF-β during the fibrotic response.147 Their primary physiologic role is contraction of early granulation tissue. Contracting matrix, in turn, provides mechanical tension that promotes further myofibroblast differentiation.147a During normal wound healing, myofibroblasts are detected transiently and disappear; their removal from the lesion by apoptosis is a crucial step in wound resolution. In pathologic fibrogenesis, myofibroblasts persist, resulting in excessively contracted ECM characteristic of chronic scar. The presence of alpha–smooth muscle actin–positive myofibroblasts expressing Thy-1 is strongly associated with fibrotic disoders and SSc, but is absent from normal skin51,101 Pericytes are mesenchymal cells that normally reside in the walls of microvessels in intimate contact with the underlying endothelium; they regulate vascular homeostasis. The microvascular pericyte compartment in SSc shows marked hyperplasia and increased expression of PDGF receptors.101 Activated pericytes can transdifferentiate into collagenproducing fibroblasts and myofibroblasts, linking microvascular injury and fibrosis.101 Under certain conditions, epithelial cells also can undergo transformation to fibroblasts. The process of epithelial-mesenchymal transition plays a vital role during vertebrate embryonic development. Epithelial-mesenchymal transition is induced by TGF-β and suppressed by bone morphogenetic protein-7. Pathologic epithelial-mesenchymal transition occurs in cancer, renal fibrosis, and idiopathic pulmonary fibrosis.148 To date, the role of epithelial cells and epithelial-mesenchymal transition in the pathogenesis of SSc has not been examined. Mesenchymal Progenitor Cells in the Circulation.  Fibrocytes are CD34+ mesenchymal cells normally ­present in small numbers in the peripheral blood that can ­synthesize collagen and present antigen.149 These bone marrow–derived cells express CD14+ (a monocyte marker) and chemokine receptors (CCR3, CCR5, and CXCR4), which allows them to traffic into and accumulate in specific tissues. The role for circulating fibrocytes and their trafficking into lesional ­tissue in the pathogenesis of fibrosis was established in animal models using neutralizing antibodies, and in mice genetically deficient in CXCR4.150 It has been suggested that fibrocytes originating from bone marrow–derived monocyte precursor cells traffic into fibrotic lesional tissue, where they undergo specialization into fibroblasts and myofibroblasts, losing the CD14 and CD34 markers in the process, and contribute to the progression of fibrosis.151 Other studies have identified

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multipotent monocyte-derived mesenchymal progenitor cells in peripheral blood.108 The role of pericytes, fibrocytes, and other ­ monocyte-derived fibroblast progenitor cells in tissue ­damage in SSc remains speculative, however.152 MOLECULAR DETERMINANTS OF FIBROSIS: TRANSFORMING GROWTH FACTOR-β The expression of ECM genes is normally tightly regulated by paracrine/autocrine mediators, cell-cell contact, hypoxia, and contact with the surrounding ECM. Of the multiple cytokines implicated in SSc (see Table 77-7), TGF-β is considered to be the master regulator of physiologic fibrogenesis (wound healing and tissue repair) and pathologic fibrosis.153 TGF-β is highly pleiotropic and plays essential roles in normal tissue repair, angiogenesis, immunoregulation, and cell proliferation and differentiation, but it also is implicated in cancer, fibrosis, and autoimmunity.154 It is likely that a dynamic interplay between TGF-β and many other cytokines and growth factors contributes to fibrosis in SSc. Most cell types secrete TGF-β as a latent, inactive complex that is sequestered within the ECM. Under appropriate conditions, latent TGF-β is converted to its biologically active form capable of inducing responses through specific TGF-β receptors expressed on the surface of target cells. The activation of latent TGF-β is mediated by integrins, thrombo­ spondins, and proteolytic enzymes. Cellular Signaling by Transforming Growth Factor-β A member of a large cytokine superfamily that also includes activin and bone morphogenetic proteins, TGF-β is secreted by platelets, monocytes/macrophages, T cells, and fibroblasts. Most cell types express specific surface receptors for TGF-β. The responses elicited by TGF-β are specific for target cell lineage and are highly context-dependent. In mesenchymal cells, TGF-β acts as a potent inducer of fibrillar collagen synthesis; stimulates fibroblast proliferation, migration, adhesion, and transdifferentiation into myofibroblasts; and suppresses the production of matrix-degrading metalloproteinases (Table 77-8). Most cells generate TGF-β as a biologically inactive precursor molecule that resides as a latent complex in the ECM reservoir and is unable to interact with the TGF-β receptors. The conversion of latent TGF-β to its active form capable of binding its cell surface receptors is a complex process mediated by thrombospondin-1, integrins αvβ6 and αvβs, and various proteases, and is under tight regulation. On its activation, TGF-β binds to the type II TGF-β receptor, triggering an intracellular signal transduction cascade that leads to the induction of target genes.155 The evolutionarily conserved canonical TGF-β signal transduction pathway involves phosphorylation of the type I TGF-β receptor activin-like kinase 5, a transmembrane serine-threonine kinase that phosphorylates a group of intracellular signaling proteins called Smads. Ligand-induced phosphorylation of Smad2/3 allows them to form heterocomplexes with Smad4 and translocate from the cytoplasm into the nucleus. Within the nucleus, the activated Smad complex specifically recognizes and binds to a cis-acting DNA sequence (CAGAC) that defines the consensus Smad-binding element. On binding to the Smad-binding

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Table 77-8  Fibrogenic Activities of Transforming Growth Factor-β Recruits monocytes Stimulates synthesis of collagens, fibronectin, proteoglycans, elastin, TIMP; inhibits matrix metalloproteinases Stimulates fibroblast proliferation, chemotaxis Induces fibrogenic cytokine production (CTGF), autoinduction; blocks synthesis and activity of interferon-γ Stimulates production of endothelin-1 Stimulates expression of surface receptors for TGF-β, PDGF Induces fibroblast mitogenic responses to PDGF-AA Promotes fibroblast-myofibroblast differentiation, monocyte­fibrocyte differentiation Promotes epithelial-mesenchymal transition Inhibits fibroblast apoptosis CTGF, connective tissue growth factor; PDGF, platelet-derived growth factor; TGF, transforming growth factor; TIMP, tissue inhibitor of metallo­ proteinases.

element, activated Smads recruit transcriptional cofactors to the DNA, resulting in induction of gene transcription. The conserved Smad-binding element is found in the promoters of many TGF-β-inducible genes, including type I collagens, plasminogen activator inhibitor 1, alpha–smooth muscle actin, and CTGF. Ligand-induced signal transduction through the Smad pathway is tightly controlled by endogenous inhibitors such as Smad7. Although the Smad pathway is the central mediator of signals from the TGF-β receptors, more recent evidence indicates the existence of alternative non-Smad pathways that also participate in TGF-β signaling.156 Non-Smad signaling molecules activated by TGF-β include protein kinases (mitogen-activated protein kinases p38 and JNK, focal adhesion kinase FAK, and TGF-β activated kinase TAK1), lipid kinases such as PI3 kinase and its downstream target Akt, the calcium-dependent phosphatase calcineurin, and the tyrosine kinase c-Abl. These non-Smad pathways interact with one another and with Smads, creating complex signaling networks. Their importance and role in physiologic and pathologic fibrogenic responses remain to be established.157 MOLECULAR EFFECTORS OF FIBROSIS: CYTOKINES, GROWTH FACTORS, CHEMOKINES, AND LIPID MEDIATORS Multiple cytokines, growth factors, chemokines, and eicosanoids regulate ECM accumulation and mesenchymal cell function, and have been found to be elevated in SSc. These soluble mediators—most prominently CTGF, PDGF, IL-4, IL-6, and IL-13—contribute to the pathogenesis of fibrosis, and represent potential targets for antifibrotic therapy. Connective Tissue Growth Factor (CCN2) CTGF, a cysteine-rich 40-kD member of the CCN earlyresponse gene family, is a matricellular growth factor implicated in angiogenesis, wound healing, and development. Tissue expression of CTGF is undetectable in normal adults, but is markedly elevated in SSc and other fibrotic

c­onditions. In SSc, the serum levels of CTGF correlate with the extent of skin and pulmonary fibrosis.140,158 In normal fibroblasts, CTGF expression can be induced by TGF-β, IL-4, and VEGF, whereas TNF-α and iloprost block stimulation.159 In vivo, CTGF induces a transient fibrotic response in mice and markedly enhances the TGF-β response.160 In vitro, CTGF stimulates fibroblast proliferation, chemotaxis, and synthesis of collagen and fibronectin. Because many CTGF effects closely parallel the effects induced by TGF-β, it has been suggested that TGF-β responses are mediated through endogenous CTGF. The fibroblast receptors for CTGF and the mechanism of action underlying CTGF profibrotic responses are still incompletely characterized. Platelet-Derived Growth Factor and Other Fibrogenic Cytokines PDGFs are disulfide-bonded heterodimeric proteins consisting of an A and a B chain that act mainly on stromal cells and regulate the wound healing process. Originally isolated from platelets, PDGF isoforms also are produced by macrophages, endothelial cells, and fibroblasts. PDGF is a potent fibroblast mitogen and chemoattractant for fibroblasts; induces the synthesis of collagen, fibronectin, and proteoglycans; and stimulates the secretion of TGF-β1, MCP-1, and IL-6. Fibroblasts from patients with SSc show elevated expression of PDGF and PDGF-β receptor,161 and PDGF levels are increased in bronchoalveolar lavage fluid.162 Serum antibodies to the PDGF receptor from patients with SSc induce fibroblast activation in vitro138; however, stimulatory antibodies to the PDGF receptor are not specific for SSc and have been detected in the sera of patients with graft-versus-host disease as well. The immunomodulatory cytokine IL-4 plays a major role in Th2 diseases. In normal fibroblasts, IL-4 stimulates proliferation, chemotaxis, collagen synthesis, and production of TGF-β, CTGF, and TIMP.152 Serum levels of IL-4 are elevated in patients with SSc,163 and the number of IL-4-producing T lymphocytes is increased in peripheral blood.114,164 Expression of IL-4 and its mRNA is markedly elevated in SSc lesional skin and cultured fibroblasts. IL-6, produced by monocytes, T lymphocytes, fibroblasts, and endothelial cells, stimulates collagen and TIMP-1 synthesis, and promotes a Th2-polarized immune response. The biologic activities of IL-6 are mediated via the Jak-Stat intracellular signaling pathway shared with other cytokines. Serum levels of IL-6 are elevated in patients with SSc and correlated with the severity of skin involvement.165 IL-13 is implicated in asthma and other fibrotic conditions. The profibrotic effects of IL-13 involve indirect mechanisms secondary to stimulation of TGF-β production by macrophages and direct stimulation of fibroblast proliferation and collagen synthesis.166-168 Serum levels of IL-13 are elevated in patients with SSc. Chemokines represent a superfamily of more than 40 lowmolecular-weight soluble mediators originally ­characterized by their chemotactic effects on leukocytes, but now recognized to have a broad range of cellular targets and biologic activities, and to play important roles in angiogenesis, wound healing, and fibrosis.169 The CC chemokine MCP-1 stimulates collagen production directly and through induction of endogenous TGF-β production. Serum levels of

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MCP-1, macrophage inflammatory protein (MIP)-1α, IL-8, CXCL8, and CCL18 are elevated in SSc and correlate with the severity of skin fibrosis.85,163,170,171 Mononuclear cells and dermal fibroblasts from SSc patients spontaneously produce these chemokines, and lesional SSc fibroblasts show constitutive upregulation of the MCP-1 receptor CCR2.172 Because MCP-1 is capable of polarizing the immune response to a Th2 predominance, the MCP-1-CCR2 axis is thought to play a major role in the pathogenesis of SSc by amplifying collagen stimulation and promoting Th2 cytokine polarization. Significantly, mice defective for MCP-1 are resistant to the development of fibrosis induced by bleomycin injection.88 Strong expression of MCP-1 and MCP-3 was noted in lesional skin in SSc, particularly in early disease.173 These chemokines promote mononuclear leukocyte migration across the endothelial layer in vitro.92 The levels of MIP-1α, CXCL8, and CCL18 also are elevated in SSc bronchoalveolar lavage fluid. One study showed that elevated CCL18 levels identified SSc patients who had pulmonary fibrosis, and changes in CCL18 serum levels showed a strong negative correlation with changes in lung function in this cohort. Additional chemokines that have been shown to be overexpressed in lesional tissue or serum in patients with SSc or in animal models of scleroderma include the CC chemokines RANTES and PARC, and the CXC chemokines IL-8, MIP-2, and fractalkine. Insulin-like growth factor binding protein-1 (IGFBP-1) stimulates collagen synthesis and fibroblast proliferation and induces TGF-β.174,175 Patients with SSc have elevated levels of IGF-1 in bronchoalveolar lavage fluids.175 Expression of IGFBP-3 is markedly elevated in SSc fibroblasts.12 Adenovirally mediated overexpression of IGFBP-5 resulted in the induction of chronic scleroderma-like fibrosis in mice.176 Intrinsic Negative Regulation of Extracellular Matrix Accumulation To prevent excessive matrix accumulation and scarring in response to injury, redundant biologic mechanisms have evolved for suppressing ECM synthesis and fibroblast proliferation and differentiation. Fibroblasts are equipped with endogenous molecules that repress ECM gene expression and TGF-β stimulation. Smad7 is an inhibitory member of the Smad family that blocks Smad-mediated TGF-β signal transduction by accelerating ubiquitin-mediated TGF-β receptor degradation. Functional impairment of Smad7 was shown in SSc fibroblasts.177,178 Other cell-intrinsic endogenous repressors of collagen synthesis include the transcription factors Sp3, Fli-1, p53, and Ras, the corepressor Nab2, and the nuclear hormone receptor peroxisome proliferatoractivated receptor (PPAR)-γ.142,157,179 In SSc, diminished expression, induction, or function of these endogenous inhibitors, or their impaired responsiveness to extracellular ligands, may be responsible for failure to extinguish fibroblast activation, contributing to ECM upregulation in fibrosis. Interferon-γ IFN-γ, produced primarily by Th1 lymphocytes, is a major negative regulator of collagen gene expression and fibroblast activation. IFN-γ represses collagen gene expression71,180,181 and abrogates stimulation induced by TGF-β.157 IFN-γ also

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is a potent inhibitor of fibroblast proliferation, fibroblast­mediated matrix contraction, and myofibroblast transdifferentiation. Significantly, some studies have shown that fibroblasts from patients with SSc are resistant to the inhibitory effects of IFN-γ.182 Clinical trials of IFN-γ in SSc have shown a modest and inconsistent improvement in skin fibrosis.183-185 SCLERODERMA FIBROBLAST Fibroblasts explanted from lesional skin or fibrotic lungs of patients with SSc display an abnormal activated phenotype that persists during their serial passage in vitro, indicating autonomous alteration in cell function.143 The “SSc phenotype” is characterized by the following: enhanced ECM synthesis, secretion of profibrotic cytokines and chemokines and increased expression of their cell surface receptors, and resistance to IFN-γ and other inhibitory signals. SSc fibroblasts show features of myofibroblast transdifferentiation, partly as a result of constitutive activation of the focal adhesion kinase FAK.186 It is not established whether the activated phenotype of SSc fibroblasts represents an abnormality intrinsic to these cells, or reflects their activation in responses to exogenous stimuli. Numerous molecules involved in intracellular signal transduction and transcriptional regulation are elevated or activated in SSc fibroblasts, including protein kinase C, Smad3, Egr-1, p300, and c-Abl. Elevated expression of the prosurvival factors Bcl-2 and Akt in SSc fibroblasts may play a role in their resistance to apoptosis.187 Because most of the SSc fibroblast characteristics can be induced in normal fibroblasts by treatment with TGF-β, it has been suggested that the SSc phenotype is due to autocrine TGF-β signaling. The levels of TGF-β receptors are elevated on SSc fibroblasts, enabling these cells to mount a robust response to endogenously produced TGF-β or to low levels of environmental TGF-β.143,188-190 SSc fibroblasts have elevated levels of thrombospondin, αvβ5 and αvβ3 integrins, which mediate latent TGF-β activation at the cell surface.191 Consistent with the autocrine TGF-β hypothesis, SSc fibroblasts show constitutive activation of intracellular TGF-β signaling, with elevated expression and nuclear accumulation of activated Smad3,31,167,177 and constitutive interaction with the transcriptional coactivator and histone acetyltranferase p300/CBP.193,194 Other studies show defective expression or function of endogenous suppressors of TGF-β signaling and ECM production, suggesting that failure to terminate fibroblast activation may represent a fundamental defect in SSc. Endogenous molecules that negatively regulate fibroblast activation include Fli-1, PPAR-γ, Nab2, and Smad7.195,196 Autocrine TGF-β activation of fibroblasts cannot fully account for all of the phenotypic hallmarks of SSc fibroblasts, such as constitutive CTGF production, indicating that Smad-independent TGF-β signaling mechanisms and non–TGF-β-mediated activation events are involved in the induction or maintenance of the SSc phenotype. The autonomous SSc phenotype also could result from abnormal integrin-mediated signaling from the surrounding ECM. More recent evidence indicates that epigenetic alterations in SSc ­fibroblasts are associated with persistent and heritable fibroblast dysfunction. Silencing the

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Fli-1 gene, an important endogenous negative regulator of collagen gene expression, by DNA methylation or chromatin histone deacetylation, suppresses its expression in ­fibroblasts from lesional skin, with resultant increase in collagen ­synthesis.196

CLINICAL FEATURES The clinical manifestations of SSc are protean, reflecting its complex underlying pathology. The frequency of various clinical features differs according to the stage and subset of disease. In addition, the severity and activity of each complication needs to be considered in making treatment decisions. Fatigue and lethargy are common throughout the illness, although usually more pronounced in its early phases. Fever is uncommon; if fever is present, other causes, such as infection or underlying malignancy, should be excluded. Reactive depression is a frequent accompaniment to this often relentless and disfiguring disorder. Patients often feel isolated or depressed, and support groups can provide an invaluable service to them.

as secondary epithelial structures recover, hair growth and sweating may return before there is softening of the affected skin. Careful assessment of the extent of skin involvement is the best clinical technique for detecting the patient at risk for life-threatening internal organ involvement. Numerous scoring systems to quantify skin sclerosis have been developed. The most widely applied system consists of a 0-to-3 grading at 17 skin sites (maximum score 51). In this grading, normal skin scores 0, mild (or equivocal) thickening scores 1, established (or definite) thickening without fixation to deeper tissues scores 2, and severe thickening with fixation to deep tissues (hidebound) scores 3. Overall within-patient variability in scoring (derived from multiple examinations) is about 5 skin-thickness units.196a Controlled trials of penicillamine and recombinant relaxin have provided insight into the natural history of skin involvement in SSc, emphasizing that after 2 to 3 years there is often plateauing or improvement of skin score even without effective treatment. Novel assessment tools for skin involvement, such as high-frequency ultrasound,196b skin deformity,197 or durometry,198 are under investigation.

SKIN MANIFESTATIONS Skin thickening and hardening are the hallmarks of SSc. In patients with limited cutaneous SSc, skin changes generally are restricted to the hands and face, with some extension to the neck and forearms, and are generally preceded by Raynaud’s phenomenon. Different patterns of skin involvement can develop. In some cases, there is puffiness and swelling of the skin, especially over the digits. In other cases, the skin changes are more atrophic with tightened fingers and loss of subcutaneous tissue. Complications of digital ischemia including pitting scars and ulceration occur (see later). The skin changes in diffuse cutaneous SSc are more consistent. Typically, the first manifestation is soft tissue edema affecting the hands, wrists, and lower limbs, followed by inflammation of the skin with intense pruritus that might persist for the first 12 to 18 months of disease. Skin thickening with dermal fibrosis and sclerosis follows. The sclerosis typically moves proximally, and at this stage of diffuse cutaneous SSc an advancing edge of involved skin can be identified. Simultaneously, involvement of truncal skin and in more severe cases upper arms and thighs may occur. Proximal skin involvement defines the diffuse cutaneous SSc subset, but may be absent in early stages of disease. The changes in the skin usually proceed through three phases: early, established, and late. The early stage can be difficult to diagnose, and a high level of suspicion is needed when the only feature may b e puffiness of the hands and feet, most marked in the mornings. Nonpitting dependent edema may occur and lead to symptoms of neural compression, including carpal tunnel syndrome. The subsequent, often sudden, development of firm, taut, hidebound skin proximal to the metacarpophalangeal joints, adherent to deeper structures such as tendons and joints and limiting their movement, permits a definitive diagnosis of SSc. The skin may be coarse, pigmented, and dry at this stage. The epidermis thins, hair growth ceases, sweating is impaired, and skin creases disappear. Later,

Ischemic Ulceration Ischemic ulceration is a common complication in limited and diffuse cutaneous forms of SSc. Ulcers may occur on the fingertips, in the finger creases, over extensor surfaces of joints, and in association with calcinosis cutis, and cause pain and functional impairment. Several pathologic mechanisms operate to cause digital ulceration and critical ischemia. The latter describes the context in which there is inadequate tissue nutrition affecting a digit, but without ulceration. It is frequently painful and generally is taken as a sign of impending ischemic ulceration. Local trauma, such as cuts or abrasions, may be an initiating event, which, in concert with impaired healing owing to poor vascular flow, dermal fibrosis, and epidermal atrophy, leads to chronic, poorly healing skin ulcerations. Management of digital ulceration requires a multifaceted approach (Fig. 77-11). Treatment of vasospasm, use of skin emollients, and treatment of secondary infection all are important. Prostacyclin infusions have been shown to improve healing of ischemic digital ulcers and may reduce recurrent ulcer formation. Endothelin receptor blockers have been shown to reduce the formation of new digital ulcers, but have no effect on healing of established ulcers.199 Cutaneous Telangiectasia Cutaneous telangiectasia, dilations of dermal blood ­vessels, occur in limited cutaneous SSc and diffuse cutaneous SSc, but are more extensive in limited cutaneous SSc, particularly the subgroup previously designated as CREST (­calcinosis, Raynaud’s phenomenon, esophageal involvement, sclerodactyly, and telangiectasia) syndrome. Telangiectasias are often prominent on the palms and lips, have a typical oval appearance, and tend to increase in number over time, possibly indicating progression of the vascular manifestations at other sites.200 Although previously considered a hallmark of limited cutaneous SSc, it seems that late-stage diffuse cutaneous SSc also is associated with extensive ­cutaneous and

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Assessment of Raynaud’s severity (e.g. RCS) Swab infected ulcer Radiography or ultrasound/MRI to examine bone and soft-tissue Doppler angiology — to assess macrovascular circulation Arteriography — usually DSA, sometimes MRA useful Exclude embolic disease Vasodilators (e.g. CCB, ARB)

Antibiotics — prolonged courses oral or iv

Analgesic — opiates often required Anti-platelet therapy e.g. clopidogrel; low MW heparin

Parenteral prostacyclin

Advanced oral vascular therapies (e.g. bosetan, sildenafil)

Surgery — radical microarteriolysis Débridement, amputation Figure 77-11  Algorithm summarizing the management of digital vasculopathy in systemic sclerosis. Manifestations of vasculopathy include Ray­ naud’s phenomenon, ischemic digital ulceration, and critical digital ischemia—fixed ischemia with threatened tissue viability, ischemic pain, and refractory digital infection. Treatment includes local measures to maximize tissue viability and quantify any large vessel pathology or source for emboli. Pain control, treatment of infection, and optimization of blood supply to ischemic territories are paramount. Modern treatments that have been effective in treatment of pulmonary arterial hypertension, such as endothelin receptor antagonists or phosphodiesterase type 5 inhibitors, have been evaluated. Prostacyclin analogues are widely used for acute management. RCS, Raynaud clinical severity.

A

B mucosal vascular lesions. The nail-fold capillaries are almost always abnormal in SSc (Fig. 77-12). Dropout of capillary loops is the cardinal abnormality, with later changes i­ncluding dilation of loops and evidence of neovascularization. Systematic examination suggests that capillary dropout is a hallmark of ­progression in SSc.201

Figure 77-12  Nail-fold capillaroscopy. Digital nail-fold capillaroscopy can identify microvascular abnormalities in patients with Raynaud’s phenomenon. In systemic sclerosis, small vessel density, diameter, and tortuosity are abnormal. A, The most prominent feature is capillary dropout. B, Even capillary distribution with tortuosity at upper limit of normal, a pattern consistent with primary Raynaud’s phenomenon.

VASCULAR FEATURES Raynaud’s Phenomenon Episodic vasospasm induced by cold or emotional stress is common in the general population, affecting a substantial number of otherwise healthy individuals. The overall

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p­ revalence of Raynaud’s phenomenon is 3% to 10% of adults worldwide, although it may affect 20% of young women. The prevalence varies depending on climate, skin color, ethnic background, and occupational exposure to vibrating machines.202 The clinical classification of Raynaud’s phenomenon and related disorders is summarized in Table 77-9. Although Raynaud’s phenomenon may occur in most connective tissue and rheumatic diseases, it is a near-universal accompaniment of SSc. Raynaud’s phenomenon can predate the development of other features of SSc by several years, particularly in patients with the limited cutaneous Table 77-9  Classification of Raynaud’s Phenomenon Isolated Raynaud’s phenomenon Occupational Raynaud’s phenomenon   Cold injury   Vibrating tools   Polyvinyl chloride exposure Secondary Raynaud’s phenomenon   Systemic sclerosis   Mixed connective tissue disease   Sjögren’s syndrome   SLE   Polymyositis/dermatomyositis   Rheumatoid arthritis   Arteritis   Antiphospholipid antibody syndrome   Primary biliary cirrhosis   Carpal tunnel syndrome   Cryoglobulinemia   Vasospastic disorders (migraine, Prinzmetal angina) Infection   Hepatitis C   Cytomegalovirus (?) Obstructive vascular disease   Atherosclerosis   Thromboangiitis obliterans   Thoracic outlet syndrome (cervical rib) Metabolic syndrome   Hypothyroid Carcinoid syndrome Drug-induced   Antimigraine   β-blocker   Bleomycin   Interferons   Ergotamine derivatives SLE, systemic lupus erythematosus.

Figure 77-13  Spectrum of ischemic tissue secondary to Raynaud’s phenomenon. In a mild form, digital ischemia contributes to the development of small hyperkeratotic plugs of ischemic scar tissue over the finger pulp. A, In patients with systemic sclerosis, these plugs evolve to form digital pitting scars. B, More severe ischemia leads to digital ulceration, digital infarction, gangrene, and mummification.

A

form. Key features that distinguish Raynaud’s phenomenon evolving into SSc include the presence of significant structural change in the nail-fold capillaries, the presence of trophic changes and pitting scars or keratin plugs on the pulp surface of digits (Fig. 77-13), and the presence of antinuclear autoantibodies. Complications of severe Raynaud’s phenomenon include critical digital ischemia and ulceration. The clinical syndrome, first described by Maurice ­Raynaud in 1862 as episodic digital ischemia provoked by cold and emotion, is classically manifest by intermittent pallor of the digits followed by cyanosis, suffusion, or pain and tingling. Blanching reflects digital arterial vasospasm, ­cyanosis reflects the deoxygenation of static venous blood, and redness reflects reactive hyperemia after the return of blood flow. Continuous blanching, blueness, or pain is not Raynaud’s phenomenon. Important clues to secondary Raynaud’s phenomenon include onset in children or adults older than 45 years; severe symptoms occurring all year round; digital ulcerations, which rarely, if ever, occur in primary Raynaud’s phenomenon; and asymmetric symptoms. The most distal parts of the skin and its appendages receive their nutrient blood supply from capillary loops that arise from and return to a vascular plexus deeper in the skin. These capillary loops can be visualized in the skin fold of the fingernail just proximal to the cuticle, where the capillary is visible over its long axis.203 The characteristic changes seen in individuals destined to develop connective tissue disease are enlargement of capillary loops and loss of capillaries, either diffusely or adjacent to enlarged capillaries. Small hemorrhages around disordered capillaries also may be seen. Tests for autoantibodies and nail-fold capillaroscopy together detect more than 90% of patients destined to develop SSc.204 Of the population with Raynaud’s phenomenon, 15% are positive for one or both findings. Conversely, these tests are even stronger as negative predictors of progression; individuals with isolated Raynaud’s phenomenon, normal nail-fold capillaroscopy, and no antinuclear antibodies almost never develop connective tissue disease.205 There is little evidence that symptomatic treatment of Raynaud’s phenomenon influences the evolution of SSc. Some individuals with little skin involvement have typical capillaroscopic and serologic features of SSc and additional features such as esophageal reflux. These patients have previously been designated as “autoimmune Raynaud’s,” but the term limited SSc might be more appropriate.206

B

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Critical Digital Ischemia Critical digital ischemia and digital gangrene represent medical emergencies that require intensive treatment. Although Raynaud’s phenomenon undoubtedly contributes to these complications, critical ischemia develops only in the setting of fixed structural vascular disease. Amputation specimens show occlusive vasculopathic changes resembling those observed in other vascular beds. Occlusive vasculopathy affects medium-sized arteries, especially the ulnar artery.207 Management of critical digital ischemia includes optimal treatment for Raynaud’s phenomenon, together with antiplatelet agents such as aspirin or clopidogrel. Parenteral prostacyclin and selective phosphodiesterase inhibitors may be helpful.208,209

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Table 77-10  Gastrointestinal Manifestations   of Systemic Sclerosis Site

Manifestation

Mouth

Perioral tight skin Reduced oral aperture Dental caries; xerostomia

Esophagus

Dysmotility, reflux Stricture, Barrett’s metaplasia

Stomach

Gastroparesis

Small bowel

Hypomotility, stasis Bacterial overgrowth Pseudo-obstruction Intestinal pneumatosis

Large bowel

Hypomotility, pseudo-obstruction Colonic pseudodiverticula

Anorectum

Sphincter incompetence

Involvement of Large Vessels Similar to other autoimmune rheumatic diseases, including systemic lupus erythematosus and rheumatoid arthritis, macrovascular disease can occur in SSc, although its frequency is unknown. Large vessel involvement has important implications for organ-based complications, such as renal disease, peripheral ischemia, and bowel involvement. Noninvasive studies have shown blood flow abnormalities in the large vessels in the cerebral and renal circulation in patients with SSc,210 and symptomatic and asymptomatic macrovascular disease are increased.211,212 A more recent study of macrovascular involvement showed a predilection for the ulnar artery.207 Postmortem studies have reported that cerebrovascular disease, especially with vascular calcification, may be disproportionately severe in patients with limited cutaneous SSc compared with macrovascular disease at other sites.212a GASTROINTESTINAL TRACT MANIFESTATIONS The gastrointestinal tract is the most commonly involved internal organ system in diffuse and limited cutaneous ­ subsets of SSc, and almost any part may be affected. ­Gastrointestinal tract involvement results in substantial morbidity. The earliest lesion is neural dysfunction, possibly resulting from arteriolar changes in the vasa nervorum42,213 or compression of nerve fibers by fibrous tissue.214 The ­burden of ­gastrointestinal complications is outlined in Table 77-10. The oral aperture becomes diminished, and there is a reduction in bulk of the lips. These changes result in compromised dental care, dental and gum disease, and dry mouth. The cosmetic effect can be substantial.215 Esophageal involvement is frequent with dysmotility and lower esophageal sphincter dysfunction, and consequent gastroesophageal reflux is almost universal in SSc.216 The earliest clinical symptoms may be subtle, or patients may experience retrosternal discomfort or even overt pain, which can be nocturnal. Over time, chronic gastroesophageal reflux disease and its complications develop. In patients with frank dysphagia, esophagoscopy may be required to identify structural changes, such as hiatal hernia, esophageal strictures, or Barrett’s metaplasia.60,217 The stomach is frequently involved, with delayed gastric emptying that can lead to postprandial bloating and vomiting.

Severe involvement of the small intestine typically occurs in patients with established SSc and can be a major cause of morbidity and mortality. In its most severe form, small intestinal involvement leads to recurrent episodes of intestinal pseudo-obstruction secondary to ileus with dilated small bowel loops. Although clinical suspicion is raised by features of pseudo-obstruction, there also are characteristic abnormalities on diagnostic imaging. Contrast studies may show the “stack of coins” sign, owing to close apposition of the valvulae conniventes. Small bowel bacterial overgrowth complicating hypomotility results in recurrent diarrhea and bloating, and in more severe cases leads to malabsorption, weight loss, malnutrition, and cachexia. The classic symptoms are change in bowel pattern, with frequent loose, floating, foul-smelling stools, and abdominal distention. Management of advanced bowel disease includes rotating antibiotics, stimulation of intestinal motility with prokinetic agents such as erythromycin or domperidone, and supplemental alimentation. In the short-term, nocturnal feeding to maintain nutrition and a nasogastric or nasojejunal feeding tube may be effective. Longer term nutritional supplementation requires percutaneous jejunostomy, or gastroscopy if stomach emptying is not delayed. When malnutrition is the major problem, intermittent parenteral hyperalimentation may be required.218 Large bowel involvement is commonly manifested by constipation, which may be complicated by sigmoid volvulus. Anorectal incontinence is a frequent manifestation. Investigations include anal manometry and imaging to assess the integrity of the internal and external anal sphincter. Atony and hypomotility of the rectum and sigmoid colon is a frequent and early manifestation of SSc that may be missed because patients are reluctant to discuss these symptoms. Constipation is initially managed conservatively with dietary manipulation and stool volume expanders. Codeine can cause constipation and should be avoided. Surgery in the gastrointestinal tract must be viewed with caution. Manometric and radiographic localization of affected segments of stomach, small intestine, and colon may allow judicious surgical resection or venting procedures, but these are not risk-free and are not always successful.219

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Vascular Abnormalities within the Gastrointestinal Tract Vascular lesions of the intestinal mucosa, a cause of chronic anemia in SSc due to intermittent bleeding, may be scattered throughout the gut (Fig. 77-14), or take the form of vascular ectasia around the cardia of the stomach. This lesion, previously called “watermelon stomach” (owing to its characteristic endoscopic appearance) is now termed gastric antral vascular ectasia.220 Vascular lesions in the intestinal tract can be treated by laser or argon plasma photocoagulation.221,222 Liver and Pancreas The liver is generally spared in SSc. The exception is primary biliary cirrhosis, which may rarely occur in patients with SSc, especially the limited cutaneous form, and has a better prognosis than isolated primary biliary cirrhosis.223 Pancreatic exocrine insufficiency can contribute to malabsorption and diarrhea. Formal pancreatic function testing indicates that pancreatic exocrine function is frequently reduced, but rarely to an extent that is clinically important.224 MUSCULOSKELETAL INVOLVEMENT Joints The fibrotic process of SSc commonly affects the tendons (causing tendon friction rubs), ligaments, and joint capsules, restricting movement. In addition, fibrosis is found in the synovium, but frank arthritis and joint destruction are uncommon. Management of soft tissue and joint problems in SSc is closely linked to skin care and to overall skeletal mobility. Resorption of the distal tufts of the digits (acro-osteolysis) is frequent in late-stage disease and is due to inadequate vascular supply required for viable bone. Other sites of bone resorption include the mandible and the ribs. Contraction of the fingers is a hallmark of SSc, may develop rapidly, and has a significant impact on hand function. Less commonly, contractures can affect large joints. Tendon friction rubs, most common in patients with early-stage diffuse cutaneous SSc,

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are correlated with rapidly progressive skin involvement and increased risk of scleroderma renal crisis.225 Tendinitis may cause severe inflammatory pain in SSc and contributes to the development of tendon contractures. Swelling of the tendons and soft tissues in the wrist often leads to median nerve compression with carpal tunnel ­syndrome. Arthralgia is common, especially in the early stage of the diffuse cutaneous form of SSc. The presence of arthralgia often causes diagnostic uncertainty, particularly in patients with early disease who have not yet developed other cardinal features of SSc, such as Raynaud’s phenomenon or esophagitis. Frank arthritis may rarely occur as a complication, or as part of an overlap syndrome; this is important to recognize because arthritis may be quite responsive to therapy, and because the combination of joint pain and reduced mobility in the context of active skin involvement in SSc often leads to particularly severe hand deformity. Symmetric polyarthritis, usually seronegative, anodular, and nonerosive, may be the presenting feature in rare patients destined to develop SSc.226 Skeletal Muscle Involvement Some degree of skeletal muscular involvement is common in SSc. Although muscle weakness and atrophy may result from disuse secondary to joint contractures or chronic disease, about 20% of SSc patients develop a true myopathy characterized by mild chronic weakness and atrophy, minimal elevation of creatine phosphokinase, subtle abnormalities on electromyography, and modest noninflammatory histologic alterations with focal replacement of myofibrils with collagen and perimysial and epimysial fibrosis. This form of myopathy is generally unresponsive to anti-inflammatory medication.227 Some patients develop inflammatory myositis indistinguishable from polymyositis. Caution must be observed with patients who develop myositis in the context of early diffuse cutaneous SSc, when treatment with high-dose corticosteroids might precipitate renal crisis. An atypical inflammatory myositis that requires special histochemical stains to show the differences in fiber size and composition has been reported in association with myocarditis

B

Figure 77-14  Mucosal vascular lesions in systemic sclerosis. Telangiectatic lesions can occur on mucosal surfaces and contribute to gastrointestinal blood loss. A, Typical lesion on the colonic mucosa is shown. B, Florid vascular dilation (arrow) can develop in the gastric antrum and lead to the development of gastric antral venous ectasia (“watermelon stomach”), with upper gastrointestinal hemorrhage.

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in some patients with diffuse cutaneous SSc. In practice, it is important to distinguish between inflammatory myositis (true SSc-myositis overlap) and a chronic low-grade, predominantly fibrotic, myopathy. CARDIAC INVOLVEMENT The frequency of significant cardiac involvement in SSc has been difficult to ascertain, although it is believed to be frequent and can have a major impact on survival.66,231,242-244 A potential consequence of myocardial involvement is reduction in the ability to cope well with intercurrent hemodynamics of cardiac stress such as that due to electrolyte disturbance, fluid shift, or acidosis. The pericardium and the myocardium are frequently affected. In contrast to myocardial involvement, abnormalities of the pericardium are easy to detect by virtue of the formation of a pericardial effusion. Thirty-five percent of SSc patients are found to have hemodynamically insignificant effusions. Larger effusions are less frequent.232 Pericardial effusions in SSc are often associated with complications such as PAH and scleroderma renal crisis, where they may precede the onset of renal failure. Numerous cardiac manifestations may develop in SSc, reflecting the disparate pathologic processes that can affect

the myocardium. Clinically, it is useful to distinguish abnormalities of cardiac rate and rhythm that reflect inflammation or fibrosis from diffuse myocardial involvement leading to altered hemodynamics. Current approaches to investigation and treatment of cardiac involvement in SSc are summarized in Figure 77-15. Cardiac involvement in SSc may be due to ischemic damage, myocarditis, replacement fibrosis, systemic hypertension, and PAH. Evidence of diastolic dysfunction, suggesting abnormal ventricle wall stiffness or defective ventricular relaxation or both, is found in most patients.233-236,248 The abnormalities predominantly affect the longitudinal (endocardial) fibers, which fits well with the histologic findings of diffuse patchy fibrosis found in more than 40% of autopsies. It has been suggested that this lesion results from intermittent vasospastic ischemia, and that therapy directed at relieving ischemia may improve outcome.238 Ambulatory monitoring shows reduced heart rate variability, suggestive of widespread autonomic dysfunction, in most patients with SSc.239 Myocardial involvement may be due to myocardial ischemia, fibrosis, and myocarditis. Potential mechanisms for ischemic damage include coronary arterial vasospasm, small vessel disease, and occlusive coronary artery disease. Histologic examination of the coronary arteries in SSc has not

Routine — baseline and regular annual assessment

ECG Echo with Doppler Clinical asessment — palpitations, dyspnea, edema Signs of heart failure

Advanced assessment

Further investigation Longer ECG monitoring MUGA Stress-Echo Thallium perfusion scan Other imaging techniques — gated MRI, backscatter echocardiography, Tissue Doppler Serum troponin, N-pro-BNP

Specialized assessment

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Left and right heart catheterization Determine cardiac index, PCWP, coronary artery disease, other abnormalities

Reduced systolic function — consider endomyocardial biopsy

Cardiac muscle abnormality myocarditis ? immunosuppression

Hemodynamically significant pericardial effusion — sometimes surgical fenestration.

Hemodynamically significant arrhythmia or conduction defect — treat — pacemaker or ICD

Diastolic dysfunction — significance unclear

Figure 77-15  Evaluation and management of cardiac complications of systemic sclerosis. All patients with systemic sclerosis should undergo cardiac assessment, including clinical evaluation, chest radiograph, electrocardiogram (ECG), and Doppler echocardiography at baseline and on an annual basis. Determination of serum markers such as NT-proBNP and troponin may be useful. Long-term monitoring is required to assess intermittent arrhythmias; generally, only hemodynamically significant cardiac manifestations are treated. When inflammatory myocarditis is suspected, steroids and immunosuppression may be appropriate. Coincidental viral myocarditis should be considered in the differential diagnosis.

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shown excess fibromuscular hypertrophy, however. The frequency of angiographically proven coronary artery disease does not seem to be increased.240 An association between cardiac mortality and myositis has been shown in SSc, raising the possibility of associated myocarditis. Myocarditis may explain the frequent occurrence of exudative pericardial effusions in SSc, endocardial lesions found on histology, and ECG evidence of conducting tissue damage. Although at present there are few published data suggesting low-grade myocarditis leading to diastolic dysfunction and the other cardiac abnormalities in SSc, we have described excess of troponin T release.241 An attractive hypothesis is that low-grade intermittent myocardial inflammation causes subtle myocardial damage in the first few years when the disease process is most active, leading to mild fibrosis with diastolic dysfunction in later stages. Gated magnetic resonance imaging (MRI) is a novel tool potentially useful for detecting myocardial fibrosis and for quantitation of abnormal contraction or relaxation.241a Sudden death in young and middle-aged patients with SSc has been reported and is believed to be caused by ischemic damage to the cardiac conduction system. PULMONARY INVOLVEMENT Although interstitial lung disease has long been recognized as a common and significant complication of SSc, PAH has been less well appreciated until more recently. Although these two major pulmonary complications of SSc are considered separately, subsequently, they commonly occur together. Additional pulmonary complications of SSc include aspiration pneumonia, pleural disease, spontaneous pneumothorax, drug-induced pneumonitis, pneumoconiosis, and cancer. Table 77-11 summarizes the respiratory complications of SSc. Pulmonary Fibrosis The most common forms of interstitial lung disease in SSc are histologically classified as usual interstitial pneumonia and nonspecific interstitial pneumonitis. Investigation and assessment of interstitial lung disease in SSc focuses on

A

early detection, assessment of severity, and determination of progression and is best performed by regular pulmonary function tests. High-resolution computed tomography (CT) remains the most valuable tool for detection of early lung fibrosis (Fig. 77-16).242 Interstitial lung disease develops insidiously and generally progresses to fibrosis. Because lung fibrosis is irreversible, early diagnosis is vital. The most common initial symptoms are breathlessness, especially on exertion, and a dry cough. Chest pain is infrequent, and hemoptysis is rare; the presence of either one indicates additional pathology. On physical examination, the most frequent finding is bilateral inspiratory crackles at the lung bases. Radiographic features consist of reticulonodular shadowing, usually symmetric and most marked at the lung bases. Because the chest radiograph is an insensitive indicator of alveolitis or early pulmonary fibrosis, however, it should be used only as an initial screen or to exclude infection or aspiration. Mildly symptomatic SSc patients often have normal chest radiographs despite interstitial lung disease, and pulmonary function tests are more discriminatory. The single-breath diffusion capacity of lung for carbon monoxide is abnormal in more than 70% of patients with diffuse cutaneous SSc, including asymptomatic patients with no complaints and an unremarkable chest radiograph.243 A reduction in diffusion capacity is the earliest detected abnormality in SSc patients who go on to develop interstitial lung disease. The Table 77-11  Pulmonary Manifestations of Systemic Sclerosis Pulmonary fibrosis, alveolitis Pulmonary hypertension   Primary (PAH)   Secondary to pulmonary fibrosis, loss of vascular beds Aspiration pneumonitis Pleural effusions, pleuritis Bronchiectasis Lung cancer PAH, pulmonary arterial hypertension.

B

Figure 77-16  Computerized chest imaging. The high-resolution CT scan provides the most sensitive method of detecting lung fibrosis in systemic sclerosis. A, The earliest CT feature of lung fibrosis is increase in interstitial opacity. Amorphous change in the absence of traction bronchiectasis may suggest alveolitis, but similar changes may be caused by fine fibrosis. Later more reticular change develops, sometimes with associated cysts. Chest CT also may identify severe esophageal involvement with air in the esophagus, and enlargement of the proximal pulmonary vascular tree in advanced pulmonary arterial hypertension. B, In contrast, chest radiography detects only more advanced fibrotic change, but can exclude other pathology. In this example, severe lung fibrosis is associated with pulmonary arterial hypertension causing increased vascular markings in the hilar region with attenuation of vascular markings peripherally.

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c­ ombination of normal lung volumes but reduced gas transfer in the face of normal chest imaging suggests pulmonary vascular disease.244 The application of high-resolution CT has been of immense value for definition and assessment of diffuse lung diseases and has revealed the character and distribution of fine structural abnormalities not visible on chest radiographs.245 The earliest detectable high-resolution CT abnormality is a narrow, often ill-defined, subpleural crescent of increased density in the posterior segments of the lower lobes.175 When more extensive, the shadowing takes on a characteristic reticulonodular appearance and becomes associated with fine, honeycomb airspaces and ultimately large cystic airspaces, an appearance that mirrors the macroscopic picture. Pleural disease and mediastinal lymphadenopathy also may be identified by high-resolution CT. It is important to perform high-resolution CT in prone and supine positions, particularly in patients with early SSc, to exclude the contribution of gravity to the radiographic appearances from vascular and interstitial pooling in the dependent areas. In addition to identifying early disease, high-resolution CT can be used to quantify the extent and delineate the pattern of lung abnormality. Management of Interstitial Lung Disease The mainstay of therapy for SSc-associated interstitial lung disease has long been corticosteroids or cyclophosphamide or both, given orally or as intermittent intravenous bolus. Two randomized controlled trials completed more recently showed a modest benefit for cyclophosphamide over placebo.246,247 Reports of treatment with mycophenolate mofetil have been encouraging.248,249 The place of immunosuppressive strategies remains uncertain, however, and requires randomized controlled trials. In idiopathic pulmonary fibrosis, more recent clinical trials of pirfenidone, etanercept, IFN-γ, and acetylcysteine (Mucodyne) have shown some efficacy, and these agents are currently undergoing further evaluation. The management of lung fibrosis in SSc is likely to be informed by the results from idiopathic pulmonary fibrosis studies.250 For selected SSc patients with advanced pulmonary involvement, lung transplantation may be an option. Single lung transplant is now considered to be the most successful transplantation approach for interstitial lung disease and for PAH.251 Pulmonary Arterial Hypertension PAH, defined as an elevation in the mean pulmonary artery pressure greater than 25 mm Hg at rest, occurs in limited and diffuse cutaneous forms of SSc and is a leading cause of mortality. The outcome in SSc-associated PAH is considerably worse than that of idiopathic PAH.252 This worse outcome may reflect comorbidity or differences in under lying pathogenetic mechanisms. In SSc, PAH resulting from intrinsic fibroproliferative abnormalities in the pulmonary vasculature, pathologically indistinguishable from idiopathic PAH, is most common, with a prevalence of approximately 10% to 15%. The second pattern of PAH occurs in association with pulmonary interstitial fibrosis and is driven by hypoxia and the destruction of the pulmonary vascular bed. PAH in SSc also occurs in the context of pulmonary fibrosis,

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and typical histologic appearance of PAH can be found in lung biopsy specimens from SSc patients with lung fibrosis. It has been suggested that coexistent vasculopathy determines outcome and survival in many cases of SSc-associated pulmonary fibrosis.253 PAH may remain asymptomatic until quite advanced. The initial symptoms include exertional breathlessness, and less often chest pain or syncope. In patients with SSc, PAH typically is discovered during regular monitoring with pulmonary function tests, Doppler echocardiography, and electrocardiography. An isolated reduction in diffusion capacity with preservation of lung volumes suggests PAH.254 Definitive diagnosis requires exclusion of thromboembolic disease by ventilation-perfusion lung scan, spiral CT scan or pulmonary angiography, and hemodynamic demonstration of a mean pulmonary artery pressure greater than 25 mm Hg at rest or greater than 30 mm Hg with exercise. There is a correlation between peak pulmonary artery pressure estimated by Doppler echocardiography and direct measurements at right heart catheterization except when pulmonary artery pressures are in the 30 to 50 mm Hg range.241 Cardiac catheterization is essential for the workup because it allows the recognition of pulmonary venous hypertension and the precise determination of pulmonary vascular resistance, cardiac output (cardiac index), and pulmonary artery pressures. Serum levels of the N-terminal pro-brain natriuretic peptide (N-pro-BNP) may be helpful for screening and monitoring PAH. The levels correlate with survival in patients with SSc-associated PAH.255 Although historically PAH was associated with a grave prognosis, substantial progress in its management has been achieved recently. Figure 77-17 is an algorithm for detection and assessment of PAH. The current focus in the evaluation is on early identification and determination of severity. The World Health Organization/New York Heart Association functional classification is useful for assessing the severity of PAH and for treatment decisions. Exercise capacity, typically assessed by the distance walked in 6 minutes under standard conditions, has prognostic implications and is used for risk stratification.256 Current approaches to the treatment of PAH in SSc are summarized in Figure 77-18. Oral anticoagulation, spironolactone, and oxygen supplementation, when appropriate, may be used as supportive therapy. Specific treatments for PAH are initiated only for advanced disease (functional class III or IV); earlier intervention may be advantageous and is under investigation.257 Treatment options for class III PAH include oral ET-1 receptor blockade258 and phosphodiesterase inhibition.259 Alternative therapies include inhaled and subcutaneous prostacyclin analogues.260 Intravenous agents generally are reserved for patients with severe or advancing PAH. Despite more recent progress, the management of PAH remains a major challenge; this is a result of the poor outcome of SSc-associated PAH compared with idiopathic PAH, and the lack of high-quality evidence addressing issues such as combination therapy and the benefits of early intervention. Our approach to the management of PAH in patients with SSc is summarized in Figure 77-18. When the diagnosis of PAH is confirmed, the contribution of associated interstitial lung disease is considered. Patients with significant hypoxemia benefit from supplemental oxygen. It is possible that lung fibrosis treatments such as immunosuppression may be

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Clinical suspicion Breathlessness Syncope Chest pain

Regular screening Annual assessment in all SSc patients

Differential diagnosis Ascertain pulmonary fibrosis Exclude thromboembolic disease Exclude pulmonary venous hypertension Other causes: HIV, portal HT, anorexigen, CTEPH, PVOD

Diagnosis ECG, CXR Doppler-echocardiography Pulmonary function tests Right heart catheter

Figure 77-17  Evaluation of pulmonary arterial hypertension (PAH) in systemic sclerosis. All patients with systemic sclerosis should have routine screening for evidence of PAH. An echocardiogram, pulmonary function test, and clinical review are recommended on at least a yearly basis. Patients who have evidence or suspicion of PAH should undergo further assessment as indicated. Diagnosis must be made by right heart catheterization. Diastolic dysfunction is common and leads to elevated pulmonary capillary wedge pressure. Other forms of PAH may require alternative therapies, such as CTEPH. The New York Heart Association/World Health Organization functional class is important in determining optimal therapy and outcome.* CTEPH, chronic thromboembolic pulmonary hypertension; PVOD, peripheral vascular occlusive disease.

Risk stratification WHO functional class*, Dyspnea index Submaximal exercise test (e.g. six minute walk) Cardiodynamic assessment: peak and mean PA pressure, cardiac index, pulmonary vascular resistance

appropriate (see later). In the absence of contraindication, supportive therapy with diuretics, oral anticoagulation, and in some cases digoxin is considered. Patients with functional class III disease are eligible for advanced therapy. Our practice is to begin treatment with an oral ET-1 receptor antagonist when functional class III is reached; lack of response prompts switching to a phosphodiesterase inhibitor, whereas partial response or transient response generally results in addition of a phosphodiesterase inhibitor. Further deterioration can be managed by adding inhaled

Therapy

iloprost or parenteral prostacyclin. Although surgical intervention may be useful for symptom control (septostomy) or long-term benefit (single lung transplant), these approaches are feasible in only a small number of SSc patients.251 RENAL MANIFESTATIONS The kidney is the internal organ that most clearly and acutely shows the consequences of blood vessel spasm and arterial damage in SSc. In contrast to PAH, which is characterized

Confirmed PAH

Lung fibrosis significant: treat as necessary

Clinical worsening

Functional class I/II

Functional class III No response Switch to alternative oral agent (Sildenafil)

Bosentan

Partial response Or

2nd oral agent (Sildenafil) Worsening

Figure 77-18  Management of pulmonary arterial hypertension (PAH). Patients with PAH in functional class II, III, or IV are candidates for therapy, generally an oral endothelin receptor antagonist as a single agent. Partial response prompts combination therapy with a 5′ phosphodiesterase (PDE5) inhibitor, whereas lack of response leads to switching to a PDE5 inhibitor. Adding inhaled iloprost or switching  to subcutaneous triprostanil or intravenous prostacyclin is considered for patients who fail to respond.

Functional class VI

Consider atrial septostomy or lung transplant

Add inhaled iloprost or withdraw one agent and add parenteral epoprotenol/iloprost/triprostanil

* Ambrisentan

PART 12 

Follow up: Renal function improvement may continue for up to 24 months after renal crisis. Antihypertensive requirements often fail. Other aspects of disease may improve. Occult cardiac disease may manifest.

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SCLERODERMA, INFLAMMATORY MYOPATHIES, AND OVERLAP SYNDROMES

SSC stage and subset

BP elevated

Renal impairment

Renal failure

Long term renal replacement

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Education, BP monitoring, avoid precipitants If hypertensive commence ACEI or ARB close observation renal function, check for MAHA and end-organ disease Hospital admission increase ACEI/ARB, additional oral antihypertensive ? prostacyclin infusion, close monitoring, renal support Transplant

Post-transplant surveillance

Figure 77-19  Management of scleroderma renal crisis. The overriding principle in management is vigilance and monitoring. Patients should be educated about the risk of renal crisis. Precipitating factors, such as corticosteroids, and potentially nephrotoxic agents, such as nonsteroidal anti-inflammatory drugs or high-dose diuretics, should be minimized. Hypertension must be treated promptly with an angiotensin-converting enzyme inhibitor (ACEI). Evidence of renal crisis, such as microangiopathic hemolytic anemia, declining renal function, or hypertensive retinopathy, mandates inpatient management. In addition to maximizing angiotensin-converting enzyme inhibition, additional antihypertensive agents may be required, and some centers introduce prostacyclin infusion in light of its effects on renal perfusion. Renal function may recover, and dialysis can be discontinued for 2 years after renal crisis. ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker.

by slowly progressive vasculopathy evolving over a long time, the vascular changes in renal scleroderma may develop rapidly, perhaps owing to the much higher levels of systemic blood pressure compared with the pulmonary circulation. In both cases, it seems likely that an abnormal response to vascular injury underlies the pathology. In scleroderma renal crisis, intrinsic systemic vasospasm leads to accelerated hypertension. Scleroderma Renal Crisis Scleroderma renal crisis, first reported in 1863,260 typically causes accelerated hypertension and acute renal failure. Until the advent of angiotensin-converting enzyme (ACE) inhibitors, scleroderma renal crisis was associated with a very high mortality. In recent decades, mortality at 1 year declined from 85% to 24%.261 Other patterns of renal involvement in SSc include chronic vasculopathy with reduced glomerular filtration rate. Patients with overlap SSc may develop inflammatory glomerular disease including glomerulonephritis, characteristically associated with serologic features. Scleroderma renal crisis occurs in 10% to 15% of patients with diffuse cutaneous SSc and only vary rarely (1% to 2%) in limited cutaneous SSc.262 Most cases occur within the first 12 months of disease, and in a quarter of patients with scleroderma renal crisis, the diagnosis of SSc is made at the time of the renal presentation.5 Typically, patients present with accelerated hypertension and progressive renal impairment. End-organ damage can result in encephalopathy with generalized seizures or flash pulmonary edema. Microangiopathic hemolytic anemia is common, and disseminated intravascular coagulation may develop. Thrombocytopenia may be present. Approximately two thirds of cases of scleroderma renal crisis require renal replacement therapy.262 Of these, half eventually recover sufficiently to discontinue dialysis; this can occur for 24 months, and decisions about renal transplantation should be postponed until that time. The possi-

bility for delayed renal recovery distinguishes scleroderma renal crisis from other causes of end-stage renal failure. Improved outcomes are achieved with early use of ACE inhibitors as routine therapy for renal crisis. The efficacy of ACE inhibitors precludes future placebo-controlled studies in treating established scleroderma renal crisis. It is unclear whether related drugs, such as angiotensin receptor blockers, are effective in preventing or abrogating scleroderma renal crisis. Corticosteroids, along with cyclosporine, have been implicated as precipitants of scleroderma renal crisis.225,263 The management of scleroderma renal crisis is summarized schematically in Figure 77-19. Currently, our approach is to hospitalize patients at diagnosis (based on new-onset accelerated hypertension with evidence of renal impairment, microangiopathic hemolysis, or significant end-organ damage in the context of SSc) and treat with a full-dose ACE inhibitor. The dose should be increased daily to achieve a blood pressure reduction of 10 to 20 mm Hg systolic per 24 hours, even if there is continued deterioration in renal function, which can be followed by daily creatinine clearance or calculated glomerular filtration rate. In Europe, patients may be given continuous low-dose prostacyclin, which may help control blood pressure and has potentially beneficial effects on renal blood flow,264 endothelial cell function, and production of proinflammatory or profibrotic factors. Additional antihypertensive agents may be useful, including combinations of angiotensin receptor blocker or ACE inhibitor drugs or calcium channel blockers, nitrates, or other vasodilator agents such as doxazosin. Care must be taken to monitor cardiac function closely because vasodilation may be associated with relative hypovolemia. The outcome of scleroderma renal crisis is poor, with early mortality approaching 10%, and half of patients needing dialysis.265 The dialysis may be temporary, and many patients requiring renal replacement therapy eventually come off dialysis 6 to 24 months after the renal crisis. For this reason, even though transplantation is no less ­successful

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in SSc than in systemic lupus erythematosus, final decisions should not be made until at least 2 years after the renal crisis.266 Renal biopsy may provide prognostic information and confirms the diagnosis. Cases of SSc with inflammatory glomerular pathology have been identified, and they require potentially very different treatment compared with classic scleroderma renal crisis. Rarely, patients have apparently primary accelerated or severe hypertension as an initial presentation of SSc.267 It is important to examine such cases carefully for the presence of this disease, and follow up clinical suspicion with appropriate investigations. The diagnosis of early SSc has been facilitated by nail-fold capillaroscopy, together with autoimmune serology, including hallmark SSc-associated autoantibodies. Not only do these investigations often confirm the clinical diagnosis of SSc, but they also can help identify patients with isolated Raynaud’s phenomenon who are at high risk of developing a connective tissue disorder.

occur, sometimes in association with specific autoantibody profiles, such as anti-U1-RNP.270 As in other connective tissue diseases, a symmetric peripheral neuropathy is sometimes identified and may occur in the setting of overlap ­vasculitis. Sicca Symptoms In addition to overlap SSc that fulfills classification criteria for Sjögren’s syndrome,273 sicca symptoms are common. These symptoms probably reflect the loss of minor exocrine glandular structures, together with the atrophic changes of associated tissues.

DIAGNOSIS AND DIAGNOSTIC EVALUATION

Other acute renal complications may occur, especially in overlap syndromes with lupus nephritis. There may be serologic clues that a patient is evolving within the connective tissue disease spectrum that anticipate clinical changes, such as the development of a rise in titer of an associated anti–double-stranded DNA antibody. It has been suggested that anti–neutrophil cytoplasmic antibody reactivity may predict unusual renal complications of SSc, such as glomerulonephritis and renal vasculitis.268 Some of these changes occur in SSc patients treated with penicillamine.269 Indolent chronic renal involvement, characterized by a slow reduction in glomerular filtration rate accompanied by proteinuria, has been described in SSc.270

The differential diagnosis for scleroderma-spectrum disorders is extensive (see Table 77-1). The list includes conditions in which skin induration is due to deposition of abnormal protein within the dermis, as in amyloidosis or scleromyxedema, or to inflammation and secondary scarring in metabolic disorders such as porphyria. The most important differential diagnoses for SSc are the scleroderma-­spectrum disorders. Features such as Raynaud’s phenomenon provide an important clinical clue of systemic involvement. The hallmark SSc autoantibodies do not occur in scleroderma-like diseases resulting from metabolic abnormalities or infiltration. The diagnosis of SSc usually is made on clinical grounds and is supported by laboratory investigations. Classification criteria were developed to discriminate SSc from other connective tissue diseases in clinical research, rather than for diagnostic purposes; patients with mild SSc or with early disease frequently fail to fulfill these criteria.

Renal Transplantation in Systemic Sclerosis

DISEASE ASSESSMENT

Considerable recovery of renal function may occur after acute scleroderma renal crisis, sometimes allowing discontinuation of dialysis. Because improvement of renal function may continue for 2 years, decisions regarding renal transplantation should be deferred. The survival of renal allografts in SSc is comparable to that seen in other autoimmune rheumatic diseases, including systemic lupus erythematosus.266 It is possible that post-transplant immunosuppressive regimens have beneficial effects on underlying disease that diminish involvement in the grafted kidney. Nonrenal manifestations of SSc also may improve after renal transplantation.271 Nevertheless, recurrent scleroderma renal disease in grafted organs has been described.272

Assessment starts with diagnosis and classification. In a patient with features of a scleroderma-spectrum disorder, the first consideration is to determine if the condition is localized disease or SSc. The simplest discriminators are the presence of Raynaud’s phenomenon and internal organ manifestations, of which the earliest is often reflux esophagitis, although Raynaud’s phenomenon and gastroesophageal reflux are common in otherwise healthy individuals. The distribution of skin involvement provides crucial information about SSc subset and classification. Acral involvement is almost universal in SSc, whereas asymmetric skin induration and acral sparing suggest localized scleroderma. Autoantibody testing is the most useful laboratory investigation (see later). Nail-fold capillary microscopy is an additional clinical investigation that helps to discrimate primary Raynaud’s phenomenon from early SSc because the latter is associated with classic changes, including capillary dropout and dilation. In localized scleroderma, capillaroscopy is entirely normal. In contrast to other connective tissue diseases, such as systemic lupus erythematosus or inflammatory arthritis, characterized by a relapsing-remitting clinical course, in SSc damage tends to occur gradually and to progress over time. It is more useful to evaluate severity and cumulative damage than disease activity. Preliminary indices for evaluating disease activity274,275 and severity275a have been proposed.

Other Forms of Renal Involvement

OTHER MANIFESTATIONS Neurologic Manifestations In early-stage diffuse cutaneous SSc, patients commonly report symptoms of median nerve compression, and many patients undergo surgical treatment for carpal tunnel ­ syndrome before the diagnosis of SSc is established. As the inflammatory phase of SSc passes, these symptoms often improve without specific therapies. Isolated, or occasionally multiple, involvement of the cranial nerves can

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Because these tools remain to be validated, they are more relevant to research than clinical practice. AUTOANTIBODIES IN ASSESSMENT Most patients with SSc have serum antinuclear autoantibodies, including hallmark autoantibodies specifically associated with SSc (see Table 77-6). The most common immunofluorescence pattern with Hep2 cell substrates is speckled; in contrast, PM-Scl, anti-fibrillarin Th/To, and anti–RNA polymerase antibodies generate a nucleolar pattern of staining. These different staining patterns are valuable in practice when patients present with an undifferentiated connective tissue disease because a scleroderma pattern of immunoreactivity can be a useful first sign of the disease. The major SSc-associated autoantibodies are anticentromere, anti–topoisomerase I, anti–RNA polymerase I/III, and antifibrillarin. These autoantibodies are almost always mutually exclusive, reflecting their immunogenetic basis linked to the MHC class II associations.276 The strongest association between an SSc autoantibody and a specific clinical pattern is between lung fibrosis and anti– ­topoisomerase I antibodies, most frequently in patients with diffuse cutaneous SSc. Anti–RNA polymerase I/III reactivity is associated with scleroderma renal crisis.277 Other autoantibodies can predict coexisting disease, such as thyroiditis, primary biliary cirrhosis,223 and overlap syndromes.

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Table 77-12  Immunomodulatory and Immuno­ suppressive Interventions Used in Systemic Sclerosis Methotrexate Cyclosporine Cyclophosphamide* Azathioprine Mycophenolate mofetil Thalidomide Antithymocyte globulin Intravenous immunoglobulin Extracorporeal photopheresis Immunoablation with autologous stem cell rescue (transplantation) *Found to be effective in a randomized, clinical trial.

There have been major advances in the treatment of organspecific complications of SSc. In particular, the management and outcome of scleroderma renal crisis has been transformed by the judicious use of ACE inhibitors. Morbidity from Raynaud’s phenomenon and esophagitis has been markedly reduced. Progress also has been made in treating PAH, and more recent reports indicate that immunosuppression using cyclophosphamide may slow the progression of interstitial lung disease complicating SSc. Despite these positive developments, no SSc therapy to date has been proved to be effective in altering the natural history of the disease. The choice and evaluation of any treatment regimen for SSc is challenging because the disease is complex, and its pathogenesis is poorly understood; it is heterogeneous in its extent, severity, and rate of progression. Treatment typically includes a combination of agents targeting the immune, vascular, and fibrotic processes underlying the pathogenesis of SSc. Therapy must be tailored to the individual patient, however, carefully taking into consideration disease subset and duration, rate of progression, and pattern and severity of internal organ involvement. Careful baseline assessment of organ-based complications and longterm follow-up are essential.

or retrospective studies suggesting benefit for cyclophosphamide in SSc-associated interstitial lung disease, two more recent randomized double-blind, placebo-controlled trials have shown a modest benefit. Intensive immunosuppression with autologous hematopoietic stem cell rescue is a promising novel form of intervention. Uncontrolled studies show the feasibility of stem cell therapy,278 and several randomized clinical trials comparing stem cell therapy with other forms of immunosuppression are currently under way. Because of its substantial cost and potential treatment-related complications, including death, stem cell therapy may be best suited for diffuse cutaneous SSc patients with severe disease. Other approaches to immunosuppression include use of antithymocyte globulin279 or anti-CD25 monoclonal antibody.280 Mycophenolate mofetil is increasingly used in diffuse cutaneous SSc, and results from pilot studies suggest that it is well tolerated and may be beneficial in SSc-­associated lung fibrosis.248,281 It is possible that immunosuppressive or antimetabolic agents also modulate nonimmune processes contributing to pathogenesis of SSc such as fibroblast activation or vasculopathy, and that drugs whose primary mode of action is believed to be antifibrotic also modulate immune cell function; examples include IFN-γ and penicillamine.95 Low-dose corticosteroids (�5 mg prednisone/day) are useful for controlling inflammatory symptoms that are frequent in early-stage SSc and are commonly used in combination with immunosuppressive agents for the treatment of lung fibrosis and of myositis. Long-term corticosteroids should be avoided, however, because they may precipitate scleroderma renal crisis (see earlier). Steroid use is ideally restricted to patients with myositis, symptomatic serositis, the early edematous phase of the skin disease, refractory arthritis, and tenosynovitis. The lowest possible therapeutically effective dose should be used in cases of SSc that require corticosteroid administration. We advise daily monitoring of blood pressure in patients at high risk.

IMMUNOMODULATORY THERAPY

ANTIFIBROTIC AGENTS

Immunosuppressive strategies in SSc are most likely to be effective in early-stage disease when inflammatory features are prominent. Numerous immunosuppressive drugs have been used, but with the exception of cyclophosphamide, none have been shown to be effective in randomized clinical trials (Table 77-12). Adding to a substantial body of ­uncontrolled

Although many current treatment strategies are immunomodulatory, in patients with established SSc, the most effective agents are likely to be those with antifibrotic ­activity. To date, no drug has been proven to be ­ effective as an ­antifibrotic, and many drugs used in the past for this indication have been shown to be ineffective in controlled trials.

TREATMENT OF SYSTEMIC SCLEROSIS

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A pilot study of a human monoclonal ­ antibody directed against TGF-β1 showed no efficacy compared with placebo.252 The antibiotic minocycline has been suggested as a potential antifibrotic agent, but a prospective controlled trial showed a lack of benefit in diffuse cutaneous SSc.282 Because oxidant stress may play a role in the pathogenesis of SSc, antioxidant agents have been considered as potential therapies. In theory, such an approach might influence the vascular, fibrotic, and immunologic processes of the disease.

occurring across numerous vascular beds; this is because of the similarity between histopathologic abnormalities within medium-sized arterial vessels in the lung, kidney, and digital circulation. Vasospasm is especially prominent in the digital circulation, but structural changes with mural fibrosis and lumen narrowing are more important in late-stage disease. With this in mind, treatment goals are to induce vasodilation or prevent vasoconstriction, and to remodel damaged blood vessels. Prevention of thrombosis is logical, but results of clinical studies with antithrombotic agents have been equivocal. Prostacyclin analogues given by intravenous infusion have been used in Europe for digital vasculopathy and Raynaud’s phenomenon.285 Antioxidants may reduce vascular damage, and some patients choose to take high-dose antioxidant vitamin supplements. Calcium channel blockers are of proven effectiveness in Raynaud’s phenomenon and are widely used.286 Losartan was superior to nifedipine in a small clinical trial.287 Serotonin reuptake inhibitors, such as fluoxetine, may be beneficial in SSc-associated Raynaud’s phenomenon.288 In contrast, the benefit of longterm ACE inhibitor therapy in Raynaud’s phenomenon is unproven.

VASCULAR THERAPIES

MANAGEMENT PRINCIPLES

Vasculopathy affecting small blood vessels is a universal feature of all forms of SSc and accounts for substantial morbidity. Many vasodilator drugs have been used as treatment for Raynaud’s phenomenon (Table 77-13). The primary goal of such treatments is to reduce vasospasm or promote vasodilation. Some agents may have broader effects on endothelial cell function or vascular remodeling, and it has been suggested that some drugs for Raynaud’s phenomenon also might have beneficial effects on other aspects of SSc.199 Oral therapy may be insufficient, and in these cases parenteral prostacyclin analogues are often used. In some cases, surgical intervention with digital sympathectomy is valuable, especially if there is a single ischemic digit or refractory ischemic digital ulceration (see Fig. 77-11). Because widespread vascular damage commonly occurs in SSc, drugs that protect injured endothelial cells and prevent platelet aggregation and subsequent release of platelet-derived mediators could be helpful. None of the drugs that have been evaluated, including ketanserin, a serotonin antagonist, dipy­ ridamole, and aspirin, were clinically effective in altering vascular damage in randomized clinical trials. The ACE inhibitor captopril has been used for the primary and possibly prophylactic treatment of vascular disease.283 However, a randomized, prospective clinical trial failed to show any long-term clinical benefit of prophylactic ACE inhibitor therapy in SSc.283a As in other autoimmune rheumatic diseases, therapy with statin drugs potentially may be beneficial for vascular disease in SSc beyond their lipid-lowering effects. There have been no controlled clinical trials, but small studies suggest that statins have possible beneficial effects on markers of endothelial cell injury.284 A recent report suggested that atorvastatin might favorably modulate the number of circulating endothelial cell precursors in patients with SSc and vascular complications.109 Although specific management approaches are considered elsewhere in this chapter, general principles apply to damage

The first principle of management is accurate diagnosis. The differential diagnosis of scleroderma-like conditions is considered in Table 77-1. Historically, SSc has been perceived as a grievous disease, and widely approached with a degree of therapeutic nihilism. In the current era, such an attitude serves the patient with SSc poorly. Instead, we prefer to view SSc as a chronic, treatable disease similar to diabetes mellitus. Ample evidence shows improved survival of patients with SSc and improved outcomes from major organ-based complications, including renal, pulmonary vascular, and interstitial lung disease. Certain aspects of the disease continue to defy effective management—most notably cardiac and lower gastrointestinal tract involvement.

Table 77-13  Therapeutic Approaches to Management of Raynaud’s Phenomenon Class of Drug

Example

Calcium channel blockers

Nifedipine

Angiotensin II receptor ­antagonists

Losartan

α-adrenergic blockade

Prazosin

Prostacyclin

Iloprost (parenteral)

Endothelin receptor blockers

Bosentan

Phosphodiesterase inhibitors

Sildenafil

Surgery

Sympathectomy

Education There is often considerable confusion among patients and health care professionals regarding the nature, clinical manifestations, and natural history of SSc, and its evaluation, monitoring, and long-term management. Education is an important component of the management.289 We find that patients who have a good understanding of their disease become active partners in its management, and cope better with its burdens over time. Screening for Organ-based Disease A mainstay of management of established SSc is regular screening for the development of new complications and for progression of abnormalities noted at baseline. Currently, we recommend that in SSc patients with early disease (i.e., the first 2 to 4 years), careful assessment for renal, cardiac, and respiratory function be performed on a yearly basis, recognizing that more than half of patients develop at least one significant complication during follow-up, and reflecting a growing body of evidence supporting ­ effectiveness

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of therapies.5 The challenge of reversing established organ damage leads to the hypothesis that earlier detection of major complications could allow treatment at an earlier stage and improve outcome. Although this is a compelling strategy and forms the basis for active management, trials of effective therapies are needed to confirm the validity of this construct, and to determine how various treatments, often potentially toxic and expensive, should be used.

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The long-term outcome of SSc is a major concern at the time of diagnosis. The heterogeneity of the disease and its major subsets necessitates careful assessment. Ideally, patients should be stratified according to the likelihood of developing major organ-based complications or of progression of already existing complications. The past 25 years have witnessed substantial improvement in the mortality of SSc, and more recent analysis indicates greater than 80% 5-year survival.5 Certain subsets of SSc have a worse outcome, however. Advanced PAH is associated with a less than 50% 2-year survival.255 Historically, the highest mortality is seen in patients with scleroderma renal crisis, with 1-year survival less than 15%.228 Major improvements followed the introduction and widespread early use of ACE inhibitors; more recent case-­control analysis suggests greater than 85% 1-year survival. Longer term outcome remains poor, with high mortality at 3 years from multiple causes. The outcome of patients with SSc-associated PAH is worse than the outcome of patients with idiopathic PAH. More recent studies have indicated improved survival in SSc-associated PAH with greater than 70% 2year survival.255 Although SSc remains a grievous disease with life-threatening complications, subsets without significant internal organ involvement and limited skin involvement have normal survival,228 and it is likely that prognosis will continue to improve.

develop along the limbs, or less commonly, on the trunk in a linear fashion, sometimes in association with plaques of morphea as a mixed pattern. Linear scleroderma on the forehead or scalp is called coup de sabre.293 Early localized scleroderma lesions are associated with inflammatory changes in the dermis and violaceous discoloration, and are often accompanied by localized itching or discomfort. With time, the lesions become indurated and sclerotic, and in late stages there may be a pale waxy central area with an erythematous border. Eventually, the skin texture softens, although pigmentary abnormalities often persist. In morphea profunda, the lesions occur in the deeper dermis, and overlying skin features are less apparent. In adults with localized scleroderma, the main concerns generally relate to discomfort and cosmetic changes; however, in children, the disease is more serious. Linear scleroderma can be associated with growth failure that may be profound; on the face, this leads to hemifacial atrophy, also known as Parry-Romberg syndrome. Occasionally, localized scleroderma is associated with extensive skin changes affecting the trunk (pansclerotic morphea) that can resemble diffuse cutaneous SSc. The absence of Raynaud’s phenomenon and normal nail-fold capillaroscopy are useful diagnostic features distinguishing all forms of localized scleroderma from SSc. Autoantibody testing is less robust for this purpose because localized scleroderma may be associated with antinuclear antibody, anti–single-stranded DNA, and other autoantibodies. Although progression of localized scleroderma to SSc almost never occurs, some patients with SSc develop plaques of morphea or areas of linear localized scleroderma. The etiology of localized scleroderma is unclear. Local triggers, such as trauma, are implicated, and association with infection, including Borrelia burgdorferi, has been described.294 Management of patients with localized scleroderma must be individualized. Adults with mild disease often do not require treatment or may be treated locally with topical immunosuppressant agents, such as tacrolimus295 or calcipotriene (a form of vitamin D3), or with phototherapy. In severe or progressive localized scleroderma, systemic therapy with corticosteroids and immunosuppressants may be appropriate. Methotrexate, penicillamine, mycophenolate mofetil, azathioprine, hydroxychloroquine sulfate, and cyclosporine have been used with variable success. In rapidly progressive disease, initial treatment may include intravenous pulses of methylprednisolone. Treatment also must include physiotherapy to minimize growth asymmetry and to maximize function. Table 77-14 summarizes approaches to evaluation and management for the major types of localized scleroderma.

LOCALIZED SCLERODERMA

MORPHEA

Localized forms of scleroderma are distinguished from SSc not only by the absence of vasospasm, structural vascular damage, and involvement of internal organs, but also by the distribution of the skin lesions.292 The three main varieties of localized scleroderma are morphea, linear scleroderma, and coup de sabre. These conditions are characterized by localized inflammation and fibrosis of the skin and underlying tissue. Patches of abnormality, termed plaque morphea,develop as single or multiple lesions. In linear scleroderma, lesions

Morphea may occur in a circumscribed or a generalized form. In circumscribed morphea, there may be just one or two lesions with no generalized spread. The changes often begin with small, violaceous or erythematous skin lesions, which enlarge and progress to firm hidebound skin with variable degrees of hypopigmentation or hyperpigmentation. These lesions eventually assume a waxy, pale ­ appearance with subsequent atrophy. Pruritus is often a problem with the early lesion. Lesions vary in diameter from 10 mm to 10 cm.

Disease Modification versus Organ-specific Strategies Therapeutic progress in SSc has largely come from the application of interventions that are valuable in related conditions. Use of these agents in SSc often requires adjustments to standard protocols, and outcomes may be different. Examples include the use of ACE inhibitors in scleroderma renal crisis, proton-pump inhibitors for gastroesophageal reflux disease, cytotoxic agents for interstitial lung disease, broad-spectrum antibiotics and enteral or parenteral nutritional supplementation for midgut disease, and novel therapies for PAH.

OUTCOME AND PROGNOSIS

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Table 77-14  Management of Localized Scleroderma in Adults and Children Pattern of Disease

Clinical Features

Treatment

Prognosis

Plaque morphea

One or a few circumscribed sclerotic plaques with hypopigmentation or hyperpigmentation and an inflamed violaceous border

Often unnecessary. Topical steroids, immunosuppression (e.g., tacrolimus) or phototherapy may be considered. Serial measurement to assess progress

Good prognosis. Lesions less active within 3 yr, but pigmentary changes often persist

Generalized morphea

Widespread pruritic lesions, often symmetric and following distribution of superficial veins

Suppress inflammatory component using corticosteroids: in ­children oral doses 15 mg/day have been used. Intravenous infusions often effective. Methotrexate, ­immunosuppressive maintenance therapy often used, although ­benefit not proven in controlled trials. Vitamin D–containing creams may be useful. Topical ­corticosteroids rarely helpful. PUVA has been used

Internal organ pathology or Raynaud’s phenomenon rare. Generally improves within 5 yr of onset, although textural and pigmentary changes may persist

Linear scleroderma

Sclerotic areas in linear distribution on limbs, asymmetric; in childhood can lead to growth defect. Serial measurements of limb length and girth essential to monitor progression

Suppress inflammatory component using Long-term effects of corticosteroids: in children oral doses ­childhood-onset form are 15 mg/day have been used. Intravenous minimized by ­effective ­infusion has been used. Methotrexate, other suppression of the ­immunosuppressive maintenance therapy ­inflammatory process and often used, although benefit not proven by good physiotherapy. in controlled trials. Vitamin D–containing Tends to resolve, but can creams may be useful. Physiotherapy and remain active for years appropriate regular exercise important to minimize growth defect in childhood ­disease. Surgical correction of limb defects may be considered when disease is inactive

Coup de sabre

Linear scleroderma affecting the face Therapeutic options as for linear s­cleroderma; or scalp, often involving the underlysystemic treatment only for active ing subcutaneous tissues, muscles, ­inflammatory lesions periosteum, and bone. ­Cerebral abnormalties also reported, including intracranial calcification

Scarring, growth defects, and alopecia persist, but the inflammatory component usually resolves

PUVA, psoralens and ultraviolet A.

The condition often resolves within 3 to 5 years, although patches may persist for more than 25 years.292 In some patients, morphea is widespread and generalized. Fingers and toes usually are spared, but the trunk and legs are generally involved. Generalized morphea can be disfiguring and may continue to extend, resulting in joint contractures, disability, and troublesome ulceration. In guttate morphea, there are multiple hypopigmented and pigmented papules 2 to 10 mm in diameter, with minimal sclerosis. These lesions are commonly localized to the neck, shoulders, and anterior chest wall, and resemble those of lichen sclerosus et atrophicus. LINEAR SCLERODERMA Linear scleroderma occurs most frequently in childhood, but also may develop in adults.296,297 In this very rare process, sclerotic areas have a linear, bandlike pattern and often follow a dermatomal distribution. Lesions generally predominate on one side of the body, although some degree of contralateral involvement may be present at later stages, suggesting that there may be a systemic process. When linear scleroderma lesions cross joint lines, they can be associated with atrophy of the soft tissue, muscle, periosteum, bone, and occasionally synovium. In some cases, the lesions cause extensive growth defects in a limb or a part thereof, which can be extremely disfiguring. Fixed valgus ­deformities occur, and scoliotic changes in the spine can develop as a

result of limb-length inequality. When the toes or fingers are affected, hammer toes or claw hand may develop. These changes are more noticeable in a growing child.298 It is common for patients to present with morphea and later develop linear lesions. This evolution should be anticipated carefully because the linear lesions tend to have much greater morbidity than the circumscribed patches of morphea. Because the linear lesions may be insidiously progressive, lengthy follow-up of these patients is important. Laboratory investigation generally reveals normal erythrocyte sedimentation rate and rheumatoid factor, but autoantibodies are often present. Some children with morphea or linear lesions or both develop synovitis, with an elevated erythrocyte sedimentation rate, rheumatoid factor, and circulating autoantibodies, and accelerated development of contractures. At the time of presentation, there may be only a small area of localized or linear scleroderma, distant from the joint ­symptoms. The evaluation of localized forms of scleroderma is challenging. Although charting of the involved areas is cumbersome and imprecise, the lesions should be carefully recorded; leg length, limb circumferences, and posture should be monitored; and muscle function and neurologic status should be assessed on a regular basis. Charting of new lesions also is essential. Thermography has been used to assess the activity of localized disease,299 and high-frequency ultrasound or MRI may help to determine the depth of localized scleroderma lesions.300

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COUP DE SABRE Linear scleroderma occurring on the face or scalp may assume a depressed, ivory appearance. The lesion was considered reminiscent of the scar from a sabre wound and termed coup de sabre. The linear lesion often is associated with ipsilateral facial hemiatrophy. It also may be associated with vascular abnormalities of the brain and distant morphea lesions. There is overlap between this form of linear scleroderma and specific localized growth defects, such as idiopathic hemifacial atrophy (Parry-Romberg syndrome). In the latter, the overlying skin may be texturally normal, however.293

PSEUDOSCLERODERMA SYNDROMES SCLEREDEMA AND SCLEROMYXEDEMA Scleredema and scleromyxedema are distinct idiopathic connective tissue disorders that must be distinguished from SSc and from localized scleroderma.31 Approximately half of cases of scleredema have diabetes mellitus, typically long-standing and insulin-dependent. The histopathologic hallmark is an increase in mucin-rich ECM in involved skin, although this may diminish as the disease becomes more long-standing.301 In scleromyxedema, there is a more florid epidermal abnormality, often with papule formation. Both conditions can be associated with an initial inflammatory cell infiltrate, but this diminishes over time.302 Histologic similarities between scleredema, scleromyxedema, and nephrogenic systemic fibrosis (see later) are striking, and suggest that similar pathogenic mechanisms may be involved.303 Scleredema and scleromyxedema may be associated with paraproteinemia and with a plasma cell dyscrasia, and less commonly with multiple myeloma.304 There have been no randomized clinical trials for evaluating treatments for scleredema and scleromyxedema. Interventions that have been reported to be effective in individual cases include immunoglobulin infusions often given together with immunosuppression, such as methotrexate or mycophenolate mofetil.305 In severe cases, immunoablation and autologous stem cell transplantation have been used.306 There have been some reports of successful treatment with plasmapheresis, although long-term outcomes have been ­disappointing.307 EOSINOPHILIC FASCIITIS Eosinophilic fasciitis (alternatively called “diffuse fasciitis with eosinophilia”) is an uncommon disorder characterized by the development of indurated subcutaneous connective tissue. The lesions most commonly occur on the lower limbs and forearms. The affected areas have a characteristic “woody” consistency on palpation. Elevation of involved territories reveals the “groove sign” as veins within indurated subcutaneous tissue empty (Fig. 77-20). This sign can be seen for superficial veins in other scleroderma spectrum disorders and is not specific for eosinophilic fasciitis. Eosinophilic fasciitis is associated with peripheral blood eosinophilia, which is often transient. In the early stage, histologically affected tissue shows thickening and inflammation in the subcutaneous fascia. The fascial infiltrate

Figure 77-20  The arm of a patient with eosinophilic fasciitis. Eosinophilic fasciitis is associated histologically with inflammation and fibrosis in the subcutaneous tissues, yielding the characteristic woody texture of distal limbs. Loss of perivascular fat tissue accounts for the groove sign when the arm is elevated. There may be contractural changes owing to shortening of the flexor tendons and tissue fibrosis. Absence of Raynaud’s phenomenon and sparing of the digits distinguish fasciitis from systemic sclerosis. Peripheral blood eosinophilia and eosinophilic infiltrates in the affected tissue are common, but may be transient. Full-thickness skin biopsy including deep fascia is required for histologic confirmation of the diagnosis.

typically, but not always, includes eosinophils.308 With ­progression, fascial inflammation is replaced by thickening and fibrosis that may extend deeper into the perimuscular tissue. Because the lesion may extend superficially to the dermis, it can clinically resemble scleroderma. Contractures at large joints and limitation of the range of movement can develop. Constitutional symptoms may occur in the early stages of the disease.40 Corticosteroids have been commonly used in the treatment of acute eosinophilic fasciitis. Other immunosuppressive agents include methotrexate, but there have been no randomized clinical trials evaluating the efficacy of any therapy. The etiology of eosinophilic fasciitis is uncertain. Some individuals develop the disorder after episodes of unaccustomed vigorous exercise. MRI has been found to be useful in confirmation of the inflammatory changes in the subcutaneous tissues, and determination of ongoing activity at later stages. Occasionally, there is evidence of other complications of eosinophilia, including myocarditis, and there are reports of paraneoplastic cases. The most common association has been with T cell lymphoma309 or with myeloma.310 Other hematologic associations include aplastic or hemolytic anemia.311 There are distinct clinical and pathologic differences between eosinophilic fasciitis and the eosinophilia-myalgia syndrome that was associated with consumption of contaminated tryptophan dietary ­supplement.40 NEPHROGENIC SYSTEMIC FIBROSIS OR NEPHROGENIC FIBROSING DERMOPATHY Nephrogenic fibrosing dermatopathy, first described in 1997 and now recognized as an emerging problem in patients with chronic renal failure, shares histopathologic and clinical features with other scleroderma-spectrum disorders, notably fasciitis and scleromyxedema. Although most patients

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are on long-term dialysis, no association with a particular route or type of renal replacement therapy could be shown, and 10% of cases occur in patients who have never received dialysis.312 Histologic hallmarks include cutaneous and subcutaneous fibrosis with accumulation of spindle-shaped cells, including numerous CD34+ cells.303 There is an increase in acid mucin accumulation in lesional skin at early stages, drawing parallels with other forms of fibromucinosis (see earlier). Serum from patients with nephrogenic fibrosing dermatopathy can stimulate fibroblast proteoglycan secretion in vitro.313 Because visceral fibrosis and skeletal muscle involvement have been described in some patients with nephrogenic fibrosing dermopathy, the term dialysis-associated systemic fibrosis has been proposed as an alternative.314 Clinical features include loss of subcutaneous fat, thickening and tightness of skin over the limbs, and contracture formation at large joints.315 The subdermal tissues become hard or “woody,” resembling established fasciitis, and there can be waxy plaques of morphea-like skin over affected areas. Raynaud’s phenomenon and hallmark SSc autoantibodies do not occur. The similarity between nephrogenic fibrosing dermatopathy and other scleroderma-spectrum disorders and environmentally induced forms of cutaneous fibrosis, such as toxic oil syndrome316 or eosinophiliamyalgia syndrome,317 is noteworthy. The development of a new syndrome suggests that a change in practice or novel environmental trigger may be responsible. Risk factors for the development of nephrogenic fibrosing dermatopathy include exposure to gadolinium-containing MRI contrast agents318 and possibly high-dose erythropoietin.319,320 Some patients with nephrogenic fibrosing dermatopathy improve with adjustment to renal replacement therapy, and others respond to renal transplantation. Agents that may be helpful in scleromyxedema or scleroderma also have been used.

Future Directions DISEASE-MODIFYING THERAPY Although there is now a much better understanding of the pathogenesis in SSc and the potential links between the key pathologic processes, there is still little that can be offered as effective disease-modifying therapy. Effective therapies likely would target key mediators, pathways, or intercellular interactions. At present, a combination of vascular, immunomodulatory, and antifibrotic strategies is envisaged, although it is possible that if vascular or immune-directed treatments were given at an early stage, some of the fibrotic consequences of SSc could be prevented. Evidence from studies of skin sclerosis suggests, however, that even in early disease, the profibrotic processes are well established. RISK STRATIFICATION The clinical heterogeneity of SSc is one of the most challenging aspects of the disease because it is difficult to determine at presentation whether and when major internal organ disease will occur. Serologic markers are of some use, and it is likely that in the future there may be genetic markers. Within each organ system, investigation is usually multifaceted, and assessments of probability have been made to try to determine the likelihood of a particular complication, such as PAH. Studies of the

hallmark serum autoantibodies in SSc have highlighted clinical associations with particular reactivities. Limited cutaneous disease and PAH are associated with anticentromere reactivity, lung fibrosis with antitopoisomerase reactivity, renal involvement, and diffuse skin disease with antibodies to RNA polymerases I and III.290,291 INDIVIDUALIZED THERAPY For most cases of SSc, therapy is individualized. Some generic aspects can be considered, such as management of Raynaud’s phenomenon and esophagitis, skin care, and disease education. The use of major potential disease-modifying therapy is considered on a case-specific basis, however. Sometimes treatment directed to one system, such as lung fibrosis or PAH, may be of more general benefit. Early Intervention—Prevention Paradigm for Internal Organ Disease Although some patients with SSc present with clinically significant internal organ disease, such as scleroderma renal crisis or PAH, this is uncommon. Even in such patients, the history often reveals preexisting clinical features of SSc. In most cases, symptoms of Raynaud’s phenomenon or skin involvement precede major organbased complications. There is often the potential for early detection and clinical intervention, especially for respiratory and gastrointestinal tract involvement. Cardiac or renal involvement may be more difficult to detect early, but clinical markers that suggest risk for these manifestations may be present (see earlier). Our recommendation is that all patients should have careful screening at diagnosis, and a program of regular follow-up should be instituted. This program must be combined with diligent patient education so that relevant symptoms are heeded, and appropriate advice is sought. The clinical heterogeneity of SSc represents a substantial challenge to the practicing rheumatologist, and precludes generalizable treatment protocols. This heterogeneity also confounds clinical trials. Nevertheless, it is assumed that outcomes could be improved and severe internal organ disease prevented, if complications are detected earlier. It is possible, although not yet formally shown, that treatments that have been shown to work in advanced disease may be beneficial at an earlier stage.

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83. Christner PJ, Peters J, Hawkins D, et al: The tight skin 2 mouse: An animal model of scleroderma displaying cutaneous fibrosis and mononuclear cell infiltration. Arthritis Rheum 38:1791-1798, 1995. 84. Gentiletti J, McCloskey LJ, Artlett CM, et al: Demonstration of autoimmunity in the tight skin-2 mouse: A model for scleroderma. J Immunol 175:2418-2426, 2005. 85. Yamamoto T, Takagawa S, Katayama I, et al: Animal model of sclerotic skin, I: Local injections of bleomycin induce sclerotic skin mimicking scleroderma. J Invest Dermatol 112:456-462, 1999. 86. Takagawa S, Lakos G, Mori Y, et al: Sustained activation of fibroblast transforming growth factor-beta/Smad signaling in a murine model of SSc. J Invest Dermatol 121:41-50, 2003. 87. Lakos G, Takagawa S, Chen SJ, et al: Targeted disruption of TGFbeta/Smad3 signaling modulates skin fibrosis in a mouse model of scleroderma. Am J Pathol 165:203-217, 2004. 88. Ferreira AM, Takagawa S, Fresco R, et al: Diminished induction of skin fibrosis in mice with MCP-1 deficiency. J Invest Dermatol 126:1900-1908, 2006. 89. Chujo S, Shirasaki F, Kawara S, et al: Connective tissue growth factor causes persistent proalpha2(I) collagen gene expression induced by transforming growth factor-beta in a mouse fibrosis model. J Cell Physiol 203:447-456, 2005. 90. Zhang Y, McCormick LL, Desai SR, et al: Murine sclerodermatous graft-versus-host disease, a model for human scleroderma: cutaneous cytokines, chemokines, and immune cell activation. J Immunol 168:3088-3098, 2002. 91. Ruzek MC, Jha S, Ledbetter S, et al: A modified model of graftversus-host-induced systemic sclerosis (scleroderma) exhibits all major aspects of the human disease. Arthritis Rheum 50:1319-1331, 2004. 92. Denton CP, Lindahl GE, Khan K, et al: Activation of key profibrotic mechanisms in transgenic fibroblasts expressing kinase-deficient type II Transforming growth factor-β receptor (TβRIIδk). J Biol Chem 280:16053-16065, 2005. 93. Samuel CS, Zhao C, Yang Q, et al: The relaxin gene knockout mouse: A model of progressive scleroderma. J Invest Dermatol 125:692-699, 2005. 94. Sonnylal S, Denton CP, Zheng B, et al: Postnatal induction of transforming growth factor beta signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma. Arthritis Rheum 56:334-344, 2007. 95. Charles C, Clements P, Furst DE: Systemic sclerosis: Hypothesisdriven treatment strategies. Lancet 367:1683-1691, 2006. 96. Kahaleh MB, Sherer GK, LeRoy EC: Endothelial injury in scleroderma. J Exp Med 149:1326-1335, 1979. 97. Cerinic MM, Valentini G, Sorano GG, et al: Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis. Semin Arthritis Rheum 32:285-295, 2003. 98. Hummers LK: Microvascular damage in systemic sclerosis: Detection and monitoring with biomarkers. Curr Rheumatol Rep 8:131-137, 2006. 99. Helmbold P, Nayak RC, Marsch WC, et al: Isolation and in vitro characterization of human dermal microvascular pericytes. Microvasc Res 61:160-165, 2001. 100. Rajkumar VS, Sundberg C, Abraham DJ, et al: Activation of microvascular pericytes in autoimmune Raynaud’s phenomenon and systemic sclerosis. Arthritis Rheum 42:930-941, 1999. 101. Rajkumar VS, Howell K, Csiszar K, et al: Shared expression of phenotypic markers in systemic sclerosis indicates a convergence of pericytes and fibroblasts to a myofibroblast lineage in fibrosis. Arthritis Res Ther 7:R1113-R1123, 2005. 102. Vancheeswaran R, Azam A, Black C, et al: Localization of endothelin-1 and its binding sites in scleroderma skin. J Rheumatol 21: 1268-1276, 1994. 103. Cambrey AD, Harrison NK, Dawes KE, et al: Increased levels of endothelin-1 in bronchoalveolar lavage fluid from patients with systemic sclerosis contribute to fibroblast mitogenic activity in vitro. Am J Respir Cell Mol Biol 11:439-445, 1994. 104. Yamane K, Miyauchi T, Suzuki N, et al: Significance of plasma endothelin-1 levels in patients with systemic sclerosis. J Rheumatol 19:1566-1571, 1992. 104a. Del Galdo F, Maul GG, Jiménez SA, Artlett CM. Expression of allograft inflammatory factor 1 in tissues from patients with systemic sclerosis and in vitro differential expression of its isoforms in response

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to transforming growth factor beta. Arthritis Rheum 54:2616-2625, 2006. 104b. Fleming JN, Nash RA, McLeod DO, et al: Capillary regeneration in scleroderma: Stem cell therapy reverses phenotype? PLoS ONE. Jan 16; 3:e1452, 2008. 105. Hebbar M, Peyrat JP, Hornez L, et al: Increased concentrations of the circulating angiogenesis inhibitor endostatin in patients with systemic sclerosis. Arthritis Rheum 43:889-893, 2000. 106. Distler O, Distler JH, Scheid A, et al: Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis. Circ Res 95:109-116, 2004. 107. Distler O, Del Rosso A, Giacomelli R, et al: Angiogenic and angiostatic factors in systemic sclerosis: Increased levels of vascular endothelial growth factor are a feature of the earliest disease stages and are associated with the absence of fingertip ulcers. Arthritis Res 4:R11, 2002. 108. Kuwana M, Okazaki Y, Yasuoka H, et al: Defective vasculogenesis in systemic sclerosis. Lancet 364:603-610, 2004. 109. Kuwana M, Kaburaki J, Okazaki Y, et al: Increase in circulating endothelial precursors by atorvastatin in patients with systemic sclerosis. Arthritis Rheum 54:1946-1951, 2006. 110. Del Papa ND, Quirici N, Soligo D, et al: Bone marrow endothelial progenitors are defective in systemic sclerosis. Arthritis Rheum 54:2605-2615, 2006. 111. Roumm AD, Whiteside TL, Medsger TA Jr, et al: Lymphocytes in the skin of patients with progressive systemic sclerosis: Quantification, subtyping, and clinical correlations. Arthritis Rheum 27: 645-653, 1984. 112. Kalogerou A, Gelou E, Mountantonakis S, et al: Early T cell activation in the skin from patients with systemic sclerosis. Ann Rheum Dis 64:1233-1235, 2005. 113. Kahari VM, Sandberg M, Kalimo H, et al: Identification of fibroblasts responsible for increased collagen production in localized scleroderma by in situ hybridization. J Invest Dermatol 90:664-670, 1988. 114. Sakkas LI, Xu B, Artlett CM, et al: Oligoclonal T cell expansion in the skin of patients with systemic sclerosis. J Immunol 168: 3649-3659, 2002. 115. Yurovsky VV, Wigley FM, Wise RA, et al: Skewing of the CD8+ T-cell repertoire in the lungs of patients with systemic sclerosis. Hum Immunol 48(1-2):84-97, 1996. 116. Sakkas LI, Platsoucas CD: Is systemic sclerosis an antigen-driven T cell disease? Arthritis Rheum 50:1721-1733, 2004. 117. Piela TH, Korn JH: Lymphocyte-fibroblast adhesion induced by interferon-gamma. Cell Immunol 114:149-160, 1988. 118. Rudnicka L, Majewski S, Blaszczyk M, et al: Adhesion of peripheral blood mononuclear cells to vascular endothelium in patients with systemic sclerosis (scleroderma). Arthritis Rheum 35:771-775, 1992. 119. York MR, Nagai T, Mangini AJ, et al: A macrophage marker, siglec-1, is increased on circulating monocytes in patients with systemic sclerosis and induced by type I interferons and Toll-like receptor agonists. Arthritis Rheum 56:1010-1020, 2007. 120. Tan FK, Zhou X, Mayes MD, et al: Signatures of differentially regulated interferon gene expression and vasculotrophism in the peripheral blood cells of systemic sclerosis patients. Rheumatology (Oxf) 45:694-702, 2006. 121. Wangoo A, Sparer T, Brown IN, et al: Contribution of Th1 and Th2 cells to protection and pathology in experimental models of granulomatous lung disease. J Immunol 166:3432-3439, 2001. 122. Lakos G, Melichian D, Wu M, et al: Increased bleomycin-induced skin fibrosis in mice lacking the Th1-specific transcription factor T-bet. Pathobiology 73:224-237, 2006. 123. Aliprantis AO, Wang J, Fathman JW, et al: Transcription factor T-bet regulates skin sclerosis through its function in innate immunity and via IL-13. Proc Natl Acad Sci U S A 104:2827-2830, 2007. 124. Kantor TV, Friberg D, Medsger TA Jr, et al: Cytokine production and serum levels in systemic sclerosis. Clin Immunol Immunopathol 65:278-285, 1992. 125. Prior C, Haslam PL: In vivo levels and in vitro production of interferon-gamma in fibrosing interstitial lung diseases. Clin Exp Immunol 88:280-287, 1992. 126. Tan FK, Stivers DN, Arnett FC, et al: HLA haplotypes and microsatellite polymorphisms in and around the major histocompatibility complex region in a Native American population with a high preva-

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lence of scleroderma (systemic sclerosis). Tissue Antigens 53:74-80, 1999. 127. Mavalia C, Scaletti C, Romagnani P, et al: Type 2 helper T-cell predominance and high CD30 expression in systemic sclerosis. Am J Pathol 151:1751-1758, 1997. 128. Atamas SP, Yurovsky VV, Wise R, et al: Production of type 2 cytokines by CD8+ lung cells is associated with greater decline in pulmonary function in patients with systemic sclerosis. Arthritis Rheum 42:1168-1178, 1999. 129. Luzina IG, Atamas SP, Wise R, et al: Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+ T cells from SSc patients. Arthritis Rheum 48:2262-2274, 2003. 130. Rottoli P, Magi B, Perari MG, et al: Cytokine profile and proteome analysis in bronchoalveolar lavage of patients with sarcoidosis, pulmonary fibrosis associated with systemic sclerosis and idiopathic pulmonary fibrosis. Proteomics 5:1423-1430, 2005. 131. Matsushita T, Hasegawa M, Yanaba K, et al: Elevated serum BAFF levels in patients with systemic sclerosis: Enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis Rheum 54:192-201, 2006. 132. Kraling BM, Maul GG, Jimenez SA: Mononuclear cellular infiltrates in clinically involved skin from patients with systemic sclerosis of recent onset predominantly consist of monocytes/macrophages. Pathobiology 63:48-56, 1995. 133. Hamilton RF Jr, Parsley E, Holian A: Alveolar macrophages from systemic sclerosis patients: Evidence for IL-4-mediated phenotype changes. Am J Physiol Lung Cell Mol Physiol 286:L1202-L1209, 2004. 134. Hu PQ, Fertig N, Medsger TA Jr, et al: Correlation of serum antiDNA topoisomerase I antibody levels with disease severity and activity in systemic sclerosis. Arthritis Rheum 48:1363-1373, 2003. 135. Casciola-Rosen L, Wigley F, Rosen A: Scleroderma autoantigens are uniquely fragmented by metal-catalyzed oxidation reactions: Implications for pathogenesis. J Exp Med 185:71-79, 1997. 136. Harris ML, Rosen A: Autoimmunity in scleroderma: The origin, pathogenetic role, and clinical significance of autoantibodies. Curr Opin Rheumatol 15:778-784, 2003. 137. Carvalho D, Savage CO, Black CM, et al: IgG antiendothelial cell autoantibodies from scleroderma patients induce leukocyte adhesion to human vascular endothelial cells in vitro: Induction of adhesion molecule expression and involvement of endothelium-derived cytokines. J Clin Invest 97:111-119, 1996. 138. Baroni SS, Santillo M, Bevilacqua F, et al: Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 354:2667-2676, 2006. 139. Henault J, Robitaille G, Senecal JL, et al: DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti-topoisomerase I autoantibodies from systemic sclerosis patients. Arthritis Rheum 54:963-973, 2006. 140. Sato S, Hasegawa M, Fujimoto M, et al: Quantitative genetic variation in CD19 expression correlates with autoimmunity. J Immunol 165:6635-6643, 2000. 141. Ramirez F, Tanaka S, Bou-Gharios G: Transcriptional regulation of the human alpha 2(I) collagen gene (COL1A2), an informative model system to study fibrotic diseases. Matrix Biol 25:365-372, 2006. 142. Ghosh AK, Varga J: Transcriptional coactivators p300/CBP and Type I collagen gene expression. Curr Sci 85:155-161, 2003. 143. Pannu J, Trojanowska M: Recent advances in fibroblast signaling and biology in scleroderma. Curr Opin Rheumatol 16:739-745, 2004. 144. Chang HY, Chi JT, Dudoit S, et al: Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc Natl Acad Sci U S A 99:12877-12882, 2002. 145. Rinn JL, Bondre C, Gladstone HB, et al: Anatomic demarcation by positional variation in fibroblast gene expression programs. PLoS Genet 2:e119, 2006. 146. Tomasek JJ, Gabbiani G, Hinz B, et al: Myofibroblasts and mechanoregulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3:349-363, 2002. 147. Kirk TZ, Mark ME, Chua CC, et al: Myofibroblasts from scleroderma skin synthesize elevated levels of collagen and tissue inhibitor of metalloproteinase (TIMP-1) with two forms of TIMP-1. J Biol Chem 270:3423-3428, 1995. 147a. Wipff PJ, Rifkin DB, Meister JJ, Hinz B: Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J Cell Biol 179:1311-1323, 2007.

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148. Kalluri R, Neilson EG: Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 112:1776-1784, 2003. 149. Abe R, Donnelly SC, Peng T, et al: Peripheral blood fibrocytes: Differentiation pathway and migration to wound sites. J Immunol 166:7556-7562, 2001. 150. Phillips RJ, Burdick MD, Hong K, et al: Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 114:438-446, 2004. 151. Quan TE, Cowper SE, Bucala R: The role of circulating fibrocytes in fibrosis. Curr Rheumatol Rep 8:145-150, 2006. 152. Postlethwaite AE, Shigemitsu H, Kanangat S: Cellular origins of fibroblasts: Possible implications for organ fibrosis in systemic sclerosis. Curr Opin Rheumatol 16:733-738, 2004. 153. Denton CP, Abraham DJ: Transforming growth factor-beta and connective tissue growth factor: Key cytokines in scleroderma pathogenesis. Curr Opin Rheumatol 13:505-511, 2001. 154. Mauviel A: Transforming growth factor-beta: A key mediator of fibrosis. Methods Mol Med 117:69-80, 2005. 155. Massague J, Seoane J, Wotton D: Smad transcription factors. Genes Dev 19:2783-2810, 2005. 156. Moustakas A, Heldin CH: Non-Smad TGF-beta signals. J Cell Sci 118:3573-3584, 2005. 157. Varga J: SSc and Smads: Dysfunctional Smad family dynamics culminating in fibrosis. Arthritis Rheum 46:1703-1713, 2002. 158. Igarashi A, Nashiro K, Kikuchi K, et al: Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders. J Invest Dermatol 106: 729-733, 1996. 159. Leask A, Abraham DJ: The role of connective tissue growth factor, a multifunctional matricellular protein, in fibroblast biology. Biochem Cell Biol 81:355-363, 2003. 160. Chujo S, Shirasaki F, Kawara S, et al: Connective tissue growth factor causes persistent proalpha2(I) collagen gene expression induced by transforming growth factor-beta in a mouse fibrosis model. J Cell Physiol 203:447-456, 2005. 161. Klareskog L, Gustafsson R, Scheynius A, et al: Increased expression of platelet-derived growth factor type B receptors in the skin of patients with systemic sclerosis. Arthritis Rheum 33:1534-1541, 1990. 162. Ludwicka A, Ohba T, Trojanowska M, et al: Elevated levels of platelet derived growth factor and transforming growth factor-beta 1 in bronchoalveolar lavage fluid from patients with scleroderma. J Rheumatol 22:1876-1883, 1995. 163. Hasegawa M, Fujimoto M, Kikuchi K, et al: Elevated serum levels of interleukin 4 (IL-4), IL-10, and IL-13 in patients with systemic sclerosis. J Rheumatol 24:328-332, 1997. 164. Tsuji-Yamada J, Nakazawa M, Minami M, et al: Increased frequency of interleukin 4 producing CD4+ and CD8+ cells in peripheral blood from patients with systemic sclerosis. J Rheumatol 28:1252-1273, 2001. 165. Sato S, Hasegawa M, Takehara K: Serum levels of interleukin-6 and interleukin-10 correlate with total skin thickness score in patients with systemic sclerosis. J Dermatol Sci 27:140-146, 2001. 166. Fichtner-Feigl S, Fuss IJ, Young CA, et al: Induction of IL-13 triggers TGF-beta1-dependent tissue fibrosis in chronic 2,4,6-trinitrobenzene sulfonic acid colitis. J Immunol 178:5859-5870, 2007. 167. Jinnin M, Ihn H, Yamane K, et al: Interleukin-13 stimulates the transcription of the human alpha2(I) collagen gene in human dermal fibroblasts. J Biol Chem 279:41783-41791, 2004. 168. Kaviratne M, Hesse M, Leusink M, et al: IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent. J Immunol 173:4020-4029, 2004. 169. Chizzolini C: Update on pathophysiology of scleroderma with special reference to immuno-inflammatory events. Ann Med 39:42-53, 2007. 170. Galindo M, Santiago B, Rivero M, et al: Chemokine expression by systemic sclerosis fibroblasts: Abnormal regulation of monocyte chemoattractant protein 1 expression. Arthritis Rheum 44:1382-1386, 2001. 171. Kodera M, Hasegawa M, Komura K, et al: Serum pulmonary and activation-regulated chemokine/CCL18 levels in patients with systemic sclerosis: A sensitive indicator of active pulmonary fibrosis. Arthritis Rheum 52:2889-2896, 2005. 172. Carulli MT, Ong VH, Ponticos M, et al: Chemokine receptor CCR2 expression by systemic sclerosis fibroblasts: Evidence for autocrine regulation of myofibroblast differentiation. Arthritis Rheum 52: 3772-3782, 2005.

173. Ong VH, Evans LA, Shiwen X, et al: Monocyte chemoattractant protein 3 as a mediator of fibrosis: Overexpression in systemic sclerosis and the type 1 tight-skin mouse. Arthritis Rheum 48:1979-1991, 2003. 174. Ghahary A, Shen Q, Shen YJ, et al: Induction of transforming growth factor beta 1 by insulin-like growth factor-1 in dermal fibroblasts. J Cell Physiol 174:301-309, 1998. 175. Harrison NK, Glanville AR, Strickland B, et al: Pulmonary involvement in systemic sclerosis: The detection of early changes by thin section CT scan, bronchoalveolar lavage and 99mTc-DTPA clearance. Respir Med 83:403-414, 1989. 176. Yasuoka H, Jukic DM, Zhou Z, et al: Insulin-like growth factor binding protein 5 induces skin fibrosis: A novel murine model for dermal fibrosis. Arthritis Rheum 54:3001-3010, 2006. 177. Asano Y, Ihn H, Yamane K, et al: Involvement of alphavbeta5 integrin-mediated activation of latent transforming growth factor beta1 in autocrine TGF beta signaling in systemic sclerosis fibroblasts. Arthritis Rheum 52:2897-2905, 2005. 178. Dong C, Zhu S, Wang T, et al: Deficient Smad7 expression: A putative molecular defect in scleroderma. Proc Natl Acad Sci U S A 99:3908-3913, 2002. 179. Czuwara-Ladykowska J, Shirasaki F, Jackers P, et al: Fli-1 inhibits collagen type I production in dermal fibroblasts via an Sp1-dependent pathway. J Biol Chem 276:20839-20848, 2001. 180. Yuan W, Yufit T, Li L, et al: Negative modulation of alpha1(I) procollagen gene expression in human skin fibroblasts: Transcriptional inhibition by interferon-gamma. J Cell Physiol 179:97-108, 1999. 181. Higashi K, Inagaki Y, Suzuki N, et al: Y-box binding protein YB-1 mediates transcriptional repression of human alpha 2(I) collagen gene expression by interferon-gamma. J Biol Chem 278:5156-5162, 2003. [Erratum in 278:12598, 2003]. 182. Chizzolini C, Rezzonico R, Ribbens C, et al: Inhibition of type I collagen production by dermal fibroblasts upon contact with activated T cells: Different sensitivity to inhibition between systemic sclerosis and control fibroblasts. Arthritis Rheum 41:2039-2047, 1998. 183. Hunzelmann N, Anders S, Fierlbeck G, et al: Systemic scleroderma: Multicenter trial of 1 year of treatment with recombinant interferon gamma. Arch Dermatol 133:609-613, 1997. 184. Polisson RP, Gilkeson GS, Pyun EH, et al: A multicenter trial of recombinant human interferon gamma in patients with systemic sclerosis: Effects on cutaneous fibrosis and interleukin 2 receptor levels. J Rheumatol 23:654-658, 1996. 185. Freundlich B, Jimenez SA, Steen VD, et al: Treatment of systemic sclerosis with recombinant interferon-gamma: A phase I/II clinical trial. Arthritis Rheum 35:1134-1142, 1992. 186. Mimura Y, Ihn H, Jinnin M, et al: Constitutive phosphorylation of focal adhesion kinase is involved in the myofibroblast differentiation of SSc fibroblasts. J Invest Dermatol 124:886-892, 2005. 187. Santiago B, Galindo M, Rivero M, et al: Decreased susceptibility to Fas-induced apoptosis of systemic sclerosis dermal fibroblasts. Arthritis Rheum 44:1667-1676, 2001. 188. Kawakami T, Ihn H, Xu W, et al: Increased expression of TGF-beta receptors by scleroderma fibroblasts: Evidence for contribution of autocrine TGF-beta signaling to scleroderma phenotype. J Invest Dermatol 110:47-51, 1998. 189. Yamane K, Ihn H, Kubo M, et al: Increased transcriptional activities of transforming growth factor beta receptors in scleroderma fibroblasts. Arthritis Rheum 46:2421-2428, 2002. 190. Pannu J, Gardner H, Shearstone JR, et al: Increased levels of transforming growth factor beta receptor type I and up-regulation of matrix gene program: A model of scleroderma. Arthritis Rheum 54:3011-3021, 2006. 191. Mimura Y, Ihn H, Jinnin M, et al: Constitutive thrombospondin-1 overexpression contributes to autocrine TGF-beta signaling in cultured scleroderma fibroblasts. Am J Pathol 166:1451-1463, 2005. 192. Yamane K, Miyauchi T, Suzuki N, et al: Significance of plasma endothelin-1 levels in patients with systemic sclerosis. J Rheumatol 19:1566-1571, 1992. 193. Bhattacharyya S, Ghosh AK, Pannu J, et al: Fibroblast expression of the coactivator p300 governs the intensity of profibrotic response to transforming growth factor beta. Arthritis Rheum 52:1248-1258, 2005. 194. Ihn H, Yamane K, Asano Y, et al: Constitutively phosphorylated Smad3 interacts with Sp1 and p300 in scleroderma fibroblasts. Rheumatology (Oxf) 45:157-165, 2006.

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195. Kubo M, Czuwara-Ladykowska J, Moussa O, et al: Persistent downregulation of Fli1, a suppressor of collagen transcription, in fibrotic scleroderma skin. Am J Pathol 163:571-581, 2003. 196. Wang Y, Fan PS, Kahaleh B: Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis Rheum 54:2271-2279, 2006. 196a. Clements PJ, Lachenbruch PA, Ng SC, et al: Skin score: A semiquantitative measure of cutaneous involvement that improves prediction of prognosis in systemic sclerosis. Arthritis Rheum 33:1256-1263, 1990. 196b. Moore TL, Lunt M, McManus B, et al: Seventeen-point dermal ultrasound scoring system—a reliable measure of skin thickness in patients with sclerosis. Rheumatology (Oxf), 42:1559-1563, 2003. 197. Balbir-Gurman A, Denton CP, Nichols B, et al: Non-invasive measurement of biomechanical skin properties in systemic sclerosis. Ann Rheum Dis 61:237-241, 2002. 198. Kissin EY, Schiller AM, Gelbard RB, et al: Durometry for the assessment of skin disease in systemic sclerosis. Arthritis Rheum 55: 603-609, 2006. 199. Korn JH, Mayes M, Matucci Cerinic M, et al: Digital ulcers in systemic sclerosis: Prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 50:3985-3993, 2004. 200. Walker JG, Stirling J, Beroukas D, et al: Histopathological and ultrastructural features of dermal telangiectasias in systemic sclerosis. Pathology 37:220-225, 2005. 201. Anderson ME, Allen PD, Moore T, et al: Computerized nailfold video capillaroscopy—a new tool for assessment of Raynaud’s phenomenon. J Rheumatol 32:841-848, 2005. 202. Herrick AL: Pathogenesis of Raynaud’s phenomenon. Rheumatology (Oxf) 44:587-596, 2005. 203. Carpentier PH, Satger B, Poensin D, et al: Incidence and natural history of Raynaud phenomenon: A long-term follow-up (14 years) of a random sample from the general population. J Vasc Surg 44: 1023-1028, 2006. 204. Cutolo M, Pizzorni C, Sulli A: Capillaroscopy. Best Pract Res Clin Rheumatol 19:437-452, 2005. 205. Spencer-Green G: Outcomes in primary Raynaud phenomenon: A meta-analysis of the frequency, rates, and predictors of transition to secondary diseases. Arch Intern Med 158:595-600, 1998. 206. LeRoy EC, Medsger TA Jr: Criteria for the classification of early systemic sclerosis. J Rheumatol 28:1573-1576, 2001. 207. Taylor MH, McFadden JA, Bolster MB, et al: Ulnar artery involvement in systemic sclerosis (scleroderma). J Rheumatol 29:102-106, 2002. 208. Fries R, Shariat K, von Wilmowsky H, et al: Sildenafil in the treatment of Raynaud’s phenomenon resistant to vasodilatory therapy. Circulation 112:2980-2985, 2005. 209. Gore J, Silver R: Oral sildenafil for the treatment of Raynaud’s phenomenon and digital ulcers secondary to systemic sclerosis. Ann Rheum Dis 64:1387, 2005. 210. Cheng KS, Tiwari A, Boutin A, et al: Carotid and femoral arterial wall mechanics in scleroderma. Rheumatology (Oxf) 42:1299-1305, 2003. 211. Youssef P, Englert H, Bertouch J: Large vessel occlusive disease associated with CREST syndrome and scleroderma. Ann Rheum Dis 52:564-569, 1993. 212. Ho M, Veale D, Eastmond C, et al: Macrovascular disease and systemic sclerosis. Ann Rheum Dis 59:39-43, 2000. 212a. Héron E, Fornes P, Rance A, et al: Brain involvement in scleroderma: Two autopsy cases. Stroke 29:719-721, 1998. 213. Greydanus MP, Camilleri M: Abnormal post-cibal gastric and small bowel motility due to neuropathy or myopathy in systemic sclerosis. Gastroenterology 96:110-115, 1989. 214. Dessein PH, Joffe BI, Metz RM, et al: Autonomic dysfunction in systemic sclerosis: Sympathetic overactivity and instability. Am J Med 93:143-150, 1992. 215. Spackman GK: Scleroderma: What the general dentist should know. Gen Dent 47:576-579, 1999. 216. Yarze JC, Varga J, Stampfl D, et al: Esophageal function in systemic sclerosis: A prospective evaluation of motility and acid reflux in 36 patients. Am J Gastroenterol 88:870-876, 1993. 217. Bonino JA, Sharma P: Barrett’s esophagus. Curr Opin Gastroenterol 22:406-411, 2006.

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218. Sallam H, McNearney TA, Chen JD: Systematic review: Pathophysiology and management of gastrointestinal dysmotility in systemic sclerosis (scleroderma). Aliment Pharmacol Ther 23:691-712, 2006. 219. Sjogren RW: Gastrointestinal motility disorders in scleroderma. Arthritis Rheum 37:1265-1282, 1994. 220. Watson M, Hally RJ, McCue PA, et al: Gastric antral vascular ectasia (watermelon stomach) in patients with systemic sclerosis. Arthritis Rheum 39:341-346, 1996. 221. Yusoff I, Brennan F, Ormonde D, et al: Argon plasma coagulation for treatment of watermelon stomach. Endoscopy 34:407-410, 2002. 222. Calamia KT, Scolapio JS, Viggiano TR: Endoscopic YAG laser treatment of watermelon stomach (gastric antral vascular ectasia) in patients with systemic sclerosis. Clin Exp Rheumatol 18:605-608, 2000. 223. Rigamonti C, Shand LM, Feudjo M, et al: Clinical features and prognosis of primary biliary cirrhosis associated with systemic sclerosis. Gut 55:388-394, 2006. 224. Shawis TN, Chaloner C, Herrick AL, et al: Pancreatic function in systemic sclerosis. Br J Rheumatol 35:298-299, 1996. 225. Steen VD, Medsger TA Jr: The palpable tendon friction rub: An important physical examination finding in patients with systemic sclerosis. Arthritis Rheum 40:1146-1151, 1997. 226. Doran M, Wordsworth P, Bresnihan B, et al: A distinct syndrome including features of systemic sclerosis, erosive rheumatoid arthritis, anti-topoisomerase antibody, and rheumatoid factor. J Rheumatol 28:921-922, 2001. 227. Akesson A, Fiori G, Krieg T, et al: Assessment of skin, joint, tendon and muscle involvement. Clin Exp Rheumatol 21(3 Suppl 29):S5S8, 2003. 228. Steen VD: Medsger TA Jr: Long-term outcomes of scleroderma renal crisis. Ann Intern Med 133:600-603, 2000. 229. Abbott KC, Trespalacios FC, Welch PG, et al: Scleroderma at end stage renal disease in the United States: Patient characteristics and survival. J Nephrol 15:236-240, 2002. 230. Bulpitt KJ, Clements PJ, Lachenbruch PA, et al: Early undifferentiated connective tissue disease, III: Outcome and prognostic indicators in early scleroderma (systemic sclerosis). Ann Intern Med 118:602-609, 1993. 231. Lee P, Langevitz P, Alderdice CA, et al: Mortality in systemic sclerosis (scleroderma). QJM 82:139-148, 1992. 232. Satoh M, Tokuhira M, Hama N, et al: Massive pericardial effusion in scleroderma: A review of five cases. Br J Rheumatol 34:564-567, 1995. 233. Plazak W, Zabinska-Plazak E, Wojas-Pelc A, et al: Heart structure and function in systemic sclerosis. Eur J Dermatol 12:257-262, 2002. 234. Candell-Riera J, Armadans-Gil L, Simeon CP, et al: Comprehensive noninvasive assessment of cardiac involvement in limited systemic sclerosis. Arthritis Rheum 39:1138-1145, 1996. 235. Armstrong GP, Whalley GA, Doughty RN, et al: Left ventricular function in scleroderma. Br J Rheumatol 35:983-988, 1996. 236. Di Bello V, Ferri C, Giorgi D, et al: Ultrasonic videodensitometric analysis in scleroderma heart disease. Coron Artery Dis 10:103, 1999. 237. Nakajima K, Taki J, Kawano M, et al: Diastolic dysfunction in patients with systemic sclerosis detected by gated myocardial perfusion SPECT: An early sign of cardiac involvement. J Nucl Med 42:183-188, 2001. 238. Alexander EL, Firestein GS, Weiss JL, et al: Reversible cold-induced abnormalities in myocardial perfusion and function in systemic sclerosis. Ann Intern Med 105:661-668, 1986. 239. Morelli S, Piccirillo G, Fimognari F, et al: Twenty-four hour heart period variability in systemic sclerosis. J Rheumatol 23:643-645, 1996. 240. Akram MR, Handler CE, Williams M, et al: Angiographically proven coronary artery disease in scleroderma. Rheumatology (Oxf) 45:1395-1398, 2006. 241. Mukerjee D, St George D, Coleiro B, et al: Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: Application of a registry approach. Ann Rheum Dis 62:1088-1093, 2003. 241a. Karwatowski SP, Chronos NA, Sinclaire H, et al: Effect of systemic sclerosis on left ventricular long-axis motion and left ventricular mass assessed by magnetic resonance. J Cardiovasc Magn Reson 2:109-117, 2000. 242. Latsi PI, Wells AU: Evaluation and management of alveolitis and interstitial lung disease in scleroderma. Curr Opin Rheumatol 15:748-755, 2003.

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243. Wells AU, Hansell DM, Rubens MB, et al: Fibrosing alveolitis in systemic sclerosis: Indices of lung function in relation to extent of disease on computed tomography. Arthritis Rheum 40:1229-1236, 1997. 244. Robertson L, Pignone A, Kowal-Bielecka O, et al: Pulmonary arterial hypertension in systemic sclerosis: Diagnostic pathway and therapeutic approach. Ann Rheum Dis 64:804-807, 2005. 245. Desai SR, Veeraraghavan S, Hansell DM, et al: CT features of lung disease in patients with systemic sclerosis: Comparison with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia. Radiology 232:560-567, 2004. 246. Tashkin DP, Elashoff R, Clements PJ, et al; Scleroderma Lung Study Research Group: Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 354:2655-2666, 2006. 247. Hoyles RK, Ellis RW, Wellsbury J, et al: A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum 54:3962-3970, 2006. 248. Nihtyanova SI, Brough GM, Black CM, et al: Mycophenolate mofetil in diffuse cutaneous systemic sclerosis—a retrospective analysis. Rheumatology (Oxf) 46:442-445, 2007. 249. Gerbino AJ, Goss CH, Molitor JA: Effect of mycophenolate mofetil on pulmonary function in scleroderma-associated interstitial lung disease. Chest 133:455-460, 2008. 250. Walter N, Collard HR, King TE Jr: Current perspectives on the treatment of idiopathic pulmonary fibrosis. Proc Am Thorac Soc 3: 330-338, 2006. 251. Schachna L, Medsger TA Jr, Dauber JH, et al: Lung transplantation in scleroderma compared with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial hypertension. Arthritis Rheum 54:3954-3961, 2006. 252. Denton CP, Humbert M, Rubin L, et al: Bosentan treatment for pulmonary arterial hypertension related to connective tissue disease: A subgroup analysis of the pivotal clinical trials and their open-label extensions. Ann Rheum Dis 65:1336-1340, 2006. 253. Steen V: Predictors of end stage lung disease in systemic sclerosis. Ann Rheum Dis 62:97-99, 2003. 254. Steen V, Medsger TA Jr: Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum 48:516-522, 2003. 255. Williams MH, Handler CE, Akram R, et al: Role of N-terminal brain natriuretic peptide (N-TproBNP) in scleroderma-associated pulmonary arterial hypertension. Eur Heart J 27:1485-1494, 2006. 256. Villalba WO, Sampaio-Barros PD, Pereira MC, et al: Six-minute walk test for the evaluation of pulmonary disease severity in scleroderma patients. Chest 131:217-222, 2007. 257. Hachulla E, Gressin V, Guillevin L, et al: Early detection of pulmonary arterial hypertension in systemic sclerosis: A French nationwide prospective multicenter study. Arthritis Rheum 52:3792-3800, 2005. 258. Barst RJ, Langleben D, Frost A, et al: STRIDE-1 Study Group: Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 169:441-447, 2004. 259. Galie N, Ghofrani HA, Torbicki A, et al: Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group: Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353: 2148-2157, 2005. 260. Rodnan GP, Benedek TG: An historical account of the study of progressive systemic sclerosis (diffuse scleroderma). Ann Intern Med 57:305-319, 1962. 261. Steen VD, Constantino JP, Shapiro AP, et al: Outcome of renal crisis in systemic sclerosis: Relation to the availability of converting enzyme inhibitors (ACE). Ann Intern Med 113:352-357, 1990. 262. Penn H, Howie A, Kingdon EJ, et al: Scleroderma renal crisis: Patient characteristics and long-term outcomes. Q J Med 100:485494, 2007. 263. DeMarco PJ, Weisman MH, Seibold JR, et al: Predictors and outcomes of scleroderma renal crisis: The high-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial. Arthritis Rheum 46:2983-2989, 2002. 264. Della Bella S, Molteni M, Mocellin C, et al: Novel mode of action of iloprost: In vitro down-regulation of endothelial cell adhesion molecules. Prostaglandins 65(2-3):73-83, 2001.

265. Walker JG, Ahern MJ, Smith MD, et al: Scleroderma renal crisis: Poor outcome despite aggressive antihypertensive treatment. Intern Med J 33(5-6):216-220, 2003. 266. Chang YJ, Spiera H: Renal transplantation in scleroderma. Medicine (Balt) 78:382-385, 1999. 267. Lally EV, Jimenez SA, Kaplan SR: Progressive systemic sclerosis: Mode of presentation, rapidly progressive disease course, and mortality based on an analysis of 91 patients. Semin Arthritis Rheum 18:1-13, 1988. 268. Locke IC, Worrall JG, Leaker B, et al: Autoantibodies to myeloperoxidase in systemic sclerosis. J Rheumatol 24:86-89, 1997. 269. Hillis GS, Khan IH, Simpson JG, et al: Scleroderma, D-penicillamine treatment, and progressive renal failure associated with positive antimyeloperoxidase antineutrophil cytoplasmic antibodies. Am J Kidney Dis 30:279-281, 1997. 270. Hietarinta M, Lassila O, Hietaharju A: Association of anti-U1RNPand anti-Scl-70-antibodies with neurological manifestations in systemic sclerosis. Scand J Rheumatol 23:64-67, 1994. 271. Gibney EM, Parikh CR, Jani A, et al: Kidney transplantation for systemic sclerosis improves survival and may modulate disease activity. Am J Transplant 4:2027-2031, 2004. 272. Pham PT, Pham PC, Danovitch GM, et al: Predictors and risk factors for recurrent scleroderma renal crisis in the kidney allograft: Case report and review of the literature. Am J Transplant 5:2565-2569, 2005. 273. Coll J, Rives A, Grino MC, et al: Prevalence of Sjogren’s syndrome in autoimmune diseases. Ann Rheum Dis 46:286-289, 1987. 274. Valentini G, Bencivelli W, Bombardieri S, et al: European Scleroderma Study Group to define disease activity criteria for systemic sclerosis, III: Assessment of the construct validity of the preliminary activity criteria. Ann Rheum Dis 62:901-903, 2003. 275. Merkel PA, Herlyn K, Martin RW, et al: Scleroderma Clinical Trials Consortium: Measuring disease activity and functional status in patients with scleroderma and Raynaud’s phenomenon. Arthritis Rheum 46:2410-2420, 2002. 275a. Medsger TA, Silman AJ, Steen VD, et al: A disease severity scale for systemic sclerosis: developing and testing. J Rheumatol 26(10):21592167, 1999. 276. Kuwana M, Inoko H, Kameda H, et al: Association of human leukocyte antigen class II genes with autoantibody profiles, but not with disease susceptibility in Japanese patients with systemic sclerosis. Intern Med 38:336-344, 1999. 277. Bunn CC, Denton CP, Shi-Wen X, et al: Anti-RNA polymerases and other autoantibody specificities in systemic sclerosis. Br J Rheumatol 37:15-20, 1998. 278. Farge D, Passweg J, van Laar JM, et al: EBMT/EULAR Registry: Autologous stem cell transplantation in the treatment of systemic sclerosis: Report from the EBMT/EULAR Registry. Ann Rheum Dis 63:974-981, 2004. 279. Stratton RJ, Wilson H, Black CM: Pilot study of anti-thymocyte globulin plus mycophenolate mofetil in recent-onset diffuse scleroderma. Rheumatology (Oxf) 40:84-88, 2001. 280. Scherer HU, Burmester GR, Riemekasten G: Targeting activated T cells: Successful use of anti-CD25 monoclonal antibody basiliximab in a patient with systemic sclerosis. Ann Rheum Dis 65:12451247, 2006. 281. Liossis SN, Bounas A, Andonopoulos AP: Mycophenolate mofetil as first-line treatment improves clinically evident early scleroderma lung disease. Rheumatology 45:1005-1008, 2006. 282. Mayes MD, O’Donnell D, Rothfield NF, et al: Minocycline is not effective in systemic sclerosis: Results of an open-label multicenter trial. Arthritis Rheum 50:553-557, 2004. 283. Maddison P: Prevention of vascular damage in scleroderma with angiotensin-converting enzyme (ACE) inhibition. Rheumatology 41:965-971, 2002. 283a. Gliddon AE, Doré CJ, Black CM, et al: Prevention of vascular damage in scleroderma and autoimmune Raynaud’s phenomenon: A multicenter, randomized, double-blind, placebo-controlled trial of the angiotensin-converting enzyme inhibitor quinapril. Arthritis Rheum 56:3837-3846, 2007. 284. Furukawa S, Yasuda S, Amengual O, et al: Protective effect of prava­ statin on vascular endothelium in patients with systemic sclerosis: A pilot study. Ann Rheum Dis 65:1118-1120, 2006. 285. Milio G, Corrado E, Genova C, et al: Iloprost treatment in patients with Raynaud’s phenomenon secondary to systemic sclerosis and the

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quality of life: A new therapeutic protocol. Rheumatology (Oxf) 45:999-1004, 2006. 286. Thompson AE, Pope JE: Calcium channel blockers for primary Raynaud’s phenomenon: A meta-analysis. Rheumatology (Oxf) 44:145-150, 2005. 287. Dziadzio M, Denton CP, Smith R, et al: Losartan therapy for Ray­ naud’s phenomenon and scleroderma: Clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial. Arthritis Rheum 42:2646-2655, 1999. 288. Coleiro B, Marshall SE, Denton CP, et al: Treatment of Raynaud’s phenomenon with the selective serotonin reuptake inhibitor fluoxetine. Rheumatology (Oxf) 40:1038-1043, 2001. 289. Samuelson UK, Ahlmen EM: Development and evaluation of a patient education program for persons with systemic sclerosis (scleroderma). Arthritis Care Res 13:141-148, 2000. 290. Bunn CC, Black CM: Systemic sclerosis: An autoantibody mosaic. Clin Exp Immunol 117:207-208, 1999. 291. Reveille JD, Solomon DH: American College of Rheumatology Ad Hoc Committee of Immunologic Testing Guidelines: Evidencebased guidelines for the use of immunologic tests: Anticentromere, Scl-70, and nucleolar antibodies. Arthritis Rheum 49:399-412, 2003. 292. Laxer RM, Zulian F: Localized scleroderma. Curr Opin Rheumatol 18:606-613, 2006. 293. Tollefson MM, Witman PM: En coup de sabre morphea and ParryRomberg syndrome: A retrospective review of 54 patients. J Am Acad Dermatol 56:257-263, 2007. 294. Weide B, Walz T, Garbe C: Is morphoea caused by Borrelia burgdorferi? Br J Dermatol 142:636-644, 2000. 295. Mancuso G, Berdondini RM: Topical tacrolimus in the treatment of localized scleroderma. Eur J Dermatol 13:590-592, 2003. 296. Marzano AV, Menni S, Parodi A, et al: Localized scleroderma in adults and children: Clinical and laboratory investigations on 239 cases. Eur J Dermatol 13:171-176, 2003. 297. Vancheeswaran R, Black CM, David J, et al: Childhood-onset scleroderma: Is it different from adult-onset disease. Arthritis Rheum 39:1041-1049, 1996. 298. Zulian F, Athreya BH, Laxer R, et al: Juvenile Scleroderma Working Group of the Pediatric Rheumatology European Society (PRES): Juvenile localized scleroderma: Clinical and epidemiological features in 750 children: An international study. Rheumatology (Oxf) 45:614-620, 2006. 299. Birdi N, Shore A, Rush P, et al: Childhood linear scleroderma: A possible role of thermography for evaluation. J Rheumatol 19: 968-973, 1992. 300. Cosnes A, Anglade MC, Revuz J, et al: Thirteen-megahertz ultrasound probe: Its role in diagnosing localized scleroderma. Br J Dermatol 148:724-729, 2003. 301. Tate BJ, Kelly JW, Rotstein H: Scleredema of Buschke: A report of seven cases. Australas J Dermatol 37:139-142, 1996. 302. Cokonis Georgakis CD, Falasca G, Georgakis A, et al: Scleromyxedema. Clin Dermatol 24:493-497, 2006. 303. Kucher C, Xu X, Pasha T, et al: Histopathologic comparison of nephrogenic fibrosing dermopathy and scleromyxedema. J Cutan Pathol 32:484-490, 2005.

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304. Dziadzio M, Denton CP, Smith R, et al: Losartan therapy for Ray­ naud’s phenomenon and scleroderma: Clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial. Arthritis Rheum 42:2646-2655, 1999. 305. Lister RK, Jolles S, Whittaker S, et al: Scleromyxedema: Response to high-dose intravenous immunoglobulin (hdIVIg). J Am Acad Dermatol 43(2 Pt 2):403-408, 2000. 306. Donato ML, Feasel AM, Weber DM, et al: Scleromyxedema: Role of high-dose melphalan with autologous stem cell transplantation. Blood 107:463-466, 2006. 307. Keong CH, Asaka Y, Fukuro S, et al: Successful treatment of scleromyxedema with plasmapheresis and immunosuppression. J Am Acad Dermatol 22(5 Pt 1):842-844, 1990. 308. Barnes L, Rodnan GP, Medsger TA, et al: Eosinophilic fasciitis: A pathologic study of twenty cases. Am J Pathol 96:493-517, 1979. 309. Eklund KK, Anttila P, Leirisalo-Repo M: Eosinophilic fasciitis, myositis and arthritis as early manifestations of peripheral T-cell lymphoma. Scand J Rheumatol 32:376-377, 2003. 310. Khanna D, Verity A, Grossman JM: Eosinophilic fasciitis with multiple myeloma: A new haematological association. Ann Rheum Dis 61:1111-1112, 2002. 311. Garcia VP, de Quiros JF, Caminal L: Autoimmune hemolytic anemia associated with eosinophilic fasciitis. J Rheumatol 25:1864-1865, 1998. 312. Cassis TB, Jackson JM, Sonnier GB, et al: Nephrogenic fibrosing dermopathy in a patient with acute renal failure never requiring dialysis. Int J Dermatol 45:56-59, 2006. 313. Edward M, Fitzgerald L, Thind C, et al: Cutaneous mucinosis associated with dermatomyositis and nephrogenic fibrosing dermopathy: Fibroblast hyaluronan synthesis and the effect of patient serum. Br J Dermatol 156:473-479, 2007. 314. Mendoza FA, Artlett CM, Sandorfi N, et al: Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum 35:238-249, 2006. 315. Mackay-Wiggan JM, Cohen DJ, Hardy MA, et al: Nephrogenic fibrosing dermopathy (scleromyxedema-like illness of renal disease). J Am Acad Dermatol 48:55-60, 2003. 316. Posada de la Paz M, Philen RM, Borda AI: Toxic oil syndrome: The perspective after 20 years. Epidemiol Rev 23:231-247, 2001. 317. Bolster MB, Silver RM: Eosinophilia-myalgia syndrome, toxic-oil syndrome, and diffuse fasciitis with eosinophilia. Curr Opin Rheumatol 6(6):642-649, 1994. 318. Swaminathan S, Ahmed I, McCarthy JT, et al: Nephrogenic fibrosing dermopathy and high-dose erythropoietin therapy. Ann Intern Med 145:234-235, 2006. 319. Grobner T: Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 21:1104-1108, 2006. 320. Antic M, Lautenschlager S, Itin PH: Eosinophilic fasciitis 30 years after—what do we really know? Report of 11 patients and review of the literature. Dermatology 213:93-101, 2006.

78

Inflammatory Diseases of Muscle and Other Myopathies KANNEBOYINA NAGARAJU  •  INGRID ­E. LUNDBERG

KEY POINTS This heterogeneous group of muscle diseases is characterized by symmetric proximal muscle weakness and frequent involvement of other organs. Myopathies are often accompanied by elevated levels of serum muscle enzymes and abnormal electromyograms. Histology shows varying degrees of inflammation and muscle fiber degeneration and regeneration. Some patients have autoantibodies to molecules involved in protein synthesis, and these antibodies are often associated with distinct clinical phenotypes. Corticosteroids and cytotoxic drugs are common therapies.

HISTORY OF INFLAMMATORY MUSCLE DISEASES Inflammatory muscle diseases are a heterogeneous group of systemic autoimmune rheumatic disorders characterized by chronic muscle weakness, muscle fatigue, and mono­nuclear cell infiltration into skeletal muscle. These disorders were described in the literature more than a century ago as g­eneralized muscle disorders affecting principally the trunk and proximal limb muscles, with or without skin involvement.1-5 It was also recognized that these diseases can range from acute and even fatal to slow, progressive, chronic, insidious conditions, with patterns of relapse and remission. Steiner’s6 summary of myositis cases in 1903 made a clear distinction between idiopathic polymyositis and other forms of myositis caused by bacteria and parasites,6 and Stertz7 in 1916 first reported an association between dermatomyositis and internal malignancy.7 At about the same time, Ba­tten8 described the first case of dermatomyositis with classic h­istologic features in a child. Since the1940s, it has been recognized that ­polymyositis may occur in the absence of cutaneous lesions, muscle pain, or constitutional symptoms, and it may present in an acute, subacute, or chronic insidious form, with some fraction of cases showing systemic features or involvement of organs and tissues.9 The differential diagnosis has been described independently by several investigators, and the most chronic form was differentiated from an adult variety of muscular dystrophy.10-12 Banker and V­ictor13 noted that dermatomyositis in children was different and involved a greater degree of vascular inflammation and thrombosis (systemic angiopathy). The first, and still widely used, classification scheme and set of diagnostic criteria for myositis were proposed by Bohan

and Peter in 1975.14,15 These include polymyositis and dermatomyositis but not the later-described subset known as inclusion body myositis (IBM). IBM was later defined by the presence of distinct histopathologic changes, including vacuoles and nuclear and cytoplasmic inclusions, as well as by distinct ­ clinical features, including resistance to ­ glucocorticoids.16,17 Debate continues whether IBM should be considered an idiopathic inflammatory myopathy (IIM). We have chosen to include information on IBM in this chapter because it is clinically relevant to the differential diagnosis of polymyositis.

EPIDEMIOLOGY The actual annual incidence of inflammatory myopathy is currently unknown. Because these diseases are so rare, no large-scale epidemiologic studies have been reported; ho­wever, several retrospective studies have reported an annual incidence of fewer than 10 per million individuals18-22 (Table 78-1). This may be an overestimate, given that the Peter and Bohan diagnostic criteria used in these studies did not distinguish IBM as a separate disease entity. The prevalence of IBM has been estimated to be 10.7 per million in the United States, 9.3 per million in Australia, and 4.9 per million in the Netherlands.23-25 The age-adjusted prevalence of IBM for those older than 50 years was reported as 16 to 35 per million.24,25 In some geographic areas, IBM appears to be the most common acquired progressive myopathy, representing 16% to 28% of all inflammatory myopathies.25 There may be referral biases in these studies. The incidence-prevalence studies need to be interpreted cautiously, given that most have not reported confidence intervals for their rates. The incidence of the various myopathies varies acc­ording to ethnicity, age, and gender. Some studies have reported that the incidence of polymyositis is higher in black patients than in white patients.18 IIMs can occur in any age group, from early childhood to late in adult life. The onset of polymyositis is usually in the late teens or older, with the mean age at onset being 50 to 60 years; dermatomyositis shows two peaks—5 to 15 years and 45 to 65 years. IBM is commonly seen in individuals older than 50 years and is rare in younger adults. Some studies have reported gender-specific incidence rates. For example, in the case of polymyositis and dermatomyositis, females are more commonly affected than males (ratio >2:1), whereas in IBM, the converse is true (again, >2:1 ratio). Inflammatory myopathies can occur in association with other autoimmune connective tissue diseases, such as scleroderma, systemic lupus erythematosus (SLE), rheu­matoid arthritis, Sjögren’s syndrome, polyarthritis nodosa, and 1353

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Table 78-1  Incidence of Inflammatory Myopathies   by Country Country

Study Dates

USA

1963-1982

Incidence (million/yr) 5.5

Reference   18

USA

1947-1968

5.0

  20

Australia

1989-1991

7.4

  21

Sweden

1984-1993

7.6

  22

Israel

1960-1976

2.1

178

sarcoidosis. Significant proportions of all myositis patients (11% to 40%) have an associated connective tissue disease.23,26,27 Several studies have also confirmed an association between malignancies and inflammatory myo­pathies. The frequency of malignancies varies widely (4% to 42%) in different studies,19,28 but in general, the incidence of malignancy is higher in dermatomyositis patients than in IBM or polymyositis patients.29 It is difficult to determine the re­lative risks for a particular malignancy because a variety of malignancies are associated with myositis, and only small numbers of individual malignancies have been reported in any one study.

CAUSE GENETIC RISK FACTORS An association with immune response genes and occasional reports of familial clustering of myositis support the role of genetic factors in these diseases.30-35 Polymorphisms in human leukocyte antigen (HLA) class I and II genes are known genetic risk factors for several autoimmune diseases, including myositis, but the mechanisms for these associations remain unclear. One possibility is that because the gene products influence T cell repertoire development, tolerance, and immune responses to foreign agents, certain polymorphisms may be selected based on environmental triggers. It appears that haplotypes HLA-DRB1*0301 and HLA-DQA1*0501 are the strongest known genetic risk factors for all forms of myositis in Caucasians; however, different phenotypes have additional HLA risk and protective factors.35,36 The HLA-B8/DR3/DR52/DQ2 ha­plotype is found in a significant proportion of IBM patients.37 The risk and protection conferred by HLA associations differ significantly among different ethnic and serologic groups. For example, in some populations (e.g., Koreans and Mesoa­mericans), there is no association with HLA genes.33 Further, HLA-DRB1*0301, which is a risk factor in C­aucasians, is a protective fa­ctor in the Japanese population.38 The HLA-DRB1*0301, HLADQA1*0501, and HLA-DQB1*0201 alleles are strongly associated with myositis-specific antibodies in polymyositis patients.39 Mechanistic data supporting the role of HLA molecules in disease pathogenesis are, unfortunately, lacking at present. Some studies have reported that maternally derived chimeric cells are present in the peripheral blood and muscle tissues of juvenile dermatomyositis patients, suggesting that HLA alleles control the occurrence of chimerism and explain the HLA association found in these disorders.40,41 Like other autoimmune disease conditions, myositis is a complex multigenic disorder involving other

Table 78-2  Possible Environmental Risk Factors Infectious Agents Viruses   Picornavirus family, enteroviruses     Polio, coxsackievirus types A and B, echoviruses   Retroviruses     HIV-1, HTLV-1   Parvovirus B19   Hepatitis C virus   Hepatitis B virus Bacteria   Staphylococci   Clostridia   Mycobacteria Parasites   Toxoplasma gondii   Trypanosoma cruzi   Borrelia burgdorferi Noninfectious Agents Drugs   D-penicillamine   Corticosteroids   Chloroquine   Statins (atorvastatin, lovastatin, pravastatin, simvastatin)   Lipid-lowering fibrates (bezafibrate, clofibrate, gemfibrozil)   l-tryptophan   Biologic agents (e.g., growth hormone, interferon-α, interleukin-2)   Vaccination for tetanus, BCG, diphtheria, hepatitis B, hepatitis A   Miscellaneous drugs (e.g., local anesthesia, hydroxyurea, le­ uprolide acetate) Ultraviolet radiation exposure Miscellaneous agents (e.g., silicone breast implants, chronic   graft-versus-host disease associated with bone marrow   transplantation, collagen injection, silica exposure) BCG, bacille Calmette-Guérin; HIV, human immunodeficiency virus; HTLV-1, human T-lymphotropic virus 1.

non-HLA immune response genes (e.g., cytokines and receptors, including tumor necrosis factor-α [TNF-α], interleukin [IL]-1, and tumor necrosis factor receptor [TNFR]-1), complement components (e.g., C4, C2), immunoglobulin heavy-chain allotypes, and T cell receptors.42 The exact contribution of the genetic component in these disorders is currently unknown, in part because of their rarity, the small number of subjects in any single cohort, and the heterogeneity in disease phenotype. International collaborative efforts are currently under way to address these issues and to identify potential genetic and environmental risk factors in myositis. ENVIRONMENTAL RISK FACTORS The temporal association of myositis onset and environmental agents in certain individuals suggests that specific exposures in the context of certain genetic backgrounds can initiate muscle inflammation. Common environmental agents implicated in myositis include infectious organisms, such as viruses and bacteria, and noninfectious agents, such as drugs and food supplements (Table 78-2). For example, enteroviruses (influenza, coxsackievirus, echoviruses) and retroviruses (human T-lymphotrophic virus-1) are known to induce muscle inflammation. The myositis associated with enteroviruses usually occurs in children and is generally self-limited. A viral cause is strengthened by the presence of high-titer antiviral antibodies and viral particles in patients’

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serum and tissue samples,43,44 as well as the induction of muscle inflammation by enteroviruses in animal models. Attempts to identify virus in the tissues of IIM patients by sensitive techniques such as polymerase chain reaction have failed, leading to doubts about the viral cause of these di­seases45 and ruling out continual viral infection as a cause of the ongoing muscle inflammation in these patients. Ho­wever, it is possible that viruses initially trigger the disease process before being eliminated by the host’s immune response, thus explaining the absence of viral genomes in the myositis muscle tissue. Similarly, some microorganisms, such as staphylococci, clostridia, and mycobacteria, are known to affect skeletal muscle and cause acute muscle inflammation, but there is no evidence that these organisms actually cause chronic, self-sustaining muscle inflammation. Parasites such as Toxoplasma gondii, Trypanosoma cruzi, and Borrelia burgdorferi have been implicated in the triggering of IIMs. The evidence in support of a parasitic cause include the recovery of parasites from some myositis patients and their serologic response to the parasites; improvement in myositis symptoms after treatment with antiparasitic drugs; a histologic picture of inflammation, including infiltration of macrophages and CD4 T cells; and induction of myositis after parasitic infection in animal models.46-51a Despite these observations, it is difficult to establish a direct link between any parasitic infections and myositis in human patients, because there is often no history of antecedent parasitic infection. Ultraviolet (UV) light irradiation is likely to be a risk factor for the development of dermatomyositis, because ep­idemiologic data that have demonstrated a latitude gradient of polymyositis and dermatomyositis, with the latter being more frequent closer to the equator and the former being more frequent in northern countries. The ratio between ­ polymyositis and dermatomyositis is ­ associated with a latitude gradient and is directly correlated with UV light irradiation. This observed correlation is particularly strong in a subset of dermatomyositis patients with anti–Mi-2 autoantibodies, indicating that UV light may be an environ­mental risk factor for its development. The association between UV light exposure and subtype of myositis suggests that UV light is an exogenous modifier that can influence the ­ clinical ­ phenotype in polymyositis and ­dermatomyositis.52 It appears that malignancy is an additional risk factor for the development of myositis, and there is a strong asso­ ciation between dermatomyositis and malignancies. This early clinical observation has been confirmed in epidemiologic studies.28,53 With regard to polymyositis and IBM, the association with malignancy is less convincing. The increased risk of malignancy associated with dermatomy­ ositis has been established both at the time of dermato­ myositis ­diagnosis and more than 10 years after diagnosis. The pathoph­ysiologic mechanism for the association between malignancy and dermatomyositis has not been clarified, but there could be several explanations. The strong association between malignancy and the onset of dermatomyositis in­dicates that the latter could be a paramalignant phenomenon; that is, the development of myositis is a consequence of the malignancy (related to autoantigens), or the malignancy and dermatomyositis share disease mechanisms. Thus, the molecular mechanisms underlying this

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unique association are currently unclear. However, there is circumstantial evidence that removal of a tumor sometimes results in amelioration of muscle weakness, and tumor reappearance sometimes coincides with muscle weakness, suggesting that these two are linked. A recent report has shed some light on this connection by showing that myositisspecific antigens are highly expressed in cancer tissues as well as in regenerating muscle cells of myositis patients.54,55 The authors propose that in cancer-associated myositis, an autoimmune response directed against cancer cross-reacts with regenerating muscle cells, enabling a feed-forward loop of tissue damage and antigen selection.56 This association must be explored further, because cancer-associated myositis patients almost never develop myositis-specific autoantibodies, which are protective for the development of cancer. For malignancies that develop during established disease, the potential explanations include the presence of chronic inflammation or prolonged immunosuppressive treatment, which could contribute to the development of malignancy. MIMICS OF MYOSITIS A variety of insults induce the clinical and pathologic sp­ectrum that mimics myositis in some individuals (see Table 78-2). A number of drugs are known to cause a myopathy that closely mimics myositis. For example, D-peni­cillamine causes clinically and histologically indistinguishable IIM.57 Likewise, commonly used lipid-lowering drugs such as statins (e.g., atorvastatin, lovastatin) can cause a myopathy that resembles inflammatory myositis. These agents inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme involved in the conversion of HMG-CoA to mevalonic acid, thereby preventing the synthesis of bioactive sterol and nonsterol metabolic intermediates in the cholesterol synthetic pa­thway. The mechanism by which these drugs cause myopathy is not known.58-60 Other drugs such as hydroxyurea can cause skin rashes that resemble dermatomyositis.61 Recent reports implicate the vaccine adjuvant aluminum hyd­roxide as a cause of macrophagic myofasciitis. The histology shows infiltration by macrophages and some CD8 T cells into the endomysium, perimysium, and epimysium, together with clinically elevated creatine kinase (CK) levels, muscle weakness, myalgias, fatigue, and arthralgias.62 Despite some reports of vaccine-induced myositis, systematic inve­stigation has failed to link any vaccine to myositis.63

PATHOGENESIS Significant advances have been made in our understa­nding of the pathogenesis of the human inflammatory myopathies.64-69 It is generally thought that IIMs are autoimmune in origin because they are frequently associated with other autoimmune diseases (e.g., Hashimoto’s thyroiditis) and collagen vascular diseases (e.g., scleroderma); many patients exhibit an autoantibody response, including the presence of myositis-specific autoantibodies; some studies provide e­vidence for lymphocyte-mediated muscle fiber injury; and a favorable response to immunosuppressive therapies in some patients supports an autoimmune cause of these disorders.

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HUMORAL IMMUNE RESPONSE More than 50% of all IIM patients have uniquely defined autoantibodies—some of which are specific to my­ositis, and some of which are merely associated with myositis. These are generally referred to as myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs), respectively. MAAs includes autoantibodies to various nuclear and cytoplasmic antigens. Antinuclear antibodies (ANAs) present in myositis are not particularly associated with any disease subgroup, whereas MSAs that are directed against antigens of the protein synthesis pathway (e.g., aminoacyl–transfer RNA [tRNA] synthetases and signal recognition particles) and nuclear components (e.g., nuclear helicase [Mi-2]) are often associated with distinct clinical disease groups and subgroups (e.g., tRNA synthetases with interstitial lung disease, and Mi-2 with dermatomyositis) (Table 78-3). Anti–histidyl tRNA synthetase antibodies are the most frequent and are present in about 16% to 20% of myositis patients.70-72 Antibodies against other aminoacyl-tRNA sy­nthetases, such as threonyl-tRNA synthetase (PL-7), alanyl-tRNA synthetase (PL-12), isoleucyl-tRNA synthetase (OJ), glycyl-tRNA synthetase (EJ), and asparaginyl-tRNA synthetase (KS), are found less frequently (1% to 3%). Anti–Mi-2 antibodies are strongly associated with dermatomyositis,73,74 with prominent features such as Gottron’s papules, heliotrope rash, the V sign, and the shawl sign. An individual usually has only one MSA, because they are often mutually exclusive. The MSAs are most common in patients with other autoimmune diseases and are infrequent or absent in IBM patients and those with malignancies, muscular dystrophies, or other myopathies. These antibodies are sometimes present before the onset of clinical disease.75 MAAs such as PM-Scl are frequently associated with a characteristic overlap syndrome that includes features of scleroderma76,77 This syndrome is characterized by mild m­uscle disease, prominent arthritis, and limited skin involvement; it frequently responds to therapy.78 Some myositis patients also have other MAAs, such as anti-snRNP, an­tiRo/SSA, anti-Ku, and anti-PMS1. Antibodies recognizing an uncharacterized 56-kD large nuclear ribonucleoprotein have been found in a majority of myositis patients (86%), and the antibody titer appears to vary with disease activity, suggesting its importance in our understanding of disease pathogenesis and its potential usefulness as a clinical disease marker.79 Some of the MSAs show strong immunogenetic associations; for example, antibodies against aminoacyltRNA synthetases are associated with HLA-DQA1*0501, anti-SRP with DR5, anti–Mi-2 with DR7, and anti–PM-Scl with DR3.35 Neither the molecular mechanisms that initiate and perpetuate the autoimmune response nor the precise role of these autoantibodies in the pathogenesis of myositis is currently known. It is likely that these autoantibodies are not the primary pathogenic event leading to muscle fiber damage because they are present in only a fraction of all myositis patients; they are directed not against musclespecific antigens but against ubiquitously expressed cellular proteins; and they are usually specific for intracellular target antigens that are not easily accessible to antibodies. However, these antibodies serve as excellent clinical markers and can help diagnose and categorize these heterogeneous disorders into homogeneous subgroups.

Table 78-3  Myositis-Specific Antibodies Autoantibodies

Clinical Disease/Features

Antisynthetase   autoantibodies*

More common in polymyositis than dermatomyositis; interstitial lung disease, arthritis, Raynaud’s phenomenon, fevers, mechanic’s hands

Signal recognition particle   (SRP)†

Polymyositis; possible severe disease and cardiac involvement

Chromodomain helicase DNA binding proteins 3 and 4   (Mi-2α and β)‡

Dermatomyositis

*Common antisynthetase antibodies found in myositis are targeted to ­histidyl-tRNA synthetase (Jo-1), threonyl-tRNA synthetase (PL-7), alanyl-tRNA synthetase (PL-12), isoleucyl-tRNA synthetase (OJ), glycyl-tRNA synthetase (EJ), and asparaginyl-tRNA synthetase (KS). † Autoantibodies commonly bind to a 54-kD SRP protein in the U.S. patient population and 72-, 54-, and 9-kD proteins in the Japanese population ‡ Targets a 240-kD helicase protein that is part of the nucleosome ­remodeling deacetylase complex.

CELL-MEDIATED IMMUNE RESPONSE At the cellular level, there are distinct differences in the ­distribution and location of the various lymphocyte subsets in the muscle tissues in different IIMs. Two major patterns of inflammatory cell infiltrates are seen in muscle tissue. The first has a predominantly perivascular distribution (Fig. 78-1A), often in perimysial areas (Fig. 78-1C), and is largely made up of CD4+ T cells, macrophages, and dendritic cells. In occasional patients, B cells are present. This pattern in seen mainly in dermatomyositis patients with skin rash, but occasionally in patients without a rash. The second pattern has a predominantly endomysial distribution (Fig. 78-1B), with mononuclear inflammatory cells often surrounding and sometimes invading non-necrotic muscle fibers. These inflammatory cellular infiltrates are made up primarily of CD8+ T cells and macrophages, but CD4+ T cells and ­dendritic cells are also present. This pattern is generally seen in patients without skin rash and often in those classified as having polymyositis or IBM. In some patients, the two patterns of inflammation are seen in the same biopsy. The two distinct locations and the varying compositions of the inflammatory cell populations in the two areas suggest two different pathogenic mechanisms—one that targets the blood vessels, and one that targets the muscle fibers. ­Notable inflammation is also seen in other organs. The vascular involvement in patients with dermatomyositis is also manifested in the skin and can be seen clinically in the form of nail-fold changes and changes in the gastrointestinal (GI) tract. The capillaries show clear hyper­ plasia, vacuolization, and necrosis, contributing to an is­chemia that could cause fiber damage.80,81 One of the earliest events in the pathogenesis of dermato­myositis appears to be activation of the complement cascade. This leads to the ­subsequent deposition of complement co­mponents, which in turn results in the deposition of lytic membrane attack complexes in the endothelial cells and the eventual loss of ­capillaries due to complement-mediated damage. The capillaries are abnormally thickened and enlarged and look like high endothelial venules, which are characteristics of vessels that facilitate lymphocyte trafficking (Fig. 78-2). The

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Figure 78-1  Hematoxylin and eosin staining of muscle biopsy showing perivascular inflammation. A, Variation in fiber size and central nucleation (star). B, Endomysial inflammation and increased fibrosis. C, Perimysial inflammation (star). D, Perifascicular atrophy (arrow).  (B, Courtesy of Dr. Inger Nemmesmo. D, Courtesy of Dr. Paul Plotz.)

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capillaries also show signs of neovascularization.82 This loss of capillaries results in some of the histopathologic features characteristic of this disease: capillary necrosis and loss, perivascular inflammation and ischemia (rarely seen), and perifascicular atrophy (a late feature; see Fig. 78-1C and D). Although no direct comparison has been reported, the pathologic changes in juvenile and adult dermatomyositis appear to be similar, except that all the basic pathologic features are more prominent in the childhood form (see later). The factors that initiate complement activation in this ­disease are poorly understood; however, the consequences of complement-mediated damage are clearly visible in dermatomyositis.83

Figure 78-2  Muscle biopsy staining with CD146 (Mel-CAM), an endothelial cell marker. Results are shown in normal (A), dermatomyositis (B), and polymyositis (C) subjects. Note the abnormal capillary size in both dermatomyositis and ­polymyositis.

The endomysial inflammatory aggregates contain a high percentage of T cells, particularly activated CD8+ T cells, macrophages, and CD4+ T cells, and very few natural killer cells. Immunoelectron microscopic studies have provided evidence of the invasion, replacement, and probable destruction of non-necrotic muscle fibers by T cells and macrophages.84 It is suggested that CD8 cytotoxic T lymphocytes (CTLs) recognize major histocompatibility complex (MHC) class I on muscle fibers and may mediate muscle fiber damage. Infiltrating CTLs express perforin-­containing granules, which are characteristically oriented toward the target muscle fiber, indicating that muscle fiber injury may be partially mediated by perforin-dependent cytotoxic mechanisms

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Figure 78-3  HLA-ABC, CD8 T cell, and granzyme B staining of polymyositis biopsy. HLA expression is evident on muscle fibers, infiltrating cells, and endothelial cells (A). HLA cell surface and sarcoplasmic staining is shown on muscle fibers (B), CD8 T cells (C), and granzyme B–positive cells (D) surrounding muscle fibers (arrow).

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(Fig. 78-3B and C).85 In polymyositis and IBM, there is evidence of clonal proliferation of CD8 T cells, both within the muscle and in the peripheral circulation.86,87 T cell lines from patients demonstrate cytotoxicity against autologous myotubes,88 suggesting that the muscle fiber injury in polymyositis and IBM is mediated by CTLs. CTLs are known to mediate target cell damage by both perforin–granzyme B and Fas-FasL pathways. The overexpression of antiapoptotic molecules such as Bcl-2, FLIP (Fas-associated death domain– like IL-1 converting enzyme inhibitory protein), and human inhibitor of apoptosis protein–like protein in skeletal muscle of myositis patients suggests that perforin-granzyme B–mediated CTL damage may play a predominant role in muscle fiber injury and dysfunction in myositis.89-91 On the basis of the data just described, two different pathways have been proposed as major mediators of muscle damage and inflammation: one mediated through T lymphocytes (CTLs) directed against muscle fibers, predominating in polymyositis and IBM, and the other directed against vessels, predominating in dermatomyositis. However, several studies have shown that the degree of inflammation does not consistently correlate with the severity of the structural changes in the muscle fibers or with the severity of the clinical disease,92 suggesting that nonimmune processes also play a role in disease pathogenesis. A role for nonimmune processes is supported by the following observations: First, marked structural changes in the muscle fibers occur in the absence of any inflammatory cells.93,94 Second, there is a lack of correlation between the degree of inflammation and the degree of muscle weakness.95 Third, some myositis patients do not respond, even to powerful anti-inflammatory therapy,96,97 Fourth, steroid treatment may eliminate inflammatory cells in myositis muscle tissue, but this removal alone may not substantially improve the clinical disease, ­suggesting that immunosuppressive therapies modulate disease activity but do not change other mediators of the disease process.98 Finally, the clinical disease may progress when identifiable inflammation has subsided,99 suggesting

a role for nonimmune mechanisms in the pathogenesis of myositis. Thus, the exact contribution of immune-mediated pathways to muscle damage is currently unknown. MHC CLASS I Normal skeletal muscle cells do not constitutively express or display MHC class I molecules, although they can be induced to do so by proinflammatory cytokines such as interferon-γ or TNF-α.93,100-102 In contrast, in human IIMs, the early and widespread appearance of MHC class I in nonnecrotic muscle cells is a striking feature, even in muscle cells distant from the lymphocytic infiltration.93,94,103 MHC class I staining is usually observed on the sarcolemma of muscle fibers, but some fibers also show staining in both the sarcolemma and the sarcoplasm (see Fig. 78-3A and B). In some patients, the expression is restricted to a few clusters (often in early disease), whereas in others, almost every fiber is positively stained, particularly in late-phase and treatment-resistant cases. The biologic significance of these observations has been explored by generating a conditional transgenic mouse model overexpressing syngenic mouse MHC class I. The overexpression of MHC class I molecules in the skeletal muscle of mice results in the development of clinical, biochemical, histologic, and immunologic features that resemble human myositis and provide a close model of the human disease. The disease in these mice is inflammatory, limited to skeletal muscles, self-sustaining, more severe in females, and often accompanied by MSAs.104 A number of observations in human myositis patients and in the mouse model of myositis suggest that MHC class I molecules themselves may mediate muscle fiber damage and dysfunction in the absence of lymphocytes. For instance, in human myositis, the induction of MHC class I antigen in muscle fibers occurs early, preceding inflammatory cell infiltration.105,106 MHC class I staining of human myositis biopsies shows both a cell surface and a sarcoplasmic reticulum pattern of internal reactivity, demonstrating that

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Figure 78-4  Nuclear factor κB(NFκB) expression in normal and myositis ­biopsy. Immunofluorescence staining with rabbit anti–NFκB and anti–rabbit  Texas red and counterstaining with 4, 6-diamino-2-phenylindole (blue nuclei). Note the cytoplasmic expression of NFκB in normal muscle (A) and a subsarcolemmal pattern in the ­myositis biopsy (B; arrow). (From Nagaraju K, Casciola-Rosen L, Lundberg I, et al: Activation of the endoplasmic reticulum stress response in autoimmune myositis: Potential role in muscle fiber damage and destruction. Arthritis Rheum 52:1824-1835, 2005.)

some of the MHC class I molecules may be retained in the endoplasmic reticulum (ER) of these fibers.69,94,107 Persistent MHC class I overexpression in muscle fibers may exist in the absence of an inflammatory infiltrate.99 The controlled induction of MHC class I in the mouse model is followed by muscle weakness before mononuclear cell infiltration.104 It has recently been shown that in vivo gene transfer of MHC class I plasmids attenuates muscle regeneration and differentiation.108 Together, these observations, and particularly the obvious retention of MHC class I within the cell in both human and murine disease, indicate that the muscle fiber damage seen in myositis may not be solely mediated by immune attack (e.g., CTLs and autoantibodies); it may also be mediated through nonimmunologic mechanisms such as the ER stress response and hypoxia. Because MHC class I assembly occurs in the ER, and because upregulation in myositis muscle fibers is widespread, even in the absence of visible inflammatory infiltrate, it is likely that ER stress plays a role in the muscle fiber damage and dysfunction associated with human myositis. The ER is intimately involved in the folding, exporting, and processing of newly synthesized proteins. When there is an imbalance between the protein load in the ER and the cell’s ability to process that load, a series of signaling pathways that adapt cells to ER stress is activated. This ER stress response can be provoked by a variety of pathophysiologic conditions, including ischemia, hyperhomocysteinemia, viral infections, and mutations that impair protein folding, as well as by excess accumulation of protein in the ER.109,110 Cells self-protect against ER stress by initiating at least four functionally distinct responses: (1) upregulation of the nuclear factor κB (NFκB) pathway (ER overload response); (2) upregulation of genes encoding ER ­ chaperone proteins, such as Bip/GRP78 and GRP94, as a means of increasing protein ­ folding activity and preventing protein aggregation; (3) translational attenuation to reduce the load of protein synthesis and to prevent the further accumulation of unfolded ­ proteins (unfolded protein response); and (4) cell death, which occurs when the ER’s functions are severely impaired. This cell death event is mediated by transcriptional activation of the gene for CHOP/GADD153, a member of the C/EBP family of transcription factors,111 and by the activation of ER-associated caspase-12.112

In myositis, it appears that overexpression of MHC class I in myofibers initiates a series of cell autonomous changes that contribute to myofiber pathology. Recent investigations have indicated that overexpression of MHC class I on muscle fibers results in activation of the NFκB and ER stress response pathway in human inflammatory myopathies and in the mouse model of myositis.69,113 NFκB can be activated within minutes by a variety of stimuli, including inflammatory cytokines such as TNF-α and IL-1, T cell activation signals, and stress inducers. It is likely that in human myositis, NFκB activates both classic (proinflammatory cytokines) and nonclassic (ER stress response) pathways.69,113-116 Further, there is evidence that downstream target genes (e.g., MHC class I, intercellular adhesion molecule [ICAM], monocyte chemoattractant protein [MCP]-1) regulated by the NFκB pathway are very highly upregulated in myositis patients.107,117,118 Recent studies have indicated that NFκB p65 is activated both in human myositis biopsies and in the mouse model,69,113,119,120 suggesting that this pathway may be directly involved in muscle fiber damage (Fig.78-4). NFκB is a potential therapeutic target in myositis, and the use of NFκB pathway inhibitors significantly reduces the pathology associated with several autoimmune disease, including diabetes, multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis, suggesting that this pathway is a ­critical player in the effector phase of autoimmune ­pathology. Thus, it appears that MHC class I expression on muscle fibers links the immune and nonimmune mechanisms of muscle fiber damage. CYTOKINES AND HYPOXIA A number of other effector molecules produced in muscle tissue by inflammatory cells, endothelial cells, and muscle fibers are thought to play a role in the pathogenesis of myositis.66 Most of the data assembled relate to cytokines, but some data related to chemokines are also available. The most consistently demonstrated cytokines in muscle tissue from patients with IIMs are cytokines with proinflammatory properties: IL-1α, IL-1β, TNF-α, and interferon-α. Recently, the DNA-binding high mobility group box 1 (HMGB1) was found to exhibit both an extranuclear and an extracellular pattern in the muscle tissue of patients with polymyositis and dermatomyositis. In addition to inducing the upregulation of MHC class I and II molecules on muscle fibers,

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Complement

Antibodies

Cytokines

CD8 T cells

Endothelial cell damage

MHC class I expression ER stress

Hypoxia

? Capillary loss

Myofiber damage

Loss of skeletal muscle fibers Figure 78-5  Mechanisms of muscle fiber damage in ­myositis. ER, endoplasmic reticulum; MHC, major histocompatibility ­complex.

cytokines may have a direct effect on muscle fiber function, as has been demonstrated for TNF-α.121 The relative importance of the various cytokines and chemokines in patients with myositis is still uncertain, but these molecules offer possible targets for therapy in these conditions. Microvessel involvement was first observed in dermatomyositis but has also become evident in polymyositis. The endothelial cells in both subsets show increased expression of adhesion molecules and proinflammatory cytokines such as IL-1α. This phenotype can be induced by tissue hypoxia, which may result from capillary loss and local tissue inflammation. Muscle tissue hypoxia can contribute to the clinical symptoms and muscle fatigue and might be associated with disease mechanisms in inflammatory myopathies.66 The hypoxia hypothesis is supported by the clinical improvement observed after exercise, but a causal connection still needs to be established. Magnetic resonance spectroscopic analysis, before and after a work load, has demonstrated reduced levels of energy substrates that are important for muscle contraction, such as adenosine triphosphate and phosphocreatine, when compared with levels in healthy individuals. This finding supports the hypothesis that an acquired metabolic disturbance occurs in chronic inflammatory myopathies and that this disturbance can contribute to impaired muscle performance. PROPOSED MECHANISMS OF MUSCLE DAMAGE Currently available data suggest that both immune (cellmediated and humoral) and nonimmune (ER stress, hypoxia) mechanisms play a role in muscle fiber damage and dysfunction in myositis. ER stress, hypoxia, and the NFκB pathway are highly active within the skeletal muscle of myositis patients, and the proinflammatory NFκB pathway connects the immune and nonimmune components contributing to muscle damage. The relative contribution of each of these pathways to muscle fiber damage is presently unclear (Fig. 78-5). Therefore, use of specific drugs to inhibit these pathways, either alone or in combination, would help define their roles in myositis and potentially serve as ­ effective ­therapeutic agents.

CLINICAL FEATURES The inflammatory myopathies may occur as distinct disease entities, or they may coexist with some other rheumatic disease. This observation is true for all three subsets of myositis,

but it is most often seen in polymyositis and dermatomyositis. The rheumatic diseases most often associated with inflammatory myopathies are systemic sclerosis, mixed connective tissue disease, Sjögren’s syndrome, and SLE; however, ­rheumatoid arthritis may also be associated with inflammatory myopathies. IBM may be associated with Sjögren’s syndrome, SLE, and others autoimmune diseases.122,123 Because the clinical features of IBM differ somewhat from those of polymyositis and dermatomyositis, they are presented separately. POLYMYOSITIS AND DERMATOMYOSITIS The predominant symptoms in patients with polymyositis or dermatomyositis are muscle weakness and low muscle ­endurance. The weakness is most pronounced in proximal muscle groups—typically in the neck, pelvic, thigh, and shoulder muscles—with a symmetric distribution. Patients generally experience more problems ­performing repetitive movements than with single strength exercises, and they report difficulty walking uphill or upstairs, working with their arms above their shoulders, or rising from chairs. The onset is often subacute, occurring over a few weeks, or it may be insidious, developing over several months. If untreated, the muscle weakness progresses slowly, and in the most severe cases, patients may become wheelchair dependent. Problems with swallowing and nutrition may occur as a result of impaired contractility of the throat muscles, possibly leading to aspiration pneumonia. In rare cases, patients develop difficulty breathing because of weakness of the diaphragm or thoracic muscles, and they may require assisted ventilation. Other striated muscles may be involved, such as in the lower part of the esophagus (causing reflux problems) or the sphincter ani (causing incontinence). Skin Dermatomyositis is characterized by the presence of ­certain types of rashes124; the same types are often seen in both children and in adults. The most specific skin manifestations are Gottron’s papules and the heliotrope rash (Fig. 78-6). Gottron’s papules are slightly elevated violaceous, pink, or dusky red papules located over the dorsal side of the metacarpal or interphalangeal joints. These papules may also occur over the extensor side of the wrist, elbow, or knee joints. Gottron’s papules are considered to be pathognomonic of dermatomyositis. A macular rash (without papules) with the same distribution as Gottron’s papules is called Gottron’s sign (see Fig. 78-6C and D). The heliotrope rash is

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a ­periorbital red or violaceous erythema of one or both eyelids, often with edema (see Fig. 78-6B). Linear erythema overlying the extensor surfaces of joints is also relatively specific to dermatomyositis (Fig. 78-7A). Many patients with dermatomyositis have photosensitive rashes, typically located on the face or scalp or over the neck (the so-called V sign), although this rash is not specific to dermatomyositis (Fig. 78-7B and C). Another common rash in dermatomyositis is located over the shoulders (shawl sign; Fig. 78-7D) or over the hips (holster sign). Pruritus is common. Patients with dermatomyositis often have skin lesions on their fingers, such as periungual erythema, nail-fold telangiectasias, and cuticular overgrowth (Fig. 78-8C). Other less common

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Figure 78-6  Characteristic features of dermatomyositis skin changes. A, Gottron’s papules.  B, Heliotrope rash. C and D, Gottron’s sign on knee (C) and elbow (D). (Courtesy of Dr. Paul Plotz.)

skin manifestations are panniculitis, livedo reticularis, and ­nonscarring alopecia. Vasculitis may be seen in children with dermatomyositis but rarely in adults. In general, the skin rash is moderate, with local erythema. In rare cases, a severe, diffuse erythema (erythroderma) may occur, occasionally with vesiculobullous lesions or ulcers. The skin rash may precede the muscle symptoms by months or even years, and in some patients, the skin manifestations may be the only clinical sign of dermatomyositis; this condition is often called amyopathic dermatomyositis or dermatomyositis sine myositis (see later). The pattern of the rash over the knuckles and dorsum of the hand is distinct, in that the rash generally affects the phalanges but

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Figure 78-7  Characteristic features of dermatomyositis skin changes. A, Linear erythema. B, Scalp rash. C, V sign. D, Shawl sign. (Courtesy of  Dr. Paul Plotz.)

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Figure 78-8  Erythematous rashes on the hand in dermatomyositis and systemic lupus erythematosus. A, Note the changes on the knuckles and dorsum of the hand in dermatomyositis (Gottron’s sign). B, Rash is absent on the knuckles but present on the phalanges in lupus. C, Capillary nail-fold changes in dermatomyositis. (Courtesy of Dr. Paul Plotz.)

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spares knuckles in SLE, and vice versa in dermatomyositis (Fig. 78-8A and B). However, no histopathologic skin features are specific for dermatomyositis; most of the features are also seen in patients with SLE. Thus, skin biopsy is rarely helpful in distinguishing between these two disorders. The cutaneous manifestations may fail to respond to immunosuppressive treatment, despite improvement in muscle ­symptoms. Thus, it is possible that different molecular pathways or disease mechanisms cause the skin rash and the muscle ­inflammation. Calcinosis, which can be severe, is found mainly in ­juvenile dermatomyositis but is occasionally seen in adults. The calcinosis occurs predominantly in sites that have been subject to friction or trauma, such as the elbows or knees. Sometimes the calcinosis can be extensive and erupt, leading to ulcers. It is most often localized to the subcutaneous tissue but can also develop in the skin, fascia, or muscle and can be visualized by radiography, computed tomography (CT), or magnetic resonance imaging (MRI). The calcinosis seems to progress as long as there is active inflammatory disease. Also, once it has developed, it is often treatment resistant. There are data, however, suggesting that the ­progress of calcinosis can be inhibited by

Figure 78-9  Mechanic’s hands in a white (A) and a black (B) patient. Note the characteristic skin changes on the lateral side of the fingers. (Courtesy of Dr. Paul Plotz.)

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effectively treating the inflammatory process in the skin and muscle.125 Another type of skin pathology seen in inflammatory myopathies is called mechanic’s hands. This rash is often associated with the presence of antisynthetase autoantibodies and can be seen in both polymyositis and dermatomyositis. The rash is a hyperkeratotic, scaling, fissuring of the ­fingers, particularly on the radial side of the index fingers (Fig. 78-9). Lungs Lung involvement is frequent in polymyositis and ­dermatomyositis and is a major risk factor for morbidity and ­mortality. Clinical symptoms such as dyspnea and cough are common. Lung involvement can be caused by ­weakness of the respiratory muscles or inflammation of the lung ­ tissue (interstitial lung disease). Weakness of the respiratory ­muscles may lead to restrictive lung disease, and involvement of the pharyngeal muscles is a risk factor for aspiration pneumonia. Interstitial lung disease, caused by inflammation in the small airways, is common in polymyositis and dermatomyositis and is often associated with antisynthetase autoantibodies;

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it may be present in up to 70% of patients when investigated with sensitive techniques such as high-resolution CT and measurement of pulmonary function and diffusion capacity.126 In most cases, the changes are present at the time of diagnosis of myositis; they rarely develop after ­immunosuppressive treatment has started. The severity of interstitial lung disease may vary from mild or even asymptomatic to rapidly progressive (Hamman-Rich like) with a fatal outcome. In most cases, the interstitial lung disease is mild and has a slowly progressive course. In some cases, improvement in lung function is seen with immunosuppressive treatment. The course and outcome vary, depending on the histopathology, suggesting that different disease mechanisms cause interstitial lung disease. In general, the clinical course and histopathology of interstitial lung disease in myositis are no different from those in idiopathic interstitial lung disease. The most common histopathologic finding is nonspecific interstitial pneumonia, but other entities such as cryptogenic organizing pneumonia, bronchiolitis obliterans organizing pneumonia, diffuse alveolar damage, and usual interstitial pneumonia are also found. Some studies suggest that bronchiolitis obliterans organizing pneumonia responds favorably to corticosteroids, whereas histopathologic changes compatible with diffuse alveolar damage, usual interstitial pneumonia, or acute interstitial pneumonia respond poorly to corticosteroids or other immunosuppressive therapies and have a poor prognosis. Arthritis Joint pain and arthritis are common in patients with ­polymyositis or dermatomyositis. The most common form of arthritis is a symmetric arthritis of the small joints of the hands and feet. This arthritis is typically nonerosive but can sometimes be erosive and destructive. Most frequently, arthritis is seen in patients with anti–Jo-1 antibodies and other antisynthetase autoantibodies, but it is also seen in patients with overlapping syndromes of other rheumatic diseases. Heart Cardiovascular disease is a risk factor for death among patients with polymyositis and dermatomyositis. However, clinically evident heart involvement is rare, perhaps indicating that cardiac involvement may be overlooked in these conditions. Subclinical manifestations are frequently ­discovered when patients with polymyositis or ­dermatomyositis are evaluated. The most frequently reported subclinical ­ manifestations are conduction abnormalities and arrhythmias detected by echocardiogram (ECG). The underlying pathophysiologic mechanisms that may lead to cardiac manifestations in patients with polymyositis or dermatomyositis are myocarditis and coronary artery disease, as well as involvement of the small vessels of the myocardium. Examination with ECG is recommended in newly diagnosed patients with polymyositis or dermatomyositis. Serum tests such as CK-MB to detect cardiac involvement are unreliable in patients with inflammatory myopathies because CK-MB can be released from regenerating skeletal muscle fibers, a common feature in biopsies from patients

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with polymyositis or dermatomyositis. The CK-MB/total CK ratio may be greater than 3%, a threshold value that is used to define myocardial damage. A more specific marker for myocardial damage in myositis patients is increased serum levels of cardiac isoform troponin-I. The other cardiac troponin isoforms, troponin C and troponin T, are less specific and are also expressed in adult skeletal muscle; increased serum levels have been reported in various muscle disorders. Gastrointestinal Tract Difficulty swallowing is frequent in patients with inflammatory myopathies, particularly those with IBM. Muscle weakness occasionally becomes severe and causes problems with nutrition and aspiration pneumonia. The pathophysiology is related to weakness in the tongue, pharyngeal muscles, and sometimes the lower esophagus. Reflux that requires special care is common, occurring in 15% to 50% of patients. Constipation, diarrhea, and stomach pain are common symptoms and may result from disturbed motility of the gut or GI tract inflammation. Vasculitis in the blood vessels of the GI tract is rare but may be complicated by intestinal bleeding. Antisynthetase Syndrome A new classification system is based on the presence of MSAs, rather than clinical and histopathologic changes. The most common of these antibodies are the ­antisynthetase autoantibodies directed against aminoacyl-tRNA synthetases. A clinically distinct subset of myositis, often called antisynthetase syndrome, has been identified in patients with antisynthetase autoantibodies.39,57 The most common of the antisynthetase autoantibodies is anti–Jo-1, which is directed against histidyl-tRNA synthetase. This autoantibody is present in approximately 20% of patients with polymyositis or dermatomyositis but is only rarely found in patients with IBM.70 Antisynthetase syndrome is characterized by the presence of antisynthetase autoantibodies and a set of clinical features that includes myositis, interstitial lung disease, Raynaud’s phenomenon, nonerosive symmetric polyarthritis of the small joints, and mechanic’s hands (see Fig. 78-9). These patients often have fever at disease onset and during flares of disease. Antisynthetase syndrome can be seen in patients with polymyositis or dermatomyositis but is more often seen in patients without skin rashes other than mechanic’s hands. Amyopathic Dermatomyositis A subset of dermatomyositis is called clinically ­amyopathic dermatomyositis. These patients have a skin rash, which is typical of dermatomyositis, but no clinical signs of ­ muscle involvement.127 The proposed definition is based on a skin biopsy consistent with dermatomyositis and a duration of 6 months or longer in the absence of clinical or laboratory evidence of myositis. Some of these patients do have subclinical myositis based on MRI or biopsy findings at presentation; others develop clinically overt myositis sometime later. Patients without clinically overt myositis, ­ however, may develop extramuscular manifestations such as ­interstitial lung disease, which may be severe. Amyopathic dermatomyositis may be

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Figure 78-10  Trichrome and ­hematoxylin and eosin staining of inclusion body myositis biopsy. Note the red-rimmed inclusions (A) and marked variation in muscle fiber size (A and B). (Courtesy of  Dr. Paul Plotz.)

A

associated with malignancies, as is the case for classic dermatomyositis. The frequency of this subset is uncertain, but some recent studies suggest that this form of dermatomyositis may be more common than ­previously thought. Juvenile Dermatomyositis The incidence of juvenile dermatomyositis (JDM) is between 1.7 and 3.0 per million children. The disease onset has two peaks—at age 6 and 11 years. JDM is more common in girls than in boys in Europe and North America; in Japan and Saudi Arabia, this difference is less prominent. The most common clinical manifestations at disease onset are muscle weakness, easy fatigability, skin rash, malaise, and in some cases fever.125 The skin rash is often pathognomonic and similar to adult dermatomyositis, with the most typical skin manifestation being heliotrope discoloration of the upper eyelids, Gottron’s papules, periungual erythema, and capillary loop abnormalities. Calcinosis, cutaneous ulceration, and lipodystrophy are more common in juvenile cases than in adults. Calcinosis is seen in 30% to 70% of children with JDM. The calcinosis is most often located at sites exposed to trauma and can be seen in the skin, fascia, or muscles. In some children, the calcinosis becomes prominent and causes contractures and ulcerations. Lipodystrophy occasionally develops, and other metabolic abnormalities, such as insulin resistance and hepatomegaly, are sometimes seen. Vasculopathy that affects the GI tract with ulceration, perforation, or hemorrhage is rare but seems to be more common in children than in adults with dermatomyositis. Because this can be a serious sign, screening for GI involvement should be included in the evaluation of patients with JDM. Interstitial lung disease is rarely seen in JDM cases. The overall prognosis is variable, but some patients have a good prognosis. Patients with JDM may go into remission, allowing the discontinuation of immunosuppressive treatment. Side effects of immunosuppressive treatment, such as growth failure, are common. In many patients, however, the disease remains chronic, with persisting disease activity into adulthood. INCLUSION BODY MYOSITIS IBM is distinguished from polymyositis and dermatomyositis on the basis of both clinical and histopathologic features.128,129 Sporadic IBM is a distinct entity from familial hereditary inclusion body myopathy, which shares some clinical and histopathologic features but lacks signs of inflammation in

B

muscle tissue. IBM was identified in the 1960s as a subset of inflammatory myopathies, distinct from polymyositis, primarily on the basis of typical histopathologic features that include sarcoplasmic and nuclear inclusions and rimmed vacuoles.16,17 A characteristic clinical phenotype was later identified, characterized by an insidious onset of muscle weakness over months to years, muscle weakness localized ­predominantly to the thigh muscles and finger flexors, and resistance to glucocorticoid treatment. IBM patients often have a history of frequent falling. Sporadic IBM cases are sometimes misdiagnosed as polymyositis, because the classic histopathologic changes (rimmed vacuoles and inclusions) may not be evident in early biopsies (Fig. 78-10). A slowly progressive clinical course, development of severe muscle atrophy in the thighs and forearms, and resistance to treatment with immunosuppressive drugs should raise the suspicion of IBM, and a second muscle biopsy should be considered. In contrast to polymyositis and dermatomyositis, IBM is more frequent in men than in women, and it is seen mainly in individuals older than 50 years. The onset is more insidious than that of polymyositis or dermatomyositis. Patients with IBM rarely have pain. The most frequent initial symptoms are difficulty climbing stairs and walking uphill and frequent falls as a result of weakness in the knee extensor muscles. Muscle weakness may become prominent, and even walking across a threshold may become a problem. Difficulty swallowing may also be an early clinical feature, reflecting the involvement of the pharyngeal muscles. The course is slowly progressive, leading to muscle atrophy that can be striking, particularly in the thigh and forearm muscles. Severe weakness may develop, and many patients become wheelchair dependent. Extramuscular organ involvement is rare, although a subgroup of patients with IBM has sicca symptoms and may develop a secondary Sjögren’s syndrome.130 There are also occasional case reports of IBM in patients with other chronic inflammatory diseases, such as SLE, systemic sclerosis, and interstitial pneumonitis. Autoantibodies are rarely present in IBM patients. IBM is usually resistant to treatment with glucocorticoids and other immunosuppressive agents. Because of this resistance to treatment, some have questioned whether IBM is an autoimmune disease or a degenerative muscle disease supported by the abnormal accumulation of proteins, such as amyloid-β, in muscle fibers. This issue is still under debate and subject to ongoing research in several institutions around the world.

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MYOSITIS ASSOCIATED WITH MALIGNANCIES An association between dermatomyositis and malignancies was observed in several early case reports. The clinical implications of this association, irrespective of the pathophysiologic mechanisms involved, are that it is imperative to screen for tumors in patients with dermatomyositis at the time of diagnosis and at relapse, particularly if the symptoms do not respond to conventional immunosuppressive treatment. The types of malignancies vary and include not only hematologic malignancies such as lymphoma but also solid tumors such as lung, ovarian, breast, and colon cancer. No specific form of cancer seems to be overrepresented in dermatomyositis. The screening for malignancies should include, at a minimum, a careful clinical examination, routine blood tests, chest radiograph, and mammography and a gynecologic examination for women. If any abnormalities are found, these should guide a more thorough investigation for malignancies.

CLASSIFICATION AND DIAGNOSTIC CRITERIA At present, there are no prospectively validated ­diagnostic or classification criteria for myositis. Dividing diseases into homogeneous subsets serves several important functions, including allowing us to estimate disease incidence and prevalence, ­understand disease pathogenesis and natural history, and evaluate the patient’s response to therapy and prognosis. More than 3 decades ago, Bohan and Peter proposed a set of five criteria to facilitate the diagnosis of IIM patients14,15 (Table 78-4). They classified IIMs into five groups: primary idiopathic polymyositis, primary idiopathic dermatomyositis, IIMs associated with malignancy, childhood IIMs associated with vasculitis, and IIMs associated with collagen vascular diseases. Exclusion criteria include signs of central or peripheral neurologic disease; family history of muscle disease (although familial myositis has been reported in dozens of cases); and symptoms and signs suggestive of muscular dystrophy, granulomatous myositis, infections (including trichinosis, schistosomiasis, trypanosomiasis, staphylococcal infection, and toxoplasmosis), drug-induced myopathy, toxic myopathy, rhabdomyolysis, metabolic disorders, endocrinopathies, myasthenia gravis, or myositis after viral infection (influenza or rubella). A weakness of the Bohan and Peter classification is that it overdiagnoses polymyositis patients and loosely defines overlap syndromes. Despite several drawbacks, these criteria have served well in diagnosing and defining patients for research purposes for the past 3 decades. IBM was later recognized as a separate disease entity characterized by a slow onset and progression and involving finger flexors or the quadriceps muscles.128,129 It can occur as a stand-alone entity or with other connective tissue diseases, and patients are often resistant to steroid therapy. Other focal and diffuse forms of myositis, such as orbital myositis, focal nodular myositis, macrophagic myositis, and eosinophilic myositis, are relatively rare. Since Bohan and Peter proposed their classification criteria, advances in clinical research have led to the identification of certain autoantibodies that are strikingly associated with some clinical phenotypes of myositis (see Table 78-3). The identification of clinical features associated with MSAs and MAAs has led to the proposal of a serologic approach

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Table 78-4  Bohan and Peter Criteria for Polymyositis and Dermatomyositis First exclude all other myopathies Symmetric proximal muscle weakness Increase in serum muscle enzymes, such as CK, AST, ALT, aldolase, and LDH Abnormal electromyographic findings, such as short, small, polyphasic motor units; fibrillations; positive sharp waves; insertional irritability; and bizarre high-frequency repetitive discharges Abnormal muscle biopsy findings, such as mononuclear infiltration, regeneration, degeneration, and necrosis Skin rashes, such as the heliotrope rash, Gottron’s sign, and Gottron’s papules ALT, alanine transaminase; AST, aspartate transaminase; CK, creatine kinase; LDH, lactate dehydrogenase.

to complement the Bohan and Peter classification system. Others have suggested that the Bohan and Peter criteria be modified to add MSA as a criterion.131 However, the inclusion of MSA has some limitations: these antibodies are not present in all patients, the immunoprecipitation techniques that are the “gold standard” for identifying these antibodies are available in only a few commercial laboratories, and the enzyme-linked immunosorbent assays often used can give false-positive or false-negative results. There is an extensive ongoing debate and dialogue within the scientific community about the nature of the diagnostic and classification criteria that could better define these disorders.64,132,133 Some emphasize a focus on histopathologic features and others on autoantibody profiles. Certainly, the addition of autoantibody profiles, ­characteristic histopathologic and immunohistochemical features, and imaging techniques such MRI would significantly strengthen the current criteria and better define these disorders. The most frequently used subclassification is based on differences in clinical, immunologic, and histopathologic features and identifies three subtypes of inflammatory myopathies: polymyositis, dermatomyositis, and IBM134 (Table 78-5).

PHYSICAL EXAMINATION Although most patients present with muscle weakness or fatigue, the IIMs are systemic connective tissue diseases, and other organs are frequently involved; therefore, a full clinical examination should be conducted when patients present with muscle symptoms. This could also be helpful in distinguishing IIMs from noninflammatory myopathies. The muscle problems reported by many patients consist not only of muscle weakness but also of muscle fatigue or reduced muscle function. Thus, the evaluation must differentiate between strength and fatigue by evaluating muscle strength and testing repetitive movements for muscle fatigue. In the early phases, atrophy is usually not a pronounced phenomenon in polymyositis or dermatomyositis. In later phases, a moderate symmetric atrophy of proximal muscles may be present. Asymmetric atrophies indicate conditions other than inflammatory myopathies. Patients with IBM often develop more severe atrophy of the quadriceps muscles and the flexor muscles of the forearms; they may also develop deformities in the finger joints and experience difficulty making fists.

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Table 78-5  Clinical and Laboratory Features of Subgroups of Idiopathic Inflammatory Myopathies Diagnostic Features

Dermatomyositis

Polymyositis

Inclusion Body Myositis

Clinical features Age Disease onset Muscle weakness Symmetry Systemic features Skin changes Calcinosis Associated connective tissue disease

Children and adults Subacute Proximal Symmetric Yes‡ Yes¶ Yes¶ Yes**

Adults* Subacute Proximal Symmetric Yes‡ No Rarely Yes**

Adults >50 yr Chronic Selective pattern† Asymmetric Yes§ No No Yes††

Associated malignancy‡‡

Yes

Yes

Yes

Normal to high Yes Perifascicular atrophy,   capillary depletion, patchy   MHC class I expression and   microinfarcts

Normal to high Yes CD8 T cell invasion of   non-necrotic fibers and MHC   class I expression on fibers

Normal to high Yes CD8 T cell invasion, MHC   expression, vacuolated fibers, and tubulofilamentous ­inclusions in fibers

Laboratory features Serum enzymes§§ Abnormal EMG¶¶ Abnormal muscle biopsy

*Rarely in children. † Early involvement of finger flexor, wrist flexor or wrist extensor weakness, and involvement of quadriceps femoris. ‡ Some patients have dysphagia, synovitis, and interstitial lung disease. § Some patients have dysphagia. ¶ Gottron’s sign and heliotrope rash. ¶ Especially in children. **Overlap with scleroderma, systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, and mixed connective tissue disease (MCTD). †† Associated with Sjögren’s syndrome but less frequently associated with other connective tissue diseases. ‡‡ Dermatomyositis is more frequently associated with cancer than are polymyositis and inclusion body myositis and not overrepresented in PM or IBM. §§ Serum creatine kinase, aspartate transaminase, lactate dehydrogenase, and aldolase vary from normal to very high levels. ¶¶ Myopathic motor unit potentials with spontaneous discharges in dermatomyositis, with and without spontaneous discharges in polymyositis, and mixed pattern of short- and long-duration motor unit potentials in inclusion body myositis. EMG, electromyogram; MCH, major histocompatibility complex.

Muscle strength can be tested in various ways. A quick screening test for weakness in proximal lower leg muscles is to ask the patient to stand up from a sitting or squatting ­position without support. A more standardized test that is easy to perform in the clinic is the manual muscle test, with grading according to the Medical Research ­Council scale. There are many variants of this test, but a short form, addressing eight muscles on the dominant side, is recommended as part of the disease activity score by the International Myositis Assessment and Clinical Studies (IMACS).135 In most patients with polymyositis or ­ dermatomyositis, muscle strength as assessed by the manual muscle test is good in most of the tested muscle groups. Typically, moderate muscle weakness is seen in the neck flexors and hip girdle muscles. Testing that involves a number of repetitions is often a more sensitive method of detecting muscle impairment. The Functional Index in Myositis-2 is a myositis-specific outcome measure that assesses a number of repetitions. With this test, proximal muscle groups are more involved than are distal muscles. This index is often used by physical therapists.136 In patients with IBM, knee extensors and finger flexors are often weak. The skin should also be examined to detect changes, including nail-fold and scalp changes. Joints can be affected by arthritis, and heart and lung changes should be carefully looked for.

LABORATORY EVALUATIONS Laboratory evaluations are critical components of both diagnosis and patient management. Combinations of laboratory tests are generally used during patient evaluations. Because

no laboratory test is highly specific for IIMs, the results of these tests are usually interpreted in the clinical context. BIOCHEMICAL Measuring serum levels of muscle enzymes is an important part of the evaluation of myositis patients. Increased levels of muscle-derived serum enzymes reflect ongoing damage to the muscle parenchyma. These measurements help differentiate IIMs from conditions such as steroid myopathy and denervation, in which atrophy is a prominent feature.137 Measurement of the serum CK level is traditionally the first step in the assessment of patients with IIM. CK exists as MM (skeletal muscle), MB (cardiac muscle), and BB (brain) isoforms in serum. In comparison to other serum muscle enzymes, CK appears to be a relatively specific and sensitive indicator of the degree of muscle fiber injury. However, the range varies significantly among patients, with levels being near normal in some patients and elevated by several hundred-fold in others. Generally, 80% to 90% of adult myositis patients show an increase in CK during the initial evaluation. However, a certain proportion of patients, especially those in advanced stages of the disease, show normal or relatively modest elevations in CK, in part because of a lack of muscle mass or the presence of inhibitors of CK activity.138,139 Normal CK is relatively more common in dermatomyositis than in polymyositis. In the absence of CK elevation, it is usually easier to diagnose dermatomyositis than polymyositis because of the presence of skin rashes in the former. It is also known

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that CK levels are generally lower in IBM patients than in those with polymyositis or dermatomyositis. Therefore, a normal CK level does not exclude a diagnosis of IIM, particularly IBM or JDM. Constantly elevated levels of CK are often a sign of inflammatory activity. A rise in CK level is generally correlated with overall disease activity over time, but not with strength or functional measures of disease activity.140,141 CK measurements are usually not useful for monitoring disease exacerbations, and they should always be evaluated in the clinical context. CK levels may normalize without clinical improvement, or they may increase without clinical worsening; however, increasing levels point to a potential flare and warrant closer clinical evaluation. CK elevations are not specific for myositis, because this enzyme is also elevated in other muscle diseases, including muscular dystrophies, rhabdomyolysis, hypothyroidism, and many drug-induced myopathies. It is important to note that serum levels of CK-MB can be elevated in patients with myositis as a result of the regeneration of skeletal muscle fibers; they are not specific for heart involvement in these patients. The cardiac isoform troponin-I has the highest specificity as an indicator of myocardial involvement and is the most reliable serum marker for detecting myocardial damage in patients with inflammatory muscle disease.142 Measurement of other serum muscle enzymes, including aldolase, aspartate transaminase (AST), alanine ­transaminase (ALT), and lactate dehydrogenase (LDH), significantly improves the chance of diagnosing myositis, especially in patients with active disease and normal CK levels. Aldolase, LDH, and AST are better correlated with disease activity in JDM patients. The main disadvantage of these enzymes is that they are also elevated in liver diseases; therefore, the muscle source needs to be identified before interpreting the data.143 The serum myoglobin level is a sensitive index of muscle fiber membrane integrity and can therefore be used to

assess the degree of disease activity. The advantage of the myoglobin assay is that it involves a nonenzymatic immunologic reaction; the disadvantages are that a significant range of serum myoglobin levels occurs in myositis patients because of circadian variation,144 and the test is less readily available than CK for routine use. Elevation of other serum components such troponin, creatine, neopterin, manganese superoxide dismutase, hyaluronate, and soluble CD30 has been shown to correlate with disease activity, but assays of these components have not been validated for use in clinical practice, and they are not available for routine analyses. IMMUNOLOGIC The immune response to self-antigens is a common ­feature of several systemic autoimmune rheumatic diseases, including IIMs. ANAs are found in approximately 60% to 70% of myositis patients. The autoantibody response in IIMs is directed to ubiquitous nuclear and cytoplasmic antigens. The presence of these antibodies is usually assessed by an indirect immunofluorescence assay. ANAs are more ­frequently found in patients with polymyositis and dermatomyositis, especially those with overlap syndrome. These are less frequently seen in IBM patients or those with malignancy-­associated myositis. High-titer ANA is a particularly ­valuable finding for ­ differentiating IIMs from dystrophies. Many IIM patients show speckled nuclear ANA patterns, and about 10% of IIM patients also show exclusive cytoplasmic patterns in indirect immunofluorescence staining.145 Many of the MSAs are associated with distinctive clinical features, such as skin rash or interstitial lung disease (Table 78-6). Certain MSAs, such as anti–Jo-1, are more frequently associated with polymyositis; others, such as Mi-2, are more frequent in dermatomyositis.

Table 78-6  Immunologic Features of Idiopathic Inflammatory Myopathies Feature

Dermatomyositis

Polymyositis

Inclusion Body Myositis

B cell infiltration

+

–/+

–/+

T cell infiltration

+

+

+

CD8 T cell infiltration in non-  necrotic fibers

–/+

+

+

Vascular membrane attack   complex

+

–

–

Immunoglobulin deposition on blood vessels

+

–

–

MHC class I expression on muscle fibers

–/+*

+

+

Cytokines and chemokines

+

+

+

Cell adhesion molecules

+

+

+

Antinuclear antibodies

+

+

+†

+

+

–/+

Anti–signal recognition particle antibodies

–/+

+

–/+

Anti–Mi-2 antibodies¶

+

–/+

–/+

Anti–PM-Scl antibodies¶

+

+

–

Anti-Jo 1 antibodies‡,§ §

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*Mostly in perifascicular areas and necrotic fibers. † Less frequently, but 20% higher than in normal population. ‡ Frequency varies among ethnicities; more frequent in polymyositis (22%) than dermatomyositis (16%) or inclusion body myositis (5%). § Present only in a proportion of polymyositis (14%), dermatomyositis (5%), and inclusion body myositis (3%) patients. ¶ Present only in a proportion of polymyositis (9%), dermatomyositis (21%), and inclusion body myositis (8%) patients. ¶ Present only in a proportion of polymyositis (7%) and dermatomyositis (6%) patients.

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HISTOLOGIC Muscle biopsy is the “gold standard” for the diagnosis of inflammatory myopathies and a critical component of the definitive diagnosis of IIMs.146,147 For optimal biopsy results, it is important to select a muscle that is moderately weak. The histologic features can be grouped into general features that are common to all IIMs and specific features unique to a particular subgroup. The general features include ­necrosis, regeneration, degeneration, variation in fiber diameter, increase in connective tissue, and inflammation. The features specific to dermatomyositis include loss of capillar­ies, alterations in the morphology of capillaries, capillary necrosis with the deposition of complement products (e.g., membrane attack complex) on the vessel walls, and, rarely, muscle infarcts. Another specific histopathologic finding, albeit a late sign, is perifascicular atrophy. The infiltrates typically have a perivascular distribution. The inflammatory infiltrates are dominated by a high percentage of CD4 T cells and macrophages at the sites of inflammation, with B cells occasionally in evidence. Although perifascicular atrophy is the hallmark of the histologic changes seen in dermatomyositis, it may not be visible if a biopsy is acquired early in the course of the disease. In early dermatomyositis, the MHC class I expression is patchy, and the perifascicular areas are usually stained. The features of polymyositis include the presence of ­macrophages and activated CD8 T cells in muscle fibers and the expression of MHC class I molecules on muscle fibers. Mononuclear cell invasion around non-necrotic muscle fibers

in endomysial areas is a characteristic feature of IIMs. The histologic features of IBM resemble those of ­polymyositis but also include unique features, such as red-rimmed vacuoles and inclusions (cytoplasmic or nuclear) and amyloid deposits.129 An increased number of cytochrome C oxidase–negative fibers can also be seen, but this change is not specific for IBM. In IBM, electron microscopy usually demonstrates 15- to 21-nm cytoplasmic and intranuclear tubulofilaments, which are not found in dermatomyositis or polymyositis. It is not uncommon to find biopsies that are negative for both rimmed vacuoles and tubulofilamentous inclusions. In this situation, if the suspicion for IBM is high, it is best to obtain another sample or to treat the patient with steroids. Nonresponsiveness to treatment further supports the diagnosis of IBM in an otherwise typical patient. Inflammation surrounding necrotic fibers is a feature of some muscular dystrophies (e.g., facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy type 2B, and Duchenne’s muscular dystrophy), where it is ­ secondary to muscle cell degeneration. Thus, the presence of a mononuclear infiltration surrounding non-necrotic muscle fibers confirms the diagnosis of IBM or polymyositis. The common and unique immunologic and histologic ­features of the various subgroups are listed in Tables 78-6 and 78-7, ­respectively. MOLECULAR One of the more tangible deliverables of the human genome product has been the development and use of microarrays for messenger RNA (mRNA) profiling. In the commonly

Table 78-7  Histologic Features of Idiopathic Inflammatory Myopathies Feature

Dermatomyositis

Polymyositis

Inclusion Body Myositis

Necrosis of muscle fibers

+

+

+

Variation in fiber diameter Regeneration of muscle fibers

+ +

+ +

+ +

Proliferation of connective tissue

+

+

+

Infiltration of mononuclear cells*

+

+

+

Perivascular and perimysial inflammation

+

–/+

–/+

Endomysial inflammation

–/+

+

+

Perifascicular atrophy

+

–

–

Abnormally dilated capillaries

+

–/+

–

Reduced capillary density

+

–/+

–

Deposition of complement on vessel walls

+

–/+

–

Microinfarcts

+

–

–

Invasion of non-necrotic fibers by cytotoxic T   lymphocytes and macrophages

–

+

+

Expression of MHC class I on muscle fibers

–/+

+

+

Rimmed vacuoles with amyloid deposits and   tubulofilaments†

–

–

+

Angulated or atrophic and hypertrophic fibers

–

–

+

Ragged red or cytochrome oxidase–negative   fibers

–

–

+

*Inflammation is absent in a small proportion of polymyositis and dermatomyositis biopsies. † Also seen in chronic neurogenic conditions and distal myopathies.

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used form of microarray, about 1 million DNA probes are placed on 1 cm2 glass slides, allowing the query of each gene of the genome. Although all genes are shared among all cells, only certain genes are expressed (turned on) in any specific cell at any specific time. Messenger RNA expression profiling using microarrays allows genome-wide assessment of the response of each gene, with a comparison of normal and pathologic states. Muscle is routinely biopsied as part of the clinical workup of muscle disease, and muscle histopathology is an important part of the diagnosis of inflammatory myopathies. Diagnostic muscle biopsies have been used for mRNA expression profiling in a series of studies, with comparisons between inflammatory myopathies (JDM, polymyositis, IBM) and dystrophic myopathies (Duchenne’s muscular dystrophy).148,149 These comparisons are important, because they differentiate between inflammation associated with downstream myofiber degeneration or regeneration (dystrophies) and inflammatory processes that may initiate the inflammatory myopathies. Microarrays have provided considerable new insights into dermatomyositis. Early on, mRNA profiling in dermatomyositis showed a predominance of type 1 interferonresponsive pathways, suggesting the possible persistence of an ­ antiviral response.148 Particularly prevalent was the dramatic ­ expression of the interferon-inducible MxA gene. This signature was confirmed and extended,150 supporting an important role of the innate immune response, with prominent plasmacytoid dendritic cell infiltration in dermatomyositis compared with the other inflammatory myopathies. The beneficial effect of intravenous immunoglobulin (IVIG) in dermatomyositis has been queried by microarrays to define the drug-responsive genes, then compared to the lack of response in IBM.151 This study suggested that IVIG suppressed a relatively small subset of inflammatory responses in dermatomyositis muscle, including complement (C1q) and inflammatory cell migration proteins (ICAM-1). Microarrays have helped elucidate an unexpectedly important role for innate immunity in dermatomyositis. They have also provided new insights into the humeral immunity in polymyositis and IBM. Specifically, mRNA expression profiling showed a high proportion of immunoglobulin transcripts as differentially expressed (59% of all detected genes in IBM, and 33% in polymyositis).152 Plasma cells, defined as those terminally differentiated B cells expressing CD138 but not CD19 or CD20, were then shown to be a key differentiating cell type within IBM and polymyositis muscle.

IMAGING MUSCLES Ultrasonograophy, CT, and MRI are the three general imaging techniques used to evaluate skeletal muscle. MRI has emerged as the method of choice for the examination of soft tissue muscle abnormalities, because it efficiently visualizes and quantifies inflammation, fat infiltration, calcification, and alterations in muscle size and localizes pathologic changes in specific muscle groups (Fig. 78-11). MRI examinations can be done on large volumes and can be helpful guides for muscle biopsy sampling. MRI is a potential ­

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outcome tool to be used in the longitudinal analysis of responses to therapy and in clinical trials, although its sensitivity to changes has not been validated.153-156 Ultrasonography is useful for detecting abnormal vascularization, and rates of blood flow can be monitored effectively with color Doppler imaging. The main disadvantage of ultrasonography is its inability to visualize deep-seated muscles in cross section. Moreover, image analyses are more subjective than with MRI and depend to a greater degree on the experience of the examiner.157 Ultrasound muscle examinations are much more frequent in countries where physicians are responsible for performing such examinations and maintaining uniform standards for their evaluation. Ultrasonography provides a safe, noninvasive, easily portable, and relatively inexpensive approach to the evaluation of muscle abnormalities.158 CT is the modality of choice for identifying calcifications in soft tissues (e.g., JDM), but it is not useful for detecting inflammatory changes in muscle tissue. Cross-sectional CT images allow quantification of muscle atrophy and fat replacement in deep muscles that may not be generally accessible to ultrasonography. A combination of MRI and P-31 magnetic resonance spectroscopy examinations produces the most comprehensive and accurate evaluation of patients.153 LUNGS Radiography and high-resolution CT of the lungs are important for detecting lung involvement and should be considered at the time of myositis diagnosis, because the prevalence of interstitial lung disease is high. In contrast, conventional radiography may not always be sensitive enough to detect interstitial lung disease. These are also important tests for assessing the effects of immunosuppressive treatment.

ELECTROMYOGRAPHY Electromyogram (EMG) changes are usually ­ nonspecific but are a useful indicator of myopathic changes. The major abnormalities include abnormal electrical irritability, decrease in the mean duration of motor unit potentials or increase in the percentage of polyphasic motor unit potentials (short duration), and rapid firing of the motor unit potentials in relation to the level of activity. Later in the course of the disease, fibers are lost from some motor units, and recruitment is reduced. Abnormal electrical irritability in dermatomyositis and polymyositis involves increased insertional activity, trains of positive sharp waves, and fibrillation potentials. Spontaneous electrical activity is a reasonable measure of disease activity in dermatomyositis and polymyositis. EMG abnormalities correlate with alterations in muscle strength and serum muscle enzymes159 and are a useful measure when serum levels and muscle strength are uninterpretable. The inflammation in IIMs is often patchy, and EMG is useful in determining which muscle should be sampled for biopsy. Because EMG can cause histopathologic changes that complicate the interpretation of the biopsy, it is best to perform EMG on one side and obtain the muscle biopsy from the same muscle on the contralateral side. Even for IBM, in which the disease is often asymmetric, this

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Figure 78-11  Magnetic resonance images (short tau inversion recovery) of the thigh. Note the symmetric inflammation in the ­affected muscle, seen as bright areas relative to unaffected muscle.

t­ echnique is useful as long as the contralateral muscle is also weak.

LUNG FUNCTION TESTS Pulmonary function tests are an important means of obtaining an objective assessment of respiratory involvement. Typically, patients demonstrate a restrictive ventilatory impairment, with decreased total lung capacity, functional residual capacity, residual volume, forced expiratory volume in 1 second (FEV1), and forced vital capacity (FVC), but with a normal or elevated FEV1/FVC ratio and reduced diffusing capacity for carbon monoxide. Pulmonary function tests are also important in estimating disease severity and response to therapy, in concert with radiographic ­examination.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of IIMs and other myopathies is important because the clinical associations and response to therapeutic interventions differ significantly. There are a variety of myopathies that closely mimic IIMs (Table 78-8). DYSTROPHIC MYOPATHIES Dysferlinopathy Genetic defects in the dysferlin gene result in limb-girdle muscular dystrophy type 2B and distal muscular dystrophy of the Miyoshi type. These diseases can appear in the late teens or early 20s, and the weakness in the limb-girdle type 2B phenotype first assumes a pelvifemoral distribution: the quadriceps muscle is affected first, followed by weakness in the arms in the later stages of the disease. A relatively acute onset with elevated levels of serum muscle enzymes points to polymyositis as a differential diagnosis. The weakness in the Miyoshi phenotype occurs predominantly in the gastrocnemius and soleus muscles, thereby affecting the ability to walk on the toes. The weakness is slowly progressive, with loss of ambulation generally occurring in the fourth decade, but earlier in some cases. Serum CK levels are very high during the active phase of the disease. In general, the muscle biopsy is dystrophic, with significant mononuclear cell infiltration and small sarcolemmal defects with thickened basal lamina structures over the defects.160

Facioscapulohumeral Muscular Dystrophy A partial deletion of the D4Z4 repeats near the chromosome 4q telomere at 4q35 leads to the facioscapulohumeral phenotype. The initial weakness usually affects the facial muscles, and the onset is insidious. Shoulder weakness is commonly seen because of the weakness of the scapular fixator muscles. The weakness is generally slowly ­progressive, with typical myopathic changes on the EMG, such as brief, small-amplitude, polyphonic voluntary motor unit potentials. The presence of perivascular, endomysial, and ­perimysial inflammation is a common feature.161 Serum CK levels are elevated and vary with age and sex. Dystrophinopathies These X-linked recessive disorders are caused by mutations in the dystrophin gene. Milder forms of Becker’s muscular dystrophy manifest as myalgias, muscle cramps, exercise intolerance, mild limb-girdle weakness, and quadriceps myopathy. The severe Becker’s phenotype that presents before age 8 years is indistinguishable from the Duchenne’s phenotype. An elevation in serum CK levels is seen in asymptomatic patients. The mean age at loss of ambulation is usually in the fourth decade. Histologic features include variation in fiber size, central nuclei, regeneration, necrosis, hypercontracted fibers, and endomysial fibrosis. In Becker’s dystrophy, the number of necrotic and regenerating fibers is decreased compared to the Duchenne phenotype, and the incidence of hypercontracted and central nuclei increases with age.162 A plasma membrane defect in non-necrotic fibers and endomysial inflammation with macrophage, T cell, mast cell, and eosinophil infiltration are also characteristic features of this disease. Proximal Myotonic Myopathy CCTG expansion in intron 1 of the zinc finger transcription factor (ZNF9) gene results in type 2 myotonic dystrophy. The myotonia is usually absent or minimal but is detectable by EMG. The weakness is mainly proximal, with minimal or no facial involvement. Smooth muscle, cardiac, and diaphragmatic involvement is common in this disease. Firstdegree heart block is the most common abnormality, and sudden death is well documented.163 Muscle biopsies show

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Table 78-8  Differential Diagnosis of Inflammatory Myopathies Disease

Key Diagnostic Features

Dystrophic Myopathies Dysferlinopathy (Miyoshi myopathy and LGMD2B)

Facioscapulohumeral muscular dystrophy Becker’s dystrophy

Proximal myotonic myopathy Sarcoglycanopathy

Mutations in dysferlin gene Progressive proximal (LGMD2B) and distal (Miyoshi myopathy) muscle weakness Onset in late teens to early 20s Increased CK levels Inflammation in muscle biopsy Nonresponsiveness to steroids Partial deletion in D4Z4 repeats near chromosome 4q telomere at 4q35 Initial facial and shoulder girdle weakness progresses to pelvic girdle and extremities Normal serum CK levels or modest elevation Mutations in dystrophin gene X-linked recessive disorders Limb-girdle weakness and cardiomyopathy High serum CK levels CCTG expansion in intron 1 of ZNF9 gene Autosomal dominant Proximal muscle weakness Mutations in sarcoglycans (α, β, γ, and δ) Limb-girdle weakness and cardiomyopathy High serum CK levels

Metabolic Myopathies Acid maltase deficiency

McArdle’s disease

Mutations in acid α-glucosidase Proximal muscle weakness Respiratory muscle involvement Abnormal irritability on EMG Increased serum CK levels Mutations in myophosphorylase gene Exercise intolerance Fixed proximal muscle weakness Increased serum CK levels

Mitochondrial Myopathies Mutations in complex I-IV, complex V, and coenzyme Q10 genes Myopathy with limb-girdle weakness Exercise intolerance and fatigue Increased serum CK levels Endocrine Myopathies Cushing’s syndrome Thyrotoxic myopathy

Insidious onset Proximal muscle weakness Normal serum CK, AST, and LDH levels Subacute onset of proximal muscle weakness Normal serum CK levels or modest elevation Respiratory muscle weakness

Infectious Myopathies HIV myopathy

Progressive myopathy Proximal symmetric muscle weakness Endomysial inflammation Increased serum CK levels

Parasitic Myopathies Clinical features of idiopathic inflammatory myopthyies Focal or diffuse inflammation Myocarditis Increased serum CK levels Drug-Induced Myopathies Zidovudine myopathy

Statin myopathy Corticosteroid myopathy D-penicillamine, IFN-α, and procainamide-induced   myopathy

Proximal muscle weakness Increased serum lactate levels Ragged red fibers and abnormal mitochondria in muscle Improves with drug discontinuation Necrotizing myopathy Acute or subacute painful proximal myopathy Increased serum CK levels Proximal and distal weakness Type 2 atrophy and vacuolar changes in muscle Increased serum CK levels Proximal muscle weakness and pain Inflammation and necrosis in muscle Skin changes Increased serum CK levels

AST, aspartate transaminase; CK, creatine kinase; EMG, electromyogram; IFN, interferon; LDH, lactate dehydrogenase; LGMD, limb-girdle muscular dystrophy. Continued

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Table 78-8  Differential Diagnosis of Inflammatory Myopathies—cont’d Disease

Key Diagnostic Features

Neuromuscular Diseases Motoneuron disease

Spinal muscular atrophy Myasthenia gravis

Upper and lower motoneuron signs Asymmetric weakness with denervation atrophy Fasciculations and fatigability Fibrillations and enlarged motor unit potentials on EMG Modest elevation in serum CK levels Symmetric muscle weakness and atrophy Neurogenic changes on EMG and biopsy Normal serum CK levels Abnormal weakness and fatigability Decremental EMG response Antiacetylcholine receptor antibodies Positive anticholinesterase drug test

­ onspecific features, such as central nuclei, sarcoplasmic n masses, and atrophy of type 1 fibers. Sarcoglycanopathy Mutations in sarcoglycans (α, β, γ, and δ) result in limb-girdle muscular dystrophy types 2C to 2F. Sarcoglycanopathies often start in childhood, with a median age of onset of 6 to 8 years. These diseases present initially as pelvic muscle weakness, including a waddling gait and difficulty performing common tasks, such as getting up from the floor, climbing the stairs, and running. The trunk muscles are prominently affected, and upper extremity involvement usually follows lower extremity involvement. Distal muscles are generally spared until later in the disease process.164 These progressive disorders result in very high levels of serum CK early in the disease; the levels decrease when patients become wheelchair bound by 12 to 16 years of age. Dilated cardiomyopathy is often seen in these disorders, and muscle biopsies show marked regeneration and necrosis. NEUROMUSCULAR DISORDERS Motoneuron Diseases These diseases, including amyotrophic lateral sclerosis (ALS), are progressive, degenerative disorders of motoneurons in the spinal cord, brainstem, and cerebral motor ­cortex that manifest clinically as amyotrophy and ­exaggerated reflexes. These diseases are characterized by a selective loss of function of upper or lower motoneurons, finally leading to a progressive loss of both types of ­ motoneurons over time. EMG shows fibrillation and ­fasciculation potentials in the muscles of the lower and upper limbs or in the bulbar muscles. Muscle biopsies show the presence of denervation ­atrophy and secondary myopathic changes in chronically ­denervated muscles. IBM is the primary muscle disorder most likely to be confused with ALS, and muscle biopsy helps differentiate the two. Serum CK levels are slightly ­elevated, particularly in the early stages of the disease and in men who are physically active.

include small and large groups of atrophic fibers in the chronic and severe forms of SMA, respectively. Histochemical changes show fiber type grouping, indicating reinnervation. Serum CK levels are slightly increased in juvenile-onset cases and normal in other forms of SMA. EMG shows abnormal spontaneous electrical activity (fibrillations, positive sharp waves, fasciculations), suggesting ongoing denervation. Myasthenia Gravis The clinical manifestations of myasthenia gravis include abnormal weakness that is worsened by repeated or ­sustained exertion and fatigability. Proximal muscles are usually more severely affected than distal muscles. This is a generalized disease that exhibits external ocular muscle involvement, positive anticholinesterase drug tests, and a decremental EMG response. Patients are often positive for ­antiacetylcholine receptor antibodies. METABOLIC MYOPATHIES Acid Maltase Deficiency This autosomal recessive glycogen storage disease is caused by acid maltase gene mutations. The disease has infantile, childhood, and adult variants. The infantile form manifests in the first few months after birth as rapidly progressive weakness and hypotonia, with death occurring as a result of cardiorespiratory failure. The childhood form manifests as a myopathy in which the weakness is usually greater in the proximal than in the distal muscles; the disease progresses relatively slowly, and patients die of respiratory failure. The adult form presents in the 20s as a progressive myopathy that resembles polymyositis or limb-girdle muscular dystrophy, with additional respiratory symptoms. Serum muscle enzymes (CK, AST, and LDH) are increased in all three forms of the disease, and EMG indicates myopathy in all three cases. Histologic examination reveals a vacuolar myopathy, with the vacuoles displaying a high glycogen content and strongly positive staining for acid phosphatase; necrotic and regenerating fibers are uncommon.

Spinal Muscular Atrophy Late-onset forms of spinal muscular atrophy (SMA) are characterized by progressive muscle weakness and atrophy and reduced tendon reflexes. EMG and muscle testing reveal neurogenic changes in the muscle. Typical muscle biopsy ­findings

McArdle’s Disease McArdle’s disease is the most common of the nonlysosomal muscle glycogenoses. Exercise intolerance is the characteristic feature of this disease, and it often manifests as early

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fatigue, myalgia, and stiffness of exercising muscle that is relieved by resting. The EMG is normal in some patients; it shows nonspecific myopathic changes in others. Forearm ischemic exercise testing shows virtually no increase in venous lactate in most patients. Serum CK levels, however, are variably ­elevated in these patients. Muscle biopsies show ­subsarcolemmal deposits of glycogen at the periphery of the fibers. MITOCHONDRIAL MYOPATHIES Mitochondrial diseases are heterogeneous and often present a diagnostic challenge. It has been suggested that myopathy is due to mutations in mtDNA in the skeletal muscle.165 The clinical course of the pure myopathy varies from rapidly progressive to almost reversible disease, with disease onset occurring from infancy through adulthood. The weakness is facioscapulohumeral and more proximal than distal, with involvement of the orbicularis and extraocular muscles. Patients often complain of exercise intolerance and fatigue and have recurrent episodes of myoglobinuria. Muscle biopsy plays a critical role in the diagnosis of these conditions, especially the use of special histochemical stains that detect succinate dehydrogenase, Cox staining, and Gomori trichrome staining. ENDOCRINE MYOPATHIES Cushing’s Syndrome Cushing’s syndrome is an endogenous glucocorticoid excess ­disease that manifests as muscle weakness and wasting. Chronic corticosteroid treatment results in similar manifestations and significant loss of strength within a few weeks of treatment. Muscle biopsy shows increased vacuolations and glycogen accumulation in type 2 muscle. The onset of weakness is usually insidious. The weakness is primarily proximal, with more severe involvement in the legs than in the arms. These patients generally show normal serum muscle enzyme levels (CK, AST, and LDH). Muscle wasting can often be reversed if the ­glucocorticoid levels are returned to the ­normal range. Hyper- and Hypothyroid Myopathy Myopathic thyroid disease is characterized primarily by proximal muscle weakness and muscle wasting. When distal weakness occurs, it often follows proximal myopathy. Exercise intolerance, fatigue, and breathlessness are common complaints, and weakness of the respiratory muscles results in respiratory insufficiency and the need for ventilatory support. Patients often have difficulty rising from a sitting position or lifting their arms above their heads. Serum muscle enzymes (CK, AST, and ALT) are often normal or low in hyperthyroidism and elevated in hypothyroidism. EMG findings are variable, with shortduration motor unit potentials and increased polyphasic potentials in proximal muscles; fibrillations and fasciculations are uncommon. Muscle biopsy shows atrophy in fiber types, nerve terminal damage, fatty infiltration, and isolated fiber necrosis, with macrophage and lymphocyte infiltration.

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INFECTIOUS MYOPATHIES HIV Myopathy Neuromuscular manifestations are common in human ­immunodeficiency virus (HIV)–induced myopathy. The clinical features typically include a myopathy of subacute onset that progresses slowly. The myopathy often starts as proximal symmetric muscle weakness with or without muscle wasting, similar to that in IIMs. Histologic features include muscle fiber necrosis, inflammation, and vacuolated muscle fibers, with a significant increase in serum CK levels. EMG shows spontaneous activity, with fibrillation potentials, positive sharp waves, and brief, low-amplitude ­ polyphasic motor unit potentials. HTLV-1 Myopathy Myositis associated with human T-lymphotropic virus 1 (HTLV-1) has been noted in certain areas of the world (e.g., Japan, Jamaica). In these patients, symptoms of ­polymyositis and IBM occur either alone or in combination with tropical spastic paraparesis.166 Typical features include weakness and increases in serum CK levels. Histologic findings include interstitial inflammation, muscle fiber necrosis in ­ polymyositis, and endomysial inflammation, vacuoles, ­amyloid deposits, and tubulofilaments in IBM. PARASITIC MYOPATHIES Diseases caused by various parasites—protozoa (e.g., toxoplasmosis, trypanosomiasis, sarcocystosis, malaria), cestodes (e.g., cystocercosis, chinococcosis, coenurosis, sparganosis), and nematodes (trichinellosis, taxocariasis, racunculiasis)—can cause myositis. The clinical features include nonspecific complaints, such as myalgia and focal swelling, and typical features of polymyositis and dermatomyositis. Each parasitic infection shows typical changes on muscle biopsy (e.g., the presence of tachyzoites and toxoplasma cysts along with perimysial and endomysial inflammation). A combination of muscle biopsy and serologic findings is useful in making a diagnosis. DRUG-INDUCED MYOPATHIES Drugs can induce myopathic changes either by acting directly on the muscle or by indirectly influencing various factors required for muscle cell survival and growth. Zidovudine Myopathy Nucleoside analogues such as zidovudine are used to treat HIV because they act as false substrates for the viral reverse transcriptase. These drugs also cause myalgias, proximal muscle weakness, and fatigue and are sometimes associated with increased levels of serum CK. EMG shows typical myopathic changes. Histologically, muscle fibers show ragged red fibers; atrophic fibers show marked sarcoplasmic changes, with rod-body formation. Pronounced abnormalities in mitochondria, myofilaments, and tubules are also noted by electron microscopy. It has been suggested that these drugs also inhibit mitochondrial DNA polymerase, thus producing the mitochondrial abnormalities. Discontinuation of therapy improves muscle strength and function. In these

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patients, zidovudine-induced mitochondrial myopathy may coexist along with HIV-induced T cell–mediated inflammatory myopathy.167 Statin Myopathy Statins are lipid-lowering drugs (e.g., lovastatin, simva­ statin) that are known to cause necrotizing myopathy. These HMG-CoA reductase inhibitors generally suppress specific cholesterol synthesis and lower plasma concentrations of low-density lipoprotein. The clinical features of this condition include myalgia, cramps, and acute and subacute painful proximal myopathy, with histologic features varying from mild, discrete, and unspecific to muscle fiber ­necrosis, mononuclear cell infiltration, and myophagocytosis and regeneration. A mild increase in serum CK levels is also noted. Other agents that are known to cause necrotizing myopathy include fibric acid derivatives (clofibrate, gemfibrozil), nicotinic acid, organophosphate poisoning, and ε-aminocaproic acid. Other Drugs D-penicillamine is known to induce clinical features reminiscent of dermatomyositis; recovery usually occurs after withdrawal of the drug. Agents such as interferon-α that are used to treat viral hepatitis and certain malignant tumors are also known to induce clinical features that resemble polymyositis. Amphiphilic drugs such as chloroquine, hydroxyl chloroquine, and amiodarone are also known to induce cytoplasmic vacuoles, necrosis, and longitudinal branching of muscle fibers.168 Drugs that affect microtubules, such as colchicines and vincristine, also induce myopathic changes, with the appearance of characteristic autophagic vacuoles in muscle fibers.

MANAGEMENT AND PROGNOSIS The recommended treatment for patients with polymyositis or dermatomyositis is based on a combination of pharmacologic therapy and physical exercise. The optimal pharmacologic treatment in polymyositis and dermatomyositis is unclear. Very few controlled trials have been undertaken, so recommendations are based on clinical observations from case series. With these limitations in mind, a suggested outline of treatment for patients with polymyositis or dermatomyositis is depicted in Figure 78-12. In addition to providing treatment, it is important to give patients adequate information about their disease and its treatment. This educational component is best provided by a rheumatology team and patient support groups. PHARMACOLOGIC TREATMENT The initial pharmacologic treatment in polymyositis and dermatomyositis is high-dose glucocorticoids: 0.75 to 1 (up to 2) mg/kg body weight per day for 4 to 12 weeks. Most experts recommend that glucocorticoid treatment be combined with another immunosuppressive drug to reduce the side effects of the glucocorticoids and to boost the immunosuppressive effect. The most frequently used immunosuppressive agents are azathioprine and methotrexate. In the

extension phase of one of the few double-blind, placebocontrolled trials that have been reported, the combination of azathioprine and glucocorticoids, as compared with prednisone alone, was associated with better functional ability and a lower requirement for prednisone after 1 and 3 years.169,170 The recommended azathioprine dosage is 2 mg/kg per day. The dosing regimen for methotrexate is similar to that for rheumatoid arthritis—up to 25 mg weekly, although there have been reports of higher doses. Pulmonary involvement related to myositis does not seem to be a contraindication for methotrexate. The combination of methotrexate and azathioprine proved to be successful in a few patients with refractory myositis in a prospective, randomized, open-label crossover study comparing two aggressive approaches. There are also newer reports that mycophenolate mofetil might be ­ effective. In patients with interstitial lung disease, cyclophosphamide could be of value. There are also a few reports that cyclosporine A or tacrolimus can be beneficial in these cases.171,172 In treatment-resistant dermatomyositis, a high dose of IVIG was found to have a beneficial effect on muscle strength when compared with placebo; however, the therapeutic effect was temporary, and repeated infusions were required.173 In patients with severe, rapidly progressive disease that might be life threatening, high-dose pulses of intravenous methylprednisolone have been reported to be beneficial. Pharmacologic treatment, including tapering of the corticosteroid dose, should be guided by clinical outcome measures. As discussed earlier, the most appropriate outcome measures are muscle endurance and muscle strength. Side effects of glucocorticoids in these high doses are frequent. Prophylaxis against osteoporosis is recommended with vitamin D and calcium and, when clinically indicated, bisphosphonates. Steroid myopathy is another possible consequence of glucocorticoid treatment that is particularly problematic in patients with inflammatory myopathies. There is no specific test to verify steroid myopathy, but in the absence of active clinical disease, steroid myopathy could contribute to muscle weakness. If steroid myopathy is suspected, tapering of the glucocorticoid dose with careful evaluation of the clinical response is recommended. Glucocorticoids may also cause hypokalemia, and if this is not corrected, it may be associated with muscle weakness and incorrectly interpreted as myositis activity. The depletion of B cells has recently emerged as a new strategy in autoimmune diseases. One approach is to use rituximab (monoclonal antibody against CD20). There are a few case series suggesting a beneficial effect of depleting B cells in patients with dermatomyositis or polymyositis.174-176 A large international multicenter trial of B cell depletion is currently under way. IBM is usually nonresponsive to glucocorticoids. There are occasional case reports of “stabilization” for a period of months, but this condition probably reflects the natural history of the disease. Prolonged administration of glucocorticoids to IBM patients may actually lead to worsening of clinical aspects of the disease, despite the improvement in CK levels and reduced T cell numbers in biopsies. Prednisone treatment also increases the number of amyloid-containing fibers. A few small studies have shown some beneficial effect of methotrexate, anti–T lymphocyte globulin, or

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PM or DM ILD? Yes

No

1. Prednisolone 0.75-1 mg/kg/d 2. Cyclophosphamide 2 mg/kg/d or cyclosporine A 3-5 mg/kg/d or tacrolimus 3. Supplemental calcium and vitamin D 4. Bisphophonates 5. Exercise

At 3-6 months PFTs improved? Improved strength? Yes 1. Taper prednisolone by 10% every 2 weeks 2. Stop cyclophosphamide, switch to azathioprine or methotrexate 15-25 mg/w, folic acid

1. Prednisolone 0.75-1 mg/kg/d 2. Azathioprine 2mg/kg/d or methotrexate 15-25 mg/w, folic acid 3. Supplemental calcium and vitamin D 4. Bisphosphonates 5. Exercise

At 6 weeks Improved strength? Yes

No

1. Taper prednisolone 2. Continue with cyclophosp. or switch to tacrolimus, or cyclosporine A or rituximab

No

Consider to increase mtx dose or sc

Taper prednisolone, slowly by 10% every 2 weeks

At 3 months improved strength? No

Yes At 12 months Improved? Yes: taper prednisolone

At 12 months Improved? Switch to cyclophosp to azathioprine or methotrexate 15-25 mg/w. No improvement: consider rituximab

At 18 months Remission? Yes: Try to stop prednisolone or taper to lowest maintenance dose. Taper aza or mtx to lowest maintenance dose

Yes At 18 months Improved or remission?

Taper prednisolone, switch aza to mtx, or v.v. and re-evaluate diagnosis

Taper prednisolone, slowly

At 6 months Improved?

Taper prednisolone, slowly to lowest maintenance dose. Taper aza to mtx to lowest maintenance dose

No

Consider rituximab or cyclosporine A or combination aza+mtx

Figure 78-12  Treatment algorithm for adult patients with polymyositis (PM) or dermatomyositis (DM). ILD, interstitial lung disease; PFT, pulmonary function test.

­ ycophenolate. Anabolic steroids and oxandrolone may m have some beneficial effects on muscle strength, although this benefit needs to be confirmed in larger studies. Most experts consider their use justified in combination with glucocorticoids for a limited period in patients who have inflammatory infiltrates on muscle biopsy, or in combination with a more aggressive immunosuppressive treatment (e.g., methotrexate, azathioprine) in patients with another connective tissue disease.

and supervised by a physiotherapist to avoid the overuse of muscles. Physical exercise is now recommended as combination therapy with immunosuppressive treatment. ASSESSING DISEASE ACTIVITY AND OUTCOME The most important variable to measure in myositis patients is muscle performance or physical function. However, it is equally important to evaluate whether impaired muscle function reflects disease activity or irreversible muscle damage.

NONPHARMACOLOGIC TREATMENT With immunosuppressive treatment, approximately 75% of patients improve, but very few recover normal muscle function, even in the absence of muscle inflammation. ­Combining exercise and immunosuppressive therapy is a safe approach and has clear beneficial effects on muscle function.176a The exercise regimen should be individualized

Muscle Examination Manual Muscle Test. There are several tools to measure muscle performance, but the most often used method in clinical practice and clinical trials is the manual muscle test with the MRC scale (see earlier). The drawback is that these tools ­measure muscle strength but not muscle

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endurance, which is often a major problem in polymyositis or dermatomyositis. Further, they have not been validated in adults with inflammatory myopathies. Previously, the number of muscle groups tested using the manual muscle test varied, and different scales were used (5 or 10 grade). Recently, a consensus was reached to assess eight muscle groups on the dominant side using a 0- to 10-point scale, where 0 is no muscle contraction, 5 is ability to hold the test position without any added pressure, and 10 is ability to hold the test position against strong pressure. The points between these scores are based on gradual increased resistance against the examiner’s pressure. The eight muscle groups tested are neck flexors, shoulder abduction (deltoid middle), biceps brachii, wrist extensors, knee extensors (quadriceps), dorsiflexion of ankle, gluteus maximus, and gluteus medius. The score achieved varies between 0 and 80. Functional Index in Myositis. The Functional Index in Myositis and its revised form, the Functional Index in Myositis-2, were developed as outcome measures for patients with polymyositis or dermatomyositis. This test measures the number of repetitions that can be performed in defined muscle groups.136,141 It is a more sensitive method of measuring impaired muscle function in patients with polymyositis or dermatomyositis.136 The drawback is that it takes a longer time to perform than the manual muscle test, and it may be difficult to use in everyday clinical practice. Preferably, the Functional Index in Myositis-2 is administered by a physiotherapist and can be combined with the manual muscle test. Extramuscular Involvement In some patients, extramuscular symptoms predominate among the clinical features. These symptoms may require other assessment tools, such as those used to evaluate interstitial lung disease. For monitoring the effects of treatment of interstitial lung disease, high-resolution CT and pulmonary function tests are recommended. Disease Activity and Damage It is also important to distinguish whether symptoms are caused by active inflammatory disease or are a consequence of organ damage. IMACS, an international collaboration, made a consensus recommendation that

outcome measures for patients with myositis include tools that measure disease activity, damage, and quality of life. The IMACS network developed one outcome measure to assess myositis disease activity and one to measure organ damage: the myositis disease activity assessment tool and the myositis damage index, respectively.135 The disease activity outcome measure is a core set that consists of the six variables listed in Table 78-9. The damage index is recorded by the physician based on the patient’s history and covers several organ systems that can be affected in patients with inflammatory myopathies. To assess the impact on general health, the generic short-form 36, a self-administered health-related quality of life questionnaire, is recommended. These outcome measures have been developed for clinical trials and research but can also be useful in clinical practice. More detailed information about these outcome measures can be found on the IMACS website: https://dir-apps.niehs. nih.gov/imacs. IMACS has also reached a consensus on what constitutes improvement. Improvement is based on the disease activity core set and is defined as greater than 20% improvement in three of the six variables of the core set, with two or fewer of the variables (except the manual muscle test) worsening by less than 25%. However, this definition of improvement must be validated in longitudinal studies.

Future Directions Application of new technologies, such as microarrays, to the inflammatory myopathies has provided new hypotheses regarding disease onset and progression and pointed to possible molecular pathways that can be targeted for therapeutic purposes. Particularly important are comparisons of specific subtypes of myositis both with one another and with other muscle diseases; this approach differentiates between downstream ­pathologic pathways that may be shared by all muscle diseases (myofiber necrosis, regeneration, fibrosis) and those that are farther upstream and more directly linked to disease cause. ­Importantly, large muscle biopsy microarray data sets inclusive of inflammatory myopathies are now in the public domain, permitting the analysis of this complex molecular data by researchers worldwide.177 This should ­effectively parallelize research on the inflammatory ­ myopathies and greatly speed our understanding of ­ molecular pathogenesis and facilitate ­ targeted ­therapeutics.

Table 78-9  Disease Activity Measure—Core Set Physician’s overall assessment of disease activity on a visual analog scale (VAS) Patient’s or parent’s overall assessment of disease activity (VAS) Functional assessment (health assessment questionnaire) Muscle strength testing (manual muscle test) Serum levels of at least two of four muscle enzymes   (CK, LDH, AST, ALT) Extramuscular score (myositis disease activity assessment VAS [MYOACT] or myositis intention to treat activity index [MITAX]), in which disease activity in seven organ systems (general symptoms, skin, joints, GI tract, pulmonary, heart, and muscles) is scored. ALT, alanine transaminase; AST, aspartate transaminase; CK, creatine kinase; GI, gastrointestinal; LDH, lactate dehydrogenase.

REFERENCES   1. Wagner E: Fall einer seltenen Muskelkranheit. Arch Heilkd 4: 282, 1863.   2. Wagner E: Ein Fall von acuter polymyositis. Dtsch Arch Klin Med 40:241, 1887.   3. Jackson H: Myositis universalis acuta infectiosa with a case. Boston Med Surg J 116:498, 1887.   4. Unverricht H: Polymyositis acuta progressiva. Z Klin Med 12: 533, 1887.   5. Unverricht H: Dermatomyositis acuta. Dtsch Med Wochenschr 17:41, 1891.   6. Steiner WR: Dermatomyositis, with report of a case which presented a rare muscle anomaly but once described in man. J Exp Med 6:407, 1903.

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SCLERODERMA, INFLAMMATORY MYOPATHIES, and overlap Syndromes

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Inflammatory Diseases of Muscle and Other Myopathies

162. Kaido M, Arahata K, Hoffman EP, et al: Muscle histology in Becker muscular dystrophy. Muscle Nerve 14:1067-1073, 1991. 163. Holt JM, Lambert EH: Heart disease as the presenting feature in myotonia atrophica. Br Heart J 26:433-436, 1964. 164. Angelini C, Fanin M, Freda MP, et al: The clinical spectrum of ­sarcoglycanopathies. Neurology 52:176-179, 1999. 165. DiMauro S: Introduction: Mitochondrial encephalomyopathies. Brain Pathol 10:419-421, 2000. 166. Higuchi I, Hashimoto K, Matsuoka E, et al: The main HTLV-Iharboring cells in the muscles of viral carriers with polymyositis are not macrophages but CD4+ lymphocytes. Acta Neuropathol (Berl) 92:358-361, 1996. 167. Dalakas MC, Illa I, Pezeshkpour GH, et al: Mitochondrial ­myopathy caused by long-term zidovudine therapy. N Engl J Med 322: 1098-1105, 1990. 168. Drenckhahn D, Lullmann-Rauch R: Experimental myopathy induced by amphiphilic cationic compounds including several psychotropic drugs. Neuroscience 4:549-562, 1979. 169. Bunch TW: Prednisone and azathioprine for polymyositis: Long-term followup. Arthritis Rheum 24:45-48, 1981. 170. Bunch TW, Worthington JW, Combs JJ, et al: Azathioprine with prednisone for polymyositis: A controlled, clinical trial. Ann Intern Med 92:365-369, 1980. 171. Vencovsky J: Cyclosporine A versus methotrexate in the treatment of polymyositis and dermatomyositis. Scand J Rheumatol 29:95-102, 2000.

172. Oddis CV, Sciurba FC, Elmagd KA, Starzl TE: Tacrolimus in ­refractory polymyositis with interstitial lung disease. Lancet 353:1762-1763, 1999. 173. Dalakas MC, Illa I, Dambrosia JM, et al: A controlled trial of ­high-dose intravenous immune globulin infusions as treatment for ­dermatomyositis. N Engl J Med 329:1993-2000, 1993. 174. Levine TD: Rituximab in the treatment of dermatomyositis: An open-label pilot study. Arthritis Rheum 52:601-607, 2005. 175. Lambotte O, Kotb R, Maigne G, et al: Efficacy of rituximab in ­refractory polymyositis. J Rheumatol 32:1369-1370, 2005. 176. Noss EH, Hausner-Sypek DL, Weinblatt ME: Rituximab as therapy for refractory polymyositis and dermatomyositis. J Rheumatol 33:1021-1026, 2006. 176a. Wiesinger GF, Quittan M, Aringer M, et al: Improvement of physical fitness and muscle strength in polymyositis/dermatomyositis patients by a training programme. Br J Rheumatol 37:196-200, 1998. 177. Bakay M, Wang Z, Melcon G, et al: Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of RbMyoD pathways in muscle regeneration. Brain 129:996-1013, 2006. 178. Benbassat J, Geffel D, Zlotnick A: Epidemiology of polymyositis-­dermatomyositis in Israel, 1960-76. Isr J Med Sci 16:197-200, 1980.

79

Overlap Syndromes ROBERT M. BENNETT

KEY POINTS Diffuse connective tissue diseases (DCTDs) are usually ­associated with autoimmunity to spliceosomal components (uridine ribonucleoprotein particles [U-RNPs], heterogeneous RNPs), nucleosomal components (nucleosomes, DNA, histones), or proteasomal components (HC9, LMP2). Apoptotic modification of molecules often renders them more antigenic. Epitope spreading often leads to a diversification of the ­antibody response in DCTDs. The diagnosis of undifferentiated connective tissue ­disease (UCTD) is usually made in patients with Raynaud’s ­phenomenon in combination with an unexplained synovitis or inflammatory myopathy.

Serious central nervous system involvement is rare in MCTD; the most common finding is trigeminal neuropathy. All patients with MCTD should be screened for pulmonary hypertension on an ongoing basis, because this is the most common cause of death in MCTD patients. The management of overlap syndromes has not been the subject of controlled trials. Therefore, management is based on an analysis of clinical features and application of the usual management strategies for inflammatory arthritis, Raynaud’s phenomenon, inflammatory muscle disease, serositis, interstitial lung disease, pulmonary hypertension, and the gastrointestinal features of scleroderma. By definition, the clinical features of an overlap syndrome are quite diverse and often change over time. Thus, a reappraisal of management strategies is needed at each patient visit.

About 55% of patients with UCTD fail to differentiate into a classic DCTD. U1-RNP antibodies predict the differentiation into a mixed connective tissue disease (MCTD). DNA antibodies predict the differentiation into systemic lupus erythematosus (SLE). Nucleolar antibodies predict the differentiation into ­scleroderma. Synthetase and PM-Scl antibodies predict the differentiation into a myositis overlap syndrome. Myositis overlap syndromes are more common than the classic descriptions of polymyositis (PM) or dermatomyositis (DM). In general, myositis overlap syndromes are more responsive to corticosteroids than the pure forms of PM and DM. Arthritis and interstitial lung disease may antedate the ­appearance of myositis in patients with antisynthetase ­antibodies. Patients with antibodies to synthetases, signal ­recognition particle, and nucleoporin are less responsive to ­corticosteroids. Antibodies to U1-RNP, Pm-Scl, or Ku are associated with ­corticosteroid responsiveness. The clinical overlap features of MCTD (i.e., scleroderma, SLE, idiopathic inflammatory myopathy) seldom occur ­concurrently; they develop sequentially over the course of months or years. Raynaud’s phenomenon is seen in nearly all patients with MCTD; if Raynaud’s is absent, the diagnosis should be ­reconsidered. About 25% of MCTD patients develop renal involvement—usually membranous glomerulonephritis; ­proliferative glomerulonephritis is uncommon in MCTD.

The clustering of symptoms and signs into readily recognizable groups has an important historic precedent in the ­classification of disease. With the progress of knowledge, such groups may become more precisely defined in terms of distinctive pathology or specific laboratory findings. According to current nosology, there are six diffuse connective tissue diseases (DCTDs): 1. Systemic lupus erythematosus (SLE) 2. Scleroderma 3. Polymyositis (PM) 4. Dermatomyositis (DM) 5. Rheumatoid arthritis (RA) 6. Sjögren’s syndrome All six classic DCTDs are descriptive syndromes ­ without a “gold standard” for diagnosis. The diagnosis of a well­differentiated DCTD is usually readily apparent without recourse to extensive investigations. However, in the early stages, there are often common features such as Raynaud’s phenomenon, arthralgias, myalgias, esophageal dysfunction, and positive tests for antinuclear antibodies (ANAs). When the diagnosis is not obvious, this is often referred to as an undifferentiated connective tissue disease (UCTD).1 Only about 35% of such patients differentiate into a clinical picture consistent with the traditional description of a DCTD.2 In some instances, one DCTD evolves into another DCTD over time. The propensity for differentiation into a classic DCTD or the maintenance of an overlap state is often associated with distinctive serologic profiles and major histocompatibilty complex (MHC) linkages. Although most rheumatologists are more comfortable thinking in terms of the classic DCTD paradigms, a case can be made for using serologic profiles and human leukocyte antigen (HLA) typing to better understand the clinical features and prognoses. In this respect, a careful analysis of the overlap syndromes and 1381

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Table 79-1  Correlations between Autoantibodies and Clinical Features Autoantigen

Clinical Associations

Rheumatoid factor

RA, erosive arthritis, cryoglobulinemia

Cyclic citrullinated peptide

RA

Nucleosome

SLE, scleroderma, MCTD

Proteasome

SLE, PM-DM, Sjögren’s syndrome, multiple sclerosis

Smith snRNP

SLE

Histones H1, H2A, H2B, H3, H4

SLE, UCTD, RA, PBC, generalized morphea

Ribosomal P

SLE psychosis

Double-stranded DNA

SLE, glomerulonephritis, vasculitis

ACL/β2-glycoprotein

SLE, thrombosis, thrombocytopenia, miscarriage

β2-glycoprotein–independent ACL

MCTD (not associated with antiphospholipid syndrome)

68-kD peptide of U1-RNP

MCTD, Raynaud’s phenomenon, pulmonary hypertension

U1-snRNP

MCTD, SLE, PM

hnRNP-A2 (also called RA-33)

MCTD, RA, erosive arthritis in SLE and scleroderma

Ro/La

Sjögren’s syndrome, SLE, congenital heart block, photosensitivity, PBC

Fodrin

Sjögren’s syndrome, glaucoma, moyamoya disease

Platelet-derived growth factor

Diffuse and limited scleroderma

Topoisomerase 1 (Scl-70)

Diffuse scleroderma with prominent organ involvement

Centromere

Limited scleroderma, CREST, Raynaud’s phenomenon, pulmonary hypertension, PBC

Th/To

Limited scleroderma

U3-snRNP

Limited scleroderma

hnRNP-I

Scleroderma (early diffuse and limited)

RNA polymerases I and III

Scleroderma (diffuse with renovascular hypertension)

Fibrillarin

Severe generalized scleroderma

Ku

Myositis overlap, primary pulmonary hypertension, Graves’ disease

U5-snRNP

Myositis overlap

PM-Scl

Myositis overlap with arthritis, skin lesions, mechanic’s hands

Signal recognition particle

Myositis overlap (severe course with cardiac disease)

Antisynthetases (Jo-1, PL-7, PL-12)

Myositis overlap with arthritis and interstitial lung disease

Mi-2

DM

Proteinase-3

Wegener’s granulomatosis, pulmonary capillaritis

Myeloperoxidase

Churg-Strauss syndrome, pauci-immune glomerulonephritis

Endothelial cell

Pulmonary hypertension, severe digital gangrene

ACL, anticardiolipin; CREST, syndrome of calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia; DM, dermatomyositis; hn, heterogeneous nuclear; MCTD, mixed connective tissue disease; PBC, primary biliary cirrhosis; PM, polymyositis; RA, rhuematoid arthritis; RNP, ribonucleoprotein particle; SLE, systemic lupus erythematosus; sn, small nuclear; UCTD, undifferentiated connective tissue disease.

their serologic associations has provided insights into the clinical heterogeneity of DCTDs and their management.3 Numerous clinical correlations of autoantibodies have been reported and are summarized in Table 79-1.

EPIDEMIOLOGY The reported prevalence of DCTDs is variable, depending on the study methodology, nature of referral bias, and patient ethnicity.4 It is generally accepted that Sjögren’s syndrome has the highest prevalence (500 to 3600 per 100,000) and that SLE is much less prevalent (about 15 to 50 per 100,000). Scleroderma, PM, and DM are relatively rare DCTDs, with prevalences less than 10 per 100,000. There is increasing realization that overlap syndromes of scleroderma and myositis are more common than the “pure” forms of the disease.5,6 The only epidemiology studies of overlap syndromes

are from Japan, where the reported prevalence of mixed connective tissue disease (MCTD) was 2.7 per 100,000.7 The syndrome of MCTD usually occurs as an isolated finding, but there are reports of a familial occurrence.8,9 Unlike SLE, precipitation by sun exposure has not been described in patients with MCTD. Likewise, drug exposure has not been related to the onset of MCTD, although the transient appearance of anti–ribonucleoprotein particle (RNP) antibodies has been seen at the initiation of procainamide therapy.10 Vinyl chloride11 and silica12 are the only environmental agents that have been associated with MCTD.

AUTOIMMUNITY There is compelling evidence that autoimmunity is often antigen driven by the components of subcellular particles—in particular, spliceosomes, nucleosomes, and proteasomes.13

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Stem-loop I

70 kDa U4

C

U1 U2

U6

Stem-loop II

U5 B

Exon

B Common sm

Intron

A

A

D E F G

Stem-loop III

B

Figure 79-1  Spliceosome. A, The spliceosome is made up of five small nuclear RNAs (snRNAs) complexed with proteins to form a small nuclear ribonucleoprotein particle (snRNP). This subcellular structure is responsible for splicing introns from premessenger RNA to form messenger RNA. Antibodies to various spliceosomal constituents are a common feature of autoimmune rheumatic disorders, and they tend to be associated with different clinical profiles. B, The U1-snRNP particle of the spliceosome is composed of U1-RNA, RNP proteins (70-kD, A, and C), and common Smith (Sm) proteins (B′B, D, E, F, and G). The structure of U1-RNA consists of single-stranded RNA and double-stranded RNA called stem-loops I, II, III, and IV. The 70-kD protein can bind directly to stem-loop I of U1-RNA, and the A protein can bind directly to stem-loop II of U1-RNA through an RNA-binding domain known as the RNP-80 motif. The common Sm proteins bind as a complex to single-stranded RNA at the position shown. Because C protein does not have an RNA-binding domain, it cannot bind directly to U1-RNA. However, it does have a zinc-finger domain that facilitates its joining U1-snRNP through protein-protein interactions (arrows) of its zinc-finger domain with the 70-kD and common Sm proteins. (B, From Hoffman RW, Greidinger EL: Mixed connective tissue disease. Curr Opin Rheumatol 12:386-390, 2000.)

AUTOIMMUNITY TO SPLICEOSOMAL COMPONENTS Certain components of the spliceosome are common targets of autoimmunity in the DCTDs.14 Further, it appears that post-translational modifications of these molecules, as occur during apoptosis, are often associated with increased immunogenicity.15 Spliceosomes are complex nuclear particles made up of some 300 distinct proteins and 5 RNAs, which are involved in the processing of premessenger RNA (premRNA) into mature “spliced RNA”16 (Fig. 79-1). There are two major spliceosomal subunits that are antigenic targets in autoimmunity: small nuclear RNPs and heterogeneous nuclear RNPs.17 The small nuclear RNPs contain small RNA species ranging in size from 80 to 350 nucleotides that are complexed with proteins. These RNAs contain a high content of uridine and are therefore called U-RNAs; five different U-RNAs were defined on the basis of immunoprecipitation (U1, U2, U4, U5, and U6).18 Autoantibodies to these complexes are directed mainly to the protein components. Anti-Sm antibodies precipitate five proteins with molecular weights of 28,000 (B�B), 16,000 (D), 13,000 (E), 12,000 (F), and 11,000 (G); five of these polypeptides are common to the U1, U2, U4, U5, and U6 RNAs. Anti-RNP antibodies precipitate three proteins with molecular weights of 68,000 (70K), 33,000 (A�), and 22,000 (C); these polypeptides are uniquely associated with U1-RNA (see Fig. 79-1).19 The clinical correlates considered to be distinctive of MCTD are associated with the 70-kD specificity, with an immunodominant epitope embracing amino acid residue 125 flanked by important conformational residues at positions 119 to 126. SLE is associated with anti-Sm antibodies.20 The heterogeneous nuclear RNPs are among the most abundant proteins in the eukaryotic cell nucleus.17 They

contain pre-mRNA associated with 30 small proteins that are all structurally related and have molecular weights of 33 to 43 kD. Nine heterogeneous nuclear RNP core proteins have been designated A1, A2, B1a, B1b, B1c, B2, C1, C2, and C3.21 An antibody termed anti-RA33, which targets the 33-kD RNP-A2, is particularly interesting because it is found in the sera of about one third of patients with RA, SLE, and MCTD.22 It also has associations with erosive arthritis in SLE, scleroderma, and MCTD23 and predicts the eventual development of RA in patients with early polyarthritis.24 Importantly, this association with anti-RA33 is not seen in scleroderma (sine erosions), PM, or overlaps of PM-scleroderma or PM-DM. The antigenic epitopes of heterogeneous nuclear RNP-A2 contain two RNA binding regions at the N-terminal end and a glycine-rich C-­terminal region. Certain disease subsets target these two RNA ­binding regions differently. For instance, RA and SLE sera preferentially react with the second RNA binding domain, whereas MCTD sera target an epitope that spans both RNA binding domains.25 AUTOIMMUNITY TO NUCLEOSOMAL COMPONENTS Nucleosomes are the compact building blocks of chromatin and consist of an octamer of two copies of histones H2A, H2B, H3, and H4, around wrapped approximately 146 base pairs of DNA (Fig. 79-2). During apoptosis, endonucleases cleave chromatin, with the liberation of nucleosomal particles. Following their release into the cytoplasm, nucleosomes migrate to the surface of the dying cell26 and thus become accessible to B cell receptors. Apoptotic cells are normally inactivated by macrophages. The development of autoimmunity has been linked to defective phagocytosis

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NH2

Ubiquitin

NH2

H3 H2A

NH2

H2B

Regulatory particle NH2

195 cap

H1 Core particle

205 core

195 cap Figure 79-2  Nucleosome. The nucleosome is the fundamental repeating unit of chromatin. The central part of the nucleosome is composed of a tetramer made up of two molecules of histones H3 and H4, flanked by two dimers of histones H2A and H2B. This central core is surrounded by two superhelical turns consisting of 146 base pairs of histone-free DNA. Histone H1 is located at the point where DNA enters and exits the nucleosome. Antibodies to the nucleosome arise early in the evolution of systemic lupus erythematosus, before anti-DNA and antihistone antibodies. Thus, the nucleosome is thought to be an important early autoantigen in the development of epitope spreading. Nucleosome antibodies are also found in scleroderma and mixed connective tissue disease. (From Amoura Z, Koutouzov S, Piette C, et al: The role of nucleosomes in lupus. Curr Opin Rheumatol 12:369-373, 2000.)

of apoptotically released constituents.26 Nucleosomal antibodies are directed to antigenic determinants on the intact nucleosome rather than its individual components—DNA and histones.27 In a study of 496 patients with 13 different DCTDs and 100 patients with hepatitis C, antinucleosome antibodies were found only in the sera of patients with SLE (71.7%), scleroderma (45.9%), and MCTD (45.0%).28 AUTOIMMUNITY TO PROTEASOMAL COMPONENTS The 26S proteasome is a large subcellular particle involved in the degradation of proteins that have been tagged with ubiquitin, resulting in the generation of peptides for presentation by the MHC class I molecules29 (Fig. 79-3). There is increasing evidence that it may be the target of an autoimmune response in DCTD.30 Antibodies to proteasomal subunits have been reported in patients with autoimmune myositis, SLE, and primary Sjögren’s syndrome. Iincreased levels of proteasome subunits have also been detected in the sera of patients with autoimmune myositis, SLE, primary Sjögren’s syndrome, RA, and autoimmune hepatitis; they are correlated with disease activity.31 GENERATION OF AUTOIMMUNITY The antibody response to just one component of an intracellular structure, such as a spliceosome, results in the uptake of the entire particle by antigen processing cells. Thus, all the proteins making up the particle are subject to antigen processing, with potential peptide presentation linked to their affinity for HLA class II antigens. Depending on the polymorphisms of the individual HLA molecules, there is a diversification of the antibody response to include some of these other antigens. This process is called epitope spreading, and it is considered pivotal in the development of the linked

265 proteasome Regulatory particle Figure 79-3  Proteasome. Most proteins in the cytosol and nucleus are degraded via the proteasome-ubiquitin pathway. The 26S proteasome is a huge complex of 2.5 mega-daltons (MD), made up of approximately 35 different subunits. It contains a proteolytic core complex, the 20S proteasome, and one or two 19S regulatory complexes that associate with the termini of the barrel-shaped 20S core. The function of proteasomes is twofold: (1) to degrade intracellular proteins that have been tagged with ubiquitin, and (2) to generate antigenic peptides for presentation by the MHC class I molecules. Antibodies to proteasomal subunits have been reported in several autoimmune diseases (especially systemic lupus erythematosus, polymyostis, and dermatomyositis), and elevated levels of proteasomes have been correlated with disease activity.

a­ ntibody responses observed in different connective tissue diseases.32 For instance, it has been shown that the induction of an immune response to one component of a U-RNP complex can induce a diversified autoantibody response to other components of the complex33 (Fig. 79-4). In this way, an immune response becomes modified over time, and this change has been associated with changes in the clinical ­picture.34 The interaction between T cell receptors and peptides presented by HLA molecules is a critical event in the generation of autoimmunity. The 70-kD anti–U1-RNP antibody response is associated with the HLA-DR4 and DR2 phenotype.35 DNA sequencing of HLA-DB genes has revealed that DR2- and DR4-positive patients share a common set of amino acids in the β chain at positions 26, 28, 30, 31, 32, 70, and 73.36 Such amino acids form a pocket for antigen binding (Fig. 79-5). It is hypothesized that these two HLA subtypes represent a critical genetic specificity for the presentation of antigenic peptides to their cognate T cell receptors. The shared epitope on HLA-DR4/DR2 associated with an anti–U1-RNP response is different from the shared epitope associated with HLA-DR4/DR1 in RA patients.37 The 68-kD polypeptide has several different epitopes, the most consistent sequence being KDK DRD RKR RSS RSR.38 This region is preferentially targeted by MCTD serum but not by SLE serum.39 The autoimmune response to the spliceosome in these three disorders is characterized by different degrees of epitope spreading. The widest range of antibodies, to both small nuclear RNPs and heterogeneous nuclear RNPs, is seen in SLE; a more restricted antispliceosomal antibody repertoire to both types of RNPs is seen in MCTD; and the antispliceosomal antibody repertoire is restricted to heterogeneous nuclear RNPs in RA.40

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Seroconverters for each specificity (%)

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1385

70 kD

70

B′B

60

A

α chain

C

50

D

40 30

30 20

32 31

28 26 70

10

73

0 First

Second

Third

Fourth

β chain

Fifth

Figure 79-4  One hundred sixty-three patients with serial serum samples from 1989 to 1999 were identified from the University of Missouri Antibody Testing Laboratory. All sera tested were initially negative for U1-RNP peptide antibodies, but over the ensuing years, they developed antibodies to at least one U1-RNP peptide. The order in which seroconversion occurred was ranked from first through fifth for 70-kD, B′B, A, C, and D. For each individual peptide, the number of patients in each group divided by the total number of seroconverters for that peptide is shown. The first RNP antibodies to appear were most often directed against the 70-kD and B′B peptides. Antibodies to the A and C peptides usually developed after other RNP peptide antibodies, and antibodies to D often emerged only after immunity to multiple other U1-RNP proteins had appeared. Thus, there seems to be an orderly pattern of emergence of U1-RNP peptide antibodies, with the 70-kD and B′B molecules being important early immunogens in the development of human RNP immunity. (From Hoffman RW, Greidinger EL: The appearance of U1 RNP antibody specificities in sequential autoimmune human antisera follows a characteristic order that implicates the U1-70 kD and B′B proteins as predominant U1 RNP immunogens. Arthritis Rheum 44:368-375, 2001.)

Figure 79-5  DR2- and DR4-positive patients with mixed connective tissue disease share a common set of amino acids in the β chain of both HLA class II molecules at positions 26, 28, 30, 31, 32, 70, and 73. These amino acids form a pocket for antigen binding and are thought to present a restricted set of processed peptides to cognate T cells. (From Kallenberg CG: Overlapping syndromes, undifferentiated connective tissue disease, and other fibrosing conditions. Curr Opin Rheumatol 4:837-842, 1992.)

instance, the U1-70K protein is cleaved by the enzyme caspase-3, converting it into a C-terminally truncated fragment that contains a major B cell epitope that is preferentially recognized by autoimmune sera.46 Over time, it is envisaged that this immune response is modified by epitope spreading, with the resulting generation of the distinctive clinical features of the classic DCTDs such as SLE and MCTD.19,32 Molecular Mimicry

In general, the autoimmune rheumatic diseases are characterized by the production of autoantibodies that recognize evolutionarily conserved molecules. The mechanisms whereby these “hidden” intracellular molecules become autoantigens is an area of ongoing research. The two main theories are apoptotic modification41 and molecular mimicry.42 Apoptotic Modification The biochemical hallmark of apoptosis is the cleavage of DNA into oligonucleotides that produce characteristic “DNA ladders” when separated on agarose gels. Interestingly, similar DNA ladders are found in the serum of lupus patients.43 Although rheumatic disease autoantigens are not unified by a common structure or function, they have the common feature of becoming clustered and concentrated in the surface blebs of apoptotic cells. A population of smaller blebs contains fragmented endoplasmic reticulum and ribosomes, as well as the ribonucleoprotein Ro. Larger blebs (apoptotic bodies) contain nucleosomal DNA, Ro, La, and the small nuclear ribonucleoproteins.44 Apoptosis also generates modified proteins, through cleavage with a class of enzymes called caspases.45 During the process of apoptosis, several enzyme systems are upregulated, resulting in posttranslational modifications of the cleaved proteins.41 These modifications, which include citrullination, phosphorylation, dephosphorylation, transglutamination, and conjugation to ubiquitin, render the molecules more antigenic. For

The initial stimulus for a first antibody response may be a non-self-protein possessing a peptide region that mimics a self-epitope—so-called molecular mimicry.47 Environmental stressors such as infections, toxins, drugs, and ultraviolet light may, under some circumstances, induce accelerated apoptosis.41 A critical limitation to molecular mimicry is the necessity for the antigenic sequence to undergo T cell receptor recognition.48 Helper T lymphocytes (CD4+) usually recognize peptides of 12 to 16 amino acids in the context of HLA class II molecules. However, in some instances, smaller peptides are recognized that may be more immunostimulatory than the parent ligand.49 Such observations indicate that antigen recognition by T cells is highly degenerative and expands the potential for molecular mimicry because the universe of molecules containing a pentapeptide, for example, is manyfold greater than those containing a 12–amino acid residue peptide. Once an immune response to one component of an immunogenic molecular complex has been elicited, other proteins or epitopes of the complex may become antigenic by the process of epitope spreading.

UNDIFFERENTIATED CONNECTIVE TISSUE DISEASE Rheumatologists frequently see patients who present with a weakly positive ANA test and nonspecific symptoms such as arthralgias, fatigue, and cold sensitivity. The critical

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q­ uestion in such patients is whether they will develop a connective tissue disease or whether they have fibromyalgia.50 The answer to this question is not always straightforward, because fibromyalgia is not a diagnosis of exclusion,51 and it is a common comorbidity with well-defined connective tissue diseases.52 In the early stages of a connective tissue disease, there may be only one or two suspicious clinical and laboratory features, and a definitive diagnosis cannot always be made. In such cases, a working diagnosis of UCTD may be appropriate.1,53 Most patients with this diagnosis have Raynaud’s phenomenon with or without an unexplained polyarthralgia and a positive ANA test.54 A 5-year follow-up study of 665 patients with UCTD reported that only 34% developed a well-defined connective tissue disease: RA, 13.1%; Sjögren’s, 6.8%; SLE, 4.2%; MCTD, 4.0%; scleroderma, 2.8%; systemic vasculitis, 3.3%; and PM-DM, 0.5%.2 The highest probability of evolution into a welldefined connective tissue disease was within the first 2 years after onset of symptoms; a complete remission of symptoms occurred in 12.3%. Similar findings have been reported in other series.55,56 An algorithm for evaluating patients with UCTD is given in Figure 79-6. Certain combinations of features are predictive for the development of certain established connective tissue diseases2: polyarthritis plus U1-RNP antibodies predicts MCTD, sicca symptoms plus anti–SS-A/SS-B antibodies predicts Sjögren’s syndrome, Raynaud’s phenomenon plus a nucleolar ANA pattern predicts scleroderma, polyarthritis plus high levels of rheumatoid factor predicts RA, and fever or serositis plus a homogeneous ANA pattern or anti–double-stranded DNA antibodies predicts progression to SLE.

SCLERODERMA OVERLAPS There is a wide variability in disease expression in scleroderma, ranging from diffuse cutaneous disease with a poor prognosis to limited cutaneous involvement with a generally good prognosis. Further, some patients with scleroderma have a prominent overlap with other connective tissue diseases.57 In many cases, these overlaps occur in patients who do not have prominent skin involvement (sine scleroderma); many such patients have features of the CREST sydrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) or incomplete CREST. Approximately 90% of patients with scleroderma have a positive ANA test. Scleroderma-related antibodies include topoisomerase 1 (Scl-70), anticentromere (ACA), heterogeneous nuclear RNP-I, RA33, p23, p25, RNA polymerase I (RNAP-I), RNAP-III, U1-RNP, PM-Scl, fibrillarin, histone, Ku, endothelial cell, and Th/To58 (see Table 79-1). Specific antibody profiles are associated with distinctive patterns of morbidity and mortality.59 Patients with ACA, anti–U3 small nuclear RNP, and anti-Th/To antibodies tend to have the limited form of scleroderma, whereas anti–Scl70, anti-ACA, and anti-RNAP are associated with diffuse skin involvement and systemic disease.59-61 Patients with anti–PM-Scl antibodies may have a myositis-scleroderma overlap and a tendency to develop pulmonary interstitial disease.62,63 Stimulatory antibodies for the platelet-derived growth factor receptor have recently been described as having a high specificity for scleroderma64; it will be interesting to see whether they are also present in scleroderma overlap

s­ yndromes. About 60% of patients with scleroderma have obvious synovitis, and 35% are positive for rheumatoid factor.65 Erosive arthritis in scleroderma has an association with anti-RA33; the scleroderma component in such overlap patients is often an incomplete form of CREST.66 The characteristic vessel pathology in scleroderma is a bland intimal proliferation. Necrotizing vasculitis is rare but has been described in association with a CREST–Sjögren’s syndrome overlap; such patients are often anti-Ro positive.67 The limited form of scleroderma has a well-documented overlap with primary biliary cirrhosis—often referred to as Reynold’s syndrome.68 The distinctive antibody association in this overlap syndrome is antimitochondrial antibodies.69 Conversely, ACA antibodies have been found in 10% to 29% of patients with primary biliary cirrhosis; approximately half developed some features of the CREST syndrome.70 Hence, a serologic overlap between the two syndromes is more prevalent than a clinical overlap. Low-grade muscle involvement is not uncommon in scleroderma, being described in between 50% and 80% of patients.71 A European review of 114 scleroderma overlap patients reported a 95% PM-Scl antibody positivity rate,72 with 80% having inflammatory myositis. This “scleromyositis” differed from MCTD by the presence of coexistent features of DM (myalgia, myositis, Gottron’s sign, heliotrope rash, calcinosis) but no features of SLE—as is characteristic of classic MCTD. Many of these patients had a deforming arthritis of the hands. In general, they had a chronic, benign course; most were steroid responsive. Scleroderma-lupus overlaps are less common. However, scleroderma patients often have ANAs other than ACA and Scl-70. In one report, anti–Scl70 antibodies were found in 25% of SLE patients.73

MYOSITIS OVERLAPS PM, DM, and inclusion body myositis (IBM) are the classic idiopathic inflammatory myopathies (IIMs), yet the same clinical picture and investigational findings may be found in patients with SLE, scleroderma, MCTD, and Sjögren’s syndrome. Such overlaps, especially with scleroderma, are reportedly more common than classic PM.5 When clinical overlaps emerge, they are most commonly associated with specific autoantibodies—namely, anti–PM-Scl, anti-Ku, U1-RNP, Jo-1, signal recognition particle (SRP), and aminoacyl–transfer RNA synthetase (ARS) antibodies.74 The arthropathy associated with PM is characterized by deforming subluxations (particularly of the distal interphalangeal joints and thumbs), with only minor erosive changes.75 Another myositis overlap syndrome is seen in patients with ARS antibodies.76 This is a family of enzymes that catalyze the transfer of a specific amino acid to its cognate transfer RNA77; the most common association is with anti–Jo-1 (histidine–transfer RNA synthetase). The clinical syndromes associated with the various antisynthetase antibodies are similar, with remissions and exacerbations characterized by inflammatory myositis, fever (80%), Ray­ naud’s phenomenon, and skin problems (mechanic’s hands in 70%).78 Arthropathy is seen in 50% to 90% of patients, and interstitial lung disease in 50% to 80%.79 Interstitial lung disease may be a presenting clinical feature of patients with ARS antibodies, with myopathy occurring much later. The association of myositis in patients with anti–U1-RNP

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Suspect a connective tissue disease?

Rule out osteoarthritis, bursitis/tendinitis, myofascial pain, and fibromyalgia

Does the patient have evidence for any of the following problems?

Persistent arthritis Rheumatoid arthritis Psoriatic arthritis Reactive arthritis Rheumatic fever SLE/MCTD Drug-induced lupus Enteropathic arthritis Ankylosing spondylitis Tophaceous gout Lyme disease Acromegaly Hemochromatosis Sarcoidosis Whipple’s disease Polymyalgia rheumatica Malignancy

Episodic arthritis Gout Pseudogout Viral arthritis Palindromic rheumatism Serum sickness Reactive arthritis Bacterial endocarditis Lyme disease Behcet’s disease Relapsing polychondritis Sarcoidosis Sjögren’s syndrome Malignancy

Muscle pain/weakness Inflammatory myositis Vasculitis Metabolic myopathy Drug reaction (e.g., statins) Hypothyroidism Acromegaly Viral infection Overuse syndrome Osteomalacia Vitamin D deficiency Sarcoidosis Polymyalgia rheumatica Sjögren’s syndrome Peripheral neuropathy Hyperparathyroidism

Raynaud’s phenomenon Primary Raynaud’s Scleroderma/MCTD/SLE CREST Myositis overlap Takayasu’s arteritis Vasculitis Thoracic outlet syndrome Antiphospholipid syndrome Thromboangiitis obliterans Atheroembolic disease Cryoglobulinemia Bacterial endocarditis Polycythemia vera Medication induced

If a specific diagnosis can be made, then manage as per contemporary guidelines

If no specific diagnosis can be made, then consider a diagnosis of a UCTD or overlap syndrome. Are any of the following features present?

Clinical features

Autoantibodies

Raynaud’s phenomenon, proximal sclerodactyly, interstitial lung disease, esophageal hypomotility, trigeminal neuropathy, puffy hands

U1-RNP, U2-RNP, U3-RNP, U4-RNP, U5-RNP, Fibrillarin, SRP, anti-trRNA synthetases, PM/Sci, RNA polymerases, anti-Ku, anti-Th

If “YES,” then follow up and treat as a potential overlap syndrome

If “NO,” then treat conservatively and follow for further developments

Figure 79-6  Algorithm for evaluating patients with undifferentiated connective tissue disease (UCTD). CREST, syndrome of calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia; MCTD, mixed connective tissue disease; SLE, systemic lupus erythematosus.

antibodies is usually seen in the context of MCTD. However, some patients with an inflammatory myositis, without Raynaud’s phenomenon, have anti–U1-RNP antibodies in association with interstitial lung disease, arthritis, and neurologic symptoms.80 Antibodies to SRP have been reported in 4% of 265 patients with scleroderma-PM overlap.81

Anti-SRP–positive patients usually have a severe, rapidly progressive myositis with prominent muscle fiber necrosis but not much inflammatory cell infiltration.82 A 2006 clinical and longitudinal study of 100 consecutive French Canadian patients with IIM concluded that the original Bohan and Peter classification of inflammatory

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Table 79-2  Suggested Classification for Inflammatory Myopathies Descriptions Pure polymyositis (PM) Pure dermatomyositis (DM) Overlap myositis (OM): myositis with at least one clinical overlap feature or an overlap autoantibody Cancer-associated myositis (CAM): clinical paraneoplastic features without an overlap autoantibody or anti–Mi-2 Bohan and Peter83 Definition of Myositis 1. Symmetric proximal muscle weakness 2. Elevation of serum skeletal muscle enzymes 3. Electromyographic triad of short, small, polyphasic motor unit potentials; fibrillations, positive sharp waves, and insertional irritability; and bizarre, high-frequency repetitive discharges 4. Muscle biopsy abnormalities of degeneration, regeneration, necrosis, phagocytosis, and interstitial mononuclear infiltrate 5. Typical skin rash of DM, including heliotrope rash, Gottron’s sign, and Gottron’s papules Definite myositis: 4 criteria (without the rash) for PM; 3 or 4 criteria (plus the rash) for DM Probable myositis: 3 criteria (without the rash) for PM; 2 criteria (plus the rash) for DM Possible myositis: 2 criteria (without the rash) for PM; 1 criterion (plus the rash) for DM Definition of Clinical Overlap Features Inflammatory myopathy plus at least one or more of the following clinical findings: polyarthritis, Raynaud’s phenomenon, sclerodactyly, scleroderma proximal to metacarpophalangeal joints, typical SSc-type calcinosis in the fingers, lower esophageal or small-bowel hypomotility, Dlco lower than 70% of normal predicted value, interstitial lung disease on chest radiograph or computed tomography scan, discoid lupus, anti-  native DNA antibodies plus hypocomplementemia, 4 or more of 11 American College of Rheumatology criteria for systemic lupus ­erythematosus, antiphospholipid syndrome Definition of Overlap Autoantibodies Antisynthetases (Jo-1, PL-7, PL-12, OJ, EJ, KS), scleroderma-associated autoantibodies (scleroderma-specific antibodies: centromeres, topoisomerase I, RNA polymerases I or III, Th; and antibodies associated with scleroderma overlap: U1-RNP, U2-RNP, U3-RNP, U5-RNP, Pm-Scl, Ku, and other autoantibodies (signal recognition particle, nucleoporins) Definition of Clinical Paraneoplastic Features Cancer within 3 yr of myositis diagnosis, plus absence of multiple clinical overlap features; plus, if cancer was cured, myositis was cured as well Adapted from Troyanov Y, Targoff IN, Tremblay JL, et al: Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: Analysis of 100 French Canadian patients. Medicine (Baltimore) 84:231-249, 2005.

myopathies should be abandoned, because 60% of patients with IIM were found to have an overlap syndrome.5 In this study, the finding of an overlap syndrome was based on the presence of an inflammatory myopathy per the Bohan and Peter classification,83 plus at least one clinical or autoantibody overlap feature (Table 79-2). The distinction between classic PM and DM and an overlap syndrome was reported to be of prognostic and therapeutic significance.Classic PM nearly always ran a chronic course, with 50% of patients being initially unresponsive to corticosteroid therapy. Pure DM was almost always chronic (92%), but 87% of patients had an initial response to corticosteroids. Myositis overlap syndromes (usually with scleroderma features) were almost always responsive to corticosteroids (~90% response rate). When overlap patients were divided according to antibody subsets, antisynthetase, SRP, and nucleoporin autoantibodies were markers for treatment-resistant myositis, whereas autoantibodies to U1-RNP, Pm-Scl, or Ku were markers for corticosteroid responsiveness.

MIXED CONNECTIVE TISSUE DISEASE Mixed connective tissue disease was described by Sharp and his colleagues84 in a 1971 paper reporting an overlap of SLE, scleroderma, and PM. This was the first overlap syndrome defined in terms of a specific antibody—namely, antibodies to a ribonuclease-sensitive extractable nuclear antigen. Over the last 30 years, many studies have explored the clinical correlates of this antibody system (now called U1-RNP).

SEROLOGIC FEATURES The basic premise of the MCTD concept is that the presence of high-titer anti–U1-RNP antibodies modifies the expression of a DCTD in ways that are relevant to prognosis and treatment.85 The first clue to diagnosing MCTD is usually a positive ANA test with a high-titer speckled pattern. The titer is often greater than 1:1000 and is sometimes greater than 1:10,000. This finding should prompt the measurement of antibodies to U1RNP, Sm, Ro, and La. It is also pertinent to note whether the serum contains antibodies to double-stranded DNA and histones, because patients destined to follow a course most consistent with MCTD have sera with predominant U1-RNP reactivity. Antibodies to double-stranded DNA, Sm, and Ro are occasionally seen as a transient phenomenon in patients with MCTD. When they are found consistently, as the predominant antibody system, the clinical picture is usually more consistent with classic SLE. Antibodies to the 70-kD antigen are most closely associated with the clinical correlates of MCTD,19 ­especially in its apoptotic form.15 CLINICAL FEATURES AND DIAGNOSIS The central premise of the MCTD concept is that of an overlap syndrome that embraces features of SLE, scleroderma, and PM-DM.86 These overlap features of MCTD seldom occur concurrently; it usually takes several years before enough overlapping features have appeared to

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Table 79-3  Diagnostic Criteria for Mixed Connective Tissue Disease Alarcon-Segovia Criteria

Kahn Criteria

Serologic criteria

Anti-RNP at hemagglutination titer of ≥1:1600

High-titer anti-RNP corresponding to a speckled ANA of ≥1:1200 titer

Clinical criteria

1. Swollen hands 2. Synovitis 3. Myositis (biologically proven) 4. Raynaud’s phenomenon 5. Acrosclerosis

1. Swollen fingers 2. Synovitis 3. Myositis 4. Raynaud’s phenomenon

MCTD present if

Serologic criterion accompanied by 3 or more   clinical criteria, one of which must be   synovitis or myositis

Serologic criterion accompanied by Raynaud’s phenomenon and at least 2 of the 3 remaining clinical criteria

ANA, antinuclear antibody; MCTD, mixed connective tissue disease; RNP, ribonucleoprotein particle. From Alarcon-Segovia D, Cardiel MH: Comparison between 3 diagnostic criteria for mixed connective tissue disease: Study of 593 patients. J Rheumatol 16:328-334, 1989; Kahn MF, Appelboom T: Syndrom de Sharp. In Kahn MF, Peltier AP, Meyer O, Piette JC (eds): Les maladies systemiques, 3rd ed. Paris, ­Flammarion, 1991, pp 545-556.

Table 79-4  Differential Features of the Classic Diffuse Connective Tissue Diseases Clinical Feature

SLE

RA

Scleroderma

PM

MCTD

Pleurisy, pericarditis

++++

+

+

−

+++

Erosive joint disease

±

++++

+

±

+

Raynaud’s phenomenon

++

−

++++

+

++++

Inflammatory myositis

+

+

+

++++

+++

Sclerodactyly

±

−

++++

−

++

Nonacral skin thickening

−

−

+++

−

−

Interstitial pulmonary fibrosis

+

+

+++

++

+

Pulmonary hypertension

++

±

+

+

+++

Butterfly rash

++++

−

−

−

++

Oral ulcers

+++

−

−

−

++

Seizures, psychosis

+++

−

−

−

−

Trigeminal neuropathy

+

−

++

−

+++

Peripheral neuropathy

++

++

±

−

++

Transverse myelopathy

+++

+

−

−

++

Aseptic meningitis

+++

+

−

−

+++

Diffuse proliferative glomerulonephritis

++++

−

−

−

+

Membranous glomerulonephritis

+++

−

−

−

++

Renovascular hypertension

+

−

++++

−

+++

Inflammatory vasculitis

++

++

+

+

+

Noninflammatory vasculopathy

−

−

++++

−

+++

Esophageal dysmotility

+

±

++++

+

+++

MCTD, mixed connective tissue disease; PM, polymyositis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.

be confident that MCTD is the most appropriate diagnosis.87 The most common clinical associations with U1-RNP antibodies in the early phase of the disease are hand edema, arthritis, Raynaud’s phenomenon, inflammatory muscle disease, and sclerodactyly.88 There are no American College of Rheumatology (ACR) criteria for the diagnosis of MCTD, but a comparative study reported that two criteria sets, those of Alarcon-Segovia89 and Kahn,90 had the best sensitivity and specificity (62.5% and 86.2%, respectively) (Table 79-3). The sensitivity could be improved to 81.3% if the term myalgia was substituted for myositis.90 In some patients initially diagnosed as having MCTD, the clinical picture evolves into one most consistent with SLE or RA; in one longterm ­follow-up, more than half the subjects continued to ­satisfy criteria for MCTD.91 A comparison of the clinical

and serologic features of MCTD, SLE, RA, scleroderma, and PM is given in Table 79-4. Early Symptoms In the early stages, most patients destined to develop MCTD cannot be differentiated from those with other classic DCTDs. The assumption that a diagnosis of MCTD implies the simultaneous presence of features usually seen in SLE, scleroderma, and PM is erroneous; it is unusual to see this overlap early in the course of MCTD, but with time, the overlapping features usually occur sequentially. Most patients complain of easy fatigability, poorly defined myalgias, arthralgias, and Raynaud’s phenomenon; at this point, a diagnosis of RA, SLE, or UCTD seems most appropriate.1 If such a patient is found to have swollen hands or puffy

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of a seronegative spondyloarthropathy (Fig. 79-8). Positive rheumatoid factor is found in 50% to 70% of patients; indeed, patients may be diagnosed as having RA and fulfill the ACR criteria for that disease.87 Joint histology in MCTD reveals a hyperplastic synovium with surface fibrinoid necrosis, increased vascularity, interstitial edema, and infiltration of macrophages, lymphocytes, neutrophils, and multinucleated giant cells.95 Skin and Mucous Membranes

Figure 79-7  Hand of a man with mixed connective tissue disease. The fingers have a generally puffy appearance, with a fusiform proximal interphalangeal joint and swelling of the third finger from inflammatory arthritis. There is a periungual infarct at the nail fold of the third finger. (Adapted from Pope JE: Other manifestations of mixed connective tissue disease. Rheum Dis Clin North Am 31:519-533, 2005.)

fingers (Fig. 79-7) in association with a high-titer speckled ANA, he or she should be carefully followed for the evolution of overlap features. A high titer of anti-RNP antibodies in a patient with UCTD is a powerful predictor of eventual evolution into MCTD19; this highlights the importance of anti-RNP antibodies as a serologic marker for MCTD.85 Less commonly, there is an acute onset of MCTD, providing few clues to the subsequent course; such presentations may include PM, acute arthritis, aseptic meningitis, digital gangrene, high fever, acute abdomen, and trigeminal neuropathy. Fever Fever may be a prominent feature of MCTD, with no obvious cause.87 Fever of unknown origin may be the initial presentation of MCTD; however, after careful evaluation, the fever can usually be traced to a coexistent myositis, aseptic meningitis, serositis, lymphadenopathy, or intercurrent infection.

Most patients with MCTD develop mucocutaneous changes sometime during the course of the syndrome. Raynaud’s phenomenon is the most common problem and one of the earliest manifestations of MCTD.96 It may be accompanied by puffy, swollen digits (see Fig. 79-7) and sometimes total hand edema.92 In some patients, skin changes commonly associated with classic SLE are prominent findings, particularly malar rash and discoid plaques.97 Other problems include buccal ulceration, sicca complex, orogenital ulceration, livedo vasculitis, subcutaneous nodules, and nasal septal perforation. Muscle Myalgia is a common symptom in patients with MCTD syndrome.98 In most cases, there is no demonstrable weakness, electromyogram abnormalities, or muscle enzyme changes. It is often unclear whether the symptom represents a lowgrade myositis, physical deconditioning, or an associated fibromyalgia syndrome. The inflammatory myopathy associated with MCTD is similar histologically to IIM,99,100 with features of both the vascular involvement of DM and the cell-mediated changes of PM101 (Fig. 79-9). In most patients, myositis occurs as an acute flare against a background of general disease activity. Such patients usually respond well to a short course of high-dose corticosteroid therapy. Another scenario is that of a low-grade inflammatory myopathy that is often insidious in onset; these patients often have a poor therapeutic response to corticosteroids. Some patients with PM associated with MCTD develop an impressive fever87; other patients may give a history of febrile myalgias that were diagnosed as “flu.” Heart

Joints Joint pain and stiffness is an early symptom in nearly all patients who develop MCTD syndrome. It has become increasingly apparent that joint involvement in MCTD is more common and more severe than in classic SLE.92 About 60% of patients eventually develop an obvious arthritis, often with deformities commonly seen in RA, such as ulnar deviation, swan neck, and boutonnière changes.93 Radiographs usually show a characteristic absence of severe erosive changes; they often resemble Jaccoud’s arthropathy. However, destructive arthritis, including arthritis mutilans, is a well-established association.93 Small marginal erosions, often with a well-demarcated edge, are the most characteristic radiographic feature in patients with severe joint disease.94 Some patients develop flexor tenosynovitis, bone edema, and pericapsular inflammation, reminiscent

All three layers of the heart may be involved in MCTD.102 An abnormal electrocardiogram (ECG) is noted in about 20% of patients. The most common ECG changes are right ventricular hypertrophy, right atrial enlargement, and interventricular conduction defects. Pericarditis is the most common clinical manifestation of cardiac involvement, being reported in 10% to 30% of patients; pericardial tamponade is rare. Involvement of the myocardium is increasingly recognized.103,104 In some patients, myocardial involvement is secondary to pulmonary hypertension, which is often asymptomatic in its early stages and thus may be underdiagnosed.105 The early detection of pulmonary hypertension is increasingly important because there are now more effective therapeutic options. In the setting of a community rheumatology practice, an elevation of the estimated right ventricular systolic pressure, consistent

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*

A

B

C

D

Figure 79-8  Magnetic resonance images of the hands in two women aged 25 and 32 years with mixed connective tissue disease and hand arthritis. A, Patient 1 has synovitis or effusion around the ulnar styloid (asterisk) and tenosynovitis of the flexor and extensor tendons (arrows) on a T1-weighted gadolinium-enhanced sequence in the axial plane. B, Patient 2 has intense synovitis of the radioulnar joint (asterisk) and extensor tenosynovitis (arrows), causing thickening of the dorsum of the hand on a T1-weighted short tau inversion recovery [STIR] sequence in the axial plane.  C, In patient 1, synovitis or effusion and pericapsular edema are seen in the second proximal interphalangeal joint. The distended capsule is indicated by arrows. D, In patient 2, intracapsular synovial effusion or synovitis of the third and fourth metacarpophalangeal joints (arrows) are seen. (Both C and  D are T1-weighted STIR sequences in the coronal plane.) (From Cimmino MA, Iozzelli A, Garlaschi G, et al: Magnetic resonance imaging of the hand in mixed connective tissue disease. Ann Rheum Dis 62:380-381, 2003.)

A

B

Figure 79-9  Right biceps muscle biopsy from a 64-year-old woman with mixed connective tissue disease complicated by an inflammatory myopathy and a “scleroderma” renal crisis. The biopsy shows a perivascular infiltrate consisting mainly of CD4+ and CD8+ lymphocytes (A). There are scattered necrotic muscle fibers but no evidence of endomysial invasion by inflammation. The walls of many capillaries, arterioles, and venules had a thickened, pipe-stem appearance (see arrow in B; magnification ×230). (From Greenberg SA, Amato AA: Inflammatory myopathy associated with mixed connective tissue disease and scleroderma renal crisis. Muscle Nerve 24:1562-1566, 2001.)

with the diagnosis of pulmonary hypertension, was found in 13% of previously undiagnosed subjects.106 This diagnosis should be suspected in patients with increasing exertional dyspnea. Two-dimensional echocardiography with Doppler flow studies is the most useful screening test.107 A definitive diagnosis requires cardiac catheterization

showing a mean resting pulmonary artery pressure greater than 25 mm Hg at rest.108 The development of pulmonary hypertension has been correlated with a nail-fold capillary pattern similar to that seen in scleroderma, anti–endothelial cell antibodies, anticardiolipin antibodies, and anti– U1-RNP antibodies.109,110

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A

B

Figure 79-10  Computed tomography scans of a patient with mixed connective tissue disease and pulmonary hypertension (A, upper zones; B, lower zones). There are bilateral pleural effusions and enlarged bilateral mediastinal lymph nodes in the right paratracheal region and left prevascular areas. The pulmonary artery has a diameter greater than that of the ascending aorta, consistent with the diagnosis of pulmonary hypertension. Both hilar pulmonary arteries are also enlarged. A fairly large pericardial effusion is present. The lung windows show evidence of a diffuse abnormality, with linear opacities and some areas of ground-glass attenuation in the upper zones. At the lung bases, there are more confluent opacities, both reticular and ground glass, and some air-space consolidation. No honeycombing is identified, and there is no distortion of the lung architecture. (From Saito Y, Terada M, Ishida T, et al: Pulmonary involvement in mixed connective tissue disease: Comparison with other collagen vascular diseases using high resolution CT. J Comput Assist Tomogr 26:349-357, 2002.)

lower lobe predominance.113 If untreated, interstitial lung disease is usually progressive, with the development of severe pulmonary fibrosis in 25% of subjects after 4 years of follow-up.112 As noted earlier, pulmonary hypertension is the most severe form of pulmonary involvement in MCTD.111 Unlike scleroderma, in which pulmonary hypertension is usually secondary to interstitial pulmonary fibrosis, pulmonary hypertension in MCTD is usually caused by a bland intimal proliferation and medial hypertrophy of pulmonary arterioles111 (Fig. 79-11). Kidney

Figure 79-11  Intimal hyperplasia and smooth muscle hypertrophy without accompanying inflammation are the characteristic features of the vasculopathy of mixed connective tissue disease. When it occurs in the lung, as shown here, it may give rise to severe pulmonary hypertension. (Note the absence of pulmonary fibrosis.) The plexiform lesion  (arrow) is a characteristic pathologic finding in this disease process. (From Bull TM, Fagan KA, Badesch DB: Pulmonary vascular manifestations of mixed connective tissue disease. Rheum Dis Clin North Am 31:451-464, 2005.)

Lung Lung involvement occurs in up to 75% of patients and is usually asymptomatic in the early stages.105 Early symptoms that should prompt a more thorough investigation are dry cough, dyspnea, and pleuritic chest pain.111 Interstitial lung disease occurs in 30% to 50% of subjects.112 High-resolution computed tomography is the most sensitive test to determine the presence of interstitial lung disease (Fig. 79-10), and lung scintigraphy with 99mTc-DTPA is proving to be a useful screening test that also shows sensitivity to improvement with immunosuppressive therapy.105 The most common high-resolution computed tomography findings are septal thickening and ground-glass opacities with a ­peripheral or

In the initial description of MCTD, renal involvement was considered rare.86 After some 3 decades of observation, it is now evident that renal involvement occurs in about 25% of patients.92 However, high titers of anti–U1-RNP antibodies are relatively protective against the development of diffuse proliferative glomerulonephritis, irrespective of whether they occur in a setting of classic SLE or MCTD.114 When patients with MCTD do develop renal changes, they usually take the form of a membranous glomerulonephritis.115 This is often asymptomatic but may sometimes cause an overt nephrotic syndrome.114 The development of diffuse proliferative glomerulonephritis or parenchymal interstitial disease has been rarely recorded in MCTD.114 There is increasing recognition that MCTD patients are at risk of developing a renovascular hypertensive crisis similar to the scleroderma kidney.92 Gastrointestinal Tract Gastrointestinal involvement is a major feature of the overlap with scleroderma, occurring in about 60% to 80% of patients.92,116 The most common abdominal problem in MCTD is disordered motility in the upper gastrointestinal tract. There have been case reports of hemoperitoneum, hematobilia, duodenal bleeding, megacolon, pancreatitis, ascites, protein-losing enteropathy, primary biliary cirrhosis,

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Figure 79-12  A, Digital angiogram showing multiple arterial occlusions with collateral formation. B, Digital angiogram showing ulnar artery ­occlusions. (From Peller JS, Gabor GT, Porter JM, Bennett RM: Angiographic findings in mixed connective tissue disease: Correlation with fingernail capillary photomicroscopy and digital photoplethysmography findings. Arthritis Rheum 28:768, 1985.)

B

portal hypertension, pneumatosis intestinalis, and autoimmune hepatitis.92 Abdominal pain in MCTD may result from bowel hypomotility, serositis, mesenteric vasculitis, colonic perforation, and pancreatitis. Malabsorption syndrome can occur secondary to small bowel dilation with bacterial overgrowth. Liver involvement in the form of chronic active hepatitis and Budd-Chiari syndrome has been described. Pseudodiverticula, identical to those seen in SCC, may be seen along the antimesenteric border of the colon. Nervous System In keeping with Sharp’s original description, central nervous system (CNS) involvement is not a conspicuous clinical feature of MCTD. There is general agreement that the most common problem is trigeminal neuropathy.117 This is of some heuristic interest, because it is also the most frequent CNS manifestation of scleroderma. In a review of 81 cases of trigeminal neuropathy seen in a neurology clinic, the most frequently associated connective tissue diseases were UCTD (47%), MCTD (26%), and scleroderma (19%).118 In a few instances, trigeminal neuropathy has been the presenting feature of MCTD. In contrast to CNS involvement in classic SLE, frank psychosis and convulsions have rarely been reported in MCTD.119 Headaches are a relatively common symptom in MCTD; in the majority of patients, they are probably vascular in origin, with many of the components of classic migraine.120 In a subset of these patients, signs of meningeal irritation develop, and examination of the cerebrospinal fluid reveals the changes of aseptic meningitis.121 Aseptic meningitis in MCTD has also been described as a hypersensitivity reaction to nonsteroidal anti-inflammatory drugs, particularly sulindac and ibuprofen. There are isolated reports of transverse myelitis, cauda equina syndrome, cerebral hemorrhage, retinal vasculitis, optic neuropathy, progressive multifocal leukoencephalopathy, cold-induced brain ischemia, myasthenia gravis, polyradiculopathy, demyelinating disorder, and peripheral neuropathy.

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Blood Vessels Raynaud’s phenomenon is an early feature in nearly all patients who are eventually diagnosed with MCTD.96 A bland intimal proliferation and medial hypertrophy affecting medium and small vessels is the characteristic vascular lesion of MCTD122 (see Fig. 79-11), and it is the characteristic pathology in pulmonary hypertension and renovascular crisis.123 This vascular lesion differs from the usual changes encountered in SLE, in which a perivascular inflammatory infiltrate and fibrinoid necrosis are more characteristic. An angiographic study reported a high prevalence of mediumsize vessel occlusion124 (Fig. 79-12). Fingernail capillaroscopy is abnormal in most MCTD patients, with the same pattern of capillary dilation and dropout that has been reported in scleroderma.124 In one study, all MCTD patients had a scleroderma-like capillaroscopy pattern; a “bushy organization” was noted in 73%—a finding reputed to have an 87% predictive value.125 It appears that a scleroderma pattern on nail-fold capillaroscopy is a distinctive feature of MCTD that is not seen in classic SLE.126 Anti–endothelial cell antibodies have been reported in 45% of patients with MCTD; the presence of these antibodies tends to correlate with pulmonary changes and spontaneous abortion.127 Anti–U1-RNP antibodies may have a pathologic role in the small vessel pathology of MCTD because they induce the release of proinflammatory cytokines from cultured endothelial cells.128 Blood Hematologic abnormalities are common in MCTD. Anemia is found in 75% of patients; the usual profile is most consistent with the anemia of chronic inflammation.92 A positive Coombs test is seen in about 60% of patients, but an overt hemolytic anemia is uncommon.129 As in SLE, a leukopenia affecting mainly the lymphocyte series is seen in about 75% of patients and tends to correlate with disease activity.92 Less common associations are

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t­ hrombocytopenia, thrombotic thrombocytopenic purpura, and red cell aplasia. Hypocomplementemia has been described in several studies,92 but it is not as prevalent as in classic SLE and has not been correlated with any particular clinical situation. Positive tests for rheumatoid factor have been found in about 50% of patients.130 The presence of rheumatoid factor is associated with more severe degrees of arthritis, especially if anti-A2/RA33 is also present.40 Anticardiolipin antibodies or lupus anticoagulants have also been reported.92 Unlike the anticardiolipin antibodies found in SLE, they are β2­glycoprotein independent131 and tend to be associated with thrombocytopenia rather than thrombotic events.132 PREGNANCY Reports of maternal and fetal morbidity in MCTD are quite diverse.133 In a comparison study of patients with MCTD and SLE, fertility rates were unaltered in both diseases, whereas parity and fetal wastage were increased in both.134 Some studies have reported an exacerbation of MCTD during pregnancy and postpartum flares,134 while others have not.87,135 The mechanism for pregnancy complications is probably an autoimmune reaction against placental tissues, with immunostaining studies showing deposits of fibrinogen, immunoglobulin (Ig) G, IgM, IgA, and complement 3 (C3) localized to the trophoblast basement membrane.136 Further, there is an association between anti–endothelial cell antibodies and spontaneous abortion in MCTD.137 A single case of neonatal “lupus” has been reported, suggesting a pathogenic role for anti–U1-RNP antibodies.138 JUVENILE MIXED CONNECTIVE TISSUE DISEASE MCTD may first become apparent in childhood. Some reports suggest that juvenile MCTD is relatively benign,139-141 while others describe a mortality pattern similar to that of juvenile SLE, DM, and scleroderma.142 Significant myocarditis, glomerulonephritis, thrombocytopenia, seizures, hemolytic uremic syndrome, acute coronary syndrome, and aseptic meningitis have been described.143-145

MANAGEMENT OF OVERLAP SYNDROMES The rational management of overlap syndromes is confounded by the absence of controlled trials. Recommendations for management are based on conventional treatments for SLE, PM, DM, RA, and scleroderma.146 General guidelines for treating specific features of the overlap syndromes are given in Table 79-5. Pulmonary hypertension is the main cause of death in MCTD, and patients should be evaluated at regular intervals for its development, because early intervention is the key to effective management.147 Recent advances in the treatment of pulmonary hypertension have led to reduced morbidity and mortality.148 Effective management requires ­anticoagulation and vasodilator therapy, such as calcium channel blockers or prostacyclin analogues. Long-term treatment with intravenous epoprostenol or prostacyclin improves exercise capacity, hemodynamics, and survival in many patients,149 as does therapy with inhaled

­iloprost.150 There is evidence that some patients respond to a regimen of intravenous cyclophosphamide and corticosteroids.151 Bosentan, an oral endothelin-1 antagonist, has been reported to improve dyspnea and slow disease progression.152,153 Many of the problems causing morbidity tend to be intermittent and responsive to corticosteroids, including aseptic meningitis, myositis, pleurisy, pericarditis, and myocarditis. Conversely, nephrotic syndrome, Raynaud’s phenomenon, deforming arthropathy, acrosclerosis, and peripheral neuropathies are usually steroid resistant. Many scleroderma-like problems can be managed according to the usual practices in treating scleroderma, such as management of renal crisis with angiotensin-converting enzyme inhibitors, Raynaud’s phenomenon with calcium channel blockers, and gastrointestinal reflux disease with proton pump inhibitors.96 As in SLE, it is worthwhile to consider the use of intravenous gammaglobulin154,155 or danazol156 in patients with steroid-resistant thrombocytopenia, refractory myositis, or hemolytic anemia. Successful autologous peripheral blood stem cell transplantation has been reported in a patient with refractory mysositis and MCTD.157 Over the long term, concern usually mounts over the total corticosteroid burden and the possibility of inducing an iatrogenic steroid myopathy, nosocomial infection, aseptic necrosis of bone, or accelerated osteoporosis. Routine evaluation of bone mineral density is warranted to detect early, presymptomatic osteoporosis and initiate therapy with antiresorptive agents. Unless contraindicated, all patients should take supplementary calcium and vitamin D. Postmenopausal patients should be offered estrogen-progesterone replacement therapy or raloxifene, unless there are specific contraindications; anecdotally, estrogen therapy has not been associated with flares of overlap connective tissue diseases. In patients requiring long-term corticosteroids, it is reasonable to use antimalarials158,159 or methotrexate160 in an attempt to minimize the cumulative steroid burden. As in SLE, the tumor necrosis factor inhibitor etanercept has been reported to exacerbate MCTD.161 Digitalis is relatively contraindicated in patients with myocarditis, owing to the risk of inducing ventricular arrhythmias. Antimalarials should be used with caution in overlap patients with fascicular or bundle branch block, owing to the risk of causing complete heart block162; these drugs can also cause an idiosyncratic hepatitis.163 Patients with severe hand deformities may be helped by soft tissue release operations and selected joint fusions. The management of pregnancy presents several special problems. Doria and colleagues164 have provided the following general advice: (1) patients should be correctly informed about the risk of becoming pregnant; (2) pregnancies should be planned when the disease is in remission, because doing so increases the probability of successful maternal and fetal outcome; (3) patients should be regularly monitored during gestation and post partum by a multidisciplinary team including a rheumatologist, obstetrician, and neonatologist; and (4) in the case of disease relapse, adequate treatment— even aggressive, if necessary—should be recommended, because active disease can be more detrimental to the fetus than drugs are.

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Table 79-5  Guidelines for Managing Overlap Syndromes Problem

Treatment

Fatigue, arthralgias, myalgias

NSAIDs, antimalarials, low-dose prednisone (<10 mg/day); trial use of modafinil

Arthritis

NSAIDs, antimalarials, methotrexate (?), TNF inhibition*

Raynaud’s phenomenon

Keep warm, avoid finger trauma, avoid beta blockers, stop smoking; dihydropyridine calcium channel blocker (e.g., nifedipine), α-sympatholytic (e.g., prazosin); consider endothelin receptor antagonist (e.g., bosentan) in recalcitrant cases

Acute-onset digital gangrene

Local chemical sympathectomy (infiltration of lidocaine at base of involved digit), anticoagulation, topical nitrates; consider hospitalization for intra-arterial prostacyclin; start endothelin receptor antagonist therapy

Pleurisy

NSAID or short course of prednisone (≈20 mg/day)

Pericarditis

NSAID or short course of prednisone (≈20 mg/day); tamponade requires percutaneous or surgical drainage

Aseptic meningitis

Discontinue NSAIDs†; short course of high-dose prednisone (≈60 mg/day)

Myositis

Acute onset, severe: prednisone 60-100 mg/day Chronic, low grade: prednisone 10-30 mg/day‡ Consider methotrexate or IVIG in recalcitrant cases

Membranous glomerulonephropathy

Mild: no treatment required Progressive proteinuria: trial of ACE inhibitor; trial of low-dose aspirin combined with dipyridamole Severe: trial of prednisone 15-60 mg/day plus monthly pulse cyclophosphamide or daily chlorambucil

Nephrotic syndrome

Steroids alone are seldom effective; low-dose aspirin combined with dipyridamole to prevent thrombotic complications; ACE inhibitor to reduce protein loss; trial of prednisone 15-60 mg/day plus monthly pulse cyclophosphamide or daily chlorambucil; dialysis or transplantation may be required

Scleroderma-like renal crisis

ACE inhibitor

Myocarditis

Trial of steroids and cyclophosphamide; avoid digoxin§

Incomplete heart block

Avoid chloroquine¶

Asymptomatic pulmonary hypertension

Trial of steroids and cyclophosphamide, low-dose aspirin and ACE inhibitors; consider endothelin receptor antagonist (oral bosentan)

Symptomatic pulmonary hypertension

Intravenous prostacyclin, ACE inhibitors, anticoagulation, endothelin receptor antagonist (oral bosentan); trial of sildenafil; heart-lung transplantation

Aseptic meningitis

Discontinue NSAIDs and give short course of high-dose prednisone (≈80 mg/day)

Vascular headache

Trial of propranolol, alternate-day aspirin 350 mg, or both; symptomatic use of a triptan   (e.g., sumatriptan, eletriptan)

Autoimmune anemia, thrombocytopenia

High-dose steroids (e.g., prednisone 80 mg/day), with taper dependent on clinical course; consider danazol, IVIG, and immunosuppression in recalcitrant cases

Thrombotic thrombocytopenic purpura

Immediate infusion of fresh frozen plasma; may require plasma exchange and transfusion of   platelet-depleted RBCs; consider splenectomy in recalcitrant cases

Dysphagia

Mild: no treatment With reflux: proton pump inhibitor; consider Nissen fundoplication Severe: calcium channel antagonist, alone or in combination with anticholinergic agent

Intestinal dysmotility

Prokinetic agents (e.g., metoclopramide) and erythromycin Small bowel bacterial overgrowth: tetracycline, erythromycin

Osteoporosis

Calcium, vitamin D supplements; estrogen replacement or raloxifene; biphosphonates; nasal   calcitonin; carboxyl truncated PTH analogues such as hPTH-(1-34)

Heartburn, dyspepsia

Raise head of bed, discontinue smoking, lose weight, avoid caffeine; H2 antagonists, H+ proton pump blockers; trial of metoclopramide; consider Helicobacter pylori infection in recalcitrant cases

Trigeminal neuropathy

No effective therapy for numbness; trial of an antiepileptic (e.g., gabapentin) or tricyclic   antidepressant (e.g., nortriptyline) for pain

*Has been associated with flares in MCTD and SLE. †Sulindac and ibuprofen have been associated with a hypersensitivity aseptic meningitis. ‡Remain alert for steroid myopathy, aseptic necrosis of bone, and accelerated osteoporosis. §Predisposes to ventricular arrhythmias. ¶Predisposes to complete heart block. ¶Cannot be used if esophagus is more than mildly involved. ACE, angiotensin-converting enzyme; IVIG, intravenous immunoglobulin; NSAID, nonsteroidal anti-inflammatory drug; PTH, parathyroid hormone; RBC, red blood cell; TNF, tumor necrosis factor.

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There is often a tendency to assume that all patients with overlap connective tissue diseases should be on long-term corticosteroids; this mistake is compounded by the assumption that all medical problems in these patients are related to their underlying disease. For instance, apparent flares of discomfort and pain in overlap syndromes may be due to myofascial pain syndrome or fibromyalgia and thus are unresponsive to corticosteroids.165,166 Likewise, malaise and easy fatigability may be related to a reactive depression or the fact that the patient has become deconditioned. There is increasing recognition that a person’s ability to deal effectively with a chronic rheumatic disease is a result of many variables, including level of education, level of aerobic fitness, associated depression, strong locus of internal control, and adequate social support framework. The management of patients with overlap syndromes requires a continual reassessment of an ever-changing pattern of clinical problems and a constant alertness to the development of iatrogenic disease. As with any disease of unknown cause, effective management of overlap syndromes presents a constant and evolving challenge.

PROGNOSIS There is increasing evidence that the prognosis for overlap syndromes is often better than that for classic DCTDs.5 For instance, Troyanov and coworkers5 reported on the follow-up of 100 patients with IIM and found that the longterm course after treatment with prednisone (with a dose and duration that initially resulted in good symptomatic improvement) was very different. All PM patients (100%) and most DM patients (92%) progressed to chronic myositis, whereas only 58% of overlap patients developed persistent muscle disease. The tendency for overlap patients to develop chronic disease was more common in those with antisynthetase and nucleoporin antibodies (95%) and less common in those with antibodies to U1-RNP, Pm-Scl, or Ku (42%). The original description of MCTD stressed two points: “a relatively good prognosis and an excellent response to corticosteroids.”86 With the benefit of more than 3 decades of experience, it is apparent that both these claims need to be qualified.167 There is now unequivocal evidence that patients with high-titer U1-RNP antibodies have a low prevalence of serious renal disease and life-threatening neurologic problems; in this sense, MCTD compares favorably with classic SLE. However, not all patients with MCTD have a favorable prognosis, and death may occur from progressive pulmonary hypertension and its cardiac sequelae.123 Rare causes of death are myocarditis,103 renovascular hypertension, and cerebral hemorrhage.168,169 A 29-year follow-up of 47 MCTD patients from Sharp’s group at the University of Missouri reported a favorable course in 62% and continuing active disease in 38%. Eleven patients (23%) had a fatal outcome; death was related to pulmonary hypertension in 9 patients, and two deaths were unrelated to MCTD.123 It is evident that the course of MCTD and other overlap syndromes is unpredictable; in many patients, the disease follows a relatively benign course, but major organ involvement ultimately dictates the morbidity and mortality of the disease.

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76. Targoff IN: Idiopathic inflammatory myopathy: Autoantibody update. Curr Rheumatol Rep 4:434-441, 2002. 77. Mathews MB, Bernstein RM: Myositis autoantibody inhibits histidyltRNA synthetase: A model for autoimmunity. Nature 304:177-179, 1983. 78. Marguerie C, Bunn CC, Beynon HL, et al: Polymyositis, pulmonary fibrosis and autoantibodies to aminoacyl-tRNA synthetase enzymes. QJM 77:1019-1038, 1990. 79. Schmidt WA, Wetzel W, Friedlander R, et al: Clinical and serological aspects of patients with anti-Jo-1 antibodies—an evolving spectrum of disease manifestations. Clin Rheumatol 19:371-377, 2000. 80. Coppo P, Clauvel JP, Bengoufa D, et al: Inflammatory myositis associated with anti-U1-small nuclear ribonucleoprotein antibodies: A subset of myositis associated with a favourable outcome. Rheumatology (Oxford) 41:1040-1046, 2002. 81. Targoff IN, Johnson AE, Miller FW: Antibody to signal recognition particle in polymyositis. Arthritis Rheum 33:1361-1370, 1990. 82. Miller T, Al Lozi MT, Lopate G, Pestronk A: Myopathy with antibodies to the signal recognition particle: Clinical and pathological features. J Neurol Neurosurg Psychiatry 73:420-428, 2002. 83. Bohan A, Peter JB, Bowman RL, Pearson CM: Computer-assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine (Baltimore) 56:255-286, 1977. 84. Sharp GC, Irvin WS, LaRoque RL, et al: Association of autoantibodies to different nuclear antigens with clinical patterns of rheumatic disease and responsiveness to therapy. J Clin Invest 50:350-359, 1971. 85. Aringer M, Steiner G, Smolen JS: Does mixed connective tissue disease exist? Yes. Rheum Dis Clin North Am 31:411-420, 2005. 86. Sharp GC, Irvin WS, Tan EM, et al: Mixed connective tissue disease: An apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen. Am J Med 52:148-159, 1972. 87. Bennett RM, O’Connell DJ: Mixed connective tisssue disease: A clinicopathologic study of 20 cases. Semin Arthritis Rheum 10: 25-51, 1980. 88. Venables PJ: Mixed connective tissue disease. Lupus 15:132-137, 2006. 89. Alarcon-Segovia D, Cardiel MH: Comparison between 3 diagnostic criteria for mixed connective tissue disease: Study of 593 patients. J Rheumatol 16:328-334, 1989. 90. Kahn MF, Appelboom T: Syndrom de Sharp. In Kahn MF, Peltier AP, Meyer O, Piette JC (eds): Les maladies systemiques, 3rd ed. Paris, Flammarion, 1991, pp 545-556. 91. van den Hoogen FH, Spronk PE, Boerbooms AM, et al: Long-term follow-up of 46 patients with anti-(U1)snRNP antibodies. Br J Rheumatol 33:1117-1120, 1994. 92. Pope JE: Other manifestations of mixed connective tissue disease. Rheum Dis Clin North Am 31:519-533, 2005. 93. Bennett RM: O’Connell DJ: The arthritis of mixed connective tissue disease. Ann Rheum Dis 37:397-403, 1978. 94. Udoff EJ, Genant HK, Kozin F, Ginsberg M: Mixed connective tissue disease: The spectrum of radiographic manifestations. Radiology 124:613-618, 1977. 95. Fujinami M, Saito K, Okawa-Takatsuji M, et al: Histological evaluation of destructive monoarthropathy in mixed connective tissue disease. Scand J Rheumatol 26:395-398, 1997. 96. Grader-Beck T, Wigley FM: Raynaud’s phenomenon in mixed connective tissue disease. Rheum Dis Clin North Am 31:465-481, 2005. 97. Gilliam JN, Prystowsky SD: Conversion of discoid lupus erythematosus to mixed connective tissue disease. J Rheumatol 4:165-169, 1977. 98. Hall S, Hanrahan P: Muscle involvement in mixed connective tissue disease. Rheum Dis Clin North Am 31:509-517, 2005. 99. Oxenhandler R, Hart M, Corman L, et al: Pathology of skeletal muscle in mixed connective tissue disease. Arthritis Rheum 20:985-988, 1977. 100. Greenberg SA, Amato AA: Inflammatory myopathy associated with mixed connective tissue disease and scleroderma renal crisis. Muscle Nerve 24:1562-1566, 2001. 101. Vianna MA, Borges CT, Borba EF, et al: Myositis in mixed connective tissue disease: A unique syndrome characterized by immunohistopathologic elements of both polymyositis and dermatomyositis. Arq Neuropsiquiatr 62:923-934, 2004. 102. Lundberg IE: Cardiac involvement in autoimmune myositis and mixed connective tissue disease. Lupus 14:708-712, 2005.

103. Whitlow PL, Gilliam JN, Chubick A, Ziff M: Myocarditis in mixed connective tissue disease: Association of myocarditis with antibody to nuclear ribonucleoprotein. Arthritis Rheum 23:808-815, 1980. 104. Lash AD, Wittman AL, Quismorio FP Jr: Myocarditis in mixed connective tissue disease: Clinical and pathologic study of three cases and review of the literature. Semin Arthritis Rheum 15:288-296, 1986. 105. Sullivan WD, Hurst DJ, Harmon CE, et al: A prospective evaluation emphasizing pulmonary involvement in patients with mixed connective tissue disease. Medicine (Baltimore) 63:92-107, 1984. 106. Wigley FM, Lima JA, Mayes M, et al: The prevalence of undiagnosed pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community-based rheumatologists (the UNCOVER study). Arthritis Rheum 52:2125-2132, 2005. 107. McGoon MD: The assessment of pulmonary hypertension. Clin Chest Med 22:493-508, 2001. 108. Chemla D, Castelain V, Herve P, et al: Haemodynamic evaluation of pulmonary hypertension. Eur Respir J 20:1314-1331, 2002. 109. Bodolay E, Csipo I, Gal I, et al: Anti-endothelial cell antibodies in mixed connective tissue disease: Frequency and association with clinical symptoms. Clin Exp Rheumatol 22:409-415, 2004. 110. Vegh J, Szodoray P, Kappelmayer J, et al: Clinical and immunoserological characteristics of mixed connective tissue disease associated with pulmonary arterial hypertension. Scand J Immunol 64:69-76, 2006. 111. Bull TM, Fagan KA, Badesch DB: Pulmonary vascular manifestations of mixed connective tissue disease. Rheum Dis Clin North Am 31:451-464, 2005. 112. Vegh J, Szilasi M, Soos G, et al: Interstitial lung disease in mixed connective tissue disease. Orv Hetil 146:2435-2443, 2005. 113. Kozuka T, Johkoh T, Honda O, et al: Pulmonary involvement in mixed connective tissue disease: High-resolution CT findings in 41 patients. J Thorac Imaging 2001; 16(2):94-98. 114. Kitridou RC, Akmal M, Turkel SB, Ehresmann GR, Quismorio FP, Jr, Massry SG: Renal involvement in mixed connective tissue disease: A longitudinal clinicopathologic study. Semin Arthritis Rheum 16:135-145, 1986. 115. Bennett RM, Spargo BH: Immune complex nephropathy in mixed connective tissue disease. Am J Med 63:534-541, 1977. 116. Marshall JB, Kretschmar JM, Gerhardt DC, et al: Gastrointestinal manifestations of mixed connective tissue disease. Gastroenterology 98:1232-1238, 1990. 117. Nitsche A, Leiguarda RC, Maldonado Cocco JA, et al: Neurological features in overlap syndrome. Clin Rheumatol 10:5-9, 1991. 118. Hagen NA, Stevens JC, Michet CJ Jr: Trigeminal sensory neuropathy associated with connective tissue diseases. Neurology 40:891-896, 1990. 119. Nadeau SE: Neurologic manifestations of connective tissue disease. Neurol Clin 20:151-178, 2002. 120. Bronshvas MM, Prystowsky SD, Traviesa DC: Vascular headaches in mixed connective tissue disease. Headache 18:154, 1978. 121. Okada J, Hamana T, Kondo H: Anti-U1RNP antibody and aseptic meningitis in connective tissue diseases. Scand J Rheumatol 32: 247-252, 2003. 122. Alpert MA, Goldberg SH, Singsen BH, et al: Cardiovascular manifestations of mixed connective tissue disease in adults. Circulation 68:1182-1193, 1983. 123. Burdt MA, Hoffman RW, Deutscher SL, et al: Long-term outcome in mixed connective tissue disease: Longitudinal clinical and serologic findings. Arthritis Rheum 42:899-909, 1999. 124. Peller JS, Gabor GT, Porter JM, Bennett RM: Angiographic findings in mixed connective tissue disease: Correlation with fingernail capillary photomicroscopy and digital photoplethysmography findings. Arthritis Rheum 28:768-774, 1985. 125. Granier F, Vayssairat M, Priollet P, Housset E: Nailfold capillary microscopy in mixed connective tissue disease: Comparison with systemic sclerosis and systemic lupus erythematosus. Arthritis Rheum 29:189-195, 1986. 126. Maricq HR, LeRoy EC, D’Angelo WA, et al: Diagnostic potential of in vivo capillary microscopy in scleroderma and related disorders. Arthritis Rheum 23:183, 1980. 127. Watanabe H, Kaise S, Takeda I, et al: Anti-endothelial cell antibodies in the sera of patients with mixed connective tissue disease—the clinical significance. Fukushima J Med Sci 43:13-28, 1997.

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SCLERODERMA, INFLAMMATORY MYOPATHIES, AND OVERLAP SYNDROMES

 128. Okawa-Takatsuji M, Aotsuka S, Uwatoko S, et al: Increase of cytokine production by pulmonary artery endothelial cells induced by supernatants from monocytes stimulated with autoantibodies against U1-ribonucleoprotein. Clin Exp Rheumatol 17:705-712, 1999.  129. Segond P, Yeni P, Jacquot JM, Massias P: Severe autoimmune anemia and thrombopenia in mixed connective tissue disease. Arthritis Rheum 21:995, 1978.  130. Mimura Y, Ihn H, Jinnin M, et al: Rheumatoid factor isotypes in mixed connective tissue disease. Clin Rheumatol 4:572-574, 2006.  131. Mendonca LL, Amengual O, Atsumi T, et al: Most anticardiolipin antibodies in mixed connective tissue disease are beta2-glycoprotein independent. J Rheumatol 25:189-190, 1998.  132. Komatireddy GR, Wang GS, Sharp GC, Hoffman RW: Antiphospholipid antibodies among anti-U1-70 kDa autoantibody positive patients with mixed connective tissue disease. J Rheumatol 24: 319-322, 1997.  133. Kitridou RC: Pregnancy in mixed connective tissue disease. Rheum Dis Clin North Am 31:497-508, 2005.  134. Kaufman RL, Kitridou RC: Pregnancy in mixed connective tissue disease: Comparison with systemic lupus erythematosus. J Rheumatol 9:549-555, 1982.  135. Kari JA: Pregnancy outcome in connective tissue diseases. Saudi Med J 22:590-594, 2001.  136. Ackerman J, Gonzalez EF, Gilbert-Barness E: Immunological studies of the placenta in maternal connective tissue disease. Pediatr Dev Pathol 2:19-24, 1999.  137. Bodolay E, Bojan F, Szegedi G, et al: Cytotoxic endothelial cell antibodies in mixed connective tissue disease. Immunol Lett 20:163-167, 1989.  138. Fujiwaki T, Urashima R, Urushidani Y, et al: Neonatal lupus erythematosus associated with maternal mixed connective tissue disease. Pediatr Int 45:210-213, 2003.  139. Tiddens HA, van der Net JJ, Graeff-Meeder ER, et al: Juvenile-onset mixed connective tissue disease: Longitudinal follow-up. J Pediatr 122:191-197, 1993.  140. van der Neti J, van der Hoeven H, Esseveld F, et al: Musculoskeletal disorders in juvenile onset mixed connective tissue disease. J Rheumatol 22:751-757, 1995.  141. Peskett SA, Ansell BM, Fizzman P, Howard A: Mixed connective tissue disease in children. Rheumatol Rehabil 17:245-248, 1978.  142. Michels H: Course of mixed connective tissue disease in children. Ann Med 29:359-364, 1997.  143. Yokota S, Imagawa T, Katakura S, et al: Mixed connective tissue disease in childhood: A nationwide retrospective study in Japan. Acta Paediatr Jpn 39:273-276, 1997.  144. Jang JJ, Olin JW, Fuster V: A teenager with mixed connective tissue disease presenting with an acute coronary syndrome. Vasc Med 9: 31-34, 2004.  145. Braun J, Sieper J, Schwarz A, et al: Widespread vasculopathy with hemolytic uremic syndrome, perimyocarditis and cystic pancreatitis in a young woman with mixed connective tissue disease: Case report and review of the literature. Rheumatol Int 13:31-36, 1993. 146. Kim P, Grossman JM: Treatment of mixed connective tissue disease. Rheum Dis Clin North Am 31:549-565, 2005.  147. Bendayan D, Shitrit D, Kramer MR: Pulmonary arterial hypertension associated with autoimmune disease: A single medical center experience. Isr Med Assoc J 8:252-254, 2006.  148. McLaughlin VV: Medical management of primary pulmonary hypertension. Expert Opin Pharmacother 3:159-165, 2002.

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149. Galie N, Manes A, Branzi A: Medical therapy of pulmonary hypertension: The prostacyclins. Clin Chest Med 22:529-537, 2001. 150. Vegh J, Soos G, Csipo I, et al: Pulmonary arterial hypertension in mixed connective tissue disease: Successful treatment with iloprost. Rheumatol Int 26:264-269, 2006. 151. Sanchez O, Sitbon O, Jais X, et al: Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension. Chest 130:182-189, 2006. 152. Cohen H, Chahine C, Hui A, Mukherji R: Bosentan therapy for pulmonary arterial hypertension. Am J Health Syst Pharm 61: 1107-1119, 2005. 153. Rubin LJ, Badesch DB, Barst RJ, et al: Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 346:896-903, 2002. 154. Godeau B, Chevret S, Varet B, et al: Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: A randomised, multicentre trial. Lancet 359:23-29, 2002. 155. Cherin P, Pelletier S, Teixeira A, et al: Results and long-term followup of intravenous immunoglobulin infusions in chronic, refractory polymyositis: An open study with thirty-five adult patients. Arthritis Rheum 46:467-474, 2002. 156. Blanco R, Martinez-Taboada VM, Rodriguez-Valverde V, et al: Successful therapy with danazol in refractory autoimmune thrombocytopenia associated with rheumatic diseases. Br J Rheumatol 36:1095-1099, 1997. 157. Myllykangas-Luosujarvi R, Jantunen E, Kaipiainen-Seppanen O, et al: Autologous peripheral blood stem cell transplantation in a patient with severe mixed connective tissue disease. Scand J Rheumatol 29:326327, 2000. 158. Wallace DJ: Antimalarials—the “real” advance in lupus. Lupus 10:385-387, 2001. 159. D’Cruz D: Antimalarial therapy: A panacea for mild lupus? Lupus 10:148-151, 2001. 160. Sato EI: Methotrexate therapy in systemic lupus erythematosus. Lupus 10:162-164, 2001. 161. Richez C, Blanco P, Dumoulin C, Schaeverbeke T: Lupus erythematosus manifestations exacerbated by etanercept therapy in a patient with mixed connective tissue disease. Clin Exp Rheumatol 23: 273, 2005. 162. Nolan RJ, Shulman ST, Victorica BE: Congenital complete heart block associated with maternal mixed connective tissue disease. J Pediatr 95:420-422, 1979. 163. Giner Galvan V, Oltra MR, Rueda D, et al: Severe acute hepatitis related to hydroxychloroquine in a woman with mixed connective tissue disease. Clin Rheumatol 9:971-972, 2006. 164. Doria A, Iaccarino L, Ghirardello A, et al: Pregnancy in rare autoimmune rheumatic diseases: UCTD, MCTD, myositis, systemic vasculitis and Behcet disease. Lupus 13:690-695, 2004. 165. Middleton GD, McFarlin JE, Lipsky PE: The prevalence and clinical impact of fibromyalgia in systemic lupus erythematosus. Arthritis Rheum 37:1181-1188, 1994. 166. Bennett R: The concurrence of lupus and fibromyalgia: Implications for diagnosis and management. Lupus 6:494-499, 1997. 167. Lundberg IE: The prognosis of mixed connective tissue disease. Rheum Dis Clin North Am 31:535, 2005. 168. Kuwana M, Kaburaki J, Okano Y, et al: Clinical and prognostic associations based on serum antinuclear antibodies in Japanese patients with systemic sclerosis. Arthritis Rheum 37:75-83, 1994. 169. Graf WD, Milstein JM, Sherry DD: Stroke and mixed connective tissue disease. J Child Neurol 8:256-259, 1993.

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VASCULITIS

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The Classification and Epidemiology of Systemic Vasculitis JOHN H. STONE

KEY POINTS Vasculitis is a heterogeneous group of disorders linked by the primary finding of inflammation within blood vessel walls. At least 20 forms of systemic vasculitis are recognized currently. Vasculitides are classified first by the size of blood vessel involved—small (capillaries and postcapillary venules), medium (muscular arteries and arterioles), or large (the aorta and its major branches). Additional considerations in classification include patient demographics, organ tropism, presence or absence of granulomatous inflammation, participation (or not) of immune complexes, finding of autoantibodies, and detection of infections associated with some vasculitides. Different forms of vasculitis have widely divergent profiles with regard to age, gender, and ethnicity. Associations between genes and vasculitis have been recognized increasingly in recent years. There also has been progress in the area of gene-environment interactions.

CLASSIFICATION Few disorders in medicine are more challenging in ­diagnosis and treatment than the systemic vasculitides. These heterogeneous disorders are linked by the common finding of destructive inflammation within the walls of blood vessels. Current classification schemes recognize approximately 20 primary forms of vasculitis and several major categories of secondary vasculitis (e.g., other rheumatologic diseases, malignancy, and infection) (Table 80-1). Over the past half century, numerous comprehensive classification schemes have been attempted.1 No attempt has been entirely satisfactory because understanding of these conditions continues to evolve. All vasculitis classification schemes are works in progress, susceptible to change as new information emerges. Current classification schemes are understood best in light of their nosologic predecessors. The first “modern”

case of systemic vasculitis was recognized in the 1860s by Kussmaul and Maier.2 That case, which involved mediumsized,muscular arteries, has served as the reference point for ­classifying many subsequently recognized forms of vasculitis. Because of the importance of that first report in the understanding and classification of vasculitis, the case is described in detail here. FIRST MODERN CASE: “PERIARTERITIS NODOSA” In 1866, Kussmaul and Maier reported the case of a 27-yearold tailor who died during a month-long hospital stay.2,3 On presentation, the patient was strong enough to climb two flights of stairs to the clinic, but “afterward felt so weak that he immediately had to go to bed.” He complained of numbness on the volar aspect of his thumb and the two neighboring fingers on the right hand. Over the ensuing days, “the general weakness increased so rapidly that he was unable to leave the bed, [and] the feeling of numbness also appeared in the left hand.” Muscle paralysis progressed quickly: “Before our eyes, a young man developed a general paralysis of the voluntary muscles … [He] had to be fed by attendants, and within a few weeks was robbed of the use of most of his ­muscles.”2,3 The patient’s weakness, caused by vasculitic neuropathy (mononeuritis multiplex), was accompanied by tachycardia, abdominal pains, and the appearance of cutaneous nodules over his trunk. His death was described as follows: “He was scarcely able to speak, lay with persistent severe abdominal and muscle pains, opisthotonically stretched, whimpering, and begged the doctors not to leave him … Death occurred … at 2 o’clock in the morning.” At autopsy, grossly visible nodules were present along the patient’s medium-sized arteries. Kussmaul and Maier suggested the name “periarteritis nodosa” for this disease because of the apparent localization of inflammation to the perivascular sheaths and outer layers of the arterial walls, leading to nodular thickening of the vessels. The name was later revised to polyarteritis nodosa (PAN), to reflect the widespread arterial involvement of this disease, and the fact that the inflammation in PAN extends through the entire thickness of the vessel wall.4,5 1401

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Table 80-1  Classification Scheme of Vasculitides ­According to Size of Predominant Blood Vessels   Involved Primary Vasculitides Predominantly Large Vessel Vasculitides Takayasu’s arteritis Giant cell arteritis (temporal arteritis) Cogan’s syndrome Behçet’s disease* Predominantly Medium Vessel Vasculitides Polyarteritis nodosa Cutaneous polyarteritis nodosa Buerger’s disease Kawasaki disease Primary angiitis of the central nervous system Predominantly Small Vessel Vasculitides Immune complex mediated   Goodpasture’s disease (anti–glomerular basement membrane disease)†   Cutaneous leukocytoclastic angiitis (“hypersensitivity ­vasculitis”)   Henoch-Schönlein purpura   Hypocomplementemic urticarial vasculitis   Essential cryoglobulinemia‡   Erythema elevatum diutinum ANCA-associated disorders§   Wegener’s granulomatosis‡   Microscopic polyangiitis‡   Churg-Strauss syndrome‡   Renal-limited vasculitis Secondary Forms of Vasculitis Miscellaneous Small Vessel Vasculitides Connective tissue disorders‡ (rheumatoid vasculitis, lupus ­erythematosus, Sjögren’s syndrome, inflammatory myopathies) Inflammatory bowel disease Paraneoplastic Infection Drug-induced vasculitis: ANCA-associated, other *May involve small, medium, and large blood vessels. †Immune complexes formed in situ, in contrast to other forms of ­immune complex–mediated vasculitis. ‡Frequent overlap of small and medium blood vessel involvement. §Not all forms of these disorders are always associated with ANCA. ANCA, antineutrophil cytoplasmic antibody.

POLYARTERITIS NODOSA AS A REFERENCE POINT In addition to its status as the first form of vasculitis recognized, several features of PAN make it a logical reference point for the classification of inflammatory vascular disease. Other forms of vasculitis usually can be differentiated from PAN through their contrasts to one or more of the following PAN characteristics: • The general confinement of the disease to mediumsized vessels*, as opposed to capillaries and postcapillary venules (small vessels) and the aorta and its major branches (large vessels) • The exclusive involvement of arteries, with sparing of veins • The tendency to form microaneurysms • The absence of lung involvement *The fact of vessel size overlap in vasculitis syndromes is acknowledged and discussed subsequently.

• The lack of granulomatous inflammation • The absence of associated autoantibodies (e.g., ­antineutrophil cytoplasmic antibodies [ANCA], anti– glomerular basement membrane [anti-GBM] antibodies, or rheumatoid factor) • The association of some cases with hepatitis B virus (HBV) infection CLASSIFICATION BY VESSEL SIZE Because the etiologies of most forms of vasculitis are unknown, the most valid basis for classifying the vasculitides is the size of the predominant blood vessels involved. Under such classification schemes, the vasculitides are categorized initially by whether the vessels affected are large, medium, or small (see Table 80-1). “Large” generally denotes the aorta and its major branches (and the corresponding vessels in the venous circulation in some forms of vasculitis, e.g., Behçet’s disease). “Medium” refers to vessels that are smaller than the major aortic branches, yet still large enough to contain four elements: (1) an intima, (2) a continuous internal elastic lamina, (3) a muscular media, and (4) an adventitia. In clinical terms, medium vessel vasculitis (see Table 80-1) is generally macrovascular (i.e., involves vessels large enough to be observed in gross pathologic specimens or visualized by angiography). “Small vessel” vasculitis, which incorporates all vessels below macroscopic disease, includes capillaries, postcapillary venules, and arterioles. Such vessels all are typically less than 500 μ in outer diameter. Because glomeruli may be viewed simply as differentiated capillaries, forms of vasculitis that cause glomerulonephritis are considered to be small vessel vasculitides. Table 80-2 presents the typical clinical manifestations associated with small, medium, and large vessel vasculitides. All discussions of vasculitis classification schemes involving vessel size must acknowledge the frequent occurrence of overlap. Although PAN primarily involves medium-sized arteries, palpable purpura—a manifestation of small vessel disease—can be observed in some cases. Despite the possibility of vessel size overlap within individual cases, the categorization of a patient’s vasculitis as primarily large, medium, or small vessel in nature remains enormously useful in focusing the differential diagnosis and initiating plans for treatment. ADDITIONAL CONSIDERATIONS IN CLASSIFICATION Many other considerations are important in the classification of vasculitis (Table 80-3): (1) the patient’s demographic profile (see Epidemiology section), (2) the disease’s tropism for particular organs, (3) the presence or absence of granulomatous inflammation, (4) the participation of immune complexes in disease pathophysiology, (5) the finding of characteristic autoantibodies in the patients’ serum (e.g., ANCA, anti-GBM antibodies, or rheumatoid factor), and (6) the detection of certain infections known to cause specific forms of vasculitis. The organ tropisms of these disorders are illustrated by the following examples. Wegener’s granulomatosis classically involves the kidneys, upper airways, and lungs. In contrast, Henoch-Schönlein purpura often affects the kidneys, but never the nose or sinuses and almost never the lungs.

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Table 80-2  Typical Clinical Manifestations of Large, Medium, and Small Vessel Involvement by Vasculitis   Constitutional symptoms: fever, weight loss,   malaise, arthralgias/arthritis (common   to vasculitides of all vessel sizes) Large

Medium

Small

Limb claudication

Cutaneous nodules

Purpura

Asymmetric blood pressures

Ulcers

Vesiculobullous lesions

Absence of pulses

Livedo reticularis

Urticaria

Bruits

Digital gangrene

Glomerulonephritis

Aortic dilation

Mononeuritis ­multiplex

Alveolar ­hemorrhage

Renovascular ­hypertension

Microaneurysms

Cutaneous extravascular necrotizing granulomas Splinter ­hemorrhages Uveitis/episcleritis/ scleritis

Renovascular ­hypertension

Table 80-3  Considerations in the Classifications   of Systemic Vasculitis Size of predominant blood vessels affected Epidemiologic features   Age   Gender   Ethnic background Pattern of organ involvement Pathologic features   Granulomatous inflammation   Immune complex deposition versus pauci-immune    ­ histopathology   Linear staining along glomerular basement membrane Presence of ANCA, anti-GBM antibodies, or rheumatoid factor in serum Demonstration of a specific associated infection (hepatitis B or hepatitis C) ANCA, antineutrophil cytoplasmic antibody; GBM, glomerular basement membrane.

In contrast to both of these forms of vasculitis, Cogan’s syndrome is defined by the simultaneous occurrence of ocular inflammation (most often interstitial keratitis) and sensorineural hearing loss (and, in 10% of cases, a large vessel vasculitis). The histopathologic findings in these three disorders are equally distinctive, ranging from granulomatous inflammation of small to medium vessels (Wegener’s granulomatosis), to IgA deposition in small vessels (HenochSchönlein purpura), to large vessel vasculitis centered on the adventitia (Cogan’s syndrome). The granulomatous features of some forms of vasculitis resemble chronic infections (e.g., infections caused by fungi or mycobacteria) or the inflammation induced by the presence of a foreign body. Granulomatous inflammation is more likely to be found in some organs (e.g., the lung) than in others (e.g., the kidney or skin). Some patients without evidence of granulomatous inflammation at early points in their courses later exhibit such features as their diseases unfold. Patients initially diagnosed with cutaneous leukocytoclastic

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Table 80-4  Forms of Vasculitis Associated   with ­Granulomatous Inflammation Giant cell arteritis Takayasu’s arteritis Cogan’s syndrome Wegener’s granulomatosis Churg-Strauss syndrome Primary angiitis of the central nervous system* Buerger’s disease† Rheumatoid vasculitis *Sometimes granulomatous. †Giant cells occur within inflammatory thrombi (and are diagnostic of Buerger’s disease), but do not occur within the blood vessel wall.

angiitis or microscopic polyangiitis may be reclassified as having Wegener’s granulomatosis if disease manifestations appear in new organs and granulomatous inflammation is found on biopsy specimens. Table 80-4 presents forms of vasculitis commonly associated with granulomatous inflammation. Immune complexes are essential to the pathophysiology of some small and medium vessel vasculitides. Immune complex–mediated tissue injury does not produce a single clinical syndrome, but rather applies to many forms of vasculitis and overlaps with injuries caused by other immune mechanisms. Anti-GBM disease (Goodpasture’s disease) is a unique form of immune complex disease in which the immune complexes form in situ rather than in the circulation.6 Complexes of IgA1 are found in Henoch-Schönlein purpura. Immune complexes comprising IgG, IgM, complement components, and the hepatitis C virion characterize most cases of mixed cryoglobulinemia. HBV surface antigen/antibody complexes are present in the circulation and involved tissues of patients with HBV-associated PAN. Rheumatoid factor and complement proteins are found within organs involved by rheumatoid vasculitis. In contrast, other small and medium vessel vasculitides, such as Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome, are disorders associated with “pauci-immune” inflammation. “Pauci-immune” refers not to a lack of immunologic involvement in these disorders, but rather to the absence of significant immunoreactant deposition (immunoglobulin or complement) within diseased tissues. Many (but not all) patients with pauciimmune forms of vasculitis have ANCA in their serum. Three decades before the description of ANCA, Godman and Churg7 observed pathologic links between these three entities, noting that the disorders “group themselves into a compass, [ranging from] necrotizing and granulomatous processes with angiitis, through mixed forms, to vasculitis without granulomata.” ANCA (see Chapter 82) are directed against antigens that reside within the primary granules of neutrophils and monocytes.8 Two types of ANCA seem to be relevant to vasculitis: (1) ANCA directed against proteinase-3 (PR-3), a serine protease found within the primary granules of neutrophils and monocytes, and (2) ANCA directed against myeloperoxidase and another serine protease found within the same granules. Although rigorous serologic assays for these antibodies are helpful in diagnosis, evidence for a

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The Classification and Epidemiology of Systemic Vasculitis

p­ rimary etiologic role of these antibodies in human forms of pauci-immune vasculitis is still lacking. In contrast, antiGBM antibodies have been proven to play a major role in the pathogenesis of Goodpastures’s disease.9 In RA, systemic rheumatoid vasculitis occurs only in patients who are rheumatoid factor positive. Rheumatoid factor is believed to play an essential role in the immune complex nature of that disease complication. Finally, although the causes of most forms of vasculitis are unknown, several infections have been linked definitively with specific forms of these diseases (e.g., HBV with some cases of PAN, and hepatitis C with type II mixed cryoglobulinemia). HISTORICAL ATTEMPTS AT CLASSIFICATION AND NOMENCLATURE For decades after this initial description of vasculitis, most forms of systemic inflammatory vascular disease were termed periarteritis nodosa. In the 1900s, two major factors led to the recognition of new forms of vasculitis: (1) The use of microscopy in the evaluation of pathologic specimens became routine, and (2) horse serum and sulfonamides came to be employed in the treatment of many medical conditions. These new therapies frequently induced small vessel vasculitides on the basis of serum sickness or “hypersensitivity” phenomena, which were observed readily through the microscope. In some cases, the histopathologicl findings of hypersensitivity reactions (e.g., serum sickness) were confused with periarteritis nodosa. The gradual recognition that these syndromes represented departures from PAN spurred interest in the first classification scheme for necrotizing angiitis. In 1952, Zeek10 identified five major categories of necrotizing angiitis. The Zeek Classification included (1) hypersensitivity angiitis, (2) allergic granulomatous angiitis (Churg-Strauss syndrome), (3) rheumatic arteritis (vasculitis associated with fulminant rheumatic fever), (4) periarteritis nodosa, and (5) temporal arteritis. This classification scheme omitted several forms of systemic vasculitis that were known but not yet described in the English medical literature (e.g., Wegener’s granulomatosis and Takayasu’s arteritis). SOURCES OF CONFUSION IN CLASSIFICATION Two forms of vasculitis, now termed microscopic polyangiitis and cutaneous leukocytoclastic angiitis, have been consistent sources of confusion in vasculitis nosology. In the current understanding of systemic vasculitides, these two conditions are separate entities. Microscopic polyangiitis affects capillaries, veins, and arteries (in contrast to PAN), and is recognized to be a disorder associated with ANCA in approximately 70% of cases.11 In 1923, Wohlwill12 observed unequivocal evidence of small vessel involvement in cases of vasculitis that he still considered part of the spectrum of “periarteritis nodosa.” Davson and colleagues13 remarked on two forms of “periarteritis nodosa” with differential effects on the kidney—one with a predilection for medium-sized, muscular arteries and the other with a predilection for small vessels, including glomerulonephritis. Davson and colleagues13 termed this latter form microscopic periarteritis nodosa. Swayed by human and animal models of hypersensitivity that showed small vessel disease involving the

kidneys, lungs, and other organs,14,15 Zeek chose to group microscopic periarteritis nodosa under the heading of hypersensitivity vasculitis.10 Over the next several decades, hypersensitivity vasculitis came to refer to an immune complex–mediated small vasculitis of the skin that spared internal organs and often followed drug exposures.16 The Chapel Hill Consensus Conference (CHCC)17 (see later) recommended eliminating the term hypersensitivity altogether because evidence for hypersensitivity is lacking in many cases. Participants in the CHCC preferred the term cutaneous leukocytoclastic angiitis because of the disorder’s typical confinement to the skin and the usual predominant cell type—the neutrophil. Although cutaneous leukocytoclastic angiitis can mimic the skin features of microscopic polyangiitis, cutaneous leukocytoclastic angiitis does not involve the kidneys, lungs, peripheral nerves, and other internal organs, and is not associated with ANCA. In 1990, the American College of Rheumatology (ACR) performed a study designed to establish criteria for the classification of vasculitis, through the identification of features that distinguished one form of vasculitis from others.18,19 An important caveat: This study was not designed to establish criteria for diagnosis, but rather to facilitate research by permitting the inclusion of similar types of patients in studies. Patients with giant cell arteritis, Takayasu’s arteritis, PAN, Wegener’s granulomatosis, Churg-Strauss syndrome, Henoch-Schönlein purpura, and hypersensitivity vasculitis were included in this study.16,20-25 The findings of the ACR study remain useful for the purposes of the study’s original intention—the insurance of uniform inclusion criteria for patients in research studies. The passage of time and the development of new insights have shown the need for updates, however. First, because the study was performed before the days of reliable and widely available assays for ANCA, ANCA positivity was not considered as a possible classification criterion. Second, the ACR Classification Criteria study did not include microscopic polyangiitis as a separate disease, but rather lumped such patients under the heading of PAN.22 Third, the study did not define classification criteria for such rarer forms of vasculitis as Cogan’s syndrome and Behçet’s disease. As noted subsequently, Behçet’s disease is rare in North America, but not in countries bordering the Old Silk Route. Diagnostic criteria for this disease have been defined.26 In 1994, the CHCC reviewed the nomenclature of systemic vasculitides. Formal diagnostic criteria were not attempted, but definitions were created for 10 forms of vasculitis (in addition to the 7 forms of vasculitis included in the ACR study, microscopic polyangiitis, Kawasaki disease, and “essential” cryoglobulinemic vasculitis were defined). The CHCC emphasized the important role that ANCA play in the diagnosis of several forms of vasculitis and carefully distinguished microscopic polyangiitis from classic PAN. The conference defined classic PAN as necrotizing inflammation of medium-sized or small arteries without glomerulonephritis.17 Microscopic polyangiitis was defined as a necrotizing vasculitis with few or no immune deposits that (1) affects small blood vessels (capillaries, venules, or arterioles), (2) often includes glomerulonephritis and pulmonary ­capillaritis, and (3) is often associated with either myelo­ peroxidase ANCA or proteinase 3 ANCA.

PART 13 

The classification of vasculitis continues to evolve. In the years since the CHCC, it has become clear that hepatitis C plays a major role in 90% of cases that formerly were termed essential mixed cryoglobulinemia. Some cases of this syndrome are not associated with hepatitis C infections, however, and probably have some other infectious etiology. Similarly, with the availability of the HBV vaccine, increasingly fewer cases of PAN are associated with this infection. Most PAN cases have no known cause. As emphasized by Churg,27 cases of PAN currently termed idiopathic do not represent a single entity, but almost certainly include several different disorders. Some of these, as indicated by low serum complement levels and measurable immune complexes in the blood, are mediated by immune complex deposition. Others seem to be independent of this mechanism. Finally, although cutaneous leukocytoclastic angiitis may be preferable to hypersensitivity vasculitis in describing small vessel vasculitis confined to the skin, the term fails to acknowledge the few cases in which lymphocytic infiltrates predominate, even early in the inflammatory lesion.

EPIDEMIOLOGY Accurate definition of the epidemiology of vasculitis confronts several challenges, as follows: (1) the uncommon nature of many forms of vasculitis, (2) the frequent difficulties in making the correct diagnosis of vasculitis (and in distinguishing one form of vasculitis from another), (3) the fact that the etiologies of most types of vasculitis remain unknown, and (4) historical uncertainty with regard to the classification of these conditions. Nevertheless, in recent years, the epidemiology of some forms of vasculitis has been defined with reasonable precision. Table 80-5 presents the major epidemiologic features of several forms of systemic vasculitis. GEOGRAPHY The epidemiologic features of systemic vasculitis vary tremendously by geography. This variation may reflect genetics, differences in environmental exposures dictated by continent and latitude, and the prevalence of other disease risk factors. Although Behçet’s disease is rare in North Americans (affecting only approximately 1 in 300,000), the condition is perhaps several hundred times more common

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among inhabitants of countries that border the ancient Silk Route.26,28 Similarly, although Takayasu’s arteritis is rare in the United States—on the order of 3 new cases per 1 million people per year—the disease is reportedly the most common cause of renal artery stenosis in India, where the incidence may be 200 to 300/1 million/yr. Several studies indicate that the prevalence of giant cell arteritis in Olmsted County, Minnesota, is similar to that of Scandinavian countries, with an annual incidence rate of approximately 240 cases for every 1 million individuals older than age 50 years.29 The similar prevalence calculations across these countries probably reflect shared genetic risk factors for this condition because many of the current inhabitants of Olmsted County are descended from Scandinavia and northern Europe. Based on 2000 U.S. Census data, the prevalence of giant cell arteritis in the United States is approximately 160,000 patients. AGE, GENDER, AND ETHNICITY Age is an important consideration in the epidemiology of vasculitis. Of patients with Kawasaki disease, 80% are younger than age 5 years.30 In contrast, giant cell arteritis virtually never occurs in patients younger than age 50, and the mean age of patients with that disease is 72. Age also may affect disease severity and outcome. In Henoch­Schönlein purpura, most cases in children (who comprise 90% of all cases) have self-limited courses, resolving within several weeks. In adults, Henoch-Schönlein purpura may have a higher likelihood of chronicity and a greater likelihood of a poor renal outcome.31 The distribution of gender varies across many forms of vasculitis. Buerger’s disease is the only form of vasculitis with a striking male predominance. The predilection of this disease for men may be explained by the greater prevalence of smoking among men in most societies. In contrast, Takayasu’s arteritis has an overwhelming tendency to occur in women (a 9:1 female-to-male ratio), a fact that presently has no explanation. Pauci-immune forms of vasculitis, such as Wegener’s granulomatosis, occur in men and women with approximately equal frequencies, but there is some evidence for a female predominance in patients with the limited form of the disease and a male predominance among patients with severe Wegener’s granulomatosis.32

Table 80-5  Epidemiology of Selected Forms of Vasculitis Incidence Disease

United States

Elsewhere

Age/Gender/Ethnic Predispositions

Giant cell arteritis

240/1 million (Olmsted County,   MN)

220-270/1 million (Scandinavian countries)

Age >50, mean age 72/Females 3:1/Northern European ancestry

Takayasu’s arteritis

3/1 million

200-300/1 million (India)

Age <40/Females 9:1/Asian

Behçet’s disease

3/1 million

3000/1 million (Turkey)

Silk Route countries

Polyarteritis nodosa

7/1 million

7/1 million (Spain)

Slight male predominance

Kawasaki disease

100/1 million*

900/1 million (Japan)

Children of Asian ancestry

Wegener’s granulomatosis

4/1 million

8.5/1 million   (United Kingdom)

Whites >> Blacks

Henoch-Schönlein purpura

In children: 135-180/1 million; in adults: 13/1 million

*Among children younger than 5 years of age. From Gonzalez-Gay MA, Garcia-Porrua: Epidemiology of the vasculitides. Rheum Dis Clin N Am 27:729-750, 2001.

Only 10% of cases occur in adults

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For some forms of vasculitis, there are striking variations in tendencies to affect specific ethnic groups. Giant cell arteritis and Wegener’s granulomatosis occur with an ­overwhelming predominance in whites.33-35 Takayasu’s arteritis and Kawasaki disease have higher incidences in patients of Asian ancestry. GENES Although genetic risk factors are undoubtedly important in the susceptibility to some forms of vasculitis, familial cases are rare (with the exception of giant cell arteritis; see later). The rarity of familial cases in vasculitis indicates that the genetics of these disorders are polygenic and complex. The strongest link between any single gene and vasculitis is the association of HLA-B51 with Behçet’s disease. In Behçet’s disease, 80% of Asian patients have the HLA-B51 gene.28 The prevalence of HLA-B51 is significantly higher among patients with Behçet’s disease in Japan than among nondisease controls (55% versus <15%). Among the sporadic cases of Behçet’s disease involving white patients in the United States, however, HLA-B51 occurs in less than 15% of cases. In addition to increasing the risk of disease susceptibility in some patients, HLA-B51 increases disease severity. Patients with this gene are more likely to have posterior uveitis, central nervous system involvement, or other severe manifestations. Reports of familial aggregation in giant cell arteritis are common. Genetic studies have indicated roles for HLA class II alleles such as HLA-DRB1*0401 and HLA-DRB1*0101, albeit the specific associations have varied from study to study.36,37 Other work indicates that certain tumor necrosis factor microsatellite polymorphisms may contribute to disease susceptibility.38 The greatest progress in understanding the relationship of genetics to systemic vasculitis has come in the area of rheumatoid vasculitis. The contribution of the “shared epitope” found on class II HLA molecules (DR4) to the development of rheumatoid arthritis (RA) has been appreciated for 2 decades.39 Possession of the shared epitope is now known to increase substantially the risk of extra-articular manifestations in RA, including vasculitis, at least in Northern European populations. A gene dosage effect for extra-­articular RA with severe organ manifestations has been noted; patients with two copies of shared epitope alleles have a substantially higher risk of extra-articular disease manifestations, many of which are mediated by vasculitis.40 One study reported an association between rheumatoid vasculitis and 0401/0404.41 In a case-control study of patients with severe extra­articular RA compared with RA patients without extraarticular disease manifestations, the presence of two HLA-DRB1*04 alleles encoding the shared epitope was associated with extra-articular RA (odds ratio 1.79; 95% confidence interval 1.04 to 3.08) and rheumatoid vasculitis (odds ratio 2.44; 95% confidence interval 1.22 to 4.89).42 In a meta-analysis of HLA-DRB1 genotyping studies of patients with rheumatoid vasculitis,43 rheumatoid vasculitis was found to be associated with the genotypes 0401/0401, 0401/0404, and 0401/0101. An association between rheumatoid vasculitis and class I molecules also has been reported. An analysis of 159 patients

with severe extra-articular RA (46 of whom had vasculitis) and 178 RA patients without extra-articular disease reported a strong association between the HLA-C3 allele and vasculitis.44 Among vasculitis patients, the allele frequency of HLA-C3 was 0.411 compared with 0.199 in RA patients without extra-articular disease (P < .001). The odds ratio for vasculitis in patients with HLA-C3 was 4.15 (95% confidence interval 2.14 to 8.08). The association between HLA-C3 and vasculitis was not due to linkage disequilibrium with HLA-DRB1, suggesting that these two genetic risk factors operate through different pathways. HLA-C3 was a strong predictor of vasculitis in patients lacking HLA-DRB1*04 shared epitope alleles, suggesting that HLA-C and HLA-DR genes influence the RA disease process through different pathways. Linkage disequilibrium with other genes in the MHC could not be excluded in this study, however. In Wegener’s granulomatosis, the allele frequency of a functional polymorphism, 620W, in the intracellular tyrosine phosphatase gene PTPN22, was found to be increased significantly among ANCA-positive patients compared with healthy controls.45 Analyses of families with multiple autoimmune disorders have identified this allele as a risk factor for type 1 diabetes, seropositive RA, systemic lupus erythematosus, and autoimmune thyroid disease. In ­Wegener’s granulomatosis, the allelic association was particularly strong among patients with generalized disease (i.e., vasculitis involving the kidney, lung, eye, and peripheral nervous system). Study of the relationships between genes and systemic vasculitis is in its infancy. Substantial progress can be anticipated in this area in the future. ENVIRONMENT Several environmental and occupational exposures have been linked to the development of vasculitis. The strongest environmental exposure, now linked convincingly to Buerger’s disease and to rheumatoid vasculitis, is cigarette smoking. Buerger’s disease does not occur in the absence of cigarette smoking. The relationship between smoking and Buerger’s disease is usually one of primary exposure (usually heavy), but cases related to second-hand smoke have been alleged. In a case-control study of patients with recent-onset RA, the interactions between smoking, shared epitope genes, and antibodies to citrullinated proteins (i.e., anti–cyclic citrullinated peptide antibodies) were studied.46 A dose-­dependent relationship between smoking and the occurrence of anti– cyclic citrullinated peptide antibodies was found. The presence of shared epitope genes was a risk factor only for RA only among patients who were positive for anti–cyclic citrullinated peptide. A major gene-­environment interaction between smoking and HLA-DR SE genes was evident in the large subgroup of patients who possessed anti–cyclic citrullinated peptide antibodies: The combination of smoking history and double copies of shared epitope alleles increased the risk of RA 21-fold. Smoking may trigger RAspecific immune reactions to citrullinated proteins in the context of shared epitope genes. Associations have been reported, but not confirmed, between exposure to inhaled silica dust and some types of

PART 13 

pauci-immune vasculitis.47 Precise definitions of the relationships between exposures and vasculitis are complicated by difficulties in obtaining reliable measurements of the ­levels of such exposures, the likelihood of recall bias among patients who are diagnosed with vasculitis, and the choice of appropriate control groups. Finally, estimates of disease prevalence in vasculitis may be subject to revision because of changing disease definitions. In the ACR Classification Criteria study, manifestations of small and medium vessel involvement were included in the criteria for PAN.22 Four years later, the CHCC defined PAN as a form of arterial inflammation limited to medium-sized vessels, sparing capillaries, arterioles, and venules.17 Under this definition, classic PAN is believed to be a rare condition. Applying the CHCC definition retrospectively, not a single case of classic PAN was reported over a 6-year period in the region of the Norwich Health Authority (United Kingdom), an area that included a population of more than 400,000.48,49 The epidemiologic differences among individual types of vasculitis raise compelling questions about the etiologies of these diseases. Ultimately, better insights into the pathogenesis of these conditions should explain these epidemiologic differences and facilitate the development of more refined classification schemes. REFERENCES   1. Lie JT: Nomenclature and classification of vasculitis: Plus ça change, plus c’est la même chose. Arthritis Rheum 37:181-186, 1994.   2. Kussmaul A, Maier R: Ueber eine bisher nicht beschriebene eigenthümliche Arterienerkrankung (Periarteritis nodosa), die mit ­Morbus Brightii und rapid fortschreitender allgemeiner Muskellähmung einhergeht. Dtsch Arch Klin Med 1:484-518, 1866.   3. Matteson E: Polyarteritis nodosa: Commemorative translation on the 130-year anniversary of the original article by Adolf Kussmaul and Rudolf Maier. Rochester, Minn, Mayo Foundation, 1996.   4. Ferrari E: Ueber Polyarteritis acuta nodosa (sogenannte Periarteritis nodosa) und ihre Beziehungen zur Polymyositis und Polyneuritis acuta. Beitr Pathol Anat 34:350-386, 1903.   5. Dickson W: Polyarteritis acuta nodosa and periarteritis nodosa. J Pathol Bacterial 12:31-57, 1908.   6. Salama AD, Pusey CD: Immunology of anti-glomerular basement membrane disease. Curr Opin Nephrol Hypertension 11:279-286, 2002.   7. Godman GC, Churg J: Wegener’s granulomatosis: Pathology and review of the literature. Arch Pathol 58:533-553, 1954.   8. Hoffman GS, Specks U: Antineutrophil cytoplasmic antibodies. Arthritis Rheum 41:1521-1537, 1998.   9. Salama AD, Levy JB, Lightstone L, et al: Goodpasture’s disease. Lancet 358:917-920, 2001. 10. Zeek PM: Periarteritis nodosa: A critical review. Am J Clin Pathol 22:777-790, 1952. 11. Guillevin L, Durand-Gasselin B, Cevallos R, et al: Microscopic polyangiitis: Clinical and laboratory findings in 85 patients. Arthritis Rheum 42:421-430, 1999. 12. Wohlwill F: On the only microscopically recognizable form of periarteritis nodosa. Virchow’s Archiv für pathologische Anatomie und Physiologie 246:377-411, 1923. 13. Davson J, Ball J, Platt R: The kidney in periarteritis nodosa. QJM 17:175-192, 1948. 14. Rich AR: The role of hypersensitivity in periarteritis nodosa. Bull Johns Hopkins Hosp 71:123-140, 1942. 15. Zeek P, Smith C, Weeter J: Studies on periarteritis nodosa, III: The differentiation between the vascular lesions of periarteritis nodosa and hypersensitivity. Am J Pathol 24:889-917, 1948. 16. Calabrese LH, Michel BA, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of hypersensitivity vasculitis. Arthritis Rheum 33:1094-1100, 1990.

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17. Jennette JC, Falk RJ, Andrassy K, et al: Nomenclature of systemic vasculitides: Proposal of an international consensus conference. Arthritis Rheum 37:187-192, 1994. 18. Hunder GG, Arend WP, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of vasculitis: Introduction. Arthritis Rheum 33:1065-1067, 1990. 19. Bloch DA, Michel BA, Hunder GG, et al: The American College of Rheumatology 1990 criteria for the classification of vasculitis: Patients and methods. Arthritis Rheum 33:1068-1073, 1990. 20. Hunder GG, Bloch DA, Michel BA, et al: The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 33:1122-1128, 1990. 21. Arend WP, Michel BA, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of Takayasu’s arteritis. Arthritis Rheum 33:1129-1134, 1990. 22. Lightfoot RW Jr, Michel BA, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum 33:1088-1093, 1990. 23. Leavitt RY, Fauci AS, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 33:1101-1107, 1990. 24. Masi AT, Hunder GG, Lie JT, et al: The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 33:1094-1100, 1990. 25. Mills JA, Michel BA, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of Henoch-­Schönlein purpura. Arthritis Rheum 33:1114-1121, 1990. 26. International Study Group for Behçet’s disease: Criteria for diagnosis of Behçet’s disease. Lancet 335:1078-1080, 1990. 27. Churg J: Nomenclature of vasculitic syndromes: A historical perspective. Am J Kidney Dis 18:148-153, 1991. 28. Sakane T, Tekeno M, Suzuki N, et al: Behçet’s disease. N Engl J Med 341:1284-1291, 1999. 29. Salvarani C, Gabriel SE, O’Fallon WM, et al: The incidence of giant cell arteritis in Olmsted County, Minnesota: Apparent fluctuations in a cyclic pattern. Ann Intern Med 123:192-194, 1995. 30. Barron KS, Shulman ST, Rowley A, et al: Report of the National Institutes of Health Workshop on Kawasaki’s Disease. J Rheumatol 26:170-190, 1999. 31. Blanco R, Martinez-Taboada VM, Rodriguez-Valverde V, et al: Henoch-Schönlein purpura in adulthood and childhood: Two different expressions of the same syndrome. Arthritis Rheum 40:859-864, 1997. 32. The Wegener’s Granulomatosis Etanercept Trial Research Group: Limited versus severe Wegener’s granulomatosis: Baseline data on patients in the Wegener’s Granulomatosis Etanercept Trial. Arthritis Rheum 48:2299-2309, 2003. 33. Regan MJ, Green WR, Stone JH: Ethnic disparity in the incidence of temporal arteritis: A 32-year experience at an urban medical center. Arthritis Rheum 47:S108, 2002. 34. Falk RJ, Hogan S, Carey TS, et al: Clinical course of anti-­neutrophil cytoplasmic autoantibody-associated glomerulonephritis and systemic vasculitis. The Glomerular Disease Collaborative Network. Ann Intern Med 113:656-663, 1990. 35. Hoffman GS, Kerr GS, Leavitt RY, et al: Wegener’s granulomatosis: An analysis of 158 patients. Ann Intern Med 116:488-498, 1992. 36. Weyand CM, Hunder GG, Hickok KC, et al: HLA-DRB1 alleles in polymyalgia rheumatica, giant cell arteritis, and rheumatoid arthritis. Arthritis Rheum 37:514-520, 1994. 37. Rauzy O, Fort M, Nourhashemi F: Relation between HLA DRB1 alleles and corticosteroid resistance in giant cell arteritis. Ann Rheum Dis 57:380-382, 1998. 38. Mattey DL, Hajeer AH, Dababneh A, et al: Association of giant cell arteritis and polymyalgia rheumatica with different tumor necrosis factor microsatellite polymorphisms. Arthritis Rheum 43:1749-1755, 2000. 39. Gregersen PK, Silver J, Winchester RJ: The shared epitope hypothesis: An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 30:1205-1213, 1987. 40. Weyand CM, Xie C, Goronzy JJ: Homozygosity for the HLA-DRB1 allele selects for extra-articular manifestations in rheumatoid arthritis. J Clin Invest 89:2033-2039, 1992. 41. Voskuhl AE, Hazes JMW, Schreuder GMT, et al: HLA-DRB!, DQA1, and DQB1 genotypes and risk of vasculitis in patients with rheumatoid arthritis. J Rheumatol 24:852-855, 1997.

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42. Turesson C, Schaid DJ, Weyand CM, et al: The impact of HLA-DRB1 genes on extra-articular disease manifestations in rheumatoid arthritis. Arthritis Res Ther 7:R1386-R1393, 2005. 43. Gorman JD, David-Vaudey E, Pai M, et al: Particular HLA-DRB1 shared epitope genotypes are strongly associated with rheumatoid vasculitis. Arthritis Rheum 50:3476-3484, 2004. 44. Turesson C, Schaid DJ, Weyand CM, et al: Association of HLA-C3 and smoking with vasculitis in patients with rheumatoid arthritis. Arthritis Rheum 54:2776-2783, 2006. 45. Jagiello P, Aries P, Arning L, et al: The PTPN22 620W allele is a risk factor for Wegener’s granulomatosis. Arthritis Rheum 52:4039-4043, 2005. 46. Klareskog L, Stolt P, Lundberg K, et al: A new model for an etiology of rheumatoid arthritis: Smoking may trigger HLA-DR (shared epi­ tope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 54:38-46, 2006. 47. Hogan SL, Satterly KK, Dooley MA, et al: Silica exposure in anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and lupus nephritis. J Am Soc Nephrol 12:134-142, 2001.

48. Watts R, Carruthers D, Scott D: Epidemiology of systemic vasculitis: Changing incidence or definition? Semin Arthritis Rheum 25:28-34, 1995. 49. Gonzalez-Gay MA: Garcia-Porrua J: Epidemiology of the vasculitides. Rheum Dis Clin N Am 27:729-750, 2001. Relevant Websites The Johns Hopkins Vasculitis Center: http://vasculitis.med.jhu.edu. The Cleveland Clinic Foundation Center for ­Vasculitis: http://www.clevelandclinic.org/arthritis/vasculitis/default.htm. The Vasculitis Foundation: http://www.vasculitisfoundation.org/. The Vasculitis Clinical Research Consortium: http://rarediseasesnetwork. epi.usf.edu/vcrc/. The National Institute of Allergy and Infectious Disease: http://niaid.nih. gov/dir/general.htm.

81

Giant Cell Arteritis, Polymyalgia Rheumatica, and Takayasu’s Arteritis DAVID B. HELLMANN

KEY POINTS Giant cell arteritis affects adults older than 50 years. The most common manifestations of giant cell arteritis are constitutional symptoms, headache, jaw claudication, and visual symptoms; almost all untreated patients have an elevated erythrocyte sedimentation rate. The diagnosis of giant cell arteritis is usually confirmed by temporal artery biopsy. Early treatment of giant cell arteritis can prevent blindness. Polymyalgia rheumatica can occur by itself or with giant cell arteritis. Polymyalgia rheumatica by itself responds to prednisone 10 to 20 mg/day, whereas giant cell arteritis requires an initial dose of prednisone of approximately 60 mg/day. Takayasu’s arteritis most frequently affects the aorta and its major branches in young women.

Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are discussed together because they affect similar epidemiologic subsets of patients and often occur together in the same individual. Although GCA is a disease of older people and Takayasu’s arteritis (TA) is a disease of younger people, their shared predilection for causing vasculitis of large arteries and their nearly identical histopathologic changes prompt their inclusion in the same chapter.

GIANT CELL ARTERITIS AND POLYMYALGIA RHEUMATICA AMERICAN COLLEGE OF RHEUMATOLOGY CRITERIA Classification criteria for the diagnosis of GCA have been proposed by the American College of Rheumatology (ACR) (Table 81-1).1 Two classification schemes have been proposed for PMR (Table 81-2).2,3 DEFINITIONS Giant Cell Arteritis GCA is the most common form of systemic vasculitis in adults.4 The disease affects primarily the extracranial ­bran­ches of the carotid artery in patients older than 50 years. The most feared complication of GCA is irreversible loss of vision. Because the cause of GCA is unknown, various names—including temporal arteritis, cranial arteritis, and

granulomatous arteritis—have been used to highlight different salient features.5,6 All the names for this disease have both merits and shortcomings. The designation temporal arteritis or cranial arteritis, for example, conveys how frequently the temporal arteries or other cranial arteries are involved but fails to capture GCA’s more widespread nature. Although granulomatous arteritis and GCA pay homage to an important pathologic finding, this focus is undeserved, because giant cells are absent in about half the cases and may be present in other forms of vasculitis. With no perfect name available, this chapter bows to convention and refers to this disease as GCA. Polymyalgia Rheumatica Polymyalgia rheumatica, a term suggested by Barber,5 is a syndrome characterized by aching in the proximal portions of the extremities and torso. Because there are no specific diagnostic tests or pathologic findings, PMR is defined by its clinical features. The features included in most definitions of PMR are as follows: (1) aching and morning stiffness lasting half an hour or longer in the shoulder, hip girdle, neck, or some combination; (2) duration of these symptoms for 1 month or longer; (3) age older than 50 years; and (4) laboratory evidence of systemic inflammation, such as an elevated erythrocyte sedimentation rate (ESR).2 Some definitions also include a rapid response to small doses of glucocorticoids, such as prednisone 10 mg/day.7 The presence of another specific disease other than GCA, such as rheumatoid arthritis (RA), chronic infection, polymyositis, or malignancy, excludes the diagnosis of PMR. EPIDEMIOLOGY The incidence of GCA varies widely in different populations, from less than 0.1 per 100,000 to 33 per 100,000 persons aged 50 years and older.8-19 The greatest risk factor for developing GCA is aging; the disease almost never occurs before age 50, and its incidence rises steadily thereafter. Nationality, geography, and race are also important, with the highest incidence figures found in Scandinavians and in Americans of Scandinavian descent. The lowest incidence of GCA is reported in Japanese, northern Indians, and African Americans. In western Europe, GCA is more common in the northern latitudes than the southern ones. The incidence of GCA has been increasing over the last 20 to 40 years, possibly because of greater physician awareness.8 Some studies have reported seasonal variations and clustering of cases, with peaks about 7 years apart.8,17,19 The prevalence of GCA in Olmsted County, Minnesota, home to many Scandinavian immigrants, is 200 per 100,000 1409

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Giant Cell Arteritis, Polymyalgia Rheumatica, and Takayasu’s Arteritis

Table 81-1  American College of Rheumatology   Classification Criteria for Giant Cell Arteritis

Table 81-2  Diagnostic Criteria* for Polymyalgia   Rheumatica

Criterion*

Definition

Criteria of Chuang and Colleagues2 (1982)

Age at disease onset ≥50 yr

Development of symptoms or findings beginning at age 50 or older

New headache

New onset or new type of localized pain in the head

Temporal artery abnormality

Temporal artery tenderness to palpation or decreased pulsation, unrelated to arteriosclerosis of cervical arteries

Age 50 yr or older Bilateral aching and stiffness for 1 mo or more and involving two of the following areas: neck or torso, shoulders or proximal regions of the arms, and hips or proximal aspects of the thighs Erythrocyte sedimentation rate (ESR) >40 mm/hr Exclusion of all other diagnoses except giant cell arteritis

Elevated erythrocyte sedimentation rate (ESR)

ESR ≥50 mm/hr by the Westergren method

Abnormal artery biopsy

Biopsy specimen with artery showing vasculitis characterized by a predominance of mononuclear cell infiltration or granulomatous inflammation, usually with multinucleated giant cells

*For purposes of classification, a patient with vasculitis is said to have ­giant cell (temporal) arteritis if at least three of these five criteria are present. The presence of any three or more criteria yields a sensitivity of 93.5% and a specificity of 91.2%. From Hunder GG, Bloch DA, Michel BA, et al: The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. ­Arthritis Rheum 33:1125, 1990.

population aged 50 years or older.16 Autopsy studies suggest that GCA may be more common than is clinically apparent. Östberg20 found arteritis in 1.6% of 889 postmortem cases in which sections of the temporal artery and two transverse sections of the aorta were examined. Genetic susceptibility to the development of GCA was initially suggested by reports of GCA in families21-23 and, more recently, by studies demonstrating an association with genes in the human leukocyte antigen (HLA) class II region.24,25 Sixty percent of GCA patients have HLA-DRB1*04 haplotype variants, which have a common sequence motif in the second hypervariable region of the B1 molecule.25 This motif differs from that found in patients with RA.25 The low prevalence of these alleles in African Americans may explain why blacks develop GCA relatively infrequently. To date, GCA is the form of systemic vasculitis most closely associated with HLA class II genes. The existence of environmental risk factors has been suggested by the geographic clustering of GCA cases. Smoking appears to increase the risk of developing GCA sixfold in women.26 Circumstantial evidence links the development of GCA to a variety of infectious agents, including Mycoplasma pneumoniae, varicella-zoster virus, parvovirus B19, and parainfluenza virus type I.17,18 The results of examining temporal artery biopsy specimens with polymerase chain reaction methods to detect parvovirus B19 or herpesvirus DNA have been negative or inconsistent.27,28 The reported association between GCA and Chlamydia pneumoniae infection has not withstood close scrutiny.29 Gender and health status also influence the development of GCA. Women are affected about twice as often as men.17 Having diabetes reduces the risk of developing GCA by 50% in women.2 Although patients with GCA have an increased risk of developing thoracic aortic aneurysms, they do not have overall higher mortality rates.17

Criteria of Healey3 (1984) Pain persisting for at least 1 mo and involving two of the following areas: neck, shoulders, and pelvic girdle Morning stiffness lasting >1 hr Rapid response to prednisone (20 mg/day or less) Absence of other diseases capable of causing the musculoskeletal symptoms Age older than 50 yr ESR >40 mm/hr *For each set of criteria, all the findings must be present for polymyalgia rheumatica to be diagnosed. From Salvarani C, Cantini F, Boiardi L, Hunder GG: Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med 347:261, 2002.

PMR is two to three times more common than GCA.17,18,30,31 In Olmsted County, Minnesota, 245 cases of PMR were diagnosed during the 22-year period from 1970 through 1991, providing an average annual incidence rate of 52.5 cases per 100,000 persons aged 50 years or older.31 The prevalence of PMR (active plus remitted cases) was approximately 600 per 100,000 persons aged 50 years and older.31 PMR is associated with the same HLA-DR4 genes as GCA.24,25,32 CAUSE, PATHOLOGY, AND PATHOGENESIS The causes of GCA and PMR are unknown. Because pathologic studies have provided important clues to the pathogenesis, they are discussed first. In GCA, inflammation is found most often in mediumsize muscular arteries that originate from the arch of the aorta.17,20,33-36 The inflammation tends to affect the arteries in a segmental fashion (possibly leading to “skip lesions” within arteries), but long portions of arteries may be involved.37 In patients who died during the active phase of GCA, the greatest frequency of severe involvement was noted in the superficial temporal arteries, vertebral arteries, and ophthalmic and posterior ciliary arteries.38 The internal carotid, external carotid, and central retinal arteries were affected somewhat less frequently.38 In other postmortem studies, lesions were commonly found in the proximal and distal aorta and internal and external carotid, subclavian, brachial, and abdominal arteries.20 Because GCA affects vessels with an internal elastic lamina and vasa vasorum, and because intracranial arteries lose these structures after penetrating the dura, it is not surprising that GCA rarely involves intracranial arteries.38-41 In some patients with GCA, follow-up biopsy or autopsy surveys showed the persistence of mild chronic inflammation, even though symptoms had resolved.42 Early in the disease, collections of lymphocytes are confined to the region of the internal or external elastic lamina or adventitia. The inflammation may be limited to the vasa vasorum in some cases.43 Intimal thickening with prominent cellular infiltration is a hallmark of more advanced cases.

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Figure 81-1  Giant cell arteritis. In this transverse section of the temporal artery, the adventitia is at the top and the intima is at the bottom center. A multinucleated giant cell (arrow) is present at the junction of the media and intima. There is extensive disruption of all layers of the vessel wall (hematoxylin and eosin, ×100). (Courtesy of Dr. J. T. Lie.)

In heavily involved areas, all layers are affected (Fig. 81-1). Transmural inflammation of portions of the arterial wall (including the elastic laminae) and granulomas containing multinucleated histiocytic and foreign body giant cells, histiocytes, lymphocytes (which are predominantly CD4+ T cells), and some plasma cells and fibroblasts are found.35,44-47 Eosinophils may be seen, but polymorphonuclear leukocytes are rare. Thrombosis may develop at sites of active inflammation; later, these areas may recanalize. The inflammatory process is usually most marked in the inner portion of the media adjacent to the internal elastic lamina. Fragmentation and disintegration of elastic fibers occur, closely associated with an accumulation of giant cells (Fig. 81-2). However, giant cells are seen in only about half of routinely examined specimens; therefore, they are not required to make the diagnosis if other features are compatible. In contrast to some other forms of systemic vasculitis (e.g., polyarteritis nodosa, microscopic polyangiitis, Wegener’s granulomatosis), fibrinoid necrosis is rarely if ever observed in GCA.43 Immunohistochemical studies demonstrate inflammatory changes that are specific for each layer of the affected artery.18,45-52 Dendritic cells, which can present antigen and activate T cells, are found in the adventitia.53-55 The adventitia is also infiltrated by CD4+ T cells that secrete interferon-γ (IFN-γ) and interleukin-2 (IL-2), and macrophages that secrete IL-1, IL-6, and transforming growth factor-β (TGF-β). This cytokine pattern is characteristic of a T helper type 1 (Th1)–mediated reaction.35,49 The adventitial T cells show evidence of clonal expansion. The media is populated mostly by macrophages that, in contrast to those in other layers, produce matrix metalloproteinases and oxygen free radicals. Closer to the intima, the macrophages secrete nitric oxide and unite to form syncytia—the giant cells—which produce platelet-derived growth factor (PDGF) and substances that stimulate intimal proliferation.35,56 Although microscopic examination of arteries in PMR are usually normal, immunohistochemical studies of apparently uninvolved temporal arteries reveal upregulation of the same macrophage-related inflammatory cytokines found in GCA.35,49 The T cell cytokine IFN-γ is abundantly expressed in GCA and is absent in arteries from patients having only

Figure 81-2  Giant cell arteritis involving the proximal aorta in a ­patient who died of a ruptured ascending aorta. This section of the ­ascending aorta is distal to the ruptured portion and shows destruction of elastic fibers (arrow) (elastic van Gieson stain, ×64). Neighboring ­sections stained with hematoxylin and eosin showed infiltrations of mono­nuclear leukocytes in the areas of disrupted fibers.

PMR.49 Pathologically, relatively little else has been found in PMR. Granulomatous myocarditis and hepatitis have been noted.57 Muscle biopsy specimens may be normal or show nonspecific type II muscle atrophy.58 However, a number of reports have shown the presence of lymphocytic synovitis in the knees, sternoclavicular joints, and shoulders and evidence of a similar reaction in sacroiliac joints.59-63 Synovitis (mostly subclinical) was shown in bone scans demonstrating an increased uptake of technetium pertechnetate in the joints of 24 of 25 patients with PMR.60 More sensitive studies using magnetic resonance imaging (MRI) and ultrasonography have convincingly demonstrated that in PMR, the principal foci of inflammation are the bursae surrounding the shoulder more than the glenohumeral joint itself.64 Sera from patients with GCA, PMR, or both demonstrate evidence of systemic inflammation, with increased levels of circulating immune complexes during active disease65,66 and elevated levels of IL-6 and IL-1.48 These observations, together with the results from experiments in which temporal arteries from patients with GCA have been implanted into mice with severe combined immunodeficiency (SCID), have been used to propose a model of the immunopathogenesis of GCA35,45,55 (Fig. 81-3). The key initiating event might be the activation of dendritic cells located in the adventitia, the only arterial layer normally penetrated by the vasa vasorum. In large and medium-size arteries, immunohistochemical studies reveal that the dendritic cells in temporal arteries have a specific phenotype and express fascin and CD11c.35,53,54,66 In GCA, activation of Toll-like receptors (TLRs) on dendritic cells appears to be the initial triggering event.53,54,67 Of the many different types of TLRs, TRL-2 and TLR-4 might be the most important in GCA. Experiments in the GCA-SCID mouse model have shown that blood-borne

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In healthy medium-sized arteries, immature, nonactivated dendritic cells reside in the adventitia near the adventitia-media border. When immature dendritic cells present antigen to T cells, the T cells are inhibited, which may be important in maintaining immune tolerance.

Immature Dendritic Cells

In temporal arteritis, a triggering antigens (e.g., an infectious agent, drug, toxin, or autoantigen) activates dendritic cells resident in the arterial wall. The activated dendritic cells release chemokines that attract T cells from the vasa vasorum and macrophages into the arterial wall. Binding of those chemokines to the dendritic cells traps them in the evolving inflammatory infiltrate. Activated Dendritic Cell

Adventitia Vasa Vasorum

T cell Chemokines

Vasa vasorum

Adventitia

External Elastic Lamina

Media Lumen

Media

Macrophage Chemokines

Internal Elastic Lamina

Temporal artery Intima

Adventitia

Endothelium

Media

The activated dendritic cells express receptors and release inflammatory cytokines (interleukin [IL] 6, IL-18) that promote activation of T cells and vascular inflammation. IL-18 up-regulates the release of interferon (IFN) γ from T cells. IFN-γ released from activated T cells promotes inflammation, granuloma formation, and macrophage activation and differentiation.

Adventitia Activated Dendritic Cells IFN-γ IL-18 IL-6

Figure 81-3  Model for the pathogenesis of giant cell arteritis. (From Shermling RH: An 81-year-old ­ women with temporal arteritis. JAMA 295:25252534, 2006.)

IL-1

Vasa Vasorum

lipopolysaccharide serves as an effective TLR ligand in temporal arteries.54 Other constituents of microorganisms or some self-antigens (e.g., oxidized lipids) may also be TLR ligands that activate the arterial dendritic cells. Once its TLRs have been engaged, dendritic cells differentiate from the resting to the active state and release cytokines such as IL-6 and IL-18, which recruit, activate, and retain CD4+ T cells in the blood vessel. The crucial role of dendritic cells in activating T cells and maintaining vasculitis has been demonstrated in the GCA-SCID mouse model: depleting the dendritc cells markedly reduces the T cell infiltrate and suppresses the vasculitis.54 In turn, these activated CD4+ T cells clonally expand and secrete IFN-γ, which causes macrophages to migrate, differentiate, and form granulomas. Production of matrix metalloproteinases and lipid peroxidation agents by macrophages in the media results in the destruction of elastic laminae. The vessel attempts to counter the tissue destruction by elaborating a variety of growth factors, including PDGF, vascular endothelial growth factor (VEGF), and TGF-β, which prompt smooth muscle cells in the media to revert from a contractile phenotype to a secretory one and migrate to the intima. Proliferation of the intimal smooth muscle cells results in occlusion of the lumen.35,45,53 PMR appears to result from a similar but less intense adaptive immune response in blood vessels (as evidenced by the in situ production of many inflammatory cytokines).49 ­According

Matrix Metalloproteinases Reactive Oxygen Intermediates

IL-6 Activated Macrophages Intima

Activated T Cells

Activated macrophages produce a variety of mediators that lead to progressive vascular inflammation, endothelial damage, disruption of the internal elastic lamina, and intimal hyperplasia. Macrophages also release cytokines (IL-1, IL-6) that may contribute to systemic features of temporal arteritis.

Lumen

Platelet-derived Growth Factor

Inflammatory infiltrate Disruption of Internal Elastic Lamina Intimal Hyperplasia

Vascular Endothelial Growth Factor

to this model, both PMR and GCA begin with the activation of dendritic cells at the adventitia-media ­ border.53,67 However, the distinguishing feature of PMR is the absence of T cells producing IFN-γ. Without IFN-γ to stimulate the recruitment and differentiation of macrophages, the level of arterial inflammation in PMR remains subclinical. Thus, the development of GCA appears to require both vascular dendritic cell activation and a disease-inducing repertoire of T cells.35,53,67 The constitutional symptoms of PMR and GCA are attributed to the high levels of inflammatory cytokines (e.g., IL-1, IL-6) found in the sera. Whether these serum cytokine elevations result from blood vessel inflammation alone or from some other source of inflammation is not yet clear. The attractiveness of this model is increased by its ability to explain why subsets of clinical features occur together. CLINICAL FEATURES The mean age at onset of GCA and PMR is approximately 70 years, with a range of about 50 to 90 years of age.17 Younger patients with PMR have been described ­occasionally. Women are affected about twice as often as men.4,31 Although the onset of the disease is usually insidious, typically evolving over weeks or months, in one third of cases, the disease begins so abruptly that some patients recall the very day they became ill.17,57

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Table 81-3  Symptoms of Giant Cell Arteritis Symptom

Frequency (%)

Headache

76

Weight loss

43

Fever

42

Fatigue

39

Any visual symptom

37

Anorexia

35

Jaw claudication

34

Polymyalgia rheumatica

34

Arthralgia

30

Unilateral visual loss

24

Bilateral visual loss

15

Vertigo

11

Diplopia

 9

Modified from Smetana GW, Shmerling RH: Does this patient have temporal arteritis? JAMA 287:92, 2002. Data from a review of 2475 patients reported in the literature.

Giant Cell Arteritis Classic Manifestations. The most common manifestations of GCA are constitutional symptoms, headache, visual symptoms, jaw claudication, and PMR17 (Table 81-3). Almost all patients experience one or more constitutional symptoms, including fatigue, weight loss, malaise, and fever. Besides constitutional symptoms, headache is the most common symptom in GCA, being present in nearly three quarters of patients.68 The pain is typically described as boring in quality, of moderate severity, and most commonly appreciated in the temporal area. However, the description of the headache varies enormously. It can be mild to so severe that the patient seeks immediate relief by presenting to the emergency department. The pain may localize to any part of the skull, including the occiput (owing to involvement of the occipital artery).17,20 The most consistent characteristic is that the patient experiences the headache as something new and unusual. In untreated patients, the headache may subside over weeks, even though the disease activity continues. Often, the headache of GCA is not associated with any particular findings on physical examination. Abnormalities of the temporal artery—including enlargement, nodular swelling, tenderness, or loss of pulse—develop in only about half of patients (Fig. 81-4). Some patients note tenderness of the scalp, which can be aggravated by brushing or combing the hair. Visual symptoms are common in GCA, especially loss of vision and diplopia. Vision loss can be unilateral or (less commonly) bilateral, transient or permanent, and partial or complete.69,70 Vision loss lasting more than a few hours usually does not reverse. Loss of vision often reflects an anterior ischemic optic neuropathy caused by occlusive arteritis of the posterior ciliary artery, the chief blood ­supply to the head of the optic nerve. The posterior ciliary artery is a branch of the ophthalmic artery (which derives, in turn, from the internal carotid artery). Less frequently, vision loss in GCA stems from a retinal artery occlusion. Regardless of the site of the culprit lesion, vision loss in GCA is usually profound, with more than 80% of patients unable to see hand waving.69 GCA patients who

Figure 81-4  Giant cell arteritis (GCA) involving the temporal artery. Short segments of curved artery were erythematous and tender (long arrows). The bandage on the scalp covers a similar artery that was biopsied  and showed GCA. A previous biopsy specimen of a proximal segment of the right temporal artery, which was normal on physical examination, was normal histologically. The faint scar from that biopsy can be seen above and anterior to the right ear (short arrows).

present with fever or other systemic symptoms are less likely to develop vision loss.71-73 One possible explanation of this protective effect of fever and other systemic manifestations is that patients with prominent systemic inflammation demonstrate more extensive angiogenesis in temporal artery biopsies.74 The angiogenesis associated with increased inflammation may result in the development of collateral circulation that reduces the chance of ischemic events.36,74 The early funduscopic appearance in the setting of blindness caused by anterior ischemic optic neuropathy is that of ischemic optic neuritis: slight pallor and edema of the optic disk, with scattered cotton-wool patches and small hemorrhages69 (Fig. 81-5). Later, optic atrophy occurs. Rarely, blindness may be the initial symptom; however, it tends to follow other symptoms by several weeks or even months. Ophthalmoscopic examination in patients without eye involvement is generally normal. In most reports, the incidence of blindness is 20% or less.7,30,39,66,69,75 In a series of 245 patients from the modern era, 34 (14%) had some permanent loss of vision.75 In 32 of these patients, the deficit developed before glucocorticoid therapy was begun; in the other 2, vision loss occurred after therapy was started. Vision loss progressed in 3 of the 32 after therapy was initiated, and it improved in 5. At 5 years’ follow-up, among the patients who had visual deficits caused by GCA at the time glucocorticoids were started, the risk of additional loss of vision was 13% over the follow-up period. If no loss had occurred at the beginning of glucocorticoid therapy, there was only a 1% risk of new loss of vision over the subsequent 5 years. Another potential ocular complication of GCA is ophthalmoplegia. Diplopia usually results from ocular motor

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Table 81-4  Atypical Manifestations of Giant Cell   Arteritis Fever of unknown origin Respiratory symptoms (especially cough) Otolaryngeal manifestations Glossitis Lingual infarction Throat pain Hearing loss Large artery disease Aortic aneurysm Aortic dissection Limb claudication Raynaud’s phenomenon Neurologic manifestations Peripheral neuropathy Transient ischemic attack, stroke Dementia Delirium Myocardial infarction Figure 81-5  Ophthalmoscopic view of the acute phase of ischemic optic neuropathy seen in patients with giant cell arteritis and loss of  vision. The optic disk is pale and swollen, the retinal veins are dilated, and a flame-shaped hemorrhage is visible. (Courtesy of Dr. J. Trautmann.)

Tumor-like lesions Breast mass Ovarian and uterine mass

nerve palsies caused by ischemia and usually resolves after therapy is started. Oculomotor nerve involvement in GCA usually spares the pupil.69 Rarely, arterial lesions cause infarction of the occipital cortex and vision loss. Intermittent claudication may occur in the muscles of mastication (jaw claudication), the extremities, and occasionally the muscles of the tongue or those involved in swallowing.17 In the jaw muscles, the discomfort is noted especially when chewing meat and may involve the muscles on one side of the mandible more than those on the other. In some instances, facial artery involvement results in spasm of the jaw muscles. More marked vascular narrowing may lead to gangrene of the scalp or tongue.

Microangiopathic hemolytic anemia

Atypical Manifestations. Approximately 40% of patients present with disease manifestations that are considered atypical55,76-78 (Table 81-4). In these patients, headache, jaw claudication, visual symptoms, and PMR do not occur or are less prominent. Fever occurs in up to 40% of patients with GCA, but it is usually low grade and overshadowed by other classic symptoms. However, 15% of GCA patients may present with fever of unknown origin (FUO) in which the temperature spikes are high, dominating the clinical picture.7,57 Although GCA causes only 2% of all cases of FUO, it is responsible for 16% of all such fevers in individuals older than 65 years.57 Approximately two thirds of patients experience shaking chills and drenching sweats, features often attributed to infection or malignancy. The median temperature is 39.1°C, and the maximum 39.8°C. The white blood cell count in GCA-induced FUO is usually normal or nearly so (at least before the initiation of prednisone). Neurologic problems occur in approximately 30% of patients.40,41,79 These are diverse, but most common are neuropathies and transient ischemic attacks or strokes. Hemiparesis or brainstem events are due to narrowing or occlusion of the carotid or vertebrobasilar artery. GCA preferentially involves the posterior circulation; the 3:2 ratio of

Syndrome of inappropriate antidiuretic hormone secretion

anterior to posterior strokes and transient ischemic attacks seen in the normal population reaches nearly 1:1 in patients with GCA.40 Delirium, reversible dementia, and myelopathy have also been reported.40 However, the assignment of an exact cause to ischemic central nervous system events is often challenging, given the older population in which GCA occurs. The neuropathies of GCA include mononeuropathies and peripheral polyneuropathies and may affect the upper or lower extremities. Presumably, they are secondary to the involvement of nutrient arteries, but little pathologic documentation is available. Among the vasculitides, GCA has a nearly unique propensity for involving the C5 nerve root, resulting in loss of shoulder abduction.40 Mononeuropathies affecting the hands and feet, so typical of polyarteritis and other forms of vasculitis, develop less often in GCA. Prominent respiratory tract symptoms occur in about 10% of patients.80 These include cough with or without sputum, sore throat, and hoarseness. When these symptoms are severe or an initial manifestation of GCA, they may direct the attention of the examining physician away from the underlying arteritis. Vasculitis may induce these symptoms by causing ischemia or hyperirritability of the affected tissues. Otolaryngeal manifestations of GCA include throat pain, dental pain, tongue pain, glossitis, and ulceration or infarction of the tongue.80,81 Clinical evidence of large artery involvement occurs in 10% to 15% of cases at presentation and in up to 27% eventually.34,36,62,63,82-85 Positron emission tomography (PET) studies using fluorodeoxyglucose (FDG) revealed that subclinical involvement of large arteries occurs in the vast majority of GCA patients. One PET study, for example, showed that 88% of 35 patients had increased FDG uptake in large arteries, with subclavian involvement in 74% and aortic involvement in 54%.86

PART 13 

Generally, clinically evident disease can be divided into early (within a year of diagnosis) and late (years after diagnosis) stages. Usually, early disease consists chiefly of large artery stenosis resulting in upper extremity claudication; bruits over the carotid, subclavian, axillary, and brachial arteries; absent or decreased pulses in the neck or arms; and Raynaud’s phenomenon (Fig. 81-6).85 Angiographic features that suggest GCA are smooth-walled arterial stenoses or occlusions alternating with areas of normal or increased caliber in the absence of irregular plaques and ulcerations, located especially in the carotid, subclavian, axillary, and brachial arteries. Late disease most frequently involves thoracic aortic aneurysm.85 The tendency for aneurysm to develop late was confirmed in one series of 41 patients in which the average time between diagnosis of GCA and recognition of this complication was 7 years.65 Thoracic aortic aneurysm is 17 times more likely to develop in patients with GCA than in persons without this disease. To place this risk in context, thoracic aortic aneurysms are twice as likely to complicate GCA as lung cancer is to result from smoking.83Abdominal aortica aneurysm is also 2.4 times more common in patients with GCA.34,65 In aggregate, nearly one out of five patients (18%) with GCA develops an aortic aneurysm or dissection.85 Patients with large artery disease often do not have headache or other classic manifestation of GCA, and less than 50% have an abnormal temporal artery biopsy. Computed tomography (CT) angiography and magnetic resonance angiography (MRA) are the imaging modalities most commonly used to detect large artery disease in GCA. In women, GCA may present as a breast or ovarian mass. The mass lesions in these tissues result from granulomatous inflammation in and around the arteries.84 Angina pectoris, congestive heart failure, and myocardial infarction secondary to coronary arteritis occur rarely. Clinical Subsets. Studies suggest that GCA is not just one disease but rather a number of clinical subsets that are explained by the differential expression of inflammatory cytokines.87,88 Ischemic events, including blindness, stroke, and large artery disease, occur more commonly in patients who express high levels of IFN-γ and low levels of IL-6.88 In contrast, patients who produce high levels of IL-6 are more likely to have strong inflammatory features (such as fever and constitutional symptoms) and are less likely to develop vision loss or other ischemic events.88-91 Polymyalgia Rheumatica As in GCA, PMR patients are characteristically in good health before their disease begins.17 Systemic manifestations, such as malaise, low-grade fever, and weight loss, are present in more than half the patients and may be the initial symptoms. High, spiking fevers are uncommon in PMR in the absence of GCA.57 Arthralgias and myalgias may develop abruptly or evolve insidiously over weeks or months.2 Malaise, fatigue, and depression, along with aching and stiffness, may be present for months before the diagnosis is made. In most patients, the shoulder girdle is the first to become symptomatic; in the remainder, the hip or neck is involved at the onset. The discomfort may begin in one shoulder or hip but usually becomes bilateral within weeks. Symptoms center on the proximal limb, axial musculature, and

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Figure 81-6  Giant cell arteritis of large arteries. Arch aortogram. Both subclavian and axillary arteries are affected. Smooth-walled segmental constrictions alternate with areas of normal caliber or aneurysmal dilation. (From Klein RG, Hunder GG, Stanson AW, Sheps SG: Large artery involvement in giant cell [temporal] arteritis. Ann Intern Med 83:806, 1975.)

tendinous attachments. Morning stiffness resembling that of RA and “gelling” after inactivity are usually prominent. If the symptoms are severe, aching is more persistent. Although movement of the joints accentuates the pain, it is often felt in the proximal extremities rather than in the joints.2 Distal joint pain and swelling occur in some cases, including diffuse distal extremity swelling with pitting edema.92 Pain at night is common, and movement during sleep may awaken the patient. Muscle strength is generally unimpaired, although pain with movement makes the interpretation of strengthtesting maneuvers difficult. Pain with movement also makes it difficult for patients to get out of bed or the bathtub. In the later stages of the syndrome, muscle atrophy may develop, and contracture of the shoulder capsule may result in limitation of passive as well as active motion. As noted, the presence of bursal inflammation and synovitis in PMR has been described by many authors and is undoubtedly the cause of many of the findings in this condition.64 A careful examination may reveal transient synovitis of the knees, wrists, and sternoclavicular joints. The shoulders and hips are covered by heavy muscles, and minimal effusions of slight synovitis are not palpable on physical examination. Synovitis has been documented by biopsies, synovial analysis, joint scintiscans, ultrasonography, and MRI.57-63,93 Relationship between Polymyalgia Rheumatica and Giant Cell Arteritis There is abundant evidence that PMR and GCA are related and should be considered different manifestations of a common disease process.17,35 The associations with age, ethnicity, geographic region, and HLA class II alleles are the same in both disorders. Moreover, both disorders involve overproduction of many of the same inflammatory cytokines. Between 30% and 50% of patients with GCA develop PMR. Approximately 10% to 15% of patients who appear to have only PMR have positive temporal artery biopsies. In the absence of symptoms of GCA (e.g., headache, jaw claudication, visual symptoms, high fever), PMR by itself does not appear to cause vision loss and responds to low doses of glucocorticoids (see later).17

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LABORATORY STUDIES Except for the findings on arterial biopsy, laboratory results in PMR and GCA are similar30 (Table 81-5). A mild to moderate normochromic anemia is usually present in both ­diseases during their active phases. Leukocyte and differential counts are generally normal. A markedly elevated ESR and C-reactive protein (CRP) level are characteristic of both. An ESR higher than 100 mm/hr (Westergren method) is common, but untreated biopsy-proven cases of GCA may be associated with normal or nearly normal levels. In a study of 167 GCA patients, 10.8% presented with an ESR of less than 50 mm/hr, and 3.6% had a rate of less than 30 mm/hr.94 Rare individuals appear to be unable to develop an elevated ESR during any inflammatory process, including active GCA.94 The ESR is also liable to be relatively low or normal in patients who have been receiving corticosteroids for another condition.95 Thus, a normal ESR does not exclude GCA, especially in a patient with otherwise classic symptoms and findings. Platelet counts are often increased. Nonspecific changes in plasma proteins are often present and include a decrease in the concentration of albumin and an increase in α2-globulins, fibrinogen, and other acutephase reactant proteins. Slight increases in gammaglobulins and complement may be present. Results of tests for antinuclear antibodies and rheumatoid factor are generally negative. Liver function test results are mildly abnormal in approximately one third of patients with GCA and in a slightly smaller fraction of those with PMR.30,66 An increased alkaline phosphatase level is the most common abnormality, but increases in aspartate transaminase and prolonged prothrombin time may also be found.96 Liver biopsy specimens are generally normal; granulomatous hepatitis has been observed.57 Renal function and urinalysis are usually normal. Red blood cell casts are found in some instances, but their presence does not correlate with clinical large artery involvement.37 Levels of serum creatine kinase and other enzymes reflecting muscle damage are normal. Electromyograms are usually normal, and muscle biopsy shows normal histologic features or only the mild atrophy characteristic of disuse.58 Synovial fluid analyses reported in GCA or PMR showed evidence of mild inflammation, including increased synovial fluid leukocyte counts, with a mean of 2900 cells/mm3 but a range from 300 to 20,000 cells/mm3, with 40% to 50% Table 81-5  Physical Findings and Laboratory   Abnormalities in Giant Cell Arteritis Feature

Frequency (%)

Any temporal artery abnormality

65

Prominent or enlarged temporal artery

47

Absent temporal artery pulse

45

Scalp tenderness

31

Any funduscopic abnormality

31

Abnormal erythrocyte sedimentation rate (ESR) ESR >50 mm/hr ESR >100 mm/hr

96 83 39

Anemia

44

Modified from Smetana GW, Shmerling RH: Does this patient have ­temporal arteritis? JAMA 287:92, 2002.

being polymorphonuclear leukocytes.61,93 Synovial fluid com­ plement levels are usually normal.97 In some instances, synovial biopsy has shown lymphocytic synovitis.59-63 Serum IL-6 levels are elevated in patients with PMR and GCA and appear to closely parallel the inflammatory activity.98 Levels of factor VIII or von Willebrand’s factor are elevated in patients with GCA and PMR.99,100 DIFFERENTIAL DIAGNOSIS The diagnosis of GCA should be considered in any patient older than 50 years who experiences loss of vision, diplopia, new form of headache, jaw claudication, PMR, FUO, unexplained constitutional symptoms, anemia, and a high ESR. GCA can cause so many forms of cranial discomfort (e.g., headache, scalp tenderness, jaw claudication, pain of the throat, gums, and tongue) that the disease should also be considered in any patient older than 50 who develops new, unexplained “above-the-neck” pain. The protean manifestations of GCA means that it should also be considered in the differential diagnosis of an older patient presenting with dry cough, stroke, arm claudication, or acute C5 radiculopathy accompanied by other classic symptoms or findings of GCA. Only a few individual symptoms or findings substantially increase or decrease the likelihood of a patient having this disease68 (Table 81-6). For example, jaw claudication, ­diplopia, abnormal temporal artery signs, scalp tenderness, and ESR greater than 50 mm/hr increase the likelihood that a patient has GCA.68 In one series of 373 patients, the ­presence of either jaw claudication or diplopia increased the likelihood of a positive biopsy by more than threefold; the presence of both jaw claudication and double vision had a 100% positive predictive value for a diagnostic temporal artery biopsy.101 Conversely, the absence of headache or temporal artery abnormalities on physical examination, the presence of synovitis, and a normal ESR reduce the likelihood of GCA. A large number of disorders can mimic GCA. There are many causes of monocular vision loss besides vasculitis, including arteriosclerosis-induced thromboembolic disease.69 Patients with nonarteritic vision loss do not have other GCA-related symptoms, signs, or findings. The funduscopic examination may help by revealing Hollenhorst plaques in cases caused by cholesterol emboli. Anterior ischemic optic neuropathy, the most common cause of vision loss in GCA, can also be caused by arteriosclerosis. Nonarteritic optic neuropathy invariably produces a small optic disk and cupto-disk ratio, whereas GCA-related optic neuropathy results in an optic disk of variable size.69 Thus, a normal size or large cup in a patient with anterior ischemic optic neuropathy suggests GCA until proved otherwise.69 Constitutional symptoms with anemia and an elevated ESR in an older person may also be produced by occult infections (e.g., tuberculosis, bacterial endocarditis, human immunodeficiency virus [HIV]) or malignancy (especially lymphoma and multiple myeloma). These diagnoses highlight the value of selective serologic tests, imaging studies, and immunoelectrophoresis in appropriate patients. Systemic amyloidosis can closely mimic GCA, being one of the few disorders other than GCA that causes jaw claudication.102 The amyloid deposits in the temporal artery may not be detected

PART 13 

Table 81-6  Likelihood Ratios* for Symptoms, Signs,   and Laboratory Findings in Giant Cell Arteritis Finding

Positive Likelihood Ratio (95% CI)

Negative Likelihood Ratio (95% CI)

4.2 (2.8-6.2) 3.4 (1.3-8.6) 1.3 (1.1-1.5) 1.2 (1.1-1.4) NS NS NS NS

0.72 (0.65-0.81) 0.95 (0.91-0.99) 0.89 (0.79-1.0) 0.7 (0.57-0.85) NS NS NS NS

NS NS

NS NS

4.6 (1.1-18.4)

0.93 (0.88-0.99)

2.6 (1.9-3.7)

0.82 (0.74-0.92)

2.0 (1.4-3.0)

0.53 (0.38-0.75)

1.6 (1.2-2.1) 0.41 (0.23-0.72) NS

0.93 (0.86-1.0) 1.1 (1.0-1.2) NS

1.1 (1.0-1.2) 1.2 (1.0-1.4) 1.9 (1.1-3.3) NS

0.2 (0.08-0.51) 0.35 (0.18-0.67) 0.8 (0.68-0.95) NS

Symptoms Jaw claudication Diplopia Weight loss Any headache Fatigue Anorexia Arthralgia Polymyalgia   rheumatica Fever Visual loss Signs Beaded temporal artery Tender temporal artery Any temporal artery abnormality Scalp tenderness Synovitis Optic atrophy Laboratory Results ESR abnormal ESR >50 mm/hr ESR >100 mm/hr Anemia

*Based on literature review, with the number of patients for each variable ranging from 68 to 2475. CI, confidence interval; ESR, erythrocyte sedimentation rate; NS, not significant. Modified from Smetana GW, Shmerling RH: Does this patient have temporal arteritis? JAMA 287:92, 2002.

unless the specimen is stained with Congo red. Polyarthritis in an older patient is much more likely caused by RA than by GCA. In one study of 520 GCA patients, less than 2% developed polyarthritis before GCA was ­diagnosed.102,103 Criteria for the classification of GCA have been formulated and can help differentiate this arteritis from other forms of vasculitis1 (see Table 81-1). Takayasu’s arteritis, like GCA, can affect the aorta and the major arterial branches to the head and arms. Takayasu’s arteritis, however, is a disease of young women. Wegener’s granulomatosis can affect the temporal artery and, along with systemic amyloidosis, is an exception to the rule that jaw claudication is pathognomonic for GCA. Wegener’s granulomatosis, however, almost always produces telltale involvement of the respiratory tract or kidneys and is associated with antineutrophil cytoplasmic antibodies. Polyarteritis nodosa can also affect the temporal artery and should be considered if the biopsy does not contain giant cells and the patient has other features atypical for GCA, such as mesenteric arteritis. Fibrinoid necrosis of the vasa vasorum occurs in polyarteritis but rarely, if ever, in GCA. Primary angiitis of the central nervous system differs from GCA in that it affects the intracranial arteries. The diagnosis of PMR is clinical and depends on eliciting the symptoms and findings noted earlier. Two sets of criteria for the diagnosis have been proposed2,3 (see Table 81-2). Several disorders can mimic PMR. Distinguishing early RA from PMR can be difficult, especially in the 15%

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of patients who are rheumatoid factor negative and in those few RA patients who have not yet developed prominent synovitis of the small joints of the hands and feet. Patients with polymyositis complain much more of weakness than of pain—the opposite symptom pattern reported by patients with PMR. In addition, in polymyositis, levels of muscle enzymes are elevated, and electromyograms are abnormal. Although patients with neoplasms may have generalized musculoskeletal aching, there is no association between PMR and malignant neoplasia. Therefore, a search for an underlying tumor is not necessary unless some clinical evidence for a tumor is present or the patient has an atypically poor response to low-dose prednisone. Some patients with chronic infections, such as bacterial endocarditis, may have findings simulating PMR, and blood cultures should be obtained in patients with fever.104 Patients with fibromyalgia usually do not have typical morning stiffness and have laboratory test results that are normal or nearly so. Rarely, the stiffness of early Parkinson’s disease can be confused with PMR if the bradykinesia and tremor of Parkinson’s disease are subtle or absent. Lumbar spinal stenosis sometimes causes patients to complain of pain and stiffness in the hip girdle area. The absence of symptoms above the waist helps differentiate it from PMR. Cholesterollowering statin drugs can produce myalgia with or without muscle enzyme elevations but rarely mimic PMR. Hypothyroidism in the elderly can mimic many conditions, including PMR.104 A peculiar syndrome of remitting, ­seronegative synovitis with pitting edema (designated RS3PE syndrome) may be difficult to differentiate from PMR,104 and they may be related disorders. Patients with the RS3PE syndrome develop acute symmetric polysynovitis of distal joints with pitting edema of the hands and feet. The RS3PE syndrome and PMR both respond to nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose prednisone.17,105 DIAGNOSTIC EVALUATION IN GIANT CELL ARTERITIS Temporal artery biopsy is the “gold standard” for diagnosing GCA.17,106 Because GCA does not involve the artery in a continuous fashion, temporal artery biopsy should be directed to the symptomatic side, if evident. Removing a small (1- to 2-cm) section of temporal artery is usually adequate in patients who have palpable abnormalities of the vessel.107 Otherwise, the surgeon should try to excise a 4- to 6-cm sample, and the pathologist should examine multiple sections.17 In skilled hands, temporal artery biopsy is virtually free of morbidity or mortality. Scalp necrosis can rarely complicate active GCA but has not developed as a consequence of temporal artery biopsy.106 Temporal artery biopsies performed at institutions experienced in treating GCA are sensitive and have a high negative predictive value. At the Mayo Clinic, the sensitivity of temporal artery biopsy is approximately 90% to 95%, meaning that only 5% to 10% of patients with negative biopsies will subsequently be proved (by additional biopsy, angiography, or autopsy) to have GCA and require corticosteroid therapy.106,108 The sensitivity figures noted previously include some patients who underwent bilateral temporal artery bi­­ o­psy. Estimates of the value of bilateral biopsies vary. Of 234 cases of biopsy-proven GCA, unilateral biopsy was

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Giant Cell Arteritis, Polymyalgia Rheumatica, and Takayasu’s Arteritis

Giant cell arteritis suspected

Temporal artery biopsy

Positive biopsy: GCA proven

Negative biopsy

GCA still strongly suspected

GCA suspicion low

Perform second biopsy of temporal artery or occipital artery or perform imaging study if large artery involvement suspected

No further biopsy

Figure 81-7  Algorithm for diagnosing giant cell arteritis (GCA).

p­ ositive in 86%, and the second biopsy was positive in 14%.105 Other studies indicate that a second temporal artery biopsy improves the diagnostic yield by only 3% to 5%.109,110 Management of a patient with a negative unilateral biopsy depends on how strongly the patient’s clinical picture suggests GCA (Fig. 81-7). When GCA is still strongly suspected, a second biopsy should be considered. Patients with chiefly occipital headache may be best diagnosed by biopsy of the occipital artery.111 Patients who have signs of subclavian and axillary disease manifested by arm claudication, unequal arm blood pressures, and supraclavicular or axillary bruits may be diagnosed by angiogram, MRA, or CT scan.88 Typically, patients with extracranial GCA have smooth, tapered stenosis or occlusion of the subclavian, axillary, and proximal brachial arteries. In one series, temporal artery biopsy was positive in only 58% of patients with larger artery involvement.88 MRI and CT are the best-established methods for detecting aortic involvement by GCA.17 Other imaging techniques have been proposed to assist in the diagnosis of GCA. Color duplex ultrasonography showed abnormalities of the temporal artery in 28 of 30 patients with GCA (sensitivity of 93%).112 The most characteristic finding was a dark halo around the lumen of the temporal artery (Fig. 81-8). However, the diagnostic value of ultrasonography remains controversial.113 One study found that ultrasonography did not improve the diagnostic accuracy of a carefully performed physical examination.114 Highresolution MRI of the superficial temporal artery has shown promise in small series bur remains experimental.115 PET has shown promise in detecting occult involvement of the aorta and great vessels by GCA, but its specifity has not been established.86,116,117 TREATMENT AND COURSE Most authorities recommend starting glucocorticoid therapy as soon as the diagnosis of GCA is strongly suspected. The main goal of treatment is to prevent loss of vision. Because

Figure 81-8  Color duplex ultrasound examination of a swollen, tender temporal artery in a patient with giant cell arteritis. The variably thickened artery wall is visible as a clear “halo” (solid arrows) around the lumen in the center (open arrow).

vision loss is almost always permanent, it seems prudent to initiate corticosteroid therapy as early as possible, even before the biopsy is performed. Fortunately, the diagnostic yield of temporal artery biopsy is not altered by corticosteroid therapy for at least 2 weeks and perhaps longer.118,119 Initial Treatment for Giant Cell Arteritis An initial dose of prednisone 40 to 60 mg/day or equivalent is adequate in nearly all cases.17 Dividing the dose for the first 1 to 2 weeks may accelerate the rate of improvement. If the patient does not respond promptly, the dose should be increased. One double-blind, placebo-controlled, randomized trial involving 27 GCA patients suggested that initiating treatment with intravenous methylprednisolone (15 mg/kg of ideal weight per day) for 3 days allowed more rapid tapering of oral corticosteroids and increased the likelihood of achieving a sustained remission.120 The small size of that study and the possible overreliance on laboratory tests to define relapse raise questions about the generalizability of these results. High-dose, intravenous-pulse methylprednisolone (1000 mg/day) for 3 days has also been tried in patients with recent loss of vision. Unfortunately, the loss remains permanent in the vast majority of patients.121 The occlusive nature of the vasculitis argues against any role of acute thrombolytic therapy in the treatment of blindness.47 Because all patients with GCA require months of glucocorticoid therapy, measures to prevent osteoporosis should be started early, as outlined in Table 81-7. In addition, because traditional risk factors for atherosclerosis (e.g., smoking, hypertension, diabetes, hypercholesterolemia) might increase the risk of vision loss or stroke in GCA,72 reducing or eliminating these risk factors is an important part of overall management. Subsequent Treatment for Giant Cell Arteritis The initial effective dose of prednisone should be continued until all reversible symptoms, signs, and laboratory abnormalities have reverted to normal.17 This usually takes 2 to 4 weeks. After that, the dose can be gradually reduced by a maximum of 10% of the total dose each week or every 2 weeks.17 The decision to reduce prednisone should be based on a composite assessment of the patient’s symptoms, signs,

PART 13 

Table 81-7  Measures to Prevent   Corticosteroid-Induced Osteoporosis   in Giant Cell Arteritis or Polymyalgia Rheumatica Avoid or stop smoking Reduce alcohol consumption if excessive Participate in weight-bearing exercise Supplement diet with calcium (1000 to 1500 mg/day) Supplement diet with vitamin D (800 IU/day) Measure bone mineral density (BMD) at lumbar spine and hip If BMD is normal, repeat BMD annually If BMD is not normal (i.e., T score below −1), prescribe   bisphosphonate Modified from American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis: Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheum 44:1496, 2001.

and laboratory markers of inflammation. The ESR and serum concentration of CRP are generally the most convenient and helpful laboratory markers of inflammation. The ESR is reliable only if performed promptly after the blood sample is obtained. Serum levels of IL-6 appear to be the most sensitive marker of activity of GCA, but this test is not widely available.122 CRP may be slightly more sensitive than ESR in detecting flares.122 At some point during drug tapering, the ESR or CRP may rise above normal again, and further reductions of prednisone should be temporarily interrupted. If, over the next week or so, the patient does not develop signs or symptoms of active GCA, reductions in prednisone (at smaller decrements and at longer intervals) can usually be resumed. Doses of 10 to 20 mg/day or more are often required for several months before further reductions are possible However, making the prednisone dose a slave to the levels of inflammatory markers without regard to the patient’s overall clinical context risks corticosteroid-related side effects. Gradual reductions allow the identification of the minimal suppressive dose and help avoid exacerbations resulting from too-rapid tapering. Even with a gradual reduction of prednisone, more than 50% of patients experience flares of disease activity during the first year.123,124 These exacerbations can usually be handled by increasing the prednisone 10 mg above the last dose at which the disease was controlled. GCA tends to run a self-limited course for several months to several years, commonly 1 or 2 years.17 ­Glucocorticoids can eventually be reduced and discontinued in some patients. Many patients require low doses of prednisone for several years or more to control musculoskeletal symptoms. The nearly universal experience of serious side effects as­­ s­ociated with daily corticosteroids has prompted the search for alternative steroid-sparing treatments. Unfortunately, to date, none has been convincingly effective. Alternateday prednisone, for example, is not effective initial therapy for GCA.125 The combination of weekly low-dose oral methotrexate and prednisone was steroid sparing in one placebo-controlled, double-blind treatment trial124 but not in another.123 These conflicting results argue against using methotrexate in combination with prednisone as initial therapy for GCA. Methotrexate may be worth adding to the treatment regimen of a patient who has experienced several exacerbations despite slow tapering of prednisone. Although it was appealing to think that anti–tumor necrosis factor

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(TNF) agents might be effective in a granulomatous vasculitic process, a recent trial demonstrated that infliximab is not effective in GCA.126 Similarly, cytotoxic drugs, dapsone, antimalarials, and cyclosporine have not been clearly shown to be effective, but they may be considered in patients who cannot achieve an acceptably low dose of prednisone.17 No prospective, double-blind trials have tested the potential adjuncitve role of aspirin or anticoagulants in the treatment of GCA. However, aspirin is theoretically appealing because, in experimental models of GCA, it inhibits IFN-γ production more effectively than prednisone.127 In addition, two retrospective studies found that GCA patients taking low-dose aspirin or anticoagulant therapy had a three- to fivefold lower risk of developing an ischemic event such as vision loss.128,129 Together, these studies suggest that it is reasonable to add low-dose aspirin in GCA patients who do not have an excessive risk of gastrointestinal bleeding. Arm claudication from GCA affecting the subclavian and axillary arteries usually improves or resolves with corticosteroid therapy. Rare GCA patients with severe upper extremity claudication unresponsive to corticosteroid therapy may benefit from balloon angioplasty. In one series of 10 patients, all improved initially after angioplasty; but 50% developd symptomatic restenosis over 24 months.130 In all cases, recurrent stenosis developed in vascular lesions that were greater than 3 cm long.130 Thoracic aortic aneurysm is greatly increased in patients with GCA.83 Although it can be present at the outset, aneurysms are usually noted late in the disease course, an average of 7 years after onset. Some authorities have recommended annual chest radiographs to detect thoracic aortic aneurysms.83 Treatment for Polymyalgia Rheumatica Patients with PMR without symptoms or signs or biopsy evidence of GCA are usually treated initially with prednisone 10 to 20 mg/day or equivalent.131 Salicylates and NSAIDs have been used but are less appealing; salicylates and NSAIDs adequately control symptoms in only a minority of patients with milder symptoms and add to overall adverse drug reactions when they are used with glucocorticoids.2,10,132 Prednisone therapy usually results in rapid (often overnight) and dramatic improvement of the musculoskeletal aching and stiffness and a more gradual return of the ESR and CRP level to normal.133 A minority of patients with isolated PMR fail to respond to prednisone 20 mg/day after 1 week and may require up to 30 mg/day as initial treatment.134 Studies suggest that these resistant cases are more likely to have ESRs greater than 50 mm/hr and very high levels of IL-6.134 Failure to respond to prednisone 30 mg/day for 1 week should prompt a search for an alternative diagnosis (Fig. 81-9). Lower doses of prednisone may not suppress an underlying arteritis if it is present. Thus, the patient must be observed carefully even though the aching improves. In patients with PMR, the dose should be reduced gradually as soon as symptoms permit. Pretreatment ESR, CRP, and IL-6 concentrations and initial responses to therapy appear to be helpful in dividing patients into subsets with different treatment requirements.131,133 If the laboratory test results become normal while the patient is receiving a smaller dose, the ­likelihood of an underlying active vasculitis seems

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Giant Cell Arteritis, Polymyalgia Rheumatica, and Takayasu’s Arteritis

Polymyalgia rheumatica without giant cell arteritis suspected

Prednisone up to 20mg/day for 7 days

No or poor response after~7 days

Increase prednisone to 30 mg/day for~7 days Excellent response No response to prednisone 30 mg/day Diagnosis supported

Figure 81-9  Algorithm for diagnosing poly­ myalgia rheumatica without giant cell arteritis.

Reject diagnosis of polymyalgia rheumatica; search for alternative diagnosis

Continue to monitor for emergence of giant cell arteritis

to be much less, and the risk of vascular complications is smaller. However, this is not true in all instances, because active arteritis has been observed even though the ESR improved.135 Once the symptoms, signs, and laboratory abnormalities of PMR have resolved (usually after 2 to 3 weeks of therapy), the daily dose of prednisone can be slowly tapered. Some experts recommend tapering prednisone by 2.5 mg every week until 10 mg/day is reached, at which point the decrements should be reduced by 1 mg each month.133 Flares are common, necessitating a dose increase to achieve remission before attempting a slower taper. The minority of patients with PMR succeed in tapering off prednisone in less than 1 year.132 Many require at least 2 years of low-dose prednisone.136 Some, but not all, studies suggest that oral methotrexate (10 mg once a week for 48 weeks) can reduce the long-term Table 81-8  American College of Rheumatology   Classification Criteria for Takayasu’s Arteritis*

need for corticosteroids in patients with PMR.137 It is not yet known whether the small but statistically significant reduction in prednisone use achieved with methotrexate results in a clinically important reduction in prednisone-related side effects.

TAKAYASU’S ARTERITIS Takayasu’s arteritis (TA), also known as pulseless disease or occlusive thromboaortopathy, is a form of vasculitis of unknown cause that chiefly affects the aorta and its major branches, most frequently in young women.138-143 The disease is named for the Japanese ophthalmologist who in 1908 described a young woman with peculiar retinal arteriovenous anastomoses caused by retinal ischemia from large vessel vasculitis.144 AMERICAN COLLEGE OF RHEUMATOLOGY CRITERIA The ACR classification criteria for the diagnosis of TA are listed in Table 81-8.145

Onset before age 40 yr Limb claudication

EPIDEMIOLOGY

Decreased brachial artery pulse

Although TA has been described worldwide, it occurs most commonly in Japan, China, India, and Southeast Asia; the disease is also prevalent in Mexico.146 Whereas the incidence of TA in Japan is nearly 150 per million per year, it is only 0.2 to 2.6 per million in western Europe and North America.146 TA affects women eight times more frequently than men. The median age of onset is 25 years; however, approximately 25% of cases begin before age 20, and 10% to 20% present after age 40.138,146,147 Immunogenetic studies in Japanese patients suggest an association with several HLAs, especially HLA-Bw52, Dw12, DR2, and DQw1.146 Different

Unequal arm blood pressure (>10 mm Hg) Subclavian or aortic bruit Angiographic evidence of narrowing or occlusion of aorta or its primary branches, or large limb arteritis *The presence of three or more of the six criteria is sensitive (91%) and specific (98%) for the diagnosis of Takayasu’s arteritis. American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 33:1129, 1990. From Hellmann DB: Takayasu arteritis. In Imboden JB, Hellmann DB, Stone JH (eds): Current Rheumatology Diagnosis and Treatment. New York, Lange Medical Books/McGraw-Hill, 2004, p 245.

PART 13 

HLA associations have been found in Koreans and Indians. No HLA association has been found in North American patients. In Mexican patients, TA has been associated with previous exposure to Mycobacterium tuberculosis.146 CAUSE AND PATHOGENESIS The cause of TA is unknown. The nearly identical pathology in TA and GCA has invited speculation that the model of immunopathogenesis of GCA described earlier (see Fig. 81-3) applies to TA as well.35,34,148 Like GCA, TA is thought to result from an autoimmune process that targets large elastic-containing arteries. Both feature panarteritis involving infiltration of dendritic cells, T cells (including αß, γδ, and cytotoxic), natural killer cells, and macrophages. In TA, the majority of lymphocytes are perforin-secreting killer lymphocytes, such as T cells and natural killer cells.149-­153 The T cell receptors in TA, as in GCA, are oligoclonal, suggesting that the vasculitis is driven in both diseases by a T cell response to a specific but unknown antigen.149,150 Chronic inflammation of the vessel wall leads to aneurysm formation, stenosis, or thrombosis more frequently in TA than in GCA. Dissection occurs in TA but is rare and less frequent than in syphilitic aortitis.152,153 The late phase of TA, like that of GCA, is characterized by intima proliferation with superimposed atherosclerosis, medial necrosis with scarring, and adventitial fibrosis. As in GCA, the inflammatory involvement in TA can be continuous or segmental, with skip areas of normal vessel interposed between involved areas.152 It is possible that the humoral immune system may play some role in the pathogenesis of TA; most TA patients possess anti–endothelial cell antibodies that can damage vessels by inducing endothelial inflammatory cytokine production, adhesion molecules, and apoptosis.154,155 The geographic clustering of cases has suggested that genetics and environmental factors participate in the pathogenesis of TA.146 However, immunogenetic studies (detailed earlier) have not identified any other universally shared genetic risk factors. The young age of onset and the female predominance in TA and in systemic lupus erythematosus have invited speculation about the influence of female hormones in promoting an autoimmune disease process. In some countries, the apparent association of TA with high rates of exposure to tuberculosis has suggested an infectious cause. An animal model of TA has been produced in mice using a herpesvirus that infects the smooth muscle cells of the media. In that model, the media of large elastic arteries serves as an immunoprivileged site that allows the herpesvirus to propagate a chronic inflammatory response in the aorta and its major branches.156 CLINICAL FEATURES Symptoms and Signs Although the presenting manifestations of TA are protean, the vast majority of patients present with symptoms and signs of vascular insufficiency (from stenosis, ­ occlusion, or aneurysm), systemic inflammation, or both138,141 (Table 81-9). In a North American series of 60 patients followed at the National Institutes of Health, the most common presenting vascular symptoms were claudication

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(35%), reduced or absent pulse (25%), carotid bruit (20%), hypertension (20%), carotidynia (20%) lightheadedness (20%), and asymmetrical arm blood pressures (15%).138 Stroke, aortic regurgitation, and visual abnormalities were present at onset in less than 10% of patients. The extreme manifestations of retinal ischemia noted in Takayasu’s original patient are rarely seen now.138 Permanent loss of vision, the major concern in GCA, rarely develops in TA. Claudication affects the arms at least twice as frequently as the legs. For many young women, arm claudication first reveals itself as arm pain or fatigue experienced while trying to hold a hair dryer. Overall, bruit is the most common sign, eventually found in 80% of patients. Although bruit over the carotid artery is most frequent, it can also be found in the supraclavicular, infraclavicular, axillary, flank, chest, abdominal, and femoral areas. One third of patients have multiple bruits.138 Unequal arm blood pressures eventually develop in half of all patients. Headache, which is common in TA, does not correlate with carotid or vertebral disease, which develops in nearly 40% of patients.138 Constitutional, musculoskeletal, and other symptoms of systemic inflammation are also common presenting complaints.138,141-143,157,158 About one in five TA patients presents with fever and malaise, which can be accompanied by night sweats and weight loss. A few patients who have minimal or no signs of vascular insufficiency may appear to have FUO for weeks or months before the diagnosis of TA becomes evident. A minority of patients present with myalgia or arthralgia (see Table 81-9). Some patients have striking Table 81-9  Clinical Features of Takayasu’s Arteritis Feature Vascular Bruit Claudication   (upper extremity) Claudication (lower extremity) Hypertension Unequal arm blood   pressures Carotidynia Aortic   regurgitation

At Presentation (%) Ever Present (%) 50 30

100 80 62

15

32

20 15

33 50

15

32 20

Central nervous system Lightheadedness Visual abnormality Stroke

30 20 10 5

57 35 30 10

Musculoskeletal Chest wall pain Joint pain Myalgia

20 10 10 5

53 30 30 15

Constitutional Malaise Fever Weight loss

33 20 20 15

43 30 25 20

Cardiac Aortic regurgitation Angina Congestive heart failure

15  8  2  2

38 20 12 10

Data based on a study of 60 North American patients reported by Kerr GS, et al: Takayasu arteritis. Ann Intern Med 120:919, 1994. From Hellmann DB: Takayasu arteritis. In Imboden JB, Hellmann DB, Stone JH (eds): Current Rheumatology Diagnosis and Treatment. New York, Lange Medical Books/ McGraw-Hill, 2004, p 243.

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Giant Cell Arteritis, Polymyalgia Rheumatica, and Takayasu’s Arteritis

Figure 81-10  Angiogram showing multiple changes of Takayasu’s  arteritis, including dilation of the aortic root (with surgical wires from previous aortic valve replacement), aneurysmal dilation of the innominate and right carotid arteries, and occlusion of the distal left common carotid artery. (From Hellmann DB, Flynn JA. Clinical presentation and natural history of Takayasu’s arteritis and other inflammatory anrteritides. In Perler BA, Becker GJ [eds]: Vascular Intervention: A Clinical Approach. New York, Thieme Medical and Scientific Publisher, 1998, pp 249-256.)

midthoracic back pain, perhaps as a result of aortic inflammation irritating nociceptive nerve fibers. Cardiac involvement occurs eventually in nearly one third of patients (see Table 81-9).138 Aortic regurgitation develops in 20% of patients as a result of aortic root dilation. Aortic regurgitation is important because it frequently progresses and may lead to left ventricular dilation with secondary mitral regurgitation and congestive heart failure. Aortic valve replacement is often required eventually. Angina can develop as a result of coronary artery disease. TA of the coronary arteries most often produces ostial lesions but can also produce either diffuse vasculitis of the coronary arteries or aneurysms.159-164 Myocarditis also occurs in TA and causes potentially reversible congestive heart failure. Pericarditis is very rare. TA is, along with Behçet’s disease, one of the few forms of vasculitis that can affect the large pulmonary arteries. Although TA of the pulmonary arteries is rare (<3%), affected patients can present with cough, chest wall pain, dyspnea, or hemoptysis. Unlike polyarteritis or Wegener’s granulomatosis, TA rarely causes peripheral neuropathies. Cutaneous manifestations develop in less than 10% of patients with TA.138 Erythema nodosum is most common, but purpura, livedo reticularis, and ulceration may rarely occur. As in GCA, a minority of TA patients with active disease have a persistent, dry cough.

Figure 81-11  Magnetic resonance image (sagittal section) through the chest showing thickening of the ascending and descending thoracic aorta in a 26-year-old woman with Takayasu’s arteritis. (From Hellmann DB: Takayasu arteritis. In Imboden J, Hellmann DB, Stone JH [eds]: Current Rheumatology: Diagnosis & Treatment. New York, McGraw-Hill, 2004, p 244.)

usually normal. Any renal abnormalities are usually secondary to hypertension; unlike antineutrophil cytoplasmic antibody– associated vasculitis, TA rarely causes glomerulonephritis. Imaging Studies Vascular abnormalities in TA can be imaged by conventional angiography, MRI, MRA, CT angiography, or ultrasonography38,138,165 (Figs. 81-10 to 81-12). Each imaging technique has advantages and disadvantages (Table 81-10).

Laboratory Findings At presentation, the ESR is more frequently elevated (80%) than the CRP (≈50%).141 Mild anemia and hypergammaglobulinemia are common. The white blood cell count is usually normal or slightly elevated. The platelet count is elevated in one third of patients and may exceed 500,000/μL in those with active disease. The serum creatinine and urinalysis are

Figure 81-12  Angiogram showing bilateral renal artery stenosis. A large left colic branch of the inferior mesenteric artery provides collateral circulation to the gut. (From Hellmann DB, Flynn JA: Clinical presentation and natural history of Takayasu’s arteritis and other inflammatory anrteritides. In Perler BA, Becker GJ [eds]: Vascular Intervention: A Clinical Aprroach. New York, Thieme Medical and Scientific Publisher, 1998, pp 249-256.)

PART 13 

Table 81-10  Comparison of Imaging Techniques   in Takayasu’s Arteritis

| 

Technique

Advantages

Disadvantages

Blood Vessel

“Gold standard” image quality Allows CAP   measurement Allows angioplasty   at same time

Invasive Radiation exposure Does not visualize vessel wall   thickness

Aorta Aortic arch or root Abdominal aorta Thoracic aorta

65 35 47 17

Subclavian artery

93

Excellent image quality Noninvasive No ionizing radiation exposure Visualizes vascular wall thickness

Image quality not “gold standard” Cannot use in patients with pacemaker CAP measurement not possible

Common carotid artery

58

Renal artery

38

Vertebral artery

35

Celiac axes

18

Common iliac artery

17

Pulmonary artery

 5

Ultrasonography

Noninvasive No ionizing radiation exposure Can visualize vessel wall edema

Image quality not “gold standard” Image quality   affected by obesity Operator   dependent CAP measurement not possible

Computed   tomography   angiography

Excellent image quality

Ionizing radiation exposure CAP measurement not possible Intravenous contrast agent required

Positron emission Can measure intensity of Ionizing radiation tomography vascular inflammation exposure Vascular anatomy not well seen CAP measurement not possible Intravenous contrast agent required CAP, central arterial blood pressure.

The ­ earliest detectable abnormality in TA is thickening of the vessel wall from inflammation. MRI, ultrasonography, and, to a lesser degree, CT can detect this early vessel wall thickening.36 Conventional angiography is invasive and provides the least sensitive method for visualizing wall thickness; however, conventional angiography is the “gold standard” for precisely delineating the stenoses, occlusions, and aneurysms that characterize the latter stages of TA.36 Also, only conventional angiography allows the direct measurement of central arterial blood pressure, which may be otherwise unobtainable in patients with stenotic lesions affecting all four extremities. PET scanning is showing promise in TA as in GCA in detecting the extent and intensity of vascular inflammation,36,166 but the value of PET scanning is not firmly established. Although MRA does not provide the same level of detail as conventional angiography, it comes close. Because MRA is not invasive and does not involve ionizing radiation, it has become the preferred imaging method for following patients with TA. The most common sites of lesions in TA are the aorta (65%) and the left subclavian arteries (93%)138 (Table 81-11). The left subclavian artery is affected slightly more frequently than the right. Carotid, renal, and vertebral arteries are also commonly affected.138 Lesions may be stenotic (93%), occluded (57%), dilated (16%), or aneurysmal (7%).139 Stenotic lesions are about four times more common

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Table 81-11  Frequency of Blood Vessel Involvement   in Takayasu’s Arteritis

Conventional angiography

Magnetic   resonance   angiography

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% Abnormal

Data based on a study of 60 North America patients reported by Kerr GS, et al: Takayasu arteritis. Ann Intern Med 120:919, 1994. From Hellmann DB: Takayasu arteritis. In Imboden JB, Hellmann DB, Stone JH (eds): Current Rheumatology Diagnosis and Treatment. New York, Lange Medical Books/ McGraw-Hill, 2004, p 245.

than aneurysmal lesions.138 Stenotic segments often extend a few centimeters and may be followed by areas of dilation (see Fig. 81-10). The majority of patients (53%) have vascular lesions above and below the diaphragm.139 However, the frequency distribution of aortic lesions varies considerably from country to country.138 DIAGNOSIS AND DIAGNOSTIC TESTS As previously noted, the ACR has established classification criteria for the diagnosis of TA (see Table 81-8). In clinical practice, the diagnosis of TA is almost always secured by an imaging procedure (see Table 81-10) that demonstrates the characteristic abnormalities of the aorta and its major branches (Fig. 81-13). Rarely, the diagnosis is first suggested when a pathologist finds granulomatous inflammation in a section of aorta or other larger artery that was removed or biopsied during a vascular surgery procedure. Unfortunately, Age <40 years and symptoms or signs of large artery disease, such as bruit, loss of pulse, claudication Yes

No Symptoms, signs of inflammation not attributable to another cause No Make another diagnosis (see Table 81-12)

Yes

Image aorta and its major branches

Normal

Yes

Abnormal

Evidence of diseases of the aorta/branches other than TA No Diagnose Takayasu’s arteritis

Figure 81-13  Algorithm for the diagnosis of Takayasu’s arteritis.  TA, Takayasu’s arteritis.

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Table 81-12  Differential Diagnosis of Takayasu’s   Arteritis: Other Diseases that Can Affect the Aorta

Table 81-13  Comparison of Giant Cell Arteritis   and Takayasu’s Arteritis

Disease Type

Specific Entities

Feature

Giant Cell

Takayasu’s

Rheumatic

Giant cell arteritis, Cogan’s syndrome, relapsing polychrondritis, ankylosing spondylitis, rheumatoid arthritis, systemic lupus erythematosus, Buerger’s disease, Behçet’s disease

Female-male ratio

2:1

8:1

Age range (yr)

�50

<40

Average age of onset (yr)

72

25

Visual loss

10%-30%

Rare

Infectious

Syphilis, tuberculosis

25%

100%

Other

Atherosclerosis, ergotism, radiation-  induced damage, retroperitoneal fibrosis, inflammatory bowel disease, sarcoidosis, neurofibromatosis, congenital coarctation, Marfan’s syndrome, Ehlers-Danlos syndrome

Involvement of aorta or its major branches Pathology

Granulomatous   arteritis

Granulomatous arteritis

Pulmonary artery   involvement

No

Possible

Renal hypertension

Rare

Common

Claudication

Uncommon

Common

Ethnic groups with highest incidence

Scandinavians

Asians

From Hellmann DB: Takayasu arteritis. In Imboden JB, Hellmann DB, Stone JH (eds): Current Rheumatology Diagnosis and Treatment. New York, Lange Medical Books/McGraw-Hill, 2004, p 243.

the diagnosis of TA is often delayed; the delay averaged 44 months in one large series.139 The most frequent impediment to a speedy diagnosis is a physician’s failure to consider TA in the differential diagnosis. Although the rarity of TA helps explain its omission from diagnostic consideration, another reason is that some patients have striking features of inflammation that camouflage or overshadow the somewhat more familiar vascular abnormalities. Indeed, a few patients with TA present chiefly with FUO. Most of these patients have other, albeit subtle, manifestations of TA such as bruits, diminished pulses, unequal arm blood pressures, or aortic regurgitation. In other patients with more striking vascular abnormalities, the physician may be lured into focusing on familiar and dramatic abnormalities such as anemia or thrombocytopenia. Thus, instead of ordering an imaging test that would explain the patient’s unequal and low blood pressure in her left arm, the physician mistakenly diverts the patient to a hematologist, gastroenterologist, or oncologist for additional blood tests and procedures that further delay the diagnosis. Many of these delays can be prevented by remembering that TA should be included in the differential diagnosis of any person younger than 40 years who presents with FUO, aortic regurgitation, hypertension, or absent pulse. Delays in diagnosis can also be reduced by carefully searching for unequal or absent upper extremity pulses and by listening for bruits not only over the carotid arteries but also above and below the clavicle (for subclavian artery bruits) and over the abdomen and flanks (for renal and other mesenteric artery bruits). Recognizing that anemia and thrombocytosis can be manifestations of active inflammatory disorders, such as vasculitis, can also help speed the diagnosis of TA. Once an imaging test demonstrates disease of the aorta or its major branches, the differential diagnosis narrows to a set of disorders that are usually easily differentiated (Table 81-12). Most rheumatic diseases that can affect the aorta are distinguished by their associated features. For example, Cogan’s syndrome typically produces ocular inflammation (especially keratitis) and vestibuloauditory dysfunction. The one rheumatic disease that can, on rare occasions, be difficult to distinguish from TA is GCA (Table 81-13). Usually, the patient’s age and the distribution of lesions allow their rapid differentiation, but distinguishing TA beginning after age 40 from GCA affecting chiefly the major branches of

Corticosteroid responsive

Yes

Yes

Bruits present

Minority

Majority

Surgical intervention   needed

Rarely

Commonly

the aorta can be difficult or even impossible. The similarity of treatment (see later) diminishes the practical importance of solving this diagnostic dilemma. Infections of the aorta are rare in most countries. Tertiary syphilis can be excluded by a negative fluorescent treponemal antibody test (the rapid plasma reagin test is falsely negative in about one quarter of patients with late syphilis). Other diseases of the aorta (see Table 81-13) are readily separated from TA by the history and physical examination. TREATMENT Medical Therapy Corticosteroids are the cornerstone of treatment of active TA.138,139,148,167 Prednisone, at a dose of 0.5 to 1 mg/kg per day, is indicated for the treatment of active disease. Criteria for active disease include new onset or worsening of two or more of the following: (1) fever or other systemic features (in the absence of other cause), (2) elevated ESR, (3) symptoms or signs of vascular ischemia or inflammation (e.g., claudication, absent pulse, carotidynia), and (4) typical angiographic lesions.138 Although about 85% of TA patients present with active disease, about 15% do not.141 The initial dose of prednisone is continued for 4 to 12 weeks before commencing a gradual taper, as is done when treating GCA (see earlier). Although nearly two thirds of patients achieve remission, more than half later relapse. Relapses are especially common as the prednisone dose falls below 20 mg per day. Relapses can be treated by increasing the prednisone dose or adding an immunosuppressive agent. No agent used for TA has been evaluated in a double-blind, placebocontrolled trial. However, open trials have suggested that weekly oral methotrexate (started at 0.3 mg/kg per week, with the ­initial dose not to exceed 15 mg/wk) is a moderately effective ­ corticosteroid-sparing drug.168 Methotrexate can be ­ gradually increased to 25 mg/wk. The emphasis is on lowering the corticosteroid dose, because methotrexate

PART 13 

seldom allows the elimination of prednisone completely; most patients continue to require at least 5 to 10 mg/day of prednisone. Small studies and series suggest that other corticosteroidsparing drugs include azathioprine (2 mg/kg per day), mycophenolate mofetil (2000 mg/day), and cyclophosphamide (2 mg/kg per day).138,148,169,170 The toxicity of cyclophosphamide in young women is so high that it is rarely used in TA.138,148 The experience using TNF inhibitors for TA has been encouraging but limited.170 In one series, anti-TNF therapy achieved improvement in 14 of 15 patients who had failed other therapies; 10 of 15 patients were able to discontinue corticosteroids.170 To prevent osteoporosis, patients on chronic corticosteroids should take calcium, vitamin D, and a ­bisphosphonate and perform weight-bearing exercises. Modifiable risk factors for atherosclerosis—especially hypertension, smoking, inactivity, diabetes, and hyperlipidemia—should be treated maximally. Surgical Therapy TA is the form of vasculitis most frequently requiring revascularization procedures.138,148,171-173 Unfortunately, medical therapy rarely reduces or reverses stenotic lesions. Treating stenotic or aneurysmal lesions may require bypass surgery (especially of stenotic cervicobrachial arteries, coronary arteries, or renal arteries), aortic valve replacement (for aortic regurgitation), or percutaneous transluminal angioplasty (especially for stenotic renal arteries causing hypertension). A review of the experience with vascular interventions in TA allows several general recommendations.148 First, the mere presence of stenosis does not necessitate intervention. The gut, for example, has such rich collaterals that even critical stenoses of the celiac, superior, or inferior mesenteric arteries usually produce no symptoms and require no surgical intervention. Moreover, many patients with arm claudication will develop collateral circulation and improve substantially over time with medical therapy alone. For upper extremity vascular insufficiency, patiently waiting for a response to medical therapy usually pays higher dividends than ­undertaking rapid surgical intervention. Second, whenever possible, surgical intervention should be deferred until TA is in remission; procedures done during active disease often produce disappointing results. Third, bypass surgery yields better results than angioplasty. With bypass graft procedures, autologous vessels give better results than synthetic grafts (restenosis rates of 9% versus 36%)148 Patients who undergo aortic surgery are liable to develop anastomotic aneurysms; such aneurysms developed in nearly 14% of patients followed for 20 years.148,171 Although angioplasty gives good short-term results, long-term results are often disappointing except for very short stenotic segments. The experience with conventional stents has been mostly disappointing.148 OUTCOME AND PROGNOSIS Twenty percent of TA patient have a self-limited disease. The rest have a relapsing-remitting or progressive course requiring chronic corticosteroid therapy. Nearly two thirds of patients experience new angiographic lesions.148 In one study from the National Institutes of Health, 74% of patients

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experienced some form of morbidity, and 47% were permanently disabled.138 No parameters at disease onset have been shown to predict mortality.148 The survival is 92.9% at 5 years, 87.2% at 10 years,141 and 73.5% at 20 years.148,171 Congestive heart failure and renal ­failure are the most common causes of death.171 Pregnancy appears to be relatively well tolerated in the presence of good medical care and in the absence of abdominal aortic involvement.138,174,175

Future Directions Two of the most pressing issues in TA are how to measure active disease and how to safely minimize the use and toxicity of corticosteroids. Serologic tests such as the ESR are helpful but lack sensitivity and specificity; active disease as reflected in inflammatory pathology has been found in patients with normal ESRs.148 Efforts are under way to determine whether imaging techniques can help assess disease activity. Unfortunately, although “edema-weighted” MRI and MRA appear to have high specificity, the positive predictive value for active disease is poor.36,176 Studies are under way to assess the ability of PET scanning, serum proteomic markers, and serum levels of inflammatory cytokines to detect active disease. The success of using biologic agents to treat RA and the good preliminary experience using infliximab for TA ­offer hope that new therapies will be more effective and less toxic than corticosteroids.

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46. Brach A, Gusler A, Martinez-Taboada, et al: Giant cell vasculitis is a T cell-dependent disease. Mol Med 3:530, 1997. 47. Weyand CM, Wagner, AD, Bjornsson J, et al: Correlation of the topographical arrangement and the functional pattern of tissue­infiltrating macrophages in giant cell arteritis. J Clin Invest 98:1642, 1996. 48. Wagner AD, Garonzy JJ, Weyand CM: Functional profile of ­tissue-infiltrating and circulating CD68+ cells in giant cell arteritis: Evidence for two components of the disease. J Clin Invest 4: 1134, 1994. 49. Weyand CM, Hicok KC, Hunder GG, et al: Tissue cytokine patterns in patients with polymyalgia rheumatica and giant cell arteritis. Ann Intern Med 121:484, 1994. 50. Weyand CM, Tetzlaff N, Bjornsson J, et al: Disease patterns and tissue cytokine profiles in giant cell arteritis. Arthritis Rheum 40: 19, 1997. 51. Grunewald J, Andersson R, Rydberg L, et al: CD4+ and CD8+ T cell expansions using selected TCR V and J gene segments at the onset of giant cell arteritis. Arthritis Rheum 37:1221, 1994. 52. Shiiki H, Shimokama T, Watanabe T: Temporal arteritis: Cell composition and the possible pathogenetic role of cell-mediated immunity. Hum Pathol 20:1057, 1989. 53. Weyand CM, Ma-Krupa W, Pryshchep O, et al: Vascular dendritic cells in giant cell arteritis. Ann N Y Acad Sci 1062:195, 2005. 54. Ma-Krupa W, Jeon MS, Spoerl S, et al: Activation of arterial wall dendritic cells and breakdown of self-tolerance in giant cell arteritis. J Exp Med 199:173, 2004. 55. Shmerling RH: An 81-year-old woman with temporal arteritis. JAMA 295:2525, 2006. 56. Kaiser M, Weyand CM, Bjornsson J, et al: Platelet-derived growth factor, intimal hyperplasia, and ischemic complications in giant cell arteritis. Arthritis Rheum 41:623, 1998.   57. Calamia KT, Hunder GG: Giant cell arteritis (temporal arteritis) presenting as fever of undetermined origin. Arthritis Rheum 24:1414, 1981. 58. Brooke MH, Kaplan H: Muscle pathology in rheumatoid arthritis, polymyalgia rheumatica, and polymyositis: A histochemical study: Arch Pathol 94:101, 1972. 59. Salvarani C, Canlini F, Oliveri I, et al: Proximal bursitis in active polymyalgia rheumatica. Ann Intern Med 127:27, 1997. 60. O’Duffy JD, Hunder GG, Wahner HW: A follow-up study of polymyalgia rheumatica: Evidence of chronic axial synovitis. J Rheumatol 7:685, 1980. 61. Healey LA: Long-term follow-up of polymyalgia rheumatica: Evidence for synovitis. Semin Arthritis Rheum 13:322, 1984. 62. Douglas WA, Martin BA, Morris JH: Polymyalgia rheumatica: An arthroscopic study of the shoulder joint. Ann Rheum Dis 42:311, 1983. 63. Chow CT, Schumacher HR Jr: Clinical and pathologic studies of synovitis in polymyalgia rheumatica. Arthritis Rheum 27:1107, 1984. 64. Cantini F, Salvarani C, Olivieri I, et al: Inflamed shoulder structures in polymyalgia rheumatica with normal erythrocyte sedimentation rate. Arthritis Rheum 44:1155, 2001. 65. Papaioannou CC, Gupta RC, Hunder GG, McDuffie FC: Circulating immune complexes in giant cell arteritis polymyalgia rheumatica. Arthritis Rheum 23:1021, 1980. 66. Smith AJ, Kyle V, Cawston TE, Hazleman BL: Isolation and analysis of immune complexes from sera of patients with polymalgia rheumatica and giant cell arteritis. Ann Rheum Dis 46:468, 1987. 67. Ma-Krupa W, Kwan M, Goronzy JJ, Weyand CM: Toll-like receptors in giant cell arteritis. Clin Immunol 115:38, 2005. 68. Smetana GW, Shmerling RH: Does this patient have temporal arteritis? JAMA 287:92, 2002. 69. Miller NR: Visual manifestations of temporal arteritis. In Stone JH, Hellmann DB (eds): Rheumatic Disease Clinics of North America. Philadelphia, WB Saunders, 2001, p 781. 70. Mehler MF, Rabinowich L: The clinical neuro-ophthalmologic spectrum of temporal arteritis. Am J Med 85:839, 1988. 71. Nesher G, Berkun Y, Mates M, et al: Risk factors for cranial ischemic complications in giant cell arteritis. Medicine 83:114, 2004. 72. Gonzalez-Gay MA, Piñeiro A, Gomez-Gigirey A, et al: Influence of traditional risk factors of atherosclerosis in the development of severe ischemic complications in giant cell arteritis. Medicine 83:342, 2004. 73. Salvarani C, Cimino L, Macchioni P, et al: Risk factors for visual loss in an Italian population-based cohort of patients with giant cell arteritis. Arthritis Rheum 53:293, 2005.

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98. Roche NE, Fulbright JW, Wagner AD, et al: Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum 36:1286, 1993. 99. Persellin ST, Daniels TM, Rings LJ, et al: Factor VIII-von Willebrand factor in giant cell arteritis and polymyalgia rheumatica. Mayo Clin Proc 60:457, 1985. 100. Olsson A, Elling P, Elling H: Serologic and immunohistochemical determination of von Willebrand factor antigen in serum and biopsy specimens from patients with arteritis temporalis and polymyalgia rheumatica. Clin Exp Rheumatol 8:55, 1990. 101. Younge BR, Cook BE Jr, Bartley GB, et al: Initiation of glucocorticoid therapy: Before or after temporal artery biopsy? Mayo Clin Proc 79:483, 2004. 102. Gertz MA, Kyle RA, Griffing WL, Hunder GG: Jaw claudication in primary systemic amyloidosis. Medicine (Baltimore) 65: 173, 1986. 103. Ginsburg WW, Cohen MD, Hall SB, et al: Seronegative polyarthritis in giant cell arteritis. Arthritis Rheum 28:1362, 1985. 104. Gonzalez-Gay MA, Garcia-Porrua C, Salvarani C, et al: The spectrum of conditions mimicking polymyalgia rheumatica in northwestern Spain. J Rheumatol 27:2179, 2000. 105. McCarty DJ, O’Duffy D, Pearson L, Hunter JB: Remitting sero­ negative symmetrical synovitis with pitting edema: RS3PE syndrome. JAMA 254:2763, 1985. 106. Hall S, Hunder GG: Is temporal artery biopsy prudent? Mayo Clin Proc 59:793, 1984. 107. Gonzalez-Gay MA: The diagnosis and management of patients with giant cell arteritis. J Rheumatol 32:1186, 2005. 108. Hall S, Lie JT, Kurland LT, et al: The therapeutic impact of temporal artery biopsy. Lancet 2:1217, 1983. 109. Boyev LR, Miller NR, Green WR: Efficacy of unilateral versus bilateral temporal artery biopsies for the diagnosis of giant cell arteritis. Am J Ophthalmol 128:211, 1999. 110. Pless M, Rizzo JF III, Lamkin JC, Lessell S: Concordance of bilateral temporal artery biopsy in giant cell arteritis. J Neuroophthalmol 20:216, 2000. 111. Jundt JW, Mock D: Temporal arteritis with normal erythrocyte sedimentation rates presenting as occipital neuralgia. Arthritis Rheum 34:217, 1991. 112. Schmidt WA, Kraft HE, Vorpahl L, et al: Color duplex ultrasonography in the diagnosis of temporal arteritis. N Engl J Med 337: 1336, 1997. 113. Hunder GG, Weyand CM: Sonography in giant cell arteritis. N Engl J Med 337:1385, 1997. 114. Salvarani C, Silingardi M, Ghirarduzzi A, et al: Is duplex ultrasonography useful for the diagnosis of giant-cell arteritis? Ann Intern Med 137:232, 2002. 115. Bley T, Wieben O, Uhl M, et al: High-resolution MRI in giant cell arteritis: Imaging of the wall of the superficial temporal artery. AJR Am J Roentgenol 184:283, 2005. 116. Blockmans D, Stroobants S, Maes A, Mortelmans L: Positron emission tomography in giant cell arteritis and polymyalgia rheumatica: Evidence for inflammation of the aortic arch. Am J Med 108: 246, 2000. 117. Turlakow A, Yeung HWD, Pui J, et al: Fludeoxyglucose positron emission tomography in the diagnosis of giant cell arteritis. Arch Intern Med 161:1003, 2001. 118. Ray-Chaudhuri N, Kiné DA, Tijani SO, et al: Effect of prior steroid treatment on temporal artery biopsy findings in giant cell arteritis. Br J Ophthalmol 86:530, 2002. 119. Achkar AA, Lie JT, Hunder GG, et al: How does previous corticosteroid treatment affect the biopsy findings in giant cell (temporal) arteritis? Ann Intern Med 120:987, 1994. 120. Mazlumzadeh M, Hunder GG, Easley KA, et al: Treatment of giant cell arteritis using induction therapy with high-dose glucocorticoids: A double-blind, placebo-controlled, randomized prosepctive clinical trial. Arthritis Rheum 54:3310-3318, 2006. 121. Hayreh SS: Steroid therapy for visual loss in patients with giant-cell arteritis: Lancet 355:1572, 2000. 122. Weyand CM, Fulbright JW, Hunder GG, et al: Treatment of giant cell arteritis: Interleukin-6 as a biologic marker of disease activity. Arthritis Rheum 43:1041, 2000. 123. Hoffman GS, Cid MC, Hellmann DB, et al: A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum 46:1309, 2002.

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Giant Cell Arteritis, Polymyalgia Rheumatica, and Takayasu’s Arteritis

124. Jover JA, Hernández-Garcia C, Morado IC, et al: Combined treatment of giant-cell arteritis with methotrexate and prednisone: A randomized, double-blind, placebo-controlled trial. Ann Intern Med 134:106, 2001. 125. Hunder GG, Sheps SG, Allen GL, Joyce JW: Daily and alternate-day corticosteroid regimens in treatment of giant cell arteritis: Comparison in a prospective study. Ann Intern Med 82:613, 1975. 126. Hoffman GS, Cid MC, Rendt-Zagar KE, et al: Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: A randomized trial. Ann Intern Med 146:621, 2007. 127. Weyand CM, Kaiser M, Yang H, et al: Therapeutic effects of acetylsalicylic acid in giant cell arteritis. Arthritis Rheum 46:457, 2002. 128. Nesher G: Low-dose aspirin and prevention of cranial ischemic complications in giant cell arteritis. Arthritis Rheum, 50:1332, 2004. 129. Lee MS, Smith SD, Galor A, Hoffman GS: Antiplatelet and anticoagulant therapy in patients with giant cell arteritis. Arthritis Rheum 54:3306, 2006. 130. Both M, Aries PM, Müller-Hülsbeck S, et al: Balloon angioplasty of arteries of the upper extremities in patients with extracranial giantcell arteritis. Ann Rheum Dis 65:1124, 2006. 131. Weyand CM, Fulbright JW, Evans JM, et al: Corticosteroid requirements in polymyalgia rheumatica. Arch Intern Med 159: 577, 1999. 132. Gabriel SE, Sunku J, Salvarani C, et al: Adverse outcomes of antiinflammatory therapy among patients with polymyalgia rheumatica. Arthritis Rheum 40:1873, 1997. 133. Schreiber S, Buyse M: The CRP initial response to treatment as prognostic factor in patients with polymyalgia rheumatica. Clin Rheumatol 14:315, 1995. 134. Weyand CM, Fulbright JW, Evans JM, et al: Corticosteroid requirements in polymyalgia rheumatica. Arch Intern Med 159:577, 1999. 135. Rynes RI, Mika P, Bartholomew LE: Development of giant cell (temporal) arteritis in a patient “adequately” treated for polymyalgia rheumatica. Ann Rheum Dis 36:88, 1977. 136. Narvaez J, Nolla-Sole JM, Clavaguera MT, et al: Longterm therapy in polymyalgia rheumatica: Effect of coexistent temporal arteritis. J Rheumatol 26:1945, 1999. 137. Caporali R, Cimmino MA, Ferraccioli G, et al: Prednisone plus methotrexate for polymyalgia rheumatica: A randomized, doubleblind, placebo-controlled trial. Ann Intern Med 141:493, 2004. 138. Kerr GS, Hallahan CW, Giordano J, et al: Takyasu arteritis. Ann Intern Med 120:919, 1994. 139. Vanoli M, Daina E, Salvarani C, et al: Takayasu’s arteritis: A study of 104 Italian patients. Arthritis Rheum 53:100, 2005. 140. Nakao K, Ikeda M, Kimata S-C, et al: Takayasu’s arteritis: Clinical report of eighty-four cases and immunological studies of seven cases. Circulation 35:1141, 1967. 141. Park M-C, Lee S-W, Park Y-B, et al: Clinical characteristics and outcomes of Takayasu’s arteritis: Analysis of 108 patients using standardized criteria for diagnosis activity assessment, and angiographic classification. Scand J Rheumatol 34:284, 2005. 142. Shelhamer JH, Volkman DJ, Parrillo JE, et al: Takayasu’s arteritis and its therapy. Ann Intern Med 103:121, 1985. 143. Lupi-Herrera E, Sanchez-Torres G, Marcushamer J, et al: Takayasu’s arteritis: Clinical study of 107 cases. Am Heart J 93:94, 1977. 144. Takayasu M: A case of a peculiar change in the central retinal vessels. Acta Soc Ophthalmol Jpn 12:554, 1908. 145. Arend WP, Michel BA, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 33:1129, 1990. 146. González-Gay MA: García-Porrúa: Epidemiology of the vasculitides. Rheum Dis Clin North Am 27:729, 2001. 147. Hellmann DB: Takayasu’s arteritis. In Imboden J, Hellmann D, Stone J (eds): Current Rheumatology Diagnosis & Treatment, 1st ed. New York, Lange Medical Books/McGraw-Hill, 2004, pp 242-247. 148. Liang P, Hoffman GS: Advances in the medical and surgical treatment of Takayasu arteritis. Curr Opin Rheumatol 17:16, 2005. 149. Seko Y, Sato O, Takagi A, et al: Restricted usage of T-cell receptor Vα-Vß genes in infiltrating cells in aortic tissue of patients with Takayasu’s arteritis. Circulation 93:1788, 1996. 150. Seko Y, Minota S, Kawasaki A, et al: Perforin-secreting killer cell infiltration and expression of a 65-kD heat-shock protein in aortic tissue of patients with Takayasu’s arteritis. J Clin Invest 93: 750, 1994.

151. Seko Y, Sugishita K, Sata O, et al: Expression of costimulatory molecules (4-1BBL and Fas) and major histocompatibility class I chainrelated A (MICA) in aortic tissue with Takayasu’s arteritis. Vasc Res 41:84, 2004. 152. Tavora F, Burke A: Review of isolated ascending aortitis: Differential diagnosis, including syphilitic, Takayasu’s and giant cell aortitis. Pathology 38:302, 2006. 153. Tavora F, Jeudy J, Gocke C, Burke A: Takayasu aortitis with acute dissection and hemopericardium. Cardiovasc Pathol 14: 320, 2005. 154. Park MC, Park YB, Jung SY, et al: Anti-endothelial cell antibodies and antiphospholipid antibodies in Takayasu’s arteritis: Correlations of their titers and isotype distributions with disease activity. Clin Exp Rheumatol 24:S10, 2006. 155. Chauhan SK, Tripathy NK, Nityanand S: Antigenic targets and pathogenicity of anti-aortic endothelial cell antibodies in Takayasu arteritis. Arthritis Rheum 54:2326, 2006. 156. Dal Canto AJ, Swanson PE, O’Guin AK, et al: IFN-gamma action in the media of the great elastic arteries, a novel immunoprivileged site. J Clin Invest 107:R15, 2001. 157. Ueda H, Morooka S, Oto I, et al: Clinical observation of 52 cases of aortitis syndrome. Jpn Heart J 10:277, 1969. 158. Ishikawa K: Natural history and classification of occlusive thromboaortopathy (Takayasu’s disease). Circulation 57:27, 1978. 159. Talwar KK, Kuman K, Chopra P, et al: Cardiac involvement in nonspecific aortoarteritis (Takayasu’s arteritis). Am Heart J 122:1666, 1991. 160. Matsubara O, Kuwata T, Nemoto T, et al: Coronary artery lesions in Takayasu arteritis: Pathological considerations. Heart Vessels Suppl 7:26, 1992. 161. Malik IS, Harare O, Al-Nahhas A, et al: Takayasu’s arteritis: Management of left main stem stenosis. Heart 89:e9, 2003. 162. Byrne JA, Cotton JM, Thomas M: Bilateral ostial coronary artery stenoses: An important presentation of Takayasu’s arteritis. Heart 85:555, 2001. 163. Amano J, Suzuki A: Coronary artery involvement in Takayasu’s arteritis: Collective review and guideline for surgical treatment. J Thorac Cardiovasc Surg 102:554, 1991. 164. Endo M, Tomizawa Y, Nishida H, et al: Angiographic findings and surgical treatment of coronary artery involvement in Takayasu arteritis. J Thorac Cardiovasc Surg 125:570, 2003. 165. Andrews J, Al-Nahhas A, Pennell DJ, et al: Non-invasive imaging in the diagnosis and management of Takayasu’s arteritis. Ann Rheum Dis 63:995, 2004. 166. Walter MA, Melzer RA, Schindler C, et al: The value of [18F]FDG-PET in the diagnosis of large-vessel vasculitis and the assessment of activity and extent of disease. Eur J Nucl Med Mol Imaging 32:674, 2005. 167. Ishikawa K: Effects of prednisone therapy on arterial angiopgrahic features in Takayasu’s disease. Am J Cardiol 68:410, 1991. 168. Hoffman GS, Leavitt RY, Kerr GS, et al: Treatment of glucocorticoid-resistant or relapsing Takayasu arteritis with methotrexate. Arthritis Rheum 37:578, 1994. 169. Koening CL, Langford CA: Novel therapeutic strategies for large vessel vasculitis. Rheum Dis Clin North Am 32:173, 2006. 170. Hoffman GS, Merkel PA, Brasington RD, et al: Anti-tumor necrosis factor therapy in patients with difficult to treat Takayasu arteritis. Arthritis Rheum 50:2296, 2004. 171. Miyata T, Sato O, Koyama H, et al: Long-term survival after surgical treatment of patients with Takayasu’s arteritis. Circulation 108: 1474, 2003. 172. Bloss RS, Duncan JM, Cooley DA, et al: Takayasu’s arteritis: Surgical consideration. Ann Thorac Surg 27:574, 1979. 173. Matsuura K, Ogino H, Kobayashi J, et al: Surgical treatment of aortic regurgitation due to Takayasu arteritis: Long-term morbidity and mortality. Circulation 112:3707, 2005. 174. Sharma BK, Jain S, Visishta K: Outcome of pregnancy in Takayasu arteritis. Int J Cardiol 75(Suppl):S159, 2000. 175. Ishikawa K, Matsuura S: Occlusive thromboaortopathy (Takayasu’s disease) and pregnancy: Clinical course and management of 33 pregnancies and deliveries. Am J Cardiol 50:1293, 1982. 176. Tso E, Flamm SD, White RD, et al: Takayasu arteritis: Utility and limitations of magnetic resonance imaging in diagnosis and treatment. Arthritis Rheum 46:1634, 2002.

82

KEY POINTS Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS) are forms of ­vasculitis that affect small to medium vessels and share a number of clinical, pathologic, and laboratory features. Antineutrophil cytoplasmic antibodies (ANCAs) may be involved in the pathogenesis of these vasculitides in at least some patients. Testing for ANCAs is a useful tool in the diagnosis of small vessel vasculitis, but its role in disease monitoring is more controversial.

Antineutrophil Cytoplasmic Antibody–Associated Vasculitis LEONARD H. CALABRESE  •  EAMONN S. MOLLOY  •  GEORGE F. DUNA or renal syndromes. Finally, all share a varying prevalence of ANCA positivity. The epidemiology of these disorders reveals a collective incidence approaching 2 per 100,000 people in the United States and approximately 1 in 10,000 in Sweden.1 Although each disease, in its characteristic form, can be distinguished from the others on clinical and histologic grounds, the distinctions are often blurred. Thus, their consideration as a group is reasonable from a pathologic as well as a clinical perspective.

WG can affect any organ or tissue but has a predilection for the upper and lower respiratory tracts and the kidneys. WG is most commonly associated with ANCA positivity by immunofluorescence and positive testing for the proteinase 3 antigen.

ANTINEUTROPHIL CYTOPLASMIC ANTIBODY

MPA can be distinguished from other forms of small vessel vasculitis by the absence of granuloma formation, the relative lack of upper airway involvement, and the predominance of perinuclear ANCA staining by immunofluorescence and ­positive testing for the myeloperoxidase antigen.

ANCAs were first described in 1982 by Davies and colleagues2 in eight patients with necrotizing pauci-immune glomerulonephritis who were suspected of having viral infections. A few years later, Hall and colleagues3 identified ANCA in four patients with systemic vasculitis. In 1985, van der Woude and colleagues4 were the first to suggest an association between ANCA and WG. Since that time, subsequent studies have established a close association between ANCA and three major vasculitis syndromes: WG, MPA, and CSS.1 ANCAs were originally described based on their immunofluorescence patterns and were divided into cytoplasmic (c-ANCA) and perinuclear (p-ANCA) categories. The antigens responsible for these patterns and closely allied with the vasculitic syndromes have also been identified: proteinase 3 (PR3) for cANCA, and myeloperoxidase (MPO) for p-ANCA. ANCA testing is now an established diagnostic tool for systemic vasculitis, and its potential role in the pathogenesis of disease and as a target for therapy is still evolving. These issues have recently been comprehensively reviewed.5

CSS can be distinguished from other forms of small vessel vasculitis on the basis of a prior history of adult-onset asthma or allergic rhinitis and tissue eosinophilia with necrotizing vasculitis and extravascular granuloma formation. Combination therapy with glucocorticoids and oral ­cyclophosphamide is required for the treatment of severe systemic small vessel vasculitis; methotrexate may be ­substituted for cyclophosphamide in non-organ- or non-­ life-threatening disease. Upon induction of disease remission, cyclophosphamide should be switched to less toxic immunosuppressive agents for the maintenance of remission.

In recent years, considerable progress has been made in understanding the nature of and relationships among the major classes of primary vasculitic syndromes. The discovery of antineutrophil cytoplasmic antibody (ANCA), its development as a diagnostic tool, and the identification of its role in the nosology of the vasculitides are of major clinical and theoretical importance. Three diseases—Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS)—are now considered together owing to their shared pathologic, clinical, and laboratory features.1 These diseases also share histologic features, preferentially involving small vessels (venules, capillaries, arterioles), and have a similar glomerular lesion (focal necrosis, crescents, absence or paucity of immunoglobulin [Ig] deposition). All three diseases also share clinical features, including a propensity to present as pulmonary

BACKGROUND

METHODOLOGY As noted previously, ANCAs were originally defined by indirect immunofluorescence assay (IFA) performed on ethanol-fixed neutrophils as substrate and broadly categorized as c-ANCA or p-ANCA (Fig. 82-1). In patients with vasculitis (WG, MPA, or CSS), specific immunochemical assays have demonstrated two major antigenic specificities responsible for these immunofluorescent patterns. In the case of c-ANCA reactivity, PR3 is responsible for more than 90% of such reactions, although other antigens may occasionally contribute, including bactericidal permeability-inducing protein (BPI) and, rarely, MPO.1,5 The p-ANCA pattern is much less closely correlated with MPO, which was found in less than 10% of 620 consecutive p-ANCA–positive sera 1429

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Figure 82-1  Immunofluorescence of diffuse or cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA; left), which is highly correlated with antibodies to proteinase 3 (PR3), and the less-specific perinuclear pattern (p-ANCA, right), which is indicative of antibodies to ­ myeloperoxidase (MPO). Although immunofluorescence was once the standard for ANCA testing, current standards require confirmatory antigen-specific testing for PR3 and MPO. (Courtesy of Dr. C. G. M. Kallenberg.)

100 P-ANCA C-ANCA 80

Sensitivity (%)

samples by IFA in one laboratory.6 Other antigens capable of producing p-ANCA reactivity include elastase, azurocidin, cathepsin G lysozyme, and lactoferrin.7 Antinuclear antibodies (ANAs) may also yield a p-ANCA pattern, further compromising IFA as a diagnostic technique. To circumvent the lack of correlation between immunofluorescent patterns and the antigens of interest (PR3 and MPO), as well as the inherent interobserver variability of IFA, antigenspecific assays have been developed and are readily available. Clinicians ordering ANCA assays need to ensure that ANCA positivity by IFA testing is confirmed by antigen-specific testing for both PR3 and MPO. With these criteria (PR3-ANCA indicating c-ANCA, with confirmatory antigenic testing for PR3; and MPO-ANCA indicating p-ANCA, with confirmatory antigenic testing for MPO), the test is highly specific for the vasculitic syndromes under discussion, even when tested in patients with connective tissue disease.8 Guidelines for testing and reporting of ANCA have been published.9

60

40

20

0

Vasculitis

Idiopathic ChurgMicroscopic Wegener’s RPGN Strauss granulomatosis polyangiitis Figure 82-2  Frequency of antineutrophil cytoplasmic antibody (ANCA) reactivity in associated vasculitic conditions, divided on the basis of proteinase 3 (PR3) ANCA and myeloperoxidase (MPO) ANCA. c-ANCA, cytoplasmic ANCA; p-ANCA, perinuclear ANCA ; RPGN, rapidly progressive glomerulonephritis.

A large number of investigations have attempted to establish the sensitivity of PR3-ANCA and MPO-ANCA in systemic vasculitis, and these have been extensively reviewed.7 In general, PR3-ANCA and MPO-ANCA are detected in a limited number of disorders, including the three small vessel vasculitic syndromes as well as the renal-limited form of vasculitis called idiopathic necrotizing crescentic glomerulonephritis. The sensitivity of ANCA varies in these disorders from 50% to more than 90%. A large, multicenter cooperative European trial attempting to standardize ANCA testing has been reported and is summarized in Figure 82-2.10 The results of this trial emphasize that a significant number of patients with idiopathic small vessel vasculitis are ANCA negative; therefore, a negative test does not rule out the diagnosis in patients with a high pretest probability of disease. In WG, the disorder most highly associated with PR3ANCA, the test is most likely to be positive in patients with triad (upper respiratory, lung, kidney) disease that is active and untreated.7 Similar correlations of end-organ damage and disease activity with ANCA positivity are less clear in the other vasculitic syndromes. The specificity of ANCA testing appears to depend on both technical factors and the nature of the control populations tested. If IFA results are combined with antigen-specific assays, the specificity of both PR3-ANCA and MPO-ANCA is exceedingly high (see Fig. 82-1). In the European cooperative study of Hagen and colleagues,10 184 disease controls were studied, including various forms of ­glomerulonephritis

and granulomatous disease, and specificity for the ANCAassociated small vessel vasculitides exceeded 99%. A study by Merkel and colleagues,8 using IFA confirmed by antigenspecific assay, examined a large cohort of well-characterized connective tissue disease patients and also reported specificity in excess of 99%. An earlier study of ANCA, which also included a large number of disease controls, demonstrated high specificity as well.11 Salient points from these large, controlled studies include the unreliability of IFA testing, even when performed by highly trained and experienced personnel, and that IFA alone is less specific than IFA combined with antigen-specific testing for PR3 and MPO. Collectively, clinicians using ANCA to diagnose vasculitis must demand substantial experience from their laboratories and require IFA testing be supplemented by antigen-specific determinations. Even when these technical criteria are met, it must still be appreciated that ANCA, like any laboratory test, provides optimal diagnostic value only when applied in a clinical context. In general, the specificity of ANCA influences disease phenotype, at least by association. In addition to the predilection of PR3 patients to develop WG and those with MPO to develop MPA, a direct comparison of patient populations reveals that PR3-positive patients have more extrarenal manifestations, granuloma formation, and relapses. Even among patients with MPA, those with PR3 ­specificity

DISEASE ASSOCIATIONS

PART 13 

are more likely to have severe disease or to die. Despite substantial overlap, there appear to be distinct clinical and pathologic differences among patients with PR3-ANCA and those with MPO-ANCA, suggesting possible differences in pathogenic mechanisms.12 Other Diseases ANCAs have been reported in a wide variety of other conditions.7 Although ANCA positivity can occur in a number of conditions that mimic systemic vasculitis, the vast majority of such cases are negative for PR3 and MPO.13 Patients with connective tissue diseases, including rheumatoid arthritis (RA),8,14,15 systemic lupus erythematosus (SLE),8 and myositis,8 occasionally display ANCA positivity, but these are largely non-MPO and non-PR3 types. Patients with infections such as those seen in cystic fibrosis,16 endocarditis,17 and human immunodeficiency virus (HIV), among others,7 are occasionally ANCA positive. This may be of particular clinical importance, because infections can mimic systemic vasculitis. As with connective tissue diseases reported to be ANCA positive, most reports of ANCA in infectious diseases are largely non-PR3 and non-MPO, underscoring the importance of confirming IFA by antigen-specific testing. ANCAs are often encountered in inflammatory bowel disease and are more frequent in ulcerative colitis than in Crohn’s disease.18,19 The antigenic target is non-PR3 or non-MPO and is largely unknown, although a multitude of targets have been reported, including cathepsin G, lactoferrin, elastase lysozyme, and BPI.18-20 Other forms of gastrointestinal (GI) disease reported to be ANCA positive (of the non-PR3, non-MPO variety) include sclerosing cholangitis and autoimmune hepatitis.21,22 Drugs may be a particularly important cause of falsepositive ANCA reactions, especially because hydralazine, propylthiouracil, d-penicillamine, and minocycline may be associated with high-titer MPO-ANCA reactivity, with or without an associated vasculitic syndrome. Minocycline has also been associated with a reversible autoimmune syndrome and MPO-ANCA.23 PATHOPHYSIOLOGY Although ANCAs are firmly entrenched in the diagnostic process for vasculitis, their role in the pathophysiology of these conditions is less so. Teleologic objections to a central role include the observation that ANCAs are not detected in a sizable portion of patients with well-documented small vessel vasculitis.24 Despite such considerable limitations, mounting evidence suggests that ANCA may either induce or augment vascular inflammation. These data have been critically reviewed by several groups.5,25,26 A variety of in vitro observations favor a pathogenic role for ANCA in some forms of vasculitis. For instance, in neutrophils, both MPO and PR3 are transported from primary granules to the cell membrane during activation and are part of the physiologic response to inflammatory mediators (e.g., tumor necrosis factor-α [TNF-α] and interleukin [IL]8).27-29 Evidence of surface expression of PR3 on circulating neutrophils and MPO release within renal lesions has been reported in WG.27,28 The binding of PR3-ANCA, MPOANCA, and other ANCAs to their cognate targets on

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neutrophils augments a variety of activation-related neutrophilic functions, including degranulation, respiratory burst, nitric oxide production, chemotaxis, adhesion molecule expression, and binding to cultured endothelial cells.27,29-31 Such binding appears to be dependent not only on binding of ANCA via the antigen-binding site but also on engagement of the Fcγ receptor.32 Collectively, these events may contribute to vascular damage. ANCAs also stabilize cell adhesion and promote migration and flow of neutrophils through endothelium.33 Whether PR3 is synthesized and expressed on endothelial cells is controversial, but PR3 does appear to be capable of passive binding to the cell surface and thus serves as a target for PR3-ANCA. Binding of PR3-ANCA to endothelial cells has been demonstrated to lead to upregulation of adhesion molecule expression and production of IL-8, both of which might contribute to vessel inflammation and injury.27,32 ANCAs are able to positively or negatively affect the proteolytic activity of PR3 or MPO, depending on epitope restriction.7,34 Thus, if these enzymes play a homeostatic role in the inflammatory response, ANCAs might have a modulatory effect. The activity of ANCAs in vivo has been demonstrated in animal models of vascular inflammation,35,36 but these have been criticized on methodologic grounds and for the lack of similarity to human disease. More recently, a murine model has strengthened the argument that ANCAs actually cause vasculitis.37 Anti-MPO antibodies alone have induced glomerulonephritis with crescent formation and systemic vasculitis in mice lacking functional T or B cells, as well as in an immunocompetent wild-type strain C57BL/6J, thus offering strong support for a direct pathogenic role. Further work with this model has demonstrated the central role of neutrophils in these glomerular lesions.38 Despite the observation that ANCAs are not present in all patients with systemic small vessel vasculitic syndromes, a number of studies have reported correlations between the presence and magnitude of ANCA and a variety of disease manifestations. Among these clinical correlates supported by many (but not all) investigations are disease activity and severity,39,40 risk of relapse,41,42 target organ distribution, and response to therapy.40 Most of these data stem from studies of PR3-ANCA in patients with WG; supporting data from other diseases such as MPA and CSS are much more limited. Despite such limitations, there is evidence that MPO-ANCA may play a similar role, including the display of MPO on the neutrophil cell membrane and its subsequent engagement, leading to degranulation, endothelial cell adhesion, and injury.43,44 The pathophysiologic significance of non-PR3- and non-­ MPO-ANCA is much less clear, but other antigen ­autoantibody systems, such as lactoferrin, may also lead to inflammatory damage at the neurophil-endothelial interface.45,46 Collectively, these studies indirectly support ANCA’s direct role in the pathogenesis of small vessel vasculitis. Figure 82-3 is a schematic representation of the pathogenic role of ANCA in vascular inflammation. DISEASE ACTIVITY Although the specificity and diagnostic value of ANCA testing are well established, there is still considerable controversy about the relative worth of such serology in monitoring

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Cytokines TNF, IL-1

Infecton or other trigger FcγR

Anti-PR3

MPO

PR3

Anti-PR3

PR3

Primed PMNs and/or monocytes

PR3

MPO

FcγR

O-

O-

Anti-PR3

O-

PR3

IL-8 MCP-1

E-selectin ICAM-1 VCAM

Cytokine-activated endothelium Figure 82-3  Schematic representation of the immune mechanisms hypothetically involved with antineutrophil cytoplasmic antibody (ANCA) ­enhancement of vascular injury. An infectious trigger or other environmental stimulus leads to a burst of cytokines, which primes the neutrophils or monocytes and may lead to the local upregulation of adhesion molecules on endothelium. The priming process within the inflammatory cells leads to enhanced expression of ANCA antigens on the cell surface. Activated neutrophils or monocytes may degranulate and release reactive oxygen species and lysosomal enzymes, leading to endothelial injury and further activation of the endothelial cell surface. The magnitude of this effect is influenced by the specificity of ANCA for proteinase 3 (PR3) or myeloperoxidase (MPO), as well as different epitopes of these respective antigens. The reaction may be further influenced by the immunoglobulin G (IgG) and Fcγ receptor phenotype engaged. Products released from degranulated inflammatory cells become bound to endothelial cells and further serve as targets of ANCA. Release of chemotactic chemokines such as interleukin-8 (IL-8) and macrophage chemoattractant protein-1 (MCP-1) serve to augment chemotaxis and inflammatory cell transmigration, in conjunction with other adhesion molecules. Thus, the scheme provides the prerequisites for endothelial and vascular injury induced by ANCA: the presence of ANCA, the expression of target antigens for ANCA on primed neutrophils and monocytes, the interaction between primed neutrophils and endothelium via adhesion molecules, and, finally, the activation of endothelial cells and ultimate efflux of inflammatory cells to the extravascular and perivascular tissues. FcγR, Fcγ receptor;  ICAM-1, intercellular adhesion molecule-1; PMN, polymorphonuclear leukocyte; TNF, tumor necrosis factor.

disease activity.7 In a pooled analysis of published data, only 48% of the rises in ANCA titers as measured by IFA were followed by relapse, and only 51% of all relapses were preceded by a rise in ANCA.47 Therefore, a rise in the ANCA titer should not be the sole basis for therapeutic decision making. A study of 100 ANCA-positive patients with vasculitis followed serially over a 2-year period found that 92% of flares were associated with rises in ANCA. The predictive values were higher for enzyme-linked immunosorbent assay (ELISA) than for IFA with regard to both PR3 and MPO. Although a substantial number of patients with rising ANCA levels did not flare, it was rare to see a flare in the absence of increased ANCA, which affirms this test’s strong negative predictive value in this setting. For all tests with high sensitivity, their greatest clinical utility is when they are negative.48

WEGENER’S GRANULOMATOSIS WG is a granulomatous necrotizing vasculitis characterized by a predilection to affect the upper and lower respiratory tracts and, in most cases, the kidneys. The disease was first described in 1931 by Heinz Klinger,49 a German medical student. In 1936 and 1939, Friedrich Wegener,50,51 a young pathologist, provided detailed information about three patients with a similar illness. Both Klinger and Wegener were struck by the

unusual distribution of disease in their patients. Involvement of the upper and lower airways was quite unlike the pattern seen in periarteritis nodosa. What later came to be known as WG remained relatively absent from the American literature until the 1950s, when Godman and Churg52 published a detailed clinicopathologic description of the disorder. In 1973, Fauci and Wolff,53 at the National Institutes of Health (NIH), recorded their observations of 18 patients with WG treated with a combination of steroids and cyclophosphamide. Sustained remissions and prolonged survival resulted, marking the beginning of a new era in the treatment of WG. EPIDEMIOLOGY No rigorous epidemiologic studies of WG have been published. The NIH experience suggests that WG affects both sexes equally, occurs in patients of all ages (mean age, 41 years; range, 9 to 78 years), and is more common in Caucasian patients (97%).54 Based on the National Hospital Discharge Survey, the estimated prevalence of WG in the 1986–1990 period was approximately 3 per 100,000 persons.55 Both sexes were equally represented. Only 0.1% of patients were younger than 19 years (versus 15% in the NIH series). Most patients were Caucasian (80.9%). Seasonal differences in dates of hospitalization were not readily apparent.

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It is likely that the prevalence of WG has been underestimated. Only since the early 1990s have we recognized the existence of mild and more indolent forms of the disease and the variability in its clinical presentation and course of illness. Future epidemiologic studies should take such factors into consideration and extend beyond the hospital setting.

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Active WG Non-organ- or life-threatening disease

MTX + GC

Organ- or life-threatening disease

± IVMP

CYC + GC

PATHOGENESIS The cause of WG is unknown. Sporadic efforts have been made to identify a genetic predisposition to WG, and a higher prevalence of human leukocyte antigen (HLA)DR156 and HLA-DQw757 has been reported among a small number of patients with WG. However, larger studies failed to identify any unique genetic markers.58 Several attempts to link infectious diseases to the development of WG have been unconvincing. Reports that the onset of disease occurs mostly in winter (a period of presumed increased respiratory illness)59 have not been confirmed in larger series.54,55 Analysis of bronchoalveolar lavage fluid and open lung biopsy specimens in patients with recent-onset disease did not reveal bacteria, fungi, mycoplasma, respiratory viruses, or virus-like inclusions.60 Although the association of PR3-ANCA antibodies and WG is now well established, the pathogenic role of these antibodies remains unclear. Many of the arguments supporting a pathogenic role were described previously. In addition, several clinical, in vitro, and ex vivo studies provide indirect evidence that these autoantibodies are more than an epiphenomenon. Clinical studies have documented that PR3-ANCA antibodies are highly specific for WG (90% to 97%).4,10 They are almost always present in active, generalized WG54,61 and may be produced by pulmonary lymphoid tissue in patients with active disease but not in those in remission.62 In vitro and ex vivo studies have shown that activation of polymorphonuclear cells and monocytes leads to the translocation of PR3 from the intracellular compartment to the cell surface, where it becomes accessible to circulating antibodies.63 ANCAs enhance neutrophil activation, degranulation, and respiratory burst, as well as adherence and damage to endothelial cells.29,31,43 Endothelial cells might also be a direct target for ANCA: PR3 is present in the cytoplasm of untreated human cultured endothelial cells, and stimulation with TNF leads to a time-dependent translocation of PR3 to the cell surface.64 These observations suggest, but do not prove, that ANCAs are directly involved in the pathogenesis of WG. Evidence of T cell involvement in WG is less direct than that supporting the pathogenic effect of ANCA. Biopsies of various tissues reveal the presence of polymorphonuclear and mononuclear infiltrates, the latter consisting of plasma cells, monocytes, and T cells, with a predominance of CD4+ cells.65,66 Increasing levels of soluble IL-2 receptors, sometimes preceding disease relapse, indicate the presence of activated T cells.67,68 In addition, autoreactive PR3-specific T cells are present in higher percentages in patients with WG compared with controls.69 The role of PR3-autoreactive T cells in ANCA production, disease activity, and pathogenesis of the granulomatous lesions remains to be established. Also, as previously mentioned, a recently described animal model of vasculitis has provided substantial support for a direct pathogenic role of ANCA by producing lesions in the kidney and lung highly reminiscent of WG and MPA through

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Remission No Yes

Rule out infection Switch to alternative induction agent

No

Yes Switch CYC to AZA or MTX

Continue MTX

Continue AZA/MTX ± low-dose prednisone Figure 82-4  Wegener’s granulomatosis (WG) treatment algorithm. AZA, azathioprine; CYC, cyclophosphamide (oral); GC, glucocorticoids; IVMP, intravenous methylprednisolone; MTX, methotrexate.

the action of anti-MPO antibodies alone.37 In this important model, the production of lesions similar to human disease in the absence of other confounding immunologic variables adds an important argument for causation by ANCA. CLINICAL FEATURES As stated earlier, WG is characterized by a predilection for the upper and lower respiratory tracts and the kidneys. Relatively mild forms of WG without renal involvement have been described. The course of illness may be indolent or rapidly progressive. Mild and indolent disease may go unrecognized for months to years, leading to delays in diagnosis and the institution of appropriate therapy. Neither clinical nor laboratory markers are able to distinguish which patients will continue to have limited, nonrenal forms of disease and which patients will experience progression in the future. A general approach to the diagnosis of WG is shown in Figure 82-4. Unexplained constitutional symptoms are often part of the initial presentation. Fever is present in about one fourth of patients at disease onset and occurs in up to half of cases during the course of illness.54 Weight loss exceeding 10% of usual body weight has been reported in 15% of patients at onset and 35% of patients overall.54 The clinical features of WG are presented in the following sections using an organ-oriented approach. For each organ system, we discuss the signs and symptoms of disease, differential diagnoses (when appropriate), clinical and laboratory methods to diagnose and assess disease activity, and aspects of disease-related morbidity. Upper Airway Manifestations Upper airway disease is the most common presenting feature of WG, occurring in more than 70% of patients at onset and ultimately developing in more than 90%.54,70,71 Otologic manifestations may be part of the initial presentation in about 25% of patients with WG and may occur in up to 60% during the course of disease.54,70-72 Serous otitis

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Figure 82-6  Computed tomography scan of the sinuses, revealing the presence of chronic sinusitis.

Figure 82-5  Saddle-nose deformity in a patient with Wegener’s granulomatosis. (Courtesy of Dr. G. Hoffman.)

media is the most common ear problem encountered (25% to 44%). It may be complicated by the presence of a suppurative infection in up to 25% of cases. Significant degrees of hearing loss (mostly conductive) may result in 14% to 42% of patients.54,70-72 Inner ear manifestations include sensorineural hearing loss and, rarely, vertigo.71,72 Nasal disease is a prominent presenting feature in about 33% of cases, but it eventually develops in 64% to 80% of patients.54,70,71 Symptoms and signs of nasal involvement in WG include mucosal swelling with nasal obstruction, crusted nasal ulcers and septal perforations, serosanguineous discharge, epistaxis (11% to 32%), and external saddle-nose deformity (9% to 29%) (Fig. 82-5).54,70,71 Sinusitis is present at initial presentation in about 50% to 67% of patients with WG and is seen in 85% during the course of disease.54,70 A simple computed tomography (CT) scan of the sinuses (Fig. 82-6) is often anatomically more informative than plain radiographs, especially in the setting of destructive or erosive bony changes. Most patients with sinus or nasal disease eventually develop a secondary infection of these tissues; Staphylococcus aureus is the predominant organism identified from cultures.70 Although laryngotracheal disease in WG may be asymptomatic, the clinical presentation can range from subtle hoarseness to stridor and life-threatening upper airway obstruction.54,71,73 The most characteristic lesion is subglottic stenosis (Fig. 82-7), which occurs in up to 16% of patients.54,73 It is important to note that in pediatric and adolescent patients with WG, the frequency of subglottic stenosis is dramatically increased, reaching an alarming prevalence of 48%.73,74 Direct laryngoscopy may reveal either active erythematous, friable mucosa or bland scar.71 Tracheal tomograms, CT, and

magnetic resonance imaging (MRI) may be useful adjuncts in the diagnosis of subglottic stenosis. Langford and coworkers75 reported that in 49% of patients, subglottic stenosis occurred in the absence of other features of active disease; in 49%, it developed during treatment with systemic immunosuppressive therapy for other disease features. Pulmonary Manifestations Pulmonary involvement is one of the cardinal features of WG. Pulmonary manifestations occur in 45% of cases at presentation and in 87% during the course of disease.54 Cough, hemoptysis, and pleuritis are the most common pulmonary symptoms. However, it is important to realize that up to one third of patients with radiographically demonstrable pulmonary lesions may not have lower airway symptoms. The most common radiographic findings include pulmonary infiltrates (67%) and nodules (58%).54 The pulmonary infiltrates in WG may be quite fleeting, appearing and resolving in some cases before the institution of therapy.53 Persistent, diffuse

Figure 82-7  Subglottic stenosis in a patient with Wegener’s granulomatosis. Magnetic resonance imaging (left) and endoscopic view (right). (Right, courtesy of Dr. G. S. Hoffman; from Hoffman GS, Kerr GS, Leavitt RY, et al: Wegener granulomatosis: An analysis of 158 patients. Ann Intern Med 116:488-498, 1992.)

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Figure 82-8  Computed tomography scan of the lungs, revealing the presence of nodules. The right-sided ­pulmonary nodule is cavitary.

interstitial infiltrates are rare (<1%) and should suggest other diagnoses. Pulmonary nodules in WG are usually multiple and bilateral and often cavitate (50%).76-78 CT of the chest may reveal infiltrates and nodules (Fig. 82-8) that were undetected by conventional radiographs in 43% to 63% of cases.77-79 Less common pulmonary manifestations of WG include pleural effusions, diffuse pulmonary hemorrhage, and mediastinal or hilar lymph node enlargement or mass.80,81 Diffuse pulmonary hemorrhage has been reported in up to 8% of cases and carries a high fatality rate (50%).53,77,82 In patients presenting with pulmonary symptoms, it is imperative to make every effort to exclude the presence of infection in a timely fashion, because pneumonia in an immunocompromised host can result in up to 50% mortality. Bronchoscopy is often needed to satisfactorily exclude infection or establish a microbiologic diagnosis by performing the appropriate stains and cultures. Pneumonia may account for up to 40% of serious infections in patients with WG and may be the cause of death in a significant proportion of cases (16%).54,76 Pulmonary morbidity in WG is significant. Pulmonary function tests may reveal obstructive defects in up to 55% of patients, generally caused by endobronchial lesions and scarring.83 Restrictive defects with reduced lung volumes and carbon monoxide diffusion capacity are observed in 30% to 40% of patients.83 In more than 17% of patients, serial pulmonary function tests document moderate to severe degrees of progressive pulmonary insufficiency, perhaps as a result of fibrosis following active disease, pneumonia, cyclophosphamide-induced pneumonitis, or some combination of these.54 Renal Manifestations The presence or absence of renal disease defines the subsets of generalized and limited WG, respectively.84,85 The exact frequency of renal involvement in WG is difficult to

­ascertain. Limited WG may go undiagnosed in patients with mild disease. By excluding such patients, published series may overestimate the frequency of renal disease in WG. Early renal disease may be clinically silent; that is, kidney biopsies may, on rare occasions, reveal focal inflammatory changes in patients with normal urinary sediment and renal function.53,84,86 In addition, patients who appear to have limited WG at one time may later develop glomerulonephritis. This observation mandates caution in patients thought to have limited WG and dictates the need for careful and close monitoring of renal status in all patients. When renal disease is defined by pathologic findings on kidney biopsy or the presence of an active urinary sediment and functional abnormalities, it is estimated to occur in 11% to 18% of patients at presentation and in 77% to 85% during the course of disease.54,70 Extrarenal manifestations often precede renal disease. Once present, renal disease may progress from asymptomatic and mild to fulminant glomerulonephritis within days or weeks, resulting in end-stage renal failure.70 If untreated, mean survival time for this subset of patients is about 5 months.87 Even when appropriate therapy is instituted, initial and recurrent renal damage may lead to chronic renal insufficiency in up to 42% of patients, often requiring dialysis (11%) and renal transplantation (5%).54 The role of microscopic urinalysis in the evaluation of patients with suspected or proven WG cannot be overemphasized. It remains the most useful tool to assess for the presence of active glomerulonephritis. The freshly collected urinary sediment should be carefully examined. The presence of red blood cell casts approaches a 100% positive predictive value for glomerulonephritis. In the absence of red blood cell casts, the presence of hematuria should lead to consideration of lower urinary tract involvement by the vasculitic process, which is uncommon, or the presence of cyclophosphamide-induced cystitis.

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Musculoskeletal Manifestations Musculoskeletal symptoms are common in patients with WG, occurring in 32% to 53% of patients at presentation and in 67% to 76% during the course of disease.54,70,94 Although most patients experience only arthralgias and myalgias, arthritis is observed in up to 28% of patients.70,94 When synovitis is present, several patterns can be observed, including monarticular disease, migratory oligoarthritis, and symmetric or asymmetric polyarthritis of small and large joints.54,94 Symmetric polyarthritis of small and large joints may be mistaken for RA.54,94 A positive test for rheumatoid factor may be observed in as many as 50% to 60% of patients, often contributing to an incorrect diagnosis.54,94 In contrast to RA, the symmetric polyarthritis of WG is generally nonerosive and nondeforming.54,70,94 Neurologic Manifestations

Figure 82-9  Computed tomography scan of the orbits, revealing the presence of a retro-orbital mass (orbital pseudotumor).

Ocular Manifestations Ocular manifestations reportedly occur in 28% to 58% of patients with WG and may be part of the initial presentation in 8% to 16% of cases.88,89 Any compartment of the eye can be affected. Keratitis, conjunctivitis, scleritis, episcleritis, nasolacrimal duct obstruction, uveitis, retroorbital pseudotumor with proptosis (Fig. 82-9), retinal vessel occlusion, and optic neuritis have all been described.88,89 Vision loss may occur in as many as 8% of patients.54,90 Although most ocular findings are nonspecific, proptosis is a diagnostically helpful finding,54,70 but it is a poor prognostic sign; about half of patients with proptosis in one series lost vision due to optic nerve ischemia.54 A complete ophthalmologic examination is an important part of the diagnostic evaluation. In patients with proptosis, CT or MRI of the orbits and sinuses may provide useful anatomic information.89,91 Ocular disease may also occur as a complication of therapy. Glucorticoid-related cataracts occurred in 21% of patients in one series.54 Glucocorticoid and cyclophosphamide therapy has been associated with opportunistic ocular infections including cytomegalovirus retinitis and herpes zoster ophthalmicus.92 Cutaneous Manifestations Cutaneous manifestations have been reported in 40% to 50% of patients with WG and may be part of the initial presentation in 13% to 25% of cases.93 The cutaneous ­manifestations of WG include ulcers, palpable purpura, subcutaneous nodules, papules, and vesicles. Although cutaneous lesions rarely dominate the clinical picture, they do tend to parallel disease activity in other organs. The presence of active skin lesions is thus a reliable clinical marker for active systemic disease and should prompt the clinician to evaluate other organ systems thoroughly.

Neurologic involvement is rarely a presenting feature of WG, but it may develop during the course of disease in 22% to 50% of cases.54,70,76,95 Multiple neurologic complications may occur in up to 11% of patients. Peripheral neuropathy is the most common single neurologic manifestation of WG (10% to 16%).54,70,76,95 Mononeuritis multiplex is the most frequent clinical pattern (12% to 15%), followed by a distal and symmetric polyneuropathy (2%).54,95 Electromyography and nerve conduction studies may be useful in demonstrating the extent and distribution of involvement and can often identify an overlapping mononeuropathy multiplex that is not apparent on clinical examination. Biopsy of the involved nerve or nerves reveals the presence of vasculitis, but biopsy is rarely necessary to establish the diagnosis or make therapeutic decisions. The overall frequency of central nervous system (CNS) involvement is difficult to estimate because the symptoms, signs, and clinical presentations of CNS disease have been variably defined and accrued in different series. In addition, significant classification overlap exists among the symptoms and signs of CNS, ocular, and sinus disease and treatment complications. Chronic pachymeningitis (Fig. 82-10), cerebral vasculitis, pituitary involvement, cerebral hemorrhage or thrombosis, and cranial neuropathies can all occur.96 Cranial neuropathy occurs in 6% to 9% of patients.54,95 Cerebrovascular events, occurring in up to 4% of cases, may include cerebral or brainstem infarction, subdural hematoma, and subarachnoid hemorrhage.54,76,95 Diffuse meningeal and periventricular white matter disease, presumably reflecting CNS vasculitis, has been reported in patients presenting with diffuse and focal CNS symptoms.96-98 In patients presenting with symptoms and signs of CNS disease, several diagnostic tests may be considered. CT or MRI of the brain may document the presence of infarcts, hemorrhage, mass lesions, diffuse meningeal enhancement, or periventricular white matter lesions. In some cases, lumbar puncture is necessary to exclude CNS infections and subarachnoid hemorrhage. Cerebral angiography is a test of low diagnostic yield in WG because, in most instances, relatively small vessels are involved.95,97,98

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Gastrointestinal Manifestations

Figure 82-10  Pachymeningitis in a patient with ­ egener’s granulomatosis. Magnetic resonance imagW ing findings.

are uncommon. Ureteral obstruction by an extrinsic inflammatory mass has been reported.102 Hemorrhagic cystitis is more commonly seen in relation to cyclophosphamide therapy, but it may be due to involvement of the bladder wall by necrotizing vasculitis.103 In an autopsy series, granulomatous or necrotizing prostatitis was found in 7.4% of patients with WG.87 Other genitourinary manifestations include necrotizing urethritis, orchitis, epididymitis, and penile necrosis.99 Microscopic examination of freshly voided urine is the most important diagnostic test. The presence of hematuria in the absence of red blood cell casts (after adequate review by the clinician) should prompt an evaluation of the lower genitourinary tract. Cystoscopy is preferred because it allows direct visualization of abnormal structures and the performance of diagnostic biopsies. This is also important in patients receiving long-term cyclophosphamide therapy. Urinary tract infections should always be considered and the appropriate cultures obtained.

The frequency of GI involvement in WG is difficult to estimate, perhaps because it is frequently asymptomatic and may be unrecognized. The literature consists mainly of individual case reports of patients with dramatic or unusual GI presentations. Abdominal pain, diarrhea, and bleeding are the most frequently reported symptoms, and they relate to the presence of ulcerations in the small intestines, large intestines, or both (enterocolitis).99 Small and large bowel perforations have been described, with dramatic and often fatal presentations.99 Other unusual presentations include cholecystitis, unexplained ascites, nonhealing perianal ulcers, recurrent acute pancreatitis, and pancreatic mass with extrahepatic obstruction.99 Steroid-induced peptic ulcers may occur, but a biopsy is required to distinguish such lesions from those due to vasculitis. Unexplained elevations of liver enzymes have also been described and may resolve with therapy.70 In autopsy series of patients with WG, the spleen was commonly involved; the majority of cases demonstrated splenic lesions with a combination of necrosis, vasculitis, and granuloma formation.87 However, clinically apparent splenic disease is rare. The occurrence of GI complaints in a patient with a known or suspected diagnosis of WG (or other systemic vasculitides) represents a medical emergency.100 In patients with abdominal pain and systemic vasculitis, especially those receiving glucocorticoids, the lack of physical signs on abdominal examination should not lead to a false sense of security. Plain abdominal radiographs may detect the presence of free air, indicative of perforation. Arteriography may not be helpful because WG most often affects small vessels, which are beyond the resolution of this technique.100 Endoscopic studies (colonoscopy, gastroscopy) may document the presence of ulcerations. Endoscopic biopsies usually demonstrate nonspecific inflammatory changes and may, on rare occasions, reveal granulomatous necrotizing vasculitis, thus establishing a histopathologic diagnosis. Histologic diagnosis is more commonly made on examination of surgical specimens because of the greater amount of tissue available.101

The frequency of cardiac involvement in WG ranges from 6% to 12% in clinical series54,70 and may reach 30% in autopsy series.87 Pericarditis is the most frequently reported cardiac manifestation in WG.104 Patients may present with asymptomatic pericardial effusions or complain of chest pain associated with a pericardial friction rub on physical examination. In the setting of advanced renal disease, the differential diagnosis includes uremic and infectious causes of pericarditis. Pericardial tamponade has rarely been reported and may require pericardiocentesis, pericardiectomy, or both.54,105,106 Pericarditis is also the most common pathologic finding in the heart, accounting for about 50% of histologically documented cardiac disease in WG.107 Necrotizing vasculitis and granuloma formation may involve the pericardium in a focal or diffuse pattern.107 Other cardiac manifestations of WG include myocardial ischemia due to coronary vasculitis, myocarditis, endocarditis, and valvulitis; arrhythmias; and conduction defects.104

Genitourinary Manifestations

ASSOCIATED CONDITIONS

Virtually every segment of the genitourinary tract distal to the kidneys may be involved in WG. The literature consists mostly of individual case reports, suggesting that such ­manifestations

Recent evidence suggests that there is an increased rate of venous thromboembolic events in patients with WG.108 A rate of 7 symptomatic events (mainly deep vein thrombosis

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and pulmonary embolus) per 100 patient-years of observation was recorded. This may be an underestimate, because ultrasonography to detect asymptomatic thromboses was not performed. Nevertheless, it is significantly greater than the rates seen in patients with SLE, RA, or the general population.108 These results were corroborated by another recent report that showed an increased rate of venous thromboembolic events in patients with WG, MPA, and renal-limited vasculitis.109 No evidence of an underlying thrombophilic disorder was found in patients tested. This has implications for the differential diagnosis of pulmonary symptoms in WG patients and complicates the approach to treatment, particularly in the setting of pulmonary hemorrhage. It has also been postulated that, similar to other ­rheumatic disorders such as RA and SLE, WG is associated with accelerated atherosclerosis.110 WG has been associated with biomarkers of coronary artery disease such as endothelial dys­ function, arterial stiffness, and carotid intimal-medial thickness.110,111 Additional data are necessary to clearly delineate the risk of atherosclerotic disease in WG, but it is prudent to address traditional cardiac risk factors in WG patients.

PATHOLOGY

General laboratory abnormalities in untreated patients may include leukocytosis, normocytic normochromic anemia, thrombocytosis, and elevated erythrocyte sedimentation rate. These are imperfect markers of disease activity and should always be interpreted in relation to organ-specific clinical and laboratory evidence of active disease. The role of ANCA testing in the evaluation of WG and other systemic vasculitides has already been discussed. The sensitivity of PR3-ANCA is about 90% in active WG and 40% when the disease is in ­ remission.4,61,112 The specificity of PR3-ANCA in the diagnosis of WG exceeds 95%.4,61,112 In general, the presence of high-titer ANCA by IFA combined with confirmatory antigen-specific assay for either PR3 or MPO in the setting of a high index of ­suspicion for ­vasculitis (i.e., high pretest probability) is sufficient for diagnosis, even in the absence of tissue confirmation.

Inflammatory lesions in WG typically include necrosis, granulomatous changes, and vasculitis.49-51,53,54,70,87 The diagnostic yield of a biopsy varies with the size of the pathologic specimen and how completely it is sectioned and studied. The small amount of tissue available in head and neck biopsies (mostly from nasal and paranasal sinuses) may make it difficult to identify all the pathologic features of WG.113-115 Vasculitis, necrosis, and granulomatous inflammation are each encountered in roughly one third to one half of pathologic specimens.113-115 Vasculitis and necrosis are seen together in only one fifth of biopsies.114,115 The frequency of combined vasculitis and granulomatous inflammation is also about one fifth.114,115 Most important, the complete diagnostic triad is seen in only 3% to 16% of biopsies.114,115 Thus, head and neck biopsies most often reveal findings compatible with, but rarely characteristic of, WG. Awareness of these limitations is required for the correct interpretation of head and neck biopsy results in patients suspected of having WG. The diagnostic yield of lung biopsies similarly reflects the sample size of pulmonary tissue obtained.54,66 Transbronchial biopsies are rarely diagnostic (<7%), whereas open lung biopsies reveal various combinations of vasculitis, granulomas, and necrosis in about 90% of cases (Fig. 82-11).54,66 Nonetheless, bronchoscopy and transbronchial biopsy remain valuable in the diagnosis or exclusion of bacterial, mycobacterial, or fungal infections that can mimic or complicate WG. Capillaritis (Fig. 82-12), a pathologic finding, has been described in 35% to 45% of WG cases in surgical biopsy and autopsy series.116,117 In one study, capillaritis was found in all 11 patients with WG presenting with diffuse pulmonary hemorrhage.118 However, the finding of capillaritis is not diagnostically specific. Capillaritis has been described in SLE, immune complex–associated vasculitides, dermatomyositis, RA, Henoch-Schönlein purpura, and even bronchopneumonias.82 Pathologically, renal disease in WG is characterized by the presence of focal and segmental glomerulonephritis (Fig. 82-13).53,54,70,76,86,87 Fibrinoid necrosis and ­proliferative changes are seen in varying degrees. In patients with

Figure 82-11  Giant cells within areas of collagenous necrosis (right) and histiocytic infiltrate (middle and left) in a lung nodule in a patient with Wegener’s granulomatosis (hematoxylin and eosin, ×20). (Courtesy of Dr. C. Farver.)

Figure 82-12  Capillaritis. Alveolar septae with congestion, neutrophilic infiltrate, and fibrinoid necrosis of capillary walls. Adjacent alveolar spaces contain hemosiderin-laden macrophages, consistent with a history of pulmonary hemorrhage (hematoxylin and eosin, ×40). (Courtesy of Dr. C. Farver.)

LABORATORY DIAGNOSIS

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i­rreversible renal impairment, epithelial crescents and sclerotic lesions are commonly encountered.54,70,87 True vasculitis of medium-sized renal arteries is only occasionally noted (3% to 15%), and granulomatous changes are equally rare (3%).52-54,70,76 Immune complex deposition, as demonstrated by immunofluorescence or electron microscopy, is distinctly unusual.54,86,119 The results of kidney biopsies are thus more often compatible with, rather than diagnostic of, WG. TREATMENT To manage WG effectively, the clinician must establish the diagnosis without delay, recognize the variability in clinical course and severity, critically monitor disease activity, and anticipate disease- and treatment-related morbidity. Therapeutic decision making should be based on a critical assessment of disease activity. Meticulous attention should be paid to complications of therapy, which often lead to permanent morbidity and, sometimes, mortality. In addition, certain complications (infections, drug reactions or toxicity, drug-induced pneumonitis, renal impairment) may be confused with active disease. The significant toxicity of currently available therapeutic agents has been the main driving force for the development of new drugs and innovative approaches to the treatment of WG and other systemic vasculitides. An overview of the approach to treatment of WG is shown in Figure 82-4. Glucocorticoids In WG, glucocorticoids are most commonly used in combination with cytotoxic agents. Although palliation of limited, indolent disease may be achieved with glucocorticoids alone, disease progression and relapses usually occur. Patients with generalized WG uniformly fail to achieve remission with glucocorticoid therapy alone. Treatment is generally initiated at a high dose, such as prednisone 1 mg/kg per day or more. High doses are maintained until all manifestations

Figure 82-13  ANCA-associated crescentic glomerulonephritis. This toluidine blue–stained plastic section demonstrates a glomerulus with a cellular crescent. There is partial obliteration of Bowman’s space by a ­proliferation of epithelial cells and macrophages. All types of crescentic glomerulonephritis appear similar by light microscopy, and immuno­ fluorescence is needed to distinguish among pauci-immune, immune complex, and anti–glomerular basement membrane subtypes. (Courtesy of Dr. J. Myles.)

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of active disease have abated (e.g., stabilization of renal function, resolution of pulmonary infiltrates). Drug tapering should begin after WG is well under control, usually about 1 month after the initiation of treatment. The literature does not provide a consensus opinion about the strategy for tapering glucocorticoids. In the initial seminal studies of WG, prednisone was reduced on an alternate-day basis.54,70,120 Currently, however, the favored approach is to taper prednisone on a daily basis, with varying regimens reported.121123 Another approach during the initiation of therapy is to use intravenous “pulse” or “bolus” methylprednisolone (e.g., 1 g daily for 3 days) for immediately life-threatening disease (e.g., diffuse pulmonary hemorrhage, rapidly progressive glomerulonephritis). However, the optimal dose and frequency of intravenous glucocorticoids have not been studied in a controlled fashion for systemic vasculitis. In addition, the short-lasting effects of pulse glucocorticoids do not obviate the need for maintenance therapy. Before the advent of glucocorticoids, the mean survival time of patients with WG was 5 months. Glucocorticoids alone modestly increased the mean survival time to 12 months.124 Five-year survival rates greater than 80% were not seen until the introduction of aggressive combination therapy with glucocorticoids and daily cyclophosphamide. Cyclophosphamide Combination therapy with daily oral cyclophosphamide and glucocorticoid has been considered the standard therapy for WG.53,54,70 Oral cyclophosphamide is generally initiated at doses of 2 mg/kg per day. In life-threatening situations (pulmonary hemorrhage or rapidly progressive glomerulonephritis), doses of 3 to 5 mg/kg per day can be used for 3 to 4 days, then reduced to the more conventional range. The leukocyte count is used to guide subsequent dosage adjustments (discussed later). Tapering and discontinuation of the glucocorticoid generally precede attempts to taper cyclophosphamide. The traditional approach to the treatment of systemic WG is to continue cyclophosphamide for at least 1 year after the patient has achieved complete remission. Orally administered cyclophosphamide is well absorbed and completely metabolized within 24 hours by the liver; the multiple active and inactive metabolites are excreted mostly in the urine. One of these metabolites, acrolein, is known to be responsible for hemorrhagic cystitis, bladder fibrosis, and bladder cancer. High oral fluid intake should be encouraged to dilute this bladder irritant and reduce the incidence of such complications. The time from initial use of cyclophosphamide to detection of bladder cancer may be as short as 7 months or as long as 10 to 15 years, even after the drug has been discontinued.54,125 Urine cytology is an insensitive diagnostic tool to detect bladder cancer. Cystoscopy is therefore necessary in any cyclophosphamide-treated patient with nonglomerular hematuria. Lifelong surveillance for bladder cancer, as well as hematologic malignancies, is indicated in all patients who have been treated with chronic daily cyclophosphamide therapy.54,125 Dose-related bone marrow suppression is a common drug-related toxicity, and blood counts should be closely observed during the course of treatment. Leukopenia is the most frequent sign of marrow suppression and should guide dosage adjustments in

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these patients. The risk of infection is increased even in the absence of leukopenia. Total leukocyte counts of less than 3500/mm3 or absolute neutrophil counts of 1500/mm3 or less should be avoided. Based on data from recent pharmacokinetic investigations, the dose of cyclophosphamide should be adjusted downward by 25% to 30% in the presence of significant renal impairment.126 Cyclophosphamide is formally contraindicated during pregnancy, and birth control should be strongly advised in women of childbearing age. When the drug is used in men considering fatherhood, they should be counseled regarding sperm banking. In a large series of 158 patients with WG followed at the NIH for up to 24 years (mean follow-up, 8 years), 84% of patients received standard therapy with daily cyclophosphamide and glucocorticoid.54 This regimen produced marked improvement in 91% of patients and complete remission in 75%. Disease relapse was seen in 50% of patients in this study, with permanent morbidity from disease occurring in 86% of that group. This included chronic renal insufficiency (42%), hearing loss (35%), cosmetic and functional nasal deformities (28%), tracheal stenosis (13%), and vision loss (8%), with many patients experiencing more than one type of morbidity. Permanent morbidity as a result of treatment with cyclophosphamide and glucocorticoid occurred in 42% of patients and included cystitis (43%), bladder cancer (2.8%—33 times the expected rate), lymphoma (1.5%—11 times the expected rate), myelodysplasia (2%), infertility (>57% of women), cataracts (21%), fractures (11%), and aseptic necrosis (3%). Moreover, 46% of patients experienced serious infectious episodes that required hospitalization and intravenous antibiotics.54 The awareness of this significant disease- and treatmentrelated morbidity in WG patients, and the recognition of more indolent forms of disease without any significant pulmonary or renal abnormalities, led to efforts to identify effective and less toxic therapeutic interventions. Approaches have focused largely on minimizing cumulative cyclophosphamide exposure, including the use of intermittent high-dose intravenous cyclophosphamide, alternative induction agents for less severe disease (e.g., methotrexate), and a staged therapeutic approach. The last of these considers the treatment of WG in two parts: remission induction and remission maintenance. The aim is to treat active disease aggressively to induce remission, typically with cyclophosphamide and glucocorticoid, as outlined earlier, and then switch from cyclophosphamide to a less toxic agent for remission maintenance. This takes advantage of the potency of cyclophosphamide as a remissioninducing agent and the lower toxicity of antimetabolites. Studies of intermittent high-dose intravenous (pulse) cyclophosphamide were motivated by its demonstrated efficacy in the treatment of lupus nephritis and the anticipation of reduced toxicity. Pulse cyclophosphamide is only rarely associated with hemorrhagic cystitis and has not been associated with bladder cancer. Several small randomized trials of 0.7 g/m2 every 3 weeks have suggested an efficacy comparable to daily oral cyclophosphamide in achieving initial remission in WG, with fewer associated infections, especially Pneumocystis carinii pneumonia, and lower mortality than oral therapy, albeit with a trend toward a greater risk of disease relapse.127,128 Several criticisms of these investigations have been voiced, including an unacceptable overall mortality rate in one trial127 and a lack of statistical power in the

other.128 To minimize bladder toxicity, some investigators recommend the use of mesna (sodium 2-­mercaptoethane sulfate).129 This can be given intravenously at the time of cyclophosphamide infusion, but owing to a short half-life, it must be administered orally 2 and 4 hours after the infusion to be effective. In addition to having its own toxicities, the technique is cumbersome; thus, many favor a high oral intake of fluids as an alternative. A multicenter randomized, controlled trial has been performed comparing oral and pulse cyclophosphamide for the treatment of WG. Until the results of this study are available, the pulse method cannot be recommended as standard treatment for WG. Azathioprine Azathioprine is a derivative of thioguanine, a purine antimetabolite. It has long been used for the prevention of transplant rejection and the treatment of many rheumatic diseases (e.g., RA, SLE) and other inflammatory conditions (e.g., inflammatory bowel disease). Azathioprine is a prodrug and is metabolized to 6-mercaptopurine. 6-Mercaptopurine is further metabolized by thiopurine methyltransferase (TPMT) and hypoxanthine phosphoribosyl transferase. Def­ iciency of TPMT leads to preferential formation of toxic metabolites and lower drug tolerance. Low levels of TPMT activity occur in 11% of the population, with very low levels occurring in 0.3%. Therefore, in an effort to reduce the incidence of azathioprine toxicity, some recommend TPMT screening before the initiation of azathioprine therapy, particularly at higher doses.130 The mechanism of action of azathioprine is related to the reduction of intracellular purine synthesis, thereby inhibiting DNA replication. This leads to a decrease in circulating B and T lymphocytes and a reduction in immunoglobulin synthesis. Recent evidence also points to the ability of azathioprine metabolites to disrupt T cell activation pathways. The most common side effects at the doses used to treat rheumatic diseases are GI intolerance, bone marrow suppression, and infection, with a potential risk for malignancy in the long term. A hypersensitivity syndrome may occur in up to 5% of patients, typically manifested by rash, fever, myalgias, malaise, and GI symptoms. Mild elevation of liver enzymes can occur, but cirrhosis has not been reported. Azathioprine has been evaluated in a multicenter randomized, controlled trial for the maintenance of remission in patients with WG and MPA.122 Remission was induced with standard therapy (oral cyclophosphamide and glucocorticoid) in 144 of 155 patients enrolled. Upon remission, patients were randomized to receive either azathioprine 2 mg/kg per day or oral cyclophosphamide 1.5 mg/kg per day in conjunction with prednisolone 10 mg/day. At 12 months, both groups were treated with azathioprine 1.5 mg/ kg per day in combination with prednisolone 7.5 mg/day. At 18 months, relapse rates were similar in both groups (azathioprine, 15.5%; cyclophosphamide, 13.7%) suggesting that the two drugs are equally efficacious for remission maintenance in WG and MPA. The adverse event rates did not differ between treatment groups, perhaps reflecting the late onset of many of the toxicities associated with cyclophosphamide. This study demonstrated that cyclophosphamide can safely be switched to azathioprine upon the induction of remission in WG.

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Methotrexate Low-dose methotrexate (MTX), such as 0.05 to 0.3 mg/kg per week, has been used to treat a variety of autoimmune diseases. MTX-related toxicity is most often mild and can be diminished by either dose reduction or temporary discontinuation of the drug. Folic or folinic acid supplementation may also reduce the incidence of certain MTX side effects, although it is unclear whether this compromises its therapeutic efficacy in RA.131,132 Mild elevations of liver enzymes are common during MTX therapy, but cirrhosis rarely occurs with careful monitoring and in the absence of risk factors. MTX appears to be less oncogenic than cyclophosphamide. Nonetheless, reversible lymphoproliferative disorders have occurred during MTX therapy for other rheumatic diseases.133,134 MTX is teratogenic and causes a high rate of malformation and abortion. Therefore, birth control is mandatory in females and is advised in males who are taking the drug. MTX has been evaluated for both remission induction and remission maintenance in WG. In a prospective openlabel study of 42 patients at the NIH, the sequential use of cyclophosphamide followed by MTX was effective at maintaining remission. Although 52% of patients suffered relapses at a median interval of 15 months, some while still on therapy, none of the relapses met prespecified criteria for severe disease.135,136 Another prospective open-label study reported a relapse rate of 36.6% among 71 patients at a mean interval of 19.4 months, at which time the mean MTX dose was 18 mg/wk.137 A limitation of this strategy is the danger of using MTX in settings of changing renal function or when the baseline value is greater than 2 mg/dL. In these situations, azathioprine is a safer option. In an effort to find an effective and safe alternative to cyclophosphamide for the induction of remission in WG, the NIH initiated an open-label study of weekly low-dose MTX plus glucocorticoid in 42 patients with biopsy-proven WG.138,139 Although none of the patients included in this study had immediately life-threatening disease (serum creatinine >2.5 mg/dL or acute pulmonary hemorrhage), 50% had active glomerulonephritis. Twenty-six patients (62%) had previously received treatment with a glucocorticoid, a cytotoxic agent, or both. These patients were enrolled because of either persistent or relapsing disease, serious toxicity from prior use of cytotoxic drugs, or both. Weekly administration of MTX (0.15 to 0.30 mg/kg per week) and glucocorticoid produced remission in 71% of patients after a median of 4.2 months. Nonetheless, relapses occurred in 36% after a median of 29 months. Treatment was not free of serious side effects: four patients developed Pneumocystis carinii pneumonia, and two of them died. This stresses the need for vigilance in monitoring for opportunistic infections, particularly in patients receiving daily steroids and a cytotoxic agent. Pneumonia prophylaxis should be standard in such patients. A recently completed unblinded, multicenter, randomized, controlled trial compared the efficacy and safety of MTX and oral cyclophosphamide for remission induction in nonsevere WG and MPA.140 Patients were newly diagnosed, without severe organ- or life-threatening manifestations. MTX and cyclophosphamide treatment led to similar remission rates within 6 months (89.8% and 93.5%, respectively), despite a slow escalation of the MTX dose from

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15 mg/wk to 20 to 25 mg/wk over a 12-week period. However, time to remission was longer in the MTX group, particularly in those patients with more extensive disease or pulmonary involvement at baseline. Relapse occurred in 69.5% of MTX-treated patients and 46.5% of cyclophosphamide-treated patients, with a median interval from remission to relapse of 13 and 15 months, respectively. These higher than expected relapse rates may reflect the fact that treatment was discontinued in both groups at 12 months. Contrasting these results with the low relapse rates observed in the previously cited study122 (in which immunosuppressive therapy was continued for 18 months) supports the practice of long-term continuation of maintenance therapy in WG. However, the optimal duration has yet to be determined. Other Maintenance Therapies Other agents that have been proposed for the maintenance of remission in WG include mycophenolate mofetil and leflunomide. Open-label studies with small numbers of patients suggest that these agents may be efficacious in preventing relapse in WG141-143; however, their use should be considered only if patients are either intolerant of or refractory to azathioprine and MTX. Antimicrobial Agents Since the original report by Wegener,51 it has been postulated that airway stimulation is necessary for disease expression. Upper or lower airway symptoms are present at disease onset in 90% of patients.54 Neutrophilic alveolitis and increased concentration of IgG c-ANCA in bronchoalveolar lavage fluid are seen in patients with active WG, but not in those in remission.60,62 Most patients with WG develop respiratory tract infections at some point during the course of their disease. Secondary infection of the paranasal sinuses occurs most frequently with S. aureus.70 An observational cohort study of 57 patients with biopsy-proven WG suggested that chronic nasal carriage of S. aureus identifies a subgroup of patients who are more prone to relapse.144 Whether infectious organisms can induce a relapse of disease activity and whether relapses can be prevented by antibiotic prophylaxis remain the subject of speculation. A reduced rate of relapse was found in a placebo-controlled trial of trimethoprim­sulfamethoxazole (TMP-SMX) for the prevention of relapse in WG; however, this reduction was accounted for by upper airway disease alone.145 In another prospective study in which infection was carefully ruled out and concomitant immunosuppressive therapy was unchanged for the previous 3 months, no patient had sustained improvement.54 In a controlled trial, TMP-SMX was clearly inferior to MTX for the maintenance of remission in patients with generalized WG.146 Because TMP-SMX seemed to increase the chance of relapse, the authors recommended against using TMPSMX alone or TMP-SMX plus prednisone for the maintenance of remission in generalized WG. Intravenous Immunoglobulin Treatment with intravenous immunoglobulin (IVIG) has been used in a wide variety of autoimmune disorders, with variable results. In systemic inflammatory diseases, several

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mechanisms of action have been postulated and reviewed.147 Of relevance to WG, anti-idiotypic antibodies present in IVIG preparations may bind to idiotypic determinants on pathogenic autoantibodies, downregulate B cell receptors for antigen, or bind to T cell receptors and influence their activation and regulatory properties.147,148 The investigational use of IVIG in the treatment of WG was prompted by the detection of anti-idiotype antibody reactivity with ANCA in IVIG preparations.148 Several small, open trials and numerous anecdotes have been published on the use of IVIG, but Jayne and colleagues149 recently published a small controlled trial. In this study, 17 patients were randomized to receive IVIG and 17 to receive placebo. Treatment responses were observed in 14 of 17 in the IVIG group and 6 of 17 in the placebo group, as measured by a vasculitis activity scale. This modest treatment effect was observed for only 3 months following a single infusion. Significant decreases in C-reactive protein were seen for up to 1 month in the IVIG group but then returned to pretreatment levels. No differences were observed in ANCA levels or cumulative exposure to immunosuppressive drugs. Reversible increases in serum creatinine occurred in four patients from the IVIG group. Thus, IVIG might be an alternative treatment for some forms of systemic vasculitis with persistent disease activity after standard therapy. Tumor Necrosis Factor Inhibitors Evidence from animal models and in vitro studies in humans suggest that TNF-α plays a prominent role in the pathogenesis of ANCA-associated vasculitis. These data, combined with encouraging results from uncontrolled studies,150-153 provided reason for optimism that anti-TNF therapy might be a safe and effective therapy in WG. However, 180 patients with WG were enrolled in a multicenter randomized, controlled trial of etanercept versus placebo in addition to standard therapy. That study found that etanercept did not add to the efficacy of standard therapy in terms of either remission induction or remission maintenance.121 Further, an increased rate of solid malignancy was observed in the etanercept (and cyclophosphamide) group. Although there is some reason to believe that infliximab might have greater efficacy than etanercept in the treatment of WG, the design of any future trial evaluating infliximab in this setting would require careful consideration of safety issues, including infection and malignancy. At present, anti-TNF therapy cannot be recommended for use in WG. Rituximab Rituximab is a chimeric mouse-human monoclonal antiCD20 antibody that selectively depletes B cells. It has demonstrated efficacy in the treatment of RA, SLE, and other autoimmune conditions, as well as B cell non-Hodgkin’s lymphoma. Rituximab has been proposed for the treatment of WG based on the role of B cells in ANCA production, antigen presentation, T cell costimulation, and proinflammatory cytokine production. A number of uncontrolled studies have suggested that rituximab may be efficacious in refractory ANCA-associated vasculitis.154-156 However, in two of these studies, contemporaneous changes in other immunosuppressive therapies made it difficult to delineate

the degree of efficacy attributable to rituximab.154,155 Further, little benefit was achieved in another series of refractory patients with predominantly granulomatous disease manifestations.157 A randomized, controlled trial comparing rituximab and oral cyclophosphamide for remission induction in WG is currently in progress. Apheresis Several small controlled trials suggest that apheresis might be of therapeutic efficacy in a subset of patients with advancing oliguric renal failure.158 These studies are methodologically diverse, and no definitive conclusions can be drawn. A recently completed multicenter randomized, controlled study compared apheresis with intravenous methylprednisolone as add-on therapy to standard treatment with oral cyclophosphamide and glucocorticoids in patients with severe renal disease,159 and final results are awaited. At present, apheresis in addition to standard therapy is reasonable in patients presenting with severe renal involvement with initial creatinine levels greater than 6 mg/dL who fail to respond to standard therapy. Other Immunosuppressive Therapies Other immunosuppressive therapies, including 15-deoxy­ spergualin,160,161 antithymocyte globulin,162 and cyclosporine163,164 have been examined in uncontrolled studies in WG, with variable degrees of efficacy reported. Many of these agents have significant toxicities and should be considered only for cases refractory to the established treatments already discussed. Surgical Intervention WG is an illness that requires a multidisciplinary approach. For instance, the management of subglottic stenosis in WG is complex and often requires individualized multimodality interventions to achieve satisfactory results. To plan strategies for treatment, it is extremely important to assess whether stenosis is due to active inflammation, noninflammatory scar tissue, or both. However, systemic immunosuppressive therapy is typically ineffective for subglottic stenosis and is best avoided if there is no evidence of active disease affecting other organ systems. Patients with severe subglottic stenosis may need temporary, and sometimes permanent, tracheostomy. Laryngotracheoplasty and microvascular lar­ yngotracheal reconstruction have been used with success in WG patients with subglottic stenosis.73 However, it can be treated effectively by a combination of mechanical dilation and intralesional glucocorticoid injection, although the procedure may need to be repeated.73,75 In a study of 20 patients with subglottic stenosis, this strategy led to tracheostomy reversal in 6 patients and avoidance of tracheostomy in the remainder.75 Other reports demonstrate the sustained efficacy of this approach, with better outcomes seen in patients who had not undergone previous surgery.165 Patients with WG might also need tympanostomies and drainage tubes for chronic otitis media, irrigation and drainage procedures (maxillary windows, Caldwell-Luc procedure) for impacted sinuses with persistent or recurrent infections, and ocular surgery for orbital pseudotumors or

PART 13 

nasolacrimal duct obstruction. Urgent surgical intervention may be needed in patients with severe pulmonary hemorrhage or GI vasculitis. Regardless of whether surgery is indicated, aggressive medical therapy is required to suppress active inflammatory processes and prevent further damage. In patients with end-stage renal failure, kidney transplantation is generally successful when recipients have been in sustained remission at the time of surgical engraftment. Although disease can recur in the transplanted kidney, renal survival is comparable to that associated with other conditions leading to renal failure.166-171 PROGNOSIS As discussed earlier, untreated systemic WG had a dismal prognosis, with a mean survival of approximately 5 months.87 Monotherapy with glucocorticoids prolonged mean survival time to just over 12 months.124 Combination therapy with oral cyclophosphamide and glucocorticoid dramatically changed the prognosis of WG, with remission anticipated in most patients and an 80% survival rate at 8 years; however, rates of adverse events and disease relapse were significant.53,54,70 A number of strategies have been implemented to address these issues, which may explain, in part, the recent data suggesting that greater than 95% survival among 82 WG patients with a median follow-up of 4.5 years is achievable.172 However, recent data from cohorts of patients followed in a controlled setting underline the fact that WG patients still experience significant disease- and treatment-related morbidity.90 This provides added impetus for continued collaborative efforts to identify safer and more effective treatments for patients with WG.

MICROSCOPIC POLYANGIITIS MPA was first recognized as a distinct entity by Davson and colleagues173 in 1948. They described it as a subgroup of polyarteritis nodosa, distinguished by the presence of segmental necrotizing glomerulonephritis. MPA was not included in the American College of Rheumatology classification scheme, and it is assumed that most of these patients were labeled as having polyarteritis or, less frequently, WG. The Chapel Hill international consensus criteria defined MPA as a necrotizing vasculitis with few or no deposits affecting small vessels (i.e., capillaries, venules, or arterioles)174; it is often associated with necrotizing glomerulonephritis and pulmonary capillaritis. MPA is occasionally referred to as microscopic polyarteritis, but MPA is preferred because it distinguishes the syndrome more clearly. CLINICAL FEATURES The general clinical features of MPA, collected from four large clinical series,175-178 are summarized in Table 82-1 and reflect the propensity for widespread target-organ involvement. The disease tends to affect males more frequently than females, with male-to-female ratios ranging from 1.0176 to 1.8.177 The age of onset is generally in the fourth or fifth decade but can range from early childhood to old age.179 The onset may be hyperacute, with rapidly progressive glomerulonephritis and pulmonary hemorrhage, presenting

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as the pulmonary renal syndrome; alternatively, it can be insidious, with several years of intermittent constitutional symptoms, purpura, mild renal disease, and even periodic bouts of hemoptysis. Renal Manifestations The universal presence of renal disease in most large series175-178 reflects both the common involvement of the kidney and the ascertainment bias of reporting by nephrology groups. Clearly, MPA can be seen in the absence of renal disease, although it is less common. The course of the renal disease is also variable, but a rapidly progressive course has been reported in series by nephrology groups. Dialysis has been required in 25% to 45% of patients in several large series.175,177 The renal lesion of MPA is that of necrotizing glomerulonephritis. The characteristic features of this lesion are segmental necrosis, crescent formation (extracapillary proliferation), slight or no endocapillary proliferation, slight or no immune deposits by immunohistology, and slight or no electron-dense deposits by electron microscopy.180 This lesion is clearly distinct from immune complex–mediated glomerulonephritis and anti–glomerular basement membrane antibody–mediated disease, but it is not distinguishable from the glomerular lesion of WG or idiopathic rapidly progressive crescentic glomerulonephritis (see Fig. 82-13). Pulmonary Manifestations Lung involvement is common in MPA and is present in more than half of reported cases in most series. Diffuse alveolar hemorrhage (DAH) is the most serious form of lung involvement and has been reported in 12% to 29% of patients in several series.175-178 The clinical manifestations may range from mild dyspnea and anemia without any hemoptysis to massive hemorrhage and bleeding with profound hypoxia, but the onset is acute in most patients. The radiographic features of DAH are nonspecific, demonstrating alveolar infiltration ranging from patchy to diffuse. The characteristic finding of alveolar infiltrates in the absence of congestive heart failure or infection is helpful, but the clinical differentiation of these disorders in an acutely ill patient may be difficult. The absence of frank hemoptysis should never dissuade serious consideration of possible, even massive, DAH, because it may be absent in up to one third of patients.181 An alternative presentation of lung involvement in MPA is that of interstitial fibrosis based on recurrent episodes of DAH. This generally occurs after a prolonged (i.e., many years) history of such events.181 The characteristic histopathology of MPA is pulmonary capillaritis (see Fig. 82-12). In this lesion, there is disruption of the alveolar interstitium, leading to loss of integrity of the constituent capillary network and resulting in red blood cell leakage into the alveolar spaces. The alveolar wall expands and becomes edematous and ultimately undergoes fibrinoid necrosis. Characteristically, there is prominent neutrophilic leukocytosis of the alveolar septum, often accompanied by leukocytoclasia. Immunohistology, similar to in the kidney, rarely demonstrates immune deposits. Other findings include capillary thrombosis, type II epithelial cell hyperplasia, and lymphoplasmacytic infiltration.181 This clinical and histologic picture can be seen in a variety of conditions

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Table 82-1  Clinical Features of Microscopic   Polyangiitis Clinical Feature

Percentage*

Constitutional symptoms

76-79

Fever

50-72

Renal disease

100

Arthralgias

28-65

Purpura

40-44

Pulmonary disease (hemorrhage, infiltrates, effusion)

50

Neurologic disease (central, peripheral)

28

Ear, nose, throat involvement

30

*Percentage of a population totaling 150 patients from four studies.175-178

and is commonly observed in WG, SLE, and in an isolated form.181,182 When DAH occurs in an isolated form, it may be in the presence or absence of MPO-ANCA.181

DIFFERENTIAL DIAGNOSIS Differentiating MPA from classic polyarteritis is often based on the pattern of renal disease, which differs dramatically between the two. In classic polyarteritis, the glomerulus is largely spared, and extraglomerular vascular disease (i.e., vascular nephropathy) is common. Pulmonary involvement is uncommon in classic disease, and hemorrhage is virtually never encountered. Hypertension and peripheral neuropathy are much more common in classic polyarteritis as well. From the laboratory perspective, classic polyarteritis is rarely PR3- or MPO-ANCA positive, and MPA is rarely associated with hepatitis B. Angiographically, classic polyarteritis nodosa is far more frequently associated with microaneurysms, which are rare in MPA.183 Differentiation from WG may be difficult because of the random nature of the granulomas in this condition. Prominent involvement of the upper respiratory tract or the presence of PR3-ANCA should raise the possibility of WG, because the occurrence of these findings are unusual, though not unheard of, in MPA.

Other Manifestations Other clinical features of MPA are similar to the other major forms of ANCA-associated small vessel vasculitis, as well as classic polyarteritis nodosa. Arthralgia, myalgia, and fever are common (see Table 82-1). Skin involvement is common and most frequently manifests as palpable purpura. Peripheral neuropathy is observed in a minority of patients and appears to be less common than in the other ANCA-associated syndromes. Involvement of the ears, nose, and throat is infrequent and, when present, should raise the suspicion of WG, with granulomas either overlooked or missed by sampling error on biopsy. DIAGNOSIS The diagnosis of MPA can be problematic. There is great variability in the presenting manifestations as well as the intensity of the illness. Clearly, MPA should be considered in any patient with the general features of a systemic vasculitis, such as prolonged unexplained fever, unexplained multisystem organ involvement (especially renal and pulmonary), and palpable purpura. MPA is prominent in the differential diagnosis of pulmonary renal syndromes, along with WG, SLE, and anti–glomerular basement membrane disease. Although the diagnosis of MPA can sometimes be based on clinical and laboratory findings, it is preferable to secure the diagnosis with histology. The most accessible and rewarding tissues are skin, kidney, and lung. It must be emphasized that in none of these organs is there a specific histopathologic picture of MPA. However, the presence of pulmonary capillaritis, necrotizing pauci-immune glomerulonephritis, or leukocytoclastic vasculitis in skin can secure the diagnosis in a patient with the appropriate degree of pretest probability and the necessary exclusions. As noted, MPO-ANCA is present in 60% to 85% of patients, but occasionally, patients may be PR3-ANCA positive. Diagnosis of MPA based solely on a positive MPO-ANCA test in a patient with low probability is fraught with risk, considering the gravity of the therapy.

TREATMENT AND PROGNOSIS The treatment of MPA is based on the same therapeutic principles as those outlined for WG (see Fig. 82-4). The majority of information on the therapy and prognosis of this disorder is based on retrospective analyses of case series.175,177,184 Most investigators agree that in the presence of serious renal or pulmonary disease, combined therapy with highdose glucocorticoid and cyclophosphamide is indicated. A recent study by the French Vasculitis Study Group,185 representing the longest follow-up of a cohort including MPA (88.3 months), reaffirmed that combined glucocorticoid and cyclophosphamide is beneficial, especially in severe disease. In this complex study representing a pooled analysis of four prospective trials of different therapeutic agents, there was an overall mortality of 30% throughout approximately 7 years of follow-up. Mortality, not surprisingly, was seen in those with a high incidence of renal, GI, cardiovascular, or CNS involvement. Survival rates were superior among the most severely ill patients treated with combination of glucocorticoid and cyclophosphamide versus those treated with glucocorticoid alone. There are limited data supporting a role of apheresis in those with advanced renal disease, including those who are dialysis dependent.186,187 There are also reports of successful therapy with IVIG.149,188 Although the rate of relapse appears to be lower in MPA than in WG,122 careful follow-up is required, including monitoring of clinical symptoms and renal function with serial examination of the urinary sediment.

CHURG-STRAUSS SYNDROME The syndrome defined by Churg and Strauss in 1951 has undergone several redefinitions but is still characterized by three histopathologic features: necrotizing vasculitis, infiltration by eosinophils, and extravascular granulomas.189 Using only pathologic features to define the disease made it a diagnostic rarity. Thus, in 1984, Lanham and colleagues190 suggested that the diagnosis be based on clinical and pathologic grounds requiring three criteria: asthma, peak eosinophil

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count greater than 1500 cells/mL, and systemic vasculitis involving two or more organs. In 1994, the international consensus conference held in Chapel Hill, North Carolina,174 defined the disease as an eosinophil-rich and granulomatous inflammation involving the respiratory tract and ­necrotizing vasculitis involving the medium-sized vessels associated with asthma and eosinophilia. Each component of these definitions (histopathology, eosinophilia in blood and tissues, asthma) helps define the disease, but none of these features individually is specific for CSS, and not every patient has all the features. Although most cases can be clearly defined, the concept of partial or incomplete CSS remains necessary.191

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stage comes next, and the clinical picture is dependent on the distribution of target organs. Finally, the vasculitic stage abates, and allergic disease dominates the clinical picture. Clearly, not all patients exhibit a sequential staging of the illness and may present with only one or two manifestations. The literature suggests that ANCA may influence the expression of the disease in certain organs. ANCA positivity, for example, is associated with a higher incidence of renal disease (particularly rapidly progressive glomerulonephritis), alveolar hemorrhage, mononeuritis multiplex, and purpura. In contrast, ANCA-negative patients were more likely to suffer from cardiomyopathy, nonhemorrhagic pulmonary infiltrates, nasal polyposis, and eosinophilic gastritis or enteritis.194,195,201

PATHOGENESIS The cause of CSS is unknown, but its association with allergy and atopic disorders is a dominant factor. Nearly 70% of patients have a history of allergic rhinitis, often associated with nasal polyposis; the association with asthma, usually adult onset, is part of most case definitions. Both peripheral blood and tissue eosinophilia is a major constituent of the syndrome, and the majority of patients tested have elevated IgE levels.190 A link between the use of leukotriene receptor antagonists and CSS has been suggested,192 but the epidemiologic link between this class of drugs and vasculitis is not proved.193 Some clinical and pathologic features of CSS are shared with the other ANCA-associated syndromes, suggesting a possible pathogenic role for ANCA in CSS. Arguing against such a role is the fact that up to 60% of patients with CSS in some series may be ANCA negative.194,195 At this point, it is best to define CSS by its unique clinical and pathologic features, regardless of ANCA status.196 CSS has been reported to occur in asthmatics following the use of either lipoxygenase inhibitors or cysteinyl leukotriene receptor type 1 antagonists, thereby raising the concern that leukotriene inhibition might function as a causative factor.197,198 Alternative explanations include an unmasking effect when these drugs are provided to a population with severe airway disease, followed by steroid tapering.199 A simple unmasking effect is unlikely, however, in patients who were not on steroids or did not taper the dose of steroids before the onset of CSS. To date, there are few data to suggest causality, but it is probably prudent to avoid these agents in patients with CSS until more definitive studies become available. CLINICAL FEATURES CSS is thought by some observers to be characterized by three distinct phases. A prodrome, dominated by allergic features, is common in patients ultimately diagnosed with CSS. Allergic rhinitis and asthma often precede the diagnosis of vasculitis by 3 to 7 years.190,200 It is interesting and important to note that asthma can abruptly abate as the patient moves into the vasculitic phase of the illness. Tissue infiltration by eosinophils, in the form of eosinophilic pneumonia (Löffler’s syndrome) and eosinophilic gastroenteritis, may also occur in the prodrome. Because these patients may have marked constitutional symptoms and high blood eosinophilia, this stage may be difficult to distinguish from the onset of frank vasculitis on other than histologic grounds. The vasculitic

Pulmonary Manifestations Pulmonary infiltrates may occur in the prodromal phase, vasculitic phase, or both, and their appearance is generally nonspecific. Their radiographic appearance is variable, but lobar, interstitial, and nodular patterns have all been described, with most abnormalities being fleeting in nature. Pleural effusions were reported in 27% of patients in one series190 and are typically rich in eosinophils. Pulmonary hemorrhage is a grave complication and may occur with or without renal involvement. Neurologic Manifestations Peripheral neurologic involvement often dominates the clinical picture and has been reported in the majority of patients.183,190,200 It was found in 62% of patients in one series.190 The pattern of involvement may be that of mononeuritis multiplex or symmetric or asymmetric polyneuropathy. Less commonly, cranial neuropathy is observed.200 CNS involvement is uncommon and tends to dominate in the latter stages of the illness.191 Collectively, involvement of the peripheral nervous system is so common that in any patient with asthma who develops neurologic symptoms, CSS should be considered. Renal Manifestations Kidney involvement is less common in CSS than in MPA or WG and, when present, is rarely the cause of death. CSS shares the same renal lesion (necrotizing crescentic pauci-immune glomerulonephritis) with the other ANCA­associated diseases. A noteworthy feature of CSS is its ­propensity to involve the lower urinary tract, including the prostate gland.202 We have seen extremely high levels of prostate-specific antigen in the setting of active CSS normalize during successful treatment. Such lower urinary tract involvement may lead to obstruction. Other Manifestations CSS may involve a wide variety of other target organs, including the skin, heart, skeletal muscle, joints, eye, and GI tract.190 Skin involvement often leads to confusion, because ChurgStrauss granuloma may be seen in other disorders. Palpable purpura has been observed in nearly 50% of CSS patients, and the histopathology may be quite nonspecific. Alternatively, inflammatory nodules with characteristic histopathology

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(necrotizing vasculitis, eosinophilic infiltration, and extravascular granulomas) are less commonly encountered.203 GI involvement may precede the vasculitic phase or coincide with it. Diarrhea, pain, and bleeding are not uncommon. Similar to classic polyarteritis, abdominal ­complications may dominate.204,205 Cardiac disease is common in postmortem series189 and may contribute heavily to morbidity and mortality.190 The cardiac pathology most frequently demonstrates granulomatous nodules in the epicardium, which may lead to ventricular dysfunction and congestive heart failure.189 Coronary arteritis may also occur. Last, a variety of ocular complications have been described, including conjunctivitis, episcleritis, panuveitis, and marginal corneal ulcerations.202

vessels accompanied by tissue infiltration with eosinophils is not specific for CSS and may also be seen in WG and polyarteritis nodosa.191 The extravascular Churg-Strauss granuloma, in its fully developed form, is highly specific for the condition. Its distinctive features include an eosinophilic core, which differentiates it from the basophilic granuloma ­(unfortunately, also referred to as Churg-Strauss granuloma), but it is frequently seen in numerous other disorders.191 It has also been suggested that ANCA status may influence the pathologic expression of disease. ANCA positivity is associated with necrotizing vasculitis; eosinophilic infiltrates, granulomas, and fibrosis are associated with the absence of ANCA.194,195,201

PATHOLOGY

LABORATORY TESTS

As noted previously, the pathologic features of CSS are ­necrotizing vasculitis, eosinophilic tissue infiltration, and extravascular granulomas (Fig. 82-14). Unfortunately, de­­ p­ending on the timing and tissue sampling, not all these features may be present.191 Necrotizing vasculitis of small

Peripheral eosinophilia at levels in excess of 1500 cells/ mm3 often occurs in the prodromal stages of CSS, associated with rhinitis and asthma. Occasionally, patients have been described without significant blood eosinophilia but with prominent tissue eosinophilia.206 There is no definite correlation between eosinophilia and disease activity, for eosinophils often rapidly decrease on initiation of glucocorticoid therapy. ANCAs have been reported in about 40% of patients,194,195 the majority of which are MPO-ANCA. A negative ANCA test should not dissuade the clinician from the diagnosis of CSS if there is a high probability. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

Figure 82-14  Churg-Strauss syndrome. Transmural eosinophilic infiltrate with scattered plasma cells and lymphocytes involving a small ­artery in the lung of a patient with Churg-Strauss syndrome (hematoxylin and eosin, ×40). (Courtesy of Dr. C. Farver.)

The diagnosis of CSS should be based on the documentation of necrotizing vasculitis with eosinophils occurring in a patient with adult-onset asthma or allergic rhinitis. The presence of extravascular granulomas adds to the specificity but is not essential. High-yield sites for biopsy include nerve and muscle in patients with clinical evidence of involvement at those sites. Differentiation of CSS from WG, MPA, and classic polyarteritis nodosa is generally straightforward (Table 82-2). Significant peripheral eosinophilia is uncommon in the other conditions, although this point is often poorly appreciated; the misconception stems from early reports describing WG

Table 82-2  Differential Diagnostic Features of the Antineutrophil Cytoplasmic Antibody–Associated Vasculitides Wegener’s Granulomatosis

Microscopic Polyangiitis

Polyarteritis Nodosa

Churg-Strauss Syndrome

Pulmonary infiltrates or nodules

+++

++

−

+++

Alveolar hemorrhage Glomerulonephritis

++ +++

++ +++

− −

+ ++

Upper airway disease

+++

+

+

++

Skin, purpura Peripheral nervous system involvement Central nervous ­system involvement

+ ++

+++ +

− ++

++ +++

+

+

+

++

Feature

CSS, Churg-Strauss syndrome; ENT, ear, nose, and throat; WG, Wegener’s granulomatosis.

Comments Asthma and ­eosinophilia in CSS Progressive renal failure uncommon in CSS ENT disease usually favors WG Often a prominent feature of CSS

PART 13 

that were contaminated with unrecognized CSS patients. Microaneurysms can be seen in both classic polyarteritis and CSS and thus do little to differentiate the conditions. Asthma is uncommon in polyarteritis, as is glomerulonephritis. CSS may be difficult to differentiate from eosinophilic infiltrative diseases. Acute (Löffler’s syndrome) and chronic eosinophilic pneumonia are not associated with ­extrapulmonary disease. Hypereosinophilic syndrome may, however, be associated with eosinophilic infiltration of numerous target organs and may be difficult to differentiate from CSS. In this disorder, there is no true vasculitis, and eosinophil counts are often much higher, possibly in excess of 100,000 cells/mm3. PROGNOSIS AND TREATMENT Some investigators consider the outcome of patients with CSS to be similar to that of patients with polyarteritis nodosa, but several factors limit these observations. The largest series comparing such patient populations is, by its own admission, contaminated by patients with both the microscopic and the classic forms of polyarteritis, owing to the more recent recognition of the former.207 Other investigators have asserted that CSS is a more benign disease.202,208,209 The work of Guillevin and colleagues210 has helped clarify this debate and has demonstrated that, as with polyarteritis, the outcome of patients with CSS is dependent on disease severity, which can be assessed clinically. Overall, the 5-year survival rate for patients with CSS was 78.9%, but five factors were associated with poor outcome: azotemia (creatinine level >1.58 mg/dL), proteinuria (>1 g/day), GI tract involvement, cardiomyopathy, and CNS involvement. Relative risk of death increased in the presence of these risk factors. Absence of these complications, such as disease limited to muscle and nerve, carried the best prognosis. Therapeutic trials are limited, but they have demonstrated that both glucocorticoid alone and glucocorticoid combined with cyclophosphamide are efficacious.211,212 Based on these data and the prognostic studies of Guillevin and colleagues, it appears reasonable to treat patients with limited disease with glucocorticoid alone and reserve combined therapy for those with immediately life-threatening or major organ–threatening disease. Patients who should be considered for combined therapy include, but are not limited to, those with any of the five prognostic factors listed earlier. The principles of such therapy are similar to those outlined for the treatment of WG. REFERENCES   1. Jennette JC, Falk RJ: Small-vessel vasculitis. N Engl J Med 337:15121523, 1997.   2. Davies DJ, Moran JE, Niall JF, et al: Segmental necrotizing glomerulonephritis with antineutrophil antibody: Possible arbovirus aetiology. BMJ 285:606, 1982.   3. Hall JB, Wadham BM, Wood CJ, et al: Vasculitis and glomerulonephritis: A subgroup with an antineutrophil cytoplasmic antibody. Aust N Z J Med 14:277, 1984.   4. van der Woude FJ, Rasmussen N, Lobatto S, et al: Autoantibodies against neutrophils and monocytes: Tool for diagnosis and marker of disease activity in Wegener’s granulomatosis. Lancet 1:425, 1985.   5. Bosch X, Guilabert A, Font J: Antineutrophil cytoplasmic antibodies. Lancet 368:404-418, 2006.

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110. Bacon P.A.: Endothelial cell dysfunction in systemic vasculitis: New developments and therapeutic prospects. Curr Opin Rheumatol 17:49-55, 2005. 111. de Leeuw K, Sanders JS, Stegeman C, et al: Accelerated atherosclerosis in patients with Wegener’s granulomatosis. Ann Rheum Dis 64:753-759, 2005. 112. Kerr GS, Fleisher TA, Hallahan CW, et al: Limited prognostic value of changes in antineutrophil cytoplasmic antibody titer in patients with Wegener’s granulomatosis [see comments]. Arthritis Rheum 36:365-371, 1993. 113. Colby TV, Tazelaar HD, Specks U, et al: Nasal biopsy in Wegener’s granulomatosis. Hum Pathol 22:101, 1991. 114. Delbuono EA, Flint A: Diagnostic usefulness of nasal biopsy in Wegener’s granulomatosis. Hum Pathol 22:107, 1991. 115. Devaney KO, Travis WD, Hoffman G, et al: Interpretation of head and neck biopsies in Wegener’s granulomatosis: A pathologic study of 126 biopsies in 70 patients. Am J Surg Pathol 14:555, 1990. 116. Myers JL, Katzenstein ALA: Wegener’s granulomatosis presenting with massive pulmonary hemorrhage and capillaritis. Am J Surg Pathol 11:895, 1987. 117. Yoshikawa Y, Watanabe T: Pulmonary lesions in Wegener’s granulomatosis: A clinicopathologic study of 22 autopsy cases. Hum Pathol 17:401, 1986. 118. Travis WD, Colby TV, Lombard C, Carpenter HA: A clinicopathologic study of 34 cases of diffuse pulmonary hemorrhage with lung biopsy confirmation. Am J Surg Pathol 14:1112, 1990. 119. Andrassy K, Erb A, Koderisch J, et al: Wegener’s granulomatosis with renal involvement: Patient survival and correlations between initial renal function, renal histology, therapy and renal outcome. Clin Nephrol 35:139, 1991. 120. Fauci AS: Alternate-day corticosteroid therapy. Am J Med 64:729, 1978. 121. Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med 352:351-361, 2005. 122. Jayne D, Rasmussen N, Andrassy K, et al: A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic ­autoantibodies. N Engl J Med 349:36-44, 2003. 123. Regan MJ, Hellmann DB, Stone JH: Treatment of Wegener’s granulomatosis. Rheum Dis Clin North Am 27:863-886, 2001. 124. Hollander D, Manning RT: The use of alkylating agents in the treatment of Wegener’s granulomatosis. Ann Intern Med 67:393, 1967. 125. Talar-Williams C, Hijazi YM, Walther MM, et al: Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med 124:477-484, 1996. 126. Haubitz M, Bohnenstengel F, Brunkhorst R, et al: Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency. Kidney Int 61:1495-1501, 2002. 127. Guillevin L, Cordier J, Lhote F, et al: A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener’s granulomatosis. Arthritis Rheum 40:2187, 1997. 128. Haubitz M, Schellong S, Gobel U, et al: Intravenous pulse administration of cyclophosphamide versus daily oral treatment in patients with antineutrophil cytoplasmic antibody-associated vasculitis and renal involvement: A prospective, randomized study. Arthritis Rheum 41:1835-1844, 1998. 129. Richmond R, McMillan TW, Luqmani RA: Optimisation of cyclophosphamide therapy in systemic vasculitis. Clin Pharmacokinet 34:79-90, 1998. 130. Clunie GP, Lennard L: Relevance of thiopurine methyltransferase status in rheumatology patients receiving azathioprine. Rheumatology (Oxford) 43:13-18, 2004. 131. Whittle SL, Hughes RA: Folate supplementation and methotrexate treatment in rheumatoid arthritis: A review. Rheumatology (Oxford) 43:267-271, 2004. 132. Khanna D, Park GS, Paulus HE, et al: Reduction of the efficacy of methotrexate by the use of folic acid: Post hoc analysis from two randomized controlled studies. Arthritis Rheum 52:3030-3038, 2005. 133. Georgescu L, Quinn GC, Schwartzman S, Paget SA: Lymphoma in patients with rheumatoid arthritis: Association with the disease state or methotrexate treatment. Semin Arthritis Rheum 26:794-804, 1997. 134. Mariette X, Cazals-Hatem D, Warszawki J, et al: Lymphomas in rheumatoid arthritis patients treated with methotrexate: A 3-year prospective study in France. Blood 99:3909-3915, 2002.

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135. Langford CA, Talar-Williams C, Barron KS, Sneller MC: Use of a cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of Wegener’s granulomatosis: Extended follow-up and rate of relapse. Am J Med 114:463-469, 2003. 136. Langford CA, Talar-Williams C, Barron KS, Sneller MC: A staged approach to the treatment of Wegener’s granulomatosis: Induction of remission with glucocorticoids and daily cyclophosphamide switching to methotrexate for remission maintenance. Arthritis Rheum 42:2666-2673, 1999. 137. Reinhold-Keller E, Fink CO, Herlyn K, et al: High rate of renal relapse in 71 patients with Wegener’s granulomatosis under maintenance of remission with low-dose methotrexate. Arthritis Rheum 47:326-332, 2002. 138. Langford CA, Talar-Williams C, Sneller MC: Use of methotrexate and glucocorticoids in the treatment of Wegener’s granulomatosis: Long-term renal outcome in patients with glomerulonephritis. Arthritis Rheum 43:1836-1840, 2000. 139. Sneller MC, Hoffman GS, Talar-Williams C, et al: An analysis of forty-two Wegener’s granulomatosis patients treated with methotrexate and prednisone. Arthritis Rheum 38:608-613, 1995. 140. De Groot K, Rasmussen N, Bacon PA, et al: Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 52:2461-2469, 2005. 141. Langford CA, Talar-Williams C, Sneller MC: Mycophenolate mofetil for remission maintenance in the treatment of Wegener’s granulomatosis. Arthritis Rheum 51:278-283, 2004. 142. Metzler C, Fink C, Lamprecht P, et al: Maintenance of remission with leflunomide in Wegener’s granulomatosis. Rheumatology (Oxford) 43:315-320, 2004. 143. Nowack R, Gobel U, Klooker P, et al: Mycophenolate mofetil for maintenance therapy of Wegener’s granulomatosis and microscopic polyangiitis: A pilot study in 11 patients with renal involvement. J Am Soc Nephrol 10:1965-1971, 1999. 144. Stegeman CA, Tervaert JW, Sluiter WJ, et al: Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis [see comments]. Ann Intern Med 120: 12-17, 1994. 145. Stegeman CA, Tervaert JW, de Jong PE, Kallenberg CG: Tri­ methoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener’s granulomatosis. Dutch Co-Trimoxazole Wegener Study Group [see comments]. N Engl J Med 335:16-20, 1996. 146. de Groot K, Reinhold-Keller E, Tatsis E, et al: Therapy for the maintenance of remission in sixty-five patients with generalized Wegener’s granulomatosis: Methotrexate versus trimethoprim/sulfamethoxazole. Arthritis Rheum 39:2052, 1996. 147. Ronda N, Hurez V, Kazatchkine MD: Intravenous immunoglobulin therapy of autoimmune and systemic inflammatory diseases. Vox Sang 64:65, 1993. 148. Rossi F, Jayne DR, Lockwood CM, Kazatchkine MD: Anti-idiotypes against anti-neutrophil cytoplasmic antigen autoantibodies in normal human polyspecific IgG for therapeutic use and in the remission sera of patients with systemic vasculitis. Clin Exp Immunol 83: 298-303, 1991. 149. Jayne DR, Chapel H, Adu D, et al: Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. QJM 93:433-439, 2000. 150. Bartolucci P, Ramanoelina J, Cohen P, et al: Efficacy of the antiTNF-alpha antibody infliximab against refractory systemic vasculitides: An open pilot study on 10 patients. Rheumatology (Oxford) 41:1126-1132, 2002. 151. Booth A, Harper L, Hammad T, et al: Prospective study of TNFalpha blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol 15:717-721, 2004. 152. Booth AD, Jefferson HJ, Ayliffe W, et al: Safety and efficacy of TNF-alpha blockade in relapsing vasculitis. Ann Rheum Dis 61:559, 2002. 153. Lamprecht P, Voswinkel J, Lilienthal T, et al: Effectiveness of TNFalpha blockade with infliximab in refractory Wegener’s granulomatosis. Rheumatology (Oxford) 41:1303-1307, 2002. 154. Eriksson P: Nine patients with anti-neutrophil cytoplasmic antibodypositive vasculitis successfully treated with rituximab. J Intern Med 257:540-548, 2005.

155. Keogh KA, Wylam ME, Stone JH, Specks U: Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis [see comments]. Arthritis Rheum 52:262-268, 2005. 156. Keogh KA, Ytterberg SR, Fervenza FC, et al: Rituximab for refractory Wegener’s granulomatosis: Report of a prospective, open-label pilot trial. Am J Respir Crit Care Med 173:180-187, 2006. 157. Aries PM, Hellmich B, Voswinkel J, et al: Lack of efficacy of rituximab in Wegener’s granulomatosis with refractory granulomatous manifestations. Ann Rheum Dis 65:853-858, 2006. 158. Klemmer PJ, Chalermskulrat W, Reif MS, et al: Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis. Am J Kidney Dis 42:1149-1153, 2003. 159. Watts R, Harper L, Jayne D, et al: Translational research in autoimmunity: Aims of therapy in vasculitis. Rheumatology (Oxford) 44:573-576, 2005. 160. Birck R, Warnatz K, Lorenz HM, et al: 15-Deoxyspergualin in patients with refractory ANCA-associated systemic vasculitis: A six-month open-label trial to evaluate safety and efficacy. J Am Soc Nephrol 14:440-447, 2003. 161. Schmitt WH, Birck R, Heinzel PA, et al: Prolonged treatment of refractory Wegener’s granulomatosis with 15-deoxyspergualin: An open study in seven patients. Nephrol Dial Transplant 20:1083-1092, 2005. 162. Schmitt WH, Hagen EC, Neumann I, et al: Treatment of refractory Wegener’s granulomatosis with antithymocyte globulin (ATG): An open study in 15 patients. Kidney Int 65:1440-1448, 2004. 163. Allen NB, Caldwell DS, Rice JR, McCallum RM: Cyclosporin A therapy for Wegener’s granulomatosis. Adv Exp Med Biol 336: 473-476, 1993. 164. Haubitz M, Koch KM, Brunkhorst R: Cyclosporin for the prevention of disease reactivation in relapsing ANCA-associated vasculitis. Nephrol Dial Transplant 13:2074-2076, 1998. 165. Hoffman GS, Thomas-Golbanov CK, Chan J, et al: Treatment of subglottic stenosis, due to Wegener’s granulomatosis, with intralesional corticosteroids and dilation. J Rheumatol 30:1017-1021, 2003. 166. Briggs JD, Jones E: Renal transplantation for uncommon diseases. Scientific Advisory Board of the ERA-EDTA Registry. European Renal Association-European Dialysis and Transplant Association. Nephrol Dial Transplant 14:570-575, 1999. 167. Deegens JK, Artz MA, Hoitsma AJ, Wetzels JF: Outcome of renal transplantation in patients with pauci-immune small vessel vasculitis or anti-GBM disease. Clin Nephrol 59:1-9, 2003. 168. Elmedhem A, Adu D, Savage CO: Relapse rate and outcome of ANCA-associated small vessel vasculitis after transplantation. Nephrol Dial Transplant 18:1001-1004, 2003. 169. Haubitz M, Kliem V, Koch KM, et al: Renal transplantation for patients with autoimmune diseases: Single-center experience with 42 patients. Transplantation 63:1251-1257, 1997. 170. Nachman PH, Segelmark M, Westman K, et al: Recurrent ANCAassociated small vessel vasculitis after transplantation: A pooled analysis. Kidney Int 56:1544-1550, 1999. 171. Wrenger E, Pirsch JD, Cangro CB, et al: Single-center experience with renal transplantation in patients with Wegener’s granulomatosis. Transpl Int 10:152-156, 1997. 172. Villa-Forte A, Clark TM, Mascha E, et al: Wegener’s granulomatosis: Customized treatment using cyclophosphamide and methotrexate. A 12 year single-practice experience. Arthritis Rheum 54:S495, 2006. 173. Davson J, Ball J, Platt R: The kidney in periarteritis nodosa. QJM 17:175, 1948. 174. Jennette JC, Falk RJ, Andrassy K, et al: Nomenclature of systemic vasculitides: Proposal of an international consensus conference. Arthritis Rheum 37:187-192, 1994. 175. Adu D, Howie AJ, Scott DGI, et al: Polyarteritis and the kidney. QJM 62:221, 1987. 176. D’Agati V, Chander P, Nash M, et al: Idiopathic microscopic polyarteritis nodosa: Ultrastructural observations on the renal vascular and glomerular lesions. Am J Kidney Dis 7:95, 1986. 177. Savage COS, Winearls CG, Evans DJ, et al: Microscopic polyarteritis: Presentation, pathology and prognosis. QJM 56:467, 1985. 178. Serra A, Cameron JS, Turner M, et al: Vasculitis affecting the kidney: Presentation, histopathology and long-term outcome. QJM 53:181, 1984. 179. Lhote F, Cohen P, Guillevin L: Polyarteritis nodosa, microscopic polyangiitis and Churg-Strauss syndrome. Lupus 7:238-258, 1998.

PART 13  180. Rosen S, Falk RJ, Jennette JC: Polyarteritis Nodosa Including ­Microscopic Form and Renal Vasculitis. New York, Igaku-Shoin, 1991. 181. Schwarz MI: The nongranulomatous vasculitides of the lung. Semin Respir Crit Care Med 19:47, 1998. 182. Jennings CA, King TE Jr: Diffuse alveolar hemorrhage with underlying isolated pauci-immune pulmonary capillaritis. Am J Respir Crit Care Med 155:1101, 1997. 183. Guillevin L, Lhote F, Amouroux J, et al: Antineutrophil cytoplasmic antibodies, abnormal angiograms and pathological findings in polyarteritis nodosa and Churg-Strauss syndrome: Indications for the classification of vasculitides of the polyarteritis nodosa group. Br J Rheumatol 35:958-964, 1996. 184. Rodgers H, Gutherie JA, Brownjohn AM, et al: Microscopic polyarteritis: Clinical features and treatment. Postgrad Med J 65:515, 1989. 185. Gayraud M, Guillevin L, le Toumelin P, et al: Long-term followup of polyarteritis nodosa, microscopic polyangiitis, and ChurgStrauss syndrome: Analysis of four prospective trials including 278 patients. Arthritis Rheum 44:666-675, 2001. 186. Hasegawa M, Kawamura N, Murase M, et al: Efficacy of granulocytapheresis and leukocytapheresis for the treatment of microscopic polyangiitis. Ther Apher Dial 8:212-216, 2004. 187. Pusey CD, Rees AJ, Evans DJ, et al: Plasma exchange in focal necrotizing glomerulonephritis without anti-GBM antibodies. Kidney Int 40:757, 1991. 188. Jayne DRW: Intravenous immunoglobulins in the therapy of systemic vasculitis. Transfus Sci 13:317, 1992. 189. Churg J, Strauss L: Allergic granulomatosis, allergic angiitis and periarteritis nodosa. Am J Pathol 27:277, 1951. 190. Lanham JG, Elkon KB, Pusey CD, et al: Systemic vasculitis with asthma and eosinophilia: A clinical approach to the Churg-Strauss syndrome. Medicine 63:65, 1984. 191. Lanham JG, Churg J: Churg-Strauss Syndrome. New York, Igaku Shoin, 1991. 192. Wechsler ME, Garpestad E, Flier SR, et al: Pulmonary infiltrates, eosinophilia and cardiomyopathy following corticosteroid withdrawal in patient with asthma receiving zafirlukast. JAMA 279:455, 1998. 193. Keogh KA, Specks U: Churg-Strauss syndrome. Semin Respir Crit Care Med 27:148-157, 2006. 194. Sable-Fourtassou R, Cohen P, Mahr A, et al: Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome. Ann Intern Med 143:632-638, 2005. 195. Sinico RA, Di Toma L, Maggiore U, et al: Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in ChurgStrauss syndrome. Arthritis Rheum 52:2926-2935, 2005. 196. Hoffman GS, Langford CA: Are there different forms of life in the antineutrophil cytoplasmic antibody universe? Ann Intern Med 143:683-685, 2005.

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197. Bielory L, Gewirtz M, Hinrichs C, Lal P: Asthma and vasculitis: Controversial association with leukotriene antagonists. Ann Allergy Asthma Immunol 87:274-282, 2001. 198. Jamaleddine G, Diab K, Tabbarah Z, et al: Leukotriene antagonists and the Churg-Strauss syndrome. Semin Arthritis Rheum 31: 218-227, 2002. 199. Weller PF, Plaut M, Taggart V, Trontell A: The relationship of asthma therapy and Churg-Strauss syndrome: NIH workshop summary report. J Allergy Clin Immunol 108:175-183, 2001. 200. Sehgal M, Swanson JW, DeRemee RA, et al: Neurologic manifestations of Churg-Strauss syndrome. Mayo Clin Proc 70:337, 1995. 201. Kallenberg CG: Churg-Strauss syndrome: Just one disease entity? Arthritis Rheum 52:2589-2593, 2005. 202. Chumbley LC, Harrison EG, DeRemee RA: Allergic granulomatosis and angiitis (Churg-Strauss syndrome). Mayo Clin Proc 52:477, 1977. 203. Crotty CP, DeRemee RA, Winkelmann RK: Cutaneous clinicopathologic correlation of allergic granulomatosis. J Am Acad Dermatol 5:571, 1981. 204. Guillevin L, Cohen P, Gayraud M, et al: Churg-Strauss syndrome: Clinical study and long-term follow-up of 96 patients. Medicine (Baltimore) 78:26-37, 1999. 205. Pagnoux C, Mahr A, Cohen P, Guillevin L: Presentation and outcome of gastrointestinal involvement in systemic necrotizing vasculitides: Analysis of 62 patients with polyarteritis nodosa, microscopic polyangiitis, Wegener granulomatosis, Churg-Strauss syndrome, or rheumatoid arthritis-associated vasculitis. Medicine (Baltimore) 84:115-128, 2005. 206. Shields CL, Shields JA, Rozanski TI: Conjunctival involvement in Churg-Strauss syndrome. Am J Ophthalmol 102:601, 1986. 207. Guillevin L, Le THD, Godeau P, et al: Clinical findings and prognosis of polyarteritis nodosa and Churg-Strauss angiitis: A study in 165 patients. Br J Rheumatol 27:258, 1988. 208. Cohen R, Conn D, Ilstrup D: Clinical features, prognosis and response to treatment in polyarteritis. Mayo Clin Proc 55:146, 1980. 209. Finan MC, Winkelmann RK: The cutaneous extravascular ­necrotizing granuloma (Churg-Strauss granuloma) and systemic disease: A review of 27 cases. Medicine 62:142, 1983. 210. Guillevin L, Lhote F, Gayraud M, et al: Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome: A prospective study in 342 patients. Medicine (Baltimore) 75:17-28, 1996. 211. Guillevin L, Gain O, Lhote F, et al: Lack of superiority of steroids plus plasma exchange to steroids alone in the treatment of polyarteritis nodosa and Churg-Strauss syndrome: A prospective, randomized trial in 78 patients. Arthritis Rheum 35:208, 1992. 212. Guillevin L, Jarrousse B, Lok C, et al: Longterm followup after treatment of polyarteritis nodosa and Churg-Strauss angiitis with comparison of steroids, plasma exchange and cytophosphamide to steroids and plasma exchange: A prospective randomized trial of 71 patients. J Rheumatol 18:567, 1991.

83

Polyarteritis and Related Disorders John S. Sergent

KEY POINTS Although in the past the term polyarteritis often was used in a generic sense to cover many types of vasculitis, today the term is used to describe an illness characterized by vasculitis of medium-sized arteries with few or no immune deposits. By that definition, polyarteritis nodosa (PAN) is a rare disease, although its actual incidence and prevalence are uncertain. The typical patient is a man (male-to-female ratio approximately 2:1) in the fifth or sixth decade who presents with an insidious illness over several weeks or months. The most common and characteristic features of PAN include purpuric skin lesions, mononeuritis multiplex, symptoms of mesenteric ischemia, and renal involvement. Renal disease in PAN usually is manifested by hypertension and mild proteinuria with or without azotemia. Occasional patients may have PAN limited entirely to the skin, known as cutaneous PAN. Most of these patients do not develop systemic disease. Buerger’s disease, also known as thromboangiitis obliterans, was previously thought of as a disease of men that began in the lower extremities, but today is increasingly recognized as a disease of both sexes and of the upper and lower extremities. In addition to digital ischemia, superficial phlebitis, often migratory, may be a presenting manifestation. The role of tobacco use in Buerger’s disease is not understood, but the only effective treatment of the disease is total abstention from all tobacco exposure. Even so, many patients still require multiple amputations over time.

have ANCAs directed against myeloperoxidase (MPO). This disease is much more common than classic PAN of medium-sized arteries (see Chapter 82), and as a result of the separation of the two, PAN, as currently defined, is a rare disease. In my experience, it accounts for less than 5% of all cases of systemic vasculitis and is severalfold less common than Wegener’s granulomatosis, although the actual incidence is unknown. Patients with classic PAN can be any age, including children, but the peak onset is in the fifth or sixth decade. There is approximately a 2:1 male-to-female preponderance in most studies.1 There are reports of polyarteritis that follow infections2-7; vaccination8,9; serous otitis media10; and the use of various drugs, especially amphetamines,11 minocycline,12,13 and interferon.14 No etiology is apparent in most cases. It is possible that some of the associations mentioned could be random events, or that PAN already was present before the exposure. Hepatitis B has been strongly linked to polyarteritis and is discussed separately later. Onset may be abrupt and catastrophic, but the typical patient has a period of weeks or months of systemic symptoms, including fever, abdominal pain, weight loss, and arthralgias. During this period the diagnosis is usually not apparent, and individuals are often treated for presumed diagnoses ranging from infections to systemic juvenile rheumatoid arthritis. In this setting, sudden events may occur, such as intestinal ischemia, digital gangrene, ischemic skin ulcers, infarction of a kidney or other major organ, or sudden loss of multiple nerves (mononeuritis multiplex). Table 83-1 shows the estimated frequency of various findings in PAN; virtually all are due to ischemia of the area involved. PATHOLOGY

POLYARTERITIS NODOSA Polyarteritis nodosa (PAN) is a necrotizing vasculitis of medium-sized arteries. Immune deposits are minimal or absent. Test results for antineutrophil cytoplasmic antibodies (ANCAs) are typically negative. PAN has undergone an impressive change in its definition. For many years, the term was used in a generic sense to include most cases of generalized vasculitis, but as understanding improved, the definitions became more specific. What was formerly “PAN complicating rheumatoid arthritis” is now termed rheumatoid vasculitis, and most cases of “polyarteritis nodosa with lung involvement” are now termed Churg-Strauss vasculitis. The most important shift in thinking about PAN came about with the finding that patients with microscopic PAN

PAN is a patchy disease, with areas of impressive necrosis and inflammation interspersed with unaffected vessels (Fig. 83-1).14-16 There is a propensity for aneurysm formation, especially in the mesenteric circulation. Other target organs include the kidney, the peripheral nerves, and the heart. There is strong correlation between the amount of fibrinoid necrosis and the number of neutrophils in the vessel wall and surrounding tissues.16,17 Because of this irregular distribution, obtaining a diagnostic biopsy specimen can be difficult. If purpura is present, a skin biopsy may be diagnostic, although a generous sample may be required. Punch biopsy may show only hemorrhage and nonspecific inflammation. In individuals with few or no localizing findings but in whom PAN is highly suspected, “blind” muscle biopsy is often performed, although about half the patients later shown to have PAN have a negative biopsy finding. 1453

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Table 83-1  Selected Clinical Manifestations   of ­Polyarteritis Nodosa Clinical Feature

Frequency (%)

Muscle pain or weakness

69

Weight loss

67

Mononeuritis multiplex

42

Polyneuropathy

36

Azotemia

40

Hypertension

37

Testicular pain

29

Skin ulcers or infarcts

27

Livedo reticularis

25

From Lightfoot RW, Michel BA, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. ­Arthritis Rheum 33:1088, 1990.

Figure 83-2  Superior mesenteric arteriogram in a patient with polyarteritis. Several small aneurysms (arrows) are present in branches of the superior mesenteric artery. (Courtesy of Dr. A. W. Stanson.)

Figure 83-1  Polyarteritis. Right lower portion of arterial wall shows fibrinoid necrosis and formation of a “microaneurysm.” Intense infiltration of leukocytes is present in and around the artery wall. (Hematoxylin and eosin, ×40.) (Courtesy of Dr. J. T. Lie.)

Mesenteric arteriography showing widespread aneurysms18 is an impressive diagnostic finding (Fig. 83-2). Mesenteric arteriography is probably the procedure of choice in patients with significant abdominal pain. Probably the most popular biopsy site today is the sural nerve.19 In patients with neuropathy, especially if sural nerve conduction is abnormal, the biopsy finding is positive more than 80% of the time. Other areas in which biopsy is occasionally performed include the testicle, especially if it is painful or if a mass is palpable, and the kidney. Laboratory findings in PAN are nonspecific. Anemia and leukocytosis are typical, and almost all patients have an elevated erythrocyte sedimentation rate (ESR). Evidence of mild liver dysfunction, such as an elevated alkaline phosphatase, may be seen. There are no specific serologic findings, and ANCAs are absent, almost by definition (see Chapter 82).

cases, there may be widespread digital cyanosis secondary to ischemia. Splinter hemorrhages and livedo reticularis (Fig. 83-4) also are commonly observed.20 Hypertension, owing to arteritis in the renal circulation, is present in approximately one third of cases and is occasionally severe. New-onset hypertension in a patient with systemic symptoms, such as fever, weight loss, and joint pain, should be a clue that vasculitis, specifically PAN, may be present. The term mononeuritis multiplex is applied to the widespread development of neuropathy involving large, mixed motor and sensory nerves. The loss of each involved nerve may be sudden, although many patients describe paresthesias or weakness of the involved area before the total loss of nerve function. Frequently affected nerves include the peroneal, median, ulnar, and sural nerves.21 The nerve injury is

SYSTEMS INVOLVED IN POLYARTERITIS NODOSA Cutaneous manifestations occur in one third of patients, usually seen as areas of palpable purpura, sometimes with ulceration (Fig. 83-3). Frequent sites include the fingers, the ankles around the malleoli, and the pretibial areas. In severe

Figure 83-3  Polyarteritis involving the skin. Sharply circumscribed skin infarcts are 1 to 1.5 cm in diameter and are in various stages of healing.

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Table 83-2  Prednisone Therapy in   Polyarteritis Nodosa Disease control (4-8 wk)

Administer prednisone, 1 mg/kg/ day in divided doses

Consolidation (1 mo)

Gradually change to a single daily dose, 1 mg/kg/day

Rapid tapering (1-2 mo)

Decrease by 5-10 mg every 2-4 wk, observing closely, until dose is 15-20 mg/day

Slow tapering (1-2 mo)

Decrease dose in increments   of 1-2 mg/day at intervals of 1-2 wk, continuing close ­observation

The musculoskeletal symptoms of PAN are typically nonspecific, with widespread arthralgias and myalgias. Joint pain is occasionally severe and debilitating, although signs of frank arthritis are uncommon. COURSE

Figure 83-4  Polyarteritis involving the skin of the legs. Livedo reticularis is most prominent over the left anterior region of the thigh, but also is visible over the right thigh, legs below knees, and dorsa of feet. Petechiae and ulcers (arrow) are present on anterior and medial portions of the lower legs.

due to ischemia and eventual infarction. The nerve injuries may progress in an asymmetric manner over days to weeks and are a major cause of long-term morbidity. Less often, a slowly progressive sensory neuropathy in a stocking-glove distribution develops. Abdominal pain, owing to mesenteric vasculitis, is usually dull and constant, but it is often worsened by eating. Some patients exhibit classic findings of mesenteric is­­ chemia, including food avoidance and rapid weight loss. Mesenteric infarction and bowel perforation are infrequent but catastrophic manifestations. The liver is frequently involved at autopsy, but clinical involvement is uncommon. Occasional patients present with appendiceal or biliary tract involvement, usually cholecystitis, and there are reports of spontaneous splenic rupture as a complication of rupture of vasculitic ­aneurysms. The testicle also is a frequent site of involvement in autopsy series, and testicular pain is occasionally seen. In addition, in a few patients, the diagnosis was made from prostatic tissue after presentation with symptoms of prostatic hypertrophy or prostatitis. Kidney involvement usually manifests only as hypertension, often with mild-to-moderate azotemia. There is no glomerulitis, and the urinalysis usually shows only moderate proteinuria with modest hematuria, or the sediment may be entirely normal. Occasional patients have sudden severe flank pain, however, as a result of renal infarction or spontaneous rupture of intrarenal aneurysms, a life-threatening event.22

Without treatment, PAN is probably nearly universally fatal, although because of changing definitions, new serologic tests, and the universal treatment of patients in this era, the true natural history is unknown. It is highly probable, however, that most patients would die within 1 to 2 years if left untreated. THERAPY Although occasional patients seem to have limited d­ isease that remains stable with minimal therapy, the risk of major organ involvement necessitates aggressive therapy in nearly all patients after the diagnosis is made. ­Treatment consists of prednisone, 1 mg/kg/day in divided doses, and, in most cases, an additional agent, usually a cytotoxic drug. The prednisone dose should be maintained until the patient is clinically stable with no evidence of ongoing active disease. The precise method of steroid reduction is a matter open to individual variation and interpretation; a typical regimen is outlined in Table 83-2. Although there are no studies comparing corticosteroids alone with corticosteroids with a second drug, virtually all rheumatologists would add a second drug to corticosteroids if major organs are threatened, or if the prednisone dose required to suppress disease activity is regarded as unacceptably high. Guillevin and coworkers23 have described five prognostic factors that predict a high probability of mortality and are considered indications for another immunosuppressive drug in addition to prednisone: (1) proteinuria greater than 1 g/day, (2) azotemia, (3) cardiomyopathy, (4) gastrointestinal involvement, and (5) central nervous system disease. With none of these factors, 5-year mortality is 12%. With two or more, 5-year mortality is 46%. Cyclophosphamide has been the drug of choice of Fauci and coworkers24 at the National Institutes of Health. Many physicians regard the diagnosis of PAN as an indication for cyclophosphamide therapy. Alternatives to cyclophosphamide are chlorambucil, azathioprine, methotrexate, dapsone, cyclosporine, plasma exchange, and others.25-28

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Table 83-3  Treatment of Polyarteritis Nodosa Drug

Dose

Comment

Oral prednisone

1 mg/kg/day

Mainstay of therapy

Methylprednisolone

1 g/day for 3-5 days

Used in fulminant disease

Cyclophosphamide

2-4 mg/kg/day   orally

Used with major organ involvement or inability to withdraw steroids

Cyclophosphamide

10-15 mg/kg/mo ­intravenously

Alternative to oral therapy, less toxic

Chlorambucil

0.1 mg/kg/day

Alternative to cyclophosphamide

Azathioprine

2-4 mg/kg/day

Less toxic and possibly less effective than cyclophosphamide

Methotrexate

15-25 mg orally   weekly

Less effective, but often used after 1-2 yr of therapy with more potent agents

Plasmapheresis

No proven benefit

Intravenous immunoglobulin

Proven benefit in vasculitis caused by parvovirus B19; may benefit others

Monoclonal antibody

Limited experience

Interferon alfa

Used in vasculitis secondary to hepatitis B

Immunoadsorption27

Investigational

Alkylating agents work quickly and are regarded as the agent of choice for seriously ill patients. ­Cyclophosphamide is used most commonly, although chlorambucil may be equally effective. Both agents have oncogenic potential. Cyclophosphamide has a disproportionate increase in bladder cancer, whereas chlorambucil has a higher incidence of secondary leukemia (see Chapter 57). If cyclophosphamide is chosen, the usual dose is 2 mg/kg, although doses of 4 mg/kg are sometimes used for short periods. When such an agent is instituted, most rheumatologists maintain patients with the alkylating agent for 1 to 2 years. An alternative is intermittent intravenous cyclophosphamide, usually given in doses of 10 to 15 mg/kg monthly, which is less toxic and may be equally effective.27 The use of high-dose intravenous methylprednisolone (≤1 g/day) is recommended occasionally in cases of fulminant vasculitis.28 Table 83-3 compares some agents that have been used in PAN. There are case reports of polyarteritis associated with familial Mediterranean fever that have been treated successfully with colchicine, with or without corticosteroids.29 More recently, case reports have shown apparently favorable responses to anti–tumor necrosis factor therapy.30 PROGNOSIS In a rare disease whose definition has undergone considerable changes and whose treatment is not standard, it is difficult to be confident about the prognosis. With a ­ combination

of prednisone and an alkylating agent, however, it seems that approximately 80% of PAN patients survive, with most entering a long-term remission.31 In classic PAN, the usual approach is to maintain prednisone at 1 mg/kg for 1 to 2 months, then slowly taper over 4 to 6 months. Some physicians favor converting patients to an alternate-day steroid regimen; others maintain daily steroids during the period of dose reduction. These crucial first 6 months of therapy require careful monitoring for toxicity of the drugs and for evidence of disease relapse. Most rheumatologists follow blood counts, urinalyses, serum chemistries, and the ESR on at least monthly intervals. At the end of 6 months or so, the goal is to have the patient in remission (no active disease) and taking little or no steroids. Patients generally are maintained with cyclophosphamide for a full year, and then it is tapered and withdrawn over 3 to 6 months.

CUTANEOUS POLYARTERITIS NODOSA Cutaneous (or limited) PAN refers to a small group of patients who have cutaneous manifestations of the disease, with characteristic histopathologic features, but no systemic features.31 By definition, the patients have no fever, weight loss, or evidence of disease in any internal organs. Cases have been associated with streptococcal infection,32 minocycline,33 and hepatitis C,34 but the etiology is unknown in most. The disease affects individuals of all ages, including children, but the peak age at onset seems to be in the 30s. PATHOLOGY Biopsy specimens of lesions show necrotizing vasculitis with transmural inflammation of small and medium-sized arteries.35 As is true of systemic PAN, the definition of cutaneous PAN has changed over the years, so that many examples in the literature would be classified today as hypersensitivity angiitis, microscopic PAN, or other entities. CLINICAL FEATURES The typical patient develops crops of tender subcutaneous nodules over the lower legs, often with scattered lesions elsewhere. Larger nodules may become necrotic, and painful ulcers develop about 50% of the time.36 In addition to the lower legs, lesions occur on the arms, the buttocks, the trunk, and occasionally the head and neck. The lesions usually occur in crops, appearing within a few days of each other. Untreated, they persist 1 to 6 months; occasional lesions persist for years. Livedo reticularis is common, and most patients complain of some joint pain, especially in joints adjacent to the lesions. No synovitis is present, however, and there are no other associated physical findings. DIAGNOSIS The results of laboratory studies are typically normal, other than mild elevation of the ESR and occasionally mild leukocytosis. There are a few reports of positive test results for ANCAs, although there are no studies to date to determine whether the presence of these antibodies describes a different set of patients who may evolve in time into microscopic PAN.

PART 13 

TREATMENT AND COURSE Acute lesions usually respond to corticosteroids, although moderate-to-high doses may be required. For that reason, combined with the tendency of the disease to relapse and remit for many years, a variety of other agents have been used, with variable success, including anti-inflammatory drugs, sulfapyridine, methotrexate,37 dapsone,38 intravenous immune globulin,39 tamoxifen,40 and thalidomide.41 The prognosis is generally good, although the painful cutaneous ulcers can be disabling. Most patients have recurrent disease for many years,42 however, and frustration with the disease and with the treatment regimen is high. Rarely, patients with cutaneous PAN develop features of systemic PAN, even after many years.43

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Granulomas containing giant cells have been reported, but many lesions contain a mixture of neutrophils, eosinophils, mononuclear cells, and fibrosis. DIAGNOSIS The diagnosis of Cogan’s syndrome is entirely clinical because there are no definitive serologic or histologic markers. As would be expected, most patients have leukocytosis, anemia, thrombocytosis, and an elevated ESR during active phases of their disease. Patients with aortitis show aortic root dilation and aortic insufficiency on echocardiography or aortography. Cases have been reported with anti–endothelial cell antibodies49 and anti-MPO antibodies.50 The significance of these antibodies, if any, is unknown.

COGAN’S SYNDROME

TREATMENT AND COURSE

Cogan’s syndrome is a rare disease, consisting of interstitial keratitis, audiovestibular symptoms, and, in most cases, systemic manifestations. It has been reported in several hundred patients since Cogan’s description of four cases in 1945.44 Cogan’s syndrome is a disease of young people, for the most part, with a median age at onset of 25 years in one large study.45,46

No prospective studies of treatment regimens have been done in this rare disease. The interstitial keratitis usually responds to topical corticosteroids. It is common practice to treat acute audiovestibular symptoms with high doses of corticosteroids. Generally, patients respond quickly or not at all so that after 2 to 4 weeks, the clinician can determine whether long-term therapy is indicated. High-dose corticosteroids, cytotoxic drugs,47 methotrexate,51 and cyclosporine52 have been used to treat the vasculitis. The course varies. Some patients have a single episode and are free of active disease thereafter. The more typical course is one of waxing and waning symptoms for months to years. Virtually all patients sustain some permanent hearing loss, and nearly half are left totally deaf. Aortic valve replacement and surgical repair of aortic aneurysms may be required.

CLINICAL FEATURES The initial manifestations are usually ocular or audiovestibular, with more than 75% of patients developing eye and ear complications within 4 months of each other. In classic Cogan’s syndrome, with interstitial keratitis as the ocular manifestation, systemic vasculitis occurs rarely; other systemic manifestations, especially aortitis with aneurysm formation or aortic insufficiency, occur in about 10% of patients. Atypical Cogan’s syndrome, in which the ocular manifestation is something other than interstitial keratitis, has a higher frequency of aortic and other systemic manifestations and a correspondingly worse prognosis.47 Atypical manifestations of eye disease in Cogan’s syndrome include episcleritis, scleritis, iritis, uveitis, and chorioretinitis. Rare cases of optic neuritis also are reported. The eye symptoms usually begin with photophobia, redness, and local irritation. The audiovestibular symptoms are abrupt in onset with partial or total hearing loss, vertigo, and ataxia. The vestibular symptoms usually improve with time, but the hearing loss rarely returns to normal. About half of patients have constitutional features, including weight loss, fever, lymphadenopathy, hepatosplenomegaly, and rash. Aortitis, causing aneurysms and aortic insufficiency, is the most serious manifestation of Cogan’s syndrome and accounts for most deaths. The aortic manifestations may follow the ophthalmic and audiovestibular features by months to several years. Rarely, patients develop widespread vasculitis, including purpura and skin necrosis.48 PATHOLOGY The aortic and other vascular lesions are characterized by a mixture of acute and chronic inflammation, often most prominent in the region of the internal elastic lamina.

BUERGER’S DISEASE Buerger’s disease, also known as thromboangiitis obliterans, is an inflammatory vaso-occlusive disease that primarily affects the lower extremities in young adult male cigarette smokers, although women and older adults also are affected. The average age at onset is 35 years. More recent reports have emphasized a higher percentage of female patients, older age at onset, and perhaps a declining overall incidence.53 The role of tobacco, especially cigarette smoking, is clear, but the pathogenesis remains unknown. No consistent HLA association has been shown.54 Antibodies against collagen, elastin, and laminin have been reported in some patients.55,56 One study showed high levels of anti– ­endothelial cell antibodies in patients with active disease, but not in patients in remission.57 ANCAs directed against MPO, lactoferrin, and elastase also have been associated with severe disease.58 PATHOLOGY In most cases, Buerger’s disease is limited to small arteries and veins in the distal extremities. There are numerous reports of visceral involvement, however, including mesenteric, coronary, and pulmonary arteries. Active lesions show a segmental inflammatory response with transmural

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i­nfiltration of polymorphonuclear leukocytes and lymphocytes and preservation of the internal elastic membrane.59 Thrombosis is prominent, and microabscesses are seen in the vessel wall and surrounding tissue. The infiltrating cells are enriched in CD3 T cells, and CD68 macrophages and S-100 dendritic cells have been reported to be increased during disease activity.60 CLINICAL FEATURES Buerger’s disease typically begins with bilateral pain and ischemia in both lower extremities, although the upper extremities may be the site of initial symptoms. At onset, the symptoms may be mild, such as paresthesias or pain only with exposure to cold. Most cases rapidly evolve, however, into a painful condition with digital cyanosis, splinter hemorrhages, vesicles, and severe claudication. Digital ulcers often occur, especially after minor trauma.61 The disease typically begins distally, with symptoms worse in the tips of the fingers and toes, but it tends to progress to larger, more proximal vessels over several years. Proximal leg claudication is uncommon, however. Superficial phlebitis occurs in about one third of patients and may be the first symptom. Elevated plasma homocysteine levels have been associated with poor prognosis.62 DIAGNOSIS Characteristic angiographic changes include multiple bilateral areas of narrowing or occlusion in the digital, palmar, plantar, ulnar, radial, tibial, and peroneal arteries. Small collateral vessels around the occlusion often take on a corkscrew appearance. More proximal lesions resemble atherosclerotic occlusion. Although these findings are typical, they are not pathognomonic; in the absence of pathologic confirmation, the disease must be differentiated from premature atherosclerosis; hyperviscosity syndrome; scleroderma and other rheumatic diseases; Takayasu’s arteritis; embolic disease including cholesterol emboli and atrial myxomas; ergot toxicity; and thoracic outlet syndrome. TREATMENT AND COURSE Treatment consists of abstinence from all forms of tobacco. In severely addicted individuals unable to stop smoking, nicotine substitutes may be employed63—it is hoped for only a brief period. Affected limbs must be protected from trauma and cold. Ulcers and cellulitis often require antibiotics and careful débridement. Calcium channel blockers and pentoxifylline reportedly have been beneficial in some patients, as has intra-arterial streptokinase.64 Most patients show little or no response to any of these measures, however. Sympathectomy likewise seems to provide little or no long-term benefit and is not usually recommended. Therapy using the transfer of the gene for vascular endothelial growth factor is under investigation.65 In individuals with Buerger’s disease who continue to smoke, about half require amputation, often multiple times as more proximal vessels are involved. If smoking is stopped, most patients stabilize, with amputation required in a few. The ischemic limb may be a source of pain and ulceration

for many years, however. Although most patients are men, the course in affected women is no different from that in men.66,67

VASCULITIS CAUSED BY VIRAL INFECTIONS The vasculitis resulting from human immunodeficiency virus infection is discussed in Chapter 103. Many other viruses have been reported to be associated with vasculitis, but the cases are so infrequent as to render the diagnosis in doubt. Two viruses, hepatitis B and parvovirus B19, clearly have an association with vasculitis, however. HEPATITIS B VASCULITIS Hepatitis B vasculitis, described simultaneously in 1970 by investigators in the United States and in France,2,3 is seen in individuals with chronic hepatitis B antigenemia, most of whom have active liver disease. The manifestations vary considerably, from diffuse small vessel vasculitis predominantly in the skin to larger vessel lesions typical of PAN.64 Clinical symptoms may include the entire spectrum of vasculitic manifestations, from purpura and other rashes to abdominal pain, hypertension, renal disease, and stroke. Patients with cryoglobulinemia almost always have concomitant hepatitis C infection (see Chapter 85). Treatment of these patients with immunosuppressive drugs has been only moderately successful; many patients die as a result of vasculitis or liver disease. Trepo and colleagues68 and more recently Guillevin and coworkers69 have reported good results using a combination of plasmapheresis, corticosteroid therapy, and antiviral therapy. Successful treatment with interferon-alfa also has been reported. PARVOVIRUS B19 VASCULITIS Although the most common rheumatic manifestation of parvovirus B19 infection is arthritis (see Chapter 104), occasional patients, usually children, have been reported to develop an impressive vasculitis, usually resembling PAN, in the setting of chronic parvovirus B19 infection.70,71 These children have responded well to intravenous immune globulin therapy, suggesting that they may have a specific immune deficit regarding an inability to mount a normal immune response to parvovirus B19, although there was no other evidence suggesting generalized immunodeficiency. REFERENCES   1. Cohen RD, Conn DL, Ilstrup DM: Clinical features, prognosis, and response to treatment in polyarteritis. Mayo Clin Proc 55:146, 1980.   2. Gocke DJ, Morgan C, Lockshin M, et al: Association between polyarteritis nodosa and Australia antigen. Lancet 2:1149, 1970.   3. Trepo C, Thivolet J: Hepatitis associated antigens and periarteritis nodosa (PAN). Vox Sang 19:410, 1970.   4. Goodman MD, Porter DD: Cytomegalovirus vasculitis with fatal colonic hemorrhage. Arch Pathol 96:281, 1973.   5. Massari M, Salvarani C, Portioli I, et al: Polyarteritis nodosa and HIV infection: No evidence of a direct pathogenic role of HIV. Infection 24:159, 1996.   6. Calabrese LH: Vasculitis and infection with the human immunodeficiency virus. Rheum Dis Clin N Am 17:131, 1991.

PART 13    7. Caldeira T, Meireles C, Cunha F, et al: Systemic polyarteritis nodosa associated with acute Epstein-Barr virus infection. Clin Rheumatol 26:1733-1735, 2007.   8. Wharton CF, Pieroni R: Polyarteritis after influenza vaccination. BMJ 2:331, 1974.   9. Bani-Sadr F, Gueit I, Humbert G: Vasculitis related to hepatitis A vaccination. Clin Infect Dis 22:596, 1996. 10. Sergent JS, Christian CL: Necrotizing vasculitis after acute serous otitis media. Ann Intern Med 81:195, 1974. 11. Bingham C, Beaman M, Nicholls AJ, et al: Necrotizing renal vasculopathy resulting in chronic renal failure after ingestion of methamphetamine and 3,4-methylenedioxymethamphetamine (“ecstasy”). Nephrol Dial Transplant 13:2654, 1998. 12. Culver B, Itkin A, Pischel K: Case report and review of minocyclineinduced cutaneous polyarteritis nodosa. Arthritis Care Res 53:468, 2005. 13. Katada Y, Harada Y, Azuma N, et al: Minocycline-induced vasculitis fulfilling the criteria of polyarteritis nodosa. Mod Rheumatol 16: 256-259, 2006. 14. Garcia-Diaz J, Garcia-Sanchez M, Busteros J, et al: Polyarteritis nodosa after interferon treatment for chronic hepatitis C. J Clin Virol 32:181, 2005. 15. Moskowitz RW, Baggenstoss AH, Slocumb CH: Histopathologic classification of periarteritis nodosa: A study of 56 cases confirmed at necropsy. Mayo Clin Proc 38:345, 1963. 16. Antonovych TT, Sabnis GG, Tuur SM, et al: Morphologic differences between polyarteritis and Wegener’s granulomatosis using light, electron and immunohistochemical techniques. Mod Pathol 24:349, 1989. 17. Cid MC, Grau JM, Casademont J, et al: Immunohistochemical characterization of inflammatory cells and immunologic activation markers in muscle and nerve biopsy specimens from patients with polyarteritis nodosa. Arthritis Rheum 37:1055, 1994. 18. Ewald EA, Griffin D, McCune WJ: Correlation of angiographic abnormalities with disease manifestations and disease severity in polyarteritis nodosa. J Rheumatol 14:952, 1987. 19. Wees SJ, Sunivoo IN, Oh SJ: Sural nerve biopsy in systemic necrotizing vasculitis. Am J Med 71:525, 1981. 20. Lightfoot RW, Michel BA, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum 33:1088, 1990. 21. Chang RW, Bell CL, Hallet M: Clinical characteristics and prognosis of vasculitic mononeuropathy multiplex. Arch Neurol 41:618, 1984. 22. Smith DL, Wernick R: Spontaneous rupture of a renal artery aneurysm in polyarteritis nodosa: Critical review of the literature and report of a case. Am J Med 87:464, 1989. 23. Guillevin L, Lhote F, Gayraud M, et al: Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome: A prospective study in 342 patients. Medicine (Balt) 75:17, 1996. 24. Fauci AS, Katz P, Haynes BF, et al: Cyclophosphamide therapy of severe systemic necrotizing vasculitis. N Engl J Med 301:235, 1979. 25. Clements PJ, Davis J: Cytotoxic drugs and their clinical application to rheumatic diseases. Semin Arthritis Rheum 15:231, 1986. 26. Guillevin L, Lhote F: Treatment of polyarteritis nodosa and microscopic polyangiitis. Arthritis Rheum 41:2100, 1998. 27. Gayraud M, Guillevin L, Cohen P, et al: Treatment of good-prognosis polyarteritis nodosa and Churg-Strauss syndrome: Comparison of steroids and oral or pulse cyclophosphamide in 25 patients. Br J Rheumatol 36:1290, 1997. 28. Fort JG, Abruzzo JL: Reversal of progressive necrotizing vasculitis with intravenous pulse cyclophosphamide and methylprednisolone. Arthritis Rheum 31:1194, 1998. 29. Balbir-Gurman A, Nahir A, Braun-Moscovici Y: Vasculitis in siblings with familial Mediterranean fever: A report of three cases and review of the literature. Clin Rheumatol 26:1183, 2007. 30. Wu K, Throssell D: A new treatment for polyarteritis nodosa. Nephrol Dial Transplant 21:1710, 2006. 31. Moreland LW, Ball GV: Cutaneous polyarteritis nodosa. Am J Med 88:426, 1990. 32. Albornoz MA, Benedetto AV, Korman M, et al: Relapsing cutaneous polyarteritis nodosa associated with streptococcal infections. Int J Dermatol 37:664, 1998. 33. Schaffer JV, Davidson DM, McNiff JM, et al: Perineuclear antineutrophil cytoplasmic antibody-positive cutaneous polyarteritis nodosa associated with minocycline therapy for acne vulgaris. J Am Acad Dermatol 44:1908, 2001.

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34. Soufir N, Descamps V, Crickx B, et al: Hepatitis C virus infection in cutaneous polyarteritis nodosa: A retrospective study of 16 cases. Arch Dermatol 135:1001, 1999. 35. Chen KR: Cutaneous polyarteritis nodosa. Am J Med 88:426, 1990. 36. Diaz-Perez JL, Winkelmann RK: Cutaneous polyarteritis nodosa. Arch Dermatol 110:407, 1974. 37. Jorrizzo JL, White WL, Wise CM, et al: Low-dose weekly methotrexate for unusual neutrophilic vascular reactions: Cutaneous polyarteritis nodosa and Behçet’s disease. J Am Acad Dermatol 24:973, 1991. 38. Gibson LE, Su WP: Cutaneous vasculitis. Rheum Dis Clin N Am 16:309, 1990. 39. Uziel Y, Silverman ED: Intravenous immunoglobulin therapy in a child with cutaneous polyarteritis nodosa. Clin Exp Rheumatol 16:187, 1998. 40. Cvancara JL, Meffert JJ, Elston DN: Estrogen-sensitive cutaneous polyarteritis nodosa: Response to tamoxifen. J Am Acad Dermatol 39:643, 1998. 41. Cejudo-Rodriguez C, Hernandez V, Rodriguez R, et al: Thalidomide in mild and severe recurrent cutaneous polyarteritis nodosa. Ann Allergy Astham Immunol 82:128, 1999. 42. Kelleman D, Kempf W, Burg G, et al: Cutaneous polyarteritis nodosa. Vasa 27:54, 1998. 43. Dervar CL, Bellamy N: Necrotizing mesenteric vasculitis after longstanding cutaneous polyarteritis nodosa. J Rheumatol 19:1308, 1992. 44. Cogan DG: Syndrome of nonsyphilitic interstitial keratitis and vestibuloauditory symptoms. Arch Ophthalmol 33:144, 1945. 45. Vollertsen RS, McDonald TJ, Younge BR, et al: Cogan’s syndrome: 18 cases and a review of the literature. Mayo Clin Proc 61:344, 1986. 46. Haynes BF, Kaiser-Kupfer MI, Mason P, et al: Cogan syndrome: Studies in thirteen patients, long-term follow-up, and a review of the literature. Medicine (Balt) 59:426, 1980. 47. VanDoornum S, McColl G, Walter M, et al: Prolonged prodrome, systemic vasculitis, and deafness in Cogan’s syndrome. Ann Rheum Dis 60:69, 2001. 48. Vollertsen RS: Vasculitis and Cogan’s syndrome. Rheum Dis Clin N Am 16:433, 1990. 49. Ottaviani F, Cadoni G, Marinelli L, et al: Anti-endothelial cell autoantibodies in patients with sudden hearing loss. Laryngoscope 109:1084, 1999. 50. Yamanishi Y, Ishioka S, Takeda M, et al: Atypical Cogan’s syndrome associated with antineutrophil cytoplasmic antibodies. Br J Rheumatol 35:601, 1996. 51. Richardson B: Methotrexate therapy for hearing loss in Cogan’s syndrome. Arthritis Rheum 37:1559, 1994. 52. Hammer M, Witte T, Mugge A, et al: Complicated Cogan’s syndrome with aortic insufficiency and coronary stenosis. J Rheumatol 21:552, 1994. 53. Olin JW, Young JR, Graor RA, et al: The changing clinical spectrum of thromboangiitis obliterans (Buerger’s disease). Circulation 82(Suppl IV):3, 1990. 54. Olin JW: Thromboangiitis obliterans. Curr Opin Rheumatol 6:44, 1994. 55. Aclar R, Papa MZ, Halpern Z, et al: Cellular sensitivity to collagen in thromboangiitis obliterans. N Engl J Med 308:1113, 1983. 56. Hada M, Sakihama T, Kamiya K, et al: Cellular and humoral immune responses to vascular components in thromboangiitis obliterans. Angiology 44:533, 1993. 57. Eichhorn J, Sima D, Lindschau C, et al: Antiendothelial cell antibodies in thromboangiitis obliterans. Am J Med Sci 315:17, 1998. 58. Halacheva KS, Manolova IM, Petkov DP, et al: Study of antineutrophil cytoplasmic antibodies in patients with thromboangiitis obliterans (Buerger’s disease). Scand J Immunol 48:544, 1998. 59. Lie JT: Diagnostic histopathology of major systemic and pulmonary vasculitic syndromes. Rheum Dis Clin N Am 16:269, 1990. 60. Kobayashi M, Ito M, Nakagawa A, et al: Immunohistochemical analysis of arterial cell wall infiltration in Buerger’s disease (endartheritis obliterans). J Vasc Surg 29:451, 1999. 61. Joyce JW: Buerger’s disease (thromboangiitis obliterans). Rheum Dis Clin N Am 16:463, 1990. 62. Olin JW, Childs MB, Bathrolomex JR, et al: Anticardiolipin antibodies and homcysteine levels in patients with thromboangiitis obliterans. Arthritis Rheum 39:547, 1996. 63. Kawallata H, Kanekura T, Gushi A, et al: Successful treatment of digital ulceration in Buerger’s disease with nicotine chewing gum. Br J Dermatol 140:187, 1999 (letter).

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64. Hussein EA, el Douri A: Intra-arterial streptokinase as adjuvant therapy for complicated Buerger’s disease: Early trials. Int Surg 78:54, 1993. 65. Isner JM, Baumgartner I, Rauch G, et al: Treatment of thromboangiitis obliterans (Buerger’s disease) by intramuscular gene transfer of vascular endothelial growth factor: Preliminary clinical results. J Vasc Surg 28:964, 1998. 66. Sasaki S, Sakuma M, Kunihara T, et al: Current trends in thromboangiitis obliterans (Buerger’s disease) in women. Am J Surg 177:316, 1999. 67. Sergent JS, Lockshin MD, Christian CL, et al: Vasculitis with hepatitis B antigenemia. Medicine (Balt) 55:1, 1976.

68. Trepo C, Ouzan D, Delmont J, et al: Superiorite d’un nouveau traitement etiopathogenique curateur des periarteritis noueuses induites par le virus de l’hepatite B grace a l’association corticotherapie breve, vidarabine, echanges plasmatiques. Presse Med 17:1527, 1988. 69. Guillevin L, Mahr A, Cohen P, et al: Short-term corticosteroids then lamivudine and plasma exchanges to treat hepatitis B virus-related polyarteritis nodosa. Arthritis Rheum 51:482, 2004. 70. Gattorno M, Picco P, Vignola S, et al: Brother and sister with different vasculitides. Lancet 353:728, 1999. 71. Finkel TH, Torok TJ, Ferguson PJ, et al: Chronic parvovirus B19 infection and systemic necrotizing vasculitis: Opportunistic infection or aetiological agent? Lancet 343:1255, 1994.

84

Isolated Angiitis of the Central Nervous System JOHN S. SERGENT

Key Points

granulomatous infections, such as tuberculosis14 and brucellosis.15

Isolated angiitis of the central nervous system (CNS) may manifest with myriad symptoms, but headache, waxing and waning altered mental status, and transient ischemic attack–like events are most common.

PATHOLOGY

Patients with CNS angiitis typically have no evidence of vasculitis elsewhere. No laboratory markers (e.g., C-reactive protein, erythrocyte sedimentation rate) are useful in making the diagnosis. Diagnosis is often based on angiography in the appropriate clinical setting, although brain biopsy is the only definitive diagnostic test. CNS angiitis is a very rare disease, and its manifestations can be mimicked by many other diseases. When CNS angiitis is confirmed, the preferred treatment is cyclophosphamide and prednisone, although residual morbidity is high.

Isolated angiitis of the central nervous system (CNS) is a rare disorder with a large differential diagnosis, making it a particularly difficult clinical challenge. Involvement of the CNS by other forms of vasculitis, especially common in disorders such as giant cell arteritis, Takayasu’s arteritis, and Wegener’s granulomatosis, is considered to be secondary CNS angiitis. By definition, in primary CNS angiitis, the vasculitis is limited to the central nervous system.

EPIDEMIOLOGY Most reported series of CNS angiitis are small, and single case reports describe unusual features or associations; the disease seems to be most frequent in the fourth and fifth decades, with case reports describing individuals of all ages, ranging from children to the elderly. Vasculitis resembling isolated CNS angiitis has been described in association with human immunodeficiency virus (HIV) infection,1-3 varicella zoster,4 amyloid angiopathy,5,6 sarcoidosis,7 parvovirus B19 infection,8 ulcerative colitis,9 drugs,10 and lymphomas.11 In children, there are numerous reports of familial hemophagocytic lymphohistiocytosis mimicking vasculitis.12 Moshous and associates13 reported a 4-year-old girl with perforin deficiency who had CNS vasculitis with no evidence of hemophagocytosis, and who was cured with a stem cell transplant from an HLA-identical brother.13 Other considerations in the differential diagnosis include

CNS angiitis was first described in 1959 by Cravioto and Fegin16 as a granulomatous vasculitis. For many years, the term granulomatous angiitis of the central nervous system was used. Pathologic studies have shown, however, that granulomas are not always present, with some cases showing only vascular necrosis or a lymphocytic or mixed cellular infiltrate.17 The site of involvement in the CNS also varies, ranging from small leptomeningeal vessels to large arteries and veins.

CLINICAL FEATURES A typical patient presents with a 1- to 3-month history of headache and various other symptoms such as intermittent confusion and focal neurologic symptoms, including transient ischemic attacks and strokes. Seizures occur in a few patients, and some patients progress rapidly to dementia.18 Paraplegia and other spinal cord syndromes are rare manifestations. Table 84-1 shows the author’s estimate of the approximate frequency of the various presenting features of the disease.

LABORATORY FINDINGS The “gold standard” for the diagnosis of primary CNS angiitis is a brain and leptomeningeal biopsy. Inflammatory indices, including the erythrocyte sedimentation rate and C-reactive protein, are typically normal or only mildly elevated. Patients may be mildly anemic, but other tests, including antineutrophil cytoplasmic antibodies, antinuclear antibodies, rheumatoid factor, and complement levels, are almost always normal.

RADIOGRAPHIC FEATURES Although angiographic features may be characteristic of the disease, they are not specific, and many entities can cause angiographic changes identical to those seen in primary CNS angiitis. Because of this fact, and because of the rarity of the disease, the clinician is urged to be wary of relying on radiography to make the diagnosis. In the author’s experience, only a few patients considered by the radiologist to have primary CNS angiitis have turned out to have the disease on further examination. With that caveat, the typical angiographic findings include stenosis or occlusion of multiple arteries, with occasional series reporting aneurysmal dilation as well (Fig. 84-1). Beading, usually in association with areas of stenosis, occasionally is found.19 1461

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Table 84-1  Estimated Presenting Symptoms   of Central Nervous System Angiitis Symptom

Frequency (%)

Headache

70

Episodic confusion

50

Focal signs

50

Seizures

30

Dementia

Rare*

*Many patients become demented late in the course.

Figure 84-1  Angiogram of a patient with primary CNS angiitis showing multiple small aneurysms.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of CNS angiitis is large, and clinicians should be especially wary of the diagnosis in the setting of migraine,20 severe hypertension,21 various vasoactive drugs,22,23 lymphoma,24 and coagulopathies, especially if antiphospholipid antibodies are present.25 Infections known to have CNS manifestations mimicking vasculitis include syphilis,26 brucellosis,27 varicella zoster,28 and HIV.29 Vasculitis in the setting of these conditions should always be considered secondary.

CLINICAL COURSE Although apparently benign forms of CNS angiitis are reported,30 most untreated cases and many that are treated have a devastating outcome, including dementia, severe paralysis, and death.

TREATMENT Treatment is empiric, and in severe cases the largest experience would suggest an approach similar to treatment of polyarteritis nodosa or Wegener’s granulomatosis using cyclophosphamide and corticosteroids. That regimen is followed by remission in more than half of cases, but significant morbidity is common.31 A particularly challenging problem is a patient with angiographic findings of CNS angiitis who presents with acute focal disease. Calabrese and colleagues32 termed this condition the reversible cerebral vasoconstriction syndrome and suggested a conservative approach using corticosteroids and calcium channel blockers. The author’s experience would

definitely support this approach, especially in the setting of any other potentially precipitating conditions, such as migraine, the postpartum period, or various drugs. REFERENCES   1. Nogueras C, Sala M, Sasal M, et al: Recurrent stroke as a manifestation of primary angiitis of the central nervous system in a patient infected with human immunodeficiency virus. Arch Neurol 59:468, 2002.   2. Ake JA, Erickson JC, Lowry KJ: Cerebral aneurysmal arteriopathy associated with HIV infection in an adult. Clin Infect Dis 43:e46-e50, 2006.   3. Nieuwhof CMG, Damoiseaux J, Tervaert JW, et al: Successful treatment of cerebral vasculitis in an HIV-positive patient with anti-CD25 treatment. Ann Rheum Dis 65:1677-1678, 2006.   4. Al-Abdulla NA, Kelley JS, Green WR, et al: Herpes zoster vasculitis presenting as giant cell arteritis with choroidal infarction. Retina 23:567-569, 2003.   5. Scolding NJ, Fady J, Kirby PA, et al: AB-related angiitis: Primary angiitis of the central nervous system associated with cerebral amyloid angiopathy. Brain 128:500-515, 2005.   6. Wong SH, Robbins PD, Knuckey NW, et al: Cerebral amyloid angiopathy presenting with vasculitic pathology. J Clin Neurosci 13: 291-294, 2006.   7. Brisman JL, Hinduja A, McKinney JS, et al: Successful emergent angioplasty of neurosarcoid vasculitis presenting with strokes. Surg Neurol 66:402-404, 2006.   8. Bilge I, Sadikoglu B, Emre S, et al: Central nervous system vasculitis secondary to parvovirus B19 infection in a pediatric renal transplant patient. Pediatr Nephrol 20:529-533, 2005.   9. Pandian JD, Henderson RD, O’Sullivan JD, et al: Cerebral vasculitis in ulcerative colitis. Arch Neurol 63:780, 2006. 10. Vanek C, Samuels MH: Central nervous system vasculitis caused by propylthiouracil therapy: A case report and literature review. Thyroid 15:80-84, 2005. 11. Albrecht R, Krebs B, Reusche E, et al: Signs of rapidly progressive dementia in a case of intravascular lymphomatosis. Eur Arch Psychiatry Clin Neurosci 255:232-235, 2005. 12. Turtzo LC, Lin DD, Hartung H, et al: A neurologic presentation of familial hemophagocytic lymphohistiocytosis which mimicked septic emboli to the brain. J Child Neurol 22:863-868, 2007. 13. Moshous D, Feyen O, Lankisch P, et al: Primary necrotizing lymphocytic central nervous system vasculitis due to perforin deficiency in a four-year-old girl. Arthritis Rheum 56:995-999, 2007. 14. Poltera AA: Thrombogenic intracranial vasculitis in tuberculous meningitis: A 20 year “post mortem” survey. Acta Neurol Belg 77: 12-24, 1977. 15. Adaletli I, Albayram S, Gurses B, et al: Vasculopathic changes in the cerebral arterial system with neurobrucellosis. AJNR Am J Neuroradiol 27:384-386, 2006. 16. Cravioto ID, Fegin I: Non-infectious granulomatous angiitis with a predilection for the nervous system. Neurology 9:599-609, 1959. 17. MacLaren K, Gillespie J, Shrestha S, et al: Primary angiitis of the central nervous system: Emerging variants. QJM 98:643-654, 2005. 18. Lie JT: Primary (granulomatous) angiitis of the central nervous system: A clinicopathologic analysis of 15 new cases and a review of the literature. Hum Pathol 23:164-171, 1992. 19. Kadkhodayan Y, Alreshaid A, Moran CJ, et al: Primary angiitis of the central nervous system at conventional angiography. Radiology 233:878-882, 2004. 20. Kurth T: Migraine and ischaemic vascular events. Cephalalgia 27: 965-975, 2007. 21. Garner BF, Burns P, Bunning BD, et al: Acute blood pressure elevation can mimic arteriographic appearance of cerebral vasculitis—a postpartum case with relative hypertension. J Rheumatol 17:93, 1990. 22. Lake CR, Gallant S, Mason E, et al: Adverse drug effects attributed to phenylpropanolamine: A review of 142 case reports. Am J Med 89:195, 1990. 23. De Silva DA, Wong MC, Lee MP, et al: Amphetamine-associated ischemic stroke: Clinical presentation and proposed pathogenesis. J Stroke Cerebrovasc Dis 16:185-186, 2007. 24. Holmoy T, Nakstad PH, Fredo HL, et al: Intravascular large B-cell lymphoma presenting as cerebellar and cerebral infarction. Arch Neurol 64:754-755, 2007.

PART 13  25. Rahemtullah A, Van Cott EM: Hypercoagulation testing in ischemic stroke. Arch Pathol Lab Med 131:890-901, 2007. 26. Asdaghi N, Muayqil T, Scozzafava J, et al: Teaching case report: The re-emergence in Canada of meningovascular syphilis: 2 patients with headache and stroke. Can Med Assoc J 176:1699-1700, 2007. 27. Karsen H, Akdeniz H, Karahocagil MK, et al: Toxic-febrile neurobrucellosis, clinical findings and outcome of treatment of four cases based on our experience. Scand J Infect Dis 6:1-6, 2007. 28. Gilden D: Varicella zoster virus and central nervous system syndromes. Herpes 11(Suppl 2):89A-94A, 2004.

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29. Tipping B, deVilliers L, Wainwright H, et al: Stroke in patients with human immunodeficiency virus infection. J Neurol Neurosurg Psychiatry 78:1320-1324, 2007. 30. Jolly M, Curran JJ, Ellman M: Benign angiopathy of the central nervous system. J Clin Rheumatol 10:80-82, 2004. 31. Calabrese LH: Vasculitis of the central nervous system. Rheum Dis Clin N Am 21:1059-1076, 1995. 32. Calabrese LH, Dodick DW, Schwedt TJ, et al: Narrative review: Reversible cerebral vasoconstriction syndromes. Ann Intern Med 146:34-44, 2007.

85

Immune Complex–Mediated Small Vessel Vasculitis JOHN H. STONE

KEY POINTS

Direct immunofluorescence studies of involved blood vessels demonstrate characteristic types and patterns of immunoglobulin (Ig) and complement deposition.

angiitis, often confused with the pauci-immune form of vasculitis now termed microscopic polyangiitis (see Chapter 82),1 was one of five disorders included in the original classification of the vasculitides in 1952.2 This chapter focuses on forms of small vessel vasculitis that are mediated by IC deposition. These disorders include hypersensitivity vasculitis, Henoch-Schönlein purpura (HSP), mixed cryoglobulinemia, urticarial vasculitis, and erythema elevatum diutinum. In addition, forms of vasculitis associated with connective tissue diseases, particularly systemic lupus erythematosus (SLE) and rheumatoid vasculitis, are discussed briefly. Anti–glomerular basement membrane disease and the pauci-immune forms of vasculitis, such as those associated with antineutrophil cytoplasmic antibodies, are discussed elsewhere (see Chapter 82). Throughout this chapter, the terms vasculitis and angiitis are used interchangeably when referring to inflammation involving small blood vessels (capillaries, venules, arterioles). Because all forms of IC-mediated vasculitis share certain elements of pathogenesis, have many cutaneous findings in common, and have overlapping differential diagnoses, these aspects of the disorders are considered together. The epidemiology, cause, distinctive pathophysiologic mechanisms, unique clinical features, and approaches to treatment are discussed separately for each condition.

Hypersensitivity vasculitis usually results from a reaction to a medication or an infection.

PATHOGENESIS

Vasculitides mediated by immune complexes (ICs) are a clinically heterogeneous group of disorders linked by ­inefficient or dysregulated clearance of ICs. The most common types of IC-mediated vasculitis are ­hypersensitivity vasculitis, Henoch-Schönlein purpura (HSP), and mixed cryoglobulinemia. Rarer forms of this condition include hypocomplementemic urticarial vasculitis and ­erythema elevatum diutinum. Connective tissue disorders such as systemic lupus erythematosus and rheumatoid arthritis can also be associated with IC-mediated vasculitis. Cutaneous involvement of small blood vessels is the most prominent feature in the majority of cases, but extracutaneous involvement occurs in some forms. The classic cutaneous finding in small vessel vasculitis is palpable purpura, but a variety of other skin lesions may be found: pustules, vesicles, urticaria, and small ulcerations. The terms vasculitis and angiitis are used interchangeably when referring to inflammation involving small blood vessels (capillaries, venules, arterioles).

HSP is associated with purpura, arthritis, glomerulonephritis, and colicky abdominal pain. IgA deposition is found within blood vessel walls. Cryoglobulinemic vasculitis is associated with long-standing hepatitis C virus infection in 90% of cases. The term mixed cryoglobulinemia is sometimes used for this disorder because the immunoreactants involved in the disease include both IgG and IgM.

The inflammation within blood vessel walls that ­characterizes vasculitis frequently leads to cellular destruction, damage to the vascular structures, compromise of blood flow to organs, and organ dysfunction. It has been known for decades that immune complex (IC)–mediated mechanisms play critical roles in many forms of systemic vasculitis, particularly those that involve primarily small blood vessels. As described in Chapter 80, the use of horse serum and sulfonamides as therapeutic agents for infectious diseases in the early 1900s frequently led to small vessel vasculitis on the basis of serum sickness or hypersensitivity ­ phenomena. Hypersensitivity

ARTHUS REACTION The Arthus reaction, described after the injection of horse serum into rabbits, forms the basis of our understanding of IC-mediated diseases.3 The formation of ICs in the Arthus reaction initiates complement activation and an influx of inflammatory cells, followed by thrombus formation and hemorrhagic infarction in the areas of most intense inflammation. ICs, formed by the combination of antibody and antigen, are continuously created (and usually cleared swiftly and efficiently) by the reticuloendothelial system as a means of neutralizing foreign antigens. Under some circumstances, however, ICs escape clearance and become deposited within joints, blood vessels, and other tissues, inciting inflammation and causing disease. ICs deposited in the blood vessel walls lead to vasculitis. Similarly, those deposited within small blood vessels of the kidney—the glomeruli—cause ­glomerulonephritis.4 IMMUNOGENICITY The fate of formed ICs is governed by several major factors, including antigen load, antibody response, efficiency of the reticuloendothelial system, physical properties of 1465

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the blood vessels (including flow dynamics and previous endothelial damage), and solubility of the ICs themselves. The ratio of antibody to antigen determines the solubility of ICs. Large ICs, formed when antibody and antigen are present in approximately equal proportions, are identified and removed easily by the reticuloendothelial system. In contrast, small ICs are formed in conditions of antibody excess. Small ICs remain in the serum and do not elicit an immune response within tissues. However, when there is a slight antigen excess, ICs precipitate from the serum and become trapped within certain vascular beds. Following the deposition of ICs in tissue, a cascade of pathologic events ensues: complement fixation, neutrophil recruitment, local inflammation, lysosomal release, oxygen free radical generation, and tissue injury.

CUTANEOUS MANIFESTATIONS Small blood vessels generally include capillaries, postcapillary venules, and nonmuscular arterioles—vessels that are typically less than 50 μm in diameter. These are found principally within the superficial papillary dermis (Fig. 85-1). Medium-sized blood vessels, those between 50 and 150 μm in diameter, contain muscular walls and are located principally in the deep reticular dermis, near the junction of the dermis and subcutaneous tissues. Vessels larger than 150 μm in diameter are not commonly found in the skin. Figure 85-1, which demonstrates the location and size of blood vessels involved in various types of cutaneous vasculitis, illustrates the types of blood vessels affected by several forms of IC-mediated disease. A blood vessel’s size correlates closely with its depth in the skin layers: the larger the vessel, the deeper its location. Although telltale signs of vasculitis may be evident on inspection of the skin’s surface, the epidermis is avascular. Therefore, the pathologic findings in cutaneous vasculitides lie within the dermis and subcutaneous tissues.

HSP

CLA

ANCA CRYO CTD/RV

Epidermis

Reticular dermis

Subcuta

neous

Muscle

Palpable purpura, synonymous with small vessel vasculitis, is the most common cutaneous finding in IC-mediated vasculitis (Fig. 85-2). Purpuric lesions result from the extravasation of erythrocytes through damaged blood vessel walls into tissue. Many other skin manifestations are possible in these conditions, including vesicles, pustules, urticaria, superficial ulcerations, nonpalpable lesions (macules and patches), and splinter hemorrhages (Fig. 85-3). These lesions frequently occur in combination, and careful examination usually reveals a purpuric component. Purpuric lesions do not blanch when pressure is applied to the skin. Following resolution, purpuric lesions may leave postinflammatory hyperpigmentation, particularly if repeated bouts occur (see Fig. 85-3F). In IC-mediated vasculitis, purpuric lesions are usually distributed in a symmetric fashion over dependent regions of the body, particularly the lower legs, because of the increased hydrostatic pressure in these areas. Purpuric lesions are not always palpable to the touch, and the existence of palpable purpura does not necessarily imply an IC-mediated pathophysiology; pauci-immune forms of vasculitis, such as Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome, for example, may present with identical skin findings (albeit distinctive histopathology; see Chapter 82).

PATHOLOGIC FEATURES Full pathologic assessment of cutaneous vasculitis involves examination of a skin biopsy specimen by both light microscopy and direct immunofluorescence (DIF). DIF is a particularly critical procedure in the evaluation of small vessel vasculitides. DIF studies must be planned at the time the biopsy is performed, because they require a fresh skin biopsy sample.

PAN

Papillary dermis

Shave biopsy

Punch biopsy

Excisional biopsy Figure 85-1  Size of the blood vessels involved in forms of cutaneous vasculitis. The types of vasculitis with an immune complex–­mediated pathogenesis include Henoch-Schönlein purpura (HSP), cutaneous leukocytoclastic angiitis (CLA), mixed cryoglobulinemia (CRYO), and connective tissue disease/rheumatoid vasculitis (CTD/RV). ANCA, antineutrophil cytoplasmic antibody; PAN, polyarteritis nodosa.

Figure 85-2  Hypersensitivity vasculitis. Palpable purpura in a patient with hypersensitivity vasculitis.

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A

C

D

B

E

F

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Figure 85-3  Other cutaneous findings of immune complex–mediated small vessel vasculitis. A, Vesicles. B, Pustules. C, Superficial ulcerations.  D, Urticaria. E, Splinter hemorrhages. F, Hyperpigmentation.

LIGHT MICROSCOPY

DIRECT IMMUNOFLUORESCENCE

Figure 85-4A displays the light microscopy findings of cutaneous vasculitis. The optimal time for skin biopsy is 24 to 48 hours after the appearance of a lesion. Biopsies should be obtained from a nonulcerated site. For ulcerated lesions—usually more of an issue with medium vessel vasculitides—biopsies should be taken from the ulcer’s edge. The cellular infiltrates in cutaneous vasculitis are usually made up of a combination of neutrophils and lymphocytes, but most cases demonstrate a predominance of one cell type or the other. Lymphocyte-rich infiltrates may be seen in specimens taken from either new (<12 hours) or old (>48 hours) lesions, regardless of the underlying type of vasculitis. Even in connective tissue disorders such as Sjögren’s syndrome, the typical finding is a leukocytoclastic vasculitis rather than a lymphocytic vasculitis.5 The essential histologic feature in any form of cutaneous vasculitis is the disruption of blood vessel architecture by an inflammatory infiltrate within and around the vessel walls. Endothelial swelling and proliferation, leukocytoclasis (degranulation of neutrophils, leading to the production of nuclear “dust”; see Fig. 85-4), and extravasation of erythrocytes may be evident in the biopsy but are not essential to the diagnosis.

Although the diagnosis of cutaneous vasculitis rests on ­routine histology, the features revealed by hematoxylin and eosin stains do not distinguish between pauci-immune and IC-mediated disorders. DIF studies complement the histologic information, provide the only way of diagnosing HSP with certainty, and yield important clues regarding the nature of the underlying disease. The performance of separate biopsies for histologic and DIF analyses is recommended if sufficient lesions exist. With DIF studies, frozen sections are incubated with fluorescein-labeled anti–human immunoglobulin (Ig) G, IgM, IgA, and C3. The staining patterns of these immunoreactants may provide insight not only into the diagnosis but also into the pathophysiology of certain conditions. Figure 85-4B displays the typical DIF findings in a skin lesion from a patient with IC-mediated vasculitis.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of IC-mediated small vessel vasculitis is shown in Table 85-1. There are three main groups of disorders in the differential diagnosis of IC-mediated small vessel vasculitis: other forms of IC-mediated disorders, forms

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A

B

Figure 85-4  Skin biopsy findings in immune complex–mediated small vessel vasculitis. A, Light microscopy findings. B, Direct immunofluorescence findings.

of small vessel vasculitis that are not mediated through ICs, and vasculitis mimickers that involve small blood vessels. A diagnostic algorithm that includes the critical laboratory and radiographic tests is shown in Figure 85-5.

CLINICAL SYNDROMES HYPERSENSITIVITY VASCULITIS (CUTANEOUS LEUKOCYTOCLASTIC ANGIITIS) The term hypersensitivity vasculitis (see Chapter 80) refers generally to an IC-mediated small vessel vasculitis of the skin that spares internal organs and usually follows drug exposures or infections. The Chapel Hill Consensus Conference recommended eliminating the term hypersensitivity vasculitis in favor of cutaneous leukocytoclastic angiitis, because of the disorder’s usual confinement to the skin and its predominant cell type, the neutrophil.1 However, hypersensitivity vasculitis remains firmly embedded in the medical literature. The disease is characterized pathologically by IC deposition in capillaries, postcapillary venules, and arterioles. A similar illness—serum sickness—is a systemic illness that includes rash and prominent arthralgias or arthritis; it occurs 1 to 2 weeks after exposure to a drug or foreign antigen. In 1990, the American College of Rheumatology (ACR) performed a study designed to identify features that distinguished one form of vasculitis from others.6 The resulting ACR classification criteria for hypersensitivity vasculitis are shown in Table 85-2.7 A long list of medications, infections, and other exposures may lead to the syndrome of hypersensitivity vasculitis. The key historical element in evaluating a patient with possible hypersensitivity vasculitis is identifying exposures that may have triggered the reaction.

However, in approximately half of all patients with this ­disorder, no inciting agent can be identified. Thorough efforts are also required to exclude disease in organs other than the skin, the finding of which would implicate another form of vasculitis (see Fig. 85-5). For example, although hypersensitivity vasculitis can mimic the skin features of microscopic polyangiitis, it does not involve the kidneys, lungs, peripheral nerves, or other internal organs and is not associated with antineutrophil cytoplasmic antibodies. Removal of the inciting agent is the most critical therapy for hypersensitivity vasculitis when the likely agent can be identified. In patients who have been exposed to multiple medications, determining the inciting agent may be difficult and may require the withdrawal of multiple agents simultaneously until the syndrome clears, typically in 1 to 2 weeks. The prognosis for patients with hypersensitivity vasculitis depends on the inciting cause. Treatment with glucocorticoids is reserved for patients with extensive disease and can usually be discontinued within several weeks. Patients who experience repeated disease flares may need low-dose glucocorticoids to prevent recurrences. Colchicine (0.6 mg twice daily) and dapsone (100 mg/day) have also been used successfully in some patients. HENOCH-SCHÖNLEIN PURPURA HSP is an IC-mediated form of small vessel vasculitis that is strongly associated with IgA deposition within blood vessel walls. Many cases of HSP are reported to occur after upper respiratory tract infections. Multiple bacterial, viral, and other infectious agents have been suggested as the cause of HSP, but the true cause remains unknown. The 1990 ACR criteria for the classification of HSP are shown in Table 85-3.8

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Table 85-1  Differential Diagnosis of Immune   Complex–Mediated Vasculitis

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Presentation consistent with small vessel vasculitis

Other Immune Complex–Mediated Vasculitides Hypersensitivity vasculitis Henoch-Schönlein purpura Mixed cryoglobulinemia Urticarial vasculitis Erythema elevatum diutinum Connective tissue disease, rheumatoid vasculitis

History: Recent new medication? Recent infection Risk factor for hepatitis C? Connective tissue disease?

Review of systems and physical examination: Exclude extracutaneous disease

Pauci-Immune Vasculitides Wegener’s granulomatosis Churg-Strauss syndrome Microscopic polyangiitis Miscellaneous Small Vessel Vasculitides Behçet’s disease Malignancy associated Infection Inflammatory bowel disease Vasculitis Mimickers Hemorrhage Pigmented purpuric dermatoses Scurvy Immune thrombocytopenic purpura Thrombosis Antiphospholipid syndrome Thrombotic thrombocytopenic purpura Livedoid vasculopathy (atrophie blanche) Warfarin-induced skin necrosis Purpura fulminans Disseminated intravascular coagulation Embolism Cholesterol emboli Atrial myxoma Vascular wall pathology Calciphylaxis Amyloidosis Infection Infective endocarditis Leprosy (Lucio’s phenomenon)

The hallmarks of HSP include an upper respiratory tract infection followed by a syndrome characterized by a purpuric rash, arthralgias, abdominal pain, and renal disease. HSP is usually viewed as a disease of childhood, and the majority of cases affect children younger than 5 years. However, adults can also be affected by HSP and have a greater tendency toward a prolonged disease course (with recurrent bouts of purpura) than do children.9 Colicky abdominal pain, presumably secondary to gastrointestinal vasculitis, is a common characteristic of HSP and frequently occurs within a week after the onset of rash. Sometimes the gastrointestinal symptoms of HSP precede the onset of purpura, leading to a diagnostic quandary and occasionally to exploratory surgery. Endoscopy may demonstrate purpura in the upper or lower intestinal tract. Mild glomerulonephritis is common and generally self-limited, although some patients develop end-stage renal disease. In children with mild manifestations, the clinical history alone may be sufficient to confirm the diagnosis. In more serious cases (e.g., in the presence of renal involvement) or when there is sufficient doubt about the diagnosis, biopsy of an involved organ is essential. Unlike in other forms of IC-mediated disease, however, DIF reveals florid IgA deposition. In the proper clinical setting, this finding is

Work-up Skin biopsy to comfirm diagnosis

Histology

Bloodwork

Direct immunofluorescence

Chest x-ray Urinalysis UPEP

CBC chemistries ANA and ENAs ANCA RF C3, C4 Cryoglobulins Hepatitis serologies SPEP

Figure 85-5  Diagnostic algorithm for immune complex–mediated small vessel vasculitis. The critical diagnostic test is usually a skin biopsy with hematoxylin and eosin (H&E) staining and direct immunofluorescence. ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; CBC, complete blood count; ENA, extractable nuclear antigen; RF, rheumatoid factor; SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis.

diagnostic of HSP. Other forms of small vessel vasculitis may have small quantities of IgA within blood vessels, but IgA is not the predominant immunoreactant in such cases. In mild cases of HSP, no specific therapy is necessary. Even for patients with glomerulonephritis, it has been difficult to demonstrate that treatment with glucocorticoids or immunosuppressive agents significantly alters the outcome. Despite this, it is prudent to treat aggressive renal involvement with an immunosuppressive regimen, including highdose glucocorticoids and another immunosuppressive agent such as cyclophosphamide, azathioprine, or mycophenolate mofetil, depending on disease severity. Table 85-2  American College of Rheumatology   1990 Criteria* for the Classification of Hypersensitivity   Vasculitis Age >16 yr Use of a possible offending medication in temporal relation to symptoms Palpable purpura Maculopapular rash Biopsy of a skin lesion showing neutrophils around an arteriole or venule *The presence of three or more criteria has a sensitivity of 71% and specificity of 84% for the diagnosis of hypersensitivity vasculitis. From Calabrese LH, Michel BA, Bloch DA, et al: American College of Rheumatology 1990 criteria for the classification of hypersensitivity vasculitis. Arthritis Rheum 33:1108-1113, 1990.

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Table 85-3  American College of Rheumatology 1990   Criteria* for the Classification of Henoch-Schönlein   Purpura

Table 85-4  Chapel Hill Consensus Conference   Definitions of Immune Complex–Mediated   Forms of Vasculitis

Palpable purpura

Disease

Definition

Age at onset <20 yr

Cutaneous leukocytoclastic angiitis

Isolated cutaneous leukocytoclastic angiitis without systemic vasculitis or glomerulonephritis

Henoch-Schönlein purpura

Vasculitis with immunoglobulin A–dominant immune deposits, affecting small blood vessels (capillaries, venules, arterioles); typically involves skin, gut, and glomeruli and is associated with arthralgias or arthritis

Essential cryoglobulinemia

Vasculitis with cryoglobulin immune deposits, affecting small blood vessels (capillaries, venules, arterioles) and ­associated with cryoglobulins in serum; skin and glomeruli often involved

Bowel angina Vessel wall granulocytes on biopsy *The presence of two criteria identified Henoch-Schönlein purpura with a sensitivity of 87% and a specificity of 88% in a group of individuals with forms of systemic vasculitis. From Mills JA, Michel BA, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of Henoch-Schönlein purpura. Arthritis Rheum 33:1114-1121, 1990.

Recurrences of skin disease, often consisting of multiple episodes occurring over many months, are not unusual. ­Generally, however, even in patients with recurrent disease, the rule is for the disorder to subside and to resolve completely over a few months to a year. In a minority of patients, some evidence of permanent renal damage persists in the form of proteinuria and hematuria. Less than 5% of patients develop renal failure as a result of HSP. CRYOGLOBULINEMIC VASCULITIS Cryoglobulins are immunoglobulins characterized by a tendency to precipitate from serum under conditions of cold.10 Such proteins, detectable to a varying degree in a wide array of inflammatory conditions, do not always cause disease. In some patients, however, cryoglobulins bind to circulating antigen (e.g., portions of the hepatitis C virion), deposit in the walls of small and medium-sized blood vessels, and activate complement, leading to cryoglobulinemic vasculitis. In contrast to most other forms of IC-mediated vasculitis, cryoglobulinemia has a tendency to involve mediumsized blood vessels as well as small ones. Thus, the syndrome of cryoglobulinemic vasculitis can be associated with the development of large cutaneous ulcers, digital ischemia, and livedo racemosa—findings characteristic of disturbances in medium-sized vessels. The Chapel Hill Consensus Conference provided a consensus definition for mixed cryoglobulinemia (Table 85-4).1 Three major types of cryoglobulinemia are recognized, defined by the specific kinds of immunoglobulins with which they are associated (Table 85-5). Type I, characterized by a monoclonal gammopathy (generally IgG or IgM),

From Jennette JC, Falk RJ, Andrassy K, et al: Nomenclature of systemic ­vasculitides: Proposal of an international consensus conference. Arthritis Rheum 37:187-192, 1994.

differs substantially from types II and III in its clinical presentation and disease associations. Type I cryoglobulinemia, associated with Waldenström’s macroglobulinemia or, less frequently, multiple myeloma, is more likely to cause syndromes related to hyperviscosity (dizziness, confusion, headache, and stroke) than necrotizing vasculitis. In contrast to the monoclonal nature of type I cryoglobulinemia, types II and III are known as mixed cryoglobulinemias because they are composed of both IgG and IgM. In type II cryoglobulinemia, more than 90% of cases are caused by hepatitis C infection, and the cryoproteins consist of monoclonal IgM and polyclonal IgG. Cases of type II cryoglobulinemia not associated with hepatitis C are sometimes termed mixed essential cryoglobulinemia, because their cause is not known. Type III cryoglobulinemia, typically associated with polyclonal IgG and polyclonal IgM, is associated with many forms of chronic inflammation, including infection and autoimmune disease. Type II and III cryoglobulinemias often present with a triad of signs and symptoms: purpura, arthralgias, and myalgias. The purpura may be extensive and confluent (Fig. 85-6), sometimes involving the trunk, upper extremities, and even the face; in most cases, however, the rash is confined to the lower extremities. Other organ systems commonly involved

Table 85-5  Types of Cryoglobulins Cryoglobulin

RF Positivity

Monoclonality

Associated Diseases

Type I

No

Yes (IgG or IgM)

Hematopoietic malignancy   (multiple myeloma, Waldenström’s macroglobulinemia)

Type II

Yes

Yes (polyclonal IgG, monoclonal IgM)

Hepatitis C Other infection Sjögren’s syndrome SLE

Type III

Yes

No (polyclonal IgG and IgM)

Hepatitis C Other infection Sjögren’s syndrome SLE

Ig, immunoglobulin; RF, rheumatoid factor.

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Figure 85-6  Confluent purpura in mixed cryoglobulinemia. Extensive purpuric lesions are often so numerous that they form confluent areas of cutaneous involvement.

in mixed cryoglobulinemia are the kidneys and peripheral nerves. Mixed cryoglobulinemia may cause a membranoproliferative glomerulonephritis that resembles lupus nephritis histopathologically. It may also cause a vasculitic neuropathy, usually with sensory symptoms predominating over motor symptoms. Skin biopsy is the most straightforward method of confirming the diagnosis. Light microscopy of purpuric lesions demonstrates leukocytoclastic vasculitis. In addition, DIF studies reveal various types of immunoglobulin and complement deposition, depending on the type. In type II cryoglobulinemia, for example, DIF reveals IgG and IgM deposition, as well as complement components. Serologic testing may also yield clues to the presence of mixed cryoglobulinemia. To assay for serum cryoglobulins, the blood is collected in a prewarmed apparatus, allowed to clot at 37°C before processing, and then refrigerated at 4°C for several days. The percentage of the serum occupied by the cryoprecipitate is referred to as the “cryocrit.” The difficulties involved in performing cryoglobulin assays often lead to false-negative results. Nonspecific serologic testing may also implicate mixed cryoglobulinemia. As noted, cryoglobulins detected are not always associated with disease. A strong clue is the presence of an extremely low level of C4, reduced out of proportion to C3. In addition, the monoclonal component of type II cryoglobulins almost invariably has rheumatoid factor activity (i.e., binds to the Fc portion of IgG). Thus, essentially all patients with type II cryoglobulinemia have high titers of rheumatoid factor. As markers of clinical disease activity, C4 levels, rheumatoid factor titers, and cryocrits all fare poorly, often remaining abnormal in the face of clinically improved disease. Treatment of the underlying cause of the cryoglobulins is the only approach that leads to a long-term response. Immunosuppression alone is insufficient to treat cryoglobulinemic vasculitis that is driven by malignancy or chronic infection. In the case of hepatitis C–associated cryoglobulinemic vasculitis, for example, the optimal therapy consists of effective control of the underlying viral infection (typically with interferon-α and ribavirin).11 In patients who experience severe consequences of cryoglobulinemia such

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as ­mononeuritis multiplex, glomerulonephritis, or extensive cutaneous ulceration, immunosuppression with high-dose glucocorticoids and cyclophosphamide may be necessary to prevent further damage. In some cases of active vasculitis, the introduction of antiviral therapy before controlling the inflammation with immunosuppression is believed to trigger disease exacerbation by altering the ­antigen-antibody ratio unfavorably. The prognosis of patients with cryoglobulinemia generally depends on the underlying cause. The outcome of type I cryoglobulinemia relates closely to the success in treating the cause. Type II or III cryoglobulinemia secondary to hepatitis C can be treated effectively if the viral infection is responsive to therapy. If patients do not tolerate antiviral therapy well or if the treatment is ineffective, they may require low to moderate doses of prednisone to control the disease. URTICARIAL VASCULITIS In contrast to common urticaria, the lesions of urticarial vasculitis (UV) last more than 48 hours, do not blanch when pressure is applied to the skin, and may leave postinflammatory hyperpigmentation. Unlike common urticaria, the lesions of UV are frequently associated with moderate pain, burning, and tenderness in addition to pruritus. Whereas common urticaria typically resolves completely within 24 to 48 hours, the lesions of UV may take days to resolve completely, often leaving residual hyperpigmentation; they may worsen without therapy. Three different syndromes of UV are recognized: normocomplementemic UV, hypocomplementemic UV, and the hypocomplementemic urticarial vasculitis syndrome (HUVS). Normocomplementemic UV is typically a selflimited subset of hypersensitivity vasculitis. In chronic cases, normocomplementemic UV must be distinguished carefully from neutrophilic urticaria, a persistent form of urticaria not associated with vasculitis. In contrast, hypocomplementemic UV is more likely to be a chronic disorder that has certain overlapping features with SLE: low serum complements, autoantibodies, and an interface dermatitis characterized by immunoreactant deposition (complement and immunoglobulins) at the dermal-epidermal junction in a pattern essentially identical to the lupus band test. Finally, HUVS is a severe form of the disease associated with extracutaneous disease and an array of organ system findings atypical of SLE.12 For example, HUVS may be associated with uveitis, chronic obstructive pulmonary disease (COPD), and angioedema. The skin lesions in UV tend to be centripetal, favoring the trunk and proximal extremities more than dependent regions. The lesions are painful and associated with a burning sensation rather than the pruritus of common urticaria. Biopsy of an urticarial wheal in UV demonstrates evidence of leukocytoclastic vasculitis, including injury to the endothelial cells of the postcapillary venules, erythrocyte extravasation, leukocytoclasis, fibrin deposition, and a perivascular neutrophilic (or, less commonly, lymphocytic) infiltrate. DIF demonstrates IC deposition around blood vessels in the superficial dermis and a striking deposition of immunoglobulins and complement along the dermalepidermal junction. In the proper setting, these findings

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(interface dermatitis as well as immunoreactant deposition within blood vessels) are diagnostic of hypocomplementemic UV. HUVS, in contrast, is a clinical diagnosis based on the presence of UV and the occurrence of typical features in extracutaneous organ systems. Some cases of hypocomplementemic UV respond to therapies commonly used for the treatment of SLE, including low-dose prednisone, hydroxychloroquine, dapsone, or other immunomodulatory agents. Serious cases of HUVS, particularly those presenting with glomerulonephritis or other forms of serious organ involvement, may require high doses of glucocorticoids and cytotoxic agents. Both COPD and cardiac valve abnormalities are associated with HUVS and may require specific treatment as well. The prognosis of UV is linked to the disorder with which it is associated. SLE, COPD, angioedema, and valvular abnormalities are all known to occur in association with this disorder and may strongly influence both quality and quantity of life. ERYTHEMA ELEVATUM DIUTINUM Erythema elevatum diutinum (EED) is a rare, distinctive form of leukocytoclastic vasculitis limited to the skin. The disorder is distinctive because of the unusual distribution of skin lesions (found symmetrically over the extensor surfaces of joints) and the prompt response to sulfone medications. The cutaneous findings are typical of any small vessel vasculitis, with a predominance of papules, plaques, and nodules. Early lesions are often pink or yellowish and then become red or purple (Fig. 85-7). The natural history of untreated lesions is to persist for years, becoming doughy or hard with time. The lesions have a predilection for the skin overlying

Figure 85-7  Erythema elevatum diutinum. Nodules typically form over the extensor surfaces of the knuckles and other joints.

the small joints of the hands and the knees; they can also affect the buttocks. The trunk is generally spared. The principal histopathologic findings of EED are leukocytoclastic vasculitis with fibrinoid necrosis. Although an IC basis is suspected in this disorder, DIF studies are not distinctive. EED has been associated with various connective tissue diseases (CTDs), rheumatoid arthritis, other forms of vasculitis such as Wegener’s granulomatosis, human immunodeficiency virus infections, and paraproteinemias (particularly IgA). EED typically responds promptly to dapsone or sulfapyridine, but chronic therapy may be required because skin lesions recur after cessation of treatment. CONNECTIVE TISSUE DISEASE–ASSOCIATED VASCULITIS Vasculitis rarely occurs in CTDs without overt manifestations of the underlying disorder. The forms of CTD typically complicated by vasculitis include those related to SLE: lupus itself, mixed CTD, Sjögren’s syndrome, and overlap CTD. Although vasculitis clearly occurs in some CTD settings, it is commonly overdiagnosed to explain perplexing disease features in patients with known rheumatic illnesses. For example, neuropsychiatric SLE is generally not caused by a true vasculitis but rather by other mechanisms that remain poorly defined. Whenever possible, the clinical hypothesis of vasculitis should be confirmed by biopsy. Cutaneous vasculitis in CTDs is associated almost invariably with hypocomplementemia and high titers of antinuclear antibodies (ANAs). DIF examination of skin lesions shows granular IgG and C3 deposition in and around dermal vessels, with or without IgM, reflecting the contribution of ICs to disease pathogenesis. The phenomenon of the “in vivo ANA” is also observed in keratinocytes and dermal cells in DIF studies (Fig. 85-8).13 Vasculitis in patients with SLE-related disorders is more likely than other forms of vasculitis to be associated with a lymphocytic predominance. One variant of CTD-associated cutaneous vasculitis, the so-called benign hypergammaglobulinemia of Waldenström, is usually a true ­lymphocytic

Figure 85-8  Direct immunofluorescence study in connective tissue disease–associated vasculitis, revealing an “in vivo antinuclear antibody” phenomenon. This phenomenon is caused by the binding of immunoreactants to targets within the nuclei of epidermal cells.

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v­ asculitis. Patients with this disorder invariably have anti-Ro antibodies, and many have subclinical Sjögren’s ­syndrome. Lymphocytic vasculitis typically demonstrates less disruption of blood vessel architecture than does leukocytoclastic vasculitis, perhaps because lymphocytes contain fewer of the destructive enzymes found within neutrophil granules. Fibrinoid necrosis, for example, is very rare in lymphocytic vasculitis. True lymphocytic vasculitis is nearly always confined to the small blood vessels of the superficial papillary dermis. RHEUMATOID VASCULITIS Rheumatoid vasculitis (RV) must be distinguished from the isolated digital (periungual) vasculitis that, in the absence of severe involvement, does not require intensive, vasculitisspecific therapy. Isolated digital vasculitis in patients with rheumatoid arthritis, characterized by splinter-like lesions in the periungual region (Bywaters’ lesions), is not necessarily associated with a poorer prognosis than rheumatoid arthritis without digital vasculitic lesions and does not require specific therapy for vasculitis. In contrast, RV is a potentially devastating complication that may involve both medium and small blood vessels and requires the most aggressive therapeutic interventions. Many clinical manifestations of RV are indistinguishable from polyarteritis nodosa, although microaneurysms are less common in RV. RV classically occurs in patients with nodular, rheumatoid factor–positive, joint-destructive disease who have few clinical indications of active synovitis at the time vasculitis begins. However, RV occasionally complicates early disease. The most common presentation of RV includes purpuric lesions with or without evidence of concomitant medium vessel vasculitis. DIF examination of the skin lesions shows granular IgM and C3 deposition in vessels, consistent with an IC-mediated pathophysiology in which rheumatoid ­factor, complement, and cryoglobulins may all participate. Deep cutaneous ulcers near the malleoli are a

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hallmark of RV and require scrupulous local care as well as judicious immunosuppression. Mononeuritis multiplex often ­complicates RV. REFERENCES   1. Jennette JC, Falk RJ, Andrassy K, et al: Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 37:187-192, 1994.   2. Zeek PM: Periarteritis nodosa: A critical review. Am J Clin Pathol 22:777-790, 1952.   3. Arthus M: Injections repetees de serum de cheval cuez le lapin. Seances et Memoire de la Societe de Biologie 55:817-825, 1903.   4. Nangaku M, Couser WG: Mechanisms of immune-deposit formation and the mediation of immune renal injury. Clin Exp Nephrol 9: 183-191, 2005.   5. Ramos-Casals M, Anaya JM, Garcia-Carrasco M, et al: Cutaneous vasculitis in primary Sjogren syndrome: Classification and clinical significance of 52 patients. Medicine (Baltimore) 83:96, 2004.   6. Hunder GG, Arend WP, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of vasculitis: Introduction. Arthritis Rheum 33:1065-1067, 1990.   7. Calabrese LH, Michel BA, Bloch DA, et al: American College of Rheumatology 1990 criteria for the classification of hypersensitivity vasculitis. Arthritis Rheum 33:1108-1113, 1990.   8. Mills JA, Michel BA, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of HenochSchönlein purpura. Arthritis Rheum 33:1114-1121, 1990.   9. Blanco R, Martinez-Taboada VM, Rodriguez-Valverde V, et al: Henoch-Schonlein purpura in adulthood and childhood: Two different expressions of the same syndrome. Arthritis Rheum 40:859-864, 1997. 10. Wintrobe MM, Buell MV: Hyperproteinemia associated with multiple myeloma: With report of a case in which an extraordinary hyperproteinemia was associated with thrombosis of the retinal veins and symptoms suggesting Raynaud’s disease. Bull Johns Hopkins Hosp 52:156, 1933. 11. Ferri C, Mascia MT: Cryoglobulinemic vasculitis. Curr Opin Rheumatol 18:54-63, 2006. 12. Davis MD, Brewer JD: Urticarial vasculitis and hypocomplementemic urticarial vasculitis syndrome. Immunol Allergy Clin North Am 24: 183-213, 2004. 13. Wahl CE, Bouldin MB, Gibson LE: Erythema elevatum diutinum: Clinical, histopathologic, and immunohistochemical characteristics of six patients. Am J Dermatopathol 27:397-400, 2005.

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Behçet’s Disease B. Asher Louden  •  Joseph L. Jorizzo

KEY POINTS

GENETICS

Behçet’s disease is a complex multisystem disease characterized by oral aphthae and other features.

A familial pattern of Behçet’s disease has been reported, but there are regional differences throughout the world. Familial occurrence is more common in Korea, Israel, Turkey, and Arab countries, compared with Japan, China, and Europe.7 Studies have shown a significant association between the human leukocyte antigen (HLA)-B51 and Behçet’s disease.8,9 The relative risk of HLA-B51–positive individuals’ developing Behçet’s disease varies, depending on geographic region.7 The causative role of HLA-B51 in Behçet’s remains unclear. It may be that HLA-B51 is not directly involved in causing the disease but is closely linked to disease-related genes.10 Candidate genes have been localized to chromosome 6 and include the major histocompatibility complex class I chain-related gene A (MICA) and, more specifically, the MICA6 allele; perth block (PERB); new organization associated with HLA-B (NOB); and transporter associated with antigen processing genes (TAP).10,11 Although Behçet’s disease has many features in common with the spondyloarthropathies, especially those associated with inflammatory bowel disease (IBD), the disorder in IBD patients generally evolves in a pattern resembling reactive arthritis, with an erosive axial arthritis; erosive arthritis and HLA-B27 are not associated with Behçet’s disease.12 Patients who are HLA-DR1 and HLA-DQw1 positive may have an innate resistance to the development of Behçet’s disease.13

Diagnosis is based on the criteria set forth by the International Study Group, including oral aphthae, genital aphthae, ocular lesions, cutaneous lesions, and a positive pathergy test. Cutaneous lesions should display a neutrophilic vascular ­reaction on histopathologic examination. Treatment is based on the degree of systemic involvement and ranges from topical corticosteroids to thalidomide to systemic immunosuppressive agents and tumor necrosis factor-α inhibitors. Prognosis is variable, and patients typically have periods of exacerbations and remissions.

Behçet’s disease is a chronic, complex multisystem disease characterized clinically by oral aphthae and at least two of the following: genital aphthae, cutaneous lesions, and ophthalmic, neurologic, or rheumatologic manifestations. The first description of Behçet’s disease was probably by Hippocrates in the fifth century bc,1 and the first modern account was presented in 1937 by the Turkish dermatologist Hulusi Behçet, who reported on a patient with recurrent oral and genital aphthae and uveitis.2

EPIDEMIOLOGY Behçet’s disease is seen worldwide, with the highest prevalence reported in Turkey (80 to 370 patients per 100,000 inhabitants)3 and Japan (13.6 per 100,000).4 Other regions with high prevalence include the Middle East and the Mediterranean (i.e., the “Silk Route”).5 It is relatively uncommon in northern Europe and the United States (0.1 to 7.5 patients per 100,000 inhabitants).3,5 Patients commonly fulfill the diagnostic criteria in their mid-20s to 30s.6 In the past, Behçet’s disease was thought to predominantly affect males, but current epidemiologic data show a more equal male-to-female ratio.7 Overall, males are more affected in the Middle East, whereas females predominate in northern Europe and the United States.7

CAUSE AND PATHOGENESIS Although the pathogenesis of Behçet’s disease remains unclear, many factors have been implicated. Heredity, immunologic factors, infectious agents, and inflammatory mediators likely contribute.

IMMUNE MECHANISMS Immune mechanisms play a major role in Behçet’s disease. Heat shock proteins, cytokines, alterations in neutrophil and macrophage activity, and autoimmune mechanisms have all been implicated.10 Heat shock proteins are released in response to stress and may be involved in stimulating a T helper type 1 immune response through interaction with Toll-like receptors.14 Most of the T lymphocytes thought to be involved in this reaction are of the γδ type.15 Cytokines such as interleukin (IL)-1, IL-8, and tumor necrosis factor-α (TNF-α) seem to be involved in the pathogenesis, and elevated levels may be a marker of disease activity.10 It should be appreciated, however, that plasma TNF-α levels may rise and fall as an acute-phase reactant along with C-reactive protein and the erythrocyte sedimentation rate. The production of these proinflammatory cytokines, which are responsible for the chronic inflammation observed, may be the result of activated macrophages.10,16 In addition to macrophage activation, neutrophil chemotaxis and phagocytosis are increased in the lesions of Behçet’s disease.10,17 This increased activity of neutrophils leads to tissue injury in the form of the neutrophilic vascular reaction seen in lesions, such as aphthae, pustular cutaneous lesions, and erythema 1475

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nodosum–like lesions. Circulating immune complexes also play a role in precipitating the characteristic neutrophilic vascular reaction.18 Finally, the role of endothelial cell dysfunction in the pathogenesis of Behçet’s disease has been suggested by decreased levels of prostacyclin in the serum of Behçet’s disease patients. Other abnormalities in the endothelium and in clotting factors have also been found.19 INFECTIOUS AGENTS Several studies have suggested a role for various infectious agents in the pathogenesis of Behçet’s disease; however, no organisms have been consistently isolated. Antistreptococcal antibodies have been isolated in the serum of patients with Behçet’s disease.20 Higher concentrations of Streptococcus sanguis have also been found in the oral flora of patients with Behçet’s disease and may play a role in the development of aphthae, which is often the initial manifestation.21 In addition to streptococcal antigens, other bacteria such as Escherichia coli and Staphylococcus aureus may have a role in Behçet’s disease through the activation of lymphocytes.22 Herpes simplex virus (HSV) DNA has been isolated from the nuclei of peripheral blood lymphocytes by polymerase chain reaction (PCR) assay in patients with Behçet’s disease.13 HSV has also been detected by PCR in biopsy samples of genital and intestinal ulcers of Behçet’s patients.22 Other studies, however, have shown no difference in the detection of HSV in Behçet’s patients with and without oral aphthae.23 In summary, although the cause and pathogenesis of Behçet’s disease are not completely understood, they likely involve an infectious or environmental trigger and subsequent inflammatory response in a genetically predisposed individual. The recent article by Zouboulis and May10 provides an excellent overview of the pathogenesis of Behçet’s disease.

CLINICAL FEATURES APHTHAE Oral aphthae, or canker sores (Fig. 86-1), are often the initial feature of Behçet’s disease and constitute a requisite diagnostic feature (although it should be pointed out that a ­number of investigators believe that this disease can occur in

Figure 86-1  Oral aphtha.

the absence of oral aphthae). Oral ulcerations usually occur in crops of more than 3 to 10s of lesions, but individual lesions may occur on the buccal mucosa, gingiva, lips, and tongue. Aphthae tend to be painful and shallow, and they heal without scarring over 1 to 3 weeks.24 Genital ulcers typically occur on the scrotum and penis in males and on the vulva or vaginal mucosa in females. These aphthae are similar in appearance to oral lesions, but they have a greater tendency to scar and may recur less frequently.24 Lesions in the oral mucosa are generally easy to distinguish from oral HSV, but with genital lesions, HSV should be excluded by viral culture or PCR before they are accepted as a diagnostic criterion. CUTANEOUS LESIONS Several cutaneous manifestations of Behçet’s disease have been described: erythema nodosum–like lesions, pyoderma gangrenosum–like lesions, Sweet’s syndrome–like lesions, cutaneous small vessel vasculitis, and pustular vasculitic lesions (Fig. 86-2), including lesions induced by trauma—the so-called pathergy lesion.24 Specimens from all these lesions demonstrate a neutrophilic vascular reaction on histopathologic analysis.25 Acneiform or pseudofolliculitis lesions should be considered nonspecific, nondiagnostic findings because of their common occurrence in acne vulgaris and folliculitis. OPHTHALMIC FEATURES A variety of ocular manifestations have been reported in Behçet’s patients, including anterior and posterior uveitis, retinal vasculitis, and hypopyon, with secondary glaucoma, cataract formation, decreased visual acuity, and synechiae formation.26 Ocular involvement occurs in 83% to 95% of men and 67% to 73% of women with Behçet’s disease.26 Although ocular involvement is not commonly the presenting feature of Behçet’s disease, it is a major source of serious morbidity, and close ophthalmologic evaluation and follow-up are critical to prevent blindness in these patients.27 BenEzra and Cohen28 suggested that if ocular disease does not present within a few years of diagnosis, it is unlikely to be a major problem.

Figure 86-2  Pustular vasculitis lesions representing a neutrophilic ­vascular reaction.

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HISTOPATHOLOGY

The arthritis of Behçet’s disease is typically a nonerosive, inflammatory, symmetric or asymmetric oligoarthritis, although polyarticular and monarticular forms are also seen. The most commonly involved joints are the knees, wrists, ankles, and elbows.29 The prevalence of arthritis among different populations ranges from 40% to 60%, and joint erosions are not observed.27 Dilsen and colleagues30 reported that 10% of patients with Behçet’s disease had a sacroiliitis. However, HLAB27–positive patients were not excluded from their series, and occult IBD was not excluded, as required by O’Duffy.40 Other studies have shown no significant difference in the occurrence of sacroiliitis between patients with Behçet’s disease and the normal population. HLA-B27–positive patients with erosive sacroiliitis should be included in the Reiter’s syndrome or enteropathic ­arthritis disease spectrum, given the erosive, axial nature of the arthritis in the HLA-B27 pattern. This contrasts with the classically nonerosive, nonaxial nature of the arthritis in Behçet’s disease. Oral aphthae, ocular lesions, erythema nodosum–like lesions, pustular vasculitis, and pyoderma gangrenosum all occur in patients with IBD.

Histopathologic analysis of specimens from the cutaneous lesions seen in Behçet’s disease reveals a neutrophilic vascular reaction or even fully developed leukocytoclastic vasculitis. Microscopic examination of dermal capillary or venule walls shows neutrophilic infiltrates, nuclear dust, and extravasation of erythrocytes, with or without fibrinoid necrosis.37 Immune complex–mediated vasculitis is the likely mechanism in the development of Behçet’s disease.38 A previously reported finding of lymphocytic vasculitis in patients with Behçet’s disease is thought to represent an older lesion.25 Biopsy specimens of synovial membranes reveal a neutrophilic reaction, with occasional plasma cells and lymphocytes. Immunofluorescence microscopy may show immunoglobulin G (IgG) deposition along the synovial membrane.27 Reports of synovial fluid analysis in patients with Behçet’s disease show leukocyte counts ranging from 300 to 36,200 cells/mm3, with a predominance of neutrophils and normal glucose levels.39 Synovitis is included as one of the O’Duffy-Goldstein criteria for the diagnosis of Behçet’s disease.40

OTHER SYSTEMIC MANIFESTATIONS Central nervous system involvement is most commonly characterized by brainstem or corticospinal tract syndromes (neuro-Behçet’s syndrome), venous sinus thrombosis, increased intracranial pressure secondary to venous sinus thrombosis or aseptic meningitis, isolated behavioral symptoms, or isolated headache.31 Rarely, ruptured aneurysms, peripheral neuropathy, optic neuritis, and vestibular involvement can occur.31 Poor prognosis is associated with a progressive course, parenchymal or brainstem involvement, and cerebrospinal fluid abnormalities.32 Cranial and peripheral nerve involvement may also occur. Patients with Behçet’s disease may have gastrointestinal lesions resembling orogenital aphthae. These occur most commonly in the ileocecal region and in the ascending colon, transverse colon, or esophagus.33 Large aphthae may lead to perforation. Presenting symptoms include abdominal pain, diarrhea, and melena. It is important to distinguish IBD from Behçet’s disease (discussed later).33 Aphthae may also affect the bladder. Pulmonary abnormalities are uncommon in Behçet’s disease. Pulmonary artery aneurysms occur most frequently, followed by other complications secondary to vasculitis affecting the small pulmonary vessels. Aneurysm, thrombosis, hemorrhage, and infarction can result34 and can cause death in patients with Behçet’s disease. Renal manifestations vary from minimal changes to proliferative glomerulonephritis and rapidly progressive crescentic glomerulonephritis. The pathogenesis likely involves immune complex deposition.35 Cardiac complications include myocardial infarction, pericarditis, arterial and venous thromboses, and aneurysm formation. Thromboses more commonly involve the venous system, sometimes leading to superior and inferior vena cava obstruction.25 Cardiac manifestations, either occlusive or aneurysmal, are postulated to occur due to a vasculitis of the vasa vasorum, which induces a thickening of the media and splitting of elastic fibers.36

DIAGNOSIS The diagnosis of Behçet’s disease can be difficult to confirm, particularly in patients with only a limited number of common features of the disease. Clinicians and investigators must rely on clinical criteria, because there are no pathognomonic laboratory findings. Several sets of diagnostic criteria have been proposed, including those by O’Duffy and Goldstein,40 Mason and Barnes,41 and a Japanese study group.42 In 1990, the International Study Group established a set of criteria based on the presence of recurrent oral aphthae and two additional findings from the following list: recurrent genital aphthae, cutaneous lesions, ocular involvement, and a positive pathergy test result (Table 86-1).43 These criteria were found to have a sensitivity of 91% and a specificity of 96%.43 Although not required by the International Study Group criteria, IBD, systemic lupus erythematosus, Reiter’s syndrome, and herpetic infections should first be excluded, because the presenting manifestations of these conditions are often similar to those of Behçet’s disease. Recurrent aphthous stomatitis and complex aphthosis, defined as recurrent oral and genital aphthae or almost constant, multiple (three or more) oral aphthae, should also be considered in the differential diagnosis of patients presenting with oral or genital aphthae.44 The O’Duffy-Goldstein criteria mandate the presence of recurrent oral aphthae plus at least two of the following:­ genital­ aphthae, synovitis, posterior uveitis, cutaneous pustular­ vasculitis, and meningoencephalitis. Patients who have only two of these findings, one being recurrent­ oral aphthae, are considered to have an incomplete form of Behçet’s disease. Another concern with regard to the International­ Study Group criteria is the inclusion of acneiform­ lesions, which are a common nonspecific finding­ in both adolescents and adults. Therefore, our group advocates­ histologic confirmation of vessel-based histology to exclude acne lesions and the use of both the O’Duffy and the international­ Study Group criteria to exclude patients with IBD and enteropathic arthritis.45

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Table 86-1  International Study Group Criteria   for the Diagnosis of Behçet’s Disease*

Recurrent oral aphthae (> 3 episodes/year)

Recurrent Oral Ulceration Minor aphthous, major aphthous, or herpetiform ulceration ­observed by physician or patient that recurred at least three   times in one 12-month period Plus two of the following criteria:

History and physical examination

Recurrent Genital Ulceration Aphthous ulceration or scarring observed by physician or patient Eye Lesions Anterior uveitis, posterior uveitis, or cells in vitreous on slit-lamp examination or Retinal vasculitis observed by ophthalmologist Skin Lesions Erythema nodosum observed by physician or patient, pseudofolliculitis, or papulopustular lesions or Acneiform nodules observed by physician in postadolescent ­patients not on corticosteroid treatment

Genital aphthae Evaluation for HSV via PCR and/or culture

*Findings applicable only in the absence of other clinical explanations. Data from International Study Group for Behçet’s Disease: Criteria for the diagnosis of Behçet’s disease. Lancet 335:1078-1080, 1990.

The initial evaluation should include referral for ophthalmologic consultation to identify insidious ocular involvement. Patients who have arthralgias, gastrointestinal symptoms, or neurologic abnormalities may require radiographic studies and evaluation by appropriate subspecialists. Cutaneous pustular lesions, erythema nodosum–like lesions, and pyoderma gangrenosum–like lesions should be biopsied (for both histologic evaluation and culture) to confirm the clinical diagnosis. A diagnostic algorithm for patients presenting with characteristic oral aphthae is presented in Figure 86-3.

TREATMENT Therapeutic options should be based on the degree of systemic involvement (Table 86-2).24 MUCOCUTANEOUS DISEASE Patients with oral and genital aphthae can be treated with intralesional, superpotent topical or aerosolized (not inhaled) corticosteroids. Topical tacrolimus can also be used, often in combination with superpotent topical corticosteroids. Other palliative therapies include oral tetracycline solutions, topical anesthetics, and rinses containing chlorhexidine gluconate. Oral colchicine, 0.6 mg two to three times daily, can decrease the size and frequency of mucocutaneous lesions.46,47 Doses can be adjusted according to the degree of gastrointestinal upset experienced by the patient. Dapsone in a dose of 50 to 150 mg/day is often helpful alone48 or in combination with colchicine.44 Patients must be monitored for the development of hemolytic anemia and methemoglobinemia; the glucose-6-phosphate dehydrogenase level should be checked in all patients before beginning therapy with dapsone.

Exclude other diagnoses: IBD Cyclic neutropenia Vitamin deficiencies (e.g., iron, folate, B12)

-

+ Herpes simplex management

Positive Result on Pathergy Testing Read by physician at 24 to 48 hr Yes

No

Yes Diagnostic criteria for Behçet’s disease (Table 86-1)?

No (i.e., other diagnoses are formed)

Treat accordingly

No Refer to therapeutic ladder for treatment (Table 86-2) and referral to appropriate subspecialists

Recurrent aphthous stomatitis vs. complex aphthosis (almost constant, > 3 oral aphthae, or recurrent oral and genital aphthae)

Figure 86-3  Diagnostic algorithm for patients presenting with characteristic oral aphthae. HSV, herpes simplex virus; IBD, inflammatory bowel disease; PCR, polymerase chain reaction.

SEVERE MUCOCUTANEOUS DISEASE Patients who fail to respond to conservative therapy as outlined for mucocutaneous disease may require thalidomide. Its mechanism of action is thought to be mediated by modulation of TNF-α and other cytokines. Previous studies have shown that thalidomide is a relatively safe and effective agent for the treatment of Behçet’s disease.49,50 Thalidomide is known to cause severe birth defects, and all patients and prescribing physicians must adhere to the System for Thalidomide Education and Prescribing Safety (STEPS) protocol, including monthly follow-up visits.51 Patients receiving thalidomide can be monitored with nerve conduction studies for the development of peripheral neuropathy, if doing so is warranted based on the clinical neurologic evaluation. Low-dose oral methotrexate (2.5 to 25 mg/wk) and low-dose prednisone are alternatives for patients with severe mucocutaneous involvement.47,52 Patients receiving methotrexate should be monitored for the development of hepatotoxicity and leukopenia. The risk of rebound upon the tapering or discontinuation of systemic prednisone greatly limits its use for mucocutaneous disease alone. In addition, interferon-α is effective for severe mucocutaneous lesions and some systemic manifestions.53,54 A review of the safety and efficacy of interferon-α by Zouboulis and Orfanos53 recommended a 3-month high-dose regimen of 9 million units three times per week, followed by a low, maintenance dose of 3 million units three times per week.

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Table 86-2  Treatment of Behçet’s Disease Mucocutaneous Disease Only Topical, intralesional, or aerosolized corticosteroids Topical sucralfate Local anesthetics Topical tacrolimus Colchicine (0.6-1.8 mg/day) Dapsone (50-150 mg/day) Combinations of these agents Severe Mucocutaneous Disease Thalidomide (50-150 mg/day) Methotrexate (2.5-25 mg/wk) Prednisone Interferon-α (3 million-9 million U/wk) Systemic Disease Prednisone Azathioprine (50-200 mg bid) Chlorambucil (4-6 mg/day) Cyclophosphamide Cyclosporine Mycophenolate mofetil (1-1.5 g bid) Intravenous immunoglobulin Anti–TNF-α agents (adalimumab, etanercept, infliximab)

SYSTEMIC DISEASE Patients with systemic disease, such as ocular and cardiovascular abnormalities, require immunosuppressive therapy, particularly in view of the risk of morbidity and mortality resulting from untreated disease. Systemic corticosteroids may be used alone or in combination with other immunosuppressive agents such as azathioprine, interferon-α, cyclosporine, cyclophosphamide, and chlorambucil.47,55 The standard of care for eye disease is prednisone plus azathioprine.56 If this combination is not successful, one of the aforementioned immunosuppressive agents can be substituted for azathioprine.55 Several of these immunosuppressive agents have associated hematologic toxicity, as well as the potential for the development of associated malignancies; therefore, close monitoring is essential. There have also been reports of Behçet’s disease treated with anti–TNFα agents. A double-blind, placebo-controlled trial showed that etanercept was successful in suppressing most of the mucocutaneous manifestations of Behçet’s disease.57 Other reports support the efficacy of adalimumab and infliximab.58,59 Larger studies looking at the long-term efficacy and safety of these agents are in progress.

PROGNOSIS Behçet’s disease has a variable clinical course in most patients, with a pattern of exacerbations and remissions. A delay in diagnosis after the initial manifestation of Behçet’s disease is not uncommon. Most patients present initially with mucocutaneous manifestations, and evidence of ocular and neurologic involvement may appear several years after diagnosis. Patients with the finding of complex aphthosis may represent a forme fruste of Behçet’s disease, and they should be monitored for the development of additional abnormalities fulfilling the diagnostic criteria through regular follow-up and referral to appropriate specialists.44 Mortality in Behçet’s disease is low and is usually related to pulmonary or central nervous system involvement or to

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bowel perforation.7 The most common cause of morbidity is ocular involvement; manifestations such as posterior uveitis and retinal vasculitis can cause blindness. REFERENCES   1. Feigenbaum A: Description of Behçet’s syndrome in the Hippocratic third book of endemic diseases. Br J Ophthalmol 40:355, 1956.   2. Behçet H: Uber rezidivierende Aphthose durch ein Virus verursachte Geschwure am Mund, am Auge, und an den Genitalien. Dermatol Wochenschr 105:1152-1157, 1937.   3. Zoubloulis CC: Epidemiology of Adamantiades-Behçet’s disease [abstract]. Ann Med Interne (Paris) 150:488-498, 1999.   4. Kontogiannis V, Powell RJ: Behçet’s disease. Postgrad Med J 76: 629-637, 2000.   5. Dilsen N: History and development of Behçet’s disease [abstract]. Rev Rhum Engl Ed 63:512-519, 1996.   6. Hegab S, Al-Mutawa S: Immunopathogenesis of Behçet’s disease. Clin Immunol 96:174-186, 2000.   7. Zouboulis CC: Epidemiology of Adamantiades-Behçet’s disease. In Bang D, Lang E-S, Lee S (eds): Behçet’s Disease: Proceedings of the 8th and 9th International Conference on Behçet’s Disease. Seoul, Design Mecca, 2000, pp 43-47.   8. Yazici H, Chamberlain MA, Schreuder I, et al: HLA antigens in Behçet’s disease: A reappraisal by a comparative study of Turkish and British patients. Ann Rheum Dis 39:344-348, 1980.   9. Ohno S, Ohguchi M, Hirose S, et al: Close association of HLA-BW51 with Behçet’s disease. Arch Ophthalmol 100:1455-1458, 1982. 10. Zouboulis CC, May T: Pathogenesis of Adamantiades-Behçet’s ­disease. Adv Exp Med Biol 528:161-171, 2003. 11. Zierhut M, Mizuki N, Ohno S, et al: Immunology and functional genomics of Behçet’s disease. Cell Mol Life Sci 60:1903-1922, 2003. 12. O’Duffy JD, Taswell HF, Elveback LR: HLA antigens in Behçet’s ­disease. J Rheumatol 3:1-3, 1976. 13. Jorizzo JL: Behçet’s disease: An update based on the 1985 ­International Conference in London. Arch Dermatol 122:556-558, 1986. 14. Direskeneli H, Saruhan-Direskeneli G: The role of heat shock ­proteins in Behçet’s disease. Clin Exp Rheumatol 21(4 Suppl 30):S44-S48, 2003. 15. Hasan A, Fortune F, Wilson A, et al: Role of gamma delta T cells in the pathogenesis and diagnosis of Behçet’s disease. Lancet 347: 789-794, 1996. 16. Sahin S, Lawrence R, Direskeneli H, et al: Monocyte activity in Behçet’s disease. Br J Rheumatol 35:424-429, 1996. 17. Takeno M, Kariyone A, Yamashita N, et al: Excessive function of peripheral blood neutrophils from patients with Behçet’s disease and from HLA-B51 transgenic mice. Arthritis Rheum 38:426-433, 1955. 18. Gupta RC, O’Duffy JD, McDuffie FC, et al: Circulating immune complexes in active Behçet’s disease. Clin Exp Immunol 34:213-218, 1978. 19. Saylan T, Mat C, Fresko I, et al: Behçet’s disease in the Middle East. Clin Dermatol 17:209-223, 1999. 20. Mizushima Y: Behçet’s disease. Curr Opin Rheumatol 3:32-35, 1991. 21. Isogai E, Ohno S, Kotake S, et al: Chemiluminescence of ­neutrophils from patients with Behçet’s disease and its correlation with an increased proportion of uncommon serotypes of Streptococcus sanguis in the oral flora. Arch Oral Biol 35:43-48, 1990. 22. Direskeneli H: Behçet’s disease: Infectious aetiology, new ­autoantigens, and HLA-B51. Ann Rheum Dis 60:996-1002, 2001. 23. Lee S, Bang D, Cho YH: Polymerase chain reaction reveals herpes simplex virus DNA in saliva of patients with Behçet’s disease. Arch Dermatol Res 288:179-183, 1996. 24. Ghate JV, Jorizzo JL: Behçet’s disease and complex aphthosis. J Am Acad Dermatol 40:1-8, 1999. 25. Jorizzo JL, Abernethy JL, White WL, et al: Mucocutaneous criteria for the diagnosis of Behçet’s disease: An analysis of clinicopathologic data from multiple international centers. J Am Acad Dermatol 32:968-976, 1995. 26. Bhisitkul RB, Foster CS: Diagnosis and ophthalmological features of Behçet’s disease. Int Ophthalmol Clin 36:127-134, 1996. 27. Kaklamani VG, Vaiopoulos G, Kaklamanis PG: Behçet’s disease. Semin Arthritis Rheum 27:197-215, 1998. 28. BenEzra D, Cohen E: Treatment and visual prognosis in Behçet’s ­disease. Br J Ophthalmol 70:589-592, 1986.

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29. Moral F, Hamuryudan V, Yurdakul S, et al: Inefficacy of azapropazone in the acute arthritis of Behçet’s syndrome: A randomized, double blind, placebo controlled study. Clin Exp Rheumatol 13:493-495, 1995. 30. Dilsen N, Konice M, Aral O: Why Behçet’s disease should be accepted as a seronegative arthritis. In Lehner T, Barnes CG (eds): Recent Advances in Behçet’s Disease. International Congress and Symposium Series no. 103. London, Royal Society of Medicine Services, 1986, pp 281-284. 31. Siva A, Kantarci OH, Saip S, et al: Behçet’s disease: Diagnostic and prognostic aspects of neurological involvement. J Neurol 248:95-103, 2001. 32. Akman-Demir G, Serdaroglu P, Tasçi B (Neuro-Behçet Study Group): Clinical patterns of neurological involvement in Behçet’s ­ disease: Evaluation of 200 patients. Brain 122:2171-2181, 1999. 33. Sakane T, Takeno M, Suzuki N, et al: Behçet’s disease. N Engl J Med 341:1284-1291, 1999. 34. Uzun O, Akpolat T, Erkan L: Pulmonary vasculitis in Behçet’s disease. Chest 127:2243-2253, 2005. 35. El Ramahi KM, Al Dalaan A, Al Shaikh A, et al: Renal involvement in Behçet’s disease: Review of 9 cases. J Rheumatol 25:2254-2260, 1998. 36. Du LTH, Wechsler B, Piette J, et al: Long-term prognosis of arterial lesions in Behçet’s disease. In Wechsler B, Godeau P (eds): Behçet’s Disease: Proceedings of the 6th International Conference on Behçet’s Disease. Paris, France, 30 June-1 July, 1993. Amsterdam, Elsevier ­Science, 1993, pp 557-562. 37. Ackerman AB: Behçet’s disease. In Ackerman AB, Chongchitnant N, Sanchez J, et al (eds): Histologic Diagnosis of Inflammatory Skin Diseases: An Algorithmic Method Based on Pattern Analysis, 2nd ed. Baltimore, Williams & Wilkins, 1997, pp 229-232. 38. Lakhanpal S, Tani K, Lie JT, et al: Pathologic features of Behçet’s syndrome: A review of Japanese autopsy registry data. Hum Pathol 16:790, 1985. 39. Yurdakul S, Yazici H, Tuzun Y, et al: The arthritis of Behçet’s disease: A prospective study. Ann Rheum Dis 42:505-515, 1983. 40. O’Duffy JD, Goldstein NP: Neurologic involvement in seven patients with Behçet’s disease. Am J Med 61:17-18, 1976. 41. Mason RM, Barnes CG: Behçet’s syndrome with arthritis. Ann Rheum Dis 28:95-103, 1969. 42. Behçet’s Disease Research Committee of Japan: Behçet’s disease: A guide to diagnosis of Behçet’s disease. Jpn J Ophthalmol 18:291-294, 1974. 43. International Study Group for Behçet’s Disease: Criteria for the ­diagnosis of Behçet’s disease. Lancet 335:1078-1080, 1990.

44. Letsinger JA, McCarty MA, Jorizzo JL: Complex aphthosis: A large case series with evaluation algorithm and therapeutic ladder from topicals to thalidomide. J Am Acad Dermatol 52:500-508, 2005. 45. Jorizzo JL: Behçet’s disease. In Fitzpatrick TB, Eisen AZ, Wolff K, et al (eds): Dermatology in General Medicine, 5th ed. New York, McGrawHill, 1999, pp 2161-2165. 46. Yurdakul S, Mat C, Tuzun Y, et al: A double-blind trial of colchicine in Behçet’s syndrome. Arthritis Rheum 44:2686-2692, 2001. 47. Kaklamani VG, Kaklamanis PG: Treatment of Behçet’s disease: An update. Semin Arthritis Rheum 30:299-312, 2001. 48. Sharquie KE, Najim RA, Abu-Raghif AR: Dapsone in Behçet’s ­disease: A double-blind, placebo-controlled, cross-over study. J Dermatol 29:267-279, 2002. 49. Hamuryudan V, Mat C, Saip S, et al: Thalidomide in the treatment of the mucocutaneous lesions of Behçet’s syndrome: A randomized double-blinded, placebo controlled trial. Ann Intern Med 128: 443-450, 1998. 50. De Wazieres B, Gil H, Vuitton DA, et al: Treatment of recurrent orogenital ulceration with low doses of thalidomide. Clin Exp Rheumatol 17:393, 1999. 51. Housman TS, Jorizzo JL, McCarty AM, et al: Low-dose thalidomide therapy for refractory cutaneous lesions of lupus erythematosus. Arch Dermatol 139:50-54, 2003. 52. Jorizzo JL, White WL, Wise CM, et al: Low-dose weekly methotrexate for unusual neutrophilic vascular reactions: Cutaneous polyarteritis nodosa and Behçet’s disease. J Am Acad Dermatol 24:973-978, 1991. 53. Zouboulis CC, Orfanos CE: Treatment of Adamantiades-Behçet disease with systemic interferon alpha. Arch Dermatol 134:1010-1016, 1998. 54. O’Duffy JD, Calamia K, Cohen S, et al: Alpha interferon treatment of Behçet’s disease. J Rheumatol 25:1938-1944, 1998. 55. Green JJ, Jorizzo JL: Behçet disease. In Lebwohl M, Heymann WR, Berth-Jones J, Coulson I (eds): Treatment of Skin Disease: ­Comprehensive Therapeutic Strategies, 1st ed. London, Harcourt, 2002, pp 86-89. 56. Yazici H, Pazarli H, Barnes CG, et al: A controlled trial of azathioprine in Behçet syndrome. N Engl J Med 322:281-285, 1990. 57. Melikoglu M, Fresko I, Mat C, et al: Short-term trial of etanercept in Behçet’s disease: A double blind, placebo controlled study. J Rheumatol 32:98-105, 2005. 58. Alexis AF, Strober BE: Off-label dermatologic uses of anti-TNF-α therapies. J Cutan Med Surg 9:296-302, 2005. 59. Van Laar JA, Missotten T, van Daele PL, et al: Adalimumab; a new modality for Behçet’s disease? ARD Online First 1-8, 2006. Available at http://ard.bmj.com.

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Gout and Hyperuricemia Robert l. wortmann

KEY POINTS Hyperuricemia is defined as a serum urate level greater than 6.8 mg/dL. Acute gouty arthritis can be treated with nonsteroidal antiinflammatory drugs (NSAIDs), colchicine, corticosteroids, or adrenocorticotropic hormone. The effectiveness of treatment depends more on how quickly the therapy is initiated than which agent is used. Before starting a specific urate-lowering agent, the patient should be treated with low-dose colchicine or NSAID in an attempt to prevent further attacks. Regardless of whether a xanthine oxidase inhibitor or uricosuric agent is used to treat hyperuricemia, the patient should receive the lowest dose that maintains the serum urate level below 6.8 mg/dL—preferably between 5 and 6 mg/dL. Individuals who are hyperuricemic should be screened for hypertension, coronary artery disease, diabetes, obesity, and alcoholism. Using a specific urate-lowering agent to manage asymptomatic hyperuricemia is not recommended. However, associated conditions such as hypertension, coronary artery disease, diabetes, obesity, and alcoholism should be managed in these patients as well as in those with symptomatic gout.

Gout has been called the “king of diseases” and the “disease of kings.” Today, the term gout is used to represent a heterogeneous group of diseases found exclusively in humans that include the following characteristics: • Elevated serum urate concentration (hyperuricemia) • Recurrent attacks of acute arthritis in which monosodium urate monohydrate crystals are demonstrable in synovial fluid leukocytes • Aggregates of sodium urate monohydrate crystals (tophi) deposited chiefly in and around joints, which sometimes lead to deformity and crippling • Renal disease involving glomerular, tubular, and interstitial tissues and blood vessels • Uric acid nephrolithiasis These manifestations can occur in various combinations.1,2   Video available on the Expert Consult Premium Edition website.

Hyperuricemia denotes an elevated level of urate in the blood. This occurs in an absolute (or physiochemical) sense when the serum urate concentration exceeds the limit of solubility of monosodium urate in the serum, which is 6.8 mg/dL at 37°C. Thus, a value greater than 6.8 mg/dL indicates supersaturation of body fluids. The serum urate concentration is elevated in a relative sense when it exceeds the upper limit of an arbitrary normal range, which is usually defined as the mean serum urate value plus two standard deviations in a sex- and age-matched healthy population. In most epidemiologic studies, the upper limit has been rounded off at 7 mg/dL in men and 6 mg/dL in women. A serum urate value in excess of 7 mg/dL begins to carry an increased risk of gouty arthritis or renal stones.

EPIDEMIOLOGY Hyperuricemia is fairly common, with prevalence ranging between 2.6% and 47.2% in various populations.3,4 A variety of factors appears to be associated with high serum urate concentrations. In adults, serum urate levels correlate strongly with the serum creatinine and urea nitrogen levels, body weight, height, age, blood pressure, and alcohol intake.5 In epidemiologic studies, body bulk (as estimated by body weight, surface area, or body mass index) has proved to be one of the most important predictors of hyperuricemia in people of many different races and cultures, with rare ­exceptions.6-8 Serum urate concentrations vary with age and sex. Children normally have a concentration in the range of 3 to 4 mg/dL because of high renal uric acid clearance.9 At puberty, serum urate concentrations increase by 1 to 2 mg/dL in males, and this higher level is generally sustained throughout life. In contrast, females exhibit little change in the serum urate concentration until menopause, when concentrations increase and approach those seen in adult men. The mechanism of lower serum urate levels in women is a consequence of sex hormones and is related to a higher fractional excretion of urate secondary to lower tubular urate postsecretory reabsorption.10 The incidence of gout varies among populations, with an overall prevalence ranging from less than 1% to 15.3%.5 1481

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This upper limit appears to be increasing.11,12 The prevalence increases substantially with age and with increasing serum urate concentration. The annual incidence rate of gout is 4.9% for urate levels greater than 9 mg/dL, 0.5% for values between 7 and 8.9 mg/dL, and 0.1% for values less than 7 mg/dL.13 For serum urate values greater than 9 mg/dL, the cumulative incidence of gout reaches 22% after 5 years.

ENVIRONMENTAL FACTORS An association between alcohol consumption and gout has been recognized for centuries. The risk of developing gout varies by the type of alcohol ingested.14 Beer, which is purine rich, carries the highest risk; this risk is substantially greater than that for liquor. Moderate wine drinking does not increase the risk of gout. The quantity of alcohol also strongly correlates with gout. Compared with men who did not consume alcohol, the relative risk of gout was 1.32 for an alcohol intake of 10.0 to 14.9 g/day, 1.49 for 15.0 to 29.9 g/day, 1.96 for 30.0 to 49.9 g/day, and 2.53 for 50 g/day and higher. Diet also influences hyperuricemia and gout. Serum urate levels increase with meat or seafood intake and decrease with dairy intake.15 Men in the highest quintile of seafood consumption have a 51% higher risk of developing gout, and those in the highest quintile of meat intake have a 41% higher risk. However, consumption of oatmeal and purinerich vegetables (e.g., peas, mushrooms, lentils, spinach, and cauliflower) is not associated with an increased risk for gout. The consumption of milk one or more times a day or yogurt consumption at least once every other day is associated with lower serum urate levels.

CLINICAL FEATURES Throughout its natural history, gout passes through three stages: (1) asymptomatic hyperuricemia, (2) episodes of acute gouty arthritis separated by asymptomatic intervals (termed intercritical or interval gout), and (3) chronic gouty arthritis, the period when tophi often become apparent. The basic pattern of clinical gout begins with acute attacks of intensely painful arthritis. The first attack is usually monarticular and associated with few constitutional symptoms. Later, attacks may become polyarticular and are associated with fever. Attacks vary in duration but are time limited. Over time, attacks recur at shorter intervals, last longer, and eventually resolve incompletely. This leads to the development of chronic arthritis that slowly progresses to a crippling disease on which acute exacerbations are superimposed. ASYMPTOMATIC HYPERURICEMIA Asymptomatic hyperuricemia is a condition in which the serum urate level is high, but gout—manifested by arthritis or uric acid nephrolithiasis—has not yet occurred. Most people with hyperuricemia remain asymptomatic throughout their lifetimes. The tendency toward acute gout increases with the serum urate concentration. The risk of nephrolithiasis increases with the serum urate level and with the magnitude of urinary uric acid excretion. The phase of asymptomatic

hyperuricemia ends with the first attack of gouty arthritis or urolithiasis. In most instances, this occurs after at least 20 years of sustained hyperuricemia. Between 10% and 40% of gouty subjects have one or more attacks of renal colic before the first articular event. ACUTE GOUTY ARTHRITIS The first attack of acute gouty arthritis usually occurs between age 40 and 60 years in men and after age 60 in women. Onset before age 25 should raise the possibility of an unusual form of gout, perhaps one related to a specific enzymatic defect that causes marked purine overproduction, an inherited renal disorder, or the use of cyclosporine. A single joint is involved in about 85% to 90% of first attacks, with the first metatarsophalangeal joint being the most commonly affected site. The initial attack is polyarticular in 3% to 14%. Acute gout is predominantly a ­disease of the lower extremities, but eventually, any joint of any extremity may be involved. Ninety percent of patients experience acute attacks in the great toe at some time during the course of their disease. Next in order of frequency are the insteps, ankles, heels, knees, wrists, fingers, and elbows. Acute attacks rarely affect the shoulders, hips, spine, sacroiliac joints, sternoclavicular joints, acromioclavicular joints, or temporomandibular joints.16,17 Acute gouty bursitis, tendinitis, or tenosynovitis can also occur.18,19 Urate deposition and subsequent gout appear to have a predilection for previously damaged joints, such as in Heberden’s nodes of older women.20 Some patients report a history of short, trivial episodes of “ankle sprains,” sore heels, or twinges of pain in the great toe before the first dramatic gouty attack. In most patients, however, the initial attack occurs with explosive suddenness and commonly begins at night after the individual has gone to sleep feeling well. Within a few hours of onset, the affected part becomes hot, dusky red, swollen, and extremely tender. Occasionally, lymphangitis may develop. Systemic signs of inflammation may include leukocytosis, fever, and elevation of the erythrocyte sedimentation rate. Radiographs usually show only soft tissue swelling during early episodes. The course of untreated acute gout is highly variable. Mild attacks may subside in several hours or persist for only a day or two and never reach the intensity described for the classic attack. Severe attacks may last days to weeks. The skin over the joint often desquamates as the erythema subsides. With resolution, the patient becomes asymptomatic and enters the intercritical period. Drugs may precipitate acute gout by either increasing or decreasing serum urate levels acutely. The occurrence of gout after the initiation of antihyperuricemic therapy is well established. In fact, the more potent the urate-lowering effect, the more likely there is to be an acute attack.21 Drug-induced gout secondary to increased serum urate levels occurs on occasion with diuretic therapy, intravenous heparin, and cyclosporine.22-24 Diuretic therapy in the elderly appears to be a particularly important precipitating factor for gouty arthritis. Other provocative factors include trauma, alcohol ingestion, surgery, dietary excess, hemorrhage, foreign protein therapy, infections, and radiographic contrast exposure.25,26 The risk of a patient with gout developing an attack during hospitalization is 20%.27

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Table 87-1  Criteria for the Classification of Acute   Gouty Arthritis The presence of characteristic urate crystals in the joint fluid, or a tophus proved to contain urate crystals by chemical means or polarized light microscopy, or the presence of 6 of the following 12 clinical, laboratory, and radiographic phenomena: More than one attack of acute arthritis Maximal inflammation developed within 1 day Attack of monarticular arthritis Joint redness observed First metatarsophalangeal joint painful or swollen Unilateral attack involving first metatarsophalangeal joint Unilateral attack involving tarsal joint Suspected tophus Hyperuricemia Asymmetric swelling within a joint (radiograph) Subcortical cysts without erosions (radiograph) Negative culture of joint fluid for microorganisms during attack of joint inflammation Adapted from Wallace SL, Robinson H, Masi AT, et al: Preliminary criteria for the classification of acute arthritis of primary gout. Arthritis Rheum 20: 895-900, 1977.

The definitive diagnosis of gout is best established by aspiration of the joint and identification of intracellular needle-shaped crystals that have negative birefringence with compensated polarized light microscopy. However, criteria have been proposed for a presumptive diagnosis.28 These include the triad of acute monarticular arthritis, hyperuricemia, and a dramatic response to colchicine therapy, and a set of criteria proposed by the American College of Rheumatology (Table 87-1).29 There are limitations to using either of these schemes. First, although the diagnosis of acute gouty arthritis can be strongly suggested by the typical presentation, not all inflammation of the great toe (podagra) in hyperuricemic patients is caused by gout.30 Second, some patients with gout are normouricemic at the time of an acute attack, a phenomenon related to alcohol use or a consequence of interleukin (IL)-6 generation by the acute inflammatory process.31-33 Third, diseases other than gout can occasionally improve with colchicine therapy; these include pseudogout, hydroxyapatite calcific tendinitis, sarcoid arthritis, erythema nodosum, serum sickness, rheumatoid arthritis, and familial Mediterranean fever.34 Finally, the simultaneous presence of both gout and septic arthritis can be confusing clinically, with the former masking the latter.35 INTERCRITICAL GOUT The terms intercritical gout and interval gout have been applied to the periods between gouty attacks. Some patients never have a second attack. However, most patients suffer a second attack within 6 months to 2 years. In Gutman’s series,36 62% had recurrences within the first year, 16% in 1 to 2 years, 11% in 2 to 5 years, and 4% in 5 to 10 years; 7% had experienced no recurrence in 10 or more years. The frequency of gout attacks usually increases over time in untreated patients. Later attacks have a less

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explosive onset, are polyarticular, become more severe, last longer, and abate more slowly. Nevertheless, recovery is complete. Radiographic changes may develop during the intercritical period despite no sign of tophi on physical examination. These changes are more likely in patients with more severe hyperuricemia and more frequent acute attacks.27,37 The diagnosis of gout in a hyperuricemic patient with a history of acute attacks of monarthritis may be difficult or inconclusive during the intercritical phase. Aspiration of an asymptomatic joint, however, can be a useful adjunct in the diagnosis of gout if urate crystals are demonstrated. Joint fluids obtained from gouty patients during the intercritical phase revealed monosodium urate crystals in 12.5% to 90% of joints.38 Such crystals in asymptomatic joints are often associated with mild synovial fluid leukocytosis, which suggests the potential to contribute to joint damage even in the intervals between attacks. CHRONIC GOUTY ARTHRITIS Eventually, the patient may enter a phase of chronic polyarticular gout with no pain-free intercritical periods. At this stage, gout may be easily confused with other types of arthritis or other conditions.39-41 The time from the initial attack to the beginning of chronic symptoms or visible tophaceous involvement is highly variable in studies of untreated patients. Hensch42 reported intervals ranging from 3 to 42 years, with an average of 11.6 years between the first attack and the development of chronic arthritis.42 Ten years after the first attack, about half the individuals were still free of obvious tophi, and most of the remainder had only minimal deposits. Thereafter, the proportion of those with nontophaceous involvement slowly declined, to 28% after 20 years. Two percent of the patients had severe crippling disease some 20 years after the initial attack. The rate of formation of tophaceous deposits correlates with both the degree and the duration of hyperuricemia. The principal determinant is the serum urate leve1.27 ­Gutman43 found the mean serum urate concentration to be 9.1 mg/dL in 722 patients without tophi, 10 to 12 mg/dL in 456 patients with minimal to moderate tophi, and greater than 11 mg/dL in 11 patients with extensive tophaceous involvement. The rate of tophus formation also increases with the severity of renal disease and the use of diuretics.22 Tophaceous gout is the consequence of the chronic inability to eliminate urate as rapidly as it is produced. As the urate pool expands, deposits of urate crystals appear in cartilage, synovial membranes, tendons, soft tissues, and elsewhere. Tophi are rarely present at the time of an initial attack of primary gout44,45; they are more likely to be present in gout secondary to myeloproliferative diseases, in juvenile gout-complicating glycogen storage diseases (GSDs), in Lesch-Nyhan syndrome, or after allograft transplantation in patients treated with cyclosporine.34,46 Tophi can occur in a variety of locations. Tophaceous deposits may produce irregular, asymmetric, moderately discrete tumescence of the fingers (Fig. 87-1), hands, knees, or feet. Tophi also form along the ulnar surfaces of the forearm, as saccular distentions of the olecranon bursa (Fig. 87-2), in the antihelix of the ear (Fig. 87-3), or as fusiform enlargements of the Achilles tendon (Fig. 87-4). The process of

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tophaceous deposition advances insidiously. Although the tophi themselves are relatively painless, acute inflammation can occur around them. Eventually, extensive destruction of the joints and large subcutaneous tophi may lead to grotesque deformities, particularly of the hands and feet, and to progressive crippling (Fig. 87-5). The tense, shiny, thin

skin overlying the tophus may ulcerate and extrude white, chalky, or pasty material composed of urate crystals. Secondary infection of tophi is rare. Typical radiographic changes, particularly erosions with sclerotic margins and overhanging edges of bone, occur with the development of tophi (Fig. 87-6).47 These may be difficult to distinguish from erosions of other causes, but the presence of a thin, overhanging calcified edge is strong evidence of gout. Calcifications can be seen in some tophi, and bony ankylosis may rarely occur. Ultrasonography, magnetic resonance imaging, and computed tomography can demonstrate tophi, with the last providing the most specific images.48 Tophi can produce a marked limitation of joint movement by involvement of the joint structure directly or of a tendon serving the joint. Any joint can be involved, although those of the lower extremity are affected primarily. Spinal joints do not escape urate deposition,41,49 but acute gouty spondylitis is unusual. Symptoms related to nerve or spinal cord compression by tophi have rarely been observed. Tophi rarely occur in myocardium, valves, cardiac conduction system, various parts of the eye, and larynx.50,51

GENETICS OF GOUT

Figure 87-1  Tophus of the fifth digit, with a smaller tophus over the fourth proximal interphalangeal joint.

Figure 87-2  Saccular tophaceous enlargements of the oclecranon bursae, with small cutaneous deposits of urate.

Since antiquity, gout has been recognized as a familial ­disorder. The familial incidences reported range from 11% to 80%.34 In two large series, one English and one American, about 40% of gouty subjects gave a positive family history of gout. These wide discrepancies may be attributed in part to variations in diligence and pursuit of genealogic data. When all available data are considered, they suggest that serum urate concentrations are controlled by polygenic traits. Several rare forms of hyperuricemia and gout, such as hypoxanthine phosphoribosyltransferase deficiency,

PART 14 

phosphoribosyl-1-­pyrophosphate synthetase overactivity, and familial hyperuricemia nephropathy, have a genetic basis and are discussed later.

ASSOCIATED CONDITIONS The association of gout with obesity and overeating is well recognized.52 In 6000 subjects, hyperuricemia was found in only 3.4% of those with a relative weight at or below the 20th percentile, in 5.7% of those between the 21st and 79th percentiles, and in 11.4% of those at or above the 80th percentile.53 Hypertriglyceridemia has been reported in 75% to 80% of patients with gout,54 and hyperuricemia is found in more than 80% of patients with hypertriglyceridemia.34 However, studies have been unable to show a correlation between serum urate and cholesterol values or a unique lipid

Figure 87-3  Tophus of the helix of the ear adjacent to the auricular  t­ ubercle. (From Swash M: Hutchinson’s Clinical Methods, 21st ed. ­Philadelphia, WB Saunders, 2001.)

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­phenotype.55 Gouty patients who drink alcohol excessively have mean serum triglyceride levels that are higher than those of their obesity-matched controls and of non–alcohol drinking gouty patients.56 Hyperuricemia has been reported in 2% to 50% of patients with diabetes mellitus, and gouty arthritis has been reported in less than 0.1% to 9%.57 Abnormal glucose tolerance tests have been noted in 7% to 74% of patients with gout, depending, in part, on the criteria used.58 Hyperuricemia has been reported in 22% to 38% of patients with untreated hypertension. This figure increases to 67% when diuretic therapy and renal disease are present.34 Hyperuricemia may be an indication of a potential risk for hypertension in adolescent males.59 Hypertension is present in one fourth to one half of patients with classic gout, but the presence of hypertension is unrelated to the duration of gout.52,53 Elevated serum urate concentrations are associated with increased tubular reabsorption of sodium.58 The serum urate concentration also correlates inversely with renal blood flow and urate clearance and correlates directly with both renovascular and total resistance. Therefore, the association between hypertension and hyperuricemia may be related to the reduction of renal blood flow in hypertension. In addition, uric acid causes smooth muscle proliferation in vitro and vascular disease in animal models through a mechanism that involves complex intracellular signaling, mitogen-activated protein kinase activation, and platelet-derived growth factor expression.60,61 The association between hyperuricemia and the manifestations of atherosclerosis has led to speculation that hyperuricemia is a risk factor for coronary artery disease. Some studies show no clear associations between blood pressure, blood glucose, or serum cholesterol and serum urate concentration when adjustments are made for the effects of age,

    Figure 87-4  Tophi of Achilles tendons and their insertions in a patient with gout.

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B

A

Figure 87-5  Radiographs (A and B) demonstrating severe destructive changes in tophaceous gout.

Figure 87-6  Radiographs show changes typical of bony tophi, including soft tissue distortion, erosions with sclerotic margins, and overwhelming edges. Joint space narrowing is minimal, despite the large erosions. (From Nakayama DA, Barthelemy C, Carrera G, et al: Tophaceous gout: A clinical and radiographic assessment. Arthritis Rheum 27:468, 1984.)

sex, and relative weight53,62-65; the serum urate concentrations of persons with coronary heart disease are not significantly different from the mean levels of the population.65,66 Other studies, however, maintain that hyperuricemia is an independent risk factor for coronary artery disease.67,68 The term metabolic syndrome has been applied to a cluster of abnormalities, including resistance to insulin-­stimulated

glucose uptake, hyperinsulinemia, hypertension, and dyslipoproteinemia, that are characterized by high levels of plasma triglycerides and high-density lipoprotein cholesterol. Hyperuricemia closely correlates with the degree of insulin resistance65-71 and, therefore, is a likely feature of metabolic syndrome. Metabolic syndrome has been associated with coronary artery disease, and hyperuricemia as a component of metabolic syndrome may explain the previously recognized association between coronary artery disease and hyperuricemia. A recent study concluded that the relationship between hyperuricemia and acute myocardial infarction is independent, but that patients who experience gouty arthritis are at an increased risk for myocardial infarction. This association could not be explained by renal function, metabolic syndrome, diuretic use, or traditional cardiovascular risk factors.72 Alcohol consumption has long been associated with hyperuricemia and gout. In susceptible persons, alcohol use can precipitate acute gouty arthritis. An epidemiologic study in Saudi Arabia, where alcohol consumption is quite rare, revealed an 8.42% prevalence of hyperuricemia but no cases of gout among the study group.73 Both a decrease in the renal excretion of uric acid and an increase in uric acid production seem to be important factors in this association.74 Ethanol increases uric acid production by accelerating the turnover of adenosine triphosphate (ATP). Among alcoholic beverages, beer may have more potent effects on uric acid production because of its high guanosine content.14 There appears to be a significant increased prevalence of hypothyroidism among both female and male patients with gouty arthritis.75 Hyperuricemia may also be more prevalent in patients with hypothyroidism. Thyroid replacement therapy is associated with a decrease in serum urate concentration caused by an increased uric acid diuresis—a change not explained solely by a change in creatinine clearance.76 Although the cause of hyperuricemia and gout in patients with hypothyroidism is unknown, it is speculated that urate metabolism is mediated by thyroid-stimulating hormone receptors in extrathyroidal tissues, including the kidney, and that these modulate urate homeostasis. Studies of acutely ill patients in intensive care units indicate that markedly increased serum urate concentrations, in the vicinity of 20 mg/dL, are associated with hypotensive events and a poor prognosis.77 This finding may be related to two factors. First, ischemic tissue may foster the ­degradation

PART 14 

A

| 

CRYSTAL-induced INFLAMMATION

1487

B

C Figure 87-7  A, Urate deposit in the medulla of the kidneys as seen in an alcohol-fixed section stained with hematoxylin and eosin (×250). B, Adjacent section of the deposit shown in A, stained with methenamine silver (×250). C, Adjacent section of the deposit shown in A seen with polarized light (×250).

of ATP to purine end products, thereby enhancing the production of urate. The finding of increased plasma ATP degradation products associated with hyperuricemia and adult respiratory distress syndrome supports this possibility.78 Second, the conversion of hypoxanthine to uric acid by xanthine oxidase during ischemia produces oxidant radicals, which are themselves associated with tissue injury.79 It is possible that inhibition of xanthine oxidase with allopurinol may be a useful therapy in this setting. Maternal serum urate concentrations normally decrease during pregnancy until the 24th week and then increase until 12 weeks after delivery.80 An increase in the serum urate level occurs in preeclampsia and toxemia of pregnancy, owing to a decrease in the renal clearance of urate.81 Perinatal mortality is markedly increased when maternal plasma urate levels are raised, usually in association with early-onset preeclampsia. The highest mortality rate is seen with serum urate concentrations higher than 6 mg/dL and diastolic blood pressures greater than 110 mm Hg. Labor itself is associated with an increased serum urate level, and it remains elevated for 1 to 2 days after delivery. Gout is rarely seen in patients with rheumatoid arthritis, systemic lupus erythematosus, or ankylosing spondylitis.18,82-84 The basis for the decreased concurrence of these disorders is unclear, although the long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) or corticosteroids may mask the clinical features of gout in some of these patients. RENAL DISEASE After gouty arthritis, renal problems appear to be the most frequent complication of hyperuricemia. Twenty percent to 40% of patients with gout have albuminuria, which is usually mild and often intermittent. Hyperuricemia alone may be

implicated as the cause of chronic kidney disease only when the concentration of urate chronically exceeds 13 mg/dL in men or 10 mg/dL in women.85 Before the routine treatment of asymptomatic hypertension, renal failure accounted for 10% of the deaths in patients with gout. Whether moderate hyperuricemia has a direct harmful effect on renal function is unclear. Some evidence suggests that urate damages the kidneys and leads to hypertension.60,61 The term urate nephropathy is used to describe the deposition of urate crystals in the interstitium of the medulla and pyramids, with a surrounding giant cell reaction—a distinctive histologic finding characteristic of the gouty kidney (Fig. 87-7). Factors such as coexistent hypertension, chronic lead exposure, ischemic heart disease, and primary preexisting renal insufficiency probably play important roles in the pathogenesis of this pathology. Although urate nephropathy appears to exist as a distinct entity, it is not believed to be an important contributor to renal function in most gouty patients.34,86 In contrast, uric acid nephropathy is the term used to describe acute renal failure resulting from the precipitation of large quantities of uric acid crystals in the collecting ducts and ureters. This complication most commonly occurs in patients with leukemia and lymphoma as a result of rapid malignant cell turnover, often during chemotherapy.87,88 This syndrome (also termed acute tumor lysis syndrome) has been more clearly defined as hyperuricemia, lactic acidosis, hyperkalemia, hyperphosphatemia, and hypocalcemia and is most commonly observed in patients with aggressive, rapidly proliferating tumors, including lymphoproliferative disorders and metastatic medulloblastoma. Uric acid nephropathy is less commonly found with other neoplasms, after epileptic seizures, after vigorous exercise with heat stress, and after angiography and coronary artery bypass surgery.34

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In the tumor lysis syndrome, the large amount of nucleic acid in nucleotides liberated with massive cytolysis is converted rapidly to uric acid. Typically, there is marked hyperuricemia, with a mean serum urate level of 20 mg/dL (range, 12 to 80 mg/dL). The pathogenesis of acute renal failure in uric acid nephropathy is related to the precipitation of uric acid in the distal tubules and collecting ducts, the sites of maximal acidification and concentration of urine. Oliguria, or even anuria, as well as azotemia may occur. There may be “gravel” or “sand” noted in the urine. The ratio of urinary uric acid to creatinine in these patients typically exceeds 1; in patients with most other causes of acute renal failure, the ratio is 0.4 ± 0.3.88 Nephrolithiasis occurs in 10% to 25% of patients with primary gout, a prevalence greater than that in the general population. The likelihood of stones in a given patient with gout increases with the serum urate concentration and with amounts of urinary uric acid excretion.89,90 It exceeds 50% with a serum urate value above 13 mg/dL or with urinary uric acid excretion rates in excess of 1100 mg every 24 hours. Uric acid calculi account for approximately 10% of all stones in patients in the United States; elsewhere, rates range from as low as 5% up to 40% in Israel and ­Australia.34 Uric acid stones can occur in patients with no history of gouty arthritis, and only 20% in this group are hyperuricemic. Other renal stone disease is associated with hyperuricemia and gout. Gouty subjects also have an increased incidence of stones that contain calcium. In addition, about 30% of patients with recurrent calcium stone disease have either an increased urinary uric acid excretion rate or hyperuricemia. A causative link between uric acid and recurrent calcium oxalate stones is provided by reports of reduced stone frequency in patients treated with allopurinol. Finally, the report of uric acid as the major constituent of a stone obtained from a patient with no apparent abnormalities of uric acid metabolism should suggest the possibility that the constituent is actually 2,8-dihydroxyadenine and that the patient has adenine phosphoribosyltransferase deficiency.91 This is because x-ray diffraction is required to distinguish uric acid from 2,8-dihydroxyadenine. Familial juvenile hyperuricemic nephropathy (FJHN), sometimes called familial juvenile gouty nephropathy, was first described in 1960.92 This disorder is inherited as an autosomal dominant trait with a high degree of penetrance and is usually associated with gout. Renal disease typically develops in the second decade of life and progresses to endstage renal failure by midlife.93-95 Histologic examination of kidney tissue reveals tubulointerstitial inflammation and splitting of thickened tubular basement membranes. The primary diagnostic criterion is a reduced fractional excretion of urate (defined as uric acid clearance factored by creatinine clearance  ×  100 equal to 5% or less; normal is 8% to 18%).96 The dramatically low fractional excretion of urate and the early onset of disease are conspicuous characteristics of FJHN and distinguish it from other autosomal dominant hyperuricemic disorders that usually appear later in life (Table 87-2). Genotype mapping has linked the gene for FJHN to chromosome 16p12-p11.94 Autosomal dominant medullary cystic kidney disease (ADMCKD) is another hereditary nephropathy that usually includes gout among its constellation of symptoms. The onset of renal dysfunction occurs later than in those with

Table 87-2  Genetics of Renal Diseases Associated   with Gout Chromosomal Location

Condition

Inheritance

FJHN

AD

16p12.3 17cenq21.3

Gene Uromodulin Hepatic nuclear factor 1β

MCKD type 1

AD

1q21

?

MCKD type 2

AD, AR

16p12.3

Uromodulin

AD, autosomal dominant; AR, autosomal recessive; FJHN, familial juvenile hyperuricemic nephropathy; MCKD, medullary cystic kidney disease.

FJHN. Renal histology reveals numerous corticomedullary and intramedullary cysts in the kidneys and increased medullary connective tissue. At least two loci appear to be responsible for ADMCKD. One, termed ADMCKD1, is located on chromosome 1; the other, ADMCKD2, is a 16p locus. ADMCKD2 and FJHN loci map to approximately the same region of chromosome 16p.97 The chromosome 16p12 locus that harbors the candidate interval for FJHN and ADMCKD2 contains six candidate genes, including the uromodulin gene (UMOD).98-100 UMOD encodes the Tamm-Horsfall protein, a glycosylphosphatidylinositol-anchored glycoprotein localized to the thick ascending limb of the loop of Henle. Amorphous deposits of uromodulin are present in the renal interstitium of patients with medullary cystic kidney disease.101 Four different mutations in exon 4 have been identified in the UMOD gene. Because mutations in the same gene are responsible for both FJHN and ADMCKD, the two entities appear to be allelic variants in UMOD that cause decreased urinary concentrations of Tamm-Horsfall protein, with resulting hyperuricemia and progressive renal failure.102 LEAD INTOXICATION Hyperuricemia and gout are well-recognized complications of chronic lead intoxication, with the prevalence of gout in patients with plumbism ranging between 6% and 50%.103 Although a renal defect is recognized, it has not been well defined.104,105 Some patients with primary gout have increased blood lead levels compared with age- and sex-matched controls, despite the absence of a history of overt lead exposure.106 This suggests that occult chronic lead intoxication may play a causative role in some cases of primary gout (up to 36% of some gout populations).103 In addition, patients with gout who have renal impairment seem to have an increased quantity of mobilized lead compared with gouty patients with normal renal function.107 These observations suggest an important role for lead in the pathogenesis of gouty nephropathy. CYCLOSPORINE-INDUCED HYPERURICEMIA AND GOUT Cyclosporine interferes with the renal excretion of uric acid. Hyperuricemia and gout occur with increased frequency among transplant recipients treated with cyclosporine and are even more common when diuretics are used concomitantly.46,108 However, serum urate levels do not correlate directly with cyclosporine levels or with the degree of

PART 14 

­ ypertension or renal insufficiency. The onset of gout may h occur soon after transplantation, with a mean of about 17 months. Gouty attacks may be typical and monarticular, or they may affect unusual sites such as the shoulder, hip, or sacroiliac joints. Polyarticular attacks and an accelerated course, with early development of tophi, may also be observed. Nephrolithiasis develops in about 3% of renal transplant patients. All calculi from azathioprine-treated patients are composed of calcium compounds, whereas 60% of the calculi from those treated with cyclosporine contain uric acid.109

PURINE METABOLISM Uric acid is a purine base composed of a six-membered pyrimidine ring fused to a five-membered imidazole ring (Fig. 87-8). Purine nucleosides are composed of a purine base plus a pentose joined to the base by an N-glycosyl bond between carbon atom 1 of the pentose and nitrogen atom 9 of the purine base. There are two series of nucleosides: the ribonucleosides, which contain D-ribose as the sugar component, and the deoxyribonucleosides, which con­ tain 2′-deoxy-d-ribose (Fig. 87-9). Purine nucleotides and deoxynucleotides consist of a nucleoside of deoxynucleoside with a phosphate group and ester linkage with carbon 5 of the pentose (Fig. 87-10). The nucleosides and deoxynucleosides exist as 5′-monophosphates, 5′-diphosphates, and 5′-triphosphates (Fig. 87-11). These compounds serve as building blocks for RNA and DNA; as precursors of the cyclic nucleotides adenosine-3′,5′-cyclic-phosphate and

OH

C N1

NH2

HC

5

2

4 3

C

7

C

N

N

C

HC

C

8

C

N

C

H2N

C

C N

N H

Adenine

N N

HOCH2

HC

HOCH2

O H

C

HO

C

H

Hypoxanthine

H

C 1'

C 2'

H

OH

H

2'-Deoxyadenosine

Base

OH P

O

CH2

H

N C

N

O H

OH

OH

OH

N

C

C N

(Lactam)

N

Base

C C

Uric acid

OH

C N

N H

P

O

5'

CH2

O

C

O HO

C

HO

C

N C

O

H

Ribonucleoside 5'-monophosphates

N H

OH

N

β

H

Xanthine

O C

C

H H C 3'

OH

C

C

N H

N

4' C

CH

C N

N

9

5'

HO

CH

C

N

O

C

C

HC

CH

9

N

OH

C N

C

CH

N H

Guanine

OH

N

N

Figure 87-9  Structures of adenosine and 2′-deoxyadenosine as examples of nucleosides and 2′-deoxynucleosides, respectively.

CH

CH

9

C

Adenosine

N

HN

1489

NH2

OH

C

N

6

CRYSTAL-induced INFLAMMATION

guanosine-3′,5′-cyclic-phosphate; as a source of chemical energy; and as precursors of various purine cofactors and coenzymes, such as nicotinamide adenine dinucleotide. Xanthine oxidase is a flavoprotein containing both iron and molybdenum that oxidizes a wide variety of purines and pteridines. A soluble form of the enzyme that has dehydrogenase activity (xanthine dehydrogenase, or D-form) is highly active in the liver and small intestine and is responsible for the formation of uric acid as the final metabolic product in human purine metabolism. This enzyme converts hypoxanthine to xanthine and xanthine to uric acid (Fig. 87-12). Purines can be synthesized de novo in cells. The initial and rate-limiting step of this biosynthetic process is the conversion of phosphoribosylpyrophosphate (PRPP) to 5′-phosphoribosylamine. This step is catalyzed by the enzyme amidophosphoribosyltransferase, and it is regulated by the concentrations of nucleoside monophosphates and PRPP. Adenylic acid (AMP) and guanylic acid (GMP) are feedback inhibitors of the enzyme. Under normal ­ conditions,

C H H C NH2

| 

N H

(Lactim)

Figure 87-8  Structure of uric acid. All purine bases may exist in the  lactam form in a reversible manner, as shown for uric acid.

H

H 3'

OH

O

β

H 2'

1'

H

H

2'-Deoxyribonucleoside 5'-monophosphates Figure 87-10  General structures of nucleosides and deoxynucleoside 5′-monophosphates.

1490

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Gout and Hyperuricemia

depletion of PRPP decreases the rate of purine biosynthesis de novo, and elevation of PRPP is associated with an increased rate of purine biosynthesis. The first branch point in the pathway leading to the de novo synthesis of AMP and GMP (see Fig. 87-12) occurs

with the synthesis of inosinic acid (IMP). IMP is used to form AMP and GMP, and these steps may be governed by the intracellular concentration of guanylic acid triphosphate (GTP). GTP is a substrate of adenylosuccinate synthetase and an inhibitor of IMP dehydrogenase. As IMP is formed, it is used for the synthesis of xanthylic acid, GMP, guanylic acid diphosphate, and GTP. As GTP reaches a critical concentration in the cell, it may increase the activity of adenylosuccinate synthetase, allowing IMP to be effectively used in the synthesis of AMP. When accelerated purine biosynthesis results in the production of surplus IMP, there is a rapid conversion of the excess ribonucleotide to uric acid rather than a continued expansion of the pools of adenyl and guanyl nucleotides. Nucleotide breakdown is regulated in a complex manner. Regulation of nucleotide degradation is critically controlled by AMP deaminase and 5′-nucleotidase activities. Release of inhibition of AMP deaminase results in accelerated production of uric acid. Regulation of dephosphorylation is complex, involving three soluble 5′-nucleotidase activities. The nucleosides formed by nucleotidase reactions are converted to the bases adenine, guanine, or hypoxanthine. These bases can be “salvaged” by reconversion to nucleosides catalyzed by purine nucleoside phosphorylase activity (hypoxanthine and guanine) or conjugated with PRPP to form ribonucleotides by phosphoribosyltransferase activities. If not salvaged, they are degraded to uric acid. Exogenous purines also significantly contribute to the total body urate pool. The magnitude of this contribution

Hypoxanthine + H2O + 2O2 Xanthine + 2O2- + 2H+ Hypoxanthine + H2O + O2

Xanthine + H2O2

Xanthine + H2O + 2O2

Uric Acid +

2O2- + 2H+ γ OH HO

P O

or α OH

β OH O

P

O

Base

P

O

CH2

O

O

H

O

H

H

OH

OH

H

NMP NDP NTP Figure 87-11  Comparison of the structures of nucleosides, monophosphates, diphosphates, and triphosphates.

Ribose-5-P + ATP 3

n itio

1

5-Phosphoribosyl-1-amine

Fe ed ba ck

Glycine

n tio ibi

Fe e

k

ib inh

h in

db ac

5-Phosphoribosyl-1-pyrophosphate (PRPP) + Glutamine

Formate

Nucleic acids

Nucleic acids

2

Guanosine 6

Guanine

7

7

7

PP

PR

5

PR

Inosine

PP

6

Adenosine

Adenylic acid PRPP

Inosinic acid

Guanylic acid

4

Adenine

Hypoxanthine 8

2,8-Dioxyadenine

Xanthine 8

Uric acid Figure 87-12  Outline of purine metabolism: (1) amidophosphoribosyltransferase, (2) hypoxanthine-guanine phosphoribosyltransferase, (3) phosphoribosylpyrophosphate (PRPP) synthetase, (4) adenine phosphoribosyltransferase, (5) adenosine deaminase, (6) purine nucleoside phosphorylase, (7) 5′-nucleotidase, (8) xanthine oxidase. (From Seegmiller JE, Rosenbloom RM, Kelley WN: Enzyme defect associated with sex-linked human neurological disorder and excessive purine synthesis. Science 155:1682, 1967.)

PART 14 

depends on the amount and type of purine in the diet, but it is often considerable. When healthy young men were given an isocaloric, purine-free formula diet, serum urate values declined in 10 days from about 4.9 to 3.1 ± 0.4 mg/dL, and urinary excretion of uric acid declined from between 500 and 600 to 336 ± 39 mg/day.110 Urinary uric acid excretion declines to constant low values after 5 to 7 days of dietary purine elimination or severe restriction. Mean values then range from 336 ± 39 to 426 ± 81 mg every 24 hours. These values reflect the continued synthesis and turnover of endogenous purines. Urinary uric acid excretion accounts for only part of the daily disposition of uric acid, however. The true rate of endogenous purine turnover cannot accurately be determined by the measurement of urinary uric acid excretion; it requires the use of isotope-dilution techniques in subjects in whom the exogenous contribution has been reduced to a minimum by severe dietary purine restriction.

| 

CRYSTAL-induced INFLAMMATION

1491

URIC ACID ELIMINATION AND EXCRETION Most uric acid is eliminated from the body by renal and extrarenal routes. Less than 2% of the turnover of the total body urate pool can be attributed to tissue uricolysis. Extrarenal routes include saliva, gastric juice, pancreatic secretions, and bowel. These routes account for about one third of the uric acid normally turned over each day. The percentage of extrarenal excretion increases, however, when serum urate concentrations rise above 12 to 14 mg/dL. Until recently, a four-component model has been used to describe the renal handling of urate and uric acid: glomerular filtration, tubular reabsorption, secretion, and postsecretory reabsorption. Although these processes were once considered sequential, it is now apparent that they are coexistent and carried out via transporters. The renal clearance of urate uses specific organic anion ­transporters (OATs), including URAT 1 (Fig. 87-13). URAT 1 and

Glomerulus Proximal tubule

Na+

Urate

Anion

Apical brush border

Na+-ion cotransporter

Na+

UAT OATVI MRP4

URAT 1

Anion

Urate

Anion

Proximal tubular cell

OAT 1 OAT 3

OAT

Renal interstitium Anion

Urate

Anion

Figure 87-13  Urate transport in the proximal tubule. MRP4, multiple drug resistance protein 4, an ATP-driven efflux pathway; OAT, organic anion transporter; OATV, voltage-driven organic anion transporter; URAT, urate transporter.

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Gout and Hyperuricemia

Table 87-3  Drugs that Are Uricosuric in Humans Acetohexamide

Glycerol guaiacolate

Amflutizole

Glycine

Ascorbic acid

Glycopyrrolate

Azapropazone

Iodopyracet

Azauridine

Iopanoic acid

Benzbromarone

Losartan

Calcitonin

Meclofenamic acid

Calcium ipodate

Orotic acid

Citrate

Outdated tetracyclines

Dicumarol

Phenolsulfonphthalein

Diflunisal

Probenecid

Estrogens

Salicylates

Fenofibrate

Sulfinpyrazone

other OATs carry urate into the proximal tubular cells from the luminal (apical) side. Once inside the cell, urate must pass to the other side, a process controlled by the voltage-dependent carrier hUAT. As a result of the activities of URAT 1 and other transporters, 8% to 12% of the urate filtered by the glomerulus is excreted as uric acid. URAT 1 is a novel transporter expressed at the apical brush border of the proximal nephron.105 Uricosuric compounds (Table 87-3) directly inhibit URAT 1 from the apical side of the tubular cell (so-called cis-inhibition).67,91 In contrast, antiuricosuric compounds (those that promote hyperuricemia) serve as the exchange anions from inside the cell, thereby stimulating anion exchange and urate reabsorption (trans-stimulation).111 There appears to be a transporter on the proximal tubule brush borders that mediates the absorption of pyrozinoate, pyruvate, lactate, nicotinate, β-hydroxybutyrate, and acetoacetate by a sodium-dependent process.106,107,112 However, these anions are also ­substrates for URAT 1.67 Consequently, when levels of these anions increase in plasma, their glomerular filtration and reabsorption into proximal tubular cells are increased. The resulting intraepithelial concentrations, in turn, induce increased urate reabsorption via URAT 1–dependent anion exchange. Sodium-dependent loading of proximal tubular cells also results in increased urate reabsorption. However, the identity of the relevant sodium-dependent anion cotransporters remains speculative.108 This mechanism probably accounts for the hyperuricemia that accompanies reduced extracellular fluid volume113 or states accompanied by elevated levels of parathyroid hormone,114 angiotensin II,114 or insulin.65 Recognition of the role of URAT 1 in urate reabsorption and anion exchange helps explain why monovalent ions such as salicylates and probenecid can induce hyperuricemia at low doses and are uricosuric at high doses.115,116 This occurs by the trans-inhibition of URAT 1 at low doses, causing antiuricosuric effects,107 and cis-inhibition at higher doses, resulting in increased uricosuria.67,117 Urate gains access to the proximal tubular cells from the renal interstitium through OAT 1 and OAT 3 transporters.118,119 This process is driven by the sodium-­dependent

uptake of divalent anions, such as α-ketoglutarate.120 Each appears to play a part in the efflux and influx of urate.119,121,122 Additional proteins believed to be involved in the renal handling of urate include the urate transporter channel (UAT, also called galectin-9), the voltage-driven organic anion transporter-1 (OATV-1), and the apical ATPdriven anion transporter multiple drug resistance protein 4 (MRP4).123-125 A variety of additional factors influence the renal clearance of urate, including urine flow, estrogens, surgery, and the autonomic nervous system. Uric acid excretion increases by more than 25% as urine flow doubles in response to oral and intravenous fluid loading in humans. Changes in clearance are at least partially responsible for lower concentrations of serum urate in children and in women before menopause.7,9 An increase in the excretion of uric acid in urine occurs in patients undergoing abdominal surgery, with little or no change taking place in the serum urate concentration. Factors such as anesthesia, increased endogenous steroids, intravenous fluids, intestinal manipulation, and vagotomy have been suggested as possibly affecting urate clearance. Several anticholinergic agents increase the renal clearance of urate, indicating that the parasympathetic nervous system plays a role in controlling the renal excretion of uric acid.

PHYSICAL PROPERTIES OF URIC ACID The weakly acidic nature of uric acid results from ionization of hydrogen ions at position 9 (pKa1  =  5.75) and position 3 (pKa2  =  10.3). The ionized forms of uric acid readily form salts, which are monosodium and disodium or potassium urates. In extracellular fluids, in which sodium is the principal cation, approximately 98% of uric acid is in the form of monosodium salt at a pH of 7.4. When the solubility limits of body fluids are exceeded, the crystals that occur in the synovial fluid or the tophi of gouty patients are composed of monosodium urate monohydrate. As mentioned earlier, actual determinations of solubility of monosodium urate in human plasma (or serum) indicate that saturation occurs at concentrations of about 7 mg/dL. Considerably higher concentrations of monosodium urate in plasma can be achieved in supersaturated solutions. Stable supersaturated solutions of monosodium urate up to 40 to 90 mg/dL have been observed in patients with leukemia or lymphoma after aggressive therapy with cytotoxic drugs in the absence of allopurinol therapy.88 The factors responsible for enhanced urate solubility in such patients are not clear and may include both the natural tendency for urate to form stable supersaturated solutions and an increase in plasma of substances capable of solubilizing urate. Studies of urate binding disclose that no more than 4% to 5% of urate is bound to plasma protein, indicating that the binding of uric acid to plasma proteins at 37°C is probably of little ­physiologic ­significance. As the urine is acidified along the renal tubule, a portion of urinary urate is converted to uric acid. The solubility of uric acid in aqueous solutions is substantially less than that of urate. At pH 5, urine is saturated with uric acid at 15 mg/dL; at pH 7, urine accommodates 158 to 200 mg/dL in solution. The limited solubility of uric acid in urine of pH 5 is of particular significance in patients with gout, many

PART 14 

of whom display a tendency toward the excretion of unusually acidic urine. Monosodium urate occurs as a monohydrate and forms needle- or rod-shaped crystals in tissue and joint fluids. Urate crystals are insoluble in ethanol, sparingly soluble in water, and markedly soluble in formalin. Free uric acid crystallizes from pure solutions in an orthorhombic system, forming rhombic plates. Crystals formed in urine incorporate pigments and exist in a variety of crystalline forms. Tissue deposits are composed of monosodium urate monohydrate, whereas urinary stones are largely composed of uric acid. Both urate and uric acid crystals are birefringent, with strong negative elongation when viewed under compensated polarized light. These features should permit ready identification of urate crystals in synovial fluid, leukocytes, or tissue deposits and, therefore, constitute an important diagnostic aid.114

CLASSIFICATION AND PATHOGENESIS OF HYPERURICEMIA AND GOUT The concentration of urate in body fluids is determined by the balance between production and elimination. Accordingly, hyperuricemia may be caused by an excessive rate of urate production, a decrease in the renal excretion of uric acid, or a combination of both events. Hyperuricemia and gout may be classified as follows (Table 87-4): Primary: These cases appear to be innate, neither secondary to an acquired disorder nor the result of a subordinate manifestation of an inborn error that leads initially to a major disease unlike gout. Some cases of primary gout have a genetic basis; others do not. Secondary: These cases develop in the course of another disease or as a consequence of drug use. Idiopathic: In these cases, a more precise classification cannot be assigned. Further subdivisions within each major category are based on the identification of overproduction, underexcretion, or both, as responsible for the hyperuricemia. Evidence of overproduction of urate is provided by determination of the 24-hour urinary uric acid excretion. For adults ingesting a purine-free diet, a total excretion of up to 600 mg/day is considered within the normal range.113 For patients on regular diets, a value in excess of 1000 mg/day is clearly abnormal and an indication of overproduction, and values between 800 and 1000 mg/day are considered borderline. It has been suggested that overproduction of uric acid can be assessed simply by determining the ratio of uric acid to creatinine in the urine or the Curate/Ccreatinine ratio. However, comparison of these two ratios with the 24-hour urinary uric acid excretion reveals a poor correlation in most patients.126,127 Exceptions include patients with specific enzymatic deficiencies or with rapid cell lysis during chemotherapy for leukemia or lymphoma. PRIMARY GOUT Renal mechanisms are responsible for the hyperuricemia in most cases of gout. Genetic factors exert an important control in the renal clearance of urate.115 A careful ­comparison of uric acid clearances and excretion rates over

| 

CRYSTAL-induced INFLAMMATION

1493

Table 87-4  Classification of Hyperuricemia and Gout Type

Metabolic ­ Disturbance

Inheritance

Not established

Polygenic

Not established

Polygenic

Primary Molecular defects undefined Underexcretion (90% of primary gout) Overproduction (10% of primary gout) Associated with specific   enzyme defects PRPP synthetase variants; increased activity HPRT deficiency, partial

Overproduction of   X-linked PRPP and uric acid Overproduction of   X-linked uric acid; increased purine biosynthesis   de novo driven by surplus PRPP;   Kelley-Seegmiller   syndrome

Secondary Associated with increased purine   biosynthesis de novo HPRT deficiency,   Overproduction of uric “virtually complete” acid; increased purine biosynthesis de novo driven by surplus PRPP; Lesch-Nyhan syndrome Glucose-6-phosphatase Overproduction plus underexcretion of   deficiency or absence uric acid; glycogen storage disease type   I (von Gierke’s   disease) Fructose-1-phosphate Overproduction plus aldolase deficiency underexcretion of   uric acid Associated with increased   ATP degradation Associated with increased Overproduction   nucleic acid turnover of uric acid Associated with   Decreased filtration   decreased renal   of uric acid,   excretion of uric acid inhibited tubular   secretion of uric   acid, or enhanced tubular reabsorption   of uric acid

Most not familial Some autosomal dominant; some not familial; most unknown

Idiopathic

Unknown

X-linked

Autosomal recessive

Autosomal recessive

ATP, adenosine triphosphate; HPRT, hypoxanthine phosphoribosyltransferase; PRPP, phosphoribosylpyrophosphate.

a wide but comparable range of filtered loads of urate indicates that most gouty subjects have a lower ratio of urate to inulin clearance (Curate/Cinulin ratio) than do nongouty subjects.113,115,128 The excretion rates and the capacity of the excretory mechanism for uric acid are the same for gouty subjects and nongouty individuals (Fig. 87-14). The excretion curve, however, is shifted. Gouty subjects require serum urate values 2 or 3 mg/dL higher than those of controls to achieve equivalent uric acid excretion rates. Theoretically, the shift in the excretion curve in gouty subjects may result from reduced filtration of urate, enhanced reabsorption, or decreased secretion. Patients classified as exhibiting an overproduction of uric acid represent less than 10% of the gouty population.

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9 8 7

UURV (mg/min)

6 5 4 3 2 1 0 4

6

8

10

12

14

16

18

20

chronic beryllium disease, acute alcohol intoxication). The renal basis of the hyperuricemia in conditions such as chronic lead intoxication, hypoparathyroidism, pseudohypoparathyroidism, and hypothyroidism remains unclear. Secondary gout can also result from urate overproduction. Four specific defects cause urate overproduction as a consequence of accelerated de novo purine biosynthesis: hypoxanthine phosphoribosyltransferase (HPRT) deficiency, PRPP synthetase overactivity, glucose-6-phosphatase deficiency, and fructose-1-phosphate aldolase deficiency. A complete deficiency of the enzyme HPRT, known as Lesch-Nyhan syndrome, is characterized by choreoathetosis, striking growth, mental retardation, spasticity, selfmutilation, and marked hyperuricemia with excessive uric acid production and uric acid crystalluria (Figs. 87-15 and 87-16).118,119,129 Adolescent and adult patients with a “partial” rather than a “complete” deficiency of HPRT—called Kelley-Seegmiller syndrome—present with uric acid calculi or gouty arthritis but do not have the devastating neurologic and behavioral features characteristic of children with a complete enzyme deficiency.121 Both the complete and ­partial deficiencies are inherited in an X chromosome– linked manner.

Plasma uric acid (mg/100 mL) Figure 87-14  Rate of uric acid excretion at various plasma urate levels in nongouty (blue symbols) and gouty (red symbols) subjects. Large symbols represent mean values; small symbols represent individual data of a few mean values selected to illustrate the degree of scatter within groups. Studies were conducted under basal conditions, after RNA feeding, and after infusions of lithium urate. (From Wyngaarden JB: Gout. Adv Metabol Dis 2:2, 1965. Data from references 90, 113, 116, and 117.)

SECONDARY GOUT Numerous secondary causes of hyperuricemia and gout can be attributed to a decrease in the renal excretion of uric acid. A reduction in the glomerular filtration rate leads to a decrease in the filtered load of urate and, consequently, to hyperuricemia. Patients with renal disease are hyperuricemic on this basis. Other factors, such as decreased secretion of urate, have been postulated in patients with some types of renal disease (e.g., polycystic kidney disease, lead nephropathy). Gout is a rare complication of the secondary hyperuricemia that results from renal insufficiency. When it occurs in this setting, there is likely to be a positive family history. Diuretic therapy currently represents one of the most important causes of secondary hyperuricemia in humans. Diuretic-induced volume depletion leads to a decreased filtered load and enhanced tubular reabsorption of urate. A number of other drugs lead to hyperuricemia by a renal mechanism. These agents include low-dose aspirin, pyrazinamide, nicotinic acid, ethambutol, ethanol, and ­cyclosporine. Decreased renal excretion of uric acid is thought to be an important mechanism for the hyperuricemia associated with several disease states. Volume depletion may be an important factor in patients with hyperuricemia associated with adrenal insufficiency or nephrogenic diabetes insipidus. An accumulation of organic acids leads to hyperuricemia. This is the case in starvation, alcoholic ketosis, diabetic ­ketoacidosis, maple syrup urine disease, and lactic acidosis of any cause (e.g., hypoxemia, respiratory insufficiency,

A

B Figure 87-15  A, Patient with hypoxanthine phosphoribosyltransferase deficiency. B, Example of self-multilating behavior. Note the patient’s agitated appearance and the attempt to bite his fingers after the wrapping is removed from his hands.

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OH

OH C

C

N

N

C

HC

C

CH + PP-Ribose-P N

Mg++

N

N

C

HC

C

CH + F N

N H

N R

Hypoxanthine

P

Inosinic acid

OH

OH

C

C

N

N

C

C

C

CH + PP-Ribose-P H2N

| 

N

Mg++

C

C

C

CH + PP

H2N

N H

N

N N

N R

The level of HPRT activity in patients with each syndrome is the same within a family, but it often differs among families, with values ranging from 0.01% to almost 70% of normal. More than 50 different mutations have been defined.34,122 Among these, major and minor deletions and rearrangements, as well as base substitutions, are represented. The excessive production of urate that characterizes partial HPRT deficiency results from accelerated de novo purine biosynthesis. This is caused by decreased consumption of PRPP and decreased reuse of hypoxanthine through at least three mechanisms. First, the deficiency leads to enhanced purine synthesis by virtue of decreased concentrations of either IMP or GMP, because these nucleotides are normally important inhibitors of de novo purine synthesis. Second, the loss of hypoxanthine reuse leads to decreased ­consumption of PRPP and increased intracellular concentrations of this compound. These increased concentrations of PRPP increase de novo purine biosynthesis by providing more substrate for amidophosphoribosyltransferase, the enzyme that catalyzes the presumed limiting step of this pathway. Third, in the absence of HPRT activity, hypoxanthine cannot be salvaged and is therefore oxidized to urate. Increased PRPP synthetase activity causes accelerated PRPP formation (Fig. 87-17). This, in turn, results in increased de novo purine biosynthesis and excessive overproduction of urate.123,124 Transmitted by X-linked ­inheritance, this disorder causes male subjects to exhibit clinical gout typically between 21 and 39 years of age; they can have renal calculi with an onset as early as 18 years of age.125

CH

CH

CH

OH

OH

D-Ribose

H2O3POCH2

OH

C CH

Figure 87-16  Reactions catalyzed by hypoxanthine-guanine phosphoribosyltransferase.

Guanylic acid

Guanine

H2O3POCH2

P

5'-phosphate

Mg++

O

O

CHOP

O

O CH

ATP

Patients with glucose-6-phosphatase deficiency (von Gierke’s disease, or GSD type I) uniformly exhibit an increased production of uric acid as well as an accelerated rate of de novo purine biosynthesis. A major cause of increased uric acid synthesis is accelerated breakdown of ATP.130 In patients with hereditary fructose intolerance caused by fructose-1-phosphate aldolase deficiency, hyperuricemia develops in part because of accelerated purine nucleotide catabolism. In homozygotes, vomiting and hypoglycemia after fructose ingestion can proceed to hepatic failure and proximal tubular dysfunction. Ingestion of fructose causes an accumulation of fructose-1-phosphate, the substrate for the enzyme, which in turn results in ATP depletion. Both lactic acidosis and renal tubular acidosis also contribute to urate retention. Heterozygous carriers develop hyperuricemia, and perhaps one third develop gout.131 In most patients with secondary hyperuricemia caused by an overproduction of uric acid, the predominant abnormality appears to be an increased turnover of nucleic acids. A number of diseases, including the myeloproliferative and lymphoproliferative disorders, multiple myeloma, secondary polycythemia, pernicious anemia, certain hemoglobinopathies, thalassemia, other hemolytic anemias, infectious mononucleosis, and some carcinomas, may be associated with increased marrow activity or increased turnover and an associated increased turnover of nucleic acids. The increased turnover of nucleic acid, in turn, leads to hyperuricemia, hyperuricaciduria, and a compensatory increase in the rate of de novo purine biosynthesis.

CH

CH OH OH

OH

OH

α 5-Phospho-D-ribosyl-1-pyrophosphate (PP-ribose-P)

OH

Figure 87-17  Reaction catalyzed by ­phosphoribosylpyrophosphate synthetase.

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EXERCISE

Lactate ATP

Lactate Glycogen (V)(III)

GLYCOLYSIS

G1P

ADP (VII)

F6P

AMP

Glucose

G6P Ammonia

S-AMP

Ammonia

IMP Inosine Hypoxanthine

Inosine Hypoxanthine

Inosine

[Liver]

Hypoxanthine

[Muscle] Xanthine Uric acid

[Blood]

Uric acid

[Urine] Figure 87-18  Mechanism of myogenic hyperuricemia in glycogen storage diseases (GSDs). In the three GSDs associated with metabolic myopathy, there is impairment of the metabolic pathways, providing the substrate necessary for adenosine triphosphate (ATP) synthesis. Thus, when ATP is consumed by muscle contraction, accelerated degradation of ATP may occur. (Adapted from Mineo I, Kono N, Hara N, et al: Myogenic hyperuricemia: A common pathophysiologic feature of glycogenosis types III, V, and VII. N Engl J Med 317:75, 1987.)

An important cause of overproduction of uric acid in secondary hyperuricemia appears to be related to the ­acceleration of ATP degradation to uric acid. This can occur with excessive alcohol consumption, myocardial infarction, acute smoke inhalation, respiratory failure, status epilepticus, and strenuous exercise.34 The resulting increase in serum urate levels can be substantial with extreme exercise, as occurs in status epilepticus. Myogenic hyperuricemia has been reported in patients with muscle involvement either in the basal state or after exercise in three GSDs121: debranching enzyme deficiency (GSD type III), myophosphorylase deficiency (GSD type V), and muscle phosphofructokinase ­deficiency (GSD type VII) (Fig. 87-18).132 Excessive formation of ATP degradation products can also occur in carnitine palmitoyltransferase deficiency, myoadenylate deaminase deficiency, and medium-chain acyl-coenzyme A dehydrogenase deficiency.133-135 ACUTE GOUT ATTACKS During the initial phase of an acute gout attack, there is an influx of polymorphonuclear leukocytes into the synovial fluid. Inflammatory cytokines stimulate the synovial lining layer to become hyperplastic and infiltrated with ­neutrophils, monocyte-macrophages, and lymphocytes. These inflammatory responses are triggered by monosodium urate crystals that are either formed de novo or released from preformed deposits in or around the joint. Debris or other factors within the synovial cavity may also provide an initial nucleus for early crystal development.136 Mast cells

may play a critical role in the initial event. They contain preformed proinflammatory substances, including histamine, cytokines, and enzymes, all of which may contribute to the promotion of downstream inflammatory cascades. Depletion of endogenous mast cells has been found to significantly inhibit neutrophil influx in a murine monosodium urate crystal–induced peritonitis model.137 It appears, however, that innate immunity—the system that provides the first line of defense against infectious agents—plays a critical role in the initial inflammatory response in acute gout.138 Monosodium urate crystals activate both the classic and the alternative complement pathways, leading to the production of C5a, which is chemotactic for leukocytes, and the formation of C5b-C9, the membrane attack complex.139 In addition, uncoated monosodium urate crystals can activate macrophages, synovial lining cells, and neutrophils through Toll-like receptor (TLR) 2 and TLR4 signal transduction.140-142 TLRs are found in the cell membrane and survey the extracellular environment for pathogens. Activation of TLR2 and TLR4 not only induces crystal phagocytosis but also is critical for the expression of proinflammatory cytokines, including nuclear factor κB. An intracellular adapter protein, myeloid differentiation factor 88 (MyD88) and another pattern recognition protein, CD14, functionally interact with TLR2 and TLR4 and mediate these inflammatory responses.143-145 Thus, monosodium urate crystals serve as a “warning signal,” just like the ­pathogen­associated molecular pattern does in activating innate immune responses.

PART 14 

The intracellular NALP3 (or calopyrin) inflammasome also appears to play a major role in the acute inflammatory response to monosodium urate crystals.146 NALP3 is expressed primarily in leukocytes.147 When NALP3 is activated, the adapter protein ASC (apoptosis-associated speck-like protein containing a CARD) connects it with caspase-1, resulting in the production of interleukin (IL)-1β and IL-18. A significant component of the early inflammatory response involves vasodilation, with increased blood flow, increased permeability to plasma proteins, and recruitment of leukocytes into the tissues. Initial endothelial activation, with expression of adhesion molecules such as E-selectin, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1, is caused by factors such as IL-1 and tumor necrosis factor-α (TNF-α) released by mast cells.137 Endothelial activation is then amplified by substances released by leukocytes upon entering the tissues and encountering crystals. Leukocyte recruitment is also enhanced by local generation of chemotactic factors, such as C5a, and chemokines, such as S100A8, S100A9, CXCL8, CXCL2, and IL-8.148,149 Uncoated crystals can activate neutrophils but may also cause membranolysis. A number of interstitial fluid proteins bind monosodium urate crystals. These include immunoglobulins (IgG and IgM), adhesion proteins (fibronectin), and complement components. The coating of crystals may protect against cell lysis150 but may activate inflammatory cascades, such as complement and kininogen, and promote direct interactions with specific cell surface receptors, such as leukocyte integrin CD11b/CD18 (CR3) and the FC receptor CD16.139,150,151 These, in turn, cause the release of soluble cellular products, which further amplify the inflammatory response, leading to both local arthritis and a systemic acute-phase response. A number of neutrophil surface receptors are believed to be involved in mediating responses to monosodium urate crystals, including CR3 (CD11b/CD18) and FcγRIII (CD16), which bind crystal-bound iC3b and IgG, respectively.151,152 As a consequence of neutrophil interaction with monosodium urate crystals, a large variety of mediators that promote vasodilation, erythema, and pain associated with the acute gout attack are synthesized and released. These include reactive oxygen species such as superoxide, hydrogen peroxide, and singlet oxygen; nitric oxide; leukotriene B4; prostaglandin E2; antimicrobial peptides; enzymes; IL-1; and the chemokines S100A8, S100A9, and IL-8.153-156 Monocytes also amplify the inflammatory response in acute gout. Following exposure to monosodium urate crystals, monocytes become activated and produce a number of proinflammatory substances, including IL-1, TNF-α, IL-6, IL-8, and prostaglandin E2.157-159 The acute gout attack is usually self-limited, resolving in 7 to 10 days even in the absence of anti-inflammatory therapy. This can be explained by several factors. Proteins coating monosodium urate crystals may significantly modify leukocyte responses during the course of the inflammatory reaction. Coating with either apolipoprotein-B-100 or apolipoprotein-E can reduce the responsiveness of neutrophils to monosodium urate crystals.160 Apolipoprotein-E has been detected on the surface of monosodium urate

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crystals recovered from patients with gout and is probably synthesized locally in synovium. Melanocortins, such as adrenocorticotropic hormone (ACTH) and melanocytestimulating hormone, may contribute to the resolution of an acute attack.161 Further, spontaneous resolution of the acute attack may involve the induction of transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ), which functions as an important negative regulator of the inflammatory response.162 PPAR-γ expression can be detected in monocytes after exposure to monosodium urate crystals and is capable of inhibiting the production of IL-1ß and TNF-α and cellular infiltration. Differentiated macrophages also play an important role in the resolution of an acute gout attack. Monosodium urate crystals can be found in asymptomatic joints of patients in the intercritical phase of gout.38 The crystals are typically found within macrophages and almost never within neutrophils. Thus, macrophage–monosodium urate crystal interaction can occur without triggering an inflammatory response and appears to reflect a differential response of monocytes and macrophages to the ­crystals.163,164 Following exposure to monosodium urate crystals, undifferentiated peripheral blood monocytes secrete proinflammatory cytokines (IL-1ß, TNF-α, and IL-6), induce endothelial activation, and promote neutrophil adhesion to endothelial cells. However, differentiation of monocytes into mature macrophages leads to loss of the capacity to release proinflammatory cytokines capable of activating endothelial cell adhesion molecule expression. This loss of the ability to secrete proinflammatory cytokines such as TNF-α is accompanied by an increased capacity to release transforming growth factor-β1 (TGF-ß1). High levels of TGF-ß1 are present in the synovial fluid of patients with acute gout, and TGF-ß1 is a key soluble factor in the suppression of monosodium urate–induced inflammation by differentiated macrophages.165,166 TOPHACEOUS GOUT Histologically, tophi are granulomas of mono- and multinucleated macrophages surrounding a core of debris and monosodium urate crystals, encased by dense connective tissue. Within the tophus, macrophages express late or mature differentiation markers and show high levels of apoptosis. However, in perivascular regions, most of the mononucleated monocyte-macrophages express surface markers of recent migration.167 Therefore, development of gouty tophi is a dynamic process consisting of low-level continuous recruitment, proinflammatory activation, maturation, and turnover of monocyte-macrophages.157,167 Tophi are frequently associated with erosion of cartilage and bone (see Fig. 87-5). Monocyte-macrophages within the gouty tophus produce matrix metalloproteinase (MMP)-2 (gelatinase-A) and MMP-9 (gelatinase-B), enzymes that are capable of degrading type IV and type V collagen, elastin, and gelatine.167 Resident stromal cells also produce MMPs on exposure to monosodium urate crystals, with chondrocytes producing MMP-3 (stromelysin 1) and synovial fibroblasts producing MMP-1 (collagenase).168,169 These enzymes likely play a role in the degradation of tissues adjacent to the tophus.

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TREATMENT OF GOUT

ACUTE GOUTY ARTHRITIS

The therapeutic aims in gout are as follows: 1. To terminate the acute attack as promptly and gently as possible 2. To prevent recurrences of acute gouty arthritis 3. To prevent or reverse complications of the disease resulting from the deposition of sodium urate or uric acid crystals in joints, kidneys, or other sites 4. To prevent or reverse associated features of the illness that are deleterious, such as obesity, hypertriglyceridemia, and hypertension

The acute gouty attack may be successfully terminated by any of several drugs. For practical purposes, the choice in most situations is among colchicine, an NSAID, a corticosteroid preparation, or ACTH. The timing of therapy initiation is more important than the choice of drug.173 With any of these agents, the sooner the drug is started, the more rapidly a complete response will be attained. Generally, colchicine is preferred for patients in whom the diagnosis of gout is not confirmed, whereas NSAIDs are preferred when the diagnosis is secure. If a patient cannot take medications by mouth or has active peptic ulcer disease, the choice is among intravenous colchicine, intra-articular glucocorticoid, or parenteral glucocorticoid. Local application of ice packs may help control the pain of an acute attack.174 In some cases, analgesics, including narcotics, may be added as well. Drugs that affect serum urate concentrations, including antihyperuricemic agents, should not be changed (either started or stopped) during an acute attack. Just as sudden fluctuations in serum urate levels tend to precipitate an acute attack, an inflammatory reaction that is already in progress may be substantially worsened by a major change in the serum urate concentration.

ASYMPTOMATIC HYPERURICEMIA The presence of hyperuricemia is rarely an indication for specific antihyperuricemic drug therapy. Rather, the finding of hyperuricemia should cause the following questions to be addressed: 1. What is the cause of the hyperuricemia? 2. Are associated findings present? 3. Has damage to tissues or organs occurred as a result? 4. What, if anything, should be done? Hyperuricemia may be the initial clue to the presence of a previously unsuspected disorder. In 70% of hyperuricemic patients, an underlying cause can be readily defined by history and physical examination. The nature of the underlying cause may be useful in predicting the potential consequences, if any, of the elevated serum urate concentration. Therefore, an underlying cause should be sought in every patient with hyperuricemia. Whether to treat hyperuricemia uncomplicated by articular gout, urolithiasis, or nephropathy is an exercise in clinical judgment, and universal agreement is lacking. When considering whether to treat asymptomatic hyperuricemia with urate-lowering agents, the following data are pertinent: • Although there is intriguing data from animal models to the contrary,170 there is no good evidence that renal function is adversely affected by elevated serum urate concentrations. • The renal disease that accompanies hyperuricemia is most often related to inadequately controlled hypertension. • Although debate exists regarding whether hyperuricemia is an independent risk factor for coronary artery disease,65-68 there is no evidence that correction of ­hyperuricemia has an effect on the development of heart disease. Thus, it seems prudent not to treat hyperuricemia with specific antihyperuricemic agents until symptoms develop. Rare exceptions include individuals with a known hereditary cause of uric acid overproduction or patients at risk for acute uric acid nephropathy. It is, however, strongly recommended that the cause of hyperuricemia be determined and any associated ­ factors related to the process, such as obesity, hyperlipidemia, ­alcoholism, and, especially, hypertension, be addressed. Fenofibrate and losartan might be appropriate agents for the treatment of hypertriglyceridemia and hypertension, respectively, in hyperuricemic individuals, because each has modest uricosuric effects.171,172

Colchicine Colchicine can be administered orally or intravenously.175 In the past, the traditional oral dosing schedule was 0.5 or 0.6 mg taken hourly until one of three things occurred: joint symptoms eased; nausea, vomiting, or diarrhea developed; or the patient had taken a maximum of 10 doses. If 10 doses were taken without benefit, the clinician questioned the accuracy of the diagnosis. Today, many clinicians recommend that doses be taken every 2 to 6 hours to reduce side effects.176 Peak plasma concentrations occur within 2 hours of oral administration. Although its plasma half-life is 4 hours, levels can be detected in neutrophils 10 days after ingestion. Colchicine has a low therapeutic index, with steadystate plasma concentrations after acute treatment ranging from 0.5 to 3.0 ng/mL and with toxic effects occurring at approximately 3 ng/mL.177 Therefore, in most patients, the side effects precede or coincide with the improvement in joint symptoms. These side effects develop in 50% to 80% of patients and include increased peristalsis, cramping abdominal pain, diarrhea, nausea, and vomiting. The drug must be stopped promptly at the first sign of gastrointestinal side effects.178 Colchicine derives its effectiveness from its ability to interfere with acute inflammatory reactions in a variety of ways. Colchicine blocks the processing of IL-1β146 and inhibits E-selectin–mediated adhesiveness to neutrophils.155 Its action diminishes neutrophil L-selectin expression, random motility, chemotaxis, phospholipase A2 activation, and IL-1 expression, as well as the stimulated elaboration of platelet-activating factor, crystal-induced chemotactic factor, and leukotriene B4. Colchicine also inhibits endothelial cell ICAM-1 expression and mast cell histamine release and downregulates TNF-α receptors on macrophages and endothelial cells.

PART 14 

Colchicine can also be given intravenously, but this route is often discouraged because adverse outcomes, including death, can occur with inappropriate dosing.179,180 When used properly, the drug abolishes the acute attack with a low incidence of gastrointestinal side effects (provided the patient is not also taking oral colchicine). An initial dose of 1 or 2 mg can be followed by one or two additional 1-mg doses administered at 6-hour intervals, if needed. The total dose of intravenous colchicine should not exceed 4 mg. Colchicine should be diluted with 20 mL of normal saline before administration and given slowly into a secure venous access to minimize sclerosis of the vein. Extravasation can lead to severe local necrosis. In addition, oral colchicine should be discontinued, and no additional colchicine should be given for at least 7 days because of the slow excretion of this drug. Nonsteroidal Anti-inflammatory Drugs In a patient with an established diagnosis of uncomplicated gout, the preferred agent is an NSAID, and indomethacin has been the traditional choice. Although this drug may be effective in doses as low as 25 mg four times a day, an initial dose of 50 to 75 mg, followed by 50 mg every 6 to 8 hours, with a maximum dose of 200 mg in the first 24 hours, has generally been recommended. To prevent relapse, it is reasonable to continue this dose for an additional 24 hours, then to taper to 50 mg every 6 to 8 hours for the next 2 days. Clinical trials have shown that oral naproxen, fenoprofen, ibuprofen, sulindac, piroxicam, and ketoprofen, as well as intramuscular ketorolac, are also effective. In fact, all members of this family of drugs can be highly effective in the treatment of acute gouty arthritis, including the cyclooxygenase-2 (COX-2) selective agents.181 Corticosteroids Intra-articular glucocorticoids are useful in the treatment of acute gout limited to a single joint or bursa.173,182 Oral, intramuscular, or intravenous glucocorticoids can also provide relief, but these agents are usually reserved for patients who are intolerant of colchicine or NSAIDs or who have medical conditions such as peptic ulcer disease or renal disease that contraindicate their use. Doses of glucocorticoids have been systematically studied, and generally, high doses (prednisone 20 to 60 mg/day) are needed. Lower doses may not be effective, as evidenced by gout flares occurring in organ transplant patients who are taking maintenance prednisone at doses of 7.5 to 15 mg a day.183 Anecdotally, rebound attacks have been reported as steroids were withdrawn. Adrenocorticotropic Hormone Single injections of intramuscular ACTH gel (25 to 80 IU) can terminate an acute gout attack.184 More often, however, repeated administration is required every 24 to 72 hours. This treatment is effective postoperatively and may be more effective than glucocorticoids, possibly related to the mechanism of action. In addition to stimulating the adrenal cortex to produce corticosteroids, ACTH interferes with the acute inflammatory response through activation of melanocortin receptor-3.161

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Prophylaxis The practice of giving small daily doses of colchicine as prophylaxis to prevent acute attacks is up to 85% effective.185 Colchicine 0.6 mg one to three times a day is generally well tolerated, although the drug may produce a reversible axonal neuromyopathy.186 This complication causes proximal muscle weakness with or without painful paresthesia and elevated serum levels of creatine phosphokinase. This is most often seen in patients with hypertension, renal dysfunction, or liver disease who are also using diuretics. Rhabdomyolysis may also occur in these settings and is more common in individuals who are also taking a statin (HMGCoA reductase inhibitor) or cyclosporine.187 In patients who are unable to tolerate even one colchicine tablet per day, indomethacin or another NSAID has been used prophylactically at low doses (e.g., 25 mg indomethacin twice a day or naproxen 250 mg/day), with some success.188 Maintenance doses of colchicine or an NSAID may make the difference between frequent incapacitation and uninterrupted daily activities. Prophylaxis is usually continued until the serum urate value has been maintained well within the normal range and there have been no acute attacks for 3 to 6 months. It is important to warn patients that colchicine discontinuation may be followed by an exacerbation of acute gouty arthritis and advise them what to do should an attack occur. Finally, prophylactic treatment is not recommended unless the clinician also uses urate-­lowering agents. Prophylactic colchicine may block the acute inflammatory response but does not alter the deposition of crystals in tissues. When deposition continues without the warning signs of recurrent bouts of acute arthritis, tophi and destruction to cartilage and bone can occur without notice. CONTROL OF HYPERURICEMIA Elimination of hyperuricemia with antihyperuricemic agents can prevent as well as reverse urate deposition. Today, opinion differs as to when in the course of gout the clinician should start antihyperuricemic therapy. Some physicians regard the first gouty attack as a late event in a disorder marked by years of antecedent silent deposition of urate crystals in cartilage and other connective tissue. Others believe that because tophi and symptomatic chronic gouty arthritis develop in only a minority of cases and ordinarily develop very slowly after many years of recurrent acute attacks, unnecessary or premature medication can be avoided without demonstrable penalty. In practice, it is the rare patient who never experiences a second attack.36 The probability of such a benign course is greatest in patients who have only minimally elevated serum urate concentrations and normal 24-hour urinary uric acid values. Arguably, a case can be made for initiating antihyperuricemia therapy after the second attack in most patients.189 Antihyperuricemic drugs provide a definitive method for controlling hyperuricemia. Although it is important to treat and prevent acute attacks of gouty arthritis with anti-inflammatory agents, it is the long-term control of hyperuricemia that ultimately modifies the manifestations of the gouty diathesis. Once started, treatment with specific urate-lowering

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agents is lifelong, and the dose must be sufficient to maintain the serum urate level below 6.8 mg/dL, and preferably between 5 and 6 mg/dL. Lowering the serum urate level from 11 mg/dL to 7.5 mg/dL may seem encouraging, but this change does not reverse the process. It merely slows the rate at which crystals continue to deposit. Generally, the lower the serum urate level achieved during antihyperuricemic therapy, the faster the reduction in tophaceous deposits.190 The 5 to 6 mg/ dL target is recommended because it is far enough below the saturation level of 6.8 mg/dL that it provides some margin for fluctuations in serum levels and avoids excessive exposure to the medication, which might increase the chance of toxicity. Reduction to target levels may be achieved pharmacologically by the use of xanthine oxidase inhibitors or uricosuric agents. Xanthine oxidase, the enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid, is inhibited by allopurinol and oxypurinol. Probenecid, sulfinpyrazone, and benzbromarone are uricosuric agents that reduce serum urate concentrations by enhancing the renal excretion of uric acid. These antihyperuricemic drugs do not have anti-inflammatory properties. For those patients with gout who excrete less than 800 mg of uric acid per day and have normal renal function, reduction of the serum urate concentration can be achieved equally well with a xanthine oxidase inhibitor or a uricosuric drug. These agents are equally effective in preventing the deterioration of renal function in patients with primary gout.191 In most cases, allopurinol is the drug of choice because it can be used with fewer restrictions compared with uricosuric agents. In general, the ideal candidate for uricosuric agents is a gouty patient who is younger than 60 years and has normal renal function (creatinine clearance >80 mL/min), uric acid excretion of less than 800 mg per 24 hours on a general diet, and no history of renal calculi. Patients prescribed uricosuric agents should be counseled to avoid salicylate use at doses greater than 81 mg/day.192 In certain situations, an inhibitor of xanthine oxidase is clearly the drug of choice in a gouty patient. Gouty individuals who excrete larger quantities of uric acid in their urine or who have a history of renal calculi of any type should be treated with allopurinol (Table 87-5). The incidence of renal calculi is about 35% in patients with primary gout who excrete more than 700 mg/day of uric acid.90 There is also a greater risk for uric acid stones on initiation of uricosuric therapy. In addition, patients with tophi generally should receive allopurinol to decrease the load of urate that must be handled by the kidney. Patients with gout and mild renal insufficiency can be given either type of agent, Table 87-5  Indications for Allopurinol Hyperuricemia associated with increased uric acid production Urinary uric acid excretion of 1000 mg or more in 24 hr Hyperuricemia associated with HPRT deficiency or PRPP   synthetase overactivity Uric acid nephropathy Nephrolithiasis Prophylaxis before cytolytic therapy Intolerance or reduced efficacy of uricosuric agents Gout with renal insufficiency (GFR <60 mL/min) Allergy to uricosurics GFR, glomerular filtration rate; HPRT, hypoxanthine phosphoribosyltransferase; PRPP, phosphoribosylpyrophosphate.

but ­ probenecid and sulfinpyrazone would not be expected to work when the glomerular filtration rate is less than 50 mL/min. Allopurinol is effective in the presence of renal insufficiency, but doses may have to be decreased in that situation. A final indication for a xanthine oxidase inhibitor is the failure of uricosuric agents to produce a serum urate concentration lower than 6 mg/dL or patient intolerance of the uricosuric agent. Allopurinol and a uricosuric drug may be used in combination for a patient with tophaceous gout in whom it is not possible to reduce the serum urate below 6 mg/dL with a single agent. In most settings, if allopurinol does not cause the serum urate to drop below 6 mg/dL, it is the result of insufficient dosing or poor patient compliance. Xanthine Oxidase Inhibitors Allopurinol is presently the only xanthine oxidase inhibitor approved for use, but others are under development. Allopurinol is a substrate for xanthine oxidase and is converted to oxypurinol by that enzyme activity. Oxypurinol is also an inhibitor of xanthine oxidase. Allopurinol is metabolized in the liver and has a half-life of 1 to 3 hours, but oxypurinol, which is excreted in the urine, has a half-life of 12 to 17 hours. Because of these pharmacokinetic properties, allopurinol is dosed on a daily basis, and the dosage required to reduce serum urate levels is lower in patients with decreased glomerular filtration rates. In 1984, guidelines for allopurinol dosing based on creatinine clearance were published (Table 87-6).193 It is now apparent that these guidelines are useful for selecting the initial dosage of allopurinol, but they do not provide the effective maintenance dose for many individuals, and ­following them does not protect against cutaneous hypersensitivity reactions.194-196 Allopurinol should be used at the lowest dose that lowers the serum urate level below 5 to 6 mg/dL. The most commonly prescribed dose is 300 mg/day, but this is insufficient to adequately reduce serum urate to the target level in 21% to 55% of individuals.21,197,198 Thus, higher doses, with a maximum of 800 mg/day, may be required. The sudden Table 87-6  Maintenance Doses of Allopurinol Based   on Creatinine Clearance Measurement* Creatinine Clearance (mL/min)

Allopurinol Dose (mg)

0

100 every 3 days

10

100 every 2 days

20

100 daily

40

150 daily

60

200 daily

80

250 daily

100

300 daily

120

350 daily

140

400 daily

*These doses represent those that might be selected when initiating therapy with allopurinol. However, urate levels should be checked and the ­dosage adjusted so that the patient is taking the lowest dose that maintains the serum urate level below 5 to 6 mg/dL. From Hande KR, Noone RM, Stone WJ: Severe allopurinol toxicity: Description and guidelines for presentation in patients with renal insufficiency. Am J Med 76:47, 1984.

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lowering of serum urate concentrations that accompanies the initiation of allopurinol therapy may trigger acute gout attacks. This risk can be minimized by beginning prophylactic colchicine or NSAlD (see the previous discussion) 2 weeks before the first dose of allopurinol. Alternatively, the clinician can start allopurinol at a dose of 50 to 100 mg/ day and increase it by similar increments weekly until the desired target is reached. About 20% of patients who take allopurinol report side effects, with 5% discontinuing the medication. Common side effects include gastrointestinal intolerance and skin rashes. The occurrence of a rash does not necessarily mean the drug should be discontinued. If the rash is not severe, the allopurinol can be withheld temporarily and resumed after the rash has cleared. Oxypurinol has been tried in patients who are sensitive to allopurinol, but its use is limited by poor gastrointestinal absorption and a high prevalence of cross-reactivity with allopurinol. Oral and intravenous protocols for desensitization to allopurinol have been successful in some patients following cutaneous reactions.188,199 Other adverse reactions include fever, toxic epidermal necrolysis, alopecia, bone marrow suppression with leukopenia or thrombocytopenia, agranulocytosis, aplastic anemia, granulomatous hepatitis, jaundice, sarcoid-like reaction, and vasculitis. The most severe reaction is the allopurinol hypersensitivity syndrome, which may include fever, skin rash, eosinophilia, hepatitis, progressive renal insufficiency, and death.193,200 Autopsies reveal diffuse vasculitis involving multiple organs. This is most likely to develop in individuals with preexisting renal dysfunction and those taking diuretics. Allopurinol is involved in relatively few drug-drug interactions. Its use potentiates the actions of other agents that are inactivated by xanthine oxidase. The most important of these are azathioprine and 6-mercaptopurine. In addition, allopurinol can reduce the activity of hepatic microsomal drug-metabolizing enzymes and prolong the half-lives of warfarin and theophylline. Rash may be more common in patients using allopurinol and ampicillin, and bone marrow suppression may be increased in those also taking cyclophosphamide. Phase III studies with febuxostat have been completed.21 Febuxostat is a potent xanthine oxidase inhibitor that differs from allopurinol in that it is of another chemical class and is a selective inhibitor of enzyme activity. These properties indicate that it would be an excellent alternative for individuals who are intolerant of or hypersensitive to allopurinol. In addition, the dosage of febuxostat does not need to be adjusted in individuals with mild to moderate renal insufficiency.

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secretory transport system is quantitatively much smaller than that for reabsorption and is located in the basolateral membrane of the tubule, when uricosuric agents are taken in very low doses, they actually decrease the renal excretion of uric acid and raise serum urate levels by inhibiting the secretory transport system. Probenecid and sulfinpyrazone are the most widely used uricosuric agents available in the United States; benzbromarone is used for this purpose in other countries as well. However, many other agents can reduce serum urate levels by enhancing the renal excretion of uric acid (see Table 87-3). Probenecid is readily absorbed from the gastrointestinal tract. Its half-life in plasma is dose dependent, varying from 6 to 12 hours. This can be prolonged by the concomitant use of allopurinol. Probenecid is metabolized in vivo, with less than 5% of the administered dose recovered in the urine. The maintenance dosage of probenecid ranges from 500 mg to 3 g per day and is administered two or three times a day. Acute gouty attacks may accompany the initiation of this medication, and, as with all uricosuric agents, patients using probenecid are at increased risk for developing renal calculi. With long-term use, up to 18% of individuals develop gastrointestinal complaints, and 5% develop hypersensitivity and rash. Although serious toxicity is rare, approximately one third of individuals eventually become intolerant of probenecid and discontinue its use. Probenecid alters the metabolism of several other agents by several mechanisms (Table 87-7). Concomitant use of probenecid can increase the potency of some agents by decreasing their renal ­excretion, delaying their metabolism, or impairing their hepatic uptake. It may decrease the effectiveness of other medications by reducing their volume of distribution. Sulfinpyrazone is completely absorbed from the gastrointestinal tract and has a half-life of 1 to 3 hours. Most of the drug is excreted in the urine as the parahydroxyl metabolite, Table 87-7  Effects of Probenecid on Metabolism   of Other Drugs Decreased Renal Excretion p-Aminohippuric acid Phenolsulfonphthalein Salicylic acid and its acyl and phenolic glucuronides Phlorizin and its glucuronide Acetazolamide Dapsone and its metabolites Sulfinpyrazone and its parahydroxyl metabolite Indomethacin Ampicillin Penicillin Cephradine Reduced Volume of Distribution

Uricosuric Agents Administration of a uricosuric agent increases the rate of renal uric acid excretion.201 In the kidney, there are separate transport systems for the secretion and reabsorption of organic ions, including uric acid. Because urate is reabsorbed by a renal tubular brush border anion transporter, the reabsorption of urate can be inhibited when uricosuric agents are present in the lumen and compete with urate for the transporter. This inhibition of reabsorptive anion transporter requires high doses of uricosuric agents. Because the

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which is also uricosuric. Sulfinpyrazone is usually given at a dosage of 300 to 400 mg/day divided into three or four doses. The rates of tolerability and types of adverse reactions are similar to those with probenecid. Benzbromarone is more potent than probenecid and sulfinpyrazone.191 It is well tolerated and effective in cyclosporine-treated renal transplant patients. It can be used in those with moderate renal dysfunction (creatinine clearance approximately 25 mL/min).

COMPLIANCE WITH TREATMENT Because the disease processes involved in gout are so well understood, the diagnosis can be definitively established. Once gout is diagnosed, the available therapies are so effective that it should be a readily treated and easily managed disease. However, too many patients, including those who are accurately diagnosed, do not do well. Failure of antihyperuricemic therapy to attain the target urate level is usually due to improper prescribing or poor compliance.194 Compliance is often a problem when treating chronic asymptomatic conditions, and associated alcoholism can be a factor. Perhaps more important is the fact that patients may need to take up to three different medications on three different schedules to control their symptoms and treat the disease. It is believed that if patients understand why they are taking medications, they are more likely to be compliant. Toward this end, an analogy has been developed that helps some patients become more compliant.202 In this analogy, urate crystals are compared to matches. The patient is told that “when the match strikes,” it causes a gout attack. To “put out the fire,” the patient takes an NSAID or colchicine. Although this resolves the attack, “the matches are still there.” To eliminate future attacks, the patient is given prophylactic colchicine, “which makes the matches damp and harder to strike,” and allopurinol (or a uricosuric agent), “which actually removes the matches from the body.”

MANAGEMENT OF GOUT AFTER ORGAN TRANSPLANTATION The management of patients with gout after organ transplantation requires careful consideration. The use of glucocorticoids, azathioprine, or cyclosporine and the precarious status of renal function in many patients pose complex problems. Colchicine and NSAIDs may be inappropriate for the management of acute gouty arthritis in this setting because of their potential toxicities. Intra-articular glucocorticoid injections may be most helpful, and one may be forced to rely more heavily on pain medications in this setting. Prophylactic colchicine can be used in patients with normal renal function, but treatment must be monitored closely. The combination of colchicine and cyclosporine has induced rhabdomyolysis.187 When considering chronic therapy, it is helpful to lower the doses of cyclosporine and eliminate the use of diuretics, if possible. Uricosuric agents can be used safely, but their usefulness declines if renal function is poor. Allopurinol can be used in patients with abnormal renal function, but the dose may need to be reduced. Allopurinol, however, may have a severe interaction with azathioprine. Azathioprine is metabolized by xanthine oxidase, and because

a­ llopurinol inhibits that enzyme, the breakdown of azathioprine is slowed, increasing the effective dose. If care is not taken, significant bone marrow toxicity can result. If azathioprine and allopurinol are used together, they can be started at 25 and 50 mg/day, respectively.203 Complete blood counts and serum urate level concentrations are then monitored weekly, and the allopurinol dose is adjusted to bring the serum urate concentration to less than 6 mg/dL. As an alternative to azathioprine, mycophenolate mofetil has been used effectively with allopurinol in some transplant patients.204 Urate oxidase has been used to drastically lower serum urate levels and shrink tophi in a small number of patients with gout after cardiac transplantation.205 This treatment has been associated with significant allergic reactions, including anaphylaxis, bronchospasm, and hemolytic anemia, but newer preparations of uricase formulated with polyethylene glycol may avoid those complications and prove more effective.206

ANCILLARY FACTORS In addition to anti-inflammatory agents, colchicine prophylaxis, and antihyperuricemic therapy, other factors may be decisive in determining whether recurrent attacks, chronic gouty arthritis, kidney stones, or nephropathy develops. Today, dietary purine restriction solely to control serum urate levels is rarely advised. A totally purine-free diet reduces the urinary excretion of uric acid by only 200 to 400 mg/day and lowers the mean serum urate value by about 1 mg/dL. In addition, the antihyperuricemic agents available today are so effective that this type of dietary manipulation is rarely needed. Nevertheless, beneficial results have been reported with a diet of moderate calorie and carbohydrate restriction and a proportionally increased intake of protein and unsaturated fat.207 Some subjects with gout are susceptible to acute attacks after the consumption of alcoholic beverages or rich foods. Others describe idiosyncratic responses, such as acute gout after eating a particular food, but such relationships are rare and questionable. A diet designed to avoid indiscretions known to precipitate acute gouty attacks in a particular individual is recommended. In addition, diet is very important with regard to other medical problems.208 Many gouty patients are overweight, and restoration of ideal body weight through regulated calorie restriction is recommended. In addition, at least 75% of patients with primary gout have hypertriglyceridemia. The initial step in managing hypertriglyceridemia is reduction to ideal body weight and elimination of alcohol ingestion. Many patients with gout consume liberal amounts of alcohol. Acute excesses may lead to exacerbations of hyperuricemia secondary to temporary hyperlactacidemia, and chronic ingestion of alcohol may stimulate increased purine production.74 The added purine load resulting from regular ingestion of beer may also be a contributing factor. Patients should be warned about the deleterious effects of excessive alcohol intake. Compliance with medication is also much worse among patients who consume alcohol. About one third of gouty subjects are hypertensive. The complications of hypertension are potentially more serious than those of hyperuricemia, and the clinician should not hesitate to use whatever drugs are necessary to control the

PART 14 

hypertension. Many hypertensive gouty patients require a thiazide diuretic. If this medication is needed to control hypertension, it should be used, with the recognition that the dosage of concomitant antihyperuricemic therapy may need to be adjusted to maintain appropriate control of serum urate levels. REFERENCES   1. Wyngaarden JD, Kelley WN: Gout and Hyperuricemia. New York, Grune & Stratton, 1976.   2. Wortmann RL, Schumacher HR Jr, Becker MA, Ryan LM: CrystalInduced Arthropathies: Gout, Pseudogout, and Apatite-Associated Syndromes. New York, Informa Healthcare, 2006.   3. Currie W: Prevalence and incidence of the diagnosis of gout in Great Britain. Ann Rheum Dis 38:101, 1979.   4. Klemp P, Stansfield S, Castle B, Robertson M: Gout is on the increase in New Zealand. Ann Rheum Dis 56:22, 1997.   5. Mikuls TR, Saag KG: New insights into gout epidemiology. Curr Opin Rheumatol 18:199, 2006.   6. Darmawan J, Valkenburg HA, Muirden KD, Wigley RD: The epidemiology of gout and hyperuricemia in a rural population in Java. J Rheumatol 19:1595, 1992.   7. Park YB, Park YS, Lee WK, et al: Clinical manifestations of Korean female gouty patients. Clin Rheumatol 19:142, 2000.   8. Chang H-Y, Pan W-H, Yeh W-T, et al: Hyperuricemia and gout in Taiwan: Results of the nutritional and health survey in Taiwan. J Rheumatol 28:1640, 2001.   9. Cameron JS, Moro F, Simmonds HA: Gout, uric acid, and purine metabolism in pediatric nephrology. Pediatr Nephrol 17:105, 1993. 10. Marinello E, Giuseppe RS, Marcolongo R: Plasma follicle-stimulating hormone, luteinizing hormone, and sex hormones in patients with gout. Arthritis Rheum 28:127, 1985. 11. Arromlee E, Michet CJ, Crowson CS, et al: Epidemiology of gout: Is the incidence rising? J Rheumatol 29:2403, 2002. 12. Wallace KL, Riedel AA, Joseph-Ridge N, Wortmann RL: Increased prevalence of gout and hyperuricemia over 10 years among older adults in a managed care population. J Rheumatol 31:1582, 2004. 13. Campion EW, Glynn RJ, deLabry LO: Asymptomatic hyperuricemia: The risks and consequences. Am J Med 82:421, 1987. 14. Choi H, Atkinson KK, Karlson E, et al: Alcohol intake and risk incidence of gout in men: A prospective study. Lancet 363:1277, 2004. 15. Choi HK, Liu S: Intake of purine-rich foods, protein, and dairy products and relationship to serum levels of uric acid: The Third National Health and Nutrition Examination Survey. Arthritis Rheum 52:283, 2005. 16. Parhami N, Feng H: Gout in the hip joint. Arthritis Rheum 36:1026, 1993. 17. Musgrave DS, Ziran BH: Monoarticular acromioclavicular joint gout. Am J Orthop 29:544, 2000. 18. Weinzweig J, Gletcher JW, Lindburg RM: Flexor tendonitis and median nerve compression caused by gout in a patient with rheumatoid arthritis. Plast Reconstr Surg 106:1570, 2000. 19. Townsend D, Vasu P: Gouty tenosynovitis—more common than we think? N Z Med J 117:1188, 2004. 20. Lally EV, Zimmerman B, Ho G, Kaplan SR: Urate-mediated inflammation in nodal osteoarthritis: Clinical and roentgenographic correlations. Arthritis Rheum 32:86, 1989. 21. Becker MA, Schumacher HR, Wortmann RL, et al: A study comparing safety and efficiency of oral febuxostat and allopurinol in subjects with hyperuricemia and gout. N Engl J Med 353:2450, 2005. 22. Hunter DJ, York M, Chaisson CE, et al: Recent diuretic use and the risk of recurrent gout attacks: The online case-crossover gout study. J Rheumatol 33:1341, 2006. 23. Khalifa P, Sereni D, Boissonnas A, et al: Attacks of gout and thromboembolic disease: Role of heparin therapy. Ann Intern Med 136:582, 1985. 24. Howe S, Edwards NL: Controlling hyperuricemia and gout in cardiac transplant recipients. J Musculoskel Med 12:15, 1995. 25. Kalia KK, Moossy JJ: Carpal tunnel release complicated by acute gout. Neurosurgery 33:1102, 1993. 26. Williamson SC, Roger DJ, Petrera P, Glockner F: Acute gouty arthropathy after total knee arthroplasty: A case report. J Bone Joint Surg Am 76:126, 1994.

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56. Tsutsumi S, Yamamoto T, Moriwaki Y, et al: Decreased activities of lipoprotein lipase and hepatic triglyceride lipase in patients with gout. Metabolism 50:952, 2001. 57. Mikkelsen WM: The possible association of hyperuricemia and/or gout with diabetes mellitus. Arthritis Rheum 8:853, 1965. 58. Denis G, Launay MP: Carbohydrate intolerance in gout. Metabolism 18:770, 1969. 59. Feig DI, Johnson RJ: Hyperuricemia in childhood primary hypertension. Hypertension 42:247, 2003. 60. Cappuccio FP, Stazzullo P, Farinaro E, Trevisan M: Uric acid metabolism and tubular sodium handling: Results from a population based study. JAMA 270:354, 1993. 61. Kang DH, Nakagawa T, Feng L, et al: A role for uric acid in the progression of renal disease. J Am Soc Nephrol 13:1288, 2002. 62. Mazzali M, Kanellis J, Han L, et al: Hyperuricemia induces primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Renal Physiol 282:F991, 2002. 63. Brand FN, McGee DL, Kannel WB, et al: Hyperuricemia as a risk factor for coronary heart disease: The Framingham Heart Study. Am J Epidemiol 121:11, 1985. 64. Gelber AC, Klag MJ, Mead LA, et al: Gout and risk for subsequent coronary heart disease: The Meharry-Hopkins Study. Arch Intern Med 157:1436, 1997. 65. Culleton BF, Larson MG, Kannel WB, Levy D: Serum uric acid and the risk for cardiovascular disease and death: The Framingham Heart Study. Ann Intern Med 131:7, 1999. 66. Grundy SM, Balady GJ, Criqui MH, et al: Primary prevention of coronary heart disease: Guidance from Framingham. A statement of health care professionals from the AHA task force on risk reduction. Circulation 97:1876, 1998. 67. Fang J, Alderman MH: Serum uric acid and cardiovascular mortality: The NHANES I Epidemiologic Follow-up Study, 1971-1992. JAMA 283:2404, 2000. 68. Verdecchia P, Schillaci G, Reboldi GP, et al: Relation between serum uric acid and risk of cardiovascular disease in hypertension: The PIUMA Study. Hypertension 36:1072, 2000. 69. Chou P, Lin K-C, Lin Y-H, et al: Gender differences in the relationship of serum uric acid with fasting serum insulin and plasma glucose in patients without diabetes. J Rheumatol 28:571, 2001. 70. Takahashi S, Moriwaki Y, Tsutsuni Z, et al: Increased visceral fat accumulation further aggravates the risks of insulin resistance in gout. Metabolism 50:393, 2001. 71. Ford ES, Giles WH, Dietz WH: Prevalence of metabolic syndrome among US adults: Findings of the Third National Health and Nutrition Examination Survey. JAMA 287:356, 2002. 72. Krishnan E, Baker JF, Furst DE, Schumacher HR: Gout and the risk of acute myocardial infarction. Arthritis Rheum 54:2688, 2006. 73. Al-Arfaj AS: Hyperuricemia in Saudi Arabia. Rheumatol Int 20:61, 2001. 74. Puig JG, Fox IH: Ethanol-induced activation of adenine nucleotide turnover: Evidence for a role of acetate. J Clin Invest 74:936, 1984. 75. Giordano N, Santacroce C, Mattii G, et al: Hyperuricemia and gout in thyroid endocrine disorders. Clin Exp Rheumatol 19:661, 2001. 76. Nordstrom DM, Merenich JA: The relationship of gout to hyperthyroidism [abstract]. Arthritis Rheum 32:S68, 1989. 77. Woolliscroft JO, Fox IH: Increased body fluid purines during hypotensive events: Evidence for ATP degradation. Am J Med 81:472, 1986. 78. Grum CM, Simon RH, Dantzker DR, Fox IH: Biochemical indicators of cellular hypoxia in critically ill patients: Evidence for ATP degradation. Chest 88:763, 1985. 79. McCord J: Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 312:159, 1985. 80. Lind T, Godfrey KA, Otun H: Changes in serum uric acid concentrations during normal pregnancy. Br J Obstet Gynaecol 91:128, 1984. 81. Liedholm H, Montan S, Aberg A: Risk grouping of 113 patients with hypertensive disorders during pregnancy, with respect to serum urate, proteinuria and time of onset of hypertension. Acta Obstet Gynecol Scand 118(Suppl):43, 1984. 82. Wooten MD, Lipsmeyer E: Gout accompanying rheumatoid arthritis: A comparison of affected women and men. J Clin Rheumatol 4:220, 1998. 83. Wall BA, Agudelo CA, Weinblatt ME, et al: Acute gout and systemic lupus erythematosus: Report of 2 cases and literature review. J Rheumatol 9:305, 1982.

84. Wong DMT, Chambers LM: Coexistent acute gouty arthritis and ankylosing spondylitis: A rare occurrence. J Rheumatol 21:773, 1994. 85. Fessel WJ: Renal outcomes of gout and hyperuricemia. Am J Med 67:74, 1979. 86. Yu TF, Berger L: Renal function in gout: Its association with hypertensive vascular disease and intrinsic renal disease. Am J Med 72:95, 1982. 87. Cohen LF, Balow JE, Poplack DG, et al: Acute tumor lysis syndrome: A review of 37 patients with Burkitt’s lymphoma. Am J Med 68:486, 1980. 88. Kelton J, Kelley WN, Holmes EW: A rapid method for the diagnosis of acute uric acid nephropathy. Arch Intern Med 138:612, 1978. 89. Gutman AB, Fu TF: Uric acid nephrolithiasis. Am J Med 45:756, 1968. 90. Yu TF, Gutman AB: Uric acid nephrolithiasis in gout: Predisposing factors. Ann Intern Med 67:1133, 1967. 91. Simmonds HA, Sahota AS, Van Acker KJ: Adenine phosphoribosyltransferase deficiency and 2, 8-dihydroxyadenine lithiasis. In Scriver CR, Beaudet AC, Sly WS, Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York, ­McGrawHill, 1995, pp 1655-1670. 92. Rosenbloom FM, Kelley WN, Carr AA, Seegmiller JE: Familial nephropathy and gout in a kindred. Clin Res 15:270, 1967. 93. McBride MB, Simmonds HA, Moro F: Genetic gout in childhood: Familial juvenile hyperuricemic nephropathy or “familial renal disease”. J Inherit Metab Dis 20:351, 1997. 94. Kamatani N, Moritani M, Yamanaka H, et al: Localization of a gene for familial juvenile hyperuricemic nephropathy causing under-excretion type gout to 16p12 by genome-wide linkage analysis of a large family. Arthritis Rheum 43:925, 2000. 95. Stacey JM, Turner JJO, Harding B, et al: Genetic mapping studies of familial juvenile hyperuricemic nephropathy on chromosome 16p13p11. J Clin Endocrinol Metab 88:464, 2003. 96. Van Goor W, Kooiker CJ, Mees FJD: An unusual form of renal disease associated with gout and hypertension. J Clin Pathol 24:354, 1971. 97. Hart TC, Gorry MC, Hart PS, et al: Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricemic nephropathy. J Med Genet 39:882, 2002. 98. Wolf MTF, Mucha BE, Attanasio M, et al: Mutations in the uromodulin gene in MCKD type 2 patients cluster in exon 4 which codes three EGF-like domains. Kidney Int 64:1580, 2003. 99. Bleyer AJ, Trachtman H, Sandhu J, et al: Renal manifestations of a mutation in the uromodulin (Tamm- Horsfall protein) gene. Am J Kidney Dis 42:E20, 2003. 100. Kudo E, Kamatani N, Tezuka O, et al: Familial juvenile hyperuricemic nephropathy: Detection of mutations in the uromodulin gene in five Japanese families. Kidney Int 65:1589, 2004. 101. Turner JJ, Stacey JM, Harding B, et al: Uromodulin mutations cause familial juvenile hyperuricemic nephropathy. J Clin Endocrinol Metab 88:1398, 2003. 102. Rezende-Lima W, Parreira KS, Garcia-Gonzalez M, et al: Homozygosity for uromodulin disorders: FJHN and MCKD-type 2. Kidney Int 66:558, 2004. 103. Halla JT, Ball GV: Saturnine gout: A review of 42 patients. Semin Arthritis Rheum 11:307, 1982. 104. Lin J-L, Tan D-T, Ho H-H, et al: Environmental lead exposure and urate excretion in the general population. Am J Med 113:563, 2002. 105. Marsden PA: Increased body lead burden—cause or consequence of chronic renal insufficiency? N Engl J Med 348:345, 2002. 106. Batuman V: Lead nephropathy, lead, and hypertension. Am J Med Sci 305:241, 1993. 107. Lin JL, Huang PT: Body lead stores and urate excretion in men with chronic renal disease. J Rheumatol 21:705, 1994. 108. Burack DA, Griffith BP, Thompson ME, Kahl LE: Hyperuricemia and gout among heart transplant recipients receiving cyclosporine. Am J Med 92:141, 1992. 109. Cantarell MC, Capdevila L, Morlans M, Piera L: Uric acid calculus in renal transplant patients treated with cyclosporine. Clin Nephrol 35:288, 1992. 110. Griebsch A, Zollner N: Effects of ribonucleotides given orally on uric acid production in man. In Sperling O, de Vries A, Wyngaarden JD (eds): Purine Metabolism in Man, Vol 41B. New York, Plenum Press, 1974, p 443.

PART 14  111. Calabrese G, Simmonds HA, Cameron JS, Davies PM: Precocious familial gout with reduced fractional urate clearance and normal purine enzymes. QJM 75:441, 1990. 112. Reynolds PP, Knapp MJ, Baraf HSB, Holmes EW: Moonshine and lead: Relationship to the pathogenesis of hyperuricemia in gout. Arthritis Rheum 26:1057, 1983. 113. Seegmiller JE, Grauze AO, Howell RR, et al: The renal excretion of uric acid in gout. J Clin Invest 41:1094, 1962. 114. Segal JB, Albert D: Diagnosis of crystal-induced arthritis by synovial fluid examination: Lessons from an imperfect test. Arthritis Care Res 12:376, 1999. 115. Emmerson BT, Nagel SL, Duffy DL, Martin NG: Genetic control of the renal clearance of urate: A study of twins. Ann Rheum Dis 51:375, 1992. 116. Nugent CA, Tyler FH: The renal excretion of uric acid in patients with gout and in nongouty subjects. J Clin Invest 38:1890, 1959. 117. Latham W, Rodnan GP: Impairment of uric acid excretion in gout. J Clin Invest 41:1955, 1962. 118. Lesch M, Nyhan WL: A familial disorder of uric acid metabolism and central nervous system function. Am J Med 36:561, 1964. 119. Kelley WN: Hypoxanthine guanine phosphoribosyltransferase deficiency in the Lesch-Nyhan syndrome and gout. Fed Proc 27:1060, 1968. 120. Caspi D, Lubert E, Graft E, et al: The effect of mini-dose aspirin on renal function and uric acid handling in elderly patients. Arthritis Rheum 43:103, 2000. 121. Kelley WN, Rosenbloom EM, Henderson JF, et al: A specific enzyme defect in gout associated with overproduction of uric acid. Proc Natl Acad Sci U S A 57:1735, 1967. 122. Chang SJ, Chang JG, Chen CJ, et al: Identification of a new single nucleotide substitution on the hypoxanthine-guanine phosphoribosyltransferase gene (HPRT[Tsou]) from a Taiwanese aboriginal family with severe gout. J Rheumatol 26:1802, 1999. 123. Sperling O, Eilam G, Persky-Brosh S, et al: Accelerated erythrocyte 5ˈ-phosphoribosylpyrophosphate synthesis: A familial abnormality associated with excessive uric acid production and gout. Biochem Med 6:310, 1972. 124. Becker MA, Losman JM, Itkin P, et al: Gout with superactive phosphoribosylpyrophosphate synthetase due to increased enzyme catalytic rate. J Lab Clin Med 99:495, 1982. 125. Takeuchi F, Hanaoka F, Yano E, et al: The mode of genetic transmission of a gouty family with increased phosphoribosylpyrophosphate synthetase activity. Hum Genet 58:322, 1981. 126. Wortmann RL, Fox IH: Limited value of uric acid to creatinine ratios in estimating uric acid excretion. Ann Intern Med 93:822, 1980. 127. Moriwaki Y, Yamamoto T, Takahashi S, et al: Spot urine uric acid to creatinine ratio used in the estimation of uric acid excretion in primary gout. J Rheumatol 28:1306, 2001. 128. Vecchio PC, Emmerson BT: Gout due to renal disease. Br J Rheumatol 31:63, 1992. 129. Seegmiller JE, Rosenbloom RM, Kelley WN: An enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis. Science 155:1682, 1967. 130. Cohen JL, Vinik A, Faller J, Fox IH: Hyperuricemia in glycogen storage disease type I: Contributions by hypoglycemia and hyperglucagonemia to increased urate production. J Clin Invest 75:251, 1985. 131. Seegmiller JE, Dixon RM, Kemp GJ, et al: Fructose-induced aberration of metabolism in familial gout identified by 31p magnetic resonance spectroscopy. Proc Natl Acad Sci USA 87:8326, 1990. 132. Mineo I, Kono N, Hara N, et al: Myogenic hyperuricemia: A common pathophysiologic feature of glycogenosis types III, V, and VII. N Engl J Med 317:75, 1987. 133. Bertorini TE, Shively V, Taylor B, et al: ATP degradation products after ischemic exercise: Hereditary lack of phosphorylase or carnitine palmitoyltransferase. Neurology 35:1355, 1985. 134. Sabina RL, Swain JL, Olanow CW, et al: Myoadenylate deaminase deficiency: Functional and metabolic abnormalities associated with disruption of the purine nucleotide cycle. J Clin Invest 73:720, 1984. 135. Davidson-Mundt A, Luder AS, Greene CL: Hyperuricemia in medium-chain acyl coenzyme A dehydrogenase deficiency. J Pediatr 120:444, 1992. 136. McGill NW, Dieppe PA: Evidence for a promoter of urate crystal formation in gouty synovial fluid. Ann Rheum Dis 50:558, 1991. 137. Getting SJ, Flower RJ, Parente L, et al: Molecular determinants of monosodium urate crystal-induced murine peritonitis: A role for endogenous mast cells and a distinct requirement for endothelialderived selectins. J Pharmacol Exp Ther 283:123, 1997.

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138. Takeda K, Akira S: Toll-like receptors in innate immunity. Int Immunol 17:1, 2005. 139. Tramontini N, Huber C, Liu-Bryan R, et al: Central role of complement membrane attack complex in monosodium urate crystal-induced neutrophilic rabbit knee synovitis. Arthritis Rheum 50:2633, 2004. 140. Liu-Bryan R, Pritzker K, Firestein GS, et al: TLR2 signaling in chondrocytes drives calcium pyrophosphate dihydrate and monosodium urate crystal-induced nitric oxide generation. J Immunol 174:5016, 2005. 141. Liu-Bryan R, Scott P, Sydlaske A, et al: Innate immunity conferred by TLR2, TLR4 and MyD88 expression is pivotal for monosodium urate crystal-induced inflammation. Arthritis Rheum 52:2936, 2005. 142. Parker LC, Whyte MK, Dower SK, Sabroe I: The expression and roles of Toll-like receptors in the biology of the human neutrophil. J Leukoc Biol 77:886, 2005. 143. Iwaki D, Mitsuzawa H, Murakami S, et al: The extra-cellular toll-like receptor 2 domain directly binds peptidoglycan derived from Staphylococcus aureus. J Biol Chem 277:24315, 2002. 144. Fujihara M, Muroi M, Tanamoto K, et al: Molecular mechanisms of macrophage activation and deactivation by lipopolysaccharide: Roles of the receptor complex. Pharmacol Ther 100:171, 2003. 145. Chen C-J, Shi Y, Hearn A, et al: MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J Clin Invest 116:2262, 2006. 146. Martinon F, Petrilli V, Mayor A, et al: Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237, 2006. 147. Martinon F, Tschopp J: NLRs join TLRs as innate sensors of pathogens. Trends Immunol 26:447, 2005. 148. Nishimura A, Akahoshi T, Takahashi M, et al: Attenuation of monosodium urate crystal-induced arthritis in rabbits by a neutralizing antibody against interleukin-8. J Leukoc Biol 62:444, 1997. 149. Terkeltaub R, Baird S, Sears P, et al: The murine homolog of the interleukin-8 receptor CXCR-2 is essential for the occurrence of neutrophilic inflammation in the air pouch model of acute urate crystal-induced gouty synovitis. Arthritis Rheum 41:900, 1998. 150. Kam M, Perl-Treves D, Caspi D, Addadi L: Antibodies against crystals. FASEB J 6:2608, 1992. 151. Barabe F, Gillvert C, Liao N, et al: Crystal-induced neutrophil activation. VI. Involvement of Fc gamma RIIIB (CD16) and CD11b in response to inflammatory microcrystals. FASEB J 12:209, 1998. 152. Onello E, Traynor-Kaplan A, Sklar L, Terkeltaub R: Mechanism of neutrophil activation by an unopsonized inflammatory particulate: Monosodium urate crystals induce pertussis toxin-insensitive hydrolysis of phosphatidylinositol 4,5-bisphosphate. J Immunol 146:4289, 1991. 153. Hachicha M, Naccache PH, McColl SR: Inflammatory microcrystals differentially regulate the secretion of macrophage inflammatory protein 1 and interleukin 8 by human neutrophils: A possible mechanism of neutrophil recruitment to sites of inflammation in synovitis. J Exp Med 182:2019, 1995. 154. Gilbert C, Poubelle PE, Borgeat P, et al: Crystal-induced neutrophil activation. VIII. Immediate production of prostaglandin E2 mediated by constitutive cyclooxygenase 2 in human neutrophils stimulated by urate crystals. Arthritis Rheum 48:1137, 2003. 155. Ryckman C, Gilbert C, De Medicis R, et al: Monosodium urate monohydrate crystals induce the release of the proinflammatory protein S100A8/A9 from neutrophils. J Leukoc Biol 76:433, 2004. 156. Desaulniers P, Marois S, Pare G, et al: Characterization of an activation factor released from human neutrophils after stimulation by tricyclic monosodium urate crystals. J Rheumatol 33:928, 2006. 157. di Giovine FS, Malawista SE, Thornton E, Duff GW: Urate crystals stimulate production of tumor necrosis factor alpha from human blood monocytes and synovial cells: Cytokine mRNA and protein kinetics, and cellular distribution. J Clin Invest 87:1375, 1991. 158. Terkeltaub R, Zachariae C, Santoro D, et al: Monocyte-derived neutrophil chemotactic factor/interleukin-8 is a potential mediator of crystal-induced inflammation. Arthritis Rheum 34:894, 1991. 159. Pouliot M, James MJ, McColl SR, et al: Monosodium urate microcrystals induce cyclooxygenase-2 in human monocytes. Blood 91:1769, 1998. 160. Terkeltaub RA, Dyer CA, Martin J, Curtiss LK: Apolipoprotein (apo) E inhibits the capacity of monosodium urate crystals to stimulate neutrophils: Characterization of intraarticular apo E and demonstration of apo E binding to urate crystals in vivo. J Clin Invest 87:20, 1991.

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161. Getting SJ, Christian HC, Flower RJ, Perritti M: Activation of melanocortin type 3 receptor as a molecular mechanism for adrenocorticotropic hormone efficacy in gouty arthritis. Arthritis Rheum 46:2765, 2002. 162. Akahoshi T, Namai R, Murakami Y, et al: Rapid induction of peroxisome proliferator-actived receptor gamma expression in human monocytes by monosodium urate monohydrate crystals. Arthritis Rheum 48:231, 2003. 163. Yagnik DR, Hillyer P, Marshall D, et al: Noninflammatory phagocytosis of monosodium urate monohydrate crystals by mouse macrophages: Implications for the control of joint inflammation in gout. Arthritis Rheum 43:1779, 2000. 164. Landis RC, Yagnik DR, Florey O, et al: Safe disposal of inflammatory monosodium urate monohydrate crystals by differentiated macrophages. Arthritis Rheum 46:3026, 2002. 165. Liote F, Prudhommeaux F, Schiltz C, et al: Inhibition and prevention of monosodium urate monohydrate crystal-induced acute inflammation in vivo by transforming growth factor beta 1. Arthritis Rheum 39:1192, 1996. 166. Yagnik DR, Evans BJ, Florey O, et al: Macrophage release of transforming growth factor beta 1 during resolution of monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum 50:2273, 2004. 167. Schweyer S, Hennerlein B, Radzun HJ, Fayyazi A: Continuouis recruitment, co-expression of tumour necrosis factor-alpha and matrix metalloproteinases, and apoptosis of macrophages in gout tophi. Virchows Arch 437:534, 2000. 168. Hseich MS, Ho HC, Chou DT, et al: Expression of matrix metalloproteinase-9 (gelatinase B) in gouty arthritis and stimulation of MMP-9 by urate crystals in macrophages. J Cell Biochem 89:791, 2003. 169. Liu R, Liote F, Rose DM, et al: Proline-rich tyrosine kinase 2 and Src kinase signaling transduce monosodium urate crystal-induced nitric oxide production and matrix metalloproteinase 3 expression in chondrocytes. Arthritis Rheum 50:247, 2004. 170. Nakagawa T, Mazzali M, Kang DH, et al: Hyperuricemia causes glomerular hypertrophy in the rat. Am J Nephrol 23:2, 2002. 171. Yamamoto T, Moriwaki Y, Tukahashi S, et al: Effect of finafibrate on plasma concentration and urinary excretion of purine bases and oxypurinal. J Rheumatol 28:2294, 2001. 172. Wurzner G, Gester JC, Chiolero A, et al: Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricemia and gout. J Hypertens 19:1855, 2001. 173. Schlesinger N, Baker DG, Schumacher HR Jr: How well have diagnostic tests and therapies for gout been evaluated? Curr Opin Rheumatol 11:441, 1999. 174. Schlesinger N, Detry MA, Holland BK, et al: Local ice therapy during bouts of acute gouty arthritis. J Rheumatol 29:331, 2002. 175. Lange U, Schumann C, Schmidt KL: Current aspects of colchicine therapy: Classical indications and new therapeutic uses. Eur J Med Res 6:150, 2001. 176. Kim KY, Schumacher H, Hunsche E, et al: A literature review of the epidemiology and treatment of acute gout. Clin Ther 25:1593, 2003. 177. Molad Y: Update on colchicine and its mechanism of action. Curr Rheum Rep 4:252, 2002. 178. Iacobuzio-Donahue CA, Lee EL, Abraham SC, et al: Colchicine toxicity: Distinct morphologic findings in gastrointestinal biopsies. Am J Surg Pathol 25:1067, 2001. 179. Wallace SL, Singer JZ: Review: Systemic toxicity associated with the intravenous administration of colchicine: Guidelines for use. J Rheumatol 15:495, 1988. 180. Evans TI, Wheeler MT, Small RE, et al: A comprehensive investigation of inpatient colchicine use shows more education is needed. J Rheumatol 23:143, 1996. 181. Schumacher HR, Boice HA, Daikh, et al: Randomized double blind trial of etoricoxib and indomethacin in treatment of acute gouty arthritis. BMJ 324:1488, 2002. 182. Fernandez C, Moguera R, Gonzalez JA, et al: Treatment of acute attacks of gout with a small dose of intraarticular triamcinolone acetonide. J Rheumatol 26:2285, 1999. 183. Clive DM: Renal transplant-associated hyperuricemia and gout. J Am Soc Nephrol 11:974, 2000.

184. Ritter L, Kerr LD, Valeriano-Marcet J, Spirea H: ACTH revisted: Effective treatment for acute crystal induced synovitis in patients with multiple medical problems. J Rheumatol 21:696, 1994. 185. Yu TF, Gutman AB: Efficacy of colchicine prophylaxis: Prevention of recurrent gouty arthritis over a mean period of five years in 208 gouty subjects. Ann Intern Med 55:179, 1961. 186. Kunck RW, Duncan G, Watson D, et al: Colchicine myopathy and neuropathy. N Engl J Med 316:1562, 1987. 187. Chattopadhyay I, Shetty HMG, Routledge PA, et al: Colchicine induced rhabdomyolysis. Postgrad Med J 77:191, 2001. 188. Fam AG: Difficult gout and new approaches for control of hyperuricemia in the allopurinol-allergic patient. Curr Rheum Rep 3:29, 2001. 189. Ferraz MB, O’Brien B: A cost effectiveness analysis of urate lowering drugs in nontophaceous recurrent gouty arthritis. J Rheumatol 22:908, 1995. 190. Perez-Ruiz F, Calabozo M, Pijoan JI, et al: Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Care Res 47:356, 2002. 191. Perez-Ruiz F, Calabozo C, Herrero-Betes A, et al: Improvement in renal function in patients with chronic gout after proper control of hyperuricemia and gouty bouts. Nephron 86:287, 2000. 192. Harris M, Bryant LR, Danaher P, Alloway J: Effect of low dose daily aspirin on serum urate levels and urinary excretion in patients receiving probenecid for gouty arthritis. J Rheumatol 27:2873, 2000. 193. Hande KR, Noone RM, Stone WJ: Severe allopurinol toxicity: Description and guidelines for presentation in patients with renal insufficiency. Am J Med 76:47, 1984. 194. Stamp L, Sharples K, Gow P, et al: The optional use of allopurinol: An audit of allopurinol use in South Auckland. Aust N Z J Med 30:567, 2000. 195. Perez-Ruiz F, Hernando I, et al: Correction of allopurinol dosing should be based on clearance of creatinine, but not plasma creatinine levels: Another insight to allopurinol-related toxicity. J Clin Rheumatol 11:129, 2005. 196. Dalbeth N, Kumar S, Stamp L, Gow P: Dose adjustment of allopurinol according to creatinine clearance does not provide ade­ quate control of hyperuricemia in patients with gout. J Rheumatol 33:1646, 2006. 197. Perez-Ruiz F, Alonso-Ruiz A, et al: Efficacy of allopurinol and benzbromarone for the control of hyperuricemia: A pathogenic approach to the treatment of primary chronic gout. Ann Rheum Dis 57:545, 1998. 198. Li-Yu J, Clayburne G, et al: Treatment of chronic gout: Can we determine when urate stores are depleted enough to prevent attacks of gout? J Rheumatol 28:577, 2001. 199. Fam AG, Dunne SM, Lazzetta J, et al: Efficacy and safety of desensitization to allopurinol following cutaneous reactions. Arthritis Rheum 44:231, 2001. 200. Singer JZ, Wallace SL: The allopurinol hypersensitivity syndrome: Unnecessary morbidity and mortality. Arthritis Rheum 29:82, 1986. 201. Weiner IM, Mudge GH: Inhibitors of tubular transport of organic compounds. In Gillman AG, Rail TW, Niew AW, Taylor P (eds): The Pharmacologic Basis of Therapeutics, 8th ed. New York, Pergamon Press, 1990, p 920. 202. Wortmann RL: The treatment of gout: The use of an analogy. Am J Med 105:513, 1998. 203. Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, Duruelo J: Treatment of gout after transplantation. Br J Rheumatol 37:580, 1998. 204. Jacobs F, Mamzer-Bruneel MF, Skhir H, et al: Safety of the mycophenolate mofetil-allopurinol combination in kidney transplant recipients with gout. Transplantation 64:1087, 1997. 205. Rozenberg S, Koeger AC, Bourgeois P: Urate-oxidase for gouty arthritis in cardiac transplant recipients. J Rheumatol 20:2171, 1993. 206. Bomalaski JS, Holtsberg FW, Ensor CM, et al: Uricase formulated with polyethyleneglycol (uricase-PEG 20): Biochemical rationale and preclinical studies. J Rheumatol 29:1942, 2002. 207. Dessein PH, Shipton EA, Stanwix AE, et al: Beneficial effects of weight loss associated with moderate calorie/carbohydrate restriction, and increased proportional intake of protein and unsaturated fat on serum urate and lipoprotein levels in gout: A pilot study. Ann Rheum Dis 59:539, 2000. 208. Fam AG: Gout, diet and the insulin resistance syndrome. J Rheumatol 29:1350, 2002.

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Key Points Autosomal dominant familial chondrocalcinosis in several kindreds has been linked to certain mutations in ANKH, a gene encoding an inorganic pyrophosphate (PPi) transporter. Both dysregulated chondrocyte differentiation and PPi metabolism are central to the pathogenesis of chondrocalcinosis. NALP3 (cryopyrin) inflammasome activation and consequent caspase-1 activation and interleukin-1β processing and secretion drive cell responses to calcium pyrophosphate dihydrate (CPPD) crystals and CPPD crystal-induced inflammation. Degenerative arthropathy due to CPPD crystal deposition disease often involves joints uncommonly affected by primary osteoarthritis, such as the metacarpophalangeal, wrist, and elbow joints. Diagnosis of CPPD deposition disease before age 50, particularly if CPPD deposition is widespread, should prompt consideration of a primary metabolic or familial disorder. In the elderly, CPPD deposition may present as diffuse pain, sometimes with fever of unknown origin, mimicking infection, polymyalgia rheumatica, and rheumatoid arthritis. Radiographic chondrocalcinosis is not detectable in all joints affected by CPPD crystal deposition disease. Joint cartilage and synovial fluid CPPD and basic calcium phosphate (BCP) crystals commonly coexist in affected joints. BCP crystals are not birefringent, although the aggregated particles of BCP crystals demonstrate edge birefringence.

PROPOSED CRITERIA FOR DISEASE The proposed diagnostic criteria for calcium pyrophosphate dihydrate (CPPD) deposition disease are summarized in Table 88-1. The diagnosis is based on detection of CPPD crystals by one or more methods. These methods include standard radiography, which detects calcifications characteristic of CPPD, as well as compensated polarized light microscopic analysis of synovial fluids or tissue sections for the detection of typical CPPD crystals. On occasion, specialized approaches to crystal analysis, including x-ray energy spectroscopy and powder diffraction analysis1,2 or atomic force   Video available on the Expert Consult Premium Edition website.

Diseases Associated with Articular Deposition of Calcium Pyrophosphate Dihydrate and Basic Calcium Phosphate Crystals ROBERT TERKELTAUB microscopy,3 may be helpful in establishing or confirming CPPD crystal deposition. When assessing deposited crystals in calcifications, determination of the calcium-to-phosphate ratio, as well as the spacing of x-ray powder diffraction lines, provides the most specific information. Consensus clinical diagnostic criteria for articular basic calcium phosphate (BCP) crystal deposition disorders do not exist. Importantly, BCP crystals (unlike urate and CPPD) do not demonstrate intrusive birefringence, although the aggregated particles of BCP crystals demonstrate edge birefringence. Hence, diagnosis is predicated on (1) ­ radiographic detection of calcifications characteristic of BCP crystals, (2) synovial fluid crystals that stain strongly for the calcium-binding dye alizarin red S (which only weakly stains CPPD crystals), and (3) BCP crystals confirmed by transmission electron microscopy or specialized crystal analytic approaches (including those mentioned earlier for CPPD and discussed later).

EPIDEMIOLOGY Studies of the prevalence of both CPPD crystal deposition disease and various forms of articular BCP crystal deposition disease have been based predominantly on characteristic plain radiographic features in limited numbers of joints. This is an incompletely sensitive and specific approach. Other studies have been based on results of synovial fluid analyses and pathologic findings on examination of articular cartilages. As such, the true prevalence of both CPPD crystal deposition disease and pathologic articular BCP crystal deposition is not known. Women may be more commonly affected by CPPD crystal deposition disease than are men.4 Chondrocalcinosis, including asymptomatic disease, increases in prevalence with age.5,6 Idiopathic or sporadic chondrocalcinosis is rare before age 50, particularly in the absence of a history of joint trauma or knee meniscectomy. In a classic study, knee meniscal calcification was detected in 16% of women aged 80 to 89 and in 30% of women older than 89,7 figures comparable to those obtained in other studies.8,9 For example, in a radiographic survey study of hands, wrists, pelvis, and knees of patients admitted to a geriatrics ward, there was a 44% prevalence of ­ chondrocalcinosis 1507

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Table 88-1  Proposed Diagnostic Criteria for Calcium ­Pyrophosphate Dihydrate (CPPD) Crystal Deposition Disease Criteria I.  Demonstration of CPPD crystals, obtained by biopsy or aspirated synovial fluid, by definitive means (e.g., characteristic x-ray ­diffraction powder pattern) II.  A. Identification of monoclinic or triclinic crystals showing a weak positive birefringence (or no birefringence) by   compensated polarized light microscopy  B. Presence of typical calcifications on radiographs (as ­discussed in text): heavy punctate and linear calcifications in ­fibrocartilage, articular (hyaline) cartilage, and joint capsules, especially if ­bilaterally symmetric III.  A. Acute arthritis, especially of knees or other large joints  B. Chronic arthritis, especially of knee, hip, wrist, carpus, elbow, shoulder, and metacarpophalangeal joints, particularly   if ­accompanied by acute exacerbations Diagnostic Categories A.  Definite: criterion I or IIA must be fulfilled B. Probable: criterion IIA or IIB must be fulfilled C. Possible: criterion IIIA or IIIB suggests possible underlying CPPD deposition disease Adapted from McCarty DJ: Crystals and arthritis. Dis Month 6:255, 1994.

in patients older than 84, a 36% prevalence in 75- to 84-year-olds, and a prevalence of 15% in 65- to 74-year-olds.10 Most elderly patients with chondrocalcinosis of the knee also have detectable chondrocalcinosis in other joints.7 In a random sample of Beijing residents older than 60 years, radiographic chondrocalcinosis was compared with the findings among whites in the American Framingham Osteoarthritis Study.11 The Chinese had a much lower prevalence of knee chondrocalcinosis, and wrist chondrocalcinosis was particularly rare in elderly Chinese.11 These findings were unexpected, because there is an excess of knee osteoarthritis (OA) in Beijing,12 and chondrocalcinosis and OA are commonly associated in the knee joint.

CAUSE The loose avascular connective tissue matrices of articular hyaline cartilage, fibrocartilaginous menisci, and certain ligaments and tendons are particularly susceptible to calcification. Calcium-containing crystals deposited in the pericellular matrix of cartilage are often in the form of CPPD (chemical formula Ca2P2O7•H2O; calcium-phosphate ratio, 1.0). This disorder is commonly termed chondrocalcinosis or pyrophosphate arthropathy; when associated with acute arthritis, it is called pseudogout. Crystals of BCP, including partially carbonate-substituted hydroxyapatite (Ca5[PO4]3OH•2H2O; calcium-phosphate ratio, 1.67), also may be deposited pathologically in articular cartilage, particularly in OA. Importantly, physiologic (and noninflammatory) deposition of hydroxyapatite (HA) is essential, because HA is the principal mineral phase laid down in growth cartilage and in bone. Inflammatory conditions also may result from deposition of HA and the closely related BCP crystals octacalcium phosphate (Ca8H2[PO4]6•5H2O; calcium-phosphate ratio, 1.33) and tricalcium phosphate or whitlockite (Ca3[PO4]2; calcium-phosphate ratio, 1.5) in periarticular structures, such as the rotator cuff (calcific tendinitis) and subacromial

bursa of the shoulder. CPPD and BCP crystal deposition disease are by far the most prevalent arthropathies associated with calcium-containing crystals. Articular calcium oxalate crystal deposition, which is less common, is reviewed in Chapter 112. Supersaturation of certain solutes in body fluids may culminate in the deposition of distinct crystals and calculi, exemplified by pathologic crystallization within extracellular fluids, such as the biliary and urinary tracts. In addition, pathologic calcification can occur in the extracellular matrix of certain connective tissues, such as the artery wall in subjects with atherosclerosis or chronic renal failure and in the synovium and articular cartilage in gout. Articular cartilage, unlike growth plate cartilage, is specialized to avoid the process of matrix calcification. However, the matrix of articular hyaline cartilage, like that of fibrocartilaginous menisci, is prone to pathologic calcification,13 particularly in association with certain changes in extracellular matrix composition caused by aging and OA.14

PATHOGENESIS Joint cartilage calcification reflects a complex interplay between organic and inorganic biochemistry, aging, molecular genetics, inflammation, oxidative stress, and dysregulated chondrocyte growth factor responsiveness and differentiation. Pathologic cartilage calcification can reflect deficiencies of certain physiologic calcification inhibitors or upregulation of mediators that actively drive stereotypical patterns of tissue injury, culminating in calcification within degenerating cartilage.15,16 Alterations in the concentrations of calcium, inorganic phosphate (Pi,), inorganic pyrophosphate (PPi), and the solubility products of these ions are clearly at work in promoting CPPD and BCP crystal formation.13-16 The levels of ambient magnesium and the composition of the chondrocyte extracellular matrix influence the dynamics of CPPD crystal formation and help determine whether predominantly monoclinic or triclinic CPPD crystals are formed.14,15 Significantly, monoclinic CPPD crystals are more inflammatory than triclinic CPPD crystals.17 Besides the physical effects of calcium, Pi, and PPi on crystal nucleation and propagation, these solutes exert a variety of mineralization-regulating effects on gene expression, differentiation, and viability in chondrocytes, mediated partly by calcium-sensing receptors and sodium-dependent phosphate cotransport in chondrocytes.18-23 Noxious effects of excess PPi on chondrocytes, including induction of matrix metalloproteinase-13 (MMP-13) expression24 and the promotion of apoptosis,25 support the terminology pyrophosphate arthropathy to describe the chronic cartilage degenerative manifestations of CPPD crystal deposition disease. DYSREGULATED INORGANIC PYROPHOSPHATE METABOLISM AND THE ROLE OF NUCLEOTIDE PYROPHOSPHATASE PHOSPHODIESTERASE 1 PPi is a potent inhibitor of the nucleation and propagation of BCP crystals.15,16 Concordantly, maintenance of physiologic extracellular PPi levels by chondrocytes and certain other cells suppresses calcification with HA, as illustrated in mouse models of deficient PPi generation and transport19,26,27 and a variant of human infantile arterial calcification ­associated

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with periarticular calcification.28 The relatively distinctive capacity of chondrocytes to produce copious amounts of extracellular PPi is double edged, because supersaturation of cartilage extracellular matrix with PPi is a major factor in promoting CPPD crystal deposition.16,29,30 Further, excess PPi generation can promote BCP crystal deposition by providing a source for increased extracellular Pi generation via PPi hydrolysis by tissue-nonspecific alkaline phosphatase (TNAP).16,29 Depending on cartilage adenosine triphosphate (ATP) and PPi concentrations and the level of activity of Pi-generating ATPases and TNAP, CPPD and HA crystal formation may be jointly promoted in cartilage, an event that commonly occurs clinically in OA (discussed later). In addition, alterations in PPi transport by the multiple-pass plasma membrane protein ANKH16,24,26 are implicated in the pathogenesis of chondrocalcinosis (discussed later with regard to familial chondrocalcinosis). Increased ANKH expression in OA cartilage is a factor in secondary chondrocalcinosis (Fig. 88-1).24 Sporadic aging-associated CPPD crystal deposition disease is consistently linked with excess chondrocyte PPigenerating nucleotide pyrophosphatase phosphodiesterase (NPP) activity and augmented PPi generation by chondrocytes.16,29-32 In this context, the NPP family isoenzymes NPP1 and NPP3 actively generate PPi by hydrolysis of nucleoside triphosphates, including ATP.16,29,30 A substantial portion of ATP used by chondrocytes to generate extracellular PPi is provided by the mitochondria.16 In idiopathic chondrocalcinosis, cartilage NPP activity and PPi levels may average approximately double those of normal subjects.33 NPP1 (formerly known as plasma cell membrane glycoprotein-1, or PC-1) plays a central role in sustaining and augmenting extracellular PPi in chondrocytes and certain other cells.16,29,30 NPP1 is one of three highly homologous NPP family isoenzymes (NPP1 to NPP3) that share NPP catalytic activity and modular type II transmembrane ectoenzyme structures.16,34 NPP1 plays the greatest role by far in augmenting extracellular PPi in chondrocytes.29,30 Significantly, marked and total NPP1 deficiency states in vivo and in vitro are associated with up to 50% less plasma and extracellular PPi.18,28 Increased NPP1 expression is associated with both calcification and apoptosis in degenerative human cartilages.29 Direct upregulation of NPP1 in chondrocytic cells stimulates calcification as well as apoptosis.25 These effects are not shared by NPP3, which likely has other intracellular “housekeeping” functions in chondrocytes.25,29 NPP2, which is also expressed in normal cartilage, functions more actively in physiology as lysophospholipase D,35 and NPP2 only modestly stimulates chondrocytes to calcify in vitro.29 The chondrocyte growth factor transforming growth factor-β (TGF-β) stimulates NPP1 expression and NPP1 sub­ cellular movement to the plasma membrane, which drives the elevation of extracellular PPi.30,36 Interleukin (IL)-1β suppresses both NPP1 expression and extracellular PPi in chondrocytes and blocks the effects of TGF-β on PPi.30,36 The capacity of TGF-β to raise chondrocyte PPi increases with aging, as does TGF-β–stimulated NPP activity,37 whereas growth-promoting effects of TGF-β decrease with aging in articular chondrocytes.32 The anabolic chondrocyte growth factor insulin-like growth factor-1 (IGF-1) normally suppresses extracellular PPi in chondrocytes.38 Moreover, chondrocyte IGF-1 resistance is characteristic

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crystal-induced inflammation

Aging OA TGFβ

NPP1 AMP ATP + PPi

CILP-1 (antagonizes IGF-I) ANKH-mediated PPi channeling

Excess extracellular PPi Matrix saturation with PPi TNAP

ATP

ATPases

Physiologic IGF-I responsiveness: inhibits increased PPi

CPPD crystals

PPi P i + Pi

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HA crystals

Cartilage matrix calcification

ADP + Pi

Physiologic PPi: inhibits HA deposition Figure 88-1  Proposed inorganic pyrophosphate (PPi)–dependent mechanisms stimulating calcium pyrophosphate dihydrate (CPPD) and hydroxyapatite (HA) crystal deposition in aging and osteoarthritis (OA). Roles of adenosine triphosphate (ATP) and PPi metabolism and inorganic phosphate (Pi) generation in pathologic cartilage calcification. This model accounts for the association of extracellular PPi excess with both CPPD and basic calcium phosphate (BCP) crystal deposition in OA and chondrocalcinosis, as well as the paradoxical association of extracellular PPi deficiency (from defective ANKH or nucleotide pyrophosphatase phosphodiesterase 1 [NPP1] expression) with pathologic calcification of articular cartilage with HA crystals in vivo. Factors ­driving pathologic calcification are indicated in green, and physiologic factors suppressing calcification in red. Excess PPi generation in cartilage in idiopathic CPPD deposition disease of aging and in OA is mediated in part by increased NPP1. In idiopathic chondrocalcinosis of aging, mean cartilage PPi and NPP catalytic activity levels are double normal. NPP1 is markedly increased at sites of meniscal cartilage calcification in vivo, and NPP1 directly induces PPi elevation and matrix calcification by chondrocytes in vitro. Depending on the extracellular availability of substrate PPi, the activity of the pyrophosphatase tissue-nonspecific alkaline phosphatase (TNAP), the availability of substrate ATP, the activity of ATPases, and other factors, such as substantial local Mg2+ concentrations, HA crystal deposition (as opposed to CPPD deposition) may be stimulated. In this model, excess extracellular PPi also may result from heightened “leakiness” of intracellular PPi via increased ANKH expression in OA and  abnormal ANKH function in familial chondrocalcinosis. Also illustrated is the role of increased expression of cartilage intermediate layer protein-1  (CILP-1) in cartilage calcification in OA and aging, which inhibits the  capacity of insulin-like growth factor-1 (IGF-1) to suppress the elevation of extracellular PPi. ADP, adenosine diphosphate; AMP, adenosine ­monophosphate; TGF, transforming growth factor.

of OA and aging cartilage.39 IGF-1 induces the expression of cartilage intermediate layer protein (CILP; see Fig. 88-1), a secreted cartilage matrix molecule whose expression increases with aging and in OA and is most abundant in the middle zone of articular cartilage, where CPPD crystal deposition is most prevalent.40 Significantly, the CILP-1 but not the CILP-2 isoform promotes increased extracellular PPi in chondrocytes indirectly by antagonizing IGF-1 at the receptor level.39 CALCIUM PYROPHOSPHATE DIHYDRATE DEPOSITION DISEASE SECONDARY TO PRIMARY METABOLIC DISORDERS Hypophosphatasia, hypomagnesemic conditions (including the Gitelman’s variant of Bartter’s syndrome), hemochromatosis, and hyperparathyroidism are the best-­characterized primary metabolic disorders linked to secondary CPPD

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crystal deposition disease.41 Increased joint fluid PPi levels in each of these condition suggests at least one common thread in the pathogenesis of chondrocalcinosis via cartilage PPi excess.42 Magnesium is a cofactor for pyrophosphatase activity, and iron excess can suppress pyrophosphatase activity. Hypercalcemia may promote CPPD crystal deposition in hyperparathyroidism by effects beyond cartilage matrix supersaturation with ionized calcium, such as calcium functioning as a cofactor in NPP1 catalytic activity, as well as chondrocyte-activating effects mediated by the calcium-sensing receptor.20,21,23,43 In addition, normal articular chondrocytes express parathyroid hormone (PTH) and PTH-related protein receptors, and functional responses of chondrocytes to PTH can promote proliferation, altered matrix synthesis, and mineralization.44,45 Hypophosphatasia is due to deficient activity of the ectoenzyme TNAP, whose activities include hydrolysis of PPi to generate Pi.19 TNAP is a major physiologic antagonist of the NPP1-mediated elevation of extracellular PPi.19 Conversely, physiologic NPP1-induced PPi generation antagonizes the essential promineralizing effects of TNAP mediated by Pi generation,19 and cartilage PPi excess presumably drives chondrocalcinosis in hypophosphatasia. NPP1 knockout mice and mice homozygous for the NPP1 truncation mutant ttw demonstrate marked articular cartilage calcification with HA and OA, as well as ankylosing spinal ligament hyperostosis and synovial joint ossific fusion.19,27 Extracellular PPi levels and mineralization disturbances in soft tissues (but not long bones) of NPP1 knockout and TNAP knockout mice are mutually corrected by crossbreeding to double knockout mice.19 FAMILIAL CALCIUM PYROPHOSPHATE DIHYDRATE CRYSTAL DEPOSITION DISEASE AND THE ROLE OF ANKH Familial chondrocalcinosis is clinically heterogeneous. For example, prominent CPPD and HA crystal deposits and cartilage and periarticular calcifications in association with OA were described in a kindred not yet linked to a specific chromosomal locus.46 A syndrome of spondyloepiphyseal dysplasia tarda, brachydactyly, precocious OA, and intra-articular calcifications with CPPD or HA crystals (or both), as well as periarticular calcifications, was linked to mutation of the procollagen type II gene in natives of the Chiloé Island region of Chile, a population with a high prevalence of familial CPPD deposition disease.47 Families multiply affected with diffuse idiopathic skeletal hyperostosis (DISH) or chondrocalcinosis have been identified in the Azores Islands, suggesting that the concurrence of DISH and chondrocalcinosis reflects an unknown, shared pathogenic mechanism.48 Two major chromosomal linkages, 8q and 5p, have been identified in studies of familial CPPD deposition disease. Linkage of chromosome 8q with both early-onset OA and chondrocalcinosis in a New England family was given the designation CCAL1.49 Chromosome 5p–linked chondrocalcinosis (CCAL2) is broadly distributed and has been studied in greater detail than 8q chondrocalcinosis.50-53 Linkage of familial CPPD crystal deposition disease to the gene ANKH on chromosome 5p has been established in these studies.50-53 A search for ANKH mutations in 95 subjects with sporadic chondrocalcinosis uncovered a unique mutation in only one subject.52

Familial Chondrocalcinosis: French kindred (M48T) Familial Chondrocalcinosis: Argentine and USA kindreds (P5L, P5T) Familial Chondrocalcinosos: British kindred (C-11T, creates new ATG start codon and 4 additional amino acids are added at the ANKH N-terminus)

N

C

Late onset Chondrocalcinosis of the sporadic type: Homozygosity for -4 G to A in ~ 4% of affected subjects

Figure 88-2  Model for multiple-pass membrane protein structure of ANKH and for ANKH mutations associated with chromosome 5p–linked autosomal dominant familial chondrocalcinosis and heritable late­onset chondrocalcinosis. The figure schematizes the putative multiplepass transmembrane protein structure of ANKH, which appears to promote bidirectional inorganic pyrophosphate (PPi) movement between the cytosol and the extracellular space. The gradient for ANKH-stimula­ted PPi movement in chondrocytes (which generate abundant PPi by both high specific activity of nucleotide pyrophosphatase phosphodiesterase 1 [NPP1] and robust matrix biosynthesis) is from the intracellular to the  extracellular space. Distinct mutations in ANKH promote differences in age  of onset and phenotypes in familial chondrocalcinosis. The figure summarizes sites of known ANKH mutations clustered near the N-terminus that are associated with chromosome 5p–linked autosomal dominant familial chondrocalcinosis (calcium pyrophosphate dihydrate [CPPD] crystal deposition disease). The figure also depicts the –4 G to A transition in the 5’-untranslated region of ANKH, for which homozygosity is seen in about 4% of late-onset chondrocalcinosis of the sporadic type, suggesting a heritable subset of otherwise typical late-onset chondrocalcinosis. As a group, these N-terminally clustered ANKH mutations linked to human chondrocalcinosis promote chronic low-grade extracellular PPi excess, resulting in CPPD crystal formation. However, some of the ANKH mutations are distinct in their effects on chondrocyte differentiation, and the M48T ANKH mutant in a French kindred appears to be functionally unique because it is associated with increased intracellular PPi..

ANKH encodes a multiple-pass transmembrane protein that functions in PPi channeling (Fig. 88- 2).26,31,54,55 ANKH promotes bidirectional movement of PPi at the plasma membrane in vitro,54 but the gradient for ANKHstimulated PPi movement in chondrocytes (which generate abundant PPi by both robust NPP1 expression and intense matrix biosynthetic activity) is from the intracellular to the extracellular space.16 Indeed, transport of PPi generated intracellularly by NPP124 is a primary means of regulating extracellular PPi levels.16 Modeling of the PPi channeling function of ANKH has proposed 10 or 12 membrane­spanning domains in ANKH with an alternating inside-out orientation and with a central channel to accommodate the passage of PPi (see Fig. 88-2).26,55 Mutations at different locations in ANKH can affect function and the skeleton, including autosomal dominant chondrocalcinosis51-54 and certain other phenotypes, such as murine progressive ankylosis in the ank/ank mouse and human craniometaphyseal dysplasia associated with apparent decreased capacity to transport PPi within bone.26,54,55 Clinical heterogeneity even for chondrocalcinosis associated with ANKH mutations51-54 suggests that different functional effects of ANKH are mediated by specific regions of the molecule. All the N-terminally

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c­ lustered ANKH mutations identified to cause familial chondrocalcinosis appear to increase PPi transport.54 However, some of the ANKH mutations have distinct effects on chondrocyte differentiation,56 and the M48T ANKH mutant in a French kindred appears to be functionally unique by association with increased intracellular PPi.57 In 5p familial chondrocalcinosis, a subtle “gain of function” of intrinsic ANKH PPi channeling activity may lead to chronic, low-grade chondrocyte PPi “leakiness,” thereby causing matrix supersaturation with PPi, CPPD crystal deposition, and cartilage degeneration.31,51 Expression of wild-type ANKH is highly regulated, and ANKH is increased in OA and chondrocalcinotic cartilage.24 Thus, secondary alterations in chondrocyte expression of both wild-type ANKH and NPP1 likely drive PPi supersaturation in cartilage in idiopathic or sporadic and OA­associated CPPD crystal deposition disease (see Fig. 88-1). Moreover, homozygosity for a single nucleotide substitution (–4 G to A) in the ANKH 5’-untranslated region that promotes increased ANKH messenger RNA expression was present in about 4% of British subjects previously thought to have idiopathic or sporadic chondrocalcinosis of aging.56

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chondrocyte maturation, with the presence of hypertrophy, as seen in histopathology of the knee cartilage in Figure 88-3; apoptosis of chondrocytes also is typically found adjacent to cartilage calcifications.58,59 Articular chondrocyte hypertrophy, promoted synergistically by mediators (including those depicted in Fig. 88-4), is associated with heightened PPi generation, increased production of calcifying cell fragments known as matrix vesicles, and certain other calcification-promoting changes in differentiation, including alteration of extracellular matrix composition.60,61 For example, hypertrophic chondrocytes express less type II collagen and aggrecan and further modify their extracellular matrix via increased aggrecanase and MMP activities, as well as expression of type X collagen, osteopontin, and several other stereotypical bone and growth plate proteins that regulate calcification (see Chapter 3). Altered TGF-β signal transduction in aging32 and OA may be involved in promoting chondrocyte hypertrophy, because expression of a truncated, kinase-defective TGF-β receptor type II promotes hypertrophy and terminal chondrocyte differentiation, along with cartilage degeneration in vivo.62

Resting chondrocyte

INFLAMMATION, ALTERED CHONDROCYTE DIFFERENTIATION, AND TRANSGLUTAMINASE 2 IN JOINT CARTILAGE CALCIFICATION Regulated changes in chondrocyte differentiation and viability appear to be part of a mechanistically unified process that promotes joint cartilage CPPD and HA crystal deposition as well as OA. Such changes include the development of foci of

PTHrP or PTH -> proliferation Calcium sensing Altered TGFβ responsiveness CXCL1, CXCL8, TNFα TG2, FXIIIA S100 calgranulins, RAGE p38 signaling

Maturation to terminal differentiation

ANKH PPi, alkaline phosphatase Pit-1-mediated Pi uptake Hypertrophic chondrocyte PPi Alkaline phosphatase Matrix vesicle release

A

TG2, FXIIIA MMP-13, ADAMts5 Cartilage matrix remodeling Mitochondrial dysfunction Promotion of apoptosis Joint cartilage calcification

B

C

Figure 88-3  Calcium pyrophosphate dihydrate (CPPD) crystal depo­ sition arthropathy of the knee joint. A, Femoral condyle. There are extensive foci of chalky white particulate deposits within the articular cartilage. This is characteristic of CPPD crystal deposition. B, Histology of CPPD crystal deposition within the hyaline articular cartilage. The hypertrophic chondrocytes adjacent to the crystal aggregates are within enlarged chondrons (hematoxylin and eosin, ×250). C, Polarized light microscopy of CPPD crystal aggregates within the hyaline articular cartilage. The individual crystals have rod and rhomboid shapes and are positively birefringent (×250). (Courtesy of Dr. Ken Pritzker, Mount Sinai Hospital Pathology Department, University of Toronto, Ontario, Canada.)

Figure 88-4  Coordinated forces promoting chondrocyte maturation to hypertrophy in joint cartilage calcification. The top portion of the figure depicts some of the major synergistic forces promoting chondrocyte maturation to hypertrophy that are likely to be operative in osteoarthritis and aging. Hypertrophic and apoptotic chondrocytes are observed adjacent to calcific crystal deposits in joint cartilages. The lower portion of the figure shows that chondrocyte hypertrophy is a differentiation state specialized for calcification, based in part on alteration of the extracellular matrix composition (with attendant dysregulation of matrix repair),  enhanced release of matrix vesicles to promote mineral seeding, increased  generation of inorganic pyrophosphate (PPi) and inorganic phosphate (Pi), and increased transglutaminase 2 (TG2) and factor XIIIA expression. The increased susceptibility of hypertrophic chondrocytes to apoptotic death is also significant because of the promineralizing effects of chondrocyte apoptosis.

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Local upregulation of PTH-related protein expression may be one of the shared features driving sequential chondrocyte proliferation and altered differentiation in growth plate chondrocytes and articular chondrocytes.44,45 In addition, Pi taken up by Pit-1 sodium-dependent cotransport and calcium sensing can modulate chondrocyte hypertrophic differentiation and apoptosis.16,22,63-65 Chondrocyte apoptosis also promotes calcification, partly through the calcifying potential of apoptotic bodies functioning as “inside-out” matrix vesicles on release from dying chondrocytes.25,66-68 Mitochondrial dysfunction, a central factor in tissue aging and an apparent mediator of OA progression in aging,69,70 can also stimulate cartilage matrix degeneration and calcification. Mitochondria are remarkably specialized to regulate calcification, and apoptosis is critically regulated by mitochondrial function.69 Moreover, chondrocyte ATP depletion is driven by the suppression of mitochondrial oxidative phosphorylation by nitric oxide (NO) as OA evolves in aging (see Chapter 89), thereby promoting increased ATP scavenging by NPP activity and consequent augmentation of extracellular PPi.70 Inflammation-associated chondrocyte hypertrophy is driven by multiple cytokines and calgranulins, oxidative stress, Pi transport, and receptor for advanced glycation end products (RAGE) signaling, and it is modulated by transglutaminase 2 (TG2) release. This process appears to drive chondrocalcinosis and the progression of OA. For example, IL-1β, which is increased in OA cartilage, stimulates articular chondrocytes to calcify the matrix.37,60 NO stimulates both apoptosis and calcification in chondrocytes.66,67,69 IL-1β stimulates inducible NO synthase expression and increased NO generation, as well as expression of other cytokines and MMPs, which can alter extracellular matrix collagen and proteoglycan composition to potentially favor calcification (see Chapters 3 and 89). IL-1 also induces TG family enzymes factor XIIIA and TG2, which cross-link numerous extracellular proteins by transamidation.37,60 IL-1β (as well as tumor necrosis factor[TNF]-α, donors of NO, and the potent oxidant peroxynitrite) also induces increased chondrocyte TG activity.37 TG2 and factor XIIIA are markers of growth plate chondrocyte hypertrophy.37,60 Significantly, there is marked upreg­ ulation of TG2 and factor XIIIA expression in hypertrophic cells in the superficial and deep zones of knee OA ­articular cartilage and the central (chondrocytic) zone of OA menisci.37 Moreover, increased factor XIIIA and TG2 activity directly stimulates calcification by chondrocytes.37 IL-1–induced increases in TG activity, related to OA severity and age, occur in chondrocytes from human knee menisci.37 TG2 is essential for IL-1β to stimulate articular chondrocytes to calcify their matrix in vitro.60 In addition, the closely related inflammatory chemokines CXCL1 and CXCL8, which are both increased in OA cartilage, stimulate increased TG activity attributed specifically to TG2.71 CXCL1 and CXCL8 stimulate chondrocyte hypertrophic differentiation and calcification in a manner that requires TG2.71 Distinct TG2-independent and TG2-dependent mechanisms promote articular chondrocyte hypertrophy and ­calcification in vitro, and increased TG2 release is sufficient to promote chondrocyte hypertrophy.60 TG2 acts as a molecular switch to induce chondrocyte hypertrophy in a β1 integrin–mediated manner, associated with rapid phosphorylation of p38 kinase and dependent on TG2 being in the

guanosine triphosphate–bound conformational state.72 TG2 transamidation activity is not required for TG2 to induce chondrocyte hypertrophy, but TG2 transamidation activity does modulate chondrocyte differentiation and function. For example, TG2 promotes the activation of TGF-β.73 The multiligand RAGE mediates several chronic vascular and neurologic degenerative diseases accompanied by low-grade inflammation.74 RAGE ligands include S100/ calgranulins, a class of small, calcium-binding polypeptides, several of which are expressed by chondrocytes. Normal human knee cartilage demonstrates constitutive RAGE and S100A11 expression, and both RAGE and S100A11 expression are increased in OA cartilage.74,75 CXCL8 and TNF-α induce S100A11 release in cultured chondrocytes.74 Further, S100A11 induces chondrocyte hypertrophy in vitro.74 CXCL1-induced and TNF-α–induced chondrocyte hypertrophy require RAGE, mitogen-activated protein kinase (MAPK)-3, and p38 MAPK signaling.74 ARTICULAR AND PERIARTICULAR BASIC CALCIUM PHOSPHATE CRYSTAL DEPOSITION CPPD and BCP crystal deposition can develop in different zones of articular cartilage and probably in distinct phases of cartilage degenerative disease, such as ongoing loss of viability in hypertrophic chondrocytes. In addition, abundant cartilage NO production may promote mitochondrial dysfunction, chondrocyte extracellular ATP depletion,70 and lowering of extracellular PPi, favoring HA over CPPD crystal deposition.76 The observation that OA and HA crystal deposition in articular cartilage (and arteries)26,28 are both promoted by extracellular PPi deficiency strikingly illustrates the deleterious effects of deprivation of physiologic extracellular PPi levels.16 Yet it is noted that joint fluid PPi and NPP levels are elevated in HA-associated shoulder arthropathy (Milwaukee shoulder syndrome),77 consistent with the model in Figure 88-1. Pathologic BCP crystal deposition may occur in periarticular sites as well as numerous organs and soft tissues.11 Significantly, the shoulder is the most common articular region affected by symptomatic BCP crystal deposition, in part reflecting unique shoulder structure and function. Degenerative changes promoted by biomechanical stress promote calcific tendinitis in the body of the rotator cuff.78 Such tendon calcifications can remain asymptomatic and may eventually resorb, but the degenerative changes can predispose to tendon rupture. Osteopontin, a factor that normally restrains BCP crystal deposition (and is regulated by PPi and Pi),18 can be detected in fibroblast-like cells and multinucleated macrophages surrounding areas of calcification in calcific tendinitis.79 In this regard, osteopontin promotes oxidative stress, MMP activation, macrophage recruitment, and osteoclast activation.18 The presence of multinucleated cells with cathepsin K expression and osteoclast-like functions at sites of tendon calcification80 suggests a mechanism for both resorption of BCP crystal deposits and tendon degeneration. CRYSTAL-INDUCED INFLAMMATION Some of the crystals deposited in cartilage can subclinically travel to joint fluid and synovium, and the crystals can directly stimulate chondrocytes, synovial lining cells,

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and intra-articular leukocytes.81-83 Inflammation triggered by CPPD and HA crystals thereby contributes to cartilage degradation and can cause worsening of OA.81-83 Many proinflammatory mechanisms active in gout (see Chapter 87) likely mediate the synovitis and cartilage degeneration associated with CPPD and HA crystal deposition.81-83 In this regard, CPPD and HA crystals activate cells partly via nonspecific activation of signal transduction pathways (e.g., MAPK activation) and induce cellular release of cyclooxygenase- and lipoxygenase-derived metabolites of arachidonic acid and cytokines, including TNF-α, IL-1, and CXCL8.81-83 Innate immune recognition of extracellular CPPD crystals by Toll-like receptor 2 (TLR2)84 and CPPD crystal-induced activation of the intracellular NALP3 (cryopyrin) inflammasome, resulting in caspase-1 activation and IL-1β processing and release, drive cell responses to CPPD crystals in vitro and CPPD crystal-induced inflammation in vivo.85 The ingress of neutrophils into the joint is central in triggering acute crystal-induced synovitis, and effects on neutrophil-endothelial interaction likely represent a major locus for both the prophylactic effects of nanomolar concentrations of colchicine and the therapeutic effects of higher concentrations of colchicine in acute disease.86 At relatively high (micromolar) concentrations, colchicine selectively suppresses crystal-induced NALP3 inflammasome activation.85 CXCL8 and related chemokines that bind the CXCL8 receptor CXCR2 (including CXCL1) appear to be critical in initiating and perpetuating neutrophil ingress in acute crystal-induced inflammation.87 Despite the fact that BCP and CPPD crystals share the capacity to activate certain cell signaling pathways and to induce several MMPs,88 BCP crystals generally trigger much less neutrophil influx into the joint than do CPPD crystals. Concordantly, free intra-articular BCP crystals likely induce less proinflammatory cytokine expression than do CPPD and monosodium urate crystals.89-91

CLINICAL FEATURES CALCIUM PYROPHOSPHATE DIHYDRATE DEPOSITION DISEASE Most elderly individuals with CPPD deposition disease in the United States have a primary (idiopathic or sporadic) disorder (Table 88-2). Idiopathic chondrocalcinosis generally appears only after the fifth decade of life, but patients with a history of repetitive joint trauma or knee ­meniscectomy may present with nonsystemic (monarticular) chondrocalcinosis before age 50. Familial forms of CPPD crystal deposition disease have been widely documented, as discussed later. Familial chondrocalcinosis often manifests in the third or fourth decade of life, but in some cases, familial disease is detected before age 20 or first pre­ sents clinically at an advanced age. CPPD crystal deposition disease is a common manifestation of a variety of hereditary and metabolic conditions (including hyperparathyroidism, dialysis-dependent renal failure, and hemochromatosis)41 in which CPPD-related arthropathy can present earlier than age 50. For unclear reasons, hemochromatosis can present predominantly as CPPD crystal deposition disease or as OA (see Chapter 111). The weight of evidence from controlled studies suggests that hypothyroidism (with the probable

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Table 88-2  Causes of Calcium Pyrophosphate   Dihydrate Crystal Deposition Disease High Prevalence Idiopathic in association with aging (most frequent) Complication of primary osteoarthritis Long-term consequence of mechanical joint trauma or knee   meniscectomy Moderate Prevalence Familial Associated with systemic metabolic disease (hyperparathyroidism, dialysis-dependent renal failure, hemochromatosis, hypomagnesemia) Low Prevalence (Largely Based on Case Reports) X-linked hypophosphatemic rickets Familial hypocalciuric hypercalcemia Ochronosis Gout Articular amyloidosis Myxedematous hypothyroidism Osteochondrodysplasias and spondyloepiphyseal dysplasias Neuropathic joints Wilson’s disease

exception of myxedematous hypothyroidism) is not associated with a significantly increased prevalence of CPPD crystal deposition disease, although both disorders are clearly more prevalent with aging.41,92,93 It has been suggested that initiation of thyroxine supplementation therapy may trigger pseudogout.94 The clinical manifestations of CPPD deposition disease vary widely (Table 88-3).95 Quite commonly, the disease is asymptomatic. Alternatively, it can mimic OA (pseudoosteoarthritis), gout (pseudogout), or acute-onset or insidious rheumatoid arthritis (pseudo–rheumatoid arthritis; Fig. 88-5), or it may present as pseudoneuropathic arthropathy. Patients with CPPD crystal deposition disease also commonly present with episodes of hemarthrosis, often Table 88-3  Common Clinical Presentations   of Calcium Pyrophosphate Dihydrate (CPPD)   Crystal Deposition Disease Asymptomatic or incidental finding (e.g., asymptomatic knee fibrocartilage chondrocalcinosis in the elderly) Recurrent acute inflammatory monarticular arthritis or pseudogout (e.g., wrist or knee, including provocation by trauma, concurrent medical or surgical illness, or intra-articular hyaluronan) Pseudoseptic arthritis Recurrent acute hemarthrosis Chronic degenerative arthritis (pseudo-osteoarthritis or pseudoneuropathic arthritis) Chronic symmetric inflammatory polyarthritis (pseudo–rheumatoid arthritis) Systemic illness (pseudo–polymyalgia rheumatica, fever of unknown origin) Destructive arthritis in dialysis-dependent renal failure Carpal tunnel syndrome Tumoral and pseudotophaceous CPPD crystal deposits Central nervous system disease complicating ligamentum flavum or transverse ligament of atlas involvement (cervical canal stenosis, cervical myelopathy, meningismus, foramen magnum syndrome, odontoid fracture)

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B Figure 88-5  Idiopathic, symmetric pseudorheumatoid calcium pyrophosphate dihydrate (CPPD) deposition arthropathy in an elderly woman. This 84-year-old woman presented with a history of past right carpal tunnel syndrome and chronic symmetric proliferative synovitis of both wrists and second and third metacarpophalangeal (MCP) joints. Physical findings included synovial and dorsal extensor tenosynovial swelling of the wrists and synovial swelling at the second to third MCP joints  (A). Changes on hand and wrist plain radiographs were consistent with the diagnosis of CPPD deposition disease. Those in the right wrist  (B) included cystic changes in multiple carpal bones, including the scaphoid and lunate; linear calcification on the ulnar side of the carpus (arrow), typical for the chondrocalcinosis of CPPD deposition; and mild narrowing of the radiocarpal joint, indicative of cartilage loss.

post-traumatic and in the knee.96 It is not clear how the form of CPPD deposited (i.e., monoclinic versus triclinic crystals) and host factors contribute to these wide differences in clinical manifestation. Overall, only a small fraction of patients with CPPD deposition disease have prolonged, recurring polyarticular inflammation. Progressive degenerative arthropathy is more common. Although CPPD deposition disease appears to be a common and significant public health problem in the elderly, the disease impact and the long-term course of CPPD-associated degenerative arthropathy in an unselected population have not been adequately evaluated. ACUTE SYNOVITIS Pseudogout is a major cause of acute monarticular or oligoarticular arthritis in the elderly. The attacks typically involve a large joint—most often the knee, less often the wrist or ankle, and, unlike gout, rarely the first metatarsophalangeal joint. Acute attacks of inflammatory pseudogout in patients with CPPD deposition disease typically have a sudden onset and can be excruciatingly painful, with pronounced periarticular erythema, warmth, and swelling,

comparable to gout. In addition, in some attacks of pseudogout, arthritis can be migratory or additive, polyarticular, and bilateral. Polyarticular pseudogout is particularly common in association with familial chondrocalcinosis and hyperparathyroidism. Pseudogout can be provoked by minor trauma or intercurrent medical or surgical conditions, including pneumonia, myocardial infarction, cerebrovascular accident, and pregnancy. Parathyroid surgery for hyperparathyroidism frequently triggers pseudogout attacks. In addition, pseudogout of the knee can be precipitated by arthroscopy or by intraarticular administration of hyaluronan,97-99 which could reflect proinflammatory mechanisms triggered through the hyaluronan receptor CD44.100,101 Parenteral administration of granulocyte colony-stimulating factor102 and bisphosphonates103,104 also can trigger pseudogout, the former likely by ignition of smoldering subclinical intra-articular inflammation and the latter (theoretically) via pyrophosphatase inhibition, because bisphosphonates are nonhydrolyzable analogues of PPi. Acute and subacute pseudogout can be associated with fever, chills, elevated erythrocyte sedimentation rate, and systemic leukocytosis, particularly with polyarticular involvement and in the elderly.105 Leukocyte counts in the synovial fluid are substantially elevated, and intraleukocytic CPPD crystals are most often (but not universally) detectable by compensated polarized light microscopy in pseudogout. The attacks typically last for 7 to 10 days, but they can also be clustered and last for weeks to months. Occasionally, the leukocyte count in pseudogout can exceed 50,000/mm3 (pseudoseptic arthritis). CHRONIC DEGENERATIVE AND INFLAMMATORY ARTHROPATHIES Acute pseudogout attacks may be interspersed with chronic arthropathy in CPPD crystal deposition disease. Chronic degenerative arthropathy in CPPD deposition disease commonly affects certain joints that are typically spared in primary OA (e.g., metacarpophalangeal joints, wrists, elbows, glenohumeral joints). The development of cartilage degenerative changes in joints both typical and atypical for primary OA suggests one or more systemic abnormalities. Degenerative cartilage disease associated with sporadic CPPD crystal deposition disease may present as destructive arthropathy of the knees, hips, or shoulders, particularly in elderly women (Figs. 88-6 and 88-7). CPPD crystal arthropathy–associated degenerative disease can be less or more destructive than that observed in primary OA. For example, patients with primary OA and CPPD crystals have been reported to require knee replacement surgery more often than those with primary OA without crystals.106 In another study, 60% of patients undergoing joint replacement had CPPD or BCP crystals (commonly both types) in their knee synovial fluid and higher mean radiographic scores correlated with the presence of calcium-containing crystals.107 However, prospective analysis of CPPD deposition disease that involved primarily the knee suggested that radiographic worsening of degenerative changes may be slow.108 Also, the disease may not appear to progress clinically in the involved knee after substantial periods of follow-up in a subset of patients, although clinical i­nvolvement may spread to other

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Figure 88-6  Radiographic features of calcium pyrophosphate dihydrate arthropathy. A, Destructive shoulder arthropathy. B, Metacarpophalangeal  joint arthropathy. C, Knee degenerative joint disease with large subchondral bone cyst. D, Wraparound patella (same patient shown in A).

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Figure 88-7  Chondrocalcinosis of the most commonly affected joints in calcium pyrophosphate dihydrate deposition disease. A, Lineal calcifications observed in knee menisci and fibrocartilage. B, Lateral view showing calcification of the articular cartilage as a line parallel to the femoral condyles.  C, Calcification of intercarpal joints and triangular ligament. D, Calcification of the symphysis pubis fibrocartilage associated with subchondral bone erosions and subchondral increased bone density.

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joints in the same time frame.108 Most patients develop changes in the radiographic extent of chondrocalcinosis over time,108 but there is no clear correlation between the extent of calcification and the progression of CPPD deposition arthropathy. There may be a relatively good prognosis for those with CPPD deposition disease in the knee presenting as acute pseudogout attacks alone.108 Pseudorheumatoid involvement in a small subset of pa­­ tients with CPPD deposition disease presents as a chronic, bilateral, symmetric, deforming inflammatory polyarthrop­ athy (see Fig. 88-5). Many of these patients have bilateral wrist and metacarpophalangeal joint involvement. Wrist tenosynovitis, carpal tunnel syndrome, cubital tunnel syndrome, and tendon rupture may develop. Ingestion of CPPD crystals­ by synovial lining cells, and lysosomal catabolism of such ingested crystals, stimulates synovial proliferation, in part via solubilization of the crystalline calcium. Such effects may contribute to regional synovial and periarticular tenosynovial proliferation promoted by CPPD crystal deposition.82 OTHER FORMS OF CALCIUM PYROPHOSPHATE DIHYDRATE CRYSTAL DEPOSITION Concentrated (tumoral or pseudotophaceous) CPPD crystal deposition can occur in periarticular structures, including tendons, ligaments, bursae, and occasionally bone.95,109 CPPD deposits in tendons (e.g., Achilles, triceps, obturator tendons) are usually fine and linear on radiographs. Pseudotophaceous deposits of CPPD crystals have been detected in the temporal bone, around the knee and hip, and in the acromioclavicular, temporomandibular, elbow, and small hand joints.109 Peripheral tumoral CPPD crystal deposits sometimes present with acute arthritic attacks. Rarely, tumoral CPPD deposits around the knee can mimic osteonecrosis.110 Tumoral CPPD crystal deposition typically is associated with tissue chondroid metaplasia and behaves like a benign but locally aggressive chondroid tumor, with some of the connective tissue invasion and destruction likely mediated by CPPD crystal-induced cell activation. Axial skeletal CPPD crystal deposition occasionally involves the intervertebral disks, sacroiliac joints, and lumbar facet joints, and radiographic findings such as linear calcification and spinal ankylosis may appear.111 Meningismus and clinical manifestations resembling herniated intervertebral disk, ankylosing spondylitis, and acute pseudogout of the lumbar facet joints have been observed.111,112 In addition, CPPD deposits within the ligamentum flavum or the transverse ligament of the atlas can be sizable and can pro­ gress, causing cervical canal stenosis, cervical myelopathy, and foramen magnum syndrome.113-115 Odontoid fracture due to the calcification of the atlantoaxial joint may occur in CPPD deposition disease.113-116 Thus, CPPD deposition disease can be a factor in the differential diagnosis of patients with neurologic disturbances and painful cervical masses, especially in the elderly. FAMILIAL CHONDROCALCINOSIS Familial CPPD deposition disease has been described in numerous countries and ethnic groups, including kindreds from Czechoslovakia, Holland, France, England, Germany, Sweden, Israel, the United States, Canada, and Japan; it

may be most prevalent in Chile and Spain.117 In one English kindred with CPPD disease linked to ANKH mutation on chromosome 5p, recurrent childhood seizures were strongly associated with the later development of CPPD deposition disease.118 With linkages to chromosome 5p,54,55 some families manifest early-onset polyarthritis, which can include ankylosing intervertebral and sacroiliac joint disease. In others, a late-onset chondrocalcinosis occurs, and the disease can be oligoarticular, mild in intensity and destructiveness, and nearly indistinguishable from idiopathic CPPD deposition disease.118 Kindreds from Argentina and the Alsace region of France with linkages to chromosome 5p shared similar phenotypic features of chondrocalcinosis, including early age at onset (third decade of life), common but not universal premature OA, some cases of pseudo–rheumatoid arthritic peripheral joint disease, and radiographic evidence of fibrocartilage and hyaline cartilage calcifications typical of CPPD deposition.50 The most commonly affected joints in these kindreds were the knees and wrists, with involvement of the pubic symphysis and intervertebral disks also described.50 BASIC CALCIUM PHOSPHATE CRYSTAL DEPOSITION AT THE JOINT Unlike the case for urate and CPPD crystal deposition, acute synovitis due to HA crystal deposition is unusual.119 However, acute inflammatory syndromes, including subacromial bursitis (see Chapter 40) and a form of pseudopodagra described in young women,120 may occur in association with periarticular HA crystal deposition in bursae, tendons, ligaments, and soft tissues. Patients with advanced chronic renal failure, particularly those on dialysis, may develop symptomatic articular and periarticular BCP crystal deposition (Fig. 88-8), which may be destructive and involve the axial skeleton.121-123 In some cases of dialysis-dependent renal failure, destructive arthropathy associated with BCP crystal deposition may resemble or be associated with CPPD deposition disease,123 and monosodium urate crystal deposits in the joint may also occur in this setting. Hyperparathyroidism can promote BCP-associated arthropathy124 and periarticular disease, including calcific bursitis. Clinically significant periarticular HA crystal deposition also may occur in certain post-traumatic conditions and in the systemic autoimmune diseases scleroderma and dermatomyositis.125 BCP crystal deposition has a predilection for the shoulder, where it may manifest as calcific tendinitis of the rotator cuff (see Chapter 40) or as a destructive process associated with rotator cuff tear, which is most prevalent in the elderly and more common in females.126 Abundant intra-articular BCP crystalline material is typically present in the distinctive noninflammatory syndrome of rotator cuff tear and marked cartilage degeneration—an entity termed Milwaukee shoulder syndrome, cuff tear arthropathy, or apatite-associated destructive arthritis.46,77,127-129 Mechanical instability of the shoulder due to rotator cuff tear may be the driving force in many of these patients, with consequent release of BCP crystals from bone fragments into the joint space, promoting secondary synovitis and connective tissue destruction. The process may be bilateral but is generally worse on the side of the dominant hand. Substantial

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Figure 88-8  Hydroxyapatite crystal-associated calcific bursitis of the shoulder in a patient with chronic renal failure and secondary hyperparathyroidism. A, Chronic soft tissue swelling involving the right shoulder due to calcific right shoulder subacromial bursitis in a middle-aged man with a history of chronic renal failure on hemodialysis. Note the convex contour of the right shoulder compared with the left. B, Radiograph showing extensive calcification within both the rotator cuff and the expanded subacromial bursa surrounding the right shoulder joint. An incidental finding is resorption of the distal end of the clavicle, consistent with secondary hyperparathyroidism in this patient. C, Subacromial bursa fluid from the right shoulder. Note the milk-white appearance, with a chalky sediment of particulate material in the fluid after centrifugation, consistent with crystal deposition disease.  D, Microscopic appearance of bursa fluid aggregates of basic calcium phosphate crystals in the absence of special stains. The particles are irregular but have approximately spherical profiles (unstained, ×250). E, Appearance of the bursa fluid under polarized light microscopy. Importantly, the aggregated particles of basic calcium phosphate crystals demonstrate edge birefringence but do not display intrusive birefringence (unstained, ×250). F, Electron photomicrograph of a mononuclear phagocyte from this bursa fluid that contained phagocytosed electron-dense (dark black) spherical aggregates of crystals of basic calcium phosphate hydroxyapatite in three phagolysosomes oriented vertically to the right of the nucleus. Hundreds of tiny needleshaped hydroxyapatite crystals are clumped in each of these dense aggregates. For perspective, the size of the mononuclear phagocyte is about 20 μm, and an individual (nonaggregated) hydroxyapatite crystal is about 0.04 × 0.01 × 0.01 μm in size (transmission electron microscopy, ×1000). G, Electron diffraction pattern of hydroxyapatite crystal aggregates. The diffraction rings are indicative of a powder pattern (i.e., small crystals). The position of the bright rings with d-spacings = 3.44 and 2.81 Å are characteristic of hydroxyapatite (calcium apatite). (Courtesy of Dr. Ken Pritzker, Mount Sinai Hospital Pathology Department, University of Toronto, Ontario, Canada.)

g­ lenohumeral joint effusions are typically seen, and synovial fluid is often blood stained but contains, at most, relatively low numbers of mononuclear leukocytes. Joints other than the shoulder, such as the knee and hip, can be affected by a condition similar to Milwaukee shoulder syndrome, sometimes in an individual with shoulder involvement.46,126,127 In contrast to primary OA, lateral tibiofemoral compartment involvement is common in BCP-associated destructive knee arthropathy. Concurrent CPPD deposition, biomechanical abnormalities, chronic renal failure, and neuropathic factors

appear to be predisposing factors. A kindred with familial OA and apparent Milwaukee shoulder-knee syndrome had an unusual type of degenerative joint disease with both intra-articular and periarticular calcifications.46 Studies of synovial fluids and cartilage specimens from OA indicated that intra-articular BCP crystalline material, including HA in the pericellular matrix of chondrocytes, is frequently detectable in the disease.58,107 Synovial fluid HA crystals are frequently present in conjunction with CPPD crystals in OA, particularly in advanced disease of the knee

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at the time of total joint replacement.107,128 Subchondral bone shards in OA cartilage that are composed of BCP crystalline material may contribute to a fraction of such crystalpositive specimens. In addition, the movement of crystals from articular cartilage to synovium82,83 can promote calcific synovial crystal deposits at or just beneath the synovial surface, and synovium-derived rice bodies can give rise to BCP crystal deposits released into the joint space.129,130 Therefore, it is difficult to quantify the precise prevalence of HA crystal deposits in articular cartilage in OA. Both HA and CPPD crystal-induced synovial proliferation, cytotoxic effects on chondrocytes, and synovial and chondrocyte MMP expression can promote OA progression.82,83

DIAGNOSIS AND DIAGNOSTIC TESTS DIFFERENTIAL DIAGNOSIS CPPD deposition disease can imitate a number of other conditions, and vice versa (see Table 88-3); therefore, attention to the diagnostic criteria for CPPD deposition disease is mandatory (see Table 88-1). Conversely, it is important to note that radiographic evidence of chondrocalcinosis is a common finding in the aged and does not necessarily indicate that the patient’s symptomatic articular problem is due to CPPD deposition disease, which is often asymptomatic. The demonstrable presence of CPPD crystals in synovial fluid or in tissues using compensated polarized light microscopy (as discussed earlier for distinguishing gout from pseudogout) is definite evidence of CPPD deposition disease. Although weakly birefringent relative to urate crystals, and often rhomboid in shape, CPPD crystals can be rod-shaped and intracellular, resembling urate crystals. Thus, the use of compensated polarized light microscopy is essential to confirm the presence of positively birefringent CPPD crystals, although it should be noted that some CPPD crystals are nonbirefringent.131 The appearance and number of CPPD crystals can change with storage. Therefore, clinicians should examine relatively fresh specimens collected in vials free of calcium-chelating anticoagulants such as EDTA. The ability of pseudogout to mimic septic arthritis (pseudo–septic arthritis), and vice versa, underscores the diagnostic importance of arthrocentesis with appropriate synovial fluid crystal analysis and, in many instances, concomitant exclusion of joint infection. Significantly, crystal deposits can be “enzymatically strip-mined” by inflammation associated with joint sepsis. Hence, CPPD crystals (as well as other crystals) may be observed in the joint fluid and within synovial fluid leukocytes in an infected joint. Chronic arthritis in CPPD deposition disease has several clinical and plain radiographic features that help differentiate it from OA. These include involvement at sites uncommon for primary OA, such as the wrist, metacarpophalangeal joints, elbow, or shoulder, as well as heavy punctate and linear calcifications in fibrocartilage, articular (hyaline) cartilage, and joint capsules on radiographs, especially if they are bilateral and symmetric (see Figs. 88-6 and 88-7). It should be noted that faint or atypical calcifications may be due to BCP-related vascular calcifications. It was thought that deposition of nonpathologic dicalcium

phosphate dihydrate (CaHPO4•2H2O; calcium-phosphate ratio, 1.0), or brushite, crystals could cause some atypical calcifications, but brushite crystals can arise as an artifact of preparation of calcified tissue for pathologic analysis.132 Patients with arthritis in whom CPPD deposition disease is part of the differential diagnosis can be adequately screened radiographically by obtaining an anteroposterior view of each knee, an anteroposterior view of the pelvis (to detect symphysis pubis involvement, which is quite common), and posteroanterior views of both hands that include visualization of both wrists (see Figs. 88-6 and 88-7). Calcific deposits may or may not be detectable by radiographic screening of these areas in CPPD deposition disease. In this case, radiographic evidence other than chondrocalcinosis may point to the correct diagnosis.133 For example, radiographic findings suggestive of CPPD deposition disease, as opposed to primary OA, include radiocarpal or marked patellofemoral joint space narrowing, especially if isolated (such as the patella “wrapped around” the femur), as well as scaphoid-lunate widening and femoral cortical erosion superior to the patella. Severe progressive degeneration in the knee, with subchondral bony collapse (microfractures), fragmentation, and formation of intra-articular radiodense bodies, is a feature of CPPD presenting as a pseudoneuropathic joint. CPPD deposition disease involving the metacarpophalangeal joints can be distinguished radiographically from rheumatoid arthritis by metacarpal squaring associated with “beaklike” osteophytes and subchondral cyst formation. Tendon calcifications (e.g., Achilles, triceps, obturator tendons) are a valuable differential diagnostic feature of CPPD deposition. Osteophyte formation is more variable with CPPD deposition disease than with OA. Diagnosis of CPPD deposition disease in a patient younger than 50 years, particularly if CPPD deposition is widespread, should prompt consideration of a primary metabolic or familial disorder (see Table 88-2). In the elderly, presentation of CPPD deposition as diffuse pain and fever of unknown origin105 can mimic infection, polymyalgia rheumatica, and rheumatoid arthritis. A false-positive rheumatoid factor test is common in the elderly (>30% positivity). Thus, patients with pseudorheumatoid CPPD deposition disease are often seropositive for rheumatoid factor. BCP crystals may be detected as nonbirefringent globular clumps within leukocytes in some synovial and bursal fluids (see Fig. 88-8), and BCP crystal clumps stain with the calcium-binding dye alizarin red S under light microscopy.119,128 CPPD crystals can also be detected using alizarin red S, but they stain more weakly than BCP crystals. The relative paucity of osteophytes (so-called atrophic degenerative arthritis) and the sizable glenohumeral joint effusions with abundant synovial fluid BCP crystalline material associated with Milwaukee shoulder syndrome help distinguish it from primary OA of the glenohumeral joint. However, destructive, neuropathic shoulder arthropathy due to syringomyelia or alcoholism sometimes merits consideration in the differential diagnosis of Milwaukee shoulder syndrome.134 Oxalate crystal deposition arthropathy can be a major differential diagnostic consideration with BCP-associated arthritis and periarticular calcifications in dialysis-dependent renal failure.135 The differential diagnosis of calcific tendinitis of the shoulder is discussed in Chapter 40.

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DIAGNOSTIC TESTS A thorough laboratory evaluation of a newly diagnosed CPPD disease patient routinely includes serum levels of calcium, phosphorus, magnesium, alkaline phosphatase, ­ferritin, iron and total iron binding capacity, and thyroid­stimulating hormone (Fig. 88-9). Conventional radiography is usually the first method to evaluate patients with suspected chondrocalcinosis, but the findings may not correlate with pathologic and clinical manifestations. For example, the correlation between radiographic and pathologic findings was only 39.2% in a study of patients via knee arthroscopy.136 Other imaging approaches to the diagnosis of CPPD deposition disease with the potential to improve sensitivity include computed tomography, magnetic resonance imaging (MRI), and ultrasonography, which can detect CPPD (as well as BCP) crystals, particularly in the knee.133,137,138 However, standard, nonenhanced MRI is less sensitive in detecting knee meniscal fibrocartilage calcification than hyaline cartilage calcification.139 Specialized techniques beyond alizarin red S staining, such as x-ray diffraction, Raman spectroscopy, Fourier transform intrared spectroscopy, atomic force microscopy, or transmission electron microscopy showing

Acute or chronic arthritis

Suspect CPPD crystal deposition disease: Elderly? History of OA or trauma Typical pseudogout or pseudo-OA Hemarthrosis Specific metabolic disorder Family history of chondrocalcinosis

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electron-dense clumps of needle-like crystals, may be needed to confirm BCP crystal deposition (see Fig. 88-8).2,3 If synovial fluid specimens are not fresh (or have not been stored at 4°C),140 Gram stain and Diff Quick staining methods for crystal analysis have been suggested as a means of obtaining information beyond that available from compensated polarized light microscopy.141,142 Demonstration of CPPD crystals in articular tissues (see Fig. 88-3) can be difficult in specimens stained with hematoxylin and eosin, because the acidity of hematoxylin solutions promotes decalcification. However, the decalcifying effect of hematoxylin can be diminished by limiting the staining period with Mayer’s hematoxylin to 3 minutes.143

TREATMENT CALCIUM PYROPHOSPHATE DIHYDRATE DEPOSITION DISEASE As in gout (see Chapter 87), therapeutic approaches to patients with CPPD deposition disease involve treatment and prophylaxis of acute arthritic attacks, as well as therapy to lessen chronic and anatomically progressive sequelae of crystal deposition (Table 88-4). Although reduced meniscal calcification was reported over a 10-year period in association with the administration of oral magnesium to a patient with secondary CPPD deposition disease due to hypomagnesemia,144 there is no specific treatment for idiopathic CPPD deposition disease. Metabolic disorders that secondarily cause CPPD crystal deposition obviously require treatment. However, the potential benefits of preventing chondrocalcinotic cartilage degeneration with the appropriate treatment of hemochromatosis and hyperparathyroidism are unclear, because the ability to detect chondrocalcinosis radiographically is usually indicative of advanced crystal deposition disease. Table 88-4  Therapeutics for Calcium Pyrophosphate Dihydrate (CPPD) Crystal Deposition Disease

Aspirate affected joint Analysis by compensated polarized light microscopy

Crystal analysis positive for CPPD, or X-ray evidence for CPPD deposition Gout excluded Joint cultures negative

Treat inflammatory arthritis: NSAIDs Intra-articular or systemic steroids or ACTH Prophylactic colchicine for recurrent pseudogout

Plain radiographs (CPPD survey includes hands/wrists, knees, AP pelvis)

Proven Benefits NSAIDs or COX-2 inhibitors Intra-articular corticosteroids Systemic corticosteroids ACTH Prophylactic low-dose colchicine Possible Benefits Already Observed Clinically

Crystal analysis and radiographs negative: assess for alternative diagnosis

Evaluate for primary metabolic disorder: serum Ca++, PO4-, alkaline phosphatase serum Mg++ serum iron, TIBC, ferritin renal function TSH

Figure 88-9  Algorithm for the evaluation and treatment of calcium  pyrophosphate dihydrate (CPPD) deposition disease.

Methotrexate for refractory chronic inflammation and recurrent pseudogout Oral magnesium (for patients with hypomagnesemia) Theoretical Benefits Phosphocitrate Caspase-1 or IL-1 antagonism for CPPD crystal-induced inflammation Hydroxychloroquine for refractory chronic inflammation TLR2 antagonism for CPPD-associated degenerative arthropathy Oral calcium supplementation to suppress PTH levels ANKH anion channel blockade (probenecid) NPP1 inhibition TG2 inhibition Polyphosphates Promotion of crystal dissolution by alkaline phosphatase or polyamines ACTH, adrenocorticotropic hormone; COX-2, cyclooxygenase-2; IL-1, interleukin-1; NPP1, nucleotide pyrophosphatase phosphodiesterase 1; NSAID, nonsteroidal anti-inflammatory drug; PTH, parathyroid hormone; TG2, transglutaminase 2; TLR2, Toll-like receptor 2.

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Episodes of pseudogout generally respond to nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 inhibitors, or intra-articular steroids, although the response is sometimes slower than in gout. Adrenocorticotropic hormone145 and systemic glucocorticoids,146 generally given as described for acute gout (see Chapter 87), are effective in most cases of acute pseudogout. The response to colchicine bolus is less consistent than that usually seen in acute gout. Intravenous colchicine is not recommended for pseudogout and can be quite dangerous in elderly patients; however, pseudogout episodes can be diminished in ­ freque­ncy­ by low-dose daily colchicine prophylaxis, as for gouty arthritis. Although most acute pseudogout attacks in the knee are self-limited, resolution can sometimes be enhanced by simple arthrocentesis and thorough drainage of the joint effusion; there are currently no data on measures such as tidal irrigation. Hydroxychloroquine may be of some benefit in patients with refractory, chronic polyarticular CPPD deposition­ disease and may reduce the flares of pseudogout.147 Methotrex­ ate­ was particularly promising in this setting in an exploratory study limited to five consecutive patients who were used as their own controls (before methotrexate treatment).148 However, at this time, there is insufficient evidence to recommend hydroxychloroquine and methotrexate as standard therapies for refractory inflammation in CPPD crystal deposition disease. Effective cartilage-preserving therapy is still lacking in idiopathic, chronic, progressive CPPD deposition disease. Some reports have suggested that OA patients with cartilage calcification respond to arthroscopic irrigation and daily low-dose colchicine,149-151 but further substantiation is needed. There is currently no evidence to support arthroscopic débridement as a treatment modality for CPPD deposition disease. There is insufficient evidence of beneficial effects of intra-articular hyaluronan therapy in CPPD deposition disease of the knee, and the risks of precipitating pseudogout appear to be significant with this treatment modality, as noted earlier. BASIC CALCIUM PHOSPHATE CRYSTAL ARTHROPATHIES NSAIDs and local glucocorticoid injection are effective treatment options for BCP crystal-associated calcific tendinitis and subacromial bursitis (see Chapter 40) (Table 88-5). BCP crystal-associated inflammation of the rotator cuff and subacromial bursa of the shoulder can be successfully treated using needle aspiration, irrigation, and steroid injections. Ultrasound-guided techniques, which promote resorption of rotator cuff and bursal calcifications, can enhance the success of such approaches.152,153 FUTURE THERAPEUTIC APPROACHES One factor that may account for the low prevalence of chondrocalcinosis in China is high oral calcium intake, which suppresses PTH production by the parathyroid. Specifically, calcium levels in tap water in Beijing were 12- to 20-fold higher than in Framingham, whereas no difference was found in magnesium levels in the aforementioned study of Chinese versus U.S. chondrocalcinosis

Table 88-5  Therapeutics for Articular and Periarticular Basic Calcium Phosphate Crystal Deposition Proven Benefits NSAIDs or selective COX-2 inhibitors Local corticosteroid injection Local irrigation Ultrasonography Theoretical Benefits Phosphocitrate Modulators of ANKH (e.g., probenecid), NPP1, or TG2 COX-2, cyclooxygenase-2; NPP1, nucleotide pyrophosphatase phosphodiesterase 1; NSAID, nonsteroidal anti-inflammatory drug; TG2, transglutaminase 2.

prevalence by Zhang and coworkers.11 Oral calcium intake suppresses PTH production, and deficient calcium intake in aging is a major public health problem in Western countries. Primary hyperparathyroidism as well as chondrocalcinosis are rare in mainland China.154 It is possible that chondrocalcinosis is more of an environmentally mediated finding than previously recognized, influenced by subclinical variability in calcium intake and parathyroid function. Given the current lack of effective, rational therapies to prevent or lessen idiopathic CPPD crystal deposition, further study of the potential prophylactic and therapeutic benefits of dietary calcium supplementation is warranted. The potential to develop therapies for both CPPD and BCP crystal-associated arthropathies based on new molecular targets has been advanced by the identification of ANKH, NPP1, and TG2 as specific molecular mediators of cartilage calcification. Intriguingly, the anion transport inhibitor probenecid suppresses ANKH-induced and TGF-β–induced increases in extracellular PPi in vitro.26,54,155 Prevention of CPPD deposition by polyphosphates or promotion of CPPD dissolution by depot alkaline phosphatase and by pyrophosphatase activation-promoting polyamines could provide alternative therapeutic approaches.156,157 However, in the past, incomplete CPPD crystal dissolution by intra-articular lavage in patients with chondrocalcinosis of the knees with disodium EDTA and magnesium ions was a therapeutic failure, in that insignificant amounts of CPPD were removed and all subjects developed postlavage attacks of pseudogout mediated by crystal shedding.158 The PPi analogue phosphocitrate, a natural compound in mammalian mitochondria and in the urinary tract, is a potent inhibitor of HA crystal formation.159 Phosphocitrate inhibits NO-induced calcification of cartilage67 and also inhibits both HA and CPPD crystal-associated cell stimulation, including induction of MMP-3 in fibroblasts.160 Systemic phosphocitrate treatment suppresses ankylosing ossification in murine progressive ankylosis of ank/ank mice.161 Moreover, an analogue of phosphocitrate (CaNaPC) decreased both the abundant meniscal cartilage HA deposition and the continual progression of OA in the Hartley guinea pig model of spontaneous knee OA.162 The CaNaPC treatment did not exert therapeutic effects in a rabbit knee hemimeniscectomy model of OA in which there was an absence of intraarticular calcification.162 Such results suggest that phosphocitrate acts on calcification-mediated mechanisms of ­dysregulation of joint biomechanics and cartilage degeneration without exerting nonspecific chondroprotective effects.

PART 14 

Further clinical development of phosphocitrate would be of interest, but it has been slowed in part by its low bioavailability unless given parenterally.159 The use of bisphosphonates as PPi analogues can be beneficial in some cases of soft tissue calcification with HA, as illustrated in disease associated with NPP1 deficiency.16,163 Last, the identified roles of TLR2 in chondrocyte responsiveness to CPDD crystals,84 of TLR4 in HA crystal-induced inflammatory responses,164 and of NALP3 inflammasomemediated caspase-1 activation and IL-1β processing in CPPD crystal-induced inflammation85 suggest that certain mediators of innate immunity, including TLR2, TLR4, caspase-1, and IL-1β, may be therapeutic targets for human forms of CPPD and HA crystal-driven inflammation and connective tissue destruction.

OUTCOME AND PROGNOSIS The presence of CPPD crystals in primary knee OA had been proposed as a predictive factor for more frequent knee replacement surgery.106 Moreover, mean radiographic scores directly correlate with the presence of calcium-containing crystals in OA patients at the time of total joint arthroplasty.107 However, degenerative cartilage disease associated with sporadic CPPD crystal deposition disease may be less destructive than that observed in primary OA. For example, a prospective analysis of CPPD deposition disease of the knee suggested that radiographic worsening of degenerative arthritis was slow to occur.108 Typically, changes in the radiographic extent of chondrocalcinosis are observed over time,108 but there is no clear correlation between the extent of calcification and progression of CPPD deposition arthropathy. In the Boston OA Knee Study (BOKS) and in the Health, Aging, and Body Composition (Health ABC) Study,165 the relationship between chondrocalcinosis and the progression of knee OA was prospectively evaluated longitudinally using MRI. In BOKS, knees with chondrocalcinosis had a decreased risk of cartilage loss compared with knees without chondrocalcinosis; there was no difference in risk in the Health ABC Study. Stratification by the presence of intact or damaged knee menisci produced comparable results within each cohort.165 In a Thai study, CPPD crystal deposition disease was identified radiographically or by synovial fluid analysis in 52.9% of 102 patients undergoing total knee arthroplasty.166 Patients with and without chondrocalcinosis did not differ in the ability to perform daily activities or treatment, and those with chondrocalcinosis did not undergo knee arthroplasty at an earlier age than those without chondrocalcinosis.166 In the setting of OA, the processes leading to matrix calcification were once thought to reflect passive secondary consequences of advanced cartilage pathology. Moreover, joint inflammation induced by deposited crystals was thought to be the primary determinant of the clinical impact of chondrocalcinosis on the progression of OA. The aforementioned studies165,166 and advances in our understanding of the pathogeneses of OA and chondrocalcinosis paint a different picture. In essence, the dysregulated cartilage matrix repair that generates cartilage calcification may be as effective (or in some cases more effective) at slowing cartilage tissue failure than other phenotypes of cartilage repair in OA.

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PART 14  68. Kirsch T, Wang W, Pfander D: Functional differences between growth plate apoptotic bodies and matrix vesicles. J Bone Miner Res 18:1872-1881, 2003. 69. Terkeltaub R, Johnson K, Murphy A, et al: The mitochondrion in osteoarthritis. Mitochondrion 1:301-319, 2002. 70. Johnson K, Svensson CI, Etten DV, et al: Mediation of spontaneous knee osteoarthritis by progressive chondrocyte ATP depletion in Hartley guinea pigs. Arthritis Rheum 50:1216-1225, 2004. 71. Merz D, Liu R, Johnson K, et al: IL-8/CXCL8 and growth-related oncogene alpha/CXCL1 induce chondrocyte hypertrophic differentiation. J Immunol 171:4406-4415, 2003. 72. Johnson KA, Terkeltaub RA: External GTP-bound transglutaminase 2 is a molecular switch for chondrocyte hypertrophic differentiation and calcification. J Biol Chem 280:15004-15012, 2005. 73. Rosenthal AK, Gohr CM, Henry LA, et al: Participation of transglutaminase in the activation of latent transforming growth factor beta1 in aging articular cartilage. Arthritis Rheum 43:1729-1733, 2000. 74. Cecil DL, Johnson K, Rediske J, et al: Inflammation-induced chondrocyte hypertrophy is driven by receptor for advanced glycation end products. J Immunol 175:8296-8302, 2005. 75. Loeser RF, Yammani RR, Carlson CS, et al: Articular chondrocytes express the receptor for advanced glycation end products: Potential role in osteoarthritis. Arthritis Rheum 52:2376-2385, 2005. 76. Johnson K, Jung AS, Andreyev A, et al: Mitochondrial oxidative phosphorylation is a downstream regulator of nitric oxide effects on chondrocyte matrix synthesis and mineralization. Arthritis Rheum 43:1560-1570, 2000. 77. Rachow JW, Ryan LM, McCarty DJ, et al: Synovial fluid inorganic pyrophosphate concentration and nucleotide pyrophosphohydrolase activity in basic calcium phosphate deposition arthropathy and Milwaukee shoulder syndrome. Arthritis Rheum 31:408-413, 1988. 78. Sano H, Ishii H, Trudel G, et al: Histologic evidence of degeneration at the insertion of 3 rotator cuff tendons: A comparative study with human cadaveric shoulders. J Shoulder Elbow Surg 8:574-579, 1999. 79. Takeuchi E, Sugamoto K, Nakase T, et al: Localization and expression of osteopontin in the rotator cuff tendons in patients with calcifying tendinitis. Virchows Arch 438:612-617, 2001. 80. Nakase T, Takeuchi E, Sugamoto K, et al: Involvement of multinucleated giant cells synthesizing cathepsin K in calcified tendinitis of the rotator cuff tendons. Rheumatology (Oxford) 39:1074-1077, 2000. 81. Liu R, O’Connell M, Johnson K, et al: Extracellular signal-regulated kinase 1/extracellular signal-regulated kinase 2 mitogen-activated protein kinase signaling and activation of activator protein 1 and nuclear factor kappaB transcription factors play central roles in interleukin-8 expression stimulated by monosodium urate monohydrate and calcium pyrophosphate crystals in monocytic cells. Arthritis Rheum 43:11451155, 2000. 82. Morgan MP, McCarthy GM: Signaling mechanisms involved in crystal-induced tissue damage. Curr Opin Rheumatol 14:292-297, 2002. 83. Sun Y, Wenger L, Brinckerhoff CE, et al: Basic calcium phosphate crystals induce matrix metalloproteinase-1 through the Ras/mitogenactivated protein kinase/c-Fos/AP-1/metalloproteinase 1 pathway: Involvement of transcription factor binding sites AP-1 and PEA-3. J Biol Chem 277:1544-1552, 2002. 84. Liu-Bryan R, Pritzker K, Firestein GS, et al: TLR2 signaling in chondrocytes drives calcium pyrophosphate dihydrate and monosodium urate crystal-induced nitric oxide generation. J Immunol 174:5016-5023, 2005. 85. Martinon F, Petrilli V, Mayor A, et al: Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237-241, 2006. 86. Cronstein BN, Molad Y, Reibman J, et al: Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. J Clin Invest 96:994-1002, 1995. 87. Terkeltaub R, Baird S, Sears P, et al: The murine homolog of the interleukin-8 receptor CXCR-2 is essential for the occurrence of neutrophilic inflammation in the air pouch model of acute urate crystalinduced gouty synovitis. Arthritis Rheum 41:900-909, 1998. 88. Halverson PB, Carrera GF, McCarty DJ: Milwaukee shoulder syndrome: Fifteen additional cases and a description of contributing factors. Arch Intern Med 150:677-682, 1990. 89. Carroll GJ, Stuart RA, Armstrong JA, et al: Hydroxyapatite crystals are a frequent finding in osteoarthritic synovial fluid, but are not related to increased concentrations of keratan sulfate or interleukin 1 beta. J Rheumatol 18:861-866, 1991.

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90. Alwan WH, Dieppe PA, Elson CJ, et al: Hydroxyapatite and urate crystal induced cytokine release by macrophages. Ann Rheum Dis 48:476-482, 1989. 91. Di Giovine FS, Malawista SE, Nuki G, et al: Interleukin 1 (IL 1) as a mediator of crystal arthritis: Stimulation of T cell and synovial fibroblast mitogenesis by urate crystal-induced IL 1. J Immunol 138:32133218, 1987. 92. Chaisson CE, McAlindon TE, Felson DT, et al: Lack of association between thyroid status and chondrocalcinosis or osteoarthritis: The Framingham Osteoarthritis Study. J Rheumatol 23:711-715, 1996. 93. Job-Deslandre C, Menkes CJ, Guinot M, et al: Does hypothyroidism increase the prevalence of chondrocalcinosis? Br J Rheumatol 32:197-198, 1993. 94. Benito-Lopez P, Ramos-Rolon G, Ysamat-Marfa R, et al: Pseudo­ gout caused by thyroid hormone replacement therapy. Rev Clin Esp 163:349-350, 1981. 95. Canhao H, Fonseca JE, Leandro MJ, et al: Cross-sectional study of 50 patients with calcium pyrophosphate dihydrate crystal arthropathy. Clin Rheumatol 20:119-122, 2001. 96. Stevens LW, Spiera H: Hemarthrosis in chondrocalcinosis (pseudo­ gout). Arthritis Rheum 15:651-653, 1972. 97. Disla E, Infante R, Fahmy A, et al: Recurrent acute calcium pyrophosphate dihydrate arthritis following intraarticular hyaluronate injection. Arthritis Rheum 42:1302-1303, 1999. 98. Bernardeau C, Bucki B, Liote F: Acute arthritis after intra-articular hyaluronate injection: Onset of effusions without crystals. Ann Rheum Dis 60:518-520, 2000. 99. Kroesen S, Schmid W, Theiler R: Induction of an acute attack of calcium pyrophosphate dihydrate arthritis by intra-articular injection of hylan G-F 20. Clin Rheumatol 19:147-149, 2000. 100. Fujii K, Tanaka Y, Hubscher S, et al: Crosslinking of CD44 on rheumatoid synovial cells augment interleukin 6 production. Lab Invest 79:1439-1446, 1999. 101. Mikecz K, Dennis K, Shi M, et al: Modulation of hyaluronan receptor (CD44) function in vivo in a murine model of rheumatoid arthritis. Arthritis Rheum 42:659-668, 1999. 102. Sandor V, Hassan R, Kohn E: Exacerbation of pseudogout by granulocyte colony-stimulating factor. Ann Intern Med 125:781, 1996. 103. Malnick SD, Ariel-Ronen S, Evron E, et al: Acute pseudogout as a complication of pamidronate. Ann Pharmacother 31:499-500, 1997. 104. Gallacher SJ, Boyle IT, Capell HA: Pseudogout associated with the use of cyclical etidronate therapy. Scott Med J 36:49, 1991. 105. Mavrikakis ME, Antoniades LG, Kontoyannis SA, et al: CPPD crystal deposition disease as a cause of unrecognised pyrexia. Clin Exp Rheumatol 12:419-421, 1994. 106. Reuge L, Lindhoudt DV, Geerster J: Local deposition of calcium pyrophosphate crystals in evolution of knee osteoarthritis. Clin Rheumatol 20:428-431, 2001. 107. Derfus BA, Kurian JB, Butler JJ, et al: The high prevalence of pathologic calcium crystals in pre-operative knees. J Rheumatol 29: 570-574, 2002. 108. Doherty M, Dieppe P, Watt I: Pyrophosphate arthropathy: A prospective study. Br J Rheumatol 32:189-196, 1993. 109. Yamakawa K, Iwasaki H, Ohjimi Y, et al: Tumoral calcium pyrophosphate dihydrate crystal deposition disease. Pathology 197:499-506, 2001. 110. Kwak SM, Resnick D, Haghighi P: Calcium pyrophosphate dihydrate crystal deposition disease of the knee simulating spontaneous osteonecrosis. Clin Rheumatol 18:390-393, 1999. 111. el Maghraoui A, Lecoules S, Lechavalier D, et al: Acute sacroiliitis as a manifestation of calcium pyrophosphate dihydrate crystal deposition disease. Clin Exp Rheumathol 17:477-478, 1999. 112. Fujishiro T, Nabeshima Y, Yasui S, et al: Pseudogout attack of the lumbar facet joint: A case report. Spine 27:396-398, 2002. 113. Pascal-Moussellard H, Cabre P, Smadja D, et al: Myelopathy due to calcification of the cervical ligamenta flava: A report of two cases in French West Indian patients. Euro Spine J 8:238-240, 1999. 114. Cabre P, Pascal-Moussellard H, Kaidomar S, et al: Six cases of ligamentum cervical flavum calcification in blacks in the French West Indies. Joint Bone Spine 68:158-165, 2001. 115. Assaker R, Louis E, Boutry N, et al: Foramen magnum syndrome secondary to calcium pyrophosphate crystal deposition in the transverse ligament of atlas. Spine 26:1396-1400, 2001. 116. Kakitsubata Y, Boutin RD, Theodorou DJ, et al: Calcium pyrophosphate dihydrate crystal deposition in and around the atlantoaxial joints: Association with type 2 odontoid fractures in nine patients. Radiology 216:213-219, 2000.

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117. Balsa A, Martin-Mola E, Gonzalez T, et al: Familial articular chondrocalcinosis in Spain. Ann Rheum Dis 49:531-535, 1990. 118. Doherty M, Hamilton E, Henderson J, et al: Familial chondrocalcinosis due to calcium pyrophosphate dihydrate crystal deposition in English families. Br J Rheumatol 30:10-15, 1991. 119. Schumacher HR, Smolyo AP, Tse RL, et al: Arthritis associated with apatite crystals. Ann Intern Med 87:411-416, 1977. 120. Fam AG, Rubenstein J: Hydroxyapatite pseudopodagra: A syndrome of young women. Arthritis Rheum 32:741-747, 1989. 121. Grinlinton FM, Vuletic JC, Gow PJ: Rapidly progressive calcific periarthritis occurring in a patient with lupus nephritis receiving chronic ambulatory peritoneal dialysis. J Rheumatol 17:1100-1103, 1990. 122. Ferrari AJ, Rothfuss S, Schumacher HR Jr: Dialysis arthropathy: Identification and evaluation of a subset of patients with unexplained inflammatory effusions. J Rheumatol 24:1780-1786, 1997. 123. Braunstein EM, Menerey K, Martel W, et al: Radiologic features of a pyrophosphate-like arthropathy associated with long-term dialysis. Skeletal Radiol 16:437-441, 1987. 124. ter Borg EJ, Eggelmijer F, Jaspers PJ, et al: Milwaukee shoulder associated with primary hyperparathyroidism. J Rheumatol 22:561-562, 1995. 125. Fam AG, Pritzker KP: Acute calcific periarthritis in scleroderma. J Rheumatol 19:1580-1585, 1992. 126. Halverson PB, Carrera GF, McCarty DJ: Milwaukee shoulder syndrome: Fifteen additional cases and a description of contributing factors. Arch Intern Med 150:677-682, 1990. 127. Doherty M, Holt M, MacMillan P: A reappraisal of “analgesic hip.” Ann Rheum Dis 45:272-276, 1986. 128. Paul H, Reginato AJ, Schumacher HR: Alizarin red S staining as a screening test to detect calcium compounds in synovial fluid. Arthritis Rheum 26:191-200, 1983. 129. van Linthoudt D, Beutler A, Clayburne G, et al: Morphometric studies on synovium in advanced osteoarthritis: Is there an association between apatite-like material and collagen deposits? Clin Exp Rheumatol 15:493-497, 1997. 130. Li-Yu J, Clayburne GM, Sieck MS, et al: Calcium apatite crystals in synovial fluid rice bodies. Ann Rheum Dis 61:387-390, 2002. 131. Ivorra J, Rosas J, Pascual E: Most calcium pyrophosphate crystals appear as non-birefringent. Ann Rheum Dis 58:582-584, 1999. 132. Keen CE, Crocker PR, Brady K, et al: Intraosseous secondary calcium salt crystal deposition: An artefact of acid decalcification. Histopathology 27:181-185, 1995. 133. Steinbach LS, Resnick D: Calcium pyrophosphate dihydrate crystal deposition disease: Imaging perspective. Curr Probl Diagn Radiol 29:209-229, 2000. 134. Hatzis N, Kaar TK, Wirth MA, et al: Neuropathic arthropathy of the shoulder. J Bone Joint Surg Am 80:1314-1319, 1998. 135. Maldonado I, Prasad V, Reginato AJ: Oxalate crystal deposition disease. Curr Rheumatol Rep 4:257-264, 2002. 136. Fisseler-Eckhoff A, Muller KM: Arthroscopy and chondrocalcinosis. Arthroscopy 8:98-104, 1992. 137. Sofka CM, Adler RS, Cordasko FA: Ultrasound diagnosis of chondrocalcinosis in the knee. Skeletal Radiol 31:43-45, 2002. 138. Foldes K: Knee chondrocalcinosis: An ultrasonographic study of the hyaline cartilage. J Clin Imaging 26:194-196, 2002. 139. Abreu M, Johnson K, Chung CB, et al: Calcification in calcium pyrophosphate dihydrate (CPPD) crystalline deposits in the knee: Anatomic, radiographic, MR imaging, and histologic study in cadavers. Skeletal Radiol 33:392-398, 2004. 140. Galvez J, Saiz E, Linares LF, et al: Delayed examination of synovial fluid by ordinary and polarized light microscopy to detect and identify crystals. Ann Rheum Dis 61:444-447, 2002. 141. Petrocelli A, Wong AL, Sweezy RL: Identification of pathologic synovial fluid crystals on Gram stains. J Clin Rheumathol 4:103-105, 1998. 142. Selvi E, Manganelli S, Catenaccio M, et al: Diff Quik staining method for detection and identification of monosodium urate and calcium pyrophosphate crystals in synovial fluids. Ann Rheum Dis 60:194-198, 2001. 143. Ohira T, Ishikawa K: Preservation of calcium pyrophosphate dihydrate crystals: Effect of Mayer’s haematoxylin staining period. Ann Rheum Dis 60:80-82, 2001. 144. Smilde TJ, Haverman JF, Schipper P, et al: Familial hypokalemia/hypomagnesemia and chondrocalcinosis. J Rheumatol 21:1515-1519, 1994. 145. Ritter J, Kerr LD, Valeriano-Marcet J, et al: ACTH revisited: Effective treatment for acute crystal induced synovitis in patients with multiple medical problems. J Rheumatol 21:696-699, 1994.

146. Roane DW, Harris MD, Carpenter MT, et al: Prospective use of intramuscular triamcinolone acetonide in pseudogout. J Rheumatol 24:1168-1170, 1997. 147. Rothschild B, Yakubov LE: Prospective 6-month, double-blind trial of hydroxychloroquine treatment of CPPD. Compr Ther 23:327-331, 1997. 148. Chollet-Janin A, Finckh A, Dudler J, et al: Methotrexate as an alternative therapy for chronic calcium pyrophosphate deposition disease: An exploratory analysis. Arthritis Rheum 56:688-692, 2007. 149. Kalunian KC, Ike RW, Seeger LL, et al: Visually-guided irrigation in patients with early knee osteoarthritis: A multicenter randomized, controlled trial. Osteoarthritis Cartilage 8:412-418, 2000. 150. Das SK, Mishra K, Ramakrishnan S, et al: A randomized controlled trial to evaluate the slow-acting symptom modifying effects of a regimen containing colchicine in a subset of patients with osteoarthritis of the knee. Osteoarthritis Cartilage 10:247-252, 2002. 151. Das SK, Ramakrishnan S, Mishra K, et al: A randomized controlled trial to evaluate the slow-acting symptom modifying effects of colchicine in osteoarthritis of the knee: A preliminary report. Arthritis Care Res 47:280-284, 2002. 152.  Farin PU, Rasenen H, Jaroma H, et al: Rotator cuff calcifications: Treatment with ultrasound-guided percutaneous needle aspiration and lavage. Skeletal Radiol 25:551-554, 1996. 153. Ebenbicher G, Erdogmus C, Resch K, et al: Ultrasound therapy for calcific tendonitis of the shoulder. N Engl J Med 340:1533-1538, 1999. 154. Bilezikian P, Meng X, Shi Y, et al: Primary hyperparathyroidism in women: A tale of two cities—New York and Beijing. Int J Fertil Womens Med 45:158-165, 2000. 155. Rosenthal AK, Ryan LM: Probenecid inhibits transforming growth factor-beta 1 induced pyrophosphate elaboration by chondrocytes. J Rheumatol 21:896-900, 1994. 156. Cini R, Chindamo D, Catenaccio M, et al: Dissolution of calcium   pyrophosphate crystals by polyphosphates: An in vitro and ex vivo study. Ann Rheum Dis 60:962-967, 2001. 157. Shinozaki T, Pritzker KP: Polyamines enhance calcium pyrophosphate dihydrate crystal dissolution. J Rheumatol 22:1907-1912, 1995. 158. Bennett RM, Lehr JR, McCarty DJ: Crystal shedding and acute pseudogout: An hypothesis based on a therapeutic failure. Arthritis Rheum 19:93-97, 1976. 159. Cheung HS: Phosphocitrate as a potential therapeutic strategy for crystal deposition disease. Curr Rheumatol Rep 3:24-28, 2001. 160. Nair D, Misra RP, Sallis JD, et al: Phosphocitrate inhibits a basic calcium phosphate and calcium pyrophosphate dihydrate crystalinduced mitogen-activated protein kinase cascade signal transduction pathway. J Biol Chem 272:18920-18925, 1997. 161. Krug HE, Mahowald ML, Halverson PB, et al: Phosphocitrate prevents disease progression in murine progressive ankylosis. Arthritis Rheum 36:1603-1611, 1993. 162. Cheung HS, Sallis JD, Demadis KD, et al: Phosphocitrate blocks calcification-induced articular joint degeneration in a guinea pig model. Arthritis Rheum 54:2452-2461, 2006. 163. Hashiba H, Aizawa S, Tamura K, et al: Inhibitory effects of etidronate on the progression of vascular calcification in hemodialysis patients. Ther Apher Dial 8:241-247, 2004. 164. Grandjean-Laquerriere A, Tabary O, Jacquot J, et al: Involvement of Toll-like receptor 4 in the inflammatory reaction induced by hydroxyapatite particles. Biomaterials 28:400-404, 2007. 165. Neogi T, Nevitt M, Niu J, et al: Lack of association between chondrocalcinosis and increased risk of cartilage loss in knees with osteoarthritis: Results of two prospective longitudinal magnetic resonance imaging studies. Arthritis Rheum 54:1822-1828, 2006. 166. Viriyavejkul P, Wilairatana V, Tanavalee A, et al: Comparison of characteristics of patients with and without calcium pyrophosphate dihydrate crystal deposition disease who underwent total knee replacement surgery for osteoarthritis. Osteoarthritis Cartilage 13:232-235, 2006. Web Sites Familial Chondrocalcinosis Recruitment Page for Wellcome Trust Centre for Human Genetics: http://www.well.ox.ac.uk/brown/chondro.shtml. Teaching resource page for radiographic images of BCP and CPPD arth­ ropathies: http://www.orthopaedicweblinks.com/Teaching_Resources/ Radiology/more3.html.

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CARTILAGE, BONE, AND HERITABLE CONNECTIVE TISSUE DISORDERS

89

Pathogenesis of Osteoarthritis PAUL E. DI CESARE  •  STEVEN B. ABRAMSON  •  JONATHAN SAMUELS

KEY POINTS Osteoarthritis is a degenerative joint disease, occurring primarily in older individuals, characterized by erosion of the articular cartilage, hypertrophy of bone at the margins (i.e., osteophytes), subchondral sclerosis, and a range of biochemical and morphologic alterations of the synovial membrane and joint capsule. Risk factors for developing osteoarthritis include age, joint location, obesity, genetic predisposition, joint malalignment, trauma, and gender. Morphologic changes in early osteoarthritis include articular cartilage surface irregularity, superficial clefts within the tissue, and altered proteoglycan distribution. Morphologic changes in late osteoarthritis include deepened clefts, increase in surface irregularities, and eventual articular cartilage ulceration, exposing the underlying bone. Chondrocytes form clusters or clones in an attempt at self-repair. Marginal osteophytes form. The matrix metalloproteinase family of proteinases degrade proteoglycans (aggrecanases) and collagen (collagenases). A suboptimal repair response of normal articular cartilage to injury typically results in secondary osteoarthritis. Chondrocytes can sense and respond to mechanical and physicochemical stimuli via several regulatory pathways. Mediators classically associated with inflammation during the course of osteoarthritis include interleukin-1β and tumor necrosis factor-α. Nitric oxide, produced by the inducible isoform of nitric oxide synthase, is a major catabolic factor produced by chondrocytes in response to proinflammatory cytokines. The expression of inducible cyclooxygenase-2 is increased in osteoarthritis chondrocytes. Low-grade inflammatory processes occur in osteoarthritic synovial tissues and contribute to disease pathogenesis. Several biomarkers have been correlated with osteoarthritis. Most current treatments aim to improve the signs and symptoms of osteoarthritis.

Osteoarthritis is a degenerative joint disease that occurs ­primarily in older individuals and is characterized by erosion of the articular cartilage, hypertrophy of bone at the margins (i.e., osteophytes), subchondral sclerosis, and a range of biochemical and morphologic alterations of the synovial membrane and joint capsule. Pathologic changes in the late stages of osteoarthritis include softening, ulceration, and focal disintegration of the articular cartilage. ­Secondary synovial inflammation also may occur. Typical clinical symptoms are pain and stiffness, particularly after prolonged activity. In industrialized societies, osteoarthritis is the leading cause of physical disability, increases in health care usage, and impaired quality of life. The impact of arthritic conditions is expected to grow as the population increases and ages in the coming decades.1 Despite its prevalence, the precise etiology, pathogenesis, and reasons for progression of osteoarthritis are not understood, primarily owing to confounding factors in human epidemiologic studies, which include individual variations in physical activity, diet, and medical history; the poor correlation between symptoms of osteoarthritis and radiographic lesions; and the inability to detect early disease. The arthritic human tissue that is subjected to study typically is obtained at surgery from patients with severe osteoarthritis and does not exhibit the features that occur early in the disease process. Many studies focus on a single tissue type from affected or at-risk joints and lack general relevance. Without a clear-cut picture of how osteoarthritis arises at the cellular or molecular level, many clinicians still consider it a result of “wear and tear”—an inevitable consequence of aging. Although the etiology of osteoarthritis is incompletely understood, the accompanying biochemical, structural, and metabolic changes in joint cartilage have been well documented. It is now known that cytokines, ­ mechanical trauma, and altered genetics are involved in its pathogenesis, and that these factors can initiate a degradative ­cascade that results in many of the characteristic alterations of ­articular cartilage in osteoarthritis. More recently, it has become apparent that osteoarthritis is a disease process that affects the entire joint structure, including cartilage, ­synovial membrane, subchondral bone, ligaments, and periarticular 1525

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Pathogenesis of Osteoarthritis

muscles. Osteoarthritis is better thought of as a group of overlapping disorders, of various etiologies and arising from a combination of systemic factors (e.g., genetics) and local factors (e.g., biomechanically or biochemically mediated events), which gradually converge to produce a condition with definable morphologic and clinical outcomes.2 Osteoarthritis may be classified as primary or secondary according to its cause or major predisposing factor; both types have in common altered cartilage physiology. Primary osteoarthritis is the most common type and has no identifiable etiology or predisposing cause. Secondary osteoarthritis, although it has an identifiable underlying cause, is pathologically indistinguishable from primary osteoarthritis. The most common causes of secondary osteoarthritis are metabolic conditions (e.g., calcium crystal deposition, hemochromatosis, acromegaly), anatomic factors (e.g., leglength inequality, developmental hip dislocation), traumatic events (e.g., major joint trauma, chronic joint injury, joint surgery), or the sequelae of inflammatory disorders (e.g., ankylosing spondylitis, septic arthritis). In cases of secondary osteoarthritis arising from inflammatory joint disease, cartilage degeneration most likely results initially from degradative enzymes released from the synovium or leukocytes within the joint space, and later from the mechanical attrition of a biomechanically altered extracellular matrix. ­Distinguishing between primary and secondary osteoarthritis may be difficult because the clinical presentation and symptoms are often similar.

ETIOLOGIC FACTORS IN OSTEOARTHRITIS Major factors that affect the degree of risk for developing osteoarthritis include age, joint location, obesity, genetic predisposition, joint malalignment, trauma, and gender. AGE Age is the risk factor most strongly correlated with ­osteoarthritis.3,4 Osteoarthritis is the most common chronic disease that develops in later life. More than 80% of individuals older than 75 years are affected, and osteoarthritis increases progressively with age at all joint sites. Radiologic changes of osteoarthritis increase as individuals age,5 although these changes do not always correlate with clinical symptoms or disability.6,7 Although an age-related disease, osteoarthritis is not an inevitable consequence of aging. Age-related morphologic and structural changes in articular cartilage include fraying, softening, and thinning of the articular surface; decreased size and aggregation of matrix proteoglycans; and loss of matrix tensile strength and stiffness. These age-related tissue changes are most often caused by a decrease in chondrocytes’ ability to maintain and repair the tissue, as chondrocytes themselves undergo age-related decreases in mitotic and synthetic activity, exhibit decreased responsiveness to anabolic growth factors, and synthesize smaller and less uniform large aggregating proteoglycans and fewer functional link proteins. Cultured chondrocytes have been shown to exhibit an age-related decline in response to insulin-like growth factor (IGF)-I, a growth factor that stimulates the production of proteoglycans, collagen, and

integrin cell receptors. Progressive chondrocyte senescence (as reflected in expression of the senescence-associated enzyme β-galactosidase), erosion of chondrocyte telomere length, and mitochondrial degeneration secondary to oxidative damage also contribute to the age-related reduction in chondrocyte function.3 There also seems to be a direct correlation between chondrocyte apoptosis and cartilage degradation leading to osteoarthritis. Age seems to be an independent factor that predisposes articular chondrocytes to apoptosis because the expression levels of specific proapoptotic genes (Fas, Fas ligand, caspase-8, and p53) is higher in aged cartilage.8,9 JOINT LOCATION Although osteoarthritis occurs most commonly in weightbearing joints,10 age affects joints differentially.11 A study comparing tensile fracture stress of cartilage in the femoral head and in the talus showed that it decreased progressively with age in the former, but not in the latter.12 Joint-specific, age-related viability in articular cartilage may explain why osteoarthritis is more common in hip and knee joints with increasing age, but occurs rarely in the ankle. Alterations in chondrocyte responsiveness to cytokines also seem to vary depending on the joint. Studies show that knee joint chondrocytes exhibit more interleukin (IL)-1 receptors than ankle joint chondrocytes, and that knee chondrocytes express mRNA for matrix metalloproteinase (MMP)-8, whereas ankle chondrocytes do not.13-15 OBESITY Obesity is another important risk factor for osteoarthritis.16-18 Greater body mass index in women and men has been shown to be associated with an increased risk of knee, but not hip, osteoarthritis.6,19,20 In a study that examined 715 paired radiographs (index and 4-year follow-up), Hart and colleagues21 reported that obesity significantly increased the risk of knee symptoms and radiographic osteophytes. An increase in mechanical forces across weight­bearing joints is probably the primary factor leading to joint degeneration. Obesity not only increases the forces at weight-bearing joints, but also may change posture, gait, and physical activity level, any or all of which may contribute further to altered joint biomechanics.22 Most obese patients, ­ particularly women, exhibit varus knee deformities that result in increased joint reactive forces in the medial ­ compartment of the knee, accelerating the degenerative process.23 Particularly in elderly obese individuals, heavy physical activity is an additional risk factor for the development of knee osteoarthritis, whereas light-to-moderate activity does not seem to increase risk for knee osteoarthritis and may alleviate symptomatic knee osteoarthritis by reducing body mass index.6,19,20 Similarly, weight loss can reduce radiographic knee osteoarthritis progression and clinical symptoms. More recent evidence indicates that in obese patients with osteoarthritis, significant weight loss dramatically improves functional status, with short-term results equivalent to the results of patients who have undergone joint replacement.24

PART 15 

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CARTILAGE, BONE, AND HERITABLE CONNECTIVE TISSUE DISORDERS

The discovery of the “obesity gene” and its product leptin may have important implications for the onset and progression of osteoarthritis and increase understanding of the link between obesity and osteoarthritis. The fact that women have a greater proportion of total body fat and higher levels of adipose-derived systemic leptin concentrations than men may partially account for the gender disparity in osteoarthritis patients. Leptin is produced not only by adipose cells, but also by osteoblasts and chondrocytes, however, suggesting that local leptin production may play a role in osteoarthritis. Significant levels of leptin were observed in the cartilage and osteophytes of subjects with osteoarthritis, but in the cartilage of healthy subjects, few chondrocytes produced leptin. Leptin also has been shown to induce anabolic activity in the chondrocytes of rats and ultimately may confer structural joint changes.25,26 Further work is required to determine whether leptin is an important systemic or local factor in the link between obesity and osteoarthritis. GENETIC PREDISPOSITION Because of the prevalence of osteoarthritis in the general population and its extensive clinical heterogeneity, the genetic contribution to its pathogenesis has been difficult to analyze.27,28 In the 1960s, Kellgren and associates29 reported that generalized nodal osteoarthritis, characterized by multiple joint involvement, including the presence of Heberden’s nodes and knee osteoarthritis, was twice as likely to occur in first-degree relatives as in controls. Population studies of patients with radiographic evidence of osteoarthritis followed in two major cohorts (the Framingham Study and the Baltimore Longitudinal Study on Aging) clearly support a significant genetic contribution to osteoarthritis, with evidence for a major recessive gene and a multifactorial component, representing either polygenic or environmental factors.30,31 Twin pair and family risk studies have indicated that the heritable component of osteoarthritis may be 50% to 65%.28,32,33 Family, twin, and population studies have indicated differences among genetic influences that determine the site of osteoarthritis (hip, spinal, knee, hand).31,34,35 Further evidence supporting a genetic predisposition to osteoarthritis is the demonstration of a significantly higher concordance for osteoarthritis between monozygotic twins than between dizygotic twins. Genetic studies have identified multiple gene variations associated with an increased risk of osteoarthritis.36 Structural genes are important for the maintenance and repair of articular cartilage and for the regulation of chondrocyte proliferation and gene expression. In some cases (e.g., chondrodysplasias), structural genes are the identifiable causes of osteoarthritis. Several candidate genes encoding for structural proteins of the extracellular matrix of the articular cartilage have been associated with early-onset osteoarthritis.37,38 Although likely of limited importance in most cases of osteoarthritis, the discovery of a point mutation (Arg519Cys in exon 31) in the cDNA coding for type II collagen in several generations of a family with spondyloepiphyseal dysplasia and polyarticular osteoarthritis37,38 has focused attention on this area. In addition to the point mutation in type II collagen, which was identified in the family mentioned in the previous paragraph,38 inherited forms of osteoarthritis may be caused by mutations in several other genes that are expressed in

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cartilage, including genes encoding types IV, V, and VI ­collagens and cartilage oligomeric matrix protein (COMP).39 It was reported more recently that mice deficient in the type IX collagen gene and the matrilin 3 gene (equivalent condition in humans not yet reported) developed age-dependent, osteoarthritis-like changes in the knee and temporal mandibular joints.40,41 Candidate genes in osteoarthritis have been identified that are not structural proteins. The haplotype of a vitamin D receptor that plays a vital role in controlling bone mineral density seems to be associated with a twofold risk of knee osteoarthritis,42-44 although the vitamin D receptor locus is very close to the COL2A1 locus on chromosome 12q, and so the association may be due to linkage disequilibrium with the latter.27 The locus of the IGF-I gene has been associated with radiographic osteoarthritis, as has an aggrecan polymorphic allele with hand osteoarthritis.27 Evidence from animal models indicates that disorders characterized by calcium crystal deposition may predispose to osteoarthritis. The defect in the progressive ankylosis (ank) mouse is in a gene that encodes a transmembrane protein that controls levels of inorganic phosphate, an inhibitor of matrix calcification.45 Analysis of the joints in the ank mouse reveals hydroxyapatite crystals in articular cartilage, with accompanying joint space narrowing, cartilage erosion, and osteophyte formation—all hallmarks of osteoarthritis. In more recent population studies, genome-wide linkage scans have highlighted seven chromosomal regions that may harbor osteoarthritis susceptibility genes.46 Chromosome 2q was positive in several scans, suggesting that this chromosome is likely to harbor one or more susceptibility genes. In a study of affected sibling pairs, a region of linkage stretching from 2q12 to 2q21 was reported for osteoarthritis of the distal interphalangeal joint, and a previous study of affected sibling pairs in the United Kingdom showed a broader region of linkage, stretching from 2q12 to 2q31.46,47 Two IL-1 genes (IL1α and IL1β) and the gene encoding IL-1Ra (IL1RN) are located on chromosome 2q13 within a 430-kb genomic fragment. Given the importance of IL-1 in the perpetuation of cartilage damage in osteoarthritis, it is possible that a proportion of the genetic susceptibility to osteoarthritis may be encoded for by variation in the activity of ILs, and that for chromosome 2q this susceptibility could reside within the IL-1 gene clusters. Loughlin and colleagues46 have ­provided evidence, however, that the IL-1 gene cluster harbors susceptibility for knee osteoarthritis, but not for hip osteoarthritis. These and other epidemiologic studies have highlighted potential ­differences in the degree of osteoarthritis heritability among different joint groups and between the two sexes.48 Genomic and postgenomic technology, in addition to defining susceptibility genotypes, is expected to lead to the discovery of genes and gene products that are overexpressed in osteoarthritis tissues and that contribute to disease pathogenesis and progression.49-51 Studies of differential gene expression in diseased tissue, in addition to elucidating pathogenic processes that lead to novel therapies, could have two other benefits: (1) identification of unique ­biomarkers that can be used for osteoarthritis diagnosis or management and (2) identification of candidate ­susceptibility genotypes, such as polymorphic variations of cytokines or growth ­factors, which may predispose to disease progression.52

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Pathogenesis of Osteoarthritis

JOINT MALALIGNMENT AND TRAUMA Joint malalignment or trauma may lead to rapid development of osteoarthritis, or it may initiate a slow process that results in symptomatic osteoarthritis years later. Probably as a result of progressive reduction in periarticular blood flow and the resultant decrease in rate of remodeling at the osteochondral junction, joints become increasingly congruent with age.53,54 Altered joint geometry may interfere with nutrition of the cartilage, or it may alter load distribution, either of which may result in altered biochemical composition of the cartilage, regardless of age.55,56 Local factors, such as stresses related to joint use and joint deformity, also influence the development of osteoarthritis. Joint incongruence (e.g., poorly reduced intra-­articular fractures, developmental dysplasia of the hip, recurrent dislocation of the patella) can lead to early-onset osteoarthritis.57 Repetitive, high-impact sports are strongly associated with joint injury and increase the risk for lower limb osteoarthritis.58,59 Repetitive trauma at a subfracture level has been shown to accelerate remodeling in the zone of calcified cartilage, with reduplication of the tidemark and thinning of the noncalcified zone, resulting in stiffening of the subchondral bone, increased wear of the overlying cartilage, and ultimately development of osteoarthritis.60 ­Regular exercise is important in maintaining articular cartilage structure and metabolic function. Recreational running and low-impact activities have not been shown to increase the risk of osteoarthritis in previously normal joints. Articular cartilage is remarkably resistant to damage by shear forces; it is, however, highly vulnerable to repetitive impact loading.61 When joints are subjected to in vitro cyclic loads that are easily borne by subchondral bone, cartilage degeneration still results.62 This vulnerability accounts for the high frequency of osteoarthritis in shoulders and elbows of pneumatic drill operators and baseball pitchers, ankles of ballet dancers, metacarpophalangeal joints of boxers, and knees of basketball players. The risk for knee osteoarthritis among participants in sports may be more closely related to previous knee injury, however, than to participation in sports alone.63 The major forces on articular cartilage, in addition to weight bearing, are due to the contraction of the muscles that stabilize or move the joint.64 In normal walking, 4 to 5 times the body weight may be transmitted through the knee, and in squatting 10 times the body weight may be transmitted.43 Articular cartilage is believed to be too thin to be an effective shock absorber under these high loads. What protects the joint under physiologic conditions of impact loading is joint motion, with the associated lengthening of muscles under tension and deformation of the subchondral bone.44,65 Cancellous subchondral bone functions as a major shock absorber owing to its material properties.60 Two thirds of subchondral bone stiffness derives from bony trabeculae, and about one third derives from intraosseous fluid.66 In the normal unloaded joint, the opposing surfaces are not congruous, but under loading, the cartilage and the bone deform so that a larger proportion of the opposing surfaces comes into contact, which increases joint congruity and results in a force distribution over the largest possible area.67 Excessive loads may cause microfractures of subchondral

trabeculae that heal via callus formation and remodeling, resulting in stiffer than normal bone that is less effective as a shock absorber, and predisposing articular cartilage to degeneration. Whether subchondral sclerosis precedes the onset of osteoarthritis or is a change secondary to cartilage degeneration is unknown. Indirect evidence supports the theory that biomechanical changes in subchondral bone may be important in osteoarthritis.66,68,69 Foss and Byers70 reported cases of femoral osteoporosis (which is associated with softening and greater compliance of the subchondral bone) that may have protected the hip from osteoarthritis. Conversely, in vitro studies have shown that stiffening of the cancellous bone with methacrylate, reducing its deformability, leads to cartilage degeneration with repetitive impact loading.71 GENDER Women are about twice as likely as men to develop osteoarthritis. Although women have a lower prevalence of osteoarthritis than men before age 50 years, there is a marked increase in prevalence among women after age 50, particularly in the knee.72 Radiographic and interview data from the National Health and Nutrition Examination ­ Survey (NHANES III), a representative cross-sectional health examination survey of the U.S. population, reported that the lifetime prevalence of radiographic knee osteoarthritis was 37.4%, and that the prevalence of symptomatic knee osteoarthritis was 12.1% in adults 60 years old and older; prevalence was greater among women than men (42.1% versus 31.2%), and women had significantly more Kellgren-Lawrence grade 3-4 changes (12.9% versus 6.5% in men).73 Women have a greater number of joints involved and are more likely to exhibit clinical symptoms of morning stiffness, joint swelling, and nocturnal pain. The gender differences in osteoarthritis incidence after age 50 may be the result of postmenopausal estrogen deficiency. Articular chondrocytes possess functional estrogen receptors (ERs), suggesting that these cells can be regulated by estrogen. Nuclear ERs have been detected in articular chondrocytes of humans,74,75 rats,75,76 monkeys,75,77 and pigs,78 and in human growth plate chondrocytes.79 Chondrocytes express two isoforms of ER—ER-α and ERβ—that may have different organ-specific roles; ER-α is expressed more predominantly in cortical bone, and ER-β is expressed more predominantly in cartilage75 and cancellous bone.80 One direct effect of estrogen on cultured chondrocytes is upregulation of ER,77 and an increase in ER has been associated with increased proteoglycan synthesis in rats.76 More recent epidemiologic studies have linked estrogen replacement therapy (ERT) with a lower than expected risk of knee and hip osteoarthritis in postmenopausal women. Clinical investigations of the association between osteoarthritis and hormonal level in women have involved measurement of circulating estrogen levels in postmenopausal women, general radiographic evaluation of postmenopausal women, and examination of the effect of ERT on such variables as knee osteoarthritis and cartilage ­volume.81-84

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In a study of more than 4000 women 65 years old or older that assessed pelvis radiographs for hip osteoarthritis, Nevitt and colleagues81 showed that women using oral estrogen were at a significantly reduced risk of hip osteoarthritis. Estrogen users for 10 years or longer had a greater reduction in risk of developing hip osteoarthritis than users for less than 10 years. Zhang and coworkers,83 using weightbearing radiographs in female participants in the Framingham Osteoarthritis Study (N = 831, mean age 73 years, age range 63 to 93 years) to study the rate of knee osteoarthritis, reported a modest but nonsignificant greater protective effect for radiographically detected osteoarthritis in women who were on ERT. They categorized their sample into three groups according to estrogen use at biennial examination: never-users (n = 349), past users (n = 162), and current users (n = 40). When incident and progressive radiographic knee osteoarthritis cases were combined, current ERT users were found to have 60% less risk for knee osteoarthritis than never-users. In a cross-sectional study of postmenopausal women from the Chingford Study (N = 606) using standard anteroposterior radiographs of hands and knees, ERT was shown to have a significant protective effect against knee osteoarthritis and a similar but not significant effect for hand osteoarthritis.85 Women who had discontinued ERT for more than 1 year had no overall protective effect of the ERT for osteoarthritis. Wluka and colleagues84 reported on the longer term use of ERT and its association with knee cartilage volume (measured by magnetic resonance imaging) in postmenopausal women; results showed that after adjusting for confounders, women using long-term ERT had more knee cartilage than controls. Beneficial effects of ERT on the severity of knee osteoarthritis in ovariectomized monkeys also have been shown.86 Further clinical evidence of the role of estrogen in osteoarthritis came from a case-control study to determine whether an association exists between ER gene polymorphisms and generalized osteoarthritis.87 The investigators analyzed 65 women with generalized osteoarthritis and compared them with 318 healthy female controls for the Pvu II and Xba I restriction fragment length polymorphisms of ER gene. The result showed that the ER genotype PpXx, with the combination of the Pvu II and Xba I restriction fragment length polymorphisms, was a significant risk factor for generalized osteoarthritis and was most prevalent in

Normal

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younger patients with severe radiographic changes. Overall, these human and animal studies show that women taking ERT may have a lower incidence of osteoarthritis, although prospective randomized trials to confirm these observations have not been done.

CHANGES IN OSTEOARTHRITIS MORPHOLOGIC CHANGES In early osteoarthritis, the articular cartilage surface becomes irregular, and superficial clefts within the tissue become apparent. Proteoglycan distribution is altered, as revealed by histochemical staining. As the condition worsens, the clefts deepen, surface irregularities increase, and the articular cartilage eventually ulcerates, exposing the underlying bone. Attempts at local self-repair can be seen as an initial increase in the number of chondrocytes in the form of clusters or clones, with 50 or more cells in a cluster (Fig. 89-1).43 Marginal osteophytes form, representing production of new bone capped by newly formed, irregularly shaped hyaline and fibrocartilage. BIOCHEMICAL CHANGES The biochemical changes that occur in the articular cartilage vary from early to later stages in the disease process. In early osteoarthritis, the water content of the articular cartilage significantly increases, causing the tissue to swell and altering its biomechanical properties. This phenomenon suggests that there has been weakening of the collagen network; the type II collagen fibers have a smaller diameter than the fibers in normal cartilage, and the normally tight weave in the midzone is relaxed and distorted.88-93 In later stages of osteoarthritis, type I collagen concentration within the extracellular matrix increases, and the proteoglycan concentration decreases to 50% or less than normal, with less aggregation and shorter glycosaminoglycan side chains.93,94 Keratan sulfate concentration decreases, and the ratio of chondroitin-4-sulfate to chondroitin-6-sulfate increases, reflecting synthesis by chondrocytes of a proteoglycan profile more typical of immature cartilage.95 Proteoglycan concentration in the cartilage diminishes progressively until the end stages, when histologic staining detects little or no proteoglycan.96

Osteoarthritis

Figure 89-1  Histologic sections of normal (left) and osteoarthritic (right) articular cartilage obtained from the femoral head. The osteoarthritic cartilage has surface irregularities, with clefts to the radial zone and cloning of chondrocytes.

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Calcium crystals (e.g., calcium pyrophosphate dihydrate [CPPD], basic calcium phosphate crystals) are commonly found in the cartilage of the elderly, and often crystal arthropathy coexists with osteoarthritis.97 It is unclear, however, whether these crystals are directly involved in the pathogenesis of osteoarthritis or are merely a by-­product or marker of the disease.98,99 That calcium crystals play a role in causing or worsening osteoarthritis is supported by clinical and laboratory studies, but the relationship is ­complex.100 Pyrophosphate is produced from adenosine triphosphate by the exoenzyme nucleoside pyrophosphohydrolase.101 In normal cartilage basal zones, there is strong staining for alkaline phosphatase and matrix vesicles indicative of cartilage calcification.102 Human osteoarthritic cartilage cultured in vitro also produces large quantities of alkaline phosphatase and pyrophosphate.102 Synovial fluid from osteoarthritis patients shows high levels of pyrophosphate, similar to those in CPPD crystal deposition disease, levels that correlate directly with severity of joint damage.103,104 Young or proliferating chondrocytes are a major source of pyrophosphate, whereas resting chondrocytes from normal adult cartilage secrete little pyrophosphate.101 It has been theorized that the increased pyrophosphate secretion in osteoarthritis cartilage may be an indication of increased chondrocyte metabolic activity toward matrix repair.105 The presence of CPPD may alter the biomechanical properties of the cartilage extracellular matrix and lead to cartilage breakdown. Hemochromatosis (hemosiderin), Wilson’s disease (copper), ochronotic arthropathy (homogentisic acid polymers), gouty arthritis (crystals of monosodium urate), and CPPD crystal deposition disease are further examples of conditions in which the abnormal entity may alter the cartilage extracellular matrix, leading to either direct or indirect chondrocyte injury by increasing the stiffness of the tissue and precipitating the development of osteoarthritis. METABOLIC CHANGES As the severity of osteoarthritis progresses, the synthesis and secretion of matrix-degrading enzymes by chondrocytes markedly increase.96,106 Early cartilage degeneration in osteoarthritis is most likely the result of the action of enzymes from the matrix metalloproteinase (MMP) family of proteinases that degrade proteoglycans (aggrecanases) and collagen (collagenases).107-109 Collagenases typically make the first cleavage in triple-helical collagen, allowing its further degradation by other proteases. Aggrecanases in conjunction with other MMPs degrade aggrecan. Serine-dependent and cysteine-dependent proteases (e.g., plasminogen activator/plasmin system and cathepsin B) and membrane-type MMPs act primarily as MMP activators.110-112 The control of these enzymes is complex, with regulation occurring at three different levels: synthesis and secretion, activation of latent enzyme, and inactivation by proteinase inhibitors.113 In osteoarthritis, the expression and production of proteinases is increased. Native collagen has been shown to be cleaved by MMP-1, MMP-8, and MMP-13; the resultant fragments may be susceptible to cleavage by other enzymes such as MMP-2 (gelatinase A), MMP-9 (gelatinase B), MMP-3 (stromelysin 1), and cathepsin B. Of the three major MMPs that degrade native collagen, MMP-13 may

be the most important in osteoarthritis because it preferentially degrades type II collagen.114 It also has been shown that expression of MMP-13 greatly increases in osteoarthritis.115 Overall, collagenase activity also markedly increases in human osteoarthritic cartilage cultures, suggesting that it is a major factor in osteoarthritis progression and cartilage matrix degradation.116,117 MMPs can degrade other cartilage extracellular matrix molecules in addition to collagen. If combined with plasmin (which has the capability of activating many MMPs), MMPs can rapidly destroy cartilage altogether. In osteoarthritis, collagenase, stromelysin, and gelatinase are secreted as proenzymes by the chondrocyte, upregulated by IL-1 or tumor necrosis factor (TNF).118,119 These proenzymes, each exhibiting a zinc-binding catalytic sequence, contain three histidine residues and a glutamine residue, all of which must be activated by proteolytic cleavage of their amino terminal sequence. The aggrecanases belong to a family of extracellular proteases known as the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs).120 Two aggrecanases, ADAMTS-4 and ADAMTS-5, seem to be major enzymes in cartilage degradation in arthritis.121 Recombinant ADAMTS-4 and ADAMTS-5 cleave aggrecan at five distinct sites along the core protein, and all resultant fragments have been identified in cartilage explants undergoing matrix degradation. Aggrecanase proteolytic activity can be modulated by altered expression, by activation via proteolytic cleavage at a furin-sensitive site, by binding to the aggrecan substrate through the C-­terminal thrombospondin motif, by activation through post-translational processing of a portion of the C-terminus, and by inhibition of activity by the endogenous inhibitor tissue inhibitor of metalloproteinases (TIMP)-3. ADAMTS-4 and ADAMTS-5 activity also has been detected in joint capsule and synovium and may be upregulated in arthritic synovium either at the message level or through post-translational processing. In addition to aggrecan, aggrecanases have been shown to degrade the nonaggregated chondroitin-sulfate proteoglycans brevican and versican. Most recently, it has been shown that ADAMTS7 and ADAMTS-12 bind to and degrade COMP (a prominent noncollagenous protein in cartilage), and that the latter is highly upregulated in osteoarthritic cartilage.122,123 ADAMTS-4, ADAMTS-19, and ADAMTS-20 also have been shown to degrade COMP in vitro; however, their in vivo activity in osteoarthritis has yet to be determined.124,125 The G1 region of aggrecan is highly resistant to proteases; however, a glutamate-alanine bond within the extended region between G1 and G2 is remarkably susceptible to proteolytic degradation.126 Low concentrations of stromelysin readily cleave the region between G1 and G2 domains, resulting in disruption of the proteoglycan aggregate structure and increased loss of proteoglycans from the extracellular matrix. A specific hyaluronidase has not been found in articular cartilage, but one or several lysosomal enzymes that can cleave hyaluronic acid and chondroitin-6-sulfate have been implicated.110 The decrease in chondroitin sulfate chain length in osteoarthritic cartilage may be due to digestion by synovial fluid hyaluronidase, which may diffuse into the matrix as its permeability increases.95 Evidence to support this theory is

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the finding that the hyaluronic acid concentration in osteoarthritis cartilage is low, even though its rate of synthesis is considerably greater than normal.96,106 These degradative enzymes serve to disrupt the proteoglycan aggregate. The early result of the MMP-induced tissue degradation is thinning of the collagen fibers, loosening of the tight collagen network, and the consequent cartilage matrix swelling seen in osteoarthritis. Many investigators consider IL-1 a prime mediator in cartilage matrix degradation (Fig. 89-2). IL-1 is synthesized by mononuclear cells (including synovial lining cells) in the inflamed joint and by chondrocytes as an autocrine activity.127-129 IL-1 stimulates the synthesis and secretion of many degradative enzymes in cartilage, including latent collagenase, latent stromelysin, latent gelatinase, and tissue plasminogen activator.130-132 With regard to aggrecanases, it seems that ADAMTS-5 is constitutively expressed, whereas IL-1 and TNF can induce ADAMTS-4.133 Plasminogen, synthesized by the chondrocyte or entering the matrix by diffusion from the synovial fluid, is the substrate for tissue plasminogen activator. The balance of active and latent enzymes is controlled to some extent by at least two enzyme inhibitors: TIMP and plasminogen activator inhibitor-1.108,134,135 TIMP and plasminogen activator inhibitor-1 are synthesized in increased

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amounts under the regulation of transforming growth factor (TGF)-β.136,137 If insufficient concentrations of or degraded TIMP or plasminogen activator inhibitor-1 are present in the matrix along with active enzymes, increased matrix degradation occurs. Expression profiling of all known members of the MMP, ADAMTS, and TIMP gene families in normal cartilage and cartilage from patients with osteoarthritis has revealed that several members are regulated in osteoarthritis. Genes that showed increased expression in osteoarthritis were MMP-13, MMP-28, and ADAMTS-16 (all at P < .001); MMP-9, MMP-16, ADAMTS-2, and ADAMTS-14 (all at P < .01); and MMP-2, TIMP-3, and ADAMTS-12 (all at P < .05). Genes with decreased expression in osteoarthritis were MMP-1, MMP-3, and ADAMTS-1 (all at P < .001); MMP-10, TIMP-1, and ADAMTS-9 (all at P < .01); and TIMP-4, ADAMTS-5, and ADAMTS-15 (all at P < .05).138 These results illustrate the complexity of the events that occur within the extracellular matrix regarding regulation of tissue-degrading enzymes. Early osteoarthritis is characterized by increases in the synthesis of proteoglycans, collagen, noncollagenous proteins, hyaluronate, and DNA (indicating cell replication and accounting for the observed chondrocyte clones or clusters).96,106 Anabolic and catabolic processes increase as cells attempt to repair or maintain tissue integrity90; this

Synovium

Cartilage breakdown products

IL-1 NO

PA/Plasmin Latent MMPs Cartilage

– TIMPs PA inhibitor

PA MMPs

PGE2 TNF-α

Aggrecanases

IL-1 NO

Mechanical forces

? TGF-β

Bone

Osteophyte Figure 89-2  Schematic of pathogenic mechanisms of osteoarthritis. Mechanical stress initiates altered metabolism characterized by the release of matrix metalloproteinases (MMPs), proinflammatory cytokines, and mediators such as nitric oxide (NO) and prostaglandin E2 (PGE2). Cartilage breakdown products play a role by stimulating the release of cytokines from synovial lining cells, and by inducing MMP production by chondrocytes. Perpetuation of cartilage damage is amplified by the autocrine and paracrine actions of interleukin (IL)-1β and tumor necrosis factor (TNF)-α produced by chondrocytes. PA, plasminogen activator; TGF-β, transforming growth factor-β.

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explains why osteoarthritis typically is slowly progressive and sometimes remains static by morphologic criteria. Eventually, osteoarthritis progresses when the cell number declines, proteoglycan synthesis declines sharply, and the chondrocytic anabolic repair processes cannot keep pace with catabolic processes, resulting in the further degeneration of cartilage extracellular matrix.90,96 The imbalance between proteoglycan synthesis and degradation is important in the pathogenesis of cartilage breakdown.139 Osteoarthritis cartilage is deficient in TIMP content. Increased proteoglycan synthesis in early osteoarthritis is compromised further by the fact that osteoarthritic chondrocytes synthesize proteoglycans in a manner different from that of normal chondrocytes with respect to the composition and distribution of their glycosaminoglycans, the size of the proteoglycan subunit, and their ability to aggregate with hyaluronic acid.90,92,95,111,140 MATRIX CHANGES Much of what is known about changes in the extracellular matrix in early osteoarthritis comes from animal models (e.g., rabbit partial meniscectomy model, canine anterior cruciate ligament–deficient model).141,142 These animal models represent secondary osteoarthritis, produced by internal derangement of the joint, and may not precisely simulate the state of affairs in primary osteoarthritis. New models for spontaneous osteoarthritis include a postmenopausal rat model, the groove model, and a joint-specific bone morphogenetic receptor–deficient mouse. Of particular interest is an iodoacetate model, validated as the first pain model of osteoarthritis, in which intra-articular injection of iodoacetate in rats has been shown to lead to cartilage degeneration associated with pain and manifesting as time-dependent and concentration-dependent alterations in hind limb weight bearing.143,144 That not all animal models of osteoarthritis are equivalent becomes clear when one considers the differences in therapeutic response between young and old animals and between spontaneous and surgical models.145 In the dog model, the first alteration seen within days after joint destabilization is an increase in cartilage water content.146 Initially, water content increases locally, in the tibial plateau and femoral condyle cartilage, but it soon spreads to the entire joint cartilage. Proteoglycans are more readily extractable from the matrix of experimental animals than from that of controls. These matrix changes also are seen in spontaneously occurring dog and steer osteoarthritis and in experimentally induced rabbit osteoarthritis.146-148 The increase in water content in osteoarthritic cartil­ age is due to loss of the collagen network’s elastic restraint, enabling the hydrophilic proteoglycans to swell more than normally.149 In early-stage osteoarthritis, proteoglycan concentration may increase, and the cartilage consequently may become thicker than normal and exhibit increased staining for proteoglycans.150-152 Shortly after the increase in cartilage water, newly synthesized proteoglycans are characterized by a higher proportion of chondroitin sulfate and a lower proportion of keratan sulfate, and proteoglycan aggregation is impaired.142,146 These abnormal changes in extracellular matrix occur before fibrillation or any other gross morphologic changes are

evident and result in a generalized decrease in stiffness that occurs in grossly normal cartilage adjacent to fibrillated areas.153 As osteoarthritis progresses, focal cartilage ulcerations develop. Proteoglycan loss is accompanied by a decrease in its ability to aggregate, persistence in abnormal glycosaminoglycan composition, and a decrease in chondroitin sulfate chain length. When proteoglycan loss reaches a critical threshold, water content, which initially increased, decreases to less than normal.154 BIOMECHANICAL CHANGES Two long-standing biomechanical theories of the pathogenesis of osteoarthritis hold that mechanical stresses injure chondrocytes, causing them to release degradative enzymes, and that mechanical stresses initially damage the collagen network (as opposed to the cells per se),155,156 leading to a breakdown of the matrix. Extracellular matrix breakdown in osteoarthritic cartilage leads to (1) loss of compressive stiffness and elasticity, resulting in greater mechanical stress on chondrocytes, and (2) an increase in hydraulic permeability, resulting in loss of interstitial fluid during compression and increased diffusion of solutes through the matrix (including the movement of degradative enzymes and their inhibitors). One important consequence is disruption of normal fluid film joint lubrication and loading dynamics owing to alterations in inflammatory synovial fluid.157-159 Joint friction, wear, lubrication, and contact mechanics are further negatively affected by the loss of cartilage proteoglycans.160-163 OSTEOPHYTE FORMATION Osteophytes—bony proliferations at the joint margins and in the floor of cartilage lesions—are partly responsible for the pain and restriction of joint movement in osteoarthritis. Human osteoarthritic joint osteophytes synthesize cartilage with significant amounts of type I collagen and nonaggregating proteoglycans.164 In experimentally induced osteoarthritis, osteophytes may develop even though the articular cartilage appears grossly normal.165 Because osteophytes may increase joint surface available for load bearing, they may contribute to some cases of regression of the early osteoarthritis cartilage changes.166 It has been theorized that osteophytes occur as a result of penetration of blood vessels into the basal layers of degenerating cartilage, or as a result of abnormal healing of stress fractures in the subchondral trabeculae near the joint ­margins.167,168 In the osteoarthritis dog model, ­periarticular osteophyte formation begins in the marginal zone, where synovium merges with periosteum and articular cartilage, 3 days after induction of knee instability.169 TGF-β is a known anabolic growth factor that increases the expression of several types of collagen and proteoglycans.170 When introduced into the joint in experimental animals, however, TGF-β induces osteophyte formation,171 and TGF-β ­expression is observed in osteophytes in patients with osteoarthritis.172 Bony proliferation may result from venous congestion. In human hip osteoarthritis, phlebography has shown the formation of medullary varices, presumably resulting from changes in the medullary sinusoids, which may be compressed by subchondral cysts and thickened subchondral

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trabeculae.173,174 Subchondral cysts in osteoarthritis may be created by entry of synovial fluid under pressure through defects in the cartilage or may develop in necrotic areas of subchondral bone.175,176 The increased venous pressure caused by the cysts and remodeled trabeculae may account for some of the pain in osteoarthritis. Immobilization and glucocorticoids (but not bisphosphonates) have been shown to decrease the size and prevalence of osteophytes in experimental models of osteoarthritis.177

BIOMECHANICS AND DISEASE MECHANISMS OF OSTEOARTHRITIS RESPONSE OF CARTILAGE TO MECHANICAL INJURY The response of normal articular cartilage to injury typically results in suboptimal repair; these injuries often can result in secondary osteoarthritis.178,179 In contrast to tissues that have the ability to regenerate injured regions with new cells and extracellular matrices that closely resemble the original tissue, articular cartilage produces a repair tissue with neither the original structure nor properties of normal cartilage.180-183 Chondrocytes in areas surrounding an injured zone are unable to migrate, proliferate, repopulate, or regenerate repair tissue with similar structure, function, and biomechanical properties of normal hyaline cartilage.154,180,184 That articular cartilage lacks regenerative power has a long history of documentation.185 Redfern186 reported that articular cartilage wounds healed with fibrous tissue, which he believed arose from chondrocyte intercellular substance. Fisher187 and Ito188 in the 1920s proposed that cartilage repair is effected by fibrous tissue resulting from proliferation of cells from bone marrow, synovial membrane, and occasionally surrounding articular cartilage. It was later observed that the fibrous tissue subsequently transforms into fibrocartilage, with occasional foci of imperfect hyaline cartilage.189-192 The common findings of these investigators was that articular cartilage lacks regenerative potential, and that the regenerative fibrous tissue and fibrocartilage tissue must have originated from undifferentiated mesenchymal tissue arising from bone marrow, synovium, or the superficial layer of articular cartilage.185 One reason the reparative process of cartilage significantly differs from the reparative processes of other tissues is that it is avascular. The healing response in vascularized tissues consists of three main phases: necrosis, inflammation, and repair.178,183 Cartilage undergoes the initial phase of necrosis in response to injury, although typically less cell death occurs than in vascularized tissues because of chondrocytes’ relative insensitivity to hypoxia.178,183 The inflammatory phase, primarily mediated (in other tissues) by the vascular system, is largely absent in partial-­thickness injuries (i.e., lesions that do not cross the tidemark), and the repair phase is severely limited given the lack of vascularity and a preceding inflammatory response. No local hyperemia results, no fibrin network is produced, no subsequent clot develops to act as a scaffold for the ingrowth of repair tissue, no mediators or cytokines are released that can stimulate cellular migration and proliferation, and no inflammatory cells that have mitotic and

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reparative potential are recruited.154,183 In lesions that do not cross the tidemark, the burden of repair falls on the chondrocytes183 in a process that has been termed intrinsic repair.193 Although fetal cartilage is capable of mitotic activity and replication, adult chondrocytes have little potential for replication and intrinsic repair.191,192 Articular cartilage lesions that cross the tidemark may undergo extrinsic repair via differentiation and proliferation of mesenchymal stem cells from para-articular connective tissues, although most often a fibrocartilaginous tissue results.193 There are three categories of articular cartilage injury: (1) microdamage or repetitive trauma to the matrix and cells; (2) partial-thickness or superficial injuries or chondral fractures, articular surface injuries that do not penetrate the subchondral plate; and (3) osteochondral (full-thickness or deep penetrating) injuries, which extend through the tidemark and into the underlying subchondral bone.178,180,183 The host response to each type of injury differs in timing and quality of repair. Microdamage to the chondrocytes or extracellular matrix or both without gross disruption of the articular surface can be caused by a single severe impact or repetitive blunt trauma.178,180,183 Repetitive loading of rabbit cartilage produces a surface loss of proteoglycans and an increase in chondrocyte metabolic activity.194 Proteoglycans become more easily extractable from the articular cartilage, with a greater percentage of nonaggregated forms.154 Several investigators have observed that cellular, metabolic, and biochemical changes after repetitive blunt trauma resemble the changes in the early stages of osteoarthritis—increased hydration, cellular degeneration or death, disruption of the collagen ultrastructure resulting in marked variation in the size and arrangements of fibers, fissuring and ulceration of the articular surface, thickening of the subchondral bone, and softening of the cartilage with loss of its compressive and tensile stiffness.154,180,195-197 Trauma induces the release of degradative enzymes and proinflammatory factors (e.g., nitric oxide, TNF, IL-1) that frequently cause degradation of the surrounding matrix.194,198,199 Eventually, the material properties of the cartilage are altered—­cartilage matrix thins and subchondral bone stiffens—which often accelerate the degenerative process.154 The point at which accumulated microdamage becomes irreversible is unknown, although it has been shown that lost proteoglycans and matrix components may be restored if damage to chondrocytes and the collagen network is limited, and the repetitive trauma is halted.180 Necrosis of neighboring chondrocytes follows chondral fractures and superficial lacerations, injuries that do not cross the tidemark.178,183,200 Within 48 to 72 hours, surviving chondrocytes bordering the defect exhibit increased synthesis rates of extracellular matrix molecules and type II collagen, sometimes accompanied by cell proliferation and formation of clusters or clones in the periphery of the injured zone.154,183,200,201 The increased metabolism and mitotic activity is transient, however, and is followed by a decrease in metabolic rate back to normal levels, typically resulting in a suboptimal repair.154,183 Chondrocytes proliferating on the border of the injured zone do not migrate into the defect, which remains unfilled by the newly synthesized

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matrix.154,180,184 In some cases, superficial lacerations in otherwise normal joints may not progress to full-thickness loss of cartilage or osteoarthritis.154 Lesions that cross the articular cartilage tidemark and disrupt the underlying subchondral plate elicit the threephase repair response normally encountered in vascularized tissues. A hematoma forms in the defect that becomes organized into a fibrin clot, activating an inflammatory response. Transformation of the fibrin clot into vascular fibroblastic repair tissue183,201 is accompanied by release of cytokines important in stimulating a repair response (e.g., TGF-β, platelet-derived growth factor, IGF, bone morphogenetic proteins).181 These cytokines help set in motion the recruitment, proliferation, and differentiation of undifferentiated cells into a fibrin network that serves as a scaffold for fibrocartilaginous repair tissue.181,202,203 The origin of these mesenchymal stem cells has been determined to be the underlying bone marrow, rather than the adjacent residual articular surface.201,203,204 These cells progressively differentiate into chondroblasts, chondrocytes, and osteoblasts and synthesize cartilage and bone matrices. At 6 to 8 weeks postinjury, the repair tissue contains a high proportion of chondrocyte-like cells surrounded by a matrix consisting of proteoglycans and type II collagen, with a lesser amount of type I collagen.204-206 Cells in the deeper layers of the defect differentiate into osteoblasts and subsequently undergo endochondral ossification to heal the subchondral bone defect.154 This regenerative tissue eventually undergoes a transformation to a more fibrocartilaginous repair accompanied by a shift in the synthesis of collagen from type II to type I.184,200,202,203,206 Typically, within 1 year from injury, the repair tissue resembles a mixture of fibrocartilage and hyaline cartilage, with a substantial component (20% to 40%) of type I collagen.205 The size of the osteochondral defect is an important factor in the quality of repair; as a general rule, the smaller the defect, the better the repair.207 Depending on the joint, there exists a critical size defect that does not repair. Fibrocartilaginous repair is susceptible to early degenerative changes because it lacks the biomechanical properties to withstand normal physiologic joint loads.203,205 MECHANOTRANSDUCTION AND GENE EXPRESSION Chondrocytes can sense and respond to mechanical and physicochemical stimuli via several regulatory pathways (e.g., upstream signaling, transcription, translation, posttranslational modification, vesicular transport).208 Physical forces also may influence the synthesis, assembly, and degradation of the extracellular cartilage matrix. Normal stimuli help chondrocytes maintain the extracelluar matrix; abnormal stimuli can disrupt this balance. Mechanotransduction influences the cell-mediated feedback between physical stimuli, the molecular structure of newly synthesized matrix molecules, and the resulting biomechanical tissue properties.209 Cell-matrix interactions are believed to be an important mediator in mechanotransduction in chondrocytes. In a study on the expression of COMP to long-term cyclic compression, it was found that with ­ uniaxial unconfined dynamic compression, COMP expression was significantly upregulated; incubation with

anti–α1 integrin blocking antibodies abolished the mechanosensitivity of COMP expression.210 Studies of cyclic and static unconfined compression of bovine articular cartilage explants showed that cyclic loading increased protein synthesis by 50% above free-swelling controls, but had an inhibitory influence on proteoglycan synthesis. Static compression was associated with a dose-dependent decrease in biosynthetic activity.211 Fibronectin and COMP were the most affected noncollagenous extracellular proteins; static compression caused a significant increase in fibronectin synthesis versus free-swelling control levels, and cyclic compression caused a significant increase in synthesis of COMP and fibronectin. These results support the theory that chondrocytes can remodel extracellular matrix in response to alterations in functional demand. Human articular chondrocytes use the α5β1 integrin as a mechanoreceptor. Mechanical stimulation initiates a signal cascade involving stretch-activated ion channels, the actin cytoskeleton, and tyrosine phosphorylation of the focal adhesion complex molecules pp125 focal adhesion kinase and paxillin, and β-catenin.212 Autocrine secretion of IL-4 ensues. After binding to its type II receptors, IL-4 induces membrane hyperpolarization of chondrocytes from normal human knee joint articular cartilage. The result is an anabolic response, manifested by increased levels of aggrecan mRNA after mechanical stimulation and decreased levels of MMP-3. Mechanically induced release of the chondroprotective cytokine IL-4 from chondrocytes acts in an autocrine and a paracrine manner and represents an important regulator of articular cartilage structure and function; dysfunction of this pathway may be implicated in osteoarthritis. Although the mechanoreceptor in osteoarthritis chondrocytes also is the α5β1 integrin, downstream signaling pathways in osteoarthritic chondrocytes differ and may contribute to changes in chondrocyte behavior, leading to increased cartilage breakdown.213 Integrins and integrin-associated signaling pathways are at least partly regulated by mechanical stimulation by activation of plasma membrane apamin-sensitive, Ca2+-activated K+ channels; the result is membrane hyperpolarization after cyclical mechanical stimulation.214 Chondrocytes from normal articular cartilage exhibit membrane hyperpolarization response to cyclic pressure-induced strain, whereas chondrocytes from osteoarthritic cartilage respond by membrane depolarization and exhibit no changes in aggrecan or MMP-3 mRNA after mechanical stimulation.215,216 These findings suggest that chondrocytes derived from osteoarthritic cartilage have a different signaling pathway via the α5β1 integrin in response to mechanical stimula­ tion; these may play a role in the phenotypic changes seen in diseased cartilage. Another study used cDNA array analysis to compare the expression profiles of mRNA from hydrostatic pressurized and nonpressurized human chondrosarcoma cells.217 Several immediate-early and regulating cell cycle and growth genes were upregulated in response to high pressure, whereas a decrease was observed in osteonectin, fibronectin, and collagen types VI and XVI mRNA. Fluid flow during dynamic compression of cartilage explants can stimulate proteoglycan and protein synthesis independent of changes in cell shape. A study using a tissue shear-loading model to uncouple fluid flow from cell

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and matrix deformation showed that deformation of cells and pericellular matrix alone stimulated protein synthesis by approximately 50% and proteoglycan synthesis by approximately 25%; even in the absence of macroscopic tissue-level fluid flow, chondrocytes can respond to a change in shape.218 The magnitude and duration of specific loads also can cause chondrocyte death and collagen damage; chondrocytes in the superficial zone seem to be more vulnerable to loadinduced injury than chondrocytes in the middle and deep zones.219,220 Indian hedgehog (Ihh) protein is a key signaling molecule that controls chondrocyte proliferation and differentiation. Ihh also may be an essential mediator of mechanotransduction in cartilage. Cyclic mechanical stress was shown to induce Ihh expression by chondrocytes.221

ROLE OF INFLAMMATORY MEDIATORS IN DISEASE PROGRESSION Among the many biochemical pathways that are activated within joint tissues during the course of osteoarthritis are mediators classically associated with inflammation, notably IL-1β and TNF-α. These cytokines autocatalytically stimulate their own production and induce chondrocytes to produce proteases, chemokines, nitric oxide, and eicosanoids such as prostaglandins and leukotrienes. The action of these inflammatory mediators within cartilage is predominantly to drive catabolic pathways, inhibit matrix synthesis, and promote cellular apoptosis. Although osteoarthritis is not conventionally considered an inflammatory disease, “inflammatory” mediators perpetuate disease progression and represent potential targets for disease modification. INFLAMMATORY MOLECULES PRODUCED BY ARTICULAR CARTILAGE Cytokines and Chemokines A characteristic feature of established osteoarthritis is the increased production of proinflammatory cytokines, such as IL-1β and TNF-α, by articular chondrocytes. IL-1β and TNF-α exert comparable catabolic effects on chondrocyte metabolism, decreasing proteoglycan collagen synthesis and increasing aggrecan release via the induction of degradative proteases.109,222-227 IL-1β and TNF-α also induce chondrocytes and synovial cells to produce other inflammatory mediators, such as IL-8, IL-6, nitric oxide, and prostaglandin E2. The actions of both cytokines are mediated partly by the activation of the transcription factor nuclear factor κB, which increases further their own expression and that of other catabolic proteins, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), creating an autocatalytic cascade that promotes self-destruction of articular cartilage (see Fig. 89-2).228,229 IL-1β and TNF-α are synthesized intracellularly as precursors, converted through proteolytic cleavage to their mature forms by caspases—membrane-bound IL-1βconverting enzyme (ICE) and TNF-α-converting enzyme (TACE)—and released extracellularly in their active forms.230 The expression of ICE and TACE has been shown to be upregulated in osteoarthritis cartilage.260-262 Inhibitors of ICE and TACE are of interest as future therapeutic

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small-molecule antagonists of downstream IL-1β and TNFα expression; studies with an ICE inhibitor are now under way in two murine models. The actions of IL-1 depend on the engagement of two specific cell surface receptors (IL-1R), designated type I and type II. The type I receptor, which spans the plasma membrane, is responsible for signal transduction, whereas the type II receptor is a “decoy” receptor, expressed at the cell membrane, but unable to signal. A deficit of the ratio of IL1Ra (the competitive inhibitor to the IL-1/IL-1R ­complex) to IL-1 has been described in osteoarthritis synovial tissue, which may permit increased IL-1 activity.231,232 Addition of IL-1Ra, or soluble types I and II IL-1 receptors, to osteoarthritis explant cultures blocks prostaglandin E2 synthesis, collagenase production, and nitric oxide ­ production227,233; addition of these antagonists in culture also results in an increase in aggrecan content, likely by inhibiting degradation of newly synthesized molecules.234 Encouraging results with IL-1Ra also have been reported in vivo, where gene therapy or the intra-articular administration of IL-1Ra has been shown to retard the progression of osteoarthritis in experimental animal models.235,236 Other lines of evidence also point to IL-1β as an essential link in the pathogenesis of cartilage damage, including proteoglycan loss produced by intra-articular injection of IL-1.235 Clinical trials using IL-1β antagonists are few and have been inconclusive. One multicenter trial with doubleblinded doses of intra-articular IL-1Ra to 14 osteoarthritis patients resulted in decreased pain without significant adverse events or acute injection reactions.237 No long-term studies of structure-modifying effects of such therapies have been reported, however. Osteoarthritic cartilage also is the site of increased production of CXC and CC chemokines. These include IL-8, monocyte chemoattractant protein-1, and RANTES (regulated on activation, normally T cell expressed and secreted), also known as CCL5, chemokine and the receptors CCR-2 and CCR-5.238-240 The expression of chemokines is low or undetectable in normal chondrocytes unless stimulated with cytokines such as IL-1 or IL-17.241 Chemokines are detected by immunohistochemistry in the superficial and mid zones of the tissue, as has been shown for other inflammatory mediators, such as iNOS, IL-1β, and TNF-α.239 RANTES induces expression of its own receptor, CCR-5, suggesting an autocrine/paracrine pathway of the chemokine within the cartilage. Monocyte chemoattractant protein-1 and RANTES promote chondrocyte catabolic activities, including induction of nitric oxide synthase, increased MMP-3 expression, inhibition of proteoglycan synthesis, and enhancement of proteoglycan release.239,242 Consistent with these effects, treatment of normal articular cartilage with RANTES increases the release of glycosaminoglycans and profoundly reduces the intensity of safranin O staining.239 Proteinases A presumed key action of cytokines and chemokines produced in osteoarthritis is to promote cartilage proteolysis via the induction of a wide array of proteases, in particular MMPs. The two main families of MMPs are (1) the collagenases that break down type II collagen (especially MMP1, MMP-8, MMP-13, and MMP-28) and proteoglycans

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(MMP-3, which also cleaves pro-MMPs into their active forms) and (2) the aggrecanases, also known as ADAMTS family, which mediate aggregan degradation in cartilage.138,149 Both families of MMPs are expressed in osteoarthritis cartilage at lesional sites, and it is presumed that they play a major role in degradation of the extracellular matrix. A comprehensive analysis of specific metalloproteinases that are overexpressed by osteoarthritis cartilage and synovium has revealed several MMPs and ADAMTSs that may be candidates as targets for disease modification.243 Among the most interesting is MMP-13, which is overexpressed in murine and human osteoarthritis cartilage and is the most efficient protease capable of cleaving type II collagen.202,244 Similarly, the aggrecanase ADAMTS-5 has surfaced as the aggrecanase required for aggrecan loss in experimental osteoarthritis245 and inflammatory joint disease.246 It has been shown that mice lacking ADAMTS-5 are protected from developing osteoarthritis.245 The expression and degradation of noncollagenous proteins and nonaggregating proteoglycans also are altered in osteoarthritis cartilage and may have a direct or indirect effect on modulating the catabolic state of the chondrocyte.247 These groups of molecules are likely to have important structural and biologic functions.248,249 From their interactions with other extracellular matrix constituents, they can influence the supramolecular assembly of the cartilage matrix and as a result affect the physical properties of the tissue; by interacting directly with chondrocytes or neighboring cells or both, they can provide biologic signals on matrix properties and influence cellular function.250 There is increased expression of fibronectin, osteonectin, and osteopontin in osteoarthritis cartilage compared with normal cartilage.251 In addition, proteolytic processes generate fragments of extracellular matrix proteins, including fibronectin and type II collagen, which seem to exert catabolic and proteolytic activities. Homandberg and others252-254 have shown that fragments of fibronectin (but not the intact fibronectin molecule) induce the production of metalloproteinases and other catabolic factors in cartilage, in a process that partly depends on IL-1 induction. More recent studies indicate that fibronectin fragments

A

­stimulate type II collagen cleavage via enhanced MMP-13 and MMP-3 production.255 The chondrolytic effects of the fragments were blocked by the addition of either a preferential MMP-13 inhibitor or IL1-Ra. Type II collagen fragments also can induce matrix resorption when abundant enough.255,256 Nitric Oxide Nitric oxide, produced by the inducible isoform of nitric oxide synthase (iNOS), is a major catabolic factor produced by chondrocytes in response to proinflammatory cytokines such as IL-1β and TNF-α.238 Considerable evidence indicates that the overproduction of nitric oxide by chondrocytes plays a role in the perpetuation of cartilage destruction in osteoarthritis (Fig. 89-3).257-259 Increased concentrations of nitrites have been shown in the synovial fluid of patients with osteoarthritis, and iNOS has been shown in osteoarthritis synoviocytes and chondrocytes by in situ hybridization and immunohistochemistry.85,260,261 Although normal cartilage does not express iNOS or produce nitric oxide without stimulation by cytokines such as IL-1, osteoarthritis cartilage explants spontaneously produce large amounts of nitric oxide.257 iNOS also is upregulated from chondrocytes by cartilage compression.262,263 Nitric oxide exerts multiple effects on chondrocytes that promote articular cartilage degradation,264 including (1) inhibition of collagen and proteoglycan synthesis,264 (2) activation of metalloproteinases,265 (3) increased susceptibility to injury by other oxidants (e.g., hydrogen peroxide),266 and (4) apoptosis.233 Several studies have implicated nitric oxide as an important mediator in chondrocyte apoptosis, a feature common in progressive osteoarthritis.266,267 Immunohistochemistry of joint tissue obtained from patients with osteoarthritis reveals colocalization of iNOS protein and apoptosis in articular cartilage cells.268 There is evidence that apoptosis results from the formation of peroxynitrite, a toxic free radical produced by the reaction of nitric oxide and superoxide anion. Peroxynitrite reacts with tyrosine residues on proteins, which can be detected by antibodies to nitrotyrosine. Immunostaining of osteoarthritis cartilage reveals

B

Figure 89-3  A and B, Immunostaining of osteoarthritic cartilage specimen for inducible nitric oxide synthase (A) and interleukin-1β (B). Note intense staining of chondrocytes in the superficial zones for both inflammatory proteins. (From Melchiorri C, et al: Enhanced and coordinated in vivo expression of inflammatory cytokines and nitric oxide synthase by chondrocytes from patients with osteoarthritis. Arthritis Rheum 41:2165-2174, 1998.)

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that chondrocytes that are highly positive for IL-1β also stain for nitrotyrosine, consistent with overproduction of peroxynitrate and oxidative damage.261 The importance of nitric oxide has been corroborated in animal models of osteoarthritis. In the Pond-Nuki canine model, the inhibition of nitric oxide reduced the progression of cartilage lesions.269 The protective effect of nitric oxide inhibition also was reflected in decreased levels in articular cartilage of metalloproteinases, caspase-2, and IL-1β, and in decreased chondrocyte apoptosis.270 Osteoarthritis pathology, including cartilage lesions and osteophyte formation, was reduced in the mutant mice. Nitric oxide also may play protective roles, however, as protease activity and proteoglycan degradation are enhanced when nitric oxide production is blocked.271 In murine models, the development of surgically induced osteoarthritis can be accelerated in mice that are knocked out for ICE or iNOS—suggesting that a certain level of these molecules may be necessary to maintain a healthy joint, and that complete pharmacologic suppression may be detrimental.272 Transforming Growth Factor-β1 In most respects, TGF-α acts as a counterregulatory molecule that opposes the effects of inflammatory mediators in cartilage. TGF-β1 has been shown to downregulate proteolytic MMP-1, MMP-13, IL-1, and TNF receptors on osteoarthritis chondrocytes.273 TGF-β2 selectively suppresses the cleavage of type II collagen by collagenases in osteoarthritis cartilage in culture and limits MMP and proinflammatory cytokine expression.222 Studies using the murine knee osteoarthritis model indicate that TGF-β3 protects articular cartilage; histologic staining for this molecule revealed a lack of TGF-β3 in damaged cartilage compared with normals. Although premature osteophyte chondrocyte clusters express high levels of TGF-β3, other data suggest that bone morphogenetic protein-2 is more responsible for late osteophyte development.274 TGF-β1 also may exert selected catabolic effects via the stimulation of ADAMTS-4 expression.273 Hyaluronic Acid Hyaluronic acid has been investigated as a marker of cartilage degradation that can be detected in synovial fluid and serum,275 but it also seems to play a role in limiting the progression of arthritis. A study by Karna and colleagues276 found that hyaluronic acid in vitro counteracts the ability of IL-1β to inhibit collagen biosynthesis. At the transcriptional and post-transcriptional levels, chondrocyte cultures with IL-1β upregulated collagen synthesis markers, whereas hyaluronic acid negated this effect. The same group found that hyaluronic acid similarly protects against IL-1-induced inhibition of collagen synthesis in human skin fibroblasts at the level of the IGF-I receptor.277 Prostaglandins The expression of inducible COX-2 is increased in osteoarthritis chondrocytes, which spontaneously produce prostaglandin E2 ex vivo.240 The effects of prostaglandins on chondrocyte metabolism are complex and include enhanced type II collagen synthesis, activation of metalloproteinases,

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and promotion of apoptosis.278 In cartilage explants, IL-1β induces COX-2 expression, and prostaglandin E2 production coordinates with proteoglycan degradation. COX-2 inhibition prevents IL-1β-induced proteoglycan degradation, which can be reversed by the addition of prostaglandin E2 to cultures.279 In contrast, in vitro evidence has accumulated that selected nonsteroidal anti-inflammatory drugs may interfere with proteoglycan synthesis.280 Another study concluded that 30% of prostaglandin E2 expression in osteoarthritis synovial tissue stems from the COX-1 pathway.4 Whether any differences exist between the effects of COX1-derived and COX-2-derived prostaglandins on cartilage metabolism is unknown. ALTERATIONS IN BONE The inflammatory mediators produced by bone in osteoarthritis are less well understood than those produced by cartilage and synovium. Biomechanical and biochemical factors seem to influence the remodeling, but the underlying pathogenesis has yet to be identified. Nitric oxide plays a role in bone cell function, which could have implications for osteoarthritis insofar as it contributes to alterations in subchondral bone. The endothelial isoform endothelial cell nitric oxide synthase is constitutively expressed in bone, where it seems to play a key role in regulating osteoblast activity and bone formation. Endothelial cell nitric oxide synthase also mediates the effects of mechanical loading on the skeleton, where it acts along with prostaglandins to promote bone formation and suppress bone resorption.281 In contrast, such proinflammatory cytokines as IL-1 and TNF induce iNOS in bone cells, and nitric oxide derived from this pathway potentiates bone loss.238 Osteophyte ­formation and subchondral bone remodeling likely result from local production of anabolic growth factors such as IGF-I and mostly TGF-β, which is highly expressed in osteophytes of the femoral head in osteoarthritis patients.282,283 Areas of increased radionuclide uptake (“hot spots”) on bone scintigraphy also have been reported to identify osteoarthritis joints more likely to progress by radiographic criteria or to require surgical intervention or both over a 5-year period.216 ALTERATIONS IN SYNOVIAL TISSUE One reason that osteoarthritis is classified as a noninflammatory arthritis is that the synovial fluid leukocyte count in osteoarthritis is typically less than 2000 cells/mm.3 Although such parameters can be misleading, low-grade inflammatory processes nevertheless occur in osteoarthritic synovial tissues and contribute to disease pathogenesis, and some degree of synovitis has been observed even in early osteoarthritis (Fig. 89-4).284 This localized synovitis may be subclinical because arthroscopic studies suggest that localized proliferative and inflammatory changes of the synovium occur in 50% of osteoarthritis patients, and the activated synovium may produce proteases and cytokines that accelerate damage to the adjacent cartilage.285 Many of the clinical symptoms and signs seen in osteoarthritis joints (e.g., joint swelling and effusion, stiffness, occasionally redness) reflect synovial inflammation. Synovial histologic changes include synovial hypertrophy and

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Pathogenesis of Osteoarthritis

Biomechanical factors Genetic

Extrinsic

Chondropathy Altered metabolism Synovium

Bone

Cartilage

Future? iNOS inhibitors IL-1 antagonists MMP inhibitors

? Inflammation Pain

Structural damage

Loss of function Synovitis

Figure 89-4  Arthroscopic view of osteoarthritic lesion of the femoral condyle (designated chondropathy). Note that proliferative synovitis is localized to the area of the osteoarthritic lesion. (Courtesy of Maxime Dougados.)

hyperplasia with an increased number of lining cells, often accompanied by infiltration of the sublining tissue with scattered foci of lymphocytes. In contrast to rheumatoid arthritis, synovial inflammation in osteoarthritis is mostly confined to areas adjacent to pathologically damaged cartilage and bone. This activated synovium can release proteinases and cytokines that may accelerate destruction of nearby cartilage.283 As described earlier, the metalloproteinases that degrade cartilage are produced not only by the cartilage itself, but also by the synovium. Although cartilage destruction might be directed by the chondrocytes, some degree of synovitis exists in patients even with mild osteoarthritis. A comprehensive analysis by Davidson and coworkers243 reported several proinflammatory genes significantly elevated in the synovium that had not previously been reported. Cartilage breakdown products, derived from the articular surface as a result of mechanical or enzymatic destruction of the cartilage, can provoke the release of collagenase and other hydrolytic enzymes from synovial cells and macrophages (Fig. 89-5).286,287 Cartilage breakdown products also are believed to result in mononuclear cell infiltration and ­vascular hyperplasia in the synovial membrane in osteo­ arthritis.288-290 A consequence of these low-grade inflammatory processes is the induction of synovial IL-1β and TNF-α, which are likely contributors to the degradative cascade.238 There also are reports of increased numbers of immune cells in synovial tissue, including activated B cells and T lymphocytes, and evidence that osteoarthritis patients express cellular immunity to the cartilage proteoglycan link protein and C1 domain.291,292 A more recent study of 10 patients with early osteoarthritis (arthroscopic specimens) and 15 patients undergoing total knee arthroplasty revealed that

ACETA, NSAIDs, Intraarticular steroids Viscosupplementation Figure 89-5  Multiple factors that predispose to, initiate, and perpetuate osteoarthritis. In the future, structure-modifying treatments will be targeted to the biochemical processes that promote disease progression. ACETA, acetaminophen; IL-1, interleukin-1; iNOS, inducible nitric oxide synthase; MMP, matrix metalloproteinase; NSAIDs, nonsteroidal antiinflammatory drugs.

synovial tissues from early osteoarthritis had higher levels of IL-1β and TNF-α and increased mononuclear cell infiltration compared with late osteoarthritis.293 In addition, although less prominent than in rheumatoid arthritis, deposits of immunoglobulin and complement can be found in the collagenous network of the superficial zone of articular cartilage in osteoarthritis, suggesting that deposition of immune complexes, perhaps containing breakdown products of the cartilage as antigens, may play a role in the chronicity of the inflammatory reaction in the joint.294 It is probable that any acquired immune-driven component of osteoarthritis is secondary, and not likely to be of major importance in future treatment strategies. Patients with distal or proximal interphalangeal osteoarthritis are generally asymptomatic when the disease is nonerosive and become symptomatic during inflammatory episodes (associated with erosive osteoarthritis changes).295 Other evidence that erosive osteoarthritis is more inflammatory comes from a study of rapidly destructive hip osteoarthritis, in which levels of MMP-3 and MMP-9 were especially elevated, not only in patients’ synovial cells, but also in their synovial fluid, plasma, and sera.296,297 In addition, in vitro studies have implicated MMP-10 expression in synovial fibroblasts from diseased osteoarthritis human tissue and in osteoarthritis synovial fluid and chondrocytes stimulated with catabolic IL-1 and oncostatin M.298 Osteoarthritis patients have been shown to express cellular immunity to the cartilage proteoglycan link protein, and C1 domain and immune complexes containing antibodies to type II collagen have been detected in the superficial layer of osteoarthritis cartilage.299 Histologic changes in osteoarthritis synovium usually show mild or moderate synovitis characterized by an increase in the number of

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i­nflammatory mononuclear cells in the sublining tissue, including activated B cells and T lymphocytes.302-307 Along the lines of acute episodes of osteoarthritis, the inflammation may result from crystal-induced synovitis (either calcium apatite or CPPD). “Milwaukee shoulder syndrome” is a rapidly destructive form of osteoarthritis with evidence of inflammation in the synovial membrane, but minimal synovial fluid leukocytosis. It is typically associated with rotator cuff degeneration, severe shoulder osteoarthritis, and hydroxyapatite crystal deposition in the synovial membrane.306 The synovial fluid typically contains few cells and high levels of active collagenase. It is theorized that crystals released from the degenerating tendons trigger the release of collagenase from synovial mononuclear cells, which leads to cartilage breakdown; cartilage breakdown products further activate release of enzymes from the synovium. This inflammation typically is associated with increases in synovial IL-1 and TNF that further potentiate the degradative cascade.307 BIOMARKERS OF OSTEOARTHRITIS Several biomarkers have been correlated with osteoarthritis, but they often lack any known pathophysiologic or biochemical function that would classify them as inflammatory mediators.308 Such markers, including C-reactive protein (CRP) and COMP, have been used to assess the diagnosis, severity, and prognosis of osteoarthritis. The formation of the National Institutes of Health (NIH)–funded osteoarthritis Biomarkers Network, a consortium of five NIH-designated sites, has proposed the “BIPED” biomarker classification with five separate categories of surrogate markers: burden of disease, investigative, prognostic, efficacy of intervention, and diagnostic.283 Some established markers for burden of disease and for prognosis for hip and knee osteoarthritis include serum COMP, serum hyaluronic acid, and urinary CTX-II.309 One study of 62 patients with knee osteoarthritis compared magnetic resonance imaging findings at baseline and 1 year and levels of serum hyaluronic acid, osteocalcin, cartilage glycoprotein 39, COMP, and urine C-telopeptide of type II collagen. This study suggested that a single measurement of serum hyaluronic acid or short-term increases in urine CTX-II would identify patients at greatest risk for progression of osteoarthritis.310 Elevated levels of the inflammatory marker CRP seem to be predictive of radiographic progression of long-term knee osteoarthritis.238 In a study of 1025 women, higher levels of serum CRP were associated with a statistically significant increase in prevalent and incident knee osteoarthritis and greater knee osteoarthritis severity. Women with bilateral knee osteoarthritis had higher CRP levels than women with unilateral knee osteoarthritis. Compared with women who did not develop knee osteoarthritis, the women who did had a higher baseline CRP than at their index test 2.5 years ­earlier.311 In another study comprising women (44 to 67 years old), CRP levels were statistically greater in 105 women with knee osteoarthritis than in 740 women without osteoarthritis. These and other studies report that CRP levels are modestly but significantly increased in women with early knee osteoarthritis, and that higher levels are predictive of osteoarthritis that will progress over time.85

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Several studies have identified COMP levels as helpful assessors of the potential for, presence of, and progression of osteoarthritis.312 This noncollagenous extracellular matrix protein, synthesized by cartilage and synovium with TGF-β1 stimulation,313 is abundant in articular cartilage.314-317 The degradation and the tissue distribution of COMP exhibit marked differences in normal and osteoarthritic human knee articular cartilage. COMP in normal cartilage is predominantly localized to the interterritorial matrix throughout all zones of the matrix, with increased staining in the deeper cartilaginous zones. COMP in osteoarthritic cartilage is predominantly localized to the superficial zones of fibrillated cartilage, with little to no immunostaining in the midzones and poor staining in the deeper cartilaginous zones. In areas of fibrocartilaginous repair in osteoarthritis, the repair matrix stained poorly for proteoglycans, but strongly for COMP; some fibrocartilaginous cells stained positively for COMP, suggesting that these cells were actively synthesizing COMP.318 Synovial fluid COMP levels were found to be higher in individuals with knee pain or injury,319 anterior cruciate ligament or meniscal injury,319,320 and osteoarthritis319,321 than in demographically matched healthy individuals. Similarly, serum levels of COMP are often higher in patients with more rapidly progressive joint damage240,242,322 with some studies showing this specifically in hip osteoarthritis247,295 and knee osteoarthritis.241 Hyaluronic acid has been investigated as a marker of cartilage degradation that can be detected in synovial fluid and serum.275 The level of hyaluronic acid in synovial fluid and serum may be reflective of cartilage metabolism, even though most circulating hyaluronic acid originates from extracartilaginous sources. It has become clear that hyaluronic acid levels reflect synovial activity, whereas proteoglycan levels reflect cartilage turnover.275,323 In addition, higher serum hyaluronic acid levels have been correlated with the number of joints involved and degree of clinical disability. These findings support the theory that serum hyaluronic acid levels reflect synovial hyperactivity. An animal model in which the anterior cruciate ligament was transected to induce osteoarthritis also showed an increase in serum hyaluronic acid level within 7 days after joint injury, an increase sustained at 13 weeks; the increase in synovial fluid hyaluronic acid levels correlated with serum levels.324 Serum hyaluronic acid levels, which also may serve as a predictor of osteoarthritis disease progression,247,325 correlated with radiographic evidence of disease progression over a 5-year period, as patients whose disease progressed had higher levels than at the outset.309

SUMMARY Osteoarthritis, although classically conceived of as a degenerative consequence of aging, is a disease with an increasingly well-characterized molecular pathophysiology. Biomechanical factors, particularly in the context of genetic predisposition, obesity, and malalignment, result in chemical alterations within the joint that promote cartilage degradation. Early, anabolic changes, characterized by proliferation of chondrocytes and increased matrix production, are followed by a predominantly catabolic state, characterized by decreased matrix synthesis, increased proteolytic degradation of matrix, and chondrocyte apoptosis.

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Pathogenesis of Osteoarthritis

Many of the ­features of the chondrocyte in the catabolic state are related to the production of inflammatory mediators by synovium and chondrocytes that act locally to perpetuate cartilage degradation. Although current treatments improve the signs and symptoms of disease, further characterization of the altered metabolism in synovium, cartilage, and bone that promote disease progression should lead to future treatments that prevent structural damage in osteoarthritis (see Fig. 89-5).

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193. Grande DA, Singh IJ, Pugh J: Healing of experimentally produced lesions in articular cartilage following chondrocyte transplantation. Anat Rec 218:142-148, 1987. 194. Radin EL, Ehrlich MG, Chernack R, et al: Effect of repetitive impulsive loading on the knee joints of rabbits. Clin Orthop 131:288-293, 1978. 195. Beim GM, Fu FH: Classification and treatment of DJD of the knee. Orthop Spec Ed 2:31-35, 1996. 196. Dekel S, Weissman SL: Joint changes after overuse and peak overloading of rabbit knees in vivo. Acta Orthop Scand 49:519-528, 1978. 197. Lee SH, Abramson SA: Stepped-care guide to osteoarthritis therapy. Orthop Spec Ed 2:7-10, 1996. 198. Farrell AJ, Blake DR, Palmer RM, et al: Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic diseases. Ann Rheum Dis 51: 1219-1222, 1992. 199. Yoshimi T, Kikuchi T, Obara T, et al: Effects of high-molecularweight sodium hyaluronate on experimental osteoarthrosis induced by the resection of rabbit anterior cruciate ligament. Clin Orthop 298:296-304, 1994. 200. Cheung HS, Cottrell WH, Stephenson K, et al: In vitro collagen biosynthesis in healing and normal rabbit articular cartilage. J Bone Joint Surg Am 60:1076-1081, 1978. 201. DePalma AF, McKeever CD, Subin DK: Process of repair of articular cartilage demonstrated by histology and autoradiography with tritiated thymidine. Clin Orthop 48:229-242, 1966. 202. Mitchell N, Shepard N: The resurfacing of adult rabbit articular cartilage by multiple perforations through the subchondral bone. J Bone Joint Surg Am 58:230-233, 1976. 203. Shapiro F, Koide S, Glimcher MJ: Cell origin and differentiation in the repair of full-thickness defects of articular cartilage. J Bone Joint Surg Am 75:532-553, 1993. 204. Cheung HS, Lynch KL, Johnson RP, et al: In vitro synthesis of tissuespecific type II collagen by healing cartilage, I: Short-term repair of cartilage by mature rabbits. Arthritis Rheum 23:211-219, 1980. 205. Furukawa T, Eyre DR, Koide S, et al: Biochemical studies on repair cartilage resurfacing experimental defects in the rabbit knee. J Bone Joint Surg Am 62:79-89, 1980. 206. Hjertquist SO, Lemperg R: Histological, autoradiographic and microchemical studies of spontaneously healing osteochondral articular defects in adult rabbits. Calcif Tissue Res 8:54-72, 1971. 207. Convery FR, Akeson WH, Keown GH: The repair of large osteochondral defects: An experimental study in horses. Clin Orthop 82:253-262, 1972. 208. Mobasheri A, Carter SD, Martin-Vasallo P, et al: Integrins and stretch activated ion channels: Putative components of functional cell surface mechanoreceptors in articular chondrocytes. Cell Biol Int 26:1-18, 2002. 209. Grodzinsky AJ, Levenston ME, Jin M, et al: Cartilage tissue remodeling in response to mechanical forces. Annu Rev Biomed Eng 2: 691-713, 2000. 210. Giannoni P, Siegrist M, Hunziker EB, et al: The mechanosensitivity of cartilage oligomeric matrix protein (COMP). Biorheology 40: 101-109, 2003. 211. Wong M, Siegrist M, Cao X: Cyclic compression of articular cartilage explants is associated with progressive consolidation and altered expression pattern of extracellular matrix proteins. Matrix Biol 18:391-399, 1999. 212. Lee HS, Millward-Sadler SJ, Wright MO, et al: Integrin and mechanosensitive ion channel-dependent tyrosine phosphorylation of focal adhesion proteins and beta-catenin in human articular chondrocytes after mechanical stimulation. J Bone Miner Res 15:1501-1509, 2000. 213. Salter DM, Millward-Sadler SJ, Nuki G, et al: Differential responses of chondrocytes from normal and osteoarthritic human articular cartilage to mechanical stimulation. Biorheology 39(1-2):97-108, 2002. 214. Millward-Sadler SJ, Wright MO, Lee H, et al: Integrin-regulated secretion of interleukin 4: A novel pathway of mechanotransduction in human articular chondrocytes. J Cell Biol 145:183-189, 1999. 215. Millward-Sadler SJ, Wright MO, Davies LW, et al: Mechanotransduction via integrins and interleukin-4 results in altered aggrecan and matrix metalloproteinase 3 gene expression in normal, but not osteoarthritic, human articular chondrocytes. Arthritis Rheum 43:2091-2099, 2000.

216. Millward-Sadler SJ, Wright MO, Lee H, et al: Altered electrophysiological responses to mechanical stimulation and abnormal signalling through alpha5beta1 integrin in chondrocytes from osteoarthritic cartilage. Osteoarthritis Cartilage 8:272-278, 2000. 217. Sironen RK, Karjalainen HM, Torronen K, et al: High pressure effects on cellular expression profile and mRNA stability: A cDNA array analysis. Biorheology 39(1-2):111-117, 2002. 218. Jin M, Frank EH, Quinn TM, et al: Tissue shear deformation stimulates proteoglycan and protein biosynthesis in bovine cartilage explants. Arch Biochem Biophys 395:41-48, 2001. 219. Chen CT, Bhargava M, Lin PM, et al: Time, stress, and location dependent chondrocyte death and collagen damage in cyclically loaded articular cartilage. J Orthop Res 21:888-898, 2003. 220. Lin PM, Chen CT, Torzilli PA: Increased stromelysin-1 (MMP-3), proteoglycan degradation (3B3- and 7D4) and collagen damage in cyclically load-injured articular cartilage. Osteoarthritis Cartilage 12:485-496, 2004. 221. Wu Q, Zhang Y, Chen Q: Indian hedgehog is an essential component of mechanotransduction complex to stimulate chondrocyte proliferation. J Biol Chem 276:35290-35296, 2001. 222. Tchetina EV, Kobayashi M, Yasuda T, et al: Chondrocyte hypertrophy can be induced by a cryptic sequence of type II collagen and is accompanied by the induction of MMP-13 and collagenase activity: Implications for development and arthritis. Matrix Biol 26:247-258, 2007. 223. Pelletier JP, Martel-Pelletier J, Abramson SB: Osteoarthritis, an inflammatory disease: Potential implication for the selection of new therapeutic targets. Arthritis Rheum 44:1237-1247, 2001. 224. Martel-Pelletier J, di Battista JA, Lajeunesse D: Biochemical factors in joint articular tissue degradation in osteoarthritis. In Reginster JY, Pelletier JP, Martel-Pelletier J, et al (eds): Osteoarthritis: Clinical and Experimental Aspects. Berlin, Springer-Verlag, 1999, pp 156-187. 225. Caron JP, Fernandes JC, Martel-Pelletier J, et al: Chondroprotective effect of intraarticular injections of interleukin-1 receptor antagonist in experimental osteoarthritis: Suppression of collagenase-1 expression. Arthritis Rheum 39:1535-1544, 1996. 226. van de Loo FA, Joosten LA, van Lent PL, et al: Role of interleukin-1, tumor necrosis factor alpha, and interleukin-6 in cartilage proteoglycan metabolism and destruction: Effect of in situ blocking in murine antigen- and zymosan-induced arthritis. Arthritis Rheum 38: 164-172, 1995. 227. Attur MG, Dave M, Cipolletta C, et al: Reversal of autocrine and paracrine effects of interleukin 1 (IL-1) in human arthritis by type II IL-1 decoy receptor: Potential for pharmacological intervention. J Biol Chem 275:40307-40315, 2000. 228. Vaillancourt F, Morquette B, Shi Q, et al: Differential regulation of cyclooxygenase-2 and inducible nitric oxide synthase by 4-hydroxynonenal in human osteoarthritic chondrocytes through ATF-2/CREB-1 transactivation and concomitant inhibition of NF-kappaB signaling cascade. J Cell Biochem 100:1217-1231, 2007. 229. Lianxu C, Hongti J, Changlong Y: NF-kappaBp65-specific siRNA inhibits expression of genes of COX-2, NOS-2 and MMP-9 in rat IL1beta-induced and TNF-alpha-induced chondrocytes. Osteoarthritis Cartilage 14:367-376, 2006. 230. Kronheim SR, Mumma A, Greenstreet T, et al: Purification of interleukin-1 beta converting enzyme, the protease that cleaves the interleukin-1 beta precursor. Arch Biochem Biophys 296:698-703, 1992. 231. Slack J, McMahan CJ, Waugh S, et al: Independent binding of interleukin-1 alpha and interleukin-1 beta to type I and type II interleukin-1 receptors. J Biol Chem 268:2513-2524, 1993. 232. Martel-Pelletier J, Alaaeddine N, Pelletier JP: Cytokines and their role in the pathophysiology of osteoarthritis. Front Biosci 4: D694-D703, 1999. 233. Alaaeddine N, DiBattista JA, Pelletier JP, et al: Osteoarthritic synovial fibroblasts possess an increased level of tumor necrosis factor-receptor 55 (TNF-R55) that mediates biological activation by TNF-alpha. J Rheumatol 24:1985-1994, 1997. 234. Kobayashi H, Saito T, Koshino T: Immunolocalization of carboxyterminal type II procollagen peptide in regenerated articular cartilage of osteoarthritic knees after reduction of mechanical stress. Osteoarthritis Cartilage 10:870-878, 2002. 235. Fernandes JC, Martel-Pelletier J, Pelletier JP: The role of cytokines in osteoarthritis pathophysiology. Biorheology 39(1-2):237-246, 2002.

PART 15 

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CARTILAGE, BONE, AND HERITABLE CONNECTIVE TISSUE DISORDERS

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Pathogenesis of Osteoarthritis

283. Abramson S, Krasnokutsky S: Biomarkers in osteoarthritis. Bull Hosp Jt Dis 64(1-2):77-81, 2006. 284. Rizkalla G, Reiner A, Bogoch E, et al: Studies of the articular cartilage proteoglycan aggrecan in health and osteoarthritis: Evidence for molecular heterogeneity and extensive molecular changes in disease. J Clin Invest 90:2268-2277, 1992. 285. Ayral X, Pickering EH, Woodworth TJ, et al: Synovitis predicts the arthroscopic progression of medial tibiofemoral knee osteoarthritis (OA). Ann Rheum Dis 60:57, 2001. 286. Evans CH: Cellular mechanisms of hydrolytic enzyme release in proteoglycan. Semin Arthritis Rheum 11:93, 1981. 287. Evans CH, Mears DC, McKnight JL: A preliminary ferrographic survey of the wear particles in human synovial fluid. Arthritis Rheum 24:912-918, 1981. 288. Haraoui B, Pelletier JP, Cloutier JM, et al: Synovial membrane histology and immunopathology in rheumatoid arthritis and osteoarthritis: In vivo effects of antirheumatic drugs. Arthritis Rheum 34:153-163, 1991. 289. Farahat MN, Yanni G, Poston R, et al: Cytokine expression in synovial membranes of patients with rheumatoid arthritis and osteoarthritis. Ann Rheum Dis 52:870-875, 1993. 290. Smith MD, Triantafillou S, Parker A, et al: Synovial membrane inflammation and cytokine production in patients with early osteoarthritis. J Rheumatol 24:365-371, 1997. 291. Krenn V, Hensel F, Kim HJ, et al: Molecular IgV(H) analysis demonstrates highly somatic mutated B cells in synovialitis of osteoarthritis: A degenerative disease is associated with a specific, not locally generated immune response. Lab Invest 79:1377-1384, 1999. 292. Nakamura H, Yoshino S, Kato T, et al: T-cell mediated inflammatory pathway in osteoarthritis. Osteoarthritis Cartilage 7:401-402, 1999. 293. Benito MJ, Veale DJ, FitzGerald O, et al: Synovial tissue inflammation in early and late osteoarthritis. Ann Rheum Dis 64:1263-1267, 2005. 294. Cooke TD: Significance of immune complex deposits in osteoarthritic cartilage. J Rheumatol 14(Spec No):77-79, 1987. 295. Verbruggen G, Veys EM: Numerical scoring systems for the anatomic evolution of osteoarthritis of the finger joints. Arthritis Rheum 39:308-320, 1996. 296. Masuhara K, Nakai T, Yamaguchi K, et al: Significant increases in serum and plasma concentrations of matrix metalloproteinases 3 and 9 in patients with rapidly destructive osteoarthritis of the hip. Arthritis Rheum 46:2625-2631, 2002. 297. Tchetverikov I, Lohmander LS, Verzijl N, et al: MMP protein and activity levels in synovial fluid from patients with joint injury, inflammatory arthritis, and osteoarthritis. Ann Rheum Dis 64:694-698, 2005. 298. Barksby HE, Milner JM, Patterson AM, et al: Matrix metalloproteinase 10 promotion of collagenolysis via procollagenase activation: Implications for cartilage degradation in arthritis. Arthritis Rheum 54:3244-3253, 2006. 299. Mort JS, Caterson B, Poole AR, et al: The origin of human cartilage proteoglycan link-protein heterogeneity and fragmentation during aging. Biochem J 232:805-812, 1985. 300. Roughley PJ, Lee ER: Cartilage proteoglycans: Structure and potential functions. Microsc Res Tech 28:385-397, 1994. 301. Neame PJ, Sandy JD: Cartilage aggrecan: Biosynthesis, degradation and osteoarthritis. J Fla Med Assoc 81:191-193, 1994. 302. Perkins SJ, Nealis AS, Dudhia J, et al: Immunoglobulin fold and tandem repeat structures in proteoglycan N-terminal domains and link protein. J Mol Biol 206:737-753, 1989. 303. Williams AF, Barclay AN: The immunoglobulin superfamily— domains for cell surface recognition. Annu Rev Immunol 6:381-405, 1988. 304. Rosenberg LC: Structure and function of dermatan sulfate proteoglycans in articular cartilage. In Kuettner KE, Schleyerbach R, Peyron JG, et al (eds): Articular Cartilage and Osteoarthritis. New York, Raven Press, 1992, pp 45-62.

305. Noyori K, Jasin HE: Inhibition of human fibroblast adhesion by cartilage surface proteoglycans. Arthritis Rheum 37:1656-1663, 1994. 306. McCarty DJ, Halverson PB, Carrera GF, et al: “Milwaukee shoulder”—association of microspheroids containing hydroxyapatite crystals, active collagenase, and neutral protease with rotator cuff defects, I: Clinical aspects. Arthritis Rheum 24:464-473, 1981. 307. Shlopov BV, Smith GN Jr, Cole AA, et al: Differential patterns of response to doxycycline and transforming growth factor beta1 in the down-regulation of collagenases in osteoarthritic and normal human chondrocytes. Arthritis Rheum 42:719-727, 1999. 308. Lohmander LS, Felson D: Can we identify a ‘high risk’ patient profile to determine who will experience rapid progression of osteoarthritis? Osteoarthritis Cartilage 12(Suppl A):S49-S52, 2004. 309. Sharif M, George E, Dieppe PA: Correlation between synovial fluid markers of cartilage and bone turnover and scintigraphic scan abnormalities in osteoarthritis of the knee. Arthritis Rheum 38:78-81, 1995. 310. Bruyere O, Genant H, Kothari M, et al: Longitudinal study of magnetic resonance imaging and standard x-rays to assess disease progression in osteoarthritis. Osteoarthritis Cartilage 15:98-103, 2007. 311. Sowers M, Jannausch M, Stein E, et al: C-reactive protein as a biomarker of emergent osteoarthritis. Osteoarthritis Cartilage 10: 595-601, 2002. 312. Jordan JM: Update on cartilage oligomeric matrix protein as a marker of osteoarthritis. J Rheumatol 32:1145-1147, 2005. 313. Black RA, Rauch CT, Kozlosky CJ, et al: A metalloproteinase disintegrin that releases tumor-necrosis factor-alpha from cells. Nature 385:729-733, 1997. 314. Oldberg A, Antonsson P, Lindblom K, et al: COMP (cartilage oligomeric matrix protein) is structurally related to the thrombospondins. J Biol Chem 267:22346-22350, 1992. 315. DiCesare PE, Morgelin M, Mann K, et al: Cartilage oligomeric matrix protein and thrombospondin 1: Purification from articular cartilage, electron microscopic structure, and chondrocyte binding. Eur J Biochem 223:927-937, 1994. 316. Hedbom E, Antonsson P, Hjerpe A, et al: Cartilage matrix proteins: An acidic oligomeric protein (COMP) detected only in cartilage. J Biol Chem 267:6132-6136, 1992. 317. Morgelin M, Heinegard D, Engel J, et al: Electron microscopy of native cartilage oligomeric matrix protein purified from the Swarm rat chondrosarcoma reveals a five-armed structure. J Biol Chem 267:6137-6141, 1992. 318. DiCesare P, Hauser N, Lehman D, et al: Cartilage oligomeric matrix protein (COMP) is an abundant component of tendon. FEBS Lett 354:237-240, 1994. 319. Lohmander LS, Saxne T, Heinegard DK: Release of cartilage oligomeric matrix protein (COMP) into joint fluid after knee injury and in osteoarthritis. Ann Rheum Dis 53:8-13, 1994. 320. Lohmander LS, Ionescu M, Jugessur H, et al: Changes in joint cartilage aggrecan after knee injury and in osteoarthritis. Arthritis Rheum 42:534-544, 1999. 321. Neidhart M, Hauser N, Paulsson M, et al: Small fragments of cartilage oligomeric matrix protein in synovial fluid and serum as markers for cartilage degradation. Br J Rheumatol 36:1151-1160, 1997. 322. Amin AR: Regulation of tumor necrosis factor-alpha and tumor necrosis factor converting enzyme in human osteoarthritis. Osteoarthritis Cartilage 7:392-394, 1999. 323. Goldberg RL, Huff JP, Lenz ME, et al: Elevated plasma levels of hyaluronate in patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum 34:799-807, 1991. 324. Manicourt DH, Cornu O, Lenz ME, et al: Rapid and sustained rise in the serum level of hyaluronan after anterior cruciate ligament transection in the dog knee joint. J Rheumatol 22:262-269, 1995. 325. Sinigaglia L, Varenna M, Binelli L, et al: Urinary and synovial pyridinium crosslink concentrations in patients with rheumatoid arthritis and osteoarthritis. Ann Rheum Dis 54:144-147, 1995.

90

Clinical Features of Osteoarthritis JÉRÉMIE SELLAM  •  FRANCIS BERENBAUM

KEY POINTS Osteoarthritis is a common and disabling musculoskeletal disorder with increasing prevalence and socioeconomic impact. Classically, clinical symptoms and signs constitute the primary diagnostic aid. The natural history of osteoarthritis varies widely—the ­diagnosis encompasses subgroups in which rapid, progressive destructive disease can occur. Imaging modalities useful in diagnosis include plain ­radiographs, although increasingly musculoskeletal ultrasound and particularly magnetic resonance imaging are being ­evaluated for clinical trial outcome and ultimately routine clinical use. The etiology of osteoarthritis is unclear, but comprises a multigene, environmental disorder. Treatment should be with a team approach and should ­include management of physical function, pain, and ­inflammation, and may require integration with orthopaedic surgical teams. There are few reliable clinical prognostic features as yet available; there is an urgent need for appropriate widely ­applicable biomarkers to identify patients with poor ­prognosis and patients with subtypes of disease that may require closer observation and earlier intervention.

Osteoarthritis is the most common chronic joint disorder. It usually results in pain and deformity, ultimately leading to chronic disability. It is rapidly becoming a significant medical and financial burden in a world whose population is aging.1,2 Osteoarthritis affects retired and working individuals and has a broad health economic impact.3 The disease is classically defined as a focal lesion of the articular cartilage, combined with a hypertrophic reaction (sclerosis) in the subchondral bone and new bone formation (osteophytes) at the joint margins. Muscle weakness, lax ligaments, misalignment, low-grade synovitis, and meniscal degeneration often occur, however, so that all three major tissues of a diarthrodal joint are usually implicated. Optimal management requires early diagnosis and awareness of the risk factors that can affect the prognosis.

PREVALENCE The prevalence of osteoarthritis depends on the precise definition used and the region of interest. Forty-eight percent of knees at autopsy have histologic evidence of osteoarthritis, whereas only 10% of these patients previously reported any clinical manifestations of knee osteoarthritis.4 In general and consistent with this observation, radiologic ­ osteoarthritis   Video available on the Expert Consult Premium Edition website.

is more prevalent than symptomatic osteoarthritis. The Rotterdam study on a population-based cohort 55 years old and younger found that 67% of women and 55% of men had radiographic hand osteoarthritis.5,6 Radiographic osteophytes are seen in only 50% of the distal interphalangeal joints of individuals with hand osteoarthritis in which Heberden’s nodes are detected on clinical examination, however, suggesting that clinical and radiographic measures may not be synchronous.7 The knee is the most clinically significant site affected—the prevalence increases with age so that 53% of women older than 80 years and 33% of men older than 80 years have radiographic knee osteoarthritis.8 Clinically symptomatic knee osteoarthritis is less frequent (16% of 80-year-old women and 5.4% of 80-year-old men). About 11% of individuals older than 64 years have symptomatic knee osteoarthritis.9 More recent data are compatible with the aforementioned studies. The age-standardized and sex-standardized incidence of hand osteoarthritis is 100/100,000 personyears, the age-standardized and sex-standardized incidence of hip osteoarthritis is 88/100,000 person-years, and the age-standardized and sex-standardized incidence of knee ­osteoarthritis is 240/100,000 person-years.10 Hand, hip, and knee osteoarthritis become more frequent with age, and more women are affected than men after age 50. The incidence of knee osteoarthritis is 1% per year in women 70 to 89 years old.10

NATURAL HISTORY OF OSTEOARTHRITIS The natural history of osteoarthritis varies greatly. Osteoarthritis generally develops progressively over several years, although symptoms may remain stable for prolonged periods within that time frame. Previous trauma, causing articular, meniscal, or ligamental damage or joint incongruity, can reveal or accelerate the disorder, especially in knee osteoarthritis. The correlation between clinical outcome and radiographic course is poor at the individual level. Although symptoms can improve, the radiographic picture rarely does—radiographic deterioration is observed in 30% to 60% of patients.11 Symptoms and structural progression are significantly correlated when groups of patients are compared. Although osteoarthritis is considered to be a degenerative chronic process, inflammatory flares can occur during the course of the disease. Inflammatory arthritis, infection, and crystal arthropathies should be excluded in such cases. Flares are not clearly defined, but are characterized by episodes of increased pain (possibly nocturnal), sudden increases in pain with increased morning stiffness, and the development of synovial effusions. Inflammatory flares should be detected and properly defined clinically because they seem 1547

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to be associated with altered rates of joint space narrowing.11 Joints occasionally may be destroyed rapidly, and such destruction is associated with a poor prognosis. Regional localization of such events has attracted discrete clinical syndromes including those affecting hips (“rapid destructive hip arthropathy”), shoulders (“Milwaukee shoulder”), the spine (“pseudotuberculosis spondylodiscitis”), and knees.

Lastly, symptomatic osteoarthritis may be associated with depression and disturbed sleep, which are additional contributors to disability. Osteoarthritis, wherever it occurs, typically causes pain, alters function, and leads to a significant deterioration in the quality of life.17

CLINICAL MANIFESTATIONS

A physical examination should be done to confirm and characterize joint involvement and to exclude pain and functional syndromes arising from other causes, especially periarticluar structures and inflammatory arthritis. A normal examination does not rule out the diagnosis of osteoarthritis, however, especially disease of early nature or of modest severity. Joint enlargement results from joint effusion or bony swelling or both, which are mainly observed in advanced disease. Bony swelling is easily recognized in superficial joints, such as the finger joints or knees. A synovial effusion may be seen during osteoarthritis flares, but also can occur during chronic phases as a persistent feature. It is most easily detected in knees by the evidence of patellar shock (tap) or by the elicitation of a fluid thrill (wave test). Joints are usually tender during active motion testing and under pressure. Limited passive movement can be the first and only physical sign of symptomatic osteoarthritis. Bursitis, tendinitis, muscle spasm, and, especially for the knee, a torn meniscus, can cause the same pain syndrome and must be sought carefully during examination.18 Crepitus, an audible or palpable sensation of crunching or crackling, is commonly felt on passive or active mobilization of an osteoarthritis joint. This sensation is due to the irregularity of the opposing cartilage surfaces or intra-articular debris. Joint deformities reflect advanced disease with joint destruction involving the cartilage and surrounding bone and soft tissue, the articular capsule, and the ligaments. This destruction contributes to misalignment, joint instability, and limb (usually manifest as leg) shortening. Misalignment also is a cause of compartmental knee osteoarthritis (e.g., varus angulation of the knee responsible for medial tibiofemoral damage and valgus angulation for lateral tibiofemoral damage). Fingers also can be misaligned in the presence of Heberden’s or Bouchard’s nodes. The physical examination should include examination of the legs with the patient standing (i.e., to facilitate detection of varus or valgus malalignment). The knees are farther apart than the feet in the frontal plane in cases of varus alignment, whereas the knees are closer together than the feet in cases of valgus alignment. Varus and valgus alignments are responsible for medial and lateral tibiofemoral osteoarthritis. Both can affect the range of motion and accelerate joint space narrowing; they may enhance the development of osteoarthritis.19-22 The presence of anterior laxity also should be evaluated because a decrease in anteroposterior laxity is associated with decreased joint space.23 A joint can lock if loose bodies or fragments of cartilage get into the joint space. This occurrence is rare, but care should be taken to distinguish between the stiffness experienced after prolonged immobilization of a limb and true mechanical locking, which suggests a meniscus lesion. Musculature and joint laxity should be evaluated because periarticular muscle spasms may occur. The circumference

The general symptoms and signs of osteoarthritis are considered first. A detailed description of characteristic features of regional osteoarthritis syndromes is given later. SYMPTOMS OF OSTEOARTHRITIS Symptoms are often initially insidious and can be highly variable, depending on the joint affected, the severity of joint involvement, and the number of joints affected.12 Pain Pain is the first and predominant symptom of osteoarthritis that sends a patient to the general practitioner. Pain typically is worsened by activities such as long distance walking for weight-bearing joints and is alleviated by rest, in contrast to inflammatory disorders. Pain begins within a few minutes of starting an activity and may persist for hours after the activity has ceased. The pain sometimes can have an onset several hours after physical activities, especially in young patients. Although osteoarthritis pain is unusual during the night or at rest, there are exceptions, including in patients with mild osteoarthritis using joints for several hours especially during sport, in advanced osteoarthritis with destructive arthropathy, and in an acute inflammatory flare of osteoarthritis mimicking inflammatory arthropathy. Associated bursitis also can be a source of pain. Pain intensity and joint damage on radiographs are poorly correlated. Finally, there is no agreement as to whether a decrease in atmospheric pressure or a change in the weather increases osteoarthritis pain.13,14 Stiffness and Loss of Movement and Function Stiffness also may occur in the morning, after a period of inactivity, or particularly in the evening. Morning stiffness generally resolves after less than 10 minutes, in contrast to the prolonged (usually >30 minutes) stiffness seen in inflammatory disorders. Loss of movement and function reflected in limited range of motion observed at physical examination is sometimes the main reason for a visit to the practitioner. Patients report limitations in their ability to perform day-to-day activities, such as kneeling for knee osteoarthritis, or cutting one’s toenails for hip osteoarthritis.15 Osteoarthritis also can hamper stair climbing, walking, and performing household chores. Limited joint function is caused by several mechanisms, including pain, decreased motion related to reduced joint space, diminished muscle strength, and instability. Joint proprioceptor sensitivity may be altered; its relationship to disability is less clear as yet, but is probably not caused by pain alone.16

PHYSICAL EXAMINATION

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of the quadriceps should be measured and compared with that of the opposite side—this may be particularly informative in asymmetric disease. A weak quadriceps femoris is a known disability factor in knee osteoarthritis. This weakness can more convincingly explain the knee “giving way” than the often suggested ligament instability. A lax joint is defined by the excess displacement or rotation of the tibia with respect to the femur in the varus-valgus direction. Joint laxity increases functional disability owing to weak muscles.24 Soft tissues and bursa areas should be examined in parallel because they can be amenable to local treatment, such as corticosteroid injections. Gait also must be assessed because hip or knee osteoarthritis results in a characteristic gait. It also is useful for examining the consequence of the pain. The appropriate use of a cane may be assessed during examination. Caution should be exercised in attributing pain to the correct region (e.g., patients with hip osteoarthritis may report pain in the knee region because of referred pain or biomechanical dysfunction). In these cases, moving the knee causes no pain, whereas hip movement is painful, and the range of hip motion is limited. Patients with hip osteoarthritis also have symptoms mimicking a cruralgia. Careful neurologic and spine examination usually rules out this diagnosis.

IMAGING The diagnosis of osteoarthritis in patients presenting with knee, hip, or hand pain is based on a comprehensive assessment of the joint, including evaluation of symptoms and signs that favor this diagnosis and exclude other diagnoses. The diagnosis of osteoarthritis is often obvious after an interview and physical examination. In straightforward presentations, radiologic investigation often is unnecessary to confirm the diagnosis of hand or forefoot osteoarthritis. Some regions and clinical scenarios require a radiologic examination, however, to exclude other diseases, including avascular osteonecrosis, Paget’s disease, algoneurodystrophy, inflammatory arthropathies, and stress fractures. Less commonly involved locations, such as the ankle, shoulder, or elbow, also require radiologic examination. Radiographic assessment not only is helpful to diagnose osteoarthritis, but also is useful to establish the severity of joint damage; to monitor disease activity, progression, and response to therapy; and to look for complications of the disorder or the treatment.25 Standard radiographs are the most common investigations, depending on the region involved. Weight-bearing radiographs are mandatory for knee and hip osteoarthritis. A standard radiograph cannot diagnose early osteoarthritis, however. The radiologic features of osteoarthritis at various sites are shown in Figure 90-1. Osteophytes at the joint margin,

C

B

A

D

1549

E

Figure 90-1  A-E, Radiologic features of osteoarthritis. A, Medial femoro-tibial knee osteoarthritis. B, Distal interphalangeal joint with ­osteoarthritis. C, Osteoarthritis of the first metatarsophalangeal joint. D, Right ankle osteoarthritis. E, Hip osteoarthritis. (Figures provided by www.lecofer.org.)

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indicating new bone formation, are the most characteristic feature of osteoarthritis and usually precede joint space narrowing.25,26 Subchondral bone sclerosis and joint space narrowing are classically seen in more advanced osteoarthritis. Clinical symptoms and radiographic findings are poorly correlated, however; many joints with radiographic evidence of osteoarthritis remain asymptomatic, and the joints of many patients with severe symptoms can appear only marginally affected on x-ray.25 Demineralization is not a classic ­feature of osteoarthritis, and its presence strongly suggests an inflammatory arthropathy. Joint space narrowing not only is related to a decreased volume of articular cartilage, but also to meniscal cartilage lesions and cartilage extrusion.27 Although standard x-rays are useful for monitoring the evolution of osteoarthritis, there are no clear guidelines about the optimal frequency of radiographs that can best inform practice. Classically, evolving radiographic features include progressive joint space narrowing, subchondral sclerosis, and joint line osteophytosis. These are the radiologic features of the most common form of osteoarthritis—“hypertrophic” osteoarthritis with bone construction. The other form, “atrophic” osteoarthritis, is rare, characterized by an absence of osteophytes and sclerosis; it usually involves the hip. Other investigations are rarely performed to confirm the diagnosis of osteoarthritis, but they are sometimes useful to exclude alternative possibilities in a difficult differential diagnosis. All the tissues involved in osteoarthritis, including cartilage lesions, fluid effusion, subchondral bone marrow edema, low-grade synovitis, and meniscus or ligament lesions, can be seen by magnetic resonance imaging (MRI).28 MRI is useful for excluding tumor, algoneurodystrophy, or avascular osteonecrosis. The pain and progression of knee osteoarthritis seem to be associated with the bone marrow edema seen on MRI, but this is controversial.29-35 Although the usual term used is bone marrow edema, autopsy examinations have revealed that necrosis, fibrosis, and abnormal remodeled trabeculae are the most common features.30 The presence of bone resorption also is clearly recognized as part of osteoarthritis progression.29,36-38 The meniscus tears seen by MRI are common in middle-aged and older adults, with or without knee pain. Although MRI accurately detects meniscus damage or injury of the anterior cruciate ligament, which are known to be associated with increased osteoarthritis progression, this finding does not influence therapeutic management and should not lead to aggressive procedures.37,39 MRI is now being used to assess the quantity and function of cartilage, synovium, and bone. The routine use of MRI in osteoarthritis clinical practice is not yet recommended, however; it should be used only for clinical research purposes at this time. Ultrasound is presently useful only for detecting joint effusions, including a minimal effusion that is below the limit of detection on clinical examination, and changes in cartilage, such as fibrillation of cartilage or cleft ­formation and the proliferation of synovium and osteophytes.40-43 Popliteal cysts also can be visualized by ultrasound, and potential ­complications, including compression of adjacent vascular structures, can be detected. Many studies are presently evaluating the advantages of this procedure in terms of early diagnosis and evaluation of pain symptoms, severity, and prognosis.44-46 Ultrasonography has been ­studied ­extensively

in knee osteoarthritis; it may be useful for detecting inflammatory flares of osteoarthritis in individual cases.45,47 Ultrasonography also may be useful in hand osteoarthritis, to differentiate between erosive and nonerosive osteoarthritis.48 Ultrasonography can be used to perform aspirations and injections within the joint and periarticular tissue.49 Ultrasound imaging is limited, however, by its inability to visualize the whole cartilage surface. Artifacts caused by the position of the probe can lead to misinterpretation. ­Ultrasonography is presently used in clinical trials, but it is likely to have a place in clinical practice for diagnosing the early phase of osteoarthritis. The examination and the interobserver and intraobserver variations must be standardized before it can be used widely in daily practice. Arthroscopy visualizes cartilage, synovial membranes, osteophytes, and meniscal lesions. This approach, similar to MRI, may detect findings of dubious significance (e.g., meniscal lesions are frequent in patients >60 years old, but rarely the cause of pain). Dissection of the meniscus could be highly deleterious by accelerating the progression of osteoarthritis.50

LABORATORY TESTS Blood tests are not routinely indicated in cases of uncomplicated chronic pain arising from clearly defined osteoarthritis. The erythrocyte sedimentation rate and concentration of the C-reactive protein are usually within the normal range for age. Low titers of rheumatoid factors can be found, reflecting the median age of patients with osteoarthritis and not differing in that respect from control populations. Some laboratory tests may be done to rule out a metabolic arthropathy (e.g., gout) or inflammatory arthritis, or to investigate the adverse effects of drugs pending the characteristics of the presentation. Synovial fluid should be examined if another arthropathy or septic arthritis is suspected. Crystal analysis by polarized light microscopy is an important part of this assessment. Analysis of synovial fluid reveals a white blood cell count of less than 2000/mm3, sterile, without any crystals.51 Biochemical markers of cartilage or bone turnover or remodeling are not currently assayed in the day-to-day management of osteoarthritis because no single marker is yet adequate for predicting or monitoring osteoarthritis in an individual patient. In the future, biomarkers probably will be used in daily clinical practice, in combination with other risk factors such as clinical or imaging findings, to predict the clinical course of osteoarthritis.52

ETIOLOGY AND PREDISPOSING FACTORS SECONDARY OSTEOARTHRITIS Because osteoarthritis may follow almost any established joint disorder, osteoarthritis is considered to be primary if it is idiopathic and secondary in cases of previous injury or disease of the target joint. Table 90-1 lists disorders responsible for secondary osteoarthritis. It is not always easy to distinguish between primary and secondary osteoarthritis, however, because a significant proportion of subjects who develop secondary osteoarthritis have some predisposition to osteoarthritis that may operate independent of the prior condition. An interview and a physical examination may

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help the physician to identify an etiology. Along with these clinical features, radiographs can help diagnose some secondary osteoarthritis conditions, such as chondrocalcinosis and Paget’s disease. PREDISPOSING FACTORS A risk factor must fulfill several criteria, including a time relationship, a strong statistical association after exclusion of confounding factors, consistent published findings, and biologic plausibility. The predisposing risk factors to idiopathic osteoarthritis act by increasing the susceptibility of Table 90-1  Etiologies of Secondary Osteoarthritis Metabolic Crystal-associated arthritis (gout, calcium pyrophosphate dihydrate arthropathy, pseudogout) Acromegaly Ochronosis Hemachromatosis Wilson’s disease Anatomic Slipped femoral epiphysis Epiphyseal dysplasias Blount’s disease Legg-Calvé-Perthes disease Congenital dislocation of the hip Unequal leg lengths Hypermobility syndromes

joints to injury, by directly damaging joints, or by impairing the process of repair of damaged joint tissue. Table 90-2 shows the main risk factors identified to date. Clinicians must differentiate between factors of occurrence and factors of progression. Clinicians also should distinguish “not modifiable” risk factors, which are valuable from a pathophysiologic point of view and in groups, and “modifiable” risk factors, which are potentially more valuable for individuals in routine practice. Obesity Obesity seems to be independently implicated in the pathogenesis of osteoarthritis and is one of the strongest risk factors for knee osteoarthritis because it precedes knee osteoarthritis by many years. Obesity is less strongly associated with hip osteoarthritis. Obesity not only is associated with weightbearing activities that cause cartilage breakdown, but also with non–weight-bearing joints secondary to different systemic factors (Fig. 90-2).53 Elevated blood glucose and Creactive protein (high-sensitivity assays) are associated with the risk of knee osteoarthritis and its progression in women. The link between obesity and osteoarthritis seems stronger in women than in men. Systemic Risk Factors

Traumatic Major joint trauma Fracture through a joint or osteonecrosis Joint surgery (e.g., meniscectomy) Chronic injury (occupational arthropathy) Inflammatory Any inflammatory arthropathy Septic arthritis

Patient age is the best recognized risk factor because the incidence of radiographic and symptomatic osteoarthritis increases sharply with age; this is probably mediated by increases in systemic and local factors, including obesity, ligament laxity, and impaired neuromuscular joint protective mechanisms.54-56 Women are at greater risk than men of developing hand, knee, and generalized osteoarthritis.10,57-59 In contrast, the frequency of hip osteoarthritis increases at about the same rate in women and men, but the disease seems to progress more rapidly in women.11 This difference

Table 90-2  Risk Factors for the Occurrence or Progression of Osteoarthritis in Knees, Hips, and Hands Location Disease Progression

Knee

Hip

Hand

Occurrence of osteoarthritis

Age151 Female151 Physical activity84,154,155 BMI84,156 Bone density157 Previous injury62,84,155,156,158-160 Hormone replacement ­therapy156,161,162 Vitamin D163 Smoking (protective)164 Alignment82 Quadriceps strength99 Intense sport activities98,165 Age173 Vitamin D163 Hormone replacement therapy174 Alignment83 Hydrarthrodial osteoarthritis171 Synovitis175 Intense sport activities98 Subchondral bone edema on MRI29

Age149 Physical activity166,167 BMI166,168 Previous injury169 Intense sport activities99

Age149 Grip strength170 BMI171 Occupation172 Intense sport activities172

Age Symptomatic activity58 Gender58 Intense sport activities98

Unknown

Progression of osteoarthritis

1551

BMI, body mass index; MRI, magnetic resonance imaging.

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Mechanical stress

Adipokines

Atherosclerosis

Diabetes ( AGE products)

Metabolism dysfunction bone-cartilage Osteoarthritis Figure 90-2  Hypothesis concerning the relationship between obesity and osteoarthritis. AGE, advanced glycation end-products.

between men and women suggests that sex hormones are involved. Involvement of sex hormones also is suggested by the fact that the occurrence of hip and knee radiographic osteoarthritis is associated with a lack of postmenopausal estrogen replacement. This link seems less clear for osteoarthritis symptoms.60 A link between bone mineral density and the occurrence of osteoarthritis has been reported, but it remains to be elucidated further. Although individuals with a high bone density are more likely to develop osteoarthritis, disease progression may be associated with local and general bone loss.61-63 The prevalence of osteoarthritis in different ethnic groups and races has been extensively studied. There is some bias—differences in weight and daily and occupational activities could explain the variability between African-American, white, and Chinese subjects.11 Some specific genetic factors have been identified in a few families with osteoarthritis.64-73 The phenotype of these patients is not similar to that of idiopathic osteoarthritis, however, having features of chondrodysplasia rather than osteoarthritis.67,74 Gene association still poses difficult interpretation because idiopathic osteoarthritis is a polygenic disease with various phenotypes. Future studies on the genetic factors of osteoarthritis are likely to lead to new insights into the pathogenesis of osteoarthritis.73,75,76 Local Mechanical Risk Factors Joint Deformity.  Joint deformity is associated with the development of osteoarthritis. Congenital abnormalities, such as acetabular ­dysplasia and slipped capital femoral epiphysis of the hip, can be considered as etiologies of secondary osteoarthritis. They act by causing the load distribution within the joint to be abnormal.77-81 Angular misalignment is the most potent risk factor for deterioration of the joint structure because it increases the degree of focal loading, creating a vicious cycle of joint damage, contributing to the development and progression of single compartment osteoarthritis of the knee.36 About 65% of the weight-bearing load is transmitted through the medial compartment in a normally aligned knee, which explains the greater frequency of tibiofemoral medial knee osteoarthritis.81 Varus misalignment increases the risk of joint space narrowing threefold to fourfold.82 Long-standing obesity seems to increase the risk of structural radiographic progression in cases of moderate misalignment, presumably owing to the combined effect of the focus of load from misalignment and the excess load from increased weight.83

Acute Injury and Repetitive Joint Loading.  Acute joint injuries, especially anterior cruciate ligament damage or tears of the knee meniscus, are associated with knee osteoarthritis and its progression.84-88 There is a combined effect of the injury itself and its biomechanical consequences, which alter load distribution on the joint.88 An acute knee injury is more likely to lead to osteoarthritis if there is an associated systemic risk factor of osteoarthritis. The development and progression of osteoarthritis may not be prevented, however, even if the damaged anterior ­cruciate ligament is surgically repaired, and the risk of developing osteoarthritis is 10-fold greater.89,90 Osteoarthritis often manifests as a slight reduction of joint space about 10 to 20 years after anterior cruciate ligament injury, but usually without any major clinical symptoms. Meniscus damage may play an important role in osteoarthritis pathophysiology. Whether meniscus damage or cartilage degradation occurs first is unknown, however. A torn meniscus and extrusion seem to be strong risk factors for the development and progression of knee osteoarthritis. Meniscectomy increases the risk of knee osteoarthritis twofold, and more if it is combined with anterior cruciate ligament damage or other ligament injury. There is a significant risk of radiographic tibiofemoral osteoarthritis 21 years after the surgical removal of a meniscus following knee injury, with the relative risk estimated to be 14-fold.87 Mixed patellofemoral and tibiofemoral osteoarthritis is common in individuals who have undergone a meniscectomy.91 Obesity dramatically increases the risk of developing osteoarthritis after medial or lateral meniscectomy.92 Partial meniscus resection is associated with less radiographic osteoarthritis over time than is total meniscectomy.92 Radiographic changes can be observed after 15 to 20 years. Repetitive activities with joint overuse increase the risk of developing osteoarthritis, particularly in the knee, hip, and distal interphalangeal joints. Obesity amplifies this effect on the knee.93,94 Professional and elite sporting activities also are associated with the development of osteoarthritis, even without major injury.95,96 Reasonable recreational sports activities leading to low-grade repetitive impact, such as recreational running, are not likely to be harmful for most individuals, in terms of the occurrence or progression of hip and knee osteoarthritis in the absence of sudden impacts.97,98 Muscle Strength and Weakness.  Quadriceps weakness is a primary risk factor for knee pain, disability, and the progression of knee osteoarthritis.99 Data are conflicting, however, as to whether quadriceps strength has a preventive or aggravating effect on osteoarthritis progression. Although quadriceps weakness has been associated with the development of radiographic knee osteoarthritis, quadriceps muscle strength also is associated with faster progression in deformed knees, suggesting that local biomechanical factors influence the load distribution.11 Consequence of Identification of a Risk Factor.  Some of the most important risk factors of osteoarthritis identified to date are “nonmodifiable”; these include female gender, joint malformation, and previous trauma. These nonmodifiable risk factors may help, however, to target measures

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designed to prevent osteoarthritis in clearly defined subpopulations at high risk of developing osteoarthritis. The finding of a modifiable risk factor of osteoarthritis does not mean that prevention or treatment of it can influence the ultimate osteoarthritis profile. Physical exercise and weight reduction have been shown to affect pain and function in knee osteoarthritis, but it is unclear that modifying footwear is effective, or that muscle strengthening leads to structural progression in patients with misaligned or lax knees.100

Table 90-3  American College of ­Rheumatology ­Radiologic and Clinical Criteria for Knee and Hip ­Osteoarthritis Osteoarthritis if the Items Are Present Hand

Clinical 1. Hand pain, aching, or stiffness for most days or prior months 2. Hard tissue enlargement of   ≥2 of 10 selected joints* 3. Metacarpophalangeal joint swelling in ≥2 joints 4. Hard tissue enlargement of ≥2 distal interphalangeal joints 5. Deformity of ≥2 of 10 selected hand joints*

1, 2, 3, 4 or 1, 2, 3, 5

Hip

Clinical and Radiographic 1. Hip pain for most days or   prior months 2. ESR of <20 mm at the first   hour 3. Femoral or acetabular ­osteophytes on radiographs 4. Hip joint space narrowing on radiographs

1, 2, 3 or 1, 2, 4 or   1, 3, 4

Knee

Clinical 1. Knee pain for most days or   prior months 2. Crepitus on active joint   motion 3. Morning stiffness lasting   ≤30 min 4. Age ≥38 yr 5. Bony enlargement of knee   on examination

1, 2, 3, 4 or 1, 2, 5 or 1, 4, 5

Clinical and Radiographic 1. Knee pain for most days or   prior months 2. Osteophytes at joint margins   on radiographs 3. Synovial fluid typical of ­osteoarthritis (laboratory) 4. Age ≥40 years 5. Crepitus on active joint   motion 6. Morning stiffness lasting   ≤30 min

1, 2 or 1, 3, 5, 6 or   1, 4, 5, 6

OSTEOARTHRITIS ASSESSMENT, CATEGORIZATION, AND OUTCOMES Most available diagnostic or prognostic criteria are much more useful in clinical trials than in routine clinical practice. Assessment in clinical trials must be separated from assessment in routine practice. There are a variety of clinical and radiologic diagnostic criteria, different scoring systems according to the target joint for a clinical or a radiologic definition of osteoarthritis, and more recently emerging guidelines for conducting clinical trials.101,102 CRITERIA FOR DEFINING OSTEOARTHRITIS The groups of patients with osteoarthritis who participate in clinical trials testing new therapies should be as homogeneous as possible, and need to fulfill a set of criteria that includes the clinical and radiologic items proposed by the American College of Rheumatology (ACR) (Table 90-3).103-105 Osteoarthritis also should be classified as primary or secondary, specifying the cause of the secondary osteoarthritis. International guidelines proposed by the Osteoarthritis Research Society International suggest that secondary osteoarthritis should be excluded.101 The sensitivity and specificity of the ACR hip criteria are estimated to be 91% and 89%, whereas the sensitivity and specificity of ACR knee criteria are estimated to be 91% and 86%. The osteoarthritic changes seen on x-ray have not been found to add to the ACR diagnostic criteria for hand osteoarthritis; the sensitivity is 92%, and the specificity is 98%. The ACR criteria are very specific. These criteria are useful for differentiating patients with osteoarthritis from patients with inflammatory disorders because the sensitivity is less impressive, but not for differentiating patients with early osteoarthritis from healthy controls. Their use in ­population-based research is less clearly defined, and the prevalence of osteoarthritis is underestimated compared with a definition based on radiographic criteria.106-109 The radiologic definition of osteoarthritis is used in epidemiologic studies and in many clinical studies. The most commonly used grading system is that of Kellgren and Lawrence, based on the presence of osteophytes, joint space narrowing, subchondral sclerosis, and bony cysts.110 This system divides osteoarthritis into five grades (0 to 4), giving a global score at various joint sites compared with a radiographic atlas. A score of 2 or more traditionally has been considered to be a definitive radiographic diagnosis of osteoarthritis and has been widely used in research. The Kellgren and Lawrence grade 1 (doubtful) is more likely to evolve to a patent osteoarthritis than is grade 0, suggesting that it corresponds to an early disease

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*Ten selected joints include bilateral second and third interphalangeal proximal joints, second and third prximal interphalangeal joints, and first carpometacarpal joint. ESR, erythrocyte sedimentation rate.

s­ ubgroup.111 Because the Kellgren and Lawrence grading system relies predominantly on osteophyte size to determine osteoarthritis severity, the atrophic form of osteoarthritis, which consists mainly of joint space narrowing, is underestimated. Many studies have shown a lack of agreement between knee pain and radiographic osteoarthritis produced by the Kellgren and Lawrence grading, with radiographic osteoarthritis detected in 15% to 53% of subjects with knee pain.25 Similar results have been obtained for hip osteoarthritis.112 MRI and biochemical markers should be included in such criteria in the future.52,75,113 Many questions remain, such as the type of target joint to be studied in clinical trials on hand osteoarthritis. The definition of the ­trapeziometacarpal joint

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as a separate entity in hand osteoarthritis is controversial. It is often associated with interphalangeal osteoarthritis, but may be involved alone in cases of constitutional hypermobility.114-118 OSTEOARTHRITIS CLINICAL ASSESSMENT The assessment of a patient with osteoarthritis should include discrete evaluations of pain and function. A patient’s overall, global pain, or disability assessment can be evaluated using a visual analog scale such as a 5-point Likert scale (none, mild, moderate, severe, very severe) or a 100-mm visual analog scale. Pain also can be assessed indirectly by estimating the symptomatic treatment required, such as the number of days per week that drugs are required or their consistent dose usage.119 Single questions about pain can be used, but the activity causing pain should be specified (e.g., resting, nocturnal, stair climbing, weight bearing). One of the instruments widely used to assess pain and disability is the Western Ontario and McMaster Universities (WOMAC) composite index.120 It is used mainly for the knee. In addition to the WOMAC questionnaire pain subscale (Table 90-4), a 0-to-100 mm visual analog scale is sometimes used to answer the question: “What pain do you have after activities in your daily life?” Functional disability resulting from knee or hip osteoarthritis usually is evaluated using the WOMAC function subscale, which is a questionnaire of 17 items related to daily activities, and the Lequesne’s algofunctional index

Table 90-4  WOMAC Questionnaire Pain Subscale (5 Questions) How much pain do you have… Walking on a flat surface? Going up or down stairs? At night while in bed? Sitting or lying? Standing upright? Stiffness Subscale (2 Questions) How severe is your stiffness after first waking in the morning? How severe is your stiffness after sitting, lying down, or resting later in the day? Function Subscale (17 Questions) What degree of difficulty do you have with… Descending stairs? Ascending stairs? Rising from sitting? Standing? Bending to floor? Walking on a flat surface? Getting in or out of a car? Going shopping? Putting on socks or stockings? Rising from bed? Taking off socks or stockings? Lying in bed? Getting in and out of the bath? Sitting? Getting on or off the toilet? Heavy domestic duties? Light domestic duties? WOMAC, Western Ontario and McMaster Universities.

(Table 90-5), which is an index including questions related to pain, performance, and function impairment.121 The Health Assessment Questionnaire also can be used.122 The Knee Osteoarthritis Outcome Score (KOOS) has been validated more recently (http://www.koos.nu).123,124 It is a 42-item, self-administered, knee-specific questionnaire covering several types of knee injury and osteoarthritis. It consists of five subscales (pain, other symptoms, function in daily living, function in sport and recreation, and kneerelated quality of life). Standardized answer options are given (five Likert boxes), and the response to each question is scored from 0 to 4. A score of 0 to 100 is calculated for each subscale; 100 is the best result.125 A difference of 10 points is considered to be clinically significant. The Foot and Ankle Outcome Score (FAOS) and Hip disability and Osteoarthritis Outcome Score (HOOS) also are available.126,127 The FAOS has been used mainly in patients with lateral ankle instability, Achilles tendinosis, and plantar fasciitis. Impaired function in hand osteoarthritis can be assessed in clinical trials using the Functional Index for Hand Osteoarthritis (FIHOA), and the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) has been validated more recently (Table 90-6).128-131 The FIHOA is a 10-item, investigator-administered questionnaire that is relevant and reliable and has been well validated externally and

Table 90-5  Lequesne’s Algofunctional Index Pain or Discomfort During nocturnal bed rest None or insignificant Only on movement or in certain   ­positions With no movement

Points* 0 1 2

Morning stiffness or regressive pain   after rising ≤1 min >1 min, but <15 min

0 1

After standing for 30 min

0 or 1

While walking None Only after walking some distance After initial walking and increasingly   with continued walking

0 1 2

With prolonged sitting (2 hr)

0 or 1

Maximum distance walked   (even with pain) Unlimited >1 km (>0.6 mile) but limited About 1 km (0.6 mile) in about   15 min 500-600 m (1640-2952 ft or   0.31-0.56 mile) in about 8-15 min 300-500 m (987-1640 ft) 100-300 m (328-985 ft) <100 m (<328 ft) With one walking stick or crutch With two walking sticks or crutches Day-to-day activities Put on socks by bending forward Pick up an object from the floor Climb up and down a standard flight   of stairs Get into and out of a car

0 1 2 3 4 5 6 1 2 0 or 2 0 or 2 0 or 2 0 or 2

*0, without difficulty; 1 (or 0.5 or 1.5), with difficulty; 2, unable.

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Table 90-6  Functional Index for Hand Osteoarthritis Are you able to turn a key in a lock? Are you able to cut meat with a knife?

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Are you able to cut cloth paper with a pair of scissors?

General Considerations

Are you able to fit a full bottle with the hand?

Osteoarthritis tends to affect the distal interphalangeal joints, thumb base, knee, hip, and intervertebral facet joints. More than one joint is commonly involved, and there is a significant association between contralateral joints that is stronger than the association between different joint groups. Knee and hip osteoarthritis are each associated with hand osteoarthritis; the association between knee and hand osteoarthritis is stronger.139-143 Wrists, elbows, metacarpophalangeal joints, and shoulders are usually less likely to be affected by osteoarthritis.

Are you able to clench your fist? Are you able to tie a knot? For women: are you able to sew? For men: are you able to use a screwdriver? Are you able to fasten buttons? Are you able to write for a long period of time? Would you accept a handshake without reluctance? Developed by Dreiser RL, Maheu E, Guillou GB: Sensitivity to change of the functional index for hand osteoarthritis. Osteoarthritis Cartilage 8(Suppl A): S25-S28, 2000.

­internally.132 The AUSCAN is a self-administered questionnaire investigating pain, stiffness, and function. This index has been designed specifically for use with hand osteoarthritis patients with acceptable reliability, construct validity, and responsiveness.130 EVALUATING STRUCTURAL SEVERITY Imaging Structural severity is still difficult to evaluate. Standard plain radiographs have been extensively evaluated and remain the “gold standard” in clinical trials, even though this method has many weaknesses.35,133 Structural progression has not yet been accurately defined, despite the fact that it is crucial for evaluating an osteoarthritic drug that has the potential to modify structure. MRI and ultrasonography should be useful tools for investigating alterations of joint structure in the future. MRI also can be used to study cartilage, subchondral bone, and synovial tissue simultaneously. Biologic Markers Many laboratories are working to find surrogate biomarkers that can reveal a correlation between joint space narrowing and the concentration of specific biologic parameters in the blood or urine.113 These biologic markers include components of matrix proteins, including several collagens and cross-linked derivative peptides and matrix metalloproteinases. There is no consensus yet as to the optimal biomarker. Time to Total Joint Replacement Total joint replacement can be considered as the best end point for clinical trials evaluating disease-modifying osteoarthritis drugs. Great efforts are being made to validate a composite index, which could define states of severity and “need for total joint replacement.”134 Many parameters other than the severity of the disease itself influence the decision for surgery, however, including socioeconomic factors and access to health services.135-138

Knee Osteoarthritis can involve the medial tibiofemoral, the lateral tibiofemoral, and the femoropatellar compartments. The lateral tibiofemoral compartment is involved mainly in women who have a genu valgum deformity. The precise location of pain can indicate which compartment of the joint is involved. Patients also sometimes report knee instability—the knee “gives way.” This instability is likely linked to decreased muscle strength rather than true meniscus damage. Posterior pain can be due to an abundant effusion. Physical examination for knee osteoarthritis should begin by investigating the gait, using a slow walk to check for an extension defect. Thereafter, any misalignment (genu valgus or genu varus) should be sought, and the presence of bone swelling should be noted (Fig. 90-3A). A popliteal (Baker’s) cyst communicating with the joint space is common and may be complicated less often by distal vascular thrombosis. Acute cyst rupture may mimic venous thrombus and should be considered in “Doppler negative” leg swelling in the acute setting. Local tenderness along the joint line is characteristic of femorotibial osteoarthritis. Crepitus is detected on passive motion of the patella or knee flexion-extension testing. The range of motion may be normal or limited by structural alterations or abundant effusion. Periarticular structure examination may reveal anserine bursitis or infrapatellar or prepatellar bursitis. Trochanteric bursitis also can cause pain radiating through the tensor fascia lata and iliotibial band to the lateral part of the knee. An acute tear of the anterior cruciate ligament may cause pain, but is unusual in middle-aged subjects. A positive Lachman’s test may be elicited. The circumference of the quadriceps muscle should be noted to detect any atrophy. Finally, the hip should be examined routinely because it may refer pain to the knee. The syndrome of femoropatellar osteoarthritis is very specific: Pain occurs mainly during climbing or descending stairs; pain during walking on level ground is usually a symptom originating in the femorotibial compartment. Involvement of the femoropatellar compartment can cause anterior or posterior pain or both. Femoropatellar pain is produced by the patella pressing on the femoral condyles, or after patella subluxation or blocking elevation of patella during quadriceps contraction when the knee is extended. Femoropatellar osteoarthritis is usually better tolerated than femorotibial osteoarthritis, but severe disability is possible. The

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A

B

Figure 90-3  A, Bone swelling in knee osteoarthritis: Right knee effusion with flexion deformity. B, Heberden’s nodes in hand osteoarthritis responsible for misalignment and disfigurement of fingers. (Figures provided by www.lecofer.org.)

femoropatellar compartment is investigated using a specific x-ray axial incidence with variable degrees of knee flexion. Radiographs should include bilateral, comparative images of both knees. The femorotibial compartment is evaluated by a standard standing anteroposterior radiograph of the extended knee to take into account any weight-bearing effect. The “schuss” view is useful for assessing the pos­ terior part of the femorotibial compartment, where early decrease in joint space may be evident.144 Squaring of the femoral condyle, intercondylar spurring, and varus or valgus misalignment of the affected limb can occur. Radiographs of the hip, knee, and ankle made on one long film with the patient standing may identify angular deformity. The patient must be able to place his or her full weight on the affected limb for a true measurement of limb deformity. A mechanical axis of 0 to 3 degrees of varus is considered to be within normal limits.145 Hand Osteoarthritis Hand osteoarthritis results in pain and reduced hand mobility and grip force, limiting activity and restricting participation in personal, occupational, and group functions. Women are more likely to have hand osteoarthritis than men, and genetic factors explain familial aggregation.146 It can affect the distal interphalangeal, proximal interphalangeal, and first carpometacarpal joints of the hand. The metacarpophalangeal joints are less commonly involved, but if implicated, consideration should be given to complicating factors, such as a coincident or causal metabolic arthropathy. Patients with hand osteoarthritis express three primary complaints: pain, disfigurement, and disability, with impaired manual dexterity a significant consequence, especially with involvement of the first metacarpophalangeal joint. Bony enlargements of the proximal interphalangeal joints are called Bouchard’s nodes, whereas enlargements of the distal

­interphalangeal joints are called Heberden’s nodes (Fig. 903B). They can be associated with mucinous cysts. As the disease progresses there is characteristic loss of mobility. In contrast, hypermobility may protect joints from radiographic osteoarthritis of the proximal interphalangeal joints.147 The disease course is usually insidious, sometimes with acute inflammatory phases mimicking inflammatory arthropathies. Sagittal deviation of the distal phalanges is frequent. Osteoarthritis frequently involves the first carpometacarpal joints, causing intense pain, tenderness, squared deformation of the radial base of the thumb, and fixed adduction that leads to severe disability. de Quervain’s tenosynovitis can be associated throughout the disease process and exacerbate this functional limitation. Posteroanterior radiographs of both hands, including the wrists, should reveal characteristic features of osteoarthritis. Erosions of the interphalangeal distal joints on radiographs (seagull erosions) are prominent features in a subset of osteoarthritis patients.148 This disorder is more frequent in middle-aged women and has an acute, inflammatory clinical presentation, leading to joint deformity and occasional ankylosis. The fingers are often significantly completely deformed within a few years, with firm bony swelling and consequent reduced joint motion—at advanced stages, flares and pain tend to subside. Patients with erosive osteoarthritis may have signs of inflammation in the interphalangeal joints. Synovitis can occur; in such cases, the differential diagnosis should consider psoriatic or less likely rheumatoid arthritis. Very rarely, multicentric reticular histiocytosis can manifest with similar features. Hip Osteoarthritis In hip osteoarthritis, hip pain is classically present during weight bearing; it is located in the buttocks and the groin region, and may radiate down to the anterior thigh. Less commonly, the sole presenting feature may be knee pain.

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months of the first ­symptoms being recognized. The common etiologies of secondary hip osteoarthritis include congenital dysplasia, avascular osteonecrosis, and previous trauma.

Superolateral Superointermediate

Superomedial

Medial

Axial

Spinal Osteoarthritis Spine and peripheral osteoarthritis share anatomic similarities and common pathophysiologic processes. The posterior facet articulations are true diarthrodial joints and as such are susceptible to osteoarthritis. Common regions of involvement include the cervical and lumbar spine, but the dorsal spine only exceptionally because of the stability provided by the thoracic cage. Osteophytes of the vertebrae can narrow the foramina and compress nerve roots. Patients also report, in addition to pain, radicular symptoms with pain, weakness, and numbness of the arms or legs. Foot and Ankle Osteoarthritis

Figure 90-4  Patterns of osteoarthritis of the hip. (From Harris E, Budd R, Firestein G, et al [eds]: Kelley’s Textbook of Rheumatology, 7th ed. ­Philadelphia, WB Saunders, 2005.)

Patients often report significant disability during activities of daily living (e.g., finding it difficult to reach their feet to cut their toenails or to tie their shoelaces) (see Table 90-5). Flares are frequent, with pain at night and morning stiffness, sometimes associated with the presence of an effusion. Advanced osteoarthritis is often preceded by a progressive phase with increasing aggravation of symptoms (between 3 months and 3 years). The symptoms seldom improve except in concentric hip osteoarthritis with marked ­osteophytosis. Limited range of movement is the main physical sign of hip osteoarthritis, although it is not always present. Limited movement may be seen in early disease only when extension is tested. Groin pain can be reproduced by palpation during physical examination. This pain also can be reproduced by passive movement of the hip, especially on internal rotation and flexion. Quadriceps muscle weakness is a further common finding. The main differential diagnoses are cruralgia (in which neurologic signs are usually present), psoas and iliopsoas lesions, and trochanteric bursitis (characterized by pain at the external surface of the hip and thigh). Consideration also should be given to intrapelvic lesions if clinical examination is entirely normal in the face of a convincing history. Radiologic examination should be bilateral and comparative, including a false profile view.149 Osteoarthritis can involve several compartments of the hip (Fig. 90-4; see Fig. 90-1). The superior-external pole is most often involved (superior-lateral, superior-intermediate and superior-medial). Medial osteoarthritis is much rarer, occurs mainly in women, and progresses slowly. Hip osteoarthritis may be rapidly destructive, defined by Lequesne and Ray150 as joint space narrowing at greater than 2 mm/yr (i.e., a loss of >50% of the joint space within 1 year). Bone sclerosis and osteophytes are rare in such patients. A hip joint replacement usually is considered within a few

Osteoarthritis commonly attacks the first metatarsophalangeal joint. Patients have difficulty walking, and the overlying skin can appear inflamed. Deformation in valgus is frequent (hallux valgus), and there may be ankylosis of the joint (hallux rigidus). There are usually radiologic features of foot and ankle osteoarthritis, even in subjects younger than 40 years old.151 The tarsal joints may be involved in cases of pes planus. Tibiotalar and subtalar osteoarthritis are generally due to trauma, misalignment, or neuropathic arthropathy. Shoulder Osteoarthritis Osteoarthritis is less common in the shoulder than in weightbearing joints. Pain occurs at movement, but pain at night also is common. Examination reveals limitation of passive movement, with rotation particularly being reduced. Shoulder osteoarthritis sometimes follows lesions of the rotator cuff, which promote ascension of the humeral head. Radiographs can show a distinction between eccentric osteoarthritis and noneccentric osteoarthritis, which is useful for therapeutic decision making. The long-term outcome of a shoulder prosthesis is better in cases of eccentric osteoarthritis. Milwaukee shoulder is a particular form of shoulder osteoarthritis characterized by hydroxyapatite deposits and severe destruction of the joint.152 The differential diagnosis includes acromioclavicular disease, in which pain is elicited on direct palpation of this particular joint. The acromioclavicular joints are often affected in individuals such as construction workers subject to direct weight bearing to the shoulder area. Shoulder osteoarthritis also can develop after vascular osteonecrosis, causing the humeral head to become aspheric. Elbow Osteoarthritis Elbow osteoarthritis is rare and generally considered to be the result of repeated vibration exposure, trauma, or metabolic arthropathy, such as pseudogout. Temporomandibular Joint Osteoarthritis Radiologic signs of osteoarthritis are common, but orofacial pain and radiographic signs of osteoarthritis are poorly correlated.153

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151. van Saase JL, van Romunde LK, Cats A, et al: Epidemiology of osteoarthritis: Zoetermeer survey: Comparison of radiological osteoarthritis in a Dutch population with that in 10 other populations. Ann Rheum Dis 48:271-280, 1989. 152. Halverson PB, McCarty DJ, Cheung HS, et al: Milwaukee Shoulder syndrome: Eleven additional cases with involvement of the knee in seven (basic calcium phosphate crystal deposition disease). Semin Arthritis Rheum 14:36-44, 1984. 153. Engel E, Lachmann S, Axmann-Krcmar D: The prevalence of radiologic TMJ findings and self-reported orofacial pain in a patient group wearing implant dentures. Int J Prosthodont 14:120-126, 2001. 154. McAlindon TE, Wilson PW, Aliabadi P, et al: Level of physical activity and the risk of radiographic and symptomatic knee osteoarthritis in the elderly: The Framingham study. Am J Med 106:151-157, 1999. 155. Felson DT, McAlindon T, Anderson JJ: Defining radiographical osteoarthritis for the whole knee. Osteoarthritis Cartilage 5:220-241, 1997. 156. Hart D, Doyle DV, Spector T: Incidence and risk factors for radiographic knee osteoarthritis in middle-aged women: The Chingford study. Arthritis Rheum 42:17-24, 1999. 157. Felson DT, Lawrence RC, Hochberg MC, et al: Osteoarthritis: New insights, Part 2: Treatment approaches. Ann Intern Med 133: 726-737, 2000. 158. Felson DT, Lawrence RC, Dieppe P: Level of physical activity and the risk of radiographic and symptomatic knee osteoarthritis in the elderly: The Framingham Study. Am J Med 106:151-157, 1999. 159. McAlindon T, Wilson PG, Aliabadi P: Level of physical activity and the risk of radiographic and symptomatic knee osteoarthritis in th ederly: The Framingham Study. Am J Med 106:151-157, 1999. 160. Rohrbough JT, Mudge MK, Schilling RC, et al: Radiographic osteoarthritis in the hands of rock climbers. Am J Orthop 27:734-738, 1998. 161. Nevitt M, Cummings SR, Lane NE: Association of estrogen replacement therapy with the risk of osteoarthritis of the hip in elderly white women: Study of Osteoporotic Fractures Research Group. Arch Intern Med 156:2056-2080, 1996.

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162. Zhang Y, McAlindon TE, Hannan MT, et al: Estrogen replacement therapy and worsening of radiographic knee osteoarthritis: The Framingham Study. Arthritis Rheum 41:1867-1873, 1998. 163. McAlindon TE, Felson DT, Zhang Y, et al: Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study. Ann Intern Med 125:353-359, 1996. 164. Felson DT, Zhang Y, Hannan MT, et al: Risk factors for incident radiographic knee osteoarthritis in the elderly: The Framingham Study. Arthritis Rheum 40:728-733, 1997. 165. Lane NE: Physical activity at leisure and risk of osteoarthritis. Ann Rheum Dis 55:682-684, 1996. 166. Flugsrud GB, Nordsletten L, Espehaug B, et al: Risk factors for total hip replacement due to primary osteoarthritis: A cohort study in 50,034 persons. Arthritis Rheum 46:675-682, 2002. 167. Coggon D, Kellingray S, Inskip H, et al: Osteoarthritis of the hip and occupational lifting. Am J Epidemiol 147:523-528, 1998. 168. Croft P: The occurrence of osteoarthritis outside Europe. Ann Rheum Dis 55:661-664, 1996. 169. Cooper C, Inskip H, Croft P, et al: Individual risk factors for hip osteoarthritis: Obesity, hip injury, and physical activity. Am J Epidemiol 147:516-522, 1998. 170. Chaisson CE, Zhang Y, Sharma L, et al: Grip strength and the risk of developing radiographic hand osteoarthritis: Results from the Framingham Study. Arthritis Rheum 42:33-38, 1999. 171. Carman WJ, Sowers M, Hawthorne VM, et al: Obesity as a risk factor for osteoarthritis of the hand and wrist: A prospective study. Am J Epidemiol 139:119-129, 1994. 172. Lawrence J: Rheumatism in Populations. London, Heineman, 1977. 173. Dougados M, Gueguen A, Nguyen M, et al: Longitudinal radiologic evaluation of osteoarthritis of the knee. J Rheumatol 19:378-384, 1992. 174. Nevitt MC, Felson DT: Sex hormones and the risk of osteoarthritis in women: Epidemiological evidence. Ann Rheum Dis 55:673-676, 1996. 175. Ayral X, Dougados M, Listrat V, et al: Arthroscopic evaluation of chondropathy in osteoarthritis of the knee. J Rheumatol 23:698-706, 1996.

91

Management of Osteoarthritis CARLOS J. LOZADA

KEY POINTS Osteoarthritis (OA) is the most common form of arthritis. Pain is the most common symptom in patients with OA. The management plan should be individualized, accounting for factors such as sources of pain and extent of accompanying inflammatory features. Nonpharmacologic interventions such as weight loss and exercise should be an integral part of the management plan for OA. Currently available pharmacologic interventions are directed at symptomatic relief Investigation continues into potential disease-modifying interventions in OA.

Osteoarthritis (OA) is the most common form of arthritis. It is often referred to by other names such as arthrosis, osteoarthrosis, or simply arthritis. Because its incidence increases with age, OA is becoming a more important health issue with the “graying” of the world’s population. OA can be defined radiographically or clinically. The most useful definition, however, includes symptoms as well as radiographic changes. If a purely radiographic definition is used, it can be demonstrated that almost all individuals older than 75 years have OA.1 Although the epidemiology of OA is well covered in Chapter 90, it has been estimated that between 10% and 30% of those affected with OA are significantly disabled, making OA the leading cause of chronic disability in the United States.2 This leads to heavy direct and indirect costs. Traditional treatment paradigms for OA have conceded the inexorable progression of the disease and concentrated on pain management.3 The importance of training physicians in the management of OA has been underscored by the development of treatment guidelines, but with the relatively rapid ­evolution in the field of rheumatology, some of these guidelines have required revision. A simplistic but potentially useful algorithm is provided in Figure 91-1. As the population ages, there will be increasing societal pressure on physicians, particularly rheumatologists, to improve the available treatments for OA.4-6 Researchers have now turned to the investigation of agents that might delay the progression of OA. Potential future interventions include the use of collagenase inhibitors, polysaccharides, and growth factor and cytokine manipulation.7

PATIENT ASSESSMENT Appropriate management of OA begins with an accurate diagnosis. As with most rheumatic illnesses, obtaining a good history is of paramount importance. Symptoms should

be carefully described, particularly pain. Duration, location, and any alleviating or exacerbating factors should be ascertained. Distinct features such as stiffness or gelling and the description of events such as “locking” or “giving way” of a joint can help direct the physical examination. The physical examination seeks to confirm the diagnostic suspicion and establish the causes of symptoms. Laboratory evaluations are not helpful in establishing the diagnosis of OA but can help in excluding alternative diagnoses. They are also useful in determining which therapeutic approaches are appropriate for a particular patient, because conditions such as renal insufficiency or anemia can be identified. Radiographs are not necessary for diagnosis in the majority of patients but can identify coexistent conditions such as chondrocalcinosis that may require further workup or ­modification of the therapeutic plan.

SOURCE OF PAIN The main symptom in OA is pain. It has many potential sources in and around the joint. These include focal synovitis, synovial effusions, subchondral bone pain receptors, and periarticular tendons and bursae. Factors complicating the determination of the source of pain may include varus or valgus deformity, weight issues, and the emotional impact of chronic pain. Once the source or sources of pain are accurately identified, a treatment plan can be formulated.

MANAGEMENT The management of OA can be divided into nonpharmacologic interventions (Table 91-1), pharmacologic interventions, and surgical options. Pharmacologic interventions can be further subdivided into symptomatic therapy and potential structure- or disease-modifying therapy. NONPHARMACOLOGIC INTERVENTIONS Psychosocial Interventions As in other types of arthritis, patient education is an important first step in OA therapy. The patient should be an integral part of the decision-making team. To do this effectively, the patient should understand the nature of OA, including its natural history and treatment options. It is often reassuring for the patient to realize that OA is a very common, slowly progressive ailment and is not typically as disabling or deforming as the inflammatory arthritides. A significant number of patients have already tried nonprescription medications or nutriceutical remedies before seeing a physician and will want to discuss these options. Physicians should emphasize 1563

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Diagnosis of OA

Consider topical agents Capsaicin

Patient education Psychosocial issues? Is patient taking nutriceuticals?

Nonpharmacologic modalities Weight loss Exercise Temperature modalities

Noninflammatory

Significant inflammatory component? (Clinical assessment of severity/inflammation)

Inflammatory

Try acetaminophen

If single joint involved, consider corticosteroid infiltration

If suboptimal response, Try NSAID (or COX-2) assess for GI and cardiovascular risk and add cardio or gastroprotective measures as needed

Try NSAID (or COX-2) assess for GI and cardiovascular risk and add cardio or gastroprotective measures as needed Consider corticosteroid or hyaluronic acid infiltration if suboptimal response to oral therapies Consider narcotic analgesics if needed for pain relief

Consider narcotic analgesics if needed for pain relief

Surgical options

Surgical options

Figure 91-1  Algorithm for the management of osteoarthritis (OA). COX, cyclooxygenase; GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug.

Table 91-1  Nonpharmacolgic Management   of Osteoarthritis Conventional Options Patient education Arthritis self-help courses Weight loss Temperature modalities Exercise Orthotics Modified activities of daily living Unconventional Options Transcutaneous electrical nerve stimulation Pulsed electromagnetic fields Static magnets Acupuncture Spa therapy Yoga

that treatment includes nonpharmacologic as well as pharmacologic interventions. Organizations such as the Arthritis Foundation can be valuable sources of information geared toward patients and can provide helpful reading materials. Some patients may develop significant emotional disturbances related to the pain and changes in normal daily activities that can stem from OA. These may include mood

disorders, such as depression, or sleep disorders. A suspicion of either condition should lead to an evaluation by a psychiatrist or a primary physician who regularly manages these types of disorders. Weight Loss Obesity is an important risk factor in the development of OA of the knee.8,9 Further, higher body mass index (BMI) has been associated with an increased risk of progression of OA of the knee.10 This can be compounded by malalignment—namely, varus and valgus deformities that modulate the effect of weight on knee OA.11 In one study, BMI was associated with OA severity in those with varus deformity but not in those with valgus. Regimens of weight loss and exercise have been associated with improvement in pain and disability in OA of the knee.12 Weight loss alone has been associated with a decrease in the odds of developing symptomatic knee OA.13 One study suggested that a reduction in the percentage body fat, rather than weight, may be significant in reducing pain from OA of the knee.14 The symptom-relieving effects of weight loss have been shown to last as long as 1 year.15 The combination of weight loss and exercise can be superior to either intervention alone.16

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Temperature Modalities Topical applications of heat or cold can be a helpful adjunct to the therapeutic plan. These are more effectively used in superficial joints, such as the knees, than in deep ones, such as the hip. An acute injury, such as a sprained ankle, calls for cold applications for the first 2 to 3 days.17 In a setting of chronic pain, most patients prefer warm applications, although if superior pain relief is obtained from cold applications, these can be continued. Warm applications can be in the form of warm soaks or heating pads. Individual sessions should not exceed a temperature of 45°C or last more than approximately 30 ­minutes.18 The application of warmth should be avoided over certain areas, such as close to the testicles, and in patients with poor vascular supply, neuropathy, or cancer. Benefits of warm applications include decreased pain and stiffness, along with relief of muscle spasm and prevention of ­contractures.

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use of splints. In one trial, 70% of patients treated with a 7-month intervention that included the use of splints were able to improve their symptoms considerably and avoid surgical intervention.30 Cane The appropriate use of a cane can be an important adjunct, particularly in OA of the hip. It has been estimated that a cane can provide up to a 40% reduction in hip contact forces during ambulation.31 The cane should be used in the hand contralateral to the affected hip or knee32 and should be advanced with the affected limb while walking. The appropriate cane size is that which results in about a 20-degree flexion of the elbow during use.33 A useful approximation is a cane that is equal to the distance from the floor to the patient’s greater trochanter. Modification in Activities of Daily Living

Exercise Periarticular structures, particularly muscles, influence the expression of OA. This is likely due to their role in providing stability to the joints and in dampening some of the forces acting across joints. Quadriceps muscle weakness has been postulated as a risk factor for OA of the knee.19 Quadriceps strengthening exercises have been advanced as fundamental to the management of conditions such as chondromalacia patellae.20 Both the dynamic and isometric exercise arms of a 16week study of patients with knee OA showed equivalent improvement in symptoms and physical functioning.21 Walking can be beneficial, and supervised fitness-­walking regimens can improve function in those with OA of the knee.20 Home-based exercise interventions also significantly improve symptoms in those with knee OA.22,23 Finally, community-based aquatic exercise programs, such as aquatic aerobics, have merit. 24 Orthotics and Bracing Orthotics—ranging from insoles to braces—can be effective in providing symptomatic relief and are probably underused by most physicians. Studies have demonstrated that lateral wedged insoles provide substantial relief to those with medial compartment knee OA, particularly those with varus deformity.25 In some studies, those with milder symptoms obtained greater benefit.26 Knee braces have been evaluated as well. Valgus bracing of patients with medial compartment OA can reduce pain and increase levels of activity.27 In one study, medial taping of the patella reduced the pain of those with patellofemoral compartment OA by 25%.28 Heel lifts have been tried in those with hip OA. In one uncontrolled study, most patients reported diminished symptoms. Time to improvement lengthened with the ­radiographic stage of OA.29 For those with calcaneal spurs or foot joint OA in general, appropriate athletic-type footwear is recommended. A good athletic shoe should provide medial arch support and calcaneal cushioning, as well as good mediolateral stability. Those with carpometacarpal joint arthritis should initially be offered conservative management, including the

Physician advice and occupational therapy can provide useful insights into modifications of daily activities to reduce OA symptoms. These interventions can range from using an elevated toilet seat or shower bench in someone with lower extremity OA to using appliances designed to open jars in patients with hand OA. Assistance from occupational therapists can be valuable. Other Interventions Other modalities have been tried in OA. These are unconventional and include magnetic field application, acupuncture, and yoga-based regimens. These are not accepted as standard therapy for OA, but some deserve further study. A significant number of these interventions are being used by patients on their own and should be formally studied not only for evidence of any benefit but also to ensure that there are no harmful effects. Studies of transcutaneous electrical nerve stimulation (TENS) have generally been small. A recent review of TENS studies in OA of the knee concluded that a trend toward symptom improvement existed, warranting larger, well-controlled studies.34 In one randomized, controlled study, patients had initial symptom reduction, but at 1 year follow-up, only two patients continued to use the device.35 TENS use for 3 weeks was compared with 3 weekly hyaluronic acid injections in 60 patients with OA of the knee. Pain relief was observed in both groups through the 6 months of follow-up. There was superior improvement in the Western Ontario McMaster Osteoarthritis Index (WOMAC) physical function subscale score for the hyaluronic acid group.36 Pulsed electromagnetic fields have been tested in double-blind, placebo-controlled trials. These fields are applied through the daily use of a brace-type device. In one study, a primary end point of pain reduction was not achieved.37 Another study did not meet its primary end point but reported an improvement in knee stiffness in subjects younger than 65 years, without an accompanying reduction in pain.38 The use of static magnets in chronic knee pain has become quite popular with some patients. In one doubleblind, randomized, placebo-controlled trial of 43 patients,

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the WOMAC pain and physical function subscales, along with a 50-foot walk, demonstrated a statistically ­significant benefit of static magnets at 2 weeks.39 Another 29-patient double-blind, placebo-controlled trial in knee OA reported a benefit over placebo after 4 hours of use, but there were no significant differences between groups at 6 weeks of continued treatment.40 The potential mechanism for any effect remains unclear, and larger, longer-term studies are needed before any clinical benefit can be postulated. Acupuncture is being formally tested in a National Institutes of Health (NIH)–sponsored multicenter clinical trial. It has been difficult to develop appropriate controls to test acupuncture’s clinical efficacy. Most recent studies have tried to employ “sham” methods in the control arm, such as the use of blunted, telescopic needles.41 Early ­ clinical trials42,43 and one literature review44 concluded that acupuncture shows promise in the treatment of knee pain from OA. A double-blind, randomized, placebo-controlled trial of acupuncture as adjunctive therapy in OA of the knee enrolled 570 patients in two outpatient clinics. Reduction in knee pain in the true acupuncture group was superior to that in the sham acupuncture group at 26 weeks by WOMAC function score, WOMAC pain score, and patient global assessment. Twenty-five percent of the patients in each of the acupuncture groups were unavailable for analysis at 26 weeks, however.45 The most recent and largest randomized, double-blind, placebo-controlled trial of acupuncture in knee OA showed a benefit of both sham and “traditional” methods of ­acupuncture over physiotherapy and as-needed nonsteroidal anti-inflammatory drugs (NSAIDs); however, there were no significant differences between the sham and “traditional” arms of the studies in terms of OA symptom relief. The ­beneficial pain-relieving effect seen in slightly more than half the patients in each of these arms appeared to be secondary to the use of the needles themselves rather than the specific locations where they were placed. Spa therapy also has advocates. It has been touted for low back pain and for lower extremity OA.46 However, randomized, controlled studies are lacking.47 Yoga has also shown some symptomatic benefit in OA of the hands, based on limited testing.48 PHARMACOLOGIC INTERVENTIONS Topical Agents Topical agents for the management of OA are available without a prescription in the United States (Table 91-2). The two most widely used types are preparations containing capsaicin and those containing topical NSAIDs. Capsaicin is a pungent ingredient found in red peppers (such as hot chili peppers). The mechanism of action is thought to be through selective stimulation of unmyelinated type C afferent neurons, causing the release of substance P. This release reversibly depletes the stores of substance P, a neurotransmitter of peripheral pain sensations.49 Capsaicin preparations are available in concentrations of 0.025% or 0.075% in either ointment or, more recently, “roll-on” form, and they can be applied up to four times daily. They have been tested in controlled, double-blind studies in OA of the hands and knees.50,51 Patient response is quite ­variable, with

Table 91-2  Symptom-Relieving Pharmacologic ­Therapies for Osteoarthritis Topical Capsaicin Topical nonsteroidal anti-inflammatory drug (NSAID) preparations Systemic Acetaminophen Nonselective NSAIDs Cyclooxygenase-2 (COX-2)–specific inhibitors Tramadol Narcotic analgesics Intra-articular Corticosteroids Hyaluronic acid derivatives

some obtaining significant pain relief and others not being able to tolerate the burning or stinging sensation ­produced by its application. Usually, the counterirritant sensation decreases gradually with repeated use, but pain relief remains. Although very safe overall, capsaicin products can be quite irritating if they come in contact with mucosal surfaces, particularly the eyes. Patients should wear disposable gloves, if possible, when applying the agents. There may be some reddening of the skin where the compound is applied. Topical NSAID preparations are popular worldwide for the treatments of OA.52,53 Safety concerns about traditional oral NSAIDs were the driving force in the use of these topical agents,54 although questions remain as to their absorption and the degree of relief obtained. Results of placebo-controlled trials in OA of the knee have been conflicting. Some demonstrated symptomatic relief with topical application of gels containing NSAIDs, such as diclofenac,55,56 whereas others showed only trends favoring the NSAID or no ­difference at all. In one recent trial, diclofenac gel was compared with placebo in 238 patients with OA of the knee over 3 weeks. The primary outcome was average pain with movement on days 1 to 14. The group on diclofenac gel had statistically superior improvement in this variable compared with those on placebo. WOMAC scores for function, pain, and disability were also significantly superior to placebo at weeks 2 and 3.57 Patients were also randomized to receive eltenac or placebo gel over 4 weeks. Eltenac is a nonselective NSAID that is structurally similar to diclofenac. The primary end point was global pain on a visual analog scale (VAS). At 4 weeks, there was a trend, but no statistical ­difference, favoring the eltenac gel. Two patients in the active treatment group and two in the placebo group had local itching, reddening, or both in the application area. There are also menthol- and salicylate-based overthe-counter topical preparations, but there are no published trials supporting their use in OA. Systemic Agents Non-narcotic Analgesics. Acetaminophen (paracetamol) has often been touted as the initial systemic intervention for the management of OA. This is mainly due to its favorable side effect profile but also to a perception of its equivalent efficacy to NSAIDs. This perception derives from studies of OA in which patients were not stratified in terms of ­degree of

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symptoms. In one study, acetaminophen 4 g/day was equivalent to ibuprofen 1200 or 2400 mg/day, with the notable exception of pain at rest.58 A meta-analysis of 10 randomized, controlled trials concluded that acetaminophen is effective in the relief of pain associated with OA. However, the effect was small, and there was no improvement in overall WOMAC score. This suggests that acetaminophen may be effective for the relief of pain and should not be expected to have a strong effect on stiffness or function.59 More recently, it has been noted that NSAIDs may have superior efficacy in patients with more symptomatic or inflammatory presentations, because acetaminophen has no anti-inflammatory effects at approved doses.60 A recent database review concluded that the available evidence suggests that NSAIDs have superior efficacy in symptomatic relief in those with hip or knee OA and also in those with moderate to severe levels of pain from OA.61 Particular concerns in patients taking acetaminophen include the concomitant use of alcohol or over-the-counter products containing acetaminophen. Either of these situations can lead to the possibility of hepatic toxicity through toxic metabolites. Nonsteroidal Anti-inflammatory Drugs. NSAIDs are the most commonly prescribed medications for the treatment of OA. Nonselective NSAIDs work through nonspecific inhibition of cyclooxygenase isoforms 1 and 2 (COX-1 and COX-2). COX-1 is constitutively expressed in renal and gastrointestinal (GI) tissues, among others. COX-2 is inducible in inflammatory responses. The major side effects of NSAIDs are GI toxicities (gastritis, peptic ulcer disease) and renal toxicities (interstitial nephritis, prostaglandin inhibition-related renal insufficiency). Because GI tissues have a higher expression of COX-1, a selective COX-2 inhibitor might spare patients the GI side effects. Unfortunately, COX-2 is expressed in renal tissue, and COX-2–specific drugs, such as traditional NSAIDs, have potential adverse renal effects. This is especially true in those with baseline renal insufficiency. Concerns about cardiovascular risks led to the voluntary withdrawal of rofecoxib from the market in the United States. There have also been concerns about celecoxib at a dose of 200 mg twice daily, owing to an increased relative risk for myocardial infarction in an adenomatous polyp trial62; this, however, has not been confirmed in six observational studies.63 All NSAIDs and COX-2–specific agents have received “black box” warnings in their package inserts addressing cardiovascular risk. Alternative mechanisms of action of NSAIDs, such as interference with receptors in the cell membrane phospholipid bilayers, have been proposed.64 Further discussion of NSAIDs can be found in Chapter 56. Nonselective NSAIDs are widely used for the management of OA. They include ibuprofen, naproxen, diclofenac, and others. NSAIDs are usually analgesic at lower doses but have both analgesic and anti-inflammatory effects at their higher recommended doses. They are prescribed either in fixed doses or “as needed” and are quite effective as symptom modifiers; however, they have no structure- or disease-modifying effects. NSAIDs should be used in the smallest dose that provides satisfactory symptom relief, because GI toxicity has been linked to dosage. Adverse GI events have also been linked to patient age, previous history of peptic ulcers or bleeding, and the ­presence of comorbid conditions such as heart disease.

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To reduce the potential for adverse GI events, misoprostol can be added to the therapeutic regimen. It is a prostaglandin E2 analogue that has been shown to reduce the GI side effects of NSAIDs when used at 200 μg three times a day.65 Diarrhea is a potential side effect. The use of a concomitant proton pump inhibitor may reduce upper GI endoscopic ulceration rates from NSAIDs, although no study has attempted to show a decrease in events such as symptomatic ulcers or bleeds.66 Over-the-counter doses of H2 blockers and antacids have not been shown to reduce either endoscopic or serious clinical GI events. COX-2–specific inhibitors are the latest drugs used in an attempt to reduce the GI adverse event profile of OA therapy. COX-2–specific inhibitors are highly selective for COX-2 in vitro. Currently, only three such agents are available: celecoxib, rofecoxib, and valdecoxib. Others are in various stages of investigation. All the available agents can reportedly reduce the rate of endoscopic ulceration by more than 50% when compared with nonselective NSAIDs. Rofecoxib and celecoxib also significantly reduce the rates of symptomatic ulcers, bleeds, perforations, and obstructions in patients not concurrently on aspirin.67,68 It remains unclear how substantial the benefits of these compounds are to patients taking aspirin. Because COX-2–specific agents can inhibit endothelial prostacyclin but do not affect platelet thromboxane, cardiovascular safety remains an area of investigation.69,70 Combination COX-lipoxygenase inhibitors are in development. It remains to be seen how these will compare with traditional NSAIDs and with COX-2 inhibitors in terms of both safety and efficacy.71 Animal studies have hinted at the possibility of a structure- and disease-modifying effect.72 Narcotic Analgesics. Although several options exist for the management of pain in OA, some patients obtain suboptimal pain relief. If a patient has failed to respond to other nonpharmacologic and pharmacologic modalities and has no additional identifiable causes of pain (such as fibromyalgia), a narcotic analgesic should be considered. The pain of OA is generally responsive to narcotic an­­ algesics. Because of concerns about potential addiction, ap­­ p­ropriate patient selection is important. Narcotic analgesics such as codeine and propoxyphene have been used effectively in patients with OA, especially in combination with non-narcotic analgesics (e.g., acetaminophen). Potential side effects include nausea, constipation, and ­somnolence. Tramadol is an oral medication with mild suppressive ef­­ f­ects on the μ opioid receptor. It also inhibits the uptake of norepinephrine and serotonin73 and is not thought to have significant addictive tendencies.74 It is available alone or in combination with acetaminophen and is not a controlledschedule medication in the United States.75 Tramadol has been used for the symptomatic relief of OA.76 Seizures and allergic reactions are potential side effects.77 The incidence of nausea can be reduced by slowly escalating the dose until the desired pain relief is achieved. One study compared tramadol and acetaminophen to the combination of codeine and acetaminophen.78 Pa­ tie­nts with OA or chronic low back pain were randomized to receive tramadol and acetaminophen (37.5 mg and 325 mg, respectively) or codeine and acetaminophen (30 mg and 300 mg, respectively) for 4 weeks. Pain relief and changes in pain intensity were equivalent in both groups. Those on

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codeine and acetaminophen had a significantly higher incidence of somnolence (24% versus 17%) and constipation (21% versus 11%). The tramadol-acetaminophen combination also provides symptomatic relief as add-on therapy in OA patients receiving NSAIDs or COX-2 agents as baseline therapy.79 Extended-release narcotic analgesics have been tested in clinical trials in OA. This approach is intended to achieve a lower level of peak to trough variability in the plasma concentration of the narcotic. An extended-release, once-a-day preparation of tramadol relieves pain in OA of the knee and hip.80 Extended-release oxymorphone dosed twice a day also provides relief in those with moderate to severe pain from OA of the hip or knee, as demonstrated by a VAS and the WOMAC composite index, as well as the subscales for pain, stiffness, and physical function.81 Transdermal fentanyl, a narcotic analgesic, has been used in the treatment of moderately to severely symptomatic knee and hip OA. It relieved pain and improved function in clinical trials as judged by a VAS and the WOMAC physical function subscale.82 Intra-articular Agents Corticosteroids. Although there is no role for ­ systemic c­ orticosteroids in OA, local intra-articular corticoid ­preparations have a long history in the management of OA. Corticosteroids have been shown to downregulate the ­expression of adhesion molecules. This, in turn, can reduce cellular infiltration into the joint and subsequent inflammation. Corticosteroid injections slow macrophage-like cell infiltration of the synovium in OA.83 The dose of steroid injected is determined by the volume of the joint being injected, with larger joints such as the knee receiving higher doses. The risk of joint infection is very low if proper technique is employed. Postinjection flares due to corticosteroid crystal synovitis can occur. There is a relative dearth of information from clinical trials of intra-articular corticosteroid injections. However, in one trial, symptomatic benefit from corticosteroid injection for OA of the knee was demonstrated in a doubleblind trial at 1 and 4 weeks post injection.84 Another trial attempted to assess the possible disease-modifying effects of corticosteroids by randomizing 68 patients to corticosteroid or saline injections of the knee every 3 months for 2 years. At the study’s end, there was no significant difference in rate of joint space narrowing; thus, no case could be made for a disease-modifying effect of corticosteroid injections. There was a trend favoring pain relief in the corticosteroid group as measured by the pain subscale of the WOMAC.85 A review of published studies of intra-articular corticosteroid ­injections in OA concluded that the short-term sympto­ matic benefits have been well established, with few adverse events, but long-term benefits have not been confirmed.86 The specific corticosteroid compound used, the frequency of injections, and other factors related to the use of corticosteroid injections in OA vary widely and are heavily influenced by the training program the rheumatologist attended and where he or she practices.87 In general, corticosteroid injections are believed to be most effective in patients with evidence of inflammation, effusions, or both. Because of concerns over possible deleterious effects, usually no more

than four corticosteroid injections per year are given in a particular joint. Further discussion of arthrocentesis can be found in Chapter 47. Hyaluronic Acid Derivatives. Synthetic and naturally ­occurring hyaluronic acid derivatives are administered intraarticularly. Two of these agents—Hyalgan and Synvisc—are approved for use in the United States for OA of the knee. Multiple injections are required, with the injections spaced 1 week apart. One medication (Synvisc) requires three injections per course of treatment; the other (Hyalgan) five ­injections. Although often mentioned as potential structuremodifying agents, these products are presently ­ considered symptom-modifying drugs. Their molecular weights vary (from <100,000 to >1 million Svedberg units), depending on the preparation. They reportedly reduce pain for prolonged periods and may improve mobility.88 Improvement in overall physical functioning has also been reported.89 The mechanisms of action are not known. However, there is evidence of an anti-inflammatory effect (particularly at high molecular weight), a short-term lubricant effect, an analgesic effect by direct buffering of synovial nerve endings, and a stimulating effect on synovial lining cells, leading to the production of normal hyaluronic acid.90 In one study, three weekly hyaluronic acid intra-­articular injections provided comparable pain relief to a single corticosteroid intra-articular injection at 1-week follow-up; at 45 days’ follow-up, hyaluronic acid was superior to the corticosteroid.91 In a Canadian study, 102 patients with OA of the knee were randomized to three weekly intraarticular injections of hylan G-F (Synvisc), hylan G-F plus an NSAID, or NSAID alone. At 26 weeks, both groups receiving hylan G-F were significantly better than the group receiving NSAIDs alone.92 Substantial clinical responses to the saline injections used as placebo in hyaluronic acid trials have sometimes made data interpretation challenging. In a double-blind, placebo-controlled trial, 495 patients with knee OA were randomized to receive five intra-articular injections of hyaluronic acid (Hyalgan) given 1 week apart, placebo, or naproxen (500 mg orally twice a day) and followed for 26 weeks.93 Patients in the group receiving hyaluronic acid had significantly greater improvement in pain on the 50-foot walk compared with placebo, and more of them had a 20-mm or greater reduction in pain as judged by a VAS. At the conclusion of the trial, more hyaluronic acid–treated patients (47.6%) had slight pain or were pain free compared with placebo-treated (33.1%) or naproxen-treated (36.9%) patients. As expected, GI adverse events were significantly more common in the naproxen group than the hyaluronic acid and placebo groups. Hyaluronic acid preparations have been tested in other randomized trials, with symptomatic relief of OA of the ankles, shoulders, and hips being reported.94-96 One multicenter, randomized, double-blind study, reported as an abstract, revisited the issue of disease modification with hyaluronic acid. Patients received three courses of three intra-articular knee injections of either hyaluronan or saline over the course of 1 year. Joint space width was assessed using standing, weight-bearing radiographs; 273 patients completed the trial and had complete data collection. This study failed to demonstrate a disease-modifying effect for

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hyaluronan therapy, because the primary end point was not met. Both the active treatment group and the placebo group had similar joint space narrowing during the study period. In those with a joint space width of 4.6 mm or greater at entry, hyaluronan use led to slightly less joint space narrowing than saline (placebo 0.55 mm ± 1.04, hyaluronan 0.13 mm ± 1.05; P = .02).97 These results have not been confirmed in other trials. Hyaluronic acid products continue to be actively investigated in shoulder joint OA, periarthritis,98 and adhesive capsulitis.99 NUTRICEUTICALS Two nutritional supplements—glucosamine and chondroitin sulfate—have received significant attention (Table 91-3). Health food stores and the lay press have been touting them as “cures for arthritis.” The mechanism of action of glucosamine sulfate is uncertain. Some in vitro experiments have shown stimulation of the synthesis of cartilage glycosaminoglycans and proteoglycans.100,101 Others have shown that glucosamine and N-acetylglucosamine inhibit interleukin (IL)-1β– and tumor necrosis factor-α (TNF-α)–induced nitric oxide production in normal human articular chondrocytes.102 N-acetylglucosamine also suppresses the production of IL-1β and stimulates IL-6 and COX-2. Glucosamine Urinary excretion of glucosamine (and other glycosaminoglycans) has been investigated and found to be elevated in both OA and rheumatoid arthritis.103 Supplementation with glucosamine sulfate, an intermediate in mucopolysaccharide synthesis, has been tried both orally and intramuscularly as therapy for OA. Glucosamine sulfate (400 mg injected intramuscularly twice weekly for 6 weeks) reduced the severity of disease as judged by the Lequesne index when compared with placebo.104 A randomized, double-blind, parallel-group study in knee OA compared 500 mg oral glucosamine sulfate three times a day to 400 mg ibuprofen three times a day for 4 weeks. The response to ibuprofen was more rapid, but at 4 weeks, there was no statistically significant difference in the response rate (reduction of at least 2 points in the Lequesne index).105 No group in the study received higher, anti-inflammatory doses of ibuprofen. An NIH-sponsored trial is currently under way in the United States to more thoroughly study the symptom-relieving and possible structure-modifying properties of glucosamine. Meanwhile, some already advocate the use of glucosamine as part of the first line of therapy for symptomatic OA.106 Glucosamine has also been compared with acetaminophen in an industry-sponsored trial. In the GUIDE trial, 318 patients with knee OA were randomized to glucosamine sulfate soluble powder 1500 mg once a day, acetaminophen 1000 mg three times a day, or placebo for 6 months. The main efficacy parameter was the 6-month change in the Lequesne index. At 6 months, the glucosamine group achieved significantly greater efficacy versus placebo. Those on acetaminophen failed to achieve a statistically significant benefit versus placebo by either the Lequesne index or WOMAC. There was no statistically significant difference between those on glucosamine and those on placebo based on WOMAC outcomes.107 Another clinical trial

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Table 91-3  Nutriceuticals for Osteoarthritis Glucosamine Chondroitin sulfate Ginger extracts Avocado and soy unsaponifiables Cat’s claw Shark cartilage S-adenosyl methionine

r­ andomized 80 patients with knee OA to either glucosamine ­sulfate 1500 mg/day or placebo for 6 months. There was no ­difference between glucosamine and placebo in the primary variable of patients’ global assessment of pain in the affected knee.108 Another trial used a unique Internet-based recruiting system and followed 205 patients with knee OA randomized to glucosamine sulfate 1500 mg/day or placebo for 12 weeks.109 The primary end point was the pain subscale of the WOMAC. At study conclusion, there was no difference in the groups with regard to pain, physical function, or overall WOMAC scores. Stratification by severity of OA, glucosamine product used, or use of NSAIDs did not alter the results. The Cochrane review of glucosamine therapy in OA analyzed a pool of 20 studies and 2570 patients. Pain and function improved by 28% and 21%, respectively, by the Lequesne index, compared with placebo. There was no improvement in the overall WOMAC pain and function scales. There has been speculation that these inconsistencies in study results may be due to a lack of standardization in glucosamine preparations.110 A recent discontinuation trial has added to the uncertainty about glucosamine’s efficacy. It found that 137 patients who had been clinically classified as moderate responders to glucosamine sulfate were equally likely to experience an OA flare whether they continued or discontinued the glucosamine. No statistically significant differences between the groups were noted in pain and WOMAC function scores after 6 months.111 Combination products containing both glucosamine and chondroitin have become quite popular in the United States, despite a dearth of clinical trial data. One small, placebo-controlled trial randomized patients with knee OA to receive a regimen of glucosamine hydrochloride (1000 mg), chondroitin sulfate (800 mg), and manganese ascorbate (152 mg) twice a day or placebo.112 Patients were evaluated at baseline and then every 2 months for 6 months using the Lequesne index of OA severity. At 4 and 6 months, those with mild to moderate radiographic OA of the knee showed significant improvement by the Lequesne index compared with those on placebo. In those with severe radiographic OA of the knee, no significant symptomatic benefit could be demonstrated. The study did not evaluate patients for structure or disease modification. Results of the NIH-sponsored Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) were recently published.113 In that study, 1583 patients with OA of the knee were randomized to placebo, glucosamine hydrochloride 1500 mg/day, chondroitin sulfate 1200 mg/day, celecoxib 200 mg/day, or glucosamine hydrochloride and chondroitin sulfate. The primary end point was the percentage of patients achieving at least 20% improvement on the

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WOMAC pain subscale at 6 months. The only statistically significant response was seen in those on celecoxib versus placebo (70.1% versus 60.1%; P = .008). Patients were then stratified for baseline severity by WOMAC pain scores, most of them falling into the mild OA pain category. In a subgroup analysis, in those with moderate to severe OA pain (WOMAC pain 301 to 400 mm), the combination of glucosamine hydrochloride and chondroitin sulfate was more efficacious than placebo as measured by a dichotomous response rate (positive = 50% improvement in pain): 79.2% versus 54.3% (P = .002). From these results, it appears that patient selection may be important in maximizing any potential benefit from glucosamine or chondroitin therapy. The NIH study also had a particularly high placebo response rate, which may reflect the enrollment of patients with less symptomatic OA, and that may have affected the results. The GAIT study also used a glucosamine hydrochloride preparation instead of the glucosamine sulfate used in most other studies, particularly those that have demonstrated efficacy. This raises the question of whether the choice of glucosamine hydrochloride negatively affected efficacy in the trial. However, one small (142 patients) Chinese trial randomized patients with OA of the knee to glucosamine sulfate 1500 mg/day or glucosamine hydrochloride 1440 mg/day for 1 month.114 No efficacy differences were noted, with a clear majority of patients in each treatment arm achieving symptomatic improvement by Lequesne scores. The study had no placebo arm. Safety assessments continued for 2 additional weeks, with no significant adverse events reported. At present, it is still unclear whether glucosamine hydrochloride preparations have the same potential clinical benefits as glucosamine sulfate preparations. Additional investigations are needed. Two European trials tried to address the subject of disease modification with glucosamine. In one study, 212 patients with OA of the knee were randomized to receive placebo or glucosamine sulfate (1500 mg/day) and were followed prospectively for 3 years.115 Fluoroscopically positioned, standing anteroposterior radiographs of the knees were taken at enrollment, 1 year, and 3 years. At 3 years, the treatment group had a joint space reduction of 0.06 mm, whereas the placebo group had a reduction of 0.31 mm. Whether this is a clinically meaningful difference in joint space is unclear. Those taking glucosamine also showed symptomatic benefit on the order of 20% to 25%, whereas those taking placebo had a slight worsening of symptoms, as judged by the WOMAC. There were no significant adverse events attributed to the use of the glucosamine sulfate. A second group of researchers randomized 202 patients to receive placebo or glucosamine sulfate (1500 mg/day) for 3 years.116 The width of the narrowest medial joint space of the tibiofemoral joint was measured serially, using visual assessments with a 0.1-mm graduated magnifying glass on standardized full-extension, weight-bearing anteroposterior radiographs of each knee. At 3 years, there was a significant difference in joint space width, with a decrease of 0.19 mm in the placebo group and an increase of 0.04 mm in the glucosamine sulfate group. Also, significantly greater improvements in the WOMAC score and the Lequesne index were seen in the glucosamine group. The favorable results of these studies have been questioned because of the radiographic technique used to assess joint space. At issue is whether the joint space seen

on standing films of the knee might be significantly affected by the symptoms of OA (i.e., pain) and whether a semiflexed film would be preferable. In one study, investigators obtained baseline radiographs (after analgesic or NSAID washout) using both standing-extended and semiflexed, fluoroscopically positioned techniques in 19 patients with knee OA.117 Radiographs were then repeated 2 to 8 weeks later after reinstitution of analgesic or NSAID therapy. Joint space width increased with effective pain relief in highly symptomatic patients if measured by standing-extended radiographs. Using the semiflexed technique, there were no significant changes in joint space width related to severity of pain or responsiveness to pain therapy. This suggests that data obtained using the standing-extended radiographic technique may need to be revisited, because the results may represent a therapeutic intervention’s effect on symptoms (pain) rather than a disease-modifying effect. More recent, ongoing trials have changed to the semiflexed, fluoroscopically positioned knee radiograph to assess potential disease modification. 118 Chondroitin Sulfate Oral chondroitin sulfate, a glycosaminoglycan composed of units of glucosamine with attached sugar molecules (molecular mass of around 14,000), has also been used as therapy for hip and knee OA. Its mechanism of action is unknown. A double-blind, placebo-controlled study included a 3-month treatment phase followed by a 2-month treatment-free phase. The major outcome parameter was NSAID ­ consumption. Those receiving chondroitin sulfate used fewer NSAIDs than the controls both at the completion of treatment and in the treatment-free phase.119 Another study compared chondroitin sulfate to diclofenac sodium. One group received chondroitin sulfate (400 mg three times a day) and the other diclofenac sodium (50 mg three times a day). Each group was also changed over to placebo at some point. The chondroitin group received the active drug for 3 months, whereas the diclofenac group received it only for 1 month before being switched to placebo. For months 4 through 6, both groups took only placebo. The diclofenac group had a quicker response to therapy, whereas the chondroitin group had a more prolonged improvement as measured by the Lequesne index, VAS for pain, four-point scale for pain, and paracetamol use (rescue medication).112,120 This study raises questions because of the different lengths of treatment with active drug in each group. Further studies are needed. One study evaluated chondroitin sulfate as a disease-modifying intervention. Three hundred patients were enrolled and randomized to chondroitin sulfate 800 mg daily or placebo for 2 years.121 Joint space width was assessed using anteroposterior semiflexed radiographs. Pain and function were assessed as secondary end points. In the placebo group, the mean change in joint space width was 0.07 mm/year, while in the treatment group, the mean change was 0.00. A similar difference was noted when the minimum joint space width was evaluated. The differences were statistically significant (mean joint space width, P = .04; minimum joint space width, P = .05), but the clinical relevance remains unclear. The changes in radiographic progression were not matched by similar differences when pain and function were analyzed. The treatment group achieved improvement in all

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WOMAC subscales of pain, function, and stiffness, but a statistically significant difference could not be shown. It has been suggested that the overall low baseline WOMAC scores created difficulties in assessing for clinical improvement. Ginger extracts have been popular “natural” remedies for OA for some time.122 Most of the world’s ginger comes from China, and its “medicinal” use dates back more than 2000 years. Ginger actually contains very small amounts of salicylate.123 In some animal models, ginger has been shown to have inhibitory effects on COX and lipoxygenase.124 One study with 247 evaluable patients revealed a small but statistically significant reduction in knee pain on standing (63% versus 50%; P = .048) after taking ginger.125 Reduction in knee pain after a 50-foot walk was also significant. Use of acetaminophen was reduced in the ginger-extract group, but the difference was not statistically significant. The extract was well tolerated, except for GI events such as dyspepsia, nausea, and eructation, which were increased over placebo. The question remains whether benefits observed represent a clinically relevant effect. Some of the more unusual agents proposed as structure or disease modifiers in OA are oral preparations of avocado and soy unsaponifiables (ASUs). These compounds are derived from unsaponifiable residues of avocado and soya oils mixed in a 1:2 ratio. In vitro studies on cultured chondrocytes showed partial reversal of IL-1β effects. The roles of IL-1β in OA are thought to include inhibition of prostaglandin synthesis by chondrocytes and stimulation of matrix metalloproteinases (MMPs) and nitric oxide production. MMPs and nitric oxide can degrade cartilage matrix and cause chondrocyte apoptosis. Use of ASUs also reportedly results in inhibited production of IL-6, IL-8, and MMPs and stimulation of collagen synthesis. Increased aggrecan synthesis has been reported as well.126 The mechanism of action is unknown, as is the active ingredient in ASUs.127 Sympto­ matic benefit in double-blind human trials in OA of the hip and knee has been reported.128 However, a double-blind, placebo-controlled trial in OA of the hip failed to show disease modification in the overall population, although a post hoc analysis reported benefit in those with more advanced OA at baseline. Some abstract presentations have suggested structure or disease modification in human hip OA.129 Other Supplements Other nutritional supplements, such as cat’s claw and shark cartilage, have become entrenched in regional and international popular cultures. Many people take them, despite limited or no data to support their use. A small, placebo-controlled trial showed improvement of OA pain with activity in those taking cat’s claw extracts.130 Shark ­cartilage contains a small amount of chondroitin sulfate.131 ­ S-adenosyl methionine (SAMe), a methyl group donor and oxygen radical scavenger, is often touted as a remedy for OA, although little evidence of its effectiveness has been published.132,133 In one double-blind, placebo-controlled study, two centers reported differing results. One center reported reductions in overall pain and rest pain, whereas the other showed no significant difference between the test group and placebo group.134 Another small, double-blind, placebo-controlled crossover study of 61 patients compared

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oral SAMe 1200 mg/day to oral celecoxib 200 mg/day for 16 weeks. After the first month of phase I, celecoxib provided superior pain relief that was statistically significantly. By the end of the second month, however, there was no statistically significant difference between the groups.135 There is insufficient evidence to recommend the use of these products in the treatment of OA. OTHER POTENTIAL STRUCTURE- OR DISEASE-MODIFYING THERAPIES The term chondroprotective has been used to describe structure- or disease-modifying agents. This is a misnomer, however, because the goal is to protect the entire joint (not only the cartilage) from the arthritic process. A workshop of the Osteoarthritis Research Society recommended that the term structure-modifying drugs be used for medications that previously would have been classified as chondroprotective.136 These drugs are intended to prevent, retard, stabilize, or even reverse the development of OA. Recently, the term disease-modifying osteoarthritis drug has been used for any such agent (Table 91-4). Such a disease-modifying effect in OA would require prolonged observation, given the typically slow progression of OA. Therefore, clinical trials in this area have been challenging, with most being designed for at least 2½ to 3 years of follow-up. Progress in the methodology used to assess structure and disease modification may shorten the length of these trials. Radiographic assessments of joint space, such as fluoroscopically positioned anteroposterior radiographs of the knee or magnetic resonance imaging, may be useful in this regard.137 Unfortunately, to date, no drug has been conclu­­­ sively proved to be structure or disease modifying. Although this chapter focuses on medication-based therapies, other approaches, such as osteochondral grafts of chondrocytes, donation of stem cells, or both, with eventual differentiation into bone and cartilage, are in various stages of development.138 Potential structure- or disease-modifying interventions under investigation include collagenase inhibitors, polysaccharides, and growth factor and cytokine manipulation. Tetracyclines, apart from any antimicrobial effect, are inhibitors of tissue metalloproteinases, perhaps owing to their ability to chelate calcium and zinc ions. There has also been research into the potential role of nitric oxide in the mechanism of action of the tetracyclines.139 Minocycline, a tetracycline-family antibiotic, has been used in the management of rheumatoid arthritis.140 Doxycycline, another tetracycline derivative, has been shown to inhibit ­ articular ­ cartilage Table 91-4  Potential Structure- and   Disease-Modifying Drugs in Osteoarthritis Tetracyclines Metalloproteinase or collagenase inhibitors Glucosamine Diacerein Growth factor and cytokine manipulation (interleukin-1 receptor antagonist [IL-1Ra], transforming growth factor-β) Gene therapy (IL-1Ra, IL-1RII) Chondrocyte and stem cell transplantation

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­collagenase activity.141,142 Doxycycline has also reduced the severity of OA in canine models. In one study, there was preservation of medial femoral condyle cartilage in treated dogs compared with the untreated group. Other lesions, such as medial trochlear ridge cartilage damage, superficial fibrillation of the medial tibial plateau, and osteophytosis, were unaffected by treatment. Collagenolytic activity and gelatinolytic activity, however, were reduced to 20% and 25% of their previous levels, respectively, compared with untreated dogs. In an in vitro model, doxycycline not only reduced collagenase and gelatinase activity in cartilage but also prevented proteoglycan loss, cell death, and deposition of type X collagen matrix.143 A multicenter, double-blind, placebo-controlled trial using doxycycline for structure or disease modification in obese female subjects with OA of the knee has been completed. In this study, 431 obese women with unilateral OA of the knee were treated with doxycycline 100 mg twice daily or placebo. The primary end point was radiographic progression. The minimum joint space width was assessed by fluoroscopically positioned anteroposterior, semiflexed, standing radiographs. Pain and function were evaluated as secondary end points. Progression of minimum joint space width at 30 months was 0.3 ± 0.60 mm in the treatment group and 0.45 ± 0.70 mm in the placebo group (P = .017). Imaging of the contralateral knee was also performed at baseline and at 30 months. Progression in the contralateral knees was no different between the groups.144 Secondary outcomes of pain and function were also recorded by WOMAC, VAS, 50-foot walk pain, and global assessment. Mean overall scores for pain were not significantly different between the groups. However, the frequency with which patients reported 20% or greater increase in knee pain was less in the treatment group (P < .05). Although a small disease-modifying effect was demonstrated in the target knee, no such effect could be demonstrated in the contralateral knee. Thus, the implications of these findings for clinical practice are uncertain. Other compounds with collagenaseinhibiting properties are being developed and investigated as structure- or disease-modifying agents not only in OA but also in rheumatoid arthritis.145 Glycosaminoglycan polysulfuric acid (GAGPS; Arteparon or Adequan) has been purported to work by reducing the activity of collagenase. It is a highly sulfated glycosaminoglycan, with a molecular weight ranging from 2000 to 16,000,146 derived from bovine tracheal cartilage. In a canine model of OA, GAGPS was administered intraarticularly twice weekly for 4 weeks.147 Four weeks after completion of the GAGPS treatment, medial femoral condylar lesions had developed to a lesser degree in the treated group than in saline-treated dogs. Swelling, an indicator of collagen network integrity, remained near control levels in the treatment group. In humans, OA of the knee was studied in a 5-year trial. There was improvement in multiple measured parameters, including less time lost from work.148 Another double-blind, placebo-controlled trial evaluated GAGPS in 80 patients with OA of the knee; patients received two series of five intra-articular injections of 25 mg (0.5 mL) GAGPS at 1-week intervals. At 14 weeks, 31% of the GAGPS group had improvement as judged by the Lequesne index, compared with 15% in the placebo group.149 Potential allergy and heparin-like effects

were observed. GAGPS is available in the United States for equine, but not human, use. Another extract, a glycosaminoglycan-peptide complex (GP-C) known as Rumalon, has been investigated. It is a highly sulfated polysaccharide derived from bovine tracheal cartilage and bone marrow and is administered intramuscularly.150 It has been shown to increase the levels of tissue inhibitor of metalloproteinases (TIMP).151 A randomized, placebo-controlled trial selected patients with hip or knee OA to receive 10 courses of injections of placebo or GP-C (2 mL) over 5 years (two courses per year). Each course consisted of 15 injections given twice weekly. GPC failed to demonstrate a structure- or disease-modifying effect.152 In addition, there were no statistical differences favoring the active treatment group when measured by the Lequesne index, pain on passive motion, or consumption of NSAIDs. GP-C is available in parts of Europe and South America. Pentosan polysulfate (Cartrofen) is a purified extract of beech hemicellulose administered intramuscularly or orally as a calcium salt. It can inhibit granulocyte elastase and has inhibited the catabolism of aggrecan in cartilage explants.153 Experimental studies in animal models suggest that it helps preserve cartilage proteoglycan content and retards ­ cartilage degradation.154,155 However, a recent blinded, placebo-­controlled study using an oral preparation in a dog model failed to demonstrate either a symptomatic benefit or a structure- or disease-modifying effect.156 Diacerein and its active metabolite rhein are anthraquinones related to senna compounds.157 They inhibit the synthesis of IL-1β in human OA synovium in vitro, as well as the expression of IL-1 receptors on chondrocytes.158 No effects have been reported on TNF or its receptors. Collagenase production and articular damage have been reduced in animal models.159-161 Early human clinical trials have shown improved pain scores compared with placebo and comparable efficacy to NSAIDs but a slower onset of action. Diarrhea is the main potential side effect. On the strength of these prior trials, diacerein has been proposed as a slowacting symptom-modifying and perhaps structure- or disease-modifying drug for OA. A double-blind, randomized, placebo-controlled trial looking at the efficacy and safety of diacerein enrolled 484 patients with symptomatic knee OA.162 They were randomized to receive placebo, diacerein 25 mg twice a day, diacerein 50 mg twice a day, or diacerein 75 mg twice a day. Using intent-to-treat analysis, diacerein 100 mg/day was significantly superior to placebo (P < .05) by the primary end point—patients’ assessment of pain on movement at week 24 (−18.3 ± 19.3 mm versus −10.9 ± 19.3 mm). It was also superior based on WOMAC and disability scores. However, no statistical difference was detected in the primary end point between placebo and 50 mg/day diacerein (−15 ± 21.0 mm) or 150 mg/day diacerein (−14.3 ± 23.7 mm). There have also been investigations into the ­ potential structure- or disease-modifying attributes of diacerein in OA.163 In one study, 507 patients with OA of the hip (according to American College of Rheumatology criteria) were randomized to receive either diacerein (50 mg orally twice a day) or placebo for 3 years. Patients were followed with yearly pelvic radiographs to assess hip joint space. Using completer analysis, the diacerein patients showed a

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s­ ignificantly lower rate of radiographic progression (0.18 versus 0.23 mm/yr). Using intent-to-treat analysis, a smaller proportion of those taking diacerein had significant joint space loss (defined as loss of ≥0.5 mm) during the study (50.7% versus 60.4%). Unfortunately, almost 50% of the patients failed to complete the 3-year study. In the placebo group, the principal reason for discontinuation was lack of efficacy, whereas in the diacerein group, it was adverse effects such as diarrhea. Curiously, the symptom-relieving effect of diacerein observed in prior studies could not be confirmed in this one. A recent meta-analysis of clinical trials of diacerein in OA concluded that available clinical evidence supports pain relief in hip and knee OA. There was no analysis of a disease-modifying effect.164 Potential methods of intervention in OA include growth factor and cytokine manipulation.165 Cytokines, such as IL-1 and TNF-α, are produced by the synovium and contribute to inflammation within osteoarthritic joints.166 Moreover, there may be deficient expression of naturally occurring anti-inflammatory compounds such as IL-1 receptor antagonist (IL-1Ra) by the chondrocytes of patients with OA.167 In some cases, increased nitric oxide production by OA articular chondrocytes may inhibit IL-1Ra synthesis.168 In a dog model of OA, IL-1Ra therapy reduced the expression of collagenase-1 in cartilage.169 The severity of cartilage lesions is also diminished.170 In a rabbit model of OA, transfer of the IL-1Ra gene to joints prevented OA progression.171 The effect of IL-1 blockade in humans with OA through the use of IL-1Ra is currently being investigated. Induction of repair in partial-thickness articular cartilage lesions by the timed release of transforming growth factor-β using liposomes has been attempted in an animal model. There was an increase in the cellularity of the defects, which were populated by cells of mesenchymal origin from the synovial membrane. The repaired cartilage resembled hyaline cartilage, and its integrity persisted up to 1 year after surgery.172 Combination therapy is another alternative. In a study of canine induced OA, sodium pentosan polysulfate, when combined with insulin-like growth factor 1, reduced stromelysin activity and increased TIMP.173 Gene therapy has been attempted as well. The control of genes such as TIMP and MMPs would, in theory, provide the opportunity to modulate the patient’s disease. As previously noted, gene expression of IL-1Ra has already been tried in rabbits and dogs, as well as in an equine model of OA using an adenovirus vector.174 Use of gene transfer– mediated overexpression of IL-1β decoy receptor has also been contemplated.175 Chondrocyte and stem cell transplants into articular cartilage defects have been tried as well. Chondrocytes transplanted (expressing a previously transfected β-galactosidase gene) into human cartilage explants survived up to 45 days in vitro in one trial.176,177 Transfection of chondrocytes with the galactosidase gene has been successful both before and after transplantation. SURGICAL INTERVENTION Surgical interventions in OA usually consist of osteotomies or joint replacements. Osteotomies can be effective painrelieving interventions and can delay the need for joint replacement surgery in selected patients. These tend to be younger subjects with OA.

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Joint replacement surgery (joint arthroplasty) is effective in providing pain relief and restoring function in many patients with OA. Hip and knee joint replacements are most common. Indications for surgery include pain that is refractory to the previously discussed interventions and significant impairment of the patient’s daily life. Therefore, patients should be the key decision makers, because they are the ones who must weigh the severity of symptoms and impairment. Patients undergoing replacement surgery should be deemed able to undertake the rehabilitation necessary to regain reasonable use of the joint involved. Infections are rare but do occur. Joint replacements have a typical life span of between 10 and 15 years. Revision surgery may be necessary, particularly in a relatively young patient who outlives the useful life of the prosthesis. Other potential rationales for surgical intervention in OA include removal of loose bodies, stabilization of joints, redistribution of joint forces (e.g., osteotomy), and relief of neural impingement (e.g., spinal stenosis, herniated disk). The value of arthroscopic debridement or lavage in OA has been questioned. A recent randomized, blinded trial failed to demonstrate significant symptomatic benefit in OA of the knee.

SUMMARY The treatment of OA includes a variety of possible nonpharmacologic and pharmacologic interventions. Treatment should be tailored to the individual and consists of a combination of modalities. These provide symptom relief but have no proven effect on the progression of disease. Structure and disease modification has yet to be achieved in OA. Trials that are under way could determine whether this is a realistic goal. Claims of structure or disease modification in OA should not be made for any drugs until well-designed, double-blind, placebo-controlled trials demonstrate that this is so. Some of the drugs being tested for structure and disease modification can provide symptom relief and can be added to our armamentarium in that capacity, even if it turns out they are not successful as structure- or disease-modifying agents. It is hoped that with the advent of disease-modifying OA drugs, treatment will eventually consist of a combination of symptom-relieving and disease-modifying interventions.

REFERENCES 1. Lawrence JS, Bremmer JM, Bier F: Osteo-arthrosis: Prevalence in the population and relationship between symptoms and x-ray changes. Ann Rheum Dis 25:1-24, 1966. 2. Peyron JG, Altman RD: The epidemiology of osteoarthritis. In ­Moskowitz RW, Howell DS, Goldberg M, Mankin HI (eds): ­Osteoarthritis: Diagnosis and Medical/Surgical Management, 2nd ed. Philadelphia, WB Saunders, 1992, pp 15-37.   3. Lozada CJ, Altman RD: Osteoarthritis: A comprehensive approach to management. J Musculoskeletal Med 14:26-38, 1997.   4. Hochberg MC, Altman RD, Brandt RD, et al: Guidelines for the medical management of osteoarthritis. I. Osteoarthritis of the hip. Arthritis Rheum 38:1535-1540, 1995.   5. Hochberg MC, Altman RD, Brandt KD, et al: Guidelines for the medical management of osteoarthritis. II. Osteoarthritis of the knee. Arthritis Rheum 38:1541-1546, 1995.   6. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines: Recommendations for the medical management of ­osteoarthritis of the hip and knee: 2000 update. Arthritis Rheum 43:1905-1915, 2000.

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32. Chan GN, Smith AW, Kirtley C, Tsang WW: Changes in knee moments with contrateral versus ipsilateral cane usage in females with knee osteoarthritis. Clin Biomech 20:396-404, 2005.  33. Blount WP: Don’t throw away the cane. J Bone Joint Surg Am 38:695-708, 1956. 34. Osiri M, Welch V, Brosseau L, et al: Transcutaneous electrical nerve stimulation for knee osteoarthritis. Cochrane Database Syst Rev 4: CD002823, 2000. 35. Taylor P, Hallett M, Flaherty L: Treatment of osteoarthritis of the knee with transcutaneous electrical nerve stimulation. Pain 11:233-240, 1981. 36. Paker N, Tekdos D, Kesiktas N, Soy D: Comparison of the therapeutic efficacy of TENS versus intra-articular hyaluronic acid injection in patients with knee osteoarthritis: A prospective, randomized study. Adv Ther 23:342-353, 2006. 37. Pipitone N, Scott DL: Magnetic pulse treatment for knee osteoarthritis: A randomised, double-blind, placebo-controlled study. Curr Med Res Opin 17:190-196, 2001. 38. Thamsborg G, Florescu A, Oturai P, et al: Treatment of knee ­osteoarthritis with pulsed electromagnetic fields: A randomized, double-blind, placebo-controlled study. Osteoarthritis Cartilage 13: 575-581, 2005. 39. Hinman MR, Ford J, Heyl H: Effects of static magnets on chronic knee pain and physical function: A double-blind study. Altern Ther Health Med 8:50-55, 2002. 40. Wolsko PM, Eisenberg DM, Simon LS, et al: Double-blind, placebocontrolled trial of static magnets for the treatment of osteoarthritis of the knee: Results of a pilot study. Altern Ther Health Med 10:36-43, 2004. 41. White AR, Filshie J, Cummings TM: International Acupuncture Research Forum: Clinical trials of acupuncture: Consensus recommendations for optimal treatment, sham controls and blinding. Complement Ther Med 9:237-245, 2001. 42. Tillu A, Tillu S, Vowler S: Effect of acupuncture on knee function in advanced osteoarthritis of the knee: A prospective, non-randomised controlled study. Acupunct Med 20:19-21, 2002. 43. Berman BM, Singh BB, Lao L, et al: A randomized trial of acupuncture as an adjunctive therapy in osteoarthritis of the knee. Rheumatology (Oxford) 38:346-354, 1999. 44. Ezzo J, Hadhazy V, Birch S, et al: Acupuncture for osteoarthritis of the knee: A systematic review. Arthritis Rheum 44:819-825, 2001. 45. Berman BM, Lao L, Langenberg P, et al: Effectiveness of acupuncture as adjunctive therapy in osteoarthritis of the knee: A randomized, controlled trial. Ann Intern Med 141:901-910, 2004. 46. Guillemin F, Virion JM, Escudier P, et al: Effect on osteoarthritis of spa therapy at Bourbonne-les-Bains. Joint Bone Spine 68:499-503, 2001. 47. Ernst E, Pittler MH: [How effective is spa treatment? A systematic review of randomized studies]. Dtsch Med Wochenschr 123:273-277, 1998. 48. Garfinkel M, Schumacher HR Jr: Yoga. Rheum Dis Clin North Am 26:125-132, 2000. 49. Rains C, Bryson HM: Topical capsaicin: A review of its pharmacological properties and therapeutic potential in post-herpetic neuralgia, diabetic neuropathy and osteoarthritis. Drugs Aging 7:317-328, 1995. 50. McCarthy GM, McCarty DJ: Effect of topical capsaicin in the ­therapy of painful osteoarthritis of the hands. J Rheumatol 19: 604-607, 1992. 51. Deal CL, Schnitzer TJ, Lipstein E, et al: Treatment of arthritis with topical capsaicin: A double-blind trial. Clin Ther 13:383-395, 1991. 52. Dreiser RL, Tisne-Camus M: DHEP plasters as a topical treatment of knee osteoarthritis: A double-blind placebo-controlled study. Drugs Exp Clin Res 19:117-123, 1993. 53. Rolf C, Engstrom B, Beauchard C, et al: Intra-articular absorption and distribution of ketoprofen after topical plaster application and oral intake in 100 patients undergoing knee arthroscopy. Rheumatology 38:564-567, 1999. 54. Goodman LS, Gilman A: The Pharmacological Basis of Therapeutics. New York, Pergamon Press, 1990. 55. Grace D, Rogers J, Skeith K, Anderson K: Topical diclofenac versus placebo: A double blind, randomized clinical trial in patients with osteoarthritis of the knee. J Rheumatol 26:2659-2663, 1999. 56. Niethard FU, Gold MS, Solomon GS, et al: Efficacy of topical diclofenac diethylamine gel in osteoarthritis of the knee. J Rheumatol 32:2384-2392, 2005.

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97. Jubb RW, Beinat L, Dacre J, et al: A one-year randomized, placebo (saline) controlled clinical trial of 500-730 kDa sodium hyaluronate (Hyalgan) on the radiological change in osteoarthritis of the knee. Int J Clin Pract 57:467-474, 2003. 98. Itokazu M, Matsunaga T: Clinical evaluation of high-molecularweight sodium hyaluronate for the treatment of patients with periarthritis of the shoulder. Clin Ther 17:946-955, 1995. 99. Rovetta G, Monteforte P: Intraarticular injection of sodium hyaluronate plus steroid versus steroid in adhesive capsulitis of the shoulder. Int J Tissue React 20:125-130, 1998. 100. Karzel K, Domenjoz R: Effects of hexosamine derivatives and uronic acid derivatives on glycosaminoglycan metabolism of fibroblast cultures. Pharmacology 5:337-345, 1971. 101. Bassleer C, Reginster JY, Franchimont P: Effects of glucosamine on differentiated human chondrocytes cultivated in clusters [abstract]. Rev Esp Reumatol 20(Suppl 1):96, 1993. 102. Shikhman AR, Kuhn K, Alaaeddine N, Lotz M: N-acetylglucosamine prevents IL-1 beta-mediated activation of human chondrocytes. J Immunol 166:5155-5160, 2001. 103. Krajickova J, Macek J: Urinary proteoglycan degradation product excretion in patients with rheumatoid arthritis and osteoarthritis. Ann Rheum Dis 47:468-471, 1988. 104. Reichelt A, Forster KK, Fischer M, et al: Efficacy and safety of intramuscular glucosamine sulfate in osteoarthritis of the knee: A randomised, placebo-controlled, double-blind study. Arzneimittelforschung Drug Res 44:75-80, 1994. 105. Muller-Fabender H, Bach GL, Haase W, et al: Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis Cartilage 2:61-69, 1994. 106. Hochberg MC: What a difference a year makes: Reflections on the ACR recommendations for the medical management of osteoarthritis. Curr Rheumatol Rep 3:473-478, 2001. 107. Herrero-Beaumont G, Roman JA, Trabado MC, et al: Effects of glucosamine sulfate on 6-month control of knee osteoarthritis sym­­ ptoms vs. placebo and acetaminophen: Results from the Glucosamine Unum in Die Efficacy (GUIDE) trial [abstract 1203]. Arthritis Rheum 52(Suppl):S460, 2005. 108. Hughes R, Carr A: A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee. Rheumatology 41:279-284, 2002. 109. McAlindon T, Formica M, LaValley M, et al: Effectiveness of glucosamine for symptoms of knee osteoarthritis: Results from an Internet-based randomized, double-blind, controlled trial. Am J Med 117:643-649, 2004. 110. Towheed T, Maxwell L, Anastassiades T, et al: Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev CD002946, 2005. 111. Cibere J, Kopec JA, Thorne A, et al: Randomized double-blind, ­placebo-controlled glucosamine discontinuation trial in knee osteoarthritis. Arthritis Care Res 51:738-745, 2004. 112. Das A Jr, Hammad TA: Efficacy of a combination of FCHG49 ­glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. Osteoarthritis Cartilage 8:343-350, 2000. 113.    Clegg DO, Reda DJ, Harris CL, et al: Glucosamine, chondroitin ­sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 354:795-808, 2006. 114. Qiu GX, Weng XS, Zhang K, et al: A multi-center, randomized, ­controlled clinical trial of glucosamine hydrochloride/sulfate in the treatment of knee osteoarthritis. Zhongua Yi Xue Za Zhi 85: 3067-3070, 2005. 115. Reginster JY, Deroisy R, Rovati LC, et al: Long-term effects of glucosamine sulphate on osteoarthritis progression: A randomised, placebocontrolled clinical trial. Lancet 357:251-256, 2001. 116. Pavelka K, Gatterova J, Olejarova M, et al: Glucosamine sulfate use and delay of progression of knee osteoarthritis: A 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med 162: 2113-2123, 2002. 117. Mazzuca SA, Brandt KD, Lane KA, et al: Knee pain reduces joint space width in conventional standing anteroposterior radiographs of osteoarthritic knees. Arthritis Rheum 46:1223-1227, 2002. 118. Le Graverand MP, Mazzuca S, Lassere M, et al: Assessment of the radiographic positioning of the osteoarthritic knee in serial radiographs: Comparison of three acquisition techniques. Osteoarthritis Cartilage 14(Suppl A):A37-A43, 2006.

119. Mazieres B, Loyau G, Menkes CJ, et al: Chondroitin sulfate in the treatment of gonarthrosis and coxarthrosis: 5-month results of a ­multicenter double-blind controlled prospective study using placebo. Rev Rhum 59:466-472, 1992. 120. Morreale P, Manopulo R, Galati M, et al: Comparison of the antiinflammatory efficacy of chondroitin sulfate and diclofenac sodium in patients with knee osteoarthritis. J Rheumatol 23:1385-1391, 1996. 121. Michel BA, Stucki G, Frey D, et al: Chondroitins 4 and 6 sulfate in osteoarthritis of the knee: A randomized, controlled trial. Arthritis Rheum 52:779-786, 2005. 122. Srivasta KC, Mustafa T: Ginger (Zingiber officinale) in rheumatism and musculoskeletal disorders. Med Hypotheses 39:342-348, 1992. 123. Swain AR, Duton SP, Truswell AS: Salicylates in foods. J Am Diet Assoc 85:950-960, 1985. 124. Mustafa T, Srivastava KC, Jensen KB: Drug development. Report 9. Pharmacology of ginger, Zingiber officinale. J Drug Dev 6:25-89, 1993. 125. Altman RD, Marcussen KC: Effects of a ginger extract on knee pain in patients with osteoarthritis. Arthritis Rheum 44:2531-2538, 2001. 126. Henrotin YE, Sanchez C, Deberg MA, et al: Avocado/soybean unsaponifiables increase aggrecan synthesis and reduce catabolic and proinflammatory mediator production by human osteoarthritic chondrocytes. J Rheumatol 30:1825-1834, 2003. 127. Henroitin YE, Labasse AH, Jaspar JM, et al: Effects of three avocado/ soybean unsaponifiable mixtures on metalloproteinases, cytokines and prostaglandin E2 production by human articular chondrocytes. Clin Rheumatol 17:31-39, 1998. 128. Maheu E, Mazieres B, Valat JP, et al: Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the knee and hip: A prospective, randomized, double-blind, placebo­controlled, multicenter clinical trial with six-month treatment period and two-month follow-up demonstrating a persistent effect. Arthritis Rheum 41:81-91, 1998. 129. Lequesne M, Maheu E, Cadet C, et al: Structural effect of avocado/ soybean unsaponifiables (ASU) on joint space loss in hip osteoarthritis (HOA) over 2 years: A placebo controlled trial. Arthritis Rheum 47:50-58, 2002. 130. Piscoya J, Rodriguez Z, Bustamante SA, et al: Efficacy and safety of freeze-dried cat’s claw in osteoarthritis of the knee: Mechanisms of action of the species Uncaria guianensis. Inflamm Res 50:442-448, 2001. 131. Nadanaka S, Clement A, Masayama K, et al: Characteristic hexa­ saccharide sequences in octasaccharides derived from shark cartilage chondroitin sulfate D with a neurite outgrowth promoting activity. J Biol Chem 273:3296-3307, 1998. 132. Barcelo HA, Wiemeyer JC, Sagasta CL, et al: Experimental osteoarthritis and its course when treated with S-adenosyl-L-methionine. Rev Clin Esp 187:74-78, 1990. 133. Montrone F, Fumagalli M, Sarzi Puttini P, et al: Double-blind study of S-adenosyl-methionine versus placebo in hip and knee arthrosis. Clin Rheumatol 4:484-485, 1985. 134. Bradley JD, Flusser D, Katz BP, et al: A randomized, double blind, placebo controlled trial of intravenous loading with S­adenosylmethionine (SAM) followed by oral SAM therapy in patients with knee osteoarthritis. J Rheumatol 21:905-911, 1994. 135. Najm WI, Reinsch S, Hoehler F, et al: S-adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: A double-blind, cross-over trial. BMC Musculoskeletal Disord 5:6, 2004. 136. Altman R, Brandt K, Hochberg M, et al: Design and conduct of clinical trials in patients with osteoarthritis: Recommendations from a task force of the Osteoarthritis Research Society. Osteoarthritis ­Cartilage 4:217-243, 1996. 137. Lozada CJ, Altman RD: Chondroprotection in osteoarthritis. Bull Rheum Dis 46:5-7, 1997. 138. Brittberg M, Lindahl A, Nilsson A, et al: Treatment of deep cartilage defect in the knee with autologous chondrocyte transplantation. N Engl J Med 331:889-895, 1994. 139. Amin AR, Attur MG, Thakker GD, et al: A novel mechanism of action of tetracyclines: Effects on nitric oxide synthases. Proc Natl Acad Sci U S A 93:14014-14019, 1996. 140. Tilley BC, Alarcon GS, Heyse SP, et al: Minocycline in rheumatoid arthritis: A 48-week, double-blind, placebo-controlled trial. Ann Intern Med 122:81-89, 1995.

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141. Cole AD, Chubinskaya S, Luchene LJ, et al: Doxycycline disrupts chondrocyte differentiation and inhibits cartilage matrix degradation. Arthritis Rheum 32:1727-1734, 1994. 142. Yu LP Jr, Smith GN Jr, Hasty KA, Brandt KD: Doxycycline inhibits type XI collagenolytic activity of extracts from human osteoarthritic cartilage and of gelatinase. J Rheumatol 18:1450-1452, 1991. 143. Brandt KD, Yu LP, Amith G, et al: Therapeutic effect of doxycycline (doxy) in canine osteoarthritis (OA). Osteoarthritis Cartilage 1: 14, 1993. 144. Brandt KD, Mazzuca SA, Katz BP, et al: Effects of doxycycline on progression of osteoarthritis: Results of a randomized, placebo-­controlled, double-blind trial. Arthritis Rheum 52:2105-2025, 2005. 145. Lewis EJ, Bishop J, Bottomley D, et al: Ro32-3555, an orally active collagenase inhibitor, prevents cartilage breakdown in vitro and in vivo. Br J Pharmacol 121:540-546, 1997. 146. Burkhardt D, Ghosh P: Laboratory evaluation of antiarthritic drugs as potential chondroprotective agents. Semin Arthritis Rheum 17 (Suppl 1):3-34, 1987. 147. Altman RD, Dean DD, Muniz OE, Howell DS: Prophylactic treatment of canine osteoarthritis with glycosaminoglycan polysulfuric acid ester. Arthritis Rheum 32:759-766, 1989. 148. Rejholec V: Long-term studies of antiosteoarthritic drugs: An assessment. Semin Arthritis Rheum 17(Suppl 1):35-53, 1987. 149. Pavelka K Jr, Sedlackova M, Gatterova J, et al: Glycosaminoglycan polysulfuric acid (GAGPS) in osteoarthritis of the knee. Osteoarthritis Cartilage 3:15-23, 1995. 150. Moskowitz RW, Reese JH, Young RG, et al: The effects of Rumalon, a glycosaminoglycan peptide complex, in a partial meniscectomy model of osteoarthritis in rabbits. J Rheumatol 18:205-209, 1991. 151. Howell DS, Altman RD: Cartilage repair and conservation in ­osteoarthritis. Rheum Dis Clin North Am 19:713-724, 1993. 152. Pavelka K, Gatterova J, Gollerova V, et al: A 5-year randomized controlled, double-blind study of glycosaminoglycan polysulphuric acid complex (Rumalon) as a structure modifying therapy in osteoarthritis of the hip and knee. Osteoarthritis Cartilage 8:335-342, 2000. 153. Munteanu SE, Ilic MZ, Handley CJ: Calcium pentosan polysulfate inhibits the catabolism of aggrecan in articular cartilage explant ­cultures. Arthritis Rheum 43:2211-2218, 2000. 154. Golding JC, Ghosh P: Drugs for osteoarthrosis. I. The effects of ­pentosan polysulphate (SP54) on the degradation and loss of proteoglycans from articular cartilage in a model of osteoarthrosis induced in the rabbit knee joint by immobilization. Curr Ther Res 32: 173-184, 1983. 155. Smith MM, Ghosh P, Numata Y, et al: The effects of orally administered calcium pentosan polysulfide on inflammation and cartilage degradation produced in rabbit joints by intra-articular injection of a hyaluronate-polylysine complex. Arthritis Rheum 37:125-136, 1994. 156. Innes JF, Barr AR, Sharif M: Efficacy of oral calcium pentosan polysulphate for the treatment of osteoarthritis of the canine stifle joint secondary to cranial cruciate ligament deficiency. Vet Rec 146: 433-437, 2000. 157. Spencer CM, Wilde MI: Diacerein. Drugs 53:98-108, 1997. 158. Martel-Pelletier J, Mineau F, Jolicoeur FC, et al: In vitro effects of diacerhein and rhein on interleukin 1 and tumor necrosis factoralpha systems in human osteoarthritic synovium and chondrocytes. J Rheumatol 25:753-762, 1998. 159. Carney SL, Hicks CA, Tree B, Broadmore RJ: An in vivo investigation of the effect of anthraquinones on the turnover of aggrecans in spontaneous osteoarthritis in the guinea pig. Inflamm Res 44: 182-186, 1995.

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160. Brun PH: Effect of diacetylrhein on the development of experimental osteoarthritis: A biochemical investigation [letter]. Osteoarthritis Cartilage 5:289-291, 1997. 161. Brandt K, Smith G, Kang SY, et al: Effects of diacerein in an accelerated canine model of osteoarthritis. Osteoarthritis Cartilage 5: 438-449, 1997. 162. Pelletier JP, Yaron M, Haraoui B, et al: Efficacy and safety of diacerein in osteoarthritis of the knee. Arthritis Rheum 43:2339-2348, 2000. 163. Dougados M, Nguyen M, Berdah L, et al: Evaluation of the structuremodifying effects of diacerein in hip osteoarthritis: ECHODIAH, a three-year, placebo-controlled trial: Evaluation of the Chondromodulating Effect of Diacerein in OA of the Hip. Arthritis Rheum 44:2539-2547, 2001. 164. Rintelen B, Neumann K, Leeb BF: A meta-analysis of controlled clinical studies with diacerein in the treatment of osteoarthritis. Arch Intern Med 166:1899-1906, 2006. 165. Pelletier JP, Roughley PJ, DiBattista JA, et al: Are cytokines involved in osteoarthritic pathophysiology? Semin Arthritis Rheum 20(Suppl 2): 12-25, 1991. 166. Smith MD, Triantafillou S, Parker A, et al: Synovial membrane inflammation and cytokine production in patients with early osteoarthritis. J Rheumatol 24:365-371, 1997. 167. Attur MG, Dave M, Cipolletta C, et al: Reversal of autocrine and paracrine effects of interleukin 1 (IL-1) in human arthritis by type II IL-1 decoy receptor: Potential for pharmacological intervention. J Biol Chem 275:40307-40315, 2000. 168. Pelletier JP, Mineau F, Ranger P, et al: The increased synthesis of inducible nitric oxide inhibits IL-1ra synthesis by human articular chondrocytes: Possible role in osteoarthritic cartilage degradation. Osteoarthritis Cartilage 4:77-84, 1996. 169. Caron JP, Fernandes JC, Martel-Pelletier J, et al: Chondroprotective effect of intraarticular injections of interleukin-1 receptor antagonist in experimental osteoarthritis: Suppression of collagenase-1 expression. Arthritis Rheum 39:1535-1544, 1996. 170. Pelletier JP, Caron JP, Evans C, et al: In vivo suppression of early experimental osteoarthritis by interleukin-1 receptor antagonist using gene therapy. Arthritis Rheum 40:1012-1019, 1997. 171. Fernandes J, Tardif G, Martel-Pelletier J, et al: In vivo transfer of interleukin-1 receptor antagonist gene in osteoarthritic rabbit knee joints: Prevention of osteoarthritis progression. Am J Pathol 154:1159-1169, 1999. 172. Hunziker EB, Rosenberg L: Induction of repair in partial thickness articular cartilage lesions by timed release of TGF-beta. Transactions of the 40th Annual Meeting of the Orthopaedic Research Society, 1994, Vol 19, Sec 1, p 236. 173. Rogachefsky RA, Dean DD, Howell DS, Altman RD: Treatment of canine osteoarthritis with insulin-like growth factor-1 (IGF-1) and sodium pentosan polysulfate. Osteoarthritis Cartilage 1:105-114, 1993. 174. Frisbie DD, Ghivizzani SC, Robbins PD, et al: Treatment of ­experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene. Gene Ther 9:12-20, 2002. 175. Attur MG, Dave MN, Leung MY, et al: Functional genomic analysis of type II IL-1beta decoy receptor: Potential for gene therapy in human arthritis and inflammation. J Immunol 168:2001-2010, 2002. 176. Doherty PJ, Zhang H, Tremblay L, et al: Resurfacing of articular cartilage explants with genetically-modified human chondrocytes in vitro. Osteoarthritis Cartilage 6:153-159, 1998. 177. Moseley JB, O’Malley K, Petersen NJ, et al: A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med 347:81-88, 2002.

92

Metabolic Bone Disease Nancy E. Lane

KEY POINTS Osteoporosis is a disease defined by low bone density and deterioration of microarchitecture, which reduces bone strength and increases fracture risk. Nearly half of all white women and about one quarter of men will suffer an osteoporotic fracture in their lifetimes. Major clinical risk factors for osteoporotic fractures include older age, low weight, family history of hip fracture, fracture occurring after age 50, glucocorticoid use, and inability to rise from a chair without assistance. Postmenopausal and age-related bone loss results from an uncoupling of bone remodeling such that bone resorption is greater than bone formation, resulting in a net loss of bone. Receptor activator of nuclear factor κB ligand (RANKL), produced mainly by osteoblasts in estrogen-deficiency bone loss, is a major stimulator of osteoclast maturation and activity. Polymorphisms in antagonists of the wnt/B catenin signaling pathway that result in a gain of function (e.g., LRP5) are associated with a reduced risk of osteoporosis. Nearly 50% of osteoporosis in men results from secondary causes. Vitamin D deficiency can result in osteoporosis and fractures. Biochemical markers measured in the serum, including C and N telopeptide cross-links of type I collagen, correlate with osteoclast activity on the bone surface. Treatment of high-turnover osteoporosis from estrogen ­deficiency with antiresorptive agents (estrogen, raloxifene, and bisphosphonates—alendronate, risedronate, zoledronic acid, ibandronate) and an anabolic agent (recombinant human parathyroid hormone 1-34) can reduce incident ­vertebral fractures. Bisphosphonates and estrogen can reduce new-incident hip fractures. C and N telopeptide cross-links of type I collagen serum levels are lowered with treatment with antiresorptive agents (estrogen, raloxifene, bisphosphonates). The workup for osteoporosis is directed toward excluding secondary causes of bone loss and includes a determination of serum calcium, phosphorus, supersensitive thyroidstimulating hormone, 25-hydroxyvitamin D (25-OHD), and intact parathyroid hormone (PTH) levels; urine calcium and creatinine levels; complete blood count; and alkaline phosphatase and liver function tests. PTH increases osteoblast maturation and life span, increases trabecular bone mass and cortical thickness, and improves bone strength.

PTH treatment (Fortéo 20 μg/day) for 18 to 20 months reduced vertebral fractures by nearly 70% and nonvertebral fractures by nearly 50%. Antiresorptive therapy is needed after a full course of PTH to maintain the newly formed bone mass. Glucocorticoid-induced bone loss results from increased osteoclast activity and reduced osteoblast activity. Glucocorticoid bone loss is most severe in the first 6 months of the therapy, but bone loss continues slowly thereafter. Prevention of glucocorticoid bone loss with bisphosphonates is effective and prevents fractures. Aromatase inhibitors reduce serum estrogen and result in rapid bone loss in postmenopausal women on adjuvant breast cancer therapy. Gonadotropin-releasing hormone agonists decrease ­testosterone and estrogen levels and cause bone loss in men being treated for prostate cancer.

Osteoporosis is characterized by low bone density and a deterioration of bone microarchitecture that reduces bone strength and increases the risk of fracture. The hallmark of osteoporosis is the loss of bone mineral and bone matrix that results in maintenance of a normal mineral-to-matrix ratio. Bone consists of an organic matrix (collagen and noncollagenous proteins) and an inorganic mineral component (calcium and phosphate in hydroxyapatite crystals; see Chapter 4). Normally, bone turnover is tightly coupled with osteoclast-mediated bone resorption followed by osteoblaststimulated bone formation. This delicate balance in bone remodeling results in no net change in skeletal mass. Osteoblasts synthesize osteoid—bone matrix that subsequently undergoes mineralization and becomes mature bone matrix. The skeleton contains approximately 80% cortical bone, which is concentrated in the appendicular skeleton and femoral neck, and 20% more metabolically active trabecular bone, which is located in the spine, epiphyses, and pelvis. Osteoporosis is characterized by reduced bone mass. Osteomalacia encompasses disorders in which there is decreased mineralization of bone matrix. Paget’s disease is a skeletal disorder characterized by increased rates of bone turnover with the development of disorganized woven bone.

OSTEOPOROSIS EPIDEMIOLOGY AND CLINICAL SIGNS Osteoporosis, the most common metabolic bone disease, affects 200 million individuals worldwide. Approximately 28 million Americans have osteoporosis or are at risk for it. 1579

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Osteoporosis, or “porous bone,” is a “disease characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures, especially of the hip, spine and wrist.”1 Although usually asymptomatic, osteoporosis can produce loss of height, pain, dowager’s hump, and increased risk of fracture. After 50 years of age, there is an exponential rise in fractures, such that 40% of women and 13% of men develop one or more osteoporotic fractures in their lifetimes. In the United States alone, there are more than 1.5 million osteoporotic fractures annually, including 250,000 hip, 250,000 wrist, and 500,000 vertebral fractures. Hip fractures are associated with a 12% to 24% mortality rate in women and a 30% mortality rate in men within the first year of fracture, and 50% of patients are unable to ambulate independently and require long-term nursing home care.2 These numbers will continue to grow exponentially as the elderly population of industrialized nations increases. Bone accretion occurs during adolescence, when there is a large increment in bone mass. Peak bone density is normally achieved after puberty and into the third decade of life. However, by age 22, most individuals have achieved their peak bone mass. At menopause, an acceleration of bone loss usually occurs over approximately 5 to 8 years, with an annual 2% to 3% loss of trabecular bone and a 1% to 2% loss of cortical bone. Both men and women lose bone with age. Over a lifetime, women lose approximately 50% of trabecular and 30% of cortical bone; men generally lose two thirds of these amounts.3 Osteoporosis was previously thought to be a silent disease that was part of the normal aging process. However, the advent of bone densitometry has made it possible to accurately and reproducibly identify patients at risk for osteoporosis so that prevention and treatment strategies can be instituted to reduce fractures. With a health care expenditure of $13.8 billion annually for osteoporosis-related fractures and a projected threefold rise in these costs over the next 40 years in the United States, the institution of effective prevention and treatment strategies to reduce fractures is of great importance.1,4 PATHOPHYSIOLOGY OF MENOPAUSAL AND AGE-RELATED BONE LOSS Bone is constantly undergoing remodeling, whereby areas of bone resorption produced by osteoclastic action are replaced by bone laid down by osteoblasts. Osteoporosis results from an imbalance between bone resorption and formation. The initiation of bone remodeling is still being debated; however, the osteocytes, or terminally differentiated osteobla­sts, located within the bone matrix and connected to one another and the bone surface may release chemical mediators that attract osteoclasts to the bone surface (Fig. 92-1). Osteoclasts originate from the colony-forming unit granulocytemonocytes, are attracted to the bone surface, attach to bone matrix, and resorb bone tissue. Generally, bone resorption is rapid, and a resorption pit is formed within 10 to 14 days. After resorption is complete, osteoblasts, derived from the bone marrow stromal cells, attach to the resorbed bone surface and produce osteoid, which is then mineralized. Bone formation can take up to 3 or 4 months. Therefore, a normal bone remodeling cycle in adults can last 4 to 6 months (see Fig. 92-1A). A number of metabolic changes

such as estrogen deficiency, immobilization, metabolic acidosis, hyperparathyroidism, and systemic and local inflammatory diseases can increase osteoclast number and activity, uncoupling bone turnover. This results in greater bone resorption than bone formation and a net loss of bone tissue. New data show that a number of local factors in bone affect the regulation of bone formation and resorption and the coupling of these processes. These include prostaglandins, insulin-like growth factors (IGFs), interleukins (IL-1, IL-6, and IL-11), tumor necrosis factor (TNF), receptor activator of nuclear factor κB ligand (RANKL), and transforming growth factor (TGF).5 Animal studies have shown that IL-1, IL-6, and TNF knockout mice do not lose bone with estrogen deficiency.6 In addition, inflammatory arthritis animal models find that TNF, IL-1, and IL-6 are all strong stimulators of osteoclastic bone resorption. This link between the immune system and the maintenance of bone mass is intriguing, but additional work is required before we can understand its significance. A number of mechanisms underlie primary osteoporosis, including a low peak bone mass as a young adult and rapid bone loss during menopause. Factors contributing to agerelated bone loss include impaired calcium absorption with age, a compensatory rise in parathyroid hormone (PTH) levels, and greater resorption than formation of bone. Estrogen deficiency is associated with the release of cytokines IL-1, IL-6, TNF, and RANKL, which leads to the recruitment and stimulation of osteoclasts in the marrow and increased production of bone-resorptive cytokines, which may contribute to menopause-related bone loss.5 Estrogen therapy, however, inhibits IL-1 release, and in oophorectomized rats, an inhibitor of IL-1 (the IL-1 receptor antagonist) suppresses bone loss.6 IL-6 levels also increase with age in human marrow cultures7 and in peripheral monocytes. IL-1 and TNF induce the production of IL-6 from osteoblasts and stromal cells. Further evidence supporting a role of IL-6 in bone turnover includes data showing that oophorectomized IL-6 knockout transgenic mice do not lose bone. Two other proteins have been identified that influence osteoclast activity: osteoprotegerin (OPG) and RANKL, which are produced by osteoblasts.8 Estrogen deficiency increases osteoblast production of RANKL, which stimulates maturation and activity of osteoclasts by attaching to RANKL on the surface of immature and mature osteoclasts. Simultaneously, estrogen deficiency decreases osteoblast production of OPG, the decoy receptor that reduces RANKL production and activity. Adenoviral delivery of OPG ameliorates bone resorption in a mouse ovariectomy model of osteoporosis.8 Both preclinical animal models and clinical trials of women with low bone mass have been completed and demonstrate that inhibition of RANKL with a monoclonal antibody (RANKL inhibitor) prevents estrogen-deficiency bone loss.9 In addition, a number of genetic, nutritional, and lifestyle risk factors predispose to the development of osteoporosis. Caucasians and Asians are at risk for low bone mass and osteoporosis, whereas African Americans have a higher bone density and one third to one half the number of fractures.1,8,9 Some studies show that African Americans have lower vitamin D and urinary calcium levels, higher PTH levels, and skeletal resistance to the effects of PTH on bone.10-12 Studies in twins and families show that up to 80% of the variance in bone mass is accounted for by genetic

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BONE REMODELING Activation Resting phase Osteoclasts Lining cells

Osteocytes

Osteocytes

Resorption

Reversal

Formation

Apoptotic osteoclasts

Osteoclasts

Osteoblasts

Preosteoblasts

Osteoid

Osteocytes

Osteocytes

A 1.4 1.3 1.2 1.1

BMD (Total [L]) = 0.596 g/cm2

BMD

1.0 0.9 0.8 0.7 0.6

+

0.5 0.4 0.3 20

B

30

40

50

60

70

Age

80

C

Region

BMD

T

Z

Neck

0.444

1.42

74%

Troch

0.491

0.41

92%

Inter

0.720

0.72

87%

TOTAL

0.596

0.87

85%

Ward’s

0.263

3.65 52% (25.0) 2.10 70% 25.0 2.45 65% (35.0) 2.83 63% (25.0) 4.03 36% (25.0)

1.08

67%

T = peak BMD matched Z = age matched

NHA

02/01/97

Figure 92-1  A, Bone remodeling cycle. Osteocytes most likely release chemicals to the bone surface that attract osteoclasts. Osteoclasts attach to the bone matrix, create a tight ring, and release acid that lowers the pH and dissolves the mineral from the bone matrix. After the mineral is released, the demineralized matrix is broken down. The osteoclast leaves the bone surface, and an osteoblast is attracted to the area of the bone that was resorbed. The resorption phase is about 10 to 14 days. Osteoblasts produce new bone, or osteoid, that fills in the resorption pit. Also, some of the osteoblasts are left within the bone matrix as osteocytes. The osteoid mineralizes over about 3 months, and the bone remodeling cycle is complete. B and C, The bone density of a postmenopausal woman is compared with that of both young, normal controls and age- and gender-matched controls. The T-score and Z-score represent the number of standard deviations below young, normal controls and age-matched controls, respectively. Because the bone density provides a gradient of fracture risk, therapies can be instituted to prevent the development of osteoporosis or to treat patients at increased risk for fracture.

factors.13 A maternal history of hip fracture, for example, is associated with a twofold increased risk of a hip fracture.14 Data from Uitterlinden and colleagues15 show that the gene encoding collagen type IA1 is associated with low bone density with increasing age and an increased risk of fracture. In the ss allele group, bone density was 12% lower at the femoral neck and 20% lower at the lumbar spine than that in the SS group, indicating an increased gene-dose effect with increasing age. However, COLIA1 is associated with a lower baseline bone density and not an increased rate of

bone loss. Further, genetically determined architectural features of bone, such as a long hip axis length, may contribute to increased fracture risk; conversely, a short hip axis length confers some protective effect.16 Recently, a family has been described whose members have very high bone mass but are otherwise phenotypically normal. This family has a mutation (an amino acid change) in the low-density lipoprotein receptor-related protein 5 (LRP5). Using in situ hybridization to a rat tibia, expression of LRP5 was detected in areas of bone involved in remodeling. Additional studies

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have reported that this LRP5 mutation increases wnt signaling, which may alter bone mass through a primary defect of bone formation. Individuals with this mutation demonstrate normal levels of bone resorption, but specific markers of bone formation are strikingly elevated. The observation that LRP5 is expressed at high levels in osteoblasts is consistent with its having a role in this area. Further work is now required to determine whether other mutations in the chromosome containing the LRP5 segment are associated with a variation in bone density in the general population.17,18 Other risk factors for osteoporosis, as enumerated in Table 92-1, include low body weight and reduced gonadal steroid levels.13 Lifestyle factors that may contribute to the development of osteoporosis include cigarette smoking, excessive alcohol intake, reduced physical activity, and inadequate calcium intake, according to some reports. Cigarette smokers have poorer health than nonsmokers, impaired calcium absorption, lower estrogen levels, earlier menopause, and more fractures, and they exercise less; smoking cessation reverses this risk of osteoporosis. In a large, prospective study of 9516 women older than 65 years, the following lifestyle factors significantly increased the risk of hip fracture: no walking for exercise, intake of more than two cups of coffee daily, current use of long-acting benzodiazepines and anticonvulsant drugs, current weight less than weight at age 25 years, height greater than 5 feet 7 inches, age older than 80 years, fracture since age 50 years, inability to stand from a chair without using arms, poor depth perception, and self-evaluation of health as fair to poor.14 Low bone density in conjunction with a fall or trauma predisposes an individual to a fracture. Poor health and compromise of neuromuscular function increase the risk of osteoporosis and falls, which in turn increase the risk of hip fracture.14 Importantly, elderly Caucasian women with both a low bone mass and more than two risk factors have a nearly 20-fold increased risk for fracture.

Table 92-1  Risk Factors for Osteoporosis Primary Previous fracture after age 30 Family history of hip fracture Cigarette smoking Weight <127 lb Low bone mineral density Secondary Nonmodifiable White race Advanced age Frailty or poor health Dementia Modifiable Low calcium intake Eating disorder Low testosterone levels (men) Premenopausal estrogen deficiency (amenorrhea >1 yr or   menopause at age <45 yr) Excessive alcohol intake Physical inactivity Impaired vision Neurologic disorder Lack of sunlight exposure

Secondary causes of bone loss that can affect women and men of all ages and races are listed in Table 92-2. Glucocorticoid therapy is the most common secondary cause of bone loss. Osteoporotic fractures develop in an estimated 30% to 50% of glucocorticoid-treated patients.19 Glucocorticoid therapy causes bone loss through a number of different mechanisms, such as producing a negative calcium balance through impaired intestinal calcium absorption, increasing urinary calcium excretion, decreasing bone formation, increasing bone resorption by stimulating osteoclast activity by macrophage colony-stimulating factor, and suppressing endogenous gonadal steroid production.19 Therapy with glucocorticoids leads to an early and, in some instances, dramatic loss of trabecular bone, with less effect on cortical bone.

Table 92-2  Medical Disorders and Medications   Associated with Bone Loss and Osteoporosis Primary osteoporosis Juvenile osteoporosis Postmenopausal osteoporosis Involutional osteoporosis Endocrine abnormalities Glucocorticoid excess Thyroid hormone excess (supraphysiologic) Hypogonadism (including from prolactinoma or anorexia nervosa) Hyperparathyroidism Hypercalciuria Processes affecting bone marrow Multiple myeloma Leukemia Gaucher’s disease Systemic mastocytosis Immobilization Space flight Gastrointestinal diseases Gastrectomy Primary biliary cirrhosis Celiac disease Renal insufficiency Chronic respiratory diseases Connective tissue disorders Osteogenesis imperfecta Homocysteinuria Ehlers-Danlos syndrome Rheumatologic disorders Ankylosing spondylitis Rheumatoid arthritis Systemic lupus erythematosus Medications Anticonvulsants Heparin Methotrexate Cyclophosphamide (Cytoxan) and GnRH agonists (hypogonadism) Lithium Cyclosporine Aluminum Excessive alcohol Premenopausal tamoxifen Aromatase inhibitors Modified from LeBoff MS: Calcium and metabolic bone disease. In Medical Knowledge Self Assessment Program. Philadelphia, American College of Physicians, 1995. GnRH, gonadotropin-releasing hormone.

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In hyperthyroidism (Graves’ disease or toxic nodule) or supraphysiologic therapy with thyroid hormone, the ensuing accelerated bone turnover may produce a reduction in bone mass when the thyroid-stimulating hormone level is suppressed, even when thyroid hormone levels are within the normal range.20 Athletic amenorrhea, ano­ rexia nervosa, and other hypogonadal states, including the use of gonadotropin-releasing hormone agonists,21,22 may result in bone loss. In addition to estrogen deficiency, women with anorexia nervosa have low levels of IGF-1 and reduced levels of adrenal androgen dehydroepiandrostenedione, which may contribute to the development of osteoporosis.23 Osteoporosis in Men Osteoporosis in men was not recognized 20 years ago but is now a major public health problem owing to men’s longer life spans. The epidemiology of osteoporosis in men is just now being evaluated. Fracture risk occurs in adolescence and young adulthood and then increases after the age of 70. Long bone fractures occur more commonly in young men, while hip and spine fractures are more prevalent in men older than 70 years. The increase in fractures in older men is just as significant as it is in women, but it occurs about 10 years later in life, with an age-adjusted incidence of hip fractures in men of about one third to one half that of women.24 Elderly men who sustain hip fractures have a greater risk of dying or being permanently disabled compared with women.24 Risk factors for osteoporosis in men include older age, low bone mineral density (BMD), history of a low-trauma fracture as an adult, and a family history of osteoporotic fractures. There are a number of secondary causes of osteoporosis in men; for instance, hypogonadism causes an increase in bone turnover and rapid bone loss as gonadal function declines with age. At this time, severe hypogonadism from androgen deprivation therapy for prostate cancer is common in elderly men. The exact role of estrogen and androgens in male skeletal health is not yet known. Although estrogen is needed for the young male skeleton, serum estrogen levels are highly correlated with bone remodeling, BMD, and rate of BMD loss in older men; the associations are stronger than with testosterone. However, serum testosterone levels are also highly correlated with indices of bone resorption and formation. The roles of estrogen and testosterone in the male skeleton need additional investigation.25 Some of the other common causes of osteoporosis in men that are not as frequent in women are alcoholism, gastrointestinal disorders, including hepatic disorders, and malabsorption.24 Osteoporosis in Rheumatic Diseases and Other Conditions Recently, studies have reported significant bone loss in patients with systemic inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), and ankylosing spondylitis. Patients with rheumatoid arthritis experience periarticular and generalized bone loss, with an increased incidence of fractures compared with the general population.26 T lymphocytes, tissue macrophages, and

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s­ ynovial-like fibroblasts release inflammatory cytokines (IL1, TNF, IL-6) and inhibitory wnt signaling proteins such as dkk-1 and RANKL, which stimulate preosteoclasts in the bone marrow and synovium to actively resorb bone; in addition, osteoblast maturation is altered.27,28 In an animal model of inflammatory arthritis induced with collagen, animals pretreated with OPG did not have bone loss within the periarticular bone or the presence of erosions.29 Additional factors that may contribute to osteoporosis in patients with rheumatic diseases include decreased mobility, glucocorticoid therapy, and systemic inflammation.30 Some data, however, show that low-dose glucocorticoid therapy in women with rheumatoid arthritis does not have adverse skeletal effects, possibly because of a decrease in disease activity in association with the suppression of inflammatory cytokines and improved physical activity and function.31,32 Ankylosing spondylitis is also associated with fractures and reduced bone density in the spine and proximal femur, even early in the disease.33 Patients with SLE have a high rate of osteoporotic fractures in the presence of low to normal bone mass, suggesting that systemic inflammation alters bone ­turnover. Increased serum levels of TNF can reduce osteoblast maturation and increase osteoclast maturation and activity; in addition, other inflammatory factors such as oxidized low-density lipoproteins and inflammatory high-density lipoproteins can direct mesenchymal stem cells to differentiate into adipocytes instead of osteoblasts and impair bone mass.34 Infiltrative processes in the marrow, such as multiple myeloma, mastocytosis, and Gaucher’s disease, may produce osteoporosis. Patients with Gaucher’s disease show an accumulation of glucocerebrosides in macrophages in the spleen, liver, and bone marrow, which causes hepatosplenomegaly, anemia, thrombocytopenia, bone infarcts and infections, fractures, and aseptic necrosis.35 The immunosuppressant drug cyclophosphamide (Cy­­ t­oxan) induces amenorrhea and hypogonadism, which may increase the risk of bone loss. Women who undergo premature menopause from cyclophosphamide therapy can have estrogen-deficiency bone loss in their 30s. Young women with SLE who try to preserve ovarian function while undergoing cyclophosphamide therapy by taking ­gonadotropin-releasing hormone agonists may also experience estrogen-deficiency bone loss. In rodent models, the immunosuppressive drug cyclosporine produces a time- and dose-dependent bone loss36; in contrast, azathioprine (Imuran) and rapamycin (sirolimus) do not appear to adversely affect skeletal homeostasis.37 Therapy with both cyclosporine and prednisone in transplant recipients is associated with early accelerated bone loss after the initiation of treatment and the development of osteoporosis and fractures with continued exposure.38 Vitamin D deficiency may also manifest as osteopenia and fractures, but this condition is both preventable and treatable.39 Vitamin D insufficiency is common in older patients and in those with SLE who do not get an adequate amount of sunlight or use very potent sunscreens. Also, patients with malabsorption syndromes and liver disease can be vitamin D deficient. Unlike the situation in osteoporosis, very low vitamin D levels are often characterized by a mineralization defect and osteomalacia. Vitamin D deficiency is reported to be present in up to 50% of women with hip fractures.39

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ASSESSMENT OF BONE DENSITY AND OSTEOPOROTIC RISK Osteoporosis may first be diagnosed when a radiograph shows signs of demineralization or a spinal film shows evidence of compression fractures of vertebral bodies. Because an estimated 25% to 50% of bone mass must be lost to show osteopenia on radiographs, conventional radiography is an insensitive technique for diagnosing bone loss. Radiographs may demonstrate signs of secondary causes of osteoporosis, such as the presence of subperiosteal resorption in hyperparathyroidism, characteristic lytic changes or bone infarcts in Gaucher’s disease, local sites of lytic destruction in malignancy, and pseudofractures in osteomalacia. Bone densitometry makes it possible to measure the amount of bone in the relevant fracture sites of the spine, forearm, and proximal femur, as well as the total body. Techniques for evaluating bone mass include dual-energy x-ray absorptiometry (DEXA) and quantitative computed tomography (CT) scanning of the spine.1,2 Bone density evaluations using DEXA incorporate the attenuation of soft tissue and bone by x-rays to calculate the BMD. DEXA is both precise and safe, with a very low radiation exposure. With reproducibility errors of approximately 0.6% to 1.5%, this technique is able to detect small changes over time.2,40,41 Further, newer DEXA techniques measure bone density rapidly, in 0.5 to 2.5 minutes. It is possible to determine the BMD of the central trabecular portion of the spine using DEXA, excluding osteophytes or extraskeletal calcifications that may falsely raise the bone density in the standard anteroposterior projection. With quantitative CT scanning, it is possible to directly measure the loss of trabecular bone in the central region of the spine, but the procedure entails a comparatively high radiation exposure and time, and precision errors are usually higher than those associated with DEXA. Figure 92-1B and C show the BMD in a postmenopausal patient compared with that of young, healthy controls to determine whether there is reduction in BMD compared with peak bone mass (percentage of young healthy controls expressed as a T-score) and with age-matched controls to assess whether BMD is diminished relative to an age-matched cohort (percentage of age-matched controls expressed as a Z-score). There is an inverse relationship between bone density and the gradient of risk for fracture.42 Prospective studies show that bone densitometry identifies patients with an increased gradient of risk for fracture. In 8134 women, a 1–standard deviation (SD) decrement in the bone density of the spine and the femoral neck compared with age-adjusted controls was associated with a 1.6- and 2.6-fold increased risk of hip fracture, respectively.43 Measurement of bone density in the hip is more predictive of hip fracture than is measurement at another site. Studies show that in women older than 65 years, hip bone density is predictive of spine and hip fracture and that conventional spine density does not add to the diagnostic utility of a single hip bone density test in assessing the risk of fracture. Although bone densitometry provides a quantitative measure of bone mass, in vitro studies using ultrasonography indicate that this technique also provides information about the mechanical properties of bone, including both density and elasticity. These qualities are strong predictors of bone strength. Ultrasound techniques include speed-of-sound and

broadband ultrasound attenuation methods; the speed-ofsound technique reflects bone density and elasticity, and broadband ultrasound attenuation is an indicator of bone density, bone structure, and composition. Approved for clinical use by the U.S. Food and Drug Administration (FDA), both ultrasound techniques have been shown to discriminate between normal and osteoporotic patients at increased fracture risk.44 The T-score parameters used by some ultrasound machines do not correspond to T-score levels as measured by DEXA. Although ultrasonography is a radiation-free technique that may provide information about the risk of fracture and bone quality, the reproducibility of this technique and the measurement sites of mainly cortical bone or low-weight-bearing locations may make it unsuitable for monitoring small changes in bone over time. Therefore, ultrasound measurements cannot reliably be used to monitor response to osteoporosis therapies. Further data are necessary to validate the clinical utility of ultrasonography. On the basis of the guidelines of the Scientific Advisory Board of the National Osteoporosis Foundation, bone densitometry is useful in determining which patients might benefit from therapy to protect the skeleton, including patients who have a deficiency of gonadal hormones (postmenopausal women younger than 65 years with one or more risk factors or older than 65 years regardless of risk factors), postmenopausal fracture, evidence of osteopenia or a vertebral abnormality on radiographs, hyperparathyroidism, or exposure to supraphysiologic doses of glucocorticoids (Table 92-3). Bone densitometry is also used to decide when to commence therapy for osteoporosis and to assess the clinical response to therapeutic interventions.40 Screening normal premenopausal women is not cost-effective. The World Health Organization (WHO) has published criteria for osteoporosis based on bone density1,45: 1. Osteopenia (low bone mass) is defined as a bone density measurement between 1 and 2.5 SD below the young-adult mean (T-score between −1 and −2.5). 2. Osteoporosis is defined as a bone density measurement less than 2.5 SD below that of young, healthy controls (T-score <2.5). 3. Established osteoporosis is defined as a T-score of less than 2.5 and the presence of a fracture. Therapy to prevent bone loss is recommended if the Tscore is −1.5 or less in a patient with risk factors or previous fracture, or if the T-score is −2 or less with no risk factors. Table 92-3  Indications for Bone Densitometry All postmenopausal women <65 yr who have one or more ­additional risk factors for osteoporosis (besides menopause) All women >65 yr regardless of additional risk factors To document reduced bone density in patients with vertebral abnormalities or osteopenia on radiographs Estrogen-deficient women at risk for low bone density who are ­considering use of estrogen or an alternative therapy, if bone density would influence the decision Women who have been on estrogen replacement therapy for prolonged periods or to monitor the efficacy of a therapeutic intervention or interventions for osteoporosis To diagnose low bone mass in glucocorticoid-treated individuals To document low bone density in patients with asymptomatic primary or secondary hyperparathyroidism

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­ reatment of osteoporosis is recommended for those in T groups 2 and 3 as defined by the preceding list. T-score cutoffs for diagnosis and treatment do not apply to secondary osteoporosis.45 The current WHO guidelines require a BMD measurement before a patient can be treated for osteoporosis. Recently, WHO developed new guidelines for osteoporosis treatment that can be applied without a BMD measurement. Other guidelines still in development will provide patients and their health care providers with a 5- and 10-year osteoporotic fracture risk determination based on clinical risk factors and BMD (if obtained). These new WHO guidelines should be available soon, and they are intended to increase the number of individuals treated for this disabling disease.46 Markers of Bone Turnover The development of sensitive biochemical markers of bone turnover makes it possible to analyze changes in bone formation and resorption at a given point in time and obtain additional information about a patient’s risk of bone loss and fracture. Only three bone formation markers are currently available. Osteocalcin, a noncollagenous matrix protein in bone, is produced exclusively by osteoblasts; it correlates with histomorphometric bone measurements. In most conditions, bone resorption and formation are tightly coupled, and osteocalcin levels reflect bone turnover. The other markers of bone formation are bone-specific alkaline phosphatase (BSAP), an enzyme that is activated as osteoblasts mature, and amino-terminal propeptide of type I procollagen, a protein whose synthesis is very high in maturing osteoblasts.47 Sensitive indicators of bone resorption derived from the degradation of mature collagen include the urine and serum markers of type I collagen cross-links, including amino-terminal telopeptide of type I collagen (N telopeptides, or NTX) or carboxy-terminal telopeptide of type I collagen (C telopeptides, or CTX). Urinary pyridinoline cross-link, NTX, and CTX levels correlate with histomorphometric determinations of bone resorption; these biomarkers increase with menopause and are high in patients with a variety of disorders characterized by accelerated bone turnover, including Paget’s disease, osteoporosis, and rheumatoid arthritis.48,49 Urinary excretion of N telopeptides is inversely related to total hip and spinal bone density and, according to some studies, may be a more specific index of bone resorption than urinary pyridinoline levels.50 The Epidimiologie de l’Ostioporose Study (EPIDOS) in elderly women showed that elevated C telopeptide and deoxypyridinoline levels are associated with an increased risk of hip fracture independent of BMD (odds ratio of 2). When it is coupled with a T-score less than −2.5, there is an increased risk of fracture, with an odds ratio of 4.8 over a 2.5-year follow-up period.51 Also, Seibel and colleagues52 reported that baseline urine resorption markers, urinary pyridinoline cross-links, were predictive of a new vertebral fracture in women over 1 year of follow-up. In clinical studies, antiresorptive agents such as estrogen and bisphosphonates induce a significant decrease (30% to 70%) first in markers of resorption and then in bone formation markers, often within 3 to 6 months. Resorption markers decrease before

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formation markers and correlate with either maintenance of or increase in BMD. A significant change in bone markers can be observed within months of antiresorptive therapy, before there are changes in BMD.52 Both bone formation and resorption marker changes over 6 to 12 months have been found to predict future fracture risk. In a study of alendronate to reduce osteoporotic fractures, patients who had more than a 30% reduction in bone alkaline phosphatase had the greatest reduction in risk for new vertebral and nonvertebral fractures. Interestingly, studies have found that reductions in markers of bone turnover, either resorption or formation markers, are associated with a reduction in fracture risk. However, long-term, prospective studies of large numbers of women are necessary to determine whether selective biochemical markers of bone turnover can predict changes in BMD or fracture risk and whether these tests should be used in standard clinical practice. Most bone turnover marker data are derived from large studies of antiresorptive agents. However, a bone-building anabolic agent, PTH, has been approved for the treat­­ m­ent of osteoporosis. PTH’s action is to stimulate osteoblast activity; therefore, osteocalcin and other markers of bone formation increase rapidly, within a few weeks of the initiation of treatment. However, activation of the osteoblast over time results in RANKL production, which stimulates osteoclast activity. With continued PTH treatment, markers of osteoclast activity also increase, reaching levels equal to those of formation markers. Because the overall result is an increase in bone mass, the bone turnover markers during PTH therapy reflect significant bone remodeling on both trabecular and cortical bone surfaces. A few small studies have found that increases in both bone formation and resorption markers predict an increase in bone mass with PTH treatment.53-55 Evaluation for Secondary Bone Loss The workup for osteoporosis is directed toward excluding secondary causes of bone loss and includes a determination of serum calcium, phosphorus, supersensitive thyroid­stimulating hormone, 25-hydroxyvitamin D (25-OHD), and intact PTH, as well as urine calcium and creatinine levels. Also, a complete blood cell count, alkaline phosphatase and liver function tests, erythrocyte sedimentation rate (in some cases), and serum and urine protein electrophoresis for patients older than 50 years may be necessary (Table 92-4). In men, additional testing for secondary causes of osteoporosis includes serum testosterone and luteinizing hormone. Further tests to rule out neoplastic or endocrinologic disorders and a bone biopsy (a decalcified bone specimen is obtained after a double tetracycline label with two different fluorescent labels) should be considered in certain patients with progressive bone loss and in those in whom osteoporosis is unlikely. Identification and appropriate therapy for underlying secondary causes of osteoporosis are important. For example, treatment of vitamin D deficiency is best accomplished with vitamin D supplements. Parathyroidectomy in patients with hyperparathyroidism characterized by hypercalcemia, hypercalciuria, nephrolithiasis, age younger than 50 years, or low cortical BMD (Z-score ≤ 2) was associated with a large (4% to 12.8%) increase in bone density over 4 years.56 Bone density was, however, stable for up to

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Table 92-4  Workup for Osteoporosis For All Patients Laboratory tests, including SMA, CBC, supersensitive TSH; ± PTH, alkaline phosphatase, 25-hydroxyvitamin D levels, and either measurement or estimate of 24-hr urinary calcium; ± serum and urine protein electrophoresis and ESR For Selected Patients* Definitive tests for endocrine, neoplastic, and gastrointestinal disorders Bone biopsy under calcified sections with double tetracycline label In some patients, markers of bone turnover to identify those at risk for increased bone loss *Children, premenopausal women, men younger than 60 yr, African Americans, patients with rapidly progressive disease. CBC, complete blood cell count; ESR, erythrocyte sedimentation rate; PTH, parathyroid hormone; SMA, sequential multiple analysis; TSH, thyroid­stimulating hormone. Adapted from Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 6th ed. Published by the American Society of Bone and Mineral Research, 2006.

6 years in patients with mild hyperparathyroidism.57 In addition, treatment of hyperthyroidism, hypercortisolism, and a variety of other disorders that may cause osteoporosis can produce increments in bone mass. Reduction in the systemic inflammation associated with rheumatic diseases, such as TNF blocking agents for rheumatoid arthritis or ankylosing spondylitis or glucocorticoid-sparing agents for SLE (e.g., azathioprine [Imuran], mycophenolate mofetil [CellCept]), can also produce increments in bone mass. TREATMENT Calcium The goals of therapy for osteoporosis are to reduce bone resorption and enhance bone formation, if possible. Bone loss occurs when the calcium intake and absorption are insufficient to balance the daily calcium losses. Prospective data show that calcium stabilizes bone.58 Table 92-5 shows the current recommendations for optimal calcium intake for women and men from the 1997 report of the Institute of Medicine to the National Academy of Sciences.59 In the absence of kidney stones or an underlying disorder of calcium metabolism, these calcium intakes are safe. To prevent negative calcium balance, premenopausal women require 1000 mg and postmenopausal women 1200 mg of total elemental calcium daily.60 Children have increasing calcium requirements during adolescence, and data show increased bone accretion with increased calcium intake in prepubescent and pubertal children. Calcium carbonate contains 40% elemental calcium and should be taken with meals because of poor absorption in achlorhydric patients in the absence of food. Calcium citrate, which contains 24% elemental calcium, has better bioavailability and is more readily absorbed.61 It is also absorbed well on an empty stomach in patients with achlorhydria. Estrogen Hormone replacement therapy (HRT) was once the mainstay of treatment in osteoporosis because estrogen inhibits bone resorption, produces a small rise in bone density, and reduces the risk of fracture by approximately 50% in

Table 92-5  Calcium Requirements Recommended   by the National Academy of Sciences (1997) Age Group

Optimal Daily Calcium Intake (mg)

Infants Birth-6 mo 6 mo-1 yr

400 600

Children 1-8 yr

500-800

Adolescents 9-18 yr 9-10 yr 11-18 yr

800-1200 1200-1500

Pregnant and nursing females

1300

Men and women 19-50 yr >50 yr (± hormone replacement therapy)

1000 1200-1500

Modified from Atkinson SA, Abrams SA, Dawson-Hughes B, et al: Calcium. In Young V (ed): Dietary Reference Intake for Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride. Washington, DC, National Academy Press, 1997, pp 91-143.

r­ etrospective observational studies. Cardiovascular disease is the leading cause of death in postmenopausal women. Previous data from longitudinal observational studies suggested that estrogen replacement had a beneficial effect on reducing primary and secondary cardiac events in postmenopausal women. However, in 1998, data from the 4-year Heart and Estrogen/Progestin Replacement Study were published.62 In this study, 2763 postmenopausal women with a previous history of heart disease were randomized to receive estrogen (0.625 mg) plus progestin (2.5 mg) or placebo alone. Results showed no reduction in the overall rate of coronary heart disease or cardiac events in the treatment group; in fact, an early increase in risk for cardiac events was noted, possibly related to increased coagulability.63 In addition, a large, multicenter, longitudinal study by the Women’s Health Initiative (WHI)—in which 162,000 women aged 50 to 79 years were randomized into a placebo group, an HRT group (if the uterus was intact), or an estrogen-only group (if the uterus was absent)—was terminated early due to an increased risk of breast and cardiovascular events. The research goals for the WHI study were to determine the effects of HRT, diet modification, and calcium and vitamin D supplements on heart disease, osteoporosis, and colorectal cancer risk. After a mean follow-up of 5.3 years in an 8.5-year study, the HRT group had an increased risk of seven more cardiac events per 10,000 women taking the drug for a year, eight more invasive breast cancers, eight more strokes, and eight more pulmonary emboli, but six fewer colorectal cancers and five fewer hip fractures.64 At this time, the general recommendation is that HRT should be used only for vasomotor symptoms that occur at the time of menopause. When these symptoms abate, it is recommended that estrogen replacement (combined estrogen and progestin for women with an intact uterus) be stopped, because the perceived cardiovascular benefits have not been substantiated, and the cardiovascular disease and breast cancer risk make the benefit-to-risk ratio unacceptable for most women. It is important to acknowledge that the estrogenonly arm of the WHI study in women without a uterus did not show an increased risk of heart disease or breast cancer.

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If a woman and her physician decide that she is going to take HRT or estrogen alone for vasomotor symptoms, in those with an increased risk of coagulability, transdermal estrogen replacement should be used.

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postmenopausal women.74,75 At this time, there is very little information on the use of raloxifene in men, so it is not recommend for male patients. Testosterone

Selective Estrogen Receptor Modulators The ideal estrogen replacement therapy would confer the beneficial effects of estrogen on bone and cardiovascular disease without increasing the risk of breast or uterine cancer. Selective estrogen receptor modulators (SERMs) are a nonsteroidal class of drugs that bind to the estrogen receptor and differ from one another in their actions on estrogenresponsive tissues, acting selectively as agonists or antagonists. Tamoxifen, the first available SERM, is an estrogen antagonist that binds to the estrogen receptor and also has estrogen-agonist effects on bone, lipids, clotting factors, and endometrium. Tamoxifen therapy in women with breast cancer produced a small increase in bone density of the spine over 2 years, with no effect on radial bone density, in association with reductions in both low-density lipoprotein and total cholesterol.65 The Breast Cancer Prevention Trial studied 13,388 women at increased risk for breast cancer, comparing treatment with tamoxifen (20 mg daily) to placebo for 5 years.66 Tamoxifen reduced the risk of invasive and noninvasive breast cancer by 50%, and a decreased risk of fracture was observed as well: 45% reduction at the hip and 29% at the spine. An increased incidence of low-grade endometrial cancer was noted, but there was no change in the risk of ischemic heart disease.66 Raloxifene,67 now FDA-approved for the prevention and treatment of osteoporosis, is a SERM that acts as an estrogen agonist on bone, with antagonist effects on the breast and uterus.68 Raloxifene (60 mg/day over a 2-year study period) increased BMD in the lumbar spine by 2.4%, in the total hip by 2.4%, and in the total body by 2%, with a reduction in fracture risk at 2 years similar to that seen with estrogen or alendronate (5 mg) treatment. Over the 2-year study period, raloxifene produced a significant reduction in vertebral fractures: fractures were present in 1.6% of raloxifenetreated women, compared with 2.9% of those in the placebo group; fractures recurred in 7.6% of treated women with a previous fracture, compared with 14.3% of those in the placebo group.69 Endometrial thickness is not increased by raloxifene, but menopausal symptoms may be made worse. Raloxifene has been shown to decrease low-density lipoprotein cholesterol by 12%, with a nonsignificant increase in high-density lipoprotein cholesterol; cardiovascular protection has not yet been determined.70 However, raloxifene, unlike estrogen, does not affect C-reactive protein, which is associated with a risk of cardiovascular disease.71,72 Raloxifene also decreased the incidence of breast cancer by 76% in patients enrolled in a clinical study of osteoporosis, with breast cancer incidence studied as a secondary end point.67 A study that evaluated the effects of raloxifene on cardiovascular disease found no effect.73 One study compared tamoxifen and raloxifene, and another study evaluated raloxifene versus placebo, in the prevention of breast cancer. The first study reported that both tamoxifen and raloxifene reduced the risk of developing breast cancer, and the second found that raloxifene reduced the risk of estrogen receptor–positive breast cancer compared with placebo in

Men with osteoporosis, hypogonadism, and symptoms of low libido may benefit from testosterone replacement therapy. This can be administered as testosterone cypionate or enanthate (50 to 400 mg intramuscularly every 2 to 4 weeks) or as a transdermal testosterone replacement patch that is applied to the scrotal area (Testoderm, 4 to 6 mg/day) or elsewhere (Androderm, 2.5 or 5 mg/day).76 Most studies find that bone mass increases with testosterone replacement when levels of testosterone were very low at the initiation of therapy. Calcitonin Calcitonin, a 32–amino acid peptide synthesized by the C cells of the thyroid gland, is a potent inhibitor of osteoclastmediated bone resorption. Although human and salmon calcitonin are commercially available, salmon calcitonin is most commonly used because of its greater potency. Based on data showing an increase in total body calcium, parenteral calcitonin was approved by the FDA for the treatment of osteoporosis in 1984, and calcitonin in a nasal spray was approved for the treatment of postmenopausal osteoporosis in 1995. Parenteral calcitonin (100 IU subcutaneously or intramuscularly three times a week or daily) can maintain bone density or produce a small increase in bone mass in the spine and, in some instances, the forearm, particularly in patients with a high bone turnover.77 Nasal spray calcitonin is absorbed through the nasal mucosa and is approximately 40% as potent as the parenterally administered drug (e.g., 50 to 100 IU of injectable calcitonin is comparable to 200 IU of nasal spray calcitonin).78 In osteoporotic women more than 5 years past menopause, nasal calcitonin (200 IU/day) increases spinal bone density 2% to 3% compared with placebo, with no effect on proximal femur bone mass; higher doses are necessary in the early menopausal period.78,79 Nasal spray calcitonin therapy in patients with osteoporosis is associated with a 36% reduction in vertebral fractures over 5 years.79 The adverse effects of parenteral calcitonin include nausea, flushing, and local irritation at the injection site. Calcitonin given intranasally is well tolerated, with rhinitis and nasal symptoms such as dryness and crusting being potential side effects. Patients treated with parenteral or intranasal calcitonin may also obtain a beneficial analgesic response in the presence of osteoporotic fractures. Bisphosphonates Bisphosphonates are analogues of pyrophosphate, with a P-C-P rather than a P-O-P core; they are absorbed by the hydroxyapatite of bone and suppress bone resorption. Modification of the side chains can result in the development of a variety of compounds with differing abilities to inhibit bone resorption (Table 92-6). Some bisphosphonates are administered intermittently because of a long skeletal half-life and prolonged retention in bone. These compounds must be taken on an empty stomach because gastrointestinal absorption is less than 10%.

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Table 92-6  Ability of Bisphosphonates to Inhibit   Metaphyseal Bone Resorption in Vivo Chemical Modification

Examples

Antiresorptive Potency

First generation: short alkyl or halide side chain

Etidronate Clodronate

1 10

Second generation: NH2-terminal group

Tiludronate* Pamidronate Alendronate

10 100 100-1000

Third generation: cyclic side chain

Risedronate Ibandronate Zoledronate

1000-10,000 1000-10,000 10,0000

*Tiludronate has a cyclic side chain, not an NH2-terminal group, but it is generally classified as a second-generation compound based on its time of development and potency. Adapted from Watts NB: Treatment of osteoporosis with bisphosphonates [review]. Endocrinol Metab Clin North Am 27:419-439, 1998.

Bisphosphonates have been used for the treatment of patients with Paget’s disease of bone, hypercalcemia of malignancy, and osteoporosis and for the prevention and treatment of glucocorticoid-induced osteoporosis. Etidronate (Didronel) administered intermittently (400 mg/day for 2 weeks in 3-month cycles) produced an approximately 5% increase in bone density of the spine and a 50% reduction in vertebral fractures at 2 years. Longer follow-up did not reveal a significant reduction in vertebral fractures compared with baseline, except in a post hoc analysis of patients with three or more fractures and low bone density.80 Etidronate is not approved by the FDA for the treatment of osteoporosis. Alendronate (Fosamax) is FDA-approved for the prevention and treatment of osteoporosis. Data in postmenopausal women with bone density at least 2.5 SD below peak bone mass show that alendronate (10 mg/day) compared with placebo produces an 8.8% and 7.8% increase in bone density in the spine and femoral trochanter, respectively, and a 5.9% increase in the femoral neck after 3 years of therapy81; there are smaller rises (2.3% to 4.4%) in bone density in the spine and proximal femur in women within 0.5 to 3 years of menopause. Fosamax treatment in women with osteoporosis (T-score <2.5) yields a significant reduction in spine and hip fractures compared with the placebo-treated patients.82 Treatment with alendronate (5 mg/day over 2 years) increased BMD in the lumbar spine by 2.9% and in the hip by 1.3%; in contrast, estrogen-progestin therapy increased BMD in these locations by 4% and 1.8%, respectively.83 Alendronate did not reduce the incidence of clinical fractures in women who had low bone mass but not osteoporosis, although longer studies may be necessary.84 Alendronate treatment is also effective in increasing bone mass in the spine, hip, and total body and helps prevent vertebral fractures and height loss in men with osteoporosis.85 Adverse effects of bisphosphonates include gastrointestinal symptoms, such as stomach pain and esophagitis (caution is advised in patients with active symptoms or a history of ulcer disease), myalgias and arthralgias, and, rarely, osteonecrosis of the jaw. A once-a-week preparation of alendronate (70 mg) is the most commonly used dose for the treatment of osteoporosis.86 This preparation increased spinal and hip bone mass similarly to alendronate 10 mg/day over a 2-year study period.

Risedronate, another oral bisphosphonate, administered at a dose of 5 mg/day increased bone mass and reduced the risk of new vertebral fractures 50% better than placebo.87-89 Another study performed to assess the effect of risedronate on hip fractures found that women with osteoporosis (defined by a femoral neck T-score of ≤ −4.0) had a significant reduction in the risk of hip fracture.90 Risedronate has been approved for the prevention and treatment of osteoporosis (35 mg once a week)91 and for the treatment of Paget’s disease (30 mg/day for 2 months, with retreatment if relapse occurs after 2 months).92 Studies show that risedronate may be well tolerated even in patients with mild gastrointestinal symptoms. Bisphosphonates may also reduce bone pain. Ibandronate (Boniva), another aminobisphosphonate, is approved for the treatment and prevention of postmenopausal osteoporosis. In phase III studies of ibandronate (2.5 mg/day) versus placebo in postmenopausal women with osteoporosis, incident vertebral fractures were reduced about 50%. Another study compared ibandronate 150 mg once a month to the daily 2.5-mg dose and found similar gains in lumbar spine and hip BMD. The FDA approved ibandronate 150 mg/month for the treatment of osteoporosis based on this bridging study.93 Recently, intravenous ibandronate in a dose of 3 mg every 3 months was found to be similar to ibandronate 2.5 mg/day in terms of increasing lumbar spine and hip BMD, and the FDA has approved intravenous ibandronate for this indication. There are no data on hip fractures for this compound.94 Studies of other new bisphosphonates in the prevention and treatment of osteoporosis are under way. Zoledronic acid (Zometa), a potent bisphosphonate, is approved for the treatment of hypercalcemia of malignancy. A phase II, dose-ranging study of zoledronic acid for the treatment of postmenopausal osteoporosis has been completed. A dose of 4 mg given at the beginning of the study increased lumbar spine bone mass by nearly 5%, and biochemical markers of bone resorption remained suppressed nearly 70% below baseline levels at the 12-month point.94a In a recently reported phase III study of intravenous zoledronic acid at a dose of 5 mg/year for 3 years, the absolute risk of new vertebral fractures was reduced by 70%, and the risk of incident hip fracture was reduced by 40% compared with placebotreated women.95 It is expected that intravenous zoledronic acid will be approved for the treatment of postmenopausal osteoporosis in the near future. Zoledronic acid at a dose of 4 mg intravenously every 4 weeks is currently approved for the prevention and treatment of bone metastases in patients with breast cancer and multiple myeloma. Parathyroid Hormone Small randomized studies have determined that the 1-34 fragment of the PTH protein can significantly increase bone mass in the spine, with small losses or no gain at the skeletal sites rich in cortical bone. Small randomized studies have also been performed to assess the anabolic effects of PTH on changes in bone mass. PTH 1-34 (400 to 500 IU/day subcutaneously) with 1,25-dihydroxyvitamin D (0.25 mg/day) produced large increases in spinal bone density, although there was a small loss of cortical bone. The use of parenteral PTH (40 μg/day) alone in women who had endometriosis treated with gonadotropin-releasing hormone agonists for

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12 months produced a 7.5% rise in lateral spinal bone density and prevented bone loss from the femoral neck, trochanter, and total body, despite severe estrogen deficiency over this time interval.96 Lindsay and coworkers97 showed that PTH 1-34 (25 μg/day) increases bone density and decreases vertebral fractures in postmenopausal women taking estrogen replacement therapy. Over a 3-year period, bone density increased 13% in the vertebrae, 2.7% in the hip, and 8% in the total body. Markers of bone formation increased by 55%, and markers of bone resorption increased 20%, demonstrating the uncoupling of bone turnover with an overall increase in formation. In 2001, a recombinant human PTH (rhPTH) composed of the 34 amino acids from the amino-terminal end of the hormone, known as Fortéo, was approved for the treatment of postmenopausal osteoporosis. In a large international, multicenter study, osteoporotic women with fracture were randomized to receive rhPTH 20 μg/day, 40 μg/day, or placebo for an average of 21 months. Lumbar spine bone mass increased between 9% and 13% in the rhPTHtreated subjects compared with the placebo-treated ones; hip bone mass also increased slightly. Most important, the risk of new vertebral fractures was reduced nearly 70% in both sets of rhPTH-treated subjects, and nonvertebral lowtrauma fractures were reduced nearly 50% compared with placebo-treated patients.98 This study was initially supposed to continue for 3 years; however, it was stopped at approximately 21 months because of preclinical evidence of malignant bone tumors in animal models. Additional studies of osteoporosis in men treated with rhPTH 1-34 have reported significant gains in bone mass.99 Fortéo is given as a daily injection. Individuals using this medication may experience headache, nausea, and flushing with initiation of treatment, but these side effects generally become less severe after a few weeks. A number of recent studies have evaluated whether rhPTH 1-34 or rhPTH 1-84 is more effective in combination with an antiresorptive agent (either bisphosphonates or raloxifene) than rhPTH alone in increasing BMD and reducing fractures.100-103 Interestingly, two studies found that the combination of PTH and alendronate was less effective in stimulating bone gain at the lumbar spine in both osteopenic women and men over 1 to 1.5 years.100,101 Another interesting study found that if PTH was cycled with alendronate for 3 months, followed by alendronate only for 3 months, the gain in lumbar spine BMD was similar to that in patients given the two medications continuously for 15 months.102 PTH stimulates new bone formation, increases bone mass, and reduces new vertebral and nonvertebral fractures, but when the medication is discontinued, the bone gained is rapidly lost. Black and coworkers103 performed a study in which patients were given PTH for 1 year, followed by 1 year of alendronate treatment. Interestingly, the BMD gain after 1 year of PTH was about 6%; when followed by alendronate, nearly 6% BMD was gained at the spine. These data suggest that although PTH is an effective monotherapy for increasing bone mass, especially in the spine, the gain in BMD should be maintained with a potent antiresorptive agent for a number of years. Recent data from Deal and colleagues104 indicate that lumbar spine BMD gained after PTH therapy is maintained with raloxifene treatment.

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PTH is the first bone anabolic agent approved for the treatment of osteoporosis. Patients give themselves a subcutaneous injection daily for 18 to 24 months. Other routes of administration are now being studied, including an intranasal route and a skin patch. Vitamin D Physiologic doses of vitamin D are important to ensure normal bone mineralization. Individuals 50 years of age and older should take at least 600 IU of vitamin D daily as a multivitamin or combined with a calcium supplement. Hypovitaminosis D is common in the elderly population, with one study demonstrating that 57% of patients in a general medical ward were vitamin D deficient.105 Low vitamin D levels increase the risk of bone loss and fracture. LeBoff and associates39 found that 50% of patients admitted with acute femur fractures had vitamin D deficiency (25-OHD level <12 ng/mL), and 36.7% had secondary hyperparathyroidism. Data show seasonal variations in vitamin D levels; low 25OHD levels during the winter and spring are associated with decreases in bone density. The importance of vitamin D to skeletal health was shown when elderly women in a nursing home treated with only 800 IU/day of vitamin D had a 40% reduction in incident hip fractures over 18 months, compared with placebo-controlled subjects.105a Although this dramatic effect on fractures in an elderly population may represent a correction of vitamin D insufficiency, this study underscores that adequate vitamin D replacement can effectively diminish fractures in older individuals. Insufficient calcium and low 25-OHD levels are common in ambulatory patients and should be identified and treated before antiresorptive or other therapies for osteoporosis are initiated. Although 200 IU of vitamin D prevents bone loss in the spine, data show that a higher daily intake (800 IU) is necessary to diminish bone loss in the hip during the winter and spring. Daily treatment with 700 IU of cholecalciferol and 500 mg of calcium carbonate reduced the rate of bone loss significantly in the femoral neck, spine, and total body and decreased the incidence of nonvertebral fractures by 50%.106 Therefore, to maintain skeletal health, patients require a vitamin D intake that results in a serum 25-OHD level of at least 30 ng/mL. To achieve this level in patients who do not receive regular sunlight, the daily intake of vitamin D needs to be higher. Replacement with 1,25-dihydroxyvitamin D (1,25[OH]2D) is not recommended, because hypercalcemia and hypercalciuria are common and require regular and costly monitoring. PREVENTIVE MEASURES Because bone loss is not completely reversible with existing therapies, prevention is essential for optimizing skeletal health. Strategies directed at increasing peak bone mass, reducing risk factors for bone loss (e.g., hypogonadism, decreased body fat, cigarette smoking, inactivity, excessive alcohol intake), and reversing the secondary causes of osteoporosis may prevent bone loss. Patients should be advised to consume adequate vitamin D and calcium and participate in a regular weight-bearing exercise program. Weight-bearing exercise increases muscle strength and may stabilize or modestly increase bone density. Emerging data

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show that increased calcium intake and exercise can add to bone accretion during adolescence and that interventions such as vitamin D and calcium supplementation can reduce fractures in older patients. Thus, it is highly recommended that preventive strategies or therapies be instituted at any age to diminish the risk of fractures, which rises exponentially with age.

GLUCOCORTICOID-INDUCED OSTEOPOROSIS Bone loss is a common sequela of therapy with glucocorticoids,107 and glucocorticoid use increases the risk of fractures in patients with rheumatic diseases.19 The severity of the bone loss in glucocorticoid-treated patients varies, with an approximately 3% to 20% decrease in bone density over 1 to 2 years. Glucocorticoid therapy is associated with increased fractures of the ribs and vertebrae, sites that contain predominantly trabecular bone, and it triples the risk of hip fracture in one third of patients after 5 to 10 years of treatment.108,109 In adults, alternate-day glucocorticoid therapy does not prevent bone loss. In patients with rheumatic diseases, concerns over the development of glucocorticoidinduced osteoporosis often limit the dose and duration of glucocorticoid therapy. The lowest possible glucocorticoid dose should be used, along with general preventive strategies such as a regular weight-bearing exercise program, adequate calcium and vitamin D intake, and reduction of other risk factors that might contribute to the development of osteoporosis. However, data show that even patients on prednisone 5 mg/day have accelerated bone loss compared with controls. General prophylactic measures to prevent glucocorticoid-induced osteoporosis are shown in Table 92-7. Intestinal calcium absorption is impaired in glucocorticoid-treated patients, and early studies showed that this could be offset with vitamin D (40 to 100 µg/day two to three times a week) or 25-OHD, which produced an increase in bone density of the forearm. However, the administration of supraphysiologic doses of vitamin D requires careful monitoring of the serum and urinary calcium concentrations in patients at high risk for bone loss (with a normal urinary calcium level and no history of nephrolithiasis). An alternative approach in patients at risk for osteoporosis and receiving long-term glucocorticoid therapy is to raise the 25-OHD level into the upper-normal range (>30 ng/mL) to ensure adequate intestinal calcium absorption. This can usually be accomplished by administering vitamin D at 800 IU/day. Because of the enhanced bone resorption in patients treated with glucocorticoids, investigators have examined the effects of inhibitors of bone resorption. The use of bisphosphonates in patients receiving chronic glucocorticoid therapy is quite beneficial for both the prevention and treatment of osteoporosis. The use of alendronate 5 or 10 mg/day for 1 year in patients receiving glucocorticoid therapy increased lumbar spine BMD by 2.1% and 2.9%, respectively, and increased femoral neck BMD by 1.2% and 1%, respectively (P < .001).109 After 1 year of treatment, there was an insignificant reduction in new vertebral fractures, but after 2 years of treatment, there was a nearly 40% reduction in new vertebral fracture risk. Risedronate 5 mg/ day was also effective in the prevention and treatment of

Table 92-7  Recommendations for the Prevention   and Treatment of Glucocorticoid-Induced   Osteoporosis Prevention Patients starting GC therapy at a dose equivalent to prednisone   ≥5 mg/day for 3 mo or longer should: Modify risk factors for osteoporosis (stop smoking, decrease   excessive alcohol consumption) Start regular weight-bearing physical exercise Initiate intake of calcium (total 1500 mg/day) and vitamin D   (400-800 IU/day) Consider BMD testing to predict risk of fracture and bone loss Initiate bisphosphonate therapy (alendronate 5 mg/day or   35 mg/wk, or risedronate 5 mg/day or 35 mg/wk) Treatment Patients on long-term GC therapy should be tested for osteoporosis using BMD measurement. If the T-score is < –1, consider: Risk factor modification, including reducing risk of falls Regular weight-bearing physical exercises Calcium and vitamin D supplementation Replacement of gonadal steroids, if deficient Bisphosphonate therapy (alendronate 10 mg/day or 70 mg/wk, or risedronate 5 mg/day or 35 mg/wk); if bisphosphonates are contraindicated or not tolerated, consider calcitonin as second-line agent, intravenous bisphosphonate (pamidronate or zolendronate), or PTH 1-34 Repeat BMD measurement annually or biannually BMD, bone mineral density; GC, glucocorticoid; PTH, parathyroid hormone. Adapted from Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. Arthritis Rheum 44: 1496-1503, 2001.

glucocorticoid-induced bone loss.110,111 Both alendronate and risedronate are approved by the FDA to reduce bone loss in glucocorticoid-treated patients. In a prospective pilot study in glucocorticoid-treated patients, intravenous infusions of pamidronate (30 mg every 3 months) increased spinal bone density 3.4% in 1 year.112 Studies of new, more potent bisphosphonates for the prevention and treatment of glucocorticoid-induced bone loss are in progress. Traditionally, postmenopausal women on glucocorticoids have been treated with HRT, and there are some data that this prevents bone loss in these women.113 However, because the earlier cited WHI results showed unacceptable cardiovascular and cancer risks associated with HRT therapy, it is no longer the standard of care. Studies of SLE subjects treated with dehydroepiandrosterone (DHEA) found an increase in lumbar spine and hip bone mass compared with placebo-treated patients.114,115 The mechanism of DHEA’s effect on bone mass is not yet known. Investigators have suggested the bone mass preservation results from DHEA metabolism to estrogen or by direct effects on IGF-1 bonepromoting factors. Additional studies are now in progress to determine whether this agent is effective for the prevention of bone loss in glucocorticoid-treated SLE patients. In addition, men on glucocorticoids can have a lowering of testosterone levels.116 They are generally asymptomatic, but if men on glucocorticoids have evidence of low serum testosterone levels and symptoms of low libido, they can be safely treated with testosterone. Bone mass increases have been observed in men with low testosterone levels on glucocorticoids who were treated with testosterone.117 However,

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because of the risks associated with testosterone treatment, it is more prudent to treat these patients with a bisphosphonate medication. Although glucocorticoids alter bone metabolism via a number of different mechanisms, inhibition of osteoblast life span and activity is the most significant. Whereas calcium and vitamin D supplementation and antiresorptive therapies can prevent bone loss as well as reduce fracture risk, they do not significantly alter osteoblast activity in the presence of glucocorticoids. Because a bone anabolic agent, rhPTH 1-34, can increase osteoblast activity and increase bone mass in postmenopausal osteoporosis, Lane and colleagues118 tested the hypothesis that rhPTH 1-34 could override the suppressive effects of glucocorticoids on osteoblast activity and reverse the bone loss. Data from a 12-month randomized trial of rhPTH 1-34 in postmenopausal women with osteoporosis currently taking glucocorticoids and estrogen replacement therapy showed an 11% increase in lumbar BMD, compared with no change in the estrogen-only group. After 1 year of treatment and 1 year of follow-up, total and femoral neck BMD increased nearly 5%, with little change in the estrogen-only group. In this study, quantitative CT of the lumbar spine, a measure of only trabecular bone, found a nearly 35% increase in PTH-treated patients compared with the estrogen-only group after 12 months of therapy.119 This information demonstrates that the major effect of PTH is to increase bone mass by thickening the existing trabeculae. In addition, 1 year of rhPTH 1-34 treatment increased the vertebral cross-sectional area, most likely by thickening of the periosteal envelope.120 Studies are now under way comparing rhPTH 1-34 to alendronate for the treatment of osteoporosis. Currently, there is no fracture information for PTH and glucocorticoid-induced bone loss. To prevent bone loss in patients with pulmonary diseases requiring glucocorticoid therapy, treatment with inhaled glucocorticoids has been studied.121,122 Inhaled glucocorticoids appear to uncouple bone turnover and increase bone loss; however, this is dose dependent. Less than 800 μg/day of inhaled budesonide dipropionate does not increase the risk of osteoporosis, but more than 800 μg/day does. New inhaled steroids are more potent than older ones; for instance, Advair 200 μg/day is equivalent to nearly 5 mg/ day of prednisone.122 Therefore, patients on chronic steroid inhalers should be screened for bone loss. Because patients receiving glucocorticoids may lose a dramatic amount of bone, it is important to monitor the efficacy of a treatment intervention, assess the need for further diagnostic evaluation for other causes of bone loss, and consider alternative treatment strategies if a given therapy is ineffective in preventing bone loss or fractures. In patients at increased risk of fracture, therapy with a potent bisphosphonate is highly recommended to slow bone loss and the rate of new fractures. Alendronate and risedronate are available for use, and future studies of more potent bisphosphonates and PTH are expected.

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PTH concentrations. A small decrease in the serum calcium concentration leads to a rise in PTH release, which promotes distal renal calcium reabsorption, proximal tubulorenal phosphorus excretion, and resorption of calcium from bone. Vitamin D is produced in the skin in the presence of ultraviolet light or absorbed in the intestine from dietary or supplemental sources. Activation of vitamin D to 25-OHD occurs in the liver and to 1,25(OH)2D in the proximal tubules of the kidney. PTH, hypocalcemia, and hypophosphatemia stimulate the renal 1-hydroxylase enzyme that converts 25-OHD to 1,25(OH)2D, which in turn indirectly enhances intestinal calcium absorption. Osteomalacia results from reduced availability of calcium or phosphate for incorporation into the hydroxyapatite of bone or from deficient absorption or activation of vitamin D.123,124 The term rickets applies to the defective mineralization of bone and the cartilaginous growth plate in growing children. As shown in Table 92-8, osteomalacia or rickets may result from decreased availability of vitamin D as a consequence of insufficient ultraviolet light exposure, insufficient vitamin intake, or malabsorption in patients with gastrointestinal or biliary disorders. Reduced levels of 25-OHD are caused by severe liver disease, increased renal excretion of vitamin D metabolites due to nephrotic syndrome, or accelerated metabolism of 25-OHD caused by anticonvulsant drugs. Decreased activation of 1,25(OH)2D

Table 92-8  Causes of Osteomalacia and Rickets Vitamin D Deficiency or Dysfunction Reduced Availability Nutritional deficit Reduced exposure to ultraviolet light Malabsorption (gastrointestinal or biliary disease, surgical resection) Alteration in Metabolism Reduced 25-hydroxyvitamin D from liver or gastrointestinal disease, nephrotic syndrome, anticonvulsant drugs Reduced 1,25-dihydroxyvitamin D from renal disease,   vitamin D–­dependent rickets type I Alteration in Action on Target Tissues Vitamin D–dependent rickets type II Phosphate Deficiency Decreased availability—dietary deficiency, phosphate-binding antacids Decreased renotubular phosphate reabsorption Familial—X-linked hypophosphatemic rickets, adult-onset vitamin D–resistant osteomalacia Acquired—hypophosphatemic osteomalacia (phosphate diabetes), oncogenic osteomalacia Generalized renotubular disorders Acidosis Renotubular acidosis Ureterosigmoidostomy Carbonic anhydrase inhibitors (acetazolamide) Miscellaneous Mineralization Defects

OSTEOMALACIA Osteomalacia is characterized by impaired mineralization of bone matrix. Calcium, phosphate, and vitamin D are necessary for the mineralization of bone. Normally, there is a steep inverse relationship between the serum calcium and

Inhibitors of mineralization—fluoride, bisphosphonates   (e.g., etidronate), chronic renal failure (aluminum) Hypophosphatasia Modified from LeBoff MS, Brown EM: Metabolic bone disease. In Hare JW (ed): Signs and Symptoms in Endocrine and Metabolic Disorders. Philadelphia, JB Lippincott, 1986, pp 239-260.

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is seen in patients with renal insufficiency due to increased phosphate levels; the resultant lower ionized calcium levels lead to secondary or tertiary hyperparathyroidism. A careful history is important in the diagnosis of osteomalacia or vitamin D insufficiency. For example, a history of a malabsorptive process such as gastrectomy, intestinal resection, sprue, primary biliary cirrhosis, or pancreatic deficiency may lead to the identification of vitamin D deficiency and osteomalacia.124 Patients with osteomalacia may present with generalized pain involving the pelvis, spine, ribs, or lower extremities or with skeletal deformities such as bowing of the long bones, kyphoscoliosis, or pelvic abnormalities. Another clinical sign of osteomalacia in adults is proximal muscle weakness, which may result in an antalgic or waddling gait and difficulty ambulating. Pain may be elicited by deep palpation of the tibia, ribs, or pubic ramus.124 One of the radiographic signs of osteomalacia is the presence of pseudofractures, or Looser’s zones, which are transverse lines of rarefaction through the cortices, with incomplete healing in the ribs, scapulae, long bones (Fig. 92-2), or pubic rami. Pseudofractures, however, may be indistinguishable from those associated with osteogenesis imperfecta or Paget’s disease. Other radiographic findings in osteomalacia are vertebral fractures or protrusio acetabuli. Vitamin D deficiency may result in irreversible cortical bone loss.124 In subtle cases of osteomalacia, a bone biopsy with a double tetracycline label may be necessary; characteristic histomorphometric findings in this disorder include increased osteoid and delayed mineralization of bone. Rickets causes abnormalities of the epiphyseal growth plate, and the clinical signs include an inability to ambulate, growth disturbances, bowing of the long bones, and short stature. Bony deformities of the skull and ribs may develop, with widened cranial sutures (craniotabes), thickened costochondral junctions (rachitic rosary), or indentation of the margins of the ribs (Harrison’s grooves). The biochemical parameters in patients with osteomalacia reflect the underlying pathophysiologic process and the compensatory biologic responses. In vitamin D ­deficiency states, the serum calcium levels are usually normal or slightly decreased, because PTH levels rise rapidly as a ­compensatory response to impaired calcium absorption.125

In renal insufficiency phosphate retention, impaired renal production of 1,25(OH)2D, hypocalcemia, and skeletal resistance to PTH are thought to lead to the development of hyperparathyroidism and resultant renal osteodystrophy, mixed osteomalacia, and osteitis fibrosa cystica.126 Also, aluminum intoxication may present with pure osteomalacia or adynamic bone disease.125,127 Chronic vitamin D defici­ ency may increase the secretory demands of the parathyroid glands, thereby producing secondary or, in some instances, tertiary hyperparathyroidism. In patients with osteomalacia without hepatobiliary disease, alkaline phosphatase levels are often elevated.124 Osteomalacia may be associated with a deficiency of phosphate, principally in patients with decreased renotubular reabsorption of phosphate. Familial hypophosphatemic vitamin D–resistant rickets in children or osteomalacia in adults usually presents with renal phosphate leak, hypophosphatemia, rachitic or osteomalacial changes, and inappropriately normal or low-normal 1,25(OH)2D level for the degree of hypophosphatemia. This X-linked dominant disorder may present in young children with the inability to walk, followed by progressive bowing and skeletal deformities, without signs of proximal myopathy. The genetic locus for X-linked hypophosphatemic rickets has been mapped to Xp22.1, and the gene is named PHEX (phosphate-regulating gene with homology to endopeptidases on the X chromosome).128 Oncogenic osteomalacia or rickets is a vitamin D–­resistant process associated with certain neoplasias, principally small, benign mesenchymal or endodermal tumors and, infrequently, certain malignant tumors (e.g., multiple myeloma; prostatic, oat cell, breast carcinomas).129,130 Such patients typically present with decreased renotubular phosphate reabsorption, hypophosphatemia, muscle weakness, diminished 1,25(OH)2D levels, and normocalcemia. The benign tumors tend to be small and difficult to identify on physical examination or radiographs. Surgical removal of these tumors results in a rise in the phosphate and 1,25(OH)2D levels and resolution of the skeletal process. Osteomalacia may also be associated with generalized renotubular disorders and the use of certain drugs that contain inhibitors of mineralization (e.g., fluoride, etidronate, aluminum). The evaluation of a patient suspected of having osteomalacia is outlined in Table 92-9. Osteomalacia is often a treatable disease, but the diagnosis may be overlooked. Vitamin D deficiency can be treated with physiologic doses of vitamin D, but higher doses (1000 to 2000 IU/day) may hasten the healing of bone. In the presence of intestinal malabsorption, and until the underlying malabsorptive process is corrected, very large doses of

Table 92-9  Workup for Osteomalacia Calcium, phosphorus, alkaline phosphatase, urinary calcium levels; 25-hydroxyvitamin D and intact parathyroid hormone levels

Figure 92-2  Osteomalacia and fractures in a 65-year-old woman with malabsorption. Shown are a pseudofracture of the left lesser trochanter and an avulsion of the right lesser trochanter. This patient also had previous bilateral pubic rami fractures.

In selected patients: 1,25-Dihydroxyvitamin D levels (e.g., renal insufficiency, vitamin D–resistant osteomalacia or rickets) Vitamin D absorption test: obtain 25-hydroxyvitamin D levels at 0, 4, and 8 hr (e.g., some cases of malabsorption) Tubular reabsorption of phosphate (e.g., vitamin D–resistant ­osteomalacia or rickets) Bone biopsy with double tetracycline labels

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vitamin D (50,000 IU once a week to three or more times a week) are often required. Careful monitoring of the serum and urinary calcium levels and 25-OHD concentrations is necessary to prevent vitamin D intoxication. Use of the active metabolite of 25-OHD (Calderol) may occasionally be necessary in resistant patients or in those with severe liver disease who cannot achieve activation of this metabolite. The potential advantages of using 25-OHD are more stable bioavailability, shorter half-life, and greater potency than the parent compound,124 although the cost is greater. In patients with hypophosphatemia and disorders of renotubular phosphate reabsorption, mineralization of bone occurs with phosphate therapy and moderately high doses of 1,25(OH)2D, the latter being necessary to prevent the secondary hyperparathyroidism associated with phos­­ phate therapy. In patients with renal insufficiency or failure, a phosphate binder (calcium acetate or calcium carbonate) should be used after meals to decrease intestinal ­phosph­ate absorption. Calcium citrate therapy should not be used because it augments aluminum absorption. In those with renal failure, 1,25(OH)2D therapy administered orally125,131 (or intravenously in some dialysis patients) suppresses parathyroid cell secretion and proliferation; a threefold elevation of the PTH level is advocated by some investigators to prevent adynamic bone disease.126 Analogues of 1,25(OH)2D that do not produce hypercalcemia but decrease levels of PTH are now available and may be useful in patients with renal insufficiency.

PAGET’S DISEASE OF BONE Paget’s disease affects approximately 2% to 3% of the population older than 50 years and is uncommon in individuals younger than 40 years.132 Paget’s disease of bone is characterized by enhanced resorption of bone by giant, multinucleated osteoclasts, followed by the formation of disorganized woven bone by osteoblasts. The resultant bone is expanded, weak, and vascular, so that affected bones may become enlarged and deformed, and the overlying skin may feel warm to the touch.133 CAUSE The cause of Paget’s disease is uncertain, although data showing the presence of viral inclusion particles in giant pagetic osteoclasts support a viral cause, possibly associated with measles, respiratory syncytial, or canine distemper virus. Paget’s disease tends to aggregate in families in an autosomal dominant pattern, and 40% of patients have at least one other family member affected.106 Recently, in a family with juvenile Paget’s disease, the disease was found to be associated with a polymorphism in the OPG allele.134 Studies of additional families with this mutation may lead to the discovery of the cause of Paget’s disease. CLINICAL FEATURES Many patients with Paget’s disease are asymptomatic, and the disease is detected by the incidental finding of an elevated alkaline phosphatase level or characteristic ­ radiographic abnormality. Other patients present with a range of symptoms that include bone pain, skeletal deformities (bowing

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Figure 92-3  Paget’s disease of the skull in a woman with signs of increasing head size and progressive hearing loss. The alkaline phosphatase level was 2100 U/L. This computerized axial tomogram shows marked thickening of the inner and outer skull tables, with osteoblastic pagetoid changes. Audiologic evaluation revealed bilateral hearing loss.

of long bones, enlarged skull, pelvic alterations), pathologic fractures, increased cardiac output (with extensive disease), and nerve compression. Paget’s disease typically includes a lytic phase, a combined lytic and blastic phase, and a sclerotic or “burned out” phase occurring late in the disease process. Radiographic signs of the three stages of Paget’s disease may be present at different sites in the same patient.132 The skeletal sites commonly involved with Paget’s disease include the skull (Fig. 92-3), vertebrae, pelvis, sacrum, and lower extremities. Degenerative joint disease may develop adjacent to the bones and cause pain that may obscure the symptoms associated with Paget’s disease.132 Ten percent to 30% of patients with Paget’s disease may experience fractures that present initially as asymptomatic or painful short fissure fractures traversing the bony cortex (Fig. 92-4). Complete fractures of the bones, such as the “chalk stick” fracture, also occur; fractures of the long bones may be a serious complication because the increased vascularity of pagetic bone may lead to excessive blood loss. Healing of fractures in pagetic bone usually occurs normally, although there have been reports of nonunion. A rare complication of Paget’s disease of bone is sarcomatous degeneration in less than 1% of patients (with osteogenic sarcomas or, less commonly, fibrosarcomas or chondrosarcomas); these patients generally have a poor prognosis. The development of a sarcoma may be heralded by the presence of a soft tissue mass, localized pain, and rise in the alkaline phosphatase level. Neurologic symptoms generally result from compression of the nerves by pagetic bone. Hearing loss is common and is caused by sensory loss and conduction abnormalities due to pagetic involvement of the bones of the inner ear. ­Paget’s disease of the skull may also produce ocular and other cranial nerve palsies. Compression of the base of the skull may lead to basilar invagination, cerebellar dysfunction, or obstructive hydrocephalus, with symptoms of ­nausea, ataxia,

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Table 92-10  Indications for Treatment of Paget’s   Disease of Bone Pain Hypercalcemia Fractures High-output cardiac failure (rare) Skull involvement Neurologic compromise Periarticular disease Prevention of progression of Paget’s disease

elevated in active Paget’s disease. Other laboratory abnormalities in patients with Paget’s disease include hypercalciuria, hyperuricuria, and hyperuricemia, possibly related to the increased turnover of osteoclasts. Serum uric acid levels should be measured periodically because of the association of Paget’s disease with gouty arthritis. DIAGNOSIS

Figure 92-4  Paget’s disease of the proximal femur. Note the coarse trabeculae, thickened cortices, lateral fissure fracture, and expanding lytic region characteristic of the “blade-of-grass” lesion.

incontinence, gait disturbances, and dementia. Neurologic compromise of the thoracic or lumbar spine may lead to spinal cord compression or, in the latter instance, cauda equina syndrome. LABORATORY FINDINGS Biochemical indices in patients with Paget’s disease usually show normal serum calcium and phosphate levels, although hypercalcemia may develop with immobilization when there is an uncoupling of bone resorption and formation. Patients with Paget’s disease may also be hypercalcemic if they coincidentally acquire primary hyperparathyroidism, which can further increase bone remodeling and worsen the disease process. Secondary hyperparathyroidism may develop in approximately 10% to 15% of patients with Paget’s disease, presumably because of inadequate calcium intake to meet the skeletal demands of the heightened bone remodeling.132 Alkaline phosphatase levels of bone origin (BSAP) are commonly elevated in patients with significant Paget’s disease because of the increased osteoblastic activity combined with bone breakdown. In the absence of liver disease, the alkaline phosphatase level typically correlates with the extent of the pagetic involvement of bone, although it may be more elevated in Paget’s disease of the skull (see Fig. 92-3). Unexpectedly, circulating osteocalcin levels do not re­­ f­lect disease activity in patients with Paget’s disease as well as bone specific alkaline phosphatase levels reflect ­ disease activity. Markers of bone resorption, such as urinary ­collagen cross-links like N telopeptides and C telopeptides are also

Bone scans are valuable tools for assessing the extent of Paget’s disease and are, therefore, useful as part of the initial evaluation.133 As diagnostic tests, however, bone scans in general are sensitive but not specific for a number of skeletal processes. Radiographs show characteristic radiologic findings such as transverse lucent areas, osteoporosis circumscripta, enlargement of the bones, expanding lytic changes, the “blade-of-grass” lesion shown in Figure 92-4, thickened cortices, a coarse trabecular pattern, or sclerotic changes. In patients with involvement of the skull and changes in mental status, a skull radiograph, magnetic resonance imaging (MRI), or QCT may be useful to diagnose platybasia and flattening of the base of the skull, basilar invagination, or the infrequent complication of hydrocephalus. Audiologic evaluation may reveal hearing loss in patients with pagetic involvement of the skull. TREATMENT The indications for treatment of Paget’s disease (Table 92-10) include pain, hypercalcemia, fractures, high-output cardiac failure (rare), and neurologic compromise. Therapy can also be used to prevent the progression of deformity or risk of nerve compression when there is pagetic involvement of the skull, a vertebral body, or a weight-bearing bone (femur) or when disease is present adjacent to a major articular joint. Treatment of symptomatic Paget’s disease is usually directed at suppression of the enhanced bone resorption and skeletal turnover with calcitonin or bisphosphonates.132,135 Response to therapy is monitored by the reduction of symptoms and maintenance of the alkaline phosphatase level in a mid-normal range, with retreatment once values rise 25% above normal. Calcitonin Salmon calcitonin and human calcitonin inhibit the function of osteoclasts, which are active in the pagetic process; both types of calcitonin preparations come in an injectable form and are FDA-approved for patients with Paget’s

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­disease.136 Salmon calcitonin therapy is usually initiated at a low dose to ensure patient tolerance and then increased to a daily dose of 100 Medical Research Council units (intramuscularly or subcutaneously). After 6 months of therapy, the patient may be maintained on 50 to 100 Medical Research Council units daily.132 Approximately two thirds of patients show a decrease in alkaline phosphatase levels of 50% or more in 2 to 6 months. Some patients experience resistance to the effects of calcitonin, which can be reversed in some instances by switching from salmon calcitonin to human calcitonin. Calcitonin is a safe drug. Calcitonin is useful in patients with expanding lytic lesions, particularly of a weight-bearing bone, or for preoperative therapy before elective orthopedic procedures. The use of calcitonin nasal spray has few systemic side effects but is not FDA-approved for the treatment of Paget’s disease. Bisphosphonates Several bisphosphonates are currently approved by the FDA for the treatment of Paget’s disease; they include etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), tiludronate, risedronate (Actonel), and zoledronic acid (Zometa). Etidronate is an orally administered drug that produces a clinical and biochemical response similar to that of calcitonin.136 The therapeutic dose for Paget’s disease is 5 mg/kg per day (400 mg/day, or a minimum of 200 mg/day for smaller patients) for 6 months; the drug is then stopped for 6 months before being reinstituted in 6-month cycles of therapy.137 As mentioned previously, higher doses of etidronate are associated with defective mineralization of bone and osteomalacia, with symptoms of pain and fractures. Measurements of alkaline phosphatase levels at 3- to 6-month intervals are useful to ensure the suppression of bone turnover; an estimated 25% of patients may become resistant to etidronate.132 However, newer, more potent bisphosphonates are very effective for the treatment of Paget’s disease. Parenteral pamidronate is also approved for the treatment of symptomatic Paget’s disease of bone in patients with a threefold or greater elevation of alkaline phosphatase concentrations. This more potent bisphosphonate is useful in patients who become resistant to etidronate and in those with more severe disease. An advantage of this therapy is that alkaline phosphatase levels may be reduced to the normal range, with a sustained response for a prolonged period (up to a year or more).132,138 The FDA-recommended dose of pamidronate for patients with Paget’s disease is 30 mg/day as a 4-hour infusion on 3 sequential days (total dose 90 mg), with retreatment possible if necessary. Other regimens for the treatment of Paget’s disease include 60 mg of pamidronate daily (infused over 3 hours) once a week for 1 or 2 weeks in patients with alkaline phosphatase levels between 300 and 400 U/L. For more extensive disease, three or four infusions of pamidronate every 1 to 2 weeks may be necessary. To assess the efficacy of these regimens for Paget’s disease, clinical symptoms should be reviewed and alkaline phosphatase levels measured 2 to 3 months later.138 Some patients treated with pamidronate may experience a transient fever, musculoskeletal and flulike symptoms, and hypocalcemia; calcium supplementation (500 mg twice

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daily in vitamin D–replete patients) can offset the hypocalcemia that results from the suppression of bone resorption. Pamidronate is available only as a parenteral drug, which restricts its use.138 Oral alendronate has been approved for the treatment of Paget’s disease at a dose of 40 mg/day for 6 months. Therapy with alendronate is recommended for patients with at least a twofold elevation in alkaline phosphatase levels or for those with specific indications for therapy (see Table 92-10). The use of alendronate produces a normalization of, or a 60% or greater reduction in, the alkaline phosphatase level in approximately 85% of patients. Studies indicate that this therapy is more effective than etidronate. (All bisphosphonates must be taken correctly to minimize gastrointestinal side effects.)139 Risedronate is another potent bisphosphonate (see Table 92-6) that is FDA-approved for the treatment of Paget’s disease. Siris and colleagues139 treated 162 patients with moderate to severe Paget’s disease with oral risedronate (30 mg/day for 84 days, followed by 112 days without treatment). This cycle was repeated if the serum alkaline phosphatase level did not normalize or increased more than 25% from its nadir value. After the first and second cycles, the serum alkaline phosphatase level decreased 65% and 69%, respectively, and urine markers decreased 50% and 66.9%, respectively. The serum alkaline phosphatase level normalized in 53.8% of patients, and a significant decrease in bone pain was noted. Risedronate is well tolerated and has few adverse effects, including a flulike syndrome, gastrointestinal symptoms, and, rarely, iritis. Other groups have shown a decrease in serum alkaline phosphatase levels of 79% and 86%, with an 85% and 100% decrease in urine markers.140 There is no evidence of osteomalacia in bone biopsies from patients treated with 30 mg of risedronate. Patients who have become resistant to etidronate appear to respond to risedronate. Patients must be instructed to have an adequate intake of calcium and vitamin D while taking risedronate. Recently, zoledronic acid was also found to be effective in the treatment of Paget’s disease, and approval is pending from the FDA.141 In addition to antiresorptive therapies, nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin are useful modalities to alleviate the joint pain and other symptoms that result from degenerative joint disease. Finally, surgical intervention is sometimes warranted in patients with Paget’s disease and bony deformities, pathologic fractures, nerve compression, or degenerative arthritis. Orthopedic procedures, such as total joint replacement and osteotomies, are associated with a reduced risk of intraoperative bleeding or other complications if patients are treated medically (e.g., with calcitonin or other bisphosphonates) to reduce the disease activity and vascularity for at least 6 weeks before the procedure.

OTHER MEDICATION-INDUCED OSTEOPOROSIS Aromatase inhibitors in women undergoing breast cancer treatment are associated with bone loss. Postmenopausal women maintain a low level of circulating estrogen because of aromatization of androgens to estrogen in tissues such as fat and muscle by cytochrome P-450 enzyme. Inhibition of

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this enzyme is now used in postmenopausal women with breast cancer. There are two classes of aromatase inhibitors: nonsteroidal reversible inhibitors (anastrozole and letrozole) and steroidal reversible inhibitors (exemestane). Because these agents prevent the conversion of androgen to estrogen, this results in very low serum estrogen levels and increased bone remodeling. Fracture rates in clinical trials of aromatase inhibitors compared with either tamoxifen or placebo ranged from 3% to 7%.142 In a 2-year study, significantly higher markers of bone turnover and nearly twice the lumbar spine bone loss and fracture rates were observed with anastrazole compared with tamoxifen.142 Although the data are just beginning to be collected regarding skeletal health in women treated for breast cancer with aromatase inhibitors, it is important to obtain a history of clinical risk factors for osteoporosis and a BMD measurement of the hip and spine. Preventive treatment should be initiated in women with normal or low bone mass and no history of fractures. Treatment of women with low bone mass (T score  ≤ –2) should be initiated with potent antiresorptive agents, and BMD should be monitored at least every 2 years. If a woman continues to lose bone mass on aromatase inhibitors despite compliance with potent antiresorptive agents, and if the patient has not had radiation to the skeleton as part of the breast cancer protocol, rhPTH 1-34 treatment can be used to build up bone mass. At this time, studies are ongoing to evaluate the efficacy of zoledronic acid and an inhibitor of RANKL for the prevention of bone loss in women treated for breast cancer with aromatase inhibitors.143 Gonadotropin-releasing hormone antagonists are used to treat women with endometriosis and men with prostate cancer. These compounds induce bone loss by lowering estrogen levels, resulting in accelerated bone turnover. A study of more than 50,000 men with prostate cancer treated with androgen-deprivation therapy consisting of either gonadotropin-releasing hormone agonists or orchiectomy found an increased risk of fracture or hospitalization due to fracture. Although the overall risk of fracture associated with androgen-deprivation therapy was only modestly increased overall, the risk of fracture was significantly associated with the number of doses of gonadotropin-releasing hormone agonists. Other studies have reported that androgen­­deprivation therapy increases bone loss at all sites, with a 2% to 8% annual loss in the lumbar spine and a 2% to 6% loss in the hip after 1 year.143a Given the high incidence of prostate cancer and the increasing use of this treatment, assessment of bone mass and the prevention of additional bone mass loss are probably appropriate. Oncologists currently recommend that BMD be measured at the time of initiation of androgen-deprivation therapy and that clinical risk factors for osteoporosis be reviewed, including history of fracture after age 30, family history of hip fracture, smoking history, use of glucocorticoids, low testesterone level, and rheumatoid arthritis. If the patient has a low BMD (Tscore < –2.5) or a T-score between –1 and –2.5 and other risk factors, treatment with calcium and vitamin D supplementation and a bisphosphonate (zoledronic acid, alendronate, risedronate, pamidronate) should be initiated. BMD of the lumbar spine and hip should be measured at least once a year while patients are maintained on androgen-deprivation therapy.144,145

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53. Lane NE, Sanchez S, Genant HK, et al: Short-term increases in bone turnover markers predict parathyroid hormone-induced spinal bone mineral density gains in postmenopausal women with glucocorticoid-induced osteoporosis. Osteoporos Int 11:434-442, 2000. 54. Buxton EC, Yao W, Lane N: Changes in serum receptor activator of nuclear factor-kappaB ligand, osteoprotegerin, and interleukin-6 levels in patients with glucocorticoid-induced osteoporosis treated with human parathyroid hormone (1-34). J Clin Endocrinol Metab 89:3332-3336, 2004. 55. Cosman F, Nieves J, Woeflert I: Alendronate does not block the anabolic effect of PTH in postmenopausal osteoporotic women. J Bone Miner Res 13:1051-1055, 1998. 56. Silverberg SJ, Gartenberg F, Jacobs TP, et al: Increased bone mineral density after parathyroidectomy in primary hyperparathyroidism. J Clin Endocrinol Metab 80:729-734, 1995. 57. Silverberg SJ, Gartenberg F, Jacobs TP, et al: Longitudinal measurements of bone density and biochemical indices in untreated primary hyperparathyroidism. J Clin Endocrinol Metab 80:723728, 1995. 58. Dawson-Hughes B, Dallal GE, Krall EA, et al: A controlled trial of the effect of calcium supplementation on bone density in postmenopausal women. N Engl J Med 323:878-883, 1990. 59. Atkinson SA, Abrams SA, Dawson-Hughes B, et al: Calcium. In Young V (ed): Dietary Reference Intake for Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride. Washington, DC, National Academy Press, 1997, pp 91-143. 60. Optimal calcium intake: NIH Consensus Conference. JAMA 272:1942-1947, 1994. 61. Nicar MJ, Pak CYC: Calcium bioavailability from calcium carbonate and calcium citrate. J Clin Endocrinol Metab 61:391-393, 1985.   62. Hulley S, Grady D, Bush T, et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 280:605-613, 1998. 63. Grady D, Herrington D, Bittner V, et al: Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/Progestin Replacement Study follow-up (HERS II). JAMA 288:58-66, 2002. 64. Writing Group for the Women’s Health Initiative Investigators: Risk and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288:321-333, 2002. 65. Love RR, Mazess RB, Barden HS, et al: Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 326:852-856, 1992. 66. Fisher B, Costantino JP, Wicherham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:13711388, 1998. 67. Cummings SR, Eckert S, Krueger KA, et al: The effect of raloxifene on risk of breast cancer in postmenopausal women: Results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA 281:2189-2197, 1999. 68. Delmas P, Bjarnason NH, Mitlak B, et al: Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 337:16411647, 1997.   69. Ettinger B, Black D, Mitlak B, et al: Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from 3 year randomized clinical trial (MORE). JAMA 282:637-645, 1999. 70. Walsh BW, Kuller LH, Wild RA, et al: Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 279:1445-1451, 1998. 71. Walsh BW, Paul S, Wild RA, et al: The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocystein in healthy postmenopausal women: A randomized controlled trial. J Clin Endocrinol Metab 85:214-218, 2000. 72. Ridker PM, Buring JE, Shin J, et al: Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 98:731-733, 1998. 73. Barrett-Connor E, Mosca L, Collins P, et al: Raloxifene Use for the Heart (RUTH) Trial Investigators. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 355:125-137, 2006.

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74. Vogel VG, Costantino JP, Wickerham DL, et al: National Surgical Adjuvant Breast and Bowel Project (NSABP). Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295:2727-2741, 2006. 75. Bradbury J: CORE breast-cancer prevention trial. Lancet Oncol 6:8, 2005. 76. Tenover JL: Male hormone replacement therapy including “Andropause.” Endocrinol Metab Clin North Am 27:969-988, 1998. 77. Gennari C, Chierichetti SM, Bigazzi S, et al: Comparative effects on bone mineral content of calcium and calcium plus salmon calcitonin given in two different regimens in postmenopausal osteoporosis. Curr Ther Res 38:455-464, 1985. 78. Overgaard K, Riis BJ, Christiansen C, et al: Nasal calcitonin for treatment of established osteoporosis. Clin Endocrinol 30:435-442, 1989. 79. Chesnut C, Silverman S, Andriono K, et al: A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: The Prevent Recurrence of Osteoporotic Fractures Study. PROOF Study Group. Am J Med 109:267-276, 2000. 80. Harris ST, Watts NB, Jackson RD, et al: Four-year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: Three years of blinded therapy followed by one year of open therapy. Am J Med 95:557-567, 1993. 81. Liberman UA, Weiss SR, Broll J, et al: Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 333:1437-1443, 1995.   82. Black DM, Cummings SR, Karpt DB, et al: Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 348:1535-1541, 1996. 83. Hosking D, Chilvers CE, Christiansen C, et al: Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. N Engl J Med 338:485-492, 1998. 84. Cummings SR, Black DM, Thompson DE, et al: Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures. JAMA 280:2077-2082, 1998. 85. Orwoll E, Ettinger M, Weiss S, et al: Alendronate for the treatment of osteoporosis in men. N Engl J Med 343:604-610, 2000. 86. Schnitzer T, Bone HG, Crepaldi G, et al: Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Aging 12:1-12, 2000. 87. Harris ST, Watts NB, Genant HK, et al: Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: A randomized controlled trial. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. JAMA 282:1344, 1999. 88. Heaney RP, Zizic TM, Fogelman I, et al: Risedronate reduces the risk of first vertebral fracture in osteoporotic women. Osteoporos Int 13:501-505, 2002. 89. Reginster J-Y, Minne HW, Sorensen O, et al: Randomized trial of the effects of risedronate on vertebral fractures in women with postmenopausal osteoporosis. Osteoporos Int 11:83-91, 2000. 90. McClung MR, Geusens P, Miller PD, et al: Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 344:333-340, 2001. 91. Delaney M, Harwitz S, Shaw J, LeBoff MS: Bone density changes with once weekly risedronate in postmenopausal women. J Clin Densitom 6:45-50, 2003. 92. Miller PD, Brown JP, Siris ES: A randomized double-blind trial of risedronate and etirdonate in the treatment of Paget’s disease of bone. Am J Med 106:513-520, 1999. 93. Reginster JY, Adami S, Lakatos P, et al: Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year results from the MOBILE study. Ann Rheum Dis 65:654-661, 2006. 94. Delmas PD, Adami S, Strugala C, et al: Intravenous ibandronate injections in postmenopausal women with osteoporosis: One-year results from the dosing intravenous administration study. Arthritis Rheum 54:1838-1846, 2006.  94a. Reid IR, Brown JP, Burckhardt P, et al: Intravenous zoledronic acid in postmenopausal women with low bone density. N Engl J Med 36:653661, 2002.

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117. Reid IR, Wattie DJ, Evans MC, et al: Testosterone therapy in glucocorticoid-treated men. Arch Intern Med 156:1173-1178, 1996. 1  18. Lane NE, Sanchez S, Modin GW, et al: Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. J Clin Invest 102:1627-1633, 1998. 119. Lane NE, Sanchez S, Genant HK, et al: Bone mass continues to increase at the hip after parathyroid hormone treatment is discontinued in postmenopausal women with glucocorticoid-induced osteoporosis. J Bone Miner Res 15: 994, 2001. 120. Rehman Q, Lang T, Lane NE: Daily treatment with parathyroid hormone is associated with an increase in vertebral cross-sectional area in postmenopausal women with glucocorticoid-induced osteoporosis. Osteoporos Int 41:374-382, 2003. 121. Wang WQ, Ip MS, Tsang KW, Lam KS: Antiresorptive therapy in asthmatic patients receiving high-dose inhaled steroids: A prospective study for 18 months. J Allergy Clin Immunol 101:445-450, 1998. 122. Sosa M, Saavedra P, Valero C, et al: Inhaled steroids do not decrease bone mineral density but increase risk of fractures: Data from the GIUMO Study Group. J Clin Densitom 9:154-158, 2006. 123. Frame B, Parfitt AM: Osteomalacia: Current concepts. Ann Intern Med 89:966-982, 1978. 124. Holick MF, Garabedian M: Vitamin D: Photobiology, metabolism, mechanism of action, and clinical applications. In Primer on the Metabolic bone diseases and disorders of mineral metabolism, 2006, pp 106-114. 125. Streeten EA, Levine MA: Hyperparathyroidism and hypoparathyroidism. In Rakel RE (ed): Conn’s Current Therapy. Philadelphia, WB Saunders, 2000, pp 627-634. 126. Hruska KA, Teitelbaum SL: Renal osteodystrophy. N Engl J Med 333:166-174, 1995. 127. Felsenfeld AJ, Llach F: Parathyroid gland function in chronic renal failure. Kidney Int 43:771-789, 1993. 128. Econs MJ, Rowe PS, Francis F, et al: Fine structure mapping of the human X-linked hypophosphatemic rickets gene locus. J Clin Endocrinol Metab 79:1351-1354, 1994. 129. Ryan EA, Reiss E: Oncogenous osteomalacia: Review of the world literature of 42 cases and report of two new cases. Am J Med 77: 501-512, 1984. 130. Drezner MK, Lyles KW, Haussler MR, et al: Evaluation of a role for 1,25-dihydroxyvitamin D3 in the pathogenesis and treatment of X-linked hypophosphatemic rickets and osteomalacia. J Clin Invest 66:1020-1032, 1980.

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131. Quarles LD, Davidai GA, Schwab SJ, et al: Oral calcitriol and calcium: Efficient therapy for uremic hyperparathyroidism. Kidney Int 34:840-844, 1988. 132. Siris ES: Extensive personal experience: Paget’s disease of bone. J Clin Endocrinol Metab 80:335-338, 1995. 133. Siris ES, Chines AA, Altman RD, et al: Risedronate in the treatment of Paget’s disease of bone: An open label, multicenter study. J Bone Miner Res 13:1032-1038, 1998. 134. Whyte MP, Obrecht SE, Finnegan PM, et al: Osteoprotegrin deficiency and juvenile Paget’s disease. N Engl J Med 347:175-184, 2002. 135. LeBoff MS, El-Hajj Fuleihan G, Brown EM: Osteoporosis and Paget’s disease of bone. In Branch WT (ed): Office Practice of Medicine, 3rd ed. Philadelphia, WB Saunders, 1994, pp 700-714. 136. DeRose J, Singer FR, Avramides A, et al: Response of Paget’s disease to porcine and salmon calcitonins: Effects of long-term treatment. Am J Med 56:858-866, 1974. 137. Krane SM: Etidronate disodium in the treatment of Paget’s disease of bone. Ann Intern Med 96:619-625, 1982. 138. Gallacher SJ, Boyce BF, Patel U, et al: Clinical experience with pamidronate in the treatment of Paget’s disease of bone. Ann Rheum Dis 50:930-933, 1991. 139. Siris E, Weinstein RS, Altman R, et al: Comparative study of alendronate versus etidronate for the treatment of Paget’s disease of bone. J Clin Endocrinol Metab 81:961-967, 1996. 140. Hosking DJ, Eusabio RA, Chines AA: Paget’s disease of bone: Reduction of disease activity with oral risedronate. Bone 22:51-55, 1998. 141. Reid IR, Miller P, Lyles K, et al: Comparison of a single infusion of zoledronic acid with risedronate for Paget’s disease. N Engl J Med 353:898-908, 2005. 142. Eastell R, Hannon RA, Cuzick J, et al: Effect of an aromatase inhibitor on BMD and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial (18233230). J Bone Miner Res 21:1215-1223, 2006. 143. Eastell R, Hannon R: Long-term effects of aromatase inhibitors on bone. J Steroid Biochem Mol Biol 95:151-154, 2005. 143a. Smith MR, Boyce SP, Moyneur E, et al: Risk of clinical fractures after GNRH agonist therapy for prostate cancer. J Urol 175:136-139, 2006. 144. Diamond TH, Higano CS, Smith MR, et al: Osteoporosis in men with prostate carcinoma receiving androgen-deprivation therapy: Recommendations for diagnosis and therapies. Cancer 100:892, 2004. 145. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS: Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 352:154-164, 2005.

93

Proliferative Bone Diseases REUVEN MADER

KEY POINTS Although diffuse idiopathic skeletal hyperostosis (DISH) usually is defined by the presence of large flowing osteophytes connecting at least four vertebrae, typically in the thoracic spine, the disease often involves the cervical and lumbar spine and peripheral joints, especially entheses. The etiology of DISH is unclear, but it is associated with a variety of metabolic abnormalities, many of which are also seen in type 2 diabetes. Treatment of spinal DISH is mostly symptomatic, but patients and physicians need to be aware of the increased fracture risk of these patients. Patients with DISH are at increased risk for heterotopic bone formation after joint surgery, and appropriate prophylactic measures should be carried out. Because of the metabolic abnormalities associated with DISH, many of which also are cardiac risk factors, the discovery of the disease, such as an incidental finding on chest x-ray, should prompt careful evaluation of known cardiovascular risk factors. Hypertrophic osteoarthropathy can be seen in many conditions, but growth factors such as platelet-derived growth factor and vascular endothelial growth factor are implicated as the common etiology of most, if not all, cases. Hypertrophic osteoarthropathy usually responds dramatically to effective treatment of the primary disease, such as surgical resection of a lung carcinoma.

Proliferative bone diseases encompass a variety of conditions characterized by exuberant bone and entheseal ossifications and calcifications. New bone formation is the main feature in diffuse idiopathic skeletal hyperostosis (DISH) and hypertrophic osteoarthropathy (HOA) and is a common finding in osteoarthritis. New bone formation also may accompany some seronegative spondyloarthropathies, such as ankylosing spondylitis, psoriatic arthritis, and sternoclavicular syndrome, also known as SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteomyelitis). New bone formation also has been described in endocrine diseases, however, such as thyroid disorders, acromegaly, and hypoparathyroidism (Table 93-1).1-3 Osteoarthritis, seronegative spondyloarthropathies, and endocrine disorders are discussed elsewhere in this book.

DIFFUSE IDIOPATHIC SKELETAL HYPEROSTOSIS DISH is a condition characterized by calcification and ossification of soft tissues, mainly ligaments and entheses. This condition was described by Forestier and Rotes-Querol

in 1950,4 and was termed senile ankylosing hyperostosis. There is a marked predilection to the axial skeleton, particularly the thoracic spine. Recognition that the condition is not limited to the spine and may involve peripheral joints led researchers to coin the name DISH, a term now widely used.5 DISH is characterized by the production of coarse, flowing osteophytes involving, in particular, the right side of the thoracic spine with preservation of the intervertebral disk space, and by ossification of the anterior longitudinal ligament. Calcification and ossification of the posterior longitudinal ligament seem to be additional skeletal manifestations of DISH. Other entheseal regions might be affected, such as the peripatellar ligaments, Achilles tendon insertion, plantar fascia, olecranon, and others.6-8 The diagnosis usually is based on the definition suggested by Resnick and Niwayama.5 This radiographic approach requires the presence of flowing, coarse osteophytes on the right side of the thoracic spine, connecting at least four contiguous vertebrae, or ossification of the anterior longitudinal ligament, preserved intervertebral disk height in the involved segment, and the absence of apophyseal joint ankylosis and sacroiliac joint involvement (Table 93-2).8 Another set of criteria, for epidemiologic purposes, was suggested by Utsinger.7 These criteria consider also peripheral enthesopathies. A definite diagnosis of DISH is established by criteria similar to those suggested by Resnick and Niwayama. A probable diagnosis of DISH is possible, however, with continuous ossification or calcification, or both, of the anterolateral aspect of at least two contiguous vertebral bodies and bilateral well-corticated enthesopathies in the heel, olecranon, and patella. EPIDEMIOLOGY DISH is more common in men than women. An autopsy study reported that in a series of 75 spines studied at autopsy, 28% had DISH.9 The reported prevalence of DISH varies according to age, ethnic origin, geographic location, and clinical setting (i.e., hospital-based versus population-based). In a study of a North American metropolitan hospital population, the prevalence in men and women older than 50 years of age was reported to be 25% and 15%, respectively, and the prevalence in men and women older than 70 years was 35% and 26%, respectively.10 Similar figures were reported for patients from Budapest.11 Higher figures were reported for Jews older than 40 years living in Jerusalem, reaching a prevalence of 46% for men older than 80.12 A much smaller prevalence was reported from Korea, barely reaching 9% in the older age group.13 Native Africans had a prevalence of 13.6% in patients older than 70 years of age with no difference 1601

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Table 93-1  Proliferative Bone Diseases Diffuse idiopathic skeletal hyperostosis

Table 93-3  Conditions Associated with Diffuse ­Idiopathic Skeletal Hyperostosis

Hypertrophic osteoarthropathy

Non–insulin-dependent diabetes mellitus

Thyroid disorders

Obesity

Acromegaly

High waist circumference ratio

Hypoparathyroidism

Dyslipidemia

Seronegative spondyloarthropathies (i.e., psoriatic arthritis, ankylosing spondylitis, SAPHO)

Hypertension

Osteoarthritis

Hyperinsulinemia

SAPHO, synovitis, acne, pustulosis, hyperostosis, and osteomyelitis.

Table 93-2  Suggested Diagnostic Criteria for Diffuse Idiopathic Skeletal Hyperostosis Flowing calcification and ossification along the anterolateral aspect of at least four contiguous vertebral bodies Preservation of intervertebral disk height in the involved vertebral segment and absence of extensive radiographic changes of degenerative disk disease Absence of apophyseal joint bony ankylosis and sacroiliac joint   erosion, sclerosis, or intra-articular osseous fusion

between men and women.14 In population-based, as opposed to hospital-based, studies, the reported prevalence was slightly greater than 10% in patients older than 70 years of age.15 Mild DISH was found in human remains dating back 4000 years. In human remains from the 6th to 8th century, the prevalence of DISH was higher in men than in women, reaching 3.7%. Although these studies were performed on different and relatively young populations, it seems that the prevalence of DISH is increasing.16,17 ETIOLOGY AND PATHOGENESIS The etiology of DISH is unknown. Several metabolic, genetic, and constitutional factors were reported to be associated with this condition, however, including obesity, a high waist circumference ratio, hypertension, diabetes mellitus, hyperinsulinemia, dyslipidemia, elevated growth hormone levels, elevated insulin-like growth factor (IGF)-I, hyperuricemia, use of retinoids, and genetic factors (Table 93-3).18-28 The association of DISH with excess body weight is well known since the early descriptions by Forestier and others.9,29 This association was reiterated in a study in which patients with DISH were compared with healthy individuals and patients with spondylosis.30 The association of DISH with diabetes mellitus was reported in several studies.23,26 It was reported more recently that the prevalence of DISH is no higher in diabetic patients than in nondiabetic subjects suggesting re-evaluation of diabetes as a risk factor for the development of DISH.31 More often, DISH was reported to be associated with more complex metabolic and endocrine derangements, with or without overt type 2 diabetes mellitus, comprising glucose intolerance, hyperinsulinemia, dyslipidemia, hyperuricemia, and elevated levels of growth hormone and IGF-I.18-20,23 Hyperinsulinemia has a profound effect on ligaments and entheses, which is independent of age and obesity. The differentiation of mesenchymal cells in ligaments into chondrocytes and the subsequent enchondral ossification is promoted by insulin.24 The enthesis provides the growth

Hyperuricemia Elevated insulin-like growth factor-1 Elevated growth hormone Use of retinoids Genetic predisposition

plate for tendons and ligaments in children and persists into adulthood. This particular structure is composed of collagen fibers, fibroblasts, chondrocytes, and calcified matrix, which is probably a target for the ossification process promoted by insulin.19 Bone morphogenetic protein-2 is a potent osteogenic factor that promotes differentiation of mesenchymal stem cells into osteoblasts and chondroblasts. It stimulates cell proliferation, alkaline phosphatase (ALP) activity, and collagen synthesis.32,33 Its ability to promote mineralization is inhibited by matrix Gla protein, which is highly expressed in bone and cartilage. Matrix Gla protein deficiency or its altered carboxylation may cause a high level of bone morphogenetic protein-2 activity that leads to hyperostosis.27 The enthesis also may be under the influence of other growth-promoting peptides. Elevated growth hormone levels were reported in DISH. Growth hormone is capable of inducing osteoblast cell proliferation and may promote local production of IGF-I, which mediates the action of growth hormone and can stimulate ALP activity in osteoblasts.20,27,34,35 ALP promotes the calcification process during bone formation and is considered a good indicator for the maturation stages of osteoblasts.36 There is no explanation yet as to why the new bone formation is localized mainly at the ligamentous and entheseal sites. In male DISH patients, growth hormone serum levels were not elevated in the serum, but were much higher in the synovial fluid.37 In the spine, vertebral blood supply could be a factor in the onset or progression of DISH.38 Intraerythrocyte growth hormone levels may exceed serum growth hormone levels and could be transported to the vertebral site by the mechanism described by Denko and colleagues.39 The expression of various genes involved in cell division and growth is regulated by nuclear factor κB (NFκB), which is capable of regulating the differentiation of multipotential cells. It was shown that activation of environmental factors such as platelet-derived growth factor (PDGF)-BB and transforming growth factor (TGF)-β1 in ligament cells stimulates the activation of NFκB, which influences the osteoblastic differentiation of mesenchymal cells. This event is accompanied by elevation of ALP activity in cells of patients with DISH and serves as an indicator of maturation stages of the osteoblast.36 Inflammatory cytokines such as PDGF-BB, TGF-β1, and others may be related to the onset of non– insulin-dependent diabetes mellitus and may be the link between this condition and the occurrence of DISH.40,41

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Vitamin A and its derivatives have been implicated in the pathogenesis of DISH owing to their ability to promote new bone formation. Levels of vitamin A were reported to be higher in patients with DISH compared with controls, and some reports showed DISH-like manifestations in young patients treated with vitamin A or its derivatives.42,43 The role of vitamin A is unclear, however, because more recent studies did not show an increased prevalence of DISH among patients treated with vitamin A in various dosages and for various lengths of time.22,25,28 Larger prospective studies are needed to elucidate the role played by this vitamin in the etiology of DISH. Familial clustering of DISH or families with very early presentation of DISH suggest a genetic background for this disorder.44,45 Ossification of the posterior longitudinal ligament is closely related to DISH, and the two conditions can coexist. COL6A1, which is the candidate gene for ossification of the posterior longitudinal ligament, was reported to be significantly associated with DISH in Japanese, but not in Czech, patients.46,47 This finding would suggest that other factors might play an important role in the genetic predisposition for the development of DISH. There are no convincing explanations for the predilection of the hyperostotic process to affect the anterolateral aspect of the thoracic spine. The limited range of motion of the thoracic spine has been cited as a possible cause for the predilection to this site. This assumption cannot explain the involvement of the extremely mobile cervical spine or the lumbar spine, however. The less frequent involvement of the left side of the thoracic spine was ascribed to the pulsation of the aorta. This assumption was based on a few reports that described left-sided bridging osteophytes in cases with a right-sided aorta, suggesting that the aortic pulsations interfere with the production of the osteophytes.48,49 Calcifications, ossification, and subsequent stiffening of ligaments and joint capsules have important pathogenetic implications. Osteoarthritis may have pathogenetic features in common with the peripheral joint manifestions of DISH. It was suggested that in the small non–weight-bearing joints in osteoarthritis, the process is caused by an increased intraarticular pressure and subsequent development of “crash” forces.50 This development was attributed to thickening of the collateral ligaments of these joints that enforce a constraint movement, and not to primary damage to the cartilage. It seems reasonable that the joints affected by DISH may develop the same “crash” forces operating in small osteoarthritis joints, as a result of this mechanism. This mechanism might explain the involvement of “atypical” joints, not commonly affected by osteoarthritis, and the hypertrophic osteoarthritic changes in the commonly affected joints.

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peripheral entheses, such as the heel, Achilles tendon, shoulder, patella, and olecranon. Pain in the axial skeleton may involve all three segments of the spine and the costosternal and sternoclavicular joints. The level of pain and disability is significantly higher compared with healthy subjects, but is not different from patients with ankylosing spondylitis.30 Complaints of pain referable to the thoracic spine are common and are accompanied by a reduced chest expansion. Although similar in some aspects to osteoarthritis of the spine, DISH is a distinct clinical entity with different characteristics.52 Classically, the portions of the spine that are involved in osteoarthritis are the lower portions of the cervical spine and the lumbar spine. Thoracic spine involvement is uncommon in osteoarthritis or occurs in late stages of the disease, as opposed to the common involvement of the thoracic spine in DISH. Thoracic spine involvement in DISH is characterized by preserved intervertebral height, whereas in spinal osteoarthritis, reduced intervertebral disk height is common. These differences in the radiologic appearance and anatomic spinal distribution probably have to do with the different pathogenetic mechanisms described earlier. It is presumed that the primary target for the osteoarthritic process is the cartilage represented in the spine by the intervertebral disks and the cartilage of the facet joints. The wear-and-tear forces operating in the extremely mobile lower cervical and lumbar portions of the spine might explain the frequent involvement of these segments in osteoarthritis, whereas the thoracic spine is the least mobile of the spinal segments. The main targets of the disease in DISH are the spinal ligaments and entheses (Fig. 93-1).5,53 These abnormalities are not limited to the thoracic spine and may involve the lumbar spine and the cervical spine (Fig. 93-2).

L

B

B

A

CLINICAL MANIFESTATIONS The lack of specific symptoms and signs of DISH, and the radiographic diagnostic criteria have raised doubts about DISH as a separate entity.51 Although the disease may be asymptomatic, it was reported to be associated with morning stiffness, dorsolumbar pain, and reduced range of motion in most patients.7,8 Patients with DISH may have extremity pain involving peripheral large and small joints and

Figure 93-1  Large, flowing, right-sided osteophytes of the thoracic spine (A). Note the translucent area between the vertebral body and the ossified ligamentous tissue (B).

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Table 93-4  Clinical Manifestations of Diffuse Idiopathic Skeletal Hyperostosis in the Cervical Spine Spontaneous Dysphagia Hoarseness Stridor Ossification of posterior longitudinal ligament Myelopathy Aspiration pneumonia Sleep apnea Atlantoaxial complications (pseudarthrosis, subluxation) Thoracic outlet syndrome Induced Endoscopic problems Intubation difficulties Fractures From Mader R: Clinical manifestations of diffuse idiopathic skeletal hyperostosis of the cervical spine. Semin Arthritis Rheum 32:130-135, 2002.

Figure 93-2  Severe bulky ossification of the anterior longitudinal ligament of the cervical spine.

In the lumbar spine, the large bridging osteophytes are not uniformly one-sided.54 These sites of ossification, and the subsequent production of large ­ osteophytes, may result in spinal stenosis55 and spinal stiffening, which increases the risk of fractures.56,57 These fractures may be unrecognized, unstable, and associated with treatment delays and permanent neurologic deficits. Severe complications may develop, especially when the cervical spine is affected, including dysphagia, hoarseness, stridor, ossification of the posterior longitudinal ligament, myelopathy, aspiration pneumonia, sleep apnea, atlantoaxial complications, thoracic outlet syndrome, esophageal obstruction, endoscopic and intubation difficulties, and fractures (Table 93-4).58 The high prevalence of coexisting intervertebral disk damage in young patients with DISH suggests an important role for DISH in the pathogenesis of spondylosis in this group of patients.59 Clinical manifestations similar or identical to those of osteoarthritis are prominent features of DISH in the peripheral joints. The peripheral joints affected by DISH have features that distinguish them from primary osteoarthritis, however. One is the more frequent involvement of joints that are not usually affected in osteoarthritis, such as the metacarpophalangeal joints, elbows, and shoulders (Fig. 93-3).60-63 Another feature is a more severe hypertrophic disease that may result in a reduced range of motion in the affected joints.64 As described previously, the primary event in DISH is thickening, calcification, or ossification of ligaments and entheses. In particular, enthesopathy affecting the peripheral joints has been described.65 The radiographic appearance of peripatellar, cruciate ligament insertion, and pericapsular osseous enthesopathies are some examples of

Figure 93-3  Severe hypertrophic osteoarthritis of the proximal and distal interphalangeal joints. Of particular interest is the involvement of the metacarpophalangeal joints with enlarged metacarpal heads, osteophytes, joint space narrowing, and subchondral sclerosis.

the contribution of DISH to stiffening of the soft tissues surrounding a joint (Fig. 93-4).66 Entheseal ossification at various sites other than joints, such as the heel, ribs, and pelvis, is a ­common finding in DISH. These enthesopathies may become symptomatic exhibiting pain and swelling in the affected region. A high probability for the presence of spinal DISH was noted for ossification of the iliolumbar and sacrotuberous ligaments, and with bony overgrowth of the inferior acetabular rim.65-67 The tendency for new bone formation puts the patient at risk for the development of heterotopic ossification after joint surgery.

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R

A

B Figure 93-4  A and B, Ossified enthesopathies in the peripatellar, olecranon, and humeral epicondyles (arrows).

Patients with DISH often have higher body weight and body mass index, waist circumference, and systolic blood pressure.30 These factors, and the metabolic abnormalities described earlier, put patients at an increased risk for cardiovascular diseases.68,69 The diagnosis of DISH should be suspected in patients with osteoarthritis in atypical locations (e.g., elbow), in patients with hypertrophic osteoarthritis, and in patients with large enthesopathies and entrapment neuropathies of uncertain origin. This is particularly true for patients with the associated diseases and metabolic abnormalities discussed before. It was shown that chest radiographs might serve as a screening tool for the diagnosis of DISH with a sensitivity of 77% and ­specificity of 97%.70 TREATMENT CONSIDERATIONS Treatment of DISH should address several issues. Treatment is expected to alleviate pain and stiffness; prevent, retard, or arrest progression; correct the associated metabolic disorders; and prevent spontaneous or induced complications (Table 93-5). Specific therapeutic interventions in DISH have not been systematically explored; this is probably related to the inclusion of DISH in the spectrum of osteoarthritis, and the assumption that the same therapeutic interventions for osteoarthritis are suitable for DISH. It was suggested more recently that serum levels of growth hormone and IGF-I might be a useful surrogate marker for assessing DISH progression and remission.34 It was estimated that a period of at least 10 years is needed for the pathologic process to evolve completely.71 This notion implies that a long observation

Table 93-5  Therapeutic Targets in Diffuse Idiopathic Skeletal Hyperostosis Symptomatic relief of pain and stiffness Prevent, retard, or arrest progression Treatment of associated metabolic disorder Prevent spontaneous complications Prevent traumatic complications Prevent complications that might emerge during diagnostic or therapeutic procedures From Mader R: Current therapeutic options in the management of diffuse idiopathic skeletal hyperostosis. Exp Opin Pharmacother 6:1313-1316, 2005.

period is needed to show that a therapeutic intervention might prevent the development of the disease, arrest its progression, or, it is hoped, reverse the pathologic changes. There are few reports about remedies to alleviate the symptoms of the disease, but some investigators have reported on the beneficial effects of light exercise, heat, analgesics, and nonsteroidal anti-inflammatory drugs (NSAIDs).31,72 More recently, the use of locally acting NSAIDs for the treatment of osteoarthritis was shown to be as effective as the same product by oral route, suggesting that locally acting NSAIDs also might be successfully employed for the symptomatic relief of pain and stiffness in the peripheral joints of patients with DISH.73,74 Treatment of symptomatic enthesopathies might be necessary to alleviate local pain and swelling; this can be achieved by local soft applications such as insoles for plantar spurs or protective bandages at other sites. Infiltration of local anesthetic with long-acting corticosteroids might offer at least temporary relief in severely symptomatic

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Symptomatic

General measures therapy Physical activity Weight loss Low carbohydrate and saturated fat diet Avoid falls Avoid aspiration

Local heat Protection of enthesopathic sites (insoles, bandages) Analgesics NSAIDs Locally acting NSAIDs Local anesthetic/corticosteroid injections

Correction of metabolic abnormalities Control of hyperglycemia and/or hyperinsulinemia preferably by biguanides Control of hyperuricemia Control of hypertension (ACE inhibitors, Ca2+-channel blockers, and α-blockers, should be preferred on thiazide diuretics and β-blockers) Prevention of complications Extra precaution in patients undergoing endotracheal intubation or upper GI endoscopy Prevention of heterotopic ossification following orthopedic surgeries: anti–vitamin K, NSAIDs, irradiation

Future perspectives (?) Interventions at the molecular level to inhibit factors that might promote mesenchymal differentiation to osteoblasts: NFκB, PDGF-BB, TGF-β1 PGI2, BMP-2

Figure 93-5  Therapeutic options in diffuse idiopathic skeletal hyperostosis. ACE, angiotensin-converting enzyme; BMP-2, bone morphogenetic ­protein-2; NFκB, nuclear factor κB; NSAIDs, nonsteroidal anti-inflammatory drugs; PDGF-BB, platelet-derived growth factor-BB; PGI2, prostaglandin I2; TGF-β1, transforming growth factor-β1. (From Mader R: Current therapeutic options in the management of diffuse idiopathic skeletal hyperostosis. Expert Opin Pharmacother 6:1313-1316, 2005.)

cases. When multiple sites are involved, the same therapeutic modalities mentioned for osteoarthritis may be used. The coexistence of many cardiovascular risk factors places patients with DISH at a higher risk for cardiovascular complications. It seems appropriate to screen these patients for known cardiovascular risk factors and to treat when appropriate. General measures such as weight reduction, adequate physical activity, and a diet low in saturated fat and carbohydrates all might be important in preventing or arresting the progression of DISH. Some of these factors may have pathogenetic implications and may become therapeutic targets. Based on present understanding, therapeutic interventions should aim at a reduction of insulin secretion and insulin resistance. In patients with non–insulin-dependent diabetes mellitus, the use of biguanides, which decrease insulin resistance, may offer an advantage over the use of sulfonylureas, which increase insulin secretion. When coexisting hypertension should be treated, medications that might improve insulin resistance, such as angiotensin-­converting enzyme inhibitors, calcium channel blockers, and α-blockers, should be preferred to medications that might worsen insulin resistance, such as thiazide diuretics and β-blockers.75 Some growth factors that might have a role in the development of DISH, such as NFκB, PDGF-BB, TGF-β1, growth hormone, and IGF-I, may become targets someday for specific therapeutic interventions. Some complications can be avoided if taken into consideration. Aspiration pneumonia can be partially avoided if instructions in proper deglutition and preservation of an upright position after meals are carefully explained to the patient. Physicians familiar with DISH can avoid or minimize damage to the cervical spine or to soft tissues in patients who might need certain diagnostic or therapeutic interventions, such as upper gastrointestinal endoscopy or ­ endotracheal

Table 93-6  Future Considerations in Diffuse   Idiopathic Skeletal Hyperostosis Establish and validate diagnostic criteria that consider also the peripheral manifestations of the disease Clarify the natural course and prognosis Study the systemic nature and the impact on quality of life and life expectancy Seek a better understanding of the pathogenetic basis for the disease Offer a disease-modifying therapeutic approach

intubation. It is reasonable to adopt the common measures to prevent falls and trauma, especially in elderly patients. Heterotopic ossification after orthopaedic surgeries, in particular hip arthroplasty, is common in patients with DISH.54 Several therapeutic interventions aimed at abolishing heterotopic ossification, such as administration of NSAIDs, anti–vitamin K, and irradiation, have been reported with variable success.76-78 Patients in the high-risk group to develop this complication, such as patients with DISH, should be considered candidates for one of these regimens. The therapeutic options are summarized in Figure 93-5.79 Many tasks lay ahead to define better, understand the pathogenesis, and delineate future effective interventions for this disorder (Table 93-6).

HYPERTROPHIC OSTEOARTHROPATHY HOA is a well-known entity characterized by skin and bone proliferation. The hallmark and main visual manifestation is a bulbous deformity of the distal end of the digits, also known as clubbing or drumsticks. Periostosis is a progressive process with predilection for the tubular bones, principally

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the tibia and fibula. Periostosis is bilateral; is symmetric; and spares the medullary cavity, the axial skeleton, and the skull. The prevalence of the condition is unknown, but it was found in skeletal human remains dating thousands of years ago.80 It may be primary or secondary to many other diseases.

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Table 93-7  Etiologies of Hypertrophic Osteoarthropathy Unilateral Hemiplegia Patent ductus arteriosus Aneurysms Bilateral

ETIOLOGY

Pulmonary Diseases

Primary HOA is an autosomal dominant disorder characterized by periostosis, clubbing, thickening of the skin of the face and scalp, seborrhea, and hyperhidrosis. It is also termed pachydermoperiostosis. There is a male predominance with a male-to-female ratio of 9:1 with one peak of presentation in the first year of life and the other in adolescence.81 Secondary forms of HOA may manifest as isolated clubbing or with the full spectrum of the disease. Clubbing may be unilateral or bilateral and has been reported to occur in a variety of diseases, including pulmonary, cardiac, gastrointestinal, neurologic, infectious, vascular, and other diseases (Table 93-7).82-86

Cystic fibrosis Pulmonary fibrosis Primary or secondary lung tumors Lung and pleural infections Pleural tumors

PATHOGENESIS

Other Diseases

HOA is characterized by excessive collagen deposition, endothelial hyperplasia, edema, and new bone formation involving mainly the distal extremity and eventually progressing proximally. Various hypotheses have been generated in an attempt to explain the development of HOA. Most cases with secondary HOA have severe lung or cyanotic heart diseases. It was suggested that megakaryocytes are fragmented into platelets during their passage in the lung capillaries. In severe lung diseases or right-to-left shunts, megakaryocytes or platelet aggregates bypass the pulmonary capillary bed, however, and lodge in the peripheral vasculature of the digits. It was shown that locally released growth factors, such as vascular endothelial growth factor (VEGF) and PDGF, were remarkably increased in tissue samples obtained from digits of patients with HOA.87 It is feasible that these substances might be responsible for the distal overgrowth of collagen and bone. VEGF was found to be produced by a lung tumor in a patient with HOA. In this case, serum levels of VEGF were very high, and resection of the tumor reversed the digital clubbing and reduced the serum VEGF levels.88 Activation of platelets and endothelial cells was supported by an increase in circulating von Willebrand factor antigen.89 Other growth factors have been associated with digital clubbing, including hepatocyte growth factor, which was found to be increased in the serum of patients with lung cancer and HOA compared with patients with lung cancer without HOA.90

Various malignancies POEMS syndrome Rheumatic diseases Thymoma AIDS Thalassemia

CLINICAL MANIFESTATIONS Often HOA is asymptomatic, and sometimes it is the patient who notes the changes in the shape of the fingers. Symptomatic patients complain about a deep-seated pain in the lower extremity and over the long tubular bones, which is exacerbated by palpation. Large joint effusions are common, and the synovial fluid is thick with few white blood cells.91,92 Skin hypertrophy may be confined to the nail beds or involve the face or larger areas overlying the tubular bones or joints. The most common and apparent clinical manifestation is digital clubbing. The bulbous deformity of the fingertips

Heart Diseases Cyanotic diseases Infective endocarditis Gastrointestinal Diseases Cirrhosis Hepatic carcinoma Intestinal and esophageal malignant tumors Inflammatory bowel diseases Intestinal polyposis

AIDS, acquired immunodeficiency syndrome; POEMS, polyneuropathy, organomegaly, endocrinopathy, M component, and skin changes.

is accompanied by a convex nail (watch-crystal nail). The skin around the nail bed becomes shiny and thin with disappearance of the creases (Fig. 93-6). Palpation of the base of the nail bed yields the sensation of a “floating” nail within the soft tissue. Cases of advanced clubbing can be identified easily. Several methods were developed, however, to diagnose early phases of the condition. Among those techniques, the digital index and the phalangeal depth ratio have been most widely used.93,94 The digital index measures the ratio between the perimeter of the nail bed and the perimeter at the distal interphalangeal joint of the 10 fingers. A ratio greater than 10 suggests clubbing. The phalangeal depth ratio measures the ratio between the depth of the distal phalanx and the depth of the distal interphalangeal joint of the index finger. A ratio greater than 1 is considered abnormal. There are no specific laboratory tests to diagnose HOA. Radiographs of the fingers and toes may show acro-­osteolysis, and periostitis manifest by cortical thickening of long bones is often observed. The process may involve few or multiple sites and can be regular or irregular in appearance. Characteristically, there is no reduction in joint space or erosions. Radioisotope bone scanning can be useful for diagnosis and for evaluating the extent of the process. Increased uptake can be seen in the cortex of long bones sometimes in the form of splints (Fig. 93-7). TREATMENT CONSIDERATIONS Asymptomatic cases need no treatment. NSAIDs are sometimes useful in symptomatic patients. Case reports have suggested that significant pain relief was observed after treatment

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Figure 93-6  Severe clubbing in a patient with advanced lung cancer.

REFERENCES

Figure 93-7  Increased non-nodular cortical bone uptake in a patient with bronchogenic carcinoma. (From Vandemergel X, Blocket D, Decaux G: Periostitis and hypertrophic osteoarthropathy: Etiologies and bone scan patterns in 115 cases. Eur J Intern Med 15:375-380, 2004; with permission from the European Federation of Internal Medicine.)

with octreotide or pamidronate.95-97 In secondary cases of HOA, all features and symptoms promptly regress with successful treatment of the primary disease, such as correction of a heart malformation, removal of tumors, and therapy of infective endocarditis or inflammatory bowel disease.

  1. Lambert RG, Becker EJ: Diffuse skeletal hyperostosis in idiopathic hypoparathyroidism. Clin Radiol 40:212-215, 1989.   2. Fatourechi V, Ahmed DDF, Schwartz KM: Thyroid acropachy: Report of 40 patients treated at a single institution in a 26 years period. J Clin Endocrinol Metab 87:5435-5441, 2002.   3. Scarpan R, De Brasi D, Pivonello R, et al: Acromegalic axial arthropathy: A clinical case control study. J Clin Endocrinol Metab 89: 598-603, 2004.   4. Forestier J, Rotes-Querol J: Senile ankylosing hyperostosis of the spine. Ann Rheum Dis 9:321-330, 1950.   5. Resnick D, Niwayama G: Radiographic and pathologic features of spinal involvement in diffuse idiopathic skeletal hyperostosis (DISH). Radiology 119:559-568, 1976.   6. Resnick D, Guerra J Jr, Robinson CA, et al: Association of diffuse idiopathic skeletal hyperostosis (DISH) and calcification and ossification of the posterior longitudinal ligament. AJR Am J Roentgenol 131:1049-1053, 1978.   7. Utsinger PD: Diffuse idiopathic skeletal hyperostosis. Clin Rheum Dis 11:325-351, 1985.   8. Resnick D, Niwayama G: Diagnosis of Bone and Joint Disorders, 2nd ed. Philadelphia, WB Saunders, 1988, pp 1563-1615.   9. Boachie-Adjei O, Bullough PG: Incidence of ankylosing hyperostosis of the spine (Forestier’s disease) at autopsy. Spine 12:739-743, 1987. 10. Weinfeld RM, Olson PN, Maki DD, et al: The prevalence of diffuse idiopathic skeletal hyperostosis (DISH) in two large American Midwest metropolitan hospital populations. Skeletal Radiol 26:222-225, 1997. 11. Kiss C, O’Neill TW, Mituszova M, et al: Prevalence of diffuse idiopathic skeletal hyperostosis in Budapest, Hungary. Rheumatology 41:1335-1336, 2002. 12. Bloom RA: The prevalence of ankylosing hyperostosis in a Jerusalem population—with description of a method of grading the extent of the disease. Scand J Rheumatol 13:181-189, 1984. 13. Kim SK, Choi BR, Kim CG, et al: The prevalence of diffuse idiopathic skeletal hyperostosis in Korea. J Rheumatol 31:2032-2035, 2004. 14. Cassim B, Mody GM, Rubin DL: The prevalence of diffuse idiopathic skeletal hyperostosis in African Blacks. Br J Rheumatol 29:131-132, 1990. 15. Julkunen H, Heinonen OP, Knekt P, et al: The epidemiology of hyperostosis of the spine together with its symptoms and related mortality in a general population. Scand J Rheumatol 4:23-27, 1975. 16. Arriaza BT: Seronegative spondyloarthropathies and diffuse idiopathic skeletal hyperostosis in ancient northern Chile. Am J Phys Anthropol 91:263-278, 1993. 17. Vidal P: A paleoepidemiologic study of diffuse idiopathic skeletal hyperostosis. Joint Bone Spine 67:210-214, 2000. 18. Littlejohn GO, Smythe HA: Marked hyperinsulinemia after glucose challenge in patients with diffuse idiopathic skeletal hyperostosis. J Rheumatol 8:965-968, 1981. 19. Littlejohn GO: Insulin and new bone formation in diffuse idiopathic skeletal hyperostosis. Clin Rheumatol 4:294-300, 1985.

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CARTILAGE, BONE, AND HERITABLE CONNECTIVE TISSUE DISORDERS

20. Denko CW, Boja B, Moskowitz RW: Growth promoting peptides in osteoarthritis and diffuse idiopathic skeletal hyperostosis—insulin, insulin-like growth factor-I, growth hormone. J Rheumatol 21: 1725-1730, 1994. 21. Nesher G, Zuckner J: Rheumatologic complications of vitamin A and retinoids. Semin Arthritis Rheum 24:291-296, 1995. 22. Van Dooren-Greebe RJ, Lemmens JAM, De Boo T, et al: Prolonged treatment of oral retinoids in adults: No influence on the frequency and severity of spinal abnormalities. Br J Dermatol 134:71-76, 1996. 23. Vezyroglou G, Mitropoulos A, Kyriazis N, et al: A metabolic syndrome in diffuse idiopathic skeletal hyperostosis: A controlled study. J Rheumatol 23:672-676, 1996. 24. Akune T, Ogata N, Seichi A, et al: Insulin secretory response is positively associated with the extent of ossification of the posterior longitudinal ligament of the spine. J Bone Joint Surg Am 83:1537-1544, 2001. 25. Ling TC, Parkin G, Islam J, et al: What is the cumulative effect of long term, low dose isotretinoin on the development of DISH? Br J Dermatol 144:628-650, 2001. 26. Kiss C, Szilagyi M, Paksy A, et al: Risk factors for diffuse idiopathic skeletal hyperostosis: A case control study. Rheumatology (Oxf) 41:27-30, 2002. 27. Sarzi-Puttini P, Atzeni F: New developments in our understanding of DISH (diffuse idiopathic skeletal hyperostosis). Curr Opin Rheumatol 16:287-292, 2004. 28. Katugampola RP, Finlay AY: Oral retinoid therapy for disorders of keratinization: Single-centre retrospective 25 years’ experience on 23 patients. Br J Dermatol 154:267-276, 2006. 29. Forestier J, Lagier R: Ankylosing hyperostosis of the spine. Clin Orthop 74:65-83, 1971. 30. Mata S, Fortin PR, Fitzcharles MA, et al: A controlled study of diffuse idiopathic skeletal hyperostosis: Clinical features and functional status. Medicine 76:104-117, 1997. 31. Sencan D, Elden H, Nacitarhan V, et al: The prevalence of diffuse idiopathic skeletal hyperostosis in patients with diabetes mellitus. Rheumatol Int 25:518-521, 2005. 32. Tanaka H, Nagai E, Murata H, et al: Involvement of bone morphogenic protein-2 (BMP-2) in the pathological ossification process of the spinal ligament. Rheumatology 40:1163-1168, 2001. 33. Kobacz K, Ullrich R, Amoyo L, et al: Stimulatory effects of distinct members of the bone morphogenetic protein family on ligament fibroblasts. Ann Rheum Dis 65:169-177, 2006. 34. Denko CW, Malemud CJ: Role of growth hormone/insulin-like growth factor-1 paracrine axis in rheumatic diseases. Semin Arthritis Rheum 35:24-34, 2005. 35. Denko CW, Malemud CJ: Body mass index and blood glucose: Correlations with serum insulin, growth hormone, and insulin-like growth factor-1 levels in patients with diffuse idiopathic skeletal hyperostosis (DISH). Rheumatol Int 26:292-297, 2006. 36. Kosaka T, Imakiire A, Mizuno F, et al: Activation of nuclear factor κB at the onset of ossification of the spinal ligaments. J Orthop Sci 5:572-578, 2000. 37. Denko CW, Boja B, Moskowitz RW: Growth factors, insulin-like growth factor-1 and growth hormone, in synovial fluid and serum of patients with rheumatic disorders. Osteoarthritis Cartilage 4:245-249, 1996. 38. el Miedany YM, Wassif G, el Baddini M: Diffuse idiopathic skeletal hyperostosis (DISH): Is it of vascular etiology? Clin Exp Rheumatol 18:193-200, 2000. 39. Denko CW, Boja B, Malemud CJ: Intra-erythrocyte deposition of growth hormone in rheumatic diseases. Rheumatol Int 23:11-14, 2003. 40. Inaba T, Ishibashi S, Gotoda T, et al: Enhanced expression of platelet-derived growth factor-beta receptor by high glucose: Involvement of platelet-derived growth factor in diabetic angiopathy. Diabetes 45:507-512, 1996. 41. Pfeiffer A, Middelberg-Bisping K, Drewes C, et al: Elevated plasma levels of transforming growth factor-beta 1 in NIDDM. Diabetes Care 19:1113-1117, 1996. 42. Abiteboul M, Arlet J, Sarrabay MA, et al: Etude du metabolisme de la vitamine A au cours de la maladie hyperostosique de Forestier et Rote’s-Querol. Rev Rhum Ed Fr 53:143-145, 1986. 43. Nesher G, Zuckner J: Rheumatologic complications of vitamin A and retinoids. Semin Arthritis Rheum 24:291-296, 1995.

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44. Gorman C, Jawad ASM, Chikanza I: A family with diffuse idiopathic hyperostosis. Ann Rheum Dis 64:1794-1795, 2005. 45. Bruges-Armas J, Couto AM, Timms A, et al: Ectopic calcification among families in the Azores: Clinical and radiologic manifestations in families with diffuse idiopathic skeletal hyperostosis and chondrocalcinosis. Arthritis Rheum 54:1340-1349, 2006. 46. Havelka S, Vesela M, Pavelkova A, et al: Are DISH and OPLL genetically related? Ann Rheum Dis 60:902-903, 2001. 47. Tsukahara S, Miyazawa N, Akagawa H, et al: COL6A1, the candidate gene for ossification of the posterior longitudinal ligament, is associated with diffuse idiopathic skeletal hyperostosis in Japanese. Spine 30:2321-2324, 2005. 48. Ciocci A: Diffuse idiopathic skeletal hyperostosis (DISH) and situs viscerum inversus: Report of a single case. Clin Exp Rheumatol 5: 159-160, 1987. 49. Carile L, Verdone F, Aiello A, et al: Diffuse idiopathic skeletal hyperostosis and situs viscerum inversus. J Rheumatol 16:1120-1122, 1989. 50. Smythe HA: The mechanical pathogenesis of generalized osteoarthritis. J Rheumatol 10(Suppl 9):11-12, 1983. 51. Hutton C: DISH…a state not a disease? Br J Rheumatol 28:277-280, 1989. 52. Mader R: Diffuse idiopathic skeletal hyperostosis: A distinct clinical entity. Isr Med Assoc J 5:506-508, 2003. 53. Fornasier VL, Littlejohn GO, Urowitz MB, et al: Spinal entheseal new bone formation: The early changes of spinal diffuse idiopathic skeletal hyperostosis. J Rheumatol 10:934-947, 1983. 54. Belanger TA, Rowe DE: Diffuse idiopathic skeletal hyperostosis: Musculoskeletal manifestations. J Am Acad Orthop Surg 9:258267, 2001. 55. Laroche M, Moulinier L, Arlet J, et al: Lumbar and cervical stenosis: Frequency of the association, role of the ankylosing hyperostosis. Clin Rheumatol 11:533-535, 1992. 56. Paley D, Schwartz M, Cooper P, et al: Fracture of the spine in diffuse idiopathic skeletal hyperostosis. Clin Orthop 267:22-23, 1991. 57. Le Hir PX, Sautet A, Le Gars L, et al: Hyperextension vertebral body fractures in diffuse idiopathic skeletal hyperostosis: A cause of intravertebral fluid-like collections on MR imaging. AJR Am J Roentgenol 173:1679-1683, 1999. 58. Mader R: Clinical manifestations of diffuse idiopathic skeletal hyperostosis of the cervical spine. Semin Arthritis Rheum 32:130135, 2002. 59. Di Girolamo C, Pappone N, Rengo C, et al: Intervertebral disc lesions in diffuse idiopathic skeletal hyperostosis (DISH). Clin Exp Rheumatol 19:310-312, 2001. 60. Littlejohn JO, Urowitz MB, Smythe HA, et al: Radiographic features of the hand in diffuse idiopathic skeletal hyperostosis (DISH). Diagn Radiol 140:623-629, 1981. 61. Beyeler C, Schlapbach P, Gerber NJ, et al: Diffuse idiopathic skeletal hyperostosis (DISH) of the shoulder: A cause of shoulder pain? Br J Rheumatol 29:349-353, 1990. 62. Utsinger PD, Resnick D, Shapiro R: Diffuse skeletal abnormalities in Forestier’s disease. Arch Intern Med 136:763-768, 1976. 63. Resnick D, Shapiro RF, Weisner KB, et al: Diffuse idiopathic skeletal hyperostosis (DISH): Ankylosing hyperostosis of Forestier and Rote’sQuerol. Semin Arthritis Rheum 7:153-187, 1978. 64. Schlapbach P, Beyeler C, Gerber NJ, et al: The prevalence of palpable finger joints nodules in diffuse idiopathic skeletal hyperostosis (DISH): A controlled study. Br J Rheumatol 31:531-534, 1992. 65. Littlejohn JO, Urowitz MB: Peripheral enthesopathy in diffuse idiopathic skeletal hyperostosis (DISH): A radiologic study. J Rheumatol 9:568-572, 1982. 66. Resnick D, Shaul SR, Robins JM: Diffuse idiopathic skeletal hyperostosis (DISH): Forestier’s disease with extraspinal manifestations. Radiology 115:513-524, 1975. 67. Haller J, Resnick D, Miller GW, et al: Diffuse idiopathic skeletal hyperostosis: Diagnostic significance of radiographic abnormalities of the pelvis. Radiology 172:835-839, 1989. 68. Mader R, Dubenski N, Lavi I: Morbidity and mortality of hospitalized patients with diffuse idiopathic skeletal hyperostosis. Rheumatol Int 26:132-136, 2005. 69. Miyazawa N, Akiyama I: Diffuse idiopathic skeletal hyperostosis associated with risk factors for stroke. Spine 31:E225-E229, 2006. 70. Mata S, Hill RO, Joseph L, et al: Chest radiographs as a screening tool for diffuse idiopathic skeletal hyperostosis. J Rheumatol 20:1905-1910, 1993.

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71. Mader R: Diffuse idiopathic skeletal hyperostosis: Isolated involvement of cervical spine in a young patient. J Rheumatol 31:620-621, 2004. 72. El Garf A, Khater R: Diffuse idiopathic skeletal hyperostosis (DISH): A clinicopathological study of the disease pattern in Middle Eastern populations. J Rheumatol 11:804-807, 1984. 73. Tugwell PS, Wells, Shainhouse JZ: Equivalence study of a topical diclofenac solution (pennsaid) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: A randomized controlled trial. J Rheumatol 31:2002-2012, 2004. 74. Roth SH, Shainhouse JZ: Efficacy and safety of a topical diclofenac solution (pennsaid) in the treatment of primary osteoarthritis of the knee: A randomized, double-blind, vehicle-controlled clinical trial. Arch Intern Med 164:2017-2023, 2004. 75. Lithell HOL: Effect of antihypertensive drugs on insulin, glucose, and lipid metabolism. Diabetes Care 14:203-209, 1991. 76. Cella JP, Salvati EA, Sculco TP: Indomethacin for the prevention of heterotopic ossification following total hip arthroplasty: Effectiveness, contraindications, and adverse effects. J Arthroplasty 3:229-234, 1988. 77. Guillemin F, Mainard D, Rolland H, et al: Antivitamin K prevents heterotopic ossification after hip arthroplasty in diffuse idiopathic skeletal hyperostosis: A retrospective study in 67 patients. Acta Orthop Scand 66:123-126, 1995. 78. Knelles D, Barthel T, Karrer A, et al: Prevention of heterotopic ossification after total hip replacement: A prospective, randomized study using acetylsalicylic acid, indomethacin and fractional or single-dose irradiation. J Bone Joint Surg Br 79:596-602, 1997. 79. Mader R: Current therapeutic options in the management of diffuse idiopathic skeletal hyperostosis. Exp Opin Pharmacother 6:13131316, 2005. 80. Martinez-Lavin M, Mansilla J, Pineda C, et al: Evidence of hypertrophic osteoarthropathy in human skeletal remains from PreHispanic era in Mesoamerica. Ann Intern Med 12:238-241, 1994. 81. Martinez-Lavin M, Pineda C, Valdez T, et al: Primary hypertrophic osteoarthropathy. Semin Arthritis Rheum 17:156-162, 1988. 82. Spicknall KE, Zirwas MJ, English JC: Clubbing: An update on diagnosis, differential diagnosis, pathophysiology, and clinical relevance. J Am Acad Dermatol 52:1020-1028, 2005. 83. Martinez-Lavin M: Hypertrophic osteoarthropathy. Curr Opin Rheumatol 9:83-86, 1997.

84. Stridhar KS, Lobo CF, Altman RD: Digital clubbing and lung cancer. Chest 114:1535-1537, 1998. 85. Vongpatanasin W, Brickner ME, Hillis LD, et al: The Eisenmenger syndrome in adults. Ann Intern Med 128:745-755, 1998. 86. Botton E, Saraux A, Laselve H, et al: Musculoskeletal manifestations in cystic fibrosis. Joint Bone Spine 70:327-335, 2003. 87. Atkinson S, Fox SB: Vascular endothelial growth factor (VEGF)— A platelet-derived growth factor (PDGF) plays a central role in the pathogenesis of digital clubbing. J Pathol 203:721-728, 2004. 88. Olan F, Portela M, Navarro C, et al: Circulating vascular endothelial growth factor concentrations in a case of pulmonary hypertrophic osteoarthropathy: Correlation with disease activity. J Rheumatol 31:614-616, 2004. 89. Matucci-Cerinic M, Martinez-Lavin M, Rojo F, et al: Von Willebrand factor antigen in hypertrophic osteoarthropathy. J Rheumatol 19: 765-767, 1992. 90. Hojo S, Fujita J, Yamadori I, et al: Hepatocyte growth factor and digital clubbing. Intern Med 36:44-46, 1997. 91. Schumacher HR Jr: Articular manifestations of hypertrophic pulmonary osteoarthropathy in bronchogenic carcinoma. Arthritis Rheum 19:629-636, 1976. 92. Schumacher HR Jr: Hypertrophic osteoarthropathy: Rheumatologic manifestations. Clin Exp Rheumatol 10(Suppl 7):35-40, 1992. 93. Vazquez-Abad D, Pineda C, Martinez-Lavin M: Digital clubbing: A numerical assessment of the deformity. J Rheumatol 16:518-520, 1989. 94. Myers KA, Farquhar DRE: Does this patient have clubbing? JAMA 286:341-347, 2001. 95. Garske LA, Bell SC: Pamidronate results in symptom control of hypertrophic pulmonary osteoarthropathy in cystic fibrosis. Chest 121: 1363-1364, 2002. 96. Amital H, Applbaum YH, Vasiliev L, et al: Hypertrophic pulmonary osteoarthropathy: Control of pain and symptoms with pamidronate. Clin Rheumatol 23:330-332, 2004. 97. Angel-Moreno Maroto A, Martinez-Quintana E, Suarez-Castellano L, et al: Painful hypertrophic osteoarthropathy successfully treated with ocreotide: The pathogenetic role of vascular endothelial growth factor (VEGF). Rheumatology 44:1326-1327, 2005.

94

Osteonecrosis CHRISTOPHER CHANG  • ADAM GREENSPAN  • M. ERIC GERSHWIN

KEY POINTS Knowledge of risk factors and early detection is crucial to the successful management of osteonecrosis.

predominantly occurs in the third to fifth decades of life.9 As a result of this age distribution, long-term morbidity can be significant.

Abnormalities in lipid metabolism might play a role in the pathogenesis of osteonecrosis.

ETIOLOGY

The most common causes of nontraumatic osteonecrosis are corticosteroid use and alcohol consumption. The final common pathway in the pathogenesis of osteonecrosis is the disruption of blood supply to a segment of bone. The femoral head is the most common site of osteonecrosis. Osteonecrosis affects younger patients than osteoarthritis and has significantly greater long-term morbidity. Nonsurgical treatment of osteonecrosis does not change the natural history of the disease. Magnetic resonance imaging is currently the optimal study for early diagnosis and identification of the extent of osteonecrosis. Although there are many variations on surgical treatment of femoral head osteonecrosis, most hips eventually require total hip arthroplasty.

Osteonecrosis literally means “bone death” (ossis [Latin] = bone; necrosis = killing or causing to die). Other synonyms include avascular necrosis, ischemic necrosis of bone, aseptic necrosis, osteochrondritis dissecans, and subchondral avascular necrosis. Hippocrates first described the concept of bone death,1 and the first description of osteonecrosis appeared in a case of sepsis-induced bone death in 1794 by Russell.2 Approximately a century later, in 1888, it was recognized that bone necrosis could occur in the absence of infection.3 The first report of osteonecrosis occurring in a deep-sea diver appeared in 1936.4 Osteonecrosis occurs as a result of partial or complete reduction in blood flow, although multiple mechanisms might be responsible for this disruption.5,6

EPIDEMIOLOGY The prevalence of osteonecrosis is unknown, but it is estimated that there are 10,000 to 20,000 new patients with osteonecrosis diagnosed per year in the United States. It occurs in 15% to 80% of patients with femoral neck fractures.7 Of the 500,000 hip replacements done in the United States every year, about 10% are thought to be the result of osteonecrosis.8 The disease primarily affects men, with a notable exception of cases related to systemic lupus erythematosus, which has a female predominance. Osteonecrosis

Osteonecrosis has been linked to numerous ­ conditions (Table 94-1). In many of these conditions, a causal rela­ tionship has yet to be determined. In others, the ­association is tenuous and may consist only of anecdotal or case reports. One accepted risk factor is corticosteroid use, first described in 1957.10 Corticosteroids also are associated with ­significant side effects when used for prolonged periods, and a high index of suspicion should be maintained for osteonecrosis. In one study, 2500 to 3300 cases of nontraumatic osteonecrosis were reported in 1988, with 34.7% related to corticosteroid use, 21.7% associated with alcohol consumption, and the rest idiopathic. Although the risk of osteonecrosis with steroid use is low, the morbidity associated with the resulting hip deformity is significant. The time interval between steroid use and the development of osteonecrosis varies among individuals. In one study of 22 patients diagnosed with stage I osteonecrosis by magnetic resonance imaging (MRI), the interval between the use of steroids and diagnosis ranged from 1 to 16 months.11 The cumulative dose of steroids in this study ranged from 1800 to 15,505 mg (mean 5928 mg) of prednisolone or the equivalent. In other studies, cumulative doses of steroids associated with osteonecrosis ranged from 48012 to 4320 mg13 of dexamethasone dose equivalence. Although corticosteroid-related osteonecrosis is dose related, additional host-inherent risk factors play a role. The incidence of osteonecrosis in a group of patients receiving glucocorticoid replacement therapy for primary or secondary adrenal insufficiency was 2.4%. In a study of renal transplantation, 26 patients who developed osteonecrosis had a higher cumulative oral dose of prednisone after 1 month and 3 months compared with 28 control transplant patients who did not develop osteonecrosis.14 A separate study estimated the incidence of osteonecrosis in renal transplant patients on steroids to be 5%.15 It is unknown why certain patients on steroids develop osteonecrosis and others do not. The minimum dosage or duration of use that can lead to osteonecrosis also is unknown. Patients with systemic lupus erythematosus and organ transplantation who are receiving corticosteroids are particularly prone to developing osteonecrosis. There is no evidence that ­topical, inhaled, or intranasal route of administration can lead to osteonecrosis. Although data are ­ limited to case reports, a link between intra-articular administration of ­corticosteroids 1611

1612 CHANG  |  Osteonecrosis

Table 94-1  Conditions Associated with Osteonecrosis Dietary, Drugs, and Environmental Factors Corticosteroids145,146 Cigarette smoking22 Dysbaric osteonecrosis4,147 Alcohol consumption22,148 Lead poisoning149,150 Bisphosphonates98,151 Musculoskeletal Conditions—Compromise in Structural Integrity Trauma152 Legg-Calvé-Perthes disease29,153 Congenital hip dislocation154,155 Hereditary dysostosis Slipped capital femoral epiphysis156,157 Metabolic Diseases—Abnormality in Fat or Other Metabolic Component Gaucher’s disease158 Fat embolism159,160 Pancreatitis62,64,161,162 Chronic liver disease163 Pregnancy37,164 Fabry’s disease165,166 Gout167 Hyperparathyroidism168 Hyperlipidemia159,160 Hypercholesterolemia167 Diabetes169 Hematologic Conditions—Abnormalities in Components of Blood Hemoglobinopathies Sickle cell anemia38,170,171 Thalassemia172 Disseminated intravascular coagulation85,173-176 Hemophilia41-43 Thrombophilia177 Marrow infiltrative disorders Hypofibrinolysis178 Thrombophlebitis/venous thrombosis179 Rheumatologic Conditions Antiphospholipid antibody syndrome180 Rheumatoid arthritis181 Systemic lupus erythematosus61,97,182-184 Inflammatory bowel disease185,186 Necrotizing arteritis187 Mucocutaneous lymph node syndrome188 Polymyositis189 Sarcoidosis63 Mixed connective tissue disease Infectious diseases HIV infection190 Osteomyelitis191 Meningococcemia173,176,192 Oncologic Disorders and Their Treatment Organ transplantation193-198 Radiation exposure199-204 Regional deep hyperthermia205 Acute lymphoblastic leukemia206,207 HIV, human immunodeficiency virus.

has been reported.16 Parenteral steroids pose a higher risk because of lipid absorption and a longer half-life. Other therapeutic interventions associated with osteonecrosis include dialysis, bisphosphonate usage, and radiation therapy. A retrospective chart review of patients with osteonecrosis in bone specimens of the maxilla and mandible

identified 23 cases associated with use of the newer generation bisphosphonates zoledronate, pamidronate, or alendronate, after exclusion of patients who did not have metastatic bone cancer in the same site and who also were treated with radiation therapy.17 Of the 23 patients, 18 were treated with the intravenous form, and the other 5, who had osteoporosis or Paget’s disease, were treated with the oral form. The association between alcohol consumption and osteonecrosis was first described in 1922.18 A study of patients with idiopathic osteonecrosis revealed that the risk of osteonecrosis increased with increasing daily consumption of alcohol. None of these patients were on corticosteroids, and the data were compared with hospital controls. The relative risk of developing osteonecrosis for three broad categories of alcohol consumption (<400 mL/wk, 400 to 1000 mL/wk, and >1000 mL/wk) was 3-fold, 10-fold, and 18-fold respectively. The data were adjusted for confounding variables such as cigarette smoking.19 Another study showed that liver damage was unnecessary for the development of osteonecrosis in alcohol-consuming patients, although abnormal liver enzymes, such as elevated serum γ-glutamyl transferase activity, have been noted.20 In another study of nearly 1200 patients who were treated medically for alcoholism, the incidence of osteonecrosis was 5.3%. Most of the cases involved the femoral head (82 of 92 lesions), and the other 10 sites involved the humeral head.21 It is generally accepted that the use of steroids and chronic alcohol usage would lead to an additive risk. Cigarette smoking is associated with osteonecrosis,19,22,23 although there is no clear cause-and-effect relationship. A significant relative risk of 3.0 was observed for current smokers, but a dose-dependent relationship was not seen, and the risk is much less than steroids. Musculoskeletal conditions in which osteonecrosis has been observed include slipped capital femoral epiphysis, Ehlers-Danlos syndrome, Legg-Calvé-Perthes disease, hereditary dysostosis, and congenital hip dislocation. Legg-Calvé-Perthes disease is a disorder first described in 191024-26 affecting children 3 to 12 years old. Femoral head osteonecrosis is a feature of the disease and has been linked to trauma,27,28 congenital hip dislocation,29 and transient synovitis.30 Bilateral involvement commonly occurs, and associated clinical manifestations include abnormal growth and stature,31,32 delayed skeletal maturation,33 disproportionate skeletal growth,32 congenital anomalies,34 and abnormal hormone levels.35,36 Metabolic disorders, such as Cushing’s syndrome, Gaucher’s disease, disorders of lipid and glucose metabolism, pancreatitis, and pregnancy, also are associated with osteonecrosis. Although the association with pregnancy is rare, most cases occur in primigravid patients, with onset of pain in the late second to third trimesters. Diagnosis can be delayed until months after delivery. Women who developed osteonecrosis tended to have a small body frame and a large weight gain during pregnancy.37 Hematologic conditions, such as sickle cell anemia, hemophilia, and intravascular coagulation, have been associated with osteonecrosis. The long-term morbidity of osteonecrosis in patients with sickle cell anemia is dismal.38 Deformities occur in 80% of these patients and persist into adulthood. Common deformities include decreased ­mobility,

PART 15 

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abnormal gait, and leg-length discrepancy.39 Osteonecrosis in hemophilia patients has been described,40-45 but the numbers are small, and no statistically reliable causal link can be established. Finally, a type of osteonecrosis known as dysbaric osteonecrosis has been described in construction workers in the Elhe tunnel exposed to high-pressure environments.46 The prevalence of dysbaric osteonecrosis is 4.2% in divers and 17% in compressed air workers.47 Patients with dysbaric osteonecrosis may have more than one lesion, and common sites besides the femoral head include the tibia and the humeral head and shaft. The condition is not related to decompression sickness, and although proper decompression procedures can reduce “the bends,” they do not have any effect on development of osteonecrosis. Osteonecrosis can occur months or years after the last exposure to high pressures.

CLINICAL FEATURES The primary presenting symptom in osteonecrosis is pain. In osteonecrosis of the femoral head, the pain is located in the hip joint and may radiate to the groin, anterior thigh, or knee. The severity of the pain can vary, depending on the size of the infarct and whether the onset of the disease is insidious or sudden. In trauma, where there is sudden and severe disruption of blood flow, and in Gaucher’s disease, dysbarism, or hemoglobinopathy, where the infarcts are large, pain can be intense and occur suddenly. In other conditions, pain can occur insidiously. The pain of osteonecrosis usually is increased with use of the joint, but in advanced disease, the pain is persistent even at rest. Limitation of range of motion except that associated with accompanying pain is usually a progressive and late symptom. The risk of developing osteonecrosis in the contralateral hip when one side is affected ranges from 31% to 55%. In addition to the femoral head, osteonecrosis can affect other sites, including the humeral head,48-51 femoral condyles52-54 and proximal tibiae,53,55-59 wrists and ankles,60 bones of the hands and feet,61 vertebrae,62-64 jaw,65,66 and bony structures of the face.67 Osteonecrosis of the humeral head is the second most commonly seen location, and pain is usually in the shoulder with limited range of motion and weakness. Pain in the ankle is the main presenting symptom in atraumatic osteonecrosis of the talus, and in some cases, disease had already progressed to Ficat and Arlet stage III by the time of presentation.60 Kienböck’s disease involves osteonecrosis of the lunate, and patients present with pain in the radiolunate joint, along with weakness and limitation of motion. Kienböck’s disease seems to be related to manual labor. The Ficat and Arlet method of staging osteonecrosis consists of four stages. Stages I and II are reversible, whereas stage III, which involves subchondral collapse, and stage IV, which involves joint space narrowing and destruction of cartilage, are irreversible. The Marcus staging system consists of six stages; the first two are reversible, and the subsequent four are irreversible. The modified Steinberg staging system is based on the Marcus system and also consists of six stages. Within each stage, the extent of head involvement is subdivided into three subclasses—A involves less than 25%; B, 26% to 50%; and C, greater than 50% of the head.

CARTILAGE, BONE, AND HERITABLE CONNECTIVE TISSUE DISORDERS 1613

Table 94-2 presents similarities and differences between the staging systems. The Association of Research Circulation Osseous (ARCO) has proposed a modification to the Ficat and Arlet system, adding a stage 0 for patients with negative imaging studies but who are at high risk for developing osteonecrosis. In addition, stages I to III are stratified further to take into account lesion size, location, and extent of collapse.68 In 2001, the Japanese Ministry of Health, Labor, and Welfare proposed revised criteria for the diagnosis and staging of osteonecrosis of the femoral head. Diagnostic criteria included the following: (1) collapse of the femoral head without joint space narrowing or acetabular abnormality on plain radiography, (2) demarcating sclerosis in the femoral head without joint space narrowing or acetabular abnormality, (3) “cold in hot” on bone scans, (4) lowintensity band on T1-weighted MRI, and (5) trabecular and marrow necrosis on histology. If a patient fulfills two of the five criteria, the diagnosis is established. The working group also proposed four types of lesions based on extensiveness, and defined stages of disease based on diagnostic imaging.

PATHOGENESIS To understand why the femoral head is preferentially affected in osteonecrosis, it is important to understand the anatomy of the femoral head and its blood supply. Three arterial networks supply the femoral head and neck. The extracapsular arterial ring consists of the lateral femoral circumflex artery and the medial femoral circumflex artery, which arise from the profunda femoris. The medial femoral circumflex artery and its branches supply most of the blood to the head and neck of the femur. The lateral circumflex artery gives rise to transverse branches, which supply the femoral head. The medial and lateral circumflex arteries anastomose with the superior and inferior gluteal branches of the internal iliac artery, providing collateral circulation between the femoral artery and the internal iliac artery. Retinacular arteries are ascending cervical branches of the extracapsular ring and form an intra-articular ring at the level of the cartilage. Epiphyseal arterial branches arise from this ring and penetrate the head and neck of the femur, including the ­epiphyses. The artery of the ligament of the head of the femur is a branch of the obturator artery and may be the sole supplier of blood to the proximal fragment of the head. These anatomic features render the femoral head particularly prone to ischemia. Numerous theories abound concerning the pathogenesis of the various risk factors associated with osteonecrosis of the femoral head. Table 94-3 presents a potential pathway for some of the disease entities associated with osteonecrosis. The common end result is the disruption of the blood supply, which can result from vascular, intravascular, or extravascular factors. Histologically, after an infarct, a rim of bony thickening or sclerosis begins to form at the margins of the infarcted area. If the necrotic lesion is within the weight-bearing region of the femoral head, subchondral fractures follow. The repair process is inadequate and itself compromises the structural integrity of the bone. With repeated microfractures and continued weight bearing, the original fracture cannot heal completely, and new fractures appear. The secondary fracture propagates along the junction between subchondral bone and the necrotic segment. As time goes

1614 CHANG  |  Osteonecrosis

Table 94-2  Various Staging Systems for   Osteonecrosis Ficat and Arlet Stage

Radiographic Appearance

Reversible

I

Normal

Yes

II

Cystic or osteosclerotic lesions; normal contour of bone; no subchondral fracture

Yes

III

Crescent sign or subchondral collapse

No

IV

Joint space narrowing; secondary distal No tibial, femoral, humeral changes (cysts, marginal osteophytes, and cartilage destruction) Marcus

Stage

Radiographic Appearance

Reversible

I

Subtle, mottled densities in weight­bearing segments of femoral head

Yes

II

Well-demarcated area of infarction

Yes

III

Crescent sign, signifying collapse or ­separation of the subchondral ­trabeculae from the articular cartilage

No

IV

Collapse of the avascular segment; ­fractures may be seen on articular surfaces

No

V

Osteoarthritis of the hip; joint space No ­narrowing; presence of cystic areas   and small osteophytes in subchondral bone

VI

Marked degenerative changes; joint   space narrowing; collapse of the ­femoral head

No

Modified Steinberg Stage

Radiographic Appearance

Reversible

I

Normal radiograph, but abnormal   bone scan or MRI

Yes

II

Lucent and sclerotic changes

Yes

III

Subchondral fracture without   flattening

No

IV

Subchondral fracture with flattening or No segmental depression of femoral head

V

Joint space narrowing or acetabular changes

No

VI

Advanced degenerative changes

No

Specific Disease Investigation ­Committee of the Japanese Ministry of Health, Labor, and Welfare Stage

Radiographic Appearance

Reversible

1

Normal radiographs, but positive   findings on MRI, bone scintigraphy,   or histology

Yes

2

Demarcating sclerosis without collapse

Yes

3A

Collapse of the femoral head, <3 mm (crescent sign) without joint space ­narrowing; mild osteophyte   formation

No

3B

Same as 3A except that femoral head ­collapse is >3 mm

No

4

Osteoarthritic changes

No

MRI, magnetic resonance imaging.

on, the ­femoral head becomes flattened and eventually collapses. A nonspherical head articulating with the acetabulum produces friction and erosion and loss of cartilage. The cycle repeats itself, and the structure of the joint deteriorates, with the appearance of degenerative changes and eventually total joint destruction.69 The association between alcohol and osteonecrosis has led investigators to study the effects of alcohol on ­ rabbit bone marrow.73 Alcohol consumption was associated with reduced superoxide dismutase activity. Histologically, the rabbit bone marrow showed adipogenesis, and fatty infiltration of the liver was found; this led to increases in fat cell hypertrophy and proliferation and a decrease in hematopoiesis in the subchondral femoral head. Osteocytes contained triglyceride deposits, and there was an increase in empty osteocyte lacunae. Alcohol also primarily affected differentiation of bone marrow stromal cells into adipocytes, and this was a dose-dependent response. Intracellular lipid deposits led to death of osteocytes. In rats fed a diet of alcohol and glucose, lower bone mineral content and density were detected compared with controls. In hamsters, alcohol led to thinning of the trabeculae of the distal part of the femur. Cytologic effects included mitochondrial swelling in osteoblasts and osteocytes. Partial osteonecrosis of the femoral head was detected in Merino sheep that were injected with ethanol. In humans, alcohol causes increased plasma calcium levels, decreased osteocalcin and circulating parathyroid hormone levels, reduced serum calcitriol, reduced bone volume, and increased osteoclast number. Alcohol also has deleterious effects on muscle, including increased oxygen free radical–related damage to muscle, reduced myocardial contractility, defective mitochondrial function, and increased tissue enzymes.75 A study investigated the effects of alcohol on the ability of mesenchymal stem cells to differentiate into osteogenic lineages. The bone marrow in the proximal head of femurs was isolated during hip replacement surgery from 33 patients with either femoral neck fractures or alcoholinduced osteonecrosis. The cells from femurs of patients with alcohol-induced osteonecrosis showed a reduced ability to differentiate into osteoblasts.76 A subsequent study compared the mesenchymal stem cells from patients with hip osteoarthritis and nontraumatic osteonecrosis associated with steroid use or alcohol use and idiopathic osteonecrosis. In alcohol-induced osteonecrosis and idiopathic osteonecrosis, the ability of mesenchymal stem cells to differentiate into osteoblasts was decreased, but in steroid-induced osteonecrosis, it was elevated, although not to a statistically significant level. The adipogenic differentiation ability was similar in all four groups.77 In corticosteroid-induced osteonecrosis, the pathogenic mechanism parallels that of alcohol-induced osteonecrosis. In both cases, fatty infiltration of osteocytes has been postulated to occur.70,72,74 Table 94-4 lists lipid-altering effects of corticosteroids and alcohol. In addition, interosseous venous stasis affects the interosseous microcirculation, which can lead to hemodynamic and structural changes in the femoral head. The resulting decrease in blood flow leads to osteonecrosis. In chickens treated with steroids, fatty infiltration of the liver and fat cell hypertrophy and proliferation in the femoral head occurred concurrently 1 week after the ­initiation of steroids. As in the case of alcohol-induced

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CARTILAGE, BONE, AND HERITABLE CONNECTIVE TISSUE DISORDERS 1615

Table 94-3  Proposed Mechanism of Disease of Common Conditions Associated with Osteonecrosis Mechanism of Action Condition

1—Secondary to

Trauma

Direct vascular injury

Sickle cell anemia

Vascular occlusion

Abnormal shape of   erythrocytes

Legg-Calvé-Perthes disease

Mechanical instability   of femoral epiphyseal   plate

Delayed expression of type X collagen during epiphyseal ossification

Alteration in expression of   insulin-like growth factor

Corticosteroids

Sinusoidal collapse

Increase in intracortical   pressure

Increase in femoral head fat   content

Pregnancy

Fat embolism

Acute fatty liver in third   trimester of pregnancy

Increased plasma lipid levels   in ­second trimester   of pregnancy

Diabetes

Fat embolism Abnormal endochondral   ossification of epiphyseal plate

2—Secondary to

3—Secondary to

4—Secondary to 

Hyperlipidemia

Pancreatitis

Fat embolism

Hereditary   dysostosis

Collapse of femoral head

Femoral head subchondral   cyst formation

Dysbaric   osteonecrosis

Occlusion of end arterioles

Formation of intravascular   gas bubbles or accumulation of nitrogen gas in the bone marrow

Intravascular   ­coagulation

Arteriolar thrombosis

Increase in plasma ­  fibrinopeptide A

Legg-Calvé-Perthes disease

Collapse of subchondral bone

Widening of joint space

Loss of endochondral ossification   Ischemia in the periosseous epiphyseal cartilage and physeal plate

Dialysis

Decreased bone strength

Increased subchondral bone resorption and formation of disorganized bone matrix

Increased bone turnover

Ehlers-Danlos ­  syndrome

Hip dislocation

Gaucher’s disease

Vascular compromise

Mass compression

Lipid-laden Gaucher cell   infiltration of bone marrow

Alcohol

Increased concentration of fat emboli in metaphyses of   femur

Venous stasis

Absence of vascular sinusoids   in bone marrow

Table 94-4  Lipid-Altering Effects of Steroids   and ­Alcohol Fatty liver Swelling and necrosis of fat cells Lipid-filled osteocytes

Hyperparathyroidism

Increased blood cortisol levels

d­ elivery to the femoral head.80 Hyperviscosity also can be seen in hyperlipoproteinemia and Legg-Calvé-Perthes disease.81 The mechanism for bisphosphonate-induced osteonecrosis might be related to the ability of bisphosphonates to inhibit bone remodeling and decrease interosseous blood flow.82

Hyperlipidemia Adipogenesis of marrow stromal cells

GENETICS OF OSTEONECROSIS

Fatty infiltration of bone marrow

The role of host factors or genetics in the pathogenesis of osteonecrosis is unknown. Studies to identify gene polymorphisms stemmed from the realization that endothelial nitric oxide synthase has beneficial effects on three systems that have been implicated in the development of osteonecrosis— skeletal, vascular, and thrombotic. Comparative analysis of the 26-base pair repeat polymorphism in intron 4 and the Glu298Asp polymorphism in exon 7 was ­performed between patients with idiopathic, steroid-induced, or alcohol-related osteonecrosis and matched control subjects. The frequency of the 4a allele was higher in patients with idiopathic osteonecrosis compared with control subjects. In addition, the frequency of the 4a/b genotype was higher in all patients with osteonecrosis compared with control subjects.

Fat emboli

osteonecrosis, adipocytes contained triglyceride vesicles. In rabbits treated with steroids, it was found that intraosseous pressure was increased, and the size of bone marrow fat cells was larger than in control rabbits.78 A histologic study of acetabular and proximal femoral bone in osteonecrosis of the femoral head revealed that osteonecrosis is more extensive in corticosteroid-induced compared with alcohol-induced or idiopathic osteonecrosis. The reason for this is unknown.79 In sickle cell anemia, the sickle cells lead to a hyperviscosity syndrome, which blocks vessels and decreases blood

1616 CHANG  |  Osteonecrosis

The 4a allele is known to be associated with reduced synthesis of endothelial nitric oxide synthase, suggesting that nitric oxide may provide a protective effect against the development of osteonecrosis.83 Forty one percent of patients with osteonecrosis compared with only 20% of controls were homozygous for the 4G/4G mutation in the plasminogen activator inhibitor-1 gene.84 The mutation causes increased hypofibrolytic plasminogen activator inhibitor activity, resulting in decreased stimulated plasminogen activator activity. This observation gives support to the role that procoagulants might play in the pathogenesis of osteonecrosis. Alcohol-induced or steroid-induced hyperlipemia, which results in increased serum free fatty acids and prostaglandins, can potentially trigger vascular inflammation and coagulation. Other triggers for intravascular coagulation include atherosclerosis and arteriolar fibroid degeneration. Jones85 proposed these changes as a possible pathologic mechanism for the development or progression of osteonecrosis from stage 1A to 1B, arguing that an inability to clear procoagulants from the blood or tissue leads to persistent levels of tissue thromboplastin, leading to arteriolar thrombosis, vascular stasis, free fatty acid–induced endothelial damage, and hypercoagulability. Studies of the levels of procoagulants in patients with osteonecrosis showed that 82% of patients with osteonecrosis had at least one abnormal procoagulant level and 47% had at least two abnormal procoagulant levels compared with 30% and 2.5% in normal controls. The procoagulants measured included free protein S, protein C, lipoprotein A, homocysteine, plasminogen activator inhibitor, stimulated tissue plasminogen activator, anticardiolipin antibodies (IgG and IgM), and resistance to activated ­protein C.86 Changes in the vasculature itself may lead to a compromise in blood flow. Examples include structural damage to arteriolar walls, degeneration of the tunica media, smooth muscle cell necrosis, and disruption of the internal elastic lamina. These changes can lead to eventual hemorrhagic infarction87 and were shown in a series of 24 core biopsy specimens from osteonecrotic femoral heads; the changes did not occur in 11 femoral heads with osteoarthrosis.88 In Legg-Calvé-Perthes disease, obstruction to venous drainage elevates intraosseous pressure and consequently elevates intra-articular pressures. In a study of patients with Legg-Calvé-Perthes disease, bone scintigraphy using Tc 99m methylene diphosphonate (Tc 99m MDP) was employed to measure arterial and venous flow in the diseased hip. Although arterial flow was normal, there was a significant disturbance in venous drainage.89 This disturbance was reproduced in a dog model in which injection of silicone was used to obstruct venous flow distal to the hip.90 Ischemia as a result of venous drainage obstruction can cause a cessation of endochondral ossification in the preosseous epiphyseal cartilage and the physeal plate. Widening of the joint space ensues followed by revascularization of the epiphysis and deposition of new immature bone. A weakened or unstable femoral epiphyseal plate results, and the subchondral bone becomes prone to segmental collapse and fracture.91 The pathologic mechanism in dysbaric osteonecrosis is unclear. The most intuitive explanation is that formation of gas bubbles in the vessels causes occlusion and ischemia. Multiple other factors might contribute to the disease,

however, including thromboembolic events such as platelet aggregation, erythrocyte clumping, lipid coalescence, intraosseous vessel compression as a result of extravascular gas bubbles, formation of fibrin thrombi, and narrowing of arterial lumens owing to myointimal thickening caused by gas bubbles. The interaction between gas and blood can lead to the formation of vessel-occluding substances. All these events may lead to redistribution of blood flow. The increased vulnerability of bone to compression disorders has been explained by several factors, including the relative rigidity of bone and inability to absorb increased gas pressure, inherent poor vascularization, and gas supersaturation of fatty marrow.92 A sheep model for dysbaric osteonecrosis has been developed. Exposure to compressed air at pressures of 2.6 to 2.9 atm for 24 hours results in extensive bone and marrow necrosis. The authors proposed that the initial event involving elevated intramedullary pressures leads to formation of nitrogen bubbles in the fatty marrow of the long bones. Radiography shows medullary opacities and endosteal thickening. Later neovascularization of previously ischemic fatty marrow occurs, followed by new bone formation. Osteonecrosis occurs in subchondral cortical bone with marrow fibrosis and osteocyte loss.93 Alteration in osteoblast function could contribute to the pathogenesis of osteonecrosis. Osteoblastic cells were obtained from bone biopsy specimens from the intertrochanteric region of the femur and of the iliac crest of 13 patients with osteonecrosis and 8 patients with hip osteoarthritis. Cell replication was measured based on proliferation rate in secondary culture. Levels of alkaline phosphatase activity, collagen synthesis, and the sensitivity to 1,25­dihydroxyvitamin D3 were measured. The results indicated that although differentiation was not affected, the proliferation rate of osteoblastic cells was reduced in samples obtained from patients with osteonecrosis compared with patients with osteoarthritic hips.94 Osteocyte death or apoptosis also is a feature of osteonecrosis. In a rat model, ischemia caused an induction in the expression of stress proteins oxygen-regulated protein (ORP150) and hemoxygenase 1 (HO1). Induction of ischemia in these rats caused DNA fragmentation and the presence of apoptotic bodies in chondrocytes, bone marrow cells, and osteocytes.95 Osteonecrosis occurs not as a result of a single factor, but as a result of an interrelated combination of factors. This is the basis for the accumulated cell stress hypothesis, first proposed by Kenzora and Glimcher in 1983.96 The contributing factors can vary for different etiologies of osteonecrosis. Although lipid anomalies might be the primary pathologic event in steroid-induced osteonecrosis, other factors, such as the production of inflammatory mediators, can play a role, explaining why the incidence varies depending on the underlying disorder for which steroids are being used. The prevalence of osteonecrosis in healthy patients being treated with steroids for head trauma was 0% compared with a rate of 52% in patients with systemic lupus erythematosus treated with steroids.97 In dysbaric osteonecrosis, the primary factor may be gas bubbles and increased interosseous pressures, but lipid abnormalities may play a lesser role. The hypothesis suggests that when the damaging effects of multiple events are added together, cells are unable to recover from the chronic stress, and osteonecrosis ensues.

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DIAGNOSIS AND DIAGNOSTIC TESTS A high index of suspicion is crucial to the diagnosis of osteonecrosis. Pain is usually the presenting symptom, but the disease may be quite advanced by the time patients present with pain, especially when the progression is insidious. In addition to obtaining a complete history, including identification of potential risk factors such as trauma, a complete examination of the affected joint must be performed. The examination should include direct observation for any obvious abnormalities, such as leg-length discrepancies, masses, and abnormal orientation. Additionally, the hip should be palpated for tenderness and to identify any masses not detected on direct visualization. The hip should be examined for range of motion, muscle strength, and gait. The Harris hip score is frequently used for evaluating hip function and is useful in monitoring effectiveness of treatment. The Harris hip score is a multidimensional observational assessment based on eight items, which address pain, walking function, daily activity, and range of motion. Scores range from 0 (maximum disability) to 100 (no disability). Figure 94-1 is an algorithm for the diagnosis of osteonecrosis. When the diagnosis is suspected, it can be confirmed either by imaging studies or by arthroscopy. Earlier employed imaging techniques, such as radiography, were inadequate in establishing the diagnosis because in very early stages of osteonecrosis radiographs are often completely normal. The earliest radiographic sign of osteonecrosis is the presence of a radiolucent crescent (so-called crescent sign) (Fig. 94-2),

CARTILAGE, BONE, AND HERITABLE CONNECTIVE TISSUE DISORDERS 1617

which is the result of structural collapse of a necrotic segment of subchondral trabecular bone. At this stage, the disease already would have progressed to an irreversible stage, however. Subsequently, the radiographs show sclerotic changes (Fig. 94-3). The appearance of radiographic “density” is secondary to compression of bone trabeculae after microfracture of the nonviable bone, calcification of detritic marrow, and repair of the necrotic area by deposition of new bone, the so-called creeping substitution. Flattening of the articular surface of bone is the sign of further bone collapse (Fig. 94-4). To show best the radiographic appearance of osteonecrosis in the hips, and for better visualization of the extent of the necrotic lesion, anteroposterior and frog-leg lateral films should be obtained. Skeletal scintigraphy (radionuclide bone scan) using technetium-labeled diphosphonates also has been used to diagnose osteonecrosis. The use of this technique in the early diagnosis of this condition depends on the fact that osteoblastic activity and blood flow are increased in the early stages of osteonecrosis. In an advanced stage of disease, the appearance may be one of increased activity in a subchondral distribution owing to osteoblastic activity at the reactive interface around the necrotic segment; however, the center of the osteonecrotic lesion may show much less radionuclide activity (Fig. 94-5), or even complete lack of activity, reflecting decreased metabolism in the necrotic focus as a result of interruption of blood supply.6 In addition to bone scintigraphy, single-photon emission computed tomography (SPECT) maximizes sensitivity.

Symptoms

Physical examination

Have a high index of suspicion

Identify host risk factors - particularly alcohol and corticosteroid use

Obtain MRI study of affected joints

Obtain liver and lipid panel to investigate role of fat metabolism in etiology

Identify environmental risk factors - as in divers and high-pressure workers

Diagnostic imaging

Obtain laboratory studies to rule out other disease

Identify co-existing illnesses with related steroid use

Bone scintigraphy for early diagnosis

Obtain procoagulant and coagulation studies to evaluate role of intravascular coagulation in etiology

Consider MRI of contralateral joint (primarily in femoral head osteonecrosis)

Arthroscopy or MRI for determining staging and extent Figure 94-1  Algorithm for the diagnosis of osteonecrosis. MRI, magnetic resonance imaging.

1618 CHANG  |  Osteonecrosis

A study comparing conventional radiography, MRI, computed tomography (CT), and Tc 99m MDP three-phase bone scan in diagnosing bisphosphonate-associated osteonecrosis of the jaw showed that CT and MRI were the best at defining the extent of the disease, but that bone scan was the best at identifying disease at an early stage. Bone scan could be an excellent screening tool for the diagnosis of osteonecrosis before further characterization of the lesions using CT or MRI.98

Figure 94-2  A radiolucent crescent in the subchondral region of the left femoral head (arrow) is an early radiographic sign of osteonecrosis.

A

CT allows more detailed examination of the femoral head. A star-shaped structure, formed by weight-bearing bone trabeculae, gave the appearance of an asterisk on CT scan (the asterisk sign).99-101 This asterisk undergoes a characteristic change in ischemic bone necrosis of the femoral head, and this change was considered important for early detection of osteonecrosis. At a later stage, the collapse of necrotic bone can be well shown (Fig. 94-6). More recently, MRI has become the “gold standard” for imaging of osteonecrosis, and the staging systems for osteonecrosis are based on changes seen on MRI appearance (Table 94-5). MRI of osteonecrosis can show changes earlier than radiography or CT. It is able to detect bone marrow edema, an early feature of osteonecrosis that is invisible on radiography or CT in early stages. The typical MRI findings are intermediate or low signal intensity on T1-weighted images and high signal on T2-weighted images (Fig. 94-7). As the disease progresses, the subchondral necrotic lesion is surrounded by a low signal line on T1-weighted images, and a high signal line is seen in T2-weighted images that is central to the low signal line. This produces the “double-line” sign (Fig. 94-8).102 In advanced osteonecrosis, the necrotic segment exhibits low signal intensity on T1-weighted and T2-weighted images (Fig. 94-9). MRI is done in the sagittal, coronal, and axial planes, and includes T1-weighted and T2-weighted sequences. There is excellent correlation between histologic findings and MRI appearance (see Table 94-5). MRI is an important tool in determining the extent of femoral head involvement in osteonecrosis. Three techniques are used to determine this. The first is estimating head involvement. This method was first proposed by ­Steinberg

B

Figure 94-3  A and B, Anteroposterior (A) and frog-lateral (B) views of the left hip show sclerotic changes of the femoral head typical of advanced osteonecrosis.

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Figure 94-4  Increased density of the femoral head, loss of the normal spherical shape, and flattening of the superior aspect are characteristic radiographic features of osteonecrosis.

and coworkers in 1984,103 and it is defined by appearance of abnormal signals on T1-weighted images. The degree of head involvement was classified into three categories: less than 15%, 15% to 30%, and greater than 30%. The second method used is the index of necrotic extent, which is determined by measuring the angle created by the extent of subchondral involvement. Lesion size was estimated using a “necrotic arc angle,” defined as the angle of the arc of the necrotic segment from the center of the femoral head. Two angles were obtained: “A,” representing the necrotic arc angle seen on midcoronal images, and “B,” representing the necrotic arc angle seen on midsagittal images. The index is a compilation of these two angles. A third method is a variation of the second, in which the angle is identified not on midcoronal or midsagittal images, but on the image that shows the maximum lesion size in the sagittal and coronal images. It was thought that this method would correct for the underestimation that may be inherent in the second method. Table 94-6 shows a comparison of various radiographic techniques used in the diagnosis and staging of osteonecrosis. Hip arthroscopy also is used in the staging of osteonecrosis. In a study comparing radiography, MRI, and arthroscopy, there was only moderate correlation among the three methods. Arthroscopy was able to detect osteochondral degeneration, not detected by radiography or MRI in 36% of postcollapse femoral heads.104,105 Recently, the measurement of serum and urine carboxy-terminal cross-linking telopeptide of type I collagen (CTX-1), a marker of bone resorption, has been proposed as a method of evaluating the risk of osteonecrosis of the jaw secondary to bisphosphonate usage.105a

BONE MARROW EDEMA Bone marrow edema is a common observation in osteonecrosis and frequently is accompanied by vascular congestion. Bone marrow edema is not specific for osteonecrosis and

CARTILAGE, BONE, AND HERITABLE CONNECTIVE TISSUE DISORDERS 1619

Figure 94-5  Bone scintigraphy of osteonecrosis of both femoral heads using Tc 99m MDP shows moderate uptake of radiopharmaceutical at the site of the osteonecrotic segment in the right femoral head and markedly increased uptake at the site of bone repair (straight arrow). The left femoral head (curved arrow) exhibits early-stage disease.

Figure 94-6  CT shows advanced osteonecrosis of the femoral head. Note increased sclerosis posteriorly (solid arrow) and subchondral ­collapse of necrotic bone anterolaterally (open arrow).

may be seen in many musculoskeletal disorders, including osteomyelitis, osteoarthritis, occult intraosseous fracture, stress fracture, osteoporosis, and sickle cell crisis. A specific syndrome known as bone marrow edema syndrome has been described and was initially thought to be a precursor to osteonecrosis, but it is now believed to be a separate entity. Bone marrow edema syndrome is a transitory,

1620 CHANG  |  Osteonecrosis

Table 94-5  Magnetic Resonance Imaging (MRI) Changes and Their Correlation with Histology in Osteonecrosis Type of Appearance

Category of Observations

Histology

MRI Appearance

A

Fatlike

Premature fatty marrow development   in the femoral neck or intertrochanteric region

Normal fat signal; sclerotic margin   may be seen circumscribing lesion

B

Bloodlike

Bone resorption; replacement by vascular granulation tissue

High signal intensity of inner border; low signal intensity of surrounding rim

C

Fluid-like

Presence of edema

Diffusely decreased signal on T1weighted images; high signal on T2-weighted images

D

Fibrotic

Sclerosis owing to reinforcement of   existing trabeculae at margin of live   bone (repair tissue interface)

Decreased signal on T1-weighted and T2-weighted images

A

B

Figure 94-7  A, On T1-weighted coronal MR image of the left hip, the osteonecrotic segment in the subchondral portion of the femoral head shows low signal intensity. B, On T2-weighted coronal image, the necrotic bone exhibits high signal intensity, surrounded by a sclerotic low-signal rim.

self-limiting condition, typically seen in middle-aged men and in women in their third trimester of pregnancy. Patients complain of pain, limited range of motion, and an abnormal gait. Osteopenia is detected on conventional radiographs and MRI (low signal on T1-weighted images and high ­signal on T2-weighted images). The three phases of bone marrow edema syndrome include an initial phase lasting about 1 month, followed by a plateau phase lasting 1 or 2 months, and finally a regression phase lasting for an additional 4 to 6 months.106 Subchondral fractures do not occur. Biopsy specimens obtained in the initial phase show diffuse interstitial edema, fragmentation of fatty marrow cells, and increased new bone formation.107 A study of 24 cases of bone marrow edema syndrome of the knee showed that although migrating bone marrow edema occurred in a third of patients at a 5-year follow-up, the patients were asymptomatic, and MRI signal alterations

had resolved. Biopsy specimens of the affected bone were obtained using arthroscopic surgery and core decompression, and histology revealed areas of bone marrow edema and vital trabeculae covered by osteoblasts and osteoid seams. None of the cases progressed to osteonecrosis.108

TREATMENT The key to the successful treatment of osteonecrosis is early detection. The choice of conservative nonsurgical versus more aggressive surgical options depends on the clinical and pathologic staging of the disease. Surgical management of femoral head osteonecrosis includes core decompression, structural bone grafting, vascularized fibula grafting, osteotomy, resurfacing arthroplasty, hemiarthroplasty, and total hip replacement.109 Arthroscopy has been used as a tool to treat ­osteonecrosis.

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It has been used to determine the position of the core ­decompression tract to the necrotic part of the femoral head,110 and arthroscopic débridement has been used in treatment of osteonecrosis of the capitellum of the humerus in adolescents,111 Kienböck’s disease,112 and osteonecrosis of the scaphoid.113

Figure 94-8  Coronal T2-weighted MR image of the right femoral head shows the double-line sign, characteristic for osteonecrosis: low ­signal line at periphery of the lesion, and high signal band located more ­centrally.

A

CARTILAGE, BONE, AND HERITABLE CONNECTIVE TISSUE DISORDERS 1621

Core decompression involves the removal of a core of bone from the femoral neck and head. The core acts as a vent to reduce intraosseous pressure and intramedullary pressure, reversing ischemia and improving symptoms. Other changes that may occur include stimulation of angiogenesis, leading to improved vascularization during the repair process. It is generally used in less advanced stages of osteonecrosis. Core decompression in the treatment of nontraumatic osteonecrosis of the femoral head was done in 34 patients with 54 affected hips.114 The average age at presentation was 38 years. The patients were monitored for a mean duration of 120 months. Success was defined as absence of symptoms, no progression of disease, and no further surgery. Clinical success was established in 26 hips (48%), and radiographic success was established in 20 hips (37%). The later the stage at which core decompression was performed, the greater the failure rate.115 Core decompression also has been used in the treatment of humeral head osteonecrosis with good outcome.116 More recently, computer-assisted core decompression has been used to provide greater precision in directing the core into the ischemic area, and to minimize the radiation exposure time to patients.117 Because early diagnosis improves outcome, and because there is a high incidence of developing osteonecrosis in a contralateral hip, core decompression is frequently done on both hips simultaneously. This approach has been shown to have little added risk over unilateral core decompression with the added benefit of better outcomes secondary to early surgical treatment of the contralateral hip.118 In structural bone grafting, or bone impaction grafting, the bone graft is inserted into the necrotic segment through the core tract. The bone graft acts in similar fashion to a stent, providing support to overlying subchondral

B

Figure 94-9  A and B, Advanced osteonecrosis of the right femoral head exhibits low signal intensity on T1-weighted (A) and T2-weighted (B) MR images.

1622 CHANG  |  Osteonecrosis

Table 94-6  Comparative Sensitivity and Specificity of Diagnostic Radiologic Imaging Modalities in Osteonecrosis Radiologic Imaging

Earliest Sign Seen

Earliest Seen (Stage)

Degree of Specificity

Radiography

Crescent sign

Sclerotic rim of reactive bone (stage 2)

High

CT

Asterisk sign

Sclerotic rim surrounding a mottled   area of osteolysis and sclerosis   (stage 2)

High

MRI

Low signal intensity on T1-weighted ­images; high signal intensity on   T2-weighted images

Bone marrow edema (stage 1)

High

Skeletal scintigraphy

Decreased uptake in subchondral ­distribution Increased uptake in subchondral ­distribution

“Cold spot” (stage 1)

Low

“Hot spot” (stage 2)

Low

CT, computed tomography; MRI, magnetic resonance imaging.

bone. The goal is to prevent collapse. This combination of ­procedures is frequently used in treating stage I or II osteonecrotic femoral heads. Allogeneic and autologous bone grafts, mostly harvested from the tibia or fibula, are used. When this technique was attempted in patients with stages III and IV lesions, the outcome was generally poor (100% failure after 2 to 4 years), with progression to collapse and further surgical procedures.119 Vascularized structural bone grafting also uses the core tract to insert a corticocancellous bone graft into the femoral neck and head along with its vascular pedicle. The vascular pedicle is anastomosed to a nearby vessel, adding a source of blood to the graft. The results of vascularized fibular grafting in the treatment of hips with osteonecrosis showed a survival of 61% of hips at 5-year follow-up, and 42% at a median time of 8 years.120 In another study, 197 patients with 226 osteonecrotic hips were treated with a combination of autologous cancellous bone impaction and pedicled iliac bone block transfer. The anastomosis was to the ascending branch of the lateral femoral circumflex artery. Fourteen hips required conversion to total hip arthroplasty because of collapse or severe pain or both. Of the remaining 212 hips, 92% were considered a clinical success, and 76% were considered radiographically successful. The success rate declined from stage II to stage IV hips (96% for stage II hips, 90% for stage III hips, and 57% for stage IV hips).121 Osteotomy of the femur involves shifting the position of the osteonecrotic segment by making a cut in the proximal femur so that the osteonecrotic segment is rotated or flexed out of the weight-bearing region of the acetabulum, and replacing the weight-bearing region with viable bone. Healing of the necrotic region can proceed without the stress of weight bearing. Several different osteotomy techniques have been attempted to salvage hips in stage II or III osteonecrosis. Resurfacing arthroplasty uses a metallic or ceramic shell placed over a femoral head that has been débrided of the necrotic area. The potential advantages of resurfacing arthroplasty include preservation of joint mechanics, bone conservation,122 more physiologic loading of the bone, a lower incidence of perioperative complications, and easier conversion to total hip arthroplasty in case of failure.123 Complications of this procedure include femoral neck fractures, a secondary osteonecrosis when

the procedure is done for other reasons,124 and increased metal ion levels.125 Resurfacing arthroplasty has been recommended for patients with later stage osteonecrosis, including patients with femoral head collapse.126 A retrospective study compared the results of limited femoral head resurfacing and total hip arthoplasty in 30 consecutive patients with Steinberg stage III or IV disease. The survival rate at a 7-year mean follow-up period for the resurfacing group was 90%, whereas the survival rate at an 8-year mean follow-up for the total hip arthroplasty group was 93%.127 In hemiarthroplasty, only part of the hip joint is replaced. The original acetabulum is preserved, but the femoral head is replaced with a prosthesis. Two kinds of prostheses are used—a unipolar prosthesis and a bipolar prosthesis. In a unipolar prosthesis, the articulation is between the artificial femoral head and the acetabulum. In the bipolar prosthesis, presently the most frequently used, the articulation is within the prosthesis itself. Failure rates for hemiarthroplasties in osteonecrosis are 50% to 60% at 3 years for unipolar prostheses and 44% for bipolar prostheses.128 Another study evaluated the success rate of Charnley/Bicentric hemiarthroplasty in the treatment of Ficat and Arlet stage III osteonecrosis of the femoral head. Failures included three hips that needed to be revised to cementless total hip replacement, two hips with radiographic changes of loosening and imminent failure, and one hip with progressive loss of joint space and secondary degenerative changes. The success rate was 84.2% after a mean of 56 months.129 Total hip arthroplasty is complete replacement of the hip joint with a prosthesis including the femoral head and the acetabulum. In a study of 55 consecutive hip arthroplasty procedures, cementless total hip arthroplasty was shown to provide favorable results in advanced-stage osteonecrosis of the femoral head. Although 10 of the 48 hips available for follow-up after a minimum of 5 years required revision, all of these patients had Ficat and Arlet stage III or IV disease.130 A study of 53 hips in 41 patients treated with cemented total hip replacement showed that at a minimum of 10 years of follow-up, 17.4% required revision. Compared with cemented total hip replacements done for other conditions, osteonecrosis had a greater risk for loosening of acetabular and femoral components.131 A survivorship analysis of cemented total hip replacements in renal transplant patients with osteonecrosis of the femoral head showed that

PART 15 

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there was excellent survival after 10 years (98.8%). After 20 years, the survival decreased to 63.8%. Nonsurgical treatment of osteonecrosis of the femoral head consists of refraining from weight bearing on the affected joint, analgesic and anti-inflammatory medications, and physiotherapy. Conservative medical treatment is effective only in the early stages for symptomatic relief. Nonsurgical management does not seem to change the natural course of the disease.132 Electric stimulation has been used in the treatment of osteonecrosis, frequently in conjunction with core decompression. Electric stimulation enhances osteogenesis and neovascularization. It also alters the balance between osteoblast and osteoclast activity so that more bone is produced, and less is resorbed, leading to an increase in bone substance. The three methods for delivery of electric stimulation include direct current, pulsed electromagnetic field, and capacitance coupling. Core decompression with placement of an electric stimulating coil in the anterosuperior segment of the femoral head was done in 11 hips in eight patients who had Ficat stage II osteonecrosis. Results were poor, with 5 of 11 hips requiring reoperation after an average of 13 months after initial placement of the electric coil, and the other 6 having progressive deterioration in function. There was minimal evidence of new bone formation around the coil under histologic examination.133 A study compared the effectiveness of nonsurgical treatment with core decompression with and without direct current electric stimulation. The clinical symptoms scores and progression to arthroplasty rates were worst in the nonoperative treatment group, whereas the results were best in the patients treated with core decompression and DC stimulation.134 Capacitive coupling is a noninvasive method of providing electric stimulation that can be administered with or without core decompression and grafting. Core decompression and grafting were done on 40 patients with stage I to III osteonecrosis; half of the patients wore active capacitive coupling units with electrodes over the femoral head for 6 months. The control group was 55 patients with osteonecrosis who were treated conservatively. Two-year to 4-year follow-up showed that core decompression with or without capacitive coupling provided better clinical and radiologic outcome than conservative treatment, but that capacitive coupling did not improve the results further when used with core decompression and grafting.135 Extracorporeal shock wave therapy has been used in the treatment of osteonecrosis of the femoral head. A study of 48 patients and 57 hips compared extracorporeal shock wave therapy with core decompression and bone grafting. Twenty-three patients with 29 affected hips were assigned to the shock wave group, and the remaining patients and hips received surgical treatment. The patients in the shock wave group were given one treatment of 6000 pulses of shock waves at 28 kV to the affected hip. The patients were evaluated by their reports of symptoms (pain), by Harris hip scores, by quality of life (daily work and activity assessment), and radiographically. Shock wave therapy produced better results than the nonvascularized bone grafting procedure, with comparatively less progression of disease.136 Conservative treatment of osteonecrosis of the talus is not promising, and the affected ankles generally ­ continue

CARTILAGE, BONE, AND HERITABLE CONNECTIVE TISSUE DISORDERS 1623

to progress, requiring either core decompression or arthro­ desis.60 Conservative treatment of bisphosphonate-induced osteonecrosis of the jaw includes cessation of bisphosphonate usage or surgical débridement.17 Good oral hygiene, regular dental assessment, and avoidance of dental procedures during bisphosphonate usage can prevent onset of osteonecrosis. Figure 94-10 is an algorithm for the treatment of osteonecrosis.

NEW MODALITIES OF TREATMENT OF OSTEONECROSIS Mesenchymal stem cells are thought to play a role in the development of osteonecrosis. Corticosteroids seem to cause enhanced adipogenesis and decreased osteogenesis by mesenchymal cells in vitro, and they cause a decrease in a potent angiogenic factor, vascular endothelial growth factor. This activity suggests that steroids shunt uncommitted osteoprogenitor cells in marrow from osteoblastic differentiation to the adipocytic pathway, leading to diminished vascularization and eventual osteonecrosis.137 Alcohol also seems to have a similar effect on the differentiation of stem cells.76 Consequently, more recent studies on the use of mesenchymal stem cells in the treatment of osteonecrosis have been performed. Multipotential mesenchymal stem cells from femoral bone marrow near osteonecrosis sites are able to express mRNA for aggrecan and collagen type II. They also can deposit immunoreactive collagen type II and sulfated proteoglycans into the bone matrix. These features are characteristics of chondrogenic differentiation. The mesenchymal stem cells can be differentiated into osteocytic lineage in vitro.138 A pilot study evaluating the effectiveness of implantation of autologous bone marrow cells in the treatment of osteonecrosis used core decompression to implant stem cells into the necrotic lesions of the femoral head.139,140 The patients were divided into two groups—one that received core decompression alone as treatment for osteonecrosis (the control group), and one that received autologous bone marrow cell implantation along with core decompression (the treatment group). The patients were followed for 24 months, and at that time, 5 of 8 hips in the control group, but only 1 of 10 in the treatment group advanced to stage III osteonecrosis. In addition, there was greater improvement in pain and joint symptoms in the treatment group, and the treatment seemed to be safe. Because of the small number of patients involved, further studies need to be done to confirm these results. More recently, 28 patients with 44 necrotic hips were treated with percutaneous decompression and autologous bone marrow mononuclear cell infusion. Patients were followed for a minimum of 2 years and evaluated for clinical and radiographic progression of the disease. There seemed to be overall slowing in the progression of disease stage. The mean Harris hip score improved from 58 to 86.141

OUTCOME AND PROGNOSIS The natural history of osteonecrosis depends on the size of the infarcted segment, the site of occurrence, and the clinical and radiologic staging of the disease. At the onset of the disease, range of motion may be well preserved, but gradually

1624 CHANG  |  Osteonecrosis Determine staging and extent of osteonecrosis

Determine Harris hip score

Therapeutic options

Conservative treatment

Monitor radiologic progression of disease

Surgical treatment

Core decompression

Rest, analgesics, anti-inflammatories, physiotherapy, no weight bearing

Structural bone grafting Vascularized structural bone grafting

Shock wave treatment Electrical stimulation treatment

Osteotomy

Monitor clinical effect, including Harris hip scores Higher level of treatment

Resurfacing arthroplasty

New modes of therapy - stem cell implantation

Hemiarthroplasty

Total hip arthroplasty

Improvement in symptoms, and radiologic and histologic progression of disease

Improved quality of life Figure 94-10  Algorithm for treatment of osteonecrosis.

deteriorates over time. Patients are frequently asymptomatic initially. By the time they present, many patients already may have later stage disease. Although spontaneous resolution of osteonecrosis of the femoral head can occur, it is rare and occurs only when lesion size is small.142 A study of the prognosis of osteonecrosis of the femoral head as a function of symptoms (pain) and radiographic findings showed that in patients who were asymptomatic and had normal radiographs, progression of the disease was slow, with only 1 of 23 hips progressing to pain and radiographic changes after 5 years. If radiographic changes are already present, disease progresses to pain in 14 of 19 patients after 5 years.143 In a study of stage I osteonecrotic lesions of the hip diagnosed with MRI, 40 patients were followed for an average of 11 years. All patients had a stage I lesion on the contralateral hip. Overall, 35 of the 40 stage I hips became symptomatic, and 29 hips showed collapse. The mean interval between diagnosis and collapse was 92 months, whereas the mean interval between symptoms and diagnosis was 80 months.144 Most stage I hips eventually progress to a more advanced stage, requiring surgery, so these hips should be monitored closely.

Future Directions The recent recognition of the role of cellular mediators or regulatory factors of inflammation in the ­pathogenesis of bone diseases may provide greater insight into completely novel modes of prevention and treatment of ­osteonecrosis in the future.

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1626 CHANG  |  Osteonecrosis 64. Sigmundsson FG, Andersen PB, Schroeder HD, et al: Vertebral osteonecrosis associated with pancreatitis in a woman with pancreas divisum: A case report. J Bone Joint Surg Am 86:2504-2508, 2004. 65. Chowdhury S, Pickering LM, Ellis PA: Adjuvant aromatase inhibitors and bone health. J Br Menopause Soc 12:97-103, 2006. 66. Van Poznak C, Estilo C: Osteonecrosis of the jaw in cancer patients receiving IV bisphosphonates. Oncology (Williston Park) 20:10531062; discussion 1065-1066, 2006. 67. Pathak I, Bryce G: Temporal bone necrosis: Diagnosis, classification, and management. Otolaryngol Head Neck Surg 123:252-257, 2000. 68. Gardeniers J: ARCO international classification of osteonecrosis. ARCO Newsletter 5:79, 1993. 69. Glimcher MJ, Kenzora JE: The biology of osteonecrosis of the human femoral head and its clinical implications, III: Discussion of the etiology and genesis of the pathological sequelae; commments on treatment. Clin Orthop 140:273-312, 1979. 70. Cui Q, Wang GJ, Balian G: Steroid-induced adipogenesis in a pluripotential cell line from bone marrow. J Bone Joint Surg Am 79:10541063, 1997. 71. Cui Q, Wang GJ, Su CC, et al: The Otto Aufranc Award. Lova­ statin prevents steroid induced adipogenesis and osteonecrosis. Clin Orthop 344:8-19, 1997. 72. Wang GJ, Cui Q, Balian G: The Nicolas Andry award. The pathogenesis and prevention of steroid-induced osteonecrosis. Clin Orthop 370:295-310, 2000. 73. Wang Y, Li Y, Mao K, et al: Alcohol-induced adipogenesis in bone and marrow: A possible mechanism for osteonecrosis. Clin Orthop 410:213-224, 2003. 74. Yin L, Li YB, Wang YS: Dexamethasone-induced adipogenesis in primary marrow stromal cell cultures: Mechanism of steroidinduced osteonecrosis. Chin Med J (Engl) 119:581-588, 2006. 75. Preedy VR, Patel VB, Reilly ME, et al: Oxidants, antioxidants and alcohol: Implications for skeletal and cardiac muscle. Front Biosci 4:e58-e66, 1999. 76. Suh KT, Kim SW, Roh HL, et al: Decreased osteogenic differentiation of mesenchymal stem cells in alcohol-induced osteonecrosis. Clin Orthop 431:220-225, 2005. 77. Lee JS, Lee JS, Roh HL, et al: Alterations in the differentiation ability of mesenchymal stem cells in patients with nontraumatic osteonecrosis of the femoral head: Comparative analysis according to the risk factor. J Orthop Res 24:604-609, 2006. 78. Miyanishi K, Yamamoto T, Irisa T, et al: Bone marrow fat cell enlargement and a rise in intraosseous pressure in steroid-treated rabbits with osteonecrosis. Bone 30:185-190, 2002. 79. Kim YH, Kim JS: Histologic analysis of acetabular and proximal femoral bone in patients with osteonecrosis of the femoral head. J Bone Joint Surg Am 86:2471-2474, 2004. 80. Laogun AA, Ajayi NO, Osamo NO, et al: Plasma viscosity in sicklecell anemia. Clin Phys Physiol Meas 1:145, 1980. 81. Kleinman RG, Bleck EE: Increased blood viscosity in patients with Legg-Perthes disease: A preliminary report. J Pediatr Orthop 1:131136, 1981. 82. Migliorati CA, Casiglia J, Epstein J, et al: Managing the care of patients with bisphosphonate-associated osteonecrosis: An American Academy of Oral Medicine position paper. J Am Dent Assoc 136:1658-1668, 2005. 83. Koo KH, Lee JS, Lee YJ, et al: Endothelial nitric oxide synthase gene polymorphisms in patients with nontraumatic femoral head osteonecrosis. J Orthop Res 24:1722-1728, 2006. 84. Glueck CJ, Fontaine RN, Gruppo R, et al: The plasminogen activator inhibitor-1 gene, hypofibrinolysis, and osteonecrosis. Clin Orthop Relat Res 366:133-146, 1999. 85. Jones JP Jr: Intravascular coagulation and osteonecrosis. Clin Orthop 277:41-53, 1992. 86. Jones LC, Mont MA, Le TB, et al: Procoagulants and osteonecrosis. J Rheumatol 30:783-791, 2003. 87. Saito S, Ohzono K, Ono K: Early arteriopathy and postulated pathogenesis of osteonecrosis of the femoral head: The intracapital arterioles. Clin Orthop 277:98-110, 1992. 88. Ohzono K, Takaoka K, Saito S, et al: Intraosseous arterial architecture in nontraumatic avascular necrosis of the femoral head: Microangiographic and histologic study. Clin Orthop 277:79-88, 1992. 89. Heikkinen ES, Puranen J, Suramo I: The effect of intertrochanteric osteotomy on the venous drainage of the femoral neck in Perthes’ disease. Acta Orthop Scand 47:89-95, 1976.

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PART 15 

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CARTILAGE, BONE, AND HERITABLE CONNECTIVE TISSUE DISORDERS 1627 141. Yan ZQ, Chen YS, Li WJ, et al: Treatment of osteonecrosis of the femoral head by percutaneous decompression and autologous bone marrow mononuclear cell infusion. Chin J Traumatol 9:3-7, 2006. 142. Cheng EY, Thongtrangan I, Laorr A, et al: Spontaneous resolution of osteonecrosis of the femoral head. J Bone Joint Surg Am 86:25942599, 2004. 143. Jergesen HE, Khan AS: The natural history of untreated asymptomatic hips in patients who have non-traumatic osteonecrosis. J Bone Joint Surg Am 79:359-363, 1997. 144. Hernigou P, Poignard A, Nogier A, et al: Fate of very small asymptomatic stage-I osteonecrotic lesions of the hip. J Bone Joint Surg Am 86:2589-2593, 2004. 145. Cruess RL: Steroid-induced avascular necrosis of the head of the humerus: Natural history and management. J Bone Joint Surg Br 58:313-317, 1976. 146. Cruess RL: Steroid-induced osteonecrosis: A review. Can J Surg 24:567-571, 1981. 147. Scotter E, Moody A: Dysbaric osteonecrosis (caisson disease). Radiogr Today 54:41-43, 1988. 148. Hungerford DS, Zizic TM: Alcoholism associated ischemic necrosis of the femoral head: Early diagnosis and treatment. Clin Orthop 130:144-153, 1978. 149. Abylaev ZhA, Bukhman AI: [Possible mechanisms of the development of osteopathies in patients with chronic lead poisoning]. Gig Tr Prof Zabol 2:31-35, 1990. 150. Kazakos K, Chatzipapas C, Xarchas KC, et al: Knee osteonecrosis due to lead poisoning: Case report and review of the literature. Med Sci Monit 12:CS85-CS89, 2006. 151. Graziani F, Cei S, La Ferla F, et al: Association between osteonecrosis of the jaws and chronic high-dosage intravenous bisphosphonates therapy. J Craniofac Surg 17:876-879, 2006. 152. Rubinstein RA Jr, Beals RK: The results of treatment of posttraumatic avascular necrosis of the femoral head in young adults: Report of 31 patients. Contemp Orthop 27:527-532, 1993. 153. Burwell RG: Perthes’ disease. J Bone Joint Surg Br 60:1-3, 1978. 154. Herold HZ: Avascular necrosis of the femoral head in children under the age of three. Clin Orthop 126:193-195, 1977. 155. Morcuende JA, Meyer MD, Dolan LA, et al: Long-term outcome after open reduction through an anteromedial approach for congenital dislocation of the hip. J Bone Joint Surg Am 79:810-817, 1997. 156. Narayanan UG: Reduction increasing osteonecrosis risk in slipped capital femoral epiphysis. J Bone Joint Surg Am 86:437; author reply, 2004. 157. Yamasaki T, Yasunaga Y, Hisatome T, et al: Bone remodeling of a femoral head after transtrochanteric rotational osteotomy for osteonecrosis associated with slipped capital femoral epiphysis: A case report. Arch Orthop Trauma Surg 125:486-489, 2005. 158. Sellman DC, Froimson AI: Long-term follow-up of a total articular resurfacing arthroplasty and a cup arthroplasty in Gaucher’s disease. Orthop Rev 21:1099-1101, 1104, 1107, 1992. 159. Irisa T, Yamamoto T, Miyanishi K, et al: Osteonecrosis induced by a single administration of low-dose lipopolysaccharide in rabbits. Bone 28:641-649, 2001. 160. Jones JP Jr: Fat embolism and osteonecrosis. Orthop Clin North Am 16:595-633, 1985. 161. Barbezat GO, Miles T, Bank S, et al: Necrosis of the femoral head in a black patient with pancreatitis. S Afr Med J 50:160, 1976 (letter). 162. Chao YC, Wang SJ, Chu HC, et al: Investigation of alcohol metabolizing enzyme genes in Chinese alcoholics with avascular necrosis of hip joint, pancreatitis and cirrhosis of the liver. Alcohol Alcohol 38:431-436, 2003. 163. Pais MJ: Disease states affecting both liver and bone. Radiol Clin North Am 18:253-267, 1980. 164. Watson RM, Roach NA, Dalinka MK: Avascular necrosis and bone marrow edema syndrome. Radiol Clin North Am 42:207-219, 2004. 165. Horiuchi H, Saito N, Kobayashi S, et al: Avascular necrosis of the femoral head in a patient with Fabry’s disease: Identification of ceramide trihexoside in the bone by delayed-extraction matrixassisted laser desorption ionization-time-of-flight mass spectrometry. Arthritis Rheum 46:1922-1925, 2002. 166. Ross G, Kuwamura F, Goral A: Association of Fabry’s disease with femoral head avascular necrosis. Orthopedics 16:471-473, 1993. 167. Mielants H, Veys EM, DeBussere A, et al: Avascular necrosis and its relation to lipid and purine metabolism. J Rheumatol 2:430-436, 1975. 168. Heaf JG: Bone disease after renal transplantation. Transplantation 75:315-325, 2003.

1628 CHANG  |  Osteonecrosis 169. Kjaergaard GH, Laursen JO: [Osteonecrosis of a knee joint in a young man with IDDM]. Ugeskr Laeger 162:4663-4664, 2000. 170. Hernigou P, Bachir D, Galacteros F: The natural history of symptomatic osteonecrosis in adults with sickle-cell disease. J Bone Joint Surg Am 85:500-504, 2003. 171. Onuba O: Bone disorders in sickle-cell disease. Int Orthop 17:397399, 1993. 172. Mahachoklertwattana P: Zoledronic acid for the treatment of thalassemia-induced osteonecrosis. Haematologica 91:1155A, 2006. 173. Campbell WN, Joshi M, Sileo D: Osteonecrosis following meningococcemia and disseminated intravascular coagulation in an adult: Case report and review. Clin Infect Dis 24:452-455, 1997. 174. Jones JP Jr: Fat embolism, intravascular coagulation, and osteonecrosis. Clin Orthop 292:294-308, 1993. 175. Jones JP Jr: Coagulopathies and osteonecrosis. Acta Orthop Belg 65(Suppl 1):5-8, 1999. 176. Seipolt B, Dinger J, Rupprecht E: Osteonecrosis after meningococcemia and disseminated intravascular coagulation. Pediatr Infect Dis J 22:1021-1022, 2003. 177. Glueck CJ, Freiberg RA, Fontaine RN, et al: Hypofibrinolysis, thrombophilia, osteonecrosis. Clin Orthop 386:19-33, 2001. 178. Glueck CJ, Freiberg R, Glueck HI, et al: Hypofibrinolysis: A common, major cause of osteonecrosis. Am J Hematol 45:156-166, 1994. 179. Strau G, Kainz L, Kienzer H: [Spontaneous osteonecrosis of the knee joint in clinically suspected thrombosis of the leg veins]. Rontgen­ blatter 41:122-124, 1988. 180. Tektonidou MG, Malagari K, Vlachoyiannopoulos PG, et al: Asymptomatic avascular necrosis in patients with primary antiphospholipid syndrome in the absence of corticosteroid use: A prospective study by magnetic resonance imaging. Arthritis Rheum 48:732-736, 2003. 181. Neidel J, Boehnke M, Kuster RM: The efficacy and safety of intraarticular corticosteroid therapy for coxitis in juvenile rheumatoid arthritis. Arthritis Rheum 46:1620-1628, 2002. 182. Abu-Shakra M, Buskila D, Shoenfeld Y: Osteonecrosis in patients with SLE. Clin Rev Allergy Immunol 25:13-24, 2003. 183. Nagasawa K, Ishii Y, Mayumi T, et al: Avascular necrosis of bone in systemic lupus erythematosus: Possible role of haemostatic abnormalities. Ann Rheum Dis 48:672-676, 1989. 184. Rascu A, Manger K, Kraetsch HG, et al: Osteonecrosis in systemic lupus erythematosus, steroid-induced or a lupus-dependent manifestation? Lupus 5:323-327, 1996. 185. Freeman HJ, Freeman KJ: Prevalence rates and an evaluation of reported risk factors for osteonecrosis (avascular necrosis) in Crohn’s disease. Can J Gastroenterol 14:138-143, 2000. 186. Stiles RG, Carpenter WA, Tigges S: Osteonecrosis of the femoral heads in inflammatory bowel disease. N Engl J Med 330:791; author reply 792, 1994. 187. Wang TY, Avlonitis EG, Relkin R: Systemic necrotizing vasculitis causing bone necrosis. Am J Med 84:1085-1086, 1988. 188. Yanagitani Y, Fujita M: Avascular necrosis of the femoral head associated with mucocutaneous lymph node syndrome. J Pediatr Orthop 6:107-109, 1986. 189. Clarke AE, Bloch DA, Medsger TA Jr, et al: A longitudinal study of functional disability in a national cohort of patients with polymyositis/dermatomyositis. Arthritis Rheum 38:1218-1224, 1995.

190. Scribner AN, Troia-Cancio PV, Cox BA, et al: Osteonecrosis in HIV: A case-control study. J Acquir Immune Defic Syndr 25:19-25, 2000. 191. Chaudhuri R, McKeown B, Harrington D, et al: Mucormycosis osteomyelitis causing avascular necrosis of the cuboid bone: MR imaging findings. AJR Am J Roentgenol 159:1035-1037, 1992. 192. Appel M, Pauleto AC, Cunha LA: Osteochondral sequelae of meningococcemia: Radiographic aspects. J Pediatr Orthop 22:511516, 2002. 193. Bradford DS, Szalapski EW Jr, Sutherland DE, et al: Osteonecrosis in the transplant recipient. Surg Gynecol Obstet 159:328-334, 1984. 194. Danzig LA, Coutis RD, Resnick D: Avascular necrosis of the femoral head following cardiac transplantation: Report of a case. Clin Orthop 117:217-220, 1976. 195. Fink JC, Leisenring WM, Sullivan KM, et al: Avascular necrosis following bone marrow transplantation: A case-control study. Bone 22:67-71, 1998. 196. Helenius I, Jalanko H, Remes V, et al: Avascular bone necrosis of the hip joint after solid organ transplantation in childhood: A clinical and MRI analysis. Transplantation 81:1621-1627, 2006. 197. Lieberman JR, Scaduto AA, Wellmeyer E: Symptomatic osteonecrosis of the hip after orthotopic liver transplantation. J Arthroplasty 15:767-771, 2000. 198. Marston SB, Gillingham K, Bailey RF, et al: Osteonecrosis of the femoral head after solid organ transplantation: A prospective study. J Bone Joint Surg Am 84:2145-2151, 2002. 199. Dzik-Jurasz AS, Brooker S, Husband JE, et al: What is the prevalence of symptomatic or asymptomatic femoral head osteonecrosis in patients previously treated with chemoradiation? A magnetic resonance study of anal cancer patients. Clin Oncol (R Coll Radiol) 13:130-134, 2001. 200. Curtis MA, Tung GA, Dawamneh MF: Radiation osteonecrosis of the clavicle. Acad Radiol 3:971-974, 1996. 201. Epstein J, van der Meij E, McKenzie M, et al: Postradiation osteonecrosis of the mandible: A long-term follow-up study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 83:657-662, 1997. 202. Holler U, Petersein A, Golder W, et al: [Radiation-induced osteonecrosis of the pelvic bones vs. bone metastases—a difficult differential diagnosis]. Aktuelle Radiol 8:196-197, 1998. 203. Niewald M, Barbie O, Schnabel K, et al: Risk factors and dose-effect relationship for osteoradionecrosis after hyperfractionated and conventionally fractionated radiotherapy for oral cancer. Br J Radiol 69:847-851, 1996. 204. Stebbings JH: Dose-response analyses of osteonecrosis in New Jersey radium workers point to roles for other alpha emitters. Health Phys 74:602-607, 1998. 205. Balzer S, Schneider DT, Bernbeck MB, et al: Avascular osteonecrosis after hyperthermia in children and adolescents with pelvic malignancies: A retrospective analysis of potential risk factors. Int J Hyperthermia 22:451-461, 2006. 206. Gurkan E, Yildiz I, Ocal F: Avascular necrosis of the femoral head as the first manifestation of acute lymphoblastic leukemia. Leuk Lymphoma 47:365-367, 2006. 207. Wei SY, Esmail AN, Bunin N, et al: Avascular necrosis in children with acute lymphoblastic leukemia. J Pediatr Orthop 20:331-335, 2000.

95

Relapsing Polychondritis JEAN-CHARLES PIETTE  •  PHILIPPE VINCENEUX

Key Points Inflammation associated with relapsing polychondritis involves the auricles (sparing the soft earlobe), the skin, and occasionally the vasculature. Relapsing polychondritis is associated occasionally with antibodies to type II collagen and with HLA-DR4. Relapsing polychondritis occasionally may extend to inflammation of cartilage of the larynx and trachea, and peripheral arthritis. Differential diagnosis includes Wegener’s granulomatosis, Behçet’s syndrome, Cogan’s syndrome, and cellulitis. Relapsing polychondritis may be seen with myelodysplasia syndromes.

DEFINITION AND CRITERIA Relapsing polychondritis is a rare, long-lasting, and potentially life-threatening disorder characterized by recurrent inflammatory episodes affecting the cartilaginous structures of the external ears, nose, larynx, and tracheobronchial tree, sometimes leading to their destruction.1-5 Systemic manifestations involving the auricles, eyes, skin, inner ears, and vessels are frequently associated. Several sets of clinical diagnostic criteria are available1-3; Table 95-1 lists the most commonly used criteria. Biopsy confirmation is not required for diagnosis except for atypical cases.

EPIDEMIOLOGY Since its first description by Jaksch-Wartenhorst in 1923, less than 800 cases of polychondritis have been published, with two series of 100 or more.3,6 Epidemiologic data are scarce. Most reported patients are white, but the disease has been found in all ethnic groups. Although ­ polychondritis may develop at any age,5,7 it usually occurs in ­mid-­adulthood, with a mean age at onset of 43 years (slightly older in men). Sex distribution is usually reported as equal, but a female predominance has been reported in more recent series,4,6 leading to a female-to-male ratio of 1:2 based on 600 patients. Familial cases are extremely rare.8 Maternofetal transmission of polychondritis, reported only once,9 has never occurred in our experience.10

PATHOPHYSIOLOGY The etiology of polychondritis is unknown. A history of mechanical insult to cartilage is infrequent. Cartilage destruction by degradative enzymes is supported by peculiar animal models8 and by electron microscopic studies.11

The release of degradative enzymes is thought to result from autoimmune reactions. The pathogenetic role of the immune system is suggested by the presence of a lymphocytic infiltrate and of immune deposits in tissue lesions,1,8,12 by humoral13-17 and cell-mediated18,19 responses to cartilage components, by frequent overlaps with various autoimmune disorders, and principally by more recent advances in animal models. Polychondritis has been induced in rats and mice by immunization with type II collagen20,21 or with matrilin-1, a noncollagenous cartilage matrix protein.22 The importance of the genetic background is shown by a murine model, using a mouse doubly transgenic for human HLADQ6 and HLA-DQ8 after immunization with type II collagen,21 and by the association of human polychondritis with HLA-DR4.23 Finally, a two-step process has been suggested in which the initiator is considered to be possibly matrilin-1 or type II collagen, among other proteins.20,24

CLINICAL FEATURES The onset is usually abrupt, with highly variable presenting manifestations including isolated general symptoms.1,18 The occurrence of chondritis may be delayed months to years.4 Table 95-2 lists the main cumulative clinical features. CHONDRITIS Auricular chondritis is a key manifestation, rarely absent in the course of the disease. Acute episodes manifest with pain, tenderness, swelling, warmth, and marked redness affecting the helix, antihelix, and sometimes tragus on one or both sides, but, importantly for the differential diagnosis, sparing the soft earlobe, which lacks cartilage. Attacks resolve spontaneously or with treatment within days, but relapses invariably occur sooner or later, their features being attenuated by steroids. Recurrent inflammation may lead to permanent sequelae, either a drooping “cauliflower” ear or more frequently an induration of the pinna (Fig. 95-1). A prior history of inflammatory episodes is necessary to confirm the diagnosis of chondritis in patients with a “flat” auricle, devoid of its normal relief. Nasal chondritis is far less obvious than auricular chondritis during acute episodes. Symptoms are restricted to nose pain, tenderness, mild swelling, and infrequent redness, sometimes accompanied by fullness, crusting, rhinorrhea, and rare epistaxis. A suggestive saddle-nose deformity resulting from cartilage collapse (Fig. 95-2) may develop progressively in the absence of apparent prior acute attacks, especially in women.3,25 Laryngeal, tracheal, or bronchial chondritis, which may extend to the subsegmental level, is frequently ­associated 1629

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Relapsing Polychondritis

Table 95-1  Empiric Diagnostic Criteria for Relapsing Polychondritis

Table 95-2  Main Cumulative Clinical Features   of Relapsing Polychondritis*

Major Criteria

Clinical Feature

Proven inflammatory episodes involving auricular cartilage Proven inflammatory episodes involving nasal cartilage Proven inflammatory episodes involving laryngotracheal cartilage

Auricular chondritis

Minor Criteria Ocular inflammation (conjunctivitis, keratitis, episcleritis, uveitis) Hearing loss Vestibular dysfunction Seronegative inflammatory arthritis Diagnosis is made by two major criteria or one major plus two minor criteria Histologic examination of affected cartilage is not required From Michet CJ Jr, McKenna CH, Luthra HS, et al: Relapsing polychondritis: Survival and predictive role of early disease manifestations. Ann Intern Med 104:74-78, 1986.

Frequency (%) 85

Nasal chondritis

65

Laryngotracheobronchial   chondritis

48

Costal chondritis

38

Arthropathy

78

Ocular inflammation

60

Fever ≥38 °C

38

Hearing loss

33

Dermatologic manifestations

33

Cardiovascular manifestations

30

Vestibular dysfunction

22

Renal involvement

13

*Compiled from published series and personal experience, totaling >500 patients. Data should be regarded as approximations.

and worsens prognosis.1,5,25-28 Laryngeal chondritis is responsible for hoarseness or aphonia, tenderness over the thyroid cartilage, and inspiratory dyspnea with stridor. Subglottic stenosis mainly occurs in women3 and may require emergency tracheostomy. Tracheobronchial manifestations (i.e., cough, chest pain, expiratory dyspnea, wheezing, and frequent infections owing to inability to clear secretions) are nonspecific. When polychondritis manifests with isolated lower respiratory tract involvement, the diagnosis may be delayed by months.29 Severe respiratory failure resulting from permanent stenoses or expiratory collapse secondary to tracheobronchomalacia or both may lead to death. Costal chondritis provokes localized parietal pain and costochondral tumefactions. This chondritis rarely results in depression of the anterior chest wall.30 OTHER MANIFESTATIONS In addition to chondritis, diverse symptoms may occur as a presenting feature or later in the disease course. Joint manifestations vary from arthralgias to an oligoarthritis or polyarthritis, either acute or episodic and migratory or, less frequently, chronic, nonerosive, nondeforming, and not accompanied by nodules.31-33 Peripheral arthropathy is usually asymmetric and mainly affects the wrists, metacarpophalangeal and proximal interphalangeal joints, elbows, knees, ankles, and parasternal joints. Synovial fluid may be paucicellular. Tenosynovitis and other para-articular manifestations are common, such as cervical or lumbar inflammatory pain.31 The presence of radiographic abnormalities in peripheral joints or in the spine is infrequent and suggestive of an overlap with another condition, mainly with spondyloarthropathies34 or rheumatoid arthritis.23,35 Eye involvement results from polychondritis itself or from associated Sjögren’s syndrome.36,37 Recurrent episcleritis/scleritis or conjunctivitis is more frequent than keratitis or uveitis. Vision is rarely threatened by retinal vasculitis, optic neuropathy, or necrotizing scleritis. Frank proptosis obligates one to rule out Wegener’s granulomatosis and ­lymphoma.38

Figure 95-1  Distortion and collapse of the external ear in a patient with relapsing polychondritis.

Audiovestibular manifestations are frequent.2 Hearing impairment may result from stenosis of the external auditory meatus, otitis media caused by eustachian tube chondritis, or more specifically from neurosensory lesions owing to vasculitis of the internal auditory artery. In the last-mentioned condition, deafness is abrupt, unilateral or bilateral, of variable magnitude, and accompanied by buzzing, and inconsistently reverses with prompt high-dose steroids. Transient vertigo may be associated or occur independently. Vascular involvement is uncommon, extremely diverse, and frequently multifocal. It carries a negative prognosis.

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1631

LABORATORY FINDINGS

Figure 95-2  Destruction of the nasal cartilage in a patient with relapsing polychondritis, creating the characteristic saddle-nose deformity. (From McKay DAR, Watson PG, Lyne AJ, et al: Relapsing polychondritis and eye disease. Br J Ophthalmol 58:600, 1974.)

Acquired inflammatory aneurysms usually affecting the ascending thoracic aorta may progressively develop late in the course of polychondritis.39-43 Large arteries at various sites also may be affected by aneurysms, stenosis, or both.44 A microvasculitic process sometimes involves the skin or organs such as kidney, brain, sclera, inner ear, or testes.3,39,45 Its implication in most cases of polychondritis remains disputed. Thrombophlebitis occasionally is related to antiphospholipid antibodies.46 Cardiac lesions include aortic failure resulting from dilated aortic anulus associated with ascending aortic aneurysms, mitral valve failure sometimes resulting from active inflammation, steroid-sensitive conduction disturbances, myocarditis, pericarditis, and coronary aneurysms.1,3,41,43,47-49 Dermatologic manifestations consist of oral or complex aphthosis, nodules, purpura, papules, sterile pustules, superficial phlebitis, livedo, ulcerations, and distal necrosis.6 Histologic findings include leukocytoclastic vasculitis, neutrophil infiltrates, and thrombosis. These lesions frequently occur in association with myelodysplasia,6 and sometimes resemble those of Behçet’s syndrome. The acronym MAGIC syndrome (mouth and genital ulcers with inflamed cartilage) has been proposed for this overlap.50,51 Kidney involvement, shown by microscopic hematuria, proteinuria, and sometimes severe loss of renal function, is usually attributed by biopsy to a crescentric pauci-immune glomerulonephritis within an accompanying micropolyangiitis.45 Less frequently, immune complex nephritis is related to overlapping systemic lupus or cryoglobulinemia. Neurologic manifestations consist of peripheral or cranial neuropathies, hemiplegia, seizures, rhombencephalitis, and lymphocytic or aseptic neutrophilic meningitis.52,53 Flares are accompanied by fever, asthenia, weight loss, and sometimes liver or lymph node enlargement.1 The clinical picture may be modified by various associated conditions, such as thyroiditis or ulcerative colitis.4

To date, the contribution of laboratory findings to diagnosis is limited. A major elevation of acute-phase reactants and erythrocyte sedimentation rate is observed during flares, with a few exceptions associated with mild-to-moderate anemia of chronic disease, leukocytosis, and thrombocytosis.1,5 Polyclonal elevation of serum IgA, IgG, or IgM is common. Tests for rheumatoid factors or antinuclear antibodies may be positive, but high titers suggest an overlap with rheumatoid arthritis, Sjögren’s syndrome, or systemic lupus erythematosus.4,23,54,55 Antineutrophil cytoplasmic antibodies devoid of proteinase-3 specificity are present in some patients.56 Antibodies to cartilage detected by indirect fluorescence staining are not routinely determined.13 Although initially claimed to be sensitive and specific,14 tests for antibodies to type II collagen have limited clinical significance.20 Preliminary data on antibodies to matrilin-1 seem promising, but require confirmation.16,17 Histologic examination of an affected cartilage, mainly auricular, is considered suggestive when it shows the association of degenerative changes with the presence of an inflammatory infiltrate (Fig. 95-3). The infiltrate, containing CD4+ lymphocytes, macrophages, neutrophils, and capillaries, ­penetrates the cartilage from its outer surface to its depth.1,8,12 Loss of basophilic staining of the matrix reflects

Figure 95-3  Biopsy specimen of the external ear in a patient with relapsing polychondritis. The specimen shows necrotizing chondritis with inflammatory cell infiltrate, depletion of matrix proteoglycans, chondrocyte degeneration, and fibrosis. (Original magnification, ×400.) (From ­Herman JH, Dennis MV: Immunopathologic studies in relapsing polychondritis. J Clin Invest 52:549, 1973; by copyright permission of the American Society for Clinical Investigation.)

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Relapsing Polychondritis

proteoglycan depletion. Chondrocytes become vacuolated and die. The destroyed cartilage is replaced by fibrous tissue where calcification or even ossification may occur. Because degenerative changes are commonly found in normal subjects age 40 or older, the biopsy specimen must be obtained during an acute flare to evaluate the infiltrate best. Acquired myelodysplasia frequently occurs in men with late-onset polychondritis.6,57,58 Chronic macrocytic nonregenerative anemia requiring regular transfusions is sometimes accompanied by leukopenia and thrombocytopenia. Myeloproliferative disorders and other forms of hematologic malignancies also have been reported.3,38

DIFFERENTIAL DIAGNOSIS Auricular chondritis is frequently misdiagnosed as infectious perichondritis, although infection does not spare the lobule and occurs in peculiar circumstances.2,8 Confusing aspects of the auricle may be observed in cellulitis, leprosy, leishmaniasis, frostbite, and after repeated trauma, such as with rugby players. Another consideration in this area would be external otitis, frequently caused by Pseudomonas aeruginosa or Staphylococcus aureus. A saddle-nose deformity may result from congenital syphilis, direct trauma, nasal septal perforation, and mainly Wegener’s granulomatosis. Rare differential diagnoses of nasal chondritis include the recessive genetic defect affecting expression of the transporter associated with antigen presentation (TAP) genes,59 and two pediatric disorders, chronic infantile neurologic cutaneous and articular syndrome60 and an autosomal dominant degenerative chondropathy.61 Early symptoms may mimic acute sinusitis. Lower respiratory tract involvement may be confused with asthma or chronic bronchitis. Stenoses occur in amyloidosis, sarcoidosis, inflammatory bowel disorders, ­tracheobronchopathia osteochondroplastica, rhinoscleroma in endemic areas, and mainly Wegener’s granulomatosis.62,63 Arterial involvement shares similarities with closely related Takayasu’s arteritis, Behçet’s disease, and Cogan’s syndrome.40,50 Involvement of the aortic root also occurs in Marfan syndrome, Ehlers-Danlos syndrome, syphilis, medial cystic necrosis, and spondyloarthropathies.49 Taken together, Wegener’s granulomatosis remains the main differential diagnosis of polychondritis. Both disorders share acquired saddle-nose deformity, subglottic stenosis, scleritis, and sometimes audiovestibular involvement or pauci-immune glomerulopathy. Auricular chondritis has been described in Wegener’s granulomatosis,45 and prop­ tosis or nasal septum perforation has been described in polychondritis.44 Key features that suggest Wegener’s granulomatosis are pansinusitis, parenchymal lung involvement, mononeuritis multiplex, granulomatous vasculitis, and antineutrophil cytoplasmic antibodies directed to proteinase-3. Conversely, diffuse tracheomalacia is a distinctive feature of polychondritis. Although these disorders are distinct entities, overlaps probably exist.39,64,65

EVALUATION, COURSE, AND PROGNOSIS Evaluation of airway disease is crucial. Pulmonary function tests using forced inspiratory and expiratory flow volume loop studies quantify the deficit and localize the structures

involved.26,28 Tracheobronchoscopy may worsen hypoxia and lead to death.26,28 In most cases, it should be replaced by computed tomography or magnetic resonance imaging.26,27,66,67 Reconstruction techniques, including virtual endoscopy, and dynamic studies easily visualize the respiratory tree without the hazards of real endoscopy. Routine echocardiograms check the valves and ascending aorta. Repeated vascular imaging is needed in patients with large artery involvement because lesions are frequently multiple and tend to recur.40,43 The use of nontraumatic methods, such as magnetic resonance angiograms, prevents the development of false aneurysms induced by arterial puncture.50 The course of polychondritis varies. Disease remains smoldering in a few patients, whereas most experience flares affecting independently cartilage, joints,33 or vessels.40 Very few patients undergo a progressive downhill course refractory to therapy. Although durable remissions may occur, polychondritis rarely evolves to extinction. Pregnancy has no influence on disease activity.10 The discrimination between tracheobronchial flare and superimposed infection may be difficult because both may coexist. Functional impairment, related to the disease itself or to treatment, frequently develops with time. The severity of prognosis reflects the frequent requirement for high-dose steroids and the extreme duration of polychondritis. The 5-year and 10-year probabilities of survival after diagnosis were 74% and 55% in the Mayo Clinic series.3 More recent data4 and our experience are much more encouraging. The leading causes of death are airway obstruction and pneumonia in women and specific cardiovascular involvement in men.3,5 In patients younger than 51 years old, saddle-nose deformity and systemic vasculitis were the worst prognostic factors.3 For older patients, only anemia predicted outcome. Survival is limited when repeated transfusions are required for myelodysplasia.57

TREATMENT Systemic treatment is empiric and should be adapted to disease activity and severity.4 Minor cases may respond to nonsteroidal anti-inflammatory drugs, colchicine, or dapsone.4,5,68 Prednisone remains the cornerstone of treatment for most patients. Initial doses are 0.5 to 1 mg/kg/day. Methylprednisolone pulses (1 g/day for 3 days) are used in frank respiratory flares, recent neurosensorial hearing loss, or systemic microvasculitis.69 Progressive tapering frequently is limited by the requirement for substantial maintenance doses. Combined immunosuppression is indicated initially in severe respiratory or vasculitic involvement or secondarily to improve disease control and allow steroid tapering. Methotrexate (0.3 mg/kg/wk) is frequently effective4,70 and carries no risk of secondary myelodysplasia. Cyclophosphamide, azathioprine, chlorambucil, and mycophenolate mofetil also have been used, and cyclosporine in case of preexisting cytopenias.1,4,5,44,45,71 In our experience, cyclophosphamide is the most potent. Infliximab has been reported to be effective in two cases,72 but our results in six patients with refractory polychondritis were disappointing. Such patients, who do not respond to plasmapheresis or high-dose immunoglobulins, might be candidates for experimental regimens, such as

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CARTILAGE, BONE, AND HERITABLE CONNECTIVE TISSUE DISORDERS

tolerance induction with oral collagen7 or autologous stem cell transplantation.73 Focal steroid treatment includes eye drops, intra-­articular injections, and inhaled steroids sometimes combined with ephedrine.74 Propranolol is used empirically to limit aortic dilation. Airway obstruction may require tracheostomy, mechanical ventilation, tracheal surgery, or stenting.26,29,75,76 Sustained disease control allows successful nasal reconstruction. The initial medium-term results of heart or arterial surgery are frequently jeopardized in the long-term by valve disinsertion or relapsing aneurysms occurring despite immunosuppression.39-41,49,50 A careful preoperative anesthesia evaluation is mandatory.77

CONCLUSION Although early recognition and conventional management have improved the prognosis of relapsing polychondritis, a better comprehension of its pathophysiology is needed to elaborate targeted intervention. REFERENCES   1. McAdam LP, O’Hanlan MA, Bluestone R, et al: Relapsing polychondritis: Prospective study of 23 patients and a review of the literature. Medicine (Balt) 55:193-215, 1976.   2. Damiani JM, Levine HL: Relapsing polychondritis: Report of ten cases. Laryngoscope (St Louis) 89:929-946, 1979.   3. Michet CJ Jr, McKenna CH, Luthra HS, et al: Relapsing polychondritis: Survival and predictive role of early disease manifestations. Ann Intern Med 104:74-78, 1986.   4. Trentham DE, Le CH: Relapsing polychondritis. Ann Intern Med 129:114-122, 1998.   5. Vinceneux P, Pouchot J, Piette JC: Polychondrite atrophiante. In Kahn MF, Peltier AP, Meyer O (eds): Maladies et Syndromes Systémiques. Paris, Flammarion Médecine-Sciences, 2000, pp 623-649.   6. Francès C, el Rassi R, Laporte JL, et al: Dermatologic manifestations of relapsing polychondritis: A study of 200 cases at a single center. Medicine (Balt) 80:173-179, 2001.   7. Navarro MJ, Higgins GC, Lohr KM, et al: Amelioration of relapsing polychondritis in a child treated with oral collagen. Am J Med Sci 324:101-103, 2002.   8. Arkin CR, Masi AF: Relapsing polychondritis: Review of current status and case report. Semin Arthritis Rheum 5:41-61, 1975.   9. Arundell FW, Haserick JR: Familial chronic atrophic polychondritis. Arch Dermatol 82:439-440, 1960. 10. Papo T, Wechsler B, Bletry O, et al: Pregnancy in relapsing polychondritis: Twenty-five pregnancies in eleven patients. Arthritis Rheum 40:1245-1249, 1997. 11. Giroux L, Paquin F, Guerard-Desjardins MJ, et al: Relapsing polychondritis: An autoimmune disease. Semin Arthritis Rheum 13:182187, 1983. 12. Riccieri V, Spadaro A, Taccari E, et al: A case of relapsing polychondritis: Pathogenetic considerations. Clin Exp Rheumatol 6:95-96, 1988. 13. Ebringer R, Rook G, Swana GT, et al: Autoantibodies to cartilage and type II collagen in relapsing polychondritis and other rheumatic diseases. Ann Rheum Dis 40:473-479, 1981. 14. Foidart JM, Abe S, Martin GR, et al: Antibodies to type II collagen in relapsing polychondritis. N Engl J Med 299:1203-1207, 1978. 15. Yang CL, Brinckmann J, Rui HF, et al: Autoantibodies to cartilage collagens in relapsing polychondritis. Arch Dermatol Res 285: 245-249, 1993. 16. Buckner JH, Wu JJ, Reife RA, et al: Autoreactivity against matrilin-1 in a patient with relapsing polychondritis. Arthritis Rheum 43:939943, 2000. 17. Hansson AS, Heinegard D, Piette JC, et al: The occurrence of autoantibodies to matrilin 1 reflects a tissue-specific response to cartilage of the respiratory tract in patients with relapsing polychondritis. Arthritis Rheum 44:2402-2412, 2001.

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18. Alsalameh S, Mollenhauer J, Scheuplein F, et al: Preferential cellular and humoral immune reactivities to native and denaturated collagen types IX and XI in a patient with fatal relapsing polychondritis. J Rheumatol 20:1419-1424, 1993. 19. Buckner JH, Van Landeghen M, Kwok WW, et al: Identification of type II collagen peptide 261-273-specific T cell clones in a patient with relapsing polychondritis. Arthritis Rheum 46:238-244, 2002. 20. Cremer MA, Rosloniec EF, Kang AH: The cartilage collagens: A review of their structure, organization, and role in the pathogenesis of experimental arthritis in animals and in human rheumatic disease. J Mol Med 76:275-288, 1998. 21. Bradley DS, Das P, Griffiths MM, et al: HLA-DQ6/8 double transgenic mice develop auricular chondritis following type II collagen immunization: A model for human relapsing polychondritis. J Immunol 161:5046-5053, 1998. 22. Hansson AS, Heinegard D, Holmdahl R: A new animal model for relapsing polychondritis, induced by cartilage matrix protein (matrilin-1). J Clin Invest 104:589-598, 1999. 23. Zeuner M, Straub RH, Rauh G, et al: Relapsing polychondritis: Clinical and immunogenetic analysis of 62 patients. J Rheumatol 24: 96-101, 1997. 24. Hansson AS, Holmdahl R: Cartilage-specific autoimmunity in animal models and clinical aspects in patients—focus on relapsing polychondritis. Arthritis Res 4:296-301, 2002. 25. McCaffrey TV, McDonald TJ, McCaffrey LA: Head and neck manifestations of relapsing polychondritis: Review of 29 cases. Otolaryngology 86:473-478, 1978. 26. Eng J, Sabanathan S: Airway complications in relapsing polychondritis. Ann Thorac Surg 51:686-692, 1991. 27. Davis SD, Berkmen YM, King T: Peripheral bronchial involvement in relapsing polychondritis: Demonstration by thin-section CT. AJR Am J Roentgenol 153:953-954, 1989. 28. Tillie-Leblond I, Wallaert B, Leblond D, et al: Respiratory involvement in relapsing polychondritis: Clinical, functional, endoscopic, and radiographic evaluations. Medicine (Balt) 77:168-176, 1998. 29. Sarodia BD, Dasgupta A, Mehta AC: Management of airway manifestations of relapsing polychondritis: Case reports and review of literature. Chest 116:1669-1675, 1999. 30. Lim MC, Chan HL: Relapsing polychondritis—a report on two Chinese patients with severe costal chondritis. Ann Acad Med Singapore 19:396-403, 1990. 31. O’Hanlan M, McAdam LP, Bluestone R, et al: The arthropathy of relapsing polychondritis. Arthritis Rheum 19:191-194, 1976. 32. Balsa A, Espinosa A, Cuesta M, et al: Joint symptoms in relapsing polychondritis. Clin Exp Rheumatol 13:425-430, 1995. 33. Gunaydin I, Daikeler T, Jacki S, et al: Articular involvement in patients with relapsing polychondritis. Rheumatol Int 18:93-96, 1998. 34. Pazirandeh M, Ziran BH, Khandelwal BK, et al: Relapsing polychondritis and spondylarthropathies. J Rheumatol 15:630-632, 1988. 35. Rajaee A, Voossoghi AA: Classical rheumatoid arthritis associated with relapsing polychondritis. J Rheumatol 16:1263-1265, 1989. 36. Isaak BL, Liesegang TJ, Michet CJ Jr: Ocular and systemic findings in relapsing polychondritis. Ophthalmology 93:681-689, 1986. 37. Letko E, Zafirakis P, Baltatzis S, et al: Relapsing polychondritis: A clinical review. Semin Arthritis Rheum 31:384-395, 2002. 38. Lichauco JJ, Lauer S, Shigemitsu HH, et al: Orbital mucosa-associated lymphoid tissue (MALT)-type lymphoma in a patient with relapsing polychondritis. Arthritis Rheum 44:1713-1715, 2001. 39. Michet CJ Jr: Vasculitis and relapsing polychondritis. Rheum Dis Clin N Am 16:441-444, 1990. 40. Piette JC, Vinceneux P, Francès C: Vascular manifestations in relapsing polychondritis. In Asherson RA, Cervera R, Abramson S, et al (eds): Vascular Manifestations of Systemic Autoimmune Diseases. Boca Raton, CRC Press, 2001, pp 351-359. 41. Del Rosso A, Petix NR, Pratesi M, et al: Cardiovascular involvement in relapsing polychondritis. Semin Arthritis Rheum 26:840844, 1997. 42. Selim AG, Fulford LG, Mohiaddin RH, et al: Active aortitis in relapsing polychondritis. J Clin Pathol 54:890-892, 2001. 43. Barretto SN, Oliveira GH, Michet CJ Jr, et al: Multiple cardiovascular complications in a patient with relapsing polychondritis. Mayo Clin Proc 77:971-974, 2002. 44. Esdaile J, Hawkins D, Gold P, et al: Vascular involvement in relapsing polychondritis. Can Med Assoc J 116:1019-1022, 1977.

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45. Chang-Miller A, Okamura M, Torres VE, et al: Renal involvement in relapsing polychondritis. Medicine (Balt) 66:202-217, 1987. 46. Empson M, Adelstein S, Garsia R, et al: Relapsing polychondritis presenting with recurrent venous thrombosis in association with anticardiolipin antibody. Lupus 7:132-134, 1998. 47. Bowness P, Hawley IC, Dearden A, et al: Complete heart block and severe aortic incompetence in relapsing polychondritis: Clinicopathologic findings. Arthritis Rheum 34:97-100, 1991. 48. Buckley LM, Ades PA: Progressive aortic valve inflammation occurring despite apparent remission of relapsing polychondritis. Arthritis Rheum 35:812-814, 1992. 49. Lang-Lazdunski L, Hvass U, Paillole C, et al: Cardiac valve replacement in relapsing polychondritis: A review. J Heart Valve Dis 4: 227-235, 1995. 50. Le Thi Huong D, Wechsler B, Piette JC, et al: Aortic insufficiency and recurrent valve prosthesis dehiscence in MAGIC syndrome. J Rheumatol 20:397-398, 1993. 51. Imai H, Motegi M, Mizuki N, et al: Mouth and genital ulcers with inflamed cartilage (MAGIC syndrome): A case report and literature review. Am J Med Sci 314:330-332, 1997. 52. Hanslik T, Wechsler B, Piette J-C, et al: Central nervous system involvement in relapsing polychondritis. Clin Exp Rheumatol 12: 539-541, 1994. 53. Kothare SV, Chu CC, VanLandingham K, et al: Migratory leptomeningeal inflammation with relapsing polychondritis. Neurology 51: 614-617, 1998. 54. Kitridou RC, Wittmann AL, Quismorio FP: Chondritis in systemic lupus erythematosus: Clinical and immuno-pathologic studies. Clin Exp Rheumatol 5:349-353, 1987. 55. Piette JC, El-Rassi R, Amoura Z: Antinuclear antibodies in relapsing polychondritis. Ann Rheum Dis 58:656-657, 1999. 56. Papo T, Piette JC, Le Thi Huong D, et al: Antineutrophil cytoplasmic antibodies in polychondritis. Ann Rheum Dis 52:384-385, 1993. 57. Piette JC, Papo T, Chavanon P, et al: Myelodysplasia and relapsing polychondritis. J Rheumatol 22:1208-1209, 1995. 58. Diebold J, Rauh G, Jäger K, et al: Bone marrow pathology in relapsing polychondritis: High frequency of myelodysplastic syndromes. Br J Haematol 89:820-830, 1995. 59. Moins-Teisserenc HT, Gadola SD, Cella M, et al: Association of a syndrome resembling Wegener’s granulomatosis with low surface expression of HLA class-I molecules. Lancet 354:1598-1603, 1999 (erratum in Lancet 356:170, 2000). 60. Prieur AM, Griscelli C, Lampert F, et al: A chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome: A specific entity analysed in 30 patients. Scand J Rheumatol 66(suppl):57-68, 1987. 61. Kurien M, Seshadri MS, Zacharia A: Inherited degenerative chondropathy—an autosomal dominant new clinical entity: Report on two cases and follow-up of four cases. J Laryngol Otol 109:433-436, 1995. 62. Loehrl TA, Smith TL: Inflammatory and granulomatous lesions of the larynx and pharynx. Am J Med 111(Suppl 8A):113S-117S, 2001.

63. Prince JS, Duhamel DR, Levin DL, et al: Nonneoplastic lesions of the tracheobronchial wall: Radiologic findings with bronchoscopic correlation. RadioGraphics 22(Spec No):S215-S30, 2002 (erratum in RadioGraphics 23:191, 2003). 64. Case Records of the Massachusetts General Hospital (case 26-1985). N Engl J Med 312:1695-1703, 1985. 65. Cauhape P, Aumaitre O, Papo T, et al: A diagnostic dilemna: Wegener’s granulomatosis, relapsing polychondritis or both? Eur J Med 2: 497-498, 1993. 66. Behar JV, Choi YW, Hartman TA, et al: Relapsing polychondritis affecting the lower respiratory tract. AJR Am J Roentgenol 178: 173-177, 2002. 67. Heman-Ackah YD, Remley KB, Goding GS Jr: A new role for magnetic resonance imaging in the diagnosis of laryngeal relapsing polychondritis. Head Neck 21:484-489, 1999. 68. Barranco VP, Minor DB, Solomon M: Treatment of relapsing polychondritis with dapsone. Arch Dermatol 112:1286-1288, 1976. 69. Lipnick RN, Fink CW: Acute airway obstruction in relapsing polychondritis: Treatment with pulse methylprednisolone. J Rheumatol 18:98-99, 1991. 70. Park J, Gowin KM, Schumacher HR Jr: Steroid sparing effect of methotrexate in relapsing polychondritis. J Rheumatol 23:937-938, 1996. 71. Svenson KLG, Holmdahl R, Klareskog L, et al: Cyclosporin A treatment in a case of relapsing polychondritis. Scand J Rheumatol 13: 329-333, 1984. 72. Saadoun D, Deslandre CJ, Allanore Y, et al: Sustained response to infliximab in 2 patients with refractory relapsing polychondritis. J Rheumatol 30:1394-1395, 2003. 73. Rosen O, Thiel A, Massenkeil G, et al: Autologous stem-cell transplantation in refractory autoimmune diseases after in vivo immunoablation and ex vivo depletion of mononuclear cells. Arthritis Res 2:327-336, 2000. 74. Gaffney RJ, Harrison M, Blayney AW: Nebulized racemic ephedrine in the treatment of acute exacerbations of laryngeal relapsing polychondritis. J Laryngol Otol 106:63-64, 1992. 75. Adliff M, Ngato D, Keshavjee S, et al: Treatment of diffuse tracheomalacia secondary to relapsing polychondritis with continuous positive airway pressure. Chest 112:1701-1704, 1997. 76. Dunne JA, Sabanathan S: Use of metallic stents in relapsing polychondritis. Chest 105:864-867, 1994. 77. Biro P, Rohling R, Schmid S, et al: Anesthesia in a patient with acute respiratory insufficiency due to relapsing polychondritis. J Clin Anesth 6:59-62, 1994. Websites http://www.emedicine.com/derm/topic375.htm http://www.orpha.net/data/patho/GB/uk-RP.html http://www.polychondritis.org/ http://rpolychondritis.tripod.com/

96

Heritable Diseases of Connective Tissue DEBORAH KRAKOW

Key Points Heritable disorders of connective tissues are a diverse group of disorders and can be associated with extreme variation in height ranging from very short (dwarfs) to tall stature. The osteochondrodysplasias or skeletal dysplasias are a heterogeneous group of more than 300 disorders frequently associated with profound short stature and orthopaedic complications. These disorders are diagnosed based on radiographic, morphologic, clinical, and molecular criteria. The molecular mechanisms have been elucidated in many of these disorders providing for improved clinical diagnosis and reproductive choices for affected individuals and their families. Treatment options have been offered in osteogenesis imperfecta and Marfan syndrome that may improve the quality of life and life span in affected individuals.

Heritable disorders of connective tissues are a heterogeneous group of disorders characterized by abnormalities in skeletal tissues including cartilage, bone, tendon, ligament, muscle, and skin. These disorders, originally defined by McKusick,1 have been classified based on clinical findings and molecular criteria. They are subclassified into disorders that primarily affect cartilage and bone (the skeletal dysplasias), and disorders that have a more profound effect on connective tissue, including Ehlers-Danlos syndrome (EDS), Marfan syndrome, and other disorders manifested by abnormal extracellular matrix molecules. The skeletal dysplasias are associated with abnormalities in the size and shape of the appendicular and axial skeleton and frequently result in disproportionate short stature. Until the early 1960s, most individuals with short stature were considered to have pituitary dwarfism, achondroplasia (shortlimb dwarfism), or Morquio disease (short-trunked dwarfism). Presently, there are more than 300 well-characterized disorders that are classified primarily on the basis of clinical, radiographic, and molecular criteria.2 Disorders of connective tissue are genetic defects that result from mutations in genes that encode extracellular matrix proteins, transcription factors, tumor suppressors, signal transducers, enzymes, chaperones, intracellular binding proteins, RNA processing molecules, and genes of unknown function.

SKELETAL DYSPLASIAS The skeletal dysplasias, or osteochondrodysplasias, are defined as disorders that are associated with a generalized abnormality in the skeleton. Although each skeletal

d­ ysplasia is relatively rare, collectively, the birth incidence of these disorders is almost 1 in 5000.3 These disorders range in severity from “precocious” arthropathy to perinatal lethality owing to pulmonary insufficiency. Individuals with these disorders can have significant orthopaedic, neurologic, and psychological complications. Many of these individuals seek medical attention for orthopaedic complaints owing to ongoing pain, arthritic complaints in large joints, and back pain primarily caused by ongoing abnormalities in bone and cartilage. EMBRYOLOGY The human skeleton (from the Greek, skeletos, “dried up”) is a complex organ consisting of 206 bones (126 appendicular bones, 74 axial bones, and 6 ossicles). The skeleton, including tendons, ligaments, and muscles in addition to cartilage and bone, has multiple embryonic origins and serves many key functions throughout life, including linear growth, mechanical support for movement, a blood and mineral reservoir, and protection of vital organs. The patterning and architecture of the skeleton occurs during fetal development (see Chapter 4). During that period, the number, size, and shape of the future skeletal elements are determined, a process that is under complex genetic control.4 Uncondensed mesenchyme undergoes cellular condensations (cartilage anlagen) at sites of future bones, and this occurs by two mechanisms.5 In the process of endochondral ossification, mesenchyme first differentiates into a cartilage model (anlagen), and then the center of the anlagen degrades, mineralizes, and is removed by osteoclast-like cells. This process spreads up and down the bones and allows for vascular invasion and influx of osteoprogenitor cells. The periosteum in the midshaft region of the bone produces osteoblasts, which synthesize the cortex; this is known as the primary ossification center. At the ends of the cartilage anlagen, a similar process leading to the removal of cartilage occurs (secondary center of ossification) leaving a portion of cartilage model “trapped” between the expanding primary and secondary ossification centers. This area is referred to as a cartilage growth plate or epiphysis. There are four chondrocyte cell types in the growth plate: reserve, resting, proliferative, and hypertrophic. These growth plate chondrocytes undergo a tightly regulated program of proliferation, hypertrophy, degradation, and replacement by bone (primary spongiosa). This is the major mechanism of skeletogenesis and is the mechanism by which bones increase in length, and the articular surfaces increase in diameter. In contrast, the flat bones of the cranial vault and part of the clavicles and pubis form by intramembranous ossification, whereby fibrous tissue, 1635

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derived from mesenchymal cells, differentiates directly into osteoblasts, which directly lay down bone.5 These processes are under specific and direct genetic control, and abnormalities in the genes that encode these pathways frequently lead to skeletal dysplasias.6-9 CARTILAGE STRUCTURE Collagen accounts for two thirds of the adult weight of adult articular cartilage and provides significant strength and structure to the tissue (Chapter 3). Collagens are a family of proteins that consist of single molecules (monomers) that combine into three polypeptide chains to form a triple helix structure. In the triple helix, every third amino acid is a glycine residue, and the general chain structure is denoted as Gly-X-Y, where X and Y are commonly proline and hydroxyproline. The collagen helix can be composed of identical chains (homotrimeric), as in type II collagen, or can consist of different collagen chains (heterotrimeric), as seen in collagen type XI.10 Collagens are widely distributed throughout the body, and 33 collagen gene products are expressed in a tissuespecific manner, leading to 19 triple helical collagens. Collagens are classified further by the structures they form in the extracellular matrix. The most abundant collagens are the fibrillar types (I, II, III, V, and XI), and their extensive cross-linking provides mechanical strength that is necessary for high stress tissue, such as cartilage, bone, and skin.11 Another collagen species is the fibril-associated collagens with interrupted triple helices, which include collagen types IX, XII, XIV, and XVI. These collagens interact with fibrillar collagens and other extracellular molecules, including aggrecan, cartilage oligomeric matrix protein, and other sulfated proteoglycans.11 Collagen types VIII and X are nonfibrillar, short-chain collagens, and type X collagen is the most abundant extracellular matrix molecule expressed by hypertrophic chondrocytes during endochondral ossification.12 The major collagens of articular cartilage are fibrillar collagen types II, IX, XI, and X. In developing cartilage, the core fibrillar network is a cross-linked copolymer of collagens II, IX, and XI.13 Mutations in genes that encode these collagens result in various skeletal dysplasias and highlight the importance of these molecules in skeletal development. CLASSIFICATION AND NOMENCLATURE As mentioned earlier, in the 1970s, there was recognition of the genetic and clinical heterogeneity of heritable disorders of connective tissue and a new awareness of the complexity of these disorders. As a result, there have been multiple attempts to classify these disorders in a manner that clinicians and scientists could use effectively to diagnose and determine their pathogenicity (International Nomenclature of Constitutional Diseases of Bone, 1970, 1977, 1983, 1992, 2001, and 2005). The initial categories were purely descriptive and clinically based. With the more recent explosion in determining the genetic basis of these diseases, the classification has evolved into one that combines the older clinical one (including the eponyms and Greek terms) and blends these disorders into families that share a molecular basis or pathway. The most recent updated classification can be

found at www.isds.ch; some of the chondrodysplasia families are listed in Table 96-1. The most widely used method for differentiating the skeletal disorders has been through the detection of skeletal radiographic abnormalities. Radiographic classifications are based on the different parts of the long bones that are abnormal (epiphyses, metaphyses, and diaphyses) (Fig. 96-1). These epiphyseal, metaphyseal, and diaphyseal disorders can be differentiated further depending on whether or not the spine is involved (spondyloepiphyseal, spondylometaphyseal, or spondyloepimetaphyseal dysplasias). Each of these classes of these disorders can be differentiated further into distinct disorders based on other clinical and radiographic findings. CLINICAL EVALUATION AND FEATURES The skeletal dysplasias are generalized disorders of the skeleton and usually result in disproportionate short stature. Affected individuals usually present because they are disproportionately short. This finding needs to be documented on the appropriate growth curves for gender and ethnicity if possible. Most individuals with disproportionate short stature have skeletal dysplasias, and individuals with proportionate short stature have endocrine, nutritional, or prenatal-onset growth deficiency, or other nonskeletal dysplasia disorders. There are exceptions to the rule, such as congenital hypothyroidism, which is associated with disproportionate short stature, and disorders such as osteogenesis imperfecta (OI) and hypophosphatasia can be associated with normal body proportions. A disproportionate body habitus may not be immediately visible on physical examination. Anthropometric dimensions, such as upper-to-lower segment (U/L) ratio, sitting height, and arm span, must be measured when considering the possibility of a skeletal dysplasia and should be measured in centimeters. Sitting height is an accurate measurement of head and trunk length, but it requires special equipment for precise measurements. U/L ratios are easy to obtain and provide an accurate measurement of proportion. The lower segment is measured from the symphysis pubis to the floor at the inside of the heel. The upper segment is measured by subtracting the lower segment measurement from the total height. McKusick14 has published standard U/L segment ratios for whites and African-Americans across ages. A white child 8 to 10 years old has a U/L segment ratio of approximately 1 and as an adult has a U/L segment ratio of 0.95. Individuals presenting with disproportionate short stature have altered U/L segment ratios depending on whether they have short limbs, short trunk, or both. An individual with short limbs and normal trunk has an increased U/L segment ratio, and an individual with normal limbs but short trunk has a diminished U/L segment ratio (Fig. 96-2). Another means of determining if there is disproportion is based on arm span measurements, which are very close to total height in an average-proportioned individual. A short-limbed individual has an arm span considerably shorter than the height. As in any disorder that has a genetic basis, it is crucial to obtain an accurate family history, and this should include any history of previously affected children or parental consanguinity. The skeletal dysplasias are genetically

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Table 96-1  Classification of the Chondrodysplasias Dysplasia

Mode of Inheritance

Chromosomal Location

Gene

AD AD AD AD AD AD AD

4p16.3 4p16.3 4p16.3 4p16.3 4p16.3 4p16.3 8p11

FGFR3 FGFR FGFR3 FGFR3 FGFR3 FGFR3 FGFR1

4p16

EVC1, EVC2

AD AD AD XLR XLD

3p14.3 3p14.3 3p14.3 Xq28 Xq28

FLNB FLNB FLNB FLNA FLNA

AR AR AR AR

5q31-q34 5q31-q34 5q31-q34 5q31-q34

DTDST DTDST DTDST DTDST

Achondroplasia Group Achondroplasia Thanatophoric dysplasia, type I Thanatophoric dysplasia, type II Achondroplasia Hypochondroplasia SADDAN* Osteoglophonic dysplasia Severe Spondylodysplastic Dysplasias Achondrogenesis IA Opsismodysplasia Spondylometaphyseal dysplasia, type Sedaghatian

AR AR AR

Metatropic Dysplasia Group Fibrochondrogenesis Schneckenbecken dysplasia Metatropic dysplasia

AR AR AD/AR (more than one form)

Short Rib Dysplasia (Polydactyly) Group Short-rib polydactyly type I/III Short-rib polydactyly type II/IV Asphyxiating thoracic dysplasia Chondroectodermal dysplasia Thoracolaryngopelvic dysplasia

AR AR AR AR AD

Omodysplasia Group Omodysplasia I Omodysplasia II

AD AR

Filamin-Related Disorders Atelosteogenesis I Atelosteogenesis III Larsen syndrome Otopalatodigital syndrome type II Osteodysplasty of Melnick and Needles Diastrophic Dysplasia Group Achondrogenesis IB Achondrogenesis II Diastrophic dysplasia Recessive multiple epiphyseal dysplasia Dyssegmental Dysplasia Group Dyssegmental dysplasia, Silverman-Handmaker type Dyssegmental dysplasia, Rolland-Desbuquois type

AR AR

HSPG2

Type II Collagenopathies Achondrogenesis II Kniest dysplasia Spondyloepiphyseal dysplasia, congenital Spondyloepiphyseal dysplasia, Strudwick type Spondyloperipheral dysplasia Arthro-ophthalmopathy (Stickler syndrome)

AD AD AD AD AD AD

12q13 12q13 12q13 12q13 12q13 12q13

COL2A1 COL2A1 COL2A1 COL2A1 COL2A1 COL2A1

AD AR AD

1p21 6p21.3 6p21.3

COL11A1 COL11A2 COL11A2

AR XLR AR AR AR AR AR AR AR

10q23-q24 Xp22 6q22-q23 18q12-q21.1 2p12 2q35-q36 2q34-q36

ATPSK2 SEDL WISP3 FLJ90130 EIF2AK3 IHH SMARCAL1

Type XI Collagenopathies Stickler dysplasia Otospondylometaepiphyseal dysplasia Weissenbacher-Zweymuller syndrome Other Spondyloepi-(meta)-physeal Dysplasias Spondyloepimetaphyseal dysplasia, Pakistani type Spondyloepiphyseal dysplasia tarda Progressive pseudorheumatoid dysplasia Dyggve-Melchior-Clausen dysplasia Wolcott-Rallison dysplasia Acrocapitofemoral dysplasia Schimke immuno-osseous dysplasia Sponastrime Spondyloepimetaphsyseal dysplasia, with joint laxity

*Severe achondroplasia with developmental delay and acanthosis nigricans. AD, autosomal dominant; AR, autosomal recessive; SP, sporadic; XLD, X-linked dominant; XLR, X-linked recessive. Continued

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Table 96-1  Classification of the Chondrodysplasias—cont’d Dysplasia

Mode of Inheritance

Chromosomal Location

Gene

Multiple epiphyseal dysplasia, types Fairbanks and Ribbing

AD

Pseudoachondroplasia

AD

6q12-q14 1p33-q32 20q13.3 2q24-q23 19p13.1 19p13.1

COL9A1 COL9A2 COL9A MATN COMP COMP

6q22-q24 1q42 2q31 Xp11.2 1q42.1 Xp22-p32

PEX7 DHAPAT AGPS EBP LBR ARSE

AD AR AR AD AR AR

3p21-p22 3p21-p22 3p21-p22 6q21-q22 9p21-p13 7q11

PTHrP PTHrP PTHrP COL10A1 RMRP SBDS

AR

20q13.11

ADA

Xp22.3 Xp22.3

SHOX SHOX

9q22

ROR2

Multiple Epiphyseal Dysplasia and ­Pseudoachondroplasia

Chondrodysplasia Punctata Chondrodysplasia punctata, rhizomelic type

AR

Chondrodysplasia punctata, Conradi-Hünermann type Hydrops-ectopic-calcifications-moth-eaten bones Chondrodysplasia punctata, brachytelephalangic type Chondrodysplasia punctata, tibial-metacarpal type

XLD AR XLR SP

Metaphyseal Dysplasias Metaphyseal chondrodysplasia, Jansen type Eiken dysplasia Bloomstrand dysplasia Metaphyseal chondrodysplasia, Schmidt type Metaphyseal chondrodysplasia, McKusik type Metaphyseal chondrodysplasia, with pancreatic   ­insufficiency, and cyclin neutropenia Adenosine deaminase deficiency Spondylometaphyseal dysplasias Spondylometaphyseal dysplasia, Koslowski type Spondylometaphyseal dysplasia, corner fracture type

AD AD

Brachyolmia Spondylodysplasias Brachyolmia (Hobek type; Toledo type) Brachyolmia (Maroteaux type) Brachyolmia (AD)

AR AR AD

Mesomelic Dysplasias Dyschondrosteosis Mesomelic dysplasia, Langer type Mesomelic dysplasia, Nievergelt type Mesomelic dysplasia, Robinow type Mesomelic dysplasia, Reinhardt type Mesomelic dysplasia, Werner type Mesomelic dysplasia, Kantapura type

XLD XLR AD AD AR AD AD AD

2q24-32

Acromelic and Acromesomelic Dysplasias Acromicric dysplasia Geleophysic dysplasia Trichorhinophalangeal dysplasia, type I Trichorhinophalangeal dysplasia, type II Acrodysplasia with retinitis pigmentosa and ­nephropathy Acrodysostosis Grebe dysplasia Acromesomelic dysplasia, Hunter-Thompson Angel-shaped phalangoepiphyseal dysplasia Acromesomelic dysplasia, Maroteaux type

SP AR AD AD AR AD AR AR

8q24.12 del8q24.11-q13

TRPS1 TRPS2

20q11.2 20q11.2

CDMP1 CDMP1

AR

9p21-12

NPRB

AD

6p21

CBFA1

AD AR

17q24.1-q25.1 5p13.1

SOX9 LIFR

Dysplasia with Prominent Membranous Bone ­Involvement Cleidocranial dysplasia Bent Bone Dysplasias Campomelic dysplasia Stuve-Wiedemann dysplasia Multiple Dislocations with Dysplasias Desbuquois syndrome Pseudodiastrophic dysplasia Spondyloepimetaphyseal dysplasia with joint laxity

AR AR AR

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A

B

D

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C

E

Figure 96-1  A-E, Classification of chondrodysplasias based on radiographic involvement of the long bones (A-C) and vertebrae (D and E). A and D are normal, B is an epiphyseal abnormality, C is a metaphyseal abnormality, and E is a “spondylo-” abnormality.

­ eterogeneous and can be inherited as autosomal dominant, h autosomal recessive, X-linked recessive, and X-linked dominant disorders, and rarer genetic mechanisms of disease, including germline mosaicism and uniparental disomy, have been seen.15-18 For many patients and families, accurate diagnosis and recurrence risk can have a significant impact on their reproductive decisions. Another consideration for patients with short stature is that there is increased nonrandom mating, which leads to reproductive outcomes that have been previously unknown.19 Homozygous achondroplasia is lethal, and many newborns who inherit two dominant mutations (compound heterozygotes) die early with severe abnormalities of the skeleton.20 It also is important to obtain an accurate history relative to the onset of short stature, and whether it developed immediately in the postnatal period or was noticed at age 2 or 3. Of the 300 skeletal dysplasias, approximately 100 of them have onset in the prenatal period, but many affected individuals do not develop disproportionate short stature and joint discomfort until childhood.21 A detailed physical examination may reveal a diagnosis or help differentiate the most likely group of possible diagnoses. It is crucial when disproportion and short stature have been established and the limbs are involved to determine which segment is involved: upper segment (rhizomelic—humerus and femur), middle segment (mesomelic—radius, ulna, tibia, and fibula), and distal segment (acromelic—hands and feet). Numerous head and facial dysmorphisms are seen in the skeletal disorders. Affected individuals frequently have disproportionately large heads. Frontal bossing and flattened nasal bridge is characteristic of ­achondroplasia, one of the most common skeletal dysplasias.22 Cleft palate and micrognathia are commonly found in the type II collagen abnormalities, abnormally flattened midface with a turnedup nose is frequently found in the chondrodysplasia punctata disorders,23 and abnormal swollen pinnae are seen in diastrophic dysplasia.24 Individuals with skeletal dysplasias should be screened for ophthalmologic and hearing abnormalities because some of these disorders are associated with eye abnormalities and hearing loss.

.80 1.00 U/L 1.25 Figure 96-2  Upper segment length/lower segment length (U/L) in  8- to 10-year-old individuals with short limb and short trunk dwarfism. The child on the left has short limbs and an increased U/L ratio; the child

Further evaluation of the hands and feet can lead to further differentiation of these disorders. Postaxial polydactyly is characteristically found in chondroectodermal dysplasia and the short-rib polydactyly disorders (see Table 96-1). Short, hypermobile, radially displaced thumbs are seen in diastrophic dysplasia. Nails can be abnormally hypoplastic in chondroectodermal dysplasia and short and broad in cartilage hair hypoplasia. Clubfeet may be seen in many disorders, including Kneist dysplasia, spondyloepiphyseal dysplasia congenita, Larsen syndrome, OI types II and III, and diastrophic dysplasia. Bone fractures occur most commonly in two types of disorders—those that result from undermineralized bone (OI, hypophosphatasia, achondrogenesis IA), or those that result from overmineralized bone (osteopetrosis syndromes and dysosteosclerosis). Organ systems other than the skeleton can be involved, although rarely. Congenital cardiac defects are seen in chondroectodermal dysplasia (atrial septal defects), the short-rib polydactyly disorders (complex outlet defects including isolated ventricular septal defects), and Larsen syndrome (ventricular septal defects). Gastrointestinal anomalies are rare among the skeletal disorders, but congenital megacolon can be seen in cartilage hair hypoplasia, malabsorption syndrome in Schwachmann-Diamond syndrome, and omphaloceles in otopalatodigital syndrome and atelosteogenesis I. DIAGNOSIS AND TESTING After obtaining a thorough family history and physical examination, the next step is to obtain a full set of skeletal radiographs. A full series of skeletal views includes anterior, lateral, and Towne views of the skull; anterior and lateral views of the entire spine; and anteroposterior views of the pelvis and extremities, with separate views of the hands and

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Figure 96-3  Radiographs showing abnormalities in the chondrodysplasias, specifically pseudoachondroplasia. A, Irregular metaphyses and small epiphyses.  B, Small, rounded vertebrae with anterior beaking.

feet, especially after the newborn period. Most of the important clues to diagnosis are in skeletal radiographs that are obtained before puberty. When the epiphyses have fused to the metaphyses, determining the precise diagnosis can be extremely challenging. If an adult is evaluated, all attempts should be made to obtain any available childhood ­radiographs. Many subtle clues in these skeletal radiographs can lead to precise diagnosis. Punctate calcifications in the areas of the epiphyses in the chondrodysplasia punctata disorders, multiple ossification centers of the calcaneus in more than 20 disorders,25 and the type of hand shortening can aid in differentiating many disorders. After obtaining radiographs, close attention should be paid to the specific parts of the skeleton (spine, limbs, pelvis, skull) involved and to the location of the lesions (epiphyses, metaphyses, and vertebrae) (Fig. 96-3). As mentioned earlier, these radiographic abnormalities can change with age, and if available, radiographs across a few years or

Figure 96-4  Radiographs illustrating skeletal differences among variants of osteogenesis imperfecta (OI). A, Dominant OI—mild, with minimal deformity. B, Moderate OI—mild epiphyseal dysplasia. C, Severe OI— marked diaphyseal narrowing and widening of the metaphysis with severe epiphyseal dysplasia. Lethal OI is not illustrated.

A

B

A

decades aid in diagnosis. Fractures can be seen in OI (all types) (Fig. 96-4; see Table 96-1) and severe hypophosphatasia. In older individuals, fractures may be seen in disorders associated with increased mineralization, such as the osteopetrosis syndromes and dysosteosclerosis. When a thorough evaluation of the radiographs reveals abnormalities, but a diagnosis still cannot be made, resources are available. The International Skeletal Dysplasia Registry (http://www.csmc. edu/3805.html) is available to provide diagnosis for these rare disorders. Morphologic studies of chondro-osseous tissue have revealed specific abnormalities in many of the skeletal dysplasias.26-28 In these disorders, histologic evaluation of chondro-osseous morphology can aid in making an accurate diagnosis, and absence of histopathologic alterations can rule out diagnoses. These studies need to be done on cartilage growth plate, and although commonly performed on perinatal lethal skeletal disorders at autopsy, ­ obtaining

B

C

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CARTILAGE, BONE, AND HERITABLE CONNECTIVE TISSUE DISORDERS

Figure 96-5  Electron micrograph of a chondrocyte from an individual with pseudoachondroplasia. Note the characteristic lamellar pattern in the rough endoplasmic reticulum.

growth plate histology on individuals with nonlethal disorders is difficult. If affected individuals (children) are undergoing surgery, an iliac crest biopsy specimen can be evaluated. Histomorphology studies done on these disorders have led to important insights on the pathogenesis of these disorders. On morphologic grounds, the chondrodysplasias can be broadly classified into disorders (1) that have a qualitative abnormality in endochondral ossification, (2) that have abnormalities in cellular morphology, (3) that have abnormalities in matrix morphology, and (4) in which the abnormality is primarily localized to the area of chondro-osseous transformation. In thanatophoric dysplasia, there is a defect in endochondral ossification with a very short, almost hypertrophic zone, shortened proliferative zone, and overgrowth of the periosteum; in pseudoachondroplasia, there is a distinct lamellar pattern (alternating electron-dense and electron-lucent lamellae) in the rough endoplasmic reticulum of chondrocytes (Fig. 96-5) and a grossly abnormal matrix in diastrophic dysplasia, which leads to a characteristic ring around the chondrocytes. All of these findings are characteristic and diagnostic for these disorders and illustrate how morphology studies can have an integral part in the investigation of these disorders. There has been significant progress in gene identification in these disorders, which has impact for affected individuals. As illustrated in Table 96-1, for disorders in which the gene is identified, molecular diagnostic testing is potentially available. Molecular diagnosis can be used to confirm a clinical and radiographic diagnosis, predict carrier status in families at risk for a recessive disorder, and, for some individuals, allow for prenatal diagnosis of at-risk fetuses. Because these are rare disorders, commercial testing is not always readily available; however, GeneTests (www.genetests.org) is a publically funded medical genetics website developed for physicians that provides information on diseases and available genetic testing. MANAGEMENT AND TREATMENT The optimal management of this diverse set of disorders requires an understanding of the medical, skeletal, and psychosocial consequences. This is often best accomplished

1641

by centers that have a multidisciplinary approach, which includes adult and pediatric physicians, orthopaedists, rheumatologists, otolaryngologists, neurologists, neurosurgeons, and ophthalmologists who are committed to the care of these patients. Most medical complications in these disorders result from orthopaedic complications, and they vary depending on the specific disorder. In disorders associated with significant odontoid hypoplasia, such as Morquio disease, type II collagenopathies, metatropic dysplasia, and Larsen syndrome, flexion-extension films should be monitored at regular intervals to assess for C1-C2 subluxation. If there is evidence for subluxation, surgery for C1-C2 fixation is indicated. Genu varum—lateral curvature of the lower extremity—is common in many skeletal disorders caused by overgrowth of the fibula; this causes knee or ankle pain in many individuals, especially children, and correction by osteotomy should be considered. Children and adults with skeletal dysplasias should have regular eye and hearing examinations because they are at increased risk for myopia, retinal degeneration, glaucoma, and hearing loss depending on the disorder. Frequently, patients with these disorders have significant joint pain and in some cases joint limitations. Because most of these disorders result from mutations in genes crucial to cartilage function, the cartilage at the joint surfaces may not provide adequate support and cushioning function. Many of these patients seek attention for joint pain. Evaluation should include radiographs and magnetic resonance imaging (MRI), when appropriate, to determine the etiology of the pain. In some disorders, such as the type II collagenopathies, pseudoachondroplasia, multiple epiphyseal dysplasia, and cartilage hair hypoplasia, by adulthood, so little cartilage remains at the knee or hips that joint replacement is indicated for pain relief. Lastly, overweight in adults with short stature is an ongoing issue and contributes to ­ inactivity, loss of function, adult-onset diabetes, hypertension, and coronary disease.29 Achondroplasia Achondroplasia is the most common of the nonlethal skeletal dysplasias (approximately 1 in 20,000) and serves as an example on how to approach these disorders. Most affected individuals are of normal intelligence, have a normal life span, and lead independent and productive lives. The mean final height in achondroplasia is 130 cm for men and 125 cm for women; specific growth charts have been developed to document and track linear growth, head circumference, and weight in these individuals.30,31 In early infancy, there is potentially serious compression of the cervicomedullary spinal cord secondary to a narrow foramen magnum, cervical canal, or both. Clinically, these infants have central apnea, sleep apnea, profound hypotonia, motor delay, or excessive sweating. MRI with flow studies is necessary to document the obstruction; if present, obstruction requires decompressive surgery.32 Other complications include nasal obstruction, thoracolumbar kyphosis, and hydrocephalus in a few individuals.32 From early childhood, and as children begin to walk, they develop several orthopaedic manifestations, which include progressive bowing of the legs owing to fibular overgrowth,

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lumbar lordosis, and hip flexion contractures. Recurrent ear infections can lead to chronic serous otitis media and deafness. Tympanic membrane tube placement is indicated in many of these patients. Craniofacial abnormalities lead to dental malocclusion, and appropriate treatment is ­necessary. In adults, the main potential medical complication is impingement of the spinal root canals. This complication can be manifested by lower limb paresthesias, claudication, clonus, or bladder or bowel dysfunction. It is crucial that these complaints are addressed because without appropriate decompression surgery, paralysis of the spinal cord can result.32 Growth hormone has not been effective in increasing height in this disorder.33 Surgical limb lengthening has been employed successfully to increase limb length by 12 inches,34 but this technique needs to be done during the teen years and is performed over a 2-year period and is associated with complications. Throughout their lives, individuals with achondroplasia and other skeletal dysplasias and their families experience various psychosocial challenges.35 These challenges can be addressed by specialized medical and social support systems. Interactions with advocacy groups such as Little People of America (http://www.lpaonline.org) can provide emotional support and medical information. BIOCHEMICAL AND MOLECULAR ABNORMALITIES Similarities in clinical and radiographic findings and histomorphology have placed bone dysplasia into families.36 These families share common pathophysiologic or pathway mechanisms. In recent years, there has been an explosion in understanding of the basic biology of these disorders. This explosion has resulted from the successful human genome project, which improved various methodologies, including candidate gene approach, linkage analysis, positional cloning, and human/mouse synteny allowing for identification of the disease genes (see Table 96-1). With gene discovery in more than 100 of these osteochondrodysplasias, these genes can be placed into several categories designed to understand their pathogenesis: (1) defects in extracellular proteins; (2) defects in metabolic pathways (enzymes, ion channels, and transporters); (3) defects in folding and degradation of macromolecules; (4) defects in hormones and signal transduction; (5) defects in nuclear proteins; (6) defects in oncogenes and tumor-suppressor genes; (7) defects in RNA and DNA processing molecules; (8) defects in intracellular structural proteins; and (9) genes of unknown function. There are still many skeletal dysplasias for which the chromosomal location and gene are unknown. Following are descriptions of some of the molecular mechanisms involved in the skeletal dysplasias.

DEFECTS IN EXTRACELLULAR STRUCTURAL PROTEINS TYPE II COLLAGEN AND TYPE XI COLLAGEN Because type II collagen was found primarily in cartilage, the nucleus pulposus, and the vitreous of the eye, it was hypothesized that skeletal disorders with significant spine and eye abnormalities would result from defects in type II collagen.

Type II collagen defects have been identified in a spectrum of disorders ranging from lethal to mild arthropathy, which include achondrogenesis II, hypochondrogenesis, spondyloepiphyseal dysplasia congenita, spondyloepimetaphyseal dysplasia, Strudwick type, Kniest dysplasia, Stickler syndrome, and “precocious” familial arthopathy. These disorders are referred to as type II collagenopathies, and they all result from heterozygosity for mutations in COL2A1.37,38 Biochemical analysis of cartilage derived from these individuals shows electrophoretically detectable abnormal type II collagen. Type I collagen is not normally present in cartilage, but in the presence of abnormal type II collagen, there is increased type I collagen in the growth plate. Mutations that result in a substitution for a triple helical glycine residue seem to be the most common type of mutation.39-41 There are some correlations between the location of the mutation and the disease phenotype. In spondyloepiphyseal dysplasia, the glycine substitutions are scattered throughout the molecule; however, in Kniest dysplasia, the mutations are in the more amino-terminal end of the molecule.42-44 Stickler syndrome (see Table 96-1) is genetically heterogeneous and results from mutations in COL2A1 and COL11A1, and nonocular forms result from mutations in COL11A2.45,46 In Stickler syndrome, the COL2A1 and COL11A1 mutations tend to be nonsense mutations resulting in premature translation stop codons; however, patients with COL11A1 mutations tend to have a more severe eye phenotype and hearing loss than patients with COL2A1 mutations. Individuals heterozygous for various COL11A2 mutations47 have a nonocular form of Stickler syndrome, consistent with the absent expression of COL11A2 in the vitreous humor. Otospondylomegaepiphyseal dysplasia is a rare autosomal recessive disorder caused by loss of function mutations in COL11A2.47 This disorder has radiographic similarities to Kniest dysplasia, but is associated with profound sensorineural hearing loss and lack of ocular involvement. CARTILAGE OLIGOMERIC MATRIX PROTEIN Heterozygosity for mutations in cartilage oligomeric matrix protein leads to pseudoachondroplasia and multiple epiphyseal dysplasia.48 Cartilage oligomeric matrix protein is a member of the thrombospondin family of proteins and consists of an epidermal growth factor domain and calcium binding, calmodulin domain.49 In pseudoachondroplasia and multiple epiphyseal dysplasia, disease-producing mutations occur in the calmodulin domain, with a few in the globular carboxy-terminal domain (Fig. 96-6). DEFECTS IN METABOLIC PATHWAYS Defects in metabolic pathways comprise defects in enzymes, ion channels, and transporters essential for cartilage metabolism and homeostasis. An example is the diastrophic dysplasia group (see Table 96-1), a spectrum of disorders (lethal to mild short stature) resulting from mutations in the DTDST gene. These disorders result from a varying defect in the degree of sulfate uptake or transport into chondrocytes.50 Lack of adequate intracellular sulfate affects the normal post-translational modification of proteoglycans and leads to abnormal chondrogenesis that is proportional to the degree of transporter compromise.50

PART 15 

NH2

2

3

4

CARTILAGE, BONE, AND HERITABLE CONNECTIVE TISSUE DISORDERS

1

2

3

4

5

6

7

8

G465D G440R ?D469 G440E ?D469

PSACH

D519N T585M

C328R ?D372 N386D ?391-394V

MED

T585R

D408Y D342Y D361Y G368R

N453S

DEFECTS IN INTRACELLULAR STRUCTURAL PROTEINS Intracellular proteins are ubiquitously expressed proteins; the finding that mutations in the genes encoding filamin A and filamin B produced primarily skeletal disorders was surprising.51-53 The filamins are cytoskeleton proteins involved in multicellular processes, including providing structure to the cell, facilitating signal transduction and transport of small solutes, allowing communication between the intracellular and extracellular environment, and participating in cell division and motility. Defects in these genes have a profound effect on the skeleton ranging from absence of bone formation to significant joint dislocations. The mechanisms by which these mutations produce disease are unclear. SUMMARY Although these osteochondrodysplasias are rare disorders, affected individuals have significant skeletal complications throughout their lives, first owing to patterning defects, then effects on linear growth, and finally loss of normal ­structural cartilage as a cushion later in life. The explosion in ­ delineating the molecular defects has shown the complexity of cartilage as a tissue and the large number of cellular processes necessary for a normal skeleton.

OSTEOGENESIS IMPERFECTA OI is a heritable disorder of bone and was one of the first disorders hypothesized to be a defect in collagen by McKusick.1 Although an osteochondrodysplasia, OI is discussed separately from the chondrodysplasias delineated previously. OI is a generalized disorder of connective tissue that predominantly affects the skeletal system54 and affects numerous individuals (estimates at about 1 in 20,000 individuals). Initially, there were four types of recognized OI in the clinical classification of Sillence.55 There are now seven types of recognized OI, and because there is enormous clinical variability in these types, the subtypes are discussed separately (Table 96-2). These disorders all share the same phenotypic finding of hypomineralization of the skeleton.

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COOH

Calmodulin-like repeats

EGF-like repeats 1

| 

N523K

Figure 96-6  Diagram of the cartilage oligomeric matrix protein  (COMP) delineating the domains— NH2 amino terminus, EGF-like (epidermal growth factor-like), calmodulin-like, COOH (carboxy-terminus), PSACH (pseudoachondroplasia), and MED (multiple epiphyseal dysplasia). Amino acid substitutions are listed below the molecule.

MILD OSTEOGENESIS IMPERFECTA (TYPE I) Affected individuals with OI type I disease have mild disease in terms of clinical course, the extent of skeletal deformity, and the radiologic appearance of the skeleton (see Fig. 96-4A and Table 96-2). They also account for most individuals with OI. Individuals are usually short for their age or their unaffected family members. Many of these individuals experience numerous fractures, especially in childhood; children with OI type I may have 20 fractures by the age of 5. The disorder is autosomal dominant, and in many cases the individual is the first affected in the family. There is mild facial dysmorphism in OI type I with a mild triangular facial shape. The sclerae are blue that become gray-topale blue in adulthood. Arcus senilis not related to lipid abnormalities may occur in some patients. Other reported ocular defects include scleromalacia, keratoconus, and retinal detachment.56 The teeth frequently show dentinogenesis imperfecta owing to the effects of mutation on the tooth dentin. The deciduous and permanent teeth have an opalescent and translucent appearance, which tends to darken with age. The enamel is normal, but the dentin is dysplastic; chipping of enamel occurs, and the teeth are subjected to erosion and breakage. Teeth of affected individuals appear discolored or gray. This finding varies in the disorder, but does cosegregate in families with OI. Dentinogenesis imperfecta can be seen in all forms of OI. During the second and third decades of life, a characteristic high-frequency sensorineural or mixed hearing loss can be detected.57 The incidence of mitral valve prolapse is not increased in these patients compared with the population at large, but individual kindreds with increased diameter of the aortic root or patients with aortic regurgitation have been reported.58 Many patients complain of easy bruising, and this may result from the effects of mutation on skin and the vessels below. Mildly affected patients may not have fractures at birth, although occasionally a fracture of a clavicle or extremity occurs during delivery. Radiographically, affected newborns have wormian bones seen on lateral views of the skull, with significant osteopenia seen through the skeleton, especially the spine. After birth, the frequency of fracture depends on the child’s activity, the need for

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Table 96-2  Characteristics of Osteogenesis Imperfecta Type

Clinical Features

Inheritance

Biochemical Abnormality

Gene

I

Normal stature; little or no ­deformity;   blue sclerae; hearing loss;   ­dentinogenesis imperfecta

AD (new mutations are   common)

50% reduction in type I ­  collagen synthesis

COL1A1

II

Lethal; minimal calvarial mineralization;   beaded ribs; compressed femurs;   long bone deformity

AD (new mutations; ­  mosaicism)

Structural alterations of   type I collagen chains— ­overmodification of type I   collagen

COL1A1

AR (rare)

III

Progressively deforming bones;   ­dentinogenesis imperfecta; hearing   loss; very short stature

AD

COL1A2 CRTAP P3H1 Structural alterations of   type I collagen chains— ­overmodification of type I   collagen

AR

COL1A1

COL1A2 CRTAP P3H1

IV

Normal sclerae in adult; mild-­  to-­moderate deformity; variable short   stature; dentinogenesis imperfecta;   some hearing loss

AD

Structural alterations of   type I collagen chains— ­overmodification of type I   collagen

COL1A1 COL1A2

V

Similar to type IV plus calcification of   interosseous membrane of forearm;   hyperplastic callus formation

AD

None described

Unknown

VI

Similar to type IV with vertebral   ­compression; mineralization defect

Unknown

None described

Unknown

VII

Moderate-to-severe; fractures at birth;   early deformity and rhizomelia

AR

None described

CRTAP

AD, autosomal dominant; AR, autosomal recessive; CRTAP, cartilage-associated protein; P3H1, prolyl-3-hydroxylase 1.

immobilization after lower extremity fractures, and the attitude of the family toward independent activity. Generally, these patients may experience 5 to 15 major fractures before puberty and several minor traumatic fractures of the digits or the small bones of the feet. Characteristically, the fracture rate declines dramatically after puberty, only to increase during later life. Mild scoliosis approximating 20 degrees is common. Osteopenia is observed in vertebral bodies and the peripheral skeleton and progresses with age. In OI type I, the long bones usually heal with no significant deformity. Compared with more severe phenotypes, children with OI type I only infrequently require the insertion of intramedullary rods and almost never experience nonunion at a fracture site. Although osteopenia with rarefaction of the medullary space and cortical thinning are observed in radiographs, many OI type I cases are so mild as to be missed on routine radiographic examination. Measurement of bone mineral density by dual-energy x-ray absorptiometry at any age discloses a significant decrease in bone mass.59 T scores (i.e., standard deviation from the young-adult mean bone mineral density) are frequently in the range of −2.5 to −4.0 at the lumbar spine or proximal femur, consistent with the diagnosis of osteoporosis as defined by the World Health Organization. Low bone mineral density in children with recurrent fractures may assist in identifying children with OI.

Molecular Pathology As in other phenotypes, OI type I is the result of mutations affecting the COL1A1(I) and COL1A2(I) polypeptide chains of type I collagen. Cultured fibroblasts from individuals with mild OI synthesize low amounts (approximately one half) of the expected amounts of type I collagen. The molecular basis for the low production of type I collagen seems to be diminished activity of one of the COL1A1(I) or COL1A2(I) collagen alleles. Many of the reported mutations in OI type I are nonsense and frameshift mutations and are predicted to lead to premature termination codons, although there are some exceptions.60,61 LETHAL OSTEOGENESIS IMPERFECTA (TYPE II) Approximately 10% of OI patients have the severe neonatal form of the disease, lethal OI. Most cases result from sporadic mutations; however, more recently, a recessive form of the disease has been documented.62-64 These infants present with severe bone fragility, multiple intrauterine fractures at various stages of healing, deformed extremities, and occasionally hydrops fetalis (Fig. 96-7). Radiographic features include wormian bones, multiple fractures, crumbled bones, and characteristic beading of the ribs owing to healing callus formation. There is a subtype of the lethal form, OI type IIC, which is autosomal recessive and is differentiated by the absence of beaded ribs (thin ribs).

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SEVERELY DEFORMING OSTEOGENESIS IMPERFECTA (TYPE III)

Figure 96-7  Radiograph of lethal osteogenesis imperfecta (type II) showing poorly mineralized calvaria, bent, crumbled bones, and ribs with fractures and callus formation.

Molecular Pathology Most cases occur de novo, as new dominant mutations; however, an autosomal recessive form has been established, as has recurrence based on germline mosaicism.62-65 The biochemical abnormality in lethal OI is the inability to synthesize and secrete normal type I collagen.66 As a result, the amount of type I collagen in bone is low, much of the secreted collagen is abnormally overmodified, and the quantity of the minor collagen types III and V is high. Bone collagen fibers are thinner than normal, and at the intracellular level, type I collagen is retained within dilated endoplasmic reticulum. Similar to other forms of OI, mutations in the genes encoding COL1A1 and COL1A2A lead to the dominant form or de novo form of lethal OI.67 Single glycine substitutions with the Gly-X-Y triplet of either COL1A1 or COL1A2 lead to this form of OI, as do some small deletions, all producing severe effects on the triple helix. The recessive form accounts for a few of these cases and results from mutations in the genes encoding either CRTAP (cartilage associated protein) or P3H1 (prolyl-3-hydroxylase 1).64 These molecules form a complex that hydroxylates (add an -OH group) to a third position residue at proline 986 (Pro986). This modification of a single residue stabilizes the collagen helix.64 Nonsense or frameshift mutations predicted to lead to premature termination codons and absent function of CRTAP or P3H1 produce this form of OI.

The deforming variant of OI is the classic form of OI. Similar to lethal OI (OI type II), most cases are inherited as autosomal dominant (or a de novo mutation), although recurrent cases based on autosomal recessive inheritance owing to CRTAP or P3H1 mutations have been described more recently.62-64 This variant is characterized by severe deformity of the limbs and marked kyphoscoliosis, ­ thorax deformity, and significant short stature. The extent of growth retardation is remarkable, and in many adults the height may not surpass 3 feet (90 to 100 cm). Abnormal cranial molding occurs in utero and during infancy, producing frontal bossing and a characteristic triangular-shaped facies. Radiographically, wormian bones and delayed closure of the fontanelles may be observed well into the first decade. Pulmonary function can be diminished because of distortion of the spine and thorax, and this can progress over time and lead to restrictive lung disease and sleep apnea. Because of diminished vital capacity, pulmonary insufficiency is a leading cause of death in patients with OI type III. Many patients with scoliosis greater than 60 degrees develop respiratory compromise and need pulmonary investigations. Many of these individuals need supplemental oxygen. Platybasia secondary to soft bone at the base of the skull may cause the external ear canals to slant upward as the base of the skull sinks on the cervical vertebrae; this may lead to communicating or obstructive hydrocephalus, cranial nerve palsies, and upper and lower motor neuron lesions. Headache, diplopia, nystagmus, cranial nerve neuralgia, decline in motor function, urinary dysfunction, and respiratory compromise are complications of basilar invagination.68 As opposed to OI type I, most affected OI type III patients have white sclerae as adults. Approximately 25% of patients with type III OI have dentinogenesis imperfecta, necessitating constant dental care throughout childhood. Severe hearing impairment occurs in 10% of patients, although milder degrees of hearing loss are more common. The skeleton in these patients has significant osteopenia, leading to multiple fractures in the upper and lower extremities and vertebral bodies, particularly before puberty. In contrast to OI type I, in which fractures tend to heal without deformity, fractures in OI type III frequently lead to skeletal deformity. Radiographs of the skeleton reveal marked osteopenia, thinning of cortical bone, narrowing of the diaphysis, and widening of the metaphysis, which merges into a dysplastic epiphyseal zone filled with whorls of partially calcified cartilage (i.e., popcorn deformity) (see Fig. 96-4C).81 Osteoporosis leads to collapse of vertebral end plates contributing to worsening kyphoscoliosis. Pectus excavatum or pectus carinatum adds to thoracic deformity. In addition, lack of weight bearing increases the severity of osteoporosis and increases the risk of fracture. Many individuals become wheelchair bound at an early age or walk with mechanical assistance. Molecular Pathology The molecular basis of OI type III is very similar to OI type II. Most cases result from heterozygosity for mutations in COL1A1(I) and COL1A2.1 These mutations are glycine substitutions scattered throughout the triple helix and ­

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in-frame deletions.69 As in OI type II, familial recurrences result from mutations in CRTAP and P3H1 and rare cases of germline mosaicism. OSTEOGENESIS IMPERFECTA OF MODERATE SEVERITY (TYPE IV) Clinically, the phenotype of patients with moderately severe OI (OI type IV) falls between the milder OI type I and OI type III. In most cases, OI type IV is inherited in an ­ autosomal dominant fashion. Fractures occur rarely at birth, and some patients may not have an initial fracture until later in the first decade. The extent of skeletal deformity involving the spine, thorax, and extremities is usually intermediate between that of OI types I and III, and these patients have short stature and frequently have scoliosis. Patients may have some mild facial dysmorphisms, but not as severe as OI type III. Hearing loss occurs, but less than in OI types I and III. Most fractures occur during childhood and may reoccur during the postmenopausal period in women or in men older than age 50 years. Long bone deformity tends to develop after fractures, which may lead to a difficulty in ambulation. Radiographs of the long bones and vertebral bodies show marked osteopenia with vertebral collapse. Although there is marked cortical thinning, bowing, and coarsening of trabeculae, the overall architecture of the bone is normal (see Fig. 96-4B). Molecular Pathology The molecular mechanisms for OI type IV are similar to the other forms. The mutations are in COL1A1(I) and COL1A2(I) and include glycine substitution and in-frame deletions.69,70 At present, there is no evidence for an autosomal recessive form of OI type IV. OSTEOGENESIS IMPERFECTA TYPE V OI type V was reported in 2000 as a variant within the heterogeneous group classified under OI type IV.71 In the initial report of seven OI patients, the phenotype was distinguished by the following criteria: moderate fracture history, hyperplastic callus formation, limitation in forearm pronation and supination as a result of intramembraneous bone formation at the joint, normal sclerae, and no dentinogenesis imperfecta. Bone biopsy specimens showed a meshlike appearance of irregularly spaced lamellae, different from the woven bone seen in OI types II, III, and IV. The etiology of this rare form has not been established, but it does not result from mutations in COL1A1(I) or COL1A2(I). OSTEOGENESIS IMPERFECTA TYPE VI The brittle bone phenotype OI type VI also was reported among the heterogeneous OI type IV group of patients. Characteristic among the eight subjects was the occurrence of a first fracture at an early age (4 to 18 months old).72 The bone is severely brittle, and affected patients have white sclerae. All patients had vertebral compression fractures, and patients showed elevated serum alkaline phosphatase levels. No type I collagen mutations were identified in this cohort.

OSTEOGENESIS IMPERFECTA TYPE VII In addition to OI types V and VI, Glorieux reported on an autosomal recessive form of OI and used the designation OI type VII.72a This form occurred with a small genetic isolate among the First Nations community in northern Quebec, Canada (S89). The phenotype includes fractures at birth, blue sclerae, osteopenia, rhizomelia, and deformities of the lower extremities. The disorder has been localized to ­chromosome 3p22-24 and has been shown to result from a hypomorphic allele in CRTAP.64 HISTOPATHOLOGY OF BONE IN OSTEOGENESIS IMPERFECTA The range of histologic appearances of bone in the different OI phenotypes is as variable as the clinical phenotypes. Undermineralization and overmineralization of bone have been recognized within the same specimen.73 Bone histomorphology appears relatively normal in OI type I, but osteopenia secondary to thin lamellar plates and diminished cortical width is evident. Immature woven bone and lamellar disarray are characteristic of more severe OI phenotypes.73 TREATMENT Over the years, there have been multiple attempts to treat OI with a variety of vitamins, hormones, and drugs, none of which has been successful. The list includes administration of mineral supplements, fluoride, androgenic steroids, ascorbic acid, and vitamin D. During the last decade, bisphosphonates administered parenterally or orally to children and adults have shown favorable results. The bisphosphonate pamidronate administered intravenously increased bone mass, decreased skeletal pain, and decreased fracture incidence in children with severe OI.74 Similar results involving cyclic administration of pamidronate have been reported by other investigators.75 Dosage regimens in different series for children and adults range from 1 to 3 mg/ kg, administered intravenously at 2- to 4-month intervals; lower dosage regimens also have been reported.76 Generally, reports indicate a significant increase in bone mass in children and a decrease in fracture rate. The effect is most marked in the spine, where vertebral remodeling may improve vertebral height. Metabolic studies have shown a decrease in serum ionized calcium and increase in serum parathyroid hormone. Urinary excretion of N-telopeptide as an index of bone resorption decreased from 61% to 73%. The major side effects of intravenous bisphosphonate treatment include the acutephase response (24 hours after infusion) and the occurrence of otitis and vestibular imbalance in a few patients. The currently recommended treatment regimen includes the use of a bisphosphonate, with adequate calcium and vitamin D supplementation to avoid the occurrence of hypercalciuria and to maintain normal serum vitamin D levels. The use of surgery to correct deformities and to facilitate weight bearing has been the subject of several reviews.77 Multiple osteotomies and realignment of a deformed bone over intramedullary rods is an option for many children with severe bowing.78 Indications include frequent fractures

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at the apex of the bow, impaired standing, and limb-length inequality owing to bowing.79 Expanding (telescoping) rods are best for growing children because they require fewer revisions. Spinal deformities are common and usually progressive. Surgical stabilization is most advisable in the teen years or early adulthood when patients are best able to tolerate these complex reconstructions.80,81 Early basilar invagination may be halted with prophylactic posterior fusion of the occipital-cervical junction with plate fixation.82 Patients with severe brainstem compression may require anterior transoral decompression and posterior instrumented fusion. Patients with various types of OI seem to be at increased risk of premature osteoarthritis, and the reasons for this are unclear. Total joint arthroplasty is usually successful in these patients, and referral is appropriate if arthroplasty is indicated.83 Every child with OI benefits from appropriate rehabilitative therapy.84,85 Bracing with lightweight plastics as the child begins to walk can minimize microfracture and bowing of the upper femurs. Muscle strengthening exercises are essential as primary care and after immobilization for fracture. Perhaps the most beneficial programs have been developed around swimming, preferably in heated pools, and as part of continuous rehabilitative medical care.

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EHLERS-DANLOS SYNDROME The heterogeneous group of disorders grouped together as EDS illustrates the genetic and clinical variability characteristic of the heritable disorders of connective tissue. The most cardinal feature of these disorders is the presence of joint hypermobility, associated with an increase in skin elasticity and skin fragility. In 1997, a simplified classification was proposed dividing EDS into six major clinical types. The classification includes the classic, hypermobility, vascular, kyphoscoliosis, arthrochalasia, and dermatosparaxis types, and several rarer EDS types grouped into “other forms.”86 Clinically, EDS can be difficult to separate, however, because of considerable overlap in phenotype findings. CLASSIC TYPE The classic type of EDS accounts for about 80% of reported cases87 and is inherited as an autosomal dominant trait. Originally, EDS was classified as types I and II, and now these types are classified as the classic form, although these subclassifications are still in use. Previously, types I and II EDS were distinguished from each other based on joint laxity and skin fragility, which are less severe in type I than in type II EDS. Most prototypic forms of EDS (Fig. 96-8) are characterized by various degrees of hyperextensibility of large and small joints, which are classic findings in EDS. It is crucial that hyperextensibility be defined, and differentiating mild “normal” laxity from hyperextensibility can be challenging. Beighton and colleagues86 have presented a clinically useful classification of joint laxity (Fig. 96-9), as follows: 1. Passive dorsiflexion of the fifth digit beyond 90 degrees = 1 point for each hand 2. Passive apposition of the thumbs to the flexor surface of the radius = 1 point for each hand 3. Hyperextension of the elbows beyond 10 degrees = 1 point for each side

C Figure 96-8  Ehlers-Danlos syndrome type I. A-C, Tissue elasticity, joint hypermobility, and tissue fragility are shown by the patient’s ability to extend her tongue to the tip of the nose (Gorlin’s sign) (A), by hyperextensibility at the knee (genu recurvatum) (B), and by characteristic “cigarette paper” or papyraceous scars of the knees and tibial skin (C). (Courtesy of V. McKusick, MD.)

4. Hyperextension of the knees beyond 10 degrees = 1 point for each knee 5. Flexion of the trunk forward so that the palms can be placed flat on the ground = 1 point A score of 5 or more points is defined as joint hypermobility. Large joint hyperextensibility is seen in varying degrees in the classic form and decreases with age. Recurrent joint dislocations, periodic joint effusion related to trauma, and the eventual appearance of osteoarthritis pose significant management problems. Bilateral synovial thickening has been observed in EDS, along with the accumulation of small masses of crystalline material in synovial villi. It has been observed that EDS patients constituted 5% of cases in a pediatric arthritis clinic population.88 There is debate about whether affected infants may be born prematurely to affected mothers because of early rupture of amniotic membranes. Patients with EDS have characteristic facies, with a broad nasal root and epicanthal folds. They may have large, lax ears, and traction on the ears or elbows reveals skin hyperextensibility. Another sign of hypermobility is the ability to touch the tip of the tongue to the nose (Gorlin’s sign). In addition, absence of the lingual frenulum is characteristic for this disorder.

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EDS type III may have virtually normal skin. Because of the extent of joint laxity affecting large and small joints, these patients experience multiple dislocations and may require surgical repair. The shoulders, patellae, and temporomandibular joints are frequently sites of dislocation. Musculoskeletal pain may mimic that of fibromyalgia syndrome, and patients frequently seek medical attention for symptoms consistent with chronic pain. One difficulty in this subtype is differentiating it from benign hypermobility syndrome. Benign hypermobility syndrome is used to describe patients with generalized joint laxity, associated musculoskeletal complaints, but normal skin.93 They do not have the classic stigmata of either EDS or Marfan syndrome. Many of these patients present in their 20s and 30s with rheumatologic symptoms that can pose problems in diagnosis and treatment. The precise approach and treatment for these patients are unclear. Structural and Molecular Pathology of the Classic and Hypermobile Types of Ehlers-Danlos Syndrome Figure 96-9  Maneuvers that may be used to establish the presence of clinically significant joint laxity found in Ehlers-Danlos syndrome. It is not unusual to find extreme laxity of the small joints and less laxity in large joints. Laxity decreases with age, so the dominant nature of most of these syndromes may not be appreciated when examining older family members. (Redrawn and modified from Wynne-Davies R: Acetabular dysplasia and familial joint laxity: Two etiological factors in congenital dislocation of the hip—a review of 589 patients and their families. J Bone Joint Surg Br 52:704, 1970.)

In EDS, the skin has a characteristically pleasant soft or “velvety” feel that can be appreciated by stroking the forearms. Thin, atrophic corrugated and hyperpigmented scars are found on the forehead, under the chin, and on the lower extremities (known as cigarette paper or papyraceous scars), although this is not a uniform finding. Typically, skin lesions heal slowly after injury or surgery. Molluscoid pseudotumors (violaceous subcutaneous tumors ranging in size from 0.5 to 3 cm) may be palpated in tissue over pressure points on the forearms and lower extremities and may be seen on radiographs. Although many patients claim to bruise easily, ecchymoses distributed on the extremities are found only in patients with the more severe forms of the disorder. Severe bilateral varicose veins are a common problem. Associated pulmonary complications of EDS include spontaneous pneumothorax, pneumomediastinum, and subpleural blebs.89 Mitral valve prolapse and tricuspid valve insufficiency may complicate classic EDS, and aortic root dilation has been reported, although the rate of progression is unknown.90,91 Skeletal abnormalities include thoracolumbar kyphoscoliosis; a long, giraffe-like neck; downward sloping of the ribs of the upper part of the thorax; and a tendency toward reversal of the normal cervical, thoracic, and lumbar curves. Anterior wedging of thoracic vertebral bodies occasionally is seen.92 HYPERMOBILITY TYPE The hypermobile type of EDS is a dominantly inherited disorder that manifests as marked joint and spine hypermobility, recurrent joint dislocations, and the typical soft skin that is neither hyperextensible nor velvety. Individuals with

Abnormally large, small, or frayed dermal collagen fibrils and disordered elastic fibers have been observed in the classic and hypermobile forms of EDS by electron microscopy.94 Type V collagen is a heterotrimeric collagen composed of the products of three genes, COL5A1(V), COL5A2(V), and COL5A3(V). Type V collagen may stabilize type I collagen by coassembling with that protein. Initially, linkage analysis was used to show that some families with the classic form of EDS (originally types I and II) were linked to COL5A1. Subsequently, it has been established that about 50% of patients with either the classic or the hypermobility type of EDS have mutations in COL5A1(V) or COL5A2(V). There seems to be no genotype-phenotype correlation in these disorders, and no mutations have been identified in COL5A3(V). In some cases of EDS classic type, heterozyosity for mutations in COL1A1(I) have been shown.94a VASCULAR TYPE The vascular type of EDS is an autosomal dominant disorder and one of the most severe forms of EDS and was formerly referred to as EDS type IV. It is associated with arterial rupture, commonly involving iliac, splenic, or renal arteries or the aorta and resulting in either massive hematomas or death.95 Arterial rupture may lead to stroke or intracompartmental bleeding in a limb. Patients with vascular EDS also are susceptible to rupture of internal viscera and may experience repeated rupture of diverticula on the antimesenteric border of the large bowel. Problems with pregnancy vary from preterm delivery to uterine or vascular rupture, although delivery is uneventful in many instances.96,97 Typical causes of death in EDS families have included gastrointestinal rupture, peripartum uterine rupture, rupture of the hepatic artery, and vascular ruptures. In contrast to the other forms of EDS, EDS type IV is not associated with hyperextensiblity of large joints, although small joints may be minimally hypermobile. These patients have thin, soft, transparent skin, through which a prominent venous pattern is seen, especially on their chest walls. Their skin is not velvety as in the classic form. Excessive bruisability may occur. Vascular EDS includes, as a subgroup, patients

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who have been described as acrogyric—having characteristically thin faces, prominent eyes, and extremities that lack subcutaneous fat, giving the appearance of premature aging. Peripheral joint contractures and acro-osteolysis have been described. Spontaneous hemopneumothorax associated with hemoptysis and mitral valve prolapse occurs frequently. Surgical repair of ruptured vessels or internal viscera is extremely difficult because of friable tissues. Anesthetic and surgical difficulties related to intubation, spontaneous arterial ­bleeding during surgery, and ligation of vessels that tear under pressure complicate surgical maneuvers. Similarly, arteriography may be dangerous in these individuals. These patients can be quite difficult to manage. Imaging studies may reveal normal-appearing aorta or other large vessels that rupture shortly after a “normal study.” Molecular Pathology Although EDS type IV was clinically recognized as a disorder distinct from the other forms of EDS, the finding that tissues from these individuals were deficient in type III collagen clearly distinguished this as a separate form of EDS. Type III collagen is a homotrimer [1(III)3] found in skin, blood vessels, and the walls of hollow viscera. Heterozygosity for mutations in the gene encoding COL3A1 leads to EDS vascular type and affects the synthesis and secretion of type III collagen.98,99 Various types of mutations have been identified, including missense, nonsense, and deletions, and there is no correlation between the clinical phenotype and type III collagen mutation.98,99 In this disorder, the ­biochemical abnormalities include decreased or absent type III collagen or production of an abnormal homotrimer that is retained in the endoplasmic reticulum and if secreted contributes to abnormal matrix. Biochemical and mutational analysis for this disorder is available (GeneTests) and should be considered because this is dominantly inherited. THERAPY IN CLASSIC, HYPERMOBILITY, AND VASCULAR TYPES OF EHLERS-DANLOS SYNDROME There are no specific treatments for the classic, hypermobility, and vascular forms of EDS. Supportive therapy is essential, however, for preservation of normal joint function and alleviation of joint pain. Planned exercise programs and muscle strengthening exercises are useful and do much to maintain a positive outlook in these individuals, who may have a poor prognosis if joint stability and articular surfaces are compromised by excessive activity or chronic trauma. Many children and young adults with large joint hypermobility are attracted to activities such as gymnastics and dance, and these activities promote hypermobility and joint damage. The presence of multiple ecchymoses raises concern about a bleeding diathesis, particularly at the time of elective surgery. Although there is no consistent basis for the hemorrhagic tendency in the classic and hyperextensibility forms of EDS, anecdotally, these patients tend to have greater blood losses than expected at surgery. In our center, we discourage pregnancy in patients with the vascular form because the mortality rate is increased.

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ARTHROCHALASIA TYPE Formerly known as EDS types VIIA and VIIB, the arthrochalasia type of EDS is another autosomal dominant form resulting from mutations that cause faulty processing of type I collagen at the N-terminus. The arthrochalasia type of EDS is characterized by pronounced and generalized joint hypermobility, moderate cutaneous elasticity, moderate bruising, a characteristic round facies with midface hypoplasia, and significant short stature. The skin has a doughy feel and is fragile and hyperelastic. Kyphoscoliosis and muscle hypotonia are frequently present. These patients experience multiple dislocations, particularly involving large joints, including the hips, knees, and ankles. These dislocations manifest in the newborn period, especially hip and ankle dislocations. Patients frequently need orthopaedic surgery for joint dislocation, and their tissues are highly friable, which complicates orthopaedic procedures. Molecular Pathology The two disorders EDS types VIIA and VIIB, now termed arthrochalasia type, result from mutations involving the N-terminal propeptide cleavage site of type I collagen.100 The arthrochalasia type of EDS has provided insight into the process of normal type I collagen fiber formation. The initial observation was of an accumulation of unprocessed procollagen within the dermis of affected individuals. With subsequent recognition that procollagen had N-terminal and C-terminal extension propeptides, and that separate enzymes were responsible for their removal, the syndrome became more sharply defined as an accumulation of procollagen with the N-terminal peptides still attached (pN collagen).101 Of the two distinctly different genetic abnormalities resulting in procollagen accumulation, the more frequent form is the mutational resistance of a procollagen cleavage site to the action of the N-terminal procollagen peptidase. The resistance results from an amino acid substitution or deletion in the proCOL1A11 (EDS type VIIA) or pro2COL2A1 (EDS type VIIB) chain, leading to a portion of the collagen chains containing an abnormal N-terminal extension; this results from mutations in COL1A11 or COL1A22 in exon 6 of the molecule, which alters the proteinase cleavage site.100 Individuals with mutations in exon 6 of COL1A11 are more severly affected than individuals with similar mutations in COL1A2.102 DERMATOSPARAXIS TYPE The dermatosparaxis type of EDS was formerly known as EDS type VIIC and is an autosomal recessive form of EDS. In this type, the skin is extremely fragile, soft, and doughy with easy bruising. The phenotype includes blue sclerae, marked joint hypermobility, micrognathia, large umbilical hernia, epiphyseal delay, and mild hirsutism.103 The dermatospa­ raxis type results from a deficiency of the procollagen N-propeptidase, in contrast to the arthrochalasia form, which involves the enzyme cleavage site, and individuals have been identified who are homozygous for mutations in the gene.104 This defect is homologous to the dermatospa­ raxis defect in sheep and cattle.105

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KYPHOSCOLIOSIS TYPE The kyphoscoliosis type of EDS, formerly known as EDS type VI, is inherited as an autosomal recessive disease. The findings in this disorder include severe kyphoscoliosis noted at birth, recurrent joint dislocations, hyperextensible skin and joints, poor tone, and reduced muscle mass.106 The skin is grossly abnormal and has been described as pale, translucent, and velvety; on trauma, the skin shows gaping wounds that heal poorly. One difference in this form of EDS is that there is significant ocular involvement. Affected individuals have microcornea, retinal detachment, and glaucoma leading to blindness in some individuals. In addition, patients with severe kyphoscoliosis may develop respiratory and cardiac compromise and ultimately cardiorespiratory failure. Molecular Pathology The kyphoscoliosis type of EDS results from lysyl hydroxylase deficiency.107 A variety of mutations within the lysyl hydroxylase gene have been defined and include premature stop codons, amino acid substitutions, internal deletions, and compound heterozygotes.107 Defective lysyl hydroxylase impairs the conversion of lysyl residues to hydroxylysine on procollagen peptides. The consequence of deficient hydroxylysine content of collagen is the effect it has on cross-linking, which helps stabilize the mature collagen molecule. OTHER EHLERS-DANLOS SYNDROME TYPES Numerous other rare forms of EDS have some overlap with other disorders or have been reported only in a small cohort of individuals, and these are not discussed in this chapter.

MARFAN SYNDROME One of the most common inherited disorders of connective tissue, Marfan syndrome is an autosomal dominant disorder with a reported incidence of 1 in 10,000 to 20,000 individuals.108 Clinical presentations range from the severe infantile form to individuals who are only mildly affected. Although the most impressive findings in Marfan syndrome are relative to the musculoskeletal, cardiac, and ocular findings, affected individuals also have pulmonary, neurologic, and psychological complications. Marfan syndrome also has become one of the few genetic disorders for which there has been advocacy for treatment to slow the progression of the disease, and physicians need to recognize the phenotype because many affected individuals present with life-threatening emergencies. CLINICAL FEATURES Marfan syndrome can be difficult to diagnose in some individuals and families, and it has been recognized that it also has been overdiagnosed. Stringent criteria for this diagnosis were proposed in 1996.108 The 1996 criteria rely on the recognition of “major” and “minor” clinical manifestations involving the skeletal, cardiovascular, dura, and ocular systems. Major criteria include four of eight typical skeletal manifestations, ectopia lentis, aortic root dilation involving the sinuses of Valsalva or aortic dissection, and ­lumbosacral

dural ectasia by computed tomography or MRI. Major criteria for establishing the diagnosis in a family member include having a parent, child, or sibling who meets major criteria independently, the presence of a fibrillin-1 mutation known to cause the syndrome, or a haplotype around fibrillin-1 inherited by descent and identified in a familial Marfan syndrome patient. Establishing the diagnosis unequivocally in the absence of a family history requires a major manifestation from two systems and involvement of a third system. If a mutation known to cause Marfan syndrome is identified, the diagnosis requires one major criterion and involvement of a second organ system. The reason is that there is a great deal of intrafamilial variability in this disorder, and there are individuals who harbor heterozygosity for mutations, but do not meet criteria for Marfan syndrome and may have different prognoses.109 Similar to other connective tissue disorders, there is wide variability in phenotypic expression. Aortic disease leading to the formation of aneurysmal dilation and dissection is the main cause of morbidity and mortality in Marfan syndrome.110 Dilation of the aorta is found in 50% of children and progresses over time. Echocardiography shows that 60% to 80% of adult patients have dilation of the aortic root that may involve other segments of the thoracic aorta, the abdominal aorta, or even the carotid and intracranial arteries. Dissection usually begins above the coronary ostia and extends the entire length of the aorta. Of Marfan syndrome patients, 60% to 70% have mitral valve prolapse with regurgitation. Heart failure and myocardial infarction may complicate the course of Marfan syndrome patients. Pregnant women are at particular risk for aortic dissection, particularly women who already have aortic root dilation, and this should be taken into consideration when treating a woman of reproductive age with Marfan syndrome.111 Arachnodactyly occurs in 90% of patients. Following are techniques that aid in determining arachnodactyly (Fig. 96-10): 1. The thumb: The Steinberg test is positive when the thumb, enclosed in the clenched fist, extends beyond the hypothenar border. 2. The wrist: The Walker-Murdoch sign is positive when there is overlap of the thumb and fifth digit as they encircle the opposite wrist. 3. The metacarpal: The metacarpal index is done by radiographic determination and is the mean value of the lengths divided by the midpoint widths of the second, third, and fourth metacarpals. In normal subjects, the metacarpal index ranges from 5.4 to 7.9, whereas this range is 8.4 to 10.4 in patients with Marfan syndrome. Thoracic kyphosis may be associated with reduced lung capacity and residual volume that may lead to pulmonary insufficiency. Dural ectasia, which may occur in 40% of patients, results from enlargement of the spinal canal owing to progressive ectasia of the dura and neural foramina and erosion of vertebral bone; this usually involves the lower spine.112 Diminished bone mineral density has been reported in several patients with Marfan syndrome.113 Ectopia lentis occurs in 50% to 80% of patients with Marfan syndrome. Subluxation of the lens is usually bilateral and appears by age 5 years. Although the lens is typically displaced upward, displacement into any quadrant may occur. Visual acuity is diminished in many patients because of lens subluxation

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Normal hands

Marfan syndrome

Elongated finger and arm bones

Figure 96-10  Marfan syndrome. The Steinberg test (thumb) and the Walker-Murdoch test (wrist) show arachnodactyly.

or secondary acute glaucoma. Secondary myopia, retinal detachment, and iritis with loss of vision contribute to most of the ocular related morbidity.114 Marfan syndrome patients have been found to develop large epidural venous plexuses in the lumbar and cervical regions, a major diagnostic criterion for the syndrome. These engorged venous plexuses, which are visualized by MRI myelography, have been associated with the syndrome of spontaneous intracranial hypotension, which also is associated with dural tears. Clinical signs are severe headache, back and leg pain, radiculopathies, and incontinence secondary to cerebral displacement.115 Spinal abnormalities in Marfan syndrome include increased interpedicle distance of nonrotated vertebrae, vertebral inversion (flattening of the normal kyphosis at the dorsal level and kyphosis or disappearance of the physiologic lordosis at the lumbar level), and vertebral dysplasia (dolichospondylic, elongated vertebral bodies with increased concavity). Scoliosis constitutes one of the major management problems in Marfan syndrome. In one series, the average age of onset was 10.5 years (range 3 to 15 years), with rapid progression during adolescence.116 If mechanical bracing or physical therapy fails to halt progression, spinal fusion should be considered, particularly when the curvature exceeds 45 to 50 degrees. DIFFERENTIAL DIAGNOSIS: HOMOCYSTINURIA Homocystinuria, which shares several skeletal and ocular features with Marfan syndrome, is the prime diagnostic consideration. Homocystinuria is an autosomal recessive disease. The characteristic features of this metabolic disorder of sulfur metabolism are marfanoid phenotype with joint laxity,

scoliosis, lens dislocation, early-onset osteoporosis, vascular thrombosis affecting arteries and veins owing to increased clotting activity and the cytotoxic effect of homocysteine on vascular endothelial cells, and mild mental retardation.117 Cystathionine β-synthase deficiency is the most common cause of homocystinuria.118 Affected individuals have elevated levels of homocystine and methionine levels, whereas cystathionine and cysteine levels in blood are decreased. This disorder is differentiated from Marfan syndrome because the direction of ectopia lentis is different than in Marfan syndrome, and there is no progressive aortic root dilation. MOLECULAR BIOLOGY OF MARFAN SYNDROME Fibrillin-1 protein is an important component of elastic and nonelastic connective tissues throughout the body.119 It is the main protein of a group of connective tissue microfibrils that are essential for normal elastic fibrillogenesis. In nonelastic tissues, the fibrillin-1-containing microfibril functions as an anchoring fiber. FBN-1 is a large gene (65 exons) located at chromosome 15q21.1. Since the first report of an FBN-1 mutation in Marfan syndrome in 1991, more than 500 different FBN-1 mutations have been described in Marfan syndrome and related disorders.120 FBN-1 mutations occur across a wide range of milder phenotypes that overlap the classic Marfan phenotype, including dominantly inherited ectopia lentis, Shprintzen-Goldberg syndrome, and familial or isolated forms of aortic aneurysms.121,122 Most of these are private mutations (occur genetically independent with no “hot spot” in the molecule). The one exception are the rare infantile Marfan syndrome mutations that cluster between exons 24 and

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26 and exon 32.123 Heterozygosity for missense, frameshifts, deletions and insertions, splice site alterations, and ­nonsense mutations all have been seen.124 Robinson and associates125 stated that at least 337 mainly unique mutations in the FBN-1 gene had been reported in Marfan syndrome up to that time. The clinical presentation of the fibrillinopathies caused by FBN-1 mutations ranged from isolated ectopia lentis to neonatal Marfan syndrome, which generally leads to death within the first 2 years of life. TREATMENT In 1972, the life span of untreated patients with classic Marfan syndrome was about 32 years. The early mortality in Marfan syndrome results primarily from complications associated with aortic dilation. This symmetric dilation of the sinuses of Valsalva is progressive throughout life and is often detectable in infancy. In the early 1970s, McKusick suggested that he might reduce the risk of aortic dissection in patients with Marfan syndrome.125a Shores and coworkers126 reported on a 10-year open-label trial of propranolol in 70 patients with Marfan syndrome. When compared with the control group, the treated individuals had a significantly slower rate of dilation of the aortic root, improved survival, and fewer treated patients reaching a clinical end point (death, congestive heart failure, aortic regurgitation, aortic dissection, or cardiovascular surgery). More recent data generated from a mouse model of Marfan syndrome suggest excessive signaling by the transforming growth factor (TGF)-β family of cytokines.127 There is evidence that aortic aneurysm in the mouse model of Marfan syndrome is associated with increased TGF-β signaling and TGF-β antagonists such as TGF-β-neutralizing antibody or the angiotensin II type 1 receptor blocker, losartan. In this mouse model, losartan (angiotensin II type 1 blockade) fully corrected the abnormalities in the aortic wall. There was some evidence that alveolar septation, which contributes to pulmonary problems in Marfan syndrome, was partially reversed with losartan treatment. The authors concluded that because this drug is in clinical use for hypertension, it merits further investigation as a preventive treatment in Marfan syndrome. Electrocardiogram monitoring is done yearly until the aortic root diameter exceeds 45 mm, at which time monitoring is done every 6 months. Elective repair of aortic root disease before enlargement to 6 cm has occurred is preferable to emergency repair required for marked dilation or dissection. Surgical intervention is considered when the aortic root diameter approaches twice the upper limit of normal for body surface area, or the absolute measurement exceeds 50 to 55 mm. Total aortic root replacement with a composite valve graft (Bentall procedure) and coronary artery implantation have become the surgical procedures of choice and are associated with an 81% 10-year survival rate and a 75% 20-year survival rate.128,129 Mitral valve replacement and coronary artery implantation may be accomplished during the same procedure. Most importantly, repeated trials have shown that patients who undergo elective repair, as opposed to emergent repair, do substantially better. Correction of scoliosis may be attempted with bracing; however, surgical repair should be considered when the curve exceeds 40 degrees. Progressive scoliosis in Marfan

syndrome may require fixation with rods, and complications of joint laxity may require orthopaedic correction. Arthropathy associated with excessive joint mobility may require orthopaedic intervention. Dislocated lenses should not be removed surgically, unless more conventional means of correcting vision are ineffective.

LOEYS-DIETZ SYNDROME In 2005, Loeys and colleagues130 described individuals with a previously undescribed autosomal dominant aortic aneurysm syndrome. This disorder, now referred to as LoeysDietz syndrome, also is characterized by hypertelorism, bifid uvula or cleft palate or both, and generalized arterial tortuosity with ascending aortic aneurysm and dissection. Other abnormal findings include craniosynostosis, structural brain abnormalities, mental retardation, congenital heart disease, and aneurysms with dissection throughout the arterial tree. Some individuals with Loeys-Dietz syndrome had a clinical phenotype that overlapped with Marfan syndrome, but none met diagnostic criteria set forth in 1996.108 Although Marfan syndrome is associated with progressive arterial disease, in Loeys-Dietz syndrome the aneurysms tended to be particularly aggressive and rupture at an earlier stage and size than seen in Marfan syndrome. Heterozygosity for mutations in TGFBR1 and TGFBR have been identified.130 From a management perspective, it is important to recognize these individuals because they are managed more aggressively than patients with Marfan syndrome. Aortic aneurysms are corrected at smaller sizes (4 cm), and complaints such as abdominal pain and headache should be thoroughly investigated because they may be associated with aneurysms.

CONGENITAL CONTRACTURAL ARACHNODACTYLY Congenital contractural arachnodactyly is an autosomal dominant condition that includes tall stature, arachnodactyly, dolichostenomelia, and multiple contractures involving large joints.131 There is a characteristic “crumpled ear” deformity as a result of a flattened helix with partial obliteration of the concha. Marked deformity of the chest cage also occurs, and scoliosis may be progressive and severe. For unknown reasons, the contractures tend to become less severe with age. Radiographically, osteopenia can be seen. The ocular and typical cardiac lesions of classic Marfan syndrome are absent. This disorder results from heterozygosity for mutation in fibrillin-2 (FNB-2).132 There are many other extremely rare disorders of connective tissue, especially with profound effects on the skin, including the group of disorders termed cutis laxa and pseudoxanthoma elasticum.133,134

SUMMARY Heritable disorders of connective tissues are a heterogeneous group of disorders characterized by abnormalities in skeletal tissues including cartilage, bone, tendon, ligament, muscle, and skin. The clinical spectrum ranges from extreme short stature to excessively tall individuals, and the types of altered genes span all of the numerous gene families and pathways. Affected individuals usually need medical

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CARTILAGE, BONE, AND HERITABLE CONNECTIVE TISSUE DISORDERS

attention their entire lives and have been victims of appearing different because they cannot mask their abnormalities. Understanding and appreciation for the unique set of medical issues in each disorder would improve these individuals’ quality of life and their life span.

REFERENCES   1. McKusick VA: Heritable Disorders of Connective Tissue. St Louis, CV Mosby, 1956.   2. Superti-Furga A, Unger S: Nosology and classification of genetic skeletal disorders: 2006 revision. Am J Med Genet A 143:1-18, 2007.   3. Orioli IM, Castilla EE, Barbosa-Neto JG: The birth prevalence rates for the skeletal dysplasias. J Med Genet 23:328-332, 1986.   4. Kornak U, Mundlos S: Genetic disorders of the skeleton: A developmental approach. Am J Hum Genet 73:447-474, 2003.   5. Rosenberg A: Bones and joints and soft tissue tumors. In Contran RS, Kumar V, Collins T (eds): Robbins Pathologic Basis of Disease, 6th ed. Philadelphia, WB Saunders, 1999, pp 1215-1221.   6. Karsenty G: Genetics of skeletogenesis. Dev Genet 22:301-313, 1998.   7. Dreyer SD, Zhou G, Lee B: The long and the short of it: Developmental genetics of the skeletal dysplasias. Clin Genet 54:464-473, 1998.   8. Shum L, Nuckolls G: The life cycle of chondrocytes in the developing skeleton. Arthritis Res 4:94-106, 2002.   9. Zelzer E, Olsen BR: The genetic basis for skeletal diseases. Nature 423:343-348, 2003. 10. Kuivaniemi H, Tromp G, Prockop DJ: Mutations in fibrillar collagens (types I, II, III, and XI), fibril-associated collagen (type IX), and network-forming collagen (type X) cause a spectrum of diseases of bone, cartilage, and blood vessels. Hum Mutat 9:300-315, 1997. 11. Eyre DR: Collagens and cartilage matrix homeostasis. Clin Orthop 427(Suppl):S118-S122, 2004. 12. Chan D, Ho MS, Cheah KS: Aberrant signal peptide cleavage of collagen X in Schmid metaphyseal chondrodysplasia: Implications for the molecular basis of the disease. J Biol Chem 276:7992-7997, 2001. 13. Eyre D: Collagen of articular cartilage. Arthritis Res 4:30-35, 2002. 14. McKusick VA: Heritable Disorders of Connective Tissue, 4th ed. St Louis, CV Mosby, 1972. 15. Rimion DL: Molecular defects in the skeletal chondrodysplasias. J Med Genet 63:106-110, 1996. 16. Superti-Furga A, Bonafe L, Rimoin DL: Molecular-pathogenetic classification of the skeleton. Am J Med Genet 106:282-293, 2001. 17. Edwards MJ, Wenstrup RJ, Byers PH, et al: Recurrence of lethal osteogenesis imperfecta due to parental mosaicism for a mutation in the COL1A2 gene of type I collagen: The mosaic parent exhibits phenotypic features of a mild form of the disease. Hum Mutat 1: 47-54, 1992. 18. Stevenson DA, Brothman AR, Chen Z, et al: Paternal uniparental disomy of chromosome 14: Confirmation of a clinically-recognizable phenotype. Am J Med Genet A 130:88-91, 2004. 19. Unger S, Korkko J, Krakow D, et al: Double heterozygosity for pseudoachondroplasia and spondyloepiphyseal dysplasia congenita. Am J Med Genet 101:140-146, 2001. 20. Pauli RM, Conroy MM, Langer LO, et al: Homozygous achondroplasia with survival beyond infancy. Am J Med Genet 16:459-473, 1983. 21. Lachman RS: Radiology of Syndromes, Skeletal and Metabolic Disorders, 4th ed. Chicago, Year Book Medical Publishers, 2007. 22. Hunter AG, Bankier A, Rogers JG, et al: Medical complications of achondroplasia: A multicentre patient review. J Med Genet 35: 705-712, 1998. 23. Sheffield LJ, Danks DM, Mayne V, et al: Chondrodysplasia punctata—23 cases of a mild and relatively common variety. J Pediatr 89:916-923, 1976. 24. Lamy M, Maroteaux P: Le nanisme diastrophique. Presse Med 68:1977-1980, 1960. 25. Cormier-Daire V, Savarirayan R, Unger S, et al: “Duplicate calcaneus”: A rare developmental defect observed in several skeletal dysplasias. Pediatr Radiol 31:38-42, 2001. 26. Rimoin DL: The chondrodystrophies. Adv Hum Genet 5:1-118, 1975.

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54. Rowe D, Shapiro J: Osteogenesis imperfecta. In Avioli I, Krane S (eds): Metabolic Bone Disease. Philadelphia, WB Saunders, 1990. 55. Sillence D: Osteogenesis imperfecta: An expanding panorama of variants. Clin Orthop 159:11-25, 1981. 56. Madigan WP, Wertz D, Cockerham GC, et al: Retinal detachment in osteogenesis imperfecta. J Pediatr Ophthalmol Strabismus 4:268-269, 1994. 57. Pedersen U: Osteogenesis imperfecta clinical features, hearing loss and stapedectomy: Biochemical, osteodensitometric, corneometric and histological aspects in comparison with otosclerosis. Acta Otolaryngol Suppl 415:1-36, 1985. 58. Hortop J, Tsipouras P, Hanley JA, et al: Cardiovascular involvement in osteogenesis imperfecta. Circulation 73:54-61, 1986. 59. Davie MW, Haddaway MJ: Bone mineral content and density in healthy subjects and in osteogenesis imperfecta. Arch Dis Child 70:331-334, 1994. 60. Willing MC, Cohn DH, Byers PH: Frameshift mutation near the 3′ end of the COL1A1 gene of type I collagen predicts an elongated Pro alpha 1(I) chain and results in osteogenesis imperfecta type I. J Clin Invest 85:282-290, 1990. 61. Mundlos S, Chan D, Weng YM, et al: Multiexon deletions in the type I collagen COL1A2 gene in osteogenesis imperfecta type IB: Molecules containing the shortened alpha2(I) chains show differential incorporation into the bone and skin extracellular matrix. J Biol Chem 271:21068-21074, 1996. 62. Cabral WA, Chang W, Barnes AM, et al: Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/ severe osteogenesis imperfecta. Nat Genet 39:359-365, 2007. 63. Barnes AM, Chang W, Morello R, et al: Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. N Engl J Med 355:2757-2764, 2006. 64. Morello R, Bertin TK, Chen Y, et al: CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell 127:291-304, 2006. 65. Edwards MJ, Wenstrup RJ, Byers PH, et al: Recurrence of lethal osteogenesis imperfecta due to parental mosaicism for a mutation in the COL1A2 gene of type I collagen: The mosaic parent exhibits phenotypic features of a mild form of the disease. Hum Mutat 1: 47-54, 1992. 66. Byers PH: Brittle bones—fragile molecules: Disorders of collagen gene structure and expression. Trends Genet 9:293-300, 1990. 67. Marini JC, Forlino A, Cabral WA, et al: Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: Regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. Hum Mutat 28:209-221, 2007. 68. Charnas LR, Marini JC: Communicating hydrocephalus, basilar invagination, and other neurologic features in osteogenesis imperfecta. Neurology 3:2603-2608, 1993. 69. Cohen-Solal L, Bonaventure J, Maroteaux P: Dominant mutations in familial lethal and severe osteogenesis imperfecta. Hum Genet 87:297-301, 1991. 70. Molyneux K, Starman BJ, Byers PH, et al: A single amino acid deletion in the alpha-2(I) chain of type I collagen produces osteogenesis imperfecta type III. Hum Genet 90:621-628, 1993. 71. Glorieux FH, Rauch F, Plotkin H: Type V osteogenesis imperfecta: A new form of brittle bone disease. J Bone Miner Res 15:1650-1658, 2000. 72. Glorieux FH, Ward LM, Rauch F: Osteogenesis imperfecta type VI: A form of brittle bone disease with a mineralization defect. J Bone Miner Res 17:30-38, 2002. 72a. Ward LM, Rauch F, Travers R, et al: Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease. Bone 31: 12-18, 2002. 73. Traub W, Arad T, Vetter U, et al: Ultrastructural studies of bones from patients with osteogenesis imperfecta. Matrix Biol 14:337-345, 1994. 74. Glorieux FH: Experience with bisphosphonates in osteogenesis imperfecta. Pediatrics 119:S163-S165, 2007. 75. Plotkin H, Rauch F, Bishop NJ, et al: Pamidronate treatment of severe osteogenesis imperfecta in children under 3 years of age. J Clin Endocrinol Metab 85:1846-1850, 2000. 76. Gonzalez E, Pavia C, Ros J, et al: Efficacy of low dose schedule pamidronate infusion in children with osteogenesis imperfecta. J Pediatr Endocrinol Metab 14:529-533, 2001.

77. Wilkinson JM, Scott BW, Clarke AM, et al: Surgical stabilisation of the lower limb in osteogenesis imperfecta using the Sheffield Telescopic Intramedullary Rod System. J Bone Joint Surg Br 80: 999-1004, 1998. 78. Zeitlin L, Fassier F, Glorieux FH: Modern approach to children with osteogenesis imperfecta. J Pediatr Orthop B 12:77-87, 2003. 79. Naudie D, Hamdy RC, Fassier F, et al: Complications of limb­lengthening in children who have an underlying bone disorder. J Bone Joint Surg Am 80:18-24, 1998. 80. Widmann RF, Laplaza FJ, Bitan FD, et al: Quality of life in osteogenesis imperfecta. Int Orthop 26:3-6, 2002. 81. Widmann RF, Bitan FD, Laplaza FJ, et al: Spinal deformity, pulmonary compromise, and quality of life in osteogenesis imperfecta. Spine 24:1673-1678, 1999. 82. Sawin PD, Menezes AH: Basilar invagination in osteogenesis imperfecta and related osteochondrodysplasias: Medical and surgical management. J Neurosurg 86:950-960, 1997. 83. Papagelopoulos PJ, Morrey BF: Hip and knee replacement in osteogenesis imperfecta. J Bone Joint Surg Am 75:572-580, 1993. 84. Binder H, Conway A, Gerber LH: Rehabilitation approaches to children with osteogenesis imperfecta: A ten-year experience. Arch Phys Med Rehabil 74:386-390, 1993. 85. Binder H, Conway A, Hason S, et al: Comprehensive rehabilitation of the child with osteogenesis imperfecta. Am J Med Genet 45: 265-269, 1993. 86. Beighton P, De Paepe A, Steinmann B, et al: Ehlers-Danlos syndromes: Revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet 77:31-37, 1998. 87. Hollister DW: Heritable disorders of connective tissue: EhlersDanlos syndrome. Pediatr Clin North Am 3:575-591, 1978. 88. Osborn TG, Lichtenstein JR, Moore TL, et al: Ehlers-Danlos syndrome presenting as rheumatic manifestations in the child. J Rheumatol 8:79-85, 1981. 89. Ayres JG, Pope FM, Reidy JF, et al: Abnormalities of the lungs and thoracic cage in the Ehlers-Danlos syndrome. Thorax 40:300-305, 1985. 90. Leier CV, Call TD, Fulkerson PK, et al: The spectrum of cardiac defects in the Ehlers-Danlos syndrome, types I and III. Ann Intern Med 92:171-178, 1980. 91. Tiller GE, Cassidy SB, Wensel C, et al: Aortic root dilatation in Ehlers-Danlos syndrome types I, II and III: A report of five cases. Clin Genet 53:460-465, 1998. 92. Coventry MB: Some skeletal changes in the Ehlers-Danlos syndrome: A report of two cases. J Bone Joint Surg Am 43A:855-860, 1961. 93. Kirk JA, Ansell BM, Bywaters EG: The hypermobility syndrome: Musculoskeletal complaints associated with generalized joint hypermobility. Ann Rheum Dis 26:419-425, 1967. 94. Holbrook KA, Byers PH: Skin is a window on heritable disorders of connective tissue. Am J Med Genet 34:105-121, 1989. 94a. Malfait F, Symoens S, DeBacker J, et al: Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers-­Danlos syndrome with a propensity to arterial rupture in early adulthood. Hum Mutat 28(4):387-395, 2007. 95. Hamel BC, Pals G, Engels CH, et al: Ehlers-Danlos syndrome and type III collagen abnormalities: A variable clinical spectrum. Clin Genet 53:440-446, 1998. 96. Gilchrist D, Schwarze U, Shields K, et al: Large kindred with EhlersDanlos syndrome type IV due to a point mutation (G571S) in the COL3A1 gene of type III procollagen: Low risk of pregnancy complications and unexpected longevity in some affected relatives. Am J Med Genet 82:305-311, 1999. 97. Rudd NL, Nimrod C, Holbrook KA, et al: Pregnancy complications in type IV Ehlers-Danlos syndrome. Lancet 1:50-53, 1983. 98. Anderson DW, Thakker-Varia S, Tromp G, et al: A glycine (415)-toserine substitution results in impaired secretion and decreased thermal stability of type III procollagen in a patient with Ehlers-Danlos syndrome type IV. Hum Mutat 9:62-63, 1997. 99. Thakker-Varia S, Anderson DW, Kuivaniemi H, et al: Aberrant splicing of the type III procollagen mRNA leads to intracellular degradation of the protein in a patient with Ehlers-Danlos type IV. Hum Mutat 6:116-125, 1995. 100. Lichtenstein JR, Martin GR, Kohn LD, et al: Defect in conversion of procollagen to collagen in a form of Ehlers-Danlos syndrome. Science 182:298-299, 1973.

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101. Byers PH, Duvic M, Atkinson M, et al: Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen. Am J Med Genet 72:94-105, 1997. 102. D’Alessio M, Ramirez F, Blumberg BD, et al: Characterization of a COL1A1 splicing defect in a case of Ehlers-Danlos syndrome type VII: Further evidence of molecular homogeneity. Am J Hum Genet 49:400-406, 1991. 103. Wertelecki W, Smith LT, Byers PH: Initial observations of human dermatosparaxis: Ehlers-Danlos syndrome type VIIC. J Pediat 121:558-564, 1992. 104. Colige A, Sieron AL, Li SW, et al: Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations in the procollagen I N-proteinase gene. Am J Hum Genet 65:308-317, 1999. 105. Nusgens BV, Verellen-Dumoulin C, Hermanns-Le T, et al: Evidence for a relationship between Ehlers-Danlos type VII C in humans and bovine dermatosparaxis. Nat Genet 1:214-217, 1992. 106. Heim P, Raghunath M, Meiss L, et al: Ehlers-Danlos syndrome type VI (EDS VI): Problems of diagnosis and management. Acta Paediatr 87:708-710, 1998. 107. Yeowell HN, Walker LC: Mutations in the lysyl hydroxylase 1 gene that result in enzyme deficiency and the clinical phenotype of EhlersDanlos syndrome type VI. Mol Genet Metab 71:212-220, 2000. 108. De Paepe A, Devereux RB, Dietz HC, et al: Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 62:417-426, 1996. 109. Montgomery RA, Geraghty MT, Bull E, et al: Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome. Am J Hum Genet 63:1703-1711, 1998. 110. Adams JN, Trent RJ: Aortic complications of Marfan’s syndrome. Lancet 352:1722-1723, 1998. 111. Elkayam U, Ostrzega E, Shotan A, et al: Cardiovascular problems in pregnant women with the Marfan syndrome. Ann Intern Med 123:117-122, 1995. 112. Ahn NU, Sponseller PD, Ahn UM, et al: Dural ectasia in the Marfan syndrome: MR and CT findings and criteria. Genet Med 2:173-179, 2000. 113. Kohlmeier L, Gasner C, Bachrach LK, et al: The bone mineral status of patients with Marfan syndrome. Bone Miner Res 10:1550-1555, 1995. 114. Maumenee IH: The eye in the Marfan syndrome. Trans Am Ophthalmol Soc 79:684-733, 1981. 115. Nallamshetty L, Ahn NU, Ahn UM, et al: Plain radiography of the lumbosacral spine in Marfan syndrome. Spine J 2:327-333, 2002. 116. Savini R, Cervellati S, Beroaldo E: Spinal deformities in Marfan’s syndrome. Ital J Orthop Traumatol 6:19-40, 1980. 117. Mudd SH, Skovby F, Levy HL, et al: The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet 37:1-31, 1985. 118. Mudd SH, Edwards WA, Loeb PM, et al: Homocystinuria due to cystathionine synthase deficiency: The effect of pyridoxine. J Clin Invest 49:1762-1773, 1970.

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119. Sakai LY, Keene DR, Engvall E: Fibrillin, a new 350kD glycoprotein, is a component of extracellular microfibrils. J Cell Biol 103: 2499-2509, 1986. 120. Collod-Beroud G, Beroud C, Ades L, et al: Marfan database (third edition): New mutations and new routines for the software. Nucleic Acids Res 26:229-233, 1998. 121. Collod-Beroud G, Boileau C: Marfan syndrome in the third millennium. Eur J Hum Genet 10:673-681, 2002. 122. Stoll C: Shprintzen-Goldberg marfanoid syndrome: A case followed up for 24 years. Clin Dysmorphol 11:1-7, 2002. 123. Wang M, Wang JY, Cisler J, et al: Three novel fibrillin mutations in exons 25 and 27: Classic versus neonatal Marfan syndrome. Hum Mutat 9:359-362, 1997. 124. Dietz HC, Pyeritz RE: Mutations in the human gene for fibrillin1 (FBN1) in the Marfan syndrome and related disorders. Hum Mol Genet 4:1799-1809, 1995. 125. Robinson PN, Booms P, Katzke S, et al: Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies. Hum Mutat 20:153-161, 2002. 125a. Halpern BL, Char F, Murdoch JL, et al: A prospectus on the prevention of aortic rupture in the Marfan syndrome with data on survivorship without treatment. Johns Hopkins Med J 129:123-129, 1971. 126. Shores J, Berger KR, Murphy EA, et al: Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan’s syndrome. N Engl J Med 330:1335-1341, 1994. 127. Habashi JP, Judge DP, Holm TM, et al: Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312:117-121, 2006. 128. Gott VL, Greene PS, Alejo DE, et al: Replacement of the aortic root in patients with Marfan’s syndrome. N Engl J Med 340:1307-1313, 1999. 129. Gott VL, Cameron DE, Alejo DE, et al: Aortic root replacement in 271 Marfan patients: A 24-year experience. Ann Thorac Surg 73:438-443, 2002. 130. Loeys BL, Chen J, Neptune ER, et al: A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 37: 275-281, 2005. 131. Beals RK, Hecht F: Congenital contractural arachnodactyly: A heritable disorder of connective tissue. J Bone Joint Surg Am 53: 987-993, 1971. 132. Putnam EA, Zhang H, Ramirez F, et al: Fibrillin-2 (FBN2) mutations result in the Marfan-like disorder, congenital contractural arachnodactyly. Nat Genet 11:456-458, 1995. 133. Ringpfeil F: Selected disorders of connective tissue: Pseudoxanthoma elasticum, cutis laxa, and lipoid proteinosis. Clin Dermatol 23:41-46, 2005. 134. Milewicz DM, Urban Z, Boyd C: Genetic disorders of the elastic fiber system. Matrix Biol 19:471-480, 2000.

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RHEUMATIC DISEASES OF CHILDHOOD

97

Juvenile Idiopathic Arthritis Kiran Nistala  •  Patricia Woo  •  Lucy R. Wedderburn

Key Points Juvenile idiopathic arthritis (JIA) is an umbrella term for childhood arthritis of unknown cause. JIA affects 1 in 1000 children. Many of the subtypes of JIA have particular features, but some complications are common to several subtypes. JIA is clearly distinct from adult rheumatoid arthritis. Progress in the understanding of the genetics and pathogenesis of JIA has revealed subtype-specific associations and some common mechanisms of disease. The principles of treating JIA are common to all subtypes because they involve a multidisciplinary approach, aiming to suppress inflammation early and maintain function.

DEFINITION AND CLASSIFICATION It has been more than a century since Still eloquently described the differences between forms of childhood ­arthritis and adult rheumatoid arthritis.1 Despite many advances in understanding of genetic, pathologic, and molecular influences on the disease, the cause or causes of juvenile arthritis are unknown, and it remains a leading cause of acquired disability in childhood. In more recent years, ­juvenile idiopathic arthritis (JIA) has become widely accepted as an umbrella term to cover this heterogeneous group of conditions.2,3 The classification of JIA (Table 97-1), proposed and subsequently revised by the International League of Associations for Rheumatology (ILAR), has now replaced previous nomenclature, including the ­ European term, ­ juvenile chronic arthritis, and the American term, juvenile rheumatoid arthritis.4 JIA is defined as arthritis in one or more joints persisting for 6 weeks or more, which begins before the 16th birthday and has no other known cause.2,3 Each category has a list of possible exclusions (see Table 97-1). A primary goal of such a system is to define mutually exclusive categories of idiopathic childhood arthritis based on predominant clinical and laboratory features, with the aim of improving therapy and management.4,5 Although the classification of JIA

is based primarily on clinical features of the disease, with emphasis on presenting features, it is widely accepted that improved knowledge should lead to a more precise definition of the types of JIA, perhaps based on genetic, pathologic, or mechanistic information, and that such a classification would need to evolve or change, as understanding of the subtypes of juvenile arthritis and their pathophysiology improves. The increasing use of one system of classification would facilitate ready comparison of data and information from many studies and clinical trials. Table 97-2 provides an overview of the main features of each type of JIA. Many of the types of childhood arthritis have distinct clinical features, and some of these features are rare in adult inflammatory arthritis. In JIA, in contrast to adult rheumatoid arthritis, large joints, such as the knees, wrists, and ankles, are typically more prominently involved than small joints. Subcutaneous nodules and rheumatoid factor (RF) seropositivity are unusual, but antinuclear antibody (ANA) seropositivity is frequent in some JIA subtypes. Some JIA subtypes have a majority onset in young childhood, although as yet there is no clear biologic explanation for why this is so. Examples include the systemiconset and oligoarticular subtypes of JIA. In contrast, some JIA subtypes have an adult counterpart, such as psoriatic arthritis and RF-positive polyarticular JIA; these subtypes tend to have a slightly older onset in children. Some complications of JIA, such as osteoporosis or uveitis, can occur in many subtypes; others are more restricted to particular subtypes. Long-term studies have shown that, as a whole, JIA is not as benign as previously thought, with rates of complete remission off medication still low in many subtypes,6 evidence for loss of quality of life in childhood,7 and 30% to 50% of patients experiencing ongoing inflammation or disability into adulthood.8,9 The imperative to investigate mechanisms of disease pathogenesis and search for new therapeutic avenues remains as strong as ever. A further drive to continue to aim for complete remission in JIA is the observation that when inflammation is fully controlled, juvenile tissues, including synovium, cartilage, and bone, can undergo remarkable “healing” with restoration of function, in sharp contrast to adult arthritis.

  Supplemental images available on the Expert Consult Premium Edition website.

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Table 97-1  International League of Associations for Rheumatology Classification of Juvenile Idiopathic Arthritis (JIA) Category

Definition

Systemic onset JIA

Arthritis in ≥1 joints with, or preceded by, fever of at least   A. Psoriasis or a history of psoriasis in the patient 2 wk duration that is documented to be daily (“quotidian”*) for   or a first-degree relative at least 3 days and accompanied by ≥1 of the following: 1. Evanescent (nonfixed) erythematous rash B. Arthritis in an HLA-B27+ male beginning after the 6th birthday 2.  Generalized lymph node enlargement C. Ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome, or acute anterior uveitis, or a history of one of these disorders in a first-degree relative 3. Hepatomegaly or splenomegaly or both D. Presence of IgM RF on at least 2 occasions at least 3 mo apart 4. Serositis†

Exclusions

Oligoarticular JIA

Arthritis affecting 1-4 joints during the first 6 mo of disease. Two subcategories are recognized: 1. Persistent oligoarthritis—affecting ≤4 joints throughout the disease course 2. Extended oligoarthritis—affecting >4 joints after the first 6 mo of disease

A, B, C, D above, plus E. Presence of systemic JIA in the patient

Polyarthritis (RF negative)

Arthritis affecting ≥5 joints during the first 6 mo of disease; a test   A, B, C, D, E for RF is negative

Polyarthritis (RF positive)

Arthritis affecting ≥5 joints during the first 6 mo of disease;   ≥2 tests for RF at least 3 mo apart during the first 6 mo of   disease are positive

A, B, C, E

Psoriatic arthritis

Arthritis and psoriasis, or arthritis and at least 2 of the following: 1. Dactylitis‡ 2.  Nail pitting§ and onycholysis 3. Psoriasis in a first-degree relative

B, C, D, E

Enthesitis-related   arthritis

Arthritis and enthesitis,ǁ or arthritis or enthesitis with at least 2 of A, D, E the following: 1. Presence of or a history of sacroiliac joint tenderness or inflammatory lumbosacral pain or both¶ 2. Presence of HLA-B27 antigen 3. Onset of arthritis in a male >6 yr old 4. Acute (symptomatic) anterior uveitis 5. History of ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome, or acute anterior uveitis in a first-degree relative

Undifferentiated arthritis

Arthritis that fulfills criteria in no category or in ≥2 of the above categories

*Quotidian fever is defined as a fever that rises to 39°C once a day and returns to 37°C between fever peaks. †Serositis refers to pericarditis, pleuritis, or peritonitis, or some combination of the three. ‡Dactylitis is swelling of ≥1 digits, usually in an asymmetric distribution, which extends beyond the joint margin. §A minimum of 2 pits on any one or more nails at any time. ǁEnthesitis is defined as tenderness at the insertion of a tendon, ligament, joint capsule, or fascia to bone. ¶Inflammatory lumbosacral pain refers to lumbosacral pain at rest with morning stiffness that improves on movement. RF, rheumatoid factor.

EPIDEMIOLOGY By definition, JIA begins before age 16 years. Young children 1 to 3 years old are most commonly affected, a pattern most noticeable in girls, in whom the disease is twice as common. Boys have a wider distribution of age at onset, with a small peak in incidence at 8 to 10 years.10,11 Systemic-onset JIA is an exception with a 1:1 female-to-male ratio.12 Studies of the incidence of childhood arthritis using either juvenile rheumatoid arthritis or juvenile chronic arthritis classifications have documented rates of 3.5 to 13.9 (confidence limits 9.9 to 18.8) per 100,000 children/yr in populationbased cohorts,13-16 and a population-based study using ILAR JIA criteria suggested a rate of 15/100,000 children/yr.11 Prevalence of chronic arthritis in childhood has been estimated as 148/100,000 children in a Norwegian study, and 400/100,000 children in a survey of 12-year-old schoolchildren.17,18 In the latter study, all children were examined by

a pediatric rheumatologist, which may explain the higher prevalence estimate. Most quoted studies are from populations of northern European descent, but some reports suggest arthritis may be less common in Japanese,19 black,20 and Asian children.20

ETIOLOGY GENETICS Despite significant advances in genetics and molecular immunology, understanding of the etiology of JIA is piecemeal. Genetic factors and environmental triggers are thought to play a part ultimately leading to abnormalities in the cellular, humoral, and innate arms of the immune system. The evidence for a genetic contribution to JIA comes from several sources. Twin studies show a high concordance

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Table 97-2  Overview of the Main Features of the Subtypes of Juvenile Idiopathic Arthritis (JIA) ILAR Subtype

Peak Age of Onset (yr)

Female: Male; % of All JIA

Arthritis Pattern

Extra-articular Features

Systemic arthritis

2-4

1:1; ~10% of JIA   cases

Polyarticular, often knees, wrists, and ankles; also   fingers, neck,   and hips

Daily fever;   evanescent   rash;   pericarditis; pleuritis

Anemia; WBC ↑↑; ESR ↑↑; CRP ↑↑; ferritin ↑;   platelets ↑↑ (normal   or ↓ in MAS)

Less responsive to standard treatment with MTX and anti-TNF agents; consider IL-1Ra in resistant cases

Oligoarthritis

<6

4:1; 50-60% of JIA (but ethnic   variation)

Knees ++; ankles, fingers +

Uveitis in ~30%

ANA positive in ~60%; other tests usually normal; may have   mildly ↑ ESR/CRP

NSAIDS and intraarticular steroids; occasionally require MTX

Polyarthritis, RF   negative

6-7

3:1; 30% of JIA   cases

Symmetric or   asymmetric; small and large joints;   cervical spine;   TMJ

Uveitis in ~10%

ANA positive in 40%; RF negative; ESR ↑ or ↑↑;   CRP ↑/normal; mild anemia

Standard therapy with MTX and NSAIDs, then if nonresponsive, anti-TNF agents or other   biologics

Polyarthritis, RF   positive

9-12

9:1; <10% of JIA   cases

Aggressive   symmetric   polyarthritis

Rheumatoid nodules   in 10%; lowgrade fever

RF positive; ESR ↑↑;   CRP ↑/normal; mild anemia

Long-term remission unlikely; early aggressive therapy is warranted

Psoriatic arthritis

7-10

2:1; <10% of JIA   cases

Asymmetric arthritis   Uveitis in 10%; of small or   psoriasis   medium sized   in 50% joints

ANA positive in 50%;   ESR ↑; CRP ↑/normal; mild anemia

NSAIDS and intraarticular steroids; second-line agents less   commonly

Enthesitis-related arthritis

9-12

1:7; 10% of JIA   cases

Predominantly   lower limb joints affected;   sometimes axial   skeleton (but less than adult AS)

80% HLA-B27+

NSAIDS and intraarticular steroids; consider sulfasalazine as alternative to MTX

Acute anterior   uveitis;   association   with reactive arthritis   and IBD

Investigations

Notes on Therapy

ANA, antinuclear antibody; AS, ankylosing spondylitis; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IBD, inflammatory bowel disease; ILAR, International League of Associations for Rheumatology; IL-1Ra, interleukin-1 receptor antagonist; MAS, macrophage activation syndrome; MTX, methotrexate; NSAID, nonsteroidal anti-inflammatory drug; RF, rheumatoid factor; TMJ, temporomandibular joint; TNF, tumor necrosis factor; WBC, white blood cell count.

of disease in monozygotic twins.21,22 A study of 164 affected sibling pairs with JIA showed a 70% concordance for gender, 73% for disease onset, and 66% for disease course, considerably higher than in a non–affected sibling pair cohort.23 First-degree relatives of children with JIA have a higher rate of autoimmune disease than controls.24 Genetic influences on JIA susceptibility and phenotype are polygenic,25 and a more recent genome-wide scan in JIA affected sibling pair families has supported the idea that multiple genetic loci contribute to JIA susceptibility.26 The strong associations of specific alleles with JIA are within the major histocompatibility complex (MHC) system and were the first to be documented.27,28 Among the MHC class I loci, HLA-B27 is strongly associated with spondyloarthropathy, which in children is now termed enthesitisrelated arthritis (ERA), whereas HLA-A*0201 is increased in oligoarthritis.29 Multiple studies have revealed an increase in HLA-DR alleles, of which the strongest are DRB1*0801 and DRB1*1101 with oligoarticular JIA and DRB1*1301, in particular in ANA-positive cases.30-32 Several haplotypes across the MHC confer an increased risk for all types of JIA, such as DRB1*08-DQA1*0401-DQB1*0402, which confers an odds ratio of 6.1 for persistent oligoarticular

JIA and 10.3 for extended oligoarticular JIA. Frequency of the DRB1*1301-DQA1*01-DQB1*06 haplotype distinguishes persistent from extended oligoarticular JIA, whereas DRB1*0801 and DRB1*1401 are associated with poly­ articular JIA.29 Together these effects may be large; in one study, the presence of the combination of the HLA-DRB1*0801, HLA-DRB1*1101, and HLA-DPB1*0201 alleles conferred a relative risk of 236.33 Some associations closely mirror the associations of the corresponding adult disease, such as the strong association of the HLA-B27 allele with ERA and the HLA-DRB1*0401 with RF-positive polyarticular JIA. Some of these allele/subtype associations show an age­specific effect, in that they confer risk over a specific age range only.34 Although systemic JIA shows weaker associations with HLA alleles, even in this subtype, specific haplotypes (e.g., DRB1*11-DQA1*05-DQB1*03) are increased compared with control subjects.29 Inflammatory cytokines have been an important target for drug development in JIA, and similarly their gene polymorphisms have been a key area of scrutiny. Several HLA-independent tumor necrosis factor (TNF) haplotypes are significantly associated with JIA, but the functional

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­consequences of these alleles are unclear.35 Some of the best characterized non-HLA genetic associations in JIA have been established in systemic JIA. The hypothesis suggesting a link between systemic JIA and interleukin (IL)-6 was proposed in 1993,36 with many of the clinical features in systemic JIA resembling the phenotype of IL-6 overexpression (e.g., fevers, stunted growth, anemia).37 A polymorphism (−174G/C) in the regulatory region of the IL-6 gene alters transcription of IL-6 in response to IL-1 and lipopolysaccharide; patients with systemic JIA have significantly lower frequency of the protective CC genotype,38 and the IL-6 − 174G allele was confirmed as a susceptibility gene for systemic JIA.39 More recent haplotype analysis of the IL-6 gene has confirmed a haplotype association with systemic JIA.40 A polymorphism in the promoter region of the macrophage inhibitory factor (MIF) gene is associated with JIA.41 This polymorphism (MIF −173*C) results in higher MIF production in the serum and synovium of JIA patients and has been shown to be predictive of outcome of intra-articular steroid injections in systemic JIA.42 The anti-inflammatory gene IL-10 was first studied in oligoarticular JIA. The “ATA” haplotype of three single nucleotide polymorphisms at the 5′ flanking end of the gene is associated with lower production of IL-10 by peripheral blood mononuclear cells, and was found more frequently in the more severe subtype of JIA, extended oligoarticular JIA, than the milder persistent oligoarticular JIA.43 IL-10 and its family member IL-20 were found to be associated with systemic JIA.44 The gene PTPN22, a negative regulator of T cell responses, has been suggested to be associated with JIA also, but current evidence is conflicting.45,46 In contrast to studies using the candidate gene approach, future novel genetic associations will be elucidated through whole-genome scanning, requiring large multicenter casecontrol cohorts. ENVIRONMENT A study of socioeconomic factors in the etiology of JIA suggested that high parental income and being an only child may be associated with a higher risk of disease,47 and in a Finnish study of more than 58,000 births, fetal exposure to smoking has been suggested to increase the risk of JIA in girls.48 The evidence that genetic risk alleles, such as those associated with HLA antigens, confer different risk of JIA across different ages, strongly suggests that crucial environmental triggers, which change with age, may be involved in the initiation of JIA.34 Microbial triggers for JIA remain elusive. Borrelia burgdoferi, the infectious agent responsible for Lyme disease; Mycoplasma pneumoniae; and several viruses, such as rubella and parvovirus, can cause a clinical picture similar to JIA, leading to the hypothesis that JIA represents an immunologic response to an infectious trigger.49 Bacterial or viral DNA can be isolated from the joints or serum of JIA patients,50,51 but no single agent has been identified as a cause of JIA, and in most cases of JIA no persisting infectious agent can be shown. Epidemiologic studies searching for infectious “outbreaks” or seasonal variation in incident JIA cases, or in pregnant mothers whose children subsequently develop JIA, have provided conflicting results.47,52-54

An alternative role for microbial pathogens in the pathogenesis of JIA has been suggested through molecular mimicry. Heat shock proteins are proteins expressed by microbial and human cells in response to stress. Bacterial heat shock proteins are strong immunogens and may generate cross-reactive immune responses to self–heat shock proteins in humans. In oligoarticular JIA, reactivity to self–heat shock proteins correlates with disease remission,55 and synovial T cells generate a regulatory cell phenotype in response to self–heat shock protein 60, which was not detectable in the more severe polyarthritis subgroup.56

PATHOGENESIS The pathologic hallmark of juvenile inflammatory arthritis is the inflamed synovium. Histology of this tissue shows thickened synovium that is highly vascular and shows marked hyperplasia of synoviocytes in the lining layer and a dense infiltrate of inflammatory cells, comprising T cells, macrophages, and in some cases B cells and natural killer cells (Fig. 97-1).57-61 The hypertrophied synovial layer is highly vascular, with endothelium expressing markers of activation such as HLA-DR and intracellular adhesion molecule 1. The vascularity is likely related to the increased production of proangiogenic factors, such as vascular endothelial growth factor, and the angiogenic chemokines.62,63 Recruitment of this inflammatory infiltrate is likely mediated by multiple chemokines shown to be increased in JIA, including CCL3, CCL5, and CXCL10; IL-8; and monocyte chemotactic protein-1.64-68 The strong association of many JIA subtypes with genetic variants at HLA loci, the central role of HLA class I and II proteins in T cell function, and the predominance of T cells in pathologic JIA synovial tissue and fluid led to intense investigation of the role of T cells in the pathology of JIA. T cells within the JIA joint are highly activated memory cells, expressing rapidly upregulated (CD69) and persistent (DR) activation markers.59,69,70 These T cells express a restricted set of T cell receptors:71,72 The clonotypes are large and long-lived, and the same hierarchy of clones reexpands during a relapse or flare of disease.71 The finding that this oligoclonality in the intra-articular T cell population is more marked in CD4+ T cells in oligoarthritis (which is associated with class II HLA-DR genes), and yet more marked in CD8+ T cells in ERA (which is associated with the class I allele HLA-B27), supports the concept that recognition of MHC-peptide complexes by T cells plays a role in the pathogenesis of JIA.72 Early work on inflammatory cytokines produced by synovial T cells suggested that these were heavily skewed toward a T helper type 1 (Th1) CCR5+CXCR3+ interferon-γ-­producing lineage.59,73,74 More recent evidence suggests, however, that another proinflammatory T cell cytokine, IL-17, produced by Th17 cells, has an important role in JIA. Th17 cells are enriched in the joint in JIA, and their ­numbers are higher in children with the more severe extended oligoarticular JIA compared with children with milder, persistent oligoarticular disease.75 Many inflammatory cytokines and chemokines are abnormally increased in JIA and found at the site of destructive synovitis. Subtype differences have emerged, which may allow a “subtype-specific” profiling of serum or synovial fluid

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A

CD3 x100

C

B

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RHEUMATIC DISEASES OF CHILDHOOD

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ICAM-1 x200

CD34 x100

in the future, although such measurements have to take into account circadian rhythms and the short half-lives of these mediators.67,76,77 Systemic JIA is associated with high levels of TNF, IL-1, IL-6, MIF, and IL-18. In cases of classic systemic JIA, the levels of IL-6 and IL-1 receptor antagonist increase and decrease in parallel with the fever and rash.78 IL-6 and MIF levels are each associated with disease activity in systemic JIA, and high synovial MIF levels predict poor response to intra-articular steroid injection.79 IL-1 has been suggested to have a major role in the pathogenesis of systemic JIA,80 although results in this field are conflicting. In addition to the proinflammatory, destructive process within the joint, there is strong evidence for ongoing immunoregulation in JIA. The existence of a mild form of arthritis in which full-blown immunopathology can resolve and disease can enter full remission (known as persistent oligoarticular JIA) provides a unique model in autoimmunity: a mild self-remitting autoimmune pathology, which can be compared with more severe clinical subtypes. Children with persistent oligoarticular JIA have evidence of immunoregulation as shown by high numbers of CD25+ foxp3+ regulatory T cells in the joint,81 and these cells correlate with clinical phenotype and outcome. In addition, T cells specific for the conserved self-antigen heat shock proteins have been shown to be present at significantly higher numbers in children destined to have a mild disease course, and these self-antigen heat shock protein–specific cells are thought to play a regulatory role.55,56 The crucial role of dendritic cells in the control of this immunoregulation of JIA is a field of intense investigation.

Figure 97-1  Sections of synovium from the knee of a child with oligoarticular juvenile idiopathic arthritis showing intense inflammatory ­ infiltrate and highly vascular hypertrophied tissue. A, Stained for CD3 (surface protein expressed on T lymphocytes) (magnification, ×100). B, Stained for ­intracellular adhesion molecule 1, which is ­ expressed on the endothelium and a proportion of the infiltrating cells (magnification, ×200). C, Stained for CD34, expressed on vascular endothelium (and hematopoietic stem cells) (magnification, ×100).

In addition to cells of the adaptive immune system, many other parts of the immune system are abnormally activated in JIA, including synovial macrophages,79 dendritic cells,82,83 and neutrophils.84,85 Modern highthroughput methods of gene expression profiling and proteomics have shown differences between JIA clinical subtypes in several cell populations and between JIA patients before and after treatment and compared with controls.63,86-89 Ultimately, the understanding of pathologic mechanisms and alterations in the balance between immune activation and regulation, during disease and in response to treatment, should lead to a new set of molecular tools with which to separate clinical subtypes, predict disease course, and select tailored therapies for every child more accurately.

PRINCIPLES OF TREATMENT JIA is a disease with great diversity, with patients ranging from a child with arthritis affecting one joint to an acutely sick child with systemic arthritis. Successfully caring for these children and their families as they progress from infancy to adulthood requires myriad skills that cannot be provided by one clinician alone. The essential principle of managing JIA is to deliver care as a multidisciplinary team, including pediatric rheumatologists, physical therapists, occupational therapists, podiatrists or orthotists, specialist nurses, psychologists, social workers, school liaison workers, ­family support groups, general practitioners, ­ ophthalmologists, dentists or orthodontists, orthopaedic surgeons, and pain

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management teams. The long-term goal is to achieve early and complete suppression of inflammation without treatment toxicity, while maintaining muscle power, joint range of movement, and function, through active physical therapy and occupational therapy input, and maximize the child’s potential for normal growth and development and educational and vocational success. A persistent block to good outcome in many areas of the world is a delay in recognition or diagnosis of JIA.90 When recognized, most children with JIA now have a good outcome, however, in terms of functional ability. Despite these good functional outcomes and educational achievements, studies of adults who had JIA as children show that JIA may still have a profound effect on quality of life and vocational achievements.9,91 ISSUES SPECIFIC TO MANAGEMENT OF CHILDHOOD ARTHRITIS The challenges of assessing and treating children with arthritis are quite distinct from managing patients with rheumatoid arthritis. The child’s symptoms are often filtered through the parents’ preconceptions and fears. A skilled pediatric rheumatologist needs to listen to the child and the parent and address the concerns of both, communicating in language that is appropriate for the parents and the developmental stage of the child. The wishes of the patient may not always mirror that of their parents, particularly with adolescents. In children, arthritis more commonly manifests with reduced function or deformity, rather than pain or swelling. The assessment of pain can be difficult in young children; pain may manifest as altered mood or restricted play, rather than localizing symptoms. The wider rheumatology team plays a vital role, which includes assessing an apprehensive child. Therapists can achieve a detailed examination by “simply” observing and interacting with the child in a natural state of play. With an older child, therapists, specialist nurses, and social workers have key roles in communicating with schools and acting as child advocates, such as requesting computer laptops to help with writing difficulties, or helping parents to engage with school authorities if their child’s educational needs are not being met. Table 97-3 provides an overview of the role of physical therapists and occupational therapists during the course of managing a long-term patient with JIA. For an adolescent who has been under the long-term care of the pediatric rheumatology team, moving to adult care is stressful and can precipitate poor adherence and disease flares. Transition is the process that builds up to the successful transfer of care. This is a “multifaceted active process that attends to the medical, psychosocial and educational­vocational needs of the adolescent as they move from child to adult-orientated care.”92 The aim is to equip an adolescent with a range of skills that gives him or her a sense of control over his or her healthcare and enables the adolescent to function independently (Table 97-4). Ideally, this transition service would be provided in a dedicated adolescent rheumatology clinic. This service may not be feasible outside large pediatric rheumatology centers, but many of the principles still can be adopted regardless of the size of the service.

Table 97-3  Overview of the Role of Physical Therapy and Occupational Therapy in Juvenile Idiopathic Arthritis Treatment Goals of Early Disease Identify and control pain (e.g., splinting) Improve function (e.g., progressive home exercise program) Educate child and family Input in Established Arthritis Limit/reverse impairments (e.g., serial casting) Teach self-management and problem-solving skills (e.g., pacing) Advocate for child (e.g., ergonomic assessment at school) Plan for the Future Support adolescent healthy living goals Vocational counseling Teach independent living skills Surgical intervention planning Adapted from Kachta G, Davidson I: Physiotherapy and occupational therapy. In Szer IS, Kimura Y, Malleson PN, Southwood TR (eds): Arthritis in Children and Adolescents. Oxford, UK, Oxford University Press, 2006, pp 381-391.

Table 97-4  Essentials of a Transitional Care Service Policy on timing of transition and transfer that agrees with adult services Preparation period Disease education program Address needs of the adolescent and parent or guardian Transfer process that is coordinated with other medical specialties Committed adult rheumatology service with key liaison personnel Administrative support Primary care involvement Involvement of adolescent   Developing his or her own individualized transition plans   As advisor to adolescent rheumatology service development   As educator of peers and health professionals Regular evaluation and audit From McDonagh JE, White P: Adolescent rheumatology services. In Szer IS, Kimura Y, Malleson PN, Southwood TR (eds): Arthritis in Children and Adolescents. Oxford, UK, Oxford University Press, 2006, pp 315-329.

GENERAL PRINCIPLES OF MEDICAL MANAGEMENT OF JUVENILE IDIOPATHIC ARTHRITIS Algorithms of suggested treatment decision routes are shown in Figures 97-2 and 97-3. Nonsteroidal anti-inflammatory drugs (NSAIDs) should be given from the time of diagnosis, and at adequate doses (Table 97-5). When there are only a few joints involved (e.g., oligoarticular JIA and some cases of psoriatic or ERA JIA), initial management should include intra-articular steroid injection with triamcinolone hexacetonide, given under sedation or general anesthetic for children. Triamcinolone hexacetonide has been found to be superior to triamcinolone acetonide, betamethasone, and methylprednisolone acetate in randomized controlled trials,93,94 and early treatment is associated with better outcome.95 When intra-articular steroid injection is inadequate to control synovitis, or arthritis involves three or more joints, methotrexate is the second-line agent of choice. Its efficacy has been confirmed in two randomized trials, with ­maximum benefit at an intermediate dose of 15 mg/m2 administered subcutaneously.96,97 The main side effects that limit use of methotrexate are nausea, vomiting, and deranged liver

PART 16 

MEDICAL MANAGEMENT OF OLIGOARTHRITIS (PERSISTENT OLIGOARTHRITIS JIA, PSORIATIC JIA AND MILD ERA)

Review every 6 months, or until 2 years, remission off treatment

Relapse

Yes

RHEUMATIC DISEASES OF CHILDHOOD

Active polyarthritis

Inject + NSAIDS

NSAID + methotrexate*

Remission?

No

No Too many injections/ inadequate response* Yes

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Active arthritis

Add methotrexate. Hip or TMJ involvement is an indication for the early use of methotrexate Yes

| 

Respond

Yes

No Add antiTNF agent*

Respond

Close monitoring of disease Yes

No Change to different anti-TNF agent or alternative biologic*

Remission? No

Rarely, anti-TNF therapy or synovectomy is considered for methotrexate-resistant cases. Figure 97-2  Algorithm to outline the treatment principles for persistent oligoarticular juvenile idiopathic arthritis (JIA), psoriatic JIA, and enthesitisrelated arthritis JIA. *There is no evidence to support a limit on the number of steroid injections per joint, and some centers have injected more than 10 times without adverse effects. NSAIDs, ­nonsteroidal anti-inflammatory drugs; TMJ, temporomandibular joint; TNF, tumor ­necrosis factor.

f­unction tests. Folic acid usually is recommended to ameliorate these effects, but there is limited evidence from pediatric studies to substantiate this practice.98 The more toxic effects of methotrexate seen in adults, such as liver cirrhosis and lung fibrosis, are extremely rare in children. Alternatives to methotrexate to consider include leflunomide, an oral inhibitor of pyrimidine synthesis, which seems to be less efficacious than methotrexate in JIA.99 Sulfasalazine is shown to be of sustained benefit in oligoarticular and polyarticular JIA, but at the cost of gastrointestinal and skin side effects.100,101 In recent years, biologic therapies have revolutionized the treatment of rheumatoid arthritis. In children, only one agent, etanercept (recombinant soluble TNF receptor), is currently licensed for use in the United Kingdom; criteria for approval include a failure of or intolerance to methotrexate, in the presence of active synovitis. In 2000, etanercept was tested in JIA using a unique placebo-controlled withdrawal design and was shown to be efficacious in patients resistant to methotrexate therapy,102 although the benefits are not equal for all subtypes.103 Longterm follow-up has confirmed its benefits and good safety record.104 A trial of infliximab showed a good response to treatment, but was not adequately powered to establish superiority to methotrexate alone.105 Treatment with 6 mg/kg of infliximab was recommended because this dose was associated with significantly fewer antibodies to the drug

Respond

Yes

No Evaluate for autologous stem cell transplantation Figure 97-3  Algorithm to outline the treatment principles for extended  oligoarticular juvenile idiopathic arthritis (JIA), and rheumatoid ­ factor– negative and rheumatoid factor–positive polyarticular JIA. *Consider joint injections or pulsed intravenous steroid and short-course oral steroid. NSAIDs, nonsteroidal anti-inflammatory drugs; TNF, tumor necrosis factor.

and ­ infusion-related adverse events than the smaller 3 mg/kg dose. Preliminary data from trials with CTLA4Ig ­ (abatacept) and adalimumab show promising results in methotrexate-naive and treated JIA patients.106,107 Patients with systemic arthritis fare less well with antiTNF-α therapy compared with other subtypes, which likely reflects the distinct etiopathogenesis of systemic JIA (see section on systemic arthritis). Early-phase trials of IL-1 receptor antagonist (anakinra)80 and IL-6 blockade108,109 offer future hope for this recalcitrant group of patients, who pose one of the greatest challenges to pediatric rheumatology. The longterm safety of immune blockade of specific mediators such as TNF-α or IL-1 is unknown; however, despite concerns about infections (e.g., tuberculosis) or malignancy, to date the available data are reassuring.103 In patients who achieve remission on methotrexate or biologic treatments it is not clear when treatment should be stopped. Without definitive clinical or biologic markers to predict relapse off treatment, most centers continue treatment for 1 to 2 years of continuous remission. MRP8 and MRP14 may be useful biomarkers to predict long-term remission off methotrexate, and a recent randomized trial comparing withdrawal at 6 versus 12 months hopes to answer this question.109a In situations where current drug therapies fail, the option of autologous stem cell transplantation has been widely used in Europe for children with severe resistant JIA. The

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Table 97-5  Doses of Common Nonsteroidal   Anti-inflammatory Drugs (NSAIDs) Used for Juvenile ­Idiopathic Arthritis (JIA) NSAID

Dose

Comments

Ibuprofen (from   6 mo of age)

30-40 mg/kg /day in   3-4 divided doses

Up to 60 mg/kg/day in sJIA in divided doses

Naproxen (>2 yrs)

20-30 mg/kg/day   in 2 divided doses

Maximum, 1 g/day

Piroxicam

<15 kg, 5 mg; 16-25 kg, 10 mg; 26-45 kg,   15 mg; >46 kg,   20 mg once a day

Diclofenac

Indomethacin   (>1 mo of age)

1-3 mg/kg/day in   2-3 divided doses

SR preparation available; maximum   150 mg/day

1-2 mg/kg/day in   2 divided doses

SR preparations useful to alleviate morning stiffness; maximum, 50 mg/day

SR, sustained release.

r­ estoration of “immune balance” by autologous stem cell transplantation has been successfully carried out in more than 65 children with severe JIA; 53% of these children have achieved remission,110,111 with good long-term disease-free survival rates.112 Children who relapse may show a milder disease phenotype, which is more easily controlled with standard therapy. Guidelines for the consideration of autologous stem cell transplantation are updated on a regular basis to include available biologic therapies.113 GROWTH DISTURBANCES IN JUVENILE IDIOPATHIC ARTHRITIS In a growing child, uncontrolled arthritis leads to secondary systemic and localized growth disturbances. Generalized growth failure is most marked in systemic JIA and is related to high levels of IL-6 and corticosteroid toxicity. Sick children are often anorexic despite their catabolic state, and dietary advice is needed to avoid compounding their existing growth failure. In older children, poor growth is associated with pubertal delay and osteoporosis. Osteoporosis should be considered in all children with prolonged active disease and is most marked in children with systemic JIA (see section on systemic arthritis). Bisphosphonates and calcium and vitamin D supplements have been used,114,115 but evidence for the optimal combination is lacking; a large multicenter trial is currently in progress to determine this (BSPAR arc website available at http://www.arc.org.uk/ news/pressreleases/15936.asp). Local growth disturbances vary according the anatomic site involved. Unrecognized arthritis affecting large joints can cause bony overgrowth, most commonly affecting the knee. Leg-length abnormalities greater than 2 cm are an indication for orthoses to prevent mechanical back pain. Muscle atrophy around affected joints is common and requires intensive physical therapy. Overgrowth of the medial tibial epiphyses leads to a valgus deformity of the knees, which may require epiphyseal stapling or osteotomy for correction. Arthritis of the temporomandibular joint is often asymptomatic, manifesting late with growth failure of the jaw, micrognathia,

retrognathia, and overbite. Arthritis of the facet joints in the cervical spine causes bony ankylosis with major functional consequences from the limited extension and rotational movements. Hip involvement is common in systemic JIA and polyarticular JIA, and the most frequent cause of reduced mobility. In early-onset hip disease, overgrowth of the femoral head coupled with a short broad femoral neck leads to anteversion and bowing of the femoral shaft. With disease onset after about age 11 years, the architecture is often normal, but protrusio acetabuli may develop.

CLINICAL FEATURES OF SUBTYPES OF JUVENILE IDIOPATHIC ARTHRITIS Table 97-2 provides a summary of the epidemiology and clinical features of the subtypes of JIA. SYSTEMIC ARTHRITIS Systemic JIA is defined as arthritis associated with systemic features, typically quotidian spiking fevers of 39°C or greater for more than 2 weeks, accompanied by at least one of the following: an evanescent rash, lymphadenopathy, serositis, or hepatosplenomegaly.3 This clinical subtype was previously known as Still’s disease and has a recognized adultequivalent condition, adult-onset Still’s disease.116 Systemic JIA occurs in young children with a peak age in most series of 2 to 4 years.16 The incidence is the same in both sexes in whites, in contrast to the other types of JIA. The prevalence of systemic JIA approximates to 10 cases per 100,000, representing about 10% of JIA as a whole, although some surveys have suggested that it may be more frequent in Japan and India.12 There is only a weak association between the HLA region and systemic JIA in whites, but there is good evidence that genetic predisposition constitutes at least part of the cause of systemic JIA. Non-HLA genes, such as those coding for macrophage MIF, have been shown to be associated with JIA as a whole, and a variant of the IL-6 gene confers susceptibility.39,41 These genes are thought to predispose the patient to a vigorous inflammatory response to stimuli, such as infectious agents, and the net effect of the interaction between proinflammatory and anti-inflammatory proteins is probably the key to the clinical features in this subtype of JIA. IL-6 and IL-1 may play a role in the pathogenesis of systemic JIA80 and have been proposed as therapeutic targets. Several monocyte-derived and neutrophil-derived proinflammatory factors also are abnormal in systemic JIA, including the myeloid-related proteins S100A8 and S100A9, and neutrophil-derived S100A12.84 Abnormalities of the adaptive immune system in systemic JIA may include a defect in perforin. Low levels are associated with severe disease, but can reverse when disease is controlled.117,118 Clinical Manifestations The fever is typically spiking in character with a peak of at least 39°C (Fig. 97-4A). It occurs once or twice a day and recurs each day (quotidian). This quotidian fever is accompanied by an evanescent salmon pink macular/urticarial rash, which can be itchy (Fig. 97-4B). The child is usually

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105

Temperature (°F)

103 102 101 100 99 98 97 Prednisolone (mg/day) 30

20 May

June

A

Time of year

Figure 97-4  A, Regular spiking fever typical of systemic juvenile idiopathic arthritis (JIA). B, Evanescent rash of systemic JIA.

B

unwell and irritable during the fever, but often recovers in between. Other accompanying symptoms are headaches (sometimes with signs of meningism), arthralgia or arthritis, myalgia, abdominal pains from serositis that can mimic an acute abdomen, breathlessness and chest pains on lying flat indicating pericarditis, and acute chest pains from pleuritis. The severity of symptoms varies widely, ranging from fever and rash for 2 to 3 weeks followed by mild arthritis, to simultaneous onset of all the above-described symptoms. In the most severe cases, children also may present with features of secondary hemophagocytic lymphohistiocytosis (also known as macrophage activation syndrome),119 with signs of anemia, jaundice, and purpura in later stages.

Laboratory Features There are no specific tests for systemic JIA, but there are characteristic patterns of laboratory abnormalities. There is typically a very high C-reactive protein and erythrocyte sedimentation rate, leukocytosis with neutrophilia, thrombocytosis, and anemia, which may be profound. Liver enzymes, ferritin, and coagulation screen may be abnormal in severe cases, and polyclonal hypergammaglobulinemia is frequent. There are no specific autoantibodies, but RF and ­complement levels are normal or high (as acute-phase ­reactants). Investigative tests that may be required to exclude other conditions include urinary vanillylmandelic acid and bone marrow aspiration (see later).

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Table 97-6  Differential Diagnosis of Systemic Juvenile Idiopathic Arthritis (JIA) Condition

Differentiating Features from Systemic JIA

Infection

Positive cultures, PCR, or specific   antibodies; continuous or irregular fever, nonquotidian; various rashes (not typical systemic JIA rash)

Leukemia

Nonquotidian fevers; bone pain; systemically unwell constantly

Neuroblastoma

Nonquotidian fevers; systemically unwell constantly

CINCA or NOMID

Fixed rash; undulating fevers; neurologic complications

Kawasaki disease

Fixed rash; mucocutaneous symptoms; coronary artery dilation

Other primary vasculitis

Undulating fevers; fixed, painful rashes or purpura; systemically ill constantly; renal involvement

SLE

Constant or nonquotidian fevers; positive ANA and dsDNA antibodies; cytopenias; other organs involved

ANA, antinuclear antibody; CINCA, chronic infantile neurologic cutaneous and articular syndrome; dsDNA, double-stranded DNA; NOMID, neonatalonset multisystem inflammatory disease; PCR, polymerase chain reaction; SLE, systemic lupus erythematosus.

Differential Diagnosis Many illnesses can mimic systemic JIA (Table 97-6). Apart from arthritis, fever is classic, and a careful fever chart often helps eliminate some of the differential diagnoses. The rash is similar to a viral exanthema, but the difference is that it is evanescent. If these criteria are not fulfilled unequivocally, it is necessary to screen for infectious agents, measure urinary vanillylmandelic acid, and obtain a bone marrow aspirate to exclude infection, neuroblastoma, and leukemia. Some physicians do these tests routinely because malignancies are often close mimics in the early stages of systemic JIA. The recurrent fever syndromes are often mistaken for systemic JIA, but the character of the fevers and the fixed rashes associated with these syndromes should alert the clinician to a different diagnosis. Between the subtypes of JIA, polyarticular disease also can manifest with an unwell child and arthritis, but an absence of systemic features (see Tables 97-1 and 97-2). Treatment Mild systemic JIA often needs nothing more than NSAIDs given to cover the whole 24-hour period (see Table 97-5). Indomethacin is helpful for fever and pericarditis. In more severe cases, steroids are needed, usually given as pulsed intravenous high-dose methylprednisolone (30 mg/kg bolus), up to a maximum dose of 1000 mg (1g), followed by tapering doses of oral prednisolone.120 Disease-modifying drugs, such as methotrexate and cyclosporine, are often used, but there is evidence that these are less effective than in polyarthritis.97 Some disease-­modifying ­antirheumatic drugs are associated with macrophage activation syndrome in patients with systemic JIA (e.g., sulfasalazine, methotrexate).119 Etanercept is less effective in systemic JIA compared with polyarticular JIA.103,121 Newer biologics to block IL-6 and IL-1 signaling

are more promising,80,108,109,122 and the results of phase II/III trials are awaited. The restoration of “immune balance” by autologous stem cell transplantation has been successfully carried out in more than 60 children with severe JIA, many of these systemic JIA (see section on general principles of medical management of JIA). The complications of systemic JIA require special consideration. Osteoporosis and growth retardation may be severe owing to disease activity itself123 and steroid use,124 and the use of growth hormone may be warranted.125 Evidence to establish a role for bisphosphonates and calcium and vitamin D supplements is currently being sought in a multicenter trial (see Growth Disturbances in JIA, earlier). Amyloidosis, previously a major cause of death in systemic JIA, is now less common, presumably as a result of better control of inflammatory activity, but still may affect severe refractory cases. There is evidence for the use of chlorambucil for this complication,126 but concerns about risk of malignancy remain. Amyloidosis is a relative contraindication to autologous stem cell transplantation.113 Outcome Systemic JIA is heterogeneous in severity, disease course, and outcome. It can be monocyclic, with remission within 2 to 4 years; relapsing, characterized by flares of systemic features with mild arthritis; or continuing with persistent destructive arthritis, usually more prominent after the regression of systemic features.12 Patients with severe disease can have flares of extra-articular features at any time and may have active arthritis into adult life despite standard therapies. An Italian study of 80 patients suggested a remission rate of only 33% 10 years after disease onset,127 whereas a retrospective analysis of active/inactive disease, including 59 patients with systemic JIA, suggested that children had only 30% of time with inactive disease (median follow-up 7 years).6 Overall, outcome in this subtype is poor with more children having long-term functional disability.127 Predictors of poor outcome include the presence of systemic features 6 months after onset, thrombocytosis, and the presence of polyarthritis with hip involvement.128,129 The mortality rate for systemic JIA is still perceived to be higher than the mortality rate associated with other subtypes of JIA in clinical practice now, although no formal figures are available. As a result of the inadequate control of the disease with the available therapies, growth failure and osteoporosis are serious and lasting complications. Social isolation and unemployment also have been described as more prevalent in this group.8 OLIGOARTHRITIS Oligoarticular arthritis is the most common form of JIA and preferentially affects girls (female-to-male ratio of 4:1), with a peak onset before 6 years of age. It affects about 60 per 100,000 white children, but rates vary in different ethnic groups.130 ­Oligoarticular JIA affects four or fewer joints in the first 6 months of disease. If more than four joints become involved after 6 months, it is defined as extended oligoarthritis; otherwise, it is known as persistent oligoarthritis.3 There are several exclusion factors (see Table 97-1), including psoriasis in the patient or a first-degree relative, systemic features, a positive IgM RF on more than one occasion 3 months apart, or a positive HLA-B27 test when in a boy in whom arthritis starts at 6 years or older.

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These details are crucial to consider if the ILAR criteria are to be used correctly; many studies are likely to include patients of other subtypes (e.g., ERA and psoriatic JIA) in the oligoarticular group inadvertently, where these exclusions are overlooked. There is a strong genetic association with the HLA alleles at class I (HLA A2) and class II (DRB1*0801, DRB1*1104, DRB1*1301) loci.29,131 The rate of extension to the extended oligoarthritis subtype has been reported as 30% to 50%.132,133 Increasing evidence for real differences between the persistent and extended subtypes include genetic29,43 and pathologic75,81 data. Currently, there is no single reliable predictor of extension,132,134 but much work is in progress to establish such predictors. Clinical Manifestations Children with oligoarthritis present with involvement of one to four joints, most commonly the knees and ankles (Fig. 97-5). Small joints of the hand are the third most commonly affected, but this pattern may portend the later

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onset of psoriatic arthritis.135 Temporomandibular joint arthritis is common, but is often detected late in the course of the disease because symptoms are uncommon. Initial wrist involvement is rare and may indicate progression to extended oligoarthritis, or polyarticular disease. Shoulders are rarely involved. Cervical spine disease may be manifest by torticollis. Most children complain of pain, morning stiffness, and gelling, and a parent may notice a limp and joint swelling, or in a young child, a reluctance to walk and return to crawling. Twenty-five percent of cases seem to be painless, however, and only swelling is observed. The most common extra-articular manifestation is iridocyclitis, also known as chronic anterior uveitis. Twenty percent to 30% of children with oligoarticular JIA develop uveitis, which is generally asymptomatic.136 The eye is neither red nor photophobic. Uveitis is more prevalent in children who are ANA positive.137 All children with oligoarticular JIA should have a mandatory slit lamp examination of the eyes by an experienced ophthalmologist at presentation and every 3 to 4 months for the first year and then for several years, with recommended screening times depending on age at onset.138,139 Some physicians decrease the surveillance to every 6 months if the ANA is negative because a positive ANA test is a predictor of uveitis.140 Laboratory Features Of children with oligoarthritis, 50% to 70% have a positive ANA test, typically 1:40 to 1:320 depending on the test system, and the rate is even higher in girls with an early onset.140,141 In some cases, a child has mildly or moderately elevated acutephase reactants, such as erythrocyte sedimentation rate or Creactive protein, and in a few cases a mild anemia is present. A high erythrocyte sedimentation rate may predict progression to the extended subtype.132 Elevated acute-phase reactants may suggest other conditions, such as subclinical inflammatory bowel disease with associated arthropathy.

A

Differential Diagnosis

B

The differential diagnosis of oligoarticular JIA includes other JIA subtypes, such as ERA and psoriatic JIA (see Table 97-1), and septic arthritis, reactive arthritis, foreign body synovitis, pigmented villonodular synovitis, arteriovenous malformation, bleeding disorders (e.g., hemophilia), or severe trauma, including nonaccidental injury. Mild trauma, such as from a fall, does not cause persistent joint swelling, and trauma is rarely a cause of joint swelling, unless there is an internal derangement seen in older, but not younger, children. Children with hypermobility can develop transient joint effusions after exercise.142 Lyme disease (in an endemic area) frequently causes knee swelling usually for less than 6 weeks, although it is frequently recurrent. Leukemia may manifest with joint swelling, commonly a monarthritis, but usually is associated with systemic manifestations, high erythrocyte sedimentation rate or lactate dehydrogenase, and more pain than in children with JIA.143

Figure 97-5  Oligoarticular juvenile idiopathic arthritis. A, Unilateral arthritis of the left knee showing swelling, flexion, and muscle atrophy. B, Unilateral arthritis of the left ankle showing valgus deformity of the hind foot. (A courtesy of Professor T. Southwood; B from Woo et al: Paediatr Rheumatol Clin Pract, 2007.)

Treatment Figure 97-2 is an algorithm showing the principles of treatment. Initial treatment should be with intra-articular

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i­njection with triamcinolone hexacetonide, 1 mg/kg large joints such as the knee and 0.5 mg/kg in smaller joints such as the ankle, given under sedation or general anesthetic for young children. Triamcinolone hexacetonide has been found to be superior to triamcinolone acetonide, betamethasone, and methylprednisolone acetate in randomized controlled trials,93,94 and early treatment is associated with better outcome.95 Levels of proinflammatory factors, such as MIF, may predict response to intra-articular steroids.79 If the arthritis recurs, joint injections can be repeated three times in a 12-month period. The response to a second joint injection is not predicted by the response of the first. NSAIDs should be given at adequate doses (see Table 97-2)120 and may help control symptoms, but do not alter the natural history. There is little evidence base for differences between NSAIDs, and choice is usually made according to preferred dosing schedules, availability of liquid preparations, and patient preference. When oligoarthritis is resistant to injections, a diseasemodifying agent, such as methotrexate or an anti-TNF-α agent, should be used, especially when extended disease develops. Some physicians add a disease-modifying agent at the time of an injection of a hip or the temporomandibular joint because these are particularly prone to destruction. In addition, the hip and the temporomandibular joint are important for function and are hard to evaluate clinically when disease has been established. Rarely, synovectomy is required. Physical therapy is required for all children with JIA, for stretches, muscle building, and consequent joint protection. Children who present late in the course of oligoarthritis already may have flexion contractures. Besides exercise and stretching, night splints and serial casting may be required. Serial casting is done two or three times a week for 1 month if needed, and is probably most effective when started just after joint injection. Some children with marked leg-length discrepancy (resulting from overgrowth of the affected knee) may require a shoe lift/raise. Screening for uveitis is compulsory for all cases of JIA. Uveitis is generally controlled with topical medications (glucocorticoids and mydriatics) and may require control of glaucoma. Where uveitis is resistant to topical therapy or side effects develop, methotrexate and anti-TNF-α agents can be effective.137,144 Newer biologics, such as adalimumab, have been used when other agents have failed.145 There are no data from randomized controlled trials of uveitis of JIA. Outcome Most children with oligoarthritis do well, and the disease remits in 68% in the persistent oligoarthritis subgroup.6,132 About 30% to 50% of cases become extended oligoarthritis, and the outcome of this subtype is not as good; these patients have high cumulative times of active arthritis.6 This picture has improved, however, since the introduction of methotrexate as the treatment of choice. Partial or complete remission is induced in 60% to 70% of patients on methotrexate in the extended oligoarticular group.96,97,146 Anti-TNF-α agents are effective in many patients who fail to respond fully to methotrexate,102 especially if given in combination with methotrexate. A continuing morbidity with poor outcome is visual loss, which is more frequent

in children with significant eye involvement at the time of the first ophthalmologic visit. Other sequelae include leg-length discrepancy, especially in patients with knee arthritis, and muscle atrophy. Later morbidity can include other joint involvement, such as the temporomandibular joint. Long-term studies of adults treated before the use of biologic agents have shown that 50% of adults who had ­oligoarticular-onset JIA may have ongoing active disease, or functional problems, in adulthood.8 POLYARTHRITIS, RHEUMATOID FACTOR NEGATIVE RF-negative polyarthritis is defined as arthritis affecting five or more joints in the first 6 months of disease, with a negative RF test.3 Patients who meet the criteria for systemic arthritis, ERA, and psoriatic arthritis are excluded. Extended oligoarthritis, another subgroup with a polyarticular course, is distinguished from RF-negative polyarthritis by having five or more affected joints after only 6 months of disease. There is a risk of misclassifying these two groups if a patient’s presentation is delayed, or progression of arthritis occurs around the time point of 6 months. RF-negative polyarthritis constitutes 20% to 30% of new cases.147 The British Paediatric Rheumatology National Diagnostic Register of 311 patients recorded a mean age of onset of 6.5 years for this subtype, with girls outnumbering boys by 3:1.16 Age-related analysis reveals a bimodal distribution of onset, however, with one peak around 3.5 years and the other around 10 to 11 years. Clinical Manifestations Arthritis is usually insidious and can be symmetric or asymmetric, affecting large and small joints. Typically, small joint synovitis is distinct from adult rheumatoid arthritis (as noted by Still1) because it frequently involves proximal interphalangeal joints, but spares metacarpophalangeal joints at onset. The cervical spine and temporomandibular joint are often involved.148,149 Some authors distinguish two clinical subgroups on the basis of ANA: (1) an ANA-positive group consisting of young girls (<6 years old) with an asymmetric-onset arthritis and at a high risk of uveitis, and (2) a slightly older group (7 to 9 years old) of ANA-negative patients having symmetric involvement of large and small joints.150 Uveitis occurs in 5% to 20% of patients in the RF-negative polyarthritis JIA subtype, generally patients with few affected joints.151 Laboratory Features Polyarthritis may be associated with elevated acute-phase reactants and mild anemia. The ANA test is positive in 40%, and the RF is negative by definition. Differential Diagnosis The differential diagnosis of RF-negative polyarthritis JIA includes other JIA subtypes, such as extended oligoarticular JIA, ERA, and psoriatic JIA. Other major diagnostic considerations include autoimmune connective tissue diseases such as systemic lupus erythematosus, particularly in older

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girls who are ANA positive, and lymphoma and leukemia. Septic polyarthritis is unusual, but Neisseria gonorrhoeae and Lyme disease can present in this way. ERA should be considered in particular in older boys (>6 years old; HLA-B27 testing is mandatory) (see later). Treatment Figure 97-3 is an algorithm showing the principles of treatment. Children with polyarthritis require a disease­modifying agent as soon as practically possible after the diagnosis has been confirmed. Methotrexate is typically the first agent of choice, but its slow onset of action may necessitate a short course of oral steroids, intravenous methylprednisolone, or multiple joint injections to control inflammation quickly and help reduce pain and stiffness. This initial rapid response to steroids also serves to gain the parents, and patient’s confidence. Most patients respond to methotrexate within 6 months, and nonresponders should be considered for the use of anti-TNF-α agents by this time.96,102 If anti-TNF-α therapy is begun, methotrexate can be continued because half of methotrexate nonresponders show a late response. The combination of methotrexate and etanercept has been shown more recently to be the only combination that prevents bony erosion in adults with RA (see Chapter 67).152 Sulfasalazine and leflunomide are still used in some centers before starting an anti-TNF-α agent in mild disease, although evidence suggests that leflunomide may be slightly less effective than methotrexate.99 As described in the section on principles of treatment of JIA, JIA with a polyarticular course of any type that does not respond well to methotrexate or etanercept is now increasingly being treated with a range of newer biologics. Physical therapy is required, as for all children with JIA, for stretches, muscle building, and consequent joint protection. Children with hand involvement need occupational therapy assessment and input.

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and the HLA-DRB1*0401 DQA1*03 DQB1*03 haplotype carries an increased odds ratio of 3.9 for this subtype, yet is protective for other subtypes of JIA.29 Anti–cyclic citrullinated peptide antibodies have been reported in 57% to 73% of this JIA subtype.156,157 Disease expression differs from adults, perhaps because of the effects of environmental factors, the effects of arthritis on a growing body, and the psychosocial impact of chronic disease during adolescence, which is itself a period of significant change in an individual’s independence and self-identity. Clinical Manifestations The arthritis is typically an aggressive, symmetric polyarthritis affecting the small joints of the hands, typically the proximal interphalangeal joints, metacarpophalangeal joints, and wrists, and with a large joint involvement in a pattern that resembles rheumatoid arthritis. Children frequently have more than 30 joints with arthritis. At onset, low-grade fever may be present, but it is distinctly different from systemic JIA. Felty’s syndrome (splenomegaly and leukopenia) (see Chapter 66) can occur in childhood RF-positive polyarthritis. Rheumatoid nodules occur in 10% of cases, most frequently around the elbow. Other extra-articular manifestations are reported less often than in adults. Uveitis is an unusual feature of this subtype. Laboratory Features Polyarthritis may be associated with elevated acute-phase reactants and anemia (normocytic, normochromic). The ANA test is positive in a few cases, and the RF is by definition positive on two occasions 3 months apart. Similar to adult rheumatoid arthritis, RF testing typically detects IgManti-IgG. In these patients, anti–cyclic citrullinated peptide antibodies may be more specific and as in adults are associated with erosive arthritis.157 Differential Diagnosis

Outcome Approximately 30% of children go into long-term remission; the chance of remission is highest in the first 5 years of disease.6,53 Symmetric arthritis and early hand involvement predicted future disability and poorer overall well-being.153 Final height maybe reduced, but usually much less than in patients with systemic arthritis. POLYARTHRITIS, RHEUMATOID FACTOR POSITIVE RF-positive polyarticular JIA is defined as arthritis affecting five or more joints in the first 6 months of disease and a positive RF test on two occasions at least 3 months apart. RF-positive polyarthritis constitutes 5% to 10% of cases under the juvenile rheumatoid arthritis or juvenile chronic arthritis classifications.154 In the JIA classification, RF testing is crucial to avoid large numbers of children with polyarthritis being unclassifiable.11 RF-positive polyarthritis is more common in girls, with reported female-to-male ratios of 5.7 to 12.8,16,155 and can be considered as part of the spectrum of rheumatoid arthritis, sharing immunogenetic and serologic factors. HLA-DRB1*0401 is strongly associated,

The differential diagnosis of RF-positive polyarthritis JIA includes other JIA subtypes, especially when there is no confirmed RF-positive test on two occasions. Such cases are frequently unclassified in the JIA system; however, management and therapy are unaffected. Treatment Figure 97-3 is an algorithm showing the principles of treatment. Children with RF-positive polyarthritis are at high risk of prolonged erosive arthritis and require a diseasemodifying agent at the time of diagnosis. Methotrexate has proven efficacy and should be given at 10 to 15 mg/m2/wk, if possible by the parenteral route.96 In view of the now well-established evidence in rheumatoid arthritis (see Chapter 67), clinicians need to consider the use of combination therapy of an anti-TNF-α agent with methotrexate because this has been shown to be superior to methotrexate alone in the prevention of bony erosions.152 Although most data exist for etanercept, a more recent randomized controlled trial of infliximab plus methotrexate suggested benefit from this combination.105 Data from children treated with

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anti-TNF-α and methotrexate are beginning to emerge from postmarketing surveillance registries.158 Some children ­benefit from multiple joint injections to maintain control of the arthritis, and all require physical and occupational therapy. Outcome Children with RF-positive polyarthritis have a poor long-term prognosis compared with the other JIA subgroups. In a study of 437 children with JIA with at least 4 years of follow-up, 65% of RF-positive polyarthritis patients achieved clinical remission on treatment, but only 5% maintained remission 12 months after cessation of medications, an outlook that was markedly worse than other subgroups.6 In long-term follow-up studies, patients with RF-positive polyarthritis were more likely to have a poorer Steinbrocker functional class health assessment questionnaire score, major arthritis-related surgery, and active erosive disease; patients with RF-negative polyarthritis had a similar functional outcome to systemic patients, which was better than the outcome of patients with RF-positive polyarthritis, but significantly worse than persistent oligoarthritis patients.9,159,160 PSORIATIC ARTHRITIS Psoriatic JIA is defined as the combination of arthritis and psoriasis, or arthritis and at least two of the following: dactylitis, nail abnormalities (two or more nail pits, or onycholysis), or family history of psoriasis in a first-degree relative. The earlier proposed ILAR classification2 included seconddegree relatives with psoriasis, but this was believed to classify too many cases incorrectly.161,162 A full family history is crucial, and without this children may be misclassified.161 Psoriatic JIA represents 2% to 15% of all JIA.11,15 In the United States, it is more common in whites than other racial groups; approximately 90% of patients are white. Girls are slightly more affected than boys, and the typical age of onset is 7 to 10 years, with psoriasis typically occurring within 2 years of the onset of arthritis, although it can follow arthritis by many years. The specific etiology is unknown, but there is a strong genetic component with 40% of patients with psoriasis having an affected relative, and several candidate HLA and non-HLA genes have been identified (see Chapter 72).29 More recent data from adults have implicated the newly identified IL-17-secreting T cells (Th17) and related cytokine IL-22 in the pathogenesis of psoriasis.163 Clinical Manifestations Arthritis is typically asymmetric and can involve large joints (commonly knees and ankles) and small joints, classically dactylitis, more commonly in the feet than in the hands, and distal interphalangeal joints. The total number of joints generally is limited, and children frequently follow an oligoarticular course. Psoriatic JIA is associated with uveitis in 15% of children. These features are typical of oligoarthritis, and many children are first classified as having oligoarticular JIA before psoriasis is manifest in the child or relative. A more recent study of childhood psoriatic arthritis argued for two distinct subpopulations. Using cluster analysis, the authors identified a younger group, median age 2.7 years, ANA-­positive with a female preponderance, all of whom had dactylitis.

The older group, median age 9.5 years, were more likely to have oligoarthritis and had higher remission rates.164 Although many adults with psoriatic arthritis have features of a spondyloarthropathy, such as sacroiliitis or enthesitis, in the JIA classification these children are classified as having ERA (see later), or, if they have psoriasis, are unclassified. Laboratory Features Children with psoriatic arthritis may have mild elevation of the erythrocyte sedimentation rate, C-reactive protein, and platelets, and a mild anemia of chronic disease. The ANA test is positive in half of children with psoriatic arthritis. RF is negative by definition. Differential Diagnosis Children with psoriatic arthritis are frequently misdiagnosed as having oligoarticular JIA if the history of psoriasis in the child or first-degree relatives is not sought. Exclusions include a positive IgM RF on more than one occasion 3 months apart, HLA-B27 if in a boy with onset after the 6th birthday, and any of the following: ERA, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome, or acute anterior uveitis, or a history of one of these disorders in a first-degree relative, or systemic features. Treatment The treatment is similar to oligoarthritis (see Fig. 97-2); intra-articular corticosteroid injections are beneficial for patients with limited arthritis (see section on general principles of medical management of JIA). NSAIDs help with symptoms, such as morning stiffness, but do not alter the long-term outcome. Methotrexate is beneficial for the skin psoriasis and arthritis and, when used in children, is recommended as a single weekly dose rather than split doses more commonly used by dermatologists for psoriasis alone.165 In children with more aggressive disease, anti-TNF-α therapy is indicated and may limit bony destruction significantly. Oral corticosteroids are rarely needed. Regular screening for uveitis is compulsory, and management is as for oligoarticular JIA (see section on oligoarthritis). Outcome There are few long-term outcome data of psoriatic JIA defined by the ILAR criteria. In a retrospective review of 63 patients with juvenile psoriatic arthritis diagnosed using the Vancouver criteria (i.e., including HLA-B27-associated disease and accepting psoriatic-like skin rash instead of physician­diagnosed psoriasis), 40% had ongoing active disease, and 8% had severe functional limitations after a mean follow-up of 7 years.166 The uveitis of psoriatic arthritis, similar to that of oligoarticular disease, is insidious and painless and can lead to blindness if untreated, so close monitoring is indicated. ENTHESITIS-RELATED ARTHRITIS ERA is a subtype that has replaced, but is not exactly overlapping with, previous definitions in children such as juvenile ankylosing spondylitis or syndrome of seronegative

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e­ nthesitis arthritis.167 ERA is defined as arthritis and enthesitis, or arthritis or enthesitis with at least two of the following: (1) sacroiliac joint tenderness, or inflammatory lumbosacral pain; (2) positive HLA-B27; (3) onset of arthritis in a boy 6 years old or older; (4) acute anterior symptomatic uveitis; or (5) history of ankylosing spondylitis, ERA, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome, or acute anterior uveitis in a first-degree relative. Exclusions include psoriasis in a first-degree relative, systemic features, and a positive IgM RF on more than one occasion 3 months apart. This form of JIA is more frequent in boys (maleto-female ratio of syndrome of seronegative enthesitis arthritis 7:1), although in some geographic areas it may be underrecognized in symptomatic girls, who can have milder disease with less axial skeleton involvement.168 The onset is typically in boys older than 6 years (commonly preteen or teenage) with peripheral arthritis affecting large joints, and there is a familial predilection. ERA is generally thought to be a form of spondyloarthropathy and has a strong association with HLA-B27. In patients who have the HLA-B27 gene, mechanisms may parallel those in adults with ankylosing spondylitis (see Chapter 70). There is overlap in terms of genetic factors and putative causative factors with reactive arthritis, although children with reactive arthritis are excluded from the ILAR criteria for JIA. Clinical Manifestations A typical feature of ERA is the presence of enthesitis (i.e., inflammation of the tendons and ligaments where they attach to bone [the enthesis]). The typical sites are the inferior pole of the patella, Achilles’ tendon, and plantar fascia insertions into the calcaneus. Not all entheses are equally significant in ERA, and some are prone to mechanical damage in other pediatric conditions, such as in OsgoodSchlatter disease. Metatarsalgia is common in children and should not count as enthesitis. The arthritis of ERA typically affects the hips, knees, or ankles, and may be symmetric or asymmetric. Joints are painful and stiff, sometimes with night pain. At onset, spinal symptoms are rare, but in a subgroup of children with ERA progress to features more typical of adult ankylosing spondylitis with sacroiliac joint and spinal inflammation. This progression is more likely in boys, who are HLA-B27 positive and have spinal or sacroiliac joint pain within 1 year of diagnosis.169 ERA is associated with an acute anterior uveitis, which typically presents as an acutely red, painful eye and needs immediate medical attention because if untreated it may lead to blindness (see Chapter 46). Laboratory Features There is no defining laboratory test, although HLA-B27 is present in 80% to 90% of cases and helps establish this diagnosis. The erythrocyte sedimentation rate may be mildly or markedly increased, and there may be a mild anemia, but these also should raise the suspicion that the patient may have subclinical inflammatory bowel disease. RF is negative by definition; ANA may be positive. Ultrasound can distinguish enthesitis.

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Differential Diagnosis Some children with prolonged reactive arthritis, or arthritis associated with inflammatory bowel disease, have enthesitis and would be classified as having ERA if the infective agent were not identified, or until inflammatory bowel disease is discovered. Other conditions that may mimic ERA include reactive arthritis in children and pain syndromes; children with widespread amplified musculoskeletal pain may have very tender entheses that can be mistaken for enthesitis. Treatment Treatment of ERA is similar to that for oligoarthritis and polyarthritis (see Figs. 97-2 and 97-3). Most patients respond to intra-articular corticosteroid injections, but many need a disease-modifying antirheumatic drug and respond well to sulfasalazine or methotrexate, although there has been no comparison of the two agents in children.170 If disease is severe, a course of intravenous pulse methylprednisolone is often helpful. Children with enthesitis require an NSAID for symptomatic relief. Many physicians empirically favor certain NSAIDs for enthesitis, specifically diclofenac and indomethacin. Occasionally, corticosteroid injection of the plantar fascial insertion on the calcaneus is helpful or, for a limited time, oral steroids. Physical therapy is central to management (as for all JIA), and orthotics and shoe modification can help greatly. These measures have not proved to modify the course of disease significantly, in particular, axial and spinal inflammation. In open label studies, the anti-TNF-α agents infliximab and etanercept have been shown to be effective agents for axial disease.171,172 Anti-TNF-α agents should be used early in the course of axial disease, before irreversible damage from spinal erosion and fusion occurs. Anti-TNF-α agents also are associated with improvement in peripheral arthritis and enthesitis.172 Outcome Long-term outcome of ERA is unknown, but a proportion of these children progress to the adult form of ankylosing spondylitis. Enthesitis can be more symptomatic in teens and young adults and improves with age. Spinal and sacroiliac joint involvement in teenagers, if left untreated, can lead to ankylosis, as in adults. Boys with HLA-B27 and hip arthritis are at higher risk of developing progressive spinal involvement. UNCLASSIFIED JUVENILE IDIOPATHIC ARTHRITIS Because of the exclusion criteria within the ILAR classification, strict adherence to the ILAR system leads to some children being defined as unclassifiable173,174; this is distinct from the previous European League Against Rheumatism or American College of Rheumatology criteria for juvenile arthritis, which did not include an unclassified group. The unclassified cases are patients who are defined as not having fulfilled sufficient inclusion criteria for any category or are excluded by fulfilling criteria for more than one category. A child in the oligoarthritis subgroup would be excluded if he or she had a family history of psoriasis in a first-degree

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r­ elative. Although this system caused considerable controversy when proposed, it is based on the premise that classification is primarily a research tool, and so the provision of an undifferentiated category would offer greater homogeneity for the remaining subgroups. For clinical purposes, treatment of such children follows the same guidelines as outlined earlier. Ultimately, the system for classifying JIA reflects current understanding of the disease’s pathophysiology. As this knowledge improves, future revisions would be increasingly useful in a clinical setting because patient categorization would offer accurate predictions of clinical response and prognosis.

CONCLUSION The modern treatment of JIA involves a range of specialists. Early use of one of numerous disease-modifying agents can suppress disease activity in many cases. Pediatric rheumatologists have in their favor the remarkable capacity for childhood growth and development to allow repair and restoration of function, in contrast to adults with inflammatory arthritis. A persistent block to good outcome in many areas of the world is a delay in recognition or diagnosis of JIA. When JIA is recognized, children who receive active treatment through a multidisciplinary approach should have an improving prognosis in the years to come. The advent of new biologic therapies and rapid translation of basic research into therapeutic strategies and an increased willingness on the part of regulatory bodies to make new therapies available to children should combine to continue to improve the outlook for children with arthritis. REFERENCES   1. Still GF: On a form of arthritis in children. Med Chir Trans 80:47, 1897. Reprinted in Arch Dis Child 16:156-165, 1941.   2. Petty RE, Southwood TR, Baum J, et al: Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J Rheumatol 25:1991-1994, 1998.   3. Petty RE, Southwood TR, Manners P, et al: International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: Second revision, Edmonton, 2001. J Rheumatol 31:390-392, 2004.   4. Southwood TR: Classification of childhood arthritis. In Szer IS, ­Kimura Y, Malleson PN, Southwood TR (eds): Arthritis in Children and Adolescents. 2006, pp 205-209.   5. Petty RE: Growing pains: The ILAR classification of juvenile idiopathic arthritis. J Rheumatol 28:927-928, 2001.   6. Wallace CA, Huang B, Bandeira M, et al: Patterns of clinical remission in select categories of juvenile idiopathic arthritis. Arthritis Rheum 52:3554-3562, 2005.   7. Gutierrez-Suarez R, Pistorio A, Cespedes Cruz A, et al: Health-related quality of life of patients with juvenile idiopathic arthritis coming from 3 different geographic areas: The PRINTO multinational quality of life cohort study. Rheumatology 46:314-320, 2007.   8. Packham JC, Hall MA: Long-term follow-up of 246 adults with juvenile idiopathic arthritis: Functional outcome. Rheumatology 41:1428-1435, 2002.   9. Foster HE, Marshall N, Myers A, et al: Outcome in adults with juvenile idiopathic arthritis: A quality of life study. Arthritis Rheum 48:767-775, 2003. 10. Cassidy JT: Juvenile rheumatoid arthritis. In: Kelley’s Textbook of Rheumatology 7th ed. Philadelphia, WB Saunders, pp 1579-1596. 11. Berntson L, Andersson Gare B, Fasth A, et al: Incidence of juvenile idiopathic arthritis in the Nordic countries: A population based study with special reference to the validity of the ILAR and EULAR criteria. J Rheumatol 30:2275-2282, 2003.

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PART 16  38. Fishman D, Faulds G, Jeffery R, et al: The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 102:1369-1376, 1998. 39. Ogilvie EM, Fife MS, Thompson SD, et al: The −174G allele of the interleukin-6 gene confers susceptibility to systemic arthritis in children: A multicenter study using simplex and multiplex juvenile idiopathic arthritis families. Arthritis Rheum 48:3202-3206, 2003. 40. Fife MS, Ogilvie EM, Kelberman D, et al: Novel IL-6 haplotypes and disease association. Genes Immun 6:367-370, 2005. 41. Donn R, Alourfi Z, Zeggini E, et al: A functional promoter haplotype of macrophage migration inhibitory factor is linked and associated with juvenile idiopathic arthritis. Arthritis Rheum 50:1604-1610, 2004. 42. De Benedetti F, Meazza C, Vivarelli M, et al: Functional and prognostic relevance of the −173 polymorphism of the macrophage migration inhibitory factor gene in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 48:1398-1407, 2003. 43. Crawley E, Kay R, Sillibourne J, et al: Polymorphic haplotypes of the interleukin-10 5′ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum 42:1101-1118, 1999. 44. Fife MS, Gutierrez A, Ogilvie EM, et al: Novel IL10 gene family associations with systemic juvenile idiopathic arthritis. Arthritis Res Ther 8:R148, 2006. 45. Hinks A, Barton A, John S, et al: Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthritis in a UK population: Further support that PTPN22 is an autoimmunity gene. Arthritis Rheum 52:1694-1699, 2005. 46. Seldin MF, Shigeta R, Laiho K, et al: Finnish case-control and family studies support PTPN22 R620W polymorphism as a risk factor in rheumatoid arthritis, but suggest only minimal or no effect in juvenile idiopathic arthritis. Genes Immun 6:720-722, 2005. 47. Nielsen HE, Dorup J, Herlin T, et al: Epidemiology of juvenile chronic arthritis: Risk dependent on sibship, parental income, and housing. J Rheumatol 26:1600-1605, 1999. 48. Jaakkola JJ, Gissler M: Maternal smoking in pregnancy as a determinant of rheumatoid arthritis and other inflammatory polyarthropathies during the first 7 years of life. Int J Epidemiol 34:664-671, 2005. 49. Pugh MT, Southwood TR, Gaston JS: The role of infection in juvenile chronic arthritis. Br J Rheumatol 32:838-844, 1993. 50. Hokynar K, Brunstein J, Soderlund-Venermo M, et al: Integrity and full coding sequence of B19 virus DNA persisting in human synovial tissue. J Gen Virol 81:1017-1025, 2000. 51. Gonzalez B, Larranaga C, Leon O, et al: Parvovirus B19 may have a role in the pathogenesis of juvenile idiopathic arthritis. J Rheumatol 34:1336-1340, 2007. 52. Pritchard MH, Matthews N, Munro J: Antibodies to influenza A in a cluster of children with juvenile chronic arthritis. Br J Rheumatol 27:176-180, 1988. 53. Oen K, Fast M, Postl B: Epidemiology of juvenile rheumatoid arthritis in Manitoba, Canada, 1975-92: Cycles in incidence. J Rheumatol 22:745-750, 1995. 54. Uziel Y, Pomeranz A, Brik R, et al: Seasonal variation in systemic onset juvenile rheumatoid arthritis in Israel. J Rheumatol 26:11871189, 1999. 55. Prakken AB, van Hoeij MJ, Kuis W, et al: T-cell reactivity to human HSP60 in oligo-articular juvenile chronic arthritis is associated with a favorable prognosis and the generation of regulatory cytokines in the inflamed joint. Immunol Lett 57:139-142, 1997. 56. de Kleer IM, Kamphuis SM, Rijkers GT, et al: The spontaneous remission of juvenile idiopathic arthritis is characterized by CD30+ T cells directed to human heat-shock protein 60 capable of producing the regulatory cytokine interleukin-10. Arthritis Rheum 48: 2001-2010, 2003. 57. Bywaters EG: Pathologic aspects of juvenile chronic polyarthritis. Arthritis Rheum 20:271-276, 1977. 58. Murray KJ, Luyrink L, Grom AA, et al: Immunohistological characteristics of T cell infiltrates in different forms of childhood onset chronic arthritis. J Rheumatol 23:2116-2124, 1996. 59. Wedderburn LR, Robinson N, Patel A, et al: Selective recruitment of polarized T cells expressing CCR5 and CXCR3 to the inflamed joints of children with juvenile idiopathic arthritis. Arthritis Rheum 43:765-774, 2000.

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82. Varsani H, Patel A, van Kooyk Y, et al: Synovial dendritic cells in juvenile idiopathic arthritis (JIA) express receptor activator of NF-kappaB (RANK). Rheumatology 42:583-590, 2003. 83. Gattorno M, Chicha L, Gregorio A, et al: Enrichment of plasmacytoid dendritic cells in synovial fluid of juvenile idiopathic arthritis. Arthritis Rheum 48:S101, 2003. 84. Foell D, Wittkowski H, Hammerschmidt I, et al: Monitoring neutrophil activation in juvenile rheumatoid arthritis by S100A12 serum concentrations. Arthritis Rheum 50:1286-1295, 2004. 85. Jarvis JN, Petty HR, Tang Y, et al: Evidence for chronic, peripheral activation of neutrophils in polyarticular juvenile rheumatoid arthritis. Arthritis Res Ther 8:R154, 2006. 86. Jarvis JN, Dozmorov I, Jiang K, et al: Novel approaches to gene expression analysis of active polyarticular juvenile rheumatoid arthritis. Arthritis Res Ther 6:R15-R32, 2004. 87. Ogilvie EM, Khan A, Hubank M, et al: Specific gene expression profiles in systemic juvenile idiopathic arthritis. Arthritis Rheum 56:1954-1965, 2007. 88. Allantaz F, Chaussabel D, Stichweh D, et al: Blood leukocyte microarrays to diagnose systemic onset juvenile idiopathic arthritis and follow the response to IL-1 blockade. J Exp Med 204:2131-2144, 2007. 89. Gibson DS, Blelock S, Brockbank S, et al: Proteomic analysis of recurrent joint inflammation in juvenile idiopathic arthritis. J Proteome Res 5:1988-1995, 2006. 90. Foster HE, Eltringham MS, Kay LJ, et al: Delay in access to appropriate care for children presenting with musculoskeletal symptoms and ultimately diagnosed with juvenile idiopathic arthritis. Arthritis Rheum 57:921-927, 2007. 91. Peterson LS, Mason T, Nelson AM, et al: Psychosocial outcomes and health status of adults who have had juvenile rheumatoid arthritis: A controlled, population-based study. Arthritis Rheum 40:2235-2240, 1997. 92. Blum RW, Garell D, Hodgman CH, et al: Transition from childcentered to adult health-care systems for adolescents with chronic conditions. A position paper of the Society for Adolescent Medicine. J Adolesc Health 14:570-576, 1993. 93. Balogh Z, Ruzsonyi E: Triamcinolone hexacetonide versus betamethasone: A double-blind comparative study of the long-term effects of intra-articular steroids in patients with juvenile chronic arthritis. Scand J Rheumatol Suppl 67:80-82, 1987. 94. Zulian F, Martini G, Gobber D, et al: Triamcinolone acetonide and hexacetonide intra-articular treatment of symmetrical joints in juvenile idiopathic arthritis: A double-blind trial. Rheumatology 43:1288-1291, 2004. 95. Lepore L, Del Santo M, Malorgio C, et al: Treatment of juvenile idiopathic arthritis with intra-articular triamcinolone hexacetonide: Evaluation of clinical effectiveness correlated with circulating ANA and T gamma/delta + and B CD5+ lymphocyte populations of synovial fluid. Clin Exp Rheumatol 20:719-722, 2002. 96. Ruperto N, Murray KJ, Gerloni V, et al: A randomized trial of parenteral methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate. Arthritis Rheum 50:2191-2201, 2004. 97. Woo P, Southwood TR, Prieur AM, et al: Randomized, placebocontrolled, crossover trial of low-dose oral methotrexate in children with extended oligoarticular or systemic arthritis. Arthritis Rheum 43:1849-1857, 2000. 98. Ramanan AV, Whitworth P, Baildam EM: Use of methotrexate in juvenile idiopathic arthritis. Arch Dis Child 88:197-200, 2003. 99. Silverman E, Mouy R, Spiegel L, et al: Leflunomide or methotrexate for juvenile rheumatoid arthritis. N Engl J Med 352:1655-1666, 2005. 100. van Rossum MA, Fiselier TJ, Franssen MJ, et al: Sulfasalazine in the treatment of juvenile chronic arthritis: A randomized, double-blind, placebo-controlled, multicenter study. Dutch Juvenile Chronic Arthritis Study Group. Arthritis Rheum 41:808-816, 1998. 101. van Rossum MA, van Soesbergen RM, Boers M, et al: Long-term outcome of juvenile idiopathic arthritis following a placebo-controlled trial: Sustained benefits of early sulfasalazine treatment. Ann Rheum Dis 66:1518-1524, 2007. 102. Lovell DJ, Giannini EH, Reiff A, et al: Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med 342:763-769, 2000.

103. Quartier P, Taupin P, Bourdeaut F, et al: Efficacy of etanercept for the treatment of juvenile idiopathic arthritis according to the onset type. Arthritis Rheum 48:1093-1101, 2003. 104. Lovell DJ, Giannini EH, Reiff A, et al: Long-term efficacy and safety of etanercept in children with polyarticular-course juvenile rheumatoid arthritis: Interim results from an ongoing multicenter, openlabel, extended-treatment trial. Arthritis Rheum 48:218-226, 2003. 105. Ruperto N, Lovell DJ, Cuttica R, et al: A randomized, placebocontrolled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum 56:3096-3106, 2007. 106. Giannini E, Ruperto N, Prieur AM, et al: Efficacy of abatacept in different sub-populations of JIA: Results of a randomized withdrawal study. Arthritis Rheum 56:s291, 2007. 107. Lovell DJ, Ruperto N, Goodman S, et al: Adalimumab is safe and effective during long term treatment of patients with juvenile rheumatoid arthritis: Results from a 2 year study. Arthritis Rheum 56:s292, 2007. 108. Woo P, Wilkinson N, Prieur AM, et al: Open label phase II trial of single, ascending doses of MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: Proof of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and demonstration of prolonged clinical improvement. Arthritis Res Ther 7:R1281R1288, 2005. 109. Yokota S, Miyamae T, Imagawa T, et al: Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 52:818-825, 2005. 109a. Foell D, Frosch M, Schulze zur Wiesch A, et al: Methotrexate treatment in juvenile idiopathic arthritis: When is the right time to stop? Ann Rheum Dis 63:206-208, 2004. 110. De Kleer IM, Brinkman DM, Ferster A, et al: Autologous stem cell transplantation for refractory juvenile idiopathic arthritis: Analysis of clinical effects, mortality, and transplant related morbidity. Ann Rheum Dis 63:1318-1326, 2004. 111. Wedderburn LR, Abinun M, Palmer P, et al: Autologous haematopoietic stem cell transplantation in juvenile idiopathic arthritis. Arch Dis Child 88:201-205, 2003. 112. Brinkman DM, de Kleer IM, ten Cate R, et al: Autologous stem cell transplantation in children with severe progressive systemic or polyarticular juvenile idiopathic arthritis: Long-term follow-up of a prospective clinical trial. Arthritis Rheum 56:2410-2421, 2007. 113. Foster H, Davidson J, Baildam E, et al: Autologous haematopoeitic stem cell rescue (AHSCR) for severe rheumatic disease in children: Guidance for BSPAR members—executive summary. Rheumatology 45:1570-1571, 2006. 114. Cimaz R: Osteoporosis in childhood rheumatic diseases: Prevention and therapy. Best Pract Res Clin Rheumatol 16:397-409, 2002. 115. Lovell DJ, Glass D, Ranz J, et al: A randomized controlled trial of calcium supplementation to increase bone mineral density in children with juvenile rheumatoid arthritis. Arthritis Rheum 54:2235-2242, 2006. 116. Yamaguchi M, Ohta A, Tsunematsu T, et al: Preliminary criteria for classification of adult Still’s disease. J Rheumatol 19:424-430, 1992. 117. Wulffraat NM, Rijkers GT, Elst E, et al: Reduced perforin expression in systemic juvenile idiopathic arthritis is restored by autologous stem-cell transplantation. Rheumatology 42:375-379, 2003. 118. Grom AA, Villanueva J, Lee S, et al: Natural killer cell dysfunction in patients with systemic-onset juvenile rheumatoid arthritis and macrophage activation syndrome. J Pediatr 142:292-296, 2003. 119. Sawhney S, Woo P, Murray KJ: Macrophage activation syndrome: A potentially fatal complication of rheumatic disorders. Arch Dis Child 85:421-426, 2001. 120. McCann L, Wedderburn LR, Hasson N: Juvenile idiopathic arthritis: Best practice. Arch Dis Child 91:29-36, 2006. 121. Kimura Y, Pinho P, Walco G, et al: Etanercept treatment in patients with refractory systemic onset juvenile rheumatoid arthritis. J Rheumatol 32:935-942, 2005. 122. Lequerre T, Quartier P, Rosellini D, et al: Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still’s disease: Preliminary experience in France. Ann Rheum Dis 67:302-308, 2008. 123. Cassidy JT, Hillman LS: Abnormalities in skeletal growth in children with juvenile rheumatoid arthritis. Rheum Dis Clin N Am 23:499522, 1997.

PART 16  124. Simon D, Lucidarme N, Prieur AM, et al: Effects on growth and body composition of growth hormone treatment in children with juvenile idiopathic arthritis requiring steroid therapy. J Rheumatol 30:2492-2499, 2003. 125. Davies UM, Rooney M, Preece MA, et al: Treatment of growth retardation in juvenile chronic arthritis with recombinant human growth hormone. J Rheumatol 21:153-158, 1994. 126. David J, Vouyiouka O, Ansell BM, et al: Amyloidosis in juvenile chronic arthritis: A morbidity and mortality study. Clin Exp Rheumatol 11:85-90, 1993. 127. Lomater C, Gerloni V, Gattinara M, et al: Systemic onset juvenile idiopathic arthritis: A retrospective study of 80 consecutive patients followed for 10 years. J Rheumatol 27:491-496, 2000. 128. Spiegel LR, Schneider R, Lang BA, et al: Early predictors of poor functional outcome in systemic-onset juvenile rheumatoid arthritis: A multicenter cohort study. Arthritis Rheum 43:2402-2409, 2000. 129. Modesto C, Woo P, Garcia-Consuegra J, et al: Systemic onset juvenile chronic arthritis, polyarticular pattern and hip involvement as markers for a bad prognosis. Clin Exp Rheumatol 19:211-217, 2001. 130. Graham TB, Glass DN: Juvenile rheumatoid arthritis: Ethnic differences in diagnostic types. J Rheumatol 24:1677-1679, 1997. 131. Thomas E, Barrett JH, Donn RP, et al: Subtyping of juvenile idiopathic arthritis using latent class analysis. British Paediatric Rheumatology Group. Arthritis Rheum 43:1496-1503, 2000. 132. Guillaume S, Prieur AM, Coste J, et al: Long-term outcome and prognosis in oligoarticular-onset juvenile idiopathic arthritis. Arthritis Rheum 43:1858-1865, 2000. 133. Hofer MF, Mouy R, Prieur AM: Juvenile idiopathic arthritides evaluated prospectively in a single center according to the Durban criteria. J Rheumatol 28:1083-1090, 2001. 134. Al-Matar MJ, Petty RE, Tucker LB, et al: The early pattern of joint involvement predicts disease progression in children with oligoarticular (pauciarticular) juvenile rheumatoid arthritis. Arthritis Rheum 46:2708-2715, 2002. 135. Huemer C, Malleson PN, Cabral DA, et al: Patterns of joint involvement at onset differentiate oligoarticular juvenile psoriatic arthritis from pauciarticular juvenile rheumatoid arthritis. J Rheumatol 29:1531-1535, 2002. 136. Petty RE, Smith JR, Rosenbaum JT: Arthritis and uveitis in children: A pediatric rheumatology perspective. Am J Ophthalmol 135:879-884, 2003. 137. Saurenmann RK, Levin AV, Feldman BM, et al: Prevalence, risk factors, and outcome of uveitis in juvenile idiopathic arthritis: A longterm followup study. Arthritis Rheum 56:647-657, 2007. 138. Edelsten C, Lee V, Bentley CR, et al: An evaluation of baseline risk factors predicting severity in juvenile idiopathic arthritis, associated uveitis, and other chronic anterior uveitis in early childhood. Br J Ophthalmol 86:51-56, 2002. 139. BSPAR Guidelines. Available at: http://bspar.org.uk/pages/clinical_ guidelines.asp. Accessed 2008. 140. Petty RE, Cassidy JT, Sullivan DB: Clinical correlates of antinuclear antibodies in juvenile rheumatoid arthritis. J Pediatr 83:386-389, 1973. 141. Schaller JG, Johnson GD, Holborow EJ, et al: The association of antinuclear antibodies with the chronic iridocyclitis of juvenile rheumatoid arthritis (Still’s disease). Arthritis Rheum 17:409-416, 1974. 142. Adib N, Davies K, Grahame R, et al: Joint hypermobility syndrome in childhood: A not so benign multisystem disorder? Rheumatology 44:744-750, 2005. 143. Trapani S, Grisolia F, Simonini G, et al: Incidence of occult cancer in children presenting with musculoskeletal symptoms: A 10-year survey in a pediatric rheumatology unit. Semin Arthritis Rheum 29:348-359, 2000. 144. Foeldvari I, Nielsen S, Kummerle-Deschner J, et al: Tumor necrosis factor-alpha blocker in treatment of juvenile idiopathic arthritisassociated uveitis refractory to second-line agents: Results of a multinational survey. J Rheumatol 34:1146-1150, 2007. 145. Biester S, Deuter C, Michels H, et al: Adalimumab in the therapy of uveitis in childhood. Br J Ophthalmol 91:319-324, 2007. 146. Ravelli A, Viola S, Migliavacca D, et al: The extended oligoarticular subtype is the best predictor of methotrexate efficacy in juvenile idiopathic arthritis. J Pediatr 135:316-320, 1999. 147. Andersson Gare B, Fasth A, Andersson J, et al: Incidence and prevalence of juvenile chronic arthritis: A population survey. Ann Rheum Dis 46:277-281, 1987. 148. Laiho K, Savolainen A, Kautiainen H, et al: The cervical spine in juvenile chronic arthritis. Spine J 2:89-94, 2002. 149. Twilt M, Mobers SM, Arends LR, et al: Temporomandibular involvement in juvenile idiopathic arthritis. J Rheumatol 31:1418-1422, 2004.

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150. Ravelli A, Felici E, Magni-Manzoni S, et al: Patients with antinuclear antibody-positive juvenile idiopathic arthritis constitute a homogeneous subgroup irrespective of the course of joint disease. Arthritis Rheum 52:826-832, 2005. 151. Chalom EC, Goldsmith DP, Koehler MA, et al: Prevalence and outcome of uveitis in a regional cohort of patients with juvenile rheumatoid arthritis. J Rheumatol 24:2031-2034, 1997. 152. van der Heijde D, Klareskog L, Rodriguez-Valverde V, et al: Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: Two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum 54:1063-1074, 2006. 153. Deleted in press. 154. Gare BA, Fasth A: Epidemiology of juvenile chronic arthritis in southwestern Sweden: A 5-year prospective population study. Pediatrics 90:950-958, 1992. 155. Bowyer S, Roettcher P: Pediatric rheumatology clinic populations in the United States: results of a 3 year survey. Pediatric Rheumatology Database Research Group. J Rheumatol 23:1968-1974, 1996. 156. van Rossum M, van Soesbergen R, de Kort S, et al: Anti-cyclic citrullinated peptide (anti-CCP) antibodies in children with juvenile idiopathic arthritis. J Rheumatol 30:825-828, 2003. 157. Ferucci ED, Majka DS, Parrish LA, et al: Antibodies against cyclic citrullinated peptide are associated with HLA-DR4 in simplex and multiplex polyarticular-onset juvenile rheumatoid arthritis. Arthritis Rheum 52:239-246, 2005. 158. Horneff G, Schmeling H, Biedermann T, et al: The German etanercept registry for treatment of juvenile idiopathic arthritis. Ann Rheum Dis 63:1638-1644, 2004. 159. Oen K, Malleson PN, Cabral DA, et al: Disease course and outcome of juvenile rheumatoid arthritis in a multicenter cohort. J Rheumatol 29:1989-1999, 2002. 160. Zak M, Pedersen FK: Juvenile chronic arthritis into adulthood: A long-term follow-up study. Rheumatology 39:198-204, 2000. 161. Ramsey SE, Bolaria RK, Cabral DA, et al: Comparison of criteria for the classification of childhood arthritis. J Rheumatol 27:1283-1286, 2000. 162. Berntson L, Fasth A, Andersson-Gare B, et al: The influence of heredity for psoriasis on the ILAR classification of juvenile idiopathic arthritis. J Rheumatol 29:2454-2458, 2002. 163. Zheng Y, Danilenko DM, Valdez P, et al: Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445:648-651, 2007. 164. Stoll ML, Zurakowski D, Nigrovic LE, et al: Patients with juvenile psoriatic arthritis comprise two distinct populations. Arthritis Rheum 54:3564-3572, 2006. 165. Lewkowicz D, Gottlieb AB: Pediatric psoriasis and psoriatic arthritis. Dermatol Ther 17:364-375, 2004. 166. Roberton DM, Cabral DA, Malleson PN, et al: Juvenile psoriatic arthritis: Followup and evaluation of diagnostic criteria. J Rheumatol 23:166-170, 1996. 167. Rosenberg AM, Petty RE: A syndrome of seronegative enthesopathy and arthropathy in children. Arthritis Rheum 25:1041-1047, 1982. 168. Burgos-Vargas R, Pacheco-Tena C, Vazquez-Mellado J: Juvenile-onset spondyloarthropathies. Rheum Dis Clin N Am 23:569-598, 1997. 169. Burgos-Vargas R, Vazquez-Mellado J, Cassis N, et al: Genuine ankylosing spondylitis in children: A case-control study of patients with early definite disease according to adult onset criteria. J Rheumatol 23:2140-2147, 1996. 170. Burgos-Vargas R, Vazquez-Mellado J, Pacheco-Tena C, et al: A 26 week randomised, double blind, placebo controlled exploratory study of sulfasalazine in juvenile onset spondyloarthropathies. Ann Rheum Dis 61:941-942, 2002. 171. Henrickson M, Reiff A: Prolonged efficacy of etanercept in refractory enthesitis-related arthritis. J Rheumatol 31:2055-2061, 2004. 172. Tse SM, Burgos-Vargas R, Laxer RM: Anti-tumor necrosis factor alpha blockade in the treatment of juvenile spondylarthropathy. Arthritis Rheum 52:2103-2108, 2005. 173. Berntson L, Fasth A, Andersson-Gare B, et al: Construct validity of ILAR and EULAR criteria in juvenile idiopathic arthritis: A population based incidence study from the Nordic countries. International League of Associations for Rheumatology. European League Against Rheumatism. J Rheumatol 28:2737-2743, 2001. 174. Merino R, De Inocencio J, Garcia-Consuegra J: Evaluation of ILAR classification criteria for juvenile idiopathic arthritis in Spanish children. J Rheumatol 28:2731-2736, 2001.

98

KEY POINTS Pediatric systemic lupus erythematosus (SLE) accounts for 11% of patients referred to pediatric rheumatology clinics and approximately 20% of all cases of SLE. Children with SLE appear to have more severe disease than adults, with an especially high incidence of renal involvement. Thrombocytopenic purpura and autoimmune hemolytic anemia may be presenting manifestations of SLE in children. With the use of aggressive treatment regimens, including intravenous cyclophosphamide and (presumably) mycophenolate mofetil, the prognosis for children with lupus nephritis has improved considerably, with greater than 90% survival and good renal function at 5 years. Neonatal lupus, characterized by rash, fever, and other systemic manifestations, with or without congenital complete heart block, is caused by maternal anti-Ro antibodies in association with other factors, one of which is maternal HLA-DR3. Inflammatory muscle disease in children almost always takes the form of juvenile dermatomyositis, with childhood polymyositis being very rare. Unlike in adults with dermatomyositis, an immune complex vasculitis is often present in childhood dermatomyositis and may be a major cause of morbidity and mortality. It has a predilection to involve the skin and the gastrointestinal tract. Myositis is present in as many as 25% of children with systemic sclerosis and may be the presenting manifestation. Localized scleroderma, including linear scleroderma and morphea, is three times more common than diffuse systemic sclerosis in children. In most cases, the disease remains localized and does not progress to diffuse disease. Although the cause of Kawasaki’s disease is still unknown, treatment with intravenous immunoglobulin (Ig) G has been shown to improve mortality results by decreasing the number and severity of coronary artery aneurysms. Henoch-Schönlein purpura, an IgA-mediated vasculitis, is the most common cause of vasculitis in children. It usually has a good prognosis, even in children with nephritis.

This chapter covers four of the major connective tissue diseases of children—systemic lupus erythematosus (SLE), juvenile dermatomyositis (JDM), scleroderma, and vasculitis—and their variants. The discussion is limited to aspects of these disorders important or unique to children,1 to avoid the repetition of data presented elsewhere in this text. Studies on the incidence and prevalence of these diseases are not as complete as those for juvenile rheumatoid arthritis (JRA).

Systemic Lupus Erythematosus, Juvenile Dermatomyositis, Scleroderma, and Vasculitis JAMES T. CASSIDY

However, data are available from a number of referral clinics in North America that provide reasonable estimates of the relative frequency of these disorders (Table 98-1).

SYSTEMIC LUPUS ERYTHEMATOSUS DEFINITION AND CLASSIFICATION SLE is an episodic multisystem disorder characterized by persistent antinuclear antibody (ANA) seropositivity, widespread inflammation, and immune complex deposition in key target organs. It is a prototype of autoimmune diseases in humans that results from a genetic predisposition and altered immunologic reactivity. EPIDEMIOLOGY SLE accounts for 11% of children referred to pediatric rheumatology clinics, and 20% of all cases of lupus are in children (see Table 98-1). The incidence of SLE in children has been estimated at 0.6 per 100,000.2 The incidence in a Canadian study was 0.36 per 100,000 (confidence interval [CI] 0.23 to 0.61).3 The disease is probably more frequent in Asians, Polynesians, Native Americans, and African Americans than in whites in the United States. The disease is generally regarded as more serious in children than in adults.4 SLE is unusual in a child younger than 4 years and becomes increasingly more common from age 9 through the teenage years. The female-to-male ratio is approximately 4.1:1 to 5:1, depending on age; in younger children, relatively more boys are affected. CAUSE AND PATHOGENESIS The pathogenesis of SLE is complex, consisting of abnormal homeostatic control of immunologic reactivity to nuclear and cytoplasmic antigens, which may be antigen driven; cytokine polymorphisms; and other immunologic perturbations. Defective antigen presentation, immune complex clearance, and Fas-mediated apoptotic cell death may also be involved. An environmental trigger such as sun exposure, drug reaction, or a slow virus infection may precipitate the onset of disease in a genetically susceptible host. Female hormones (estrogen, prolactin) are associated with the development of SLE in the F1 hybrid NZB/NZW mouse and potentially in humans.

  Supplemental images available on the Expert Consult Premium Edition website.

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Systemic Lupus Erythematosus, Juvenile Dermatomyositis, Scleroderma, and Vasculitis

Table 98-1  Frequency of the Major Pediatric   Connective Tissue Diseases Disease

Table 98-2  Clinical Manifestations of Systemic   Lupus Erythematosus in Childhood

Number

Percentage

Juvenile rheumatoid arthritis

7368

65.2

Systemic lupus erythematosus

1214

10.7

658

5.8

Systemic scleroderma

Juvenile dermatomyositis

90

0.8

Localized scleroderma

340

3.0

Polyarteritis nodosa

42

0.4

Kawasaki’s disease

259

2.3

Henoch-Schönlein purpura

838

7.4

Other vasculitides

491

4.3

Data based on 57,729 diagnoses from 48,934 consecutive patients entered into the Pediatric Rheumatic Disease Registry of the Pediatric Rheumatology Database Research Group, 1992-2002. Courtesy of Suzanne Bowyer, MD.

Genetics In approximately 1 in 10 families in which a person is afflicted with SLE, another connective tissue disease is identified. This observation emphasizes the heritability of this disorder; however, susceptibility is complex and polygenic. Lupus has been described in identical twins with a concordance rate of 24%, compared with 2% in dizygotic twins.5 It is also associated with selective immunoglobulin A (IgA) deficiency and inherited deficiencies of complement components such as C2, C1q, C1r, and C1 esterase inhibitor. The C4A null allele is strongly associated with SLE; human leukocyte antigen (HLA)-DR3 is increased in frequency in whites, and HLA-DR2 is increased in African Americans.

Manifestation

Occurrence (%)

Skin   Malar erythema   Photosensitivity   Raynaud’s phenomenon   Alopecia

15-80 55 40 25 20

Kidneys   Hypertension   Renal failure

85-100 30 10

Musculoskeletal system   Arthritis   Myositis

20-95 75 20

Cardiopulmonary system   Pericarditis   Pleuritis   Pulmonary hemorrhage

30-50 45 35 5

Gastrointestinal tract   Oral or nasopharyngeal ulcerations   Mesenteric thrombosis   Sterile peritonitis   Hepatosplenomegaly

5-20 15 10 5 45

Nervous system   Central   Peripheral

30-40 30 5

one to the other has been identified in sequential biopsies. In membranous glomerulonephritis, which is uncommon in children, immune complexes form along the subepithelial surface of the glomerular basement membrane and obliterate the foot processes. CLINICAL FEATURES

Drug-Induced Lupus Acute SLE is precipitated by a drug reaction in some children. Implicated medications include anticonvulsant drugs, hydralazine, D-penicillamine, isoniazid, penicillin, minocycline, and the sulfonamides. Most of these disorders are self-limited and abate on withdrawal of the offending agent. The most frequent clinical manifestations are fever, dermatitis, and pleuropericardial disease. Antibodies to doublestranded DNA (dsDNA) are usually not present; however, ANA reactivity specific for histones is characteristic (but is also found in children with idiopathic SLE). The serum complement concentration remains normal; central nervous system (CNS) disease and nephritis are uncharacteristic. Pathology The basic inflammatory lesion is an immune complex vasculitis with fibrinoid necrosis, inflammatory cell infiltrates, and sclerosis of collagen. Vascular deposition of immune complexes affects both arterioles and venules and is widespread throughout the parenchymal organs, in supporting tissues underlying the dermis and panniculus, and in mucosal and serosal surfaces. In the kidney, immune complexes are deposited in the mesangium and in subendothelial spaces beneath the glomerular basement membrane. Diffuse proliferative glomerulonephritis may represent a more severe form of focal proliferative nephritis, and progression from

Clinically, SLE is an extremely variable and diverse disease and may develop with any degree of severity, ranging from an acute, rapidly fatal illness to an insidious, chronic disability with repeated exacerbations (Table 98-2).6 Constitutional symptoms such as fever, malaise, and weight loss are common. Mucocutaneous involvement and a malar erythematous rash in a butterfly distribution are characteristic of acute disease. Hepatomegaly and splenomegaly are common. Lupus hepatitis is an infrequent complication. Arthritis affects most children with SLE and involves both large and small joints. Characteristics of this arthritis are its transient nature and the fact that it may be migratory. Pain is often more severe than expected based on objective signs of inflammation. The arthritis of SLE seldom results in permanent deformity; however, SLE may evolve from JRA in a few children. Raynaud’s phenomenon, with digital vasculitic ulcerations, is a common finding and is often present at disease onset. Ischemic necrosis of bone, particularly of the femoral heads and tibial plateaus, is frequent in longstanding disease, especially after treatment with glucocorticoids. Pericarditis is the most common manifestation of cardiac involvement, although asymptomatic abnormalities of myocardial perfusion or dysfunction may be more common than generally suspected.7 Valvular insufficiency may occur; Libman-Sacks verrucous endocarditis is characteristic and, based on echocardiographic studies, is more common

PART 16 

than was previously thought. Abnormalities of pulmonary ­function and pleuritis, along with a basilar pneumonitis, are frequent. Pulmonary hemorrhage, mesenteric thrombosis, and acute pancreatitis are often life-threatening events. Autoimmune endocrinopathies occur with increased frequency in affected children. The two affected systems most closely correlated with survival are the CNS and the kidneys. Disease of the CNS and the peripheral nervous system is a common cause of morbidity in children.8 Severe recurrent headaches, seizures, chorea closely resembling that of acute rheumatic fever, and neuropsychiatric manifestations ranging from disordered personality to frank psychosis occur in a majority of children. A labile, inappropriate affect is particularly characteristic in older children and adolescents. Intracranial hemorrhage and cerebral vein thrombosis may result from hypertension, thrombocytopenia, or the presence of antiphospholipid antibodies. Pseudotumor cerebri may be a complication of SLE or of glucocorticoid therapy. Magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) aid in differentiating functional and potentially reversible lesions from organic defects. Systemic polyneuropathy, Guillain-Barré syndrome, transverse myelopathy, and involvement of the cranial nerves have all been reported. The so-called cytoid body of retinal vasculitis is often associated with CNS vasculitis or a lupus crisis that may also present as optic neuropathy or a visual field defect. Lupus nephritis is present to some degree in virtually all children with SLE. Nephritis may not be reflected initially in changes in creatinine clearance, proteinuria, or abnormal urinary sediment. Clinically evident nephritis, if it is going to develop, usually manifests within a few years of disease onset. Continuing evidence of immune complex disease, such as increased levels of anti-dsDNA antibodies or hypocomplementemia, correlates with active nephritis in most children. It is generally agreed that prognostically important renal lesions are more common in young patients than in adults, and the prognosis in children with renal disease is more guarded. DIAGNOSIS AND DIAGNOSTIC TESTS The 11 criteria developed by the American College of Rheumatology (ACR) for the classification of SLE, as modified in 1994, are applicable to children.9,10 The presence of four criteria has a sensitivity of 90% and a specificity of 98%. A skin biopsy is occasionally helpful diagnostically because soluble immune complexes containing IgG and C3 are deposited in the vascular endothelium and along the dermoepidermal junction in both involved and uninvolved skin. This finding is known as the lupus band test. Persistent leukopenia is particularly characteristic of SLE. Most children are leukopenic at onset, with a predominance of neutrophils in the peripheral white blood cell count. Leukocytosis may not develop to an appropriate degree, however, even with severe infection. Thrombocytopenia is common (30% to 50% of cases). SLE may present as thrombocytopenic purpura with or without hemolytic anemia; Coombs’ antibodies are often present in these children. Thrombotic thrombocytopenic purpura is a rare diagnosis of exclusion. Other causes of anemia include posthemorrhagic conditions, septicemia, and gastrointestinal bleeding.

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ANAs are a hallmark of the immunologic abnormalities of SLE and are present in nearly all children with the disease. They generally occur in high titers in a homogeneous or peripheral immunofluorescent pattern on indirect immunofluorescent testing. The peripheral nuclear pattern is diagnostic of the presence of anti-dsDNA antibodies, which are associated with active systemic disease, and especially with nephritis. Antigen-antibody complex deposition leads to widespread vasculopathy and lupus nephritis. Serum antibodies in children with SLE also include those that are tissue specific (e.g., antiplatelet antibodies) and result in specific manifestations of the disease, such as thrombocytopenia. Other antibodies may be associated with an acute hemolytic anemia and leukopenia. An elevated partial thromboplastin time may signal the presence of a lupus anticoagulant. Anticardiolipin antibodies lead to recurrent thromboses (in about 10% of cases) and are associated with the development of neuropsychiatric lupus, chorea,11,12 epilepsy,13 and the catastrophic antiphospholipid syndrome.14 This antibody, a specificity of B2-glycoprotein I–dependent anticardiolipin antibodies, is also directed against cardiolipin substrate in the serologic reaction for syphilis. Both these specificities are more common in children than in adults. A young person with a false-positive result on these tests for syphilis is at risk for the development of SLE. Antiribosomal P and antineuronal antibodies are also characteristics of children with CNS disease and psychosis. Rheumatoid factors are often present in high titer. Cold agglutinins and cryoglobulins may also be present, resulting in peripheral anoxic phenomena and gangrene. Both the classic and alternative complement pathways are activated in the immune complex vasculitis of SLE. A depressed whole hemolytic complement determination (CH50 assay) reflects the status of the total complement cascade; a low concentration of C3 or C4 is usually a reliable indicator of active disease, if persistent. Dyslipoproteinemia is characteristic of active disease and is also a consequence of glucocorticoid therapy. A number of other diseases should be considered in the differential diagnosis of a child with suspected SLE. Among these are polyarticular or systemic-onset JRA, acute poststreptococcal glomerulonephritis, idiopathic hemolytic anemia, immune thrombocytopenic purpura, leukemia, allergic or contact dermatitis, idiopathic seizure disorder, mononucleosis, acute rheumatic fever, septicemia, and infectious endocarditis. Sjögren’s syndrome is a multisystem disorder that may be misdiagnosed as SLE, particularly in the presence of high titers of multiple autoantibodies, including anti-Ro/La. It is often insidious in onset and slowly progressive. Primary Sjögren’s syndrome is rare in children and may present as recurrent parotid and lacrimal swelling, dry mouth, and persistent keratoconjunctivitis. TREATMENT Because SLE is an extremely serious and complex disease, most children benefit from management by the same multidisciplinary medical team over the course of their illness. Long-term supportive care includes adequate nutrition, prompt treatment of infections, and control of ­hypertension, if present. Unnecessary restraints on a child’s

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general level of activity and psychosocial peer group interactions are undesirable. The prophylactic measures of avoiding unnecessary drug exposure, transfusion, and excessive ­sunlight should be emphasized. Appropriate clothing and sunscreens are prescribed to minimize exposure to ultraviolet ­radiation. Nonsteroidal anti-inflammatory drugs (NSAIDs), except for ibuprofen, are helpful in treating minor manifestations of SLE such as arthralgia and myalgia. Aspirin or anticoagulation may be indicated for the antiphospholipid antibody syndrome (see Chapter 76). Hydroxychloroquine is used as an adjunctive medication to control dermatitis or to moderate the glucocorticoid dosage.15 Glucocorticoids are, however, the mainstay of treatment. Prednisone is the preferred analogue for oral administration. The lowest dose that achieves the objectives of the treatment program should be prescribed. Initial therapy usually requires a split dosage regimen. Low-dose therapy, defined as 0.5 mg/kg per day, is used to treat persistent fever, dermatitis, arthritis, or serositis. These manifestations are often suppressed promptly. A period of weeks is usually required to control anemia and achieve a serologic remission, with suppression of antidsDNA antibodies and return of serum complement levels toward normal. A low-dose program is often sufficient to control clinical disease in children with mesangial or focal glomerulonephritis. Treatment of children with active SLE is monitored by the clinical course and periodic assessments of anti-dsDNA antibodies and serum complement levels. Exacerbation of the disease during steroid tapering may be signaled by a deterioration in the serologic indices and clinical measures of disease activity. High-dose prednisone therapy, defined as 1 to 2 mg/kg per day in divided doses, is indicated for lupus crisis, CNS disease, acute hemolytic anemia, and the more severe forms of nephritis. Intravenous (IV) pulse therapy with methylprednisolone is preferred for acute exacerbations in a variety of protocols at a dose of 10 to 30 mg/kg. Although the approach to the diagnosis and therapy of nephritis is controversial, the precise glucocorticoid regimen and the decision whether to add immunosuppressive drugs must be based on the degree and type of kidney involvement. Renal biopsy is warranted in most children with SLE to establish the type, activity, and chronicity of the disease, unless there is no clinical or serologic evidence of kidney involvement. In addition to glucocorticoids, immunosuppressive agents are required in some children. Although azathioprine has been employed extensively, and methotrexate more recently, clinical experience suggests that IV cyclophosphamide pulse therapy (500 to 750 mg/m2 every 4 weeks for 6 months, followed by maintenance therapy) is preferable in patients with severe nephritis.16,17 Data on the use of mycophenolate mofetil in children are limited, but studies in adults indicate that it is superior to cyclophosphamide in patients with active nephritis.18 Dialysis and kidney transplantation have been used in end-stage renal disease.19 Stem cell transplantation is currently being evaluated. Resistant cutaneous disease may respond to topical tacrolimus. Clinical measures of therapeutic responsiveness20 and preliminary core measures of disease activity and severity have been developed for clinical assessment and response to therapy.21

OUTCOME SLE is characterized by repeated exacerbations and remissions; active disease usually lasts for many years. Predicting the outcome for a specific child is difficult, and ­generalizations about outcome are especially unreliable during the first 1 to 2 years after disease onset. Later, a more realistic determination can be made, depending on the degree of systemic activity and the observed response to therapy. Outcome is poorest in children with diffuse proliferative nephritis or an organic brain syndrome; it is best in children with minimal or controlled systemic disease or mesangial nephritis or in those who respond promptly to steroid therapy. Morbidity is often underestimated, however.22 There was no definite association between poor outcome and male sex or nonwhite ethnicity in one study,23 but in others, nonwhite children were at increased risk of nephritis and a poor outcome.24,25 Although the course of the disease and its severity are highly variable, prognosis has improved dramatically during the past 3 decades.105 Life-table analysis in a study from Minnesota indicated that survival in 21 children with diffuse proliferative glomerulonephritis was only 70% at 10 years.26 In more recent studies, the survival rate was 91% at 5 years and 94% among children followed for at least 11 years.24,27 Although nephritis and CNS disease continue to be leading causes of death, infection has replaced them in some series as the most common preterminal event. Functional asplenia may predispose children to an increased risk of septicemia. Accelerated atherosclerosis of the coronary arteries may be a late complication and cause of death in approximately one fourth of cases. Cumulative organ damage occurs in many children.28 Duration of disease, hypertension, total glucocorticoid dose, and use of cyclophosphamide were associated with evidence of organ damage in 61% of 71 children followed until a mean age of approximately 26 ± 10 years.29 Osteopenia is common and is related to disease severity and duration and to medication (glucocorticoids).30 NEONATAL LUPUS SYNDROMES Children of mothers who have active SLE or are at risk of developing it may present with lupus-like syndromes in the neonatal period related to transplacental passage of maternal IgG autoantibodies.31 Neonatal lupus is divided into two types: a transient syndrome and congenital complete heart block.32 In a study of 128 infants born to mothers with anti-Ro antibodies, 16% developed cutaneous neonatal lupus and 1.6% developed complete heart block.33 Transient neonatal lupus syndrome results from the trans­ placental transport of maternal anti-Ro/La ribonucleoprotein antibodies in the presence of specific HLA-DR and DQ genes. In some infants, malar erythema develops in conjunction with discoid or annular lesions either immediately after birth or within a few months (Fig. 98-1). In most babies, there is no associated systemic disease, and serologic abnormalities abate in the first few months of life with the metabolic decay of maternal immunoglobulin. Thrombocytopenia may be present along with mild hemolytic anemia or leukopenia. CNS involvement may occur.34 Usually, this form of the syndrome requires no specific

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treatment. Occasionally, glucocorticoids are indicated for severe dermatologic disease or gastrointestinal bleeding. An autoimmune disease may develop in young adults who have had neonatal lupus,35 although there is apparently no increased risk of SLE.36 Congenital complete heart block, alone or associated with other cardiac defects such as myocarditis, septal and endocardial cushion defects, and endomyocardial fibroelastosis, is a distinct and permanent neonatal lupus syndrome. Congenital complete heart block can be diagnosed in utero by fetal echocardiography. Extreme bradycardia results in fetal hydrops. The correct obstetric approach is unclear, but it includes treating the mother with glucocorticoids (dexamethasone), plasmapheresis, and intrauterine pacing. The neonatal death rate is approximately 15%, and survival at 3 years is only 20%. Most of the remaining children require pacemakers. Approximately one third of affected babies are born to mothers who have or are at risk for the development of SLE or an associated autoimmune disease.37,38 More than 90% of these mothers are HLA-DR3-positive. Anti-Ro (SSA) antibodies directed against a small cytoplasmic RNA protein complex and, in most cases, antibodies to the La (SSB) ribonucleoprotein complex have been found in virtually every child and mother with this syndrome who have been studied. The predominant anti-Ro specificity is for the 52-kD peptide. These antibodies result in the absence or degeneration and fibrosis of the atrioventricular node, which results in heart block ­during maturation of the fetal heart at approximately 16 to 18 weeks.

Figure 98-1  Neonatal lupus. Four-month-old girl with the erythematous rash of neonatal lupus across the bridge of the nose, lower eyelids, and  superior forehead. This baby was born at 33 weeks’ gestation with complete congenital heart block. Her mother had high titers of anti-Ro  antibody.

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JUVENILE DERMATOMYOSITIS DEFINITION AND CRITERIA JDM is a multisystem disease characterized by nonsuppurative inflammation of striated muscle, skin, and the gastrointestinal tract.39 It is characterized early in its course by an immune complex vasculitis of varying severity and later by the development of calcinosis. An acute onset of proximal muscle weakness accompanied by the characteristic dermatitis is pathognomonic for JDM. The 25% of children who do not have the classic rash almost invariably have an atypical rash that still suggests this diagnosis. Polymyositis—that is, inflammatory myositis without dermatitis—is an unusual presentation in children. Serum “muscle” enzymes are elevated in 98% of affected children, and sequential measurements are important for diagnosis and to monitor the effectiveness of therapy. Atrophy, fatty infiltration, or signal abnormalities indicative of active disease can be demonstrated by MRI. A muscle biopsy is sometimes indicated during the initial evaluation to determine prognosis and provide support for the institution of long-term glucocorticoid therapy or immunosuppressive drugs. The muscle undergoing biopsy should be clinically involved but not atrophied. The best site is generally the deltoid or quadriceps. Diagnostic histopathologic changes involve striated ­mus­cles, skin, and the gastrointestinal tract. The initial lesion is an acute patchy, inflammatory lymphocytic infiltration (Fig. 98-2). Concomitant degeneration and regeneration of striated muscle fibers follow, resulting in a moderate variation in fiber size. Areas of focal necrosis are replaced during the healing phase by an interstitial proliferation of connective tissue and fat. An immune complex necrotizing vasculitis occurs in arterioles, capillaries, and venules and is especially characteristic in children with this disorder.

Figure 98-2  Muscle biopsy specimen in juvenile dermatomyositis. In the center is a perivascular, mononuclear cell inflammatory infiltrate, with arterial thickening and prominent endothelial cells (hematoxylin and eosin, ×100).

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­ iffuse linear and occasionally granular deposits of IgM, D C3d, and fibrin are present in the areas of noninflammatory vasculopathy. Electromyography is often not attempted in children because of difficulty in obtaining cooperation during the painful procedure. Notable electromyographic changes include myopathy and denervation. EPIDEMIOLOGY JDM is relatively uncommon and accounts for approximately 6% of children with major connective tissue diseases in pediatric rheumatology clinics (see Table 98-1). Incidence in a study from the United Kingdom and Ireland was 0.19 per 100,000 (95% CI 0.14 to 0.26).40 In the United States, it was 2.5 to 4.1 cases per 1 million (4-year average, 3.2; 95% CI 2.9 to 3.4) in children 2 to 17 years of age.41 The disease is more frequent in girls. Onset is especially common between ages 5 and 14 years. CAUSE AND PATHOGENESIS Although the cause of JDM remains unknown, data support a dynamic model of autoimmune disease involving muscle, the vascular system, and immune regulation in a genetically susceptible child.42 Immune complex vasculitis may be an important initiating or perpetuating event,43 with immunoglobulins and complement deposited in the walls of small blood vessels in skeletal muscle. Shared epitopes between skeletal muscle and Streptococcus pyogenes M5 protein may be targets of immune responses.44 HLA-DQA1*0501 is increased in frequency in white children45 and is associated with an increase in the TNFα-308A allele.46 JDM has occurred after a history of respiratory infections or gastrointestinal complaints, vaccinations, hypersensitivity reactions to drugs, and sunburn. Acute transient inflammatory myositis has been reported after viral and parasitic infections (e.g., coxsackievirus B, influenza, toxoplasmosis) in otherwise normal children. A fatal myositis has been described in children with agammaglobulinemia in association with echovirus infection. JDM has been reported in patients with selective IgA deficiency and C2 complement component deficiency. Maternal cell chimerism has been identified in mononuclear cells in the vascular compartment and in muscle in 80% to 90% of children with JDM.47-49 It was present in 25% of siblings and 15% of controls in these reports. Reed and colleagues49 found chimeric cells in 60 of 72 children with JDM, in 11 of 48 unaffected siblings, and in 5 of 29 healthy controls. In all groups, microchimerism was associated with the maternal HLA-DQA1*0501 allele.50 CLINICAL FEATURES Proximal muscle weakness, dermatitis, fever, and cons­ti­ tutional symptoms such as fatigue, malaise, weight loss, and anorexia are presenting features of this disorder (Table 98-3).51 The limb girdle muscles of the lower extremities are affected initially, followed by the shoulder girdle and proximal arm muscles. Affected muscles are occasionally edematous and indurated. A child may also complain of muscle pain, tenderness, or stiffness or may stop walking or be unable to climb stairs or dress. An inability to get up off the floor without the classic Gower’s maneuver or to get out of bed is common.

Table 98-3  Clinical Manifestations of Juvenile   Dermatomyositis Manifestation

Occurrence (%)

Musculoskeletal system   Muscle weakness     Proximal pelvic girdle     Proximal shoulder girdle     Neck flexors     Pharyngeal muscles     Distal muscles of the extremities     Facial and extraocular muscles   Arthritis

100

Skin   Periungual and articular rash   (Gottron’s papules)   Heliotrope rash of eyelids and periorbital edema   Malar rash   Photosensitivity   Ulcerations   Raynaud’s phenomenon   Calcinosis

85-100

Gastrointestinal tract   Pharyngitis   Dysphagia   Hemorrhage

10-60 40 10 5

Lungs   Restrictive disease   Fibrosis

15-80 80 <1

95 75 60 45 30 5 25 80 15 40 40 25 15 40

It has been proposed that the course of JDM in most c­ hildren can be divided into four clinical phases:52 1. A prodromal period of weeks to months with nonspecific symptoms 2. Progressive muscle weakness and dermatitis that lasts days to weeks 3. Persistent myositis and dermatitis of 1 to 2 years’ duration 4. Recovery with residual muscle atrophy and contractures with or without calcinosis Although muscle weakness may be impressive, deep tendon reflexes are preserved. Weakness of the anterior neck flexors and back leads to an inability to hold the head upright or maintain a sitting posture. Facial and extraocular muscles are uncommonly involved. Ten percent of children develop pharyngeal, hypopharyngeal, or palatal muscle weakness. Dysphonia results along with dysphagia, which may be related to esophageal hypomotility. These children are at risk for sudden and often fatal aspiration. Palatal speech and nasal regurgitation of liquids are early warning signs of potential respiratory compromise. Profound involvement of the thoracic and respiratory muscles occurs in a few children. Later in the disease, or in children with an acute onset, the distal muscles of the extremities may be affected. Rarely, there is generalized acute inflammation of the entire striated musculature; this may be more characteristic of an infantile onset. CNS involvement is rare. Most children have the classic rash of JDM over the malar area, the upper eyelids (with periorbital edema), and the dorsal surfaces of the knuckles (Fig. 98-3), elbows, and knees. The basic lesion is angiitis on a background of cutaneous photosensitivity. At onset, indurative edema of the

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Figure 98-4  Abnormal nail-fold capillary pattern of juvenile dermatomyositis (×100). The vessels are thickened and tortuous and show a peripheral pattern of arborization (arrow). There are clear areas of capillary dropout. (Courtesy of Dr. Jay Kenik.) Figure 98-3  Gottron’s papules present since the age of 18 months in a 4-year-old girl with juvenile dermatomyositis. Raised hypopigmented papules are present on an erythematous base over the dorsum of the hand, with accentuation over the metacarpophalangeal, proximal interphalangeal, and distal phalangeal joints.

skin and subcutaneous tissues is often present. Later there is epidermal thinning and atrophy of the accessory structures, with loss of hair and telangiectases. Vasculitic ulcers at the corners of the eyes, around the axillae, and in “stretch marks” may be difficult to treat. Although a few children have calcinosis at disease onset, the development of calcification and dystrophic mineralization with hydroxyapatite is more characteristic of the healing phase. Nail-fold capillary loop abnormalities are identifiable through the +40 lens of an ophthalmoscope in half the children and have prognostic importance.53 The nail folds show simultaneous dilation of isolated loops, dropout of surrounding vessels, and an arborized cluster of capillary loops—all distinctive features of JDM (Fig. 98-4). Dermatomyositis sine myositis or amyopathic dermatomyositis is rare in children, although the classic rash may occur before clinical muscle involvement. However, in a review of established dermatomyositis sine myositis by ­Plamondon and Dent,54 none of their 27 patients developed clinical myopathy at a mean follow-up of 32.8 months. Polymyositis is rare in childhood. The association of lipodystrophy with JDM may be more common than previously recognized (20% to 50%).41,55 The disorder may be generalized, localized, or unilateral. It is characterized by a slow and progressive loss of subcutaneous and visceral fat, often most noticeable over the upper body and face, accompanied by hirsutism, acanthosis nigricans, clitoral enlargement, hepatic steatosis, insulin resistance, abnormal glucose tolerance, and ­hypertriglyceridemia.

DIAGNOSIS AND DIAGNOSTIC TESTS Serum concentrations of the muscle enzymes creatine kinase, aldolase, aspartate aminotransferase, and alanine aminotransferase are elevated in active disease. The extent of the increase is variable, but levels can range from 20 to 40 times normal for creatine kinase or aspartate aminotransferase. Detection of MB bands on the creatine kinase isozyme pattern is usually evidence of regeneration of striated muscle, not cardiac damage. Nonspecific tests of inflammation tend to correlate with the degree of clinical activity. Leukocytosis and anemia are uncommon at disease onset, except in children with associated gastrointestinal bleeding. The occurrence of rheumatoid factors and ANAs is variable. Myositis-specific and myositis-associated antibodies have been described in only a minority of children.39,56 Half of the affected children had circulating immune complexes. The serum concentration of von Willebrand’s factor VIII antigen is elevated in active disease (evidence of vasculitis), as is the serum neopterin concentration. Considerations in the differential diagnosis include the other multisystem connective tissue diseases. JDM that presents predominantly with arthritis may be confused with either an acute systemic onset of JRA or SLE. Scleroderma poses unique diagnostic problems, in that approximately 25% of children with the disorder have a primary myositis. Although early cutaneous abnormalities of scleroderma and JDM are different, the skin changes tend to merge and become more similar later in the course of the two diseases. In children with muscular dystrophy, there is a selective pattern of muscle weakness, an insidious onset of progressive or remitting illness, and a positive family history. Dermatitis is absent. The serum creatine kinase concentration is elevated in first-degree relatives, especially in the mothers of children with X-linked disease. Congenital myopathies,

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myotonias, hypotonic syndromes, and the metabolic and endocrine myopathies, especially hypothyroidism, must also be considered. Paroxysmal myoglobulinuria and thyrotoxic myopathy may occasionally be encountered. Myasthenia gravis is rare in children. Rhabdomyolysis may be a complication of an acute infection, trauma, or extreme muscular exertion. Onset is abrupt and is characterized by profound weakness, myoglobinuria, and occasionally oliguria and renal failure. Trichinosis and toxoplasmosis cause myositis of varying severity, and severe pustular acne may occasionally be associated with inflammatory disease of muscle. Influenza B, coxsackievirus B infection, poliomyelitis, and Guillain-Barré syndrome are other diagnostic considerations. TREATMENT The presence of a noninflammatory vasculopathy is associated with a poorer outcome and is an important prognostic factor in survival. Zonal loss of the capillary bed, areas of focal infarction of muscle, lymphocytic non-necrotizing vasculopathy, and a noninflammatory endarteropathy have been associated with progressive infarction of muscle and the gastrointestinal tract and with cutaneous ulcerations. Smooth muscle is not affected, except for isolated vasculitis. The heart is generally not involved in the primary pathologic process. A few children with cardiac disease have been described with focal myocardial fibrosis and contraction band necrosis. General supportive care and a coordinated team approach are vital and should include scheduled, individualized rest and positioning. Muscle strengthening should be added only when clinical evidence of acute inflammation has subsided. During the convalescent phase, physical therapy is focused on normalizing function as much as possible and minimizing the development of contractures secondary to muscle weakness or atrophy. The Childhood Health Assessment Questionnaire is a valid measure to assess physical function.57 Preliminary core measures of disease activity and damage assessment have been developed.58 Osteopenia is almost universally present.30,59 The introduction of glucocorticoids dramatically im­­ pro­ved the prognosis of JDM. For initial treatment of acute disease, it is generally necessary to use 2 mg/kg per day of prednisone in four divided doses for at least the first month; then, if indicated by clinical response and a decrease in the serum muscle enzyme concentrations, a lower dose in the range of 1 mg/kg per day can be prescribed. Thereafter, the daily steroid dose is slowly tapered in amount and frequency of administration, as determined by improvement in clinical status, degree of muscle weakness (repeated testing on a 0 to 5 scale), and level of serum muscle enzymes. Satisfactory control is not achieved until enzyme levels have returned to normal or nearly normal and remain there ­during tapering of the steroid dose and as the child’s level of physical activity increases. IV methylprednisolone pulse therapy is indicated for acute exacerbations and should be considered as initial treatment to minimize the daily steroid dose. Alternate-day steroid therapy may be useful only late in the recovery phase. Addition of hydroxychloroquine aids in controlling the dermatitis and appears to be steroid ­sparing.

Acute complications (e.g., cutaneous ulcerations) and failure to respond to steroids may be indications for the use of immunosuppressive agents or alternative therapeutic regimens, which include methotrexate, IV cyclophosphamide, IV immunoglobulin (IVIG),60 cyclosporine, mycophenolate mofetil, hydroxychloroquine, plasmapheresis, ­ extracorporeal photochemotherapy, and potentially ­ monoclonal antibody to tumor necrosis factor-α (TNFα). Experience with stem cell transplantation is limited. Cutaneous disease can be approached with emollients and agents such as tacrolimus. Many approaches to the therapy of calcinosis have been advocated, including colchicine, probenecid, aluminum salts, warfarin, and bisphosphonates. None of these has been uniformly successful in studies with adequate numbers of patients. Surgical excision of calcific tumors in areas of ulceration or pressure remains an option. Chronicity of disease and pathologic calcifications have been associated with the presence of the TNFα-308A allele.46 Hypercalcemia has been described during resolution of the calcinosis. OUTCOME The basic nature of the inflammatory disease, its initial response to treatment, and the presence or absence of vasculitis or progressive involvement of other organ systems, such as the gastrointestinal tract and lungs, are major factors that influence outcome. Children with varying degrees of disease activity have decreased aerobic and work capacity.61 A duration of active myositis as short as 8 months has been reported. In up to 60% of children, the disease course lasts approximately 2 years and consists of only one or two exacerbations. The remaining 40% continue to have acute exacerbations and remissions; a disease that is more typical of systemic vasculitis eventually develops in a few. In a small number of children, sclerodactyly and cutaneous atrophy or areas of lipoatrophy associated with insulin resistance may develop late in the course. New data emphasize the potential role of leptin deficiency in the abnormalities characteristic of lipodystrophy.62 Acanthosis nigricans or a recurrence of arthritis may occur. Even years after onset, some children have persistent elevations of serum muscle enzymes, especially creatine kinase, and characteristic histopathologic features of the disease may be noted on repeat biopsy. The course of the dermatitis often does not follow that of the myositis. Many clinicians are convinced that children who have a generalized rash and cutaneous ulcerations have the worst prognosis. The characteristic nail-fold capillary loop abnormalities of thickening and arborization, along with a noninflammatory vasculopathy, correlate with more severe disease. During the healing phase of the myositis, ­calcium salts (hydroxyapatite or fluorapatite) are deposited in skin and subcutaneous tissues, around the joints, and within interfascial planes of the muscles in up to half of children. Later, calcification may be slowly resorbed spontaneously (Figs. 98-5 and 98-6). It has been proposed that early use of IV pulse steroid therapy may minimize the later development of calcinosis.39 Despite these findings, the average child progressively improves to achieve functional recovery (Table 98-4). The

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B

Figure 98-5  Massive deposits of calcium salts in the subcutaneous tissue and fascia about the right knee in an 11-year-old boy. Calcinosis followed the acute phase of juvenile dermatomyositis by 3 years. A, Anteroposterior view. B, Lateral view.

A

B

Figure 98-6  Same patient as in Figure 98-5, but 2 years later. Much of the calcification has been resorbed spontaneously. A, Anteroposterior view,  B, Lateral view.

outcome is best in children who are diagnosed early and receive vigorous treatment. Most children should be able to function independently as adults, although some have residual atrophy of skin or muscle groups. Difficulties during pregnancy have been described in women who have had JDM. In the preglucocorticoid era, JDM was associated with a mortality rate that approached 50%. Surviving children often had devastating residual problems, including contractures, muscle atrophy, and widespread calcinosis. At present, the long-term survival rate approaches 90%, and functional outcome has been greatly improved. The greatest risk of death is within the first 2 years after onset. An acute gastrointestinal complication or respiratory insufficiency

leading to hypoxia with or without aspiration is a serious, often preterminal event.

SCLERODERMA The sclerodermas are systemic or localized connective tissue diseases of unknown cause. Often, their development is unrecognized initially because these disorders are so rare. A classification is presented in Table 98-5. Systemic disease is divided into diffuse cutaneous scleroderma and limited cutaneous scleroderma. The localized forms of the disease, such as morphea or linear scleroderma,63 are often regarded as more dermatologic than rheumatic in nature. Some

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Table 98-4  Outcome for Children with Juvenile ­Dermatomyositis Outcome

Occurrence (%)

Complete functional recovery

65

Minimal disease (atrophy   or contracture)

25

Calcinosis

20-40

Significant disability   or dependence

5

Death

7 L

Table 98-5  Classification of Scleroderma Systemic Disease

M

Scleroderma   Diffuse   Limited Overlap syndromes   Sclerodermatomyositis or other connective tissue diseases   Mixed connective tissue disease Localized Disease Morphea Generalized morphea Linear scleroderma Eosinophilic fasciitis

r­ heumatologists also include mixed connective tissue disease and eosinophilic fasciitis in this category. DIFFUSE CUTANEOUS SYSTEMIC SCLERODERMA The early clinical presentation of diffuse cutaneous systemic scleroderma (DCSS) is often subtle. Although not validated in children, the ACR classification criteria seem to be applicable to this age group.64 Epidemiology DCSS is rare and accounts for about 1% of major connective tissue disorders in pediatric rheumatology clinics (see Table 98-1).65 Girls are affected more frequently than boys in a ratio of 3:1, except in the youngest age group.1 There is no peak age at onset during childhood and no racial predilection. Familial clustering has been demonstrated.66

Figure 98-7  Renal arteriole from a patient who died of scleroderma and hypertensive crisis. There is virtual obliteration of the vessel lumen (L) by intimal proliferation and medial mucoid hyperplasia (M).

the ­pathogenesis.67,68 Although not uncommon in healthy adults, microchimerism is increased in scleroderma but may be detected only in bone marrow or affected tissues.69 Angiitis is regarded as the basic initial lesion. The skin and gastrointestinal tract are involved early, along with the lungs, heart, and kidneys. Perivascular infiltrates of mononuclear cells are often present and have been identified in some studies to consist predominantly of T lymphocytes. Arterioles eventually undergo hyalinization and fibrosis (Fig. 98-7). In the skin, there is thinning of the epidermis, loss of the rete pegs, and atrophy of the dermal appendages. In the deeper layers, homogenization of the collagen fibers, with loss of structural detail; increased density and thickness of collagen deposition; and predominance of embryonal fibers are characteristic.

Cause and Pathogenesis Scleroderma-like disease occurs in children with insulindependent (type 1) diabetes mellitus, phenylketonuria, and progeria and has developed after exposure to vinyl chloride, bleomycin, and pentazocine. It occurred in an epidemic in Spain related to a toxin in adulterated rapeseed oil. The pathogenesis is basically unknown. There is an increased number of high collagen-producing fibroblasts in the skin. Endothelial perturbation is present, with accelerated endothelial cell apoptosis and anti–endothelial cell antibodies. The similarities between scleroderma and graft-versus-host disease in bone marrow transplant recipients has led to the hypothesis that a persistence of fetal progenitor cells and microchimerism may be involved in

Clinical Features Clinical manifestations of DCSS are summarized in Table 98-6. The onset is often marked by the appearance of Raynaud’s phenomenon; tightening, thinning, and atrophy of the skin of the hands and face; or the appearance of cutaneous telangiectases about the face, upper trunk, and hands. There is often a diagnostic delay of years because of the subtle, insidious nature of the presentation of this disease. Raynaud’s phenomenon occurs in most children with DCSS and often antedates the onset of cutaneous abnormalities. It is characterized by obstructive digital arterial disease and sympathetic hyperactivity. Vascular spasm within

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Table 98-6  Clinical Manifestations of Systemic ­Scleroderma in Childhood Manifestation

Occurrence (%)

Skin Raynaud’s phenomenon Digital ulcerations Telangiectases Subcutaneous calcification Pigmentary changes

100 75 60 30 25 20

Gastrointestinal tract Abnormal esophageal motility Dysphagia Colonic sacculations Duodenal dilation

75-100 75 20 20 5

Lungs Dyspnea Abnormal diffusion Decreased vital capacity

75-100 20 75 70

Musculoskeletal system Joint contractures Resorption of digital tufts Muscle weakness and pain

25-75 75 75 40

Heart Electrocardiographic abnormalities   and arrhythmias Cardiomegaly Congestive failure

15-30 30 15 15

viscera such as the esophagus may accompany the peripheral anoxia. Digital gangrene may supervene, with the development of small atrophic pits on the fingertips. Characteristic abnormalities of the nail-fold capillaries have been identified. There is a reduction in the number of vessels and a marked tortuosity and “puddling” of the remaining capillaries. Scattered white fibrotic areas are prominent. Skin tightening is virtually universal and tends to become more generalized with time. Hypopigmentation and hyperpigmentation are characteristic, as are subcutaneous calcification and deposition of calcium salts around joints (Fig. 98-8). Erythema and ulcerations may develop over the elbows, knees, and malleoli. Many children have contractures about joints, and a few have objective evidence of arthritis. A crepitant tenosynovitis develops in others. Muscle pain and tenderness are present in approximately 20%. Elevation of the serum muscle enzymes tends to be mild to moderate and not as striking as in JDM. Dyspnea on exertion may be related to skin tightness, muscle weakness, or interstitial pulmonary fibrosis. Myocarditis and cardiomyopathy also lead to dyspnea, arrhythmia, and signs of heart failure. Although widespread gastrointestinal involvement occurs in most children, symptomatic disease is often confined to the esophagus, with complaints of dysphagia or reflux esophagitis. Esophageal ulceration and constriction may develop. Malabsorption may become severe and lead to a fatal ­outcome. Renal blood flow is characteristically decreased, especially in the cortex, although normal glomerular filtration may be preserved by intrarenal shifts in blood flow. Plasma renin levels correlate with the degree of histologic abnormality of the renal arteries and arterioles. Renal arteriography may document arterial narrowing, tortuosity of the interlobular and arcuate arterioles, cortical hypoperfusion,

Figure 98-8  Subcutaneous nodule of periarticular calcification in a teenage girl with acrosclerosis.

and other changes that accompany malignant hypertension. Kidney size is small to normal. Diagnosis and Diagnostic Tests High-titer ANAs with speckled patterns are present in the serum in most children. Distinct antigenic specificity may be present, with anticentromere in limited disease, anti-Scl 70 (topoisomerase 1) in diffuse disease, or antinucleolar antibodies. Pulmonary diffusion testing and spirometry are sensitive measures of involvement of the respiratory tract and document a decrease in the timed vital capacity and forced expiratory flow, an early decrease in diffusion, and an increase in functional residual volume. High-resolution CT may confirm the presence of pulmonary disease despite a normal chest radiograph. Even in early asymptomatic disease, upper gastrointestinal fluoroscopy often documents disordered peristalsis of the distal esophagus. Esophageal motility studies by manometry, however, are more sensitive indicators of functional abnormalities, and a 24-hour pH probe study for potential reflux is helpful. Dilation of the second portion of the duodenum and pseudosacculations of the colon may also be present. Acro-osteolysis of the digits, accompanied by focal areas of soft tissue calcification, may be present on radiographs of the hands (Fig. 98-9). Plethysmography confirms abnormal vascular responses in affected digits in children with Raynaud’s phenomenon and documents both obstructive vascular disease and overactivity of the sympathetic nervous system. Arteriography should be performed with care, if at all, because it may exacerbate digital anoxia.

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the treatment of hypertension and may have some longterm beneficial effect on abnormalities of the skin and subcutaneous tissues. Autologous stem cell transplantation is being evaluated.70,71 Raynaud’s phenomenon is best managed with calcium channel blockers such as nifedipine, α-adrenergic blocking agents such as phenoxybenzamine or prazosin, and potentially new agents such as sidenofil. Prostacyclin analogues appear to be safe and effective for the treatment of severe vaso-occlusive disease.72 Biofeedback has been advocated for the management of less threatening vasospasm. Children with Raynaud’s phenomenon must also dress appropriately for the season and avoid cold liquids and objects that exacerbate peripheral arteriolar constriction. Outcome

Figure 98-9  Hand of a girl with complaints of Raynaud’s phenomenon for 2 years. Arrow points to early resorption of the tuft of a distal phalanx (acro-osteolysis).

The prognosis for pediatric patients with diffuse ­scleroderma is poor, especially for those with DCSS.73 Death is often related to cardiopulmonary failure or gastrointestinal complications, including severe inanition. Cardiac arrhythmias may develop during the course of the disease secondary to myocardial fibrosis, and congestive heart failure is often a terminal event. Pulmonary interstitial disease and vascular lesions are probably universal. Renal failure or acute hypertensive encephalopathy supervenes as a potentially fatal outcome in a few children; in adults, these complications are more likely to occur early in the course of the disease. A child may live decades after the onset of systemic scleroderma; therefore, an optimistic but realistic attitude should prevail in discussions with parents. Patients with limited disease were originally thought to have a more favorable prognosis, but evidence is lacking because of the rarity of this subtype. LOCALIZED SCLERODERMA

Considerations in the differential diagnosis include JDM, SLE, and, less frequently, JRA. Patients with limited disease may have features of the previously designated CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectases), now referred to as limited cutaneous systemic scleroderma. Other overlap syndromes, mixed connective tissue disease, and eosinophilic fasciitis should also be considered. Treatment No uniformly effective therapy is available.1 NSAIDs may relieve some of the musculoskeletal symptoms. Vigorous physical therapy is important in most patients to prevent or minimize joint contractures. D-penicillamine or colchicine may be useful in the management of cutaneous manifestations, if prescribed early; cyclosporine, methotrexate, and cyclophosphamide have been suggested. Because of its apparent safety and tolerability, mycophenolate mofetil has been advocated as a potential immunomodulatory agent for maintenance. Glucocorticoid drugs are contraindicated in most children, because these agents may exacerbate small blood vessel disease and renal involvement with hypertension. Malignant hypertension demands immediate lowering of the blood pressure to normal and merits expert intensive care. Angiotensin-converting enzyme inhibitors are effective in

The localized sclerodermas are three times as common as systemic disease in children and adolescents (accounting for about 3% of referrals; see Table 98-1). Linear scleroderma is approximately twice as frequent as morphea, which has an estimated incidence of 2.7 per 100,000 children.63,74 Linear scleroderma develops primarily in the first 2 decades of life. Laboratory abnormalities are few, with the exception of ANAs in almost half the children.75 Antibodies to centromere or Scl 70 are generally not present. In the localized syndromes, fibrosis of the connective tissues most commonly affects the dermis, subdermis, and superficial striated muscle. However, in a multinational review of 750 children, extracutaneous disease developed in approximately one fourth.76 Trauma often precedes the onset of cutaneous disease. It has been proposed that morphea be subdivided into five types: (1) single or multiple plaques, (2) smaller lesions in a more generalized distribution (guttate morphea), (3) bullous, (4) linear, and (5) deep.77 All these subtypes demonstrate homogenization of collagen bundles. In early disease, acute inflammatory erythema and edema are present in one or more circumscribed lesions, followed by hypopigmentation and induration surrounded by areas of hyperpigmentation (Fig. 98-10). Lesions may be located anywhere on the trunk or extremities and may coalesce or enlarge ­centrifugally to involve larger areas of the body. Paresthesia or pain may be present over these lesions.

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Figure 98-10  Lesions of morphea with central hypopigmentation and active borders on the thorax of a young girl. Another extensive lesion is present on the outer left arm.

Linear scleroderma is the most common subtype in children and is characterized by the presence of one or more areas of linear involvement of the skin of the head, trunk, or extremities. Underlying bone is often affected, with resultant abnormalities of growth or joint contractures. Linear scleroderma often affects only one side of the body, producing hemiatrophy of involved areas. Indeed, it is this lack of normal development, such as in hemifacial atrophy and failure of an extremity to grow in proportion to its opposite member, that causes the most severe disabilities (Fig. 98-11). Linear scleroderma is also associated with syndromes of progressive facial hemiatrophy (Parry-Romberg syndrome) or uveitis.78 Because linear lesions of the face or scalp may have the appearance of dueling scars, the term scleroderma en coup de sabre has been used. D-penicillamine may be effective in the more generalized form of morphea if used early. Hydroxychloroquine has been recommended by some experts, and ultraviolet A1 phototherapy is advocated by others. Glucocorticoids, as well as methotrexate, may be indicated in clinically active disease. Local emollients and steroid ointments and, more recently, imiquimod may also result in cutaneous improvement. Lo­­ c­alized scleroderma may regress spontaneously without treatment, or fibrosis of the involved skin and subcutaneous tissues may progress to produce “hide binding” and marked con­ tractures of an extremity. Active disease is often characterized by exacerbations and remissions occurring over many months to a few years. Prognosis is generally satisfactory in the absence of severe deformity or systemic involvement. Occasionally, visceral disease or a seizure disorder develops late in the course of linear scleroderma. In a few children, the disease may evolve into an overlap syndrome with another connective tissue disease, such as SLE.

Figure 98-11  Linear scleroderma affecting the right leg of a 14-year-old girl. The disease began at age 6 years and resulted in severe atrophy and shortening of the extremity.

morphea in some children. This disorder is exceptionally rare in the pediatric population. Affected children present with marked induration of cutaneous and subcutaneous tissues of the upper or lower extremities and occasionally the trunk or face. Unusual physical exertion may precede the onset of disease. Raynaud’s phenomenon, nail-fold capillary abnormalities, and visceral disease are absent. Diagnosis is confirmed by a full-thickness biopsy of skin, fascia, and muscle. Inflammation is present in all layers, but the most characteristic features are thickened fascia, with infiltration of histiocytes and often eosinophils, and a prominent perivascular infiltrate of lymphocytes and plasma cells. IgG, IgM, and C3 may be deposited in areas of inflammation. Associated laboratory findings include hypergammaglobulinemia and a remarkable peripheral eosinophilia of 40% to 60%. Eosinophilic fasciitis must be differentiated from the eosinophilia-myalgia syndrome. As originally reported, eosinophilic fasciitis was self-limited, with spontaneous resolution after months to years. There was often marked relief with the administration of low-dose glucocorticoids. Occasionally, a more severe form of the disease with hematologic abnormalities evolved. These complications may be more common with childhood-onset disease.

EOSINOPHILIC FASCIITIS

MIXED CONNECTIVE TISSUE DISEASE

Controversy continues over whether eosinophilic fasciitis is a distinct clinicopathologic entity or an unusual variant of deep morphea.79 It is also associated with plaque

Mixed connective tissue disease was initially reported as a disorder associated with a favorable prognosis and an excellent initial response to relatively low-dose ­ glucocorticoid

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therapy. It had a frequency of 0.3% in the U.S. Pediatric Rheumatology Data Base. Children present with arthritis, myositis, and cutaneous disease characteristic of scleroderma, SLE, or JDM.80 Progression to a more scleroderma-like disease has occurred, with sclerodactyly and gastrointestinal involvement, or an SLE-like disease may evolve.81,82 Nephritis may be more frequent and more severe in children than in adults. Children often have less pulmonary disease (hypertension) and more hematologic complications (thrombocytopenia) than adults. ANAs are present in very high titers, often in a speckled pattern, to an extractable nuclear antigen and ribonucleoprotein (RNP). Epitope specificity is to U1RNP and the associated 70-kD A and C polypeptides and, in some instances, to U1RNA.83 The predominant HLA associations in these patients are to DR2 and DR4. Other ANAs delineate a subset of children with an overlap syndrome who have the immune complex characteristics of SLE. Antibodies to dsDNA and to the Sm nuclear antigen are present in this latter group.

VASCULITIS Inflammatory vasculitis is a prominent component of virtually all the systemic connective tissue diseases. The current classification of idiopathic vasculitis is somewhat unsatisfactory,84 but it is based on the size of the vessels predominantly involved, the type of visceral involvement, and whether the predominant histopathologic feature is vessel wall necrosis or a granulomatous response.1 All forms of vasculitis, except for Henoch-Schönlein purpura and Kawasaki’s disease, are rare in children (Table 98-7). In national diagnostic registries, the various forms of vasculitis account for 1% to 6% of the pediatric rheumatic diseases.3,85,86 A major study of classification criteria for the vasculitic diseases (predominantly in adults) has been published by a committee of the ACR,87 with modification by a consensus conference.88 NECROTIZING VASCULITIS OF MEDIUM AND SMALL ARTERIES Medium-sized muscular arteries are involved in necrotizing vasculitis; the predominant histopathologic change is fibrinoid necrosis of the entire thickness of the vessel wall.89 Lesions tend to be segmental, with a predilection for bifurcations of the vessels. Biopsy specimens usually

Table 98-7  Relative Frequencies of Vasculitides   in Childhood U.S. Registry Disease

No. of Patients (N = 434) Percentage

Kawasaki’s disease

  97

Henoch-Schönlein purpura

213

22.4 49.1

Wegener’s granulomatosis

   6

  1.4

Polyarteritis nodosa

  14

  3.2

Takayasu’s arteritis

   8

  1.8

Unclassified

  96

22.1

Data from Bowyer S, Roettcher P: Pediatric rheumatology clinic populations in the United States: Results of a 3 year survey. J Rheumatol 23:1968-1974, 1996.

d­ emonstrate vasculitis in all stages of development from acute to chronic. Polyarteritis Nodosa Polyarteritis nodosa (PAN) was initially described more than a century ago, and small numbers of patients have periodically been reported in the pediatric literature. The classic disease remains rare and accounts for approximately 0.4% of referrals to pediatric rheumatology clinics (see Table 98-1). The course and progression of this disease are highly variable, and multisystem involvement leads to diagnostic confusion with numerous other disorders. Early diagnosis and correct classification are often difficult (Table 98-8).90 Clinical Features. Although the onset of PAN is frequently insidious, constitutional symptoms of fever and weight loss are often the presenting complaints. The renal, gastrointestinal, and cardiovascular systems are prominently involved, as are both the central and peripheral nervous systems (Table 98-9). The initial clinical diagnosis may be renovascular hypertension or a surgical abdomen. Severe sensorimotor peripheral neuropathy that is often asymmetric in distribution—so-called Table 98-8  Proposed Criteria for the Diagnosis   of Polyarteritis Nodosa in Childhood* Major Criteria Renal disease Musculoskeletal findings Minor Criteria Cutaneous findings Gastrointestinal involvement Peripheral neuropathy Central nervous system disease Hypertension Cardiac disease Lung disease Constitutional symptoms Increased acute-phase reactants Presence of hepatitis B surface antigen *Diagnosis requires the presence of five criteria, including at least one major criterion. Antinuclear antibody and anti–double-stranded DNA must be absent. From Ozen S, Besbas N, Saatci U, et al: Diagnostic criteria for polyarteritis nodosa in childhood. J Pediatr 120:206-209, 1992.

Table 98-9  Clinical Manifestations of Polyarteritis ­Nodosa in Childhood Manifestation

Occurrence (%)

Hypertension Gastrointestinal tract

80 68

Musculoskeletal system

74

Skin

69

Nervous system

45

Central nervous system

16

Peripheral neuropathy

10

Heart

21

Kidneys

25

Lungs

7

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Table 98-10  Criteria for the Diagnosis of Kawasaki’s Disease Criterion*

Occurrence (%)

1.  Fever lasting 5 days or more

100

2. Changes in lips and oral cavity   a. Dry, red, vertically fissured lips   b. Strawberry tongue   c. Diffuse erythema of mucous membranes

  90

3.  Bilateral nonsuppurative bulbar conjunctivitis

  85

4. Polymorphous rash (primarily on trunk)

  80

5. Changes in peripheral extremities   a. Erythema of palms and soles   b. Indurative edema of hands and feet   c. Desquamation from digital tips

  70

6. Acute nonpurulent enlargement of cervical   lymph node to >1.5 cm in diameter

  70

*Five criteria are required for diagnosis, or four criteria plus coronary aneurysms on echocardiography. For criteria 2 and 5, any one of the three findings will suffice. Modified from Sakaguchi M, Taka A, Endo M, et al: On the mucocutaneous lymph node syndrome or Kawasaki disease. In Yu PN, Goodwin JF (eds): Progress in Cardiology 13. Philadelphia, Lea & Febiger, 1985, p 97.

Figure 98-12  Marked digital cyanosis and swelling in a young boy with polyarteritis nodosa. The digital anoxia was accompanied by chronic pain that was exacerbated during acute vasospastic episodes.

study to study. Death is most commonly secondary to renal failure, myocardial infarction, or hypertensive encephalopathy. Kawasaki’s Disease

mononeuritis multiplex—may be present. Cutaneous lesions are frequent and include purpura, peripheral gangrene, and nodular vasculitis (Fig. 98-12). The degree and extent of multisystem involvement are often reflected in anemia, leukocytosis, marked elevation of the erythrocyte sedimentation rate, urinary sediment changes, and abnormalities in serum immunoglobulin concentrations. Rheumatoid factor and ANA seropositivity are unusual. Increased levels of von Willebrand’s factor and β-thromboglobulin are associated with activity of the vascular disease. Immune complexes may be present. A few children (<5%) demonstrate seropositivity for hepatitis B– or C–associated antigens. Diagnosis depends on confirmation by biopsy of an involved, accessible site (skin, muscle, nerve) or an angiogram that demonstrates aneurysms in the celiac or renal vasculature.89,91 Treatment. Glucocorticoid therapy is the mainstay of treatment. Suppressive amounts of prednisone are indicated, in the range of 1 to 2 mg/kg per day in divided doses. The aggressiveness of the therapeutic program must be closely monitored, according to the extent of cardiac and renal involvement and the presence of hypertension. A child may not respond adequately to oral prednisone alone or to IV steroid pulse therapy. Extensive systemic involvement, particularly of the abdominal vasculature with aneurysms and thrombosis, is generally accepted as an indication for the use of intermittent IV pulse therapy with cyclophosphamide in conjunction with glucocorticoids. Outcome. PAN is characterized by a chronic relapsing course of many years’ duration, with eventual remission possible in some children. Mortality varies widely from

Definition and Classification Criteria. An acute febrile illness associated with systemic vasculitis that primarily affects infants and young children was initially reported in 1967 by Kawasaki in Japan.92 The first descriptions in the English literature appeared in 1974 under the designation “mucocutaneous lymph node syndrome.” Previously, a number of infants with a febrile illness that lasted a few weeks to months and was often fatal were described with a syndrome referred to as “infantile polyarteritis nodosa,” which probably represented undiagnosed Kawasaki’s disease. Clinical criteria were established by Japanese investigators in 1974 to aid in diagnosis. The revised criteria are listed in Table 98-10, but they remain imperfect guidelines with less than optimal sensitivity or specificity.93 Atypical or incomplete disease may be common in a number of geographic areas.94 Epidemiology. Kawasaki’s disease has occurred sporadically and in mini-epidemics in the United States, with an incidence of 6 to 7.6 per 100,000 children younger than 5 years.95 It is currently the leading cause of acquired heart disease in children in developed countries. The disease accounts for approximately 3% of referrals to U.S. pediatric rheumatology clinics (see Table 98-1) and has not changed in incidence during the last decade.96 The disease is distinctly more common among the Japanese. In Japan, an incidence of 90 per 100,000 was recorded.97 In the United States, the risk of developing Kawasaki’s disease is 17 times greater among children of Japanese ancestry than among white children. In North America, a seasonal variation is often present, with most cases occurring in the spring.98 The mean age at onset is around 1.5 years, and the male-to-female ratio is 1.5:1. Kawasaki’s disease is more common in very young boys, and the single most important complication, coronary aneurysm, is also most frequent

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in these children. This disease rarely occurs after the age of 11 years. A diagnosis of Kawasaki’s disease in adults has been problematic: patients may have this disease or another similar disorder, such as toxic shock syndrome or severe scarlet fever. Cause and Pathogenesis. The seasonality and temporal clustering of Kawasaki’s disease suggest an infectious vector that is currently unidentified; however, secondary cases in a home are unusual. Many causative factors have been suggested but none have been proved, despite 40 years of research. A relationship to heat shock proteins, mycobacterial superantigens, staphylococcal toxins, or Epstein-Barr virus has been postulated. A recent study demonstrated IgA-secreting plasma cells in the vasculature of children who died of Kawasaki’s disease, suggesting that a pathogenic organism or antigen had gained entry through mucosal surfaces.99 Numerous immunologic abnormalities have been reported.100 The pathogenesis probably represents, in part, a generalized stimulation of the inflammatory response, with increased production of cytokines resulting in cytokine-mediated endothelial damage.101 A family-based study suggested that genetic variation in the IL-4 gene or linked regions was involved in susceptibility and pathogenesis102 or in the receptor-ligand pair CCR5 and CCL3L1.103 The extreme thrombocytosis (550,000 to 1 million/mm3) observed may contribute to thrombus forma­ tion on damaged vascular endothelium. Von Willebrand’s factor concentrations are elevated in children with active vasculitis. There is no simple relation to antigens of the major histocompatibility complex in North American white children. A similar disease can be induced in mice by intraperitoneal injection of Lactobacillus casei.104 Clinical Features. The usual monocyclic course has been ­divided into three phases that aid in diagnosis and approach to treatment. The acute febrile onset of the disease has already been described. The subacute period begins with ­return of the temperature to normal and elevation of the platelet count. The convalescent phase follows, with a return of the platelet count to normal. Recurrences are unusual.106 In rare instances, systemic involvement continues in a pattern indistinguishable from that of undifferentiated vasculitis. Fever is universal at onset and is usually sustained and remittent. Temperatures of 40°C are common and may be higher. The febrile phase lasts 5 to 25 days, with a mean of about 10 days. Young children may present with a febrile seizure, although other causes of CNS involvement must be carefully excluded. Cerebrospinal fluid protein may be elevated, and pleocytosis is common. Extreme irritability is common. Mucocutaneous changes are also prominent. Nonsuppurative conjunctival injection may persist for several weeks. Erythema of the lips, with cracking, peeling, and bleeding, is present in most children. Pharyngeal erythema and a strawberry tongue often accompany these changes. A polymorphous rash develops in most children and represents a small vessel vasculitis and perivasculitis of the dermis and subcutaneous tissues. This rash accompanies the fever throughout the acute phase of the disease and then gradually fades. Pruritus is frequently present; vesiculation and purpura do not occur. Painful erythema and edema of the hands, fingers, feet, and toes occur within a few days after onset, and the child may refuse to walk. During recovery, desquamation of the hands and feet occurs, with peeling of the skin beginning underneath the

tips of the nails. This feature is most common during the third week after onset and persists for 1 to 2 weeks. Desquamation and indurative edema can also occur elsewhere, including the perineal area, early in the course (a valuable diagnostic clue). Beau’s lines of the nails develop 1 to 2 months after onset. Although lymphadenopathy occurs in about half the children, it is often not prominent and resolves rapidly toward the end of the febrile period. Involvement of the cervical nodes is common and may be unilateral; a sentinel cervical node 1 to 2 cm in diameter is the most characteristic physical finding. Involvement of almost any system can occur. Relatively common at presentation and during the initial course are pneumonitis, with the development of nodules in some children; tympanitis; meningitis; photophobia and uveitis; diarrhea; meatitis; and sterile pyuria. Arthritis or arthralgia occurs in more than one third of children. Relatively uncommon clinical findings are pleural effusions, severe abdominal colic, hydrops of the gallbladder, intestinal pseudo-obstruction, jaundice, and tonsillar exudate. The kidneys are not involved. The most serious manifestations are myocarditis and coronary vasculitis. It is assumed that a panmyocarditis is universal during the acute febrile phase of the disease. In a variable number of children, the disease progresses to coronary vasculitis with vessel wall necrosis, aneurysm formation, or thrombosis. Coronary artery aneurysms are often present at onset or as early as the second week of the illness. Development of these aneurysms reaches a peak during the subacute period; they are usually multiple and are identified in approximately 20% of children with Kawasaki’s disease in the United States. In children with risk factors for coronary artery aneurysms (i.e., male, age at onset of 18 months or younger or older than 6 years, Japanese ancestry, prolonged febrile course with early clinical myocarditis), their frequency increases to greater than 50%. Aneurysms also occur in arteries other than the coronaries, such as the brachial, subclavian, and axillary vessels. Diagnosis and Diagnostic Tests. Acute-phase indices are elevated early in the course. Abnormalities of the transaminase enzymes and sterile pyuria may be present. Two-dimensional echocardiography is the most sensitive technique for delineating proximal coronary vasculitis and aneurysms (Fig. 98-13). This study should be performed immediately in a child with fever and rash in whom there is a high index of suspicion of Kawasaki’s disease. Echocardiography should also be repeated during the course of the disease—for example, at 1 week, 6 weeks, and 3 months—with the timing and frequency dependent on the course of disease and whether aneurysms were initially detected. A committee of the American Heart Association has issued general recommendations based on disease severity.107 These recommendations have recently been reviewed.93,108 Angiography in selected children may demonstrate multiple lesions of the proximal or peripheral cardiac vessels. Abnormal lipoprotein patterns have been described,109 as well as elevated levels of osteoprotegerin.110 Treatment. The current approach to treatment is divided into two parts: (1) aspirin in anti-inflammatory doses and then as an antiplatelet agent and (2) IVIG.93,111,112 In the presence of developing, progressive, or unstable cardiac disease, close observation in the hospital with cardiac monitoring is extremely

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A LCA

R AO

PA

AO

LA

A

B

Figure 98-13  A, Echocardiographic demonstration of an aneurysm of the left coronary artery (arrow) in a young boy with Kawasaki’s disease.  B, Angiogram of this giant aneurysm (arrow). AO, aorta; LA, left atrium, LCA, left coronary artery; PA, pulmonary artery.

important. Only by detecting the initial signs of cardiac decompensation or arrhythmia can appropriate emergency measures be taken in a severely affected child. High-dose aspirin (e.g., 100 mg/kg per day in divided doses) is traditionally instituted during the acute phase of the illness, although this practice has been questioned.113-115 During the subacute period (resolution of fever and development of thrombocytosis), antiplatelet dosages are prescribed (e.g., 5 mg/kg per day in a single dose). This dosage is continued for months to years in children with or at risk for coronary artery involvement. Controlled studies have demonstrated that a single high dose of IVIG (2000 mg/kg) is efficacious.111,116,117 This therapy is probably most effective if given within the first 10 days of the illness. Children often have a dramatic response to IVIG in terms of fever, constitutional symptoms, and general well-being. In addition, IVIG therapy reduces the frequency, size, and severity of coronary aneurysms and improves the outcome compared with control groups. Glucocorticoids are generally contraindicated because of early studies that reported an increased frequency of coronary aneurysms in children who received steroids compared with those receiving no therapy or aspirin alone. Use of these agents may be considered, however, in a subgroup of children with recurrent disease or severe active myocarditis118 or in IVIG-resistant disease.119-121 Additional recommendations include the use of infliximab.122 Thrombolytic therapy with tissue plasminogen activator or urokinase should be considered in cases of acute coronary thrombosis. Coronary abnormalities may require prolonged medication, interventional catheterization, or cardiac surgery.

with calcification and occlusion.126,127 Extensive scarring, arterial calcification, multiple areas of stenosis, or recanalization may develop in children who survive an initial severe coronary insult and result in progressive ­myocardial dysfunction.124,128 Selected children may be candidates for coronary bypass surgery and revascularization.129-131 A careful history to uncover previous Kawasaki’s disease is indicated in all older children and young adolescents who present for pre-sports physical examinations, because there may be long-term persistence of vascular ­abnormalities.124,132,133 If the history includes a febrile illness accompanied by features suggestive of the disorder, clinical evaluation must include specific measures of cardiac function (e.g., stress testing, echocardiography).

Outcome. Long-term damage to the coronary arteries occurs in approximately one fourth of children.123 Almost all early deaths and most cases of long-term disability are related to cardiac involvement.95,97,124 Myocardial infarction has been described in approximately 2.5% of reported cases and occurs most commonly in the subacute phase. Death may be due to infarction, coronary thrombosis, or rupture of an aneurysm. Giant aneurysms (>8 mm) represent an especially serious development.125 Late death several years after onset has occurred as a result of aneurysm rupture or premature athero­sclerosis

Henoch-Schönlein Purpura

NECROTIZING VASCULITIS OF SMALL VESSELS Necrotizing vasculitis that affects smaller vessels, including postcapillary venules, is referred to as leukocytoclastic vasculitis.89 In these disorders, the vessel wall undergoes necrosis and is infiltrated with polymorphonuclear leukocytes, and nuclear debris is scattered around the lesions. Fibrinoid necrosis is present, and deposition of immunoglobulin and complement can often be demonstrated by fluorescent microscopy. This form of vasculitis may be encountered as a sequela to drug hypersensitivity, infectious endocarditis, or hematologic malignancy. Cryoglobulinemia, either essential or secondary to another disease, causes an immune complex vasculitis that mimics various forms of vasculopathy.

Definition and Criteria. Henoch-Schönlein purpura (HSP) is common in children and adolescents89,134,135 between 3 and 15 years of age and is more frequent in boys than in girls (1.5:1). It is recognized as a putative IgA-mediated immune vasculitis. Diagnosis is based on the clinical tetrad of arthritis, abdominal pain, hematuria, and nonthrombocytopenic purpura.136 The classic purpuric skin rash (palpable purpura) is generally regarded as essential for diagnosis (Fig. 98-14). HSP is relatively uncommon in adults and often more severe.137,138

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Figure 98-14  Petechial and papular rash over the lower extremities of a teenage boy with Henoch-Schönlein purpura.

Epidemiology. An incidence of 13.5 per 100,000 children was reported from Belfast, Northern Ireland.139 HSP accounts for about 8% of new patient referrals (see Table 98-1). It commonly occurs after an upper respiratory tract infection, often in the spring. Streptococcal disease has been implicated in some cases, and others have been related to vaccination, varicella, hepatitis B infection, insect bites, dietary allergens, malignancy, or mycoplasma infection. Occasionally, a familial occurrence is reported, but no definite HLA association has been demonstrated. HSP occurs more frequently in children with C2 complement component deficiency. It is more frequent in the Middle East in children who also have familial Mediterranean fever. Clinical Features. Disease onset is often acute, with sequential manifestations appearing over a few days to weeks. A leukocytoclastic vasculitis with deposition of IgA, IgG, fibrin, C3, and properdin occurs in all affected organs,89 although the skin, gastrointestinal tract, joints, and kidneys are the primary structures affected. Vasculitic involvement may lead to an acute scrotal syndrome. The universal vascular deposition of IgA suggests that HSP is an IgA-mediated immune response and may operate through the alternative complement pathway. The CNS may be involved, and an isolated cerebral vasculitis has been described. Pulmonary disease with hemorrhage can occur. Purpura is the first sign in more than half the children. The buttocks and lower extremities are most often affected; the trunk is usually spared. The lesions often appear in crops; some may have central hemorrhage or ulceration, and others mimic urticaria. Individual purpuric lesions often coalesce to form larger areas of involvement interspersed with petechiae. Subcutaneous edema is observed in 25% of children. It commonly involves the dorsa of the hands and feet and, less commonly, the scalp, forehead, periorbital areas, perineum, and scrotum. Extensive edema is most common in children younger than 2 years. Acute hemorrhagic edema of infancy may be a variant of HSP.

More than 85% of affected children have gastrointestinal signs and symptoms. These include colicky abdominal pain, melena, ileus, vomiting, and hematemesis. Extensive submucosal and mucosal edema, hemorrhage, perforation, and intussusception occur in less than 5% of children and are more common in children older than 4 years. Clinical evidence of glomerulitis is found in up to 50% of cases.139-141 The degree of renal involvement varies from mild endocapillary glomerulitis to extensive crescentic disease. Mesangial involvement is prominent at onset and is similar to Berger’s (IgA) nephropathy in adults.142 Arthritis that is symmetric or asymmetric and predominantly involves the larger joints is a prominent finding in about 75% of children. Although often initially painful, with limitation of motion, it may be less dramatic and is usually not migratory. The knees and ankles are most commonly affected, but wrists, elbows, and fingers may also be involved with prominent periarticular swelling and tenderness, usually without erythema or warmth. Joint effusions per se are unusual. The arthritis is transient, often resolves within a few days, and leaves no residual damage. A moderate leukocytosis occurs, along with a normocytic, normochromic anemia that may be related in part to gastrointestinal blood loss. The platelet count is normal. Activated C3d is present in the circulation, and concentrations of properdin and factor B are decreased in half the children during the acute illness. Serum IgA and IgM concentrations are elevated in half the patients. Fibrin split products are increased in the circulation and urine, providing evidence of involvement of the fibrinolytic system. Diagnosis and Diagnostic Tests. HSP must be differentiated from a wide variety of other illnesses of childhood, including poststreptococcal glomerulonephritis, rheumatic fever, SLE, septicemia, and disseminated intravascular coagulation. Other causes of an acute surgical abdomen or gastrointestinal bleeding must be considered, along with intussusception and pancreatitis. CT in HSP may delineate multifocal areas of bowel wall thickening, mesenteric edema, vascular engorgement, or intussusception. Although the presence of purpura is traditionally required for a diagnosis of HSP, there are undoubtedly children who either do not develop purpura or do not have it at disease onset. Biopsy of a cutaneous lesion may be diagnostic in difficult cases if it demonstrates a leukocytoclastic vasculitis characterized by deposition of IgA and C3. Treatment. General supportive measures are critical in seriously ill children with HSP. In general, glucocorticoids have potential therapeutic value only for the management of gastrointestinal vasculitis and hemorrhage or in severe symptomatic disease in a carefully selected group of patients. The response to their use in these cases may be dramatic. Prednisone, 1 to 2 mg/kg per day in divided doses, is used for at least a week and is then gradually tapered, based on clinical improvement and extent of bleeding. There is no concrete evidence that prednisone otherwise modifies the clinical expression of the disease, shortens its course, or has any direct effect on the frequency or severity of renal involvement.143 Clinical studies have not thoroughly evaluated the efficacy of steroids administered early to children with nephritis; however, in children with progressive renal disease, consideration should be given to their use and to cytotoxic agents and antiplatelet drugs.

PART 16 

Kidney biopsy is generally not indicated, except to clarify the extent and nature of renal disease in children who are severely affected. Azathioprine, cyclosporine, and IVIG have also been recommended for severe nephritis. Renal transplantation has been successfully performed in children, and nephritis does not generally recur in the allografts.144 Outcome. HSP is usually a self-limited disease and often consists of a single episode of clinical involvement. In most children, the disease runs its course in 4 to 6 weeks. Although approximately 30% of young children have a second or third exacerbation, an increasing percentage of older children have recurrences: the younger the child and the shorter the course, the fewer recurrences that are expected. Exacerbations usually occur within the initial 6-week period, but an occasional child may develop recurrences for as long as 2 years after onset. The prognosis is generally excellent and depends on the extent of systemic involvement and the age of the child, being better in younger children. Morbidity and mortality are predominantly related to involvement of the gastrointestinal tract or kidneys.140 Nephrotic syndrome, decreased creatinine clearance, severe histopathology, and persistence of urinary abnormalities are ominous signs.145 Pregnancy may exacerbate occult renal disease. Mortality was less than 1% in the Belfast study, and the morbidity rate was 1.1%.139 Other Forms of Leukocytoclastic Vasculitis Smaller blood vessels, including arterioles, capillaries, and venules, are typically involved in hypersensitivity angiitis.89,134 A form of this disease, serum sickness, was once more common than at present; it occurred secondary to the therapeutic use of heterologous antisera and the introduction of sulfa drugs and penicillin. In addition to these medications, many other drugs have been implicated in the pathogenesis. Cutaneous disease is common and consists of painful, palpable purpura or hemorrhagic infarcts. The vascular inflammatory lesions are at similar stages of evolution in all vessels; the cellular infiltrate often contains many eosinophils. Immune complexes can often be demonstrated in the circulation. Arthritis is usually a prominent component of the clinical presentation; Cogan’s syndrome is rare. Hypersensitivity angiitis is characterized by a variable course whose outcome is often determined by the presence and severity of cardiac, pulmonary, or renal abnormalities. Prednisone is usually effective in suppressing this disorder and in preventing severe complications or death. The disease generally runs its course in approximately 6 weeks. Isolated cutaneous polyarteritis, usually without systemic or constitutional symptoms, is occasionally encountered in a child who presents with palpable purpura, painful nodules, or inflammatory ridges that develop along the course of medium and small vessels of the dermis and panniculus.146 The clinical course is variable but is characterized by benign remissions and recurrences, often over many years. Few children develop systemic involvement. Although each exacerbation may respond to glucocorticoids or occasionally to aspirin, this disease is frequently of such long duration that it is difficult to treat a growing child with prednisone during its entire course. Alternate-day dosing may offer a more rational approach to therapy.

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Hypocomplementemic urticarial vasculitis, although occ­urring primarily in young women, has also been described in children.147 The eruption affects principally the face, upper extremities, and trunk but also occurs on the palms and soles. The urticarial lesions last 2 to 4 days with each exacerbation and then fade without scarring. Systemic features of variable severity (arthritis, myositis, uveitis, serositis, involvement of the lungs or kidneys) accompany the cutaneous disease. The degree of hypocomplementemia parallels the severity of the illness. In some patients, the condition warrants treatment with glucocorticoid drugs. Microscopic polyarteritis is a rare form of vasculitis and glomerulonephritis in childhood. It is associated with perinuclear antineutrophil cytoplasmic and antimyeloperoxidase antibodies. Many children progress to end-stage renal disease.148 Therapy generally includes glucocorticoids and cyclophosphamide. GIANT CELL ARTERITIS Characteristic features of giant cell arteritis are involvement of the aorta and its major branches, disruption of the internal elastic lamina, intimal proliferation, and infiltration of vessel walls with mononuclear cells and giant cells. Systemic giant cell arteritis is rare and involves major branches or segments of the aorta at single or multiple locations. The child may present with constitutional symptoms, fever of unknown origin, or hypertension. A diagnosis is established by angiography combined with biopsy of a vessel, if accessible (Fig. 98-15). Vascular occlusion leads to peripheral anoxia, cyanosis, and gangrene. Recanalization may occur spontaneously or during treatment with glucocorticoid drugs. Cranial or temporal arteritis is generally a disease of older adults, but it has been described in children and is characterized by a persistent, severe headache and localized pain and tenderness over a cranial or temporal vessel. The erythrocyte sedimentation rate is dramatically elevated. The threat of blindness from involvement of the ophthalmic and central retinal arteries is an important consideration and an indication for the prompt initiation of glucocorticoid therapy. Diagnosis is established by biopsy of an affected vessel, with care taken to secure a generous specimen. CNS vasculitis occurs secondary to a variety of conditions.149 Takayasu’s Arteritis Takayasu’s arteritis is a giant cell arteritis that occurs predominantly in children and adolescents, especially teenage girls (female-to-male ratio 8:1), and involves the aorta and its major branches and the pulmonary arteries.150 Features of the disease include stenosis, occlusion, dilation, and aneurysms. Takayasu’s arteritis has been referred to as “pulseless disease” or “reverse coarctation” because of the characteristic obliteration of the radial pulses. These signs of peripheral vascular insufficiency often direct attention to the correct diagnosis, which is confirmed by angiography,151 ultrasonography, MRI, or magnetic resonance angiography.152 Criteria for diagnosis have been developed by the ACR.153 This disorder is more common in Asians, Hispanics, Se­­ phardic Jews, and African Americans. It occasionally occurs in the families of children with other connective tissue diseases or in conjunction with other rheumatic disorders and

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Figure 98-15  Angiogram demonstrating tortuosity and dilation of the lower aorta (arrow) in a 6-year-old girl with giant cell arteritis of the  abdominal vessels. Note involvement of the right renal artery.

has been reported in monozygotic twin sisters. Hypertension is frequent during the course of the disease and is related in part to stenosis of the renal arteries. Calcification is sometimes identified in affected vessels on plain films. The course of the disease may be as short as 3 to 6 months or as long as many years. Survival rates in one study were 93% at 5 years and 87% at 10 years.154 It is generally believed that glucocorticoids are effective if used early, before stenosis and thrombosis develop (after a negative cutaneous purified protein derivative test, because of a putative association with tuberculosis in some areas of the world), but there have been insufficient clinical studies to confirm the efficacy of either this therapeutic approach or the use of cyclophosphamide, azathioprine, or methotrexate. NSAIDs are useful to relieve symptoms during the early phases of the illness. Anticoagulants and antiplatelet agents may be indicated if there is widespread chronic occlusion of vessels. Vessel grafts have been successful late in the course of the disease for vascular occlusion,155 which is the most common indication for surgical intervention.156

disease.89,157-159 Onset of the disease has been described as early as 3 months of age. Constitutional symptoms are prominent. Unexplained pain, rhinorrhea, mucosal ulceration, or bleeding from the upper respiratory tract is characteristic. Destruction of nasal cartilage may result in a saddle nose. Hemoptysis and pleuritic pain are frequent. Chest radiographs demonstrate multiform pulmonary infiltrates; pulmonary disease may progress to hemorrhage, obstruction, atelectasis, or repeated episodes of infection. More than 80% of affected children have renal disease, which may become rapidly progressive, although hypertension is less common than in other types of nephritis. Necrotizing granulomas also occur in the skin, heart, CNS, gastrointestinal tract, and synovia. Limited forms of Wegener’s granulomatosis have been described, possibly including midline granuloma, which is exceedingly rare in children. The differential diagnosis includes berylliosis, Löffler’s syndrome, tuberculosis, syphilis, and lymphoma. Goodpasture’s syndrome, lymphomatoid granulomatosis, relapsing polychondritis, and other forms of vasculitis are sometimes confused with Wegener’s granulomatosis. Sarcoidosis can occur in children with systemic necrotizing vasculitis, cutaneous vasculitis, or granulomatous arteritis. Biopsy of an affected site, generally nasal mucosa or lung, is essential to an early diagnosis. Necrotizing granulomas with leukocytic, lymphocytic, and giant cell infiltration are present.89 Overt vasculitis may not be evident. Antineutrophil cytoplasmic antibodies directed against serine protease 3 are characteristic of Wegener’s granulomatosis.160 The perinuclear pattern of staining, usually associated with antibodies to myeloperoxidase, is less specific and has been described in other forms of vasculitis and connective tissue diseases. In untreated children, death from renal or pulmonary complications usually occurs in a matter of months, but long-term survival in the absence of specific therapy has been reported. Glucocorticoid drugs and trimethoprim-sulfamethoxazole may be useful early in the disease, but studies confirm that cyclophosphamide is the most effective treatment.158 The use of methotrexate as an alternative immunosuppressive agent has been proposed to avoid the long-term morbidity associated with cyclophosphamide.161 Allergic granulomatosis (Churg-Strauss syndrome) is a systemic vasculitis that occurs predominantly in males on a background of chronic asthma and peripheral eosinophilia.89 Other manifestations are similar to those characteristic of PAN, especially in the gastrointestinal tract, CNS, and musculoskeletal system. Renal disease is, however, less frequent. Pulmonary involvement is often the single most important manifestation. The histopathologic pattern in biopsy specimens is that of a necrotizing vasculitis with an eosinophilic infiltrate and extravascular necrotizing granulomas. Administration of glucocorticoid drugs is the main approach to treatment, occasionally in combination with cyclophosphamide. Prognosis is variable; death often results from cardiopulmonary failure.

Granulomatous Arteritis

REFERENCES

Wegener’s granulomatosis is a rare example of granulomatous arteritis in children and is characterized by the clinical triad of upper and lower respiratory involvement and renal

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54. Plamondon S, Dent PB: Juvenile amyopathic dermatomyositis: Results of a case finding descriptive survey. J Rheumatol 27:2031-2034, 2000. 55. Huang JL: Juvenile dermatomyositis associated with partial lipodystrophy. Br J Clin Pract 50:112-113, 1996. 56. Feldman BM, Reichlin M, Laxer RM, et al: Clinical significance of specific autoantibodies in juvenile dermatomyositis. J Rheumatol 23:1794-1797, 1996. 57. Huber AM, Hicks JE, Lachenbruch PA, et al: Validation of the Childhood Health Assessment Questionnaire in the juvenile idiopathic myopathies. Juvenile Dermatomyositis Disease Activity Collaborative Study Group. J Rheumatol 28:1106-1111, 2001. 58. Ruperto N, Ravelli A, Murray KJ, et al: Preliminary core sets of measures for disease activity and damage assessment in juvenile systemic lupus erythematosus and juvenile dermatomyositis. Rheumatology (Oxford) 42:1452-1459, 2003. 59. Falcini F, Bindi G, Simonini G, et al: Bone status evaluation with calcaneal ultrasound in children with chronic rheumatic diseases: A one year followup study. J Rheumatol 30:179-184, 2003. 60. Lang BA, Laxer RM, Murphy G, et al: Treatment of dermatomyositis with intravenous gammaglobulin. Am J Med 91:169-172, 1991. 61. Hicks JE, Drinkard B, Summers RM, et al: Decreased aerobic capacity in children with juvenile dermatomyositis. Arthritis Rheum 47: 118-123, 2002. 62. Oral EA, Simha V, Ruiz E, et al: Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570-578, 2002. 63. Nelson AM: Localized scleroderma including morphea, linear scleroderma, and eosinophilic fasciitis. Curr Probl Pediatr 26:318-324, 1996. 64. LeRoy EC, Medsger TA Jr: Criteria for the classification of early systemic sclerosis. J Rheumatol 28:1573-1576, 2001. 65. Uziel Y, Miller ML, Laxer RM: Scleroderma in children. Pediatr Clin North Am 42:1171-1203, 1995. 66. Mayes MD: Scleroderma epidemiology. Rheum Dis Clin North Am 29:239-254, 2003. 67. Nelson JL, Furst DE, Maloney S, et al: Microchimerism and HLAcompatible relationships of pregnancy in scleroderma. Lancet 351: 559-562, 1998. 68. Johnson KL, Nelson JL, Furst DE, et al: Fetal cell microchimerism in tissue from multiple sites in women with systemic sclerosis. Arthritis Rheum 44:1848-1854, 2001. 69. Lemaire R, Farina G, Kissin E, et al: Mutant fibrillin 1 from tight skin mice increases extracellular matrix incorporation of microfibril­associated glycoprotein 2 and type I collagen. Arthritis Rheum 50: 915-926, 2004. 70. Wulffraat NM, Sanders LA, Kuis W: Autologous hemopoietic stem-cell transplantation for children with refractory autoimmune disease. Curr Rheumatol Rep 2:316-323, 2000. 71. Farge D, Marolleau JP, Zohar S, et al: Autologous bone marrow transplantation in the treatment of refractory systemic sclerosis: Early results from a French multicentre phase I-II study. Br J Haematol 119:726-739, 2002. 72. Zulian F, Corona F, Gerloni V, et al: Safety and efficacy of iloprost for the treatment of ischaemic digits in paediatric connective tissue diseases. Rheumatology (Oxford) 43:229-233, 2004. 73. Scalapino K, Arkachaisri T, Lucas M, et al: Childhood onset systemic sclerosis: Classification, clinical and serologic features, and survival in comparison with adult onset disease. J Rheumatol 33:1004-1013, 2006. 74. Peterson LS, Nelson AM, Su WP, et al: The epidemiology of morphea (localized scleroderma) in Olmsted County 1960-1993. J Rheumatol 24:73-80, 1997. 75. Rosenberg AM, Uziel Y, Krafchik BR, et al: Antinuclear antibodies in children with localized scleroderma. J Rheumatol 22:2337-2343, 1995. 76. Zulian F, Vallongo C, Woo P, et al: Localized scleroderma in childhood is not just a skin disease. Arthritis Rheum 52:2873-2881, 2005. 77. Peterson LS, Nelson AM, Su WP: Classification of morphea (localized scleroderma). Mayo Clin Proc 70:1068-1076, 1995. 78. Lehman TJ: The Parry Romberg syndrome of progressive facial hemiatrophy and linear scleroderma en coup de sabre: Mistaken diagnosis or overlapping conditions? J Rheumatol 19:844-845, 1992. 79. Grisanti MW, Moore TL, Osborn TG, et al: Eosinophilic fasciitis in children. Semin Arthritis Rheum 19:151-157, 1989. 80. Mier RJ, Shishov M, Higgins GC, et al: Pediatric-onset mixed connective tissue disease. Rheum Dis Clin North Am 31:483-496, 2005. 81. Michels H: Course of mixed connective tissue disease in children. Ann Med 29:359-364, 1997. 82. Yokota S, Imagawa T, Katakura S, et al: Mixed connective tissue disease in childhood: A nationwide retrospective study in Japan. Acta Paediatr Jpn 39:273-276, 1997.

83. Hoffman RW, Cassidy JT, Takeda Y, et al: U1-70-kd autoantibodypositive mixed connective tissue disease in children: A longitudinal clinical and serologic analysis. Arthritis Rheum 36:1599-1602, 1993. 84. Ozen S: Problems in classifying vasculitis in children. Pediatr Nephrol 20:1214-1218, 2005. 85. Bowyer S, Roettcher P: Pediatric rheumatology clinic populations in the United States: Results of a 3 year survey. Pediatric Rheumatology Database Research Group. J Rheumatol 23:1968-1974, 1996. 86. Symmons DP, Jones M, Osborne J, et al: Pediatric rheumatology in the United Kingdom: Data from the British Pediatric Rheumatology Group National Diagnostic Register. J Rheumatol 23:1975-1980, 1996. 87. Hunder GG, Arend WP, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of vasculitis: Introduction. Arthritis Rheum 33:1065-1067, 1990. 88. Jennette JC, Falk RJ, Andrassy K, et al: Nomenclature of systemic vasculitides: Proposal of an international consensus conference. Arthritis Rheum 37:187-192, 1994. 89. Lie JT: American College of Rheumatology Subcommittee on Classification of Vasculitis: Illustrated histopathologic classification criteria for selected vasculitis syndromes. Arthritis Rheum 33:1074-1087, 1990. 90. Ozen S, Anton J, Arisoy N, et al: Juvenile polyarteritis: Results of a multicenter survey of 110 children. J Pediatr 145:517-522, 2004. 91. Brogan PA, Davies R, Gordon I, et al: Renal angiography in children with polyarteritis nodosa. Pediatr Nephrol 17:277-283, 2002. 92. Kawasaki T: Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children. Jpn J Allergy 16:178-222, 1967. 93. Newburger JW, Takahashi M, Gerber MA, et al: Diagnosis, treatment, and long-term management of Kawasaki disease: A statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics 114:1708-1733, 2004. 94. Falcini F, Cimaz R, Calabri GB, et al: Kawasaki’s disease in northern Italy: A multicenter retrospective study of 250 patients. Clin Exp Rheumatol 20:421-426, 2002. 95. Taubert KA, Rowley AH, Shulman ST: Nationwide survey of Kawasaki disease and acute rheumatic fever. J Pediatr 119:279-282, 1991. 96. Holman RC, Curns AT, Belay ED, et al: Kawasaki syndrome hospitalizations in the United States, 1997 and 2000. Pediatrics 112: 495-501, 2003. 97. Nakamura Y, Yanagawa H, Kato H, et al: Mortality rates for patients with a history of Kawasaki disease in Japan. Kawasaki Disease Follow-up Group. J Pediatr 128:75-81, 1996. 98. Chang RK: Hospitalizations for Kawasaki disease among children in the United States, 1988-1997. Pediatrics 109:e87, 2002. 99. Rowley AH, Eckerley CA, Jack HM, et al: IgA plasma cells in vascular tissue of patients with Kawasaki syndrome. J Immunol 159: 5946-5955, 1997. 100. Falcini F, Trapani S, Turchini S, et al: Immunological findings in Kawasaki disease: An evaluation in a cohort of Italian children. Clin Exp Rheumatol 15:685-689, 1997. 101. Nakatani K, Takeshita S, Tsujimoto H, et al: Circulating endothelial cells in Kawasaki disease. Clin Exp Immunol 131:536-540, 2003. 102. Burns JC, Shimizu C, Shike H, et al: Family-based association analysis implicates IL-4 in susceptibility to Kawasaki disease. Genes Immun 6:438-444, 2005. 103. Burns JC, Shimizu C, Gonzalez E, et al: Genetic variations in the receptor-ligand pair CCR5 and CCL3L1 are important determinants of susceptibility to Kawasaki disease. J Infect Dis 192:344-349, 2005. 104. Lehman TJ, Walker SM, Mahnovski V, et al: Coronary arteritis in mice following the systemic injection of group B Lactobacillus casei cell walls in aqueous suspension. Arthritis Rheum 28:652-659, 1985. 105. Urowitz MB, Gladman DD, Abu-Shakra M, et al: Mortality studies in systemic lupus erythematosus: Results from a single center. III. Improved survival over 24 years. J Rheumatol 24:1061-1065, 1997. 106. Nakamura Y, Yanagawa H, Ojima T, et al: Cardiac sequelae of Kawasaki disease among recurrent cases. Arch Dis Child 78:163-165, 1998. 107. Dajani AS, Taubert KA, Takahashi M, et al: Guidelines for longterm management of patients with Kawasaki disease: Report from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation 89:916-922, 1994.

PART 16  108. Kushner HI, Bastian JF, Turner CH, et al: Rethinking the boundaries of Kawasaki disease: Toward a revised case definition. Perspect Biol Med 46:216-233, 2003. 109. Weng KP, Hsieh KS, Huang SH, et al: Serum HDL level at acute stage of Kawasaki disease. Chung Hua Min Kuo Hsiao Erh Ko I Hsueh Hui Tsa Chih 39:28-32, 1998. 110. Simonini G, Masi L, Giani T, et al: Osteoprotegerin serum levels in Kawasaki disease: An additional potential marker in predicting children with coronary artery involvement. J Rheumatol 32: 2233-2238, 2005. 111. Newburger JW, Takahashi M, Beiser AS, et al: A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med 324: 1633-1639, 1991. 112. American Academy of Pediatrics: Kawasaki syndrome. In Pickering LK (ed): Red Book: 2003 Report of the Committee on Infectious Diseases. Elk Grove Village, Ill, American Academy of Pediatrics, 2003, pp 392-395. 113. Sundel RP, Baker AL, Fulton DR, et al: Corticosteroids in the initial treatment of Kawasaki disease: Report of a randomized trial. J Pediatr 142:611-616, 2003. 114. Hsieh KS, Weng KP, Lin CC, et al: Treatment of acute Kawasaki disease: Aspirin’s role in the febrile stage revisited. Pediatrics 114: e689-e693, 2004. 115. Wooditch AC, Aronoff SC: Effect of initial corticosteroid therapy on coronary artery aneurysm formation in Kawasaki disease: A metaanalysis of 862 children. Pediatrics 116:989-995, 2005. 116. Yanagawa H, Nakamura Y, Sakata K, et al: Use of intravenous gamma-globulin for Kawasaki disease: Effects on cardiac sequelae. Pediatr Cardiol 18:19-23, 1997. 117. Oates-Whitehead RM, Baumer JH, Haines L, et al: Intravenous immunoglobulin for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev CD004000, 2003. 118. Lang BA, Yeung RS, Oen KG, et al: Corticosteroid treatment of refractory Kawasaki disease. J Rheumatol 33:803-809, 2006. 119. Hashino K, Ishii M, Iemura M, et al: Re-treatment for immune globulinresistant Kawasaki disease: A comparative study of additional immune globulin and steroid pulse therapy. Pediatr Int 43:211-217, 2001. 120. Takeshita S, Kawamura Y, Nakatani K, et al: Standard-dose and short-term corticosteroid therapy in immunoglobulin-resistant Kawasaki disease. Clin Pediatr (Phila) 44:423-426, 2005. 121. Tsai MH, Huang YC, Yen MH, et al: Clinical responses of patients with Kawasaki disease to different brands of intravenous immunoglobulin. J Pediatr 148:38-43, 2006. 122. Burns JC, Mason WH, Hauger SB, et al: Infliximab treatment for refractory Kawasaki syndrome. J Pediatr 146:662-667, 2005. 123. Burns JC: Kawasaki disease: The mystery continues. Minerva Pediatr 54:287-294, 2002. 124. Kato H, Sugimura T, Akagi T, et al: Long-term consequences of Kawasaki disease: A 10- to 21-year follow-up study of 594 patients. Circulation 94:1379-1385, 1996. 125. Levy DM, Silverman ED, Massicotte MP, et al: Longterm outcomes in patients with giant aneurysms secondary to Kawasaki disease. J Rheumatol 32:928-934, 2005. 126. Fukushige J, Takahashi N, Ueda K, et al: Long-term outcome of coronary abnormalities in patients after Kawasaki disease. Pediatr Cardiol 17:71-76, 1996. 127. Dadlani GH, Gingell RL, Orie JD, et al: Coronary artery calcifications in the long-term follow-up of Kawasaki disease. Am Heart J 150:1016, 2005. 128. Burns JC, Shike H, Gordon JB, et al: Sequelae of Kawasaki disease in adolescents and young adults. J Am Coll Cardiol 28:253-257, 1996. 129. Kitamura S: The role of coronary bypass operation on children with Kawasaki disease. Coron Artery Dis 13:437-447, 2002. 130. Tsuda E, Kitamura S: National survey of coronary artery bypass grafting for coronary stenosis caused by Kawasaki disease in Japan. Circulation 110:II61-II66, 2004. 131. Wong D, Harder J, Jadavji T: Kawasaki disease, myocardial infarction and coronary artery revascularization. Can J Cardiol 21:601-604, 2005. 132. Hirata S, Nakamura Y, Matsumoto K, et al: Long-term consequences of Kawasaki disease among first-year junior high school students. Arch Pediatr Adolesc Med 156:77-80, 2002. 133. Cimaz R, Falcini F: An update on Kawasaki disease. Autoimmun Rev 2:258-263, 2003.

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134. Michel BA, Hunder GG, Bloch DA, et al: Hypersensitivity vasculitis and Henoch-Schönlein purpura: A comparison between the 2 disorders. J Rheumatol 19:721-728, 1992. 135. Fukuda T, Ishibashi M, Shinohara T, et al: Follow-up assessment of the collateral circulation in patients with Kawasaki disease who underwent dipyridamole stress technetium-99m tetrofosmin scintigraphy. Pediatr Cardiol 26:558-564, 2005. 136. Mills JA, Michel BA, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of Henoch-Schönlein purpura. Arthritis Rheum 33:1114-1121, 1990. 137. Garcia-Porrua C, Calvino MC, Llorca J, et al: Henoch-Schönlein purpura in children and adults: Clinical differences in a defined population. Semin Arthritis Rheum 32:149-156, 2002. 138. Uppal SS, Hussain MA, Al Raqum HA, et al: Henoch-Schönlein’s purpura in adults versus children/adolescents: A comparative study. Clin Exp Rheumatol 24:S26-S30, 2006. 139. Stewart M, Savage JM, Bell B, et al: Long term renal prognosis of Henoch-Schönlein purpura in an unselected childhood population. Eur J Pediatr 147:113-115, 1988. 140. Goldstein AR, White RH, Akuse R, et al: Long-term follow-up of childhood Henoch-Schönlein nephritis. Lancet 339:280-282, 1992. 141. Chang WL, Yang YH, Wang LC, et al: Renal manifestations in Henoch-Schönlein purpura: A 10-year clinical study. Pediatr Nephrol 20:1269-1272, 2005. 142. Blanco R, Martinez-Taboada VM, Rodriguez-Valverde V, et al: Henoch-Schönlein purpura in adulthood and childhood: Two different expressions of the same syndrome. Arthritis Rheum 40:859-864, 1997. 143. Huber AM, King J, McLaine P, et al: A randomized, placebocontrolled trial of prednisone in early Henoch-Schönlein purpura [ISRCTN85109383]. BMC Med 2:7, 2004. 144. Hasegawa A, Kawamura T, Ito H, et al: Fate of renal grafts with recurrent Henoch-Schönlein purpura nephritis in children. Transplant Proc 21:2130-2133, 1989. 145. Tarshish P, Bernstein J, Edelmann CM Jr: Henoch-Schönlein purpura nephritis: Course of disease and efficacy of cyclophosphamide. Pediatr Nephrol 19:51-56, 2004. 146. Sheth AP, Olson JC, Esterly NB: Cutaneous polyarteritis nodosa of childhood. J Am Acad Dermatol 31:561-566, 1994. 147. Martini A, Ravelli A, Albani S, et al: Hypocomplementemic urticarial vasculitis syndrome with severe systemic manifestations. J Pediatr 124:742-744, 1994. 148. Valentini RP, Smoyer WE, Sedman AB, et al: Outcome of antineutrophil cytoplasmic autoantibodies-positive glomerulonephritis and vasculitis in children: A single-center experience. J Pediatr 132: 325-328, 1998. 149. Lanthier S, Lortie A, Michaud J, et al: Isolated angiitis of the CNS in children. Neurology 56:837-842, 2001. 150. Mwipatayi BP, Jeffery PC, Beningfield SJ, et al: Takayasu arteritis: Clinical features and management: report of 272 cases. Aust N Z J Surg 75:110-117, 2005. 151. McCulloch M, Andronikou S, Goddard E, et al: Angiographic features of 26 children with Takayasu’s arteritis. Pediatr Radiol 33: 230-235, 2003. 152. Saltoglu N, Tasova Y, Midikli D, et al: Fever of unknown origin in Turkey: Evaluation of 87 cases during a nine-year-period of study. J Infect 48:81-85, 2004. 153. Arend WP, Michel BA, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 33:1129-1134, 1990. 154. Park MC, Lee SW, Park YB, et al: Clinical characteristics and outcomes of Takayasu’s arteritis: Analysis of 108 patients using standardized criteria for diagnosis, activity assessment, and angiographic classification. Scand J Rheumatol 34:284-292, 2005. 155. Miyata T, Sato O, Koyama H, et al: Long-term survival after surgical treatment of patients with Takayasu’s arteritis. Circulation 108: 1474-1480, 2003. 156. Fields CE, Bower TC, Cooper LT, et al: Takayasu’s arteritis: Operative results and influence of disease activity. J Vasc Surg 43: 64-71, 2006. 157. Leavitt RY, Fauci AS, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of Wegener’s ­granulomatosis. Arthritis Rheum 33:1101-1107, 1990.

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158. Rottem M, Fauci AS, Hallahan CW, et al: Wegener granulomatosis in children and adolescents: Clinical presentation and outcome. J Pediatr 122:26-31, 1993. 159. Belostotsky VM, Shah V, Dillon MJ: Clinical features in 17 ­paediatric patients with Wegener granulomatosis. Pediatr Nephrol 17:754-761, 2002.

160. Hoffman GS: Classification of the systemic vasculitides: Antineutrophil cytoplasmic antibodies, consensus and controversy. Clin Exp Rheumatol 16:111-115, 1998. 161. Gottlieb BS, Miller LC, Ilowite NT: Methotrexate treatment of Wegener granulomatosis in children. J Pediatr 129:604-607, 1996.

Part

17

INFECTION AND ARTHRITIS

99

Bacterial Arthritis GEORGE HO, Jr.  •  DAWD S. SIRAJ  •  PAUL P. ­COOK

Key Points Acute bacterial arthritis is a medical emergency that warrants rapid, accurate diagnosis and immediate treatment. Most instances of native joint infection are the result of bacteremic seeding. Staphylococcus aureus is the most frequent microorganism in adult nongonococcal septic arthritis. The initial selection of an antibiotic regimen should be broad enough to take into account host factors, clinical ­characteristics, likely causative microorganisms, and regional antibiotic sensitivity data pending confirmation of bacteria by culture and sensitivities. An infected joint must be adequately drained, and an ­antibiotic course that is sufficiently long to cure the infection must be instituted. Surgical drainage must be considered without delay if needle aspirations are unsuccessful. Poor prognostic factors in bacterial joint infection include old age, underlying rheumatoid arthritis, and infection in a prosthetic joint. To optimize the outcome, prompt aggressive treatment must be instituted, and consultations with orthopaedic surgery, rheumatology, infectious diseases, and physical medicine and rehabilitation should be sought. Late prosthetic joint infections require antibiotic treatment directed at the isolated microorganism and the complete removal of the infected prosthesis before reimplantation of a new prosthesis in a one-stage or two-stage operation. Reducing the risk of a prosthetic joint infection involves a thorough preoperative evaluation, perioperative use of antibiotics, and the careful use of antibiotic prophylaxis when a patient with a prosthesis is exposed to transient bacteremia during an invasive dental procedure.

EPIDEMIOLOGY Bacterial infections of the joint are usually curable with treatment, but morbidity and mortality are still significant in patients with underlying rheumatoid arthritis (RA), patients with prosthetic joints, elderly patients, and patients who have severe and multiple comorbidities. Goldenberg1

wrote in 1994, “Treatment and outcome (of septic arthritis) have not improved substantially over the past 20 years.” This statement is probably still true today. Incremental knowledge of the pathogenesis of septic arthritis caused by two common organisms, Neisseria gonorrhoeae and Staphylococcus aureus, and understanding of the pathobiology of prosthetic devices may lead to innovations in the management and prevention of bacterial joint infections, however. The normal diarthrodial joint is very resistant to bacterial infection because of local and systemic host defenses. Bacteria can reach the synovial-lined joint, however, via the hematogenous route and result in septic arthritis. The large joints are affected more commonly than the small joints, and monarticular infection is the rule, with polyarticular infection (more than one joint involved) in less than 20% of cases. A prospective series from a community-based population in the Netherlands reflected a representative distribution of joint involvement: knee 55%, ankle 10%, wrist 9%, shoulder 7%, hip 5%, elbow 5%, sternoclavicular joint 5%, sacroiliac joint 2%, and foot joint 2%.2 The incidence of septic arthritis ranges from 2 to 5/100,000/yr in the general population, 5.5 to 12/100,000/yr in children, 28 to 38/100,000/yr in patients with RA, and 40 to 68/100,000/yr in patients with joint prostheses.3,4 The organisms causing bacterial arthritis depend on the epidemiologic circumstances (Table 99-1).5 Monarthritis of a prosthetic joint in an elderly man is likely due to Staphylococcus, whereas a migratory arthritis in a sexually active woman with skin lesions is likely due to disseminated gonococcal infection.

ETIOLOGY AND PATHOGENESIS Most cases of septic arthritis result from hematogenous seeding of the synovial membrane. The abundant vascular supply of the synovium and the lack of a limiting basement membrane allow organisms to target joints during bacteremia. Less common causes of septic arthritis include direct inoculation after joint aspiration or corticosteroid injection of a joint6; animal or human bites; nail puncture wounds or plant thorn injury7; joint surgery, especially hip and knee arthroplasties; and spread by contiguous osteomyelitis, cellulitis, or septic 1701

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Bacterial Arthritis

Table 99-1  Etiologic Organisms Causing Joint Infection in Various Hosts Adults

Children ≤5 yr old

Children >5 yr old

Neonates

Prosthetic

Common Staphylococcus aureus

Common S. aureus

Common S. aureus

Common S. aureus

Streptococcus pneumoniae β-Hemolytic streptococci (mainly Lancefield groups   A, G, and B) Neisseria gonorrhoeae (adult   and sexually active adolescent) Enterobacteriaceae (age >60 or predisposing condition) Salmonella

Haemophilus influenzae* Group A streptococci

Group A streptococci

Group B streptococci Enterobacteriaceae

Common Coagulase-negative staphylococci S. aureus

S. pneumoniae

Rare Pseudomonas Mycobacterium tuberculosis

Rare Salmonella H. influenzae

Rare

Rare Pseudomonas H. influenzae

H. influenzae Neisseria meningitidis Pasteurella Anaerobes Mycoplasma/Ureaplasma Fungi (Sporothrix, dimorphic fungi, Cryptococcus) Borrelia burgdorferi

N. meningitidis N. gonorrhoeae Kingella kingae M. tuberculosis B. burgdorferi

N. meningitidis N. gonorrhoeae Kingella kingae M. tuberculosis B. burgdorferi

N. gonorrhoeae

Less Common Corynebacterium Enterococci and ­streptococci Pseudomonas aeruginosa Enterobacteriaceae Propionibacterium Other anaerobes Candida M. tuberculosis

*Rare in children immunized with Hib vaccine. Adapted from Atkins BL, Bowler IC: The diagnosis of large joint sepsis. J Hosp Infect 40:263-274, 1998.

bursitis. Arthrocentesis is a common procedure frequently used in conjunction with corticosteroid administration in patients with various forms of joint diseases. Septic arthritis after joint aspiration and injection is extremely rare, occurring in 0.0002% of patients.8 Arthroscopic surgery also is a common procedure that is complicated by a very low incidence of septic arthritis (<0.5% of procedures).9,10 Coagulase-positive and coagulase-negative staphylococci account for more than 87% of these infections. In rare cases of septic arthritis of the knee related to anterior cruciate ligament repair, the tissue allografts were identified as the source of the infection.11 Cultures yielded gram-negative organisms, such as Pseudomonas aeruginosa, Citrobacter, Klebsiella oxytoca, and mixed infection with S. aureus, Enterococcus faecalis, and P. aeruginosa. Acute bacterial arthritis usually is designated gonococcal or nongonococcal. In the case of gonococcal arthritis, N. gonorrhoeae possesses a variety of virulence factors on the cell surface. N. gonorrhoeae is able to attach to cell surfaces via filamentous outer-membrane appendages, or pili. Another outer membrane protein, protein I, has forms IA and IB. Protein IA binds the host factor H and inactivates complement component, C3b, circumventing the host’s complement system.12 Protein IA also prevents phagolysosomal fusion in neutrophils, enabling survival of the organism within the phagocytes. Lipo-oligosaccharide is a gonococcal molecule similar to lipopolysaccharide of other gram-negative bacteria and possesses endotoxin activity, which contributes to the joint damage seen in gonococcal arthritis.13 S. aureus is the most common organism that causes nongonococcal arthritis. The virulence of S. aureus is associated with its ability to attach to host tissue within the joint, evade host defenses, and cause damage to the joint. Table 99-2 lists some of these virulence factors and their mechanisms of action. The attachment of S. aureus to the joint tissues is facilitated by microbial surface components recognizing

adhesive matrix molecules (MSCRAMMs). MSCRAMMs are embedded in the cell wall peptidoglycan of S. aureus (Fig. 99-1).14,15 They bind to host matrix proteins, including collagen, fibrinogen, elastin, vitronectin, laminin, and fibronectin. Knockout gene experiments in animal models showed that the gene coding for the protein that binds ­collagen is an important virulence factor for S. aureus joint infections.16 Most S. aureus isolates also express the fibronectin-binding proteins, FnbpA and FnbpB. Disruption of the respective genes, fnbpA and fnbpB, by knockout gene experiments completely obliterates adherence of S. aureus to fibronectin-coated surfaces (e.g., prosthetic joints).17 The genes of several S. aureus cell surface proteins (e.g., protein A, fibronectin-binding proteins, coagulase) and exotoxins (e.g., toxic shock syndrome toxin-1 [TSST-1], enterotoxin B, proteases, and hemolysins) are regulated by the accessory gene regulator agr.18,19 At low cell numbers, such as at the time of infection, production of cell surface proteins for attachment to host tissues is facilitated by the agr gene. When the cells have attached to tissue or an orthopaedic device and have passed from exponential to stationary phase of growth, agr represses the expression of genes coding for cell surface proteins and activates genes coding for exotoxins and tissue-destroying exoenzymes. Because of this complex effect on the different stages of infection, inhibitors of agr may reduce tissue destruction, but enhance tissue colonization. This effect could have implications for chronic infections such as occur with prosthetic joints. Adherence receptors may allow for the intracellular movement of S. aureus into host cells (e.g., osteoblasts, endothelial cells, and neutrophils).20 When internalized, the organism is protected from the host’s immune system and from antimicrobial agents. After adherence to the joint tissue, the bacteria activate the host immune response. Opsonization and phagocytosis are key defenses to ­eradicate the organism. S. aureus possesses two virulence factors,

PART 17 

Table 99-2  Virulence Factors of Staphylococcus aureus and Their Mechanisms of Action Virulence Factor

Mechanism of Action

Collagen-binding protein

Binds collagen

Clumping factor A and B

Binds fibrinogen

Fibronectin-binding protein A and B

Binds fibronectin

Capsular polysaccharide

Antiphagocytic

Protein A

Binds fragment crystallizable portion of IgG

Toxic shock syndrome toxin-1

Superantigen

Enterotoxins

Superantigens

Enterotoxin B

TSST-1 α-toxin

Coagulase Protein A

Exotoxins

Collagen binding protein

Fibronectin binding protein

Clumping factor Figure 99-1  Schematic diagram of Staphylococcus aureus. Many of the cell-surface proteins are regulated by the agr locus (see text). At low cell concentrations, agr facilitates the production of the cell-surface proteins, which facilitate attachment to tissue. At higher cell concentrations, as ­occurs with establishment of infection, agr downregulates production of the cell-surface proteins and activates genes coding for exotoxins.

p­ rotein A and capsular polysaccharide, which interfere with these defenses. Protein A interferes with binding of complement by binding to the fragment crystallizable (Fc) portion of IgG. Protein A has been termed a superantigen for B cells because 30% of human B cells show Fab-mediated binding of the protein A molecule.21 Binding of protein A by B cells leads to activation and subsequently to depletion of B cells through apoptosis.22 This process may have implications regarding the ability of the immune system to control infection with S. aureus. The gene coding for protein A had been experimentally disrupted, and joint infection caused by the altered strain in a mouse model resulted in less joint destruction than infection caused by the wild-type strain.23 Capsular polysaccharide interferes with opsonization and phagocytosis. Of the 11 reported capsule serotypes of S. aureus, types 5 and 8 account for 85% of clinical ­infections.24 The capsule of these two serotypes is ­thinner,

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which ­ facilitates the attachment to host fibronectin and fibrin.25 When attached to these host proteins, capsule production is upregulated to form a thicker capsule, which makes the bacteria more resistant to opsonization and phagocytosis. The thicker capsule also is able to conceal the highly immunogenic adherence proteins (MSCRAMMs).26 A mutant of the type 5 capsule in a murine model had a lower rate of infection and resulted in less severe arthritis compared with mice infected with the wild-type strain.27 A vaccine consisting of types 5 and 8 polysaccharide reduced S. aureus bacteremia by more than half in hemodialysis patients.28 The duration of protection was approximately 40 weeks after a single vaccination. S. aureus exotoxins (e.g., TSST-1 and enterotoxins) act as superantigens that bind to host major histocompatibility complex (MHC) class II molecules and T cell receptors, resulting in clonal expansion and activation of some T cells. This activation triggers the release of numerous cytokines, including interleukin (IL)-2, interferon-γ, and tumor necrosis factor (TNF)-α.29 Induction of these cytokines results in systemic toxicity and joint damage. The stimulated T cells initially proliferate, but later disappear, likely owing to apoptosis, and result in immunosuppression.30 Internalized organisms that had been protected from this inflammatory response may cause fulminant or persistent infection. Mice injected with strains of S. aureus lacking TSST-1 and enterotoxins rarely develop arthritis; when arthritis is induced, it is much milder compared with arthritis in animals injected with the wild-type strain.29 Vaccination of mice with a mutated, recombinant form of enterotoxin A devoid of superantigen function was associated with a significant reduction in mortality.31 In response to bacterial infection of the joint space, the host releases a variety of cytokines and inflammatory mediators. Initially, IL-1β and IL-6 are released into the joint space, leading to an influx of inflammatory cells. These neutrophils and macrophages engulf invading bacteria and release additional cytokines, including TNF-α, IL-1, IL-6, and IL-8. Blocking TNF-α with a monoclonal antibody and IL-1 with an IL-1 receptor antagonist inhibited leukocyte infiltration into the joint by 80% in a rabbit model of S. aureus–induced arthritis when the cytokine inhibitors were given simultaneously with S. aureus.32 When the same inhibitors were given 24 hours after infection, however, there was no effect on leukocyte infiltration, suggesting the crucial roles of TNF-α and IL-1 in the early stages of S. aureus–induced arthritis. Release of interferon-γ is associated with the influx of T cells, which occurs a few days after infection. In a mouse model of S. aureus septic arthritis, interferon-γ has been associated with a worsening of the severity of arthritis, while protecting the animals from septicemia.33 The host’s early cytokine response may aid the clearance of organisms and limit infection in the host. A late cytokine response may amplify the destructiveness of an established infection.

CLINICAL FEATURES Acute bacterial arthritis is most commonly monarticular. Polyarticular infection occurs in 5% to 8% of pediatric cases and in 10% to 19% of adult nongonococcal cases.34,35 The differential diagnosis of acute monarthritis overlaps with

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many causes of polyarthritis because virtually any arthritic disorder can initially manifest as a single swollen joint. The three main etiologies to consider when a patient presents with acute monarticular arthritis are trauma, infection, and crystal-induced synovitis such as gout or pseudogout. Polyarticular septic arthritis is usually seen in patients with systemic inflammatory disorders such as the spondyloarthropathies, RA, systemic lupus erythematosus, and other connective tissue diseases or patients with overwhelming sepsis.36 Disseminated gonococcal infection occurs in 1% to 3% of patients infected with N. gonorrhoeae. Gonococcal arthritis is the most common cause of acute monarthritis in sexually active young adults. In the preantibiotic era, gonococcal arthritis was a well-recognized illness in neonates. Disseminated gonococcal infection is three times more common in women than men. Women are more commonly affected because they are more likely to have asymptomatic and untreated primary infections. Bacterial dissemination has been associated with intrauterine devices and has occurred during menstruation, pregnancy, and pelvic operation.37-39 Patients with gonococcal joint disease typically present with one of two forms. The first form is characterized by fever, shaking chills, vesiculopustular skin lesions, tenosynovitis, and polyarthralgias. Blood cultures are frequently positive, whereas synovial fluid cultures are rarely positive. N. gonorrhoeae can be cultured from genital, rectal, and pharyngeal sites. Tenosynovitis of multiple tendons of the wrist, fingers, ankle, and toes is a unique feature of this form of disseminated gonococcal infection and distinguishes it from other forms of infectious arthritis. In the second form of gonococcal infection, patients have purulent arthritis, most commonly of the knee, wrist, or ankle, and more than one joint can be infected simultaneously. N. gonorrhoeae frequently can be cultured from the synovial fluid.40 The classic presentation of nongonococcal septic arthritis is the acute onset of pain and swelling in a single joint. Large joints are affected most commonly. In adults, the knee is involved in more than 50% of cases; hip, ankle, and shoulder infections are less common.41 In infants and small children, the hip is more often involved.42 Patients with septic arthritis often have underlying illnesses and predispositions to infections. Many are immunocompromised; are intravenous drug abusers; have prosthetic joints; and have diseases such as neoplasia, renal failure, and RA. Table 99-3 lists the risk factors that predispose to septic arthritis.3,6,43-45 Most patients with bacterial arthritis are febrile, although chills are unusual. Fever may be absent in elderly patients. In children, septic arthritis usually is accompanied by fever, malaise, poor appetite, irritability, and progressive reluctance to use the affected limb. Physical examination typically reveals warmth and tenderness of the affected joint, joint effusion, and limited active and passive range of motion. Septic arthritis among patients with RA has been a special challenge to clinicians because of the high incidence of infection and the poor outcome. Septic arthritis in patients with RA is associated with poor joint outcome and high mortality.34,46-50 In many cases, it is difficult to differentiate septic arthritis in a joint already affected by RA from rheumatoid flare. Whenever bacterial arthritis is suspected, the most important diagnostic procedure is arthrocentesis and examination of the synovial fluid. For joints that are

Table 99-3  Risk Factors for the Development   of Septic Arthritis Age >80 years3 Diabetes mellitus3 Presence of a prosthetic joint in the knee or the hip3 Recent joint surgery3 Skin infection3 Previous septic arthritis43 Recent intra-articular injection6 HIV or AIDS Intravenous drug abuse End-stage renal disease on hemodialysis Advanced hepatic disease Hemophilia with or without AIDS Sickle cell disease Underlying malignancy Hypogammaglobulinemia (susceptible to Mycoplasma infections)45 Late complement-component deficiency (susceptible to Neisseria infections)44 Low socioeconomic status with high rate   of comorbidities43 AIDS, acquired immunodeficiency syndrome; HIV, human immunodefi­ ciency virus.

deep and more difficult to aspirate, ultrasound-guided or fluoroscopy-guided needle aspiration should be done.

DIAGNOSIS AND DIAGNOSTIC TESTS Arthrocentesis and synovial fluid analysis should be done for all patients who present with an inflamed joint. Normal joints contain a small amount of synovial fluid that is clear, is highly viscous, and has very few white blood cells (WBCs). The protein concentration is approximately one third that of plasma, and the glucose concentration is similar to that of plasma. Infected synovial fluid is usually purulent with an elevated leukocyte count typically greater than 50,000 WBC/mm3 and often exceeding 100,000 WBC/mm3 with polymorphonuclear cell predominance. Synovial fluid levels of glucose, lactate dehydrogenase, and total protein have limited value in the diagnosis of septic arthritis. Although a low synovial fluid glucose (<40 mg/dL or less than half the serum glucose concentration) and an elevated lactate dehydrogenase suggest bacterial infection, they are not sufficiently sensitive or specific for the diagnosis.51 Figure 99-2 is an algorithm for synovial fluid analysis; Table 99-4 lists the differential diagnoses of septic arthritis and the known causes of pseudoseptic arthritis.6,52,53 A definite diagnosis of bacterial arthritis can be made only by visualizing bacteria on a Gram-stained smear or by culturing bacteria from the synovial fluid. In patients not previously treated with antibiotics, synovial fluid cultures are positive in 70% to 90% of cases of nongonococcal bacterial arthritis.54,55 Blood cultures are positive in 40% to 50% of cases of septic arthritis and are the only method of identifying the pathogen in about 10% of cases. An extraarticular site of infection offers a clue to the etiologic organism infecting the joint. Examples include septic arthritis in

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Table 99-4  Differential Diagnosis of Septic Arthritis   or Reported Causes of Pseudoseptic Arthritis*

Diagnostic arthrocentesis: (always try to tap the joint dry) Note which joint Total volume of synovial fluid Gross description of fluid, bloody or nonbloody

Partially treated septic arthritis Rheumatoid arthritis Juvenile rheumatoid arthritis Gout Pseudogout

Nonbloody fluid: Note color, turbidity, and viscosity

Bloody fluid: Consider the following differential diagnosis of hemarthrosis: Trauma with or without fracture Over anticoagulation Hemophilia Other bleeding disorders Pigmented villonodular synovitis or other tumors Traumatic tap

Apatite-related arthropathy Reactive arthritis Psoriatic arthritis Systemic lupus erythematosus Sickle cell disease Dialysis-related amyloidosis Transient synovitis of the hip Plant thorn synovitis Metastatic carcinoma Pigmented villonodular synovitis Hemarthrosis

Synovial fluid WBC 50,000 WBC/mm3

Neuropathic arthropathy

+

Synovitis after injection of hylan

–

Markedly inflammatory fluid: Consider empiric antibiotic therapy pending culture results

Noninflammatory to moderately inflammatory fluid: Consider a broad differential diagnosis from OA to RA. However, septic arthritis is less likely but still possible

Crystals? Under polarized light –

+

Inflammatory arthritis not due to crystals

Gout or pseudogout at least

Gram stain and/or culture positive?

Gram stain and/or culture positive?

–

+

+

–

Septic arthritis Markedly inflammatory fluid not due to crystals or infection: Consider the other possibilities listed in Table 99-4, reported causes of pseudoseptic arthritis

Crystal-induced arthritis defined by the nature of the crystals

Figure 99-2  Algorithm for synovial fluid analysis in septic arthritis. OA, osteoarthritis; RA, rheumatoid arthritis; WBC, white blood cells.

*Extremely inflammatory synovitis with negative culture is referred to as pseudoseptic arthritis. Typically, synovial fluid analysis shows ≥50,000 white blood cells (WBC)/mm3. Often the WBC count is >100,000 WBC/mm3. Data from references 6, 52, and 53.

association with pneumococcal pneumonia, Escherichia coli urinary tract infection, and cellulitis caused by staphylococci or streptococci. Gram-positive cocci are identified in 50% to 75% of synovial fluid Gram-stained smears, but gram-negative bacilli are identified less than 50% of the time in culture-proven cases.55 Culture for N. gonorrhoeae is almost always negative in skin lesions and is positive in less than 50% of synovial ­fluids and in less than one third of blood cultures; this may be the result of the fastidious growth requirements of N. gonorrhoeae. The organism can be easily recovered from other sites (i.e., the genitourinary tract). Alternatively, immune response to the organism or its components may be responsible for some of the clinical manifestations of disseminated gonococcal infection. The tenosynovitis and dermatitis associated with disseminated gonococcal infection may not yield viable organisms. Polymerase chain reaction techniques can detect gonococcal DNA in the synovial fluid of some culture-negative cases of suspected gonococcal arthritis, but the technique is not standardized and is not widely avilable.56,57 When culturing the synovial fluid, it should be brought directly to the laboratory and placed on conventional broth and solid media or into aerobic and anaerobic blood culture bottles. Inoculating blood culture bottles with 5 to 10 mL of joint fluid or smaller volumes into isolator tubes may increase the yield of positive cultures beyond that of standard techniques.58,59 Synovial fluid culture using the BACTEC Peds Plus/F bottle and the BACTEC 9240 instrument (Becton Dickinson Diagnostic Systems, Sparks, Md) detected significantly more pathogens and fewer contaminants than culture by the agar-plate method.60

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Table 99-1 lists the common organisms that cause joint infections according to the age of the patient and whether the joint is native or prosthetic.5 Overall, S. aureus is the most common etiologic agent among children of all age groups, followed by group A streptococci and Streptococcus pneumoniae. Neonates and infants younger than 2 months old are more susceptible to group B streptococci and gram-negative enteric bacilli than older children. Rarely, Pseudomonas, N. gonorrhoeae, and Candida albicans may be responsible in very young children. Since the introduction of the Haemophilus influenzae type b vaccine, the incidence of septic arthritis caused by H. influenzae has declined dramatically.61,62 In sexually active adolescents, N. gonorrhoeae must be considered.63 P. aeruginosa and Candida are potential pathogens in adolescent intravenous drug abusers. Patients with sickle cell anemia are prone to develop Salmonella arthritis, and immunocompromised children are at higher risk for infection with gram-negative bacilli. Other unusual joint pathogens in children include Neisseria ­meningitidis, anaerobes, Brucella, and Kingella kingae. The organisms causing nongonococcal septic arthritis in adults are 75% to 80% gram-positive cocci and 15% to 20% gram-negative bacilli.64 S. aureus is the most common organism in native and prosthetic joint infections. Staphylococcus epidermidis is common in prosthetic joint infections, but is a rare cause of native joint infections. The streptococci, including S. pneumoniae, are the next most common group of gram-positive aerobes. Streptococcus pyogenes is followed by groups B, G, C, and F in frequency. Patients with non– group A streptococcal disease often have comorbidities, such as immunosuppression, diabetes mellitus, malignancy, and severe genitourinary or gastrointestinal infections.65 Group B streptococcal arthritis in adults is uncommon, but it can be a serious infection in adult diabetics and patients with late prosthetic hip infections.66 Aggressive polyarthritis caused by group B streptococci resulted in serious functional damage and permanent morbidity.67,68 Patients predisposed to gramnegative bacillary infections include patients with a history of intravenous drug abuse, very young and very old patients, and immunocompromised patients.69 The most common gram-negative organisms are E. coli and P. ­aeruginosa. Anaerobes account for 5% to 7% of septic arthritis.2,3,54 Common anaerobes include Bacteroides, Propionibacterium acnes, and various anaerobic gram-positive cocci. Predisposing factors include wound infections, joint arthroplasty, and immunocompromised hosts. Foul-smelling synovial fluid or air in the joint space should raise the suspicion of ­ anaerobic infection, and appropriate cultures should be obtained and held for at least 2 weeks. Anaerobes and coagulase-­negative staphylococci are more common in prosthetic joint infections. Polyarticular septic arthritis is much less common than monarticular infection.34,36 Many of the patients have one or more comorbidities, and some have been intravenous drug abusers. Occurrence of polyarticular septic arthritis is high in patients with RA and averages 25% (range 18% to 35%).70 Although S. aureus is the most common pathogen, group G streptococci, H. influenzae, S. pneumoniae, or mixed aerobic and anaerobic bacteria have been responsible for polyarticular infections. Involvement of more than one joint also can occur in certain patient populations, such as neonates and patients with sickle cell anemia, or with

­certain organisms, such as N. gonorrhoeae, N. meningitidis, and Salmonella.71 Polymicrobial (two or more bacterial species), polyarticular (two or more joints) septic arthritis is a rare clinical entity. Large joints are usually affected. Among five reported cases, the knee was affected in four cases (bilaterally in two); the elbow and wrist were affected in three cases, and the shoulder was affected in two cases. The mean number of joints infected was three. Bacteremia was present in all but one case (80%) and always involved the same organisms that were in the synovial fluids. Most bacterial species isolated were the usual organisms seen in septic arthritis. Combinations of gram-positive aerobic and anaerobic organisms were common. A characteristic of most cases (80%) was the extension of locally destructive processes as a result of the contiguous spread of infection from the affected joints, such as osteomyelitis, fasciitis with compartment syndrome, and abscess or sinus tract formation. Systemic complications, including septic shock, multiorgan failure, and toxic shock syndrome, were noted in 60% of cases. The mortality rate of polymicrobial, polyarticular septic arthritis in this small series was 60%.72 Plain radiographs in septic arthritis are usually normal early in the course of the infection, but baseline films should be obtained to look for evidence of other disease and contiguous osteomyelitis. Radiographs often show nonspecific changes of inflammatory arthritis, including periarticular osteopenia, joint effusion, soft tissue swelling, and joint space loss. In more advanced infection, periosteal reaction, marginal or central erosions, and destruction of subchondral bone may be seen. Bony ankylosis is a late sequela of septic arthritis. Dislocation or subluxation of the femoral head is unique to hip infection of neonates.42 Ultrasound of the hip is the modality of choice to detect fluid collections in this deep joint and can serve as a guide in its aspiration. Ultrasound can be similarly used in other joints, such as the popliteal cyst of the knee, shoulder, acromioclavicular, or sternoclavicular joints. Triple-phase bone scan using technetium 99m is often done in children to identify an associated metaphyseal osteomyelitis or avascular necrosis of the femoral head. Whole-body bone scan is preferred in young children because, despite focal ­symptoms, septic arthritis and osteomyelitis may be multifocal in this age group.73 In septic arthritis of all age groups, the periarticular distribution of increased uptake is seen on the early “blood-pool” phase and the delayed images of the joint. Bone scans provide only nonspecific information, however, and cannot differentiate septic from noninfectious causes of joint inflammation. A suggestive bone scan must be interpreted in the proper clinical context and supported by microbiologic data for a definitive diagnosis of joint or bone infection. In joints that are difficult to evaluate otherwise or that have complex anatomic structures, computed tomography (CT) and magnetic resonance imaging (MRI) can provide useful images to delineate the extent of the infection.74 MRI is highly sensitive in early detection of joint fluid and is superior to CT in the delineation of soft tissue structures. These images can show early bone erosion; reveal soft tissue extension; and facilitate arthrocentesis of joints such as shoulders, hips, acromioclavicular,75 sternoclavicular, sacroiliac, and facet joints of the spine.

PART 17 

TREATMENT Treatment of septic arthritis must begin immediately after the clinical evaluation is complete and all appropriate cultures are taken. A serious clinical suspicion of a joint infection warrants the initiation of antibiotic therapy before culture confirmation is available. Delays in treatment allow the infection to become more established in the joint and damage permanently the articular cartilage. Untreated, there is the opportunity for the joint infection to spread to other body sites via the hematogenous route and become more widespread and more difficult to cure. The principles of treatment of an infected joint, whether natural or prosthetic, follow those of treatment of an infected body cavity in which antibiotics must be used in conjunction with adequate drainage of the infected closed space. The clinical circumstances and the preliminary laboratory data aid the selection of antibiotic agents. Host factors, any extra-articular sites of infection, and the Gram-stained smear of the synovial fluid are the best early guides for the antibiotic agents with which to start. Table 99-5 lists antibiotic agents for adults,76-80 and Table 99-6 lists agents for children.71 Narrow antibiotic coverage is indicated if gram-­positive cocci are found in the synovial fluid, and the clinician suspects a primary source of staphylococcal infection from the skin. Appropriate monotherapy in this case may be a penicillinase-resistant penicillin or vancomycin if methicillin resistance is likely. If gram-negative bacilli are noted in the synovial fluid, and the patient has a kidney infection, specific agents (e.g., ampicillin or a cephalosporin) against E. coli and other common urinary tract pathogens may be used. In healthy, sexually active individuals with community-acquired septic arthritis and a negative synovial fluid Gram-stained smear, a reasonable initial empiric therapy to cover gonococci, S. aureus, and streptococci can be ceftriaxone or cefotaxime pending final culture results. In elderly debilitated patients with an acute monarthritis, if the Gram-stained smear of synovial fluid is nonrevealing, and no clue is found after searching for an extra-articular source of infection, broad antibiotic coverage against a wide variety of organisms should be given initially. A typical regimen includes an antistaphylococcal agent, an aminoglycoside against gram-negative bacilli, and an antipseudomonal penicillin or a third-generation cephalosporin. When the identity and the sensitivities of the organism are known, antibiotic therapy should continue with the most efficacious agent that has the best safety profile and the lowest cost. The parenteral route of antibiotic administration is the preferred initial treatment. Continued antibiotic therapy may be switched to oral agents if adequate blood levels can be achieved and maintained by this route. There is no evidence that the direct intra-articular instillation of drugs is necessary or preferable in septic arthritis because there is no barrier against the free diffusion of antibiotic agents from the blood to the synovial fluid. In cases in which uncertainty exists, serum and synovial fluid levels of antibiotic drugs can be measured to ensure that therapeutic levels are reached. Most individuals with septic arthritis respond adequately to appropriate antimicrobial agents after initial joint ­aspiration for fluid analysis. In experimental infectious

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arthritis cases, early antibiotic therapy was shown to reduce the loss of collagen and erosion of articular surface, which should minimize the need for open surgical drainage.81 It is generally accepted that prompt and adequate drainage of the septic joint is essential to decrease the risks of substantial loss of articular function; however, the best approach to drain the joint remains controversial.82 From retrospective studies, daily aspiration of an infected joint showed better functional outcome than open surgical drainage, although the former had higher overall mortality.83-85 An explanation for higher mortality could be the higher comorbid conditions of patients who had daily aspirations than the ones who were more fit and underwent open surgical drainage.83 If the synovial fluid cell count and polymorphonuclear percentage decrease with ­successive aspiration, the antimicrobial therapy is probably effective.54,86 If needle aspiration is technically difficult (as in the hip or the shoulder) or does not provide thorough drainage of the joint, if the joint effusion does not resolve promptly, if sterilization of the joint fluid is delayed, if the infected joint is already damaged by preexisting rheumatoid disease, or if infected synovial tissue or bone needs débridement, surgical drainage should be considered sooner rather than later.54,55,87 Arthroscopy is emerging as an alternative to arthrotomy with the advantage of reduced surgical morbidity. Wound healing is faster, and rehabilitation time is shortened.88 During the first few days of management, immobilization of the infected joint by external splinting and adequate analgesic administration ensure patient comfort. Physical therapy, starting with passive then graduating to active motion, should be instituted as soon as the patient can tolerate mobilization of the inflamed joint because early active range-of-motion exercises are beneficial for ultimate functional recovery. Involving the orthopaedic surgeon and the physical therapist early on in the course of treatment facilitates the best choice of drainage procedure and results in the best functional outcome.89 The optimal duration of antibiotic treatment has not been prospectively studied. For native joint infections, antibiotic administration can be 2 weeks for uncomplicated infection by susceptible microorganisms or 4 to 6 weeks for more extensive infection in an immunocompromised host. For septic arthritis caused by H. influenzae, streptococci, or gram-negative cocci, 2 weeks of antibiotic therapy is usually adequate. Staphylococcal septic arthritis usually requires 3 to 4 weeks of therapy, and for pneumococcal or gram-negative bacillary infections, therapy should be continued for at least 4 weeks.87,90

PROSTHETIC JOINT INFECTIONS Total joint replacement for advanced arthritis is one of the major advances in medicine in the 20th century and continues to improve in the 21st century. Infection of prosthetic joints is an uncommon, but devastating complication of joint replacement surgery. Approximately 600,000 joint replacements are done each year in the United States, with an infection rate of 1% to 3%.91 The infection rate is higher for knee arthroplasty (1% to 2%) compared with hip and shoulder arthroplasty (0.3% to 1.3%) and is much higher in patients undergoing reimplantation because of infection

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Table 99-5  Antibiotic Agents Used in Adults Synovial Fluid Gram Stain

Organism

Antibiotic

Dose

Gram-positive cocci (clusters)

Staphylococcus aureus   (methicillin-sensitive)

Nafcillin/oxacillin

2 g IV q4h

S. aureus (methicillin-resistant)

Gram-positive cocci (chains)

Gram-negative diplococci

Gram-negative bacilli

Streptococcus

Neisseria gonorrhoeae

Enterobacteriaceae (E. coli, Proteus, Serratia) Pseudomonas

Polymicrobial infection

S. aureus, Streptococcus,   gram-­negative bacilli

or Cefazolin Vancomycin or Clindamycin or Linezolid

1-2 g IV q8h 1 g IV q12h 900 mg IV q8h 600 mg IV q12h

Nafcillin or Penicillin or Cefazolin

2 g IV q4h

Ceftriaxone or Cefotaxime or Ciprofloxacin

2 g IV q24h

Ceftriaxone or Cefotaxime Cefepime or Piperacillin or Imipenem plus Gentamicin Nafcillin/oxacillin* plus Ceftriaxone or Cefotaxime or Ciprofloxacin

2 million U IV q4h 1-2 g IV q8h

1 g IV q8h 400 mg IV q12h 2 g IV q24h 2 g IV q8h 2 g IV q12h 3 g IV q6h 500 mg IV q6h 7 mg/kg IV q24h 2 g IV q4h 2 g IV q24h 2 g IV q8h 400 mg IV q12h

*If penicillin allergic, vancomycin plus third-generation cephalosporin or ciprofloxacin. IV, intravenously; q4h, every 4 hours; q6h, every 6 hours; q8h, every 8 hours; q12h, every 12 hours; q24h, every 24 hours. Data from references 76-80.

of the initial prosthesis (3% for hips and 6% for knees).92-94 The risk of infection is about twofold higher in patients with RA compared with patients with osteoarthritis.95 The risk of infection is related to many factors. In a retrospective study of 462 infected orthopaedic implants, the most important risks for infection included (1) a surgical site infection at a site other than the prosthesis (odds ratio 35.9), (2) a score of 2 on the National Nosocomial Infections Surveillance System surgical patient risk index (odds ratio 3.9), (3) the presence of a malignancy (odds ratio 3.1), and (4) a history of joint arthroplasty (odds ratio 2.0).96 Certain patient populations are at increased risk of infection because of comorbid conditions (e.g., diabetes mellitus and RA). Orthopaedic implants adversely affect host defenses. Prosthetic devices impair opsonic activity and diminish the ability of neutrophils to kill bacteria.97 Polymorphonuclear leukocytes release lysosomal enzymes and superoxide into the area surrounding the prosthesis, resulting in tissue damage and local devascularization.98 Phagocytes may be focused on removal of the foreign body such that fewer cells are available to fight infection.99 Finally, polymethyl methacrylate bone cement can inhibit neutrophil and complement functions,

and the heat produced by the polymerization of polymethyl methacrylate can damage adjacent cortical bone and result in a devascularized necrotic area, which is ideal for bacterial growth. After implantation, prosthetic joints are immediately coated by host proteins, including albumin, fibrinogen, and fibronectin. S. aureus, which possesses numerous host protein binding receptors (MSCRAMMs), is a common pathogen in infection of prosthetic joints. Patients with a prosthetic joint who develop S. aureus bacteremia have an approximate one in three chance of developing an infection of the implant.100 Another phenomenon crucial to development of infection is the ability of organisms to form biofilms on the surface of the prosthetic device. A biofilm is defined as “an assemblage of microbial cells that is irreversibly associated with a surface and enclosed in a matrix of primarily polysaccharide material.”101 Biofilm formation is a natural process. Organisms grow on indwelling medical devices, potable water system pipes, and living tissues. S. epidermidis is particularly adept at attaching to and forming biofilms on foreign bodies, such as prosthetic joints. Small numbers of these organisms from the patient’s skin or mucous membranes, or from the hands of the surgeons or clinical staff, contaminate and

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Table 99-6  Antibiotic Agents Used in Children Age

Likely Pathogen

Antibiotic

Dosage (mg/kg/day)

Doses/day

Neonate

Staphylococcus aureus;   group B streptococci;   gram-­negative bacilli

Nafcillin plus Cefotaxime or Gentamicin

100

4

150

3

5-7.5

3

S. aureus; Haemophilus ­ influenzae*; group A ­streptococci;   Streptococcus ­pneumoniae

Nafcillin†

150

4

100-150

3-4

50

1-2

Child <5 yr old

plus Cefotaxime or Ceftriaxone or Cefuroxime

150-200

3-4

Child >5 yr old

S. aureus; group A streptococci

Nafcillin† or Cefazolin

150

4

50

3-4

Adolescent   (sexually active)

Previous organisms;   Neisseria gonorrhoeae

Ceftriaxone

50

1-2

*Decreased

incidence in children fully immunized with Hib vaccine. patient is penicillin allergic, alternatives include vancomycin (40 mg/kg/day divided into four doses) or clindamycin (20-40 mg/kg/day divided into four doses). Adapted from Gutierrez KM: Infectious and inflammatory arthritis. In Long SS, Pickering LK, Prober CG (eds): Principles and Practice of Pediatric Infectious Diseases, 2nd ed. New York, Churchill Livingstone, 2002, pp 475-481. †If

colonize the orthopaedic device at the time of implantation. Staphylococcal surface proteins, SSP-1 and SSP-2, are fimbria-like polymers that facilitate adherence of S. ­epidermidis to polystyrene.102 S. epidermidis produces a polysaccharide/ adhesin substance crucial to the formation of this extracellular matrix known as slime. Polysaccharide/adhesin mutants have been shown to be less virulent than the wildtype strain in a rabbit model of endocarditis.103 Prosthetic joint infections are divided into early onset (<3 months after placement), delayed (3 to 24 months postsurgery), and late onset (>24 months after placement).104 Early and delayed infections usually are related to surgical contamination at the time of the implantation, whereas late infections usually result from hematogenous seeding of the joint. Owing to its high virulence, S. aureus accounts for most early and late infections (see Table 99-1). Delayed infections usually are caused by less viruent microorganisms, such as coagulase-negative staphylococci and P. acnes. Because these low-virulence organisms are common skin contaminants, it is important to interpret culture results carefully. Clinically, the most common symptom in patients with prosthetic joint infection is pain of the affected joint. Differentiating pain from mechanical loosening of the prosthesis from pain related to infection can be difficult. Typically, a patient with mechanical loosening but no infection has pain only with motion, whereas a patient with infection experiences pain at rest and with motion. Warmth at the implant site, effusion, erythema, and fever frequently are associated with early and late, but not delayed, infections. This difference in clinical presentation likely represents the virulence of the most common organisms associated with the three categories of infection. The presence of a sinus tract with purulent discharge suggests involvement of the implant and is an indication for removal of the prosthesis. Laboratory tests are not useful in the diagnosis because an elevated C-reactive protein or erythrocyte sedimentation rate may be part of the underlying disease process, such as RA. Serial plain radiographs may be helpful; the presence

of subperiosteal bone growth and transcortical sinus tracts is specific for infection.105 Bone scans using technetium 99m–labeled methylene diphosphonate are very sensitive, but lack specificity because the bone scan is typically positive for 6 to 12 months after the original implantation.106 Bone scans may be a useful screening test for patients with suspected late prosthetic joint infection. CT has limitations because of the imaging artifacts caused by the metal implant. MRI can be performed only in patients with titanium or tantalum implants. Aspiration of the joint may be helpful in differentiating infection from noninfectious causes of joint pain, particularly in patients without RA. In one study, a synovial fluid leukocyte count of greater than 1700/mm3 had a sensitivity of 94% for determining infection, whereas a differential count of greater than 65% neutrophils had a sensitivity of 97%.107 The specificities of these two measurements were 88% and 98% in patients without underlying inflammatory diseases such as RA. Gram-stained smear of the synovial fluid has a low sensitivity (<20%), but a high specificity (>97%).108,109 Cultures of drainage from a sinus tract are not helpful, unless the culture grows S. aureus.110 Generally, at least three tissue specimens should be taken at the time of surgery, including tissue from the joint capsule, synovial lining, bone-cement interface, and samples from purulent material or sequestrum.109,111 Swabs of the joint have a low sensitivity and should be avoided. Unless the patient is septic or otherwise systemically ill, antimicrobial therapy should be discontinued a minimum of 2 weeks before the revision surgery, and perioperative antibiotics should not be administered until all of the tissue cultures have been obtained. Using this methodical approach, there is a direct correlation of the number of tissue specimens positive for a particular microorganism and the probabiltiy of infection. The probability of infection has been estimated to be less than 5% if all tissue specimens are negative, and greater than 94% if three or more tissue specimens are positive for growth.109 Finally, the location of the prosthesis is

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helpful in the interpretation of the positive culture. The isolation of P. acnes from a single tissue culture from a knee prosthesis is more likely to be a contaminant than if the same organism is obtained from a shoulder prosthesis.112 Medical therapy of patients with prosthetic joint infections is challegning. Organisms existing in biofilms are much more resistant to antimicrobial agents for several reasons. First, the drugs have difficulty penetrating the biofilm layer. The biofilm-associated organisms also grow much more slowly than organisms in suspension. As a result, antimicrobial agents such as vancomycin, penicillins, and cephalosporins, which act on rapidly dividing organisms, are not effective in treating device-related infections.113 Rifampin and fluoroquinolones may be more effective because they are active against organisms in the stationary phase of growth.114,115 The role of newer antibiotics, such as linezolid, daptomycin, and tigecycline, is unclear at this time.116,117 In a rabbit experimental model of S. aureus osteomyelitis, the combination of tigecycline and rifampin eradicated infection in 100% of 14 rabbits.118 Treatment of late prosthetic joint infections is complex. In most patients, effective therapy requires a combination of antibiotics with the removal of the orthopaedic device. Failure to remove the infected prosthesis is frequently associated with an unacceptably high rate of relapse, probably related to biofilm formation on the orthopaedic implant. Removal of the joint prosthesis, débridement of infected bone, and placement of a new prosthesis during the same operation has been associated with a high rate of recurrence of infection,119,120 but studies indicate that single-stage revision or débridement with retention of the prosthesis may be effective in certain situations.121-124 Patients whose symptoms of pain and swelling of the joint have been less than 8 days124 or less than 3 weeks,125 and who have a stable prosthesis with little soft tissue damage and no sinus tract are candidates for débridement with retention of the prosthesis if the preoperative synovial fluid cultures are negative, or if the cultures grow an easily treatable organism (Fig. 99-3). The treatment of choice for most patients is a two-stage process involving removal of the infected prosthesis and débridement of infected bone, stabilization of the joint using an antibiotic-impregnated methyl methacrylate spacer, and 6 weeks of intravenous antibiotics (first stage), followed by reimplantation of a second orthopaedic implant (second stage).126 Using this approach, the success rate is approximately 80% to 90%. Rarely, antibiotic treatment is continued indefinitely in a patient in whom the risk of removing the infected prosthesis is too great, the prosthesis is not loose, and the organism responsible for the infection can be reasonably suppressed by the use of an oral antibiotic agent.127 The pathogenesis of bacterial infection in prosthetic joints is complex. Anatomic, virulence, and host factors affect prognosis and approach to therapy. An understanding of these interactions may lead to novel therapeutic and preventive strategies, such as vaccines against capsule antigens or surface adhesins in patients undergoing elective joint replacements.

PREVENTION OF PROSTHETIC JOINT INFECTIONS There is consensus that preoperative evaluation of a patient for occult infection, such as periodontal disease or bacteriuria, is warranted, and corrective steps to eradicate any

Symptoms < 8 days Stable implant No sinus tract

Yes

Débridement with retention

Intact or minimally damaged soft tissue

One-stage exchange

Damaged soft tissue, abscess, or sinus tract

Two-stage exchange with short interval (2-4 weeks)

Difficult-to-treat microorganism

Two-stage exchange with long interval (6-8 weeks)

Inoperable

Long-term suppressive antimicrobial treatment

High risk for re-infection

Removal of implant without replacement

Figure 99-3  Algorithm for the management of an infected joint prosthesis. (Adapted from Trampuz A, Zimmerli W: Prosthetic joint infections: Update in diagnosis and treatment. Swiss Med Wkly 135:243-251, 2005.)

infection are essential before joint replacement. There also is consensus that perioperative antibiotic prophylaxis significantly reduces the rate of early postoperative infection, and this practice is routine. The role of antibiotic prophylaxis to prevent late prosthetic joint infection before diagnostic or therapeutic procedures that lead to transient bacteremia, especially dental treatment, is controversial. In 2003, the American Dental Association and the American Academy of Orthopedic Surgeons jointly updated an advisory on antibiotic prophylaxis for dental patients with total joint replacements.128 The advisory stated that antibiotic prophylaxis is not routinely indicated for most dental patients with total joint replacements. All patients with a total joint replacement within 2 years of the implant procedure, and some immunocompromised patients with total joint replacements who may be at higher risk for hematogenous infections, should be considered, however, to receive antibiotic prophylaxis before undergoing dental procedures with a higher bacteremic risk. Other orthopaedic and oral and maxillofacial surgeons have argued that there is “no scientific evidence to support the view that patients with arthroplasties, even in the high-risk groups, require antibiotic prophylaxis during dental treatment.”129 Professional societies take opposing positions citing evidence from clinical experience, descriptive studies, and reports of expert committees.130-132 Surveys of physicians and dentists have shown that most are in favor of the use of antibiotic prophylaxis before bacteremia-producing procedures to prevent prosthetic joint infection.133-135 Proponents believe the prevention of prosthetic joint infection is analogous to the prevention of bacterial endocarditis.136 Other reasons are fear of litigation and previous experience of dealing with the catastrophe of a late prosthetic joint

PART 17 

infection. Opponents to prophylactic antibiotic use cite the lack of data to support a clear-cut relationship between transient bacteremia and infection of a prosthetic joint. Others object because of the concern for antibiotic resistance in bacteria from the excessive use of antibiotics, and the cost and consequences of unnecessary drug use. There are no data from randomized controlled trials, cohort or casecontrol studies, or multiple time series with or without the intervention. In the absence of good evidence-based data, opting for antibiotic for the purpose of prophylaxis is a reasonable choice of the well-informed clinician.137 The incidence of late infection of a prosthetic joint as a result of procedurerelated bacteremia is extremely low—10 to 100 cases per 100,000 patients with total joint replacement per year. The cost of providing antibiotic prophylaxis to all patients with prosthetic joints before all procedures that are associated with transient bacteremia is substantial. The efficacy of such antibiotic prophylaxis is unknown. Cost-effective analyses have shown mixed results.138-141 These discrepancies are due to the lack of reliable data and the different assumptions used in the calculations. In the patient with the greatest risk of infection, an invasive procedure that leads to bacteremia sometimes can result in an infected total joint replacement. Counseling these patients on the risks and benefits of antibiotic prophylaxis would lead to an informed decision on which the patient and the physician can agree.52 As we gain experience since 1999 with the use of biologic agents in the management of RA and other ­inflammatory arthritides, there remains the conundrum of whether the increased risk of infection from TNF inhibitor and methotrexate warrants holding them before an elective orthopaedic procedure. A retrospective analysis of 10 cases of postoperative infections showed the use of a TNF inhibitor was significantly associated with the development of a serious infection (OR 4.4).142 A meta-analysis of the clinical literature on TNF inhibitors through December 2005 found an increased risk of serious infection and dose-related increased risk of malignancy in RA patients treated with TNF inhibitors.143 The risks and benefits must be weighed carefully, and the patients must be fully informed on how these agents should be used on a case-by-case basis.

OUTCOME AND PROGNOSIS In the 21st century, patients with septic arthritis as a group are becoming older, with more risk factors for infection and more comorbidities. The number of patients with prosthetic joints is increasing as the population of older patients grows and people live longer. It is not surprising to see more cases of infection in total joint replacements. The organisms have not changed significantly, however. Staphylococci (44% to 66%) are still the dominant organism followed by streptococci (18% to 28%) and gram-negative bacilli (9% to 19%).144 The emerging challenges in the treatment of septic arthritis are how to improve outcome, how to deal with resistant organisms, and how to overcome host factors that portend a poor prognosis. The outcome of the treatment of septic arthritis can be measured as mortality, as the functional outcome of the infected joint, or as short-term and long-term outcomes. Among the survivors, loss of articular cartilage, loss of

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Table 99-7  Factors That May Portend a Poor   Outcome in Septic Arthritis Older age Preexisting arthritis, especially rheumatoid arthritis, but also osteoarthritis and tophaceous gout Presence of synthetic material (e.g., total joint replacement) Delay in diagnosis or long duration of symptoms before seeking medical attention Polyarticular infection, especially if >3 joints and small hand joints are affected Presence of bacteremia Infection caused by virulent or difficult-to-treat organisms   (e.g., Staphylococcus aureus, Pseudomonas aeruginosa,   or some gram-negative bacilli) Patients receiving immunosuppressive therapy Serious underlying comorbidities (e.g., liver, kidney, or heart   diseases) Peripheral leukocytosis at presentation Worsening renal function Data from references 36, 43, 49, 145-147.

motion, or increase in pain in the affected joint would be considered poor functional outcomes. Loss of the limb to infection and need for surgery to fuse the joint or restore function also are poor outcomes. Most studies report the outcome at the time of hospital discharge, and long-term data on adults with septic arthritis are unavailable. The rate of development of degenerative joint disease, the rate of relapse or recurrence of infection, and the rate of ­progression of functional impairment in the affected joint over time have not been well studied. Many retrospective studies have characterized features that may increase the chance of a poor outcome at the time of hospital discharge (Table 99-7).36,43,49,145-147 One prospective community-based study of adults and children found poor joint outcome in 33% of survivors among 154 patients with bacterial arthritis and noted older age, preexisting joint disease, and an infected joint containing synthetic material as negative prognostic factors by univariate analysis.147 These investigators noted no association between poor outcome and young age, comorbidity, immunosuppressive medication, functional class, multiple infected joints, type of organism, or treatment delay. In a large retrospective study from the United Kingdom on the outcome of 243 patients, 11.5% died secondary to septic arthritis, and additional morbidity was noted in 31.6% of patients. Multivariate analysis suggests that important predictors of death are confusion at presentation, age 65 years or older, multiple joint sepsis, and involvement of the elbow joint. Predictors of morbidity were age 65 years or older, diabetes mellitus, open surgical drainage, and gram-positive infections other than S. aureus.84 REFERENCES   1. Goldenberg DL: Bacterial arthritis. Curr Opin Rheumatol 6:394400, 1994.   2. Kaandorp CJE, Dinant HJ, van de Laar MAFJ, et al: Incidence and sources of native and prosthetic joint infection: A community based prospective survey. Ann Rheum Dis 56:470-475, 1997.

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86. Goldenberg DL, Reed JI: Bacterial arthritis. N Engl J Med 312: 764-771, 1985. 87. Smith JW, Piercy EA: Infectious arthritis. Clin Infect Dis 20: 225-231, 1995. 88. Parisien JS, Shafer B: Arthroscopic management of pyoarthrosis. Clin Orthop 275:243-247, 1992. 89. Ho G Jr: How best to drain an infected joint: Will we ever know for certain? J Rheumatol 20:2001-2003, 1993. 90. Ross JJ, Saltzman CL, Carling P, et al: Pneumococcal septic arthritis: Review of 190 cases. Clin Infect Dis 36:319-327, 2003. 91. Darouiche RO: Device-associated infections: A macroproblem that starts with microadherence. Clin Infect Dis 33:1567-1572, 2001. 92. Lidgren L, Knutson K, Stefansdottir A: Infection and arthritis: Infection of prosthetic joints. Best Pract Res Clin Rheumatol 17:209-218, 2003. 93. Hanssen AD, Rand JA: Evaluation and treatment of infection at the site of a total hip or knee arthroplasty. Instr Course Lect 48:111-122, 1999. 94. Sperling JW, Kozak TK, Hanssen AD, et al: Infection after shoulder arthroplasty. Clin Orthop 382:206-216, 2001. 95. Robertsson O, Knutson K, Lewold S, et al: The Swedish Knee Arthroplasty Register 1975-1997: An update with special emphasis on 41,223 knees operated on in 1988-1997. Acta Orthop Scand 72:503-513, 2001. 96. Berbari EF, Hanssen AD, Duffy MC, et al: Risk factors for prosthetic joint infection: Case-control study. Clin Infect Dis 27:1247-1254, 1998. 97. Zimmerli W, Waldvogel FA, Vaudaux P, et al: Pathogenesis of foreign body infection: Description and characteristics of an animal model. J Infect Dis 146:487-497, 1982. 98. Roisman FR, Walz DT, Finkelstein AE: Superoxide radical production by human leukocytes exposed to immune complexes: Inhibitory action of gold compounds. Inflammation 7:355-362, 1983. 99. Wang JY, Wicklund BH, Gustilo RB, et al: Prosthetic metals impair murine immune response and cytokine release in vivo and in vitro. J Orthop Res 15:688-697, 1997. 100. Murdoch DR, Roberts SA, Fowler VG, et al: Infection of orthopedic prostheses after Staphylococcus aureus bacteremia. Clin Infect Dis 32:647-649, 2001. 101. Donlan RM: Biofilms: Microbial life on surfaces. Emerg Infect Dis 8:881-890, 2002. 102. Veenstra GJ, Cremers FF, van Dijk H, et al: Ultrastructural organization and regulation of a biomaterial adhesin of Staphylococcus epidermidis. J Bacteriol 178:537-541, 1996. 103. Shiro H, Muller E, Gutierrez N, et al: Transposon mutants of Staphylococcus epidermidis deficient in elaboration of capsular polysaccharide/adhesin and slime are avirulent in a rabbit model of endocarditis. J Infect Dis 169:1042-1049, 1994. 104. Zimmerli W, Trampuz A, Ochsner PE: Prosthetic-joint infections. N Engl J Med 351:1645-1654, 2004. 105 . Tigges S, Stiles RG, Roberson JR: Appearance of septic hip prosthesis on plain radiographs. AJR Am J Roentgenol 163:377-380, 1994. 106. Smith SL, Wastie ML, Forster I: Radionuclide bone scintigraphy in the detection of significant complications after total knee joint replacement. Clin Radiol 56:221-224, 2001. 107. Trampuz A, Hanssen AD, Osmon DR, et al: Synovial fluid leukocyte count and differential for the diagnosis of prosthetic knee infection. Am J Med 117:556-562, 2004. 108. Spangehl MJ, Masri BA, O’Connell JX, et al: Prospective analysis of preoperative and intraoperative investigations for the diagnosis of infection at the sites of two hundred and two revision total hip arthroplasties. J Bone Joint Surg Am 81:672-683, 1999. 109. Atkins BL, Athanasou N, Deeks JJ, et al: Prospective evaluation of criteria for microbiological diagnosis of prosthetic-joint infection at revision arthroplasty. The OSIRIS Collaborative Study Group. J Clin Microbiol 36:2932-2939, 1998. 110. Mackowiak PA, Jones SR, Smith JW: Diagnostic value of sinus-tract cultures in chronic osteomyelitis. JAMA 239:2772-2775, 1978. 111. Kamme C, Lindberg L: Aerobic and anaerobic bacteria in deep infections after total hip arthroplasty: Differential diagnosis between infectious and non-infectious loosening. Clin Orthop 154:201-207, 1981. 112. Steckelberg J, Osmon D: Prosthetic joint infections. In Waldvogel F, Bisno A (eds): Infections Associated with Indwelling Medical Devices, 3rd edition. Washington, DC, American Society for Microbiology Press, 2000. 113. Stewart PS, Costerton JW: Antibiotic resistance of bacteria in biofilms. Lancet 358:135-138, 2001.

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114. Widmer AF, Frei R, Rajacic Z, et al: Correlation between in vivo and in vitro efficacy of antimicrobial agents against foreign body infections. J Infect Dis 162:96-102, 1990. 115. Widmer AF, Wiestner A, Frei R, et al: Killing of nongrowing and adherent Escherichia coli determines drug efficacy in device-related infections. Antimicrob Agents Chemother 35:741-746, 1991. 116. Trampuz A, Widmer AF: Infections associated with orthopedic implants. Curr Opin Infect Dis 19:349-356, 2006. 117. Razonable RR, Osmon DR, Steckelberg JM: Linezolid therapy for orthopedic infections. Mayo Clin Proc 79:1137-1144, 2004. 118. Yin LY, Lazzarini L, Fan L, et al: Comparative evaluation of tigecycline and vancomycin, with and without rifampicin, in the treatment of methicillin-resistant Staphylococcus aureus experimental osteomyelitis in a rabbit model. J Antimicrob Chemother 55:995-1002, 2005. 119. Brandt CM, Sistrunk WW, Duffy MC, et al: Staphylococcus aureus prosthetic joint infection treated with debridement and prosthesis retention. Clin Infect Dis 24:914-919, 1997. 120. Raut VV, Siney PD, Wroblewski BM: One-stage revision of total hip arthroplasty for deep infection: Long term followup. Clin Orthop 321:202-207, 1995. 121. Giulieri SG, Graber P, Ochsner PE, et al: Management of infection associated with total hip arthroplasty according to a treatment algorithm. Infection 32:222-228, 2004. 122. Callaghan JJ, Katz RP, Johnston RC: One-stage revision surgery of the infected hip: A minimum 10-year followup study. Clin Orthop 369:139-143, 1999. 123. Ure KJ, Amstutz HC, Nasser S, et al: Direct-exchange arthroplasty for the treatment of infection after total hip replacement: An average ten-year follow-up. J Bone Joint Surg Am 80:961-968, 1998. 124. Marculescu CE, Berberi EF, Hanssen AD, et al: Outcome of prosthetic joint infections treated with debridement and retention of components. Clin Infect Dis 42:471-478, 2006. 125. Trampuz A, Zimmerli W: Prosthetic joint infections: Update in diagnosis and treatment. Swiss Med Wkly 135:243-251, 2005. 126. Brandt CM, Duffy MCT, Berbari EF, et al: Staphylococcus aureus prosthetic joint infection treated with prosthesis removed and delayed reimplantation arthroplasty. Mayo Clin Proc 74:553-558, 1999. 127. Stein A, Bataille JF, Drancourt M, et al: Ambulatory treatment of multi-drug resistant Staphylococcus-infected orthopedic implants with high-dose oral co-trimoxazole. Antimicrob Agents Chemother 42:3086-3091, 1998. 128. American Dental Association, American Academy of Orthopedic Sur­ geons Advisory statement: Antibiotic prophylaxis for dental patients with total joint replacements. J Am Dent Assoc 134:895-899, 2003. 129. Sandhu SS, Lowry JC, Morton ME, et al: Antibiotic prophylaxis, dental treatment and arthroplasty: Time to explode a myth. J Bone Joint Surg Br 79:521-522, 1997. 130. American Society for Gastrointestinal Endoscopy: Antibiotic prophylaxis for gastrointestinal endoscopy. Gastrointest Endosc 58: 475-482, 2003.

131. American Society of Colon and Rectal Surgeons: Practice parameters for antibiotic prophylaxis to prevent infective endocarditis or infected prosthesis during colon and rectal endoscopy. Dis Colon Rectum 44:899, 2001. 132. Working Party of the British Society for Antimicrobial Chemotherapy: Case against antibiotic prophylaxis for dental treatment of patients with joint prostheses. Lancet 339:301, 1992. 133. Howell RM, Green JG: Prophylactic antibiotic coverage in dentistry: A survey of need for prosthetic joints. Gen Dent 33:320-323, 1985. 134. Meyer GW, Artis AL: Antibiotic prophylaxis for orthopedic prostheses and GI procedures: Report of a survey. Am J Gastroenterol 92:989-991, 1997. 135. Shrout MK, Scarbrough F, Powell BL: Dental care and the prosthetic joint patient: A survey of orthopedic surgeons and general dentists. J Am Dent Assoc 125:429-436, 1994. 136. Dajani AS, Taubert KA, Wilson W, et al: Prevention of bacterial endocarditis: Recommendations by the American Heart Association. JAMA 277:1794-1801, 1997. 137. Mason JC, Dollery CT, So A, et al: An infected prosthetic hip: Is there a role for prophylactic antibiotics? BMJ 305:300-302, 1992. 138. Jacobson JJ, Schweitzer SO, Kowalski CJ: Chemoprophylaxis of prosthetic joint patients during dental treatment: A decision-utility analysis. Oral Surg Oral Med Oral Pathol 72:167-177, 1991. 139. Jaspers MT, Little JW: Prophylactic antibiotic coverage in patients with total arthroplasty: Current practice. J Am Dent Assoc 111: 943-948, 1985. 140. Krijnen P, Kaandorp CJE, Steyerberg EW, et al: Antibiotic prophy­ laxis for haematogenous bacterial arthritis in patients with joint disease: A cost effective analysis. Ann Rheum Dis 60:359-366, 2001. 141. Tsevat J, Durand-Zaleski I, Pauker SG: Cost-effectiveness of antibiotic prophylaxis for dental procedures in patients with artificial joints. Am J Public Health 79:739-743, 1989. 142. Giles JT, Bartlett SJ, Gelber AC, et al: Tumor necrosis factor inhibitor therapy and risk of serious postoperative orthopedic infection in rheumatoid arthritis. Arthritis Care Res 55:333-337, 2006. 143. Bongartz T, Sutton AJ, Sweeting MJ, et al: Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: Systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295:2275-2285, 2006. 144. Dubost JJ, Soubrier M, De Champs C, et al: No change in the distribution of organisms responsible for septic arthritis over a 20 year period. Ann Rheum Dis 61:267-269, 2002. 145. Ho G Jr, Su EY: Therapy for septic arthritis. JAMA 247:797-800, 1982. 146. Yu LP, Bradley JD, Hugenberg ST, et al: Predictors of mortality in non-post-operative patients with septic arthritis. Scand J Rheumatol 21:142-144, 1992. 147. Kaandorp CJE, Krijnen P, Moens HJB, et al: The outcome of bacterial arthritis: A prospective community-based study. Arthritis Rheum 40:884-892, 1997.

100

Lyme Disease Linda K. Bockenstedt

KEY POINTS Lyme disease is due to infection with tick-transmitted spirochetes of the genus Borrelia burgdorferi sensu lato, and has a worldwide distribution. Variation in genospecies may account for differences in the clinical expression of Lyme disease, with neurologic and late skin disease more common in Europe and arthritis more common in North America. Lyme disease has a characteristic pattern of signs and symptoms (see Table 100-1) and usually begins with the hallmark skin lesion erythema migrans. Earlier recognition and treatment has led to a decline in the incidence of carditis and acute neurologic and late disease manifestations. Musculoskeletal manifestations occur in more than 50% of patients and at all stages of infection, but frank arthritis is now considered a sign of late disease and is uncommon (<10% of patients). The diagnosis of Lyme disease should be suspected when a patient who lives, works, or vacations in an endemic area presents with signs and symptoms of B. burgdorferi infection. Two-tiered (enzyme-linked immunosorbent assay and immunoblot) serologic tests can be negative with early infection, but become positive in most patients with disease of greater than 1 month’s duration. Most patients are cured with 2 to 4 weeks of antibiotic therapy, although the time to disease resolution may extend beyond the duration of therapy, and irreversible tissue damage may occur. Coinfection with other tick-borne pathogens (Babesia microti or Anaplasma phagocytophilum) can lead to more severe symptoms and should be suspected in patients who have a poor response to treatment for Lyme disease. Antibiotic-refractory arthritis occurs in less than 10% of patients who develop arthritis secondary to Lyme disease and may be due to persistent foreign antigen, abnormal regulation of the inflammatory response, or infection-induced autoimmunity. These patients respond to nonsteroidal anti-inflammatory drugs and hydroxychloroquine, and arthritis typically resolves over 4 to 5 years. A minority of patients have persistent debilitating complaints of fatigue, mild cognitive dysfunction, and musculoskeletal pain after antibiotic treatment for Lyme disease. Viable B. burgdorferi cannot be detected in these individuals, and controlled treatment trials show no benefit of prolonged antibiotic therapy over placebo. Although maternal-fetal transmission of B. burgdorferi can occur, there is no evidence that the organism causes a congenital syndrome. B. burgdorferi infection in the mother should not cause harm to the fetus if pregnant patients with Lyme disease are treated with recommended antibiotic regimens.

Lyme disease is a multisystem disorder caused by the tickborne spirochete Borrelia burgdorferi.1 The disease first came to medical attention in the late 1970s with the investigation of a clustering of cases of juvenile arthritis in the region of Lyme, Connecticut.2 A characteristic skin rash described as single or multiple expanding red macules often heralded the onset of arthritis.2 This rash, termed erythema migrans (EM), had been linked in Europe to the bite of Ixodes ticks and the subsequent development of neurologic abnormalities.3 Further investigation revealed that arthritis was one manifestation of a systemic disorder affecting the skin, heart, joints, and nervous system. In 1982, Burgdorfer4 isolated the causative agent, the spirochete B. burgdorferi, from Ixodes ticks. Demonstration that Lyme disease patients developed antibodies to this organism and its eventual culture from skin, cerebrospinal fluid (CSF), and synovial tissue confirmed the infectious etiology of the disorder.5 It is now the most common vector-borne disease in the United States.1

ECOLOGY AND EPIDEMIOLOGY OF LYME DISEASE Lyme disease has a worldwide distribution, with most cases reported in North America, Europe, and Asia.6 On each of these continents, hard-shelled ticks of the Ixodes family serve as vectors for the disease. The incidence of Lyme disease varies geographically and is determined by the prevalence of B. burgdorferi–infected ticks. In the United States, cases of Lyme disease have been reported in 49 states and the District of Columbia, but most are clustered in the Northeast and mid-Atlantic region, upper Midwest, and northern California. In 2005, 23,305 cases were reported to the Centers for Disease Control and Prevention, with 93% originating from eight states: New York, Pennsylvania, New Jersey, Massachusetts, Connecticut, Maryland, Minnesota, and Delaware.7 The spirochetes associated with Lyme disease reside within the genus B. burgdorferi sensu lato (sl) and include B. burgdorferi sensu stricto (ss), Borrelia garinii, and Borrelia afzelii.6 All three genospecies can be found in Europe, whereas only B. burgdorferi ss is found in North America. Variation among the genospecies may account for the differences in clinical expression of Lyme disease between the two continents, with B. garinii associated with neurologic disease, B. afzelii associated with late skin involvement, and B. burgdorferi ss associated with arthritis. Because of the prominence of musculoskeletal manifestations with B. burgdorferi ss infection, the only genospecies in North America, this chapter focuses on Lyme disease in the United States. 1715

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TICKS AND LYME DISEASE Lyme disease is found primarily in temperate climates where humans can have incidental exposure to questing ticks. Ixodes ticks have a 2-year life span in which they pass through three developmental stages—larva, nymph, and adult—feeding only once per stage.8,9 B. burgdorferi is not passed transovarially and is maintained by passage between a reservoir host and ticks. Small rodents are the main reservoirs for B. burgdorferi ss and B. afzelii, whereas birds are the principal haven for B. garinii in Europe.6 In the southern United States, ticks feed preferentially on lizards, which are not competent reservoirs for B. burgdorferi; this may explain in part the rarity of Lyme disease in this region. Larvae acquire B. burgdorferi after feeding on an infected reservoir host in early spring, then molt to nymphs, which lay dormant until the following late spring and summer. The peak incidence of Lyme disease is in the summer months when humans come in contact with questing nymphs, which have more promiscuous feeding patterns.8 Engorged nymphs molt into adult ticks, which feed almost exclusively on deer. B. burgdorferi does not persist in deer, which serve to maintain and propagate the tick population.

PATHOGENESIS BORRELIA BURGDORFERI INVASION OF THE MAMMALIAN HOST During tick feeding, B. burgdorferi migrates from the tick midgut to the salivary glands for egress into the blood meal host.9 Migration takes about 24 hours, during which time spirochetes multiply and undergo phenotypic changes that permit the survival of B. burgdorferi in the new host. Spirochetes multiply first at the tick bite site in the skin, and if not dealt with by the innate immune system, they can disseminate through tissues and the bloodstream to infect any organ system at least transiently. The degree to which B. burgdorferi causes disease in tissues depends on spirochete virulence, growth conditions that allow it to persist at a particular site, and host factors that modulate the inflammatory response. Analysis of the B. burgdorferi genome has revealed no known virulence factors common to other bacterial pathogens to help explain the pathogenesis of Lyme disease.10 Instead the genome is remarkably rich in genes encoding putative lipoproteins, only a handful of which have been studied in detail. Outer surface protein (Osp) A is a midgut adhesin required for spirochete infection of ticks.11 Osp C is essential for initial infection of the mammal, but is dispensable after spirochetes have disseminated and colonized other tissue.12 To do so, B. burgdorferi harnesses host plasmin to move through tissues and expresses adhesins, including decorin binding proteins A and B, BBK32, and p66, which allow it to bind to extracellular matrix proteins and integrins on cells. PATHOLOGY OF LYME DISEASE Because intact spirochetes are seen only rarely in tissue specimens, the inflammatory response to B. burgdorferi components rather than tissue destruction by the spirochete itself

is believed to underlie the pathology of Lyme disease. Histopathologic studies of EM lesions, cardiac tissue, synovial biopsy specimens, and limited nervous system tissue (meninges, spinal cord, and nerve roots) reveal varying degrees of monocytic and lymphoplasmacytic infiltrates, especially perivascular, that stain positively for cell surface markers for macrophages, T cells, and B cells.13 The joint effusions of patients with Lyme arthritis reveal acute inflammation with elevated leukocyte counts, whereas the synovium resembles that of rheumatoid arthritis, with chronic inflammation mediated by mononuclear cell infiltration and pseudolymphoid follicles formed by T cells, B cells, and plasma cells. In the synovium and less commonly the epineural area, perivascular infiltrates can be associated with endarteritis obliterans, but B. burgdorferi infection does not typically cause a true vasculitis. IMMUNE RESPONSE TO BORRELIA BURGDORFERI Innate immune cells respond to B. burgdorferi through engagement of the Toll-like receptor (TLR) family of pattern recognition receptors, especially TLR2 (lipoproteins), TLR5 (flagellin), and TLR9 (spirochete DNA).14 As a consequence, proinflammatory cytokines (including interleukin1β and tumor necrosis factor-α), chemokines (interleukin-8), nitric oxide, and prostaglandins are produced that recruit inflammatory cells to the site of infection.14,15 B. burgdorferi also induces matrix metalloproteinase expression in tissues through TLR-dependent and non–TLR-dependent pathways that contribute to pathology.16 Humoral immunity is a key host defense against B. burgdorferi infection. B. burgdorferi lipoproteins are B cell mitogens, and antibodies that arise in the absence of T cell help are sufficient to resolve inflammation and prevent challenge infection in the mouse model of Lyme borreliosis.17,18 With the induction of adaptive immunity, IgG-containing immune complexes and cryoglobulins can be found in the serum of patients with Lyme disease and are concentrated in the joints of patients who develop Lyme arthritis.19 Evidence of pathogen-specific intrathecal antibody production can be found in patients with neuroborreliosis20; some of these antibodies also can bind neural glycolipid antigens.21,22 B. burgdorferi infection primes CD4+ and CD8+ T cells, and the predominance of T helper type 1 responses correlates with more severe arthritis and neuroborreliosis.23,24 There is an association between T cell and B cell responses to Osp A and the development of antibiotic-refractory Lyme arthritis.25,26 Although evidence has been presented to suggest an autoimmune etiology (see later section on antibiotic­refractory arthritis), the self-limited nature of Lyme arthritis also raises the possibility that the immune responses detected are appropriate and directed toward eliminating persisting antigens rather than viable organisms. Alternatively, prolonged arthritis may be due to abnormal or delayed regulation of the host immune response when the pathogen and its inflammatory products have been eliminated. Deficiency in CD25+ T regulatory cells prolongs murine Lyme arthritis,27 and synovial fluid γδ T cells isolated from patients with Lyme arthritis can modulate B. burgdorferi–specific CD4+ T cell responses by inducing apoptosis in a Fas-dependent fashion.28

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MECHANISMS OF SPIROCHETE PERSISTENCE When visualized in vivo, B. burgdorferi resides primarily in the extracellular matrix in connective tissue.13 Despite occasional sightings of spirochetes inside cells,29 an intracellular phase of the B. burgdorferi life cycle has not been shown. B. burgdorferi employs immune evasion strategies of an extracellular pathogen, which are directed toward deterring phagocyte ingestion and antibody and complement­mediated lysis.14 B. burgdorferi expresses Erp and complement regulator–acquiring surface proteins that bind host factor H to prevent complement-mediated lysis. To impede antibody-mediated clearance, B. burgdorferi undergoes antigenic variation30 and reduces expression of lipoproteins as infection progresses.31 The vlsE gene undergoes random rearrangement of its expression locus, producing antigenically distinct variants of VlsE, a protein essential for spirochete survival in vivo. In the chronic phase of B. burgdorferi infection in mice, spirochetes can be visualized in the extracellu­ lar matrix of connective tissue, especially the skin, without an associated inflammatory response.32

CLINICAL FEATURES OF LYME DISEASE Lyme disease occurs in stages that reflect the immune response to the spirochete as it establishes infection in the skin and later disseminates to distant organ sites (Table 100-1). Presenting clinical manifestations depend on the stage of the illness in which patients first seek medical attention. A characteristic feature of Lyme disease is that clinical signs can resolve without specific therapy, and patients may present in later stages of the illness without exhibiting signs of early disease. EARLY LOCALIZED INFECTION The hallmark of Lyme disease is the skin lesion EM, which is present in 80% to 90% of patients (Fig. 100-1).33 The lesion arises within 1 month (median 7-10 days) at the tick bite site, especially in skin folds or where clothes bind in adults and around the hairline in children. EM begins as a red macule that expands at the rate of 2 to 3 cm/day, enlarging to more than 70 cm in diameter. Characteristic lesions greater than 5 cm in diameter in an appropriate clinical setting are sufficient for establishing the diagnosis of Lyme disease.34 EM most often manifests with uniform erythema, but central clearing can occur in larger lesions, producing a classic “bull’s eye” appearance (see Fig. 100-1D). Vesicular or necrotic centers are rarer, but even these EM lesions have relatively few symptoms other than a tingling or burning sensation. Intense pruritus or pain is unusual and should raise concern for alternative diagnoses. EM may be accompanied by systemic flulike symptoms, including low-grade fever, malaise, neck pain or stiffness, arthralgias, and myalgias.8 Particularly severe systemic symptoms should alert the physician to possible coinfection with another tick-borne pathogen, such as Babesia microti or Anaplasma phagocytophilum (the agent of human granulocytic anaplasmosis, formerly known as human granulocytic erhlichiosis). Lyme disease also can manifest with systemic symptoms alone in the absence of EM.35,36 Absence of upper respiratory or gastrointestinal symptoms may help distinguish Lyme disease from common viral infections.

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Table 100-1  Clinical Manifestations of Lyme Disease Early Localized Infection Occurs 3±30 days after tick bite Erythema migrans (EM) in 80%-90% of patients; single lesion,   occasionally associated with fever, malaise, neck pain or stiffness, arthralgias and myalgias Systemic symptoms noted above in the absence of EM during   summer months Borrelial lymphocytoma (rare, seen primarily in Europe) Early Disseminated Infection Occurs weeks to months after tick bite Profound malaise and fatigue common Multiple EM lesions with systemic symptoms similar to early localized infection Musculoskeletal   Migratory polyarthralgias and myalgias Carditis (<3% of untreated patients)   Varying degrees of atrioventricular nodal block   Mild myopericarditis Neurologic (<10% of untreated patients)   Cranial neuropathies (especially facial nerve palsy)   Lymphocytic meningitis   Radiculoneuropathies   Encephalomyelitis Late Disease Occurs months to years after tick bite Arthritis (<10% of patients)   Acute monarticular or migratory pauciarticular inflammatory ­arthritis, usually involving the knee   Chronic antibiotic-refractory arthritis (<10% of patients with ­arthritis) Neurologic (rare)   Peripheral neuropathies   Mild encephalopathy   Encephalomyelitis (primarily seen in Europe) Skin   Acrodermatitis chronica atrophicans (primarily seen in Europe)

Musculoskeletal complaints and debilitating fatigue associated with Lyme disease should be distinguished from fibromyalgia and chronic fatigue syndrome, which typically are more insidious in onset and are not associated with objective findings or laboratory abnormalities. A newly recognized southern tick–associated rash illness (STARI) can produce a skin lesion similar to the bull’s eye form of EM.37 The rash is associated with the bite of the Lone Star tick, Amblyomma americanum, which is endemic to the southeastern and south-central states, but which also can be found as far north as Maine or west as central Texas and Oklahoma. Similar to EM, systemic symptoms can accompany the rash of STARI, but disease in organs other than the skin does not occur. The etiology of STARI is unknown. Although a noncultivatable spirochete named Borrelia lonestari has been found in A. americanum, STARI patients do not develop positive Lyme serologies, and the organism has not been found in skin biopsy specimens of the STARI lesions. Antibiotics resolve EM and STARI, but STARI patients recover more quickly from systemic symptoms than do patients with EM.

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A

B

C

D

Figure 100-1  Classic erythema migrans rash of Lyme disease. A and B, Right inner thigh. C, Multiple lesions on back. D, Right lateral posterior thorax (bull’s eye). E, Anterior side.

E

EARLY DISSEMINATED INFECTION Within weeks of the onset of infection, B. burgdorferi can disseminate through the skin, blood, and lymphatics to infect multiple tissues. Clinically apparent disease at this stage is usually seen, however, in the skin, heart, or nervous system. Patients with disseminated infection have debilitating fatigue and appear ill. Specific localizing signs and symptoms may fluctuate, but profound fatigue is a consistent complaint. SKIN DISEASE Fifty percent of patients with untreated Lyme disease develop multiple EM lesions, a sign of disseminated infection (see Fig. 100-1C).33 Secondary lesions are typically smaller and can occur anywhere on the body, but are most noticeable on the trunk. The lesions usually appear as flat macules and can develop partial central clearing. EM lesions may be accompanied by migratory muscle, joint, and periarticular pain that lasts hours to days, but frank arthritis is now considered a late manifestation. CARDIAC DISEASE The incidence of cardiac involvement has declined to 1% to 3% in recent years, possibly owing to earlier recognition and treatment of B. burgdorferi infection. It most often occurs within the first 2 months of infection and manifests as varying degrees of atrioventricular block, occasionally accompanied by mild myopericarditis.38 Electrophysiologic studies have mapped the conduction defect to the area above the

bundle of His and involving the atrioventricular node, although multiple levels can be affected. Overt congestive heart failure is rare, and chronic cardiomyopathy, reported in Europe, has not been documented to occur in the United States.39 Patients with Lyme carditis often have a history of EM and may have concomitant arthralgia and myalgia at the time of presentation. Absence of valvular heart disease helps distinguish Lyme carditis from acute rheumatic fever, and prominent myocardial dysfunction or pericardial involvement should suggest other infectious etiologies. NERVOUS SYSTEM INVOLVEMENT Acute neurologic Lyme disease occurs in less than 10% of patients and most commonly manifests as cranial nerve palsy or meningitis, although radiculopathy and encephalomyelitis also are occasionally seen.40-42 Cranial palsy usually affects the seventh nerve, resulting in unilateral or bilateral facial palsy. Even in endemic areas, however, onset of seventh nerve palsy in the nonwinter months is due to B. burgdorferi infection in only 25% of cases. Bilateral facial palsy is seen in only a few other conditions—Guillain-Barré syndrome, human immunodeficiency virus infection, sarcoidosis, and other causes of chronic meningitis—all of which are readily distinguished from Lyme disease. Rarely, other cranial nerves (III, IV, V, VI, or VIII) may be involved. Lyme meningitis manifests with fever, headache, and stiff neck similar to viral meningitis, along with a CSF lymphocytosis and elevated protein.43 In children, meningitis may occur with EM, cranial nerve involvement, and increased ­intracranial

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pressure (papilledema), which is rare in adults.42,44 Lyme radiculopathy typically manifests as pain, weakness, numbness, and reflex loss in a dermatomal distribution, resembling mechanical radiculopathies.42 Lyme disease should be considered when there is no obvious precipitating factor for disk-related symptoms, and imaging studies do not delineate pathology at the appropriate root level. Untreated Lyme radiculopathy can progress to become bilateral, which helps distinguish it from mechanical disease. When truncal involvement causes unilateral chest or abdominal pain, Lyme radiculopathy is often mistaken for visceral disease or early herpes zoster before the development of vesicular lesions. OTHER ORGAN SYSTEM INVOLVEMENT A variety of other organs can exhibit pathology with disseminated B. burgdorferi infection, including the eye (keratitis), the ear (sensorineural hearing loss), the liver (hepatitis), the spleen (necrosis), skeletal muscle (myositis), and subcutaneous tissue (panniculitis).45 In general, other, more classic manifestations of Lyme disease are present concurrently or have been present in the recent past to suggest the diagnosis. LATE DISEASE Months after the onset of infection, untreated patients can develop late manifestations of Lyme disease, usually involving the joints (discussed separately later), nervous system, and the skin. At this stage of infection, two-tier (enzymelinked immunosorbent assay [ELISA] and IgG immunoblot) serologic testing for B. burgdorferi should be positive. Late Neurologic Disease Late neurologic Lyme disease is now rare; patients may present with encephalomyelitis, peripheral neuropathy, or encephalopathy.46,47 Encephalomyelitis, seen predominantly in Europe with B. garinii infection, is a slowly progressive, unifocal or multifocal inflammatory disease of the central nervous system, with increased T2 signals in the white matter on MRI. CSF examination often reveals a lymphocytic pleocytosis, elevated protein, and normal glucose, and serum IgG to B. burgdorferi and intrathecal antibody production can be found. These findings help distinguish Lyme encephalomyelitis from multiple sclerosis, which may rarely be associated with positive IgG reactivity to B. burgdorferi in serum and CSF samples, but there is no intrathecal antibody production.48 Multiple sclerosis patients with positive Lyme serologies do not respond to antibiotics used for neurologic Lyme disease. Late peripheral nervous system involvement manifests as a mild sensorimotor neuropathy in a “stocking and glove” distribution, with evidence of a mild confluent mononeuritis multiplex on electrophysiologic studies.49 Patients may have intermittent limb paresthesias and occasionally radicular pain. The most common finding on physical examination is reduced vibratory sensation in the lower extremities. Serum IgG to B. burgdorferi should be present, but CSF examination is normal, consistent with disease confined to the peripheral nervous system. Patients with this form of neuropathy should

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be evaluated for other infectious diseases (syphilis, human immunodeficiency virus, and hepatitis C virus), metabolic disorders (especially vitamin B12 deficiency, diabetes mellitus, and thyroid disease), and autoimmune diseases (antinuclear antibody [ANA] or rheumatoid factor associated). Patients with Lyme encephalopathy complain of memory impairment and cognitive dysfunction that is best shown by formal neuropsychologic testing.50,51 Occasionally, patients may have CSF abnormalities with elevated protein, lymphocytic pleocytosis, and intrathecal antibody to B. burgdorferi, but CSF examination also can be normal. Serum IgG to B. burgdorferi should be present, however, to consider the diagnosis. The mild cognitive dysfunction seen in patients with Lyme encephalopathy must be distinguished from neurocognitive deficits secondary to chronic stress, sleep deprivation, fibromyalgia, chronic fatigue syndrome, or aging. As for any chronic encephalopathy, toxic-metabolic causes should be excluded. Brain imaging studies generally are normal or show only nonspecific abnormalities and are not useful in establishing a diagnosis of encephalopathy associated with Lyme disease. Late Skin Disease The late skin lesion acrodermatitis chronica atrophicans is found mainly in Europe because of its association with B. afzelii infection, although any B. burgdorferi species can cause the lesion. Acrodermatitis chronica atrophicans develops insidiously over years and most often is found on the dorsum of the hands or feet.52 It begins as a unilateral bluish red discoloration and swelling, which evolves to atrophic, cellophane-like skin with prominent appearance of the blood vessels. About 60% of patients also have a peripheral sensory neuropathy affecting the involved extremity. A prominent lymphoplasmacytic infiltrate is shown on the skin biopsy specimen. Antibiotics can lead to improvement in pain and swelling, but atrophic skin remains.

LYME ARTHRITIS AND OTHER MUSCULOSKELETAL MANIFESTATIONS OF LYME DISEASE Musculoskeletal symptoms are common in all stages of Lyme disease and include migratory pain in joints, tendons, bursae, and muscles.53 Typically, musculoskeletal pain affects one or two sites at a time, lasts only hours to a few days at any one location, and is associated with significant fatigue. The incidence of frank arthritis has declined from 50% in early studies to less than 10% in more recent years.15 ELISA and IgG immunoblot for B. burgdorferi are positive when arthritis appears, and B. burgdorferi DNA can be detected by polymerase chain reaction (PCR) in synovium and synovial fluid even though cultures are usually negative. Although Lyme arthritis can resemble pauciarticular juvenile arthritis or reactive arthritis, patients generally test negative for ANA, rheumatoid factor, and anti–cyclic citrullinated peptide antibodies, and do not have an increased frequency of HLAB27 alleles. Joint fluid analysis and synovial histopathology cannot distinguish these entities. Axial and sacroiliac joint involvement is not a feature of Lyme disease, but enthesitis can be seen. Most patients with Lyme arthritis have positive two-tier serologic tests for B. burgdorferi infection.

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Arthritis usually begins months or years after B. burgdorferi infection and is predated by migratory arthralgias in half of patients.53 The most typical pattern is a monarticular or oligoarticular arthritis involving one or a few large joints (fewer than five total), with the knee affected in 80% of cases. Joints are warm with large effusions, often greater than 100 mL in the knee, but comparatively little pain. Synovial fluid is inflammatory with white blood cell counts ranging from approximately 2000 to 70,000/mm3 (median approximately 24,000/mm3), with a predominance of neutrophils.54 Depending on the chronicity of the arthritis, synovial biopsy specimens reveal only mononuclear cell infiltration or more advanced changes consistent with rheumatoid synovium.13 Large effusions can lead to Baker cyst formation and rupture. The temporomandibular joint also is frequently involved and in one study was the first joint to be affected in 25% of patients with arthritis.53 Other joints commonly affected include the shoulder, ankle, elbow, wrist, and hip. Lyme arthritis is often intermittent, with episodes lasting a few weeks to months. Recurrent episodes are notable for smaller effusions and progressive synovial hypertrophy, bony erosion, and cartilage destruction. A small percentage (<10%) of patients with intermittent arthritis settle into a pattern of chronic arthritis, generally affecting only a single joint, often the knee. Inflammation of a single joint that persists for more than 12 months would be an unusual presenting manifestation of Lyme arthritis, as is the prominent involvement of small joints. The natural history of Lyme arthritis suggests that it is a self-limited disorder. In the late 1970s, before the use of antibiotics for Lyme disease, 21 patients who presented with EM and later developed Lyme arthritis were followed for 1 to 8 years without antimicrobial therapy.53 Six patients had only a single episode of arthritis, and the remaining 15 had recurrent episodes that decreased in frequency over the study period. On average, the number of patients who continued to experience episodes of arthritis decreased by 10% to 20% each year. Similar results were found in children in whom antibiotic treatment for arthritis was delayed 4 years.55 ANTIBIOTIC-REFRACTORY LYME ARTHRITIS A few patients treated with standard antibiotic regimens for Lyme arthritis have persistent joint inflammation and proliferative synovitis that does not respond to further antimicrobial therapy.15,56 The pathogenesis of “antibioticrefractory” Lyme arthritis is unknown, but may be due to persistent spirochetes or their antigens, infection-induced autoimmunity, or inadequate regulation of the inflammatory response.15 Patients with antibiotic-refractory Lyme arthritis no longer have PCR evidence for spirochete DNA in tissues56 and have an increased frequency of the rheumatoid arthritis–related alleles HLA DRB1*0401, HLA DRB1*0101, and HLA DRB1*0404, suggesting a genetic predisposition to joint inflammation.57 Because of the high prevalence of B cell and T cell responses to B. burgdorferi Osp A in patients with antibiotic-refractory arthritis, it has been proposed that immune responses to Osp A triggered by infection may be perpetuated by a self-antigen after the pathogen has been eliminated.15 An Osp A peptide corresponding to amino acids 163 through 175 (Osp A163-175) was

found to share an epitope with human leukocyte ­function– associated antigen 1α, an adhesion molecule expressed on inflamed tissues.58 The leukocyte function–associated antigen 1α peptide stimulated Osp A163-175-specific T cells only weakly, however, and did not promote production of the T helper type 1 cytokine interferon-γ normally found in antibiotic-refractory arthritis.59 Antibodies to cytokeratin 10, a constituent of synovial capillaries, have been found in the blood and synovial tissue of patients with antibiotic-refractory Lyme arthritis.60 These antibodies also react with Osp A and may contribute to ongoing inflammation when infection is cleared. If autoimmunity is responsible for antibioticrefractory Lyme arthritis, it must eventually succumb to immune regulation because even this form of Lyme arthritis generally resolves within 4 to 5 years.53,56

DIAGNOSIS The diagnosis of Lyme disease should be considered in individuals who present with an appropriate clinical history, and who have a reasonable risk of exposure to B. burgdorferi– infected ticks (Fig. 100-2).20 Supporting serologic evidence is necessary to secure the diagnosis for all stages of infection except for early localized disease in which EM can be recognized by morphologic features alone. Routine laboratory tests are nonspecific, with some patients exhibiting mildly elevated white blood cell (neutrophil) counts, erythrocyte sedimentation rates, and liver function tests. Culture or microscopic visualization of spirochetes in clinical samples is not sensitive enough for routine use in diagnosis. Culture of a skin biopsy specimen taken from the leading margin of an EM lesion is an exception, with B. burgdorferi detected in more than 40% of samples, but is rarely necessary to identify EM. SEROLOGIC TESTING Detection of antibodies to B. burgdorferi is the mainstay of laboratory testing for Lyme disease.20 Presence of antibodies to B. burgdorferi at best indicates previous exposure to the organism, however, and should not be considered evidence of active infection. In nonendemic areas, about 5% of normal human serum samples yield positive results on serologic tests for Lyme disease. In endemic areas, asymptomatic IgG seroconversion to B. burgdorferi has been found in about 7% of subjects.61 A two-tiered approach is recommended for detection of B. burgdorferi–specific antibodies.62 An ELISA or an indirect immunofluorescence assay to detect IgM and IgG reactivity to B. burgdorferi should be used as an initial screening test, followed by an immunoblot (Western blot) to confirm that positive or equivocal results are due to antibodies that bind B. burgdorferi antigens. ELISA and immunofluorescence assay are highly sensitive tests, but lack specificity because of cross-reactivity of B. burgdorferi antigens with other bacterial pathogens.20 A positive or equivocal ELISA or immunofluorescence assay should be confirmed by immunoblot analysis of B. burgdorferi proteins (Table 100-2). Banding patterns characteristic of early infection include antibodies to the 41-kD flagellin protein and Osp C, which has a molecular weight ranging from 21 to 24 kD depending on the B. burgdorferi strain used

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INFECTION AND ARTHRITIS

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Table 100-2  Criteria for Western Blot ­Interpretation   in the Serologic Confirmation of Lyme Disease

93 66

Duration of Disease Isotype Tested

Criteria for Positive Test

58

First month of ­infection

IgM

Two of the following   3 bands are present: 23 kDa (OspC), 39 kDa (BmpA), and 41 kDa (Fla)

After first month   of infection

IgG

Five out of 10 bands are present: 18 kDA, 21 kDa, 28 kDa, 39 kDa, 41 kDa, 45 kDa, 58 kDa (not GroEL), 66 kDa, and   93 kDa

45 41 39

41 39

| 

30 28

Adapted from Centers for Disease Control and Prevention: Recommendations for Test Performance and Interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. Morb Mort Wkly Rept MMWR 44:590-591, 1995.

OspC OspC

18

1 1

2

2

3

4

3

Figure 100-2  Left, Selected IgM immunoblot reactivities. Lane 1, Serum band locator control showing several bands, including the significant 41-kD protein, 39-kD protein, and OspC (arrows). Lane 2, Serum sample from a patient with early Lyme borreliosis with erythema migrans. Lane 3,   Serum sample from a patient with early disseminated Lyme borreliosis with multiple erythema migrans lesions. Note the larger number of bands observed in a serum sample of the patient with early disseminated Lyme borreliosis. Right, Selected IgG immunoblot reactivities. Lane 1, Serum band locator control showing several immunoreactive bands, including those considered significant in the IgG blot criteria (arrows). Lane 2,   Serum sample from a patient with early disseminated Lyme borreliosis with neurologic involvement. Lane 3, Serum sample from a patient with Lyme arthritis. Lane 4, Serum sample from an individual who received three doses of OspA vaccine; note the strong reactivity with OspA (31 kD)  and other antigens below OspC. (From Aguero-Rosenfeld ME, Wang G, Schwartz I, et al: Diagnosis of Lyme borreliosis. Clin Microbiol Rev 18:484, 2005.)

(Fig. 100-3). With disseminated infection and especially with late Lyme disease, IgG reactivity to an expanding array of B. burgdorferi proteins can be seen (see Fig. 100-3). Some commercial laboratories have developed assays using recombinant antigens or employ criteria for the interpretation of immunoblots that have not been validated and published in peer-reviewed literature.63 For this reason, the Centers for Disease Control and Prevention advises using only validated tests approved by the Food and Drug Administration (FDA) for serologic diagnosis of Lyme disease. Two-tier testing for IgM and IgG should be performed for individuals with suspected Lyme disease and signs and symptoms of less than 1 month’s duration, whereas only IgG results should be considered for illnesses of longer duration.62 Positive IgM serologies alone after 1 month of illness are most often false-positive tests, which arise in the setting of other infectious diseases (especially infectious mononucleosis and other spirochetal and tick-borne infections), rheumatoid arthritis (with or without rheumatoid factor), and conditions associated with a positive ANA (systemic lupus erythematosus).64 No further testing is recommended if ELISA or immunofluorescence assay results are negative. Two-tier testing has overall sensitivities of 29% to 40% in

EM during the acute phase; 29% to 78% for EM in the convalescent phase; and greater than 95% in neurologic, arthritis, and other manifestations of late disease.20 A new peptide-based immunoassay that uses a highly conserved invariant region of the VlsE protein, termed C6 (IR6), is now commercially available.65,66 Although the C6 peptide ELISA measures only IgG reactivity, it has a high degree of sensitivity and specificity in all stages of Lyme disease and may be particularly useful in early Lyme disease.66 After antibiotic therapy, IgM and IgG titers to B. burgdorferi measured by either whole cell ELISA or the C6 peptide ELISA (IgG only) generally decrease slowly, but can remain positive for years.67,68 Repeat serologic testing is not recommended as a means for assessing response to treatment. DETECTION OF ANTIBODIES TO BORRELIA BURGDORFERI IN CEREBROSPINAL FLUID In suspected cases of neuroborreliosis, intrathecal antibody production usually is assessed by measuring the ratio of IgG to B. burgdorferi in CSF and serum.20,69 Intrathecal antibody production is more commonly found in European neuroborreliosis than in North American Lyme disease, which may be due to the higher prevalence of B. garinii in central nervous system infection than B. burgdorferi ss. Antibodies to B. burgdorferi may persist in CSF after treatment for Lyme disease and should not be used to assess efficacy of therapy. POLYMERASE CHAIN REACTION PCR has been used to detect B. burgdorferi DNA in a variety of clinical specimens with variable success.70 The greatest utility of PCR clinically is in Lyme arthritis, in which the sensitivity of PCR for detection of B. burgdorferi DNA is 85%. In contrast, the sensitivity of PCR for detecting B. burgdorferi DNA in CSF is low (<40%) and most often positive in patients with a CSF pleocytosis. PCR of urine specimens is not recommended because of inconsistent sensitivity and documented nonspecific amplification of non–B. burgdorferi DNA targets.20 Although certain commercial laboratories currently offer PCR tests for B. burgdorferi DNA in blood or urine specimens, these have not been validated.63 There are no FDA-approved tests for PCR-based molecular techniques for detecting B. burgdorferi DNA in patient specimens.

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Tick bite engorged nymphal Ixodes tick

No testing

No testing

Flu-like symptoms Headache, muscle or joint pain, without respiratory or GI symptoms in summer months

Skin erythema migrans

No testing

IgM or IgG ELISA equivocal or positive

IgM or IgG Western blot See criteria for IgM and IgG positivity (Table 100-2) Convalescent sample often needed

Consider oral therapy if high prevalence of B. burgdorferiinfected ticks

Co-infection More severe flu-like symptoms with high fever in summer months

Standard blood tests Anaplasmosis Babesiosis Leukopenia Thrombocytopenia, May cause false or in severe cases, positive IgM Lyme hemolytic anemia serology

Active babesiosis Intravenous clindamycin and oral quinine or oral atovaquone and azithromycin

Oral therapy Doxycycline, 100 mg bid for 10 days

Oral therapy (see Table 100-3)

A

Joint Mono-or oligoarticular arthritis

Nervous system Meningitis Facial palsy Radiculoneuritis alone Encephalopathy Polyneuropathy

Heart AV block

Optional

Optional

PCR testing of joint fluid

IgG ELISA Negative

Reconsider diagnosis

Equivocal or positive

IgG Western blot positive (see criteria Table 100-2)

Joint Oral therapy (see Table 100-3)

B

IgM, IgG, and IgA antibody capture test for intrathecal antibody production

Heart 1°

2°

3°

Nervous system Facial palsy alone

Other manifestations

Intravenous therapy (see Table 100-3)

Figure 100-3  A, Algorithm for early Lyme disease. B, Algorithm for later organ involvement in Lyme disease. (From Steere AC, Coburn J, Glickstein L: The emergence of Lyme disease. J Clin Invest 113:1093-1101, 2004.)

OTHER TESTS FOR LYME DISEASE A urine antigen test, immunofluorescent staining for cell wall–deficient forms of B. burgdorferi, and lymphocyte transformation assays are offered by some commercial ­laboratories

to aid in the diagnosis of Lyme disease. These tests have not been adequately validated for accuracy or clinical usefulness, and the Centers for Disease Control and Prevention cautions against their use.63

PART 17 

DIAGNOSTIC IMAGING Imaging studies have a limited role in the evaluation of patients with Lyme disease because no feature is sufficiently distinctive to confirm the diagnosis. Plain radiographs of arthritic joints show changes consistent with an inflammatory arthropathy, including joint effusions, synovial hypertrophy, periarticular osteoporosis, cartilage loss, bony erosions, and calcified entheses.71 MRI of arthritic joints can confirm the radiographic findings and reveal associated myositis and adenopathy, which may be useful in distinguishing Lyme arthritis from septic arthritis in children.72 Cranial and spinal MRI findings in neuroborreliosis can reveal focal nodular lesions or patchy white matter lesions on T2-weighted images, consistent with inflammatory or demyelinating processes.73,74 These lesions typically resolve after treatment for Lyme disease,74 in some cases only after several years.75 In patients with post–Lyme disease syndrome, cerebral MRI and the more sensitive technique of fluid-attenuated inversion recovery are normal in about 50% of cases or show nonspecific findings of small white matter lesions.76 Positron emission tomography and single-photon emission computed tomography studies are often normal or show only nonspecific changes with subcortical and cortical hypoperfusion.77,78

TREATMENT AND PROGNOSIS Updated guidelines for the clinical assessment and treatment of Lyme disease have been published (Table 100-3).79 Because many of the manifestations of Lyme disease resolve without specific therapy, the goal of antibiotic treatment is to hasten resolution of signs and symptoms and to prevent later clinical manifestations. Generally, oral antibiotics are sufficient therapy for EM, disseminated EM, uncomplicated facial palsy, mild carditis (first-degree atrioventricular block), and arthritis. Disseminated infection and late manifestations of Lyme disease may require longer courses of antibiotics, and there is often a greater lag time to symptom resolution compared with early disease. Doxycycline is the antibiotic of choice in nonpregnant adults and children 8 years old and older because it is also effective against A. phagocytophilum, which may occur with early Lyme disease.79 Amoxicillin and cefuroxime axetil are acceptable alternatives for the treatment of EM, facial palsy, and other non-neurologic manifestations of Lyme disease. Macrolide antibiotics are less effective than other antimicrobials and should be used only in individuals who cannot take doxycycline, amoxicillin, or cefuroxime axetil. First-generation cephalosporins are not effective therapy for Lyme disease. Documented nervous system involvement (other than isolated facial palsy) and symptomatic cardiac involvement are the two main indications for intravenous antibiotic therapy.79 Ceftriaxone administered intravenously for 2 to 4 weeks is the preferred antimicrobial, with parenteral cefotaxime or penicillin G acceptable alternatives. There is increasing evidence, however, that oral doxycycline, which is well absorbed and has a high central nervous system penetration, may be effective for meningitis or radiculopathy. Lumbar puncture is recommended in individuals with cranial nerve palsies who have symptoms of meningeal irritation because a CSF pleocytosis would be an indication to

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treat with intravenous therapy. Asymptomatic CSF pleocytosis can occur in the setting of facial palsy and is not an indication for intravenous therapy. Repeat treatment is not recommended for chronic neurologic abnormalities, unless objective signs of relapse are present. Patients with symptomatic cardiac involvement (chest pain, shortness of breath, syncope) or with significant conduction system disease (first-degree atrioventricular block with P-R intervals ≥0.3 msec, or second-degree or thirddegree block) should be hospitalized for cardiac monitoring and intravenous antibiotic therapy. Consultation with a cardiologist is recommended and placement of a temporary pacemaker may be necessary. Oral antibiotics can be substituted for intravenous antibiotics at the time of hospital discharge to complete the course of therapy.79 For arthritis, a 1-month course of oral doxycycline or amoxicillin is recommended, with a repeat course of oral therapy if inflammation does not resolve within 3 months of treatment.79 For patients with moderate-to-severe joint swelling after a 1-month course of oral antibiotics, intravenous ceftriaxone for 2 to 4 weeks can be used80; when inflammation is mild, an additional 1-month course of oral antibiotics can be considered, although arthritis usually resolves without additional therapy. Longer courses of antibiotics provide no additional benefit when PCR for B. burgdorferi in joint fluid is negative.56 In this situation, nonsteroidal anti-inflammatory drugs and hydroxychloroquine are recommended for treatment of antibiotic­refractory Lyme arthritis. In rare patients who fail to respond to these disease-modifying antirheumatic drugs, methotrexate, and tumor necrosis factor-α inhibitors have been anecdotally used with success. Arthroscopic synovectomy is curative in most patients who fail to respond to medical management.81 Intra-articular corticosteroids may be associated with a higher rate of antibiotic unresponsiveness and are rarely used.56 PREGNANCY AND LYME DISEASE Pregnant and lactating women with Lyme disease can be treated with the same antibiotic regimens recommended for nonpregnant patients except that doxycycline should be avoided.79 Maternal-fetal transmission of B. burgdorferi does occur,82 but in contrast to syphilis in pregnancy, there is no evidence that the organism causes a congenital syndrome.83,84 Pregnant patients should be reassured that with recommended therapy for Lyme disease, B. burgdorferi infection in the mother should not cause harm to the fetus.84 EXPECTED OUTCOMES Most patients treated for Lyme disease with recommended courses of antibiotics experience resolution of all signs and symptoms of the disorder.43,85,86 About 15% of patients treated for Lyme disease may experience a Jarisch­Herxheimer reaction, a self-limited worsening of symptoms within 24 to 48 hours of initiation of antibiotic therapy.14 Within the first week of treatment, patients may rarely show evolution of disease, such as the development of new EM lesions or facial nerve palsy, but these signs should improve as therapy progresses. Most patients with Lyme arthritis experience resolution of joint inflammation after a 1-month

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Lyme Disease

Table 100-3  Recommended Treatment of Lyme Diseasea Manifestation

Drug

Adult Dosage

Pediatric Dosage

Duration (days) (Range)

Erythema migrans   (Recommended)

Doxycyclineb

100 mg PO bid

14 days (10-21)

Amoxicillin

500 mg PO tid

Cefuroxime axetil

500 mg PO bid

<8 years: not recommended ≥8 years: 4 mg/kg/day in   2 divided doses (max 100 mg/dose) 50 mg/kg/day in 3 divided doses 30 mg/kg/day in 2 divided doses

Azithromycin

500 mg PO qd

7-10 days

Clarithromycin Erythromycin

500 mg PO bid 500 mg PO qid

10 mg/kg qd (max 500 mg/day) 7.5 mg/kg bid 12.5 mg/kg qid   (max 500 mg/dose)

Erythema migrans   (Alternative)c

Acute neurologic disease   Cranial nerve palsyd   Meningitis or ­radiculopathye   (Alternative IV)

Cardiac diseasef

Same as oral regimens for erythema migrans Ceftriaxone 2 g IV qd Cefotaxime

2 g IV q8h

Penicillin G

18-24 million units

50-75 mg/kg IV qd in single dose (max 2 g/day) 150-200 mg/kg/day IV in 3-4 divided doses   (max 6 g/day) 200,000-400,000 U/kg/day divided q4h (max 18-24 million U/day)

14 days (10-21) 14 days (10-21)

14-21 days 14-21 days

14 days (10-21) 14 days (10-28)

Same as for erythema migrans or IV regimen as for neurologic disease

14 days (10-21) 14 days (10-21)

Late disease   Arthritis without neurologic involvement

Same as for erythema migrans

28 days (28)

Recurrent arthritis after   oral regimen

Repeat oral regimen or IV regimen as for neurologic disease

14 days (14-28)

Central or peripheral   nervous system disease

IV regimen as for acute neurologic disease

14 days (14-28)

aComplete response to treatment may be delayed beyond the treatment period, regardless of the clinical manifestation, and relapse may recur. Patients with objective signs of relapse may need a second course of treatment. bTetracyclines are relatively contraindicated in pregnant or lactating women and in children < 8 years of age. cDue to their lower efficacy, macrolides are reserved for patients who are unable to take or who are intolerant of tetracyclines, penicillins, and cephalo­ sporins. dPatients without clinical evidence of meningitis may be treated with an oral regimen. The recommendation is based on experience with seventh cranial nerve palsy. Whether oral therapy would be as effective for patients with other cranial neuropathies is unknown; the decision between oral and parenteral therapy should be individualized. eFor nonpregnant adult patients intolerant of β-lactam agents, doxycycline 200-400 mg/day orally (or IV if unable to take oral medications) in two divided doses may be adequate. For children ≥ 8 years of age, the dosage of doxycycline for this indication is 4-8 mg/kg/day in two divided doses (maximum daily dosage of 200-400 mg). fA parenteral antibiotic regimen is recommended at the start of therapy for patients who have been hospitalized for cardiac monitoring; an oral regimen may be substituted to complete a course of therapy or to treat outpatients. A temporary pacemaker may be required for patients with advanced heart block.

course of oral antibiotics, and less than 10% of patients progress to antibiotic-refractory arthritis, which nevertheless resolves within 4 years.56 Subjective complaints of fatigue and musculoskeletal pain may persist for months after treatment for Lyme disease.87 When patients complain of persistent pain and fatigue, evaluation for coinfection with B. microti or A. phagocytophilum should be performed.88 Patients with coinfection tend to be more symptomatic at presentation and can have a delayed resolution of symptoms compared with patients with Lyme disease alone. Objective, nonprogressive signs, such as mild facial weakness after facial palsy, likely are due to irreversible tissue damage, and further antibiotic therapy does not seem to be beneficial.89,90

POST–LYME DISEASE SYNDROMES There is a great deal of controversy over the potential for Lyme disease to cause life-altering chronic morbidity in patients. As noted earlier, it is unusual to have objective signs after recommended antibiotic regimens, and when such signs (e.g., Lyme arthritis) are present, further antibiotic therapy does not alter outcome.56 Even when objective signs are present, they usually are nonprogressive (e.g., residual facial weakness after facial palsy) or resolve over time (as is the case for Lyme arthritis). The term chronic Lyme disease, which implies ongoing infection, is invalid. A few patients treated for Lyme disease may have fatigue, musculoskeletal pain, and complaints of memory

PART 17 

i­mpairment despite conventional or prolonged courses of antibiotic therapy.89,91 In several controlled, populationbased cohort studies that used validated standardized measures of outcomes (e.g., SF-36), patients with Lyme disease had more joint pain, symptoms of memory impairment, and worse functional status because of pain compared with controls.86,92,93 These complaints could not be documented by abnormalities on physical examination or by neurocognitive testing, however, and a follow-up study showed that quality-of-life measures improved with time.94 Children are less likely than adults to have persistent complaints after treatment for Lyme disease.93 Two randomized, double-blind, placebo-controlled trials of antibiotic therapy were conducted on seropositive and seronegative patients with chronic symptoms (>6 months) after treatment for Lyme disease.90 Patients were randomly assigned to receive either intravenous ceftriaxone for 1 month followed by 2 months of oral doxycycline or matched intravenous and oral placebos. An interim analysis of the first 129 subjects enrolled (78 seropositive, 51 seronegative) resulted in termination of the study because no differences in outcome between groups receiving antibiotics or placebo were found, and evidence of ongoing infection could not be documented. Another trial of antibiotics for post-treatment Lyme disease symptoms found that fatigue, as assessed by the Fatigue Severity Scale–11, improved in the group receiving intravenous ceftriaxone, but cognitive dysfunction did not.95 Individuals who had positive IgG immunoblots for Lyme disease and who had not received prior treatment with intravenous antibiotics were more likely to have improvement in fatigue. An open pilot study provided evidence that gabapentin may be effective in the treatment of chronic pain syndromes after Lyme disease.96 A growing number of patients with similar subjective complaints are being treated for months or years with antibiotics for presumed B. burgdorferi infection.97-100 Often these patients have no serologic evidence of B. burgdorferi exposure despite years of not feeling well, and they experience only partial resolution of their symptoms owing to antibiotics. Occasionally, patients may have other conditions, such as rheumatoid arthritis or fibromyalgia, for which therapy has been delayed because of a misdiagnosis of Lyme disease.97 Musculoskeletal pain is common in the general population; 20% to 30% of adults complain of chronic fatigue.101 In the absence of a clinical history with objective manifestations of Lyme disease or positive two-tiered serologic tests, definitive attribution of symptoms to B. burgdorferi infection cannot be made. Caution should be exercised when attributing the response of symptoms to the antimicrobial effects of antibiotics because ceftriaxone and other β-lactam antibiotics can modulate neurotransmitter activity,102 and tetracyclines inhibit matrix metalloproteinases.103 Prolonged antibiotic use is not without risk. Minor side effects are common, and serious adverse events, such as biliary complications from ceftriaxone therapy or indwelling catheter–related infections, occur at high enough rates to warrant only judicious use of antibiotics.90,99

PREVENTION The most effective way to prevent Lyme disease is to reduce exposure risk to B. burgdorferi–infected ticks through personal protective measures and environmental controls.104

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These measures include avoidance of tick habitats such as wooded areas, stone fences, woodpiles, and tall grass; wearing protective clothing; and performing daily surveillance and prompt removal of ticks (within 24 hours of feeding). Other effective measures include use of DEETcontaining insecticide sprays, yearly application of acaricides to property to kill ticks, construction of four-poster bait stations that apply acaricides onto deer as they feed, and tall fences to prevent deer from incidentally transporting ticks to an area. A single 200-mg dose of doxycycline (or 4 mg/kg up to 200 mg for children ≥8 years old) has been shown to reduce the incidence of Lyme disease after a recognized tick bite,105 but is not routinely recommended because of the low rate of infection.79 An FDA-approved recombinant Osp A–based vaccine to prevent Lyme disease was withdrawn because of low market demand and concern for potential vaccinerelated side effects.106,107

SUMMARY Lyme disease is a localized or systemic infection that usually manifests with skin and musculoskeletal signs and symptoms, but it can involve other organ systems, especially the heart and nervous system. The diagnosis should be based on objective clinical findings consistent with Lyme disease and supporting serologic tests. Most patients are cured with 2 to 4 weeks of antibiotic therapy, although the time to disease resolution may be prolonged, especially for individuals in whom therapy was delayed; irreversible tissue damage may occur. A poor response to antibiotic therapy should raise concern for alternative diagnoses or coinfection with other tick-borne pathogens. Antibiotic-refractory Lyme arthritis occurs in less than 10% of patients. Treatment with nonsteroidal anti-inflammatory drugs and hydroxychloroquine usually resolves arthritis within 4 to 5 years. Some patients treated for Lyme disease develop a post–Lyme disease syndrome of fatigue, headaches, mild memory impairment, and musculoskeletal pain. Ongoing infection cannot be shown and controlled treatment trials show no benefit of prolonged antibiotic therapy over placebo. Referral to an academic medical center with experience in the diagnosis and treatment of Lyme disease should be considered when patients do not respond as expected to therapy. REFERENCES   1. Bockenstedt LK, Malawista SE: Lyme disease. In Cecil RL, Goldman L, Bennett JC (eds): The Cecil Textbook of Medicine, 23rd ed. Philadelphia, WB Saunders, 2008, pp 2289-2294.   2. Steere AC, Malawista SE, Snydman DR, et al: Lyme arthritis: An epidemic of oligoarticular arthritis in children and adults in three Connecticut communities. Arthritis Rheum 20:7-17, 1977.   3. Weber K, Pfister HW: History of Lyme borreliosis in Europe. In Weber K, Burgdorfer W (eds): Aspects of Lyme borreliosis. Berlin, SpringerVerlag, 1993, pp 1-20.   4. Burgdorfer W, Barbour AG, Hayes SF, et al: Lyme disease—a tickborne spirochetosis? Science 216:1317-1319, 1982.   5. Steere AC, Grodzicki RL, Kornblatt AN, et al: The spirochetal etiology of Lyme disease. N Engl J Med 308:733-740, 1983.   6. Piesman J, Gern L: Lyme borreliosis in Europe and North America. Parasitology 129(Suppl):S191-S220, 2004.   7. Centers for Disease Control and Prevention: Reported Lyme disease cases by state, 1993-2005. Available at: http://www.cdc.gov/ncidod/ dvbid/lyme/Id_rptdLymeCasesbyState.htm. Accessed 2006.

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  8. Steere AC, Coburn J, Glickstein L: The emergence of Lyme disease. J Clin Invest 113:1093-1101, 2004.   9. De Silva AM, Fikrig E: Borrelia burgdorferi genes selectively expressed in ticks and mammals. Parasitol Today 13:267-270, 1997. 10. Fraser CM, Casjens S, Huang WM, et al: Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi. Nature 390:580-586, 1997. 11. Pal U, de Silva AM, Montgomery RR, et al: Attachment of Borrelia burgdorferi within Ixodes scapularis mediated by outer surface protein A. J Clin Invest 106:561-569, 2000. 12. Tilly K, Krum JG, Bestor A, et al: Borrelia burgdorferi OspC protein required exclusively in a crucial early stage of mammalian infection. Infect Immun 74:3554-3564, 2006. 13. Duray PH: Histopathology of clinical phases of human Lyme disease. Rheum Dis Clin N Am 15:691-710, 1989. 14. Bockenstedt LK: Lyme disease. In Stone JH, Crofford LJ, White PH (eds): Primer on the Rheumatic Diseases, 13th ed. Springer Science+Business Media, 2008, pp 282-289. 15. Steere AC, Glickstein L: Elucidation of Lyme arthritis. Nat Rev Immunol 4:143-152, 2004. 16. Behera AK, Hildebrand E, Uematsu S, et al: Identification of a TLRindependent pathway for Borrelia burgdorferi-induced expression of matrix metalloproteinases and inflammatory mediators through binding to integrin alpha 3 beta 1. J Immunol 177:657-664, 2006. 17. Fikrig E, Barthold SW, Chen M, et al: Protective antibodies in murine Lyme disease arise independently of CD40 ligand. J Immunol 157:1-3, 1996. 18. McKisic MD, Barthold SW: T-cell-independent responses to Borrelia burgdorferi are critical for protective immunity and resolution of Lyme disease. Infect Immun 68:5190-5197, 2000. 19. Hardin JA, Steere AC, Malawista SE: Immune complexes and the evolution of Lyme arthritis: Dissemination and localization of abnormal C1q binding activity. N Engl J Med 301:1358-1363, 1979. 20. Aguero-Rosenfeld ME, Wang G, Schwartz I, et al: Diagnosis of Lyme borreliosis. Clin Microbiol Rev 18:484-509, 2005. 21. Dai Z, Lackland H, Stein S, et al: Molecular mimicry in Lyme disease: Monoclonal antibody H9724 to B. burgdorferi flagellin specifically detects chaperonin-HSP60. Biochim Biophys Acta 1181:97-100, 1993. 22. Aberer E, Brunner C, Suchanek G, et al: Molecular mimicry and Lyme borreliosis: A shared antigenic determinant between Borrelia burgdorferi and human tissue. Ann Neurol 26:732-737, 1989. 23. Gross DM, Steere AC, Huber BT: T helper 1 response is dominant and localized to the synovial fluid in patients with Lyme arthritis. J Immunol 160:1022-1028, 1998. 24. Widhe M, Jarefors S, Ekerfelt C, et al: Borrelia-specific interferongamma and interleukin-4 secretion in cerebrospinal fluid and blood during Lyme borreliosis in humans: Association with clinical outcome. J Infect Dis 189:1881-1891, 2004. 25. Kalish RA, Leong JM, Steere AC: Association of treatment-resistant chronic Lyme arthritis with HLA-DR4 and antibody reactivity to OspA and OspB of Borrelia burgdorferi. Infect Immun 61:2774-2779, 1993. 26. Lengl-Janssen B, Strauss AF, Steere AC, et al: The T helper cell response in Lyme arthritis: Differential recognition of Borrelia burgdorferi outer surface protein A in patients with treatment-resistant or treatment-responsive Lyme arthritis. J Exp Med 180:2069-2078, 1994. 27. Iliopoulou BP, Alroy J, Huber BT: CD28 deficiency exacerbated joint inflammation upon Borrelia burgdorferi infection, resulting in the development of chronic Lyme arthritis. J Immunol 179:8076-8082, 2007. 28. Vincent MS, Roessner K, Lynch D, et al: Apoptosis of Fas(high) CD4+ synovial T cells by borrelia-reactive Fas-ligand(high) gamma delta T cells in Lyme arthritis. J Exp Med 184:2109-2117, 1996. 29. Chary-Valckenaere I, Jaulhac B, Champigneulle J, et al: Ultrastructural demonstration of intracellular localization of Borrelia burgdorferi in Lyme arthritis. Br J Rheumatol 37:468-470, 1998. 30. Norris SJ: Antigenic variation with a twist—the Borrelia story. Mol Microbiol 60:1319-1322, 2006. 31. Liang FT, Nelson FK, Fikrig E: Molecular adaptation of Borrelia burgdorferi in the murine host. J Exp Med 196:275-280, 2002. 32. Barthold SW, de Souza MS, Janotka JL, et al: Chronic Lyme borreliosis in the laboratory mouse. Am J Pathol 143:959-971, 1993. 33. Edlow JA: Erythema migrans. Med Clin North Am 86:239-260, 2002.

34. Centers for Disease Control and Prevention: Case definitions for infectious conditions under public health surveillance: Lyme disease (revised 9/96). MMWR Morb Mortal Wkly Rep 46:1-51, 1997. 35. Feder HM Jr, Gerber MA, Krause PJ, et al: Early Lyme disease: A flu-like illness without erythema migrans. Pediatrics 91:456-459, 1993. 36. Steere AC, Dhar A, Hernandez J, et al: Systemic symptoms without erythema migrans as the presenting picture of early Lyme disease. Am J Med 114:58-62, 2003. 37. Centers for Disease Control and Prevention: Southern tick-associated rash illness. Available at: http://www.cdc.gov/ncidod/dvbid/stari/ 38. Steere AC, Batsford WP, Weinberg M, et al: Lyme carditis: Cardiac abnormalities of Lyme disease. Ann Intern Med 93:8-16, 1980. 39. Sangha O, Phillips CB, Fleischmann KE, et al: Lack of cardiac manifestations among patients with previously treated Lyme disease. Ann Intern Med 128:346-353, 1998. 40. Reik L, Steere AC, Bartenhagen NH, et al: Neurologic abnormalities of Lyme disease. Medicine (Balt) 58:281-294, 1979. 41. Halperin JJ, Pass HL, Anand AK, et al: Nervous system abnormalities in Lyme disease. Ann N Y Acad Sci 539:24-34, 1988. 42. Halperin JJ: Lyme disease and the peripheral nervous system. Muscle Nerve 28:133-143, 2003. 43. Nachman SA, Pontrelli L: Central nervous system Lyme disease. Semin Pediatr Infect Dis 14:123-130, 2003. 44. Eppes SC, Nelson DK, Lewis LL, et al: Characterization of Lyme meningitis and comparison with viral meningitis in children. Pediatrics 103:957-960, 1999. 45. Steere AC: Lyme disease. N Engl J Med 321:586-596, 1989. 46. Logigian EL, Kaplan RF, Steere AC: Chronic neurologic manifestations of Lyme disease. N Engl J Med 323:1438-1444, 1990. 47. Halperin JJ: Central nervous system Lyme disease. Curr Neurol Neurosci Rep 5:446-452, 2005. 48. Coyle PK, Krupp LB, Doscher C: Significance of reactive Lyme serology in multiple sclerosis. Ann Neurol 34:745-747, 1993. 49. Halperin JJ, Little BW, Coyle PK, et al: Lyme disease: Cause of a treatable peripheral neuropathy. Neurology 37:1700-1706, 1987. 50. Halperin JJ, Krupp LB, Golightly MG, et al: Lyme borreliosis-associated encephalopathy. Neurology 40:1340-1343, 1990. 51. Logigian EL, Kaplan RF, Steere AC: Successful treatment of Lyme encephalopathy with intravenous ceftriaxone. J Infect Dis 180: 377-383, 1999. 52. Asbrink E, Hovmark A, Olsson I: Clinical manifestations of acrodermatitis chronica atrophicans in 50 Swedish patients. Zentralbl Bakteriol Mikrobiol Hyg [A] 263:253-261, 1986. 53. Steere AC, Schoen RT, Taylor E: The clinical evolution of Lyme arthritis. Ann Intern Med 107:725-731, 1987. 54. Steere AC, Malawista SE, Hardin JA, et al: Erythema chronicum migrans and Lyme arthritis: The enlarging clinical spectrum. Ann Intern Med 86:685-698, 1977. 55. Szer IS, Taylor E, Steere AC: The long-term course of Lyme arthritis in children. N Engl J Med 325:159-163, 1991. 56. Steere AC, Angelis SM: Therapy for Lyme arthritis: Strategies for the treatment of antibiotic-refractory arthritis. Arthritis Rheum 54: 3079-3086, 2006. 57. Steere AC, Klitz W, Drouin EE, et al: Antibiotic-refractory Lyme arthritis is associated with HLA-DR molecules that bind a Borrelia burgdorferi peptide. J Exp Med 203:961-971, 2006. 58. Gross DM, Forsthuber T, Tary-Lehmann M, et al: Identification of LFA-1 as a candidate autoantigen in treatment-resistant Lyme arthritis. Science 281:703-706, 1998. 59. Trollmo C, Meyer AL, Steere AC, et al: Molecular mimicry in Lyme arthritis demonstrated at the single cell level: LFA-1 alpha L is a partial agonist for outer surface protein A-reactive T cells. J Immunol 166:5286-5291, 2001. 60. Ghosh S, Seward R, Costello CE, et al: Autoantibodies from synovial lesions in chronic, antibiotic treatment-resistant Lyme arthritis bind cytokeratin-10. J Immunol 177:2486-2494, 2006. 61. Steere AC, Sikand VK, Schoen RT, et al: Asymptomatic infection with Borrelia burgdorferi. Clin Infect Dis 37:528-532, 2003. 62. Centers for Disease Control and Prevention: Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. MMWR Morb Mortal Wkly Rep 44:590-591, 1995.

PART 17  63. Centers for Disease Control and Prevention: Notice to readers: Caution regarding testing for Lyme disease. MMWR Morb Mortal Wkly Rep 54:125, 2005. 64. Aguero-Rosenfeld ME, Nowakowski J, Bittker S, et al: Evolution of the serologic response to Borrelia burgdorferi in treated patients with culture-confirmed erythema migrans. J Clin Microbiol 34:1-9, 1996. 65. Bacon RM, Biggerstaff BJ, Schriefer ME, et al: Serodiagnosis of Lyme disease by kinetic enzyme-linked immunosorbent assay using recombinant VlsE1 or peptide antigens of Borrelia burgdorferi compared with 2-tiered testing using whole-cell lysates. J Infect Dis 187:1187-1199, 2003. 66. Liang FT, Steere AC, Marques AR, et al: Sensitive and specific serodiagnosis of Lyme disease by enzyme-linked immunosorbent assay with a peptide based on an immunodominant conserved region of Borrelia burgdorferi vlsE. J Clin Microbiol 37:3990-3996, 1999. 67. Kalish RA, McHugh G, Granquist J, et al: Persistence of immunoglobulin M or immunoglobulin G antibody responses to Borrelia burgdorferi 10-20 years after active Lyme disease. Clin Infect Dis 33:780-785, 2001. 68. Peltomaa M, McHugh G, Steere AC: Persistence of the antibody response to the VlsE sixth invariant region (IR6) peptide of Borrelia burgdorferi after successful antibiotic treatment of Lyme disease. J Infect Dis 187:1178-1186, 2003. 69. Wilske B, Schierz G, Preac-Mursic V, et al: Intrathecal production of specific antibodies against Borrelia burgdorferi in patients with lymphocytic meningoradiculitis (Bannwarth’s syndrome). J Infect Dis 153:304-314, 1986. 70. Schmidt BL: PCR in laboratory diagnosis of human Borrelia burgdorferi infections. Clin Microbiol Rev 10:185-201, 1997. 71. Lawson JP, Steere AC: Lyme arthritis: Radiologic findings. Radiology 154:37-43, 1985. 72. Ecklund K, Vargas S, Zurakowski D, et al: MRI features of Lyme arthritis in children. AJR Am J Roentgenol 184:1904-1909, 2005. 73. Kalina P, Decker A, Kornel E, et al: Lyme disease of the brainstem. Neuroradiology 47:903-907, 2005. 74. Agosta F, Rocca MA, Benedetti B, et al: MR imaging assessment of brain and cervical cord damage in patients with neuroborreliosis. AJNR Am J Neuroradiol 27:892-894, 2006. 75. Steinbach JP, Melms A, Skalej M, et al: Delayed resolution of white matter changes following therapy of B burgdorferi encephalitis. Neurology 64:758-759, 2005. 76. Morgen K, Martin R, Stone RD, et al: FLAIR and magnetization transfer imaging of patients with post-treatment Lyme disease syndrome. Neurology 57:1980-1985, 2001. 77. Logigian EL, Johnson KA, Kijewski MF, et al: Reversible cerebral hypoperfusion in Lyme encephalopathy. Neurology 49:1661-1670, 1997. 78. Fallon BA, Keilp J, Prohovnik I, et al: Regional cerebral blood flow and cognitive deficits in chronic Lyme disease. J Neuropsychiatry Clin Neurosci 15:326-332, 2003. 79. Wormser GP, Dattwyler RJ, Shapiro ED, et al: The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: Clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 43: 1089-1134, 2006. 80. Dattwyler RJ, Wormser GP, Rush TJ, et al: A comparison of two treatment regimens of ceftriaxone in late Lyme disease. Wien Klin Wochenschr 117:393-397, 2005. 81. Schoen RT, Aversa JM, Rahn DW, et al: Treatment of refractory chronic Lyme arthritis with arthroscopic synovectomy. Arthritis Rheum 34:1056-1060, 1991. 82. Schlesinger PA, Duray PH, Burke BA, et al: Maternal-fetal transmission of the Lyme disease spirochete, Borrelia burgdorferi. Ann Intern Med 103:67-68, 1985. 83. Williams CL, Strobino B, Weinstein A, et al: Maternal Lyme disease and congenital malformations: A cord blood serosurvey in endemic and control areas. Paediatr Perinat Epidemiol 9:320-330, 1995.

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84. Strobino BA, Williams CL, Abid S, et al: Lyme disease and pregnancy outcome: A prospective study of two thousand prenatal patients. Am J Obstet Gynecol 169:367-374, 1993. 85. Shapiro ED: Long-term outcomes of persons with Lyme disease. Vector Borne Zoonotic Dis 2:279-281, 2002. 86. Shadick NA, Phillips CB, Sangha O, et al: Musculoskeletal and neurologic outcomes in patients with previously treated Lyme disease. Ann Intern Med 131:919-926, 1999. 87. Wormser GP, Ramanathan R, Nowakowski J, et al: Duration of antibiotic therapy for early Lyme disease: A randomized, double-blind, placebo-controlled trial. Ann Intern Med 138:697-704, 2003. 88. Krause PJ, McKay K, Thompson CA, et al: Disease-specific diagnosis of coinfecting tickborne zoonoses: Babesiosis, human granulocytic ehrlichiosis, and Lyme disease. Clin Infect Dis 34:1184-1191, 2002. 89. Asch ES, Bujak DI, Weiss M, et al: Lyme disease: An infectious and postinfectious syndrome. J Rheumatol 21:454-461, 1994. 90. Klempner MS, Hu LT, Evans J, et al: Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 345:85-92, 2001. 91. Bujak DI, Weinstein A, Dornbush RL: Clinical and neurocognitive features of the post Lyme syndrome. J Rheumatol 23:1392-1397, 1996. 92. Shadick NA, Phillips CB, Logigian EL, et al: The long-term clinical outcomes of Lyme disease. A population-based retrospective cohort study. Ann Intern Med 121:560-567, 1994. 93. Seltzer EG, Gerber MA, Cartter ML, et al: Long-term outcomes of persons with Lyme disease. JAMA 283:609-616, 2000. 94. Shadick NA, Phillips CB, Sangha O, et al: Diminished health-related quality-of-life improves over time in Lyme disease: The 12 yr followup from the Nantucket Lyme disease cohort study. IX International Conference on Lyme Borreliosis and Other Tick-borne Diseases, New York, 2002, O-36. 95. Krupp LB, Hyman LG, Grimson R, et al: Study and treatment of post Lyme disease (STOP-LD): A randomized double masked clinical trial. Neurology 60:1923-1930, 2003. 96. Weissenbacher S, Ring J, Hofmann H: Gabapentin for the symptomatic treatment of chronic neuropathic pain in patients with late-stage Lyme borreliosis: A pilot study. Dermatology 211:123-127, 2005. 97. Sigal LH: Summary of the first 100 patients seen at a Lyme disease referral center. Am J Med 88:577-581, 1990. 98. Steere AC, Taylor E, McHugh GL, et al: The overdiagnosis of Lyme disease. JAMA 269:1812-1816, 1993. 99. Reid MC, Schoen RT, Evans J, et al: The consequences of overdiagnosis and overtreatment of Lyme disease: An observational study. Ann Intern Med 128:354-362, 1998. 100. Qureshi MZ, New D, Zulqarni NJ, et al: Overdiagnosis and overtreatment of Lyme disease in children. Pediatr Infect Dis J 21:12-14, 2002. 101. Wessely S: Chronic fatigue: Symptom and syndrome. Ann Intern Med 134:838-843, 2001. 102. Rothstein JD, Patel S, Regan MR, et al: Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433:73-77, 2005. 103. Sadowski T, Steinmeyer J: Effects of tetracyclines on the production of matrix metalloproteinases and plasminogen activators as well as of their natural inhibitors, tissue inhibitor of metalloproteinase-1 and plasminogen activator inhibitor-1. Inflamm Res 50:175-182, 2001. 104. Hayes EB, Piesman J: How can we prevent Lyme disease? N Engl J Med 348:2424-2430, 2003. 105. Nadelman RB, Nowakowski J, Fish D, et al: Prophylaxis with singledose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med 345:79-84, 2001. 106. Steere AC, Sikand VK, Meurice F, et al: Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. Lyme Disease Vaccine Study Group. N Engl J Med 339:209-215, 1998. 107. Hanson MS, Edelman R: Progress and controversy surrounding vaccines against Lyme disease. Expert Rev Vaccines 2:683-703, 2003.

101

Mycobacterial Infections of Bones and Joints Walter G. Barr  •  J. Timothy Harrington  •  John P. Flaherty

KEY POINTS Global rates of tuberculosis disease have been increasing as a result of the expanding HIV pandemic and the growing problem of antituberculous drug resistance; rheumatologists have seen an increase in tuberculosis disease in response to the expanded use of anti-TNF agents. Musculoskeletal tuberculosis typically presents as a chronic localized infection, most commonly involving the spine, less often the hip or knee. Diagnosis may be very difficult and requires biopsy for histopathology and culture of the bone or synovium; rapid diagnostic test techniques have not yet proven reliable in bone and joint specimens. The tuberculin skin test can be helpful in identifying latent tuberculosis prior to treatment with anti-TNF agents, but it is limited by false-positive and false-negative results; the availability of interferon-gamma release assays might improve test specificity. Treatment requires multiple agents selected on the basis of susceptibility testing for 6 to 9 months and has been complicated by the increasing incidence of drug resistance.

The recognition of tuberculosis (TB) and other mycobacterial infections of the musculoskeletal system has become a major challenge for rheumatologists in the United States and other developed countries. Before 1999, most rheumatologists could easily go an entire year without seeing a single case of mycobacterial infection. Such cases were rare even at academic centers, where they would likely be presented as unusual teaching cases at clinical conferences. However, 1999 introduced the routine clinical use of anti–tumor necrosis factor (TNF) therapy in the United States, and with it came an unexpected increase in TB cases. These infections have been notably extrapulmonary in their proclivity, with 5% to 7% of TB cases emerging after the initiation of anti-TNF therapy reported to occur in bone, joint, or tendon. Fortunately, routine screening with tuberculin skin test (TSTs) led to a sharp decline in the number of new cases. However, the limitations of TSTs in assessing for latent TB and the expanding indications for anti-TNF therapy mandate continued vigilance in these patients. Another major force driving the increase in mycobacterial infections is the human immunodefiency virus (HIV) epidemic that continues to be a worldwide problem. By 1991, 21% of extrapulmonary TB cases in the United States were associated with acquired immunodeficiency syndrome (AIDS). In developing countries, the HIV pandemic has led to marked increases in osteoarticular TB coinfection.1 These cases are distinguished by disseminated multifocal disease

suggestive of hematogenous spread, rapid ­ progression, and more common coexistence with pulmonary infection.2,3 HIV testing should be a routine part of the workup of any patient presenting with a musculoskeletal infection secondary to Mycobacterium tuberculosis. The good news is that since the introduction of effective antiretroviral therapy, the incidence of TB and nontuberculous mycobacteria in HIV/ AIDS patients has sharply declined in the United States. Although TB is uncommon among the non–­HIV-infected population in the developed world (in the United States, TB is steadily declining among the general population), it remains a major problem in developing countries. There, TB continues to ravage the population, with 9 million new cases of active disease and 1.6 million deaths each year.4 Worldwide, it is the number two infectious disease killer after HIV/AIDS. Someone in the world is newly infected with TB bacilli every second. About one third of the world’s population is infected with TB, providing a reservoir that will continue to complicate its global control.5 More alarming is the emergence of extremely drug-resistant TB (XDR-TB).6 These strains fail to respond to all first-line and most secondline TB agents. An outbreak of XDR-TB in South Africa was associated with a mortality rate of 100%, with a median survival of only 16 days after diagnosis. Globalization of the world economy is encouraging increased contact between populations of the developed and developing worlds. Recent immigrants to the United States from endemic areas constitute an expanding reservoir of patients with latent TB. The challenge of diagnosing musculoskeletal mycobacterial infection reaches beyond the rarity of the disease. Such infections are often indolent and lack the pain, fevers, chills, and other prominent symptoms that typically accompany bacterial infections of the musculoskeletal system. In addition, unless the diagnosis of TB is a consideration from the outset, routine culture techniques will not isolate the organism. Delay in the diagnosis of mycobacterial infections of the musculoskeletal system is often measured in extended periods of 6 to 9 months. Unless we lower our threshold of suspicion for mycobacterial infection, it is unlikely that such delays will be substantially shortened. For all these reasons, 21st-century rheumatologists need to be well informed about a set of diseases they have had little or no experience with during their formal medical training.

CLINICAL SCENARIOS To appreciate the entire spectrum of clinical problems a rheumatologist may encounter in dealing with mycobacterial infections, it is useful to think in terms of several distinct categories. Franco-Paredes and colleagues7 provided 1729

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a clinically useful division of mycobacterial infections into four major categories. The following sections reflect that division. DIRECT INVOLVEMENT OF THE MUSCULOSKELETAL SYSTEM Musculoskeletal infections caused by mycobacteria typically manifest with chronic, indolent, localized involvement of the bones, spine, peripheral joints, or soft tissues that produces a focus of nonspecific pain and, less often, swelling. In infections initiated by direct tissue inoculation, the traumatic event is often trivial or remote in time from the onset of clinical disease. Diagnosis may be delayed for months to years, in part because of minimal early symptoms and attribution of those symptoms to a noninfectious disorder until disease progression and disability prompt a more aggressive diagnostic investigation. Constitutional symptoms are typically subtle or absent, and laboratory indicators of inflammation are often normal. Synovial effusion is frequently minimal, and the fluid, if it is obtainable, shows nonspecific inflammation. Radiographic abnormalities may be delayed, although newer imaging techniques have allowed the earlier detection of abnormalities and the distinction of TB from other infections and neoplasm.8,9 Characteristic pulmonary or extrapulmonary findings are not always present; for example, more than 50% of osteoarticular TB manifests without evidence of past or present pulmonary disease. Tuberculin and other skin tests may provide useful clues to the cause, but results are not invariably positive, especially in debilitated or immunosuppressed patients. Correct diagnosis is highly dependent, in most cases, on demonstration of the infectious agent by microscopic examination and culture of affected tissue. In HIV-infected patients, mycobacterial infections are often diagnosed before the patients’ HIV-positive status is known, sometimes leading to its recognition.10 Atypical pulmonary TB and extrapulmonary (often multifocal) infection are common; extrapulmonary infection occurs in 60% to 70% of such cases, compared with 16% of all TB patients. The clinical patterns of musculoskeletal TB include spondylitis, osteomyelitis, peripheral joint infection, and soft tissue abscess. In a series of 230 consecutive cases of TB from the preantibiotic era, 5.2% had skeletal involvement; the spine was affected in 60% of cases.11 The incidence of extrapulmonary and osteoarticular disease has risen during the last decade at a rate exceeding that of lung involvement. TB of the bones and joints is spread hematogenously. The sites most commonly affected are the spine and hips, followed by the knees and wrists; other joint involvement is rare. Constitutional symptoms are unusual in musculoskeletal TB and, when present, suggest TB in other organs. Vertebral collapse due to spinal TB may initially be attributed to the more common osteoporosis-caused spinal compression fracture. TB only rarely involves skeletal muscle but must be considered in the differential diagnosis of an enlarging muscle lesion.12-16 Isolated cases involving tendons,17 trochanteric bursa,18 and fascia lata19 illustrate the variety of possibilities. Biopsy and culture are required for diagnosis. Imaging studies do not distinguish TB from neoplasm.

Table 101-1  Causes of False-Negative Purified   Protein Derivative Test Old age (>70 yr) Steroid use (prednisone ≥15 mg/day) Hypoalbuminemia (<2 g/dL) Azotemia Impaired cellular immunity HIV infection

In nonendemic areas, skeletal TB usually occurs in elderly, debilitated patients, most often in the form of solitary osteolytic lesions in the axial skeleton. The development of skeletal disease is often remote from the initial infection, which strongly implies reactivation of previous subclinical disease. Patients may have false-negative tuberculin tests for several reasons, including long-term corticosteroid use or coexisting debilitating diseases, such as rheumatoid arthritis or chronic renal failure, that compromise resistance (Table 101-1).20,21 The occurrence of spinal disease in children has largely been eliminated by effective medical therapy of pulmonary infection. In contrast, in endemic areas with high infectivity rates, those infected are more commonly children and young to middle-aged adults. These individuals have a higher incidence of multifocal skeletal involvement in the ribs, pelvis, vertebral appendages, cervical spine, feet, and long bone diaphyses, and they show positive TST reactivity.22 Bone seeding occurs through hematogenous spread, sometimes secondarily from another extrapulmonary site. When pulmonary findings are present, a miliary pattern is typical. Spread to bone may also occur from infected nodes, either by direct extension or through draining lymph channels.23 Spondylitis The spine is the dominant site of involvement in skeletal TB, accounting for 50% to 60% of cases.24 Between 48% and 67% of lesions occur in the lower thoracic and thoracolumbar spine in HIV-negative patients, whereas the lumbar spine is most commonly involved in HIV-positive patients.2 The cervical spine is less often involved. Unilateral sacroiliac involvement is not uncommon. Infection usually begins in the anterior subchondral bone of a single vertebra adjacent to the intervertebral disk (Figs. 101-1 and 101-2). Progression to bone changes takes 2 to 5 months and begins with extension from cancellous to cortical bone, and then across the disk space to adjacent vertebrae (Fig. 101-3). Bone destruction may lead to vertebral collapse. Isolated neural arch involvement and intraspinal abscess may also occur. Paravertebral abscess begins with the extension of infection under the anterior longitudinal ligament. In the thoracic spine, this may extend into the pleural space and lung parenchyma. In the cervical region, it may present in the posterior cervical triangle or retropharyngeal space. In the lumbar spine, a cold abscess characteristically produces lateral displacement of the psoas muscle and may ­dissect along its length to present as a mass in the inguinal triangle, gluteal muscle, or upper thigh. In isolated cases, a cold abscess occurs with inapparent bone involvement.

PART 17 

A particular variant of this presentation is subligamentous TB, in which infection spreads up and down the spine beneath the ­ longitudinal ligament, producing scalloping of multiple anterior vertebral bodies without disk involvement. This pattern is more common in the cervical spine.25 The clinical presentation of spinal TB usually consists of localized pain, often accompanied by low-grade fever, weight loss, chills, and nonspecific constitutional symptoms. Patients may also present initially with abscess formation or kyphosis, or there may be symptoms of spinal cord

4

1

2

5

3

Figure 101-1  Tuberculous spondylitis: sites of involvement. ­ Tuberculous lesions can localize in the vertebral body (1) or, more rarely, the posterior osseous or ligamentous structures (2). Extension to the intervertebral disk (3) or prevertebral tissues (4) is not infrequent. Subligamentous spread (5) can lead to erosion of the anterior vertebral surface. (From Resnick D: Diagnosis of Bone and Joint Disorders, 3rd ed. Philadelphia, WB Saunders, 1995, p 2464.)

A

B

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or nerve root involvement. Paraparesis and paraplegia have been reported in 1% to 27% of patients in various series. In comparison to pyogenic and brucellar vertebral osteomyelitis, spinal TB more often presents with a prolonged clinical course, thoracic segment involvement, absence of fever, spinal deformity, neurologic deficit, and paravertebral or epidural masses.25 On occasion, tuberculous spondylitis may present with chronic inflammatory-type back pain more typical of the spondyloarthropathies.26 Mycobacterial colony counts in bone biopsy specimens are relatively low. Only 40% of smears and cultures from psoas abscesses are positive. Among patients meeting strict clinical and radiographic criteria in one series, between 73% and 82% had compatible histologic features on biopsy; of these, 80% to 95% had positive culture results.23 The differential diagnosis, which is extensive, includes pyogenic and fungal osteomyelitis, primary and metastatic tumors, sarcoidosis, multiple myeloma, and eosinophilic granuloma. Cervical spine involvement is relatively rare, acco­unting for only 0.4% to 1.2% of cases of extrapulmonary TB in the United States.27 The most common presenting symptoms are neck pain and stiffness, although hoarseness, dysphagia, torticollis, fever, anorexia, and neurologic disorders may also occur. Spinal involvement can progress to myelopathy because of delays in diagnosis. Radiographs may show characteristic osteolysis of the anterior vertebral body with sparing of the posterior portion, gibbus deformity, disk involvement, and a partially calcified paraspinous mass. Computed tomography (CT) or magnetic resonance imaging (MRI) is useful for assessing compromise of the spinal canal. Retropharyngeal infection may extend into the craniocervical junction and, if not promptly recognized, may cause atlantoaxial dislocation and neurologic complications.28,29 The sacroiliac joint is involved in up to 10% of cases of skeletal TB, often without other evidence of disease.30 Infection, and TB in particular, should be suspected in all cases of unilateral sacroiliitis. Emigration from an endemic area and a past history of TB increase the likelihood of this cause. Buttock pain on the involved side is the presenting symptom and is often accompanied by proximal leg or radicular pain. Examination reveals sacroiliac tenderness to palpation and stress maneuvers. Sacroiliac films show joint widening and erosion in all cases. An elevated erythrocyte sedimentation rate (ESR) and anemia are common, and a

Figure 101-2  Tuberculous spondylitis: diskovertebral lesion. A, The initial radiograph ­reveals subchondral destruction of two vertebral bodies, with mild surrounding eburnation and loss of intervertebral disk height. The appearance is identical to that in pyogenic spondylitis. B, Several months later, an osseous response is evident. Note the increased sclerosis. Osteophytosis and improved definition of the osseous margins can be seen. (From Resnick D: Diagnosis of Bone and Joint Disorders, 3rd ed. Philadelphia, WB Saunders, 1995, p 2465.)

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Figure 101-3  Tuberculous spondylitis: spinal cord compression. Magnetic resonance image of the lumbar spine shows destruction of contiguous vertebral bodies and an inflammatory mass pressing on the spinal cord. This patient was successfully treated with medical therapy alone.

positive tuberculin reaction is typical. Biopsy of the sacroiliac joint shows granulomatous histologic features or nonspecific inflammation and a positive culture in most cases. Atypical spinal lesions, which occur in about 10% of cases, may lead to delayed diagnosis and treatment. Atypical radiographic presentations in single vertebra include concentric collapse, sclerotic foci, and selective involvement of the vertebral arches and costotransverse joints. Multiple vertebrae may be involved either in continuity or as skipped lesions. Atypical clinical presentations may suggest a herniated intervertebral disk, failed back syndrome, spinal tumor, meningeal granuloma, or cold abscess without vertebral destruction.24,31 Tuberculous Osteomyelitis Bone lesions begin with hematogenous implantation of organisms in the medullary area. Metaphyseal involvement is most common, and lesions may spread through the growth plate to involve the adjacent joint, usually late in the disease course. Lesions are typically destructive. Lytic lesions in unusual areas, such as the pubic symphysis, sacroiliac joint, and elbow, can be misdiagnosed as malignancy.32 Osteomyelitis may develop in a bone or joint that has been previously exposed to trauma. Sternal osteomyelitis due to M. tuberculosis has been described following coronary artery bypass surgery. Tuberculous osteomyelitis occurs in both children and adults.33 Although any bone can be involved, the femur and tibia are most commonly affected. Dactylitis may also occur in children. In one large series from an endemic area,34 such cases represented 19% of bone and joint TB and 15% of cases of osteomyelitis of hematogenous origin. Bone pain was the most common presentation; a draining sinus, abscess formation, and local swelling and tenderness were also common. The average delay before diagnosis was 28 months.

Multifocal osteoarticular TB is a less common variant of the disease,35 but TB should be considered in all patients from endemic areas who present with multiple destructive skeletal lesions. For a definitive diagnosis of osteoarticular TB, a biopsy specimen of an affected site must be obtained.19 Soft tissue lesions characteristically demonstrate rim enhancement on CT examination. CT may also facilitate percutaneous needle biopsy or abscess drainage.36 Histologic examination generally reveals granulomatous inflammation. In one series of 121 cases, biopsy showed a positive culture in 33%, granulomatous histologic features in 46% and both in 21%.37 Radiographic findings include cavity formation with a thin adjacent layer of sclerosis in about 50% of cases, sometimes containing a sequestrum. The true extent of bone involvement may be difficult to detect because of clinically silent lesions. Bone imaging with technetium 99, although more sensitive than conventional radiographs, provides false-negative information in some cases of early, indolent, or highly destructive disease. Tuberculin test reactions are positive in 92% of cases. Treatment with chemotherapy is generally effective. In a minority of cases, surgical débridement is required for healing. Initiation of therapy on the basis of histologic findings is appropriate pending culture results. Sinus cultures are commonly positive for pyogenic bacteria both before and after antituberculous therapy, but these are presumed to be contaminants. Healing is associated with sclerosis at the margin of lesions. Misdiagnosis of the condition as pyogenic osteomyelitis may lead to unnecessary surgery or to delayed antituberculous treatment, resulting in extension of infection into the joint and chronic disability. Septic Arthritis Tuberculous joint involvement is second in frequency to vertebral infection.24 The typical pattern is a monarticular arthritis involving the large and medium joints, most commonly the hip and knee (Figs. 101-4 and 101-5).38,39 Other joints less commonly involved include the sacroiliac, shoulder, elbow, ankle, carpal, and tarsal joints. Infection begins in the synovium, with progression of destructive changes being slower than in pyogenic septic arthritis. The diagnosis of tuberculous arthritis is often missed. A consecutive series spanning the years 1970 to 1984 emphasized typical features.40 Of 23 cases of musculoskeletal TB, 9 involved the spine, 1 the hip, and the remaining 13 the peripheral joints. Most patients were men older than 50 years. The history of TB or exposure was generally forgotten. In all cases, presenting symptoms were joint pain and swelling. Four patients had evidence of active pulmonary TB, and in two patients with sterile pyuria, M. tuberculosis grew from the urine. Only 5 of 10 patients tested had a positive tuberculin reaction. Radiographs showed changes of erosive arthritis in 7 and no changes in 4 of 11 joints studied. The median delay in diagnosis was 8 months. Arriving at a correct diagnosis requires vigorous pursuit and usually a synovial biopsy and culture. Initial studies are often misleading and may contribute to delayed diagnosis or misdiagnosis. Synovial fluid findings are variable and do not distinguish this arthropathy from other inflammatory or septic arthritides.41 Cell counts more often suggest inflammatory

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Figure 101-4  Tuberculous arthritis of the knee. On conventional computed tomography, typical marginal and central osseous erosions (arrows) accompany tuberculous arthritis. Osteoporosis is not prominent. (From Resnick D: Diagnosis of Bone and Joint Disorders, 3rd ed. Philadelphia, WB Saunders, 1995, p 2480.)

rather than septic arthritis and may contain a preponderance of neutrophils. Synovial fluid glucose tends to be low and more than 10 mg/dL below fasting serum levels, but nonfasting determinations are often misleading. The diagnosis may be facilitated if the organism is observed on an acid-fast smear of synovial fluid, but only 10% to 20% of reported cases are positive. In contrast, 79% of synovial fluid cultures are positive. Radiographic changes are similar to those seen in other septic arthritides, beginning with juxta-articular bone demineralization and progressing to marginal bone erosion and articular cartilage destruction (see Fig. 101-4). With the open biopsy technique, granulomatous histologic features and positive cultures are present in 94% of cases. No data are available for direct amplification tests in mycobacterial arthritis, but their use can be considered in suspected cases to provide an earlier diagnosis. The histologic examination alone may be confusing, because granulomatous synovitis can also be found in nontuberculous mycobacterial infection, sarcoidosis, erythema nodosum, brucellosis, Crohn’s disease, and foreign body reaction. As noted earlier, synovial acid-fast smear is of limited value. Tuberculous arthritis is also reported in children, sometimes early in the disease course; synovial biopsy and culture are recommended in patients with monarthritis and a positive tuberculin reaction.42 TB must be considered among the possible causes of septic arthritis occurring in patients with preexisting rheumatoid arthritis,43 although it is not widely seen in developed countries.43,44 Conversely, rheumatoid factor may be present in TB, leading to diagnostic confusion in the presence of chronic monarthritis.44

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Figure 101-5  Tuberculous arthritis following total hip replacement. A sinus tract emerges from the scar following total hip arthroplasty for childhood destructive arthritis of unknown cause. The young man was originally from Vietnam.

EMERGENCE OF TUBERCULOSIS DURING THE TREATMENT OF RHEUMATIC DISEASES Many patients with systemic rheumatic disease have dysregulated immune systems that are treated with immunosuppressive drugs. Such an impaired immune response may permit the reactivation of latent TB. TNF-α plays a key role in granuloma formation and stabilization, which promotes the containment of M. tuberculosis. The rate of TB among patients with rheumatoid arthritis before the widespread use of anti-TNF drugs was approximately 6 cases per 100,000. In one large patient registry, the estimated incidence of TB associated with infliximab in rheumatoid arthritis patients was in excess of 1000 per 100,000 person-years of exposure during the years 2000–2001.45 Etanercept may be associated with a lower risk for TB reactivation than infliximab: 10 cases per 100,000 person-years of exposure with etanercept, versus 41 per 100,000 person-years with infliximab, according to an analysis of Food and Drug Administration data.46 Early experience with adalimumab (13 cases in 2400 treated patients) suggests that it may be associated with a relatively high risk for TB reactivation. Monoclonal antibodies to TNF may play a greater role in destabilizing granulomas than TNF receptors. Nonetheless, similar precautions should be taken with any TNF antagonist. These reactivations in the face of anti-TNF therapy typically occur within 6 to 12 months of treatment and often present as extrapulmonary disease. The institution of a TB screening protocol in rheumatoid arthritis patients, and treatment of latent TB before infliximab administration,

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resulted in a 78% decrease in active TB.47 Strategies to treat latent TB infection that are tailored to the at-risk population can effectively and safely lessen the likelihood of active TB in patients treated with TNF antagonists. Although screening for latent TB infection has reduced the incidence of active disease, false-negative TSTs can undermine such good intentions (see Table 101-1). The approach to a patient with latent TB who needs anti-TNF therapy has not been determined. Patients with positive TSTs and normal chest radiographs who have never been treated for TB should probably receive at least 1 to 2 months of therapy before beginning an anti-TNF drug. Patients discovered to have active TB should receive a complete course of a standard antituberculous regimen before any consideration is given to using an anti-TNF drug. Other biologic agents, including abatacept and rituximab, may pose a lower risk for reactivation of TB because the mechanisms of action are not intimately involved with host defense related to intracellular organisms. Patients treated with abatacept in clinical trials were prescreened with a TST and excluded if positive, thus making a direct comparison difficult. There is little or no evidence that B cells play a major role in containing TB, and no recommendation for TST screening is included in the labeling for rituximab. Glucocorticoid use also poses a significant hazard for patients with latent TB. Many mechanisms account for this effect, including impairment of cellular immune responses and monocyte chemotaxis and function, including the monocyte’s production of TNF-α. The use of glucocorticoids has recently been associated with a five times increased risk for the development of TB in a case-control study based on a large general practice database in the United Kingdom.48 The risk appeared to be dose related but was seen even at the physiologic dose of prednisone 7.5 mg/day. Just as with anti-TNF therapy, the risk for TB is greatest early in the course of treatment. Although anti-TNF therapy and steroids stand out as particular risk factors for the development of TB, all rheumatic disease patients treated with immunosuppressives that impair cellular immunity should be considered at risk. This is especially true in the elderly, the malnourished, and immigrants from countries with high endemic rates of TB. RHEUMATIC DISORDERS PRECIPITATED BY THE TREATMENT OF TUBERCULOSIS A variety of rheumatic conditions may be precipitated by drugs used in the treatment of TB. These include druginduced lupus caused by isoniazid (INH) and rifampin. As with other cases of drug-induced lupus, they are associated with positive antinuclear antibodies and the presence of antihistone antibodies. Typically, these patients follow a benign course, with reversal of disease after the drug is discontinued. Arthropathy and tendinopathy have been described with the use of fluoroquinolones, especially ciprofloxacin and levofloxacin. The risk of tendon rupture (usually the Achilles tendon) is greatest in patients older than 50 years and increases with the concomitant use of corticosteroids.

Pyrazinamide interferes with the renal tubular excretion of uric acid and has been associated with the development of hyperuricemia and gout in adults. Some patients develop a paradoxical worsening of their condition upon the initiation of antituberculous therapy. Such a development may raise questions about a flare of the underlying disease, especially if immunosuppressive therapy has been withdrawn in the face of infection. Symptoms include fever, malaise, weight loss, and increasing respiratory symptoms. The mechanism for such reactions is not completely understood but has been categorized within the spectrum of immune reconstitution inflammatory syndromes. Such reactions are more common in HIV patients and have also been seen in patients treated with infliximab following cessation of the anti-TNF therapy.49 All these drug-induced syndromes occur rarely but should be recalled in appropriate circumstances. REACTIVE IMMUNOLOGIC PHENOMENON IN THE SETTING OF TUBERCULOSIS A variety of reactive immunologic phenomena have been associated with M. tuberculosis infection. These are uncommonly found in clinical practice. Poncet’s disease is an aseptic inflammatory polyarthritis that occurs in the presence of active TB. Although any joints can be involved, the most commonly affected are the knees, ankles, and elbows.50 The mechanism is thought to be similar to other forms of reactive arthritis secondary to remote infection. Most cases resolve after satisfactory treatment of the TB. A reactive arthritis has been described following the intravesicular instillation of bacille CalmetteGuérin (BCG) vaccine for bladder cancer.51 Other seldom-encountered immune reaction patterns described with M. tuberculosis include erythema nodosum, erythema induratum, and amyloidosis (AA type).

DIAGNOSIS TUBERCULIN SKIN TEST The TST—also called the purified protein derivative (PPD)—has been in use for nearly a century and remains the most widely used screening test for TB. It is routinely administered in rheumatology offices that prescribe anti-TNF therapy. The test represents a crude mix of antigens from M. tuberculosis and is plagued by both false-positive and falsenegative results. It is unable to distinguish latent infection from active disease and may be negative in the face of severe active TB. Corticosteroids (≥15 mg/day prednisone) may render the PPD negative in the face of latent TB. Elderly and malnourished patients may not exhibit a positive TST. Table 101-1 provides a partial list of causes for a false-­negative TST that are of special interest to rheumatologists. False-positive results may likewise occur in the case of in­­ fection with nontuberculous mycobacteria or previous BCG vaccine. PPD positivity degrades over time in BCG-vaccinated patients, at a variable rate. The degree of positivity is influenced by a number of factors, including the number of BCG vaccinations and the number of subsequent PPD tests performed. Some patients may retain a response as long as 15 years after BCG vaccine. However, a PPD result of

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20 mm or greater is rarely due to BCG. In addition, if faced with a high-risk situation, such as the initiation of anti-TNF therapy, one should probably make a presumption of latent TB even if the induration measures as little as 5 mm. The important message for rheumatologists is that the TST is an important but imperfect screening tool for M. tuberculosis, with a sensitivity and specificity in the range of 70%. A negative TST should not eliminate the clinician’s vigilance in monitoring patients being treated with antiTNF therapy for reactivated or new-onset TB, especially in high-risk populations.

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assays measure the production of interferon-γ by wholeblood mononuclear cells stimulated by specific M. tuberculosis antigens. The interferon-γ release assays (IGRAs) appear to be promising as a test for latent TB and have good sensitivity and specificity for latent TB infection.58 These assays may prove particularly helpful in distinguishing TB from nontuberculous mycobacteria and in patients who have had recent BCG vaccines. They also offer the opportunity to circumvent operator error with TST administration and do not require patients to return for a reading. IGRAs have replaced the TST in some centers for routine screening for latent TB infection.

IMAGING Although imaging patterns suggestive of TB have been discussed, there are no pathognomonic skeletal radiographic features that can establish the diagnosis. Early features on radiographs may be equivocal or nonexistent. Chest radiographs are often normal or fail to show features characteristic of TB. Conventional radiography is generally a useful approach for defining bone destruction, the extent of disease, and adjacent soft tissue lesions.52 MRI is more effective in identifying early disease; it may help distinguish TB from other infections and neoplasm and can aid in evaluating the extent of disease.8,53 Scintiscans with technetium and gallium may also be helpful in localizing bone and soft tissue lesions, but early false-negative findings are not uncommon.54 CT can be helpful in guiding diagnostic needle biopsy. Fine-needle biopsy is an acceptable alternative to core-needle biopsy and open biopsy for the diagnosis of osteoarticular TB in both the axial and peripheral skeleton, and it has the advantage of obviating general anesthesia.55,56 Both CT and MRI may also be helpful in monitoring therapy.57 CULTURE Nearly all species of Mycobacteria are slow growing, with M. tuberculosis being the slowest. Other bacteria may rapidly outgrow mycobacteria if the specimen is not inoculated on special isolation media. The small number of mycobacteria found in clinically infected areas further challenges the ability to confirm mycobacterial infection and accounts for the dismally low yield of positive Ziehl-Neelsen staining (10% to 20%) in synovial fluid and other biologic fluids. Synovial fluid and other bodily fluids are less likely than tissue to yield a positive culture. If a joint is suspected of harboring TB, a synovial biopsy should be obtained. Arthroscopically derived tissue yields higher positive cultures than needle biopsies do. CT-guided needle aspiration and biopsy can provide invaluable information in the case of spinal involvement. Characteristic features on tissue pathology, including caseating and noncaseating granulomas, may allow an early presumptive diagnosis of TB pending culture results, which may take 4 to 6 weeks to be finalized. ADVANCED DIAGNOSTIC TESTING Interferon-γ Release Assays The limitations of the traditional PPD skin test in terms of specificity and sensitivity in identifying latent TB have led to the development of new T cell–based testing. These

Nucleic Acid Amplification Molecular diagnostics using nucleic acid amplification may be helpful in patients with low mycobacterial loads. The presence of polymerase chain reaction inhibitors, especially in extrapulmonary specimens, can lead to false-negative results. Despite more than a decade of experience, the role of nucleic acid amplification tests in diagnosing TB infection is still being defined. These assays must be interpreted with caution in extrapulmonary tissue specimens and when the clinical suspicion of infection is low.59-61 Although the specificity is quite good, the sensitivity is actually lower than with traditional cultures.

TREATMENT The appropriate management of tuberculous infections of bones and joints is a complex and evolving process. Proper selection of antibiotic regimens and ongoing disease monitoring should involve comanagement with an infectious disease consultant. Nonetheless, rheumatologists should be familiar with the basic treatment principles. Treatment of M. tuberculosis infections that involve the musculoskeletal system consists of the same combination chemotherapy regimens that are effective in pulmonary TB. Treatment regimens for infections of the bone and spine traditionally involved 12- to 18-month courses of antibiotics, even when much shorter courses were recommended for lung disease and other extrapulmonary sites. The longer courses for musculoskeletal disease were based on poor tissue penetration into osseous tissues and high rates of relapse. Experience with regimens that include rifampin indicate that a 9-month course of therapy is effective in musculo­ skeletal disease. In some cases, 6 months may be adequate. Current guidelines on the treatment of TB published jointly by the Centers for Disease Control, American Thoracic Society, and Infectious Diseases Society of America recommend a 6-month course of therapy for all sites except the bone (6 to 9 months) and the central nervous system (9 to 12 months).62 Rifampin is the critical component that allows shorter-course therapy. The standard approach to TB therapy (both pulmonary and extrapulmonary) in the United States currently includes four drugs to start: isoniazid, rifampin, ethambutol, and pyrazinamide—known as IREZ therapy. Once the bacillus is confirmed to be sensitive to INH, the ethambutol can be discontinued. Pyrazinamide is administered for 2 months, and rifampin and INH are continued for the duration of therapy.

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Longer courses of therapy are required for patients who are slow to respond. Radiographic features of mycobacterial disease may not change much after 6 months of treatment, and response to treatment is based mainly on clinical features, including reduction in pain, resolution of constitutional symptoms, and emergence of increased mobility. Longer courses are also advised for cases of relapse and resistant organisms. Surgical intervention is seldom indicated for the initial management of osteoarticular TB. Possible exceptions at presentation include patients with advanced or progressive disease or spinal kyphosis of 40 degrees or greater. Patients who have extensive joint destruction and immobility after an adequate course of chemotherapy may also be candidates for surgery. Following successful antibiotic therapy, arthroplasty of the hip and knee may be undertaken and is usually successful. Recurrence of disease in the prosthetic joint is less likely if the surgery is performed years after the infection and the tissue obtained at surgery is culture negative. This may be impractical, however, when a patient is unable to ambulate following an adequate course of therapy. In such cases, the TB therapy is continued through surgery and for at least 3 months postoperatively. If TB recurs in the prosthetic joint, it can sometimes be managed with antibiotic therapy alone. However, in many cases, removal of the prosthesis is necessary for complete resolution of the infection. The increasing incidence of drug-resistant TB complicates the selection of appropriate drugs.63-65 Primary monoresistance to isoniazid occurs in about 7% of TB isolates in the United States. When identified, this does not substantially impact the treatment outcome. Multidrug-resistant TB (MDR-TB) refers to isolates that are resistant to isoniazid and rifampin. The rate of MDR-TB in the United States has been relatively stable for the past decade, at less than 1%. In other parts of the world, MDR-TB rates may exceed 6% for new cases and 30% in previously treated individuals. The treatment of MDR-TB is complex and often requires the use of multiple (often toxic) second-line agents for 18 to 24 months or longer. XDR-TB—that is, strains resistant to all first-line TB drugs and at least three second-line agents—has been reported in at least 17 countries, with

Figure 101-6  Hand demonstrating tenosynovitis and synovitis secondary to M. marinum.

p­ articularly high rates in Kazakhstan, Iran, and South Africa.66 The options for treatment of XDR-TB are very ­limited, and treatment failure and death are the likely outcome. Incomplete adherence with treatment is a particularly important risk factor for secondary drug resistance, and the likelihood of drug resistance increases following relapse after treatment. Directly observed therapy is strongly advocated to reduce the spread of infection and the frequency of drugresistant TB.67

OSTEOARTICULAR INFECTIONS CAUSED BY NONTUBERCULOUS (ATYPICAL) MYCOBACTERIA Nontuberculous mycobacteria have a ubiquitous presence in the environment, including soil, water, and animal reservoirs. They are not typically spread from human to human. In normal hosts, they usually result in localized infections of the skin. Some infections are the result of aspiration and may spread hematogenously to other sites.68 Immunosuppressed hosts may develop nontuberculous mycobacterial infections of the musculoskeletal system, but these infections are much less common than TB. In contrast to TB, nontuberculous infection is more likely to cause tenosynovitis, synovitis, or osteomyelitis and less likely to cause spinal infection. Although there are some 50 species of nontuberculous mycobacteria, the majority of musculoskeletal infections are caused by Mycobacterium marinum, Mycobacterium kansasii, and Mycobacterium avium-intracellulare (also called M. avium complex, or MAC). Three distinct patterns of musculoskeletal involvement are reported: tenosynovitis, synovitis, and osteomyelitis.69,70 Tenosynovitis typically presents as chronic unilateral hand and wrist swelling (Figs. 101-6 to 101-8).71 Synovitis typically presents as chronic indolent asymmetric swelling in a knee, hand, or wrist. A number of species have been associated with these syndromes, and the number isolated from immunosuppressed patients is growing.10 Predisposing factors, in addition to immunosuppression and direct inoculation, include environmental exposure and preexisting joint disease.72

Figure 101-7  Radiograph of the hand in Figure 101-6 demonstrates joint destruction secondary to M. marinum.

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Figure 101-8  The hand depicted in Figures 101-6 and 101-7, infected with M. marinum, shows extensive tenosynovitis at the time of synovectomy.

Correct diagnosis usually requires tissue biopsy and culture. Synovial fluid, when it is obtainable, is typically inflammatory, and a culture may be helpful only if mycobacterial techniques are requested. Identification of acid-fast bacilli on smear and granulomatous inflammation from a tissue biopsy specimen often provides direction for an appropriate microbiologic investigation, but histologic features do not consistently demonstrate granuloma formation. With a compatible clinical presentation and histologic findings, mycobacterial culture, including special techniques for M. marinum, should be requested. Direct amplification testing may be useful for more rapid identification of mycobacterial species in tissue specimens, but data from musculoskeletal cases are limited.59,73 In addition to mycobacteria, other causes of granulomatous synovitis include fungi, brucellosis, sarcoidosis, inflammatory bowel disease, and nonmetallic foreign bodies. Mycobacteria other than M. tuberculosis are responsible for a significant proportion of these cases.74 MAC has become the most common mycobacterial infectious agent affecting patients with HIV/AIDS, in whom it has a greater tendency to cause disseminated disease.10 Fortunately, there has been a sharp decline in the incidence of MAC following the introduction of effective antiretroviral therapy and MAC prophylaxis. When dealing with TB, isolation of the organism is always clinically significant. In contrast, when dealing with a nontuberculous mycobacterial isolate, the clinician must judge whether it is a contaminant, represents insignificant colonization, or is the cause of disease. Certain guidelines have proved useful in this respect72,75-77: • The illness should be consistent with one or more syndromes associated with mycobacterial infection. • Other causes of disease, such as TB and fungi, should be excluded. • A mycobacterial species should be isolated that is associated with human disease, the most significant being those that are not common environmental contaminants (M. kansasii, M. marinum, M. simiae, M. szulgai, and M. ulcerans). • The site of isolation of the organism should favor true infection over contamination or colonization.

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• Heavier growth suggests significant infection. • With significant disease, multiple isolations of the responsible organism are the rule. Because laboratory identification of the organism and sensitivities may take weeks to months, initial therapy often includes multiple drugs to cover both TB and other mycobacteria. One common approach to initial empiric therapy is to link standard IREZ therapy for TB with clarithromycin until cultures return. The latest American Thoracic Society guidelines for the treatment of nontuberculous mycobacteria were published in 2007.78 Surgical débridement of infected tissue may play an important role in the treatment of selected patients, especially for resistant organisms. The most efficacious drugs remain controversial, prolonged treatment is often necessary, and relapses are not uncommon. As with TB, therapy customized to the individual patient is crucial with nontuberculous mycobacteria infection. The key to effective therapy lies in the unique characteristics of the culture and sensitivity of the particular isolate. REFERENCES   1. Shafer RW, Kim DS, Weiss JP, et al: Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. Medicine (Baltimore) 70:384, 1991.   2. Jellis JE: Human immunodeficiency virus and osteoarticular tuberculosis. Clin Orthop 398:27, 2002.   3. Havlir DV, Barnes PF: Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 340:367, 1999.   4. Global Tuberculosis Control: Surveillance, Planning, Financing. WHO Report WHO/HTM/TB/2007.376. Geneva, World Health Organization, 2007.   5. Bloom BR: Tuberculosis—the global view. N Engl J Med 346:1434, 2002.   6. Gandhi NR, Moll A, Sturm AW, et al: Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 638:1575, 2006.   7. Franco-Paredes C, Diaz-Borjon A, Senger M, et al: The ever­expanding association between rheumatologic diseases and tuberculosis. Am J Med 119:470, 2006.   8. Moore SL, Rafii M: Imaging of musculoskeletal and spinal infections: Imaging of musculoskeletal and spinal tuberculosis. Radiol Clin North Am 39:329, 2001.   9. Griffith JF, Kumta SM, Leung PC, et al: Imaging of musculoskeletal tuberculosis: A new look at an old disease. Clin Orthop 398:32, 2002. 10. American Thoracic Society and the Centers for Disease Control: Mycobacterioses and the acquired immunodeficiency syndrome. Am Rev Respir Dis 136:492, 1987. 11. La Fond EM: An analysis of adult skeletal tuberculosis. J Bone Joint Surg Am 40:346, 1958. 12. Ashworth MJ, Meadows TH: Isolated tuberculosis of a skeletal muscle. J Hand Surg Br 17:235, 1992. 13. Hasan N, Baithun S, Swash M, Wagg A: Tuberculosis of striated muscle. Muscle Nerve 16:984, 1993. 14. Indudhara R, Singh SK, Minz M, et al: Tuberculous pyomyositis in a renal transplant recipient. Tuber Lung Dis 73:239, 1992. 15. George JC, Buckwalter KA, Braunstein EM: Tuberculosis presenting as a soft tissue forearm mass in a patient with a negative tuberculin skin test. Skeletal Radiol 23:79, 1994. 16. Abdelwahab IF, Kenan S, Hermann G, et al: Tuberculous gluteal abscess without bone involvement. Skeletal Radiol 27:36, 1998. 17. Albornoz MA, Mezgarzedeh M, Neumann CH, et al: Granulomatous tenosynovitis: A rare musculoskeletal manifestation of tuberculosis. Clin Rheumatol 17:166, 1998. 18. King AD, Griffith J, Rushton A, et al: Tuberculosis of the greater trochanter and the trochanteric bursa. J Rheumatol 25:391, 1998. 19. Chen W-S: Tuberculosis of the fascia lata. Clin Rheumatol 17:77, 1998.

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20. Alvarez S, McCabe WR: Extrapulmonary tuberculosis revisited: A review of experience at Boston City and other hospitals. Medicine (Baltimore) 63:25, 1984. 21. el-Shahawy MA, Gadallah MF, Campese VM: Tuberculosis of the spine (Pott’s disease) in patients with end-stage renal disease. Am J Nephrol 14:55, 1994. 22. Jacobs P: Osteo-articular tuberculosis in coloured immigrants: A radiologic study. Clin Radiol 15:59, 1964. 23. Gorse GJ, Pais MJ, Kusske JA, Cesario TC: Tuberculous spondylitis. Medicine (Baltimore) 62:178, 1983. 24. Chapman M, Murray RD, Stoker DJ: Tuberculosis of bones and joints. Semin Roentgenol 14:266, 1985. 25. Colmenero JD, Jimenez-Mejias ME, Sanchez-Lora FJ, et al: Pyogenic, tuberculous, and brucellar vertebral osteomyelitis: A descriptive and comparative study of 219 cases. Ann Rheum Dis 56:709, 1997. 26. Cantini F, Salvarani C, Olivieri I, et al: Tuberculous spondylitis as a cause of inflammatory spinal pain: A report of 4 cases. Clin Exp Rheumatol 16:305, 1998. 27. Slater RR Jr, Beale RW, Bullitt E: Pott’s disease of the cervical spine. South Med J 84:521, 1991. 28. Krishnan A, Patkar D, Patankar T, et al: Craniovertebral junction tuberculosis: A review of 29 cases. J Comput Assist Tomogr 25:171, 2001. 29. Bhojraj SY, Shetty N, Shah PJ: Tuberculosis of the craniocervical junction. J Bone Joint Surg Br 83:222, 2001. 30. Pouchot J, Vinceneus P, Barge J, et al: Tuberculosis of the sacroiliac joint: Clinical features, outcome, and evaluation of closed needle biopsy in 11 consecutive cases. Am J Med 84:622, 1988. 31. Pande KC, Babhulkar SS: Atypical spinal tuberculosis. Clin Orthop 398:64, 2002. 32. Tsay MH, Chen MC, Jaung GY, et al: Atypical skeletal tuberculosis mimicking tumor metastasis: Report of a case. J Formos Med Assoc 94:428, 1995. 33. Shih HN, Hsu RW, Lin TY: Tuberculosis of the long bone in children. Clin Orthop 335:246, 1997. 34. Babhulkar SS, Pande SK: Unusual manifestations of osteoarticular tuberculosis. Clin Orthop 398:114, 2002. 35. Muradali D, Gold WL, Vellend H, Becker E: Multifocal osteoarticular tuberculosis: Report of four cases and review of management. Clin Infect Dis 17:204, 1993. 36. Coppola J, Muller NL, Connell DG: Computed tomography of musculoskeletal tuberculosis. J Can Assoc Radiol 38:199, 1987. 37. Martini M, Adjrad A, Boudjemaa A: Tuberculous osteomyelitis: A review of 125 cases. Int Orthop 10:201, 1986. 38. Babhulkar S, Pande S: Tuberculosis of the hip. Clin Orthop 398:93, 2002. 39. Hoffman EB, Allin J, Campbell JAB, Leisegang FM: Tuberculosis of the knee. Clin Orthop 398:100, 2002. 40. Evanchick CC, Davis DE, Harrington TM: Tuberculosis of peripheral joints: An often missed diagnosis. J Rheumatol 13:187, 1986. 41. Wallace R, Cohen AS: Tuberculous arthritis: A report of two cases with a review of biopsy and synovial fluid findings. Am J Med 61:277, 1976. 42. Jacobs JC, Li SC, Ruzal-Shapiro C, et al: Tuberculous arthritis in children: Diagnosis by needle biopsy of the synovium. Clin Pediatr 33:344, 1994. 43. Sorio LM, Sole JMN, Sacanell AR, et al: Infectious arthritis in patients with rheumatoid arthritis. Ann Rheum Dis 51:402, 1992. 44. Davidson PT, Horowitz I: Skeletal tuberculosis: A review with patient presentations and discussion. Am J Med 48:77, 1970. 45. Gomez-Reino JJ, Carmona L, Rodriquez Valverde V, et al: Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to a significant increase in tuberculosis risk: A multicenter active surveillance report. Arthritis Rheum 48:2122, 2003. 46. Mohan AK, Cote TR, Block JA, et al: Tuberculosis following the use of etanercept, a tumor necrosis factor inhibitor. Clin Infect Dis 39:295, 2004. 47. Carmona L, Gomez-Reino JJ, Rodriquez Valverde V, et al: Effectiveness of recommendations to prevent reactivation of latent TB infection in patients treated with tumor necrosis antagonists. Arthritis Rheum 52:1766, 2005. 48. Jick SS, Lieberman ES, Rahman MU, et al: Glucocorticoid use, other associated factors, and the risk of tuberculosis. Arthritis Rheum (Arthritis Care Res) 55:19, 2006. 49. Garcia Vidal C, Rodriquez Fernandez S, Martinez Lacasa J, et al: Paradoxical response to antituberculous therapy in infliximab-treated patients with disseminated tuberculosis. Clin Infect Dis 40:756, 2005.

50. Dall L, Long L, Standford J: Poncet’s disease: Tuberculous rheumatism. Rev Infect Dis 11:105, 1989. 51. Pancaldi P, Van Linthoudt D, Aborino S, et al: Reiter’s syndrome after intravesical bacillus Calmette-Guerin treatment for superficial bladder carcinoma. Br J Rheumatol 32:1096, 1993. 52. Resnick D: Osteomyelitis, septic arthritis, and soft tissue infection. In Resnick D (ed): Diagnosis of Bone and Joint Disorders, 4th ed. Philadelphia, WB Saunders, 2002, pp 2510-2624. 53. Gupta RK, Gupta S, Kumar S, et al: MRI in intraspinal tuberculosis. Neuroradiology 36:39, 1994. 54. Lifeso RM, Weaver P, Harder EH: Tuberculous spondylitis in adults. J Bone Joint Surg Am 67:1405, 1985. 55. Mondal A: Cytological diagnosis of vertebral tuberculosis with fineneedle aspiration biopsy. J Bone Joint Surg Am 76:181, 1994. 56. Masood S: Diagnosis of tuberculosis of bone and soft tissue by fineneedle aspiration biopsy. Diagn Cytopathol 8:451, 1992. 57. Omari B, Robertson JM, Nelson RJ, Chiu LC: Pott’s disease: A resurgent challenge to the thoracic surgeon. Chest 95:145, 1989. 58. Menzies D, Madhakur PA, Comstock G: Meta-analysis: New tests for the diagnosis of latent tuberculosis infection: Areas of uncertainty and recommendations for research. Ann Intern Med 146:340, 2007. 59. Harrington JT: The evolving role of direct amplification tests in diagnosing osteoarticular infections caused by mycobacteria and fungi. Curr Opin Rheumatol 11:289, 1999. 60. Catanzaro A, Perry S, Clarridge JE, et al: The role of clinical suspicion in evaluating a new diagnostic test for active tuberculosis: Results of a multicenter prospective trial. JAMA 283:639, 2000. 61. Woods GL: Molecular techniques in mycobacterial detection. Arch Pathol Lab Med 125:122, 2001. 62. Recommendations for the treatment of tuberculosis. MMWR 52: 1-77, 2003. 63. Hannachi MR, Martini M, Boulahal F, et al: A comparison of three daily short-course regimens in osteoarticular tuberculosis in Algiers. Bull Int Union Tuberc 57:46, 1982. 64. Parsons LM, Driscoll JR, Taber HW, et al: Antimicrobial resistance: Drug resistance in tuberculosis. Infect Dis Clin North Am 11:906, 1997. 65. Bradford WZ, Daley CL: Emerging infectious diseases: Multiple drugresistant tuberculosis. Infect Dis Clin North Am 12:157, 1998. 66. Raviglione MC, Smith IM: XDR tuberculosis: Implications for global health. N Engl J Med 356:656, 2007. 67. Chaulk CP, Kazandjian VA: Directly observed therapy for treatment completion of pulmonary tuberculosis: Consensus statement of the Public Health Tuberculosis Guidelines Panel. JAMA 279:943, 1998. 68. Brown-Elliot BA, Wallace RJ: Infections caused by nontuberculous mycobacteria. In Mandell GL, Bennett JE, Dolin R (eds): Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 6th ed. Philadelphia, Churchill Livingstone, 2005, pp 2909-2916. 69. Kelly PJ, Karlson AG, Weed LA, et al: Infection of synovial tissues by mycobacteria other than Mycobacterium tuberculosis. J Bone Joint Surg Am 49:1521, 1967. 70. Marchevsky AM, Damsker B, Green S, Tepper S: The clinicopathological spectrum of non-tuberculous mycobacterial osteoarticular infections. J Bone Joint Surg Am 67:925, 1985. 71. Zenone T, Boibieux A, Tigaud S, et al: Non-tuberculous mycobacterial tenosynovitis: A review. Scand J Infect Dis 31:221, 1999. 72. Glickstein SL, Nashel DJ: Mycobacterium kansasii septic arthritis complicating rheumatic disease: Case report and review of the literature. Semin Arthritis Rheum 16:231, 1987. 73. Weigl JAI, Haas WH: Postoperative Mycobacterium avium osteomyelitis confirmed by polymerase chain reaction. Eur J Pediatr 159:64, 2000. 74. Sutker WL, Lankford LL, Tompsett R: Granulomatous synovitis: The role of atypical mycobacteria. Rev Infect Dis 1:729, 1979. 75. Wolinsky E: When is an infection disease? Rev Infect Dis 3:1025, 1981. 76. Wallace RJ Jr, O’Brien R, Glassroth J, et al: Diagnosis and treatment of disease caused by nontuberculous mycobacteria. Am Rev Respir Dis 142:940, 1990. 77. Ahn CH, McLarty JW, Ahn SS, et al: Diagnostic criteria for pulmonary disease caused by Mycobacterium kansasii and Mycobacterium intracellulare. Am Rev Respir Dis 125:388, 1992. 78. Griffith DE, Aksamit T, Brown-Elliot BA, et al: An official ATSIDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Resp Crit Care Med 175:367-416, 2007.

102

Fungal Infections of the Bones and Joints J. Timothy Harrington  •  John P. Flaherty  •  Walter G. Barr

KEY POINTS Fungi are an infrequent but clinically important cause of osteoarticular infections. A high index of suspicion is required to diagnose and correctly treat these infections, because they are often indolent in onset and masquerade as other disorders. Travel and immigration have affected the geographic ­localization of several important fungal infections. Immunocompromise, including antirheumatic biologic ­therapies, predisposes to fungal infections, often resulting in more acute and widely disseminated disease. Although diagnosis may be assisted by clinical presentation and serologic testing, examination and culture of infected tissue are critical. New antifungal therapies have broadened the effective options, but choice of drugs, duration of treatment, and ­combined surgical débridement must be carefully considered to achieve optimal outcomes.

Fungal infection is a relatively infrequent but important cause of osteomyelitis and arthritis. Fungal diseases that commonly cause osteomyelitis include coccidioidomycosis, blastomycosis, cryptococcosis, candidiasis, and sporotrichosis (Table 102-1). Fungal arthritis is less common and is most often associated with sporotrichosis, coccidioidomycosis, blastomycosis, candidiasis, and, occasionally, other species. The epidemiology of these fungal infections, their musculoskeletal presentations, and their treatment are considered in this chapter. Additional information may be accessed by electronic search at UpToDate. The epidemiology and clinical features of individual deep mycoses may suggest the diagnosis in some cases, but their indolent presentation, which often resembles that of other noninfectious diseases, may be misleading. Travel and immigration have blurred their geographic localization. Infection may be acute and overwhelming in immunocompromised patients, for whom disseminated fungal infections are a major risk. Anticytokine treatments for rheumatic diseases are associated with disseminated fungal infection,1 as are acquired immunodeficiency syndrome (AIDS), pregnancy, and treatments for transplantation and malignancies,2 in some cases. For rheumatologists, disseminated fungal infections are an important diagnostic consideration in some patients and must be considered before starting biologic treatments in those at risk; they may also complicate the clinical course of other arthritides.

Fungal infections are generally diagnosed by histologic examination or culture of involved tissues. Improved biopsy techniques facilitate the diagnosis, provided the possibility of fungal infection is considered and proper studies are requested. Synovial fluid leukocyte counts and culture results vary among fungal infections and in individual cases and may be misleading. Serologic testing may also assist in diagnosing and staging several fungal infections. Detecting fungal antigens and DNA in blood and tissue is now possible in some cases, but the clinical use of these methods is still under investigation.3

COCCIDIOIDOMYCOSIS Coccidioides immitis, a soil fungus, generally causes a primary respiratory illness after spores are inhaled. A self-limited acute pneumonia may result, associated with systemic manifestations such as arthralgia and erythema nodosum (valley fever), but infection is often inapparent and only infrequently becomes chronic or disseminated.4 Coccidioidomycosis is endemic to the southwestern United States and areas of Central and South America, but cases are increasingly diagnosed in nonendemic areas because of travel, infection from fomites, and reactivation of remote infection. Cases increase when soil is disturbed and in windy conditions. Direct human-to-human transmission is rare. Extrapulmonary infection is almost always caused by hematogenous spread from an initial pulmonary focus. The bones and joints are frequent sites of dissemination, particularly in immunocompromised hosts. Septic arthritis of the knee is common, generally arising from direct infection of the synovium. Other joint infections are caused by spread from a contiguous osteomyelitis involving the vertebrae, wrists, hands, ankles, feet, pelvis, and long bones.5 The onset is characterized by gradually increasing pain and joint stiffness, with little swelling but early radiographic changes. In one series, arthritis was the only manifestation of disseminated coccidioidomycosis in 51 of 57 patients and was an aspect of more generalized disease in the remaining 6 patients.6 Diagnostic confusion is common in osteoarticular coccidioidomycosis because of the delayed dissemination (months to years) after primary infection and because of atypical clinical presentations. The criteria for diagnosis include compatible clinical features, serologic studies, histologic examination, and culture. Early infections, often before systemic spread, are associated with a positive antibody precipitin test that detects immunoglobulin (Ig) M antibody. Complement fixation serologic values detecting IgG antibodies are in a range indicative of disseminated disease in a majority of patients and show a significant decrease with 1739

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Table 102-1  Fungi Causing Osteoarticular   Infections Infection

Geographic ­Distribution

Infection Site

Coccidioidomycosis

Southwestern US, Central and South America, elsewhere

Bones and joints, especially knee

Blastomycosis

North-central and southern US

Bones and joints

Cryptococcosis

Ubiquitous

Bones; rarely joints

Candidiasis

Ubiquitous

Bones; rarely joints

Sporotrichosis

Ubiquitous

Bones and joints

Aspergillosis

Ubiquitous

Spine, ribs; rarely joints

Histoplasmosis

Midwestern and southeastern US

Rarely bones and joints; hypersensitivity arthritis

Scedosporiosis

Undefined

Bones and joints

effective treatment. The definitive diagnosis is most commonly made by the demonstration of granulomatous synovitis and typical spherules in a biopsy specimen, confirmed in some cases by positive culture and direct amplification testing. Synovial fluid, when it is obtainable, does not necessarily demonstrate septic leukocyte counts, and it is culture positive in less than 5% of cases. Radioisotope bone scans may be helpful to identify areas of infection.7 With early diagnosis of effusive synovitis, antifungal treatment alone is appropriate. With more widely disseminated infection or involvement of critical areas such as the spine, and in high-risk hosts, the choice and duration of treatments are often complicated.8 Indications for combined medical and surgical treatment include (1) chronic joint inflammation with pannus formation and progressive disease during medical treatment, (2) involvement of contiguous bone, (3) rising complement fixation titers, and (4) extra-articular dissemination. Combined antifungal and surgical treatment is superior to either medical or surgical treatment alone.6,9 A high priority for combined treatment is identified by a complement fixation titer at or above 1:128. For skeletal infections, itraconazole is more effective than fluconazole and has been successful in some patients who relapsed after previous treatment with amphotericin or ketoconazole.10,11 New antifungal agents such as voriconazole and posaconazole are under investigation.8 Coccidioidal synovitis may also occur in a noninfectious inflammatory variety that complicates either primary pulmonary or disseminated disease and is typically a polyarthritis. It is accompanied by fever, erythema nodosum or multiforme, eosinophilia, and hilar adenopathy. It abates in 2 to 4 weeks.4,12

BLASTOMYCOSIS Blastomycosis, caused by Blastomyces dermatitidis, is endemic in the north-central and southern United States. Infection most commonly produces sporadic or clustered cases of pulmonary disease and is induced by exposure to soil or dust containing decomposed wood and, presumably, contaminated with the organism.13 Affected individuals

do not appear to have any distinguishing or predisposing characteristics except for exposure to the organism during work or recreation. Clinical presentation includes high fever and other constitutional symptoms, pulmonary and skin involvement, and a significant mortality rate. Hematogenous dissemination is common; skin disease and osteoarticular disease occur most frequently. Bone involvement occurs in 25% to 60% of disseminated cases, and arthritis is estimated to occur in 3% to 5%.14 The skeletal areas most commonly affected are the long bones, vertebrae, and ribs (Fig. 102-1).15-17 Arthritis is usually monarticular in the knee, ankle, or elbow but may rarely be polyarticular.14,18 Joint infection is an isolated skeletal disorder in only a few cases; joint radiographs more commonly show punched-out bone lesions (Fig. 102-2A). Synovial fluid is commonly purulent, and organisms are evident on microscopic examination as well as by culture. The synovial histologic examination shows epithelioid granulomas with budding yeast forms (Fig. 102-2B). The diagnosis is also commonly made from involved nonarticular sites. Urinary antigen testing appears to be very sensitive. The therapeutic response to amphotericin B or itraconazole is generally favorable.13,19,20

CRYPTOCOCCOSIS Cryptococcus neoformans, the fungus causing cryptococcosis, is geographically ubiquitous and is found in pigeon feces; a related species, Cryptococcus gattii, is associated with certain types of eucalyptus trees in tropical climates. It is a common pathogen only in association with defects in cell-­mediated host defense, including human immunodeficiency virus (HIV) infection,21 transplantation, lymphoreticular malignant neoplasms, tumor necrosis factor-α (TNF-α) antagonist treatment,22 and corticosteroid therapy. Cryptococcosis varies in acuteness, usually affecting the lungs in its primary form, but it sometimes disseminates hematogenously to a wide variety of sites, including the central nervous system and skin. Although bone infection is common, causing osteolytic lesions in 5% to 10% of cases, articular involvement is rarely reported.23 Bone lesions may be confused with metastatic neoplasm (Fig. 102-3). Cryptococcal arthritis is an indolent monarticular arthritis in about 60% of reported cases and a polyarthritis in the remainder.24,25 The knee is most commonly involved. A single case of tenosynovitis with carpal tunnel syndrome has been recognized. The majority of cases reported from the pre-AIDS era also demonstrated radiographic evidence of periarticular osteomyelitis. These patients were young adults, did not have debilitating disease or other evidence of dissemination, and had pulmonary involvement in only 50% of cases. Synovial tissue showed acute and chronic synovitis, multinucleate giant cells, prominent granuloma formation, and large numbers of budding cryptococci with special stains. Most recently reported cases are associated with immunosuppression and disseminated infection. Myositis and fasciitis have also been reported.26,27 Serum cryptococcal antigen testing appears to be very sensitive, in part because osteoarticular infection results from hematogenous dissemination. The choice of treatment for cryptococcal disease depends on both the anatomic sites of involvement and the host’s immune status, with amphotericin B and

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A200

R

A

B

L

P200

Figure 102-1  A, Blastomycosis osteomyelitis of a rib and chest wall. B, Computed tomography scan appearance. Primary infection in the blood may spread to the skeleton. (Courtesy of John Flaherty, MD, Feinberg School of Medicine, Northwestern University.)

fl­ uconazole being considered most effective.25,28 5-Flucytosine is often added to amphotericin B or fluconazole in cases of severe cryptococcal infections.

CANDIDIASIS Candida species are widely distributed yeasts. Candida albicans is a normal commensal of humans, and other species can probably live in nonanimal environments such as soil. Since the advent of antibiotic therapy in the 1940s, and related to the common use of immunosuppression and parenteral lines, candidiasis has been responsible for an increasing incidence of mucocutaneous and deep-organ infections.29 Osteomyelitis, though rarely reported, is a potentially serious complication of hematogenous dissemination in both adults and children.30,31 It may also occur from direct tissue inoculation during surgery or by injection of contaminated heroin,32 and bone infection may emerge after successful amphotericin B treatment of other sites. Infection is commonly located in two adjacent vertebrae33 or in a single long bone. Surgical inoculation has occurred in the sternum, spine, and mandible. A few patients have had multiple sites of involvement. The clinical presentation is localized pain. Other symptoms and laboratory abnormalities vary. Bone changes of osteomyelitis are commonly demonstrated by radiographs of the symptomatic site. The diagnosis is established when culture of involved bone obtained by either open or needle biopsy has identified a variety of Candida species. Use of direct amplification testing has been reported.34 ­Treatment

with ketoconazole, itraconazole, or amphotericin B is effective.35,36 The use of surgical débridement must be individualized. With vertebral involvement but no neurologic complications, medication alone has been effective. Candidiasis is an uncommon cause of monarticular arthritis.37-41 Reported cases commonly involve a knee, occur in the context of multifocal extra-articular Candida infection, and are accompanied by constitutional symptoms. Both children and adults have been affected. Predisposing conditions include gastrointestinal and pulmonary disorders, narcotic addiction, intravenous catheters, leukopenia, immunosuppressive treatment, broad-spectrum antibiotics, and corticosteroids. Some involved joints were previously affected by arthritis, and infection has followed arthrocentesis in isolated cases. In most cases, radiographs reveal coincident osteomyelitis. Synovial fluid leukocyte counts may vary; Candida species have been cultured from synovial fluid in all cases but are not commonly identified on smear. Histologic studies of synovium show nonspecific chronic inflammation rather than granulomas. Muscle infection by Candida has also been reported in neutropenic patients, in the form of either diffuse myositis or localized abscess.42-44

SPOROTRICHOSIS Sporotrichosis is caused by Sporothrix schenckii, a saprophyte found widely in soil and plants. Infection in humans occurs through inoculation of the skin or, rarely, inhalation into the respiratory tract; it is a source of infection among ­agricultural

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Left

Figure 102-3  Cryptococcosis (torulosis). Discrete osteolytic foci with surrounding sclerosis and, in some places, periosteal reaction are seen (arrows). This involvement of bone protuberances, such as the calcaneus, is not unexpected in this disease. The resulting appearance simulates that of other fungal diseases, especially coccidioidomycosis, as well as neoplastic disorders. (From Resnick D: Diagnosis of Bone and Joint Disorders, 3rd ed. Philadelphia, WB Saunders, 1995, p 2507.)

B Figure 102-2  Blastomycosis joint infection. A, Radiographs commonly show punched-out bone lesions. B, Synovial histology shows epithelioid granulomas with budding yeast forms. (Courtesy of John Flaherty, MD, Feinberg School of Medicine, Northwestern University.)

workers in tropical and subtropical areas. It most commonly involves the skin and lymphatics but may disseminate from the lungs to the central nervous system, eyes, bones, and joints.45 In immunocompetent hosts, a single site is typically involved; in immunocompromised hosts, including patients on anticytokine therapy, multifocal disease may occur.46 In contrast to the relatively common occurrence of skin infection, articular sporotrichosis is a rare disorder.47,48 In 84% of patients in one series, there was no accompanying skin involvement, suggesting entry through the lungs. Sporotrichosis most often occurs in individuals with a chronic illness that alters host defense, such as alcoholism or a myeloproliferative disorder. Sporotrichosis arthritis is most often indolent and infects a single joint or multiple joints in equal proportions. The knee, hand, wrist, elbow, and shoulder are most frequently involved; hand and wrist involvement distinguishes this from other fungal arthritides. Articular infection shows a propensity to spread to adjacent soft tissues, forming draining sinuses. Constitutional symptoms are unusual. Radiographic changes vary from juxta-articular osteo­ penia to the commonly observed punched-out bone lesions.

When it is obtainable, synovial fluid is inflammatory. Synovitis is characterized on gross evaluation by destructive pannus and on microscopic examination by granulomatous histologic features or, less frequently, by nonspecific ­inflammation. Organisms are difficult to identify in tissue, and the diagnosis is often made by positive culture of joint fluid or involved tissue. Serologies may aid in the diagnosis of disseminated infection. In a small number of cases, sporotrichosis may disseminate to cause a potentially fatal infection characterized by low-grade fever, weight loss, anemia, osteolytic bone lesions, arthritis, skin lesions, and involvement of the eyes and central nervous system.49-52 These infections occur in immunosuppressed patients with either hematologic malignant neoplasias or HIV ­infection. In 44 cases reported in 1979, treatment was optimal with combined joint débridement and high-dose intravenous amphotericin B (11 of 11 cured) and slightly less effective with amphotericin alone (14 of 19 cured).47 Oral potassium iodide (5 of 15 cured) and other forms of treatment were not adequate. More recently, itraconazole has proved effective for initial therapy of most patients, with amphotericin B being reserved for those with extensive involvement and for itraconazole failures. In contrast, fluconazole has demonstrated only modest success in osteoarticular ­sporotrichosis.53,54

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Figure 102-4  Aspergillosis vertebral osteomyelitis and diskitis. A, Aspergillus may spread directly from the lung to adjacent vertebrae, disk spaces, and ribs (more often in children) or through the bloodstream. B, Infected tissue may show characteristic organisms. (Courtesy of John Flaherty, MD, ­Feinberg School of Medicine, Northwestern University.)

ASPERGILLOSIS Aspergillus species are ubiquitous, but infection occurs only rarely in normal individuals. In contrast, invasive infection is an important life-threatening complication in immunocompromised adults and children.55-57 It may spread directly from the lung to adjacent vertebrae, disk spaces, and ribs (more often in children) or through the bloodstream (Fig. 102-4).58-60 Rare cases of monarthritis with adjacent osteomyelitis are also reported.61 The organism may be observed in infected tissue (see Fig. 102-4B). Treatment with combined surgical débridement and antifungal therapy is an ongoing challenge.57,60 Voriconazole is superior to amphotericin in invasive pulmonary aspergillosis and appears to be the treatment of choice for all cases of invasive aspergillosis.62,63

HISTOPLASMOSIS Histoplasma capsulatum is a soil fungus that causes endemic disease in the midwestern and southeastern United States.24,64 Bone and joint involvement is rare but has been reported in the knee, wrist, and ankle. Immunosuppression, including the use of TNF antagonists, predisposes to disseminated histoplasmosis in adults and children, which may be confused clinically with sarcoidosis, tuberculosis, and reactive inflammatory conditions.65-67 Diagnosis depends on appropriate use of fungal staining and culture methods, antigen detection, and serologic antibody testing.68 A case

report emphasizes the rare occurrence of fungal prosthetic joint arthritis.69 The more common osteoarticular involvement with histoplasmosis is a hypersensitivity syndrome accompanying acute pulmonary infection; it is characterized by self-limited polyarthritis, erythema nodosum, and erythema multiforme. Amphotericin B is the preferred treatment for severe infection and itraconazole for less severe cases.70,71

SCEDOSPORIOSIS Scedosporium species are environmental molds that have recently been identified as fungal pathogens in both immunocompetent and immunocompromised hosts. They may cause focally invasive and disseminated infection after cutaneous inoculation. Scedosporium prolificans has a predilec­tion for bone and cartilage, leading to both septic arthritis and osteomyelitis. Infections are difficult to eradicate with surgery and antifungal agents.72,73 Case reports suggest improved infection control with voriconazole.74,75

TREATMENT OF FUNGAL INFECTION Antifungal chemotherapy has improved over the past several decades, first with the introduction of amphotericin B and then with the oral antifungal agents flucytosine, ketoconazole, fluconazole, and itraconazole. More recent advances include the development of less toxic formulations

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Table 102-2  Drug Treatment of Osteoarticular   Mycotic Infections Infection

Drug ­Recommended

Infection-Specific References

Coccidioidomycosis

Itraconazole*

6, 9–11

Blastomycosis

Itraconazole*

19, 20

Cryptococcosis

Fluconazole†

25, 28

Candidiasis

Fluconazole‡

35–41

Sporotrichosis

Itraconazole*

47, 53, 54

Aspergillosis

Voriconazole

56, 59

Histoplasmosis

Itraconazole

70, 71

Scedosporiosis

Voriconazole

72-75

*Amphotericin B is indicated for severe infections. †Amphotericin B plus 5-flucytosine is indicated for severe infections. ‡Caspofungin is indicated for infections due to Candida krusei and ­Candida glabrata.

of amphotericin B, liposomal amphotericin B, and amphotericin B lipid complex. Voriconazole and posaconazole, which are broad-spectrum antifungals, have demonstrated improved activity against aspergillosis and mucormycosis, respectively. The echinocandin antifungal agents caspofungin, micafungin, and anidulafungin have emerged as alternative therapies for aspergillosis and as the treatments of choice for some Candida infections. For detailed treatment guidelines, several excellent reviews are available.76-85 In choosing an appropriate drug (Table 102-2) and course of treatment, the clinician must consider the infecting agent, clinical manifestations of the disease, immune status of the host, antimicrobial resistance, drug side effect profile, and direct and indirect costs of treatment. Treatment has become more complex because of immune system compromise in infected patients being treated for transplant rejection, autoimmune disorders, malignant disease, and AIDS. In AIDS-related cases, after the initial control of infection, lifelong oral suppressive therapy is mandated by the high frequency of recurrence, although successful antiretroviral therapy may modify this risk.86 Itraconazole has become the first choice for treatment of the endemic mycoses—blastomycosis, histoplasmosis, and sporotrichosis. The initial dose is 200 mg/day, which should be increased to twice daily if a clinical response is not obtained in 2 to 3 weeks. At least 6 months of ­treatment is required, and some patients may need up to a year of therapy. For cryptococcosis, fluconazole is the recommended azole.25,28 Amphotericin B is the preferred drug for ­meningeal and lifethreatening infections. Specific treatment protocols and detailed side effect profiles are presented in reviews76-84 and infection-specific references (see Table 102-2). REFERENCES    1. Giles JT, Bathon JM: Serious infections associated with anticytokine therapies in the rheumatic diseases. J Intensive Care Med 19: 320-334, 2004.    2. Blair JE, Smilack JD, Caples SM: Coccidioidomycosis in patients with hematologic malignancies. Arch Intern Med 165:113-117, 2005.    3. Bialek R, Gonzalez GM, Begerow D, Zelck UE: Coccidioidomycosis and blastomycosis: Advances in molecular diagnosis. FEMS Immunol Med Microbiol 45:355-360, 2005.

    4. Chiller TM, Galgiani JN, Stevens DA: Coccidioidomycosis. Infect Dis Clin North Am 17:41-57, 2003.     5. Holley K, Muldoon M, Taskar S: Coccidioides immitis osteomyelitis: A case series review. Orthopedics 25:827-831, 2002.     6. Bayer AS, Guze LB: Fungal arthritis. II. Coccidioidal synovitis: Clinical, diagnostic, therapeutic, and prognostic considerations. Semin Arthritis Rheum 8:200-211, 1979.     7. Stadalnik RC, Goldstein E, Hoeprich PD, et al: Diagnostic value of gallium and bone scans in evaluation of extrapulmonary coccidioidal lesions. Am Rev Respir Dis 121:673-676, 1980.     8. Galgiani JN, Ampel NM, Blair JE, et al: Treatment guidelines for coccidioidomycosis. Clin Infect Dis 41:1217-1223, 2005.     9. Bried JM, Galgiani JN: Coccidioides immitis infections in bones and joints. Clin Orthop Relat Res 211:235-243, 1986. 10. Galgiani JN, Catanzaro A, Cloud GA, et al: Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis: A randomized, double-blind trial. Ann Intern Med 133:676-686, 2000.   11. Graybill JR, Stevens DA, Galgiani JN, et al: Itraconazole treatment of coccidioidomycosis. Am J Med 89:282-290, 1990.   12. Smith CE: Coccidioidomycosis. Pediatr Clin North Am 62:109-125, 1955.   13. Bradsher RW, Chapman SW, Pappas PG: Blastomycosis. Infect Dis Clin North Am 17:21-40, 2003.   14. Bayer AS, Scott VJ, Guze LB: Fungal arthritis. IV. Blastomycotic arthritis. Semin Arthritis Rheum 9:145-151, 1979.   15. MacDonald PB, Black GB, MacKenzie R: Orthopaedic manifestations of blastomycosis. J Bone Joint Surg Am 72:860-864, 1990.   16. Pritchard DJ: Granulomatous infections of the bones and joints. Orthop Clin North Am 6:1029-1047, 1975.   17. Saccente M, Abernathy RS, Pappas PG, et al: Vertebral blastomycosis with paravertebral abscess: Report of eight cases and review of the literature. Clin Infect Dis 26:413-418, 1998.   18. Abril A, Campbell MD, Cotten VR, et al: Polyarticular blastomycotic arthritis. J Rheumatol 25:1019-1021, 1998.   19. Bradsher RW: Therapy of blastomycosis. Semin Respir Infect 12: 263-267, 1997. 20. Chapman SW, Bradsher RW Jr, Campbell DG, et al: Practice guidelines for the management of patients with blastomycosis. Clin Infect Dis 30:679-683, 2000.   21. Levitz SM: The ecology of Cryptococcus neoformans and the epidemiology of cryptococcosis. J Infect Dis 13:1163-1169, 1991.   22. True DG, Penmetcha M, Peckham SJ: Disseminated cryptococcal infection in rheumatoid arthritis treated with methotrexate and in­fliximab. J Rheumatol 29:1561-1563, 2002.   23. Behrman RE, Masci JR, Nicholas P: Cryptococcal skeletal infections: Case report and review. Rev Infect Dis 12:181-190, 1900.   24. Bayer AS, Choi C, Tillman DB, Guze LB: Fungal arthritis. V. Cryptococcal and histoplasmal arthritis. Semin Arthritis Rheum 9:218-227, 1980.   25. Bruno KM, Farhoomand L, Libman BS, et al: Cryptococcal arthritis, tendonitis, tenosynovitis, and carpal tunnel syndrome: Report of a case and review of the literature. Arthritis Rheum 47:104-108, 2002   26. Gave AA, Torres R, Kaplan L: Cryptococcal myositis and vasculitis: An unusual necrotizing soft tissue infection. Surg Infect 5:309-313, 2004.   27. Basaran O, Emiroglu R, Arikan U, et al: Cryptococcal necrotizing fasciitis with multiple sites of involvement in the lower extremities. Dermatol Surg 29:1158-1160, 2003. 28. Saag MS, Graybill RJ, Larsen RA, et al: Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis 30:710-718, 2000.   29. Edwards JE Jr: Candida species. In Mandell GL, Bennett JE, Dolin R (eds): Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. Philadelphia, Churchill Livingstone, 2000, pp 2656-2674.   30. McCullers JA, Flynn PM: Candida tropicalis osteomyelitis: Case report and review. Clin Infect Dis 26:1000-1001, 1998.   31. Arias F, Mata-Essayag S, Landaeta ME, et al: Candida albicans osteomyelitis: Case report and literature review. Int J Infect Dis 8:307-314, 2004.   32. Lafont A, Olive A, Gelman M, et al: Candida albicans spondylodiscitis and vertebral osteomyelitis in patients with intravenous heroin drug addiction: Report of 3 new cases. J Rheumatol 21:953-956, 1994.

PART 17    33. Chia SL, Tan BH, Tan CT, Tan SB: Candida spondylodiscitis and epidural abscess: Management with shorter courses of anti-fungal therapy in combination with surgical debridement. J Infect 51:17-23, 2005.   34. Harrington JT: The evolving role of direct amplification tests in diagnosing osteoarticular infections caused by mycobacteria and fungi. Curr Opin Rheumatol 11:289-292, 1999.   35. Martin MV: The use of fluconazole and itraconazole in the treatment of Candida albicans infections: A review. J Antimicrob Chemother 44:429-437, 1999. 36. Pappas PG, Rex JH, Sobel JD, et al: Guidelines for treatment of candidiasis. Clin Infect Dis 38:161-189, 2004.   37. Bayer AS, Guze LB: Fungal arthritis. I. Candida arthritis: Diagnostic and prognostic implications and therapeutic considerations. Semin Arthritis Rheum 8:142-150, 1978.   38. Barson WJ, Marcon MJ: Successful therapy of Candida albicans arthritis with a sequential intravenous amphotericin B and oral fluconazole regimen. Pediatr Infect Dis J 15:1119-1122, 1996.   39. Weers-Pothoff G, Havermans JF, Kamphuis J, et al: Candida tropicalis arthritis in a patient with acute myeloid leukemia successfully treated with fluconazole: Case report and review of the literature. Infection 25:109-111, 1997.   40. Evdoridou J, Roilides E, Bibashi G, et al: Multifocal osteoarthritis due to Candida albicans in a neonate: Serum level monitoring of liposomal amphotericin B and literature review. Infection 25:112-116, 1997.   41. Fraucher J-F, Thiebaut M-M, Reynes J, et al: Unusual outcome of disseminated candidiasis treated with fluconazole: A matter of pharmacodynamics. Clin Infect Dis 26:197-198, 1998.   42. Arena FP, Perlin M, Brahman H: Fever, rash, and myalgias of disseminated candidiasis during antifungal therapy. Arch Intern Med 141:1233, 1981.   43. Fornadley JA, Parker GS, Rickman LS, et al: Candida myositis manifesting as a discrete neck mass. Otolaryngol Head Neck Surg 102: 74-76, 1990.   44. Behar SM, Chertow GM: Olecranon bursitis caused by infection with Candida lusitaniae. J Rheumatol 25:598-600, 1998.   45. Morris-Jones R: Sporotrichosis. Clin Exp Dermatol 27:427-431, 2002.   46. Gottlieb GS, Lesser CF, Holmes KK, Wald A: Disseminated sporotrichosis associated with treatment with immunosuppressants and tumor necrosis factor-α antagonists. Clin Infect Dis 37:838-840, 2003.   47. Bayer AS, Scott VJ, Guze LB: Fungal arthritis. III. Sporotrichal arthritis. Semin Arthritis Rheum 9:66-74, 1979.   48. Crout JE, Brewer NS, Tompkins RB: Sporotrichosis arthritis: Clinical features in seven patients. Ann Intern Med 86:294-297, 1977.   49. Wilson DE, Mann JJ, Bennett JE, Utz JP: Clinical features of extracutaneous sporotrichosis. Medicine (Baltimore) 46:265-279, 1967.   50. Lynch PJ, Voorhees JJ, Harrell ER: Systemic sporotrichosis. Ann Intern Med 73:23-30, 1970.   51. Oscherwitz SL, Rinaldi MG: Disseminated sporotrichosis in a patient infected with human immunodeficiency virus. Clin Infect Dis 15: 568-569, 1992.   52. al-Tawfiq JA, Wools KK: Disseminated sporotrichosis and Sporothrix schenckii fungemia as the initial presentation of immunodeficiency infection. Clin Infect Dis 26:1403-1406, 1998.   53. Sharkey-Mathis PK, Kauffman CA, Graybill JR, Stevens DA: Treatment of sporotrichosis with itraconazole: Am J Med 95:279-285, 1993. 54. Kauffman CA, Hajjeh R, Chapman SW: Practice guidelines for management of patients with sporotrichosis. For the Mycoses Study Group, Infectious Diseases Society of America. Clin Infect Dis 30:684-687, 2000.  55. Cuellar ML, Silveira LH, Espinoza LR: Fungal arthritis. Ann Rheum Dis 51:690-697, 1992.  56. Kontoyiannis DP, Bodey GP: Invasive aspergillosis in 2002: An update. Eur J Microbiol Infect Dis 21:161-172, 2002.  57. Dotis J, Roilides E: Osteomyelitis due to Aspergillus spp. in patients with chronic granulomatous disease: Comparison of Aspergillus nidulans and Aspergillus fumigatus. Int J Infect Dis 8:103-110, 2004.  58. Pasic S, Abinun M, Pistignjat B, et al: Aspergillus osteomyelitis in chronic granulomatous disease: Treatment with recombinant gammainterferon and itraconazole. Pediatr Infect Dis J 15:833-834, 1996.  59. Vinas FC, King PK, Diaz FG: Spinal aspergillus osteomyelitis. Clin Infect Dis 28:1223-1229, 1999.  60. Paterson DL: New clinical presentations of invasive aspergillosis in nonconventional hosts. Clin Microbiol Infect 10(Suppl 1):24-30, 2004.

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1745

  61. Steinfeld S, Durez P, Hauzeur J-P, et al: Articular aspergillosis: Two case reports and review of the literature. Br J Rheumatol 36: 1331-1334, 1997. 62. Perfect JR, Marr KA, Walsh TJ, et al: Voriconazole treatment for less-common, emerging, or refractory fungal infections. Clin Infect Dis 36:1122-1131, 2003.   63. Stratov I, Korman TM, Johnson PD: Management of aspergillus osteomyelitis: Report of failure of liposomal amphotericin B and response to voriconazole in an immunocompetent host and literature review. Eur Clin Microbiol Infect Dis 22:277-283, 2003.   64. Wheat J: Histoplasmosis: Recognition and treatment. Clin Infect Dis 19(Suppl 1):S19-S27, 1994.   65. Weinberg JM, Ali R, Badve S, Pelker RR: Musculoskeletal histoplasmosis: A case report and review of the literature. J Bone Joint Surg Am 83:1718-1722, 2001.   66. Lee JH, Slifman NR, Gershon SK, et al: Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Arthritis Rheum 46: 2565-2570, 2002.   67. Wood KL, Hage C, Knox KS, et al: Histoplasmosis after treatment with anti-tumor necrosis factor-α therapy. Am J Respir Crit Care Med 167:1279-1282, 2003.   68. Wheat LJ: Laboratory diagnosis of histoplasmosis: Update 2000. Semin Respir Infect 16:131, 2001.   69. Fowler VG, Nacinovich FM, Alspaugh JA, et al: Prosthetic joint infection due to Histoplasma capsulatum: Case report and review. Clin Infect Dis 26:1017, 1998. 70. Wheat J, Sarosi G, McKinsey D, et al: Practice guidelines for management of patients with histoplasmosis. Infectious Diseases ­Society of America. Clin Infect Dis 30:688-695, 2000.   71. Mocherla S, Wheat JL: Treatment of histoplasmosis. Semin Respir Infect 16:141-148, 2001.   72. Wilson CM, O’Rourke EJ, McGinnis MR, Salkin IF: Scedosporium inflatum: Clinical spectrum of a newly recognized pathogen. J Infect Dis 161:102-107, 1990.   73. Levine NB, Kurokawa R, Fichtenbaum CJ, et al: An immunocompetent patient with primary Scedosporium apiospermum vertebral osteomyelitis. J Spinal Disord Tech 15:425-430, 2002.   74. Steinbach WJ, Schell WA, Miller JL, Perfect JR: Scedosporium prolificans osteomyelitis in an immunocompetent child treated with voriconazole and caspofungin, as well as locally applied polyhexamethylene biguanide. J Clin Microbiol 41:3981-3985, 2003.   75. Studahl M, Backteman T, Staulhammar F, et al: Bone and joint infection after traumatic implantation of Scedosporium prolificans treated with voriconazole and surgery. Acta Paediatr 92:980-982, 2003.   76. Terrell CL, Hughes CE: Antifungal agents used for deep-seated mycotic infections. Mayo Clin Proc 67:69-91, 1992.   77. Sarosi GA, Davies SF: Therapy for fungal infections. Mayo Clin Proc 69:1111-1117, 1994.   78. Meier JL: Mycobacterial and fungal infections of the bones and joints. Curr Opin Rheumatol 6:408-414, 1994.   79. Martino P, Girmenia C: Are we making progress in antifungal therapy? Curr Opin Oncol 9:314-320, 1997.   80. Perez-Gomez A, Prieto A, Torresano M, et al: Role of the new azoles in the treatment of fungal osteoarticular infections. Semin Arthritis Rheum 27:226-244, 1998.   81. Rapp RP, Gubbins PO, Evans ME: Amphotericin B lipid complex. Ann Pharmacother 31:1174-1186, 1997.   82. Alexander BD, Perfect JR: Antifungal resistance trends toward the year 2000: Implications for therapy and new approaches. Drugs 54:657-678, 1997.   83. Espinel-Ingroff A: Clinical relevance of antifungal resistance. Infect Dis Clin North Am 11:929-944, 1997.   84. Summers KK, Hardin TC, Gore SJ, Graybill JR: Therapeutic drug monitoring of systemic antifungal therapy. J Antimicrob Chemother 40:753-764, 1997.   85. Mora-Duarte J, Bettis R, Rotstein C, et al: Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 347:20202029, 2002.   86. Currier JS, Williams PL, Koletar SL, et al: Discontinuation of Mycobacterium avium complex prophylaxis in patients with anti-retroviral therapy-induced increases in CD4+ cell count: A randomized doubleblind, placebo-controlled trial. AIDS Clinical Trials Study Group 362 Study Team. Ann Intern Med 133:493-503, 2000.

103

KEY POINTS With patients with human immunodeficiency virus (HIV) living longer as a result of more effective and available treatments, the challenges of HIV-associated rheumatic manifestations are growing. Certain diseases seem to be particular to HIV infection (i.e., HIV-associated arthritis, diffuse infiltrative lymphocytosis syndrome [DILS], HIV-associated polymyositis). Other diseases, specifically CD4-mediated diseases such as rheumatoid arthritis and systemic lupus erythematosus, tend to go into remission with disease activity and flare with antiretroviral treatment. Effective antiretroviral therapy has resulted in certain diseases (i.e., DILS, late opportunistic infections) decreasing in prevalence, but also is associated with new side effects (e.g., osteonecrosis, myopathy, rhabdomyolysis). With immune reconstitution after antiretroviral therapy, a new spectrum of autoimmune and autoinflammatory disease has emerged requiring special attention.

In the years since acquired immunodeficiency ­ syndrome (AIDS) was initially described in 1981, the human immunodeficiency virus (HIV) pandemic has become one of the leading global health crises. According to new data in the UNAIDS 2006 report, the AIDS epidemic seems to be ­ slowing down globally, but new cases are continuing to increase at alarming rates in certain regions, such as southern Africa, Eastern Europe, and central and eastern Asia. An estimated 39 million people are living with HIV worldwide (Fig. 103-1). Approximately 4.1 million people became newly infected with HIV in 2005, and 2.8 million people died. More than 92% of new cases occur in ­developing countries. Progress in dealing with the HIV epidemic, including in education and public health awareness, has undoubtedly influenced the decrease in prevalence seen among young people in some countries in recent years. As availability of newer treatment strategies and better access to health care result in increased life expectancy in the next decade, it is expected that HIV infection increasingly will be managed as a chronic illness, and complications such as musculoskeletal and rheumatic conditions associated with HIV infection and its treatment are expected to increase (Table 103-1). Among the rheumatologic disorders, clinicians face the challenge of treating potentially disabling inflammatory disorders with immunosuppressive therapy in the face of ongoing viral-induced immunocompromise. Diagnosing infection is especially important in an immunocompromised patient because the probability of an opportunistic ­infection

Rheumatic Manifestations of Human Immunodeficiency Virus Infection john D. reveille  •  rashmi m. maganti

as a cause for a musculoskeletal complaint increases with advancing stages of the patient’s HIV disease. At early stages (CD4+ count >300/μL), opportunistic infections are unlikely, although bacterial infections (especially tuberculosis) still can occur. There should be a very high threshold to using immunosuppressive drugs in this population.

HUMAN IMMUNODEFICIENCY VIRUS– ASSOCIATED BONE AND JOINT DISEASE HUMAN IMMUNODEFICIENCY VIRUS–ASSOCIATED ARTHRALGIA Forty-five percent of HIV-positive patients may have otherwise unexplained arthralgia (Table 103-2); arthralgias and myalgias also form a part of the constitutional symptoms of HIV seroconversion. Whether the arthralgia can be attributed to circulating viral and host immune complexes owing to HIV infection per se or to other infections (e.g., hepatitis C) has not been determined. The pathogenesis is unclear, but may involve cytokines or transient bone ischemia.1 Patients presenting with arthralgia alone rarely progress to inflammatory joint disease, however. The most appropriate treatment is non-narcotic analgesics and reassurance. PAINFUL ARTICULAR SYNDROME Painful articular syndrome is a self-limited syndrome lasting less than 24 hours, associated with few objective clinical findings, and characterized by severe bone and joint pain.2 It occurs predominantly in the late stages of HIV infection. Its etiology is unknown, and there is no evidence of synovitis in these patients. The knee is most commonly affected, but the elbow and shoulders also can be involved. Radiographic features are nonspecific; occasionally, periarticular osteopenia is seen. Treatment is symptomatic. HUMAN IMMUNODEFICIENCY VIRUS–ASSOCIATED ARTHRITIS The first reports of a seronegative arthritis associated with HIV infection appeared in 1988, with frequencies of 12% (Table 103-3). HIV-associated arthritis seems to be most common in sub-Saharan Africa, where HIV infection is pandemic. In the Congo, where the seroprevalence of HIV infection is 7% to 8%, AIDS is the leading cause of aseptic arthritis (60% of cases).3 This is usually an oligoarthritis, 1747

1748 REVEILLE  |  Rheumatic Manifestations of Human Immunodeficiency Virus Infection

Adult prevalence 15.0 - 34.0% 5.9 - 15.0% 1.0 - <5.0% 0.5 - <1.0% 0.1 - <0.5% <0.1%

Figure 103-1  A global view of human immunodeficiency virus (HIV) infection—39 million living with HIV in 2005. (Extracted from 2006 Report on the Global AIDS Epidemic. UNAIDS, 2006.)

predominantly involving the lower extremities, and tends to be self-limited, lasting less than 6 weeks.2,4 Most commonly involved are the knees (84%), ankles (59%), and metatarsophalangeal joints (23%) in the lower limbs and the wrists (41%), elbows (29%), and metacarpophalangeal and interphalangeal joints (25%) in the upper limbs, similar to other viral arthritides. Some patients have been reported as having a longer course, however, with joint destruction.5,6

The etiology is unclear; there is no association with HLA-B27 or any other known genetic factor. Synovial fluid cultures are typically sterile, although one report described the presence of tubuloreticular inclusions, suggesting a viral etiology, possibly HIV itself.2,4 Radiographs of the affected joints are usually normal except in uncommon cases with prolonged symptoms, in which joint space narrowing and destruction can occur. Treatment includes nonsteroidal

Table 103-1  Rheumatic Diseases Associated with or Occurring in Patients with Human Immunodeficiency   Virus (HIV) Infection Unique to HIV Infection

Encountered in HIV-Infected Patients

Ameliorated by HIV Infection but Worsening or Reappearing with IRIS

Diffuse infiltrative leukocytosis syndrome

HIV-associated Reiter’s syndrome

Rheumatoid arthritis

HIV-associated arthritis

Polymyositis

Systemic lupus erythematosus

Zidovudine-associated myopathy

Psoriatic arthritis

Painful articular syndrome

Polyarteritis nodosa Giant cell arteritis Hypersensitivity angiitis Wegener’s granulomatosis Henoch-Schönlein purpura Behçet’s syndrome Infectious arthritis (bacterial, fungal)

IRIS, immune reconstitution inflammatory syndrome.

Table 103-2  Distribution of Various Rheumatic Diseases from Various Sites Feature

Cincinnati, Ohio

Houston, Texas

Madrid, Spain

No. patients

1100

4467

556

HIV-associated arthralgia

NA

0.7%

1.6%

Myalgia

0.7%

0.6%

4.5%

PsA/Reiter’s syndrome

0.5%

0.6%

0.5%

HIV-associated arthritis

0%

0.47%

0.4%

DILS/Sjögren’s syndrome

NR

3%-4%

NR

DILS, diffuse infiltrative lymphocytosis syndrome; HIV, human immunodeficiency virus; NA, not applicable; NR, not reported; PsA, psoriatic arthritis.

PART 17 

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INFECTION AND ARTHRITIS 1749

Table 103-3  Contrasting Features of Human Immunodeficiency Virus (HIV)–Associated Arthritis   and Reiter’s Syndrome Feature

HIV-Associated Arthritis

HIV-Associated Reactive Arthritis

Joint involvement

Asymmetric oligoarthritis/polyarthritis

Asymmetric oligoarthritis/polyarthritis

Mucocutaneous involvement

Absent

Present

Enthesopathy

Absent

Frequent

Synovial fluid white blood cell count

500-2000/μL

2000-10,000/μL

Synovial fluid cultures

Negative

Negative

Microorganisms in synovial membranes

HIV-1 virus (?)

Chlamydia*

HLA-B27 association

Absent

70%-90%†

*Shown in non–HIV-associated Reiter’s syndrome. Reports of such infections in patients with HIV-associated Reiter’s syndrome are lacking. †In whites.

anti-inflammatory drugs (NSAIDs) and, in more severe cases, low-dose glucocorticoids. Hydroxychloroquine and sulfasalazine also have been used.7 REACTIVE ARTHRITIS OCCURRING IN HUMAN IMMUNODEFICIENCY VIRUS INFECTION Early reports in the United States suggested that reactive arthritis occurred more commonly in the setting of HIV infection; however, later studies showed that this may be reflective of the sexually active nature of the population at highest risk for HIV infection.8 This contention is not borne out in studies from sub-Saharan Africa, where HLA-B27 is rare, as were reports of spondyloarthritis before the HIV epidemic. With the arrival of AIDS, a dramatic upsurge in the prevalence of reactive arthritis and undifferentiated spondyloarthritis, and less often psoriatic arthritis,6,9 was seen, suggesting a pathogenic role of HIV infection. The typical presentation is a seronegative lower extremity peripheral arthritis, usually accompanied by enthesitis (sausaging of toes or fingers, Achilles tendinitis, and plantar fasciitis). Mucocutaneous features are common, especially keratoderma blennorrhagicum (Fig. 103-2) and circinate balanitis. Extensive psoriaform skin rashes can occur. The clinical overlap makes it difficult sometimes to distinguish HIV-associated reactive arthritis from psoriatic arthritis.10 Urethritis occurs in similar frequency as in HIV-negative reactive arthritis. Axial involvement and uveitis seem to be less common, but do occur. Longitudinal studies from Africa have described an aggressive course with a poor prognosis.11,12 HLA-B27 is found in 80% to 90% of patients with HIVassociated reactive arthritis, at least in whites.10 Studies from Africa have found most to be HLA-B27 negative, however.6,9 Some studies suggest the presence of HLA-B27 antigen may slow the progression to AIDS.11,12 In asymptomatic HIV-infected, HLA-B27–positive individuals, cytotoxic T lymphocyte response is dominated by recognition of a gagencoded p24 protein epitope that is not seen in HIV-positive, HLA-B27–negative individuals.13,14 Other HLA class I antigens that have been associated with a better outcome in HIV infection also have been implicated in psoriasis and psoriatic arthritis and include HLA-B13 and HLA-B17 (B57, B58).12,13 HLA-B*2703 was protective against HIV progression in a Zambian population.15

Figure 103-2  Keratoderma blennorrhagicum in a patient with Reiter’s syndrome and human immunodeficiency virus infection.

Treatment The treatment is similar to that for HIV-negative patients with reactive arthritis. NSAIDs are the mainstay; in particular, indomethacin is recommended, not only for its efficacy, but also for its inhibition of HIV replication that has been observed in vitro, which seems to be unique to this NSAID.16 Patients frequently have an inadequate response to NSAIDs alone. Sulfasalazine has been shown to be effective in some studies at doses of 2 g/day, and one study suggested that it ameliorated HIV infection.17,18 Methotrexate was initially believed to be contraindicated because of its immunosuppressive effect, but with careful monitoring of HIV viral loads, CD4+ counts, and the patient’s clinical ­status, more recent studies have suggested a place for methotrexate in the treatment of reactive arthritis and psoriatic arthritis occurring in HIV infection.19

1750 REVEILLE  |  Rheumatic Manifestations of Human Immunodeficiency Virus Infection

although with the usual cautions (see earlier) because frequent polymicrobial infections while on the drug resulted in its discontinuation in some patients.30

Hydroxychloroquine also has been reported to be e­ fficacious not only in treating HIV-associated reactive arthritis, but also in reducing HIV replication in vitro and in reducing HIV viral loads in vivo.20 The arthritis and the ­cutaneous lesions of HIV-associated reactive arthritis and psoriatic arthritis have been found to respond to etretinate (0.5 to 1 mg/kg/day),21 although because of the side effects of this drug, its use should be reserved for patients unresponsive to other treatments. Tumor necrosis factor blockers also have been used,22,23 although these agents should be used with extreme caution and only in patients with CD4+ counts greater than 200 mm3 and HIV viral load less than 60,000 copies/mm3.24,25

Symptoms of reactive arthritis or psoriatic arthritis are found in patients who do not otherwise develop full-blown disease, such as enthesopathy (plantar fasciitis, ­ Achilles tendinitis).31 The treatment is symptomatic (NSAIDs, intralesional corticosteroid injections), although sulfasalazine should be considered in patients with more extensive disease.

PSORIASIS AND PSORIATIC ARTHRITIS

AVASCULAR NECROSIS OF BONE

The psoriatic rash can be extensive (Fig. 103-3) in HIVpositive patients, especially in patients not on antiretroviral treatment.26 A report from Zambia found 27 of 28 African patients with psoriatic arthritis to be HIV positive.27 The arthritis was predominantly polyarticular, lower limb, and progressive. Psoriasis was commonly an extensive guttateplaque admixture and, in contrast to the articular disease, was nonremittive with onset of AIDS.28 Antiretroviral treatment has been shown to be effective in treating HIVassociated psoriasis and its associated arthritis.29 Phototherapy may improve the skin rash, but also may enhance viral ­replication and worsen HIV disease. Other agents reported to be efficacious include cyclosporine (although renal function must be monitored carefully) and etretinate. Methotrexate also can be used, albeit with caution.19 Tumor necrosis factor blockers may be used in patients with ­refractory disease,

Most cases of osteonecrosis have occurred after the introduction of highly active antiretroviral therapy (HAART).32 Dyslipidemia associated with protease inhibitors has been implicated most frequently, although there have been no controlled studies to establish if antiretroviral drugs per se predispose to this.33 Other contributing factors include alcohol abuse and use of corticosteroids, megestrol acetate, and antiphospholipid antibodies.34 The most common presenting symptom of osteonecrosis is pain on weight bearing and activity.35 Some patients may be asymptomatic, and the diagnosis is made based on incidental findings in ­radiologic studies. Most patients tend to present when subchondral collapse already has occurred. Radiographs, computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine studies have been used successfully to diagnose osteonecrosis, as in HIV-negative patients.

UNDIFFERENTIATED SPONDYLOARTHRITIS

HYPERTROPHIC PULMONARY OSTEOARTHROPATHY Hypertrophic pulmonary osteoarthropathy affects bones, joints, and soft tissues and can develop in HIV-infected patients with Pneumocystis carinii pneumonia. It is characterized by severe pain in the lower extremity; digital clubbing; arthralgia; nonpitting edema; and periarticular soft tissue involvement of the ankle, knees, and elbows. The skin over the affected areas is glistening, edematous, and warm. Radiography reveals extensive periosteal reaction and subperiosteal proliferative changes in the long bones of the lower extremity. A bone scan shows increased uptake along the cortical surfaces. Treatment of P. carinii pneumonia usually alleviates this condition.36 OSTEOPENIA AND OSTEOPOROSIS

Figure 103-3  Disseminated psoriasis vulgaris in a patient with human immunodeficiency virus–associated psoriasis.

Osteopenia and osteoporosis occur more than three times as commonly in HIV-infected patients regardless of antiretroviral treatment37 and can result in pathologic fractures. Abnormal bone metabolism was attributed to the HIV infection itself by some authors.38 Risk factors for the development of osteopenia are use of protease inhibitors, longer duration of HIV infection, high viral load, high lactate levels, low bicarbonate levels, increased alkaline phosphatase level, and lower body weight before antiretroviral therapy.39 Bisphosphonates and, in patients with HIV wasting syndrome, ­ testosterone have been used to preserve bone density.40

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HUMAN IMMUNODEFICIENCY VIRUS–ASSOCIATED MUSCLE DISEASE Muscle involvement in HIV infection varies from uncomplicated myalgias or asymptomatic creatine kinase elevation to severe, disabling, HIV-associated polymyositis or pyomyositis. HIV seroconversion also can coincide with myoglobinuria and acute myalgia, suggesting that myotropism for HIV may be present early in the infection. MYALGIA AND FIBROMYALGIA One third of HIV-positive outpatients complain of myalgias,41 and 11% complain of fibromyalgia.42 Fibromyalgia is associated with longer disease duration and a history of depression. Treatment is similar to that for fibromyalgia in the non-HIV setting. NONINFLAMMATORY NECROTIZING MYOPATHY AND HUMAN IMMUNODEFICIENCY VIRUS–RELATED WASTING SYNDROME Severe wasting from chronic infections, malignancy, malabsorption, and nutritional deficiency often accounts for weakness and disability in patients with AIDS. This wasting leads to loss of lean body and muscle mass. Cachexia and muscle wasting associated with HIV is called “slim’s disease” in Africa. A noninflammatory necrotizing myopathy of unclear pathogenesis has been described, accounting for 42% of patients diagnosed with myopathy.43 Even in patients without significant wasting, muscle biopsy ­specimens have shown diffuse atrophy, mild neurogenic atrophy, or thick filament loss without conspicuous inflammation. Whether this condition is immune mediated, as some have suggested,44 or due to metabolic or nutritional factors is unclear. Corticosteroids have been reported to restore muscle strength and mass.45 NEMALINE MYOPATHY Nemaline myopathy is a rare disorder that has been described in some HIV-positive patients, in addition to occurring as a congenital disorder. Nemaline myopathy represents a nonspecific myofibril alteration resulting from Z band disruption.46 Muscle biopsy specimens disclose prominent, randomly distributed atrophic type 1 fibers with numerous intracytoplasmic rod bodies in the centers of the fibers, corresponding to nemaline rods at electron microscopy. Necrotic fibers and inflammatory infiltrates usually are not found. Some patients have been described to have associated monoclonal gammopathy.47 Although there is no inflammation, corticosteroids may be useful.

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INFECTION AND ARTHRITIS 1751

s­ uggested in one pathologic study,49 or from an autoimmune response of the HIV host, as suggested by another study.50 The most common manifestation is a subacute, progressive proximal muscle weakness occurring in the setting of an elevated creatine kinase. Myalgia is not a prominent presenting feature. Skin involvement is unusual, as is involvement of extraocular muscles and facial muscles.51 On MRI, T2-weighted studies with or without fat saturation show high signal intensity without rim enhancement, in contrast to in pyomyositis, in which rim enhancement is seen.52 MRI also is helpful in guiding muscle biopsy, the definitive diagnostic test. Electromyographic studies reveal myopathic motor unit potentials with early recruitment and full interference patterns and fibrillation potentials, positive sharp waves, and complex repetitive discharges indicative of an irritative process. Light microscopy of muscle biopsy specimens shows interstitial inflammatory infiltrates of variable intensity accompanied by degenerating and regenerating myofibrils, similar to those seen in polymyositis without HIV-1 (Fig. 103-4). Concomitant vasculitis rarely occurs. In specimens from HIV-positive and HIV-negative patients with myositis, the predominant cell populations were CD8+ T cells and macrophages invading or surrounding healthy muscle fibers that express major histocompatibility complex (MHC) class I antigens on their cell surfaces.53 The endomysial infiltrates in specimens from HIV-positive patients differed from patients with polymyositis without HIV infection only by a significant reduction of CD4+ cells.50 Treatment is similar to that for other inflammatory myopathies. The creatine kinase elevation and the ­muscle weakness respond to moderate-dose glucocorticoids.48 Refractory cases may require immunosuppressive agents, such as methotrexate, azathioprine, or mycophenolate mofetil. Intravenous immunoglobulin has been used with some success. These agents should be used with caution, however, with careful monitoring of the patient’s clinical status, CD4+ counts, and HIV mRNA levels (Table 103-4). Creatine kinase elevation is commonly encountered in outpatients with HIV infection, secondary to HIV per se, behaviors associated with higher risk for HIV infection (e.g., cocaine use), or HIV treatment.48 In most patients, these elevations are transient and of little consequence, but they require careful follow-up for any sign of clinical deterioration before electrodiagnostic and biopsy studies are undertaken.

HUMAN IMMUNODEFICIENCY VIRUS–ASSOCIATED POLYMYOSITIS HIV-associated polymyositis most typically manifests early in the course of HIV infection and may be the presenting feature. In one large series of HIV-positive outpatients from a county clinic in Texas, the frequency was 2.2/1000.48 The pathogenesis of HIV-associated polymyositis is unclear— possibly stemming from direct viral invasion (leading to a cytopathic effect and subsequent muscle necrosis), as

Figure 103-4  Muscle biopsy specimen from a patient with human immunodeficiency virus–associated polymyositis.

1752 REVEILLE  |  Rheumatic Manifestations of Human Immunodeficiency Virus Infection

Table 103-4  Myopathies Associated with Human Immunodeficiency Virus (HIV) Infection HIV-Associated Myopathies

Myopathies Secondary to Antiretrovirals

Others

HIV polymyositis

Zidovudine myopathy

Opportunistic infections involving muscle

Inclusion-body myositis

Toxic mitochondrial myopathies related   to other NRTIs

Tumor infiltrations of skeletal muscle

Nemaline myopathy

HIV-associated lipodystrophy syndrome

Rhabdomyolysis

Diffuse infiltrative lymphocytosis syndrome

Immune restoration syndrome related   to HAART

HIV-wasting syndrome Vasculitic processes Myasthenia gravis and other myasthenic ­  syndromes Chronic fatigue and fibromyalgia HAART, highly active antiretroviral therapy; NRTIs, nucleoside-analogue reverse-transcriptase inhibitors.

INCLUSION BODY MYOSITIS Inclusion body myositis has been recognized as a complication of HIV infection.54 This condition is clinically, histologically, and immunologically identical to sporadic inclusion body myositis. Muscle biopsy specimens suggest two concurrently ongoing processes—an autoimmunemediated process by cytotoxic T cells and a degenerative process manifested by the vacuolated muscle fibers and deposits of amyloid-related proteins. Of particular interest has been the finding of elevated mRNA levels and constitutive expression of Toll-like receptor 3, which is known to mediate inflammatory stimuli from pathogens and endogenous danger signals and to link the innate and adaptive immune system, in muscle fibers of patients with HIV-associated inclusion body myositis in close proximity of infiltrating mononuclear cells.55 MYOPATHY ASSOCIATED WITH TREATMENT A reversible toxic mitochondrial myopathy occurring in patients who received high doses of zidovudine has been described, which manifests as myalgias, muscle tenderness, and proximal muscle weakness mimicking HIV polymyositis.56 Histologically, it is characterized by the presence of ragged red fibers, a term coined to designate atrophic ragged red fibers with marked myofibril alterations, including thick myofilament loss and cytoplasmic body formation,57 and minimal inflammatory infiltrates. The symptoms tend to improve as the drug is discontinued, with creatine kinase levels returning to normal within 4 weeks of discontinuing the drug, and muscle strength returning within 8 weeks. In any HIV-infected patient presenting with an elevated creatine kinase, especially when symptoms of myalgia or muscle weakness are present, zidovudine should be discontinued for 4 weeks and the patient re-evaluated before electromyography or muscle biopsies are undertaken. RHABDOMYOLYSIS Rhabdomyolysis can occur at all stages of HIV infection and may be separated into three groups: (1) HIV-­associated rhabdomyolysis, including rhabdomyolysis in primary HIV infection, recurrent rhabdomyolysis, and isolated ­rhabdomyolysis; (2) drug-induced rhabdomyolysis; and (3) rhabdomyolysis at

the end stage of AIDS, associated or not with opportunistic infections of muscle. Drugs implicated in rhabdomyolysis in HIV patients include didanosine, lamivudine, trimethoprimsulfamethoxazole, ritonavir, and indinavir.58

DIFFUSE INFILTRATIVE LYMPHOCYTOSIS SYNDROME Diffuse infiltrative lymphocytosis syndrome (DILS), found exclusively in HIV-positive patients, is characterized by salivary gland enlargement and peripheral CD8 lymphocytosis often accompanied by sicca symptoms and other extraglandular features. The prevalence of DILS is declining since the introduction of HAART.59 Using parotid enlargement as a criterion, the prevalence in Houston, Texas, was 4% in the pre-HAART era, declining to 0.8% after the introduction of aggressive HIV therapy.59,60 In another study from Greece, using xerophthalmia and xerostomia as the defining criteria (and requiring confirmatory minor salivary gland biopsy specimen and technetium scintigraphy),61 the prevalence of DILS was 7.8% and decreased dramatically after the introduction of HAART. The primary immunogenetic association has been with HLA-DRB1 alleles expressing the ILEDE amino acid sequence in the third diversity region—usually HLADRB1*1102, DRB1*1301, and DRB1*1302.59,62 The de­­ layed progression to AIDS in patients with DILS has been attributed to delay in the evolution of the HIV-1 virus from the less aggressive M-tropic strain to the more rapidly replicating T-tropic strain by a more effective CD8 lymphocyte response.62 This response has been attributed in part to the finding of sequence homology of a six-residue epitope shared by HLA-DRB1 alleles associated with DILS with a V3 loop on M-tropic HIV strains. Studies of immunophenotypes of circulating and tissue-infiltrating lymphocytes and salivary gland T cell receptor sequence analysis suggested that DILS represents an MHC-restricted, antigen-driven, oligoclonal selection of CD8+, CD29− lymphocytes that express selective homing receptors and infiltrate the salivary glands, lungs, and other organs, where they are postulated to suppress HIV-1 replication.63 Minor salivary gland biopsy specimens show a focal sialadenitis, similar to that observed in Sjögren’s syndrome, although there tends to be less destruction of the salivary glands (Fig. 103-5). CD8+ lymphocytes constitute most of

PART 17 

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INFECTION AND ARTHRITIS 1753

Figure 103-5  Minor salivary gland biopsy specimen from a patient with diffuse infiltrative lymphocytosis syndrome. Note the relative preservation of the glandular architecture, even with significant interstitial inflammation.

the inflammatory infiltrate,64,65 in contrast to that seen in primary (non–HIV-associated) Sjögren’s syndrome. Lymphoepithelial cysts are seen frequently in the parotid glands of patients with DILS, leading to inspissated salivary secretions that may be painful. The characteristic, if not defining, presentation of DILS is painless parotid enlargement, often massive (Fig. 103-6). This enlargement is accompanied by sicca symptoms in greater than 60% of patients. Although parotid and submandibular enlargement is nearly universal in this disorder, certain extraglandular features also are prominent (Table 103-5). DILS and Sjögren’s syndrome share some similarities and differences (Table 103-6). Diagnostic criteria have been proposed for DILS as follows66: 1. HIV seropositive by enzyme-linked immunosorbent assay and Western blot analysis 2. Bilateral salivary gland enlargement or xerostomia persisting for more than 6 months 3. Histologic confirmation or salivary or lacrimal gland lymphocytic infiltration in the absence of granulomatous or neoplastic enlargement Minor salivary gland biopsy specimens are usually positive (see Fig. 103-5). Gallium-67 scintigraphy (Fig. 103-7) of the salivary glands has been used when lip biopsy was not feasible or equivocal. Tc 99m pertechnetate scanning offers little diagnostic help. Scintigraphy is being used as a primary diagnostic aid in patients on protease inhibitors because minor salivary gland biopsy specimens are rarely positive in patients on these drugs. CT also has been used to determine the extent of glandular swelling and in the evaluation of parotid cysts and possible salivary glandular malignancy (Table 103-7). Patients with asymptomatic glandular swelling and mild, if any, sicca symptoms can be observed over time. ­Antiretroviral treatment is effective in treating the glandular swelling and sicca symptoms associated with DILS and complications such as neuropathy.59 We have found also that moderate doses of corticosteroids (30 to 40 mg/day of prednisone) are effective in treating the glandular swelling and sicca symptoms of DILS without adversely affecting the frequency of opportunistic infections, increasing the viral

Figure 103-6  Massive bilateral asymmetric salivary gland enlargement in a patient with diffuse infiltrative lymphocytosis syndrome. This was the presenting feature of human immunodeficiency virus infection in this patient. CT revealed this to be a solid mass. At follow-up 2 years after this photograph was taken, the gland had not changed in size.

Table 103-5  Extraglandular Features of Diffuse   Infiltrative Lymphocytosis Syndrome Pulmonary Lymphocytic interstitial pneumonitis* Neurologic Cranial nerve VII palsy† Aseptic lymphocytic meningitis Peripheral neuropathy Gastrointestinal Lymphocytic hepatitis Renal Renal tubular acidosis Interstitial nephritis Musculoskeletal Peripheral arthritis Polymyositis Hematologic Lymphoma‡ *25% to 50%, but decreasing. †Owing to mechanical compression by inflamed parotid tissue. ‡Poor prognostic indicator.

loads, or depressing the CD4+ counts, although the effect is transient. Lymphocytic interstitial pneumonitis may require higher doses of corticosteroids (60 mg/day of prednisone), sometimes for extended periods. Radiation therapy should be avoided. Cranial nerve VII palsy tends to respond poorly to any treatment. Combination antiretroviral therapy also

1754 REVEILLE  |  Rheumatic Manifestations of Human Immunodeficiency Virus Infection

Table 103-6  Similarities and Differences between Diffuse Infiltrative Lymphocytosis Syndrome (DILS)   and Sjögren’s Syndrome Feature

DILS

Sjögren’s Syndrome

Parotid swelling

Ubiquitous

Uncommon

Sicca symptoms

Common

Very common

Extraglandular symptoms

Common

Uncommon

Autoantibodies (antinuclear antibodies,   anti-Ro/La)

Rare

Common

HLA class II association

DRB1*1102, DRB1*1301, DRB1*1302

DRB1*0301, DQA1*0501, DQB1*0201

Table 103-7  Treatment of Diffuse Infiltrative   Lymphocytosis Syndrome Reassurance and education Regular dental care No specific treatment for asymptomatic individuals Effective antiretroviral treatment Pilocarpine (5-10 mg) or cevimeline (30 mg orally 3 times daily) for sicca symptoms Systemic glucocorticoids Drainage and instillation of corticosteroids into parotid lymphoepithelial cysts Radiation of parotid cysts

Figure 103-7  The “snowman” sign. Gallium-67 scintigraphy of the parotid glands of a patient with diffuse infiltrative lymphocytosis syndrome occurring in the setting of hemophilia.

has been reported to be effective in resolving parotid epithelial cysts, although when refractory the cysts can be managed by aspiration and instillation of 1 mL of a depot steroid into the cyst (Fig. 103-8). Frequent recurrence may necessitate surgical excision.

VASCULITIS ASSOCIATED WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION A wide spectrum of vasculitis has been described in patients with HIV infection.66 Fevers, malaise, weakness, rashes, headaches, and neurologic symptoms are common in HIVpositive patients, and the triggers of vasculitis range from specific infective agents and drugs to idiopathic vasculitis. Among infective causes, cytomegalovirus and tuberculosis are probably the most common. Inflammatory vasculitides are less common rheumatologic diseases that occur in less than 1% of HIV patients. One series found 34 (23%) of 148 “symptomatic” HIVpositive patients to have vasculitis.67 Of these patients, 11 met American College of Rheumatology criteria for a

Figure 103-8  Aspiration of a parotid epithelial cyst in a patient with diffuse infiltrative lymphocytosis syndrome.

distinct category of vasculitis, including hypersensitivity vasculitis in 6, polyarteritis nodosa in 4, and Henoch-Schönlein purpura in 1.Wegener’s granulomatosis and pulmonary microscopic polyangiitis can occur in patients with high CD4+ counts and during immune reconstitution. Behçet’s syndrome and relapsing polychondritis occur in HIV infection68 and respond to HAART.69 A rapidly progressive focal necrotizing vasculitis of the aorta and large arteries with aneurysm formation and rupture has been described in Africans with HIV infection.70 Giant cell arteritis likewise has been described in patients with HIV infection with aortic root dilation.71 Kawasaki disease has been reported

PART 17 

in HIV-positive children and adults. Cryoglobulinemic vasculitis with associated lymphocytic interstitial pneumonia occurs with and without hepatitis C coinfection.66,67 Patients with isolated central nervous system angiitis usually present with organic brain syndromes and neurologic deficit.72 In children and in one case report in an adult, HIV-associated cerebral aneurysmal arteriopathy was described causing multiple fusiform aneurysms in the circle of Willis.73 Central nervous system vasculitis may manifest as recurrent strokes. Although imaging studies (MRI, angiography) may be helpful, brain biopsy may be necessary to establish the diagnosis. Although this syndrome is rarely encountered clinically, perivascular mononuclear cell infiltrates have been described in brain tissue specimens collected at autopsy from five of six children with AIDS.74 Necrotizing granulomatous vasculitis not limited to the central nervous system has been reported in patients with low CD4+ counts that responds to antiretroviral therapy.71 More recently, there has been a case report of leukocytoclastic cerebral vasculitis treated with anti-CD25 antibody.75 Diagnosis is based on a high degree of suspicion and angiography and biopsy of specific organ beds. Similar to in immunocompetent patients, perinuclear antineutrophil cytoplasmic antigen (pANCA) and cytoplasmic antineutrophil cytoplasmic antigen (cANCA) may be useful with Wegener’s granulomatosis or microscopic polyangiitis. Biopsy with cultures is important to rule out infectious mimics, however. Corticosteroids are the mainstay of treatment of HIVassociated vasculitis, although cytotoxic agents such as cyclophosphamide, intravenous immunoglobulin, and plasmapheresis have been used in refractory cases. Painful neuropathy secondary to vasculitis responds well to high-dose glucocorticoids, in contrast to HIV-associated peripheral neuropathy.76

PRIMARY PULMONARY HYPERTENSION Pulmonary hypertension is a severe life-limiting disease, often affecting younger patients. Patients with AIDS and primary pulmonary hypertension present with a higher degree of pulmonary hypertension than non-AIDS patients.77,78 The predominant histopathologic finding has been a plexogenic pulmonary arteriopathy, although thromboembolic changes also have been reported. One group found an association with HLA-DRB1*1301 and HLA-DRB1*1302 and with the linked allele HLA-DRB3*0301.79 A potential role of human herpes virus-8 and occult Kaposi’s sarcoma has been postulated.85 Symptoms are progressive shortness of breath, pedal edema, nonproductive cough, fatigue, syncope or nearsyncope, and chest pain. Pulmonary function tests show mild restrictive patterns with variably reduced diffusing capacities. In a review of 131 reviewed cases of pulmonary hypertension associated with HIV infection, the interval between the diagnosis of HIV disease and the diagnosis of pulmonary hypertension was 33 months. The median length of time from diagnosis to death was 6 months.80 The responses to vasodilator agents—calcium channel blockers, sildenafil, intravenous and inhaled prostanoids, and endothelin antagonists—and HAART vary, with some studies showing improved mortality.81

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INFECTION AND ARTHRITIS 1755

HUMAN IMMUNODEFICIENCY VIRUS–ASSOCIATED MUSCULOSKELETAL INFECTIONS PYOMYOSITIS Pyomyositis is a primary infection of skeletal muscle not arising from contiguous infection, presumably hematogenous in origin, and often associated with abscess formation. Rarely seen in developed countries, infectious myositis nonetheless is an important complication of HIV infection in areas most endemic for HIV, such as Africa and India. It tends to occur in later stages of the infection with CD4+ counts less than 200/μL. Staphylococcus aureus is the most common pathogen.82 Other organisms that have been implicated include Streptococcus pyogenes, Cryptococcus neoformans, Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, Nocardia asteroides, Salmonella enteritidis, ­Escherichia coli, Citrobacter freundii, Morganella morganii, Pseudomonas aeruginosa, and group A streptococci. The clinical course of pyomyositis can be roughly divided into three stages—invasive, suppurative, and late. The first stage, which typically lasts 1 to 3 weeks, is characterized by localized cramplike pain and induration in conjunction with a low-grade fever. Large muscle groups, particularly those of the lower extremities, are most often affected. The degrees of pain and fever increase in the second stage, which is characterized further by the development of edema and pus in the affected muscle. Untreated, the disease progresses to the third stage; within 3 weeks of onset, sepsis and death can occur.83 The mortality rate associated with pyomyositis has been estimated to range from 1% to 20%.Ultrasound and MRI with contrast enhancement are effective in localizing infection, although sometimes tagged white blood cell scans may be needed. Oral and intravenous antibiotics in conjunction with surgical drainage are often required.52 BACTERIAL ARTHRITIS AND OSTEOMYELITIS There are no data to suggest that bacterial infections of bones or joints occur more frequently in patients with HIV infection. S. aureus is the most common infectious agent encountered, but parenteral drug use and not HIV infection per se may account for this. Many other organisms have been reported to cause osteomyelitis in HIV-infected patients, including Salmonella, N. asteroides, Streptococcus pneumoniae, Neisseria gonorrhoeae, cytomegalovirus, invasive Aspergillus, Toxoplasma gondii, Torulopsis glabrata, C. neoformans, and Coccidioides immitis. Osteomyelitis is associated with mortality rates of greater than 20% in HIV-infected patients. The most frequently involved bones are the wrist, tibia, femoral heads, and thoracic cage, but other rare sites, such as the patella and the mandible, have been reported.52 MUSCULOSKELETAL TUBERCULOSIS Musculoskeletal involvement, the fourth most common extrapulmonary manifestation of tuberculosis, is found in about 1% to 5% of patients with tuberculosis. It can mimic many skeletal diseases and can manifest in various locations. Less than 50% of reported patients with musculoskeletal tuberculosis have radiographic evidence of pulmonary

1756 REVEILLE  |  Rheumatic Manifestations of Human Immunodeficiency Virus Infection

tuberculosis. M. tuberculosis disseminates hematogenously after an acute or reactivated pulmonary infection. Usually the skeletal tuberculosis lesions in immunocompetent patients are solitary, but in AIDS patients they may have a multicentric distribution in about 30% of cases.84 The vertebrae are the most common site involved, mostly the lower thoracic or upper lumbar segments. The frequency of tuberculous spondylitis is 50% to 66%; peripheral arthritis, 20% to 30%; osteomyelitis, 10% to 20%; and tenosynovitis and bursitis, about 1% to 3%. Treatment includes four-drug antitubercular therapy and often surgical intervention. ATYPICAL MYCOBACTERIAL INFECTIONS Musculoskeletal infections caused by atypical mycobacterial species are unusual in immunocompetent individuals. Atypical mycobacterial species most commonly implicated in causing septic arthritis or osteomyelitis in HIV include M. avium-intracellulare complex, Mycobacterium kansasii, Mycobacterium haemophilum, Mycobacterium terrae, and Mycobacterium fortuitum. M. haemophilum has been most frequently implicated in skeletal infection, accounting for more than half of cases, and M. kansasii is second, accounting for an additional 25%. These are systemic infections that have involved several joints or skeletal sites. Cutaneous lesions, such as nodules, ulcers, and draining sinus tracts, occur in approximately 50% of patients.85 These infections tend to occur late in the course of HIV, usually when the CD4+ T lymphocyte count is less than 100/μL. Along with standard antituberculosis therapy, clarithromycin is effective.

FUNGAL INFECTIONS In addition to bacterial infections, patients with advanced HIV infection (CD4+ T lymphocyte count <100/μL) are at high risk for fungal musculoskeletal infections, particularly infections caused by Candida albicans86 and Sporothrix schenckii.87 S. schenckii can manifest with oligoarticular or even polyarticular involvement, with tendon sheath effusions (Fig. 103-9), and can be particularly difficult to eradicate, requiring long-term suppressive antifungal therapy. Various disseminated fungal infections, such as histoplasmosis, cryptococcosis, and blastomycosis, occur in HIV and often cause osteomyelitis. PARASITIC INFECTIONS

BACILLARY ANGIOMATOSIS OSTEOMYELITIS Bacillary angiomatosis is a multisystem infectious disease caused by two closely related organisms—Bartonella henselae and Bartonella quintana—initially described in patients with AIDS by Stoler and colleagues in 1983.85a It seems to be a disease unique to HIV-infected patients and to a lesser degree to other immunocompromised patients.1

Figure 103-9  A, Third metacarpophalangeal synovitis and common extensor digitorum longus tendon sheath effusion at the dorsal surface of the wrist. B, Dissecting a Baker’s cyst in the same patient with disseminated Sporotrichum schenckii infection (organism cultured from synovial fluid obtained from both sites).

The name bacillary angiomatosis came from the descriptions of the vascular proliferation, seen on histologic examination of clinical specimens, and from the bacilli identified on Warthin-Starry silver stain. The bacterial infection results in a vascular proliferative response ensuing in lesions in the skin (resembling Kaposi’s sarcoma), lymph nodes (adenitis), central nervous system (aseptic meningitis or intracranial masses), bone (osteomyelitis), and liver (peliosis hepatis). Osteomyelitis is found in about one third of the patients in association with skin disease. These lesions usually are characterized by extensive destruction of the cortical bone, periostitis, medullary invasion, and an overlying soft tissue mass that might resemble cellulitis. A complete remission of bacillary angiomatosis after doxycycline or erythromycin therapy occurs, although bone lesions may need surgical drainage.

A

Muscle toxoplasmosis is found in profoundly immunodepressed patients, typically presenting with a painful subacute myopathy and concurrent multivisceral toxoplasmosis.88 Toxoplasma cysts are observed mainly in muscle fibers in ­muscle biopsy specimens, and identification of cysts as Toxoplasma may be easier by using specific antibodies or electron microscopy. Muscle weakness such as in polymyositis

B

PART 17 

can occur in muscle toxoplasmosis. Treatment is based on a combination of drugs acting synergistically against T. gondii, including pyrimethamine and sulfadiazine or trisulfapyrimidines.

RESPONSE OF OTHER RHEUMATIC DISEASES TO HUMAN IMMUNODEFICIENCY VIRUS INFECTION Early reports suggested that rheumatoid arthritis went into remission in the face of HIV infection. Early reports likewise suggested that HIV infection might reduce activity of systemic lupus erythematosus, particularly at times of low CD4+ T cell counts. With the emergence of the newly described immune reconstitution syndrome, most autoimmune diseases appear de novo or recur with institution of HAART and increase in CD4+ counts.10

HIGHLY ACTIVE ANTIRETROVIRAL THERAPY–RELATED IMMUNE RECONSTITUTION SYNDROME The coverage of antiretroviral therapy has increased from 7% in 2003 to 20% in 2005. Immune reconstitution inflammatory syndrome is a paradoxical clinical deterioration in patients with HIV who receive HAART, as a result of improvement in cellular immunity. It was initially described with the recrudescence of infections, but more recently autoinflammatory and autoimmune phenomena are being described. Shelburne and coworkers89 put forth four criteria required for the diagnosis of immune reconstitution inflammatory syndrome, as follows: 1. Patient has been diagnosed with AIDS. 2. Treatment with anti-HIV therapy results in increased CD4+ counts and decreased HIV-1 viral load. 3. Infectious and inflammatory symptoms appear during therapy. 4. Symptoms cannot be explained by a new etiology. More recent understanding of the immunology of im­mune reconstitution inflammatory syndrome has helped elucidate how atypical, hyperaccentuated inflammatory host responses to preexisting or coexisting infections can occur in HIV patients taking HAART. HIV infection causes a relentless decline in CD4+ memory and naive cells, an increase in activated T cells in the peripheral blood, and thymic dysfunction. HAART can lead to sustained suppression of HIV and a concomitant repopulation of T cell counts in a biphasic mode.90 The first phase represents the release of predominantly memory CD4+ cells and lasts a few weeks to months. The second phase, from approximately 6 months on, represents the main phase of naive T cell proliferation and is accompanied by changes in T helper cytokine production profiles.91,92 Immune reconstitution inflammatory syndrome can occur during both phases of immune recovery, and different infections and autoimmune phenomena occur in phase 1 compared with phase 2. Organ-specific autoimmune phenomena have been described more often than generalized systemic autoimmune disease and tend to occur later during reconstitution. These

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INFECTION AND ARTHRITIS 1757

phenomena may be a manifestation of naive T cell release as opposed to memory T cell reconstitution. Graves’ thyroiditis occurring about 21 months after initiation of HAART has been described in about 17 cases.93 Terminal ileitis, alopecia universalis, cerebral CD8 lymphocytosis, and Guillain-Barré syndrome90,94 have been reported. Polymyositis,95 rheumatoid arthritis,102 systemic lupus erythematosus,96 Kawasakilike febrile illness, and sarcoidosis97,98 newly developing after initiation of HAART also have been described. These conditions tend to occur earlier during reconstitution compared with the organ-specific autoimmunity. If a diagnosis of immune reconstitution inflammatory syndrome is made, HAART is continued, and most symptoms resolve with little or no therapy. If the inflammatory symptoms involve areas where significant damage secondary to uncontrolled inflammation is likely to occur, such as in the central nervous system or eye, HAART should be stopped, and careful use of corticosteroids should be considered. Immune reconstitution inflammatory syndrome is less likely to occur if the CD4+ count is greater than 200/μL when HAART is initiated. More systematic analysis is needed, however, and guidelines need to be established for defining the autoimmunity associated with immune reconstitution. The prognosis for most immune reconstitution inflammatory syndrome cases is favorable because a robust inflammatory response may predict an excellent response to HAART in terms of immune reconstitution and, perhaps, improved survival.

RHEUMATOLOGIC COMPLICATIONS OF HUMAN IMMUNODEFICIENCY VIRUS TREATMENT The myopathy associated with nucleoside transcriptase inhibitors such as zidovudine and osteonecrosis and parotid lipomatosis associated with the use of protease inhibitors have been discussed previously. In addition to these conditions, cases of adhesive capsulitis, Dupuytren’s contractures, tenosynovitis, and temporomandibular joint dysfunction have been reported as a consequence of indinavir treatment.99

LABORATORY ABNORMALITIES ASSOCIATED WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION Humoral immunologic abnormalities are frequent in patients with HIV, but are rarely associated with severe clinical signs. The most common laboratory abnormality is polyclonal hyperglobulinemia, found in 45% of HIVpositive individuals.100 Hypocomplementemia is rare. Rheumatoid factor and antinuclear antibodies, usually in low titer, have been described in 17% of patients with HIV infection in some series.100 IgG anticardiolipin antibodies are found in 95% of patients with AIDS, particularly in patients with advanced disease, and in 20% to 30% overall of HIV-positive individuals.101 Cryoglobulinemia is decreasing in this population since the introduction of HAART.102 cANCA and pANCA have been described in the serum of HIV-positive individuals, in frequencies of 43% by enzyme-linked immunosorbent assay and 18% by indirect immunofluorescence.103

1758 REVEILLE  |  Rheumatic Manifestations of Human Immunodeficiency Virus Infection

CONCLUSION The impact of the global HIV pandemic continues to grow, and rheumatologists need to keep aware of the wide spectrum of rheumatic diseases that occur in HIV-positive patients. HAART has changed the natural history of HIV infection: It has modified the frequency and expression of some HIVrelated clinical syndromes and has been associated directly (toxicity) and indirectly (immune reconstitution) with the development of new ones. With longer survival and newer refinements in treatment, the spectrum of rheumatic disease seen in HIV-positive patients is very much a “moving target” for rheumatologists that is likely to continue to evolve. REFERENCES   1. Biviji AA, Paiement GD, Steinbach LS: Musculoskeletal manifestations of human immunodeficiency virus infection. J Am Acad Orthop Surg 10:312-320, 2002.   2. Rynes RI, Goldenberg DL, DiGiacomo R, et al: Acquired immunodeficiency syndrome-associated arthritis. Am J Med 84:810-816, 1988.   3. Bileckot R, Mouaya A, Makuwa M: Prevalence and clinical presentations of arthritis in HIV-positive patients seen at a rheumatology department in Congo-Brazzaville. Rev Rhum Engl Ed 65:549-554, 1998.   4. Berman A, Cahn P, Perez H, et al: Human immunodeficiency virus infection associated arthritis: Clinical characteristics. J Rheumatol 26:1158-1162, 1999.   5. Reveille JD: The changing spectrum of rheumatic disease in human immunodeficiency virus infection. Semin Arthritis Rheum 30: 147-166, 2000.   6. Mody GM, Parke FA, Reveille JD: Articular manifestations of human immunodeficiency virus infection. Best Pract Res Clin Rheumatol 17:265-287, 2003.   7. Ornstein MH, Sperber K: The antiinflammatory and antiviral effects of hydroxychloroquine in two patients with acquired immunodeficiency syndrome and active inflammatory arthritis. Arthritis Rheum 39:157-161, 1996.   8. Clark MR, Solinger AM, Hochberg MC: Human immunodeficiency virus infection is not associated with Reiter’s syndrome: Data from three large cohort studies. Rheum Dis Clin N Am 18:267-276, 1992.   9. Njobvu P, McGill P: Human immunodeficiency virus related reactive arthritis in Zambia. J Rheumatol 32:1299-1304, 2005. 10. Reveille JD, Conant MA, Duvic M: Human immunodeficiency virus-associated psoriasis, psoriatic arthritis, and Reiter’s syndrome: A disease continuum? Arthritis Rheum 33:1574-1578, 1990. 11. Kaslow RA, Carrington M, Apple R, et al: Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat Med 2:405-411, 1996. 12. Carrington M, O’Brien SJ: The influence of HLA genotype on AIDS. Annu Rev Med 54:535-551, 2003. 13. Altfeld M, Kalife ET, Qi Y, et al: HLA alleles associated with delayed progression to AIDS contribute strongly to the initial CD8(+) T cell response against HIV-1. PLoS Med 3:e403, 2006. 14. Frahm N, Kiepiela P, Adams S, et al: Control of human immunodeficiency virus replication by cytotoxic T lymphocytes targeting subdominant epitopes. Nat Immunol 7:173-178, 2006. 15. Lopez-Larrea C, Njobvu PD, Gonzalez S, et al: The HLA-B*5703 allele confers susceptibility to the development of spondylarthropathies in Zambian human immunodeficiency virus-infected patients with slow progression to acquired immunodeficiency syndrome. Arthritis Rheum 52:275-279, 2005. 16. Bourinbaiar AS, Lee-Huang S: The non-steroidal anti-inflammatory drug, indomethacin, as an inhibitor of HIV replication. FEBS Lett 360:85-88, 1995. 17. Njobvu PD, McGill PE: Sulphasalazine in the treatment of HIVrelated spondyloarthropathy. Br J Rheumatol 36:403-404, 1997. 18. Disla E, Rhim HR, Reddy A, et al: Improvement in CD4 lymphocyte count in HIV-Reiter’s syndrome after treatment with sulfasalazine. J Rheumatol 21:662-664, 1994.

19. Maurer TA, Zackheim HS, Tuffanelli L, et al: The use of methotrexate for treatment of psoriasis in patients with HIV infection. J Am Acad Dermatol 31:372-375, 1994. 20. Chiang G, Sassaroli M, Louie M, et al: Inhibition of HIV-1 replication by hydroxychloroquine: Mechanism of action and comparison with zidovudine. Clin Ther 18:1080-1092, 1996. 21. Louthrenoo W: Successful treatment of severe Reiter’s syndrome associated with human immunodeficiency virus infection with etretinate: Report of 2 cases. J Rheumatol 20:1243-1246, 1993. 22. Gaylis N: Infliximab in the treatment of an HIV positive patient with Reiter’s syndrome. J Rheumatol 30:407-411, 2003. 23. Ting PT, Koo JY: Use of etanercept in human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) patients. Int J Dermatol 45:689-692, 2006. 24. Filippi J, Roger PM, Schneider SM, et al: Infliximab and human immunodeficiency virus infection: Viral load reduction and CD4+ T-cell loss related to apoptosis. Arch Intern Med 166:1783-1784, 2006. 25. Beltran B, Nos P, Bastida G, et al: Safe and effective application of anti-TNF-alpha in a patient infected with HIV and concomitant Crohn’s disease. Gut 55:1670-1671, 2006. 26. Arnett FC, Reveille JD, Duvic M: Psoriasis and psoriatic arthritis associated with human immunodeficiency virus infection. Rheum Dis Clin N Am 17:59-78, 1991. 27. Njobvu P, McGill P: Psoriatic arthritis and human immunodeficiency virus infection in Zambia. J Rheumatol 27:1699-1702, 2000. 28. Espinoza LR, Berman A, Vasey FB, et al: Psoriatic arthritis and acquired immunodeficiency syndrome. Arthritis Rheum 31: 1034-1040, 1988. 29. Duvic M, Crane MM, Conant M, et al: Zidovudine improves psoriasis in human immunodeficiency virus-positive males. Arch Dermatol 130:447-451, 1994. 30. Bartke U, Venten I, Kreuter A, et al: Human immunodeficiency virus-associated psoriasis and psoriatic arthritis treated with infliximab. Br J Dermatol 150:784-786, 2004. 31. McGonagle D, Reade S, Marzo-Ortega H, et al: Human immunodeficiency virus associated spondyloarthropathy: Pathogenic insights based on imaging findings and response to highly active antiretroviral treatment. Ann Rheum Dis 60:696-698, 2001. 32. Gerster JC, Camus JP, Chave JP, et al: Multiple site avascular necrosis in HIV infected patients. J Rheumatol 18:300-302, 1991. 33. Allison GT, Bostrom MP, Glesby MJ: Osteonecrosis in HIV disease: Epidemiology, etiologies, and clinical management. AIDS 17:1-9, 2003. 34. Gutierrez F, Padilla S, Masia M, et al: Osteonecrosis in patients infected with HIV: Clinical epidemiology and natural history in a large case series from Spain. J Acquir Immune Defic Syndr 42: 286-292, 2006. 35. Morse CG, Mican JM, Jones EC, et al: The incidence and ­ natural history of osteonecrosis in HIV-infected adults. Clin Infect Dis 44: 739-748, 2007. 36. Gunnarsson G, Karchmer AW: Hypertrophic osteoarthropathy associated with Pneumocystis carinii pneumonia and human immunodeficiency virus infection. Clin Infect Dis 22:590-591, 1996. 37. Brown TT, Qaqish RB: Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: A meta-analytic review. AIDS 20: 2165-2174, 2006. 38. Pan G, Yang Z, Ballinger SW, et al: Pathogenesis of osteopenia/osteoporosis induced by highly active anti-retroviral therapy for AIDS. Ann N Y Acad Sci 1068:297-308, 2006. 39. Amorosa V, Tebas P: Bone disease and HIV infection. Clin Infect Dis 42:108-114, 2006. 40. Lin D, Rieder M: Interventions for the treatment of decreased bone mineral density associated with HIV infection. Cochrane Database Syst Rev CD005645, 2007. 41. Buskila D, Gladman D: Musculoskeletal manifestations of infection with human immunodeficiency virus. Rev Infect Dis 12:223-235, 1990. 42. Simms RW, Zerbini CA, Ferrante N, et al: Fibromyalgia syndrome in patients infected with human immunodeficiency virus. The Boston City Hospital Clinical AIDS Team. Am J Med 92:368-374, 1992. 43. Miro O, Pedrol E, Cebrian M, et al: Skeletal muscle studies in patients with HIV-related wasting syndrome. J Neurol Sci 150:153159, 1997.

PART 17  44. Gherardi R, Chariot P, Authier FJ: [Muscular involvement in HIV infection]. Rev Neurol (Paris) 151:603-607, 1995. 45. Simpson DM, Bender AN, Farraye J, et al: Human immunodeficiency virus wasting syndrome may represent a treatable myopathy. Neurology 40:535-538, 1990. 46. Miro O, Masanes F, Pedrol E, et al: [A comparative study of the clinical and histological characteristics between classic nemaline myopathy and that associated with the human immunodeficiency virus]. Med Clin (Barc) 105:500-503, 1995. 47. Nakagawa M, Hirata K: [Adult onset nemaline myopathy and monoclonal gammopathy]. Ryoikibetsu Shokogun Shirizu 35:406-413, 2001. 48. Johnson RW, Williams FM, Kazi S, et al: Human immunodeficiency virus-associated polymyositis: A longitudinal study of outcome. Arthritis Rheum 49:172-178, 2003. 49. Seidman R, Peress NS, Nuovo GJ: In situ detection of polymerase chain reaction-amplified HIV-1 nucleic acids in skeletal muscle in patients with myopathy. Mod Pathol 7:369-375, 1994. 50. Leon-Monzon M, Lamperth L, Dalakas MC: Search for HIV proviral DNA and amplified sequences in the muscle biopsies of patients with HIV polymyositis. Muscle Nerve 16:408-413, 1993. 51. Reveille JD: The changing spectrum of rheumatic disease in human immunodeficiency virus infection. Semin Arthritis Rheum 30: 147-166, 2000. 52. Tehranzadeh J, Ter-Oganesyan RR, Steinbach LS: Musculoskeletal disorders associated with HIV infection and AIDS, Part I: Infectious musculoskeletal conditions. Skeletal Radiol 33:249-259, 2004. 53. Illa I, Nath A, Dalakas M: Immunocytochemical and virological characteristics of HIV-associated inflammatory myopathies: Similarities with seronegative polymyositis. Ann Neurol 29:474-481, 1991. 54. Cupler EJ, Leon-Monzon M, Miller J, et al: Inclusion body myositis in HIV-1 and HTLV-1 infected patients. Brain 119(Pt 6):1887-1893, 1996. 55. Schreiner B, Voss J, Wischhusen J, et al: Expression of toll-like receptors by human muscle cells in vitro and in vivo: TLR3 is highly expressed in inflammatory and HIV myopathies, mediates IL-8 release and up-regulation of NKG2D-ligands. Faseb J 20:118-120, 2006. 56. Walsh K, Kaye K, Demaerschalk B, et al: AZT myopathy and HIV-1 polymyositis: One disease or two? Can J Neurol Sci 29:390393, 2002. 57. Dalakas MC, Illa I, Pezeshkpour GH, et al: Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 322: 1098-1105, 1990. 58. Authier FJ, Gherardi RK: [Muscular complications of human immunodeficiency virus (HIV) infection in the era of effective anti-retroviral therapy]. Rev Neurol (Paris) 162:71-81, 2006. 59. Basu D, Williams FM, Ahn CW, et al: Changing spectrum of the diffuse infiltrative lymphocytosis syndrome. Arthritis Rheum 55: 466-472, 2006. 60. Williams FM, Cohen PR, Jumshyd J, et al: Prevalence of the diffuse infiltrative lymphocytosis syndrome among human immunodeficiency virus type 1-positive outpatients. Arthritis Rheum 41:863-868, 1998. 61. Kordossis T, Paikos S, Aroni K, et al: Prevalence of Sjogren’s-like syndrome in a cohort of HIV-1-positive patients: Descriptive pathology and immunopathology. Br J Rheumatol 37:691-695, 1998. 62. Itescu S, Rose S, Dwyer E, et al: Certain HLA-DR5 and -DR6 major histocompatibility complex class II alleles are associated with a CD8 lymphocytic host response to human immunodeficiency virus type 1 characterized by low lymphocyte viral strain heterogeneity and slow disease progression. Proc Natl Acad Sci U S A 91:11472-11476, 1994. 63. Itescu S, Dalton J, Zhang HZ, et al: Tissue infiltration in a CD8 lymphocytosis syndrome associated with human immunodeficiency virus-1 infection has the phenotypic appearance of an antigenically driven response. J Clin Invest 91:2216-2225, 1993. 64. Kazi S, Cohen PR, Williams F, et al: The diffuse infiltrative lymphocytosis syndrome: Clinical and immunogenetic features in 35 patients. AIDS 10:385-391, 1996. 65. Itescu S, Winchester R: Diffuse infiltrative lymphocytosis syndrome: A disorder occurring in human immunodeficiency virus-1 infection that may present as a sicca syndrome. Rheum Dis Clin N Am 18: 683-697, 1992. 66. Garcia-Garcia JA, Macias J, Castellanos V, et al: Necrotizing granulomatous vasculitis in advanced HIV infection. J Infect 47:333-335, 2003.

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67. Gherardi R, Belec L, Mhiri C, et al: The spectrum of vasculitis in human immunodeficiency virus-infected patients: A clinicopathologic evaluation. Arthritis Rheum 36:1164-1174, 1993. 68. Belzunegui J, Cancio J, Pego JM, et al: Relapsing polychondritis and Behcet’s syndrome in a patient with HIV infection. Ann Rheum Dis 54:780, 1995. 69. Cicalini S, Gigli B, Palmieri F, et al: Remission of Behcet’s disease and keratoconjunctivitis sicca in an HIV-infected patient treated with HAART. Int J STD AIDS 15:139-140, 2004. 70. Chetty R, Batitang S, Nair R: Large artery vasculopathy in HIV-positive patients: Another vasculitic enigma. Hum Pathol 31:374-379, 2000. 71. Javed MA, Sheppard MN, Pepper J: Aortic root dilation secondary to giant cell aortitis in a human immunodeficiency virus-positive patient. Eur J Cardiothorac Surg 30:400-401, 2006. 72. Brannagan TH III: Retroviral-associated vasculitis of the nervous system. Neurol Clin 15:927-944, 1997. 73. Ake JA, Erickson JC, Lowry KJ: Cerebral aneurysmal arteriopathy associated with HIV infection in an adult. Clin Infect Dis 43: e46-e50, 2006. 74. Katsetos CD, Fincke JE, Legido A, et al: Angiocentric CD3(+) T-cell infiltrates in human immunodeficiency virus type 1-associated central nervous system disease in children. Clin Diagn Lab Immunol 6: 105-114, 1999. 75. Nieuwhof CM, Damoiseaux J, Cohen Tervaert JW: Successful treatment of cerebral vasculitis in an HIV-positive patient with antiCD25 treatment. Ann Rheum Dis 65:1677-1678, 2006. 76. Bradley WG, Verma A: Painful vasculitic neuropathy in HIV-1 infection: Relief of pain with prednisone therapy. Neurology 47: 1446-1451, 1996. 77. Coplan NL, Shimony RY, Ioachim HL, et al: Primary pulmonary hypertension associated with human immunodeficiency viral infection. Am J Med 89:96-99, 1990. 78. Morse JH, Barst RJ, Itescu S, et al: Primary pulmonary hypertension in HIV infection: An outcome determined by particular HLA class II alleles. Am J Respir Crit Care Med 153:1299-1301, 1996. 79. Gutierrez F, Masia M, Padilla S, et al: Occult lymphadenopathic Kaposi’s sarcoma associated with severe pulmonary hypertension: A clinical hint about the potential role of HHV-8 in HIV-related pulmonary hypertension? J Clin Virol 37:79-82, 2006. 80. Mehta NJ, Khan IA, Mehta RN, et al: HIV-related pulmonary hypertension: Analytic review of 131 cases. Chest 118:1133-1141, 2000. 81. Nunes H, Humbert M, Sitbon O, et al: Prognostic factors for survival in human immunodeficiency virus-associated pulmonary arterial hypertension. Am J Respir Crit Care Med 167:1433-1439, 2003. 82. Ansaloni L: Tropical pyomyositis. World J Surg 20:613-617, 1996. 83. Scharschmidt TJ, Weiner SD, Myers JP: Bacterial pyomyositis. Curr Infect Dis Rep 6:393-396, 2004. 84. Jellis JE: Human immunodeficiency virus and osteoarticular tuberculosis. Clin Orthop 398:27-31, 2002. 85. Hirsch R, Miller SM, Kazi S, et al: Human immunodeficiency virusassociated atypical mycobacterial skeletal infections. Semin Arthritis Rheum 25:347-356, 1996. 85a. Stoler MH, Bonfiglio TA, Steigbigel RT, et al: An atypical subcutaneous infection associated with acquired immune deficiency syndrome. Am J Clin Pathol 80:714-718, 1983. 86. Edelstein H, McCabe R: Candida albicans septic arthritis and osteomyelitis of the sternoclavicular joint in a patient with human immunodeficiency virus infection. J Rheumatol 18:110-111, 1991. 87. Heller HM, Fuhrer J: Disseminated sporotrichosis in patients with AIDS: Case report and review of the literature. AIDS 5:1243-1246, 1991. 88. Gherardi R, Baudrimont M, Lionnet F, et al: Skeletal muscle toxoplasmosis in patients with acquired immunodeficiency syndrome: A clinical and pathological study. Ann Neurol 32:535-542, 1992. 89. Shelburne SA III, Hamill RJ, Rodriguez-Barradas MC, et al: Immune reconstitution inflammatory syndrome: Emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Balt) 81:213-227, 2002. 90. DeSimone JA, Pomerantz RJ, Babinchak TJ: Inflammatory reactions in HIV-1-infected persons after initiation of highly active antiretroviral therapy. Ann Intern Med 133:447-454, 2000. 91. Hardy G, Worrell S, Hayes P, et al: Evidence of thymic reconstitution after highly active antiretroviral therapy in HIV-1 infection. HIV Med 5:67-73, 2004.

1760 REVEILLE  |  Rheumatic Manifestations of Human Immunodeficiency Virus Infection 92. Lederman MM, Connick E, Landay A, et al: Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: Results of AIDS Clinical Trials Group Protocol 315. J Infect Dis 178:70-79, 1998. 93. Chen F, Day SL, Metcalfe RA, et al: Characteristics of autoimmune thyroid disease occurring as a late complication of immune reconstitution in patients with advanced human immunodeficiency virus (HIV) disease. Medicine (Balt) 84:98-106, 2005. 94. Gray F, Bazille C, dle-Biassette H, et al: Central nervous system immune reconstitution disease in acquired immunodeficiency syndrome patients receiving highly active antiretroviral treatment. J Neurovirol 11(Suppl 3):16-22, 2005. 95. Calza L, Manfredi R, Colangeli V, et al: Polymyositis associated with HIV infection during immune restoration induced by highly active anti-retroviral therapy. Clin Exp Rheumatol 22:651-652, 2004. 96. Calabrese LH, Kirchner E, Shrestha R: Rheumatic complications of human immunodeficiency virus infection in the era of highly active antiretroviral therapy: Emergence of a new syndrome of immune reconstitution and changing patterns of disease. Semin Arthritis Rheum 35:166-174, 2005. 97. Schneider J, Zatarain E: IRIS and SLE. Clin Immunol 118:152-153, 2006.

98. Ferrand RA, Cartledge JD, Connolly J, et al: Immune reconstitution sarcoidosis presenting with hypercalcaemia and renal failure in HIV infection. Int J STD AIDS 18:138-139, 2007. 99. Florence E, Schrooten W, Verdonck K, et al: Rheumatological complications associated with the use of indinavir and other protease inhibitors. Ann Rheum Dis 61:82-84, 2002. 100. Kaye BR: Rheumatologic manifestations of infection with human immunodeficiency virus (HIV). Ann Intern Med 111:158-167, 1989. 101. Petrovas C, Vlachoyiannopoulos PG, Kordossis T, et al: Anti-phospholipid antibodies in HIV infection and SLE with or without antiphospholipid syndrome: Comparisons of phospholipid specificity, avidity and reactivity with beta2-GPI. J Autoimmun 13:347-355, 1999. 102. Bonnet F, Pineau JJ, Taupin JL, et al: Prevalence of cryoglobulinemia and serological markers of autoimmunity in human immunodeficiency virus infected individuals: A cross-sectional study of 97 patients. J Rheumatol 30:2005-2010, 2003. 103. de Habegger SA, Motta P, Iliovich E, et al: [Anti-neutrophil cytoplasmic antibodies (ANCA) in patients with symptomatic and asymptomatic HIV infection]. Medicina (B Aires) 57:294-298, 1997.

104

Viral Arthritis Stanley J. Naides

KEY POINTS Acute-onset, symmetric polyarthritis suggests viral infection, especially when accompanied by rash. Always take exposure, travel, occupation, and vaccination histories. Parvovirus B19 is the most common viral arthritis in the United States. In adults with parvovirus B19 infection, rash may be subtle or absent. Rubella arthritis occurs in young adults. Rubella vaccination has reduced the overall incidence of rubella infection but has shifted the peak age to young adults. Arthralgia, arthritis, or neuropathic pain may occur after rubella vaccination; these conditions are usually self-limited in duration. Alphaviruses are mosquito-borne causes of arthritis and rash. Outbreaks occur in endemic areas associated with rising mosquito populations and should be considered in travelers entering the United States. Hepatitis B virus infection presents as an arthritis-urticaria syndrome. Hepatitis C virus infection causes cryoglobulinemia and vasculitis. Cryoglobulinemic vasculitis often presents as palpable purpura of the lower legs. The history of risk behaviors associated with hepatitis C virus infection may be remote.

Viruses are candidate causative agents for various rheumatic diseases in part because arthralgia and arthritis are prominent features of certain viral infections. Understanding how viruses cause arthritis and the nature of virus-host cell interactions may suggest how viruses precipitate, establish, or maintain chronic inflammatory arthritis such as rheumatoid arthritis. Viral effects in a given host may depend on host factors such as age, gender, genetic background, infection history, and immune response. The ability of a given virus to infect a host may also depend on the viral mode of host entry, tissue tropism, replication strategy, cytopathologic effects, ability to establish persistent infection, viral expression of hostlike antigens, and ability to alter host antigens. Viral modification of the regulation of cellular gene expression may contribute to autoimmunity. Infected cells may die by classic cell necrosis, programmed cell death (apoptosis), or autophagy. Initiation of an immune response to virally encoded antigens on the cell surface may target that cell

for destruction and alter cell-cell interactions. The antibody response may generate immune complexes that are deposited locally at the site of viral infection or systemically in synovium. Alternatively, cells may survive, but their behavior may be altered by the expression of viral genes. Transactivation of cellular genes by viral gene products may induce the cell cycle or cytokines that elicit or perpetuate an immune response targeting host cells. Molecular mimicry of host autoantigens by viral proteins may break immune tolerance. Viral components may elicit “danger signals” that trigger an immune response.1,2

PARVOVIRUS B19 Human parvovirus B19 is a member of the family Parvoviridae, subfamily Parvovirinae, genus Erythrovirus. It consists of the small, single-stranded DNA viruses that autonomously replicate in erythroid precursors (hence the genus name). B19 has no envelope and is approximately 23 nm in diameter. Productive infection occurs in erythroid precursors; infection of nonerythroid tissues occurs but is restricted, which means that if assembly of virions occurs, it is inefficient, or that nonstructural but not capsid structural viral genes are expressed, preventing virion assembly. Parvoviruses are species specific and not known to readily cross species barriers. The common canine parvovirus does not infect humans. EPIDEMIOLOGY B19 infection is common and occurs worldwide. B19 is typically transmitted by respiratory secretions but may also be transmitted via pooled blood products. Outbreaks commonly occur in late winter and spring, when close contact is most common, although epidemics may also occur in summer and fall. Most B19 infections, especially in children, remain asymptomatic or are diagnosed as nonspecific viral illnesses. Outbreaks tend to occur in 3- to 5-year cycles, representing the time required for a new cohort of susceptible children to enter school. Up to 60% of adults have serologic evidence of past B19 infection.3,4 Susceptible adults in occupations with multiple exposures to children, such as schoolteachers and pediatric nurses, are at greatest risk (up to 50%) of acquiring infection during outbreaks.4,5 Sporadic cases do occur during nonepidemic periods. The diagnosis should be entertained even in the absence of surveillance data suggesting an outbreak. PATHOGENESIS The onset of joint symptoms and rash is associated temporally with appearance of serum anti-B19 immunoglobulin (Ig) M antibody, suggesting a role for circulating immune complexes 1761

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during the acute phase of the illness.6 Although there is little evidence of circulating virus in patients who have chronic joint symptoms, B19 DNA may be found in the bone marrow and synovium of patients with chronic B19 arthropathy. Persistence in chronic B19 arthropathy may be facilitated by failure to develop IgG antibodies to the N-terminal region of the minor capsid protein VP1, known to encode neutralizing epitopes.6 The presence of antibody to the B19 nonstructural protein NS1 in some cases of chronic B19 arthropathy probably reflects immune response to NS1 on the surface of B19 virions or NS1 spilled during cell death.7 NS1 protein itself, however, may play a pathogenic role in perpetuating chronic B19 arthropathy through its interaction with cellular genes.8 NS1 protein upregulates in vitro transcription from the interleukin-6 (IL-6) promoter and from human immunodeficiency virus (HIV) long terminal repeats in the presence of tat and an intact tar element.9,10 A high prevalence of B19 DNA and proteins in synovium from rheumatoid arthritis patients was reported in association with enhanced synovial production of IL-6 and tumor necrosis factor-α.8 These findings remain controversial.11 B19 may induce apoptosis through NS1, which is known to be toxic to cells.12,13 Production of NS1 in nonpermissive synoviocytes could theoretically induce autoimmunity by disrupting normal patterns of cell interactions and intercellular regulation. DIAGNOSIS Clinical Features The incubation period from B19 infection to symptom onset is 7 to 18 days. B19 causes transient aplastic crisis in the setting of chronic hemolytic anemia.6 In otherwise healthy children, B19 causes erythema infectiosum, or fifth disease, characterized by bright red “slapped cheeks” and a macular or maculopapular eruption on the torso and extremities. Up to 70% of infected children may be asymptomatic; others may have mild flulike symptoms including fever, headache, sore throat, cough, anorexia, vomiting, diarrhea, and arthralgia. In adults, the rash tends to be subtler, and the slapped-cheek rash is usually absent. Uncommon dermatologic manifestations include vesicular or hemorrhagic vesiculopustular eruptions, purpura with or without thrombocytopenia, Henoch-Schönlein purpura, and a “socks and gloves” acral erythema. B19 infection may be associated with paresthesias in the fingers and, rarely, with numbness of the toes. Progressive arm weakness has been associated with mild nerve conduction slowing and decreased motor and sensory potential amplitudes. B19 may cross the placenta to infect the fetus, which may develop hydrops fetalis on the basis of B19-induced anemia or viral cardiomyopathy. Less commonly, B19 may cause pancytopenia, isolated anemia, thrombocytopenia, leukopenia, myocarditis, neuropathy, or hepatitis.14 Reports suggest that B19 may be associated with vasculitis, including giant cell arteritis.15,16 Patients with congenital or acquired immunodeficiencies, including prior chemotherapy or acquired immunodeficiency syndrome (AIDS) due to HIV infection, may develop persistent B19 infection with chronic or recurrent anemia, thrombocytopenia, or leukopenia. B19 infection is the leading cause of pure red cell aplasia in patients with AIDS.17,18

Table 104-1  Prevalence of Joint Symptoms   in Fifth Disease by Age: Port Angeles, Washington,   1961-1962 Prevalence (%) by Age 0-9 Years

10-19 Years

>20 Years

Pain

Symptom

5.1

11.5

77.2

Swelling

2.8

5.3

59.6

Data from Ager EA, Chin TDY, Poland JD: Epidemic erythema infectiosum. N Engl J Med 275:1326, 1966.

In a study of an erythema infectiosum outbreak in Port Angeles, Washington, in which subjects were identified on the basis of rash, the incidence of arthralgia and joint swelling increased with age (Table 104-1).19 In adults, a severe flulike illness consisting of fever, chills, malaise, and myalgias may precede or accompany sudden-onset, moderately severe, symmetric polyarthritis in a rheumatoid-like distribution. The arthritis is characterized by prominent involvement of the finger proximal interphalangeal, metacarpophalangeal, wrist, knee, and ankle joints. Within 24 to 48 hours of onset, all affected joints become involved. Axial skeleton involvement is uncommon. Joint symptoms are usually self-limited. After the initial infection, objective joint swelling, heat, and erythema, when present, tend to resolve over several weeks. A minority of patients have prolonged symptoms that fall into one of two patterns. Approximately two thirds have continuous morning stiffness and arthralgias with intermittent flares. The other third are symptom free between flares. Chronic B19 arthropathy may last months to years. Pain remains a prominent feature during flares; patients commonly report morning stiffness. Approximately 12% of patients presenting with “early synovitis” have B19 infection, most of whom are women.6 Laboratory Tests Viremia lasts 5 to 6 days and is associated with an absence of reticulocytosis and, in otherwise normal individuals, a minimal decrease in the concentrations of hemoglobin, neutrophils, and lymphocytes. Flulike symptoms may occur during viremia. An IgM antibody response follows the initial viremia in 4 to 6 days and is associated with clearing of viremia and cessation of nasal shedding of virus. The antibody response is associated with the second phase of clinical illness, characterized by rash and joint symptoms. Onset of the anti-B19 IgG antibody response occurs almost concurrently with the IgM response. The two clinical phases of illness often overlap. Low to moderate titers of rheumatoid factor and anti-DNA, antilymphocyte, antinuclear, and antiphospholipid antibodies may be present initially.20-24 During viremia, immune electron microscopy may detect virions in serum. However, this method is not readily available to clinicians. B19 DNA may be detected during viremia. However, because adult patients usually present after the onset of joint symptoms, the most useful diagnostic test is anti-B19 IgM serology. Radioimmunoassays and enzymelinked immunosorbent assays have been used to detect B19 antigen and specific antibody to B19 capsid.6,25,26 The antiB19 IgM antibody response is usually positive for 2 months

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after the acute illness and may wane shortly thereafter. In some patients, anti-B19 IgM may be detected for 6 months or longer. A positive anti-B19 IgG antibody test in the absence of anti-B19 IgM is usually not diagnostically helpful because of the high seroprevalence of anti-B19 IgG in the adult population. Reports of B19 DNA in normal synovium suggest that testing for B19 DNA in these tissues is of little clinical utility in the absence of anti-B19 IgM.27

d­ emographic profile from children to college students and adults. The incubation period from infection to rash is 14 to 21 days. Viremia precedes rash by 6 to 7 days, peaks just before the onset of rash, and clears within 48 hours after the onset of rash. Nasopharyngeal shedding of virus is detectable from 7 days before the appearance of rash until 14 days afterward, but it is maximal from just before the rash until 5 to 6 days later.29

Differential Diagnosis

Pathogenesis

Many patients with B19 arthropathy meet the American Rheumatism Association criteria for a diagnosis of rheumatoid arthritis: morning stiffness lasting more than an hour; symmetric involvement; involvement of at least three joints; and involvement of the finger proximal interphalangeal, metacarpophalangeal, and wrist joints. Rheumatoid factor may be present at low to moderate titers. Absence of rheumatoid nodules and joint destruction differentiates B19 arthropathy from classic, erosive rheumatoid arthritis. Occasionally, B19 infection may present with features of systemic lupus erythematosus (SLE). Whether this represents a clinical mimic or indicates that B19 plays a role in initiating or precipitating SLE in these patients remains to be determined.6 Rubella in adults may present with rash and symmetric polyarthralgia or polyarthritis that is clinically indistinguishable from B19 infection. A history of prenatal rubella testing, prior rubella vaccination, or rubella exposure may aid in choosing the appropriate diagnostic serologies.

Rubella virus can persistently infect synoviocytes and chondrocytes in vitro. An inadequate humoral immune response to specific rubella envelope glycoprotein epitopes may allow rubella virus to persistently infect synovium and lymphocytes in chronic rubella arthritis patients. The onset of rash and arthritis is concurrent with antibody production, suggesting a role for antibody or immune complexes.29 Concentrations of rubella antibody are higher in synovial fluid than in serum. Synovial lymphocytes from infected individuals spontaneously secrete rubella antibody in vitro, suggesting that there is also an immune response to rubella infection in the joint.30

TREATMENT AND PROGNOSIS There is no specific treatment or vaccine for B19 infection. Treatment is therefore symptomatic, with nonsteroidal antiinflammatory drugs. Intravenous immunoglobulin has been successful in the treatment of bone marrow suppression and B19 persistence in immunocompromised patients,18 but initial studies suggest that this is not applicable to chronic arthropathy patients. Long-term prognosis is good. Although subjective arthralgias and morning stiffness may be prolonged, joint destruction is not a feature of chronic B19 arthropathy. B19’s role as a cofactor in the development of classic erosive rheumatoid arthritis has not been confirmed.

TOGAVIRUSES The family Togaviridae includes the Rubivirus and Alphavirus genera. RUBELLA VIRUS Rubella virus is the sole member of the genus Rubivirus. It consists of enveloped, single-stranded RNA viruses. The rubella virion is spherical and measures 50 to 70 nm in diameter, with a 30-nm dense core. Envelope glycoproteins form 5- to 6-nm spikelike projections that contain hemagglutination activity.28 Epidemiology Transmission is by nasopharyngeal secretions, with a peak incidence in late winter and spring. Vaccination has re­ duced the incidence of rubella outbreaks and shifted the

Diagnosis Clinical Features. Asymptomatic infection occurs in children and adults. Low-grade fever, malaise, coryza, and ­prominent lymphadenopathy involving posterior cervical, postauricular, and occipital nodes may precede rash by 5 days. A morbilliform rash may initially appear on the face and then spread to the torso, upper extremities, and lower extremities over 2 to 3 days. The facial rash may coalesce and clear as the extremities become involved. In some cases, the rash is only a transient blush. Joint symptoms commonly occur in women beginning 1 week before or 1 week after the appearance of the rash. Symmetric or migratory arthralgias are more common than synovitis. Morning stiffness is prominent. Joint symptoms usually resolve over a few days to 2 weeks. Proximal interphalangeal, metacarpophalangeal, wrist, elbow, ankle, and knee joints are most frequently affected. Periarthritis, tenosynovitis, and carpal tunnel syndrome may be seen. In some patients, symptoms may persist for months to years.31,32 Live attenuated rubella vaccines have caused a high frequency of postvaccination myalgia, arthralgia, arthritis, and paresthesia—symptoms similar to those in natural infection—beginning 2 weeks after inoculation and lasting less than a week. However, in some patients, symptoms may persist for more than a year. RA27/3, the vaccine strain in current use, may cause postvaccination joint symptoms in 15% or more of recipients.31,32 Two rheumatologic syndromes may complicate natural infection or vaccination in children. In the catcher’s crouch syndrome, a lumbar radiculoneuropathy causes popliteal fossa pain on arising in the morning. Exacerbation of the pain by knee extension encourages the assumption of a baseball catcher’s crouch position (Fig. 104-1). The pain gradually subsides through the day but recurs the next morning. In the arm syndrome, brachial neuropathy causes arm and hand pain and dysesthesias that are worse at night. Both syndromes may occur beginning 1 to 2 months after

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infection or vaccination, with the initial episode lasting up to 2 months. Episodes recur for up to 1 year but eventually resolve without long-term sequelae.33 Laboratory Tests. Although rubella may be cultured from tissues and body fluids, including throat swabs, detecting antirubella IgM antibody usually establishes the diagnosis of acute rubella infection. Diagnosis by anti-IgG antibody seroconversion requires paired acute and convalescent sera. IgM and IgG are usually present at the onset of joint symptoms. IgM antibody levels peak 8 to 21 days after symptom

onset and wane by 5 weeks. Antirubella IgG rises rapidly over a period of 1 to 3 weeks and is long lived. A single positive IgG serum sample or a set of untitered IgG-positive screens only documents immunity.29 Differential Diagnosis. Rubella arthritis needs to be differentiated from other viral arthritides and from inflammatory arthritides, including rheumatoid arthritis. It may be confused with parvovirus B19 infection. Treatment and Prognosis Nonsteroidal anti-inflammatory drugs are useful to control symptoms. Some investigators have suggested the use of low to moderate doses of steroids to control symptoms and viremia.34 Long-term prognosis is good. ALPHAVIRUSES The members of the genus Alphavirus are enveloped, singlestranded RNA viruses transmitted by mosquitoes.35 Several cause acute febrile arthropathy, and their names reflect local appreciation of their clinical impact. For example, chikungunya means ‘that which twists or bends up’ (Tanzania). The related o’nyong-nyong virus means ‘joint breaker’ in the Acholi (Uganda) dialect. Igbo-ora is ‘the disease that breaks your wings.” Epidemiology

Figure 104-1  Typical stance of a child with post–rubella vaccination “catcher’s crouch” syndrome. (From Schaffner W, Fleet WF, Kilroy AW, et al: Polyneuropathy following rubella immunization: A follow-up study and review of the problem. Am J Dis Child 127:684, 1974.)

Chikungunya, o’nyong-nyong, and igbo-ora viruses form a serologically related group. Chikungunya virus was isolated during an epidemic of febrile arthritis in Tanzania between 1952 and 1953. Similar epidemics probably occurred in Africa, Asia, India, Indonesia, and possibly the southern United States as early as 1779.35 Mosquitoes responsible for transmission to humans define its geographic distribution (Table 104-2). A feared consequence of global warming is spread of the geographic range of infected mosquitoes.36-39

Table 104-2  Mosquito Vectors and Reservoirs of Alphaviruses Virus

Mosquito

Reservoir

Region

Chikungunya virus

Aedes species Mansonia africana

Baboons, monkeys, Scotophilis   bat species

Africa, Asia

O’nyong-nyong virus

Anopheles funestus Anopheles gambiae

Unknown

Africa

Igbo-ora virus

Anopheles funestus Anopheles gambiae

Unknown

Ivory Coast

Ross River virus

Aedes vigilax Aedes camptorbynchus Culex annulirostris Mansonia uniformus Aedes polynesiensis Aedes aegypti

Rodents, marsupials, domestic   animals

Australia, New Zealand, Papua New Guinea, Pacific islands

Barmah forest virus

Aedes species Anopheles species Culex species

Unknown

Australia

Sindbis virus

Aedes species Culex species Culiseta species

Unknown

Sweden, Finland, Karelian   isthmus of Russia

Mayaro virus

Haemagogus janthinomys

Marmosets

Bolivia, Brazil, Peru

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Chikungunya fever occurs endemically and in epidemics.40 Outbreaks have been described in the Indian Ocean islands, Malaysia, and Hong Kong.41-44 An outbreak occurred in Italy in 2007. A large-scale outbreak of the serologically related o’nyong-nyong virus occurred in the Acholi province of northwestern Uganda in February 1959; this outbreak spread through Uganda and the surrounding region at a rate of 2 to 3 kilometers daily, affecting more than 2 million people within 2 years.45 After the initial o’nyong-nyong epidemic, clinical disease was not detected again until it re-emerged in the Acholi region in 1996.46 Despite the absence of outbreaks in the intervening years, serologic surveys have demonstrated that o’nyong-nyong virus is endemic.47 Weber’s line is a hypothetical demarcation separating the Australian and Asiatic geographic zones. Antibodies to chikungunya virus are found west of Weber’s line, and Ross River virus antibodies are found only east of it. Ross River virus causes epidemics of fever and rash in ­Australia, New Zealand, and the western Pacific islands.48 In the Fiji Islands from 1979 to 1980, Ross River virus caused febrile polyarthritis in more than 40,000 individuals.49 In ­Australia, endemic cases and epidemics occur in tropical and temperate regions annually.50 Most cases occur in Queensland and New South Wales territories, where high rainfall and subsequent increases in mosquito populations usually precede epidemic periods. Infection rates in ­Australia range from 0.2% to 3.5% per year. Male and female infection rates are similar, but there is a female predominance in presenting cases. Most infected adults are symptomatic; the case rate for children is lower. Barmah Forest virus, another alphavirus with an increasing incidence in Australia, may manifest in a fashion similar to Ross River virus.51-56 Individuals involved in outdoor activities or occupations in forested areas in Sweden, Finland, and the neighboring Karelian isthmus of Russia are at greatest risk for infection with Sindbis virus; in those regions, it is known as Okelbo disease, Pogosta disease, and Karelian fever, respectively. Birds are the intermediate host.57 It has also been reported in central Africa, Zimbabwe, South Africa, and Australia in sporadic cases or small outbreaks.35 Mayaro virus, first recognized in Trinidad in 1954, is endemic in the tropical rain forests of Bolivia, Brazil, and Peru. Cases have been imported into the United States in individuals traveling from endemic areas.58 Diagnosis Clinical Features. Chikungunya fever presents with an explosive onset of high fever and severe arthralgia after a 1- to 12-day incubation period. The fever lasts 1 to 7 days. Typically, a macular or maculopapular, sometimes pruritic rash on the torso, extremities, and occasionally the face, palms, and soles occurs on day 2 to 5 of illness as the patient defervesces. The rash may last 1 to 5 days and may recur with fever. Isolated petechiae and mucosal bleeding may occur. In some patients, involved skin desquamates.59,60 Chemosis is prominent. Headache, photophobia, retro-orbital pain, pharyngitis, anorexia, nausea, vomiting, and abdominal pain may be present. Diffuse myalgia and back and shoulder pain are common. Migratory polyarthralgia, stiffness, and

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swelling affect predominantly the small joints of the hands, wrists, feet, and ankles. Large joints are less severely affected. Previously injured joints may be disproportionately affected. Large effusions are uncommon. Symptoms in children tend to be milder. Low-titer rheumatoid factor may be found in those with long-standing symptoms. O’nyong-nyong fever is clinically similar to chikungunya fever.61,62 In 1984, igbo-ora caused an epidemic of fever, myalgias, arthralgias, and rash in four Ivory Coast villages. Sequencing the isolates from the 1996 outbreak of o’nyongnyong fever suggested that igbo-ora virus is a variant of o’nyong-nyong virus.46 Ross River virus polyarthralgia is severe, incapacitating, and often migratory and asymmetric.63 Symptoms follow a 7- to 11-day incubation period. Finger interphalangeal and metacarpophalangeal joints, wrists, knees, ankles, shoulders, elbows, and toes are often involved. Polyarticular swelling and tenosynovitis are common. Arthralgias are worse in the morning and after inactivity. Rash is macular, papular, or maculopapular and may be pruritic. Vesicles, papules, or petechiae are typically seen on the trunk and extremities. The palms, soles, and face may be involved. Rash typically appears 1 to 2 days before joint symptoms, but it may occur anywhere from 11 days before to 15 days after the onset of arthralgias, and it resolves by fading to a brownish discoloration or by desquamation. Half of patients have no fever, and those who do may have only modest fevers lasting 1 to 3 days. Nausea, headache, and myalgia are common. Respiratory symptoms, mild photophobia, and lymphadenopathy may occur. Up to a third of patients have paresthesias and palm or sole pain. Carpal tunnel syndrome may be seen. Arthritis is less common and less prominent in Barmah Forest virus infection than in Ross River virus infection, but the rash is more common and florid.64,65 Rash and arthralgia are the presenting symptoms in Sindbis virus infection, although one may precede the other by a few days. Constitutional symptoms are usually mild and include low-grade fever, headache, fatigue, malaise, nausea, vomiting, pharyngitis, and paresthesias. A macular rash typically begins on the torso and then spreads to the arms and legs, palms, soles, and occasionally head. Macules evolve to form papules that tend to vesiculate. Vesiculation is prominent on pressure points, including the palms and soles. As the rash fades, a brownish discoloration is left. Vesicles on the palms and soles may become hemorrhagic. The rash may recur during convalescence.66 A Mayaro virus outbreak in Belterra, Brazil, in 1988 was characterized by sudden onset of fever, headache, dizziness, chills, and arthralgias in the wrists, fingers, ankles, and toes. The clinical attack rate was 80%. Joint swelling, unilateral inguinal lymphadenopathy, and leukopenia may be present. A maculopapular rash on the trunk and extremities lasts about 3 days.67 Laboratory Tests. The diagnosis of alphavirus infection requires laboratory confirmation. Any febrile patient ­residing in or returning from an endemic area should have a laboratory investigation. Chikungunya virus may be isolated from serum on days 2 through 4 of illness.68 Neutralizing antibody, hemagglutination inhibition activity, and complement fixation tests may be used to detect antibodies. ­Chikungunya virus–specific IgM antibodies may be found for

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6 months or longer.69 O’nyong-nyong virus may be isolated by intracerebral injection into suckling mice, in which it produces alopecia, rash, and runting. Hemagglutination inhibition or complement fixation tests identify o’nyong-nyong virus.70,71 Because chikungunya and o’nyong-nyong viruses are closely related serologically, mouse antisera raised to chikungunya virus or o’nyong-nyong virus react equally well with o’nyong-nyong virus, but o’nyong-nyong antisera does not react well with chikungunya virus. Molecular detection methods have improved diagnostic specificity.72-75 Specific reverse-transcriptase polymerase chain reaction–based assays for viral RNA detection have been developed.73,76 In chikungunya fever, synovial fluid shows decreased viscosity, poor mucin clot, and 2000 to 5000 white blood cells/mm3. Ross River virus has been isolated only from antibody-negative sera. In the Australian epidemics before 1979, patients were antibody positive at the time of presentation. In contrast, patients in the Pacific island epidemics of 1979 to 1980 remained viremic and seronegative for up to 1 week after the onset of the symptoms. Synovial fluid cell counts range from 1500 to 13,800 cells/mm3, predominantly monocytes and vacuolated macrophages.77 Barmah Forest virus infection is confirmed by rising titers of specific IgG.64 Diagnosis of Sindbis virus infection is confirmed by specific serology. Pathogenesis Little is known about the pathogenesis of chikungunya fever or arthritis. Involved skin shows erythrocyte extravasation from superficial capillaries and perivascular cuffing. The virus adsorbs to human platelets, causing aggregation, suggesting a mechanism for bleeding. Synovitis probably results from direct viral infection of synovium. In one patient with chronic arthropathy, the synovium appeared atrophic on arthroscopy and was histologically normal.78 The mechanisms of o’nyong-nyong virus pathogenesis are unknown. However, the virus was isolated from peripheral blood mononuclear cells in a patient in Chad.79 Ross River virus antigen may be detected early in monocytes and macrophages by immunofluorescence, but intact virus is not identifiable by electron microscopy or cell culture.80 Erythematous and purpuric rashes show mild dermal perivascular mononuclear cell infiltrates, mostly T lymphocytes. Purpuric areas also show erythrocyte extravasation. Viral antigen may be detected in epithelial cells in erythematous and purpuric skin lesions and in perivascular zones in erythematous lesions.81 Sindbis virus has been isolated from a skin vesicle in the absence of viremia. Skin lesions show perivascular edema, hemorrhage, lymphocytic infiltrates, and areas of necrosis. Anti–Sindbis virus IgM may persist for years, raising the possibility that Sindbis virus arthritis is associated with viral persistence.82 Treatment and Prognosis Management is supportive. Nonsteroidal anti-inflammatory agents are useful, but aspirin should be avoided in view of the tendency for alphavirus rashes to develop a hemorrhagic component. Chloroquine has been used in chikungunya fever when nonsteroidal anti-inflammatory agents failed.83

During the acute attack, range-of-motion exercises may decrease stiffness. In general, the management of alphavirus infection is symptomatic; patients recover without sequelae. After acute chikungunya fever, symptoms may persist for months before resolution. Approximately 10% of patients still have joint symptoms 1 year after infection.78 A few patients may develop chronic arthralgia. Case reports suggest that a few patients with chronic arthropathy develop destructive joint lesions, but a second process cannot be ruled out. For persons with Ross River virus arthritis, mild exercise tends to improve joint symptoms. Half of all patients are able to resume their daily activities within 4 weeks, although residual polyarthralgia may be present. Joint symptoms may recur.84 Arthralgia, myalgia, and lethargy may continue for at least 6 months in up to half of patients.64 Relapsing episodes gradually resolve, but joint symptoms have been reported in a few patients for up to 3 years.63,85 Nonerosive chronic arthropathy is common after Sindbis virus infection, with up to one third of patients having arthropathy 2 years or longer after onset. A smaller number have symptoms as long as 5 to 6 years.82 Mayaro virus– infected patients have persistent arthralgias for months.

HEPATITIS B VIRUS Hepatitis B virus (HBV), a member of the family Hepadnaviridae, genus Orthohepadnavirus, is an enveloped, double-stranded, icosahedral DNA virus measuring 42 nm in diameter.86,87 EPIDEMIOLOGY HBV occurs worldwide and is transmitted by parenteral and sexual routes. Prevalence is highest in Asia, the Middle East, and sub-Saharan Africa. In China, the prevalence is as high as 10%, compared with 0.01% in the United States. In endemic regions, infection occurs at an early age, frequently perinatally. Early HBV infection is usually asymptomatic. Rates of HBV carriage and specific antibody positivity decline with age. In the West, most infections are acquired during adulthood through sexual or needle exposures, leading to acute hepatitis. Of those with hepatitis, 5% to 10% develop persistent infection. In endemic regions, HBV is a common cause of chronic liver disease and a leading cause of hepatocellular carcinoma.86 CLINICAL FEATURES The time from infection to clinical hepatitis is usually 45 to 120 days. A preicteric prodromal period lasts several days to a month and may be associated with fever, myalgia, malaise, anorexia, nausea, and vomiting. Joint involvement is usually sudden in onset and often severe, with symmetric and simultaneous involvement of several joints. Alternatively, arthritis may be migratory or additive.88,89 The joints of the hand and knee are most often affected, but wrists, ankles, elbows, shoulders, and other large joints may be involved as well. Fusiform swelling occurs in the small joints of the hand. Morning stiffness is common. Arthritis and urticaria may precede jaundice by days to weeks and persist for ­several weeks, but they usually subside soon after the onset of ­clinical jaundice. Arthritis

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is usually limited to the preicteric prodrome. Those who develop chronic active hepatitis or chronic HBV viremia may have recurrent polyarthralgia or polyarthritis.90 Polyarteritis nodosa may be associated with chronic hepatitis B viremia.91 DIAGNOSIS Urticaria in the presence of polyarthritis should suggest the possibility of HBV infection. Acute hepatitis may be asymptomatic, but elevated bilirubin and transaminases are usually present when arthritis appears. At the onset of arthritis, peak levels of serum hepatitis B surface antigen (HBsAg) are detectable. Virions, viral DNA, polymerase, and hepatitis B antigen may be detectable in serum. Anti–hepatitis B core antigen IgM antibodies indicate acute HBV infection rather than past or chronic infection.92

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arthritis, palpable purpura, and cryoglobulinemia—is associated with HCV infection in most cases. Cryoglobulinemia in HCV infection is also seen in the absence of arthritis and purpura.105 Cryoglobulinemia may be associated with necrotizing vasculitis. The presence of anti-HCV antibodies in essential mixed cryoglobulinemia is associated with more severe cutaneous involvement, such as Raynaud’s phenomena, purpura, livedo, distal ulcers, and gangrene.106 HCV RNA may be found in 75% of cryoprecipitates from patients with essential mixed cryoglobulinemia and anti-HCV antibodies.107 DIAGNOSIS

Significant viremia occurs early in infection. Soluble immune complexes with circulating HBsAg form as anti-HBsAg antibodies are produced. An immune complex–mediated arthritis usually results, with immune complex deposition in synovium. Immune complexes containing HBsAg, antibody, and complement components may be detected.

Serologic tests use an array of antigens in an enzyme immunoassay. A recombinant antigen strip immunoblot assay is confirmatory.108 Polymerase chain reaction–based diagnostics allow confirmation of HCV viremia, viral load, and genotype.100,101 A minority of patients may have HCV RNA detectable by polymerase chain reaction amplification methods in the absence of positive serologic findings.108-113 A liver biopsy for staging of liver disease is usually indicated in patients who have serum anti-HCV antibody or RNA, even in the setting of normal liver enzymes, because liver enzymes do not reflect liver histology. A number of algorithms based on blood measures of liver involvement have been proposed to aid in staging.114-118

HEPATITIS C VIRUS

PATHOGENESIS

Hepatitis C virus (HCV), a member of the family Flaviviridae, is an enveloped, single-stranded, spherical RNA virus measuring 38 to 50 nm in diameter.93,94

HCV infection persists despite antibody response to viral epitopes. Increased CD4+CD25+ regulatory T lymphocytes may blunt the immune response to HCV.118 A high rate of mutation in the envelope protein is responsible for the emergence of neutralization-escape mutants and quasi-­species.119 HCV may contain an IgG Fc binding region on its surface; humoral immune response to HCV would, by epitope spreading, also target bound immunoglobulin Fc structures.120 Chronic HCV infection leads to cirrhosis, end-stage liver failure, and hepatocellular carcinoma after a period of up to 20 years, but the frequency of these sequelae is debated and the mechanisms by which they occur are unknown.121

PATHOGENESIS

EPIDEMIOLOGY HCV infection occurs worldwide. Like HBV infection, seroprevalence is higher in Africa and Asia, where it may cause one fourth of acute and chronic hepatitis cases. In Japan, up to 50% of hepatitides may be caused by HCV.95 In the United States, an estimated 2.7 million individuals are infected.96,97 HCV is transmitted by the parenteral route. Sexual transmission may occur but is uncommon.98 More than half of all cases of non-A, non-B hepatitis are attributable to HCV infection.99 Multiple HCV genotypes and quasi-species are organized into six major groups. They differ in pathogenicity, severity of disease, and response to interferon.99-103 CLINICAL FEATURES Acute HCV infection is usually benign. Up to 80% of posttransfusion infections are anicteric and asymptomatic. Liver enzyme elevations, when present, are usually minimal. Normal transaminase levels do not exclude HCV infection. Community-acquired cases may present more symptomatically and with significant transaminase elevations. Acute fulminant HCV hepatitis is rare. Acute HCV infection may be accompanied by acute-onset polyarthritis in a rheumatoid distribution, including the small joints of the hand, wrists, shoulders, knees, and hips.104 HCV is often associated with mixed (type II and III) cryoglobulinemia. Essential mixed cryoglobulinemia—a triad of

TREATMENT Interferon-α2b at a dose of 3 million units or higher three times weekly for 6 months suppresses viral titers and ameliorates HCV liver disease in about half of patients and may benefit HCV-associated cryoglobulinemia.122 Relapse after completion of the initial course of therapy is common. The use of pegylated interferons to increase drug half-life and decrease clearance and the addition of ribavirin have improved outcomes.123 There is controversy whether interferon therapy precipitates autoimmune diseases such as autoimmune thyroiditis.124,125 Those with cryoglobulinemia who fail interferon therapy require immunosuppressive therapy when vasculitis is present.

HUMAN T-LYMPHOTROPIC VIRUS TYPE 1 Human T-lymphotropic virus type 1 (HTLV-1), a retrovirus, is endemic in southern Japan, where it has been associated with oligoarthritis and a nodular rash (Fig. 104-2).

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Figure 104-2  Nodular synovitis associated with human T-­lymphotropic virus type 1 infection. (From Yancey WB Jr, Dolson LH, Oblon D, et al: HTLVI-associated adult T-cell leukemia/lymphoma presenting with nodular synovial masses. Am J Med 89:676, 1990.)

Anti-HTLV serology is positive. Type C viral particles are found in skin nodules. Synovial tissue is infiltrated by leukemic T lymphocytes with lobulated nuclei.126-128

OTHER VIRUSES There are numerous other commonly encountered viral syndromes in which joint involvement occasionally occurs. Children with varicella rarely develop brief monarticular or pauciarticular arthritis.129 Mumps in adults is occasionally associated with small or large joint synovitis preceding or following the onset of parotitis by up to 4 weeks. Mumps arthritis may last several weeks.130 Infection with adenovirus and coxsackieviruses A9, B2, B3, B4, and B6 has been associated with recurrent episodes of polyarthritis, pleuritis, myalgia, rash, pharyngitis, myocarditis, and leukocytosis.131 Epstein-Barr virus–induced mononucleosis is frequently accompanied by polyarthralgia, but monarticular knee arthritis sometimes occurs. A few cases of polyarthritis, fever, and myalgias due to echovirus 9 infection have been reported.132 Arthritis associated with herpes simplex virus or cytomegalovirus infection is rare, but a severe cytomegalovirus polyarthritis has been described in several immunocompromised bone marrow transplant recipients.133 Herpes hominis occasionally causes arthritis of the knee in wrestlers, a condition referred to as herpes gladiatorum.134 Knee arthritis after vaccinia inoculation has been reported as a rare complication.135 REFERENCES    1. Pennisi E: Teetering on the brink of danger. Science 271:1665, 1996.    2. Albert LJ, Inman RD: Molecular mimicry and autoimmunity. N Engl J Med 341:2068, 1999.    3. Gillespie SM, Cartter ML, Asch S, et al: Occupational risk of human parvovirus B19 infection for school and day-care personnel during an outbreak of erythema infectiosum. JAMA 263:2061, 1990.    4. Bell LM, Naides SJ, Stoffman P, et al: Human parvovirus B19 infection among hospital staff members after contact with infected patients. N Engl J Med 321:485, 1989.    5. Anderson MJ, Higgins PG, Davis LR, et al: Experimental parvoviral infection in humans. J Infect Dis 152:257, 1985.

   6. Naides SJ: Rheumatic manifestations of parvovirus B19 infection. Rheum Dis Clin North Am 24:375, 1998.    7. Von Poblotzki A, Hemauer A, Gigler A, et al: Antibodies to the nonstructural protein of parvovirus B19 in persistently infected patients: Implications for pathogenesis. J Infect Dis 172:1356, 1995.    8. Takahashi Y, Murai C, Shibata S, et al: Human parvovirus B19 as a causative agent for rheumatoid arthritis. Proc Natl Acad Sci U S A 95:8227, 1998.    9. Hsu TC, Tzang BS, Huang CN, et al: Increased expression and secretion of interleukin-6 in human parvovirus B19 non-structural protein (NS1) transfected COS-7 epithelial cells. Clin Exp Immunol 144:152, 2006.   10. Sol N, Morinet F, Alizon M, et al: Trans-activation of the long terminal repeat of human immunodeficiency virus type 1 by the parvovirus B19 NS1 gene product. J Gen Virol 74:2011, 1993.   11. Peterlana D, Puccetti A, Beri R, et al: The presence of parvovirus B19 VP and NS1 genes in the synovium is not correlated with rheumatoid arthritis. J Rheumatol 30:1907, 2003.   12. Poole BD, Karetnyi YV, Naides SJ: Parvovirus B19-induced apoptosis of hepatocytes. J Virol 78:7775, 2004.   13. Poole BD, Zhou J, Grote A, et al: Apoptosis of liver-derived cells induced by parvovirus B19 nonstructural protein. J Virol 80:4114, 2006.   14. Karetnyi YV, Beck PR, Markin RS, et al: Human parvovirus B19 infection in acute fulminant liver failure. Arch Virol 144:1713, 1999.   15. Gabriel SE, Espy M, Erdman DD, et al: The role of parvovirus B19 in the pathogenesis of giant cell arteritis: A preliminary evaluation. Arthritis Rheum 42:1255, 1999.   16. Veraldi S, Mancuso R, Rizzitelli E, et al: Henoch-Schönlein syndrome associated with human parvovirus B19 primary infection. Eur J Dermatol 9:232, 1999.   17. Heegaard ED, Rosthoj S, Petersen B, et al: Role of parvovirus B19 infection in childhood idiopathic thrombocytopenic purpura. Acta Paediatr 88:614, 1999.   18. Frickhofen N, Abkowitz JL, Safford M, et al: Persistent B19 parvovirus infection in patients infected with human immunodeficiency virus type 1 (HIV-1): A treatable cause of anemia in AIDS. Ann Intern Med 113:926, 1990.   19. Ager EA, Chin TDY, Poland JD: Epidemic erythema infectiosum. N Engl J Med 275:1326, 1966.   20. Naides SJ, Field EH: Transient rheumatoid factor positivity in acute parvovirus B19 infection. Arch Intern Med 148:2587, 1988.   21. Kerr JR, Boyd N: Autoantibodies following parvovirus B19 infection. J Infect 32:41, 1996.   22. Lunardi C, Tiso M, Borgato L, et al: Chronic parvovirus B19 infection induces the production of anti-virus antibodies with autoantigen binding properties. Euro J Immunol 28:936, 1998.   23. Meyer O: Parvovirus B19 and autoimmune diseases. Joint Bone Spine 70:6, 2003.   24. von Landenberg P, et al: Antiphospholipid antibodies in pediatric and adult patients with rheumatic disease are associated with parvovirus B19 infection. Arthritis Rheum 48:1939, 2003.   25. Anderson LJ, Tsou C, Parker RA, et al: Detection of antibodies and antigens of human parvovirus B19 by enzyme-linked immunosorbent assay. J Clin Microbiol 24:522, 1986.   26. Cohen BJ: Detection of parvovirus B19-specific IgM by antibody capture radioimmunoassay. J Virol Methods 66:1, 1997.   27. Soderlund M, von Essen R, Haapasaari J, et al: Persistence of parvovirus B19 DNA in synovial membranes of young patients with and without chronic arthropathy. Lancet 349:1063, 1997.   28. Frey TK: Molecular biology of rubella virus. Adv Virus Res 44:69, 1994.   29. Chantler J, Wolinsky JS, Tingle A: Rubella. In Knipe DM, Howley PM, et al (eds): Fields Virology, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2001, pp 963-990.   30. Mims CA, Stokes A, Grahame R: Synthesis of antibodies, including antiviral antibodies, in the knee joints of patients with arthritis. Ann Rheum Dis 44:734, 1985.   31. Tingle AJ, Allen M, Petty RE, et al: Rubella-associated arthritis. I. Comparative study of joint manifestations associated with natural rubella infection and RA 27/3 rubella immunization. Ann Rheum Dis 45:110, 1986.   32. Howson CP, Katz M, Johnston RB Jr, et al: Chronic arthritis after rubella vaccination. Clin Infect Dis 15:307, 1992.

PART 17    33. Schaffner W, Fleet WF, Kilroy AW, et al: Polyneuropathy following rubella immunization: A follow-up study and review of the problem. Am J Dis Child 127:684, 1974.   34. Mitchell LA, Tingle AJ, Shukin R, et al: Chronic rubella vaccineassociated arthropathy. Arch Intern Med 153:2268, 1993.   35. Griffin DE: Alphaviruses. In Knipe DM, Howley PM, et al (eds): Fields Virology, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2001, pp 917-962.   36. Bryan JH, Foley DH, Sutherst RW: Malaria transmission and climate change in Australia. Med J Aust 164:345, 1996.   37. Jetten TH, Focks DA: Potential changes in the distribution of dengue transmission under climate warming. Am J Trop Med Hyg 57:285, 1997.   38. Reiter P: Climate change and mosquito-borne disease. Environ Health Perspect 109(Suppl 1):141, 2001.   39. Rydzanicz K, Kiewra D, Lonc E: Changes in range of mosquito-borne diseases affected by global climatic fluctuations. Wiad Parazytol 52:73, 2006.   40. Halstead SB, Nimmannitya S, Margiotta MR: Dengue and chikun­ gunya virus infection in man in Thailand, 1962-1964. II. Observations on disease in outpatients. Am J Trop Med Hyg 18:972, 1969.   41. Sam IC, AbuBakar S: Chikungunya virus infection. Med J Malaysia 61:264, 2006.   42. Schuffenecker I, Iteman I, Michault A, et al: Genome microevolution of chikungunya viruses causing the Indian Ocean outbreak. Plo S Med 3:e263, 2006.   43. Lee N, Wong CK, Lam WY, et al: Chikungunya fever, Hong Kong. Emerg Infect Dis 12:1790, 2006.   44. AbuBakar S, Sam JC, Wong PF, et al: Reemergence of endemic Chikungunya, Malaysia. Emerg Infect Dis 13:147, 2007.   45. Williams MC, Woodall JP, Gillett JD: O’nyong-nyong fever: An epidemic in East Africa. VII. Virus isolations from man and serological studies up to July 1961. Trans R Soc Trop Med Hyg 59:186, 1965.   46. Lanciotti RS, Ludwig ML, Rwaguma EB, et al: Emergence of epidemic o’nyong-nyong fever in Uganda, after a 35 year absence. Virology 252:258, 1998.   47. Marshall TF, Keenlyside RA, Johnson BK, et al: The epidemiology of o’nyong-nyong in the Kano Plain, Kenya. Ann Trop Med Parasitol 76:153, 1982.   48. Harley D, Sleigh A, Ritchie S: Ross River virus transmission, infection, and disease: A cross-disciplinary review. Clin Microbiol Rev 14:909, 2001.   49. Bennett NM, Cunningham AL, Fraser JR, et al: Epidemic polyarthritis acquired in Fiji. Med J Aust 1:316, 1980.   50. Mudge PR, Aaskov JG: Epidemic polyarthritis in Australia, 19801981. Med J Aust 2:269, 1983.   51. Lindsay MDA, Johansen CA, Broom AK, et al: Emergence of Barmah Forest virus in western Australia. Emerg Infect Dis 1:22, 1995.   52. Harvey L, Dwyer D: Recent increases in the notification of Barmah Forest virus infections in New South Wales. N S W Public Health Bull 15:199, 2004.   53. Liu C, Broom AK, Kurcz N, et al: Communicable Diseases Network Australia: National Arbovirus and Malaria Advisory Committee annual report 2004-05. Commun Dis Intell 29:341, 2005.   54. Quinn HE, Gatton ML, Hall G, et al: Analysis of Barmah Forest virus disease activity in Queensland, Australia, 1993-2003: Identification of a large, isolated outbreak of disease. J Med Entomol 42:882, 2005.   55. Liu C, Johansen C, Kurucz N, et al: Communicable Diseases Network Australia: National Arbovirus and Malaria Advisory Committee annual report, 2005-06. Commun Dis Intell 30:411, 2006.   56. Kelly-Hope LA, Kay BH, Purdie DM, et al: The risk of Ross River and Barmah Forest virus disease in Queensland: Implications for New Zealand. Aust N Z J Public Health 26:69, 2002.   57. Brummer-Korvenkontio M, Vapalahti O, Kuusisto P, et al: Epidemiology of Sindbis virus infections in Finland 1981-96: Possible factors explaining a peculiar disease pattern. Epidemiol Infect 129:335, 2002.   58. Tesh RB, Watts DM, Russell KL, et al: Mayaro virus disease: An emerging mosquito-borne zoonosis in tropical South America. Clin Infect Dis 28:67, 1999.   59. Moore CG: Aedes albopictus in the United States: Current status and prospects for further spread. J Am Mosq Control Assoc 15:221, 1999.   60. Halstead SB, Udomsakdi S, Singharaj P, et al: Dengue and chikun­ gunya virus infection in man in Thailand, 1962-1964. III. Clinical, epidemiologic, and virologic observations on disease in non-indigenous white persons. Am J Trop Med Hyg 18:984, 1969.

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INFECTION AND ARTHRITIS

1769

  61. Sanders EJ, Rwaguma EB, Kawamata J, et al: O’nyong-nyong fever in south-central Uganda, 1996-1997: Description of the epidemic and results of a household-based seroprevalence survey. J Infect Dis 180:1436, 1999.   62. Kiwanuka N, Sanders EJ, Rwaguma EB, et al: O’nyong-nyong fever in south-central Uganda, 1996-1997: Clinical features and validation of a clinical case definition for surveillance purposes. Clin Infect Dis 29:1243, 1999.   63. Fraser JRE: Epidemic polyarthritis and Ross River virus disease. Clin Rheum Dis 12:369, 1986.   64. Flexman JP, Smith DW, Mackenzie JS, et al: A comparison of the diseases caused by Ross River virus and Barmah Forest virus. Med J Aust 169:159, 1998.   65. Passmore J, O’Grady KA, Moran R, et al: An outbreak of Barmah Forest virus disease in Victoria. Commun Dis Intell 26:600, 2002.   66. Julkunen I, Brummer-Korvenkontio M, Hautanen A, et al: Elevated serum immune complex levels in Pogosta disease, an acute alphavirus infection with rash and arthritis. J Clin Lab Immunol 21:77, 1986.   67. Pinheiro FP, Freitas RB, Travassos da Rosa JF, et al: An outbreak of Mayaro virus disease in Belterra, Brazil. I. Clinical and virological findings. Am J Trop Med Hyg 30:674, 1981.   68. Nimmannitya S, Halstead SB, Cohen SN, et al: Dengue and chikungunya virus infection in man in Thailand, 1962-1964. I. Observations on hospitalized patients with hemorrhagic fever. Am J Trop Med Hyg 18:954, 1969.   69. Nakitare GW, Bundo K, Igarashi A: Enzyme-linked immunosorbent assay (ELISA) for antibody titers against chikungunya virus of human serum from Kenya. Trop Med 25:119, 1983.   70. Williams MC, Woodall JP, Porterfield JS: O’nyong-nyong fever: An epidemic virus disease in East Africa. V. Human antibody studies by plaque inhibition and other serological tests. Trans R Soc Trop Med Hyg 56:166, 1962.   71. Williams MC, Woodall JP, Porterfield JS: O’nyong-nyong fever: An epidemic virus disease in East Africa. Trans R Soc Trop Med Hyg 59:186, 1965.   72. Hasebe F, Parquet MC, Pandey BD, et al: Combined detection and genotyping of chikungunya virus by a specific reverse transcriptionpolymerase chain reaction. J Med Virol 67:370, 2002.   73. Pfeffer M, Linssen B, Parke MD, et al: Specific detection of chikungunya virus using a RT-PCR/nested PCR combination. J Vet Med B Infect Dis Vet Public Health 49:49, 2002.   74. Corwin A, Simanjuntak CH, Ansari A: Emerging disease surveillance in Southeast Asia. Ann Acad Med Singapore 26:628, 1997.   75. Junt T, Heraud JM, Lelarge J, et al: Determination of natural versus laboratory human infection with Mayaro virus by molecular analysis. Epidemiol Infect 123:511, 1999.   76. Pastorino B, Bessaud M, Grandadam M, et al: Development of a TaqMan RT-PCR assay without RNA extraction step for the detection and quantification of African chikungunya viruses. J Virol Methods 124:65, 2005.   77. Aaskov JG, Mataika JU, Lawrence GW, et al: An epidemic of Ross River virus infection in Fiji, 1979. Am J Trop Med Hyg 30:1053, 1981.   78. Brighton SW, Prozesky OW, De la Harpe AL: Chikungunya virus infection: A retrospective study of 107 cases. S Afr Med J 63:313, 1983.   79. Bessaud M, Peyrefitte CN, Pastorino BA, et al: O’nyong-nyong virus, Chad. Emerg Infect Dis 12:1248, 2006.   80. Fraser JR, Cunningham AL, Clarris BJ, et al: Cytology of synovial effusions in epidemic polyarthritis. Aust N Z J Med 11:168, 1981.   81. Fraser JR, Ratnamohan VM, Dowling JP, et al: The exanthem of Ross River virus infection: Histology, location of virus antigen and nature of inflammatory infiltrate. J Clin Pathol 36:1256, 1983.   82. Niklasson B, Espmark A, Lundstrom J: Occurrence of arthralgia and specific IgM antibodies three to four years after Ockelbo disease. J Infect Dis 157:832, 1988.   83. Brighton SW: Chloroquine phosphate treatment of chronic chikungunya arthritis: An open pilot study. S Afr Med J 66:217, 1984.   84. Mylonas AD, Brown AM, Carthew TL, et al: Natural history of Ross River virus-induced epidemic polyarthritis. Med J Aust 177:356, 2002.   85. Laine M, Luukkainen R, Jalava J, et al: Prolonged arthritis associated with Sindbis-related (Pogosta) virus infection. Rheumatology (Oxford) 41:829, 2002.

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Viral Arthritis

  86. Robinson WS: Hepatitis B viruses: General features (human). In Webster RG, Granoff A (eds): Encyclopedia of Virology. San Diego, Academic Press, 1994, pp 554-559.   87. Bendinelli M, Pistello M, Maggi F, et al: Blood-borne hepatitis viruses: Hepatitis B, C, D, and G viruses and TT virus. In Specter S, Hodinka RL, Young SA (eds): Clinical Virology Manual. Washington, DC, ASM Press, 2000, pp 306-337.   88. Hollinger FB, Liang TJ: Hepatitis B virus. In Knipe DM, Howley PM, Griffin DE, et al (eds): Fields Virology, Philadelphia, Lippincott Williams & Wilkins, 2001, pp 2971-3036.   89. Alarcon GS, Townes AS: Arthritis in viral hepatitis: Report of two cases and review of the literature. Johns Hopkins Med J 132:1, 1973.   90. Csepregi A, Rojkovich B, Nemesanszky E, et al: Chronic seropositive polyarthritis associated with hepatitis B virus-induced chronic liver disease: A sequel of virus persistence. Arthritis Rheum 43:232, 2000.   91. Guillevin L, Lhote F, Cohen P, et al: Polyarteritis nodosa related to hepatitis B virus: A prospective study with long-term observation of 41 patients. Medicine (Baltimore) 74:238, 1995.   92. Hoofnagle JH: Serologic markers of hepatitis B virus infection. Annu Rev Med 32:1, 1981.   93. Gronboek KE, Jensen OJ, Krarup HB, et al: Biochemical, virological and histopathological changes in Danish blood donors with antibodies to hepatitis C virus. Dan Med Bull 43:186, 1996.   94. Lindebach BD, Rice CM: Flaviviridae: The viruses and their replication. In Knipe DM, Howley PM, Griffin DE, et al (eds): Fields Virology. Philadelphia, Lippincott Williams & Wilkins, 2001, pp 991-1041.   95. Kuboki M, Shinzawa H, Shao L, et al: A cohort study of hepatitis C virus (HCV) infection in an HCV epidemic area of Japan: Age and sex-related seroprevalence of anti-HCV antibody, frequency of viremia, biochemical abnormality and histological changes. Liver 19:88, 1999.   96. Alter MJ, Mast EE: The epidemiology of viral hepatitis in the United States. Gastroenterol Clin North Am 23:437, 1994.   97. Williams I: Epidemiology of hepatitis C in the United States. Am J Med 107:2S, 1999.   98. Neumayr G, Propst A, Schwaighofer H, et al: Lack of evidence for the heterosexual transmission of hepatitis C. QJM 92:505, 1999.   99. Bhandari BN, Wright TL: Hepatitis C: An overview. Annu Rev Med 46:309, 1995. 100. Pawlotsky JM: Hepatitis C virus genetic variability: Pathogenic and clinical implications. Clin Liver Dis 7:45, 2003. 101. Pawlotsky JM: Use and interpretation of hepatitis C virus diagnostic assays. Clin Liver Dis 7:127, 2003. 102. Davis GL: Hepatitis C virus genotypes and quasispecies. Am J Med 107:21S, 1999. 103. Simmonds P, Bukh J, Combet C, et al: Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology 42:962, 2005. 104. Siegel LB, Cohn L, Nashel D: Rheumatic manifestations of hepatitis C infection. Semin Arthritis Rheum 23:149, 1993. 105. Arranz FR, Diaz RD, Diez LI, et al: Cryoglobulinemic vasculitis associated with hepatitis C virus infection: A report of eight cases. Acta Derm Venereol (Stockh) 75:234, 1995. 106. Sansonno D, Cornacchiulo V, Iacobelli AR, et al: Localization of hepatitis C virus antigens in liver and skin tissues of chronic hepatitis C virus-infected patients with mixed cryoglobulinemia. Hepatology 21:305, 1995. 107. Munoz-Fernandez S, Barbado FJ, Martin Mola E, et al: Evidence of hepatitis C virus antibodies in the cryoprecipitate of patients with mixed cryoglobulinemia. J Rheumatol 21:229, 1994. 108. van der Poel CL: Hepatitis C virus: Into the fourth generation. Vox Sang 67(Suppl 3):95, 1994. 109. Schmidt WN, Klinzman D, LaBrecque DR, et al: Direct detection of hepatitis C virus (HCV) RNA from whole blood, and comparison with HCV RNA in plasma and peripheral blood mononuclear cells. J Med Virol 47:153, 1995. 110. Schmidt WN, Wu P, Cederna J, et al: Surreptitious hepatitis C virus (HCV) infection detected in the majority of patients with cryptogenic chronic hepatitis and negative HCV antibody tests. J Infect Dis 176:27, 1997.

111. Stapleton JT, Klinzman D, Schmidt WN, et al: Prospective comparison of whole-blood- and plasma-based hepatitis C virus RNA detection systems: Improved detection using whole blood as the source of viral RNA. J Clin Microbiol 37:484, 1999. 112. Schmidt W, Stapleton JT: Whole-blood hepatitis C virus RNA extraction methods. J Clin Microbiol 39:3812, 2001. 113. George SL, Gebhardt J, Klinzman D, et al: Hepatitis C virus viremia in HIV-infected individuals with negative HCV antibody tests. J Acquir Immune Defic Syndr 31:154, 2002. 114. Colletta C, Smirne C, Fabris C, et al: Value of two noninvasive methods to detect progression of fibrosis among HCV carriers with normal aminotransferases. Hepatology 42:838, 2005. 115. Wilson LE, Torbenson M, Astemborski J, et al: Progression of liver fibrosis among injection drug users with chronic hepatitis C. Hepatology 43:788, 2006. 116. Zaman A, Rosen HR, Ingram K, et al: Assessment of FIBROSpect II to detect hepatic fibrosis in chronic hepatitis C patients. Am J Med 120:e9, 2007. 117. Adams LA, Bulsara M, Rossi E, et al: Hepascore: An accurate validated predictor of liver fibrosis in chronic hepatitis C infection. Clin Chem 51:1867, 2005. 118. Bolacchi F, Sinistro A, Ciaprini C, et al: Increased hepatitis C virus (HCV)-specific CD4+CD25+ regulatory T lymphocytes and reduced HCV-specific CD4+ T cell response in HCV-infected patients with normal versus abnormal alanine aminotransferase levels. Clin Exp Immunol 144:188, 2006. 119. Shimizu YK, Hijikata M, Iwamoto A, et al: Neutralizing antibodies against hepatitis C virus and the emergence of neutralization escape mutant viruses. J Virol 68:1494, 1994. 120. Wunschmann S, Medh JD, Klinzmann D, et al: Characterization of hepatitis C virus (HCV) and HCV E2 interaction with CD81 and the low density lipoprotein receptor. J Virol 74:10055, 2000. 121. Seeff LB: Natural history of hepatitis C. In Liang TJ, Hoofnagle JH (eds): Hepatitis C. San Diego, Academic Press, 2000, pp 85-105. 122. Gish RG: Standards of treatment in chronic hepatitis C. Semin Liver Dis 19(Suppl 1):35, 1999. 123. Baker DE: Pegylated interferon plus ribavirin for the treatment of chronic hepatitis C. Rev Gastroenterol Disord 3:93, 2003. 124. Morisco F, Mazziotti G, Rotondi M, et al: Interferon-related thyroid autoimmunity and long-term clinical outcome of chronic hepatitis C. Dig Liver Dis 33:247, 2001. 125. Rocco A, Gargano S, Provenzano A, et al: Incidence of autoimmune thyroiditis in interferon-alpha treated and untreated patients with chronic hepatitis C virus infection. Neuroendocrinol Lett 22:39, 2001. 126. Yancey WB Jr, Dolson LH, Oblon D, et al: HTLV-I-associated adult T-cell leukemia/lymphoma presenting with nodular synovial masses. Am J Med 89:676, 1990. 127. Masuko-Hongo K, Nishioka K: HTLV-I associated arthropathy (HAAP)—a review. Ryoikibetsu Shokogun Shirizu 32:525, 2000. 128. Nishioka K, Nakajima T, Hasunuma T, et al: Rheumatic manifestation of human leukemia virus infection. Rheum Dis Clin North Am 19:489, 1993. 129. Chen MK, Wang CC, Lu JJ, et al: Varicella arthritis diagnosed by polymerase chain reaction. J Formos Med Assoc 98:519, 1999. 130. Gordon SC, Lauter CB: Mumps arthritis: A review of the literature. Rev Infect Dis 6:338, 1984. 131. Bayer AS: Arthritis associated with common viral infections: Mumps, coxsackievirus, and adenovirus. Postgrad Med 68:55, 1980. 132. Blotzer JW, Myers AR: Echovirus-associated polyarthritis: Report of a case with synovial fluid and synovial histologic characterization. Arthritis Rheum 21:978, 1978. 133. Burns LJ, Gingrich RD: Cytomegalovirus infection presenting as polyarticular arthritis following autologous BMT. Bone Marrow Transplant 11:77, 1993. 134. Shelley WB: Herpetic arthritis associated with disseminated herpes simplex in a wrestler. Br J Dermatol 103:209, 1980. 135. Silby HM, Farber R, O’Connell CJ, et al: Acute monarticular arthritis after vaccination: Report of a case with isolation of vaccinia virus from synovial fluid. Ann Intern Med 62:347, 1965.

105

Poststreptoccocal Arthritis and Rheumatic Fever ALLAN Gibofsky  •  John B. Zabriskie

KEY POINTS Acute rheumatic fever (ARF) is a delayed, nonsuppurative sequela of a pharyngeal infection with group A streptococci. Although there has been a dramatic decline in the severity and the mortality of the disease, there have been reports of its resurgence in the United States. Adequate treatment of documented streptococcal pharyngitis markedly reduces the incidence of subsequent ARF. ­Appropriate antimicrobial prophylaxis prevents recurrences of disease in known patients with ARF. The clinical presentation of ARF varies. The lack of a single pathognomonic feature has resulted in the development of the revised Jones criteria, which should be used to establish a diagnosis. The terms migrating and migratory are often used to describe the polyarthritis of ARF, but these designations are not meant to signify that the inflammation disappears in one joint when it appears in another. Rather, the various localizations usually overlap in time, and the onset, as opposed to the full course of the arthritis, “migrates” from joint to joint. Many investigators have suggested that poststreptococcal migratory arthritis (in adults and children) in the absence of carditis might be a entity distinct from ARF. Although these features may be seen (admittedly rarely), migratory arthritis without evidence of other major Jones criteria but supported by two minor manifestations still should be considered ARF, especially in children. Antibiotic prophylaxis with penicillin should be started ­immediately after the resolution of the acute episode. The optimal regimen consists of oral penicillin VK, 250,000 U twice a day, or parenteral penicillin G, 1.2 million U intramuscularly every 4 weeks.

Acute rheumatic fever (ARF) is a delayed, nonsuppurative sequela of pharyngeal infection with group A streptococci. After the initial streptococcal pharyngitis, there is a latent period of 2 to 3 weeks. The onset of disease usually is charac-­ terized by an acute febrile illness, which may manifest itself in one of three classic ways: (1) The patient may present with migratory arthritis predominantly involving the large joints of the body. (2) There may be concomitant clinical and laboratory signs of carditis and valvulitis. (3) There may be involvement of the central nervous system, manifesting as Sydenham’s chorea. The clinical episodes are self-­limiting, but damage to the valves may be chronic and progressive, resulting in cardiac decompensation and death. Although there has been a dramatic decline in the sever-­ ity and the mortality of the disease since the turn of the 20th century, there have been reports in recent years of its

­resurgence in the United States1 and in many military instal-­ lations throughout the world, a reminder that the disease remains a public health problem even in developed coun-­ tries. In addition, the disease continues essentially unabated in many developing countries. Estimates suggest there will be 10 to 20 million new cases per year in countries where two thirds of the world population lives.

EPIDEMIOLOGY The incidence of ARF began to decline long before the introduction of antibiotics into clinical practice, decreasing from 250 to 100 patients/100,000 population from 1862 to 1962 in Denmark.2 The introduction of antibiotics in 1950 rapidly accelerated this decline, until by 1980 the incidence ranged from 0.23 to 1.88 patients/100,000, with disease occurring primarily in children and teenagers. A notable exception has been in the native Hawaiian and Maori popu-­ lations (both of Polynesian ancestry), where the incidence continues to be 13.4/100,000 hospitalized children/year.3 Only a few M serotypes (types 5, 14, 18, and 24) have been identified with outbreaks of ARF, suggesting that cer-­ tain strains of group A streptococci may be more “rheu-­ matogenic” than others.4 In Trinidad, types 41 and 11 have been the most common strains isolated from the oropharynx of patients with ARF, however. In our own series, gathered over a 20-year period (Table 105-1), many different M sero-­ types were isolated, including six strains that could not be typed. Kaplan and colleagues5 isolated several M types from patients seen during an outbreak of ARF in Utah, and these strains were mucoid and nonmucoid in character. Whether or not certain strains are more “rheumatogenic” than others remains unresolved. What is true, however, is that a strep-­ tococcal strain capable of causing well-documented phar-­ yngitis is generally capable of causing ARF, although some notable exceptions have been recorded.6

PATHOGENESIS Although there is little evidence for the direct involve-­ ment of group A streptococci in the affected tissues of ARF patients, there is a large body of epidemiologic and immu-­ nologic evidence indirectly implicating group A strepto-­ cocci in the initiation of the disease process: (1) It is well known that outbreaks of ARF closely follow epidemics of either streptococcal sore throat or scarlet fever.6 (2) Ade-­ quate treatment of documented streptococcal pharyngitis markedly reduces the incidence of subsequent ARF.7 (3) Appropriate antimicrobial prophylaxis prevents recur-­ rence of disease in known patients with ARF.8 (4) If one tests the sera of most ARF patients for three ­ antistreptococcal 1771

1772 GIBOFSKY  |  Poststreptoccocal Arthritis and Rheumatic Fever

Table 105-1  Positive Throat Cultures for Group A   β-Hemolytic Streptococci among Rockefeller   University Hospital Rheumatic Fever   Patients (N = 87) M Type

RHD

No RHD

Total

Nontypable

1

5

6

1

1

1

2

2

0

1

1

5

1

1

2

6

1

1

2

12

0

2

2

18

2

2

4

19

2

1

3

28

1

0

1

Total

9

11

23

Joint Myocardium Capsule Cell wall Protein (M, R, T) Group carbohydrate

Valvular tissue Myocardial sarcolemma Vascular intima

Mucopeptide

Myocardial antigen

Protoplast membrane

Skin

Lipoteichoic acid

Kidney

Brain HLA antigen B cell antigen

RHD, patients with rheumatic heart disease; No RHD, patients without rheumatic heart disease.

a­ ntibodies (streptolysin O, hyaluronidase, and streptoki-­ nase), most ARF patients (whether or not they recall an antecedent streptococcal sore throat) have elevated anti-­ body titers to these antigens.9 A note of caution is necessary concerning documentation (either clinical or microbiologic) of an antecedent strep-­ tococcal infection. The frequency of isolation of group A streptococci from the oropharynx is extremely low even in populations with limited access to antibiotics. There seems to be an age-related discrepancy in the clinical documen-­ tation of an antecedent sore throat. In older children and young adults, the recollection of a streptococcal sore throat approaches 70%; in younger children, this rate approaches only 20%.1 It is important to have a high index of suspicion of ARF in children or young adults presenting with signs of arthritis or carditis or both even in the absence of a clini-­ cally documented sore throat. Another intriguing, and as yet unexplained, observation has been the invariable association of ARF only with strep-­ tococcal pharyngitis. Although there have been many out-­ breaks of impetigo, ARF almost never occurs after infection with these strains. In Trinidad, where impetigo and ARF are common infections, the strains colonizing the skin are different from the strains associated with ARF, and did not influence the incidence of ARF.10 The explanation for these observations remains obscure. Group A streptococci fall into two main classes based on differences in the C repeat regions of the M protein.11 One class is associated with streptococcal pharyngeal infection, and the other (with some exceptions) is commonly associated with impetigo. The particular strain of streptococci may be crucial in initiating the disease process. The pharyngeal site of infection with its large repository of lymphoid tissue also may be important in the initiation of the abnormal humoral response by the host to the antigens cross-reactive with tar-­ get organs. Finally, although impetigo strains do colonize the pharynx, they do not seem to elicit as strong an immuno-­ logic response to the M protein moiety as do the pharyngeal strains.12,13 This may prove to be an important factor, espe-­ cially in light of the known cross-reactions between various streptococcal structures and mammalian proteins.

Figure 105-1  Schematic representation of the various structures of group A streptococci. Note the wide variety of cross-reactions between its antigens and mammalian tissues.

GROUP A STREPTOCOCCI Figure 105-1 is a schematic cross-section of group A strepto-­ cocci. The capsule is composed of equimolar concentrations of N-acetyl glucosamine and glucuronic acid and is struc-­ turally identical to hyaluronic acid of mammalian tissues.14 Although numerous attempts to produce antibodies to this capsule have been unsuccessful,15,16 Fillet and colleagues17 were able to show high antibody titers to hyaluronic acid using techniques designed to detect nonprecipitating anti-­ bodies in the sera of immunized animals. Similar antibod-­ ies have been noted in humans.18 The data establishing the importance of this capsule in human infections have been almost nonexistent, although Stollerman19 commented on the presence of a large mucoid capsule as being one of the more important characteristics of certain “rheumatogenic” strains. With respect to the M protein moiety, investigations by Lancefield and others spanning almost 70 years20 have estab-­ lished that the M protein molecule (at least 80 distinct sero-­ logic types) is perhaps the most important virulence factor in group A streptococcal infections of humans. The protein is a helical, coiled-coil structure and bears a striking structural homology to the cardiac cytoskeletal proteins, tropomyo-­ sin and myosin, and to many other coil-coiled structures, including keratin, DNA, lamin, and vimentin. When the amino acid sequence of many M proteins was delineated, it was possible to localize specifically the cross-reactive areas of the molecules. The studies of Dale and Beachey21 showed that the segment of the M protein involved in the opsonic reaction also cross-reacted with human sarcolemma antigens. Sargent and coworkers22 more precisely localized this cross-reaction to the M protein amino acid residues 164-197. The evidence implicating these cross-reactions in the pathogenesis of ARF remains scant. Antibodies to myosin have been detected in the sera of ARF patients, but they also are present in a high percentage of the sera obtained from individuals who had a streptococcal infection, but did

PART 17 

A

INFECTION AND ARTHRITIS 1773

Figure 105-2  A and B, Photomicrographs of immunofluorescent staining of heart sections with rabbit serum immunized with group A streptococcal membranes (A) and human serum obtained from a patient with acute rheumatic fever (B). Note the identical ­sarcolemmal staining patterns of both sera.

B

not subsequently develop ARF.23 The significance of this observation is unclear because myosin is an internal protein of cardiac muscle cells and not easily exposed to M protein cross-reacting antibodies. The group-specific carbohydrate of the streptococcus is a polysaccharide chain consisting of repeating units of rhamnose capped by N-acetyl glucosamine molecules. The N-acetyl glucosamine is immunodominant and gives rise to the serologic group specificity of group A streptococci.24 Goldstein and associates25 first described the cross-­reaction between group A carbohydrate and valvular ­ glycoproteins, and the reactivity was related to the N-acetyl glucosamine moiety present in both structures. Goldstein and ­Caravano26 noted that rheumatic fever (RF) sera reacted to the heart valve glycoprotein. Fillet (unpublished data) observed strong reactivity of RF sera with purified proteoglycan material. These cross-reactions could involve the sugar moiety pres-­ ent in the proteoglycan portion of the glycoprotein and the carbohydrate. It generally has been assumed that group A anticarbohy-­ drate antibodies do not play a role in phagocytosis of group A streptococci. Salvadori and coworkers27 showed, how-­ ever, that human sera containing high titers of anti–group A carbohydrate antibody promoted opsonization and phago-­ cytosis of many different M protein–specific strains, and the opsonophagocytic antibodies were directed to the N-­acetyl glucosamine moiety of the group A carbohydrate. The mucopeptide portion of the cell wall is the “backbone” of the organism and quite rigid in structure. It is composed of repeating units of muramic acid and N-acetyl glucosamine, cross-linked by peptide bridges.28 It is particularly difficult to degrade and induces a wide variety of lesions when injected into various species, including arthritis in rats29 and myo-­ cardial granulomas in mice resembling (but not identical to) RF Aschoff lesions.30 The relationship of cell wall mucopeptides to the patho-­ genesis of ARF remains obscure. Elevated levels of antimu-­ copeptide antibody not only have been detected in the sera of patients with ARF, but also in the sera of patients with

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rheumatoid arthritis and juvenile rheumatoid arthritis31; however, its pathogenetic relationship to clinical disease has been difficult to establish. There is no evidence that cell wall antigens are present either in the Aschoff lesion or in the myocardial tissue obtained from patients with ARF. Perhaps the most significant cross-reactions lie in the strep-­ tococcal membrane structure. We have shown that immu-­ nization with membrane material32 elicited antibodies that bound to heart sections in a pattern similar to that observed with acute RF sera (Fig. 105-2). Kingston and Glynn33 were the first to show that ­animals immunized with streptococcal antigens developed antibod-­ ies in their sera that stained astrocytes. Husby and asso-­ ciates34 showed that sera from ARF patients with chorea exhibited antibodies that were specific for caudate cells. Absorption of the sera with streptococcal membrane anti-­ gens eliminated the reactivity with caudate cells. Numer-­ ous other cross-reactions between streptococcal membranes and other organs also have been reported (e.g., renal base-­ ment membranes, basement membrane proteoglycans, and skin, particularly keratin). In the context of this chapter, space does not permit an exhaustive discussion of these cross-reactions, and the reader is referred to a previous review35 for a more detailed discussion. Whether or not these cross-reactions (especially the cross-reactions seen with basement membranes and skin) play a role in the dis-­ ease awaits further study.

GENETICS The concept that ARF might be the result of a host genetic predisposition has intrigued investigators for more than a century.36 It has been variously suggested that the disease gene is transmitted in an autosomal dominant fashion,37 or autosomal recessive fashion with limited penetrance,38 or that it is possibly related to the genes conferring blood group secretor status.39 Renewed interest in the genetics of ARF occurred with the recognition that gene products of the human major histocompatibility complex (MHC)

1774 GIBOFSKY  |  Poststreptoccocal Arthritis and Rheumatic Fever

were associated with certain clinical disease states. Using an alloserum from a multiparous donor, an increased frequency of a B cell alloantigen was reported in several genetically distinct and ethnically diverse populations of ARF patients and was not MHC related.40 More recently, a monoclonal antibody (D8/17) was prepared by immunizing mice with B cells from an ARF patient.41 A B cell antigen identified by this antibody was found to be expressed on increased numbers of B cells in 100% of rheumatic patients of diverse ethnic origins, and only in 10% of normal individuals. The antigen defined by this monoclonal antibody showed no association with or linkage to any of the known MHC haplotypes, and it did not seem to be related to B cell activation antigens. Stud-­ ies with D8/17 have been expanded to a larger number of patients with RF (see Table 105-1) of diverse ethnic origins with essentially the same results. As discussed subsequently, the presence or absence of elevated levels of D8/17+ B cells in cases of questionable RF has been helpful in establishing or ruling out the diagnosis. These studies are in contrast to other reports in which an increased frequency of HLA-DR4 and HLA-DR2 has been seen in white and black patients with rheumatic heart disease (RHD).42 Other studies have implicated HLA-DR1 and HLA-DRW6 as susceptibility factors in South African black patients with RHD.43 More recently, Guilherme and associates44 have reported an increased frequency of HLADR7 and HLA-DW53 in RF patients in Brazil. These seemingly conflicting results concerning HLA anti-­ gens and RF susceptibility prompt speculation that these reported associations might be of class II genes close to (or in linkage disequilibrium with), but not identical to the putative RF susceptibility gene. Alternatively, and more likely, suscep-­ tibility to ARF is polygenic, and the D8/17 antigen might be associated with only one of the genes (i.e., genes of the MHC complex encoding for DR antigens) conferring susceptibil-­ ity. Although the explanation remains to be determined, the presence of the D8/17 antigen does seem to identify a popula-­ tion at special risk of contracting ARF (Table 105-2).

ETIOLOGIC CONSIDERATIONS Although a large body of immunologic and epidemio-­ logic evidence has implicated group A streptococci in the ­induction of the disease process, the precise pathologic mechanisms involved remain obscure. At least three main theories have been proposed. The first theory is concerned with the question of whether persistence of the organism is important. Despite several controversial reports, no investi-­ gators have been able to show consistently and reproducibly live organisms in RF cardiac tissues or valves.45 The second theory revolves around the question of whether deposition of toxic products is required. Although an attractive hypothesis, little or no experimental evidence has been obtained to support this concept. Halbert and colleagues46 have suggested that streptolysin O (an extra-­ cellular product of group A streptococci) is cardiotoxic and might be carried to the site by circulating complexes containing streptolysin O and antibody. Despite an inten-­ sive search for these products, no such complexes in situ have been identified, however.47,48 Renewed interest in these extracellular toxins has emerged more recently with

Table 105-2  Frequency of the D8/17 Marker   in Patients with Rheumatic Fever, Patients with Other Diseases, and Controls in Various Geographic   Populations No.

% Positive

Rheumatic Fever Patients New York New Mexico Utah* Russia (Georgian) Russia (Moscow) Mexico Chile

43/45 30/31 18/18 27/30 50/52 35/39 45/50

93 97 100 90 96 89 90

4/78 6/68 8/50 6/72

5 8 16 8

2/42 0/10 1/25 1/12

4 0 4 9

Normals Russia New York Chile Mexico Other Diseases Rheumatoid arthritis Ischemic heart disease Multiple sclerosis Systemic lupus erythematosus *Acute patients.

the observation by Schlievert and coworkers49 that certain streptococcal pyrogenic toxins (A and C) may act as super­ antigens. These antigens may stimulate large numbers of T cells through their unique bridging interaction with T cell receptors of specific Vβ types and class II MHC molecules. This interaction is distinct from conventional antigen pre-­ sentation in the context of the MHC complex. When activated, these cells elaborate tumor necrosis factor, inter-­ feron-γ, and numerous interleukin moieties, contributing to the initiation of pathologic damage. It has been suggested50 that in certain disease states, such as rheumatoid arthritis, autoreactive cells of specific Vβ lineage may “home” to the target organ. Although an attractive hypothesis, no data concerning the role of these superantigens in ARF have yet been forth-­ coming. Perhaps the best evidence to date favors a third theory of an abnormal host immune response (humoral and cellular) in a genetically susceptible individual to the ­streptococcal antigens cross-reactive with mammalian tis-­ sues. The evidence supporting this theory may be divided into three broad categories. (1) Employing a wide variety of methods, numerous investigators have documented the presence of heartreactive antibodies in ARF sera. The prevalence of these antibodies has ranged from 33% to 85% in various series. Although these antibodies are seen in other individuals (notably i­ndividuals with uncomplicated streptococcal infections that do not progress to RF and patients with poststreptococcal glomerulonephritis), the titers are always lower than the titers seen in RF and decrease with time during the convalescent period (Table 105-3). An impor-­ tant point in terms of diagnosis and prognosis has been the observation by Zabriskie and associates51 that these heartreactive antibody titers decline over time. By the end of 3 years, these titers are essentially undetectable in patients

PART 17 

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INFECTION AND ARTHRITIS 1775

Table 105-3  Heart-Reactive Antibody Titers in Sera of Patients with Acute Rheumatic Fever Compared   with Uncomplicated Streptococcal Infections and Other Arthritic Infections Serum Dilutions Clinical Disorder

No. Patients

1:5

1:10

1:20

Average ASO Titer

Acute rheumatic fever (grade I)

34

4+

2+

+*

700

Uncomplicated streptococcal   infections (grade II)

40

1+

0

0

561

APSGN

20

+/−

0

0

520

Rheumatoid arthritis

10

0

0

0†

ND

Systemic lupus erythematosus

10

0

0

0

ND

*Serum samples obtained at onset of rheumatic fever and at a comparable time in the group with uncomplicated scarlet fever. †Serum samples obtained during active disease. APSGN, acute poststreptococcal glomerulonephritis; ASO, antistreptolysin O; ND, not determined.

4

Average intensity of staining

Serum dilutions 1:5 1:10 1:20

3

2

1

0

1

2

3

1

6

5

4

2

3 Years

Months

4

Figure 105-3  Serial heart-reactive antibody titers in 40 patients with documented acute rheumatic fever. Note the slow decline of these titers over the first 2 years after the initial episode and the absence of these antibodies 5 years after the initial attack.

5

M.P. 3 yrs 1st admission 5/26/55

Streptococcal isolation Heart-reactive antibody titer 1:5 1:10 1:20

120 80 40 0 + CRP oooooooi o 1200 2000 ASO titer

o

o

300

300

GRAT12

4+ 2+ 1

2

3

6

Months

12

o o 2+ o

o

250 1800 800 1800 Titers all neg 2-5 years

Erythrocyte sedimentation rate

GRG

6

1000

8 Years

who had only a single attack (Fig. 105-3). This pattern is consistent with the well-known clinical observations that recurrences of RF most often occur within the first 2 to 3 years after the initial attack and become rarer 5 years after an initial episode. As illustrated in Figure 105-4, this pattern of titers also has prognostic value. During the 2- to 5-year period after the initial attack, a patient’s titers decreased to undetectable levels. With a known break in prophylaxis starting in year 6, at least two streptococcal infections occurred, as evidenced by an increase in antistreptolysin O (ASO) titers during that period. The concomitant increase in heart-reactive

oo

GRAT12

None

7

3+ooo6+3+ooo2+9+ 1600 1000 800

9 10

1

2

3

Months

6

Figure 105-4  Heart-reactive antibody titers and laboratory data obtained from a patient with rheumatic fever who had two well-documented acute attacks 11 years apart. Note absence of the heart-  reactive antibody during years 2 to 5 and its  reappearance during years 6 to 10 after evidence of two intercurrent streptococcal infections secondary to breaks in penicillin prophylaxis (see antistreptolysin O [ASO] titers). High titers of heart-reactive antibody appeared with the second attack. CRP, C-reactive protein.

antibody titers was notable. The final infection was followed by a clinical recurrence of classic rheumatic ­ carditis com-­ plete with isolation of the organism, elevated heart-reactive antibodies, and acute-phase reactants 11 years after the ini-­ tial attack. (2) Sera from patients with ARF also contain increased levels of antibodies to myosin and tropomyosin compared with sera from patients with pharyngeal streptococcal infec-­ tions that do not progress to ARF. These myosin affinity purified antibodies also cross-react with M protein moieties, suggesting this molecule could be the antigenic stimulus for the production of myosin antibodies in these sera.23,52

1776 GIBOFSKY  |  Poststreptoccocal Arthritis and Rheumatic Fever

Table 105-4  Composition of Mononuclear Cellular Infiltrates in Acute and Chronic Active Rheumatic Valvulitis Composition of Infiltrate (%) Patient

Type of Valve

Type of ­Valvulitis*

HLA-DR+

CD1+†

CD20+‡

CD3+§

CD4+¶

CD8+ǁ

CD4/CD8 Ratio

Acute Acute Acute Acute Acute

58.9 49.8 52.7 63.9 68.1

42.6 43.1 51 42 56

5.1 6.9 3.9 5.5 7.4

49.5 43.1 38.1 52.4 33.7

75.6 58.7 65.9 75.4 71.6

23.9 34.3 26.5 18.9 22

3.1 1.9 2.3 4 1.9

Chronic active Chronic active Chronic active Chronic active Chronic active Chronic active Chronic active Chronic active

49.4 48.8 67.8 41.8 69.6 55.4 80.4 46.1

47.4 39.1 35 23.4 48.7 24.2 34.1 29.6

7.4 1.4 4 8 6.2 8.1 13.4 0.8

44.3 53.9 36.8 65.9 30.1 59.8 44.4 65.6

53.7 45.2 47.5 57.3 58.2 64.9 44.8 61.6

38.8 51.5 49.1 33.3 32.6 24.7 50.9 33.3

1.4 0.9 1 1.7 1.8 2.6 0.9 1.8

Acute Valvulitis 1 2 3 4

Mitral Mitral Aortic Mitral Aortic

Chronic Valvulitis 4 5 6 7 8 9

Mitral Mitral Aortic Mitral Aortic Mitral Mitral Mitral

*Determined in the frozen valve samples studied. †(63D3) monocytes/macrophages. ‡(Leu 16) B cells. §Pan T cells. ¶Helper T cells. ǁSuppressor cells.

(3) Finally, as indicated earlier, autoimmune antibodies are a prominent finding in chorea, another major clinical manifestation of ARF, and these antibodies are directed against the cells of the caudate nucleus. The titer of this anti-­ body corresponds with clinical disease activity.34 Although not autoimmune in nature, the presence of elevated levels of immune complexes in ARF has been well documented in the sera and in the joints of ARF patients.53 Elevated levels of immune complexes, which may be as high as the levels seen in classic poststreptococcal glomerulonephritis, may be responsible for the immune complex vasculitis seen in ARF tissues and may provide the initial impetus for vascular damage, followed by the secondary penetration of autoreac-­ tive antibodies. Support for this concept is the close clinical similarity of RF arthritis to experimentally induced serum sickness in animals or the arthritis seen secondary to drug hypersensitivity. Deposition of host immunoglobulin and complement also is seen in the cardiac tissues of ARF patients, suggest-­ ing autoimmune deposition of immunoglobulins in or near the Aschoff lesions. At a cellular level, there is now ample evidence for the presence of lymphocytes and macrophages at the site of pathologic damage in the heart in patients with ARF.54 The cells are predominantly CD4+ helper lympho-­ cytes during acute stages of the disease (4:1). The ratio of CD4+ to CD8+ lymphocytes (2:1) more closely approxi-­ mates the normal ratio in chronic valvular specimens. Most of these cells express DR antigens. A potentially important finding has been the observation that macrophage-like fibroblasts present in the diseased valves express DR anti-­ gens55 and might be the antigen-presenting cells for the CD4+ lymphocytes. Increased cellular reactivity to strepto-­ coccal antigens also has been noted in the peripheral blood mononuclear cell preparations of ARF patients compared with these cells isolated from nephritis patients.56 This abnormal reactivity peaks at 6 months after the attack, but may persist for 2 years after the initial episode.

The reactivity was specific only for the strains associated with ARF, suggesting an abnormal humoral and cellular response to streptococcal antigens unique to RF-associated streptococci. Support for the potential pathologic impor-­ tance of these T cells is strengthened further by the observa-­ tion that lymphocytes obtained from experimental animals sensitized to cell membranes, but not cell walls, are specifi-­ cally cytotoxic for syngeneic embryonic cardiac myofibers in vitro.57 In humans, normal mononuclear cells primed in vitro by M protein molecules from an RF-associated strain also are cytotoxic for myofibers, but specificity solely for car-­ diac cells was lacking in the human studies.58 Similar studies have not been performed yet using lymphocytes from active ARF patients (Table 105-4).

CLINICAL FEATURES The clinical presentation of ARF varies, and the lack of a single pathognomonic feature has resulted in the develop-­ ment of the revised Jones criteria (Table 105-5),59 which are used to establish a diagnosis. These criteria were established only as guidelines for the diagnosis and were never intended to be “etched in stone.” Depending on the age, geographic location, and ethnic population, emphasis on one criterion for the diagnosis of ARF may be more important than others. Manifestations of RF that are not clearly expressed pose a dilemma because of the importance of identifying a first rheu-­ matic attack definitively to establish the need for prophylaxis of recurrences (see later). Some of the isolated manifesta-­ tions, particularly polyarthritis, may be difficult or impossible to distinguish from other diseases, especially at their onset. The diagnosis can be made, however, when “pure” chorea is the sole manifestation because of the rarity with which this syndrome is due to any other cause. More recently, the World Health Organization updated the Jones criteria to allow for the diagnosis of recurrent ARF in patients with established RHD and chronic RHD (Table 105-6).

PART 17 

Table 105-5  Revised Jones Criteria for Diagnosis   of Acute Rheumatic Fever Major Manifestations

Minor Manifestations

Carditis Polyarthritis Chorea Erythema marginatum Subcutaneous nodules

Fever Arthralgia Previous RF or RHD

Laboratory Findings Elevated acute-phase reactants   C-reactive protein   Erythrocyte sedimentation rate Prolonged P-R interval rate Supporting evidence of preceding streptococcal infection   Increased ASO or other streptococcal antibodies   Positive throat culture for group A β-hemolytic streptococci   Recent scarlet fever ASO, antistreptolysin O; RF, rheumatic fever; RHD, rheumatic heart disease.   From Jones Criteria 1992 update: Guidelines for diagnosis of rheumatic fever. JAMA 268:2069-2070, 1992.

ARTHRITIS In classic, untreated cases, the arthritis of ARF affects sev-­ eral joints in quick succession, each for a short time. The legs usually are affected first, and the arms are affected later. The terms migrating and migratory are often used to describe the polyarthritis of ARF, but these designations are not meant to signify that the inflammation disappears in one joint when it appears in another. Rather, the various local-­ izations usually overlap in time, and the onset, as opposed to the full course of the arthritis, “migrates” from joint to joint. Joint involvement is more common, and also more severe, in teenagers and young adults than in children. Arthritis is usually the earliest symptomatic manifestation of the disease, although asymptomatic carditis may precede it. Rheumatic polyarthritis may be excruciatingly painful, but is almost always transient. The pain is usually more prominent than the objective signs of inflammation. When the disease is allowed to express itself fully, unmodified by anti-­inflammatory treatment, more than half of patients studied show a true polyarthritis, with inflammation in 6 to 16 joints. Classi-­ cally, each joint is maximally inflamed for only a few days, or a week at the most; the inflammation decreases, perhaps lingering for another week or so, and then disappears com-­ pletely. Radiographs at this point may show a slight effusion, but most likely are unremarkable. In routine practice, many patients with arthritis or arthralgias are treated empirically with salicylates or other nonsteroidal anti-inflammatory drugs, and arthritis subsides quickly in the joints already affected and does not migrate to new joints. Therapy may deprive the diagnostician of a use-­ ful sign. In a large series of patients with ARF and ­associated arthritis, most of whom had been treated, involvement of only a single large joint was common (25%). One or both knees were affected in 76%, and one or both ankles were affected in 50%. Elbows, wrists, hips, or small joints of the feet were involved in 12% to 15% of patients, and shoul-­ ders or small joints of the hand were affected in 7% to 8%. Rarely affected joints included the lumbosacral (2%), cervi-­ cal (1%), sternoclavicular (0.5%), and temporomandibular

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INFECTION AND ARTHRITIS 1777

Table 105-6  Summary of 2002 World Health ­Organization Criteria for the Diagnosis of Rheumatic ­Fever and Rheumatic Heart Disease Diagnostic Categories

Criteria

Primary episode of RF

Two major or one major and two minor manifestations plus evidence of a preceding group A streptococcal infection

Recurrent attack of RF in   patients without   established RHD

Two major or one major and two minor manifestations plus evidence of a preceding group A streptococcal infection

Recurrent attack of RF in   patients with established   RHD

Two minor manifestations plus evidence of a preceding group A streptococcal infection

Rheumatic chorea, insidious   onset of rheumatic carditis

One major manifestation or evidence of a preceding group A streptococcal infection

Chronic valve lesions of RHD   (i.e., patients presenting for the first time with pure mitral stenosis, mixed mitral valve ­disease, and aortic valve disease)

Do not require any other criteria to be diagnosed as having RHD

RF, rheumatic fever; RHD, rheumatic heart disease.   From Rheumatic Fever and Rheumatic Heart Diseases. Report of a WHO expert consultation. WHO technical report series no. 923. World Health Organization, 2004.

(0.5%). Involvement of the small joints of the hands or feet alone occurred in only 1% of these patients.60 ­Analysis of the synovial fluid in well-documented cases of ARF with arthritis generally reveals a sterile, inflammatory fluid. There may be a decrease of the complement components C1q, C3, and C4, indicating their consumption by immune complexes in the joint fluid.9 POSTSTREPTOCOCCAL REACTIVE ARTHRITIS Numerous investigators61-63 have suggested that poststrep-­ tococcal migratory arthritis (in adults and children) in the absence of carditis might be a distinct entity from ARF for the following reasons: (1) The latent period between the antecedent streptococcal infection and the onset of post-­ streptococcal reactive arthritis is shorter (1 to 2 weeks) than the 3 to 4 weeks usually seen in classic ARF. (2) The response of the poststreptococcal reactive arthritis to aspirin and other nonsteroidal medications is poor compared with the dramatic response seen in classic ARF. (3) Evidence of carditis is not usually seen in these patients; the severity of the arthritis is marked. (4) Extra-articular manifestations (e.g., tenosynovitis and renal abnormalities) are often seen in these patients. Although these features may be seen (admittedly rarely), migratory arthritis without evidence of other major Jones criteria, if supported by two minor manifestations (see Table 105-5), still must be considered ARF, especially in children. Variations in the response to aspirin in these children often are not documented with serum salicylate levels, and an unusual clinical course is insufficient to exclude the diag-­ nosis of ARF. Appropriate prophylactic measures should be taken.64 Support for this concept may be found in the work of Crea and Mortimer.65 In their series of patients

1778 GIBOFSKY  |  Poststreptoccocal Arthritis and Rheumatic Fever

with ARF, 50% of the children who presented solely with signs of migratory arthritis went on to develop significant ­valvular damage. RF in adults also occurs. Although migra-­ tory arthritis is a common presenting symptom, an outbreak in San Diego Naval Training Camp66 revealed a 30% inci-­ dence of valvular damage in these patients. The importance of clearly defining this reactive arthritis as an RF variant has obvious implications for secondary prophylactic treatment. As suggested by some investigators, poststreptococcal reac-­ tive arthritis is a benign condition without need for pro-­ phylaxsis. Because these patients largely do fulfill the Jones criteria (one major, two minor), they should be considered as having RF and in our opinion treated as such.

clinical evaluation of patients during the Utah outbreak, 91% of patients had carditis,1 however, indicating that, with more sensitive measurements of cardiac dysfunction, almost all ARF patients have signs of acute carditis. RHEUMATIC HEART DISEASE RHD is the most severe sequela of ARF. Usually occurring 10 to 20 years after the original attack, it is the major cause of acquired valvular disease in the world. The mitral valve is mainly involved, and aortic valve involvement occurs less often. Mitral stenosis is a classic RHD finding and can mani-­ fest as a combination of mitral insufficiency and stenosis, secondary to severe calcification of the mitral valve. When symptoms of left atrial enlargement are present, mitral valve replacement may become necessary. In various studies, the incidence of RHD in patients with a history of ARF has varied. In Bland and Jones’67 classic follow-up study of patients with ARF, after 20 years, one third of patients had no murmur, another one third died, and the remaining one third were alive with RHD. Most of the patients who died had RHD. Although the classic dogma is that patients with RHD invariably had more than one attack of ARF, more recent analysis of our patients at the Rockefeller University Hospital disproves this notion. The population studied was 87 patients who had only one documented attack of ARF, without any evidence (clini-­ cal or laboratory) of a recurrence during a 20-year followup under close supervision. Greater than 80% had carditis at admission, and approximately 50% now have organic murmurs (see Table 105-7). Valvular damage manifesting as organic murmurs later in life is still likely to occur in 50% of the patients, particularly if they presented with evi-­ dence of carditis at initial diagnosis. All of the patients in our population who ended up with RHD had carditis at ­diagnosis.

CARDITIS Cardiac valvular and muscle damage can manifest in a variety of signs or symptoms. These manifestations include organic heart murmurs, cardiomegaly, congestive heart failure, and pericarditis. Mild-to-moderate chest discomfort, pleuritic chest pain, and a pericardial friction rub are indications of pericarditis. On clinical examination, the patient can have new or changing organic murmurs, most commonly mitral regurgitant murmurs and occasionally aortic regurgitant murmurs and systolic ejection murmurs, caused by acute val-­ vular inflammation and deformity. Rarely, a Carey Coombs mid-diastolic murmur caused by rapid flow over the mitral valve is heard. If the valvular damage is severe, and there is concurrent cardiac dysfunction, congestive heart failure can occur. Congestive heart failure is the most life-threatening clinical syndrome of ARF and must be treated aggressively and early with a combination of anti-inflammatory drugs, diuretics, and, occasionally, steroids to decrease cardiac inflammation acutely. Electrocardiogram abnormalities may include all degrees of heart block, including atrtioventricular dissociation, but first-degree heart block is not associated with a poor progno-­ sis. Second-degree or third-degree heart block occasionally can be symptomatic. If heart block is associated with con-­ gestive heart failure, temporary pacemaker placement may be required. The most common manifestation of carditis is cardiomegaly, as seen on radiograph. Among patients at the Rockefeller University Hospital who were diagnosed with ARF between 1950 and 1970 with an average of 20 years of follow-up, 90% had evidence of carditis at diagnosis (Table 105-7). In Bland and Jones’67 classic review of 1000 patients with ARF, only 65% of the patients were diagnosed with carditis. When Doppler sonography was employed in the

CHOREA Sydenham’s chorea (chorea minor or St. Vitus’ dance) is a neurologic disorder consisting of abrupt, purposeless, non-­ rhythmic involuntary movements, muscular weakness, and emotional disturbances. Involuntary movements disappear during sleep, but may occur at rest and may interfere with voluntary activity. Initially, it may be possible to suppress these movements, which may affect all voluntary muscles, with the hands and face usually the most obvious. Grimaces and inappropriate smiles are common. Handwriting usually

Table 105-7  Physical Signs and Symptoms of Acute Rheumatic Fever: Rockefeller University Hospital, 1950 to 1970 RHD (n = 40) (%) Carditis

100

No RHD (n = 47) (%)

Total (N = 87) (%)

Bland and Jones (%)

83

90.1

65.3 41

Arthritis

67.5

68.1

67.8

Epistaxis

0

10.6

5.7

27.4

Chorea

5

2.1

3.4

51.8

Pericarditis

2.5

4.3

3.4

13

Subcutaneous nodules

7.5

0

3.4

8.8

Erythema marginatum

0

4.3

2.3

7.1

PART 17 

becomes clumsy and provides a convenient way of following the patient’s course. Speech is often slurred. The movements are commonly more marked on one side and occasionally are completely unilateral (­hemichorea). The muscular weakness is best revealed by asking the patient to squeeze the examiner’s hands: The pressure of the patient’s grip increases and decreases continuously and capriciously, a phenomenon known as relapsing grip, or milking sign. The emotional changes manifest in outbursts of inappropriate behavior, including crying and restlessness. In rare cases, psychological manifestions may be severe and may result in transient psychosis. The neurologic examina-­ tion fails to reveal sensory losses or pyramidal tract involve-­ ment. Diffuse hypotonia may be present. Chorea may follow streptococcal infections after a latent period, which is longer, on the average, than the latent period of other rheumatic manifestations. Some patients with chorea have no other symptoms, but other patients develop chorea weeks or months after arthritis. In both cases, examination of the heart may reveal murmurs. It has been known for years that often the early ­symptoms of chorea may manifest as emotional or behavioral changes in the patient,68 and only later do the choreiform motor ­symptoms appear. It also was noted that many chorea patients years after the choreiform symptoms had subsided would present with behavioral disorders, such as tics or obsessivecompulsive disorders. These earlier observations combined with the known presence of antibrain antibodies in the sera of Sydenham’s chorea patients raised the question of whether a prior streptococcal infection (or infection with other microbes) might induce antibodies cross-reactive with brain antigen involved in neural pathways associated with behav-­ ior. Two more recent articles69,70 indicate there is a strong association of the D8/17 B cell marker (described earlier) with children with obsessive-compulsive disorder (see Table 105-6). Although Swedo and coworkers69 selected patients on the basis of a strong history of prior streptococcal infec-­ tions, Murphy and colleagues70 noted a strong association of the marker in patients with obsessive-compulsive dis-­ order without a history of streptococcal infections. These preliminary studies suggest that streptococci and probably other microbes may induce antibodies that functionally dis-­ rupt the basal ganglia pathways leading not only to classic chorea, but also to behavioral disorders in these children without evidence of classic chorea. SUBCUTANEOUS NODULES The subcutaneous nodules of ARF are firm and pain-­ less. The overlying skin is not inflamed and usually can be moved over the nodules. The diameter of these round lesions varies from a few millimeters to 1 or 2 cm. They are located over bony surfaces or prominences or near tendons. Their number varies from a single nodule to a few dozen and averages three or four; when numerous, they are usu-­ ally symmetric. Nodules are rarely present for more than 1 month. They are smaller and more short-lived than the nodules of rheumatoid arthritis. Although in both diseases the elbows are most frequently involved, the rheumatic nodules are more common on the olecranon, whereas nod-­ ules of rheumatoid arthritis are usually found 3 or 4 cm distal to it. Rheumatic subcutaneous nodules generally

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INFECTION AND ARTHRITIS 1779

appear only after the first few weeks of illness, usually only in patients with carditis. ERYTHEMA MARGINATUM Erythema marginatum is an evanescent, nonpruritic skin rash, pink or faintly red, affecting usually the trunk, some-­ times the proximal parts or the limbs, but not the face. This lesion extends centrifugally, while the skin in the center returns gradually to normal—hence the name erythema marginatum. The outer edge of the lesion is sharp, whereas the inner edge is diffuse. Because the margin of the lesion is usu-­ ally continuous, making a ring, it is also termed erythema annulare. The individual lesions may appear and disappear in a matter of hours, usually to return. A hot bath or shower may make them more evident or may reveal them for the first time. Erythema marginatum usually occurs in the early phase of the disease. It often persists or recurs, even when all other manifestations of disease have disappeared. Occa-­ sionally, the lesions appear for the first time, or, more likely, are noticed for the first time, late in the course of the illness or even during convalescence. This disorder usually occurs only in patients with carditis. MINOR MANIFESTATIONS Fever Temperature is increased in almost all ARF attacks and ranges from 38.4°C to 40°C. Usually fever decreases in approximately 1 week without antipyretic treatment and may become low grade for another 1 or 2 weeks. Fever rarely lasts for more than 3 to 4 weeks. Abdominal Pain The abdominal pain of RF resembles that of other conditions associated with acute microvascular mesenteric inflamma-­ tion and is nonspecific. It usually occurs at or near the onset of the RF attack so that other manifestations may not yet be present to clarify the diagnosis. In many cases, abdominal pain may mimic acute appendicitis. Epistaxis In the past, epistaxis occurred most prominently and severely in patients with severe and protracted rheumatic carditis. Early clinical studies reported a frequency of 48%, but it probably occurs even less frequently now (see Table 105-6). Although epistaxis has been correlated in the past with the severity of rheumatic inflammation, it is difficult to assess retrospectively the possible thrombasthenic effect of large doses of salicylates, administered for prolonged periods in protracted attacks. Rheumatic Pneumonia Pneumonia may appear during the course of severe rheumatic carditis. This inflammatory process is difficult or impossible to distinguish from pulmonary edema or the alveolitis asso-­ ciated with respiratory distress syndromes owing to a variety of pathophysiologic states.

1780 GIBOFSKY  |  Poststreptoccocal Arthritis and Rheumatic Fever

LABORATORY FINDINGS The diagnosis of ARF cannot readily be established by labo-­ ratory tests. Nevertheless, such tests may be helpful in two ways: first, in showing that an antecedent streptococcal infec-­ tion has occurred and, second, in documenting the presence or persistence of an inflammatory process. Serial chest radio-­ graphs may be helpful in following the course of carditis, and an electrocardiogram may reflect the inflammatory process on the conduction system. Throat cultures are usually negative by the time ARF appears, but an attempt should be made to isolate the organism. It is our practice to take three throat cul-­ tures during the first 24 hours, before administration of anti-­ biotics. Streptococcal antibodies are more useful because (1) they reach a peak titer at about the time of onset of ARF; (2) they indicate true infection, rather than transient carriage; and (3) by performing several tests for different antibodies, any sig-­ nificant recent streptococcal infection can be detected. To show a rising titer, it is useful to take a serum speci-­ men when the patient is first seen and to take another 2 weeks later for comparison. The specific antibody tests that have been used to diagnose streptococcal infections most frequently are those directed against extracellular ­products, including ASO, anti-DNAse B, antihyaluronidase (anti–diphosphopyridine nucleotide [anti-DPNase]), and antistreptokinase. ASO has been the most widely used test and is generally available in U.S. hospitals. ASO titers vary with age, season, and geography. They reach peak levels in elementary school–age children; titers of 200 to 300 Todd units/mL are common in healthy children. After streptococ-­ cal pharyngitis, the antibody response peaks at about 4 to 5 weeks, which is usually during the second or third week of ARF (depending on how early it is detected). Thereafter, antibody titers decrease rapidly in the next several months, and after 6 months, they decline more slowly. Because only 80% of cases of documented ARF exhibit an increase in the ASO titer, it is recommended that other antistreptococcal antibody tests be done in the absence of a positive ASO titer. These include anti-DNAse B, antihyal-­ uronidase, or anti-Streptozyme (which is a combination of various streptococcal antigens). Streptococcal antibodies, when increased, support, but do not prove the diagnosis of ARF, and they are not a measure of rheumatic activity. Even in the absence of intercurrent streptococcal infection, titers decline during the rheumatic attack despite the persistence or severity of rheumatic activity. ACUTE-PHASE REACTANTS Acute-phase reactants are elevated during ARF, just as they are during other inflammatory conditions. C-reactive pro-­ tein and erythrocyte sedimentation rate are almost invari-­ ably elevated during the active rheumatic process, if they are not suppressed by antirheumatic drugs. These values may be normal, however, during episodes of pure chorea or persis-­ tent erythema marginatum. Particularly when treatment has been discontinued or is being tapered off, C-reactive protein and erythrocyte sedimentation rate are useful in monitor-­ ing “rebounds” of rheumatic inflammation, which indicate that the rheumatic process is still active. If either C-reactive protein or erythrocyte sedimentation rate remains normal a few weeks after discontinuing antirheumatic therapy, the

attack may be considered ended unless chorea appears. Usu-­ ally, there is no exacerbation of the systemic inflammation, and chorea is present as an isolated manifestation. ANEMIA A mild, normochromic, normocytic anemia of chronic infec-­ tion or inflammation may be seen during ARF. Suppressing the inflammation usually improves the anemia; hematinic therapy usually is not indicated. OTHER SUPPORTING FINDINGS As noted in Figures 105-3 and 105-4 and Table 105-2, two other tests have been helpful in our experience in confirm-­ ing the diagnosis of ARF, especially when the diagnosis is in doubt. First, one can detect elevated titers of heart-reactive antibodies directed against sarcolemmal antigens in most ARF patients. Elevated levels of these antibodies are not seen in either uncomplicated streptococcal infections or acute poststreptococcal glomerulonephritis. Using enzymelinked immunosorbent assay, antibodies directed against cytoskeletal constituents such as myosin and ­ tropomyosin also are elevated in ARF patients and might be helpful in determining whether or not cross-reactive antibodies unique to ARF exist.50 Second, the use of the D8/17 mono-­ clonal antibody mentioned earlier also has proved helpful in the differential diagnosis of ARF from other disorders. In our hands, all RF patients express abnormal levels of D8/17+ B cells, especially during the acute attack. In cases in which the diagnosis of ARF has been doubtful, the presence of ele-­ vated levels of D8/17+ B cells has proved to be very helpful in establishing the correct diagnosis.40

CLINICAL COURSE AND TREATMENT The mainstay of treatment for ARF has always been antiinflammatory agents, most commonly aspirin. Dramatic improvement in symptoms usually is seen after the initiation of therapy. Usually 80 to 100 mg/kg/day in children and 4 to 8 g/day in adults is required for an effect to be seen. Aspirin levels can be measured; 20 to 30 mg/dL is the therapeutic range. Duration of anti-inflammatory therapy can vary, but needs to be maintained until all symptoms are absent, and laboratory values are normal. If severe carditis also is present (as indicated by significant cardiomegaly, congestive heart failure, or third-degree heart block), steroid therapy can be instituted. The usual dosage is 2 mg/kg/day of oral predni-­ sone during the first 1 to 2 weeks. Depending on clinical and laboratory improvement, the dosage is tapered over the next 2 weeks, and during the last week, aspirin may be added in the above-recommended dose, sufficient to achieve 20 to 30 mg/dL. As noted by Cillers71 in a clinical review, studies have shown no difference in the risk of cardiac disease at 1 year in groups treated with either aspirin or corticosteroids. Simi-­ larly, although nonsteroidal anti-inflammatory drugs also have been used to treat the acute inflammation, none have been the subject of randomized controlled trials. Whether or not signs of pharyngitis are present at the time of diagno-­ sis, antibiotic therapy with penicillin should be started and maintained for at least 10 days, given in doses recommended

PART 17 

for the eradication of streptococcal pharyngitis. Addition-­ ally, all family contacts should be cultured and treated for streptococcal infection if positive. If compliance is an issue, depot penicillins (i.e., benzathine penicillin G, 600,000 U in children and 1.2 million U in adults) should be given. Recurrences of ARF are most common within 2 years of the original attack, but can occur at any time. The risk of recurrence decreases with age. Recurrence rates have been decreasing, from 20% in past years to 2% to 4% in more recent outbreaks. This decrease might be due to better sur-­ veillance and treatment.

PROPHYLAXIS Antibiotic prophylaxis with penicillin should be started immediately after the resolution of the acute episode. The optimal regimen consists of oral penicillin V potassium, 250,000 U twice a day, or parenteral penicillin G, 1.2 mil-­ lion U intramuscularly every 4 weeks. One study suggests, however, that injections every 3 weeks are more effective than every-4-week injections at preventing ARF recur-­ rences.72 If the patient is allergic to penicillin, erythromy-­ cin, 250 mg/day, can be substituted. The end point of prophylaxis is unclear; most authors believe it should continue at least until the patient is a young adult, which is usually 10 years from an acute attack with no recurrence. In our opinion, individuals with docu-­ mented evidence of RHD should be on continuous prophy-­ laxis indefinitely because our experience has been that ARF recurrences can occur even in the fifth or sixth decade. A potential problem for ARF recurrences are young children in the household who could transmit new group A streptococ-­ cal infections to RF-susceptible individuals. The alternative to long-term prophylaxis in an individual with ARF would be the introduction of streptococcal vaccines designed not only to prevent recurrent infections in susceptible individu-­ als with previous ARF, but also to prevent streptococcal dis-­ ease in general.

STREPTOCOCCAL VACCINES The difficulties in developing a streptococcal vaccine have been related mainly to the numerous reports that strepto-­ coccal antigens are known to cross-react with mammalian tissues.64 Despite these caveats, more recent work indicates progress in this area. Perhaps the most advanced has been the work of Dale and colleagues,73 in which they synthe-­ sized short peptides (20 to 30 amino acids) of many different M proteins and linked them together and showed that they can develop type-specific antibodies that also are opsonic. Little toxicity or cross-reactivity to human tissues has been noted with the antigen or the antibodies. Phase II trials are now in progress. A second approach revolves around the C-repeat region of the M protein moiety, which is common to all group A streptococci. Bessen and Fischetti74 used a commensural organism commonly found in the oral mucosa of humans in which by genetic engineering they inserted the C-repeat of the M protein, which is preferentially displayed on the sur-­ face of the organism. This induces IgA antibodies, prevent-­ ing oral colonization of mice by live group A streptococci. Others75 have confirmed these results using a different

| 

INFECTION AND ARTHRITIS 1781

M-type organism. Good and colleagues76 used similar meth-­ ods except that they added additional amino acids making their antibodies opsonic. Based on the observation by Lancefield77 that human sera rarely, if ever, contained more than one type-specific M protein antibody, Salvadori and coworkers27 examined other possible streptococcal antigens that might explain the broad-based immunity to streptococcal infections that occurs with increasing age. Their studies indicated that the streptococcal group A carbohydrate (GRA-CHO) might be a good immunogen for the following reasons. Antibodies to GRA-CHO are present in human sera, increase with age, and are opsonic for several distinct M+-type strains. Active and passive immunization with GRA-CHO in mice exhib-­ ited protection against a live lethal challenge in mice. No cross-reactive antibodies have been detected. Two other candidates also are under consideration. Ji and associates78 described a surface antigen present on group A streptococci called C5a peptidase. This enzyme specifically cleaves the human serum chemotoxin C5a at the polymor-­ phonuclear binding site. These observations led to experi-­ ments in which intranasal inoculation with C5a peptidase resulted in the appearance of antibodies that clearly reduced the potential of several different M+ strains to colonize mice.78 Finally, Lukomski and colleagues79 showed that the pres-­ ence of SPEB markedly increases the virulence of a given group A streptococcal strain. Inactivation of the SPEB gene markedly decreases the lethality (IP challenge) of at least two strains—type 49 and S43 type 6. The mechanism whereby SPEB− strains decrease the lethality of the strain seems to be related to the fact that polymorphonuclear neutrophils were able to clear the mutant strain from the circulation and tissues much more rapidly than the wildtype strain.79

CONCLUSION Despite its disappearance in many areas of the world, ARF continues to be a serious problem in the geographic areas where two thirds of the population live. Even in developed countries with full access to medical care, better nutrition, and housing, the resurgence of the disease in these areas emphasizes the need for continued vigilance of physicians and other health officials in diagnosing and treating ARF. Whether this resurgence represents a change in the viru-­ lence of the organism or failure to recognize the importance and adequate treatment of an antecedent streptococcal infection remains an area of intense debate and requires careful and controlled epidemiologic surveillance. The importance of early diagnosis and therapy cannot be overemphasized. Although the joint manifestations are transient and self-limiting, the cardiac sequelae are chronic and life-threatening. Nevertheless, ARF remains one of the few autoimmune disorders known to occur as a result of infection with a specific organism. The confirmed obser-­ vation of an increased frequency of a B cell alloantigen in several populations of rheumatic patients suggests that it might be possible to identify susceptible individuals to ARF at birth. If so, from a public health standpoint, (1) these individuals would be prime candidates for immunization with any streptococcal vaccine that might be developed in the future; (2) careful monitoring of streptococcal disease in

1782 GIBOFSKY  |  Poststreptoccocal Arthritis and Rheumatic Fever

the susceptible population could lead to early and effective antibiotic strategies, resulting in disease prevention; and (3) in individuals previously infected, who later present with subtle or nonspecific manifestations of the disease, the pres-­ ence or absence of the marker could be valuable in arriving at a diagnosis. The continued study of ARF as a paradigm for micro-­ bial-host interactions also has important implications for the study of autoimmune diseases in general and rheumatic diseases in particular. Further insights into this intriguing host-parasite relationship may shed additional light into diseases where the infection is presumed, but has not been identified yet. REFERENCES   1. Veasy LG, Orsmond GS, et al: Resurgence of acute rheumatic fever in the intermountain area of the United States. N Engl J Med 316:421427, 1987.   2. Gordis L: The virtual diappearance of rheumatic fever in the United States: Lessons in the rise and fall of disease. Circulation 72: 1155-1162, 1985.   3. Pope RM: Rheumatic fever in the 1980s. Bull Rheum Dis Arthritis Foundation 38:1-8, 1989.   4. Markowitz M, Gordis L: Rheumatic Fever, 2nd ed. Philadelphia, WB Saunders, 1972.   5. Kaplan EL, Anthony BF, Chapman SS, et al: The influence of the site of infection on the immune response to group A streptococci. J Clin Invest 49:1405-1414, 1970.   6. Whitnack E, Bisno AL: Rheumatic fever and other immunologically mediated cardiac diseases. In Parker C (ed): Clinical Immunology, vol II. Philadelphia, WB Saunders, 1980, pp 894-929.   7. Denny FW Jr, Wannamaker LW, Brink WR, et al: Prevention of rheumatic fever: Treatment of the preceeding streptococcal infection. JAMA 143:151-153, 1950.   8. Markowitz M: Rheumatic fever: Recent outbreaks of an old disease. Conn Med 51:229-233, 1987.   9. Stollerman GH, Lewis AJ, Schultz I, et al: Relationship of the immune response to group A streptococci to the cause of acute, chronic and recurrent rheumatic fever. Am J Med 20:163-169, 1956. 10. Potter EV, Svartman M, Mohammed I, et al: Tropical acute rheu-­ matic fever and associated streptococcal infections compared with concurrent acute glomerulonephritis. J Pediatr 92:325-333, 1978. 11. Bessen D, Jones KF, Fischetti VA: Evidence for the distinct classes of streptococcal M protein and their relationship to rheumatic fever. J Exp Med 169:269-283, 1989. 12. Kaplan EL, Johnson DR, Cleary PP: Group A streptococcal serotypes isolated from patients and sibling contacts during the resurgence of rheumatic fever in the United States in the mid 1980’s. J Infect Dis 159:101-103, 1989. 13. Bisno AL, Nelson KE: Type-specific opsonic antibodies in streptococ-­ cal pyoderma. Infect Immun 10:1356-1361, 1975. 14. Kendall F, Heidelberger M, Dawson M: A serologically inactive poly-­ saccharide elaborated by mucoid strains of group A hemolytic strep-­ tococcus. J Biol Chem 118:61-82, 1937. 15. Seastone CV: The virulence of group C hemolytic streptococci of animal origin. J Exp Med 70:361-378, 1939. 16. Quinn RW, Singh KP: Antigenicity of hyaluronic acid. Biochem J 95:290-301, 1957. 17. Fillet HM, McCarty M, Blake M: Induction of antibodies to hyal-­ uronic acid by immunization of rabbits with encapsulated strepto-­ cocci. J Exp Med 164:762-776, 1986. 18. Faarber P, Capel PJ, Rigke PM, et al: Cross reactivity of anti DNA antibodies with proteoglycans. Clin Exp Immunol 55:402-412, 1984. 19. Stollerman GH: In Rheumatic Fever and Streptococcal Infection. New York, Grune & Stratton, 1975, p 70. 20. Fischetti VA: Streptococcal M protein: Molecular design and bio-­ logical behavior. Clin Microbiol Rev 2:285-314, 1989. 21. Dale JB, Beachey EH: Multiple cross reactive epitopes of streptococ-­ cal M proteins. J Exp Med 161:113-122, 1985.

22. Sargent SJ, Beachey EH, Corbett CE, et al: Sequence of protective epitopes of streptococcal M proteins shared with cardiac sarcolemmal membranes. J Immunol 139:1285-1290, 1987. 23. Cunningham MW, McCormack JM, Talaber LR, et al: Human mono-­ clonal antibodies reactive with antigens of the group A streptococcus and human heart. J Immunol 141:2760-2766, 1988. 24. McCarty M: The streptococcal cell wall. The Harvey Lectures Series 65:73-96, 1970. 25. Goldstein I, Rebeyrotte P, Parlebas J, et al: Isolation from heart valves of glycopeptides which share immunological properties with strepto-­ coccus haemolyticus group A polysaccharides. Nature 219:866-868, 1968. 26. Goldstein I, Caravano R: Determination of anti group A streptococ-­ cal polysaccharide antibodies in human sera by an hemagglutination technique. Proc Soc Exp Biol Med 124:1209-1212, 1967. 27. Salvadori LG, Blake MS, McCarty M, et al: Group A streptococcusliposome ELISA antibody titers to group A polysaccharide and opso-­ nophagocytic capabilities of the antibodies. J Infect Dis 171:593-600, 1995. 28. Chetty C, Schwab JH: Chemistry of endotoxins. In Rietschel ET (ed): Handbook of Endotoxin, vol 1. Amsterdam, Elsevier Science, 1984, pp 376-410. 29. Cromartie WJ, Craddock JB, Schwab JH, et al: Arthritis in rats after systemic injection of streptococcal cells or cell walls. J Exp Med 146:1585-1602, 1977. 30. Cromartie WJ, Craddock JB: Rheumatic-like cardiac lesions in mice. Science 154:285-287, 1966. 31. Heymer B, Schleifer KH, Read SE, et al: Detection of antibodies to bacterial cell wall peptidoglycan in human sera. J Immunol 117:23-26, 1976. 32. Zabriskie JB: Rheumatic fever: The interplay between host genetics and microbe. Circulation 71:1077-1086, 1985. 33. Kingston D, Glynn LE: A cross-reaction between Streptococcus pyogenes and human fibroblasts, endothelial cells and astrocytes. Immu-­ nology 21:1003-1016, 1971. 34. Husby G, van de Rijn I, Zabriskie JB, et al: Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever. J Exp Med 144:1094-1110, 1976. 35. Froude J, Gibofsky A, Buskirk DR, et al: Cross reactivity between streptococcus and human tissue: A model of molecular mimicry and autoimmunity. Curr Top Microbiol Immunol 145:5-26, 1989. 36. Cheadle WB: Harvean lectures on the various manifestations of the rheumatic state as exemplified in childhood and early life. Lancet 1:821-832, 1889. 37. Wilson MG, Schweitzr MD, Lubschez R: The familial epidemiology of rheumatic fever. J Pediatr 22:468-482, 1943. 38. Taranta A, Torosdag S, Metrakos JD, et al: Rheumatic fever in mono-­ zygotic and dizygotic twins. Circulation 20:778-792, 1959. 39. Glynn LE, Halborrow EJ: Relationship between blood groups, secre-­ tion status and susceptibility to rheumatic fever. Arthritis Rheum 4:203, 1961. 40. Patarroyo ME, Winchester RJ, Vejerano A, et al: Association of a B cell alloantigen with susceptibility to rheumatic fever. Nature 278: 173-174, 1979. 41. Khanna AK, Buskirk DR, Williams RC Jr, et al: Presence of a nonHLA B cell antigen in rheumatic fever patients and their families as defined by a monoclonal antibody. J Clin Invest 83:1710-1716, 1989. 42. Ayoub EA, Barrett DJ, Maclaren NK, et al: Association of class II human histocompatibility leucocyte antigens with rheumatic fever. J Clin Invest 77:2019-2026, 1986. 43. Maharaj B, Hammond MG, Appadoo B, et al: HLA-A, B, DR and DQ antigens in black patients with severe chronic rheumatic heart disease. Circulation 765:259-261, 1987. 44. Guilherme L, Weidenbach W, Kiss MH, et al: Association of human leucocyte class II antigens with rheumatic fever or rheu-­ matic heart disease in a Brazilian population. Circulation 83: 1995-1998, 1991. 45. Watson RF, Hirst GK, Lancefield RC: Bacteriological studies of car-­ diac tissues obtained at autopsy from eleven patients dying with rheu-­ matic fever. Arthritis Rheum 4:74-85, 1961. 46. Halbert SP, Bircher R, Dahle E: The analysis of streptococcal infec-­ tions, V: Cardiotoxicity of streptolysin O for rabbits in vivo. J Exp Med 113:759-784, 1961.

PART 17  47. Wagner BM: Studies in rheumatic fever, III: Histochemical reactivity of the Aschoff body. Ann N Y Acad Sci 86:992-1008, 1960. 48. Zabriskie JB: Unpublished data, 1959. 49. Schlievert PM, Johnson LP, Tomai MA, et al: Characterization and genetics of group A streptococcal pyrogenic exotoxins. In Ferretti J, Curtis R (eds): Streptococcal Genetics. Washington, DC, ASM, 1987, pp 136-142. 50. Paliard X, West SG, Lafferty JA, et al: Evidence for the effects of superantigen in rheumatoid arthritis. Science 253:325-329, 1991. 51. Zabriskie JB, Hsu KC, Seegal BC: Heart-reactive antibody associated with rheumatic fever: Characterization and diagnostic significance. Clin Exp Immunol 7:147-159, 1970. 52. Khanna AK, Nomura Y, Fischetti VA, et al: Antibodies in the sera of acute rheumatic fever patients bind to human cardiac tropomyosin. J Autoimmun 10:99-106, 1997. 53. van de Rijn I, Fillit H, Brandis WE, et al: Serial studies on circulating immune complexes in post-streptococcal sequelae. Clin Exp Immu-­ nol 34:318-325, 1978. 54. Kemeny E, Grieve T, Marcus R, et al: Identification of mononuclear cells and T cell subsets in rheumatic valvulitis. Clin Immunol Immu-­ nopathol 52:225-237, 1989. 55. Amoils B, Morrison RC, et al: Aberrant expression of HLA-DR anti-­ gen on valvular fibroblasts from patients with acute rheumatic cardi-­ tis. Clin Exp Immunol 66:84-94, 1986. 56. Read SE, Reid HFM, Fischetti V, et al: Serial studies on the cellular immune response to streptococcal antigens in acute and convalescent rheumatic fever patients in Trinidad. J Clin Immunol 6:433-441, 1986. 57. Yang LC, Soprey PR, Wittner MK, et al: Streptococcal induced cell mediated immune destruction of cardiac myofibers in vitro. J Exp Med 146:344-360, 1977. 58. Dale JB, Beachey EH: Human cytotoxic T lymphocytes evoked by group A streptococcal M proteins. J Exp Med 166:1825-1835, 1987. 59. Jones Criteria 1992 update: Guidelines for diagnosis of rheumatic fever. JAMA 268:2069-2070, 1992. 60. Feinstein AR, Spagnulo M: The clinical patterns of rheumatic fever: A reappraisal. Medicine 41:279-305, 1962. 61. Goldsmith DP, Long SS: Poststreptococcal disease of chlidhood—a changing syndrome. Arthritis Rheum 25:S18, 1982 (abstract). 62. Arnold MH, Tyndall A: Post-streptococcal reactive arthritis. Ann Rheum Dis 48:681-688, 1989. 63. Fink CW: The role of streptococcus in post streptococcal reactive arthritis and childhood polyarteritis nodosa. J Rheumatol 18:14-20, 1991. 64. Gibofsky A, Zabriskie JB: Rheumatic fever: New insights into an old disease. Bull Rheum Dis Arthritis Foundation 42:5-7, 1994.

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65. Crea MA, Mortimer EA: The nature of scarlatinal arthritis. Pediat-­ rics 23:879-884, 1959. 66. Wallace MR, Garst PD, Papadimos TJ, et al: The return of acute rheumatic fever in young adults. JAMA 262:2557-2561, 1989. 67. Bland EF, Jones TD: Rheumatic fever and rheumatic heart disease: A twenty year report on 1,000 patients followed since childhood. Circulation 4:836-843, 1951. 68. Osler W: On Chorea and Choreioform Movements. HK Lewis & Co, 1894. 69. Swedo SE, Leonard HL, Mittleman BB, et al: Children with PAN-­ DAS (pediatric autoimmune neuropsychiatric disorders associated with strep. infections) are identified by a marker associated with rheumatic fever. Am J Psychiatry 154:110-112, 1997. 70. Murphy T, Goodman W: D8/17 reactivity as an immunologic marker of susceptibility to nonpsychiatric disorders. J Am Acad Child Ado-­ lesc Psychiatry 41:98-100, 2002. 71. Cillers AM: Rheumatic fever and its management. BMJ 333: 1153-1156, 2006. 72. Lue HC, Mil-Wham W, Hsieh KH, et al: Rheumatic fever recur-­ rences: Controlled study of 3 week verus 4 week benzathine penicil-­ lin prevention programs. J Pediatr 108:299-304, 1986. 73. Dale JB, Simmons M, Chiang EC, et al: Recombinant, octavalent group A streptococcal M protein vaccine. Vaccine 14:944-948, 1996. 74. Bessen D, Fischetti VA: Influence of intranasal immunization with synthetic peptides corresponding to conserved epitopes of M pro-­ tein on mucosal colonization by group A streptococci. Infect Immun 56:2666-2672, 1988. 75. Bronze MS, Courtney HS, Dale JB: Epitopes of group A streptococ-­ cal M protein that evoke cross protection local immune responses. J Immunol 148:888-893, 1992. 76. Good MF, Brandt ER, Currie B, et al: Strategies for developing a group A streptococoal vaccine based on the M protein. Presented at the XIV Lancefield International Symposium on Streptococci and Streptococcal Diseases, Auckland, New Zealand, 1999. 77. Lancefield RC: Persistence of type specific antibodies in man ­following infection with group A streptococci. J Exp Med 110:271292, 1959. 78. Ji Y, Carlson B, Kondagunta A, et al: Intranasal immunization with C5a peptidase prevents nasopharyngeal colonization of mice by the group A streptococcus. Infect Immun 65:2080-2087, 1997. 79. Lukomski S, Burns EH, Wyde PR, et al: Genetic inactivation of an extracellular cysteine protease (SPEB) expression by Streptococcus pyogenes decreases resistance to phagocytosis and dissemination to organs. Infect Immun 66: 771-776, 1998.

Part

18

arthritis accompanying systemic disease

106

Amyloidosis David C. Seldin  •  Martha Skinner

KEY POINTS

CLASSIFICATION AND EPIDEMIOLOGY

Amyloidosis is a term for systemic diseases in which aggregated proteins deposit in tissues of the body, eventually leading to organ failure and death if not effectively treated.

Amyloid diseases are defined by the biochemical nature of the protein in the deposited fibril. The proteins are diverse and unrelated in primary amino acid sequence, resulting in amyloid diseases being classified according to whether they are systemic or localized, whether they are acquired or inherited, and their recognized clinical patterns (Table 106-1).3 Each amyloid disease has a shorthand nomenclature, expressed asA for amyloidosis and an abbreviation for the biochemical nature of the fibrils: for example, AL is amyloid of immuno­globulin light chain origin. The discussion in this chapter is limited to the systemic amyloidoses because these are the diseases that can involve the joints and are potentially ­confused with autoimmune rheumatologic disorders. The acquired systemic amyloidoses are AL (immunoglobulin light chain, or primary), AA (reactive, secondary), and Aβ2M (β2-microglobulin, dialysis-associated) types. The AL type is most common, although epidemiologic data are limited. One study based on National Center for Health Statistics data estimated the incidence as 4.5 per 100,000.4 AL amyloidosis usually manifests after age 40 years and is associated with rapid progression, multisystem involvement, and a short survival. AA amyloidosis is rare, occurring in less than 1% of patients with chronic inflammatory diseases in the United States and Europe, but it is more common in ­Turkey and the Middle East, where it occurs in association with familial Mediterranean fever.5-7 It may begin within 1 year after onset of the underlying inflammatory disease or many years later. It is the only type of amyloidosis that occurs in children. Aβ2M amyloidosis is a chronic rheumatologic complication that occurs in a few patients on long-term dialysis and is related to a high concentration of β2-microglobulin.8 The inherited amyloidoses are rare, with an estimated incidence of less than 1 per 100,000.9 They are autosomal dominant diseases in which a variant plasma protein forms amyloid deposits beginning in midlife. The most common form is caused by variant transthyretin (TTR), of which there are nearly 100 known to be associated with amyloidosis.10 One variant, Val-122-Ile, has a carrier frequency that may be 4% of the black population and is associated with late-onset cardiac amyloidosis.11 Even wild-type TTR can form fibrils, leading to senile systemic amyloidosis, which

Patients with amyloidosis can present with joint symptoms and soft tissue deposits that mimic rheumatologic disorders, and chronic inflammation or infection can lead to secondary AA amyloidosis. The diagnosis of amyloidosis requires a tissue biopsy that demonstrates green birefringence of deposits on polarization microscopy after staining with Congo red. Appropriate treatment depends upon the accurate biochemical or immunochemical identification of amyloid type, distinguishing hereditary genetic from acquired forms of amyloidosis.

The term amyloidosis comprises diseases that have in common the extracellular deposition of insoluble fibrillar proteins in tissues and organs. These diseases are a subset of a growing group of disorders recognized to be caused by misfolding of proteins; these disorders include Alzheimer’s and other neurodegenerative diseases, prion diseases, serpinopathies, some of the cystic fibroses, and others. A unifying feature of amyloidoses is that the deposits share a common β-pleated sheet structural conformation that confers unique staining properties. The name “amyloid” is attributed to the pathologist Virchow, who in 1854 thought such deposits in autopsy livers were cellulose because of their peculiar staining reaction with iodine and sulfuric acid.1 In the 20th century, “amyloid” was found to be a proteinaceous fibrillar deposit in tissues.2 Biochemical characterization of the fibril proteins from clinical cases proved the “amyloidoses” to be a spectrum of diseases, many with a fatal outcome owing to progressive deposition of amyloid fibrils in major organs. A growing number of treatments are available to target the source of the ­abnormal protein and, for some types, to inhibit the amyloidogenic protein misfolding process.

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Table 106-1  Classification of Amyloidosis Systemic (S) or Localized (L)

Term

Fibril Composition

AL

Immunoglobulin light chains (κ or λ)

S, L

Primary; myeloma-associated; systemic or localized in skin, lymph nodes, bladder, tracheobronchial tree

AA

Amyloid A protein

S

Secondary; reactive; familial Mediterranean fever

Aβ2M

β2-microglobulin

S

Long-term hemodialysis or ambulatory peritoneal dialysis

ATTR

Transthyretin (92 familial variants); wild-type TTR in   senile systemic amyloidosis

S

Familial amyloidotic polyneuropathy and cardiomyopathy; senile systemic amyloidosis

AApoA

Apolipoprotein A-I (11 familial variants)   or apolipoprotein A-II (4 familial variants)

S

Familial polyneuropathy with nephropathy

AGel

Gelsolin (variant Asn 187, Tyr 187)

S

Familial polyneuropathy with lattice corneal dystrophy, cranial neuropathy, nephropathy

AFib

Fibrinogen A alpha (3 familial variants)

S

Familial amyloidosis with nephropathy

ALys

Lysozyme (4 familial variants)

S

Familial amyloidosis with nephropathy

Aβ

Amyloid β protein

L

Alzheimer’s disease; Down syndrome; cerebral amyloid angiopathy (Dutch)

ACys

Cystatin C (variant with N-terminal deletion and Glu 68)

S

Cerebral amyloid angiopathy (Icelandic)

AIAPP

Islet amyloid polypeptide

L

Type 2 diabetes mellitus; insulinoma

ACal

Calcitonin

L

Medullary carcinoma of the thyroid

AANF

Atrial natriuretic factor

L

Atrial amyloid, localized

predominantly affects the heart, in older patients.12,13 Other familial amyloidoses, caused by variant apolipoprotein A-I, A-II, gelsolin, fibrinogen Aα, or lysozyme, are reported in only a few families worldwide.

PATHOLOGY AND PATHOGENESIS OF AMYLOID FIBRIL FORMATION PATHOLOGIC FEATURES Amyloid deposits are widespread in AL amyloidosis and can be present in the extracellular spaces and the blood vessels of all organs. Deposits in AA amyloidosis usually develop in the kidneys, liver, and spleen, although widespread deposits can be found late in the course of the disease. In Aβ2M amyloidosis, deposits tend to occur in synovial membrane, cartilage, and bone, but visceral organs are sometimes aff­ ected. In ATTR amyloidosis, the nervous system, heart, and thyroid are frequently affected organs, with only small deposits found elsewhere. All amyloid deposits stain with Congo red dye and exhibit a unique green birefringence by polarized light microscopy,14 although the deposits also can be recognized on routine hematoxylin and eosin–stained sections. By electron microscopy, amyloid fibrils are 8 to 10 nm wide and of varying lengths, with a 2.5- to 3.5-nm filamentous subunit arranged along the long axis of the fibril in a slow twist.15 Typing of amyloid deposits can be done with conventional immunohistochemical staining. False-positive results can occur, however, owing to the presence of nonamyloid serum proteins, and immunoelectron microscopy can provide more definitive immunologic identification of the protein in the fibril itself.16 Fibrils can be extracted from tissues, and their composition can be analyzed by mass spectrometry, providing a definitive identification; however, this is not available yet as a routine clinical test.

Clinical Syndrome

PATHOGENESIS OF AMYLOID FIBRIL FORMATION The exact mechanism of fibril formation is unknown and may differ among the various types of amyloid.17,18 Studies suggest there may be a common underlying mechanism, however, in which a partially unfolded protein intermediate forms multimers and then higher order polymers. Factors that contribute to fibrillogenesis include variant or unstable protein structure, extensive β-conformation of the precursor protein, proteolytic processing of the precursor protein, association with components of the serum or extracellular matrix (e.g., amyloid P-component, amyloid enhancing factor, apolipoprotein E, or glycosaminoglycans), and physical properties including pH of the tissue site. AL amyloidosis is a plasma cell dyscrasia with an excess of clonal plasma cells in the bone marrow; it can occur in isolation or along with multiple myeloma. Similar cytogenetic changes have been identified in both plasma cell diseases, suggesting they may have a common molecular pathogenesis.19 By two-dimensional gel electrophoresis and mass spectrometry, it can be seen that the amyloid fibril deposits are composed of intact 23-kD monoclonal immunoglobulin light chains and C-terminal truncated fragments.20 Although all κ and λ light chain subtypes have been identified in amyloid fibrils, λ subtypes predominate, and the λ VI subtype seems to have unique structural properties that predispose it to fibril formation,21 often in the kidney.22 AL amyloidosis is usually a rapidly progressive disease with amyloid deposits in multiple tissue sites. The AA type of amyloidosis is a complication of severe, long-standing inflammation, as occurs in rheumatic diseases or infection. The AA amyloid fibrils usually are composed of an 8-kD, 76-amino acid amino-terminal portion of the 12-kD precursor, serum amyloid A (SAA).23 SAA is a polymorphic protein encoded by a family of SAA genes, which are acute-phase apoproteins synthesized in the liver and

PART 18 

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ARTHRITIS ACCOMPANYING SYSTEMIC DISEASE

formation.28 The role of aging is intriguing because patients with the variant proteins do not have clinically apparent disease until midlife or later, despite the lifelong presence of the abnormal protein.29 Further evidence of an age-related trigger is that senile cardiac amyloidosis, caused by the deposition of fibrils derived from normal TTR, is exclusively a disease of elderly ­individuals.13

transported by a high-density lipoprotein, HDL3, in the plasma.24 An underlying inflammatory disease of several years’ duration causing an elevated SAA usually precedes fibril formation, although infections can produce AA deposition more quickly. AA fibril formation can be accelerated by an ­amyloid enhancing factor present in high concentration in the spleen (which may be early SAA aggregates or deposits), by basement membrane heparan sulfate proteoglycan, or by seeding with AA or heterologous fibrils.25,26 Factors related to β2-microglobulin fibril formation are under investigation. The high prevalence of Aβ2M disease in patients undergoing long-term dialysis argues against an amyloidogenic variant β2-microglobulin molecule. Permeability of dialysis membranes may be a factor because the molecular weight of β2-microglobulin is 11.8 kD, above the porosity of standard membranes. It has been hypothesized that dialysis membranes may be bioincompatible and induce proinflammatory mediators that stimulate β2-microglobulin and contribute to fibril formation.27 In ATTR (also called familial amyloidotic polyneuropathy), and all other forms of familial amyloidosis, inherited mutations or polymorphisms in the genes encoding large serum proteins produce amyloid-prone variants. The process of fibrillogenesis has been best studied for TTR, in which variant TTR molecules seem to be prone to dissociation from stable tetramers and to unfolding, leading to misfolding, polymerization, and fibril

DIAGNOSIS A tissue biopsy specimen showing amyloid fibrils is necessary for the diagnosis of amyloidosis (Fig. 106-1). The least invasive biopsy is the abdominal fat aspirate, which is positive in 80% to 90% of patients with either AL or ATTR amyloidosis and in 60% to 70% of patients with AA amyloidosis.30,31 It is easy to perform after local injection of anesthetic and has a low rate of infectious or hemorrhagic complications (Fig. 106-2). If the aspirate is negative, but clinical suspicion for disease persists, a more invasive tissue biopsy should be done. Although a biopsy specimen of a clinically involved organ is recommended, almost any tissue biopsy specimen is likely to be positive if the patient has systemic amyloidosis: In a series of 100 patients with AL amyloidosis, 85% of 249 tissue biopsy specimens were positive, including all samples from the kidney, heart, and liver.32 When the diagnosis of amyloidosis is made, a careful evaluation of the entire

Tissue biopsy (abdominal fat aspirate) Negative

Positive

More invasive biopsy of heart, kidney, liver, etc. Negative

Positive To determine type

Look for:

No further work-up

AL (primary)

Monoclonal protein in serum or urine Multisystem involvement Macroglossia

AA (secondary)

Underlying chronic inflammation Renal involvement

Familial

1787

ATTR

Mutant transthyretin protein Family history Polyneuropathy, cardiomyopathy Vitreous opacities

AApoA-I

Mutant apolipoprotein A-I Renal disease

AFib

Mutant fibrinogen Renal disease

AGel

Mutant gelsolin Cranial neuropathy

ALys

Mutant lysozome, renal, gastrointestinal disease

Figure 106-1  Algorithm for the diagnosis of amyloidosis and determination of type.

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c­ linical picture, including manner of presentation, organ system involvement, underlying diseases, and family history should provide a clue to the type of amyloid. Identification of a plasma cell dycrasia distinguishes AL from other types of amyloidosis (Fig. 106-3). More than 90% of patients have a serum or urine monoclonal immunoglobulin protein or a free light chain on testing by immunofixation electrophoresis or by a recently available nephelometric assay for free light chains.33,34 In addition, there is often an increased percentage of plasma cells in the bone marrow, which are monoclonal on immunohistochemical staining (Fig. 106-4).35 A monoclonal serum protein by itself is not diagnostic of amyloidosis because monoclonal gammopathy of uncertain significance is common in older patients. When “monoclonal gammopathy of uncertain significance” is present in a patient with biopsy-proven amyloidosis, however, the AL type is strongly suspected. Immunohistochemical

staining by light or electron microscopy should be done by a laboratory familiar with the techniques and able to perform appropriate controls.16 Mass spectrometry–based microsequencing of small amounts of protein extracted from fibril deposits ultimately may be the most reliable way to identify the components of the fibrils.36 AA amyloidosis is suspected in patients with renal amyloidosis and a chronic inflammatory condition or infection. AL and ATTR amyloidosis must be ruled out. AA amyloidosis must be confirmed by immunohistochemical staining for AA protein. Familial amyloidosis must be excluded in every patient who does not have a plasma cell dyscrasia or the AA type of amyloidosis. Although the disease has a dominant ­inheritance, family history may not be apparent when the disease occurs later in life; also, some cases occur through new mutations. Variant TTR proteins usually can be detected by isoelectric focusing (Fig. 106-5).37 Abnormal isoelectric focusing should prompt genetic testing to determine the precise TTR mutation. Genetic testing should be employed when screening tests fail to identify the fibril protein. Using polymerase chain reaction–based sequencing, abnormal fibrinogens and apolipoproteins and variant TTRs can be detected.38

CLINICAL FEATURES AND TREATMENT OF SYSTEMIC AMYLOIDOSES AL AMYLOIDOSIS A

B Figure 106-2  A and B, Subcutaneous fat aspirate stained with Congo red viewed by light microscopy (A) and viewed under polarized light  (B) (×200). The staining and birefringence is evident in the walls and connective tissue surrounding the adipose cells.

Figure 106-3  A, Pretreatment serum immunofixation electro­phoresis shows an IgG κ monoclonal protein. B, Post-treatment serum immuno­ fixation electrophoresis shows absence of the monoclonal protein.

A

ELP

G

A

M

AL amyloidosis usually occurs in middle-aged or older individuals, but also can occur in the third or fourth decade of life. It has a wide spectrum of organ system involvement, and presenting features reflect the organs most prominently affected.39,40 Initial symptoms of fatigue and weight loss are frequent, but the diagnosis is rarely made until symptoms referable to a specific organ appear. The kidneys are commonly affected; renal amyloidosis is manifested by proteinuria, sometimes massive with edema and hypoalbuminemia. Mild renal dysfunction is frequent, but rapidly progressing renal failure is rare. Cardiac involvement, often with congestive heart failure, is a common presentation.41 The electrocardiogram may show low voltage with a pattern of myocardial infarction. The echocardiogram frequently shows concentrically thickened ventricles and a normal or mildly reduced ejection fraction. Nerv­ ous system features include peripheral sensory neuropathy, carpal tunnel syndrome, and autonomic dysfunction with

K

L

B

ELP

G

A

M

K

L

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1789

Figure 106-6  Enlarged tongue of a patient with AL amyloidosis.

Figure 106-4  Bone marrow biopsy specimen stained with antibody to λ light chain shows preferential staining of plasma cells and staining of amyloid deposit around a blood vessel (×400).

1

2

3

Figure 106-7  Periorbital ecchymoses in a patient with AL amyloidosis.

Figure 106-5  Isoelectric focusing of serum samples shows bands of var­ iant and wild-type TTR protein (arrow) from a patient with ATTR (lane 2)   and a single band of wild-type TTR in normal subjects (lanes 1 and 3).

g­ astrointestinal motility disturbances (early satiety, ­diarrhea, constipation) and orthostatic hypotension. Macroglossia, a classic feature pathognomonic of AL amyloidosis, is found in 10% of patients (Fig. 106-6). Hepatomegaly may be massive with mild cholestatic abnormalities of liver function, although liver failure is uncommon, even when hepa­ tomegaly is massive. The spleen is frequently involved, and there may be functional hyposplenism even in the absence of significant splenomegaly. Cutaneous ecchymoses are common, particularly around the eyes, giving the “raccooneyes” sign, and appear spontaneously or when provoked by minor trauma (Fig. 106-7). Other findings include nail dystrophy (Fig. 106-8), alopecia, and amyloid arthropathy with thickening of synovial membranes. We have reviewed the soft tissue and joint manifestations of AL amyloidosis in a

series of almost 200 patients.42 Symptoms and signs mimicking rheumatologic diseases, with arthropathy, subcutaneous tissue deposits, muscle pseudohypertrophy, adenopathy, carpal tunnel syndrome, submandibular gland enlargement, and macroglossia occur in more than 40% of patients with AL amyloidosis, particularly in patients with light chain deposits. Timely diagnosis of AL amyloidosis is crucial. Patients with any of these clinical syndromes should have immunofixation electrophoresis performed. The sensitivity of serum or urine protein electrophoresis without immunofixation is inadequate for diagnosis.

Figure 106-8  Fingernail dystrophy in a patient with AL amyloidosis.

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Extensive multisystem involvement typifies AL amyloidosis, and median survival with no treatment is usually only about 1 year from diagnosis. Current therapies target the clonal bone marrow plasma cells using chemotherapy approaches employed for multiple myeloma (Table 106-2). Cyclic oral melphalan and prednisone can decrease the plasma cell burden, but produce complete hematologic rem­ission in only a small percentage of patients, and modestly increase median survival.32,43 Substitution of highdose dexa­methasone for prednisone seems to increase response rates markedly.44 High-dose intravenous melphalan followed by autologous stem cell transplantation is highly effective. Of more than 300 patients treated on such protocols at Boston Medical Center, approximately 40% of evaluable patients achieve a hematologic complete response, and most of these experience significant improvement or stabilization of organ function.45 Median survival in the treated patients exceeds 4.5 years. Other centers have replicated these results.46-48 Patients with amyloidosis and organ impairment have a high rate of treatment-related morbidity and mortality with aggressive treatment, however, particularly at centers without extensive multidisciplinary experience in the management of the disease. Factors that contribute to mortality are amyloid cardiomyopathy, nutritional status as measured by weight loss, performance status, and, in some studies, number of involved organs. The bleeding diathesis resulting from absorption of clotting factor X to amyloid fibrils also confers high mortality during myelosuppressive therapy. Age alone49 or renal failure50 should not exclude patients from such treatment, however. For patients with impaired cardiac function or arrhythmias owing to amyloid involvement of the myocardium, median survival is only about 6 months without treatment,

and stem cell mobilization and high-dose chemotherapy are associated with great morbidity. In a few such patients, ­cardiac transplantation has been performed followed by treatment with intravenous melphalan and stem cell rescue to prevent fibrillogenesis in the transplanted heart or other organs. New agents that are efficacious in reducing the plasma cell burden in multiple myeloma are being tested for AL amyloidosis. The immunomodulators thalidomide and lena­ lidomide have activity in AL amyloidosis,51,52 although the former is not well tolerated. Excellent responses have been seen with lenalidomide and dexamethasone, even in heavily pretreated patients. The proteasome inhibitor bortezomib is being tested in a multicenter trial. Innovative approaches target the amyloid fibrils themselves or accessory binding proteins. The anthracycline derivative 4′-iodo-4′-deoxydoxorubicin (IDOX) was serendipitously noted to cause resorption of amyloid deposits in model systems, but preliminary trials with single-agent IDOX have not produced clinically significant respon­ ses.53,54 The agent R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) binds serum amyloid P protein and accelerates clearance from the circulation and from amyloid fibrils.55 The efficacy of CPHPC in promoting fibril resorption and reducing amyloid disease has so far not been shown. Supportive treatment is recommended for patients with all types of amyloidosis (Table 106-3). At times, supportive treatments are lifesaving (e.g., heart or kidney transplantation, renal dialysis, cardiac pacemaker, and nutritional support). Digitalis, calcium channel blockers, and β-blockers are relatively contraindicated because toxicity has been observed at therapeutic levels. AA AMYLOIDOSIS

Table 106-2  Major Treatment Options   for Amyloidosis AL Amyloidosis Intravenous melphalan with autologous stem cell rescue Granulocyte colony-stimulating factor mobilized peripheral blood stem cell collection Intravenous melphalan 100-200 mg/m2 Autologous stem cell reinfusion Cyclic oral melphalan and dexamethasone Melphalan 0.22 mg/kg/day × 4 days Dexamethasone 20-40 mg/day × 4 days Repeat administration every 4 wk Immunomodulators Thalidomide 50-200 mg/day or lenalidomide 5-15 mg/day × 21 days Dexamethasone 20-40 mg/day × 4 days Repeat administration every 4 wk Proteasome inhibitors Intravenous bortezomib, in clinical trials AA Amyloidosis Aggressive treatment of underlying inflammatory disease Medical or surgical treatment of underlying infection Colchicine 1.2-1.8 mg/day for AA amyloidosis secondary to familial Mediterranean fever Antifibril drug, eprosidate (FDA approval pending) ATTR Amyloidosis Orthotopic liver transplantation Diflunisal in clinical trials

AA amyloidosis can occur at any age. The primary clinical manifestation is proteinuria or renal insufficiency or both.5 A study from Finland found AA amyloidosis to be the most common cause of nephrotic syndrome in patients with rheumatoid arthritis.56 Hepatomegaly, splenomegaly, and autonomic neuropathy frequently occur as the disease progresses; cardiomyopathy occurs rarely. With chronic inflammatory diseases, amyloid progression is slow, and survival is often more than 10 years, particularly with treatment for endstage renal disease. In contrast, untreated infections, such as osteomyelitis, tuberculosis, or leprosy, can produce a more rapidly progressive amyloid syndrome, which remits with effective medical or surgical treatment of the infection. The major therapy in AA amyloidosis is treatment of the underlying inflammatory or infectious disease. Treatment that suppresses or eliminates the inflammation or infection also decreases the serum amyloid A (SAA) protein. For familial Mediterranean fever, colchicine, 1.2 to 1.8 mg/day, is the appropriate treatment. Colchicine has not been helpful for AA amyloidosis of other causes or for other amyloidoses. A multicenter trial using a new antiamyloid drug, eprodisate, has been completed, and the drug was found to delay significantly worsening of renal function in patients with AA amyloidosis.57 Eprodisate interferes with the interaction of AA amyloid protein and glycosaminoglycans in tissues and prevents fibril formation and deposition.

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Table 106-3  Supportive Treatment for All Types of Amyloidosis Organ System

Symptom

Treatment Options

Cardiac

Congestive failure

Salt restriction of 1-2 g/day Diuretics: furosemide, spironolactone, metolazone Pacemaker Automatic implantable cardiac defibrillator Antiarrhythmics

Arrhythmia

Renal

Nephrotic syndrome

Autonomic nervous

Orthostatic hypotension

Renal failure

Gastric atony or ileus

Gastrointestinal

Diarrhea

Macroglossia Peripheral nervous

Sensory neuropathy

Motor neuropathy Hematologic

Intracutaneous bleeding Factor X deficiency

Salt restriction of 1-2 g/day Elastic stockings, leg elevation Maintain dietary protein Angiotensin-converting enzyme inhibitor, if blood pressure tolerates Dialysis (long-term ambulatory peritoneal dialysis or hemodialysis) Midodrine Increase dietary salt or add fludrocortisone, depending on edema Elastic stockings Small frequent feedings (6/day) low in fat Oral nutritional supplements Jejunostomy tube feeding Parenteral nutrition Low-fat diet (≤40 g) Psyllium hydrophilic muciloid (Metamucil) Loperamide hydrochloride (Imodium) Tincture of opium Parenteral nutrition Soft solid diet Partial glossectomy (rarely effective) Avoid trauma Gabapentin (Neurontin) 100-300 mg 3 times daily Amitriptyline, 25-50 mg at bedtime Carbamazepine (Tegretol) Ankle/foot orthotics for footdrop Physical therapy Avoid trauma, antiplatelet agents Factor replacement (recombinant factor VIIa, prothrombin complex concentrates) Splenectomy if massively enlarged spleen

Aβ2M AMYLOIDOSIS Several distinct rheumatologic conditions are observed in Aβ2M amyloidosis, including carpal tunnel syndrome, persistent joint effusions, spondyloarthropathy, and cystic bone lesions. Carpal tunnel syndrome is usually the first symptom of disease. Persistent joint effusions accompanied by mild discomfort occur in 50% of patients on dialysis for more than 12 years. Involvement is bilateral, and large joints (shoulders, knees, wrists, and hips) are more frequently affected. The synovial fluid is noninflammatory and β2-microglobulin amyloid deposits can be found if the sediment is ­examined with Congo red staining. Spondyloarthropathy with destructive changes of the intervertebral disks and paravertebral erosions have occurred in association with β2-microglobulin amyloid deposits. Cystic bone lesions sometimes leading to pathologic fractures have been described in the femoral head, acetabulum, humerus, tibial plateau, vertebral bodies, and carpal bones. Although less common, visceral β2-microglobulin amyloid deposits occasionally occur in the gastrointestinal tract, heart, tendons, and subcutaneous tissues of the buttocks. The treatment for Aβ2M amyloidosis is difficult because the 11-kD β2-microglobulin molecule is too large to pass through a dialysis membrane. Consistent with a postulated role of copper in initiating Aβ2M fibrillogenesis,58 copperfree dialysis membranes seem to reduce the incidence of disease. Patients on continuous ambulatory peritoneal dialysis

usually have lower plasma levels of β2-­microglobulin than patients on hemodialysis and may not develop amyloid deposits as quickly. Symptoms of arthropathy are common, and prevalence may approach 100% of individuals on dialysis for more than 15 years. Patients who have received kidney transplants after developing Aβ2M report an improvement in symptoms. ATTR FAMILIAL AMYLOIDOSIS The clinical features of ATTR amyloidosis overlap AL amyloidosis such that the diseases cannot be reliably distinguished on clinical grounds alone. A family history makes ATTR more likely, but many patients seem to present sporadically with new mutations. Within each family, disease begins at nearly the same age, and symptoms usually include neuropathy or cardiomyopathy or both. Peripheral neuropa­ thy begins as a lower extremity sensory and motor neuropathy and progresses to the upper extremities. Autonomic neuropathy is manifest by gastrointestinal symptoms of diarrhea with weight loss and orthostatic hypotension. Patients with TTR Val-30-Met, the most common mutation, have normal echocardiograms, but may have conduction system defects and require a pacemaker. Patients with TTR Thr60-Ala and several other mutations have myocardial thickening similar to that caused by AL amyloidosis, although heart failure is less common, and the prognosis is better.

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Vitreous opacities caused by amyloid deposits are pathognomonic of ATTR amyloidosis. The TTR variant, Val 122 Ile, is a common allele in African-Americans and seems to be associated with cardiomyopathy. In a large referral population, 25% of ­African-American patients with amyloidosis had this TTR variant.59 This disease likely is underdiagnosed because of a lack of physician awareness and the difficulty of distinguishing amyloid and hypertensive cardiomyopathy without an endomyocardial biopsy.11 Without intervention, survival after ATTR disease onset is 5 to 15 years. Orthotopic liver transplantation, which removes the major source of variant TTR production and replaces it with normal TTR, is the major treatment for ATTR amyloidosis.60,61 Liver transplantation arrests disease progression, and some improvement in autonomic and peripheral neuropathy can occur.62 Cardiomyopathy does not improve, and in some patients seems to worsen, after liver transplantation.63 Long-term outcome and the timing of transplantation are being evaluated.64 An international multicenter randomized placebo-controlled clinical trial is under way to test the efficacy of the nonsteroidal anti-­inflammatory drug, diflunisal, for the treatment of TTR ­amyloidosis (www.bu.edu/amyloid/doctors/trials/html). Laboratory studies have suggested that diflunisal stabilizes ­variant TTRs and prevents unfolding and aggregation.65

SUMMARY Treatment of the amyloidoses begins with recognition of the clinical amyloid syndromes and obtaining appropriate biopsy specimens and screening tests to rule in or out AL amyloidosis. For difficult cases and for identification of variant serum proteins, amyloid referral centers can provide specialized diagnostic techniques. Effective therapy is now available for AL, AA, and ATTR amyloidosis. An understanding of the biophysical properties of amyloid proteins and of the mechanisms of protein misfolding in a wide variety of diseases would enable the further development of more specific and less toxic antifibril drugs. Acknowledgments This chapter was supported by grants from the National Institutes of Health (HL 68705), the Gerry Foundation, the Young Family Amyloid Research Fund, and the Amyloid Research Fund at Boston University.

REFERENCES   1. Virchow VR: Ueber einem Gehirn and Rueckenmark des Menchen auf gefundene Substanz mit chemischen reaction der Cellulose. ­Virchows Arch Pathol Anat 6:135-138, 1854.   2. Cohen AS, Calkins E: Electron microscopic observations on a fibrous component in amyloid of diverse origins. Nature 183:1202-1203, 1959.   3. Westermark P, Benson MD, Buxbaum JN, et al: Amyloid: Towards terminology clarification. Report from the Nomenclature Committee of the International Society of Amyloidosis. Amyloid J Protein ­Folding Disorders 12:1-4, 2005.   4. Simms RW, Prout MN, Cohen AS: The epidemiology of AL and AA amyloidosis. Baillieres Clin Rheumatol 8:627-634, 1994.   5. Gertz MA, Kyle RA: Secondary systemic amyloidosis: Response and survival in 64 patients. Medicine 70:246-256, 1991.   6. David J, Vouyiouka O, Ansell BM, et al: Amyloidosis in juvenile chronic arthritis: A morbidity and mortality study. Clin Exp Rheumatol 11:85-90, 1993.

  7. Livneh A, Langevitz P, Shinar Y, et al: MEFV mutation analysis in patients suffering from amyloidosis of familial Mediterranean fever. Amyloid 6:1-6, 1999.   8. Drueke TB: Beta 2-microglobulin and amyloidosis. Nephrol Dial Transplant 15(Suppl 1):17-24, 2000.   9. Benson MD: Amyloidosis. In Scriver CR, Beaudet AL, Sly WS, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, 8th ed, Vol IV. New York, McGraw Hill, 2001, pp 5345-5378. 10. Connors LH, Lim A, Prokaeva T, et al: Tabulation of human transthyretin (TTR) variants, 2003. Amyloid J Protein Folding Disorders 10:160-184, 2003. 11. Jacobson DR, Pastore RD, Yaghoubian R, et al: Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med 336:466-473, 1997. 12. Kyle RA, Spittell PC, Gertz MA, et al: The premortem recognition of systemic senile amyloidosis with cardiac involvement. Am J Med 101:395-400, 1996. 13. Ng B, Connors LH, Davidoff R, et al: Senile systemic amyloidosis presenting with heart failure: A comparison with light chain-associated amyloidosis. Arch Intern Med 165:1425-1429, 2005. 14. Bennhold H: Eine spezifische Amyloidfarbung mit Kongorot. Munch Med Wochenschr 69:1537-1538, 1922. 15. Shirahama T, Cohen AS: High-resolution electron microscopic analysis of the amyloid fibril. J Cell Biol 33:679-708, 1967. 16. Arbustini E, Morbini P, Verga L, et al: Light and electrom microscopy immunohistochemical characterization of amyloid deposits. Amyloid Int J Exp Clin Invest 4:157-170, 1997. 17. Bellotti V, Mangione P, Merlini G: Review: Immunoglogulin light chain amyloidosis—the archetype of structural and pathologic variability. J Struct Biol 130:280-289, 2000. 18. Lansbury PT: Evolution of amyloid: What normal protein folding may tell us about fibrillogenesis and disease. Proc Natl Acad Sci U S A 96:3342-3344, 1999. 19. Hayman SR, Bailey RJ, Jalal SM, et al: Translocations involving the immunoglobulin heavy-chain locus are possibly early genetic events in patients with primary systemic amyloidosis. Blood 98:2266-2268, 2001. 20. Lavatelli F, Perlman DH, Spencer B, et al: A proteomic approach to the study of systemic amyloidosis. In Skinner M, Berk JL, Connors LH, et al (eds): XIth International Symposium on Amyloidosis. Boca Raton, CRC Press, 2007, pp 360-362. 21. Solomon A, Frangione B, Franklin EC: Bence Jones proteins and light chains of immunoglobulins: Preferential association of the V lambda VI subgroup of human light chains with amyloidosis AL (lambda). J Clin Invest 70:453-460, 1982. 22. Teng J, Russell WJ, Gu X, et al: Different types of glomerulopathic light chains interact with mesangial cells using a common receptor but exhibit different intracellular trafficking patterns. Lab Invest 84:440-451, 2004. 23. Husby G, Marhung G, Dowton B, et al: Serum amyloid A (SAA): ­Biochemistry, genetics, and the pathogenesis of AA amyloidosis. Amyloid Int J Exp Clin Invest 1:119-137, 1994. 24. Kluve-Beckerman B, Dwulet FE, Benson MD: Human serum amyloid A. J Clin Invest 82:1670-1675, 1988. 25. Johan K, Westermark G, Engstrom U, et al: Acceleration of amyloid protein A amyloidosis by amyloid-like synthetic fibrils. Proc Natl Acad Sci U S A 95:2558-2563, 1998. 26. Kluve-Beckerman B, Manaloor J, Liepnieks J: A pulse-chase study tracking the conversion of macrophage-endocytosed serum amyloid A into extracellular amyloid. Arthritis Rheum 46:1905-1913, 2002. 27. Zingraff J, Drueke T: Beta2-microglobulin amyloidosis: Past and future. Artif Organs 22:581-584, 1998. 28. Hammarstrom P, Wiseman RL, Powers ET, et al: Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science 299:713-716, 2003. 29. Suhr OE, Svendsen IH, Ohlsson P, et al: Impact of age and amyloidosis on thiol conjugation of transthyretin in hereditaty transthyretin amyloidosis. Amyloid Int J Exp Clin Invest 6:187-191, 1999. 30. Libbey CA, Skinner M, Cohen AS: Use of abdominal fat tissue aspirate in the diagnosis of systemic amyloidosis. Arch Intern Med 143:1549-1552, 1983. 31. Duston MA, Skinner M, Shirahama T, et al: Diagnosis of amyloidosis by abdominal fat aspiration: Analysis of four years’ experience. Am J Med 82:412-414, 1987. 32. Skinner M, Anderson J, Simms R, et al: Treatment of 100 patients with primary amyloidosis: A randomized trial of melphalan, prednisone, and colchicine versus colchicine only. Am J Med 100:290-298, 1996.

PART 18  33. Abraham RS, Clark RJ, Bryant SC, et al: Correlation of serum immunoglobulin free light chain quantification with urinary Bence Jones protein in light chain myeloma. Clin Chem 48:655-657, 2002. 34. Akar H, Seldin DC, Magnani B, et al: Quantitative serum free lightchain assay in the diagnostic evaluation of AL amyloidosis. Amyloid J Protein Folding Disorders 12:210-215, 2005. 35. Swan N, Skinner M, O’Hara C: Bone marrow core biopsy specimens in AL (primary) amyloidosis: A morphologic and immunohistochemical study of 100 cases. Am J Clin Pathol 120:610-616, 2003. 36. Lim A, Wally J, Walsh MT, et al: Identification and localization of a cysteinyl posttranslational modification in an amyloidogenic kappa 1 light chain protein by electrospray ionization and matrix-assisted laser deposition/ionization mass spectrometry. Anal Biochem 295:45-56, 2001. 37. Connors LH, Ericsson T, Skare J, et al: A simple screening test for variant transthyretins associated with familial transthyretin amyloidosis using isoelectric focusing. Biochim Biophys Acta 1407:185-192, 1998. 38. Benson MD: Amyloidosis. In Scriver CR, Beaudet AL, Sly WS, et al (eds): The Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York, McGraw-Hill, 1999, pp 4159-4191. 39. Falk RH, Comenzo RL, Skinner M: The systemic amyloidoses. N Engl J Med 337:898-909, 1997. 40. Merlini G, Bellotti V: Molecular mechanisms of amyloidosis. N Engl J Med 349:583-596, 2003. 41. Dubrey SW, Cha K, Anderson J, et al: The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement. QJM 91:141-157, 1998. 42. Prokaeva T, Spencer B, Kaut M, et al: Soft tissue, joint, and bone manifestations of AL amyloidosis: Clinical presentation, molecular features, and survival. Arthritis Rheum 56:3858-3868, 2007. 43. Kyle RA, Gertz MA, Greipp PR, et al: A trial of three regimens for primary amyloidosis: Colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med 336:1202-1207, 1997. 44. Pallidini G, Perfetti V, Obici L, et al: Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood 103:2936-2938, 2004. 45. Skinner M, Sanchorawala V, Seldin DC, et al: High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: An 8-year study. Ann Intern Med 140:85-93, 2004. 46. Dispenzieri A, Kyle RA, Lacy MQ, et al: Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: A case-control study. Blood 103:3960-3963, 2004. 47. Schonland SO, Lokhorst H, Buzyn A, et al: Allogeneic and syngeneic hematopoietic cell transplantation in patients with amyloid lightchain amyloidosis: A report from the European Group for Blood and Marrow Transplantation. Blood 107:2578-2584, 2006. 48. Perfetti V, Siena S, Palladini G, et al: Long-term results of a riskadapted approach to melphalan conditioning in autologous peripheral blood stem cell transplantation for primary (AL) amyloidosis. Haematologica 91:1635-1643, 2006. 49. Seldin DC, Anderson JJ, Skinner M, et al: Successful treatment of AL amyloidosis with high-dose melphalan and autologous stem cell transplantation in patients over age 65. Blood 108:3945-3947, 2006.

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50. Casserly LF, Fadia A, Sanchorawala V, et al: High-dose intravenous melphalan with autologous stem cell transplantation in AL amyloidosis-associated end-stage renal disease. Kidney Int 63:1051-1057, 2003. 51. Seldin DC, Choufani EB, Dember LM, et al: Tolerability and efficacy of thalidomide for the treatment of patients with light chain-­associated (AL) amyloidosis. Clin Lymphoma 3:241-246, 2003. 52. Sanchorawala V, Wright DG, Rosenzweig M, et al: Lenalidomide and dexamethasone in the treatment of AL amyloidosis: Results of a phase II trial. Blood 109:492-496, 2007. 53. Gianni L, Bellotti V, Gianni AM, et al: New drug therapy of amyloidoses: resorption of AL-type deposits with 4′-iodo-4′-­deoxydoxorubicin. Blood 86:855-861, 1995. 54. Gertz MA, Lacy MQ, Dispenzieri A, et al: A multicenter phase II trial of 4′-iodo-4′-deoxydoxorubicin (IDOX) in primary amyloidosis (AL). Amyloid J Protein Folding Disorders 9:24-30, 2002. 55. Pepys MB, Herbert J, Hutchinson WL, et al: Targeted pharmacological depletion of serum amyloid P component (SAP) for treatment of human amyloidosis. Nature 417:254-259, 2002. 56. Helin HJ, Korpela MM, Mustonen JT, et al: Renal biopsy findings and clinicopathologic correlations in rheumatoid arthritis. Arthritis Rheum 38:242-247, 1995. 57. Dember LM, Hawkins PN, Hazenberg BPC, et al: Eprodisate for the treatment of AA amyloidosis. N Engl J Med 356:2349-2360, 2007. 58. Morgan CJ, Gelfand M, Atreya C, et al: Kidney dialysis-associated amyloidosis: A molecular role for copper in fiber formation. J Mol Biol 309:339-345, 2001. 59. Berg A, Falk RH, Connors LH, et al: Transthyretin ILE-122 in a series of black patients with amyloidosis. In Kyle RA, Gertz MA (eds): ­Amyloid and Amyloidosis 1998. New York, Parthenon Publishing Group, 1999. 60. Holmgren G, Steen L, Ekstedt J, et al: Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30). Clin Genet 40:242-246, 1991. 61. Lewis WD, Skinner M, Simms RW, et al: Orthotopic liver transplantation for familial amyloidotic polyneuropathy. Clin Transplant 8: 107-110, 1994. 62. Bergethon P, Sabin T, Lewis D, et al: Improvement in the polyneuropathy associated with familial amyloid polyneuropathy after liver transplantation. Neurology 47:944-951, 1996. 63. Dubrey SW, Davidoff R, Skinner M, et al: Progression of ventricular wall thickening after liver transplantation for familial amyloidosis. Transplantation 64:74-80, 1997. 64. de Carvalho M, Conceicao I, Bentes C, et al: Long-term quantitative evaluation of liver transplantation in familial amyloid polyneuropathy (Portuguese V30M). Amyloid J Protein Folding Disorders 9:126-133, 2002. 65. Sekijima Y, Dendle MA, Kelly JW: Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis. Amyloid J Protein Folding Disorders 13:236-249, 2006.

107

Sarcoidosis Lee S. Newman  •  Holly M. Sackett

KEY POINTS Sarcoidosis is a multisystem inflammatory disease of ­unknown cause. Sarcoidosis occurs worldwide and affects people of all racial and ethnic backgrounds. No single infectious agent or antigen has consistently been linked to sarcoidosis. Some clinical subtypes, especially Löfgren’s syndrome and acute resolving sarcoidosis, have an immunologic and genetic basis that is distinct from other forms of sarcoidosis. Rheumatologic manifestations are common in sarcoidosis and are often overlooked or misdiagnosed. Magnetic resonance imaging has improved the detection of musculoskeletal involvement in sarcoidosis. New treatment modalities, including tumor necrosis ­factor-α inhibitors, appear to be promising for the treatment of ­extrathoracic sarcoidosis based on case series, although ­randomized controlled trials have shown limited benefit in cases of pulmonary involvement.

EPIDEMIOLOGY Sarcoidosis occurs worldwide and affects people of all racial and ethnic backgrounds, both genders, and all ages.1 Most patients are diagnosed in early adulthood, before age 40 years; there is a slight female predominance and a peak incidence in the 20 to 29 age group. Estimated prevalence rates vary from 1 to 80 per 100,000 population. Similarly, there is a range of age-adjusted annual incidence rates, from 10.9 per 100,000 for whites to 35.5 per 100,000 for African Americans in the United States. Similar rates have been reported in many countries; however, the published rates, including those for the United States, are likely underestimates, because many cases go undiagnosed or are misdiagnosed. Familial and twin studies demonstrate much higher prevalence of disease in first-generation relatives of those with sarcoidosis.3 The highest risk for familial sarcoidosis occurs in African Americans (although familial risk has also been demonstrated in whites), women, and patients with active disease. Interestingly, when sarcoidosis occurs in siblings, the clinical pattern of illness often differs between the siblings.4

CAUSE AND PATHOGENESIS

Sarcoidosis is a multisystem immunologic disorder that preferentially involves the lungs. Characterized by noncaseating granulomas in virtually any organ, sarcoidosis is the consequence of an antigen-specific immune and inflammatory response to unidentified triggering agents. Clinically, sarcoidosis often presents with hilar lymphadenopathy, pulmonary infiltration, and ocular and skin lesions. With protean clinical manifestations, this disease can mimic many inflammatory and infectious disorders.1 Particular targets include the lungs, lymphatics, eyes, skin, liver, bones, and neurologic system. This chapter emphasizes the rheumatologic and immunologic aspects of this condition. The American Thoracic Society (ATS), European Respiratory Society (ERS), and World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) criteria for the diagnosis of sarcoidosis include (1) the presence of a consistent clinical and radiographic picture; (2) the demonstration of noncaseating granulomatous disease (Fig. 107-1), often in more than one affected organ; and (3) the exclusion of other conditions that can produce similar pathology, including a panoply of infections, autoimmune disorders, and inhalation diseases, as discussed in the differential diagnosis section.2

The cause of sarcoidosis remains unknown. However, available evidence strongly supports the hypothesis that the disease develops when a specific environmental exposure with antigenic properties occurs in a genetically susceptible individual. Spatial and temporal clustering of cases, reports of community outbreaks, and reports of work-related risks for health care workers suggest either shared environmental exposure or possibly person-to-person transmission. Environmental investigation of new cases has uncovered clusters of disease among nurses, firefighters, and military personnel. A case-control study of a sarcoidosis cluster on the Isle of Mann demonstrated that a greater percentage of cases than controls reported previous contact with a sarcoidosis patient, although this study has been criticized for its information and recall biases. A recent case-control study identified exposure to industrial organic dust as an occupational risk factor, as well as occupations in the building material, hardware, gardening supplies, and education trades.5 No single infective agent or antigen has been consistently linked to sarcoidosis. Numerous studies have investigated the possibility that mycobacteria and viruses cause sarcoidosis, but to date, no infectious agent evaluated has fulfilled Koch’s postulates. However, recent studies strongly suggest a role of mycobacteria antigens in a sizable proportion of cases.6-9 This is compatible with immunologic evidence of oligoclonal T cells, presumably due to antigen-driven accumulation of T cells in sarcoidosis patients’ affected organs, as reflected 1795

1796

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Sarcoidosis

A

B

C

Figure 107-1  A, The typical pathologic appearance of sarcoidosis consists of non-necrotizing granulomas, which are mononuclear cell infiltrates with varying degrees of adjacent collagen deposition. Shown here is tissue from the lung, the most commonly affected organ, infiltrated by multiple noncaseating granulomas adjacent to vessels and bronchioles (hematoxylin and eosin, ×100). B, This photomicrograph (×400) demonstrates the classic, but not pathognomonic, features of noncaseating granulomas, including multinucleated giant cell (center), abundant lymphocytes, macrophages, epithelioid cells, mast cells, plasma cells, and fibroblasts. C, Although uncommon, sarcoidosis can cause a non-necrotizing granulomatous vasculitis in virtually any organ. Shown here is a pulmonary artery using an elastic tissue Verhoeff-van Gieson stain (×200). The elastic lamina (dark stain) is intact. Within the intima is a large area of non-necrotizing granulomatous inflammation, producing a narrowing of the vessel lumen. Efforts must be made to exclude other causes of vasculitis, as discussed in the text. Prognosis is generally poor for this form of sarcoidosis.

by bronchoalveolar lavage. Evidence of an upregulated T helper type 1 (Th1) pattern of cytokine production, along with tumor necrosis factor-α (TNF-α) release, suggests that regardless of whether the granulomatous inflammation of sarcoidosis is initiated by a microbe-related antigen, the pathologic consequence is due to enhanced immune reactivity, as discussed later. A case-control etiologic study of sarcoidosis (ACCESS) examined 706 affected and unaffected pairs but did not identify a single proximate cause of sarcoidosis by questionnaire.10 Questionnaire results suggested a possible role for exposure in the work environment, including environments rich in microbial bioaerosols and occupational exposure to insecticides. A previous case-control study evaluated the rural predominance of the disease and identified exposure to wood stoves or fireplaces as potential risk factors.11 A more recent study found that these inhalational exposures are principally associated with pulmonary

sarcoidosis,12 providing little insight into the triggering exposure for ­nonpulmonary forms of the disease. Similarly, seasonal and geographic variations in sarcoidosis risk raise questions about cause. In one study, the incidence of sarcoidosis varied by season, with symptoms presenting more often in spring and less often in winter.13 Available lines of immunologic evidence suggest that sarcoidal granulomas form as a result of antigen exposure, an antigen-­specific cell­mediated immune response, and inflammatory or innate immune responses that amplify and perpetuate the antigenspecific immunologic reaction. The disease is mediated primarily through CD4+ T helper cells and cells derived from mononuclear phagocytes.14 These cells accumulate within affected tissue, where they organize into noncaseating granulomas.1,2,15 The earliest manifestation of sarcoidosis is a mononuclear infiltration of the target organ, thought to be mediated primarily by CD4+ T lymphocytes and a host of other ­inflammatory cells

PART 18 

(e.g., macrophages, mast cells, fibroblasts), as well as epithelial and endothelial cells, which promotes the nonspecific inflammatory response and leads to increased tissue permeability and cell migration. Mononuclear cell recruitment is enhanced by the production of chemokines, as well as adhesion molecules and selectins, which are chemoattractants and promote cell binding. In the early stages of disease, an elevated lymphocyte count and a marked increase in the CD4/CD8 T lymphocyte ratio is observed in affected organs, such as the lungs. Antigen presenting cells, such as dendritic cells and macrophages, present antigen to T cells and drive the production of proinflammatory cytokines such as interleukin (IL)-12 and IL-15, resulting in a Th1 pattern of cytokine production, including the release of interferon-γ and IL-2. IL-15 may act synergistically with IL-2 and TNF-α to stimulate further T cell proliferation. Naive T cells become activated, undergo clonal expansion, and differentiate into effector and central memory T cells. In sarcoidosis, it appears that most T cells have been previously stimulated, likely in regional lymph nodes, and have migrated back to the affected organ. Studies of the T lymphocyte antigen receptor (TCR) repertoire in sarcoidosis demonstrate that the disorder is initiated by an antigen-specific immune response, based on observed oligoclonal expansion of T lymphocyte subsets bearing particular, restricted αβ TCRs. Notably, in patients with Löfgren’s syndrome and in those with acute, remitting sarcoidosis, there is a strong association between a lung-restricted expansion of AV2.3 CD4+ T cells and the expression of one of two specific class II major histocompatibility complex (MHC) molecules (HLA-DRB3*0101 and *0301),16,17 suggesting that the combination of a specific TCR and a particular MHC class II molecule interacts with the putative sarcoidosis antigen to trigger the acute form of disease. The release of inflammatory cytokines serves to recruit additional peripheral blood monocytes to the affected organ, where they differentiate into exudate macrophages that show enhanced antigen-presenting capacity and release many cytokines, particularly TNF-α and IL-1β. Notably, from a therapeutic perspective, TNF-α upregulates endothelial cell adhesion molecule expression, drives the acute-phase response via IL-6, promotes downstream cytokine release in tissues, and can promote systemic features of disease, including fatigue and altered cognitive function. The net result of cytokine cascade is an amplification loop involving antigen recognition, proinflammatory cytokine release, cell activation, cell recruitment, and granuloma formation. Progression from granulomatous inflammation to increasing amounts of fibrosis may be a prognostically bad sign in sarcoidosis. Factors leading from granuloma to fibrosis are poorly understood but probably involve changes in local cytokine production toward a Th2 pattern. Substantial evidence suggests that genetic susceptibility is important to disease development and that multiple genes account for this genetic predisposition. Both ­German and U.S. genome-wide sibling pair analyses have been performed. In the United States, African Americans with sarcoidosis show linkage on chromosome 1p22, 2p25, 5p15-13, 5q11, 5q35, 9q34, 11p15, and 20q13.18 Disease is two to four times more common among monozygotic than dizygotic twins. Up to 19% of affected African American

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families and 5% of affected white families have more than one member with sarcoidosis.19 An analysis of nearly 11,000 first-degree relatives and more than 17,000 second-degree relatives of the 706 ACCESS case-control pairs yielded an adjusted familial relative risk of developing sarcoidosis of 4.7 (95% confidence interval 2.3 to 9.7). White cases had a much higher familial relative risk than did African American cases (18.0 versus 2.8; P = .098).20 The distribution of human leukocyte antigen (HLA) and angiotensin­converting enzyme (ACE) polymorphic alleles in German families suggests an excess of specific alleles among affected first-degree relatives.21-23 Further analysis of ACE gene polymorphisms in a population study found differences between the natural history of disease (acute versus chronic) and presentation (Löfgren’s syndrome versus non-Löfgren’s).24 Interestingly, Biller and colleagues25 provided evidence that the ACE genotype should be taken into account when examining the clinical significance of sarcoidosis patients’ ACE activity levels in serum. Using a candidate gene approach, and based on our understanding of immune mechanisms, both case-control studies and microsatellite linkage analysis in familial sarcoidosis strongly support the existence of a susceptibility locus for sarcoidosis on chromosome 6 in the HLA region. Studies of Löfgren’s syndrome and other acute, resolving forms of sarcoidosis in Sweden, Holland, and England have largely elucidated the genetic basis of this particular clinical phenotype. HLA-DR17 (DRB1*03) was found nearly four times as often in patients with these forms of disease as in normal controls.26 In a large population of British and Dutch cases and controls, HLA-DQB1*0201 was strongly associated with reversible disease.27 A more recent Polish study showed a combined effect of HLA-DRB1*03 and interferon-γ 3,3 homozygosity in increasing the risk of Löfgren’s syndrome, suggesting a complex gene-gene interaction.28 Within racial groups, HLA-DRB1*1101 is a significant susceptibility risk factor for both black and white Americans, with population-attributable risks of 16% and 9%, respectively. However, different clinical patterns, such as specific organ involvement29 and chronic, severe disease, are also associated with particular genetic patterns in HLA.30 In patients with small fiber neuropathy, there is an association with HLA-DQB1 alleles.31 Investigation of other genes in the MHC region has yielded significant associations with antigen transporter protein TAP1 and 2 polymorphisms and with polymorphic alleles in the TNF-α gene promoter.32 Recently, a variant of the butyrophilin-like 2 (BTNL2) gene, which resides in the MHC class II region and probably encodes for a protein that functions as a T cell costimulatory molecule, has been associated with sarcoidosis susceptibility in both Caucasian German and U.S. populations. Haplotypes for this gene show a significantly weaker association with sarcoidosis risk in African Americans.33,34 Other candidate gene studies have yielded negative or confounding results, with a few notable exceptions. Various C-C chemokine receptor genes are of particular interest, because studies in three distinct populations (Japanese, Czech, and Dutch) identified both strong positive and negative associations between specific polymorphic alleles and sarcoidosis. In one study, a particular haplotype of the C-C chemokine receptor A was strongly associated with Löfgren’s ­ syndrome,

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even after adjusting for other known risk factors for this sarcoidosis variant, such as HLA haplotype and female sex.35 However, data from a recent family-based study suggest that the gene of interest might not be the C-C chemokine receptor itself but rather other genes in the surrounding area.36

CLINICAL FEATURES The clinical presentation of sarcoidosis is diverse, ranging from asymptomatic disease captured on an incidental chest radiograph to acute febrile illness to chronic insidious organ failure. Although the disease appears typically between the ages of 20 and 50 years, both childhood and geriatric cases occur with some regularity. The vast majority of patients (>90%) have evidence of pulmonary involvement. However, sarcoidosis can affect any organ and thus can present with symptoms referable to any organ. Some patients present with nonspecific but debilitating symptoms, including fatigue, fever, anorexia, and weight loss. A distinct subgroup of sarcoidosis patients is characterized by an acute presentation, classically with Löfgren’s syndrome. This presentation consists of acute erythema nodosum or other skin lesions, such as vesicles or maculopapular rash; bilateral hilar lymphadenopathy; uveitis; fever; and polyarthritis. Acute iritis, conjunctivitis, and even conjunctival nodules are common. Bell’s palsy may occur prior to or concomitant with the acute symptoms. In a study of 55 patients with acute sarcoidosis arthritis, Visser and colleagues17 found that four clinical features—symmetric ankle arthritis, symptoms for less than 2 months, age younger than 40 years, and erythema nodosum—provided a high degree of diagnostic certainty in an outpatient rheumatology practice in the Netherlands. In acute disease, bone cysts are rare; however, hypercalcemia and hypercalciuria may be found in approximately 20% of patients. Chest radiographs are typically normal or show significant hilar and mediastinal lymphadenopathy without pulmonary infiltrates. Arrhythmias may occur due to acute granulomatous cardiac involvement. The acute form of disease has a higher probability of spontaneous resolution. Although relapse may occur, it is thought to be less common than in those patients with a more chronic presentation. Prognosis is generally good. Although a true dividing line between chronic and acute forms of the disease does not exist, certain features of sarcoidosis enhance the likelihood that the disease will persist. Chronic disease is usually insidious in onset and occurs in older patients. Skin lesions in chronic disease are more typically plaques, keloids, nodules within ­surgical incision lines and scars, or lupus pernio, which is a persistent, disfiguring, violaceous rash over the nose, cheeks, and ears. Chronic eye involvement includes chronic uveitis, cataracts, glaucoma, or keratoconjunctivitis sicca, which can be confused with Sjögren’s syndrome. Bone involvement is much more common in chronic than acute cases, as are pulmonary infiltrates, nephrocalcinosis, and cardiac involvement with cor pulmonale. Persistence of disease and recurrence after treatment are common in the chronic form. The remainder of this section focuses specifically on the rheumatologic manifestations of sarcoidosis.

BONE Sarcoidal changes in bone are most commonly found in the hands or feet. Bone lesions are reported in approximately 3% to 13% of cases. This is likely an underestimation because osseous lesions are typically asymptomatic, and imaging procedures not performed routinely.37 There is a higher prevalence of radiographically evident osseous disease in the progressive, chronic form of sarcoidosis; in patients with pulmonary involvement; among African American patients; and in those who have granulomatous skin lesions, especially lupus pernio. Asymptomatic bone cysts are more common in females and in patients with lupus pernio.38 Bone involvement is usually bilateral and asymptomatic; however, it may present as localized pain, swelling, and stiffness. Lesions are most commonly lytic, sometimes with associated expansion of the shaft, pathologic fractures, and cavitation. Lesions also may be sclerotic, starting with progressive cortical tunneling and remodeling, and they are sometimes associated with rapid destruction, periosteal reaction, and secondary involvement of joint surfaces.39,40 Involvement of the metacarpals, metatarsals, and phalanges of the hands and feet are typical, although any bone can be affected; case reports and case series have described vertebral, iliac, scapular, and even skull sarcoidosis.37,41-47 The classic lacy, reticular (lytic) radiographic appearance of sarcoidosis usually produces little disturbance of adjacent soft tissues, although subchondral lesions sometimes extend into the joint space.37 Figure 107-2 illustrates the range of radiographic findings in osseous sarcoidosis, from early disease to the more typical abnormalities found in untreated, advanced disease. Bone cysts have also been observed, sometimes large enough to result in pathologic fractures.40 Periostitis is rare. Recent reports suggest that bone scans using either technetium 99m methylene diphosphonate or gallium 67 citrate may detect bone changes not seen on plain radiographic films. However, abnormalities on these scans are not specific for sarcoidosis and may represent other pathology, even in a patient with biopsyproven sarcoidosis elsewhere.48,49 Magnetic resonance imaging (MRI) is more sensitive than plain radiographs for the detection of osseous sarcoidosis. On MRI, the lesions may appear hypointense on T1-weighted images and hyperintense on T2-weighted images.50 Scintigraphy may be superior in detecting multiple bone involvement or osteonecrosis associated with glucocorticoid therapy. MRI offers the greater precision needed if biopsies are to be performed or if osteonecrosis is suspected.51 When diagnostic biopsies are performed, they can demonstrate noncaseating granulomas in both the bone marrow and the bone cortex.40 Sarcoid dactylitis is characterized by diffuse soft tissue swelling of the affected digit; when the terminal phalanx is involved, the proximal nail becomes distorted, thickened, and dystrophic. Dactylitis is often associated with painful stiffness of the adjacent joints and tenderness. The overlying skin may be erythematous. There is marked angular deformity or ankylosis due to bone loss or joint damage in severe cases. Bone involvement may also be associated with tenosynovitis, as has been reported in several cases involving the wrists.52-54 Osteopenia and osteoporosis occur in up to two thirds of patients with sarcoidosis, partly as a ­consequence

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of dysregulated calcium metabolism.55,56 Case series data support the existence of bone loss in untreated sarcoidosis; some authors suggest that this occurs independent of dysregulated calcium and vitamin D metabolism and is instead related to osteoclast activation by granulomas.40 Because of the common use of corticosteroids to treat the disease, patients are also at risk for ­ glucocorticoidrelated bone loss. This is particularly true of ­postmenopausal women, whose loss of bone mineral density is significantly greater than that of other sarcoidosis patients on ­prednisone therapy.57 Although there is no ­standardized approach to

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the management of this problem in sarcoidosis, a few small studies have attempted to address the issue. One trial randomized 30 sarcoidosis patients who were being started on prednisone therapy to receive either alendronate or placebo. After 1 year of follow-up, the alendronate group demonstrated a slight increase in bone mineral density, whereas the placebo group demonstrated a statistically significant decrease (4.5%) in bone mineral density.58 In a nonrandomized study, a group of glucocorticoid-treated sarcoidosis patients was followed, and a subset was treated with salmon calcitonin for 15 months. This additional

C

B

D

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E

Figure 107-2  A, This plain film demonstrates multiple areas of radiolucency, including cystic changes in the small finger metacarpal and proximal phalanx and the index finger proximal and middle phalanges. A destructive process can also be seen in the ulnar styloid, whereas the joint space is well maintained. B, A closer view of the same hand reveals large cystic lesions involving the subchondral bone adjacent to the proximal interphalangeal joint of the index finger. Similar lesions involve the middle phalanx of the long finger, with a reticular pattern of radiolucency. Unrelated osteoarthritis changes can be noted at the proximal and distal interphalangeal joints. C, This bone scan demonstrates increased uptake of technetium 99m methylene diphosphonate in the left long finger proximal to the interphalangeal joint region. This corresponds to a subtle lesion visible on the plain film (see D). D, The subtle lesion is seen as an increase in radiolucency in the distal portion of the long finger proximal phalanx, as well as associated fusiform soft tissue swelling. E, This plain film demonstrates an unusual destructive lesion at the ulnar styloid and a sharply demarcated cyst in the trapezium in a patient with sarcoidosis arthritis.

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F

G

Figure 107-2 Cont’d  F, This radiograph highlights advanced destructive sarcoidosis arthritis involving all the proximal and distal interphalangeal joints. A cystic lesion is present in the head of the long finger metacarpal bone, and a destructive lesion can be noted in the head of the index finger metacarpal bone, with preservation of the joint space. G, In this study, a cystic region of radiolucency with a reticular pattern on the head of the metatarsal bone of the great toe is associated with destruction of the cortical margin. It is important to note the absence of periarticular osteopenia or uniform joint space loss, which would be observed in rheumatoid arthritis.

treatment resulted in significant benefit in terms of maintenance of bone mineral density. The efficacy of salmon calcitonin is supported by at least one other nonrandomized trial.59,60 In practice, most sarcoidosis clinics apply the same primary and secondary treatment strategies advocated for the management of other patients with glucocorticoid-induced osteoporosis. However, it is particularly important to monitor serum and urinary calcium levels more frequently when introducing therapy with cholecalciferol or bisphosphonates. Calcitriol should be avoided owing to the risk of inducing hypercalcemia in sarcoidosis patients receiving corticosteroids, especially because pretreatment serum calcitriol levels are usually elevated in this disease. JOINT Sarcoidal joint involvement produces symmetric arthralgia or arthritis, often with accompanying erythema nodosum. Sarcoidosis most commonly affects the larger joints (ankles, knees, wrists, elbows), although any joint can be involved. Joint pain and stiffness may be the presenting symptoms of the disease. In the acute form of disease presentation, the arthropathy is symmetric, peripheral, and most often associated with erythema nodosum. The majority of these patients report bilateral ankle arthralgias.17 Within a few weeks to a few months, the arthralgias tend to subside, without recurrence or joint deformity. If the joint disease persists, it can result in joint destruction. In such cases, the arthritis is usually accompanied by chronic skin lesions. Arthralgias without erythema nodosum are more common in white males with hilar adenopathy, whereas arthralgias associated with

­erythema nodosum are more frequent in women. Chronic polyarthritis without involvement of the adjacent bone has been reported mostly in African American patients. The prevalence of spondyloarthropathy in sarcoidosis patients is estimated at 6.6%,61 with a number of cases well described in the literature.62,63 Acute sarcoid arthritis is diagnosed mainly on clinical grounds. When performed, synovial fluid analysis typically demonstrates a sterile lymphocytosis and elevated protein.40 Synovial biopsies of involved joints tend to be indeterminate, demonstrating a mild inflammatory synovitis, but often without granulomas.64-66 Chronic destructive joint disease occurs in a minority of patients. It is often associated with other manifestations of more severe disease, such as lupus pernio and chronic uveitis.40 Synovial biopsies in this form of arthritis show inflammatory infiltrates of lymphocytes and plasma cells, proliferation of fibroblasts, and noncaseating granulomas.40 Löfgren’s syndrome, or acute erythema nodosum with bilateral hilar lymphadenopathy, may be accompanied by fever, arthralgias or arthritis, anterior uveitis, and lung involvement. In a retrospective review of 187 cases, Mana and colleagues67 reported a significant seasonal clustering in spring and winter for erythema nodosum and Löfgren’s syndrome. Asymptomatic myopathy was common. This disease was self-limited in most cases. In a review of sequential clinical cases of erythema nodosum, Garcia-Porrua and coworkers68 found that approximately one third were due to sarcoidosis. They emphasize that other causes must be excluded, including nonstreptococcal upper respiratory tract infection and pharmaceutical use, particularly oral contraceptives.

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MUSCLE Muscle involvement is usually subclinical. Symptomatic muscle involvement occurs in less than 0.5% of cases.40 When it does occur, it is often in concert with osseous disease. In systemic sarcoidosis without clinical manifestations of muscle disease, 50% to 80% of patients are found to have granulomas on muscle biopsy. Gastrocnemius muscle biopsy has been evaluated as a diagnostic tool in patients presenting with hilar adenopathy but no muscle symptoms. In one series of 22 patients, this procedure was 100% sensitive and specific for diagnosing sarcoidosis.69 Other studies have found that muscle biopsy is not useful in asymptomatic patients, and it is not routinely performed to establish a diagnosis in this patient population.40 When clinically evident, sarcoidosis muscle involvement takes one of three major forms: chronic myopathy, nodular, and granulomatous myositis. The most common form is a chronic, progressive myopathy of gradual onset. It is associated with proximal muscle wasting in the extremities, trunk, and neck. It must be distinguished from glucocorticoid-induced myopathy. Of note, cardiac muscle involvement is often found concurrently with this form of sarcoid muscle disease.40 Electromyography is often normal, but it can sometimes help distinguish between myopathic and neuropathic disorders. The nodular form of muscular sarcoidosis is the next most common form and may present as small nodules or as a frank soft tissue mass, which is often mistaken for a soft tissue neoplasm.70 Some characteristic findings of this presentation on MRI include the “dark star” sign on axial images, which consists of a star-shaped central structure of decreased signal intensity, and the “three stripes” sign seen on coronal and sagittal images, which consists of an inner stripe of decreased signal intensity and outer stripes of increased signal intensity. Gallium 67 scanning can sometimes help distinguish between a sarcoidosis nodule (significantly greater uptake) and a soft tissue mass.40 The rarest form of muscle involvement is granulomatous myositis, which typically presents with an acute to subacute onset of proximal muscle weakness, muscle pain or tenderness, and weight loss. The majority of these patients are female and African American, have an elevated creatine phosphokinase level and erythrocyte sedimentation rate, and demonstrate a myopathic pattern on electromyography.40 Even rarer clinical presentations include respiratory muscle weakness and painful ophthalmoplegia due to enlargement of the extraocular muscles.71-73 The diagnosis of myositis or myopathy may be suggested by MRI and gallium or technetium scanning; however, the increased uptake during scintigraphy is nonspecific.74 As noted previously, MRI findings may be more characteristic in the nodular form of the disease. The “gold standard” for diagnosis in all forms of muscle involvement is muscle biopsy. Biopsies may demonstrate typical noncaseating granulomas, muscle fiber degeneration and regeneration, perivascular inflammation, and occasional vasculitis. Neurogenic atrophy and granulomatous infiltration of nerves are also common in sarcoidal myositis.75 Fine-needle aspiration biopsies can be strongly suggestive of the diagnosis, demonstrating multinucleated giant cells, epithelioid histiocytes, or both.70,76 MRI of sarcoidosis patients with ­musculoskeletal symptoms shows nonspecific marrow and soft tissue lesions

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that often go undetected on plain radiographs.77 Myelopathy, cranial neuropathies, and encephalopathy may also be detected more readily on MRI. VASCULITIS Systemic vasculitis is a rare but serious form of sarcoidal involvement. Either large or small vessels may be affected in virtually any organ. Biopsies may demonstrate vasculitis associated with noncaseating granulomas78 (see Fig. 107-1C) or frank necrotizing sarcoidal granulomas. Although the relationship between sarcoidosis and vasculitis is unclear in some cases, associations have been reported between sarcoidosis and such diverse vasculitic processes as Takayasu’s arteritis,79,80 hypersensitivity vasculitis, polyarteritis nodosa, microscopic polyangiitis,81 and Churg-Strauss syndrome.82 Significant morbidity and relapse despite corticosteroid therapy are common. Discovery of vasculitis in one organ generally implies involvement elsewhere.

DIAGNOSIS AND DIAGNOSTIC TESTS Diagnosis of sarcoidosis is a two-step process: (1) identifying clinical and pathologic features consistent with the disease, and (2) excluding other conditions that have clinical overlap. Diagnostic considerations for pulmonary granulomatous inflammation include infections with mycobacteria, bacteria, fungi, spirochetes, and protozoa (Table 107-1). Diseases caused by occupational and environmental inhaled agents must also be considered, including hypersensitivity pneumonitis due to inhaled organic and inorganic antigens and metal-induced disorders such as chronic beryllium disease83 and silicosis.84 Tissue biopsy is recommended to diagnose multiorgan sarcoidosis, depending on the clinical presentation.85 Neoplasms can be associated with granulomatous inflammation. Local sarcoidal reactions can occur, especially in skin, but they are not associated with systemic symptoms and lack multiorgan distribution.1,2 Sarcoidosis must be distinguished from inflammatory conditions of unknown cause, especially the autoimmune disorders, as discussed later. Sarcoidosis has been associated with the elevation of various autoantibodies in serum, including nonspecific elevations of rheumatoid factor and antinuclear antibody (ANA). In a recent retrospective study of 34 patients with sarcoidosis, ANA positivity was observed in one third of patients, two of whom had antibodies to double-stranded DNA. None of these antibody-positive patients developed systemic lupus erythematosus during the 10- to 15-year follow-up.86 Several researchers have suggested an association between autoimmune endocrinopathies and sarcoidosis. One series demonstrated significantly higher levels of antibodies against thyroid peroxidase and purified thyroglobulin, as well as Hashimoto’s thyroiditis, in sarcoidosis patients compared with diseased and nondiseased controls.87 Similarly, in another series of 78 sarcoidosis patients, nearly 20% had evidence of autoimmune endocrine disease such as polyglandular autoimmune syndromes, Graves’ disease, and autoimmune thyroiditis.88 Finally, a Japanese group found an association between antiphospholipid antibodies and sarcoidosis, with 21 of 55 sarcoidosis patients having either immunoglobulin (Ig) G or IgM antiphospholipid antibodies. The antibody-positive subset was found to have significantly more

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Table 107-1  Differential Diagnosis of Granulomatous Disease Cause Infectious agents Mycobacteria Fungi Bacteria Spirochetes Metazoa Parasites

Disease Examples Tuberculosis, atypical mycobacterial infections Histoplasmosis, coccidioidomycosis Brucellosis Syphilis Schistosomiasis Leishmaniasis, toxoplasmosis

Neoplasms

Carcinoma, sarcoma, malignant nasal granuloma

Hypersensitivity pneumonitis

Farmer’s lung, bird fancier’s lung, suberosis, bagassosis

Metals

Chronic beryllium disease, zirconium granuloma, aluminum granuloma

Silicates

Silicosis with granulomatous inflammation

Vasculitic granulomatoses and autoimmune disorders

Wegener’s granulomatosis, Churg-Strauss, lymphomatoid granulomatosis, polyarteritis nodosa, bronchocentric granulomatosis, systemic lupus erythematosus, primary biliary cirrhosis, juvenile rheumatoid arthritis

Other conditions

Chronic granulomatous disease (children), Whipple’s disease, lymphocytic infiltration after cancer chemotherapy, Blau’s syndrome, local sarcoidal reactions

extrathoracic organ involvement and a longer persistence of abnormal chest radiographs.89 The putative link between sarcoidosis and autoimmunity is supported by cases of concurrent diagnoses, as well as by some of the obvious similarities between sarcoidosis and the autoimmune diseases. Although sarcoidosis is rare in children, when it does occur in preschool children, it may mimic the manifestations of juvenile rheumatoid arthritis, with skin, eye, and joint involvement without lung disease. Distinction between the two entities usually requires biopsy of skin, synovium, lymph node, or liver.90-93 In contrast, the clinical presentations of rheumatoid arthritis and sarcoidosis in adults are quite distinct. Interestingly, the coexistence of the two diseases, with biopsy verification of both, has been demonstrated in numerous case reports, suggesting a possible etiologic similarity.94-97 Sjögren’s syndrome also occurs concurrently with or is difficult to distinguish from sarcoidosis, particularly when there is lung involvement. Both diseases can present with keratoconjunctivitis sicca, parotid swelling, lung involvement, and cutaneous anergy. Some authors suggest that labial minor salivary gland biopsy or lung biopsy can distinguish between the two diseases, but even biopsy findings are sometimes inconclusive.98-104 Table 107-2 summarizes the recommended baseline and follow-up tests used in the evaluation and management of sarcoidosis.1 These recommendations are based on the

Table 107-2  Recommended Baseline and Follow-up Clinical Evaluation for Sarcoidosis Baseline Occupational and environmental history Medication history Examination emphasizing lungs, lymphatics, skin, eyes, liver, heart, joints Biopsy of an affected organ, with special stains and cultures Chest radiography Pulmonary function tests, including gas exchange Electrocardiogram Slit-lamp examination Liver function tests, renal function tests Serum calcium 24-hour urinary calcium excretion Other tests, depending on clinical presentation and organ systems involved Follow-up Monitoring for resolution or progression. Tracking of organs previously involved using least invasive method. Monitoring for new involvement of common disease target organs.

expected major organs targeted by sarcoidosis. Other tests may be appropriate, depending on which other organs are affected. As a general principle, because there is no single specific diagnostic test for sarcoidosis, the diagnosis depends on establishing the compatible clinicopathologic picture and excluding other granulomatous diseases. Ideally, the evaluation should provide histologic confirmation of disease and negative cultures and special stains for organisms. The clinical impact of sarcoidosis depends on the extent of granulomatous inflammation and the particular organs affected. In determining the extent and severity of disease, clinicians should use noninvasive tools whenever possible to assess which organs are clinically involved and to assess the extent and severity of organ injury. Asymptomatic organ involvement may be missed, but it is usually of little or no clinical significance, with two significant exceptions. A slit-lamp examination is recommended for all patients with suspected sarcoidosis, to look for clinically undetected uveitis. Subclinical hypercalciuria, even in the absence of hypercalcemia, is associated with nephrolithiasis; therefore, a baseline 24-hour urine calcium measurement is advisable. Additionally, periodic electrocardiograms should be obtained to screen for rare but potentially life-threatening cardiac arrhythmias and conduction abnormalities. A baseline complete blood count is recommended to evaluate for anemia, leukopenia, and thrombocytopenia. Serum calcium and liver enzymes may reflect organ involvement meriting treatment. Serum ACE activity is frequently elevated in sarcoidosis. It is not specific but can be useful to monitor disease progression and response to therapy. As discussed earlier, in the future, ACE activity may be more useful when interpreted in the context of a person’s ACE genotype. Tests for cutaneous anergy may suggest a diagnosis of sarcoidosis and help rule out tuberculosis, but the anergy panel is neither sensitive nor specific. In patients who present with arthritic or bone symptoms, a chest radiograph or, in some cases, a high-resolution computed tomography scan of the thorax can detect evidence of hilar or mediastinal lymphadenopathy. In the proper ­clinical

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setting, this can help make the diagnosis of sarcoidosis and also point to a logical site for biopsy, because the majority of patients with hilar adenopathy are found to have pulmonary granulomas when transbronchial lung biopsies are performed by bronchoscopy. Kveim-Siltzbach skin testing—using a preparation of sarcoidosis spleen that is intradermally injected—has been used in the past to establish a diagnosis of sarcoidosis in patients with unexplained erythema nodosum, uveitis, liver granulomas, or hypercalciuria. However, this is not approved for general use in the United States and is not recommended. Gallium 67 citrate scanning adds no specificity to the diagnosis of sarcoidosis, except in the case of patients with lacrimal and salivary gland involvement, in which case the so-called panda sign is observed due to increased uptake in those sites.105 Monitoring for disease progress, regression, or response to therapy should be customized, relying on the least invasive markers of disease activity and vital organ involvement. The clinician must remain vigilant, given the tendency of this disorder to relapse and emerge in new organs.

TREATMENT In the majority of patients with sarcoidosis, the disease resolves spontaneously. However, the natural history and prognosis of sarcoidosis are highly variable. It is not known why some sarcoidosis patients recover and others progress, although some clues are coming from the emerging genetics literature discussed earlier. Although general rules can be applied, there are many exceptions. Acute-onset sarcoidosis is more likely to resolve spontaneously than is chronic, insidious disease. The presence of multiorgan involvement at the time of initial presentation portends a more protracted and clinically severe illness. Even after apparent recovery, a proportion of patients may relapse months or years later. Factors associated with worse prognosis include older age at diagnosis, African American race, duration of illness longer than 6 months, pulmonary infiltrates, splenomegaly, lupus pernio, and greater number of organs involved. A more favorable prognosis has been found in patients with acute disease who expressed HLA-DR3 and -DQ2, regardless of whether erythema nodosum was present.17,106,107 Because sarcoidosis can resolve spontaneously without treatment, most treatment protocols incorporate a period of observation whenever possible. A detailed summary of current pharmacotherapy in sarcoidosis has been the subject of several recent reviews.8,108,109 This section addresses the general treatment of sarcoidosis, with an emphasis on rheumatologic manifestations when data are available. Oral corticosteroids remain the first-line therapy in most cases; however, there is no consensus about when corticosteroids should be initiated.109 Further, there is evidence that corticosteroids may actually be detrimental in some cases. Their use is aimed at the relief of symptoms and the modulation of disease activity in vital organs. It is debatable whether all these goals can be achieved, especially in light of corticosteroid side effects. In a synthesis of data from eight randomized trials of oral or inhaled corticosteroids in pulmonary sarcoidosis that included control groups, Paramothayan and Jones109 concluded that oral corticosteroids improved chest radiographs after 6 to 24 months of treatment and produced

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a small improvement in lung function and gas exchange. They found no evidence of sustained improvement after the withdrawal of corticosteroids.109 Only two of the eight trials examined the efficacy of inhaled corticosteroid therapy. In these trials, there was no effect on chest radiograph abnormalities, no consistent effects on lung function, and only a small improvement in symptoms in one of the studies. In another review, Reich110 suggested that patients with a recent diagnosis of stage II or III sarcoidosis might experience more long-term harm than benefit from systemic steroids; that the effect on those with disease of intermediate duration is neutral; and that patients with chronic, progressive pulmonary disease respond favorably, at least in the intermediate term.111-115 A review of oral corticosteroid use in sarcoidosis patients in Japanese hospitals reported that eye involvement, followed by lung and heart involvement, was the main reason for steroid treatment. Doses ranged from 30 to 60 mg/day. Approximately 70% to 80% of those treated responded well to oral corticosteroids in an unblinded case series.116 The ATS-ERS-WASOG consensus statement suggests that patients with acute pulmonary sarcoidosis should not be treated. The lack of randomized, controlled clinical trials, especially for all the various forms of organ involvement, limits the conclusions that can be drawn. Studies examining outcomes at greater than 2 years suggest no significant benefit from corticosteroid therapy in asymptomatic sarcoidosis patients with more advanced forms of pulmonary involvement. In a British Thoracic Society study,117 patients not meeting the criteria for immediate therapy were observed for 6 months. At that point, participants were assigned to receive either long-term corticosteroid therapy or corticosteroids based on symptoms. After 2 years, the long-term therapy group showed modest improvements in pulmonary function compared with the symptom-based treatment group. Based on the available literature and a survey of clinical practice in the United States and abroad, it is our general recommendation that corticosteroids should not be initiated until after a period of clinical observation, unless there is a life- or sight-threatening reason to treat, such as cardiac, neurologic, or eye disease that failed topical therapy. There is no consensus regarding the optimal initial dosage of corticosteroids. The ATS consensus statement suggests a starting dose of 20 to 40 mg of prednisone or its equivalent, either daily or on alternate days. The British Thoracic Society similarly used prednisolone 30 mg/day as a starting dose. After an initial period of treatment lasting approximately 8 to 18 weeks, those who objectively improve on corticosteroids can start tapering to as low a dose as tolerated without a return of symptoms or organ dysfunction, usually 5 to 10 mg daily or on alternate days. The ATS statement recommends that for those who respond to steroids, treatment should be continued for at least 1 year. If intolerable side effects occur or if the disease does not respond to steroid therapy, patients are considered candidates for the addition of a second-line immunosuppressive agent. If patients suffer relapse on maintenance therapy, there are many options, none of which has been substantiated by rigorous clinical research. In many practices, such patients are placed back on higher-dose prednisone, and a second-line agent is considered. Patients who have evidence of a clinical response to corticosteroids are reevaluated using objective measures before attempts to

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completely withdraw immunosuppressive medication. Even patients who are believed to have entered remission should be followed periodically, given the tendency for sarcoidosis to relapse. The use of other immunosuppressive agents in sarcoidosis should be reserved for those patients who experience symptomatic disease progression despite the use of systemic corticosteroids or who require therapy but cannot tolerate steroid side effects. Methotrexate (MTX) has emerged as one of the preferred second-line drugs. One randomized clinical trial of MTX in sarcoidosis indicated steroid-sparing benefits.118 The largest published experience comes from Lower and Baughman,119 who reported improvement in 33 of 50 patients treated with MTX for a minimum of 2 years. A follow-up report of 209 patients showed that 52% on MTX entered remission and 16% remained stable, with or without low-dose prednisone.120 Other reports confirm the beneficial effects of MTX in cutaneous and musculoskeletal sarcoidosis.121,122 In a study by Kaye and colleagues,121 low-dose MTX (average 10 mg/wk; range, 7.5 to 15 mg) used for an average of 30 months controlled clinical symptoms in patients with musculoskeletal involvement and helped reduce the corticosteroid dose. In most studies, treatment doses of MTX range from 5 to 15 mg/week, usually taken as a single or divided oral dose one day per week. MTX may take up to 6 months to become fully effective in sarcoidosis. During this period, patients are usually maintained on corticosteroids. Case reports on the benefits of cyclosporine A in sarcoidosis have not been supported by larger cohort studies.123-125 The first study to examine cyclosporine in a more rigorous fashion found that when administered at doses that achieved blood levels between 150 and 250 ng/mL, cyclosporine failed to produce clinical improvement in 20 patients who had pulmonary involvement, despite 6 months of therapy.124 Cyclosporine was undetectable in bronchoalveolar lavage fluid, suggesting poor penetration into the lung as a possible reason for its failure. A more recent study, using a standardized treatment protocol, found the combination of prednisone and cyclosporine to be no better and possibly worse than prednisone alone in treating pulmonary sarcoidosis.125 Azathioprine may be an effective second-line agent in a subset of sarcoidosis patients. It is frequently used in titrated oral doses up to 100 to 150 mg/day, despite a paucity of published studies examining the drug’s efficacy in sarcoidosis.126 Some data suggest that it may be efficacious for extrapulmonary disease. Two more recent case series evaluated combined therapy with azathioprine and corticosteroids in patients with chronic pulmonary sarcoidosis. A retrospective review of 10 patients demonstrated sustained improvement in lung function in only 2 patients, but a prospective evaluation of 11 patients demonstrated symptomatic relief and improvement in lung physiology and radiographic abnormalities in 9 after an average of 20 months of therapy. Thus, azathioprine may be an effective second-line agent in a subset of sarcoidosis patients.127,128 Chloroquine has proved effective in treating cutaneous manifestations of sarcoidosis,129 hypercalcemia and hypercalciuria associated with sarcoidosis, and steroid-refractory neurosarcoidosis.130,131 Generally, chloroquine therapy is initiated at a dosage of 500 mg/day and may be titrated up to a maximum of 1000 mg/day and decreased to a low of 250 mg/ day. Hydroxychloroquine may be used instead, at a dosage

of 200 to 400 mg/day, because of the lower risk of ophthalmic toxicity. In one study of chronic pulmonary sarcoidosis, after an average of 19.7 months of treatment, subjects who received maintenance therapy with low-dose (250 mg/day) chloroquine demonstrated a significantly slower decline in lung function and a trend toward fewer relapses compared with those who were simply observed. Cyclophosphamide is employed in selected cases of ­corticosteroid-refractory sarcoidosis.132,133 It appears to be beneficial for both cardiac and neurosarcoidosis. Oral cyclophosphamide is given at a dose of 1 to 2 mg/kg per day, up to a maximum dose of 150 mg/day. Therapy is maintained for several months before tapering. Intravenous monthly pulse cyclophosphamide has been used for the treatment of neurosarcoidosis at a dosage of 0.75 to 1.5 g/month.133 Based on our present understanding of cytokine expression in sarcoidosis, it is logical to expect that anti–TNF-α therapies such as etanercept, infliximab, and adalimumab, and surrogates for this mode of action such as thalidomide and pentoxifylline, should be effective. There are individual published cases and small case series supporting the use of thalidomide in patients with cutaneous sarcoidosis, including lupus pernio.134-138 High doses of pentoxifylline improved lung function in a group of patients with mild pulmonary sarcoidosis.139 A prospective, open-label study with etanercept was terminated before full enrollment owing to excessive treatment failures; however, design flaws limit the extent to which conclusions can be drawn. Case reports and case series support the use of infliximab in the treatment of lupus pernio, neurosarcoidosis, and progressive cutaneous sarcoidosis.140-142 Results of a recent major clinical trial demonstrated that at 24 weeks, patients with chronic, ­steroid-treated pulmonary sarcoidosis who received infliximab showed a small but statistically significant improvement in forced vital capacity compared with those who received placebo. A more sizable improvement was seen in the subgroup of patients who entered the study with more severe pulmonary impairment. No differences in the frequency of adverse events were seen between placebo-treated and infliximab-treated subjects at week 24. In light of these studies, infliximab has joined the armamentarium of secondline treatments for patients with refractory, debilitating, or life-threatening sarcoidosis, but it must be recognized that the benefit for mild or moderate pulmonary involvement may be small.143 Tuberculosis should be carefully excluded in these patients before and during treatment, although it is a rare complication. Combined regimens are increasingly being used to treat sarcoidosis, although there have been few trials. Most of these regimens include corticosteroids and one or more second-line agents.

Future Directions Larger, better-controlled studies of diagnostic tests used in the detection of musculoskeletal sarcoidosis are needed. Attention must be paid to the clinical subtypes of sarcoidosis when applying current literature to the treatment of patients. Controlled clinical trials that examine nonpulmonary outcomes in patients with extrathoracic sarcoidosis are needed.

PART 18 

SUMMARY Sarcoidosis should be considered in any patient presenting with systemic and multiorgan symptoms or whenever granulomatous inflammation is discovered on histology. Therapeutic advances based on an understanding of immune mechanisms will likely improve our approaches to the medical management of this enigmatic condition. REFERENCES   1. Newman LS, Rose CS, Maier LA: Sarcoidosis. N Engl J Med 336: 1224-1234, 1997.   2. Statement on sarcoidosis. Joint statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med 160:736-755, 1999.   3. Baughman RP, et al: Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 164:1885-1889, 2001.   4. Judson MA, et al: Comparison of sarcoidosis phenotypes among affected African-American siblings. Chest 130:855-862, 2006.   5. Barnard J, et al: Job and industry classifications associated with sarcoidosis in a case-control etiologic study of sarcoidosis (ACCESS). J Occup Environ Med 47:226-234, 2005.   6. Drake WP, et al: Molecular analysis of sarcoidosis tissues for mycobacterium species DNA. Emerg Infect Dis 8:1334-1341, 2002.   7. Song Z, et al: Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. J Exp Med 201:755-767, 2005.   8. Moller DR: Treatment of sarcoidosis—from a basic science point of view. J Intern Med 253:31-40, 2003.   9. Drake WP, Newman LS: Mycobacterial antigens may be important in sarcoidosis pathogenesis. Curr Opin Pulm Med 12:359-363, 2006. 10. Newman LS, et al: A case control etiologic study of sarcoidosis: Environmental and occupational risk factors. Am J Respir Crit Care Med 170:1324-1330, 2004. 11. Kajdasz DK, et al: A current assessment of rurally linked exposures as potential risk factors for sarcoidosis. Ann Epidemiol 11:111-117, 2001. 12. Kreider ME, et al: Relationship of environmental exposures to the clinical phenotype of sarcoidosis. Chest 128:207-215, 2005. 13. Sipahi Demirkok S, et al: Analysis of 87 patients with Lofgren’s syndrome and the pattern of seasonality of subacute sarcoidosis. Respirology 11:456-461, 2006. 14. Hunninghake GW, et al: Inflammatory and immune processes in the human lung in health and disease: Evaluation by bronchoalveolar lavage. Am J Pathol 97:149-206, 1979. 15. Moller DR, Chen ES: Genetic basis of remitting sarcoidosis: Triumph of the trimolecular complex? Am J Respir Cell Mol Biol 27:391-395, 2002. 16. Grunewald J, et al: Lung restricted T cell receptor AV2S3+ CD4+ T cell expansions in sarcoidosis patients with a shared HLADRbeta chain conformation. Thorax 57:348-352, 2002. 17. Visser H, et al: Sarcoid arthritis: Clinical characteristics, diagnostic aspects, and risk factors. Ann Rheum Dis 61:499-504, 2002. 18. Iannuzzi MC, et al: Genome-wide search for sarcoidosis susceptibility genes in African Americans. Genes Immun 6:509-518, 2005. 19. Rybicki BA, et al: Genetics of sarcoidosis. Clin Chest Med 18: 707-717, 1997. 20. Rybicki BA, et al: Familial aggregation of sarcoidosis: A case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med 164:2085-2091, 2001. 21. Schurmann M, et al: HLA-DQB1 and HLA-DPB1 genotypes in familial sarcoidosis. Respir Med 92:649-652, 1998. 22. Schurmann M, et al: Familial sarcoidosis is linked to the major histocompatibility complex region. Am J Respir Crit Care Med 162: 861-864, 2000. 23. Schurmann M, et al: Angiotensin-converting enzyme (ACE) gene polymorphisms and familial occurrence of sarcoidosis. J Intern Med 249:77-83, 2001.

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55. Rizzato G, et al: Multi-element follow up in biological specimens of hard metal pneumoconiosis. Sarcoidosis 9:104-117, 1992. 56. Conron M, Young C, Beynon HL: Calcium metabolism in sarcoidosis and its clinical implications. Rheumatology (Oxford) 39:707-713, 2000. 57. Montemurro L, et al: Bone loss in prednisone treated sarcoidosis: A two-year follow-up. Ann Ital Med Int 5:164-168, 1990. 58. Gonnelli S, et al: Prevention of corticosteroid-induced osteoporosis with alendronate in sarcoid patients. Calcif Tissue Int 61:382-385, 1997. 59. Rizzato G, et al: Bone protection with salmon calcitonin (sCT) in the long-term steroid therapy of chronic sarcoidosis. Sarcoidosis 5:99103, 1988. 60. Montemurro L, et al: Prevention of corticosteroid-induced osteoporosis with salmon calcitonin in sarcoid patients. Calcif Tissue Int 49: 71-76, 1991. 61. Erb N, et al: An assessment of back pain and the prevalence of sacroiliitis in sarcoidosis. Chest 127:192-196, 2005. 62. Kremer P, et al: Sarcoidosis and spondylarthropathy: Three casereports. Rev Rhum Engl Ed 63:405-411, 1996. 63. Kotter I, Durk H, Saal JG: Sacroiliitis in sarcoidosis: Case reports and review of the literature. Clin Rheumatol 14:695-700, 1995. 64. Kremer JM: Histologic findings in siblings with acute sarcoid arthritis: Association with the B8,DR3 phenotype. J Rheumatol 13:593-597, 1986. 65. Palmer DG, Schumacher HR: Synovitis with non-specific histological changes in synovium in chronic sarcoidosis. Ann Rheum Dis 43: 778-782, 1984. 66. Scott DG, et al: Chronic sarcoid synovitis in the Caucasian: An arthroscopic and histological study. Ann Rheum Dis 40:121-123, 1981. 67. Mana J, et al: Lofgren’s syndrome revisited: A study of 186 patients. Am J Med 107:240-245, 1999. 68. Garcia-Porrua C, et al: Erythema nodosum: Etiologic and predictive factors in a defined population. Arthritis Rheum 43:584-592, 2000. 69. Andonopoulos AP, et al: Asymptomatic gastrocnemius muscle biopsy: An extremely sensitive and specific test in the pathologic confirmation of sarcoidosis presenting with hilar adenopathy. Clin Exp Rheumatol 19:569-572, 2001. 70. Yamamoto T, et al: Aspiration biopsy of nodular sarcoidosis of the muscle. Diagn Cytopathol 26:109-112, 2002. 71. Ost D, Yeldandi A, Cugell D: Acute sarcoid myositis with respiratory muscle involvement: Case report and review of the literature. Chest 107:879-882, 1995. 72. Dewberry RG, et al: Sarcoid myopathy presenting with diaphragm weakness. Muscle Nerve 16:832-835, 1993. 73. Cornblath WT, Elner V, Rolfe M: Extraocular muscle involvement in sarcoidosis. Ophthalmology 100:501-505, 1993. 74. Otake S, Ishigaki T: Muscular sarcoidosis. Semin Musculoskelet Radiol 5:167-170, 2001. 75. Prayson RA: Granulomatous myositis: Clinicopathologic study of 12 cases. Am J Clin Pathol 112:63-68, 1999. 76. Guo M, Lemos L, Baliga M: Nodular sarcoid myositis of skeletal muscle diagnosed by fine needle aspiration biopsy: A case report. Acta Cytol 43:1171-1176, 1999. 77. Moore SL, Teirstein AE: Musculoskeletal sarcoidosis: Spectrum of appearances at MR imaging. Radiographics 23:1389-1399, 2003. 78. Diri E, Espinoza CG, Espinoza LR: Spinal cord granulomatous vasculitis: An unusual clinical presentation of sarcoidosis. J Rheumatol 26:1408-1410, 1999. 79. Weiler V, et al: Concurrence of sarcoidosis and aortitis: Case report and review of the literature. Ann Rheum Dis 59:850-853, 2000. 80. Schapiro JM, et al: Sarcoidosis as the initial manifestation of Takayasu’s arteritis. J Med 25:121-128, 1994. 81. Fernandes SR, Singsen BH, Hoffman GS: Sarcoidosis and systemic vasculitis. Semin Arthritis Rheum 30:33-46, 2000. 82. Ohori N, Arita K, Ohta M: [A case of Churg-Strauss syndrome overlapping with sarcoidosis]. Rinsho Shinkeigaku 38:631-636, 1998. 83. Newman LS: Metals that cause sarcoidosis. Semin Respir Infect 13:212-220, 1998. 84. Safirstein BH, et al: Granulomatous pneumonitis following exposure to the World Trade Center collapse. Chest 123:301-304, 2003. 85. Teirstein AS, et al: The spectrum of biopsy sites for the diagnosis of sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 22:139-146, 2005.

86. Weinberg I, Vasiliev L, Gotsman I: Anti-dsDNA antibodies in sarcoidosis. Semin Arthritis Rheum 29:328-331, 2000. 87. Nakamura H, et al: High incidence of positive autoantibodies against thyroid peroxidase and thyroglobulin in patients with sarcoidosis. Clin Endocrinol (Oxf) 46:467-472, 1997. 88. Papadopoulos KI, et al: High frequency of endocrine autoimmunity in patients with sarcoidosis. Eur J Endocrinol 134:331-336, 1996. 89. Ina Y, et al: Antiphospholipid antibodies: A prognostic factor in sarcoidosis? Chest 105:1179-1183, 1994. 90. Sarigol SS, Hay MH, Wyllie R: Sarcoidosis in preschool children with hepatic involvement mimicking juvenile rheumatoid arthritis. J Pediatr Gastroenterol Nutr 28:510-512, 1999. 91. Sahn EE, et al: Preschool sarcoidosis masquerading as juvenile rheumatoid arthritis: Two case reports and a review of the literature. Pediatr Dermatol 7:208-213, 1990. 92. Ukae S, et al: Preschool sarcoidosis manifesting as juvenile rheumatoid arthritis: A case report and a review of the literature of Japanese cases. Acta Paediatr Jpn 36:515-518, 1994. 93. Sakurai Y, et al: Preschool sarcoidosis mimicking juvenile rheumatoid arthritis: The significance of gallium scintigraphy and skin biopsy in the differential diagnosis. Acta Paediatr Jpn 39:74-78, 1997. 94. Fallahi S, et al: Coexistence of rheumatoid arthritis and sarcoidosis: Difficulties encountered in the differential diagnosis of common manifestations. J Rheumatol 11:526-529, 1984. 95. Kucera RF: A possible association of rheumatoid arthritis and sarcoidosis. Chest 95:604-606, 1989. 96. Menard O, et al: Association of histologically proven rheumatoid arthritis with pulmonary sarcoidosis. Eur Respir J 8:472-473, 1995. 97. Yutani Y, et al: A rare case of sarcoidosis with rheumatoid arthritis. Osaka City Med J 41:85-89, 1995. 98. Justiniani FR: Sarcoidosis complicating primary Sjogren’s syndrome. Mt Sinai J Med 56:59-61, 1989. 99. Radenne F, et al: [Sjogren’s syndrome and necrotizing sarcoid-like granulomatosis]. Rev Mal Respir 16:554-557, 1999. 100. Giotaki H, et al: Labial minor salivary gland biopsy: A highly discriminatory diagnostic method between sarcoidosis and Sjogren’s syndrome. Respiration 50:102-107, 1986. 101. Miyata M, et al: Primary Sjogren’s syndrome complicated by sarcoidosis. Intern Med 37:174-178, 1998. 102. Lois M, et al: Coexisting Sjogren’s syndrome and sarcoidosis in the lung. Semin Arthritis Rheum 28:31-40, 1998. 103. Drosos AA, et al: Sicca syndrome in patients with sarcoidosis. Rheumatol Int 18:177-180, 1999. 104. Gal I, Kovacs J, Zeher M: Case series: Coexistence of Sjogren’s syndrome and sarcoidosis. J Rheumatol 27:2507-2510, 2000. 105. Oates E, Metherall J: Images in clinical medicine: Sarcoidosis. N Engl J Med 329:1394, 1993. 106. Grunewald J, et al: T-cell receptor variable region gene usage by CD4+ and CD8+ T cells in bronchoalveolar lavage fluid and peripheral blood of sarcoidosis patients. Proc Natl Acad Sci U S A 91:49654969, 1994. 107. Grunewald J, et al: Restricted V alpha 2.3 gene usage by CD4+ T lymphocytes in bronchoalveolar lavage fluid from sarcoidosis patients correlates with HLA-DR3. Eur J Immunol 22:129-135, 1992. 108. Vourlekis JS, Sawyer RT, Newman LS: Sarcoidosis: Developments in etiology, immunology, and therapeutics. Adv Intern Med 45:209-257, 2000. 109. Paramothayan S, Jones PW: Corticosteroid therapy in pulmonary sarcoidosis: A systematic review. JAMA 287:1301-1307, 2002. 110. Reich JM: Adverse long-term effect of corticosteroid therapy in recent-onset sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 20: 227-234, 2003. 111. Young RL, et al: Pulmonary sarcoidosis: A prospective evaluation of glucocorticoid therapy. Ann Intern Med 73:207-212, 1970. 112. Harkleroad LE, et al: Pulmonary sarcoidosis: Long-term follow-up of the effects of steroid therapy. Chest 82:84-87, 1982. 113. Israel HL, Fouts DW, Beggs RA: A controlled trial of prednisone treatment of sarcoidosis. Am Rev Respir Dis 107:609-614, 1973. 114. Eule H, et al: The possible influence of corticosteroid therapy on the natural course of pulmonary sarcoidosis: Late results of a continuing clinical study. Ann N Y Acad Sci 465:695-701, 1986. 115. Zaki MH, et al: Corticosteroid therapy in sarcoidosis: A five-year, controlled follow-up study. N Y State J Med 87:496-499, 1987.

PART 18  116. Sugisaki K, et al: Clinical characteristics of 195 Japanese sarcoidosis patients treated with oral corticosteroids. Sarcoidosis Vasc Diffuse Lung Dis 20:222-226, 2003. 117. Gibson GJ, et al: British Thoracic Society sarcoidosis study: Effects of long term corticosteroid treatment. Thorax 51:238-247, 1996. 118. Baughman RP, Winget DB, Lower EE: Methotrexate is steroid sparing in acute sarcoidosis: Results of a double blind, randomized trial. Sarcoidosis Vasc Diffuse Lung Dis 17:60-66, 2000. 119. Lower EE, Baughman RP: Prolonged use of methotrexate for sarcoidosis. Arch Intern Med 155:846-851, 1995. 120. Baughman RP, Lower EE: Alternatives to corticosteroids in the treatment of sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 14:121-130, 1997. 121. Kaye O, et al: Low-dose methotrexate: An effective corticosteroidsparing agent in the musculoskeletal manifestations of sarcoidosis. Br J Rheumatol 34:642-644, 1995. 122. Webster GF, et al: Weekly low-dose methotrexate therapy for cutaneous sarcoidosis. J Am Acad Dermatol 24:451-454, 1991. 123. Rebuck AS, et al: Cyclosporin for pulmonary sarcoidosis. Lancet 1:1174, 1984. 124. Martinet Y, et al: Evaluation of the in vitro and in vivo effects of cyclosporine on the lung T-lymphocyte alveolitis of active pulmonary sarcoidosis. Am Rev Respir Dis 138:1242-1248, 1988. 125. Wyser CP, et al: Treatment of progressive pulmonary sarcoidosis with cyclosporin A: A randomized controlled trial. Am J Respir Crit Care Med 156:1371-1376, 1997. 126. Pacheco Y, et al: Azathioprine treatment of chronic pulmonary sarcoidosis. Sarcoidosis 2:107-113, 1985. 127. Lewis SJ, Ainslie GM, Bateman ED: Efficacy of azathioprine as second-line treatment in pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 16:87-92, 1999. 128. Muller-Quernheim J, et al: Treatment of chronic sarcoidosis with an azathioprine/prednisolone regimen. Eur Respir J 14:1117-1122, 1999. 129. Zic JA, et al: Treatment of cutaneous sarcoidosis with chloroquine: Review of the literature. Arch Dermatol 127:1034-1040, 1991.

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130. O’Leary TJ, et al: The effects of chloroquine on serum 1,25­dihydroxyvitamin D and calcium metabolism in sarcoidosis. N Engl J Med 315:727-730, 1986. 131. Sharma OP: Effectiveness of chloroquine and hydroxychloroquine in treating selected patients with sarcoidosis with neurological involvement. Arch Neurol 55:1248-1254, 1998. 132. Demeter SL: Myocardial sarcoidosis unresponsive to steroids: Treatment with cyclophosphamide. Chest 94:202-203, 1988. 133. Lower EE, et al: Diagnosis and management of neurological sarcoidosis. Arch Intern Med 157:1864-1868, 1997. 134. Carlesimo M, et al: Treatment of cutaneous and pulmonary sarcoidosis with thalidomide. J Am Acad Dermatol 32:866-869, 1995. 135. Rousseau L, et al: Cutaneous sarcoidosis successfully treated with low doses of thalidomide. Arch Dermatol 134:1045-1046, 1998. 136. Lee JB, Koblenzer PS: Disfiguring cutaneous manifestation of sarcoidosis treated with thalidomide: A case report. J Am Acad Dermatol 39:835-838, 1998. 137. Oliver SJ, et al: Thalidomide induces granuloma differentiation in sarcoid skin lesions associated with disease improvement. Clin ­Immunol 102:225-236, 2002. 138. Baughman RP, et al: Thalidomide for chronic sarcoidosis. Chest 122:227-232, 2002. 139. Zabel P, et al: Pentoxifylline in treatment of sarcoidosis. Am J Respir Crit Care Med 155:1665-1669, 1997. 140. Baughman RP, Lower EE: Infliximab for refractory sarcoidosis. ­Sarcoidosis Vasc Diffuse Lung Dis 18:70-74, 2001. 141. Pettersen JA, et al: Refractory neurosarcoidosis responding to infliximab. Neurology 59:1660-1661, 2002. 142. Mallbris L, et al: Progressive cutaneous sarcoidosis responding to antitumor necrosis factor-alpha therapy. J Am Acad Dermatol 48:290293, 2003. 143. Baughman RP, et al: Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 174:795-802, 2006.

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Hemochromatosis GAYE CUNNANE

Key Points Elevated ferritin (>200 μg/L) and transferrin saturation (>45%) in the absence of other causes are useful screening measures for hereditary hemochromatosis (HHC). Genetic testing should be reserved for patients with ­suggestive biochemical abnormalities or a positive family ­history of HHC or both. Disease phenotype varies greatly among individuals with similar genetic mutations. Diet, alcohol intake, and other risk factors for chronic liver disease all influence the clinical expression of HHC. Phlebotomy is effective treatment for decreasing iron stores. Some clinical manifestations of disease improve with ­treatment (constitutional symptoms, diabetes mellitus, liver enzyme abnormalities), whereas others are unaltered (­arthritis, hypogonadism, cirrhosis). Atypical osteoarthritis or chondrocalcinosis should trigger a search for an underlying metabolic disorder. The earlier the diagnosis, the better the prognosis.

Hemochromatosis refers to the presence of excess iron in body tissues because of increased iron absorption. Primary or hereditary hemochromatosis (HHC) is an autosomal recessive disease, whereas secondary hemochromatosis refers to iron overload as a result of increased iron availability, ineffective erythropoiesis, or inherited abnormalities of iron metabolism (Table 108-1). Hemochromatosis was first recognized in the 1880s in a series of case reports that described “bronze diabetes” and “pigmented cirrhosis,” but von Recklinghausen is credited with the first use of the term in 1889.1 In 1935, the familial pattern of HHC was described by Sheldon,2 who suggested that the disease was due to an inborn error of metabolism. Finch and Finch in 19553 showed that HHC was caused by abnormal iron absorption in the presence of a normal diet. At that time, premorbid recognition of the problem was uncommon, however, and most cases were diagnosed at autopsy. In 1972, serum ferritin became available as a measure of iron stores. Three years later, Simon and colleagues4 discovered that the HHC gene was present on chromosome 6, close to the HLA-A locus. It took 21 more years for the mutated gene, HFE, to be described, and in the last decade it has been recognized that other gene mutations also can cause iron overload.5 Genetic testing has revolutionized the diagnosis of HHC, although the phenotype of any given mutation may vary greatly.6 Nevertheless, the detection of such genes has greatly improved the overall prognosis of this condition by allowing the disease to be diagnosed at

a preclinical stage in high-risk individuals. This discovery has helped many patients with HHC achieve a normal life expectancy.

NORMAL IRON METABOLISM The average total body iron content in adults is 3 to 4 g, mostly contained within hemoglobin, but also present in myoglobin and cytochromes in addition to the storage proteins ferritin and hemosiderin. Of a typical daily Western diet of 10 to 20 mg of iron, 1 to 2 mg is absorbed by duodenal enterocytes each day.7,8 Heme dietary sources from fish and meat have a higher bioavailability than nonheme sources, such as vegetables. The addition of ascorbic acid to the meal increases absorption of nonheme iron, whereas tannins, bran, and phytates inhibit iron absorption.9,10 The rate of iron absorption is thought to be controlled by numerous mechanisms, including recent dietary iron intake, the extent of iron stores in the body, and a putative erythroid regulator that signals the state of bone marrow erythropoiesis to the intestine.7 When there is poor dietary iron intake or body iron stores are low, or in the presence of increased or ineffective erythropoiesis, iron absorption is increased. When iron stores are normal, however, iron is retained in the intestinal cells by the protein mobilferritin and is subsequently excreted when these cells are shed. Iron homeostasis is regulated at the level of intestinal absorption.7,11 There is no effective control mechanism, however, if the absorption process becomes disturbed. When body iron stores reach an adequate level, ferritin production is increased to facilitate storage, and the transferrin receptor is downregulated to minimize the entry of iron into the cells. The iron responsive element binding protein mediates this process by detaching from ferritin mRNA so that more ferritin can be produced.12 With increasing iron stores, circulating transferrin becomes saturated, and iron is preferentially offloaded to tissue sites that contain cells with high levels of transferrin receptors, such as liver, heart, thyroid, gonads, and pancreatic islet cells.13

IRON OVERLOAD SYNDROMES OTHER THAN HEREDITARY HEMOCHROMATOSIS Because there is no physiologic mechanism to increase iron excretion, the inevitable result of increased iron entry into the body is iron overload. This iron overload may occur because of ineffective erythropoiesis or excessive intake of iron by oral or parenteral means. Chronic liver disease also is associated with increased iron deposition in hepatic parenchymal cells, accompanied by high ferritin, but normal serum iron concentrations. Transferrin saturation levels 1809

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Table 108-1  ­Metabolism Ferritin

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Hemochromatosis

Definitions of Terms Used in Iron Major iron storage protein ↑ in iron storage diseases and inflammation Preferentially ↑ in adult-onset Still’s disease Plasma levels reflect iron stores   (e.g., 1 ng/mL ferritin = 10 mg iron)

Transferrin

Transporter protein for iron in plasma Synthesized in liver Increased in iron deficiency states

Transferrin   saturation

Serum iron (μg/dL) ÷ TIBC (μg/dL) × 100 ↓ in iron deficiency/anemia of chronic disease/ferroportin mutation ↑ in hemochromatosis/ineffective   erythropoiesis/iron overload states/  severe liver failure

Iron regulatory   proteins

Maintain iron homeostasis by modulating synthesis of transferrin receptors/  ferritin/duodenal iron transporter

HFE protein

Identified in cells of deep crypts of   duodenum and in Kupffer cells Modulates uptake of transferrin-bound iron into duodenal crypt cells

Iron exporter   proteins

Ferroportin/Hephaestin/divalent metal transporter 1 (DMT1)

Hepcidin

Acute-phase reactant produced by liver Intrinsic antimicrobial activity Negative regulator of iron absorption Reduces iron release from macrophages Thought to interact with and inactivate ferroportin Hepcidin mutations found in some families with juvenile HHC

Hemojuvelin

Modulates hepcidin expression

Hemosiderin

Histologic identification of iron stain in tissues

HCC, hereditary hemochromatosis; TIBC, total iron-binding capacity.

are usually within the high-normal range in chronic liver disease, in contrast to long-standing HHC, in which such levels are typically very high.

GENETICS OF HEMOCHROMATOSIS Four types of HHC have now been described, all linked to gene mutations (Table 108-2).14 Classic HHC (type 1) is an autosomal recessive disorder, with a mutation of the HFE gene, located on chromosome 6. Although numerous such mutations have been described, the most common is a single amino acid substitution of tyrosine for cysteine at position 282 (C282Y). This particular mutation is thought to have arisen in a Celtic/Viking ancestor more than 2000 years ago and is now one of the most common genetic defects in individuals of Northern European origin. This anomaly had no reproductive implications, but may have had survival advantages by protecting against iron deficiency in a susceptible population. Homozygosity for this mutation is a risk factor for organ damage secondary to iron deposition, although phenotypic expression varies widely. Other mutations of the HFE gene include the replacement of histidine with aspartic acid at position 63 (H63D) and the substitution of serine for cysteine at position 65 (S65C). The clinical manifestations of the latter mutations seem to be less

Table 108-2  Hereditary Hemochromatosis Pattern of Inheritance

Name

Gene

Gene Product

HFE-related HHC Type 1

HFE, 6p21.3

HFE

Autosomal recessive

Juvenile type HHC Type 2a

HJV, 1q21

Hemojuvelin

Autosomal recessive

HAMP, 19q13.1

Hepcidin

TfR2, 7q22

Transferrin   receptor 2

Autosomal recessive

Ferroportin

Autosomal dominant

Type 2b TfR2-related HHC Type 3

Ferroportin-related HHC Type 4 SLC40A1, 2q32 HHC, hereditary hemochromatosis.

serious, although compound heterozygosity of such defects may be associated with evidence of iron overload. Mutations of the HFE gene cause adult HHC that becomes clinically obvious in middle age. In contrast, hemo­ juvelin or hepcidin mutations result in juvenile HHC (type 2), which may manifest in the teens or twenties. The rate of iron accumulation seems to be greater than in adult HHC and is often associated with widespread organ involvement and early mortality.15 In contrast to the Northern European inheritance of HFE mutations, juvenile HHC has been most commonly reported in Italy.16 The clinical manifestations of transferrin receptor mutations (type 3) seem to resemble the manifestations of the classic HFE-related HHC. Such mutations are rare, and few cases have been described.17,18 Ferroportin is an iron regulatory protein that helps in the export of iron from enterocytes, macrophages, and hepatocytes. Ferroportin mutations are inherited in an autosomal dominant fashion and have been described in European and Australian families.19,20 Phenotypic expression varies, with some patients having the effects of iron overload in a similar manner to classic HHC, and others showing minimal evidence of organ damage.21 Many other inherited iron overload syndromes have been identified. The African iron overload syndrome occurs in a few Africans who drink locally brewed beer containing extremely high levels of iron (80 mg/L). Not all Africans who drink this beer develop hemochromatosis, leading to suggestions that additional genetic factors contribute to the development of disease. It is thought that a polymorphism of the ferroportin 1 gene is involved.22 Separately, there is a familial association with a syndrome of very high ferritin levels (>1000 ng/mL) and bilateral congenital cataracts. This “hereditary hyperferrinemia-cataract syndrome” involves several mutations in the iron responsive element of L-­ferritin and is inherited in an autosomal dominant ­fashion. The cataracts are thought to be due to excessive ferritin production within the lens fibers.23

EPIDEMIOLOGY Although HHC previously was thought to be a rare condition, the availability of genetic testing has revealed that it is one of the most common inheritable disorders. Although 5

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out of every 1000 individuals of Northern European origin is homozygous for the HFE mutation, phenotypic expression varies, and clinical cases are much fewer in number. In study of nearly 100,000 individuals from primary care practices in the United States, the prevalence for C282Y homozygosity was as follows: white, 0.44%; Native American, 0.11%; Hispanic, 0.027%; African-American, 0.014%; Pacific Islander, 0.012%; and Asian, 0.0004%.24 Peak age at time of diagnosis is 40 to 60 years for classic HHC. Clinical manifestations vary widely between individuals with the same mutation, however, suggesting that the disease may be influenced by other factors, including diet, alcohol intake, smoking, and comorbid features such as chronic liver disease.25 Gender is an obvious influencing factor because premenopausal women are likely to have lower iron stores secondary to menstrual blood loss.

PATHOGENESIS Inappropriate absorption of iron by cells of the gastrointestinal tract is the hallmark of HHC. The duodenal cells seem to be iron deficient with abnormally low ferritin levels, which may be due to a local defect of the enterocytes or an aberration of a regulatory signal elsewhere.14,26 Two theories have been suggested to explain the pathophysiology of iron overload in HHC. The crypt-programming model, first mooted in 1997, proposes that anomalous iron absorption by duodenal crypt cells is associated with the perception of iron deficiency despite adequate iron stores.27 The mutated HFE protein cannot interact normally with transferrin receptor-1. Upregulation of an iron transporter protein (divalent metal transporter 1) has been shown in these cells allowing continued absorption of iron from the intestinal lumen, regardless of the extent of iron stores. Macrophages in HHC also have been found to reflect an iron-deficient state, suggesting that they share the same defect as the enterocytes in this condition.14,28 The second theory, called the hepcidin model, proposes that the abnormal HFE protein is unable to influence levels of hepcidin, an iron inhibitory protein. Normally, when plasma iron levels are adequate, hepcidin manufacture increases, slowing down release of iron from enterocytes and macrophages by interacting with iron transport proteins. In HHC, it is thought that hepcidin levels are inappropriately low, allowing excessive iron absorption to occur.29 Absence of hepcidin results in early severe iron loading, whereas overexpression of this protein can improve iron deposition significantly in a mouse model of HHC.30 If the genetic subtypes of HHC have been identified, why does the phenotypic expression vary so greatly? The answer to this question is unknown, but it is postulated that the presence of modifier genes may affect disease manifestations. Abnormalities of the genes associated with hepcidin, hemojuvelin, or transferrin receptor in addition to abnormalities involved in fibrogenesis and antioxidation all may influence the age and extent of disease onset in patients with HFErelated HHC.31-33 Other factors include lifestyle risk factors, such as smoking, alcohol intake, and diet. The presence of chronic liver conditions, such as chronic hepatitis, hepatic porphyrias, and thalassemias, may accelerate the development of cirrhosis in patients with HHC.34-37 Chronic iron overload is thought to cause organ damage via several mechanisms, including weakening of lysosomal

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membranes and consequent discharge of enzymes into the cytoplasm. Increased free radical formation contributes to lipid peroxidation of cell membranes. There is accelerated fibrogenesis and a reduction in the stores of vitamins C and E that are essential for tissue viability.38,39 Iron deposition in HHC occurs first in parenchymal cells, with reticuloendothelial involvement a late feature, in contrast to transfusional iron overload, in which the reticuloendothelial cells are primarily involved.36

CLINICAL FEATURES EXTRA-ARTICULAR MANIFESTATIONS HHC is more common in men than women and typically manifests in middle-aged adults as iron stores gradually accumulate, often reaching 20 to 30 g. Organ involvement varies and is unpredictable, although the liver, as the major site of iron storage, is typically affected. Commonly, abnormalities of the liver enzymes, checked as part of a routine health screen, are the initial indication of disease. The degree of iron overload has a direct impact on the life expectancy of the affected individual. Without an early diagnosis, progressive fibrosis leading to cirrhosis may occur.36,40 The risk of hepatocellular carcinoma is greatly increased in patients with established cirrhosis.41 Glucose intolerance tends to be a late finding in HHC and is due to progressive iron accumulation in pancreatic beta cells causing low C-peptide and insulin levels. Alpha cell function is usually preserved, however, and serum glucagon levels are normal or increased.42 The risk of diabetes mellitus also is higher in C282Y heterozygotes with no clinical evidence of HHC compared with controls.43 Iron deposition in the heart can result in conduction system abnormalities and heart failure.44 It is unclear whether or not HHC is associated with an increased risk of atherosclerosis, with different studies showing conflicting results.45 Pituitary involvement in HHC is due to iron deposition resulting in reduced serum levels of secreted hormones from this gland. Low levels of gonadotropic hormone cause loss of libido and erectile dysfunction.36,46 Hypothyroidism in HHC is thought to be due to a direct toxic effect of iron on thyroid cells and is associated with low thyroxine and elevated thyroid-stimulating hormone.47 Such endocrine abnormalities may contribute to the development of osteoporosis in these individuals. Skin discoloration occurs as a result of extra melanin and iron in the epidermis. It is a late finding, and the development of “bronze diabetes” represents the end stage of years of iron accumulation in the tissues. Patients with HHC have increased susceptibility to certain infections. High serum iron concentrations may increase bacterial virulence, whereas excess iron in macrophages is thought to reduce phagocytosis.48 Particular caution is advised with uncooked seafood because of the risk of septicemia from Vibrio vulnificus. In addition, Yersinia enterocolitica, Listeria monocytogenes, Salmonella enteritidis serotype typhimurium, Klebsiella pneumoniae, Escherichia coli, Rhizopus arrhizus, and Mucor species all have been reported to cause severe illness in patients with iron overload.7

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Hemochromatosis

ARTICULAR FEATURES Arthritis is a common symptom in HHC, affecting 50% to 80% of patients and significantly interfering with quality of life.49-54 Although it tends to be a late feature, joint pain may nevertheless be the presenting symptom of HHC, alerting a diligent physician to the presence of an underlying metabolic disorder. Articular involvement may be widespread, but changes to the second and third metacarpophalangeal joints are most characteristic.55 Arthritis also may be present in the proximal interphalangeal joints, wrists, shoulders, hips, knees, and ankles.49-56 Patients notice pain and stiffness of the involved joints, but evidence of synovitis is usually absent. Hip damage develops in approximately 25% of individuals with HHC, and after hip arthroplasty, there is an increased risk of aseptic loosening of the prosthesis.57,58 The differential diagnosis of HHC-related arthropathy includes severe osteoarthritis, rheumatoid arthritis, other forms of inflammatory arthritis, and crystal arthritis. Rheumatoid factor is typically negative, however, and the radiographs, in established cases, show distinctive findings, such as joint space narrowing of the second and third metacarpophalangeal joints, hooklike osteophytes on the radial aspect of the metacarpal heads, and chondrocalcinosis particularly of the triangular fibrocartilage adjacent to the ulnar styloid. The pathogenetic mechanism underlying HHC-related arthritis is unknown, and the prevalence of joint pains in this condition has not been found to correlate with body iron stores. Toxic effects from local iron deposition, the acceleration of cartilage defects, and immunologic mechanisms all have been implicated.52,53,59 Using light microscopy, the involved synovium shows iron deposits, particularly in the lining cells, but inflammatory cell infiltration is not typical.60,61 Apatite and calcium pyrophosphate dihydrate crystals may be observed, but why they are preferentially expressed in HHC is unknown. In association with the increased incidence of calcium pyrophosphate dihydrate deposition disease in HHC, a putative role for a parathyroid hormone fragment (PTH 44-68) also has been suggested.62

INVESTIGATIONS A high index of suspicion is helpful when a patient presents with joint pains and abnormal liver enzymes. Although the differential diagnosis is wide, the presence of elevated ferritin and transferrin saturation levels (serum iron × 100/total iron-binding capacity) strongly points to the answer. Serum iron should be measured with the patient fasting because concentrations may be increased after a meal.36 High ferritin levels also may be caused by systemic inflammation or malignancy, but these conditions tend to be associated with a reduced transferrin saturation. Other causes of elevated transferrin saturation include high serum iron secondary to hepatic cytolysis or low transferrin levels secondary to liver failure, and these possibilities should be excluded. If ferritin measures greater than 200 μg/L, and transferrin saturation is greater than 45%, genetic screening is recommended.14,24 The finding of homozygosity for the C282Y mutation or compound heterozygosity for C282Y/H63D confirms the diagnosis.

Liver biopsy may be considered for prognostic purposes in established cases.6,13,36,63 HHC can be distinguished histologically from alcoholic cirrhosis by the preferential distribution of iron in the hepatocytes in the former and in the Kuffper cells in the latter.36 Magnetic resonance imaging of the abdomen also can be used to determine iron overload in the internal organs. Gradient T2-weighted sequences show decreased signal intensity and correlate highly with liver iron concentrations. This imaging method also can identify other locations of iron deposition (e.g., in the spleen, pancreas, lymph nodes, and heart).36 Because HHC is a systemic condition, other investigations should include a search for diabetes, thyroid disease, hypogonadism, osteoporosis, and cardiomyopathy. ­ Disease mimickers, such as porphyria cutanea tarda, ­ ineffective erythropoiesis, and chronic alcohol excess, should be excluded.

SCREENING Greater disease awareness and the availability of genetic screening have meant that HHC is increasingly likely to be diagnosed before the classic triad of cirrhosis, diabetes, and skin hyperpigmentation develops. Late presentation with evidence of end-organ damage does occur, however, particularly in patients with additional risk factors for iron overload or liver disease. HHC is an attractive clinical target for population screening because of its high prevalence, potential disease severity, availability of effective treatment, and impact of early diagnosis on the morbidity and mortality of affected individuals. Certain groups are more at risk than others, however, and the disease prevalence is higher in white than nonwhite individuals.6,24,64 Biochemical measures, such as transferrin saturation, may be a cost-effective method of screening in whites during routine health checks and in individuals who complain of nonspecific symptoms, such as excessive fatigue and arthralgias. Levels of transferrin saturation greater than 45% in men and greater than 35% in premenopausal women, in the absence of other causes, warrant further investigation.13,14 Genetic testing should be reserved for patients with suggestive biochemical abnormalities or a family history of HHC. Routine population screening for C282Y or H63D mutations is not recommended because of the variable clinical penetrance of these genes and the potential negative consequences of a positive result in asymptomatic patients, such as financial, legal, insurance, and psychological implications.14 When a case of HHC is diagnosed, however, and two gene mutations are identified (i.e., C282Y/C282Y or C282Y/H63D), siblings also should be tested for these mutations. H63D/H63D homozygotes are not thought to be at risk of clinical disease. Children of a patient with HHC or of an individual with C282Y/H63D heterozygosity are at risk only if the other parent also carries hemochromatosis gene mutations. For individuals in whom genetic testing has identified a risk of HHC, but with no clinical evidence of disease, yearly biochemical screening should be done, with measures of ferritin, transferrin saturation, and liver enzymes. Such monitoring allows early detection of organ compromise and timely initiation of treatment (Fig. 108-1).

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Symptoms: Arthralgias, transaminitis

Rule out other causes

Lab: ferritin and transferrin saturation First-line genetic screening C282Y/C282Y or C282Y/H63D Initial genetic screen negative

C282Y/C282Y or C282Y/H63D

Serum ferritin persistently raised

Hereditary hemochromatosis Genetic tests negative

Liver biopsy

Second-line genetic testing: HAMP, HJV, HFE, TfR2

Indicative of hemochromatosis

Mutations present

Probable hereditary hemochromatosis

Hereditary hemochromatosis

Figure 108-1  Algorithm for the diagnosis of hereditary hemochromatosis.

MANAGEMENT Removing excess iron before the development of organ damage significantly abrogates the adverse consequences of HHC. Target groups for treatment include asymptomatic individuals with biochemical evidence of high iron stores, in addition to patients with overt clinical disease. Some features of HHC improve with bloodletting, including constitutional symptoms, diabetes, and liver enzyme abnormalities. Phlebotomy has no effect, however, on arthritis, hypogonadism, and liver fibrosis.13 When cirrhosis is established, the risk of hepatocellular carcinoma is greatly increased, even after a satisfactory reduction in iron stores.13,65 Phlebotomy is an effective method of removing excess iron. The use of chelating agents is rarely necessary. Every 500 mL of whole blood contains 200 to 250 mg of iron, depending on the hematocrit. Phlebotomy can be arranged once or twice weekly, as tolerated by the patient, aiming for a serum ferritin of 50 ng/mL and a transferrin saturation of less than 45%. It can take more than 1 year for iron stores to normalize with this regimen. Iron deficiency anemia should always be avoided, and when ferritin levels reach their target, the frequency of bloodletting may be reduced. Phlebotomy continues for life, and the maintenance schedule depends on the patient’s ability to sustain the ferritin level in the low-normal range. Blood removal in HHC is not without risks. In particular, life-threatening cardiac arrhythmias may

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develop during rapid mobilization of iron stores. Vitamin C supplementation may precipitate such problems by facilitating iron release and increasing pro-oxidant and free radical activity.13 Patients undergoing phlebotomy for HHC should not take extra vitamin C, but can continue to eat fresh produce containing this vitamin. Other dietary recommendations include a reduction or avoidance of food containing high doses of iron, such as red meat and internal organs. Uncooked shellfish is a particular hazard because of the risk of contamination with V. vulnificus. Some alcoholic drinks contain iron, and all are potentially hepatotoxic. Alcohol should be consumed only occasionally because it seems to have a synergistic effect in the presence of iron overload on the development of cirrhosis and hepatocellular carcinoma.37 Just as the pathogenesis of joint pain in HHC is unclear, the treatment of arthritis in this condition is unsatisfactory. The arthritis may continue to progress despite effective phlebotomy. Nonsteroidal anti-inflammatory drugs, colchicine, and intra-articular corticosteroids may be helpful in some cases. It is important to recognize osteoporosis as a potential disease complication, particularly in the setting of hypogonadism or reduced thyroid function. Hormone replacement, if indicated, should be instituted, although some patients may require additional treatment with calcium and bisphosphonates.

PROGNOSIS The earlier HHC is diagnosed, the better the prognosis because morbidity and mortality are directly related to the extent of iron overload and consequent organ damage. The development of cirrhosis is a serious indicator of reduced longevity. For patients with HHC-related hepatic failure who undergo liver transplantation, survival rates are lower compared with individuals who receive liver transplants for other reasons. Postoperative death in these circumstances is typically due to cardiac complications or infection.13,66 In the absence of cirrhosis or diabetes, patients with HHC have a normal life expectancy. Given the importance of timely recognition of this common metabolic problem, a vigilant physician can make an enormous difference to the lives of patients who present with early symptoms of this disease. In this context, the rheumatologist has a particularly relevant role in keeping a high index of suspicion for the diagnosis of HHC in patients with atypical osteoarthritis or chondrocalcinosis.

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Hemochromatosis

   6. Olynyk JK, Cullen DJ, Sina Aquilia BA, et al: A population based study of the clinical expression of the hemochromatosis gene. N Engl J Med 341:718-724, 1999.   7. Andrews NC: Disorders of iron metabolism. N Engl J Med 341:1986-1995, 1999.    8. Finch CA, Huebers H: Perspectives in iron metabolism. N Engl J Med 306:1520-1528, 1982.    9. Hallberg L, Brune M, Rossander L: The role of vitamin C in iron absorption. Int J Vitam Nutr Res Suppl 30:103-108, 1989.  10. Hallberg L, Rossander L, Skanberg AB: Phytates and the inhibitory effect of bran on iron absorption in man. Am J Clin Nutr 45:988-996, 1987.  11. Fleming RE, Bacon BR: Orchestration of iron homeostasis. N Engl J Med 352:1741-1744, 2005.  12. Dix DJ, Lin PN, Kimata Y, et al: The iron regulatory region of ferritin mRNA is also a positive control element for iron-dependent translation. Biochemistry 31:2818-2822, 1992. 13. Tavill AS: Diagnosis and management of hemochromatosis. Hepatology 33:1321-1328, 2001. 14. Pietrangelo A: Hereditary hemochromatosis—a new look at an old disease. N Engl J Med 350:2383-2397, 2004.  15. Cazzola M, Cerani P, Rovati A, et al: Juvenile genetic hemochromatosis is clinically and genetically distinct from the classical HLA-related disorder. Blood 92:2979-2981, 1998.  16. Lanzara C, Roetto A, Daraio F, et al: Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood 103: 4317-4321, 2004.  17. Roetto A, Totaro A, Piperno A, et al: New mutations inactivating transferrin receptor 2 in hemochromatosis type 3. Blood 97: 2555-2560, 2001.  18. Girelli D, Bozzini C, Roetto A, et al: Clinical and pathologic findings in hemochromatosis type 3 due to a novel mutation in transferrin receptor 2 gene. Gastroenterology 122:1295-1302, 2002.  19. Njajou OT, Vaessen N, Joosse M, et al: A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet 28:213-214, 2001.  20. Montosi G, Donovan A, Totaro A, et al: Autosomal dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest 108:619-623, 2001.  21. Cremonesi L, Forni GL, Soriani N, et al: Genetic and clinical heterogeneity of ferroportin disease. Br J Haematol 131:663-670, 2005.  22. Gordeuk VR, Caleffi A, Corradini E, et al: Iron overload in Africans and African-Americans and a common mutation in the SLC40A1 (ferroportin 1) gene. Blood Cells Mol Dis 31:299-304, 2003.  23. Cazzola M: Role of ferritin and ferroportin genes in unexplained hyperferritinaemia. Best Pract Res Clin Haematol 18:251-263, 2005. 24. Adams PC, Reboussin DM, Barton JC, et al: Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 352:1769-1778, 2005.  25. Waalen J, Nordestgaard BG, Beutler E: The penetrance of hereditary hemochromatosis. Best Pract Res Clin Haematol 18:203-220, 2005.  26. Pietrangelo A, Rocchi E, Casalgrandi G, et al: Regulation of transferrin, transferrin receptor and ferritin genes in human duodenum. Gastroenterology 102:802-809, 1992.  27. Parkkila S, Waheed A, Britton RS, et al: Immunohistochemistry of HLA-H, the protein defective in patients with hereditary hemochromatosis, reveals unique pattern of expression in gastrointestinal tract. Proc Natl Acad Sci U S A 94:2534-2539, 1997.  28. Cairo G, Recalcati S, Montosi G, et al: Inappropriately high iron regulatory protein activity in monocytes of patients with genetic hemochromatosis. Blood 89:2546-2553, 1997. 29. Bridle KR, Frazer DM, Wilkins SJ, et al: Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homeostasis. Lancet 361:669-673, 2003.  30. Nicolas G, Viatte L, Lou DQ, et al: Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet 34:97-101, 2003.  31. Pietrangelo A, Caleffi A, Henrion J, et al: Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes. Gastroenterology 128:470-479, 2005.  32. Jacolot S, Le Gac G, Scotet V, et al: HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype. Blood 103:2835-2840, 2004.

 33. Le Gac G, Scotet V, Ka C, et al: The recently identified type 2A juvenile hemochromatosis gene (HJV), a second candidate modifier of the C282Y homozygous phenotype. Hum Mol Genet 13:1913-1918, 2004.  34. Thorburn D, Curry G, Spooner R, et al: The role of iron and hemochromatosis gene mutations in the progression of liver disease in chronic hepatitis C. Gut 50:248-252, 2002.  35. Bonkovsky HL, Poh Fitzpatrick M, Pimstone N, et al: Porphyria cutanea tarda, hepatitis C and HFE gene mutations in North America. Hepatology 27:1661-1669, 1998. 36. Chung RT, Misdraji J, Sahani DV: Case 33-2006: A 43-year-old man with diabetes, hypogonadism, cirrhosis, arthralgias and fatigue. N Engl J Med 355:1812-1819, 2006.  37. Stal P, Olsson J, Svoboda P, et al: Studies on genotoxic effects of iron overload and alcohol in an animal model of hepatocarcinogenesis. J Hepatol 27:562-571, 1997.  38. Bacon BR, Britton RS: Hereditary hemochromatosis and alcohol: A fibrogenic cocktail. Gastroenterology 122:563-565, 2002.  39. von Herbay A, DeGroot H, Hegi U, et al: Low vitamin E content in plasma of patients with alcoholic liver disease, hemochromatosis and Wilson’s disease. J Hepatol 20:41-46, 1994.  40. Adams PC, Deugnier Y, Moirand R, et al: The relationship between iron overload, clinical symptoms and age in 410 patients with genetic hemochromatosis. Hepatology 25:162-166, 1997.  41. Elmberg M, Hultcrantz R, Ekbom A, et al: Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives. Gastroenterology 125:1733-1741, 2003.  42. Yaouanq JM: Diabetes and hemochromatosis: Current concepts, management and prevention. Diabetes Metab 21:319-329, 1995.  43. Salonen JT, Tuomainen TP, Kontula K: Role of C282Y mutation in haemochromatosis gene in the development of type 2 diabetes in healthy men. BMJ 320:1706-1707, 2000.  44. Gore JM, Fallon JT: Case 31-1994: A 25 year old man with recent onset of diabetes and congestive heart failure. N Engl J Med 331: 460-466, 1994.  45. Ellervik C, Tybjaerg-Hansen A, Grande P, et al: Hereditary hemochromatosis and risk of ischemic heart disease. Circulation 112: 185-193, 2005.  46. Cundy T, Butler J, Bomford A, et al: Reversibility of hypogonadotropic hypogonadism associated with genetic haemochromatosis. Clin Endocrinol 38:617-620, 1993.  47. Edwards CQ, Kelly TM, Ellwein G, et al: Thyroid disease in hemochromatosis. Arch Intern Med 143:1890-1893, 1983.  48. van Asbeck BS, Verbrugh HA, van Oost VA, et al: Listeria monocytogenes meningitis and decreased phagocytosis associated with iron overload. BMJ 284:542-544, 1982.  49. Bulaj ZJ, Ajioka RS, Phillips JD, et al: Disease-related conditions in relatives of patients with hemochromatosis. N Engl J Med 343: 1529-1535, 2000.  50. Ross JM, Kowalchuk RM, Shaulinsky J, et al: Association of heterozygous hemochromatosis C282Y gene mutation with hand osteoarthritis. J Rheumatol 30:121-125, 2000.  51. von Kempis J: Arthropathy in hereditary hemochromatosis. Curr Opin Rheumatol 13:80-83, 2001. 52. Schumacher HR: Haemochromatosis. Bailliere’s Best Pract Clin Res Rheumatol 14:277-284, 2000.  53. Ines LS, da Silva JA, Malcata AB, et al: Arthropathy of genetic hemochromatosis: A major and distinctive manifestation of disease. Clin Exp Rheumatol 19:98-102, 2001.  54. Adams PC, Speechley M: The effect of arthritis on the quality of life in hereditary hemochromatosis. J Rheumatol 23:707-710, 1996.  55. Cunnane G, O’Duffy JD: The iron salute sign of haemochromatosis. Arthritis Rheum 38:558, 1995.  56. Carroll GJ: Primary osteoarthritis in the ankle joint is associated with finger metacarpophalangeal osteoarthritis and the H63D mutation in the HFE gene. J Clin Rheumatol 12:109-113, 2006.  57. Axford JS, Bomford A, Revell P, et al: Hip arthropathy in genetic hemochromatosis: Radiographic and histologic features. Arthritis Rheum 34:357-361, 1991.  58. Lunn JV, Gallagher PM, Hegarty S, et al: The role of hereditary hemochromatosis in aseptic loosening following primary total hip arthroplasty. J Orthop Res 23:542-548, 2005.  59. Arosa FA, Oliveira L, Porto G, et al: Anomalies of the CD8+ T cell pool in haemochromatosis. Clin Exp Immunol 107:548-554, 1997.

PART 18   60. Schumacher HR: Ultrastructural characteristics of the synovial membrane in idiopathic hemochromatosis. Ann Rheum Dis 31:465-473, 1972.  61. Walker RJ, Dymock IW, Ansell ID, et al: Synovial biopsy in hemochromatosis arthropathy. Ann Rheum Dis 31:98-102, 1972.  62. Pawlotsky Y, Le Dantec P, Moirand R, et al: Elevated parathyroid hormone 44-68 and osteoarticular changes in patients with genetic hemochromatosis. Arthritis Rheum 42:799-806, 1999.  63. Tavill AS, Adams PC: A diagnostic approach to hemochromatosis. Can J Gastroenterol 20:535-540, 2006.

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 64. Tavill AS: Clinical implications of the hemochromatosis gene. N Engl J Med 341:755-757, 1999.  65. Niederau C, Fischer R, Purschel A, et al: Long term survival in patients with hereditary hemochromatosis. Gastroenterology 110:1107-1119, 1996.  66. Kowdley KV, Brandhagen DJ, Gish RG, et al: Survival after liver transplantation in patients with hepatic iron overload: The national hemochromatosis transplant registry. Gastroenterology 129:494-503, 2005.

109

Hemophilic Arthropathy KATHERINE S. UPCHURCH  •  DOREEN B. BRETTLER

Key Points Severe hemophilia, if not aggressively treated, is most often complicated by recurrent hemarthrosis. Recurrent hemarthrosis causes chronic arthropathy with overlapping clinical and pathologic features of osteoarthritis and rheumatoid arthritis. Septic arthritis should be considered in hemophilic patients with risk factors (previous arthrocentesis, intravenous drug use, human immunodeficiency virus infection), and acute monarticular arthritis. Soft tissue and muscle hemorrhage are frequent ­complications of hemophilia. With continuous factor infusion, surgical procedures, ­including total joint replacements, can be done safely in hemophilic patients. The best treatment for hemophilic arthropathy is prevention of recurrent hemarthrosis through regular prophylactic factor replacement.

Although spontaneous joint hemorrhage has been described in a variety of inherited disorders of coagulation,1-3 and in the setting of anticoagulation therapy,4 it occurs most frequently in hemophilia. Bleeding into the joints is the complication of hemophilia that most often requires therapeutic intervention and, when it is recurrent, can lead to chronic, deforming arthritis that is independent of bleeding ­episodes. Hemophilia refers to a group of inherited diseases in which there is a functional deficiency of a specific clotting factor. The most common are hemophilia A (classic hemophilia) and hemophilia B (Christmas disease); the deficient factors are factor VIII (hemophilia A) and factor IX (hemophilia B). The incidence and severity of hemorrhagic complications of hemophilia are directly related to the severity of the underlying coagulation defect. Although the intrinsic pathway of coagulation is severely impaired in hemophilia, the extrinsic tissue-dependent pathway remains intact and is probably the major hemostatic regulatory system. Normal synovial tissue and cultures of synovial fibroblasts have been found to be deficient in tissue factor,5 which suggests that in synovium-lined joints, hemophiliacs have functional inactivity of intrinsic and extrinsic coagulation pathways. This situation may explain the marked propensity toward hemorrhage in joints compared with other tissue sites in these patients.

CLINICAL FEATURES The spectrum of articular disease in hemophiliacs has been the subject of numerous comprehensive reviews6-10 and includes acute hemarthrosis, subacute or chronic arthritis, and end-stage hemophilic arthropathy. The usual distribution of joint involvement is shown in Figure 109-1. Involvement of the small joints of the hands and feet also may occur, although infrequently. ACUTE HEMARTHROSIS Nearly all patients with severe hemophilia A or B (<1% activity of the deficient factor) and half of patients with moderate disease activity experience hemarthrosis. Acute hemarthroses generally first occur when a child begins to walk and continue, usually cyclically, into adulthood, when the frequency diminishes. Patients frequently have premonitory symptoms, such as stiffness or warmth in the affected joint, followed by intense pain, which may be due partly to rapid joint capsule distention. Pain is accompanied by objective clinical findings of warmth, a tense effusion, tenderness, limitation of motion, and a joint that is often held in a flexed position. Joint pain responds rapidly to replacement of the deficient clotting factor. If hemostasis is achieved early after onset of hemarthrosis, full joint function may be regained within 12 to 24 hours. If the hemorrhage is more advanced, however, blood is resorbed slowly over 5 to 7 days, and full joint function is regained within 10 to 14 days. SUBACUTE OR CHRONIC ARTHRITIS Recurrent hemarthroses, particularly in patients with severe factor deficiency, may lead to a self-perpetuating condition in which joint abnormalities persist in intervals between bleeding episodes. The involved joint is chronically swollen, although painless and only slightly warm. Chronic synovitis, including prominent synovial proliferation with or without effusion, may be present. There may be mild limitation of motion, often with a flexion deformity. Factor replacement does not modify these findings. END-STAGE HEMOPHILIC ARTHROPATHY Long-standing end-stage hemophilic arthropathy has features in common with degenerative joint disease and adv­anced rheumatoid arthritis. The joint appears enlarged and “knobby,” owing to osteophytic bone overgrowth. Synovial thickening and effusion are not prominent, however. Range of motion is severely restricted, and fibrous ­ankylosis 1817

1818

UPCHURCH 

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Hemophilic Arthropathy

Percentage joints with:

Any Many hemarthrosis hemarthroses

Figure 109-1  Distribution of acute hemarthrosis based on a study of 139 patients with hemophilia. Clinical and radiologic features of chronic arthritis in hemophilia. (Adapted from Steven MM, Yogarojah S, Madhok R, et al: ­Haemophilic arthritis. QJM 58:181, 1986.)

Chronic pain

Synovitis

Limitation of motion

Any radiologic abnormality

34.5

13.3

13.9

—

16.9

21.6

54.0

38.5

13.8

9.8

27.0

52.6

28.6

8.0

5.4

—

19.8

18.8

63.1

50.9

26.8

11.6

27.0

50.2

60.8

42.8

15.2

2.2

34.2

52.4

is common. ­ Subluxation, joint laxity, and malalignment are frequently present. Hemarthroses decrease in frequency, however. SEPTIC ARTHRITIS Until the early 1980s, septic arthritis rarely occurred in hemophiliac patients. With the widespread occurrence of human immunodeficiency virus (HIV) infection as a result of contaminated factor concentrates, the incidence of this complication has increased significantly.11,12 Septic arthritis is seen more often in adult than in pediatric hemophiliacs and is most commonly monarticular, usually involving the knee. In contrast to spontaneous hemarthrosis, septic arthritis is significantly associated with a temperature greater than 38°C within 12 hours of presentation and articular pain that does not improve with replacement therapy.11 Peripheral leukocyte count may not be elevated, particularly in HIVpositive patients.13 A predisposing factor other than hemophilic arthropathy is often identifiable, including previous arthrocentesis or arthroplasty, intravenous drug use, and infected indwelling venous access catheters. Staphylococcus aureus is the most frequently identified organism even in HIVinfected patients, followed by Streptococcus pneumoniae.13 MUSCLE AND SOFT TISSUE HEMORRHAGE Bleeding into muscles and soft tissue is common in hemophiliacs and may be more insidious than hemarthrosis because of the lack of premonitory symptoms. Bleeding into the iliopsoas and gastrocnemius muscles and the forearm results in well-described syndromes with which the rheumatologist should be familiar. Iliopsoas hemorrhage produces acute groin pain with marked pain on hip extension and a hip flexion contracture. Rotation is preserved, in contrast to intra-articular hemorrhage. If untreated, the expanding soft tissue mass may compress the femoral nerve, causing signs and symptoms of femoral neuropathy.6,14 Bleeding into the gastrocnemius muscle can cause an equinus deformity from heel cord contracture.6 Finally, hemorrhage into closed compartments can cause acute muscle necrosis and nerve compression.15 Of particular importance is bleeding into the volar compartment of the forearm, which can cause flexion deformities of the wrist and fingers. If a

­compartment syndrome is suspected, compartment pressures should be measured to confirm the diagnosis. A large intramuscular hemorrhage uncommonly results in the formation of a simple muscle cyst, which clinically appears to be an encapsulated soft tissue area of swelling overlying muscle. Cyst formation in this setting is confined by the muscular fascial plane and most likely results from inadequate resorption of blood and clot. Subperiosteal or intraosseous hemorrhage, in contrast, may lead to a pseudotumor, a rare skeletal complication of hemophilia. Hemophilic pseudotumors are of two types: the adult type, which occurs proximally, usually in the pelvis or femur; and the childhood type, which occurs distal to the elbows or knees and carries a better prognosis.16,17 Conservative early management of muscle cysts and childhood-type pseudotumors is indicated, including immobilization and factor replacement. In adult-type pseudotumors, which are usually refractory to conservative therapy, and in progressive childhood pseudotumors, surgical removal is indicated16 to prevent serious complications, such as spontaneous rupture, fistula formation, neurologic or vascular entrapment, and fracture of adjacent bone. Aspiration of a pseudotumor or cyst is contraindicated.

DIAGNOSTIC IMAGING RADIOGRAPHS The earliest radiographic changes in hemophilic a­ rthropathy are confined to the soft tissue and reflect acute hemarthrosis. The joint capsule is distended with displacement of fat pads, and there is an increased hazy density caused by intra-articular blood. Hemarthrosis before epiphyseal plate closure may result in epiphyseal ­overgrowth and irregularity. Occasionally, premature epiphyseal closure is seen. With the progression of chronic proliferative synovitis, irreversible radiologic changes appear.18 These changes reflect the inflammatory and the degenerative nature of chronic hemophilic arthropathy (Table 109-1 and Fig. 109-2A). Certain changes unique to hemophilic arthropathy occur as well (Table 109-1 and Fig. 109-2B). A study of serial radiographs of symptomatic joints in ­ hemophilic patients suggests that serial scoring with conventionally

PART 18 

accepted techniques may be a cost-effective alternative to magnetic resonance imaging (MRI) in predicting progressive synovial hypertrophy.19 OTHER IMAGING METHODS MRI is now routinely used to stage hemophilic arthritis accurately to determine optimal treatment and to follow response to therapy.20 A scoring system based on MRI has been proposed.21 Additionally, MRI and ultrasonography are useful in the detection and the quantitation of soft tissue bleeding, cysts, and pseudotumors.22,23 Table 109-1  Radiologic Manifestations of Chronic ­Hemophilic Arthropathy Characteristic

Also Seen in

Periarticular soft tissue swelling

RA

Periarticular demineralization

RA

Marginal erosions

RA

Subchondral irregularity and   cyst formation

RA, OA

Decreased joint space

OA

Osteophyte formation

CPPD*

Chondrocalcinosis Specific Femoral intercondylar notch   widening Squaring of distal patellar   margin (lateral view) Proximal radial enlargement   (see Fig. 109-2B) Talar flattening ± ankle   ankylosis† CPPD, calcium pyrophosphate deposition disease; OA, osteoarthritis; RA, rheumatoid arthritis. *From Jensen PS, Putnam CE: Chondrocalcinosis and hemophilia. Clin ­Radiol 28:401, 1977. †From Schreiber RR: Musculoskeletal system: Radiologic findings. In ­Brinkhous KM, Hemker HC (eds): Handbook of Hemophilia, I. New York, American Elsevier, 1975.

A

B

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ARTHRITIS ACCOMPANYING SYSTEMIC DISEASE

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PATHOLOGIC FEATURES AND PATHOGENESIS Pathologic studies of human hemophilic arthropathy have been limited to synovial specimens obtained at surgery24,25 or at postmortem examination and reflect changes of adv­anced disease only. Studies of experimentally produced ­hemarthrosis in animals,26,27 post-traumatic hemarthrosis in nonhemophilic humans,28 and canine and murine models of hemophilia A29-31 have provided an understanding of the earliest changes induced by acute hemarthrosis and their evolution to chronic arthritis. As reviewed more recently,32 the process most likely includes catabolic activation of synovial cells by exposure to blood components with subsequent cartilage destruction and a direct destructive effect of intra-articular blood on cartilage. A single synovial hemorrhage induces serial changes in the synovial membrane, including early focal villous synovial proliferation and subsynovial diapedesis of erythrocytes, followed by the appearance of perivascular inflammatory cells, patchy subsynovial fibrosis, and intracellular iron accumulation in synovial cells and subsynovial macrophages. With repeated hemarthroses, the synovium becomes grossly hypertrophied and hyperpigmented, with eventual organization into a pannus that invades and erodes marginal cartilage. On histologic examination, villous hyp­ ertrophy and subsynovial fibrosis progress, but inflammatory cells are scarce (Fig. 109-3).25 Seventy-five percent of synoviocytes contain siderosomes (electron-dense, iron-filled deposits within lysosomes), in contrast to 10% in normal synovium and 25% in rheumatoid synovium.33 Iron deposits are associated with the production of proinflammatory cytokines and synovial inhibition of the formation of human cartilage matrix. Although the inflammatory synovial changes are mild, the synovial production of proinflammatory mediators, including interleukin-1 and interleukin-6 and tumor ­necrosis factor-α, approaches that of rheumatoid synovium.32 The articular cartilage is grossly and microscopically abnormal in the setting of recurrent hemarthrosis.26 There are areas of cartilaginous fissuring and rarefaction

Figure 109-2  Radiographic cha­nges of hemophilic arthropathy. A, Early arthritis of the knee, show­ing­ soft ­tissue swelling, widening of the femoral condyles and tibial plateau, irregularity of the distal femoral epiphysis, and a few subchondral bone cysts. B, More advanced arthritis involving the elbow, showing almost complete loss of joint space and extensive subchondral cyst formation. The widening of the proximal radius is characteristic of ­hemophilic arthropathy.

1820

UPCHURCH 

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Hemophilic Arthropathy

Individuals with factor VIII or IX levels of 1% or less of the normal level have joint and muscle hemorrhages requiring therapy an average four or five times per month. Such patients are classified as having severe hemophilia. Individuals with factor VIII or IX levels greater than 5% of normal are considered to have mild hemophilia and usually bleed only with trauma or at surgery. Occasional “spontaneous” hemarthrosis may occur in such patients, especially in joints damaged by previously undertreated hemorrhage. Patients whose factor VIII or IX levels fall between these two ranges are considered to have moderately severe hemophilia, and their clinical picture falls somewhere between the extremes. If such patients have had multiple untreated or suboptimally treated hemarthroses with subsequent joint damage, the anatomic instability of these joints would cause frequent and severe bleeding, and the condition would appear clinically more severe than the factor VIII or IX assay might suggest. Figure 109-3  Proliferative synovitis of hemophilia. Villous hypertrophy of synovium with pigment deposition in superficial cells. The reaction is mainly synovial cell hyperplasia. Infiltrating inflammatory cells are scarce (Hematoxylin and eosin, ×2500).

exposing sclerotic bone. The remaining cartilage is thin and unevenly distributed, often freely protruding into the joint cavity. Bone erosions appear at weight-bearing surfaces. There is loss of matrix glycosaminoglycan, which also is seen in degenerative arthritis.25,34 Current studies suggest that recurrent hemarthrosis ind­uces joint destruction in hemophilic arthropathy through direct and indirect effects of iron on the synovium33,35 and cartilage,34,36 by the degradative effect of the proliferative synovium,37 and through an alteration in cartilage biochemical composition similar to that seen in degenerative arthritis. There may be a relationship between hemarthrosis-induced overexpression of oncogenes (e.g., c-myc and mdm-2) and the dysregulated, tumor-like proliferation of hemophilic synovium.38,39

DIAGNOSIS In most cases of congenital coagulopathy, the diagnosis has been made before presentation to a rheumatologist. In the case of hemophilia, if there is an affected family member, prenatal diagnosis is possible. Because the spontaneous mutation rate in hemophilia is significant, the diagnosis may not be suspected until infancy, when recurrent, large ecchymoses or sustained oral hemorrhages commonly develop in most affected patients. In the case of hemophilia A or hemophilia B, hemarthrosis is usually a later manifestation, but it may be the initial symptom of other, less severe coagulopathies, even in adulthood. When a coagulopathy is suspected, baseline screening tests, including prothrombin time, activated partial thromboplastin time, and platelet count, should be performed. In patients with hemophilia, the prothrombin time and platelet count are normal, and the activated partial thromboplastin time is prolonged, denoting a defect in the intrinsic clotting cascade. Referral to a hematologist, who obtains the appropriate factor assays, is the next step.

TREATMENT OF HEMOPHILIA Until recent years, in most hemophilia centers factor rep­ lacement therapy has been given on demand; that is, factor concentrate has been infused at the earliest sign of a hemorrhage. With the introduction of highly purified, safe concentrates, prophylactic treatment is now much more common in countries where this product is available, especially in pediatric patients.40,41 Instead of being infused when a hemorrhage has occurred, factor concentrate is given regularly three times per week to prevent bleeds. Prophylaxis is started before any joint damage has occurred, usually at approximately 2 years of age, with the goal of minimizing bleeding episodes to no more than four to six per year. Indwelling catheters, such as Port-A-Cath and Hickman lines, are required for factor administration because frequent venipunctures are painful and cumbersome. More recent data suggest that the institution of prophylactic factor infusion would significantly decrease the long-term joint sequelae of hemophilia and decrease lifetime disability.42-44 With adequate factor replacement, all types of surgery, including joint replacements, can be done. Surgical in­tervention in a patient with hemophilia should be done, however, only at specialized centers with blood bank and coagulation laboratory support and with the participation of a hematologist who specializes in clotting disorders. A surgeon who feels comfortable operating on patients with clotting disorders also is essential. Constant-infusion techniques for administering factor concentrate during and after surgery have made adequate factor levels easier to maintain and have decreased overall perioperative use of factor concentrates.45 Many types of commercial factor VIII ­concentrate are available, most of which are manufactured with recombinant technology. FACTOR VIII REPLACEMENT All plasma-derived factor concentrates are virally inactivated by various methods, including exposure to solvent detergent, heat, and pasteurization. Recombinant factor VIII concentrates, manufactured by inserting the human factor VIII gene into a mammalian cell line, are widely ava­ilable and used almost exclusively, especially in ­developed

PART 18 

­countiries.46,47 Because human plasma is not used in their production, transfusion-transmitted diseases, such as hepatitis and HIV-1, are no longer a risk. Recombinant concentrates at doses similar to those of plasma-derived concentrates have been efficacious in the treatment of hemorrhages. Half-life and recovery times for the infused factor VIII are similar to those for plasma-derived concentrates. Current prices range from $0.35 to $0.90 per unit for factor VIII plasma-derived concentrates and from $1.00 to $1.20 per unit for recombinant factor VIII. In most hemophilia centers in the United States, recombinant factor concentrates are the only concentrates used, although high-purity, plasma-derived concentrates are still available. Because these concentrates have made early and intensive home therapy possible, overall costs of health care have greatly declined for patients treated with these materials. Arginine vasopressin (desmopressin), a vasopressin analogue, can be used in the treatment of mild hemophilia A to increase the endogenous factor VIII level. Desmopressin increases the baseline factor VIII level about threefold, so a baseline level of at least 10% is required for efficacy.48 Because this is not a blood product, it poses no danger of transmitting blood-borne viruses. Although cryoprecipitate contains factor VIII, its use has been discouraged because it is not virally inactivated. It is less safe than concentrates. FACTOR IX REPLACEMENT Factor IX is not found in either cryoprecipitate or factor VIII concentrate; these two materials are totally ineffective for the treatment of hemophilia B. Fresh-frozen plasma does contain factor IX and has been used in the past. Most freshfrozen plasma products are not virally inactivated, however, and are less safe than factor IX concentrates. The principles of treatment are similar to those for factor VIII replacement. Because the half-life of factor IX is longer, however, it can be given less frequently. Demand therapy is still commonly used; as for factor VIII deficiency, however, prophylaxis is beginning to be used in pediatric patients. Several plasma-derived factor IX concentrates are available, all virally inactivated. In the past, all such concentrates also contained factors II, VII, and X (prothrombin complex concentrates). Currently, only pure factor IX concentrates are used to treat factor IX deficiency. As with factor VIII concentrates, a recombinant factor IX concentrate is available and is widely used. Recovery is less than that of its plasma-derived counterpart, however, and higher doses (approximately 1.5 times calculated levels) must be infused to reach appropriate levels. COMPLICATIONS OF FACTOR REPLACEMENT THERAPY Inhibitor Antibodies Inhibitor antibodies may develop after exposure to factor concentrate. They occur most often in patients with severe hemophilia after 9 to 30 exposures of replacement therapy, usually before the age of 5 years. There may be a familial predisposition to the development of this complication. Because bleeding cannot be reliably controlled in patients

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ARTHRITIS ACCOMPANYING SYSTEMIC DISEASE

1821

with inhibitor antibodies, elective surgery in these patients should be done only after careful deliberation. Inhibitor antibodies in factor VIII–deficient hemophiliacs are IgG antibodies (usually IgG4) and may have an unpredictable natural history. Low titer and clinically weak antibodies sometimes are easily neutralized by factor VIII and do not undergo anamnestic increases in titer after multiple factor VIII challenges. Such antibodies may rarely become high in titer. In other patients, antibody titers increase after each exposure to factor VIII. Still other patients seem to lose antibody spontaneously despite multiple subsequent factor VIII challenges. The type of antibody response to factor VIII infusion and the patient’s clinical response dictate therapy. Therapy for patients with inhibitor antibodies has been reviewed more recently.49 Induction of immune tolerance through frequent administration of factor VIII successfully eliminates inhibitors in 80% of patients. In patients in whom immune tolerance therapy is unsuccessful, there are several approaches for management of acute bleeding episodes, including the administration of activated prothrombin complex concentrate or, more recently, recombinant activated factor VIIa (rVIIa, Novo-Seven; Novo Nordisk, Bagsvaerd, Denmark). rVIIa is thought to function directly at the site of injury, causing activation of factor IX and the extrinsic clotting system locally. Porcine factor VIII, which has limited cross-reactivity with the human antibody, was used previously, but has been removed from the market because of contamination with porcine parvovirus. A recombinant form of this protein is being investigated. The use of immunosuppressives or glucocorticoids has been abandoned in most centers owing to lack of efficacy in this condition and serious side effects. Regimens of regular factor VIII infusions for induction of tolerance have been successful in eliminating the antibody. It has been suggested by some groups that an immune tolerance regimen be started as early as possible after an inhibitor develops. Rituximab may be useful to suppress inhibitor titers in refractory patients.50 Inhibitor antibodies against factor IX are exceedingly rare. There is no generally accepted efficacious therapy. Treatment usually includes large and frequent doses of factor IX concentrate. Induction of immune tolerance with elimination of the antibody also has been used, but with less success than with antibodies to factor VIII. Using large doses of purified factor IX concentrate in some patients with inhibitor antibodies to factor IX has resulted in anaphylactic reactions and nephrotic syndrome secondary to immune complex formation and deposition in the kidney.51,52 Human Immunodeficiency Virus HIV was introduced into the U.S. blood supply in the 1970s. By the late 1970s, factor concentrate was widely contaminated. By 1982, approximately 50% of patients with hemophilia were infected with HIV.53 Currently, approximately 10% to 20% of American hemophiliacs are infected with HIV. As with other infected individuals, CD4+ lymphocyte counts and HIV titers are used to guide treatment regimens. Since 1985, in the manufacture of plasma-derived ­concentrates a triple barrier to viral contamination of plasma-derived concentrates has been employed: (1) self exclusion for donors, (2) donor screening with serologic

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tests for HIV, and (3) viral inactivation during concentrate production. Recombinant concentrates also are now widely available. Acquisition of HIV-1 through factor concentrate in patients with hemophilia has been virtually nonexistent since 1985.

Acute arthritis in hemophilia

Factor infusion

Viral Hepatitis A second infectious side effect of either cryoprecipitate or factor concentrate is hepatitis, which may be a result of parenterally transmitted hepatitis A, B, C, or G virus; cytomegalovirus; or other as yet unidentified pathogens. In most series, most patients with hemophilia treated before the 1980s have plasma levels of hepatitis B virus surface antibody, and a few (2% to 5%) carry hepatitis B virus surface antigen. Approximately 80% of hemophiliacs transfused before 1990 have antibody to hepatitis C virus,54 which, in contrast to hepatitis B virus antibody, is a marker for ongoing infection. Virucidal concentrate treatment methods have reduced, but not eliminated, parenteral transmission of hepatitis B and C viruses. Transmission of hepatitis A and G viruses also has been reported with the use of plasma-derived concentrates. Vaccination against hepatitis B and hepatitis A is now recommended for infants born in the United States, and vaccination against hepatitis A is recommended for infants with hemophilia. Transmission of hepatitis has decreased dramatically because almost all pediatric patients are treated with recombinant products. THERAPY FOR MUSCULOSKELETAL COMPLICATIONS OF HEMOPHILIA Acute Hemarthrosis The most important measure in therapy for acute hemarthrosis is prompt correction of the clotting abnormality by administration of the deficient factor. Arthrocentesis, if it is accomplished within 24 hours of the onset of symptoms (but after factor replacement), may be symptomatically beneficial in advanced acute hemarthrosis; however, for diagnostic and potentially therapeutic purposes, it should be considered mandatory at any time if suspicion of infection is high.12,14 Analgesia and brief joint immobilization for no more than 2 days often aid in pain control. Subsequently, passive range-of-motion isometric exercise should be initiated to reduce the likelihood of joint contracture (Fig. 109-4). Chronic Hemophilic Arthropathy Conservative. A variety of conservative measures can bring remarkable benefit in the setting of chronic hemophilic ­arthropathy,55-58 including the following: Prophylactic factor infusions Intensive physical therapy for muscle building and ­increased joint stability Periods of avoidance of weight bearing to allow regression of synovitis Correction of flexion contractures by wedging casts, night splints, or the judicious use of traction Training in sports to allow future maintenance of muscle mass

Monarticular

Oligoarticular

? Infection risk factors; ? T>38°C; ? no pain relief Yes Aspirate to exclude infection

Polyarticular

Analgesia, joint immobilization No Analgesia, joint immmobilization

Figure 109-4  Algorithm of acute arthritis in hemophilia.

In modern treatment programs, aspiration of joints with chronic synovial effusions is rarely necessary or of lasting benefit. Failure of these conservative modalities to relieve symptoms or produce regression of synovitis should prompt consideration of other options, including local corticosteroid injections (which have been described as useful more recently),59 the use of nonsteroidal anti-inflammatory drugs (NSAIDs), synovectomy, and joint replacement in the end stage. Despite the obvious theoretical contraindications to the use of NSAIDs in hemophilia (i.e., the antiplatelet effects), several NSAIDs may be used safely for short periods as adjuncts to the conservative regimen. Ibuprofen, salsalate, and magnesium salicylate have been shown in a few patients to be safe and efficacious in reducing joint pain and analgesic dependence,60,61 although long-term regression of synovitis and modification of the course of chronic hemophilic arthropathy have not been shown with any NSAID. The selective cyclooxygenase-2 inhibitors class of NSAIDs do not have significant antiplatelet effects and theoretica­ lly should be safer than conventional NSAIDs in patients with hemophilia. Rofecoxib and valdecoxib have been withdrawn from the market because of a causative link to increased risk of cardiovascular events. Although others are in development, celecoxib, the only remaining cyclooxygenase-2 inhibitor on the market, has not been specifically tested in hemophilic patients and, similar to other NSAIDs, should be used with caution. Synovectomy. Synovectomy in the setting of hemophilic arthritis has been shown to reduce the incidence of recurrent hemarthrosis and the severity of synovitis. This procedure can be accomplished surgically, arthroscopically, or through intra-articular injections of radioactive colloids. Patients should be considered for synovectomy if, despite aggressive ­ conservative measures as outlined previously, persistent hemarthroses continue with ongoing chronic ­synovitis. In our center, specific indications for synovectomy include persistence of at least two hemarthroses per month

PART 18 

in the same joint accompanied by symptoms and signs of chronic synovitis despite at least 4 months of conservative therapy, including intensive factor replacement. The major drawback to surgical synovectomy remains the observation, confirmed in most series,62,63 that joint motion is reduced postoperatively compared with preoperative baseline joint motion, despite intensive rehabilitation. To overcome this finding and the high cost of hospitalization and factor replacement therapy attendant with surgical synovectomy, arthroscopic synovectomy has been employed in chronic hemophilic arthritis in recent years. Most follow-up series report that this technique is as successful as surgical synovectomy and results in less loss of motion,64-66 particularly when continuous passive motion is used in the postoperative period.67 The total cost of the procedure is less than that of surgical synovectomy, as is the rehabilitation period. Postoperative bleeding after arthroscopic synovectomy has been associated with poor results. An alternative to surgical or arthroscopic synovectomy is ablation of the synovium using either radioisotopic or chemical agents, as reviewed more recently.41,68,69 Such a nonoperative approach has been successful in reducing bleeding episodes by 70% to 80% in patients with hemophilia70 and is especially useful in patients with circulating factor inhibitors, in whom surgery is relatively contraindicated. Commonly used radioisotopes in the United States include colloidal 32P chromic phosphate, yttrium 90, and radioactive colloidal gold (198Au). Theoretical long-term carcinogenic and teratogenic effects remain the major concerns associated with this technique in patients who may have long life expectancies and are still of reproductive age; these effects have limited the use of radioisotopes in the United States, but less so in Europe. Chemical synovectomies using osmic acid, rifampicin, and hyaluronic acid have been attempted in some European centers with modest success, especially in children.68 The short-term results of radioactive and chemical synovectomies are similar, although long-term outcomes may be superior in radioisotopic synovectomy.41 Radio­ active and chemical synovectomies remain experimental in the United States. Both have the advantages of being minimally invasive, requiring little factor replacement, and resulting in little morbidity, and both are much less expensive than operative procedures. Total Joint Replacement. Major orthopaedic ­procedures, including total joint replacements,71-74 have been employed safely and successfully in end-stage hemophilic arthropathy, including in patients with inhibitor antibodies.75 The primary indication for total joint replacement is pain in an involved joint that is refractory to all conservative measures. Careful preoperative planning is ­imperative, including assessment for the presence of inhibitors, planning for factor replacement, and planning for a multidisciplinary rehabilitative program.76 It is concerning, ­ however, that most hemophilic patients in need of total joint replacement are young and may, if they are not infected with HIV, have a long life expectancy. If the procedure is performed at a young age, this virtually ensures the need for one or more revisions during the patient’s lifetime. In addition, patients are at increased risk for complications of surgery because of their underlying coagulopathy, and loosening is observed more commonly than

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in nonhemophilic patients in long-term follow-up. These findings suggest that total joint replacement should be reserved for the most severe cases of hemophilic arthropathy and deferred as long as possible. A comprehensive recent review details the many orthopaedic procedures that are now available for alleviating the pain and deformity resulting from hemophilic arthropathy.77

CONCLUSION Gene therapy or repair to cure hemophilia may someday be a reality, although this approach currently is still fraught with serious safety concerns.78,79 Until then, the best therapy for hemophilic arthropathy remains its prevention, and prevention is now achievable in many patients. With improvement in the safety and availability of factor concentrates, prophylactic infusion is now feasible. Through a combination of prevention of hemarthrosis or correction of the hemostatic defect at the earliest symptom of joint hemorrhage, education of the patient, application of comprehensive care, and emphasis on the importance of physical activity to maintain muscle mass, the incidence of new or progressive arthropathy can be significantly reduced. REFERENCES   1. Roberts HR, Escobar M, White GC: Hemophilia A and hemophilia B. In Lichtman MA, Beutler E, Kaushansky K, et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005, pp 1867-1886.   2. Larrieu MJ, Caen JP, Meyer DO, et al: Congenital bleeding disorders with long bleeding time and normal platelet count, II: Von Willebrand’s disease (report of thirty-seven patients). Am J Med 45: 354-372, 1968.   3. Ahlberg A, Silwer J: Arthropathy in von Willebrand’s disease. Acta Orthop Scand 41:539-544, 1970.   4. Wild JH, Zvaifler NJ: Hemarthrosis associated with sodium warfarin therapy. Arthritis Rheum 19:98-102, 1976.   5. Green D, Ryan C, Malandruccuolo N, et al: Characterization of the coagulant activity of cultured human fibroblasts. Blood 37:47-51, 1971.   6. Hilgartner MW: Hemophilic arthropathy. Adv Pediatr 21:165-193, 1975.   7. Arnold WD, Hilgartner MW: Hemophilic arthropathy: Current concepts of pathogenesis and management. J Bone Joint Surg Am 59:287-305, 1977.   8. Gilbert MS: Musculoskeletal manifestations of hemophilia. Mt Sinai J Med 44:339-358, 1977.   9. Steven MM, Yogarajah S, Madhok SY, et al: Hemophilic arthritis. QJM 58:181-197, 1986. 10. Rodriguez-Merchan EC: Pathogenesis, early diagnosis, and prophylaxis for chronic hemophilic synovitis. Clin Orthop 343:6-11, 1997. 11. Ellison RT, Reller LB: Differentiating pyogenic arthritis from spontaneous hemarthrosis in patients with hemophilia. West J Med 144: 42-45, 1986. 12. Gilbert MS, Aledort LM, Seremetis S, et al: Long term evaluation of septic arthritis in hemophilic patients. Clin Orthop 328:54-59, 1996. 13. Merchan EC, Magallon M, Manso F, et al: Septic arthritis in HIV positive haemophiliacs. Int Orthop 16:302-306, 1992. 14. Helm M, Horoszowski H, Seligsohn U, et al: Iliopsoas hematoma: Its detection, and treatment with special reference to hemophilia. Arch Orthop Trauma Surg 99:195-197, 1982. 15. Madigan RP, Hanna WT, Wallace SL: Acute compartment syndrome in hemophilia. J Bone Joint Surg Am 63:1327-1329, 1981. 16. Gilbert MS, Kreel I, Hermann G: The hemophilic pseudotumor. In Hilgartner MW, Pochedly C. (eds): Hemophilia in the Child and Adult. New York, Raven Press, 1989. 17. Magallon M, Monteagudo J, Altisent C, et al: Hemophilic pseudotumor: Multicenter experience over a 25-year period. Am J Hematol 45:103-108, 1994.

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18. Kilcoyne RF, Nuss R: Radiological evaluation of hemophilic arthropathy. Semin Thromb Hemost 29:43-48, 2003. 19. Ng WH, Chu WCW, Shing MK, et al: Role of imaging in management of hemophilic patients. AJR Am J Roentgenol 184:1619-1623, 2005. 20. Kilcoyne RF, Nuss R: Radiological assessment of haemophilic arth­ ropathy with emphasis on MRI findings. Haemophilia 9(Suppl 1): 57-64, 2003. 21. Soler R, Lopez-Fernandez F, Rodriguez E, et al: Hemophilic arthropathy: A scoring system for magnetic resonance imaging. Eur Radiol 12:836-843, 2002. 22. Wilson DA, Prince JR: MR imaging of hemophilic pseudotumors. AJR Am J Roentgenol 150:349-350, 1988. 23. Wilson DJ, McLardy-Smith PD, Woodham CH, et al: Diagnostic ultrasound in haemophilia. J Bone Joint Surg Br 69:103-107, 1987. 24. Ghadially FN, Ailsby RL, Yong NK: Ultrastructure of the hemophilic synovial membrane and electron-probe x-ray analysis of hemo­ siderin. J Pathol 120:201-208, 1976. 25. Roosendaal G, Mauser-Bunschoten EP, De Kleijn P, et al: Synovium in hemophilic arthropathy. Haemophilia 4:502-505, 1998. 26. Roy S, Ghadially FN: Pathology of experimental hemarthrosis. Ann Rheum Dis 25:402-415, 1966. 27. Hoaglund FT: Experimental hemarthrosis. J Bone Joint Surg Am 49:285-298, 1967. 28. Roy S, Ghadially FN: Ultrastructure of synovial membrane in human hemarthrosis. J Bone Joint Surg Am 49:1636-1646, 1967. 29. Swanton MC, Wysocki GP: Pathology of joints in canine hemophilia A. In Brinkhous KM, Hemker HC (eds): Handbook of Hemophilia. Part I. New York, American Elsevier, 1975. 30. Bi L, Lawler AM, Antonarakis SE, et al: Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A. Nat Genet 10:119-121, 1995. 31. Valentino LA, Hakobyan N, Kazarian T, et al: Experimental synovitis in a murine model of human haemophilia. Haemophilia 10:280-287, 2004. 32. Hoots WK: Pathogenesis of hemophilic arthropathy. Semin Hematol 43(1 Suppl 1):S18-S22, 2006. 33. Morris CJ, Blake DR, Wainwright AC, et al: Relationship between iron deposits and tissue damage in the synovium: An ultrastructural study. Ann Rheum Dis 45:21-26, 1986. 34. Hough AJ, Banfield WG, Sokoloff L: Cartilage in hemophilic arthropathy. Arch Pathol Lab Med 100:91-96, 1976. 35. Okazaki I, Brinckerhoff CE, Sinclair JF, et al: Iron increases collagenase production by rabbit synovial fibroblasts. J Lab Clin Med 97:396402, 1981. 36. Choi YC, Hough AJ, Morris GM, et al: Experimental siderosis of articular chondrocytes cultured in vitro. Arthritis Rheum 24: 809-823, 1981. 37. Mainardi CL, Levine PH, Werb Z, et al: Proliferative synovitis in hemophilia: Biochemical and morphologic observations. Arthritis Rheum 21:137-144, 1978. 38. Wen FQ, Jabbar AA, Chen YX, et al: c-myc protooncogene expression in hemophilic synovitis: In vitro studies of the effects of iron and ceramide. Blood 100:912-916, 2002. 39. Hakobyan N, Kazarian T, Jabbar AA, et al: Pathobiology of hemophilic synovitis I: Overexpression of mdm2 oncogene. Blood 104:2060-2064, 2004. 40. Berntorp E, Michiels J: A healthy hemophilic patient without arthropathy: From concept to clinical reality. Semin Thromb Hemost 29:5-10, 2003. 41. Hilgartner MW: Current treatment of hemophilic arthropathy. Curr Opin Pediatr 14:46-49, 2002. 42. Nilsson IM, Berntorp E, Lofqvist T, et al: Twenty-five years’ experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 232:25-32, 1992. 43. Astermark J, Petrini P, Tengborn L, et al: Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized. Br J Haematol 105:1109-1113, 1999. 44. Fischer K, van der Bom J, Mauser-Bunschoten EP, et al: The effects of postponing prophylactic treatment on long-term outcome in patients with severe hemophilia. Blood 99:2337-2341, 2002. 45. Varon D, Martinowitz U: Continuous infusion therapy in hemophilia. Haemophilia 4:431-435, 1998.

46. White GC, MacMillan CW, Kingdon HS, et al: Use of recombinant hemophilic factor in the treatment of two patients with classic ­hemophilia. N Engl J Med 320:166-170, 1989. 47. Schwartz RS, Agilgaard CF, Aledort LM, et al: Human recombinant DNA derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. N Engl J Med 323:1800-1805, 1990. 48. Mannucci PM, Ruggeri ZM, Pareti FI, et al: DDAVP in haemophilia. Lancet 2:1171-1172, 1977. 49. Young G: New approaches in the management of inhibitor patients. Acta Haematol 115:172-179, 2006. 50. Mathias M, Khair K, Hann I, et al: Rituximab in the treatment of alloimmune factor VIII and IX antibodies in two children with severe haemophilia. Br J Haematol 125:366-368, 2004. 51. Warrier I: Factor IX antibody and immune tolerance. Vox Sang 77(Suppl 1):70-71, 1999. 52. Ewenstein B, Takemoto C, Warrier I, et al: Nephrotic syndrome as a complication of immune tolerance in hemophilia B. Blood 89: 1115-1116, 1997 (letter). 53. Levine PH: The acquired immune deficiency syndrome in persons with hemophilia. Ann Intern Med 103:723-726, 1985. 54. Brettler DB, Alter, Dienstag JL, et al: Prevalence of hepatitits C virus antibody in a cohort of hemophilia patients. Blood 76:254-256, 1990. 55. Miser AW, Miser JS, Newton WA: Intensive factor replacement for management of chronic synovitis in hemophilic children. Am J Pediatr Hematol Oncol 8:66-69, 1986. 56. Buzzard BM: Physiotherapy for prevention and treatment of chronic hemophilic synovitis. Clin Orthop 343:42-46, 1997. 57. Schumacher P: Discussion paper: Orthotic management in hemophilia. Ann N Y Acad Sci 240:344, 1975. 58. Atkins RM, Henderson NJ, Duthie RB: Joint contractures in the hemophilias. Clin Orthop 219:97-106, 1987. 59. Fernandez-Palazzi F, Caviglia HA, Salazar JR, et al: Intraarticular dexamethasone in advanced chronic synovitis in hemophilia. Clin Orthop 343:25-29, 1997. 60. Thomas P, Hepburn B, Kim HC, et al: Non-steroidal anti-­inflammatory drugs in the treatment of haemophilic arthropathy. Am J Hematol 12:131-137, 1982. 61. Inwood MJ, Killackey B, Startup SJ: The use and safety of ibuprofen in the haemophiliac. Blood 61:709-711, 1983. 62. Montane I, McCollough NC, Lian EC-Y: Synovectomy of the knee for hemophilic arthropathy. J Bone Joint Surg Am 68:210-216, 1986. 63. Post M, Watts G, Telfer M: Synovectomy in hemophilic arthropathy: A retrospective review of 17 cases. Clin Orthop 202:139-146, 1986. 64. Weidel JD: Arthroscopic synovectomy for chronic hemophilic synovitis of the knee. Arthroscopy 1:205-209, 1985. 65. Weidel JD: Arthroscopic synovectomy of the knee in hemophilia: 10- to 15-year follow-up. Clin Orthop 328:46-53, 1996. 66. Klein KS, Aland CM, Kin HC, et al: Long-term follow-up of arthroscopic synovectomy for chronic hemophilic synovitis. Arthroscopy 3:231-236, 1987. 67. Limbird TJ, Dennis SC: Synovectomy and continuous passive motion (CPM) in hemophiliac patients. Arthroscopy 3:74-79, 1987. 68. Heim M: The treatment of intra-articular synovitis by the use of chemical and radioactive substances. Haemophilia 8:369-371, 2002. 69. Schneider P, Farahati J, Reiners C: Radiosynovectomy in rheu­ matology, orthopedics and hemophilia. J Nucl Med 46(Suppl 1): 48S-54S, 2005. 70. Siegel HJ, Luck JV. Jr, Siegel ME, et al: Phosphate-32 colloid radiosynovectomy in hemophilia: Outcome in 125 patients. Clin Orthop 392:409-417, 2001. 71. Birch NC, Ribbans WJ, Goldman E, et al: Knee replacement in haemophilia. J Bone Joint Surg Br 76:165-166, 1994. 72. Kelley SS, Lachiewicz PF, Gilbert MS, et al: Hip arthroplasty in hemophilic arthropathy. J Bone Joint Surg Am 77:828-834, 1995. 73. Thomason HC, Wilson FC, Lachiewicz PF, et al: Knee arthroplasty in hemophilic arthropathy. Clin Orthop 360:169-173, 1999. 74. Norian JM, Ries MD, Karp S, et al: Total knee arthroplasty in hemophilic arthopathy. J Bone Joint Surg Am 84:1138-1141, 2002. 75. Rodriguez-Merchan EC, Wiedel JD, Wallny T, et al: Elective orthopedic procedures for hemophilia patients with inhibitors. Semin Hematol 41(Suppl 1):109-116, 2004.

PART 18  76. Ingerslev J, Hvid I: Surgery in hemophilia: The general view: Patient selection, timing, and preoperative assessment. Semin Hematol 43(Suppl 1):S23-S26, 2006. 77. Rodriguez-Merchan EC: Orthopedic surgery of haemophilia in the 21st century: An overview. Haemophilia 8:360-368, 2002.

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78. Lozier J: Gene therapy of the hemophilias. Semin Hematol 41: 287-296, 2004. 79. Gan SU, Kon OL, Calne RY: Genetic engineering for haemophilia A. Exp Opin Biol Ther 6:1023-1030, 2006.

110

Rheumatic Manifestations of Hemoglobinopathies Kenneth C. kalunian  •  bob sun

KEY POINTS Rheumatic manifestations are common in various ­hemoglobinopathies owing to the profound intravascular effects of these diseases. Sickle cell disease is associated with arthritis, dactylitis, ­osteomyelitis, septic arthritis, avascular necrosis (AVN), ­hyperuricemia, and gout. Recent studies using magnetic resonance imaging suggest that the prevalence of AVN in sickle cell disease is more than 40%. Prevalence rates of hyperuricemia in sickle cell disease ­approach 50%, but gout is rare. Because of functional asplenia, abnormal opsonization and complement function, and poor antibody responses to polysaccharide components of bacterial capsules, patients with sickle cell disease are predisposed to osteomyelitis with encapsulated organisms. Precipitation of α-globin chains occurs in the thalassemias, accounting for a variety of bone and joint problems.

Because the maintenance and survival of bone and joint structures are dependent on the proper circulation of blood, rheumatic manifestations are common in various hemoglobinopathies such as sickle cell disease and thalassemias, diseases that have profound intravascular effects. Common bone and joint complications from sickle cell disease include an associated arthritis, dactylitis, osteomyelitis, septic arthritis, avascular necrosis (AVN), hyperuricemia, and gout. In thalassemias, precipitation of α-globin chains occurs, and a variety of clinical manifestations, including bone and joint problems, can arise. Treatment for iron overload, which is common in ß-thalassemia, can also lead to arthropathy.

CAUSE Sickle cell diseases are an inherited group of disorders that cause production of abnormal hemoglobin. The most widely recognized disorder is sickle cell anemia (HbSS). Other hemoglobinopathies that are common variants of this ­ disease include sickle cell trait (HbSA), sickle cell– ­hemoglobin C disease (HbSC), and sickle cell–α thalassemia (HbS-αThal). HbSS is a result of the substitution of a valine for glutamic acid as the sixth amino acid of the β-globin chain, which produces a hemoglobin tetramer that is poorly soluble when deoxygenated.1 HbSC is less common and is caused by the substitution of lysine for ­ glutamine acid in

the β-globin chains. Sickling of erythrocytes in small vessels is thought to be responsible for the painful vaso-occlusive ­crises, with important interactions between erythrocytes and vascular endothelium. Hemolysis and pain caused by vaso-occlusive crises are clinical hallmarks of this disease.2 Complications from sickle cell disease can range from pulmonary disorders such as acute chest syndrome to rare hematologic disorders such as hemophagocytic syndrome. Acute chest syndrome is thought to arise from vasoconstriction, which eventually results in chest pain, a new infiltrate on chest radiographs, and fever, usually without ­bacteremia.2 It is the most frequently reported cause of death in adults with sickle cell disease. There has been one case report of a patient with sickle cell disease who developed thrombocytopenia, microcytic anemia, elevated ­ ferritin, and ­hemophagocytic syndrome on biopsy.3 Complex interactions of sickled cells with endothelium can induce red cell binding to the endothelial cell–receptor complex of glycoproteins Ib, Ix, and V; endothelial CD36; and ­vascular cell adhesion molecule-1 (VCAM-1), providing potential ­targets for therapy.4 Repeated vaso-occlusive crises are thought to significantly contribute to some of these manifestations through decreased blood flow, which can lead to impaired nourishment of critical structures such as the femoral head and vertebral bodies (Fig. 110-1).5 ß-Thalassemia is a result of the impaired production of ß-globin chains, which leads to a relative excess of α-globin chains.6 The degree of impaired ß-globin production leads to various phenotypes of this disease, including ß-thalassemia major, intermedia, and minor. Among the clinical features of patients with ß-thalassemia are hemolytic anemia, which is usually severe and often causes transfusion dependence in homozygotes; splenomegaly; and hyperplastic bone marrow, with changes apparent on skeletal radiographs. These excess α-globin chains are unstable and incapable of ­forming ­soluble tetramers on their own.7

EPIDEMIOLOGY Prevalence studies of the various rheumatic manifestations of the hemoglobinopathies are generally limited to reports from small case series. Arthritis associated with HbSS has been studied in a prospective series of 70 patients followed over a 6- to 18-month period; 32 patients developed arthritis that affected primarily the knees and, less commonly, the elbows, hands, and lumbar and sacral spine.8 In another series, it appeared that by 2 years of age, as many as 45% of all children with HbSS developed dactylitis.9 The prevalence of osteomyelitis was 12% in a French study of a cohort of 299 patients.10 The estimated risk of Salmonella osteomyelitis in HbSS patients appears to be 100 times greater than 1827

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Figure 110-2  Shortened metacarpal in an adult with hemoglobin SC disease. Longitudinal growth of the fourth metacarpal was arrested in childhood as a result of infarction of the growth plate and subsequent premature epiphyseal fusion. (Courtesy of Richard H. Gold, MD.)

Figure 110-1  Cuplike indentation of vertebral bodies in a radiograph of a patient with sickle cell disease.

in the normal population.11 In some case series, Staphylococcus aureus is the most common pathogen responsible for HbSS-related osteomyelitis.12 AVN of the femoral head is found in individuals of all ages, including children as young as 5 years.13 The true prevalence of AVN is difficult to estimate because of the lack of sensitive methods for detection. In a study of 2590 patients with HbSS, plain radiographic evidence of AVN of the femoral head was found in 9.8% of patients.13 In contrast, recent studies using magnetic resonance imaging (MRI) found that the prevalence of AVN was as high as 41% in adults with HbSS.14 Among adults with HbSS, the prevalence of hyperuricemia appears to be about 50%15; however, gout rarely occurs. Arthritis has been described in patients with ß-thalassemia major. In one case series, 24 of 50 patients from 5 to 23 years of age had ankle joint pain.16 Up to 52% of patients with ß-thalassemia minor had arthralgias in one case series.17 In studies of ß-thalassemia patients from the United Kingdom and India treated with deferiprone, the frequency of arthralgias was 33% and 38%, respectively.18

PATHOGENESIS The pathogenesis of some hemoglobinopathy-related rheumatic manifestations is a direct result of the vaso-­occlusion caused by the sickling of red blood cells. Hand-foot syndrome, also known as dactylitis, results from repeated vasoocclusive crises involving the small bones of the hands and

feet; it classically presents at about 6 months of age, when ­hemoglobin S reaches pathologic levels.19 AVN in HbSS occurs when vaso-occlusion results in infarction of the articular surfaces and heads of the long bones (Fig. 110-2).20 Progressive occlusion of the microcirculation within the femoral head leads to increased intraosseous pressure and subsequent cell death.21 Patients with HbSS have functional asplenia, abnormal opsonization and complement function, and poor antibody responses to the polysaccharide components of bacterial capsules.22 As a result, these patients are predisposed to osteomyelitis with encapsulated organisms such as Salmonella and S. aureus.23 Hyperuricemia and uric acid overproduction are often present and are thought to be due to the high turnover in red blood cells associated with HbSS. The pathogeneses of the arthritis associated with HbSS and thalassemias are unknown, as is the pathogenesis of deferiprone-associated arthralgias.

CLINICAL FEATURES Episodes of sickle cell crisis are the most common type of vaso-occlusive event. Acute pain is the first symptom of disease in more than 25% of patients and is the most frequent symptom after the age of 2 years.2 The episodes can affect any area of the body, with the back, chest, abdomen, and extremities being most commonly affected. Arthritis associated with HbSS involves primarily the knees but can also involve elbows, hands, and the lumbar and sacral spine.8 Episodes of arthritis correlate temporally with episodes of sickle cell crisis. In one series of 70 patients with HbSS, 32 had arthritis that was thought to be associated with hemoglobinopathy.8 Of these 32 patients, 13 had synovial fluid studies performed; 8 patients had fluid of an inflammatory type, and 5 five had noninflammatory fluid. The synovial white cell count varied from 600 to 270,000 cells/mm3. None of the patients had synovial evidence of

PART 18 

crystals or infection. Most patients had recurrent episodes of arthritis that were transient in nature, with each episode lasting an average of 5 days. However, chronic synovitis with destruction of hyaline articular cartilage has been reported in two patients with sickle cell anemia.24 Patients with dactylitis typically experience an acute onset of symmetric swelling of the hands and feet, with mild erythema and a low-grade fever (Fig. 110-3) . In addition, severe anemia and leukocytosis may be present. Radiographic changes are seen an average of 10 days after the onset of symptoms; these consist of subperiosteal new bone formation in the hands and feet. Cortical thinning, ­multiple ­irregular intramedullary deposits, and areas of spotty destruction and formation of periosteal new bone may be seen later.25 These changes can lead to a “moth-eaten” appearance.25 In osteomyelitis, many sites can be involved, and the process can be symmetric. The diaphysis is most commonly affected, with occasional epiphyseal involvement and progression to pyarthrosis.26 Clinically, patients present with persistently high fever, leukocytosis, and severe local pain in the affected bones. Seeding of the bone is usually hematogenous, although infection occasionally spreads locally from a septic joint. AVN typically affects the femoral heads and, less commonly, the heads of the humeri, knees, and small joints of the hands and feet. Pain and limited motion of the affected joint are usually the first symptoms noted. Pain is constant and increases with weight bearing on the limb when the lower extremities are involved. Gouty attacks in patients with HbSS, though very rare despite the high frequency of hyperuricemia, are similar to attacks in patients with primary gout. Patients with HbSS are generally younger than patients with primary gout, and urate clearance is greater in younger individuals; this may account for the low frequency of secondary gout in HbSS.27 There are descriptions of patients with ß-thalassemia major developing arthritis. One case series reported that 24 of 50 patients from 5 to 23 years of age had ankle joint pain.16 Two of these patients had effusions that were not inflammatory. Radiographic changes included marked ­ reduction

Figure 110-3  Diffusely swollen hands are seen in the hand-foot ­syndrome of young children with sickle cell disease.

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in trabecular and cortical bone, consistent with severe ­osteoporosis, and the presence of microfractures.16 Sporadic case reports and series have described the arthropathy of ß-thalassemia minor as an oligoarticular or monarticular process. Gerster and colleagues28 reported that over a 10-year period, 4 of 32 patients developed acute-onset oligoarticular pain that lasted 2 to 10 days and occurred approximately 2 to 10 times per year. The erythrocyte sedimentation rate was consistently low in all these patients, and joint effusions were found in two of the four patients. Dorwart and ­Schumacher29 reported a case of a woman with ß-­thalassemia and persistent nonerosive seronegative knee arthritis; synovial fluid analyses in this patient revealed that the fluid was noninflammatory. Regular blood transfusions are often required for ß-thalassemia; these transfusions often lead to iron overload that requires subsequent treatment with deferiprone to chelate iron and prevent iron-related visceral and cardiac toxicity.30 A common side effect of deferiprone therapy is arthropathy of the knees. One case series of ß-thalassemia patients treated with deferiprone found that 3 of 16 patients developed bilateral knee pain on exertion, morning stiffness, and joint warmth and swelling.31 In studies of ß-thalassemia patients treated with deferiprone in the United Kingdom and India, the frequency of arthralgias was 33% and 38%, respectively.18 Radiography of affected joints revealed joint effusion, subchondral bone irregularity, and patellar beaks. MRI revealed thickening and enhancement of the synovium and irregularly thickened epiphyseal and articular cartilage overlying subchondral bone defects.18

DIAGNOSIS AND DIAGNOSTIC TESTS The histopathology of sickle cell arthropathy has been ­evaluated using needle synovial biopsies in patients with HbSS-related joint disease.32 Focal intimal lining cell proliferation and scattered chronic inflammatory cells were ­identified in most patients. Small vessel congestion, ­evidence of microvascular thrombosis, and electron microscopic confirmation of occluded vessels was also observed, suggesting that red cells can sickle in the hypoxic ­environment of the joint. When considering the diagnosis of a rheumatic manifestation related to hemoglobinopathies, a high index of suspicion for infection is essential. For example, dactylitis and other types of painful vaso-occlusive crises are ­difficult to distinguish from osteomyelitis. Recent studies have attempted to address the difficulty of distinguishing these entities, focusing on newer imaging modalities. In one study that retrospectively assessed the use of sequential radionuclide bone marrow and bone scans, bone ­ infarction during a vaso-occlusive crisis appeared to be associated with reduced activity of radionuclide on bone marrow scans and ­corresponding abnormal activity on bone scans.33 In contrast, acute osteomyelitis resulted in normal activity on bone marrow scans and abnormal activity on bone scans.33 MRI can also be useful for the diagnosis of acute osteomyelitis. A small study demonstrated that contrast-enhanced MRI might allow one to differentiate between acute infarction and osteomyelitis.34 Despite advances in imaging modalities, sensitivity and specificity can be limited, and a

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definitive diagnosis of osteomyelitis still depends on clinical assessment combined with positive cultures from blood or bone obtained by aspiration or biopsy. The diagnosis of AVN is obtained through clinical assessment combined with typical radiographic findings. ­Initially, radiographs demonstrate local sclerosis near the joint margin. Patchy lucencies then develop and may include a lucency between sclerotic and intact bone. Flattening, separation of the necrotic fragment, and secondary osteoarthritis may be seen later. MRI can detect AVN earlier than plain radiographs and can potentially distinguish it from other causes of acute pain, such as osteomyelitis. The diagnosis of gout in the setting of hemoglobinopathies is similar to that of idiopathic gout. There are no specific diagnostic tests for arthritis associated with HbSS, ßthalassemia–related arthritis, or deferiprone-related arth­ ropathy; these diagnoses should be considered when other causes of arthritis, such as septic arthritis, have been excluded.

TREATMENT For most patients with transient arthritis associated with HbSS crises, treatment usually involves analgesics and hydration. Intra-articular corticosteroids are not useful. There are no data on treatment strategies to prevent or treat chronic synovitis associated with HbSS. Transfusion therapy can improve the oxygen carrying capacity during aplastic or splenic sequestration crisis and can provide protection during acute chest syndrome, but it has not been helpful in treating arthritis associated with HbSS crises. It can, however, decrease the frequency of painful crises. Treatment of dactylitis typically consists of hydration and analgesic and anti-inflammatory medications. Recurrent episodes may warrant the use of hydroxyurea. Antibiotics directed toward the involved pathogen are the optimal treatment for osteomyelitis. Salmonella infections respond well to antibiotics, and surgical drainage is generally not required. The treatment of hemoglobinopathy-related gout is the same as the treatment of primary gout. There are no proven treatment approaches for AVN; conservative methods, such as avoidance of weight bearing with crutches and bed rest, have been used; however, these approaches have a drastic impact on quality of life, and their success rates are low.35 Core decompression is a common procedure used to treat early stages of AVN; however, failure rates in some studies of HbSS-related AVN are as high as 50% at 5 years.36 Joint replacement is usually required in later stages of AVN. Evidence of effective treatment strategies for ß-thalassemia–related arthritis is scarce. Nonsteroidal anti-inflammatory drugs and intra-articular corticosteroids appear to be ineffective.28,29 Arthropathy from deferiprone therapy is usually self-limited; however, if the arthropathy persists, a few case series have reported some success with intra­articular corticosteroid injections.

PROGNOSIS The prognosis of the various rheumatic manifestations of hemoglobinopathies has not been well defined. However, studies have attempted to identify predictors of adverse outcomes in patients with HbSS. The presence of ­dactylitis

in a patient with HbSS may suggest a poorer outcome. In an observational study of children with HbSS, dactylitis along with a hemoglobin of less than 7 g/dL and leukocytosis correlated significantly with adverse outcomes later in childhood.37 Another longitudinal study demonstrated that children diagnosed with dactylitis before the age of 6 months are more likely to have severe events later in life, such as cerebrovascular accident and acute chest syndrome (defined as the presence of a new pulmonary infiltrate, a defect on radionuclide imaging of the chest, or both, in association with an acute respiratory tract illness).38 Surgical treatment of AVN in HbSS patients can lead to a higher incidence of perioperative complications such as excessive blood loss, acute chest syndrome, and prosthesis failure.39 REFERENCES   1. Bunn HF: Pathogenesis and treatment of sickle cell disease. N Engl J Med 11:762-769, 1997.   2. Bainbridge R, Higgs DR, Maude GH, et al: Clinical presentation of homozygous sickle cell disease. J Pediatr 106:881-885, 1985.   3. Kio E, Onitilo A, Lazarchick J, et al: Sickle cell crisis associated with hemophagocytic lymphohistiocytosis. Am J Hematol 77:229-232, 2004.   4. Hebbel RP: Blockade of adhesion of sickle cells to endothelium by monoclonal antibodies. N Engl J Med 342:1911, 2000.   5. Smith JA: Bone disorders in sickle cell disease. Hematol Oncol Clin North Am 10:1345-1356, 1996.   6. Adams JG, Coleman MB: Structural hemoglobin variants that produce the phenotype of thalassemia. Semin Hematol 27:229-238, 1990.   7. Rund D, Rachmilewitz E: ß-Thalassemia. N Engl J Med 353: 1135-1146, 2005.   8. Espinoza LR, Spilberg I, Osterland CK, et al: Joint manifestations of sickle cell disease. Medicine 53:295-305, 1971.   9. Stevens MC, Padwick M, Serjeant GR: Observations on the natural history of dactylitis in homozygous sickle cell disease. Clin Pediatr 20:311-317, 1981. 10. Neonato MG, Guilloud-Bataille M, Beauvais P, et al: Acute clinical events in 299 homozygous sickle cell patients living in France. French Study Group on Sickle Cell Disease. Eur J Haematol 65:155-164, 2000. 11. Chambers JB, Forsythe DA, Bertrand SL, et al: Retrospective review of osteoarticular infections in a pediatric sickle cell age group. J Pediatr Orthop 20:682-685, 2000. 12. Okorama EO, Agbo DC: Childhood osteomyelitis. Clin Pediatr 23:411-413, 1984. 13. Milner PF, Kraus AP, Sebeds JI, et al: Sickle cell disease as a cause of osteonecrosis of the femoral head. N Engl J Med 21:1476-1481, 1991. 14. Cordner S, De Ceulaer K: Musculoskeletal manifestations of hemoglobinopathies. Curr Opin Rheumatol 15:44-47, 2003. 15. Reynolds MD: Gout and hyperuricemia associated with sickle cell anemia. Semin Arthritis Rheum 12:404-413, 1983. 16. Gratwick GM, Bullough PG, Bohne WH, et al: Thalassemic osteoarthropathy. Ann Intern Med 88:494-501, 1978. 17. Arman MI, Butun B, Doseyen A, et al: Frequency and features of rheumatic findings in thalassemia minor: A blind controlled study. Br J Rheumatol 31:197, 1992. 18. Kellenberger CJ, Schmugge M, Saurenmann T: Radiographic and MRI features of deferiprone-related arthropathy of the knees in patients with ß-thalassemia. Am J Radiol 183:989-994, 2004. 19. Gill FM, Sleeper LA, Weiner SJ, et al: Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease. Blood 86:776-783, 1995. 20. Mukisi-Mukaza M, Elbaz A, Samuel-Leborgne Y, et al: Prevalence, clinical features, and risk factors of osteonecrosis of the femoral head among adults with sickle cell disease. Orthopedics 23:357-363, 2000. 21. Hawker H, Neilson H, Hayes RJ, et al: Haematological factors associated with avascular necrosis of the femoral head in homozygous sickle cell disease. Br J Haematol 50:29-34, 1982. 22. Aguilar C, Vichinsky E, Neumayr L: Bone and joint disease in sickle cell disease. Hematol Oncol Clin North Am 19:929-941, 2005.

PART 18  23. Burnett MW, Bass JW, Cook BA: Etiology of osteomyelitis complicating sickle cell disease. Pediatrics 101:296-297, 1998. 24. Schumacher HR, Dorwart BB, Bond J, et al: Chronic synovitis with early cartilage destruction in sickle cell disease. Ann Rheum Dis 36:413-419, 1977. 25. Babhulkar SS, Pande K, Babhulkar B: The hand-foot syndrome in sickle-cell haemoglobinopathy. J Bone Joint Surg 77:310-312, 1995. 26. Anand AJ, Glatt AI: Salmonella osteomyelitis and arthritis in sickle cell disease. Semin Arthritis Rheum 24:211-221, 1994. 27. Diamond HS, Meisel A, Sharon E, et al: Hyperuricosuria and increased tubular secretion of urate in sickle cell anemia. Am J Med 59:796-802, 1975. 28. Gerster JC, Dardel R, Guggi S: Recurrent episodes of arthritis in thalassemia minor. J Rheumatol 11:352-354, 1984. 29. Dorwart BB, Schumacher HR: Arthritis in β thalassaemia trait: Clinical and pathological features. Ann Rheum Dis 40:185-189, 1981. 30. Kontoghiorghes GJ, Pattichi K, Hadjigavriel M, et al: Transfusional iron overload and chelation therapy with deferoxamine and deferiprone (L1). Transfus Sci 23:211-223, 2000. 31. Berkovitch M, Laxer RM, Inman R, et al: Arthropathy in thalassaemia patients receiving deferiprone. Lancet 343:1471-1472, 1994. 32. Schumacher HR, Andrews R: McLaughin G: Arthropathy in sickle cell disease. Ann Intern Med 78:203, 1973.

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33. Skaggs DL, Kim SK, Greene NW, et al: Differentiation between bone infarction and acute osteomyelitis in children with sickle-cell disease with use of sequential radionuclide bone-marrow and bone scans. J Bone Joint Surg 83:1810-1813, 2001. 34. Umans H, Haramati N, Flusser G: The diagnostic role of gadolinium enhanced MRI in distinguishing between acute medullary bone infarct and osteomyelitis. Magn Reson Imaging 18:255-262, 2000. 35. Garino JP, Steinberg ME: Total hip arthroplasty in patients with avascular necrosis of the femoral head: A 2- to 10-year follow-up. Clin Orthop Relat Res 334:108-115, 1997. 36. Bishop AR, Roberson JR, Eckman JR, et al: Total hip arthroplasty in patients who have sickle-cell hemoglobinopathy. J Bone Joint Surg 70:853-855, 1988. 37. Miller ST, Sleeper LA, Pegelow CH, et al: Prediction of adverse outcomes in children with sickle cell disease. N Engl J Med 342:8389, 2000. 38. Foucan L, Ekouevi D, Etienne-Julan M, et al: Early onset dactylitis associated with the occurrence of severe events in children with sickle cell anaemia. The Paediatric Cohort of Guadeloupe. Paediatr Perinat Epidemiol 20:59-66, 2006. 39. Vichinsky EP, Neumayr LD, Haberkern C, et al: The perioperative complication rate of orthopedic surgery in sickle cell disease: Report of the National Sickle Cell Surgery Study Group. Am J Hematol 62: 129-138, 1999.

111

Arthritis Accompanying Endocrine and Metabolic Disorders JOHN S. SERGENT

Key Points The diabetic stiff hand syndrome (cheirarthropathy) is related to both the duration of disease and the degree of ­hyperglycemia. It is predictive of other end-organ ­complications of diabetes. Other important complications of diabetes affecting the musculoskeletal system include frozen shoulder, Charcot joints, especially in the feet, Dupuytren’s contractures, ­trigger fingers, and diabetic amyotrophy, also known as diabetic muscle infarction. Patients with mild primary hyperparathyroidism may present with fractures due to osteoporosis as their initial symptom, and patients with unexplained osteoporosis should also be screened for hyperparathyroidism. Renal osteodystrophy is largely a complication of secondary hyperparathyroidism due to phosphate retention, among other factors. Proximal weakness, which can be profound and intermittent, is commonplace in hyperthyroidism from any cause, and patients with unexplained weakness should also be screened for hyperthyroidism. Hyperthyroidism can cause myopathy as well, and may be ­associated with elevated creatine kinase levels, but the ­degree of weakness is usually mild to moderate. Hypothyroid arthropathy is associated with viscous joint ­effusion, usually in joints previously affected by osteoarthritis. It resolves quickly with correction of the hypothyroidism. Carpal tunnel syndrome can be the first symptom of several endocrine disorders, including diabetes mellitus, acromegaly, and hypothyroidism. Complications of exogenous corticosteroid therapy include osteoporosis, avascular necrosis, and steroid myopathy. Untreated acromegaly is virtually always associated with severe osteoarthritis and degenerative disk disease.

A rheumatologist or primary care physician must always be cognizant of the many ways that systemic diseases affect muscles and joints. These may be manifest in numerous ways, as follows: 1. A primary endocrine or metabolic disorder may occur with important musculoskeletal problems (e.g., proximal muscle weakness in Cushing’s syndrome, carpal tunnel syndrome in diabetes mellitus, and ­acromegaly). 2. A patient with long-standing endocrine or metabolic disease may develop musculoskeletal complications (e.g., diabetic stiff-hand syndrome).

3. A patient with a well-established rheumatic disease may develop an endocrine disorder (e.g., hypothyroidism in scleroderma). 4. An endocrine or metabolic disorder may develop as a result of therapy for a rheumatic disease (e.g., iatrogenic Cushing’s syndrome). Many of these disorders can be subtle when occurring in previously normal individuals. When they occur in association with preexisting rheumatic disease, or when their manifestations are atypical, considerable skill is often necessary to establish the diagnosis.

DIABETES MELLITUS Diabetes mellitus is associated with a wide variety of complications involving joints. In many of these complications, there is a direct cause; in others, there is a reported epidemiologic association, although the actual cause-and-effect relationship is unproven (Table 111-1). The hand is an important target for diabetic complications. The diabetic stiff-hand syndrome, also known as diabetic cheirarthropathy and the limited joint-mobility syndrome, is a common complication of type 1 and type 2 diabetes mellitus (Fig. 111-1).1 The condition is believed to be due to excessive glycosylation of collagen in the skin, blood vessels, and periarticular structures2 and to decreased collagen degeneration and removal,3 resulting in thick, inelastic tissues. In its advanced stages, the fingers remain permanently contracted at the metacarpophalangeal and proximal interphalangeal joints, and the thick, shiny skin may resemble that of scleroderma.4 This complication, usually only bothersome and not disabling, increases in association with the duration of the disease.5 As might be expected, it is predictive of renal, retinal, and other diabetic complications6,7 and occurs in 30% of patients with long-standing diabetes.8 Therapy with aldose reductase inhibitors has been reported to be beneficial for the stiff-hand syndrome9 and has improved nerve conduction in diabetic neuropathy,10 but further use has been limited by side effects. Dupuytren’s contractures may be seen in patients with diabetic stiff-hand syndrome, or they may occur independently. It is thought that the pathogenesis is similar to stiffhand syndrome, with glycosylation and increased collagen deposition playing a role. In contrast to most cases of stiffhand syndrome, Dupuytren’s contractures may be seen early in the course of the disease. The prevalence of Dupuytren’s contractures in adult diabetics is about 30%.8 Trigger fingers, a catching and snapping of the fingers, occasionally painful, also is frequent in diabetic patients. This complication is due to flexor tenosynovitis and believed to have the same pathogenesis as stiff-hand syndrome.11 1833

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Table 111-1  Joint Complications of Diabetes   Mellitus Manifestation

Typical Joint Involved

Diabetic stiff-hand syndrome

Metacarpophalangeal, proximal interphalangeal joints

Dupuytren’s contractures

Fourth (and other) flexion tendons

Trigger fingers

Flexor tendons

Adhesive capsulitis

Shoulders

Reflex sympathetic dystrophy

Shoulders, hands

Carpal tunnel syndrome

First 4 fingers

Charcot’s arthropathy

Foot, ankle

Diffuse idiopathic skeletal ­hyperostosis

Spine

Osteomyelitis

Foot

Diabetic angiotrophy

Shoulder, back, thighs

Adhesive capsulitis of the shoulders, with or without calcific tendinitis, is well established as a complication of diabetes.12,13 It can be associated with reflex sympathetic dystrophy.14 Although sometimes associated with recurrent painful tendinitis and bursitis, the loss of motion can be painless and insidious. Carpal tunnel syndrome occurs in about 25% of individuals with diabetes mellitus8 and can be subtle, especially in patients with preexisting peripheral neuropathy. Because nocturnal paresthesias are common in both, the clinician must be alert to the possibility of carpal tunnel syndrome to intervene early in disease to prevent thenar muscle ­atrophy. Charcot’s arthropathy in diabetes usually involves the ankle or midfoot and invariably occurs in individuals with sensory neuropathy.15 The onset can be sudden,16 occasionally in association with minor trauma. The abrupt onset, with swelling and radiographs showing the bone fragments and disorganization, can lead an unwary clinician on an unnecessary search for infection. As with Charcot joints of other causes, treatment is generally unsatisfactory, with little more to offer than splinting and bracing. Diffuse idiopathic skeletal hyperostosis (see Chapter 93) is associated with diabetes, although it is unclear whether the relationship is to diabetes per se, relative insulin resistance, or other factors that make up the metabolic syndrome. This complication is seen most prominently in obese patients with type 2 diabetes. It also has been seen in nondiabetic individuals with abnormal insulin responses to hyperglycemia.17 It is manifest by proliferative new bone formation at joint margins, particularly in the axial skeleton. Clinically, patients may have diminished mobility similar to that seen in ankylosing spondylitis. There is no evidence to date that diabetic control improves the condition or delays diffuse idiopathic skeletal hyperostosis, although no careful studies have yet been done to evaluate the relationship. The pathophysiologic mechanism of the condition also has not yet been elucidated, although it may be related more to hyperlipidemia and other metabolic factors than to diabetes itself.18,19 Osteomyelitis in the foot is a major problem in long­standing diabetics. Because of the peripheral sensory

Figure 111-1  The prayer sign in the diabetic stiff-hand syndrome. As a result of progressive thickening of tendons, joint capsules, and subcutaneous tissues, progressive stiffness and flexion contractures develop in these patients.

neu­ropathy, foot injuries and pressure ulcers tend to be under­ appreciated, and patients may not realize anything is seriously wrong until advanced osteomyelitis has developed. In addition, subcutaneous foreign bodies, such as needles and splinters, can be present for weeks or months before a diabetic patient is aware of them. There is good evidence that infections and other complications of these problems can be markedly diminished by meticulous foot care.20,21 Diabetic amyotrophy, also known as diabetic muscle infarction, is a rare condition associated with the abrupt onset of pain and rapid atrophy in large muscle groups, usually the thighs, the perispinous muscles, and the shoulder girdle.22,23 Fasciculations are often prominent, and electromyography reveals a neuropathic picture. Severe pain is the most frequent complaint, although profound weakness of the affected muscles also is a problem. This problem slowly resolves in most cases.

PARATHYROID DISORDERS Hyperparathyroidism has major effects on the skeleton, the most important of which is osteopenia (see Chapter 92). The most important joint manifestation of primary hyperparathyroidism is chondrocalcinosis with associated calcium pyrophosphate dihydrate deposition disease (see Chapter 88).24 Although the most common arthritic manifestation is acute pseudogout, the entire spectrum of arthropathies associated with calcium pyrophosphate dihydrate may be seen in this disorder, including a crippling and slowly progressive polyarthritis.25 Most patients with long-standing ­ hyperparathyroidism have proximal muscle weakness, a condition rapidly reversed by removal of the parathyroid adenoma.26,27 In these patients, the muscle enzymes are normal, and ­ electromyography

PART 18 

and muscle biopsy show a picture most consistent with denervation. Patients with secondary hyperparathyroidism associated with advanced renal disease have numerous abnormalities in the bones and joints. The changes of renal osteodystrophy resulting from secondary hyperparathyroidism include an erosive arthritis in the hands,28 resorption of the distal clavicle,29 and erosions in the axial skeleton.30 In children, the widespread bone deformities of osteitis fibrosa cystica can be crippling.31 Other musculoskeletal manifestations of advanced renal failure include aluminum-induced osteomalacia32 and β2-microglobulin amyloidosis (see Chapter 92). Hypoparathyroidism, usually secondary to ­ surgical rem­oval of the parathyroid glands, most commonly causes ­ proximal muscle weakness related to the degree of ­hypocalcemia. This condition responds dramatically to treatment with vitamin D and calcium. Idiopathic hypoparathyroidism is a rare disorder, usually seen as part of the DiGeorge syndrome with thymic hypoplasia. Pseudohypoparathyroidism, known as Albright’s hereditary osteodystrophy, is due to end-organ resistance to the effect of parathyroid hormone. These patients have persistent hypocalcemia and hyperphosphatemia, but parathyroid hormone levels are consistently elevated. Type Ia pseudohypoparathyroidism, which is autosomal dominant, is associated with short stature, calcification of the perispinal ligaments, and, usually, mental retardation. Most patients have an impressive shortening of the fourth metacarpal and metatarsal bones that can be seen by having the patient clench the fist. Instead of the usual knuckle appearance over the fourth metacarpal head, these individuals have a dimple. Patients with type Ib pseudohypoparathyroidism also have resistance to parathyroid hormone, but have normal phenotype. Patients with pseudohypoparathyroidism have a defect in the genes encoding the alpha subunit of the cell ­membrane– associated guanine nucleotide stimulating unit of adenyl cyclase.33 Type Ia pseudohypoparathyroidism is almost always inherited maternally,34 and type Ib is inherited paternally.35 The musculoskeletal manifestations of osteomalacia and rickets are covered in Chapter 92.

THYROID DISORDERS Hyperthyroidism (Graves’ disease) may affect the musculoskeletal system in several ways. The most common complication is osteopenia and frank osteoporosis, which can be a major problem in patients with idiopathic Graves’ disease or in patients with iatrogenic hyperthyroidism.36 Failure to recognize the declining need for thyroid replacement with age is an important cause of iatrogenic hyperthyroidism in older women. For that reason, patients with hypothyroidism who are on thyroid hormone and estrogen therapy should have thyroid-stimulating hormone levels monitored and the dose readjusted to keep the thyroid-stimulating hormone level within the normal range.37,38 Bone density has been shown to increase after correction of the hyperthyroid state.39 Pretibial myxedema is a syndrome of painless nodules that occur over the pretibial areas. Virtually all affected patients have concomitant Graves’ ophthalmopathy.40 The lesions vary in size, ranging from nodules of 1-cm diameter to very large lesions covering most of the pretibial surface. They are

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variably colored, ranging from pink to a light purple hue, and can mimic erythema nodosum. In contrast to erythema nodosum, these lesions are painless. They are caused by the accumulation of hyaluronic acid in the skin,41 and in some cases they have a shiny appearance resembling scleroderma or morphea. Hyperthyroidism also can be associated with numerous changes in the nails,42 including onycholysis, or elevation of the nail from the nail bed, and clubbing. Clubbing is usually part of the condition known as thyroid acropachy, a rare manifestation of hyperthyroidism also associated with periostitis around the metacarpal joints and distal soft tissue swelling of the digits. The condition is not clearly related to the levels of thyroid hormone because it may be seen after the patient has reverted to the euthyroid state. Proximal muscle weakness is a common complication of hyperthyroidism and is present in most patients. Most of these patients have lost weight and have other evidence of loss of muscle mass. The proximal muscle weakness corrects rapidly with correction of the hyperthyroid state.43 Perhaps related to the proximal myopathy, adhesive capsulitis of the shoulder seems to be increased in patients with ­hyperthyroidism. In these patients, the condition can be insidious and difficult to treat, with frozen-shoulder syndrome often the initial manifestation. There are strong relationships between Graves’ disease and Hashimoto’s disease and other rheumatic diseases. Seventy-five percent to 90% of patients with Graves’ disease44 and a smaller percentage of patients with Hashimoto’s thyroiditis have antinuclear antibodies, and many have antiDNA antibodies as well, despite the fact that overt systemic lupus erythematosus (SLE) is uncommon. There is a true increased incidence of hypothyroidism in patients with scleroderma, and there is some evidence that other rheumatic diseases also are associated with an increased incidence, including SLE, rheumatoid arthritis (RA), mixed connective tissue disease, Sjögren’s syndrome, and polymyositis. Graves’ disease is associated with HLA-B8, HLA-A1, HLA-Cw7, and HLA-DR3, and combinations of these antigens correlate with persistent disease.45 Hashimoto’s disease is associated with HLA-B8, HLA-DR3, HLA-Aw30, and HLA-DR5. These diseases occur with increased frequency in individuals with other autoimmune diseases that are associated with these HLA antigens.46 Hypothyroidism in its idiopathic form is almost always caused by Hashimoto’s thyroiditis and can be associated with an unusual arthropathy. Patients present with swelling and stiffness in large joints, usually the knees. The hands also may be involved, and this is often very impressive in joints previously involved with osteoarthritis. Examination of the swollen joint reveals a thick, gelatinous sensation that causes a very slow fluid wave (bulge sign). Synovial thickening on palpation can be impressive. Aspiration of the fluid from patients with the arthropathy of myxedema reveals noninflammatory fluid that is extremely viscous with very high hyaluronic acid levels. Calcium pyrophosphate dihydrate crystals may be present, but inflammation is not.47 This arthropathy resolves quickly with correction of the hypothyroid state. The myopathy of hypothyroidism can be confusing. Many patients have proximal muscle weakness; however,

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some complain only of generalized lassitude and fatigue. In one study, 25% of hypothyroid patients had muscle symptoms, although creatine kinase levels were ­usually normal.48 Occasionally, levels can be quite elevated, and rhabdomyolysis has been reported.49 Muscle biopsy specimens are usually normal, although moderate inflammatory changes are sometimes present.50 This condition can resemble either polymyalgia rheumatica or polymyositis, depending on the predominance of stiffness versus ­weakness. Carpal tunnel syndrome is increased in patients with hypothyroidism, and in one study hypothyroidism was present in 7% of patients with carpal tunnel syndrome.51 It is frequent enough that most patients with idiopathic carpal tunnel syndrome should be screened for early myxedema. Because of all these considerations, the clinician encountering patients with musculoskeletal complications must always keep thyroid disorders in mind. Many of these conditions can be subtle, and the musculoskeletal manifestations—ranging from myopathy to pretibial myxedema to frank arthropathies—can be the presenting manifestation of thyroid disorders.

ADRENAL DISORDERS Iatrogenic Cushing’s syndrome secondary to exogenous glucocorticoid therapy of an underlying inflammatory disease is the most common condition involving adrenal hormones seen in patients with rheumatic diseases (see Chapter 55). A few complications of iatrogenic Cushing’s syndrome warrant special comment. Osteonecrosis is a common late complication of glucocorticoid therapy52 and may first become evident months or years after glucocorticoid therapy has been discontinued. It also can be seen following short courses of therapy, however, or after intermittent high-dose intravenous therapy.53 Because many patients receiving glucocorticoid therapy have diseases associated with joint pain, the clinician must be alert to this condition. When it affects the hip, which is the most common joint involved, the pain is usually dull, located in the groin, increased by weight bearing, and progressive. An increased incidence of osteonecrosis has been seen in patients on replacement glucocorticoid therapy, pointing out the need to treat with the lowest acceptable dose of the drug.54 Steroid myopathy can be particularly perplexing in pati­ ents being treated for primary or secondary inflammatory myopathies. Steroid myopathy is characteristically more severe in the pelvic girdle and can be so severe that patients are bedridden. It may come on gradually or abruptly, heralded by weakness and muscle aching. Biopsy specimens show type II fiber atrophy, and muscle enzymes are normal. There is evidence that longer acting and fluorinated compounds are more likely to cause myopathy.55 When myopathy has developed, it usually requires nearly total discontinuation of the glucocorticoids before any improvement is seen, and even then it may be weeks or months before strength begins to return. Osteopenia (see Chapters 55 and 92) is related to the dose and the duration of glucocorticoid therapy. No “safe” dose has yet been established. Because osteoporosis can develop rapidly after beginning glucocorticoid therapy, prophylaxis is recommended in most patients. Regimens shown to be

effective at preventing or treating glucocorticoid-induced osteoporosis include calcium and vitamin D3,56 calcitonin,57 and bisphosphonates.58,59 Idiopathic Cushing’s syndrome may be confused with primary musculoskeletal disease. More than 50% of patients have muscle weakness, and a similar percentage have back pain, often secondary to osteoporotic fractures. In patients with Cushing’s syndrome secondary to ectopic adrenocorticotropic hormone production, glucocorticoid levels may be extremely high, resulting in profound myopathy and other features such as steroid psychosis. Because weight loss, rather than typical centripetal obesity, is often present in these patients, the appearance may not be typical of idiopathic Cushing’s syndrome of pituitary origin. Other effects of glucocorticoids on the musculoskeletal system are less well understood. Some patients complain of intense joint pain, usually most severe in the knees, when high doses of glucocorticoids are first administered. This pain typically resolves even if the dose is left unchanged. The so-called steroid withdrawal syndrome consists of widespread arthralgias, myalgias, malaise, and sometimes low-grade fever.60 It may be seen when glucocorticoids have been used for nonrheumatic conditions, such as asthma or inflammatory bowel disease, and does not require suppression of the pituitary-adrenal axis. Finally, the abrupt reduction of the dose of a glucocorticoid can cause a severe rebound flare in the underlying disease. This may be seen even though the dose of the glucocorticoid remains in the pharmacologic range. Patients with idiopathic Addison’s disease present with weakness, weight loss, abdominal pain, hyperpigmentation, nausea, and hypotension. Iatrogenic Addison’s disease can be much more subtle. Because mineralocorticoids are still being produced, salt wasting, hyperkalemia, and postural hypotension are usually less impressive, and hyperpigmentation is not seen because the pituitary is suppressed. As in idiopathic Addison’s disease, the features may not be impressive unless the individual undergoes a second exogenous stress, such as surgery or an infection. In that setting, addisonian crisis has been seen even in individuals still receiving physiologic or “replacement” doses of glucocorticoids. It should be assumed that individuals taking glucocorticoids at more than the equivalent of 5 mg/day of prednisone have a pituitary-adrenal axis unable to respond to severe stress, and appropriate increases in the glucocorticoid dose should be considered. In addition, the development of idiopathic Addison’s disease in individuals receiving low-dose glucocorticoids can result in similar diagnostic difficulty.61

ACROMEGALY Growth hormone levels tend to decline with age, and there is evidence that treatment of the elderly with growth hormone increases muscle mass62 and, in some cases, increases bone density as well. At this time, the most important musculoskeletal manifestations related to growth hormone are those seen in acromegaly. Growth hormone is secreted primarily in nocturnal pulses, and it stimulates hepatocytes to produce somatomedin C, or insulin-like growth factor. Somatomedin C has variable effects on adult tissues, but osteocytes, chondrocytes, and fibroblasts all are responsive in adults. Acromegaly, caused

PART 18 

by an adenoma in the anterior pituitary gland, is an insidious disease, and often years have passed before the diagnosis is made. During those years, a variety of musculoskeletal consequences have usually developed. Carpal tunnel syndrome occurs in about half of patients with acromegaly and is one of the few musculoskeletal manifestations that may develop early in the disease course.63 It is due to enlargement of the nerve and to expansion of the transverse carpal ligament and other soft tissues. Raynaud’s phenomenon owing to compression of the distal arteries by soft tissues occurs in about one third of patients with acromegaly. If the diagnosis is not made early, and it rarely is, premature osteoarthritis almost inevitably develops. The knee is the most frequently involved joint, followed by the hip and the spine. The hypertrophied cartilage tends to fissure and ulcerate, and the ligaments of the knee become elongated and lax. This combination of instability and abnormal cartilage can lead to severe disability.64 Other areas affected include the temporomandibular joints and the small joints of the hands and feet. The reason that glove size increases in acromegalics is not because bones grow; it is because ­cartilage in each joint increases in thickness, and the soft tissues proliferate. The early radiographic picture of acromegalic joints shows joint space widening as a result of cartilage hypertrophy. In the spine, disk spaces also may be widened. Later, as the inevitable degeneration occurs, the changes are indistinguishable from those of idiopathic osteoarthritis. Back pain is a particularly troubling feature of acromegaly. Most patients complain of dull, diffuse pain in the lumbar spine. The pain does not radiate into the legs and is often present at rest and with activity. These changes are caused by several factors, including disk space enlargement, osteophyte production, and ligamentous calcifications. Some patients improve when growth hormone levels are reduced after surgery, radiation, or treatment with a somatostatin analogue.65 Most acromegalic patients develop proximal muscle weak­ ness, which is occasionally an early symptom. Muscle enzymes are normal. Biopsy specimens show no inflammation, but do reveal abnormal variations in fiber size.

PREGNANCY The pregnant state produces a complex series of musculoskeletal changes in normal individuals. Probably the most common is the near-universal problem of low back pain, especially during the third trimester. This pain is believed to be primarily mechanical in nature and is due to the increased lumbar lordosis. In addition, the increased mobility of the sacroiliac and other joints of the pelvic girdle, under the influence of the hormone relaxin, may be a factor in many women. Carpal tunnel syndrome is common in the last trimester, resulting primarily from increased fluid retention. It is usually mild and responsive to wrist splints. It resolves quickly after delivery. Pregnancy has impressive effects in patients with inflammatory rheumatic diseases. Virtually all the rheumatic diseases, especially RA and SLE, have been reported to develop in the early postpartum period.

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There is evidence that rheumatoid factor positivity during pregnancy predicts subsequent RA.66 This finding could be interpreted in several ways, but a likely interpretation is that the pregnant state itself has delayed the clinical onset of the disease until the postpartum period. In other words, the true incidence of RA may be unaffected by pregnancy, but the time of its onset is. This observation would be compatible with the well-known improvement in the course of RA in about three fourths of patients when they become pregnant. This improvement usually begins in the first trimester, but virtually all patients relapse in the first 3 or 4 months postpartum. Many investigators have attempted to explain this amelioration of the disease during the pregnant state. HLA incompatibilities in DRB1, DQA1, and DQB1 all have been associated with a greater likelihood of disease improvement during pregnancy.67 In addition, cytokines are affected by the pregnant state. Interleukin-2 production is decreased, and production of soluble tumor necrosis factor receptors is increased.68 In other rheumatic diseases, the situation during pregnancy is more complex. In SLE, fetal wastage is increased, and there is some evidence that the disease is more apt to flare during the postpartum period. The relationship between SLE and pregnancy is discussed in detail in Chapter 75. The use of hormone therapy to treat rheumatic diseases has had a stormy history. Based partly on murine studies showing that SLE can be made worse by estrogen and improved by androgen,69 SLE has been the subject of extensive study. Patients with SLE metabolize the active metabolite of estrogen (i.e., estrone) preferentially to the feminizing metabolites 16-hydroxyestrone and estriol.70 In addition, there is some evidence that testosterone levels are lower and that inactive forms predominate.71 This has led to some interest in using dehydroepiandrosterone, which also has been reported to be low in patients with SLE, in treatment of fatigue and other manifestations of the disease.72 The role of birth control pills also has been investigated. Studies have suggested that oral contraceptive use diminishes the lifetime risk of RA.73 In contrast, SLE may flare more often in women taking birth control pills containing estrogen.74 If progesterone-only birth control pills are used, however, SLE activity may be decreased. At this time, the decision to use oral contraceptives in patients with SLE requires careful considerations of the risks, which are probably small, versus the benefits. If an oral contraceptive is chosen, the lowest effective dose of estrogen or a progesterone-only preparation should be used.75 There is no evidence to suggest that postmenopausal hormone replacement therapy with estrogen adversely affects the course of SLE. REFERENCES   1. Kapoor A, Sibbitt WL Jr: Contractures in diabetes mellitus: The syndrome of limited joint mobility. Semin Arthritis Rheum 18:168, 1989.   2. Sheetz MJ, King GL: Molecular understanding of hyperglycemia adverse effects for diabetic complications. JAMA 288:2579, 2002.   3. Seibold JR, Uitto J, Dorwart BB, et al: Collagen synthesis and collagenase activity in dermal fibroblasts from patients with diabetes and digital sclerosis. J Lab Clin Med 105:664, 1985.   4. Iwasaki T, Kohama T, Houjou S, et al: Diabetic scleroderma and scleroderma-like changes in a patient with maturity onset type diabetes of young people. Dermatology 188:228, 1994.

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  5. Gamstedt A, Holm-Glad J, Ohlson CG, et al: Hand abnormalities are strongly associated with the duration of diabetes mellitus. J Intern Med 234:189, 1993.   6. Lawson PM, Maneschi F, Kohner EM: The relationship of hand abnormalities to diabetes and diabetic retinopathy. Diabetes Care 6:140, 1983.   7. Rosenbloom AL, Silverstein JH, Lezotte DC, et al: Limited joint mobility in diabetes mellitus indicating increased risk for microvascular disease. N Engl J Med 305:191, 1981.   8. Chammas M, Bousquet P, Renard E, et al: Dupuytren’s disease, carpal tunnel syndrome, trigger finger, and diabetes mellitus. J Hand Surg Am 20:109, 1995.   9. Eaton P, Sibbitt WL Jr, Harsh A: The effect of an aldose reductase inhibiting agent on limited joint mobility in diabetic patients. JAMA 253:1437, 1985. 10. Goto Y, Hotta N, Shigeta Y, et al: Effects of an aldose reductase inhibitor, Epalrestat, on diabetic neuropathy. Biomed Pharmacother 49:296, 1995. 11. Benedetti A, Noacco C, Simonatti M, et al: Diabetic trigger finger. N Engl J Med 306:1552, 1982. 12. Arkkila PE, Kantola IM, Viikari JS, et al: Shoulder capsulitis in type I and II diabetic patients: Association with diabetic complications and related diseases. Ann Rheum Dis 55:907, 1996. 13. Boyle-Walker KL, Gabard DL, Bietsch E, et al: A profile of patients with adhesive capsulitis. J Hand Ther 10:222, 1997. 14. Lequesne M, Dang N, Benasson M, et al: Increased association of diabetes mellitus with capsulitis of the shoulder and shoulder-hand syndrome. Scand J Rheumatol 6:53, 1997. 15. Serra F, Mancini L, Ghirlanda G, et al: Charcot’s foot. RAYS 22:524, 1997. 16. Armstrong DG, Lavery LA: Acute Charcot’s arthropathy of the foot and ankle. Phys Ther 78:74, 1998. 17. Julkunen H, Heinonen OP, Pyorala K: Hyperostosis of the spine in an adult population: Its relationship to hyperglycemia and obesity. Ann Rheum Dis 30:605, 1971. 18. Daragon A, Mejjad O, Czernichow P, et al: Vertebral hyperostosis and diabetes mellitus: A case-control study. Ann Rheum Dis 54:375, 1995. 19. Vezyroglou G, Mitropoulos A, Antoniadis C: A metabolic syndrome in diffuse idiopathic skeletal hyperostosis: A controlled study. J Rheumatol 23:672, 1996. 20. Suico JG, Marriott DJ, Vinicor F, et al: Behaviors predicting foot lesions in patients with non-insulin-dependent diabetes mellitus. J Gen Intern Med 13:482, 1998. 21. Rith-Najarian S, Branchaud C, Beulieu O, et al: Reducing lowerextremity amputations due to diabetes: Application of the staged diabetes management approach in a primary care setting. J Family Pract 47:127, 1998. 22. Thomas PK: Classification, differential diagnosis, and staging of diabetic peripheral neuropathy. Diabetes 46(Suppl 2):S54, 1997. 23. Naftulin S, Fast A, Thomas M: Diabetic lumbar radiculopathy: Sciatica without disc herniation. Spine 18:2419, 1993. 24. Rynes RI, Merzig EG: Calcium pyrophosphate crystal deposition disease and hyperparathyroidism: A controlled, prospective study. J Rheumatol 5:460, 1978. 25. Resnick DL: Erosive arthritis of the hand and wrist in hyperparathyroidism. Radiology 110:263, 1974. 26. Frame B, Heinze EG, Block M, et al: Myopathy in primary hyperparathyroidism: Observations in 3 patients. Ann Intern Med 68:1022, 1968. 27. Nudelman I, Deutsch AA, Reiss R: Surgical treatment of primary hyperparathyroidism in the elderly patient. Isr J Med Sci 19:150, 1983. 28. Rubin LA, Fam AG, Rubenstein J, et al: Erosive azotemic osteoarthropathy. Arthritis Rheum 27:1086, 1984. 29. Pecovnik-Balon B, Kramberger S: Tumoral calcinosis in patients on hemodialysis: Care report and review of the literature. Am J Nephrol 17:93, 1997. 30. Kuntz D, Navean B, Bardin T, et al: Destructive spondyloarthropathy in hemodialyzed patients. Arthritis Rheum 27:369, 1984. 31. Dabbagh S: Renal osteodystrophy. Curr Opin Pediatr 10:190, 1998. 32. Pei Y, Hercz G, Greenwood C, et al: Risk factors for renal osteodystrophy: A multivariant analysis. J Bone Miner Res 10:149, 1995.

33. Ringel MD, Schwindinger WF, Levine MA: Clinical implications of genetic defects in G proteins: The molecular basis of McCuneAlbright syndrome and Albright hereditary osteodystrophy. Medicine 75:171, 1996. 34. Hayward BE, Kamiya M, Strain L, et al: The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins. Proc Natl Acad Sci U S A 95:10038, 1998. 35. Juppner H, Schipani E, Bastepe M, et al: The gene responsible for pseudohypoparathyroidism type Ib is paternally imprinted and maps in four unrelated kindreds of chromosome 20Q13.3. Proc Natl Acad Sci U S A 95:11798, 1998. 36. Jodar E, Munoz-Torres M, Escobar-Jimenez F, et al: Bone loss in hyperthyroid patients and in former hyperthyroid patients controlled on medical therapy: Influence of etiology and menopause. Clin Endocrinol 47:279, 1997. 37. Chiovato L, Mariotti S, Pinchera A: Thyroid diseases in the elderly. Baillieres Clin Endocrinol Metab 11:251, 1997. 38. Shetty KR, Duthie EH Jr: Thyroid disease and associated illness in the elderly. Clin Geriatr Med 11:311, 1995. 39. Rosen CJ, Alder RA: Longitudinal changes in lumbar bone density among thyrotoxic patients after attainment of euthyroidism. J Clin Endocrinol Metab 75:1531, 1992. 40. Fatourechi V, Pajouhi M, Fransway AF: Dermopathy of Graves disease (pretibial myxedema): Review of 150 cases. Medicine 73:1, 1994. 41. Kriss JP: Pathogenesis and treatment of pretibial myxedema. Endocrinol Metab Clin N Am 16:409, 1987. 42. Nixon DW, Samols E: Acral changes associated with thyroid diseases. JAMA 212:1175, 1970. 43. Ramsey ID: Muscle dysfunction in hyperthyroidism. Lancet 2:931, 1966. 44. Katakura M, Yamada T, Aizawa T, et al: Presence of antideoxyribonucleic acid antibody in patients with hyperthyroidism of Graves’ disease. J Clin Endocrinol Metab 64:405, 1987. 45. Baldini M, Pappalettera M, Lecchi L, et al: Human lymphocyte antigens in Graves’ disease: Correlation with persistent course of disease. Am J Med Sci 309:43, 1995. 46. Torfs CP, King M, Huey B, et al: Genetic interrelationship between insulin-dependent diabetes mellitus, the autoimmune thyroid diseases, and rheumatoid arthritis. Am J Hum Genet 38:170, 1986. 47. Dorwart BB, Schumacher HR: Joint effusions, chondrocalcinosis and rheumatic manifestations of hypothyroidism. Am J Med 59:780, 1975. 48. Hartl E, Finsterer J, Grossegger C, et al: Relationship between thyroid function and skeletal muscle involvement in subclinical and overt hypothyroidism. Endocrinologist 11:217, 2001. 49. Bhansazi A, Chandran V, Ranesh J, et al: Acute myoedema: An unusual presenting manifestation of hypothyroid myopathy. Postgrad Med J 76:99, 2000. 50. Mastaglia FL, Ojeda VJ, Sarnat HB, et al: Myopathies associated with hypothyroidism: A review based upon 13 cases. Aust N Z J Med 18:799, 1988. 51. Katz JN, Larson MG, Sabra A: The carpal tunnel syndrome: Diagnostic utility of the history and physical examination findings. Ann Intern Med 112:321, 1990. 52. Weiner ES, Abeles M: Aseptic necrosis and glucocorticosteroids in systemic lupus erythematosus: A reevaluation. J Rheumatol 16:604, 1989. 53. Wollheim FA: Acute and long-term complications of corticosteroid pulse therapy. Scand J Rheumatol Suppl 54:27, 1984. 54. Vreden SG, Hermus AR, van Liessum PA, et al: Aseptic bone necrosis in patients on glucocorticoid replacement therapy. Neth J Med 39:153, 1991. 55. Lane RJ, Mastaglia FL: Drug-induced myopathies in man. Lancet 2:562, 1978. 56. Buckley LM, Leib ES, Cartularo KS, et al: Calcium and vitamin D3 supplementation prevents bone loss in the spine secondary to low dose corticosteroids in patients with rheumatoid arthritis. Ann Intern Med 125:961, 1996. 57. Adachi JD, Bensen WG, Bell MJ, et al: Salmon calcitonin nasal spray in the prevention of corticosteroid-induced osteoporosis. Br J Rheumatol 36:255, 1997. 58. Saag KG, Emkey R, Schnitzer TJ, et al: Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. N Engl J Med 339:292, 1998.

PART 18  59. Adachi JD, Bensen WG, Brown J, et al: Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med 337:382, 1997. 60. Dixon RB, Nicholas PC: On the various forms of corticosteroid withdrawal syndrome. Am J Med 68:224, 1980. 61. Cronin CC, Callaghan N, Kearney PJ, et al: Addison disease in patients treated with glucocorticoid therapy. Arch Intern Med 157:456, 1997. 62. Schwartz RS: Trophic factor supplementation: Effect on the age­associated changes in body composition. J Gerontol Series A 50(Spec. No.):151, 1995. 63. Baum H, Ludecke DK, Herrmann HD: Carpal tunnel syndrome and acromegaly. Acta Neurochirurg 83:54, 1986. 64. Bluestone R, Bywaters EG, Hartog M, et al: Acromegalic arthropathy. Ann Rheum Dis 30:243, 1971. 65. Layton MW, Fudman EJ, Barkan A, et al: Acromegalic arthropathy: Characteristics and response to therapy. Arthritis Rheum 31:1, 1990. 66. Iijima T, Tada H, Hidaka Y, et al: Prediction of postpartum onset of rheumatoid arthritis. Ann Rheum Dis 57:460, 1998. 67. Van der Horst-Bruinsma IE, de Vries RR, de Buck PD, et al: Influence of HLA-class II incompatibility between mother and fetus on the development and course of rheumatoid arthritis of the mother. Ann Rheum Dis 57:286, 1998.

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68. Russell AS, Johnston C, Chew C, et al: Evidence for reduced Th1 function in normal pregnancy: A hypothesis for the remission of rheumatoid arthritis. J Rheumatol 24:1045, 1997. 69. Van Vollenhoven RF, McGuire JL: Estrogen, progesterone, and testosterone: Can they be used to treat autoimmune diseases? Cleve Clin J Med 61:276, 1994. 70. Lahita RG: The role of sex hormones in systemic lupus erythematosus. Curr Opin Rheumatol 11:352, 1999. 71. Lahita RG, Bradlow HL, Ginzler E, et al: Low plasma androgens in women with systemic lupus erythematosus. Arthritis Rheum 30:241, 1987. 72. Van Vollenhoven RF, Morabito LM, Engleman EG, et al: Treatment of systemic lupus erythematosus with dehydroepiandrosterone: 50 patients tested up to 12 months. J Rheumatol 25:285, 1998. 73. Hazes JM, Dijkmans BA, Vandenbroucke JP, et al: Reduction of the risk of rheumatoid arthritis among women who take oral contraceptives. Arthritis Rheum 33:173, 1990. 74. Julkunen HA: Oral contraceptives in systemic lupus erythematosus: Side effects and influence on the activity of SLE. Scand J Rheumatol 20:427, 1991. 75. Buyon JP: Oral contraceptives in women with systemic lupus erythematosus. Ann Intern Med 147:259, 1996.

112

Musculoskeletal Syndromes in Malignancy ELIZA F. CHAKRAVARTY

Key Points Musculoskeletal and rheumatic syndromes can occasionally be the first presentation of an underlying malignancy. Older age of onset, prominent constitutional symptoms, atypical features of rheumatic disease, and absence of response to glucocorticoids or other conventional therapy may be sugges­ tive of a paraneoplastic process. Data from numerous cohorts have confirmed an elevated (> threefold)­ incidence of malignancy associated with derma­ tomyositis. Solid organ tumors, including lung, colon, and ovarian in European populations and nasopharyngeal tumors in Asian populations, are among the most common tumors found in dermatomyositis patients; most malignancies are diagnosed within 1 year of diagnosis of myopathy. Although to a lesser magnitude than dermatomyositis, poly­ myositis has been associated with an increased incidence of malignancies in several large population-based studies. Chronic autoimmune conditions including Sjögren’s syn­ drome, rheumatoid arthritis, and systemic lupus erythemato­ sus are associated with an increased risk for the development of lymphoid malignancies compared to the general popula­ tion. This is felt to be, at least in part, due to chronic inflamma­ tion and immune stimulation. Commonly used immunosuppressive medications have been associated with later development of malignancies, some of which may be related to reactivation of latent Epstein-Barr virus. Possible associations between anti-TNF-α therapy and increased risk of development of lymphoma are confounded by increased disease activity and previous DMARD use in patients who receive biologic therapy. Patients with systemic sclerosis are at increased risk for the development of solid organ tumors primarily involving tissues affected by the fibrotic process.

Musculoskeletal syndromes seem to be associated with malignancy in a variety of ways. Cause and effect are difficult to define clearly in many situations, however. Certain rheumatic diseases have been associated with an increased risk of the subsequent development of malignancy; one example is the development of lymphoma in an individual with ­ primary Sjögren’s syndrome. The converse situation also exists, in that certain rheumatic diseases are seen more frequently in the presence of an underlying malignancy, such as dermatomyositis. Little is understood regarding the

pathogenesis of connective tissue disease in association with neoplastic disease. Other factors can contri­bute to the association of musculoskeletal syndromes and malignancy. Many of the medications used to treat rheumatic diseases modulate the immune system and may be associated directly or indirectly with an increased risk for the subsequent development of malignancy. In unusual circumstances, musculoskeletal involvement occurs as a paraneoplastic process, defined as a hormonal, neurologic, hematologic, or biochemical disturbance associated with malignancy, but not directly related to invasion by the neoplasm or its metastases.1

PARANEOPLASTIC SYNDROMES Musculoskeletal syndromes can develop as a manifestation of a paraneoplastic process and occasionally can be the first presentation of an underlying malignancy. Hematologic malignancies, lymphoproliferative disorders, and solid tumors are associated with a wide variety of paraneoplastic rheumatic syndromes. Older age of onset, atypical features of rheumatic disease, and absence of response to glucocorticoids or other conventional therapy may suggest a paraneoplastic process. Knowledge of the associations with rheumatic syndromes and underlying malignancy is crucial when caring for these patients. Hypertrophic osteoarthropathy, amyloidosis, and secondary gout are reviewed in Chapters 93, 106, and 87. Table 112-1 lists common paraneoplastic associations. CARCINOMATOUS POLYARTHRITIS The term carcinomatous polyarthritis is used to describe the development of arthritis in association with malignancy, but it is distinct from arthritis associated with metastasis or direct tumor invasion. Table 112-2 lists common features of carcinomatous polyarthritis. It generally occurs in patients who are older in age, has an explosive onset, and often develops in close temporal correlation with the discovery of the malignancy. Although it can have various presentations and may mimic the appearance of rheumatoid arthritis (RA),2 carcinomatous polyarthritis is more often a seronegative asymmetric disease with predominant involvement of the lower extremities and some sparing of the small joints of the hands. There is no evidence of direct tumor extension or metastasis and no specific identifying histologic or radiographic appearance. Carcinomatous polyarthritis can occur in association with many types of malignancy, but has been reported in the greatest frequency in association with breast, colon, lung, and ovarian cancers and with lymphoproliferative disorders.3 The underlying pathogenesis of 1841

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Musculoskeletal Syndromes in Malignancy

Table 112-1  Paraneoplastic Syndromes Connective Tissue Disease

Malignancy

Clinical Setting

Clinical Alert

Carcinomatous   polyarthritis

Multiple types of solid   tumors, including breast;   lymphoproliferative disorders

See Table 112-2

See Table 112-2

Vasculitis

Lymphopoietic and   hematopoietic malignancies

Cutaneous vasculitis most   common; systemic   vasculitis rare

Vasculitis not related to infections,   medications, or autoimmune   disease

Mixed   cryoglobulinemia

Non-Hodgkin’s lymphoma

Immune complex–mediated   disease with cutaneous   vasculitis, neuropathy, fatigue,   and visceral organ involvement

Usually appears 5-10 yr after   diagnosis of cryoglobulinemia

Panniculitis

Hematologic malignancies;   pancreatic, breast, and   prostate cancers

Induration of skin and deeper   tissues; eosinophilia often   present

Usually refractory to prednisone

Fasciitis

Ovarian, breast, gastric, and   pancreatic cancers

Palmar fasciitis with inflammatory   polyarthritis; similar in presentation   to reflex sympathetic dystrophy

Bilateral presentation; severe   fibrosis and contractures;   aggressive course

Reflex sympathetic   dystrophy syndrome

Multiple cancer types;   Pancoast tumors

Tumors may invade stellate ganglion   or brachial plexus on affected side

Absence of typical antecedent   factors; failure to respond to   conventional therapies

Erythromelalgia

Myeloproliferative   disorders

Often seen in setting of   thrombocytosis

—

Atypical polymyalgia   rheumatica

Renal, lung, and colon   cancer; multiple myeloma

—

Age <50 yr; asymmetric   involvement; poor response   to prednisone

Digital necrosis

Gastrointestinal and   pulmonary tumors

Severe Raynaud’s phenomenon   with onset >50 yr old

Asymmetric features; digital   necrosis

Remitting seronegative   symmetric synovitis   with pitting edema

Several tumor types

Abrupt onset of arthritis and   edema surrounding wrists   and small joints of hands

Presence of fever, weight loss;   poor response to prednisone

Multicentric   reticulohistiocytosis

Lung, stomach, breast,   cervix, colon, and   ovarian carcinomas

—

—

Lupus-like syndromes

Variety of solid tumors and   lymphoproliferative disorders

—

Rare associations with   malignancy limited to   case reports

Antiphospholipid   antibodies

Multiple cancer types

Association between antibodies,   cancer, and risk of thrombosis   unclear

Higher presence of antibodies   found in patients with   malignancy

Osteogenic   osteomalacia

Solid tumors and tumors of   mesenchymal origin

Bone pain and muscle weakness

Diligent search is indicated in   all patients with late-onset   apparent idiopathic   osteomalacia

Sarcoidosis

Cervical, bladder, gastric, lung,   breast, and renal cancers and   cutaneous and pulmonary   squamous cell carcinomas

Highest incidence of “malignancy”   during first 4 yr after detection   of granulomas

Malignant tumors can cause   sarcoid-like tissue reactions   leading to mistaken diagnosis   of sarcoidosis before   recognition of malignancy

Lymphomatoid   granulomatosis

Lymphoma

Unusual granulomatous form of   vasculitis with angiodestructive   infiltration of various tissues

—

this process has not been elucidated; however, the arthritic symptoms may be improved with successful treatment of the malignancy.4 VASCULITIS Vasculitis in association with malignancy is uncommon and has a reported prevalence of only 8% of patients with malignancy.5 The association seems to be significantly higher with lymphoproliferative and myeloproliferative disorders

than with solid tumors, and vasculitis commonly predates the identification of malignancy. The vasculitic process is most often small vessel and cutaneous and only rarely involves significant organs. Treatment often requires the use of glucocorticoids and therapy directed against the underlying malignancy, although it seems this is often ineffective. Table 112-1 shows malignancies associated with vasculitis. In the setting of malignancy, it is believed that the persistent antigen stimulation from the tumor results in T cell activation or immune complex formation and deposition.

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Table 112-2  Features of Carcinomatous Polyarthritis Close temporal relationship between onset of arthritis and discovery of malignancy Late age of onset of arthritis Asymmetric joint involvement Explosive onset Predominant lower extremity involvement with sparing of wrists and small joints of hands Absence of rheumatoid nodules Absence of rheumatoid factor No family history of rheumatoid disease Nonspecific histopathologic appearance of synovial lining No periosteal reaction

The development of small vessel vasculitis has been reported to antedate and postdate the development of lymphoproliferative and myeloproliferative diseases. One group looked at 222 patients with vasculitis retrospectively and identified 11 who had developed an associated malignancy. Of these 11 patients, 7 had hematologic neoplasia, and 4 had malignant solid tumors. Nine of the patients manifested cutaneous vasculitis, and the remaining two had vasculitic involvement in the bowel. In four of the patients, the development of vasculitis antedated the diagnosis of malignancy.6 Similar findings were reported by investigators who found an underlying malignancy in 8 of 192 patients with cutaneous vasculitis. Most malignancies were hematologic (six of eight) and predated (five of eight) the diagnosis of cancer.7 In a retrospective ­ analysis of 23 patients with cutaneous vasculitis and hematologic malignancies, the authors were able to attribute the presence of vasculitis to the malignancy itself in 61% of cases.8 Systemic vasculitis is much less commonly associated with underlying malignancy. Case reports and small series have found antineutrophil cytoplasmic antibody (ANCA)– negative and ANCA-positive vasculitis associated with hematologic malignancies.9-11 Wegener’s granulomatosis has likewise been associated with the development of several types of malignancies, including lymphoproliferative disorders, bladder cancer, and renal cell carcinoma.12,13 In some cases, the malignancy was diagnosed within months of the diagnosis of Wegener’s granulomatosis,12 and in other reports, cancer developed many years after diagnosis and treatment of vasculitis,13 making it unclear whether the malignancies were a result of the vasculitis or possibly the treatment. A group from the Cleveland Clinic did a retrospective study to assess directly the temporal relationship between vasculitis and cancer.14 During an 18-year study period, the authors found only 12 cases of vasculitis and cancer diagnosed within the same 12-month period: Six patients had lymphoproliferative disorders, and six had solid tumors. In most cases, the vasculitis responded partially to immunosuppressive therapy, but the investigators observed a more impressive improvement of vasculitis with definitive treatment for the underlying malignancy. A more recent study found 20 cases of malignancy among 200 patients with ANCA-positive vasculitis; 6 were diagnosed concurrently with diagnosis of vasculitis, and 14 predated vasculitis by a median of 96 months.15 Only 4 of 20 malignancies in this

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series were lymphoproliferative; the remaining malignancies were solid organ tumors. Vasculitis associated with underlying malignancy is often poorly responsive to conventional therapy directed against the vasculitis. In one series of 13 patients with cutaneous vasculitis and lymphoproliferative or myeloproliferative disorders, symptoms of vasculitis were poorly responsive to therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, antihistamines, and antiserotonin agents. Although the investigators reported a lessening of the severity of the vasculitis after chemotherapy directed against the malignancy, they generally found chemotherapy to be ineffective. Of the 13 patients identified, 10 died as a direct result of the malignancy.16 Similarly, Hutson and Hoffman14 found a general concurrence between improvement in vasculitic syndrome with definitive treatment for the associated underlying malignancy. CRYOGLOBULINEMA Cryoglobulins are immunoglobulins that precipitate at reduced temperature. Cryoglobulinemia can be characterized by hyperviscosity symptoms or by vasculitis. Patients often have fatigue, arthralgia or arthritis, cutaneous vasculitis or purpura, neuropathy, digital ischemia, and visceral organ involvement (renal or pulmonary). There are three types of cryoglobulins, as follows: Type I: Monoclonal immunoglobulin, either IgG or IgM; this type is associated with lymphoproliferative disorders. Type II: Monoclonal IgM directed against polyclonal IgG; type II cryoglobulins were initially thought to be idiopathic and were known as mixed essential cryoglobulinemia. With the identification of hepatitis C virus (HCV), it has been discovered that most of these patients have HCV infection that is directly involved in the pathogenesis of the cryoglobulins. Specific epitopes of HCV antigens are recognized by IgG components of immune complexes, and viral particles are found in the cryoprecipate.17 One study found clonal B cell populations in the peripheral blood of 48% of HCV-positive patients with type II cryoglobulemia, many of whom were eventually diagnosed with a B cell malignancy.18 Overall, it is estimated that approximately 5% to 8% of patients with mixed cryoglobulinemia may go on to develop non-Hodgkin’s lymphoma, usually after 5 to 10 years of cryoglobulinemia.19,20 The risk of developing non-Hodgkin’s lymphoma among HCV-positive cryoglobulinemic patients may be 35 times higher than that in the general population.21 Other data suggest that HCV infection may be associated with other hematologic malignancies.22,23 At this time, the subset of patients with mixed cryoglobulinemia who will develop lymphoma cannot be predicted. Type III: Mixed polyclonal IgG and IgM; type III cryoglobulins are commonly seen with a variety of illnesses, including connective tissue diseases (systemic lupus erythematosus [SLE] and RA) and infections. In one study of 607 patients diagnosed with mixed cryoglobulinemia, 27 cases of hematologic malignancies were identified. Of these, systemic autoimmune diseases were detected in 56% of the cases of non-Hodgkin’s lymphoma.23

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PANNICULITIS

ERYTHROMELALGIA

The fasciitis-panniculitis syndrome, which includes eosinophilic fasciitis, is characterized by swelling and induration of the skin that extends into deeper subcutaneous tissues and is associated with fibrosis and chronic inflammation. Patients may develop arthritis and subcutaneous nodules similar to those seen in erythema nodosum. The arthropathy seems to be secondary to periarticular fat necrosis, can be monarticular or polyarticular,24 and may mimic RA or juvenile RA.25 Blood and tissue eosinophilia is commonly, but not always, present.26 This syndrome can be idiopathic and have a benign course, or it can be secondary to a variety of infectious, vascular, or traumatic etiologies. In a few patients, the fasciitis-panniculitis syndrome is associated with an underlying malignancy. Hematologic malignancies are most often associated with this syndrome and are usually diagnosed concurrently or within the first year.27,28 Pancreatic cancer and pancreatitis also can be associated with this syndrome.24,25 Patients with cancer-associated fasciitis-­panniculitis syndrome are predominantly female and are generally refractory to prednisone.27

Erythromelalgia is an enigmatic condition characterized by attacks of severe burning, erythema, and warmth of the extremities with symptoms predominantly involving the feet.38,39 Symptoms are often exacerbated when the extremities are placed in a dependent position, during ambulation, or during exposure to increased temperatures. Partial relief can be obtained through elevation or cooling of the extremity. This disorder can occur idiopathically (60%) or secondary to another disease (40%).38,40 Myeloproliferative disorders, including polycythemia vera and essential thrombocytosis, are common primary causes and have been found to precede the diagnosis of erythromelalgia by several years.39,41 The underlying pathophysiology of this disease is unknown; however, it is often associated with thrombocythemia. In the largest published retrospective cohort, 168 patients at the Mayo Clinic were identified with this diagnosis between 1970 and 1994.42 The authors found that after a mean follow-up of 8.7 years, 31.9% of patients reported worsening of disease, 26.6% reported no change, 30.9% reported improvement, and 10.6% reported complete resolution of symptoms. Kaplan-Meier survival curves revealed a significant decrease in survival compared with controls. A history of myeloproliferative disease was found in 15 of 168 patients. The exact cause of the symptoms is unclear, but microvascular arteriovenous shunting has been hypothesized.43 The most effective therapy seems to be the use of daily aspirin, leading to a significant relief of symptoms, which is believed to be related to inhibition of cyclooxygenase-1. A host of other therapies have been tried with varying success.44 Because of the association with myeloproliferative diseases, routine monitoring with complete blood counts is prudent.

PALMAR FASCIITIS Palmar fasciitis and arthritis is a syndrome characterized by progressive bilateral contractures of the digits, fibrosis of palmar fascia, and inflammatory polyarthritis.29,30 The metacarpophalangeal and proximal interphalangeal joints are most commonly affected; other affected joints include the elbows, wrists, knees, ankles, and feet. Palmar fasciitis is almost uniformly associated with the presence of an underlying malignancy, most often ovarian, breast, gastric, and pancreatic tumors.30-32 Although initially thought to be an atypical variant of reflex sympathetic dystrophy, the severity of manifestations, bilateral presentation, and strong association with occult malignancy suggest that, in these cases, palmar fasciitis is a distinct entity that behaves as a paraneoplastic syndrome. Glucocorticoids, chemotherapy, or both do not seem to result in improvement, although fasciitis occasionally regresses with treatment of the underlying malignancy.29 REFLEX SYMPATHETIC DYSTROPHY SYNDROME Reflex sympathetic dystrophy and a variant, shoulder-hand syndrome, are characterized by regional pain, swelling, vasomotor instability, and focal osteoporosis in a given limb; this condition is thought to be caused by sympathetic dysfunction. The absence of associated antecedent factors, such as stroke, myocardial infarction, or trauma, and failure to respond to conventional therapy warrant a search for an underlying malignancy. A variety of malignancies have been associated with the development of reflex sympathetic dystrophy or its variants.33,34 Pancoast tumor of the lung apices or other malignancies that infiltrate the stellate ganglion or brachial plexus have been described in patients with reflex sympathetic dystrophy.35-37 Therapy directed against the underlying malignancy may lead to some amelioration of symptoms associated with reflex sympathetic dystrophy.

POLYMYALGIA RHEUMATICA Polymyalgia rheumatica is a disorder affecting older adults that manifests with discomfort and stiffness in the shoulder and hip girdle, fatigue, anemia of chronic disease, and elevated erythrocyte sedimentation rate (ESR). Classically, this condition responds to moderate doses of prednisone within 48 hours. A variety of other conditions can have presentations that mimic polymyalgia rheumatica, including other rheumatic disorders, systemic infections, and malignancy.45 Although the association between polymyalgia rheumatica and malignancy has been controversial, atypical features of polymyalgia rheumatica may suggest the presence of occult malignancy, including age younger than 50 years, limited or asymmetric involvement of typical sites, ESR less than 40 mm/hr or greater than 100 mm/hr, severe anemia, proteinuria, and poor or delayed response to 20 mg daily of prednisone. Kidney, lung, and colon cancer and multiple myeloma are most often found in patients presenting with atypical polymyalgia rheumatica.46-48 One study of patients undergoing evaluation for possible polymyalgia rheumatica found 10% to have a diagnosis of malignant neoplasms.49 In contrast, several prospective studies have shown that patients who present with classic polymyalgia rheumatica or temporal arteritis do not seem to have an increased risk of developing malignancy over age-matched controls.50-52

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DIGITAL NECROSIS The development of digital necrosis or profound Raynaud’s phenomenon may suggest the presence of infection, inflammatory disease, or an underlying malignancy. In patients older than age 50 years, the development of Raynaud’s phenomenon, particularly in an asymmetric fashion or in association with digital necrosis, should raise the possibility that this is a paraneoplastic process. These features often antedate the diagnosis of the malignancy by an average of 7 to 9 months.53,54 A variety of solid tumors and lymphoproliferative disorders have been associated with this syndrome.53-59 Mechanisms ­proposed include cryoglobulinemia, immune complex–induced vasospasm, hypercoagulability, marantic endocarditis with emboli, and necrotizing vasculitis.59 Therapy with interferon-α also has been reported in association with the development of Raynaud’s phenomenon and digital necrosis.60-62 REMITTING SERONEGATIVE SYMMETRIC SYNOVITIS WITH PITTING EDEMA Remitting seronegative symmetric synovitis with pitting edema is an uncommon disorder primarily affecting the metacarpophalangeal joints and the wrists. Although the underlying etiology and pathogenesis of this illness are unclear, lymphoma, myelodysplastic syndrome, and several solid tumors, mostly adenocarcinoma, all have been reported in association with it.63-67 Characteristics that suggest possible underlying malignancy include the presence of systemic features, such as fever or weight loss, and a poor response to glucocorticoids.65,66 MULTICENTRIC RETICULOHISTIOCYTOSIS Multicentric reticulohistiocytosis is a rare condition characterized by the presence of cutaneous papules; it is often associated with a destructive arthritis. The papules are fleshcolored to brown-yellow and are classically present in the periungual region and on the dorsal hands and face. Arthritis mutilans may develop in 50% of cases. The characteristic histologic appearance of tissue infiltration with histiocytes and multinucleated giant cells can be found in affected skin, joints, and occasionally internal organs.68 Multicentric reticulohistiocytosis has been reported in association with hyperlipidemia, malignancies, and autoimmune diseases. Malignancy has been associated in 25% to 31% of cases.69 The most frequently seen malignancies include carcinoma of the lung, stomach, breast, cervix, colon, and ovary.68 LUPUS-LIKE SYNDROMES Lupus-like syndromes are rarely associated with underlying malignancy. Isolated case reports have described lupus-like syndromes with ovarian carcinoma70,71 and hairy cell leukemia72; subacute cutaneous lupus was reported in a patient with breast carcinoma.73 Studies on the presence of antinuclear antibodies (ANAs) in patients with cancer have yielded mixed results. Two studies were unable to find a significantly increased prevalence of ANAs in patients with solid tumors or lymphomas compared with healthy controls.74,75 In contrast, one smaller study found an increased prevalence in patients with non-Hodgkin’s lymphoma

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c­ ompared with controls (21% versus 0),76 and another study found a prevalence of ANAs in 274 patients with various malignancies of 27.7% compared with 6.45% of 140 healthy controls.77 There do not seem to be any predictive features that suggest occult malignancy in patients presenting with lupus-like syndromes or positive ANAs. ANTIPHOSPHOLIPID ANTIBODIES Antiphospholipid antibodies and their association with thromboses have been described as a primary syndrome and a secondary phenomenon in autoimmune diseases, ­primarily SLE. More recently, antiphospholipid antibodies have been associated with a variety of malignancies. Correlations between antiphospholipid antibodies in cancer patients and thromboembolic events have been less clear, however. Several studies have shown the presence of antiphospholipid antibodies in patients with solid tumors and lymphoproliferative disorders at a higher frequency than the 1% to 5% seen in the general population.78,79 An early study of 216 consecutive patients with cancer found 22% positive for anticardiolipin antibodies compared with 3.4% in controls. This study found a twofold increase in the development of thromboembolism in patients with positive antibodies compared with patients with negative serologies; it also indicated that most thromboembolic events occurred in patients with higher antibody titers.80 Other studies have confirmed the association between malignancy and antiphospholipid antibodies (12.5% to 68%), but have been unable to show a correlation with thromboembolic events.76,78,81-85 A correlation between antibody titer and disease activity has been shown in some studies,81,83 and decreased survival in others.85 A review of the literature concluded that antiphospholipid antibodies resolve in one third of cancer patients after treatment for the underlying malignancy.86 Studies of the prevalence of antiphospholipid antibodies in unselected patient populations have shown an association with underlying malignancy. A prospective study in France found that 7% of 1014 consecutive patients admitted to a medical ward had antiphospholipid antibodies.87 In antibody-positive patients, cancer was the most frequently associated disease. A more recent study in patients presenting with a first ischemic stroke found a significantly higher rate of development of cancer within 12 months in patients who had anticardiolipin antibodies (19% versus 5%).88 OSTEOMALACIA Osteomalacia is the softening of bones often associated with the failure of adequate calcification secondary to renal dysfunction or a lack of vitamin D. Osteomalacia has been associated with benign and malignant solid tissue and mesenchymal tumors.89 Tumors causing oncogenic osteomalacia have been shown to overproduce fibroblast growth factor 23 (FGF-23), and elevated serum levels of FGF-23 can be detected in patients with this paraneoplastic condition.90 Octreotide scintigraphy may be a useful tool for identifying occult tumors.91 With removal of the tumor, there often seems to be resolution of the osteomalacia and normalization of serum FGF-23 levels.90

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SARCOIDOSIS Noncaseating granulomas can occur in numerous settings and are not pathognomonic for sarcoidosis. Granulomas resembling those of sarcoidosis may be found in lymph nodes that drain sites of malignancy. These tumor-related tissue reactions resulting in granuloma formation have been described with many types of malignant lesions, including solid tumors and lymphomas.92,93 The clinical and radiographic presentation of sarcoidosis and cancer can be virtually indistinguishable, making it important to pursue aggressive evaluation in a patient with sarcoidosis.94 The risk of malignancy developing in patients with established diagnoses of sarcoidosis is controversial. Some studies have shown an increased risk of developing lung cancer and lymphoma,95,96 whereas others have shown no increased risk of cancer over the general population.94,97 LYMPHOMATOID GRANULOMATOSIS Lymphomatoid granulomatosis is a rare disorder with angiodestructive and lymphoproliferative features involving the lung and, less often, the skin and central nervous system. Although lymphocytic infiltration of vessels is a hallmark of the disease, lymphomatoid granulomatosis now seems to fall within the spectrum of lymphoproliferative disorders. Despite the predominance of T cells within inflammatory infiltrates, studies have suggested that an Epstein-Barr virus (EBV)–associated B cell proliferation may underlie the pathogenesis of the disease.98,99 Prognosis is generally poor with a median survival from diagnosis of 14 months,100 although more recent reports suggest some response to rituximab therapy.101,102 Frank lymphomas evolve in 25% of cases.103

INFLAMMATORY MYOPATHIES The inflammatory myopathies in adult populations encompass a group of illnesses characterized by an idiopathic immunemediated attack on skeletal muscle that results in muscle weakness. There have been many associations between the inflammatory myopathies and the presence of malignancy, but the etiology of the association is controversial.104 Dermatomyositis has classically been associated with occult malignancies, whereas the associations between polymyositis and inclusion body myositis are less clear. A further issue is whether the inflammatory myopathy predates the malignancy and can be considered a primary rheumatic disease with known risks of developing malignancy, or whether it simply represents a manifestation of a paraneoplastic process. On average, the prevalence of malignancy in association with the inflammatory myopathies has been approximately 25%. The frequency of malignancy has ranged, however, from 6% to 60% in patients with dermatomyositis and from 0 to 28% in patients with polymyositis.104 Other estimates have placed the incidence of cancer in patients with inflammatory myopathies at five to seven times that of the general population.104 Dermatomyositis has been associated with a wide range of malignancies. Most common are ovarian, lung, and gastric tumors in European populations, and nasopharyngeal malignancies in Asian populations. Studies have confirmed a strong association between dermatomyositis and malignancy. Hill and colleagues105 studied

a pooled cohort of patients from Sweden, Denmark, and Finland and found 198 cases of cancer in 618 patients with dermatomyositis. The standardized incidence ratio (SIR) for malignancy with dermatomyositis was 3. Similar results were found in a Scottish cohort of 286 patients with dermatomyositis.106 Of patients, 77 were found to have underlying malignancies, with an SIR of 3.3 to 7.7. Buchbinder and coworkers107 used strict histopathologic criteria to classify myositis in patients from Victoria, ­Australia. This group found 36 cases of cancer in 85 patients diagnosed with dermatomyositis and an SIR of 4.3 to 6.2. In contrast to the previous work, studies of Asian populations have shown a higher association of nasopharyngeal carcinomas with dermatomyositis. In a Taiwanese study, 18% of 91 patients with dermatomyositis were found to have an underlying malignancy, the most common of which was nasopharyngeal cancer, followed by lung cancer.108 In a smaller study, 66.6% of 15 dermatomyositis patients in Singapore had malignancies, most of which were nasopharyngeal carcinoma.109 Eight white patients with nasopharyngeal carcinoma within 1 year of diagnosis of dermatomyositis were reported more recently in Tunisia.110 In polymyositis, the relative risk for developing internal malignancies seems to be lower than that for dermatomyositis, but it is consistently increased over that expected in the general population. Studies have found a 14% to 30% prevalence of cancer among patients with polymyositis with SIRs increased to 1.2 to 2.1.105-108 Small numbers of many types of cancers were found in these studies. These more recent studies confirm results found in previous large studies of Swedish and Finnish populations and a 1994 meta-analysis of all published case-control and cohort studies of malignancy and myositis that identified an odds ratio for the association of cancer with dermatomyositis of 4.4 and of cancer with polymyositis of 2.1.111 In amyopathic dermatomyositis, a variant of dermatomyositis in which typical cutaneous manifestations are present with subclinical or no identifiable muscle disease, the association with underlying malignancy is controversial, and published reports are limited to small groups of patients.109,112-114 A systematic review of the amyopathic dermatomyositis literature has suggested similar associations between amyopathic dermatomyositis and internal malignancies.115 Far less is known about the association of inclusion body myositis and underlying malignancy. In Buchbinder’s study from Northern Europe, 52 patients were identified with inclusion body myositis. Of the patients, 12 were found to have internal malignancies, with an SIR of 2.4. The numbers of each type of cancer seen were too small to find specific associations.107 Not all studies concur regarding the association between the inflammatory myopathies and malignancy.116,117 In a study done at the Mayo Clinic, patients with myositis did not seem to be at a statistically significant risk for the development of malignancy. No clinical differences were seen between patients who developed a malignancy and patients who did not.117 Despite the negative results of some studies, it seems that most work supports the notion of an increased risk of malignancy in association with dermatomyositis and polymyositis. For patients in whom an inflammatory myopathy has been diagnosed, a workup for the presence of malignancy should be done. The extent of this workup has been debated, ­however,

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because extensive undirected searches often result in a very low yield. It is probably rare for an undirected workup to yield evidence of malignancy in polymyositis and dermatomyositis patients118; any workup should be tailored to the individual patient’s age, symptoms, and signs. Studies have suggested that imaging of the chest, abdomen, and pelvis may increase the potential for discovery of underlying malignancy.119,120 Other studies have suggested the use of serum tumor markers (CA125 and CA19-9) to augment detection of patients with dermatomyositis or polymyositis at highest risk for associated malignancy.121 Malignancies associated with inflammatory myopathies have been known to develop many years after the diagnosis of muscle disease, so continued vigilance and repeated screening for malignancy are warranted. There are certain cohorts in whom the risk of malignancy may be higher, including patients who have active dermatomyositis but exhibit a normal creatine kinase level,122 patients with evidence of distal extremity weakness,123 and patients with prominent pharyngeal and diaphragmatic involvement.123 Patients with myositis-associated autoantibodies may be at less risk for the development of malignancy.123,124 More recent work has suggested that

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the presence of leukocytoclastic vasculitis125 or cutaneous ulceration123 increases further the risk of underlying malignancy. Although the pathogenesis is unknown, the types of malignancy associated with the inflammatory myopathies have been varied, including adenocarcinomas of the breast, ovaries, and stomach. Most cases of dermatomyositis and malignancy seem to occur within 1 year of each other, with myositis diagnosed first in most cases.104 When identified, removal of the malignancy may result in improvement of the myopathic process, which further supports the paraneoplastic nature of myositis in some cases.126

RISKS OF DEVELOPING LYMPHOPROLIFERATIVE DISORDERS IN RHEUMATIC DISEASES Since the 1960s, there have been increasing reports of the association between rheumatic diseases and the development of malignancies, particularly lymphoproliferative disorders. Table 112-3 shows preexisting connective ­tissue

Table 112-3  Preexisting Connective Tissue Diseases Associated with Malignancy Connective Tissue Disease

Malignancy

Associated Factors

Clinical Alert

Sjögren’s syndrome

Lymphoproliferative disorders

Glandular features—  lymphadenopathy, parotid   or salivary enlargement

Clues to progression from   pseudolymphoma to lymphoma   include worsening of clinical features,  disappearance of rheumatoid factor,   and decline of IgM

Extraglandular features—  purpura, vasculitis,   splenomegaly, lymphopenia,   low C4 cryoglobulins Rheumatoid arthritis

Lymphoproliferative   disorders

Presence of paraproteinemia,   greater disease severity, longer   disease duration,   immunosuppression, Felty’s   syndrome

Rapidly progressive, refractory flare in   long-standing rheumatoid   disease may suggest an   underlying malignancy

SLE

Lymphoproliferative   disorders

—

Non-Hodgkin’s lymphoma should be   considered in SLE patients who   develop adenopathy or masses;   lymphoma of the spleen is   another cause of splenic   enlargement in SLE

Discoid lupus   erythematosus

Squamous cell   epithelioma

Found in oldest plaques, ≥20 yr   after onset of discoid lesion,   primarily in men 30-60 yr old

Poorly healing skin lesion within   discoid plaques should be   evaluated

Systemic sclerosis   (scleroderma)

Alveolar cell carcinoma

Pulmonary fibrosis, interstitial   lung disease Areas of scleroderma and fibrosis   in the skin Barrett’s metaplasia

Annual chest radiograph after   fibrosis is detected Change in skin features or poorly   healing lesions should be evaluated Esophagoscopy and biopsy, if   indicated, of distal esophageal   constricting lesions

Nonmelanoma   skin cancer Adenocarcinoma of the   esophagus Paget’s disease of bone

Osteogenic sarcoma

Development of severe pain;   increasing incidence with age

Swelling and bone destruction in   preexisting Paget’s disease may   be sarcoma; diagnosis may   require biopsy

Dermatomyositis

Ovarian, lung, and gastric cancer   in Western populations;   nasopharyngeal carcinoma   in Asian populations

Older in age, normal creatinine   kinase levels, presence of   cutaneous vasculitis; less likely   in setting of myositis-specific   antibodies

Malignancy evaluation needs to   be tailored to individual patient’s   age, symptoms, and signs

SLE, systemic lupus erythematosus.

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diseases that have been associated with malignancy. Much of what is known about associations between rheumatic disease and malignancy is drawn from retrospective and prospective cohort studies, registry-linkage studies, small series, and case reports. In addition, certain confounding factors need to be considered when assessing the risk of the development of malignancy, including the potential oncogenic properties of many of the immunosuppressive and cytotoxic medications prescribed to treat autoimmune diseases. Lymphoproliferative disorders have developed in patients with rheumatic diseases and in recipients of solid organ transplantations treated with immunosuppressive agents. EBV has been implicated in the development of lymphoid neoplasia in immunosuppressed patients. In the following sections, many of the rheumatic diseases and the therapies used to treat them are discussed. SJÖGREN’S SYNDROME Sjögren’s syndrome, an autoimmune exocrinopathy, is characterized by a benign lymphocytic infiltrate of salivary and lacrimal glands that leads to the development of sicca syndrome (keratoconjunctivitis and xerostomia). The development of lymphoproliferative disorders in the setting of Sjögren’s syndrome is perhaps the prototypic example of chronic autoimmune disease and an increased risk of malignancy. In 1964, investigators first reported the development of four cases of lymphoproliferative disorders in a cohort of 58 patients with Sjögren’s syndrome.127 In 1978, 7 of 136 patients with sicca syndrome were identified as having developed non­Hodgkin’s lymphoma. Compared with the expected incidence of cancer among women of the same age range, there was a 44-fold increased risk of developing non-Hodgkin’s lymphoma.128 These findings have been reproduced numerous times in other cohorts. Lymphoproliferative disorders complicate approximately 4% to 10% of cases of primary Sjögren’s syndrome.129-133 The relative risk for development of lymphoproliferative disorders in patients with primary Sjögren’s syndrome ranges from 6 to 44,128,134-139 and a metaanalysis of cohort studies has found a pooled SIR of 18.8.136 Most lymphoproliferative disorders were non-Hodgkin’s lymphoma, specifically low-grade B cell lymphoma, diffuse large B cell lymphoma, and lymphoma of mucosa-associated lymphoid tissue. Waldenström’s macroglobulinemia, chronic lymphocytic leukemia, and multiple myeloma were more rarely reported.128,132,133,135 Generally, the development of lymphoma is a late manifes­ tation of Sjögren’s syndrome, often seen after 6.5 years of disease.130,131,140 Several clinical and laboratory features seem to be associated with or predictive of development of lympho­ proliferative disorders, including palpable purpura,127,132,133,139 cutaneous ulcerations,129 cryoglobulinemia,133 low serum complement levels,132,133,139,141 monoclonal gammopathies,142,143 cytopenias,127,139 splenomegaly,127 and adenopathy.129 Progression to high-grade lymphoma portends a poor prognosis.130,132,133,140 In contrast, the incidence of other malignancies or all-cause mortality was not increased in patients with Sjögren’s syndrome compared with the general population.135,139,144 It is believed that chronic B cell stimulation may lead to the malignant transformation of clonal lines characteristic of Sjögren’s syndrome. The presence of a viral trigger accounting for malignant transformation is one ­possible

theory. EBV, among other viruses, has been implicated, but studies have failed to find EBV or other viral particles in lymphoma specimens associated with Sjögren’s syndrome.145 There also have been reports of chromosomal translocations being present with increased frequency in patients with Sjögren’s syndrome who have developed lymphoma. One group of investigators identified the presence of translocations of the proto-oncogene bcl-2146 in five of seven patients with Sjögren’s syndrome and lymphoma by the use of polymerase chain reaction. Such translocations were found in peripheral blood or bone marrow in 5% of unselected patients with Sjögren’s syndrome without evidence of lymphoma in another study.147 Conversely, no evidence of bcl-2 translocations was present in 50 salivary gland biopsy specimens of patients with Sjögren’s syndrome without evidence of lymphoma.148 Analysis of biopsy specimens taken before the development of lymphoma from the seven patients previously mentioned showed no evidence of bcl-2 translocation. Translocation seemed to correlate with the development of lymphoma in at least a subset of patients with Sjögren’s syndrome, and the use of polymerase chain reaction technology may allow for early detection of malignant transformation.147-149 RHEUMATOID ARTHRITIS Data from numerous studies since the 1970s are persuasive that RA is associated with a twofold to threefold increased risk for the development of lymphoproliferative disorders, the magnitude of which has remained constant despite dramatic changes in therapy. Many factors, including chronic inflammation and immune dysregulation, in addition to potential oncogenic properties of immunosuppressive therapies for the treatment of RA, must be considered when evaluating the risk of the development of hematologic malignancies. It is often difficult to separate the effects of medication use from the underlying severity of inflammation that makes medication use necessary or indicated, a concept termed confounding by indication.150 This association has been highlighted further with widespread use of tumor necrosis factor (TNF)-α inhibitors for patients with refractory disease and the potential for these medications to interfere with innate immune tumor surveillance. In 1978, an SIR of 2.7 for lymphoma was reported in a group of 46,101 Finnish RA patients compared with the general population.151 A similarly increased risk of 2.4 for lymphoma was seen later in a group of 20,699 Danish patients152; an SIR of 1.9 to 2 was reported in a large cohort of 76,527 Swedish patients.153,154 In the United States, an increased risk of 1.9 was found in a cohort of 18,527 patients,155 and an SIR of 2.2 was found in a separate cohort of 8458 patients 65 years old and older.156 ­ Similar results were seen in the United Kingdom: A SIR of 2 to 2.4 for lymphoma was observed in an inception cohort of 2015 patients with inflammatory arthritis in England compared with the general population,157 and an SIR of 2.04 to 2.39 was seen for non-Hodgkin’s lymphoma in a cohort of 26,623 RA patients in Scotland.158 A meta-analysis of nine cohort studies of RA patients found a pooled SIR of 3.9 for lymphoma using a random effects model.137 Canadian investigators found an increased risk of leukemia (SIR 2.47) among RA patients, but were unable to confirm elevated

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rates of lymphomas compared with the general population.159 Data from case-control studies of patients with non-Hodgkin’s lymphoma have shown similar results: Odds ratios of 1.3 to 1.5 were found for underlying RA.136,138 In general, lymphomas in patients with RA do not seem to be different with respect to grade, histology, or immunophenotype from the lymphomas seen in the general population.160 Lymphoma patients with underlying RA, although having similar overall survival, seemed in one study to have a lower risk of progression, relapse, or death from lymphoma.161 Most studies have suggested that the risk for the development of lymphoma is related to the degree of inflammation. The Swedish group identified high inflammatory activity (defined by ESR, swollen and tender joint counts, and the physician’s global assessment of disease activity) as a significant risk factor, with an odds ratio of 25.8 compared with low disease activity.162 No association between any specific drug and the development of lymphoma was identified; however, the cohort examined was treated between 1965 and 1983, and few of these patients were apparently treated with immunosuppressive drugs, making the lack of association less certain.162 In a follow-up case-control study of 378 lymphomas in a Swedish group of RA patients published more recently, a 71-fold increased risk of lymphoma in patients with high cumulative disease activity compared with low disease activity was seen.163 Immunosuppressive therapy did not seem to modify risk for lymphoma in this study. Patients with active RA often exhibit elevated immunoglobulin levels. In most cases, this is polyclonal in origin and may reflect the presence of rheumatoid factor. The possibility exists, however, that the paraprotein may be of monoclonal B cell origin and may reflect early development of a lymphoproliferative disorder. The incidence of monoclonal gammopathy in patients with RA has been estimated to be 1% to 2%,164 which is comparable to the incidence of monoclonal gammopathy of unknown significance in the general population.165 Other factors, such as the presence of secondary Sjögren’s syndrome or the presence of urinary free light chains, seem to be of less prognostic significance for the development of a lymphoproliferative disorder.164 Patients with Felty’s syndrome (a variant of RA associated with neutropenia and splenomegaly) were found in a Veterans Affairs study of 906 men to have a 2-fold increase in total cancer incidence, but a 12-fold increase in risk of non-Hodgkin’s lymphoma.166 Traditional Disease-Modifying Antirheumatic Drug Therapy Several studies have looked at the contribution of diseasemodifying antirheumatic drug (DMARD) therapy to the elevated risk of malignancies in RA patients. A prospective, observational study was performed in a group of Canadian RA patients enrolled in a DMARD registry.167 Although this study found an increased rate of lymphoproliferative disorders in this cohort compared with the general Canadian population (SIR 8.05), there were no significant differences in DMARD exposure between patients who developed malignancy and patients who did not. A second group of Canadian investigators similarly identified an increased risk for the development of lymphoma and myeloma in RA patients overall compared with control groups.168 In this study, the risk of lymphoma and myeloma seemed to be 4-fold greater

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in the RA group when DMARD use was not controlled for and 3.4-fold greater when individual DMARD use was controlled for. Despite the low level of DMARD exposure in this population, no strong effect of DMARD use was seen. Similar effects of DMARD use were seen in the study of Swedish patients with RA and lymphoma: Treatment with any DMARD (odds ratio 0.9), or specific use of methotrexate (odds ratio 0.8), did not seem to be associated with increased risk of lymphoma compared with DMARD-naive RA patients; however, no patients had been treated with TNF inhibition.166 In contrast, a European cohort of RA patients enrolled in a DMARD registry was evaluated longitudinally for the development of malignancies.169 These investigators found an increased risk of lymphoproliferative disorders in patients with the highest cumulative exposure to DMARDs compared with patients with less than 1 year of exposure (SIR 4.82). Although inconclusive, data from these studies when taken together suggest a possible increased risk for the development of lymphoproliferative disorders in RA patients treated with DMARDs. More recent studies have suggested, however, that this increased risk may be due to the duration and severity of the underlying disorder, rather than to specific medication use. Methotrexate The recognition that erosion and joint destruction begin early has increased the use of DMARDs earlier in the course of disease, and methotrexate has become the most commonly used DMARD for the treatment of RA. Numerous long-term clinical studies have shown mixed data regarding the risk of lymphoproliferative diseases specifically related to treatment with methotrexate in patients with RA.138,155,166,170 More than 50 cases of non-Hodgkin’s lymphoma in RA patients treated with methotrexate have been cited in the literature170; most patients are reported to have B cell lymphoma, and extranodal involvement is common. Only 17 of these cases were assayed for the presence of EBV, of which 7 (41%) were positive.170 This rate is less than that seen in post-transplantation patients or in patients with acquired immunodeficiency syndrome (AIDS) who develop lymphoma, but it is still significantly higher than that for lymphoma in the general population.171 It has been postulated that, although methotrexate may carry a small risk of EBV-associated lymphoma in patients with RA, its ability to reduce disease activity of RA (which is an established risk factor for development of lymphoproliferative disorders) may lead in time to an overall reduction in the rate of malignancies seen in the RA population.172 Of the 50 original cases of B cell lymphoma cited in the literature, 8 patients have been reported to experience spontaneous remission after stopping methotrexate; of these, 4 patients were positive for EBV.170 Of the patients who developed Hodgkin’s disease in the French study, none treated with withdrawal of methotrexate alone achieved remission.171 This finding suggests that, in at least a few methotrexate-treated patients with non-Hodgkin’s lymphoma, the lymphoma might go into remission spontaneously, and that a brief period of observation without immunosuppressive therapy might be considered, particularly in patients found to be EBV positive.170,172 The mechanisms by which lymphoma may develop in RA patients and be potentiated by methotrexate include persistent immunologic stimulation,

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which might lead to clonal selection and malignant transformation of CD5+ B cells; reactivation of latent EBV173; direct oncogenic action; decreased apoptosis of infected B cells; and decreased natural killer cell activity.170 Tumor Necrosis Factor Inhibitors The advent and widespread use of TNF-α inhibitors has dramatically changed the treatment options for patients with RA. Because of the role of TNF in innate immune tumor surveillance and cytotoxic response to B cell lymphomas, long-term use of such inhibitors brings concerns regarding further increases in risk for lymphoma development in RA patients.174 After an initial report to the U.S. Food and Drug Administration of 26 cases of lymphoma in patients treated with etanercept and infliximab for RA or Crohn’s disease,175 numerous additional studies have examined the roles played by these agents with conflicting results. Wolfe and Michaud155 found an SIR of 2.9 in U.S. RA patients (10,012 patient-years) receiving anti-TNF therapy compared with 1.9 for all participating RA patients (29,314 patient-years), regardless of therapy. A larger Swedish study evaluated 4160 RA patients receiving TNF inhibitors and found an SIR of 2.9 for lymphoma compared with the general population.181 Further analysis found a nonsignificant adjusted relative risk of lymphoma in the anti-TNF– treated group of 1.1 compared with 56,770 TNF-naive RA patients.176 This study was followed by an analysis of pooled administrative databases in North America, which found a nonsignificant hazard ratio (1.1) for the development of lymphoma among RA patients 65 years old and older using biologic agents, primarily TNF inhibitors (N = 1152), compared with patients receiving methotrexate (N = 7306).156 In contrast, a population-based study from Sweden evaluating 757 anti-TNF–treated patients (1603 patient-years) found an extremely high SIR of 11.5 compared with an SIR of 1.3 for TNF-naive patients (3948 patient-years).177 A meta-analysis specifically evaluating harmful events occurring during nine randomized, clinical trials of infli­ ximab and adalimumab (data on etanercept were not included) has been published.178 The authors found an odds ratio of developing any malignancy of 3.3 for patients receiving in­fliximab or adalimumab compared with patients receiving placebo. The odds ratio remained elevated after malignancies occurring within 6 weeks of initiating antiTNF therapy and all nonmelanoma skin cancers were excluded. Of the 29 malignancies found in anti-TNF– treated patients, 4 were lymphomas. Criticisms of this study include heterogeneity of patient populations, concomitant medications, and comorbidities among clinical trials179; differential follow-up between placebo and treated groups; and an unusually low rate of malignancy seen in the ­placebotreated patients.180 Overall, these data raise the possibility that TNF inhibition further increases risks of lymphoproliferative disorders in patients with RA. Several factors make these possible associations far from conclusive: Patients with RA already seem to be at an increased risk for the development of lymphoproliferative disorders; patients with the highest disease activity may be at the highest risk; and these patients also are more likely to have received previous immunomodulatory agents, to be on multiple agents in combination, and

to be receiving anti-TNF therapy. Separating the impact of disease activity, other DMARD therapy including prior or concomitant methotrexate, and the role of TNF inhibition on the risk of lymphoma is impossible; these confounders will always be present to some degree in studies of malignancy in relation to RA and its treatment. Risk of Solid Tumors in Patients with Rheumatoid Arthritis Despite persuasive evidence of increased risks of lympho­ proliferative disorders associated with underlying RA, rates of overall all-site malignancies do not seem to be higher compared with the general population.151-153,158,159 The overall “null” result of all malignancies is due to the combination of an increased risk of lymphoproliferative disorders offset by an apparent decreased risk of colorectal malignancies.151-153,158,159,181 The decreased risk of colorectal cancer has been attributed to long-term use of NSAIDs among RA patients.182 Aside from lymphoproliferative disorders, only a few solid tumors have been associated with RA, including lung cancer and nonmelanoma skin cancer. An increased risk of lung cancer in RA patients has been seen in multiple ­studies.151-153,158,159,181 A study evaluating three separate RA cohorts (an inpatient registry of 53,067 prevalent cases of RA, an inception cohort of 3703 incident RA cases, and a registry of 4160 RA patients treated with TNF inhibitors) found a consistently increased risk of lung cancer in all cohorts (SIR 1.48 to 2.4) compared with the general population.181 This association may be related to tobacco use, which seems to be a common risk factor for the development of RA in addition to its well-known association with lung cancer,183 although the particular association of lung cancer among RA patients who smoke is unknown. A slightly increased risk for the development of nonmelanoma skin cancer has been noted in several studies,151,152,181,184 although the significance of these tumors, which carry a low probability of metastasis, is unclear. SYSTEMIC LUPUS ERYTHEMATOSUS The risks of developing malignancy in association with SLE have been difficult to estimate in the past. Small series and cohort studies have noted that patients with SLE might be at increased risk for malignancy, including non-­Hodgkin’s lymphomas, sarcomas, and breast carcinoma.185-189 Other small series have not found differences,190 however, or have found infrequent associations191 in numbers or types of malignancy between patients with lupus and the general population.190 Conflicting results also are seen in case-control studies of larger groups of patients, with some cohorts showing an increased overall risk of malignancy,192-194 whereas others have failed to do so.195-198 Some studies that did not find an increased risk of overall malignancies in patients with SLE have shown an increased risk of lymphoproliferative disorders, however.136,138,196-198 Confounding factors complicating interpretation of these studies include possible incomplete ascertainment of malignancies, inclusion of nonrepresentative cohorts of patients with SLE, and selection of inappropriate control populations.199

PART 18 

To determine more adequately whether individuals with SLE are at an increased risk, systematic reviews and metaanalyses of pooled data are necessary. The SIR of individual studies has ranged from 1.1 to 2.6.200 A meta-analysis of six of the clinical cohort studies found a slightly increased risk of overall malignancies in cohorts of patients with SLE, with an SIR of 1.58.201 This analysis showed an increased risk of lymphomas in these cohorts, with an SIR of 3.57 for non-Hodgkin’s lymphoma and 2.35 for Hodgkin’s disease. A separately performed meta-analysis of the incidence of lymphoma in patients with SLE found an SIR of 7.4.137 Individual hospital discharge database studies have shown a consistently higher risk of non-Hodgkin’s lymphoma (SIR 3.72 to 6.7), but these studies examined only hospitalized patients with SLE.200 Pooled analysis showed a slightly elevated risk for the development of breast cancer, with an SIR of 1.53, but they did not find an increased risk of lung or colorectal cancers in these patients.201 The same confounding factors influencing the individual studies are a factor in interpreting these pooled data. A more recent series of studies analyzing nearly 9500 lupus patients (approximately 77,000 patient-years of observation) in a multinational cohort study has helped to define better potential associations with malignancy.202,203 The authors of these studies have found a slightly increased risk of malignancies overall (SIR 1.15) and higher risks for the development of hematologic ­ malignancies (SIR 2.75), particularly non-Hodgkin’s lymphoma (SIR 3.64).202 Forty-two cases of non-Hodgkin’s lymphomas were identified, most of which were of aggressive ­histologic subtypes.204 The elevated risk of non-Hodgkin’s lymphoma seemed to be independent of race or ethnicity in this cohort, although white patients seemed to have higher rates of malignancy in general compared with patients of other ethnicities.205 Several studies have additionally raised concerns about an increased risk of gynecologic malignancies among women with SLE.192,201,203 Data supporting an increased risk of developing breast cancer have been mixed; however, increased risks may have been masked by differential rates of known risk factors for breast cancer compared with women in the general population.203 Women with SLE have been shown to have less exposure to oral contraceptives and greater prevalence of nulliparity, obesity, and tobacco use, all of which may mitigate the numbers of breast or other hormonal malignancies seen in this population.206 The number of breast cancers seen in large cohorts of women with SLE well exceeds what would be expected based on traditional Gail model risk factors, including age, parity, family history, reproductive history, and use of exogenous estrogens (SIR 2.1).207,208 Breast cancers in women with SLE do not seem to be diagnosed at earlier stages than in the general population, making surveillance bias an unlikely explanation for the associations seen.209 One study suggested that women with SLE receive ageappropriate screening mammography less frequently than do healthy women.210 The relative prevalence of cervical cancer in SLE patients is more difficult to estimate because national cancer registries often do not record malignancies in situ. In the large multinational study performed more recently, the SIR for invasive cervical cancer was found to be elevated at 1.26,

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albeit with confidence intervals that cross the null.202 Other studies have confirmed an increased risk of abnormal Pap smears and cervical dysplasia in women with SLE.211-214 Different studies have implicated increased prevalence of human papillomavirus infection and other sexually transmitted diseases,213,215 oral contraceptive use,215 and immunosuppression212,215 that may partly explain this association. Similarly to mammography, women with SLE seem less likely to undergo routine Pap testing than women in the general population.210 Although the exact etiology of the association is unknown, several theories have arisen to explain the possible connection between SLE and malignancy, especially B cell lymphoma. Some authors have postulated that ­ certain immunologic defects may predispose patients to SLE and B cell lymphoma, including apoptosis dysfunction, chronic antigenic stimulation, and overexpression of bcl-2 oncogene.200,216 Viruses, EBV in particular, also have been postulated as part of the development of SLE and lymphoma.200,216 Studies have not conclusively validated any of these theories to date, however. Overall, the presence of SLE seems to carry a small increased risk for the development of lymphoproliferative disorders, particularly non-Hodgkin’s lymphoma. The underlying cause of this association is unknown. The association does not seem to be related to the use of immunosuppressive or cytotoxic agents.185,196,198,200 Data also suggest that lupus patients may be less likely to receive recommended cancer screening.210 SYSTEMIC SCLEROSIS Although data are conflicting, most evidence suggests that individuals with systemic sclerosis seem to have an increased risk of developing malignancy.217 The malignancies that have been implicated are often in organs affected by inflammation and fibrosis, including the lung, breast, esophagus, and skin. The SIR of malignancy in the scleroderma population is 1.5 to 5.1 compared with that of the general population.218-223 There is an apparent increase in the observed number of cases of lung cancers that occur in the setting of pulmonary fibrosis but not in association with tobacco use.222,224 There also seems to be a temporal correlation between the onset of systemic sclerosis and the development of breast cancer, although not an increased incidence of breast cancer.218 Older age at the time of diagnosis with systemic sclerosis seems to be a significant risk factor for the development of cancer.219 Data are mixed regarding associations between systemic sclerosis–specific autoantibodies and the development of cancer: Selected studies support potential associations,221,225 whereas others do not.222,226 Although the SIR for all malignancies is 1.5 to 2.4, the incidence ratio for lung cancer can be as high as 7.8 and for non-Hodgkin’s lymphoma 9.6. Cases of non-Hodgkin’s lymphoma seem to be more likely to occur within the first year of the diagnosis of systemic sclerosis.220 Elevations in incidence also were found for other specific cancers, including nonmelanoma skin cancers (4.2), primary liver cancers (3.3), and hematopoietic cancers (2.3)—all having a higher incidence than that in the general population. The greatest risk seems to correspond to areas commonly affected by fibrosis, particularly the lung and skin. ­Esophageal ­involvement,

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common to limited and diffuse systemic sclerosis, is the likely etiology for an increased incidence of Barrett’s esophagus (12.7%)227 and development of esophageal cancer (SIR 9.6).223 Potential biologic explanations for a possible increased incidence of carcinoma of the tongue seen in one cohort of systemic sclerosis patients are less clear.228 In contrast to the above-mentioned data, one study found no increase in overall or specific malignancies in patients with systemic sclerosis (SIR 0.91 overall).226 Localized scleroderma, including morphea or linear scleroderma, does not seem to convey an increased risk of malignancy.229 Several reports have described the development of postirradiation morphea in patients treated for breast cancer.230

PRIMARY TUMORS AND METASTATIC DISEASE PRIMARY MUSCULOSKELETAL TUMORS This section does not provide in-depth knowledge of the primary tumors of the musculoskeletal system. Rather, it provides a reference to the most common primary malignant musculoskeletal tumors and symptoms that may arise in association with them. The primary tumors of bone, including benign and malignant tumors, are discussed in more detail in Chapter 114. A primary malignant bone cancer is any neoplasm that develops from the tissues or cells found within bone that has the ability to metastasize. Neoplasms may develop or arise from any of the types of cells present within the bone—osteoblasts, chondrocytes, adipose and fibrous tissue, vascular cells, hematopoietic cells, and neural tissue.231 A neoplasm developing from any of these tissues is called a sarcoma, which signifies that it is derived from mesenchymal tissue. The bone sarcomas are named for the predominant differentiated tissue type, such as osteosarcomas, chondrosarcomas, liposarcomas, and angiosarcomas.231 The most common manifestation of these tumors is the development of pain in the area of the lesion, which may be accompanied by a sympathetic effusion or stiffness in the surrounding joint. This discomfort does not seem to be activity related and is often worse at night. These tumors can manifest, however, as painless masses or as pathologic fractures. Systemic features, such as fatigue, malaise, weight loss, fevers, and night sweats, are rare with all of these tumors except for Ewing’s sarcoma.231 Primary malignant bone tumors are uncommon, particularly compared with other types of cancer. They have their highest incidence in childhood and adolescence and constitute 3.2% of childhood malignancies that occur before age 15 years. The incidence has been reported in this age group as 3 per 100,000 individuals.232 These tumors commonly arise out of areas of rapid growth, with the most common site of primary bone sarcomas being the metaphysis near the growth plate.232 Table 112-4 lists the most common types of primary malignant bone tumors. Osteosarcoma is the most common of the tumors and generally occurs in individuals in the ­second decade of life or in elderly individuals.233 Osteosarcoma also can occur secondary to radiation therapy ­ delivered as treatment for other malignancies. Paget’s disease of bone can rarely (<1% of cases) proceed to malignant transformation.234 Severe pain in the ­setting of Paget’s disease may signal ­transformation to

Table 112-4  Primary Bone Tumors Nonosseous Tumors

Osseous Tumors

Multiple myeloma

Osteosarcoma

Round cell tumors

Chondrosarcoma Giant cell tumors Fibrosarcoma

osteogenic sarcoma. Tumors most frequently affect the femur, humerus, skull, and pelvis and can result in pathologic fractures. Survival is usually less than 1 year. Differentiating malignancy from Paget’s disease may require a biopsy.235,236 Chondrosarcoma has been reported as the second most common of the malignant bone tumors. This tumor may occur as a primary tumor or as a malignant transformation in the setting of benign lesions, such as an enchondroma or osteochondroma.237 Fibrosarcoma is significantly less common than the previously mentioned tumors and accounts for less than 4% of primary malignant bone tumors.238 As a group, round cell tumors include primary ­lymphomas of bone, Ewing’s sarcoma, and metastatic neuroblastoma. Ewing’s sarcoma is a common primary bone tumor of ­childhood. Giant cell tumors as a group account for 4.5% of bone tumors. They usually arise from the metaphysis or epiphysis of long bones, generally around the knee. Most are benign, but a few are malignant lesions, usually arising out of a previously irradiated benign giant cell tumor.231 In addition to the primary malignancies of bone, there are a plethora of malignant tumors that can arise from mesenchymal connective tissue; these are also known as ­sarcomas.238,239 They can result in joint complaints, but more often result in soft tissue complaints. They are very rare. Rhabdomyosarcoma is a malignant tumor arising from muscle tissue. It is the fourth most common solid tumor in children and is responsible for more than half of all soft tissue sarcomas in children. Rhabdomyosarcoma rarely occurs in adults. It can appear at any site, and the symptoms are most often referable to the site involved. Most commonly, rhabdomyosarcoma affects the orbits, genitourinary tract, limbs, head and neck, and parameningeal areas. It commonly metastasizes to the lymph nodes, lungs, and bone.232,240 METASTATIC DISEASE When bone lesions are identified, primary tumors need to be considered, although most malignant lesions in bone are metastatic. Metastasis rarely affects muscles, joints, or adjacent connective tissue. More commonly, it affects bone. The most common sites of metastasis are the spine and pelvis. It is uncommon to find metastatic lesions distal to the elbow, and, although rare, metastasis to the foot is more common than to the hand.241 When distal or acral metastasis is identified, it is often associated with lung cancer.242 Primary tumors generally associated with metastases to bone include tumors in the prostate, thyroid, lung, breast, and kidney.243 Although most skeletal metastases do not produce pain, one of the most common causes of cancer pain is the infiltration of bone. The pain can be intense and stabbing or dull. It is often constant rather than intermittent, is worse at night, and often is worse with weight bearing and movement.244 Rheumatic or arthritic complaints often can occur before lesions are easily identified on radiographs. Arthritis associated with metastatic carcinoma

PART 18 

Table 112-5  Frequent Features of Arthritis   Resulting from Metastatic Carcinoma Presence of constitutional symptoms Prior history of malignancy Protracted clinical course Negative culture results, negative crystal analysis

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result in spondyloarthritis or inflammatory arthritis. Interferon-α administration can result in seropositive nodular RA and myalgia and arthralgia.252,253 The use of interferon also can result in autoantibody formation and features suggestive of SLE and autoimmune thyroid disease.253-255

Rapid reaccumulation of hemorrhagic noninflammatory effusion

LYMPHOPROLIFERATIVE AND MYELOPROLIFERATIVE DISEASES

Radiologic evidence of destructive process

LEUKEMIA

Medical therapeutic failure

is most commonly monarticular and most commonly affects the knee. Metastases to the hip, ankle, wrist, hand, and foot have been reported, but occur less frequently. Breast and lung carcinomas are present in most patients.245 ­Metastases to the extremities can simulate gout, osteomyelitis, tenosynovitis, or acro-osteolysis. The development of joint involvement can be related to direct synovial implantation or involvement of the juxta-articular or subchondral bone.246 Table 112-5 presents­ the clinical features suggestive of underlying metastases. Radiographic features of bone tumors can be significant when interpreting the duration of disease and the type of malignancy. Lesions may be lytic or blastic, and patterns of destruction often reflect the aggressiveness of tumors. Well-circumscribed lesions may be more indicative of slower growth, whereas a “moth-eaten” pattern with evidence of cortical destruction typically signifies a more rapid rate of growth. What has been described as a permeative pattern suggests an extremely rapid rate of destruction and is often associated with an extraosseous soft tissue mass.231 Computed tomography, magnetic resonance imaging, and radionucleotide imaging also can provide significant information for diagnosis, staging, prognosis, and therapy. POSTCHEMOTHERAPY RHEUMATISM Several rheumatic or musculoskeletal manifestations can develop in patients after administration of chemotherapy for the treatment of malignancy. Postchemotherapy rheumatism has been best described in patients treated for breast cancer, but also has been described in other malignancies, including ovarian cancer and non-Hodgkin’s lymphoma.247-249 The phenomenon has been described as a noninflammatory, selflimited, migratory arthropathy. Typically, symptoms develop several weeks to several months after the completion of chemotherapy and often include myalgia, stiffness, arthralgia, and arthritis involving the small joints of the hands, ankles, and knees.248 It can be mistaken for RA based on its symptoms; however, most patients have little or no evidence of synovial thickening and have no radiographic or serologic evidence to suggest RA. The pathogenesis of this process is unknown; however, it is self-limited, usually lasting less than 1 year, and is best treated in a conservative fashion. Evaluation should be performed to exclude recurrent carcinoma or another inflammatory condition. The medications most frequently implicated in this phenomenon include cyclophosphamide, 5-fluorouracil, methotrexate, and tamoxifen.249-251 Other immunomodulatory agents also have been linked to the development of musculoskeletal findings. Tamoxifen use has been associated with the development of an acute inflammatory arthritis similar to RA.251 Use of interleukin-2 can

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Leukemia can result in the development of musculoskeletal complaints. Bone pain is the most common musculoskeletal manifestation, and it has been reported to occur in 50% of adults with leukemia.256 Long bone pain is more common in children, whereas axial pain is more common in adults. Generally, the bone pain is more common in the lower than the upper extremities.257 Overt synovitis can develop in association with acute and chronic leukemia and can result in the development of monarticular or polyarticular arthritis.258 The pathogenesis seems to be leukemic infiltration of the synovium and subperiosteal tissue. Bleeding or hemorrhage in the joint also may be associated with the process. Most cases of arthritis associated with leukemia are seen in children— 14% to 50% compared with 4% to 16.5% in adults.259-261 In a series of adult patients with acute leukemia studied over a 10-year period, 5.8% (8 of 139) of the patients presented with rheumatic manifestations. On average, symptoms of arthritis preceded the diagnosis of leukemia by 3.25 months.262 The most common patterns of presentation were an asymmetric large joint involvement in association with low back pain, followed by symmetric polyarthritis mimicking early RA. Rheumatic manifestations included morning stiffness, low back pain, nonarticular bone pain, pain out of proportion to objective findings, low-grade fever, and elevation of the ESR. The response to NSAIDs, glucocorticoids, and conventional antirheumatic therapy was reportedly poor, but tumor-directed chemotherapy resulted in substantial improvement of the rheumatic manifestations. Patients with these manifestations also were more likely to exhibit early osteopenia or lytic bone lesions. Ultimately, prognosis and mortality rates were no different between patients presenting with or without rheumatic manifestations.262 In contrast, a large retrospective study of children with ­leukemia found 21.4% (36 of 168) with acute lymphoblastic leukemia and 10.5% (6 of 57) with acute ­nonlymphoblastic leukemia developed symptoms associated with bones and joints. Thirteen of these patients with acute lymphoblastic leukemia had evidence of bony lesions on radiographs.263 Many of these children had been incorrectly treated for juvenile RA or osteomyelitis before the diagnosis of ­ leukemia. The group with bone lesions seemed to do very well, and their condition might fall into a subgroup of childhood leukemia that has a better prognosis.258,263 A more recent study found that the presence of subtle blood count changes and nighttime pain may help distinguish leukemia from juvenile RA.261 MULTIPLE MYELOMA Multiple myeloma is a neoplastic proliferation of plasma cells, a nonosseous malignant tumor arising in the marrow. In contrast to the other primary tumors of bone, which

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have their highest incidence in children and adolescents, myeloma is a tumor of adults, occurring most commonly in the fifth and sixth decades of life. The most common musculoskeletal feature of this disease is the development of bone pain. Other hallmark features are diffuse pain and stiffness. Patients characteristically develop osteopenia, and osteolytic lesions are seen on radiographs. The lytic lesions, which can occur in any area of the skeleton, are produced by focal accumulations of plasma cells. Osteosclerotic lesions also have been reported.264 True arthritis is rare, but cases of arthritis secondary to articular and periarticular invasion with malignant cells have been reported in multiple myeloma and in Waldenström’s macroglobulinemia.265 A secondary feature of the disease, which can often lead to additional musculoskeletal complaints, is the development of hyperuricemia and secondary gout. Sjögren’s syndrome and other autoimmune phenomena also have been described in association with multiple myeloma.266 LYMPHOMA Musculoskeletal symptoms have been reported in 25% of cases of non-Hodgkin’s lymphoma.267 The most common musculoskeletal problem associated with lymphoma is the development of bone pain associated with metastases or lymphoma in the bone. By report, more than 50% of patients have evidence of bone lesions at autopsy; however, few patients actually present with arthritis or bone pain.258,268 Nonetheless, non-Hodgkin’s lymphoma has been reported to manifest as a seronegative arthritis with or without other features, such as lymphadenopathy and hepatomegaly, ­typically seen with this disease. Monarticular and polyarticular involvement can occur. Cases have been reported of polyarthritis simulating RA in the setting of nonHodgkin’s lymphoma.269 Although it is unusual to see direct ­involvement of the synovium, this also has been reported. There have been cases with radiographic evidence of bone destruction associated with non-Hodgkin’s lymphomatous arthropathy.270 Suspicion of lymphoma should be heightened in patients in whom severe constitutional symptoms seem out of proportion to the degree of arthritis, especially in patients who are negative for rheumatoid factor.267 ANGIOIMMUNOBLASTIC LYMPHADENOPATHY Angioimmunoblastic lymphadenopathy is a rare lymphoproliferative disorder marked by the clinical features of lymphadenopathy, hepatosplenomegaly, rash, and hypergammaglobulinemia. Patients can develop a nonerosive, symmetric, seronegative polyarthritis concurrent with other features or as an initial complaint of the disease.271-273 Similar features have been reported with intravascular lymphoma, with a report of a patient presenting with a symmetric polyarthritis accompanied by fever.274 Table 112-6 lists musculoskeletal complaints found with hematologic malignancy. GRAFT-VERSUS-HOST DISEASE Graft-versus-host disease is a complication of bone marrow transplantation and a major cause of morbidity and mortality in the transplant population. Numerous ­musculoskeletal

Table 112-6  Musculoskeletal Manifestations   of ­Hematologic Malignancy Malignancy

Pathogenesis

Leukemia

Infiltration of synovium

Lymphoma

Metastases or invasion of   bone, rarely joint

Angioblastic lympha-  denopathy

Vasculitis, cryoglobulinemia

Multiple myeloma

Metastasis or invasion of   bone, hyperuricemia

complaints arise in the setting of acute graft-versus-host disease (lasting 0 to 3 months) and in chronic graft-versushost disease (lasting >3 months after transplantation). The most frequent manifestation is the involvement of the skin, which in many cases can progress to resemble the changes of systemic sclerosis. Skin changes consistent with eosinophilic fasciitis also have been reported.257 Graft-versus-host disease can lead to symptoms of keratoconjunctivitis sicca and xerostomia resembling Sjögren’s syndrome. Other features including arthralgias, arthritis, myositis, Raynaud’s phenomenon, and serositis also have been reported.257,275

ASSOCIATION OF IMMUNOMODULATORY AGENTS WITH MALIGNANCY Many of the medications used to treat rheumatic diseases are modulators of the immune system. As such, they may be associated directly or indirectly with an increased risk of the subsequent development of malignancy associated with the underlying disorder. An individual agent may confer this risk through direct mutagenesis of DNA, through generalized immunosuppression with the risk of developing an EBV-associated lymphoproliferative disorder, or through injury to an unintended organ system, such as the bladder with the use of cyclophosphamide. Longer duration of use of these agents has been associated with increasing risk of developing subsequent malignancies.276 It is often difficult, however, to differentiate adequately the individual risk of an agent, particularly in the background of an autoimmune disease that itself can convey an increased risk for the development of malignancy. Table 112-7 provides an overview of the potential oncologic risks of various immunomodulatory therapies. CYCLOPHOSPHAMIDE Cyclophosphamide is an alkylating agent that kills resting and cycling cells and has cytotoxic, mutagenic, and carcinogenic potential. It is used predominantly for the treatment of vasculitis, glomerulonephritis, and other life-­threatening or organ-threatening manifestations of rheumatic disease. The use of cyclophosphamide in RA seems to result in an increased risk of the development of bladder cancer, skin cancer, and hematologic malignancies including nonHodgkin’s lymphoma and leukemia.277,278 Risk factors for the development of neoplasia include higher total dosage, longer duration of therapy, and tobacco use.279 The overall relative risk of developing malignancy seems to be 1.5 to 4.1 for those treated compared with controls, and the increased

PART 18 

Table 112-7  Immunomodulatory Agents and Risk   of Malignancy DMARD

Risk of Malignancy

Cyclophosphamide

Non-Hodgkin’s lymphoma, ­leukemia, bladder cancer, skin cancer

Azathioprine

Non-Hodgkin’s lymphoma

Cyclosporine

Immunosuppression-associated lymphoma

Methotrexate

Immunosuppression-associated lymphoma

Gold salts

None known

Hydroxychloroquine

None known

Penicillamine

None known

Sulfasalazine

None known

Leflunomide

None known

Biologic response modifiers

Unknown, possible lymphoma

DMARD, disease-modifying antirheumatic drug.

risk of bladder cancer continues more than 17 years after cyclophosphamide therapy.278,279 The increased incidence of bladder cancer and other malignancies in patients with Wegener’s granulomatosis treated with cyclophosphamide has been shown in a series of studies from Sweden.280,281 Patients with Wegener’s granulomatosis treated with cyclophosphamide had a twofold increased risk for cancer overall, with higher risks for specific tumors: bladder cancer (SIR 4.8), leukemia (SIR 5.7), and lymphoma (SIR 4.2).280 As with RA patients, higher cumulative doses of cyclophosphamide were associated with higher risks of developing bladder cancer.281 The increased risk for the development of bladder cancer is believed to be a direct result of high concentrations of active metabolites in the bladder, such as acrolein. The overall risks of bladder cancer may be less with pulsed, intravenous treatment than with daily oral cyclophosphamide. The use of cyclophosphamide generally is restricted to life-threatening or organ-threatening disease in which the risks associated with treatment are outweighed by the serious effects of untreated rheumatic disease. METHOTREXATE Methotrexate is one of the most commonly used agents in the treatment of rheumatic diseases and generally has a favorable side-effect profile. Similar to many other immunomodulatory agents, questions have been raised regarding the oncogenic potential of methotrexate when used to treat autoimmune or inflammatory disorders. There has been no strong evidence to suggest that methotrexate conveys an increased risk for the development of solid tumors. There have been reports, however, of a relationship between methotrexate use and the development of lymphomas, as previously discussed in the section on RA-associated malignancies. Despite this possible association, methotrexate has been shown to reduce all-cause, cardiovascular, and noncardiovascular mortality in patients with RA compared with RA patients treated with other agents.282 Although this work may not directly address questions regarding the use of methotrexate in RA and the risk of developing ­malignancy,

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it helps to answer the overall question of whether this agent’s benefits outweigh its risks. Studies have been published regarding the possible association of methotrexate use in the treatment of RA and the development of lymphoproliferative disorders associated with EBV, as was previously mentioned in the section on RA-associated malignancies. EBV has been reported in non-Hodgkin’s lymphoma, Hodgkin’s disease, and T cell lymphomas in RA patients treated with methotrexate.171,172,283,284 One set of investigators reviewed all reported cases of lymphoproliferative disorders in RA patients treated with methotrexate.285 They subsequently identified most of the cases as non-Hodgkin’s B cell lymphomas, either large cell or diffuse mixed type. In many of the cases, there was extranodal involvement. In patients tested, 46% showed evidence of EBV infection, and in 14 patients treated solely by withdrawal of methotrexate, 8 achieved full remission. The rate of EBV association is less than that seen in post­transplantation patients or in patients with AIDS who develop lymphoma, but it is nevertheless higher than that for lymphoma in the general population.285 Further investigation into the association of immunomodulatory agents for the treatment of rheumatic diseases and the development of lymphoproliferative disorders also has shown an association with EBV. After analyzing 10 EBV-associated lymphoid neoplasms in patients with RA or dermatomyositis using polymerase chain reaction, investigators found that these lymphoproliferative disorders can harbor EBV strain type A or B, with type A being the most prevalent; this is similar to what has been reported in post–solid organ transplantation, immunosuppression-associated lymphoproliferative disorders. EBVlatent membrane protein-1 deletions seem to occur in one third of the cases, but are not required for the neoplasm to develop.286 It is possible that, although not increasing the overall risk for the development of lymphoproliferative disorders, treatment with methotrexate may carry a small risk for the development of EBV-associated lymphoid malignancies similar to malignancies seen in other immunosuppressed individuals. A subset of these patients may respond with regression of the tumor after discontinuation of methotrexate. AZATHIOPRINE Azathioprine is a purine analogue that leads to inhibition of purine synthesis and direct cytotoxic effects. The use of azathioprine is associated with an increased risk of lymphoma and nonlymphoproliferative cancers.278,287-289 Compared with the risk to the general population, azathioprine treatment can result in a 10-fold increased risk for the development of lymphoproliferative disorders289; this amounts to 1 case of lymphoma per 1000 patient-years of azathioprine treatment.288 A correlation between the cumulative dose of azathioprine used and the incidence of cancer has been seen.278,289 Leukemia also has been reported in association with azathioprine use.290,291 In contrast, one study reported outcomes of 148 SLE patients treated with azathioprine compared with 210 unexposed SLE patients.292 In this 24-year longitudinal study, only 5.4% of azathioprine-treated patients developed malignancies (none were ­ lymphoma)

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compared with 6.7% of azathioprine-naive patients (three with lymphoma).

than the patients in the placebo group and were less likely to have newly diagnosed Wegener’s granulomatosis.296

CYCLOSPORINE

RADIATION

Cyclosporine is currently used for the treatment of RA and SLE, particularly for lupus nephritis. Based on ­experience with solid organ transplantation in which post-­transplantation lymphoproliferative disorders are well recognized as complications arising in allograft recipients treated with immunosuppressive drugs, there has been a concern for an increased risk of the development of malignancy, especially lympho­ proliferative disorders, with cyclosporine treatment of rheumatic diseases. Although cyclosporine has been used formally in the treatment of RA since the 1980s, there have not been sufficient numbers of patients followed longitudinally for sufficient time to determine whether the drug may convey an increased risk for the ­development of malignancy. Cyclosporine has been associated with the development of EBV-associated lymphomas in some patients with RA293; however, a retrospective study looked at more than 1000 RA patients treated with cyclosporine in clinical trials and concluded that the use of cyclosporine did not increase the potential risk for the development of malignancy or the type of malignancy beyond that seen with the use of other DMARDs.294 A second retrospective and case-control study found that cyclosporine treatment in RA patients does not increase the risk of malignancies in general or the risk of malignant lymphoproliferative disorders.295 This finding may be due partly to the lower doses generally used for the treatment of rheumatic diseases compared with allograft recipients.278

Radiation therapy is no longer used for the treatment of inflammatory arthritis. Its use in ankylosing spondylitis in the early part of the 20th century resulted in significant increases in malignancies, including leukemia; lymphoma; myeloma; and esophageal, colon, pancreas, lung, bone, soft tissue, prostate, bladder, and kidney cancers. It also resulted in an increased relative risk of mortality of 1.3 compared with expected deaths. There were clear dose-response relationships between the amount of radiation and the development of individual cancers.210,211

LEFLUNOMIDE Leflunomide is a selective inhibitor of de novo pyrimidine synthesis and leads to cell cycle arrest in rapidly replicating cell lines, such as activated T cells in RA. Currently, there does not seem to be evidence that leflunomide conveys an increased risk for the development of malignancy. As is so important with the introduction of any new medication, long-term safety studies and postmarketing surveillance are necessary to ascertain whether there is increased risk at 10 and 20 years.

BIOLOGIC RESPONSE MODIFIERS As a group, commercially available biologic response modifiers include TNF inhibitors and interleukin-1 antagonists. Risk of developing malignancies in association with TNF inhibitors in patients with RA is discussed in detail in the section on RA-associated malignancies. A study examined the incidence of malignancies developing in 180 patients with Wegener’s granulomatosis participating in a randomized controlled multicenter clinical trial of etanercept or placebo in addition to conventional therapy for induction of remission followed by monotherapy for maintenance.296 No hematologic malignancies were seen during the study. All solid malignancies found during the trial were in subjects receiving etanercept in addition to cyclophosphamide during the trial. There is a suggestion that etanercept may increase the risk of solid tumors above that expected from treatment with cyclophosphamide alone; however, patients randomly assigned to etanercept were nearly 5 years older

CONCLUSION A plethora of factors contribute to the development of musculoskeletal syndromes in the setting of autoimmune disease and malignancy. There are a great many autoimmune disorders, and for most, the underlying etiology and pathogenesis have not been elucidated. This incredible diversity often makes understanding the relationship between associated symptoms difficult. To make any generalizations regarding association between an autoimmune disorder and the subsequent development of malignancy, large numbers of patients must be studied longitudinally for exceptionally long periods. Other confounders complicate the picture. Many of the agents used in the treatment of connective tissue and autoimmune disorders modulate the immune system. These agents may have direct carcinogenic potential, whereas others may affect the immune system in a way that may decrease tumor surveillance and subsequently lead to the development of a neoplasm. Intricately entwined are the unique differences of individual immune systems not only in healthy individuals, but also in individuals whose immune systems are already altered based on an underlying autoimmune disorder. Although uncommon, it is plausible that virtually any of the autoimmune-based diseases and the agents used to treat them might be associated with malignancy in certain circumstances. Most important, when musculoskeletal symptoms arise, malignancy or paraneoplastic syndromes should be considered in the differential diagnosis, especially when patients present with atypical features of autoimmune disease or are refractory to conventional treatment. In addition, the potential for any agent to induce a neoplastic process must be weighed against its proposed benefits before initiating it as therapy. REFERENCES   1. Stedman’s Medical Dictionary, 26th ed. Baltimore, Williams & Wilkins, 1995.   2. Caldwell DS: Carcinoma polyarthritis: Manifestations and differential diagnosis. Med Grand Rounds 1:378, 1982.   3. Chan MK, Hendrickson CS, Taylor KE: Polyarthritis associated with breast carcinoma. West J Med 137:132, 1982.   4. Stummvoll GH, Aringer M, Machold KP, et al: Cancer polyarthritis resembling rheumatoid arthritis as a first sign of hidden neoplasms. Scand J Rheumatol 30:40, 2001.   5. Gonzalez-Gay MA, Garcia-Porrua C, Salvarani C, et al: Cutaneous vasculitis and cancer: A clinical approach. Clin Exp Rheumatol 18:305, 2000.

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189. Menon S, Snaith ML, Isenberg DA: The association of malignancy with SLE: An analysis of 150 patients under long-term review. Lupus 2:177, 1993. 190. Lopez Dupla M, Khamashta M, Pintado Garcia V, et al: Malignancy in systemic lupus erythematosus: A report of five cases in a series of 96 patients. Lupus 2:377, 1993. 191. Sulkes A, Naparstek Y: The infrequent association of systemic lupus erythematosus and solid tumors. Cancer 68:1389, 1991. 192. Ramsey-Goldman R, Mattai SA, Schilling E, et al: Increased risk of malignancy in patients with systemic lupus erythematosus. J Invest Med 46:217, 1998. 193. Mellemkjaer L, Andersen V, Linet MS, et al: Non-Hodgkin’s lymphoma and other cancers among a cohort of patients with systemic lupus erythematosus. Arthritis Rheum 40:761, 1997. 194. Bjornadal L, Lofstrom B, Yin L, et al: Increased cancer incidence in a Swedish cohort of patients with systemic lupus erythematosus. Scand J Rheumatol 31:66, 2002. 195. Sweeney DM, Manzi S, Janosky J, et al: Risk of malignancy in women with systemic lupus erythematosus. J Rheumatol 22:1478, 1995. 196. Abu-Shakra M, Gladman DD, Urowitz MB: Malignancy in systemic lupus erythematosus. Arthritis Rheum 39:1050, 1996. 197. Nived O, Bengtsson A, Jonsen A, et al: Malignancies during follow-up in an epidemiologically defined systemic lupus erythematosus inception cohort in southern Sweden. Lupus 10:500, 2001. 198. Sultan SM, Ioannou Y, Isenberg A: Is there an association of malignancy with systemic lupus erythematosus? An analysis of 276 patients under long-term review. Rheumatology 39:1147, 2000. 199. Ramsey-Goldman R, Clarke AE: Double trouble: Are lupus and malignancy associated? Lupus 10:388, 2001. 200. Bernatsky S, Clarke A: Ramsey-Goldman R: Malignancy and systemic lupus erythematosus. Curr Rheum Rep 4:351, 2002. 201. Bernatsky S, Boivin J, Clarke A, et al: Cancer risk in SLE: A metaanalysis. Arthritis Rheum 44:S244, 2001. 202. Bernatsky S, Boivin JF, Joseph L, et al: An international cohort study of cancer in systemic lupus erythematosus. Arthritis Rheum 52:1481, 2005. 203. Bernatsky S, Ramsey-Goldman R, Clarke A: Exploring the links between systemic lupus erythematosus and cancer. Rheum Dis Clin N Am 31:387, 2005. 204. Bernatsky S, Ramsey-Goldman R, Rajan R, et al: Non-Hodgkin’s lymphoma in systemic lupus erythematosus. Ann Rheum Dis 64:1507, 2005. 205. Bernatsky S, Boivin JF, Joseph L, et al: Race/ethnicity and cancer occurrence in systemic lupus erythematosus. Arthritis Rheum 53:781, 2005. 206. Bernatsky S, Boivin JF, Joseph L, et al: Prevalence of factors influencing cancer risk in women with lupus: Social habits, reproductive issues, and obesity. J Rheumatol 29:2551, 2002. 207. Bernatsky S, Ramsey-Goldman R, Boivin JF, et al: Do traditional Gail model risk factors account for increased breast cancer in women with lupus? J Rheumatol 30:1505, 2003. 208. Bernatsky S, Clarke A, Ramsey-Goldman R, et al: Hormonal exposures and breast cancer in a sample of women with systemic lupus erythematosus. Rheumatology (Oxf) 43:1178, 2004. 209. Bernatsky S, Clarke A, Ramsey-Goldman R, et al: Breast cancer stage at time of detection in women with systemic lupus erythematosus. Lupus 13:469, 2004. 210. Bernatsky SR, Cooper GS, Mill C, et al: Cancer screening in patients with systemic lupus erythematosus. J Rheumatol 33:45, 2006. 211. Dhar JP, Kmak D, Bhan R, et al: Abnormal cervicovaginal cytology in women with lupus: A retrospective cohort study. Gynecol Oncol 82:4, 2001. 212. Ognenovski VM, Marder W, Somers EC, et al: Increased incidence of cervical intraepithelial neoplasia in women with systemic sclerosis treated with intravenous cyclophosphamide. J Rheumatol 31:1763, 2004. 213. Lai-Shan T, Chan AYK, Chan PKS: Increased prevalence of squamous intraepithelial lesions in systemic lupus erythematosus. Arthritis Rheum 50:3619, 2004. 214. Tam LS, Chan AYK, Chan PKS, et al: Increased prevalence of squamous intraepithelial lesions in systemic lupus erythematosus. Arthritis Rheum 50:3619, 2004. 215. Bernatsky S, Ramsey-Goldman R, Gordon C, et al: Factors associated with abnormal Pap results in systemic lupus erythematosus. Rheumatology (Oxf) 43:1386, 2004.

PART 18  216. Xu Y, Wiernik PH: Systemic lupus erythematosus and B-cell hematologic neoplasm. Lupus 10:841, 2001. 217. Pearson JE, Silman AJ: Risk of cancer in patients with scleroderma. Ann Rheum Dis 62:697, 2003. 218. Roumm AD, Medsger TA Jr: Cancer and systemic sclerosis: An epidemiologic study. Arthritis Rheum 28:1336, 1985. 219. Abu-Shakra M, Guillemin F, Lee P: Cancer in systemic sclerosis. Arthritis Rheum 36:460, 1993. 220. Rosenthal AK, McLaughlin JK, Linet MS, et al: Scleroderma and malignancy: An epidemiological study. Ann Rheum Dis 52:531, 1993. 221. Higuchi M, Horiuchi T, Ishibashi N, et al: Anticentromere antibody as a risk factor for cancer in patients with systemic sclerosis. Clin Rheumatol 19:123, 2000. 222. Hill CL, Nguyen AM, Roder D, et al: Risk of cancer in patients with scleroderma: A population based cohort study. Ann Rheum Dis 62:728, 2003. 223. Derk CT, Rasheed M, Artlett CM, et al: A cohort study of cancer incidence in systemic sclerosis. J Rheumatol 33:1123, 2006. 224. Hesselstrand R, Scheja A, Akesson A: Mortality and causes of death in a Swedish series of systemic sclerosis patients. Ann Rheum Dis 57:682, 1998. 225. Rothfield N, Kurtzman S, Vazques-Abad D, et al: Association of antitopoisomerase I with cancer. Arthritis Rheum 35:724, 1992. 226. Chatterjee S, Dombi GW, Severson RK, et al: Risk of malignancy in scleroderma: A population-based cohort study. Arthritis Rheum 52:2415, 2005. 227. Wipff J, Allanore Y, Soussi F, et al: Prevalence of Barrett’s esophagus in systemic sclerosis. Arthritis Rheum 52:2882, 2005. 228. Derk CT, Rasheed M, Spiegel JR, et al: Increased incidence of carcinoma of the tongue in patients with systemic sclerosis. J Rheumatol 32:637, 2005. 229. Rosenthal AK, McLaughlin JK, Gridley G, et al: Incidence of cancer among patients with systemic sclerosis. Cancer 76:910, 1995. 230. Reddy SM, Pui JC, Gold LI, et al: Postirradiation morphea and subcutaneous polyarteritis nodosa: Case report and literature review. Semin Arthritis Rheum 34:728, 2005. 231. Rosier RN, Konski A, Boros L: Bone tumors. In Rubin P (ed): Clinical Oncology: A Multidisciplinary Approach for Physicians and Students, 7th ed. Philadelphia, WB Saunders, 1993, pp 509-530. 232. Arndt CA, Crist WM: Common musculoskeletal tumors of childhood and adolescence. N Engl J Med 341:342, 1999. 233. Hayden JB, Hoang BH: Osteosarcoma: Basic science and clinical implications. Orthop Clin North Am 37:1, 2006. 234. Weber KL: What’s new in musculoskeletal oncology. J Bone Joint Surg Am 87:1400, 2005. 235. Hadjipavlou A, Lander P, Srolovitz H, et al: Malignant transformation in Paget’s disease of bone. Cancer 70:2802, 1992. 236. Mankin HJ, Hornicek FJ: Paget’s sarcoma: A historical and outcome review. Clin Orthop 438:97, 2005. 237. Terek RM: Recent advances in the basic science of chondrosarcoma. Orthop Clin North Am 37:9, 2006. 238. Rosier RN, Constine LS III: Soft tissue sarcoma. In Rubin P (ed): Clinical Oncology: A Multidisciplinary Approach for Physicians and Students, 7th ed. Philadelphia, WB Saunders, 1993, pp 487-507. 239. Mankin HJ, Hornicek FJ: Diagnosis, classification, and management of soft tissue sarcomas. Cancer Control 12:5, 2005. 240. Breitfeld PP, Meyer WH: Rhabdomyosarcoma: New windows of opportunity. Oncologist 10:518, 2005. 241. Spjut HJ, Dorfman HD, Fechner RE, et al: Tumors of Bone and Cartilage. Washington, DC, Armed Forces Institute of Pathology, 1983. 242. Mirra JM: Bone Tumors: Diagnosis and Treatment. Philadelphia, JB Lippincott, 1989. 243. Stummvol GH, Aringer M, Machold KP, et al: Cancer polyarthritis resembling rheumatoid arthritis as a first sign of hidden neoplasms. Scand J Rheumatol 30:40, 2001. 244. Patt RB: Basic and advanced methods of pain control. In Rubin P (ed): Clinical Oncology: A Multidisciplinary Approach for Physicians and Students, 7th ed. Philadelphia, WB Saunders, 1993, pp 709-733. 245. Murray GC, Persellin RH: Metastatic carcinoma presenting as monarticular arthritis: A case report and review of the literature. Arthritis Rheum 23:95, 1980. 246. Dunne C, Illidge T: Arthritis and carcinoma. Ann Rheum Dis 52:86, 1993.

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ARTHRITIS ACCOMPANYING SYSTEMIC DISEASE

1861

247. Raderer M, Scheithauer W: Postchemotherapy rheumatism following adjuvant therapy for ovarian cancer. Scand J Rheumatol 23: 291-292, 1994. 248. Loprinzi CL, Duffy J, Ingle JN: Postchemotherapy rheumatism. J Clin Oncol 11:768-770, 1993. 249. Kim MJ, Ye YM, Park HS: Chemotherapy-related arthropathy. J Rheumatol 33:1364, 2006. 250. Creamer P, Lim K, George E, et al: Acute inflammatory polyarthritis in association with tamoxifen. Br J Rheumatol 33:583-585, 1994. 251. Warner E, al Keshavjee N, Shupak R, et al: Rheumatic symptoms following adjuvant therapy for breast cancer. Am J Clin Oncol 20:322, 1997. 252. Passos de Souza E, Evangelista Segundo PT, Jose FF, et al: Rheumatoid arthritis induced by alpha-interferon therapy. Clin Rheumatol 20:297, 2001. 253. Raanani P, Ben-Bassat I: Immune-mediated complications ­ during interferon therapy in hematological patients. Acta Haematol 107:133, 2002. 254. Wandl UB, Nagel-Hiemke M, May D, et al: Lupus like autoimmune disease induced by interferon therapy for myeloproliferative disorders. Clin Immunol Immunopathol 65:70, 1992. 255. Ronnblom LE, Alm GV, Oberg KE: Autoimmunity after alpha­interferon therapy for malignant carcinoid. Ann Intern Med 115:178, 1991. 256. Thomas LB, Forkner CE, Frei E III, et al: The skeletal lesions of acute leukemia. Cancer 14:608, 1961. 257. Rennie JAN, Auchterlonie IA: Leukaemias and GVH disease. Baillieres Clin Rheumatol 5:231, 1991. 258. Ehrenfeld M, Gur H, Shoenfeld Y: Rheumatologic features of hematologic disorders. Curr Opin Rheumatol 11:62, 1999. 259. Silverstein MN, Kelly P: Leukemia with osteoarticular symptoms and signs. Ann Intern Med 59:637, 1963. 260. Spilberg I, Meyer GJ: The arthritis of leukemia. Arthritis Rheum 15:630, 1972. 261. Jones OY, Spencer CH, Bowyer SL: A multicenter case-control study on predictive factors distinguishing leukemia from juvenile rheumatoid arthritis. Pediatrics 117:840, 2006. 262. Gur H, Koren V, Ehrenfeld M, et al: Rheumatic manifestations preceding adult acute leukemia: Characteristics and implication on course and prognosis. Acta Haematol 101:1, 1999. 263. Kai T, Ishii E, Matsuzaki A, et al: Clinical and prognostic implications of bone lesions in childhood leukemia at diagnosis. Leuk Lymphoma 23:119, 1996. 264. Lacy MZ, Gertz MA, Hanson CA, et al: Multiple myeloma associated with diffuse osteosclerotic bone lesions: A clinical entity distinct from osteosclerotic myeloma (POEMS syndrome). Am J Hematol 56:288, 1997. 265. Roux S, Fermand JP, Brechignac S, et al: Tumoral joint involvement in multiple myeloma and Waldenström’s macroglobulinemia: Report of 4 cases. J Rheumatol 23:2175, 1996. 266. Terpos E, Angelopoulou MK, Variami E, et al: Sjögren’s syndrome associated with multiple myeloma. Ann Hematol 79:449, 2000. 267. Hermaszewski RA, Ratnavel RC, Denman DJ, et al: Immunodeficiency and lymphoproliferative disorders. Baillieres Clin Rheumatol 5:277, 1991. 268. Falcini F, Bardare M, Cimaz R, et al: Arthritis as a presenting feature of non-Hodgkin’s lymphoma. Arch Dis Child 78:367, 1998. 269. Nishiya K, Tanaka Y: Co-existence of non-Hodgkin’s lymphoma in the leukemic phase and polyarthritis simulating rheumatoid arthritis. Intern Med 36:227, 1997. 270. Dorfman HD, Siegel HL, Perry MC, et al: Non-Hodgkin’s lymphoma of the synovium simulating rheumatoid arthritis. Arthritis Rheum 30:155, 1987. 271. Davies PG, Fordham JN: Arthritis and angioimmunoblastic lymphadenopathy. Ann Rheum Dis 42:516, 1983. 272. Layton MA, Musgrove C, Dawes PT: Polyarthritis, rash and lymphadenopathy: Case reports of two patients with angioimmunoblastic lymphadenopathy presenting to a rheumatology clinic. Clin Rheumatol 17:148, 1998. 273. Tsochatzis E, Vassilopoulos D, Deutsch M: Antioblastic T-cell lymphoma-associated arthritis: Case report and literature review. J Clin Rheumatol 11:326, 2005. 274. von Kempis J, Kohler G, Herbst EW, et al: Intravascular lymphoma presenting as symmetric polyarthritis. Arthritis Rheum 41:1126, 1998.

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Musculoskeletal Syndromes in Malignancy

275. Tichelli A, Duell T, Weill M, et al: Late-onset keratoconjunctivitis sicca syndrome after bone marrow transplantation: Incidence and risk factors—European Group or Blood and Marrow Transplantation (EBMT) Working Party on Late Effects. Bone Marrow Transplant 17:1105, 1996. 276. Asten P, Barrett J, Symmons D: Risk of developing certain malignancies is related to duration of immunosuppressive drug exposure in patients with rheumatic diseases. J Rheumatol 26:1705, 1999. 277. Baltus JA, Boersma JW, Hartman AP, et al: The occurrence of malignancies in patients with rheumatoid arthritis treated with cyclophosphamide: A controlled retrospective follow-up. Ann Rheum Dis 42:368, 1983. 278. Kinlen LJ: Incidence of cancer in rheumatoid arthritis and other disorders after immunosuppressive treatment. Am J Med 21:44, 1985. 279. Radis CD, Kahl LE, Baker GL, et al: Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis: A 20-year follow-up study. Arthritis Rheum 38:1120, 1995. 280. Knight A, Askling J, Ekbom A: Cancer incidence in a populationbased cohort of patients with Wegener’s granulomatosis. Int J Cancer 100:82, 2002. 281. Knight A, Askling J, Granath F, et al: Urinary bladder cancer in Wegener’s granulomatosis, risks and relation to cyclophosphamide. Ann Rheum Dis 63:1307, 2004. 282. Choi HK, Hernan MA, Seeger JD, et al: Methotrexate and mortality in patients with rheumatoid arthritis: A prospective study. Lancet 359:1173, 2002. 283. Liote F, Pertuiset E, Cochand-Priollet B, et al: Methotrexate-related B lymphoproliferative disease in a patient with rheumatoid arthritis: Role of Epstein-Barr virus infection. J Rheumatol 22:1174, 1995. 284. Bachman TR, Sawitzke AD, Perkins SL, et al: Methotrexate­associated lymphoma in patients with rheumatoid arthritis: Report of two cases. Arthritis Rheum 39:325, 1996. 285. Sibilia J, Liote F, Mariette X: Lymphoproliferative disorders in rheumatoid arthritis patients on low-dose methotrexate. Rev Rhum Engl Ed 65:267, 1998. 286. Natkunam Y, Elenitoba-Johnson KS, Kingma DW, et al: EpsteinBarr virus strain type and latent membrane protein 1 gene deletions in lymphomas in patients with rheumatic diseases. Arthritis Rheum 40:1152, 1997.

287. van Wanghe P, Dequeker J: Compliance and long-term effect of azathioprine in 65 rheumatoid arthritis cases. Ann Rheum Dis 41(Suppl 1):40, 1982. 288. Silman AJ, Petrie J, Hazleman B, et al: Lymphoproliferative cancer and other malignancy in patients with rheumatoid arthritis treated with azathioprine: A 20-year follow-up study. Ann Rheum Dis 47:988, 1988. 289. Pitt PI, Sultan AH, Malone M, et al: Association between azathioprine therapy and lymphoma in rheumatoid disease. J R Soc Med 80:428, 1987. 290. Vasquez S, Kavanaugh AF, Schneider NR, et al: Acute nonlymphocytic leukemia after treatment of systemic lupus erythematosus with immunosuppressive agents. J Rheumatol 19:1625, 1992. 291. Seidenfeld AM, Smythe HA, Ogryzlo MA, et al: Acute leukemia in rheumatoid arthritis treated with cytotoxic agents. J Rheumatol 11:586, 1984. 292. Nero P, Rahman A, Isenberg DA: Does long term treatment with azathioprine predispose to malignancy and death in patients with systemic lupus erythematosus? Ann Rheum Dis 63:325, 2004. 293. Zijlmans JM, van Rijthoven AW, Kluin PM, et al: Epstein-Barr virusassociated lymphoma in a patient with rheumatoid arthritis treated with cyclosporine. N Engl J Med 326:1363, 1992. 294. Arellano F, Krupp P: Malignancies in rheumatoid arthritis patients treated with cyclosporin A. Br J Rheumatol 32(Suppl 1):72, 1993. 295. van den Borne BE, Landewe RB, Houkes I, et al: No increased risk of malignancies and mortality in cyclosporin A-treated patients with rheumatoid arthritis. Arthritis Rheum 41:1930, 1998. 296. Stone JH, Holbrook JT, Marriott MA: Solid malignancies among patients in the Wegener’s Granulomatosus Etanercept Trial. Arthritis Rheum 54:1608, 2006. 297. Darby SC, Doll R, Gill SK, et al: Long-term mortality after a single course with x-rays in patients treated for ankylosing spondylitis. Br J Cancer 55:179, 1987. 298. Weiss HA, Darby SC, Doll R: Cancer mortality following x-ray treatment for ankylosing spondylitis. Int J Cancer 59:327, 1994.

113

Familial Autoinflammatory Syndromes Anna Simon  •  Jos W. M. van der Meer  •  Joost P. H. Drenth

KEY POINTS Autoinflammatory disorders are characterized by recurrent or chronic inflammation without signs of infection or autoimmune phenomena. Dysregulation of the interleukin-1β pathway is central to many familial autoinflammatory syndromes, especially the cryopyrin-associated periodic syndromes and familial ­Mediterranean fever. The need for a definite diagnosis in the familial autoinflammatory syndromes has increased because of advances in treatment options. A severe complication of these disorders is type AA amyloidosis, which often leads to renal failure; the risk of this complication is greatly reduced when patients receive adequate treatment. In a substantial portion of patients presenting with a clear phenotype of recurrent inflammation, with or without family history, the diagnosis can remain elusive, which indicates that other disorders remain to be discovered.

DEFINITION The familial autoinflammatory syndromes, often referred to as hereditary periodic fever syndromes, comprise rare disorders with a common phenotype of lifelong, recurrent inflammatory episodes, with fever and usually accompanied by other inflammatory symptoms, such as abdominal pain, diarrhea, rash, or arthralgia.1 Between the fever episodes, patients generally feel healthy and function normally. Routine laboratory investigations during a fever attack invariably reveal a severe acute-phase response with a high erythrocyte sedimentation rate, leukocytosis, and high concentrations of acute-phase proteins such as C-reactive protein (CRP), serum amyloid A (SAA), and several proinflammatory cytokines. The episodes of fever occur without an obvious trigger, although some patients note a relationship to physical stimuli (e.g., exposure to cold), emotional stress, or the menstrual cycle. The episodes resolve spontaneously in days or weeks. Patients with periodic fever occur go undiagnosed for years, generating a high level of discouragement and frustration for patients and physicians when no diagnosis is made.2,3 The term autoinflammatory, coined by McDermott and colleagues in 1999,4 adequately describes the phenotype of recurrent, acute inflammatory responses. It is preferable to the term autoimmune in these cases because typical autoimmune phenomena are not found. Several distinct types of hereditary autoinflammatory syn­dromes are recognized. Despite the common phenotype described previously, these genetically distinct types often

can be differentiated clinically by numerous specific characteristics, in particular by the mode of inheritance, age of onset, average duration of the fever episodes and the feverfree interval, geographic region of origin of the patient’s family, and occurrence of long-term complications such as amyloidosis or deafness (Table 113-1 and Fig. 113-1). A significant number of patients with a periodic fever phenotype still do not fit into this genetically based classification, probably representing additional (genetic) defects that can lead to periodic fevers. This chapter describes six different types of familial autoinflammatory syndromes that have been cha­racterized at this time.

DIFFERENTIAL DIAGNOSIS When a patient has had recurrent fever episodes for more than 2 years, it is increasingly unlikely that these are caused by an infection or a malignant disorder. The differential diagnosis at that time may include numerous inflammatory disorders, such as juvenile rheumatoid arthritis, adult-onset Still’s disease, inflammatory bowel disease, Schnitzler syndrome, and Behçet’s disease, in addition to the hereditary periodic fever syndromes (Table 113-2). Because the hereditary syndromes are rare (except for familial Mediterranean fever [FMF] in individuals with a distinct ethnic background), the more common diagnoses should be excluded first. The mainstay of the diagnosis of hereditary periodic fever is clinical assessment, with a detailed medical and family history, and preferably at least one observation of the patient during a fever episode because physical examination of the patient in a period of remission is seldom abnormal. Another helpful clue, although not pathognomonic, in dif­ ferentiating the familial autoinflammatory syndromes is often gained from knowing the patient’s ethnic origin. This clinical assessment often yields enough information to build a differential diagnosis of the specific familial autoinflammatory syndromes (see Table 113-1), to determine the direction of genetic testing (Fig. 113-2).

FAMILIAL MEDITERRANEAN FEVER EPIDEMIOLOGY FMF (Mendelian Inheritance in Men [MIM] 249100) is the most prevalent disorder among the hereditary autoinflammatory syndromes, with more than 10,000 patients affected worldwide. It occurs primarily in people originating from the Mediterranean basin, including Armenians, Sephardic Jews, Arabs, and Turks. FMF is an autosomal recessively inherited disorder. Most families reported with an apparent autosomal dominant inheritance pattern of FMF5 represent 1863

<20

<2

Erysipelas-like erythema

Monarthritis   common

Sterile peritonitis common

Uncommon

Erysipelas-like erythema

MEFV

Pyrin   (marenostrin)

Age at Onset (yr)

Duration of attack (days)*

Cutaneous Involvement

Musculoskeletal Involvement

Abdominal Involvement

Eye Involvement

Distinguishing Clinical Symptoms

Gene Involved

Protein Involved

Uncommon

Splenomegaly, pain may   occur

Arthralgia   common

Morbilliform   rash

4-5

<1

Autosomal   recessive

Mevalonate kinase

MVK Mevalonate kinase

MVK

Prominent   Dysmorphic cervical   features,   lymphadenopathy neurologic symptoms

Uncommon

Splenomegaly,   severe pain   common

Arthralgia,   occasional   oligoarthritis

Maculopapular   rash

4-6

<1

Autosomal   recessive

Mevalonic Aciduria

?

?

Lymphadeno­ pathy may occur

Uncommon

May occur

Arthralgia

Maculopapular rash

6-8

<10

?

Variant HIDS

Type 1 tumor necrosis   factor receptor

TNFRSF1A

Migratory nature of   myalgia and rash,   periorbital edema

Conjunctivitis and   periorbital edema   very common

Severe pain very   common

Severe myalgia   common; occasional frank monarthritis

Migratory rash,   overlying area   of myalgia

>14

<20

Autosomal dominant

Urticaria-like rash

1-2

<20

Autosomal   dominant

Muckle-Wells Syndrome (MWS)

Urticaria-like lesions

?

<1

Autosomal   dominant

Chronic Infantile Neurologic Cutaneous and Articular Syndrome (CINCA)

Cryopryin Diseases

Cryopyrin

CIAS1

Cold-induced   urticaria-like   lesions

Conjunctivitis

None

Cryopyrin

CIAS1

Sensorineural   hearing loss

Conjunctivitis;   sometimes optic   nerve elevation

May occur

Cryopyrin

CIAS1

Chronic aseptic   meningitis,   sensorineural hearing loss, arthropathy

Papilledema with   possible loss   of vision, uveitis

Hepatosplenomegaly

Arthralgia common;   Lancing limb pain,   Epiphyseal bone   occasional   arthralgia common; formation mild myalgia arthritis can occur

Cold-induced   urticaria-like   lesions

<2

<1

Autosomal   dominant

Familial Cold Auto­inflammatory Syndrome (FCAS)

Note. For details on Blau syndrome and pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome, see text. *Duration may vary; this is a typical duration. Adapted from Hull KM, Shoham N, Chae JJ, et al: The expanding spectrum of systemic autoinflammatory disorders and their rheumatic manifestations. Curr Opin Rheumatol 15:61-69, 2003.

Autosomal ­recessive

Mode of Inheritance

Familial Mediterranean Fever (FMF)

Tumor Necrosis Factor Receptor– Associated Periodic Syndrome (TRAPS)

| 

Classic Hyper– immunoglobulin D syndrome (HIDS)

simon 

Mevalonate Kinase Deficiencies

Table 113-1  Differential Diagnosis of Familial Autoinflammatory Syndromes

1864 Familial Autoinflammatory Syndromes

PART 18 

| 

Cervical lymphadenopathy, erythematous macules, abdominal pain, vomiting, arthralgia

Body temperature (°C)

Body temperature (°C)

Peritonitis, vomiting, arthritis, erysipelas-like skin lesions 40

FMF

39 38 37 36

1

0

3

2

1865

ARTHRITIS ACCOMPANYING SYSTEMIC DISEASE

40

HIDS

39 38 37 36 0

1

3

2

Time (days)

4

5

6

7

8

9 10

Time (days)

Conjunctivitis, erythematous skin lesions, myalgia/arthralgia, abdominal pain

Rash, chills, polyarthralgias, conjunctivitis 40 FCAS Body temperature (°C)

Body temperature (°C)

TRAPS 40 39 38 37 36

0 2 4 6 8 10 12 14 16 18 20 22 2426 Time (days)

39 38 37 36

MWS

39 38 37 36 0

1

2

3

41

5

Time (days)

10

12

CINCA/NOMID

40 39

Any temperature curve

38 37 36

4

4 6 8 Time (hours)

2

0

Deformative arthropathy, chronic meningitis

Body temperature (°C)

Body temperature (°C)

Chills, arthralgias, erythematous rash, conjunctivitis 40

Cold exposure

0

1

2

3 5 4 Time (days)

6

7

8

Figure 113-1  Characteristic patterns of body temperature during inflammatory attacks in the familial autoinflammatory syndromes. There is considerable interindividual variability for each syndrome, and even for the individual patient, the fever pattern may vary greatly from episode to episode. Note the different time scales on the x-axes. See text for abbreviations.

examples of pseudodominant inheritance owing to consanguinity combined with the high carrier frequency of FMF mutations in certain populations5-7; however, at least three families studied do seem to show a true dominant inheritance, even after extensive genetic analysis.7 ETIOLOGY In 1997, two groups independently traced the genetic background of FMF to a hitherto unknown gene on the short arm of chromosome 16, dubbed the MEditteranean FeVer (MEFV) gene.8,9 At least 67 disease-linked mutations in the MEFV gene have been described so far, most of which are clustered in the 10th exon of this gene (for details see the online mutation database at http://fmf.igh.cnrs.fr/

infevers/). Most are missense mutations that produce a ­single amino acid change in the protein (Fig. 113-3). There are six common mutations, accounting for almost 99% of all FMF chromosomes: M694V (occurring in 20% to 65% of cases, depending on the population examined10), V726A (in 7% to 35%), M680I, M694I, V694I, and E148Q. For the first three mutations mentioned here, a founder effect has been established,9 pointing to common ancestors at least 2500 years ago. The high frequency of the mutated MEFV gene in more than one Middle Eastern population has led to the hypothesis that heterozygous carriers have an as-­ yet-unknown advantage, possibly a heightened (inflammatory) resistance to an as-yet-unidentified endemic pathogen of the Mediterranean basin.9 In about 30% of patients, only one or no mutations in the MEFV gene can

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Table 113-2  Differential Diagnosis of Periodic Fever 1. Hereditary (see Table 113-1) 2. Nonhereditary     a. Infectious          i. Hidden infectious focus (e.g., aortoenteric fistula, Caroli’s disease)    ii. Recurrent reinfection (e.g., chronic meningococcemia, host defense defect)   iii. Specific infection (e.g., Whipple’s disease, malaria)    b. Noninfectious inflammatory disorder        i. Adult-onset Still’s disease      ii.  Juvenile chronic rheumatoid arthritis        iii. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA)         iv. Schnitzler syndrome           v.  Behçet’s syndrome        vi.  Crohn’s disease       vii. Sarcoidosis   viii. Extrinsic alveolitis     ix.  Humidifier lung, polymer fume fever     c. Neoplastic         i. Lymphoma (e.g., Hodgkin’s disease, angioimmunoblastic lymphoma)   ii. Solid tumor (e.g., pheochromocytoma, myxoma, colon carcinoma)    d.  Vascular          i. Recurrent pulmonary embolism     e.  Hypothalamic      f.  Psychogenic periodic fever    g.  Factitious or fraudulent

be detected; the etiology in these patients still needs to be determined. PATHOGENESIS The MEFV gene encodes for a protein of 781 amino acids, known as pyrin or marenostrin. Pyrin is expressed as a cytoplasmic protein in mature monocytes in association with microtubules,11 but is predominantly found in the nucleus in granulocytes, dendritic cells, and synovial fibroblasts.12 The expression of pyrin is induced by inflammatory mediators such as interferon-α and tumor necrosis factor (TNF).13 The pyrin domain is shared by many proteins involved in apoptosis and inflammation and is a member of the death-domain superfamily that includes death domains, death-effector domains, and caspaserecruitment domains. Pyrin binds specifically to other proteins that contain a pyrin domain, which include the adapter protein “apoptosis-­associated specklike-like protein with a CARD” (ASC). The proinflammatory cytokine interleukin (IL)-1β is central in the pathogenesis of FMF. This cytokine is ex­­ pressed as an inactive precursor, which is cleaved by caspase-1 to yield the active IL-1β. Caspase-1 itself first needs to be activated through the interaction with a protein complex termed an inflammasome. Several inflammasomes have been described so far. The major inflammasome complex involved in the activation of caspase-1 and IL-1β is the cryopyrin or NALP3 inflammasome.14,15 Two hypotheses have been proposed regarding the effect of pyrin on IL1β processing. The “sequestration hypothesis” holds that pyrin has an inhibitory effect on caspase-1-mediated activation of IL-1β, through its prevention of the formation of the cryopyrin inflammasome by competitive binding of

the adapter protein ASC and procaspase-1 and binding caspase-1.16,17 Under this hypothesis, FMF mutations are thought to interfere with the inhibiting interactions of pyrin, resulting in decreased regulation of IL-1β activation.17 The second hypothesis, proposed by Yu and coworkers,18 suggests that pyrin can form its own specific inflammasome for activation of IL-1β, although not all the components of this proposed inflammasome have been specified so far. The FMF mutations would increase the sensitivity of this putative pyrin inflammasome. Apart from its role in regulation of IL-1β, there also is conflicting evidence for the effect of pyrin on regulation of nuclear factor κB (NFκB) or apoptosis, varying from inhibition to stimulation.14 CLINICAL FEATURES In approximately 90% of FMF patients, symptoms start before age 20 years.19 The inflammatory attacks of FMF usually last only 1 to 3 days, and their frequency can vary widely; 2 to 4 weeks is the most common interval (see Fig. 113-1). Fever is the principal symptom in FMF and is usually accompanied by symptoms of serositis (peritonitis, pleuritis, or synovitis). Abdominal pain of 1 or 2 days’ duration occurs in 95% of patients, varying in severity from severe peritonitis resembling an acute abdomen to only mild abdominal pain without overt peritonitis.20 Arthritis (rarely destructive) is often confined to one large joint, such as the knee, ankle, or wrist, and may be the only symptom. Chest pain resulting from pleuritis is usually unilateral and associated with a friction rub or transient pleural effusion. Skin involvement occurs in approximately 30% of patients, most often as erysipelas-like skin lesions on the shins or feet (Fig. 113-4).21 Other, more uncommon, symptoms are pericarditis, occurring in less than 1%22; acute scrotal swelling and tenderness23; aseptic meningitis; and severe protracted myalgia, especially of the legs. Fertility problems are encountered in FMF. For a variety of reasons, including peritoneal adhesions and ovulatory dysfunction, subfertility in women is common.24 In men, subfertility secondary to azoospermia (sometimes secondary to testicular amyloidosis) or impairment of sperm penetration has been found.25 DIAGNOSIS AND DIAGNOSTIC TESTS FMF is still primarily a clinical diagnosis. There is a set of validated diagnostic criteria with a reported sensitivity and specificity of 96% to 99% (Table 113-3).26 These criteria were validated in a population with a very high prevalence of FMF and low prevalence of the other autoinflammatory disorders, however, and the ethnic origin of the patient needs to be taken into account. Because the location of FMF mutations is known, it is possible to establish a molecular diagnosis of FMF. Genetic laboratories usually screen for the five most common mutations, and rare mutations are missed. MEFV mutations occur on both alleles in only 70% of typical cases,27 whereas in the remaining 30%, only one or no mutation can be detected, even after sequencing. There also is evidence of reduced penetrance. Despite these limitations, molecular testing can be used as a confirmatory test in cases in which there is a high

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ARTHRITIS ACCOMPANYING SYSTEMIC DISEASE

1867

Skin rash

Length of attack FMF

1 day 1-3 days

Erysipelas-like Migrating erythema

TRAPS

Urticaria

4-6 days >7 days

Pyoderma gangrenosum

CAPS

Acne

continuous

Granulomatous

HIDS

Trigger

Ethnic origin

PAPA

Cold

Mediterranean, Jewish

Vaccination

Northwestern Europe

Blau/EOS

Physical trauma

Specifics FMF

Age of onset

Success colchicine

in 1st year

Serositis

TRAPS

>10 years of age

Orbital edema Meningitis

CAPS

Hearing loss

Inheritance

Patellar overgrowth

HIDS

Dominant

Lymphadenopathy

Recessive PAPA

Aphthous ulcers Pyogenic arthritis

Blau/EOS

Uveitis

Figure 113-2  Differential diagnosis of the familial autoinflammatory syndromes. First exclude other, more common causes of fever and inflammation in the patient. When a familial autoinflammatory syndrome seems likely, check the clinical characteristics found in the patient on the right and left of the diagram, and assign one point to each syndrome that is linked to these characteristics by a line (one characteristic could lead to or point to more than one syndrome). The final combined score assigns a rank for the likelihood of the disorders in this patient and offers help in deciding on the correct subsequent diagnostic tests. This algorithm is not evidence-based, but is solely derived from expert opinion. See text for abbreviations.

pyrin-D R42W

B S108R L110P 335ins E148Q E148V

E163A E167D E230K T267I E319K

P369S

CC R408Q E474K H478Y F479L

index of suspicion. Whether or not the results are positive, treatment with colchicine is warranted in symptomatic cases of fitting ethnic origin fulfilling the diagnostic criteria.28,29 No specific biologic marker is available to distinguish an inflammatory FMF attack from an infectious fever or

B30.2 I591T P646L L649P R653H E656A S675N G678E M680L M680I

T681I Y688X 1692del M694del M694V M694I M694L

K695R V704I I720M V726A A744S R761H

Figure 113-3  Schematic representation of pyrin (marenostrin) protein, with four conserved domains, including a pyrin domain, a B-box (B), coiled-coil domain (CC), and a B30.2 domain. Indicated are mutations as found in familial Mediterranean fever (FMF), with the five most common missense mutations in bold type.

a­ ppendicitis. During an inflammatory attack, there is an acute-phase response, which includes elevation of SAA, CRP, and plasma fibrinogen and polymorphonuclear leukocytosis. Proteinuria in patients with FMF is highly suggestive of renal amyloidosis.

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Table 113-3  Diagnostic Criteria for Familial ­Mediterranean Fever* Major Criteria Typical attacks† with peritonitis (generalized) Typical attacks with pleuritis (unilateral) or pericarditis Typical attacks with monarthritis (hip, knee, ankle) Typical attacks with fever alone Incomplete abdominal attack Minor Criteria Incomplete attacks‡ involving chest pain Incomplete attacks involving monarthritis Exertional leg pain Favorable response to colchicine

Figure 113-4  Erysipelas-like eruption in a patient with a familial Mediterranean fever attack. (Courtesy of Professor A. Livneh, Heller Institute of Medical Research, Tel Hashomer, Israel.)

*Requirements for diagnosis of familial Mediterranean fever are ≥1 major criteria or ≥2 minor criteria. †Typical attacks are defined as recurrent (≥3 of the same type), febrile (≥38°C), and short (lasting between 12 hours and 3 days). ‡Incomplete attacks are defined as painful and recurrent attacks not fulfilling the criteria for a typical attack. From Livneh A, Langevitz P, Zemer D, et al: Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 40:1879-1885, 1997.

TREATMENT Colchicine is the first-line of treatment for patients with FMF. Its efficacy was established in three controlled clinical trials in 1974.30-32 Colchicine prevents inflammatory attacks in 60% of patients, and it significantly reduces the number of attacks in an additional 20% to 30%.25 The average dose in adults is 1 mg daily, but this may be increased to 3 mg in cases in which no response is seen at the lower dose. This regimen is usually well tolerated; gastrointestinal side effects, including diarrhea and abdominal pain, generally resolve with dose reduction. More serious side effects, such as myopathy, neuropathy, and leukopenia, are rare and occur primarily in patients with renal or liver impairment. During a fever attack, oral or intramuscular nonsteroidal anti-inflammatory drugs (NSAIDs) can be used for pain relief. Glucocorticoids have limited efficacy. Compliance with colchicine use is important because colchicine has been shown to prevent the occurrence of amyloidosis. Since the introduction of colchicine therapy, the incidence of amyloidosis in FMF has decreased dramatically, whereas in areas with a high prevalence of FMF where colchicine is not routinely available, such as Armenia, amyloidosis is still common. Colchicine’s principal effect at the cellular level is to depolymerize microtubules by interacting with tubulin, inhi­ biting motility and exostosis of intracellular granules. It has a powerful antimitotic effect, causing metaphase arrest. It has been speculated, in cases of infertility in patients treated with colchicine, that this medication causes azoospermia. Colchicine does not have a significant adverse effect on sperm production or function, however.33 Unfounded fear of teratogenic effects of colchicine often wrongly leads to cessation of this drug in young women who wish to get pregnant, with a subsequent increased frequency and severity of attacks, which enhances problems with fertility and pregnancy. Colchicine has proved to be safe, even in early pregnancy, and treatment should not be interrupted for this reason.24,34 It also can be used while breastfeeding.25 Not all patients respond well to colchicine, in some cases because of poor intestinal resorption of the drug. Lidar and

colleagues35 used parenteral colchicine in such refractory cases. We have observed that the IL-1β inhibitor anakinra worked in such a patient (unpublished observation). Chae and coworkers17 reported the successful use of anakinra in an FMF patient with amyloidosis who could not tolerate colchicine because of side effects. OUTCOME AND PROGNOSIS Recurrent attacks of peritonitis may lead to intra-abdominal or pelvic adhesions, resulting in complications such as small bowel obstruction or reduced fertility in female patients. Another serious long-term complication of FMF is amyloid A (AA) amyloidosis. This amyloidosis is primarily found in the kidneys, resulting in renal failure, but also can occur in the gastrointestinal tract, liver, and spleen, and eventually in the heart, testes, and thyroid. The prevalence of amyloidosis varies, especially depending on the ethnic origin, but is high in untreated patients. It is common among Se­­ phardic Jews, but rare in Ashkenazi Jews.36

HYPER–IMMUNOGLOBULIN D SYNDROME EPIDEMIOLOGY Hyper-IgD syndrome (HIDS) (MIM 260920) also is an autosomal recessively inherited disorder, but it is far less prevalent than FMF. The International Hyper-IgD Syndrome Registry, based in Nijmegen, the Netherlands, in which clinical information is actively collected from physicians worldwide, currently holds data on approximately 220 patients. Approximately 75% of these patients are from Western Europe, and 50% are from the Netherlands and France. Most HIDS patients are white. These observations can be explained partly by a founder effect.37 In the Netherlands, the carrier frequency of a hyper-IgD mutation is estimated to be 1:530.38 Men and women are affected in equal numbers.

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K13X H20P H20N

ARTHRITIS ACCOMPANYING SYSTEMIC DISEASE

R215Q

W62X S52N

| 

S135L

P167L A148T Y149X S150L

T209A T243I G211A

N301T S272F R277C

A334T

1869

R388X

G326R

V377I G309S L264F V310M L265P I268T Figure 113-5  Mevalonate kinase, with four conserved domains represented by colored boxes. Indicated are missense mutations, nonsense mutations, and two deletions, which have been identified in mevalonate kinase deficiency. In bold are mutations found in mevalonic aciduria patients; in bold and italic are mutations found in classic hyper-IgD syndrome (HIDS) and mevalonic aciduria. L35S L39P

G202R

ETIOLOGY HIDS in its classic form is caused by mutations in the gene encoding for the enzyme mevalonate kinase, located on the long arm of chromosome 12 (for details, see the online mutation database available at http://fmf.igh.cnrs. fr/­infevers/).39-41 Patients with classic HIDS are most often compound heterozygotes for two different missense mutations in the mevalonate kinase gene (Fig. 113-5). Two mutations (leading to a valine-to-isoleucine change, V377I, and to a isoleucine-to-tyrosine change, I268T) account for greater than 85% of the patients described to date.42,43 Not all patients with HIDS have a gene defect of mevalonate kinase. We have designated these patients as variant HIDS (see Table 113-1).41 PATHOGENESIS Mevalonate kinase is part of the isoprenoid pathway; it is involved in the next step after 3-hydroxy-3-methyl­glutaryl–coenzyme A (HMG-CoA) reductase by phosphorylating mevalonic acid. The isoprenoid pathway has many diverse end products that include cholesterol, dolichol, and ubiquinone, and it leads to isoprenylation of proteins, with a post-translational modification directing these proteins, such as Rho and Ras, to the cell membrane.44 The HIDS mutations lead to a constantly diminished activity of mevalonate kinase to about 5% to 15% of normal levels, and these levels decrease further during a fever attack.45 Because of this reduced enzyme activity, the substrate mevalonic acid accumulates in serum and urine. Higher levels are found during the episodes of fever. There does not seem to be a dramatic shortage of any specific end product; concentrations of cholesterol, ubiquinone, and dol­ ichol in patients are normal to slightly decreased.14 Another syndrome already was linked to mutations in the mevalonate kinase gene before the discovery of HIDS46— classic mevalonic aciduria. Patients with mevalonic aciduria carry specific mutations that cause a more severe reduction of mevalonate kinase enzyme activity, often reducing it to undetectable levels. These patients constantly produce large amounts of mevalonic acid and often have more than 1000 times as much mevalonic acid in their urine than do HIDS patients.47 Patients with mevalonic aciduria also have a more severe phenotype, which is described in the next section. Classic mevalonic aciduria and HIDS seem to be two extremes of a continuous spectrum of disease related to mevalonate kinase deficiency.48

The pathogenetic link between mevalonate kinase defi­ ciency and inflammation is still unclear, but there is increasing evidence for a connection between the isoprenoid pathway and inflammation. Inhibition of the isoprenoid pathway by statins, the inhibitors of HMG-CoA reductase (the enzymatic step before that of mevalonate kinase) can have anti-inflammatory effects, ranging from increased apoptosis of inflammatory cells to reduction of expression of cytokines.49,50 In other settings, statins seem to be proinflammatory, most notably in a study in which stimulation with Mycobacterium tuberculosis or mitogens in combination with statins increased caspase-1 activation and IL-1β secretion by monocytes, through a decrease of geraniolgeraniol.14 The ex vivo production of IL-1β is increased in HIDS,51-53 whereas treatment with the IL-1 blocker anakinra is beneficial.54 This links HIDS to the autoinflammatory disorders with a direct defect of inflammasome function. A defect in apoptosis also may contribute to the pathogenesis of HIDS. Lymphocytes from HIDS patients (who had no fever at the time of blood sampling) showed a decrease in apoptosis when stimulated with anisomycin, which was not found in patients with TNF receptor–associated periodic syndrome (TRAPS) or FMF patients.55 Such a decrease in apoptosis would result in increased survival of lymphocytes and may delay the resolution of the inflammatory response. An ordinarily innocuous stimulus in HIDS patients would more easily lead to a full-blown fever episode. Whether the pathophysiologic effects of mevalonate kin­ase deficiency are due to a transient deficiency of one or more isoprenoid end products or toxicity of mevalonate accumulation still needs to be clarified. The cause of the characteristic high serum concentrations of IgD in this syndrome, which have led to its name, also is still unexplained. CLINICAL FEATURES Ninety percent of patients with classic HIDS experience their first fever episode in the first year of life,40 and these episodes become most frequent in childhood and ­adolescence. The high fevers may lead to seizures, especially in young children. Vaccination, minor trauma, surgery, and physical or emotional stress are factors that provoke a fever episode, although often a triggering factor is not obvious. The fevers often begin with cold chills and a sharp increase in body temperature.1 They are almost always accompanied by (cervical) lymphadenopathy and abdominal pain with ­vomiting

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Figure 113-8  Aphthous ulceration detected on the tongue of a patient with hyper-IgD syndrome. (Courtesy of Dr. K. Antila, North Carelian Central Hospital, Joensuu, Finland.) Figure 113-6  Facial erythematous macules and papules in a hyper-IgD syndrome patient during an attack.

every 4 to 6 weeks, although this may vary from patient to patient or in an individual patient. The phenotype of variant HIDS differs slightly from and is milder than that of classic HIDS.41 Patients with mevalonic aciduria, the metabolic disorder that also is caused by mevalonate kinase gene mutations, experience similar inflammatory episodes as HIDS patients, but these are often of less importance compared with the severity of the rest of the phenotype, which consists of psychomotor retardation, ataxia, failure to thrive, cataracts, and dysmorphic facies. These patients usually die in early childhood.47 An intermediary clinical phenotype between classic mevalonic aciduria and HIDS has been described.48 DIAGNOSIS AND DIAGNOSTIC TESTS

Figure 113-7  Petechiae on the leg of a hyper-IgD syndrome patient during a febrile attack.

and diarrhea. Other frequent symptoms are headache, myalgia, and arthralgia. Apart from the lymphadenopathy, physical signs frequently consist of splenomegaly and a skin rash with erythematous macules and papules (Fig. 113-6) or petechiae (Fig. 113-7).56 Sometimes there are also signs of frank arthritis (principally large joints) and hepatomegaly. About 40% of patients report painful aphthous ulcers in the mouth, vagina, or scrotum (Fig. 113-8). The fever disappears spontaneously after 3 to 5 days, although it may take longer before the symptoms in joints or skin disappear completely. These inflammatory attacks occur, on average, once

HIDS is diagnosed based on a combination of characteristic clinical findings and continuously elevated IgD concentrations (>100 IU/mL) (Table 113-4). There are numerous caveats concerning IgD serum concentration, however: Values may be normal in very young patients (especially patients <3 years old),57 persistently normal levels have been reported in a few patients with classic HIDS,39 and patients with other familial autoinflammatory syndromes also may have elevated IgD concentrations, although these are usually only slightly elevated. More than 80% of HIDS patients combine a high concentration of IgD with high IgA levels.57,58 During fever attacks, a brisk acute-phase response is observed, including leukocytosis, high levels of SAA and CRP, and activation of the cytokine network.52,59 The diagnosis of classic HIDS can be confirmed by DNA analysis of the mevalonate kinase gene. The best approach is to start with screening for the two most prevalent mutations, V377I and I268T. If this screening is negative, but the clinical suspicion remains high, sequencing of the entire gene can be considered. A good alternative is the measurement of urinary mevalonic acid concentrations during an attack, which are slightly elevated. Gas chromatography– mass spectroscopy is necessary to detect this slight increase,

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Table 113-4  Diagnostic Indicators   of Hyper–­Immunoglobulin D Syndrome At Time of Attacks Elevated erythrocyte sedimentation rate and leukocytosis Abrupt onset of fever (≥38.5°C) Recurrent attacks Lymphadenopathy (cervical) Abdominal distress (e.g., vomiting, diarrhea, pain) Skin manifestations (e.g., erythematous macules and papules) Arthralgias and arthritis Splenomegaly Constantly Present Elevated IgD (≥100 U/mL) measured on 2 occasions at least 1 mo apart* Elevated IgA (≥2.6 g/L) Classic Hyper–Immunoglobulin D Syndrome Only Mutations in mevalonate kinase gene Decreased mevalonate kinase enzyme activity *Extremely high serum concentrations of IgD are characteristic, but not obligatory.

however.60 The measurement of mevalonate kinase enzyme activity is complicated and time-consuming and should be reserved for research purposes. TREATMENT There is no established treatment regimen for HIDS. A double-blind, placebo-controlled, crossover trial of the HMG-CoA reductase inhibitor simvastatin showed a beneficial effect of this drug, with a reduction in number of days of illness in five out of six patients.61 Takada and associates62 reported a favorable preliminary experience with the TNF antagonist etanercept.54 In one report, use of the IL1β inhibitor anakinra curtailed the fever episode in a HIDS patient.54 Some individual patients have been reported to have benefited from treatment with corticosteroids, colchicine, intravenous immunoglobulin, or cyclosporine, but these results have not been repeated in most patients.56 Thalidomide did not have an effect on disease activity in a placebocontrolled trial.63 OUTCOME AND PROGNOSIS The long-term outcome in classic and variant HIDS is relatively benign in most patients. In many patients, the fever episodes occur less frequently and become less severe later in life, starting from late adolescence. Joint destruction is rare, but abdominal adhesions are seen, resulting from repeated abdominal inflammation or (unnecessary) diagnostic laparotomy because of suspected acute abdomen. Until more recently, no cases of amyloidosis had been seen in HIDS patients since its first description in 1984. Since 2004, four HIDS patients 19 to 27 years old have been reported who developed renal failure because of AA amyloidosis.64-66 Regular screening for proteinuria also may be advisable in HIDS patients, especially patients with frequent and severe fever episodes.

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1871

TUMOR NECROSIS FACTOR RECEPTOR–ASSOCIATED PERIODIC SYNDROME EPIDEMIOLOGY TRAPS (MIM 142680) has an autosomal dominant inheritance pattern. It was originally described in a large family from Irish and Scottish descent as “familial Hibernian fever.”67 It is found primarily in patients from northwestern Europe, but also has been described in families from Australia, Mexico, Puerto Rico, Portugal, and the Czech Republic.68 Any ethnic group may be affected. Other previous nomenclature for this syndrome includes “autosomal dominant familial periodic fever”69 and “familial perireticular amyloidosis.”70 ETIOLOGY Mutations are found in the gene for the type I TNF receptor (TNFRSF1A), which is located on the short arm of chromosome 12.4 These are mainly single-nucleotide missense substitutions, located in exons 2, 3, and 4, which encode for the extracellular domain of TNFRSF1A. Many of these mutations disrupt one of the highly conserved cysteine residues involved in extracellular disulfide bonds of the 55-kD type I TNF receptor protein (Fig. 113-9) (for details, see the online mutation database available at http://fmf.igh.cnrs. fr/infevers/). There are some general genotype-phenotype correlati­ ons, especially when mutations are grouped in cysteine and noncysteine mutations. Noncysteine mutations have, overall, a lower penetrance than cysteine mutations, and amyloidosis is seen far more often in association with cysteine mutations.71 Two missense mutations in TNFRSF1A, P46L and R92Q, have a particularly low penetrance and are found in approximately 1% to 10% of control chromosomes.71-73 R92Q has been observed in higher prevalence in a group of patients with arthritis. It is thought that the clinical manifestations of patients with an R92Q mutation depend on other so-far-unidentified modifying genes, environmental factors, or both.71 PATHOGENESIS The TRAPS mutations are supposed to be gain-of-function mutations, leading to increased TNF-α signaling. TNF-α is a pleiotropic molecule, which induces cytokine secretion, activation of leukocytes, fever, and cachexia. Activation of the receptor by TNF-α causes cleavage and shedding of its extracellular part into the circulation, where it acts as an inhibitor of TNF-α. When an in vitro shedding defect was shown for numerous TRAPS mutations, the “shedding hypothesis” was postulated for the pathogenesis of TRAPS. Reduced shedding of the type I TNF receptor would lead to prolonged TNF-α signaling and uncontrolled inflammation. Not all TRAPS mutations cause decreased shedding, however, and although serum concentrations of the shedded soluble TNFRSF1A in TRAPS patients during periods without symptoms are often found to be significantly reduced compared with normal subjects, this is not always the case.14 The hypothesis of reduced shedding, although

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Cytoplasmic domain

Extracellular domain

Y20H H22Y C30R

C29F

C43R

C33G C33Y

C30S

G36E Y38C

P46L T50M

C52F C52R

C96Y

S86P

C55S L67P

C73R

C70R C70S C70Y

C88R C88Y

F112I

D93E Death domain R92P R92Q

Cysteine-rich domain Cysteine residue

Figure 113-9  Schematic representation of the tumor necrosis factor (TNF) receptor type 1 protein (TNFRSF1A), depicting mutations found in TNF receptor–associated periodic syndrome (TRAPS) up to this time (except for one intron mutation affecting a splice site). Mutations disrupting cysteine residues are in boldface type.

attractive by its simplicity, is not supported as the sole cause of the fever attacks in TRAPS, and additional mechanisms seem to be at work. A new hypothesis suggests that the increased inflammation in TRAPS is independent of the TNF-signaling function of the mutated type I receptor.74,75 It has been shown that there is less binding of TNF-α to the mutated receptor,76,77 less cell surface expression,77-79 and decreased TNF-induced NFκB-activation.78,80 The mutated TNFRSF1A is retained intracellularly, pooled in the endoplasmic reticulum.74,77,81 Mutant TNFR1 cannot associate with the wild-type version, but can form aggregates by self-interaction.74,75 Either this cytoplasmic receptor aggregation results in ligandindependent signaling,75 or accumulation of the misfolded mutant protein in the endoplasmic reticulum turns on an exaggerated unfolded protein response leading to induction of cytokines such as IL-1β.74 This new hypothesis also might offer an explanation for the observation that blocking IL-1β works better in some TRAPS patients than blocking TNF.82 CLINICAL FEATURES The clinical features can vary much more between individual TRAPS patients than is generally seen in FMF or HIDS.68 The age of onset can vary, even within the same family, with a documented range of 2 weeks to 53 years old.68,83 There also is a large variation in duration and frequency of the fever episodes in TRAPS. On average, attacks last 3 to 4 weeks and recur two to six times each year, but episodes also may be limited to a few days (see Fig. 113-1). Although the index patient, through whom the diagnosis is made, often displays well-defined inflammatory attacks, affected family members may have less typical symptoms, such as episodic mild arthritis. During inflammatory attacks, a high, spiking fever can be accompanied by skin lesions, myalgia and arthralgia, abdominal distress, and ocular symptoms. The most ­common cutaneous manifestation is a centrifugal, migratory, erythematous patch, which may overlie a local area of

Figure 113-10  Migrating erythematous rash during a tumor nec­ rosis factor receptor–associated periodic syndrome attack. (Courtesy of Dr. T. Fiselier, University Medical Center St. Radboud, Nijmegen, The Netherlands.)

myalgia (Fig. 113-10),84 but urticarial plaques also may be seen. Myalgia is often located primarily in the muscles of the thighs, but it may migrate during the fever episode, affecting all of the limbs and the torso, face, and neck.68 Arthralgia primarily affects large joints, including hips, knees, and ankles. Frank synovitis is rarer, and when it does occur it is nonerosive, asymmetric, and monarticular.68 Abdominal pain occurs in 92% of TRAPS patients during inflammatory attacks; other gastrointestinal symptoms often seen include vomiting and constipation. Ocular involvement is characteristic in TRAPS, and it may involve ­conjunctivitis, periorbital edema, or periorbital pain in one or both eyes. Severe uveitis and iritis have been described, and any TRAPS patient with ocular pain should be examined for these complications.68,84 Other, less frequently observed symptoms during fever attacks in TRAPS are chest pain, breathlessness, pericarditis, and testicular and scrotal pain, which may be caused by inflammation of the tunica vaginalis.68,83 One case report described a patient who presented with psychosis without fever.85 It has been suggested from

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Table 113-5  Diagnostic Indicators of Tumor Necrosis Factor Receptor–Associated Periodic Syndrome 1. Recurrent episodes of inflammatory symptoms spanning >6 mo duration (several symptoms generally occur simultaneously)   a.  Fever b. Abdominal pain  c. Myalgia (migratory) d. Rash (erythematous macular rash occurs with myalgia)  e.  Conjunctivitis or periorbital edema   f.  Chest pain g. Arthralgia or monarticular synovitis 2. Episodes last >5 days on average (although variable) 3. Responsive to glucocorticosteroids, but not colchicine 4. Affects family members in autosomal dominant pattern   (although may not always be present) 5. Any ethnicity may be affected From Hull KM, Drewe E, Aksentijevich I, et al: The TNF receptor-associated periodic syndrome (TRAPS): Emerging concepts of an autoinflammatory ­disorder. Medicine (Balt) 81:349-368, 2002.

observation in one of the first families with TRAPS that this disorder is associated with an increased incidence of indirect inguinal hernias,86 but this has not been shown in other patients. Lymphadenopathy is rare in TRAPS. DIAGNOSIS AND DIAGNOSTIC TESTS As in the other familial autoinflammatory syndromes, laboratory investigations during inflammatory attacks show a clear acute-phase response, and even in between fever atta­ cks, such an inflammatory response may be measured. Autoantibodies generally are not detected in TRAPS. The IgD level may be elevated, but the value is almost always less than 100 IU/mL.83,86 Most patients exhibit a significantly lower concentration of soluble TNFRSF1A, most prominently in symptom-free intervals, compared with ­ appropriate controls,86 although this does not seem to be a ­universal rule.68 Also, because soluble TNFRSF1A is cleared by the kidneys, TRAPS patients with renal insufficiency (e.g., owing to renal amyloidosis) may have normal or elevated plasma concentrations of this protein.87 Hull and colleagues68 proposed a set of clinical diagnostic criteria for TRAPS (Table 113-5). These criteria are not validated by epidemiologic measures, but they may be used as a first step in evaluation of patients. TRAPS is ultimately a genetic diagnosis, defined by a missense mutation in the gene for TNFRSF1A. Clinical penetrance of TRAPS mutations is not 100%, however, even for cysteine mutations, and asymptomatic carriers are common. Also, the finding of a R92Q or P46L variant in this gene would pose a difficulty. Because they have many characteristics of a polymorphism rather than a direct disease-causing mutation (see etiology), it is debatable whether such a finding should lead to a diagnosis of TRAPS. TREATMENT NSAIDs and glucocorticoids in high doses (>20 mg/day of oral prednisone) alleviate the symptoms of fever and inflammation in most TRAPS patients, although they do not alter the frequency of attacks. They can be used beneficially at

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times of attack, and glucocorticoids usually can be tapered in the course of 1 or 2 weeks, as tolerated. In mild cases of TRAPS, NSAIDs are often sufficient. Intravenous infusion of a synthetic TNFRSF1A fusion protein was tried in one patient by Drewe and coworkers,88 but this seemed to provoke a severe attack. Use of etanercept, a fusion product of TNFRSF1B (the receptor that is not defective) has been more successful.68,71,88,89 A study with twice-weekly administration of etanercept (25 mg for adults or 0.4 mg/kg for children) in nine TRAPS patients with various mutations revealed an overall 66% response rate as determined by decreased number of attacks over a 6-month period.68 Another study with the same dosage of etanercept for 24 weeks in seven TRAPS patients also showed a clear beneficial effect without serious adverse events.88 A similar regimen of etanercept reversed the nephrotic syndrome in a patient with amyloidosis.90 Drewe and colleagues91 described one patient whose sym­ptoms were resistant to administration of etanercept, who responded favorably to use of oral sirolimus (4 to 6 mg daily). Infliximab, a monoclonal antibody against TNF, has been shown to be less effective than etanercept in TRAPS and seems to cause increased symptoms.88,91,92 In one patient with severe inflammatory attacks of TRAPS resistant to etanercept, we have seen a good response to the IL-1β inhibitor anakinra.82 There is no response to colchicine or immunosuppressive drugs, such as azathioprine, cyclosporine, thalidomide, or cyclophosphamide.68 OUTCOME AND PROGNOSIS Reactive AA amyloidosis is the principal systemic complication of TRAPS. It occurs in about 15% to 25% of patients4,71 and generally leads to renal impairment. Amyloidosis in a patient with TRAPS places other affected family members at high risk for this complication. It is principally associated with TNFRSF1A mutations affecting cysteine residues.71 Because proteinuria is the initial manifestation of renal amyloidosis, it is advisable to screen urine samples from TRAPS patients regularly by dipstick examination, especially affected family members of a TRAPS patient with amyloidosis.

CRYOPYRIN-ASSOCIATED PERIODIC SYNDROME Cryopyrin-associated periodic syndrome (CAPS) encompasses three clinical syndromes that all have been traced to mutations in one common gene: Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and chronic infantile neurologic cutaneous and articular syndrome (CINCA), also known as neonatalonset multisystemic inflammatory disease (NOMID). After the recognition of the genetic defect, it became clear that there is considerable overlap between these three disorders. Most notably, families have been described with features of MWS and FCAS.93 FCAS, MWS, and CINCA/NOMID might represent a spectrum of disease, with FCAS the mildest and CINCA the most severe form. Given their common genotype, they are discussed under one heading here, but clinical features and outcomes are dealt with separately.

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pyrin-D

LRR

NACHT

V198M A374N R260W D303N T348M L264H L305P A352V Q306L L353P D309S H358R

R488K T436N A439T A439V

F523L

E627G

M662T G569R Y570C F573S Figure 113-11  Cryopyrin protein, containing an N-terminal pyrin domain, a nucleotide binding site (NACHT), and a leucine-rich repeat (LRR) domain. Indicated are missense mutations identified in patients with familial cold autoinflammatory syndrome (FCAS) (red), Muckle-Wells syndrome (MWS) (green), or chronic infantile neurologic cutaneous and articular syndrome (CINCA/NOMID) (blue), and mutations found in common in two or all of these clinical syndromes (black).

EPIDEMIOLOGY All three syndromes are rare, autosomal dominantly inherited syndromes. Most articles on FCAS, first described in 1940, describe large families from Europe and North America with extensive pedigrees, but sporadic cases have been described. There seems to be a founder effect in American families of Northern European extraction.94 MWS was first described in 1962 and has since been described in large families, although it does occur in isolated cases and small nuclear families. Most affected families come from France and the United Kingdom.95 CINCA is rare, and, to date, some 70 cases and only a few families have been described. Most patients come from France and Argentina, but cases also are seen in other European countries and the United States.96,97 ETIOLOGY The first indications that MWS and FCAS are allelic stem from early linkage studies showing that FCAS and MWS were linked to the same region on the long arm of chromosome 1 (1q44).95,98 In 2001, the gene for FCAS and MWS was identified. In a large-scale, positional cloning effort using three families with FCAS and one family with MWS, missense mutations in a new gene were found. This gene, CIAS1 (synonyms are NALP3 and PYPAF), encodes for a protein denoted cryopyrin. Later studies showed that CIAS1 mutations also were associated with CINCA.97,99 Practically all mutations are missense mutations found in exon 3 of the CIAS1 gene, which encodes for the NOD domain of cryopyrin.100 Some mutations occur in MWS and FCAS (R260W) or in MWS and CINCA (D303N) (Fig. 113-11) (for details, see the online mutation database available at http://fmf.igh.cnrs.fr/infevers/).97 PATHOGENESIS Cryopyrin was a previously unknown protein at the time of the discovery of the mutations involved in these syndromes. Since that time, it has become the focus of numerous studies, which have led to a new concept—the inflammasome.101 Cryopyrin is a member of the NOD-LRR protein family.102 Alternative names include NALP3 (Nacht domain–, leucine-rich repeat– and PYD-containing protein) and PYPAF1 (Pyrin domain-containing APAF-like protein). It consists

of a pyrin domain (PYD), a NOD (also known as NACHT domain), and a LRR domain. Cryopyrin is mainly expressed in monocytes and neutrophils, but also is found in human chondrocytes.99,103,104 Cryopyrin is thought to be an intracellular sensor of path­ ogens or danger signals, regulating innate immunity. On stimulation with various ligands, which include bacterial RNA, imidazoquinolone compounds,105 gram-positive bacterial toxins nigericin and maitotoxin, adenosine triphosphate,106,107 and uric acid crystals,108 cryopyrin forms interactions with adapter proteins ASC and cardinal, which results in a multiprotein complex termed the cryopyrin inflammasome.101 The cryopyrin inflammasome activates caspase-1, which subsequently cleaves pro-IL-1β to the active IL-1β.109,110 There is conflicting evidence for a role of cryopyrin in regulation of transcription factor NFκB.14 Possibly, the ultimate effect on NFκB is determined by interaction of multiple proteins. Four more recent publications by independent groups that each developed a cryopyrin-deficient mouse showed no effect, however, on NFκB activation in these mice, whereas they did show a clear deficiency in caspase-1-mediated IL-1β activation.105-108 Monocytes from patients with mutations in the NOD of cryopyrin show increased activation of caspase-1 and subsequently increased release of IL-1β.110,111 The key role of IL-1β in CAPS is confirmed by the success of treatment with the IL-1 blocker anakinra in all three clinical syndromes (see treatment section). The exact effect of the cryopyrin mutations is still unclear. An attractive hypothesis involves a possible autoinhibitory loop of cryopyrin.110 Mutations in the NOD could interfere with this autoinhibitory mechanism of cryopyrin, leading to undue and excessive activation of caspase-1 and IL-1β. CLINICAL FEATURES AND OUTCOME Familial Cold Autoinflammatory Syndrome FCAS (MIM 120100) is characterized by episodes of rash, fever, and arthralgia after generalized exposure to cold (see Fig. 113-1). The disease occurs in large families as an autosomal dominant inherited disorder with an almost complete penetrance.94 The rash usually starts on the exposed extremities and, in most episodes, extends to the remainder of the body. It consists of erythematous macules and plaques

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Figure 113-12  Fine, confluent, erythematous macules on the upper leg of a patient with familial cold autoinflammatory syndrome. (Courtesy of Dr. Johnstone, Medical College of Georgia, Augusta, Ga.)

(Figs. 113-12 and 113-13), urticarial lesions, and sometimes petechiae,112 and can cause a burning or itchy sensation. In one case report, FCAS was associated with Raynaud’s disease.113 In some cases, localized edematous swelling of extremities is reported. The arthralgias, present in 93% of cases, most often affect the hands, knees, and ankles, but also can involve feet, wrists, and elbows.114 Frank arthritis is not seen. Most patients (84%) also report conjunctivitis during a fever episode. Other symptoms include myalgia, profuse sweating, drowsiness, headache, extreme thirst, and nausea. A typical feature of FCAS is the requirement of cold exposure to trigger the symptoms. The delay between cold and onset of symptoms varies from 10 minutes to 8 hours.114 When Hoffman and colleagues115 provoked an inflammatory attack in FCAS patients by generalized cold exposure in a cold room, they saw that patients developed rash, fever, and arthralgias within 1 to 4 hours. The occurrence of these symptoms could be blocked by pretreatment with the IL-1β inhibitor anakinra.115 The subsequent fever attack varies in length, depending on the degree of cold exposure; generally it lasts a few hours to a maximum of 3 days. These episodes start at an early age, with 95% of patients having had their first fever episode in the first year of life—60% even within the first days of life. The symptoms tend to become less severe with advancing age.112 Type AA amyloidosis complicated by renal insufficiency has been described in three FCAS families.114 Muckle-Wells Syndrome MWS (MIM 191900) is a rare autosomal dominant inflammatory disorder with incomplete penetrance. Patients have recurrent episodes of fever, abdominal pain, myalgia, urticarial rash (Figs. 113-14 and 113-15), and conjunctivitis, frequently accompanied by arthralgias, arthritis with limb pain, or both. Attacks start in adolescence and can be provoked by hunger, by tiredness, and sometimes by exposure to cold.116 The inflammatory episodes generally last 24 to 48 hours (see Fig. 113-1) and start with ill-defined malaise and transient chills and rigor, followed by aching or ­lancinating

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Figure 113-13  Detail of upper leg with fine, confluent, erythematous macules in familial cold autoinflammatory syndrome. (Courtesy of Dr. Johnstone, Medical College of Georgia, Augusta, Ga.)

Figure 113-14  Urticarial skin rash in a patient with Muckle-Wells syndrome. (Courtesy of Dr. D.L. Kastner, National Institute of Health, Bethesda, Md.)

pains in the distal limbs and larger joints. Arthralgia is a common feature of the attacks, but synovitis of the large joints is less common.117 The rash consists of usually aching and sometimes pruritic erythematous papules 1 to 7 cm in diameter. In a few cases, genital and buccal aphthous ulcers have been seen.118 Ocular symptoms include uveitis and conjunctivitis. Symptoms typically start in adolescence, although they have been reported at an earlier age. Late-onset development of perceptive deafness is common in MWS. Bone involvement, such as clubbing of nails and pes cavus, can be seen as well. Most often, patients have a positive family history for the disease, which is indicative of autosomal dominant inheritance, but isolated cases have been reported. The most feared complication of the inflammatory attacks is type AA amyloidosis, which affects the

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Figure 113-15  Urticarial skin rash on the arm of a patient with MuckleWells syndrome. (Courtesy of Dr. D.L. Kastner, National Institute of Health, Bethesda, Md.)

Figure 113-16  Severe deformational arthropathy of the knees in a patient with chronic infantile neurologic cutaneous and articular syndrome. (Courtesy of Dr. A.M. Prieur, Hôpital Necker-Enfants Malades, Paris, France.)

kidneys first, leading to proteinuria and subsequent rapid progression to renal failure. Chronic Infantile Neurologic Cutaneous and Articular Syndrome CINCA or NOMID (MIM 607115) is a rare congenital disorder defined by the presence of the triad of (1) neonatal-onset skin lesions, (2) chronic aseptic meningitis, and (3) recurrent fever along with joint symptoms.119 CINCA is an autosomal dominant inherited disorder.97 The key clinical feature of CINCA is a skin rash accompanied by peculiar joint manifestations and central nervous system invo­lvement. The symptoms in CINCA begin right after birth or in the first months of life with a generalized skin rash. The disease follows an unpredictable course with persistent nonpruritic and migratory rash with fever, hepatosplenomegaly, and lymphadenopathies. Central nervous system

Figure 113-17  Radiograph of the knee in a patient with chronic infantile neurologic cutaneous and articular syndrome showing greatly enlarged epiphyses and patella with punctate increased density. (Courtesy of Dr. A.M. Prieur, Hôpital Necker-Enfants Malades, Paris, France.)

involvement is not obvious from the outset, although occasional patients present with seizures, spasticity, or transient episodes of hemiplegia. In most patients, there are signs of chronic persistent aseptic meningitis.120 Cerebrospinal fluid analysis may show mild pleiocytosis, and there may be an increased intracranial pressure. Brain imaging shows mild ventricular dilation, prominent sulci, central atrophy, and, in long-standing cases, calcifications of fauces and dura. In older children, headache is often a prominent feature as a sign of chronic meningitis. Mental retardation is present in almost all cases. Progressive sensorineural impairment leading to high-frequency hearing loss can be seen in a few cases. Ocular manifestations are prominent, with optic disk changes, such as optic disk edema, pseudopapilledema, and optic atrophy, and anterior segment manifestations, such as chronic anterior uveitis.96 These symptoms may lead to visual impairment. Hoarseness, especially in older children, is typical. Joint and bone symptoms are a prominent feature of CINCA, and these manifest as bone inflammation, which gives rise to major arthropathies secondary to epiphyseal and metaphyseal disorganization. Growth cartilage alterations, such as enlarged epiphyses and patellar overgrowth, can be an impressive feature of the disease (Figs. 113-16 and 113-17). Erosive changes occur, especially in the phalanges of hands and feet. There are typical dysmorphic features, such as frontal bossing and a saddle nose. These common physical features are the reason CINCA patients give the impression that (totally) unrelated patients are siblings. The prognosis of these patients is grave; 20% die in childhood because of infections, vasculitis, and amyloidosis.119 DIAGNOSIS AND DIAGNOSTIC TESTS Diagnosis starts with a thorough patient and family history (see Table 113-1). Hoffman and coworkers114 suggested a set of diagnostic criteria for FCAS after studying six large families with this syndrome (Table 113-6), but these have not been validated in an independent cohort. Laboratory examination during a fever episode in CAPS shows an acute-phase response with polymorphonuclear ­leukocytosis

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Table 113-6  Diagnostic Criteria for Familial Cold ­Autoinflammatory Syndrome 1. Recurrent intermittent episodes of fever and rash that primarily follow generalized cold exposures 2. Autosomal dominant pattern of disease inheritance 3. Age of onset <6 mo 4. Duration of most attacks <24 hr 5.  Presence of conjunctivitis associated with attacks 6. Absence of deafness, periorbital edema, lymphadenopathy, and serositis From Hoffman HM, Wanderer AA, Broide DH: Familial cold autoinflamma­tory syndrome: Phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol 108:615-620, 2001.

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BLAU SYNDROME/EARLY-ONSET SARCOIDOSIS EPIDEMIOLOGY Blau syndrome,129 also known as familial granulomatous arthritis (OMIM 186580), and early-onset sarcoidosis (OMIM 609464) (BS/EOS) are now recognized as the same disorder.130,131 “Pediatric granulomatous arthritis” has been suggested as a new name to describe this syndrome,132 although this might, erroneously, give the impression that the disease occurs only in children. Little is known about its epidemiology, although it is thought to occur worldwide.130 ETIOLOGY

and increased erythrocyte sedimentation rate, but this does not differentiate among the periodic fever disorders. Symptoms such as an urticarial rash after cold exposure highly favor a diagnosis of FCAS. The ice cube test (i.e., holding an ice cube to a patch of skin to provoke urticaria), which is diagnostic in acquired cold urticaria, is negative in FCAS. Typical facial features, such as frontal bossing, and a long pediatric history, including chronic aseptic meningitis, point to CINCA/NOMID. Genetic testing of the CIAS1 gene can subsequently help to establish the genetic diagnosis. Usually, exon 3 of this gene is screened for mutations. There seems to be genetic heterogeneity in CINCA because not all patients have CIAS1 mutations. TREATMENT In recent years, daily treatment with the IL-1 inhibitor anakinra has emerged as beneficial for patients with any of the cryopyrin-associated periodic syndromes.51,113,115,121126 Most of these studies were close observations of single patients or small groups of patients, which is inevitable because of the rarity of these syndromes, but the results have since been confirmed in clinical practice. The largest study was by Goldbach-Mansky and colleagues,126 who studied 18 patients with CINCA/NOMID, 12 of whom had mutations in the cryopyrin gene. All of them had a rapid and sustained response to daily subcutaneous injection of anakinra (1 to 2 mg/kg body weight), with decrease of symptoms, acute-phase response and leptomeningeal lesions as seen on MRI.126 Withdrawal of the drug in 11 patients after 3 months resulted in a disease flare within days; subsequent retreatment with anakinra led to rapid improvement. No serious adverse events were observed.126 Mirault and associates127 described improvement of sensorineural deafness in a patient with MWS on treatment with anakinra. Prom­ising new inhibitors of IL-1, such as IL1-trap from Regeneron (Tarrytown, NY), are presently being developed for therapeutic use. Since the advent of IL-1 inhibition, it is the treatment of choice for patients with severe forms of cryopyrin-­associated periodic syndrome. Previously, high-dose oral corticosteroids were often used and found to be beneficial in some patients.114,116,128 NSAIDs, disease-modifying antirheumatic drugs, and cytotoxic drugs generally do not help.

The inheritance pattern of BS/EOS is autosomal dominant. In many cases, a de novo mutation is found, which explains the relatively high incidence of sporadic cases. These sporadic cases were often classified as early-onset sarcoidosis precisely because of the absence of affected relatives, but Blau syndrome and early-onset sarcoidosis have now been shown to be caused by mutations in the nucleotide-binding oligomerization domain 2/caspase recruitment domain 15 gene (NOD2/CARD15).131,133,134 Nine different mutations have been described, all located in exon 4 of NOD2/CARD15. The predominant mutations are two missense mutations at position 334 (R334Q and R334W).132 PATHOGENESIS The NOD2/CARD15 protein is considered to be an intracellular sensor for pathogenic components, analogous to the Toll-like receptors. Activation of NOD2/CARD15 results in a wide array of downstream effects that are still not well understood, including activation of NFκB and mitogen-­activated protein kinase pathways, turning on an innate immune response of diverse cytokines (e.g., IL-1β) and defensins.135 Seven of the nine different mutations of NOD2/CARD15 linked to BS/EOS are located in the NOD domain of the protein, similar to the mutations in cryopyrin in the cryopyrin-associated syndromes. The two most common mutations affect a codon at a homologous position in the NOD domain to the location of the cryopyrin R260W mutation.136 This suggests a similar pathophysiologic effect on the function of the protein. Polymorphisms in another part of this same NOD2/ CARD15 gene on chromosome 16 are associated with incre­ased susceptibility to Crohn’s disease137; the risk of developing Crohn’s disease is increased 40-fold in individuals homozygous for these polymorphisms. Whether these polymorphisms result in a gain or loss of function of this protein is debated.137 There are some shared features between the two diseases: Both are characterized by granulomatous inflammation, and although bowel inflammation is not seen in Blau syndrome, Crohn’s ­disease can manifest with uveitis, arthritis, and skin rash. CLINICAL FEATURES AND OUTCOME The clinical phenotype of BS/EOS consists of recurrent granulomatous inflammations. The three typical sites affected are joints, eyes, and skin. The granulomatous arthritis is most

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often polyarticular, with a synovitis or tenosynovitis.130 The uveitis associated with this disorder tends to follow a chronic, persistent course. It can be an acute anterior uveitis, but it often extends to a panuveitis.132 Cataracts, secondary glaucoma, and significant visual impairment can result. Involvement of the skin results in a papular, erythematous skin rash with associated dermal granulomas, usually generalized and intermittent, on trunk and extremities.138 Other symptoms include campylodactyly (contracture of multiple interphalangeal joints), cranial neuropathies, fever, and arteritis.133 In some severely affected patients, granulomatous inflammation can disseminate at an advanced stage into a systemic disease, with granulomas in liver, lung, and kidney.132 Age of onset is generally before age 5. In familial cases, genetic anticipation is often observed (i.e., the course of disease tends to be more severe in later generations). The major long-term complications are joint deformity and visual impairment.130 DIAGNOSIS The most important aspect of diagnosis is the histologic evidence of granulomas at the site of inflammation. This evidence can be obtained by biopsy of any involved site, of which skin is least invasive. A study showed that skin biopsy was diagnostic in all cases with the typical skin rash, whereas synovial biopsy was not positive in all patients, perhaps owing to sampling error.132 Genetic testing is available for NOD2/CARD15 mutations, but in some series, not all patients with a typical clinical phenotype carried a mutation in this gene.133 TREATMENT There are no controlled studies of management of BS/EOS patients. There tends to be a poor response to NSAIDs. A good response to the TNF inhibitor infliximab (5 to 10 mg/ kg every 4 to 8 weeks) was published in abstract form,139 although some degree of synovitis always remained, and the response of the uveitis is more dubious.130 The panuveitis usually is managed by topical, subconjunctival, or systemic corticosteroids.130

PYOGENIC STERILE ARTHRITIS, PYODERMA GANGRENOSUM, AND ACNE SYNDROME EPIDEMIOLOGY Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome (MIM 604416) is an autosomal dominant disorder first described by Lindor and colleagues.140 So far, it is the rarest disorder described here; less than 10 families have been reported. These reports have come from the United States, Italy, the Netherlands, and New Zealand. ETIOLOGY Wise and coworkers141 identified mutations in the CD2binding protein 1 (CD2BP1) gene as the cause of PAPA syn­ drome. CD2BP1, also known as proline-serine-­threonine phosphatase interacting protein 1 (PSTPIP1), is highly expressed in neutrophils.100 At this time, three missense

mutations within one domain of this gene are known (see the online mutation database available at http://fmf.igh. cnrs.fr/infevers/). PATHOGENESIS PSTPIP1 can form interactions with pyrin, the protein mutated in FMF.142 The mutations in PAPA syndrome result in hyperphosphorylation of PSTPIP1,142-144 which incre­ases the strength of the interaction between PSTPIP1 and pyrin.142 This increased interaction of PSTPIP1 and pyrin leads to increased IL-1β production. This activity correlated with a higher IL-1β production in response to lipopolysaccharide stimulation of peripheral blood leukocytes from a PAPA patient ex vivo compared with a healthy control.142 It places PAPA syndrome in the same pathogenic pathway as FMF. Other studies report an increased production of TNFα.145,146 Dysregulated apoptosis also may be involved.147 CLINICAL FEATURES AND OUTCOME The episodic inflammation in this syndrome includes, as the name aptly indicates, symptoms of pyogenic sterile arthritis, pyoderma gangrenosum, and severe cystic acne. Lesions generally occur at the site of mild physical trauma, but sometimes no obvious trigger can be discerned.140 The inflammation can be severe and eventually may lead to destruction of joints, muscle, and skin. Fever is not prominent in this syndrome. Age of onset has been reported as 1 to 16 years of age.140,148 The acne generally starts early in puberty and persists in adulthood. DIAGNOSIS No specific diagnostic test exists. Diagnosis is based on a finding of the typical constellation of symptoms and a positive family history. A specialized DNA diagnostics department would be able to perform the genetic test for PAPA syndrome. At this time, it is unknown whether this genetic test would detect all patients, or whether other genes could be involved. TREATMENT Diverse anecdotal evidence only is available on treatment options in PAPA syndrome. High-dose steroids generally have a positive effect on the pyoderma gangrenosum, but may be associated with increased acne.140 Pyogenic arthritis is often responsive to glucocortoids intra-articularly and orally.148 Varying results have been reported with anticytokine treatment. The TNF inhibitor etanercept was beneficial in one report,145 whereas the IL-1 inhibitor anakinra was successful in two other reports.142,149 Stichweh and colleagues150 reported on a patient with severe pyoderma gangrenosum, however, who did not respond to either etanercept or anakinra, but in whom the other TNF inhibitor infliximab did prove very successful.

CONCLUSION The familial autoinflammatory syndromes are characterized by recurrent episodes of fever and inflammation. This group of disorders should be considered in a patient with a history

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Table 113-7  Summary of Treatment Options Disorder

Treatment Options

FMF

Colchicine In refractory cases or intolerance of colchicine: intravenous colchicine; IL-1 inhibition (anakinra)

HIDS

Simvastatin; etanercept; IL-1 inhibition (anakinra)

TRAPS

NSAIDs; etanercept; IL-1 inhibition (anakinra)

CAPS

IL-1 inhibition (anakinra)

BS/EOS

Corticosteroids; infliximab?

PAPA

High-dose steroids; IL-1 inhibition (anakinra); etanercept; infliximab

See text for details. IL, interleukin; NSAIDs, nonsteroidal anti-inflammatory drugs.

of years of such inflammatory attacks with symptom-free intervals in between (except for CINCA/NOMID, in which some symptoms and morphologic features persist). Dysregulation of the IL-1β pathway is central to many familial autoinflammatory syndromes, especially CAPS and FMF. The discovery of the causative genes has had an enormous impact in the field of periodic fevers. This discovery has been made possible because of the accurate phenotypic characterization of patients with periodic fever. Careful ana­ lysis and proper clustering of these patients is indispensable to allow the elucidation of the genetic background and the evaluation of possible treatment options (Table 113-7). Central periodic fever registries have afforded the opportunity to appreciate previously unrecognized symptoms, to give insight into the long-term prognosis, and to allow better evaluation of drug regimens. Despite these efforts at classification, however, many patients with periodic fever do not fall in one of the previously mentioned disease categories. It is to be expected that in the future other periodic fever syndromes and corresponding genes will be discovered. REFERENCES   1. Drenth JPH, van der Meer JWM: Hereditary periodic fever. N Engl J Med 345:1748-1757, 2001.   2. Knockaert DC, Vanneste LJ, Bobbaers HJ: Recurrent or episodic fever of unknown origin: Review of 45 cases and survey of the literature. Medicine (Balt) 72:184-196, 1993.   3. de Kleijn EM, Vandenbroucke JP, van der Meer JWM: Fever of unknown origin (FUO), I: A prospective multicenter study of 167 patients with FUO, using fixed epidemiologic entry criteria. The Netherlands FUO Study Group. Medicine (Balt) 76:392-400, 1997.   4. McDermott MF, Aksentijevich I, Galon J, et al: Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97:133-144, 1999.   5. Yuval Y, Hemo-Zisser M, Zemer D, et al: Dominant inheritance in two families with familial Mediterranean fever (FMF). Am J Med Genet 57:455-457, 1995.   6. Aksentijevich I, Torosyan Y, Samuels J, et al: Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet 64:949-962, 1999.   7. Booth DR, Gillmore JD, Lachmann HJ, et al: The genetic basis of autosomal dominant familial Mediterranean fever. QJM 93:217-221, 2000.

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114

Tumors and Tumor-like Lesions of Joints and Related Structures ANDREW E. Rosenberg

KEY POINTS

NON-NEOPLASTIC LESIONS

Most mass lesions in and around joints are benign, with ­synovial cysts being the most common. These are not true cysts because they lack an epithelial lining. They may involve joints (Baker’s cyst) or tendon sheaths (ganglion cysts). ­Treatment depends on the symptoms, with many ganglion cysts better left alone.

SYNOVIAL AND GANGLION CYSTS

Synovial chondromatosis is an uncommon benign condition characterized by nodules of hyaline cartilage, often ossif ied, within the subsynovial connective tissue, most frequently involving the knee. Treatment is removal of nodules. Tenosynovial giant cell tumor of joints and tendon sheaths, previously known as pigmented villonodular synovitis, affects both sexes equally, usually in the third or fourth decade. Lesions are most often monarticular, with the knee being involved in 80% of cases. Studies have shown that the disease is due to a translocation resulting in overexpression of colonystimulating factor-1. Although they can be locally destructive, the tumors do not metastasize; treatment is removal. The most common primary malignant tumor of joints is synovial sarcoma, which usually affects children and young adults. The disease has an aggressive course, with a long-term survival of around 50%. Lymphoproliferative diseases may involve joints, especially acute leukemia. Joint involvement is most common in children, where the reported incidence of joint involvement ranges from 12% to 65%. Arthritis can occur at any time in the course of the disease and can be the presenting complaint. It is due to leukemic infiltration into the synovium.

Joints and periarticular structures are often involved by non-neoplastic, mass-forming lesions, such as synovial cysts and loose bodies. These structures are affected infrequently, however, by benign or malignant neoplasms. Joint neoplasms can be divided into tumors that are primary or arise de novo within the joint and tumors that are secondary and access the joint by invading from neighboring bones and soft tissues or spreading from distant sites via the vascular system. Primary joint neoplasms are more common and tend to recapitulate the phenotype of tissues that normally construct the joint—synovium, fat, blood vessels, fibrous tissue, and cartilage. Regardless of the histologic type, the benign variants greatly outnumber their malignant counterparts, and as a group these tumors tend to develop in the synovium and not the other periarticular structures. These biologically and morphologically diverse lesions often pose significant challenges in diagnosis and treatment, and their clinicopathologic features are the focus of this chapter.   Video available on the Expert Consult Premium Edition website.

Cysts are defined as closed compartments or sacs that are lined by epithelium and frequently filled with fluid. Neither the synovial cyst nor the ganglion cyst is considered a true cyst because each lacks an epithelial lining. Synovial cysts are common and form from the synovial lining of a joint, tendon, or bursa. They are non-neoplastic lesions and are caused by herniation of the synovium through the joint capsule or tendon sheath into the neighboring tissues or expansion of a preexisting bursa. In adults, synovial cysts frequently develop in association with a variety of joint disorders, including trauma, osteoarthritis, crystal arthropathies, infection, and rheumatoid arthritis or one of its variants. Most synovial cysts have an anatomic relationship to a joint, and most originate in the posterior aspect of the knee, where they are known as a popliteal or Baker’s cyst, followed in frequency by the shoulder and hip. The posteromedial region of the knee may be prone to the development of synovial cysts because the synoviallined joint capsule in this anatomic site may not provide adequate structural support.1 Synovial cysts of the posterior knee joint are purported to affect 2.4% of children, who, in contrast to adults, are usually asymptomatic and have an otherwise normal knee joint.2 Synovial cysts can enlarge as they become increasingly distended with synovial fluid.1-4 Consequently, they may manifest as a periarticular mass, produce progressive joint pain and swelling, limit joint mobility, and compress adjacent neurovascular structures. An example of the lastmentioned occurs in the spine, where synovial cysts that arise from facet joints may impinge on spinal nerves and cause radicular pain.5 Other complications of synovial cysts, which sometimes can produce dramatic clinical findings, are acute rupture and secondary infection. A variety of radiographic techniques have been used to image synovial cysts. The imaging modalities that provide the most diagnostic information are arthrography, ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI).1-4 All of these modalities reveal synovial cysts to be simple or septated thin-walled structures associated with joints and periarticular structures and filled with fluid whose density is similar to that of water (Fig. 114-1). Grossly, synovial cysts usually range in size from 1 to 10 cm. Their inner surface is smooth, glistening, and translucent; however, prior hemorrhage or secondary infection may distort this surface by virtue of attached blood clot and inflammatory debris or the generation of granulation tissue. The cyst wall comprises an inner surface lined by flattened or plump cuboidal synoviocytes arranged one or several 1883

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F

T

Figure 114-3  Round, firm ganglion cyst bulging from the dorsal aspect of the hand.

C

Figure 114-1  MR image shows high T2 signal intensity, large, ovalshaped synovial cyst that extends from the knee joint into the posterior calf. C, synovial cyst; F, fibula; T, tibia.

cell layers thick, which are surrounded by an outer sheath of fibrous tissue (Fig. 114-2). Sometimes the synovial lining cells may be hyperplastic and form papillary fronds, and occasionally there are scattered subsynovial collections of hemosiderin-laden macrophages, which are indicative of previous hemorrhage. The treatment of synovial cysts varies and depends on their location and associated symptoms. These cysts may be managed successfully with conservative therapy; however, in certain situations surgical excision is required.1-5

Figure 114-2  Wall of synovial cyst, composed of an inner lining of synoviocytes overlaying a layer of dense, fibrous tissue.

Ganglion cysts have been recognized for centuries; Hippocrates described them as being composed of “mucoid flesh.”6 They are more common than synovial cysts and arise from tendon sheaths, ligaments, menisci, joint capsules, and bursae.6 Occasionally, they develop de novo in the subchondral areas of bone, and rarely they arise within skeletal muscle and lack communication with a joint. Ganglion cysts are distinguished from synovial cysts by virtue of the fact that they lack a surface lining and do not communicate directly with a joint cavity or synovial lining. A variety of hypotheses have been proposed to explain their pathogenesis, but none have been proven.6 The most accepted theory is that ganglia develop from mucoid cystic degeneration of periarticular structures. They are commonly associated with repetitive motion activities, inflammatory arthritides, and trauma. Most ganglia arise along the dorsal and volar aspects of the wrists and fingers, and the dorsum of the feet.6,7 They are usually asymptomatic and typically manifest as a slowly growing, mobile, firm mass that moves with the structure from which it has arisen (Fig. 114-3). Ganglia may be painful if traumatized and can compress adjacent neurovascular structures producing a variety of symptoms. The radiographic characteristics of ganglia are similar to those of synovial cysts, and they appear on images as small, fluidfilled cystic structures.1,7 Macroscopically, most ganglia are round, but they may form elongate cylindrical structures if they track along a tendon sheath. Ganglia are uniloculated or multiloculated, have thin walls, and are filled with translucent mucoid fluid (Fig. 114-4). The cyst lacks an inner cell lining, and the bulk of the wall consists of dense fibrous tissue, which is usually surrounded by areolar tissue (Fig. 114-5). In many instances, the cyst wall is distorted by variable amounts of reactive myxoid tissue and muciphages, which result from small ruptures and extravasation of fluid. When ganglion cysts form, they may remain stable for years or spontaneously resolve, and ganglia that disappear may subsequently redevelop. Treatment is frequently conservative because of their innocuous nature. Ganglia occasionally require aspiration or surgical excision, however, especially if they are symptomatic.

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Figure 114-6  Large nodular loose body formed from a semilunarshaped piece of articular cartilage that is surrounded by newly formed cartilage.

Loose bodies and joint mice are generic terms for free-floating structures within a joint cavity. They are the most common tumor-like lesion of joints and may be exogenous, such as fragments of a bullet, or endogenous, such as pieces of articular cartilage, osteophytes, menisci, ligaments, or bone.8,9 When not otherwise specified, the term loose bodies refers to detached pieces of articular cartilage or subchondral bone (osteoarticular loose bodies) or both that lie free within the joint or that have become secondarily embedded in the synovium. Loose bodies can cause pain, crepitance, and locking, and they can limit joint range of motion.

Osteoarticular loose bodies are a secondary complication of a variety of conditions, including trauma, osteochondritis dissecans, and arthritides of various etiologies. When dislodged, the sloughed articular cartilage remains viable because it receives its nourishment from the synovial fluid, but the bone dies because it derives its nutrition solely from blood vessels. Over time, as the loose body tumbles in the joint, its edges become rounded and smooth; however, it eventually becomes embedded within the synovium. When the synovium encompasses the loose body, either it digests and resorbs it, or adjacent subsynovial connective tissue cells undergo a proliferative and metaplastic response. These cells produce layers of newly formed fibrocartilage and hyaline cartilage, which may undergo enchondral ossification and which are deposited on the surface of the loose body (Fig. 114-6). These layers of newly formed tissue surround the centrally located loose body similar to the cambium layers of a tree and provide a mechanism for the whole structure to increase gradually in size and become significantly larger than the initial osteochondral defect from which it originated (Figs. 114-7 and 114-8). As the loose body enlarges, the innermost portion of original articular cartilage cannot be supported adequately by diffusion of

Figure 114-5  Ganglion cyst wall composed of scattered flattened fibroblasts on the luminal surface and a well-formed layer of fibrous tissue.

Figure 114-7  Loose body with visible layers of newly formed tissue.

Figure 114-4  Intact ganglion cyst with threadlike pedicle that attaches to a periarticular structure.

LOOSE BODIES

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Figure 114-8  Loose body composed of sloughed articular hyaline cartilage (bottom) covered by consecutive layers of newly formed metaplastic hyaline cartilage and bone.

synovial fluid, and it dies and calcifies. This combination of events causes the loose body to appear as dense speckled and ringlike calcifications on x-rays (Fig. 114-9). Radiographically and histologically, the differential diagnosis includes synovial chondromatosis. Treatment is simple excision, which can be done arthroscopically.9 INTRA-ARTICULAR OSSICLES Small bony nodules normally occur in the knees of some rodents10 and other mammals and may rarely occur in humans.11,12 In rodents, they are constantly found in the anterior portions of the joint and frequently in the posterior portions as well. In humans, these nodules develop within the substance of the meniscus of the knee joint adjacent to its attachments to the tibia. The exact etiology of such structures is unknown, although they probably either are true sesamoid bones, as seen in rodents, or represent ossification secondary to local injury. This latter possibility is supported by the fact that previous knee trauma has been noted in numerous reported cases. The main symptom of meniscal ossicles is pain after exertion, such as walking or prolonged standing, with relief when the knee is at rest. Radiographs may reveal an intraarticular calcification that can be confused with a loose body.12 MRI shows the ossicle to be a corticated marrowcontaining structure that has increased signal intensity on T1-weighted images and decreased signal intensity on T2weighted images.11,12 The ossicle is located within either the lateral or the medial meniscus and appears as a small (approximately 1 cm in diameter), palpable bony nodule (Fig. 114-10). If the ossicle is symptomatic, it should

Figure 114-9  Knee with an osteoarticular loose body in the suprapatellar region.

be excised; however, if it is an incidental finding, it can be managed conservatively.11

NEOPLASMS FATTY LESIONS OF THE SYNOVIUM Although the subsynovial connective tissue of diarthrodial joints is rich in fat, a true lipoma of the synovium is rare. When these rare tumors develop, they most frequently affect the knee joint and the synovial sheaths of tendons

Figure 114-10  Intra-articular ossicle embedded in the fibrocartilage of the meniscus.

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Figure 114-11  Lipoma arborescens manifesting as a suprapatellar mass.

of the hands, ankles, and feet, where they are more common in the extensor than the flexor synovial sheaths.13,14 Synovial lipomas can be sessile or pedunculated, and when pedunculated they may produce pain if they twist on their stalks and become secondarily ischemic. Synovial lipoma, similar to its subcutaneous counterpart, comprises lobules of mature white adipocytes that are delineated by a thin fibrous capsule. A more common but still unusual fatty lesion of the joint is lipoma arborescens, also known as villous lipomatous proliferation of the synovium.15,16 This disorder is characterized by a diffuse increase in the quantity of subsynovial fat, which bulges into the overlying synovial lining producing a villous architecture. It is uncertain whether the proliferating fat is neoplastic (lipomatosis) or a manifestation of a hyperplastic or reactive process. Affected patients are usually adults because the lesion infrequently develops during childhood.17 Lipoma arborescens causes chronic effusions, pain, and swelling, and restricts joint motion.16 The duration of symptoms is often long, and symptoms may be present for 30 years; however, acute onset also has been documented. Lipoma arborescens most commonly arises in the knee (Fig. 114-11), especially the suprapatellar portion, although it also has been observed in the hip, ankle, and wrist joints. It is typically localized to one joint, but several cases of bilateral knee involvement have been described.16 Laboratory studies are unremarkable, and the joint fluid is clear and yellow.16 Plain films show joint fullness, and findings of osteoarthritis are often present. Arthrography reveals multiple lobulated filling defects, which on CT represent a villonodular mass of low signal intensity that on MRI has the density of fat (Fig. 114-12).18 At surgery, the affected synovium has a prominent villous or villonodular architecture and is tanyellow (Fig. 114-13). Histologically, the lesion ­ comprises

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Figure 114-12  MR image of lipoma arborescens shows villonodular mass in the knee joint

sheets of mature adipocytes admixed with nutrient blood vessels, all of which are partially compartmentalized by fibrous septa, and is covered on its intra-articular surface by several layers of synovial cells (Fig. 114-14). Synovectomy may relieve the symptoms and prevent effusions, but the associated osteoarthritis may be progressive.16

Figure 114-13  Lipoma arborescens composed of a villonodular mass of fatty tissue covered by glistening synovium.

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Figure 114-14  Lipoma arborescens with subsynovial compartment filled with mature adipocytes and covered by synoviocytes.

The clinicopathologic differential diagnosis includes diffuse tenosynovial giant cell tumor, synovial chondromatosis, and synovial hemangioma. These lesions can be distinguished easily from lipoma arborescens by their distinct histologic features. Another disorder that should be included in the differential diagnosis is Hoffa’s disease, a condition of irritation, inflammation, and hyperplasia of the synovial lining in regions where fat is normally present, such as adjacent to the patella or patellar ligament.19

patients who have had long-term symptoms and recurrent hemarthrosis. Rarely, calcified phleboliths are apparent; however, they are associated more often with a soft tissue arteriovenous malformation with secondary joint involvement than an isolated intra-articular hemangioma (Fig. 114-15). Arthrography may show an intra-articular filling defect, and arteriography may be negative in small localized capillary hemangiomas, but contrast material may collect in the more diffuse lesions that contain cavernous or large ectatic vascular spaces (Fig. 114-16). CT reveals a lobulated soft tissue mass with mild enhancement after contrast injection.22,23 MRI may show the tumor to have a low signal on T1-weighted images and high signal intensity on T2-weighted images.24 Macroscopically, the localized hemangioma tends to be small, but larger lesions (8 cm) have been documented. It may be sessile or stalked, is well circumscribed, and ranges in color from red to dark blue-purple. Microscopically, the hemangioma is usually of the cavernous or venous type with large dilated blood-filled vessels lined by cytologically benign endothelial cells. In the diffuse form, the entire synovium may be edematous and beefy red or stained brown by hemosiderin, and consists of prominent tortuous, congested vessels that may penetrate the joint capsule and extend into the neighboring soft tissues. Histologically, the vessels recapitulate architecturally abnormal arteries, veins, and capillaries; have abnormal interconnections; and are arranged in a disorganized tangle.23 Therapy for a localized hemangioma is marginal surgical excision, which usually is curative. Diffuse lesions frequently are difficult to eradicate because of their extensive nature.

VASCULAR LESIONS OF THE SYNOVIUM Benign vascular tumors of the synovium are rare. They are subclassified according to their growth pattern into localized and diffuse variants. Both tend to predominate in adolescence and young adulthood, but symptoms frequently can be traced back to childhood.20 The joint most commonly involved is the knee, but hemangiomas also have been described in the elbow, ankle, tarsometatarsal, and temporomandibular joints, and the tendon sheaths of the wrist and ankle.21 Unusual complications of synovial hemangiomas include a secondary destructive arthritis and Kasabach-Merritt syndrome. Synovial hemangiomas produce a variety of symptoms, including unilateral, intermittent, joint pain and enlargement, which may result in limitation of motion, locking, buckling, and hemarthrosis, especially after minimal trauma.21 Classically, the affected joint diminishes in size if sufficiently elevated to allow the blood to drain out of the lesion. On physical examination, the joint is swollen and doughy, and nearby cutaneous hemangiomas may be evident. Joint aspiration frequently yields bloody fluid. Preoperative diagnosis of localized hemangioma is difficult, and the differential diagnosis includes localized tenosynovial giant cell tumor, and in the knee includes discoid meniscus, meniscal tears, cysts, and ossicles.22 The diffuse hemangioma is more easily identified, but it can mimic diffuse tenosynovial giant cell tumor and hemophilic arthropathy. Radiographic evaluation may show nothing more than a vague soft tissue shadow indicative of a swollen synovium and distended joint capsule or regional osteoporosis in

Figure 114-15  Localized synovial hemangioma with phleboliths prominently seen in the joint. The patient is 16 years old with many years’ history of painful swelling when standing and relief of this pain when the knee is flexed.

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Figure 114-17  Fibroma of tendon sheath manifests as a well-circumscribed, tan-white mass.

Figure 114-16  Arteriogram of an arteriovenous malformation in the soft tissues of the thigh and leg with involvement of the knee joint. The extensive vascular blush in the knee indicates aberrant synovial and capsular vasculature.

Incomplete excision or debulking may be the only surgical option. Radiation therapy is not indicated. FIBROMA OF TENDON SHEATH Fibroma of tendon sheath is an uncommon benign lesion that clinically mimics giant cell tumor of tendon sheath, but is morphologically distinct. Fibroma of tendon sheath first was identified as a clinicopathologic entity in 1936, and since that time more than 220 cases have been reported.24,25 Although it is uncertain whether this lesion is some sort of reactive process, hyperplasia, or a benign neoplasm, the more recently identified translocation involving chromosomes 2 and 11 in this tumor support the concept that it is neoplastic. Fibroma of tendon sheath usually arises from the tendons and sheaths of the flexor surfaces of the distal extremities; approximately 70% involve the fingers or hand. Of the fingers, the thumb is affected most frequently followed in descending order by the index and middle fingers.24 Less commonly, large diarthrodial joints such as the knee and rarely the elbow and ankle are sites of origin.24,25 Patients range in age from infants to the elderly, but the median is in the early fourth decade of life.24,25 Most series report a male predominance, with the largest study of 138 cases having a male-to-female ratio of 3:1.24 Patients present with a slow-growing, painless mass that usually has been noted for several months to a year.25 In 6% to 10% of cases, there is a history of antecedent trauma. Plain x-rays show soft tissue fullness; rarely is there evidence of bony erosion.24 CT or MRI shows a solid well­circumscribed mass of soft tissue density. At surgery, the tumors usually are attached directly to the tendon or tendon

sheath. They are rubbery, oblong, well circumscribed, or encapsulated; average 1.5 to 1.8 cm in greatest dimension; and have a tan-white cut surface (Fig. 114-17).24,25 Microscopically, fibroma of tendon sheath is multilobular with clefts interposed between adjacent lobules. The lobules are composed of spindle and stellate fibroblasts enmeshed in a collagenous and sometimes myxoid stroma (Fig. 114-18). Immunohistochemically, the tumor cells have the staining profile of myofibroblasts, and ultrastructurally, the cells have features of fibroblasts and myofibroblasts.26 The natural history of fibroma of tendon sheath is a slow growth that eventually ceases. The treatment of choice is surgical excision, but there is a 24% recurrence rate.24 SYNOVIAL CHONDROMATOSIS Synovial chondromatosis is an uncommon condition characterized by the formation of multiple nodules of hyaline cartilage within the subsynovial connective tissue. If the cartilage nodules undergo enchondral ossification, the term synovial osteochondromatosis is appropriate. It is unclear

Figure 114-18  Fibroma of tendon sheath composed of a hypocellular collagenous mass.

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whether the proliferating cartilage is metaplastic or neoplastic; however, more recent cytogenetic abnormalities involving chromosome 6 found in the cartilage of these lesions support a neoplastic process.27 Regardless, synovial chondromatosis is benign and does not metastasize. Synovial chondromatosis most commonly affects middleaged men with an average age in the fifth decade of life.28 Middle-aged women are more likely to develop the disease in the temporomandibular joint. The genders are equally affected with regards to hand and foot involvement, and patients with hand and foot involvement are usually in their sixth decade. Patients commonly complain of joint pain, swelling, stiffness, crepitance, and limitation of motion with a locking or grating sensation on movement.28 The symptoms usually are long-standing, recurrent, and progressive. Synovial chondromatosis typically arises in large diarthrodial joints. The knee is affected in more than 50% of the cases, usually as a monarticular condition.28 Other common sites include the hip, elbow, shoulder, and ankle. Infrequently, synovial chondromatosis arises in the small joints of the hands and feet29 and the temporomandibular joint.30 When the cartilage nodules develop in the synovial lining of bursae, tendons, and ligaments, it is known as extra-­articular synovial chondromatosis.31 The extra-articular variant most commonly affects the fingers, followed by the toes, hand, wrist, foot, and ankle, and more than one synovial sheath may be involved.31 The plain x-ray findings largely depend on whether the cartilage nodules are calcified or ossified, and if they erode the adjacent bony structures. Visible calcifications are absent in 5% to 33% of cases; however, in most there are multiple oval intra-articular radiodensities that range in size from a few millimeters to several centimeters (Fig. 114-19).32 The pattern of

Figure 114-19  Synovial chondromatosis of the elbow. Multiple large calcified bodies fill the joint space and are adjacent to bone.

mineralization varies and may appear as irregular flecks that represent calcified cartilage or show a trabecular architecture, which is a manifestation of enchondral ossification. Lesions that are not mineralized can be seen on an arthrogram because they produce multiple filling defects.32 In approximately 11% of cases, the nodules erode the neighboring skeleton, especially along the anterior aspect of the distal femur. CT may show masslike nodules in the synovium that have a density similar to skeletal muscle. CT also can detect small calcifications and erosions before they are apparent on plain films. MRI shows that the nodules of cartilage have low signal intensity on T1-weighted sequences and high intensity on T2-weighted sequences, which reflects the high water content of the hyaline cartilage.32 Areas of calcification or mineralized bone have a low signal intensity on T1weighted and T2-weighted sequences. CT and MRI scans are helpful in identifying the intra-articular source of the lesion and its anatomic extent. In long-standing disease, the involved joints also may be osteoporotic and show changes of secondary osteoarthritis. The cartilage in extra-articular synovial chondromatosis has similar radiographic changes. The nodules of cartilage are more frequently mineralized and may appear as a linear arrangement of small calcific densities that are aligned along the sheath and that can span many joints (Fig. 114-20). The radiographic differential diagnosis of synovial chondromatosis includes osteochondritis dissecans, osteoarthritis with loose bodies, tuberculosis, hemopathic arthropathies, pseudogout with extensive synovial calcification, and synovial tumors. In many instances, the clinical presentation and radiographic picture should lead to the correct diagnosis. There are many cases, however, in which the x-rays and clinical picture are vague so that only a biopsy specimen can remove all doubts about the diagnosis. Characteristic of synovial chondromatosis is a thickened synovium containing numerous opalescent firm nodules of cartilage that bulge from the surface in a cobblestone pattern (Fig. 114-21). The nodules are usually less than 5 cm in size and may lose their attachment to the synovium and form loose bodies, sometimes hundreds of them. The calcified cartilage is white, and areas of ossification manifest as gritty tan trabeculae, which may house fatty marrow. The synovium adjacent to the cartilage may show reactive changes, such as edema, hyperemia, hyperplasia, and villous transformation.

Figure 114-20  Synovial chondromatosis of the hand and forearm. There are multiple calcified nodules of varying size in the soft tissues of the fingers, wrist, and forearm.

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Figure 114-21  Intraoperative appearance of synovial chondromatosis. Innumerable nodules of cartilage fill the joint. Figure 114-23  Nodules of hyaline cartilage merging with the surrounding connective tissue in synovial chondromatosis.

The cartilage develops in the connective tissue of the subsynovial compartment (Fig. 114-22). The mesenchymal cells give rise to uniformly small round chondrocytes, which produce the hyaline matrix and eventually form individual nodules that blend peripherally with the surrounding tissues (Fig. 114-23). In some cases, the cartilage is hypercellular, and the chondrocytes are large, binucleate, and hyperchromatic similar to the chondrocytes in intraosseous chondrosarcoma (Fig. 114-24). Despite these ominous histologic findings, experience has shown that these hypercellular lesions with atypical chondrocytes usually behave in a benign fashion. Infrequently, the disease manifests as a single, extremely large nodule of cartilage, which may undergo partial enchondral ossification. This giant intraarticular osteochondroma can severely limit joint motion and be confused clinically with other types of neoplasms.33 Over time, the nodules of cartilage attached to the synovium are invaded by blood vessels. This invasion results in enchondral ossification with woven and lamellar bone formation and the development of a medullary cavity with fatty marrow (Fig. 114-25). If these nodules lose their synovial attachments and become free-floating, they may continue to increase in size because the cartilage derives its

Figure 114-22  Synovial chondromatosis with nodules of hyaline cartilage in the synovium.

nourishment from synovial fluid, although the osseous portion and marrow die. The treatment of choice for synovial chondromatosis is excision of the involved synovium and removal of all loose bodies. The prognosis is good, although there may be recurrences if removal is incomplete. Most recurrences develop in the setting of diffuse involvement of the synovium. Synovial chondromatosis rarely undergoes malignant transformation into chondrosarcoma, although in one series this phenomenon occurred in 5% of cases. A significant percentage of the few reported cases of synovial chondrosarcomas has shown evidence of underlying synovial chondromatosis, however.34-36 CHONDROMA OF TENDON SHEATH AND PERIARTICULAR STRUCTURES A solitary soft tissue chondroma is considered to be a benign neoplasm. It commonly arises in tendon sheaths and infrequently involves joint capsules or other periarticular structures.

Figure 114-24  The cartilage in synovial chondromatosis can be cellular, and the chondrocytes may exhibit limited cytologic atypia.

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Figure 114-25  Nodules of cartilage in synovial chondromatosis undergoing enchondral ossification.

Tendon sheath chondromas usually arise in the flexor tendon sheaths of the distal extremities and are about three times more common in the hands than in the feet.37-39 They affect the sexes equally and are detected in early to mid adulthood as they present as a painless, slowly growing firm mass. Radiographically, tendon sheath chondromas appear as an extraosseous, well-delineated soft tissue mass that contains calcifications that are either punctate or ringlike in 33% to 70% of cases.42,43 Grossly, the tumors are ovoid, firm, blue-white, well-circumscribed masses of hyaline cartilage that are usually 1 to 2 cm in dimension, and, in contrast to synovial chondromatosis, are solitary. Histologically, the hyaline cartilage is well formed with occasional small foci of myxoid change. The cartilage can be cellular, and the chondrocytes may show cytologic atypia, which causes confusion with chondrosarcoma.40 The treatment of choice is simple excision. Although these tumors may recur in a few cases, they are benign and do not metastasize.38-40 The intracapsular and periarticular regions are uncommon sites for soft tissue chondromas. When they occur, they usually originate in the anterior infrapatellar region of the knee (Fig. 114-26).41 In this location, the chondroma can achieve a large size (8 cm) and mechanically interfere with knee motion. Morphology and biologic behavior are similar to soft tissue chondromas that arise elsewhere. Intracapsular chondromas have been reported in knees of three members of a family with familial dysplasia epiphysealis hemimelica.42 Two other cases have been described in which cartilaginous hamartomas of the volar plates of the proximal and distal interphalangeal joints of the hands and feet were associated with peculiar hypertrophic skin lesions of the hand and hemihypertrophy of the limb. It is possible that these peculiar cartilaginous lesions represent an abnormality in which primitive cartilage tissue persists in joint sites similar to the involvement of bones in multiple enchondromatosis (Ollier’s disease). TENOSYNOVIAL GIANT CELL TUMOR Tenosynovial giant cell tumor comprises a group of benign tumors that affect the synovial lining of joints, tendon sheaths, and bursae.43 These lesions have been previously

Figure 114-26  Intra-articular solitary chondroma of the knee in the infrapatellar region; it is a well-delineated mass with amorphous dense calcification, suggesting mineralized cartilage. (Courtesy of Dr. C. Campbell.)

known as giant cell tumor of tendon sheath and pigmented villonodular synovitis. Tenosynovial giant cell tumor may be localized or diffuse and may be locally aggressive in that it may invade into bone, grow through joint capsules, extend along tendons, and infiltrate into adjacent soft tissues. Despite their destructive potential, they do not have the capacity to metastasize. The common histologic denominator of these lesions is the neoplastic proliferation of synovial-like cells that may form a localized mass or spread along the synovial surface and invade downward into the subsynovial connective tissue. The growing cells expand the subsynovial compartment producing finger-like extensions, villi, and redundant folds. These projections often fuse into nodules and form convoluted lobulated masses admixed with a tangle of hairlike villi. The process may be a local phenomenon involving only part of the synovial lining, or it may be extensive with the whole synovial surface affected. Until more recently, the etiology of tenosynovial giant cell tumor was unknown. Previously considered a reactive process, possibly in response to repeated hemorrhage, many tenosynovial giant cell tumors now have been shown to result from a translocation between chromosomes 1p13 and 2q35 in which the gene encoding colony-stimulating factor-1 is fused to collagen VI alpha-3 (COL6A3) gene.43,44 Consequently, there is overexpression of colony-­stimulating factor-1 in the neoplastic cells, which account for only 2% to 16% of the cells in mass.44 The remaining cells largely represent non-neoplastic inflammatory cells that are recruited into the tumor because they contain the ­receptor for colony-stimulating factor.44,45 This phenomenon has been termed a landscape effect; it also is observed in certain types of lymphomas.

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Tenosynovial Giant Cell Tumor of Joints and Tendon Sheaths—Diffuse Type (Synonym: Pigmented Villonodular Synovitis)

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The diffuse type of tenosynovial giant cell type of the joint involves large areas of the synovial lining, although uninvolved areas are invariably present. Its incidence is approximately 1.8 per 1 million. Although it may occur in all age groups spanning children to the elderly, most affect young adults in the third to fourth decades of life.46 The sexes tend to be equally affected, although some series have reported a predominance of either males or females.46-48 Diffuse tenosynovial giant cell tumor of the joint usually manifests as monarticular arthritis. Bilaterality or involvement of multiple separate sites has been infrequently reported. Some patients with polyarticular disease also have had significant congenital anomalies. The main complaints include pain and mild intermittent or repeated bouts of swelling. The symptoms develop insidiously and progress slowly over a long time ranging from months to years.46,48 The involved area may be stiff, swollen, and warm, and a palpable mass sometimes can be appreciated. Point tenderness can be detected in approximately 50% of patients. Anatomic instability of the involved joint is uncommon. The knee joint is affected most commonly and is involved in about 80% of cases.46,48 The next most frequent sites are the hip, ankle, calcaneocuboid joints, elbow, and tendon sheaths of fingers and sometimes toes. Occasionally, the palm, the sole of the foot, and unusual locations such as the temporomandibular joint and posterior elements of the spine are involved. Bursal involvement is rare, but if it happens, it usually occurs in the popliteal and ­iliopectineal

b­ ursae and the bursa anserina. Infrequently, the disease affects large tendon sheaths proximal to the ankle and wrist and produces a periarticular soft tissue mass.49,50 It is thought that some of these lesions dissect through either a joint capsule or a tendon sheath and extend along fascial planes to produce a soft tissue mass.49 Invasion of bone on either side of a joint can be seen with intra-articular, bursal, or tendon sheath involvement. This most frequently occurs when the tumor involves “tight” joints, such as the hip, elbow, wrist, and feet, or when tendon sheaths are closely opposed to neighboring bones (Fig. 114-27).51,52 Rarely, only one bone may be invaded by an intra-articular lesion, and in this situation it may be difficult to distinguish from a primary bone tumor (Fig. 114-28).53 Joint aspiration frequently yields blood-tinged brown fluid that lacks diagnostic abnormalities.54 Synovial fluid analysis may show a low glucose content, minimally elevated protein level, and a fair mucin clot. The inflammatory cell count is usually low, but may be elevated. Similar findings also can be seen in trauma, Charcot joint, bleeding disorders, sickle cell disease, and Ehlers-Danlos syndrome. In at least two thirds of cases, a soft tissue density, which is due to the tumor or effusion or both, can be visualized on a plain film.58 Joint narrowing or calcification is uncommon. Arthrography may show numerous nodular filling defects that extend into an expanded joint space. Arteriograms are unusually striking owing to the prominent vascularity of the tumor. There tends to be an inverse correlation between the degree of vascularity and the amount of fibrosis or scarring of the lesion.

Figure 114-27  Pigmented villonodular synovitis involving the small joints of the foot with multiple bone erosions. No calcification is present in the lesion.

Figure 114-28  Pigmented villonodular synovitis involving the tibiofibular joint with an adjacent extensive soft tissue mass and eccentric erosion of the both bones, simulating a primary bone tumor. The knee joint is normal.

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Figure 114-30  Diffuse type of tenosynovial giant cell tumor growing with a villonodular architecture. Invading cells produce the nodular configuration. Figure 114-29  Diffuse type of tenosynovial giant cell tumor consisting of mottled brown-yellow-red villonodular mass.

CT and MRI are useful in delineating the extent of disease and can detect intralesional lipid and hemosiderin deposits that are important diagnostic features.55-57 ­Extension into the bone manifests radiographically as multiple, well-­marginated, subchondral cystlike lucencies or juxtacortical oval pressure erosions (see Figs. 114-27 and 114-28).52,53 In the knee, the femoral area adjacent to the intercondylar region is the site most frequently invaded as the tumor grows along the cruciate ligamentous insertions. Periarticular osteopenia, periosteal reactions, and joint destruction are unusual because the joint space is preserved until late in the course of the disease.56,57 The radiographic differential diagnosis of a given case includes (1) tuberculosis, which generally has more osteopenia and joint destruction; (2) hemophilia, which also is associated with more extensive joint destruction; (3) synovial chondromatosis, which frequently has calcified radiopaque bodies; and (4) rheumatoid arthritis, which shows more severe osteopenia and joint narrowing. Grossly, the synovium in diffuse tenosynovial giant cell tumor is red-brown to mottled orange-yellow and looks like a plush angora rug (Fig. 114-29). Matted masses of villous projections and synovial folds are prominent and are admixed with sessile or pedunculated, rubbery-to-soft nodules (0.5 to 2 cm in diameter). The synovial membrane is thick and succulent, and is often coated with a fibrinous exudate. Red-brown or golden brown tissue may extend deep into subsynovial structures or invade the joint capsule. If a tendon sheath is involved, a sausage-shaped mass may be evident as the sheath is distended by the proliferating tumor. If the joint capsule is invaded, adjacent soft tissue structures, including nerves and vessels, may be covered by wispy, red-brown tissue. If soft tissue invasion is extensive, the lesion may appear as a soft-to-rubbery, red-brown mass with foci of hemorrhagic cysts. Similar tissue may be present near the chondro-osseous junction or wrapped around vascular and ligamentous attachments to bone surfaces, which

represent entrance points into the interior of the bone. Although other conditions, such as hemochromatosis and hemosiderosis, also may discolor the synovium brown, the nodular component is usually absent; in addition, microscopic features are definitive for separating these entities (see later). Microscopic examination reveals marked synovial cell hyperplasia with surface proliferation and, more important, subsynovial invasion by masses of mitotically active polygonal or round cells with moderate amounts of eosinophilic cytoplasm and round nuclei (Figs. 114-30 and 114-31). Included among the invading synovial cells are scattered lymphocytes, multinucleated giant cells (osteoclast, Touton, or foreign body type), hemosiderin-laden macrophages, and fibroblasts. Hemosiderin also can be seen between cells and in synovial lining cells and polygonal cells. Foci of hemorrhage are common and are surrounded peripherally by giant cells and macrophages (Fig. 114-32). Scattered collections of foamy macrophages (xanthoma cells) filled with lipid also

Figure 114-31  Synovial lining cells covering the mass of proliferating polyhedral cells admixed with multinucleated giant cells.

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Figure 114-32  Sheets of macrophages containing abundant hemo­ siderin.

are a frequent finding. These different cell populations fill and distend the synovial villi and cause them to fuse with adjacent ones, forming nodules. In some nodules, there may be abundant collagen deposition with hyalinization causing confusion with neoplastic bone. Immunohistochemical studies of these tumors have not yielded consistent results and have been interpreted to support a synovial cell or fibrohistiocytic phenotype.26,58 Importantly, the cells that harbor the translocation express colony-stimulating factor-1. Flow cytometric analyses have shown that some of these tumors, especially tumors that have large extra-articular soft tissue components, may be aneuploid and have high proliferative indices.50 Although these flow cytometric findings may help predict which cases would be more locally aggressive, examples of diffuse tenosynovial cell tumors with these attributes have not been shown to metastasize.50 The treatment of diffuse tenosynovial giant cell tumor of the joint is not standardized and has included radiation therapy, total synovectomy, arthrodesis, bone grafting, and primary arthroplasty.59 Although no single therapy has been consistently successful, currently, wide synovectomy is the recommended treatment.46,48 It is difficult to perform an actual complete synovectomy, however; residual involved synovium frequently remains causing a local recurrence rate of 16% to 48%.60-62 Tumors arising in the knee have a higher rate of recurrence compared with tumors arising in other joints.63 Rarely, recurrent disease or tumors with large extra-articular components may require more radical surgery, such as ray resection or amputation.50 More recent studies have shown that moderate doses of radiation may control and even cure patients with such extensive disease, possibly obviating the need for radical surgery or ­amputation. Malignant Diffuse Tenosynovial Giant Cell Tumor Malignant tenosynovial giant cell tumor is a rare lesion with only a handful of cases having been reported.64,65 The knee has been the joint most commonly affected, and in many cases there was coexisting benign-appearing, diffuse tenosynovial giant cell tumor. In the malignant variant, the neoplastic mononuclear polyhedral cells are ­ cytologically

Figure 114-33  Localized tenosynovial giant cell tumor of the joint with attached pedicle. The mass is well circumscribed and brown-yellow.

malignant. These tumors have the capacity to behave aggressively; almost 50% of patients have died from metastatic disease.64 Localized Tenosynovial Giant Cell Tumor of the Joint (Synonyms: Benign Giant Cell Synovioma, Benign Synovioma, Localized Nodular Synovitis) Localized tenosynovial giant cell tumor of the joint manifests as a solitary, well-circumscribed mass. It usually consists of a single sessile or pedunculated, sometimes lobulated, mass that ranges from 1 to 8 cm in diameter (Fig. 114-33). Most commonly, it is unilateral, arises in the knee, and is equally distributed between the sexes.66 Symptoms are similar to those of diffuse tenosynovial giant cell tumor except that in the localized variant there is a higher frequency of joint locking because the mass interferes with motion.66 A few patients may present with acute severe joint pain caused by torsion and infarction of the tumor. Effusions are common, but the synovial fluid tends to be less bloody than in pigmented villonodular synovitis and may be clear. Imaging studies show a heterogeneous nodular mass that contains lipid and hemosiderin deposits (Fig. 114-34). In the knee joint, the tumor frequently arises in the suprapatellar notch, in the femoral notch, and between the meniscus and joint capsule.66 There is usually no bone invasion. Marginal excision is usually curative.67 Small lesions can be extirpated arthroscopically.66 Histologically, localized tenosynovial giant cell tumor of the joint is identical to the nodules of the diffuse variant. The main difference is that the prominent synovial villi present in the diffuse variant are absent or sparse.

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Figure 114-34  MR image shows well-delineated dark mass in posterior knee joint. Figure 114-35  Tenosynovial giant cell tumor manifesting as a mobile, solid, firm mass.

Localized Tenosynovial Giant Cell Tumor of the Tendon Sheath (Synonyms: Giant Cell Tumor of Tendon Sheath, Fibroxanthoma of Tendon Sheath) Localized tenosynovial giant cell tumor of the tendon sheath usually involves the hand or wrist, and less frequently the foot or ankle.47 Localized tenosynovial giant cell tumor of the tendon sheath is the most common soft tissue tumor of the hand. It usually arises from the flexor tendon sheaths of the fingers; the index finger is affected most frequently, followed in descending order of frequency by the middle ­finger, ring finger, little finger, and thumb. Finger tumors predominate in females with a ratio of at least 2:1,47,68 and tumors of the toes have an equal sex distribution.47 On average, patients are in the third to fifth decades and present with a painless, palpable, firm, mobile mass. Clinically, the mass is usually solitary and located on the flexor surface, but it may bulge into the extensor or lateral aspects of the digits (Fig. 114-35). The tumors are slow growing, and the intervals between detection and surgical treatment have ranged from several weeks to greater than a decade with an average of slightly more than 2 years.47,68 Radiographically, tumors appear as well-circumscribed soft tissue masses, and in about 25% of cases, there is adjacent extrinsic excavation of the cortical bone that has a sclerotic margin (Fig. 114-36).47,68 MRI reveals the lesions to have a hypointense signal on T1-weighted images and either a hypointense or a hyperintense signal on T2-weighted images. These findings are helpful in distinguishing giant cell tumor of tendon sheath from other soft tissue tumors.69

The gross pathology is that of a well-circumscribed, multinodular, round, rubbery mass, generally not larger than 5 cm in diameter, which is firmly attached but easily peeled off the involved tendon (Fig. 114-37). Sometimes at surgery, the variegated red-brown-tan lesion may “pop out” of the

Figure 114-36  The cortex of the phalanx is eroded by the tenosynovial giant cell tumor.

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Figure 114-37  Well-delineated, white-yellow and focally brown tenosynovial giant cell tumor.

i­ ncision. The cut surface reveals a solid mass that ranges from hues of yellow to orange-brown, depending on the amount of lipid and blood pigments present. Often there are bands or septa of white fibrous tissue that subcompartmentalize the lesion. Microscopically, the cell types present are identical to those in the diffuse variant (Fig. 114-38).70 Ultrastructurally, the proliferating cells have features similar to type A and type B synovial lining cells.68-71 Their antigenic and enzymatic profiles have suggested a synovial or monocyte/macrophage lineage, the latter being similar to osteoclasts.72 Flow cytometry has been performed on a few cases, and all have been diploid.50 Cytogenetics show that many of these tumors have a translocation between 1p13 and 2q35.44,45,73 These tumors are benign and do not metastasize. Rarely have malignant giant cell tumors of tendon sheath been reported.64,74 The treatment of choice is conservative surgical excision, which is usually curative. There may be local recurrence if excision is incomplete.47,68

Figure 114-39  Angiosarcoma of synovium of the knee joint. The hemorrhagic tumor erodes into the distal femur and proximal tibia.

MALIGNANT TUMORS OF THE JOINT Malignant tumors of joints are uncommon and are classified into primary and secondary types. Primary malignancies are virtually always sarcomas and usually arise within the synovium of large diarthrodial joints, especially the knee. The patients are adults who present with the chronic symptoms of pain, swelling, and effusion, and most of the tumors are either chondrosarcomas or synovial sarcomas. Rarely, other sarcomas originate within a joint; we have experience with intra-articular myxoinflammatory fibroblastic sarcoma, pleomorphic fibrosarcoma, extraskeletal myxoid chondrosarcoma, conventional chondrosarcoma, malignant tenosynovial giant cell tumor, and angiosarcoma (Fig. 114-39). Secondary malignant tumors of joints, by definition, originate beyond the confines of the joint, and most are sarcomas that extend from neighboring bones or surrounding soft tissues. Although synovial tissue is very vascular, metastases or involvement of the synovium by carcinoma, lymphoma, or leukemia is uncommon. PRIMARY SARCOMAS OF JOINTS Conventional Chondrosarcoma

Figure 114-38  Mitotically active polyhedral cells and scattered osteoclast-type giant cells in tenosynovial giant cell tumor.

Conventional chondrosarcoma arising in the synovium is unusual, and less than 50 cases have been reported in the English language.34-36,65,75 In approximately 50% of these cases, the chondrosarcoma arose in association with ­preexisting synovial chondromatosis.36,37,76,77 The patients are usually in the fifth to seventh decade and have an equal sex distribution.77 Typically, they present with a progressively enlarging mass in the joint that may cause mechanical dysfunction, pain, and stiffness. In patients who have pre­existing synovial chondromatosis, the duration of symptoms

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is usually long, and in some instances, symptoms may be present for 25 years.77 Most chondrosarcomas arise in the knee joint, followed by the hip and elbow joints. Radiographic studies usually show a periarticular soft tissue mass that may have dense irregular or ringlike calcifications. Occasionally, invasion into the medullary cavity of adjacent bone is present. The radiographic differential diagnosis varies according to the presence of calcification and includes synovial chondromatosis, synovial sarcoma, diffuse tenosynovial giant cell tumor, and chronic synovitis.77 Grossly, the involved joint is filled with synovium massively thickened by innumerable nodules of opalescent bluewhite cartilage. The nodules of cartilage vary in size and may be free-floating in the joint cavity. In several cases, the tumor has extended into the adjacent soft tissue and bone. Microscopically, the tumor usually is composed of malignant hyaline and myxoid cartilage. Rarely, the matrix is entirely myxoid and has the features of extraskeletal myxoid chondrosarcoma.76 The neoplastic cartilage is cellular and contains cytologically atypical chondrocytes. The periphery of the lobules of cartilage is typically the most cellular, and in this region some of the tumor cells are spindled. Other findings include necrosis and permeation of invaded bone.77 Coexisting synovial chondromatosis can be identified by its well-formed nodules of hyaline cartilage that are less cellular, containing cytologically banal-appearing chondrocytes and a matrix that is frequently mineralized. Treatment is usually surgical extirpation with consideration given for chemotherapy in high-grade lesions or lesions that have metastasized. Inadequate surgical removal virtually ensures local recurrence, which may necessitate subsequent radical excision. Metastases have occurred in approximately one third of the reported patients, with the lung being the most common site for systemic spread.77

A

Synovial Sarcoma Synovial sarcoma is a common sarcoma and accounts for approximately 6% to 10% of soft tissue sarcomas. It usually develops in the deep soft tissues and rarely arises in joints (Fig. 114-40), but may secondarily invade articular synovium from neighboring soft tissues. Earlier descriptions of this tumor attest to its wide spectrum of morphology because such names as adenosarcoma and synovial fibrosarcoma were used until the term synovial sarcoma, first introduced in 1936, became commonplace. The morphology of synovial sarcoma mimics a joint in its early stage of development in that it contains cleftlike spaces and glands delineated by large polygonal (epithelioid) cells that are surrounded by fascicles of spindle cells. The clefts and glands simulate a microscopic “joint space” that is bounded by synovial lining cells and supported by subsynovial mesenchymal cells. Because either the epithelioid or the spindle cells may predominate, synovial sarcoma has been subtyped into biphasic and monophasic spindle cell and epithelioid types. Synovial sarcoma commonly affects adolescents and young adults. In a series of 121 cases, the age range was 9 to 74 years with a median of 34 years; however, it occurs in children with significant frequency.77,78 Although the term synovial sarcoma implies that the tumor originates from the synovium, less than 10% of cases are intra-articular or in continuity with a synovial ­lining.79,80 The fact that many synovial sarcomas arise near

B Figure 114-40  A, MR image of a rare example of intra-articular synovial sarcoma. The infrapatellar tumor is well circumscribed and has a focal inhomogeneous appearance. B, The gross specimen shows that the tan,

joints also was misconstrued as supporting its synovial origin.81 Approximately 60% to 70% of synovial sarcomas arise in the extremities, especially the lower limb, in the vicinity of large joints, particularly the popliteal area of the knee and foot.82 Regions of the thigh, hand, leg, and digits may be affected, and in the distal extremities, the tumors often are adjacent to joint capsules or tendon sheaths or both. Tumors also have been reported in the neck, torso, craniofacial region, retroperitoneum, orbit, tongue, mediastinum, soft palate, kidney, lung, pleura, and prostate. There are no clinical features specific to synovial sarcoma that distinguishes it from other sarcomas. The most common complaint is the development of a slowly enlarging, deep-seated palpable mass that is painful in about 50% of the cases.78,82 Symptoms may be present for an unusually long time before medical evaluation is sought, ranging from months to 25 years with an average of about 6 months to

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B

Figure 114-41  A, Focally mineralized synovial sarcoma in the deep soft tissues in the vicinity of the elbow joint. B, Axial CT scan shows intratumoral calcification.

2.5 years.78,82 Delay in diagnosis is more frequent with tumors that are located in the deep soft tissues compared with tumors based in the more superficial and clinically noticeable regions. In some cases involving the knee region, vague mild pain over several months may occur before a mass is appreciated, and if the tumor reaches a large size, limitation of motion finally may occur. Head and neck lesions produce symptoms related to their specific sites, such as hoarseness and breathing or swallowing difficulties. Rarely, a patient may present with symptoms secondary to pulmonary metas­ tases such as hemoptysis.82 Classically, the plain film findings of synovial sarcoma are a well-circumscribed, deep-seated soft tissue mass. Synovial sarcoma is one of the few primary soft tissue tumors that frequently calcifies. Approximately 30% to 50% of cases have radiographically detectable calcifications that can have a fine, stippled, or dense appearance (Fig. 114-41).83 The calcification may be focal or present throughout most of the tumor.84 Periosteal reaction of the adjacent bone is elicited in approximately 20% of cases, but the bone is rarely invaded by the tumor. CT is more sensitive than plain radiographs in showing calcification or periosteal reaction. MRI is important in delineating the anatomic extent of the tumor and usually shows a large inhomogeneous mass with areas of hemorrhage. The radiographic differential diagnosis includes hemangioma, lipoma, synovial chondromatosis, soft tissue chondrosarcoma or osteosarcoma, myositis ossificans, aneurysms, and other sarcomas. The gross pathology of synovial sarcoma reveals a welldemarcated, pink-tan, fleshy mass that easily detaches or “shells out” from its tumor bed (see Fig. 114-40B). The cut surface is usually uniform, gray-yellow, and rubbery. The calcified areas are gritty and hard. In larger tumors, areas of hemorrhage or necrosis or both with cystification and gelatinous breakdown of tissue also may be seen. Synovial sarcoma sometimes grows between tendons, muscle, and fascial planes or wraps around neurovascular bundles. Synovial sarcoma is subtyped into three patterns on the basis of predominant microscopic findings: monophasic spindle cell, monophasic epithelioid, and biphasic variants. There is some subjectivity in the use of such a classification

system because many of these tumors have a variable histologic picture. A useful differential observation is that marked cellular pleomorphism and atypia are usually not present in synovial sarcoma, and when present, tend to point to some other type of neoplasm, such as pleomorphic fibrosarcoma. Microscopically, the hallmark of the more common biphasic synovial sarcoma is the two different populations of neoplastic cells consisting of epithelioid and spindle cells (Fig. 114-42). The epithelioid cells may be ­ cuboidal or columnar and similar to true epithelium have welldefined cytoplasmic borders. These cells may form glandlike spaces, line papillae, or cleftlike spaces, or grow in cohesive groups (see Fig. 114-42). The epithelioid cells usually are surrounded by fascicles of uniform small and plump spindle cells. The spindle cell fascicles are densely cellular and frequently are arranged in a “herringbone” pattern. In most biphasic synovial sarcomas, the spindle cell component predominates, and it is in the spindle cell regions in which calcification of hyalinized stroma most frequently occurs. Some tumors may have bone formation, which may be present in the spindle or epithelioid areas. In the monophasic variants, either the spindle or the epithelioid cells predominate

Figure 114-42  Biphasic synovial sarcoma with epithelial cells forming glands and papillary structures. The spindle cell component surrounds the glands.

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be achieved by limb salvage surgery combined with radiation.90,91 Because the regional lymph nodes may be involved, their status should be evaluated carefully, and they should be treated if enlarged. Systemic treatment consists of various chemotherapy regimens, which have been of questionable benefit, although adjuvant chemotherapy usually is recommended for patients who are at high risk—patients with tumors larger than 5 cm.90,91 SECONDARY MALIGNANT TUMORS OF THE JOINT Sarcomas

Figure 114-43  Monophasic spindle cell variant of synovial sarcoma with the fascicles of tumor cells forming a herringbone pattern.

(Fig. 114-43; see Fig. 114-42). Pure epithelioid synovial sarcomas are extraordinarily rare. Immunohistochemistry has shown that the epithelioid and the spindle cell components frequently stain with antibodies to keratin and epithelial membrane antigen, which usually are associated with epithelial neoplasms.85-87 This pattern of reactivity has helped make it possible to separate synovial sarcoma from other morphologically similar tumors, such as fibrosarcoma and malignant peripheral nerve sheath tumor.87 Also, it has provided evidence that synovial sarcoma does not arise from or recapitulate the synovium because normal synovial cells do not stain with these antibodies.88 Cytogenetic studies of synovial sarcomas have detected a consistent translocation t(X;18)(p11.2;q11.2) in almost all cases regardless of whether the tumor is biphasic or monophasic.89 This finding provides insight into the genesis of synovial sarcoma and can be used as a diagnostic feature. There is no consensus regarding its utility in providing prognostic information. The prognosis of synovial sarcoma is poor. In one study of 150 patients with nonmetastatic disease, the 5-year, 10-year, and 15-year disease-free survival rates were 59%, 52%, and 52%.90 Many factors influence prognosis. Tumors that are small (<5 cm), that arise in patients younger than 25 years old, and that lack poorly differentiated areas have a high rate of cure.78 In contrast, large tumors (≥5 cm) that arise in patients 25 years old or older and that contain poorly differentiated areas have a dismal outcome.78 The impact of histologic subtype has been controversial. Some studies have indicated that the monophasic spindle cell variant behaves the most aggressively, and tumors that are heavily calcified do the best.84 The natural history of synovial sarcoma is local recurrence, which may be repetitive. Most recurrences manifest within 2 years after initial treatment, but intervals longer than 10 years are not exceptional. Ultimately, metastases develop in many patients with the most common site being the lungs; regional lymph node involvement has been reported in a few patients.90 About 10% of patients die within 1 year after diagnosis with metastatic disease, 90% of whom have massive pulmonary metastases. Treatment must contend with issues involved with local and systemic therapy. Successful local control usually can

Primary sarcomas of bone, such as osteosarcoma and chondrosarcoma, infrequently involve a joint because intact articular cartilage usually acts as a barrier to direct tumor extension. When joint invasion does occur, however, it is usually via a pathway created by a transarticular fracture, via growth along tendoligamentous structures, or through capsule insertion sites. This circumstance may make it difficult to distinguish on histologic grounds alone some forms of synovial chondromatosis from a low-grade intraosseous chondrosarcoma that has secondarily spread into the joint. Similarly, primary soft tissue sarcomas gain access into the interior of a joint by growing through the joint capsule in conduits occupied by preexisting vascular structures or along tendons and ligaments. This complication can make adequate therapy challenging because treatment may require en bloc resection of the joint. Metastatic Carcinoma The synovium, in contrast to other richly vascular tissues, is rarely the site of metastatic carcinoma; this may reflect the fact that only clinical cases in which joint symptoms prevail are reported because at autopsy joints are not routinely examined. Most carcinomas that metastasize to the synovium originate in the lung, followed by the gastrointestinal tract and breast.92,93 Affected patients are usually elderly, and the knee is the most frequently involved joint. In many reported cases, the underlying bone also contains metastatic deposits. Malignant Lymphoproliferative Disease The various types of malignant lymphoproliferative diseases, including leukemia, lymphoma, and myeloma, can involve the synovium and produce osteoarticular symptoms.94-96 This complication occurs most frequently in leukemia and is seen in the acute and chronic forms.96 Joint symptoms have been observed in 12% to 65% of children and in 4% to 13% of adults with leukemia.96 The arthritis can develop at any time during the disease course and can be the presenting complaint. Large joints are affected more commonly than small joints, and the arthritis is often pauciarticular, asymmetric, migratory, and severe. The symptoms may result from leukemic infiltration of the synovium or irritation of the neighboring periosteum. When arthritis is the major presenting symptom, it may cause confusion with septic arthritis, rheumatic fever, subacute bacterial endocarditis, or rheumatoid arthritis.

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REFERENCES   1. Fritschy D, Fasel J, Imbert JC, et al: The popliteal cyst. Knee Surg Sports Traumatol Arthrosc 14:623, 2006.   2. Seil R, Rupp S, Jochum P, et al: Prevalence of popliteal cysts in children: A sonographic study and review of the literature. Arch Orthop Trauma Surg 119:73, 1999.   3. Labropoulos N, Shifrin DA, Paxinos O: New insights into the development of popliteal cysts. Br J Surg 91:1313, 2004.   4. Beaman FD, Peterson JJ: MR imaging of cysts, ganglia, and bursae about the knee. Magn Reson Imaging Clin N Am 15:39, 2007.   5. Choudhri HF, Perling LH: Diagnosis and management of juxtafacet cysts. Neurosurg Focus 20:E1, 2006.   6. McEvedy BV: Simple ganglia. Br J Surg 49:40, 1962.   7. Nahra ME, Bucchieri JS: Ganglion cysts and other tumor related conditions of the hand and wrist. Hand Clin 20:249, 2004.   8. Milgram JW: The classification of loose bodies in human joints. Clin Orthop 124:282, 1977.   9. Clarke HD, Scott WN: The role of debridement: through small portals. J Arthroplasty 18:10, 2003. 10. Cooper G, Schiller AL: Anatomy of the Guinea Pig. Cambridge, Harvard University Press, 1975. 11. Kato Y, Oshida M, Saito A, et al: Meniscal ossicles. J Orthop Sci 12:375, 2007. 12. Van Breuseghem I, Geusens E, Pans S, et al: The meniscal ossicle revisited. Jbr-Btr 86:276, 2003. 13. Hirano K, Deguchi M, Kanamono T: Intra-articular synovial lipoma of the knee joint (located in the lateral recess): A case report and review of the literature. Knee 14:63, 2007. 14. Sonoda H, Takasita M, Taira H, et al: Carpal tunnel syndrome and trigger wrist caused by a lipoma arising from flexor tenosynovium: A case report. J Hand Surg Am 27:1056, 2002. 15. Allen PW: Lipoma arborescens. In: Tumors and Proliferations of Adipose Tissue. Chicago, Year Book Medical Publishers, 1981, p 129. 16. Kloen P, Keel SB, Chandler HP, et al: Lipoma arborescens of the knee. J Bone Joint Surg Br 80:298, 1998. 17. Cil A, Atay OA, Aydingoz U, et al: Bilateral lipoma arborescens of the knee in a child: A case report. Knee Surg Sports Traumatol Arthrosc 13:463, 2005. 18. Davies AP, Blewitt N: Lipoma arborescens of the knee. Knee 12:394, 2005. 19. Hoffa A: The influence of the adipose tissue with regard to the pathology of the knee joint. JAMA 43:795, 1904. 20. Devaney K, Vinh TN, Sweet DE: Synovial hemangioma: A report of 20 cases with differential diagnostic considerations. Hum Pathol 24:737, 1993. 21. Lichtenstein L: Tumors of synovial joints, bursae, and tendon sheaths. Cancer 8:816, 1955. 22. Greenspan A, Azouz EM, Matthews J 2nd, et al: Synovial hemangioma: Imaging features in eight histologically proven cases, review of the literature, and differential diagnosis. Skeletal Radiol 24:583, 1995. 23. Cotten A, Flipo RM, Herbaux B, et al: Synovial haemangioma of the knee: A frequently misdiagnosed lesion. Skeletal Radiol 24:257, 1995. 24. Chung EB, Enzinger FM: Fibroma of tendon sheath. Cancer 44:1979, 1945. 25. Pulitzer DR, Martin PC, Reed RJ: Fibroma of tendon sheath: A clinicopathologic study of 32 cases. Am J Surg Pathol 13:472, 1989. 26. Maluf HM, DeYoung BR, Swanson PE, et al: Fibroma and giant cell tumor of tendon sheath: A comparative histological and immunohistological study. Mod Pathol 8:155, 1995. 27. Buddingh EP, Naumann S, Nelson M, et al: Cytogenetic findings in benign cartilaginous neoplasms. Cancer Genet Cytogenet 141:164, 2003. 28. Davis RI, Hamilton A, Biggart JD: Primary synovial chondromatosis: A clinicopathologic review and assessment of malignant potential. Hum Pathol 29:683, 1998. 29. Hettiaratchy SP, Nanchahal J: Synovial chondromatosis of the metacarpophalangeal joint. J Hand Surg Br 27:104, 2002. 30. Mandrioli S, Polito J, Denes SA, et al: Synovial chondromatosis of the temporomandibular joint. J Craniofac Surg 18:1486, 2007. 31. Sim FH, Dahlin DC, Ivins JC: Extra-articular synovial chondromatosis. J Bone Joint Surg Am 59:492, 1977. 32. Murphey MD, Vidal JA, Fanburg-Smith JC, et al: Imaging of synovial chondromatosis with radiologic-pathologic correlation. RadioGraphics 27:1465, 2007.

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33. Edeiken J, Edeiken BS, Ayala AG, et al: Giant solitary synovial chondromatosis. Skeletal Radiol 23:23, 1994. 34. Sah AP, Geller DS, Mankin HJ, et al: Malignant transformation of synovial chondromatosis of the shoulder to chondrosarcoma: A case report. J Bone Joint Surg 89:1321, 2007. 35. Taconis WK, van der Heul RO, Taminiau AM: Synovial chondrosarcoma: Report of a case and review of the literature. Skeletal Radiol 26:682, 1997. 36. Ontell F, Greenspan A: Chondrosarcoma complicating synovial chondromatosis: Findings with magnetic resonance imaging. Can Assoc Radiol J 45:318, 1994. 37. Dahlin DC, Salvador AH: Cartilaginous tumors of the soft tissues of the hands and feet. Mayo Clin Proc 49:721, 1974. 38. Chung EB, Enzinger FM: Chondroma of soft parts. Cancer 41:1414, 1978. 39. Lichtenstein L, Goldman RL: Cartilage tumors in soft tissues, particularly in the hand and foot. Cancer 17:1203, 1964. 40. Jones WA, Ghorbal MS: Benign tendon sheath chondroma. J Hand Surg Br 11:276, 1986. 41. Gonzalez-Lois C, Garcia-de-la-Torre P, SantosBriz-Terron A, et al: Intracapsular and para-articular chondroma adjacent to large joints: Report of three cases and review of the literature. Skeletal Radiol 30:672, 2001. 42. Hensinger RN, Cowell HR, Ramsey PL, et al: Familial dysplasia epiphysealis hemimelica, associated with chondromas and osteochondromas: Report of a kindred with variable presentations. J Bone Joint Surg 56:1513, 1974. 43. Rubin BP: Tenosynovial giant cell tumor and pigmented villonodular synovitis: A proposal for unification of these clinically distinct but histologically and genetically identical lesions. Skeletal Radiol 36:267, 2007. 44. West RB, Rubin BP, Miller MA, et al: A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proc Natl Acad Sci U S A 103:690, 2006. 45. Moller E, Mandahl N, Mertens F, et al: Molecular identification of COL6A3-CSF1 fusion transcripts in tenosynovial giant cell tumors. Genes Chromosomes Cancer 47:21, 2008. 46. Tyler WK, Vidal AF, Williams RJ, et al: Pigmented villonodular synovitis. J Am Acad Orthop Surg 14:376, 2006. 47. Rao AS, Vigorita VJ: Pigmented villonodular synovitis (giant-cell tumor of the tendon sheath and synovial membrane): A review of eighty-one cases. J Bone Joint Surg Am 66:76, 1984. 48. Mendenhall WM, Mendenhall CM, Reith JD, et al: Pigmented villonodular synovitis. Am J Clin Oncol 29:548, 2006. 49. Somerhausen NS, Fletcher CD: Diffuse-type giant cell tumor: Clinicopathologic and immunohistochemical analysis of 50 cases with extraarticular disease. Am J Surg Pathol 24:479, 2000. 50. Abdul-Karim FW, el-Naggar AK, Joyce MJ, et al: Diffuse and localized tenosynovial giant cell tumor and pigmented villonodular synovitis: A clinicopathologic and flow cytometric DNA analysis. Hum Pathol 23:729, 1992. 51. Carpintero P, Gascon E, Mesa M, et al: Clinical and radiologic features of pigmented villonodular synovitis of the foot: Report of eight cases. J Am Podiatr Med Assoc 97:415, 2007. 52. De Schepper AM, Hogendoorn PC, Bloem JL: Giant cell tumors of the tendon sheath may present radiologically as intrinsic osseous lesions. Eur Radiol 17:499, 2007. 53. Jergesen HE, Mankin HJ, Schiller AL: Diffuse pigmented villonodular synovitis of the knee mimicking primary bone neoplasms: A report of two cases. J Bone Joint Surg 60:825, 1978. 54. Myers BW, Masi AT: Pigmented villonodular synovitis and tenosynovitis: A clinical epidemiologic study of 166 cases and literature review. Medicine (Balt) 59:223, 1980. 55. Lin J, Jacobson JA, Jamadar DA, et al: Pigmented villonodular synovitis and related lesions: The spectrum of imaging findings. AJR Am J Roentgenol 172:191, 1999. 56. Al-Nakshabandi NA, Ryan AG, Choudur H, et al: Pigmented villo­ nodular synovitis. Clin Radiol 59:414, 2004. 57. Masih S, Antebi A: Imaging of pigmented villonodular synovitis. Semin Musculoskel Radiol 7:205, 2003. 58. O’Connell JX, Fanburg JC, Rosenberg AE: Giant cell tumor of tendon sheath and pigmented villonodular synovitis: Immunophenotype suggests a synovial cell origin. Hum Pathol 26:771, 1995. 59. Flandry F, Hughston JC: Pigmented villonodular synovitis. J Bone Joint Surg 69:183, 1987.

1902

Rosenberg 

| 

Tumors and Tumor-like Lesions of Joints and Related Structures

60. Sharma H, Rana B, Mahendra A, et al: Outcome of 17 pigmented villonodular synovitis (PVNS) of the knee at 6 years mean follow-up. Knee 14:390, 2007. 61. Chiari C, Pirich C, Brannath W, et al: What affects the recurrence and clinical outcome of pigmented villonodular synovitis? Clin Orthop 450:172, 2006. 62. Flandry FC, Hughston JC, Jacobson KE, et al: Surgical treatment of diffuse pigmented villonodular synovitis of the knee. Clin Orthop 300:183, 1994. 63. Adem C, Sebo TJ, Riehle DL, et al: Recurrent and non-recurrent pigmented villonodular synovitis. Ann Pathol 22:448, 2002. 64. Bertoni F, Unni KK, Beabout JW, et al: Malignant giant cell tumor of the tendon sheaths and joints (malignant pigmented villonodular synovitis). Am J Surg Pathol 21:153, 1997. 65. Bhadra AK, Pollock R, Tirabosco RP, et al: Primary tumours of the synovium: A report of four cases of malignant tumour. J Bone Joint Surg Br 89:1504, 2007. 66. Dines JS, DeBerardino TM, Wells JL, et al: Long-term follow-up of surgically treated localized pigmented villonodular synovitis of the knee. Arthroscopy 23:930, 2007. 67. Rydholm U: Pigmented villonodular synovitis. Acta Orthop Scand 69:203, 1998. 68. Ushijima M, Hashimoto H, Tsuneyoshi M, et al: Giant cell tumor of the tendon sheath (nodular tenosynovitis): A study of 207 cases to compare the large joint group with the common digit group. Cancer 57:875, 1986. 69. Kitagawa Y, Ito H, Amano Y, et al: MR imaging for preoperative diagnosis and assessment of local tumor extent on localized giant cell tumor of tendon sheath. Skeletal Radiol 32:633, 2003. 70. Monaghan H, Salter DM, Al-Nafussi A: Giant cell tumour of tendon sheath (localised nodular tenosynovitis): Clinicopathological features of 71 cases. J Clin Pathol 54:404, 2001. 71. Alguacil-Garcia A, Unni KK, Goellner JR: Giant cell tumor of tendon sheath and pigmented villonodular synovitis: An ultrastructural study. Am J Clin Pathol 69:6, 1978. 72. Wood GS, Beckstead JH, Medeiros LJ, et al: The cells of giant cell tumor of tendon sheath resemble osteoclasts. Am J Surg Pathol 12:444, 1988. 73. Nilsson M, Hoglund M, Panagopoulos I, et al: Molecular cytogenetic mapping of recurrent chromosomal breakpoints in tenosynovial giant cell tumors. Virchows Arch 441:475, 2002. 74. Wu NL, Hsiao PF, Chen BF, et al: Malignant giant cell tumor of the tendon sheath. Int J Dermatol 4:543, 2004. 75. Bertoni F, Unni KK, Beabout JW, et al: Chondrosarcomas of the synovium. Cancer 67:155, 1991. 76. Gebhardt MC, Parekh SG, Rosenberg AE, et al: Extraskeletal myxoid chondrosarcoma of the knee. Skeletal Radiol 28:354, 1999. 77. Okcu MF, Munsell M, Treuner J, et al: Synovial sarcoma of childhood and adolescence: A multicenter, multivariate analysis of outcome. J Clin Oncol 21:1602, 2003.

78. Bergh P, Meis-Kindblom JM, Gherlinzoni F, et al: Synovial sarcoma: Identification of low and high risk groups. Cancer 85:2596, 1999. 79. Dardick I, O’Brien PK, Jeans MT, et al: Synovial sarcoma arising in an anatomical bursa. Virchows Arch A Pathol Anat Histol 397:93, 1982. 80. McKinney CD, Mills SE, Fechner RE: Intraarticular synovial sarcoma. Am J Surg Pathol 16:1017, 1992. 81. DeSanto DA, Tennant R, Rosahn P: Synovial sarcomas in joints, bursae, and tendon sheaths. Surg Gynecol Obstet 72:72, 1961. 82. Cadman NL, Soule EH, Kelly PJ: Synovial sarcoma: An analysis of 134 tumors. Cancer 18:613, 1965. 83. Milchgrub S, Ghandur-Mnaymneh L, Dorfman HD, et al: Synovial sarcoma with extensive osteoid and bone formation. Am J Surg Pathol 17:357, 1993. 84. Varela-Duran J, Enzinger FM: Calcifying synovial sarcoma. Cancer 50:345, 1982. 85. Corson JM, Weiss LM, Banks-Schlegel SP, et al: Keratin proteins and carcinoembryonic antigen in synovial sarcomas: An immunohistochemical study of 24 cases. Hum Pathol 15:615, 1984. 86. Fisher C: Synovial sarcoma. Diag Pathol 1:13, 1994. 87. Olsen SH, Thomas DG, Lucas DR: Cluster analysis of immunohistochemical profiles in synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma. Mod Pathol 19:659, 2006. 88. Miettinen M, Virtanen I: Synovial sarcoma—a misnomer. Am J Pathol 117:18, 1984. 89. Amary MF, Berisha F, Bernardi F, et al: Detection of SS18-SSX fusion transcripts in formalin-fixed paraffin-embedded neoplasms: Analysis of conventional RT-PCR, qRT-PCR and dual color FISH as diagnostic tools for synovial sarcoma. Mod Pathol 20:482, 2007. 90. Guadagnolo BA, Zagars GK, Ballo MT, et al: Long-term outcomes for synovial sarcoma treated with conservation surgery and radiotherapy. Int J Radiat Oncol Biol Phys 69:1173, 2007. 91. Brecht IB, Ferrari A, Int-Veen C, et al: Grossly-resected synovial sarcoma treated by the German and Italian Pediatric Soft Tissue Sarcoma Cooperative Groups: Discussion on the role of adjuvant therapies. Pediatr Blood Cancer 46:11, 2006. 92. Younes M, Hayem G, Brissaud P, et al: Monoarthritis secondary to joint metastasis: Two case reports and literature review. Joint Bone Spine 69:495, 2002. 93. Capovilla M., Durlach A., Fourati E., et al: Chronic monoarthritis and previous history of cancer: Think about synovial metastasis. Clin Rheumatol 26:60, 2007. 94. Ehrenfeld M, Gur H, Shoenfeld Y: Rheumatologic features of hematologic disorders. Curr Opin Rheumatol 11:62, 1999. 95. Gur H, Koren V, Ehrenfeld M, Ben-Bassat I, et al: Rheumatic manifestations preceding adult acute leukemia: Characteristics and implication in course and prognosis. Acta Haematol 101:1, 1999. 96. Evans TI, Nercessian BM, Sanders KM: Leukemic arthritis. Semin Arthritis Rheum 24:48, 1994.

Index

A

AA. See Adjuvant arthritis. α1-Antichymotrypsin, as proteinase inhibitor, 122, 124t α2-Antiplasmin, as proteinase inhibitor, 122, 124t Abatacept, 1131 for rheumatoid arthritis, 954–958 clinical studies of, 954–957, 955t, 956f current role of, 957 pathogenesis of rheumatoid arthritis and, 958 safety issues with, 957 Abatacept in Inadequate Responders to Methotrexate trial, 955, 955t, 1131 Abatacept Study of Safety in Use with Other RA Therapies trial, 957 Abatacept Trial in Treatment of Anti-TNF Inadequate Responders, 955, 955t, 956, 956f, 1131 Abdomen, acute, in systemic lupus ­erythematosus, 1292 Abdominal pain in acute rheumatic fever, 1779 in polyarteritis nodosa, 1455 in systemic lupus erythematosus, 1278 Abdominal reflex, in neck pain, 582 ACA. See Acrodermatitis chronica ­atrophicans. ACCESS study, 1796 Accessory nerve testing, in neck pain, 580t ACE. See Angiotensin-converting enzyme. Acetabular joint, arthrocentesis technique for, 732–733, 733f Acetaminophen, 19 analgesic actions of, 846 cyclooxygenase inhibition by, 347 for fibromyalgia, 564 for low back pain, 621t for osteoarthritis, 1566–1567 for rheumatoid arthritis, 1134 Acetylcholine receptor, in skeletal muscle, 96t Acetylsalicylic acid, 842t, 843–844 action of, molecular basis of, 840 for antiphospholipid syndrome, in ­pregnancy, 1290 cardiovascular benefits of, 850 in cartilage, 40t, 41 combined with nonsteroidal anti­inflammatory drugs and coxibs, 850–851 creation of, 834 cyclooxygenase inhibition by, 840 for fibromyalgia, 564 for giant cell arteritis, 1419 for Kawasaki disease, in children, 1693 for systemic lupus erythematosus, in ­pregnancy, 1289 for thrombosis, in antiphospholipid ­syndrome, 1307 thromboxane inhibition by, 348 Achilles bursitis, therapeutic injection in, 724 Achilles tendinitis, therapeutic injection in, 724 Achilles tendinosis, 647

Achilles tendon, 530 ankle pain and, 645–646, 645t arthrocentesis technique for, 734 enthesitis of insertion, 530, 530f in rheumatoid arthritis, 1096 Achondroplasia, 1641–1642 fibroblast growth factor in, 76 Acid maltase deficiency, differential diagnosis of, 1371t, 1372 ACLE. See Acute cutaneous lupus ­erythematosus. ACR20 response criteria, 456, 459, 470–471 ACR70 response criteria, 456 Acrodermatitis chronica atrophicans, 696, 697 Acromegaly, 1836–1837 polyarthritis secondary to, 551 Acromioclavicular joint arthrocentesis technique for, 729 disorders of, shoulder pain due to, 604–605, 605f examination of, 519 ACTH. See Adrenocorticotropic hormone. Actin α-actin as, in skeletal muscle, 96t neutrophil chemotaxis and, 221 in skeletal muscle, 96t, 99 Activation fragment assays, 330t, 331, 331t Activation-induced cell death, 170 Activation-induced cytidine deaminase as antigen-activated B cell marker, 191t B cell maturation and, 190 Activator protein-1, in rheumatoid arthritis, 1069 Activities of daily living modification of, in osteoarthritis, 1564 in rheumatoid arthritis, 1138 Acupuncture, 508 for osteoarthritis, 1566 Acute abdomen, in systemic lupus ­erythematosus, 1292 Acute cutaneous lupus erythematosus, 688–689, 689f Acute hemorrhagic edema of childhood, 695 Acute rheumatic fever. See Rheumatic fever. Acute-phase reactants, 767–773 in acute rheumatic fever, 1780 acute-phase response and, 768–770, 768f C-reactive protein and, 768–769, 769f, 769t cytokines and, 770, 770t ferritin and, 769–770 serum amyloid A and, 769 erythrocyte sedimentation rate and, 770, 771t practical use of, 772 in rheumatic disease management, 770–772 adult-onset Still’s disease as, 772 ankylosing spondylitis as, 772 giant cell arteritis as, 771–772 osteoarthritis as, 772 polymyalgia rheumatica as, 771–772 rheumatoid arthritis as, 770–771 systemic lupus erythematosus as, 771 AD. See Alzheimer’s disease. Adalimumab, 935–936, 1129. See also Tumor necrosis factor inhibitors, TNF-α. for ankylosing spondylitis, 1183–1184, 1185t

Adalimumab (Continued) clinical trials with, 932 dose for, 936 efficacy of, 936 pharmacokinetics of, 935 structure of, 935 ADAM gene family, matrix degradation and, 119t, 121–122, 123t in rheumatoid arthritis, 130 ADAM proteinases, in cartilage degradation, 53, 53t ADAMTS gene family as biomarkers, 480 joint destruction and, in rheumatoid ­arthritis, 1077 matrix degradation and, 118, 119t, 121–122 in osteoarthritis, 131 in rheumatoid arthritis, 130 in osteoarthritis, 1530, 1536 ADAPT. See Arthritis, Diet, and Activity Promotion Trial. Adapter proteins, T lymphocyte activation and, 161–162 Adaptive immunity, 277, 291–300, 292t complement system in, 329 effector T cell types and, 300 innate immunity compared with, 277, 278t innate mechanisms’ influence on, 285–286, 285f lymphocyte migration paradigms and, 291–294 egress from lymph nodes and, 294 for extravasation, 291–293 immunologic synapses maintaining antigen-specific interactions with dendritic cells and, 293–294 interstitial, tissue organization and, 293 thymus-sphingosine-1-phosphate and, 294 lymphoid tissues and primary, 294–295 secondary, 295–299 tertiary, 299–300 Addison’s disease, 1836 as autoimmune disease, 261t eosinophils and, 230–231 Adenoma Prevention with Celecoxib trial, 849 Adenomatous Polyp Prevention On Vioxx trial, 846, 849, 856 Adenosine, 883 transmethylation reaction inhibition by, 884–885 Adenosine triphosphate, concentration of, buffering of, in muscle, 102–103 Adenovirus arthritis, 1768 Adhesion molecules. See Cell adhesion ­molecules; Intercellular adhesion molecule(s); Vascular cell adhesion molecule-1. Adhesive capsulitis of shoulder, in diabetes mellitus, 1834 shoulder pain due to, 607–608 Adipokines, in cartilage destruction, 56 Adiponectin, in cartilage destruction, 56 Adjuvant arthritis, animal models of, 397, 398t, 399, 400t ADLs. See Activities of daily living.

Note: Page numbers followed by b indicate boxed material; those followed by f indicate figures; those followed by t indicate tables



ii

Index

ADM. See Amyopathic dermatomyositis. ADMCKD. See Autosomal dominant ­medullary cystic kidney disease. Adolescents, systemic lupus erythematosus in, 1290 ADR. See Artificial disk replacement. Adrenocorticotropic hormone for calcium pyrophosphate dihydrate ­deposition disease, 1520 for gouty arthritis, 1499 proinflammatory cytokines and, 869, 869f Adverse events, in health outcome assessment, 466 AER. See Apical ectodermal ridge. Aerobic exercise, in physical medicine and rehabilitation, 1027 Afferent nerve fibers, 966–967, 968t sensitization of, 969–970 Age. See also specific age groups. bone loss related to, pathophysiology of, 1580–1583, 1581f, 1582t at onset, of rheumatoid arthritis, 1089–1090 osteoarthritis and, 1526, 1551 vasculitis and, 1405 Aggrecan in cartilage, 40t, 41 aged, 58 in menisci, 12 proteinase degradation of, 129 Aggrecanases as biomarkers, 477t in cartilage degradation, 53, 53t joint destruction and, in rheumatoid ­arthritis, 1077 in osteoarthritis, 1530 Aging. See also Geriatric patients. of muscle, 104 Agranulocytosis with dapsone, 922 with sulfasalazine, 896 AIA. See Antigen-induced arthritis. AICD. See Activation-induced cell death. AID. See Activation-induced cytidine ­deaminase. AIM trial. See Abatacept in Inadequate ­Responders to Methotrexate trial. AIMS. See Arthritis Impact Measurement Scale. AION. See Anterior ischemic optic ­neuropathy. AIRE. See Autoimmune regulator. Akt, apoptosis prevention by, 385 Albright’s hereditary osteodystrophy, 1835 Alcohol consumption gout and, 1482, 1486, 1502 hyperuricemia and, 1486 osteonecrosis and, 1612, 1615t Alefacept, for psoriatic arthritis, 1216 Alendronate for osteoporosis, 1588 for Paget’s disease of bone, 1595 Alkaline phosphatase as bone marker, 80 bone mineralization and, 80 Alkaptonuria. See Ochronosis. Alkylating agents, 909–914. See also specific drugs. Allele(s), definition of, 309t Allele sharing, 316, 316f Allergic arthritis, 1018 Allergic reactions mast cells in, 240 to nonsteroidal anti-inflammatory drugs, 847t, 852–853 Alloantisera, definition of, 309t Allocative efficiency, in health economics, 442

Allopurinol drug interactions of, 913, 916 for hyperuricemia control, 1500–1501, 1500t Alopecia with cyclophosphamide, 913 in systemic lupus erythematosus, 1268 Alpha, in clinical trials, 457, 457f Alpha granules, in platelets, 250, 250t α1-Proteinase inhibitor, 122, 124t α2-Macroglobulin, as proteinase inhibitor, 122, 124t Alphavirus arthritis, 1764–1766 diagnosis of, 1765–1766 epidemiology of, 1764–1765, 1764t pathogenesis of, 1766 prognosis of, 1766 treatment of, 1766 Alternative medical systems. See also ­Complementary and alternative medicine. definition of, 502t Alternative pathway equivalent, 330t Alveolar hemorrhage diffuse, in microscopic polyangiitis, 1443 in systemic lupus erythematosus, 1292 Alzheimer’s disease acetylsalicylic acid in, 852 nonsteroidal anti-inflammatory drugs in, 851–852 Ambulation. See also Gait. in osteoarthritis, adduction moment during, 109 Amitriptyline for chronic pain, 988, 989t for fibromyalgia, 564 Amlodipine, drug interactions of, 919 Amoxicillin, for Lyme disease, 1723 Amphiarthroses, 1 Amyloid arthropathy polyarthritis in, 550 synovial histopathology in, 712 Amyloidosis, 1785–1792 AA clinical features and treatment of, 1790 diagnosis of, 4, 1787, 1787f pathogenesis of amyloid fibril formation in, 1786–1787 pathology of, 1786 AL clinical features and treatment of, 1788–1790, 1789f, 1790t, 1791t diagnosis of, 1787, 1787f pathogenesis of amyloid fibril formation in, 1786 pathology of, 1786 ATTR clinical features and treatment of, 1791–1792 diagnosis of, 1787, 1787f, 1788 pathogenesis of amyloid fibril formation in, 1787 Aβ2M clinical features and treatment of, 1791 pathogenesis of amyloid fibril formation in, 1787 β2-microglobulin, imaging in, 822–823, 823f classification of, 1785–1786, 1786t clinical features of, 1788–1792 in AA amyloidosis, 1790 in AL amyloidosis, 1788–1790, 1789f, 1790t, 1791t in ATTR familial amyloidosis, 1791–1792 in Aβ2M amyloidosis, 1791 diagnosis of, 1787–1788, 1787f–1789f epidemiology of, 1785 pathogenesis of, 1786–1787 pathology of amyloid fibril formation in, 1786 rheumatoid arthritis vs., 1106

Amyloidosis (Continued) skin lesions in, 698 treatment of, 1791t for AA amyloidosis, 1790 for AL amyloidosis, 1790 in ATTR familial amyloidosis, 1792 for Aβ2M amyloidosis, 1791 Amyopathic dermatomyositis, 691 Amyotrophy, diabetic, 1834 Anakinra, 941, 1130 for autoimmune diseases, 941 clinical trials of, 932t dose for, 941 efficacy of, 941 mechanism of action of, 941 pharmacokinetics of, 941 structure of, 941 toxicity of, 942 Analgesics. See also specific drugs and drug types. for chronic pain, 984–987 cyclooxygenase inhibition by, 841 for fibromyalgia, 564 nonopioid for chronic pain, 984 for osteoarthritis, 1566–1567 for rheumatoid arthritis, 1134 opioid for chronic pain, 984–987, 984f, 985t, 986f, 987f, 988t for osteoarthritis, 1567–1568 for rheumatoid arthritis, 1134 for rheumatoid arthritis, 1134 Anandamide actions of, 352 production of, 351–352, 352f Anaphylactic degranulation, 237, 238f Anaphylaxis with cyclophosphamide, 913 mast cells in, 240 Anaphylotoxins, 324 complement regulation by, 326t receptors for, 326t ANAs. See Antinuclear antibodies. ANCA. See Antineutrophil cytoplasmic antibody. Anchorin CII apoptotic cell detection using, 387 in cartilage, 40t chondrocyte interactions with, 47, 48 Androgen(s) aging of muscle and, 104 bone mineral density and, 78 bone remodeling and, 77 for osteoporosis, 1587 Androgenic-anabolic steroids, muscle and, 104 Anemia in acute rheumatic fever, 1780 hemolytic, autoimmune, 261t pernicious, as autoimmune disease, 261t in rheumatoid arthritis, 1100–1101 sickle cell, osteonecrosis and, 1615t in systemic lupus erythematosus, 1277–1278 Anergy, B cell, 192 Anesthetics. See also specific drugs. injection of for foot and ankle pain, 648 in shoulder pain, 597–598 intradiscal, for low back pain, 622 Angiitis. See Vasculitis. Angina. See also Chest pain. in Takayasu’s arteritis, 1422 Angiogenesis, 357–363 adhesion receptors in, 362 in cartilage, 48 chemokines in, 360–362, 361f, 361t

index Angiogenesis (Continued) inhibition of, in antirheumatic therapy, 362–363 intercellular adhesion molecules and, 357–359, 359t leukocyte-endothelial cell adhesion ­regulation and, 362 mast cells and, 241–242 regulation of, 362 in rheumatoid arthritis, 1072–1073, 1072f vascular endothelium morphology and ­function and, inflammation, 357 Angioimmunoblastic lymphadenopathy, 1854, 1854t rheumatoid arthritis vs., 1106–1107 Angiotensin-converting enzyme, in sarcoidosis, 1797 ANKH, familial calcium pyrophosphate ­dihydrate deposition disease and, 1510–1511, 1510f Ankle(s) anatomy of, 643 anterior, 645, 645t arthrocentesis technique for, 734–735 biomechanics of, 643 central, 645, 645t examination of, 529–531, 530f fusion of, 648 imaging in, 644–645, 644f in juvenile chronic arthritis, imaging of, 788 lateral, 645t, 646 medial, 645t, 646 monarticular and periarticular syndromes affecting, 536t osteoarthritis in, 1557 physical examination in, 643–644, 644f posterior, 645–646, 645t in reactive arthritis, imaging of, 791 in rheumatoid arthritis, 1096–1097, 1096f, 1097f imaging of, 784, 785f synovial swelling of, 530 treatment of nonoperative, 647–648 operative, 648–649, 649f Ankle arthroplasty, 648–649, 649f Ankylosing spondylitis, 1169–1184, 1170t ankylosis in, 1174 assessment and monitoring in, 1180–1181, 1181t bacteria and, 1173–1174 cause of, 1172 chest expansion in, 1177 classification of, 1170, 1171t clinical manifestations of, 1175–1177 core sets for clinical trials in, 464t costs of, 447–448 diagnosis of, 1179, 1179t enthesitis in, 1177 epidemiology of, 1170–1172 burden of disease and, 1171–1172, 1172t incidence and, 1171 prevalence and, 1170–1171 racial distribution and, 1171, 1171t extraskeletal, 1176–1177 future directions for, 1184 gender and, 1179–1180 genetics of, 1172–1174 animal models and, 1173 HLA genes beyond HLA-B27 and, 1172–1173 HLA-B27 and, 1172 human studies of, 1173 hypotheses concerning, 1173 historical background of, 1169–1170 imaging in, 810–815, 1177–1179

Ankylosing spondylitis (Continued) computed tomography for, 811, 814, 814f, 1178–1179 conventional radiography for, 813, 813f, 1177–1178, 1178t in extraspinal locations, 814–815, 815f magnetic resonance imaging for, 811–812, 813–814, 814f, 1178–1179, 1178f of sacroiliac joints, 811–812, 811f of spine, 812–814, 812f–814f laboratory tests in, 1177 management of, 1181–1184, 1182f, 1182t acute-phase reactants in, 772 adalimumab for, 936 biologic therapies for, 934, 1183–1184, 1185t etanercept for, 935 leflunomide for, 892 pharmacologic, 1182–1183 physiotherapy in, 1182, 1183t sulfasalazine for, 896 surgical, 1184 therapeutic injection in, 723 neck pain in, 575, 584 nomenclature for, 1170 pathology of, 1174–1175 extraspinal, 1174–1175 in sacroiliac joint, 1174 in spine, 1174 polyarthritis in, 550 posture in, 1177 preaxial, 1179 prognosis of, 1180, 1180t rheumatoid arthritis vs., 1107 sacroiliitis in, 1177 skeletal, 1175 spinal mobility in, 1177 synovial histopathology in, 712 of temporomandibular joint, 668 differential diagnosis of, 667t uveitis in, 678 Ankylosis, in ankylosing spondylitis, 1174 Annexin(s) annexin V as. See Anchorin CII. in skeletal muscle, 96t Antacids, drug interactions of, 921 Antalgic gait, 643–644 in hip examination, 524 Anterior ischemic optic neuropathy, 682–683, 682f Antibiotics. See also specific drugs. for bacterial arthritis, 1707, 1708t, 1709t drug interactions of, 866 for reactive arthritis, 1198, 1198t for undifferentiated spondyloarthropathy, 1195 Anti-Borrelia, in polyarthritis, 546t Anticitrullinated protein autoantibodies, 755, 756f biochemical and immunochemical properties of, 758 diagnostic tests for, 755, 756 incidence of, 757 in rheumatoid arthritis, 760–761 Anticonvulsants, for chronic pain, 988, 989t, 990 Anti-CP autoantibodies. See Anticitrullinated protein autoantibodies. Antidepressants. See also specific drugs and drug types. for chronic pain, 988, 989t for fibromyalgia, 564 Anti-DNA antibodies, in systemic lupus ­erythematosus, 746–747 Anti-DNA antibody tests, 746 Anti-dsDNA antibodies, in systemic lupus erythematosus, 1234, 1279

iii

Antiepileptic drugs, for chronic pain, 988, 989t, 990 Antifibrotic agents, for systemic sclerosis, 1339–1340 Antigen(s) cartilage-specific, autoimmunity to, ­rheumatoid arthritis and, 1045 foreign and self-, discrimination between, 191 nonarticular, autoimmunity to, rheumatoid arthritis and, 1046 presenting of, autoimmunity and, 271–272 processing of, 144–145, 148f, 149f Antigenic assays, 330t, 331, 331t Antigen-induced arthritis, animal models of, 400t, 401–402 Antiglobulin testing, 330t Antihistone antibodies, in systemic lupus erythematosus, 747 Antihyperuricemic drugs, 1499–1502, 1500t Anti-inflammatory cells, mast cells as, 241 Anti-inflammatory diet, 503–506 evidence for, 504–505 obesity and inflammation and, 505–506 recommendations for, 506, 506t Anti-inflammatory drugs. See also specific drugs and drug types. apoptosis and, 390 Antikinetochore, in scleroderma, 748, 749t Antimalarials. See also specific drugs. actions of, 897–898 chemical structure of, 897, 897f contraindications to, 900 dosing with, 899 drug interactions of, 900 efficacy of, 895t indications for, 898–899 mechanism of action of, 895t pharmacology of, 898 for systemic lupus erythematosus, 1281 toxicity of, 895t, 899–900 Antimicrobial agents. See also Antibiotics; specific drugs. for Wegener’s granulomatosis, 1441 Antimicrobial peptides, 285 Antimuscarinic M3 receptor, in Sjögren’s syndrome, 1152 Antineutrophil cytoplasmic antibody, 1429–1442, 1429–1447 disease associations of, 1430–1431, 1430f historical background of, 1429 methodology for, 1429–1430, 1430f vasculitis associated with Churg-Strauss syndrome as. See Churg-Strauss syndrome. disease activity and, 1431–1432 microscopic polyangiitis as, 1443–1444 pathophysiology of, 1431, 1432f Wegener granulomatosis. See Wegener’s granulomatosis. Antinuclear antibodies, 741–753, 742t in antiphospholipid antibody syndrome, 751–752 clinical utility of, 752–753, 752f detection of, 742, 746 anti-DNA antibody tests for, 746 counterimmunoelectrophoresis for, 746 enzyme-linked immunosorbent assay for, 742, 746 immunodiffusion for, 746 immunofluorescence for, 741, 742, 745f historical background of, 741–742, 743t–744t inflammatory muscle diseases associated with, 749–750, 750t myositis overlap autoantibodies and, 750

iv

Index

Antinuclear antibodies (Continued) myositis-specific autoantibodies and, 749–750 in juvenile rheumatoid arthritis, 751 mixed connective tissue disease associated with, 751 overlap syndromes associated with, 751 in polyarthritis, 546t in Raynaud’s phenomenon, 751 scleroderma associated with, 748–749, 749t antikinetochore and anti-topoisomerase I and, 748 anti-polymyositis-scleroderma and, 749 anti-RNA-polymerases and, 748 Sjögren’s syndrome associated with, 750–751, 751t in systemic lupus erythematosus, 1279 systemic lupus erythematosus associated with, 746–748, 747t antiribosomes and, 748 chromatin-associated antigens and, 746–747 ribonucleoproteins and, 747–748 Antiphospholipid antibodies, paraneoplastic, 1842t, 1845 Antiphospholipid Antibody in Stroke Study, 1307 Antiphospholipid syndrome, 1301–1309 animal model of, 334 antinuclear antibodies in, 751–752 catastrophic, 1304, 1305t, 1306–1307 treatment of, 1308 cause of, 1301–1302 clinical features of, 1304 definition of, 1301, 1302t diagnosis of, 1304–1307 differential diagnosis and, 1306–1307 laboratory studies in, 1304–1305, 1306f magnetic resonance imaging in, 1305 pathology and, 1305 epidemiology of, 1301 pathogenesis of, 1302–1304, 1303f in pregnancy, 1304, 1306–1307, 1307–1308 treatment of, 1290, 1307–1308 prognosis of, 1309 in systemic lupus erythematosus, 1290 treatment of, 1307–1309 antimalarials for, 898–899 in antiphospholipid antibody-­negative patients with clinical events, 1308–1309 in antiphospholipid antibody-positive ­patients with ambiguous events, 1308 in asymptomatic patients, 1308 in catastrophic antiphospholipid ­syndrome, 1308 in pregnancy, 1290, 1307–1308 for thrombosis, 1307, 1307t Anti-polymyositis-scleroderma antibodies, in scleroderma, 749, 749t Antipyretic drugs, cyclooxygenase inhibition by, 841 Antirheumatic therapy. See also specific drugs and drug types. angiogenesis inhibition in, 362–363 cell adhesion inhibition in, 362–363 chemokine inhibition in, 362–363 neutrophil functions and, 227 Antiribosomal antibodies, in systemic lupus erythematosus, 1279 Antiribosomes, in systemic lupus ­erythematosus, 748 Anti-RNA-polymerases, in scleroderma, 748, 749t Anti-Ro/SS-A, in systemic lupus ­erythematosus, 748

Anti-Smith (anti-Sm) antibodies, in systemic lupus erythematosus, 1235 Anti-ssDNA antibodies, in systemic lupus erythematosus, 1234, 1279 Antistreptolysin O, in polyarthritis, 546t Antisynthetase syndrome, 1363 Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy trial, 930t, 932, 1128 Anti-TNF-α therapy. See Tumor necrosis factor inhibitors, TNF-α. Anti-topoisomerase, in scleroderma, 748, 749t Anti-tRNA synthetases, in inflammatory muscle diseases, 750t Antiviral protein regulation, in rheumatoid arthritis, 1069–1070 Aortic regurgitation, in Takayasu’s arteritis, 1422 Aortitis, granulomatous, in rheumatoid ­arthritis, 1104 AP50. See Alternative pathway equivalent. APASS. See Antiphospholipid Antibody in Stroke Study. APC trial. See Adenoma Prevention with Celecoxib trial. APECED. See Autoimmune polyendocrine syndrome 1. Apheresis, for Wegener’s granulomatosis, 1442 Aphthae, in Behçet’s disease, 1476, 1476f Aphthous ulcers, in hyper-IgD syndrome, 1870, 1870f Apical ectodermal ridge, 5 Apley compression test, 631–632 Apley grind test, 529 Apolipoprotein H, in antiphospholipid ­syndrome, 1301–1302 Apolipoproteins, secreted by macrophages, 150t Apoptosis, 379, 380f accelerated, in degenerative rheumatic disorders, 390 antiapoptotic proteins and, 384–385 biochemistry of, 382, 382t biologics and, 391 Caenorhabditis elegans paradigm of, 379, 380f caspases and, 385–386 defective, of immune cells, 388 defective uptake and processing of apoptotic cells and, 388–389 detection of, 387–388 caspase activation and, 387–388 cell membrane alterations and, 387 chromatin condensation and DNA ­fragmentation and, 388 loss of mitochondrial membrane potential and, 387 in diffuse connective tissue diseases, 1385 drugs affecting apoptotic pathways and, 390–391 endoplasmic reticulum stress and, 384 genotoxic injury and, 384 glandular destruction and, in Sjögren’s syndrome, 1151–1152 mitochondrial pathways of, in rheumatoid arthritis, 206–207 mitochondrial stress and, 384 neutrophils and, 217 prolonged exposure to growth factors and, 389, 389f receptor-mediated, in rheumatoid arthritis, 207 regulation of, 852–853 removal and degradation of apoptotic cells and, 386–387, 387f in rheumatoid arthritis, 1070–1071 fibroblast-like synoviocytes and, 206–207

Apoptosis (Continued) genes regulating, 1070–1071 therapeutic interventions increasing, 1071 signal transduction in, 339–341 Bcl-2 family signaling and, 340–341 death receptor signaling and, 340 p53 and cell cycle arrest and, 341 systemic lupus erythematosus and, 1244 therapeutic induction of, 391 therapeutic intervention and, 391–392, 391f tissue injury in organ-specific autoimmunity and, 389–390 Apprehension test, in patellofemoral pain, 633, 633f APPROVe trial. See Adenomatous Polyp Prevention On Vioxx trial. APRIL, in rheumatoid diseases, 370t APS. See Antiphospholipid syndrome. Aquatic exercise, in physical medicine and rehabilitation, 1027–1028 Arachidonic acid intake of, 505 metabolism of, cyclooxygenase pathway of, 344, 346f metabolites of neutrophil production of, 222–223, 223f in synovial fluid, in rheumatoid arthritis, 1056 Arachidonic acid cascade, 836 Arachnodactyly, contractural, congenital, 1652 ARAMIS database, 871–872 ARF. See Rheumatic fever. Arginine-rich end leucine-rich repeat protein, in cartilage, 40t, 41 Arm abduction test, in neck pain, 582 Arm syndrome, in rubella arthritis, 1763–1764 ARMADA trial, 932t, 936 Aromatase inhibitors, osteoporosis induced by, 1595–1596 Arteritis. See also Giant cell arteritis; ­Polyarteritis nodosa; Takayasu’s arteritis. coronary, in rheumatoid arthritis, 1104 Arthralgia arthritis vs., 551, 552t HIV-related, 1747, 1748t in Sjögren’s syndrome, 1154 in systemic sclerosis, 1332 Arthritis. See also specific types of arthritis. of acute rheumatic fever, 1777 arthralgia vs., 551, 552t autoimmune, mononuclear phagocytes and, 149 in Behçet’s disease, 1477 collagen-induced, 264 in dermatomyositis, 1363 destructive, apatite-associated, 1516 in Henoch-Schönlein purpura, in children, 1694 HIV-related, 1747–1749, 1749t mast cells in, 242–243, 242f, 242t in acute arthritis, 242, 243f in chronic arthritis, 242–243 mononuclear phagocytes and, 149 in polymyositis, 1363 self-management of, 993–996 assistive devices for, 994 cognitive coping for, 994 exercise for, 993–994 fatigue management for, 994 program effectiveness and, 994–995 tips for clinicians about, 995–996 in sickle cell disease, 1828 susceptibility to, regulation of, 407, 407f in systemic lupus erythematosus, 1269, 1269f

index Arthritis, Diet, and Activity Promotion Trial, 435t, 437, 509 Arthritis Impact Measurement Scale, 465 Arthritis, Rheumatism, and Aging Medical Information System database, 871–872 Arthritis robustus, 1090 Arthritis Self-Management Program, 1137 Arthrocentesis complications of, 726–727, 726t contraindications to, 725, 725t current and future trends in, 735–736 indications for, 721, 722t materials for, 727 postprocedure instructions and care for, 728 regional techniques for, 728–735 in ankle and foot, 734–735 in anterior chest wall, 728 in cervical spine area, 728 in elbow, 729–730 in knee, 733–734 in pelvic girdle, 732–733 in shoulder, 728–729 in temporomandibular joint, 728 in wrist and hand, 730–732 site preparation and technique for, 727–728 in synovial fluid analysis, 704, 704f Arthrodesis, of ankle, 648 Arthrography, 777 in hip pain, 640 in shoulder pain, 593–595, 594f Arthroplasty ankle, 648–649, 649f foot, 648, 649 hemiarthroplasty as, for osteonecrosis, 1622 for hemophilic arthropathy, 1823 hip, total for osteonecrosis, 1622–1623 rates in OECD countries, 447 for osteoarthritis, 1573 resurfacing, for osteonecrosis, 1622 Arthroscopy in hand and wrist pain, 653 in osteoarthritis, 1550 in shoulder pain, 596 Arthus reaction, 1465 animal model of, 333 neutrophils and, 226 Artificial disk replacement, for low back pain, 623 ASA. See Acetylsalicylic acid. ASAS. See ASsessment in Ankylosing ­Spondylitis international working group. Ascites, in systemic lupus erythematosus, 1279 Aspartate proteinases, in cartilage degradation, 53, 53t Aspartic proteinases inhibitors of, gene expression of, 125–126 matrix degradation and, 115, 116t Aspergillosis, 1743, 1743f Aspiration, in hand and wrist pain, 652–653 ASPIRE trial, 930t, 932 Aspirin. See Acetylsalicylic acid. ASsessment in Ankylosing Spondylitis ­international working group, 457 Asset and Health Dynamics of the Oldest Old Survey, 509 Assistive devices for arthritis self-management, 994 in physical medicine and rehabilitation, 1030 ASSURE. See Abatacept Study of Safety in Use with Other RA Therapies trial. Asthma eosinophils and, 229–230 mast cells in, 240 nonsteroidal anti-inflammatory drugs and, 847t, 852–853

ASUs. See Avocado-soybean unsaponifiables. Atherosclerosis C-reactive protein and, 773 in general population, 422, 423f glucocorticoid-induced, 876 in rheumatoid arthritis, 421–429, 1103 assessment of, 427–429 epidemiology of, 421–422 future research directions for, 429 lessening risk via inflammatory ­suppression, 426–427 pathogenesis of, 422–426 Atlantoaxial impaction, in rheumatoid ­arthritis, imaging of, 809–810, 811f Atlantoaxial subluxation, in rheumatoid ­arthritis, imaging of, 809, 810, 810f Atlanto-occipital joint, 571, 573 Atorvastatin, to lessen coronary heart disease risk, in rheumatoid arthritis, 427 ATP. See Adenosine triphosphate. ATTAIN. See Abatacept Trial in Treatment of Anti-TNF Inadequate Responders. ATTRACT. See Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy trial. Audiovestibular manifestations, in relapsing polychondritis, 1630 Auranofin, for rheumatoid arthritis, 1123–1124 Auricular chondritis, in relapsing ­polychondritis, 4, 1629, 1630f AUSCAN. See Australian/Canadian ­Osteoarthritis Hand Index. Auspitz sign, 685 Australian/Canadian Osteoarthritis Hand Index, 465, 1554–1555 Autoadjuvants, 260 Autoantibodies, 260 anticitrullinated protein. See A ­ nticitrullinated protein ­autoantibodies. antinuclear. See Antinuclear antibodies. rheumatoid factor. See Rheumatoid factors. in systemic lupus erythematosus, 1233–1235, 1235t correlation with clinical manifestations, immune complexes, and T cells, 1252, 1252t genes associated with production of, 1238 in systemic sclerosis assessment of, 1339 pathogenesis and, 1323, 1323t Autoantigens, in Sjögren’s syndrome, 1152 Autoimmune diseases, 259–272. See also specific diseases. anakinra for, 941 animal models of, 263–265 with disease after genetic manipulation, 265 with disease induced by immunologic manipulation, 264–265 with spontaneous disease, 263–264 cellular mechanisms of, 269–272 antigen presenting and tissue ­environment and, 271–272 B cells and, 271 cytokines and, 262 helper T cell subsets and, 262 T cells and, 269–271, 270t environmental triggers and influences on, 268–269 genetic contributions to, 265–268 human Mendelian autoimmune diseases and, 268 major histocompatibility complex genes and, 266–267 non-major histocompatibility complex genes and, 267–268 HLA-DQ associations with, 312–313



Autoimmune diseases (Continued) mast cells and, 241 occupation-related, 494t organ-specific, 2, 261t, 262f overlapping susceptibility genes and ­pathways for, 318 pathogenesis of, 259–263 autoreactivity vs. autoimmunity and, 261–262 disease classification by pattern of organ damage and effector cell type, 260, 261t, 262f model for, 262–263, 262f, 263t self-recognition and tissue damage ­requirements and, 259–260 systemic, 260, 262f monarticular arthritis associated with, 541 with TNF inhibitors, 940 Autoimmune hemolytic anemia, 261t Autoimmune hepatitis, 261t Autoimmune lymphoproliferative syndrome. See Canele-Smith syndrome. Autoimmune neutropenia, 261t Autoimmune polyendocrine syndrome 1, 268 Autoimmune regulator autoimmune disease and, 263t, 264, 268 T cell development and, 294–295 Autoimmunity, 755 B cell costimulation and, 194, 196 initiation and propagation of, 193 molecular mimicry and, 193–194, 194t, 195f origin of autoreactive B cells and, 193 signaling thresholds and, 196 to cartilage-specific antigens, rheumatoid arthritis and, 1045 to citrullinated peptides, rheumatoid arthritis and, 1044–1045, 1044f in diffuse connective tissue disease generation of, 1384–1385, 1385f to nucleosomal components, 1383–1384, 1384f to proteosomal components, 1384, 1384f to spliceosomal components, 1383, 1383f to glucose-6-phosphate isomerase, rheumatoid arthritis and, 1046 to gp39, rheumatoid arthritis and, 1045 to heat shock proteins, rheumatoid arthritis and, 1046 to heavy-chain binding protein, rheumatoid arthritis and, 1046 to heterogeneous nuclear ribonucleoproteinA2, rheumatoid arthritis and, 1046 humoral, systemic sclerosis pathogenesis and, 1323 multiorgan, 264–265 to nonarticular antigens, rheumatoid ­arthritis and, 1046 organ-specific, tissue injury in, 389–390 rheumatoid arthritis and, 1043–1046 rheumatoid factor and, 1043–1044, 1043f systemic sclerosis pathogenesis and, 1321–1324 autoantibodies and, 1323, 1323t B cell activation and function and, 1323–1324 humoral autoimmunity and, 1323 monocytes and macrophages and, 1323 T helper type 2 polarized immune ­responses and, 1322–1323 T helper type 1/T helper type 2 balance and, 1322–1323 to type II collagen, rheumatoid arthritis and, 1045, 1045t

vi

Index

Autoinflammatory diseases, 260 familial syndromes as, 1863–1879. See also specific syndromes. definition of, 1863, 1864t, 1865f differential diagnosis of, 1863, 1866t, 1867f uveitis in, 679 Autologous stem cell transplantation, for AM amyloidosis, 1790 Autonomic nervous system, in fibromyalgia, 559 Autophagy, 380 Autoreactivity autoimmune disease vs., 261–262 reduction of, by regulatory T cell inhibition of immunologic synapse formation, 298 Autosomal dominant medullary cystic kidney disease, 1488, 1488t Avascular necrosis, of bone. See Osteonecrosis. Avocado-soybean unsaponifiables, 507–508 Axial compression test, in neck pain, 582 Axillary nerve testing, in neck pain, 580t Axis, 571, 573 Axon reflex, inflammation and, 413, 415f Azathioprine, 914–916 dosage for, 915 drug interactions of, 916, 921 for inflammatory bowel disease, 1225 malignancy associated with, 1855–1856 mechanism of action of, 910t, 913 pharmacology of, 914–915 for polyarteritis nodosa, 1456t for psoriatic arthritis, 1215 for rheumatoid arthritis, 1124 for sarcoidosis, 1804 structure of, 914 for systemic lupus erythematosus, 1281, 1283, 1284t, 1286t for Takayasu’s arteritis, 1425 toxicity of, 915–916 for Wegener’s granulomatosis, 1440 Azithromycin, drug interactions of, 919 Azoles, drug interactions of, 919 Azurophilic granules, of neutrophils, 216, 217f, 217t

B

B cell(s), 177–197, 196f activation of, 185–191 of B1 cells, 189 downstream pathways and, 187 of follicular B cells, 189–190, 189f inhibitory phosphatases and, 188 intracellular kinases and, 187 of marginal zone B cells, 189 maturation in germinal centers and, 190–191, 190f, 191f, 191t negative regulators of, 187–188 positive regulators of, 186–187, 186f regulation of, 185–186 signal transduction in immature vs. mature B cells and, 188–189 autoimmunity and, 193–196, 271 costimulation and, 194, 196 initiation and propagation of, 193 molecular mimicry and, 193–194, 194t, 195f origin of autoreactive B cells and, 193 signaling thresholds and, 196 autoreactive, origin of, 193 B1 subset of, 181–182, 182t activation of, 189 B2 subset of, 182 cytokine release and, in chronic ­inflammation, 376 development of, 181–185

B cell(s) (Continued) bone marrow stages of, 182–184, 183t, 294 germinal center stage of, 184–185 sites of, 181 subsets and, 181–182 follicular, activation of, 189–190, 189f homing of, 185 immunoglobulin synthesis by, 177, 178f. See also Immunoglobulin(s). interactions with fibroblast-like synoviocytes, in rheumatoid arthritis, 210 marginal zone, activation of, 189 maturation of in germinal centers, 190–191, 191f, 191t selection checkpoints during, 196, 196f memory, 184–185 plasma cells and, 185 repertoire selection and, 191–193 active tolerance and, 193 anergy and, 192 central and peripheral tolerance and, 191–192 deletion and, 192–193 negative, 191 receptor editing and, 192 in Sjögren’s syndrome, 1151 synovial, in rheumatoid arthritis, 1051–1053 cytokine regulation of, 1052 depletion of, 1052–1053 maturation of, 1052 in systemic lupus erythematosus, 1245–1247, 1245t inadequate idiotypic circuits controlling, 1252 systemic sclerosis pathogenesis and, B cell activation and function and, 1323–1324 targeting of, 947–953, 948f rituximab for, 948–953 B effector cells, 196 B lymphocyte stimulator protein, in rheumatoid diseases, 370t B lymphocyte-induced maturation protein 1 as antigen-activated B cell marker, 191t T lymphocyte activation and, 164 B23 nuclear phosphoprotein, in scleroderma, 749, 749t Babinski’s test, in neck pain, 582 Bacillary angiomatosis osteomyelitis, HIV-associated, 1756 Bacille Calmette-Guérin–induced arthritis, 1229–1230 Back pain. See also Low back pain. costs of, 449 Bacterial arthritis, 1701–1711 clinical features of, 1703–1704, 1704t diagnosis of, 1704–1706, 1705f, 1705t epidemiology of, 1701, 1702t etiology and pathogenesis of, 1701–1703, 1703f, 1703t HIV-associated, 1755 outcome and prognosis of, 1711, 1711t prosthetic joint infections and, 1707–1711, 1710f prevention of, 1710–1711 synovial fluid in, 705t treatment of, 1707, 1708t, 1709t in children, 1709t Bacterial endocarditis polyarthritis in, 550 rheumatoid arthritis vs., 1107–1108 in systemic lupus erythematosus, prevention of, 1287–1288

Bacterial infection(s). See also specific infections. ankylosing spondylitis and, 1173–1174 Behçet’s disease and, 1476 mast cell defense against, 240 rheumatoid arthritis and, 1041–1042, 1041f Bactericidal/permeability-inducing protein, neutrophils and, 217 Bacteroides infections, ankylosing spondylitis and, 1173–1174 Baker’s cysts, 636 in osteoarthritis, 1555 Balanitis, circinate, in Reiter’s syndrome, 686 Ballet, osteoarthritis associated with, 495t Bamboo spine, 812, 812f, 1174 Barmah Forest virus arthritis, 1765 Basal joint arthropathy, 658–659, 658f BASDAI. See Bath Ankylosing Spondylitis Disease Activity Index. Baseball, osteoarthritis associated with, 495t Basic calcium phosphate crystal deposition disorders, 1507–1521 cause of, 1508 clinical features of, 1516–1518, 1517f diagnostic tests for, 1519 differential diagnosis of, 1518 epidemiology of, 1507–1508 pathogenesis of, 1508–1513 ANKH and, 1510–1511, 1510f articular and periarticular basic calcium phosphate crystal deposition and, 1512 cartilage calcification and, 1511–1512, 1511f crystal-induced inflammation and, 1512–1513 inorganic pyrophosphate metabolism ­dysregulation and, 1508–1509, 1509f in metabolic disorders, 1509–1510 nucleotide pyrophosphatase phospho­ diesterase 1 and, 1509 treatment of, 1520–1521, 1520t Bath Ankylosing Spondylitis Disease Activity Index, 465, 466 Baxter’s nerve entrapment, 647 Bcl-2 antiapoptotic effects of, 206–207 B cell deletion and, 192–193 death receptor inhibition by, 385 signaling in apoptosis and, 340–341 surface, as antigen-activated B cell marker, 191t BCP crystal deposition disorders. See Basic calcium phosphate crystal deposition disorders. Be cells, 196 Becker muscular dystrophy, 101, 102t differential diagnosis of, 1371t Behçet’s disease, 1475–1479 cause and pathogenesis of, 1475–1476 clinical features of, 1476–1477 diagnosis of, 1477–1478, 1478f, 1478t epidemiology of, 1405t, 1475 genetics of, 1475 histopathology of, 1477 immune mechanisms in, 1475–1476 infectious agents and, 1476 polyarticular arthritis in, 549 prognosis of, 1479 skin lesions in, 699 treatment of, 1478–1479, 1479t uveitis in, 679 Belief systems, 510 Bentall procedure, 1652 Bernard-Soulier disease, 249 Beta, in clinical trials, 457, 457f Beta carotene, 1011

index Betamethasone for injection, 725t pharmacodynamics of, 865t during pregnancy, 866 structure of, 864f β-Thalassemia, 1827, 1829 clinical features of, 1828–1829, 1829f diagnosis of, 1829–1830 epidemiology of, 1827–1828 pathogenesis of, 1828, 1828f prognosis of, 1830 treatment of, 1830 β2GPI, in antiphospholipid syndrome, 1301–1302 β2-Microglobulin amyloidosis, imaging in, 822–823, 823f Bias, in clinical trials, 461 Bicipital rupture, shoulder pain due to, 603–604 Bicipital tendinitis, shoulder pain due to, 603–604 Bicipital tendon, arthrocentesis technique for, 729 Biglycan, in cartilage, 40t, 41 aged, 58 Biliary cirrhosis, primary, as autoimmune disease, 261t Biofield therapies, definition of, 502t Biologic agents. See also Disease-modifying antirheumatic drugs, biologic; specific agents. for ankylosing spondylitis, 1183–1184, 1185t apoptosis and, 391 in combination disease-modifying antirheumatic drug therapy, for rheumatoid arthritis, 901–902 malignancy associated with, 1856 neutrophil functions and, 227–228 for psoriatic arthritis, 1216 to reduce inflammation, lessening vascular risk in rheumatoid arthritis via, 426 Biologically based therapies, definition of, 502t Biomarkers, 475–485, 476f, 477t “BIPED” classification of, 1539 bone, 80 of bone loss, 1585 extracellular matrix, 476–483 cartilage oligomeric matrix protein as, 480–481 collagen, 477–480, 477t, 478f hyaluronan as, 480 metalloproteinase, 481 panels of, 483 proteoglycan, 477t, 480 in synovial tissue, 481–483, 482f genomics-based, 483–484 immunologic, 475–476 inflammatory, 475–476 metabolomics-based, 484 in osteoarthritis, 1539, 1555 proteomics-based, 484 systems biology and, 484 validation of, 484–485 Biomechanics, of joints. See Joint ­biomechanics. Biophysical factors, bone remodeling and, 78 Biostimulation, 508–509 “BIPED” biomarker classification, 1539 Bisphosphonates apoptosis and, 391 for calcium pyrophosphate dihydrate ­deposition disease, 1521 for osteoporosis, 1587–1588, 1588t for Paget’s disease of bone, 1595 Bite appliances, for temporomandibular joint pain, 668 Bladder cancer, with cyclophosphamide, 912 Blastomycosis, 1740, 1741f, 1742f

Blau syndrome, 1877–1878 clinical features of, 1877–1878 diagnosis of, 1878 epidemiology of, 1877 etiology of, 1877 outcome of, 1878 pathogenesis of, 1877 treatment of, 1878 uveitis in, 679 Blimp-1. See B lymphocyte-induced maturation protein 1. Blinding, for clinical trials, 455–456 Blindness in giant cell arteritis, 682, 1413, 1413f in Wegener’s granulomatosis, 1436 Blood antigens from, detection by spleen and liver, 295–296, 296f, 297f in mixed connective tissue disease, 1393–1394 Blood pressure. See Hypertension. Blood transfusions, for β-thalassemia, 1829 Blood vessels, in mixed connective tissue disease, 1393 BLyS. See B lymphocyte stimulator protein. BMD. See Bone mineral density. BMP-2, limb development and, 5–6 BMP(s). See Bone morphogenetic proteins. Body weight. See also Obesity. diffuse idiopathic skeletal hyperostosis and, 1602 loss of with leflunomide, 893 in osteoarthritis, 1564 redistribution of, glucocorticoids and, 877 BOKS. See Boston OA Knee Study. Bone. See also Osteo- entries; Skeletal entries; Skeleton. age-related loss of, pathophysiology of, 1580–1583, 1581f, 1582t alterations in, in osteoarthritis, 1537 architecture of, 81–84 blood supply and, 84, 84f cortical drifts and, 83 macroscopic, 81–83, 82f, 83f metaphyseal reshaping and, 83 remodeling and, 83–84 avascular necrosis of. See Osteonecrosis. biomarkers and, 80 biopsy of, in monarticular arthritis, 543 destruction of animal models of, 407–408, 408f regulation by RANKL, in rheumatoid arthritis, 1078, 1078f diseases of, arthritis vs., 552–553 fractures of. See Fractures. interface with synovium, immunohistology of, 715–716, 716f lamellar, 81, 82–83, 83f loss of. See also Osteoporosis. cyclophosphamide and, 1583 menopausal, pathophysiology of, 1580–1583, 1581f, 1582t secondary, evaluation for, 1585–1586, 1586t mechanical properties of, 84–87 mechanical signaling and, 86–87 strength as, 85 structural adaptation and, 85–86 toughness as, 85 mineralization of, 80–81 nucleation and, 80–81 turnover and, 81, 81f nonsteroidal anti-inflammatory drug toxicity and, 852 nucleation of, 80–81

vii

Bone (Continued) Paget’s disease of, 1593–1595 cause of, 1593 clinical features of, 1593–1594, 1593f, 1594f diagnosis of, 1594 laboratory findings in, 1594 treatment of, 1594–1595, 1594t remodeling of. See Bone remodeling. resorption of, in rheumatoid arthritis, 130–131 structural adaptation in, 85–86 peak strain magnitudes in functionally loaded bone and, 85–86 strain-regulated adaptation and, 86 structure of, morphometric assessment of, 80 subchondral, interactions with articular cartilage, 13 turnover of, markers of, 1585 woven, 81–82, 82f Bone cancer, primary, 1852, 1852t Bone cysts, in rheumatoid arthritis, 783 Bone grafting, for osteonecrosis, 1621–1622 Bone marrow B cell development in, 182–184, 183t, 294 immature B cell stage of, 184 mature B cell stage of, 184 pre-B cell stage of, 183–184 pro-B cell stage of, 182–183 transitional B cell stage of, 184 edema of imaging in, 804–805, 806f in osteonecrosis, 1619–1620 methotrexate toxicity and, 888 suppression of, with chlorambucil, 914 as synoviocyte origin, 26 Bone marrow cells autologous, for osteonecrosis, 1623 in rheumatoid arthritis, 1054 Bone matrix, composition of, 78–80 Bone mineral density morphometric assessment of, 80 regulation of, 78 Bone morphogenetic proteins in cartilage metabolism, 50, 50t in cartilage morphogenesis, 6 mediators of chondrocyte responses to, 51, 51f type X, 7 Bone pain, differential diagnosis of, 534 Bone remodeling, 71–75 biophysical stimuli in, 78 bone mineral density regulation and, 78 calcium metabolism and, 77 calcitonin and, 77 calcium-regulating factors and, 77 parathyroid hormone and, 77 vitamin D and, 77 of cortical bone, 83–84 mast cells and, 241 osteoblasts and, 71–73 differentiation of, 2 function of, 71–72, 72f, 72t transgenic models of pathophysiology and, 72–73 osteoclasts and, 73–75 differentiation of, 74 function of, 73–74, 74f transgenic models of pathophysiology and, 74 osteocytes and, 73, 73f in psoriatic arthritis, 1213 sex steroids and, 77–78 Bone sialoprotein, as biomarker, 477t Bone-specific alanine phosphatase, as ­biomarker, 477t

viii

Index

Bony erosions in juvenile chronic arthritis, imaging of, 786 in rheumatoid arthritis, 782–783 Borrelia burgdorferi. See also Lyme arthritis; Lyme disease. host invasion by, 1716 immune response to, 1716 resistance mechanisms of, 1717 Boston OA Knee Study, 1521 Botanicals, 508 Boutonnière deformity, 522–523 Bowel. See also Crohn’s disease; Inflammatory bowel disease; Ulcerative colitis. large, in systemic sclerosis, 1331 Boxing, osteoarthritis associated with, 495t Braces, in physical medicine and rehabilitation, 1029 Brachial plexus, testing of, in neck pain, 580t Brachial plexus neuritis neck pain due to, 583 shoulder pain due to, 609 Bracing, for osteoarthritis, 1564 Brain, pain projection to, 971, 972f, 972t Breastfeeding. See Lactation. British Isles Lupus Assessment Group Scale, 1265 Bronchiolitis, in rheumatoid arthritis, 1103 Bronchiolitis obliterans, in systemic lupus erythematosus, 1276t Brucella arthritis, 1226, 1227 BSP. See Bone sialoprotein. Btk, B cell activation and, 187 Buerger’s disease, 1457–1458 clinical features of, 1458 diagnosis of, 1458 epidemiology of, 1406 pathology of, 1457–1458 treatment and course of, 1458 Bulbocavernosus reflex, in neck pain, 582 Bullous diseases, as autoimmune disease, 261t Bullous eruptions, 690 Bunion(s), 644, 644f, 646 Bunionettes, 646 Bursae, 12 Bursitis Achilles, therapeutic injection in, 724 differential diagnosis of, 534, 536 ischiogluteal, arthrocentesis technique for, 732 of knee, 528 monarticular arthritis vs., 534, 536 prepatellar, 635–636 therapeutic injection in, 724 trochanteric, 525–526 Bypass arthritis-dermatitis syndrome, 1227, 1228f Bywaters’ lesions, 687

C

C1 inhibitor, complement regulation by, 326t, 328, 328f C1 inhibitor function assay, 330t C2 gene, in systemic lupus erythematosus, 1238 C4 gene, in systemic lupus erythematosus, 1237, 1238 Cachectin. See Tumor necrosis factor(s), TNF-α. Cadherins cadherin II as, in synovial macrophages, 24 in synovial macrophages, 24–25 Calcific periarthritis, rheumatoid arthritis vs., 1108 Calcific tendinitis, of shoulder, 600–601 Calcitonin calcium metabolism and, 77 for osteoporosis, 1587 for Paget’s disease of bone, 1594–1595

Calcitonin gene-related peptide, inflammation and, 412–413, 412f Calcium metabolism of, 77 calcitonin and, 77 factors regulating, 77 parathyroid hormone and, 77 vitamin D and, 77 muscle force generation and shortening and, 100 muscle relaxation and, 100 for osteoporosis, 1586, 1586t T lymphocyte activation and, 162 Calcium channel(s) excitation-contraction coupling and, 97 neuromuscular transmission and, 96–97 Calcium channel antagonists, drug interactions of, 919 Calcium hydroxyapatite crystal deposition disease, imaging in, 799–800, 800f Calcium pyrophosphate dihydrate crystal(s), in synovial fluid, detection of, 706–707, 706f Calcium pyrophosphate dihydrate crystal ­deposition disease, 540, 1507–1521 cause of, 1508 clinical features of, 1513–1516, 1513t, 1514f chronic degenerative and inflammatory arthropathies as, 1514, 1515f, 1516 familial chondrocalcinosis as, 1516 pseudogout as, 1514 criteria for, 1507, 1508t diagnosis of, 1518–1519 differential diagnosis and, 1518 tests for, 1519, 1519f epidemiology of, 1507–1508 imaging in, 798–799, 799f in osteoarthritis, 1530 outcome of, 1521 pathogenesis of, 1508–1513 ANKH and, 1510–1511, 1510f articular and periarticular basic calcium phosphate crystal deposition and, 1512 cartilage calcification and, 1511–1512, 1511f crystal-induced inflammation and, 1512–1513 inorganic pyrophosphate metabolism ­dysregulation and, 1508–1509, 1509f in metabolic disorders, 1509–1510 nucleotide pyrophosphatase ­phosphodiesterase 1 and, 1509 polyarthritis secondary to, 549, 551 prognosis of, 1521 rheumatoid arthritis vs., 1108 treatment of, 1519–1521 Calcium-ATPase, in skeletal muscle, 96t Calculi, uric acid, 1488 Calpains, matrix degradation and, 116t, 117 Calpastatin, as proteinase inhibitor, 124t Calsequestrin, in skeletal muscle, 96t CAM. See Complementary and alternative medicine. cAMP. See Cyclic adenosine monophosphate. Campath-1H, 958 Canalicular system, 249 Cancer. See also Malignancy(ies). of bladder, with cyclophosphamide, 912 of bone, primary, 1852, 1852t cervical, in systemic lupus erythematosus, 1851 metastatic, 1852–1853, 1853t, 1900 prevention of, nonsteroidal anti­inflammatory drugs and, 852–853 in rheumatoid arthritis, 1100

Candidiasis, 1741 oral, in Sjögren’s syndrome, 1153 Cane(s) in osteoarthritis, 1564 in physical medicine and rehabilitation, 1030 Canele-Smith syndrome, 170–171, 388 Canker sores, in Behçet’s disease, 1476, 1476f Capacitative coupling, for osteonecrosis, 1623 Caplan’s syndrome, 494t CAPS. See Cryopyrin-associated periodic syndrome. Capsaicin, 508 for chronic pain, 989t for osteoarthritis, 1566 Carbamazepine, for chronic pain, 988, 989t Carcinoma(s), metastatic, 1900 Carcinomatous polyarthritis, 1841–1842, 1842t, 1843t CARD15, in inflammatory bowel disease, 1222, 1223f CARD proteins. See Caspase activation and recruitment domain proteins. Cardiotoxicity, of cyclophosphamide, 913 Cardiovascular disease in amyloidosis, 1791t in ankylosing spondylitis, 1176 of Behçet’s disease, 1477 in dermatomyositis, 1363 in Lyme disease, 1718 in polymyositis, 1363 in psoriatic arthritis, 429 in rheumatoid arthritis, 421, 1103–1104. See also Atherosclerosis, in rheumatoid arthritis. in systemic lupus erythematosus, 429, 1275–1277, 1275f, 1292 in systemic sclerosis, 1317, 1333–1334, 1333f in Takayasu’s arteritis, 1422 in Wegener’s granulomatosis, 1437 Cardiovascular toxicity of antimalarials, 899 of leflunomide, 893 of nonsteroidal anti-inflammatory drugs, 847t, 848–851 minimizing, 855, 855t Carditis, in acute rheumatic fever, 1778, 1778t Carotenoids, 506t Carotid IMT atherosclerosis and, in rheumatoid arthritis, 424 measurement of, in rheumatoid arthritis, 428–429 Carpal boss, 655 Carpal joint, examination of, 521–522, 521f Carpal tunnel syndrome, 521, 653 in acromegaly, 1837 arthrocentesis technique for, 731, 731f in diabetes mellitus, 1834 in hypothyroidism, 1836 imaging in, 825, 826f in pregnancy, 1837 shoulder pain in, 609–610 therapeutic injection in, 724 Carpometacarpal joint, of thumb, ­arthrocentesis technique for, 731, 732f Cartilage, articular. See also Chondrocytes. adverse effects on with arthrocentesis, 726–727, 726t with therapeutic injection, 726–727, 726t angiogenesis in, 48 appearance of, 37 calcification of, in calcium pyrophosphate dihydrate deposition disease, 1511–1512, 1511f

index Cartilage, articular (Continued) cell density in, 38 collagens of, 37, 38, 39, 41 craniofacial, development of, 8 destruction of animal models of, 407–408, 408f pannus-cartilage junction and, 1074–1075, 1075f in psoriatic arthritis, matrix ­metalloproteinases and, 1213 in rheumatoid arthritis, 37, 52, 1074–1075, 1075f development of, 8 embryonic, 8 endochondral ossification of, 37 extracellular matrix of components of, 13, 13t degradation and turnover in, markers of, 59 structure-function relationships of ­components of, 39, 40t, 41 fibrillation of, 58 fibroblast-like synoviocyte attachment to, in rheumatoid arthritis, 207–208 formation of, 5–7 inflammatory molecules produced by, in osteoarthritis, 1535–1537 interface with synovium, immunohistology of, 715–716, 716f mature, 13, 13t, 14f mechanical injury of, osteoarthritis and, 1533–1534 metabolism of, 48–52 bone morphogenetic protein in, 50, 50t cytokine signaling pathways involved in, 57–58, 57f fibroblast growth factor in, 49 insulin-like growth factor-1 in, 48–49 transforming growth factor in, 49–50, 50t morphogenesis of, 6 movement of, synovial facilitation of, 30 in osteoarthritis, imaging of, 794 physical properties of, 39 proteinase destruction of extracellular matrix degradation and, 128–129, 129f in osteoarthritis, 128–129, 131 in rheumatoid arthritis, 129–130, 130f regions of, 38, 38f repair of, 58–60 cartilage aging and, 58 cartilage matrix degradation and turnover markers and, 59 chondrocyte aging and, 58 structure of, 37–39, 38f, 39f, 1636 subchondral bone interactions with, 13 Cartilage explant cultures, 45 Cartilage intermediate layer protein, 40t Cartilage matrix protein, 40t Cartilage oligomeric matrix protein, 1642, 1643f as biomarker, 477t, 480–481 in cartilage, 40t, 41 matrix metalloproteinase degradation of, 129 as osteoarthritis biomarker, 1539 Cartilage-specific antigens, autoimmunity to, rheumatoid arthritis and, 1045 Cartilaginous joints, 107 Case-control studies, 435t, 436 CASPAR trial. See Classification of Psoriatic Arthritis trial. Caspase(s), 385–386 activation of, apoptotic cell detection using, 387–388 apoptosis and, 386 functional subgroups of, 386 regulation of, 386 T lymphocyte activation and, 162

Caspase activation and recruitment domain proteins, as pattern-recognition receptors, 282, 283, 286 CAT. See Computer adaptive testing. Catabolin, 54 Cataracts, glucocorticoid-induced, 876 Catcher’s crouch syndrome, in rubella arthritis, 1763–1764, 1764f Cathepsin(s) cathepsin B in cartilage degradation, 53t gene expression of, 125–126 matrix degradation and, 116t, 117 in osteoarthritis, 1530 in rheumatoid arthritis, 209 in synovial macrophages, 24 cathepsin D in cartilage degradation, 53t matrix degradation and, 115, 116t in synovial macrophages, 24 cathepsin G in cartilage degradation, 53t link protein degradation by, 129 matrix degradation and, 116t, 117 cathepsin K in cartilage degradation, 53t gene expression of, 125, 126 matrix degradation and, 116t, 117 in rheumatoid arthritis, 209 cathepsin L in cartilage degradation, 53t gene expression of, 125, 126 matrix degradation and, 116t, 117 in rheumatoid arthritis, 209 in synovial macrophages, 24 cathepsin S in cartilage degradation, 53t matrix degradation and, 116t, 117 joint destruction and, in rheumatoid ­arthritis, 1076–1077 Cationic peptides, secreted by macrophages, 150t Cat’s claw, for osteoarthritis, 1571 Cauda equina syndrome, mobility of, 1176 Causalgia. See Reflex sympathetic dystrophy. Cbfa 1. See Runt-domain transcription factor. C4-binding protein, complement regulation by, 326t CCL19, B cell homing and, 185 CCL20, B cell homing and, 185 CCL21, B cell homing and, 185 CCN2. See Connective tissue growth factor. CCR5, as dendritic cell maturation marker, 141t CCR6, as dendritic cell maturation marker, 141t CCR7, as dendritic cell maturation marker, 141t CD1a, as dendritic cell maturation marker, 141t CD2, as surface marker on T cells, 167t CD3 complex, T lymphocyte activation and, 160, 160f CD3, as surface marker on T cells, 167t CD4+ cells, 300 Borrelia burgdorferi and, 1716 functions of, 165 inadequate downregulation by, in systemic lupus erythematosus, 1251–1252 inflammation and, 171 in organ-specific autoimmunity, 390 T helper, in sarcoidosis, 1796–1797 T lymphocyte activation and, 161 CD4, T lymphocyte development and, 156, 158–159 CD4+CD25+ cells, T lymphocyte activation and, 164–165

ix

CD5, B cell activation and, 188 CD5-1C, 958 CD7, as surface marker on T cells, 167t CD8 T lymphocyte activation and, 161 T lymphocyte development and, 156, 158–159 CD8+ cells, 300 Borrelia burgdorferi and, 1716 functions of, 165 inadequate downregulation by, in systemic lupus erythematosus, 1251–1252 inflammation and, 171 CD10 as B cell maturation marker, 183t surface, as antigen-activated B cell marker, 191t CD11a, in synovial macrophages, 24 CD11a/CD18, as surface marker on T cells, 167t CD11b in synovial lining, 9 in synovial macrophages, 24 CD11c, in synovial macrophages, 24 CD14 as dendritic cell maturation marker, 141t in synovial lining, 9 CD16. See FcτRIII. CD18, in synovial macrophages, 24 CD19 B cell activation and, 187 as B cell maturation marker, 183t CD20 as B cell maturation marker, 183t surface, as antigen-activated B cell marker, 191t CD21 B cell activation and, 187 as B cell maturation marker, 183t CD22 B cell activation and, 187 as B cell maturation marker, 183t CD23, as B cell maturation marker, 183t CD26, as surface marker on T cells, 167t CD28, T lymphocyte activation and, 162–163, 164 CD29, as surface marker on T cells, 167t CD31, in synovial vascular endothelial lining cells, 28, 29f CD34 as B cell maturation marker, 183t in synovial vascular endothelial lining cells, 28, 29f CD36, 145t CD38 as B cell maturation marker, 183t surface, as antigen-activated B cell marker, 191t CD40 as B cell maturation marker, 183t as dendritic cell maturation marker, 141t platelets and, 252 CD44 in cartilage, 40t chondrocyte interactions with, 47, 48 as surface marker on T cells, 167t in synovial lining, 9–10 in synovial subintimal layer, 27 CD45 B cell activation and, 186–187 as B cell maturation marker, 183t in synovial macrophages, 24, 26f CD45RA, as surface marker on T cells, 167t CD45RO, as surface marker on T cells, 167t CD47. See Integrin-associated protein.



Index

CD54 as surface marker on T cells, 167t in synovial subintimal layer, 27 CD55. See Decay-accelerating factor. in synovial lining, 9 CD58, as surface marker on T cells, 167t CD59, complement regulation by, 326t CD68 in synovial lining, 9 in synovial macrophages, 24, 26f CD72, B cell activation and, 188 CD77, surface, as antigen-activated B cell marker, 191t CD80 as dendritic cell maturation marker, 141t T lymphocyte activation and, 162–163 CD83, as dendritic cell maturation marker, 141t CD86 as dendritic cell maturation marker, 141t T lymphocyte activation and, 162–163 CD95. See Fas. CD97, in synovial macrophages, 24, 26f CD99, neutrophil diapedesis and, 221 CD123, as dendritic cell maturation marker, 141t CD163 in synovial lining, 9 in synovial macrophages, 24, 26f CDAI, 1135 Cefazolin, for bacterial arthritis, 1708t, 1709t Cefepime, for bacterial arthritis, 1708t Cefotaxime, for bacterial arthritis, 1708t, 1709t Ceftriaxone for bacterial arthritis, 1708t, 1709t for Lyme disease, 1723 Celecoxib, 840, 843t, 845–846 adverse effects of, 848, 849, 850 development of, 834 for osteoarthritis, 1567 Celecoxib Long-Term Arthritis Safety Study, 845–846, 848 Celiac disease, 1227–1228 Celiac sprue, as autoimmune disease, 261t Cell adhesion, inhibition of, in antirheumatic therapy, 362–363 Cell adhesion molecules, 138. See also ­Intercellular adhesion molecule(s). in angiogenesis, 362 glucocorticoid effects on, 868 neural cell, condensation and, 5 platelet-endothelial cell, angiogenesis and, 359, 359t vascular. See Vascular cell adhesion ­molecule-1. Cell cycle arrest, p53 and, 341 Cell death apoptotic. See Apoptosis. intrinsic pathways of, 384–385 nonapoptotic, 380 Cell-mediated immune response, myositis and, 1356–1358, 1357f, 1358f Cellular debris, removal of, by complement system, 330 Central nervous system angiitis of. See Vasculitis, of central nervous system. pain projection to brain and, 971, 972f, 972t spinal cord and, 573–574, 573f pain transmission to, 970–971, 970f sensitization at, 971 Central nervous system disorders in Behçet’s disease, 1477 painful, 976 Centroblasts, 190 Centrocytes, 190, 191t

Centromere, in scleroderma, 748, 749t Cervical cancer, in systemic lupus ­erythematosus, 1851 Cervical radiculopathy, shoulder pain due to, 609 Cervical spine arthrocentesis technique for, 728 rheumatoid arthritis of, 1090–1091, 1091f, 1092f Cervicogenic headache, 575, 577 Cevimeline, for Sjögren’s syndrome, 1161, 1161t CGRP. See Calcitonin gene-related peptide. CH50. See Whole complement assay. Charcot-Leyden crystals, eosinophils and, 228, 230 Charcot’s joints. See Neuropathic arthropathy. CHD. See Coronary heart disease. Chédiak-Higashi syndrome, 224–225, 224t Cheilectomy, 649 Cheirarthropathy, diabetic, 1833, 1834t Chemoattractants, neutrophils and, 217–218 Chemokines, 357, 359–360, 360t. See also specific chemokines. in angiogenesis, 360–362, 361f, 361t B cell homing and, 185 C, 360, 360t in cartilage destruction, 56, 56t CC, 359–360, 360t in angiogenesis, 361 regulation during leukocyte recruitment, 362 classification of, 359, 360t CXC, 359, 360, 360t in angiogenesis, 360–361 regulation during leukocyte recruitment, 362 inhibition of, in antirheumatic therapy, 362–363 as mast cell mediators, 239 in osteoarthritis, 1535 production of during leukocyte recruitment, regulation of, 362 regulation during leukocyte recruitment, 362 receptor signaling by, T cell extravasation and, 292 receptors for, 360 in rheumatoid arthritis, 1064 secreted by macrophages, 150t T lymphocyte homing and, 159–160 Chemotaxis deficiency of, 224–225, 224t neutrophils and, 221 Chest expansion, in ankylosing spondylitis, 1177 Chest pain in ankylosing spondylitis, 1175 in Sjögren’s syndrome, 1154 in systemic lupus erythematosus, 1276t in Takayasu’s arteritis, 1422 Chest wall, anterior, arthrocentesis technique for, 728 CHF. See Congestive heart failure. Chikungunya virus arthritis, 1764–1765, 1764t Chilblain lupus, 690 Childhood, mixed connective tissue disease in, 1394 Children. See also Juvenile entries. bacterial arthritis in, treatment of, 1709t dermatomyositis in. See Dermatomyositis, juvenile. diffuse cutaneous systemic scleroderma in, 1686–1688 cause and pathogenesis of, 1686, 1686f

Children (Continued) clinical features of, 1686–1687, 1687f, 1687t diagnosis of, 1687–1688, 1688f epidemiology of, 1686 outcome of, 1688 treatment of, 1688 eosinophilic fasciitis in, 1689 localized scleroderma in, 1688–1689, 1689f mixed connective tissue disease in, 1689–1690 systemic lupus erythematosus in. See ­Systemic lupus erythematosus, in children. vasculitis in, 1690–1696, 1690t giant cell, 1695–1696, 1696f necrotizing, of medium and small arteries, 1690–1693 of small vessels, 1693–1695 Chitinase 3-like protein, in cartilage, 40t, 41 CH3L. See Chitinase 3-like protein. Chlamydia, rheumatoid arthritis and, 1042 Chlorambucil, 913–914 dosage for, 914 drug interactions of, 913 mechanism of action of, 910t, 913 pharmacology of, 913–914 for polyarteritis nodosa, 1456t structure of, 913 toxicity of, 913 Chloroquine. See also Antimalarials. chemical structure of, 897, 897f for sarcoidosis, 1804 Cholesterol, structure of, 864f Cholestyramine, drug interactions of, 893 Chondritis costal, 519 in relapsing polychondritis, 1630 in relapsing polychondritis, 1629–1630, 1630f, 1631f Chondroadherin, in cartilage, 40t, 41 Chondrocalcinosis familial, 1516 imaging in, 798 Chondrocytes, 37 aging of, 58 autologous, transplantation of, 59 in cartilage pathology, 52–58, 52f cartilage matrix-degrading proteinases and, 52–53, 53t cytokine signaling pathways and, 57–58, 57f cytokines and, 53–56, 54f, 54t cartilage repair and, 58–60 cartilage aging and, 58 cartilage matrix degradation and turnover markers and, 59 chondrocyte aging and, 58 cell lines of, 46 cell origin of, 42 classification of, 42–43, 44f cultures of cartilage explant, 45 monolayer, 45 three-dimensional, 46 differentiation of, 42–43, 44f function of normal, adult, 17 synthetic, 43–44 hypertrophic, 46 interactions with extracellular matrix, 46–48 cell surface receptors and, 47–48 integrins and, 47 mechanotransduction of, osteoarthritis and, 1534 metabolism of in articular chondrocytes, 45–46 culture models for study of, 44–46, 45f

index Chondrocytes (Continued) morphology of, 42 nutrition of, 32 prehypertrophic, 46 responses to growth and differentiation ­factors, mediators of, 50–52, 51f terminal differentiation of, 6–7 Chondrogenesis, 37 Chondroitin, dietary, 507 Chondroitin sulfate chondroitin sulfate E as, as mast cell ­mediator, 239 in osteoarthritis, 1530–1531, 1570–1571 Chondroma(s), of tendon sheath and ­periarticular structures, 1891–1892, 1892f Chondromalacia, polyarthritis secondary to, 551 Chondromatosis, synovial, 1889–1891, 1890f–1892f Chondrosarcoma(s), 1852 conventional, of joint, 1897–1898 Chordin, in osteoarthritis cartilage, 52 Chordin-like, in osteoarthritis cartilage, 2, 52 Chorea, in acute rheumatic fever, 1778–1779 Chromatin, condensation of, apoptotic cell detection using, 388 Chronic infantile neurologic cutaneous and articular syndrome, 1864t, 1873, 1876, 1876f skin lesions in, 700 Chronic pain assessment of, 979–983, 980t management of, abbreviations related to, 963b pain-sleep connection and, 979 psychiatric comorbidities in, 976–979, 978t identification of, 981–983 treatment of adjunctive medications for, 987–988, 989t, 990 analgesics for, 984–986, 984f, 985t, 986f, 987f managing problems with long-term ­opioids for, 986–987, 988t mechanism-based approach to, 983–989 pain specialist or multidisciplinary pain program for, 990 Chronicity, psychosocial management and, 999 Churg-Strauss syndrome, 1403, 1444–1447, 1453 antineutrophil cytoplasmic antibodies and. See Antineutrophil cytoplasmic antibody. in children, 1696 clinical features of, 1445–1446 diagnosis and differential diagnosis of, 1446–1447, 1446t differential diagnostic features of, 1446t eosinophils and, 230 laboratory tests in, 1446 pathogenesis of, 1445 pathology of, 1446, 1446f prognosis of, 1447 skin lesions in, 695–696 treatment of, 1447 Chymase as mast cell mediator, 239 matrix degradation and, 116t, 117 CIA. See Collagen-induced arthritis. Cigarette smoke. See also Smoking. as rheumatic disease trigger, 269 CILP. See Cartilage intermediate layer protein. Cimetidine, drug interactions of, 913 CINCA syndrome. See Chronic infantile neurologic cutaneous and articular syndrome. C1-inhibitor, 122, 124t

Ciprofloxacin, for bacterial arthritis, 1708t Circinate balanitis, in Reiter’s syndrome, 686 Circumduction-adduction shoulder maneuver, 590, 592f Citalopram, for chronic pain, 989t Citrullinated peptides, autoimmunity to, rheumatoid arthritis and, 1044–1045, 1044f Citrulline arthritis, passive, animal models of, 406 Clancy test, 590, 592f CLASS. See Celecoxib Long-Term Arthritis Safety Study. Classification of Psoriatic Arthritis trial, 1204 Claudication intermittent, in giant cell arteritis, 1414 in Takayasu’s arteritis, 1421–1422 Clavicular osteolysis, distal, 604 Claw toes, 646 Clinical relevance, of trial results, 461 Clinical trials, 453–462. See also specific trials. analysis of, 458–461 confounding and, 461 hypothesis testing and, 458–459 incomplete data and, 459–460 intention to treat and, 459–460 presentation of results and, 460 safety analysis interpretation and, 461 statistical significance and clinical ­relevance and, 461 core sets for, 463, 464t Declaration of Helsinki and, 457–458 measurement in, 456–457 noninferiority designs and, 458 randomized, 453–458 blinding and, 455–456 design considerations for, 454 follow-up and, 455 informed consent for, 455 outcome variable choice for, 456 randomization and, 453–454 subject selection for, 454–455 sample size and statistical power and, 457, 457f Clomipramine, for chronic pain, 988, 989t Clopidogrel platelets and, 254 for ulcer prevention, 855 Clotrimazole, for xerostomia, in Sjögren’s syndrome, 1161 CMP. See Cartilage matrix protein. CMV. See Cytomegalovirus. COBRA (Combinatietherapie Bij Reumatoide Artritis) trial, 900, 1134, 1135 “Cock-up” toe deformities, in rheumatoid arthritis, 1096–1097 Codeine for chronic pain, 985 for osteoarthritis, 1567–1568 for rheumatoid arthritis, 1134 Cogan’s syndrome, 1457 clinical features of, 1457 diagnosis of, 1457 pathology of, 1457 treatment and course of, 1457 uveitis in, 679 Cognitive behavioral therapy for fibromyalgia, 564 in physical medicine and rehabilitation, 1031 Cognitive coping, for arthritis self-management, 994 Cognitive dysfunction, in systemic lupus ­erythematosus, 1275 Cohort studies, 435t, 436–437 COL1A genes, in osteogenesis imperfecta, 1645–1646

xi

COL10A1, type X, 7 Colchicine, 19 anti-inflammatory effects of, 844 for Behçet’s disease, 1478 cyclooxygenase inhibition by, 841 for familial Mediterranean fever, 1868 for gouty arthritis, 1498–1499, 1499 neutrophil functions and, 227 Cold exposure, familial cold autoinflammatory syndrome and, 1864t, 1873, 1874–1875, 1875f Cold modality for osteoarthritis, 1564 in physical medicine and rehabilitation, 1028 Colitis microscopic, 1228–1229, 1229f ulcerative. See also Inflammatory bowel disease. as autoimmune disease, 261t Collagen(s) in aged cartilage, 58 as biomarkers, 477–480, 477t, 478f in bone matrix, 79, 79f in cartilage, 1636 organization of, 111, 111f, 112f cross-links of, 479 fibrillation of, chronic, 111 joint tissue biomechanics and, 110–111, 111f, 112f in ligaments, 11–12 in menisci, 12 proteinase resistance of, 129 synthesis of, 479–480 regulation of, in systemic sclerosis, 1324, 1324t type I as biomarker, 477–478, 477t in cartilage, 38 joint formation and, 3, 4f in osteoarthritis, 1529 in synovial subintimal layer, 27 type II autoimmunity to, rheumatoid arthritis and, 1045, 1045t as biomarker, 477t, 478–479 in cartilage, 37, 39, 40t chondrocyte-extracellular matrix ­interactions and, 47 defects in, 1642 joint formation and, 3, 4f in rheumatoid arthritis, 761 synthesis of, 59 type IIA, in cartilage, 39 type III as biomarker, 477t joint formation and, 3, 4f in synovial subintimal layer, 27 type V matrix metalloproteinase degradation of, 129 in synovial subintimal layer, 27 type VI in cartilage, 39, 40t, 41 proteinase resistance of, 129 type IX, 3 in cartilage, 39, 40t, 41 type X in cartilage, 39, 40t endochondral ossification and, 7 matrix metalloproteinase degradation of, 129 type XI in cartilage, 39, 40t, 41 defects in, 1642 joint formation and, 3, 4f

xii

Index

Collagen(s) (Continued) matrix metalloproteinase degradation of, 129 type XII, in cartilage, 39, 40t, 41 type XIV, in cartilage, 39, 40t, 41 type XVI, in cartilage, 40t type XXVII, in cartilage, 40t Collagen cross-links, 479 Collagenase(s). See also Matrix metalloproteinases, MMP-1; Matrix metalloproteinases, MMP-13. in cartilage degradation, 52, 53t matrix degradation and, 116t, 118t, 119–120 Collagen-induced arthritis, 264 animal models of, 397, 398t, 399–400, 400t, 401f of passive arthritis, 405 of type II arthritis, 398t complement activation in, 334 Collars, in physical medicine and ­rehabilitation, 1029 Collateral ligaments, examination of, 629 Communication, physician-patient, 1004, 1005b COMP. See Cartilage oligomeric matrix protein. Compensation, cyclooxygenases and, 836 Complement C4, autoimmune disease and, 263t in synovial fluid, in rheumatoid arthritis, 1056–1057 Complement receptors, 329 complement receptor 1 as, 326t, 329 complement regulation by, 326t complement receptor 2 as, 326t, 329 complement receptor 3/4 as, 326t, 329 immune recognition and, 143, 147t Complement system, 323–335 activation cascades and, 324–328, 327f alternative pathway as, 324, 324f, 327 classic pathway as, 324, 324f, 325, 325t, 327f lectin pathway as, 324, 324f, 325–326 membrane attack complex and, 327–328 activation of animal models of complement deficiency and, 333–334 gene targeted deficiencies and, 334 models of inflammatory disease featuring, 333–335 in polyarthritis, 334–335 adaptive immunity and, 329 alternative pathway and, 324, 324f, 327 complement deficiency and, 332 classic pathway and, 324, 324f, 325, 325t, 327f complement deficiency and, 331–332 proteins of, 324, 325t clearance of dead, damaged, and apoptotic cells by, 330 complement deficiency and, 331–333, 331t, 332t acquired, 332–333 alternative pathway and, 332 animal models of, 333–334 classic pathway and, 331–332 gene targeted, 334 lectin pathway and, 332 complement measurement and, 330–331, 330t, 331t function of, 323–324, 324f historical background of, 323 immune complex clearance by, 330 innate immunity and, 329, 329f, 329t lectin pathway and, 324, 324f, 325–326 complement deficiency and, 332

Complement system (Continued) nomenclature for, 324, 324f, 325t, 326t regulation of, 328–329 fluid-phase and membrane inhibitors and, 328–329, 328f physiologic, 328 regulatory proteins of, 324, 326t therapeutic implications of, 335, 335t Complementary and alternative medicine, 501–511 acupuncture and, 508 belief systems and, 510 biostimulation and, 508–509 categories of, 501, 502t coping and, 510 definition of, 501 diet and, 503–506 anti-inflammatory, evidence for, 504–505 obesity and inflammation and, 505–506 dietary supplements in, 506–508 epidemiology and, 501–502 historical background of, 501 integration into clinical care, 510–511, 511t mind/body interventions and, 509–510 patient approach in, 502–503 knowledge base for, 503 patient and clinician education and, 503, 503t, 504t predictors of use of, 501 prevalence of, 501 regulation of, 502, 502t, 503t in rheumatoid arthritis, 1138 Complex regional pain syndromes, 976 Compression fractures, epiphyseal, in juvenile chronic arthritis, imaging of, 787 Computed tomography, 777–778. See also under specific conditions. clinical application of, 778 in hand and wrist pain, 652 in hip pain, 640 in knee pain, 634 quantitative, for bone mineral density ­assessment, 80 in shoulder pain, 595, 595f, 596f technical considerations in, 777–778, 778f Computed tomography myelography, in neck pain, 582 Computer adaptive testing, 471 Conduction defects, in rheumatoid arthritis, 1104 Condylar hyperplasia, differential diagnosis of, 667t Condylar hypoplasia, differential diagnosis of, 667t Confounding in clinical trials, 461 in ecologic studies, 434 Congenital camptodactyly and arthropathy, rheumatoid arthritis vs., 1108 Congenital contractural arachnodactyly, 1652 Congenital muscular dystrophy, 102t Congestive heart failure with TNF inhibitors, 940 with tumor necrosis factor inhibitors, 1130 Connective tissue, joint classification ­according to, 1 Connective tissue disease diffuse. See Diffuse connective tissue diseases. mixed. See Mixed connective tissue disease. undifferentiated, 1385–1386, 1387f vasculitis associated with, 1472–1473, 1472f Connective tissue growth factor, fibrosis and, in systemic sclerosis, 1326 CONSORT guidelines, 460 Construct validity, 470

Contractile proteins, 93, 96t Contractural arachnodactyly, congenital, 1652 Conventional radiography, 777. See also under specific conditions. in hand and wrist pain, 652 in hip pain, 639, 639f, 640f in knee pain, 633–634, 634f, 635f in monarticular arthritis, 543 in neck pain, 582 in shoulder pain, 593, 593f Conversion disorder, 977–978 Convertases, complement regulation by, 326t Coping, 510 Copper, in nutrition, 1013 Core binding factor. See Runt-domain ­transcription factor. Core decompression, for osteonecrosis, 1621 Coronary arteritis, in rheumatoid arthritis, 1104 Coronary heart disease, in rheumatoid arthritis, 421. See also Atherosclerosis, in rheumatoid arthritis. Corsets, in physical medicine and ­rehabilitation, 1029 Corticosteroids. See also specific drugs. for ankylosing spondylitis, 1183 apoptosis and, 390 in combination disease-modifying antirheumatic drug therapy, for rheumatoid arthritis, 901 injections of. See also Therapeutic injection. for carpal tunnel syndrome, 653 for foot and ankle pain, 648 during lactation, 1288 live vaccine contraindication with, 1288 for low back pain, 621t for neurologic disorders, in Sjögren’s ­syndrome, 1162 osteonecrosis induced by, 1611–1612, 1615t for sarcoidosis, 1803–1804 for systemic lupus erythematosus, 1281–1283, 1286t Cortisol, pharmacodynamics of, 865t Cortisone effects on hypothalamic-pituitary-adrenal axis, 869–870 pharmacodynamics of, 865t structure of, 864f Cost(s) cost items and estimates and, 441, 441t cost-of-illness studies, 441–442 direct, of illness, 440, 441t in health outcome assessment, 466 indirect, of illness, 440, 441t intangible, of illness, 440–441, 441t of musculoskeletal conditions, 443–449, 444f, 444t ankylosing spondylitis as, 447–448 back pain as, 449 osteoarthritis as, 446–447 osteoporosis as, 448–449 rheumatoid arthritis as, 445–446 opportunity, 440, 442 Cost minimization studies, 442 Cost utility analysis, 442 Cost-benefit analysis, 442 Cost-effectiveness analysis, 442 Costimulatory molecules, targeting of, 954–958, 954f Costochondritis, 519 in relapsing polychondritis, 1630 Cough, in Sjögren’s syndrome, 1154 Counterimmunoelectrophoresis, for antinuclear antibody detection, 746 Coup de sabre, 1342t, 1343 COX. See Cyclooxygenase entries.

index COX-2 inhibitors, 834. See also Nonsteroidal anti-inflammatory drugs; specific drugs. for low back pain, 621t molecular basis of, 840–841 for rheumatoid arthritis, 1134 selective, 840 Coxibs. See also specific drugs. aspirin combined with, 850–851 toxicities of, 847t Coxsackievirus arthritis, 1768 CPPD. See Calcium pyrophosphate dihydrate crystal(s); Calcium pyrophosphate ­dihydrate crystal deposition disease. C1q, in systemic lupus erythematosus, 1238–1240 CR(s). See Complement receptors. “Cracker sign,” in Sjögren’s syndrome, 1153 Cranial arteritis. See Giant cell arteritis. Cranial nerve examination, in pain assessment, 982 Cranial neuropathy, in Sjögren’s syndrome, 1156 treatment of, 1162 Cranial settling, in rheumatoid arthritis, ­imaging of, 809–810, 811f CRD, 145t C-reactive protein, 767 acute-phase response and, 768–769, 769f, 769t association with nonrheumatologic ­conditions, 773 inflammation and, 422 as inflammatory biomarker, in rheumatoid arthritis, 476 as osteoarthritis biomarker, 1539 in systemic lupus erythematosus, 1239 Crepitation, examination for, 518 Crescent sign, in osteonecrosis, 1617, 1618f CREST syndrome, 1314t, 1386 Sjögren’s syndrome secondary to, 1158 Cricket, osteoarthritis associated with, 495t Cricoarytenoid joints examination of, 519 rheumatoid arthritis of, 1092 Crithidia test, 746 Critical illness, serum urate concentrations in, 1486–1487 Crohn’s disease. See also Inflammatory bowel disease. as autoimmune disease, 261t IL-23 receptor associated with, 318 Cross-bridges, 100, 100f Cross-chest adduction test, 590, 592f Cross-linked carboxyterminal telopeptide, 478 Cross-sectional surveys, 434, 435t, 436 Crouch position, in rubella arthritis, 1763–1764, 1764f CRP. See C-reactive protein. Cruciate ligament anterior, examination of, 629–630, 630f posterior, examination of, 630–631, 631f Crutches, in physical medicine and ­rehabilitation, 1030 Cryoglobulin(s), types of, 1470–1471, 1470t Cryoglobulinemia, mixed, 1470 essential, 1405 paraneoplastic, 1842t, 1843 skin lesions in, 695 Cryoglobulinemic vasculitis, 1470–1471, 1470t, 1471f Cryopyrin-associated periodic syndrome, 1864t, 1873–1877 clinical features of, 1874–1876 diagnosis of, 1876–1877, 1877t epidemiology of, 1874

Cryopyrin-associated periodic syndrome (Continued) etiology of, 1874, 1874f outcome of, 1874–1876 pathogenesis of, 1874 treatment of, 1877 Cryptococcosis, 1740–1741, 1742f Crystal arthropathies. See also specific ­arthropathies. imaging in, 796–801 synovial histopathology in, 712 Crystal-induced arthritis, 540 Csk family of kinases, T lymphocyte activation and, 161 CSS. See Churg-Strauss syndrome. CT. See Computed tomography. CTLA4. See Cytotoxic T lymphocyte antigen 4. Cubital tunnel syndrome, 653–654 shoulder pain in, 609–610 Cuff-tear arthropathy, 600, 606–607, 1516 Cultures in monarticular arthritis, 542 of synovial fluid, 707 Curcumin, in anti-inflammatory diet, 504 Cushing’s syndrome, 1836 differential diagnosis of, 1371t, 1373 Cutaneous leukocytoclastic angiitis, 1404, 1405, 1465, 1468, 1469t skin lesions in, 695 Cutaneous lupus erythematosus, acute, 688–689, 689f Cutaneous lupus-lichen planus overlap, 690 Cutaneous manifestations. See also Skin; Skin lesions; specific manifestations. of Behçet’s disease, 1476, 1476f in cutaneous (limited) polyarteritis nodosa, 1456 in dermatomyositis, 1360–1362, 1361f, 1362f in immune complex-mediated vasculitis, 1466, 1466f, 1467f in Lyme disease, 1718, 1719 in polyarteritis nodosa, 1454, 1454f in relapsing polychondritis, 1631 in systemic sclerosis, 1328–1329 of Takayasu’s arteritis, 1422 in Wegener’s granulomatosis, 1436 Cutaneous toxicity, of nonsteroidal anti-inflammatory drugs, 847t Cutis laxa, 1652 CVD. See Cardiovascular disease. CXCL12, B cell homing and, 185 CXCL13, B cell homing and, 185 CXCR4, as dendritic cell maturation marker, 141t CXCR5, B cell homing and, 185 Cyclic adenosine monophosphate, neutrophils and, 219 Cycling, osteoarthritis associated with, 495t Cyclooxygenase biochemistry and structure of, 837–838, 838f, 839f COX-1, 834–840, 835f arachidonic acid cascade and prostaglandin biosynthesis and action and, 836 biochemistry and structure of, 837–838, 838f, 839f compensation and, 836 inhibition of, molecular basis of, 840–841 inhibitors of, 834. See also Nonsteroidal anti-inflammatory drugs. molecular biology of, 838–840 resolution of inflammation and, 836–837, 837f variants of, 836

xiii

Cyclooxygenase (Continued) COX-2, 834–840, 835f arachidonic acid cascade and prostaglandin biosynthesis and action and, 836 biochemistry and structure of, 837–838, 838f, 839f compensation and, 836 discovery of, 833–834 inhibition of. See COX-2 inhibitors. molecular biology of, 838–840 resolution of inflammation and, 836–837, 837f variants of, 836 COX-3, 836 isoform selectivity and, 840–841 Cyclooxygenase pathway, 344–347 COX-1 and, 345 COX-2 and, 345–346 COX-3 and, 347 products of, 347–348 endocannabinoids as, 351–352, 352f isoeicosanoids as, 351, 352f isoprostanes as, 351 lipoxins as, 350–351, 351f prostacyclin as, 347–348 prostaglandins as, 347 thromboxanes as, 348 prostaglandin synthases and, 347 Cyclophosphamide, 909–913 apoptosis and, 391 bone loss due to, 1583 clinical role of, 913 dosage and route of administration for, 911, 911t drug interactions of, 913 malignancy associated with, 1854–1855 mechanism of action of, 909–910, 910f, 910t for neurologic disorders, in Sjögren’s ­syndrome, 1162 pharmacology of, 910–911 for polyarteritis nodosa, 1455, 1456, 1456t in pregnancy, 1288 for sarcoidosis, 1804 structure of, 909 for systemic lupus erythematosus, 1283–1284, 1284t, 1285t, 1287 in children, 1680 in end-stage renal disease, 1291 for Takayasu’s arteritis, 1425 toxicity of, 911–913 for Wegener’s granulomatosis, 1439–1440 Cyclosporine, 916–919 apoptosis and, 390–391 clinical role of, 913 cyclosporine A as, for sarcoidosis, 1804 dosage for, 917–918, 918t drug interactions of, 866, 919, 919t gout induced by, 1488–1489 hyperuricemia induced by, 1488–1489 malignancy associated with, 1856 mechanism of action of, 910t, 916–917, 917f pharmacology of, 917 for psoriatic arthritis, 1215 for rheumatoid arthritis, 1124 structure of, 916 for systemic lupus erythematosus, 1284t, 1286 toxicity of, 918–919 Cyst(s) bone, in rheumatoid arthritis, 783 ganglion. See Ganglia. retinacular, 659 synovial, 1883–1884, 1884f Cystatin C, as proteinase inhibitor, 124t Cystatin S, as proteinase inhibitor, 124t

xiv

Index

Cysteine proteinases in cartilage degradation, 53, 53t inhibitors of, 122, 124t gene expression of, 125–126 matrix degradation and, 115, 116t, 117 Cysteine-rich domain, 145t Cytokine(s), 367–377. See also specific cytokines. activities of, 376 acute-phase response and, 770, 770t agonist/antagonist activities of, in chronic inflammation, 374 atherosclerosis and, in rheumatoid arthritis, 425 autoimmunity and, 272 B cell activation and, 194, 196 bone destruction and, 407–408, 408f in cartilage degradation, 53–56, 54f, 54t cartilage destruction and, 407–408, 408f classification of, 367, 368f cognate cellular interactions and, 373–374, 375, 376f effector function of, 369, 370t–375t, 371–376 in acute inflammation, 371 in chronic inflammation, 371–376 expression of, regulation of, 368–369, 369f function of, assessment of, 367–368 glucocorticoid effects on, 868 inflammatory, in juvenile idiopathic arthritis, 1659–1660 inhibitory, 55 as mast cell mediators, 239 myositis and, 1359–1360 networks of, in cartilage destruction, 54–55 neutrophil production of, 223 in osteoarthritis, 1535 reducing expression of, 1573 production of, DMARD modulation of, 375 proinflammatory, adrenocorticotropic ­hormone and, 869, 869f in psoriasis, 1212–1213 receptors for, 368. See also specific receptors. regulating MMP expression, in rheumatoid arthritis, 208–209 secreted by macrophages, 150t in Sjögren’s syndrome, 1151 soluble cytokine receptors and, in ­rheumatoid arthritis, 1066 T cell. See T lymphocytes. T cell-derived, 167, 168t–169t, 170 as targets in susceptibility and destruction, 406–408 Cytokine binding proteins, in rheumatoid arthritis, 1066 Cytokine receptors, 368. See also specific ­receptors. Cytomegalovirus rheumatoid arthritis and, 1042 systemic sclerosis and, 1312–1313 Cytomegalovirus arthritis, 1768 Cytotoxic drugs. See also specific drugs. apoptosis and, 391 in pregnancy, 1288 for systemic lupus erythematosus, in severe, life-threatening disease, 1286–1287 Cytotoxic T lymphocyte antigen 4 autoimmune disease and, 263t in systemic lupus erythematosus, 1239–1240

D

DAB486IL-2 fusion toxin, 958 Dactylitis, 522 in reactive arthritis, 1196, 1197f sarcoid, 1798 in sickle cell disease, 1829, 1829f DAH. See Diffuse alveolar hemorrhage.

Damage indices, in health outcome assessment, 466 Dancer(s), musculoskeletal disorders in, 497, 499 DANCER trial. See Dose-ranging Assessment: International Clinical Evaluation of Rituximab in RA trial. Dapsone, 922–923 for Behçet’s disease, 1478 dosage for, 923 mechanism of action of, 910t, 922 pharmacology of, 913 toxicity of, 922–923 DAS. See Disease Activity Scale; Disease ­activity score. DCAT. See Double-contrast arthrotomography. DCs. See Dendritic cells. DC-SIGN, 145t as dendritic cell maturation marker, 141t DCSS. See Diffuse cutaneous systemic ­scleroderma. DCTDs. See Diffuse connective tissue diseases. de Quervain’s tenosynovitis, 521, 658 arthrocentesis technique for, 731, 731f therapeutic injection in, 724 Death. See also Mortality. in health outcome assessment, 466 Death by neglect, 269 Death ligands, 382, 383–384 in immune regulation, 383–384 therapeutic use of, 391–392 Death receptor(s), 382–383 inhibition of, 385 signal transduction and, 382–383, 383f Death receptor signaling, 340 Decay-accelerating factor complement regulation by, 326t in synovial macrophages, 24 Declaration of Helsinki, 457–458 Decorin in cartilage, 40t, 41 in menisci, 12 Dectin-1, 145t as pattern-recognition receptors, 280 Deep tendon stretch reflexes, in neck pain, 581 Defensins, neutrophils and, 217 Deformity(ies). See also specific sites and ­deformities. examination for, 518 in rheumatoid arthritis, 783 Degenerative arthritis, of temporomandibular joint, differential diagnosis of, 667t Degenerative disk disease, imaging in, 817–818, 817f magnetic resonance imaging for, 817, 817f Degenerative rheumatic disorders, apoptosis in, acceleration of, 390 Degrees of freedom, of joints, 108–109, 108f, 109f Deletion, B cell, 192–193 Demyelinating diseases. See also specific diseases. optic neuritis in, 682 with TNF inhibitors, 940 Demyelination in systemic lupus erythematosus, 1275 with tumor necrosis factor inhibitors, 1130 Dendritic cells, 135 antigen-specific interactions with, ­immunologic synapses maintaining, 293–294 follicular, B cell maturation and, 190, 191f immature, T cell imprinting determination by tissue environment of, 299 maturation of, 139, 141, 141f, 141t mobilization of, 139, 140f, 141–142, 141f, 141t myeloid, 135–136

Dendritic cells (Continued) in rheumatoid arthritis, 1053 synovial, immunohistology of, 715 Dense granules, in platelets, 250, 250t Dental caries, in Sjögren’s syndrome, 1153, 1154 Depression psychosocial management of rheumatic diseases and, 1000–1001 psychotic, pain and, 978t Dermatitis acrodermatitis chronica atrophicans as, 696, 697 in bypass arthritis-dermatitis syndrome, 1227, 1228f granulomatous, palisaded, 688 neutrophilic palisaded, 688 rheumatoid, 227, 688 Dermatologic toxicity of antimalarials, 899 of glucocorticoids, 876 of leflunomide, 893 of sulfasalazine, 896 Dermatomyositis amyopathic, 691, 1361, 1363 in children, 1683 malignancy-associated, 1846 amyotrophic, 1363 apoptosis in, 390 clinical features of, 1360–1364 in amyotrophic dermatomyositis, 1363–1364 antisynthetase syndrome as, 1363 arthritis, 1363 cardiovascular, 1363 cutaneous, 1360–1362, 1361f, 1362f gastrointestinal, 1363 in juvenile dermatomyositis, 1364 pulmonary, 1362–1363 differential features of, 1389t glucocorticoid therapy for, 870t imaging in, 809, 809f juvenile, 1364, 1681–1685 cause and pathogenesis of, 1682 clinical features of, 1682–1683, 1682t, 1683f criteria for, 1681–1682, 1681f definition of, 1681 diagnosis of, 1683–1684 epidemiology of, 1682 outcome of, 1684–1685, 1685f, 1686t treatment of, 1684 malignancy-associated, 1846, 1847t skin lesions in, 689, 691–692, 692f Dermatomyositis sine myositis, in children, 1683 Descriptive analysis, of trial results, 460 Desipramine, for chronic pain, 989t Devil’s claw, 507 DEXA. See Dual energy X-ray absorptiometry. Dexamethasone for injection, 725t pharmacodynamics of, 865t during pregnancy, 866 structure of, 864f Dextromethorphan, for chronic pain, 989 DHPRs. See Dihydropyridine receptors. Diabetes mellitus arthritis associated with, 1833–1834, 1834f, 1834t glucocorticoid-induced, 876 imaging in, 806–807, 807f osteonecrosis and, 1615t peripheral neuropathy in, 976 type 1, as autoimmune disease, 261t Diabetic cheirarthropathy, 1833, 1834t

index Diabetic stiff-hand syndrome, 1833, 1834t Diacerein, for osteoarthritis, 1572–1573 Dialysis osteonecrosis and, 1615t shoulder pain due to, 611 in systemic lupus erythematosus, 1290–1291 Diapedesis, of neutrophils, 220–221, 220f Diarrhea with leflunomide, 892 with sulfasalazine, 896 Diarthrodial joints, 1–2, 2f, 107–108 developmental biology of, 2–8, 2f, 3f articular cartilage development and, 8 cartilage formation and, 5–6 enchondral ossification and, 6–7 interzone formation and joint cavitation and, 2–4, 4f joint capsule development and, 7 of nonarticular joints, 7–8 synovium development and, 7 mature, 8–12 bursae and, 12 innervation of, 10–11 ligaments and, 11–12 menisci and, 12 synovium and, 8–10, 9f tendons and, 11 Diclofenac, 842t adverse effects of, 849, 850, 852 for juvenile idiopathic arthritis, 1664t with misoprostol, 842t for osteoarthritis, 1566 Diet anti-inflammatory, 503–506 evidence for, 504–505 obesity and inflammation and, 505–506 recommendations for, 506, 506t gout and, 1482 hyperuricemia and, 1482, 1502 Mediterranean, 504–505 in rheumatoid arthritis, 1138 systemic lupus erythematosus and, 1244 vegetarian, 505 Dietary Supplement and Non-Prescription Drug Consumer Protection Act, 502 Dietary Supplement Health and Education Act of 1994, 502 Differentiation factors, secreted by ­macrophages, 150t Diffuse alveolar hemorrhage in microscopic polyangiitis, 1443 in systemic lupus erythematosus, 1292 Diffuse connective tissue diseases, 1381–1396, 1382t autoimmunity and, 1382–1385 generation of autoimmunity and, 1384–1385, 1385f to nucleosomal components, 1383–1384, 1384f to proteosomal components, 1384, 1384f to spliceosomal components, 1383, 1383f classic, 1381–1382, 1382t epidemiology of, 1382 mixed connective tissue disease and. See Mixed connective tissue disease. myositis overlaps and, 1386–1388, 1388t overlap syndrome management and, 1394, 1395t, 1396 scleroderma overlaps and, 1386 undifferentiated connective tissue diseases and, 1385–1386, 1387f Diffuse cutaneous systemic scleroderma, in children, 1686–1688 cause and pathogenesis of, 1686, 1686f clinical features of, 1686–1687, 1687f, 1687t diagnosis of, 1687–1688, 1688f

Diffuse cutaneous systemic scleroderma, in children (Continued) epidemiology of, 1686 outcome of, 1688 treatment of, 1688 Diffuse idiopathic skeletal hyperostosis, 1601–1606, 1603t clinical manifestations of, 1603–1605, 1603f–1605f, 1604t in diabetes mellitus, 1834 epidemiology of, 1601–1602 etiology and pathogenesis of, 1602–1603, 1602t imaging in, 819–820, 819f, 820f treatment of, 1605–1606, 1605t, 1606f, 1606t Diffuse infiltrative lymphocytosis syndrome, 1752–1754, 1753f, 1753t, 1754f, 1754t Sjögren’s syndrome vs., 1158 Diflunisal, 842t DiGeorge anomaly, 159 Digits. See also Finger(s); Thumb(s); Toes. ischemia of, critical, in systemic sclerosis, 1331 necrosis of, paraneoplastic, 1842t, 1845 Dihydropyridine receptors excitation-contraction coupling and, 97 in skeletal muscle, 96t DIL. See Drug-induced lupus. DILS. See Diffuse infiltrative lymphocytosis syndrome. Diltiazem, drug interactions of, 919 Diplopia, in giant cell arteritis, 1413, 1413t Dipyrone, 19 DIRE score, 986–987, 988t Disability definition of, 1024 in health outcome assessment, 466 Disability insurance, 1001–1002 Disability scales, in health outcome assessment, 465 Discography, provocative, in low back pain, 620 Discoid lupus erythematosus, 1267, 1268f antimalarials for, 898 malignancy associated with, 1847t skin lesions of, 689–690, 690f Discoidin domain receptor2, in cartilage, 40t Discrimination, in clinical trials, 456 Disease activity indexes, for systemic lupus erythematosus, 1264–1266, 1265t, 1266t Disease Activity Scale, 456–457, 463, 466 Disease activity score, 518 DAS28, 466, 471, 518 Disease self-management, in health outcome assessment, 466 Disease-modifying antirheumatic drugs. See also specific drugs. biologic, 1127–1132 interleukin-1 receptor antagonist as, 1130 new therapeutic classes of, 1131–1132 protein A immunoabsorption column and, 1130 for rheumatoid arthritis, 1130 safety of, 1129–1130 tumor necrosis factor inhibitors as, 1127–1129 chemokine production and, 363 combination therapy with, in rheumatoid arthritis, 900–902 biologic agents in, 901–902 corticosteroids in, 901 in early rheumatoid arthritis, 900 historical background of, 900 patient selection for, 902

xv

Disease-modifying antirheumatic drugs (Continued) in patients with active disease despite methotrexate, 900–901, 901f cytokine production and, 375 for Felty’s syndrome, 1147 malignancy associated with, 1849 for psoriatic arthritis, 1215 for reactive arthritis, 1198–1199 to reduce inflammation, lessening vascular risk in rheumatoid arthritis via, 426 for rheumatoid arthritis, 871, 1119–1124, 1120f, 1121t combination therapy using, 1125–1126, 1125f–1128f treatment strategies using, 1124–1125, 1125f toxicity index score for, 871–872 for undifferentiated spondyloarthropathy, 1195 Disease-modifying osteoarthritis drugs, 1571, 1571t DISH. See Diffuse idiopathic skeletal ­hyperostosis. Distraction test, for meniscal injury, 529 DLE. See Discoid lupus erythematosus. DM. See Dermatomyositis. DMARDs. See Disease-modifying ­antirheumatic drugs; specific drugs. DNA fragmentation, apoptotic cell detection using, 388 Docosahexaenoic acid. See Omega-3 fatty acids. DOF. See Degrees of freedom. Dorsal root reflex, inflammation and, 414–415, 415f, 416f Dose-ranging Assessment: International ­Clinical Evaluation of Rituximab in RA trial, 949, 949t, 952 Double-blind studies, 435t, 437 Double-contrast arthrotomography, in shoulder pain, 593–594, 594f Doxepin, for chronic pain, 988 Doxycycline for Brucella arthritis, 1227 for Lyme disease, 1723 for osteoarthritis, 1571–1572 for rheumatoid arthritis, 1123 d-Penicillamine, myositis induced by, 1371t, 1374 DR2 gene, in systemic lupus erythematosus, 1238 DR3 gene, in systemic lupus erythematosus, 1238 Drawer test, 529 Drug-induced disorders Cushing’s syndrome as, glucocorticoid­induced, 1836 diabetes mellitus as, glucocorticoid-induced, 876 dyslipidemia as, glucocorticoid-induced, 877 glaucoma as, glucocorticoid-induced, 876 gout as, cyclosporine-induced, 1488–1489 hyperuricemia as, cyclosporine-induced, 1488–1489 lupus as, 1290, 1291t mood disturbances as, glucocorticoid­induced, 877–878 myopathy as, differential diagnosis of, 1371t, 1373–1374 myositis as, d-penicillamine-induced, 1371t, 1374 osteonecrosis as, corticosteroid-induced, 1611–1612, 1615t osteopenia as, glucocorticoid-induced, 1836

xvi

Index

Drug-induced disorders (Continued) osteoporosis as, 1595–1596 drug-induced, 1595–1596 glucocorticoid-induced, 874–875, 1590–1591, 1590t gonadotropin-releasing hormone ­antagonist-induced, 1596 peptic ulcer disease as, glucocorticoid­induced, 875 psychosis as, glucocorticoid-induced, 877 systemic lupus erythematosus as, 1244, 1290, 1291t in children, 1678 systemic sclerosis as, 1313–1314 Drug-induced lupus, 1290, 1291t Dry eye, in Sjögren’s syndrome, 1152–1153, 1153f treatment of, 1160–1161 Dry mouth, in Sjögren’s syndrome, 1153–1154, 1153f, 1155 treatment of, 1161 Dual energy X-ray absorptiometry, 1584 for bone mineral density assessment, 80 Duchenne muscular dystrophy, 101, 102t Ductus arteriosus, closure of, drug therapy and, 851 Duloxetine, for fibromyalgia, 564 Dupuytren’s contractures, in diabetes mellitus, 1833 Dysbaric osteonecrosis, 1616 Dysferlin, in skeletal muscle, 96t Dysferlinopathy, differential diagnosis of, 1370, 1371t Dyslipidemia, glucocorticoid-induced, 877 Dyspepsia, in systemic lupus erythematosus, 1278 Dysphagia in Sjögren’s syndrome, 1155 in systemic lupus erythematosus, 1278 Dyspnea, in Sjögren’s syndrome, 1154 Dystrinopathy, differential diagnosis of, 1370 Dystrophin muscular dystrophy and, 101 in skeletal muscle, 96t

E

Eagle’s syndrome, as temporomandibular ­disorder mimic, 666t Ear(s) disorders of, in Wegener’s granulomatosis, 1433–1434 hearing loss in Wegener’s granulomatosis and, 1434 ossicles of, rheumatoid arthritis of, 1092 otitis media and as temporomandibular disorder mimic, 666t in Wegener’s granulomatosis, 1433–1434 EBV. See Epstein-Barr virus. Ecchymoses, cutaneous, in AM amyloidosis, 1789 Echovirus 9 arthritis, 1768 ECLAM. See European Consensus Lupus Activity Measure. ECM. See Extracellular matrix. Ecologic fallacy, 434 Ecologic studies, 434, 435t Economics, health. See Health economics. Edema of bone marrow, in osteonecrosis, 1619–1620 hemorrhagic, of childhood, 695 Educational level, psychosocial management and, 1003–1004, 1003t EED. See Erythema elevatum diutinum. EF. See Eosinophilic fasciitis. Efalizumab, cell adhesion molecules and, 363

Efficiency, in health economics, 442 Ehlers-Danlos syndrome, 1647–1650 arthrochalasia type of, 1649 classic type of, 1647–1648, 1647f, 1648f dermatosparaxis type of, 1649 hypermobility type of, 1648 osteonecrosis and, 1615t treatment of, 1649 vascular type of, 1648–1649 Eicosanoids, 343. See also Leukotrienes; Lipoxins; Prostacyclin; Prostaglandin(s); Thromboxanes. biosynthesis of, 343–347 cyclooxygenase pathway of, 344–347 immune response regulation by, 354 inflammatory response regulation by, 354 production of, precursor fatty acid ­modulation of, 354–355 receptors for, 352–355 leukotriene receptors as, 353 lipoxin receptors as, 353–355 prostaglandin receptors as, 352–353 Eicosapentaenoic acid. See Omega-6 fatty acids. Elastase, neutrophils and, 217 Elastin, in menisci, 12 Elbow arthrocentesis technique for, 729–730, 729f examination of, 519–520, 520f monarticular and periarticular syndromes affecting, 536t osteoarthritis in, 1557 rheumatoid arthritis of, 1093 imaging of, 784 Electric stimulation, for osteonecrosis, 1623 Electromagnetic stimulation, 508–509 Electromyography in myopathy, 1369–1370 in shoulder pain, 597 Electrotherapy, in physical medicine and ­rehabilitation, 1028–1029 Electrothermal treatment, intradiscal, for low back pain, 622 ELISA. See Enzyme-linked immunosorbent assay. Elongation factor 1α, in inflammatory muscle diseases, 750t EM. See Erythema migrans. Emery-Dreifuss muscular dystrophy, 102t EMG. See Electromyography. Employment psychosocial factors affecting, 1001–1002 work capacity assessment and, 1025–1026 EMR2, as dendritic cell maturation marker, 141t En coup de sabre, 692–693, 693f, 1342t, 1343 Enamelysin, in cartilage degradation, 53t Enchondroma(s), 1852 Endocannabinoids actions of, 352 production of, 351–352, 352f Endocardial inflammation, in rheumatoid arthritis, 1103–1104 Endocarditis, bacterial polyarthritis in, 550 rheumatoid arthritis and, 1107–1108 in systemic lupus erythematosus, prevention of, 1287–1288 Endochondral ossification, 6–7, 37 Endocrine adverse effects, of glucocorticoids, 876–877 Endocytosis, 144–145, 148f, 149f Endoplasmic reticulum, stress of, apoptosis and, 384 Endothelial cells, leukocyte interactions with, regulation of, 362

Endothelial dysfunction, atherosclerosis and, in rheumatoid arthritis, 424–425 Endothelial progenitor cells, atherosclerosis and, in rheumatoid arthritis, 425 Endothelium, synovial, immunohistology of, 715 End-stage renal disease, in systemic lupus erythematosus dialysis for, 1290–1291 renal transplantation for, 1291–1292 Energy therapies, definition of, 502t Enlimomab, trials of, 362–363 Enteric reactive arthritis, 1225–1227 causes of, 1225–1226, 1226t diagnosis of, 1226 epidemiology of, 1225 outcome of, 1227 pathogenesis of, 1226 treatment of, 1226–1227 Enteropathic arthritis, 541, 1219–1230, 1220f bacille Calmette-Guérin–induced, 1229–1230 Brucella arthritis as, 1227 bypass arthritis-dermatitis syndrome as, 1227 celiac disease and, 1227–1228 enteric reactive arthritis as, 1225–1227 causes of, 1225–1226, 1226t diagnosis of, 1226 epidemiology of, 1225 outcome of, 1227 pathogenesis of, 1226 treatment of, 1226–1227 gut physiology and, 1219, 1220f gut-associated lymphoid tissue and, 1220, 1221f, 1222f inflammatory bowel disease and, 1220, 1222–1225 microscopic colitis and, 1228–1229 polyarticular, 549, 550 Poncet’s disease and, 1229–1230 spondyloarthropathies as, 1220 Whipple’s disease and, 1228 Enteropathic arthropathies, imaging in, 791 Enthesis(es), 11 diffuse idiopathic skeletal hyperostosis and, 1602 in psoriasis, 1212 Enthesitis, 1193–1194 anatomy and, 1193, 1193f in ankylosing spondylitis, 1177 clinical assessment of, 1194 future directions in, 1194 histology of, 1193 imaging of, 1194, 1194f therapy for, 1194 Enthesitis-related arthritis, 1659, 1659t, 1670–1671 Enthesitis-related juvenile idiopathic arthritis, 1659, 1659t, 1670–1671 clinical manifestations of, 1671 differential diagnosis of, 1671 laboratory features of, 1671 outcome of, 1671 treatment of, 1671 Entrapment syndromes, pain generation with, 975 Environmental factors. See also specific factors. in physical medicine and rehabilitation, 1031 systemic sclerosis and, 1313 Environmental triggers, for autoimmune diseases, 268–269 Enzyme(s) inflammatory, glucocorticoid effects on, 868 secreted by macrophages, 150t

index Enzyme-linked immunosorbent assay for antinuclear antibody detection, 742, 746 in antiphospholipid syndrome, 1305 Eosinophil(s), 228–231 activation and distribution of, 229 development and morphology of, 228–229, 228t function of, normal, 229 in rheumatic disease, 229–231 Addison’s disease and, 230–231 asthma and, 229–230 primary eosinophilic syndromes and, 230 Eosinophilia, in rheumatoid arthritis, 1101 Eosinophilia-myalgia syndrome, 230 Eosinophilic esophagitis, 230 Eosinophilic fasciitis, 230, 1343, 1343f antimalarials for, 899 in children, 1689 skin lesions in, 693, 693f Eosinophilic pneumonia, with sulfasalazine, 896 EPCs. See Endothelial progenitor cells. Epicondyle(s) lateral, arthrocentesis technique for, 730, 730f medial, arthrocentesis technique for, 730, 730f Epicondylitis lateral, 520 medial, 520 therapeutic injection in, 724 Epidemiology, 433–438, 435t, 437–438. See also under specific conditions. methods in, 433–434 incidence and, 433–434, 434f measures of effect and, 434 prevalence and, 433 study designs in, 434, 435t, 436–438 case-control studies as, 435t, 436 clinical trials as, 435t, 437–438 cohort studies as, 435t, 436–437 cross-sectional surveys as, 434, 435t, 436 ecologic, 434, 435t Epigallocachectin-3-gallate, in anti-inflammatory diet, 504 Epimyoepithelial islands, in Sjögren’s ­syndrome, 1150 Epiphycan/PG-Lb, in cartilage, 41 Epiphyseal compression fractures, in juvenile chronic arthritis, imaging of, 787 Epistaxis, in acute rheumatic fever, 1779 Epitope, 480, 846 Epitope spreading, 194, 195f, 271 in diffuse connective tissue diseases, 1384 Epstein-Barr virus as rheumatic disease trigger, 268 rheumatoid arthritis and, 1042 in Sjögren’s syndrome, 1152 systemic lupus erythematosus and, 1242–1243 Epstein-Barr virus arthritis, 1768 EQ-5D, 465 ERA. See Enthesitis-related arthritis. Erectile dysfunction, in systemic sclerosis, 1318 Erythema, linear, in dermatomyositis, 1361, 1361f Erythema elevatum diutinum, 695, 1472, 1472f Erythema marginatum, in acute rheumatic fever, 1779 Erythema migrans, 696–697 Erythema nodosum, acute, with bilateral hilar lymphadenopathy, 1800 Erythematous macules, in hyper-IgD syndrome, 1870, 1870f Erythrocyte sedimentation rate acute-phase response and, 770, 771t

Erythrocyte sedimentation rate (Continued) as inflammatory biomarker, 475 in rheumatoid arthritis, 476 Erythromelalgia, paraneoplastic, 1842t, 1844 Erythromycin, drug interactions of, 866, 919 Escherichia coli infection, ankylosing spondylitis and, 1174 Esomeprazole, for ulcer prevention, 855 Esophagitis, eosinophilic, 230 Esophagus, in systemic sclerosis, 1331 ESR. See Erythrocyte sedimentation rate. Essential fatty acids, 343 in anti-inflammatory diet, 505 Essential mixed cryoglobulinemia, 1405 Estrogens aging of muscle and, 104 bone mineral density and, 78 bone remodeling and, 77–78 for osteoporosis, 1586–1587 systemic lupus erythematosus and, 1243–1244 Etanercept, 934–935, 1127–1128. See also Tumor necrosis factor inhibitors, TNF-α. for ankylosing spondylitis, 1183–1184, 1185t apoptosis and, 391 chemokine production and, 363 clinical trials with, 931t dose for, 934 efficacy of, 934–935 pharmacokinetics of, 934 for psoriatic arthritis, 1216 structure of, 934 Ethambutol, for tuberculosis, 1735 Ethnicity, vasculitis and, 1406 Etidronate for osteoporosis, 1588 for Paget’s disease of bone, 1595 Etodolac, 840, 842t actions of, 845 Etoricoxib, 840, 843t adverse effects of, 848 Euflexxa, for injection, 725t EULAR Disease Activity Score, 1210 EULAR response criteria. See European League against Rheumatism response criteria. European Consensus Lupus Activity Measure, 1265 European League against Rheumatism response criteria, 456–457 Excitation-contraction coupling, 97, 98f Exercise, 509–510 aerobic, in physical medicine and ­rehabilitation, 1027 aquatic, in physical medicine and ­rehabilitation, 1027–1028 for arthritis self-management, 993–994 in fibromyalgia, 510, 563–564 high-intensity vs. low-intensity, in physical medicine and rehabilitation, 1028 home-based, in physical medicine and ­rehabilitation, 1027 muscle adaptation to, 103–104 in osteoarthritis, 1564 in physical medicine and rehabilitation, 1027 range-of-motion, in physical medicine and rehabilitation, 1027 for rheumatoid arthritis, 1137–1138 strengthening, in physical medicine and rehabilitation, 1027 Extensor carpi ulnaris subluxation, 657 Extensor carpi ulnaris tendinitis, 657 Extensor pollicis longus tendinopathies, 655 External validity, 453 Extracellular matrix accumulation in systemic sclerosis, intrinsic negative regulation of, 1327

xvii

Extracellular matrix (Continued) biomarkers reflecting remodeling of, 476–483 cartilage oligomeric matrix protein as, 480–481 collagen, 477–480, 477t, 478f hyaluronan as, 480 metalloproteinase, 481 panels of, 483 proteoglycan, 477t, 480 in synovial tissue, 481–483, 482f of cartilage, structure-function relationships of, 39, 40t, 41 cellular determinants of, in systemic ­sclerosis, 1324 chondrocyte interactions with, 46–48 components of, production by fibroblasts, 201 degradation of fibroblasts and, 203 in rheumatoid arthritis, 208–209 fibroblast attachment and interaction with, 201–202, 202f, 203f molecular determinants of, in systemic sclerosis, 1324 of muscle, 93–94 in osteoarthritis, 1532 proteinases degrading, 115–131 aspartic, 115, 116t cysteine, 115, 116t, 117 endogenase proteinase inhibitors and, 122, 124–125, 124t joint destruction and, 128–131 metalloproteinases as, 116t, 118–122, 118t, 119t regulation of, 125–128 serine, 116t, 117–118 in synovial subintimal layer, 27 Extrapyramidal reaction, limitation of ­mandibular movement in, 666t Eye(s), 677–683, 678t. See also Ocular entries. anatomy and physiology of, 677, 678f in ankylosing spondylitis, 1176 dry, in Sjögren’s syndrome, 1152–1153, 1153f treatment of, 1160–1161 ocular immune response and, 677–678 optic neuritis and, 682–683, 682f orbital disease and, 682 in relapsing polychondritis, 1630 in rheumatoid arthritis, 1098, 1099f scleritis and, 681–682, 681f in systemic lupus erythematosus, 1279 uveitis and, 677, 678–681, 678f, 678t, 679f, 679t, 680f

F

FABER test, in hip pain, 638 FABERE maneuver, 525 Facet joint osteoarthritis, imaging in computed tomography for, 818, 818f magnetic resonance imaging for, 818, 818f Facioscapulohumeral muscular dystrophy, 102t differential diagnosis of, 1370, 1371t FACS. See Familial cold autoinflammatory syndrome. Factitious disorder, 978t, 979 Factor H, complement regulation by, 326t Factor I, complement regulation by, 326t Factor replacement therapy, for hemophilia complications of, 1821–1822 with factor VIII, 1820–1821 with factor IX, 1821 Factor XIIIA, in calcium pyrophosphate ­dihydrate deposition disease, 1512 FAK. See Focal adhesion kinase.

xviii

Index

Familial autoinflammatory syndromes, 1863–1879. See also specific syndromes. definition of, 1863, 1864t, 1865f differential diagnosis of, 1863, 1866t, 1867f treatment of, 1878–1879, 1879t Familial chondrocalcinosis, 1516 Familial cold autoinflammatory syndrome, 1864t, 1873, 1874–1875, 1875f Familial granulomatous arthritis. See Blau syndrome. Familial granulomatous synovitis. See Blau syndrome. Familial juvenile hyperuricemic nephropathy, 1488, 1488t Familial Mediterranean fever, 1863, 1864t, 1865–1868 clinical features of, 1866, 1868f diagnosis of, 1866–1867, 1868t etiology of, 1865–1866, 1867f genetic mapping of, 316 monarticular arthritis associated with, 541 neutrophils in, 227 outcome of, 1868 pathogenesis of, 1866 rheumatoid arthritis vs., 1108 skin lesions in, 699 treatment of, 1868 Family relationships, psychosocial management of rheumatic diseases and, 1000 FANA. See Fluorescent antinuclear antibody test. FAOS. See Foot and Ankle Outcome Score. Farr radioimmunoassay, 746 Fas autoimmune disease and, 263t death of T cells and, 170–171 death receptor signaling and, 340 signaling from, 382–383, 383f surface, as antigen-activated B cell marker, 191t Fasciitis eosinophilic, 230 in children, 1689 paraneoplastic, 1842t, 1844 FasL, as death ligand, 383–384 FAST. See Fitness and Arthritis in Seniors Trial. Fat redistribution, glucocorticoid-induced, 877 Fatigue history taking and, 517 management of, for arthritis self-management, 994 psychosocial management of rheumatic diseases and, 1000 Fatty acids, 1014–1018 essential, 343 historical background of, 1014 omega-3, 506t, 1015–1017, 1015f, 1017f animal studies of, 1016–1017 in anti-inflammatory diet, 504, 505 human studies of, 1017 in rheumatoid arthritis, 1138 vascular diseases and, 1017–1018 omega-6, 506t, 1014–1015, 1014f animal studies of, 1014–1015 in anti-inflammatory diet, 504, 505 eicosanoid synthesis modulation by, 354–355 human studies of, 1015 precursor, eicosanoid synthesis modulation by, 354–355 FBN-1, Marfan syndrome and, 1651–1652 Fc gene cluster, in systemic lupus erythematosus, 1239 Fc receptors, immune recognition and, 143–144, 148f FCEs. See Functional capacity evaluations.

FcγR polymorphisms, of neutrophils, 225 FcγRIIA, autoimmune disease and, 267 FcγRIIB, autoimmune disease and, 267 FcγRIIB1, B cell activation and, 187–188 FcγRIII, in synovial macrophages, 24 FcγRIIIa, in synovial lining, 9 FCRL3, in systemic lupus erythematosus, 1239 FDA. See Food and Drug Administration. FDCs. See Follicular dendritic cells. Feasibility, in clinical trials, 456 Febuxostat, for hyperuricemia control, 1501 Feet. See Foot. Felons, 660 Felty’s syndrome, 1145–1148 clinical features of, 1146, 1146t complications of, 1146 differential diagnosis of, 1147 epidemiology of, 1145 genetics of, 1145, 1146f hematologic features of, 1146–1147 management of, 1147 methotrexate for, 886–887 pathogenesis of, 1145–1146 platelets in, 253 prognosis of, 1147–1148 serologic features of, 1146–1147 Femoral trochanteric pain syndromes, therapeutic injection in, 724 Fenoprofen, 842t Fentanyl for chronic pain, 985 for osteoarthritis, 1568 Ferritin, 1810t acute-phase response and, 769–770 in rheumatoid arthritis, 762 Fertility antimalarials and, 899 cyclophosphamide and, 912–913 in familial Mediterranean fever, 1866 hydroxychloroquine and, 888t leflunomide and, 888t, 893 methotrexate and, 888t, 889 sulfasalazine and, 888t, 897 Fever in acute rheumatic fever, 1779 in giant cell arteritis, 1414 in Kawasaki disease, in children, 1692 in mixed connective tissue disease, 1390 FGF. See Fibroblast growth factor. Fiber, dietary, 505, 506t Fibrillin-1, Marfan syndrome and, 1650 Fibroblast(s), 201–204 activation of, stable, in rheumatoid synovium, 204–205, 205f, 206f fibrosis and, in systemic sclerosis, 1324–1325 functions of, 201–203 attachment to and interactions with extracellular matrix as, 201–202, 202f, 203f extracellular matrix component production as, 201 extracellular matrix degradation as, 203 heterogeneity of, 203 in rheumatic diseases, 203–204, 204f physiologic characteristics of, 201, 202f in rheumatoid arthritis, 1060–1067, 1061t perpetuation of synovitis by, 1066–1067, 1066f proinflammatory, 1061–1065 suppressive, 1065–1066 synoviocytes resembling. See Synoviocytes, fibroblast-like. Fibroblast growth factor in achondroplasia, 76 in cartilage metabolism, 49 in cartilage morphogenesis, 6

Fibroblast growth factor (Continued) joint formation and, 2–3 in rheumatoid arthritis, 209, 1065 Fibroblast-like cells. See also Synoviocytes, fibroblast-like. in meniscus, 12 Fibrochondrocytes, in meniscus, 12 Fibrodysplasia ossificans progressiva, osteoblasts in, 72–73 Fibroma(s), of tendon sheath, 1889, 1889f Fibromodulin, in cartilage, 40t, 41 Fibromyalgia, 555–566 arthritis vs., 553 assessment in, 561–562 diagnosis and, 562 physical measures for, 561–562 in primary, secondary, and concomitant fibromyalgia, 562 self-report measures for, 561 clinical features of, 559–561, 560f, 560t controversy over, 555 criteria for, 555–556, 556f, 556t definition of, 555–556, 556f depression in, 1001 differential diagnosis of, 562 epidemiology of, 557–558 etiology and pathophysiology of, 558–559 exercise for, 510 historical background of, 555 in HIV infection, 1751 management of, 562–566 cognitive behavioral therapy for, 564 diagnosis and, 563 education in, 563 exercise for, 563–564 nonpharmacologic treatments for, 564–565 pharmacotherapy for, 564 practical recommendations for, 565–566 medicolegal issues and, 566 objections to concept of, 556–557, 557f, 558f outcome of, 566 rheumatoid arthritis vs., 1108 Fibromyalgia Impact Questionnaire, 561 Fibronectin in cartilage, 40t matrix metalloproteinase degradation of, 129 in synovial subintimal layer, 27 Fibronectin type II domain, 145t Fibrosarcoma, 1852 Fibrosis, systemic sclerosis pathogenesis and, 1324–1325 cellular determinants of fibrosis and, 1324–1325 collagen synthesis regulation and, 1324, 1324t molecular and cellular determinants of extracellular matrix and, 1324 molecular determinants of fibrosis and, 1325–1326 molecular effectors of, 1326–1327 Fibrous joints, 107 Fibroxanthoma(s), of tendon sheath, 1896–1897, 1896f, 1897f FIHOA. See Functional Index for Hand ­Osteoarthritis. Filopodia, of synoviocytes, type A, 23 Finger(s). See also Digits. infections of, 660–661 mallet, 523, 659–660 osteoarthritis of, 660, 660f swelling of, 522 trigger, 521, 521f, 659 arthrocentesis technique for, 732 in diabetes mellitus, 1833 Finger escape sign, in neck pain, 582

index Fingernails, examination of, 523 Finkelstein test, 521 Fin-RA (Finland Rheumatoid Arthritis) trial, 900 FIN-RACo trial, 1125, 1135–1136 FIQ. See Fibromyalgia Impact Questionnaire. Fish oil supplements, 505 Fist, ability to form, 523–524 Fistula(s), development of, in rheumatoid arthritis, 1100 Fitness and Arthritis in Seniors Trial, 509 FJHN. See Familial juvenile hyperuricemic nephropathy. FK506. See Tacrolimus. Flare glandular, swelling of, in Sjögren’s syndrome, 1153–1154 postinjection with arthrocentesis, 726, 726t with joint injection, 726, 726t in relapsing polychondritis, 1631 Flare models, of arthritis, 402, 403f Flavonoids, 506t Flexor carpi radialis tendinitis, 654 Flexor carpi ulnaris tendinitis, 654 Flexor tenosynovitis, arthrocentesis technique for, 732 FLIP, death receptor inhibition by, 385 Flu-like symptoms, with methotrexate, 889 Fluorescent antinuclear antibody test, 741, 742, 745f Fluoxetine, for fibromyalgia, 564 Flurbiprofen, 840, 842t FMF. See Familial Mediterranean fever. Focal adhesion kinase, fibroblast attachment to extracellular matrix and, 202 Foci, in Sjögren’s syndrome, 1150 Fodrin, in Sjögren’s syndrome, 751, 751t, 1152 Folic acid supplementation, with sulfasalazine, 896 Follicular dendritic cells, B cell maturation and, 190, 191f Follistatin, in osteoarthritis cartilage, 52 Follow-up, for clinical trials, 455 Food allergies, arthritis due to, 1018 Food and Drug Administration, dietary supplements and, 502 Foot. See also Toes. anatomy of, 643 arthrocentesis technique for, 734–735 biomechanics of, 643 in juvenile chronic arthritis, imaging of, 788, 789f monarticular and periarticular syndromes affecting, 536t in osteoarthritis, 1557 imaging of, 795 in psoriatic arthritis, imaging of, 790–791 in reactive arthritis, imaging of, 791, 792f in rheumatoid arthritis, 1096–1097, 1096f, 1097f imaging of, 784 Foot and Ankle Outcome Score, 1554 Foot arthroplasty, 648, 649 Foot pain forefoot, 645t, 646, 647f in heel, 645t, 647 hindfoot, 645t, 646–647 imaging in, 644–645, 644f midfoot, 645t, 646 physical examination in, 643–644, 644f treatment of nonoperative, 647–648 operative, 648–649, 649f Football, osteoarthritis associated with, 495t Forearm fractures, costs of, 448

Forefoot fusion, 648 Forssman shock, animal model of, 333–334 FoxP3, autoimmune disease and, 263t Fractalkine, 360 in angiogenesis, 362 antibody to, 363 Fractures compression, epiphyseal, in juvenile chronic arthritis, imaging of, 787 of forearm, costs of, 448 of hamate, 654, 654f of hip, costs of, 448 sacral, insufficiency, imaging in, 780, 821f scaphoid, 659 nonunion and, 659 stress, ankle pain and, 645, 646 vertebral, costs of, 448 Free radicals, 1010–1011, 1010f, 1011f Frozen shoulder syndrome, 607–608 FSS. See Frozen shoulder syndrome. Fukuyama congenital muscular dystrophy, 102t Function, loss of, in osteoarthritis, 1548 Functional capacity evaluations, 1026 Functional index, in myositis, 1376 Functional Index for Hand Osteoarthritis, 1554–1555, 1555t Functional restoration programs, in physical medicine and rehabilitation, 1030–1031 Fungal infections, 1739–1744, 1740t. See also specific infections. HIV-associated, 1756, 1756f treatment of, 1743–1744, 1744t Fusion, 648 Fyn, B cell activation and, 187

G

G proteins, neutrophils and, 218–219 Gabapentin for chronic pain, 989 for neurologic disorders, in Sjögren’s ­syndrome, 1162 for peripheral nerve pain, 975 GAG(s). See Glycosaminoglycan(s). GAGPS. See Glycosaminoglycan polysulfuric acid. GAIT. See Glucosamine/Chondroitin Arthritis Intervention Trial. Gait in hip examination, 524 in hip pain, 637 in knee pain, 628–629, 629f in pain assessment, 982 Galeazzi sign, 525 GALT. See Gut-associated lymphoid tissue. Ganglia, 655, 1883–1884, 1884f, 1885f arthrocentesis technique for, 731 volar, 659 Gastric antral vascular ectasia, in systemic sclerosis, 1332 Gastroesophageal reflux disease in Sjögren’s syndrome, treatment of, 1162 in systemic sclerosis, 1331 Gastrointestinal disorders. See also specific disorders. in amyloidosis, 1791t of Behçet’s disease, 1477 in Henoch-Schönlein purpura, in children, 1694 in mixed connective tissue disease, 1392–1393 in polymyositis, 1363 in systemic sclerosis, 1317, 1331–1332, 1331t in Wegener’s granulomatosis, 1437

xix

Gastrointestinal toxicity of antimalarials, 899 of azathioprine, 916 of coxibs, minimizing, 854–855 of glucocorticoids, 875 of leflunomide, 892 of methotrexate, 888t of nonsteroidal anti-inflammatory drugs, 847, 847t minimizing, 854–855 of sulfasalazine, 896 Gaucher’s disease, osteonecrosis and, 1615t GCA. See Giant cell arteritis. GCS. See Glasgow Coma Scale. G-CSF. See Granulocyte colony-stimulating factor. GDF-5, joint formation and, 3 Gelatinases in cartilage degradation, 53t gelatinase-A as. See Matrix metalloproteinases, MMP-2. gelatinase-B as. See Matrix metalloproteinases, MMP-9. granules of, of neutrophils, 217, 217t matrix degradation and, 116t, 118t, 120–121 Gender osteoarthritis and, 1528–1529 rheumatoid arthritis etiology and pathogenesis and, 1039 systemic lupus erythematosus and, 1243–1244 vasculitis and, 1405 Gene(s). See also specific genes. interzone formation and joint cavitation regulation by, 2–3 in muscle myogenesis, 94 Gene therapy, for osteoarthritis, 1573 Genetic diseases. See also specific diseases. with skeletal manifestations, 76 Genetics, 305–318. See also specific genes and disorders. human leukocyte antigen and. See Human leukocyte antigen. major histocompatibility complex and. See Major histocompatibility complex. in whole-genome era, 314–318 association studies and, 316, 317f, 318 overlapping susceptibility genes and pathways for autoimmune diseases and, 318 screening entire genome for disease genes and, 315–316, 316f size of genetic contribution to rheumatoid diseases and, 314–315, 315t Genitourinary disorders. See also specific disorders. in Wegener’s granulomatosis, 1437 Genomics, biomarkers based on, 483–484 Gentamicin, for bacterial arthritis, 1708t, 1709t GERD. See Gastroesophageal reflux disease. Geriatric patients antimalarials in, 899 hydroxychloroquine in, 888t leflunomide in, 888t, 892 methotrexate in, 887–888, 888t sulfasalazine in, 888t, 896 German Collaborative Arthritis Centres study, 446 GGHP. See Glucosyl-galactosyl-pyridinoline. GH. See Growth hormone. Giant cell arteritis, 1409–1419 ACR criteria for, 1409, 1410t blindness in, 682 in children, 1695–1696, 1696, 1696f clinical features of, 1413–1414, 1413t, 1413f atypical, 1414–1415, 1414t, 1415f

xx

Index

Giant cell arteritis (Continued) definition of, 1409 diagnostic evaluation in, 1417–1418, 1418f differential diagnosis of, 1416–1417, 1417t epidemiology of, 1405t, 1409–1410 laboratory studies in, 1415, 1416t monarticular arthritis associated with, 541 pathology and pathogenesis of, 1410–1412, 1411f, 1412f relationship to polymialgia rheumatica, 1415 rheumatoid arthritis vs., 1111–1112 as temporomandibular disorder mimic, 666t treatment of, 1418, 1419t acute-phase reactants in, 771–772 Giant cell synovioma(s), benign, 1895, 1895f, 1896f Giant cell tumor(s), 1852 tenosynovial, 1892–1897 diffuse, 1893–1895, 1893f–1895f localized, 1895–1897, 1895f–1897f malignant, 1895 Giardia lamblia infection(s), enteric reactive arthritis and, 1226 Gignac’s Work Activity Limitations Scale, 466 Gillworth’s Work Instability Scale, 466 Ginger, 506–507 “Glandular flares,” swelling of, in Sjögren’s syndrome, 1153–1154 Glanzmann thrombasthenia, 250 Glaucoma, glucocorticoid-induced, 876 Glenohumeral joint arthrocentesis technique for, 728–729, 729f disorders of, shoulder pain due to, 605 instability of, shoulder pain due to, 608–609 Glucocorticoid(s), 863–878. See also specific drugs. adverse effects of, 874–878, 875t behavioral, 877–878 cardiovascular, 876 dermatologic, 876 endocrine, 876–877 gastrointestinal, 875 immunologic, 875–876 monitoring for, 878, 878t ocular, 876 skeletal, 874–875 apoptosis and, 390 biologic characteristics of, 865 for calcium pyrophosphate dihydrate ­deposition disease, 1520 Cushing’s syndrome induced by, 1836 drug interactions of, 866, 866f effects of, 867–870 genomic mechanisms and, 867–868, 867f on hypothalamic-pituitary-adrenal axis, 869–870 on immune system, 868 nongenomic, 867 future directions for, 878 injection of, 874 in shoulder pain, 597–598 for juvenile dermatomyositis, 1684 for myositis, 1374 neutrophil functions and, 227 osteopenia induced by, 1836 osteoporosis due to, 1582, 1590–1591, 1590t pharmacodynamics of, 865–866, 865t pharmacokinetics of, 865 for rheumatoid arthritis, 1132–1133 structure and classification of, 863, 864f, 865, 865t therapeutic consequences of, 865 treatment with, 870–874, 870t alternate-day regimens for, 872 chronobiology and, 872

Glucocorticoid(s) (Continued) dosage adaptations for, 873 glucocorticoid-sparing agents and, 873 indications for, 870, 870t intralesional and intra-articular injections and, 597–598, 874 perioperative care and, 873 pulse therapy and, 873–874 in rheumatoid arthritis, 870–872 sensitivity and resistance to, 872 stress regimens for, 873 withdrawal regimens for, 873, 873t for Wegener’s granulomatosis, 1439 Glucocorticoid withdrawal syndrome, ­rheumatoid arthritis vs., 1108 Glucosamine dietary, 507 for osteoarthritis, 1569–1570 Glucosamine/Chondroitin Arthritis ­Intervention Trial, 435t, 437, 507 Glucose intolerance glucocorticoid-induced, 876 in hemochromatosis, 1811 Glucose transporter proteins, chondrocytes and, 43 Glucose-6-phosphatase deficiency, 1495 Glucose-6-phosphate isomerase, in rheumatoid arthritis, 761 Glucose-6-phosphate isomerase arthritis, animal models of, 400t, 405 Glucose-6-phosphate isomerase, autoimmunity to, rheumatoid arthritis and, 1046 Glucosyl-galactosyl-pyridinoline, 479 Glutamate, inflammation and, 413, 414f Gluten enteropathy. See Celiac sprue. GLUTs. See Glucose transporter proteins. Glycolysis, in muscle, 103 Glycoprotein-39 autoimmunity to, rheumatoid arthritis and, 1045 in cartilage, 40t Glycoprotein IIb/IIIa, platelets and, 249–250, 251–252 Glycoprotein IIb/IIIa blockers, platelets and, 254 Glycosaminoglycan(s) as biomarkers, 477t bone mineralization and, 80 in synovial subintimal layer, 27 Glycosaminoglycan polysulfuric acid, for ­osteoarthritis, 1572 Glycosaminoglycan-peptide complex, for osteoarthritis, 1572 GM-CSF. See Granulocyte-macrophage colony-stimulating factor. Gold salts, for rheumatoid arthritis, 871, 1123–1124 Golfer’s elbow, 520 Gonadotropin-releasing hormone antagonists, osteoporosis induced by, 1596 Gonococcal arthritis, polyarticular, 547 Goodpasture’s syndrome, 1404 as autoimmune disease, 261t systemic lupus erythematosus vs., 1281 Gordon phenomenon, 229 Gottron’s papules, 691, 692f in dermatomyositis, 1360, 1361f Gottron’s sign, in dermatomyositis, 1360, 1361f Gout. See also Hyperuricemia. acute gout attacks and, 1496–1497 classification and pathogenesis of, 1493–1497, 1493t acute gout attacks and, 1496–1497 primary gout and, 1493, 1494f secondary gout and, 1494–1496, 1494f–1496f tophaceous gout and, 1497

Gout (Continued) clinical features of, 1482–1484 conditions associated with, 1485–1489 environmental factors in, 1482 epidemiology of, 1481–1482 genetics of, 1484–1485 imaging in, 797–798, 797f, 798f intercritical (interval), 1483 mononuclear phagocytes and, 149 neutrophils in, 225 occupation-related, 494t polyarticular arthritis in, 549 primary, 1493, 1494f rheumatoid arthritis vs., 1108–1109 secondary, 1494–1496, 1494f–1496f in sickle cell disease, 1829 synovial fluid in, 705t of temporomandibular joint, 669 differential diagnosis of, 667t tophaceous, 1483–1484, 1484f–1486f, 1497 treatment of, 1498–1502 for acute gouty arthritis, 1498–1499 ancillary factors in, 1502–1503 with asymptomatic hyperuricemia, 1498 compliance with, 1502 following organ transplantation, 1502 for hyperuricemia control, 1499–1502, 1500t organ transplantation for, 1502 wrist pain in, 656 Gouty arthritis, 540 acute clinical features of, 1482–1483, 1483t treatment of, 1498–1499 chronic, clinical features of, 1483–1484, 1484f–1486f glucocorticoid therapy for, 870t gp39. See Glycoprotein-39. GP 130 arthritis, animal models of, 398–399, 398t, 403–404 GP-C. See Glycosaminoglycan-peptide ­complex. GPI arthritis. See Glucose-6-phosphate ­isomerase arthritis. Graft-versus-host disease, 1854 Sjögren’s syndrome vs., 1158 Gram stain, of synovial fluid, 707 Granulocyte colony-stimulating factor for Felty’s syndrome, 1147 in rheumatoid diseases, 375t Granulocyte-macrophage colony-stimulating factor in rheumatoid arthritis, 1063–1064 in rheumatoid diseases, 375t T cell-derived, 169t Granulocytopenia. See Felty’s syndrome. Granuloma annulare, in rheumatoid arthritis, 1099 Granulomatosis, lymphomatoid, ­paraneoplastic, 1842t, 1846 Granulomatous aortitis, in rheumatoid ­arthritis, 1104 Granulomatous arteritis. See Giant cell arteritis. Granulomatous arthritis, familial. See Blau syndrome. Granulomatous disease, chronic, 224t, 225 GRAPPA. See Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. Graves’ disease, 260, 261t, 682, 1835 osteoporosis associated with, 1583 Gremlin, in osteoarthritis cartilage, 52 Grip-release test, in neck pain, 582 Groin, anterior, pain in, 526 Group A streptococci, 1772–1773, 1772f, 1773f

index Group for Research and Assessment of Psoriasis and Psoriatic Arthritis, 1209, 1214 Growth disturbance, in juvenile chronic ­arthritis, imaging of, 786–787 Growth factors. See also specific growth factors. in chronic inflammation, 376 as mast cell mediators, 239 for osteoarthritis, 1573 prolonged exposure to, apoptosis and, 389, 389f secreted by macrophages, 150t Growth hormone acromegaly and, 1836–1837 muscle adaptation and, 104 Growth plates development of, 6 elongation of, parathyroid hormone-related peptide and, 76 Guaifenesin, for xerotrachea, in Sjögren’s syndrome, 1162 Gut-associated lymphoid tissue, 1220 Guyon’s canal, 654 Gymnastics, osteoarthritis associated with, 495t

H

HA. See Hyaluronic acid. HAART. See Highly active antiretroviral therapy. Haemophilus influenzae type B vaccine, in systemic lupus erythematosus, 1288 Hair loss with cyclophosphamide, 913 in systemic lupus erythematosus, 1268 Hallux valgus deformity, 644, 644f, 646 Hamate fracture, 654, 654f Hammer toes, 646 Hand(s). See also Digits; Finger(s). arthrocentesis technique for, 730–732 in juvenile chronic arthritis, imaging of, 787–788 mechanic’s, 1362, 1362f monarticular and periarticular syndromes affecting, 536t osteoarthritis in, 1551t, 1556, 1556f imaging of, 794–795, 794f in psoriatic arthritis, imaging of, 790–791, 790f, 791f rheumatoid arthritis of, 1093–1095, 1093f–1095f imaging of, 783–784, 783f, 784f strength of, 524 swelling of, in sickle cell disease, 1829, 1829f Hand pain anatomy in, 651, 652f arthroscopy in, 653 digital, etiologies for, 659–660 history taking in, 651 imaging in, 652 injections and aspirations in, 652–653 neurodiagnostic tests in, 652 palmar, etiologies for, 659 physical examination in, 651–652 Haplotype, definition of, 309t HAQ. See Health Assessment Questionnaire. HAQ-DI. See Health Assessment ­Questionnaire–Disability Index. HAQ-II. See Health Assessment ­Questionnaire–II. Harpagophytum procumbens, 507 Harris Hip Score, 637 Hashimoto’s disease as autoimmune disease, 261t Graves’ disease related to, 1835 Headache cervicogenic, 575, 577 in giant cell arteritis, 1413

Health, Aging, and Body Composition (Health ABC) Study, 1521 Health Assessment Questionnaire, 463, 1025, 1134–1135 Health Assessment Questionnaire–Disability Index, 465 Health Assessment Questionnaire–II, in ­fibromyalgia, 561 Health care usage, determinants of, 1002–1003 Health economics, 439–449 evaluations for, 442–443, 443t of illness, 439–442 cost items and estimates and, 441, 441t cost-of-illness studies and, 441–442 direct costs and, 440, 441t indirect costs and, 440, 441t intangible costs and, 440–441, 441t musculoskeletal conditions and, 443–449, 444f, 444t Health outcome(s) in health economics, 442 satisfaction with, 466 selecting to meet measurement need, 468–471, 468f Health outcome assessment, 463–472 adaptation to ongoing disease and, 472 growth areas in, 471 outcome selection for, 468–471, 468f reasons for, 467 relationships among, 467, 467f score interpretability and, 470–471 target population for, 468 technology used in, 471–472 tools for, 463–467 disease-specific measures as, 463, 464t, 465–466 emerging domains and, 466–467 what to measure and, 467–468 Health status, 465 Health Utility Index, 465 Hearing loss, in Wegener’s granulomatosis, 1434 Heart. See also Cardiovascular entries. iron deposition in, in hemochromatosis, 1811 in mixed connective tissue disease, 1390 Heart disease coronary, in rheumatoid arthritis, 421. See also Atherosclerosis, in rheumatoid arthritis. valvular in rheumatoid arthritis, 1104 in systemic lupus erythematosus, 1276 Heart failure, congestive with tumor necrosis factor inhibitors, 940, 1130 Heat modality for osteoarthritis, 1564 in physical medicine and rehabilitation, 1028 Heat shock proteins autoimmunity to, rheumatoid arthritis and, 1046 in bacille Calmette-Guérin–induced arthritis, 1230 in tuberculous arthritis, 1230 Heavy-chain binding protein, autoimmunity to, rheumatoid arthritis and, 1046 Heavy-chain polypeptide, of immunoglobulins, 177, 178–180, 179t Heberden’s nodes, 1547 Heliotrope rash, in dermatomyositis, 1360–1361, 1361f Hemangioma(s), synovial, 1888–1889, 1888f, 1889f

xxi

Hemarthrosis(es) in hemophilia, 1817 treatment of, 1822, 1822f monarticular, 541 synovial fluid in, 705t Hematologic disorders. See also specific disorders. in amyloidosis, 1791t osteonecrosis and, 1612–1613 in rheumatoid arthritis, 1100–1101 Hematologic toxicity of azathioprine, 915 of chlorambucil, 914 of cyclophosphamide, 911 of dapsone, 922 of leflunomide, 893 of methotrexate, 888t of nonsteroidal anti-inflammatory drugs, 853 of sulfasalazine, 896 Hemiarthroplasty, for osteonecrosis, 1622 Hemochromatosis hereditary. See Hereditary hemochromatosis. imaging in, 800–801, 801f polyarthritis secondary to, 551 rheumatoid arthritis vs., 1109 synovial histopathology in, 712 Hemodialysis osteonecrosis and, 1615t shoulder pain due to, 611 in systemic lupus erythematosus, 1290–1291 Hemoglobinopathies, 1827–1830 cause of, 1827, 1828f clinical features of, 1828–1829, 1829f diagnosis of, 1829–1830 epidemiology of, 1827–1828 pathogenesis of, 1828 prognosis of, 1830 rheumatoid arthritis vs., 1109 treatment of, 1830 Hemojuvelin, 1810t Hemolysis with dapsone, 922 with sulfasalazine, 896 Hemolytic anemia, autoimmune, 261t Hemolytic assays, 330t Hemophilia, imaging in, 801–802, 802f, 803f Hemophilic arthropathy, 1817–1823 clinical features of, 1817–1818, 1818f diagnosis of, 1820 diagnostic imaging in, 1818–1819 radiography for, 1818–1819, 1819f, 1819t end-stage, clinical features of, 1817–1818 pathology and pathogenesis of, 1819–1820, 1820f rheumatoid arthritis vs., 1109 therapeutic injection in, 723 treatment of, 1820–1823 complications of factor replacement therapy and, 1821–1822 factor VIII replacement for, 1820–1821 factor IX replacement for, 1821 for musculoskeletal complications of hemophilia, 1822–1823 Hemorrhage(s) alveolar diffuse, in microscopic polyangiitis, 1443 in systemic lupus erythematosus, 1292 of muscle and soft tissue, in hemophilia, 1818 pulmonary, in systemic lupus erythematosus, 1277 splinter, in immune complex-mediated vasculitis, 1466, 1467f Hemosiderin, 1810t Hemostasis, platelets and, 251, 251f

xxii

Index

Henoch-Schönlein purpura, 695, 1468–1470, 1470t in children, 1693–1695 definition of, 1693 clinical features of, 1694 criteria for, 1693, 1694f diagnosis of, 1694 outcome of, 1695 treatment of, 1694–1696 epidemiology of, 1405t monarticular arthritis associated with, 541 Heparin for antiphospholipid syndrome, in pregnancy, 1290, 1308 as mast cell mediator, 239 Hepatic disease. See also specific disorders. cyclophosphamide in, 910 in polyarteritis nodosa, 1455 in systemic lupus erythematosus, 1279 in systemic sclerosis, 1332 Hepatitis autoimmune, 261t in Sjögren’s syndrome, 1155 lupoid, 1279 Hepatitis B arthritis, 1766–1767 clinical features of, 1766–1767 diagnosis of, 1767 epidemiology of, 1766 pathogenesis of, 1767 Hepatitis B vasculitis, 1458 Hepatitis C, in Sjögren’s syndrome, 1155 Hepatitis C arthritis, 1767 Hepatotoxicity of leflunomide, 892–893 of methotrexate, 888t of nonsteroidal anti-inflammatory drugs, 847t, 852 Hepcidin, 1810t HERA trial, 1134, 1135 Hereditary hemochromatosis, 1809–1813, 1810t clinical features of, 1811–1812 articular, 1812 extra-articular, 1811 epidemiology of, 1810–1811 genetics of, 1810, 1810t investigations in, 1812 management of, 1813 normal iron metabolism and, 1809 pathogenesis of, 1811 prognosis of, 1813 screening for, 1812, 1813f Hereditary osteodystrophy, Albright’s, 1835 Hereditary osteonecrosis, osteonecrosis and, 1615t Herpes hominis arthritis, 1768 Herpes simplex virus Behçet’s disease and, 1476 rheumatoid arthritis and, 1042 Herpes simplex virus arthritis, 1768 Herpes zoster infection, reactivation of, pain generation with, 975 Heterogeneous nuclear ribonucleoprotein-A2, autoimmunity to, rheumatoid arthritis and, 1046 Heterozygosity, definition of, 309t Heterozygote, definition of, 309t HFE protein, 1810t HHC. See Hereditary hemochromatosis. Hidradenitis, eccrine, neutrophilic, 227 HIDS. See Hyper-IgD syndrome. HIF-1α, chondrocytes and, 43 High endothelial venules, 712, 712f High mobility group box chromosomal protein, in rheumatoid diseases, 375t High-intensity exercise, in physical medicine and rehabilitation, 1028

Highly active antiretroviral therapy, immune reconstitution syndrome related to, 1757 Hindfoot fusion, 648 Hip(s) abduction of measurement for, 525 testing of, 526 in ankylosing spondylitis, 1175 imaging of, 814, 815f anterior, pain in, 526 arthrocentesis technique for, 732–733, 733f congenital disease of, examination for, 525 contractures of, 524 degenerative disease of, sports-related, 496–497 examination of, 524–526 extension of measurement for, 525 testing of, 526 flexion deformity of, 524 fractures of, costs of, 448 in juvenile chronic arthritis, imaging of, 788 monarticular and periarticular syndromes affecting, 536t osteoarthritis in, 1551t, 1556–1557, 1557f imaging of, 795 rheumatoid arthritis of, 1095, 1095f imaging of, 785, 785f swelling around, 525 Hip arthroplasty, total, for osteonecrosis, 1622–1623 Hip Disability and Osteoarthritis Outcome Score, 1554 Hip pain, 636–641 arthrography for, 640 differential diagnosis of, 641 history taking in, 636–637 imaging in, 639–640 computed tomography for, 640 magnetic resonance imaging for, 640, 641f radiography for, 639, 639f, 640f scintigraphy for, 640, 641f physical examination in, 637–639, 638f, 639f Histamine, as mast cell mediator, 239 Histone, in inflammatory muscle diseases, 750t Histoplasmosis, 1743 History taking, 515–517 fatigue and, 517 limitation of motion and, 516 pain and, 515–516 stiffness and, 516 swelling and, 516 weakness and, 516–517 HIV. See Human immunodeficiency virus infection. HIV myopathy, differential diagnosis of, 1371t, 1373 HLA. See Human leukocyte antigen. HMGB1. See High mobility group box chromosomal protein. HOA. See Hypertrophic osteoarthropathy. Hoffa’s disease, 1888 Hoffmann’s sign, in neck pain, 582 Home-based exercise, in physical medicine and rehabilitation, 1027 Homeostatic proliferation, of T lymphocytes, 160 Homing, of B cells, 185 Homing receptors, T cells and, 159–160 Homocystinuria, Marfan syndrome vs., 1651 Homotypic aggregation, of neutrophils, 219 Honda sign, 820 HOOS. See Hip Disability and Osteoarthritis Outcome Score. Horizontal adduction test, 590, 592f

Hormone(s). See also specific hormones. muscle adaptation and, 104 steroid, as rheumatic disease triggers, 269 Hormone therapy, for rheumatic disease, 1837 Howship’s lacunae, 73, 74f HP. See Hydroxylysylpyridinoline. HPETE. See Hydroxyperoxy-eicosatetraenoic acid. HPRT. See Hypoxanthine phosphoribosyltransferase deficiency. H2-receptor blockers, for ulcer prevention, 855 HSP. See Henoch-Schönlein purpura. HSV. See Herpes simplex virus. HTLV-1. See Human T-cell leukemia virus type 1. Human Genome Project, 314 Human immunodeficiency virus infection, 1747–1758, 1748f, 1748t arthritis in, polyarticular, 547 bone and joint disease associated with, 1747–1750 arthralgia as, 1747, 1748t arthritis as, 1747–1749, 1749t avascular necrosis of bone as, 1750 hypertrophic pulmonary osteoarthropathy as, 1750 osteopenia as, 1750 osteoporosis as, 1750 painful articular syndrome as, 1747 psoriatic arthritis as, 1750, 1751f reactive arthritis as, 1749–1750, 1749f undifferentiated spondyloarthritis as, 1750 diffuse infiltrative lymphocytosis syndrome associated with, 1752–1754, 1753f, 1753t, 1754f, 1754t after factor replacement therapy, 1821–1822 laboratory abnormalities associated with, 1757 muscle disease associated with, 1751–1752 fibromyalgia as, 1751 inclusion body myositis as, 1752 myalgia as, 1751 myopathy associated with treatment and, 1752 nemaline myopathy as, 1751 noninflammatory necrotizing myopathy as, 1751 polymyositis as, 1751, 1751f, 1752t rhabdomyolysis as, 1752 wasting syndrome as, 1751 musculoskeletal infections associated with, 1755–1757 reaction of rheumatic diseases to, 1757 rheumatoid arthritis vs., 1109 treatment of highly active antiretroviral therapyrelated immune reconstitution syndrome and, 1757 rheumatic complications of, 1757 vasculitis associated with, 1754–1755 Human leukocyte antigen ankylosing spondylitis and, 1172–1173 antigen-specific T cell recognition and, 305 class I molecules of, 305–306, 306–307, 306f, 307f class II molecules, diffuse connective tissue diseases and, 1384 HLA-B27 ankylosing spondylitis and, 1172 enteric reactive arthritis and, 1226 in polyarthritis, 546t spondyloarthropathies and, 310–311 uveitis and, 678–679 HLA-B51 Behçet’s disease and, 1475 vasculitis and, 1406 HLA-C3, vasculitis and, 1406

index Human leukocyte antigen (Continued) HLA-DQ, as dendritic cell maturation marker, 141t HLA-DQ2/HLADQ8, celiac disease and, 1227 HLA-DR as dendritic cell maturation marker, 141t susceptibility to and severity of rheumatoid arthritis and, 1037–1038, 1037t HLA-DR17, in sarcoidosis, 1797 HLA-DRB1, vasculitis and, 1406 linkage disequilibrium of, 309–310 myositis and, 1354 polymorphic nature of, 308–309, 309t rheumatoid disease associations with, 310–314 alternatives to case-control method for detecting, 313–314, 313f autoimmune diseases and, 311, 312–313 multiple-risk genes and, 314 population association studies of, 310, 310t, 311t, 313 rheumatoid arthritis and, 311–312, 312f, 312t spondyloarthropathies and, 310–311 in Sjögren’s syndrome, 1149–1150 Human T-cell leukemia virus type 1 arthritis induced by, 1767–1768, 1768f HTLV-induced arthritis, animal models of, 398t, 403 infection by, Sjögren’s syndrome vs., 1158 myositis associated with, differential ­diagnosis of, 1373 Humoral autoimmunity, systemic sclerosis pathogenesis and, 1323 Humoral immune response, myositis and, 1356, 1356t HUVS. See Hypocomplementemic urticarial vasculitis syndrome. Hyalgan, for injection, 725t Hyaluronan, as biomarker, 477t, 480 Hyaluronic acid in aged cartilage, 58 in cartilage, 40t for injection, 725t lubrication and, 30 in osteoarthritis, 1537 in synovial fluid, 14 in synovial macrophages, 24 in synovial vascular endothelial lining cells, 28, 29f Hyaluronic acid derivatives injection of, 724 for osteoarthritis, 1568–1569 Hydrarthrosis, intermittent, rheumatoid arthritis vs., 1110 Hydrocodone, for chronic pain, 985 Hydrocortisone effects on hypothalamic-pituitary-adrenal axis, 869–870 for injection, 725t preoperative, 873, 873t Hydromorphone, for chronic pain, 985 Hydroxyapatite in bone matrix, 79–80 bone mineralization and, 80 Hydroxychloroquine. See also Antimalarials. actions of, 897–898 for calcium pyrophosphate dihydrate ­deposition disease, 1520 chemical structure of, 897, 897f for reactive arthritis, in HIV infection, 1750 for rheumatoid arthritis, 1120–1121 special considerations with, 888t for systemic lupus erythematosus, 1281 in children, 1680

Hydroxylysylpyridinoline, 479 Hydroxyperoxy-eicosatetraenoic acid, 348–349 Hypercytokine syndrome, rheumatoid arthritis vs., 1109 Hypereosinophilic syndrome, 1447 idiopathic, 230 Hyperflexion test, for meniscal injury, 529 Hyper-IgD syndrome, 1864t, 1868–1871 clinical features of, 1869–1870, 1870f diagnosis of, 1870–1871, 1871t epidemiology of, 1868 etiology of, 1869, 1869f outcome of, 1871 pathogenesis of, 1869 prognosis of, 1871 treatment of, 1871 Hyper-IgE syndrome, 224t Hyperinsulinemia, diffuse idiopathic skeletal hyperostosis and, 1602 Hyperlipoproteinemia, rheumatoid arthritis vs., 1109 Hyperparathyroidism, 1834–1835 Hypersensitivity reactions with azathioprine, 916 with cyclophosphamide, 913 Hypersensitivity vasculitis, 1404, 1405, 1465, 1468, 1469t skin lesions in, 695 Hypertension coxibs and, 850, 851 with cyclosporine, 918 in gout, 1502–1503 with leflunomide, 893 nonsteroidal anti-inflammatory drugs and, 850, 851 in polyarteritis nodosa, 1454 pulmonary. See Pulmonary hypertension. Hyperthyroidism, 1835 osteoporosis associated with, 1583 Hypertriglyceridemia, in gout, 1485 Hypertrophic osteoarthropathy, 1606–1608 clinical manifestations of, 1607, 1608f etiology of, 1607, 1607t pathogenesis of, 1607 rheumatoid arthritis vs., 1109 treatment of, 1607–1608 Hyperuricemia, 1481–1503. See also Gout. asymptomatic, 1482 treatment of, 1498 classification and pathogenesis of, 1493–1497, 1493t acute gout attacks and, 1496–1497 primary gout and, 1493, 1494f secondary gout and, 1494–1496, 1494f–1496f tophaceous gout and, 1497 clinical features of, 1482–1484 in acute gouty arthritis, 1482–1483, 1483t in asymptomatic hyperuricemia, 1482 in chronic gouty arthritis, 1483–1484, 1484f–1486f in intercritical gout, 1483 conditions associated with, 1485–1486 control of, 1499–1502, 1500t environmental factors in, 1482 epidemiology of, 1481–1482 physical properties of uric acid and, 1492–1493 purine metabolism and, 1489–1491, 1489f, 1490f uric acid elimination and excretion and, 1491–1492, 1491f, 1492t Hypochondriasis, 977, 978t Hypocomplementemic urticarial vasculitis syndrome, 695, 1471 Hypophosphatasia, calcium pyrophosphate dihydrate deposition disease secondary to, 1510

xxiii

Hypothalamic-pituitary-adrenal axis, ­glucocorticoid effects on, 869–870, 877 Hypothesis testing, 458–459 Hypothyroidism, 1835–1836 in gouty arthritis, 1486 polyarthritis secondary to, 551 Hypoxanthine phosphoribosyltransferase deficiency, 1494–1495, 1494f Hypoxia, myositis and, 1359–1360 Hysteria, 977 limitation of mandibular movement in, 666t

I

IAPs. See Intracellular inhibitors of apoptosis. Ibandronate, for osteoporosis, 1588 IBD. See Inflammatory bowel disease. IBM. See Inclusion body myositis. IBP. See Interferon regulatory factor-4 binding protein. Ibuprofen, 842t adverse effects of, 849, 850 for juvenile idiopathic arthritis, 1664t time dependence and, 840 IC(s). See Immune complex(es). ICC. See Interclass correlation coefficient. ICF. See International Classification of ­Functioning, Disability and Health. ICIP. See Cross-linked carboxyterminal ­telopeptide. Idiopathic hypereosinophilic syndrome, 230 with arthritis, rheumatoid arthritis vs., 1109–1110 Idiopathic thrombocytopenic purpura as autoimmune disease, 261t platelets in, 253 IDOX. See 4'-Iodo-4'-deoxydoxorubicin. IELs. See Intestinal intraepithelial lymphocytes. IgA. See Immunoglobulin(s), IgA. Igbo-ora virus arthritis, 1764–1765, 1764t IgD. See Immunoglobulin(s), IgD. IgE. See Immunoglobulin(s), IgE. IGF-1. See Insulin-like growth factor-1. IGFBP(s). See Insulin-like growth factor ­binding protein(s). IgG. See Immunoglobulin(s), IgG. IgM. See Immunoglobulin(s), IgM. Ihh. See Indian hedgehog. IKKΣ, in rheumatoid arthritis, 1069–1070 IL-1Ra. See Interleukin-1 receptor antagonist. IL-1 Trap, 941–942 IL-23 receptor, Crohn’s disease and, 318 Iliotibial band, 525 ILLs. See Innate-like lymphocytes. IMACS, in myositis, 1376, 1376t Imaging, 777–825. See also specific imaging modalities and under specific conditions. Imipenem, for bacterial arthritis, 1708t Imipramine, for chronic pain, 988, 989t Immune adherence, 324 Immune cells, apoptosis of, defective, 388 Immune complex(es) Arthus reaction and, 1465 complement system clearance of, 330 mast cell activation and, 237–238 in synovial fluid, in rheumatoid arthritis, 1055–1056 in systemic lupus erythematosus, 1236, 1236t correlation with clinical manifestations, autoantibodies, and T cells, 1252, 1252t inadequate clearing of, 1251 in vasculitis, 1403 Immune complex arthritis animal models of, 397, 398t, 399t, 404–406 passive, animal models of, 406

xxiv

Index

Immune recognition, 142–144 complement receptors and, 143, 147t Fc receptors and, 143–144, 148f NOD-like receptors and, 144 non-toll-like receptors and, 143, 143f, 144f, 145t, 146f, 147f toll-like receptors and, 142–143, 142f Immune regulation, Fas and FasL in, 383–384 Immune response(s) adaptive, mast cells and, 241 to Borrelia burgdorferi, 1716 eicosanoid regulation of, 354 innate naive vs. memory T cells in, 166–167, 167t natural killer cells in, 166 τδ T cells in, 165–166 Th17 T cells in, 170 Th1 vs. Th2 T cells in, 167, 168t–169t, 170 ocular, 677–678 of peripheral blood lymphocytes, in synovial fluid, in rheumatoid arthritis, 1057–1058 suppression of, by T lymphocytes, 164–165 Immune system glucocorticoid effects on, 868, 868t, 875–876 nonsteroidal anti-inflammatory drug effects on, 852–853 Immune tolerance peripheral, 261 induction under steady-state conditions, 298 in systemic lupus erythematosus, 1250–1251 Immunity. See Adaptive immunity; Autoimmunity; Innate immunity; ­Rheumatoid arthritis, immunity in ­etiology and pathogenesis of. Immunizations, in systemic lupus ­erythematosus, 1288 Immunoadsorption, for polyarteritis nodosa, 1456t Immunodiffusion, for antinuclear antibody detection, 746 Immunofluorescence assay, for complement activation, 330t Immunoglobulin(s), 177–181. See also ­Intravenous immunoglobulin. α, as B cell maturation marker, 183t angiogenesis and, 358–359, 359t β, as B cell maturation marker, 183t complementarity-determining regions of, 177 constant region of, 179–180, 179t heavy chains of, 177, 178–180, 179t IgA properties of, 179, 179t surface, as antigen-activated B cell marker, 191t IgD properties of, 179t, 180 surface, as antigen-activated B cell marker, 191t surface, as B cell maturation marker, 183t IgE mast cell activation and, 237, 238f properties of, 179–180, 179t surface, as antigen-activated B cell marker, 191t IgG mast cell activation and, 237–238 properties of, 178–179, 179t surface, as antigen-activated B cell marker, 191t

Immunoglobulin(s) (Continued) IgM properties of, 178, 179t surface, as antigen-activated B cell marker, 191t surface, as B cell maturation marker, 183t light chains of, 177, 180 structure of, 177 synthesis of, 177, 178f variable region of, 180–181 diversity of, 180–181 gene rearrangement in, 180, 181f Immunoglobulin binding protein, in ­rheumatoid arthritis, 761 Immunologic synapse, 163–164, 163f Immunologic tolerance, 259 Immunomodulatory drugs. See also specific drugs. apoptosis and, 390–391 malignancy associated with, 1854–1856, 1855t for systemic sclerosis, 1329t, 1339 Immunoreceptor tyrosine-based activation motifs B cell activation and, 186, 186f, 187 T lymphocyte activation and, 160, 161 Immunoregulation, abnormalities in, in systemic lupus erythematosus, 1246t, 1250–1252 Immunosuppressive agents, for systemic lupus erythematosus, 1281, 1283, 1284t, 1285–1286, 1286t, 1287f in children, 1680 IMPACT 1. See Infliximab Multinational ­Psoriatic Arthritis Controlled Trial 1. IMPACT 2. See Infliximab Multinational ­Psoriatic Arthritis Controlled Trial 2. Impingement sign, 590, 592f, 600, 600f Impingement syndrome imaging in, 823–825, 825f shoulder pain and, 599–600, 600f Impingement test, 592–593 Impotence, in systemic sclerosis, 1318 Incidence, in epidemiology, 433–434, 434f Inclusion body myositis, 1353, 1364, 1364f HIV-associated, 1752 Incomplete data, in clinical trials, 459–460 Indian hedgehog, growth plate development and, 6 Indomethacin, 840, 842t for gouty arthritis, 1499 for juvenile idiopathic arthritis, 1664t Infection(s). See also specific infections. with arthrodesis, 726, 726t atypical, skin lesions caused by, 697 with azathioprine, 916 Behçet’s disease and, 1476 with chlorambucil, 914 with cyclophosphamide, 912 in hand, 660–661 with joint injection, 726, 726t lymph node changes during, 298–299 neck pain and, 575, 584 nonodontogenic, limitation of mandibular movement in, 666t odontogenic, limitation of mandibular movement in, 666t as rheumatic disease triggers, 269 in rheumatoid arthritis, 1100 rheumatoid arthritis and, 1040–1043 bacteria and, 1041–1042, 1041f toll-like receptors and inflammasome in joint and, 1040–1041 viruses and, 1042–1043 rheumatoid arthritis vs., 1110 soft tissue, differential diagnosis of, 536

Infection(s) (Continued) susceptibility to, in hemochromatosis, 1811 in systemic lupus erythematosus, 1276t life-threatening, 1292 prevention of, 1287–1288 with tumor necrosis factor inhibitors, 1129 Infectious arthritis, 537, 539–540. See also ­Bacterial arthritis; Septic ­arthritis. HIV-associated, 540 Lyme, 540, 541 of temporomandibular joint, 669 differential diagnosis of, 667t Infectious spondylitis imaging of computed tomography for, 816 magnetic resonance imaging for, 816–817 scintigraphy for, 816 tuberculous, imaging of, 816, 816f Inflammasome, 369 rheumatoid arthritis and, 1040–1041 Inflammation acute, cytokines in, 371 in ankylosing spondylitis, 1175 anti-inflammatory diet and, 503–506 evidence for, 504–505 obesity and inflammation and, 505–506 recommendations for, 506, 506t chronic cytokines in, 371–376 T cell effector function in, 371–373, 372t tertiary lymphoid tissues generated at sites of, 299–300 complement activation and, models of, 333–335 crystal-induced, 1512–1513 endocardial, in rheumatoid arthritis, 1103–1104 in general population, 422, 423f metabolic response to, 1009 microvascular dysfunction mediated by, myocardial ischemia in rheumatoid arthritis caused by, 426 neurogenic, mast cells and, 241 neurological regulation of, 411–416 axon reflex and, 413, 415f clinical significance of, 416 dorsal root reflex and, 414–415, 415f, 416f future research directions for, 417 glutamate and, 413, 414f neuropeptides and, 412–413, 412f primary afferent fibers and, 411–412 signal transduction and, 413 sympathetic nervous system and, 415–416 unresolved issues in, 416 nonallergic, mast cells in, 240–241 obesity and, 505–506 resolution of, cyclooxygenase-2 mediated, 836–837, 837f systemic sclerosis pathogenesis and, 1321–1324 T cells at sites of, 171 vascular endothelium in, morphology and function of, 357 Inflammatory arthritis animal models of, 408 of antigen-induced arthritis, 401–402 autoimmunity to cartilage components in, 399–400 cartilage and bone destruction and, 407–408, 408f cytokines as targets in susceptibility and destruction and, 406–408 flare, 402, 403f immune complex, 398t, 399 of immune complex arthritis, 405–406 induced, 397–398, 398t

index Inflammatory arthritis (Continued) infectious agents and exogenous triggers in, 400–401 regulation of arthritis susceptibility and, 407, 407f response to nonspecific immunologic stimuli in, 399 transgenic, 398–399, 399t, 403–404 of hip, 637 juvenile, sulfasalazine for, 896 shoulder pain due to, 605, 606f therapeutic injection in, 722–723, 722t wrist pain in, 656 Inflammatory bowel disease, 1220, 1222–1225. See also Crohn’s disease; ­Ulcerative colitis. antineutrophil cytoplasmic antibodies and, 1431 arthritis associated with, sulfasalazine for, 896 causes of, 1222–1223, 1223f clinical features of, 1224, 1224t, 1225f diagnosis of, 1224 epidemiology of, 1220, 1222, 1222t imaging in, 791 outcome in, 1225 pathogenesis of, 1223 treatment of, 1224–1225 uveitis in, 679 Inflammatory cells interactions with fibroblast-like synoviocytes, in rheumatoid arthritis, 209–210 in Sjögren’s syndrome, trafficking and ­adhesion of, 1151 Inflammatory muscle diseases, 1353–1376. See also Dermatomyositis; Inclusion body myositis; Myositis; Polymyositis. antinuclear antibodies in, 749–750, 750t myositis overlap autoantibodies and, 750 myositis-specific autoantibodies and, 749–750 cause of, 1354–1355 classification of, 1365 clinical features of, 1360–1365 in dermatomyositis, 1360–1364 in inclusion body myositis, 1364, 1364f in malignancy-associated myositis, 1365 in polymyositis, 1360–1364 diagnostic criteria for, 1365, 1365t–1367t differential diagnosis of, 1370, 1371t–1372t, 1372–1374 drug-induced myopathies and, 1373 dystrophic myopathies and, 1369–1370, 1371t endocrine myopathies and, 1371t, 1373 infectious myopathies and, 1371t, 1373 metabolic myopathies and, 1371t, 1372–1373 mitochondrial myopathies and, 1371t, 1373 neuromuscular disorders and, 1372, 1372t parasitic myopathies and, 1373 electromyography in, 1369–1370 epidemiology of, 1353–1354, 1354t future directions for, 1377 historical background of, 1353 imaging in, 1369 of lungs, 1369 of muscles, 1369, 1370f laboratory evaluations in, 1366–1369 biochemical, 1366–1367 histologic, 1368, 1369t immunologic, 1367, 1368t molecular, 1368–1369 lung function tests in, 1370

Inflammatory muscle diseases (Continued) management of, 1374–1376, 1375f assessment of disease activity and outcome and, 1375–1376, 1376t nonpharmacologic, 1375 pharmacologic, 1374–1375 pathogenesis of, 1355–1360 cell-mediated immune response and, 1356–1358, 1357f, 1358f cytokines and, 1359–1360 humoral immune response and, 1356, 1356t hypoxia and, 1359–1360 mechanisms of muscle damage and, 1360, 1360f MHC class I molecules and, 1358–1359, 1359f physical examination in, 1365–1366 risk factors for environmental, 1354–1355, 1354t genetic, 1354 Inflammatory myopathy apoptosis in, 390 methotrexate for, 887 Inflammatory response eicosanoid regulation of, 354 mast cells and, 347 platelets in, 252–253, 252t Infliximab, 930–934, 1128–1129. See also ­Tumor necrosis factor inhibitors, TNF-α. for ankylosing spondylitis, 1183–1184, 1185t apoptosis and, 391 chemokine production and, 363 clinical trials with, 930, 930t dose for, 931 efficacy of, 931–934 for inflammatory bowel disease, 1225 pharmacokinetics of, 931 for psoriatic arthritis, 1216 structure of, 930, 933f Infliximab Multinational Psoriatic Arthritis Controlled Trial 1, 933 Infliximab Multinational Psoriatic Arthritis Controlled Trial 2, 933–934 Influenza vaccine, in systemic lupus ­erythematosus, 1288 Informed consent, for clinical trials, 455 Inhibitor antibodies, after factor replacement therapy, 1821 Injections, therapeutic. See Therapeutic ­injection. Innate cell lineages, in chronic inflammation, 376 Innate immunity, 277–287, 278t adaptive immunity compared with, 277, 278t cell types mediating, 284–285 antimicrobial peptides as, 285 innate-like lymphocytes as, 284 complement system in, 329, 329f, 329t disease associations involving, 286–287 effector mechanisms of, 284 evolutionary origins of, 277–278, 279f influence on adaptive immunity, 285–286, 285f mast cells as sentinels of, 240–241 pathogen recognition and, 278–284 pathogen-associated molecular patterns and, 278 pattern-recognition receptors and, 278–284, 280t Innate-like lymphocytes, 284 Innervation in developing joint, 7 of mature diarthrodial joints, 10–11 Insomnia, pain and, 979

xxv

Instability examination for, 518 in rheumatoid arthritis, 783 Instrumentalists, musculoskeletal disorders in, 497, 498t–499t Insulin, muscle adaptation and, 104 Insulin-like growth factor-1 in cartilage metabolism, 48–49 muscle adaptation and, 104 Insulin-like growth factor binding protein(s) in cartilage metabolism, 49 fibrosis and, in systemic sclerosis, 1327 Integrin(s) angiogenesis and, 358, 359t β1, in synovial macrophages, 25 β3, in synovial macrophages, 25 in cartilage, 40t chondrocyte interactions with, 47 fibroblast attachment o extracellular matrix and, 201–202, 202f, 203f neutrophil adhesion and, 220, 220f in rheumatoid arthritis, fibroblast-like ­synoviocyte attachment to cartilage and, 207–208 T cell extravasation and, 292–293 Integrin-associated protein, neutrophil ­diapedesis and, 220–221 Integrin-deficient congenital muscular ­dystrophy, 102t Intention to treat, 459 Intercellular adhesion molecule(s), 357–359, 359t cartilage angiogenesis and, 48 ICAM-1 angiogenesis and, 359, 359t regulation of, in rheumatoid arthritis, 1073–1074 in synovial lining, 9–10 N-CAM, condensation and, 5 neutrophil adhesion and, 220 PECAM-1, angiogenesis and, 359, 359t in synovial macrophages, 24 VCAM-1 angiogenesis and, 358, 359t fibroblast-like synoviocyte attachment to cartilage and, in rheumatoid arthritis, 208 regulation of, in rheumatoid arthritis, 1074 in synovial lining, 9–10 in synovial macrophages, 24 Interclass correlation coefficient, 469 Interferon(s) IFN-α, for polyarteritis nodosa, 1456t IFN-α/β, in rheumatoid diseases, 375t IFN-γ in chronic inflammation, 372 fibrosis and, in systemic sclerosis, 1327 production by Th1 cells, 167 in psoriasis, 1212 in rheumatoid diseases, 371t T cell-derived, 169t type 1, in systemic lupus erythematosus, 1240 Interferon regulatory factor-4 binding protein, B cell activation and, 194 Interferon regulatory factor-5 systemic lupus erythematosus susceptibility associated with, 318 type 1, 1240 Interferon-γ release assays, for tuberculosis ­diagnosis, 1735 INTERHEART study, 773 Interleukin(s) IL-1, 940–942. See also Anakinra; IL-1 Trap. in cartilage degradation, 53, 54

xxvi

Index

Interleukin(s) (Continued) in cartilage destruction, 55 cartilage metabolism and, 57, 57f neutrophil functions and, 228 neutrophil production of, 223 in osteoarthritis, 1531, 1531f in rheumatoid arthritis, 208, 1061 in rheumatoid diseases, 370t IL-1α, T cell-derived, 168t IL-1β in osteoarthritis, 1535 in psoriasis, 1212 in rheumatoid arthritis, interaction of fibroblasts and T cells and, 210 IL-2 production by Th1 cells, 167 in psoriasis, 1212 in rheumatoid diseases, 371t T cell-derived, 168t T lymphocyte activation and, 162 IL-3, T cell-derived, 168t IL-4 fibrosis and, in systemic sclerosis, 1326 as inhibitory cytokine, 55 production by Th2 cells, 167 in rheumatoid diseases, 371t T cell-derived, 168t IL-5 eosinophil development and, 228 production by Th2 cells, 167 in rheumatoid diseases, 371t T cell-derived, 168t IL-6, 373t in cartilage destruction, 54–55 fibrosis and, in systemic sclerosis, 1326 in juvenile idiopathic arthritis, 1660 osteoporosis and, 1580 production by Th2 cells, 167 in rheumatoid arthritis, 1062–1063 T cell-derived, 168t IL-7 autoimmunity and, 272 in rheumatoid arthritis, interaction of fibroblasts and T cells and, 210 IL-8 in rheumatoid arthritis, interaction of fibroblasts and T cells and, 210 T cell-derived, 168t IL-9, T cell-derived, 168t IL-10 as inhibitory cytokine, 55 in juvenile idiopathic arthritis, 1660 production by Th2 cells, 167 in rheumatoid arthritis, 1065, 1065f in systemic lupus erythematosus, 1239 T cell regulation by, 372t T cell-derived, 168t IL-12 in rheumatoid arthritis, 1063 T cell regulation by, 372t T cell-derived, 169t IL-13 fibrosis and, in systemic sclerosis, 1326 as inhibitory cytokine, 55 production by Th2 cells, 167 T cell-derived, 169t IL-14, T cell-derived, 169t IL-15 interaction of fibroblasts and T cells and, 210 in rheumatoid arthritis, 210, 1063 T cell regulation by, 372t T cell-derived, 169t IL-16, in rheumatoid arthritis, interaction of fibroblasts and T cells and, 210

Interleukin(s) (Continued) IL-17 in cartilage degradation, 53–54, 54t in cartilage destruction, 55 in chronic inflammation, 372 in rheumatoid arthritis, 209 in rheumatoid diseases, 371t IL-18 in cartilage degradation, 54, 54t in cartilage destruction, 55 in rheumatoid arthritis, 1062 IL-19, T cell regulation by, 372t IL-20, T cell regulation by, 372t IL-21, T cell regulation by, 372t IL-22, T cell regulation by, 372t IL-23, T cell regulation by, 372t IL-24, T cell regulation by, 372t IL-32, in rheumatoid arthritis, 1063 IL-32α-β, in rheumatoid diseases, 375t Interleukin-1 receptor antagonist, 1130 as inhibitory cytokine, 55 in rheumatoid arthritis, 1065, 1065f Interleukin-1 receptor antagonist arthritis, animal models of, 398t, 400t Interleukin-1 transgenic arthritis, animal models of, 398, 398t, 404, 405f Intermittent claudication, in giant cell arteritis, 1414 Intermittent hydrarthrosis, rheumatoid arthritis vs., 1110 Internal validity, 453 International Classification of Functioning, Disability and Health, 467, 467f activities and participation and, 1030–1031 body functions and structures and, 1026–1028 contextual factors and, 1031 goal of, 1023–1024, 1023–1031, 1024f orthotics and, 1029 physical modalities and, 1028–1029 role in rehabilitation in rheumatic diseases, 1024–1025, 1025f role of assessments in rehabilitation cycle, 1025 work capacity assessment and, 1025–1026 International Skeletal Dysplasia Registry, 1640 International Study Group criteria, for Behçet’s disease, 1477, 1478t Interosseous nerve, posterior, testing of, in neck pain, 580t Interphalangeal joints arthrocentesis technique for, 731–732 examination of, 522–524, 523f Intersection syndrome, 658 Interstitial fluid proteins, responses to monosodium urate crystals and, 1497 Interstitial lamellae, 83 Interstitial lung disease management of, 1335 in systemic lupus erythematosus, 1276–1277, 1276t in systemic sclerosis, 1317, 1317f, 1334–1335 Interstitial pneumonitis, in rheumatoid ­arthritis, 1102–1103 Intervertebral discs cervical, 573 development of, 8 Intestinal intraepithelial lymphocytes, 159 Intracellular inhibitors of apoptosis, 385 Intracellular kinases, B cell activation and, 187 Intracellular structural proteins, defects in, 1643 Intraspinous ligament, 573 Intrauterine growth restriction, in systemic lupus erythematosus, 1289 Intravascular coagulation, osteonecrosis and, 1615t

Intravenous gamma globulin for polyarteritis nodosa, 1456t for systemic lupus erythematosus, 1286 Intravenous immunoglobulin for Kawasaki disease, in children, 1693 for neurologic disorders, in Sjögren’s ­syndrome, 1162 for Wegener’s granulomatosis, 1441–1442 4'-Iodo-4'-deoxydoxorubicin, for AM ­amyloidosis, 1790 IREZ therapy, for tuberculosis, 1735 IRF5. See Interferon regulatory factor-5. Iridocyclitis, in ankylosing spondylitis, 1176 Iron metabolism of, normal, 1809 in nutrition, 1013 Iron exporter proteins, 1810t Iron overload, 1809–1810. See also ­Hemochromatosis; Hereditary ­hemochromatosis. with blood transfusions, 1829 Iron regulatory proteins, 1810t IRT. See Item response theory. Ischemia, digital, critical, in systemic sclerosis, 1331 Ischemic ulceration, in systemic sclerosis, 1328, 1329f Ischiogluteal bursitis, arthrocentesis technique for, 732 Isernhagen Work System, 1026 Isoeicosanoids actions of, 351, 352f production of, 351 Isoflavones, 506t in anti-inflammatory diet, 504 Isoniazid, for tuberculosis, 1735 Isoprostanes actions of, 352 production of, 352 ITAMs. See Immunoreceptor tyrosine-based activation motifs. Item response theory, 471 ITP. See Idiopathic thrombocytopenic ­purpura. ITT. See Intention to treat. IVIG. See Intravenous immunoglobulin. Ivory phalanx, in psoriatic arthritis, 790–791

J

J sign, in patellofemoral pain, 633 Jaccoud’s arthritis, 1269 JAK proteins, signal transduction and, 339 JAK/STAT signaling pathway, cartilage ­metabolism and, 57 Jaw, monarticular and periarticular syndromes affecting, 536t JDM. See Dermatomyositis, juvenile. JIA. See Juvenile idiopathic arthritis. JNKs, cartilage metabolism and, 57, 58 Joint(s). See also specific joints. cartilaginous, 107 Charcot’s. See Neuropathic arthropathy. classification of, 1–2, 2f by connective tissues present, 1 histologic, 1, 2f by shape, 1 definition of, 107 deformity of, osteoarthritis and, 1552 destruction of proteinases and, 128–131 in rheumatoid arthritis, proteases and, 1075–1077 diarthrodial. See Diarthrodial joints. fibrous, 107 function of, synovial fluid as indicator of, 15

index Joint(s) (Continued) injection of. See Therapeutic injection. injury of, osteoarthritis and, 1528, 1552 malalignment of, osteoarthritis and, 1528 in mixed connective tissue disease, 1390, 1391f movement of, as synovial function, 28–30 nonarticular, development of, 7–8 in osteoarthritis, 1526 pain in, mechanisms of, 11 prosthetic infections of, 1707–1711, 1710f prevention of, 1710–1711 repetitive loading of, osteoarthritis and, 1552 in sarcoidosis, 1800 synovial, 1, 2f in systemic sclerosis, 1332 Joint biomechanics, 107–113 anatomy and, 107–108 at cellular level, 111–112 cellular loads and deformations and, 111–112 joint pathology and, 112 importance to rheumatologists, 112–113 joint motion and, 108–109, 108f, 109f loads and, 109–110, 109f, 110f at tissue level, 110–111, 111f, 112f joint tissue degeneration and, 111 Joint capsule, development of, 7 Joint mice, 1885–1886, 1885f, 1886f Joint space abnormalities in juvenile chronic arthritis, imaging of, 786 narrowing as, in rheumatoid arthritis, 783 JRA. See Juvenile rheumatoid arthritis. Juvenile chronic arthritis, imaging in, 786–788, 788t abnormalities in specific sites and, 787–788 general imaging features and, 786–787 Juvenile idiopathic arthritis, 1657–1672 classification of, 1657, 1658t, 1659t clinical features of, 1664–1672 definition of, 1657 enthesitis-related, 1659, 1659t, 1670–1671 clinical manifestations of, 1671 differential diagnosis of, 1671 laboratory features of, 1671 outcome of, 1671 treatment of, 1671 epidemiology of, 1658 etiology of, 1658–1660 environmental factors in, 1660 genetic factors in, 1658–1660 glucocorticoid therapy for, 870t methotrexate for, 887 oligoarthritis as, 1659t, 1666–1668 clinical manifestations of, 1657f, 1667 differential diagnosis of, 1667 laboratory features in, 1667 outcome of, 1668 treatment of, 1667–1668 outcome of, 1666 pathogenesis of, 1660–1661, 1661f polyarthritis as, rheumatoid factor negative, 1659t, 1668–1669 clinical manifestations of, 1668 differential diagnosis of, 1668–1669 laboratory features of, 1668 outcome of, 1669 treatment of, 1669 polyarthritis as, rheumatoid factor positive, 1659t, 1669–1670 clinical manifestations of, 1669 differential diagnosis of, 1669 laboratory features of, 1669

Juvenile idiopathic arthritis (Continued) outcome of, 1670 treatment of, 1669–1670 psoriatic arthritis as, 1659t, 1670 systemic, 1659t, 1664–1666 clinical manifestations of, 1664–1665, 1665f differential diagnosis of, 1666, 1666t laboratory features in, 1665 treatment of, 1666 systemic arthritis as, 1659t, 1664–1666 treatment of, 1661–1664 unclassified, 1671–1672 uveitis in, 680, 680f Juvenile inflammatory arthritis, sulfasalazine for, 896 Juvenile rheumatoid arthritis antinuclear antibodies in, 751 complement activation in, 334 monarticular, 540 nutrition in, 1010 platelet count in, 253 skin lesions in, 688 therapeutic injection in, 723

K

Kallikreins, matrix degradation and, 116t, 117–118 Kallistatin, as proteinase inhibitor, 122, 124t Karelian fever, 1765 Kawasaki disease in children cause and pathogenesis of, 1692 classification criteria for, 1691, 1691t clinical features of, 1692 definition of, 1691 diagnosis of, 1692, 1693f epidemiology of, 1691–1692 outcome of, 1693 treatment of, 1692–1693 epidemiology of, 1405t skin lesions in, 696 uveitis in, 679 Keliximab, 958 Kelley-Seegmiller syndrome, 1494 Keratan sulfate in cartilage, 41 in osteoarthritis, 1529 Keratocan, in cartilage, 41 Keratoderma blennorrhagicum in HIV infection, 1749, 1749f in Reiter’s syndrome, 686, 686f Ketanserin, for systemic sclerosis, 1340 Ketoconazole, drug interactions of, 866 Ketoprofen, 842t Ketorolac, 842t for gouty arthritis, 1499 Kidneys. See Renal entries. Kienböck’s disease, 655–656, 656f Kinetochore, in Sjögren’s syndrome, 751t Kininogens, as proteinase inhibitors, 124t KJ, in inflammatory muscle diseases, 750t Klebsiella pneumoniae infection(s), ankylosing spondylitis and, 1174 Knee(s) adduction moment at, 109, 110f in ankylosing spondylitis, 1175 arthrocentesis technique for, 733–734, 733f bursitis of, 528 catching of, 526 as diarthrodial joint, 107–108 examination of, 526–529, 527f, 528f give-way of, 526 in juvenile chronic arthritis, imaging of, 788, 789f

xxvii

Knee(s) (Continued) ligamentous instability of, 528 ligamentous laxity of, 528–529 locking of, 526, 628 meniscus of, cells of, 12 monarticular and periarticular syndromes affecting, 536t motion of, 109, 109f osteoarthritis of, 1551t, 1555–1556, 1556f imaging of, 795, 796f, 797f in reactive arthritis, imaging of, 791 rheumatoid arthritis of, 1095–1096, 1096f imaging of, 784–785 swelling of, 628 Knee Osteoarthritis Outcome Score, 1554 Knee pain, 627–636 differential diagnosis of, 635–636 history taking in, 627–628 imaging in, 633–635 computed tomography for, 634 conventional radiography for, 633–634, 634f, 635f magnetic resonance imaging for, 635, 636f scintigraphy for, 634–635, 636f ultrasound for, 634 in periarticular syndromes, arthrocentesis technique for, 734 physical examination in, 628–633 general, 628–629, 628f–630f of infrapatellar tendon, 633 of ligaments, 629–631, 630f–632f of menisci, 631–632, 632f with patellofemoral pain, 633, 633f of quadriceps tendon, 632, 633f Koebner’s phenomenon, 685, 1211 KOOS. See Knee Osteoarthritis Outcome Score. Kostmann’s syndrome, 223, 224t KRN arthritis, animal models of, 398, 398t, 403 Ku, in inflammatory muscle diseases, 750t Kwashiorkor, metabolic response to inflammation and, 1009

L

Labral tears, shoulder pain due to, 607 Lachman test, 529 Lacrimal glands, in systemic sclerosis, 1318 Lacrimation, increased, in ankylosing spondylitis, 1176 Lacrosse, osteoarthritis associated with, 495t Lactation anakinra and, 942 antimalarials and, 899 corticosteroids and, 1288 glucocorticoids and, 866 hydroxychloroquine and, 888t leflunomide and, 888t, 893 methotrexate and, 888t, 889 sulfasalazine and, 888t, 897 TNF inhibitors and, 938 Lactoferrin, neutrophils and, 217 LADs. See Leukocyte adhesion deficiencies. Lamellae, interstitial, 83 Laminectomy, decompressive, for low back pain, 622 Laminins in synovial subintimal layer, 27 transmembrane link to, 101, 101f Lamotrigine, for chronic pain, 989 Landscape effect, 1892 Large bowel, in systemic sclerosis, 1331 Large granulocytic lymphocyte syndrome, methotrexate for, 886–887 Laryngotracheal reconstruction, for Wegener’s granulomatosis, 1442

xxviii

Index

Laryngotracheoplasty, for Wegener’s ­granulomatosis, 1442 Larynx, chondritis of, in relapsing ­polychondritis, 1630 Laser therapy, low-level, 508 La/SS-B in Sjögren’s syndrome, 751, 751t in systemic lupus erythematosus, 748 LAT. See Linker for activation of T cells. Launios’ deformity, 791 LBP. See Low back pain. LE. See Lupus erythematosus. Lead intoxication gout and, 1488, 1488t hyperuricemia and, 1488, 1488t Lectins, 145t Leflunomide, 890–893 actions of, 890–891, 891f chemical structure of, 890, 890f contraindications to, 893 dose and administration of, 892 drug interactions of, 893 efficacy of, 895t in geriatric patients, 892 indications for, 892 malignancy associated with, 1856 mechanism of action of, 895t pharmacology of, 891–892 for psoriatic arthritis, 1215 for rheumatoid arthritis, 1122–1123 special considerations with, 888t toxicity of, 892–893, 895t Legg-Calvé-Perthes disease monarticular arthritis associated with, 541 osteonecrosis and, 1615t, 1616 Leg-length discrepancy, measurement for, 525 LEP. See Lupus erythematosus panniculitis. Leptin, in cartilage destruction, 56 Lequesne’s algofunctional index, 1554, 1554t Lesch-Nyhan syndrome, 1494 Leucine zipper proteins, chondrocyte ­differentiation and, 43 Leucine-rich repeats, 142 as pattern-recognition receptors, 281–283 Leukemia, 1852 with chlorambucil, 914 Leukemia inhibitory factor, 373t Leukocyte(s) extravasation into synovium, 357, 358f glucocorticoid effects on, 868, 868t interactions with endothelial cells, ­regulation of, 362 recruitment of, 360 regulation of chemokine production ­during, 362 Leukocyte adhesion deficiencies, 223–224, 224t Leukocytoclastic vasculitis, 226 in children, 1695 cutaneous, 1404, 1405, 1465, 1468, 1469t skin lesions in, 695 Leukocytosis, in Henoch-Schönlein purpura, in children, 1694 Leukopenia with chlorambucil, 914 with sulfasalazine, 896 in systemic lupus erythematosus, 1277–1278 Leukotrienes C4, as mast cell mediator, 239 neutrophil production of, 222 receptors for, 353 Lhermitte’s sign, in neck pain, 582 Lidocaine patch, for chronic pain, 989t Lift-off test, 592

Ligaments, 11–12 of cervical spine, 573, 573f Ligamentum flavum, 573 Light chain, as B cell maturation marker, 183t Light-chain polypeptide, of immunoglobulins, 177, 180 Limb-girdle muscular dystrophy, 102t Limited joint-mobility syndrome, 1833, 1834t Limping, in hip examination, 524 Linezolid, for bacterial arthritis, 1708t Link protein in cartilage, 40t matrix metalloproteinase degradation of, 129 Linkage, definition of, 309t Linkage analysis, 315–316, 316f Linkage disequilibrium definition of, 309t of human leukocyte antigens, 309–310 Linker for activation of T cells, T lymphocyte activation and, 161 Linolenic acid. See Omega-6 fatty acids. Lipids as mast cell mediators, 239 secreted by macrophages, 150t Lipodystrophy, with juvenile dermatomyositis, 1683 Lipoma arborescens, 1887–1888, 1887f imaging in, 823, 824f Lipoprotein receptor-related protein 5, ­osteoporosis and, 1581–1582 Lipoxins actions of, 350–351 neutrophil production of, 222, 223f production of, 350, 351f receptors for, 353–355 nuclear, 353 Lipoxygenase pathways, 348–350, 349f products of, 349–350 Live vaccines contraindication with corticosteroids, 1288 in systemic lupus erythematosus, 1288 Livedo reticularis, in antiphospholipid ­syndrome, 1304, 1304f Liver. See also Hepat- entries. antigen detection by, 296 Localized nodular synovitis, 1895, 1895f, 1896f LOD. See Log of the odds score. Loeys-Dietz syndrome, 1652 Löffler’s syndrome, eosinophils and, 230 Löfgren’s syndrome, 1800 Log of the odds score, 315 Longitudinal ligament anterior, 573, 573f posterior, 573, 573f Loose bodies, 1885–1886, 1885f, 1886f Lost work productivity, as indirect cost of ­illness, 440 Low back pain, 617–624, 618t in acromegaly, 1837 in ankylosing spondylitis, 1175 depression in, 1001 diagnosis of, 618–620 history taking and, 618, 619f imaging studies for, 618, 620 physical examination for, 618, 620t provocative testing for, 620 public health campaigns and, 623 treatment of pharmacologic, 620–621, 621t physical modalities for, 621 surgical, 622–623 Low-intensity exercise, in physical medicine and rehabilitation, 1028 Low-molecular-weight GTP-binding proteins, neutrophils and, 219 LP. See Lysylpyridinoline.

LRP5. See Lipoprotein receptor-related protein 5. LRRs. See Leucine-rich repeats. LT. See Lymphotoxin. Lubrication, of joints, 30 by synovial fluid, 15–16 Lubricin, 16 in cartilage, 40t lubrication and, 30 in synovial macrophages, 24 Lumbar spine fusion in, for low back pain, 622–623 rheumatoid arthritis of, 1091–1092 Lumican, in cartilage, 40t, 41 Lumiracoxib, 840, 843t adverse effects of, 849 Lunate, dislocation of, 523 Lungs. See also Pulmonary entries. in mixed connective tissue disease, 1392, 1392f tumors of, shoulder pain with, 611 Lunotriquetral ligament injury, 657–658 Lupus Activity Index, 1265 Lupus anticoagulant test, in antiphospholipid syndrome, 1305 Lupus erythematosus. See also specific types of lupus erythematosus. neonatal, 1289 skin lesions in, 691 skin lesions in, 688–691 lupus-specific, 688–691, 689f, 690f nonspecific, 691 synovial histopathology in, 712 Lupus erythematosus panniculitis, skin lesions of, 690, 690f Lupus nephritis, 1270–1274 algorithm for treatment of, 1286, 1287f cyclophosphamide for, 911, 911t immunopathology of, 1270, 1271t laboratory findings in, 1270–1271 monitoring of, 1272–1273 pregnancy and, 1289 prognosis and risk stratification and, 1273–1274 renal biopsy in, 1271–1272 urinalysis in, 1271, 1271f Lupus pernio, 698–699, 699f Lupus syndrome, neonatal, skin lesions in, 691 Lupus-like syndromes, paraneoplastic, 1842t, 1845 Lyme arthritis, 540, 541, 1719–1720 antibiotic-refractory, 1720 clinical features of, manifestations of, 1719–1720 polyarticular, 550 Lyme disease, 1715–1725 chronic, 1724 clinical features of, 1717–1719, 1717t cardiac, 1718 cutaneous, 1718, 1719 in early disseminated infection, 1718 in early localized infection, 1717, 1718f in late disease, 1719 neurologic, 1718–1719 diagnosis of, 1720–1723, 1721f antibody detection in cerebrospinal fluid and, 1721 imaging for, 1723 polymerase chain reaction for, 1721 serologic testing for, 1720–1721, 1721t, 1722f ecology of, 1715 epidemiology of, 1715 myositis and, 1355 outcome of, 1723–1724 pathogenesis of, 1716–1717 post-Lyme disease syndromes and, 1724–1725

index Lyme disease (Continued) prevention of, 1725 rheumatoid arthritis vs., 1110 skin lesions in, 696–697, 697f ticks and, 1716 treatment of, 1723, 1724t pregnancy and, 1723 uveitis in, 679 Lymph drainage, in physical medicine and rehabilitation, 1027 Lymph nodes antigen detection in from mucosal surfaces, 296–297, 297f from solid organs, 297–298, 298f changes in, during infection or vaccination, 298–299 Lymphadenopathy angioimmunoblastic, 1854, 1854t rheumatoid arthritis and, 1106–1107 in Kawasaki disease, in children, 1692 in systemic lupus erythematosus, 1276t, 1277 Lymphocyte(s). See also B cell(s); T lymphocytes. synovial, immunohistology of, 714–715 in synovial fluid, in rheumatoid arthritis, 1055 Lymphocyte migration, 291–294 egress from lymph nodes and, 294 immunologic synapses maintaining antigenspecific interactions with dendritic cells and, 293–294 interstitial, tissue organization and, 293 multistep model of, for extravasation, 291–293 thymus-sphingosine-1-phosphate and, 294 Lymphocytosis, in rheumatoid arthritis, 1101 Lymphoid tissues. See also B cell(s); T lymphocytes. primary, 294–295 secondary, 295–299 germinal center reactions and, 299, 299f liver as, 296 lymph node changes during infection or vaccination and, 298–299 mesenteric lymph nodes as, 296–297 peripheral lymph nodes as, 297–298, 298f peripheral tolerance induction under steady-state conditions and, 298 Peyer’s patches as, 296, 297f regulatory T cells and, 298 spleen as, 295–296, 296f, 297f T cell imprinting determination by tissue environment of immature dendritic cells and, 299 tertiary, 299–300 Lymphoma(s) with methotrexate, 889 non-Hodgkin, 1853–1854 in Sjögren’s syndrome, 1157, 1157t systemic lupus erythematosus vs., 1281 in systemic sclerosis, 1851 Sjögren’s syndrome vs., 1159 Lymphomatoid granulomatosis, paraneoplastic, 1842t, 1846 Lymphoproliferative disorders. See also specific disorders. malignant, 1900 in Sjögren’s syndrome, 1157, 1157t Lymphoproliferative syndrome, autoimmune. See Canele-Smith syndrome. Lymphotactin, 360 Lymphotoxin α, in rheumatoid diseases, 370t T cell-derived, 169t Lyn, B cell activation and, 187

Lysosomes, in platelets, 250, 250t Lysylpyridinoline, 479

M

MA-I, in Sjögren’s syndrome, 751, 751t MAAs. See Myositis-associated autoantibodies. MAC. See Membrane attack complex. MacMaster Toronto Arthritis Preference ­Disability Questionnaire, 466, 1025 Macrocytosis, with sulfasalazine, 896 Macroglossia, in AM amyloidosis, 1789, 1789f Macrophage(s) in gout, 1497 phenotype immunomodulation and, 148, 151t in rheumatoid arthritis, 1060–1067, 1061t perpetuation of synovitis by, 1066–1067, 1066f proinflammatory, 1061–1065 suppressive, 1065–1066 secretory products of, 148, 150t synovial, 24, 26f immunohistology of, 715 interactions with fibroblast-like synoviocytes, in rheumatoid arthritis, 210 systemic sclerosis pathogenesis and, 1323 tissue, origin of, 135 Macrophage colony-stimulating factor osteoclasts and, 74, 75 in rheumatoid diseases, 375t Macrophage inhibitory factor, in rheumatoid diseases, 375t Macrophage inhibitory protein-1α, in cartilage destruction, 56, 56t Macrophage inhibitory protein-1β, in cartilage destruction, 56, 56t Macrophage mannose receptor, as pattern-recognition receptors, 280 Macrophage receptor with collagenous ­structure, 145t as pattern-recognition receptors, 281 MACTAR. See MacMaster Toronto Arthritis Preference Disability Questionnaire. Magnet(s), static, for osteoarthritis, 1564–1565 Magnetic resonance imaging, 778–780. See also under specific conditions. in ankle pain, 644–645, 644f clinical application of, 779–780, 779f, 780f in foot pain, 644–645, 644f in hand and wrist pain, 652 in hip pain, 640, 641f in knee pain, 635, 636f in low back pain, 618, 618t, 620 in monarticular arthritis, 543 in neck pain, 582 in rheumatoid arthritis, 785–786, 786f, 787f in shoulder pain, 597, 598f Magnetic stimulation, 508–509 Major histocompatibility complex, 305–310. See also Human leukocyte antigen. autoimmune diseases and, 266–267 class I molecules of, myositis and, 1358–1359, 1359f class II molecules of, in systemic lupus ­erythematosus, 1236 genetic organization of, 307–308, 308f human leukocyte antigens and. See Human leukocyte antigen. in juvenile idiopathic arthritis, 1659 multiple-risk genes within, 314 non-class II, associations in rheumatoid arthritis, 1038, 1038t in psoriatic arthritis, 1211 in systemic lupus erythematosus, 1236, 1238

xxix

Malignancy(ies), 1841–1856. See also Cancer; specific types of malignancy. arthritis vs., 552 with azathioprine, 916 biologic response modifiers and, 1856 with chlorambucil, 914 with cyclophosphamide, 912 with cyclosporine, 918–919 immunomodulatory agents associated with, 1854–1856, 1855t inflammatory myopathies associated with, 1846–1847 metastatic, 1852–1853, 1853t with methotrexate, 889 musculoskeletal metastatic, 1852–1853, 1853t primary, 1852, 1852t myositis and, 1355 myositis associated with, 1365 paraneoplastic syndromes and, 1841–1846, 1842t postchemotherapy rheumatism and, 1853 radiation therapy and, 1856 rheumatoid arthritis vs., 1110 secondary, of joint, 1900 in systemic lupus erythematosus, 1276t screening for, 1288 with TNF inhibitors, 940 with tumor necrosis factor inhibitors, 1129–1130 Malingering, 978t, 979 Mallet fingers, 523, 659–660 Mallet toes, 646 Malnutrition, protein-energy, metabolic response to inflammation and, 1009 Manipulative and body-based methods, definition of, 502t Mannan-associated serine proteases lectin pathway and, 325–326 receptors of, 324, 326t Mannan-binding lectin, 279–280, 281f Mannose receptor, 145t secreted by macrophages, 150t Mannose-binding lectin, in rheumatoid arthritis, 761 Manual muscle test, in myositis, 1376 Manual therapy, in physical medicine and rehabilitation, 1026–1027 Manubriosternal joint examination of, 519 rheumatoid arthritis of, 1092 MAPKs. See Mitogen-activated protein kinases. Marasmus, metabolic response to inflammation and, 1009 MARCO. See Macrophage receptor with ­collagenous structure. Marfan syndrome, 1650–1652 clinical features of, 1650–1651, 1651f differential diagnosis of, homocystinuria and, 1651 molecular biology of, 1651–1652 treatment of, 1652 Martial arts, osteoarthritis associated with, 495t MASPs. See Mannan-associated serine ­proteases. Massage, in physical medicine and ­rehabilitation, 1027 Mast cells, 235–244 activation of, 237–238 cell-cell contact and, 238 by danger and injury, 238 IgE and, 237, 238f IgG and, 237–238 immune complexes and, 237–238

xxx

Index

Mast cells (Continued) inhibitory signals and, 238 soluble mediators and, 238 in allergic disease, 240 in arthritis, 242–243, 242f, 242t acute, 242, 243f chronic, 242–243 in connective tissue, 241–242 functions of, 237 development and tissue distribution of, 235–237 functions and, 237 heterogeneity and, 235–236 stem cell factor and, 236–237 T lymphocytes and, 237 heterogeneity of, 235–236 inflammatory responses and, 347 mediators of, 238–239 in models of disease, 239–240, 240t mucosal, functions of, 237 in nonallergic inflammation, 240–241 in rheumatoid arthritis, 1053 Masticatory myalgia, 672–674 clinical findings in, 672–673 diagnosis of, 673, 673t etiology of, 672f, 673 treatment of, 673–674, 674f Matrilin-1. See Cartilage matrix protein. Matrilin-3. See Cartilage matrix protein. Matrilysin in cartilage degradation, 53t matrix degradation and, 116t, 118t, 121 Matrix metalloproteinases ADAMTS family. See ADAMTS gene family. as biomarkers, 477t, 481 in cartilage degradation, 52–53, 53t cartilage destruction and in psoriasis, 1213 in rheumatoid arthritis, 129–130, 130f expression in synovium, in rheumatoid arthritis, 1076, 1077f extracellular matrix degradation and, 129, 203 furin-activated, matrix degradation and, 116t, 118t, 121 gene expression of, 125, 126t joint destruction and, in rheumatoid ­arthritis, 1075–1077, 1076t membrane-anchored matrix degradation and, 116t, 118t, 121 pericellular docking of, 128 MMP-1, 129, 130, 131 as biomarker, 481 matrix degradation and, 116t, 118t, 119–121 in osteoarthritis, 1530 in psoriatic arthritis, 1213 in rheumatoid arthritis, 208, 209 MMP-2, 129, 130, 131 as biomarker, 481 matrix degradation and, 116t, 118t, 120–121 in osteoarthritis, 1530 tophi and, 1497 MMP-3, 129, 130, 131 as biomarker, 481 in cartilage degradation, 53t expression in synovium, in rheumatoid arthritis, 1076, 1077f matrix degradation and, 116t, 118t, 121 in osteoarthritis, 1530 in psoriatic arthritis, 1213 in rheumatoid arthritis, 208, 209 MMP-7, 129, 130, 131 matrix degradation and, 116t, 118t, 121

Matrix metalloproteinases (Continued) MMP-8, 129, 130, 131 matrix degradation and, 116t, 118t, 119–120 in osteoarthritis, 1530 MMP-9, 129, 130, 131 as biomarker, 481 matrix degradation and, 116t, 118t, 120–121 neutrophils and, 217 in osteoarthritis, 1530 tophi and, 1497 MMP-10, 129 matrix degradation and, 116t, 118t, 121 in rheumatoid arthritis, 209 MMP-11, matrix degradation and, 116t, 118t, 121 MMP-12, matrix degradation and, 116t, 118t, 121 MMP-13, 129, 130, 131 matrix degradation and, 116t, 118t, 119–120 in osteoarthritis, 1530 in rheumatoid arthritis, 208 MMP-14, 128, 129, 130, 131 matrix degradation and, 116t, 118t, 121 MMP-15, 128, 129 matrix degradation and, 116t, 118t, 121 MMP-16, 128, 129, 130 matrix degradation and, 116t, 118t, 121 MMP-17, matrix degradation and, 116t, 118t MMP-19, 129 matrix degradation and, 116t, 118t, 121 MMP-20, 129 matrix degradation and, 116t, 118t, 121 MMP-21, matrix degradation and, 116t, 118t, 121 MMP-23, matrix degradation and, 116t, 118t MMP-24, 128 matrix degradation and, 116t, 118t, 121 MMP-25, 128 matrix degradation and, 116t, 118t MMP-26, matrix degradation and, 116t, 118t, 121 MMP-27, matrix degradation and, 116t, 118t, 121 MMP-28, matrix degradation and, 116t, 118t, 121 in neutrophils, 216 in osteoarthritis, 1535–1536 production of, regulation of, 1075–1076 proto-oncogene regulation of, 205 in rheumatoid arthritis expression of, 208 regulation of, 208–209 secreted-type activation of, 127–128, 128t matrix degradation and, 116t, 118t, 119–121 transcriptional activation of, 203 type X, 7 upregulation of, 47 zymogens of, activation mechanisms of, 126–128, 127f Mayaro virus infection, 1765 MBL. See Mannan-binding lectin. MC(s). See Mast cells. McArdle’s disease, differential diagnosis of, 1371t, 1372–1373 MCID. See Minimally clinical important ­difference. McMurray test, 529, 631, 632f MCP-1. See Monocyte cheomattractant protein-1. M-CSF. See Macrophage colony-stimulating factor. MCTD. See Mixed connective tissue disease.

MDHAQ. See Multi-Dimensional Health ­Assessment Questionnaire. Mechanic’s hands, 1362, 1362f Mechanotransduction, osteoarthritis and, 1534 Meclofenamate, 842t MEDAL study program. See Multinational Etoricoxib and Diclofenac Arthritis Long-term study program. Median nerve, testing of, in neck pain, 580t Medicolegal issues, with fibromyalgia, 566 Mediterranean diet, 504–505 Megakaryocytes, 250 Meloxicam, 840, 842t actions of, 845 Melphalan, for AM amyloidosis, 1790 Membrane attack complex, 327–328 complement regulation by, 326t regulation of, 328 Membrane cofactor protein, complement regulation by, 326t Membrane proteins, in cartilage, 40t Meniscus(i), 12 cells of, 12 examination of, 631–632, 632f injury of osteoarthritis and, 1552 tests for, 529 Menopause, bone loss related to, pathophysiology of, 1580–1583, 1581f, 1582t Mental status examination, in pain assessment, 982 Mercaptopurine, 914–916 dosage for, 915 drug interactions of, 916 mechanism of action of, 910t, 913 pharmacology of, 914–915 structure of, 914 toxicity of, 915–916 Merosin-deficient congenital muscular ­dystrophy, 102t Merosin-positive congenital muscular ­dystrophy, 102t Mesenchymal cells plasticity of, fibrosis and, in systemic ­sclerosis, 1325 progenitor cells and, fibrosis and, in systemic sclerosis, 1325 Mesenchymoid transformation, 711 Metabolic arthritis, of temporomandibular joint, 669 Metabolic disorders. See also specific disorders. calcium pyrophosphate dihydrate deposition disease secondary to, 1509–1510 osteonecrosis and, 1612 Metabolic pathways, defects in, 1642 Metabolic response to inflammation, 1009 Metabolic syndrome, 1486 Metabolic toxicity, of antimalarials, 899 Metabolites, secreted by macrophages, 150t Metabolomics, biomarkers based on, 484 Metacarpal index, in Marfan syndrome, 1650 Metacarpophalangeal joints arthrocentesis technique for, 731–732 examination of, 522–524, 522f Metalloproteinases. See also Matrix ­metalloproteinases. ADAM family, matrix degradation and, 121–122, 123t glandular destruction and, in Sjögren’s syndrome, 1152 membrane-anchored, matrix degradation and, 116t, 118t, 121 secreted-type, matrix degradation and, 116t, 118t, 119–121 tissue inhibitors of. See Tissue inhibitors of matrix metalloproteinases.

index Metastatic disease, 1852–1853, 1853t, 1900 Metatarsalgia, 646 Metatarsophalangeal joints, arthrocentesis technique for, 735 Methadone, for chronic pain, 985–986 Methemoglobinemia, with dapsone, 922 Methotrexate, 883–890 actions of, 883–886, 884f, 885f for ankylosing spondylitis, 1183 apoptosis and, 391 for Behçet’s disease, 1478 chemical structure of, 883, 884f contraindications to, 890 dose and administration of, 887–888 for geriatric patients, 887–888, 888t drug interactions of, 890, 893 efficacy of, 895t for giant cell arteritis, 1419 indications for, 886–887 for juvenile idiopathic arthritis, 1669, 1670 malignancy associated with, 1849–1850, 1855 mechanism of action of, 895t neutrophil functions and, 227 pharmacology of, 886 for polyarteritis nodosa, 1456t for polymyalgia rheumatica, 1420 in pregnancy, 1288 for psoriatic arthritis, 1215 for reactive arthritis, in HIV infection, 1750 to reduce inflammation, lessening vascular risk in rheumatoid arthritis via, 426 for relapsing polychondritis, 1632 for rheumatoid arthritis, 871, 1121–1122 combination disease-modifying antirheumatic drug therapy for patients with active disease despite, 900–901, 901f for sarcoidosis, 1804 special considerations with, 888t for systemic lupus erythematosus, 1284t, 1286 for Takayasu’s arteritis, 1424–1425 toxicity of, 888–890, 895t for Wegener’s granulomatosis, 1441 N-Methyl-d-aspartate, inflammation and, 413 Methylprednisolone drug interactions of, 866 effects on hypothalamic-pituitary-adrenal axis, 869–870 for giant cell arteritis, 1418 for injection, 725t for juvenile idiopathic arthritis, 1666 pharmacodynamics of, 865t for polyarteritis nodosa, 4, 1456t during pregnancy, 866 pulse therapy using, 874 structure of, 864f for systemic lupus erythematosus, 1282 in children, 1680 for Wegener’s granulomatosis, 1439 Met-RANTES, leukocyte infiltration and, 363 Mevalonic aciduria, 1864t, 1869 Mexiletine, for chronic pain, 989t MHC. See Major histocompatibility complex. Mi-2, in inflammatory muscle diseases, 750t Microsatellites, 314 Microscopic colitis, 1228–1229 Microscopic polyangiitis, 1403, 1404, 1443–1444, 1465 antineutrophil cytoplasmic antibodies and. See Antineutrophil cytoplasmic antibody. clinical features of, 1443–1444 diagnosis of, 1444 differential diagnosis of, 1444, 1446t treatment and prognosis of, 1444

Microvasculature, synovial, immunohistology of, 715 MIF. See Macrophage inhibitory factor. Migratory polyarthritis, 545 Milnacipran, for fibromyalgia, 564 Milwaukee shoulder, 606–607, 1516, 1518 Mimecan/osteoglycin, in cartilage, 41 Mind/body interventions, 509–510 definition of, 502t Mineralocorticoids actions, of glucocorticoids, 876 Minimally clinical important difference, 454 Minocycline for osteoarthritis, 1571 for rheumatoid arthritis, 1123 MIP-1α. See Macrophage inhibitory ­protein1α. MIP-1β. See Macrophage inhibitory protein-1β. Misoprostol, for ulcer prevention, 855 Mitochondria loss of membrane potential by, apoptotic cell detection using, 387 stress of, apoptosis and, 384 Mitochondrial myopathy, differential diagnosis of, 1371t, 1373 Mitogen-activated protein kinases in rheumatoid arthritis, 1067–1069, 1068f signal transduction and, 337–338 Mixed connective tissue disease, 1382, 1388–1394 antinuclear antibodies in, 751 in children, 1689–1690 clinical features and diagnosis of, 1388– 1394, 1389t blood and, 1393–1394 blood vessels and, 1393, 1393f early symptoms and, 1389–1390, 1390f fever and, 1390 gastrointestinal tract and, 1392–1393 heart and, 1390–1391 joints and, 1390, 1391f kidneys and, 1392 lungs and, 1392, 1392f muscle and, 1390, 1391f nervous system and, 1393 skin and mucous membranes and, 1390 glucocorticoid therapy for, 870t juvenile, 1394 in pregnancy, 1394 serologic features of, 1388 Mixed cryoglobulinemia, 1470 essential, 1405 paraneoplastic, 1842t, 1843 MM creating phosphokinase, in skeletal muscle, 96t MMPs. See Matrix metalloproteinases. MMR. See Macrophage mannose receptor. Mobility devices, in physical medicine and rehabilitation, 1030 Molecular mimicry, 170 B cell autoimmunity and, 193–194, 194t, 195f in diffuse connective tissue diseases, 1385 Monarticular arthritis, 533–543 diagnostic studies in, 542–543 bone biopsy as, 543 cultures as, 542 laboratory studies as, 542–543 magnetic resonance imaging as, 543 nuclear medicine as, 543 radiography as, 543 synovial biopsy as, 543 synovial fluid analysis as, 542 ultrasonography as, 543 differential diagnosis of, 533–534, 534f, 535t, 536–537, 536t

xxxi

Monarticular arthritis (Continued) bone pain and, 534 internal derangement and, 533 muscular pain syndromes and, 537 neuropathic pain and, 536 soft tissue infection and, 536 tendinitis and bursitis and, 534, 536 history taking in, 537 inflammatory, acute, 537, 539–540, 539f crystal-induced, 540 infectious, 537, 539–540 with systemic manifestations, 540–541 without systemic manifestations, 540–541 inflammatory, chronic, 541, 542f noninflammatory, 541–542 synovial histopathology in, 710–711, 710f Monocyte(s), 135 in gout, 1497 systemic sclerosis pathogenesis and, 1323 Monocyte chemoattractant protein-1 in cartilage destruction, 56, 56t fibrosis and, in systemic sclerosis, 1326–1327 Monolayer chondrocyte cultures, 45 Mononeuritis multiplex, in polyarteritis ­nodosa, 1454–1455 Mononeuropathies, pain generation with, 975 Mononuclear phagocytes, 135–151, 136f, 137t future research directions for, 150–151 gene expression and secretion and, 146, 148–149, 150t, 151t heterogeneity of, 136–138, 138f, 139f, 139t life history of, 136–138, 138f, 139f, 139t mobilization of, 139, 140f, 141–142, 141f, 141t phagocytosis and endocytosis and, 144–145, 148f, 149f recognition and, 142–144 complement receptors and, 143, 147t Fc receptors and, 143–144, 148f NOD-like receptors and, 144 non-toll-like receptors and, 143, 143f, 144f, 145t, 146f, 147f toll-like receptors and, 142–143, 142f rheumatic diseases and, 149–150 signaling responses in, 145–146 Monosodium urate crystals, 540 Monounsaturated oils, 506t Mood disturbances, glucocorticoid-induced, 877–878 Morphea, 1341–1342, 1342t generalized, 1342t plaque, 1342t skin lesions in, 692–693, 693f Morphine, for chronic pain, 985 Mortality. See also Death. in mixed connective tissue disease, 1394 in rheumatoid arthritis, 1113–1114 in systemic lupus erythematosus, 1293 Morton’s neuroma arthrocentesis technique for, 735, 735f foot pain and, 646 therapeutic injection in, 724 Motion. See also Range of motion entries. limitation of examination for, 517–518 history taking and, 516 Motion against resistance testing, in neck pain, 581 Motoneuron disease, differential diagnosis of, 1372, 1372t Mouth dry, in Sjögren’s syndrome, 1153–1154, 1153f, 1155 treatment of, 1161 in systemic sclerosis, 1331

xxxii

Index

Movement, loss of, in osteoarthritis, 1548 MPA. See Microscopic polyangiitis. MPD. See Myofascial pain and dysfunction. MRI. See Magnetic resonance imaging. MSAs. See Myositis-specific autoantibodies. MT-MMP(s) MT-MMP-1, in cartilage degradation, 53t in rheumatoid arthritis, 208 Muckle-Wells syndrome, 1864t, 1873, 1875–1876, 1875f, 1876f Mucocutaneous manifestations in Kawasaki disease, in children, 1692 in systemic lupus erythematosus, 1266–1269, 1267t Mucocutaneous side effects, of methotrexate, 889 Mucosal surfaces, antigens from, detection in Peyer’s patches and mesenteric lymph nodes, 296–297, 297f Mucous membranes in mixed connective tissue disease, 1390 in systemic lupus erythematosus, 1268–1269 Multicentric reticulohistiocytosis paraneoplastic, 1842t, 1845 rheumatoid arthritis vs., 1110 Multi-Dimensional Health Assessment ­Questionnaire, in fibromyalgia, 561 Multidrug-resistant tuberculosis, 1736 Multinational Etoricoxib and Diclofenac ­Arthritis Long-term study program, 458 Multiorgan autoimmunity, 264–265 Multiple myeloma, 1853–1854 Multiple sclerosis as autoimmune disease, 261t optic neuritis in, 682 in Sjögren’s syndrome, 1157 Mumps arthritis, 1768 Munchausen syndrome, 979 Murphy sign, 523 Muscle(s), 93–104 cell regeneration in, 93, 94f development of, 93–94, 94f, 95f, 96t examination of, 531 extracellular matrix of, 93–94 imaging of, in myopathy, 1369, 1370f in mixed connective tissue disease, 1390, 1391f in rheumatoid arthritis, 1097–1098 in sarcoidosis, 1801 structure of, 94–96 fiber types and, 95–96, 97t of muscle tissue, 94–95 in systemic sclerosis, 1332–1333 trauma to, in fibromyalgia, 558–559 Muscle contraction, 96–101 aging and, 104 cocontraction and, 109 contractile apparatus and, 97–100, 99f energetics of, 102–103 adenosine triphosphate concentration and, buffering of, 103 glycolysis and, 103 oxidative phosphorylation and, 103 excitation-contraction, 97, 98f fatigue and, 103 force generation and shortening and, 100, 100f force transmission to exterior and, 101 cell matrix adhesions and, 101, 101f myotendinous junction and, 101–102 neural control of, 96 neuromuscular transmission and, 96–97, 98f plasticity and, 103–104 adaptation to exercise and, 103–104 endocrine control of, 104

Muscle contraction (Continued) recovery following, 103 relaxation and, 100 Muscle disorders. See also specific disorders. arthritis vs., 552 inflammatory. See Dermatomyositis; Inclusion body myositis; Inflammatory muscle diseases; Myositis; Polymyositis. Muscle fibers number of, 94 types of, 95–96, 97t Muscle relaxants, for low back pain, 621, 621t Muscle strength osteoarthritis and, 1552 testing of, 529 in hip examination, 526 of knee, 529 in neck pain, 581 of shoulder, 591–592, 592f Muscle weakness in dermatomyositis, juvenile, 1682, 1682t history taking and, 516–517 in hyperparathyroidism, 1834 osteoarthritis and, 1552 Muscle-eye-brain congenital muscular ­dystrophy, 102t Muscular dystrophy classification of, 101, 102t cytoskeletal protein defects linked to, 101, 102t Muscular pain, differential diagnosis of, 537 Musculocutaneous nerve, testing of, in neck pain, 580t Musculoskeletal disorders. See also specific disorders. in osteonecrosis, 1612 in systemic lupus erythematosus, 1269–1270 in Wegener’s granulomatosis, 1436 Musculoskeletal examination in pain assessment, 982–983 recording, 518–519 of specific joints, 519–531. See also specific joints. systematic method of, 517–518 of crepitation, 518 of deformity, 518 of instability, 518 of limitation of motion, 517–518 of swelling, 517 of tenderness, 517 Musicians, musculoskeletal disorders in, 497, 498t–499t MWS. See Muckle-Wells syndrome. Myalgia in HIV infection, 1751 masticatory, 672–674 clinical findings in, 672–673 diagnosis of, 673, 673t etiology of, 672f, 673 treatment of, 673–674, 674f Myasthenia gravis as autoimmune disease, 261t differential diagnosis of, 1372, 1372t Mycobacterial infection(s) atypical, HIV-associated, 1756 M. marinum, skin lesions due to, 697 nontuberculous, osteoarticular infections caused by, 1736–1737, 1736f, 1737f tuberculous. See Tuberculosis. Mycophenolate mofetil, 920–921 dosage for, 921 drug interactions of, 921 mechanism of action of, 910t, 913 pharmacology of, 913 in pregnancy, 1288 structure of, 920

Mycophenolate mofetil (Continued) for systemic lupus erythematosus, 1281, 1283, 1284t, 1285–1286, 1287 for Takayasu’s arteritis, 1425 toxicity of, 920–921 Mycoplasma infection(s), rheumatoid arthritis and, 1042 Myeloma, multiple, 1853–1854 Myelopathy, cervical, 575, 576, 578 Myeloperoxidase deficiency of, 224t neutrophils and, 216 Myelosuppression, with chlorambucil, 914 Myoblasts, 93, 95f Myocardial disorders. See also specific disorders. in systemic lupus erythematosus, 1275–1276, 1275f in systemic sclerosis, 1333–1334 Myocardial infarction, risk of, with nonsteroidal anti-inflammatory drugs, 849–850 Myocardial ischemia, in rheumatoid arthritis, inflammation-mediated microvascular dysfunction as cause of, 426 Myocarditis as autoimmune disease, 261t in Kawasaki disease, in children, 1692 in rheumatoid arthritis, 1103 in Takayasu’s arteritis, 1422 Myofascial pain, therapeutic injection in, 724 Myofascial pain and dysfunction, 672–674 clinical findings in, 672–673 diagnosis of, 673, 673t etiology of, 672f, 673 treatment of, 673–674, 674f Myofibrils, 93, 97–98, 99f Myofibroblasts, fibrosis and, in systemic ­sclerosis, 1325 Myofilaments, 98 Myopathy glucocorticoid-induced, 875 HIV treatment and, 1752 of hypothyroidism, 1835–1836 inflammatory. See also Dermatomyositis; Inclusion body myositis; Inflammatory muscle diseases; Polymyositis. apoptosis in, 390 methotrexate for, 887 necrotizing, noninflammatory, in HIV ­infection, 1751 nemaline, in HIV infection, 1751 steroid, 1836 Myosin, in skeletal muscle, 96t Myositis limitation of mandibular movement in, 666t mimics of, 1355 overlap with other connective tissue ­diseases, 1386–1388, 1388t in systemic lupus erythematosus, 1269–1270 Myositis ossificans, limitation of mandibular movement in, 666t Myositis overlap autoantibodies, 750 Myositis-associated autoantibodies, 1356 Myositis-specific autoantibodies, 749–750, 1356 Myotendinous junction, 101–102 Myotonic muscular dystrophy, 102t Myxedema, pretibial, muscle weakness, in hyperthyroidism, 1835

N

Nabumetone, 843t NADPH. See Nicotinamide adenine ­dinucleotide phosphate oxidase. Nafcillin, for bacterial arthritis, 1708t, 1709t

index Nails dystrophy of, in AM amyloidosis, 1789, 1789f examination of, 523 in psoriasis, 686 NALP3, inflammatory response to ­monosodium urate crystals and, 1497 Naproxen, 842t adverse effects of, 849 for fibromyalgia, 564 for gouty arthritis, 1499 for juvenile idiopathic arthritis, 1664t National Institutes of Health SLE Index Score, 1265 Natural killer cells innate immune response and, 166 as innate immunity mediators, 284, 287 in rheumatoid arthritis, 1053 Nausea, with sulfasalazine, 896 N-CAM. See Neural cell adhesion molecule. Nebulin, in skeletal muscle, 96t, 99–100 Neck, range of motion in, 574 Neck pain, 571–584 anatomy and, 571, 572f–574f, 573–574, 574t axial, 574–575, 576 clinical examination in, 578–582, 580t, 581t diagnostic evaluation in, 582–583 differential diagnosis of, 583–584, 583t epidemiology of, 571, 572f history taking in, 576 myelopathy and, 575, 576 pain generator localization and, 577–578, 577t, 578t, 579f radiculopathy and, 575–576 treatment of, 583 Necrobiosis, 687 Necrosis, 379–380, 381f digital, paraneoplastic, 1842t, 1845 removal and degradation of necrotic cells and, 386–387, 387f shrinkage, 379 Necrotizing vasculitis, primary, skin lesions in, 694–696 granulomatous, 695–696 large vessel, 696 leukocytoclastic small vessel vasculitis as, 694–695, 694f polyarteritis nodosa as, 696 Negative selection, 269 Neisseria gonorrheae infection(s), bacterial arthritis caused by, 1702, 1704 diagnosis of, 1705 Nemaline myopathy, in HIV infection, 1751 Neonatal lupus erythematosus, skin lesions in, 691 Neonatal-onset multisystemic inflammatory disease, 1864t, 1873, 1876, 1876t Neonates, systemic lupus erythematosus in, 1680–1681, 1681f Neoplasms, 1886–1897. See also Cancer; Malignancy(ies); specific neoplasms. chondroma of tendon sheath and periarticular structures as, 1891–1892, 1891f fatty, of synovium, 1886–1888, 1887f, 1888f fibromas of synovial sheath as, 1889, 1889f of hand, 660 inflammatory monarticular arthritis associated with, 541 knee pain and, 636 limitation of mandibular movement in, 666t malignant. See Malignancy(ies). neck pain and, 575, 584 shoulder pain due to, 611 synovial chondromatosis as, 1889–1891, 1890f–1892f

Neoplasms (Continued) of temporomandibular joint, differential diagnosis of, 667t temporomandibular joint pain due to, 672 tenosynovial giant cell tumor as, 1892–1897 vascular, of synovium, 1888–1889, 1888f, 1889f Nephritic syndrome, in systemic lupus ­erythematosus, 1270 Nephritis, lupus. See Lupus nephritis. Nephrogenic fibrosing dermopathy, 694, 1343–1344 Nephrogenic systemic fibrosis, 1343–1344 Nephrolithiasis, in gout, 1488 Nephrotic syndrome, in systemic lupus ­erythematosus, 1270 Nephrotoxicity, of cyclosporine, 918 Nerve conduction studies in hand and wrist pain, 652 in shoulder pain, 597 Nerve damage with arthrocentesis, 726, 726t with joint injection, 726, 726t Nerve entrapment syndromes shoulder pain due to, 609–610 therapeutic injection in, 724 Nerve fibers, afferent, 966–967, 968t sensitization of, 969–970 Nerve roots, cervical, 574 Nested case-control studies, 435t, 437 Neural cell adhesion molecule, condensation and, 5 Neuritis, brachial plexus, neck pain and, 583 Neurodiagnostic tests, in hand and wrist pain, 652 Neuroendocrine dysregulation, in fibromyalgia, 559 Neurogenic inflammation. See also ­Inflammation, neurological regulation of. mast cells and, 241 Neurologic disorders. See also specific disorders. in amyloidosis, 1791t in ankylosing spondylitis, 1176 arthritis vs., 552 in Churg-Strauss syndrome, 1445 in giant cell arteritis, 1414 in Lyme disease, 1718–1719 in mixed connective tissue disease, 1393 pain generation with, 974–976 in peripheral nerve disorders, 974–976 in relapsing polychondritis, 1631 in Sjögren’s syndrome, 1156–1157 in systemic lupus erythematosus, 1274–1275, 1274f, 1274t, 1275t in systemic sclerosis, 1338 in Wegener’s granulomatosis, 1436, 1437f Neurologic examination, in pain assessment, 982 Neuroma, interdigital. See Morton’s neuroma. Neuromodulation therapy, percutaneous, for low back pain, 622 Neuromuscular diseases, differential diagnosis of, 1372, 1372t Neuromuscular junction, 96–97, 98f Neuromuscular toxicity, of antimalarials, 899 Neuron specific esterase, in synovial ­macrophages, 24 Neuropathic arthropathy in diabetes mellitus, 1834 imaging in, 805–807, 806f monarticular, 541 Neuropathic pain, differential diagnosis of, 536 Neuropathy, in polyarteritis nodosa, 1454–1455 Neuropsychiatric systemic lupus erythematosus, 1274–1275, 1274f, 1274t, 1275t treatment of, 1283

xxxiii

Neurotoxicity of coxibs, 851–852 of nonsteroidal anti-inflammatory drugs, 847t, 851–852 Neurotransmitters, peripheral, inflammation and, 412–413 Neutropenia autoimmune, 261t benign, chronic, 224t congenital, 223, 224t cyclic, 224t Neutrophil(s), 215–228 activation and function of, 217–222, 218f chemotaxis and, 221 degranulation and, 222f, diapedesis and, 220–221, 220f G proteins and, 218–219 kinases and kinase cascades and, 219 of NADPH oxidase and 221–222 neutrophil adhesion and, 219–220, 220f phagocytosis and, 221 second messengers and, 219 stimuli and receptors and, 217–218 clearance of, 216 development of, 215–216 heritable disorders of, 223–225, 224t of diminished neutrophil number, 223 granule defects as, 224–225 leukocyte adhesion deficiencies as, 223–224 oxidase deficiencies as, 225 morphology and content of, 216–217, 216f, 217t proinflammatory mediator production by, 222–223 of arachidonic metabolites, 222–223, 223f of cytokines, 223 rheumatic disease and, 225–228 antirheumatic agent effects on, 227–228 in dermatoses, 227 in familial Mediterranean fever, 227 FcγR polymorphisms and, 225 in gout, 225 in rheumatoid arthritis, 226 tissue destruction mediated by, 225 in vasculitis, 226 surface receptors of, responses to ­monosodium urate crystals and, 1497 Neutrophil elastase link protein degradation by, 129 matrix degradation and, 116t, 117 Neutrophilic dermatitis palisaded, 688 rheumatoid, 227, 688 Neutrophilic dermatoses, 687–688 NFD. See Nephrogenic fibrosing dermopathy. NFκB. See Nuclear factor κB. Nicardipine, drug interactions of, 919 Nicotinamide adenine dinucleotide ­phosphate oxidase, reduced, neutrophils and, 221–222, 222f Nifedipine, drug interactions of, 919 Nimesulide, 840 actions of, 844–845 Nitric oxide in cartilage destruction, 55, 56 in neutrophils, 219 in osteoarthritis, 1536–1537, 1536f in rheumatoid arthritis, synovium and, 1070 NK cells. See Natural killer cells. NLE. See Neonatal lupus erythematosus. NLRs. See NOD-like receptors. NMDA. See N-Methyl-d-aspartate. NO. See Nitric oxide.

xxxiv

Index

Nociceptors, peripheral, pain generation in, 966–967, 967f, 968t, 969 NOD-like receptors, 135 immune recognition and, 144 Nodular synovitis, localized, 1895, 1895f, 1896f NOMID. See Neonatal-onset multisystemic inflammatory disease. Non-Hodgkin lymphoma(s), 1853–1854 in Sjögren’s syndrome, 1157, 1157t systemic lupus erythematosus vs., 1281 in systemic sclerosis, 1851 Noninferiority designs, 458 Noninferiority margin, 454 Noninflammatory arthritis, therapeutic ­injection in, 722t, 723–724 Nonsteroidal anti-inflammatory drugs, 833–856. See also specific drugs. actions of, 844–845 analgesic, 846 anti-inflammatory, 844 antipyretic, 846 on bone, 852 cardiovascular, 848–851 gastrointestinal, 847–848, 847t hematologic, 853 hepatic, 852 immunologic, 852–853 neurologic, 851–852 ovarian, 854 renal, 851 uterine, 854 adverse effects of, 346 for ankylosing spondylitis, 1182–1183 apoptosis and, 390 aspirin combined with, 850–851 for calcium pyrophosphate dihydrate ­deposition disease, 1520 carboxylate-containing, cyclooxygenase inhibition by, 840 for carpal tunnel syndrome, 653 classification of, 841, 842t–843t, 843f cyclooxygenase inhibition by, 346 time dependence and competition and, 840 cyclooxygenase-independent effects of, 19, 841 design after discovery of cyclooxygenase-2, 845–846 for diffuse idiopathic skeletal hyperostosis, 1605 drug interactions of, 919 for fibromyalgia, 564 future of, 855–856 gastrointestinal toxicity of, need to reduce, 844 for gouty arthritis, 1499 historical background of, 834 for inflammatory bowel disease, 1225 for juvenile idiopathic arthritis, 1668 for low back pain, 621, 621t metabolism of, 841, 843 neutrophil functions and, 227 for osteoarthritis, 1566, 1567 platelets and, 254 for psoriatic arthritis, 1215 for reactive arthritis, 1198 for rheumatoid arthritis, 871, 1133–1134 selecting therapy using, 854–855 general therapeutic considerations for, 854 minimizing cardiovascular risk and, 855, 855t minimizing gastrointestinal risk and, 854–855 patient risk assessment and, 854 for systemic lupus erythematosus, 1281 in children, 1680 therapeutic effects of, 844–846 for undifferentiated spondyloarthropathy, 1195

Non-toll-like receptors, 136 immune recognition and, 143, 143f, 144f, 145t, 146f, 147f NOR 90, in scleroderma, 749, 749t Nortriptyline, for chronic pain, 989t Nose, chondritis of, in relapsing polychondritis, 1629, 1631f NPSLE. See Neuropsychiatric systemic lupus erythematosus. NSAIDs. See Nonsteroidal anti-inflammatory drugs. NTRs. See Non-toll-like receptors. Nuclear factor κB cartilage metabolism and, 58 in fibroblast-like synoviocytes, 206 inflammation and, 413 in rheumatoid arthritis, 1067, 1068f signal transduction and, 338–339, 339f Nuclear medicine, in monarticular arthritis, 543 Nucleic acid amplification, for tuberculosis diagnosis, 1735 Nucleosomal components, autoimmunity to, 1383–1384, 1384f Nucleosomal ladder, 379 Nucleosome antibodies, in systemic lupus erythematosus, 747 Nucleotide pyrophosphate phosphodiesterase, calcium pyrophosphate dihydrate and basic calcium phosphate crystal deposition and, 1509 Nutriceuticals, for osteoarthritis, 1569–1571, 1569t Nutrition, 1009–1018, 1010t allergic arthritis and, 1018 antioxidant vitamins in, 1011–1012 of chondrocytes, 32 fatty acids in. See Fatty acids. free radicals and, 1010–1011, 1010f, 1011f inflammation and, 1009 of joints, by synovial fluid, 16 in juvenile rheumatoid arthritis, 1010 in rheumatoid arthritis, 1009–1010 trace elements in, 1012–1013 vascular diseases and, 1017–1018 Nystatin, for xerostomia, in Sjögren’s ­syndrome, 1161

O

OA. See Osteoarthritis. Obesity inflammation and, 505–506 osteoarthritis and, 1526–1527, 1551, 1552f, 1564 polyarthritis secondary to, 551 rheumatoid arthritis and, 509 O’Brien’s test, 590–591 Occlusive thromboaortopathy. See Takayasu’s arteritis. Occupation-related musculoskeletal disorders, 491–493, 492t Occupation-related rheumatic diseases, 493–494 osteoarthritis as, 493–494, 493t, 494t Ochronosis imaging in, 801, 802f synovial histopathology in, 712 Ocular manifestations. See also Eye(s). of Behçet’s disease, 1476 in Cogan’s syndrome, 1457 in Wegener’s granulomatosis, 1436, 1437f Ocular surgery, for Wegener’s granulomatosis, 1442–1443 Ocular toxicity of antimalarials, 899 of glucocorticoids, 876

Oculopharyngeal muscular dystrophy, 102t Odontogenic infection, limitation of ­mandibular movement in, 666t O’Duffy-Goldstein criteria, for Behçet’s disease, 1477 OI. See Osteogenesis imperfecta. Oil-induced arthritis, animal models of, 398t Okelbo disease, 1765 Oleanic acid, in anti-inflammatory diet, 504 Olecranon bursa, arthrocentesis technique for, 730 Olecranon nodules, arthrocentesis technique for, 730 Omega-3 fatty acids, 506t, 1015–1017, 1015f, 1017f animal studies of, 1016–1017 in anti-inflammatory diet, 504, 505 human studies of, 1017 in rheumatoid arthritis, 1138 vascular diseases and, 1017–1018 Omega-6 fatty acids, 506t, 1014–1015, 1014f animal studies of, 1014–1015 in anti-inflammatory diet, 504, 505 eicosanoid synthesis modulation by, 354–355 human studies of, 1015 OMERACT. See Outcome Measures in ­Rheumatoid Arthritis Clinical Trials. OMERACT Health Economics Working Group, 442–443 Oncostatin M, 373t O’nyong-nyong virus arthritis, 1764–1765, 1764t Oophoritis, as autoimmune disease, 261t OPG. See Osteoprotegerin. Opioid analgesics. See also specific drugs. for chronic pain, 984–987, 984f, 985t, 986f, 987f troubleshooting problems with, 986–987, 988t for low back pain, 621t for osteoarthritis, 1567–1568 for rheumatoid arthritis, 1134 Opportunity cost, 440, 442 Opsonins, secreted by macrophages, 150t Optic neuritis, 682–683, 682f Oral anticoagulation, for antiphospholipid ­syndrome, in systemic lupus ­erythematosus, 1290 Oral contraceptives drug interactions of, 866 rheumatoid arthritis and, 1039, 1107, 1837 Orbital disease, 682 Orbital pseudotumor, in Wegener’s ­granulomatosis, 1436, 1436f Orchitis, as autoimmune disease, 261t Orthotics for foot and ankle pain, 647–648 for osteoarthritis, 1564 in physical medicine and rehabilitation, 1029 Orthovisc, for injection, 725t Ortolani maneuver, 525 OspA, molecular mimicry and, 170 Ossicles of ear, rheumatoid arthritis of, 1092 intra-articular, 1886, 1886f Osteoadherin, in cartilage, 41 Osteoarthritis, 1525–1540, 1547–1557 in ankle, 1557 biochemical changes in, 1529–1530 biomarkers of, 1539, 1555 biomechanics and disease mechanisms of, 1533–1535 biomechanical changes and, 1532 cartilage response to mechanical injury and, 1533–1534

index Osteoarthritis (Continued) mechanotransduction and gene expression and, 1534–1535 calcium pyrophosphate dihydrate deposition disease vs., 1516 cartilage destruction in, by proteinases, 131 cartilage roughening in, 109–110 clinical assessment of, 1554–1555, 1554t, 1555t clinical manifestations of, 1548–1549 core sets for clinical trials in, 464t costs of, 446–447 criteria for defining, 1553–1554, 1553t depression in, 1002–1003 distribution of, 1551t, 1555–1557 in elbow, 1557 erosive, antimalarials for, 899 etiology of, 1526–1529 age and, 1526 gender and, 1528–1529 genetic predisposition and, 1527 joint location and, 1526 joint malalignment and trauma and, 1528 obesity and, 1526–1527 facet joint, imaging in, 818, 818f computed tomography for, 818, 818f magnetic resonance imaging for, 818, 818f in foot, 1557 generalized, primary, 551 glucocorticoid therapy for, 870t of hands, 1551t, 1556, 1556f polyarticular, 550–551, 551f of hip, 637, 1551t, 1556–1557, 1557f imaging in, 793–796, 1549–1550, 1549f abnormalities in specific sites and, 794–796 computed tomography for, 818, 818f general imaging features and, 793–794, 793f, 794f magnetic resonance imaging for, 796, 818, 818f inflammatory, imaging in, 795–796, 797f inflammatory mediators in, 1535–1539 biomarkers of osteoarthritis and, 1539 bone alterations and, 1537 produced by articular cartilage, 1535–1537 synovial tissue alterations and, 1537–1539, 1538f joint biomechanics in, 107 of knee, 1551t, 1555–1556, 1556f depression in, 1001 laboratory tests in, 1550 management of, 1563–1573, 1564t acute-phase reactants in, 772 gene therapy for, 1573 neutriceuticals for, 1569–1571, 1569t nonpharmacologic interventions for, 1563–1566 pharmacologic, 1566–1569, 1571–1573, 1571t surgical, 1573 matrix changes in, 1532 metabolic changes in, 1530–1532, 1531f monarticular, 541–542 morphologic changes in, 1529, 1529f natural history of, 1547–1548 occupation-related, 493–494, 493t osteophyte formation in, 1532–1533 patient assessment in, 1563 physical examination in, 1548–1549 predisposing factors for, 1551–1553, 1551t prevalence of, 1547 recreation- and sports-related, 494, 495–496, 496t rheumatoid arthritis vs., 1110–1111, 1111t secondary, 1550–1551, 1551t

Osteoarthritis (Continued) to metabolic diseases, 551 in shoulder, 1557 shoulder pain due to, 606, 606f source of pain in, 1563 in spine, 1557 structural severity evaluation in, 1555 synovial fluid in, 705t of temporomandibular joint, 665–668, 1557 clinical findings in, 665 diagnosis of, 667 imaging in, 665–667 treatment of, 667–668 therapeutic injection in, 723, 724 tidal irrigation for, 735 total joint replacement for, time to, 1555 walking and, adduction moment during, 109 Osteoarthropathy, hypertrophic. See ­Hypertrophic osteoarthropathy. Osteoblasts, 71–73 differentiation of, 2 function of, 71–72, 72f, 72t pathophysiology of, transgenic models of, 72–73 prostaglandin E2 secretion by, 77 skeletal growth and, 76, 76f Osteocalcin as biomarker, 80, 477t in bone matrix, 79 Osteochondral defects, ankle pain and, 645 Osteochondritis dissecans, monarticular ­arthritis associated with, 541 Osteochondroma(s), 1852 Osteochondroma coronoid, limitation of ­mandibular movement in, 666t Osteochondromatosis, synovial, 1889–1891, 1890f–1892f primary, imaging in, 821–822, 822f Osteochondrosis, degenerative disk disease and, 817 Osteoclasts, 73–75 differentiation of, 74 function of, 73–74, 74f pathophysiology of, transgenic models of, 74 Osteocytes, one remodeling, 73, 73f Osteodystrophy, hereditary, Albright’s, 1835 Osteogenesis imperfecta, 1643–1647, 1644t bone histology in, 1646 lethal (type II), 1644–1645, 1644t, 1645f mild (type I), 1643–1644, 1644t of moderate severity (type IV), 1644t, 1646 severely deforming (type III), 1644t, 1645–1646 treatment of, 1646–1647 type V, 1644t, 1646 type VI, 1644t, 1646 type VII, 1644t, 1646 Osteoid, 71, 78 Osteolysis, clavicular, distal, 604 Osteomalacia, 1591–1593, 1591t, 1592f, 1592t paraneoplastic, 1842t, 1845 Osteomyelitis in foot, in diabetes mellitus, 1834 HIV-associated, 1755 in bacillary angiomatosis, 1756 in sickle cell disease, 1829 tuberculous, 1732 Osteonecrosis, 1611–1624, 1836 with arthrocentesis, 726, 726t bone marrow edema in, 1619–1620 clinical features of, 1613, 1614t corticosteroid-related, 1611–1612, 1615t diagnosis of, 1617–1619, 1617f–1621f, 1620t, 1622t dysbaric, 1616 epidemiology of, 1611

xxxv

Osteonecrosis (Continued) etiology of, 1611–1613, 1612t future directions for, 1624 genetics of, 1615–1616 glucocorticoid-induced, 875 in HIV infection, 1750 imaging in, 802–805, 803f–805f, 804t with joint injection, 726, 726t monarticular arthritis associated with, 541, 542 outcome of, 1623–1624 pathogenesis of, 1613–1615, 1615t prognosis of, 1623–1624 shoulder pain due to, 606 in sickle cell disease, 1829 in systemic lupus erythematosus, 1270 treatment of, 1620–1623, 1624f Osteons, 82–83, 83f Osteopenia glucocorticoid-induced, 1836 in HIV infection, 1750 in juvenile chronic arthritis, imaging of, 786 Osteophytes ankle pain and, 645 formation of, in osteoarthritis, 1532–1533 Osteoporosis, 1579–1591 in ankylosing spondylitis, 1176–1177 apoptosis in, acceleration of, 390 bone density assessment and, 1584, 1584t bone turnover markers in, 1585 core sets for clinical trials in, 464t costs of, 448–449 drug-induced, 1595–1596 epidemiology and clinical signs in, 1579–1580 glucocorticoid-induced, 874–875, 1590–1591, 1590t in men, 1583 pathophysiology of, 1580–1583, 1581f, 1582f prevention of, 1589–1590 in rheumatic diseases and other conditions, 1583 in rheumatoid arthritis, 782 risk of, 1584–1586 secondary bone loss in, evaluation for, 1585–1586, 1586t treatment of, 1586–1589 bisphosphonates for, 1587–1588, 1588t calcitonin for, 1587 calcium for, 1586, 1586t estrogen for, 1586–1587 parathyroid hormone for, 1588–1589 selective estrogen receptor modulators for, 1587 testosterone for, 1587 vitamin D for, 1589 Osteoprotegerin, in rheumatoid diseases, 370t Osteosarcoma, 1852 Osteotomies, for foot and ankle pain, 649 Osterix, 72 Otitis media as temporomandibular disorder mimic, 666t in Wegener’s granulomatosis, 1433–1434 Otologic disorders, in Wegener’s ­granulomatosis, 1433–1434 Outcome(s) definition of, 456 surrogate, 456 Outcome Measures in Rheumatoid Arthritis Clinical Trials, 456, 1209 Outcome variables, for clinical trials, 456 Ovaries, nonsteroidal anti-inflammatory drugs and, 854 Overlap syndromes, 1386–1396 antinuclear antibodies in, 751 management of, 1394, 1395t, 1396

xxxvi

Index

Overlap syndromes (Continued) mixed connective tissue disease and. See Mixed connective tissue disease. monarticular arthritis associated with, 541 myositis overlaps and, 1386–1388, 1388t prognosis of, 1396 scleroderma overlaps and, 1386 Overweight. See also Obesity. diffuse idiopathic skeletal hyperostosis and, 1602 Oxacillin, for bacterial arthritis, 1708t Oxaprozin, 842t Oxcarbazepine, for chronic pain, 990 Oxidase deficiencies, 224t, 225 Oxidative phosphorylation, in muscle, 103 Oxycodone, for chronic pain, 985, 988 Oxypurinol, for hyperuricemia control, 1501

P

p53, fibroblast activation and survival and, in rheumatoid arthritis, 205 p53 apoptosis and, 384 signaling in apoptosis and, 341 p14, deficiency of, 224t PAF. See Platelet activating factor. Paget’s disease of bone, 1593–1595, 1852 cause of, 1593 clinical features of, 1593–1594, 1593f, 1594f diagnosis of, 1594 laboratory findings in, 1594 malignancy associated with, 1847t occupation-related, 494t treatment of, 1594–1595, 1594t PAH. See Pulmonary arterial hypertension. PAI(s). See Plasminogen activator inhibitors. Pain, 963–990. See also specific location. abnormal processing of, in fibromyalgia, 559 articular, neurobiology of, 972–974, 973f central nervous system disorders causing, 976 central sensitization at spinal cord, 971 chronic. See Chronic pain. in complex regional pain system, 976 decreased inhibition of, in fibromyalgia, 559 definitions related to, 963b epidemiology of, 964–966, 965t generation of with nervous system disorders, 974–976 in peripheral nociceptors, 966–967, 967f, 968t, 969 history taking and, 515–516 in joints, mechanisms of, 11 in osteoarthritis, 1548 source of, 1563 peripheral nerve disorders causing, 974–976 polyarticular, differential diagnosis of, 551–553 primary afferent neuron sensitization and, 969–970 psychogenic, 977, 978t arthritis vs., 553 psychophysiologic, 978 psychosocial management and, 999 in sickle cell crises, 1828 transmission of modulation in central nervous system, 972 projection to brain and, 971, 972f, 972t to spinal cord, 970–971, 970f widespread, depression in, 1001 Pain disorder, 977, 978t Pain management resources for, 991b in rheumatoid arthritis, 1137 Pain programs, multidisciplinary, 990 Pain specialists, 990

Pain-depression syndrome, 978t Painful articular syndrome, HIV-related, 1747 Paired immunoglobulin-like receptor-A, B cell activation and, 188 Palindromic rheumatism, antimalarials for, 899 Palisaded neutrophilic and granulomatous dermatitis, 688 Palmar aponeurosis, 521 Palmar fasciitis, paraneoplastic, 1842t, 1844 PALS. See Periarterial lymphoid sheath. Pamidronate for osteogenesis imperfecta, 1646 for Paget’s disease of bone, 1595 PAMPs. See Pathogen-associated molecular patterns. PAN. See Polyarteritis nodosa. p-ANCAs, in Sjögren’s syndrome, 751, 751t Pancoast tumor(s) neck pain and, 583 shoulder pain with, 611 Pancreatic disorders. See also specific disorders. in Sjögren’s syndrome, 1155 in systemic sclerosis, 1332 Pancreatitis, osteonecrosis and, 1615t Panniculitis paraneoplastic, 1842t, 1844 skin lesions in, 697–698, 698t PAPA syndrome. See Pyogenic sterile arthritis, pyoderma gangrenosum, and acne ­syndrome. Papular-purpuric gloves and socks syndrome, 697 Papules, in hyper-IgD syndrome, 1870, 1870f Parachuting, osteoarthritis associated with, 495t Paralysis, rheumatoid arthritis and, 1090 Paraneoplastic syndromes, 1841–1846, 1842t Paraproteinemia, in rheumatoid arthritis, 1101 Parasitic infection(s) HIV-associated, 1756–1757 mast cell defense against, 240 myositis and, 1355 Parasitic myopathy, differential diagnosis of, 1371t, 1373 Parathyroid hormone, calcium metabolism and, 77 Parathyroid hormone-related peptide growth plate elongation and, 76 skeletal development and, 75 Parathyroid hormone-related protein, growth plate development and, 6 Parecoxib, 843t Parkinson’s disease, rheumatoid arthritis vs., 1111, 1111f Paronychia, 660 Parotid gland, enlargement of, in diffuse infiltrative lymphocytosis syndrome, 1753–1754, 1753f, 1754f Parotitis, as temporomandibular disorder mimic, 666t Paroxetine, for chronic pain, 989t Parry-Romberg syndrome, 692–693 Parsonage-Turner syndrome. See Brachial plexus neuritis. Parvovirus B19 arthritis, 1761–1763 diagnosis of, 1762–1763 epidemiology of, 1761 pathogenesis of, 1761–1762 prognosis of, 3 treatment of, 3 Parvovirus B19 vasculitis, 1458 Parvovirus infection(s) rheumatoid arthritis and, 1042 skin lesions in, 697 PASI. See Psoriasis Assessment Severity Index. Patella, stability of, assessment of, 528

Patellar tendon, examination of, 633 Patellofemoral malalignment, 528 Patellofemoral pain, physical examination in, 633, 633f Pathogen-associated molecular patterns, 278 Patient education in physical medicine and rehabilitation, 1030 in rheumatoid arthritis, 1137 Patient Reported Outcomes Measurement Information System, 471 Patrick’s test, 525 in hip pain, 638 Pattern-recognition receptors, 278–284, 280t endocytic, 280t of lectin family, 279–280, 281f with leucine-rich repeat domains, 281–283 of scavenger receptor family, 281 secreted, 280t signaling, 280t Pauciarticular arthritis, peripheral, 547 Pauci-immune vasculitis, 1407 p80-Coilin, in Sjögren’s syndrome, 751, 751t PCR. See Polymerase chain reaction. PD1. See Programmed death 1. PD-1, B cell activation and, 188 PDCD1. See Programmed cell death 1. PDGF. See Platelet-derived growth factor. PECAM-1. See Platelet-endothelial cell adhesion molecule-1. Pelvic girdle, arthrocentesis technique for, 732–733 Pemphigus, as autoimmune disease, 261t Penetrance, definition of, 309t Penicillamine, for rheumatoid arthritis, 1124 Penicillin, for bacterial arthritis, 1708t Pentosan polysulfate, for osteoarthritis, 1572 Pentraxins, as pattern-recognition receptors, 280 Peptic ulcer disease, glucocorticoid-induced, 875 Peptides, antimicrobial, 285 Performance-enhancing drugs, muscle and, 104 Performing arts-related musculoskeletal ­disorders, 497, 498t, 499 Periarterial lymphoid sheath, 296 Periarticular disorders, shoulder pain due to, 599–601 Periarticular structures, chondroma of, 1891–1892, 1892f Pericarditis in rheumatoid arthritis, 1103 in systemic lupus erythematosus, 1275 Perichondrium, 75 Pericoronitis, as temporomandibular disorder mimic, 666t Pericytes, fibrosis and, in systemic sclerosis, 1325 Periosteum, 75 Periostitis arthritis vs., 553 in juvenile chronic arthritis, imaging of, 786 Peripheral blood, in Sjögren’s syndrome, ­immunologic alterations in, 1150 Peripheral blood lymphocytes, immune ­responses of, in synovial fluid, in ­rheumatoid arthritis, 1057–1058 Peripheral immune tolerance, 261 induction under steady-state conditions, 298 Peripheral nerve disorders, painful, 974–976 Perlecan, in cartilage, 40t, 41 Permeability factors, glucocorticoid effects on, 868 Pernicious anemia, as autoimmune disease, 261t Peroxisome proliferator-activated receptor γ, in cartilage destruction, 55–56

index Personal factors, in physical medicine and rehabilitation, 1031 Personality disorders, pain and, 978t, 979 PET. See Positron-emission tomography. PET scale, 466 Petechiae, in hyper-IgD syndrome, 1870, 1870f Peyer’s patches, antigen detection in, 296, 297f PGEs. See Prostaglandin(s). PGP.95, in synovial macrophages, 24 Phagocytosis, 136, 144–145, 148f, 149f of apoptotic cells, 387, 389 of neutrophils, 221 Phalen’s test, 610 Phemister’s triad, 792 Phenylbutazone adverse effects of, 853 introduction of, 834 Phenytoin, for chronic pain, 988, 989t Phlebotomy, for hemochromatosis, 1813 Phosphatases, inhibitory, B cell activation and, 188 Phosphatidylserine, in apoptotic cells, 386, 387t Phosphocitrate, for calcium pyrophosphate dihydrate deposition disease, 1520–1521 Phospholipases A2 biosynthesis of, 343 as mast cell mediator, 239 C, biosynthesis of, 343–344 D, phospholipid hydrolysis by, 344, 345f neutrophils and, 219 Phospholipids antibodies associated with, in systemic lupus erythematosus, 1235 hydrolysis of, by phospholipase D, 344, 345f Phosphorylation, oxidative, in muscle, 103 Photophobia, in ankylosing spondylitis, 1176 Photosensitivity with sulfasalazine, 896 in systemic lupus erythematosus, 1267, 1268 Physical medicine and rehabilitation, 1023–1031 goals of, 1023 interdisciplinary vs. multidisciplinary ­rehabilitation and, 1023 International Classification of Functioning, Disability and Health and. See International Classification of ­Functioning, Disability and Health. Physician-patient communication, 1004, 1005b Physiotherapy, for ankylosing spondylitis, 1182, 1183t Piecemeal degranulation, of mast cells, 238 Pigmented villonodular synovitis, 1893–1895, 1893f–1895f imaging in, 820–821, 821f, 821t, 822f magnetic resonance imaging for, 821, 821t, 822f inflammatory monarticular arthritis ­associated with, 541 rheumatoid arthritis vs., 1111 synovial fluid in, 705t Pilocarpine, for Sjögren’s syndrome, 1161, 1161t Piperacillin, for bacterial arthritis, 1708t PIR-A. See Paired immunoglobulin-like ­receptor-A. Piroxicam, 842t for juvenile idiopathic arthritis, 1664t Pisotriquetral arthritis, 658 Pituitary gland, in hemochromatosis, 1811 PLA2. See Phospholipases, A2. Plant sterols, 506t Plantar fascia, arthrocentesis technique for, 735

Plantar fasciitis, 647 therapeutic injection in, 724 Plantar nerve, lateral, entrapment of, 647 Plasma cells, 185 synovial, immunohistology of, 714–715 Plasma kallikrein, matrix degradation and, 116t, 117 Plasmapheresis, for polyarteritis nodosa, 1456t Plasmin, matrix degradation and, 116t, 117 Plasminogen activator(s), in cartilage ­degradation, 53t Plasminogen activator inhibitors, 122, 124t plasminogen activator expression and, 127t Platelet(s), 249–254 antibodies against, in systemic lupus ­erythematosus, 1235 characteristics of, 249–250, 250t function of, 251–253 glycoprotein IIb/IIIa and, 251–252 hemostasis as, 251, 251f inflammatory response and, 252–253, 252t in rheumatic diseases, 253–254 alterations in number in, 253 pathogenetic role and, 253–254 platelet inhibition by pharmacologic agents and, 254 Platelet activating factor, 353–354, 353f inflammatory effects of, 353–354 Platelet microparticles, 251 Platelet-derived growth factor fibrosis and, in systemic sclerosis, 1326 release of, 252 in rheumatoid arthritis, 209, 1064–1065 Platelet-endothelial cell adhesion molecule-1, angiogenesis and, 359, 359t PLC. See Phospholipases, C. PLD. See Phospholipases, D. Pleural disease in rheumatoid arthritis, 1102 in systemic lupus erythematosus, 1276–1277, 1276t Pleural effusion, in systemic lupus ­erythematosus, 1276t Pleurisy, in systemic lupus erythematosus, 1276t Pleuritis, in systemic lupus erythematosus, 1276 Plica syndrome, 528 PMR. See Polymyalgia rheumatica. PM-Scl, in inflammatory muscle diseases, 750t PN-1. See Proteinase nexin-1. Pneumocystis jiroveci infection(s), in systemic lupus erythematosus, prevention of, 1287–1288 Pneumonia in acute rheumatic fever, 1779 eosinophilic, with sulfasalazine, 896 in systemic lupus erythematosus, 1276t Pneumonitis interstitial, in rheumatoid arthritis, 1102–1103 methotrexate and, 889 in systemic lupus erythematosus, 1276t, 1277 Podagra, 540 POEMS syndrome, skin lesions in, 693–694 Pogosta disease, 1765 Poikiloderma, 692 Polyangiitis, microscopic, 1403, 1404, 1443–1444, 1465 antineutrophil cytoplasmic antibodies and. See Antineutrophil cytoplasmic antibody. clinical features of, 1443–1444 diagnosis of, 1444 differential diagnosis of, 1444, 1446t treatment and prognosis of, 1444

xxxvii

Polyarteritis nodosa, 1401, 1453–1457, 1454t in children clinical features of, 1690–1691, 1690t, 1691f outcome of, 1691 treatment of, 1690–1691, 1690t, 1691, 1691f course of, 1455 cutaneous (limited), 1456–1457 clinical features of, 1456 diagnosis of, 1456 pathology of, 1456 treatment and course of, 1457 differential diagnostic features of, 1446t pathology of, 1453–1454, 1454f prognosis of, 1456 as reference point for vasculitis classification, 1402 systems involved in, 1454–1455, 1454f, 1455f therapy for, 1455–1456, 1455t, 1456t Polyarticular arthritis, 545–553 carcinomatous, 1841–1842, 1842t, 1843t diagnostic principles for, 546, 547t, 548f differential diagnosis of, 551–553, 552t history taking in, 545–546 inflammatory ankylosing spondylitis as, 550 with axial involvement, 550 enteropathic, 550 psoriatic, 550 in Reiter’s syndrome, 550 in Whipple’s disease, 550 laboratory tests in, 546, 546t migratory, 545 noninflammatory, 550–551 in chondromalacia, 551 of hands, 550–551, 551f in metabolic diseases, 551 primary generalized, 551 peripheral, 547, 549–550 in adult rheumatic fever, 549 in amyloid arthropathy, 550 in bacterial endocarditis, 550 in Behçet’s disease, 549 in calcium pyrophosphate dihydrate, 549 enteropathic, 549 gonococcal, 547 in gout, 549 in Lyme disease, 550 pauciarticular, 547 psoriatic, 547, 549, 549f reactive, 549 in relapsing polychondritis, 549 rheumatoid arthritis as, 547 in sarcoidosis, 549–550 in scleroderma, 547 in systemic lupus erythematosus, 547 viral, 547 physical examination in, 546 radiographic features of, 546 synovial histopathology in, 711–712, 711f, 712f Polyarticular pain, differential diagnosis of, 551–553 Polychondritis, rheumatoid arthritis vs., 1111 Poly-l-lysine-lysozyme arthritis, animal models of, 398t, 405, 406f Polymerase chain reaction, of synovial fluid, 708 Polymorphism definition of, 309t of human leukocyte antigens, 308–309, 309t Polymorphonuclear leukocytes, in rheumatoid arthritis, 1053

xxxviii

Index

Polymorphonuclear neutrophils, in synovial fluid, in rheumatoid arthritis, 1054–1055 Polymyalgia rheumatica arthritis vs., 552 atypical, paraneoplastic, 1842t, 1844 clinical features of, 1415 relationship to giant cell arteritis, 1415 definition of, 1409 differential diagnosis of, 1417 epidemiology of, 1410 glucocorticoid therapy for, 870t laboratory studies in, 1415, 1416t management of, acute-phase reactants in, 771–772 monarticular arthritis associated with, 541 pathology and pathogenesis of, 1411, 1412 rheumatoid arthritis vs., 1111–1112 treatment of, 1419–1420, 1420f Polymyositis apoptosis in, 390 apoptosis induction in, 391 clinical features of, 1362–1363 antisynthetase syndrome as, 1363 arthritis, 1363 cardiovascular, 1363 gastrointestinal, 1363 pulmonary, 1362–1363 differential features of, 1389t glucocorticoid therapy for, 870t HIV-associated, 1751, 1751f, 1752t imaging in, 809, 809f malignancy-associated, 1846 Poncet’s disease. See Tuberculous arthritis. Popliteal cysts, 636 in osteoarthritis, 1555 Population association studies, of HLA disease associations, 310, 310t, 311t, 313 Positron-emission tomography clinical application of, 782 in rheumatoid arthritis, 782–786 technical considerations in, 782 Postinjection “flare” with arthrocentesis, 726, 726t with joint injection, 726, 726t Poststreptococcal reactive arthritis, 1777–1778 Posture, in ankylosing spondylitis, 1177 Potassium channels, neuromuscular ­transmission and, 97 pp75, in Sjögren’s syndrome, 751t PPARγ. See Peroxisome proliferator-activated receptor γ. Prayer sign, in diabetic stiff-hand syndrome, 1834f Pre-B cell receptor, as B cell maturation marker, 183t Prednisolone effects on hypothalamic-pituitary-adrenal axis, 869–870 for injection, 725t during lactation, 866 pharmacodynamics of, 865t for rheumatoid arthritis, 871 structure of, 864f for systemic lupus erythematosus, in ­pregnancy, 1289 timing of administration of, 872 Prednisone drug interactions of, 866, 866f effects on hypothalamic-pituitary-adrenal axis, 869–870 enlargement of, diffuse infiltrative ­lymphocytosis syndrome, 1753 for giant cell arteritis, 1418, 1419 for gouty arthritis, 1499 for Henoch-Schönlein purpura, in children, 1694

Prednisone (Continued) during lactation, 866, 1288 for myositis, 1374 pharmacodynamics of, 865t for polyarteritis nodosa, 1455, 1456t, 1691 for polymyalgia rheumatica, 1419 for relapsing polychondritis, 1632 structure of, 864f for systemic lupus erythematosus, 1282, 1286t in children, 1680 for Takayasu’s arteritis, 1424 withdrawal regimen for, 873, 873t Pregabalin for chronic pain, 989 for fibromyalgia, 564 Pregnancy, 1837 anakinra in, 942 antimalarials in, 899 in antiphospholipid syndrome, 1304, 1306–1307, 1307–1308 treatment of, 1290 aspirin during, 851 coxibs during, 851 cytotoxic drugs in, 1288 glucocorticoids in, 866 hydroxychloroquine in, 888t leflunomide in, 888t, 893 Lyme disease and, 1723 methotrexate in, 888t, 889 mixed connective tissue disease in, 1394 nonsteroidal anti-inflammatory drugs during, 851 osteonecrosis and, 1615t rheumatoid arthritis and, 1039 serum urate concentrations in, 1487 sulfasalazine in, 888t, 897 in systemic lupus erythematosus, 1288–1290, 1289t treatment and, 1288, 1289–1290 TNF inhibitors in, 937–938 PRELP. See Arginine-rich end leucine-rich repeat protein. PREMIER trial, 932t, 936 PREN, in rheumatoid arthritis, fibroblast-like synoviocytes and, 206 Prepatellar bursitis, 635–636 Prevalence, in epidemiology, 433 Primary afferent fibers, inflammation and, 411–412 Primary biliary cirrhosis as autoimmune disease, 261t Sjögren’s syndrome secondary to, 1158 Primary Care Evaluation of Mental Disorders, 982 Primary granules, eosinophilic, 228, 228t Primary synovial osteochondromatosis, imaging in, 821–822, 822f magnetic resonance imaging for, 821–822, 822f PRIME-MD. See Primary Care Evaluation of Mental Disorders. Pristane-induced arthritis, animal models of, 398t, 399 Probenecid, for hyperuricemia control, 1501, 1501t Probiotics, 506t Prognosis, in rheumatoid arthritis, variables related to, 1114 Programmed cell death, 379. See also ­Apoptosis. of T cells, 170–171 Programmed cell death 1, in systemic lupus erythematosus, 1239, 1240 Programmed death 1, 164 Progressive systemic sclerosis. See Scleroderma.

Proinflammatory cytokines, adrenocorticotropic hormone and, 869, 869f Proline, in cartilage, 41 PROMIS. See Patient Reported Outcomes Measurement Information System. Propoxyphene, for chronic pain, 985 Prospective cohort studies, 435t, 436–437 Prostacyclin actions of, 348 production by cyclooxygenase pathway, 347–348 Prostaglandin(s) actions of, 836 biosynthesis of, 836 D2, as mast cell mediator, 239 E1, 354 E2 actions of, 347 calcium metabolism and, 77 in osteoarthritis, 1537 production by cyclooxygenase pathway, 347 receptors for, 352–353 structure of, 347 Prostaglandin synthases, 347 Prosthetic joints infections of, 1707–1711, 1710f prevention of, 1710–1711 Proteases cysteine. See Cathepsin(s). inhibitors of, in rheumatoid arthritis, 1077–1078 joint destruction and, in rheumatoid ­arthritis, 1075–1077 neutrophil, 217 Proteasomes in inflammatory muscle diseases, 750t in Sjögren’s syndrome, 751t Protein A immunoabsorption column, 1130 Protein C inhibitor, 122, 124t Protein kinases C, neutrophils and, 219 mitogen-activated neutrophils and, 219 in rheumatoid arthritis, 1067–1069, 1068f Protein tyrosine kinases, T lymphocyte ­activation and, 161 Protein tyrosine phosphatase PTPN22, in ­systemic lupus erythematosus, 1239, 1240 Proteinase(s), 115–131 aspartic, 115, 116t in cartilage degradation, 52–53, 53t cysteine, 115, 116t, 117 inhibitors of, endogenous, 122, 124t gene expression of, 125–126, 126t, 127t inhibitors of endogenous, 122, 124–125, 124t gene expression of, 125–126, 126t, 127t joint destruction and, 128–131 bone resorption in rheumatoid arthritis and, 130–131 cartilage destruction in osteoarthritis and, 131 cartilage destruction in rheumatoid ­arthritis and, 129–130, 130f extracellular matrix degradation in ­cartilage and, 128–129, 129f rheumatoid synovitis monitoring by serum MMP-3 levels and, 130 metalloproteinases as. See Matrix ­metalloproteinases; Metalloproteinases. in osteoarthritis, 1535–1536 proteinase-3 matrix degradation and, 116t neutrophils and, 217

index Proteinase(s) (Continued) regulation of, 125–128 activation mechanisms of zymogens of ­metalloproteinases and, 126–128, 127f gene expression of proteinases and ­inhibitors and, 125–126 pericellular docking of matrix ­metalloproteinases and, 128 serine, 116t, 117–118 inhibitors of, endogenous, 122, 124t Proteinase nexin-1 plasminogen activator expression and, 127t as proteinase inhibitor, 122, 124t Protein-energy malnutrition, metabolic ­response to inflammation and, 1009 Proteinuria, in pregnancy, in systemic lupus erythematosus, 1289 Proteoglycan(s) in aged cartilage, 58 as biomarkers, 477t, 480 in bone matrix, 79 in cartilage, 3, 40t, 41 in osteoarthritis, 1529, 1535–1536 in synovial subintimal layer, 27 Proteoglycan-induced arthritis, animal models of, 398t, 399–400, 401 Proteomics, biomarkers based on, 484 Proteosomal components, autoimmunity to, 1384, 1384f Proto-oncogenes, in fibroblast-like ­synoviocytes, altered expression of, 205–206 Provocative discography, in low back pain, 620 Proximal myotonic myopathy, differential diagnosis of, 1370, 1371t, 1372 PRRs. See Pattern-recognition receptors. Pseudo-angina pectoris, 578, 579f Pseudogout in calcium pyrophosphate dihydrate ­deposition disease, 1514 glucocorticoid therapy for, 870t synovial fluid in, 705t of temporomandibular joint, 669 differential diagnosis of, 667t Pseudohyperparathyroidism, 1835 Pseudolymphoma(s), in Sjögren’s syndrome, 1157 Pseudoscleroderma syndromes, 1343–1344 Pseudotumor(s), orbital, 682 Pseudoxanthoma elasticum, 1652 Psoriasis in HIV infection, 1750, 1750f skin lesions in, 685–686, 686f Psoriasis Assessment Severity Index, 1209, 1210t Psoriatic arthritis, 1201–1216 adalimumab for, 936 clinical course of, 1209 clinical features of, 1201, 1202f–1205f, 1204, 1206 core sets for clinical trials in, 464t diagnosis of, 1208, 1210f, 1210t differential diagnosis of, 1206, 1206t epidemiology of, 1201 future directions in, 1216 in HIV infection, 1750 imaging in, 790–791 abnormalities in specific sites and, 790–791 general imaging features and, 790 spinal involvement and, 815, 815f juvenile idiopathic arthritis as, 1670 laboratory features of, 1206 outcome domains and instruments in, 1209–1210, 1210f, 1210t

Psoriatic arthritis (Continued) outcome of, 1209 pathogenesis of, 1210–1213 animal models of, 1211 bone remodeling in, 1213 cytokines in, 1212–1213 environmental factors in, 1211 genetic factors in, 1211 immunopathology and, 1211–1212 matrix metalloproteinases and cartilage destruction and, 1213 polyarticular, 547, 549, 549f, 550 radiographic features of, 1206–1208 on magnetic resonance imaging, 1208, 1209f on plain radiography, 1206–1207, 1207f on ultrasound, 1207–1208, 1208f synovial fluid in, 705t synovial histopathology in, 712 of temporomandibular joint, 668 differential diagnosis of, 667t treatment of, 1213–1216, 1215f biologic agents for, 1216 etanercept for, 935 glucocorticoid therapy for, 870t infliximab for, 933–934 leflunomide for, 892 methotrexate for, 887 sulfasalazine for, 895–896 traditional agents for, 1214–1215 uveitis in, 679 vascular risk in, 429 Psychiatric disorders. See also specific disorders. with chronic pain, 976–979, 978t identification of, 981–983 Psychogenic pain, 977, 978t arthritis vs., 553 Psychological abnormalities, in fibromyalgia, 559 Psychopharmacologic interventions, 1005 Psychophysiologic pain, 978 Psychosis glucocorticoid-induced, 877 pain and, 978t, 979 in systemic lupus erythematosus, 1275 Psychosocial interventions, for osteoarthritis, 1563–1564 Psychosocial management, 999–1005 depression and, 1000–1001 disability insurance and, 1001–1002 employment and, 1001–1002 family relationships and, 1000 fatigue and, 1000 health care utilization and, 1002–1003 illness experience and, 999 chronicity and, 999 pain and, 999 physician-patient communication and, 1004, 1005b psychosocial interventions and, 1004– 1005 reading and educational levels and, 1003–1004, 1003t Psychotherapy, 1005 Psychotropic drugs, for fibromyalgia, 564 PTH. See Parathyroid hormone. PTHrp. See Parathyroid hormone-related ­peptide; Parathyroid hormone-related protein. PTKs. See Protein tyrosine kinases. PTPN22, in vasculitis, 1406 Pulmonary arterial hypertension, in systemic sclerosis, 1335–1336, 1336f Pulmonary capillaritis in microscopic polyangiitis, 1443–1444 in systemic lupus erythematosus, 1276t

xxxix

Pulmonary disorders. See also specific disorders. in ankylosing spondylitis, 1176 of Behçet’s disease, 1477 in dermatomyositis, 1362–1363 in giant cell arteritis, 1414 in microscopic polyangiitis, 1443–1444 in polymyositis, 1362–1363 in rheumatoid arthritis, 1102–1103 in Sjögren’s syndrome, 1154–1155 in systemic lupus erythematosus, 1276–1277, 1276t Pulmonary embolism, in systemic lupus ­erythematosus, 1276t Pulmonary fibrosis in rheumatoid arthritis, 1102–1103 in systemic sclerosis, 1317, 1334–1335, 1334f Pulmonary function tests, in myopathy, 1370 Pulmonary hemorrhage, in systemic lupus erythematosus, 1277 Pulmonary hypertension in mixed connective tissue disease, 1394 primary, HIV-associated, 1755 in rheumatoid arthritis, 1103 in systemic lupus erythematosus, 1276t Pulmonary infarction, in systemic lupus ­erythematosus, 1276t Pulmonary infiltrates in Churg-Strauss syndrome, 1445 in systemic lupus erythematosus, 1288 in Wegener’s granulomatosis, 1434–1435, 1435f Pulmonary surfactant proteins, as pattern-recognition receptors, 280 Pulmonary toxicity of cyclophosphamide, 913 of leflunomide, 893 of methotrexate, 888–889 of sulfasalazine, 896 Pulpitis, as temporomandibular disorder mimic, 666t Pulsed electromagnetic fields, for osteoarthritis, 1564 Pulseless disease. See Takayasu’s arteritis. Purines, metabolism of, 1489–1491, 1489f, 1490f Purpura in Henoch-Schönlein purpura, in children, 1694 palpable, in immune complex-mediated vasculitis, 1466, 1466f in Sjögren’s syndrome, 1156, 1156f PVNS. See Pigmented villonodular synovitis. Pyoderma gangrenosum, 687–688 neutrophils in, 227 Pyogenic sterile arthritis, pyoderma ­gangrenosum, and acne syndrome, 1878 Pyomyositis, HIV-associated, 1755 Pyrazinamide, for tuberculosis, 1735 Pyridinolines, as biomarkers, 477t PYRIN domain proteins, as pattern-recognition receptors, 282, 283–284, 286 Pyruvate dehydrogenase, in Sjögren’s ­syndrome, 751t

Q

QALYs. See Quality-adjusted life-years. Quadriceps femoris muscle, atrophy of, 527 Quadriceps tendon, examination of, 632, 633f Quadrilateral space syndrome, 610 Quality-adjusted life-years, 442 Quantitative computed tomography, for bone density assessment, 1584 Quinacrine. See also Antimalarials. chemical structure of, 897, 897f

xl R

Index

RA. See Rheumatoid arthritis. RA 33, in rheumatoid arthritis, 762 “Raccoon-eyes” sign, in AM amyloidosis, 1789, 1789f Radial nerve, testing of, in neck pain, 580t Radiation, systemic sclerosis and, 1314 Radiation therapy, malignancy associated with, 1856 Radiculopathy, cervical, 575–576, 583 Radiocarpal joint, arthrocentesis technique for, 730, 730f Radiofrequency ablation, for low back pain, 622 Radiographic Patient Outcomes trial, 931t, 935, 1128 Radiography, conventional. See Conventional radiography; under specific conditions. Radionuclide scintigraphy, 781–782 clinical application of, 781–782 RAG(s). See Recombination-activating genes. Ragged red fibers, in myopathy associated with HIV treatment, 1752 RA-HAQ, 1025 Raloxifene, for osteoporosis, 1587 Randomization, in clinical trials, 453–454 Randomized clinical trials. See Clinical trials. Randomized Evaluation of Long-term Efficacy of Rituximab in RA trial, 949t, 950, 951, 952 Range of motion, of joint degrees of freedom, 108–109 Range of motion exercise, in physical medicine and rehabilitation, 1027 Range of motion testing, in neck pain, 580–581 RANK, in rheumatoid diseases, 370t RANKL. See Receptor activator of NFκB. RANTES, in cartilage destruction, 56, 56t Rapamycin. See Sirolimus. Rashes with antimalarials, 899 with azathioprine, 916 in dermatomyositis, 1360–1362, 1361f, 1362f juvenile, 1682–1683, 1683f in human T-cell leukemia virus type 1 ­infection, 1767–1768, 1768f in hyper-IgD syndrome, 1870, 1870f with leflunomide, 893 in Muckle-Wells syndrome, 1875, 1875f, 1876f with sulfasalazine, 896 in systemic lupus erythematosus, 1266–1268 acute, 1266–1267, 1267f chronic, 1267, 1268f subacute, 1267, 1268f Raynaud’s phenomenon antinuclear antibodies in, 751 in diffuse cutaneous systemic scleroderma, 1688 imaging of, 807, 808f in mixed connective tissue disease, 1393 occupation-related, 494t in Sjögren’s syndrome, 1156 in systemic sclerosis, 1329–1330, 1330f, 1330t treatment of, 1340, 1340t RCIs. See Clinical trials. Reactive arthritis, 1196–1199 cause of, 1196, 1196t clinical features of, 1196–1197, 1197f, 1197t definition of, 1196 enteric, 1225–1227 causes of, 1225–1226, 1226t diagnosis of, 1226 epidemiology of, 1225

Reactive arthritis (Continued) outcome of, 1227 pathogenesis of, 1226 treatment of, 1226–1227 epidemiology of, 1196 genetics of, 1196 glucocorticoid therapy for, 870t in HIV infection, 1749–1750, 1749f treatment of, 1749–1750 imaging in, 791 laboratory tests in, 1197 natural history of, 1197–1198, 1198t pathogenesis of, 1196 polyarthritis in, 550 polyarticular, 549 poststreptococcal, 1777–1778 rheumatoid arthritis vs., 1107 skin lesions in, 686–687, 686f synovial fluid in, 705t synovial histopathology in, 712 treatment of, 1198–1199 in HIV infection, 1749–1750 sulfasalazine for, 896 uveitis in, 679 Reactive oxygen species platelets and, 253 in rheumatoid arthritis, synovium and, 1070 Reading level, psychosocial management and, 1003–1004, 1003t Recall bias, in cohort studies, 436 Receptor activator of NFκB bone destruction regulation by, 1078, 1078f osteoclasts and, 74, 75 osteoporosis and, 1580 in psoriatic arthritis, 1213 in rheumatoid arthritis, osteoclastogenesis and, 210 Receptor editing, 271 RECK, as MMP inhibitor, 10t, 125 Recombination-activating genes gene 1 as B cell maturation marker, 183t VDJ gene rearrangement and, 180 gene 2 as B cell maturation marker, 183t VDJ gene rearrangement and, 180 Recreation-related musculoskeletal disorders, 494–497, 495t, 496t REFLEX. See Randomized Evaluation of Long-term Efficacy of Rituximab in RA trial. Reflex sympathetic dystrophy occupation-related, 494t pain generation with, 975 paraneoplastic, 1842t, 1844 shoulder pain due to, 611 Regression toward the mean, 455 Rehabilitation goals of, 1023 interdisciplinary vs. multidisciplinary, 1023 International Classification of Functioning, Disability and Health and. See International Classification of ­Functioning, Disability and Health. Reiter’s syndrome. See Reactive arthritis. Relapsing polychondritis, 1629–1633 clinical features of, 1629–1631, 1630t course of, 1632 criteria for, 1629, 1630t definition of, 1629 differential diagnosis of, 1632 epidemiology of, 1629 evaluation in, 1632 laboratory findings in, 1631–1632, 1631f pathophysiology of, 1629 polyarthritis in, 549

Relapsing polychondritis (Continued) prognosis of, 1632 skin lesions in, 698 treatment of, 1632–1633 uveitis in, 679 Relapsing seronegative symmetric synovitis, rheumatoid arthritis vs., 1112 Reliability, test-retest, 470 Renal biopsy, in systemic lupus erythematosus, 1271–1272 evaluation and interpretation of specimens and, 1272, 1272f, 1273f indications for, 1271–1272 Renal disorders. See also specific disorders. in amyloidosis, 1791t in ankylosing spondylitis, 1176 of Behçet’s disease, 1477 in Churg-Strauss syndrome, 1445 in hyperuricemia, 1487–1488, 1487f, 1488t in microscopic polyangiitis, 1443 in mixed connective tissue disease, 1392 in polyarteritis nodosa, 1455 in relapsing polychondritis, 1631 in rheumatoid arthritis, 1102 in Sjögren’s syndrome, 1155 in systemic lupus erythematosus, 1270–1274 in systemic sclerosis, 1336–1338 in Wegener’s granulomatosis, 1435 Renal fibrosis, in systemic sclerosis, 1317 Renal toxicity of coxibs, 851 of cyclophosphamide, 910–911 of nonsteroidal anti-inflammatory drugs, 847t, 851 Renal transplantation in systemic lupus erythematosus, 1291–1292 in systemic sclerosis, 1338 Renal tubular acidosis, in Sjögren’s syndrome, 1155 treatment of, 1162 Reproductive toxicity, of nonsteroidal anti-inflammatory drugs, 847t Rest in physical medicine and rehabilitation, 1026 for rheumatoid arthritis, 1137 Reticulohistiocytosis, multicentric paraneoplastic, 1842t, 1845 rheumatoid arthritis vs., 1110 skin lesions in, 699–700 synovial histopathology in, 712 Retinacular cysts, 659 Retinal vasculitis, 679 Retinopathy, with antimalarials, 899 Retropatellar pain, 528 Retrospective cohort studies, 435t, 437 Retroviral infection, rheumatoid arthritis and, 1042–1043 Revascularization procedures, for Takayasu’s arteritis, 1425 Reynold’s syndrome, 1386 RFs. See Rheumatoid factors. Rhabdomyolysis, HIV-associated, 1752 RHD. See Rheumatic heart disease. Rheumatic fever, 1771–1782 adult, polyarticular arthritis in, 549 clinical course of, 1780–1781 clinical features of, 1776–1779, 1777t arthritis as, 1777 carditis as, 1778, 1778t chorea as, 1778–1779 erythema marginatum as, 1779 minor, 1779 reactive arthritis as, 1777–1778 rheumatic heart disease as, 1778 subcutaneous nodules as, 1779

index Rheumatic fever (Continued) epidemiology of, 1771, 1772t etiology of, 1774–1776, 1775f, 1775t, 1776t genetics of, 1773–1774, 1774t group A streptococci and, 1772–1773, 1772f, 1773f laboratory findings in, 1780 pathogenesis of, 1771–1772 prophylaxis of, 1781 rheumatoid arthritis vs., 1112 treatment of, 1780–1781 glucocorticoid therapy for, 870t Rheumatic heart disease, 1778 as autoimmune disease, 261t Rheumatism palindromic, antimalarials for, 899 postchemotherapy, 1853 Rheumatoid arthritis abatacept for, 954–958 clinical studies of, 954–957, 955t, 956f current role of, 957 pathogenesis of rheumatoid arthritis and, 958 safety issues with, 957 acute-phase reactants for, 770–771 adalimumab for, 936 adhesion molecules in, regulation of, 1073–1074 anakinra for, 941 angiogenesis in, 1072–1073, 1072f of ankle, 1096–1097, 1096f, 1097f anticitrullinated protein in, 760–761 antimalarials for, 898 atherosclerosis in, 421–429 assessment of, 427–429 epidemiology of, 421–422 future research directions for, 429 lessening risk via inflammatory ­suppression, 426–427 pathogenesis of, 422–426 as autoimmune disease, 260, 267–268 biomarkers in, 476 bone destruction in, regulation by RANKL, 1078, 1078f bone resorption in, 130–131 burden of disease and, 1087 cancer in, 1100 cardiac complications of in, 1103–1104 cartilage destruction in, 37, 52 pannus-cartilage junction and, 1074–1075, 1075f by proteinases, 129–130, 130f of cervical spine, 1090–1091, 1091f, 1092f collagen type II in, 761 combination disease-modifying ­antirheumatic drug therapy for, 900–902 biologic agents in, 901–902 corticosteroids in, 901 in early rheumatoid arthritis, 900 historical background of, 900 patient selection for, 902 in patients with active disease despite methotrexate, 900–901, 901f complement activation ion, 334 complementary and alternative medicine for, 1138 core sets for clinical trials in, 464t costs of, 445–446 course of, 1113–1114 assessment of individual patient and, 1114, 1115t mortality and, 1113–1114 variables related to prognosis and, 1114 of cricoarytenoid joints, 1092 depression in, 1001

Rheumatoid arthritis (Continued) diagnosis of, 1104, 1105t differential diagnosis of, 1104–1113, 1106t adult-onset Still’s disease and, 1104–1106, 1106t amyloidosis and, 1106 angioimmunoblastic lymphadenopathy and, 1106–1107 ankylosing spondylitis and, 1107 bacterial endocarditis and, 1107–1108 calcific periarthritis and, 1108 calcium pyrophosphate dihydrate ­deposition disease and, 1108 congenital camptodactyly and arthropathy and, 1108 familial Mediterranean fever and, 1108 fibromyalgia and, 1108 giant cell arteritis and, 1111–1112 glucocorticoid withdrawal syndrome and, 1108 gout and, 1108–1109 hemochromatosis and, 1109 hemoglobinopathies and, 1109 hemophilic arthropathy and, 1109 HIV and, 1109 hypercytokine syndrome and, 1109 hyperlipoproteinemia and, 1109 hypertrophic osteoarthropathy and, 1109 idiopathic hypereosinophilic syndrome with arthritis and, 1109–1110 infectious diseases and, 1110 intermittent hydrarthrosis and, 1110 Lyme disease and, 1110 malignancy and, 1110 multicentric reticulohistiocytosis and, 1110 oral contraceptive-associated arthritis and, 1107 osteoarthritis and, 1110–1111, 1111t Parkinson’s disease and, 1111, 1111f pigmented villonodular synovitis and, 1111 polychondritis and, 1111 polymyalgia rheumatica and, 1111–1112 reactive arthritis and, 1107 relapsing seronegative symmetric synovitis and, 1112 rheumatic fever and, 1112 sarcoidosis and, 1112 seronegative spondyloarthropathy and, 1107 systemic lupus erythematosus and, 1112 Thiemann’s disease and, 1112 thyroid disease-associated arthritis and, 1107 vasculitis and, 1112 Whipple’s disease and, 1113 differential features of, 1389t disease-modifying antirheumatic drugs for, 871 distal interphalangeal joint involvement in, 523, 523f early, 1087–1090 onset patterns of, 1088 unusual patterns or variants of, 1089–1090 of elbow, 1093 epidemiology of, 1087 etanercept for, 934–935 extra-articular complications of, 1097 eyes in, 1098, 1099f ferritin in, 762 fibroblast-like synoviocytes in, 204–210 altered proto-oncogene expression and, 205–206 attachment to cartilage and, 207–208 interactions with inflammatory cells, 209–210

xli

Rheumatoid arthritis (Continued) matrix degradation and, 208–209 resistance against apoptosis and, 206–207 stable fibroblast activation in synovium and, 204–205, 204f, 206f fibroblasts in, 204 fistula development in, 1100 of foot, 1096–1097, 1096f, 1097f glucocorticoid therapy for, 870–872, 870t radiologic joint damage and, 871–872, 871f signs and symptoms and, 870–871 glucose-6-phosphate isomerase in, 761 of hand, 1093–1095, 1093f–1095f hematologic abnormalities in, 1100–1101 of hip, 1095, 1095f HLA-DRB1 associations with, 311–312, 312f, 312t imaging in, 782–786 abnormalities in specific sites and, 783–786 general imaging features and, 782–783 magnetic resonance imaging for, 785–786, 786f, 787f, 810, 811f with spinal involvement, 809–810, 810f, 811f immunity in etiology and pathogenesis of, 1035–1046 autoimmunity and, 1043–1046 gender and, 1039 HLA-DR and, susceptibility and severity and, 1037–1038, 1037t infectious agents and, 1040–1043 innate immunity and, 1035, 1036f rise and fall of rheumatoid arthritis and, 1040, 1040f, 1040t single-nucleotide polymorphisms and, 1038–1039, 1038t tobacco and, 1039 immunoglobulin binding protein in, 761 infection in, 1100 infectious triggers for, 269 infliximab for, 931–933 joint destruction in inhibitors of protease activity and, 1077–1078 proteases as mediators of, 1075–1077 joint involvement in, 1088, 1088t juvenile. See Juvenile rheumatoid arthritis. of knee, 1095–1096, 1096f leflunomide for, 892, 892t of lumbar spine, 1091–1092 macrophage and fibroblast cytokines in, 1060–1067, 1061t perpetuation of synovitis by, 1066–1067, 1066f proinflammatory, 1061–1065 suppressive, 1065–1066 malignancy associated with, 1847t, 1848–1850 solid tumors and, 1850 mannose-binding lectin in, 761 of manubriosternal joint, 1092 methotrexate for, 886 monarticular, 540 muscle in, 1097–1098 neck pain in, 583–584, 583t neutrophils in, 226 nutrition in, 1009–1010 obesity and, 509 occupation-related, 494t onset of acute, 1088 age and, 1089–1090 insidious, 1088 intermediate, 1088 palindromic pattern of, 1089, 1089t

xlii

Index

Rheumatoid arthritis (Continued) of ossicles of ear, 1092 paralysis and, 1090 platelets in, 253 pathogenesis and, 253–254 polyarticular, 547 polymorphonuclear neutrophils and, 1054–1055 arachidonate metabolites and, 1056 complement and, 1056–1057 immune complexes and, 1055–1056 peripheral blood lymphocyte immune responses and, 1057–1058 T lymphocytes and, 1055 prognosis of in, estimating, 1136–1137 pulmonary disease in, 1102–1103 RA 33 in, 762 renal disease in, 1102 rheumatoid factor in, 757, 759–760, 760f rheumatoid nodules in. See Rheumatoid nodules. risk factors for, 1087 rituximab for, 948–953 clinical studies of, 948–951, 949t, 950f, 951f current role of, 952–953 disease modification and, 951 duration of benefit of, 952 future directions for, 953 safety issues with, 951–952 of sacral spine, 1091–1092 scleritis in, 681 of shoulder, 1092–1093, 1093f signal transduction and transcription factors in, 1067–1070 activator protein-1 as, 1069 antiviral protein regulation and, 1069–1070 mitogen-activated protein kinases as, 1067–1069, 1068f NFκB as, 1067, 1068f transcription and, 1069 skeleton in, 1097 skin lesions in, 687–688, 687f, 1098 of sternoclavicular joint, 1092 synovial cells in, 1070–1072 apoptosis and, 1070–1071 nitric oxide and, 1070 reactive oxygen and, 1070 tumor-suppressor genes and, 1071–1072 synovial fluid in, 705t, 1054–1058 synovial histopathology in, 711–712, 711f, 712f synovial pathology and biology in, 1046–1054, 1047b, 1047f B cells and, 1051–1053 bone marrow cells and, 1054 dendritic cells and, 1053 in early vs. late rheumatoid arthritis, 1054 mast cells and, 1053 natural killer cells and, 1053 polymorphonuclear leukocytes and, 1053 synoviocytes and, 1047–1049 T lymphocytes and, 1049–1051 T cell cytokines in, 1058–1060, 1058t regulatory T cells as, 1059–1060 synovial cell activation by cell-cell ­contact with T lymphocytes and, 1060 T helper cell cytokine imbalance and, 1060 T helper type 1, 1058–1059 T helper type 2, 1059 T helper type 17, 1059 of temporomandibular joint, 668, 1092 differential diagnosis of, 667t of thoracic spine, 1091–1092 tissue repair in, 1078–1079

Rheumatoid arthritis (Continued) treatment of, 1119–1138. See also specific drugs. activities of daily living and, 1138 adjunctive drug therapy for, 1132–1134 cardiovascular disease risk and, 426–427 combination therapy for, 1125–1126, 1125f–1128f diet and, 1138 disease-modifying antirheumatic drugs for, 1119–1124, 1120f, 1121t. See also Disease-modifying antirheumatic drugs; specific drugs. early, 1135–1136 education and, 1137 exercise and, 1137–1138 future directions for, 1139 pain control and, 1137 prognosis and, 1136–1137 response to, assessing, 1134–1135 rest and, 1137 rheumatologist’s role in management and, 1138 sulfasalazine for, 895 treatment strategies and, 1124–1125, 1125f tumor necrosis factor inhibitors for, 1130 vasculitis in, 1101–1102, 1101f of wrist, 1093–1095, 1093f–1095f Rheumatoid factors, 755–757, 756f autoimmunity and, 1043–1044, 1043f biochemical and immunochemical properties of, 758 diagnostic tests for, 755–756 diseases commonly associated with, 756, 757t in health and nonrheumatologic disease, 758–759, 758t incidence of, 756–757, 757t in polyarthritis, 546t in pregnancy, 1837 in rheumatoid arthritis, 757, 759–760, 760f Rheumatoid neutrophilic dermatitis, 227, 688 Rheumatoid nodules, 687, 687f, 782, 783f differential diagnosis of, 1099 in hands, 522, 522f with methotrexate, 889 Rheumatoid nodulosis, 1090 Rheumatoid vasculitis, 687, 1453, 1473 Rheumatologists, role in rheumatoid arthritis management, 1138 Ribonucleoproteins, anti-small nuclear, in systemic lupus erythematosus, 747–748 Rickets, 1591, 1591t, 1592 Rifampicin, for Brucella arthritis, 1227 Rifampin drug interactions of, 866, 866f, 893, 921 for tuberculosis, 1735 Risedronate for osteoporosis, 1588 for Paget’s disease of bone, 1595 Rituximab, 1131–1132 apoptosis and, 391 for rheumatoid arthritis, 948–953 clinical studies of, 948–951, 949t, 950f, 951f current role of, 952–953 disease modification and, 951 duration of benefit of, 952 future directions for, 953 safety issues with, 951–952 for systemic lupus erythematosus, 953, 1284–1285 for Wegener’s granulomatosis, 1442 RNPs, in inflammatory muscle diseases, 750t Ro molecules, systemic lupus erythematosus and, 1244

Rofecoxib, 840, 846 adverse effects of, 848, 849 development of, 834 withdrawal from market, 848–849 Ro/La, antibodies against proteins associated with, in systemic lupus erythematosus, 1235 Roquin autoimmune disease and, 263t B cell activation and, 194 Ross River virus infection, 1765, 1766 Ro/SS-A, in Sjögren’s syndrome, 751, 751t Rotator cuff arthrocentesis technique for, 729f tears of diagnosis of, 601–602 imaging in, 823–825, 825f pathophysiology of, 601 shoulder pain due to, 601–603 treatment of, 602–603 tendinopathy of, shoulder pain and, 599–600, 600f Rowell’s syndrome, 1267 Rubella arthritis, 1763–1764 diagnosis of, 1763–1764, 1764f epidemiology of, 1763 pathogenesis of, 1763 prognosis of, 1764 treatment of, 1764 Rubella virus, rheumatoid arthritis and, 1042 Rugby, osteoarthritis associated with, 495t Running, osteoarthritis associated with, 495–496, 495t, 496t Runt-domain transcription factor chondrocyte differentiation and, 42–43 type X, 7 Runx2. See Runt-domain transcription factor. RUNX2, osteoblast maturation and, 72 Ryanodine receptor, in skeletal muscle, 96t

S

S protein, complement regulation by, 326t SAA. See Serum amyloid A. Sacral fractures, insufficiency, imaging in, 780, 821f Sacral spine, rheumatoid arthritis of, 1091–1092 Sacroiliac joint(s) in ankylosing spondylitis, 1174 imaging of, 811–812, 811f hip pain and, 638 in juvenile chronic arthritis, imaging of, 788 in osteoarthritis, imaging of, 795 in psoriatic arthritis, imaging of, 791 in reactive arthritis, imaging of, 791, 792f in rheumatoid arthritis, imaging of, 785 Sacroiliitis, in ankylosing spondylitis, 1177 Saddle-nose deformity in relapsing polychondritis, 1631f, 1632 in Wegener’s granulomatosis, 1434, 1434f S-adenosylmethionine, 507 for osteoarthritis, 1571 Safety analysis, interpretation of, 461 St. Vitus’ dance, in acute rheumatic fever, 1778–1779 Salicylate, 19 Saliva, reduction in, in Sjögren’s syndrome, 1153–1154, 1153f Salivary glands swelling of, oral, 1153, 1153f in systemic sclerosis, 1318 Salix species, 506 Salsalate, 842t SAMe. See S-adenosylmethionine. Sample size, 457, 457f Sarcoglycanopathy, differential diagnosis of, 1371t, 1372

index Sarcoid dactylitis, 1798 Sarcoidosis, 1795–1805, 1796f cause and pathogenesis of, 1795–1798 clinical features of, 1798–1801, 1799f–1800f joint involvement as, 1800 muscular, 1801 vasculitis as, 1801 diagnosis of, 1801–1803, 1802t epidemiology of, 1795 future directions for, 1804 monarticular arthritis associated with, 541 paraneoplastic, 1842t, 1846 polyarthritis in, 549–550 rheumatoid arthritis vs., 1112 Sjögren’s syndrome vs., 1158–1159 skin lesions in, 698–699, 699f treatment of, 1803–1804 methotrexate for, 887 uveitis in, 679–680, 679f Sarcoma(s), 1852. See also Chondrosarcoma(s). primary, of joints, 1897–1900 secondary, of joint, 1900 synovial, 1898–1900, 1898f–1900f Satisfaction with health outcomes, 466 Sausage digits, 522 Scaphoid fracture, 659 nonunion and, 659 Scapholunate interosseous ligament injury, 656, 657f Scapular winging, 610 Scavenger receptors, as pattern-recognition receptors, 281 Scedosporiosis, 1743 SCF. See Stem cell factor. SCFE. See Slipped capital femoral epiphysis. Schamberg’s purpura, 687 Schizophrenia, pain and, 978t Schwannomas, neck pain and, 583 Schwartzmann phenomenon, 226 Scintigraphy in hip pain, 640, 641f in knee pain, 634–635, 636f in shoulder pain, 593 SCLE. See Subacute cutaneous lupus ­erythematosus. Sclera, 677 Scleredema, 1343 Scleritis, 681–682, 681f in rheumatoid arthritis, 1098, 1099f Scleroderma, 693, 693f antinuclear antibodies in, 748–749, 749t antikinetochore and anti-topoisomerase I and, 748 anti-polymyositis-scleroderma and, 749 anti-RNA-polymerases and, 748 in children, 1685–1690, 1686t diffuse cutaneous, 1686–1688 classification of scleroderma-spectrum disorders and, 1311–1312, 1312t, 1313f–1315f, 1314t differential features of, 1389t eosinophils and, 230 imaging in, 807–808, 808f limitation of mandibular movement in, 666t linear, 692, 693f, 1342, 1342t coup de sabre as, 1342t, 1343 localized, 1341–1343, 1342t in children, 1688–1689, 1689f linear, 1342, 1342t morphea as, 1341–1342, 1342t mast cells and, 241 occupation-related, 494t overlap with other connective tissue ­diseases, 1386 polyarthritis in, 547 Sjögren’s syndrome secondary to, 1158

Scleroderma (Continued) skin lesions in, 692–694 systemic, 693, 693f synovial histopathology in, 712 Scleroderma fibroblast, fibrosis and, 1327–1328 Scleroderma renal crisis, 1337–1338, 1337f Scleroderma-like syndromes, occupation­related, 494t Scleromalacia perforans, 1098 Scleromyxedema, 1343 skin lesions in, 694 Scleromyxoderma, skin lesions in, 694 Sclerosis, systemic. See Scleroderma. Sclerosteosis, osteoblasts in, 72 Sclerostin gene, osteoblasts and, 72 SCW arthritis. See Streptococcal cell wall arthritis. SDAI. See Simplified Disease Activity Index. Second messengers, neutrophils and, 219 Secretagogues, for Sjögren’s syndrome, 1162 Secretory stimulants, for Sjögren’s syndrome, 1161, 1161t Secretory vesicles, of neutrophils, 217, 217t Seizures, in systemic lupus erythematosus, 1275 Selectins angiogenesis and, 358, 359t neutrophil adhesion and, 219–220, 220f T cell extravasation and, 291–292 Selective estrogen receptor modulators, for osteoporosis, 1587 Selective serotonin reuptake inhibitors, for chronic pain, 988, 989t Selenium, in nutrition, 1013 Sensation testing, in neck pain, 581 Septic arthritis calcium pyrophosphate dihydrate deposition disease vs., 1516 in hemophilia, 1818 imaging in, 792–793, 793f polyarticular, 1706 shoulder pain due to, 607 tuberculous, 1732–1733, 1733f Serine proteinases in cartilage degradation, 53t gene expression of, 125, 127t inhibitors of, 122, 124t gene expression of, 125, 127t matrix degradation and, 116t, 117–118 SERMs. See Selective estrogen receptor modulators. Seronegative spondyloarthropathy, rheumatoid arthritis vs., 1107 Serpins, as proteinase inhibitors, 122, 124t Sertraline, for fibromyalgia, 564 Serum amyloid A, acute-phase response and, 769 Serum sickness, animal model of, 333 SF-36, 465, 982 Shark cartilage, for osteoarthritis, 1571 Shawl sign, linear, 1361, 1361f SH2-domain-containing leukocyte protein of 76 kD, T lymphocyte activation and, 161 “Shining corner” sign, 812, 812f SHIP, B cell activation and, 188 Shoewear, for foot and ankle pain, 647 Shoulder(s) adhesive capsulitis of, in diabetes mellitus, 1834 in ankylosing spondylitis, 1175 imaging of, 814 arthrocentesis technique for, 728–729 monarticular and periarticular syndromes affecting, 536t osteoarthritis in, 1557 range of motion of, 588 in rheumatoid arthritis, imaging of, 784, 784f rheumatoid arthritis of, 1092–1093, 1093f

xliii

Shoulder pain, 587–611, 588t, 589f anatomy and function and, 587, 590f, 591f causes of, 599–609 acromioclavicular disorders as, 604–605, 605f adhesive capsulitis as, 607–608 bicipital tendinitis and rupture as, 603–604 brachial neuritis as, 609 cervical radiculopathy as, 609 cuff-tear arthropathy as, 606–607 glenohumeral disorders as, 605 glenohumeral instability as, 608–609 hemodialysis as, 611 inflammatory arthritis as, 605, 606f labral tears as, 607 neoplasms as, 611 nerve entrapment syndromes as, 609–610 osteoarthritis as, 606, 606f osteonecrosis as, 606 periarticular disorders as, 599–601 reflex sympathetic dystrophy as, 611 rotator cuff tear as, 601–603 septic arthritis as, 607 sternoclavicular arthritis as, 610–611 diagnosis of, 588, 590–599, 599t arthrography for, 593–595, 594f arthroscopy for, 596 clinical evaluation for, 588 computed tomography for, 595, 595f, 596f electromyography for, 597 history taking and, 588 injection for, 597–598 magnetic resonance imaging for, 597, 598f nerve conduction velocity studies for, 597 physical examination for, 588, 590–593, 592f radiographic assessment for, 593, 593f scintigraphy for, 593 ultrasonography for, 595–596, 597f Shoulder-hand syndrome. See Reflex sympathetic dystrophy. SHP-1, B cell activation and, 188 SHP-2, B cell activation and, 188 Shrinkage necrosis, 379 Shrinking-lung syndrome, in systemic lupus erythematosus, 1276t, 1277 Sialadenitis, autoimmune, Sjögren’s syndrome and, 1150, 1150f Sicca symptoms, in systemic sclerosis, 1338 Sicca syndrome/complex, 1149. See also Sjögren’s syndrome. Sickle cell diseases anemia as, osteonecrosis and, 1615t cause of, 1827, 1828f Sickness Impact Profile, 465 Signal rejection particle, in inflammatory muscle diseases, 750t Signal transduction, 337–341 in apoptosis, 339–341 Bcl-2 family signaling and, 340–341 death receptor signaling and, 340 p53 and cell cycle arrest and, 341 by death receptors, 382–383, 383f infectious mononucleosis B cells, immature vs. mature, 188–189 inflammation and, 413 JAK/STAT/SOCS family and, 339 MAPKs and, 337–338 neutrophils and, 217, 218f NFκB and, 338–339, 339f in rheumatoid arthritis, 1067–1070 activator protein-1 and, 1069 antiviral protein regulation and, 1069–1070

xliv

Index

Signal transduction (Continued) mitogen-activated protein kinases and, 1067–1069, 1068f nuclear factor κB and, 1067, 1068f toll-like receptors and, 339, 340f Silica dust systemic sclerosis and, 1313 vasculitis and, 1406–1407 Silicone synovitis, imaging in, 823, 824f Simplified Disease Activity Index, 1134, 1135 Sindbis virus arthritis, 1765, 1766 Singers, musculoskeletal disorders in, 497 Single-nucleotide polymorphisms, in ­rheumatoid arthritis, 1038–1039, 1038t Sinusitis, in Wegener’s granulomatosis, 1434, 1434f SIP. See Sickness Impact Profile. Sirolimus, 920 mechanism of action of, 910t Sjögren’s syndrome, 1149–1162 antimalarials for, 899 antinuclear antibodies in, 750–751, 751t apoptosis induction in, 391 autoantigens in, 1152 autoimmune sialadenitis and, 1150, 1150f clinical manifestations of, 1152–1154 autoimmune thyroid disease as, 1156, 1156f gastrointestinal, 1155 hepatic, 1155 lymphoproliferative disease as, 1157, 1157t musculoskeletal, 1154, 1154t neurologic, 1156–1157 ocular, 1152–1153, 1153f oral, 1153–1154, 1153f pancreatic, 1155 pulmonary, 1154–1155 renal, 1155 vascular, 1156, 1156f clinical outcomes in, 1158 cytokine profile in, 1151 definition of, 1149 differential diagnosis of, 1158–1159, 1159t epidemiology of, 1149, 1150t glandular destruction in, mechanisms of, 1151–1152 HLA associations with, 313 immunogenetics of, 1149–1150 immunologic alterations in peripheral blood and, 1150 infiltrating lymphocytes in, phenotype of, 1151 inflammatory cell trafficking and adhesion in, 1151 malignancy associated with, 1847t, 1848 primary, glucocorticoid therapy for, 870t secondary, 1157–1158 skin lesions in, 691 treatment of, 1160–1162 for ocular disease, 1160–1161 for oral disease, 1161 secretory stimulation for, 1161, 1161t for systemic disease, 1161–1162 workup in, 1159–1160, 1159f, 1160t Skeletal adverse effects, of glucocorticoids, 874–875 Skeletal blastema, 5 Skeletal dysplasias, 1635–1642 biochemical and molecular abnormalities in, 1642 cartilage structure in, 1636 classification and nomenclature of, 1636, 1637t–1638t, 1639f clinical evaluation and features of, 1636, 1639

Skeletal dysplasias (Continued) diagnosis of, 1639–1641, 1640f, 1641f embryology of, 1635–1636 management and treatment of, 1641 Skeletal hyperostosis, idiopathic, diffuse. See Diffuse idiopathic skeletal hyperostosis. Skeletal toxicity, of nonsteroidal anti-inflammatory drugs, 847t Skeleton development of, 75–76 genetic abnormalities and, 76 growth and, 75–76, 76t in rheumatoid arthritis, 1097 SKG arthritis, animal models of, 398–399, 398t, 400t, 403–404 Skin. See also Cutaneous entries; Dermatologic toxicity. discoloration of, in hemochromatosis, 1811 in mixed connective tissue disease, 1390 in psoriasis, 1212 in rheumatoid arthritis, 1098 in systemic sclerosis, 1316 Skin biopsy, 685 Skin lesions, 685–700 in amyloidosis, 698 atypical infections causing, 697 in Behçet’s disease, 699 in chronic infantile neurologic cutaneous and articular syndrome, 700 in dermatomyositis, 691–692, 692f diagnosis of, 685 in eosinophilic fasciitis, 693, 693f in familial Mediterranean fever, 699 in juvenile rheumatoid arthritis, 688 in lupus erythematosus, 688–691 lupus-specific, 688–691, 689f, 690f nonspecific, 691 in Lyme disease, 696–697, 697f in morphea, 692–693, 693f in multicentric reticulohistiocytosis, 699–700 in neonatal lupus syndrome, 691 in nephrogenic fibrosing dermopathy, 694 in panniculitis, 697–698, 698t in parvovirus infections, 697 in POEMS syndrome, 693–694 in primary necrotizing vasculitis, 694–696 granulomatous, 695–696 large vessel, 696 leukocytoclastic small vessel vasculitis as, 694–695, 694f polyarteritis nodosa as, 696 in psoriasis, 685–686, 686f in Reiter’s syndrome, 686–687, 686f in relapsing polychondritis, 698 in rheumatoid arthritis, 687–688, 687f in sarcoidosis, 698–699, 699f in scleroderma, 692–694, 693, 693f in scleromyxedema, 694 in Sjögren’s syndrome, 691 in Still’s disease, 688 SLAP lesions. See Superior labrum anterior posterior lesions. SLCs. See Synoviocytes. SLE. See Systemic lupus erythematosus. SLEDAI. See Systemic Lupus Erythematosus Disease Activity Index. Sleep disturbance of, in fibromyalgia, 558 pain and, 979 Slipped capital femoral epiphysis, monarticular arthritis associated with, 541 SLP-76. See SH2-domain-containing leukocyte protein of 76 kD. SMA. See Spinal muscular atrophy.

SMAD pathway, mediation of chondrocyte responses by, 51, 51f Small airways disease, in rheumatoid arthritis, 1103 Small intestine, in systemic sclerosis, 1331 Smoking osteonecrosis and, 1612 rheumatoid arthritis and, 1039 vasculitis and, 1406 SNPs. See Single-nucleotide polymorphisms. Soccer, osteoarthritis associated with, 495t SOCS proteins, signal transduction and, 339 Sodium channels, neuromuscular transmission and, 97 Soft tissue changes, in rheumatoid arthritis, 782 Soft tissue damage with arthrocentesis, 726, 726t with joint injection, 726, 726t Soft tissue infection(s), differential diagnosis of, 536 Solid organs, antigens from, detection in ­peripheral lymph nodes, 297–298, 298f Soluble mannose binding protein. See Mannan-binding lectin. Somatization disorder, 977, 978t Somatoform disorders, 977–978, 978t Sox family, in cartilage morphogenesis, 6 SOX proteins, chondrocyte differentiation and, 42 Sp1, in scleroderma, 749, 749t S1P1. See Sphingosine-1-phosphate. Spa therapy, non-narcotic, 1566 Specific granules deficiency of, 224t eosinophilic, 228–229, 228t neutrophilic, 216–217, 217t Speed’s test, 593 Sphingosine-1-phosphate, T lymphocyte migration and, 294 Spinal cord, 573–574, 573f pain transmission to, 970–971, 970f sensitization at, 971 Spinal cord myelopathy, in systemic lupus erythematosus, 1292 Spinal muscular atrophy, differential diagnosis of, 1372, 1372t Spinal stenosis, imaging in, 818–819 Spine in ankylosing spondylitis, 1174 imaging of, 812–814, 812f–814f mobility of, 1177 bamboo, 812, 812f, 1174 cervical anatomy of, 571, 572f–574f, 573–574, 574t arthrocentesis technique for, 728 in juvenile chronic arthritis, imaging of, 788, 790f rheumatoid arthritis of, 1090–1091, 1091f, 1092f degenerative disease of, imaging of, 817–820 diseases of, arthritis vs., 552 infective spondylitis affecting, imaging of, 815–817, 816f lumbar fusion in, for low back pain, 622–623 rheumatoid arthritis of, 1091–1092 osteoarthritis in, 1557 psoriatic arthritis affecting, imaging of, 815, 815f reactive arthritis affecting, imaging of, 815 rheumatoid arthritis affecting, imaging of, 779–810, 810f, 811f sacral, rheumatoid arthritis of, 1091–1092 Spinomesencephalic tract, 971, 972f, 972t

index Spinoreticular tract, 971, 972f, 972t Spinothalamic tract, 971, 972f, 972t Spleen antigen detection by, 295–296, 296f, 297f cutaneous, 1789 Splenectomy, for Felty’s syndrome, 1147 Splenomegaly, in systemic lupus erythematosus, 1277 Spliceosomal components, autoimmunity to, 1383, 1383f Splinter hemorrhages, in immune complex­mediated vasculitis, 1466, 1467f Splinting for carpal tunnel syndrome, 653 in physical medicine and rehabilitation, 1029 Spondylitis infectious, imaging in, 815–817, 816f tuberculous, 1730–1732, 1731f, 1732f Spondyloarthritis. See also specific conditions. classification of, 1191–1192, 1192t future directions in, 1195 undifferentiated, 1191–1195 diagnosis of, 1192–1193 enthesitis in, 1193–1194 in HIV infection, 1750 signs, symptoms and course of, 1193 treatment of, 1195 Spondyloarthropathy. See also specific conditions. classification of, 1170, 1170t HLA-B27 and, 310–311 seronegative monarticular, 540–541 synovial fluid in, 705t of temporomandibular joint, 668 therapeutic injection in, 723 Sporotrichosis, 1741–1742 inflammatory monarticular arthritis ­associated with, 541 Sports-related musculoskeletal disorders, 494–497, 495t, 496t Spur(s), ankle pain and, 645 Spurling test, 590 in neck pain, 582 SR-a I/II, 145t Src family of kinases, T lymphocyte activation and, 161, 162 SS-A, in Sjögren’s syndrome, 1152 SS-B, in Sjögren’s syndrome, 1152 SSc. See Systemic sclerosis. SSRIs. See Selective serotonin reuptake ­inhibitors. SSZ. See Sulfasalazine. Stanford Health Assessment Questionnaire, 982, 1114, 1115t Staphylococcus aureus infection(s), bacterial arthritis caused by, 1702–1703, 1703t STAT proteins, signal transduction and, 339 Statin(s) drug interactions of, 919 to lessen coronary heart disease risk, in rheumatoid arthritis via, 427 for systemic sclerosis, 1340 Statin myopathy, differential diagnosis of, 1371t, 1374 Statistical analysis, of trial results, 460 Statistical power, 457, 457f Statistical significance, of trial results, 461 Stefin A, as proteinase inhibitor, 124t Stefin B, as proteinase inhibitor, 124t Steinberg test, in Marfan syndrome, 1650 Stem cell factor, mast cells and, 236–237 STEPS protocol. See System for Thalidomide Education and Prescribing Safety protocol.

Sternoclavicular joint examination of, 519 rheumatoid arthritis of, 1092 shoulder pain due to arthritis of, 610–611 Sternocostal joint, examination of, 519 Steroid(s). See also Corticosteroids; Glucocorticoid(s); specific steroids. androgenic-anabolic, muscle and, 104 injections of, for low back pain, 622 to reduce inflammation, lessening vascular risk in rheumatoid arthritis via, 426 systemic absorption of with arthrocentesis, 726, 726t with joint injection, 726, 726t Steroid psychosis, glucocorticoid-induced, 877 Steroid withdrawal syndrome, 1836 Sterols, plant, 506t Stevens-Johnson syndrome, with leflunomide, 893 Stiff-hand syndrome, diabetic, 1833, 1834t Stiffness in ankylosing spondylitis, 1175 history taking and, 516 in osteoarthritis, 1548 Still’s disease adult-onset imaging in, 788 management of, acute-phase reactants in, 772 rheumatoid arthritis vs., 1104–1106, 1106t skin lesions in, 688 Stomach, in systemic sclerosis, 1332 Stratified randomization, 454 Strengthening exercise, in physical medicine and rehabilitation, 1027 Streptococcal cell wall arthritis, animal models of, 397, 398t, 400–401, 400t Streptococcal infection(s), in psoriatic ­arthritis, 1211 Streptococcal vaccines, 1781 Stress in fibromyalgia, 558–559 psoriatic arthritis and, 1211 Stress fractures, ankle pain and, 645, 646 Stromal mesenchymal cells, synovial, ­immunohistology of, 715 Stromolysin. See Matrix metalloproteinases, MMP-3. Structure-modifying drugs, for osteoarthritis, 1571 Subacromial bursa, arthrocentesis technique for, 729f Subacute cutaneous lupus erythematosus, 689, 689f, 1267, 1268f Subcutaneous nodules, in acute rheumatic fever, 1779 Subglottic stenosis, in Wegener’s ­granulomatosis, 1434, 1434f Subintima, synovial, 27–28 categories of, 27, 27f components of, 27 lymphatics of, 28, 29f nerve supply of, 28, 29f vasculature of, 28, 29f Subject selection, for clinical trials, 454–455 Subluxation. See specific sites. Substance abuse disorder, pain and, 978t Substance P afferent nerves containing, 11 inflammation and, 412, 412f, 413 Subtalar joint, arthrocentesis technique for, 734, 734f Succinylcholine, drug interactions of, 913

xlv

Sudeck’s atrophy. See Reflex sympathetic dystrophy. Sulfasalazine actions of, 894 for ankylosing spondylitis, 1183 chemical structure of, 893, 894f contraindications to, 897 dosing with, 896 drug interactions of, 897, 916 efficacy of, 895t indications for, 895–896 mechanism of action of, 895t neutrophil functions and, 227 pharmacology of, 894–895 for reactive arthritis, in HIV infection, 1750 for rheumatoid arthritis, 871, 1121 special considerations with, 888t toxicity of, 895t, 896–897 Sulfinpyrazone, for hyperuricemia control, 1501–1502 Sulfone syndrome, 922 Sulindac, 842t adverse effects of, 852 SUMO-1, Fetal alcohol syndrome (FAS) regulation by, 207 Supartz, for injection, 725t Superficial zone cells, in meniscus, 12 Superficial zone protein, in cartilage, 40t Superior labrum anterior posterior lesions, 591, 607 Superoxide dismutase, 1011, 1011f Suprascapular nerve entrapment syndrome, 610 Supraspinous ligament, 573 Surgery, preoperative glucocorticoid therapy for, 873, 873t Surrogate outcomes, 456 Swan neck deformity, 522, 523f in Parkinson’s disease, 1111, 1111f in rheumatoid arthritis, 1094, 1095f Sweat volume, in Sjögren’s syndrome, 1154 Sweet’s syndrome, 687–688 neutrophils in, 227 Swelling. See also specific sites. examination for, 517 history taking and, 516 Sydenham’s chorea, in acute rheumatic fever, 1778–1779 Syk B cell activation and, 187 T lymphocyte activation and, 161 Sympathetic nervous system, inflammation and, 415–416 Symphyses, 1 Synarthroses, 1 development of, 8 Synchondroses, 1 Syndecans fibroblast attachment to extracellular matrix and, 202, 203f syndecan-3 in cartilage, 40t chondrocyte interactions with, 47, 48 Syndesmophytes, 812, 812f Syndesmoses, 1 Synostoses, 1 Synovectomy, for hemophilic arthropathy, 1822–1823 Synovial biopsy, 708–709 arthroscopically guided, 709 in inflammatory arthritis, predicting therapeutic response and, 716 in monarthritis, 710–711, 710f percutaneous, blind, 708–709 in polyarthritis, 711–712, 711f, 712f processing tissue samples for, 709

xlvi

Index

Synovial cells, activation by cell-cell contact with T lymphocytes, in rheumatoid arthritis, 1060 Synovial chondromatosis, 1889–1891, 1890f–1892f Synovial cysts, 1883–1884, 1884f, 1885f Synovial fluid, 14–16 accumulation of synovial effusions and, 703–704 cartilage lubrication by, 15–16 cartilage nutrition by, 16 characteristics of, 705t clearance of, 15 components of, 14–15, 15f formation of, 30–32, 32f generation of, 14 in health, 703 as joint function indicator, 15 in rheumatoid arthritis, 1054–1058 arachidonate metabolites in, 1056 complement in, 1056–1057 immune complexes in, 1055–1056 lymphocytes in, 1055 peripheral blood lymphocyte immune responses and, 1057–1058 polymorphonuclear neutrophils in, 1054–1055 Synovial fluid analysis, 703–708 in arthritis research, 708 arthrocentesis and, 704, 704f biochemical analysis for, 708 culture for, 707 cytology in, 705–706 Gram stain for, 707 gross examination for, 704–705 leukocyte count in, 705, 705t in monarticular arthritis, 542 polymerase chain reaction for, 708 wet smear, by polarized microscopy, 706–707, 706f, 707f Synovial immunohistology, 712–716 of microvasculature, endothelium, and stromal mesenchymal cells, 715 sampling and quantitative analysis in, 712–713 of synovial lining cell layer, 713–714, 713f, 714f of synovial lymphocytes and plasma cells, 714–715 of synovial sublining macrophages and dendritic cells, 715 of synovial-cartilage-bone interface, 715–716, 716f Synovial intima, 8, 9–10 Synovial joints. See Diarthrodial joints. Synovial lining, 8, 9–10 Synovial lining cells. See Synoviocytes. Synovial macrophages, 24, 26f Synovial membrane. See also Synovial lining. in health, 709–710, 710f Synovial pathology, in inflammatory arthritis, predicting therapeutic response and, 716 Synovial sarcoma(s), 1898–1900, 1898f–1900f Synovial tissue alterations in, in osteoarthritis, 1537–1539, 1538f biomarkers in, 482f, 481–483 Synoviocytes, 23–26 fibroblast-like, in rheumatoid arthritis, 204–210, 1048–1049, 1049f altered proto-oncogene expression and, 205–206 attachment to cartilage and, 207–208 interactions with inflammatory cells, 209–210 matrix degradation and, 208–209

Synoviocytes (Continued) resistance against apoptosis and, 206–207 stable fibroblast activation in synovium and, 204–205, 204f, 206f origin of, 26 turnover of, 26 type A and type B, in rheumatoid arthritis, 1047–1049 ultrastructure of, 23, 24f, 25f immunohistochemical profile of, 24–25 Synovioma, giant cell, benign, 1895, 1895f, 1896f Synovitis. See also Tenosynovitis; specific sites. acute, in calcium pyrophosphate dihydrate deposition disease, 1514 early, rheumatoid arthritis and, 1088–1089 mycobacterial, 1736–1737 nodular, localized, 1895, 1895f, 1896f perpetuation of, by macrophage-fibroblast cytokine networks, 1066–1067, 1066f rheumatoid, monitoring of, by serum MMP-3 levels, 130 seronegative, symmetric, remitting, with pitting edema, paraneoplastic, 1842t, 1845 silicone, imaging in, 823, 824f in Sjögren’s syndrome, 1154 symmetric, seronegative, relapsing, rheumatoid arthritis vs., 1112 villonodular, pigmented, 1893–1895, 1893f–1895f Synovium, 23–33 biopsy of, in monarticular arthritis, 543 blood flow of, regulation of, 10 definition of, 7 deformability of, 28 development of, 7 fatty lesions of, 1886–1888, 1887f, 1888f function of, 28–32 chondrocyte nutrition as, 32 joint movement as, 28–30 synovial fluid formation as, 30–32, 32f histopathology of, in early vs. late ­rheumatoid arthritis, 1054 leukocyte extravasation into, 357, 358f lubrication as function of, 30 of mature joint, 8–10, 9f nonadherence of, 29 in psoriasis, 1212 in rheumatoid arthritis apoptosis and, 1070–1071 matrix metalloproteinase expression in, 1076, 1077f nitric oxide and, 1070 reactive oxygen and, 1070 tumor-suppressor genes and, 1071–1072 structure of, 23–28, 24f of subintimal layer, 27–28, 27f of synovial lining cells, 23–26 subintimal layer of, 27–28 vascular lesions of, 1888–1889, 1888f, 1889f vasculature of, 10 Synpolydactyly, osteoblasts in, 72 Synvisc, for injection, 725t Syringomyelia, imaging in, 807 System for Thalidomide Education and ­Prescribing Safety protocol, 922, 1478 Systemic Lupus Activity Measure, 1265 Systemic lupus erythematosus in adolescents, 1290 antimalarials for, 898 antinuclear antibodies in, 746–748, 747t antiribosome, 748 chromatin-associated, 746–747 ribonucleoprotein, 747–748 antiphospholipid syndrome in, 1290 as autoimmune disease, 267, 268

Systemic lupus erythematosus (Continued) in children, 1290, 1677–1681 cause and pathogenesis of, 1677–1678 classification of clinical features of, 1678–1679, 1678t definition of diagnosis of, 1679 drug-induced, 1678 epidemiology of genetic factors in, 1678 in neonates, 1680–1681, 1681f outcome of, 1680 pathology of, 1678 treatment of, 1679–1680 classification of activity and damage indices and, 1264–1266, 1265t, 1266t classification criteria for diagnosis and, 1264 criteria for, 1264, 1264t clinical features of, 1266–1279 cardiovascular, 1275–1277, 1275f correlation with T lymphocytes, immune complexes, and autoantibodies, 1252, 1252t gastrointestinal, 1278 hematologic, 1277–1278 hepatic, 1279 mucocutaneous, 1266–1269, 1267t musculoskeletal, 1269–1270 neurologic, 1274–1275, 1274f, 1274t, 1275t ophthalmic, 1279 renal, 1270–1274, 1290–1292 complement deficiency in, 331–333, 331t, 332t core sets for clinical trials in, 464t critical illness in, 1292–1293 assessment and referral guidelines for, 1292, 1292t prognosis, morbidity, and mortality and, 1293 diagnosis of, 1279–1281 antibodies to extractable nuclear antigens and, 1279 antinuclear antibodies and, 1279 differential diagnosis of and, 1280–1281 typical and atypical presentations and, 1280, 1280t dialysis in, 1290–1291 differential features of, 1389t drug-induced, 1290, 1291t end-stage renal disease in, 1290–1292 dialysis and, 1290–1291 renal transplantation and, 1291–1292 epidemiology of, 1263 genetic factors in, 1236–1242 autoantibody production and, 1238 human studies of, 1236–1238, 1237t individual HLA genes predisposing to systemic lupus erythematosus and, 1238 murine studies of, 1241–1242 nonleukocyte antigen genes predisposing to systemic lupus erythematosus and, 1238–1241 glucocorticoid therapy for, 870t historical background of, 1263 human leukocyte antigen class II ­associations with, 311 imaging in, 808–809, 808f immunizations in, 1287–1288 infection prevention in, 1287–1288 infectious triggers for, 269 malignancy associated with, 1847t, 1850–1851 screening for, 1288

index Systemic lupus erythematosus (Continued) management of acute-phase reactants in, 771 evidence-based recommendations for, 1293, 1293t–1294t monarticular arthritis associated with, 541 neonatal, 1680–1681, 1681f occupation-related, 494t pathogenesis of, 1233–1253, 1234f apoptosis in, 1244 B cell abnormalities in, 1245–1247, 1245t correlation among clinical manifestations, autoantibodies, immune complexes, and T cells in, 1252, 1252t effectors in, 1233–1236 environmental factors in, 1242–1243, 1242t gender and, 1243–1244 genetic factors in, 1236–1242 immunoregulatory abnormalities in, 1246t, 1250–1252 T cell abnormalities in, 1245t, 1247–1250 polyarthritis in, 547 in pregnancy, 1288–1290, 1289t cytotoxic drugs and, 1288 treatment of, 1288, 1289–1290 pulmonary infiltrates in, 1288 renal transplantation in, 1291–1292 rheumatoid arthritis vs., 1112 Sjögren’s syndrome secondary to, 1158 susceptibility to, IRF5-associated, 318 treatment of, 1281–1286 adjunct therapy for, 1288 cytotoxic drugs in severe, life-threatening disease and, 1286–1287 general principles of management for, 1281 leflunomide for, 892 methotrexate for, 887 for mild disease without major organ involvement, 1281 for moderate-to-severe disease, 1281–1286, 1281t, 1282t in pregnancy, 1288 rituximab for, 953 vascular risk in, 429 Systemic Lupus Erythematosus Disease ­Activity Index, 1265, 1265t Systemic Lupus International Collaborating Clinics/ACR damage index, 1265–1266, 1266t Systemic sclerosis, 1311–1344. See also ­Scleroderma. animal models of, 1318–1320, 1319t genetic manipulations and, 1320 heritable, 1318–1319 inducible, 1319–1320 classification of scleroderma-spectrum disorders and, 1311–1312, 1312t, 1313f–1315f, 1314t clinical features of, 1328–1338 cardiac, 1333–1334, 1333f cutaneous, 1328–1329 gastrointestinal, 1331–1332, 1331t musculoskeletal, 1332–1333 neurologic, 1338 pulmonary, 1334–1336, 1334t renal, 1336–1338 sicca symptoms as, 1338 vascular, 1329–1331 cutaneous diffuse, 1314t limited, 1314t diagnosis of, 1338–1339 autoantibodies in, 1339 disease assessment in, 1338–1339

Systemic sclerosis (Continued) epidemiology of, 1312 etiology of, 1312–1314 drugs and, 1313–1314 environmental exposures and, 1313 genetic factors in, 1312 radiation and, 1314 viruses in, 1312–1313 future directions for, 1344 malignancy associated with, 1847t, 1851–1852 outcome of, 1341 pathogenesis of, 1320–1328 fibrosis and, 1324–1327 inflammation and autoimmunity and, 1321–1324 scleroderma fibroblast and, 1327–1328 vasculopathy and, 1320–1321, 1321f pathology of, 1314–1318, 1316f cardiovascular, 1317 cutaneous, 1316 gastrointestinal, 1317 pulmonary, 1317, 1317f renal, 1317, 1318f tissue fibrosis and, 1315–1316 vascular, 1315, 1316f prognosis of, 1341 treatment of, 1339–1341 antibiotic agents for, 1339–1340 glucocorticoid therapy for, 870t immunomodulatory therapy for, 1339–1341, 1339t–1341t management principles and, 1340–1341 methotrexate for, 887 vascular therapies for, 1340, 1340t Systemic sclerosis sine scleroderma, 1314t SZP. See Superficial zone protein.

T

T cell anergy, 270 T cell extravasation, multistep paradigm for, 291–293 T cell receptors inflammation and, 171 in sarcoidosis, 1797 T lymphocyte activation and, 160, 160f, 162 T lymphocyte development and, 155–159 T lymphocytes, 155–171 activation of, 160–165 adapter proteins and, 161–162 costimulation and, 162–163 downstream transcription factors and, 162 immunologic synapse and, 163–164, 163f T cell receptors and, 160, 160f tolerance and control of autoreactive T cells and, 164–165 tyrosine kinases and, 160–161 autoimmunity and, 269–271, 270t autoreactive, tolerance and control of, 164 clinical studies of, 958 costimulatory signals provided by, B cell autoimmunity and, 194, 196 development of, 155–159, 157f–159f abnormalities of, 159 extrathymic, 159 signaling molecules required for, 156, 157f, 158 in thymus, 294–295, 295f effector, types of, 300 future directions for, 959 γδ, innate immune response and, 165–166 helper, autoimmunity and, 272 innate-like, 284 mast cell development and, 237 peripheral, 165–171

xlvii

T lymphocytes (Continued) CD4 and CD8, 165 death of, 170–171 γδ T cells as, 165–166 at inflammation sites, 171 in innate immune response, 165–170 molecular mimicry and, 170 naive vs. memory, 166–167, 167t natural killer cells as, 166 Th17, 170 Th1 vs. Th2, 167, 168t–169t, 170 peripheral migration of, 159–160 recruitment of, in rheumatoid arthritis, 209–210 regulatory, autoreactivity reduction by inhibition of immunologic synapse formation and, 298 in rheumatoid arthritis, 1058–1060, 1058t activation of synovial cells by cell-cell contact with, 1060 helper, imbalance of, 1060 helper, type, 1, 1058–1059 helper, type, 2, 1059 helper, type, 17, 1059 regulatory, 1059–1060 in Sjögren’s syndrome, 1151 synovial, in rheumatoid arthritis, 1049–1051 immunohistologic patterns of, 1049 lymphoid aggregate formation regulation and, 1049–1050 restoration of T cell tolerance and, 1051 synovial T cell immune response and, 1051 synovial T cell phenotype and, 1050, 1050f in systemic lupus erythematosus, 1245t, 1247–1250 correlation with clinical ­manifestations, immune complexes, and ­autoantibodies, 1252, 1252t inadequate downregulation by, 1251–1252 inadequate idiotypic circuits controlling, 1252 systemic sclerosis pathogenesis and T helper type 1/T helper type 2 balance and, 1322–1323 T helper type 2 polarized immune ­responses and, 1322–1323 targeting of, 958–959 in Wegener’s granulomatosis, 1433 TA. See Takayasu’s arteritis. Tabes dorsalis, imaging in, 807 Tacrolimus, 919–920 apoptosis and, 390–391 dosage for, 920 mechanism of action of, 910t, 919 pharmacology of, 919–920 for rheumatoid arthritis, 1124 structure of, 919 Takayasu’s arteritis, 1420–1425 ACR criteria for, 1420, 1420t cause and pathogenesis of, 1421 in children, 1695–1696 clinical features of, 1421–1423 imaging and, 1422–1423, 1422f, 1423t laboratory findings and, 1422 signs and symptoms and, 1421–1422, 1421t diagnosis of, 1423–1424, 1423f, 1424t epidemiology of, 1405t, 1420–1421 future directions for, 1425 monarticular arthritis associated with, 541 outcome of, 1425 prognosis of, 1425 treatment of, 1424–1425 medical therapy in, 1424–1425 surgical therapy in, 1425

xlviii

Index

Tamm-Horsfall protein, encoding of, 1488, 1488t Tamoxifen, for osteoporosis, 1587 TANK binding kinase 1, in rheumatoid ­arthritis, 1069–1070 Target population, of health outcome ­assessment, 468 TARGET trial, 849 Tarsal tunnel syndrome arthrocentesis technique for, 735 therapeutic injection in, 724 TB. See Tuberculosis. TBK1. See TANK binding kinase 1. TCRs. See T cell receptors. Tdt, as B cell maturation marker, 183t Tec family of kinases, T lymphocyte activation and, 161 Technical efficiency, in health economics, 442 Technology, in health outcomes assessment, 471–472 Teeth, dental caries and, in Sjögren’s syndrome, 1153, 1154 Telangiectasia, cutaneous, in systemic sclerosis, 1328–1329, 1329f Temperature modalities, for osteoarthritis, 1564 TEMPO trial. See Radiographic Patient Outcomes trial. Temporal arteritis. See Giant cell arteritis. Temporal artery abnormalities of, in giant cell arteritis, 1413, 1413f biopsy of, in giant cell arteritis, 1417, 1418f Temporomandibular joint arthrocentesis technique for, 728 development of, 7–8 examination of, 519 osteoarthritis in, 1557 rheumatoid arthritis of, 1092 Temporomandibular joint pain, 665–675, 666t, 667t agenesis and, 667t arthritis and, 665–669 degenerative, 665–668 infectious, 668–669 metabolic, 668–669 rheumatoid, 668 spondyloarthropathies and, 668 traumatic, 668–669 internal derangements causing, 669–672 clinical findings in, 669–670, 670f etiology of, 670–671 imaging in, 671 treatment of, 671–672, 671f myofascial pain and dysfunction and, 672–674 clinical findings in, 672–673 diagnosis of, 673, 673t etiology of, 672, 672f treatment of, 673–674, 674f neoplasms causing, 672 Tenascin, in synovial subintimal layer, 27 Tenascin-C, in cartilage, 40t, 41 Tender points, in fibromyalgia, examination of, 561–562 Tenderness in ankylosing spondylitis, 1175 examination for, 517 Tendinitis arthritis vs., 551–552, 552f differential diagnosis of, 534, 536 monarticular arthritis vs., 534, 536 therapeutic injection in, 724 Tendon(s), 11 insertion sites of, 11 Tendon rupture with arthrocentesis, 726, 726t with joint injection, 726, 726t

Tendon sheath chondroma of, 1891–1892, 1892f fibromas of, 1889, 1889f fibroxanthoma of, 1896–1897, 1896f, 1897f giant cell tumor of, 1896–1897, 1896f, 1897f Tendon weakening with arthrocentesis, 726, 726t with joint injection, 726, 726t Tennis elbow, 520 Tenosynovial giant cell tumor, 1892–1897 diffuse, 1893–1895, 1893f–1895f malignant, 1895 localized, 1895–1897, 1895f–1897f Tenosynovitis de Quervain’s, 521, 658 arthrocentesis technique for, 731, 731f therapeutic injection in, 724 flexor, arthrocentesis technique for, 732 mycobacterial, 1736, 1736f, 1737f in systemic lupus erythematosus, 1269 TENS. See Transcutaneous electrical nerve stimulation. Teratogenicity, of cyclophosphamide, 913 Testicles, in polyarteritis nodosa, 1455 Testosterone aging of muscle and, 104 bone mineral density and, 78 for osteoporosis, 1587 Test-retest reliability, 470 Tetanus, limitation of mandibular movement in, 666t Tetanus toxoid, in systemic lupus erythematosus, 1288 Tetracyclines, for osteoarthritis, 1571–1572 TFCC. See Triangular fibrocartilage complex injury. TG2, in calcium pyrophosphate dihydrate deposition disease, 1512 TGF-β. See Transforming growth factor-β. Th1 cells, 300 in innate immune response, 167, 168t–169t, 170 systemic sclerosis pathogenesis and, 1322–1323 Th2 cells, 300 in innate immune response, 167, 168t–169t, 170 systemic sclerosis pathogenesis and, 1322–1323 Th17 cells, in innate immune response, 170 Th snoRNP, in scleroderma, 749t Thalidomide, 921–922 for ankylosing spondylitis, 1183 dosage for, 913 mechanism of action of, 910t, 913 pharmacology of, 913 structure of, 921 toxicity of, 921–922 THC. See Total hemolytic assay. Therapeutic injection complications of, 726–727, 726t contraindications to, 725, 725t corticosteroid, 724–725, 725t for osteoarthritis, 1568 current and future trends in, 735–736 glucocorticoid, 874 in hand and wrist pain, 652–653 in inflammatory arthritis, 722–723, 722t in nonarticular conditions, 722t, 724 in noninflammatory arthritis, 722t, 723–724 for osteoarthritis, 1568 preparations for, 724–725 Thick filaments, 98, 99f Thiemann’s disease, rheumatoid arthritis vs., 1112 Thin filaments, 98–100, 99f

Thomas test, 637–638, 638f Thoracic spine, rheumatoid arthritis of, 1091–1092 Three-dimensional chondrocyte culture systems, 46 Thromboaortopathy, occlusive. See Takayasu’s arteritis. Thrombocytopenia in rheumatoid diseases, 253 in systemic lupus erythematosus, 1278, 1278t Thrombocytosis, in rheumatoid arthritis, 1101 Thrombopoietin, 250 Thrombosis, in antiphospholipid syndrome, treatment of, 1307, 1307t Thromboxanes actions of, 348 production by cyclooxygenase pathway, 348 Thumb(s) basal joint arthropathy and, 658–659, 658f carpometacarpal joint of, arthrocentesis technique for, 731, 732f muscles moving, 524 Thymocytes development of, 156 metabolic disorders affecting, 159 Thymus, T lymphocyte development in, 294–295, 295f Thyroid disease. See also specific disorders. arthritis associated with, rheumatoid arthritis vs., 1107 autoimmune, in Sjögren’s syndrome, 1156 Thyroid gland, in systemic sclerosis, 1317–1318 Thyroid hormones, muscle adaptation and, 104 Thyroiditis, 260, 261t autoimmune, steroid hormones and, 269 Hashimoto’s as autoimmune disease, 261t Graves’ disease related to, 1835 Thyrotoxic myopathy, differential diagnosis of, 1371t, 1373 Tibial tendinitis, posterior, 647 Tibiofemoral joint, medial and lateral margins of, palpation of, 527 Tibiotalar joint, arthrocentesis technique for, 734, 734f Tic douloureux, 975 Ticlopidine, platelets and, 254 Tidal irrigation, for osteoarthritis, 735 Tietze’s syndrome, 519 Time constraints, psychosocial interventions and, 1005 TIMPs. See Tissue inhibitors of matrix metalloproteinases. Tinel’s sign, 610, 646 in cubital tunnel syndrome, 653 Tissue fibrosis mast cells and, 241 in systemic sclerosis, 1315–1316 Tissue inhibitors of matrix metalloproteinases in chondrocytes, 52 gene expression of, 125, 126t as proteinase inhibitors, 122, 124–125, 124t in psoriatic arthritis, 1213 in rheumatoid arthritis, 209 Tissue kallikrein, matrix degradation and, 116t, 117–118 Tissue repair, in rheumatoid arthritis, 1078–1079 Tissue-type plasminogen activator matrix degradation and, 116t, 117 plasminogen activator expression and, 127t Titin, in skeletal muscle, 96t, 99 TLE. See Tumid lupus erythematosus. TLR(s). See Toll-like receptors. TLR7, autoimmune disease and, 263t TMJ. See Temporomandibular joint entries.

index TMP-SMX. See Trimethoprim­sulfamethoxazole. TNF. See Tumor necrosis factor entries. TNF transgenic arthritis, animal models of, 398t, 400t, 404 TNFRs. See Tumor necrosis factor receptor(s). Toes. See also Digits. claw, 646 hammer, 646 mallet, 646 Toll-like receptors, 135, 136 B cell activation and, 194 Borrelia burgdorferi and, 1716 cytokine production and, 362 in giant cell arteritis, 1411–1412 in gout, 1496 immune recognition and, 142–143, 142f as pattern-recognition receptors, 282–283, 282f rheumatoid arthritis and, 1040–1041 rheumatoid factor and, in rheumatoid ­arthritis, 759–760 signal transduction and, 339, 340f in systemic lupus erythematosus, ­autoantibody production and, 1238 Tolmetin, 842t Tooth, dental caries and, in Sjögren’s ­syndrome, 1153, 1154 Tophaceous gout, 1497 Tophi, 1497 in gout, 1483–1484, 1484f–1486f in rheumatoid arthritis, 1099 Topoisomerase II, in scleroderma, 749t Torticollis, 578 Total arthroplasty for hemophilic arthropathy, 1823 of hip for osteonecrosis, 1622–1623 rates in OECD countries, 447 Total hemolytic assay, 330–331, 330t, 331t Toxic epidermal necrolysis, with leflunomide, 893 Toxic nodules, osteoporosis associated with, 1583 Toxic oil syndrome, 1313 Toxicity, in health outcome assessment, 466 Toxoplasma gondii infection(s), myositis and, 1355 tPA. See Tissue-type plasminogen activator. Trace elements, in nutrition, 1012–1013 Trachea, dry, in Sjögren’s syndrome, treatment of, 1162 Tracheal dryness, in Sjögren’s syndrome, 1154 Tracheobronchial chondritis, in relapsing polychondritis, 1630 Traction test, in neck pain, 582 TRAIL R1, death receptor signaling and, 340 TRAIL RII, death receptor signaling and, 340 Tramadol for chronic pain, 985 for fibromyalgia, 564 for osteoarthritis, 1567 Transactivation, 867, 867f Transcutaneous electrical nerve stimulation for osteoarthritis, 1564 in physical medicine and rehabilitation, 1028–1029 Transferrin, 1810t Transferrin saturation, 1810t Transforming growth factor-β calcium pyrophosphate dihydrate and basic calcium phosphate crystal deposition and, 1509 in cartilage metabolism, 49–50 cartilage repair and, 59–60

Transforming growth factor-β (Continued) fibrosis and, in systemic sclerosis, 1325–1326, 1326t mediators of chondrocyte responses to, 51, 51f neutrophil production of, 223 in osteoarthritis, 1537 platelets and, 252–253 in rheumatoid arthritis, 209, 1065–1066 skeletal growth and, 76 T cell-derived, 169t Transmembrane heparan sulfate proteoglycans, fibroblast attachment o extracellular matrix and, 202, 203f Transmission disequilibrium test, 314 Transrepression, 867, 867f TRAPS. See Tumor necrosis factor receptor­associated periodic syndrome. Trastuzumab, 483–484 Traumatic arthritis, of temporomandibular joint, 668–669 differential diagnosis of, 667t Trendelenburg gait, in hip examination, 524 Trendelenburg lurch, in hip pain, 637, 638f Trendelenburg test, in hip examination, 524–525 Triamcinolone for injection, 724–725, 725t for juvenile idiopathic arthritis, 1668 pharmacodynamics of, 865t structure of, 864f Triangular fibrocartilage complex injury, 656, 657 Tricyclic antidepressants. See also specific drugs. for chronic pain, 988, 989t for cranial neuropathy, in Sjögren’s ­syndrome, 1162 for low back pain, 621, 621t Trigeminal neuralgia, 975 as temporomandibular disorder mimic, 666t Trigger fingers, 521, 521f, 659 arthrocentesis technique for, 732 in diabetes mellitus, 1833 Trigger point injections, for low back pain, 622 Trigger point therapy, in physical medicine and rehabilitation, 1026 Trimethoprim-sulfamethoxazole, for Wegener’s granulomatosis, 1441 Trochanteric bursitis, 525–526 Trochanteric pain syndrome, arthrocentesis technique for, 732, 732f “Trolley-track” sign, 813, 813f Tropomyosin, in skeletal muscle, 96t Troponin, in skeletal muscle, 96t Trotter’s syndrome, as temporomandibular disorder mimic, 666t Truthfulness, in clinical trials, 456 Trypanosoma cruzi infection, myositis and, 1355 Tryptase as mast cell mediator, 238–239 matrix degradation and, 116t, 117 Tuberculin skin test, 1734–1735 Tuberculosis, 1729–1737 clinical features of, 1729–1734 direct musculoskeletal system ­involvement and, 1730–1733, 1730t emergence during treatment of disease and, 1733–1734 reactive immunologic phenomenon in setting of tuberculosis and, 1734 rheumatic diseases precipitated by ­treatment and, 1734 diagnosis of, 1734–1735 culture for, 1735 imaging for, 1735 interferon-γ release assays for, 1735

xlix

Tuberculosis (Continued) nucleic acid amplification for, 1735 tuberculin skin test for, 1734–1735 inflammatory monarticular arthritis ­associated with, 541 multidrug-resistant, 1736 musculoskeletal, HIV-associated, 1755–1756 in systemic lupus erythematosus, prevention of, 1287–1288 treatment of, 1735–1736 with tumor necrosis factor inhibitors, 1129 Tuberculous arthritis, 1229–1230 imaging in, 792–793 Tuberculous osteomyelitis, 1732 Tuberculous spondylitis, 1730–1732, 1731f, 1732f imaging of, 816, 816f Tumid lupus erythematosus, skin lesions of, 690 Tumor(s). See Cancer; Malignancy(ies); ­Neoplasms; specific tumors. Tumor necrosis factor(s) osteoporosis and, 1580 in rheumatoid arthritis, 1062 TNF-α apoptosis and, in rheumatoid arthritis, 207 as biomarker, in rheumatoid arthritis, 476 in cartilage degradation, 53, 54 in cartilage destruction, 55 death receptor signaling and, 340 neutrophil functions and, 228 in osteoarthritis, 1535 production by Th1 cells, 167 in psoriasis, 1212–1213 in rheumatoid arthritis, 209, 1038, 1038t in rheumatoid diseases, 368, 370t T cell-derived, 169t T lymphocyte activation and, 164 TNF-β, production by Th1 cells, 167 Tumor necrosis factor inhibitors, 1127–1129 malignancy associated with, 1849–1850, 1850 for reactive arthritis, in HIV infection, 1750 for rheumatoid arthritis, 1130 safety of, 1129–1130 TNF-α, 929–940, 930t–933t. See also specific drugs. apoptosis and, 391 for autoimmune conditions, 937 mechanisms of action of, 936–937, 937t monitoring and, 937 in pregnancy and lactation, 937–938 for sarcoidosis, 1804 toxicity of, 938–940, 938t for undifferentiated spondyloarthropathy, 1195 for Wegener’s granulomatosis, 1442 Tumor necrosis factor receptor(s) as death receptors, 382 signaling from, 382–383, 383f Tumor necrosis factor receptor pathway, ­cartilage metabolism and, 57 Tumor necrosis factor receptor-associated ­periodic syndrome, 1864t, 1871–1873 clinical features of, 1872–1873, 1872f diagnosis of, 1873, 1873t epidemiology of, 1871 etiology of, 1871, 1872f outcome of, 1873 pathogenesis of, 1871–1872 prognosis of, 1873 treatment of, 1873 Tumor suppressor genes fibroblast activation and survival and, in rheumatoid arthritis, 205 in rheumatoid arthritis, synovium and, 1071–1072



Index

TUNEL assay, 388 Tympanostomies, for Wegener’s granulomatosis, 1442 Type I error, 457, 457f Type II error, 457, 457f Tyrosine kinases, T lymphocyte activation and, 160–161

U

U3 snoRNP in inflammatory muscle diseases, 750t in scleroderma, 749, 749t UCTD. See Undifferentiated connective tissue disease. UDPGD. See Uridine diphosphoglucose ­dehydrogenase. Ulcer(s) aphthous, in hyper-IgD syndrome, 1870, 1870f ischemic, in systemic sclerosis, 1328, 1329f Ulcerative colitis. See also Inflammatory bowel disease. as autoimmune disease, 261t Ulna, subluxation of, 521, 521f Ulnar nerve entrapment of, 653–654, 654 testing of, in neck pain, 580t Ulnocarpal impaction syndrome, 656–657, 657f Ultrasound, 780–781. See also under specific conditions. for arthrocentesis, 735 clinical application of, 781 in hand and wrist pain, 652 for joint injection, 735 in knee pain, 634 in monarticular arthritis, 543 in physical medicine and rehabilitation, 1029 in shoulder pain, 595–596, 597f technical considerations in, 780–781 Ultraviolet light myositis and, 1355 systemic lupus erythematosus and, 1242 UMOD. See Uromodulin gene. Undifferentiated connective tissue disease, 1385–1386, 1387f Unfolded protein response, 267 u-PA. See Urokinase-type plasminogen ­activator. Urate nephropathy, 1487, 1487f Uric acid elimination and excretion of, 1491–1492, 1491f, 1492t physical properties of, 1492–1493 in polyarthritis, 546t Uric acid calculi, 1488 Uric acid nephropathy, 1487 Uricosuric drugs, 1492, 1492t for hyperuricemia control, 1501–1502, 1501t Uridine diphosphoglucose dehydrogenase, in synovial macrophages, 24 Urokinase-type plasminogen activator matrix degradation and, 116t, 117 plasminogen activator expression and, 127t Urologic toxicity, of cyclophosphamide, 912 Uromodulin gene, 1488, 1488t Ursolic acid, in anti-inflammatory diet, 504 Urticaria, with cyclophosphamide, 913 Urticarial vasculitis, 1471–1472 Uterus, nonsteroidal anti-inflammatory drugs and, 854 Utility scales, in health outcome assessment, 465 Utility value, in health economics, 442 Uvea, 677

Uveitis, 677, 678–681, 678f, 678t, 679f, 679t, 680f in ankylosing spondylitis, 1176 as autoimmune disease, 261t

V

V sign, linear, 1361, 1361f Vaccines live contraindication with corticosteroids, 1288 in systemic lupus erythematosus, 1288 lymph node changes associated with, 298–299 Vaccinia arthritis, 1768 Vaginal dryness, in Sjögren’s syndrome, 1154 Valdecoxib, 840, 843t adverse effects of, 848, 849 withdrawal of, 849 Validity construct, 470 external, 453 internal, 453 Valvular heart disease in rheumatoid arthritis, 1104 in systemic lupus erythematosus, 1276 van Buchem’s disease, osteoblasts in, 72 Vancomycin, for bacterial arthritis, 1708t VAS. See Visual analog scales. Vascular cell adhesion molecule-1 angiogenesis and, 358, 359t in rheumatoid arthritis fibroblast-like synoviocyte attachment to cartilage and, 208 regulation of, 1074 in synovial lining, 9–10 in synovial macrophages, 24 Vascular disorders. See also specific disorders. in relapsing polychondritis, 1630–1631 in systemic sclerosis, 1315, 1316f, 1329–1331 systemic sclerosis pathogenesis and, 1320–1321, 1321f Vascular endothelial growth factor cartilage angiogenesis and, 48 in rheumatoid arthritis, 1073 type X, 7 Vascular endothelium, in inflammation, ­morphology and function of, 357 Vascular occlusion, in antiphospholipid ­syndrome, 1304 Vascular therapies, for systemic sclerosis, 1340, 1340t Vasculitis, 1401–1407. See also Arteritis; specific conditions; specific disorders. antineutrophil cytoplasmic antibodies and, 1430–1431, 1430f arthritis vs., 552 of central nervous system, 1461–1462 clinical course of, 1462 clinical features of, 1461, 1462t differential diagnosis of, 1462 epidemiology of, 1461 laboratory findings in, 1461 pathology, 1461 radiographic features of, 1461, 1462f treatment of, 1462 in children, 1690–1696, 1690t giant cell, 1695–1696, 1696f necrotizing, of medium and small arteries, 1690–1693 of small vessels, 1693–1695 Churg-Strauss. See Churg-Strauss syndrome. classification of, 1401–1405, 1402t, 1403t confusion in, sources of, 1404–1405 historical attempts at, 1404 by vessel size, 1402, 1403t

Vasculitis (Continued) coronary, in Kawasaki disease, in children, 1692 cryoglobulinemic, 1470–1471, 1470t, 1471f epidemiology of, 1405–1407, 1405t age and, 1405 environment and, 1406–1407 ethnicity and, 1406 gender and, 1405 genetics anc, 1406 geography and, 1405 hepatitis B, 1458 HIV-associated, 1754–1755 hypersensitivity, 1404, 1405 skin lesions in, 695 large vessel, skin lesions in, 696 leukocytoclastic, 226 in children, 1695 cutaneous, 695, 1404, 1405, 1465, 1468, 1469t mesenteric, in systemic lupus erythematosus, 1278 with methotrexate, 889 methotrexate for, 887 neutrophils in, 226 paraneoplastic, 1842–1843, 1842t parvovirus B19, 1458 pauci-immune, 1407 retinal, 679 rheumatoid, 687, 1453 in rheumatoid arthritis, 1101–1102, 1101f rheumatoid arthritis vs., 1112 in sarcoidosis, 1801 in Sjögren’s syndrome, 1156 small vessel, immune complex-mediated, 1465–1473 Arthus reaction and, 1465 connective tissue disease-associated, 1472–1473, 1472f cryoglobulinemic, 1470–1471, 1470t, 1471f cutaneous manifestations of, 1466, 1466f, 1467f differential diagnosis of, 1467–1468, 1469f, 1469t erythema elevatum diutinum as, 1472, 1472f Henoch-Schönlein purpura as, 1468–1470, 1470t hypersensitivity, 1465, 1468, 1469t immunogenicity and, 1465–1466 pathogenesis of, 1465–1466 pathologic features of, 1466–1467 rheumatoid, 1473 urticarial, 1471–1472 small vessel, leukocytoclastic, skin lesions in, 694–695, 694f systemic glucocorticoid therapy for, 870t platelets in, 253 urticarial, 1471–1472 Vasculogenesis, defective, systemic sclerosis pathogenesis and, 1321, 1322f Vasoactive amines, as mast cell mediators, 239 Vasodilators, for Raynaud’s phenomenon, in systemic sclerosis, 1340, 1340t Vaso-occlusive diseases, arthritis vs., 552 VCAM-1. See Vascular cell adhesion molecule-1. Vegetarian diet, 505 VEGF. See Vascular endothelial growth factor. Venlafaxine for chronic pain, 989t for fibromyalgia, 564 Verapamil, drug interactions of, 919 Versican, in cartilage, 40t, 41

index Vertebrae, development of, 8 Vertebral fractures, costs of, 448 VIGOR. See Vioxx Outcomes Research Study. Vioxx Outcomes Research Study, 846, 848, 856 Viral arthritis, 1761–1768 adenovirus, 1768 alphavirus, 1764–1766 diagnosis of, 1765–1766 epidemiology of, 1764–1765, 1764t pathogenesis of, 1766 prognosis of, 1766 treatment of, 1766 coxsackievirus, 1768 cytomegalovirus, 1768 echovirus, 9, 1768 Epstein-Barr virus, 1768 hepatitis B, 1766–1767 clinical features of, 1766–1767 diagnosis of, 1767 epidemiology of, 1766 pathogenesis of, 1767 hepatitis C, 1767 Herpes hominis, 1768 herpes simplex virus, 1768 HTLV-1, 1767–1768, 1768f mumps virus, 1768 parvovirus B19, 1761–1763 diagnosis of, 1762–1763 epidemiology of, 1761 pathogenesis of, 1761–1762 prognosis of, 3 treatment of, 3 polyarticular, 547 rubella virus, 1763–1764 diagnosis of, 1763–1764, 1764f epidemiology of, 1763 pathogenesis of, 1763 prognosis of, 1764 treatment of, 1764 vaccinia, 1768 Viral hepatitis after factor replacement therapy, 1822 hepatitis B arthritis and, 1766–1767 clinical features of, 1766–1767 diagnosis of, 1767 epidemiology of, 1766 pathogenesis of, 1767 hepatitis B vasculitis and, 1458 hepatitis C as arthritis and, 1767 in Sjögren’s syndrome, 1155 Viral infection(s). See also specific infections. Behçet’s disease and, 1476 rheumatoid arthritis and, 1042–1043 Vision loss in giant cell arteritis, 682, 1413, 1413f in Wegener’s granulomatosis, 1436 Visual analog scales, in fibromyalgia, 561 Vitamin(s) A, diffuse idiopathic skeletal hyperostosis and, 1603 antioxidant, 1011–1012 B6, for carpal tunnel syndrome, 653 C, 1011–1012 D, 1012 calcium metabolism and, 77 deficiency of, osteomalacia and, 1591–1593, 1591t deficiency of, osteoporosis and, 1583 deficiency of, rickets and, 1591, 1592 for osteoporosis, 1589 E, 1011 Vitronectin. See S protein. VLA-4, cell adhesion molecules and, in ­rheumatoid arthritis, 1074 Vocal artists, musculoskeletal disorders in, 497

Vocational rehabilitation, in physical medicine and rehabilitation, 1030 Volar ganglion, 659 von Gierke’s disease, 1495 von Willebrand factor, 249 von Willebrand’s disease, 249

W

Walker(s), in physical medicine and ­rehabilitation, 1030 Walker-Murdoch sign, in Marfan syndrome, 1650 Walker-Warburg congenital muscular ­dystrophy, 102t Walking. See also Gait. in osteoarthritis, adduction moment during, 109 Walking aids, in physical medicine and ­rehabilitation, 1030 Warfarin for antiphospholipid syndrome, in systemic lupus erythematosus, 1290 drug interactions of, 916 for thrombosis, in antiphospholipid ­syndrome, 1307 Warm-reactive IgG non-Rhesus, in systemic lupus erythematosus, 1235 Wasting syndrome, in HIV infection, 1751 Water intoxication, with cyclophosphamide, 913 “Watermelon stomach,” in systemic sclerosis, 1332 Weber’s line, 1765 Wegener’s granulomatosis, 1403 antineutrophil cytoplasmic antibodies and. See Antineutrophil cytoplasmic antibody. cyclophosphamide for, 911, 911t differential diagnostic features of, 1446t epidemiology of, 1405t, 1406 leflunomide for, 892 orbital disease in, 682 paraneoplastic, 1843 scleritis in, 681 skin lesions in, 695 Weight loss with leflunomide, 893 in osteoarthritis, 1564 Weightlifting, osteoarthritis associated with, 495t Western Ontario and McMaster Universities osteoarthritis index, 465, 637, 1554, 1554t WG. See Wegener’s granulomatosis. Wheelchairs, in physical medicine and ­rehabilitation, 1030 Whipple’s disease, 1228 polyarthritis in, 550 rheumatoid arthritis vs., 1113 uveitis in, 679 Whitlow, 660–661 Whole complement assay, 330–331, 330t, 331t Whole-genome association studies, 316, 317f, 318 Willow bark, 506 Wilson’s disease, imaging in, 801, 801f Wnt-14, joint formation and, 3 Wnt pathway, bone mineral density and, 78 Wnt signaling chondrocytes and, 42 limb development and, 5 osteoblasts and, 72 WOMAC. See Western Ontario and McMaster Universities osteoarthritis index. Work capacity, assessment of, 1025–1026 Work hardening programs, in physical ­medicine and rehabilitation, 1030–1031

li

Work productivity, in health outcome ­assessment, 466 World Medical Association, Declaration of Helsinki of, 457–458 Wound healing, mast cells and, 241 Wrestling, osteoarthritis associated with, 495t Wrist(s) arthrocentesis technique for, 730–732 dorsal, tendons of, arthrocentesis technique for, 730–731 examination of, 521–522, 521f in juvenile chronic arthritis, imaging of, 787–788 monarticular and periarticular syndromes affecting, 536t muscle function of, 521–522 in osteoarthritis, imaging of, 794–795 in rheumatoid arthritis, imaging of, 783–784, 783f, 784f rheumatoid arthritis of, 1093–1095, 1093f–1095f swelling of, 521 synovitis of, 521 Wrist pain anatomy in, 651, 652f arthroscopy in, 653 at base of thumb, etiologies for, 658–659 dorsal, etiologies for, 655–656 history taking in, 651 imaging in, 652 injections and aspirations in, 652–653 neurodiagnostic tests in, 652 palmar, etiologies for, 653–654 physical examination in, 651–652 radial, etiologies for, 658, 659 ulnar, etiologies for, 656–658

X

Xanthine oxidase inhibitors, for hyperuricemia control, 1500–1501, 1500t Xanthomatosis, in rheumatoid arthritis, 1099 Xerophthalmia, in Sjögren’s syndrome, 1152–1153, 1153f treatment of, 1160–1161 Xerostomia, in Sjögren’s syndrome, 1153–1154, 1153f, 1155 treatment of, 1161 Xerotrachea, in Sjögren’s syndrome, 1154 treatment of, 1162

Y

YKL-40 as biomarker, 477t in cartilage, 40t YKL-40/HC-gp39. See Chitinase 3-like protein. Yoga, 510 for osteoarthritis, 1566

Z

ZAP-70 autoimmune disease and, 263t T lymphocyte activation and, 161 Zeel Classification, 1404 Zidovudine myopathy, differential diagnosis of, 1371t, 1373–1374 “Zigzag” deformity, in rheumatoid arthritis, 1093 Zinc, in nutrition, 1012–1013 Zingiber officinale, 506–507 Zoledronic acid, for osteoporosis, 1588 Zone of polarizing activity, 5 ZPA. See Zone of polarizing activity. Zygomatic arch, depressed, limitation of ­mandibular movement in, 666t Zymogens, of matrix metalloproteinases, ­activation mechanisms of, 126–128, 127f